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SPM (ARSH) > Weeks 5-8 > Flashcards

Weeks 5-8 Flashcards

1
Q

Identify the type of necrosis.

  • In its appearance, what are its microscopic features?
  • What are features of its gross appearance?
A
  • Liquefactive necrosis
    • Gross: produces a gelatinous and purulent (aka pus)
    • Microscopic: infiltration of ghost cells and debris by neutrophils (multilobed)
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2
Q

What are the two types of splicing mutations that can occur and provide examples of diseases that may result from these mutations?

A
  • Invariant GT and AG dinucleotides in the 5’ and 3’ splice site boundaries causing the intron to be maintained in mature mRNA
    • CFTR
    • Beta thalassemia
  • Mutations in an ESE can alter dsmRNA splicing by affecting binding of splicing proteins
    • Spinal Muscular Atrophy
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3
Q

Explain CRISPR.

A
  • CRISPR
    • CRISPR/Cas are RNA guided site-specific DNA nucleuses
    • CRISPR located mutated gene via RNA sequence
    • Nuclease activity removes mutated gene and replaces with donor non-mutated DNA
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4
Q

Explain how GATA regulates genes involved with hematopoiesis?

A
  • GATA TFs are developmental regulators of genes involved in hematopoiesis
    • GATA2 is elevated in early erythroid progenitors
    • High levels of GATA2 → enhancement of GATA1 expression → high levels of GATA1 → GATA1 competitively binds to FOG1 → GATA2 suppression
    • GATA1 has higher affinity for GATA sequences, so it can no longer go backwards in development → destined to be an erythrocyte
  • GATA upregulates various forms of beta-globin synthesis needed at different points in development by binding LCR (locus control region = enchancer) and respective promoter
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5
Q

What happens if a mutation in BRCA2 occurs?

A
  • Mutations in BRCA2 (tumor suppressor gene)
  • In the absence of active BRCA2, HR is defective and other, more error-prone pathways such as NHEJ take over, leading to mutations, genomic instability and transformation
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6
Q

What is the purpose and composition or irregular dense connective tissue fibers?

A
  • Purpose - resists stretching and distension (skin dermis/colon)
  • Composition
    • Mostly collagen fibers that are irregular (random orientation)
    • Sparse amounts of cells, mostly fibroblasts
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7
Q

What are the steps of Base Excision Repair?

A
  1. DNA glycosylase identifies and excises damaged base → abasic site
  2. An endonuclease creates nick in strand
  3. dRpase removes ribose
  4. DNA polymerase inserts correct nucleotide
  5. DNA ligase seals nick on strand
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8
Q

Identify this picture.

A

Ground substance.

HINT:

ITS BLUE MOFO

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9
Q

What are the mechanisms of Oxygen based endogenous damage?

A

ROS attacks guanine to form 8-oxoguanine → pairs with A on opposite strand → A pairs with T at replication, eliminating G on original strand

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10
Q

Differentiate necrosis from apoptosis.

A
  • Necrosis is initiated by exogenous stimuli leading to the denaturation of cellular components
    • Has inflammation
  • Apoptosis is initiated by intracellular signals and leads to phagocytosis
    • Does not have inflammation response
    • Caused by deprivation of GFs or from radiation/chemotherapy
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11
Q

What are the mechanisms of ALKYALTION based exogenous damage?

A
  • Alkylating agents: nitroso compounds (NOCs) come from cigarette smoke, exhaust, etc. → interstrand bulky ducts with guanine
  • Cisplatin binds to guanine in DNA to form bulky monoadduct
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12
Q

How are chromosomal microdeletions detected?

A
  • Chromosomal microdeletions cannot be detected by karyotyping but by FISH (uses WBCs to fluoresce chromosomes)
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13
Q

How does the loss of RB1 or the intervention of CKIs cause cells to proliferate?

A
  • RB1 controls the cell cycle at various checkpoints
  • Cyclin-dependent kinase inhibitors (CKIs such as p21) inhibit cyclin-dependent kinases (CDKs) → if CKIs have mutations, the RB pathway is disrupted → cancer
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14
Q

Compare the mechanisms and effects of drugs (3) that target transcription of Estrogen Receptors.

A
  • Estrogen Receptors (ER)
    • In ER+ breast cancer, the ER is implicated in its pathogenesis
    • Selective Estrogen Receptor Modulators (SERMs) competitively inhibit ERs, not allowing for necessary conformational change to bind co-regulators
      • Tamoxifen
      • Raloxifene
    • Selective Estrogen Receptor Downregulators (SERDs) covalently bind ERs, causing degradation
      • Fulvestrant
    • Aromatase Inhibitors
      • Aromatase converts testosterone to estrogen
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15
Q

What signals for splicing of introns to occur?

  • Mutation here causes what?
A
  • Introns begin and end with highly conserved nucleotides
    • 5’ GU…AG 3’ for RNA
  • Mutations in these four nucleotides will result in disease pathologies
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16
Q

What is the pathway that Ras takes leading to cancer (compared to the normal)?

A
  • Cancer: Ras is unresponsive to GAP and cannot hydrolyze GTP, leaving Ras in active form
  • Normal: growth exchange factor (GEF) binds Ras-GDP → exchange of GDP for GTP → Ras-GTP is active → GAP binds Ras-GTP → GAP hydrolyzes Ras-GTP → Ras-GDP is inactive
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17
Q

What are the mechanisms of CHEMICAL based exogenous damage?

A
  • Chemical agents → creates bulky adducts → requires AGT/MGMT Direct Reversal Pathway
    • Benzo(a)pyrine from cigarette smoke gets metabolized in the body → BPDE (diol epoxide form) → guanine adduct → causes G:C to T:A transversion mutations
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18
Q

Explain the PARP inhibitor mechanim.

A

Normal PARP1: repairs SSBs

PARP inhibition causes accumulation of SSBs → cause DSBs because no BRCA2 to repair via HR → apoptosis

PARP inhibitors do not affect normal cells because they have BRCA2 and functioning HR pathway

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19
Q

What are the three main locations of regular dense connective tissue fibers?

A
  • Tendon (muscle to bone)
  • Ligaments (bone to bone)
  • Aponeuroses (muscle to muscle)
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20
Q

What are polygenic genes?

Explain how GWAS relates?

A
  • Multiple genes have the ability to affect phenotypic pathologies
  • GWAS
    • Maps single nucleotide polymorphisms across the human genome to look for statistically significant differences in nucleotides
    • Statistically significant SNPs can correlate to mutation of genes nearby
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21
Q

What are the two disorders of elastic fibers?

A
  • Marfan’s Syndrome
  • Solar Elastosis of Skin
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22
Q

What tissues are most affected in Ehlers-Danlos Syndrome?

A
  • Tissues rich in collagen, such as skin and hollow organs (GI and blood vessels) are most affected
    • Tissues lack tensile strength → hyperextensile skin, hypermobile joints
      • joint dislocation
    • Skin is stretchable, fragile, prone to trauma,
    • Internal organs → rupture (GI, great vessels)
    • Rupture of cornea and retinal detachment
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23
Q

What occurs in Burkitt’s Lymphoma?

A
  • Burkitt’s Lymphoma: translocation and subsequent fusion of genes on chromosome 8 and 14 → overexpression of c-myc → transcription of genes that stimulate cell proliferation
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24
Q

What are six different drugs used that inhibit RTKs? What does each selectively inhibit?

A
  • Gleevec – selective inhibitor of Bcr-Abl
  • Gefitinib – selective inhibitor of EGFRs
  • Erlotinib – selective inhibitor of EGFRs for palliative care treatment
  • Trastuzumab – selective inhibitor of HER2
  • Cetuximab – selective inhibitor of EGFRs
  • Rituximab – selective inhibitor of CD20 antigen
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25
Q

What is the mechanims behind Cockayne’s Syndrome?

A
  • Mutations in CSA and CSB → defect in TCR pathway → unable to bind to stalled polymerase → premature aging with no increased risk for cancer
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26
Q

What is the mechanism of action of hydroxyurea?

A

MOA: inhibits ribonucleotide reductase, prohibiting conversion of ribose to deoxyribose for use in DNA synthesis

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27
Q

Explain dominat negative mutations.

A

Dominant negative mutations: a loss of function dominant mutation that poses a negative effect on the wildtype

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28
Q

How does the kidney respond to normal and low oxygen levels?

A
  • Normoxia: normal oxygen supply → HIF-alpha’s proline residues are hydroxylated → VHL binds → ubiquitinates HIF-alpha → degradation
  • Hypoxia: inadequate oxygen supply → nuclear translocation of HIF-alpha → dimerizes with ARNT → binds to hypoxic response element (HRE) → transcription of various genes (i.e HPO for erythropoiesis, transferrin, angiogenesis)
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29
Q

What are the mechanisms of UV based exogenous damage?

A
  • UV light → creates cross-linking between adjacent pyrimidines → base mispair during DNA replication → requires nucleotide-excision repair
  • UVB light cause DNA damage (cross links)
  • UVA causes oxidative stress (leading to endogenous damage)
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30
Q

What are the steps in Mismatch Repair (MMR)?

A
  1. Mismatches and single displaced bases are recognized by hMutS-alpha. Larger insertions and deletions are recognized by hMutS-beta
  2. Mut S recruits MutL, which recognizes the template strand based on the methyl groups or ss breaks on newly synthesized DNA
  3. MutH also attaches to form a Mut-complex and creates a kink in the DNA.
  4. Mut-complex then directs exonucleases to nick in daughter strand
  5. DNA polymerase and ligase fill the strand and seal the nick.
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31
Q

What does a nonfunctional MYH result in?

Why?

A
  • MYH – a DNA glycosylase for 8-oxoG
    • Cells with mutated MYH show increased G to T mutations in original strand
    • G to T mutations in APC gene → familial adenomatous colon polyposis (FAP)
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32
Q

What are two main regulators of the cell cycle and what are their pathways?

A
  • RTK activates Ras-GTP → → activates cyclin dependent kinases → phosphorylate Rb → allows for cell proliferation
  • P53 activates p21 → p21 deactivates cyclin
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33
Q

What type of tissue is depeicted in the image?

A

Dense Irregular Connective

HINT:

Fibers in irregular pattern

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34
Q

What are the two chromatin higher-order structures responsible for DNA compaction in interpahse nuclei and metaphase chromosomes?

A

30-nm Fibers and Loops

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35
Q

What occurs in chronic myeloid leukemia?

A
  • Chronic Myeloid Leukemia: translocation and subsequent fusion of genes on chromosome 9 and chromosome 22 →increased expression of tyrosine kinase → cancer
    • Imatinib binds to tyrosine kinase → inactivation
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36
Q

Which enzymes can change the topology (relaxed vs supercoiled) of DNA?

What are the two types of this enzyme and how do they work?

A

Topoisomerases

  • Topoisomerase I
    • Makes a temporary single-stranded break that allows relaxation of a superhelix
  • Topoisomerase II
    • Makes a temporary double-stranded break to pass around another portion of DNA
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37
Q

What are the two different types of the antimitotic agents, topoisomerase inhibitors? What is one example of each? What are the two contrasting mechanisms of action? What phase of the cell cycle do these drugs work in?

A
  • Occurs in S phase
  • Topoisomerase II inhibitors
    • Example: etoposide
    • MOA: topoisomerase II induces ds breaks to unwind DNA and inhibitors prevent resealing by the enzyme
  • Topoisomerase I inhibitors
    • Example: topotecan
    • MOA: collision between replication fork and topoisomerase I – DNA complex → ds breaks → cell death
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38
Q

Identify the type of necrosis.

  • In its appearance, what are its microscopic features?
  • What are features of its gross appearance?
A
  • Caseous necrosis
    • Gross: cottage cheese appearance
    • Microscopic: cell debris walled off by WBCs
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39
Q

Differentiate neoplasia from hyperplasia, metaplasia, and dysplasia by defining each one of them.

A
  • Neoplasia: irreversible and uncontrolled growth from a clonal cell
  • Hyperplasia: increase in number of cells
  • Metaplasia: replacement of one cell type with another
  • Dysplasia: “disordered growth” from loss of uniformity and loss of organization of individual cells
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40
Q

For acute inflammation,

  • What is the gross appearance?
  • What is the microcopic appearance?
  • What occurs to the blood vessels?
  • What is an example?
A
  • Exudation of fluid (high protein, thick fluid)
  • Neutrophilic infiltration (multilobed)
  • Vasodilation with increased vascular permeability
  • Example: acne
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41
Q

What is the mechanism of action of overstimulation of LHRH and GnRH receptors?

A

Overstimulation of LHRH and GnRH receptors with LHRH and GnRH analogues → negative feedback inhibition → internalization and desensitization of receptors → decrease in testosterone and estrogen

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42
Q

Identify the type of necrosis.

  • In its appearance, what are its microscopic features (necrotic)?
  • What are features of its gross appearance?
A
  • Fibrinous necrosis
    • Microscopic: autoimmune deposits of antigen-antibody onto blood vessel walls
      • Inflammation of blood vessels (vasculitis) causes pinkish tint
    • No gross appearance as it cannot be visualized grossly
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43
Q

What do nucleosomes fold into in cells undergoing mitosis or meiosis?

A
  • Loops
    • Nucleosomes fold into this in cells undergoing mitosis or meiosis to keep DNA in a more accessible form
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44
Q

Describe tRNA formation.

What enzyme is used?

What are the two functions of this enzyme?

A
  • Formation
    • tRNA charged with an AA using 2 high energy bonds
      • AA + ATP → aminoacyl-AMP + PPi
    • Aminoacyl-tRNA Synthetase matches AA with anticodon on tRNA
    • Aminoacyl-tRNA Sythetase proofreads match
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45
Q

What are two examples of drugs and their mechanism of action of antiestrogens, a type of hormonal agent?

A
  • Tamoxifen, fulvestrant
  • MOA: inhibits ERs
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46
Q

Compare and contrast extrinisic vs intrinsic apoptotic pathways.

  • Where do they both converge?
A
  • Extrinsic: activation of death receptors → caspases pathway
  • Intrinsic: directly activates caspases
  • Both converge at mitochondria on caspase3 and release of cytochrome C from mitochondria → death
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47
Q

Describe the example of Her2/Neu in resistance to therapy. What drug is involved initially and what drug is involved to circumvent the resistance?

A
  • Her2/Neu example of mutations that drive resistance to therapy
    • Trastuzumab can bind to Her2/Neu Receptor, signaling for immune response
      • Mutation in receptor leads to insensitivity to drug, requiring new treatment
    • Lapatinib is a 2nd generation Her2/Neu drug, but acts intracellularly on the receptor, tagging it for degradation
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48
Q

How does mTOR regulate translation?

How is it related to cancer?

What drug targets mTOR?

A
  • mTOR phosphorylates “blocking” proteins on eIF4E (4E-BP) and eIF4A (PDCD4) → eIF4E and eIF4A are free to bind to eIF4G → form eIF4F (entire eIF4 complex) → initiation of translation
    • Since mTOR promotes cell growth and proliferation it can be targeted for cancer drugs therefore reducing cell growth
      • Rapamycin
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49
Q

Identify the type of epithelia.

A

Simple Columnar

Found in GI tract

Function: absorption and secretion

Can be ciliated (respiratory tract and fallopian tube)

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50
Q

What is the mechanism of action of aromatase inhibitors, a type of hormonal agent? Who is it given to? What is one example of a drug used?

A
  • Anastrozole
  • Given to post-menopausal women
  • MOA: acts by inhibiting aromatase which prevents conversion of antrostenedione to estrone in the adrenal gland
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51
Q

Steps of termination of translation in eukaryotes?

A
  • Steps
    1. RF1 mimics tRNA structure and binds to stop codon in A-site
    2. RF3 terminates translation by disassociating ribosome subunits from mRNA via GTP hydrolysis
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52
Q

What is the “Gleevac” example of mutations that drive resistance to therapy?

A
  • Minor populations of cells containing total resistance mutations in Bcr-Abl gene before treatment can grow up as new population in tumor
  • Overexpression of BCR-ABL leads to resistance
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53
Q

How was the experiment by Payton Rous with Rous Sarcoma Virus (RSV) conducted?

  • What was the impact and the conclusion?
A
  • Extracted sarcoma from chicken 1 → injected into chicken 2 → chicken 2 develops sarcoma
  • Impact: defines system for cancer research
  • Later found that cancer is derived from our own genome
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54
Q

What percentage of cells are killed with 1 log kill drugs, 2 log kill drugs, and 3 log kill drugs?

A
  • 1 log kill drug = 90% cells killed
  • 2 log kill drug = 99% cells killed
  • 3 log kill drug = 99.9% cells killed
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55
Q

What are the six features of malignant neoplasms?

A

Malignant Neoplasms

  • Pleomorphism – nuclei vary in shape and size
  • Nuclear changes – hyperchromasia (dark chromatin), prominent nucleoli (increased rRNA – lots of protein synthesis), and increased Nucleus/Cytoplasm ratio
  • Increased mitotic activity and abnormal mitoses
  • Loss of polarity – inability to differentiate between basal and apical cells
  • Giant cells
  • Anaplasia – lack of differentiation, encompasses many of the above features
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56
Q

What are -nib, -mab, and -mib classes of drugs?

A
  • -nib class of drugs act on RTKs
  • –mab class of drugs are monoclonal antibodies that bind to extracellular receptor or to the hormone
    • monoclonal because only antibody produced by immune cell
  • –mib class of drugs act on intracellular receptors
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57
Q

What is the mechanims behind Xeroderma Pigmentosum?

A

Caused by autosomal recessive mutations in NER genes → increased mutations due to UV exposure

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58
Q

What is the purpose and composition of regular dense connective tissue?

A
  • Purpose - strength
  • Composition
    • Collagen fibers in parallel array and densely packed
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59
Q
  • What are toposiomerase inhibitors and what are they used as?
  • What are the two examples? How do they work?
A
  • Topoisomerase Inhibitors: supercoil accumulation can lead to apoptosis of the cell
    • Doxorubicin: inhibits topoisomerase II, allowing superhelical turns to accumulate and signal apoptosis
    • Etoposide: inhibits topoisomerase II by binding the enzyme-complex and trapping the complex in its cleavable state
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60
Q

Define denaturation (melting) of the double helix and how it occurs.

  • What else can cause denaturation?
A
  • Denaturation (melting): double helix unravels and separates into single strands by breaking hydrogen bonds
    • Each sequence of DNA has specific melting temperature Tm based on GC ratio
    • Heat, low pH, low salt concentration
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61
Q

What kind of therapeutics can be used to treat splicing mutations?

  • What is an example that treats the premature stop codon in Duchenne’s Muscular Dystrophy?
A
  • Therapeutics
    • Oligonucleotides repress splicing mutations: cover up cryptic splice sites and direct splicing patterns back to wild type
  • Premature Stop Codon: DMD
    • Eteplirsen: an oligonucleotide therapeutic can cover up stop codon and help make limited functional proteins (BMD)
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62
Q

Why are mutations not equal?

A

some mutations (i.e. p53) cause greater genomic instability, allowing for accumulation of mutations

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63
Q

What are the mechanisms of ALKYLATION based endogenous damage?

A

Adds CnHn+2 group to bases

SAM and nitroso compounds (NOC) alkylate all DNA bases

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64
Q

How/when does Ferritin and Transferrin Receptor Regulation occur?

A
  • Low intracellular Fe+2: Iron Response Protein (IRP) has no Fe+2 bound
    • Binds 5’ UTR at Iron Response Element (IRE) region → stops initiation in translation → no synthesis of ferritin
    • Binds 3’ UTR at IRE region → stabilizes mRNA → synthesis of TfR
  • High intracellular Fe+2: IRP has Fe+2 bound → change in conformation of protein → cannot bind IRE regions
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65
Q

What is the reverse process of EMT and when is it used?

A
  • MET is the reverse process once the tumor cell lodges at secondary site
    • Secondary tissue lacks signals to induce EMT, so reverts to MET
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66
Q

Why do steps in progression ≠ number of mutated genes?

A

different mutations may take several steps (two-hit hypothesis in tumor suppressor genes)

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67
Q

Define insulators in transcription.

A
  • Insulators: CTCF protein can stabilize loop domains of DNA and can act to either enhance a group of genes or silence them
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68
Q

Why is Temozolamide usedto treat cancer?

A
  • Temozolamide (TMZ) is an alkylating agent that triggers glioblastoma cells for death
  • O6-benzylguanine is administered in conjunction with TMZ to inhibit MGMT
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69
Q

How does Ehlers-Danlos Syndrome occur and what is it a defect in (what subtype specifically)?

A
  • Defect:
    • Collagen Type III
    • mutation in lysyl hydroxylase → abnormal cross-linking of collagen fibers
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70
Q

What type of tissue is surrounding the black circle?

A

Loose Connective

*Circle is the mammary gland.

HINT:

abundant cells in layer and irregular pattern

71
Q

What are drug transporters, the gene encoding them, and how do they cause drug resistance?

A
  • Drug Transporters: ATPases that transport small molecules out of the cell
    • P-glycoprotein encoded by mdr1 gene
    • Upregulation causes more drug to be pumped out
72
Q

What is the significance of mRNA localization?

  • How does it occur?
  • Provide an example of a protein that takes part in this process
A
  • mRNA can be translated at different sites across a cell by transportation via microtubule
    • Translation of mRNA in dendrites can be activated by depolarization of membrane
    • FMRP: acts as a chaperone to repress mRNA translation until it reaches target location
73
Q

What are the 4 cellular adaptive processes?

A
  • Hypertrophy - increase in size of terminally differentiated cells
  • Hyperplasia - increase in number of cells in an organ
  • Atrophy - decrease in number of cells
  • Metaplasia - changing from one cell type to another
74
Q

What is an inhibitor of p53 and what does it result in?

A
  • Inhibitors of p53
    • MDM2 – binding to p53 leads to degradation and downregulation of transcription
75
Q

What are the steps of Global Genome Repair (GGR)?

A
  1. XPE or XPC binds NER lesions
  2. Recruits XPA, which recruits helicase TFIIH
  3. TFIIH unwinds DNA strand
  4. XPG and XPF are endonucleases that cut each side of lesion
  5. DNA Polymerase and DNA Ligase fills and seals gap
76
Q

Identify the type of necrosis.

  • In its appearance, what are its microscopic features (necrotic)?
  • What are features of its gross appearance?
A
  • Gangrenous necrosis
    • Gross: skin looks black and dead
    • Microscopic: initially coagulative necrosis (dry) and then liquefactive necrosis (wet)
77
Q

What are the mechanisms (2) of WATER based endogenous damage?

A

Depurination: water attacks guanine, creating abasic site

Deamination: water attacks cytosine, creating uracil

78
Q

What are Kozak sequences?

A

Kozak Consensus Sequence: ribosome will ignore AUG sequences until A or G is at -3 position upstream and G at +4 position downstream

79
Q

What occurs to produce mRNA from pre-mRNA?

A
  1. 5’ Cap
    • eIF4 binds to initiate protein synthesis
  2. Splicing
    • Introns: non-coding region
    • Exons: codes for AAs
  3. 3’ End Formation with PolyA Tail
  4. Export to Cytosol
80
Q

What do nucleosomes fold into in terminally differentiated cells?

A
  • 30-nm Fibers
    • Nucleosomes fold into this in terminally differentiated cells because DNA is not needed
81
Q

Define the function of ferretin and transferrin receptors.

A
  • Ferritin: large intracellular iron storage protein
  • Transferrin Receptor (TfR): recognizes iron-bound transferrin and transport it into cell
82
Q

Identify tissue fiber.

A

Elastic fibers

HINT:

long fibers look like slinky(s)

83
Q

How can the disruption of apoptosis regulators lead to cancer?

  • Discuss this in terms of anti-apoptosis and prop-apoptosis.
  • Give examples of families of proteins related to each.
A
  • Disruption of apoptosis regulators in cancer
    • Anti-apoptosis: upregulation of these proteins leads to cancer
      • Bcl2 family of proteins
    • Pro-apoptosis: down regulation of these proteins leads to cancer
      • Bax family of proteins
84
Q

What are 4 processes that are considered to be epigenetic?

A
  • Developmentally regulated transcriptional factors
  • Post-translational histone modifications
  • Regulatory RNA transcription
  • DNA methylation reproduced through cell divisions
85
Q

What causes solar elastosis of the skin and where do the defects lie?

A
  • Repeated exposure to ultraviolet radiation → premature aging (wrinkling, solar elastosis, irregular pigmentation)
  • UV radiation → degradation of collagen and remodeling of fibrillin microfibrils → truncated → nonfunctional elastic fibers → decreased skin elasticity
  • Seen as irregular fibers and bluish discoloration in dermis
86
Q

Steps in NHEJ (non-homologous end joining)?

A
  1. Ku70/80 binds DSBs and recruits DNA-PK kinase
  2. DNA-PK activates Artemis exo- and endonucleases which trim sticky ends
  3. DNA Polymerase and DNA Ligase combines strands
87
Q

What type of tissue is depicted in the image?

A

Dense regular connective

HINT:

fibers in parrallel pattern

88
Q

What is the Ras activation pathway? (Its huge and detailed)

A
  • Ligand binds to one subunit of Receptor Tyrosine Kinase (RTK) → cross-phosphorylation of RTK dimer at cytoplasmic tyrosines → SH2 domains on proteins bind to phosphotyrosine depending on the 3 AA residues after Y → recruits SOS → SOS complex acts on Ras-GDP to replace with Ras-GTP → Ras-GTP binds signaling partners → activates kinases → activate TFs → transcription
89
Q

What are the steps of Steps of Transcription Coupled Repair (TCR)?

A
  1. Bulky adduct stalls RNA polymerase
  2. CSA and CSB binds to stalled polymerase and recruits XPA
  3. TFIIH unwinds DNA strand
  4. XPG and XPF are endonucleases that cut each side of lesion
  5. DNA Polymerase and DNA Ligase fills and seals gap
90
Q

What are the types of collagenopathies (diseases of collagen)

A
  • Osteogenesis Imperfecta
  • Ehlers-Danlos Syndrome
91
Q

Define ehancers in transcription and where is it located on a gene.

A
  • Enhancers: bind transcription factors that brings enhancer and promoter into close proximity by looping DNA activating transcription
    • Can be upstream or downstream from gene
92
Q

Steps in HR (homologous recombination)?

A
  1. BRCA1 does 5’-3’ resection (creates sticky ends)
  2. BRCA2 attaches to sticky ends and recruits Rad51
  3. Rad51 mediates strand invasion into homologous chromatid
  4. Formation of Holliday Junction
  5. Branched migration via RNA polymerase
  6. Two strands form
93
Q

What is the difference between grading and staging?

A
  • Grading is based on histologic appearance (mitotic spindles, differentiation of tissue)
  • Staging is based on tumor size, presence in lymph nodes, and presence of metastasis
    • Presence of metastasis automatically makes cancer a stage four
94
Q

What are the three different types of the antimitotic agents, microtubule inhibitors? What are the two contrasting mechanisms of action? What phase of the cell cycle do these drugs work in?

A
  • Vinca alkaloids
    • MOA: prevents assembly of microtubules by binding to tubulin dimers that go into structure
  • Taxanes
    • MOA: prevents disassembly of microtubules by binding to assembled microtubules
  • Estramustine
95
Q
  • Describe how the conversion of dUMP to dTMP occurs. What enzyme is used?
  • Describe how the conversion of DHF to THF occurs. What enzyme is used?
A
96
Q

What is one example of a angiogenesis inhibitor? What RTK does it selectively inhibit?

A

Bevacizumab – selective inhibitor of VEGF

97
Q

Identify the type of epithelia.

A

Stratified Squamous

Found in large exocrine gland ducts and anorectal junction

Function: barrier and conduit

98
Q

How does aneuploidy appear and name 5 disorders (the chromosome they effect and symptoms asssociated with them)?

A
  • 2n-1 is monosomic
  • 2n+1 is trisomic
  • Disorders (13, 18, 21 → PED)
    • Trisomy 13 – Patau Syndrome: 47,XX,+13
    • Trisomy 18 – Edward Syndrome: 47,XX,+18
    • Trisomy 21 – Down Syndrome: 47,XX,+21
    • Monosomy X – Turner Syndrome: 45,X
      • Female with infertility and adult stature
    • Trisomy XXY – Klinefelter Syndrome: 47,XXY
      • Male with tall stature, long extremities, hypogonadism, and breasts
99
Q

How is TNFR targeted for anti-inflammatory therapies?

A
  • TNFR antibodies block inflammation by blocking TNFR pathway, blocking phosphorylation of IKB, therefore sequestering NK-kB in cytosol
100
Q

What is the general description of Fragile X Syndrome and what three nucleotide segment repeats?

A
  • Fragile X
    • DNA polymerase slippage that causes trinucleotide repeat expansion
    • Repeating nucleotides: CGG
101
Q

What is the pro-inflammatory pathway?

What are its target genes?

A
  • Cytokine (pro-inflammatory) binds TNFR (cell surface receptor) → TNFR activates IKK → phosphorylating IKB → release of NK-kB (TF) → pro-inflammatory transcription
  • Target genes include pro-inflammatory cytokines, interleukins (IL variants), nitric oxide synthase, and COX-2
  • Positive feedback loop due to further transcription of pro-inflammatory cytokines
102
Q

Identify the type of epithelia.

A

Stratified Columnar

Found in large exocrine gland ducts and anorectal junction

Function: barrier and conduit

103
Q

What are the two ATP-dependent chromatin remodelers?

A

SWI/SNF and ISWI

104
Q

What is the physiology of a normal RTK (receptor tyrosine kinase) and a mutated RTK (two examples)?

A
  • Normal RTK: ligand-dependent firing/dimerization
    • Deactivation of RTK occurs through endocytosis
  • Mutated RTK
    • Signal point mutations or deletions in the tyrosine kinase receptor can cause ligand-independent firing/dimerization
    • Autocrine Signaling: through activation of GF gene, cells can self-produce ligand for RTK
105
Q

What are the steps in the formation of metastases (in depth)?

A
  • Primary tumor formation → angiogenesis due to hypoxic conditions → permeable tumor vasculature → EMT → intravasation (enters blood) → transport through blood → arrest in microvessels → extravasation (leaves blood) → formation of micrometastasis site → dormant or colonization to create primary tumor at secondary location
106
Q

What are several examples of antitumor antibiotics and what is their mechanism of action?

A
  • Examples: anthracyclines, dactinomycin, and bleomycin
  • MOAs
    • Intercalation into DNA – structure is flat so they can slide between base pairs of DNA, preventing DNA and RNA polymerases from acting
    • Generation of ROS – causes DNA cleavage
    • Binding to cell membranes – hydrophobic regions disrupt processes
107
Q

What is the mechanism of action of progestin, a type of hormonal agent? What is one cancer it is used to treat?

A
  • MOA: agonists for PRs; triggers cell differentiation of immature cancer cells
  • Used to treat endometrial cancer
108
Q

What are examples of alkylating agents, the general mechanism of action, and side effects?

A
  • Examples: Nitrogen mustards, cisplatin, temozolomide (TMZ)
  • MOA: effectively attacks DNA of dividing cells
  • Side Effects: non-specifically attacks normal dividing cells
    • Hair follicles: hair loss
    • RBCs: anemia
    • WBCs: immunosuppression
    • Epithelial cells of GI tract: GI issues
109
Q

What is one example of a proteasome inhibitor?

A

Bortezomib – specific and reversible inhibitor of proteasomes that degrades pro-apoptotic proteins

110
Q

How/Why does a keloid occur?

A
  • Hypertrophic scar, due to excessive collagen accumulation in response to injury
  • Does not regress on its own but extends beyond boundary of injury
111
Q

What are two examples of chromosomal rearrangement to the genesis of an oncogene and how do they occur?

A
  • Burkitt’s Lymphoma – t(8,14)
    • Results in fusion of c-myc (transcription factor) to immunoglobin gene → overexpression
  • Chronic myelogenous leukemia – t(9,22)
    • Results in fusion of abl (tyrosine kinase gene) and bcr genes → constitutively active tyrosine kinase
112
Q

How does the angiogenic switch in tumor cells occur allowing for metastasis?

A
  • Tumor cells become hypoxic → express HIF-1alpha → transcription of VEGF and PDGF → proliferation/migration and increase in “more permeable” tumor vasculature network
  • This permeable vasculature allows for tumor invasion and expansion (read: metastasis)
113
Q

Identify the type of epithelia.

A

Simple Cuboidal

Found in glands and tubules

Function: absorption, secretion, barrier, and conduit

114
Q

What is the purpose of the collagen fibers?

A

Allow for flexiblity with tensile strength

115
Q

Structure of of NR (nuclear receptors)?

A
  • Nuclear Receptor (NR) Transcription Factors
    • Steroid hormone receptors (homodimer)
      • Zinc Finger TF
        • Steroid-binding pocket binds ligand → changes conformation → two zinc fingers bind major groove of DNA
    • Heterodimeric nuclear receptors
116
Q

What is the mechansim of splicing regulator proteins?

A
  • mRNA strand contains regions of pre-mRNA that act as enhancers and silencers (ESSs, ESEs, ISSs, ISEs) → detected by SR proteins → recruitment of spliceosome depends on balance between the silencers and enhancers of SR proteins determines whether a particular exon will be included in transcript
117
Q

Identify what is around the green circle.

A

Adipose

HINT:

white globs

118
Q

What is Von Hippel-Lindau Disease?

pathway?

A
  • Von Hippel-Lindau (VHL) Disease
    • Autosomal dominant
    • Mutations inhibit HIF-alpha degradation → overexpression of HIF-target genes → cell proliferation → cancer
119
Q

How does ISWI work?

A
  • Uses ATP to slide supercoiled DNA down, opening up more linker DNA
120
Q

What does the upregulation of L-asparaginase do in cancer cells? What is the enzyme it counteracts and the two amino acids being interconverted.

A
  • Function of L-asparaginase is to convert asparagine to aspartate intracellularly
  • Function of Asparagine synthetase is to convert aspartate to asparagine intracellularly
  • In cancer cells, existing low levels of Asparagine synthetase and induced high levels of L-asparaginase → insufficient [asparagine] → decrease in protein synthesis and cell growth
121
Q

How does RB function in relation to E2F, p21, p53, and Cyc/CDK4?

A
122
Q

What order of reaction is cell killing?

A

First order.

123
Q

Of reticular fibers, what is the:

  • purpose
  • location
  • composition (what type of collagen)
  • synthesizing cell
A
  • Purpose: provide supportive framework for cells
  • Location: supporting stroma in lymph nodes, spleen
  • Composition: Type III Collagen fibers, mesh-like arrangement (like a cage)
  • Synthesis: by fibroblast mostly
124
Q

What are the mechanisms of X-RAY based exogenous damage?

A
  • X-rays → causes ss breaks → requires base excision repair (BER)
125
Q

What type of tissue is the arrow pointing to?

A

Loose Connective

HINT:

abundant cells in layer and irregular pattern

126
Q

When/how does 3’ UTR AU-Rich Elements (AREs) Mediated mRNA Turnover occur?

  • What is an example?
A
  • Rapid, regulated turnover of specific mRNAs
  • ARE regions can be bound by destabilizing or stabilizing factors which can either degrade mRNA or extend mRNA’s half-life for more translation
  • Example: TTP destabilizes mRNA allowing for deadenylation/decapping and HuR stabilizes mRNA, prolonging its half-life
127
Q

Explain virsus-mediated gene introduction.

A
  • Virus-mediated Gene Introduction
    • Extract patient’s HSCs (hematopoietic stem cells) → treated with lentivirus with non-mutated genes → non-mutated gene is inserted into patients stem cell → inserted back into the patient
    • Patient’s previous mutated somatic cell is eradicated by chemotherapy
128
Q

What are the steps of iniation of translation in eukaryotes?

A
  1. eIF3 is bound to small subunit of ribosome (prevents large subunit from attaching)
  2. eIF2 → eIF2B dissociation triggers replacement of GDP by GTP on eIF2 by eIF5 → allows for binding to met-tRNA → binds to eIF3
  3. eIF4E domain binds the m7GTP cap
  4. eIF4 complex with mRNA binds to eIF3 complex
  5. eIF4A domain unwinds secondary structures in 5’ region until AUG is found
  6. GTP is hydrolyzed to GDP, releasing initiation factors
  7. Large subunit binds to small subunit
  8. Translation
129
Q

Of elastic fibers, what is the:

  • purpose
  • location
  • composition (what type of collagen)
  • synthesizing cell(s)
A
  • Purpose: allows tissue to stretch/distend, but return to original shape
  • Location: major part of vertebral ligaments, elastic arteries, larynx)
  • Composition: branching network
    • Central core of elastin
    • Surrounded by fibrillin microfibril - organizes elastin
    • Random coiling → elasticity
  • Synthesis: fibroblasts and smooth muscle cells
130
Q

Identify the type of epithelia

A

Pseudostratified Columnar

All cells attached to basement membrane with nuclei at varying heights

Found in: respiratory system and male reproductive tract

Function: secretion, absorption, and conduit

Can be ciliated

131
Q

What is the fundamental basis of clonal evolution in tumor cells?

A
  • One cell sustains initial mutation → proliferates based on survival advantage → further mutations sustained → cancer
132
Q

What are the two main subtypes of connective tissue?

  • Name subtypes of these subytypes if any
A

Loose and Dense (Regular & Irregular)

133
Q

Identify the type of epithelia.

A

Stratified Cuboidal

Found in gland ducts

Function: conduit (transports between gland and lumen)

134
Q

What are glucocorticoid receptors?

Ligands? Functions?

A
  • Glucocorticoid Receptors (GRs)
    • Ligand-activated TF
      • Natural ligand: cortisol
      • Synthetic ligand: dexamethasone
    • Functions
      • Activates transcription of anti-inflammatory genes
      • Block transcription of inflammation genes
135
Q

What are the three protective mechanisms of inflammation?

A
  • Three protective mechanisms of inflammation
    • Eliminate necrotic tissue
    • Destruction of etiologic agent
    • Initiate repair
136
Q

How many ATP are used in a single peptide bond formation?

A

4

137
Q

Describe teleomeres.

A
  • Protect chromosomal ends from shortening during replication
  • Is defined by the sequence: AGGGTT
  • Telomeres shorten with each cell division, and too much shortening can block cell division
  • Telomeres are replenished by telomerases in germ-line cells. They contain RNA-dependent DNA polymerase
  • Telomerases are also found in cancer cells allow for indefinite cell division
138
Q

For chronic inflammation,

  • What occurs to the blood vessels?
  • What occurs on a microscopic level?
  • Provide an example.
A
  • Chronic inflammation
    • Scarring of angiogenic vasculature
    • Leukocyte infiltration (mononuclear)
    • Example: rheumatoid arthritis (autoimmune)
139
Q

What are internal ribosome entry sites?

A

Internal Ribosome Entry Sites: sites where ribosome attaches to mRNA because 5’ UTR has too many secondary structures and is too far from start codon

140
Q

Identify this.

A

Cartilage matrix

HINT:

Little blue cells with two dots - classical sign of collgen - Caleb

141
Q

What is the purpose and location of loose connective tissue?

A
  • Purpose - anchoring, support, source of cells
  • Location:
    • Underneath epithelium
    • Site of initial attack by bacteria - but will be destroyed by immune cells (i.e. mammary gland, gut epithelium) → swelling/edema
142
Q

What are Androgen Receptors?

What drug blocks an ARs action? How?

A
  • Androgen Receptors (ARs)
    • Androgen is critical in male sexual development and in pathogenesis of prostate cancer
      • Ligand is dihydrotestosterone (DHT)
    • Enzalutamide
      • Three targets: competitively binds to AR, inhibits translocation of activated AR, and inhibits AR binding to DNA
143
Q

What is the pathway of normal proteomyelocute differentiation and what steps occur to acetylate a gene?

A
  • Normal Pathway: retinoic acid binds retinoic acid receptor alpha (RARa) → conformational change → HDAC disassociates → HAT binds → acetylation → transcription of gene
144
Q

What is the composition of loose connective tissue?

A
  • Composition
    • Loosely arranged fibers that are irregular/disorganized
    • Sparse collagen fibers
    • Abundant ground substance
    • Abundant cells (immune cells)
145
Q

Explain iPSC.

A
  • Harvest patient’s somatic diseased cells → generate iPSCs via pluripotency transcription factors (OSKM) → correct disease-causing mutation via nucleases → differentiate specific cell types → inject into patient
146
Q

Identify the type of necrosis.

  • In its appearance, what are its microscopic features?
  • What are features of its gross appearance?
A
  • Coagulative necrosis
    • Gross: occurs after an ischemic event and the architecture is preserved (wedge shape)
    • Microscopic: ghost cells maintain cell outline
147
Q

What is the defective pathway that ultimately causes the gene to be unexpresed in promyelocytic leukemia?

A
  • Defective Pathway: retinoic acid receptor alpa (RARa) cannot bind retinoic acid → no conformational change → HDAC stays bound → gene stays silenced in nucleosome → no transcription
148
Q

What are the two main treatments for acute promyelocytic leukemia?

A
  • Treatments
    • Increase in [retinoic acid]
    • HDAC inhibitors, such as trichostatin A (bad because not specific)
149
Q

Identify the epithelia.

A

Simple Squamous

Fried egg structure

Found in lining of cavities (mesothelium) and lining of blood vessels (endothelium)

Function: filtration, exchange, barrier

150
Q

What are the three consequneces of p53 mutation or loss?

A
  • Cell loses ability to produce CKIs that inhibit CDKs and block the cell cycle to allow for DNA repair
  • Cell loses ability to undergo apoptosis and die
  • Loss of p53 increases genomic instability – increase in accumulation of additional mutations due to lack of repair mechanisms
151
Q

What are possible treatments for anemia using the HIF-alpha pathway?

A

Prolyl hydroxylase inhibitors → block VHL binding → no ubiquination → no degradation → elevated HIF-alpha → more erythropoiesis → more RBCs

152
Q

What mutation occurs in Cri-du-chat, where does it occur, and what are some characteristics of the disease?

A
  • Cri-du-chat
    • 5p monosomy – deletion of the short arm of chromosome 5
    • Characteristics: cry similar to meowing kitten, widely spaced eyes, developmental delay
153
Q

What two drugs act on RNA polymerases and what polymerases do they act on?

A
  • Drugs
    • Alpha-amanitin (from a mushroom) – affects RNA polymerase II and III
    • Rifampicin – inhibits prokaryotic RNA polymerase
154
Q

Identify the type of epithelia.

A

Transitional/Urothelium

Found in urinary tract

Function: barrier and dispensability (stretch)

Can be identified by the rounded snout on the apical surface

155
Q

How does EMT occur?

A
  • Normal endothelial and tumor cells express e-cadherin → acts as cell-cell junction protein with tumor cells and binds beta-catenin intracellularly → e-cadherin repression → loss of cell-cell adhesion properties → tumor cell enters blood stream → beta-catenin is released → beta-catenin acts as TF (dangerous in the tumor cell)
156
Q

What type of fiber is depicted in the image below?

A

Reticular fiber

HINT:

mesh like structure.

157
Q

What mutation occurs in Wolf-Hirschhorn, where does it occur, and what are some characteristics of the disease?

A
  • Wolf-Hirschhorn
    • 4p- syndrome – deletion of the short arm of chromosome 4
    • Characteristics: seizures, developmental delays, heart defects
158
Q

Describe tRNA structure.

A

tRNA – inverse L shaped loop structure that contains anticodon and binds AA to 3’ end

159
Q

What are the 4 cytoplasmic decay pathways?

A
  • Deadenylation/decapping-dependent pathways
  • Nonsense mediated decay (quality control)
  • 3’ UTR AU-Rich Elements (AREs) Mediated mRNA Turnover
  • Micro RNA / RNAi-dependent pathway
160
Q

What are the six mechanisms that may lead to loss of hetrozygosity?

A
  • Six ways of eliminating one allele
    • Nondisjunction (chromosome loss)
    • Nondisjunction and duplication
    • Mitotic recombination
    • Gene conversion
    • Deletion
    • Point mutation
161
Q

What is Direct Repair?

2 Pathways.

A
  • Direct Repair (DR)
    • Alkylated bases (O6G) → unalkylated bases via AGT/MGMT
      • Not an enzyme because it must be degraded after one use
    • Methylated bases → unmethylated bases via ALKB family
162
Q

How does SWI/SNF work?

A
  • Uses ATP to open nucleosome so DNA can be more easily read
163
Q

How is activation of NF-kB is blocked by glucocorticoids?

A
  • Sequesters NF-kB in nucleus
  • Promotes transcription of IKB, which sequesters NF-kB in cytosol
164
Q

What is the major cell of connective tissue and what is its function?

A
  • Major cell is the fibroblast
    • Function: synthesizes ECM/proteins (collagen/reticular fibers/elastic fibers)
165
Q

How are miRNA’s processed?

A
  • Drosha recognizes Pri-miRNA and removes 3’ and 5’ ends → exportin exports into cytoplasm → Dicer splits ds-miRNA into ss-miRNA sequences → ss-miRNA sequences complex with RNA-induced silencing complex (RISC) → RISC uses ss-miRNA as a template to bind cytosolic mRNA → signals for mRNA cleavage or mRNA translational repressor
166
Q

What is a type of chromosomal microdeletion disease?

  • What chromosome and what gene is included in the deletion?
  • What are some characteristics?
A
  • Williams Syndrome
    • Chromosomal 7 microdeletion, including the gene elastin
    • Characteristics: “cocktail party” personality, circulatory system and heart defects
167
Q

Steps of elongation of translation in eukaryotes?

A
  • E-site is exit, P-site is peptidyl, A-site is acceptor
  • Steps
  1. eEF1 binds GTP and aminoacyl-tRNA → transfers to A-site
  2. Anticodon-codon binding causes GTP hydrolysis
  3. Release of eEF1
  4. Growing peptide in P-site is transferred to AA on tRNA in A-site
    1. The ribosome acts as ribozyme to catalyze reaction
  5. eEF2 binds GTP → hydrolysis to GDP → movement of ribosome by three nucleotides
168
Q

What is the regulation pathway of translation at eIF2?

What causes this?

A
  • Phosphorylation of eIF2 → eIF2B stays bound to eIF2 → decreased GDP/GTP exchange → inactivates eIF2 → blocks binding of met-tRNA → stops initiation of translation
    • Stress Response: cause phosphorylation of eIF2, blocking initiation
      • Nutrient deprivation, oxidative stress, ER stress, dsRNA
169
Q

What two enzymes are used in acetylation of histones and what do they do?

A
  • HDAC (histone deacetylase) – promotes nucleosome folding → inactivating gene
  • HAT (histone acetyltransferase) – destabilizes nucleosome folding → activating gene
170
Q

What is one example and the mechanism of action of glucocorticoids, a type of hormonal agent?

A
  • Prednisone
  • MOA: used for liquid tumors to bind to intracellular receptors and affect gene transcription
171
Q

What does normal fibrinous tissue look like?

A
172
Q

How is retinoic acid involved in the production of granulocytes and what defect in this process causes acute promyelocytic leukemia?

A
  • Retinoic acid promotes the maturation of promyelocutes into granulocytes, one of the main types of WBCs
  • In PML the promylocyte does not respond to retinoic acid induction, so promylocytes hyperproliferate.
173
Q

List two chromosomal deletion diseases.

A
  • Cri-du-chat (5p deletion)
  • Wolf Hirshhorn (4p deletion)
174
Q

Where does the defect lie in Marfan’s Syndrome?

What function does this defect affect and where is this protein abundant in?

A
  • Inherited defect in Fibrillin1 (glycoprotein)
  • Fibrillin1 is the scaffolding upon which tropoelastin is deposited to form elastic fibers
    • Particularly abundant in aorta, ligaments, and lens
      • Aortic Rupture

SPM (ARSH) (5 decks)

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