ROBex 2020 Flashcards

Question

2020-D3. Measurement of which one of the following chromosomal aberrations in peripheral blood lymphocytes many years following a putative whole body radiation exposure would provide the best estimate as to the dose received? A. Reciprocal translocations B. Rings C. Dicentrics D. Chromosome breaks E. Chromatid breaks

Answer 1

Answer: A Reciprocal translocations are relatively stable and therefore can be detected at long times after exposure to ionizing radiation. All of the other chromosome aberrations are highly unstable and therefore can be detected only for a few cell generations at most after exposure before the irradiated cells or their progenitors die.

Answer 2

Answer: B The formation of a dicentric chromosome is most likely to trigger the events during mitosis that lead to mitotic catastrophe and the death of the cell (although it should be noted that some dicentrics are stable and long-lived) The other chromosomal aberrations listed are not as likely to result in cellular death. For example, inversion, translocations, and insertions do not produce acentric gragments. They could potentially play an important role in carcinogenesis if the portion of the chromosome altered results in the inactivation of a tumor suppressor gene or activation of an oncogene.

Answer 3

Answer: E In blood samples obtained for cytogenetic evaluation within a few days to weeks after total body irradiation, the frequency of asymmetric aberrations (dicentrics and rings) in the lymphocytes reflects the dose received.

Answer 4

Answer: C A symmetrical translocation positions genetic information on different chromosomes but usually doesn't interfere with its expression. Many other chromosome aberrations, such as dicentric chromosomes and acentric fragments, usually result in lethality when cells attempt to divide. X-rays produce damage by indirect action. Chromatid aberrations result from irradiation of cells in late S or G2. Dicentric and ring chromosomes are unstable aberrations

Answer 5

Answer: C Two DNA segments in inversion will pair but the pairing will be via formation of a loop such that appropriate gene loci can come close

Answer 6

Answer: B Only the anaphase bridge is a chromatid abberation. Most chromosome aberrations lead to cell death. Prime examples of inevitably lethal aberrations: * Ring chromosome * Dicentric chromosomes * Anaphase bridge (chromatid aberration) Prime examples of chromosomal aberrations, potentially non-lethal: * Symmetric translocations * Small deletions Note that all of these radiation-induced aberrations require two double-stranded DNA breaks.

Answer 7

Answer: B The process of apoptosis involves chromatin condensation, cleavage of the DNA by endonucleases and cell shrinkage. In contrast, the process of necrosis is associated with cell swelling and lysis and can be distinguished from apoptosis by histology and other assays.

Answer 8

Answer: E The DNA in chromatin is considered to be the primary radiation target in cells

Answer 9

Answer: B The intrinsic apoptotic pathway is tightly regulared in mammalian cells by 2 groups of proteins, one favoring apoptosis and the other inhibiting it. They all belong to a single protein family the Bcl-2 family. Bax and Bad are pro-apoptotic members of the family and are believed to be inbolbed in the intial formation of pores in the mitochondrial membrane. Bcl-2 (the first discovered member) and Bcl-xL are important anti-apoptotic proteins that prevent pore formation and cytochrome C release. Whether a stimulus that cuases cell stress produces cell destruction will therefore depend on the balance between the pro-apoptotic and anti-apoptotic proteins.

Answer 10

Answer: C The Fas protein is a member of the tumor necrosis factor receptor super family. Killer T cells, which are able to signal target cells to undergo apoptosis, carry on their surface a protein complementary to Fas called the Fas ligand. When this binds to Fas on a target cell, it stimulates the initiation of apoptosis. First an adaptor protein, the Fas activated death domain (FADD) binds to the cytosolic domain of the Fas receptor Procaspase-8 then binds as a cluster to the FADD-receptor complex and is activated by cleavage. Once active, caspase-8 is formed and a proteolytic caspse cascade ensues, leading to activation of the same effector caspases as in the intrinsic pathway.

Answer 11

Answer: C Apoptosis does not stimulate an inflammatory response

Answer 12

Answer: E All of the statements A-D are characteristic of apoptosis

Answer 13

Answer: D Autophagy or type III programmed cell death is a tightly regulared, ordered cell death process that is a response to nutrient deprivation, hypoxia, crowding, sensence and genotoxic stress such as radiation. It is a mechanism to eliminate damaged proteins or organelles. Cells that undergo excessive autophagy are induced to die in a non-apoptotic manner as organelles and other cell components are sequestered in autophagosomes that fuse with lysosomes causing degradation of the autophagosomal contents (self-digestion).

Answer 14

Answer: E Cell senescence is a p53/p16 dependent permanent cell cycle arrest that occurs in some cell types in response to telomere loss. All of the other choices either involve cell death or a reversible (G0) exit from the cell cycle.

Answer 15

Answer: A The most appropriate approach to assess cellular survival to radiation for an actively dividing population of cells is to determine what fraction of the irradiated cells is capable of clonogenic survival (colony formation). Division delay would measure the amount of cell cycle perturbation caused by radiation, but occurs in all actively dividing cells regardless of whether they ultimately live or die. Apoptosis is just one form of death and can occur at many different times after irradiation. The formation of giant cells with multiple nuclei is a manisfestation of cells undergoing mitotic catastophe following the formation of chromosome aberrations but is not the only mechanism of radiation induced cell death. Likewise, detection of necrotic cells would only provide the graction of cells that undergo this form of cell death and would not give an overall sense of cellular lethality that could also occur through apoptosis, autophagy, mitotic catastrophe or senescence.

Answer 16

Answer: E It is likely that following a dose of 4 Gy, many cells that may be reproductively dead will still be able to divide for several days following irradiation until they undergo mitotic catastrophe It would be anticipated that a minority of carcinoma cells would undergo apoptosis and exhibit annexin V staining. NOTE: In flow cytometry, annexin V is commonly used to detect apoptotic cells by its ability to bind to phosphatidylserine, a marker of apoptosis when it is on the outer leaflet of the plasma membrane. MNEMONIC: "A for A" Possession of a mutation in P53 would likely not substantially affect the radiosensitivity of carcinoma cells. It is only tumor cells such as lymphomas that have a pronounced pro-apoptotic capacity for which a p53 mutation results in radioresistance (since the apoptotic pathway is inhibited in these mutant cells).

Answer 17

Answer: C In classical target theory, the "**D0"** is the dose that reduces cell survival to 37% of some intial value as measured on the exponential portion of the radiation survival curve. The "**D0"** dose also produced an average of one lethal lesion per cell in a population of irrdiated cells; this can be derived from a Poisson distribution in which there is an average of one lethal hit in a series of targets. In this instance 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 sub lethal 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 recieved in a single target) for a cell to be killed. The "**Dq"** would be a manisfestation of the width of the shoulder of a survival curve.

Answer 18

Answer: C Mammalian cells exhibit large (up to 100x) variations in "a"-coefficients and much smaller (up to 3x) variations in "b" coefficients.

Answer 19

Answer: D Cells in radiosensitive phases of the cell cycle will be selectively killed leaving an increased proportion of resistant S-phase cells that survive

Answer 20

Answer: B Each 5 Gy reduces the level of survival by a factor of 10. Therefore 40 Gy will result in a surviving fraction of 10^-8. Since tumor initially containted 10⁹ cells, it is anticipated that 10¹ will survive.

Answer 21

Answer: C The "a" defines the initial slope of the survival curve

Answer 22

Answer: D Cells comprising tumors with pro-apoptotic tendencies are gnerally characterized with a high "a/b" value. ALWAYS think clnically about lymphoma with pro-apoptotic tumors; these have high a/b.

Answer 23

Answer: C The effective survival curve for a multi-fraction regimen generally follows an exponential response. Cells that display survival curves with large "a/b" values tend to show relatively little sparing with fractionation since "a" inactivation will dominate. The "a/b" ratio is the dose (not level of survival) at which the linear and quadratic contributions to cell killing are equal. The initial killing is caused by the production of irreparable damage while the quadratic portion of the survival curve results from the accumulation of sub lethal damage. The radiosensitivies of normal tissues from different individuals usually exhibit relatively little variation.

Answer 24

Answer: A Adjuvant therapies (gene therapy, drugs, microencironmental manipulation) may affect repair rates of beta-type injury will have little effect on tissue sensitivity to radiation.

Answer 25

Answer: E Radiosensitization is observed as a leftward shift of cell survival curves which is described by all the above A-D

Answer 26

Answer: C The shoulder of the survival curve (the "b" component) is most pronounced for low LET radiation and minimal for high LET radiations. For a given particle the LET goes down as the energy goes up. For a given energy, the LET increases with the mass of the particle. Electrons are by far the lightest of the particles listed; pi mesons are the next lightest, then neutrons with alpha particles the heaviest. NOTE: Photons cannot be described by LET. Remember that the definition of LET is the amount of energy that an ionizing particle transfers to the material traversed per unit distance.

Answer 27

Answer: D The OER decreases as LET increases, falling to 1.0 at very high LETs (alpha). Neutrons are intermediate in ionization density and thus have intermediate LET calues and therefore an OER typically about 1.6.

Answer 28

Answer: E LET is proportional to the size and charge of a particle and inversely proportional to energy including the fast electrons created by interaction of photons with atoms and molecules NOTE: In this explanation, the photon/x-ray "LET" infers to secondary electrons technically, not the photon itself Remember that the lower energy for a given particle, the higher the LET

Answer 29

Answer: A The major rationale for neutron therapy was the reduced OER observed in cell and tissue radiobiology experiments that might improve therapeutic ratio

Answer 30

Answer: C OER decreases with increasing LET. Maximum effectiveness and therefore RBE reaches a peak for radiation whose LET is approximately 100 keV/um. The RBE of high LET radiation is generally high resulting in low values for D0. The survival curves resulting from irradiation of cells with high LET radiations are typically exponential. LET is the term that describes the density of ionizations or the aberage amount of energy lost (in keV) to the medium per unit of track length (um)

Answer 31

Answer: B RBE and "a/b" ratio increase with LET

Answer 32

Answer: D The a-particles have a survival curve characterized by a small n and D0 even under hypoxic conditions. The D0 is expected to increase for x-rays under hypoxic conditions. High energy protons have similar biologic properties to x-rays. NOTE: Remember that n is the extrapolation number which is the slope projected back to the Y axis, always at minimum of 1. The broader the shoulder before starting the slope (AKA the more sub lethal damage repair occuring), the higher the extrapolation number.

Answer 33

Answer: B High LET radiations are generally characterized by exponential survival curves. RBE reaches a peak around 100 keV per micron. High LET radiations generally exhibit higher RBEs than low LET radiations resulting in greater cellular sensiticity and lower D0 values. Oxygen plays a diminished role in high LEt compared to low LET radiations as large numbers of lethal DNA damages are produced in cells indepedent of damage fixation by oxygen. There is less cell cycle variation in sensiticity for high LET compared to low LET radiations.

Answer 34

Answer: A Proportionally greater amounts of direct DNA damage result as the density of ionization (high LET) increases. This damage occurs regardless of the degree of oxygen concentration so that the effects of oxygen on radiation effects is minimized.

Answer 35

Answer: B Bromodeoxyuridine, gemcitabine, and 5-FU can act as radiosensitizers but their mechanisms of action are different from those of the hypoxic cell radiosensitizers and sensitization does not occur preferentially in hypoxia. Dimethylsulfoxide is a radioprotector. NOTE: The "-azoles" tend to be hypoxic cell radiosensitizers

Answer 36

Answer: C The OER is defined as the ratio of radiation doses required to produce the same effect under hypoxic conditions vs normoxic conditions. The D0 is the dose of radiation that reduces survival by 63%. So a ratio of D0 values under hypoxic vs. normoxic conditions measures radiation effects at the same level.

Answer 37

Answer: D In any tumor the percent of hypoxic cells is always around 15%

Answer 38

Answer: B Half maximal radiosensitization is usually observed at an oxygen pressure of roughly 3-5 mm Hg

Answer 39

Answer: C The radiosensitivity of mammalian cells changes very little at O2 tensions above those found in venous blood (20-40 mm Hg)

Answer 40

Answer: C For single doses the x-ray OER is usually about 3. Oxygen must be present during or within miliseconds of irradiation to observe full radiosensitization. Radiosensitization is observed at oxygen pressures lower than that typical of venous blood. Oxygen plays a diminished role in cells exposed to high LET vs low LET radiations. As a result of re-oxygenation, hypoxic cells usually become aerated within hours or days following an x-ray treatment

Answer 41

Answer: B The cells are capable of accumulating sub-lethal damage

Answer 42

Answer: E All are true

Answer 43

Answer: E When dose delivered in 2 fractions, increase in cell survival because shoulder of the curve must be expressed each time. As the time interval between the 2 dose fractions is increased, there is a rapid increase in the fractions of cell surviving due to the prompt repair of sub lethal damage. SLD is significant for x-rays but almost nonexistent for neutrons. Repair of SLD reflects repair of DNA (DSB) breaks before they can interact to form lethal chromosomal aberration (multi-track)

Answer 44

Answer: D The component of radiation damage that can be modulated by post irradiation menipulations is known as PLDR. PLDR can occur if cells are inhibited to divide for a period of 6+ hours; the results is an increase in cell survival. In general PLD is repaired and the fraction of cells surviving a given dose is enhanced if post irradiation conditions are sub optimal for growth so that cells do not have to attempt the complex process of mitosis while their chromosomes are damaged. If mitosis is delayed by suboptimal growth conditions. DNA damage can be repaired. PLDR is significant for low LET radiations but does not take place after high LET irradiations.

Answer 45

Answer: D Exposure to an x-ray dose in 2 fractions, rather than a single dose, results in a hgiher level of survival due to repair of sublethal damage between the fractions. Repair of sublethal damage takes place in both normal and malignant cells. The killing of cells by high-LET radiations involves a greater proportion of irreparable damages rather than the accumulation of sublethal lesions that are reparable. Very little SLDR occurs during a high dose rate irradiation. Hyperthermia can inhibit repair of sublethal damage

Answer 46

Answer: C SCID mice have a mutation which causes deregulation of DNA dependent protein kinase (DNA-PK) and a concomitant deficiency in the repair of DNA double strand breaks. This also leads to a deficiency in production of immunoglobulin and immunodeficiency

Answer 47

Answer: C Tumor control (TCD₅₀) provides dta of most obvious relevance to radiotherapy. In experiemnts of this kind a large number of animals with tumors of uniform size are divided into separate groups and the tumors are irradiated locally with graded doses. The tumors subsequently are observed regularly for recurrence or local control. The proportion of tumors that are locally controlled can be plotted as a function of dose and data of this kind are amenable to a statistical analysis to determine the TCD₅₀, the dose at which 50% of the tumors are locally controlled.

Answer 48

Answer: C In tissues limited diffusion distance of oxygen causes cells to live in chronic hypoxia. Many tumor cells can remain hypoxic for a long period of time. Because it is unlikely they become re-oxygenated, the cells remain hypoxic until they die usually by necrosis. Chronic hypoxia is due to a limited oxygen diffusion within the tumor interstitium at distances \>100-200 um. The tumor vasculature is malformed and a tumor blood vessel may temporarily close or its flow being interrupted. This causes what has classically been termed "acute" hypoxia. Once the blood flow is restored, cells close to the blood vessel may regain normal oxygen levels. Indeed this process is dynamic with complex kinetics which involves cycle times that range from a few cycles per hour to many hours or days and it is now termed cyclic hypoxia. The spatial characteristics of cycling hypoxia most commonly involves networks of microvessels as opposed to isolated blood vessels. As such it can involve large tumor regions as opposed to occuring in isolation. Hypoxic cells are radioresistant due to the abscence of oxygen to make the radiation induced damage permanent (oxygen fixation hypothesis). Particularly in the case of low LET radiation exposure, radioresistant chronic and acute hypoxic cells may still be able to proliferate and therefore to drive malignant progression. Besides radioresistance, hypoxia has been linked to disease aggressiveness and metastatic potential.

Answer 49

Answer: E HIF-1 exerts anti-apoptic functions: its transcription activates anti-apoptotic proteins for example, like those of the Bcl-2 family or inhibitor of apoptosis (IAPs). HIF-1 is a transcription factor that contains 2 subunits, HIF-1a and HIF-1b. Under normally oxygenated conditions, a family of prolyl hydrozylases hydrozylates proline residues in the oxygen depndent degradation (ODD) domain of HIF-1a for recognition by the von Hippel-Lindau (VHL) complex, which subsequently targets it for degradation via the proteasome. By contrast under hypoxic conditions, the prolyl hydroxylases cease to function properly leading to increased levels of HIF-a which bind to HIF-1b. The HIF-1a/1b complex heterodimerizes in the nucleus and binds to hypoxia responsive elements in the promoter region of many genes involved in angiogenesis, tumor metabolism, metabolic adaptation to hypoxia, resistance to oxidative stress, increased invasive properties

Answer 50

Answer: C It has been shown that an increase in blood viscosity and slowing flow are linked to hypoxic red blood cells (RBCs) that shrink and become stiffer than normally oxygenated cells. A key hallmark of the tumor microenvironment is angiogenesis, a process where new blood vessels are created from pre-existing vasculature which are often malformed.

Answer 51

Answer: B During the embryonic stage vasculogenesis refers to the initial events in vascular growth in which endothelial cell precursors (angioblasts) migrate to discrete locations, differentiate in situ and assemble into solid endothelial cords, later forming a plexus with endocardial tubes. The sebsequent growth, expansion, and remodeling of these primitive vessels into a mature vascular network is referred to as angiogenesis. By contrast tumors use both mechanisms to grow their vasculature: circulating cells support the formation of de novo blood vessels (vasculogenesis) and through angiogenesis vessels sprout from pre-existing vessels in the surrounding normal tissues.

Answer 52

Answer: A Patients who have tumors with relatively low median pO2 levels and therefore hypoxic regions, tend to have more aggressive tumors and therefore exhibit lower levels of survival regardless of their treatment NOTE: While technically temporary closing of a blood vessel is acute hypoxia, repeated episodes of this can lead to cyclic episodes of hyoxia that can cause chronic hypoxia. Remember that hypoxia occurs \>100 um, not 1 mm

Answer 53

Answer: D HIF-a is the main transcriptional activator of VEGF, PDGF, and cFGF stimulates angiogenesis. Some tumors such as astrocytomas, can initiate growth by growing along normal blood vessels. The extent of angiogenesis is not a consistent predictor of tumor aggressiveness. Anti-angiogenesis agents may inhibit the development of metastasis.

Answer 54

Answer: B The CDK1/ Cyclin A complex is critical for transition of cells from G1 phase into S-phase. NOTE: G1 (G0) -\> S -\> G2 -\> M G1 -\> S (Cyclin D + Cdk4/6), (Cyclin E + Cdk2) S -\> G2 (Cyclin A + Cdk2) G2 -\> M (Cyclin A/B + Cdk1)

Answer 55

Answer: A The cell cycle checkpoint activation and arrest response idcued by ionizing radiation exposure halts cell cycle progression to better coordinate with DNA repair. The function of cell cycle checkpoints is to prevent genomic stability and promote cell survival.

Answer 56

Answer: D Since cell cycle time is equal to the time for S phase divided by the labeling index (10 hr/ 0.2), under these conditions the cell time is calculated to be 50 hr.

Answer 57

Answer: D The percent labeled mitosis technique is used to determine the individual cell cycle phase durations and overall cell cycle time of a proliferating cell population either in vitro or in vivo

Answer 58

Aswer: D Cells in radiosensitive phases of the cell cycle will be selectively killed leaving an increased proportion of resistant S-phase cells that survive

Answer 59

Answer: D The cell cycle proceeds by a defined sequence of events where late events depend upon completion of early events. The aim of the dependency of events is to distribute complete and accurate replicas of the genome to daughter cells. To monitor this dependency, cells are equipped with the checkpoints that are set at various stages of the cell cycle. When cells have DNA damages that have to be repaired, cells activate DNA damage checkpoints that arrests cell cycle. According to cell cycle stages, DNA damage checkpoints are classified into at least 3 checkpoints: * G1/S (G1) checkpoint * Intra-S phase checkpoint * G2/M checkpoint Upon perturbation of DNA REPLICATION BY DRUGS THAT INTERFERE WITH DNA synthesis or DNA lesions, cells activate DNA replication checkpoint that arrests cell cycle at G2/M transition until DNA replication is complete. There are more checkpoints such as spindle and morphogenesis checkpoint. The spindle checkpoint arrests cell cycle at M phase until all chromosomes are aligned on spindle. This checkpoint is very important for equal distribution of chromosomes.

Answer 60

Answer: C PTEN dephosphorylates the 3' phosphate of the inositol ring in PIP3 resulting in the bi-phosphate product PIP2. This de-phosphrylation is important because it results in inhibition of the Akt signaling pathway.

Answer 61

Answer: D MGMT promoter methylation has been shown to be a common alteration in gliomas and has been associated with increased sensitivity to temozolomide

Answer 62

Answer: E Carcinogenesis is a multi step process and a single alteration that leads to the actiation of an oncogene or loss of a tumor suppressor gene is unlikely to result in a solid tumor. In common solid tumors such as those derived from the colon, breast, brain, or pancreas, an average of 60 genes display subtle somatic mutations. At the other end of the spectrum, pediatric tumors and leukemias harbor on average ~10 point mutations per tumor. Example of driver mutations are: * Loss of heterozygosity (LOH) as in the retinoblastoma protein (pRB) * Point mutations as in the genes of the Ras family * Large scale rearrangements that generally fuse 2 genes to create an oncogene (such as BCR-ABL in CML) * Deletions as seen in PTEN

Answer 63

Answer: C Burkitt lymphoma (BL) is not hereditary. It is a highly aggressive B cell non Hodgkin lymphoma originating from mature, germinal or post germinal center B cells. BL manifests as 3 clinical subtypes, all of which have chromosomal translocation type rearrangements of the MYC oncogene, causing constitutive overexpression of c-myc and rapid cell division driving the proliferation of BL.

Answer 64

Answer: B Ataxia telangiectasia (AT) is an autosomal recessive disorder primarily characterized by cerebellar degeneration, telangiectasia, immunodeficiency, cancer susceptibility, and radiation sensitvity. Irradiation and radiomimetic compounds like those used for cancer chemotherapy induce DSBs and other DNA lesions whose repair is severely impaired when ATM is absent. As a consequence, patients with AT display a hypersensitive skin reaction to ionizing radiation and DNA breaking agents but not to UV light. ATM is also involved in the activation of cell cycle checkpoints; it controls the passage of cells trhrough the S phase.

Answer 65

Answer: C TGF-b is responsible for the activation or inhibition of genes through either SMAD dependent or independent pathways. On the other hand TGF-b can promote the activity of several signaling pathways other than Smad including mitogen activated protein kinases (MAPKs) and phosphoinositide 3' kinase (PI3K). The TGF-b signaling pathway is instrumental in tumor suppression yet paradoxically it can also promote tumor cell invasiveness and metastasis. Suppression involves cell proliferation mechanisms mainly by inhibiting cell cycle progression trhough G1 arrest. TGF-B also regulates apoptosis likely through Smad-dependent pathways and genomic instability mainly linked to the induction of the epithelial to mesenchymal transition. TGF-b promotes the deposition of various extra cellular matrix proteins via modulation of synthesis of collagen, glycosoaminoglycans, hyluronic acid, and fibronectin. It has been shown that rapidly after radiation exposure both intracellular and extracellular localization of TGF-b greatly increase in the periepithelial stromal sheath and are dramatically induced in the adipose stroma. Collagen III expression undergoes extensive remodeling which includes novel expression in the adipose stroma in a pattern that co-localized with novel TGF-b expression.

Answer 66

Ras is a family of genes frequently found to harbor a mutation in human tumors. This family consists of 3 functional genes H-Ras, K-Ras, and N-Ras. They are mutated in 20-25% of human tumors. Ras proteins are binary molecular switches that cycle between active guanosine triphosphate (GTP)-bound and inactive guanosine diphosphate (GDP) bound states. Ras are oncogenes, their gain of function prevents the need for external signals from growth factors to activate them. The Ras/PI3K/Akt/TOR (target of rapamycin) pathways has long been known to be important in regulating cell growth through insulin signaling. Recent observations have brought to light the occurances of various germline ras mutations occuring in association with various hereditary familal developmental syndromes (RASopathies) such as neurofibromatosis type 1.

Answer 67

Answer: B p53 gene is a tumor suppressor gene which is inactivated in at least 50% of all cancers. Its role is to prevent the replication of cells with damaged DNA. p53 protein is normally present at very low levels in the cell since it is broken down very quickly after its synthesis. However, proteins that recognize lengths of single stranded DNA formed by strand breaks or stalled transcription, phosphorylate p53 and stabilize it, increasing its concentration. p53 is a transcription factor but it causes the production of proteins which halt the cell cycle. It also stimulates production of DNA repair enzymes but not the ones that replace telomere sequences lost during cell division. The DNA repair enzymes produced give the cell the opportunity to repair its damaged DNA but if it fails to do so in a reasonable time, p53 protein stimulates production of proteins which push the cell into apoptosis.

Answer 68

Answer: D Tumor surpressor genes code for proteins that normally control progression through a cell cycle checkpoint. These genes only contribute to a cancer when both copies are mutated in a way that produces an inactive protein product. When genes coding for proteins forming part of a growth factor signaling pathway or coding for proteins which help prevent apoptosis become mutated and contribute to cancers they become oncogenes. Oncogenes produce proteins that have gained a function. They contribute to cancers by stimulating cell growth or by preventing a damaged cell from killing itself. Mutations in genes coding for DNA repair enzymes contribute to cancers in the same way that tumor suppressor genes do because in their absence, damaged DNA cannot be repaired, but they are not conventionally regarded as tumor surpressors.

Answer 69

Answer: B The Ras gene codes for a GTPase switch protein that forms part of a growth factor signaling pathway. Stimulation of this protein via a ligand bound growth factor receptor causes it to activate by exchanging a molecule of GDP for GTP. The activated Ras protein then activates downstream proteins which ultimately activate transcription factors. Normally the Ras signal is sel limtiing because the protein has intrinsic GTPase activity so it hydrolyses its bound GTP to GDP, switching the signal off. There are several known mutations of the Ras gene, but the best studied example is a point mutation of the gene with a single amino acid change at the GTP binding site. This severely reduces the protein's GTPase activity making it very slow to self inactivate once it has been activated. This prolongs the growth signal effectively allowing the cell to be stimulated without a growth factor signal.

Answer 70

Answer: D Molecular subtype of gene expression, basal-like is more common in inflammatory breast cancer (IBC). IBC shows high S-phase (ki-67 level) and has high levels of p53 and epidermal growth factor but lacks of ER expression. HER2/neu overexpression is no more common than non-IBC.

Answer 71

Answer: C The telomeric DNA protects the chromosome ends from repair enzymes that might otherwise detect them as sites of DNA damage and push the cell into an inappropriate DNA damage response. It is also progressively lost on chromosome replication and in being sacrified, protects the real chromosomal DNA carrying the genes. In rapidly dividing embryoniccells and stem cells telomerase replenishes the lost telomeric DNA. However somatic cells do not contain telomerase so that once the telomere is reduced to a critical length of cell division ceases. The immortalization of cancer cells has been shown to depend on telomere maintenance. Most though not all cancerous cells have been foudn to have telomerase activity, unlike the normal cells from which they develop.

Answer 72

Answer: E All of the examples listed are correct. The importance of epigenetic alterations as driving forces of tumor initiation clearly emerged from studies of pediatric brain tumors which are characterized by few or no recurrent mutations and are instead defined by their aberrant epigenetic patterns. Efforts to sequence the genomes of thousands of human cancers over the past decade have elucidated the presence of frequent alterations in numberous epigenetic regulators, recognizing unambiguously the key role of epigenetic deregulation in carcinogenesis.

Answer 73

Answer: E Numerous enzymes which direct histone modifications have been identified and characterized based on their specific activity and residues modified. Most of the modifications are dynamic and enzymes that removes the modifications have been identified as well. Acetyltransferase and deacetylase coordinate histone acetylation; methyltransferases and demethylases control histone methylation and have high catalytic specificity; serine/threonine kinases and histone ubiquitin ligases promote respectively histone phosphrylation and ubiquitination.

Answer 74

Answer: A Cancer cells often have a different epigenome or epigenetic profile than normal cells. DNA with less than normal amounts of DNA methylation are hypo-methylated. DNA with more methylation is hyper-methylated. A cancer cell's epigenetic profile is typically characterized by decreased methylation accross much of the genome (global DNA hypo-methylation). The decreased methylation affects the activity of large numbers of genes. Because methylation is associated with decreased gene activity, the overall effect of hypo-methylation is to increase hte activity of the affected genes, If genes involved in cell growth have decreased methylation, the increased activity and resulting cell divison an lead to the development of cancer. DNA methylation changes do not have to be within protein encoding genes to be imporant.

Answer 75

Answer: E Owing to the genomic complexity of cancers, precision medicine has been enabled by a growing body of knowledge that identifies key drivers of oncogenesis, occupied with advances in tumor analysis by next generation sequencing. NGS can enable the simultaneous analysis of a broad spectrum of genomic alterations, including mutations, copy number variations, translocations, and fusions in multiple genes. It therefore provides a more efficient, cost and tissue saving tumor analysis as compared to serial single biomarker analyses, particularly in the context of the genomic complexity that is known to exist within tumors.

Answer 76

Answer: D Potential clinical uses of blood based CTC and ctDNA that are not offered by tumor tissue sequencing include monitoring the persistence of radiologically undetectable tumors (e.g. minimal or molecular residual disease), prediction of recurrence (e.g. persistent CTC associaed with risk of relapse in breast cancer), monitoring of treatment response, early detection of resistance mechanisms, as well as assessment of tumor burden. You could also track the clonal evolution of tumors and dynamic evaluation of immune biomarkers such as PDL1 expression and tumor mutation burden.

Answer 77

Answer: A Tumor mutation burden (TMB) is defined as the total number of coding mutations in the tumor genome and has emerged as a promising predictive biomarker of repsonse to anti PD1/PDL1 agents in several prospective trials.

Answer 78

Answer: A One of the well established biomarkers that drive treatment decisions for patients with breast cancer is the human epidermal growth factor receptor 2 (HER2) over-expression or amplification in the tumor

Answer 79

Answer: D Lung toxicity (pneumonitis) is observed after a whole lung dose of approximately 17.5 Gy in daily doses of 1.8-2.0 Gy. Althought radiation fibrosis is frequently seen in areas of prior penumonitis, radiation fibrosis can also develop in areas of lung that show no evidence of radiation penumonitis. Different mouse strains exhibit significant differences in both extent and time of fibrosis induction that are genetically defined. The probability of injury and the severity of radiation pneumonitis increase with the volume of lung irradiated. The apex of the lung appears to be less sensitive to radiation induced lung injury than the base of the lung. Many of the drugs used to condition patients for transplant, including bleomycin, doxorubicin, and BCNU also injure the lungs. Pneumonitis therefore can occur in the abscence of irradiation or in patients who have recieved low doses of whole lung radiation combined with these drugs.

Answer 80

Answer: C Many factors are accepted as affecting the development of osteoradionecrosis. These include the site of the primary tumor (mouth floor and oropharynx carrying the greatest risk), proximity of the tumor to the bone, and radiation dose. Tooth extraction and dental disease also have long been recognized as major risk factors. In addition, age, sex, nutritional status as well as alcohol and tobacco use may influence onset. Although the inclusion of the bone marrow sinusoids may affect the hematopoietic effects of the irradiation, they appear to have no effect on the development of osteoradionecrosis.

Answer 81

Answer: D The growth factor bFGF protects blood vessels by preventing apoptotic activity of vascular endothelial cells. NOTE: Rapidly dividing self-renewing tissues respond early to the effects of radiation; * Early-responding tissues: skin, intestinal epithelium, bone-marrow * Late-responding tissues: spinal cord, lung, kidney Early or late radiation response reflects different cell turnover rates

Answer 82

Answer: D Even in children less than 1 year of age, doses \>= 10 Gy delivered as part of a standard fractionated protocol are generally required to induce cataracts

Answer 83

Answer: B Chronic lesions have classically been described in terms of de-myelination, vasculopathies and necrosis, and are generally confined to the white matter alone. Raidaiton induced brain injury can lead to both acute and chronic changes. The acute lesions include an increase in blood brain barrier permeability and edema due in part to a rapid burst of apoptotic cell death, which is seen in a variety of normal brain cells, including endothelial cells. Interestingly it has been noted to radiation induced tissue changes are more frequently observed in AVM (arteriovenous malformation) patients than tumor patients, suggesting that dose-volume relationships should be studied separately in these 2 different patient groups.

Answer 84

Answer: E Recognition of these "non-cytocidal" radiation effects has enhanced understanding of normal tissue radiation toxicity and allowed an integrated systems biology based approach to modulating radiation responses and providing a mechanistic rationale for interventions to mitigate or treat radiation injuries.

Answer 85

Answer: C NOTE: There are no pathognomonic features observed in the irradiated kidney. Irradiation of the kidneys leads to radiation nephropathy, seen clinically some six months or more after irradiation as anemia, azotemia and an increased blood pressure. These functional changes are accompanied by changes in renal histology. Radiation nephropathy is associated with functional and morphologic changes. The latter consist of changes in all components of the nephron, including the glomerulus and the tubules. These morphologic lesions are progressive, leading to glomerulosclerosis, tubulointerstitial fibrosis, and ultimately renal failure.

Answer 86

Answer: D The growth factor bFGF protects blood vessels by preventing apoptotic activity of vascular endothelial cells. NOTE: Rapidly dividing self-renewing tissues respond early to the effects of radiation; * Early-responding tissues: skin, intestinal epithelium, bone-marrow * Late-responding tissues: spinal cord, lung, kidney Early or late radiation response reflects different cell turnover rates

Answer 87

Answer: D Bone marrow transplantation is likely to only be a reasonable response after acute total body irradiation in the range from 8-10 Gy. With lower dosese, survival is likely with appropriate supportive care. With higher doses, survival is unlikely and death is usually the result of failure of the GI system.

Answer 88

Answer: A The a/b ratio for pericarditis has been estimated at roughly 2-3 indicating a large impact of fraction size. Classic studies performed in rabbits showed that the cells of the greatest radiobiological importance in the heart are endothelial cells of the blood capillaries whereas the cardiac myocytes are post mitotic cells and are therefore much less radio responsive. Large clinical studies on both Hodgkin's and breast cancer patients have identified risk factors for the development of cardiac sequelae and these include fraction size, dose, and volume with 2 separate trials indicating that age, particularly \>60 years has a strong influence

Answer 89

Answer: E Repeat question; all of the above are true

Answer 90

Answer: B Most data suggest a correlation between fibroblast radiosensitivity and late effects in normal tissues

Answer 91

Answer: E In general the larger the number of clonogenic target cells per FSU, the greater will be its radiation tolerance. For an organ in which the FSUs are arranged in parallel damage to one part of the organ will not necessarily result in organ dysfunction as the remaining FSUs can function independently. The spinal cord is an example of an organ in which the FSUs are arranged in series, not parallel so taht damage to one portion of the organ can render the whole organ dysfunctional. The tolerance dose generally decreases with increasing volume of tissue irradiated. FSUs have been identified in parallel organs such as the nephron in the kidney or lobule of the liver.

Answer 92

Answer: B Hierarchial tissues with limited stem cells will express radiation damage more rapidly. NOTE: Michalowski has described tissues as either hierarchical or flexible, based on their cell populations. In this model, there are 3 cell types: * Stem cells which exist to replicate, producing daughter cells which maintain the stem cell population or differentiate into other types of cells. These cells make up the basal layer of the skin, or live in the crypts of the gut. * Functional cells which are fully differentiated and incapable of further division. These include the mature epithelial cells of the gut and skin, or the neutrophils and erythrocytes of the blood. * Maturing partially differentiated cells which exist in between these two states. For example, in the bone marrow cells may follow a number of pathways between the original stem cell and the eventual blood cell. These cells may still divide and give rise to progeny; however the capability for division is limited as they do not possess telomerase. Hierarchical tissues (H-type) have populations of all three types, with stem cells constantly giving rise to maturing cells which eventually fully differentiate and become functional cells. * Hierarchical tissues include most epithelial layers and the bone marrow. Flexible tissues (F-type) are different in that the cells rarely divide but may be induced to by damage. Their cells are functional but retain the ability to re-enter the cell cycle if required. * F-type tissues include the liver, thyroid and the dermis of the skin. Many tissues are a hybrid of these two types, and their response to radiation varies. * In general, H-type tissues respond rapidly to radiation damage as the stem cell population is killed. * F-type tissues may not display damage for some time, particularly if the dose is small, because not all cells enter the cell cycle immediately.

Answer 93

Answer: D The colume of an organ irradiated may be of greater importance for an organ which suffers from a diminished functional reserve. Cellular radiosensitivity is assumed to be uniform across all stem cells in a given normal tissue. Volume effects vary for late effects in different tissues. A volume effect is observed for all dose fractionation schemes and for organs in which the FSUs are arranged ineither a serial or parallel fashion

Answer 94

Answer: C IL-6 is a directly inducible pro-inflmmatory cytokine which is not a hematopoietic radioprotector. That role falls to IL-1.

Answer 95

Answer: A When stem cells are killed, tissue effects appear only when functional cells serve out their lifetimes

Answer 96

Answer: E The 2 main pathways that repair DSBs are the end joining (EJ) repair pathway and the homologous recombination (HR) repair pathway. In human cells, HR can only occur after replication has occured and thus when a sister chromatid is available, namely in G2 and S phase. Therefore it seems reasonable ot hypothesize that HR may be more prominent in the fast proliferating tissues. If this is the case, then the tissues with a high a/b ratio are also the same which have higher amounts of HR and which are spared less by fractionation. Since the FR pathway is characterized by a very long repair halftime, in some instances of more than 24 hours the repair of DNA damage between fractions may be less complete in these tissues. In other words, the sparing effect of fractionation may be smaller in fast proliferating tissues as a consequence of the long repair halftimes for homologous recombination.

Answer 97

Answer: E Late responding tissues typically have more "memory" than their early counterparts and provide more of a barrier for re-treatment Late effects take months to years to develop and may be progressive in some tissues. Other tissues may undergo some repair of their damage over time allowing them to tolerate further doses in the future. Late responding tissues demonstrate differences in remembered dose. Some tissues in which there is progressive changes such as lung fibrosis and the kidney show worsening re-treatment tolerances over time. Others such as spinal cord show improved tolerance with time.

Answer 98

Answer: B Nausea will be produced in humans after acute whole body doses of 1-2 Gy

Answer 99

Answer: A The life span of mice, rats, and dogs is reduced by about 5% per Gray

Answer 100

Answer: E This can be determined from the estimated risk factor (for doses less than 0.2 Sv) of: (4 x 10^-2)/ (person-Sv) for radiation induced fatal cancers. In this study (10⁷ people) (10^-3 Sv) (4 x 10^-2)/ (person-Sv) = number of excess cancer deaths

Answer 101

Answer: B Children are at greater risk for the development of cataracts

Answer 102

Answer: D The lifetime of sperm cells is relatively long and depletion of stem cells by radiation will be expressed after 2-3 months NOTE: Epilation is hair loss. The threshold range for transient erythema and temporary epilation is 2-5 Gy; prolonged erythema and permanent partial epilation have threshold ranges of 5-10 Gy.

Answer 103

Answer: D During the latent phase of the acute radiation syndrome, although patient may appear and feel well, there is a substantial depletion of stem cells in bone marrow and cells lining the GI tract. The latent stage lasts 1-6 weeks post exposure.

Answer 104

Answer: B The GI full syndrome will usually occur with a dose greater than approximately 10 Gy (1000 cGy) although some symptoms may occur as low as 6 Gy or 600 cGy. Survival is extremely unlikely with this syndrome. Destructive and irreparable changes in the GI tract and bone marrow usually cause infection, dehydration, and electrolyte imbalance. Death usually occurs within 2 weeks.

Answer 105

Answer: C The classical 4 stages of the ARC syndrome are: 1. Prodromal stage: The classic symptoms for this stage are nausea, vomiting, as well as anorexia and possibly diarrhea (depending on dose) which occur from minutes to days following exposure 2. Latent stage: Patient looks and feels generally healthy for a few hours or even up to a few weeks 3. Manifest illness stage: Symptoms depend on the specific syndrome and last from hours up to several months 4. Recovery or death: Most patients who do not recover will die within several months of exposure. The recovery process lasts from several weeks up to 2 years.

Answer 106

Answer: E In order to develop a fulll ARS, the following conditions need to occur: * The radiation dose must be large (\>0.7 Gy). Mild symptoms may be observed with doses as low as 0.3 Gy. * The dose must be external. Radioactive materials deposited inside the body have produced some ARS effects only in extremely rare cases. * The radiation must be penetrating (i.e. able to reach internal organs). High energy x-rays, gamma rays, and neutrons are penetrating radiations. * The entire body or a significant portion of it must have received the dose. Most radiation injuries are local, frequently involving the hands and these local injuries seldom cause classical signs of ARS * The dose must be delivered in a short time (usulally a matter of minutes)

Answer 107

Answer: C Hypofractionated radiation therapy could maintain equivalent late sequelae while yielding a higher biologically effective dose

Answer 108

Answer: E Therapeutic gain is obtained only when a change in the treatment regimen increases the therapeutic ratio by providing an increased effect on tumor relative to that in normal tissues

Answer 109

Answer: C The effect of the hypoxic cells will clearly dominate the surviving cell population so the problem should be solved by ignoring the well-oxygenated cells. The number of hypoxic cell in the tumor is 10⁹ with a D₀ of 3 Gy. Remember that D₁₀ = 2.3 x D₀ so this would be 6.9 Gy in this case. To get to 90% tumor control would need a surviving fraction of 10^-1 which means 10^-10 logs of kill. 69 Gy in 2 Gy fractions would be 35 fx.

Answer 110

Answer: D When tumor control rates lie between 10-85%, a useful practical description of the slope of the tumor control probability (TCP) curves is the percentage point change in TCP for a 1% change in tumor dose, the y-value. The y-value is determined by clonogenic radiosensitivity, the curve being steeper the more sensitive the tumor cells.

Answer 111

Answer: B Certain level of dose threshold is required in order to observe cure. After that it will be determined by the killing of the last surviving clonogens, which will be a sigmoid curve.

Answer 112

Answer: B Although it is true that use of an accelerated treatment without decreasing the total dose may result in a greater severity of damage in early responding organs, this does not directly support the hypothesis that late responding tissues are characterized by small a/b values. This result likely reflects reduced proliferation during treatment.

Answer 113

Answer: E In early responding normal tissues, the rapid turnover of the cells in the tissue leads to a rapid expression of radiation injury and therefore to the initiation of rapid, compensatory proliferation during a conventional radiotherapy regimen. Protracting the regimen of irradiation allows proliferation of the critical cell population which results in a decrease in the severity of the early radiation reactions. In contrast cells in late responding normal tissues turn over slowly, radiation injury therefore becomes manifest long after the end of conventional radiotherapy regimens. Compensatory proliferation then cannot be induced and protacting the course will not protect against hte late reactions of these tissues.

Answer 114

Answer: B Accelerated fractionation may be indicated for rapidly proliferating tumors NOTE: Remember that RTOG 9003 was a Stage 3/4 H&N SCC trial comparing 4 different dose regimens: 1. _Standard_: 70 Gy/35 daily fractions/7 weeks 2. _Hyperfractionated_: 81.6 Gy/68 BID fractions/ 7 weeks 3. _Accelerated-Split course_: 67.2 Gy/42 fractions/6 weeks with a 2-week rest after 38.4 Gy 4. _Accelerated-Continuous_: 72 Gy/42 fractions/6 weeks. The 3 experimental arms were to be compared with standard FX. At 5 years, only hyperfractionation improved LRC and overall survival for patients with locally advanced SCC without increasing late toxicity.

Answer 115

Answer: C BED = nd (1 + d/(a/b)) = 68 x (1 + 2/4) = 68 x 1.5 = 102 Now for 4 Gy/ fx equivalent dose: 102 = "nd" (1+4/4) "nd" = 102/2 = 51

Answer 116

Answer: D For late effects, the duration of the treatment does not affect the probability or severity of late effects Therefore the greatest BED for the 5 protocols listed using the equation BED = nd[1+d/(a/b)], is for the 16 Gy @3.3 Gy/fx which yields a BED of 111. NOTE: For early effects, the longer the treatment, the more likely for repopulation to kick in which can help normal tissue sparing.

ROBex 2020 Flashcards

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