APP Basis of Disease

Question 1

Bilirubin

Answer 1

• typical RBC lifespan = 90 days
• RBCs made up of heme and globin
• globin is broken down into AA
• heme is fixed by cells in reticuloendothelial system: heme –> biliverdin –> bilirubin
• bilirubin can’t enter liver by itself, bound to albumin
• when liver is inflamed, bilirubin cannot be processed and bilirubin levels continually increase

Question 2

Tumor suppressor genes: p53

Answer 2

• p53 controls cell proliferation and apoptosis - detects cellular stress and prevent propagation of damaged cells
• p53 is bound to MDM2 gene, which causes its degradation and short half-life
• upon cellular stress (hypoxia, DNA damage, overexpression of mitogenic factors) p53 is released from the complex, which increases its half-life and activates its transcription factor activity
• active p53 stimulates transcription of CDK inhibitor p21:
• leads to G1 growth arrest
• activates DNA repair systems (GADD45)
• p53 is one of most commonly mutated genes in human cancer (over 70%)
• mutations or loss of p53 leads to accumulation and propagation of mutated and damaged cells
• also allows survival of cells with overexpressed or deregulated mitogenic factors
• germline mutations in p53 gene cause Li-Fraumeni syndrome (LFS is dominant) associated with highly elevated risk of development of a number of tumors, including soft-tissue sarcomas, osteosarcomas, brain tumors, breast cancer
• tumors develop at a younger age than sporadic and often in multiple locations

Question 3

Benign vs. Malignant Tumors

Answer 3

Benign

• well differentiated cells with preserved specialized features of the parent cells (e.g. hormone release).
• well demarcated, often encapsulated masses, no invasion of surrounding tissue
• no distant metastases

Malignant

• lack of differentiation, anaplasia
• locally invasive, infiltrating surrounding tissues
• frequently present distant metastases

Question 4

Ischemia-Reperfusion Injury

Answer 4

• when ischemic tissue is reperfused, generally cause more damage than ischemia
• under oxidative stress, cells begin to release chemokines and other inflammatory markers
• thus reperfusion will cause a massive inflammatory response commonly seen in myocardial infarction/strokes

Question 5

Atrophy

Answer 5

decrease in size of tissue organs resulting from a decrease in cell size or in number of cells causes include disuse, loss of trophic stimuli (i.e. loss of innervation), insufficient nutrients, decreased blood flow, persistent cell injury, and aging cells decrease cellular machinery, decrease oxygen/glucose needs, decrease number of organelles

Question 6

Consequences of p53 mutations

Answer 6

• loss of function - mutant p53 is not functional, but does not interfere with actions of wild type allele
• dominant negative mutant - mutant p53 forms a complex with wild type allele and prevents its binding to target gene promoters
• gain of function - mutant p53 binds to different DNA sequences and activates different target genes, which can lead to stimulation of cell proliferation, instead of cell cycle arrest and apoptosis

Question 7

Tumor cells can adapt to low oxygen levels

Answer 7

normal tissue on the left → effective production of ATP ∙when normal tissue doesn’t have oxygen, it uses anaerobic processes tumor tissue learns a pathway in between ∙uses some oxygen, but also produces a lot of ATP using anaerobic pathway ∙uses a lot of glucose, not very efficient → Warburg Effect ∙large use of glucose can be used in diagnosis (PET)

Question 8

Telomerase activity

Answer 8

due to shortening of telomeres, most normal cells have a capacity of 60-70 doublings, after this the cells enter a nonreplicative senescence telomerase is an enzyme which in stem cells maintain normal telomere length preventing their senescence in most of the cancers telomerase is up-regulated, which allows unlimited cells divisions

Question 9

Hypertrophy

Answer 9

increase in cell size, and thus an increase in amount of functioning tissue mass results from an increased workload imposed on an organ or body part involves an increase in the functional components of the cell that allows it to achieve equilibrium b/w demand and functional capacity

Question 10

Dysplasia

Answer 10

characterized by deranged cell growth of a specific tissue that results in cells that vary in size, shape and appearance ∙thought of as replacement of mature cell by immature cells, that can differentiate into different cell types involves sequential mutations in proliferating cell populations pattern is most frequently encountered in metaplastic squamous epithelium of respiratory tract and uterine cervix strongly implicated as a precursor to cancer

Question 11

Familial vs. sporadic form of retinoblastoma: Classical Knudson two-hit model

Answer 11

retinoblastoma = pediatric tumor developing in retina due to deletion of RB tumor suppressor gene in sporadic form of retinoblastoma, both mutations in RB gene are acquired after birth, thus frequency of tumor is relatively low in familial form, one mutation in RB protein is inherited, therefore only one additional mutation have to occur in one of the retinal cells ∙due to this, frequency of retinoblastoma is very high and tumors often arise bilaterally although this gene mutation is present in all cells, only in the retina do cells with cancerous mutations evade cell death to create cancerous growth NOTE that familial cancers are a very small percentage of total tumors

Question 12

Angiogenesis

Answer 12

growth of capillary blood vessels necessary for tumor growth and metastasis ∙perfusion supplies nutrients, growth factors and oxygen, preventing hypoxia-induced apoptosis (p53 pathway) normal angiogenesis is tightly controlled by both angiogenic factors and inhibitors of angiogenesis ∙in tumors, this process is deregulated → imbalance b/w pro- and anti-angiogenic factors leads to disturbances in vessel architecture ∙early in their growth, tumors do not induce neovascularization and remain dormant → the angiogenic switch initiates progressive growth of tumors →in avascular phase, there is a balance b/w proliferation and apoptosis, so the tumor is stable endogenous inhibitors of angiogenesis are often product of cleavage of extracellular matrix proteins, such as collagen

Question 13

Metaplasia

Answer 13

reversible change in which one adult cell type is replaced by another adult cell type ∙only kind of cell of that is replaced is present, i.e. epithelial cells are replaced by a different type of epithelial cell thought to involve the reprogramming of undifferentiated stem cells that are present in tissue usually occurs in response to chronic irritation and inflammation which allows for substitution of cells that are better able to survive seen in Barrett’s esophagus

Question 14

Proto-oncogenes: Nuclear transcription factors

Answer 14

stimulate expression of several growth-related genes, such as cyclin-dependent kinases (CDKs) include MYC, MYB, JUN, FOS and REL proteins can occur through translocation or amplification

Question 15

Tumors: Unorganized organs

Answer 15

tumors are complex tissues containing tumor cells, fibroblasts, immune cells, blood vessels (endothelial cells) and lymphatic vessels, and they should be treated as such

Question 16

Hypoxia

Answer 16

hypoxia = lack of oxygen ∙ischemia = lack of blood flow ∙ischemia can cause hypoxia without oxygen, 2 things happen in cell ∙inability to make ATP affects polarization of membrane ∙not having O2 changes us from aerobic metabolism to anaerobic metabolism

Question 17

Apoptosis

Answer 17

programmed cell death very clean, very easy rapidly cleared so it does not elicit an inflammatory response propagated by a family of proteases called caspases intrinsic pathway → something happens w/in cell that makes cell recognize it must die ∙elicited through mitochondria, will turn on caspases extrinsic pathway → something outside of the cell recognizes that that cell needs to go (old, too many cells, etc.) ∙have factors coming to cell from outside ∙apoptosis elicited through receptors on cellular membrane

Question 18

Free Radical Injury

Answer 18

ROS: reactive oxygen species → anything with an unpaired electron ∙the danger is that the unpaired electron goes and takes an electron from somewhere else, causing damage to whatever molecule they take from ∙they like to take them from larger molecules that are unable to take electron back → membrane, DNA molecules, large proteins w/in cell frequently formed in inflammation and metabolism

Question 19

Tumor suppressive genes: Proliferative breaks

Answer 19

tumor suppressor genes encode proteins, which normally inhibit cell proliferation or stimulate apoptosis upon cell damage tumor suppressor genes are inactivated in cancer cells by mutations truncation, deletions or methylation, leading to uncontrolled growth mutations of tumor suppressor genes are usually recessive → two alleles must be altered to lose their function inherited mutations of tumor suppressor genes contribute to familial cancers hereditary cancers develop earlier in age than sporadic malignancies and often arise in multiple locations

Question 20

What is cancer?

Answer 20

neoplasia (tumor) - abnormal growth of tissue resulting from loss of responsiveness to growth control signals cancer - malignant neoplasia

Question 21

3 Possible Outcomes of Hepatitis

Answer 21

HBsAg totally cleared = immune stage inactive carrier stage = no injury or inflammation of hepatocytes but patient can suffer from acute flares if virus cannot be cleared and replication continues for >6 months = chronic hepatitis

Question 22

Chronic inflammation

Answer 22

chronic disease states once T cells are in the area, they release a lot of factors (i.e. TNF), causing fibroblast proliferation ∙normal response for immune system macrophages cause release of ROS, which in chronic inflammation can cause chronic tissue injury

Question 23

Proto-oncogenes: Growth factor receptors

Answer 23

mutated or truncated forms of the receptors with constitutive activity ∙epidermal growth factor (EGF) receptor - ERBB1 is truncated in glioblastoma →intracellular part stays, but you lose the extracellular (control) part of the receptor, meaning that the receptor is constantly stimulating growth over-expression of growth factor receptors ∙ERBB1 in squamous cell carcinomas of the lung ∙ERBB2 (HER2) in breast cancer (considered more aggressive)

Question 24

Tumor Progression

Answer 24

Timeline: mutation inactivates suppressor gene → cells proliferate → mutations inactivate DNA repair genes → proto-oncogenes mutate to oncogenes → more mutations, more genetic instability, metastatic disease benign tumor cells grow only locals and cannot spread by invasion or metastasis malignant cells invade neighboring tissues, enter blood vessels and metastasize to different sites Colorectal cancer ∙classical example of progression ∙first event is loss of tumor suppressor gene ∙this is followed by mutational activation of K-ras, ultimately leads to loss of p53

Question 25

HBsAG

Answer 25

hepatitis B is a DNA hepadnavirus ∙blood borne pathogen transmitted by inoculation of infected blood or by sexual contact ∙present in saliva, semen and vaginal secretions highest risk groups include patients and staff at hemodialysis centers, physicians, dentists, nurses, and personal working in clinical and pathology labs and blood banks half of all patients with acute hepatitis B have previously been incarcerated or treated for an STD

Question 26

Tumor suppressor genes: DNA repair genes

Answer 26

DNA repair genes usually are not directly involved in cell cycle regulation ∙however, lack of DNA repair activity leads to genetic instability and facilitates mutations in other genes, including oncogenes and tumor suppressors hereditary nonpolyposis colorectal cancer (HNPCC): associated with defects of DNA mismatch repair genes Xeroderma pigmentosum: increased risk of UV-induced skin cancers due to defects in nucleotide excision repair system responsible for removal of UV-cross-linked residues

Question 27

Tumor progression: Clonal Evolution

Answer 27

morphologic changes and tumor progression result from accumulating genetic changes such changes accumulate over years due to genetic instability of tumor cells and lead to heterogeneity of neoplasia despite is initial clonal origin not all cancers progress according to their pattern ∙in pediatric tumors changes are usually rapid, often dependent on mutation in one of the crucial growth-controlling genes, even initial clones of tumor cells can have a malignant phenotype

Question 28

Familial tumors caused by mutations in oncogenes

Answer 28

anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase preferentially expressed in central and peripheral nervous systems germline activating mutations of ALK have been associated with familial neuroblastoma, which segregates as autosomal-dominant disease with limited penetrance mutations and amplification of ALK occur also in sporadic cases of neuroblastoma

Question 29

Cell death

Answer 29

cells either die via apoptosis or necrosis both start the same → cells form blebs the difference is that blebs break down into smaller, more manageable pieces in apoptosis, while in necrosis the blebs fuse and become larger and then the membrane ruptures

Question 30

Free Radicals

Answer 30

3 major effects: ∙lipid peroxidation ∙oxidative modification of proteins ∙DNA effects

Question 31

Cellular Reaction

Answer 31

once the cells get to the area, how they clear the injury, affect damaged cells ∙when leukocytes do their thing

Question 32

Mechanisms of tumor suppressor inactivation

Answer 32

can be point mutations or deletions, as with changes in proto-oncogenes can also be epigenetic changes (i.e. methylation of the promoter) ∙promoter is blocked, so the gene will not be expressed

Question 33

Cancer prefixes point to location

Answer 33

adeno → gland chondro → cartilage hemangio → blood vessels lipo → fat myelo → bone marrow myo → muscle

Question 34

Tumor suppressor genes: APC

Answer 34

adenomatous polyposis coli (APC) gene encodes cellular protein regulating cell proliferation and adhesion ∙involved in colon cancers APC protein interacts with beta-catenin, a signaling molecule in WNT pathway in absence of WNT, APC binds beta-catenin and stimulates its degradation upon WNT stimulation, APC releases beta-catenin, beta-catenin translocates to the nucleus and activates genes promoting cell cycle germline mutations of APC gene lead to development of multiple benign tumors (polyps) in colon, which in almost 100% cases transform to malignant cancer ∙this transformation is associated with loss of second APC allele APC mutations also occur in majority of sporadic colorectal cancers

Question 35

Apoptosis in Pathophysiology

Answer 35

growth of cancers viral infections neurodegenerative disorders

Question 36

Cancer suffixes

Answer 36

-oma → benign -carcinoma, -sarcoma → malignant

Question 37

Cancer nomenclature

Answer 37

carcinomas - cancer of epithelial origin ∙lung cancer, breast cancer, colon, bladder, prostate sarcomas - malignant neoplasms of mesenchymal origin ∙fat, bone and muscle

Question 38

Normal growth regulation

Answer 38

in adult organism, most of the cells are quiescent, cell proliferation is limited to certain types of cells and processes, such as: ∙bone marrow myeloblasts ∙immune cells ∙epidermal cells ∙epithelial cells (e.g. gut) ∙regenerating tissues cell proliferation is a tightly regulated process involving factors stimulating and inhibiting cell divisions cell damage or perturbation in cell cycle leads to cell death (apoptosis)

Question 39

Vascular Reaction

Answer 39

ability to bring more blood to the area ∙dilation of vessels, increased vascular permeability

Question 40

Cancer etiology: Viruses

Answer 40

viruses can contribute to cancer development by: ∙RNA viruses →introduction of viral oncogenes, such as V-SRC, V-ABL, V-MYB (not known in humans) →insertion of strong retroviral promoters next to the cellular oncogenes, which results in its overexpression → Human T-cell leukemia virus-1 (HTLV-1) ∙DNA viruses →synthesis proteins inactivating human genes involved in cell cycle control (HPV) →expression of proteins stimulating cell proliferation (EBV, HBV) →tissue injury leading to induction of regeneration processes (HBV)

Question 41

Invasion and metastasis

Answer 41

normally most tumors are epithelial tumors first step of invasion is disruption of intercellular junctions ∙lose attachment with surrounding cells then the attachment to the extracellular matrix is altered this is followed by increased activity of matrix degrading enzymes → metalloproteinases ∙metalloproteinases will be released by tumor cells, cleave ECM into fragments cells can now migrate through ECM ∙migration mediated by autocrine motility factors and stimulated by chemoattractants

Question 42

What is pathophysiology?

Answer 42

not only cellular and organ changes that occur with disease, but with the effects that these changes have on total body function

Question 43

miRNAs in cancer

Answer 43

miRNAs can work in 2 ways: either cause degradation of RNA or block translation of the RNA oncogenic microRNAs target tumor suppressors, causing loss of tumor suppressor genes tumor suppressor miRNAs target oncogenes ∙loss of miRNAs here cause accumulation of oncogenes alteration of their balance can trigger/facilitate malignant transformation

Question 44

Vascular dissemination and homing of tumor cells

Answer 44

Steps of metastasis ∙Primary tumor →invasion of extracellular matrix →intravasation of tumor cells into blood and lymphatic vessels ∙Blood stream →evasion of cell death induced by lack of attachment - anoikis ∙Metastatic site →adherence of circulating tumor cells to endothelium →invasion of extracellular matrix →formation of colonies and growth of new tumors Homing of tumor cells in the metastatic site ∙site of metastasis may depend on location of primary tumor and its vascular and lymphatic drainage, as well as on tropism of the tumor cells (tumor-specific adhesion molecules recognize their ligands expressed in endothelium of particular organs)

Question 45

Depletion of ATP

Answer 45

Na-K transporter is first affected ∙uses ATP to pull sodium out of cell and potassium into cell ∙maintains polarization of membrane, keeps cell intact loss of ATP means that this pump begins to fail ∙when pump fails, membrane depolarizes, see increase of intracellular calcium resulting in cellular swelling ∙this is reversible, but at some point the swelling will get so bad as to cause cell lysis depletion of ATP also causes the cell to switch to anaerobic metabolism ∙end product here is lactic acid ∙lactic acid causes decrease in cellular pH ∙when cellular pH decreases to a specific point (irreversible cell injury), lysosomes will lyse →once you lyse the lysosome, it will cause the degradation of the organelles and membrane of the cell

Question 46

p53 is a tetrameric transcription factor

Answer 46

p53 protein is a transcription factor, which binds to a characteristic DNA sequence in promoters of genes encoding proteins responsible for cell cycle arrest and apoptosis p53 functional form is a tetramer tumor-associated mutations of p53 genes very often affect DNA-binding domain (DBD)

Question 47

Features of cancer cells

Answer 47

1. self-sufficiency in growth signals
2. insensitivity to growth-inhibitory signals
3. evasion of apoptosis limitless replicative potential
4. sustained angiogenesis
5. ability to invade and metastasize
6. evasion of host immune response

Question 48

Normal growth regulation: Stimulation of proliferation

Answer 48

growth factors initiates proliferation signals ∙released by other cells, tells cell to proliferate ∙for it to work, must have receptor on surface signal-transducing proteins are activated by receptor-growth factor interaction ∙then activates other proteins, which activate other proteins → often phosphorylation cascade at some point, one of the transducing protein translocates to nucleus and activates transcription factors transcription factors then initiate transcription, allowing cell cycle progression ∙allows DNA replication, etc.

Question 49

Steps of angiogenesis

Answer 49

proteolytic degradation of parent vessel basal membrane migration of endothelial cells and endothelial progenitors toward angiogenic stimulus proliferation of endothelial cells recruitment of endothelial progenitors maturation of vessels ∙inhibition of endothelial cell prolferation, capillary tube formation, recruitment of pericytes and vascular smooth muscle cells

Question 50

Lead

Answer 50

no threshold of lead that is safe for the body able to cross blood-brain barrier ∙confuses calcium transporters and takes the place of calcium ∙unique to lead ∙once it gets into CNS, we don’t have a way to get it out causes an increase in ROS (reactive oxygen species), and a decrease in antioxidant system can affect kidney → glomerular fibrosis and proximal tubule mitochondrial damage

Question 51

HBV

Answer 51

two major pathophysiologic mechanisms of liver injury ∙direct cellular injury by the virus ∙induction of the immune response

Question 52

Apoptosis in Physiology

Answer 52

removal of proliferating cell populations (intestinal epithelia) death of host cells that have served their useful purpose embryogenesis (Webbing b/w the toes) control of immune cell numbers hormone-dependent involution of endometrial cells during menstrual cycle

Question 53

Chromosomal translocation and oncogenes activation

Answer 53

when two different chromosomes trade parts of their genetic sequence 2 ways can activate proto-oncogenes ∙change in transcriptional control elements → basically factors that up-regulate transcription are moved to new places of chromosomes ∙synthesis of a novel fusion protein → new sequence created causes production of malignant transformation

Question 54

Tumor suppressor genes: RB (retinoblastoma)

Answer 54

RB encodes DNA-binding protein, which controls G1-S checkpoint in quiescent cells, an active hypophosphorylated RB prevents activation of S-phase genes upon growth factor stimulation, Rb protein is inactivated by cyclin-dependent phosphorylation, which allows progression of cell cycle deregulation of G1-S checkpoint by mutations in one of these genes has been found in majority of cancers

Question 55

Inflammation

Answer 55

immune response is solution to many problems however, the longer we live, we see that inflammation is also the cause of many chronic disease states (i.e. atersclerosis, diabetes, autoimmune diseases) acutely, inflammation causes vascular and cellular reaction

Question 56

Tumor suppressor genes: BRCA1 & BRCA2

Answer 56

breast cancer predisposition gene 1 (BRCA1) ∙germline mutation (truncation, inactivating frameshift mutations) are associated with increased risk of breast and ovarian cancers (85% and 50%, respectively) ∙mutations of BRCA1 have been found in 40-50% of families with multiple breast cancer cases ∙no BRCA1 mutations have been described in sporadic breast cancer,s while incidence in sporadic ovarian cancers is only 5% BRCA2 ∙germline mutations lead to increased risk of breast cancer (80%0, while ovarian cancers are not as common (risk~10%) ∙BRCA2 mutations are associated with increased risk (6%) of male breast cancer both BRCA1 and BRCA2 encode nuclear proteins involved in response to DNA damage and in DNA repair

Question 57

MYC

Answer 57

most commonly involved in human cancer MYC overexpression of MYC can occur due to translocation or amplication –>in Burkitt lymphoma, overexpressed due to a translocation to the chromosome 14, in close proximity to a Ig gene –>in breast, lung and other cancers overexpressed due to gene amplification –>similarly, amplification of related genes N-MYC and L-MYC are common in neuroblastoma and cell cancer of lung, respectively

Question 58

Hyperplasia

Answer 58

increase in number of cells in an organ or tissue ∙can only occur in tissues that are capable of mitotic division controlled process that occurs in response to an appropriate stimulus and ceases after stimulus has been removed more dangerous than hypertrophy → b/c of increased division, increased risk of cancer example: prostate, uterus/breast tissue in pregnancy/puberty

Question 59

Proto-oncogenes

Answer 59

proto-oncogenes encode proteins, which normally stimulate cell proliferation altered forms of proto-oncogenes are designated as oncogenes in cancers, the oncogenes have sustained gain-of-function alterations resulting from point mutations, chromosomal rearrangements or gene amplification mutations of proto-oncogenes usually arise somatically in tumor cells and are dominant

Question 60

Tumor immunity

Answer 60

genetic alterations in malignant tumor cells may result in expression of new, altered proteins, which can be recognized by immune system as non-self ∙this tarts immune defense against tumors Cellular effectors of anti-tumor immunity ∙cytotoxic T lymphocytes (CD8+) recognize peptide antigens present by major histocompatibility complex (MHC) class I molecules, require sensitization in presence of co-stimulatory molecules ∙Natural killer cells (NK) are capable of destroying cells without prior sensitization, do not require MHC-I co-stimulation, recognize stress proteins ∙Macrophages are activated by interferon-y released from T lymphocytes and NK cells, kill tumor cells by release of reactive oxygen metabolites and tumor necrosis factor (TNF) tumor cells can escape immune response of the host by the following mechanisms: ∙selective outgrowth of antigen negative cells ∙loss of expression of MHC-I and/or co-stimulators ∙secretion of immunosuppressants, such as transforming growth factor-β (TGF-β)

Question 61

Necrosis

Answer 61

unscheduled, unregulated cellular death contents of cell spilled into tissue → debris can damage other cells elicits an inflammatory response in general, you get depolarization of membrane that allows calcium to enter, causes lysosome rupture and allows cathepsin release end product can be grangrene

Question 62

Chemical Agents

Answer 62

similar to poisons that can cause cellular damage lead causes problems in body b/c unlike a lot of other substances, there is no threshold of lead that is safe for the body ∙very high levels of lead can cause mental retardation, coma, convulsion and death ∙low levels of lead can cause reduced IQ and attention span, impaired growth, reading and learning disabilities, hearing loss and a range of other health/behavioral effects

Question 63

Mechanisms of Cell Injury

Answer 63

can be complex some agents (like heat) produce direct cell injury some agents (like genetic derangement) produce effects indirectly through metabolic disturbances and altered immune responses most are caused by: ∙depletion of ATP ∙free radical formation ∙disruption of intracellular calcium homeostasis

Question 64

Deregulation of apoptotic mechanisms

Answer 64

deregulation of apoptosis leads to propagation of damaged, mutated cells apoptosis can be triggered by factors outside the cell, or via an internal pathway Some ways this can go wrong: 1. reduced levels of CD95 2. inativation of death-induced signaling complex by FLIP protein 3. upregulation of anti-apoptotic BCL2 (i.e. due to translocation near Ig genes in B-cell lymphoma) 4. down-regulation of pro-apoptotic BAX due to lack of p53 5. loss of APAF-1 6. inactivation of caspase 8 gene due to methylation

Question 65

What causes cancer?

Answer 65

some chemicals, some viruses or bacteria, or radiation genotoxic carcinogens - interact with DNA causing mutations and DNA replication errors non-genotoxic carcinogens - act by changes in expression of genes involved in DNA repair, DNA methylation, cell signaling and proliferation UV, x-rays, radionuclides ∙act via direct damage of DNA, usually cause chromosome breakage and translocations ∙associated with skin cancer, leukemia, as well as other cancers effect of carcinogenic agents is modified by individual susceptibility to cancer development, defined by variations in host proteins, such as enzymes involved in metabolism of chemical carcinogens or DNA repair, as well as host immune response

Question 66

Cell cycle regulation

Answer 66

After stimulation with growth factors, cells enter cell cycle Progression of the cell cycle is driven by cyclins and cyclin-dependent kinases (CDKs) Cell cycle is tightly controlled by CDK inhibitors Transition from G1 to S phase is a particularly important checkpoint Dysregulation of cyclin and CDK expression or their mutations occur often in cancer cells and promote proliferation. The most common perturbations affect proteins involved in G1-S transition: ∙Overexpression of cyclin D (breast, esophagus, liver cancers, lymphomas) ∙Amplification of CDK4 (melanomas, sarcomas, glioblastomas)

Question 67

Clinical signs of inflammation of liver

Answer 67

fatigue hepatomegaly athralgias polyarteritis nodosa (serious blood vessel disease in which small and medium-sized arteries become swollen and damaged) membranoproliferative glomerulonephritis jaundice

Question 68

Proto-oncogenes: Growth factors

Answer 68

overexpression of autocrine growth factors • platelet-derived growth factor (PDGF) in glioblastomas • transforming growth factor a (TGF-a) in sarcomas

Question 69

Gangrene

Answer 69

Dry gangrene ∙any time you interfere with arterial blood supply ∙almost always found in extremities (specifically lower extremities) ∙turns black b/c bacteria growth takes iron from heme and turns it into iron sulfide (which is black) ∙can be caused by atherosclerosis, neuropathy Wet gangrene ∙any time you interfere with venous blood supply ∙stagnation of blood causes bacterial growth ∙forms very cold, black tissue ∙usually found in patients with bed sores (commonly in sacral region)

Question 70

Levels of Cellular Injury

Answer 70

stress causes cell to adapt, but at some point it will eventually cause injury injuries can lead to cell death, but at some point along cellular pathway, the injury can be reversible at some point, the injury becomes irreversible, and the cell will die, either by apoptosis or necrosis Stresses: mechanical forces (usually superficial injuries), electrical injuries, (electricity can carry heat that damages, electrical impulses can change electrical balance w/in body), nutritional imbalances, biological agents (viruses/bacteria), poisons

Question 71

Liver failure

Answer 71

reduced liver protein synthesis impaired glycogenolysis and gluconeogenesis reduced production of bile salts impaired processing of endogenous steroid hormones

Question 72

Proto-oncogenes: Signal-transducing proteins

Answer 72

Ras ∙one of the most common abnormalities in human cancer, particularly high incidence in colon and pancreatic cancers ∙encodes p21 G protein, which transmits mitogenic signal from the activated growth factor receptors, through the phosphorylation cascade of other transducing proteins, to the nucleus ∙point mutations changing amino acids in the pocket binding GTP (codons 12 & 13) and region essential for GTP hydrolysis (codon 61) lead to constitutive activation of RAF-MAPK mitogenic cascade →GTP will not be hydrolyzed and RAS will be active forever ABL ∙mutation occurs in chronic myeloid leukemia ∙non-receptor tyrosine kinase, promotes apoptosis ∙in chronic myeloid leukemia, ABL gene is translocated to chromosome 22, where it fuses with part of the breakpoint cluster region (BCR) gene →aberrant chromosome 22 is designated chromsome Philadelphia ∙BCR-ABL fusion protein retains in cytoplasm and, due to its high tyrosine kinase activity, stimulates several pathways, including RAS-RAF mitogenic cascade

Question 73

Mechanisms of oncogene activation

Answer 73

2 different mechanisms point mutations → small changes in DNA sequence which cause change is function gene amplification → when part of the chromosome is present in many copies overexpression → high expression of gene causes increased levels of mRNA and therefore increased levels of protein

Question 74

Extremes of Temperature

Answer 74

Heat ∙accelerates cell metabolism ∙inactivates temperature sensitive enzymes (can alter metabolism) ∙disrupts the cell membrane ∙coagulation of blood vessels ∙coagulation of tissue proteins Cold ∙increases blood viscosity ∙induces vasoconstriction (SNS) ∙ice crystal formation ∙capillary stasis ∙arteriolar and capillary thrombosis

Question 75

Chronic Hepatitis

Answer 75

commonly due to poor T cell response in immunocompromised host ∙HIV ∙neonates continual destruction and regeneration of liver parenchyma ∙increases risk of cirrhosis and carcinoma if superinfection with hepatitis D occurs ∙risk of chronic liver disease and filminant hepatitis