Rad Bio 2019/2020 study guide

Pimonidazole staining detects what?

hypoxic cells

The traditional dose-rate effect is most pronounced with reduced cell killing between dose rates of ___ Gy/min and ___ Gy/hour

0.01-->1gy/min

The minimum whole body radiation dose that can be detected through the measurement of dicentric chromosomes in peripheral blood lymphocytes is approximately:

0.25 Gy

What is the D0 for most mammalian cells irradiated with X-rays in vitro under well aerated conditions?

1-2 Gy

Prostate drug overview - 17 α-hydroxylase/C17,20 lyase (CYP17A1) inhibitor = ? - Androgen receptor antagonist drug = ? - Luteinizing hormone releasing hormone (LHRH) agonist = ? - Luteinizing hormone releasing hormone (LHRH) ANTagonist = ? - Bone seeking alpha-particle emitter - Inhibits the ligand for osteoprotegerin and functions as a key factor for osteoclast differentiation and activation - Lu-177-PSMA

- 17 α-hydroxylase/C17,20 lyase (CYP17A1) inhibitor = Abiraterone - Androgen receptor antagonist drug = Enzalutamide - Luteinizing hormone releasing hormone (LHRH) agonist = Luprolide - Luteinizing hormone releasing hormone (LHRH) ANTagonist = abarelix or degarelix - Bone seeking alpha-particle emitter = Ra-223 (Xofigo) - Inhibits the ligand for osteoprotegerin and functions as a key factor for osteoclast differentiation and activation = RANKL inhibitor = Denosumab - Lu-177-PSMA = Lutetium

NOTE: Key to answer the following slightly more complicated D0/D10 type questions. You need to know how to calculate the following (formulas on opposite side of card) # of cells you need to kill off as it relates to a certain number of doublings = ? Dose reduction factor for a radioprotector = ?

# of cells you need to kill off - i typically just think if they say 10^6 cells and you need to get to 1 cell left over - that's 6 logs of cell kill. Sometimes you need to be able to figure out how to get 1 cell when you have something like 8 x 10^6 --> 6 logs would give you 8 cells left over. 7 logs would give you 0.8 (so 7 x the D10 wouldn't technically give you the right answer). In these cases, you can use the following formulate to figure out how to get rid of 8 cells or 8x more cells (works for 1000 cells or 1000x more cells) # of cells = e^(Dose/effD0) solve for D to get the extra dose needed to kill those cells. To figure out how many cells is added in a certain number of doublings: 2^(number of doublings) = # of extra cells that produced. Note: Important to recognize volumetric changes -- to go from 0.1 cm diameter tumor to 1 cm diameter tumor is NOT 10x bigger. (1/0.1)^3 = 1000x bigger. So that change adds 1000x more cells. Example: if you said you have 10^6 cells and you want to kill off 6 logs and have 1 cell left, but there are three doublings. You have to account for 2^3 = 8x more cells being around after those 6 logs. Now you have 8 cells, not 1 cell left. can say 8 = e^(D/effD0) --> D = ln(8)xeffD0 and that tells you the extra dose needed to deal with those cells. You can start from the beginning and say you have 8x10^6 and solve that way for the total dose needed. Dose reduction factor for a radioprotector = DRF = Dose required to cause an outcome with a radioprotector / the dose required to cause an outcome without said radioprotector DRF >1 --> means the radioprotector is protecting and the dose needed to cause the effect with it is HIGHER than the dose needed if you don't have the radioprotector.

What are the three ways to generate synchronous cell populations? Inverse dose rate vs dose rate effect?

1. Mitotic harvest 2. Hydroxyurea (kills cells in S phase and causes G1/S block) 3. inverse dose rate effect: Give 0.37 Gy/h or less (cells all accumulate at G2/M and are more sensitive to RT) The dose rate effect is the repair of SLD that occurs and is most dramatic between 0.1-1 Gy/min -- above 1 Gy/min there is little additional increase in cell death with increasing dose rate

The minimum energy needed to ionize an atom is of the order of:

10 eV (corresponds to <100 nm) 10-100 eV with peak at 25 eV Absorption of 5 eV is sufficient to break intramolecular binding; e.g., 4.9 eV for the C=C and 5.2 eV for H—OH (the chemical energy)

List 4 scans that can non-invasively assay for hypoxia in a patient? What type of PET is specifically NOT good for measuring hypoxia.

18-F--> FMISO-PET 123-I --> radioiodinated azomycin arabinosides - SPECT 64-Cu --> Cu-ATSM-PET EPRI - electron paramagnetic resonance imaging Note: FDG-F18 PET is specifically NOT good for looking at hypoxia because it would be more useful to measuring glycolytic activity.

Approximately what amount of energy is released per ionization event during X-ray irradiation of water?

33 eV

The D0 is the dose that results in an average of one lethal event per cell. When there is no repair of sub-lethal damage, exposure of cells with a D0 dose will result in which of the following survival fraction?

37%

what is a 6-4 photoproduct?

6-4 photoproducts are produced by UV and not ionizing radiation. sounds like UV = photo

at what does of radiation exposure are lympocyte dicentrics detactable?

>0.25 Gy

Two of the main proteins involved in mismatch repair are: A. MSH2/MLH1 B. DNA ligase IV (LIG4)/XRCC4 C. KU70 (XRCC6)/KU80 (XRCC5) D. XPA/XPG (ERCC5) E. DNA-PKcs (PRKDC)/Artemis

A. MSH2/MLH1 MSH2 and MLH1 play a central role in mismatch repair. XPA/XPG are involved in nucleotide excision repair (Answer Choice D). DNA Ligase IV, Ku70, and DNA-PKcs all play roles in NHEJ (Answer Choices B, C, and E).

Which of the following has been shown to be a reliable surrogate marker for DNA double strand breaks (DSBs) in the cells? A. Phosphorylated histone variant H2AX (or gammaH2AX) B. Degraded histone H2AX C. Dephosphorylated H2AX D. Cleavage of Caspase 3 E. DNA methylation

A. Phosphorylated histone variant H2AX (or gammaH2AX) The level of phosphorylated H2AX has been shown correlate with the level of DNA double strand breaks

Which of the following best describes the action of an exonuclease enzyme? A. Seals breaks in a DNA strand B. Adds a new nucleotide to the end of DNA during DNA synthesis. C. Produces nicks within intact DNA strands D. Generates new species of mRNA E. Removes nucleotides from the ends of DNA strands

An exonuclease cleaves one nucleotide at a time beginning at the end of a DNA strand.

Sequestration of portions of the cytoplasm and organelles into a double-membrane vesicle hallmark of?

Autophagy - think LC3 cleavage

Which of the following in vivo assays of radiation response does NOT depend on a functional endpoint? A. LD50 B. Skin nodule formation C. Myelopathy D. Breathing rate E. Cognitive impairment

B A functional endpoint for radiation response is a measured endpoint that is downstream of clonogenic survival and may involve measurement of tissue/organ function, the incidence of toxicity, or whole animal survival. Clonogenic endpoints directly measure the replicative capacity of cells (e.g., colony formation). Skin nodule formation is not a functional endpoint; it is a clonogenic assay measuring survival of individual epidermal cells regrowing in situ. All of the other assays cited represent non-clonogenic, functional endpoints for assaying radiation damage.

Double-strand DNA breaks caused by ionizing radiation trigger the transcription of DNA damage response genes. Which of the following proteins is a transcriptional transactivator? A. p21 (CDKN1A) B. p53 (TP53) C. ATM D. CHK1 (CHEK1) E. TRAIL (TNFSF10)

B In response to various forms of DNA damage, including double-strand breaks, p53 is stabilized and binds to the promoters of numerous target genes, including p21, activating their transcription. This transcriptional transactivation by p53 is an important component of the cellular DNA damage response. ATM and CHK1 are protein kinases that are activated in response to double-strand breaks (Answer Choices C and D). TRAIL is a ligand that induces cell death through the extrinsic apoptosis pathway (Answer Choice E).

Which of the following statements is FALSE when describing tumor hypoxia? A. In rodent tumors, the hypoxic cell fraction is generally within the range of 5-50% B. Hypoxia is rarely observed in common human solid tumors C. Oxygen diffusion and delivery is limited in some parts of tumors D. Hypoxia can enhance tumor progression by means of hypoxia-related changes in gene expression E. Hypoxia induces gene amplification and mutation

B. Hypoxia is rarely observed in common human solid tumors Hypoxia in tumors has been detected using both imaging and direct electrode measurements. The other statements are true.

Rapamycin, everolimus and temsirolimus may act as a radiosensitizers by inhibiting: A. K-ras B. mTOR C. MAPK D. p38 E. EGFR

B. mTOR Rapamycin, everolimus and temsirolimus are all inhibitors of the mTOR (mammalian target of rapamycin) protein. mTOR functions downstream of PI(3)K to promote cell survival. Inhibition of mTOR blocks these pro-survival pathways.

CDC2 (CDK1)/cyclin B = ? CDK4/6-cyclin D = ? CKD2/cyclin E = ? CDK2/cyclin A = ? CDC2 (CDK1)/cyclin A = ?

CDC2 (CDK1)/cyclin B = G2 into M (activated by CDC25C/inhibited by Weet1/myt1) CDK4/6-cyclin D = G1-S (early) - inhibited by p16 CKD2/cyclin E = G1-S (late) - inhibited by p21 CDK2/cyclin A = S phase (early) CDC2 (CDK1)/cyclin A = S phase (late)

Very odd concept What pro-apoptotic executioner caspase serves a paracrine signal function from dying cells to stimulate proliferation of surviving cells?

Caspase 3 very odd -- apparently new discovery

what is often the major factor that determines the tumor volume doubling time

Cell loss is often the major factor that determines the tumor volume doubling time

Are acutely or chronically hypoxic cells more radioresistant?

Chronically hypoxic ones Without reoxygenation, it is unlikely that a tumor comprised of any significant proportion of hypoxic cells (even as low as 1%), would be controlled following total doses used in typical radiotherapy protocols. It has been shown that in addition to the absence of the direct effect of oxygen "fixation" on DNA damage, chronically hypoxic cells upregulate pathways leading to greater radiation resistance than acutely hypoxic cells.

In an untreated tumor with a potential doubling time of 3 days and a cell loss factor of 80%, the volume doubling time is: A. 2.4 days B. 3.5 days C. 3.75 days D. 15 days E. 20 days

D The cell loss factor (Φ) is equal to 1-(Tpot/TD). Rearranging this, TD = Tpot/(1-Φ). TD = 3 days/(1-0.8) = 15 days.

Which of the following is NOT recommended as part of routine management of the gastrointestinal radiation syndrome after accidental total body irradiation: A. Antiemetics B. Antibiotics C. Antidiarrheals D. Corticosteroids E. Oral nutritional support

D. Corticosteroids Systemic corticosteroids are not recommended, without a specific indication for use - this would be more related to cerebrovascular syndrome

An agent that inhibits non-homologous end joining (NHEJ) repair of radiation-induced DNA double-strand breaks might be expected to do all of the following, EXCEPT: A. Affect the immune response B. Sensitize cells to low dose rate irradiation C. Decrease normal tissue tolerance during fractionated radiotherapy D. Increase cellular radioresistance E. Inhibit sublethal damage recovery

D. Increase cellular radioresistance Inhibition of non-homologous end joining (NHEJ) would be expected to decrease cellular radioresistance. An effect on immune response would be anticipated because inhibition of NHEJ would affect V(D)J recombination, thereby affecting antigen recognition (Answer Choice A). Cells and tissues would be sensitized to low dose-rate irradiation since the recovery that occurs at low dose-rates depends at least in part upon repair of double-strand breaks by NHEJ (Answer Choice B). Normal tissue tolerance doses would likely decrease due to radiosensitization (Answer Choice C). Sublethal damage recovery would be inhibited since this process depends at least in part on the repair of double-strand breaks (Answer Choice E).

Data suggests that treatment breaks are detrimental to tumor control in head and neck cancer. The radiobiological basis of this phenomenon is: A. Redistribution B. Reoxygenation C. Repair D. Repopulation E. Radiosensitization

D. Repopulation Accelerated repopulation is triggered several weeks after the initiation of a course of radiation therapy. A dose increase of approximately 0.6 Gy per day is needed to compensate for this repopulation. Hence, any interruptions in treatment, once it has begun, can compromise tumor control due to accelerated repopulation.

All of the following statements as to why larger tumors are more difficult to control with radiotherapy than smaller tumors are true, EXCEPT: A. Larger tumors generally contain a greater number radioresistant hypoxic cells than smaller tumors B. In order to deliver a curative total dose to a large tumor, the volume of irradiated adjacent normal tissue may become so large as to exceed normal tissue tolerance C. A larger primary tumor volume is associated with a higher risk of regional and distant metastatic spread D. The fraction of rapidly proliferating cells tends to increase with the size of the tumor

D. The fraction of rapidly proliferating cells tends to increase with the size of the tumor Larger tumours tend to have large necrotic centers where hypoxic radioresistant cells largely reside. In almost all cancer types, the size of a primary tumour correlates with the risk of regional and distant metastatic spread. Hence, in the AJCC staging system, the T stage is often defined by size. The fraction of proliferating cells therefore tends to decrease with increasing tumor volume.

Which of the following tumors are NOT considered to be highly radiogenic? A. breast B. leukemia C. thyroid D. cervical E. bladder

D. cervical Data from the atomic bomb survivors demonstrate that breast cancer, thyroid cancer, bladder cancer, and non-CLL leukemia were all significantly induced following exposure to radiation (Answer Choices A, B, C, and E). Cancer of the cervix is tightly linked to HPV viral infection and is not considered to be a highly radiogenic tumor (Answer Choice D).

SCID mice are deficient in what

DNA-PK -- thus cannot do NHEJ

Sanger sequencing reaction requires what in limiting amounts?

Di-deoxynucleotide triphosphates Sanger sequencing utilizes limiting amounts of di-deoxynucleotide trisphosphates in four separate reactions (one each for ddATP, ddTTP, ddCTP, and ddGTP)

The α/β ratio is equal to the: A. Surviving fraction at which the amount of cell killing caused by the induction of irreparable damage equals the amount of cell killing caused by the accumulation of sublethal damage B. Optimal fraction size to use in a fractionated radiotherapy regimen C. Dose below which a further decrease in fraction size will not affect the surviving fraction for a particular total dose D. Dq E. Dose at which the αD component of cell kill is equal to the βD2 contribution to cell killing

E. Dose at which the αD component of cell kill is equal to the βD2 contribution to cell killing The α/β ratio represents the dose at which the αD component of cell killing, assumed to result from single hit killing, is equal to the lethality produced by the βD2 component of cell killing that results from multi hit killing.

A mutation in which of the following genes is LEAST likely to cause an increase in sensitivity to ionizing radiation: A. NBS1(NBN) B. BRCA1 C. ATM D. MRE11 E. XPC

E. XPC XPC is a gene whose product is involved in nucleotide excision repair (NER). Mutations in XPC result in the human genetic disease xeroderma pigmentosum, which is characterized by extreme sensitivity to ultraviolet light. Mutations in all of the other genes result in human genetic diseases characterized by sensitivity to ionizing radiation, including Nijmegen breakage syndrome (NBS1), familial breast cancer (BRCA1), ataxia telangiectasia (ATM), and ataxia telangiectasia-like disorder (MRE11).

What major factor for comparing dose/fraction regimens does the standard BED equation NOT take into account? BED = nd(1+d/a:b)

IT DOES NOT TAKE TIME INTO ACCOUNT so you can't compare courses that are very different in terms of total time of the treatment course A heavily accelerated course like CHART trial will greatly limit cellular repair and limits accelerated repopulation -- so the BED would be calculated as lower -- but there is significant biological impact to dose delivered on this schedule

Weird wording Contributor to the total collective effective dose from medical uses of radiation implicated in cause tissue reactions in addition to stochastic effects

Interventional radiology and cardiology

Radioactive iodine accumulates in the thyroid gland. Where do plutonium and americium tend to accumulate?

Like Radium, Plutonium (Pu) and Americium (Am) accumulate in the bones - important to recognize based on potential need for bone marrow transplant

Bcl-xL (BCL2L1) inhibition of apoptosis takes place at the:

Mitochondrion Bcl-xL prevents apoptosis primarily through inhibition of cytochrome c release from the mitochondria

Mitotic death in irradiated cells results primarily from: A. The mis-rejoining of DNA single strand breaks. B. DNA ladder formation. C. Stimulation of the extrinsic death pathway. D. Mis-assortment of genetic material into daughter cells. E. An alteration in cell membrane permeability.

Mitotic death in most irradiated cells results primarily from mis-assortment of genetic material into daughter cells as a result of the formation of asymmetrical chromosome aberrations. This aberrant mitosis triggers mitotic catastrophe, which is characterized by cells exhibiting multiple tubulin spindles and centrosomes as well as the formation of multinucleated giant cells that contain uncondensed chromosomes. Mitotic death can be of any molecular mechanism, including apoptosis or necrosis. Single strand breaks are repaired rapidly and do not appear to play an important role in cell lethality (Answer Choice A). DNA ladder formation is characteristic of apoptosis (Answer Choice B). An alteration in cell permeability occurs in cells undergoing necrosis (Answer Choice E).

Defects in HR or NHEJ more likely to cause radiation sensitivity?

NHEJ defects confer higher sensitivity to radiation than HR

Does hypoxia correlate with tumor size?

NO

Is lactate a surrogate of hypoxia in cancer cells?

NO - this is a tricky concept because we typically say that where there is hypoxia, there is anaerobic glycolysis producing lactate so increased lactate and decreased pH is usually found in areas where there is more hypoxia in the body. HOWEVER - there is this thing called The Warburg Effect in cancer cells where they will actually take up high levels of glucose and do aerobic glycolysis producing lots of lactate, EVEN IN THE PRESCENCE OF OXYGEN. Still not very well understood why they prefer this less efficient means of energy utilization, but it is well documented that they do this. Therefore, in cancer, lactate is NOT a good surrogate to mean that there must be hypoxia.

mitotic catastrophe most often leads to what type of cell death?

Necrosis

PARP is involved as an important component of what type of DNA repair?

PARP plays a major role as one of the first components of the SSBR pathway (which is often considered a part of the BER pathway).

What does PD-1 stand for? a. Programmed cell death 1 receptor b. Presentation determinant 1 c. Pre-determinant molecule 1 d. Pattern determinant 1 e. Principal determinant 1

Programmed cell death 1 receptor

1 lethal hit per cell occurs with SF = ?

SF = e-1 = 0.37 This is the definition of the D0 D10 = 2.3xD0 be able to solve a question like in the pic -- key, recognize the dose they are giving is reducing cell survival by a log of cells. Ie. 3 Gy to kill a log = which means the D10 = 3 gy If you have the D10, you can easily solve for the D0. With this info, you can't figure out the Dq or the n without having at least one of those.

examples of secreted cytokines that are immunosuppressive

TGF-beta, IL-10 and adenosine

what is the role of artemis in NHEJ

The main role for Artemis is to cleave (through its nuclease activity) any residual DNA loops or hairpins that form during non-homologous end-joining. It prepares the ends for ligation by ligase.

All forms of EM radiation travel at what speed in a vacuum?

The speed of light

CD20 labeled w/ I-131? CD20 labeled w/ y90?

Tositumomab - Bexxar - CD20 labeled w/ I-131 Ibritumomab - CD20 labeled w/ Y90 - Contraindicated if: >25% bone marrow NHL involvement - radioimmunotherapy agent used to treat NHL

Transfer of DNA into cells using cationic lipids is referred to as what?

Transfection

Tumors A and B have identical single dose TCD50 values. However, the cell survival dose response curve for tumor A is characterized by an a/b ratio of 2 Gy, while the curve for tumor B has an a/b ratio of 30 Gy. If these tumors are both treated with a fractionated protocol using daily dose fractions of approximately 2 Gy in the same overall treatment time, the total dose to yield a TCD50 for tumor A compared with tumor B will be: a. Lower b. Greater c. Equal d. Less for a lower probability of tumor control and greater for a higher probability of control e. Impossible to determine from the information provided

Tumor A has a low a/b ratio and therefore this tumor will exhibit a high degree of sparing with dose fractionation. In contrast, tumor B, which has a high a/b ratio will exhibit correspondingly less sparing with fractionation. Thus, the TCD50 for a fractionated protocol will be higher for tumor A compared with tumor B. Important to recognize that they said the SINGLE DOSE TCD50 is the same. The alpha beta ratio then gives you info about how they respond to fractionation based on that. Low a/b tissues are much more sensitive to high dose per fraction, so a single dose would be more toxic for them relative to high a/b tissues. Remember: Sensitive to: low alpha/beta = TOTAL DOSE + FRACTION SIZE high alpha/beta= TOTAL DOSE + shorter overall treatment time (repopulation) Low a/b tissues have a high capacity for SLDR so if you give them time to repair, they survive much better. High a/b tissues don't do SLDR quite as well, so benefit relatively less from lower fraction size or lower dose rate.

chemo's that can and can't penetrate the BBB

Typically good CNS penetration - alkylating agents - antimetabolites - nucleoside analogs NOT good CNS penetration - vinca alkalkoids - taxanes - topoisomerases

Which of the following organs has the highest tissue weighting factor (WT)? a. Breast b. Bladder c. Brain d. Gonads e. Kidney

a. Breast Because different tissues have different sensitivities with respect to radiation carcinogenesis, for risk estimation and radiation protection purposes, tissues are assigned "weighting factors" (WT) that correct the absorbed dose a tissue receives for biological equivalence. For example, the breast is assigned a WT = 0.12, whereas bladder and gonads have WT's = 0.05, and brain and kidney, 0.01. TWF = that tissue's specific likelihood of secondary cancer.

Which of the following statements concerning complications arising from pelvic irradiation is FALSE? a. Diarrhea is the most common manifestation of radiation injury to the bowel b. Diarrhea usually does not appear until at least 6 months following the completion of radiotherapy c. Late bowel reactions include mucosaI atrophy, stenosis, ulceration, obstruction, adhesions and perforation. d. Bowel stenosis is a late complication of radiation therapy e. Adhesions following irradiation contribute to late bowel injury and usually develop 2-7 months after irradiation

b. Diarrhea usually does not appear until at least 6 months following the completion of radiotherapy Diarrhea usually occurs about 3 weeks after the start of fractionated radiotherapy.

The TD5 as a function of length of spinal cord irradiated: a. Decreases as a linear function of increasing cord length b. Initially decreases with increasing cord length, and then remains relatively constant for higher total doses c. Increases steeply for lengths greater than approximately 10 cm d. Decreases with decreasing cord length e. Increases with cord length before reaching a plateau

b. Initially decreases with increasing cord length, and then remains relatively constant for higher total doses The TD5 (as a function of length irradiated for the spinal cord) decreases with increasing cord length and then remains relatively constant. this makes sense if you remember that high dose to small volume is the problem in spinal cord, so as you increase the cord length, the dose needs to decrease to result in the same chance of an outcome -- then it plateaus at a point

Which of the following radiation-induced malignancies has the shortest median latent period? a. Colorectal cancer b. Leukemia c. Bone sarcoma d. Breast cancer e. Lung cancer

b. Leukemia Radiation-induced leukemias have a medium latent period of 3-7 years, whereas solid tumors do not appear for at least 10 years following irradiation, if not several decades later.

Mutations in RAS are associated with which response to radiation? a. Severe toxicity b. Radioresistance c. Senescence d. Autophagy e. No effect on radioresponse

b. Radioresistance Mutations in RAS are associated with decreased radioresponsiveness. This is likely due to constitutive signaling through the Ras-MAPK pathway.

One of the mechanisms by which gemcitabine is thought to act as a radiosensitizer is through an effect on: a. RAD50 b. Ribonucleotide reductase c. ATM d. DNA pol a (POLA1) e. DNA topoisomerase II alpha (TOP2A)

b. Ribonucleotide reductase dFdCDP formed in cells treated with gemcitabine interferes with ribonucleotide reductase, causing depletion of deoxynucleotide triphosphates necessary for DNA synthesis. This is thought to be a mechanism leading to radiosensitization.

Which of the following effects is typically observed within a week following irradiation of the small intestine? a. Hypertrophic villi b. Lymphocyte infiltration c. Atrophic villi d. Mucosal atrophy e. Bowel stenosis

c. Atrophic villi Late bowel reactions include mucosaI atrophy, stenosis, ulceration, obstruction, adhesions and perforation Atrophic villi would likely be observed within a week following the start of irradiation of the small intestine, since the cells lining the villi have relatively short life spans.

Which of the following proteins are involved in the G1 cell cycle checkpoint? a. EGFR b. Stat1 c. Cyclin D1 d. Cyclin X e. Cdc25

c. Cyclin D1 The G1 checkpoint is controlled by p16, which inhibits CDK 4/6 to prevent it from interacting with cyclin D1. When complexed, cyclin D1/CDK4/6 phosphorylates Rb, which in turn de-represses the E2F transcription factors to allow cell cycle progression. Interrupting any of these intermediates may alter cell cycle progression Kind of a shitty question because CDC25A is a regulator of cyclin E-CDK2 which is also part of the G1 checkpoint.

The thyroid of a developing fetus will incorporate radioactive iodine: a. At no point during gestation b. At any point during gestation c. From about the 10th week of gestation onward d. Only during the first trimester of gestation e. Only during the third trimester of gestation

c. From about the 10th week of gestation onward The thyroid of a developing fetus will incorporate radioactive iodine from about the 10th week of gestation onward. The Society of Nuclear Medicine recommends that females of child-bearing age and capability should have a pregnancy test within 72 hours prior to I-131 treatment.

If the dose-limiting, normal tissue toxicity of interest is characterized by an a/b ratio of 6 Gy, and the corresponding tumor possesses an a/b ratio of 2 Gy, it is most likely that a patient being treated for this type of cancer would benefit from: a. Split course treatment b. Accelerated treatment c. Hypofractionation d. Hyperfractionation e. Low dose rate brachytherapy

c. Hypofractionation If the a/b ratio is less for a patient's tumor than their dose-limiting normal tissue, such a patient may benefit from the use of large fraction sizes, because the tumor would be more sensitive to fraction size than the dose limiting normal tissue and would be preferentially damaged by hypofractionation. think prostate cancer (low a/b) and rectum oar (higher a/b)

Thymic irradiation during infancy has been shown to increase the incidence of: a. Breast cancer b. Leukemia c. Thyroid cancer d. Bone tumors e. Head and neck cancers

c. Thyroid cancer Individuals treated as infants with radiation therapy for an enlarged thymus were found to have an increased incidence of thyroid cancer.

What is the most common type of cancer identified in children who were in the vicinity of the Chernobyl nuclear power plant when it exploded in 1986? a. Osteosarcoma b. Leukemia c. Thyroid cancer d. Glioma e. Mesothelioma

c. Thyroid cancer Thyroid cancer was the most common cancer observed among children who lived in the Chernobyl area at the time of, and subsequent to, the accidental radiation release., This was a result of the high level of environmental contamination with radioactive iodine which homed to the thyroid.

Approximately how many excess, fatal cancers would be induced by the use of CT scanning if 10 million people receiving this type of radiologic examination got an average effective dose equivalent of 10 mSv? a. 25 b. 150 c. 800 d. 5,000 e. 20,000

d. 5,000 Using the risk estimate of 0.05/Sv for a general population exposed to X-rays from CT scanning, it would be anticipated that (10^7 people) x (0.01 Sv per person) x (0.05 radiation- induced fatal cancer deaths) = 5,000 excess cancer deaths.

Bortezomib (Velcade) inhibits the activity of: a. Tyrosine kinases b. KIT c. mTOR (FRAP1) d. Proteasomes e. VEGF

d. Proteasomes

ICRP estimates that the heritable risk of radiation is ___%/Sv for the: - general population - working population

general = 0.2%/Sv working = 0.1%/Sv

Half life of a free radical?

micro-mili second

TBI syndrome card

order of blood cells affected: lymphocytes --> granulocytes --> platelets --> RBCs

order of EM spectrum in terms of increasing energy (decreasing wavelength)

radio waves, microwaves, infrared radiation, visible light, UV and X-rays.

how does p53 activate puma?

remember that p53 is a transcription factor that transactivates transcription of factors like PUMA it isn't a kinase, so if you see p53 phosphorylates something -- that's wrong.

Consider tumor cells with α/β = 10 Gy. What approximate percentage of the total amount of damage is repairable at 2 Gy? a. 100% b. 80% c. 60% d. 40% e. 20%

repairable damage is the beta component a/b10 --> alpha = 10 --> alphaD = 10x2 Gy = 20 a/b10 --> beta = 1 --> bd^2 --> 1x2^2 = 4 20/4 = 5x beta component is 1/5 alpha = 20% of damage at that dose is repairable for that tissue

_______ is a type of irreversible cell cycle arrest resulting from the activation of p53 and RB and silencing of G1/S transition genes via chromatin modification

senescence

Virus mediated delivery of nucleic acids into cells = ?

transduction

a degenerative cellular process involving fragmentation of the nucleus and the breakup of the chromatin into unstructured granules

karyorrhexis

NUMBER MEMORIZATION CARD - Parent exposed to RT - probability of hereditary disorder in child (per Sv)? - GSD from diagnostic radiology proc in US in humans - GDD in humans - NIRL = ? - RT worker acute and chronic risk of cancer per Sv - Gen pop acute and chronic risk of cancer per Sv - ERR (excess relative risk) detectable from as little as ___ mSv.

- Parent exposed to RT - probability of hereditary disorder in child (per Sv) = 0.002/Sv (0.2%) - GSD in humans = 0.3 mSV - GDD in humans = 1.5 Sv - NIRL = <0.01 mSv - RT worker acute and chronic risk of cancer per Sv --> 4% vs 8% per chronic vs acute exposure - Gen pop acute and chronic risk of cancer per Sv --> 5% vs 10% per chronic vs acute exposure - ERR (excess relative risk) detectable from as little as 34 mSv (most studies say 100 mSv).

What is the total dose after a therapeutic iodine-131 treatment for follicular thyroid cancer following GTR?

0.5-1 Gy Total body dose -- can cause bone marrow suppression or nausea

Major pathways regulated by stability of HIF1a in hypoxic conditions?

1. Angiogenesis (VEGF transcription activated as part of the HRE by dimerization of HIF1a/b) 2. glycolysis stimulated (GLUT1) 3. erythropoiesis (EPO) 4. pH (CA9) p53 is NOT activated by HIF1a. If it activated in hypoxia, but this isn't part of what HIF1a does.

Congenital anomalies (neural tube defects, cleft lip, etc) apparent at birth occur at what rate in the world wide human population (in the absence of any specific exposure to medical radiation)?

5-10%

TCD50 question The impact of a radiosenisitizer upon tumor control will be most readily detected for experimental protocols that result in a ___% rate of tumor cure

50% The impact of a radiosenisitizer upon tumor control will be most readily detected for experimental protocols that result in a 50% rate of tumor cure, since even a small level of sensitization will significantly decrease the TCD50 in this portion of the curve. This curve demonstrates that 50% of the tumors will be controlled by a dose of 60 Gy (ie. TCD50 = 60 Gy), whereas 70 Gy increases tumor cure to >90%. NTCP stands for normal tissue complication probability. The additional dose to increase cures from 50% to 60% is relatively small because the TCD50 is on the steep part of the dose-response curve, but to increase cure rates from 90% to 100%, a much larger dose is required. At 50 Gy, approximately 10% of the tumors will be controlled.

Late effect timeline definition?

>60 days after irradiation

Which of the following pairs of radiation type and approximate LET value is CORRECT? A. 150 MeV protons - 0.5 keV/um B. 1 GeV Fe ions - 20 keV/um C. 60Co g-rays - 15 keV/um D. 2.5 MeV a-particles - 5 keV/um E. 250 kV X-rays - 10 keV/um

A 150 MeV protons have an LET of approximately 0.5 keV/um. Of note, lower energy protons have higher LET (they are more likely to deposit energy) 1 GeV Fe ions - 143 2.5 MeV a-particles 166 keV/um 60Co g-rays 0.2 keV/um 250 kV X-rays 2 keV/um

Which of the following CDK or cyclin is paired with the correct phase transition? A. CDK1 (CDC2) - G2 into M B. CDK4 - S into G2 C. cyclin A - G2 into M D. cyclin B - S into G2 E. cyclin D - M into G1

A CDK1 (and cyclin A/B) is associated with the G2 to M cell cycle phase transition. The other CDKs and Cyclins are appropriately paired as follows: o G1 phase → S phase: CDK4 and Cyclin D1; CDK2 and Cyclin E o S phase → G2 phase: CDK2 and Cyclin A o G2 phase → M phase: CDK1 and Cyclin B/A

Which of the following proteins is most involved in homologous recombinational repair of radiation-induced DNA double-strand breaks? A. RAD51 B. XPG (ERCC5) C. DNA-PKcs (PRKDC) D. CHK1 (CHEK1) E. TFIIH

A RAD51 is a recombinase and plays a critical role in homologous recombinational repair of DNA double-strand breaks. XPG is an endonuclease that cleaves the DNA strand on the 3' side of the damage site. It also stabilizes the nucleotide excision repair pre-incision complex that is essential for the 5' incision by the XPF (ERCC4) endonuclease (Answer Choice B). The catalytic unit of DNA protein kinase (DNA-PKcs) plays a central role in non-homologous end joining of DNA double-strand breaks through its recruitment by the KU70 (XRCC6)/80 (XRCC5) heterodimer to sites of DNA double-strand breaks, forming the DNA-dependent protein kinase holo-enzyme complex (DNA-PK; Answer Choice C). CHK1 is a serine/threonine protein kinase and a key mediator of the DNA damage-induced checkpoint pathway (Answer Choice D). TFIIH is associated with nucleotide excision repair (Answer Choice E).

The approximate minimum photon energy required to cause ionization is: A. 10-25 eV B. 100-250 eV C. 1-2.5 keV D. 10-25 keV E. 100-250 keV

A. 10-25 eV On average, about 25 eV is required to create an ion pair in water, although the minimum energy needed to eject an electron is only 12.6 eV.

The most likely explanation for why a tumor, composed of cells with short cell cycle times, would have a long volume doubling time is a: a. High cell loss factor b. Small percentage of cells entering G0 following mitosis c. Large growth fraction d. Large hypoxic fraction e. Abnormally long S phase

A The most likely reason why a tumor made up of cells with a short cell cycle time would grow slowly is most likely due to a high cell loss factor. A large growth fraction would contribute to a short volume doubling time. A small percentage of cells entering G0 would increase the fraction of cycling cells and thus promote a short volume doubling time. A large hypoxic fraction may indirectly affect cell cycle time and cell loss factor, but is not the best answer of the choices given. A long S phase is at odds with the premise of the question, given a short cell cycle time. The majority of variation in cell cycle time occurs during G1, not S phase

What type of an enzyme is telomerase?

A reverse transcriptase it generates a "cap" at the terminal ends of the chromosomes to protect the coding sequence from getting progressively shorter on the lagging strand with successive rounds of DNA replication. Mammalian telomeres consist of repeating arrays of TTAGGG sequence

methods to look at chromosome aberrations

A typical chromosome aberration assay would need to block cells at metaphase, and then visualize the condensed chromosomes using conventional staining (A) or fluorescent labeling of a specific set of chromosomes (B and C), and then identify the aberrated chromosomes. Newer technology such as copy number variation (CNV) can also be used to identify the regional chromosome deletion or amplification. An imaging analysis of the interphase nucleus is unlikely able to be identify aberrated chromosomes.

Based on animal studies, the most radiosensitive gestational age in terms of embryonic mortality in humans is approximately: A. 0-1 weeks B. 1-4 weeks C. 4-8 weeks D. 8-15 weeks E. 15-40 week

A. 0-1 weeks The most sensitive period during gestation is when radiation exposure may cause embryonic lethality. Based on animal studies, this period of time occurs immediately following conception but prior to implantation within the uterine wall.

Which statement regarding next generation sequencing (NGS) is FALSE: A. Unlike capillary sequencing, NGS requires the cloning and amplification of DNA sequence-containing phage libraries B. NGS is a massively parallel process with a million or more simultaneous DNA sequence reads. C. NGS is not hampered by homopolymer repeat sequences. D. NGS generally performs short DNA reads of less than 100 bases. E. In NGS, bases are read by sequential computer-mediated image analysis.

A. Unlike capillary sequencing, NGS requires the cloning and amplification of DNA sequence-containing phage libraries Capillary sequencing requires in vivo cloning and amplification whereas next generation sequencing (NGS) utilizes adaptor ligation of DNA fragments and binding to a matrix for DNA sequencing.

A scientist is planning an experiment in which he wants to determine whether his exponential cultures of human HCT116 colorectal cancer cells express wild-type p53 protein. Which of the following experimental assays would NOT be an effective readout for this purpose? A. Western blotting with the p53 protein-specific antibody B. Performing flow cytometry in order to analyze the cycling characteristics of HCT116 cells 12 h after exposure to 6 Gy X-Rays C. Northern blotting to measure WAF1/CIP1 mRNA expression in HCT116 cells 3 h after exposure to 6 Gy X-Rays. D. Immunoblotting with a cyclin E-specific antibody in order to detect cyclin E activity 12 hours after exposure to 6 Gy X-Rays. E. Immunoblotting with an antibody against p53, phosphorylated at the serine 15 residue, 1 hour after exposure to 6 Gy X-Rays.

A. Western blotting with the p53 protein-specific antibody Wild-type p53 protein is not detectable, because its mRNA is short-lived (T½ = 8 min) in unstressed cells. The induction of DNA double strand breaks by X-ray irradiation initiates a p53-dependent signal transduction cascade. One downstream target of this cascade includes the induction of WAF1/CIP1 mRNA, which encodes the p21 protein. Upregulation of WAF1/CIP1 protein inhibits the cyclin E/cyclin-dependent kinase 2 complex, an event that is able to stop cells from progressing through G1. Phosphorylation of p53 at serine-15 in response to ionizing radiation correlates with both accumulation of total p53 as well as its transactivation of downstream genes.

Temozolomide improves survival in patients with glioblastoma that receive radiation therapy, particularly if the tumor demonstrates: A. epigenetic silencing of O6-methylguanine-DNA methyltransferase (MGMT) B. epigenetic silencing of microRNA expression C. epigenetic silencing of PTEN D. expression of the mutant receptor EGFRvIII E. expression or amplification of Her2/neu

A. epigenetic silencing of O6-methylguanine-DNA methyltransferase (MGMT) Methylation of the promoter for MGMT (O6-methylguanine-DNA methyltransferase) via an epigenetic mechanism (not via a gene mutation) decreases expression of this DNA repair gene. When tumor cells do express MGMT they are able to repair the alkylation of DNA caused by temozolomide. Therefore, patients with MGMT-expressing glioblastomas derive little benefit from concurrent temozolomide and radiation therapy. In contrast, when MGMT is silenced, temozolomide is able to achieve significant DNA damage via alkylation, which ultimately increases its radiosensitivity.

Which of the following assays would best determine whether a particular radiation sensitivity syndrome is characterized by defective repair of DNA double-strand breaks? A. quantitation of g-H2AX foci B. western blot C. alkaline comet assay D. southern hybridization E. northern hybridization

A. quantitation of g-H2AX foci Quantitation of DNA repair foci using a monoclonal antibody raised against g-H2AX is currently considered the most sensitive assay for the repair of DNA double-stranded breaks, although there is some controversy regarding whether g-H2AX foci are also formed in response to other types of DNA changes. The neutral comet assay can also be used to measure DNA double-strand breaks, although it is generally considered less sensitive than g-H2AX.

NCRP annual occupational lens exposure limit

According to Zeman was 50 mSv/year (down from 150 mSv/yr) According to rad onc q bank - this is now 50 mGy/yr

What is the only radioprotective drug approved by the FDA?

Amifostine - free radical scavenger -- taken up by normal tissues more rapidly than tumors

A multifraction protocol for cells exposed to x-rays produces an effective survival curve that is: a. Linear-quadratic b. Bell-shaped c. Linear d. Parabolic e. Exponential CAREFUL -- trick question

Answer is E Remember this produces a linear appearing plot described by S = e^-aD or S = e^(-Dose/D0) BUT It is plotted logarithmically so it is actually EXPONENTIAL

Your clinic has a fancy new treatment planning system that uses radiobiologic tumor control probability (TCP) and normal tissue complication probability modeling (NTCP) to help select the best treatment plan. Your dosimetrist has come up with 4 plans to review. Based on the TCP/NTCP curves below, which of the following plans would you choose? Curves on other side - answer on next card

Answer on next card

chromatin condensation double strand breaks in linker regions between nucleosomes ~185 bp sequences producing ladder on gel cells round up and detach from neighbor hallmarks of?

Apoptosis

Which syndrome is caused by a deficiency in the repair-associated protein MRE11?

Ataxia-telangiectasia-like disorder

Which of the following assays would NOT be useful for the purpose of quantifying the response of a tumor to irradiation? A. Lung colony assay B. Number of tumors per animal C. Time to reach a certain size D. Growth delay E. Colony forming ability of cells explanted from the tumor

B An increase in the number of tumors per animal would be a reflection of metastatic spread of the tumor, and would not necessarily reflect the radiation response of the primary tumor per se. All of the other assays can be used to quantify the response of tumors to irradiation.

Which of the following would best be used to estimate the proportion of radiation resistant viable hypoxic cells in an experimental tumor model? a. Comparison of radiation response with and without breathing of hyperbaric oxygen b. Paired survival curve analysis in vitro following irradiation in vivo under standard conditions and conditions where blood flow to the tumor has been stopped c. Extrapolation of the initial exponential portion of the cell survival curve for cells comprising the tumor d. Comparison of radiation responses with and without misonidazole administration e. Comparison of radiation responses of the tumor treated with high versus low dose-rate radiation

B The paired survival curve technique is used to determine the proportion of viable clonogenic cells in a tumor that is hypoxic. In this assay, animals possessing tumors are irradiated while breathing either room air (typical tumor response), or where they are clamped to block blood flow. The ratio of the surviving fractions for the cells, under aerated to fully anoxic conditions, provides an estimate of the fraction of the cells in the tumor that are hypoxic under normal conditions. While misonidazole is a hypoxic radiosensitizer, it's effects on hypoxic tumors are not complete, and it can have antineoplastic activity in some well-oxygenated cancer cells as well. Thus an assay involving administration of misonidazole would be "contaminated" by incomplete activity against hypoxic cell and "off-target" killing of normoxic cells. In addition, any assay utilizing a pharmacologic intervention assumes equal distribution throughout the tumor, which may not be the case due to inconsistent vascularization.

Which of the following statements is FALSE concerning the cell cycle? a. Irradiation of cells causes a delay in progression from G1 into S phase of the cell cycle b. Cells in M phase typically have X-ray survival curves with low a/bratios c. Cells are most resistant in late S phase of the cell cycle d. G1 is the cell cycle phase most variable in duration e. The G0 phase of resting cells is within G1

B The survival fraction for mitotic cells exposed to radiation is dominated by the linear (or alpha) component of cell killing . Mitotic cells possess little-to-no capacity for sublethal damage repair, which results in low quadratic (or beta) component of cell death. Therefore, mitotic cells are characterized by high a/b ratios.

The dose rate range over which SLDR most contributes to the dose rate effect for X-rays is: a. a.0.001 - 0.01 Gy/min b. 0.01 - 1 Gy/min c. 1 - 5 Gy/min d. 5 - 10 Gy/min e. 10 - 20 Gy/min

B As the dose rate decreases from about 1 Gy/min to 0.01 Gy/min, the greatest increase in cell survival due to SLDR is observed for most X-irradiated cell lines. Decreasing the dose rate further may permit an even greater increase in the surviving fraction, but this further increase would be due to repopulation that may take place if the dose is delivered at a very low dose rate over a long interval.

The Tpot for most head and neck tumors is in the range of: a. 1-2 days b. 2-6 days c. 6-24 days d. 24-100 days e. Greater than 100 days

B The Tpot for most head and neck tumors is in the range of 2-6 days. Overall tumor growth is a combination of Tpot (which accounts for growth fraction, Tpot = TC/GF where TC = cell cycle time, GF = growth fraction) and cell loss factor (Cell loss factor = 1 - (Tpot/TD), where TD = tumor doubling time.

The most commonly used biologically active molecule for positron emission tomography (PET) scanning is a fluoridinated analog of which of the following: A. Phosphate B. Glucose C. Calcium D. Albumin E. Sphingomyelin

B. Glucose Secondary to the predominant use by tumors of glycolysis instead of oxidative phosphorylation for energy production, 18-Fluorodeoxyglucose is the most helpful and therefore most commonly used metabolic radiotracer for PET scanning for malignancies...

In estimating the doses to individuals and their critical organs, and also in assessing potential risks to both individuals and populations, various correction factors are required. Which one of the following statements regarding these terms is FALSE? A. For a particular tissue or organ, the proportion of the risk for stochastic effects resulting from uniform, whole-body irradiation is called the "tissue weighting factor" B. The dose equivalent to the most sensitive tissue or organ following uniform, whole-body irradiation is called the "committed dose equivalent" C. The sum of the individual dose equivalents received over a defined time period by an irradiated population is called the "collective dose" D. The average absorbed dose in a particular tissue or organ that is weighted for radiation quality is called the "equivalent dose" E. The sum of weighted equivalent doses for all tissues and organs of the body is called the "effective dose"

B The dose equivalent to the most sensitive tissue or organ following uniform, whole-body irradiation is called the "committed dose equivalent" The "committed dose equivalent" is the dose equivalent to a tissue or organ that will be received over a 50-year period from the ingestion of radioactive material(s).

Which radiation-induced immune effect would be counterproductive to effective anti-tumor immunity? A. Radiation-induced release of danger signals B. Radiation-induced increase in regulatory T cells C. Radiation-induced increase in MHC class I expression D. Release of pro-inflammatory cytokines E. Radiation-induced epitope spreading

B. Radiation-induced increase in regulatory T cells Danger signals, MHC class I expression, pro-inflammatory cytokines and epitope spreading would support the development of an immune response with the purpose of achieving anti-tumor immunity, while activation of regulatory T cells would not. Regulatory (suppressor) T cells are a subset of CD4+ T cells that express the transcription factor forkhead box P3 (FOXP3). FOXP3 is a potent suppressor of immune responses to self and non-self and is essential to the maintenance of peripheral immunological tolerance. Tregs suppress the activation, proliferation, and cytokine production of CD4+ and CD8+ T cells, and are additionally thought to suppress B cells and dendritic cells. They exert their suppressive activity through cell-to-cell contact and via the production of soluble suppressive/inhibitory messengers (i.e. TGF-beta, IL-10 and adenosine). Loss of function mutations in the Foxp3 gene underlie the lymphoproliferative disease of the Scurfy mouse and the homologous autoimmune lymphoproliferative disorder in man, termed Immune dysregulation Polyendocrinopathy Enteropathy−X (IPEX) linked syndrome. Of note, despite the immune suppressive function, the infiltration of tumors by Tregs doesn't necessarily indicate worse prognosis as it is also an indicator for a T cell inflamed tumor phenotype, (i.e. a (positive) sign for immune reactivity). Recognition of danger signals such as pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) by pattern recognition receptors on APCs initiates cellular maturation and confers to these cells the ability to process and present antigens to T cells (signal 1) as well as achieve co-stimulation (signal 2), both of which are necessary to induce T cell activation. Antigen presentation without signal 2 can cause T cell anergy. Antigenic peptides are presented within the MHC cleft on the cell surface with the assumption is that an increase in MHC class I expression would be supportive of better antigen presentation thereby making tumor cells more 'visible' to T cells. Tumor cell death in response to immunotherapy may lead to the release of secondary (nontargeted) tumor antigens that prime subsequent immune responses. Epitope spreading (or antigen cascade, antigen spread, determinant spread) describes a phenomenon where the immune response evolves and expands from focusing on a single antigenic epitope, into a multi-epitopic response be it naturally or following therapeutic intervention e.g. vaccination or radiotherapy. This process is dynamic and may continue to expand over time. Antigen spreading of the anti-tumor immune response from one antigen to another antigen has been linked to superior clinical outcome with the assumption that it counteracts tumor immune evasion.

The enzyme inhibited by 5-fluorouracil that is most closely associated with both its cytotoxic and radiosensitizing effects is: A. Dihydrofolate reductase B. Thymidylate synthase C. RAD50 D. Tyrosine kinase E. Ligase IV

B. Thymidylate synthase Thymidylate synthase is the enzyme inhibited by 5-fluorouracil, leading to the inhibition of DNA synthesis as well as the synthesis of both ribosomal and messenger RNA. This accounts for the drug's cytotoxic and radiosensitizing effects.

Hypofractionation is being used to definitively treat many different malignancies including breast and prostate cancer. Which of the following is TRUE about its use in prostate cancer? A. Treatment of the whole prostate using the same total dose but higher dose per fraction allows safe dose escalation while sparing normal tissues B. Treatment of the whole prostate to the the same biologically effective dose (BED) to tumor but higher dose per fraction allows shorter treatment time and little to no change in the therapeutic ratio C. Treatment of the whole prostate to the the same BED to tumor but higher dose per fraction allows a shorter treatment time and selective sparing of the adjacent normal tissues D. The BED to normal tissues is significantly higher with hypofractionated regimens and therefore stereotactic methods must be used to treat the prostate

B. Treatment of the whole prostate to the same biologically effective dose (BED) to tumor but higher dose per fraction allows shorter treatment time and little to no change in the therapeutic ratio The goal of hypofractionation is to provide more convenient (shorter) treatments to patients while maintaining or improving the therapeutic ratio. Hypofractionation for low- and intermediate-risk prostate cancer typically involves treatment of the prostate cancer to an EQD2 of 74-78 Gy (assuming α/β of 1-3 for tumor). The most thoroughly tested regimens include 70 Gy in 28 fractions (RTOG 0415) and 60 Gy in 20 fractions (UK CHHIP and PROFIT). In general, these regimens were tested for non-inferiority against roughly biologically equivalent conventional regimens (73.8 Gy/41 fractions for RTOG 0415, 74 Gy/37 fractions for UK CHHIP, and 78 Gy/39 fractions for PROFIT). A major concern about hypofractionation was the possibility of significantly increased acute and late toxicity not predicted by linear quadratic modeling. The above trials have demonstrated this not to be the case, so long as appropriate dose constraints are achieved. There is some evidence, however, of a small increase in acute GI toxicity across trials. Answer A is incorrect, as maintaining the same total dose (e.g., 78 Gy) while hypofractionating (e.g., 20 fractions) would increase the BED to both tumor and normal tissues. While this would improve the likelihood of tumor control, it also would move rightward along the normal tissue probability curve with a disproportionate increase in NTCP, thereby decreasing the therapeutic ratio. Answer C is incorrect, as hypofractionation regimens maintaining an equivalent BED compared to an effective conventional regimen are not expected to significantly spare normal tissues (although the BED to normal tissues may be marginally less depending on the alpha/beta used for tumor). Answer D is incorrect, as the BED to normal tissues for the regimens mentioned above is not significantly different from conventional regimens. As a result, both predicted toxicity and measured toxicity are not significantly different. Daily image guidance was not mandatory on UK CHHIP (~30% treated with it) but was required on PROFIT and RTOG 0415; none of these trials used real-time tracking methods. However, daily image guidance is typically preferred, especially if treating according to the respective protocol.

Nucleotides can be radiolabeled before they are incorporated into newly forming DNA and can therefore be assayed to track their incorporation. In a set of experiments, a resident-faculty research team used labeled thymidine nucleotides and introduced these into the culture of dividing human cells as a 30-min pulse. Which of the following questions might be answered by such a method? a. How many cells are produced by the culture per hour? b. What is the length of the S phase of the cell cycle? c. What proportion of cells are undergoing autophagy? d. How many picograms of DNA are made per cell cycle? e. When do spindle fibers attach to chromosomes?

B. What is the length of the S phase of the cell cycle? The incorporation of radioiotopes into the DNA and autoradiography is the technique to estimate the length of S phase as a fraction of the whole cycle (labelling index) in dividing cells. In 1953, Alma Howard and S.R. Pelc discovered the cell cycle by observing that a radioisotope (32P or 35S) is taken up in the nucleus of plant cells at a distinct interval after mitosis. This led them to conclude that the DNA in the nucleus is replicated during only a limited portion of interphase and called this period of DNA synthesis the S phase of the cell cycle. Howard and Pelc studied the meristem of the bean root tip. They found a 30 h cell cycle for these meristem cells, with 4 h for mitosis (M), 6 h for DNA synthesis (S), a time post-division to DNA synthesis (12 h for G1), and another time interval from after DNA synthesis to mitosis (8 h for G2) (G = gap). Variations of this technique, including 3H thymidine autoradiography and bromodeoxyuridine incorporation, have been used to estimate cell cycle time periods for other species. Cell cycle times in mammalian cells vary widely, from less than 8 h to more than a year in adult animals, with most of the variability being in the length of the G1 phase.

Beclin protein is involved in which form of cell death?

Beclin = Autophagy Beclin is a protein important in the development of the autophagosome for autophagy. It is also important and used in some pathways of apoptosis. It plays no role in necrosis (which is an unscheduled death and not programmed in any way) or the other forms of death listed.

Where does thermotolerance occur in hyperthermia therapy?

Below the break point at 43 degrees C -- so its not true that it doesn't happen between 41-42 Thermotolerance occurs only AFTER heating when above the breakpoint. At temperatures ABOVE 43 degrees, thermotolerance cannot occur during heating --

If a cell line exhibiting a strictly exponential radiation survival curve is exposed to a dose that produces an average of one lethal "hit" per cell, the surviving fraction after this dose would be approximately: A. 0.01 B. 0.10 C. 0.37 D. 0.50 E. 0.90

C Assuming that all cells in the cell population are identical and that cell killing is a random, probabilistic process that follows a Poisson distribution, one model that can calculate the radiation dose that produces an average of one lethal hit is the single-target single-hit model. From the equation that describes this model, S = e, the dose, D, at which there would be an average of one hit per cell would be equal to D0, the constant of proportionality. Therefore, S = e-1 ~ 0.37.

For single, large radiation doses delivered at a high dose rate, the ratio of the OER for X-rays divided by the OER for alpha particles is approximately: A. 0.3 B. 1 C. 2 D. 4 E. 10 What is the standard OER for X-rays? What is OER for 15 MeV Neutrons?

C Since the X-ray OER is typically about 3 and the OER for 15 MeV neutrons is about 1.6, the ratio of the OERs is about 2.

For a cell line whose single-dose survival curve is characterized by an n of 10, increasing fraction size causes the effective D0 to: a. Remain the same b. Increase c. Decrease d. Decrease over a low dose range, but increase at high doses e. Increase over a low dose range, but decrease at high doses

C - DECREASE The point here is they are asking the standard question the other way around. The effD0 ALWAYS increases when you fractionate. They are saying the opposite, if you HYPOfractionate, or increase fraction size, this will cause more cell killing for a call line with such a high n value, and this will effectively reduce the D0.

How many ion clusters are formed by 55 keV/μm silicon ion along a 1 μm segment of the ion trajectory through the cell nucleus? Assume silicon ion irradiation with the beam parallel to a cellular monolayer and that ion clusters are uniformely spaced along the silicon ion track A. 0.5 cluster every 1 μm or 1 cluster every 2 μm B. 5.5 clusters every 1 μm C. 500 clusters every 1 μm D. 5,500 clusters every 1 μm E. 55,000 clusters every 1 μm Important to be able to answer: - 1 ion cluster requires ____ eV

C On average, the formation of a three-ion cluster requires dissipation of 110 eV. Therefore, 55 𝑘𝑒𝑉𝜇×1000 𝑒𝑉1 𝑘𝑒𝑉 × 1 𝑖𝑜𝑛 𝑐𝑙𝑢𝑠𝑡𝑒𝑟110 𝑒𝑉= 500 𝑖𝑜𝑛 𝑐𝑙𝑢𝑠𝑡𝑒𝑟𝑠/𝜇 or 1 cluster every 20 Ǻ (1 μm = 10,000 Ǻ). This spacing of ion clusters along the silicon ion track corresponds to a 20 Ǻ diameter of of the DNA helix.

Which of the following effects is associated with improved survival in patients treated with radiation therapy and cetuximab for head and neck cancer: A. Hair loss B. Erythema C. Acneiform rash D. Desquamation E. Pruritis

C. Acneiform rash Data suggests that patients treated with definitive radiation and cetuximab who develop a Grade 2 or greater acneiform rash experience increased overall survival compared to patients who develop either no rash or grade 1 rash (HR 0.49).

Which of the following agents does not target the PD-1/PDL-1 axis? A. Pembrolizumab B. Avelumab C. Ipilimumab D. Durvalumab E. Nivolumab

C. Ipilimumab Inhibitors of programmed cell death 1 (PD-1) receptor include pembrolizumab and nivolumab. Inhibitors of programmed death ligand 1 (PD-L1) include atezolizumab, durvalamab, and avelumab. Ipilimumab is an example of a Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) inhibitor. Ipilimumab functions by disinhibiting the native ability of T cells to recognize and destroy cancer cells.

Cisplatin has all the following properties EXCEPT: A. It inhibits DNA synthesis more than RNA or protein synthesis B. It is cell-cycle non-specific C. It is similar in efficacy to its isomer, trans-platinum D. It causes both inter-strand and intra-strand crosslinking E. It is used as a radiosensitizer with concurrent radiation therapy.

C. It is similar in efficacy to its isomer, trans-platinum Cisplatin is a chemotherapeutic agent that causes DNA synthesis inhibition by causing both interstrand and intrastrand crosslinking (Answer Choices A and D). It is cell-cycle non-specific (Answer Choice B). It is used as a radiosensitizer with concurrent radiation therapy (Answer Choice E). It is much more effective than its isomer, trans-platinum.

Radiation effects in the nervous system typically arise as a consequence of damage to: A. Axons B. Neurons C. Oligodendrocytes and glial cells D. The perikaryon E. Dendrites

C. Oligodendrocytes and glial cells The effects of radiation on the nervous system arise primarily as a consequence of damage to oligodendrocytes and glial cells. Although radiation likely does cause some damage to neurons as well, this alone does not seem to manifest itself as a frank nervous system injury.

Approximately 10,000-20,000 cases of lung cancer each year in the United States are attributed to alpha-particles produced by: A. Nuclear weapon testing B. Decrease in the ozone layer C. Radon gas D. Chemical contamination

C. Radon gas Alpha-particles are emitted during the decay of radionuclides, such as radon, that occur in nature. Radon gas escapes from the soil and builds up inside homes where it is inhaled and can cause lung cancer.

The following nucleoside has been radiolabeled in an effort to image DNA synthesis using positron emission tomography (PET): A. Adenosine B. Guanosine C. Thymidine D. Uridine E. Cytidine

C. Thymidine 18-Fluorine labeled thymidine has been used to image DNA synthesis in humans in vivo. The other nucleosides would not differentiate DNA from RNA.

Pathways that trigger apoptosis culminate in widespread intracellular proteolysis. Which of the following proteases is a downstream executioner that directly participates in the breakdown of numerous cellular proteins? A. caspase-8 (CASP8) B. caspase-9 (CASP9) C. caspase-3 (CASP3) D. caspase-10 (CASP10) E. XIAP (BIRC4) -- what is this one?

C. caspase-3 (CASP3) Apoptotic signals trigger a series of proteolytic events known as the caspase cascade. There are at least 14 human caspases, which fall into two categories: the initiator caspases (caspases-2, -8, -9 and -10), which activate the downstream caspases, and the executioner caspases (caspases-3, -6 and -7), which cleave cellular substrates. The actions of the executioner caspases produce the cellular effects that distinguish apoptosis from other forms of cell death. XIAP is a protein that binds to and inhibits the action of caspases.

The cancer stem cell theory gained prominence when cell samples from acute myeloid leukemia patients were shown to: a. contain one characteristic cell type b. have high clonogenicity in vitro and in immune suppressed mice c. have a small subset of CD34++CD38− cells with a high capacity for self-renewal and initiated tumors on transplantation into NOD/SCID mice d. contain a small subset of CD34++CD38− cells with a high capacity to differen

C. have a small subset of CD34++CD38− cells with a high capacity for self-renewal and initiated tumors on transplantation into NOD/SCID mice Bonnet and Dick showed that most of the AML cells were non-tumorigenic but a small population of tumor initiating cells existed that grew in NOD/SCID immune deficient mice.

Which one of the following is NOT a method for studying gene expression at the protein level? A. immunohistochemistry B. ELISA C. northern blots D. western blots E. two-hybrid screening

C. northern blots C Northern blotting is used to study RNA.

Which of the following statements is CORRECT? The genetically significant dose (GSD) is: A. of particular concern with respect to radon inhalation B. approximately 1 Sievert (Sv) and corresponds to the average annual dose received from all medical procedures involving ionizing radiation performed in the United States C. the annual average gonadal dose to a population adjusted for the relative child expectancy of that population D. an estimate of the number of children born each year with a radiation-induced mutation E. the extrapolated lifetime gonadal dose for an individual

C. the annual average gonadal dose to a population adjusted for the relative child expectancy of that population The genetically significant dose (GSD) is the annual average gonadal dose to a population adjusted for the relative child expectancy of that population. Exposure to radon does not contribute significantly to the GSD because the decay products of radon are deposited almost entirely in the lung (Answer Choice A). The GSD resulting from medical procedures performed annually in the United States is estimated to be 0.3 mSv, not 1 Sv (Answer Choice B). Although the GSD can be utilized to estimate the number of children born each year with a radiation-induced mutation, the GSD itself is an estimate of the average gonadal dose to the population (including potential parents), not an estimate of the effects on offspring (Answer Choice D) The GSD is an annual population dose, not an individual lifetime dose (Answer Choice E).

Which of the following is not an immune checkpoint? a. LAG3 b. PD-1 c. TIM3 d. OX40 e. CTLA-4 More importantly, know which ones ARE immune checkpoint

Classic immune checkpoints that come up are: these are all co-inhibitory receptors PD-1 (binds PDL1/2) CTLA-4 LAG3 (binds MHCII) TIM3 OX40 is not one - it is a COSTIMULATORY receptor. Other examples are: 4-1BB, CD40L, GITR, ICOS and CD27

Which ONE of the following is a morphological or biochemical feature of apoptosis? A. Random cleavage of DNA B. Cellular swelling C. Lack of dependence on ATP as an energy source D. Chromatin condensation E. Rupture of the plasma membrane

D During the apoptotic process, endonucleases cut the DNA at precise sites corresponding to the linker region between nucleosomes. This leads to the formation of fragments that are multiples of 80 bp units. Major features of apoptosis: precise DNA cleavage (multiples of 80 bps), cell shrinkage, chromatin condensation, ATP requirement as apoptosis is an energy dependent process, and the plasma membrane initially remains intact but later fragments and surrounds the apoptotic bodies. Cell swelling --> necrosis

What is the approximate eD10 (effective D10) for a particular cell line if the eD0 is 4 Gy? A. 2 Gy B. 4 Gy C. 6 Gy D. 9 Gy E. 12 Gy

D. 9 Gy eD10 is the dose required to kill 90% of population eD10 = 2.3 x D0 The eD10 is equal to the eD0 multiplied by 2.3, or 4 Gy x 2.3 = 9.2 Gy

Which of the following is the best measure for the presence of radiation-induced chromosome aberrations in interphase cells? A. Reciprocal translocations B. Ring chromosomes C. Dicentric chromosomes D. Micronuclei E. Chromatid breaks

D. Micronuclei Individual chromosome aberrations can, in general, be detected readily only during mitosis. However, some chromosome aberrations lead to the formation of micronuclei, which develop when a pseudo nuclear membrane forms around acentric chromosome fragments or whole chromosomes that did not segregate properly into daughter cells during the previous mitosis. Micronuclei are observed in peripheral lymphocytes and thus can be seen in interphase cells.

Radiosensitization produced by gemcitabine is associated with the inhibition of which of the following enzymes? A. Topoisomerase I B. DNA-PKcs (PRKDC) C. DNA polymerase D. Ribonucleotide reductase E. Sphingomyelinase

D. Ribonucleotide reductase In its active metabolite form, gemcitabine inhibits ribonucleotide reductase, which likely accounts for its action as a radiosensitizer. The inhibition of this enzyme affects DNA synthesis by preventing the de novo biosynthesis of deoxyribonucleoside triphosphate precursors.

Which one of the following is NOT a tumor suppressor gene? A. PTEN B. BRCA2 C. WT1 D. NF1 E. ABL

E. ABL ABL is an oncogene whereas PTEN, BRCA2, WT1, and NF1 are all tumor suppressor genes.

has been used to measure the radiation sensitivity of bone marrow stem cells in vivo? A. Dicentric assay B. BrdU (BrdUrd) assay C. Endpoint dilution assay D. In vivo/in vitro excision assay E. Spleen colony assay

E. Spleen colony assay This involves the ability of donated bone marrow stem cells, injected intravenously into lethally-irradiated recipient mice, to form discrete splenic colonies. The higher the radiation dose received by the donated marrow, the fewer colonies (relative to the number of cells injected) will form in the recipients spleen.. This technique allows a cell survival curve to be generated in vivo.

Which of the following statements is CORRECT? Cancers induced in humans following exposure to low-dose whole-body irradiation: A. include excess breast cancers in female radium dial painters B. can be distinguished from those occurring naturally C. clearly follow an exponential dose response D. exhibit similar latency periods for both leukemias and solid tumors E. are more likely to appear in individuals who were young at the time of exposure

E. are more likely to appear in individuals who were young at the time of exposure The susceptibility to radiation-induced cancer decreases with increasing age at the time of irradiation. Radium dial painters ingested significant quantities of radium-containing paint by repeatedly licking the paint brushes they used. These women subsequently developed an excess number of osteosarcomas due to the incorporation of radium into their growing bones and the continuous low-dose-rate irradiation received by these tissues over the next decades (Answer Choice A). At this time, cancers induced by radiation cannot be distinguished from cancers that occur naturally, although molecular markers for radiation exposure may eventually be identified (Answer Choice B). The current consensus among radiation protection organizations is that the most appropriate dose response curve for radiation carcinogenesis is one that increases linearly with increasing radiation dose and without a dose threshold (linear no-threshold or LNT model). This hypothesis, however, has been challenged by those who believe that exposure to low radiation doses may be less harmful than what is predicted by the LNT model, and possibly even beneficial (often referred to as hormesis). The LNT model has also been criticized by those who believe that bystander effects may result in an increased risk at low doses over those predicted by the LNT model (Answer Choice C). Hematological malignancies have shorter latency periods compared to solid tumors (Answer Choice D).

Regarding the regulation of apoptosis, which of the following pairs of mammalian proteins and their apoptosis-related functions is FALSE? A. p53 (TP53) --- upregulation of PUMA B. DIABLO --- caspase activation C. XIAP (BIRC4) --- caspase inhibition D. BAX --- cytochrome c release E. caspase-3 (CASP3) --- initiator caspase

E. caspase-3 (CASP3) --- initiator caspase -- this is an EXECUTIONER caspase (3/6/7) The characteristic changes associated with apoptosis are due to activation of a family of intracellular cysteine proteases, known as caspases. Initiator caspases are the first to be activated, and include caspases-2, -8, -9 and -10. Initiator caspases cleave and activate the effector/executioner caspases, including caspases-3, -6, and -7, which then cleave, degrade or activate other cellular proteins. Activation of caspases is regulated by members of the BCL2 family and by the inhibitors of apoptotic protein (IAP) family. BAX is one of a series of pro-apoptotic members of the BCL2 family. These pro-apoptotic BCL2 family members regulate the release of cytochrome c from mitochondria and elicit the subsequent activation of caspases. Another important function of p53 is that it causes upregulation of pro-apoptotic PUMA. X-linked IAP (XIAP) inhibits the activity of caspases directly. DIABLO is a pro-apoptotic protein that prevents IAPs from inhibiting caspases. BAX and p53 are required for some forms of DNA damage-induced apoptosis.

Which of the following statements is TRUE concerning the products of the INK4A/ARF locus? A. p16INK4A (CDKN2A) stimulates the hyper-phosphorylation of the RB (RB1) protein resulting in release of the E2F transcription factor B. p14ARF is induced by the RAS/MEK/MAPK pathway and stimulates cell growth C. p16INK4A is encoded by a proto-oncogene D. p16INK4A is activated by the PI(3)K/AKT pathway and increases synthesis of cyclin D E. p14ARF inhibits the MDM2-mediated degradation of p53

E. p14ARF inhibits the MDM2-mediated degradation of p53 p14 ARF inhibits the MDM2-mediated degradation of p53. p16INK4A is a cell cycle inhibitor that prevents phosphorylation of RB by CDK4. p14ARF is an MDM2 inhibitor thereby causing p53 levels to increase, resulting in greater cell cycle inhibition. p16 INK4A is encoded by a tumor suppressor gene.

Buzzwords cell cycling vs non-cycling state single fraction (not split dose) delayed plating (a way to delay cell cycling) changing the post-irradiation environment think what

Potentially lethal damage repair idea being change the environment to prevent cell cycling in one subset and then plate them later (delayed plating)

Which of the following may increase a patient's susceptibility to experience an immune related adverse event? A. History of autoimmune disease B. Abnormal thyroid function C. Previous use of checkpoint blockade therapy D. Previous radiation therapy E. All of the above F. A, C and D

F. A, C and D

Extrinsic apoptotic pathway activated by what ligands?

FAS-L and TRAIL The extrinsic apoptotic pathway involves stimulation of TNFR family members.

Mechanism of cysteamine radioprotection?

Free radical scavenger AND donates a hydrogen atom to provide direct chemical repair at sites of DNA damage This generally applies to radioprotectors that have an -SH group

Genetically engineered mouse models (GEMMs) are becoming more popular for preclinical tumor studies with and without radiation. Which of the following is the most correct regarding the advantages of GEMMs over xenograft-based studies? a. Intact immune system b. Tumors are orthotopic in location c. Tumors contain mutations that are relevant for human tumors d. Intact extracellular tumor microenvironment e. Tumors develop more rapidly

In order to grow xenographs, you have to do it in nude mice that won't reject them, so the role of the immune system is dramatically minimized in those models compared to GEMMS. A In vivo studies are necessary in order to examine agents that act on the tumor microenvironment or other non-cell autonomous cancer cell processes, such as anti-angiogenic agents. The majority of in vivo studies involve immunocompromised mice with mutations in DNA response and repair pathways, including athymic, severe combined immune-deficiency (SCID) or NOD-SCID mice. The abnormal DNA repair mechanisms in these mice limit the applicability of results with radiosensitizers given the integral role of DNA damage to the biologic effect of radiation therapy. Furthermore, anti-tumor effects of radiotherapy may be mediated by the immune system. Therefore, immunocompromised mice are not optimal in this regard given that they lack a functional immune system. As a result of these limitations, genetically engineered mouse models (GEMMs) are becoming more widely used in preclinical studies with and without radiotherapy (24331186 and 23863691). The correct answer is "a". The other answers are possible for both GEMMs and xenograft tumor models.

TS mutants often inherited as one bad allele in the germline. Only case of an inherited oncogene?

MEN2 - RET proto-oncogene Oncogenes are gain of function mutations - only need one mutant copy TS are loss of function mutations -- meaning you have to lose both copies to get cancer. However, these syndromes usually are inherited in an autosomal dominant type fashion with malignancy happening after LOH of the remaining normal allele

Neutral comet assay alkalkine comet assay

Neutral comet assay = DSB only alkalkine comet assay = SSB + DSB

IMPORTANT CONCEPTS - there is a steep increase in late complications with increasing dose per fraction because LATE responding tissues (low a/b) have a more "curvy" shape in the low dose region (alpha component) -- leading to a lower survival at high dose per fraction when compared to early responding tissues (see graph). - early responding tissues (high a/b) are not as sensitive to change in fraction size as low a/b tissues are. So hyperfractionating would have little negative impact on tumor control, but significant increase in survival in the late responding tissues improving the therapeutic ratio. See graph

Point made in this graph is that if you pick dose B instead of dose A, this would not kill THAT much more of the early responding tissues (survival not that much lower), but it kills substantially more of the late responding tissues. Shaded region represents the effect of fractionating --

What departmnet provides 24-hour assistance with medical problems associated with radiation exposure in the US?

Radiation Emergency Assistance Center/Training site (REAC/TS)

Really great explanation of the alpha beta ratio and its relationship to cell killing

S = e^-(aD+bD^2) The alpha/beta ratio is the dose at which the linear component of cell kill is equal to the quadratic component of cell kill. The likelihood of this type of cell kill is relatively lower and increases with increasing radiation dose in a linear fashion. Of note, high LET radiation tends to do alpha killing much more efficiently because of all the damage it does along its track. So this is why high let has a linearly appearing survival curve. alpha killing means a single particle track is responsible for creating two hits in one place in the DNA resulting in lethal damage. beta killing means that two different tracks had to pass through the same area and damage the two regions of the dna in the same place in order to cause a lethal event. The likelihood of this increases disproportionally at higher doses (more tracks around) - thus in a exponential way. Different tissues have differing degrees to which type of cell killing will happen at which doses -- so different tissues have different alpha beta ratios -- different doses where there is more alpha or more beta killing happening. This idea kind of correlates with intrinsic radiosensitivity. If you look at a HNSCC with a high alpha beta ratio compared to the nearby spinal cord with a low alpha beta ratio, the point can be illustrated well. HNSCC has a high alpha beta ratio (10 or higher) and that means there is a strong alpha component to cell kill happening so for each extra Gy of radiation, it will cause a predictable and linear amount of cell killing. Its beta component is cell kill is fairly low, meaning that as you increase the dose, you don't really see a disproportionate amount of cell killing. This means, for HSNCC, there isn't much advantage to continually increasing the dose given in a single fraction (it will kill a little more, but not a ton more of the cells). In contrast, the spinal cord on the other hand is a low alpha beta tissue, which means that for every extra Gy per fraction that is given, there will be an exponential increase in the cell death that occurs for that dose. So if your goal was to paralyze a person while protecting their HN cancer, it would be best to give a single high dose of radiation -- the HN cancer would probably survive it, but the spinal cord would not. Alternatively, if you wanted to spare the spinal cord and kill the cancer, giving many smaller doses would be ideal as the spinal cord really isn't sensitive to many small doses, but the linear portion of the carcinoma kill is high so you are doing relatively more damage to the cancer that way. Both are sensitive to total dose Early tissues -- total treatment time course matters MORE Late tissues -- dose/fraction matters MORE

A dose of 10 Gy of X-rays reduces the tumor cell surviving fraction to 0.001 in an animal irradiated while breathing air, and to 0.1 in an animal irradiated under nitrogen. An estimate of the hypoxic fraction for this tumor in the air-breathing mice would be: A. 0.0001 B. 0.01 C. 0.25 D. 10 E. 25

The fraction of cells in a tumor that are hypoxic can be estimated using the paired survival curve method. This corresponds to the surviving fraction of cells irradiated in normally oxygenated tumors divided by the surviving fraction of cells from a tumor made fully hypoxic by asphyxiating the host with nitrogen immediately prior to irradiation, which is assumed to render all of the tumor cells radiobiologically hypoxic. Thus, the estimate for the fraction of hypoxic cells would be 0.001/0.1 = 0.01.

The whole 1000-2000 base pair damages 1000 ssb 100 dna-protein cross links 40 dsb 30 dna cross links thing that applies to what dose of radiation?

This means a cell exposed to a D0 dose (enough to reduce survival of the population to 37% in the exponential portion)

What is the approximate surviving fraction following 5 doses of 0.5 Gy of carbon ions, assuming that the surviving fraction following one dose is 0.4? a. 0.01 b. 0.10 c. 0.37 d. 0.50 e. 0.90

a. 0.01 A Since the survival curve for high LET carbon ions is exponential, the surviving fraction following 5 irradiations with a dose that results in a surviving fraction of 0.4 would be (0.4)^5 = 0.01.

Patients who are treated for breast cancer are at higher risk than the normal population for developing second malignancies. Approximately what proportion of secondary malignancies in breast cancer survivors are attributable to radiation therapy? a. 5% b. 20% c. 30% d. 50%

a. 5% Regardless of the receipt of radiotherapy, breast cancer patients are at a higher risk of second malignancies, including a higher risk of contralateral breast, gynecologic, and thyroid cancer. Receipt of radiation further increases risk, particularly in the esophagus, lung, and soft tissues. However, the estimated percentage of second malignancies (excluding non-melanomatous skin cancers) attributable to radiation therapy is only 3.4-9%. As many patients are concerned about secondary malignancy risk, it is important to counsel them that the risk of getting a future non-radiation-related cancer is much higher than a radiation-related one. Furthermore, the risk of cancer recurrence without radiation treatment is often much higher than the risk of a second, radiation-attributable cancer. However, for younger women treated with breast cancer radiotherapy, the risk of a future second cancer can be nearly double that of age-matched controls.

All of the following organs can tolerate 70 Gy (delivered in 2 Gy fractions) to 5% of their volume, except the: a. Spinal cord b. Kidney c. Lung d. Liver e. Heart

a. Spinal cord Irradiation of a small volume of the spinal cord to 70 Gy can cause myelopathy because of the serial arrangement of the FSUs in this organ (i.e., inactivation of a single FSU can compromise the function of the entire organ), whereas the FSUs in the other organs are arranged in parallel, meaning that these organs have a large functional reserve and therefore can tolerate high doses provided the irradiated volume is small.

Which of the following statements concerning whole body effects of radiation is TRUE? a. The time to death from the hematopoietic syndrome is 1-2 months b. The time to death from the cerebrovascular syndrome is 2-4 weeks c. The time to death from the gastrointestinal syndrome is 2-4 months d. The threshold dose for the gastrointestinal syndrome is 1 Gy e. The threshold dose for the hematopoietic syndrome is 10 Gy

a. The time to death from the hematopoietic syndrome is 1-2 months The time to death from the hematopoietic syndrome is about 1-2 months. The latent period before death from the cerebrovascular syndrome is 1-2 days. The threshold doses (the minimum dose at which these syndromes may be detectable in some people in an irradiated population), for hematopoietic and gastrointestinal syndromes are approximately 1 Gy and 5 Gy, respectively. However, it should be noted that doses of approximately 2.5 Gy and 8 Gy are necessary before a substantial portion of an irradiated population would exhibit pronounced symptoms of hematopoietic and gastrointestinal syndromes, respectively. The latent period until death from GI syndrome is about 3-10 days.

The following nucleoside has been radiolabeled in an effort to image DNA synthesis with PET: a. Adenosine b. Guanosine c. Thymidine d. Uridine e. Cytidine

c. Thymidine 18-Fluorine labeled thymidine has been used to image DNA synthesis in humans in vivo.

Avastin (bevacizumab) is a monoclonal antibody that targets: a. ERBB3 b. DNA-PK c. VEGF d. Sphingomyelinase e. Caspase 3

c. VEGF

look at the flow cytometry plot on the other side and tell the phase that would be most resistant to radiation

confusing because i thought they were getting at the fact that BrdU is a radiosensitizer...and thus the cells that had incorporate the most BrdU would be most sensitive -- not what they meant at all they were going for the fact that BrdU is incorporated during S phase and that G0/1 are 2n DNA whereas G2/M with doubled DNA are 4n DNA and thus the BrdU level shifts up to location B and C and then back down after cell division to location D. PI is a DNA-intercalating dye that stains cells proportionally to the amount of DNA present in the cell. A: G0/1 cells B: early S phase cells when Brdu is getting incorporated but not yet all doubled their DNA -- which is by there are continuous dots between B and C C: late S phase with 4n DNA D: G2/M C is most radioresistant (late S phase) D is most radiosensitive (G2/M) Radioresistance in late S phase is believed to be because the cells can now do HRR w/ sister chromatid as the template.

The shape of the dose response curve for the induction of late effects is best described as: a. Gompertzian b. Linear c. Threshold d. Sigmoidal e. Linear-quadratic

d. Sigmoidal The dose response for the induction of late normal tissue damage is sigmoidal in shape. Think about the skin breast cancer RT study example showing isoeffect -- it is SIGMOIDAL

The importance of DNA repair in preventing carcinogenesis is demonstrated by all of the following clinical/experimental findings, EXCEPT: a. People suffering from hereditary non-polyposis colon cancer syndrome often exhibit mutations in DNA mismatch repair genes b. Mutations in tumor suppressor genes may play an important role in cancer progression c. Xeroderma pigmentosum patients show an elevated incidence of skin cancers d. Virtually all tumor cell lines analyzed have been found to have one or more DNA repair deficiencies e. Mutations in an oncogene may be an early step in carcinogenesis

d. Virtually all tumor cell lines analyzed have been found to have one or more DNA repair deficiencies Although a germline DNA repair deficiency may lead to greater cancer proneness, and somatic mutatons may lead to a higher mutation rate in cancers, it is not true that cells derived from all human tumors have such deficiencies.

Which of the following agents has a mechanism of action similar to that of paclitaxel (Taxol)? a. Methotrexate b. Camptothecin c. Carboplatin d. Dactinomycin e. Vincristine

e. Vincristine Both vincristine and paclitaxel affect microtubules. However, vincristine binds to tubulin dimers, inhibiting assembly of microtubule structures. Taxol affects microtubule formation through hyper-stabilization.

What is a drawback of pure hyperfractionation?

increased acute effects like mucositis and dysphagia Benefit is less late effects hyperfractionation - same time course, higher number of fractions, usually dose is ~10-15% higher Acceleration is same dose, shorter time course. even WORSE acute effects.

What does PD-1 stand for? A. Programmed cell death 1 receptor B. Presentation determinant 1 C. Pre-determinant molecule 1 D. Pattern determinant 1 E. Principal determinant 1

A

Which of the following statements concerning irradiation of the spinal cord is FALSE? a. One of the main manifestations of transient demyelination is Lhermitte's sign b. Transient demyelination is a strong predictor for later permanent myelopathy. c. Irreversible radiation myelopathy typically occurs months after the completion of treatment. d. Irreversible radiation myelopathy is characterized by demyelination and white matter necrosis e. The spinal cord demonstrates a certain degree of recovery following irradiation, if there is sufficient time between courses.

A Early myelopathy differs from transient demyelination because it is more severe and progressive, not less so.

Which of the following statements is TRUE concerning radiation effects on the bone marrow? A. The absolute lymphocyte count rate of decrease over 2 days may estimate the severity of total body irradiation induced injury. B. Following total body irradiation, thrombocytopenia is typically observed before neutropenia C. Lymphocyte counts do not decrease until several weeks after total body irradiation D. Individuals suffering from bone marrow syndrome usually die of severe anemia E. There is no late effect pathology associated with bone marrow irradiation

A Following total body irradiation, neutropenia is observed prior to thrombocytopenia. For even modest doses, a decrease in lymphocyte count can be detected within 1-2 days following total body irradiation. Serial blood counts over this period can be useful in assessing dose and guiding treatment after an accidental exposure. The Andrews lymphocyte nomogram can be used to estimate the severity of injury following total body irradiation. Individuals suffering from bone marrow syndrome usually die of infection and/or hemorrhage. Survivors of total bone marrow irradiation demonstrate a late loss of bone marrow architecture characterized by tissue replacement with lipid cells.

Reducing the dose rate at which a continuous γ-irradiation is delivered may affect its cell killing efficacy due to several different biological processes. For a total dose of 6 Gy, which pair of dose rate ranges and biological processes resulting in altered cell killing is INCORRECT? A. 10 - 1 Gy/min : reoxygenation B. 1 - 0.1 Gy/min : repair C. 0.1 - 0.01 Gy/min : redistribution D. 0.01 - 0.001 Gy/min : repopulation You must know the time that each of these events takes place within.

A Reoxygenation generally occurs over a period of hours to days. Little to no reoxygenation of hypoxic cells is therefore likely during irradiation performed at dose rates in the 1-10 Gy/min range since, for a total dose of 6 Gy, the irradiation times would only vary from 0.6-6 minutes. Repair: If the total treatment time is long enough that significant repair of sublethal damage (half-time on the order of 0.5-1.0 hour) can occur during irradiation, repair does influence cell survival. The irradiation time would vary from 6-60 minutes for dose-rates in the range of 1-0.1 Gy/min and significant repair would occur (Answer Choice B). Redistribution: Movement of the surviving cells through the cell cycle (causing redistribution of viable cells from resistant phases into sensitive phases) can influence the radiosensitivity of the cell population when irradiation times are increased to several hours (for the dose-rate range of 0.1-0.01 Gy/min, times of 1-10 hours would be needed to produce 6 Gy; Answer Choice C). Repopulation can lead to an increase in the number of cells during irradiation and, hence, to an increase in the total number of surviving cells when a radiation dose is delivered over days (10-100 hours are required to produce a total dose of 6 Gy over a range of 0.01-0.001 Gy/min; Answer Choice D). Repair - 30 - 60 minutes Redistribution - 1-2 hours Repopulation - hours - days Reoxygenation - hours - days Calculate each of the times by 6 Gy / rate = time

A standard treatment protocol for a particular type of cancer is 60 Gy delivered in once-daily 2 Gy fractions. If the fraction size is decreased to 1.3 Gy in an attempt to reduce the incidence of late effects, approximately what total dose should be delivered to maintain the same level of tumor control? (Assume an equal effect per fraction, no repopulation, and an a/b ratio for the tumor of 10 Gy.) A. 64 Gy B. 68 Gy C. 72 Gy D. 76 Gy E. 80 Gy

A Since there is the assumption of an equal effect per fraction and no repopulation, the basic BED equation can be used:, 𝐵𝐸𝐷=𝑛𝑑 ⌊1+ 𝑑(𝛼/𝛽)⌋ Thus, the standard treatment results in a BED of: 𝐵𝐸𝐷=30×2 ⌊1+ 2(10)⌋ =72 𝐺𝑦10 Therefore, in order to determine the number of fractions to be used if the fraction size is reduced to 1.3 Gy: 72 𝐺𝑦10=𝑛𝑑 ⌊1+ 1.3(10)⌋ 𝑛𝑑=64 𝐺𝑦 Thus, 49 fractions of 1.3 Gy should be used, to a total dose of 64 Gy.

2. Till and McCulloch's studies of the radiation response of murine hematological colony forming units (CFU's) represent the first: a. demonstration of the presence of rare, pluripotent stem cells in a normal tissue b. clonogenic assay of mammalian cell survival after irradiation c. attempt at bone marrow transplantation d. demonstration that pre-irradiation of a bone marrow recipient could enhance the "take rate" of donated marrow e. demonstration that bone marrow transplantation can rescue lethally-irradiated recipients

A During the early 1960s, Till and McCulloch performed a series of experiments in which bone marrow cells were injected into lethally-irradiated mice, some of which went on to form colonies/nodules of bone marrow cells in the spleens of the recipient mice 9-10 days later. Only a small fraction of injected bone marrow is able to form spleen colonies because most bone marrow cells are too differentiated upon harvest and have lost that ability to produce progeny. This was the first demonstration that normal tissues possess pluripotent stem cells. In addition, for some experiments, they irradiated the donor mice and showed that with increasing dose, greater numbers of cells were necessary to produce spleen nodules in the recipient mice. This represented the first in vivo radiation dose response curve for a normal tissue (although radiation survival assays for cells in vitro had been developed a few years earlier by Puck & Markus in 1956). In recognition of this work, they were awarded the 2005 Albert Lasker Prize for Basic Medical Research.

Which of the following medically-useful ionizing radiation types is densely ionizing? a. Gamma rays from Iodine-125 decay b. Gamma rays from Cobalt-60 decay c. Gamma rays produced in the annihilation reaction d. Protons used in radiation therapy e. Beta particles emitted by Yttrium-90

A Important thing here, it is the low energy one that has more ionizations per unit track length and thus higher LET technically speaking. For a given charged particle, the density of ionization events along a track (i.e. LET) decreases with increasing energy. The iodine-125 decay mechanism is electron capture to form the nearly-stable tellurium-125. This is followed by gamma decay at 35 keV and Auger electron emission at 50-500 eV. LET values for these low energy gamma rays and Auger electrons is greater than 30 keV/μm. Energy of gamma rays from Cobalt-60 decay and gamma rays produced in the annihilation reaction is in a 1-MeV range and LET ~ 0.2 keV/μm. Yttrium-90 is a high-energy beta-emitting isotope. The maximum energy of the beta particles is 2.27 MeV with a mean of 0.93 MeV. These electrons are sparsely ionizing. Protons used in the clinic have an energy of about 200MeV and are sparsely ionizing for the most part with a high LET component at the Bragg-peak. Source LET I-125 (avg E 29 KeV) ~30 KeV/um 200 keV X rays 2.5 KeV/um Co-60 (avg E ~1.25 MeV) 0.2 KeV/um So, higher the energy, the lower the LET for the same particle type.

Which suggests a classic synthetic lethal interaction between two genes, genes X and Y? a. X null mutation and Y null mutation=cell death b. X null mutation and Y null mutation=cell survival c. X wild-type and Y wild-type=cell death d. X wild-type and Y null mutation=cell death e. X null mutation and Y wild-type=cell death

A The concept of synthetic lethality has gained significant attention in adult oncology in recent years. Two genes or pathways are considered to be synthetically lethal if inactivation of either does not kill cells, while simultaneous inactivation of both is lethal. Thus, if a tumor harbors a mutation in one gene of a "synthetic lethal pair", targeting the corresponding gene in the pair will selectively kill cancer cells while sparing normal cells without the cancerous mutation. This concept has also been extended to include oncogenic mutations and unique translocations. One of the most well-known examples of synthetic lethality is the interaction between the two double-strand break (DSB) repair genes, BRCA1 and BRCA2, and poly (ADP-ribose) polymerase-1 (PARP-1). BRCA1 and BRCA2 play key roles in homologous recombination repair, while PARP-1 is involved in base excision and single-strand break (SSB) repair. Inhibition of PARP activity is thought to increase the number of SSBs in cells, which are then converted to DSBs during replication. As replication- associated DSBs appear to require the homologous recombination repair pathway for repair almost exclusively, PARP inhibition induces significant cell death in tumors with loss-of-function mutations in BRCA1 or BRCA2. Importantly, normal cells are not affected by PARP inhibition because BRCA1 or BRCA2 function is intact. This discovery was ultimately translated to the clinic, where PARP inhibitors were shown to have single agent activity in metastatic patients with BRCA-deficient tumors.

Which of the following is TRUE regarding the use of the hypoxic radiosensitizer nimorazole in treating head and neck cancers with radiotherapy? A. The DAHANCA 5-85 trial showed improved locoregional control but not overall survival when nimorazole. B. Low plasma concentrations of osteopontin were associated with worse outcomes compared to higher concentrations in the DAHANCA 5 trial but was also associated with a higher benefit from the addition of nimorazole. C. The addition of nimorazole improves locoregional control in p16-positive tumors but not p16-negative tumors. D. The addition of nimorazole to radiation is associated with increased acute mucositis and late fibrosis compared to placebo.

A The DAHANCA 5-85 Trial examined the addition of nimorazole to conventionally fractionated radiotherapy for pharyngeal and supraglottic larynx cancers. The trial demonstrated that nimorazole improved_locoregional control and disease-specific survival compared to placebo but did not significantly improve overall survival. Nimorazole was reasonably well-tolerated in the DAHANCA 5-85 Tria, although only 60% of patients completed the treatment, and it was associated with a higher rate of nausea/vomiting, flushing, dizziness, and skin rash; patients also had trouble swallowing the large capsules of the drug. There was no increase in mucositis or late complications with the addition of nimorazole (Answer Choice D). Additional subset analyses of the trial showed that high osteopontin concentration was associated with worse disease-specific mortality, but also improved response to nimorazole in terms of locoregional control and disease-specific mortality (Answer Choice B). The benefit of nimorazole also appears to be isolated to p16-negative tumors, whereas p16-positive

Which of the following statements concerning hypoxia is TRUE? a. Hypoxic cell radiosensitizers produce a greater increase in the therapeutic index when used with conventional fractionated radiotherapy than for treatment with one or a few large radiation doses b. A biphasic survival curve would result from low LET irradiation of a mixed population of both aerated and hypoxic cells c. The OER is defined as the dose to produce a given effect in aerated cells divided by the dose to produce the same effect in hypoxic cells d. The diffusion distance of oxygen in air is typically less than 100 μm e. For low LET radiation, the maximum OER is typically observed only when the tissue oxygen concentration reaches about 20%

A biphasic survival curve, in which the survival curve initially displays a steep slope followed by a shallower response, would be predicted for irradiation of a mixed population of aerated and hypoxic cells. This type of dose response would be anticipated since the initial portion of the survival curve reflects the killing of radiosensitive aerated cells; whereas the survival curve obtained at higher doses primarily reflects the killing of radioresistant hypoxic cells. A fractionated protocol would be expected to decrease the effect of a hypoxic cell radiosensitizer to enhance tumor control, compared with an acute treatment, since reoxygenation would cause aeration of many of the hypoxic cells between fractions thereby diminishing the apparent effectiveness of the radiosensitizer. The OER is the dose to produce an effect in hypoxic cells divided by the dose to produce the same effect in aerated cells. The diffusion distance in air for oxygen is much greater than 100 μm. Maximum OER is typically observed only when the oxygen concentration reaches about 3-5%.

Which of the following statements concerning the oxygen effect is TRUE? A. OER values obtained for high energy protons used in radiotherapy are similar to those measured for X-rays B. During irradiation, an oxygen partial pressure of about 30 mm Hg is required to produce full radiosensitization. C. The OER is defined as the ratio of the surviving fraction of cells irradiated with a particular X-ray dose under hypoxic conditions divided by the surviving fraction of cells irradiated with the same dose under aerated conditions D. Tumors are thought to contain regions of both acute and chronic hypoxia; however, only chronically hypoxic cells can reoxygenate E. The oxygen effect is principally a manifestation of the reaction of O2 with organic radicals (R•) to form ROO

A) OER values obtained for high energy protons used in radiotherapy are similar to those measured for X-rays Since the high energy protons used in radiotherapy have an LET similar to that of X-rays, their OER values are also similar. An oxygen partial pressure greater than about 2-3% during irradiation will result in essentially full radiosensitization (Answer Choice B). The OER is defined as the ratio of the radiation dose needed to cause a certain biological effect in hypoxic cells divided by the dose needed to produce the same effect in aerated cells (Answer Choice C). Both acutely and chronically hypoxia cells can reoxygenate (Answer Choice D). The increased cell killing resulting from irradiation in the presence of oxygen is thought to be the result of increased radical damage and damage fixation by oxygen. The initial number of ionizations produced by radiation in the aerated and hypoxic cells would be the same (Answer Choice E).

The most dramatic change in radiation sensitivity occurs over which of the following ranges of oxygen tension (in units of mm Hg or Torr)? A. 0-20 B. 20-60 C. 60-100 D. 100-250 E. 250-760

A. 0-20 The most dramatic change in radiation sensitivity occurs over an oxygen tension range of 0-30 mm Hg (Torr). Cells irradiated under an oxygen partial pressure at the low end of this range are maximally radioresistant, whereas irradiation at 30 mm Hg oxygen results in near maximum radiosensitization.

The phenomenon of "oncogene addiction" most correctly refers to which of the following clinical scenarios. A. A Chronic Myeloid Luekemia (CML) patient treated with imatinib B. An EGFR-mutant lung adenocarcinoma patient treated with bevacizumab C. A BRAF-mutant melanoma patient treated with ipilimumab D. An EML4-ALK positive lung adenocarcinoma patient treated with olaparib E. A Chronic Myeloid Luekemia (CML) patient treated with interferon.

A. A Chronic Myeloid Luekemia (CML) patient treated with imatinib Oncogene addiction" was first coined by Bernard Weinstein and refers to the dependence of some tumors on a single dominant oncogene for continued growth and survival and that inhibition of this specific oncogene product is sufficient to halt the neoplastic phenotype. Answer Choice A is correct because imatinib is correctly paired with its target, BCR-ABL. The other answers are examples of oncogene-addicted cancers that are incorrectly paired with agents that do not target the dominant oncogene product.

Which of the following statements is FALSE regarding the symptoms that make up the prodrome after total body irradiation: A. After receiving 2 Gy, almost 80% of those affected experience nausea and vomiting within 1 hour B. Serotonin-receptor antagonists are recommended in the management of nausea and vomiting after total body irradiation C. Time to onset of prodromal symptoms is inversely related to radiation dose D. Diarrhea is a prodromal symptom E. The severity of prodromal symptoms is directly related to radiation dose

A. After receiving 2 Gy, almost 80% of those affected experience nausea and vomiting within 1 hour- NOT TRUE After exposure to 2 Gy, 50% or less will experience nausea and vomiting. Typically, this occurs within 2-6 hours of exposure.

What is the definition of a radiation mitigator? a. Agents delivered at the time of irradiation or after irradiation is complete with the intent preventing the manifestation of normal tissue toxicity b. Agents delivered prior to irradiation with the intent of preventing or reducing damage to normal tissues c. Agents delivered to ameliorate established normal tissue toxicity d. Agents delivered at the time of irradiation with the intent preventing the manifestation of normal tissue toxicity e. Agents delivered to increase the therapeutic ratio of clinical radiotherapy

A. Agents delivered at the time of irradiation or after irradiation is complete with the intent preventing the manifestation of normal tissue toxicity Radiation-induced late normal tissue toxicity is increasingly being appreciated as a phenomenon of ongoing changes in tissue after radiation but prior to the manifestation of toxicity. These events include ongoing mitotic cell death and perpetually active cytokine cascades that can lead to vascular damage, tissue hypoxia, and excessive extracellular matrix deposition. Radiation mitigators aim to interrupt these cascades or intervene to prevent the perpetuation of damage and thus reduce the expression of toxicity. Alternatively, radiation mitigators can be agents delivered during or shortly after exposure to repopulate a critical cell compartment such as the mucosa or bone marrow. In this instance, the mitigator is used to prevent acute toxicity. For radiologic terrorism and space research, much of the focus of mitigators has been in the field of developing chemopreventatives to reduce carcinogenesis of total body exposures (20413641). Most correct answer is "a". Answer "b" is a radioprotector; "c" is treatment; "d" could be either a protector or mitigator; and "e" could be a radiosensitizer or radioprotector.

Which of the following pairs of chemicals could be used with flow cytometry to determine the S phase fraction of a cell population and estimate of relative DNA content? A. Bromodeoxyuridine (BrdU) and propidium iodide B. Tritiated thymidine and hydroxyurea C. Dichlorohydrofluorescein and cytochrome c D. H2AX and ethidium bromide E. Sphingomyelin and ceramide

A. Bromodeoxyuridine (BrdU) and propidium iodide Bromodeoxyuridine (BrdU) is incorporated into DNA in place of thymidine, so it can be used to label cells in S-phase. The incorporated bromodeoxyuridine is assayed using a fluorescently-labeled anti-BrdUrd antibody. Propidium iodide fluoresces when incorporated into DNA. The amount of fluorescence is directly proportional to the DNA content, which, in turn, is a reflection of the cell cycle phase in which the cell is located.

Which of the following statements concerning chronically hypoxic cells in tumors is TRUE? Chronically hypoxic cells: A. Can be selectively targeted for killing with certain bioreductive drugs B. Are resistant to hyperthermia C. Are located within 10 m of capillaries D. Exist in a high pH microenvironment E. Are a consequence of intermittent blood flow

A. Can be selectively targeted for killing with certain bioreductive drugs Chronically hypoxic regions in a tumor can be targeted for elimination by administering certain bioreductive drugs that preferentially kill hypoxic, but not aerobic, cells. Chronically hypoxic cells tend to be sensitive to hyperthermia. This is because they exist in an acidic (low pH) microenvironment (Answer Choices B and D). Acutely hypoxic cells are a consequence of intermittent blood flow in tumors (Answer Choice E). It has been shown via model calculations of oxygen consumption rates in respiring tissues and through the use of hypoxia markers that chronically hypoxic cells rarely appear closer than about 70 m from capillaries (Answer Choice C).

Which of the following has a half-life of 30 years? A. Cesium-137 B. Iridium-192 C. Iodine-125 D. Iodine-131 E. Gold-198

A. Cesium-137 Cesium-137 has a half-life of 30 years. Iridium-192 has a half-life of 74.2 days. Iodine-125 has a half-life of 60.2 days. Iodine-131 has a half-life of 8.0 days. Gold-198 has a half-life of 2.7 days.

Oncogenes were first discovered from the study of: A. Chicken Retroviruses B. Bacteria C. Yeast D. Mice E. Human cells in culture

A. Chicken Retroviruses Retroviruses, viruses with genomes composed of RNA instead of DNA, can cause cancers in animals (example: Rous sarcoma virus [RSV] in chickens). Usually, this occurs because the retroviruses contain modified (often mutated) proto-oncogenes captured from the genomes of their vertebrate hosts.

Which of the following statements concerning possible long-term consequences of radiotherapy is FALSE? A. Compared to the general population, individuals who survive an initial cancer are at a decreased risk for developing a second cancer B. There is an increased incidence of second tumors among patients initially treated for soft tissue sarcomas C. Radiotherapy to the breast or chest wall of young women is associated with long-term cardiotoxicity and an increased risk of second breast cancers D. Breast cancer patients with a BRCA2 defect are at increased risk of developing ovarian cancers as well as second breast cancers in either the treated or untreated breast E. Children who receive cranial irradiation as part of their treatment for leukemia have a significantly increased risk for developing meningiomas

A. Compared to the general population, individuals who survive an initial cancer are at a decreased risk for developing a second cancer Cancer survivors constitute 3.5% of the US population, but second primary malignancies among this high-risk group now account for 16% of all cancers diagnosed. A high frequency of second primary tumors among patients diagnosed with soft tissue sarcoma patients has been reported, with a particularly high risk of developing a new soft tissue sarcoma (Answer Choice B). Radiotherapy to the breast or chest wall of young women is associated with long-term cardiotoxicity and an increased risk of second breast cancers (Answer Choice C). Genetic factors, as well as the potential carcinogenic effects of treatment, can affect the probability of second cancers in survivors. Patients with the BRCA2 mutation demonstrate an increased risk of subsequent ovarian cancer, as well as cancers in the irradiated and unirradiated breast. Patients with Li-Fraumeni syndrome and other familial cancer syndromes would likewise be at increased risk of developing second malignancies unrelated to the carcinogenic effects of their initial treatments (Answer Choice D). Children who receive cranial irradiation as part of their treatment for leukemia are at a significant increased risk for developing meningiomas.

Which of the following pairs of a targeted agents and its potential target is CORRECT? A. Crizotinib - anaplastic lymphoma kinase (ALK) B. Imantinib - programmed cell death 1 (PD-1) C. Cetuximab - ABL kinase D. Sunitinib - Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) E. Sorafenib - CD20

A. Crizotinib - anaplastic lymphoma kinase (ALK) Crizotinib is a small molecular inhibitor of ALK and ROS1 kinases; it is FDA approved from non-small cell lung carcinomas bearing the EML4-ALK fusion gene. Imantinib is a small molecular inhibitor of receptor tyrosine kinases. It is most selective for BCR-ABL, but also targets c-kit and PDGF-R (Answer Choice B). Cetuximab is a monoclonal antibody against EGFR (Answer Choice C). Sunitinib and sorafenib are "dirty" multi-targeted receptor tyrosine kinase inhibitors (Answer Choices D and E). Inhibitors of programmed cell death 1 (PD-1) receptor include pembrolizumab and nivolumab. Inhibitors of programmed death ligand 1 (PD-L1) include atezolizumab, durvalamab, and avelumab. Ipilimumab is an example of a Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) inhibitor. Ipilimumab functions by disinhibiting the native ability of T cells to recognize and destroy cancer cells. Rituximab is an example of a CD20 inhibitor

Which of the following statements concerning gel electrophoresis is TRUE? A. DNA molecules are negatively charged so they will migrate toward the positive electrode of the electrophoresis apparatus B. SDS is a detergent used for the separation of DNA molecules of different size C. The higher the concentration of agarose in a gel, the faster DNA molecules will migrate D. Polyacrylamide gels are used to separate large DNA molecules whereas agarose gels are used for smaller-sized DNAs E. The higher the molecular weight of the molecule, the faster it will migrate through a gel

A. DNA molecules are negatively charged so they will migrate toward the positive electrode of the electrophoresis apparatus In gel electrophoresis, DNA molecules are negatively charged and therefore migrate towards the positive electrode. Sodium dodecyl sulfate (SDS), a detergent, is used to denature proteins, not DNA, so that the proteins can be separated by size on a gel. The higher the concentration of agarose in the gel, the slower DNA molecules will migrate. Polyacrylamide gels are generally used to separate small DNA molecules whereas agarose gels are used for large sized DNA. The lower the molecular weight of the molecule, the more rapidly it will migrate through a gel.

Which of the following statements is FALSE? A. DNA repair by homologous recombination occurs preferentially in the G1 phase of the cell cycle B. Non-homologous end joining is an error-prone repair pathway that involves DNA-PKcs (PRKDC)-associated repair of DNA double-strand breaks C. The DNA repair proteins MRE11, NBS1 (NBN) and RAD50, localize at nuclear foci corresponding to presumed sites of DNA damage following exposure to DNA-damaging agents D. A defect in nucleotide excision repair is the basis for the hereditary disorder xeroderma pigmentosum and can lead to increased rates of skin cancer E. Following the production of DNA double-strand breaks, ATM is converted from an inactive dimer to an active monomer form

A. DNA repair by homologous recombination occurs preferentially in the G1 phase of the cell cycle Homologous recombination requires a second copy of the relevant DNA duplex. Although homologous recombination can take place in G1 phase, using the homologous chromosome as the template for repair, it occurs much more frequently after replication when the template strand is the sister chromatid located in close proximity to the damaged strand. The sister chromatid is created during S-phase and serves as a template from which to copy the intact DNA sequence to the site of the damaged strand of DNA. It has been estimated that homologous recombination occurs 1000-fold more frequently in S and G2 than in G1. In G1, the principal form of DNA double-strand break repair is non-homologous recombination

Which of the following is associated with cardiac toxicity? A. Doxorubicin B. Cisplatin C. Bleomycin D. Methotrexate E. Docetaxol

A. Doxorubicin Doxorubicin (Adriamycin) is associated with dose-related cardiomyopathy. Cumulative lifetime doses greater than 450 mg/m2 are associated with increased risk of heart failure similar to dilated cardiomyopathy. The mechanism behind cardiac toxicity is unclear, but appears to be associated with oxidative stress and is quite distinct from its antineoplastic actions. Cisplatin has been linked to ototoxicity and renal toxicity (Answer Choice B). Bleomycin is associated with an increased risk of pulmonary toxicity (Answer Choice C). Methotrexate is associated with mucositis and gastrointestinal toxicity (Answer Choice D). Docetaxel and other microtubule poisons are associated with peripheral neuropathy (Answer Choice E).

Which of the following statements is CORRECT? Following acute irradiation of the skin: A. Epilation and the loss of sebaceous gland secretions follow similar time courses B. The first visible reaction is moist desquamation, typically observed within 24 hours of irradiation C. Epilation is only observed at doses much greater than those that cause the main wave of erythema observed at about one week D. Pigment changes are typically seen within days due to the high proliferation rate of melanoblasts E. It is usually possible to predict the extent of late reactions based on the severity of early reactions

A. Epilation and the loss of sebaceous gland secretions follow similar time courses Following irradiation of the skin, the dose and time course for epilation and loss of sebaceous gland secretion are similar. Following skin irradiation, the first visible evidence of damage is a transient erythema that is observed within 24 hours following irradiation, whereas moist desquamation would only be observed after a few weeks. Epilation is observed at doses similar to those that cause the main wave of erythema that is typically manifested about one week following irradiation. Pigment changes typically appear long after irradiation due to the low proliferation rate of melanoblasts. It is usually not possible to predict the extent of late reactions based upon the severity of early reactions because early reactions result from killing of epidermal stem cells, whereas late reactions likely occur due to vascular damage in the dermis.

Which of the following pairs of a chemotherapeutic agent and its potential target is CORRECT? A. Etoposide - topoisomerase II B. Topotecan - microtubules C. Bevacizumab - EGFR D. Sunitinib - histone deacetylase E. 5-fluorouracil - glutathione

A. Etoposide - topoisomerase II Etoposide targets topoisomerase II. Topoisomerases are enzymes that participate in the overwinding or underwinding of DNA. Topoisomerase I catalyzes the transient breaking and rejoining of a single strand of DNA which lets the broken strand rotate around the intact strand, whereas Topoisomerase II cuts both strands of the DNA helix simultaneously in order to manage DNA tangles and supercoils. Topoisomerase I inhibitors include irinotecan and topotecan; Topoisomerase II inhibitors include etoposide (VP-16), doxorubicin, daunorubicin, and mitoxantrone. Topotecan targets topoisomerase I (Answer Choice B). Bevacizumab targets the VEGF ligand (Answer Choice C). Sunitinib is a tyrosine kinase inhibitor with multiple targets including EGFR, FLT3, VEGFR and KIT (Answer Choice D). 5-fluorouracil targets thymidylate synthase (Answer Choice E).

Which of the following statements regarding radiation-related inflammatory effects is FALSE? A. Following radiation injury, the extent of neutrophil infiltration into the irradiated volume is positively correlated with the severity of the late complication B. A distinct inflammatory phase is a major component of many acute tissue reactions C. In both experimental animals and humans, late infiltrations of activated macrophages have been noted in irradiated tissues such as lung and oral mucosa D. Total body irradiation to doses of 1 Gy or more can lead to abnormalities in T cell immunity

A. Following radiation injury, the extent of neutrophil infiltration into the irradiated volume is positively correlated with the severity of the late complication Although transient neutrophil infiltration is a recognized early step in the normal wound healing process, it appears to play little or no part in the development of radiation-induced late effects. Radiation has both direct and indirect effects on various components of the inflammatory system (Answer Choice B). Indirectly, radiation exposure can be considered pro-inflammatory, with an "-itis" being a commonly observed early radiation response in many tissues and organs, e.g. lung (pneumonitis), skin (radiodermatitis) and the alimentary tract (mucositis). In many of these tissues, the inflammation is mediated by activated macrophages that recognize the chronic dysregulation characteristic of irradiated tissues during the development of late effects (Answer Choice C). However, radiation's direct effects on inflammatory cells are more anti-inflammatory in nature. For example, it has been recognized both in the Japanese A-bomb survivors and in the Chernobyl cleanup workers that total body irradiation (TBI) doses of 1 Gy and above can lead to abnormal T cell immunity, possibly due to altered T cell differentiation and increased cell killing (Answer Choice D).

Blood perfusion through normal and tumor tissues can be modified by heating. Which of the following statements is FALSE? A. For both tumors and normal tissues, all functional capillaries are open and used to capacity. B. Normal tissues have a relatively high ambient blood flow, which increases in response to thermal stress. C. Tumor tissues have unresponsive neo-vasculature to heat and are incapable of augmenting blood flow. D. Hyperthermia can induce compression and occulusion of tumor blood vessels. E. Tumors get hotter than surrounding normal tissues because of ineffective dissipation of heat.

A. For both tumors and normal tissues, all functional capillaries are open and used to capacity. As a result of poor oxygen delivery by tumor neo-vasculature, tumor capillaries with functioning vasomotor control generally are open and used to capacity. In normal tissues, however, vasomotor activity is related to demand. When demands for oxygen delivery and homeothermy are normal many capillaries are closed.

Data has suggested that overall treatment time is crucial for which of the following tumors: A. Head and neck cancer B. Endometrial cancer C. Melanoma D. Breast cancer E. Basal cell carcinoma

A. Head and neck cancer Data has shown that local tumor control is decreased by about 1.4% for each day that treatment is prolonged for head and neck cancer and 0.5% for uterine cervix cancer. There is no data suggesting a similar effect in melanoma, breast, or basal cell cancer.

Which of the following is the main reason why the volume doubling time of a tumor rarely equals its potential doubling time? A. High cell loss factor B. High metastatic propensity C. Long cell cycle time D. Low hypoxic fraction E. Low growth fraction

A. High cell loss factor A tumor's volume doubling time rarely equals its potential doubling time because most tumors have a high cell loss factor. Formation of metastases represents only one of many reasons for cell loss, and usually is only a minor contributor (Answer Choice B). Human tumor cells typically have cell cycle times of a few days whereas tumor volume doubling times are generally on the order of months (Answer Choice C). The presence of a high hypoxic fraction would probably contribute to a low growth fraction, which would affect both Tpot and volume doubling time. If hypoxia were a significant cause of cell death, it would affect the cell loss factor and therefore affect the volume doubling time. The presence of non-proliferating cells affects both the tumor volume doubling time and the potential doubling time, and does not cause a difference between them. In addition, non-viable cells (whether hypoxic or aerobic) have similar effects on the tumor volume doubling time and the potential doubling time (Answer Choice E).

A new agent that can alter blood flow is being assessed for its potential clinical usefulness in combination with radiation therapy. Which of the following effects on blood flow would be expected to result in therapeutic gain and thus lead to a potentially useful agent in the clinic? A. Increased in both tumors and normal tissues B. Increased in normal tissues but decreased in tumors C. Decreased in normal tissues and in tumors D. Not altered in normal tissue but decreased in tumors E. Increased in normal tissues and not altered in tumors

A. Increased in both tumors and normal tissues In order for there to be a therapeutic gain, the differential between the radiation response of tumor and normal tissue must be increased. Since blood flow is usually not compromised in normal tissues, the radiobiological oxygen effect would not be enhanced by increasing blood flow. However, since many tumors contain hypoxic cells, increasing blood flow to the tumor could result in radiosensitization. In contrast, decreasing blood flow to tumors would not be expected to be advantageous, since it could cause increased hypoxia and thus radiation resistance.

Wee1 inhibitors have been tested as radiosensitizers because they: A. Interfere with the G2/M checkpoint B. Block phosphorylation of MAPK-related proteins C. Suppress NHEJ repair D. Are selectively toxic in hypoxic tumor cells

A. Interfere with the G2/M checkpoint Ionizing radiation induces a G2/M checkpoint arrest, thereby allowing sufficient time for the repair of double strand breaks (DSBs) before the initiation of mitosis, since cell division in the presence of an unrepaired DSB could lead to mitotic catastrophe. Blockade of this checkpoint via inhibition of Wee1, which typically enforces it, would lead to significant radiosensitization. The Wee1 inhibitor, MK1775, has been tested in diffuse intrinsic pontine glioma (DIPG) and glioblastoma as a radiosensitizer

Which of the following about alectinib is FALSE? A. It is an anaplastic lymphoma kinase (ALK) inhibitor and is FDA approved for the treatment of anaplastic lymphoma and ALK-fusion gene positive non-small cell lung cancer (NSCLC). B. Alectinib improves disease-free survival in first-line treatment of ALK fusion-positive NSCLC compared to the 1st-generation ALK-inhibitor crizotinib. C. Alectinib has lower rates of Grade 3+ toxicity compared to crizotinib. D. Alectinib has improved efficacy for brain metastases compared to crizotinib.

A. It is an anaplastic lymphoma kinase (ALK) inhibitor and is FDA approved for the treatment of anaplastic lymphoma and ALK-fusion gene positive non-small cell lung cancer (NSCLC). Alectinib received full FDA approval in 2017 for the treatment of ALK-fusion positive NSCLC [not anaplastic lymphoma] after the J-ALEX and ALEX trials showed improved PFS compared to crizotinib (Answer Choice B). In both trials, alectinib had a lower rate of Grade 3+ adverse effects compared to crizotinib (Answer Choice C). The most common side effects with either drug are GI upset, transaminitis, and anemia. In the ALEX trial, 122 patients had brain metastases at baseline, of whom 46 had received prior radiation therapy. Time to CNS progression was longer with alectinib compared to crizotinib in both patients with brain metastases at baseline as well as those without brain metastases at baseline (Answer Choice D).

Concerning the p21 (CDKN1A) protein, which of the following statements is TRUE? A. Its transcription is transactivated by p53 (TP53) in response to ionizing radiation exposure. B. It is required for entry into S phase of the cell cycle. C. It is up-regulated only in cells exposed to radiation doses greater than 1 Gy. D. Overexpression of p21 causes arrest in the G2 phase of the cell cycle. E. It binds to Bcl-xL (BCL2L1) to promote apoptosis.

A. Its transcription is transactivated by p53 (TP53) in response to ionizing radiation exposure. p21 is one of the most strongly p53-transactivated genes, and codes for the p21 protein. It responds robustly at both the mRNA and protein levels to ionizing and UV radiation as well as to most other stress-inducing agents. p21 is a CDK inhibitor (CDK2-cyclin E at G1 checkpoint; p16 inhibits CDK4/6-cyclin D in early G1) and also binds to PCNA to prevent entry of cells into S phase. The predominant role of p21 appears to be in mediating G1 phase arrest, although it also plays roles in differentiation, senescence, and regulation of apoptosis.

Tumor cells may escape the host's immune response by a plethora of innate and adaptive mechanisms. Which of the following would NOT be considered such a mechanism? A. Loss of b2-microtubulin expression leading to decreased MHC class I expression B. Tumor cell intrinsic alterations in signaling pathways such as WNT/b-catenin, loss of PTEN, and IFNγ that inhibit T cell priming and infiltration C. Recruitment of myeloid suppressor cells D. Loss of antigen expression through immune selection E. Increased expression of immune inhibitory factors such as Indoleamine 2,3-Dioxygenase (IDO) and PD Ligand 1 (PD-L1)

A. Loss of b2-microtubulin expression leading to decreased MHC class I expression Beta-2-microglobulin (β2-microglobulin, B2M; not β2-microtubulin) is a crucial component of major histocompatibility complex (MHC) class I molecules. MHC class I molecules are heterodimers made of two, non-covalently linked polypeptide chains, α and B2M. The conformation of the MHC class I protein is highly dependent on the presence of B2M. B2M is essential for proper MHC class I folding and transport to the cell surface. Its deficiency has long been recognized as a genetic mechanism of acquired resistance to immunotherapy.

For a standard course of radiotherapy, which of the following properties of a tumor would NOT be expected to adversely affect tumor control? A. Low SF2 B. Short Tpot C. Slow reoxygenation D. Large number of tumor clonogens E. Early onset of repopulation

A. Low SF2 A low value for SF2 indicates that the surviving fraction of tumor cells following irradiation with 2 Gy is low. This should be advantageous for radiotherapy, as it suggests that the tumor cells are relatively radiosensitive. That being said, a consistent, positive correlation between low SF2 and high tumor control probability has yet to be established. The potential doubling time (Tpot) is the time required for a tumor to double in size, taking into account the number of cells in the cell cycle and the speed of progression through the cell cycle. A short Tpot would be deleterious to tumor control because it suggests a high potential for vigorous repopulation during the course of treatment (Answer Choice B). Slow reoxygenation may also limit the effectiveness of treatment as hypoxic cells would remain hypoxic and radioresistant for a longer portion of the overall treatment time than if they had reoxygenated rapidly and efficiently (Answer Choice C). A large number of clonogenic cells would require a higher total dose for eradication; this might increase the probability of adverse normal tissue effects (Answer Choice D). Early onset of repopulation would also be deleterious as the tumor cells would be proliferating for a longer time during the course of radiotherapy and the cell population that must be killed to cure the tumor would therefore be larger (Answer Choice E).

Which of the following statements is CORRECT? Base excision repair (BER): A. May increase mutation rate when defective, but usually does not dramatically alter cellular radiosensitivity B. Is the principal pathway responsible for the repair of UV-induced DNA damage C. Involves the XP and CS genes D. Acts primarily on bulky DNA lesions induced by polycyclic aromatic hydrocarbons E. Is defective in patients with Li-Fraumeni Syndrome

A. May increase mutation rate when defective, but usually does not dramatically alter cellular radiosensitivity Defects in base excision repair (BER) may increase mutation rate but generally do not alter cell survival after ionizing radiation with the exception of mutation of the XRCC1 gene, which would confer a slight increase in radiation sensitivity. Defects in nucleotide excision repair (NER) increase sensitivity to UV radiation but not to ionizing radiation (Answer Choice B). The xeroderma pigmentosum (XP) and Cockayne Syndrome (CS) genes are involved in NER (Answer Choice C). BER acts to remove damaged bases from DNA, including those damaged by ionizing radiation, but NER acts on pyrimidine dimers, single-strand breaks, and bulky adducts (Answer Choice D).

Which of the following is TRUE regarding radiation exposure to the United States population? A. Medical exposure is the leading contributor to the average annual effective dose. B. Exposure related to nuclear reactors has resulted in the doubling of the average annual effective dose over the past 40 years. C. Natural background radiation contributes very minimally to the average annual effective dose. D. The average annual effective dose secondary to medical procedures is much lower in the United States compared to that seen in other developed countries. E. Of the available diagnostic radiographic procedures in the United States, computed tomography (CT) scans contribute the least to the average annual effective dose.

A. Medical exposure is the leading contributor to the average annual effective dose. Medical exposure contributes more than 50% of the average annual effective radiation dose, slightly higher than that contributed by environmental exposures, and has significantly increased since the 1980s. The average annual effective dose related to population and occupational exposure from nuclear reactors remains minimal, at 0.0005 mSv to 0.005 mSv (Answer Choice B). Following medical exposures, natural background radiation is the next largest contributor to the average annual effective dose, contributing approximately 37% of all radiation exposure (Answer Choice C). The US population has a higher average annual effective dose from medical procedures compared to that of other developed countries. CT scans represent the greatest contributer followed by nuclear medicine procedures.

Which of the following represents a potential/actual therapeutic target in the oncogene-addicted tumor? A. Mutated KIT and/or PDGFR in gastrointestinal stromal tumors (GIST). B. Translocated ABL1 (previous symbol ABL) in T-cell acute lymphoblastic leukemia. C. Amplified MYC in non-small cell lung carcinoma. D. Translocated ALK in small cell lung carcinoma. E. Mutated Notch1 in chronic myeloid leukemia.

A. Mutated KIT and/or PDGFR in gastrointestinal stromal tumors (GIST). The oncogene addiction model postulates that some tumors rely on the continued activity of single dominant oncogene for growth and survival. Thus, according to the oncogene addition model, inactivation of this key single oncogene will halt malignant proliferation by inducing cell-cycle arrest, differentiation, senescence, or other forms of cell death, depending on tissue context. Each of the listed oncogene products in this question is an addictive oncoproteins in human cancer, however Choices B-E are incorrectly paired to the listed cancer. The receptor kinases KIT and/or PDGFR display activating mutations in more than 90% of gastrointestinal stromal tumors (GIST) (choice A). This observation supported the use of the multi-target small-molecule tyrosine kinase inhibitor imatinib mesylate (Gleevac) in GISTs. The correct matches in other choices are: - translocated ABL1 in chronic myeloid leukemia (Answer Choice B) - amplified MYC in small-cell lung carcinoma (Answer Choice C); - translocated ALK in non-small cell lung carcinoma (Answer Choice D); - mutated Notch1 in T-cell acute lymphoblastic leukemia (Answer Choice E).

Which of the following statements is CORRECT? Normal tissue regeneration/repopulation: A. Occurs in acutely responding normal tissues during the course of a standard course of radiotherapy B. Interferes with reoxygenation C. Is the reason that prolonging overall treatment time spares late responding normal tissues D. Occurs at the same rate after irradiation in acutely and late responding tissues E. Is the reason why accelerated fractionation protocols increase reactions in late responding normal tissues

A. Occurs in acutely responding normal tissues during the course of a standard course of radiotherapy Regeneration/repopulation can occur in early responding tissues such as skin during the course of a standard course of radiotherapy, decreasing the tolerance of these tissues to radiation. The apparent slower kinetics of late responding tissues suggests that no repopulation occurs in these tissues compared to acutely responding tissues. If such were to take place, then this would reduce, not increase, late effects, irrespective of the fractionation schedule. \ Repopulation/regeneration plays no role in reoxygenation.

Which of the following statements concerning the cell cycle kinetics of tumors is TRUE? A. Often, the cell loss factor (Φ) decreases several weeks after the start of radiotherapy B. The growth fraction (GF) is the ratio of the number of viable cells to the sum of viable and non-viable cells C. If the volume doubling time (TD) is 60 days and the potential doubling time (Tpot) is 3 days, then the cell loss factor is 5% D. Tpot has proven useful in predicting tumor response to accelerated radiotherapy E. Typically, the cell loss factor is not of major importance in determining a tumor's volume doubling time

A. Often, the cell loss factor (Φ) decreases several weeks after the start of radiotherapy The cell loss factor (Φ) often appears to decrease several weeks after the start of radiotherapy, which has the net effect of slowing tumor regression - think of the Withers hockey stock plot where repopulation increases after ~3-4 weeks The growth fraction is the ratio of the number of proliferating cells to the sum of proliferating and quiescent cells (Answer Choice B). If the the observed tumor volume doubling time (TD) is 60 days and the potential doubling time (Tpot) calculated from the cell cycle time and the growth fraction is 3 days then the cell loss factor is 95% (Answer Choice C). Although Tpot (as measured from a tumor biopsy derived from patients previously given bromodeoxyurdine) has not proven to be a robust predictor of long-term outcome after accelerated radiotherapy, it might still be useful for the pre-selection of patients most likely to benefit from accelerated treatment (Answer Choice D). For carcinomas, the cell loss factor is usually the major determinant of the discrepancy between a tumor's potential doubling time and its overall volume doubling time (Answer Choice E).

Which of the following statements is TRUE concerning the effects of radiation on the gonads? A. Older women are more sensitive to radiation-induced sterility than younger women B. An acute dose of 3 Gy can both destroy the gametogenic epithelium and eliminate the production of sex hormones in adult men C. Spermatids and spermatozoa are quite radiosensitive whereas spermatogonia are relatively radioresistant D. A minimum waiting period of 5 years is recommended for both men and women before attempting procreation following radiotherapy, in order to reduce the risk of radiation-induced genetic effects E. If sterility in the male is not produced within the first month after the start of radiotherapy, it is unlikely to ever occur

A. Older women are more sensitive to radiation-induced sterility than younger women Older women are more sensitive to the induction of radiation-induced sterility than younger women, presumably due to the diminished number of oocytes compared with that seen in younger women. A dose of 3 Gy can destroy the gametogenic epithelium, but would not eliminate the production of sex hormones in adult men. Spermatids and spermatozoa are more radioresistant than spermatogonia. Based on animal data, a minimum waiting period of 3-6 months is recommended for both men and women before attempting procreation following radiotherapy in order to reduce the risk of radiation-induced genetic effects. A modest radiation dose is unlikely to kill many of the more mature members of the spermatogenic series, although it could be lethal to most of the spermatogonial stem cells. Thus, even if there is no significant drop in sperm count within the first 30 days after the start of irradiation, this does not preclude the possibility that sterility could occur about a month or two later. This is a reflection of the turnover time (approximately 70 days) required for a spermatogonia stem cell to develop into a mature spermatozoa.

Which one of the following statements concerning radiolabeled immunoglobin therapy is FALSE? A. One disadvantage associated with the use of 90Y-labeled antibodies is that the relatively low energy (<100keV) and short range of the -particles emitted limit the so-called "crossfire effect." B. Both ibritumomab tiuxetan (Zevalin) and tositumomab (Bexxar) target CD20. C. Radiation safety is an important issue regarding the use of 131I-labeled compounds because this isotope emits -rays that may pass through the patient. D. The dose-limiting organ associated with the use of tositumomab (Bexxar) is the bone marrow.

A. One disadvantage associated with the use of 90Y-labeled antibodies is that the relatively low energy (<100keV) and short range of the -particles emitted limit the so-called "crossfire effect." 90Y emits b-particles with a relatively high energy (0.9 MeV) and long range that can penetrate several millimeters into the tissue. Thus, there is a significant crossfire effect, i.e., cells adjacent to those that have taken up the radioisotope are also irradiated. Radioimmunotherapy (RIT) involves treatment with a targeted radiopharmaceutical that combines a tumor-selective monoclonal antibody conjugated to a radionuclide, typically a medium-range b-emitter. Two radiopharmaceuticals have been approved by the FDA for the management of relapsed and refractory CD20-positive low-grade B-cell non-Hodgkin's lymphoma (NHL): 90Y-ibritumomab tiuxetan (Zevalin) and 131I-tositumomab (Bexxar; Answer Choice B). Both drugs are composed of a murine antibody selective for the CD20 surface antigen found on over 95% of NHL B-cells (in addition to all normal mature B cells). 90Y is a pure b-emitter with a short effective half-life; therefore, very little of the radioactivity produced by Zevalin escapes the patient, minimizing the radiation safety hazard. However, a surrogate imaging isotope, such as 111-In, must be incorporated into the Zevalin framework to allow positional localization. Bexxar incorporates 131-I, which is a medium-energy, mixed-spectrum b- and g-emitter with a g emission at 364 keV that can be detected using a gamma camera. Because of the penetrating g-rays of 131-I and eight-day half-life, more rigorous radiation safety precautions must be used with Bexxar (Answer Choice C). Hematologic toxicity is the major dose-limiting toxicity for RIT (Answer Choice D).

Prenatal death as a result of radiation exposure in utero is most likely to occur during: A. Pre-implantation B. Implantation C. Early organogenesis D. Late organogenesis E. The fetal period

A. Pre-implantation Radiation exposure is most likely to be lethal in the earliest phase of the prenatal period, after conception, before implantation.

Considering our current knowledge of typical alpha/beta values and basic radiobiological concepts, which of the following organ sites would be most likely to gain therapeutic benefit with hypofractionation? A. Prostate B. Head and Neck C. Breast D. Bladder

A. Prostate

The largest contributor to radiation exposure of the US population each year is: A. Radon B. Cosmic radiation C. Computed Tomography D. Industrial activity E. Consumer products

A. Radon Per the National Council on Radiation Protection and Measurements (NCRP), Report No. 160, the average annual radiation dose per person in the United States is approximately 6.2 millisieverts (mSv) or 620 millirem (mrem). The majority (37%) of this dose can be attributed to background radiation sources including Radon and Thoron. These gases are created when other naturally occurring elements undergo radioactive decay. Cosmic radiation contributes 5% of the average annual dose (Answer Choice B). An additional 48% of the average dose to an individual in the United States is from medical procedures (not including dose received during therapeutic radiation). Of these, Computed Tomography (CT) scans comprise approximately 24% of radiation dose (Answer Choice C). Industrial activity contributes only a very small amount of the average annual dose to the average American (<0.1%, or 0.003 mSv). Consumer products contributes approximately 2% of the average annual dose (Answer Choice E)

Which of the following statements concerning photodynamic therapy is INCORRECT? Photodynamic therapy: A. Reduces tumor burden via direct tumor cell killing rather than indirectly via damage to tumor vasculature B. Is generally used to treat either superficial tumors or those that can be accessed with fiberoptic probes C. Involves the use of a drug activated by visible light D. Is toxic through the formation of singlet oxygen E. Is maximally effective in aerobic tissues

A. Reduces tumor burden via direct tumor cell killing rather than indirectly via damage to tumor vasculature Photodynamic therapy (PDT) requires a photosensitizer, oxygen, and visible light to produce the cytoxic highly reactive singlet oxygen radical, which ultimately achieves tumor cell killing indirectly via damage to the tumor vasculature (Answer Choices A, C, D). Although direct tumor cell killing may occur, particularly when there is a long drug-light exposure that allows free diffusion of the photosensitizer into tumor tissue, in most instances, the main photosensitizing effect occurs while the drug is confined to the tumor vasculature and results in damage to these endothelial cells, which leads to the indirect killing of tumor cells as a result of the vascular damage. PDT has been used to treat both superficial tumors as well as more deep-seated tumors that can be accessed endoscopically and exposed to light using fiberoptic probes (Answer Choice B). Because oxygen is required for the PDT reaction, PDT is ineffective in hypoxic conditions (Answer Choice E).

For irradiation with X-rays, the increased cell survival observed when a given total dose is delivered at a low dose-rate (~1 Gy/hr) versus high dose-rate (~1 Gy/min) is due primarily to: A. Repair of DNA double-strand breaks B. Decreased production of DNA double-strand breaks C. Induction of free radical scavengers D. Activation of cell cycle checkpoints E. Down-regulation of apoptosis

A. Repair of DNA double-strand breaks Therapeutic radiation at a low dose-rate (essentially the same as fractionation) of ~1 Gy/hr is associated with increased cell survival compared to higher dose-rates primarily due to cellular repair - and is generally assumed to be secondary to repair of DNA double-strand breaks produced as a result of radiation.

Which of the following statements is CORRECT regarding studies of the Japanese A-bomb survivors by the Radiation Effects Research Foundation (RERF)? A. Significantly more mutations were not noted in children who had at least one parent who was exposed to ionizing radiation prior to conception. B. The RERF Life Span Study provides the basis for the estimated doubling dose estimates for radiation-induced genetic mutations in humans. C. More than 60% of the survivor cohort received acute exposures greater than 100 mSv D. A significant limitation of the RERF study is the lack of available dosimetric data E. Risk estimates for radiation-induced late effects and genetic effects continue to evolve as the survivor cohort ages and their children and grandchildren are followed

A. Significantly more mutations were not noted in children who had at least one parent who was exposed to ionizing radiation prior to conception. Studies of the Japanese A-bomb survivors by RERF have served as a "gold standard" for radiation epidemiology. One of the key findings is that there has NOT been found to be a statistically significant increase in mutations identified in the F1 generation (approximately 70,000 individuals), despite the original expectation that there might be based on animal experiments. The doubling-dose estimate for radiation-induced genetic mutations in humans is therefore based on mouse data coupled with estimates of human spontaneous mutation rates (Answer Choice B). A majority of the survivor cohort received relatively low radiation exposure of less than 100 mSv (Answer Choice C). A recently revised dosimetry model (DS02) provides improved estimates of individual exposures received by individuals who survived the Japanese A-bomb (Answer Choice D). The Adult Health Study cohort members even today continue to undergo a thorough clinical exam every two years. By providing data and biological samples these participants remain an important resource for future analyses (Answer Choices D and E).

Fluoroscopy for medical purposes can contribute the most dose to and cause the greatest clinical effects within which organ? A. Skin B. Brain C. Lungs D. Heart E. Bone

A. Skin The maximum dose with fluoroscopy is to the skin. Early transient erythema may occur with doses of 2 Gy, dry desquamation with single doses of 14 Gy, and moist desquamation with single doses of 18 Gy or more.

Which of the following statements is CORRECT when comparing the abscopal effect versus the bystander effect in the context of radiation responses? A. The abscopal effect describes a response that occurs distant from the irradiated site (in the same organism), whereas the radiation-induced bystander effect refers to general biological effects in unirradiated cells that are in close proximity to irradiated cells (in vivo or in vitro). B. The abscopal effect describes a phenomenon where an irradiated tumor regresses while another unirradiated metastatic site (in the same organism) accelerates in tumor growth, whereas the radiation-induced bystander effect refers to general biological effects in unirradiated cells that are in close proximity to irradiated cells (in vivo or in vitro). C. During an abscopal response, one irradiated tumor regresses with at least two unirradiated tumor metastatic sites responding as well (in the same organism), whereas the radiation-induced bystander effect refers to the phenomenon when only half of a tumor is irradiated but the whole tumor regresses. D. Both phenomena essentially go hand in hand because non-irradiated bystander cells travel to non-irradiated distant tumors sites and cause an immune-mediated regression.

A. The abscopal effect describes a response that occurs distant from the irradiated site (in the same organism), whereas the radiation-induced bystander effect refers to general biological effects in unirradiated cells that are in close proximity to irradiated cells (in vivo or in vitro). The abscopal effect describes a situation whereby a patient being treated with radiation therapy to a site of metastatic disease experiences concurrent regression of a distant site of metastatic disease that is not being directly irradiated. The abscopal hypothesis was first described in 1953 to refer to the effects of ionizing radiation occurring "at a distance from the irradiated volume but within the same organism." In contrast, the bystander effect describes the induction of biologic effects in cells that are in close proximity to cells that are directly traversed by a charged particle.

Which statement concerning transforming growth factor beta 1 (TGF-β1) and basic fibroblast growth factor (bFGF/FGF2) is TRUE? A. The pro-fibrotic activities and role in radiation-induced fibrosis of TGF- β1 are mediated by SMAD3 B. Stimulation of TGF-1 synthesis should improve the therapeutic ratio C. bFGF has been shown to sensitize endothelial cells to radiation-induced apoptosis D The serum concentration of TGF-1 always decreases following lung irradiation

A. The pro-fibrotic activities and role in radiation-induced fibrosis of TGF- β1 are mediated by SMAD3 Transforming growth factor beta 1 (TGF-β1) plays a central role in radiation-induced fibrosis as it causes epithelial to mesenchymal cell trans-differentiation and promotes the influx of fibroblasts as well as the production of extracellular matrix. TGF-β1 activates SMAD proteins, including SMAD3, which modulates the transcription of target genes with pro-fibrotic activities. It is thought that stimulation of TGF-β1 synthesis causes fibrosis and would therefore decrease the therapeutic ratio. Basic fibroblast growth factor (bFGF/FGF2) has been shown to protect (not sensitize) endothelial cells from radiation-induced apoptosis. In addition, TGF-β1 has anti-inflammatory activity. The clinical interpretation of serum TGF-β1 levels during thoracic irradiation is complex; on the one hand, levels are elevated in patients who develop radiation pneumonitis while, on the other hand, lung tumors may self-generate TGF-β1 synthesis of which is therefore expected to fall during treatment).

In some experiments, tumors treated with radiation and concurrent molecularly-targeted drugs against EGFR and VEGFR displayed longer regrowth delays, but not higher tumor control probabilities, compared to tumors that were treated with radiation only. Which of the following statements provides the most likely explanation for this? A. The treatment is effective for the bulk of tumor cells, but not for cancer stem cells. B. The drug did not reach most of the cells due to poor vascular perfusion in the tumor. C. Experimental error accounts for this, because growth delay and tumor control assays usually yield similar results. D. Tumor cells generally do not express receptors that are targeted by these drugs. E. The radiosensitivity of tumor cells does not depend on vascular supply or physiology.

A. The treatment is effective for the bulk of tumor cells, but not for cancer stem cells. There are indeed some examples in the literature showing a discrepancy between growth delay and tumor control probability. In these experiments, various molecular targeting approaches in combination with radiation were investigated. Though difficult to prove, the assumption of a differential effect on cancer stem cells and non-cancer stem cells is the mostly likely explanation for these results. It is likely that the drug reached the tumor since there was an effect on tumor growth. Cancer cells generally express EGFR and cell survival following irradiation is affected by vascular supply. The observed discrepancy between growth delay and local tumor control in some experimental settings suggests that the latter assay is the preferable endpoint to evaluate new therapeutic approaches with curative intent.

Assuming no difference in overall treatment time, which of the following statements is CORRECT concerning isoeffect curves? A. Tissues with a greater repair capacity have steeper isoeffect curves. B. Increased proliferation of the critical cell population during the course of radiotherapy will decrease the slope of the isoeffect curve. C. Tissues with steep isoeffect curves have high / ratios. D. Isoeffect curves for tumor control will be steeper if significant reoxygenation occurs between dose fractions.

A. Tissues with a greater repair capacity have steeper isoeffect curves. An isoeffect curve describes the relationship between total dose for a given level of tissue effect and the different fractionation parameters (overall time, dose per fraction, number of fractions, etc). Isoeffect curves are often plotted with the log of the total dose on the y-axis and the log of the fraction size (from high to low) on the x-axis. Tissues with a greater repair capacity will show greater sparing with increasing fractionation (smaller fraction sizes) and therefore will have steeper isoeffect curves. Increased proliferation will cause an increase in the slope of an isoeffect curve because it would take a higher total dose to kill the larger number of cells produced during the course of treatment (Answer Choice B). Tissues with steep isoeffect curves have low, not high, / ratios (Answer Choice C). Reoxygenation decreases the slope of the isoeffect curve because it decreases the number of radioresistant hypoxic cells and hence reduces the total dose required to control the tumor, everything else being equal (Answer Choice D).

The formation of dicentric chromosome aberrations follows a linear-quadratic dose response curve. This has been interpreted to mean that the production of dicentric chromosomes results from: A. Two chromosome breaks, produced either by one or by two separate radiation tracks B. Two chromosome breaks produced by two separate radiation tracks C. Two chromosome breaks produced by a single radiation track D. One chromosome break produced by two separate radiation tracks E. One chromosome break produced by a single track of radiation

A. Two chromosome breaks, produced either by one or by two separate radiation tracks The formation of dicentric chromosomes is linear at low radiation doses but follows a quadratic function at higher doses. Two distinct mechanisms are thought to be responsible for these two components of the linear-quadratic dose response curve. The linear portion of the dose response relationship is assumed to result from the simultaneous induction of two chromosome breaks by a single track. The quadratic portion is assumed to result from the two chromosome breaks being produced by two separate radiation tracks.

A prostate cancer patient is planned to go through conventionally fractionated IMRT treatment. Your clinic's standard for planning has been to use 10 mm margins in every dimension except 7 mm posteriorly without daily image guidance. Which of the following strategies would NOT improve the therapeutic ratio of the treatment? A. The addition of a hydrogel spacer between the rectum and prostate B. The use of daily cone-beam CT for image guidance C. The use of smaller PTV margins (i.e., 5 mm except 3 mm posteriorly) D. The use of daily cone-beam CT plus smaller margins

Answer key says A, but then the answer seems to indicate that the answer is actually C. C. The use of smaller PTV margins (i.e., 5 mm except 3 mm posteriorly) -- implies you are going to reduce the margins w/o image guidance which could result in miss All of the proposed interventions would improve the therapeutic ratio except the use of smaller PTV margins without image guidance. Image guidance increases the fidelity of setup and reduces the risk of geometric miss, particularly in the setting of variability in bladder and rectal filling. The use of reduced PTV margins can improve the therapeutic ratio by limiting the volume of normal tissue treated, but only if the dose to tumor is not compromised. The margins proposed in answer C would not be sufficient to cover tumor without image guidance. Lastly, hydrogel spacers have been shown to displace the rectum posteriorly and reduce GI toxicity.

For a population of patients with identical tumors, assuming that: 1) each tumor has 2x10^9 cells, 2) after treatment with 25 fractions of 2 Gy, the effective survival is 10^-9; 3) there is no regrowth of the tumor during the treatment, 4) the tumor may recur even if there is only one viable tumor cell survive. What is a patient's probability to be recurrence-free from the original tumor? a. 50.0% (or 1/2) b. 13.5% (or e^2) c. 0.01 (or 10^-2) d. 0%, because the each of the patients will have 2 surviving cells e. None of the above

B Among the identical patients treated, there will be a distribution for the actual number of survived cells, although the average number of cells to survive should be 2 (or 2x109 * 109). The probability of having no cell to survival (thus recurrence-free) fits the Poison distribution. It can be calculated as: p=e-n, where n is the average number of survived cells. Because the average number of survived tumor cells is 2, the probability to have no tumor cells survived should be: e-2.

A total dose of 12 Gy of X-rays delivered in 3 Gy fractions reduces cell survival to 10-4. Assuming that cell killing can be modeled using an exponential survival curve, what dose would be required to reduce the surviving fraction to 10-6? A. 9 Gy B. 18 Gy C. 24 Gy D. 36 Gy E. 72 Gy

B An exponential survival curve can be modeled using the single-target, single-hit equation (S = e), or the simplified form of the linear quadratic equation in which beta is zero (S = e-alphaD). Again, they are saying beta is zero because its multifraction and allows for SLDR and the summation of the 4 shoulder curves gives you an effective straight line without a shoulder. So they effective D0 is higher for a fractionated curve. Since four 3 Gy fractions reduce the surviving fraction to 10-4, and assuming an equal effect per fraction, each 3 Gy fraction reduces the surviving fraction by 10-1. Accordingly, two additional 3 Gy fractions (producing a total dose of 18 Gy) would yield a surviving fraction of 10-6.

Which of the following types of ionizing radiation has the highest LET? a. 2.5 MeV alpha particles b. 75 MeV/nucleon argon ions c. 1 GeV/nucleon carbon ion d. 18 MeV/nucleon carbon ions e. 150 MeV protons

B Clinically relevant 75 MeV per nucleon argon ions have LET 250 keV/μm. 1 GeV/nucleon and 18 MeV/nucleon carbon ions have LET values of approximately 10 keV/μm and 108 keV/μm, respectively. 2.5 MeV alpha particles have an LET value of approximately 170 keV/μm. 150 MeV protons are considered low LET, with values in the range of 0.5 keV/μm. This is kind of a tough question to get. The idea is simple, larger stuff has higher LET with x-rays/gamma rays/protons being considered "low" LET. With particles, the LET actually goes down as energy goes up, so a hint is DONT pick the highest energy one, that usually has lower LET (less likely to actually interact at super high E and more likely to just pass through). In general, neutrons are actually intermediate range LET with lower E being in the ~80ish KeV/um range and higher E ones being lower like 3-30 KeV/um. Things like Carbon < Argon < Iron are actually in the high LET range and energies are sometimes in the GeV range. Again generally speaking, don't pick ones in the GeV range (1 GeV carbon is only 10 KeV/um whereas 18 MV carbon is 160 KeV/um). However, Argon is heavier (A = 18 vs A=12 for carbon) so for two energies in the MV range, pick the heavier option.

Which of the following would be the most accurate way to measure reproductive integrity of cells exposed to ionizing radiation? a. Caspase cleavage assay b. Clonogenic survival assay c. 3-day growth assay d. Micronucleus assay e. Tumor regrowth delay assay

B Clonogenic cell survival assays (CSAs) are considered the "gold standard" for the assessment of IR response patterns in vitro. Importantly, these assays can be used to determine whether the effect of a given drug on IR-induced cell killing is additive versus synergistic. Caspase assays measure apoptosis, which is a common mechanisms cell death in lymphoma and leukemia cells, but it is not as predominant in epithelial cancers. The 3-day growth assay and the micronucleus assay may correlate with clonogenic survival, but the don't measure true clonogenicity, which can take many more days to manifest.

Which of the following statements concerning RBE is TRUE? The RBE: A. Is lower for neutrons than for protons over the therapeutic energy range B. Is greater for high LET particles in hypoxic cells as compared to oxygenated cells of the same type C. Is diminished for carbon ions when delivered over several fractions as compared to a single dose D. Is greatest for heavy charged particles at the beginning of the particle track E. Increases for MeV alpha-particles with increasing dose

B Relative Biological Effectiveness (RBE) is defined as: Dose of Reference Radiation (250 keV X-Rays) Dose of Test Radiation to give the same biological effect The reference radiation for calculation of RBE is low LET radiation, such as 250 keV X-rays or Co-60. The dose of the reference radiation that will achieve the same level of cell killing as high LET particles in hypoxic cells will be greater because there is little to no oxygen effect for high LET radiation (Answer Choice B). The RBE is greater for neutrons than it is for protons in the therapeutic energy range because the high energy protons used in radiotherapy are of a relatively low LET and therefore possess an RBE of approximately 1.1 (Answer Choice A). The RBE for carbon ions, or any other type of high LET radiation, is greater for fractionated irradiation compared with an acute exposure due to the substantial sparing exhibited with reference X-rays with fractionation (Answer Choice C). The RBE for charged particles is low at the beginning of the particle track and greatest near the end of the track, in the Bragg peak region (Answer Choice D). RBE does show a fractionation dependence; it decreases with increasing fraction size. The RBE for 4 MeV alpha particles will decrease with increasing dose because there is more sublethal damage repair with low-LET X-rays at lower doses, and therefore more survival compared with high-LET radiation (Answer Choice E).

Concerning fast neutron interactions with matter, which of the following is FALSE? A. They do not interact with atomic electrons of biological media B. They interact primarily with oxygen in water C. They may cause the ejection of an alpha particle D. They may activate the target nucleus. E. They may transfer a large fraction of its energy in the process of eleastic scattering.

B Fast neutrons with kinetic energy between a few and several tens of MeV are slowed down in biological media mainly by elastic collisions with hydrogen nuclei (protons) of the cellular water. A fraction of energy lost by fast neutrons in elastic collision with oxygen nuclei is less than 10% of that which occurs with hydrogen nuclei. For the beams of neutrons used in radiation therapy, recoil protons from elastic collisions produce a large density of ionizations along their tracks. Neutrons do not interact with atomic electrons but, instead, interact with atomic nuclei. Alpha particles can be produced by neutron capture reactions with isotopes of both carbon and oxygen, but the probability is strongly dependent on the neutron energy and target material. Example: 17O + n → 14C + α Neutron absorption in a target nucleus is called activation. This is a process by which neutron radiation induces radioactivity in materials. It occurs when atomic nuclei capture free neutrons, becoming heavier and entering excited states. The excited nucleus often decays immediately by emitting gamma rays, beta particles, alpha particles, fission products, and/or neutrons (in nuclear fission). Neutron activation is a potential health hazard in therapy with high energy photons because when photons with energy > 10 MeV are utilized, neutrons are generated in linacs via the interaction of photons with nuclei of high atomic number materials within the linac head and the beam collimator systems. These photoneutrons can have an energy of 0.1 to 2 MeV, are highly penetrating, have a quality factor of 20, and can significantly add to a patient's off-field dose.

In an attempt to generate a radiation survival curve for a new cell line, four cell culture dishes were seeded with 102, 103, 104 and 105 cells, and X-irradiated with 0, 3, 6 and 9 Gy, respectively. At the end of a two-week incubation period, a total of 40 colonies was counted on each dish. Which one of the following statements is TRUE? A. The D0 for this cell line is 3 Gy B. The survival curve for this cell line is exponential C. The n and Dq values for this survival curve are large D. The cell surviving fraction after a dose of 3 Gy is 0.04 E. The alpha-beta ratio for this cell line is small

B - the cell survival curve for this cell line is exponential The survival curve for this cell line is exponential because each incremental dose of 3 Gy decreased the surviving fraction by an additional factor of 0.1. Thus, this survival curve can be modeled using an exponential equation which can be expressed as either S= e-alphaD (linear-quadratic model) or S = e-D/D0 (target theory model). Remember multifraction survival curve is one of these two formulas: S= e-alphaD S = e-D/D0 The D0 is equal to the D10/2.3, or 1.3 Gy, not 3 Gy. The n and Dq values for this survival curve are equal to 1 and 0 Gy, respectively, and are therefore small, not large. The surviving fraction after a single dose of 3 Gy can be calculated from the colony forming efficiency of the irradiated cells (40/1000), divided by the plating efficiency (PE) of the unirradiated cells (40/100), which is equal to 0.04/0.4 or 0.1. Since this survival curve can be represented by S = e-alphaD, the beta term of the linear-quadratic equation must approach zero, so the alpha/beta would be very high, and in fact will be undefined if the beta term is actually zero.

Which of the following is the most plausible explanation for the decreased clonogenic survival observed among the progeny of cells that survived a prior irradiation? a. Increased expression of genes which encode repair enzymes b. Genomic instability c. Increased synthesis of glutathione d. Adaptive response e. Decreased expression of caspase 8

B Genomic instability can be induced in cells surviving a prior irradiation, and this would be inherited by those cells' progeny, which may contribute to their showing a decreased clonogenic survival. All of the remaining explanations have the potential to increase, not decrease, survival.

The Km for radiosensitization by oxygen (the oxygen concentration at which cellular radiosensitivity is halfway between the fully aerobic and fully hypoxic response) corresponds to an oxygen concentration of approximately: A. 0.02% B. 0.5% C. 3% D. 15% E. 30%

B. 0.5% The Km value occurs at an oxygen concentration of roughly 0.5-1% or 3-8 mm Hg.

If the mitotic index of a cell line is 5%, the growth fraction is 100%, the cell cycle time is 14 hours, and the correction factor, λ, is 0.7, what is the approximate length of mitosis (TM)? A. 0.2 hours B. 1 hour C. 2 hours D. 4 hours E. 8 hours

B. 1 hour Using the equation MI = λTM/TC, where MI is the mitotic index, TM is the length of mitosis and TC is the total cell cycle time, then TM = (MI)(TC/ λ) = (0.05)(14 hours)/0.7 = 1 hour. Of note, the TM for most mammalian cells is typically ~1 hour.

The typical cell cycle time (TC) for proliferating cells in human tumors is in the range of: A. <1 day B. 1-5 days C. 6-25 days D. 26-100 days E. >100 days

B. 1-5 days The typical TC for tumor cells in vivo is generally in the range of 1-5 days.

The lifetime of an OH• radical is approximately: A. 10-15 second B. 10-9 second C. 10-1 second D. 1 second E. 1 minute

B. 10-9 second The initial ionization process takes approximately 10-15 second. The primary radicals produced by the ejection of an electron typically have a lifetime of 10-10 second. The resulting hydroxyl radical has a lifetime of approximately 10-9 second. The DNA radicals subsequently produced have a lifetime of approximately 10-5 second.

Of the following pairs of individuals and maximum annual effective dose equivalents permitted, which is CORRECT? (These values exclude doses from exposure to background radiation, both natural and man-made) A. A radiation oncologist - 200 mSv per year B. A member of the general public - 1 mSv per year C. A sixteen-year old high school student who works part time in a laboratory - 0 mSv per year D. A nuclear power plant worker - 10 mSv per year E. A patient's relative who transports a radiotherapy patient to and from treatment - 20 mSv per year

B. A member of the general public - 1 mSv per year A member of the general public is permitted 1 mSv per year for "chronic" radiation exposure over extended periods of time, or 5 mSv per year for an infrequent exposure. Radiation workers, including radiation oncologists and nuclear power plant employees, may receive 50 mSv per year (Answer Choice A). A person under the age of 18 may be exposed to radiation up to 1 mSv per year if the potential exposure occurs as part of an educational or training program (Answer Choice C). A patient's relative transporting a patient to and from radiotherapy treatment, presumably an infrequent event, would be considered to be a member of the general public and therefore would be allowed 5 mSv per year (Answer Choice E).

The two most frequently activated signaling pathways in prostate cancer are driven by androgen receptor (AR) and PI(3)K-Akt. Inhibitors of the PI(3)K pathway are in early clinical trials, while androgen-deprivation therapy (ADT) via inhibition of the AR is able to confer a clinical response in most patients. Which of the following statements most CORRECTLY describes the relationship between these two pathways and explains mechanistically why single inhibition of AR or the PI(3)K-Akt pathways rarely induces tumor regression in preclinical models? A. ADT represses an AR gene program governing DNA repair and inhibits repair of ionizing radiation-induced DNA damage B. AR and PI(3)K pathways regulate each other by reciprocal negative feedback, such that inhibition of one activates the other C. ADT represses the PI(3)K/Akt/target of rapamycin (TOR) pathway D. ADT activates the unfolded protein response E. All of the above

B. AR and PI(3)K pathways regulate each other by reciprocal negative feedback, such that inhibition of one activates the other Prostate cancer is characterized by its dependence on androgen receptor (AR) signaling as well as frequent activation of PI(3)K signaling. AR transcriptional output is decreased in human and murine tumors with PTEN deletion. In addition, PI(3)K pathway inhibition activates AR signaling by relieving feedback inhibition of HER kinases. Similarly, AR inhibition activates Akt signaling by reducing levels of the Akt phosphatase, PHLPP. These two oncogenic pathways therefore cross-regulate each other by reciprocal feedback. Inhibition of one pathway leads to activation of the other thereby maintaining tumor cell survival. Combined pharmacologic inhibition of PI(3)K and AR signaling causes near complete prostate cancer regression in a PTEN-deficient murine prostate cancer model and in human prostate cancer xenografts, indicating that both pathways coordinately support survival.

Which of the following is a phosphoinositol 3-kinase like kinase (PIKK) that serves as the central orchestrator of the signal transduction response to DSBs? A. Ku70/80 B. ATM C. Rad50 D. MSH2 E. p53 (TP53)

B. ATM Ataxia Telangictasis Mutated (ATM) serves as the central orchestrator of the signal transduction response to DSBs. Cells deficient in ATM activity display cell cycle checkpoint defects and sensitivity to ionizing radiation.

Which statement is CORRECT concerning the ataxia telangiectasia-mutated (ATM) gene and Rad3-related (ATR) genes and proteins? A. Ionizing radiation induced phosphorylation of Chk1 requires either ATM or ATR. B. ATM is recruited to double strand breaks by the Mre11-Rad50-Nbs1 complex C. ATR activation and Chk1 phosphorylation occurs prior to ATM activation D. Cells derived from patients with AT typically display increased levels of p53 (TP53) phosphorylation E. Irradiation causes autophosphorylation of ATM which converts it from an active monomer to an inactive dimer

B. ATM is recruited to double strand breaks by the Mre11-Rad50-Nbs1 complex The ATM protein contains a highly conserved C-terminal kinase domain resembling a phosphatidylinositol-3-kinase (PI(3)K); this kinase is an important component of a number of DNA damage repair pathways. Both ATM and ATR are required for IR-induced Chk1 phosphorylation. ATM is recruited to double strand breaks by the Mre11-Rad50-Nbs1 complex. ATR is recruited to single stranded DNA at sites of stalled replication forks by ATR-interacting protein (ATRIP).. Cells derived from patients with AT typically display decreased levels of p53 phosphorylation. Irradiation causes autophosphorylation of ATM which converts it from an inactive dimer into the active monomeric form, not vice versa. ATM activation and Nbs1 recruitment to damaged DNA occurs prior to ATR recruitment and Chk1 phosphorylation.

Which of the following statements regarding angiogenesis is FALSE? A. For a multi-cellular organism to grow, it must have the capacity to recruit new blood vessels via angiogenesis B. Angiogenesis is normally regulated by pro-angiogenic, but not anti-angiogenic molecules C. Angiogenesis is dysregulated in a neoplastic environment D. Without a nearby blood vessel or effective angiogenesis, a tumor cannot grow beyond a critical size or metastasize to other organs E. Viable cells are located within 70 um of blood vessels due to the diffusion limits of oxygen

B. Angiogenesis is normally regulated by pro-angiogenic, but not anti-angiogenic molecules Since oxygen is unable to diffuse more than approximately 70 μm from the arterial end of a capillary, tumours require the ability to develop new blood vessels in order to grow (Answer Choice A). This process is normally regulated by a balance of both pro-(including VEGF, FGF, PDGF) and anti-(thrombospondin, angiostatin, endostatin) angiogenic molecules.

Regarding pair production and annhilation, which of the following is true? A. The incident photon is scattered with reduced energy B. Annihilation photons always have an energy of 0.511 MeV each C. A pair of orbital electrons are ejected from the atom D. Two positrons are emitted at 180 degrees E. It cannot occur if the photon energy is above 1.02 MeV

B. Annihilation photons always have an energy of 0.511 MeV each Annihition photons always have an energy of 0.511 MeV each, which is equal to the rest energy of the positron and electron.

The death of a person 30-60 days following a total body radiation dose close to the LD50 would likely be due to damage to the: A. Heart B. Bone marrow C. Central nervous system D. Brain E. Gastrointestinal system

B. Bone marrow The death of a person 30-60 days following a total body radiation dose close to the LD50 would be due to damage to the bone marrow, resulting in the gradual reduction in the level of peripheral blood elements. Infection due to loss of white blood cells and/or hemorrhage due to the loss of platelets are typically the cause(s) of death. Usually, death from ablation of the bone marrow would not be manifest until about a month or two after irradiation; this is a reflection of the normal turnover rates of the mature blood components, which would not be replaced in the absence of functioning bone marrow stem cells. Death from radiation damage to the heart, liver, or kidney would not occur within two months following irradiation. Death due to damage to the gastrointestinal system usually takes place within 5-16 days following irradiation and would not be likely with a dose near the LD50 since it requires higher doses to manifest.

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B. CD133 is a putative marker for cancer stem cells CD133 has been described as a putative marker for cancer stem cells in glioblastoma. Injection of 100 CD133+ cells is sufficient to initiate tumor formation in >30% of nude mice, supporting CD133 as a potential cancer stem cell marker. The unsorted bulk cells contain cancer stem cells; given, however, that 100-1,000 more cells are required in order to form the same number of tumors as that seen when purified CD133+ cells are injected, it appears that <1% of the cells in the tumor are stem cells. CD133- cells were derived from a glioblastoma and are therefore not normal, although they possess a very limited ability to form tumors de novo. In this experiment, no data are provided regarding the sensitivity of the cell lines (or sublines) to radiation.

Panitumumab is now FDA-approved for the management of k-ras wild-type metastatic colorectal cancer that has progressed through primary chemotherapy. In regards to mechanism of action, panitumumab is most similar to which of the following agents? A. Rituximab B. Cetuximab C. Bevacizumab D. Infliximab E. Sunitinib

B. Cetuximab Panitumumab is a humanized IgG2 monoclonal antibody to the epidermal growth factor receptor (EGFR). Cetuximab is a chimeric IgG1 antibody also targeting the EGFR and is used in the treatment of metastatic k-ras wild-type colorectal cancers as well as in head and neck cancers. In contrast, Rituximab targets CD20 (primarily in B-cell lymphomas; Answer Choice A). Bevacizumab targets the VEGF-A ligand (Answer Choice C). Infliximab is a monoclonal antibody against tumor necrosis factor (TNF)-α and is used in the treatment of autoimmune disorders such as rheumatoid arthritis and psoriasis (Answer Choice D). Sunitinib is a multi-tyrosine kinase receptor inhibitor (Answer Choice E).

Which of the following is a small molecule tyrosine kinase inhibitor? A. Trastuzumab B. Erlotinib C. Bevacizumab D. Sirolimus E. Cetuximab

B. Erlotinib Erlotinib (Tarceva) is a small molecule inhibitor of the epidermal growth factor (tyrosine kinase) receptor (EGFR). It reversibly binds to the ATP binding site of the receptor, which prohibits the formation of phosphotyrosine residues and subsequent downstream signaling cascades. Trastuzumab (Herceptin) is a monoclonal antibody against the Her2/neu receptor (Answer Choice A). It binds to domain IV of the extracellular segment of the Her2/neu receptor, leading to arrest during the G1 phase of the cell cycle and decreased proliferation, downregulation of Akt, and suppression of angiogenesis. Bevacizumab (Avastin) is a recombinant humanized monoclonal antibody that blocks angiogenesis via the inhibition of the vascular endothelial growth factor (VEGF)-A ligand (Answer Choice C). Sirolimus (Rapamycin) binds to the FKBP12 complex and inhibits mTOR (FRAP1), a downstream target of the PI(3)K/AKT pro-survival signaling pathway that is activated by radiation exposure (Answer Choice D). Cetuximab is a chimeric (mouse/human) monoclonal antibody against EGFR (Answer Choice E).

Increased numbers of chromosome aberrations, especially quadriradials, are frequently found even in the absence of radiation in which of the following human syndromes? A. Xeroderma pigmentosum B. Fanconi anemia C. Cockayne's syndrome D. Niemann-Pick disease E. Li-Fraumeni syndrome

B. Fanconi anemia Blood cells from individuals with Fanconi anemia are often found to have high numbers of chromosome aberrations, especially quadriradials. These complex aberrations increase dramatically with exposure to DNA cross-linking agents such as mitomycin C. Quadriradial chromosomes are 4-armed, aberrant chromosomes probably formed by unresolved recombination between homologous chromosomes -- when cross linked have been formed and not repaired.

Which of the statements is TRUE regarding the activation of one type of apoptotic pathway? A. Apoptosis is initiated by PARP B. Fas ligand binding its receptor initiates apoptosis C. Caspases involved in the execution of apoptosis are also involved in the execution of necrosis D. Bcl2 is a pro-apoptotic protein. E. Anti-apoptotic Bax dimerizes and translocates to the mitochondria.

B. Fas ligand binding its receptor initiates apoptosis. Fas ligand binds its receptor and triggers the external death receptor pathway --> activation of Caspase 8 Cleavage of PARP-1 by caspases is considered to be a biochemical hallmark of apoptosis (Answer Choice A). Different caspases play different roles in the initiation and execution of apoptosis and are not involved in necrosis. Necrosis is the unregulated digestion of cellular components as a result of external factors (Answer Choice C). Bcl-2 inhibits apoptosis while Bax stimulates apoptosis (Answer Choices D and E).

Which of the following statements is TRUE regarding the appearance of giant multinucleated cells following radiation? A. Giant multinucleated cells exhibit an exponential survival curve B. Giant multinucleated cells are a characteristic seen just prior to mitotic catastrophe C. The presence of giant multinucleated cells is associated with dose response D. Giant multinucleated cells are radioresistant mitotic cells E. Giant multinucleated cells demonstrate increased apoptosis

B. Giant multinucleated cells are a characteristic seen just prior to mitotic catastrophe Radioresistant cells display mitotic catastrophe caused by aberrant mitosis, which is associated with the formation of giant multinucleated cells that contain uncondensed chromosomes.

Chemotherapeutic agents frequently produce DNA double-strand breaks (DSBs) by causing stalling and collapse of DNA replication forks. Which of the following pathways has a dominant role in the repair of replication-associated double-strand breaks? A. Non-homologous end-joining (NHEJ) B. Homologous recombination (HR) C. Single-strand annealing (SSA) D. Translesional DNA synthesis (TLS) E. Nucleotide excision repair (NER)

B. Homologous recombination (HR) Several DNA repair pathways, including translesional DNA synthesis (TLS), nucleotide excision repair (NER), and homologous recombination (HR) can be mobilized at stalled DNA replication forks depending on the type of fork-blocking lesion. Chemotherapy-induced DNA lesions, such as interstrand crosslinks, interfere with the progress of the replicative DNA helicase or DNA polymerases, thereby leading to replication fork blockage or demise and producing DNA gaps or one-sided DNA double-strand breaks (DSBs). Uncoupling of the replicative DNA helicase from the polymerases may occur generating excessive single-stranded DNA, which could in turn be the target of endonucleolytic processing, resulting in a one-sided DSB. In addition, single-stranded breaks induced by endogenous and exogenous sources may lead to the formation of one-sided DSBs due to runoff of the replication fork. In the repair of one-sided DSBs, HR appears to be the only pathway leading to their productive resolution. This entails resection of the DSB to form a 3′-tailed end for Rad51 filament assembly and DNA strand invasion and ultimately reconstruction of the replication fork.

Hyperthermia combined with radiation may be effective in cancer therapy because: A. Tumor cells are intrinsically more sensitive to heat than normal cells B. Hyperthermia can restore aeration to hypoxic tumor cells by increasing blood flow, thereby increasing radiorsensitivity. C. Heat increases the number of ionizations produced by a given dose of radiation D. Hyperthermia induces radiosensitization by potentiating radiation damage to DNA. E. Heat can produce maximum radiosensitization even if delivered several days after irradiation

B. Hyperthermia can restore aeration to hypoxic tumor cells by increasing blood flow, thereby increasing radiorsensitivity. Tumor cells are more likely to be hypoxic and demonstrate a low pH compared to normal cells, which can contribute to their relative radioresistance. Hyperthermia can increase the radiosensitivity of tumor cells by increasing blood flow, leading to increased aeration and radiosensitivity. Tumor cells are not intrinsically more sensitive to heat than normal cells (Answer Choice A). Heat does not affect the number of ionizations produced by a given dose of radiation (Answer Choice C). Hyperthermia induces radiosensitization by targeting proteins, not DNA (Answer Choice D).

Which of the following conditions is NOT an expected manifestation of radiation-induced heart disease? A. Accelerated coronary atherosclerosis B. Hypertrophic cardiomyopathy C. Cardiac fibrosis D. Pericarditis E. Cardiac myocyte degeneration

B. Hypertrophic cardiomyopathy Hypertrophic cardiomyopathy is not considered a common feature of radiation-induced heart disease. Accelerated coronary atherosclerosis, on the other hand, is an important source of morbidity and mortality after irradiation of intra- or peri-thoracic tumors. Cardiac myocyte degeneration and cardiac fibrosis (adverse cardiac remodeling) may contribute to post-radiation congestive heart failure. Fibrotic thickening of the pericardium and pericardial exudate may occur and could lead to constrictive pericarditis.

The principal reason for choosing brachytherapy rather than external beam radiation is: A. Brachytherapy is associated with lower risk of exposure to hospital staff. B. Implant of a brachytherapy source within the tumor provides a distinct geometrical advantage for sparing the surrounding normal tissues. C. Brachytherapy from a single dwell position provides a uniform dose within the implanted tissue. D. The dose rates that can be achieved with brachytherapy are exquisitely cytotoxic in all tumor types. E. A precise brachytherapy implant delivers similar dose rate to both normal tissues and the tumor.

B. Implant of a brachytherapy source within the tumor provides a distinct geometrical advantage for sparing the surrounding normal tissues. The principal reason for choosing brachytherapy rather than external beam radiation is that a brachytherapy implant within the tumor provides a distinct geometrical advantage for sparing the surrounding normal tissues. Brachytherapy is associated with higher risk of exposure to hospital staff. There is a steep dose rate gradient around an implanted radioactive source that results in a variation in the dose and associated cell killing (Answer Choice C). Dose rates associated with brachytherapy are equal to or less than external beam radiation and would not be more cytotoxic (Answer Choice D). The cell killing is highest immediately adjacent to the source, within the tumor. This has the advantage in a well-placed implant of lower dose rate to the normal tissues that are at a greater physical distance from the sources (Answer Choice E).

Which of the following represents a possible mechanism by which a novel compound could INCREASE tumor response to fractionated radiotherapy if applied prior to each dose fraction? A. Prevention of cell cycle redistribution B. Induction of G2 phase arrest C. Inhibition of reoxygenation D. Radioprotection of normal tissues E. Stimulation of DNA repair

B. Induction of G2 phase arrest An agent that arrested cells in the radiosensitive G2 phase of the cell cycle could increase tumor response to a fractionated treatment protocol if provided prior to each dose of radiation. Prevention of cell cycle redistribution would diminish response to fractionated radiotherapy because surviving cells would remain in a radioresistant portion of the cell cycle rather than being permitted to traverse into a more radiosensitive phase of the cell cycle (Answer Choice A). Inhibition of reoxygenation would reduce tumor response to fractionated radiotherapy due to the prevention of the conversion of surviving radioresistant hypoxic cells to more sensitive aerated cells (Answer Choice C). Radioprotection of normal tissues would have no bearing on tumor response per se, although it could improve the therapeutic ratio overall, assuming the tumor was not similarly protected (Answer Choice D). Stimulation of DNA repair would reduce tumor response to fractionated radiotherapy because a greater proportion of tumor cells may survive if treated with an agent with enhanced capacity for DNA repair.

Studies with laboratory animals have shown that all of the following interventions can reduce lethality after total body irradiation, EXCEPT: A. Fluid and electrolyte therapy B. Inhibitors of poly(ADP-ribose) polymerase (PARP) C. Antibiotics D. Probiotics E. Blood product administration

B. Inhibitors of poly(ADP-ribose) polymerase (PARP) The radiation dose-dependent lethality and reduction in gut crypt cell survival is significantly potentiated, not reduced, in PARP-deficient mice and in mice treated with a PARP inhibitor. Treatment with fluids, electrolytes, antibiotics, and blood products is part of the standard supportive care after exposure to total body irradiation. Manipulation of the gut ecosystem through administration of probiotics has been demonstrated to prevent radiation‐induced enteritis in animals.

One proposed mechanism through which cisplatin acts as a radiosensitizer is by: A. Inhibiting the production of dTMP B. Interfering with DNA repair C. Inhibiting the proteasome D. Blocking growth factor receptors E. Deacetylating histones

B. Interfering with DNA repair Cisplatin binds to DNA to create adducts, leading to intrastrand and, at a lower frequency, interstrand cross-links. One mechanism that has been proposed to account for the radiosensitizing effect of cisplatin is through the inhibition of DNA double-strand break repair.

A clustered lesion: A. Results from the creation of multiple DNA double-strand breaks (DSBs) within a particular exon of a gene following exposure to high LET radiation B. Involves the formation of several DNA lesions within a highly localized region of DNA C. Occurs more frequently as the LET of the radiation decreases D. Represents the repair of multiple lesions within a gene E. Results from transcription-coupled DNA repair

B. Involves the formation of several DNA lesions within a highly localized region of DNA A clustered lesion, which has been hypothesized to play an important role in cell lethality, involves the formation of several DNA damages within a highly localized region of DNA.

Which of the following targeted agents is an immune checkpoint inhibitor? A. Bevacizumab B. Ipilimumab C. Imatinib D. Cetuximab E. Crizotinib

B. Ipilimumab Ipilimumab is an antibody against the immune checkpoint molecule CTLA-4. Bevacizumab is a humanized monoclonal antibody that inhibits vascular endothelial growth factor A (VEGF-A) ligand (Answer Choice A). Imantinib is a small molecular inhibitor of receptor tyrosine kinases. It is most selective for BCR-ABL, but also targets c-kit and PDGF-R (Answer Choice C). Cetuximab is a monoclonal antibody against EGFR (Answer Choice D). Crizotinib is a small molecular inhibitor of ALK and ROS1 kinases (Answer Choice E).

Which of the following statements concerning radiation-induced damage to the eye is TRUE? A. The threshold radiation dose for cataract formation is approximately 10 Gy B. It is often possible to distinguish between a radiation-induced cataract from an age-induced cataract C. The neutron RBE for cataract formation is about 5 for low total doses D. The tolerance dose for the development of blindness is lower than the tolerance dose for cataract formation E. The length of the latency period for cataract formation is independent of radiation dose

B. It is often possible to distinguish between a radiation-induced cataract from an age-induced cataract It is often possible to distinguish a radiation-induced cataract from an age-related cataract as a radiation-induced cataract usually begins at the posterior portion of the lens (central/deep) and an age-related cataract more commonly appears in the anterior portion of the lens (peripheral/superficial). The threshold dose for cataract formation is now known to be well below 10 Gy (Answer Choice A). Several recent studies, which included early lens opacities as well as cataracts that interfere with vision, have longer follow-up times than that presented in previous research as well as greater statistical power. This work suggests a low threshold (<1 Gy) for cataract development and is statistically consistent with no threshold for cataract induction. The low-dose neutron RBE for cataract formation is greater than 20 (Answer Choice C). The tolerance dose for the production of blindness is greater than that for cataract formation (Answer Choice D). The latency period for the induction of a radiation-induced cataract decreases with increasing dose (Answer Choice E).

Which of the following pairs of total body radiation effects and approximate threshold dose is CORRECT? A. Gastrointestinal syndrome - 2 Gy B. LD50 (no medical intervention) - 3.5 Gy C. LD50 (best current medical treatment) - 15 Gy D. Cerebrovascular syndrome - 5 Gy E. Hematopoietic syndrome - 0.2 Gy

B. LD50 (no medical intervention) - 3.5 Gy The human LD50 (dose to result in lethality in 50% of an irradiated population) in the absence of medical intervention is estimated at 3.5 Gy. The dose thresholds for the hematopoietic, gastrointestinal and cerebrovascular syndromes are roughly 2 Gy, 8 Gy and 20 Gy, respectively. The LD50 with the best current medical treatment is about 7 Gy.

The SF2 (surviving fraction at 2 Gy) for an irradiated population of cells is most closely correlated with the: A. Level of g-H2AX 30 minutes after irradiation B. Level of g-H2AX present 24 hours after irradiation C. Acetylation of H2AX on lysine 4 D. Rate of DNA single-strand break repair E. Rate of thymine glycol repair

B. Level of g-H2AX present 24 hours after irradiation The nucleosome contains an octamer of core histones: H3, H4, H2A, and H2B. Histone variants and their post-translational modifications regulate chromosomal functions; the post-translational modifications include acetylation, methylation, and phosphorylation. Histone H2A has nine subtypes, among them the H2AX variant, which is involved in the response to DNA damage. Production of DNA double-strand breaks (DSBs) by ionizing radiation leads to the rapid phosphorylation of histone H2AX on serine 139 (g-H2AX). The specificity of this reaction provides a reliable yardstick for DSBs and the means to spatially localize DSBs within the nuclei of cells (the g-H2AX focus assay). The degree of H2AX phosphorylation measured at a specific time after induction of the DSBs represents a balance between the rate of phosphorylation following DNA damage and the dephosphorylation that occurs as DNA repair progresses. SF2, the cell surviving fraction after 2 Gy, is a model-independent measure of radiation sensitivity. The numbers of phosphorylated gammnaH2AX foci shortly after the irradiation represent the initial level of DNA damage, but the number of phosphorylated H2AX foci at 24 hours after irradiation represent the residual level of unrepaired DNA double strand break at this time. It has been shown that the number of phosphorylated sites remaining 24 hours after irradiation directly correlates with intrinsic radiosensitivity. In contrast, after a 30 minute incubation, H2AX has been phosphorylated, but there has been little time for repair. A correlation between cell survival and the repair of either DNA single-strand breaks or thymine glycols has not been observed.

Which of the following statements best describes the "abscopal effect?" A. Localized irradiation of a tumor is associated with improved disease-related symptoms that are not associated with the treated tumor. B. Localized irradiation of a tumor is associated with a decrease in size not only of the irradiated tumor but also of a tumor that is far from the irradiated area C. Localized irradiation of a tumor is associated with a decrease in size not only of the irradiated tumor but also of a tumor that is far from the irradiated area when given with concurrent immunotherapy D. Localized irradiation of a tumor is associated with a decrease in size not only of the irradiated tumor but also of a tumor that is far from the irradiated area when given with concurrent chemotherapy

B. Localized irradiation of a tumor is associated with a decrease in size not only of the irradiated tumor but also of a tumor that is far from the irradiated area The abscopal response is defined as the influence of ionizing radiation on cell killing outside of a field of radiation. For example, an abscopal response would be considered if an unirradiated tumor is shown to have decreased in size following the irradiation of a tumor located in a distant area.

A terrorist preparing a "dirty bomb" containing 210Po received a total body dose equivalent of approximately 8 Sv resulting from an accidental ingestion of this radioisotope. He did not seek medical attention and died 7 days later from acute radiation toxicity. Which of the following would you expect to see at autopsy? A. Complete bone marrow aplasia B. Mitotic arrest of intestinal crypt cells C. Cerebral edema D. Microvasculitis E. Brain necrosis

B. Mitotic arrest of intestinal crypt cells This individual will experience the GI syndrome and die before his bone marrow would become completely aplastic, although there probably would be some hypoplasia in the marrow, spleen, and lymph nodes. A characteristic feature observed in people who die from the GI syndrome is mitotic arrest in the intestinal crypt cells. The other listed changes (cerebral edema, microvasculitis, brain necrosis) would be expected with the cerebrovascular syndrome, which would not occur unless the total dose received was at least 3-4 fold higher than 8 Sv.

Which of the following statements is TRUE concerning the retinoblastoma protein (RB1)? RB1: A. Is an important downstream effector controlling the G2 checkpoint B. Once phosphorylated, releases E2F C. Is encoded by an oncogene D. Is phosphorylated by ATM E. Activity is altered in approximately 10% of cancers

B. Once phosphorylated, releases E2F RB1 is the product of the RB1 tumor suppressor gene (not an oncogene). Once phosphorylated by CDK4/6, RB1 releases E2F, which then activates genes associated with the G1 checkpoint. RB1 is functionally inactivated in virtually all human cancers, either directly or indirectly, via p53 (TP53). p53-dependent induction of p21 (CDKN1A) regulates cyclin E/CDK2 (late G1) and cyclin A/CDK2 (early S phase) complexes, both of which phosphorylate RB1. The RB1 and p53 signaling pathways are dysregulated in nearly all human cancers.

Which of the following is an example of adaptive immune resistance? A. Process whereby a patient is tolerant to a tumor associated antigen (i.e. NY-ESO or PSCA) before starting immunotherapy but develops immunity to it once beginning treatment. B. Process by which tumor cells change phenotype in response to an immune response (cytotoxicity or inflammation) in an attempt to avoid recognition (i.e. the induction of PD-1, PD-L1, and IDO following antigen recognition and the production of IFNγ). C. Process by which tumors, following radiotherapy, undergo accelerated proliferation with an increased incidence of failure. D. Process by which there is increased resistance to radiotherapy due to reactive response by the immune system.

B. Process by which tumor cells change phenotype in response to an immune response (cytotoxicity or inflammation) in an attempt to avoid recognition (i.e. the induction of PD-1, PD-L1, and IDO following antigen recognition and the production of IFNγ).

All of the following proteins are involved in non-homologous end-joining of DNA double-strand breaks, EXCEPT: A. XRCC4 B. RAD52 C. Artemis (DCLRE1C) D. KU70 (XRCC6)/KU80 (XRCC5) E. DNA ligase IV (LIG4)

B. RAD52 RAD52 plays a central role in homologous recombinational repair (HR) of DNA double-strand breaks through recruitment of RAD51 to single-stranded DNA complexed with RPA. RAD52 does not appear to be involved in NHEJ. XRCC4 is an adaptor protein that tightly complexes with DNA ligase IV, which directly mediates DNA-strand joining by NHEJ (Answer Choice A). The KU70/KU80 heterodimer recruits DNA-PKcs (PRKDC) to the site of DNA double-strand breaks to form a multiprotein complex that keeps broken DNA ends in close proximity and provides a platform for the enzymes required for end processing and ligation (Answer Choice D). DNA-PKcs phosphorylate the Artemis protein, thereby activating it for endonucleolytic activity. The Artemis:DNA-PKcs complex cleaves 5´ and 3´ nucleotide overhangs, which prepares double-strand breaks

Which of the following statements concerning the landmark "mega-mouse" study of radiation mutagenesis, is CORRECT? A. The dose response curve for radiation-induced mutagenesis was linear with a threshold B. Radiation dose-rate was found to significantly affect mutagenesis. C. Males were less susceptible to radiation-induced mutagenesis than females D. Mutation rates at the different loci studied did not vary widely E. The estimated doubling dose for mutations was approximately 2 Gy

B. Radiation dose-rate was found to significantly affect mutagenesis. Fruit flies -- no effect of dose rate Mice and Humans -- there IS AN EFFECT of dose rate The mutation rate decreased significantly when the dose rate was reduced. This was attributed to repair processes that take place during irradiation at low dose rates. Interestingly, this is different than what was observed in the fruit fly study, which demonstrated that dose rate had no effect on the mutagenesis rate. The dose response curve for radiation-induced mutagenesis was found to be linear WITHOUT a threshold (Answer Choice A). Males were found to be MORE susceptible to radiation-induced mutation than females (Answer Choice C). Mutation rates at the different loci studied DID vary widely (Answer Choice D) The estimated doubling dose for mutations was approximately 1 Gray Answer Choice E).

With respect to radiation-induced toxicity in the lung, which of the following statements is FALSE? A. The likelihood of the injury is dependent on the volume irradiated B. Radiation pneumonitis is a characteristic late effect of lung radiotherapy that occurs 6-12 months after treatment completion. C. The dose response curve for lung injury following whole lung irradiation is steep regardless of the dose per fraction used D. Lung toxicity is enhanced when radiation is combined with carboplatin-paclitaxel. E. Several cell types are involved in the development of pulmonary late effects, including the type II pneumocyte, the alveolar macrophage and vascular endothelial cells.

B. Radiation pneumonitis is a characteristic late effect of lung radiotherapy that occurs 6-12 months after treatment completion. Radiation pneumonitis is a characteristic late effect of lung radiotherapy that occurs approximately 2-3 months after treatment completion. In patients receiving concurrent chemoradiation therapy for non-small cell lung cancer, the risk of fatal pneumonitis for V20 = 20-29.9% is 1% V20 = 30-39.9% is 2.9% V20 ≥ 40% is 3.5% The volume of lung irradiated has been shown to be a particularly critical factor with respect to the degree of pulmonary toxicity observed (Answer Choice A). Many radiation oncologists are using the V20 or V30, the volume of lung receiving 20 or 30 Gy, as a defining limiting factor. Regarding lung tolerance dose, as expected, large single doses to the entire lung induce steep dose responses, with incidences of radiation pneumonitis being reported at ~5% following 8.2 Gy, but rising to 50% following 9.3 Gy (Answer Choice C). With increasing fractionation, higher total doses can be tolerated, yet the dose response curves remain steep, with a reported 5% incidence following a dose of 26.5 Gy, rising to a 50% probability when the total dose is increased to 30 Gy, the latter frequently being observed in the pediatric population. Tolerance doses are affected significantly by a broad range of chemotherapeutic agents, which have been shown to act synergistically or independently to enhance toxicity (Answer Choice D). Laboratory animal models have identified multiple cell types that appear to play critical roles in the development of radiation-induced late effects in the lung (Answer Choice E).

Exponentially growing cells were maintained at 37oC in 95% air/5% CO2 and irradiated with either a single dose of 8 Gy of X-rays or two 4 Gy fractions separated by either 2 hours or 8 hours. The surviving fractions for the three treatments were 0.02, 0.15, and 0.08, respectively. The two processes that best account for these differences in survival are: A. Reassortment and repopulation B. Repair and reassortment C. Reoxygenation and repair D. Repopulation and reassortment E. Repair and reoxygenation

B. Repair and reassortment Compared to the cell surviving fraction after the single 8 Gy dose, the increase in cell survival noted for the two 4 Gy doses delivered with a 2 hour interfraction interval was due to sublethal damage repair (SLDR). Although SLDR also occurred when the interfraction interval was 8 hours, cells surviving the first dose also reassorted from the radioresistant phases they were in at the time of the initial irradiation (e.g. late S) into more radiosensitive phases (e.g. G2 and M), thereby resulting in an overall surviving fraction for the 8 hour interval that was lower than that for the split dose protocol with a 2 hour interval between fractions. It is unlikely that much repopulation would take place during the total time of 8 hours needed to complete the irradiations. Reoxygenation would not be an issue for cells maintained in a well-aerated 95% air environment.

Sulfhydryl radioprotectors reduce radiation-induced toxicity by: A. Preventing the formation of free radicals B. Scavenging free radicals C. Stimulating host immune responses D. Inhibiting ion pair formation E. Increasing intracellular oxygen

B. Scavenging free radicals Sulfhydryl radioprotectors reduce radiation toxicity by scavenging free radicals. Amifostine, the only FDA approved radioprotector, is a prodrug that is hydrolysed in vivo by alkaline phosphatase to the active sulfhydryl compound, WR-1065.

Following a total body dose of 12 Gy, an exposed individual will not show the bone marrow syndrome because: A. Single Dose - Higher doses than 12 Gy are needed to cause the bone marrow syndrome B. Single Dose - The individual will likely die within 5-16 days from the GI syndrome, before overt symptoms of the bone marrow syndrome occur C. Single Dose - This dose is not sufficiently high to cause any radiation syndrome D. Single Dose - A bone marrow transplant will likely have been given and would mask the symptoms of the bone marrow syndrome E. At this dose the radiation syndrome prodrome will be so severe it will overshadow the bone marrow syndrome

B. Single Dose - The individual will likely die within 5-16 days from the GI syndrome, before overt symptoms of the bone marrow syndrome occur Following a total body dose of 12 Gy, an irradiated individual will likely die within 5-16 days from the GI syndrome. Thus, death will occur before the symptoms of the bone marrow syndrome are manifest, usually starting at about 20 days and resulting in death at 30-60 days. The bone marrow syndrome, resulting from damage to bone marrow stem cells, occurs after doses in the 2-8 Gy region.

The following conditions have been reported after high-dose human embryonic/fetal irradiation, EXCEPT: A. Microcephaly B. Spina bifida C. Mental deficiency D. Cardiac abnormalities E. Ear abnormalities

B. Spina bifida Spina bifida is a neural tube defect typically associated with folate deficiency, not ionizing radiation exposure.

Antigen recognition by T cells is imperative for the development of cellular adaptive immunity. How does a T cell recognize an antigen? A. T cells recognizes antigens via pattern recognition receptors B. T cells recognizes antigenic determinants presented in the MHC cleft by the T cell receptor C. T cells recognize antigens via the Fc receptor binding to membrane-bound IgD antibodies D. T cells recognize antigens via PD-1 binding

B. T cells recognizes antigenic determinants presented in the MHC cleft by the T cell receptor The surface of each T cell has approximately 30,000 antigen-receptor polypeptide chains, T-cell receptor α (TCRα) and β (TCRβ), that are linked by a disulfide bond. The TCR is very similar in structure to the Fab fragment of an immunoglobulin molecule and account for antigen recognition by most T cells. A minority of T cells has an alternative, but structurally similar, receptor made up of a different pair of polypeptide chains designated γ and δ. Unlike B cells, which can recognize a protein antigen in its native state, T cells recognize an antigen via the TCR only after it has been processed into peptides and loaded onto major histocompatibility complex (MHC) molecules. During the endogenous antigen presentation pathway (performed by the majority of cells), an intracellular antigen is degraded by the proteasome into peptides (typically 9-10 amino acids long) and then loaded onto MHC class I molecules in the Endoplasmic Reticulum (ER). In the exogenous pathway, an extracellular antigen is taken up by antigen presenting cells (APCs) and degraded into peptides (typically 11-19 amino acids long) within endosomes and then bound to MHC class II molecules. In both pathways, full MHC-peptide complexes are transported to the cell surface for recognition by the TCR on CD8+ cytotoxic T cells (MHC I) or CD4+ T helper cells (MHC II). Cross-presentation is the display of peptides from extracellular antigens on MHC class I and is only performed by APCs.. Pattern recognition receptors (PPRs) such as Toll-like receptors (TLRs) are predominantly found on APCs and other innate immune cells and are used for the detection of danger signals such as pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). The engagement of PPRs initiates the maturation of APCs, especially dendritic cells, thereby allowing them to stimulate T cells by providing the first signal (signal 1: antigen) to the TCR and the second signal (signal 2: co-stimulation) to CD28, which then amplifies signal 1. PD-1 is an immune checkpoint that inhibits proximal signaling of the TCR by sequestering Src Homology Region-Containing Protein Tyrosine Phosphatase-2 (SHP-2) and facilitating Csk-mediated inhibitory phosphorylation of Lck.

What is the most probable range of cell cycle time (Tc) and tumor doubling time (Td) for human tumors? A. Tc, 1 to 5 days and Td, 20 to 30 days B. Tc, 1 to 5 days and Td, 40 to 100 days C. Tc, 0.5 to 1 days and Td, 20 to 30 days D. Tc, 0.5 to 1 days and Td, 40 to 100 days E. Tc, 1 to 2 days and Td, 120 to 300 days

B. Tc, 1 to 5 days and Td, 40 to 100 days The volume doubling time (TD) of human tumors is characteristically 40 to 100 days, while the cell cycle time is relatively short, generally between 1 to 5 days. This has important implications, which often are overlooked, in the use of cell cycle-specific chemotherapeutic agents or radiosensitizing drugs for which it is the cell cycle time that is relevant.

Which of the following statements regarding cell death following radiotherapy is TRUE? A. The majority of solid epithelial tumors regress during treatment because of radiation-induced apoptosis B. The intrinsic apoptotic pathway can be triggered either by radiation-induced DNA damage or by sphingomyelin-mediated damage to the outer plasma membrane C. A novel drug that abolishes the G1 checkpoint would be expected to reduce the incidence of mitotic catastrophe in irradiated cells. D. Cells that undergo replicative senescence following radiotherapy are characterized by increased membrane blebbing and DNA fragmentation E. The presence of -H2AX histone foci in irradiated cells is indicative of sphingomyelin activation

B. The intrinsic apoptotic pathway can be triggered either by radiation-induced DNA damage or by sphingomyelin-mediated damage to the outer plasma membrane The intrinsic apoptotic pathway can be triggered either by damage to DNA or by damage to the plasma membrane. Radiation acts directly on the plasma membrane, activating acid sphingomyelinase, which generates ceramide by enzymatic hydrolysis of sphingomyelin. Ceramide then acts as a second messenger in initiating an apoptotic response via the mitochondrial system. Mitotic catastrophe, and not apoptosis, is the major mechanism of cell death in epithelial tumors in response to radiation. Inhibition of the G1 checkpoint in irradiated cells may increase the probability of mitotic catastrophe since cells are more likely to enter mitosis with damaged chromosomes. Radiation-induced senescent cells cease dividing and can remain metabolically active for extended periods before dying, but do not show membrane blebbing and DNA fragmentation, which are characteristic of apoptosis. g-H2AX foci noted in the nuclei of irradiated cells are indicative of the presence of DNA double-strand breaks - phosphorylated by ATM after ATM autophosphorylation and complete activation by the mrn complex (mre11,NBS1,rad50)

Which of the following statements is TRUE concerning irradiation of the salivary glands? A. Serous acinar cells die only by mitotic catastrophe after irradiation B. The serous acinar cells of the parotid and submaxillary glands are considered the target cells for radiation-induced salivary gland damage C. Salivary dysfunction is a late radiation effect rarely observed earlier than six months following treatment D. Mucous cells are more radiosensitive than serous cells E. Dose fractionation results in significant sparing of serous cells

B. The serous acinar cells of the parotid and submaxillary glands are considered the target cells for radiation-induced salivary gland damage The serous acinar cells of the parotid and submaxillary glands are considered to be the targets for radiation-induced salivary gland damage. Serous acinar cells typically die by apoptosis and not mitotic catastrophe following irradiation. Salivary dysfunction is an early radiation response that often begins while radiotherapy is still ongoing. Mucous cells are more radioresistant than serous cells (think saliva gets thicker during radiation, mucous cells still doing their job). Fractionation results in relatively little sparing from radiation-induced killing of serous cells, as is typical for cells with a pro-apoptotic tendency.

Paclitaxel appears to be effective in radiosensitizing tumors in vivo for all the following mechanisms, EXCEPT: A. Induction of apoptosis B. Upregulation of HIF-1 C. Oxygenation of radioresistant hypoxic cells D. Arrest of cells in the radiosensitive G2/M phase E. Decrease of interstitial fluid pressure

B. Upregulation of HIF-1 Paclitaxel stabilizes microtubule polymers and protects them from disassembly. As a result, mitosis is consequently blocked and apoptosis is activated. Paclitaxel has been shown to increase the radiation sensitivity of tumors by inducing apoptosis, increasing oxygenation of hypoxic cells in tumors, arresting cells in the radiosensitive G2/M phase of the cell cycle, and decreasing interstitial fluid pressure. Some of these studies have been conducted in animal models while others have been performed in clinical trials of human breast cancer patients. No studies have demonstrated upregulation of HIF-1 following treatment with paclitaxel; indeed, one might expect HIF-1 to be degraded more rapidly following reoxygenation.

A human disorder thought to be due to a DNA repair deficiency is which of the following: A. Lesch-Nyhan syndrome B. Xeroderma pigmentosum C. Tay-Sachs disease D. Phenylketonuria E. Down syndrome

B. Xeroderma pigmentosum

BLM protein = ?

BLOOM syndrome protein (gene is REQCL3 - this is a 3'-5' helicase) bloom think high rate of sister chromatid exchange, hyperrecombination, failure to dissolve holiday junctions

One hallmark of the apoptotic process is the display of phosphatidylserine residues on the outer surface of the plasma membrane. This is an important event in terms of the tissue response to ionizing radiation because it: A. Helps recruit death ligands expressed by neighboring cells to receptors on the cell surface B. Stimulates an inflammatory response to remove dying cells from the tissue= C. Signals the recruitment of phagocytes that engulf the dying cells without causing an inflammatory response D. Is required for DNA condensation and fragmentation E. Leads to increased ceramide levels

C Apoptosis helps maintain tissue homeostasis because cells that are undergoing an apoptotic response recruit phagocytes that clear the dying cells, also known as "apoptotic corpses", from the tissue without stimulating an inflammatory response. In fact, uptake of apoptotic cells by macrophages can actually lead to the release of anti-inflammatory mediators such as TGF-β and IL-10, and the attenuation of the RIG-I/IRF-3 pathway and the cGAS/STING pathway through proteolytically inactivating RIP kinase 1 or the degradation of cytoplasmic DNA. As a result, apoptosis can decrease the expression of interferons and other inflammatory factors. Of note, the concept that apoptosis is entirely non-inflammatory isn't always strictly true. An example is the induction of apoptosis in hepatocytes following FAS activation that causes a strong inflammatory response probably because they can't get cleared fast enough by phagocytes. The exposure of phosphatidylserines (phospholipids) on the exterior of the plasma membrane is the signal that initially recruits phagocytes. Ordinarily, phosphatidylserine is sequestered within the phospholipid bilayer and is not displayed on the cell's surface. The process of necrosis, which involves rupture of the cell membrane and the leakage of cellular contents into the surrounding tissue, does elicit an inflammatory response. While DNA condensation and fragmentation are important steps in the apoptotic process, they are not coordinated directly through the exposure of phosphatidylserine on the plasma membrane. A number of stimuli lead to increased ceramide levels, including TNF, FasL and ionizing radiation, but not phosphatidylserine.

Which of the following statements about tirapazamine is FALSE? A. A trial examining the utility of the drug in the definitive treatment of locally advanced cervical cancer was conducted but failed to fully accrue due to lack of drug availability. B. Addition of tirapazamine failed to improve 2-year overall survival in head and neck patients treated with cisplatin-based chemoradiation compared to chemoradiation alone without tirapazamine. C. The use of tirapazamine was not associated with higher rates of esophagitis in limited stage small cell lung cancer patients treated with definitive chemoradiation compared to historical controls. D. In GOG 219, tirapazamine increased gastrointestinal toxicity while having no effect on progression free survival.

C In the SWOG 0222 trial, tirapazamine was associated with higher rates of esophagitis compared to historical estimates. Tirapazamine was developed as a hypoxic cytotoxin to potentially enhance tumor responses and showed promise in single-arm phase II trials in several disease sites. However, the phase III trials failed to show efficacy above the control arms. These include GOG 219, which examined the efficacy of the drug when added to standard chemoradiation for locally advanced cervical cancer. The trial failed to accrue due to lack of drug availability. Of a planned accrual of 750 patients, only 379 were eligible and evaluable; no difference in overall or progression-free survival was seen, but there was an increase in grade 3+ leukopenia, GI toxicity, and hepatic/renal dysfunction. The TROG examined tirapazamine's utility and safety in head and neck cancers in the HeadSTART TROG 02.02 Trial. There was no overall survival or failure-free survival benefit of tirapazamine when added to cisplatin-based chemoradiation in this trial. The authors reported more frequent muscle cramps, diarrhea, and skin rash in the experimental arm.

Which statement regarding radiation-induced nuclear foci is correct? A. ATR is the main apical kinase that responds to radiation-induced double-strand breaks B. ERCC1-containing foci indicate the presence of radiation-induced single-strand breaks C. Gamma-H2AX foci can be detected within 15 minutes of radiation exposure D. p53 forms ATR-dependent foci within minutes of radiation exposure

C One important characteristic of the cellular response to DNA lesions is the spatiotemporal manner by which repair and other proteins are recruited to the site of damaged DNA. Frequently, these protein accumulations can be visualized as subnuclear "foci" using immunofluorescence microscopy. Ionizing radiation-induced DNA double-strand breaks activate ATM kinase, which phosphorylates multiple damage response and repair proteins. ERCC1 (think Cockayne sydnrome) is involved in nucleotide excision repair, in addition to roles in homologous recombination and replication fork repair but does not form subnuclear foci. Histone H2AX is phosphorylated by ATM within 15 minutes after irradiation and can be visualized using a phospho-specific antibody. These gamma-H2AX foci are regarded a marker for radiation-induced DNA double-strand breaks in cells. p53 itself does not form foci, though specific ATM-dependent phospho-forms of p53 might be detected as foci. ATM functions in response to double strand breaks. By contrast, ATR is activated during every S-phase to regulate the firing of replication origins, the repair of damaged replication forks and to prevent the premature onset of mitosis. Although ATR is activated in response to many different types of DNA damage including double strand breaks (DSB), a single DNA structure that contains a single-stranded DNA may be responsible for its activation. Furthermore, p53 does not form ATR-dependent foci.

The mechanism of the radiation bystander effect is thought to involve all of the following, EXCEPT: a. Communication through gap junction b. Presence of reactive oxygen species c. Aberrant signaling in cancer cells d. Extracellular signaling molecules e. Involvement of specific cytokines

C The bystander effect has been documented in both cancer cell lines and normal, untransformed cells, with no indication that abnormal cellular signaling plays a role. The use of chemical gap junction inhibitors and connexin knock-out cells has shown a large inhibitory effect on bystander endpoints, as has the use of radical scavengers. Some aspect of bystander signaling however, is transmissible through medium transfer, and extracellular molecules such as TGF-beta have been implicated.

Which of the following pairs of photon energy and predominant atomic interaction at the specified photon energy is correct? A. 1 keV - pair production B. 50 keV - triplet production C. 100 keV - compton process D. 2 MeV - photoelectric effect

C The predominant atomic interaction for 100 keV photons is the Compton process. Sources provide different answers on minimum energy for triplet production with some stating 2mC2 (1.02 MeV) and some stating 4mC2 (2.04 MeV) The photoelectric effect is predominant for photon energies in the range of 10 keV.

Which one of the following assays would be the most appropriate to use for quantitative measurement of DNA double-strand breaks (DSBs) in cells immediately following exposure to ionizing radiation? A. Alkaline elution B. Western blotting C. Neutral comet assay D. PCR E. BrdU incoporation assay

C - The neutral comet assay is used to measure DNA double-strand breaks (DSBs). The comet assay is the electrophoresis of single-cells in order to detect DNA damage and its repair. Cells are exposed to ionizing radiation, embedded in agarose, and then subjected to an electrical gradient to move the DNA into the gel. The negatively charged DNA in the cell moves through the agarose toward the positive electric pole. If there are no breaks, the cell's DNA moves all together in a small ball. Double-strand DNA breaks creates DNA fragments that are smaller than the unbroken DNA and migrate further into the agarose making what appears like a comet's tail. Alkaline conditions cause the separation of the two strands of the DNA helix and allows the visualization of DNA fragments created by both double-strand and single-strand DNA breaks. In neutral pH conditions, the DNA helix is intact so single-strand breaks do not result in separate fragments and you can only see the fragments created by double-strand DNA breaks.

Which of the following statements concerning tumor angiogenesis is TRUE? A. Even without angiogenesis, tumors can grow up to 2 cm in diameter 42 B. For most tumor types a high microvessel density has been negatively correlated with metastatic spread C. Vascular endothelial growth factor (VEGF) is induced under hypoxic conditions D. Angiostatin and endostatin are stimulators of angiogenesis E. Basic fibroblast growth factor (bFGF) is a negative regulator of angiogenesis

C - Vascular endothelial growth factor (VEGF) is induced under hypoxic conditions Expression of vascular endothelial growth factor (VEGF) and downstream angiogenesis is induced under hypoxic conditions via hypoxia-inducible transcription factors that bind to the VEGF promoter to stimulate its transcription. In the absence of angiogenesis, tumors would only be expected to reach a diameter of about 2 mm, not 2 cm (Answer Choice A). Microvessel density, a measure of angiogenesis, has been correlated positively with metastatic spread for most tumor types (Answer Choice B). Angiostatin and endostatin are inhibitors of angiogenesis while basic fibroblast growth factor (bFGF) is a positive regulator of angiogenesis (Answer Choice D and E).

Which of the following statements is TRUE concerning SLDR and PLDR? a. As the dose rate is reduced and exposure time increased for an X-ray treatment, the biological effectiveness of a given dose of radiation increases b. PLDR is best demonstrated with a split dose experiment c. There is an inverse correlation between the /ratio of an acute dose X-ray survival curve and the amount of SLDR in a fractionated irradiation d. The magnitude of PLDR and SLDR is greater following exposure to high LET compared to low LET radiation e. PLDR plays an important role in the decreased survival seen with fractionated irradiation to the normal lung as compared to lung cancer cells

C Cell lines whose X-ray survival curves have low /ratios generally display a large capacity for SLDR, whereas cells whose X-ray survival curves have high /ratios show relatively little SLDR. As the dose rate is lowered and exposure time increased, the biological effect of an X-ray dose diminishes due to SLDR. PLDR is best demonstrated with a "delayed plating" experiment, and is operationally defined as an increase in the surviving fraction resulting from prolonged incubation of cells under non-growth conditions following irradiation. There is little or no SLDR or PLDR following exposure to high LET radiation. Fractionated irradiation would be expected to increase survival (not decrease it) in normal lung tissue compared to lung cancer cells, and this would result from SLDR, not PLDR.

Which of the following statements concerning the interaction of photons with matter is CORRECT? A. The probability of the photoelectric effect decreases with the atomic number of the absorber B. The predominant interaction of 10 keV photons with soft tissue is the Compton process C. In the Compton process, the energy of the scattered photon is less than that of the incident photon D. Pair production occurs for photons with energies less than 1.02 MeV E. There is only partial absorption of the energy of the incident photon in the photoelectric effect

C In the Compton process, the energy of the scattered photon is less than that of the incident photon In the Compton process, a photon interacts with an atom causing the ejection of an orbital electron. The incident photon, now with reduced energy, continues along a deflected path. The probability of the photoelectric effect increases with the atomic number of the absorber (Ansswer Choice A). The predominant interaction of 10 keV photons in soft tissue is the photoelectric effect (Answer Choice B). Pair production occurs for photons with energies greater than 1.02 MeV and results in the complete conversion of the photon's energy into the production of a positron and electron (Answer Choice D). For the photoelectric effect, there is complete absorption of the photon's energy, resulting in ejection of an electron that possesses kinetic energy equal to the difference between the incident photon's energy and the electron's binding energy (Answer Choice E).

For a given biological system, the D37 in the presence of O2 was determined to be 2 Gy for a particulate radiation of energy A and 1 Gy for the same particle with energy B. Under hypoxic conditions, the D37 was 6 Gy for A and 1.5 Gy for B. Which of the following statements best describes the relationship between the two radiations? a. Radiation A has a higher LET than type B. b. The OER for radiation A is 2. c. If a given dose of radiation B was delivered at a low dose rate, the amount of cell killing would not differ markedly from that produced at a high dose rate. d. Radiation B likely has a higher energy than radiation A. e. None of the above Multiple concepts packed into this one question.

C Radiation type B likely has a higher LET than type A since less of an oxygen effect was observed for type B. Thus, if the radiation delivered by type B was delivered at a low dose rate allowing for reoxygenation, the amount of cell killing would not differ substantially from that produced at a high dose rate. The OER for radiation type A is 3.0 since three times the dose was required to produce the same biological effect (D37) for the cells under hypoxic conditions than aerated conditions. Since types A and B are the same form of ionizing radiation, then type B would likely be lower energy than type A since LET is inversely proportional to energy of the particle.

Using the linear-quadratic survival curve model, what would the cell surviving fraction be following a dose of 2 Gy delivered acutely (use =0.3 Gy-1 and =0.1 Gy-2)? A. 0.01 B. 0.10 C. 0.37 D. 0.50 E. 0.90

C. 0.37 note: α = 0.3 Gy^-1 and β = 0.1 Gy^-2 corresponds to an α/β of 3 Gy. Using the equation S = e^-(αD+βD2) the surviving fraction would be: e-[(0.3)(2)+(0.1)(2)2] = e-[(0.6)+(0.4)] = e-1= 0.37

Once a pregnancy is declared, the maximum permissible dose to the fetus is: A. 0.005 mSv per month B. 0.05 mSv per month C. 0.5 mSv per month D. 5 mSv per month E. 50 mSv per month

C. 0.5 mSv per month Once a pregnancy is declared, the maximum permissible dose to the fetus is 0.5 mSv per month subsequent to this declaration. Prior to declaration, there are no special limits except for the general limits for radiation workers.

A conventional treatment for a particular type of tumor is 25 fractions of 2 Gy delivered once per day. A hyperfractionated regimen is proposed that would consist of 1.2 Gy fractions delivered twice per day. What would be the approximate therapeutic gain in changing from the standard to hyperfractionated schedule if both were designed to produce the same probability of late complications? (Assume that there is no tumor cell repopulation during treatment, full repair of sublethal damage occurs, the tumor has an a/b ratio of 10 Gy and the normal tissue has an a/b ratio of 2 Gy.) A. 0.8 B. 1.0 C. 1.2 D. 1.4 E. 1.6

C. 1.2 The BEDs for the standard protocol are 60 Gy10 and 100 Gy2, respectively, for the tumor and late-responding normal tissue, as determined from the equation: 𝐵𝐸𝐷=𝑛𝑑 ⌊1+ 𝑑(𝛼/𝛽)⌋ Assuming the BED of 100 Gy2 for the normal tissue is maintained for the hyperfractionated protocol, this would correspond to a total dose of 1.2 Gy per fraction multiplied by 52 fractions, or 62.4 Gy. Putting these values into the BED equation for the tumor, the BED would increase from 60 Gy10 for the standard treatment, to 70 Gy10 for the hyperfractionated treatment. The therapeutic index (TI), BEDtumor-hyperfractionated/BEDtumor-standard divided by BEDnormal-hyperfractionated /BEDnormal-standard, equals 70 Gy10/60 Gy10/100 Gy2/100 Gy2 = 1.2.

A woman begins working at a nuclear power plant on her 18th birthday. According to current NCRP guidelines, once she reaches her 20th birthday she will have been permitted a total work-related lifetime effective dose equivalent of: A. 5 mSv B. 50 mSv C. 100 mSv D. 200 mSv E. 300 mSv

C. 100 mSv A radiation worker is permitted either 50 mSv per year for each year that the person was engaged in radiation work or else a lifetime dose equal to his/her age multiplied by 10 mSv, whichever is less. Based on the lifetime dose rule, this woman would have been permitted 200 mSv as of her 20th birthday. The 50 mSv per year rule dictates that her maximum allowable dose would be only 100 mSv.

The survival curve for a cell population irradiated with a form of high LET radiation is characterized by a D10 of 3 Gy. For a starting population of 10^8 cells, approximately how many cells will survive when a single dose of 18 Gy is given? A. 10^0 B. 10^1 C. 10^2 D. 10^3 E. 10^4

C. 10^2 For high LET radiation it can be assumed that the survival curve is exponential, or near exponential, and cell survival can be modeled using the single-target, single-hit equation (S = e), or the simplified form of the linear quadratic equation in which beta is zero (S = e-alphaD). Using either of these equations, 3 Gy reduces the surviving fraction to 10^-1, and a dose of 18 Gy therefore would reduce survival to 10^-6. Therefore, irradiating 10^8 cells with 18 Gy would result in the survival of: (10^8 cells) x (10^-6 surviving fraction) = 10^2 cells. Important to remember when throwing around alpha and beta components of kill. Just remember alpha is single particle causing hit and lethality and beta is when that hit requires two tracks. This is a process that is dependent on higher dose to happen - and at lower doses, SLDR can usually fix this - at higher doses it can't. That's why both terms of incorporated to give you a linear appearing curve at high doses when beta is contributing more to cell kill. At either slow dose rates or high LET radiation the beta component is contributing less to cell kill and the simplified linear portion can be used (S = e^-aD).

Of the fatal cancers that develop among patients previously treated with total body irradiation, approximately what percentage are leukemias? A. 0.1% B. 2% C. 15% D. 40% E. 80%

C. 15% Approximately 15% of the fatal cancers dignosed among patients previously treated with total body irradiation are leukemias.

What is the approximate maximum diffusion distance of oxygen from a normally-oxygenated capillary through a typical respiring tissue? A. 5 nm B. 15 um C. 200 um D. 900 um E. 2.6 mm

C. 200 um -- zeeman say 70 um (but this is the closest one to that, so whatever, close enough) In a typical respiring tissue, the approximate distance that oxygen can diffuse from a normally oxygenated capillary before cellular hypoxia is detectable is ranges from approximately 70-200 μm. The oxygen diffusion distance will depend on the partial pressure of oxygen in the capillary and on the rate of oxygen consumption by the tissue, and therefore shows some variability. Thomlinson and Gray measured 150 μm in their landmark experiments in 1955. Olive et al. (IJROBP 1992) determined that the maximum oxygen diffusion distance using solid tumor cubes incubated with fluorescent probes and found it to range from 107 um to 192 μm, depending on the cell line. Torres Filho et al. (Proc. Natl. AcadUSA 1994) measured in vivo oxygen concentration in a SCID mouse model and found hypoxia to occur at distances >200 μm.

When irradiating a cell population with a dose that causes an average of one lethal event per cell, this will likely result in a survival fraction of: A. 0% of cell survival. B. 10% of cell survival. C. 37% of cell survival D. 63% of cell survival E. 100% of cell survival

C. 37% of cell survival When the irradiated cell population receives an average of 1 lethal hit, it results in 37% cell survival based on Poisson statistics.

Which of the following fractionation schedules would likely produce the highest incidence of late normal tissue toxicity? (Assume a/b = 2 Gy for the critical normal tissue injury) A. 20 Gy in 4 fractions over 1 week B. 24 Gy in 6 fractions over 2 weeks C. 45 Gy in 15 fractions over 3 weeks D. 50 Gy in 25 fractions over 5 weeks E. 60 Gy in 60 fractions over 6 weeks

C. 45 Gy in 15 fractions over 3 weeks Since the focus of this question concerns late effects, the overall treatment time (a maximum of 6 weeks) should not be an important determinant of outcome. The BEDs calculated for each of the different fractionation schedules are 70, 72, 113, 100 and 90 Gy2, respectively. The protocol of 45 Gy delivered in 15 fractions results in the greatest value for BED and, therefore, should be the most likely to produce late normal tissue complications. This illustrates the point that both fraction size and total dose play important roles in determining the probability of late effects.

Which of the following total doses, given as daily 1.5 Gy fractions, is approximately equivalent to a conventional schedule of 30 fractions of 2 Gy for late normal tissue reactions? Assume the / ratio is equal to 3 Gy. A. 53 Gy B. 60 Gy C. 67 Gy D. 75 Gy E. 81 Gy

C. 67 Gy Can use BED formula or EQD2 here Just means BED1 = BED2 and solve for dose 2 or EQD2 = 60 = D[(d+a/b)/(2+a/b) --> solve for D This can be calculated using the linear-quadratic formula that allows comparison of two different fractionation schedules and the resulting relative biological effective dose (BED). 𝐵𝐸𝐷=𝑛𝑑 ⌊1+ 𝑑(𝛼/𝛽)⌋ n - number of fractions d - dose per fraction a and b - tissue specific dose response curve parameters If the two schedules are isoeffective, BED1 = BED2, which reduces to n1d1/n2d2 = (a/b+d2)/(a/b+d1).

For individuals accidentally exposed to radiation, a bone marrow transplant is potentially useful when the radiation dose is within a narrow range. That dose window is approximately: A. 1-2 Gy B. 3-4 Gy C. 8-10 Gy D. 15-20 Gy E. Bone marrow transplants have no potential usefulness at any dose

C. 8-10 Gy Bone marrow transplants are only useful when the radiation dose to the exposed person is within about 8-10 Gy. At lower doses, an exposed person will likely survive with appropriate medical care. For doses above 10 Gy death from effects on the GI tract will occur even despite use of all effective currently available treatments.

Mental retardation as a result of radiation exposure in utero is most likely to occur when the radiation is given during which weeks of gestation? A. 0-4 weeks B. 5-8 weeks C. 8-15 weeks D. 16-25 weeks E. 26-40 weeks

C. 8-15 weeks Radiation exposure during weeks 8-15 of gestation is mostly likely to cause mental retardation (MR) compared to the other periods of gestation. The incidence of severe MR has been found to be linear during this period of time, with a risk coefficient of 0.4 per Gy. During weeks 16-25, the risk has been found to be lower (by approximately 4-fold). A dose threshold of 0.3 Gy to appreciate development of MR has previously been reported. Mental retardation is thought to be secondary to effects of radiotherapy on neural cell migration.

An employee working in a nuclear power plant is accidentally exposed to a total body -ray dose of 2 Gy. Ten days after the accident, you draw blood and submit it for hematologic analysis. Which of the following would you expect to see? A. A decrease in hemoglobin concentration and platelet counts B. A decrease in platelet count and an increase in lymphocyte count C. A decrease in lymphocyte count, but no effect on hemoglobin concentration D. An increase in neutrophil count, but no effect on hemoglobin concentration E. No effect on lymphocytes, hemoglobin, neutrophils or platelets

C. A decrease in lymphocyte count, but no effect on hemoglobin concentration Ten days after a total body dose of 2 Gy, one would expect lymphocyte and neutrophil counts to decrease, but hemoglobin concentration and platelet counts to remain normal. Platelets will not decrease until ~20 days after a 2 Gy exposure. Hemoglobin will not decrease unless much higher doses are received and a longer time period has elapsed.

What is the function of the LAG-3 molecule? A. LAG-3 is a tyrosine kinase receptor located on the cell surface. B. Acetylation of histones. C. A negative regulator of the immune system. D. Regulates p53 function.

C. A negative regulator of the immune system. LAG-3 (Lymphocyte-activation gene 3, CD223) is a cell surface molecule present on T cells and other various immune system cells. LAG3's main ligand is MHC class II. LAG-3's physiological function appears to be as an immune checkpoint receptor (i.e. negatively regulation of T cell proliferation and activation) in a similar fashion to CTLA-4 and PD-1. Ongoing trials suggest that LAG-3 and PD-1 synergistically regulate T-cell function in such a way as to allow an anti-tumoral immune response to be blunted effectively by inhibiting both pathways.

Which chemical or compound CANNOT be used to mitgate hypoxia-related radioresistance? A. Nicotinamide and carbogen B. Perfluorocarbon C. Amifostine D. Misonidazole E. Nimorazole

C. Amifostine Amifostine is a drug whose active metabolite contains a sulfhydrl moiety and acts as a free radical scavenger. It has been studied as a radioprotectant in several clinical and preclinical settings. As a radioprotectant, it does not sensitize hypoxic cells. Carbogen is a mixture of 95% oxygen and 5% carbon dioxide and has been used to mitigate chronic hypoxia. Nicotinamide, used concurrently with carbogen, is intended to mitigate acute intermittent hypoxia seen in tumor vessels by preventing intermittent vessel closure (Answer Choice A). Perfluorocarbons such as perflubron have been shown to improve tumor oxygenation in preclinical cancer models but have not yet shown clinical utility. Both misonidazole and nimorazole are nitroimidazoles that have radiosensitizing properties in hypoxia cells (Answer Choice E).

Which of the following statements concerning amifostine is TRUE? A. Amifostine is most effective when administered orally B. Amifostine's dose-limiting toxicity is peripheral neuropathy C. Amifostine does not readily cross the blood-brain barrier D. Maximum radioprotection against acute toxicities is achieved when amifostine is administered after irradiation E. Amifostine does not require metabolic activation for its activity as a radioprotector

C. Amifostine does not readily cross the blood-brain barrier Amifostine does not readily cross the blood brain barrier and therefore affords little radioprotection to tissues in the CNS. Amifostine must be administered intravenously for maximal efficacy (Answer Choice A). Hypotension, nausea/vomiting, fatigue, and fever/rash are the main toxicities associated with amifostine (Answer Choice B). Amifostine should be administered 15-30 minutes before radiotherapy, not after (Answer Choice D). It is a pro-drug that is metabolized by alkaline phosphatase to the free thiol metabolite that acts as the direct radioprotective agent (Answer Choice E).

Which of the following substrates and target sites of the ATM kinase are implicated in the control of the G2-checkpoint in irradiated cells? A. CHK2 (CHEK2) and MDM2 B. NBS1 (NBN) and CHK2 49 C. CHK2 and CDC25C D. CHK2 and p53 (TP53) E. PUMA and p53 (TP53)

C. CHK2 and CDC25C Regulation of the G2 checkpoint by ATM is thought to occur via the activation of CHK2, which phosphorylates CDC25C phosphatase thereby preventing it from dephosphorylating CDK1 (CDC2), a step necessary for the progression from G2 into M phase. The remaining proteins listed are all targets for phosphorylation by the ATM kinase, and, consequently, are implicated in various cell cycle control pathways although not the G2 checkpoint. CHK2 and MDM2 are involved in control of the G1-S phase transition (Answer Choice A). ATM also phosphorylates MDM2, which reduces the ability of MDM2 to negatively regulate p53. NBS1 and CHK2 are implicated in S phase progression (Answer Choice B). Upon phosphorylation by CHK2, p53 is stabilized and causes cell cycle arrest in G1 (Answer Choice D). PUMA ("p53-upregulated modulator of apoptosis") is a pro-apoptotic gene that can induce cell death via a p53-dependent pathway.

Which of the following statements is CORRECT? Multi-drug resistance: A. Generally leads to cross-resistance to radiation B. Is often induced by pre-exposure to ionizing radiation C. Can be caused by either an increase in p-glycoprotein or other proteins that increase drug efflux D. Generally results in relatively small changes in sensitivity of cells or tumors to chemotherapy agents E. Is a transient response to intensive treatment and usually resolves within 4-6 weeks

C. Can be caused by either an increase in p-glycoprotein or other proteins that increase drug efflux Multi-drug resistance develops relatively frequently in cells and tumors exposed to chemotherapeutic agents. The primary mechanism by which this occurs is an increase in levels of p-glycoprotein or a different protein that non-specifically effluxes xenobiologics from cells. These multidrug resistant cells rapidly and efficiently efflux foreign molecules and thus maintain low, non-toxic intracellular drug levels even in the presence of high extracellular drug concentrations that would normally be lethal. Induction of multi-drug resistance by one drug can lead to resistance to a broad spectrum of related and unrelated drugs, which kill cells by different mechanisms. Cells or tumors that have become multi-drug resistant through this mechanism do not become radioresistant, as radiation cannot be effluxed (Answer Choice A). Radiation exposure does not cause multi-drug resistance (Answer Choice B). The differences in the sensitivity of multi-drug resistant and non-resistant cells can be very large, often producing differences of several orders of magnitude in survival for a given drug dose (Answer Choice D). Multidrug resistance represents a permanent change in the cell phenotype and is not transient (Answer Choice E). Other changes in tumor cells can also increase resistance to multiple drugs. For example, increased glutathione levels would increase resistance to a spectrum of drugs with a mechanism of action involving formation of radicals. Similarly, an increase in the activity of a DNA repair pathway could lead to the improved repair of drug damage and increased survival. Resistance from these mechanisms is not nearly as dramatic as the drug resistance induced by the efflux proteins described above, but is important to radiotherapy because the changes can also cause small increases in radioresistance.

What is the main reason for the great disparity between the cell cycle time of individual dividing cells and the overall doubling time of the tumor? A. Intratumor oxygen partial pressure (pO2) B. Growth fraction C. Cell loss factor D. Body temperature where the tumor grows E. Extra- and intra-cellular acidity (pH)

C. Cell loss factor The high rate of cell loss in human tumors largely accounts for the great disparity between Tc and the volume doubling time (TD).Values for the cell-loss factor vary from 0% to more than 90% for tumors in laboratory animals.

Which of the following pairs of cancer type and corresponding genetic alterations in that cancer is FALSE? A. Pancreatic — K-RAS B. Lung adenocarcinoma — ALK C. Colon — PTCH D. Thyroid — RET E. Melanoma - BRAF

C. Colon — PTCH Carcinogenesis is a multistep process with multiple genetic alterations occurring at particular stages of cancer progression. PTCH = basal cell skin carcinoma and medulloblastoma. EGFR and VEGF are frequently overexpressed in colon cancer, but their lack of a relationship with progression and survival has led to their prognostic value being questioned. For example, over 90% of human pancreatic cancers harbor an activating point mutation in the K-RAS gene at codon 12. Hereditary medullary thyroid carcinoma (MTC) is caused by autosomal dominant gain-of-function mutations in the RET proto-oncogene. BRAF mutation is present in 50% of cutaneous melanomas and provide the therapeutic target for vemurafenib. Alk mutation is present in ~5% of lung adenocarcinomas and provides a target for crizotinib.

At a distance of 150 μm from the nearest tumor blood vessel, one might expect all of the following microenvironmental conditions, EXCEPT: A. Increased hypoxia B. Decreased pH C. Decreased interstitial fluid pressure D. Decreased glucose

C. Decreased interstitial fluid pressure Solid tumors develop regions of increased hypoxia (decreased pO2), decreased pH, decreased glucose, and increased (not decreased) interstitial fluid pressure. Oxygen can diffuse about 70 μm from the arterial end of a capillary.

Which of the following is an example of a stochastic effect of exposure to high-dose radiation: A. Mental retardation following exposure of the fetus in utero B. Acute mucositis C. Development of breast cancer 20 years following exposure to radiation as a teenager D. Cardiac toxicity E. Cataracts

C. Development of breast cancer 20 years following exposure to radiation as a teenager Development of cancer after high dose radiation is an example of a stochastic effect. A stochastic effect fulfills two criteria: 1) the probability of an outcome of interest increases with increasing dose, typically without a threshold dose; and 2) the severity of an outcome of interest is not altered by dose (all or none) In contrast, deterministic effects, such as mental retardation, cardiac toxicity, cataracts and acute toxicity, have a threshold dose below which it does not occur and have increased severity with increased dose.

Which of the following pairs of transcription factors and genes they directly regulate is INCORRECT? A. HIF-1 and VEGF (VEGFA) B. p53 (TP53) and p21(CDKN1A) C. FOS and BRCA2 D. E2F and CDC25A E. p53 and PUMA

C. FOS and BRCA2 FOS is a transcription factor that has been shown to modulate a variety of genes involved in stress responses, but has not been shown to modulate BRCA2. HIF-1 is a hypoxia inducible factor known to regulate the expression of the VEGF gene and thus the regulation of angiogenesis (Answer Choice A). p53 is a transcription factor that induces expression of p21 (Answer Choice B). E2F is known to regulate a large number of proteins involved in cell cycle progression, including CDC25A (Answer Choice D). PUMA is the major mediator of p53-dependent apoptosis following ionizing radiation in most cell types. PUMA, a pro-apoptotic BH3-only member of BCL2 family protein promotes BAX/BAK and mitochondria-dependent apoptosis in various cell types (Answer Choice E).

Which of the following choices is considered to be a general conclusion from epidemiological studies of irradiated human populations? A. Most regulatory and advisory committees recommend that risk estimates derived from acute exposures be reduced by a Dose and Dose-Rate Effectiveness Factor (DDREF) of approximately 3-4 in order for these estimates to be properly applicable to chronic, low dose, and low dose-rate exposures B. Analyses of the Japanese A-bomb survivor data indicate that radiation risk is not dependent on gender C. For solid tumors in A-bomb survivors, a linear fit to the data is significantly better than a linear-quadratic fit D. Studies of populations living near nuclear power plants and exposed to elevated background radiation form our primary quantitative estimates of risk following exposure to radiation. Based on the BEIR VII estimates, human exposure to ionizing radiation accounts for a lifetime excess cancer risk (both fatal and non-fatal) of roughly 5% per 100 mSv

C. For solid tumors in A-bomb survivors, a linear fit to the data is significantly better than a linear-quadratic fit The risk estimates based on the Radiation Effects Research Foundation (RERF) analyses for solid tumors are well-fit using a linear model; a linear-quadratic model provides a much better fit to the leukemia dose response data. Although the BEIR VII Committee conducted an analysis of the data related to the DDREF, and uses a value of 1.5 for its own risk estimations, the factor of 2.0 has historically been applied to adjust for lower doses and dose-rates (Answer Choice A). RERF data clearly indicate that radiation risk is dependent on gender, as well as age at exposure and time since exposure (Answer Choice B). Population studies frequently have more limitations compared to more quantitative case-control studies, including smaller population sizes and uncertainties associated with dose estimations, confounding factors, and lack of relevant control populations (Answer Choice D). The BEIR VII estimates the lifetime additional cancer risk is about 1% following 100 mSv (Answer Choice E).

Which of the following statements concerning hyperthermia is TRUE? A. Heat-induced radiosensitization occurs because heat directly damages DNA B. Following exposure to hyperthermic conditions, heat shock proteins (HSPs) bind to and activate the heat shock transcription factor (HSF1). C. Hyperthermia leads to the activation of HSF1, which subsequently binds to HSE and increases expression of HSPs. D. Hyperthermia increases expression of HSPs, which bind to the HSE, leading to increased expression of HSF1. E. Heat-induced radiosensitization occurs secondary to HSP-mediated aggregation of nuclear proteins.

C. Hyperthermia leads to the activation of HSF1, which subsequently binds to HSE and increases expression of HSPs. At normal body temperature, heat shock proteins (HSPs), such as Hsp90 or Hsp70, are bound to heat shock transcription factor (HSF1), thereby keeping it in its inactive state. Following exposure to higher temperatures, HSPs dissociate from HSF1 in order to stabilize degenerated proteins. HSF1 is then activated and translocates into the nucleus to bind to Heat Shock Element (HSE), the promoter for HSPs, leading to enhanced transcription of the HSP gene. HSPs are molecular chaperones that bind to non-native or (partially) unfolded proteins and assist in their correct assembly by preventing their non-productive aggregation. An additional major mechanism for heat-induced radiosensitization is inhibition of the re-polymerization step in the repair of radiation-induced base damage. Heat therefore does not cause DNA damage directly (Answer Choices A and E). Hyperthermia leads to HSPs dissociating from HSF1, thereby leading to its activation (Answer Choice B). Hyperthermia leads to HSP dissociation from HSF1, which is then activated and binds to the HSE, leading to increased expression of HSPs (Answer Choice D). Heat-induced cell death may additionally occur by prompt apoptosis or by delayed death secondary to mitotic failure. In addition, apoptosis-resistant cells may die a necrotic death or die due to permanent cell cycle arrest following a heat treatment.

Which of the following best describes the mechanism of action of the chemotherapeutic agent, irinotecan? A. Inhibits ribonucleotide reductase B. Stimulates thymidylate synthase C. Interferes with the action of topoisomerase I D. Generates DNA crosslinks

C. Interferes with the action of topoisomerase I Irinotecan (Camptosar) is an inhibitor of the topoisomerase I enzyme. Its active metabolite, CPT-11, is a camptothecin analog that specifically inhibits DNA replication and transcription. Gemcitabine inhibits the ribonucleotide reductase enzyme (Answer Choice A). 5-Fluorouracil (5-FU) stimulates thymidylate synthase (Answer Choice B). Cisplatin is an example of an exogenous agent that causes formation of a covalent linkage (crosslink) between nucleotides of DNA (Answer Choice D). Other choices can include carmustine and mitomycin C.

Which of the following statements is TRUE concerning experimental support for the hypothesis that late-responding tissues have lower a/b ratios than early-responding tissues? A. High LET radiations exhibit RBEs that are greater for early effects than for late effects B. The use of hyperfractionation results in an increased severity of late effects if the dose is titrated to produce equal early effects C. Isoeffect curves are steeper for late effects than for early effects D. When a treatment plan is changed from many small doses to a few large fractions and the total dose is titrated to produce equal early effects, late effects tend to be less severe

C. Isoeffect curves are steeper for late effects than for early effects Isoeffect curves are steeper for late effects than for early effects, meaning that late-responding tissues are more sensitive to changes in dose per fraction than early-responding tissues (and tumors). RBEs for high LET forms of radiation are greater for late effects compared to early effects when hyperfractionation is used (Answer Choice A). Hyperfractionation would reduce the severity of late effects if the total dose was titrated to maintain the same level of early effects (Answer Choice B). When a treatment plan is changed from many small doses to a few large fractions and the total dose is titrated to produce equal early effects, late effects would be more severe (Answer Choice D).

Which of the following is TRUE for potentially lethal radiation damage (PLD)? A. It is irreversible and irreparable. B. It is the damage that can be repaired efficiently if cells are allowed to progress through the cell cycle immediately following IR. C. It is thought to be primarily complex or "dirty" double strand breaks. D. It can be observed in a "split dose" experiment. E. It cannot be detected in tumors in vivo.

C. It is thought to be primarily complex or "dirty" double strand breaks. PLD is believed to be complex double strand breaks (DSBs) that are repaired slowly as compared to simple DSBs. Therefore, cells that are left in stationary phase after irradiation display enhanced survival as they have time to repair complex DSBs before resuming progression through the cell cycle.

Iridium-192 is characterized by the following EXCEPT: A. It is the most widely used radionuclide for brachytherapy procedures in the US. B. It has a small source size. C. It is used for permanent implants. D. The lower photon energy makes radiation protection easier than radium or cesium. E. It is available for use with computer-controlled remote afterloaders.

C. It is used for permanent implants. Iridium-192 is the most widely used radionuclide in part because of its convenience, its small size, its low photon energy simplifying radiation protection, and its ability to be used in remote afterloaders. It is used for temporary implants and is not used for permanent implants.

Which of the following types of blood cells is most radioresistant? A. Granuocyte/monocyte colony forming cells (GM-CFC) B. Spleen-colony forming units (CFU-S) C. Macrophages D. Unprimed T-helper cells E. B-cells

C. Macrophages Macrophages are among the most radioresistant cells in the body and are capable of surviving large doses of radiation. GM-CFC and CFU-S, which are progenitor cells, are radiosensitive, as are unprimed T-cells and B-cells.

5 Gy of X-rays is delivered at a high dose rate (1 Gy/min) rather than a low dose rate (1 Gy/hr). Which of the following statements about the effects of this change on cell survival is TRUE? A. The surviving fraction would change the least for a cell line with a radiation survival curve characterized by a low / ratio B. Treatment of cells during irradiation with an agent that inhibits DNA repair would have a greater impact on the surviving fraction of cells irradiated at the high dose rate C. More cell killing would occur following treatment at the high dose rate D. The difference in the surviving fractions between the two protocols results primarily from repopulation E. The total number of ionizations produced is decreased with treatment at the high dose rate

C. More cell killing would occur following treatment at the high dose rate When a dose of 5 Gy is delivered at a dose rate of 1 Gy/min, irradiation requires 5 minutes. When 5 Gy is delivered at 1 Gy/hr, irradiation requires 5 hours. Extensive repair of sublethal damage will occur during the low dose rate, but will not be able to occur during high dose rate irradiation. As a result, the beta component of cell killing will decrease and result in a strictly exponential and shallow survival curve. More cell killing would therefore occur when a dose of 5 Gy is delivered at a high dose rate rather than a low dose rate. The surviving fraction would change the least for a cell line with a radiation survival curve characterized by a high, not low, alpha/beta ratio (Answer Choice A). Treatment with an agent that inhibits DNA repair would have little impact during the 5 minute period of irradiation that would occur at the high dose rate (Answer Choice B). In contrast, such a treatment would markedly reduce cell survival for the 5 hour irradiation required at the low dose rate since, in the absence of the agent, substantial repair would take place during the course of the irradiation. The increase in the surviving fraction for this low dose rate irradiation is primarily a consequence of sublethal damage recovery and not repopulation, as the repopulation would only occur for overall treatment times on the order of days (Answer Choice D). The number of ionizations produced is a reflection of the total dose delivered and does not vary with the dose rate (Answer Choice E).

Which of the following statements concerning the response of NF-kB to ionizing radiation exposure is FALSE? A. NF-kB is a transcription factor B. The Inhibitor of Nuclear factor (NF)-kB, IkB, is phosphorylated by ATM and subsequently degraded, allowing NF-kB to move from the cytoplasm into the nucleus C. NF-kB generally acts to stimulate apoptosis and enhance the radiosensitivity of cells D. Both DNA double-strand breaks and reactive oxygen species generated by radiation exposure can activate NF-kB E. NF-kB is sequestered as an inactive form in the cytoplasm by interaction with an inhibitory subunit of the IkB

C. NF-kB generally acts to stimulate apoptosis and enhance the radiosensitivity of cells Nuclear factor (NF)-kB generally exerts a pro-survival influence through interference with apoptotic signals. It accomplishes this via the TNF receptor signaling pathway which, upon activation by an apoptotic signal, is coupled via the FADD adaptor to a caspase cascade involving the initiator caspases-8 or -10. In some cell types, however, this may not occur, since it may be opposed through the parallel triggering by TNF of a signaling pathway that activates NF-kB via the TRADD and TRAF adaptors. Active NF-kB induces transcription of a set of genes that encode the anti-apoptotic IAPs ("inhibitors of apoptosis"). NF-kB can also exert an anti-apoptotic effect by inducing transcription of anti-apoptotic proteins, such as Bcl-xL (BCL2L1), which act to prevent cytochrome c release and the subsequent caspase-9 activation. IkB binds to NF-kB to prevent its translocation to the nucleus. Following formation of DNA double-strand breaks and reactive oxygen species in irradiated cells, kinases (including ATM) phosphorylate IkB, targeting it for ubiquitination and degradation, which allows NF-kB to translocate to the nucleus from the cytoplasm where it can act as a transcription factor. NF-kB can exist as hetero- or homodimers of five different subunits. Different heterodimers activate different sets of genes while p50 and p52 homodimers, lacking transactivation domains, can selectively repress expression of their target genes. Post-transcriptional modifications and cofactor binding also help shape the specificity of the NF-kB response. Competition between p53 (TP53) and NF-kB for CBP/p300 may play an important role in determining the balance between apoptosis and cell cycle arrest following irradiation.

Acute radiation esophagitis presents as dysphagia or a substernal burning sensation as early as 2 weeks after the start of conventionally fractionated radiation therapy. Medical management most often involves: A. Angiotensin converting enzyme inhibitors B. Gene therapy with manganese superoxide dismutase C. Non-steroidal anti-inflammatory drugs D. Pentoxifylline E. Vitamin E

C. Non-steroidal anti-inflammatory drugs NSAIDs can help prevent esophagitis by decreasing inflammation. Although ACE-Inhibitors have been proven effective in the treatment of radiation nephropathy and pneumopathy, there are no data supporting their use in the treatment of radiation-induced esophagitis (Answer Choice A). Intra-esophageal administration of MnSOD-plasmid liposomes has been shown to protect the mouse esophagus from both single dose and fractionated irradiation. These studies have been recently been translated to a phase I clinical trial, but a benefit of this approach has not been proven in humans (Answer Choice B). Both pentoxifylline and vitamin E have been shown, in combination, to prevent as well as induce significant regression of radiation-induced fibrosis in breast cancer patients treated with radiotherapy.

Sorafenib is FDA approved for use in treatment of the following cancers, except?? A. Hepatocellular carcinoma B. Thyroid cancer C. Pancreatic cancer D. Non-small cell lung cancer E. Kidney cancers

C. Pancreatic cancer Sorafenib is a targeted agent that has been approved by the FDA for use in patients with advanced renal cell carcinoma, hepatocellular carcinoma, and radioactive iodine resistant advanced thyroid carcinoma. Sorafenib is a small molecule multi-kinase inhibitor that targets RAF1, KIT, FLT3, VEGFR (KDR) and PDGFR. RAF1 is a component of the RAS signaling cascade, a pathway that is often overactive in cancer, including renal cell carcinoma. Sorafenib also inhibits other kinases, including ones involved in tumor angiogenesis. Weird this question originally asked which cancers it was approved in -- and the answer is several of those. They said C which is the only one not listed to be approved. Misprint

For children who, historically, were treated for tinea capitis using ionizing radiation, which of the following organs did NOT demonstrate an excess relative risk for a radiation-induced malignancy? A. Brain B. Thyroid C. Pharynx D. Bone marrow E. Breast

C. Pharynx Among the population of children who were treated for tinea capitis (ringworm) using ionizing radiation, an excess incidence was not detected for head and neck cancers. Brain cancers, thyroid cancers, adenomas, (non-CLL) leukemias, and late development of breast cancer were all observed at an excess incidence among children that were previously treated with X-Rays compared with children who only received topical medications.

Which of the following X-ray interactions with matter is most important for producing high-contrast diagnostic radiographs? A. Compton process B. Pair production C. Photoelectric effect D. Nuclear disintegration E. Coherent scattering

C. Photoelectric effect The photoelectric effect is the predominant interaction responsible for producing high quality diagnostic radiographs. At relatively low photon energies, the photoelectric effect is the most likely photon interaction and is the desirable type of photon/tissue interaction since there is complete photon absorption with no production of secondary photons. The other possible tissue interactions at the photon energies used in diagnostic radiology are the Compton effect and coherent scattering. For these interactions, a deflected photon traveling in an altered direction is produced at the site of interaction. If these secondary photons are permitted to reach the film, there would be a reduction in image sharpness and loss of spatial resolution. Furthermore, with the photoelectric effect, absorption of photons is dependent on the cube of the atomic number of the material. The resultant differential of absorption in tissue allows for the ability to differentiate between bone, soft tissue, and air.

Which of the following pairs of genes or portions of genes and corresponding descriptors is CORRECT? A. Tumor suppressor genes - activated in many human tumors B. Exon - the non-coding region of a gene C. Promoter - involved in regulating gene transcription D. DNA repair gene - EGFR E. Oncogene - activated through loss of heterozygosity

C. Promoter - involved in regulating gene transcription The promoter region is the regulatory portion of a gene that plays a critical role in directing whether a gene is transcribed or not. Tumor suppressor genes are generally inactivated in many cancers, typically resulting in a loss of control over cell proliferation. Exons are the expressed, or coding, regions of genes, whereas introns are the non-coding sequences. The protein encoded by the EGFR (epidermal growth factor receptor) gene is a cell surface tyrosine kinase receptor that is activated by epidermal growth factor (EGF) ligand, among others, and is important for cell proliferation. Loss of heterozygosity is a common mechanism by which tumor suppressor genes are inactivated. Oncogenes are generally activated by mechanisms including deletion/point mutation, chromosome rearrangement, retroviral integration, or gene amplification.

Regarding radiation fibrosis, which of the following statements is TRUE? A. Fibrosis occurs in only a select few tissues and organs B. The severity of late fibrosis can be predicted based on radiotherapy treatment parameters and is not tissue-dependent C. Radiation fibrosis is typically inhomogenous; some affected areas could be densely collagenous whereas others may have only a few fibrous bands, despite both areas having received the same dose D. Irradiated bone marrow commonly develops regions of fibrosis E. Increases in collagen deposition are associated with down-regulation of fibrogenic cytokines.

C. Radiation fibrosis is typically inhomogenous; some affected areas could be densely collagenous whereas others may have only a few fibrous bands, despite both areas having received the same dose Fibrosis is one of the most common late radiation effects and can be noted in a majority of irradiated tissues and organs. Although the appearance of fibrosis is both time- and dose-dependent, its extent and severity can vary not only within a single organ, but also across different individuals. Bone marrow is one of the few tissues where fibrosis is rarely seen; in general, fibrosis only appears within the marrow if a tumor or inflammatory lesion was present prior to irradiation. Bone marrow is usually replaced by adipose tissue. Much of the regulation of collagen deposition is mediated through the action of fibrogenic cytokine families and is characterized by the upregulation of such cytokines as TGF-β1.

If a tumor is comprised of cells characterized by a high growth fraction and a short cell cycle time, which of the following would most likely describe its behavior prior to and after treatment with a curative dose of radiation? A. Slow growth, slow regression B. Slow growth, rapid regression C. Rapid growth, rapid regression D. Rapid growth, slow regression

C. Rapid growth, rapid regression Tumor types with a high growth fraction and short cell cycle time would be expected to grow more rapidly. Such a tumor would also be expected to regress rapidly after irradiation since irradiated cells generally die as they attempt to progress through mitosis.

Irradiation of an exponentially-growing population of cells in culture with a dose that kills 90% of cells tends to select surviving cells that are initially in which phase of the cell cycle? A. G0 B. G1 C. S D. G2 E. M

C. S A dose that kills 90% of the cells in the population would leave a surviving cell population heavily enriched in the radioresistant cells in late S phase. Radiosensitivity across the cell cycle is ranked as follows from least to most sensitive: Late S, Early S, G1, G2≈M.

Which of the following statements concerning the prognostic significance of pre-therapy [18-F] fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging in patients is CORRECT? A. SUV score values are directly correlated with local tumor control. B. SUV score values are inversely proportional to a patient's body weight. C. SUV score values can be used to distinguish between quiescent and proliferating tumors. D. SUV score values are insensitive to extending the time between radioisotope injection and completion of the PET scan. E. Typical doses of FDG for the clinically useful PET imaging are in a range of 15 Ci.

C. SUV score values can be used to distinguish between quiescent and proliferating tumors. The standard uptake value (SUV) is a standard method of quantifying the radioactive uptake observed in a positron emission tomography (PET) scan image. As a cancer detection method, fluorodeoxyglucose (FDG) PET is based on the observation that in normoxic conditions tumor cells primarily use glycolysis for energy production instead of mitochondrial oxidative phosphorylation as normal cells do. This phenomenon is known as the Warburg effect. SUV scores of >15 g/mL usually indicate a tumor that is highly dependent on glucose metabolism and is therefore more aggressive rather than indolent. It therefore follows that SUV scores inversely correlate with local tumor control (Answer Choice A) The SUV is calculated as follows: SUV [g/ml] = (Tissue activity (mCi/ml))/(injected dose (mCi)) × patient's body weight (g). SUV score values are therefore proportional to a patient's body weight (Answer Choice B) SUV values increase in value if the PET scan is delayed after FDG injection (Answer Choice D). The tissue activity (mCi) per lesion volume (mL) is derived from pixel intensities of PET (or PET/CT) images. This quanitity is then divided by the amount of radioactive tracer injected into the patient (mCi) per unit of his/her body weight (g) (specific activity). The typical dose of FDG administered to adult patient is approximately 10-18 mCi (Answer Choice E).

What portion of the gastrointestinal tract generally exhibits the greatest acute radiation-induced injury for a given dose? A. Stomach B. Oropharynx C. Small intestine D. Large intestine E. Esophagus

C. Small intestine In documented cases of humans dying from gastrointestinal syndrome after whole-body irradiation, the small intestine typically showed the most denudation relative to the other sites, likely due to the greater presence of radiosensitive crypt cells.

Which of the following compounds CANNOT be used to protect mammalian cells from radiation damage? A. WR-2721 B. WR-638 C. Taxanes D. Cysteine E. Amifostine

C. Taxanes Taxanes bind to microtubules and adversely affect their function by enhancing and preventing disassembly. Taxanes act as mitotic inhibitors by blocking cells in the G2/M phase of the cell cycle and, if the concentration is sufficient, killing them in this phase. WR-2721 (WR-1065 is the active metabolite), also known as Amifostine or Ethyol, is the only FDA-approved radioprotective drug used for the prevention of xerostomia in head and neck cancer patients treated with radiation (Answer Choices A and E). WR-638, also known as Cystaphos, has been proposed as a radioprotector (Answer Choice B). Cysteine as well as cysteamine are radioprotective sulfhydryl (SH) compounds but unfortunately associated with debilitating toxicity (Answer Choice D).

Which of the following statements concerning the Arrhenius analysis of mammalian cell killing by heat is TRUE? A. An Arrhenius curve plots the log of the slope (1/D0) of heat survival curves as a function of temperature B. The break point in the Arrhenius plot is defined as the temperature at which the slope of the plot significantly increases. C. The Arrhenius relationship has been used to define the temperature dependence of mechanisms of cell killing D. The results of these analysis suggested the nuclear matrix may be a target of heat-induced cell killing E. The break point in the Arrhenius plot is different between rodent and human cancer cells.

C. The Arrhenius relationship has been used to define the temperature dependence of mechanisms of cell killing The Arrhenius plot demonstrates the temperature at which the mechanisms underlying cell killing changes, potentially reflecting different targets for cytotoxicity above the break point (43oC) The Arrenhius analysis plots survival data of cell cultures exposed to increasing temperatures. The X-axis plots 1/D0, where D0 represents the time at a given temperature required to reduce the fraction of surviving cells to 37% of the initial population. The Y-axis plots 1/T, where T is the absolute temperature (Answer Choice A). The slope of the Arrhenius plot provides the activation energy of the chemical process involved in the cell killing. At some point (1/T), corresponding to approximately 43o, there is a significant and abrupt decrease in the slope (Answer Choice B). The results of these analysis suggested that the target for heat cell killing may be a protein. The break point in the Arrhenius plot occurs at a temperature of approximately 43oC, and is the same across mammalian cells (Answer Choice E).

Which of the following is TRUE about the thyroid carcinomas that occurred secondary to radiation exposure following the Chernobyl nuclear power plant accident? A. The carcinomas were induced by 137 Cesium radiation that settled on the ground. B. Most of the tumors involved rearrangements of Bcl2 and Myc C. The tumors could have been reduced in number by administering potassium iodide (KI) to the population. D. Initial cancers were induced predominantly in adults that had been exposed. E. The peak in incidence was approximately 30 years after exposure.

C. The tumors could have been reduced in number by administering potassium iodide (KI) to the population. Administration of potassium iodide (KI) to the children that had been exposed to 131 Iodide (131I) as a result of the accident would have reduced the number of thyroid cancers by decreasing exposure to the radioactive iodide. While 137 Cesium (137Cs) was released as part of the accident, 131I was the cause of the thyroid cancers that occurred (Answer Choice A). Most of the tumors demonstrated rearrangements of the RET and PTC genes (Answer Choice B). The majority of the tumors occurred predominantly in children within 7-10 years following exposure (Answer Choices D-E).

One type of radiation-induced bone injury is mandibular radionecrosis (MORN). Which of the following is NOT a risk factor for MORN? A. Presence of teeth B. Pre-existing dental disease C. Use of fluorinated water D. Tooth extraction after radiotherapy E. Use of large doses per fraction during treatment

C. Use of fluorinated water Use of fluorinated water as a part of normal dental hygiene would, if anything, help prevent dental caries and reduce the risk of MORN. MORN is most commonly precipitated by post-radiotherapy tooth extraction secondary to poor dentition. Early studies from the 1960's and 1970's at MD Anderson Cancer Center showed that patients with teeth were at a significantly greater risk of MORN than patients without teeth. However, current treatment practices do not require the removal of all teeth prior to radiotherapy, but rather, recommend careful dental care. Radiation tolerance of the mandible is also affected by pre-irradiation dental disease, fraction size and gender (males more susceptible).

Following exposure of cells to 3 Gy from a 6 MV X-ray beam, the ATM protein is activated and phosphorylates multiple intracellular targets. Which of the following is NOT a target for ATM phosphorylation? A. Histone H2AX B. p53 (TP53) C. VEGF (VEGFA) D. BRCA1 E. Artemis

C. VEGF (VEGFA) ATM is a kinase that is activated in response to the presence of DNA double-strand breaks, such as following exposure to ionizing radiation. Activated ATM phosphorylates multiple distinct target proteins, including histone H2AX, p53, BRCA1, and Artemis. Phosphorylation of H2AX (to g-H2AX) results in chromatin modification that facilitates the recruitment of factors needed for DNA repair (Answer Choice A). The tumor suppressors, p53 and BRCA1, activate cell cycle checkpoint and/or DNA repair processes in response to genotoxic stress (Answer Choices B and D). VEGF is a secreted factor that promotes angiogenesis and is not a direct target of ATM phosphorylation (Answer Choice C). In NHEJ, Artemis endonuclease DNA repair protein is involved in processing strand breaks prior to DNA ligation

Which of the following statements concerning computed tomography (CT) is CORRECT? A. Tissues that strongly absorb X-rays appear black while others that absorb poorly appear white on CT images. B. Iodine-based contrast agents are mainly used in the imaging of the digestive system via CT scanning. C. Water has an X-ray attenuation of 0 Hounsfield units (HUs). D. Organ-specific radiation doses from CT scans are negligibly low compared to those associated with conventional radiography. E. CT devices and image reconstruction software are regulated by the U.S. Nuclear Regulatory Commission (NRC).

C. Water has an X-ray attenuation of 0 Hounsfield units (HUs). The Hounsfield unit (HU) scale relates X-ray attenuation in various tissue types (μ) to X-ray attenuation in water μ(water) through the equation: HU = 1000 × 𝜇−𝜇(𝑤𝑎𝑡𝑒𝑟)𝜇(𝑤𝑎𝑡𝑒𝑟) Based on the above equation, the HU of water is 0. Other choices are incorrect. Barium-based rather than iodine-based contrast agents are used in the imaging of the digestive system by CT. Organ doses from diagnostic CT procedures are typically estimated to be in the range of 1 cGy per scan and as much as 10 cGy from multiple CT scans. For example, cumulative doses from 2-3 head CTs to the brain are 5-6 cGy. For comparison, X-ray doses from chest radiography are 0.01 cGy (0.1 mGy) and X-ray doses from mammography are 0.04 cGy (0.4 mGy). The Nuclear Regulatory Commission (NRC) is responsible for the regulation of radioactive materials used medically; this includes the diagnostic radionuclides used in positron emission tomography (PET) imaging. On the other hand, CT scanners, image reconstruction software, as well as other "medical devices" such as linear accelerators and associated treatment planning software are regulated by the United States Food and Drug Administration (FDA).

The Maximum Permissible Dose (MPD) recommended annually for radiation workers: A. is the dose workers would receive if the workplace adhered strictly to the principles of ALARA B. is 100 times higher than that for members of the general public C. does not include dose received from medical procedures D. includes dose contributions from man-made sources only E. is the same under both NCRP and ICRP guidelines

C. does not include dose received from medical procedures The Maximum Permissible Dose (MPD) defines the recommended occupational exposure dose limits and does not include any dose received from medical procedures or natural background radiation (Answer Choices C and D). Radiation workers (including residents) are considered subject to occupational exposure limits. Medical students are considered subject to the education and training exposure limits. In nearly all cases, the MPD is greater than the dose that would be obtained with strict adherence to the principles of ALARA, which stipulate that personnel should receive doses "as low as reasonably achievable" (Answer Choice A). The MPD recommendations for radiation workers are typically 10-50 fold higher than for members of the general public (Answer Choice B). The NCRP and ICRP guidelines treat age differently in establishing the MPD. The effective dose limit for occupational exposure per the NRCP guidelines is 10 mSv per year of age or 50 mSv per year and per the ICRP guidelines is 20mSv per year (averaged over 5 years) or 50mSv per year. The MPD for younger workers is therefore greater under NCRP guidelines than under ICRP guidelines, but the MPD for older workers is greater under ICRP guidelines than under the NCRP guidelines (Answer Choice E).

Which of the following pairs of gestational stage and radiation-induced developmental defect is CORRECT? A. preimplantation - congenital malformations B. organogenesis - prenatal death C. early fetal period - mental retardation D. late fetal period - neonatal death E. entire gestation period - malformations of the kidney

C. early fetal period - mental retardation Irradiation during the early fetal period, corresponding to weeks 8-15 of gestation in humans, is associated with the greatest risk for mental retardation. The main risks during preimplantation, organogenesis, and the late fetal period are prenatal death, congenital malformations, growth retardation and carcinogenesis, respectively. There is an increased risk of carcinogenesis following irradiation throughout the gestation period.

Radiation-induced cellular senescence is often the result of: A. Cellular nutrient deprivation B. Oxidative stress secondary to mitochondrial dysfunction C. p16-mediated cell cycle arrest D. Telomere shortening E. Mitotic catastrophe

C. p16-mediated cell cycle arrest The term "senescence" refers to the loss of cellular replicative potential leading to a reduced capability to repopulate a tissue after exposure to genotoxic agents, including ionizing radiation. Senescence is most often the result of a permanent arrest in G1, associated with elevated expression of the cell cycle inhibitors p16INK4A (CDKN2A) and p21 (CDKN1A, WAF1/CIP1). Importantly, senescence is not a type of cell death per se because cells remain morphologically intact and metabolically active when senescent. Depending on the level of tumor suppressor proteins and the oncogenic signal, senescence can be reversible in a small subset of cells though in most cells this process is irreversible. A clinically relevant scenario for radiation-induced senescence is the loss of salivary gland function and xerostomia commonly seen in head and neck cancer patients undergoing radiotherapy. Another one is radiation-induced premature senescence in fibroblasts that triggers proinflammatory and profibrotic senescence associated secretory phenotype (SASP) and ultimately drives fibrosis in the lung. Mitochondrial dysfunction is a hallmark of apoptotic cell death, not senescence (Answer Choice B). Telomere shortening occurs in most normal somatic cells as part of each cell cycle ("end replication problem") and triggers senescence once a critical low threshold is reached, but telomere shortening tends not to be the cause for radiation-induced senescence which is driven by DNA-damage and cell cycle arrest (Answer Choice D). Nutrient deprivation can lead to autophagy, and ultimately autophagic death cell distinct from apoptosis -- think LC3 cleavage assay

When in the cell cycle do chromatid aberrations happen

Chromatid type of chromosome aberrations are caused by chromatid breaks in S or G2 phase. The breaks induced in G1 phase often display as chromosome type of aberrations. What is the difference between chromosome aberrations and chromatid aberrations? Ionizing radiation induces chromosome-type aberrations (symmetric aberrations), like dicentrics, inversions, ring chromosomes, in the G0 or G1 stage of the cell cycle (i.e. prior to replication), while chromatid type aberrations (asymmetric aberrations), like breaks and gaps, are produced during the S or G2 stage This admittedly doesn't make a ton of sense to me since chromatin isn't supposed to condense into chromatids until prophase of mitosis...

Which assay or endpoint would provide the best estimate of the radiation response of putative cancer stem cells? A. Time to first evidence of tumor shrinkage following irradiation B. Tumor regrowth delay C. Determining the fraction of proliferating tumor cells 2 weeks after irradiation D. 50% tumor control dose E. Quantifying the number of apoptotic tumor cells 6 hours after irradiation

D It has been suggested that a small proportion (< 1%) of all cells in a tumor are cancer stem cells. If correct, this hypothesis suggests that all cancer stem cells must be inactivated in order to achieve permanent local tumor control. In theory, one surviving cancer stem cell would be sufficient to cause a local recurrence following irradiation. Thus, the rate of permanent local tumor control is a direct measure of radiation response of cancer stem cells. In contrast, tumor shrinkage and growth delay are dominated by the response of the bulk of cancer cells and not specific for the radiation response of cancer stem cells. Cancer cells with a limited proliferative capacity, as well as doomed cancer stem cells, might undergo a number of cell divisions before they permanently stop proliferating and ultimately die. Determination of proliferating cells will therefore not provide information regarding the radiation response of cancer stem cells. Cancer cells can die following exposure to radiation in different ways, including interphase death (i.e. apoptosis) and mitotic catastrophe (apoptosis, autophagy, or necrosis). None of these modes of cell death is likely to be specific for cancer stem cells. Given that many solid tumors exhibit resistance to undergoing apoptosis and the controversial data from studies comparing the rate of apoptosis with radiation response of tumors, it is unlikely that the rate of apoptosis after irradiation will be a proper parameter to determine the response of irradiated cancer stem cells.

Assume that a particular tumor contains 10^10 cells. Find the dose required to ensure that a single cell within the tumor has one chance in 100 to survive. Assume exponential survival and a mean lethal dose of 1 Gy. a. 23.4 Gy b. 34.5 Gy c. 30.5 Gy d. 27.6 Gy e. 29.7 Gy

D Mean lethal dose = they mean the D0. D0 is the dose to reduce the survival to 37% in the exponential portion of the curve. It is the reciprocal of the slope. 2.3xD0 = 1 log of cell kill. Ways they will describe the D0: - mean lethal dose - D37 - D0 The required dose must reduce the cell population by a factor of 1010 × 102 = 1012. The mean lethal dose, usually denoted D0 and sometimes D37 , is the dose required to reduce the population of cells by a factor of 0.37 from its initial value (thus kill 63% of the population). In this example, D0 =1 Gy. In solving problems similar to this one, it is convenient to use the dose required to reduce the population by a factor of 10 (from 0.1 to 0.01, from 0.01 to 0.001, etc) instead of D0. It is easy to see that D10 = D0 loge 10 = 2.3 · D0. In this example, D10 = 2.3 Gy. Since the survival is reduced by a factor of 10 with each dose of 2.3 Gy, required dose = 12 × 2.3

Concerning RBE, OER, and LET, which of the following statements is TRUE? A. Maximum cell killing per dose delivered occurs at an LET corresponding to approximately 1000 keV/μm B. RBE changes the most over the LET range of 0.1 to 10 keV/μm C. The relationship between OER and LET is bell-shaped D. RBE decreases with increasing LET above about 100 keV/μm E. OER increases with LET

D RBE decreases with increasing LET above approximately 100 keV/μm (essentially wasted energy transfer depositing where damage has already been done). This is thought to be due to the "overkill" effect in which many more ionizations (and damage) are produced in a cell traversed by a very high LET particle than are minimally necessary to kill it, thereby "wasting" some of the energy. Maximum cell killing occurs at an LET of approximately 100 keV/μm, not 1000 keV/μm (Answer Choice A). RBE shows the greatest changes for LET values between roughly 20 and 100 keV/μm (Answer Choice B). OER decreases slowly with increasing LET for low LET values, but falls rapidly after LET exceeds about 60 keV/μm and, therefore, does not follow a bell-shaped curve (Answer Choices C and E).

The components typically required for the analysis of a standard, adherent cell clonogenic survival assay require all of the following, EXCEPT: A. Calculation of a plating efficiency B. Colony formation rates at a range of cell densities, for several radiation doses C. A cell line capable of multiple cell divisions D. Intact apoptosis pathways E. Nonirradiated control

D The clonogenic survival assay measures the ability of single cells to divide continuously after a given exposure, and typically measures colony formation 7-14 days after exposure to the agent. It requires a normalization in which the number of colonies formed is divided by the number of cells seeded (in the absence of any DNA damaging agent), which yields the plating efficiency. Surviving fraction is then calculated for each dose of a given agent by dividing the number of colonies formed by the number of cells seeded and normalizing to the "0 Gy" plating efficiency. Multiple doses and cell densities typically are needed for the adequate analysis of cell survival. This is not a short-term growth delay assay, and thus a cell capable of multiple cell divisions is needed. DNA damaging-agents induce cell death via a number of pathways, including apoptosis. However, apoptosis is not the sole cell death pathway.

A set of data defining the survival of cells irradiated with graded doses of X-rays is well-fitted by the mathematical expression for a single-hit survival curve having an SF2 of 0.37. The best estimate for the parameter that describes this survival response is: a. 0.1 Gy^-1 b. 0.01 Gy^-1 c. 0.05 Gy^-1 d. 0.5 Gy^-1 e. 2.0 Gy^-1 JUST RECOGNIZE HOW TO SOLVE THIS

D The formula for a single-hit survival curve is S = e^-aD Because the SF2 (the surviving fraction following a dose of 2 Gy) is 0.37, 0.37 = e-D or D = 1 = (2 Gy). Hence, a = 0.5 Gy-1

Which statement regarding the roles of non-homologous end-joining (NHEJ) and homologous recombination (HR) in the repair of ionizing radiation-induced DNA double-strand breaks (DSBs) is TRUE? A. HR removes DSBs from the genome at a faster rate than NHEJ B. Defects in HR compromise DSB repair but do not affect the repair of damage at DNA replication forks C. NHEJ requires homologies of 200-600 nucleotides between broken ends of DNA D. Defects in NHEJ increase radiosensitivity more than defects in HR in mammalian cells.

D Two principal recombinational DNA repair pathways have been identified, homologous recombination (HR) and non-homologous end-joining (NHEJ), each of which employs separate protein complexes. DSB repair by HR requires an undamaged template molecule that contains a homologous DNA sequence, typically derived from the sister chromatid in the S and G2 phase cells. In contrast, NHEJ of double-stranded DNA ends, which can occur in any cell-cycle phase, does not require an undamaged partner and does not rely on extensive homologies between the recombining ends (typically 2-6 bp of microhomology are used). Defective HR can be causally linked to impaired DNA replication, genomic instability, human chromosomal instability syndromes, cancer development, and cellular hypersensitivity to DNA damaging agents. Cells with genetic defects in NHEJ (such as mutation of DNA-PK, XRCC4, or DNA ligase IV) display a more pronounced hypersensitivity to ionizing radiation than cells defective in HR (such as mutation of BRCA1, BRCA2, or RAD51).

What important feature distinguishes autophagy from other modes of programmed death? a. Loss of mitochondrial membrane potential b. Influx of extracellular fluid and ions c. Leakage of proteases and lysosomes d. Reversibility e. Wallerian degeneration

D Autophagy is a REVERSIBLE process in which cells generate energy and metabolites by digesting their own organelles and macromolecules and as such it is a survival mechanism. Autophagy allows a starving cell, or a cell that is deprived of growth factors to survive up to a point. Cells that do not receive nutrients for extended periods ultimately digest all available substrates and die through autophagic death. Supplying nutrients before this critical point would restore the cell's health. Loss of mitochondrial membrane potential occurs during apoptosis. Choices B and C occur during necrosis. Wallerian degeneration occurs after axonal injury in both the peripheral and central nervous systems..

In irradiated cells, oxygen: a. acts as a radical scavenger by converting free radicals to non-reactive species b. acts as a radioprotector c. reacts with hydrogen radicals to form water, thus reducing the number of free radicals formed d. modifies the level and spectrum of free radical damage produced in DNA e. is unlikely to play a role in the indirect effect of radiation

D In irradiated cells, oxygen increases the number and/or type of free radicals and thereby acts as a radiosensitizer, effectively increasing the level of damage produced. Oxygen reacts with free radicals resulting in the production of different radical species, which may be longer lived, and therefore more damaging than the original radicals. For example, oxygen may react with hydrogen radicals to produce peroxyl radicals. Through its reaction with free radicals formed from the radiolysis of water, oxygen plays a role in the indirect effect of radiation.

Which of the following molecules is NOT an immune checkpoint receptor protein? A. LAG3 B. PD-1 C. TIM3 D. OX40 E. CTLA-4

D - OX40 Lymphocyte Activating 3 (LAG3) is a cell surface immune checkpoint receptor protein that is expressed on activated T cells and negatively regulates cellular prol and is activated by Major Histocompatibility Class (MHC) II. Programmed cell death protein (PD)-1 is a cell surface immune checkpoint receptor protein that is bound by its two ligands, PD-L1 and PD-L2 and functions to suppress T cell inflammatory activity and promotes self tolerance. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is another immune checkpoint receptor protein that is activated by CD80 and CD86 and functions to downregulate the immune response. More recently identified as a potential immune checkpoint target, T-cell immunoglobulin and mucin domain-3 (TIM-3) is activated by Galectin-9 (Gal-9), Phosphatidylserine, HMGB-1, and Cecam-1 and plays a role in T cell exhaustion. LAG3, PD-1, CTLA-4, and TIM3 all act as co-inhibitory receptors that limit or inhibit the activation of T cells even if the TCR is engaged. In contrast, OX40 (OX40L) is a co-stimulatory receptor that does promote T cell activation by driving T-cell proliferation, memory, cytotoxic effector function, and cytokine production. Other examples of co-stimulatory molecules are 4-1BB, CD40L, GITR, ICOS, and CD27. Of these, CTLA-4 and PD-1 are probably the most studied to date. CTLA4 counteracts the activity of the T cell co-stimulatory receptor, CD28, both sharing identical ligands: namely, CD80 (B7.1) and CD86 (B7.2). Although CTLA-4 is active on CD8+ T cells, it seems that most of its effects are derived from down-modulation of helper T cell activity and enhancement of Treg immunosuppressive activity. On the other hand, PD-1 limits the activity of T cells in peripheral tissues at the time of an inflammatory response to infection and functions to limit autoimmunity by, for example, suppressing immune system activation within the tumor microenvironment. PD-1 expression is induced following T cell activation. When engaged by one of its ligands, PD-1 inhibits kinases that are involved in T cell activation through the phosphatase SHP250, although additional signaling pathways are also likely induced. The general concept is that blocking CTLA-4 affects early T cell activation whereas blockade of PD-1 signaling is more relevant later, at the tissue site, thereby explaining why the CTLA-4 inhibitors are associated with more significant toxicity.

Based on the information presented in the previous question, what would be the TCD90 if a surgical excision removed 99% of the tumor clonogens prior to radiotherapy (assume that the surgery did not otherwise affect the growth fraction of the tumor). A. 24 Gy B. 32 Gy C. 40 Gy D. 48 Gy E. 56 Gy

D. 48 Gy Again no key, but if surgery removes 99% of the tumor. That only actually takes it from 10^7 --> 10^5 (0.01 of 10^7 = 10^5). So now you need 6 logs of cell kill to achieve TCD90 So 6 x 8 Gy = 48 Gy

What are the NCRP maximum permissible annual dose limits for the eye and to localized skin areas for radiation workers? A. 50 mSv to the eye and skin B. 150 mSv to the eye and skin C. 50 mSv to the eye and 150 mSv to the skin D. 50 mSv to the eye and 500 mSv to the skin E. 500 mSv to the eye and 150 mSv to the skin

D. 50 mSv to the eye and 500 mSv to the skin A radiation worker is currently permitted 50 mSv to the eye and 500 mSv to the skin in any given year. This is a recent change from the previous NCRP recommendations for which the annual dose equivalent limit for the lens the eye was 150 mSv. These limits are based on risk estimates for the production of radiation-induced deterministic effects. The ICRP recommends an annual equivalent absorbed dose limit for the lens of the eye to be 15 mSv for the public. For chronic occupational exposures, the ICRP recommends an equivalent dose limit for the lens of the eye of 20 mSv in a year, averaged over defined periods of 5 years, with no single year exceeding 50 mSv.

In the United States, the average annual effective dose equivalent from all sources of radiation is closest to: A. 0.2 mSv B. 1 mSv C. 3 mSv D. 6 mSv E. 15 mSv

D. 6 mSv The average annual effective dose for a person residing in the US is approximately 6 mSv. This total includes an average radon contribution of 2 mSv; cosmic, terrestrial and internal radioactivity of 1 mSv. In addition, an average of 3 mSv from man-made sources, primarily from diagnostic and nuclear medicine procedures, is received. This increase from the often quoted 1980 figure of 0.5 mSv associated with medical procedures is the result primarily from the significant increase in the use of CT scans over the past 30 years. CT scans deliver relatively high radiation doses compared with other imagining modalities. Trick question -- if asked what is the largest contributor -- pick radon if the manmade option is specifically CT scans (its the largest contributer to the manmade source, but not the largest overall). 48% of medical radiation is from medical procedures, 24% from CT scans -- so only ~1.5 mSv is from CT scans specifically <2 mSv from radon.

Which of the following statements is TRUE concerning bortezomib? Bortezomib is: A. An agent that stimulates ubiquitin-mediated degradation of IκB B. FDA-approved for use in the treatment of renal cell carcinoma C. A drug that specifically targets EGFR signaling pathways D. A proteasome inhibitor E. A monoclonal antibody

D. A proteasome inhibitor Bortezomib (Velcade) is a proteasome inhibitor approved for the treatment of multiple myeloma and mantle cell myeloma (Answer Choices D and B). In normal cells, the proteasome facilitates the degradation of abnormal or misfolded proteins or those tagged via ubiquitylation. Bortezomib acts by inhibiting the activity of the 26S proteasome and, therefore, the degradation of proteins. NF-kB is not directly targeted by proteasome inhibitors, however, proteasome inhibitors indirectly promote NF-kB being kept in its inactive form by blocking the ubiquitin-mediated degradation of its repressor, IkB (Answer Choice A). EGFR signaling pathways are not a target for bortezomib (Answer Choice C). Bortezomib is an N-protected dipeptide, not a monoclonal antibody (Answer Choice E).

Which of the following pairs of molecular events and their functional consequences is INCORRECT? A. VHL inactivation ---- angiogenesis B. cyclin D1 repression --- inhibition of proliferation C. cytochrome c release --- apoptosis D. ATM phosphorylation ---- epistasis E. miRNAs mis-expression --- carcinogenesis

D. ATM phosphorylation ---- epistasis Epistasis is a form of gene interaction in which an allele for one trait (at one locus) influences the expression of an allele, at a different locus, for a separate and independent trait; this process is unrelated to ATM phosphorylation. Inactivation of the VHL (von Hippel-Lindau tumor suppressor) gene results in overexpression of many environmental stress-inducible mRNAs, including those involved in energy metabolism, apoptosis, and angiogenesis via the activation of vascular endothelial growth factor (VEGF; Answer Choice A). Cyclin D1 repression is associated with anti-proliferation effects. Its overexpression has been observed in human cancers, including pancreatic, lung, and esophageal (Answer Choice B). Release of cytochrome c and apoptosis-inducing factor (AIF) from mitochondria into the cytoplasm is a primary mitochondrial apoptogenic activity (Answer Choice C). MicroRNAs (miRNAs) are small non-protein-coding RNAs that function as negative regulators of gene expression under normal physiological conditions. Mis-expression of, or mutations in, miRNAs are associated with the development of a variety of human cancers, including B-cell chronic lymphocytic leukemia, colorectal cancer, and breast cancer.

Which of the following is FALSE regarding superoxide dismutase (SOD) mimetics? A. The chemical structure of a SOD mimetic contains a redox active metal ion that is oxidized in the presence of superoxide (O2●-) B. Their mechanism of action involves converting superoxide (O2●-) into hydrogen peroxide (H2O2) C. Their ability to protect against radiation- and chemotherapy-related oral mucositis in head and neck cancer is currently being evaluated in clinical trials D. An SOD mimetic has yet to be identified that protects against radiation toxicity in normal tissues without also protecting tumor tissue

D. An SOD mimetic has yet to be identified that protects against radiation toxicity in normal tissues without also protecting tumor tissue One SOD mimetic, GC4419, that is currently in clinical trials is able to selectively protect normal cells from radiation- and chemotherapy-related toxicity without protecting tumor cells. Superoxide dismutase (SOD) mimetics contain a redox active metal ion as part of their chemical structure (Answer Choice A). In the presence of superoxide (O2●-), the redox active metal ion is oxidized (loses an electron) and the superoxide is reduced to hydrogen peroxide (Answer Choice B). SOD mimetics have been evaluated in phase 1 and 2 clinical trials regarding their ability to protect against radiation- and chemotherapy- induced oral mucositis; a phase 3 clinical trial is currently underway (Answer Choice C).

Which of the following statements is TRUE concerning the use of PET imaging? A. 18F-2-deoxy-2-fluoro-D-glucose (18F-FDG) has a radioactive half-life of approximately 10 days B. A PET imaging camera detects positrons generated from the decay of radiopharmaceuticals C. The uptake of 18F-FDG is typically lower in areas of inflammation D. An important advantage to using 18F-FDG-PET/CT fusion images for radiotherapy treatment planning is that they provide both functional and anatomical information E. Tumors tend to show a reduced uptake of 18F-FDG

D. An important advantage to using 18F-FDG-PET/CT fusion images for radiotherapy treatment planning is that they provide both functional and anatomical information An important advantage to the use of FDG-PET/CT fusion imaging for radiotherapy treatment planning is that it provides both functional and anatomical information. The radioactive half-life of 18F is 110 minutes, not 10 days. PET imaging cameras detect the 0.51 MeV photons produced by the annihilation resulting from the interaction of a positron and electron. The uptake of 18F-FDG is typically higher, not lower, in areas of inflammation and in tumors.

Which of the following statements regarding anti-angiogenic therapy strategies is FALSE? A. Anti-angiogenic therapies interfere with activators of angiogenesis B. Anti-angiogenic therapies target receptor tyrosine kinases and related signal transductions C. Anti-angiogenic therapies seek to amplify endogenous suppressors of angiogenesis. D. Anti-angiogenic therapies use colchicine as an anti-angiogenic agent. E. Anti-angiogenic therapies ultimately target VEGFR-1 in order to achieve inhibition of angiogenesis.

D. Anti-angiogenic therapies use colchicine as an anti-angiogenic agent. Colchicine is an anti-inflammatory agent that binds tubulin. Colchicine itself induces vascular damage but only at doses that are limited by toxicity and therefore not used in the clinical setting for this purpose.

With respect to the morphologic changes associated with radiation-induced liver disease (RILD), notably veno-occlusive disease (VOD), all of the following may be observed, EXCEPT: A. Heavy congestion in the sinusoids B. Atrophy of the liver plates C. Fiber-filled lumen of the sublobular veins D. Apoptotic Kupffer cells filled with hematoxylin E. Subacute morphological changes

D. Apoptotic Kupffer cells filled with hematoxylin The Kupffer cells, hepatic-specific phagocytes, often increase in size during the progression of veno-occlusive disease (VOD) and can contain large amounts of hemosiderin, a pigment that is a breakdown product of hemoglobin derived from phagocytized erythrocytes that have leaked from damaged vasculature. Hematoxylin is a nuclear stain widely used in histology that would not be expected to be found in the liver. Although the VOD lesion presents at about 90 days post-irradiation and is technically a late effect, nonetheless it is typically defined clinically and morphologically as a "subacute" effect. The morphologic hallmark of VOD is the presence of lesions with severely congested sinusoids in the central zones of the lobules, and an accompanying atrophy of the central portion of the liver plates. The lumen of the central and sublobular veins are filled with a dense network of reticulin fibers that frequently contain trapped red cells.

Which of the following statements is TRUE regarding BRCA1 and BRCA2: A. BRCA1 and BRCA2 mutations account for only a few cases of familial hereditary breast and ovarian cancer B. BRCA1-deficient cells are resistant to the DNA crosslinking agent mitomycin C C. The prevalence of BRCA1 mutation is higher than that of BRCA2 mutations D. BRCA1 and BRCA2 predominantly regulate homologous recombination as opposed to non-homologous end joining E. The breast cancer risks for carriers of BRCA1 and BRCA2 mutations are similar but with later age of disease onset for the BRCA1 mutation

D. BRCA1 and BRCA2 predominantly regulate homologous recombination as opposed to non-homologous end joining

Yttrium-90, a beta-emitting radioisotope, is used in the management of several malignant conditions. It can be medically used in all the following forms EXCEPT: A. Bound to an anti-CD20 antibody in the treatment of certain types of non-Hodgkin lymphoma. B. Bound to resin microspheres in the treatment of hepatic metastases from colorectal cancer. C. Bound to glass microspheres in the treatment of hepatocellular carcinoma. D. Bound to metal needles in the local treatment of primary breast adenocarcinoma.

D. Bound to metal needles in the local treatment of primary breast adenocarcinoma. Ibritumomab tiuxetan is an anti-CD20 antibody tagged with yttrium-90 (Y90) used for the systemic radioisotope based-treatment of widespread B-cell lymphomas (Answer Choice A). Y90 containing resin microspheres are FDA-approved for the treatment of hepatic metastases from colorectal cancer (Answer Choice B). Y90 containing glass microspheres are approved for the treatment of primary hepatocellular carcinomas (Answer Choice C).

Which of the following molecularly-targeted agents is an epidermal growth factor receptor inhibitor? A. Bevacizumab B. Nivolumab C. Imatinib D. Cetuximab E. Rituximab

D. Cetuximab All the choices are examples of targeted agents, but of those listed, only cetuximab specifically targets the epidermal growth factor receptor (EGFR), a member of an important family of transmembrane signaling proteins. EGFR signaling regulates normal cell growth and differentiation as well as tumorigenesis and disease progression in malignant tissues. EGFR is over-expressed in most solid tumors (breast, lung, colorectal cancers), and high levels of expression are positively correlated with aggressive tumor growth, reduced survival, and radioresistance. Because tumor cells depend on continued stimulation by growth factors, inhibition of the EGFR pathway is a therapeutic strategy in several tumor types. Bevacizumab (Avastin) targets VEGF ligand and inhibits angiogenesis (Answer Choice A). Nivolumab (Opdivo) is a human IgG4 monoclonal antibody that binds to the programmed death (PD)-1 receptor and blocks its interaction with its ligands, PD-L1 and PD-L2 (Answer Choice B). Imatinib (Gleevec) is an inhibitor of a small family of tyrosine kinases, including BCR-ABL, KIT (think GIST) and PDGFR; specifically, imatinib blocks the ATP-binding site of the p210 tyrosine kinase domain of the BCR-ABL fusion protein in chronic myeloid leukemia (Answer Choice C). Rituximab is a monoclonal antibody against CD20, which has a direct anti-tumor effect in CD20-positive lymphomas by inducing apoptosis and cell lysis (Answer Choice E).

Which of the following statements concerning hypoxic cell sensitizers and bioreductive drugs is TRUE? A. One possible reason that clinical trials of hypoxic cell radiosensitizers yielded disappointing results is the dose limitation imposed by severe neurological toxicity that often developed in patients receiving higher doses of the drugs B. Bioreductive drugs are synthesized in a pro-drug form that, upon administration, are oxidized and thereby activated to a cytotoxic intermediate C. Bioreductive drugs are more toxic to aerobic cells than to hypoxic ones D. Clinical trials of nimorazole have yielded results indicating a significant improvement in both local control and overall survival in patients with head and neck cancer treated with this drug and radiotherapy E. Hypoxic cell radiosensitizers are most effective in combination with hyperfractionated radiotherapy

D. Clinical trials of nimorazole have yielded results indicating a significant improvement in both local control and overall survival in patients with head and neck cancer treated with this drug and radiotherapy Metaanalysis has shown that when combined with radiotherapy, nimorazole significantly improves both local control and overall survival in select subsets of patients with head and neck cancer. One reason that clinical trials of hypoxic cell sensitizers may have yielded disappointing results was because of the dose-limiting peripheral neuropathy; this cumulative toxicity severely limited the total dose of sensitizers that could be given over a course of radiotherapy (Answer Choice A). Bioreductive drugs are compounds that are metabolically-reduced under hypoxic conditions to yield cytotoxic species (Answer Choice B). Because the bioreduction occurs preferentially under hypoxic conditions, these drugs are selectively toxic to hypoxic cells and not aerobic ones (Answer Choice C). In laboratory studies, hypoxic cell radiosensitizers are most effective when given in high doses and with large radiation doses; their effectiveness in model tumor systems decreases with increasing fractionation (Answer Choice E). One would expect from these laboratory studies that radiosensitizers would be more effective in combination with hypofractionated radiotherapy regimens or radiosurgery, rather then with standard radiotherapy regimens or hyperfractionated regimens.

Which of the following statements concerning cytokines is TRUE? A. NF-kB is the critical cytokine responsible for the development of lung fibrosis following irradiation B. A paracrine response is the result of a cytokine targeting the same cell that produced the cytokine C. Most cytokines are tyrosine kinases D. Cytokines are proteins released by irradiated cells that stimulate tissues to produce a biological response E. An autocrine response is the result of a cytokine targeting cells adjacent to the cell that produced the cytokine

D. Cytokines are proteins released by irradiated cells that stimulate tissues to produce a biological response Cytokines are proteins released by cells, including irradiated cells, that stimulate tissues to mount a biological response. NF-kB is a transcription factor (not a cytokine). TGF-b1 (TGFB1) is an important example of one of the cytokines that has been associated with the development of lung fibrosis following irradiation (Answer Choice A). A paracrine response is the result of a cytokine that acts upon a cell, other than itself, within a tissue or organ (Answer Choice B). In contrast, an autocrine response is the result of a cytokine targeting the cell from which it was produced (Answer Choice E). Cytokines generally do not have tyrosine kinase activity (Answer Choice C).

Which of the following best describes radiation-induced bystander effects? A. Damage to unirradiated normal tissue noted after irradiation of a tumor B. Cell killing that results from irradiation of the cell's cytoplasm in the absence of direct irradiation of the nucleus C. Radiation-induced increase in cell membrane permeability that causes increased sensitivity to cytotoxic drugs D. DNA and/or chromosomal damage that occurs in unirradiated cells that are nearby irradiated cells E. Intercellular communication that modifies the shoulder region of the radiation survival curve

D. DNA and/or chromosomal damage that occurs in unirradiated cells that are nearby irradiated cells While damage to cellular DNA was long considered the major initiator of cellular responses to ionizing radiation, more recent evidence suggests the involvement of non-targeted pathways, including radiation-induced bystander effects. Bystander effects are defined as radiation-like effects observed in cells that are not themselves irradiated, but that are in communication with irradiated cells through their location near these cells or by stimuli transferred from the irradiated cells through the intracellular medium. Various endpoints have been measured as bystander effects, including enhanced cell killing, induction of apoptosis, presence of chromosome aberrations and micronuclei, presence of DNA double-strand breaks, increased oxidative stress, genetic effects (including induction of mutations, and neoplastic transformation) and altered gene expression

Which of the following statements is TRUE regarding ionizing radiation-induced mutagenesis? A. Mutations that are induced by ionizing radiation can be identified by T to A nucleotide transitions B. High LET radiation tends to cause small deletions, while low LET radiation tends to cause large deletions C. The spectrum of mutations observed following exposure to ionizing radiation is similar to the spectrum of mutations observed following exposure to ultraviolet (UV) light. D. Exposure of sperm to low dose-rate radiation usually results in fewer mutations than exposure of sperm to the same dose but at a higher dose-rate. E. The relative dose to double the rate of mutagenesis is 5 Gy.

D. Exposure of sperm to low dose-rate radiation usually results in fewer mutations than exposure of sperm to the same dose but at a higher dose-rate. Low dose-rate exposure usually results in fewer mutations than the same dose given at a high dose rate. T to A transitions are usually found following exposure to ultraviolet (UV) light, but not to ionizing radiation (Answer Choice A). High LET radiation tends to cause large deletions, while low LET radiation tends to cause small deletions (Answe Choice B). The types of mutations observed following exposure to ionizing radiation can differ from the spectrum of mutations observed following exposure to UV radiation (Answer Choice C). The relative dose to double the rate of mutagenesis is estimated to be 1 Gy (Answer Choice E).

The use of one or a few large radiation doses is generally contraindicated for radiotherapy because of an increased likelihood of late normal tissue complications compared to more conventional fractionation. However, special procedures such as stereotactic radiosurgery and intraoperative radiotherapy employ large doses, apparently without an increase in late effects. The best explanation for this finding is that: a. These special procedures have not been in use long enough for all of the anticipated late complications to manifest themselves b. Normal tissue radioprotectors are usually administered along with the high dose treatments c. Radioresistance caused by tissue hypoxia is more pronounced when large doses are used rather than small doses d. Extra care is taken in these procedures to produce the most conformal treatment plan possible, so as to minimize the amount of late-responding normal tissue irradiated e. DNA repair systems in tumor cells are more easily saturated following one or a few large doses than in the surrounding normal tissue cells incidentally irradiated

D. Extra care is taken in these procedures to produce the most conformal treatment plan possible, so as to minimize the amount of late-responding normal tissue irradiated Although stereotactic radiosurgery or intraoperative radiotherapy employ large fraction sizes in which the entire treatment dose may be delivered in one irradiation, the incidence of late complications from these regimens has generally not been significantly elevated compared with a standard protocol because the dose is delivered to avoid irradiation of normal tissue. In addition, the biologic mechanisms for achieving tumor control and production of normal tissue damage may differ substantially for very large dose fractions compared with standard 2 Gy dose fractions. For many trials, a sufficient follow-up period has been realized so that most late effects, if they were to develop, would have appeared. Normal tissue radioprotectors are not routinely used in conjunction with these procedures. Although radioresistance by tissue hypoxia is more pronounced when large doses are used and there is less opportunity for hypoxic tissue to reoxygenate with only one or a small number of fractions, in most instances, normal tissues do not contain hypoxic regions. There is no evidence that DNA repair systems would saturate more readily in tumor cells than normal cells, if at all.

The cells thought to be responsible for radiation-induced cognitive dysfunction reside in: A. Medulla oblongata B. Cerebral cortex C. Substantia nigra D. Hippocampus E. Hypothalamus

D. Hippocampus Cognition = Think MEMORY Radiation-induced cognitive impairment is marked by decreased verbal memory, spatial memory, attention, and novel problem-solving ability. The incidence and severity of radiation-induced cognitive impairment increases over time. The hippocampus houses neuronal stem cells and is one of only two areas where neurogenesis continues after birth. The hippocampus plays an important role in learning and memory consolidation. The importance of sparing the hippocampus was demonstrated in the recently reported phase III NRG-CC001 trial of whole-brain radiotherapy plus memantine, with or with hippocampal avoidance. Patients were randomly assigned to memantine plus whole-brain radiotherapy (30 Gy in 10 fractions) vs memantine plus hippocampal-avoidant whole-brain radiotherapy (30 Gy in 10 fractions). Hippocampal-avoidant whole-brain radiotherapy plus memantine reduced the risk of cognitive function failure by 26% (P = .033).

Which of the following responses is LEAST likely to be observed? A. Exposure to hypoxia increases the expression of angiogenesis-promoting genes B. Anti-angiogenic therapy improves tumor oxygenation C. A chronically hypoxic environment increases the metastatic potential of tumor cells D. Hypoxia inhibits apoptosis in tumor cells E. Exposure to hypoxia inhibits cell proliferation

D. Hypoxia inhibits apoptosis in tumor cells An increased apoptotic index is often observed in hypoxic regions of tumors. The gene for vascular endothelial growth factor (VEGF/VEGFA) is one of the major genes under the control of the hypoxia responsive promoter, HRE, which binds the transcription factor, hypoxia-inducible-factor (HIF)-1 (Answer Choice A). Studies in animal models have indicated that treatment with anti-angiogenics can cause "normalization" of tumor blood vessels and result in a transient improvement in tumor oxygenation before vessels start to deteriorate (Answer Choice B). Pre-clinical studies with animal models as well as clinical studies have linked increased hypoxia in tumors to increased tumor aggressiveness and metastatic potential (Answer Choice C). Exposure to severe hypoxia halts progression of cells through the cell cycle and therefore inhibits proliferation.

Which of the following statements concerning tumor hypoxia is TRUE? A. Hypoxic regions in tumors may be detected using labeled bortezomib B. As a tumor increases in size, the hypoxic fraction of cells decreases C. Regions of chronic hypoxia may develop in tumors due to the intermittent opening and closing of blood vessels D. In the absence of reoxygenation it is unlikely that all hypoxic cells would be eliminated from a tumor following a typical course of radiotherapy E. Acutely hypoxic tumor cells usually exhibit slow reoxygenation while chronically hypoxic tumor cells reoxygenate rapidly

D. In the absence of reoxygenation it is unlikely that all hypoxic cells would be eliminated from a tumor following a typical course of radiotherapy In the absence of reoxygenation it is unlikely that all hypoxic cells would be eliminated following a typical course of radiotherapy from a tumor possessing even a small percentage of hypoxic cells because hypoxic cells demonstrate approximately 3-fold greater radioresistance compared with aerated cells. Hypoxic regions in tumors can be detected using a labeled nitroimidazole compound. Bortezomib (Velcade) is a proteasome inhibitor (Answer Choice A). Although not without exceptions, as tumors increase in size the hypoxic fraction generally also increases. This is because the typically abnormal tumor vasculature is insufficient to maintain oxygen demand (Answer Choice B). Regions of acute or transient hypoxia may develop in tumors due to intermittent blood flow via the intermittent closing down of blood vessels. Chronic hypoxia, on the other hand, is defined as diffusion-limited hypoxia due to the inability of oxygen to diffuse farther than 100 um from a blood vessel (Answer Choice C). Acutely hypoxic cells that tend to exhibit rapid reoxygenation, whereas chronically hypoxic cells generally reoxygenate more slowly (Answer Choice E).

Which of the following statements is correct? After total body irradiation, the prodrome of the radiation syndrome: A. Is not seen unless doses exceed 10 Gy B. Occurs after the exposed person has recovered from the GI syndrome C. Can be ameliorated through treatment with amifostine approximately 3-5 hours after the exposure D. Includes GI symptoms such as anorexia, nausea, and vomiting that occur within minutes to hours following exposure and lasting hours to days, depending on the radiation dose E. Is characterized by hematopoietic system damage, but no effects related to the gastrointestinal system

D. Includes GI symptoms such as anorexia, nausea, and vomiting that occur within minutes to hours following exposure and lasting hours to days, depending on the radiation dose The prodrome of the radiation syndrome is a spectrum of early symptoms that occur shortly after whole body irradiation, lasts for a limited amount of time, and varies in time of appearance, duration, and severity depending on the dose. GI symptoms such as anorexia, nausea, and vomiting occur when an individual is exposed to doses near the LD50; at higher doses, symptoms such as fever and hypotension are also seen. The radioprotector amifostine would not be expected to ameliorate these symptoms if given after irradiation.

An exponentially-growing, asynchronous population of cells is maintained under normal physiological conditions. Which of the following experimental manipulations would potentiate cell killing following radiotherapy as measured by a clonogenic assay? A. Cell synchronization in S-phase at the time of irradiation B. Irradiation under hypoxic conditions C. Irradiation with the dose split into two fractions with a 24-hour interval between fractions rather than given as an acute exposure to the same total dose D. Incorporation of bromodeoxyuridine into the DNA prior to irradiation E. Addition of cysteine to the cellular growth medium prior to irradiation

D. Incorporation of bromodeoxyuridine into the DNA prior to irradiation Bromodeoxyuridine incorporated into cellular DNA in place of thymidine acts as a radiation sensitizer, so cell killing would be enhanced, not reduced. S-phase is the most radioresistant phase of the cell cycle, so cell killing would be decreased relative to that for an asynchronous population (Answer Choice A). Oxygen is a radiation sensitizer, so cell killing would decrease in cells made hypoxic before irradiation (Answer Choice B). Splitting the dose into two fractions separated by 24 hours would allow sublethal damage recovery and possibly enable cellular proliferation to take place between fractions. Cell killing would therefore be less than if the total dose had been delivered acutely (Answer Choice C). Cysteine is a sulfhydryl-containing compound that scavenges radiation-induced free radicals; it therefore acts as a radioprotector and reduces cell killing (Answer Choice E).

Concerning the effects of heat on cells, which of the following statements is FALSE? A. Cells of low pHe (extracellular pH) or low Phi (intracellular pH) are sensitive to heat. B. Cycling cells are more sensitive to heat than non-cycling cells. C. Both aerated and acutely hypoxic cells have similar sensitivity to heat. D. Initial shoulder of hyperthermic survival curve suggests the repair of sublethal damage. E. Hyperthermia doesn't affect the repair of radiation-induced DNA damage

D. Initial shoulder of hyperthermic survival curve suggests the repair of sublethal damage. Due to the difference in the mode of action, it is important not to draw conclusions for heat based on the interpretation of radiation dose-response curves. The amount of energy involved in cell inactivation is a thousand times greater for heat than for x-rays.

Which of the following cytokines is generally considered both antiinflammatory and immunosuppressive? A. Interleukin 1 B. Interleukin 6 C. Interleukin 8 D. Interleukin 10 E. Tumor necrosis factor alpha (TNF⍺)

D. Interleukin 10 IL-10 is produced by a variety of different cell types, particularly monocytes/macrophages and lymphocytes. It is a major anti-inflammatory cytokine that inhibits the initiation and effector phases of cellular immune responses as well as a variety of inflammatory responses. PROINFLAMMATORY: IL-1, IL-6, IL-8, and TNF⍺ ANTIINFLAMMATORY: IL-10 There is considerable overlap between the activities of TNF⍺ and IL-1. TNF⍺ is secreted mainly by activated monocytes/macrophages and has profound pro-inflammatory effects. It also stimulates the secretion of many other cytokines, including IL-1, IL-6, and IL-8. IL-1 is also a key mediator of host response to infection and inflammation. The main cellular sources of IL-1 are cells of the monocyte and macrophage lineage. Similar to TNF⍺, IL-1 induces several secondary cytokines, including IL-6 and IL-8. Upon stimulation by IL-1 and/or TNF⍺, IL-6 and IL-8 are produced by a large number of different cell types, including monocytes, fibroblasts, endothelial cells and epithelial cells.

All of the following are used for brachytherapy implants EXCEPT: A. Cesium-137 B. Iridium-192 C. Iodine-125 D. Iodine-131 E. Gold-198

D. Iodine-131 Cesium-137, Iridium-192, Iodine-125, and Gold-198 are all available for brachytherapy implants. Iodine-131 is an unsealed isotope that is administered systemically for diagnostic or therapeutic purposes.

When a live human cell is irradiated by gamma-rays, which one of the following events may eventually cause most of the damage to DNA? A. Absorption of radiation energies by the chemical bonds in the DNA molecules B. Ionization and excitation on atoms within the DNA structure C. Ionization and excitation on atoms within the histones that are bound to DNA D. Ionization and excitation of the water molecules that surround DNA E. Direct damage to the lipids that may later oxidize DNA

D. Ionization and excitation of the water molecules that surround DNA The indirect effect mediated by free-radical reactions involving water are most responsible to cause DNA damage upon low LET irradiation

Which of the following statements is correct? Compared with damage from low LET radiation, damage from high LET radiation: A. Is reduced to a greater extent in the presence of sulfhydryl compounds B. Shows more potentially lethal damage recovery C. Exhibits a greater OER D. Is less subject to split-dose recovery E. Shows greater sparing when the irradiation is given at a low dose rate

D. Is less subject to split-dose recovery There is little or no split-dose recovery following high LET radiation exposure because the single dose survival curves for high LET radiations have little or no shoulder. There is also little or no potentially lethal damage recovery, oxygen effect or radioprotection afforded by the presence of sulphydryl compounds. Delivery of a radiation dose at a low dose rate leads to less sparing for a high LET radiation compared with a low LET radiation. Split dose recover = assay for SLDR Delayed plating = potentially lethal damage repair

Which of the following statements concerning LET is INCORRECT? A. LET is proportional to charge density of a medium B. LET is proportional to charge (squared) of the particle moving through a medium C. LET is inversely proportional to speed (squared) of the particle D. LET is inversely proportional to mass of the particle moving through a medium E. LET is related to density of ionizations along the particle's track

D. LET is inversely proportional to mass of the particle moving through a medium LET is a measure of local energy deposition along a track of medium. It is inversely proportional to the energy of a given charged particle. The local transfer of energy to medium is more probable at lower energies.

Which statement concerning the linear energy transfer (LET) is CORRECT? A. LET is equal to the energy transferred by ionizing radiation to soft tissue per unit mass of soft tissue B. LET is equal to the number of ion pairs formed per unit track length C. Once a photon transfers all its energy to an electron, the LET is that of the electron D. LET is the quotient of the average energy that a particle lost in causing ionization to the average distance it travels between two consecutive ionizations E. The track average method and the energy average method for calculating LET give different numerical values for therapy protons in soft tissue

D. LET is the quotient of the average energy that a particle lost in causing ionization to the average distance it travels between two consecutive ionizations think of this as density of energy deposition per unit track length Photons, such as 250 KV X-rays, in passing through tissue produce no ionizations directly but only by setting in motion atomic electrons of tissue molecules. Electrons set in motion by incident photons have a broad energy distribution which is dissipated in tracts with LET ranging from about 0.4 to 40 keV/μm. Radiation therapy high energy photons can generate neutrons with energy between 0.1 to 2 MeV through photon interactions with nuclei of high atomic number materials that constitute the linac head and collimator systems. These neutrons in passing through tissue also produce no ionization directly but by setting protons in motion by knock on collitions with hydrogen nuclei of the cellular water molecules. Protons set in motion by photoneutrons dissipate energy over a range of LET up to about 90 keV/μm. Answer choice E mainly pertains to neutrons, not protons, where the average method and the energy method for calculating LET give significantly different numbers.

Which of the following metastatic cancers is predicted to have the LOWEST response rate from checkpoint blockade? A. Melanoma B. Lynch syndrome-associated endometrial cancer C. Non-small cell lung cancer D. Microsatellite-stable colorectal cancer

D. Microsatellite-stable colorectal cancer The somatic mutation load of cancers is thought to be a major determinant of response to immune checkpoint blockade through the generation of neoantigens targetable by the immune system. Mismatch repair (MMR) deficiency and microsatellite instability (MSI) are essentially synonymous for the purposes of mutagenicity, as the former leads to the latter. MMR deficiency is seen in 10-20% of patients with sporadic colorectal cancer and approximately 20% of sporadic endometrioid endometrial adenocarcinomas. MMR deficiency is also the hallmark of Lynch syndrome, which predisposes patients to these tumors as well as others. Although MSI is not a hallmark of melanoma and NSCLC, these diseases are typically associated with high mutational burden attributed to the instigating mutagenicity of ultraviolet light and tobacco exposure, respectively. HIGH Tumor mutational burden = better response predicted to immune checkpoint blockade

Which of the following pairs of chemotherapy drugs and the dependence of their toxicity on oxygenation status is INCORRECT? A. Bleomycin - more toxic under aerated conditions B. Tirapazamine - more toxic under hypoxic conditions C. 5-Fluorouracil - no difference in toxicity between aerated and hypoxic conditions D. Mitomycin C - more toxic under aerated conditions E. Misonidazole - more toxic under hypoxic conditions

D. Mitomycin C - more toxic under aerated conditions The bioreductive properties of mitomycin C make it more toxic to many cells under hypoxic conditions. Bleomycin induces DNA breaks and is dependent on the presence of oxygen (Answer Choice A). Tirapazamine is activated to a toxic radical only at a very low levels of oxygen, such as in human tumors. Tirapazamine has been shown to produce hydroxyl or benzotriazinyl radicals to damanage DNA. Misonidazole is a hypoxic radiosensitizer (Answer Choice E).

Which of the following concerning autophagy is INCORRECT? A. Autophagy is a reversible process that can contribute both to tumor cell death and survival B. Anti-malarial drugs, chloroquine and hydroxychloroquine, are the only U.S. Food and Drug Administration-approved inhibitors of autophagy C. Autophagy contributes to cellular metabolism by degradation of damaged protein aggregates and organelles D. Mitophagy referes to autophagy in mitotic cells E. Autophagy is controlled by the Atg family of proteins

D. Mitophagy referes to autophagy in mitotic cells Autophagy can be nonselective or selective. Nonselective autophagy, bulk degradation of cytoplasm and organelles by autophagy provides material to support metabolism during periods of cellular stress. For example, autophagy provides internal nutrients, when external ones are unavailable. Whether mechanisms exist to prevent bulk autophagy from consuming essential components, such as a cell's final mitochondrion, remains unclear, and in some cases such consumption may lead to cell death. Selective autophagy of proteins and of organelles such as mitochondria (mitophagy), ribosomes (ribophagy), endoplasmic reticulum (reticulophagy), peroxisomes (pexophagy), and lipids (lipophagy) occurs in specific situations. Autophagy ('self-eating') tends to refer to macroautophagy: the sequestration process of cytoplasmic material for degradation. (Microautophagy and chaperone-mediated autophagy are other types.) After initiation, an isolation membrane encloses a small portion of cytoplasmic material, including damaged organelles and unused proteins, to form a double-membraned structure called an "autophagosome" that subsequently fuses with lysosomes to become an "autolysosome", in which the cytoplasmic material is degraded by lysosomal enzymes. The whole process is tightly regulated through at least 30 Atg-autophagy related genes that orchestrate initiation, cargo recognition, packaging, vesicle nucleation expansion and fusion and breakdown. The initial steps center around the Atg1 complex (Atg1-Atg13-Atg17- Atg29-Atg31) that translocates to the ER, (thought to be the major membrane source for autophagy). This leads to recruitment of the autophagy-specific form of the PI(3)K complex, which includes Vps34, Vps15, Atg6/Beclin-1 and Atg14, to the ER. To form an autophagosome, elongation and closure of the isolation membrane requires 2 protein conjugation systems, the Atg12-Atg5-Atg16 complex and the Atg8/LC3-phosphatidylethanolamine (PE) complex. Detection of autophagy relies on the redistribution of GFP-LC3 fusion proteins into vesicular structures (which can be autophagosomes or autolysosomes). 'Autophagic cell death' is the excessive version of autophagy, that occurs in the absence of chromatin condensation. In contrast to apoptotic cells, there is little or no association of autophagic cells with cells phagocytes. Although the expression 'autophagic cell death' is a linguistic invitation to believe that cell death is executed by autophagy, the term simply describes cell death with autophagy.

Which of the following statements concerning irradiation of the CNS is FALSE? A. Selective damage to gray matter would preclude radiation as the cause of injury B. Demyelination and white matter necrosis are common manifestations of radiation-induced injury to the CNS C. Oligodendrocytes and vascular endothelial cells are considered to be the principal target cells for radiation-induced damage to the CNS D. Most forms of radiation injury to the CNS are characterized by distinct pathognomonic characteristics specific to radiation-induced damage E. Cognitive deficits are a late effect seen in both children and adults

D. Most forms of radiation injury to the CNS are characterized by distinct pathognomonic characteristics specific to radiation-induced damage There are typically no distinct pathognomonic characteristics of CNS injury that would unambiguously identify radiation as the causative agent.

Directly ionizing radiation includes all of the following EXCEPT: A. Electrons B. Positrons C. Alpha particles D. Neutrons E. Betas

D. Neutrons Neutrons are not charged particles and, therefore, cannot ionize atoms directly. They do, however, transfer some of their energy to protons or light nuclei, which then cause ionization. They are, therefore, indirectly ionizing.

Oxygen enhancement ratio (OER) changes depend on the type of radiation. Which of the following combinations is FALSE? A. OER 3.0 for x-rays B. OER 1.6 for neutrons C. OER 3.0 for protons D. OER 0.5 for carbon ions E. OER 1.0 for alpha-particles

D. OER 0.5 for carbon ions OER for energized ions should be 1.0. By definition, OER cannot be smaller than 1.0.

Which one of the following is a radiolysis product of water responsible for the molecular damage caused by the indirect action of ionizing radiation? A. eaq B. 1O2 C. OH- D. OH• E. O2-

D. OH• 65-75% of the damage caused by indirect action is mediated by the hydroxyl radical, OH•. Little biological damage is caused by the hydrated electron (eaq; Answer Choice A). 1O2 is produced primarily by photosensitizers and, rarely, by ionizing radiation (Answer Choice B). Neither OH- nor O2- are primary radiolysis products, although O2- can be produced secondarily by reaction of eaq with O2 (Answer Choices C and E).

A local tumor recurrence after radiotherapy can be caused by: A. Any surviving cancer cell B. Any proliferating cancer cell C. Only cancer cells with the ability to form colonies in vitro D. Only cancer cells with unlimited proliferative potential E. Only cancer cells that were well-oxygenated during irradiation

D. Only cancer cells with unlimited proliferative potential Results from tumor transplantation experiments indicate that only a small proportion of all cancer cells have an unlimited proliferative capacity and demonstrate the capacity of self-renewal. In analogy to in vitro assays, tumor cells that demonstrate the ability to achieve a local recurrence following radiotherapy have been termed "clonogenic cells" and correspond to putative "cancer stem cells". The existence of cancer stem cells, defined by the ability for self-renewal and generation of the heterogeneous lineage of cells within a tumor, has been hypothesized.

With regard to the retreatment tolerance of previously-irradiated normal tissues, which of the following statements is FALSE? A. The lung is capable of long-term recovery after doses that are below the tolerance dose for radiation pneumonitis B. Re-irradiation tolerance for acute damage in rapidly-dividing mucosal tissues is generally observed C. The spinal cord is capable of moderate long-term recovery after irradiation D. Re-irradiation tolerance of the kidney increases with increasing time interval between treatments, indicating continuous repair of sub-threshold damage E. The onset of late bladder damage occurs much earlier in animals that were re-irradiated following a low sub-tolerance intital radiation dose, as opposed to being treated to tolerance in a single course of therapy

D. Re-irradiation tolerance of the kidney increases with increasing time interval between treatments, indicating continuous repair of sub-threshold damage In the kidney, the tolerance to retreatment decreases with time, indicating a continuous progression of renal injury in the interval between treatments. Experimental studies in mice given initial radiation doses approximately 30-50% of the biologically effective tolerance dose (BEDt) showed that the lungs could be re-irradiated with doses equivalent to the BEDt provided a sufficient time interval between the first and second treatments had elapsed. Re-irradiation tolerance for acute damage in rapidly dividing mucosal tissues is commonly observed. Rodent and monkey data indicate that, contrary to popular belief, the spinal cord is capable of considerable recovery from the injury caused by an initial radiation treatment and can subsequently be retreated with at least a partial tolerance dose. In the bladder, the latency period before expression of injury is shorter in animals that were re-irradiated, as opposed to being treated to tolerance in a single course of therapy, even after low, sub-tolerance initial radiation doses.

Which of the following statements concerning radiation-induced effects among survivors of the atomic bombings of Hiroshima and Nagasaki is TRUE? A. There is no change in the incidence of heart disease among survivors who received less than 5 Gy B. Susceptibility to radiation-induced breast cancer increases with increasing age at the time of exposure C. The latency period between irradiation and the appearance of most solid tumors is 1-3 years D. Statistically significant increases in mortality from non-cancer causes with increasing dose have been observed E. For a population of 1,000 people, each exposed to an acute, whole body dose of 1 Sv, roughly 8 would die from a radiation-induced cancer according to current radiation risk estimates Bonus: what % of people dies from a radiation induced cancer from 1 Sv exposure?

D. Statistically significant increases in mortality from non-cancer causes with increasing dose have been observed Statistically significant increases in non-cancer disease mortality with increasing radiation dose have been observed, particularly for diseases of the circulatory, digestive, and respiratory systems. Survivors who received less than 5 Gy demonstrate an increased risk of heart disease (Answer Choice A). Among the Japanese A-bomb survivors, susceptibility to radiation-induced breast cancer was found to dramatically decrease with increasing age at time of exposure, with women over 50 years of age showing little or no excess (Answer Choice B). The latency period for the appearance of most radiation-induced solid tumors is far greater than 1-3 years, ranging from 10-60 years post-exposure (Answer Choice C). It is estimated that 8% of people exposed to 1 Sv would die from a radiation-induced cancer. Thus, in a population of 1,000 people, approximately 80 would develop and die from a fatal cancer (Answer Choice E).

Which of the following pairs of radiobiological process and corresponding assay method is CORRECT? A. Reoxygenation - HIF-1a (HIF1A) phosphorylation by ATM B. Potentially lethal damage recovery - tritiated thymidine uptake C. cell cycle "age response" - paired survival curve method D. Sublethal damage recovery - split dose experiment E. Repopulation - mitotic shakeoff procedure

D. Sublethal damage recovery - split dose experiment Sublethal damage recovery is operationally defined and demonstrated using a split dose protocol. Potentially lethal damage repair is detected by changing the post-irradiation environment and observing the effect on survival (Answer Choice B). Incorporation of tritiated thymidine into DNA = DNA synthesis and other forms of DNA repair. Reoxygenation would best be assayed by performing repeat measurements during the course of radiotherapy by using an oxygen electrode or by treating with a hypoxia maker, such as pimonidazole, that is metabolized and incorporated exclusively into hypoxic cells (Answer Choice A). Cell cycle age response is best demonstrated by performing cell synchronization followed by irradiation of cohorts of cells in particular cell cycle phases and then performing the clonogenic survival assay as a readout (Answer Choice C). Repopulation can be assayed in vitro by counting the number of cells present as a function of time after irradiation. The mitotic shake off technique is used to collect synchronous populations of cells for use in experiments examining age response functions (Answer Choice E).

Which of the following statements concerning chromosome aberrations is TRUE ? A. A ring chromosome is an example of a chromatid-type aberration B. A dicentric is a stable chromosome aberration C. Breakage of a single chromatid in G2 often leads to the formation of an anaphase bridge D. Terminal deletions are induced as a linear function of dose E. For low LET radiation, the yield of dicentric chromosomes is inversely proportional to the dose-rate

D. Terminal deletions are induced as a linear function of dose Terminal deletions are induced as a linear function of dose since they result from a single chromosomal break. A ring chromosome is an example of a chromosome-type aberration, not a chromatid-type aberration (Answer Choice A). A dicentric is an unstable aberration since it results in the formation of an acentric fragment and ultimately causes cell death (Answer Choice B). Breaks in two chromatids, followed by illegitimate rejoining, produce an anaphase bridge (Answer Choice C). The yield of dicentric chromosomes increases with increasing dose-rate for low LET radiation (Answer Choice E)

Which of the following statements concerning the effects of radiation on the heart is TRUE? A. Radiation associated valvular disease is rare in patients receiving ≥ 35 Gy to the heart. B. In the absence of concurrent chemotherapy, cardiomyopathy is observed during or shortly after the completion of radiotherapy C. An increased incidence of cardiovascular disease among Hodgkin's disease survivors who received mediastinal radiotherapy has not been observed D. The critical structure associated with the pathogenesis of radiation-induced heart disease appears to be the endothelial lining of blood vessels E. An excess relative risk for myocardial infarction has been detected in the Japanese atomic bomb survivors, but only among those who received doses greater than 10 Gy

D. The critical structure associated with the pathogenesis of radiation-induced heart disease appears to be the endothelial lining of blood vessels The critical target structure associated with the development of radiation-induced heart disease appears to be the endothelial lining of blood vessels, particularly arteries. Irradiation of endothelial cells is thought to induce early stimulation of a pro-inflammatory signaling cascade that enhances arteriosclerosis and microvascular dysfunction. Historically, radiation pericarditis represented a significant complication of large-volume radiation therapy to the breast or mediastinum to doses greater than 40 Gy. With current treatment methods, however, a much smaller heart volume is irradiated, so radiation pericarditis is now infrequently observed. Radiotherapy-induced valvular disease may occur in greater than 80% of patients receiving ≥ 3 Gy to the heart (Answer Choice A). Cardiomyopathy during or shortly after radiotherapy is only observed in patients who received combined anthracycline chemotherapy (Answer Choice B). Following mediastinal radiotherapy for treatment of Hodgkin's Lymphoma, a statistically-significant increase in the risk of fatal cardiovascular disease, primarily attributable to myocardial infarction, has been reported among patients surviving 10 years or more (Answer Choice C). Similarly, an increased risk of myocardial infarctions has also been reported after post-operative radiotherapy for breast cancer. One of the most important recent findings among the survivors of the Japanese atomic bombings is that mortality from myocardial infarction is significantly increased more than 40 years after receiving acute doses as low as 1-2 Gy (Answer Choice E).

Which of the following statements concerning radiation-induced late effects is TRUE? A. Most late effects develop primarily as a direct result of endothelial cell killing B. Most late effects are due to the loss of parenchymal cell clonogens C. Radiation-induced late effects produce unique pathological responses D. The development of late effects shares many elements in common with both acute and chronic wound-healing responses in normal tissues E. Once present, late effects are irreversible

D. The development of late effects shares many elements in common with both acute and chronic wound-healing responses in normal tissues Despite the recent surge in interest in radiation-induced late effects, the precise mechanisms responsible for their development and progression remain unclear. Historically, late effects were considered to be a consequence of the radiation-induced killing of either parenchymal or vascular target cell populations, and as such, were thought to be inevitable, progressive, and untreatable. More recent findings suggest that this hypothesis is overly simplistic. Radiation-induced late effects are now viewed as the result of dynamic interactions between multiple cell types within the tissue. The parenchymal cells are no longer viewed as passive bystanders, merely dying as they attempt to divide, but rather are thought to be active participants in an orchestrated, yet limited, response to injury. In general, irradiating late-responding normal tissues leads to an acute inflammatory response followed by an aberrant chronic inflammatory/wound healing response in which vascular and parenchymal cell dysfunction and cell loss, associated with chronic overproduction of particular cytokines and growth factors, result in fibrosis and/or necrosis, depending on the particular organ involved. This new paradigm promises novel approaches to the mitigation of radiation-induced normal tissue complications, including the possibility that late effects might be reduced by the application of therapies directed at altering steps in the cascade of events leading to the clinical expression of the injury. There are no pathognomonic features characteristic of irradiated late-responding normal tissues.

Which of the following statements is TRUE regarding effects of radiation exposure on the male and female reproductive systems? A. The dose to induce temporary sterility in the female is 2 Gy B. The latent period for temporary sterility in the female is 1 year C. Radiation sterility in the male affects hormone balance, libido, and physical capability D. The dose that will cause oligospermia and reduced fertility in the male is 0.15Gy E. The dose that will cause permanent sterility in the premenopausal (post-pubertal) in the female is 1 Gy

D. The dose that will cause oligospermia and reduced fertility in the male is 0.15Gy The dose that will lead to oligospermia and reduced fertility in the male is estimated to be 0.15 Gy. There is neither a latent period nor temporary sterility in the female following exposure to radiation (Answer Choices A and B). Radiation sterility does not affect hormone balance, libido, or physical capability in the male, but can induce permanent ovarian failure and menopausal symptoms in the female (Answer Choice C). The dose that will lead to permanent sterility in the female is 12 Gy in the prepubertal woman and 2 Gy in the premenopausal (mature) woman (Answer Choice E).

Which one of the following statements is TRUE concerning radiation mutagenesis? A. Radiation produces unique mutations not otherwise seen spontaneously B. It has been reported that the children of patients who had been treated with ionizing radiation prior to conception demonstrate an increased incidence of genetic abnormalities compared to children whose parents had not been irradiated prior to conception C. Roughly 25% of the spontaneous mutations in humans can be attributed to exposure to background radiation D. The genetic doubling dose for humans has been estimated to be 1-2 Sievert (Sv) E. The absolute mutation rate in humans is approximately 8% per Sv

D. The genetic doubling dose for humans has been estimated to be 1-2 Sievert (Sv) The dose required to double the incidence of mutations in humans has been estimated to be approximately 1-2 Sv. Radiation does not induce characteristic mutations; it only increases the incidence of mutations that are known to occur spontaneously (Answer Choice A). A higher incidence of genetic abnormalities was not found in the children with at least one parent who previously received treatment with ionizing radiation prior to conception (Answer Choice B). The best estimates are that no more than 1-6% of spontaneous mutations in humans are due to exposure to background radiation (Answer Choice C). The absolute mutation rate for humans has been estimated to be approximately 0.1-0.6% per Sv.

With regard to the latency period for the expression of radiation-induced normal tissue injury, which of the following statements is CORRECT? A. The latency period for early-responding tissues decreases markedly with increasing radiation dose B. Shortening the overall treatment time by accelerating radiotherapy substantially reduces the latency period for early-responding tissues C. Shortening the overall treatment by accelerating radiotherapy tends to increase the latency period for late-responding tissues D. The higher the total radiation dose, the shorter the latency period for many late-responding tissues E. The latency period for early-responding tissues depends on the rate of vascular endothelial cell turnover

D. The higher the total radiation dose, the shorter the latency period for many late-responding tissues KEY TO THIS QUESTION: Remember -- early responding tissues (high a/b) (early normal and tumor) are sensitive to (worse early reaction side effects/improved tumor control): - TOTAL DOSE - Decreased TOTAL time of treatment late responding tissues (low a/b) (mostly normal tissue and some slow growing tumors) are sensitive to (worse late effects or SHORTENED LATENCY TO ONSET) - TOTAL DOSE - Increased DOSE PER FRACTION The "latency" of early responding tissues is irrelevant - those are controlled by the length of time the cell takes to go from the basal stem cell compartment to the mature functioning cell type. Increasing the dose or shortening the treatment time won't have any effect on the "latency" but might increase the SEVERITY of these changes. Test explanation: Early-responding tissues exhibit radiation-induced injury during or shortly after a course of radiotherapy. Late reactions are manifested months or years following the completion of radiotherapy. The classical model of radiation-induced normal tissue injury hypothesizes that normal tissue injury involves the loss of specific target cell clonogens. In early-responding tissues such as the skin and oral mucosa, clonogenic cell turnover is rapid, as is clonogenic cell death. Thus, the latency period, i.e., the period before the expression of radiation-induced injury, is short. This latency period is fixed in early-responding tissues, since it depends on the time it takes for cells to move from the stem cell compartment through the transit compartment, and finally to the terminally-differentiated, non-dividing parenchymal cell that is lost through normal wear and tear. In contrast, target cell turnover is slow or non-existent in late-responding tissues and therefore the latency period is long. Shortening the overall treatment time may cause greater cell depletion and increase the severity of early reactions since the time available for cell repopulation would be limited under these circumstances. This might result in more pronounced "consequential" late effects; however, the latent period for these late effects would, if anything, decrease, rather than increase. According to classical theory, the decrease in the latency period with dose for late effects was thought to be due to the enhanced cell killing resulting from the use of higher doses. It is now recognized that this cell killing likely plays only a limited role in the development of most late responses. In contrast, it is thought that when irradiation of a tissue may give rise to a late radiation reaction, there is initially an acute inflammatory response followed by an aberrant chronic inflammatory/wound healing response. Vascular and parenchymal cell dysfunction and cell loss then occur which are accompanied by a chronic overproduction of particular cytokines and growth factors, ultimately resulting in the manifestation of radiation toxicity. Thus, it is now thought that the process ultimately leading to the development of late radiation effects actually begins relatively quickly after irradiation. Presumably, the speed and/or intensity of this process is somewhat dose dependent such that the length of time necessary before a late effect is observed clinically decreases with increasing dose. There is no relationship between the latency period for early-responding tissues and endothelial cell turnover; if anything, the latter has been considered a target cell for injuries in late-responding tissues.

With respect to radiation-induced heart disease (RIHD), which one of the following statements is FALSE? A. Individuals 20-65 years of age have a lower risk for the development of radiation-induced coronary artery disease compared with other age groups B. The parietal pericardium may be damaged by radiation therapy, with the injury typically presenting as an increased thickness of the fibrous layer C. The risk of pericarditis increases with increasing dose per fraction D. The majority of cardiac complications observed are consistent with the hypothesis that the most radiosensitive cells are the cardiomyocytes E. Cardiac effects are described as "delayed", and typically appear months to years after radiotherapy

D. The majority of cardiac complications observed are consistent with the hypothesis that the most radiosensitive cells are the cardiomyocytes Vascular endothelial cells are the most radiosensitive cells in the heart, with direct radiation damage to this population leading to protein leakage, fibrin deposition and the up-regulation of such cytokines as transforming growth factor beta 1 (TGF-b1). Many other cell types within the heart contribute to the development of radiation-induced heart disease (RIHD), but of them all, the cardiac myocyte, a fixed post-mitotic cell, is the most radioresistant. A number of large clinical trials, particularly those performed in Hodgkin's disease patients, have indicated that the populations most at risk for RIHD are young females and the elderly, and that the important factors governing tissue tolerance are total dose, fraction size, and volume irradiated. Typically, late effects in the heart occur months to years after treatment completion. One structure that may be affected by radiation therapy is the parietal pericardium, with an associated fibrous thickening due to collagen replacing the external adipose layer.

Immune related adverse events (irAEs) describe a range of immune-mediated toxicities that can result from treatment with immune checkpoint inhibitors. Which statement regarding irAEs is NOT correct: A. Skin, gut, endocrine, lung and musculoskeletal irAEs are relatively common, whereas cardiovascular, hematologic, renal, neurologic and ophthalmologic irAEs occur much less frequently. 83 B. irAEs typically have a delayed onset and prolonged duration compared to adverse events from chemotherapy. C. irAEs are discrete toxicities caused by tissue-specific inflammation and activation of the immune system, and can affect almost any organ system. D. The overall incidence of irAEs following treatment with anti-CTLA-4 monotherapy tends to be lower than those with anti-PD-1/PD-L1 agents E. The incidence of irAEs with ipilimumab and pembrolizumab is dose-dependent, with greater toxicity at higher dose levels;

D. The overall incidence of irAEs following treatment with anti-CTLA-4 monotherapy tends to be lower than those with anti-PD-1/PD-L1 agents Most common toxicities from targeting immune checkpoints relate to breaking tolerance. Targeting of PD-1 or PD-L1 tends to be less toxic than targeting CTLA-4 on average, presumably because they regulate different components in the evolution of an immune response. The cytotoxic T-lymphocyte-associated antigen 4 (CTLA4)-mediated immune checkpoint is induced in T cells at the time of their initial response to antigen. The level of CTLA4 induction depends on the amplitude of the initial T cell receptor (TCR)-mediated signaling. High-affinity ligands induce higher levels of CTLA4, which dampens the amplitude of the initial response. The key to the regulation of T cell activation levels by the CD28-CTLA4 system is the timing of surface expression. Naïve and memory T cells express high levels of cell surface CD28 but do not express CTLA4. Instead, CTLA4 is sequestered in intracellular vesicles. After the TCR is triggered by antigen encounter, CTLA4 is transported to the cell surface. The stronger the stimulation through the TCR (and CD28), the greater the amount of CTLA4 that is deposited on the T cell surface. Therefore, CTLA4 functions as a signal dampener to maintain a consistent level of T cell activation in the face of widely varying concentrations and affinities of ligand for the TCR. By contrast, the major role of the programmed cell death protein 1 (PD1) pathway is not at the initial T cell activation stage but rather to regulate inflammatory responses in tissues by effector T cells recognizing antigen in peripheral tissues. Activated T cells upregulate PD1 and continue to express it in tissues. Inflammatory signals in the tissues induce the expression of PD1 ligands, which downregulate the activity of T cells and thus limit collateral tissue damage in response to a microorganism infection in that tissue. The best characterized signal for PD1 ligand 1 (PDL1; also known as B7-H1) induction is IFNγ, which is predominantly produced by T helper 1 (TH1) cells, although many of the signals have not yet been defined completely. Excessive induction of PD1 on T cells in the setting of chronic antigen exposure can induce an exhaustive or anergic state.

Which of the following is an example of synthetic lethality? A. Retroviral overexpression of p53 in tumor cells to induce apoptosis B. Infusion of chimeric antigen receptor-expressing T cells to induce an anti-tumor immune response C. The use of taxane-containing nanoparticles to take advantage of leaky tumor vasculature and cause improved tumor cell kill while limiting normal tissue toxicity D. The use of poly-ADP ribose polymerase inhibitors to abrogate repair of DNA damage in BRCA1/2-mutant tumors and thus promote lethal DNA damage

D. The use of poly-ADP ribose polymerase inhibitors to abrogate repair of DNA damage in BRCA1/2-mutant tumors and thus promote lethal DNA damage Synthetic lethality is the situation whereby a defect in one of a pair of genes has little to no effect on cell survival, while defects in both genes results in death. A clinically relevant example of this is the use of poly-ADP ribose polymerase (PARP) inhibitors such as olaparib in BRCA1/2 mutated breast cancers. Because BRCA1/2-mutated cancers have defective homologous recombination repair (HRR), they depend on error-prone alternative DNA repair pathways for genome maintenance and survival. PARP binds to single-strand DNA breaks to initiate non-homologous repair. Inhibition of PARP by compounds such as olaparib interrupt this process, promote stalled replication forks, and result in double strand breaks. BRCA1/2-wild type cells with intact HRR do not depend on this pathway and are therefore not sensitive to PARP inhibition. When you see PARP inhibitors - think synthetic lethality

Which of the following statements about carbon ion therapy is FALSE? A. For a given dose to the tumor in the Bragg peak, carbon ions produce better sparing of normal tissues in the entrance region of the beam than either protons or photons B. Carbon ions have a high RBE in the Bragg peak region C. There is reduced scattering in both the lateral and longitudinal directions for carbon ions compared to protons D. There is a greater variation in radiosensitivity between oxygenated and hypoxic tumor cells using carbon ions compared with photons E. PET verification can be used for carbon ion treatment

D. There is a greater variation in radiosensitivity between oxygenated and hypoxic tumor cells using carbon ions compared with photons Carbon ions represent a high LET form of radiation and, as such, display less dependence upon oxygen for cell killing (and therefore have a lower OER). Hence, there should be fewer hypoxic tumor cells surviving carbon ion therapy than following treatments using either X-rays or protons. Basic research with light ions established that carbon ions suitable for radiotherapy (~400 MeV/amu) have superior depth-dose profiles from the entrance region of the beam up through the Bragg peak (Answer Choice A). Two centers, one at the HIMAC in Chiba, Japan, and the other at the HIT in Heidelberg, Germany, have been treating with carbon ions using a gantry for over a decade and a number of other centers have come online since then. Carbon ions show an increased RBE for both cells irradiated in vitro and tissues exposed in vivo. The exact RBE depends on the energy of the beam and the characteristics of the cells at risk (Answer Choice B). An additional advantage of treatment with carbon ions is the reduction in lateral and longitudinal scatter (Answer Choice C). It is possible to verify the carbon ion treatment plan using PET since a small fraction of the ions undergo nuclear fragmentation when a beam of carbon ions penetrates a thick absorber. Often, one or two neutrons are stripped, converting the stable 12C to the positron emitting isotopes 11C and 10C. These isotopes travel with almost the same velocity as the main beam and stop in nearly the same location. They have short half-lives and as the emitted positron combines with an electron in an annihilation reaction, two 0.51 MeV photons are produced that can be detected by a PET scanner. As a consequence, the high dose treatment volume can be visualized (Answer Choice E).

In children, which of the following organs is the most sensitive to the induction of both benign and malignant tumors by X-rays? A. Bone marrow B. Intestine C. Breast D. Thyroid E. Lung

D. Thyroid Both benign nodules and malignant tumors of the thyroid can be induced by radiation. None of the other sites shows such an increased incidence of benign tumors following treatment with ionizing radiation.

Which of the following statements concerning vasculogenesis is TRUE? A. The process of vasculogenesis is specific to the developing embryo B. Vasculogenesis refers to a subset of angiogenesis, in that it describes the formation of only venous vessels as tumors grow beyond 1-2 mm3 C. Tumors use vasculogenesis or angiogenesis in a mutually exclusive fashion D. Vasculogenesis is critical for a tumor to achieve local tumor recurrence following radiotherapy E. Vasculogenesis utilizes pre-existing blood vessels during the early stages of tumor development to facilitate tumor growth

D. Vasculogenesis is critical for a tumor to achieve local tumor recurrence following radiotherapy Whereas angiogenesis is the sprouting of endothelial cells from nearby blood vessels, vasculogenesis is the formation of blood vessels from circulating endothelial progenitor cells (i.e. the bone marrow). Vasculogenesis is of particular importance following treatment with anti-angiogenic agents as well as following irradiation. During early tumor development, both vasculogenesis and angiogenesis are likely utilized. Because tumor irradiation abrogates local angiogenesis, the tumor must rely on the vasculogenesis pathway for re-growth following irradiation. Tumor irradiation produces a marked influx of CD11b+ myeloid cells into tumors and are critical in order for a tumor to achieve formation of blood vessels after irradiation as well as for tumor recurrence.

All of the following could affect the slope of a tumor control probability (TCP) curve, EXCEPT: A. Tumor size B. Tumor oxygenation C. Intrinsic tumor cell radiosensitivity D. Volume of normal tissue in the radiation field E. Histopathological tumor type and grade

D. Volume of normal tissue in the radiation field The slope of a tumor control probability (TCP) curve is determined by factors that introduce heterogeneity into the population of tumors under study. Tumor heterogeneity can be caused by variations in tumor size, oxygenation, tumor cell radiosensitivity, or histological type and grade of the tumor. While it may be important for toxicity and therefore for the therapeutic ratio, the volume of normal tissue in the radiation field does not affect the tumor control probability.

Cells from individuals diagnosed with which of the following diseases/syndromes would be expected to have an X-ray survival curve with a relatively large D0? A. Nijmegen breakage syndrome B. LIG4 syndrome C. ATR-Seckel syndrome D. Xeroderma pigmentosum E. Ataxia telangiectasia

D. Xeroderma pigmentosum D0 is a measurement of radiosensitivity made on the exponential part of the survival curve. It is defined as a dose that gives an average of one lethal hit per cell. A dose of D0 Gy reduces survival from 1 to 0.37. Hence, the smaller D0 is, the more radiosensitive the cells are. Cells derived from an individual diagnosed with xeroderma pigmentosum are defective in nucleotide excision repair (NER). These cells are sensitive to UV radiation because this form of radiation produces damages such as pyrimidine dimers that are removed through the nucleotide excision repair pathway. Because DNA double-strand breaks are important lesions responsible for lethality in cells exposed to X-rays and because DNA double-strand break repair is generally normal in cells derived from a person diagnosed with xeroderma pigmentosum, the D0 determined from a radiation survival curve for these cells would not be particularly small. People with Nijmegen breakage syndrome (NBS1, part of the MRN complex involved in HR), LIG4 syndrome (involved in NHEJ), ATR-Seckel syndrome and ataxia telangiectasia (ATR involved in DNA replication and ATM involved in both NHEJ and more so in HR -autophosphorylates and then fully activated by MRN complex and phosphorylates H2AX and brca1/palb1/brca2; RPAs bind to the single strands to recruit others and keep open, if 53bp1 is bound to the dsb, this prevents resection and leads to NHEJ, if brca is upregulated then it displaces 53bp1 and leads to HR. Those who possess mutations in either NBS1, LIG4, ATR or ATM, respectively, are all characterized by defects in strand break repair or repair-related signaling. Therefore, at least a small increase in radiosensitivity (a decrease in the D0) would be expected in cells derived from people with these syndromes.

Pulsed-field gel electrophoresis can be used in order to: A. determine a cell's karyotype B. detect DNA interstrand crosslinks C. separate protein molecules on the basis of both molecular weight and charge D. monitor the repair/rejoining of large pieces of DNA after the production of double-strand breaks E. determine the rate of base versus nucleotide excision repair

D. monitor the repair/rejoining of large pieces of DNA after the production of double-strand breaks Pulsed-field gel electrophoresis is a technique in which a gel is subjected to electrical fields that are alternating in orientation, thereby allowing very large DNA fragments to migrate and separate. This technique enables the detection of the repair/rejoining of DNA double-strand breaks following irradiation with a biologically-relevant dose.

Which statement is TRUE concerning the role of p53 (TP53) and p21 (CDKN1A) in the response of the cells to radiation? A. p21 phosphorylates NBS1 (NBN), thereby stimulating homologous recombinational repair of DNA double-strand breaks B. p53-mediated G1 phase arrest results from the inactivation of p21 C. A decrease in the amount of p53 can trigger apoptosis or G1 arrest D. p21 inhibits CDK-cyclin activity thereby decreasing phosphorylation of RB1 E. DNA damage initiates a signal transduction pathway that results in a marked increase in transcription of the p53 gene

D. p21 inhibits CDK-cyclin activity thereby decreasing phosphorylation of RB1 p21 inhibits CDK-cyclin activity, which has the effect of decreasing the phosphorylation of RB1. ATM, and not p21, phosphorylates NBS1 thereby stimulating homologous recombinational repair. p53-mediated G1 arrest results from transactivation of p21 by p53. An increase in the amount of p53 can result in apoptosis or G1 arrest. DNA damage does initiate a signal transduction pathway that results in increased amounts of p53, however this occurs by stabilization of the existing protein, rather than by increased transcription of the gene that encodes it.

Which of the following statements is TRUE concerning p53 (TP53)? A. MDM2 binding to p53 inhibits its degradation B. Irradiation of cells stimulates ATM to act as a phosphatase and remove phosphate groups from p53 C. Following irradiation, p53 activates Cdc25C to stimulate the G2 to M phase transition D. p53 stimulates the activity of BAX and BID in irradiated cells, resulting in apoptosis

D. p53 stimulates the activity of BAX and BID in irradiated cells, resulting in apoptosis p53 stimulates the activity of BAX and BID in irradiated cells, resulting in apoptosis. MDM2 binding to p53 stimulates degradation of p53. Irradiation of cells activates ATM to add phosphate groups to p53. Following irradiation, p53 inhibits CDC25C which inhibits the G2 to M phase transition. Lymphocytes and thymocytes with a mutant p53 tend to be more radioresistant than their normal counterparts.

Which of the following has the highest radiation tolerance dose (TD5/5) for whole organ irradiation? a. Kidney b. Ureter c. Colon d. Stomach e. Liver

E I don't understand this at all -- the question doesn't even have skin as an option and this is the answer they give: Temporary epilation can be caused by a 3 Gy acute exposure, and is observed around 3 weeks after irradiation. The doses and times to appearance for the other skin reactions are: Temporary erythema - 2 Gy - 1 day Permanent epilation - 7 Gy - 3 weeks Dry desquamation - 14 Gy - 4 weeks Moist desquamation - 18 Gy - 4 weeks I agree if skin is an option, it has essentially 100% re-treatment ability- specifically epidermis, but it isn't an option....I think based on the question as it is written, the answer is ureter

Which of the following types of chromosome aberrations is most responsible for the formation of micronuclei observed after irradiation? A. Sister chromatid exchanges B. Chromatid gaps C. Inversions D. Quadriradials E. Acentric fragments

E Micronuclei are created due to the presence of acentric fragments, which form in the progeny of irradiated cells that undergo mitosis in the presence of one or more asymmetrical chromosome aberrations. Sister chromatid exchanges are reciprocal exchanges between chromatids of the same chromosome that are not readily induced by ionizing radiation (Answer Choice A). Chromatid gaps appear as loss of genetic material from a single chromatid arm and may be caused by incomplete breaks (Answer Choice B). Inversions result when two breaks are produced in a single chromosome and the resulting excised chromosomal fragment reinserts itself back into the chromosome, but with the opposite polarity (Answer Choice C). A quadriradial is a chromatid-type aberration that may arise from illegitimate interchromosomal recombination, accompanied by crossing-over (think FANCONI syndrome)

Which of the following molecular events occurs earlier than the other events following the creation of a double-strand DNA break? A. Destabilization of the mitochondrial outer membrane B. Inactivation of the CDC25 phosphatases C. Phosphorylation of CHK1 (CHEK1) D. Activation of p21 (CDKN1A) transcription E. Phosphorylation of histone H2AX

E Phosphorylation of histone H2AX to g-H2AX occurs within several minutes of a cell being irradiated. This modification is triggered by ATM and serves to mark the chromosomal site of the DNA break for the subsequent recruitment of signaling proteins, such as CHK1 kinase. Activated CHK1 phosphorylates and inactivates CDC25 proteins, thereby causing the arrest of the cell cycle. P21 transcription is induced several hours after DNA damage, following the stabilization of p53 (TP53).

The oral mucosa and skin present with many similar pathological features during their progression toward radiation toxicity. Which of the following statements regarding the overlapping pathologies observed in these tissues is FALSE? A. Oral mucositis is a result of the death and consequent desquamation of the epithelial layers, and is therefore an analogous event to the radiodermatitis (dry/moist desquamation) seen as an early response in irradiated skin B. Erythema secondary to vasodilation is observed in skin following doses greater than about 2 Gy, similar to the case for mucositis C. Radiation effects in both oral mucosa and skin are dependent on total dose, fraction size, and volume irradiated D. Possible late effects in both skin and oral mucosa include ulceration and fibrosis E. The development of dental caries following oral radiotherapy is similar mechanistically to the infections that accompany radiation-induced dermal ulcers; both result from ischemic necrosis due to the loss of small blood vessels

E The oral mucosal response to irradiation is indeed similar to that seen in skin. However, the formation of dental caries is a direct consequence of the killing of saliva-secreting acini cells in the salivary glands, ultimately leading to xerostomia. This results in the loss of saliva's normal antibacterial action and acidification of the mouth. This is in contrast to the infections observed in irradiated skin which are a downstream consequence of damage to small blood vessels.

Which of the following statements best describes the "normalization hypothesis" proposed to explain the survival benefit associated with combining anti-angiogenics with traditional chemotherapy agents? A. Anti-angiogenic therapy stimulates the formation of leaky blood vessels thereby enhancing access of chemotherapy agents to the tumor parenchyma B. Anti-angiogenic therapy transiently reduces pericyte coverage of tumor blood vessels, which would otherwise form a significant mechanical and biochemical barrier to the delivery of chemotherapy to the tumor C. Tumor cell-derived pro-angiogenic factors render endothelial cells resistant to chemotherapy-induced apoptosis. Anti-angiogenic therapy eliminates this protection and restores endothelial cell sensitivity to chemotherapeutic agents D. Anti-angiogenic therapy reduces the secretion of anti-apoptotic factors by vascular endothelial cells that would otherwise render nearby cancer cells relatively resistant to chemotherapeutic agents E. Anti-angiogenic therapy transiently restores the normal balance of pro- and anti-angiogenic factors in tumor tissue thereby reducing tumor vessel leakiness, dilation, and tortuosity as well as increasing pericyte coverage

E Anti-angiogenic therapy transiently restores the normal balance of pro- and anti-angiogenic factors in tumor tissue thereby reducing tumor vessel leakiness, dilation, and tortuosity as well as increasing pericyte coverage When administered as a single agent, several anti-angiogenic drugs have not yielded a long-term survival benefit. In contrast, delivery of anti-angiogenic agents with chemotherapy has produced a significant survival benefit in colon cancer and previously untreated lung and breast cancers. If the anti-angiogenic agent were destroying tumor vasculature in combination regimens, one would expect decreased tumor blood flow and compromised delivery of chemotherapy to the tumor. The survival benefits produced by the addition of an anti-angiogenic drug to traditional chemotherapeutic regimens therefore appears paradoxical. One possible explanation for this has been termed the "normalization hypothesis." Under the pressure of pro-angiogenic factors, tumor vasculature is structurally and functionally abnormal. Anti-angiogenic therapy (transiently) restores the balance of pro- and anti-angiogenic factors. Consequently, immature and leaky blood vessels are pruned, pericyte coverage increases, and the basement membrane becomes more homogenous and normalized. As a result, the resultant vascular bed achieves greater organization by being less leaky, dilated, and tortuous. These morphological changes also result in functional changes, including decreased interstitial fluid pressure, increased tumor oxygenation, and improved penetration of drugs into the tumor parenchyma. Due to improved drug delivery, chemotherapy is more efficacious. Sustained or high-dose anti-angiogenic therapy, however, may drive an imbalance favoring anti-angiogenic factors leading to inadequate tumor blood supply and compromise of the efficacy of systemic therapies.

Which of the following statements is TRUE concerning the irradiation of a series of cell lines derived from breast carcinomas with an X-ray dose of 4 Gy? a. Most cells will die within several hours b. Annexin V staining will be detectable in the majority of cells within minutes c. A majority of cells will undergo apoptosis before completing mitosis d. Cells derived from tumors with a mutant p53 (TP53) are radioresistant e. Many cells will continue to divide for several days

E Important thing to recognize here is that they said SOLID -- not lymphoma cells. The whole p53 mutants are apoptosis resistant applies to situations where the dominant mode of cell death is apoptosis -- at low doses in those cases, p53 mutants would lack p53-PUMA mediated apoptosis initiation and would be radioresistant. In solid tumors, a MINORITY of the cells will die by apoptosis. Rather, these will be more likely to die by mitotic catastrophe and thus can divide a few times before dying.

Which of the following statements concerning cell survival curve analysis is TRUE? A. The β parameter generally increases as the radiation dose rate decreases B. The inverse of the Dq corresponds to the final slope of the survival curve C. The extrapolation number, n, of a survival curve increases with increasing LET of the radiation D. D0 is a measure of the incremental increase in cell survival when a given dose is fractionated E. If n = 1, then D37 = D0

E Parameters to define a radiation cell survival curve include: the initial slope (D1), a final slope (D0), and some quantity that is a measure of the width of the shoulder. This quantity can be the extrapolation number (n) or the quasi-threshold dose (Dq). If n=1, the survival curve has no shoulder and D37 (dose resulting in a survival fraction of 0.37) equals the D0. If n isn't 1, that means there is a shoulder region, and thus the surviving fraction to go from 1 --> 0.37 doesn't equal to the D0 dose. You have to move further down on the exponential portion in order for say 0.01 --> 0.0037 to equal the D0 dose. For the same radiation dose, radiation delivered at a lower dose rate may produce less cell killing than radiation delivered at a higher dose rate because sublethal damage repair occurs during the protracted exposure. As the dose rate is reduced, the slope of the survival curve becomes shallower and the shoulder tends to disappear because α does not change significantly but β trends to zero in the linear quadratic model - the component of b-kill increases if the dose rate increases as there is less capacity to repair SLD. The inverse of the D0, not the Dq, is equal to the final slope of the survival curve. For densely ionizing radiation (increasing LET), the shoulder of the survival curve tends to disappear. N, therefore, decreases, until it reaches a value of 1.0 for very high LET radiations. The D0 would not necessarily be a good predictor for the effect of fractionation on survival; Dq or n would be better.

The volume doubling time (in days) for a tumor with a cell loss factor of 90% and a Tpot of 20 days would be estimated as: a. 5 b. 20 c. 50 d. 100 e. 200

E The volume doubling time can be estimated from the equation cell loss factor = 1-(Tpot/Tvol) Therefore, 0.9 = 1 - (20 days/Tvol) or Tvol = 200 days.

Which of the following statements regarding the tumor microenvironment is FALSE? A. Blood vessel supply is heterogeneous and irregular B. Blood flow through micro-vessels may be sluggish C. There tends to be an increase in vessel density compared to normal tissue D. There are a greater number of hypoxic regions within the microenvironment of a tumor compared to that seen in normal tissue E. Nutritional support to the tumor microenvironment is adequate and homogeneous

E - Nutritional support to the tumor microenvironment is adequate and homogeneous Tumor masses exhibit abnormal blood vessel networks that fail to provide adequate and homogeneous nutritional support.

A tumor is characterized by a cell cycle time of 10 days, a growth fraction of 0.5 and a cell loss factor of 1.0. Assuming these kinetic parameters remain constant over a one month period, how much would the tumor volume have increased during that time? a. Increase 2-fold b. Increase 3-fold c. Increase 4-fold d. Increase 5-fold e. Remain the same What's the key to understand here?

E Since the cell loss factor is equal to 1.0, the tumor would remain the same size since for every new cell produced, one existing cell would die and slough off the tumor. cell loss factor is 1 or 100% which means that there is no NET increase in cells over time. Cell loss factor is typically 0.9 for human tumors (90% lost and don't contribute to growth of the tumor).

Suppose that on her 21st birthday, the same radiation worker was described in the previous question declared that she was 3 months pregnant. What additional dose limit to the fetus has the NCRP recommended for the duration of her pregnancy? A. She would not be allowed any additional radiation exposure once the pregnancy was declared B. 1 mSv C. 10 mSv D. 50 mSv, assuming that she had no measurable exposure yet that year E. 0.5 mSv per month

E. 0.5 mSv per month The NCRP recommendations state that a worker who has declared a pregnancy may receive a maximum dose of 0.5 mSv per month to the fetus.

A clinician changes from the usual fractionation schedule of 1.8 Gy given once per day to an accelerated treatment using 1.6 Gy fractions delivered twice per day. In order to avoid the possibility of reduced normal tissue tolerance due to incomplete repair, what should be the minimum inter-fraction interval for the accelerated schedule? A. 0.5-1 hour B. 1-2 hours C. 2-3 hours D. 3-6 hours E. 6-8 hours

E. 6-8 hours Results from clinical trials of hyperfractionation and accelerated fractionation employing more than one fraction per day have shown worse late complications when the time between fractions was less than 6 hours. This finding has been attributed to incomplete repair, because sublethal damage recovery is generally slower in late-responding tissues. It has since been suggested that even an inter-fraction interval of 6 hours may not be sufficient for those normal tissues with the slowest repair rates and that a longer time between fractions may be necessary to avoid a reduction in tolerance dose.

A 1 cm-diameter tumor that contains 107 clonogenic cells is irradiated with daily dose fractions of 1.8 Gy. The effective dose response curve has been determined and is exponential with a D10 of 8 Gy. What total dose will correspond to the TCD90 (90% probability of tumor control), assuming no cell proliferation between dose fractions? A. 32 Gy B. 40 Gy C. 48 Gy D. 56 Gy E. 64 Gy

E. 64 Gy No answer key for this one, but i'm pretty sure that's right. TCD90 = e^-0.1 --> that means 1/10 of a cell left or 10^-1 If you started with 10^7 --> 10^-1 that means 8 logs of cell kill. D10 is a log of cell kill which is 8 Gy here. So 8 Gy x 8 logs = TCD90 requires 64 Gy

Which immune-mediated mechanism plays a role in cancer prevention? A. Detection and elimination of tumor cells B. Allergic responses C. Prevention of chronic inflammation D. Protection against viral infection and integration E. A, C and D

E. A, C and D

Which of the following organ systems may be affected by an immune adverse event in a lung cancer patient receiving radiotherapy plus immune check point blockade? A. Pulmonary B. Endocrine C. Gastrointestinal D. Skin E. All of the above

E. All of the above Immune related adverse events (irAEs) are a distinctive range of immune-mediated toxicities which may affect any body system. irAEs can occur at any time during or after treatment and they can be life-threatening. Early identification and swift management (typically corticosteroids) are key in avoiding life threatening-severity.

All of the following complications have been observed after high-dose irradiation of a short segment of bone, EXCEPT: A. Osteoradionecrosis B. Stress fractures C. Growth retardation after irradiation of epiphyseal plates in children D. Radiation-induced bone sarcomas E. Bone marrow failure

E. Bone marrow failure Bone marrow failure is not a concern after localized irradiation because of the limited volume of bone marrow irradiated and compensation from the unirradiated marrow volume. Osteoradionecrosis and stress fractures, on the other hand, can be major problems (Answer Choices A-B). In children, growth retardation is a concern after irradiation of growth zones (Answer Choice C). Bone sarcoma is the most common secondary neoplasm following irradiation of bony structures (Answer Choice D).

The cell loss factor represents the ratio of the rate of cell loss to the rate of new cell production. Which of the following is not a dominant cause of cell loss in tumors? A. Death from inadequate nutrition B. Apoptosis (programmed cell death) C. Death from immunologic attack D. Metastasis E. Cell migration

E. Cell migration Cell migration within a tumor has recently been described from the study of microbeam radiation therapy (MRT). Since cell migration occurs within 200 um (the interspace between microbeams), the cells still stay in the tumor mass without affecting cell loss from the tumor.

Which one of the following statements concerning the induction of chromosome aberrations is INCORRECT? A. Primary radiation-induced breaks can reconstitute without apparent morphological change to the chromosome, rejoin illegitimately with another break site to produce an intra- or inter-chromosomal aberration, or remain "open," leading to a simple break B. The induction and interaction of DNA double-strand breaks is the principal mechanism for the production of chromosome aberrations C. Dicentrics, centric rings, and translocations are formed following X-irradiation of cells in the G0/G1 phase of the cell cycle, and their formation follows a linear-quadratic dose response D. Fluorescence in situ hybridization (FISH) using multi-colored probes has allowed chromosome aberration complexity to be studied in detail E. Chromatid type aberrations are observed when cells are irradiated during the G1 phase of the cell cycle

E. Chromatid type aberrations are observed when cells are irradiated during the G1 phase of the cell cycle Chromatid type aberrations are produced in cells only when irradiation follows DNA synthesis in S phase.

Continuous hyperfractionated accelerated radiation therapy (CHART) involved all of the above EXCEPT: A. Short overall treatment time of 12 consecutive days B. Three fractions of radiation per day C. Total dose of 50 - 54 Gy D. Low dose per fraction (1.4 - 1.5 Gy) E. Concurrent chemotherapy

E. Concurrent chemotherapy The CHART protocol was performed in the 1990s in the UK for the treatment of head and neck squamous cancers and non-small cell lung cancer. It involved 36 fractions over 12 consecutive days with three fractions delivered daily. Each fraction was between 1.4 - 1.5 Gy with a total dose of 50 - 54 Gy. The strategy was based on the thought that low dose/fraction would minimize late effects and a short treatment time would maximize tumor control. There was no concurrent chemotherapy given. Long-term results showed no differences in disease outcomes for head and neck cancer patients, but there was an improvement in late morbidity with CHART compared to conventional fractionation. For NSCLC, there was an improvement in local progression and overall survival. Despite these promising results, CHART has had limited adoption due to the resource intensive nature of the treatment as well as the more widespread use of concurrent chemotherapy.

The TUNEL assay used to identify apoptotic cells detects: A. The action of BAX on the mitochondria B. Membrane integrity C. Mitochondrial release of cytochrome c D. Binding of TNF (TNF) to its receptor E. DNA fragmentation

E. DNA fragmentation The terminal deoxynucleotidyl transferase (TdT) mediated deoxyuridine triphosphate (dUTP) nick end-labeling (TUNEL) technique has been used to identify apoptotic cells. It is based upon the binding of TdT to the exposed 3'-OH terminal ends of DNA fragments generated during apoptosis and catalyzes the addition of modified deoxynucleotides, conjugated with biotin or fluorescein, to the DNA termini.

Which of the following statements is correct? One goal of hyperfractionation is to: A. Decrease toxicity to early-responding tissues B. Deliver the total radiation dose in a shorter overall time C. Reduce the number of fractions used D. Prevent tumor cell repopulation E. Decrease the incidence of late effects while maintaining or improving tumor control

E. Decrease the incidence of late effects while maintaining or improving tumor control One goal of hyperfractionation is to improve the therapeutic ratio by decreasing the incidence of late reactions, while maintaining or improving tumor control. Therapeutic gain can be achieved only if the late-responding normal tissue has a lower a/b ratio than that of the tumor. Hyperfractionation would be likely to have no effect on early-responding tissues or may slightly increase toxicity; it would not decrease these toxicities (Answre Choice A). For hyperfractionation, the larger number of smaller-sized dose fractions is typically delivered over about the same overall treatment time as conventional therapy, meaning that there would be no change in the potential of surviving tumor clonogens to repopulate (Answer Choices B, C, and D).

Which of the following pairs of drug and description is CORRECT? A. Glutathione - hypoxic cell cytotoxin B. Nimorazole - most abundant cell sulfhydryl C. Tirapazamine - radioprotector D. Amifostine - bioreductive drug E. Gefitinib - small molecule tyrosine kinase inhibitorE. Gefitinib - small molecule tyrosine kinase inhibitor

E. Gefitinib - small molecule tyrosine kinase inhibitor Gefitinib is a small molecule tyrosine kinase inhibitor approved in the US for use in non-small cell lung cancer (NSCLC) harboring deletion of EGFR exon 19 or mutation of EGFR exon 21 (L858R). Glutathione is a cellular sulfhydryl compound that acts as an antioxidant (Answer Choice A). Nimorazole is a hypoxic cell radiosensitizer, while sufhydryls are considered radioprotectors (Answer Choice B). Tirapazamine (bioreductive drug) is a hypoxic cell cytotoxin and therefore a radiosensitizer (Answer Choice C). Amifostine is a radioprotector that acts by detoxifying reactive metabolites of platinum and alkylating agents, and also scavenges free radical (Answer Choice D).

A total dose of 70 Gy delivered in 2 Gy fractions is used to treat a particular tumor. Assume that the tumor is characterized by an a/b ratio of 2 Gy and a Tpot of 30 days. For the dose-limiting normal tissue, the a/b ratio is 4 Gy. Which one of the following treatment schedules would most likely yield the highest therapeutic ratio? A. Standard fractionation B. Accelerated treatment C. Split-course treatment D. Hyperfractionation E. Hypofractionation

E. Hypofractionation In principle, a hypofractionated protocol would yield the highest therapeutic ratio because if treating with either standard or small fraction sizes (i.e., hyperfractionation) there would be greater sparing of this tumor (a/b ratio = 2 Gy) than for the critical dose-limiting normal tissue (a/b ratio = 4 Gy). There would not be much point to using accelerated treatment since this is a relatively slow-growing tumor (Tpot = 30 days), nor would split course treatment be indicated since, again, the a/ß ratio suggests greater recovery in the tumor versus the normal tissue.

Which of the following statements about ionizing radiation (IR) induced DNA damage is correct? A. IR causes only DNA double-strand breaks B. IR may produce thymine glycols, but much less frequently than DNA double strand breaks C. IR can cause more clustered lesions at low dose rates than at high dose rates D. IR cannot cause oxidization of nucleotide bases E. IR is unlikely to produce pyrimidine dimers

E. IR is unlikely to produce pyrimidine dimers In contrast with the other forms of damage listed, pyrimidine dimers are principally produced following absorption of photons in the ultraviolet wavelength range and are not produced by X-rays. Pyrimidine dimers are cytotoxic, but more of these DNA lesions are required in order to achieve cell death compared to the DNA lesions produced by X-rays. It is estimated that the number of DNA lesions per cell from X-rays necessary to kill 63% of the cell population (thereby allowing 37% to survive - IE 1 log of cell kill) is 40 double-stranded DNA breaks (DSBs). In comparison, 1,000,000 pyrimidine dimers from ultraviolet (UV) radiation are needed to kill 63% of the cell population. IR can produce not only DSBs, but also other forms of damage including single strand breaks, thymine glycols, and base damage. These other forms of DNA damage, however, are more readily repaired and are less likely to result in cell death.

Which of the following statements concerning tumor kinetics is TRUE? A. Cell-cycle times (Tc) are longer than potential doubling times (Tpot) because of the presence of non-proliferating cells B. The Tpot is usually shorter than the volume doubling time because the growth fraction (GF) is usually less than 100% C. Tpot can be determined if the mitotic index (MI) and the duration of S phase (Ts) are known D. Tumors with long values for Tpot are good candidates for accelerated radiotherapy E. In the absence of cell loss, Tpot would equal the volume doubling time (TD) of the tumor

E. In the absence of cell loss, Tpot would equal the volume doubling time (TD) of the tumor The cell loss factor (Φ) is equal to 1-(Tpot/TD). Therefore, if the cell loss factor were zero, then the Tpot would equal the TD. The mean TC is shorter than the Tpot because Tpot also considers the presence of quiescent cells, and the growth fraction in tumors is generally less than 100% (Answer Choice A). For solid tumors the Tpot is generally much shorter than the TD because the cell loss factor is typically quite high. The GF is taken into account in the determination of Tpot, so it does not affect the relationship between the Tpot and the TD (Answer Choice B). Tpot can be calculated from the labeling index (LI) and the duration of S phase (TS) using the equation Tpot = λTS/LI. (where λ is a constant ranging from about 0.6 to 1.0; Answer Choice C). It has been suggested that tumors with short pretreatment values for Tpot, (suggesting the presence of rapidly proliferating cells and a high growth faction), would be most likely to benefit from accelerated radiotherapy, but this has not been confirmed in clinical trials performed to date (Answer Choice D).

Which of the following is NOT a feature of apoptosis? A. Chromatin condensation B. Cell shrinkage C. DNA fragmentation D. Rapid engulfment by neighboring cells E. Inflammatory response

E. Inflammatory response There is no inflammatory response in apoptosis. While an inflammatory response is more a feature of necrosis than apoptosis, there are situations in which apoptosis can stimulate an inflammatory response.

Which of the following statements is TRUE concerning p53 (TP53)? p53: A. Is encoded by an oncogene that is activated in the majority of human cancers B. Is activated in the presence of drug-induced DNA damage C. Inhibits expression of the GADD45A, p21 (CDKN1A) and PCNA genes D. Can be inactivated by Epstein-Barr virus (EBV) E. Is modified by phosphorylation in response to DNA damage

E. Is modified by phosphorylation in response to DNA damage p53 is modified post-translationally by phosphorylation or by acetylation in response to DNA damage. p53 is encoded by a tumor suppressor gene (not an oncogene) that is inactivated in more than half of all human cancers. The DNA repair pathways that regulate p53 include not only NHEJ and HRR, but also MMR, BER, and NER so that p53 plays a universal role in DNA damage surveillance and repair. DNA damage causes p53 to become stabilized and active, not inactive. p53 increases expression of GADD45A, p21, and PCNA. Viruses that contain proteins that inactivate p53 include HPV, SV40 and adenovirus, but not EBV.

Hyperthermia and radiotherapy perform complementary actions in achieving tumor cell killing. Which of the following statements is FALSE? A. Hyperthermia causes protein damage while radiotherapy causes DNA double strand breaks in cells B. Hyperthermia preferentially kills cells in S phase and radiotherapy cells in G2/M phases of the cell cycle C. Hyperthermia causes damage preferentially in hypoxic regions, while radiotherapy primary affects aerobic regions of tumors D. Hyperthermia above 43oC inhibits repair of radiotherapy-induced damage E. Long-duration mild hyperthermia (42oC) cannot inhibit the repair of sublethal radiation damage because of the low temperature

E. Long-duration mild hyperthermia (42oC) cannot inhibit the repair of sublethal radiation damage because of the low temperature

The TCD50 assay: A. Measures radiation-induced tumor growth delay B. Can be conducted using mouse tumors but not human tumor xenografts C. Gives a measure of the number of cells required to produce a tumor in a mouse D. Yields results independent of the immune competence of the host animal E. Measures tumor cure, making it a relevant endpoint for extrapolation to the clinic

E. Measures tumor cure, making it a relevant endpoint for extrapolation to the clinic The TCD50 assay quantifies the dose required to cure 50% of a group of matched tumors and is therefore a highly relevant endpoint for extrapolation to the clinic. The assay can be conducted using mouse tumors or human tumor xenografts (Answer Choice B), although suppression of the host immune system when using xenografts is crucial in order to minimize misleading results due to rejection of implanted cells (Answer Choice D). The TD50 assay can be used to measure the number of cells required to cause a tumor in mice and has historically been used to determine tumor cell survival curves, to assess the number of clonogens in a tumor, and to study host factors that influence tumor development (Answer Choice C).

All of the following processes could be involved in the increased efficacy and safety of conventionally fractionated radiation in the clinic compared to single or hypofractionated treatment, EXCEPT: A. Sublethal damage repair in normal tissues between fractions B. Reoxygenation in tumors C. Redistribution/reassortment of cells in tumors D. Repopulation of critical cell populations in normal tissues E. Potentially lethal damage repair in tumors

E. Potentially lethal damage repair in tumors Sublethal damage repair (SLDR) and repopulation in normal tissues treated with fractionated radiation therapy may contribute to reduced toxicity associated with treatment. Reoxygenation in tumors and possible redistribution of proliferating tumor cells into more sensitive phases of the cell cycle may contribute to increased efficacy of dose fractionation, at least in theory. Potentially lethal damage repair in tumors would not contribute to the efficacy of dose fractionation as this would enhance the survival of tumor cells.

Which of the following statements is correct? High LET radiations: A. Include 250 kVp X-rays, 200 MeV protons, and 1.1 MV X-rays B. Produce much higher yields of OH radicals than do either X-rays or -rays C. Are components of solar flares but not of cosmic rays D. Produce less dense ionization tracks than X-rays E. Produce increased numbers of clustered lesions in DNA than X-rays

E. Produce increased numbers of clustered lesions in DNA than X-rays High linear energy transfer (LET), or densely ionizing, radiations include particles such as 290 MeV carbon ions, X-particles, and neutrons. 250 kVp X-rays, 200 MeV protons and 1.1 MV X-rays are all low LET, or sparsely ionizing, radiations (Answer Choice A). Although high LET radiations produce more clustered lesions (multiply damaged sites) in DNA than low LET radiations (Answer Choice E), they actually produce lower yields of OH radicals because of the extensive ion and radical recombination within spurs and blobs (Answer Choice B). High LET radiations, such as iron or carbon ions, are components of cosmic rays, while solar flares are composed largely of energetic protons (which are low LET; Answer Choice C).

Which of the following radiobiological processes contributes to the inverse dose-rate effect? A. Repair of sublethal damage B. Accumulation of cells in S phase C. Proliferation D. Repair of potentially lethal damage E. Redistribution

E. Redistribution Decreasing the dose rate over the range from 1 Gy/min to 0.01 Gy/min generally results in an increase in the surviving fraction following irradiation with a specific dose of radiation due to repair of sublethal damage (SLDR). The inverse dose-rate effect is the observation that, as the dose rate declines further over a critical range, cellular survival decreases as the same constant dose is delivered. This effect relates to reassortment/redistribution of cells into the radiosensitive phase of the cell cycle by progressing through the DNA damage-induced G2 block. It would not be anticipated that SLDR, the accumulation of cells in S phase, proliferation, or repair of potentially lethal damage (PLDR) would cause an inverse dose-rate effect, since each of these processes would increase cell survival. I generally have an issue with the wording of this question because the inverse dose rate effect implies that cells all accumulate at the G2 block because of the DNA damage, and then when allowed to progress, are al simultaneously more sensitive

Accelerated fractionation is used to: a. Counteract the inherent radioresistance of some tumor cells b. Overwhelm DNA repair processes in tumor cells c. Overcome the radioresistance of hypoxic tumor cells d. Increase the potential for repopulation by cells in normal tissues e. Reduce the potential for tumor cell repopulation

E. Reduce the potential for tumor cell repopulation An accelerated treatment schedule is used primarily to limit the amount of tumor cell repopulation that may occur before the completion of radiotherapy. The repopulation that may occur, particularly for tumors with short Tpot values, can severely limit the effectiveness of treatment. high a/b tissues - tumors - sensitive to total dose and shortened treatment time (to reduce repopulation) -- not significantly affected by fraction size low a/b tissues - normal tissues/late effect -- sensitive to total dose and higher dose per fraction (can do less SLDR if dose per fraction or dose rate is increased) -- not significantly affected by duration of treatment.

Which of the following 5Rs of radiobiology likely has a negative impact on severely hypofractionated schedules (1-5 fractions) used in stereotactic body radiotherapy? A. Radiosensitivity B. Repair/recovery C. Redistribution/reassortment D. Repopulation E. Reoxygenation

E. Reoxygenation Most human tumors except for very small ones have radioresistant hypoxic cells. The negative influence of hypoxic cells against local tumor control is greater in hypo-fractionated radiotherapy compared to conventional therapy. SBRT treatments are usually completed within <1 to 2 weeks and re-oxygenation during the course of SBRT therapy is very limited to negligible. Laboratory and clinical data suggest an intra-fraction interval of at least 3 days to increase possibility for re-oxygenation of tumor cells between fractions.

Which statement regarding the Hounsfield unit scale is CORRECT? The Hounsfield unit scale is: A. Specific to ultrasound imaging (US) B. Specific to positron emission tomography (PET) C. Specific to single photon emission computed tomography (SPECT) D. Specific to magnetic resonance imaging (MRI) E. Specific to computed tomography (CT)

E. Specific to computed tomography (CT) The Hounsfield unit scale is a standardized approach to interpreting reconstructed images obtained with a computerized tomography (CT) scanner. CT is a technique that relies on differential levels of X-ray attenuation by tissues within the body to produce digital images reflecting anatomy. Hounsfield units (HU) are numerical values that reflect these differences in density and composition, and thus X-ray attenuation, between various tissue types. Radiologists use software that automatically assigns HUs to every voxel of a CT scan to enable efficient scan interpretation. In oral radiology, approximate HUs can be derived using grayscale levels in cone beam CT (CBCT) images.

Exponentially growing cells are pulse-labeled with tritiated thymidine and sampled as a function of time thereafter. The time required for the percent of labeled mitoses to reach 50% of its maximum value corresponds approximately to: A. TS B. TC C. TG2 D. TG1 + TS/2 E. TG2 + TM/2

E. TG2 + TM/2 The length of time required for the first radioactively-labeled S phase cells to first enter mitosis, as measured using the percent-labeled mitosis technique, would correspond to the duration of the G2 phase (TG2). The additional time required for the cells to completely fill the mitotic compartment (i.e., 100% labeled mitoses) would be equal to the length of M (TM). The time to reach 50% of the maximum point, therefore, corresponds to TG2 plus TM/2.

For normal tissues such as spinal cord, a small dosimetric hotspot could be disastrous in terms of increasing the likelihood for a serious late complication. However, a small volume receiving a high dose during lung irradiation may not lead to any late sequelae. The best explanation for this observation is that: A. The spinal cord has a large functional reserve, but the lung does not B. Target cells in the lung are better able to repair radiation damage than their counterparts in the spinal cord C. Surviving clonogens in the lung can repopulate rapidly, whereas those in the spinal cord cannot D. Migration of cells from outside the irradiated volume helps to augment lung function, but this process does not occur in the spinal cord E. The putative functional subunits in the lung are arranged in parallel, whereas those in the spinal cord are arranged in series

E. The putative functional subunits in the lung are arranged in parallel, whereas those in the spinal cord are arranged in series The reason why a large dose to a small length of the spinal cord may cause severe radiation injury, such as myelopathy, is that the inactivation of even a single functional subunit (FSU) can disrupt the function of the entire organ for tissues whose FSUs are arranged in a serial fashion. In contrast, a high dose to a small volume of the lung may have little impact because the remainder of the lung will continue to function normally because its FSUs are arranged in parallel.

Which of the following statements concerning intensity-modulated radiation therapy (IMRT) is CORRECT? A. IMRT employs significantly higher energy photon beams than unmodulated radiation dose-delivery techniques. B. IMRT results in fewer radiation therapy-induced second cancers in the pediatric population as compared to adults. C. IMRT is most conformal if used in the conventional 1.8-2.0 Gy/fraction format D. IMRT allows for higher doses to acutely responding normal tissues while decreasing dose to late responding normal tissues. E. The whole-body patient dose is increased with IMRT, compared to treatment plans involving unmodulated beams due to leakage from the head and scatter from the collimator.

E. The whole-body patient dose is increased with IMRT, compared to treatment plans involving unmodulated beams due to leakage from the head and scatter from the collimator. The whole-body patient dose is higher with intensity modulated radiation therapy (IMRT) technique because, in addition to leakage from the head, there is scatter from the collimator. IMRT usually employs a linear accelerator at mega-voltage energies, which are similar to or lower than energies used to deliver treatment doses with an unmodulated field (Answer Choice A). The higher risk of IMRT radiotherapy-induced second cancers in pediatric patients than in adult patients is a direct consequence of the smaller size of the body of a child compared with an adult. As originally discussed by Hall (2006), radiogenic organs are closer to the treatment site in a child and thus receive larger radiation doses than when a comparable treatment is delivered to an adult (Answer Choice B). IMRT is most conformal if all target volumes are treated simultaneously using different fraction sizes (Answer Choice C). This permits graded dose levels to the gross tumor with embedded normal tissues and tissues at risk for tumor spread (normal tissues surrounding the gross tumor and lymph nodes). Such a treatment strategy is called the simultaneous integrated boost (SIB). The SIB strategy uses the same plan for the entire course of treatment to deliver prescribed doses to treated volumes. The effect of modified fractionation on acute and late toxicity of normal tissue is taken into account during treatment planning (Answer Choice D). The SIB-IMRT fraction sizes are estimated using an isoeffect relationship based on the linear-quadratic (LQ) equation using the values of LQ model parameters (such as α/β ratios and tumor doubling time) for the isodose calculations for various tissues components in the treatment volume.

Which of the following statements concerning thermotolerance is TRUE? A. Thermotolerance is a heritable resistance to heat-induced cell killing B. A brief exposure to a temperature above 43C results in resistance to a subsequent additional heat treatment delivered immediately after the 43C treatment, but at a lower temperature C. Thermotolerance develops during the heating of tissues at temperatures higher than 43C D. Thermotolerance limits the clinical utility of hyperthermia E. Thermotolerance results in decreased likelihood of subsequent thermotolerance.

E. Thermotolerance results in decreased likelihood of subsequent thermotolerance. Step-down heating results in greater sensitivity to a subsequent heat treatment at a lower temperature due to inhibition of the development of thermotolerance following the initial 43oC treatment (Answer Choices E and B). Once the protein damage is removed by HSPs after heat treatment, the HSPs rebind HSF1, thereby decreasing the level of HSPs in an autoregulatory loop and restoring normal heat sensitivity. Thermotolerance is an acquired transient resistance to heat that is not heritable by the progeny of the treated cells (Answer Choice A). Thermotolerance develops during the heating of tissues at temperatures lower than 43 C (Answer Choice C). The onset and decay of thermotolerance correlates with the appearance and disappearance of heat shock proteins, and is not related to the repair of DNA damage (Answer Choice D).

The regulation of hypoxia-inducible factor-1a (HIF-1a; HIF1A) by oxygen concentration is best described by which of the following statements? A. Under hypoxic conditions, HIF-1a transcription and translation are upregulated as well as translocation of HIF-1a from the cytosol to the nucleus B. Under aerobic conditions, the HIF-1a heme moiety becomes oxygenated. This drives a conformational change in the protein that limits DNA binding and prevents upregulation of target genes C. Under hypoxic conditions, HIF-1a is activated by bioreduction, thereby promoting the up-regulation of target genes D. Under hypoxic conditions, the HIF-1a heme moiety becomes deoxygenated. This induces a conformational change in the protein that leads to enhancing DNA binding and subsequent upregulation of target genes E. Under aerobic conditions, HIF-1a is hydroxylated by HIF prolyl hydroxylases that target the protein for ubiquitination and subsequent proteosomal degradation, thereby preventing the up-regulation of target genes

E. Under aerobic conditions, HIF-1a is hydroxylated by HIF prolyl hydroxylases that target the protein for ubiquitination and subsequent proteosomal degradation, thereby preventing the up-regulation of target genes Hypoxia-inducible factor-1 (HIF-1) is a heterodimer that acts as a key regulator of several oxygen-responsive proteins, including erythropoietin and vascular endothelial growth factor (VEGF). HIF-1 was first identified as a DNA-binding protein that mediated the up-regulation of the erythropoietin gene under hypoxic stress. Subsequent studies have implicated HIF-1 in the regulation of a broad range of oxygen responsive genes including VEGF, VEGF receptors, angiopoietins, nitric oxide synthase, fibroblast growth factors and platelet-derived growth factor (PDGF). Under aerobic conditions, HIF-1a is hydroxylated by HIF prolyl hydroxylases (PHDs). Hydroxylation at two prolyl residues targets HIF-1a to the von Hippel-Lindau (VHL) E3 ubiquitin ligase and results in HIF-1a ubiquitination and subsequent proteosomal degradation, thereby limiting upregulation of target genes. Because the hydroxylation catalyzed by prolyl hydroxylases requires molecular oxygen, HIF-1 escapes inactivation under hypoxic conditions.

For tumors exhibiting central hypoxia, what strategy is most likely to improve the therapeutic ratio of treatment? A. Stimulation of repair in hypoxic tumor cells B. Inhibition of reoxygenation in tumor cells C. Use of a systemic radioprotector drug that reaches both tumor and normal cells D. Inhibition of DNA repair in tumor and normal cells E. Use of a systemic radioprotector drug that preferentially accumulates in normal tissues

E. Use of a systemic radioprotector drug that preferentially accumulates in normal tissues Normal tissues are typically well-oxygenated, but some tumors may contain a fraction of radioresistant hypoxic cells. Larger tumors are more likely to harbor hypoxic regions. In order for a radioprotector to be efficacious and improve the therapeutic ratio, it must have a preferential effect on normal tissues either through increased selectivity for normal tissues or decreased selectivity for tumor cells. Amifostine is the prototypical radioprotector with Phase III data and meta-analyses demonstrating mucositis and xerostomia without affecting progression-free survival or overall survival. The disadvantages of amifostine include the need for IV infusion, moderate rates of nausea/vomiting, and risk of hypotension. Answers A and B describe strategies that would protect tumor cells. Answer C describes radioprotection of both normal tissues and tumor, which is not expected to change the therapeutic ratio. Answer D describes inhibition of DNA repair in both normal and tumor cells and would be expected to sensitize both populations but not change the therapeutic ratio.

Based on functional genomic studies using microarray profiling, which one of the following statements best describes the transcriptional response of irradiated cells and tissues? A. Many genes are up-regulated by radiation exposure, but down-regulation of genes is rarely observed B. The transcriptional response to radiation is complex, but for a given cell line similar responses will be seen between 2- and 24-hours post-irradiation C. The transcriptional response is dynamic and varies with time after irradiation, but overall is similar for most cell lines examined to date D. Transcriptional responses depend on the time elapsed after irradiation and on the cell's tissue of origin but do not vary significantly between cell types derived from the same tissue or between different individuals E. Variability observed in transcriptional profiles between individuals may provide a basis for prediction of individual therapeutic responses in the future as a basis for individualized medicine

E. Variability observed in transcriptional profiles between individuals may provide a basis for prediction of individual therapeutic responses in the future as a basis for individualized medicine Many genes are both up- and down-regulated following irradiation in both a time and tissue-dependent manner. In addition, variation is also seen between cells derived from the same tissue and between tissue samples taken from different individuals. This inter-individual variation is seen both in the response to stressors such as ionizing radiation and in the normal basal gene expression patterns. One of the major driving factors in the science of microarray profiling is the hope that a better understanding of this variability in gene expression may lead to a more "personalized" diagnosis of disease, prognosis and prediction of the best therapeutic approach for cancer and other diseases.

Bevacizumab (avastin) is a monoclonal antibody that targets: A. Basic fibroblast growth factor (bFGF; FGF2) B. Hypoxia-inducible factor-1 (HIF-1; HIF1A) C. Von Hippel-Lindau (VHL) protein D. Ras E. Vascular endothelial growth factor (VEGF; VEGFA)

E. Vascular endothelial growth factor (VEGF; VEGFA) Bevacizumab (avastin) binds to and neutralizes vascular endothelial growth factor (VEGF)-A ligand, thereby preventing its interaction with cell surface receptors, including the VEGF receptor (VEGFR). The fibroblast growth factors (FGFs) are a family of pluripotent growth factors that stimulate proliferation of mesodermal or neuroectodermal cells and can play a role in angiogenesis (Answer Choice A). FGFs have yet to be successfully targeted pharmaceutically. Hypoxia-inducible factor (HIF)-1a is a transcription factor that detects hypoxia and enhances angiogenesis (Answer Choice B). The Von Hippel-Lindau (VHL) protein belongs to a complex that is involved in the ubiquitination and degradation of HIF (Answer Choice C). The Ras proteins are a family of small GTPases involved in the activation of signaling cascades following activation of receptors. Ras is frequently mutated in human cancers but is difficult to target pharmacologically (Answer Choice D).

siRNAs and miRNAs: A. bind to and inhibit the replication of specific genes B. stimulate RNA synthesis C. are typically 1 kb in size D. stimulate protein synthesis E. inhibit the translation of specific genes

E. inhibit the translation of specific genes The use of microRNAs (miRNAs) and small interfering RNAs (siRNAs) has become an important tool for so-called "gene silencing" or RNA interference (RNAi). miRNAs and siRNAs bind to and inhibit the transcription of specific genes and/or they can silence cytoplasmic mRNAs either by stimulating their cleavage or by inhibiting translation. miRNAs and siRNAs are 21-26 nucleotide (nt) RNA molecules that can be distinguished based on the mechanisms through which they were created. miRNAs are produced from transcripts that form stem-loop structures, whereas siRNAs are produced from long double-stranded RNA precursors. In the initiation phase of RNAi, the ribonuclease-III enzyme Dicer cleaves double-stranded RNA molecules into 21-23-nt short interfering siRNA duplexes. In the effector phase of RNAi, the siRNA becomes unwound and assembles into RISC (RNA-induced silencing complex). The activated effector complex recognizes the target by siRNA-mRNA base pairing and cleaves the mRNA strand with its endoribonuclease activity.

IMPORTANT CONCEPTS Important points in variation of treatment schedule for early vs late tissues Early tissues: Late tissues:

Early tissues: - extending treatment time reduces efficacy of tumor kill (effect of proliferation) -- 1-2% LC loss for each day beyond lag phase -- so ideally deliver the dose in the SHORTEST possible time that you can without exceeding early normal tissue tolerance (think mucositis) - minimizes time for tumor repopulation -- this was the idea behind accelerated fractionation (2 or 3 dose fractions daily to about conventional size and the same total dose - just more quickly) - late tissues wouldn't care as much and is good for tumor control, but the early normal tissues can't tolerate this (think confluent mucositis) - NOT as sensitive to changes in dose per fraction as late tissues Late tissues: - extending treatment time DOES NOT affect late tissues. They do not repopulate. - VERY sensitive to dose per fraction. As long as you deliver the same total dose for tumor control, the smaller the fraction you can use, the lower the risk of late effects (this is why hyperfractionating is helpful for late effects) -- the problem is that without accelerating, it would take too long to deliver the dose and allow tumor repopulation - so if you hyperfractionate without accleration, you have to give a higher total dose to accommodate for tumor repopulation.

The extrinsic pathway of apoptotic cell death requires: A. Signals derived from changes in chromatin conformation B. Activation of death receptors that translocate from the plasma membrane to the nucleus and degrade DNA C. Engagement of death receptors located on the plasma membrane that lead to activation of the initiator caspase-8 (CASP8) D. p53 (TP53) activation E. The triggering of changes in mitochondrial membrane potential Good breakdown of intrinsic vs extrinsic pathways here as well.

Engagement of death receptors located on the plasma membrane that lead to activation of the initiator caspase-8 (CASP8) There are two principal pathways that can lead to apoptotic death. One of these, the extrinsic pathway, involves extracellular signaling through death receptors located on the plasma membrane such as TRAILR-1 (TNFRSF10A), TRAILR-2 (TNFRSF10B) or FAS (CD95/APO-1). These death receptors are activated in response to ligand binding of TRAIL (TNFSF10) or FAS ligand (FASLG/CD95-L) and signal through a series of adapter molecules such as the adapter molecule Fas- associated death domain (FADD) within the death-inducing signaling complex (DISC). Upon recruitment and oligomerization FADD then binds pro-caspases-8 and -10, causing their homodimerization and activation. The activation of procaspase-8 is thought to occur via an induced proximity model leading to its conversion to the active enzyme, caspase-8. Ionizing radiation can elicit activation of the extrinsic pathway leading to apoptosis. The other pathway by which ionizing radiation can elicit an apoptotic response is the intrinsic pathway (PUMA BH3 only Bcl2 fam member --> inhibits bcl2/bcl-xl/mcl1 which allows bax/bak to go to mitochondria). This can be stimulated by DNA damage leading to signaling to mitochondria, changes in mitochondrial membrane potential, release of cytochrome c, and activation of procaspase-9. In most cases, activated caspase-8 induces apoptosis through activation of pro-caspase-3 at the DISC independently of mitochondria. However, in some cells, especially when only a low amount of active caspase-8 is generated (and hence not sufficient amounts of pro-caspase-3), caspase-8 cleaves the 'Bcl-2 homology (BH) 3-only protein' Bid, generating an active fragment (tBid) that activates the (intrinsic) mitochondrial death pathway. In this manner, the extrinsic death signal may be amplified through formation and activation of the apoptosome which contributes to effector caspase activation. In other words, the extrinsic pathway can feed into the intrinsic one and additionally change mitochondrial membrane potential.

Which of the following statements concerning the effect of oxygen is TRUE? A. Oxygen acts as a radiosensitizer because it inhibits chemical repair of DNA B. The OER and RBE both increase with increasing LET C. Based on pO2 microelectrode measurements, few human tumors contain regions of hypoxia D. At an oxygen partial pressure of about 20 mM Hg E. Exposure of cells to hypoxia may stimulate gene transcription

Exposure of cells to hypoxia may stimulate gene transcription Exposure of cells to hypoxia, as in other stress situations, leads to changes in expression of a number of stress genes, many of which are responsive to the transcription factor, hypoxia-inducible factor-1a (HIF-1a) (HIF1A). Under normoxic conditions, HIF-1a is hydroxylated on proline residues by oxygen-dependent prolyl hydroxylases. The hydroxylated prolines bind to the von Hippel-Lindau (VHL) protein, which is a component of the E3 ubiquitin-protein ligase complex that ubiquitinates HIF-1a and targets it for degradation. Oxygen acts as a radiosensitizer principally through its ability to "fix" radiation-induced DNA damage and does not inhibit DNA repair (Answer Choice A). The OER decreases with increasing LET, whereas the RBE increases with LET until reaching a maximum at approximately 100 keV/μm, and then decreases (Answer Choice B). Measurements with pO2 microelectrodes and bioreductive probes have demonstrated that hypoxic cells are often present in human tumors (Answer Choice C). The Km of radiosensitivity for cells (i.e., the concentration at which there is 50% radiosensitivity compared to oxic conditions) is close to 0.5-1%, not 3%.

Which of the following is TRUE about potential risks associated with the exposure of the embryo or fetus in utero to ionizing radiation? A. Exposure to ionizing radiation in utero between weeks 8 and 15 of gestation is associated with the highest risk of development of mental retardation, while there is lower risk at 15-25 weeks of gestation. B. Exposure to ionizing radiation in utero has not been demonstrated to be associated with increased risk of carcinogenesis to the fetus. C. Exposure to ionizing radiation during the preimplantation phase has been shown to result in permanent growth retardation. D. The LD50 for oocyte killing in humans is approximately 5 Gy. E. Exposure of the fetus in utero has not been associated with changes in school performance or intelligence quotient (IQ).

Exposure to ionizing radiation in utero between weeks 8 and 15 of gestation is associated with the highest risk of development of mental retardation, while there is lower risk at 15-25 weeks of gestation. Exposure to ionizing radiation in utero has been shown to be associated with a higher risk for mental retardation (MR), and can be accompanied by lower intelligence quotient (IQ) and poor school performance (Answer Choices A and E). The risk of development of MR has been shown to be greatest between weeks 8 and 15 of gestation, while this risk decreases by approximately 4-fold between 15 and 25 weeks of gestation. Ultrasound is generally utilized for monitoring the fetus in utero due to concerns regarding radiation carcinogenesis (Answer Choice B). Exposure to ionizing radiation during the pre-implantation phase has been shown to be associated with pre-natal death (Answer Choice C). The LD50 for oocytes has been shown to be approximately 0.5Gy (Answer Choice D).

Relative to the surviving fraction of cells maintained in a non-cycling state for several hours after irradiation, decreased cell survival observed in cells forced to re-enter the cell cycle immediately following irradiation is evidence for: A. Rejoining of chromosome breaks B. Sublethal damage recovery C. Cell cycle reassortment D. Translesion of DNA synthesis E. Expression of potentially lethal damage

Expression of potentially lethal damage - think delayed plating assay Potentially lethal damage recovery is operationally defined as an increase in cell survival after delivery of a large, single radiation dose under environmental conditions not conducive to progression of cells through the cell cycle for several hours after irradiation. If non-cycling cells are forced to re-enter the cell cycle immediately after irradiation, rather than remaining quiescent, potentially lethal damage will be "expressed" and therefore the surviving fraction will be lower. Sublethal damage recovery is operationally defined as an increase in cell survival noted when a total radiation dose is delivered as two fractions with a time interval between the irradiations, as opposed to a single exposure (Answer Choice B). Repair of DNA damage and rejoining of chromosome breaks presumably underlie both the sublethal and potentially lethal damage recovery (Answer Choice A). Cell cycle reassortment has a sensitizing effect on a population of cells receiving multi-fraction or protracted irradiation regimens. This is because surviving cells that were in a resistant phase of the cell cycle during the initial irradiation may progress through the cell cycle between fractions and reassert into a more sensitive phase of the cell cycle by the time of delivery of the next fraction. This process is irrelevant under the conditions described here, in which only a single radiation dose was administered. Translesion DNA synthesis is an error-prone process during which certain DNA polymerases synthesize DNA using a damaged DNA strand as a template, resulting in error-prone DNA synthesis (Answer Choice D).

What is the one FDA approved radiation mitigator after whole body radiation exposure?

G-CSF (filgrastim/neupogen) - must be given w/in 48 hours of exposure to myelosuppressive doses of RT

Michalowski's classification of tissues What are examples of H type tissues vs F type tissues?

H = Hierarchical tissues = stem cells that undergo progressive differentiation to functional cells - intestinal epithelium - Bone marrow (hematopoietic system) - and epidermis F type population = Flexible tissues = no strict hierarchy and any cells can be triggered to divide by damage to the tissue or organ, including functional cells - liver - dermis - thyroid

If treating a tumor w/ a low alpha beta ratio that is in close proximity to a high alpha beta normal tissue like the colon, what is the best fractionation scheme?

HYPOfractionation -- think prostate here For tumors w/ a low alpha beta ratio (of say 3), any dose given per fraction above 3 Gy gives exponentially more cell kill. For tissues w/ a high alpha beta (of say 10), single doses of >10 Gy must be given to reach the exponential cell kill.

The yield of initial DNA double-strand breaks produced in an irradiated mammalian cell will be influenced by all of the following, EXCEPT: a. Radiation dose b. Lack of oxygen during irradiation c. Presence of amifostine during irradiation d. Absence of histone proteins e. Absence of RAD51

Histones protect DNA from Radiation Damage -- absence would worsen things. Rad51 would only affect the ability to repair DSBs, not the initial yield E The absence of RAD51, which is a recombinase that plays a role in homologous recombinational repair, may affect the repairability of DNA double-strand breaks, but not their initial yield. The number of double- strand breaks produced increases with radiation dose. A lack of oxygen will decrease the number of initial breaks because the free radicals formed through interactions with oxygen that may result in the formation of DNA double-strand breaks will not be created if oxygen is at a diminished level. In tissues, amifostine is converted to a compound that is a radical scavenger whose presence would decrease the number of breaks induced by a particular dose of radiation. Nuclear proteins play a critical role in protecting DNA from radiation damage. Thus removal of histones greatly enhances the sensitivity of mammalian cells to radiation damage.

For a tumor that requires 18 days to double its diameter, what is the approximate cell cycle time of its constituent cells (assume no cell loss and that all cells are actively dividing)? A. 6 days B. 9 days C. 12 days D. 15 days E. 18 days

I was wrong about this one initially -- no key on the 2019 version. The 2020 version had the same question with an answer. Even with no cell loss factor, the answer can't be 18 days because they are essentially tricking you by seeing if you recognize that the tumor is growing in 3D rather than 2D and they told you 18 days to double its DIAMETER. Assuming that all cells are proliferating, the number of cells in a tumor that doubled in diameter would increase approximately 8-fold as the number of cells can be approximated from the volume of a sphere which is equal to pi-d3/6. An 8-fold increase in the cell number would require three cell doublings. Since it took 18 days to achieve this increase, the cell cycle time can be estimated at 6 days. Answer here is A

Which of the following statements concerning the a/b ratio for tumors and normal tissues is TRUE? a. The a/b ratio is generally low for early responding tissues and high for late responding tissues b. The a/b ratio corresponds to the dose at which the survival curve begins to bend and deviate from its initial slope c. In vivo, a/b ratios for normal tissues and tumors are derived from an analysis of isoeffect data derived from multi-fraction experiments d. The a/b ratio tends to be low for cells with a pro-apoptotic tendency e. The a/b ratio represents the surviving fraction at which the linear and quadratic contributions to cell killing are equal

In vivo, a/b ratios for normal tissues and tumors are derived from an analysis of isoeffect data derived from multi-fraction experiments An analysis of multifraction isoeffect data for normal tissues and tumors in vivo forms the basis for the determination of the a/b ratio. This is accomplished by generating a so- called reciprocal dose plot ("Fe plot"), a type of isoeffect curve in which the reciprocal of the total dose to produce an isoeffect is plotted as a function of the dose per fraction used in multifractionation experiments. Based on such an isoeffect curve (which should be linear in shape assuming the linear-quadratic model provides a good fit to the data), the a/b ratio would be equal to the intercept of the curve extrapolated to zero dose divided by its slope. The ab/ is generally high for early responding tissues and low for late responding tissues. The flexure dose, not the a/b ratio, is the dose at which the survival curve first begins to bend away from its initial slope. The a/b ratio tends to be high, not low, for cell types with a pro-apoptotic tendency. The a/b ratio is the dose at which the linear and quadratic contributions to cell killing are equal.

Tirapazamine (a hypoxic cytotoxin) has recently been developed. Which of the following statements is FALSE when describing the mechanisms and effects of tyrapazamine? A. If it loses one electron in hypoxic conditions it becomes cytotoxic B. When two electrons are extracted in aerobic conditions, it becomes less toxic C. In normoxic conditions, it can also sensitize cells to radiation D. Its uptake is greater for cells in hypoxic conditions than cells in aerobic conditions E. The potency of some chemotherapy agents can be enhanced by the presence of this cytotoxin

Its uptake is greater for cells in hypoxic conditions than cells in aerobic conditions There is no difference in the uptake of the chemical by aerobic and hypoxic cells, but there is an obvious difference in the action of cell kill due to the amount of oxygen available in the cells.

For the same α/β used in the previous problem, what would be the approximate surviving fraction if the 2 Gy dose were delivered at a low dose rate over a 6 hour period instead of acutely (assume no repopulation takes place during the irradiation)? A. 0.10 B. 0.20 C. 0.37 D. 0.55 E. 0.90

Key here is to recognize that the S formula for a multifraction curve removes the β^2 quadratic region because SLDR is considered at each point (you get the downward sloping humps in the curve that averages out to a straight linear line). so in that case, you use S = e^-αD (just kick off the β portion) S = e^-(0.3x2Gy) = 0.55 Doesn't account for any repopulation that would happen but is accounting for SLDR at each fraction or at low dose rate as in this case. Low dose rate = fractionation for the purposes of these survival curves Another way to look at this formula is if you have the effective D0 (averaged out linear curve) - S = e^-(D/effD0) If the dose was delivered at a low dose rate, the surviving fraction would increase due to repair of sublethal damage during the course of irradiation. If one assumes that there is full repair of sublethal damage during the 6 hr irradiation (which is probably an oversimplification), sublethal damage would not contribute to cell killing. The beta component of the LQ equation would therefore approach zero, leaving the alpha component to dominate. Remember the alpha component is the single hit mode of death where a single track produces a two proximate lesions and results in a lethal event. Beta requires two different tracks to produce two proximate lesions and thus happens when dose is higher (more tracks around). If you are presuming that the beta component of cell kill is getting repaired because you are fractionating/giving more time, that means that the only mode of cell kill that contributes to decreased survival is the alpha component, which increases linearly with increasing dose. The surviving fraction can therefore be estimated as e-(0.3)(2) = e-0.6 = 0.55

Necrosis vs necroptosis as a form of cell death?

Necrosis is passive cell death Necroptosis is a programmed form of cell death involving RIP1 and RIP3.

Which of the following statements concerning DNA repair is CORRECT? A. Cells deficient in nucleotide excision repair tend to display hypersensitivity to ionizing radiation B. A person with LIG4 syndrome is radiation sensitive C. Mismatch repair involves the action of a DNA glycosylase and an AP endonuclease D. People with Fanconi anemia exhibit normal sensitivity to DNA cross-linking agents E. A mutation in p53 (TP53) produces an immune deficient phenotype in SCID mice

People diagnosed with LIG4 syndrome are radiation sensitive because these individuals are deficient in the DNA ligase IV enzyme (LIG4), which plays a central role in non-homologous end joining (NHEJ) of double-strand breaks. Cells deficient in nucleotide excision repair exhibit normal sensitivity to ionizing radiation, since this repair process plays little or no role in the repair of damages induced by ionizing radiation, but are very sensitive to UV radiation (Answer Choice A). Base excision repair (BER), not mismatch repair, involves the action of a DNA glycosylase and an AP endonuclease (Answer Choice C). People with Fanconi anemia are highly sensitive to DNA cross-linking agents due to inhibition of the mono-ubiquitination of FANCD2, a downstream Fanconi anemia protein, following genotoxic stress (Answer Choice D). The immune deficient phenotype in SCID mice is caused by a defect in XRCC7 (DNA-PKcs), which is critical for NHEJ as well as V(D)J rejoining. As a result, a defect in XRCC7 leads to a radiosensitive phenotype as well as the immune deficits seen in the SCID mouse. Defects in several genes are now known to cause SCID phenotypes; the mutation in the common human disease of the same name (severe combined immunodeficiency) differs from that in the well-known mouse strain.

0617 constraints - question was messed up

Per the recently completed RTOG 0617 where the standard treatment arm combined 60 Gy delivered over 30 fractions with concurrent carboplatin and paclitaxel, the mean dose to the esophagus should be < 34 Gy, lung V20 < 37%, 60 Gy < 1/3 of the heart, mean lung dose ≤ 20 Gy, and 45 Gy < 2/3 of the heart.

What is an FDA approved treatment to protect against Cs-137 exposure (from a "dirty bomb" for example)

Prussian blue -- oral administration Prussian blue (potassium ferric hexacyanoferrate) is approved as a treatment for radioactive cesium poisoning -- it binds to cesium in the GI tract and promotes excretion from the intestines and indirectly from the blood

How do cell survival curves for heat differ from radiation cell survival curves?

Radiation cell survival curves do not reliably and consistently develop resistance tails, while heat cell survival curves may develop resistance tails from approximately 41.5 - 42.5 C.

Isochromatid breaks and subsequent union between the sister chromatids = ?

Radiation-induced anaphase bridges

mechanism of cisplatin radiosensitivity

Radiotherapy usually induces DNA SSBs which can be sublethal and repaired under normal conditions unless a lesion on the opposite strand occurs in the immediate neighboring strand -- which can occur if cisplatin binds and forms adducts between the DNA strands which inhibits repair by DNA polymerase

Which of the following statements about cancer versus normal cell metabolism is TRUE? a. Cancer versus normal cell metabolism cannot be used to improve the diagnosis or treatment of cancer with radio-chemotherapy b. Cancer versus normal cell metabolism can be visualized with FDG-PET imaging but not spectroscpy c. The differences between cancer versus normal cell metabolism are drastically affected by radiation therapy d. The differences between cancer versus normal cell metabolism of oxygen have nothing to do with free radical or reactive oxygen species production e. Warburg was one of the first scientists to recognize that the regulation of glucose and oxygen metabolism was very different between cancer and normal cell

Says the answer is A....seems more like it should be E? e. Warburg was one of the first scientists to recognize that the regulation of glucose and oxygen metabolism was very different between cancer and normal cell

What is the shape of TCD50 or LD50 curves for homogenous populations?

Sigmoidal with 0-100% in cell death over a narrow range of doses for a homogenous population For a heterogenous population, it will be a less narrow range and a more horizontal appearing slope. Radiation-induced cell killing is random, and the probability follows a Poisson distribution; a tumor will be controlled only when no clonogenic cells remain. The dose at which a specific tumor is controlled will be determined by the probability of killing the last clonogenic cell in that tumor. However, this will not be the same for each tumor because of the random nature of radiation damage and of cell death. The result of this, statistically, is that the tumor control probability plotted as a function of dose on a linear scale will yield a steep, sigmoid-shaped curve that reflects only the random variation in the dose needed to kill the last clonogenic cell in the tumor. Heterogeneity between the tumors (e.g., differences in size/cell number), or heterogeneity within the tumor cell population (e.g., heterogeneity in the radiosensitivity of the cells because of their position in the cell cycle, oxygenation status, or genotype), would broaden the dose range over which the sigmoidal increase in tumor control probability occurred, and the resulting tumor control probability curve would be shallower.

Which of the following statements concerning chromosome aberrations produced in cells after whole body X-irradiation is TRUE? A. The formation of terminal deletions follows an exponential dose response B. Translocations are an unstable type of chromosome aberration C. The number of dicentric chromosomes detected in peripheral blood lymphocytes remains relatively constant with time D. SKY (spectral karyotyping) is a useful method for detection of stable aberrations decades following irradiation E. The minimum dose that can be estimated by scoring dicentric chromosomes is 2 Gy

Spectral karyotyping (SKY) uses fluorescence staining of chromosomes employing uniquely-colored probes specific for individual chromosomes, thus allowing them to be distinguished from each other on the basis of color. Stable translocations are revealed using SKY as a single chromosome that appears to be multi-colored. The formation of terminal deletions follows a linear dose response since these are single-hit aberrations (Answer Choice A). Translocations can be stable aberrations since they do not necessarily lead to cell death (Answer Choice B). The number of dicentric chromosomes detected in peripheral blood lymphocytes decreases with time after irradiation since these are unstable aberrations that ultimately cause the death of the lymphocyte progenitors and stem cells (Answer Choice C). The minimum dose that can be detected through scoring dicentric chromosomes is roughly 0.25 Gy (Answer Choice E).

What is the Arrhenius plot and what temp is the break point?

The Arrhenius plot demonstrates the temperature at which the mechanisms underlying cell killing changes, potentially reflecting different targets for cytotoxicity above the break point (43oC) There is less activation energy required above 43 C suggesting different proteins are targetted at different temperatures. The Arrenhius analysis plots survival data of cell cultures exposed to increasing temperatures. The X-axis plots 1/D0, where D0 represents the time at a given temperature required to reduce the fraction of surviving cells to 37% of the initial population. The Y-axis plots 1/T, where T is the absolute temperature

If the TS, LI and (the correction factor for the non-linear distribution of cells through the cell cycle) were determined for a tumor to be 10 hours, 0.2 and 0.7, respectively, then the Tpot is: a. 2 hours b. 10 hours c. 18 hours d. 25 hours e. 35 hours

The Tpot is equal to TS /LI = (0.7)(10 hours)/0.2 = 35 hours.

Which of the following is false for the split dose experiment and sublethal damage (SLD)? A. The survivors of the first dose are mainly S phase. B. The fraction of cells surviving a split dose increases as the time interval between the two doses increases due to the repair of SLD. C. When cells are cycling during the split dose experiments, there is a dip (decrease) in cell survival caused by reassortment. D. SLD can be repaired before they can interact to form lethal chromosomal damage. E. SLD is demonstrated by low-LET radiation

The answer key says B -- but its asking for the false answer. So not sure what to do with that The fraction of cells surviving a split dose increases with increasing time between the two doses because of the repair of SLD. i think C is closer to being false

Through a Compton scattering event with water, a photon will produce: 1) a free electron with high energy 2) an ionized water molecule 3) the original photon with reduced energy. Which of the following subsequent reactions is considered an indirect effect of the original photon? a. The high-energy free electron further interacts with a different water molecule to cause another ionization event b. The ionized water molecule encounters another water molecule, and produces a hydroxyl free radical c. The original photon continues to ionize other water molecules d. Czerenkov radiation is given off e. All of the above

The interaction of ionized water molecule with another water molecule to produce new species of free radicals is considered the indirect effect. The newly produced electron with high energy and the remaining photon can be considered secondary radiation and their interactions with the absorbing materials are considered part of the physical interactions with matters, or direct effect. However, when the high-energy free electron slows down to form an aqueous electron, it can interact with other water molecules to trigger indirect effects.

Which of the following gene mutations would be expected to cause the greatest increase in sensitivity after exposure to a DNA damaging agent that induces double-strand breaks (DSBs)? A. DNA-PKcs null mutation B. P53 null mutation C. Activiating K-Ras mutation D. MLH1 nonsense mutation E. XRCC1 null mutation

The key says E is correct, but I think that's a misprint -- it has to be A (that's the only one involved in DSB repair through NHEJ). XRCC1 is involved in BER and works with ligase III to repair some single strand breaks. Ionizing radiation produces multiple types of DNA damage, including DNA double strand breaks (DSB), single strand breaks (SSBs), and base damage. Many more instances of SSBs and base damage are induced compared to DSBs. Although DSBs are the most lethal form of damage, this is not due to an inability to detect or repair these lesions, but instead because DSBs have the strongest impact on cell viability through the generation of lethal chromosome aberrations.

Which of the following results from the recombination of the initial water radiolysis products? A. Solvated electron B. Solvated proton C. Hydrogen ion D. Water E. Only A and B

The main initial products of resulting from irradiation of pure water are the short-lived free radicals, hydrogen radical (H•) (10%), hydroxyl radical (•OH) (45%), and the solvated electrons (e-aq ) (45%). These react with DNA or with each other. Therefore, •OH + H• → H2O The remaining recombination reactions of free radicals are: e-aq + e-aq +2 H2O → H2 + 2 OH- •OH + •OH → H2O2 H• + H• → H2 These reactions always compete with reactions that lead to direct damage of the biological molecules. The relative efficiency of the recombinations will depend on the separation of the short-lived free radicals after the passage of the charged particle, and therefore depend on LET. At low LET values, the spacing of the ionizations is large. As a result, •OH radicals are widely separated thereby decreasing the probability of recombination to form H2O2. As LET increases, the spacing between ionizations decreases and the probability of production of an •OH from one ionization event as well as an •OH from another ionization event along a single track increases. The yield of hydrogen peroxide increases rapidly with LET of about 20 - 150 keV/μm, the range of LET where direct damage to DNA dominates over indirect damage from the free radicals.

How does OER change for doses <2 Gy compared to doses >10 Gy per fraction for low LET radiation.

The oxygen enhancement ratio (OER) is the ratio of radiation doses in hypoxic to aerobic conditions needed to achieve the same degree of cell kill. This is lower (~1.5-2.0) for X-ray doses <2 Gy and higher (~3.0) for doses >10 Gy. OER = dose in hypoxia/dose in aerobic conditions You can see in the survival curve that there is less of a difference at low doses and more of a difference at high doses.

What cellular compartment is the Ras enzyme associated with?

The plasma membrane -- Ras is anchored to the inner surface of the plasma membrane and exerts its cellular functions from the plasma membrane of the cells.

Mild hyperthermia (41-41.5) can increase radiation sensitivity through what mechanism? Does this work at 43.5 C and up?

This enhances oxygenation between 40-41.5 -- prolonged hyperthermia even at 43.5 causes vascular damage over time which leads to DECREASED oxygenation At 43.5 initial oxygenation occurs, but after an hour the median tumor oxygenation is decreased drastically due to vascular damage.

What is a delta ray?

This is a secondary electron with enough energy to escape a significant distance away from the primary beam and produce further ionization

The survival curve is described by Dq = 3 Gy and D0 = 1 Gy. What is the surviving fraction at 2 Gy (SF2Gy) for the cell line? Super tricky question. Just recognize the issue with this question.

This was confusing as hell for me. The point they are making is the the D0, Dq, n stuff is really based on the old target models and those DO NOT hold up at low dose. These numbers really only apply when you are talking about fractional doses that would put you in the exponential portion of cell kill (straight part of the line plotted on log/lin scale). Below these doses, the formula for: ln(n)=dq/d0 gives you a curve with a 0 initial slope where no cell kill is happening at low doses. The linear quadratic model has a non-zero initial slope and predicts this better. Their point here is that you really can't answer this question for a 2 Gy SF. So they pick e^0 = 1 because according to this old model, below the doses that get you to the exponential portion of the curve, you still have 100% survival (which really isn't true). They would have to give you a dose given that is larger than the semi-threshold (quazi threshold) dose of 3 Gy (below that, the slope is just flat). Still important to know that D10 = log of cell kill = 2.3 x D0 ==> that gives you the dose to reduce cell survival to 10% and that the D0 is the dose to reduce survival to 37% (but specifically at doses beyond the Dq).

Which of the following pairs of tumor suppressor proteins and their corresponding functions is INCORRECT? A. APC — signal transduction B. RB1 — cell cycle regulation C. p53 (TP53) — cell cycle and apoptosis regulation D. WT1 — post-translational regulation E. BRCA1 — DNA damage repair

WT1 is a transcription factor which, when mutated or absent, is associated with the development of Wilms tumor. Loss of APC plays a role in gastrointestinal carcinogenesis due to its normal involvement in cell signal transduction. RB1 and p53 are both tumor suppressors that regulate cell cycle progression; p53 also regulates apoptosis. BRCA1 protein is part of the DNA repair complex, but likely has several other functions as well, including regulation of the cell cycle and maintenance of genomic stability.

The Tpot for a tumor can be calculated from the cell cycle time of the cells comprising the tumor, the tumor's growth fraction and with the assumption that the cell loss factor is: a. 0 b. 1.0 c. 0.2 d. 0.6 e. Nearly 1.0 when the tumor is small, but decreasing exponentially as the tumor grows

a. 0 A Tpot represents the time it would take a tumor to double its cell number in the absence of cell loss (i.e., cell loss factor = 0). The difference between Tpot and Td (actual double time) is the cell loss factor Cell loss factor = 1 - Tpot/Td

The phenomenon of "oncogene addiction" most correctly refers to which of the following clinical scenarios? a. A CML patient treated with imatinib b. An EGFR-mutant lung adenocarcinoma patient treated with bevacizumab c. A BRAF-mutant melanoma patient treated with ipilimumab d. An EML4-ALK positive lung adenocarcinoma patient treated with olaparib e. A CML patient treated with interferon

a. A CML patient treated with imatinib Oncogene addiction is a term first coined by Weinstein. Oncogene addiction is the phenomenon that despite the diverse array of genetic lesions typical of cancer - some tumors rely on one single dominant oncogene for growth and survival, so that inhibition of this specific oncogene product is sufficient to halt the neoplastic phenotype (21953712). Answer "a" is correct as imatinib targets BCR-ABL. The other answers are all examples of oncogene addicted cancers that are treated with agents that do not target the dominant oncogene product.

Multiple phase III clinical trials have demonstrated a combinatorial beneficial effect of radiation therapy and androgen deprivation therapy (ADT) in localized and locally advanced prostate cancer. What is the most current molecular mechanism for this beneficial combinatorial effect? a. ADT represses an androgen receptor gene expression program governing DNA repair and inhibits repair of ionizing radiation-induced DNA damage b. ADT downregulates VEGF expression in prostate cancer cells via hypoxia-inducible factor 1α c. ADT represses the PI3K-AKT-mTOR pathway d. ADT activates the unfolded protein response e. All of the above

a. ADT represses an androgen receptor gene expression program governing DNA repair and inhibits repair of ionizing radiation-induced DNA damage Answer "a" is the most correct answer (24027197 and 24027196). Successful treatment by genotoxic modalities including radiotherapy is commonly hampered by treatment resistance in advanced cancers. Two new studies reveal that androgen receptor signaling transcriptionally upregulates a large subset of DNA repair genes, thereby enhancing the repair capacity and promoting radioresistance of prostate cancer. These results provide a mechanistic rationale for a combined treatment by ionizing radiation and androgen deprivation therapy. All the other answers do not apply to ADT + radiation synergy. ADT can actually induce the PI3K-AKT-mTOR pathway

What is the mechanism of action of the radiation protector/mitigator flagellin that binds to the Toll-like receptor 5? a. Activation of the NF-κB pathway b. Activation of BCL2 anti-apoptotic pathway c. Activation of the EGFR growth factor signaling pathway d. Activation of the IL-6 cytokine signaling pathway e. Activation of the MnSOD anti-oxidant pathway

a. Activation of the NF-κB pathway The NF-κB pathway mediates transcriptional upregulation of (i) anti-apoptotic genes; (ii) cytokines and growth factors that induce proliferation and survival of HP and other stem cells; and (iii) potent ROS-scavenging antioxidant proteins, such as MnSOD. Mice with a genetic defect in NF-κB signaling displayed heightened GI radiosensitivity. Pharmacological activators of NF-κB, like flagellin, were found that exploited the natural mechanisms by which the innate immune system responds to microbial infections. Various pathogen- associated molecular patterns (PAMPs) are recognized by host cells due to their specific interaction with Toll-like receptors (TLRs), which leads to activation of NF-κB

Transforming growth factor-beta (TGF-beta) protein levels in the plasma of patients exposed to radiotherapy has been extensively correlated to which of the following? a. Acute radiation lung injury b. Acute radiation dermatitis c. Radiation mucositis d. Radiation induced gliosis e. Leukemia

a. Acute radiation lung injury Plasma TGF-beta levels have extensively been evaluated as a measure of and predictor for acute and chronic radiation lung injury. Although some controversy exists, newer literature confirms that TGF-beta can play a role in determining which patients are at highest risk of lung injury from radiation

Rad-223, Sam-153 and Str-89 are radiopharmaceuticals in clinical use for bone metastatic disease. What physical property makes Rad-223 more tolerable than the other two agents? a. Alpha particle emitter b. Beta and gamma particle emitter c. Gamma particle emitter d. Alpha, gamma and beta particle emitter e. Beta particle emitter

a. Alpha particle emitter The use of radium-223 to treat metastatic bone cancer relies on the ability of alpha radiation from radium-223 and its short-lived decay products to kill cancer cells. Radium is preferentially absorbed by bone by virtue of its chemical similarity to calcium, with most radium-223 that is not taken up by the bone being cleared, primarily via the gut, and excreted. Although radium-223 and its decay products also emit beta and gamma radiation, over 95% of the decay energy is in the form of alpha particle radiation. Alpha particle radiation has very short range in tissues, around 2-10 cells, compared to beta or gamma radiation. This reduces damage to surrounding healthy tissues, producing an even more localized effect than the beta-emitter strontium-89, also used to treat bone cancer. Taking account of its preferential uptake by bone and the alpha particles' short range, radium-223 is estimated to give targeted osteogenic cells a radiation dose at least 8 fold higher than other non-targeted tissues (Ref. 23863050). The most correct answer is "a". All other answers are incorrect because they are either not true ("b", "c" and "e") or are not the primary reason for the tolerability of Ra-223 (answer "d")

What are driver genes in oncogenesis? a. An early mutation that drives the cancer and usually involves a dominant or recessive oncogene. b. They occur exclusively late in the development of the cancer and drive the development of the metastasis. c. Mutations that occur in DNA repair genes d. Mutations that are induced by radiation and other mutagens. e. Errors introduced during the process of DNA repair

a. An early mutation that drives the cancer and usually involves a dominant or recessive oncogene. A driver gene is a mutation event that occurs most often early in the development of the cancer and drives the cell to oncogenesis; it is usually in dominant or recessive oncogenes. Other answers are wrong: B drive mutations are most often early in oncogenesis and do not just drive metastasis; C they can but do not necessarily occur in DNA repair genes; D they can be induced by radiation and other mutagens but are not exclusively induced in such a way; E they can be introduced during the process of DNA repair, but they are not exclusively so. None of these answers provides a definition of driver genes except A.

Which of the following statements is TRUE concerning the structure of eukaryotic genes? a. An exon can generally be identified by its lack of stop codons b. Introns represent only a small percentage of the total genome c. Most human genes do not contain intronic regions d. Introns represent the coding sequences of genes e. The RNA transcribed from a DNA template is translated directly on the ribosomes

a. An exon can generally be identified by its lack of stop codons Exons can generally be identified by their lack of stop codons, since only a single one appears per mature mRNA strand. Exons are coding regions of a gene and introns are intervening sequences whose function is unknown. It is estimated that up to 99% of DNA is intronic, non-coding DNA. The primary transcript (RNA) is the exact copy of the entire gene, including introns as well as exons. The difference between the primary transcript and DNA is the base difference of thymine (DNA) --> uracil (RNA). The process of splicing removes the introns from the RNA and joins the exons together to create the messenger RNA (mRNA). The mRNA contains the coding sequence (CDS), which is translated into a string of amino acids based on the three-letter mRNA genetic code. CDS starts with the start codon, AUG (methionine). The mRNA also includes an untranslated region on each end, the 5'UTR and 3'UTR. The 3'UTR sequence starts with one of three stop codons (UAG, UAA, or UGA) that end the process of translation.

Which of the following statements concerning the radiation-induced effects of fractionated total body irradiation in children being prepared for a bone marrow transplant is FALSE? a. Approximately half of the children develop severe restrictive pulmonary disease b. The majority will develop cataracts c. Thyroid cancer is the main second malignancy observed d. The younger the child at the time of irradiation, the greater the risk for the development of osteochondroma e. Manifestations of hypogonadism are common in both boys and girls

a. Approximately half of the children develop severe restrictive pulmonary disease Only about 1% of children develop severe restrictive pulmonary disease, although the majority develop some symptoms More interestingly the others are apparently true. -The majority will develop cataracts -Thyroid cancer is the main second malignancy -The younger the child at the time of irradiation, the greater the risk for the development of osteochondroma -- obvious -Manifestations of hypogonadism are common in both boys and girls

Which of the following statements is FALSE? a. BRCA1 is deleted in the majority of breast cancers b. An increased incidence of CLL has not been found in irradiated populations c. A translocation between chromosome 9 and 22 is often present in CML d. DCC is a tumor suppressor gene that has been found altered in colon cancer e. A mutated mismatch repair gene is often found in people with hereditary non-polyposis colon cancer (HNPCC)

a. BRCA1 is deleted in the majority of breast cancers Although a mutation in BRCA1 results in a susceptibility for the development of breast cancer, it is not deleted in the majority of breast cancers.

Which of the following statements is FALSE concerning cytokines? a. Basic fibroblast growth factor (bFGF or FGF2) enhances radiation-induced apoptosis of endothelial cells b. High levels of transforming growth factor-beta (TGFb1) have been reported to be associated with an increased risk of pulmonary fibrosis following radiotherapy c. Interleukin-1 (IL-1) is a bone marrow radioprotector d. Vascular endothelial growth factor (VEGF) transcription is stimulated by hypoxia as a result of hypoxia inducible factor (HIF-1) binding to a hypoxia responsive element (HRE) within the VEGF promoter e. A paracrine response involves production of cytokines in which the target cells are located in the vicinity of the expressing cell

a. Basic fibroblast growth factor (bFGF or FGF2) enhances radiation-induced apoptosis of endothelial cells bFGF protects against, rather than enhances, radiation-induced apoptosis of endothelial cells Odd that IL1 acts as a bone marrow radioprotector -- its pro-inflammatory. But i guess its true!

Which of the following disorders associated with chromosomal instability does NOT predispose to cancer? a. Cockayne's syndrome b. Bloom's syndrome c. Fanconi's anemia d. Nijmegen breakage syndrome e. Ataxia telangectasia

a. Cockayne's syndrome People with Cockayne's syndrome are deficient in transcription-coupled nucleotide excision repair and are characterized by stunting of growth, impaired development of the nervous system, photosensitivity and premature aging. However, there is no evidence for cancer proneness. The other syndromes are associated with the following cancers: Bloom's syndrome - RECQL3 - hyperrecombination/high rate of sister chromatid exchange - failure of holiday junction dissolution --> leukemia and lymphoma Fanconi's anemia - FANC-L genes - development of quadriradials - interstrand crosslink repair defect - leukemia Nijmegen breakage syndrome - NBS1 defect - MRN complex -- thus HR affected - lymphoma ataxia telangiectasia - ATM - important in both HR > and NHEJ --> leukemia, lymphoma

Please choose the correct chronologic sequence of cancer therapies, ranked from the earliest first use to the most recent first use: a. Coley's toxins; radiation therapy; Bacillus-Calmette-Guérin; interferon; trastuzumab; ipilimumab b. Radiation therapy; Bacillus-Calmette-Guérin; Coley's toxins; interferon; trastuzumab; ipilimumab c. Bacillus-Calmette-Guérin; radiation therapy; Coley's toxins; interferon; ipilimumab; trastuzumab d. Bacillus-Calmette-Guérin; radiation therapy; interferon; Coley's toxins; ipilimumab; trastuzumab

a. Coley's toxins; radiation therapy; Bacillus-Calmette-Guérin; interferon; trastuzumab; ipilimumab Despite its recent attention, cancer immuno-therapeutics have existed since the 19th century. A notable example is the 1893 report from William Coley of the use of erysipelas inoculations to treat sarcomas. In the paper he describes several remarkable tumor responses from both inadvertent and intentional erysipelas infections. He would later develop a heat-inactivated mixture of S. pyogenes and B. prodigious termed "Coley's toxins." While he reported many successes in treating patients, Coley's toxins fell out of favor due to limited reproducibility and supplantation by radiation therapy and then chemotherapy. The first claimed use of radiation to treat cancer was by Emil Grubbe in 1896. Much later, the Bacillus-Calmette-Guérin (BCG) would be shown in the 1950s-1970s to have anti-tumor effects in mice and then in human cancers. However, it too was superseded by other therapeutics except for the treatment of superficial bladder cancers. Interferon was discovered in 1957 but not shown to have anti-cancer effects until 1984 when it demonstrated a response against hairy cell leukemia; it was later used for chronic myelogenous leukemia and melanoma. Soon after, high-dose interleukin-2 was shown effective in renal cell carcinoma and melanoma, with FDA approvals in 1992 and 1998, respectively. Trastuzumab was developed in 1990s as the first antibody-based therapy in breast cancer treatment and was approved for use in 1998. Ipilimumab was the first immunotherapeutic based on immune checkpoint blockade and was FDA-approved in 2011.

A hyperfractionated protocol is being proposed in an effort to reduce the incidence of late effects following radiotherapy for head and neck cancer. Compared to standard fractionation, it is likely that this alternate schedule will result in a(n): a. Comparable probability of tumor control b. Increased probability of tumor control c. Decreased probability of tumor control d. Increased probability of early effects e. Decreased probability of early effects

a. Comparable probability of tumor control Since the a/b ratio for head and neck cancers tends to be high, whereas the a/b ratios for late effects are low, it would be anticipated that a hyperfractionated schedule could produce a decrease in late effects while maintaining a level of tumor control similar to that produced by the standard protocol.

In normal tissues, the radiation tolerance dose is hypothesized to depend on the ability of tissue clonogens to maintain an adequate number of mature functioning cells. The relationship between organ function and clonogenic cell survival is dependent on the structural organization of functional subunits (FSUs) within the particular tissue. Which of the following statements concerning FSUs is TRUE? FSUs: a. Contain a relatively set number of clonogens b. Cannot be repopulated from a single surviving clonogen c. Are defined as units with clear anatomical demarcation d. Are usually dependent on one another in a functional sense e. Cannot be repopulated from an adjacent FSU

a. Contain a relatively set number of clonogens FSUs contain a relatively constant number of clonogens. FSU's can be repopulated from a single surviving clonogen, and, for certain tissues, from clonogens that migrate from an adjacent FSU. For some tissues, FSUs are anatomically discrete structures (such as the nephron in the kidney), although for other tissues, there may not be any clear structural or anatomical unit that corresponds to an FSU (such as in the CNS and skin). FSUs are thought to be functionally independent of each other, even though they may be structurally interdependent.

Which of the following correctly describes differences between the dose-depth profiles of therapeutic beams of photons and protons? a. Dose in front of the tumor is higher than dose behind the tumor with protons b. Entrance dose with photons is always higher than with protons c. The Bragg peak can be spread out by changing proton fluence d. Photon dosimetry is more affected than proton dosimetry by in-depth tissue inhomogeneities e. Lateral proton beam penumbra is advantageous compared with the penumbra of external beam photon therapy

a. Dose in front of the tumor is higher than dose behind the tumor with protons The depth dose distribution of proton beams differs significantly from that of photon beams. Protons show an increasing energy deposition with penetration distance leading to a maximum, named the Bragg-peak, near the end of the range of the proton beam. In front of the Bragg-peak, the dose level is modest as compared to photon beams; beyond the Bragg- peak the dose falls practically to zero. By choosing appropriate proton beam energies, the depth of the Bragg-peak can be adjusted according to the depth and extent of the target volume. Hence, excellent conformality can be achieved compared to conventional or intensity modulated radiotherapy. The increased skin dose for proton therapy is known to complicate treatments of tumors that are not deep seated. Less widely realized is that it is difficult to achieve a lateral proton beam penumbra that is clearly advantageous compared with the penumbra of external beam photon therapy. The position of the Bragg peak in tissue is determined by proton energy, not fluence; Fluence = (Number protons )/Area.

Which of the following techniques provides a non-invasive means to assay the extent and location of hypoxia in tumors and correlates with 50% probability of tumor control? a. Electron paramagnetic resonance oxygen imaging b. Hyperpolarized magnetic resonance imaging of oxygen c. Proton resonance shift magnetic resonance imaging d. Diffusion tensor imaging of oxygen partial pressures e. Photoacoustic imaging of oxy- and deoxy-hemoglobin

a. Electron paramagnetic resonance oxygen imaging EPR O2 imaging is a good surrogate for TCD50

Which of the following statements concerning the tolerance of normal tissues to re-irradiation is TRUE? a. Evidence from animal studies suggests that the spinal cord can be re-irradiated to at least partial tolerance provided at least 6 months have passed since an initial course of treatment b. Soft tissue or bone necrosis has not been observed in patients receiving re-irradiation of recurrent or new primary head and neck tumors c. Mouse lungs appear incapable of tolerating a second course of fractionated radiation, regardless of the total dose given during the initial course of radiotherapy d. Rapidly dividing mucosal tissues cannot be re-irradiated, even several years after completion of the initial treatment e. Animal experiments show that the kidney can be re-irradiated to 80-90% of a full tolerance dose as long as 3 months have elapsed since the initial treatment

a. Evidence from animal studies suggests that the spinal cord can be re-irradiated to at least partial tolerance provided at least 6 months have passed since an initial course of treatment Evidence from animal studies suggests that at least a partial recovery and re-irradiation tolerance occurs in the spinal cord provided at least 6 months have passed since an initial course of treatment. Soft tissue or bone necrosis has been observed in clinical studies involving re-irradiation of recurrent or new primary head and neck tumors. Mouse lungs are capable of tolerating a second course of fractionated irradiation, depending on the total dose given during the first course (the higher the initial total dose, the less tolerance to re- irradiation, and vice versa). Full re-irradiation tolerance for acute damage in rapidly dividing mucosal tissues is generally observed, provided at least a month or two has passed since the initial treatment course. Animal experiments have shown that the kidney does not appear to recover from radiation injury, as it will not tolerate re-irradiation even after a period of several years following the original treatment course.

Overexpression of BCL2 promotes tumorigenesis because BCL2 over-expressing cells: a. Exhibit diminished levels of apoptosis b. Proliferate more rapidly than their normal counterparts c. Have increased angiogenesis d. Are more likely to be hypoxic e. Have a decreased ability to repair DNA double strand breaks

a. Exhibit diminished levels of apoptosis BCL2 is an anti-apoptotic protein that counters the release of cytochrome c from the mitochondria, a necessary step in the intrinsic apoptotic pathway. Therefore, BCL2 over- expressing cells are resistant to apoptosis. BCL2 over-expressing cells do not proliferate rapidly, do not have increased angiogenesis, are not necessarily hypoxic, and do not have decreased DNA double strand break repair.

RAS functions as a: a. GTPase b. Protein kinase c. Phosphatidyl inositol kinase d. Phosphatase e. Transcription factor

a. GTPase A RAS is a GTPase. In the active form, Ras is bound to GTP; in the inactive form, it is bound to GDP. The GTPase activity of Ras is activated by GTPase activating proteins (GAPs), which promote Ras to cleave GTP into GDP and inorganic phosphate. Ras-GTP = active Ras-GDP = inactive NF1 is a RAS GAP --> inactivates Ras RAS-Gaps = inactivate ras RAS-GEFs = activate ras Ras --> Raf --> MEK --> MEKK --> MAPK/ERK --> Fos/Fox/Jun, RAC/RHO/PLC/PI3K/AKT

What is the typical shape of a tumor growth curve? a. Gompertzian b. Exponential c. Parabolic d. Linear e. Linear-quadratic

a. Gompertzian If a tumor increases its volume by a constant fraction per unit time, then it would display exponential growth as per the equation V = e(.693)(T/Tv), where T is the total elapsed time and Tv is the tumor's volume doubling time. In practice however, this is rarely observed because as a tumor grows, generally the growth fraction decreases and cell loss increases. This type of progressively slowing growth curve is best fit using the Gompertz equation, where V0 is the volume at time zero and A and B are growth parameters specific for the particular tumor. At small times for t, the equation is exponential with V = V0e^At At long times, e^-Bt becomes very small, so the volume reaches a maximum of V0e^A/B.

Human papillomavirus (HPV) is a significant cause of cancer worldwide; it is associated with cancers of the uterine cervix, penis, anus, vulva/vagina, and oropharynx. The most common oncogenic subtype is: a. HPV-16 b. HPV-6 c. HPV-11 d. HPV-55 e. HPV-77

a. HPV-16 HPV-16. The estimated worldwide prevalence of infection with HPV in women without a diagnosis is 11-12%. The most prevalent subtype is HPV-16 at 3.2% followed by HPV-18 at 1.4%. HPV-55 is also considered a high-risk subtype, but occurs much less frequently. HPV-6 and HPV-11 are associated with the development of genital warts; they are not considered high-risk subtypes for malignant transformation. (Forman D et al. Vaccine 2013;305:F12- 23).

Defects in mismatch repair proteins have been associated with which one of the following tumors? a. Hereditary non-polyposis colorectal cancer b. Neurofibromatosis c. Ovarian carcinoma of the serous type d. Glioblastoma e. Retinoblastoma

a. Hereditary non-polyposis colorectal cancer Hereditary non-polyposid carcinomas of the colon have displayed mutations in mismatch repair genes. Neurofibromatosis and retinoblastoma are associated with the loss of tumor suppressor genes. Ovarian cancers and glioblastomas have been reported to harbor numerous gene defects.

What does a promoter-bashing assay accomplish? a. Identifies regions of genes that are required for gene expression. b. Identifies proteins that bind to DNA c. Measures DNA double-strand breaks d. Identifies miRNA binding regions in mRNA e. Quantitates gene expression

a. Identifies regions of genes that are required for gene expression. Promoter bashing experiments involve the deletion of regions around the start of transcription of a gene in the promoter itself to identify sequences that are required for transcription under certain cicrumstances. (Hall and Giaccia, Fig. 17.22 has an example). Proteins bound to promoters are identified in electrophoretic mobility shift assays (EMSA). Double strand breaks are detected by several means: comet assay, gamma-H2Ax antibody binding, pulsed field gel electrophoresis and others. Most often sequence similarity is used to identify miRNA binding regions in mRNA. Many methods quantitate gene expression: Northwestern blots, microarray mRNA assays, RT-PCR, protein expression assays and more.

Which of the following is the most likely consequence of EGFR activation? a. Increased proliferation b. Apoptosis c. Cell cycle arrest d. Stabilization of microtubules e. Autophagy

a. Increased proliferation EGFR is activated in tumors by overexpression or mutation and functions to induce proliferation. EGFR activation would prevent, not promote, apoptosis, autophagy, and cell cycle arrest. The pathways activated by EGFR may also stimulate DNA repair, and promote angiogenesis. As such, it is an important target for therapy.

The first application of the CRISPR/Cas9 system applied to human cells was to induce gene knockout. When the CRISPR/Cas9 system is used for this purpose, it does so by: a. Inducing small insertions, deletions, and frameshifts b. Excising the target gene from the genome c. Preventing RNA synthesis by DNA-dependent RNA polymerase d. Inducing the degradation of target mRNA e. Inducing target protein degradation

a. Inducing small insertions, deletions, and frameshifts CRISPR/Cas9-mediated gene knockout is a secondary response to imperfect DNA damage repair. The CRISPR/Cas9 system is composed of 2 elements: the guide RNA (gRNA) and the Cas9 protein. The gRNA is an RNA molecule that directs the Cas9 protein to a specific area of the protein-encoding genome by complementary base paring. Cas9 is bacterial DNA endonuclease that cuts double-stranded DNA at the location directed by the gRNA. Once Cas9 cuts at the designated location, the host cell DNA damage response attempts repair. This primarily occurs through imperfect non-homologous end joining (NHEJ), which results in small insertions, deletions, and frameshifts that result in disrupted protein expression. The bulk of the DNA for the target gene remains in the genome, but is not expressed. mRNA degradation is the primary mechanism of gene suppression by RNA interference technology. Of note, subsequent applications of the CRISPR/Cas9 system have been developed to increase (CRISPR activation, or CRISPRa) or decrease (CRISPR interference, or CRISPRi) the transcription of specific genes. Increased gene transcription is accomplished by expressing a fusion protein of an endonuclease defective Cas9 (dCas9, which localized to gRNA-directed DNA but does not cut DNA) fused with a protein that recruits the transcriptional machinery to induce transcription. In this case the gRNA is designed to target the Cas9-transcription activator fusion protein to the promoter of the target gene. Conversely, suppression of gene transcription is accomplished in a similar way, but the dCas9 protein is fused with a transcriptional repressor protein. Subsequent generations of the CRISPR/Cas9 system have been developed to specifically alter epigenetic modifications at specific sites in the genome.

Abiraterone is an FDA approved agent for metastatic castration resistant prostate cancer. Clinical trials utilizing this promising agent with radiation in the localized setting are due to commence. What is the mechanism of action of Abiraterone? a. Inhibits 17 α-hydroxylase/C17,20 lyase (CYP17A1), an enzyme which is expressed in testicular, adrenal, and prostatic tumor tissues b. Inhibits the ligand for osteoprotegerin and functions as a key factor for osteoclast differentiation and activation c. Luteinizing hormone releasing hormone (LHRH) agonist d. Bone seeking alpha-particle emitter e. Third generation androgen receptor antagonist drug

a. Inhibits 17 α-hydroxylase/C17,20 lyase (CYP17A1), an enzyme which is expressed in testicular, adrenal, and prostatic tumor tissues

Which of the following statements is FALSE concerning NFkB? NFkB: a. Inhibits non-homologous end-joining of DNA double strand breaks b. Typically inhibits apoptosis c. Is a transcription factor d. Activation is associated with tumor progression e. Can be activated following irradiation

a. Inhibits non-homologous end-joining of DNA double strand breaks A NFkB does not inhibit non-homologous end-joining of DNA double strand breaks. It does: - inhibit apoptosis - act as a transcription factor - is associated with tumor progression - can be activated after irradiation - is inhibited by I-kB

Which of the following isotopes is most commonly used for HDR brachytherapy? a. Ir-192 b. Pd-103 c. I-125 d. Co-60 e. Y-90

a. Ir-192 Ir-192 is most commonly used for HDR brachytherapy. Pd-103 and I-125 are used in LDR brachytherapy. Co-60 is used in external beam radiotherapy. Y-90 is used in radioimmunotherapy.

Palifermnin decreases mucositis after irradiation and stem cell transplant by signaling through which pathway? a. Keratinocyte growth factor binding to fibroblast growth factor receptor 2b b. Epidermal growth factor (EGF) binding to EGF receptor c. Hepatocyte growth factor binding to the MET receptor d. TGF-beta binding to TGF-beta receptor e. Blocking ATM in mucosal cells

a. Keratinocyte growth factor binding to fibroblast growth factor receptor 2b Palifermin is a truncated human recombinant keratinocyte growth factor that stimulates proliferation of mucosal cells of the gastrointestinal tract to proliferate and thus to decrease the severity. It has been shown to reduce the duration and severity of mucositis after transplantion for hematologic malignancies.

Tumor cells can escape the host's immune response using a plethora of mechanisms. Which of the following examples is FALSE? a. Loss of beta2-microtubulin expression that decreases MHC class I expression b. Tumor cell intrinsic alterations in signaling pathways such as WNT/b-catenin, loss of PTEN, IFN-g that block T cell priming and infiltration and effectiveness c. Recruitment of myeloid suppressor cells d. Loss of antigen expression through to immune selection e. Increased expression of immune inhibitory factors such as IDO, PD-L1

a. Loss of beta2-microtubulin expression that decreases MHC class I expression Beta-2-microglobulin (β2-microglobulin, B2M) (not beta2-microtubulin) is a crucial component of major histocompatibility complex (MHC) class I molecules, present on all nucleated cells (excluding red blood cells). MHC I are heterodimers made of two, non-covalently linked polypeptide chains, α and B2M and the conformation of MHC I is highly dependent on the presence of B2M. B2M is essential for proper MHC class I folding and transport to the cell surface, and its deficiency has long been recognized as a genetic mechanism of acquired resistance to immunotherapy.

Which of the following processes is NOT a typical mechanism for the activation of a proto-oncogene to an oncogene? a. Loss of heterozygosity b. Point mutation c. Retroviral insertion d. Chromosomal rearrangement e. Gene amplification

a. Loss of heterozygosity Loss of heterozygosity of a tumor suppressor gene, not an oncogene, often occurs during malignant progression, and involves the loss of a protein that otherwise would play a role in inhibiting cell proliferation.

Which of the following is the correct temporal sequence for the appearance of the stated radiation effect on peripheral blood components? a. Lymphocytopenia, granulocytopenia, thrombocytopenia, anemia b. Anemia, lymphocytopenia, granulocytopenia, thrombocytopenia c. Granulocytopenia, thromobocytopenia, anemia, lymphocytopenia d. Lymphocytopenia, anemia, granulocytopenia, thrombocytopenia e. Lymphocytopenia, thrombocytopenia, granulocytopenia, anemia

a. Lymphocytopenia, granulocytopenia, thrombocytopenia, anemia The chronological order for decline of the components of peripheral blood after irradiation is lymphocytes, granulocytes, platelets and lastly erythrocytes.

A patient you are seeing as a consult for bilateral vestibular schwannoma has a past medical history of neurofibromatosis type 2. Which of the following statements regarding the NF2 signaling pathway is false? a. Merlin is encoded by the gene NF2 and facilitates transports YAP to the nucleus b. In schwannomas, YAP stimulates expression of PDGFR, Her2, Her 3, and PDGF c. PDGFRb, Her2, and Her3 are cell surface receptors that can stimulate the AKT pathway d. The AKT pathway promotes cell survival and is associated with Schwannoma growth e. NF2 is a tumor suppressor gene and a transcription factor

a. Merlin is encoded by the gene NF2 and facilitates transports YAP to the nucleus Merlin is a tumor suppressor protein encoded by the NF2 gene on chromosome 22. Loss of function mutations in NF2 cause neurofibromatosis type 2. Patients with neurofibromatosis type 2 may develop bilateral vestibular schwannomas, meningiomas, and ependymomas. In Schwann cell, merlin blocks YAP nuclear accumulation and thereby inhibits cell proliferation (PMID: 24558021). YAP, or Yes-associated protein 1, is a transcriptional regulator of the cell surface receptors PDGF, PDGFRb, Her3, and Her2. PDGF, PDGFR, Her3, and Her2 receptors can accumulate on the cell surface and promote proliferation and survival. Neurofibromin is a tumor suppressor protein encoded by the NF1 gene on chromosome 17.

Which cell types are implicated as the major course of collagen production in radiation fibrosis? a. Myofibroblasts b. Keratinocytes c. Endothelial cells d. Pneumocytes e. Macrophages

a. Myofibroblasts Myofibroblasts and fibroblasts are the predominant cells that elaborate the collagen responsible for radiation fibrosis. Myofibroblasts may originate from a variety of cells including local fibroblasts, epithelial cells, endothelial cells, and other progenitors. To produce collagen these non-fibroblast cells must first undergo epithelial or endothelial to mesenchymal transition

Which of the following sets of transcription factors, often called Yamanaka factors, are commonly used to induce pluripotent stem cells (iPSCs) from somatic cells? a. Oct4, Sox2, Klf4, c Myc b. c-jun, c-fos, K-Ras, B-Raf c. NF-kB, Akt, IRF2, Nrf2 d. BAX, BAM, ATM, TP53 e. P38, c-Jun, C-Fos, Akt

a. Oct4, Sox2, Klf4, c Myc Yamanaka factors or OKFM induce pluripotent stem cells (iPSCs) from mature cells, such as skin cells or fibroblasts, and earned Yamanaka the 2012 Nobel Prize for Physiology or Medicine.

The lacrimal gland is comparable to which of the following organs/glands in terms of its radioresponse? a. Parotid b. Heart c. Liver d. Sebaceous e. Skin

a. Parotid The lacrimal gland is comparable to the parotid in terms of both its structure and the tendency of secreting cells to undergo radiation-induced interphase death (another way to say apoptosis)

Generally, the sparing effect during dose fractionation increases with increasing time between fractions. Under certain irradiation conditions however, an increase in the interval between fractions results in decreased cell survival. This occurs because of: a. Reassortment b. Repopulation c. Repair d. Reoxygenation e. Adaptive response

a. Reassortment A Generally, increasing the time between fractions in a split dose treatment results in a higher cell surviving fraction due to repair at relatively short interfraction intervals of a few hours, or due to repopulation for longer times between fractions. However, under certain irradiation conditions and depending on the cell line, the initial dose may cause inhibition of progression from G2 into M phase. Therefore, the second dose may be delivered when the majority of the surviving cells have reassorted into G2, a radiosensitive phase of the cell cycle. Thus, even though repair of sublethal damages has occurred in these cells, which by itself would lead to a greater surviving fraction, this may be more than counterbalanced by reassortment sensitization, resulting in lower cell survival. Hypoxic conditions would not be expected for cells grown in tissue culture, so reoxygenation, which could lead to greater cell killing if it were to occur, is unlikely. The adaptive response in which cells treated with an initial low "priming" dose of radiation exhibit greater resistance to a second, higher, "challenge" dose, would increase, not decrease, cell survival.

The maximum permissible dose per year for a member of the general population includes dose contributions received from: a. Storage of radioactive waste material b. Radioactive elements in the earth's crust c. A course of radiotherapy d. Exposure to radon e. Mammography

a. Storage of radioactive waste material According to NCRP guidelines, a member of the public may receive a maximum of 1 mSv per year resulting from exposure to radioactive waste materials. Background radiation and the radiation exposure resulting from medical exposures, that are performed to either diagnose or treat disease, do not count towards this annual limit.

The tumorigenicity of cancer stem cells is best assessed by what assay? a. TD50 assay b. TCD50 assay c. In vivo - in vitro assay d. Tumor regrowth assay e. Ability to metastasize

a. TD50 assay Cancer stem cells are highly tumorigenic. This can be shown by injecting graded numbers of different cancer cell populations into mice (also called limiting dilution assay) to determine the number that are needed to grow tumors in 50% of sites, which is the tumor dose 50 (TD50 -- think "Take Dose"). This is why they are also called "tumor initiating cells". Human cancer stem cells can be grown in immune deficient mice using the same approach. TD50 tends to be inversely correlated with TCD50 indicating the lower tumor radiocurability with rising levels of cancer stem cells. TD50 = tumor formation - # of tumor cells it takes to make tumors in 50% of sites TCD50 = tumor control dose to control 50% of tumors

Which of the following statements concerning the human LD50 is TRUE? a. The LD50/60 associated with an acute whole body irradiation is approximately 3.5 Gy for people who do not receive appropriate medical care following irradiation. b. Even with optimal medical care, the LD50/60 cannot be increased. c. The most common cause of death in people who receive a dose close to the LD50/60 is severe anemia. d. A person who received a whole body dose close to the LD50/60 would exhibit severe diarrhea within 24 hours. e. The LD50/60 is the dose that leads to death within 50 days of 60% of the population.

a. The LD50/60 associated with an acute whole body irradiation is approximately 3.5 Gy for people who do not receive appropriate medical care following irradiation. The LD50/60 for an acute, whole body irradiation is estimated to be 3.5 Gy without medical intervention and approximately 7 Gy with optimal medical care. The principal causes of death for people who receive a dose close to the LD50/60 are infections and hemorrhage. A person who received a dose of about 3.5 Gy would not exhibit the symptoms associated with the GI syndrome, such as severe diarrhea. The LD50/60 is the dose that leads to death within 60 days of 50% of the population.

Which of the following statements concerning retinoblastoma and the RB (RB1) protein is TRUE? a. The RB protein suppresses cell proliferation by binding to the E2F transcription factor, thereby inhibiting gene expression E2F-dependent gene transcription b. Cell cycle dependent kinases add hydroxyl groups to the RB gene product causing it to release E2F c. A mutant RB gene is inherited from one parent in the sporadic form of retinoblastoma d. The RB protein product is phosphorylated by CDK1 e. In the familial form of retinoblastoma, patients are only at elevated risk for retinoblastoma, and not other cancers

a. The RB protein suppresses cell proliferation by binding to the E2F transcription factor, thereby inhibiting gene expression E2F-dependent gene transcription The RB protein suppresses cell growth by binding to the E2F transcription factor, preventing it from activating the transcription of cell cycle-related proteins that allow the cell to transition from G1 to S phase. Cell cycle dependent kinases add phosphate, not hydroxyl, groups to the RB gene product causing it to release E2F. A mutant RB gene is inherited from one parent in the familial form of retinoblastoma, not the sporadic form. The RB protein product is phosphorylated by CDK4, not CDK1. In the familial form, people who inherit a mutated copy of the RB gene exhibit an increased incidence not only of retinoblastoma, but also osteosarcomas, as well as carcinomas of the lung, kidney and bladder.

Which of the following statements comparing proton with neutron therapy is correct? a. Tissues demonstrate higher α/β with neutron compared to proton irradiation b. Therapeutic energy protons lose the fractionation dose-sparing effect for early but not late responding tissues c. Proton but not neutron doses are described using the term "equivalent dose" d. Protons and neutrons transfer energy to tissue via nuclear reactions e. "Scanning" the beam describes energy-modulated broad beam neutron irradiation

a. Tissues demonstrate higher α/β with neutron compared to proton irradiation Therapy-relevant protons are low-LET beams, whereas neutrons are high-LET beams. There is much less changes in isoeffective total doses with decreasing dose per fraction for high- LET compared to low-LET, and correspondingly higher α/β with neutron compared to proton irradiation. Proton doses are described in gray equivalents or GyE. The GyE is equal to the physical dose in grays times proton RBE taken to be equal 1.1. Thus, proton dose is 10% lower than photon dose in a radiation therapy setting. The term "equivalent dose" is the term used in radiation protection and measured in Sievert (Sv); 1 Sv = 1 Gy times radiation weighting factor (Q) which is 1 for protons and energy-dependent for neutrons (Q=20 for 1-10 MeV neutrons). The ICRP has recommended a new name for this radiation protection dose, "radiation weighted dose" to avoid confusion.

Which of the following are needed to carry out a successfully CRISPR modification on a target sequence? a. gRNA, cas9 nuclease b. miRNA, caspase 9 c. gDNA, repetitive palindromic DNA d. RNA primer, telomerase e. snRNA, DNase A

a. gRNA, cas9 nuclease The CRISPR reaction needs the guide RNA and the cas9 (CRISPR associated protein 9) in order to take place. The other ingredients in the answer are used in other reactions, but none of them are needed for CRISPR.

How does single-cell RNA-seq differ from ChIP-seq? a. scRNA-seq provides gene expression data from individual cells whereas ChIP-seq tests for protein-DNA interactions. b. Both techniques measure the amount of RNA but only single-cell RNA seq can detect mitochondrial RNA. c. Both techniques measure the RNA transcripts, but only ChIP-seq is performed on a micro-chip. d. Only ChIP-seq has reverse transcription, amplification, library generation and sequencing as part of the work-flow.

a. scRNA-seq provides gene expression data from individual cells whereas ChIP-seq tests for protein-DNA interactions. Single-Cell RNA-Seq is a powerful technique that allows transcriptional profiling of tens of thousands of individual cells which helps to understand not only what genes are expressed, but also how this might differ within a heterogeneous sample. Cellular subpopulations can be identified and interrogated on an individual basis with some limitations. By comparison, more conventional bulk RNA-Seq and microarrays can only provide the expression profile as an average for all cells in a sample and therefore critical differences between different cellular subsets will be lost. A typical workflow for scRNA-seq involves isolation of a single cell, reverse transcription and barcoding, amplification, sequencing library preparation, sequencing and bioinformatic data analysis. ChIP-seq, on the other hand, is a method that uses chromatin immunoprecipitation combined with DNA sequencing in order to identify binding sites of DNA-associated proteins, i.e. most often transcription factors. Steps in the protocol involve cross-linking proteins to DNA, chromatin fragmentation, immunoprecipitation, DNA recovery and purification, sequencing. Although, RNA might also be cross-linked to the protein, it won't be reversed transcript or sequenced.

What would be the estimated surviving fraction of V79 Chinese hamster cells irradiated with an X-ray dose of 5 Gy delivered acutely? (Assume a=0.2 Gy-1 and b=0.05 Gy-2) a. 0.01 b. 0.10 c. 0.37 d. 0.50 e. 0.90

b. 0.10 As is typical of most mammalian cell lines, the dose response curve for X-irradiated V79 Chinese hamster cells is linear-quadratic in shape, and can be modeled using the expression S = . Using the parameters provided, the surviving fraction following a dose of 5 Gy would be S = e-[(0.2)(5)+(0.05)(25)] = e-(1+1.25) = e-2.25 ~ 0.1.

The genetically significant dose (GSD) resulting from diagnostic radiology procedures performed in the U.S. annually has been estimated to be: a. 0.03 mSv b. 0.3 mSv c. 3 mSv d. 30 mSv e. 3 Sv

b. 0.3 mSv The GSD or genetically significant dose, which represents the average dose to the gonads weighted to reflect the child-bearing potential of the people that comprise that population, is estimated at 0.3 mSv for radiation exposures from "man-made" radiation (imaging procedures, commercial nuclear power, air travel, weapons testing fallout, ect).

What is the approximate rate of grade 3+ autoimmune toxicity from anti-PD1 immunotherapy? a. 5% b. 15% c. 30% d. 50%

b. 15% Checkpoint inhibitor therapy has a different toxicity profile compared to conventional cytotoxic chemotherapy, namely the absence of cytopenia and low-grade nausea. However, there is an approximate 10-20% risk of grade 3+ autoimmune toxicity, mainly thyroid dysfunction, colitis, and pneumonitis. These estimates come from anti-PDL1 monotherapy trials including KEYNOTE-024 (pembrolizumab/NSCLC), KEYNOTE-006, (pembrolizumab/melanoma), CheckMate-066 (nivolumab/melanoma), and CheckMate-025 trial (nivolumab/renal cell carcinoma).

Suppose a chemotherapeutic agent that killed tumor cells, independently of radiation, was also employed during the aforementioned course of treatment. It is known from previous data that this drug regimen results in a surviving fraction of 10^-4 for the tumor under treatment. Now what is the total radiation dose required to produce a 37% chance of tumor cure (still assuming that the 10^6 cells go through an extra three cell divisions)? a. 12 Gy b. 17 Gy c. 24 Gy d. 36 Gy e. 48 Gy

b. 17 Gy Since the chemotherapy results in a surviving fraction of 10^-4, the number of clonogens in the tumor would be reduced from 8x10^6 to 8x10^2. Since the D10 for this tumor is 5.75 Gy, then a dose of approximately 17 Gy would produce a 37% control rate. They are saying that 800 cells --> 80 --> 8 --> 0.8 is three logs of cell kill. So 17 Gy is to actually give you S = e^-.8 --> actually a 44% chance of cure technically Another way to more precisely determine the answer to this problem is to recognize that since the chemotherapy results in a surviving fraction of 10^-4, the amount of radiation dose, D, NOT needed is given by SF = e(-D/D0) = 10^-4. Therefore -D/D0 = ln 10^-4 or D = -(D0)(-ln 10-4)= -(2.5)(-9.2) = 23 Gy and so the final dose required is 34.5 + 5.2 - 23 = 16.7 Gy. Alternatively, with use of chemotherapy, the number of clonogens is reduced from 8x106 to 8x102, so the dose D now required for 37% cure is given by D = (2.5)[ln(8 x 10^2)] = (2.5)(6.7) = 16.8 Gy.

Two patients are diagnosed on the same day with tumors of approximately the same size. However, the Tpot for patient A's tumor was determined to be 5 days while the Tpot for patient B's tumor was calculated as 20 days. Assuming that there was no cell loss taking place and the tumor's growth fractions did not change, if treatment was delayed for 20 days, the ratio of the number of cells in the tumors of patient A to patient B would have been approximately: a. 16:1 b. 8:1 c. 1:1 d. 1:8 e. 1:16

b. 8:1 If the treatment was delayed for 20 days , then the number of cells in the tumor in patient B would double the number of cells present when the cancer was diagnosed. In contrast, the tumor in patient A is growing more rapidly with a Tpot of 5 days. Therefore, if treatment was delayed for 20 days, the cancer in this patient would go through 4 doubling times, leading to 2 x 2 x 2 x 2 = 16 times as many cells. Thus, the ratio of the number of cells in the tumors in patients A and B would be 8:1. Examples like this illustrate how tumors of varying degrees of growth will experience large differences in volume across time. Math here if this was more complicated is: 2^n = number of cells n = number of divisions Patient A: 2^4 = 16 cells (after 4 divisions) Patient B: 2^1 = 2 cells (after 1 division) Therefore 16:2 or 8:1

The two most frequently activated signaling pathways in prostate cancer are driven by androgen receptor (AR) and PI3K-AKT pathway. Inhibitors of the PI3K pathway are in early clinical trials and AR inhibitors confer clinical responses in most patients. Which statement most correctly describes the relationship between these two pathways and explains mechanistically why single inhibition of AR and PI3K-AKT pathways rarely induce tumor regression in preclinical models? a. ADT represses an androgen receptor gene expression program governing DNA repair and inhibits repair of ionizing radiation-induced DNA damage b. AR and PI3K pathways regulate each other by reciprocal negative feedback, such that inhibition of one activates the other c. ADT represses the PI3K-AKT-mTOR pathway d. ADT activates the unfolded protein response e. All of the above

b. AR and PI3K pathways regulate each other by reciprocal negative feedback, such that inhibition of one activates the other Prostate cancer is characterized by its dependence on androgen receptor and frequent activation of PI3K signaling. AR transcriptional output is decreased in human and murine tumors with PTEN deletion and that PI3K pathway inhibition activates AR signaling by relieving feedback inhibition of HER kinases. Similarly, AR inhibition activates AKT signaling by reducing levels of the AKT phosphatase PHLPP. Thus, these two oncogenic pathways cross-regulate each other by reciprocal feedback. Inhibition of one activates the other, thereby maintaining tumor cell survival. However, combined pharmacologic inhibition of PI3K and AR signaling causes near complete prostate cancer regressions in a PTEN-deficient murine prostate cancer model and in human prostate cancer xenografts, indicating that both pathways coordinately support survival.

Which one of the following conditions treated with radiation is associated with an increased incidence of leukemia? a. Breast cancer b. Ankylosing spondylitis c. Cervical cancer d. Brain tumors e. Enlarged thymus

b. Ankylosing spondylitis Treatment of ankylosing spondylitis, which at one time involved radiation therapy, has been associated with an increased incidence of leukemia.

Immunosuppression observed within 24 hours following exposure to a whole body dose of 5 Gy X-rays would be due primarily to: a. Death of hematopoietic progenitor cells b. Apoptosis of peripheral blood lymphocytes c. A loss of circulating granulocytes d. Decreased activity of NK cells e. Inactivation of circulating antibodies

b. Apoptosis of peripheral blood lymphocytes. Immunosuppression observed within 24 hours after irradiation would be the consequence of the rapid death of lymphocytes due to radiation-induced apoptosis. A much longer period than 24 hours would be required for the death of progenitor cells and a loss of granulocytes. Doses much greater than 5 Gy would be necessary to cause decreased activity of NK cells and inactivation of circulating antibodies.

The Quantitative analysis of normal tissue effects in the clinic (QUANTEC) suggested that prevent of severe xerostomia (long term salivary function <25% of the pre-treatment baseline) requires which of the following dose constraints on the parotid glands: a. At least one parotid gland should receive a mean dose <50 Gy b. At least one parotid gland should receive a mean dose <20 Gy c. Both parotid glands should receive a mean dose <50 Gy d. Both parotid glands should receive a mean dose <20 Gy e. None of the above

b. At least one parotid gland should receive a mean dose <20 Gy At least one parotid gland should receive a mean dose <20 Gy. The QUANTEC report provided guidelines on normal tissue toxicity and recommendations on dose constraints to prevent long-term toxicity. For severe xerostomia, the recommendation was that - one parotid should receive a mean dose less than 20 Gy or both parotid glands should receive a mean dose less than 25 Gy

All of the following are phosphatidyl inositol 3-kinase like kinases, EXCEPT: a. ATM b. BRCA1 c. ATR d. mTOR e. DNA-PK (PRKDC)

b. BRCA1 BRCA1 is not a phosphatidyl inositol 3-kinase like kinase, whereas ATM, ATR, mTOR and DNA-PK all fall into this category of protein. PI3K-like kinases = ATM, ATR, mTOR, DNA-PK

Which of the following crucial observations was made by Till and McCulloch during bone marrow cell transfer in mice? a. Prevention of late hematopoietic lethality in mice after whole body irradiation (WBI) b. Bone marrow clones that arise during regeneration after WBI form colonies in the spleen of mice obvious within 10 days after exposure c. Bone marrow-derived cells that give rise to colonies within 10 days in the spleen of WBI mice are relatively radioresistant d. Repair does not take place over the first 24 hours after bone marrow irradiation e. Bone marrow rescue following WBI required more stem cells in smaller compared to larger animals

b. Bone marrow clones that arise during regeneration after WBI form colonies in the spleen of mice obvious within 10 days after exposure Till and McCulloch - considered as the "fathers of stem cell science"- showed that bone marrow-derived colonies arose within 10 days in the spleens of WBI mice (endogenous assay) or after injection of bone marrow cells (exogenous assay) and prevented acute hematopoietic death. They used this assay to show that the bone marrow was very radiosensitive in general and described in vivo repair and repopulation after radiation exposure. The pluripotent stem cell in the bone marrow is however rare, relatively quiescent and radioresistant and best assessed by cobblestone area forming assay in vitro, or by flow cytometry.

What is the effect on both RBE and the /ratio as the LET for the type of radiation increases up to 100 keV/m? a. Both remain the same b. Both increase c. Both decrease d. The RBE decreases while the /increases e. The RBE increases while the /decreases

b. Both increase Excellent thought question -- Obviously RBE increases with increase in LET because the dose required of X-ray low LET radiation to produce the same biological effect as high LET radiation increases as the LET increases (up to 100 KeV/um). High LET radiation results in essentially all alpha irreparable kill and beta approaches zero which means the a/b ratio is essentially infinitely high -- thus they both increase.

Which of the following is a gene editing technology? a. Luciferase b. CRISPR c. GWS d. RT-PCR e. ChIP

b. CRISPR CRISPR Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) are used as gene editing tools so that single base-pair changes can be made in a large genome. Luciferase is a reporter gene. GWS is genome-wide sequencing. RT-PCR (real time-PCR) is a method used to quantitate mRNA. ChIP, chromatic immunoprecipitation allows for detection of sequences bound to DNA, most often promoter sequences.

Which of the following proteins is involved in the G2 checkpoint? a. Cyclin D1 b. Cdc25C c. Cyclin D8 d. Smad3 e. Rb

b. Cdc25C CDC25C is pro-cell cycle progression which dephosphorylates CDK1/cyclin B to activate it. CHK2 is a negative regulator of CDC25C (increased by ATM) to attempt to shut down the cell cycle at that checkpoint. Of note, Wee1/Myt1 are kinases that phosphorylate CDK1/cyclin B to inactivate it as well (thus oppose CDC25C)

Radiation-induced epilation occurs before dermatitis because: a. Basal cells in the epidermis have shorter cell cycle times than the germinal matrix of the hair bulb b. Cells in the germinal matrix of the hair bulb have shorter cell cycle times than the basal cells of the epidermis c. Of the exquisite sensitivity of sebaceous glands d. Of vascular endothelial cell death in the connective tissue at the distal end of the hair follicle e. Of keratin synthesis inhibition in the hair follicle

b. Cells in the germinal matrix of the hair bulb have shorter cell cycle times than the basal cells of the epidermis Radiation-induced epilation occurs before dermatitis due to the short cell cycle time of the cells in the germinal matrix of the hair bulb, compared to that of the basal cells of the epidermis.

Which of the following statements concerning hyperthermia is TRUE? a. G2 cells are the most resistant with respect to both heat and X-rays b. Cells maintained in a low pH microenvironment tend to be more sensitive to heat than cells maintained at physiologic pH c. Acutely hypoxic tumor cells are more sensitive to hyperthermia than chronically hypoxic ones d. In laboratory rodents, hyperthermia tends to increase blood flow in tumors, but decrease blood flow in most normal tissues e. The amount of killing produced in a population of cells heated at 43ºC for 10 minutes will be greater than for cells heated at 46ºC for 5 minutes

b. Cells maintained in a low pH microenvironment tend to be more sensitive to heat than cells maintained at physiologic pH Tissues maintained under conditions of low pH tend to be sensitive to heat. G2 cells are quite radiosensitive, but somewhat more resistant to heat killing,comparatively speaking. It is the chronically hypoxic cells in tumors (that typically exist in acidic microenvironments) that tend to be more sensitive to heat than acutely hypoxic cells. In laboratory rodents, hyperthermia usually results in increased blood flow in normal tissues and decreased blood flow in most tumors, not vice versa. Because the vasculature in normal tissues is generally more "mature" and responsive to external stimuli than tumor vasculature, it can more readily respond to elevated temperatures by dilating and increasing blood flow so as to carry away excess heat and restore normal physiologic temperature. The amount of cytotoxicity produced by a hyperthermic treatment at 43ºC for 10 minutes would be less, not more, than that produced by 46ºC for 5 minutes. This would be predicted from the thermal dose calculation (applicable for heat exposures at 43ºC and above) t2/t1 = 2T1-T2, where t1 and t2 are the exposure times at temperatures T1 and T2 to produce equal biological effects. Thus, if T1 is 46 ºC and T2 is 43ºC, then the treatment at the lower temperature would need to be 8 times as long as at the higher temperature to produce the same amount of cell killing.

Cancer stem cells (CSCs) are most correctly defined by which of the following statements. a. Tissue specific cell surface markers, examples include CD133 for lung CSCs or CD34 for AML CSCs b. Cells that can self-renew and also give rise to daughter cells that have more limited proliferative potential and are destined to differentiate c. Cells following Hoechst 33342 based flow cytometry that reside in the side-population d. Cells that express higher levels of the enzyme aldehyde dehydrogenase (ALDH) e. Cells that resist chemotherapy treatment

b. Cells that can self-renew and also give rise to daughter cells that have more limited proliferative potential and are destined to differentiate The correct answer is "b" while the other answers are all surrogate markers or features of CSCs (19249645). Stem cells must be able to self-renew. Importantly, self-renewal and cellular proliferation are not synonymous, since in addition to cell d ivision the former term encompasses both the differentiation and future mitotic potential of the daughter cells. Secondly, stem cells must give rise to daughter cells (i.e. progenitors) that have limited proliferative potential and are destined to differentiate. Through this process stem cells give rise to the mature effector cells that perform a given tissue's biological functions.

The epidermal growth factor receptor (EGFR) is a target of which of the following agents? a. Bevacizumab b. Cetuximab c. Celecoxib d. Sirolimus e. Bortezomib

b. Cetuximab Cetuximab is a monoclonal antibody that blocks the epidermal growth factor receptor. The combination of cetuximab and radiation has been shown to be an effective treatment for cancers of the head and neck. Bevacizumab is a monoclonal antibody against VEGF and acts by interfering with angiogenesis. Celecoxib is a nonsteroidal anti-inflammatory drug that inhibits the cyclo-oxygenase 2 enzyme. Sirolimus is an immunosuppressant whose mode of action is to bind the FK-binding protein 12 (FKBP12), which in turn inhibits the mammalian target of rapamycin (mTOR) pathway. Bortezomib is a proteasome inhibitor that is used to treat multiple myeloma.

If mammalian cells receive a go-ahead signal at the G2/M checkpoint, they will: a. Move directly into telophase b. Complete the cycle and divide c. Exit the cycle and switch to a nondividing state d. Show a drop in M-Phase Promoting Factor (MPF) concentration e. Complete cytokinesis and form new cell walls

b. Complete the cycle and divide The checkpoints are accessories of the cell cycle control machinery and inactive under normal physiological conditions. When the cell misbehaves by a set of specific criteria that define what is "normal", the checkpoint is activated and the cell is forced to halt before its entry into the next phase. While the M checkpoint is best studied, the G1 checkpoint is arguably more important because it prevents passing defective DNA to daughter cells by initiating repair processes. The M phase consists of nuclear division (mitosis) and cytoplasmic division (cytokinesis). Mammalian cells do not have a cell wall. MPF = the M-phase-promoting factor (former "maturation-promoting factor"). MPF first discovered in mature unfertilized Xenopus eggs (which are arrested in M phase), is a ubiquitous inducer of mitosis.

Which statement is true for CyTOF? a. CyTOF stands for Cytometry of fluorescence and is a techniques that allows the staining of cells with antibodies similar to flow cytometry only with the added capability of measuring mRNA levels on a per cell basis. b. CyTOF is a mass spectrometry technique that is based on staining cells with metal-conjugated antibodies with fewer limitation of spectral overlap than flow cytometry. c. CyTOF uses antibodies-coupled with radioisotopes to measure protein levels in and on cells. d. CyTOF is a gas chromatography technique that analyses antibody-stained cells on a single-cell basis and is much more powerful than flow cytometry.

b. CyTOF is a mass spectrometry technique that is based on staining cells with metal-conjugated antibodies with fewer limitation of spectral overlap than flow cytometry. Mass cytometry (or CyTOF -cytometry by time of flight) is a technique that combines two experimental platforms: flow cytometry and elemental mass spectrometry. Cells are stained with a cocktail of antibodies or probes coupled with unique stable, heavy-metal isotopes. Cells are passed in a single-cell suspension into a nebulizer, prior to entering the mass cytometer. Cells travel through an argon plasma, in which covalent bonds are broken to produce free atoms, which become charged in the process. The resulting ion cloud is passed through a quadrupole, enriched for heavy-metal reporter ions, and separated by their mass-to-charge ratio in a time-of- flight mass spectrometer. The ion counts are converted to electrical signals and ultimately into a data matrix in which every column represents a distinct isotope measured and each row represents a single mass scan of the detector. Essentially, it is a high-throughput single-cell analysis platforms similar to flow cytometry but at increased resolution and parameterization and used to identify different cell subsets in a mixture of cells and/or physiological endpoints such as cell signaling or activation status.

Tumor cell repopulation during treatment causes the BED value to: a. Increase b. Decrease c. No effect d. Increase, but only if Tpot is greater than 5 days e. Increase, but only if the /ratio for the tumor is large

b. Decrease Tumor cell repopulation during treatment would cause a decrease in the BED, since the cell divisions that take place during the course of therapy could counteract some, if not all, of the toxicity of the radiation. This can be calculated from the equation BED = nd[1+d/(a/b)] - [(0.693)(T)/(alpha)(Tpot)] where n is the number of fractions, d is the dose per fraction, a and b are the parameters characterizing the underlying dose response curve for the tumor, T is the length of time during treatment that repopulation occurs and Tpot is the potential doubling time (the time it would take the tumor to double its cell number in the absence of cell loss).

The best way to spare the parotid gland is to: a. Use hyperfractionated radiotherapy b. Decrease the irradiated volume of the parotid gland c. Increase the overall treatment time d. Use hypofractionated radiotherapy e. Accelerate treatment

b. Decrease the irradiated volume of the parotid gland The best way to spare the parotid gland is to decrease the volume of the gland irradiated. The parotid exhibits relatively little sparing with fractionation so use of either a hyperfractionated or hypofractionated protocol would have only a modest impact. Prolongation or acceleration of treatment would have little effect on the parotid.

As the dose to an organ increases, the latency period prior to the development of a late complication generally: a. Increases b. Decreases c. Remains the same d. Increases, but only for an accelerated protocol e. Decreases, but only for a hyperfractionated protocol

b. Decreases The latent period prior to the manifestation of a late effect generally decreases with increasing dose to the irradiated organ

Which of the following types of chromosomal aberrations is most likely to cause lethality? a. Insertion b. Dicentric c. Translocation d. Inversion e. Anaphase bridge

b. Dicentric Dicentric is a chromosomal type aberration. Anaphase bridge is a chromatid aberration

Which statement comparing carbon ion with proton beam radiotherapy is FALSE? Both carbon ions and protons: a. Provide the type of precision radiotherapy needed to treat certain tumors located near critical structures b. Display a lower OER compared with X-rays c. Exhibit a Bragg peak. d. Represent particulate forms of radiation e. Both are positively charged and generated using a cyclotron

b. Display a lower OER compared with X-rays Although carbon ions exhibit a reduced OER, the OER for protons is high and similar to that for X-rays.

For which of the following types of radiation is the description provided FALSE? a. Carbon ions - have both depth-dose and biological advantages for radiotherapy b. Electrons - useful for the treatment of deep-seated tumors c. Protons - dose distribution advantages, but with an RBE approximately equal to 1.0. d. Photons - most common type of radiation used for radiotherapy e. Neutrons - relatively poor dose distributions, but with greater biologic effectiveness

b. Electrons - useful for the treatment of deep-seated tumors Electrons are useful only for relatively superficial treatments. Based on the energies used for radiotherapy, they are not capable of penetrating very far into tissue.

An antibody would be used to screen which type of library? a. Genomic b. Expression c. cDNA d. Intronic e. Endonuclease

b. Expression An antibody would be useful to screen an expression library, which synthesizes the protein encoded by each gene in the library. If nucleotide sequences are not available as probes for library screening (eg. sequence is not known), antibodies could be used for screening, if available. To do this one must create an expression library (ie. a library that not only contains the DNA fragments of interest but one that can actually manufacture the protein coded by the fragment) so that it may be detected by the antibody. This requires that the cDNA fragment within the vector be inserted downstream of a bacterial promoter, which will cause the inserted fragment to be expressed.

Which of the following drugs is an anti-metabolite? a. Melphalan b. Gemcitabine c. Etoposide d. Taxol e. Mitomycin

b. Gemcitabine Gemcitabine is a nucleoside analog of deoxycytidine in which the hydrogens at the 2' carbons in the sugar are replaced by fluorines. Once incorporated into DNA, the presence of this analog inhibits further DNA synthesis. In contrast, the other drugs listed cause toxicity either due to the damage they produce or by interfering with normal cellular processes. Melphalan and mitomycin c are alkylating agents. Etoposide is a topoisomerase II poison. Taxol stabilizes microtubule formation.

The most commonly used biologically active molecule for PET scanning is a fluoridinated analog of which of the following: a. Phosphate b. Glucose c. Calcium d. Albumin e. Sphingomyelin

b. Glucose 18-Fluorodeoxyglucose is the most commonly used metabolic radiotracer for PET scanning at present.

Which "wonder drug" established the concept of oncogene addiction and revolutionized chronic myologenous leukemia (CML) therapy? a. Gefitinib b. Imatinib c. Bevacizumab d. Temozolomide e. Loperamide

b. Imatinib Chronic Myelogenous Leukemia (CML) was once thought to be incurable until the 1990's, until Brian Druker and Charles Sawyers worked together to develop a novel, targeted approach to treat CML. Their therapy, imatinib, is a tyrosine kinase inhibitor which targets the key 9:22 BCR:ABL translocation associated with the disease. A once fatal disease led to 90% cure rates, with survival increasing from 5-6 years to 15-20 years [10]. Their work is important because it further supports the concept that many tumor cells become dependent on their oncogenes for cell survival, which is referred to as oncogene addiction.

Clonal evolution is primarily driven by: a. Oncogene activation b. Imperfect DNA damage repair c. Cell cycle progression d. Checkpoint inhibition e. Tumor suppressor inactivation

b. Imperfect DNA damage repair Clonal evolution describes the phenomenon whereby the clonal makeup of a tumor changes over time. This is driven by mutations in individual cells that arise over time. Imperfect DNA damage repair results in mutations, even if a cell contains no overt DNA damage repair deficiencies (e.g., NHEJ). By random chance some of these mutations will be disadvantageous for the cell, while fewer will provide a fitness advantage. Advantageous mutations become enriched in the overall tumor sample over time as they outcompete nearby cells without such advantageous mutations.

What is the most correct mechanism by which Hsp90 inhibitors may result in radiosensitization? a. Inhibition of the microtubular machinery b. Inhibition of DNA damage response and repair pathways c. Reassortment of cancer cells into the S-phase of the cell cycle d. Inhibition of accelerated tumor repopulation e. All of the above

b. Inhibition of DNA damage response and repair pathways Existing in highly proteotoxic environments, tumor cells are subjected to chronic and acute hypoxia, increased levels of DNA damage, high levels of reactive oxygen species, and protein complex imbalances due to aneuploidy. Survival under these conditions is enabled by the aid of efficient cellular stress response machinery, such as heat shock protein 90. Hsp90 inhibition imparts radiosensitization through multiple mechanisms via downregulation of multiple HSP90 clientele that function in: (1) reassortment of cancer cells into G2-M; (2) downregulation of radioresistance signal transduction pathways like the PI3K- AKT-mTOR pathway; and (3) downregulation of the DNA checkpoint and repair pathways such as the ATR-Chk1 pathway (23863691). Only "b" is correct. Hsp90 inhibition does not result in answer "a", "c" or"d" and furthermore, S-phase is the most radioresistant phase of the cell cycle (answer "c").

p16INK4A (CDKN2A): a. Is an oncogene b. Is a CDK inhibitor c. Is rarely found mutated in tumors d. Over-expression is associated with metastatic potential e. Is inactivated in hypoxic cells

b. Is a CDK inhibitor -- specifically CDK4/6 p16INK4A is an inhibitor of CD4 and CDK6. The gene coding for it is a tumor suppressor that is found mutated in many cancers, particularly melanomas and pancreatic cancers. Inactivation of the gene is associated with an increased metastatic potential, but presumably plays no role vis-à-vis tumor hypoxia. Elevations in p16 are seen in HPV-driven cancers due to a failed negative feedback loop where cells become insensitive to the levels of p16 due to E7-dependent inhibition of Rb.

During which phases of the cell cycle does homologous recombination occur as a mechanism of DNA double strand break repair? a. G1-early S b. Late S-G2 c. M d. G0 e. All of the above

b. Late S-G2 Homologous recombination occurs predominantly during G2 and S phases, when another copy of DNA is available as a template for error-free repair. Data show that non-homologous end joining (NHEJ) dominates throughout the cell cycle, even during S phase and G2, however during S/G2 the cell also has the additional ability to undergo HR.

With the increasingly sophisticated refinements in radiation therapy techniques, more attention is now being paid to normal tissue dose and volume factors as they relate to the probability of treatment- associated late effects. Which of the following statements concerning the volume dependence of late complications is FALSE? a. The parameter that best predicts for lung complications after radiotherapy is the V20/V30 b. Length irradiated is a critical factor in determining the tolerance dose for the esophagus c. The percent volume of rectal wall that receives 40-50 Gy positively correlates with the likelihood of rectal bleeding d. Late effects are more sensitive to changes in fractionation than early effects e. Small volume irradiation of the brain can lead to focal radiation necrosis

b. Length irradiated is a critical factor in determining the tolerance dose for the esophagus The volume of normal tissue included in the irradiation field can have significant effects in the subsequent development of late effects. Despite being a serially arranged tissue like the rectum and spinal cord, several recent studies have shown that increasing the length of the esophagus in the treatment field does not predict the severity or duration of radiation- induced esophagitis. The morphological structure of the lung makes it difficult to define precise threshold limits. However, the best predictor for late effects has been found to be the V20/V30, that is, the percentage of normal lung volume that receives 20 Gy or 30 Gy, respectively. In contrast, in the rectum, it is the percentage of the wall that has received 40- 50 Gy that determines the likelihood of rectal bleeding, although the extent of reserve, unirradiated tissue is also a factor. The liver is deemed an organ whose FSU's are arranged in parallel. Early estimates of Veff gave a value of 0.32, but with changes in the standard of care over time, this value has risen to 0.94, emphasizing the importance of treatment volume in the probability of late complications. In the brain, the complex structure and morphology allows for focal radiation necrosis to be distinguished from diffuse white matter changes. The latency period for cerebral necrosis ranges from 6 months to several years post- radiation.

Assuming that the target cells do not have a pro-apoptotic tendency, the time to the expression of radiation damage in early-responding tissues typically correlates best with the: a. Radiosensitivity of the cells b. Lifespan of the mature functional cells of the tissue c. Ability of the cells to perform homologous recombinational repair of DNA damage d. Lifespan of the stem cells comprising that tissue e. Type of radiation used to irradiate the organ

b. Lifespan of the mature functional cells of the tissue Assuming that the mature differentiated cells comprising a tissue do not have a pro-apoptotic tendency, the time to expression of radiation damage in an early-responding tissue correlates best with the lifespan of the mature functional cells. This occurs because tissues with a hierarchical structure (i.e., most early-responding tissues) depend on the constituent stem cells to reproduce and supply new cells to replace the mature ones, when they reach the end of their lifespan. However, because stem cells are likely to be killed by radiation, there is a lack of "replacement" cells when the mature cells reach the end of their lifespan. Therefore, the time scale for the appearance of the radiation injury mimics to a first approximation the lifespan of the mature cells.

Activation of the immune system by localized radiation of orthotopic pancreatic tumors may be achieved by which of the following methods: a. Stereotactic radiation therapy that normalizes aberrant vasculature to aid efficient recruitment of tumor-specific T cells b. Low dose irradiation that normalizes aberrant vasculature to aid efficient recruitment of tumor- specific T cells c. Stereotactic radiation therapy that programs tumor-associated macrophages to recruit Tregs into the tumor d. Low dose irradiation that programs tumor-associated macrophages to recruit Tregs into the tumor e. Localized radiation that induces iNOS in tumor-associated macrophages which suppresses TH1 chemokine

b. Low dose irradiation that normalizes aberrant vasculature to aid efficient recruitment of tumor- specific T cells In this model, local low-dose radiation of pancreatic cancers in mice efficiently normalizes aberrant tumor vasculature to recruit effector T cells into tumors for enhanced tumor rejection and improved survival. This is mediated by iNOS induction in tumor- associated macrophages that amplify TH1 chemokines and inhibit angiogenic and immune suppressive cytokines. These effects were not observed with high-dose radiation (possibly because of lack of normalization of vasculature, lymphopenia induced by concomitant irradiation of the spleen, or other nearby immunologic effector organs and tissues).

Which of the following is NOT a delayed effect following head and neck radiation therapy? a. Stricture b. Mucositis c. Persistent xerostomia d. Telangiectasia e. Ulcer

b. Mucositis Mucositis is an acute response, not a late effect, and is one of the main dose-limiting toxicities in the management of head and neck and digestive track carcinomas with radiation therapy. The remaining toxicities are some of the chief late complications seen in these patients.

Which of the following statements regarding p53 (TP53) is FALSE? p53: a. Is targeted by MDM2 for degradation b. Mutation in lymphoma cells usually renders these cells radiosensitive c. Is a substrate for the ATM protein kinase d. Serves as a transcription factor and upregulates p21 (CDKN1A) e. Upregulates the pro-apoptotic factors BAX and PUMA

b. Mutation in lymphoma cells usually renders these cells radiosensitive Since p53-mediated apoptosis is the main way lymphoma cells die following irradiation, possession of a mutation in the p53 gene renders these cells radioresistant, not radiosensitive. At higher RT doses, p53-mut cells die by mitotic catastrophe due to lack of p53 mediated cell senescence which would allow for DNA repair.

Which of the following techniques can be used to directly evaluate the induction and repair of DNA double strand breaks? a. Northern blotting b. Neutral comet assay c. Alkaline comet assay d. Polymerase chain reaction e. Western blotting

b. Neutral comet assay The comet assay is a method of single cell electrophoresis which allows the DNA of a cell to be separated based on the weight of the DNA. Cells with many breaks will have smaller fragments of DNA and thus the fragments will move faster from the original location of the nucleus. Under neutral conditions, DNA remains bound to its complimentary strand, and double strand breaks are measured. Under alkaline conditions, the complementary strands dissociate, thus, single strand breaks are measured. A northern blot is used to assess RNA and a western blot is used to evaluate proteins. Thus, neither a northern nor western blot would play a role in the direct assessment of DNA double strand break repair. Polymerase chain reaction (PCR) is used to amplify specific segments of DNA but is not generally used to evaluated DNA double strand breaks or their repair.

Two isoeffect curves, one corresponding to a given level of tumor control and the other for a given probability of a late complication in a critical normal tissue, are found to intersect. If the curves were plotted as total dose on the Y-axis and dose per fraction on the X-axis, the most important application of this information would be to predict the: a. Tumor control probability b. Optimal range of fraction sizes to use for treatment c. Optimal overall treatment time d. Outcomes when split course treatment is used e. Normal tissue complication probability

b. Optimal range of fraction sizes to use for treatment The dose per fraction, at which the isoeffect curves for tumor control and late effects intersect, helps to define the range over which the desired tumor control probability can be achieved while also staying at or below the tolerance dose for the late responding normal tissue. Since the use of smaller-than-conventional fraction sizes generally results in greater sparing of late effects relative to tumor control, treatment protocols involving the use of fraction sizes smaller than the point of intersection between the two isoeffect curves would yield the desired level of tumor control while not exceeding normal tissue tolerance. This type of analysis would not provide any information as to the actual extent of tumor control or the extent of normal tissue damage anticipated since these are already specified by the chosen isoeffect. (It would be necessary to determine TCP and NTCP curves (note: both sigmoidal) to obtain this information, independent of any isoeffect analysis.) Also, these isoeffect curves provide no information as to the effects of changing overall treatment time, since the type of isoeffect curve plot as stated evaluates the influence of dose per fraction and not time (and further, it is assumed that overall time remains fairly constant in this analysis, and that it is only dose per fraction that changes). Likewise, the effect of a split course treatment could not be evaluated in this case, because data as to the tumor's potential doubling time are not provided

Temporary growth inhibition would most likely be observed for a developing mouse irradiated during which stage of gestation? a. Preimplantation b. Organogenesis c. Early fetal period d. Mid fetal period e. Late fetal period

b. Organogenesis Temporary growth inhibition would most likely be observed if a developing mouse was irradiated during the organogenesis period of gestation. Mice irradiated during this gestational stage tend to have low birth weights due to cell depletion, however they usually catch up in size during infancy.

Concerning radiation induced liver disease (RILD), all of the following statements are true, EXCEPT: a. RILD is a clinical syndrome of ascites, elevated liver enzymes, and hepatomegaly in the absence of jaundice b. RILD is rarely observed earlier than six months following the completion of radiotherapy c. Suprahepatic vein obstruction and veno-occlusive liver disease are seen in RILD d. Pathologic changes in RILD include marked venous congestion in the central portion of each lobule - with sparing of the larger veins - and atrophy of hepatocytes adjacent to the congested veins e. Killing of vascular endothelial cells appears to be of greater importance than hepatocyte lethality in the pathologic changes observed in RILD

b. RILD is rarely observed earlier than six months following the completion of radiotherapy RILD typically occurs between 2 weeks and 3 months after completion of radiotherapy. RILD = Radiation induced liver disease - Time course: 2 weeks - 3 months - Symptoms: Anicteric hepatomegaly, ascites, fever, RUQ pain Classic: normal AST/ALT, elevated Alk-P - defined by veno occlusive disease, characterized by areas of marked venous congestion in the central portion of the hepatic lobules Nonclassic: - 1 week - 3 months - ELEVATION OF AST/ALT >5 times normal - Path - Veno-occlusive disease due to progressive fibrin deposition within the blood vessels, macrophage infiltration and consumption of fibrin products → further occlusion of blood vessels - or a decline in liver function (measured by a worsening of Child-Pugh score by 2 or more), in the absence of classic RILD

Which radiation-induced immune effect would be counterproductive to anti-tumor immunity? a. Radiation-induced release of danger signals b. Radiation-induced increase in regulatory T cells c. Radiation-induced increase in MHC class I expression d. Release of pro-inflammatory cytokines e. Radiation-induced epitope spreading

b. Radiation-induced increase in regulatory T cells Tregs are immunosuppressive Danger signals, MHC I expression, pro-inflammatory cytokines and epitope spreading would support the development of an immune response including anti- tumor immunity, regulatory T cells would not. Regulatory T cells (or suppressor T cells) are a subset of CD4+ T cells Recognition of danger signals such as pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) by pattern recognition receptors on antigen presenting cells e.g. dendritic cells (DCs) initiates their maturation and allows these cells to process and present antigens to T cells (signal 1) with the necessary secondary signal (co-stimulation or signal 2), both of which are necessary to induce T cell activation.

Which of the following is not a hallmark of cancer, as defined by Hahahan and Weinberg (2011)? a. Inducing angiogenesis b. Resist treatment c. Sustaining proliferative signaling d. Enable replicative immortality e. Evading growth suppressors

b. Resist treatment Originally published in 2000, the Hallmarks of Cancer represent six fundamental biological characteristics cells acquire in order to transform. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. An update was published in 2011, which added reprogramming of energy metabolism and evading immune destruction. Underlying these hallmarks are the processes of genome instability and inflammation. While all of the hallmarks of cancer can potentially be exploited therapeutically, none of them specifically reference therapy; they only refer to the natural history of cancer.

Which of the following statements is TRUE? a. A mature mRNA contains the information present only in the DNA introns b. Sequencing of a cDNA can be used to predict the amino acid sequence of the protein encoded by the gene c. A functional complementation assay involves hybridization of a probe to its complementary sequence in genomic DNA d. A cDNA library is created using whole genomic DNA e. A unique oligonucleotide probe for a particular gene can be "backwards engineered" from the amino acid sequence of the protein encoded by that gene

b. Sequencing of a cDNA can be used to predict the amino acid sequence of the protein encoded by the gene Sequencing of a cDNA can be used to predict the amino acid sequence of the protein encoded by the original gene, since this represents the expressed portion of a gene. The cDNA is synthesized from the mature, processed mRNA, and therefore contains only the information from the DNA's exons. A functional complementation assay involves the transfer of a gene to a mutant cell in order to determine whether doing so restores the normal phenotype. A cDNA library is created from mature mRNAs, not whole genomic DNA. A unique oligonucleotide probe for a particular gene cannot be backwards engineered from the amino acid sequence of the protein encoded by that gene due to the redundancy in the genetic code (i.e., a particular amino acid can be designated by more than one triplet codon).

What is chromothripsis? a. Staining method for individual genes on chromosomes b. Shattering of chromosome portions and rejoining together randomly c. Translocations and small deletions d. Flourescence staining of cells with chromatic dyes e. An enzyme induced by radiation

b. Shattering of chromosome portions and rejoining together randomly Chromothripsis is a catastrophic chromosomal event where portions of the chromosome are broken apart and then joined together in a random way. This leads to several oncogenic changes with a single event. FISH will allow for staining of individual genes on chromosomes. Translocations and small deletions are non-lethal chromosomal aberrations. The other answers are not relevant.

Which of the following assays would NOT be used for the detection of single nucleotide polymorphisms (SNPs)? a. TaqMan assay b. Subtractive hybridization c. Single-stranded conformation polymorphism (SSCP) d. Invader assay e. Molecular beacons

b. Subtractive hybridization Subtractive hybridization is a technique that compares amounts of mRNA in different samples. All the other assays are used to analyze genomic alterations. Single nucleotide polymorphisms are ancestral genetic variations that occur when a single nucleotide in a genome is altered. Variations in the DNA sequences of humans can affect how humans develop diseases and respond to pathogens, radiation, chemicals, drugs, etc. This research is generally performed by comparing regions of the genome between matched cohorts with and without a disease or reaction. The increased interest in SNPs has been reflected by the development of a diverse range of SNP genotyping methods, including the single-strand conformation polymorphism (SSCP) assay, TaqMan assay, invader assay and the use of molecular beacons. TaqMan is based on PCR and is limited to applications that involve a small number of SNPs, since optimal probes and PCR reaction conditions must be designed for each SNP. Molecular beacons make use of a specially engineered probe. If the probe encounters a complementary sequence, it undergoes a conformational change, which allows the molecule to fluoresce. Alternatively, if the probe encounters a target sequence with as little as one non-complementary nucleotide, the molecular beacon will remain in its original state and no fluorescence will be observed. The invader assay utilizes a specific endonuclease that catalyzes structure-specific cleavage. This cleavage is highly sensitive to mismatches and can be used to interrogate SNPs with a high degree of specificity. Single strand conformation polymorphism (SSCP) involves the electrophoretic separation of single- stranded nucleic acids, based on subtle differences in sequence (often a single base pair) which results in a different secondary structure and a measurable difference in mobility through a gel. The mobility of double-stranded DNA in gel electrophoresis is dependent on strand size and length, but is relatively independent of the particular nucleotide sequence. The mobility of single strands, however, is noticeably affected by very small changes in sequence, possibly one changed nucleotide out of several hundred. Small changes are detectable because of the relatively unstable nature of single-stranded DNA; in the absence of a complementary strand, the single strand may experience intrastrand base pairing, resulting in loops and folds that give the single strand a unique 3D structure, regardless of its length. A single nucleotide change could dramatically affect the strand's mobility through a gel by altering the intrastrand base pairing and its resulting 3D conformation

Antigen recognition by T cells is imperative for the development of cellular adaptive immunity. How does a T cell recognize antigen? a. T cells recognizes antigens via pattern recognition receptors b. T cells recognizes antigenic determinants presented in the MHC cleft via the T cell receptor c. T cells recognize antigens via Fc receptor binding to membrane-bound IgD antibodies d. T cells recognize antigens via PD-1 binding e. Comparison of radiation responses of the tumor treated with high versus low dose-rate radiation

b. T cells recognizes antigenic determinants presented in the MHC cleft via the T cell receptor Each T cell has about 30,000 antigen-receptor molecules on its surface, consisting of two different polypeptide chains, termed T-cell receptor α (TCRα) and β (TCRβ) chains, linked by a disulfide bond. α/β TCRs are very similar in structure to the Fab fragment of an immunoglobulin molecule, and they account for antigen recognition by most T cells. A minority of T cells has an alternative, but structurally similar, receptor made up of a different pair of polypeptide chains designated γ and δ. Unlike B cells, that can recognize a protein antigen in its native state, T cells via their TCR recognize antigens only after they have been processed into peptides and loaded onto MHC molecules. During the endogenous antigen presentation pathway (most cells can perform this), intracellular proteins are degraded by the proteasome into peptides (typically 9-10 amino acids long), prior to loading onto MHC class I in the ER. In the exogenous pathway, extracellular antigens are taken up by antigen presenting cells (APCs) and degraded to peptides within endosomes (typically 11-19 amino acids long) and bound to MHC class II. During either pathway, full MHC-peptide complexes are transported to the cell surface for recognition by the TCR on CD8+ cytotoxic T cells (MHC I) or CD4+ T helper cells (MHC II). Cross-presentation (only done by APCs) is the display of peptides from extracellular antigens on MHC class I. Pattern recognition receptors (PPRs) such as Toll-like receptors are predominantly found on APCs and other innate immune cells and are used for the detection danger signals such as pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). The engagement of PPRs initiates maturation of APCs, especially dendritic cells who are then, and only then, able to adequately stimulate T cells by providing signal 1 (antigen) to the TCR and signal 2 (co-stimulation) to CD28 that amplifies signal 1. PD-1 is an immune checkpoint, that inhibits TCR proximal signaling by sequestering SHP-2 phosphatase and facilitating Csk-mediated inhibitory phosphorylation of Lck.

Which of the following statements concerning tumor suppressor genes is FALSE? a. Loss of heterozygosity is a mechanism for the inactivation of tumor suppressor genes b. The products of tumor suppressor genes generally accelerate cell growth c. One or more tumor suppressor genes are typically mutated or absent in human cancers d. The most commonly altered tumor suppressor gene is p53 (TP53) e. The first tumor suppressor gene discovered was RB (RB1)

b. The products of tumor suppressor genes generally accelerate cell growth B The products of tumor suppressor genes generally inhibit cell growth, not stimulate it.

Which of the following statements concerning radiation cataractogenesis is TRUE? a. The lens of the eye is capable of eliminating cells damaged by radiation, which has the net effect of decreasing the incidence of cataracts b. There is a shorter latency period for the development of cataracts following a large radiation dose than a small one c. The neutron RBE for fast neutrons regarding cataract is approximately 3.0 d. For an acute exposure, the threshold dose for the induction of an X-ray-induced cataract is 15 Gy e. As is true for most radiation-induced injuries, there are no pathognomonic characteristics specific for a radiation-induced cataract

b. There is a shorter latency period for the development of cataracts following a large radiation dose than a small one Increasing the radiation dose decreases the latent period for cataract formation. The lens does not have the ability to eliminate damaged fibers. The RBE for cataract formation following irradiation with a series of small doses is in the range of 50-100 since there is substantial sparing associated with the X-irradiation, thereby substantially increasing the threshold dose to induce a cataract by X-rays. In contrast, the neutron dose to induce a cataract is relatively unaffected by the magnitude of the individual doses. Hence, the RBE, which is the ratio of the X-ray dose divided by the test radiation (neutrons) dose to induce an effect (cataract formation), increases with decreasing fraction size. The threshold dose for the induction of a radiation-induced cataract following an acute X-ray dose is 2 Gy or less. A radiation-induced cataract is one of the few examples of a radiation injury which does have distinct pathognomonic characteristics that identify it as having been induced by ionizing radiation; radiation-induced cataracts typically begin in the posterior portion of the lens (deep/central/posterior), unlike age-related cataracts. Radiation = deep/central/posterior Age = Peripheral, superficial

The Cancer stem cell hypothesis describes specific characteristics of this population of cells. Which of the following is incorrect? a. They are often relatively rare in tumors b. They share a common exclusive phenotypic marker c. They have high anti-oxidant levels d. They often increase after radiation exposure e. They express the multiple drug resistant gene product mdr1

b. They share a common exclusive phenotypic marker Cancer stem cells are heterogeneous but are generally more radioresistant and chemoresistant than the more proliferative tumor cell populations, which can be attributed to high anti-oxidant levels, slow cycling, mdr1 expression, and reprogramming. They have characteristic phenotypic markers that can be used to identify and purify them, but there is no single common marker that is shared by all cancer stem cells univocally identifying them.

Stereotactic body radiation therapy (SBRT) has proven to be a highly effective treatment for a variety of cancers. Proposals to further optimize SBRT efficacy include the concurrent use of hypoxic cell radiosensitizers. The most correct answer below describes the radiobiologic rationale for the addition of such an agent. a. Fractionation of radiation greatly mitigates the protection afforded by tumor hypoxia because of the phenomenon of reoxygenation which could be further augmented with a hypoxic cell radiosensitizer b. Tumor hypoxia is a major negative factor in limiting the curability of tumors by SBRT due to loss of the phenomenon of reoxygenation and this negative effect of hypoxia could be overcome by the addition of a hypoxic cell radiosensitizer c. Hypoxic cell radiosensitization with SBRT causes acute damage to the endothelial cells of the tumor vasculature d. Only a small proportion of tumor cells are clonogenic cancer stem cells and these could be preferentially killed by a hypoxic cell radiosensitizer e. Hypoxia cell sensitizers are needed for SBRT to stimulate neovascularization of the tumor between fractions

b. Tumor hypoxia is a major negative factor in limiting the curability of tumors by SBRT due to loss of the phenomenon of reoxygenation and this negative effect of hypoxia could be overcome by the addition of a hypoxic cell radiosensitizer The hypoxic environment of many tumors treated with radiotherapy is overcome with conventional radiotherapy by allowing reoxygenation to occur between the many doses of treatment. By using fewer fractions, reoxygenation does not occur as readily during SBRT, and therefore hypoxic cell radiosensitizers could be advantageous (20832663). Answer "a" is true, but SBRT is defined by 1-5 fractions so this answer does not apply well to the question. SBRT is thought to cause acute damage to endothelial cells of the tumor vasculature (1275052) with or without a hypoxic cell radiosensitizer. Cancer stem cells (CSCs) have been hypothesized to reside in hypoxic regions (19249645), but hypoxic cell radiosensitizer targeting of CSCs has not been tested thoroughly. Answer "e" is not correct.

Many types of congenital abnormalities, and of varying severity, have been noted in laboratory animals irradiated during the organogenesis period of gestation. This wide spectrum of effects is due primarily to: a. The sex of the irradiated fetus b. Which organs were actively developing at the time of irradiation c. The type of ionizing radiation to which the fetus was exposed d. Innate differences in radiosensitivity of the different cell types e. Maternal age at conception

b. Which organs were actively developing at the time of irradiation The organs that are actively undergoing development, (i.e., those that have high rates of cell division and ongoing differentiation), at the time of irradiation are the most susceptible to radiation injury during gestation.

Dose conformality in IMRT is usually achieved by: a. Use of multiple monoenergetic pencil beams b. Deflecting the beam with multiple collimators so that it conforms to the desired shape of the target volume c. "Inverse" treatment planning based on CT images of the target volume d. Prompt gamma-based imaging from excitation of oxygen and nitrogen nuclei e. Reducing the time to deliver each dose per fraction

c. "Inverse" treatment planning based on CT images of the target volume Intensity-modulated radiation therapy (IMRT) is a method of radiation therapy which is able to modulate the intensity of the overlapping radiation beams projected on the target and to use multiple-shaped treatment fields. It uses a device (a multileaf collimator, MLC) which, coupled to a computer algorithm, allows for "inverse" treatment planning. The radiation oncologist delineates the target on each slice of a CT scan and specifies the target's prescribed radiation dose, acceptable limits of dose heterogeneity within the target volume, adjacent normal tissue volumes to avoid, and acceptable dose limits within the normal tissues. Based on these parameters and a digitally reconstructed radiographic image of the tumor and surrounding tissues and organs at risk, computer software optimizes the location, shape, and intensities of the beams ports, to achieve the treatment plan's goals. Prompt gammas from excitation of oxygen and nitrogen nuclei can be used for in-beam proton dosimetry, that is, for defining the proton beam margin in tissue. Choice A and B could describe a "gamma knife" for radiosurgery and a "scanning" method for achieving a desired field size in particle therapy, respectively. The time to deliver a dose fraction by IMRT is much longer than with other technologies.

The probability of a hereditary disorder in the first generation born to parents exposed to radiation is estimated to be approximately: a. 0.02/mSv b. 0.2/mSv c. 0.002/Sv d. 0.02/Sv e. 0.2/Sv

c. 0.002/Sv The current estimate for the development of a hereditary disorder in the children of an irradiated person is 0.002/Sv.

What dose to an embryo or fetus during the 10 day to 25 week period of gestation is considered the threshold above which a physician should discuss with a pregnant patient the risk of radiation-induced birth defects, and possible actions to be taken? a. 0.001 Gy b. 0.01 Gy c. 0.1 Gy d. 1.0 Gy e. 10 Gy

c. 0.1 Gy A dose of 0.1 Gy to an embryo or fetus at the 10 day to 25 week period of gestation (organogenesis: 10 days - 6 weeks; fetal period: 6 weeks - 9 months) is generally accepted as the minimum dose above which a physician should discuss with a pregnant patient the risk of radiation-induced birth defects (including possible congenital abnormalities and mental retardation), and possible actions to be taken, including therapeutic abortion.

What would be the approximate surviving of V79 Chinese hamster cells had 5 Gy X-rays been delivered over a 10 hour period? (Assume a=0.2 Gy-1 and b=0.05 Gy-2)period? A. 0.01 B. 0.10 C. 0.37 D. 0.50 E. 0.90

c. 0.37 Super helpful question just to make you realize that if you FRACTIONATE or REDUCE THE DOSE RATE, that essentially allows the cells to do SLDR. If they can do SLDR, this removes the fraction of cells that are otherwise killed by beta kill (those cells now don't die, but can repair their injuries) - so the mathemetical function looks more like a straight line (without the exponential cell killing that happens if cells can't repair damage) -- so it looks more like S = e^-aD --> here equals 37% this is the amount of cell killing that 5 Gy accomplishes if you ONLY factor in cell killing that happens because of alpha kill -- presuming that the lesions that are formed by different tracks got repaired before the cell died because of them. If the 5 Gy dose is delivered over a 10 h period, then the dose rate equals 5 Gy/10 h = 0.5 Gy/h. Assuming that relatively few (human) cells divide during the 10 hour irradiation interval, the surviving fraction will increase due to repair of sublethal damage and the b parameter value will approach zero.

Consider cells with α/β = 3 Gy. What is the ratio of irreparable to repairable damage at 9 Gy? a. 3:1 b. 1:1 c. 1:3 d. 1:9 e. 9:1

c. 1:3 C The fraction of cell killing due to single-track damage (a*D) does not change with fractionation whereas as the multi-track portion (b* D2) does. This is because in the latter case individual DNA breaks can interact forming complex lesion, which can be separated in time by splitting the dose and hence they become repairable. Example - alpha=3 and beta=1, so irreparable damage is alpha x dose = 3 x 9 = 27, and repairable damage is beta x dose squared = 1 x 81 = 81. Giving ratio of 27:81 or 1:3

The ratio of the human genetic doubling dose to the average annual genetically significant dose (GSD) resulting from diagnostic X-ray procedures performed in the U.S. is closest to: a. 1 b. 20 c. 3,000 d. 100,000 e. 600,000

c. 3,000 It is estimated that an average of 0.3 mSv to the gonads are received each year resulting from use of diagnostic X-rays, although this value may now be somewhat greater due to the increased use of CT scanning. In contrast, the human genetic doubling dose is estimated at 1-2 Gy. Thus the ratio of these values is closest to 3,000.

Based on the same parameters as provided in the previous question, what additional dose must be added to still achieve a 37% chance of tumor cure, if the clonogens in the tumor went through three cell divisions during treatment (assuming that there is no cell loss)? a. 1 Gy b. 2 Gy c. 5 Gy d. 10 Gy e. 20 Gy

c. 5 Gy Three cell divisions would result in an 8-fold increase in the number of cells. Therefore, the dose would need to be increased by a dose D, where e(D/D0) = 8. Therefore, D = 2.5 x ln 8 = 5.2 Gy of additional dose would be needed to achieve the same level of tumor control. It is also worth remembering that 3.3 times the number of cell doublings corresponds to one log10 of cell kill - don't see how that one is that useful...math doesn't work out as far as i can tell...

Which of the following agents acts in a cell cycle specific fashion? a. Cisplatin b. Ifosfamide c. 5-FU d. BCNU e. Epirubicin

c. 5-FU 5-FU affects thymidylate synthase and inhibits the synthesis of nucleotides required for DNA synthesis. Accordingly, it primarily affects cells in S phase of the cell cycle. All of the other agents can create damage throughout the cell cycle, and do not have any phase specificity.

An agent which must be present at the time of irradiation to reduce normal tissue injury is called what? a. A radiation sensitizer b. A radiation mitigator c. A radiation protector d. An antifibrotic e. A radiation mimetic agent

c. A radiation protector A radiation protector is an agent that reduces the injury caused by ionizing radiation, often through a chemical process such as free radical scavenging. These agents must be present at the time of or very shortly after irradiation (10-3 seconds after irradiation) to exert their effects. Radiation mitigators reduce the damage from radiation by inhibiting or altering processes initiated after irradiation but before expression of injury. Radiation sensitizers enhance the cell killing from irradiation. Anti-fibrotics would be considered a treatment of radiation injury that has already been established.

It is important for radiologists to use medical X-rays judiciously and avoid ordering unnecessary tests for all of the following reasons, EXCEPT: a. Radiation-induced cancers caused by diagnostic X-ray procedures are thought to account for at least 1% of all cancer deaths each year b. There is no dose of radiation that can be considered "safe" c. According to Medicare regulations, an order for a diagnostic X-ray examination may be based not only upon medical need, but also for the purpose of limiting legal liability d. The use of X-rays for medical diagnosis has been increasing e. Diagnostic X-rays are the greatest source of man-made background radiation exposure in the human population

c. According to Medicare regulations, an order for a diagnostic X-ray examination may be based not only upon medical need, but also for the purpose of limiting legal liability An order for a diagnostic X-ray examination may only be based upon medical need and not for the purpose of limiting legal liability for the radiologist. Using the current estimate, that the average annual effective dose equivalent associated with diagnostic radiology is 3 mSv, calculations suggest that (3 x 10-3 Sv)(5 x 10-2 radiation-induced fatal cancers/Sv)(3 x 10^8 people) = 45,000 fatal, radiation-induced cancers would be produced per year from imaging procedures. This would constitute about 8% of all cancer deaths each year in the U.S. This risk estimate is based on the currently accepted, linear, no threshold model of radiation carcinogenesis. There is reason to believe that this number may be an over- estimate since the majority of people receiving these medical exposures tend to be older adults who are less susceptible to radiation carcinogenesis than young people. Nevertheless, even accounting for age differences in sensitivity to radiation carcinogenesis, the risk estimate for radiation-induced cancers still would suggest that more than 1% of fatal cancers are induced by medical radiation. However, not all scientists agree that use of the linear, no threshold model is appropriate in the case of such small radiation doses, especially given the amount of extrapolation necessary, and therefore that these risk estimates are probably over-estimates. Nevertheless, how much of an over-estimate remains to be seen.

Which of the following statements is TRUE concerning radiation effects on lymphoid tissues? a. T cells are generally more radiosensitive than B cells b. Filter function in lymph nodes is unaffected by radiation c. Altered immunity is an important factor in gastrointestinal syndrome following whole body irradiation d. Morphologically, the spleen shows few late effects e. The thymus appears almost fully functional following irradiation, with doses in the range typically used in radiotherapy, for cancers in which this organ is in the radiation field

c. Altered immunity is an important factor in gastrointestinal syndrome following whole body irradiation Although increased permeability of the mucosa in the GI tract is also a key determinant, the altered immunity associated with effects on the lymphoreticular system plays a leading role in the infection that characterizes mortality from the gastrointestinal syndrome. B cells, those that mature in the bone marrow, are more radiosensitive than T cells, due to the sensitivity of the progenitor cells. However, there can be a persistent depression in T cell numbers. Localized radiation to the thymus can predispose a patient to a series of late effects due to the radiation sensitivity of both thymocytes and other thymic cell populations. There is a decrease in spleen size following radiation, as well as marked fibrosis, thickened capsule, and obliteration of the sinusoids.

Which of the following statements concerning molecular techniques is FALSE? a. Fluorescence in situ hybridization (FISH) can be used to identify the chromosome location of a gene of interest b. A restriction fragment length polymorphism (RFLP) may result if the copy number of a particular DNA fragment varies c. An exonuclease produces a cut in the middle of a DNA strand d. A Western blot can be used to detect and characterize a particular protein e. A restriction endonuclease typically cuts DNA at a specific sequence

c. An exonuclease produces a cut in the middle of a DNA strand An exonuclease is an enzyme that hydrolyzes the phosphodiester bonds of DNA to cleave nucleotides sequentially from the end of a polynucleotide chain.

Which of the following flow cytometry methods or the combination of methods are used to estimate cell cycle distribution in mammalian cells? a. Analysis of annexin V stained cells b. Analysis of cells treated with a high dose (2 mM or more) thymidine c. Analysis of propidium iodide stained cells d. Analysis of cells labeled with an H3 antibody e. Analysis of cells pulse-labeled with 3H-thymidine

c. Analysis of propidium iodide stained cells The cell cycle can be analysed by flow cytometry using a fluorescence-activated cell sorter (FACS). Cells are treated with a DNA-binding dye, such as propidium iodide. The amount of cellular DNA is proportional to the amount of fluorescence detected by dye binding. For a proliferating cell population, a plot of cell number versus DNA content yields the percentage of cells in G1 (with 1 arbitrary unit of DNA or 2N), in G2 + M (with 2 arbitrary unit of DNA or 4N), and in S (cells with more than 1 but less 2 units of DNA. Annexin V conjugates provide a method for studying the externalization of phosphatidylserine, an indicator of intermediate stages of apoptosis, by flow cytometry. Nuclear fragmentation, mitochondrial membrane potential flux, and caspase-3 activation precede phosphatidylserine "in-out flipping" during apoptosis, whereas permeability to propidium iodide occur later. Antibody staining for caspase 8 can also be measured using flow cytometry to detect apoptosis and is not used for cell cycle analysis. Treatment with a high dose of thymidine can stop DNA synthesis, because of deoxyribonucleotide feedback inhibition. This will lead to a build-up of cells at the G1/S checkpoint. Radioactive labeling is not used in flow cytometry.

Which of the following statements about cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) is true? a. CTLA-4 is the target of the immune therapeutic nivolumab b. CTLA-4 is exclusively expressed on regulatory T cells (Tregs) c. CTLA-4 competes with CD28 for binding to CD80/CD86 to promote T-cell inactivation d. Ipilimumab is a small molecule inhibitor of CTLA-4

c. CTLA-4 competes with CD28 for binding to CD80/CD86 to promote T-cell inactivation CTLA-4 is a critical molecule in immune regulation. CTLA-4 is upregulated by T-cell activation and allows for a negative feedback loop to prevent an inappropriately prolonged T-cell response. It binds to CD80 and CD86 on antigen-presenting and B cells thus competing for the T-cell costimulatory protein CD28, thus limiting T cell activation. It is also expressed by regulatory T cells to promote immune suppression. Without CTLA-4, mice develop a massive lymphoproliferative disorder and die within 2-3 weeks of birth. CTLA-4 expression is expressed by activated effector T cells and not just Tregs; it can also be expressed variably by tumor cells. Ipilimumab is a monoclonal antibody targeting CTLA-4 and was the first immune checkpoint inhibitor to see clinical use, namely in the treatment of melanoma.

Which of the following statements on radiation induced carcinogenesis is correct? a. Internally deposited radioactive materials confer equal cancer risk to all organs b. External and whole body exposure to radiation confers the equal cancer risk to all organs c. Cancer is a stochastic effect of radiation because its severity is not determined by the radiation dose, but the probability to occur is d. Cancer is a deterministic (or non-stochastic) effect of radiation because its severity and the probability to occur are determined by the radiation dose e. Cancer is a stochastic effect of radiation because its severity and the probability to occur are determined by the radiation dose

c. Cancer is a stochastic effect of radiation because its severity is not determined by the radiation dose, but the probability to occur is Cancer is a stochastic effect of radiation. Its severity is not determined but the probability to occur is determined by radiation dose. Different organs have dissimilar radiation induced cancer risks. For internally deposited radioisotopes, the sites of deposition are additional factors of organ specific cancer risk.

Cisplatin is a common chemotherapy agent used to treat a variety of solid-tumor malignancies. A common acute toxicity associated with cisplatin therapy is kidney toxicity. Which of the following statements is false regarding cisplatin induced acute kidney injury? a. Cisplatin induces the greatest damage to proximal tubular cells b. Serum creatinine increases of ≥ 1.5x baseline is considered acute kidney injury c. Cisplatin induces intrastand DNA crosslinks typically between pyrimidine bases d. Cisplatin induces superoxide anion formation in the glomerulus and proximal tubules e. Acute kidney injury is more commonly associated with cisplatin delivered q3 weeks at 100 mg/m2 compared to weekly at 40 mg/m2

c. Cisplatin induces intrastrand DNA crosslinks typically between pyrimidine bases Cisplatin induces acute kidney injury (AKI) in 20-30% of treated patients with typical onset occurring 3-5 days following cisplatin dose. Cisplatin forms intrastrand crosslinks between DNA, predominantly between purine bases. The sensitivity of cells to cisplatin correlates both with the density of mitochondria and mitochondrial membrane potential. The proximal tubular cells have the highest density of mitochondria in the kidney and are therefore the most sensitive to ciplsatin injury. (PMID: 16107504; PMID: 17016583 ) Cisplatin can induce superoxide anion formation in the glomerulus and proximal tubulues but not the distal tubules

The optimal time to deliver heat (relative to radiation) in order to achieve the greatest radiosensitization is: a. Two hours prior to RT b. One hour prior to RT c. During RT d. One hour after RT e. Two hours after RT

c. During RT The greatest heat radiosensitization is produced when the heat is delivered as close to the time of irradiation as possible, since a likely mechanism for the sensitizing effect is heat denaturation of the proteins (enzymes) associated with the repair of radiation damage.

Protons used for cancer radiotherapy: a. Show the greatest potential in the treatment of tumors with high hypoxic fractions and/or poor reoxygenation rates b. Are typically in the 1 - 10 MeV range c. Exhibit LET values <10 keV/um d. Exhibit an RBE of approximately 5 e. Are densely ionizing

c. Exhibit LET values <10 keV/um Protons used for radiotherapy must be of a very high energy (> 100 MeV) in order to be sufficiently penetrating and are therefore of relatively low LET, typically less than 10 keV/μm. Since radiotherapy protons are low LET, they exhibit an OER in the range of 2-3 and therefore, like X-rays, would not be particularly effective at eradicating hypoxic tumor cells. Protons are only slightly more biologically effective than X-rays and have an RBE of ~1.1.

In cancer treatment, there has been clinical interest in targeting the RAS oncogene product using: a. HDAC inhibitors b. Cyclin-dependent kinases c. Farnesyl transferase inhibitors (FTIs) d. I-kB e. Iressa

c. Farnesyl transferase inhibitors In order to become active, the RAS protein must be prenylated by the action of farnesyl transferases. Hence, RAS activation in cells can be prevented by farnesyl transferase inhibitors (FTIs). It has been postulated that this could decrease the growth of cancer cells and should cause radiation sensitization, since some studies have found a correlation between RAS expression and radioresistance. In clinical studies however, FTIs have had less effect than anticipated on cancer cells because RAS can also be geranylated by geranylgeranyl transferases, which the FTIs do not block. It now appears that FTIs may have additional cellular effects, which are still under investigation. HDAC (histone deacetylase) inhibitors alter chromatin configuration and may be radiation sensitizers cyclin-dependent kinases are intracellular enzymes involved in regulating the cell cycle I-kB is an intracellular inhibitory molecule that regulates the transcription factor NF-kB Iressa is an inhibitor of ERBB1.

After irradiation, cells with intact checkpoint activation arrest in which phases of the cell cycle? a. Only S b. G2 and M c. G1, S and G2 d. M and S e. G0

c. G1, S and G2 C is just the most complete answer because G1-S (normal cells), G2-M (all cells) and intra-S phase (less important for this test) are ALL points where XRT causes cell cycle arrest.

Which of the following statements is TRUE concerning the response of the kidney to radiation? The kidney: a. Is considered a relatively radiosensitive organ because of the marked sensitivity of cells that comprise the nephron b. Exhibits little sparing with increasing dose fractionation c. Has a relatively low tolerance dose because of the limited number of clonogens within each functional subunit d. Displays substantial re-treatment tolerance e. Manifests symptoms of radiation nephropathy generally within 3 months following the completion of radiotherapy

c. Has a relatively low tolerance dose because of the limited number of clonogens within each functional subunit The kidney has a relatively low tolerance dose because of the limited number of clonogens within each nephron, although the cells comprising the functional subunits of the kidney are not particularly radiosensitive. The kidney exhibits substantial sparing with fractionation and displays little or no tolerance to re-irradiation. A much longer latent period than 3 months is required before the appearance of radiation nephropathy.

It is believed that viral oncoproteins E6 and E7 are activated and then inactivate both p53 and pRb, thereby leading to the development of cancer. This process occurs after infection with which virus? a. Herpes simplex virus 1 b. Herpes simplex virus 2 c. Human papillomavirus d. Epstein-Barr virus e. Cytomegalovirus

c. Human papillomavirus Human papillomavirus. Human papillomavirus (HPV) has been linked to cancers of multiple subsites, including the anus, cervix, oropharynx, vulva, vagina, and penis. The oncogenic subtypes are believed to produce the early proteins E6 and E7. E6 goes on to inactivate p53 and E7 goes on to inactive pRb (Chaturvedi A et al. Epidemiology, Pathogenesis, and Prevention of Head and Neck Cancer 2010. These changes in the tumor suppressors then cause subsequent development of cancer through dysregulation of cell cycle checkpoints. Herpes simplex viruses 1 and 2 are not related to cancers. Epstein-Barr virus is linked to the development of nasopharynx cancer, among others, but do not result in E6 and E7 production.

Clinical studies in prostate cancer radiotherapy study whether moderate hypofractionation (2.4-4 Gy/fractions) is superior or at least not inferior to conventional fractionation (1.8-2 Gy/fraction). Which of the following most correctly describes the radiobiological rationale that is used to justify hypofractionation. a. Hypofractionated radiotherapy delivers a higher biologically equivalent dose than conventional fractionation b. Hypofractionated radiotherapy takes place over a shorter period of time (from first treatment to last treatment) than conventional fractionation c. Hypofractionated radiotherapy is useful when cancer cells have an alpha/beta ratio equal to or lower than surrounding tissues and organs at risk d. Hypofractionated radiotherapy is more precise than conventional radiotherapy e. Hypofractionated radiotherapy does less damage to late-reacting normal tissues

c. Hypofractionated radiotherapy is useful when cancer cells have an alpha/beta ratio equal to or lower than surrounding tissues and organs at risk Hypofractionated radiotherapy may be useful when cancer cells (such as prostate cancer) are thought to have an alpha/beta ratio similar to or less than the alpha/beta ratio of surrounding normal tissues. A is incorrect because the biologically equivalent dose depends on dose per fraction and total dose. B is incorrect because hypofractionation refers to fewer fractions than would be delivered in conventional fractionation, not the rate of dose delivery (answer B describes accelerated radiotherapy). D is incorrect because hypofractionation does not specify the delivery technique (although most hypofractionated treatments are delivered using precise delivery techniques to avoid normal tissue toxicity). E is incorrect because hypofractionation generally uses larger than conventional fraction sizes, which are generally associated with more late effects.

The main cause of death from the hematopoietic syndrome is: a. Hypotension arising from microvascular destruction b. Hemolytic anemia c. Infection and hemorrhage resulting from loss of white cells and platelets d. Loss of erythrocytes resulting in organ ischemia e. Dehydration due to extravasation of fibrin from blood vessels

c. Infection and hemorrhage resulting from loss of white cells and platelets Death from the hematopoietic syndrome usually results from infection and hemorrhage due to radiation-induced loss of white cells and platelets.

An accidental exposure to a radiation source is reported one month following irradiation of a person not wearing a dosimeter. Which of the following assays would represent the best method to estimate the radiation dose received by this person? a. Alkaline elution b. Staining with a monoclonal antibody to -H2AX c. Karyotyping peripheral blood lymphocytes d. Pulsed-field gel electrophoresis e. Neutral comet assay

c. Karyotyping peripheral blood lymphocytes The most reliable approach to estimate dose one month following a radiation exposure is to karyotype peripheral blood lymphocytes to detect chromosomal aberrations, particularly dicentric chromosomes, which are normally not found in unirradiated people. Alkaline elution would detect single strand DNA breaks while -H2AX, pulsed-field gel electrophoresis and the neutral comet assay can all measure DNA double strand breaks. These would not be useful assays to measure a dose that had been received one month prior to tissue being obtained as virtually all DNA single and double-strand breaks would be repaired by this time.

Of the following, the organ/tissue least able to tolerate re-irradiation is the: a. Spinal cord b. Oral mucosa c. Kidney d. Lung e. Liver

c. Kidney The kidney exhibits little or no re-irradiation tolerance, whereas the other organs, including the spinal cord, exhibit at least some recovery following irradiation.

During which phases of the cell cycle can homologous recombination of DNA double strand breaks occur? a. G0/G1 b. G1/Early-S c. Late-S/G2 d. G2/M e. M/G1

c. Late-S/G2 Homologous recombination involves the repair of a damaged section of DNA by having the homologous sister chromatid provide a template for repair. This can only occur at times when a sister chromatid exists (late G2 and late S phases).

Which statement regarding oncogenes and tumor suppressor genes is TRUE? a. A gain of function mutation of an oncogene would be recessive on a cellular level b. A gain of function mutation in a tumor suppressor gene would stimulate malignant progression of a tumor c. Loss of function of a tumor suppressor would appear as a dominant inheritance patter on pedigree with respect to cancer susceptibility d. A loss of function mutation in a tumor suppressor gene would be dominant on a cellular level e. A loss of function mutation in an oncogene would be dominant in a pedigree in regard to cancer susceptibility

c. Loss of function of a tumor suppressor would appear as a dominant inheritance patter on pedigree with respect to cancer susceptibility A loss of function mutation in a tumor suppressor gene would be dominant in a pedigree. This is highly dependent on gene penetrance but is true for a highly penetrant gene. This is observed because inheritance of a mutated copy of a tumor suppressor would result in the inactivation of one copy of the tumor suppressor gene in all cells in the body. It is likely that, during the course of such an individual's life, the other copy of the tumor suppressor gene would be lost through loss of heterozygosity in at least some cells, thereby creating conditions to promote malignant transformation. A gain of function mutation of an oncogene would be dominant on a cellular level since the protein encoded by the oncogene would then be overexpessed and stimulate malignant progression. A gain of function mutation in a tumor suppressor gene may, if anything, inhibit malignant progression of a tumor since it would likely be inhibitory of cell growth. A loss of function mutation in a tumor suppressor gene is recessive on a cellular level since the remaining normal copy of the gene should encode sufficient protein. A loss of function mutation in an oncogene would probably have either no effect or potentially inhibit cancer susceptibility since there may be a diminished level of the gene product which could reduce cell growth.

Which one of the following effects that may be caused by irradiation, represents a possible deterministic effect? a. Breast cancer b. Phenylketonuria c. Mental retardation d. Leukemia e. Galactosemia

c. Mental retardation Radiation-induced mental retardation resulting from in utero irradiation is a deterministic effect that has a threshold dose below which the effect is not observed. It should be noted that some forms of mental retardation can occur from mutation-induction in eggs or sperm. However, some forms of mental retardation induced by mutations in eggs or sperm would be stochastic. In contrast, cancer (breast and leukemia) and inherited genetic disorders (phenylketonuria and galactosemia) are stochastic effects, characterized by a no dose threshold and endpoints that are "all or nothing".

Epigenetic modification of DNA-associated histones can occur through all of the following mechanisms, EXCEPT: a. Phosphorylation b. Acetylation c. Nitrosylation d. Methylation e. Ubiquitination

c. Nitrosylation Epigenetic regulation of genes can occur at the level of the histone proteins intimately associated with the DNA. Modification of the histones that surround the DNA can lead to complex signaling that directs the packing and unpacking of the DNA double helix. Epigenetic regulation of histones can occur through acetylation, phosphorylation, methylation and ubiquitination. Nitrosylation does not occur.

Which one of the statements regarding proton beam therapy is TRUE: a. Treatments with proton beams typically result in no entrance dose b. Proton beams are superior to photon beams because its RBE (relative biological effectiveness) is approximately 3.5 c. Prescription dose of proton beam treatments is described in CGE (Cobalt Gray Equivalent) d. Compared to photon beams, proton beams create more single strand DNA breaks e. Compared to proton beams, photon beams are known to have a higher LET (Linear Energy Transfer)

c. Prescription dose of proton beam treatments is described in CGE (Cobalt Gray Equivalent) Entrance Dose in a proton beam plan is typically reduced, but not eliminated. Relative Biological Effectiveness (RBE) of proton beam is 1.1. Proton Beam dose is typically described in Cobalt Gray Equivalent, which is RBE x dose in Gy. Proton beams, as well as other charged particle beams, are known to create more double strand DNA breaks. Proton beams are known to have a higher linear energy transfer compared to photons, especially at the Bragg Peak region.

Pathogenic mutations of the KRAS oncogene function by: a. Recycling GTP b. Phosphorylating B-Raf c. Preventing GTP hydrolysis d. Preventing KRas protein degradation e. Localizing KRas to the plasma membrane

c. Preventing GTP hydrolysis Common mutations in KRAS function by preventing GTPase activity. The KRas protein is active in the GTP-bound form and inactive in the GDP-bound form. Guanine nucleotide exchange factors (GEFs) exchange GDP for GTP, thereby activating KRas. GTPase activating proteins (GAPs) are proteins that, when bound to KRas, can induce GTP hydrolysis into GDP. Pathologic mutations of KRAS, including those at positions G12 and G13, prevent KRas from hydrolyzing GTP. Thus KRas remains in the active GTP-bound state, with resultant downstream signaling.

The term stochastic is used to describe an effect of radiation in which the: a. Severity of the effect depends on the dose above a threshold b. Severity of the effect depends on the dose without a threshold c. Probability of occurrence is a function of dose, with no threshold d. Probability of occurrence is a function of dose above a threshold e. Dependency is on age at exposure

c. Probability of occurrence is a function of dose, with no threshold The term stochastic is used to describe an effect of radiation that occurs by chance. Cancer induction and radiation induced hereditary effects are examples of stochastic effects. Deterministic effects depend on dose, dose rate, and dose fraction and have a threshold below which the effect does not occur.

Which one of the following reagents is NOT used for a reporter gene assay? a. Chloramphenicol acetyltransferase (CAT) b. Firefly luciferase c. RNA polymerase d. b-galactosidase e. Green fluorescent protein (GFP)

c. RNA polymerase RNA polymerase is an enzyme that transcribes a copy of a DNA template into RNA. This would likely not serve as a useful reporter gene since it does not produce a product that can be detected easily.

The correlation between MET and ionizing radiation is characterized by which of the following: a. Radiation-induced MET results in a decrease in clonogenic survival b. Radiation-induced MET results in an induction of apoptosis c. Radiation induces MET via the ATM-NF-kB pathway d. Radiation induces MET via the wnt-b-catenin pathway e. Radiation-induced MET inhibits epithelial-mesenchymal transition

c. Radiation induces MET via the ATM-NF-kB pathway MET induction by radiation induces radioresistance via the ATM-NF-kB pathway. MET activation by radiation stimulates invasion through epithelial to mesenchymal transition and makes cells resistant to apoptosis.

The Ras proteins are involved in various cellular functions including proliferation, differentiation, and survival. Which of the following statements regarding Ras proteins is false? a. Approximately 10-30% of cancer patients have a Ras mutation b. HRAS, KRAS, and NRAS have similar DNA sequence homology and function c. Ras proteins cycle between an inactive GTP-bound state and active GDP-bound state d. Ras proteins may be attached to the cell membrane by the process of prenylation and palmitoylation

c. Ras proteins cycle between an inactive GTP-bound state and active GDP-bound state It is estimated that 10-30% of cancers have a Ras mutation with a recent publication demonstrated that 19% of cancer patients have a Ras mutation (PMID: 32209560). HRAS (Harvey sarcoma virus), KRAS (Kirsten sarcoma virus), and NRAS (human neuroblastoma cells) are ubiquitously expressed genes that have similar DNA sequence and function. Ras proteins cycle between an active (GTP-bound) and inactive (GDP-bound state). Ras is attached to the cell membrane by the addition of hydrophobic residues including prenyl groups (prenylation) and palmitic acid (palmitoylation).

Neoadjuvant radiation therapy can negatively affect wound healing following surgical resection of a tumor. Which of the following is the last step in the process of wound closure? a. Inflammation and fibroblast activation b. Fibroblast migration and collagen deposition c. Remodeling and collagen degeneration d. Keratinocyte activation and wound contraction e. Inflammation and stem cell homing

c. Remodeling and collagen degeneration The three main steps of wound healing include inflammation, proliferation, and remodeling. Initially, pro-inflammatory cytokines stimulate angiogenesis and fibroblast activation as well as keratinocyte activation and wound contraction. Fibroblasts then migrate to the wound and granulation tissue formation and collagen deposition. The final step of wound healing is remodeling which includes regression of capillaries and collagen degeneration.

Which of the following pathways have been implicated in the loss of clonogenic capacity in irradiated tumor cells harboring wild type p53? a. Dedifferentiation b. Sublethal damage repair c. Senescence d. Telomere inversion e. Oncogene activation

c. Senescence Senescence is a possible response to genotoxic insult that can result in loss of replication capacity. This can be observed in normal tissues and in tumor cells with a wild type p53. Tumor cells that harbor a mutant p53 may be at least partially immune to radiation induced senescence.

The prostate-specific membrane antigen (PSMA) is a promising, well-characterized biomarker of prostate cancer. Attempts to image PSMA by SPECT using the agent 111In-Capromab Pendetide (ProstaScint™) is approved by the FDA. Which statement best describes the limitations of 111In-Capromab Pendetide? a. Limitations of antibody-mediated imaging of quick blood-pool clearance b. Rapid tumor penetration c. The 7E11-C5.3 antibody on which 111In-Capromab Pendetide is based binds to an intracellular epitope of PSMA d. Poor specificity with high-volume disease e. Inherent limitations of PET imaging

c. The 7E11-C5.3 antibody on which 111In-Capromab Pendetide is based binds to an intracellular epitope of PSMA The prostate-specific membrane antigen (PSMA) is a promising, well-characterized biomarker of prostate cancer and is associated with tumor aggressiveness. Histologic studies have associated high PSMA expression with metastasis, androgen independence, and progression. PSMA imaging by SPECT using the agent 111In-Capromab Pendetide (ProstaScint™), approved by the Food and Drug Administration, demonstrated poor performance due to several factors, including: - the inherent limitations of intact antibody - mediated imaging (poor tumor penetration and slow blood-pool clearance) - the relatively coarse resolution of SPECT - the fact that the 7E11-C5.3 antibody on which Indium-111 Capromab Pendetide is based binds to an intracellular epitope of PSMA. Radiolabeled antibodies with their poor tumor penetration and slow blood-pool clearance tend to have lower tumor-to-background ratios (23590171). The correct answer is "c". The other answers are incorrect and are not true of 111Incapromab pendetide as this agent has poor tumor penetration, slow blood-pool clearance, lower tumor-to-background ratios for low volume disease and is a SPECT imaging agent. Answer "c" is correct. The other answers incorrect describe 111Incapromab pendetide.

Which of the following statements regarding the development of radiation-induced lung damage is TRUE? a. The volume of lung irradiated has relatively little effect on the tolerance dose b. Radiation-induced pneumonitis is delineated by the treatment field c. The majority of patients who develop radiation pneumonitis go on to develop pulmonary fibrosis d. The TD5/5 for whole lung irradiation with a single dose is approximately 17.5 Gy e. Fractionation has little or no effect on lung tolerance

c. The majority of patients who develop radiation pneumonitis go on to develop pulmonary fibrosis The majority of patients who develop clinically-detectable pneumonitis will progress to fibrosis. It is strongly suspected that many of the patients who develop lung fibrosis in the apparent absence of pneumonitis did, in fact, have pneumonitis, but that it was asymptomatic and had gone unrecognized. Lung is a very sensitive, dose-limiting organ with a steep dose response curve for single dose, whole organ irradiation, characterized by a TD5/5 of 7 Gy (the TD5/5 for fractionated radiotherapy using a conventional dose per fraction is about 17.5 Gy). Both volume irradiated and fractionation pattern have large effects on the tolerance dose. A number of investigators have identified regions of pneumonitis that extend outside of the treatment field, known as abscopal effects, however the mechanism for their development remains unclear. TD5/5 single fraction = 7 Gy TD5/5 multi fraction = 17.5 Gy

Single nucleotide polymorphisms (SNPs) are used in cancer research primarily because: a. Alterations in protein sequence always arise from SNPs. b. They can be associated with DNA repair defects. c. They can be associated with specific clinical outcomes. d. They are causal in specific clinical outcomes. e. They are due to specific mutational processes. f. All of the above.

c. They can be associated with specific clinical outcomes. SNPs are changes at a single locus with a minor allele frequency of greater than 1% in at least 1 population. There are approximately 10 million SNPs in the human genome. The basis of SNP research in cancer is purely correlative; the existence of a SNP does not indicate any particular functional consequence of that SNP, but rather only an association with a tested outcome (disease likelihood, chemo response, disease-free survival, overall survival, etc.). SNPs that are recurrently associated with a phenotype may be associated with the underlying cause of the phenotype by linkage disequilibrium and not by a true functional outcome of the SNP itself. Thus, answer D is incorrect. If present in a protein coding region, SNPs may be silent or result in an alteration in protein sequence. The biased manner of most research examining SNPs (i.e., the "candidate gene approach") means that often only protein encoding regions of specific genes are examined, however the vast majority of SNPs occur in noncoding regions of DNA.

Which of the following is true about jejunal stem cells? a. They reside in the villus b. They include relatively radiosensitive LGR5- basal columnar epithelial cells that lie interspersed between Paneth cells c. They include a quiescent reserve stem cell population that may be activated after injury d. They can give rise to regenerating clonogens that can be counted under the microscope within a few hours of exposure >10 Gy e. They give rise to rapidly proliferating progenitor/transit cells in the top of villus

c. They include a quiescent reserve stem cell population that may be activated after injury There are two populations of intestinal stem cells both residing in the crypt: rapidly active intestinal stem cells (LGR5+), and the more quiescent, reserve intestinal stem cells that have proliferative potential and can re-enter the cell cycle to help repopulating the crypt. The LGR5+ stem cells are relatively radiosensitive and depleted after irradiation which is when the Bmi-1+ population comes into play and starts to rapidly proliferate to replenish the LGR5+ population. Cells in the villus are non-proliferating functional cells that are more radioresistant but fairly rapidly lost after irradiation according to their short natural life span. The stem cell compartment regenerates within a few days (crypt turnover time is approximately 3-5 days) before differentiating to replace the functional cells in the villus.

A primary advantage of high dose rate (HDR) brachytherapy for the treatment of prostate cancer is that: a. The oxygen enhancement ratio (OER) is expected to be lower for HDR than for low dose rate (LDR) brachytherapy b. The probability of late normal tissue damage decreases with increasing fraction size c. Tumor response should be improved by using larger fraction sizes because of the lower /ratio associated with prostate cancer compared with that for the surrounding normal tissues d. Radiation safety issues are generally of less concern for the radioisotopes used for HDR brachytherapy vs/ those for LDR brachytherapy because of their reduced shielding requirements e. HDR brachytherapy allows for better coverage of regional lymphatics

c. Tumor response should be improved by using larger fraction sizes because of the lower a/b ratio associated with prostate cancer compared with that for the surrounding normal tissues Most clinical evidence now indicates that prostate cancers have unusually low a/b ratios, possibly as low as 1.5 Gy, and significantly less than the a/b ratio of roughly 3 Gy assumed for late complications in the normal tissues surrounding the prostate. This low a/b ratio suggests that prostate tumors should be especially sensitive to the large fraction sizes used for HDR brachytherapy. Since the OER usually increases with dose and dose rate, it would be expected to be greater for HDR than LDR brachytherapy. The probability of late normal tissue complications could increase with HDR because of the high doses per fraction used, but the high conformality of the dose makes this less of an issue compared with the use of external beam irradiation. The radioisotopes such as I-125 and Pd-103 used for LDR brachytherapy require relatively little shielding (HVLs of 0.025 mm and 0.008 mm lead, respectively), and are generally delivered as a permanent seed implant. In contrast, Ir-192, an isotope commonly used for HDR brachytherapy, has an HVL of 2.5 mm lead and is typically administered through a catheter-based after-loading technique.

Which of the following cells is the dominant contributor to neovascularization following irradiation? a. Bone marrow-derived cells that are recruited to irradiated tumors b. Pericytes surrounding tumor vasculature that form new endothelial cells c. Tumor-associated endothelial cells that survive a course of radiotherapy d. Trans-differentiated cancer cells that form new endothelial cells e. Trans-differentiated cancer stem-like cells that form new endothelial cells

c. Tumor-associated endothelial cells that survive a course of radiotherapy Tumor response following radiation has been described to occur in 4 discrete stages where: Stage I involves massive endothelial apoptosis or at least stopping of endothelial proliferation. Stage II involves tumor regression via tumor cell death. Stage III involves early regrowth of vessels from remnant endothelial and tumor cells with some growth factor support from myeloid bone marrow-derived cells. Stage IV involves late recurrence due to the tumor bed effect mediated by defective neovascularization.

According to classical target theory, D0 is a measure of the: a. Amount of sublethal damage a cell can accumulate before lethality occurs b. total number of targets that must be inactivated to kill a cell c. dose required to produce an average of one lethal lesion per irradiated cell d. width of the shoulder region of the cell survival curve e. total number of hits required per target to kill a cell

c. dose required to produce an average of one lethal lesion per irradiated cell D0 = mean lethal dose = D37 = dose to reduce survival to 37% or kill 63% In classical target theory, the D0 is the dose that reduces cell survival to 37% of some initial value, as measured on the exponential portion of the radiation survival curve. In essence, D0 is the dose that produces an average of one lethal lesion per cell in a population of irradiated cells; Because the radiation-induced ionizations are random, discrete events , the probability to be killed follows a Poisson distribution with the assumption that one hit is enough to kill. In this instance (at D0), 37% of the targets will not receive a lethal hit and will survive. It is the quasi-threshold dose, Dq, which is an approximation of the total amount of sublethal damage that a cell can accumulate before lethality occurs. The extrapolation number, n, represents the total number of targets that must be inactivated (or hits that must be received in a single target) for a cell to be killed. The Dq would be a manifestation of the width of the shoulder of a survival curve.

Genetic principle that involves restoring a normal copy of a gene in the setting of biallelic mutation = ?

complementation

Process that happens between bacteria that involves the transfer of a plasmid = ?

conjugation

A detectable change in blood count would be expected following a minimum whole body dose of approximately: a. 0.001 Gy b. 0.01 Gy c. 0.1 Gy d. 1 Gy e. 10 Gy

d. 1 Gy A drop in the level of white cells and platelets may be observed following a whole body dose of approximately 1 Gy, although it has been detected at doses as low as 0.5Gy.

A treatment schedule consisting of 25 daily fractions of 1.8 Gy was found to be biologically equivalent to a schedule consisting of 17 daily fractions of 2.5 Gy with respect to complication probability in a critical normal tissue. The a/b ratio for this tissue is closest to: a. 1 Gy b. 3 Gy c. 6 Gy d. 10 Gy e. 20 Gy

d. 10 Gy The a/b ratio for this tissue can be determined by setting n1d1 [1 + d1/(a/b)] = n2d2 [1 + d2/(a/b)], where n1 and n2 are the number of fractions and d1 and d2 are the doses per fractions used for the first and second protocols, respectively. Thus, (25)(1.8 Gy)(1+1.8 Gy/a/b) = (17)(2.5 Gy)(1+2.5 Gy/a/b) = 45 Gy + 81 Gy2/a/b = 42.5 Gy + 106.25 Gy2/a/b or a/b = 25.25 Gy2/2.5 Gy = 10.1 Gy. Shockingly this is exactly how I did it to. If you calculate it plugging in the options for each of the BED equations, you see that they only match for a/b 10 also as a second check

The EPA estimates that the fraction of the total number of U.S. lung cancer deaths annually caused by indoor radon is approximately: a. Zero for non-smokers b. 0-0.1% c. 1-2% d. 10-20% e. 40-60%

d. 10-20% The EPA has estimated that approximately 20,000 of the annual 160,000 lung cancer deaths in the U.S. each year are due to exposure to indoor radon through the production of a-particles resulting from the decay of radon to a-emitting daughter products.

Based on experience in head and neck cancers, accelerated repopulation likely begins how many dates after the initiation of fractionated radiation therapy? a. 7 days b. 14 days c. 21 days d. 28 days e. None of the above

d. 28 days D 28 days. Based on studies by Withers and colleagues, clonogen repopulation in head and neck cancer begins approximately 28 days after the initiation of radiation therapy. This suggests that there should be attempts to minimize treatment breaks once therapy is started.

Assuming that the D10 for a tumor cell population is 4 Gy and the extrapolation number n equals 1, the single dose to achieve a TCD90 for a tumor containing 100 million clonogenic cells is closest to: a. 18 Gy b. 24 Gy c. 28 Gy d. 36 Gy e. 44 Gy

d. 36 Gy In order to achieve a 90% tumor control probability, it is necessary to reduce the number of tumor cells to 0.1 (on average). Since the extrapolation number is 1 for the cells comprising the tumor, it can be assumed that there is little or no "shoulder" on the survival curve. Thus, for a tumor with 10^8 cells initially, the surviving fraction would need to be 10^-9. This would be achieved by a dose of 4 Gy x 9 logs = 36 Gy.

The cells comprising a patient's tumor are characterized by an SF2 of 0.3 and a doubling time of 3 days. Due to an unexpectedly severe skin reaction, the patient is put on a 3 week break during treatment to allow some healing to occur. How much extra dose would be required to achieve the same probability of tumor control if the treatment had not been interrupted? (Assume that treatment is given as daily, 2 Gy fractions, the multifraction survival curve for the cells comprising this tumor is exponential, and that radiation-induced cell cycle perturbations are negligible.) a. 2 Gy b. 4 Gy c. 6 Gy d. 8 Gy e. 10 Gy

d. 8 Gy During a 3 week (21 day) break, cells with a 3 day doubling time will undergo 7 additional doublings, leading to an increase in the number of tumor cells by a factor of 128. Solving for x in the equation (0.3)x = 1/128, where x is the number of fractions, yields x ≈ 4. (Taking the logarithm of both sides of the equation gives x log 0.3 = - log 128, so x = 2.10/0.52). Thus, "compensating" for the extra cells produced by proliferation would require an additional 4 fractions of 2 Gy, or 8 Gy. My solution was to say you have 128x more cells so you need to reduce that by 1/128th to have the same chance of cure and since each 2 Gy fraction reduces survival by 0.3 (0.3)^x = 1/128 x = 4 fractions x 2 Gy = 8 Gy

The sequence of temperatures (in degrees C) used in a round of PCR to amplify a particular DNA fragment would most likely be: a. 95, 72, 57 b. 57, 95, 72 c. 72, 57, 95 d. 95, 57, 72 e. 72, 95, 57

d. 95, 57, 72 The basic steps of a polymerase chain reaction (PCR) are denaturing, annealing, and extending. The 95 C denatures the DNA, a temperature of approximately 57 C permits binding of primers to the DNA (depending on the primer sequence and length, the temperature may vary around this range), and then -extension at 72 C which is the optimal temperature for synthesis of DNA by Taq polymerase.

Which of the following statements is FALSE concerning radiation carcinogenesis? a. The use of prenatal X-rays during the 1950's and 1960's increased the risk for the development of childhood cancer among children who received these diagnostic examinations while in utero b. For radiation protection purposes, it is assumed that the shape of the dose response curve for radiation-induced solid tumors is linear with no threshold c. Evidence for radiation-induced leukemia comes from epidemiological studies of children irradiated in utero and from the Japanese A-bomb survivors d. A radiation oncologist with a lifetime dose equivalent of 250 mSv has about a 10% chance of developing a fatal radiation-induced cancer e. In the 1920s the association of radium exposure to development of osteosarcoma was identified in women who worked to detail watch dials with the radioactive paint

d. A radiation oncologist with a lifetime dose equivalent of 250 mSv has about a 10% chance of developing a fatal radiation-induced cancer Using a low dose rate risk estimate for the working population of 0.04 radiation-induced fatal cancers per Sv, and assuming a linear extrapolation of the risk estimate to 0.25 Sv, it would be anticipated that this person would have a 1% excess risk for the development of a cancer resulting from his/her activities as a radiation oncologist.

Iodine-131 tositumomab (Bexxar) is: a. A radiolabeled small molecule tyrosine kinase inhibitor used to treat lung cancer b. Used to treat thyroid cancer c. Of limited clinical utility because of its high toxicity to the GI tract d. A radiolabeled antibody against the CD20 antigen over-expressed in non-Hodgkin's lymphoma cells e. Highly effective at cell killing because of the high LET -particle emissions from the I-131

d. A radiolabeled antibody against the CD20 antigen over-expressed in non-Hodgkin's lymphoma cells D I-131 tositumomab (Bexxar) is a radiolabeled antibody against the CD20 cell surface antigen found in a very high percentage of B cell non-Hodgkin's lymphomas. The b- and g- emitting (not a-emitting) radioisotope I-131 is used for treatment of thyroid cancer, and is administered singly, not attached to any antibody. The primary clinical toxicity from I-131 tositumomab is a dose-related, reversible, hematopoietic suppression.

The CRISPR/Cas9 system is a recent advancement that has revolutionized basic research and has promising potential therapeutic implications. The most proximate host cellular effect immediately downstream of Cas9 protein activity is: a. Induction of apoptosis b. Activation of the immune response c. Suppression of protein expression d. Activation of the dsDNA damage response e. Suppressing protein activity

d. Activation of the dsDNA damage response The Clustered Regularly Interspased Short Palindromic Repeats (CRISPR)/Cas9 system is a versatile system to modulate target gene expression. It is composed of 2 elements: the guide RNA (gRNA) and Cas9 protein. The gRNA is an RNA molecule that directs the Cas9 protein to a specific area of the protein-encoding genome by complementary base paring. Cas9 is an endonuclease of bacterial origin that cuts double-stranded DNA at the location directed by the gRNA. This dsDNA break induces the host DNA damage response in an attempt to repair the cut. While some percentage of cuts will be repaired by error-free homologous recombination (HR), the majority of cuts are repaired by error prone non-homologous end joining (NHEJ) often resulting in small insertions and deletions (aka "indels"). These can cause the protein coding sequence of the gene to be altered in such a way as to disrupt protein expression and/or function. The net effect is a reduction in functional protein expression. Note that if the dsDNA cut is repaired perfectly, it re-creates the target sequence for the CRISPR/Cas9 system to cut yet again. It will do so until the target is repaired imperfectly and is no longer recognized by the gRNA.

Irinotecan: a. Acts directly on RNA polymerase b. Is activated intracellularly to camptothecin c. Is a proteasome inhibitor d. Acts by stabilizing the topoisomerase I cleavable complex e. Is a derivative of cyclophosphamide

d. Acts by stabilizing the topoisomerase I cleavable complex D Irinotecan is a synthetic analogue of camptothecin (CPT) and inhibits topoisomerase I by trapping the cleavable complex formed between this enzyme and DNA. CPT is a natural product derived from the bark and stem of Camptotheca (Happy Tree) with remarkable anticancer activity, but also low solubility and high adverse reactions. Because of these disadvantages, synthetic derivatives have been developed. The other CPT synthetic analogue used in cancer chemotherapy is topotecan. Proteasome inhibitors are drugs that block the action of proteasomes, the cellular complexes that break down proteins, such as p53. Examples of proteasome inhibitors include bortezomib, the first proteasome approved for use in the US, and salinosporamide A currently in clinical trials for multiple myeloma. Cyclophosphamide (Cytoxan) is an alkylating agent.

Which of the following statements concerning telomerase is TRUE? Telomerase: a. Is activated when telomeres decrease below a critical size b. Plays a central role in base excision repair c. Is present at high levels in senescent cells relative to normal cells d. Adds DNA sequence repeats onto the ends of chromosomes e. Therapeutic activation in tumor cells represents a promising cancer treatment strategy

d. Adds DNA sequence repeats onto the ends of chromosomes Telomerase adds specific repeat sequences onto and caps the ends of chromosomes, thereby creating telomeres. This both prevents the ends of chromosomes from shortening with each cell division as well as from unraveling and/or inappropriate identification by the cellular DNA repair enzymes as double strand breaks. Telomerase is generally active in normal stem cells and many tumor cells, but not other differentiated, normal cells, which confers on them unlimited replicative potential, i.e., "immortality". Telomerase does not play a central role in base excision repair and tends to be present at low levels in senescent cells. Inhibition, not stimulation, of telomerase represents a potential means to inhibit proliferation of cancer cells.

Glutathione peroxidases (GPx) play several roles in cells including maintaining H2O2 homeostasis. Which of the following statements regarding glutathione peroxidases is false? a. Selenocysteine is present at the active site of GPx1-4 and GPx6 b. Knockdown of GPx1 in human prostate cancer cells enhances the formation of radiation induced micronuclei c. GPx2 is upregulated in upregulated in colon cancer and squamous cell carcinomas d. All GPx can reduce hydroperoxides within cell membranes e. GPx1 can be found in the cytosol in mitochondria and also in peroxisomes

d. All GPx can reduce hydroperoxides within cell membranes Glutathione peroxidases (GPx) are enzymes that detoxify peroxides and hydroperoxides. Selenocysteine is present in the active site of many GPx and facilitate the reduction of peroxides into alcohols. Knockdown of GPx1 in human prostate cancer cells enhances the formation of radiation induced micronuclei. GPx2 is upregulated in colorectal cancer, Barrett's esophagus, squamous cell carcinoma, and lung adenocarcinoma's of smokers. GPx4 is the only GPx that is able to reduce hydroperoxides within membranes.

Oncogenes: a. Can be activated by epigenetic silencing b. Are inherited in familial cancers c. Are induced by gene loss d. Can be activated by point mutation e. Are important barriers to prevent tumor formation

d. Can be activated by point mutation Oncogenes are frequently activated by point mutations. Examples include single nucleotide mutations in K-ras or in receptor tyrosine kinases that result in constitutive activation. Oncogene activation drives tumor proliferation and carcinogenesis. Epigenetic silencing and gene loss are events that inactivate tumor suppressors. Familial cancers are caused by inheritance of defective tumor suppressors. The only inherited oncogene i can think of is RET proto-oncogene in MEN2 syndrome.

Which one of the following treatment modifications would NOT be expected to alter the radiation response of normal tissues to fractionated radiotherapy? a. Changing the fraction size b. Step down in field size c. Scheduling a gap d. Co-administration of nimorazole e. Administration of amifostine

d. Co-administration of nimorazole The use of an hypoxic cell radiosensitizer, such as nimorazole, would not be expected to affect the response of normal tissues to radiotherapy since normal tissues generally do not possess regions of hypoxia. A change in fraction size may affect both the incidence and the severity of the radiation response in normal tissues, particularly late-responding tissues. A step down in field size would spare at least some normal tissues the full treatment dose. A gap in treatment may lessen the severity of the response in acutely-responding normal tissue, as repopulation of surviving cells during the gap would compensate to some extent for the damage caused by the radiation. Administration of amifostine, a radioprotector, also may protect normal tissues.

Which of the following intermediates is thought to play a critical role in the pro-fibrotic signaling of transforming growth factor-beta (TGF-beta)? a. Insulin like growth factor, IGF b. Heat shock protein 90, Hsp90 c. Checkpoint kinase 1, Chk1 d. Connective tissue growth factor, CTGF e. p53

d. Connective tissue growth factor, CTGF CTGF, or connective tissue growth factor, is a downstream effector of TGF beta signaling. It is known to be involved in wound repair, fibrosis, and several pathologic states associated with increased extracellular matrix production

Which of the following would probably NOT be noted in an individual who received an acute, whole body dose of 5 Gy of X-rays and received no medical care? a. Infection b. Nausea c. Bleeding d. Death within 1 week following irradiation e. Epilation

d. Death within 1 week following irradiation Death from the gastrointestinal syndrome could occur within one week following irradiation, but is unlikely following a whole body dose of 5 Gy. However, a person irradiated with this dose who did not receive appropriate medical care has a greater than 50% chance of dying within a 1-2 month period from bone marrow syndrome. Following a whole body dose of 5 Gy, infections are likely due to loss of white blood cells and lack of treatment with antibiotics. Nausea would be observed during the early prodromal period. Epilation and bleeding would occur during the period before the person dies from hematopoietic syndrome.

Which of the following statements is TRUE concerning irradiation of the testes? a. Spermatids and spermatozoa are relatively radiosensitive, whereas spermatogonia tend to be radioresistant b. A substantial drop in testosterone levels can be detected following a scattered X-ray dose of 0.1 Gy to the testes of an adult man c. If sterility in the male is not observed within one month following irradiation, it is unlikely to occur at a later time d. Dose fractionation increases the risk for sterility in the male e. Full recovery of a normal sperm count following radiation-induced azoospermia caused by exposure to a dose of 6 Gy of X-rays generally occurs within 6 months

d. Dose fractionation increases the risk for sterility in the male Dose fractionation increases the risk for sterility in the male; the TD5 and TD50 for sterility are 2 Gy and 8 Gy, respectively, for a single dose of X-rays, whereas these values decrease to 1 Gy and 2 Gy for fractionated irradiation. This effect results from spreading the dose over time permitting reassortment sensitization to occur for spermatogonia, which have a large variation in radiation sensitivity through the course of their cell cycle, and more than compensating for any repair that might occur between fractions. Thus, spermatogonia located in a relatively radioresistant portion of the cell cycle may progress into a more radiosensitive part of the cell cycle at the time of the second and subsequent irradiations. Spermatids and spermatozoa are relatively radioresistant, whereas spermatogonia are radiosensitive. A drop in testosterone levels would not be detectable following a scattered dose of 0.1 Gy to the testes, particularly to an adult. Following a moderate dose of radiation, which kills a large number of spermatogonia, there may be relatively little effect on the levels of spermatocytes, spermatids and spermatozoa initially, since a period of 67 days is required for maturation of a spermatogonial stem cell to a mature spermatozoan. Hence, there may be very little drop in sperm count for the first month following irradiation, although the sperm count will decrease at a later time. Full recovery of a normal sperm count following radiation-induced azoospermia caused by exposure of the testes to a dose of 6 Gy, would require a period of at least 2 years.

Iressa (gefitinib) is a(n): a. Monoclonal antibody against VEGF b. Analog of nitrogen mustard c. COX-2 inhibitor d. EGFR inhibitor e. Anti-HER2 antibody

d. EGFR inhibitor Iressa is a small molecule EGFR-tyrosine kinase inhibitor. Monoclonal antibodies directed against vascular endothelial growth factor (VEGF) such as Avastin may benefit some patients with colorectal, breast and lung cancers. Nitrogen mustards are used as antineoplastic agents in cancer therapy as nonspecific DNA alkylating agents. The antitumor activity of nitrogen mustards has been connected with their ability to cross-link the twin strands of DNA which if not repaired, can inhibit DNA replication and transcription, eventually leading to cell cycle arrest, apoptosis, and the inhibition of tumor growth. Cyclooxygenase (COX) inhibitors are compounds that block the action of COX enzymes, which are produced in response to inflammation and by precancerous and cancerous tissues. An example of a COX inhibitor is Celecoxib. Antibodies against HER-2 receptor, which is overexpressed in some breast cancers, include trastuzumab (Herceptin).

Which one of the following is NOT a part of the RAS pathway that stimulates radioprotective and growth promoting signals following irradiation? a. RAF1 b. MEK c. MAPK (ERK) d. FADD e. RHO

d. FADD FADD (FAS-associated death domain) protein plays an important role in the extrinsic apoptotic pathway through activation of caspase 8. FADD is associated with the Fas receptor at the plasma membrane. Activated RAS stimulates cellular proliferation through activation of multiple pathways including the RAF, MAPK/ERK, MEK, JNK, RAC/RHO, PLC and PI3K/AKT pathways.

The best method to locate a gene on a chromosome is: a. Promoter bashing b. ELISA c. Two-hybrid screen d. FISH e. RFLP

d. FISH Fluorescent in situ hybridization or FISH involves the use of a fluorescently-labeled probe for a particular gene in order to identify the location of that gene on a chromosome. Promoter bashing is used to identify that portion of a promoter where a transcription factor binds. The Enzyme-Linked ImmunoSorbent Assay, or ELISA, is used to detect the presence of an antibody or an antigen in a sample. A two-hybrid screen is used to characterize protein- protein interactions. A restriction fragment length polymorphism (RFLP) results when the location cut by restriction enzymes varies between individuals, due to insertions, deletions or transversions.

Several mechanisms have been proposed as to why cancer stem cells are more radioresistant than non-stem cancer cells. One such example is: a. Cancer stem cells have lower levels of free radical scavengers b. Cancer stem cells tend to down-regulate developmental pathways such as Wnt/b-catenin, Notch, Hedgehog, and TGF-b c. Hypophosphorylation of checkpoint kinases CHK1/2 in cancer stem cells d. Hyperactivation of anti-apoptosis pathways in cancer stem cells e. Overexpression of MHC class I

d. Hyperactivation of anti-apoptosis pathways in cancer stem cells Cancer stem cells appear to have higher levels of free radical scavengers, abnormal activation of developmental pathways, hyperphosphorylation of checkpoint kinases which collectively tend to drive their superb resistance to radiation.

Which of the following observations is most closely associated with G1/S arrest in wild type-p53 cells following X-irradiation? a. Increase in bromouridine incorporation b. Increase in the labeling index c. Formation of the cyclin E/A-Cdk2 complex d. Inreased transcription of the p21Waf1 (CDKN1A) gene e. Increased transcription of the p53 (TP53) gene

d. Increased transcription of the p21Waf1 (CDKN1A) gene p21 inhibits cyclin A-Cdk2 and cyclin E-Cdk2 activity, which in turn prevents G1 cells from entering into S phase. The cyclin E/A-Cdk2 complex is required for entry of G1 cells into S- phase. The induction of p21 in X-irradiated cells is dependent on functional p53. p53 is a transcription factor which is activated in response to a wide variety of genotoxic stresses, frequently via post-translational modification. In response to ionizing radiation-induced DNA damage the existing p53 protein is modified by phosphorylation at multiple sites. The modified p53 becomes more stable (that is, its half-time is significantly increased), which results in increased amounts of the p53 protein, and confers its activity as a transcription factor. The labeling index is the fraction of cells in S-phase, relative to the total number of cells in a proliferating cell population. Choices A and B imply the paradoxical increase in the number of the S-cell population following G1/S arrest.

Which of the following statements about Transforming growth factor-beta (TGFb1) is FALSE? TGFb: a. Is a chemo-attractant for granulocytes b. Is a suppressor of T lymphocytes c. Increases proliferation of fibroblasts and smooth muscle cells d. Increases proliferation of epithelial cells e. Requires activation to be biologically active

d. Increases proliferation of epithelial cells TGFb1 generally has an inhibitory effect on epithelial cell proliferation. TGFb1 is an important fibrogenic cytokine. It increases proliferation of mesenchymal cells and extracellular matrix deposition, and appears to be mechanistically involved in radiation fibrosis. It is secreted as a biologically inactive (latent) homodimer that is complexed with latency-associated peptide (LAP), and requires activation in order to exert its biological activities. TGFb1 is one of the strongest known chemotactic factors for granulocytes, and on a molar basis, has been estimated to be about 1000-fold more potent than cyclosporine as a T-cell suppressor.

Brachytherapy has been used to treat ocular melanoma using multiple radionuclides. There is clinical data on the use of all of these isotopes EXCEPT: a. Ruthenium-106 b. Cobalt-60 c. Iodine-125 d. Iodine-131 e. Palladium-103

d. Iodine-131 Iodine-131. Ocular melanoma is the most common intraocular malignancy in adults. Randomized trials have shown that definitive radiation therapy did not alter the risk of melanoma-related mortality (Collaborative Ocular Melanoma Study Group, Archives of ophthalmology 2006;124:1684-1693); hence, definitive radiation has become the standard of care for medium sized tumors (Singh AD et al. Ophthalmology 2011; 118:1881-1885). There have been clinical reports of the use of Cobalt-60, Iodine-125, palladium, and Ruthenium-106 for these treatments. And Strontium i think Iodine-131 is used in nuclear medicine applications for treatment of thyroid.

Which of the following targeted agents is an immune checkpoint inhibitor? a. Bevacizumab b. Imatinib c. Crizotinib d. Ipilimumab e. Cetuximab

d. Ipilimumab Antitumor immunity is often ineffective due to the tight regulation associated with the maintenance of immune homeostasis. One of the major limitations results from chronic exposure to antigens and is characterized by the upregulation of inhibitory immune checkpoint receptors in order to prevent uncontrolled immune reactions. Blocking of one or several of these immune checkpoints with monoclonal antibodies (mAbs) has been shown to rescue otherwise exhausted antitumor T cells, and most importantly, has been associated with objective clinical responses in cancer patients. The first immune-checkpoint inhibitor to be tested in a clinical trial was ipilimumab (Yervoy, Bristol-Myers Squibb), an anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) mAb. CTLA-4 belongs to the immunoglobulin superfamily of receptors, which also includes programmed cell death protein 1 (PD-1), B and T lymphocyte attenuator, T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and V- domain immunoglobulin suppressor of T cell activation. In 2011, the US Food and Drug Administration approved the use of ipilimumab in patients with metastatic melanoma, either as initial therapy or after relapse (24161671). Bevacizumab is the humanized monoclonal antibody that inhibits vascular endothelial growth factor A (VEGF-A). Imantinib is a small molecular inhibitor of receptor tyrosine kinases most selective for Bcr-Abl, but also less so against c-kit and PDGF-R. Cetuximab is a monoclonal antibody against EGFR. Crizotinib is a small molecular inhibitor of ALK and ROS1 kinases.

Which of the following is true about PD-1? a. It stands for Protein of Differentiation-1 b. It binds to PD-L1/PD-L12 to induces apoptosis in PD-L1/PD-L2-expressing cells c. It down-regulates regulatory T cells d. Its expression is upregulated by T cell receptor activation

d. Its expression is upregulated by T cell receptor activation PD-1 stands for programmed cell death protein-1. It is expressed on a variety of cells but most notably activated T cells, and its upregulation is seen after T-cell receptor (TCR) activation.

What causes the decrease in the amount of cyclin at a specific point in the cell cycle? a. An increase in production once the checkpoint is passed b. The cascade of increased production once its protein is phosphorylated by a partner Cdk c. Assembling new histones into chromatin d. Its self-degradation e. Covalent modification in the cytoplasm

d. Its self-degradation Transition through the checkpoints are regulated by a combination of cyclins, cyclin dependent kinases (Cdk) and cyclin kinase inhibitors (CKI). CKIs bind to Cdk or to Cdk-cyclin complex and inhibit the kinase activity of CdK. Cyclins are present only during short periods within the cell cycle and are controlled by their own degradation. The Cdks remain throughout the cell cycle but are inactive without their corresponding cyclins. Cdks are activated in a cascade with the cyclins, and have several control CKIs, such as p16, p27 and p21 that serve as regulators and indicators of cell physiological conditions, including nuclear DNA damage. New histones are synthesized along with the new DNA molecule during S-phase. Cyclins are degraded by the ubiquitin proteosome system.

Cyclooxygenase (COX)-2: a. Tends to be down-regulated in tumors. b. Is constitutively produced by most normal tissues. c. Inhibits prostaglandin synthesis. d. Mediates synthesis of eicosanoids from arachidonic acid. e. Is specifically inhibited by erlotinib.

d. Mediates synthesis of eicosanoids from arachidonic acid. Cyclooxygenase (COX)-2 mediates synthesis of eicosanoids from arachidonic acid. It tends to be over-expressed in tumors, is not constitutively produced in most normal tissues and stimulates, rather than inhibits, prostaglandin synthesis. EGFR is inhibited by erlotinib.

Renal irradiation can lead to the development of radiation nephropathy, which is characterized by proteinuria, anemia, hypertension and a chronic, progressive decrease in renal function. The decline in kidney function characteristic of radiation nephropathy can be: a. Treated with anti-hypertensive agents such as beta blockers b. Prevented using anti-inflammatory agents c. Reversed using calcium channel blockers d. Mitigated using drugs that block the renin-angiotensin system e. Accelerated at lower radiation doses

d. Mitigated using drugs that block the renin-angiotensin system There is an extensive series of laboratory studies that have established a clear role for the renin-angiotensin system in the pathogenesis of radiation nephropathy. Administration of angiotensin-converting enzyme inhibitors (ACEI), such as captopril, and angiotensin type 1 receptor antagonists (AT1RA), such as L-158,809, have been shown to be effective as prophylactic agents and as mitigators of injury when administered after irradiation. The decline in renal function observed in a patient presenting with radiation nephropathy following TBI was reported to be prevented by administration of losartan, an AT1RA. At present, there are no randomized clinical studies to suggest that renal function will improve following treatment with ACEI or AT1RA. The ability of these agents to modulate radiation nephropathy is not due to a reduction in blood pressure; ACEI are effective at doses that do not affect blood pressure. Moreover, administration of antihypertensive agents does not ameliorate radiation nephropathy. The decline in kidney function is not accelerated at low radiation doses.

In the Childhood Cancer Survivor Study, the incidence of which of the following cancers was NOT elevated in irradiated children compared to those who did not receive radiotherapy as part of their cancer treatment? a. Skin cancer b. Sarcoma c. Meningioma d. Pancreatic e. Thyroid cancer

d. Pancreatic In the Childhood Cancer Survivor Study, there was no evidence of an increase in pancreatic cancer, however increased incidences of skin cancer, sarcoma, meningioma and thyroid cancer were observed in childhood cancer survivors who received radiotherapy as part of their treatment.

A drug used to treat fibrosis and osteoradionecrosis is: a. Amifostine b. Tirapazamine c. Nicotinamide d. Pentoxifylline e. Misonidazole

d. Pentoxifylline There is clinical evidence that pentoxifylline may be helpful for the treatment of radiation fibrosis and osteoradionecrosis.

Following irradiation, which of the following events involving ATM occurs? ATM: a. Activation is inhibited by the MRN complex b. Is phosphorylated by the MRN complex and undergoes monomerization resulting in its activation c. Causes phosphorylation of MDM2, stimulating its inhibitory action against p53 d. Phosphorylates CHEK2 and inhibits CDC25C activity e. Dephosphorylates gH2AX

d. Phosphorylates CHEK2 and inhibits CDC25C activity Following irradiation, ATM activates CHEK2, which then phosphorylates CDC25C phosphatase, preventing it from dephosphorylating CDK1, a step necessary for progression from G2 into M. Although the mechanism for activation of ATM following irradiation is not clear, it has been suggested that the MRN complex stimulates, not inhibits, its activation. Following irradiation, ATM is autophosphorylated and converted from an inactive dimer to an active monomer. ATM causes phosphorylation of MDM2 and inhibits its inhibitory activity against p53. H2AX is a substrate for ATM kinase activity causing addition of phosphate groups resulting in gH2AX.

Which of the following statements is FALSE concerning exposure to radiation? a. The largest contributor to background radiation exposure in the United States is radon b. The average annual dose equivalent resulting from the combined exposure to cosmic, terrestrial, and internal background radiation is roughly 1 mSv c. The effective dose equals the equivalent dose only under conditions where the whole body is irradiated d. Radiation exposure from medical diagnostic tests constitutes about 2% of the average total radiation dose residents of the United States receive each year e. Background radiation exposure increases with increasing altitude at which an individual resides

d. Radiation exposure from medical diagnostic tests constitutes about 2% of the average total radiation dose residents of the United States receive each year Historically, the annual dose equivalent received from medical diagnostic tests in the US is quoted as approximately 0.4-0.5 mSv per year, which constitutes about 15% of average yearly radiation exposure. This is in comparison to the 3 mSv received from natural background radiation sources (including radon), and the 0.1 mSv from other sources. However, as a result of the large increase in the use of CT scanning, for which the doses are higher than for most other diagnostic tests, the average annual dose equivalent resulting from use of medical X-rays may now be as high as 3 mSv (or closer to 50% of the total average annual dose). Also, background radiation exposure generally increases with increasing altitude since there would be less atmosphere to attenuate the cosmic rays from space.

The tolerance dose for xerostomia resulting from treatment of a head and neck tumor with 3 Gy fractions compared to 2 Gy fractions would be expected to: a. Increase substantially b. Increase slightly c. Decrease substantially d. Remain about the same e. Either increase or decrease depending upon the particular patient

d. Remain about the same Killing of serous cells in the parotid gland, which causes xerostomia in many head and neck cancer survivors who received radiotherapy, would not be substantially affected by fraction size.

Mutations in growth factor receptors are common alterations in cancer that may: a. Signal cells to enter senescence b. Directly inhibit protein translation c. Cause formation of -H2AX foci in cell nuclei d. Result in constitutive kinase activity that signals cells to proliferate e. Stimulate ubiquitination of caspase 3 to induce apoptosis

d. Result in constitutive kinase activity that signals cells to proliferate D Growth factor receptors generally have three domains: an extracellular ligand-binding domain, a trans-membrane domain that spans the plasma membrane of the cell, and an intracellular kinase domain. Mutations can occur in all three domains in ways that contribute to cancer development. The resultant changes in the protein often lead to constitutive kinase activity, which signals the cell to proliferate, not to undergo senescence. Kinases are proteins that attach phosphate groups to other molecules. Such receptor mutations have not been shown to stimulate general protein translation, cause DNA damage that would stimulate formation of g-H2AX foci or affect caspase 3, which is normally activated by cleavage, not ubiquitination, to cause apoptosis.

Which of the following is NOT a phenotypic characteristic of a person diagnosed with ataxia telangiectasia? a. Neurodegeneration b. Abnormalities in ocular blood vessels c. Immune system defects d. Sensitivity to UV induced cancers e. Radiosensitivity

d. Sensitivity to UV induced cancers People with ataxia telangiectasia do not exhibit an increased sensitivity to UV induced damage which is repaired by nucleotide excision repair. People with ataxia telangiectasia do exhibit progressive ataxia beginning in childhood, telangiectasias of sun exposed skin and the sclera, hypogammaglobulinemia, dysphagia, dysarthria, and chronic lung diseases. They also have an increased susceptibility to various cancers, especially leukemias and lymphomas, with an approximate 25% lifetime risk.

Treatment with an antiangiogenic agent may cause a tumor to exhibit increased sensitivity to a subsequent radiation dose. It has been hypothesized that this reflects the fact that: a. Most antiangiogenic agents are also chemical radiosensitizers b. Vascular damage decreases tumor perfusion and results in longer retention of the toxic, radiation- induced free radicals c. Vascular damage increases hypoxia, which increases expression of HIF-1 in tumor cells, which in turn increases cellular radiosensitivity d. Some antiangiogenic agents transiently "normalize" tumor vasculature, resulting in increased oxygenation of the tumor and increased radiosensitivity e. Transient normalization of the tumor vasculature can occur after treatment with some antiangiogenic agents, resulting in a more uniform radiation dose delivery

d. Some antiangiogenic agents transiently "normalize" tumor vasculature, resulting in increased oxygenation of the tumor and increased radiosensitivity It has been suggested that the transient increase in radiation response reflects the transient normalization of the tumor vasculature, which results in increased perfusion and increased oxygen delivery, leading to a decrease in tumor hypoxia and decreased hypoxia- induced radioresistance.

The slopes of isoeffect curves for late responding tissues compared to early responding tissues and tumors are typically (assume data are plotted on a log-log scale): a. Variable, depending upon the specific tissue b. Comparable c. Shallower d. Steeper e. Flat

d. Steeper When plotted as the log of the total dose to produce a given isoeffect as a function of the log of the dose per fraction (plotted on a reverse scale), most late responding normal tissues are characterized by steep isoeffect curves, whereas those for early responding normal tissues and most tumors tend to be shallow.

Which one of the following is NOT a fundamental assumption underlying the use of the jejunal crypt cell assay to measure cell survival in vivo? a. All crypts contain approximately the same number of stem cells b. Surviving stem cells (and their progeny) in the irradiated volume do not migrate between crypts during regeneration c. Stem cells from outside the irradiated volume do not migrate into the area and contribute to the regeneration of the crypts d. Stem cells can be identified morphologically and distinguished from differentiated cells e. Stem cells in all crypts proliferate within 3 days after irradiation

d. Stem cells can be identified morphologically and distinguished from differentiated cells This and other in vivo clonogenic assays do not require that the investigator be able to unambiguously identify the stem cell or distinguish it from its differentiated progeny. Instead, the stem cell is identified functionally, by its ability to produce progeny; its survival is assayed by the ability to repopulate the depleted crypt after irradiation. Crypt turnover time is approximately 3-5 days. There are two populations of intestinal stem cells: rapidly active intestinal stem cells (LGR5+) that are very radiation sensitive, and the more quiescent, and radioresistant reserve intestinal stem cells that have proliferative potential and can re-enter the cell cycle to help repopulating the crypt. All of the other factors would compromise the accuracy of the assay. A wide variation in the number of stem cells (e.g., 1 in some crypts, 10 or 50 in others) would result in large variations in the extrapolation number, n, of the radiation survival curve, and therefore in the vertical position of the exponential region of the survival curve. Such variability would make the assay unusable. The clonogenic assay also assumes that the presence of one (or more) surviving stem cells in an irradiated crypt leads to the regeneration of that crypt, and that a crypt where no stem cells survive does not regenerate. The migration of surviving stem cells from one regenerating crypt into a neighboring crypt that had no surviving stem cells, or the repopulation/survival of dying crypts as a result of the migration of unirradiated stem cells from outside of the irradiated volume, would result in an overestimation of the survival of the irradiated crypt stem cells. Conversely, if some stem cells survived, but did not proliferate for several days after irradiation, their crypts would not regenerate during the relatively short observation period used in this assay and the stem cells would erroneously be scored as dead. Stem cell survival would be underestimated in this case.

The p53 tumor suppressor protein protects against radiation-induced lymphomagenesis by detecting the following radiation-induced lesion. a. Radiation-induced single-stranded and double-stranded breaks detected by the DNA damage response machinery b. Radiation-induced double-stranded breaks detected by the DNA damage response machinery c. Radiation-induced single-stranded detected by the DNA damage response machinery d. Sustained mitogenic stimulation detected by the p19ARF machinery from radiation-induced oncogenic mutations e. Sustained mitogenic stimulation detected by the p16INK4a machinery from radiation-induced oncogenic mutations

d. Sustained mitogenic stimulation detected by the p19ARF machinery from radiation-induced oncogenic mutations Correct answer is "d". Several studies have called into question the widely held view that the DNA-damage response is integral to the actions of p53 as a tumor suppressor (16957739, 14729946, and 10082576). The possibility that the acute DNA damage response may be dispensable for p53-mediated tumor suppression has intriguing implications. First, although DNA damage is very efficient at triggering p53-dependent cell death, as evident from the widespread apoptosis of radiosensitive tissues following irradiation, it is highly inefficient at generating tumor cells: mice lacking p53 are immune to much of the pathological cell death induced by irradiation yet still take months to develop rare, clonal tumors. Thus, only a tiny number of damaged cells that p53 kills would ever have evolved into tumors had they survived. Widespread activation of p53 following DNA damage is therefore, at best, an unwieldy tool with which to cull a few potential tumor cells. In contrast, because p19ARF is induced only in those rare preneoplastic cells that, as a consequence of DNA damage, acquire oncogenic mutations, its expression is highly specific to those few cells set on a neoplastic trajectory. Second, the p53-dependent DNA-damage response mediates much of the life-threatening pathology and side effects that accompany radiation exposure and chemotherapy. Restoring p53 function only at a later time abrogates all of the pathology yet, by focusing p53 activity only on those incipient tumor cells expressing p19ARF, preserves much of the tumor suppression. Such observations suggest that transient pharmacological inhibition of p53 during, or shortly after, acute genotoxic injury may be helpful in ameliorating the pathology, without compromising subsequent tumor suppression. Perhaps, most perversely, it is even possible that the linkage between p53 and DNA damage actually drives erosion of the efficacy of p53 as a tumor suppressor by imposing a lifelong selective pressure to inactivate p53 in cells sustaining such damage. Once lost, p53 is then unavailable to act as a tumor suppressor.

What does TCR sequencing measure? a. TCR-seq identifies the entire DNA sequence of the TCR on each T cell in a sample. b. It identifies and quantifies the variable and constant region of each TCR. c. The output of TCR-seq is the sequence and abundance of the Tim-3 complex receptors in a lymphocyte sample and an estimate its diversity. d. TCR-seq determines the sequence and abundance of all T cell receptors in a sample and can be used to describe an entire T cell repertoire. e. It sequences and quantifies the expression of the T cell receptor mRNA after VDJ gene splicing.

d. TCR-seq determines the sequence and abundance of all T cell receptors in a sample and can be used to describe an entire T cell repertoire. TCRseq (also called immunosequencing) is a high-throughput next generation sequencing technology that allows the identification of every T cell clone in a sample, be it whole blood, PBMC or tumor infiltrating lymphocytes or other tissues. It is based on sequencing a subsection of the T cell receptor (TCR). TCRs are heterodimers on T cells consisting of a and b chains or in some rare cases of g and d chains. ab TCRs recognize and bind peptides presented within the MHC molecule. During lymphocyte development random recombination events amongst the VDJ gene segments that take place in the thymus yield the immensely diverse repertoire of ab T cells (about 1018 different abTCRs) which is then further shaped through negative and positive clonal selection. In most cases, TCR sequencing tend to focus on the hypervariable complementary determining region 3 (CDR3) which is a short region spanning the VD and DJ junction on the TCR b subunit that comes in direct contact with the MHC-bound peptide and the region with the most variability, i.e. unique to each TCR. VDJ recombination is done at the DNA level and does not involve RNA splicing. Most commercial TCRseq platforms are in fact based on DNA, although mRNA can also be used.

Midway through the course of a standard external beam treatment for breast cancer, the patient discovered she was pregnant and near the end of her first trimester. Which of the following statements about this situation is TRUE? a. The woman should be advised to discontinue treatment until she gives birth b. The fetus is quite resistant to radiation during this gestational stage, so there is no need to discuss options with the patient c. The scattered dose already delivered to the fetus is sufficiently high that a miscarriage or stillbirth is probable d. The fetus will be at an increased risk for the development of a radiation-induced cancer later in life, even if the scattered dose is relatively small e. The fetus probably received less than 0.01 cGy, so no remedial action is necessary

d. The fetus will be at an increased risk for the development of a radiation-induced cancer later in life, even if the scattered dose is relatively small Prenatal irradiation puts individuals at a dose-dependent, increased risk for the development of a radiation-induced cancer at some time later in life. The woman should not be advised to discontinue treatment until reaching term, as the scattered dose to her fetus is likely small. Her personal risk in delaying therapy, while her cancer continues to progress, would effectively present a much greater concern. In addition to carcinogenesis, the fetus would also be at (an even higher) risk for radiation-induced congenital abnormalities, because irradiation took place during the first trimester of pregnancy when most of the organs are undergoing active development. The scattered dose to the fetus would certainly not be large enough to result in death and miscarriage or stillbirth, however it is likely greater than 0.01 cGy. 0-2 weeks loss of pregnancy 2-6 weeks congenital malformations OR perinatal death if they now lack a critical organ 8-15 weeks Microcephaly - 0.1-0.2 Gy increases risk Mental retardation 4x more common if in this range - 40% risk increase per Gy beyond 16 weeks short stature increased carcinogenesis Between 2-28 weeks, recommended to discuss termination at exposures of 0.1 Gy or more. Generally -- small heads, shorter babies, lighter birth weight, higher risk of congenital abnormalities (if 2-6 week esp)

Immune related adverse events (irAEs) describe a range of immune-mediated toxicities that can result from treatment with immune checkpoint inhibitors. Which statement regarding irAEs is NOT correct: a. Skin, gut, endocrine, lung and musculoskeletal irAEs are relatively common, whereas cardiovascular, hematologic, renal, neurologic and ophthalmologic irAEs occur much less frequently b. irAEs typically have a delayed onset and prolonged duration compared to adverse events from chemotherapy c. irAEs are discrete toxicities caused by tissue-specific inflammation and activation of the immune system, and can affect almost any organ system d. The overall incidence of irAEs following treatment with anti-CTLA-4 monotherapy tends to be lower than those with anti-PD-1/PD-L1 agents e. The incidence of irAEs with ipilimumab and pembrolizumab is dose-dependent, with greater toxicity at higher dose levels

d. The overall incidence of irAEs following treatment with anti-CTLA-4 monotherapy tends to be lower than those with anti-PD-1/PD-L1 agents Most common toxicities from targeting immune checkpoints relate to breaking tolerance. Targeting of PD-1 or PD-L1 tends to be less toxic than CTLA-4 on average, presumably because they regulate different components in the evolution of an immune response. The cytotoxic T lymphocyte-associated antigen 4 (CTLA4)-mediated immune checkpoint is induced in T cells at the time of their initial response to antigen. The level of CTLA4 induction depends on the amplitude of the initial T cell receptor (TCR)-mediated signaling. High-affinity ligands induce higher levels of CTLA4, which dampens the amplitude of the initial response. The key to the regulation of T cell activation levels by the CD28-CTLA4 system is the timing of surface expression. Naive and memory T cells express high levels of cell surface CD28 but do not express CTLA4 on their surface. Instead, CTLA4 is sequestered in intracellular vesicles. After the TCR is triggered by antigen encounter, CTLA4 is transported to the cell surface. The stronger the stimulation through the TCR (and CD28), the greater the amount of CTLA4 that is deposited on the T cell surface. Therefore, CTLA4 functions as a signal dampener to maintain a consistent level of T cell activation in the face of widely varying concentrations and affinities of ligand for the TCR. By contrast, the major role of the programmed cell death protein 1 (PD-1) pathway is not at the initial T cell activation stage but rather to regulate inflammatory responses in tissues by effector T cells recognizing antigen in peripheral tissues. Activated T cells upregulate PD-1 and continue to express it in tissues. Inflammatory signals in the tissues induce the expression of PD-1 ligands, which downregulate the activity of T cells and thus limit collateral tissue damage in response to a microorganism infection in that tissue. The best characterized signal for PD-1 ligand 1 (PD-L1; also known as B7 H1) induction is IFNg, which is predominantly produced by T helper 1 (TH1) cells, although many of the signals have not yet been defined completely. Excessive induction of PD-1 on T cells in the setting of chronic antigen exposure can induce an exhaustive or anergic state.

Which of the following statements is TRUE concerning the DAHANCA trial testing the effectiveness of nimorazole with radiotherapy for the treatment of supraglottic and pharyngeal tumors? a. Nimorazole radiosensitizes through depletion of natural sulfhydryl compounds present in the cell b. No significant improvement was noted with respect to either loco-regional tumor control or disease- free survival c. Nimorazole has greater radiosensitizing efficiency than other compounds in its chemical class d. The toxicity produced by nimorazole was relatively mild. e. Due to the negative results, the authors of this trial concluded that nimorazole has no role in the treatment of head and neck cancers

d. The toxicity produced by nimorazole was relatively mild. The DAHANCA trial of nimorazole reported that this 5-nitroimadazole hypoxic cell radiosensitizer can be delivered without serious, dose-limiting side effects. Because nimorazole has its NO2 group at the 5 rather than the 2 position on the imidazole ring, it is a less efficient radiosensitizer than either misonidazole or etanidazole. Loco-regional failure and disease-specific mortality were more frequent in patients assigned to the radiation plus placebo arm of the trial than for those patients given radiation plus nimorazole. Thus, it was the recommendation of the authors of this study that nimorazole should be used routinely in the treatment of these types of head and neck cancer.

Within 4 days of an accidental whole body radiation exposure at a nuclear power plant, 8 workers develop severe diarrhea. Assuming that 3 of the workers are female and 5 male, what is their likely prognosis? a. All will live, but will likely develop radiation-induced cancers. b. Approximately 50% will survive. c. All will live, but with an increased risk of cataracts. d. They will all die in less than a month following the irradiation. e. The men will be sterilized, but the women will remain fertile.

d. They will all die in less than a month following the irradiation A whole body dose that results in severe diarrhea within 4 days of irradiation is likely to be lethal (probably 8 Sv or higher). Therefore, all of the people would be expected to die within 1-2 weeks following irradiation due to GI syndrome. Diarrhea rare if dose <6 Gy 6-8 Gy causes diarrhea in 6-9 days >8 Gy causes diarrhea in 4-5 days Diarrhea w/in a week = maybe survivable, need transplant Diarrhea in 4-5 days = you gonna die boy

Nanoparticle-mediated hyperthermia sensitizes tumors to radiation therapy via: a. Decreased perfusion of tumors and resultant increase in necrosis b. Vascular disruption and resultant increase in hypoxia c. Induction of epithelial-to-mesenchymal transition d. Tumor stem cell sensitization e. Increased glucose delivery and increased cellular metabolism

d. Tumor stem cell sensitization Hyperthermia using gold nanoshells results in preferential sensitization of tumor stem cells.

Which of the following statements is correct? Radioactive microsphere therapy: a. Uses radioactive iron nanospheres to improve thermal dose distribution in tumors b. Uses α-particle emitters to radiolabel antibodies against HIF in hypoxic tumors c. Uses positron emitters to label to radiolabel antibodies against the CD20 antigen d. Uses encapsulated yttrium-90 to deliver very high radiation doses to hepatic tumors e. Uses encapsulated iodine-131 to deliver very high radiation doses to hepatic tumors

d. Uses encapsulated yttrium-90 to deliver very high radiation doses to hepatic tumors The transarterial administration of yttrium-90 microspheres is U.S. Food and Drug Administration-approved liver-directed cancer therapy. Yttrium-90 is pure high-energy (~ 1 MeV) beta emitter with an average range of penetration of 2.5 mm in tissue. Iodine-131 is a mixed-spectrum emitter, 10% of radiation dose is via gamma decay and the other 90% of radiation dose is via beta decay. Iodine-131 is the most commonly used gamma-emitting industrial tracer. Non-radioactive iron (oxide) nanospheres and nanocubes have been proposed for magnetic field-induced hyperthermia.

What best describes the use of whole exome sequencing (WES) versus genome-wide association (GWAS) studies? a. GWAS is based on sequencing the entire genome while WES looks at the non-coding regions of genes. b. WES quantifies and sequences mRNAs levels post splicing while GWAS captures disease-specific mRNA prior to splicing. c. WES forms a part of GWAS. WES determines the mutations in coding regions of genes which then get aligned with GWAS data on the intron mutations. d. WES is a next-generation sequencing test that looks at the coding regions of genes while GWAS is used to identify genetic loci with phenotypic traits.

d. WES is a next-generation sequencing test that looks at the coding regions of genes while GWAS is used to identify genetic loci with phenotypic traits. Whole exome sequencing (WES), is a genomic technique for sequencing all of the protein-coding regions of genes in a genome (known as the exome, about 1.5% of all DNA). The term exon was derived from "EXpressed regiON," since these are the regions that get translated, or expressed as proteins, as opposed to the intron, or "INTRagenic regiON" which is not represented in the final protein. It generally involves two steps: selection of the protein coding region on the DNA prior to sequencing using any high-throughput DNA sequencing technology. Exome sequencing is a good choice for scientists today who are looking for rare mutations, especially when used as a complement to studies of common variation like GWAS. GWAS (whole genome association study) captures a genome-wide set of genetic variants in different individuals to see if any variant is associated with a trait. They typically focus on associations between single-nucleotide polymorphisms (SNPs) and traits like major human diseases. The entire genome is being probed, in contrast to methods that specifically test a small number of pre-specified genetic regions.

The oxygen enhancement ratio is: a. equal to the survival of cells irradiated under hypoxic conditions divided by the survival under aerobic conditions for a fixed radiation dose b. greater at low radiation doses than at high radiation doses c. the same regardless of radiation quality (LET) d. equal to the dose of radiation under hypoxic conditions divided by the dose of radiation under aerobic conditions that results in the same biological effect e. equal to the survival of cells irradiated under aerobic conditions divided by the survival under hypoxic conditions for a fixed dose

d. equal to the dose of radiation under hypoxic conditions divided by the dose of radiation under aerobic conditions that results in the same biological effect remember, RBE and OER are DOSE ratios

Which of the following statements is FALSE? a. RAS stimulates the MAPK pathway b. CDK1/cyclin B constitute the mitosis promoting factor (MPF) c. The first oncogene discovered was in a retrovirus (Rous sarcoma virus) d. p21 (CDKN1A) levels decrease in irradiated cells e. ATM acts upstream of p53

d. p21 (CDKN1A) levels decrease in irradiated cells p21 levels increase in irradiated cells. Also interesting point that CDK1/cyclin B constitute the mitosis promoting factor (MPF)

For a particular cell line characterized by a D0 of 1 Gy and n equal to 1, what would be the approximate percentage of cells killed by a dose of 3 Gy? a. 5 b. 10 c. 37 d. 50 e. 95

e = 95% killed, 5% survival Critical to recognize this. If they tell you n = 1, you automatically know that there is NO SLDR and that there is no quazi-threshold dose to reach the exponential portion of the curve. You can prove this by doing ln (n) = dq/d0 --> dq = 0. This means that you are dealing with an entirely linear curve (log-lin) that is mathematically modeled by S = e^-aD or e^-D/effD0 So you can simply say if D0 = 1 gy, D10 = 2.3 Gy. So just qualitatively you now that 3 gy will give you more than a log of cell kill -- 90% killed, 10% out of 100% survived. So that means e is the only possible answer. Alternatively, you can use the formulas above: S = e^-(3/1) --> S= 0.05.

A treatment prescription of 72 Gy delivered in 2 Gy fractions is changed to deliver 3 Gy fractions, with the total dose adjusted accordingly so that the new prescription would be isoeffective with respect to late complications in a normal tissue characterized by an /ratio of 2 Gy. If the /ratio for the tumor is 10 Gy, what is the approximate change in biologically effective dose to the tumor, assuming no change in overall treatment time? a. +14% b. +7% c. 0 d. -7% e. -14%

e. -14% E The BED equation that can be used for this problem is BED = nd[1+d/(/)], where n is the number of fractions and d is the dose per fraction. (It is not necessary to correct for either tumor cell proliferation, since the regimens are specified as having the same overall treatment time, or incomplete repair, since these are both once-per-day treatments.) Thus, the late effects BED associated with the use of 2 Gy fractions is (36)(2 Gy)(1+2 Gy/2 Gy) = 144 Gy2. Since it is indicated that the new treatment schedule is isoeffective with respect to late effects, then the BED for the second protocol will also be 144 Gy2. The number of 3 Gy fractions to use can be calculated using 144 Gy2 = n(3 Gy)(1+ 3 Gy/2 Gy) = 7.5n or n = 19 fractions. The tumor BED for the first schedule is (36)(2 Gy)(1+2 Gy/10 Gy) = 86 Gy10. The BED for the second protocol is (19)(3 Gy)(1+3 Gy/10 Gy) = 74 Gy10. Thus, there is a decrease of 12 Gy10 for the second compared with the first protocol, or a [(86 Gy10 - 74 Gy10)/86 Gy10] (100%) = 14% decrease. An alternative method to compute the answer to this problem is to use the biologically equivalent in 2 Gy fractions dose (EQD2), which is EQD2 = D[(d+/)/(2 Gy+/)]) where D is the total dose and d is the dose per fraction. Thus, the EQD2 for the standard 2 Gy protocol is (72 Gy)[(2 Gy+ 2 Gy)/(2 Gy +2 Gy) = 72 Gy (clearly, the EQD2 equals D for all protocols involving a fraction size of 2 Gy). Since it is indicated that the new treatment schedule is isoeffective with respect to late effects, then the EQD2 for the second protocol will be 72 Gy. With /= 2 Gy for late effects, the total dose (D) to use in 3 Gy fractions can be calculated using 72 Gy = D(3 Gy+ 2 Gy)/(2 Gy+ 2 Gy) = 1.25D or D = 57.6 Gy. For the nearest integral number of 3 Gy fractions (19), this is a total dose of 57 Gy. With / = 10 Gy for tumor, the tumor EQD2 for the second protocol is (57 Gy)[(3 Gy + 10 Gy)/(2 Gy+ 10 Gy)] = 61.75 Gy. Thus, there is a decrease in EQD2 of 10.25 Gy for the new treatment compared with the standard protocol which had an EQD2 of 72 Gy (once again, the EQD2 is equal to D for all 2 Gy protocols) or a [10.25 Gy/72 Gy] (100%) = 14% decrease. Note, it is critical to recognize the distinction between the BED (biologically effective dose) and the EQD2 (biologically equivalent dose in 2 Gy fractions), which has also been referred to as the NTD (normalized total dose) or the LQED (linear quadratic equivalent dose). A loss of this distinction can result in miscalculations that may lead to crucial errors in treatment dose calculations.

The X-ray survival curve for a particular cell line is characterized by a= 0.4 Gy-1 and b= 0.2 Gy-2. What is the dose at which the amount of single-hit cell killing equals the amount of multi-hit cell killing? a. 0.08 Gy b. 0.16 Gy c. 0.4 Gy d. 0.6 Gy e. 2 Gy

e. 2 Gy definition of the ab ratio

A tumor contains 10^6 clonogenic cells. Its effective dose response curve has been determined for dose fractions of 2 Gy/day, and is characterized by no shoulder and a D0 of 2.5 Gy. What is the total dose required to give a 37% chance of tumor cure, assuming sufficient time between fractions to allow full repair of sublethal damage and no cell proliferation between doses? a. 5 Gy b. 14 Gy c. 21 Gy d. 28 Gy e. 35 Gy

e. 35 Gy In order to achieve a 37% tumor control probability, the total dose delivered must reduce the number of surviving clonogenic cells to an average of 1. This is based on the equation P = e-(M)(SF), where P is the probability of tumor cure (37% or 0.37 in this case), M is the initial number of tumor clonogens (10^6), and SF is the surviving fraction resulting from the irradiation protocol. Thus, for 10^6 clonogenic cells, a total dose that reduces the surviving fraction to 10^-6 (i.e., 1 surviving clonogen) must be used to achieve a 37% control rate. Since the survival curve is exponential with a D10 of 5.75 Gy (D10, = D0 X ln 10 = 2.5 X 2.3 = 5.75 Gy) it would be necessary to use a dose of 34.5 Gy.

For conventional fractionation, the tolerance dose for a particular normal tissue complication is found to be 30 Gy. If a patient is treated with a drug that has a dose reduction factor of 1.3, then the new tolerance dose for this tissue should be roughly: a. 23 Gy b. 30 Gy c. 33 Gy d. 36 Gy e. 39 Gy

e. 39 Gy The dose reduction factor (DRF) is a parameter used to measure the effectiveness of a radioprotector. DRF = (the dose to produce a certain effect in the presence of a radioprotector)/(the dose to produce the same effect in the absence of the protector). Thus, 1.3 = x/30 Gy, so x = 39 Gy.

The TCD90 for a series of 0.1 cm diameter tumors receiving fractionated radiotherapy in 1.8 Gy daily fractions was determined to be 56 Gy. Assuming that the tumors each contained 10^6 clonogenic cells, what dose would be necessary to maintain the 90% control rate if the tumors were allowed to continue growing until they reached a 1 cm diameter? (Assume that the growth fraction remained constant during the course of treatment.) a. 48 Gy b. 56 Gy c. 64 Gy d. 71 Gy e. 80 Gy

e. 80 Gy To produce a TCD90 for a series of tumors containing 10^6 clonogenic cells would require a total dose that would reduce the surviving fraction to 10^-7. Since 56 Gy produced this level of control, the D10 for these cells must be approximately 56 Gy/7 logs = 8 Gy. The relative increase in the number of clonogens resulting from an increase in tumor diameter from 0.1 cm to 1 cm is (1/0.1)^3 = 10^3, so the number of cells would increase from 10^6 to 10^9. To produce 90% control, would require 8 Gy x 10 logs = 80 Gy. Depending on the normal tissue(s) of concern in the radiation field, its tolerance dose, and how much of its volume would need to be irradiated, delivering a total dose of 80 Gy may or may not be feasible. Can also use the D10 = 8 Gy to say the D0 = 8 Gy/2.3 = 3.47 if you know the effD0 you can calculate the dose needed to reduce 1000 extra cells: # of cells to reduce = e^(D/effD0) D = 24 Gy. total dose = 56 + 24 Gy = 80 Gy

Amifostine selectively radioprotects normal tissue by which mechanism(s)? a. Scavenging free radicals b. Selective uptake in normal tissues compared to tumor tissues c. Reduction of oxygen tension in normal tissues d. Stabilizing oxygenated hemoglobin e. A and B

e. A and B Amifostine is a sulfhydryl compound that scavenges free radicals. It also concentrated more rapidly by normal tissues compared to tumor. Although amifostine may cause hypotension, there is no evidence that this contributes to its selectivity. Amifostine has no known impact on hemoglobin.

Which of the following immune mediated mechanisms facilitates cancer prevention? a. Detection and elimination of tumor cells b. Allergic responses c. Prevention of chronic inflammation d. Protection against viral infection and integration e. A, C and D

e. A, C and D

What is the most correct mechanism by which the HIV protease inhibitor nelfinavir may result in radiosensitization? a. Enhance the effect of ionizing radiation on endothelial cell function b. Downregulate VEGF expression in tumor cells via hypoxia-inducible factor 1α c. Inhibition of the PI3K-AKT-mTOR pathway d. Activation of the unfolded protein response e. All of the above

e. All of the above

Which of the following pathways has been linked to radiation fibrosis? a. TGF-beta signaling b. PDGF signaling c. Reactive oxygen species d. Angiontensin signaling e. All of the above

e. All of the above All of these pathways have been implicated in the initiation or perpetuation of radiation fibrosis. TGF-beta is well described as a mediator of radiation fibrosis through downstream signaling and is often considered a drive of the fibrotic process. Reactive oxygen species generated at the time of irradiation and by infiltrating immune cells are also thought to contribute to the perpetuation of injury and can further activate TGF-beta signaling. PDGF has been implicated as a mitogenic signal from multiple cell types that can initiate collagen and extracellular matrix production by myofibroblasts.

Which of the following growth factors appear to play a role in radiation -induced lung fibrosis? a. Transforming growth factor-beta (TGFb1) b. Basic fibroblast growth factor (bFGF or FGF2) c. Connective tissue growth factor (CTGF) d. Platelet derived growth factor (PDGF) e. All of the above

e. All of the above TGFb, bFGF, CTGF and PDGF all appear to play a role in radiation- induced lung fibrosis. Key with these is that they try to bait you into picking tgfb1 as a knee jerk -- look for these other option tho because these other major growth factors are also involved and usually the answer is all of the above

Enzalutamide is an FDA approved agent for metastatic castration resistant prostate cancer. Clinical trials utilizing this promising agent with radiation therapy are due to commence. What is the mechanism of action of Enzalutamide? a. Inhibits 17 α-hydroxylase/C17,20 lyase (CYP17A1), an enzyme which is expressed in testicular, adrenal, and prostatic tumor tissues b. Inhibits the ligand for osteoprotegerin and functions as a key factor for osteoclast differentiation and activation c. Luteinizing hormone releasing hormone (LHRH) agonist d. Bone seeking alpha-particle emitter e. Androgen receptor antagonist drug

e. Androgen receptor antagonist drug

Herceptin (trastuzumab) is a: a. mTOR/FRAP inhibitor b. FLT-3 inhibitor c. siRNA that targets ATM d. Inhibitor of RAS e. Anti-HER2 antibody

e. Anti-HER2 antibody Herceptin is an anti-HER2 antibody. An example of a mTOR/FRAP inhibitor is Rapamycin, which inhibits translation initiation. Activating mutations of FMS-like tyrosine kinase 3 (FLT3) are present in approximately 30% of patients with de novo acute myeloid leukemia (AML) and are associated with lower cure rates from standard chemotherapy-based treatment. Targeting the mutation by inhibiting the tyrosine kinase activity of FLT3 is cytotoxic to cell lines and primary AML cells harboring FLT3 mutations. An example of FLT3 inhibitor is CEP- 701. RAS mutations may result in constitutive activation of the RAS/RAF/MEK/ERK kinase signaling pathway, and have been found to occur frequently in human tumors. Multiple kinase inhibitors of this pathway are being evaluated.

Which of the following statements concerning late radiation effects in the brain is FALSE? a. The classical late radiation effect in the brain is localized necrosis generally limited to the involved white matter, with focal coagulative necrosis and demyelination as dominant features b. Symptoms of late radiation effects include motor, sensory and/or speech/receptive deficits, seizures and symptoms of increased intracranial pressure c. The "somnolence syndrome" is observed 1-6 months post-irradiation d. During the 3-6 month period following completion of RT, a general neurologic deterioration may occur that results from transient, diffuse demyelination e. Arterial cerebrovasculopathy is commonly observed

e. Arterial cerebrovasculopathy is commonly observed Arterial cerebrovasculopathy is an infrequent, not common, occurrence.

The transcriptional activity of the tumor suppressor p53 has been shown to be regulated by all of the following, EXCEPT: a. Phosphorylation of p53 (TP53) by ATM b. Changes in the subcellular localization of p53 c. Changes in the ubiquitination of MDM2 d. p19ARF-induced changes in acetylation of p53 e. Binding of FAS ligand (FASLG/CD95-L) to FAS (CD95/APO-1)

e. Binding of FAS ligand (FASLG/CD95-L) to FAS (CD95/APO-1) All of the processes listed, except binding of FAS ligand to FAS receptor on the plasma membrane, have been associated with p53 activation. Binding of FAS ligand to FAS receptor activates the extrinsic pathway to apoptosis, which does not appear to involve p53. Note: p19ARF in mice = p14ARF in humans

Which of the following drugs is used clinically as a radiosensitizer of cancer cells? a. Curcumin b. Ciprofloxacin c. Amifostine d. Neomycin e. Cisplatin

e. Cisplatin Cisplatin has a substantial amount of laboratory- and clinical-based evidence supporting its action as a radiosensitizing chemotherapeutic in tumor cells. Curcumin has been shown to reduce DNA damage-induced foci formation by certain DSB repair genes, although further studies are needed. Amifostine is thought to act as a radioprotector although its true clinical efficacy has been questioned recently and thus is controversial. Neomycin and ciprofloxacin are not thought to have radiosensitizing effects.

A young woman is concerned about ovarian irradiation secondary to a screening mammogram she had received with respect to possible deleterious effects on her future offspring. The radiologist should inform her that: a. Transient changes in hormonal balance will likely result from the ovarian dose received during mammography, but these should not affect future offspring b. Mature ova are highly radiosensitive and those present at the time of irradiation were probably killed, so future offspring cannot be affected c. Her ovaries received no scattered dose from screening mammography d. Her ovaries received the equivalent of a genetic doubling dose for mutations e. Effects on possible future offspring cannot be excluded but are highly unlikely

e. Effects on possible future offspring cannot be excluded but are highly unlikely The dose to the breasts associated with a screening mammogram is on the order of 10 mSv, with the scattered dose to the ovaries being only a small fraction of this dose. The estimated risk for a mutation being produced in the child of an irradiated individual is only about 0.2% per Sv, so the probability that this woman's future children would inherit a radiation-induced mutation is very small. For this low a dose, no hormonal effects would be expected and no ova should be killed. It would be incorrect to tell the woman that her ovaries received no dose since there would always be some amount of scattered radiation, although the total dose received would be extremely low. The dose to her ovaries would be far lower than the estimated 1-2 Sv assumed to be the approximate "genetic doubling dose" for humans. The doubling dose is the dose that doubles the spontaneous incidence of mutations among offspring of irradiated parents.

Which one of the statements regarding fast neutron beam therapy is TRUE: a. Fast neutron beam energies range between 500 to 700 MeV b. Fast neutron beams have lower LET (Linear Energy Transfer) compared to photon beams c. Fast neutron beams have an RBE (relative biological equivalent) of approximately 250 d. Fast neutron beams create DNA damage primarily via Compton Effect e. Fast neutron beams are associated with a low oxygen enhancement ratio

e. Fast neutron beams are associated with a low oxygen enhancement ratio Fast neutron beam energies are typically 50 - 70 MeV. Fast neutron beams have a higher LET compared to photons. RBE of fast neutron beams are typically 2-20. Photons create DNA damage via Compton Effect. Fast neutrons, as well as other charged particles, are associated with low oxygen enhancement ratio.

The prostate-specific membrane antigen (PSMA) is a promising, well-characterized biomarker of prostate cancer. Newer agents such as N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-fluorobenzyl-L-cysteine (DCFBC) is a low-molecular-weight, urea-based inhibitor of PSMA. What statement best describes the principles that make 18F-DCFBC a better molecular tracer than 111In-Capromab Pendetide (ProstaScint™)? a. Slower tumor penetration and blood-pool clearance b. Faster tumor penetration and slower blood-pool clearance c. Higher sensitivity with high-volume disease d. Better specificity with high-volume disease e. Inherent limitations of SPECT versus PET imaging

e. Inherent limitations of SPECT versus PET imaging The prostate-specific membrane antigen (PSMA) is a promising, well-characterized biomarker of prostate cancer and is associated with tumor aggressiveness. Histologic studies have associated high PSMA expression with metastasis, androgen independence, and progression. Low molecular weight molecules have inherent advantages over antibodies, such as rapid tumor uptake and clearance from nontarget sites. Many low-molecular-weight inhibitors of PSMA are in development including DCFBC. 18F-DCFBC PET/CT may be superior molecular imaging of prostate cancer versus 111In-Capromab Pendetide for several reasons. As a druglike molecule, it should have rapid and high tumor penetration along with rapid blood-pool clearance, compared with radiolabeled antibodies, allowing for higher tumor-to- background ratios. It targets a more accessible, external binding domain of PSMA, rather than an intracellular domain. Additionally, PET allows for higher resolution and is highly amenable to quantification in contrast to SPECT, and the relatively long (110 min) physical half-life of 18F enables regional clinical distribution (23590171). Answer "e" is correct. The other answers describe characteristics of an imaging agent that are not ideal for a highly efficacious molecular imaging agent.

All of the following are properties of cancer stem cells, EXCEPT: a. Self-renewal capacity b. Tumorigenicity c. Pluripotency d. Relative chemoresistancy e. Involved in tumor regression

e. Involved in tumor regression

Which of the following radiation-induced effects could be a cause of death one year after total body irradiation of a patient being prepared for a bone marrow transplant? a. Hematopoietic syndrome b. Gastrointestinal syndrome c. Cerebrovascular syndrome d. Brain necrosis e. Lung fibrosis

e. Lung fibrosis A person who dies one year following total body irradiation would not die from any of the conventional whole-body radiation syndromes. These syndromes cause death at about 1-2 days (cerebrovascular), 1-2 weeks (gastrointestinal) or 1-2 months (hematopoietic), respectively, following irradiation. Since the dose received was not sufficiently high to cause death from the GI syndrome (i.e., at least 8 Sv), it would likewise not be high enough to cause brain necrosis. However, the treatment dose may have been high enough to cause lung fibrosis, which may result in death, within one year after irradiation.

Tumor-bearing mice are randomized into a control group and groups treated with localized irradiation of the tumor alone, an anticancer drug alone, or radiation in combination with the drug. Which of the following represents the most rigorous, reliable and informative approach to comparing the effectiveness of the different treatments? a. Killing the mice at a predetermined time after treatment, removing and weighing the tumors, and calculating the ratio of the volumes of the treated and control tumors b. Measuring three diameters of the tumors with calipers at a predetermined time after treatment, calculating the volume and computing the ratio of the volumes of the treated and control tumors c. Measuring the tumors 3x per week until the treated tumors return to their pre-irradiation volume and calculating the mean time needed for each group to reach that volume d. Measuring the tumors 3x per week until the control tumors reach 4 times the volume at the time of treatment, and comparing the mean volume of the tumors in each treatment group at that time e. Measuring the tumors 3x per week until each tumor reaches 4 times the volume at the time of treatment and calculating the mean time needed for the tumors in each group to reach that volume

e. Measuring the tumors 3x per week until each tumor reaches 4 times the volume at the time of treatment and calculating the mean time needed for the tumors in each group to reach that volume The tumor regrowth delay assay measures the average time necessary for a treated tumor to reach a pre-determined size compared to the time it takes for control tumors. Of the assays listed, the tumor regrowth assay is most informative as to the effect of radiation and/or drug treatment.

Which of the following pairs of chemotherapeutic agents and their mechanism of action is FALSE? a. Chlorambucil - DNA alkylator b. Gleevec - tyrosine kinase inhibitor c. Etoposide - topoisomerase II poison d. Doxyrubicin - DNA intercalator e. Methotrexate - thymidylate synthase inhibitor

e. Methotrexate - thymidylate synthase inhibitor MTX is a dihydrofolate reductase inhibitor Methotrexate is a competitive inhibitor of dihydrofolate reductase (DHFR) and thus prevents the formation of reduced folate. Reduced folate is required for transfer of methyl groups in the biosynthesis of purines and in the conversion of deoxyuridine monophosphate (dUMP) to thymidine monophosphate (dTMP). Reduced folate becomes oxidized to folic acid in this reaction and its regeneration is dependent on DHFR for reduction to its active form.

Which of the following statements about tumor mutational signatures is true? a. Each tumor contains a single mutational signature b. Each cancer cell contains a single mutational signature c. Mutational signatures are specific to the tissue of origin d. Mutational signatures are constant across time e. Mutational signatures are caused by specific mutational and DNA repair processes

e. Mutational signatures are caused by specific mutational and DNA repair processes Mutational signatures are defined as specific patterns of alterations in DNA bases. This analysis takes into account the alteration of a specific base as well as the base context on the 5' and 3' ends (i.e., the base's immediate neighbors). While many other types of DNA alterations occur in cancer, including but not limited to insertions, deletions, and translocations, mutational signatures refer only to point mutations. While point mutations are randomly distributed throughout the genome, the likelihood of any one specific base to be mutated is heavily dependent on the chemistry of the base itself and its immediate neighbors. This is influenced by 1.) the specific mutagen, and 2.) the DNA damage repair processes at work. There are currently approximately 30 identified mutational signatures, including aging, smoking, APOBEC, mismatch repair deficiency, and UV. Practically, understanding mutational signatures will allow researchers to determine the specific underlying cause(s) of a patient's cancer.

Which of the following may increase a patient's chance to experience an immune related adverse event? a. History of autoimmune disease b. Previous use of checkpoint blockade therapy c. Previous radiation therapy d. All of the above e. None of the above

e. None of the above No explanation. Seems weird.

Which technique would best be used to investigate gene expression? a. Western blot b. EMSA c. Southern blot d. DNase I footprinting e. Northern blot

e. Northern blot A Northern blot, in which RNA is subjected to gel electrophoresis and screened with a probe for a particular RNA transcript, would best be used to study the expression of a particular gene. A Western blot is used to detect the presence of a particular protein, using an antibody to detect it. The electrophoretic mobility gel shift assay, or EMSA, is used to map transcription factor binding sites in the regulatory portions of genes, and is based on the reduced electrophoretic mobility of a DNA-protein complex compared to unbound DNA. For a Southern blot, DNA is cut with a restriction enzyme and then separated with gel electrophoresis. The DNA fragments are transferred onto a membrane and probed for a particular DNA sequence. DNAase I footprinting is used to identify a protein binding site in DNA.

Which one of the following is a tumor suppressor gene? a. NEU b. RET c. BRAF d. RAS e. PTEN

e. PTEN PTEN is a tumor suppressor gene. It converts phosphatidylinositol (3,4,5)-triphosphate (PI(3,4,5)P3 into phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P2, which directly counteracts the action of PI3K in converting PI(4,5)P2 into PI(3,4,5)P3. NEU, also known as HER2, is a member of the EGFR family. RET is a receptor tyrosine kinase and is mutated in multiple endocrine neoplasias type 2A and 2B. RAS is a family of key proto-oncogenes with at least 32 members involved in many cancers. They are all classified as small GTPases and are mutated in approximately 25% of all human cancers. The most well-known family members are HRAS, KRAS, and NRAS. BRAF, one of 3 RAF genes, is a proto-oncogene that acts downstream of RAS and upstream of ERK.

A new biological response modifier will be of value in combination with radiotherapy only if it: a. Acts synergistically with radiation on the cellular level b. Selectively modulates the radiation response of proliferating cells c. Selectively modulates the radiation response of the vasculature d. Has minimal cytotoxicity to cells in normal tissues e. Produces a therapeutic gain

e. Produces a therapeutic gain -- could be said improves the therapeutic ratio (D would be correct if they also specified that it increases killing in tumor cells) The critical factor in determining whether a new agent will be clinically valuable when combined with radiation is whether it produces a therapeutic gain, that is, it increases tumor toxicity or reduces normal tissue toxicity without a commensurate increase or decrease, respectively, in the other tissue. Synergy with radiation will not produce a therapeutic gain if it occurs equally in both tumor and critical normal tissues. A therapeutic gain will not be produced unless the proliferation in tumors and critical normal tissues show significant differences that result in the modulator producing a selective increase in the radiation response of the tumor. A therapeutic gain cannot be achieved unless the vasculature in tumors and critical normal tissues show differences that result in the modulator producing a selective increase in the radiation response of the tumor. The cytotoxicity of most biological response modulators is minimal and manageable; their efficacy as cancer treatments result primarily from their ability to modulate radiation sensitivity. Minimal normal tissue toxicity alone does not necessarily lead to a therapeutic gain; in fact, a therapeutic gain can be obtained despite significant toxicity in normal tissue, provided the relative cytotoxic effect is greater in the tumor.

Cisplatin causes cell lethality due to: a. Microtubule depolymerization b. Inhibition of thymidylate synthase c. Inhibition of ribonucleotide reductase d. The formation of cyclobutyl bonds between adjacent bases e. Production of DNA crosslinks

e. Production of DNA crosslinks Cisplatin causes cellular lethality due to the formation of crosslinks between the two DNA strands. This prevents normal DNA synthesis.

Which of the following statements concerning methods to produce local tumor heating is FALSE? a. Microwaves produce uniform temperature distributions at shallow depths, but treatment of more deeply-seated tumors leads to hotspots on the body surface that can limit treatment b. The presence of bone or air cavities during ultrasound heating compromises thermal dosimetry c. Uniform temperature distributions may be achieved in soft tissues through use of ultrasound for heating d. For readily accessible tumors, the use of implanted microwave or radio-frequency sources results in good temperature distributions e. Radiofrequency ablation combined with radiotherapy produces radiosensitization

e. Radiofrequency ablation combined with radiotherapy produces radiosensitization Radiofrequency ablation is accomplished by inserting a RF probe into or near a tumor mass, and then heating it to temperatures that produce frank tissue necrosis. RF ablation is typically used singly, not simultaneously with radiation therapy.

A DNA ligase: a. Performs the resynthesis step of nucleotide excision repair b. Is responsible for the initial step in non-homologous end joining of DNA double strand breaks c. Recognizes a particular type of DNA damage and produces single strand breaks on either side of the damaged nucleotide d. Recognizes and removes a damaged base from DNA e. Rejoins simple strand breaks

e. Rejoins simple strand breaks A DNA ligase rejoins simple strand breaks. A DNA polymerase performs the resynthesis step during nucleotide excision repair. DNA ligase IV plays an important role in the final step of non-homologous end joining repair of DNA double strand breaks. During nucleotide excision repair, DNA endonuclease recognizes a particular type of damage and produces single strand cuts on either side of the damaged nucleotide to remove it. An AP endonuclease recognizes and removes a damaged base from DNA as an initial step in base excision repair.

Which of the following statements is TRUE concerning a female worker at a radioactive waste reprocessing facility who accidentally receives an estimated 3 Gy acute whole body g-ray dose? a. Antibiotic treatment should not be initiated until signs of infection. b. Tissue typing should be done for a possible bone marrow transplant. c. Within one week she will become dehydrated, suffer infections, develop bloody diarrhea and likely die. d. She should be sent home and advised to schedule an appointment with a physician about 6 months later, as this represents the minimum latency period prior to the manifestation of radiation injury. e. She should be monitored carefully to watch for symptoms of infection

e. She should be monitored carefully to watch for symptoms of infection A person exposed to 3 Gy of g-rays should be carefully watched for symptoms of infection and hemorrhage resulting from loss of white blood cells and platelets, with the critical period being 2-4 weeks following irradiation. Prophylactic administration of antibiotics should be initiated immediately following the accident, rather than waiting for overt signs of infection. A bone marrow transplant would likely be of no value at this dose, so tissue typing is not necessary, since use of antibiotics and transfusion of blood components, as necessary, would substantially enhance the probability for survival without the use of a transplant. The dose the worker received was too low for her to develop symptoms of the GI syndrome, which include dehydration and bloody diarrhea, likely culminating in death. If the dose received was less than 2 Gy, it would be reasonable to be monitored from home, but following a dose of 3 Gy a person should be hospitalized in reverse air flow isolation with supportive care, including antibiotic administration immediately.

Which of the following pairs of radiation are BOTH high LET and have a Bragg peak? a. Gamma rays and X-rays b. P+ and C-ions c. Neutrons and C-ions d. Neon ions and neutrons e. Si ions and C-ions

e. Si ions and C-ions Gamma-rays and X-rays are low LET and have no Bragg peaks. p+ and C-ions both have Bragg peaks, but p+ are low LET. Neutrons and C-ions are high LET, but neutrons do not have a Bragg peak. Neon ions and neutrons are both high LET, Neon ions have a Bragg peak, but neutrons do not. Both Si and C are high LET and have Bragg peaks.

Which of the following ions (or particles) have optimal OER and RBE values for radiation therapy? a. Hydrogen b. Helium c. Carbon d. Neutron e. Silicon

e. Silicon Based on historic in vitro and in vivo data, therapeutic energy silicon ions have the highest RBE of ~ 3.5 and the lowest OER of ~ 1.5, and neutrons are the first runner-ups on the list with RBE of ~ 2 and OER of ~ 2. Hydrogen ions (protons) and helium ions have RBE of 1.1 and OERs between 2.5 and 3.

Which of the following statements is FALSE about targeted radiotherapy strategies? a. Targeted radiotherapies can involve the use of both a diagnostic nuclide coupled with therapy nuclides which represent a new class of theragnostic approaches. b. Peptide receptors that are differentially expressed on cancer versus normal cells represent easily exploitable targets for theragnostic approaches. c. Somatostatin receptors represent a class of targets amenable to theragnostic approaches. d. Targeted radiotherapy approaches are FDA approved for selective tumor types. e. Targeted radiotherapies can't be used for bone metastasis.

e. Targeted radiotherapies can't be used for bone metastasis.

Which of the following statements concerning hyperthermia is TRUE? a. There is little or no age response through the cell cycle for hyperthermia b. Hyperthermia is thought to enhance the effect of radiation primarily by creating additional DNA damage c. Once thermotolerance develops, it becomes a permanent, heritable phenotype in the heated cells d. Step-up heating may be useful clinically because it inhibits the development of thermotolerance e. The thermal enhancement ratio is the dose of radiation to produce a given effect in cells or tissues irradiated at normal physiologic temperature, divided by the dose of radiation for cells or tissues irradiated at elevated temperature to produce the same effect

e. The thermal enhancement ratio is the dose of radiation to produce a given effect in cells or tissues irradiated at normal physiologic temperature, divided by the dose of radiation for cells or tissues irradiated at elevated temperature to produce the same effect The thermal enhancement ratio (TER) is defined as the radiation dose to produce an effect in cells or tissues irradiated at normal physiologic temperature divided by the dose of radiation for cells or tissues irradiated at elevated temperature to produce the same effect. There are large differences in the sensitivity of cells to heat depending on their position in the cell cycle ("age response"), with S phase cells being most sensitive. This is the opposite of radiation's age response, in which S phase cells exhibit the greatest resistance. This "complementarity" of toxicities of heat and radiation forms part of the basis for combining the two modalities. A second justification for combining radiation and heat is that heat enhances radiation injury by denaturing proteins/enzymes needed for the repair of radiation damage; heat does not create additional DNA damage in and of itself. Thermotolerance is an acquired resistance to heat, and is thought to be mediated by so-called heat shock proteins, cellular chaperones that help stabilize structures damaged by heating (membranes, proteins, cytoskeleton, etc.). The time course for the appearance, maintenance and eventual disappearance of heat shock proteins in cells undergoing hyperthermia mirrors the time course for the development and decay of thermotolerance. The development of thermotolerance is not a genetic change and therefore is not heritable in the progeny of previously-heated cells. Step-up heating may be useful clinically only if it can be used to protect normal tissues selectively; the procedure involves a pre-heating at mild hyperthermic temperatures so as to induce thermotolerance, followed by high temperature heating sufficient to produce cytotoxicity. Step-down heating has also been attempted for the purposes of sensitizing tumors to hyperthermia. In this case, a tumor is pre-heated at a very high temperature - which temporarily inhibits the development of thermotolerance - followed by heating at a somewhat lower, but still cytotoxic temperature.

Overgaard has published a meta-analysis of clinical trials in which agents such as oxygen and hypoxic cell radiosensitizers were used to address the problem of radioresistant hypoxic cells. He concluded that the overall effect of these hypoxia-directed interventions on tumor control and patient survival was that: a. Tumor control remained the same, but survival improved b. Tumor control improved, but survival remained the same c. Tumor control decreased, but survival improved d. Neither tumor control nor survival were affected e. There was an improvement in both tumor control and survival

e. There was an improvement in both tumor control and survival Overgaard has published a meta-analysis using data obtained from over 10,000 patients in 86 randomized trials who received radiotherapy and either oxygen or nitroimidazoles as hypoxic cell radiosensitizers, compared to radiotherapy alone. His findings were that these attempts at modification of tumor hypoxia significantly improved the effect of radiotherapy, with an odds ratio of 0.77 for loco-regional tumor control and an associated significant survival benefit (with an odds ratio of 0.87).

A 22-year-old man completed a course of radiation therapy for Hodgkin's lymphoma one year ago. For the previous 6 months, he and his wife tried unsuccessfully to conceive a child. He expressed concern to his radiation oncologist that the radiation exposure (gonadal dose of 0.83 Gy) may have left him sterile. How should the radiation oncologist respond? a. The radiation dose likely caused permanent sterility b. The dose of radiation should have had no effect on the patient's sperm count and probably isn't the cause of the couple's fertility problems c. The patient should not even be attempting to conceive a child due to a significantly increased risk for radiation-induced mutations in the offspring of irradiated individuals d. Hormonal dysfunction caused by the radiation, and not lowered sperm count per se, probably accounted for the couple's fertility problems e. This dose should interfere with fertility for no more than about a year, so the patient should keep trying to conceive a child Bonus question -- how long should he wait to avoid higher risk of mutation?

e. This dose should interfere with fertility for no more than about a year, so the patient should keep trying to conceive a child A dose of 0.83 Gy will cause a significant drop in the sperm count that may result in oligospermia and infertility for about a year following the irradiation. After a period of about six months following irradiation, the more differentiated members of the spermatogenic series that were susceptible to mutation will have all matured and been lost. Based on studies with laboratory rodents, this period of time should also be adequate to permit a return to the baseline population risk for mutations in offspring. In males, a dose >6Gy to the testes may cause permanent disability. Also, a dose of 0.83 Gy would be too low to cause a hormonal dysfunction. As low as 2-3 Gy if fractionated tho can produce permanent sterility. As little as 15 cGy can cause temporary azoospermia and single dose of up to 2 Gy can cause temporary sterility for ~1 year.