Week 4 Flashcards

1
Q

inactived X chromosomes, seen in Kleinfelter syndrome

A

Barr bodies

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2
Q

normal phenomenon where one of the 2 X chromosomes in every cell of a female individual is inactivated during embryonic development

A

lionization

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3
Q

what percent of women have X inactivation ration

A

90%

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4
Q

Why is the normal X chromosome inactivated in balanced X autosome translocation?

A

inactivation of X chromosome causes an imbalance of gene expression

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5
Q

Sons of an affected male are usually unaffected in ____, while daughters are obligate carriers

A

X linked inheritance

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6
Q

expressed in all males who receive mutation, can skip generation, no father to son transmission

A

X linked recessive

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7
Q

CCG triplet expansion in 5’ FMR1 (gene not expressed), 56-200 repeats= unstable mutation, promoter silencing by CpG methylation= no FMR1 expression
anticipation DNA methylation and haplotype effect (arrangement of neighboring loci on the same chromosome)

A

Fragile X (XD with reduced penetrance)

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8
Q

mutation in MECP2 gene (Xq28, methyl-CpG-binding protein-2), transcriptional silencing, and epigenetic regulation of methylated DNA
95% de novo mutations, almost exclusively in male germline
manifests after 6-18 months of age in females, men die in utero or after birth
Impairments in language and coordination and repetitive hand movements like wringing/squeezing or clapping/tapping, slower growth, difficulty walking, smaller head size, seizures, scoliosis, and sleeping problems
variable expressivity

A

Rett syndrome (XD)

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9
Q

mutation in F8 (Type A) and F9 (Type B)
most cases of severe type A due to intron 22 inversion results in 2 incomplete transcripts
acute and recurrent hemarthrosis (bleeding into joints) and hematomas
with age, severity, and frequency of episodes increase
bleeds in brain are life-threatening
F9 expression increases by 1/3 at puberty

A

Hemophilia A and B (XR)

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10
Q

X linked recessive + X inactivation:
Mutation in dystrophine gene
Large deletions (60-65%), large duplications (5-10%), small deletions, insertions, or nucleotide changes (25-30%)

33% de novo mutations
14% germline mosaicism → 7% reccurerence risk in apparent noncarrier mothers with affected child
Progressive degeneration of skeletal muscle, usually after a latency period of seemingly normal development and function (>2 yrs), difficulty in climbing stairs, frequent falls, and progressive difficulty in rising from floor are early features. Pseudohypertrophy of calves, mild mental retardation, cardiomyopathy (95%), 50-60% carrier females have cardiac abnormalities, and slightly elevated serum CK levels even in absence of other symptoms

A

Duschene Muscular Dystrophy

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11
Q

X linked recessive
Mucopolysaccharidosis type II (MPS II), accumulation of glycosamingoglyicas (GAGs) in lysosome
Mutation is IDS= iduronate-2-sulfatase
break down of 2 ECM proteoglyvans, dematan sulfate and herpan sulfate is impared
Born normal then, abdominal hernias, ear infection, runny noses, colds, coarseness of facial features, prominent forehead, nose with flattened bridge, an enlarged tongue, large head, hepatosplenomegaly, aggressive behavior

A

Hunter Syndrome (XR)

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12
Q

X linked recessive
Mutation in Bruton tyrosine kinase (BTK), stops B-cell maturation at pre-B cell stage. T cell immunity remains in tact
No antibodies in blood, newborns normal, present w/ lung infections, ear infections, pink eye, and sinus infection. Infections that cause diarrhea, Note: live attenuated vaccines could be dangerous because of no immune response (live polio, MMR)

A

Bruton Agammaglobulinemia
(aka X Linked agammaglobinulinemia XLA)

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13
Q

X linked recessive

Incomplete penetrance in heterozygous female because random x inactivation
Mutation in a-galactosidase A → accumulation of glycolipid globotriaosylceramide in walls of blood vessels
Multisystem disorder (kidneys, heart, NS, skin, eyes), full body or localized pain to extremities (deposits in nerve fibers) or GI tract, angiokeratomas, proteinuria, kidney failure, cardiac hypertrophy, valve disease, anhidrosis, corneal clouding

A

Fabry Disease

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14
Q

X linked recessive
Deficiency in HGPRT 1, overproduction of uric acid (hyperuricema)
Failure of purine salvage pathway = accumulation of breakdown product and stimulation of de novo synthesis pathway
Sand like crystals of uric acid in diapers, gout, kidney stones, bladder, ureter, hypotonia, aggressiveness, finger biting, patients poorly use vitamin B12 → megaloblastic anemia, death usually due to kidney failure or complications from hypotonia

A

Lesch Nyhan Syndrome

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15
Q

X linked recessive
Mutation in GPR143 (OA1) product GPCR like protein localizes to melanosomes and involved in melanosomal biogenesis. Activation of OA1 receptor by L-DOPA → secretion of neurotropic factor by retinal pigment epithelium helps in normal retinal development
Reduced coloring of iris and retina (ocular hypopigementation, eye appears blueish pink); foveal hypoplasia, rapid involuntary eye movement (nystagmus), poor vision and depth perception, increased sensitivity to light
Astigmatism and lazy eye/strabismus

A

Ocular Albinism

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16
Q

X linked recessive
OTC deficiency, failure to convert carbon phosphate to citrulline, most common urea cycle disorder → hyperammonemia
Male infant by the second day of life becomes irritable, lethargic, stops feeding, poorly controlled body temperature and respiratory rates, may experience seizures, metabolic encephalopathy develops, and can progress to coma and death within the first week of life

Treatment goal = reduce periods of hyperammonemia
*Gene therapy

A

Ornithine transcarbamylase deficiency

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17
Q

X linked recessive
Mutation in WAS gene, can also cause X linked thrombocytopenia (XLT), mainly expresses in hematopoietic cells, nucleation promoting factor (NPF) for Arp2/3 complex (binds actin)

Mucrothrombocytes were observed only else in ARPC1B deficiency
Immune deficiency, Thrombocytopenia (low platelet count), Eczema, Recurrent infections, bloody diarrhea,
First signs- petechiae and bruising
Serum IgM low (IgG normal)
Spontaneous nose bleeds and blood diarrhea
Increased risk of leukemia and lymphoma

A

Wiskott Aldrich Syndrome

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18
Q

X linked recessive
G6PD deficiency, only enzyme in erythrocytes that supplies NADPH , depletion → oxidation of Hb, RBC turnover, production of bilirubin and jaundice
Yellow skin, dark urine, shortness of breath, fatigue, hemoglobinuria, acte hemolytic anemia, acute kidney failure. Anemia and jaundice in newborns, pale, extreme tired, tachycardia, dyspnea, splenomegaly
Triggers: infection, medication (aspirin or antimalaria quinin), stress of fava beans (favism)

A

G6PD deficiency

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19
Q

When homozygotes have more severe phenotypes than heterozygotes or compound heterozygotes, almost all disease with dominant inheritance are in this group

A

incomplete dominance

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20
Q

when you have similar phenotype in homozygotes, heterozygotes, and compound heterozygotes

A

pure dominant

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21
Q

disease manifests most often when both alleles are mutated (homozygotes or compound heterozygotes), assuming no mosaicism

A

autosomal recessive

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22
Q

when a person has 2 or more genetically different sets of cells in his or her body

A

mosaicism

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23
Q

if case is not isolated, others affected are usually in same sibship (not observed by parents, offspring, or other relatives) because of low probability, males and females typically equally effected, parents typically asymptomatic, parents may be consanguineous

A

autosomal recessive

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24
Q

most molecular basis of recessive disorders involves enzyme deficiencies:

A

inborn errors of metabolism

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25
Q

allelic variation may have little to no effect on enzyme activity

A

polymorphism

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26
Q

effects of reduced enzyme activity

A
  1. accumulation of substrate
  2. deficiency of product
  3. new (toxic) product/alternate pathway
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27
Q

AR

VARIABLE EXPRESSIVITY
Genetic and environmental modifiers

Most common fatal AR in white populations
CFTR gene (most common F508 deletion - 70%)
Exocrine pancreatic insufficiency, obstructive azoospermia (no sperm- 95% bc bilateral absence of vas deferens), elevate sweat Cl-, growth failure, meconium elius, idiopathic chronic pancreatitis but some lack clinical signs= partial phenotype

A

Cystic fibrosis

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28
Q

AR

HETEROZYGOUS ADVANTAGE, novel property mutation, compound heterozygosity, ethnic variation
B- globin (HBB) Glu6Val mutation decreases solubility of deoxy Hb → form gelatinous network of stiff fibrous polymers that distort RBC → sickle shape

Sickled erythrocytes occlude capillaries → infarction
Anemia, functional asplenia (inc susceptibility to bacterial infections= major cause of death), failure to thrive, splenomegaly, repeated infections, and dactylitis (painful swelling of hands/feet from occlusion of capillaries, child won’t want to stand),

Newborn screening- initiate antibiotic prophylaxis through age 5

higher level of Hb Fetal associated with lower morbidity and mortality
BCL11A gene- TF that silences gamma-globin expression, silencing can increase HbF (HBG) expression

MYB- TF silences HBG. trisomy 13- high HbF bc miR-15a and miR16-1 target MYB encoded on chromosome 13

A

Sickle Cell Anemia

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29
Q

AR

Mutation in ATP7B gene- 90% (transports excess Cu2+ into bile, excreted in waste products)

Cu2+ metabolism (needed for cytochrome c oxidase/ complex IV and other enzymes) Cu2+ accumulates in liver, brain, and eye
Kayser-Fleischer rings in cornea, low serum caeruplasmin (Cu2+ transport protein), Cu2+ accumulates in liver → hepatitis and cirrhosis and in basal ganglia (brain) → severe progressive neurological disability
Vomiting, weakness, fluid build up in abdomen, swelling of legs, yellow skin, itchiness, tremors, muscle stiffness trouble speaking, personality changes, anxiety, psychosis

A

Wilson’s Disease

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30
Q

AR

Heterozygote advantage (malaria)
Defect/deletion in a-chains of Hb, excess B- chains → nonfunctional B4 tetramers= HbH, precipitate and forms inclusions → removal in spleen and anemia
Infants w/ severe type and high levels of Hb Bart’s (gamma 4) suffer severe intrauterine hypoxia and massive fluid accumulation= hydrops fetalis

Treatment: transfusion (iron overload), bone marrow transplant, gene therapy, hypoxyurea and thalidomide (to induce HbF)

More a-chains lost → inc severity of disease

A

A-thalassemia

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31
Q

AR
Reduces (B+) or absent (B°) synthesis of b-globin chains of Hb tetramer

B chain imp only in postnatal period= later onset

Point mutations (not deletions)
A- thalassemia genes are modifiers for B-thalassemia
Hypochromic, microcytic anemia and an imbalance in globin synthesis due to excess a- chains which precipitate (Heinz bodies)

A

B-thalassemia

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32
Q

AR
Mutation in dynein arms, DNAH5 and DNAl1
80% full term infants present w/ respiratory distress within 24hr of birth, productive “wet” cough begin under 6mo, chronic airway infection, inflammation, progressive obstruction, bronchiectasia (widening of airways), 50% situs inversus totalis (flipped organs), infertility due to sperm and cilial immotility

A

Kartagener Syndrome
Aka Primary Ciliary Dyskinesia (PCD)

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33
Q

AR

Most compound heterozygotes
Mutations in PKHD1, protein polycystin/polyductin (or fibrocystin/polyductin, FPC)

FPC- present in primary cilia of renal tubules and intrahepatic bile ducts
Abdominal discomfort, abdominal mass, polyuria, polydipsia, hypertension with progression to end stage kidney disease by age 15, small # live longer, but have liver dysfn

A

Autosomal Recessive Polycystic Kidney Disease (ARPKD)

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34
Q

AR

Lysosomal storage disease, ethnic variation, genetic drift (Ashkenazi jews), pseudodeficency, population screening
Defect in hexosaminidase (Hex A; GM2→ GM3)

Age at onset: infancy through adulthood
Infants normal til 3-6 mo, then progressive neurological deterioration and loss of motor skills (turning over, sitting, crawling), seizures, vision, and hearing loss, paralysis, cherry red spot on retina (neuronal death), neurodegeneration underlying cause of death at 2-4 yrs

A

Tay-Sachs Disease

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35
Q

AR
Mutation in acid alpha glucosidase (accumulation of glycogen in lysosomes) usually glycogen taken up with autophagy
Progressive muscle weakness (myopathy), born normal, by 3 mo feeding and swallowing problemsn, macroglossia, respiratory difficulties and infections, muscle weakness (floppy baby), hypotonia, hypertrophic cardiomyopathy, die by 2 years

A

Pompe Disease

Aka glycogen storage disease type II/ floppy baby syndrome

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36
Q

AR

Allele heterogeneity
alpha-L-idurondase defect (breaks down unsulfated a-L-iduronic acid found in dermatan sulfate and heparan sulfate- ECM proteoglycans)

Mucopolysaccharidosis type IH (MPSIH) accumulation of glycosamingoglycans (GAGs) in lysosome
Coarsening of facial features, large head with prominent frontal bones, elongates skill, corneal clouding, hearing impairment, hepato- cardio- splenomgaly, umbilical hernia, skeletal abnormalities, lips large, hold jaw open

Life expectancy ~9 yr, bone marrow transplant helps increase survival

A

Hurler Syndrome

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37
Q

AR
Allele heterogeneity

OCA1-deficiency (absence) of enzyme for melanin (tryosinase)
OCA2-defect in the P protein
OCA3- mutation in tyrosinase related proteins
Complete lack or severe reduction of melanin → hypopigmentation of hair, skin, and eyes,
Photosensitivity and reduced visual acuity w/ OCA1- deficiency (most severe)

A

Oculocutaneous albinism

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38
Q

Describes the inheritance where homologous regions at tips of X and Y chromosomes do meiotic recombination which ALLOWS FOR MALE-TO-MALE TRANSMISSION

A

pseudoautosomal inheritance

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39
Q

homologous regions at tips of X and Y chromosomes ____; genetic loci located in these regions are called ____

A

pseudoautosomal regions
pseduoautosomal loci

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40
Q

Dominant

Affects mainly females
SHOX gene mutation
Disproportionate short stature, mesomelic shortening of limbs, bowing of tibia, increased muscle size, deformity of forearms

A

Leri Weill Dyschondrosteosis

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41
Q

male limited precocious puberty meaning only males affected because mutation in luteinizing hormone receptor –> (+) of LHR even without ligand, premature growth spurt, FATHER TO SON TRANSMISSION distinguishes from X linked, mutation in LCGR gene encoding leutenzing hormone receptor

A

sex-limited AD inheritance

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42
Q

Y linked inheritance
(father to son transmission)
Deletion in AZF (azoospermia factor), region of Y chromosome
Mutation in USP9Y
Azoospermina (no mature sperm), oligospermia (low sperm count),

A

Y chromosome infertility

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43
Q

Y linked inheritance
(father to son transmission)
Mutation in SRY (sex determining region Y)
46, XY w/ female external genitalia
No ovaries (“streak gonads”), gonadectomy to prevent gonadoblastoma, hormone replacement therapy to induce menstruation, can become pregnant w/ donated eggs or embryo, no estrogen, breast, or ovaries

A

Swyer Syndrome

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44
Q

transmitted through maternal germline, smaller, circular DNA, homoplasy and heteroplasmy (DNA copies are identical, DNA variant copies), replicative segregation (cell division), disease threshold
Multiple organs affected esp those w/ high energy demands- nerve, muscle, kidneys

A

Mitochondrial inheritance

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45
Q

why does mitochondria need its own translational apparatus?

A

because genes in mtDNA are using genetic code which is different than that used in nucleus

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46
Q

all children of homoplasmic females- WILL inherit mutation
all children on homoplasmic OR heteroplasmic males- WILL NOT inherit mutation
all children of heteroplasmic females- WILL inherit mutation, but not heteroplasmy level

A

mitochondrial inheritance

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47
Q

heteroplasmic deletions not heritable, pleiotropy, variable expressivity, variability in mutation loads btw tissue, father will not have affected children

A

mitochondrial inheritance

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48
Q

Mitochondrial inheritance

Reduced penetrance in females (more males affected
11778 G → A (transition) mutation in MT-ND6 (complex I)
Degeneration of retinal ganglion cells (RGCs) and axons, acute or subacute central vision loss, tobacco and alcohol risk factors, color vision affected visual acuity may improve

A

Leber’s hereditary optic neuropathy (LHON)

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49
Q

Mitochondrial inheritance
3243 A → G (transition) mutation in MT-TL1
Difficulty understanding/thinking, temporary muscle weakness or paralysis (hemiparesis), seizures, hallucinations
Inc in lactic acidosis- vomiting, abdominal pain, fatigue, muscle weakness
Stroke like- weakness/paralysis of an arm or leg or side of body, slurred speech, problems thinking of or saying right word

A

MELAS
(mitochondrial encephalomyopathy, lactic acidosis, and stroke like episodes)

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50
Q

not inherited, unstable expansion within affected gene of a segment of DNA consisting of repeating subunits of 3 or more nucleotides in tandem (CAG –> CAGCAGCAGCAG), both germline and tissue specific somatic instability, replication, repair, and recombination contribute to instability,
ANTICIPATION
disease occurs when number of repeats exceeds some threshold (ex Huntington’s)

A

Dynamic mutation

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51
Q

disease manifests itself at earlier age as it moves through subsequent family generations –> more severe symptoms

A

anticipation

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52
Q

AD

ANTICIPATION

Parental transmission bias from father (more severe)
CAG (glutamine) repeat expansion in HTT gene (HD gene), stretch of Glu residues sequesters TFs → TFs not available → gene expression affected
Jerky, random, uncontrollable movements=chorea, rigidity, abnormal posture and facial expression, ⅓ psychiatric abnormalities, ⅔ cognitive and motor abnormalities

A

Huntington Disease

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53
Q

how do we get increased number of repeats in Huntington’s diseases when transmitted through germline

A

when CAG repeats gets replicated, the DNA strand may slip back by 3 nucleotides or more and increase number of repeats

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54
Q

X linked dominate

Mainly men affected

Somatic mosaicism

ANTICIPATION

Most commonly inherited causing intellectual disability
CGG triplet repeat expansion in 5’ FMR1 gene,
200-1000 repeats= affected , 56-200 repeats= “unstable mutation” (inc risk in next generation)
Promoter silencing by CpG methylation- no FMR1 expression
Post puberty- long face w/ prominent jaw and forehead, large ears, macroorchidism, repeat length mosaicism and methylation determines severity

A

Fragile X Syndrome

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55
Q

AD
1 in 500 Quebec
CTG expansion in 3’ untranslated region of DM1 protein kinase (DMPK1), OR CCTG repeat expansion in intron of CNB gene

DM1 is spliceopathy (abnormal splicing of genes) (CCG serves to bind splicing factors)
Muscle weakness, cataracts, mytonia, “warm up phenomenon”, appears more pronounced after rest and improves w/ muscle activity. Distal muscle weakness, impairment of fine motor tasks, myopathic face or “hatchet face”

A

Myotonic Muscular Dystrophy

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56
Q

AR
GAA expansion in Frataxin (FXN), involved in iron handling and Fe-S cluster biogenesis (esp in mitochondria)
Gene silencing due to abnormal repeats
Difficulty walking and poor balance (ataxia), loss of sensation in arms and legs, impaired speech (dysarthria), scoliosis, primary cause of death= cardiomyopathy

A

Friedreich Ataxia

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57
Q

Centromere in middle, arms same length

A

metacentric

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58
Q

centromere shifted towards telomere

A

submetacentric

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59
Q

chromsomes 13,14,15,21,22, involved in urban translocation, centromere moved to very extreme of one of the arms

A

acrocentric

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60
Q

Most prominent cause of chromosomal abnormality disorders

A

Nondisjunction
abnormal chromosome segregation

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61
Q

when chromosome number does not equal 46

A

heteroploid

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62
Q

chromosomal number = n x 23 (23, 46, 69, 92), covers both normal and abnormal

A

euploid

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63
Q

23 chromosomes (gametes only)

A

haploid

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64
Q

46 chromosomes (normal)

A

diploid

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65
Q

69 chromsomes, can be liveborn

A

triploid

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66
Q

92 chromosomes, fetuses are always spontaneously aborted

A

tetraploid

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67
Q

not euploid, any number of chromosomes, ex) Trisomy 13, 18, 21
ex) XXX syndrome and Klinefelter syndrome (XXY)

A

aneuploid

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68
Q

arises from meiotic nondisjunction or failure of chromosomes to separate in 1 out of 2 divisions of meiosis, 2 chromosomes in same

A

nondisjuction

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69
Q

arises from meiotic nondisjunction or failure of chromosomes to separate in 1 out of 2 divisions of meiosis, 2 chromosomes in same

A

nondisjunction

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70
Q

the genome has the normal complement of chromosomal material, 1 in 500, often no phenotype, can interrupt genes reciprocal and non-reciprocal translocation, inversions, or require alternate segregation in meiosis, alternate segregation

A

balanced rearrangement

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71
Q

some material is either added or missing in genome, can be stable or unstable, adjacent segregation, less frequent, partial trisomy (duplication), partial monosomy (deletion, more harmful), marker chromosomes (supernumerary)

A

unbalanced

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72
Q

most common type of translocation, reciprocal, 2 acrocentric chromosomes that fuse near centromere region w/ loss of short arms, often pseudodicentric (centromere inactivated)
chromosomal deletions or addition result in syndromes of multiple malformations, including trisomy 13 (Patau syndrome) and trisomy 21 (Down syndrome).

A

Robertsonian translocation

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73
Q

Can be paracentric (happens in one chromosomal arm) or pericentric (around centromere), fetuses with unbalanced chromosomes from meiosis of paracentric are not viable

A

inversions

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74
Q

What is the similarity and difference between Robertsonian and isochromosomes?

A

Robertsonian- form of translocation where 2 acrocentric chromosomes fuse at centric ends, forms one large metacentric chromosome and one small fragment, leads to Trisomy 13 and 21
Isochromosomes- made of mirror images of one arms of chromosomes, partial trisomy in isochrome and partial monosomy in lost arm, happens in X chromosome and acrocentric, leads to Turner syndrome

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75
Q

range of signs and symptoms that can occur in different people with same genetic condition ex) cystic fibrosis

A

variable expressivity

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76
Q

both alleles of a gene are partially expressed, resulting in an intermediate or different phenotype, most dominant diseases ex) achondroplasia

A

incomplete dominance

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77
Q

similar phenotype in homozygous, heterozygous, and compound heterozygous

A

pure dominant

78
Q

not all individuals with disease show disease ex) Fabry disease, BRCA 1 do not always show result in breast or ovarian cancer

A

incomplete penetrance

79
Q

one gene contributes to multiple phenotypic effects ex) untreated PKU manifests with light skin, intellectual disability, musty body odor

A

pleiotropy

80
Q

if a patient inherits or develops a mutation in a TSG, the wild type allele must be deleted/mutated/eliminated before cancer develop, not true of oncogenes
ex) retinoblastoma and the “2 hit hypothesis”

A

loss of heterozygosity

81
Q

exerts a dominant effect, a heterozygote produces a nonfunctional altered protein that also prevents the normal gene product from functioning ex) osteogenesis imperfecta

A

dominant negative mutations

82
Q

usually due to defects in structural genes, many generations, both males and females affected, only need one allele to be affected
often pleiotropic (multiple apparently unrelated effects) and variable expressive (different between individuals)
with one affected (heterozygous) parent, each child has 50% chance of being affected

A

autosomal dominant

83
Q

with 2 carrier (heterozygous) parents, on average: each child has 25% chance of being affected, 50% chance of being carrier, 25% chance of not being affected
usually seen in one generation, more severe than dominant disorders, unaffected individual with affected sibling has 2/3 probability of being a carrier

A

autosomal recessive

84
Q

sons of heterozygous mothers have 50% chance of being affected. no male to male transmission skips generations, commonly more severe in males, females must be homozygous to be affected

A

X linked recessive

85
Q

transmitted through both parents, children of affected mothers have 50% chance of affected. 100% of daughters and 0% sons of affected fathers will be affected

A

X linked dominant

86
Q

variable expression in a population or even within a family due to heteroplasmy

A

Mitochondrial inheritance

87
Q

both alleles are mutated (a1a2)

A

compound heterozygosity

88
Q

presence of genetically distinct cell lines in same individual ex) McCune Albright syndrome

A

mosaicism

89
Q

most cases, only men affected, can skip generations

A

X linked recessive

90
Q

Families with multiple childhood cancers, specific rare cancers, 2 of more primary cancers
Increased risk of cancers: sarcomas, breast, brain, CNS, adrenal, leukemia

Orphan disease (rare),
No sex predilection, hereditary pattern, cancer incidence varies due to penetrance, cancer present at any age

A

Li-Fraumeni Syndrome

91
Q

AD
TP53 mutation, p53 protein damaged and unable to function properly

p53= checkpoint proteins in cell cycle, repairs damaged DNA, Tumor suppressor gene

TP53 mutation testing

Sarcoma diagnosed before age 45, first degree relative with any cancer before age 45, first degree or second degree relative with any cancer before age 45 or sacroma at any age

A

Li-Fraumeni Syndrome

92
Q

Any cancer: weight loss, pain, night sweats; breast cancer: lump, breast changes, breast discharge, CNS cancers: headaches and weakness, leukemia: easy bruising or bleeding, fatigue, recurrent infection
Physical Signs
Any cancer: temporal wasting, cachexia
Breast cancer: palpable mass, peau d’orange, breast changes
CNS: focal neurologic deficits
Leukemia: bruising, pallor,

Genetic counseling, cancer screening, early detection, investigative therapies

A

Li-Fraumeni Syndrome

93
Q

Risk increases > 45 year old, hereditary syndromes, weight loss, Fe+ deficiency anemia in men, Fe+ deficiency anemia in post-menopausal woman, change in stool caliber or bowel habits, blood in stool

Increases w/ age especially after 45
40 per 100,000 with age over 50, men>women, 20% due to heredity factors, risk factors: red meat and fat consumption, family history, inflammatory bowel disease

A

Colon Cancer

94
Q

APC inactivation + KRAS activation+ TP53 inactivation

APC= TSG (1st hit) allows for early proliferation
Ras (+) → inc cell cycle → cancer
TP53= TSG

Germline or sporadic APC mutation-
germline= FAP- 100s of polyps, sporadic- most colon cancers

Microsatellite or chromosome instability

A

Colon Cancer

95
Q

Commonly asymptomatic, weight loss, fatigue and weakness, blood in stool, obstructive symptoms (pain, constipation, stool caliber change), family history of cancer

Pallor, weight loss, fecal blood (occult +, hematochezia) and advanced disease (palpable mass, hepatomegaly, jaundice)
Screening- immunohistochemical testing, colonoscopy, imaging- “apple core” lesion, colonoscopy w/ biopsy
Surgical resection and chemotherapy for localized disease

Chemotherapy and radiation for metastatic disease

A

colon cancer

96
Q

Weight loss and fatigue, cough, shortness of breath, chest pain, hemoptysis, exposure risk with tobacco use and occupational

Most common cause of cancer death, uncommon below age 40, male > female, 10x increase w/ smoking, occupational exposure

A

Lung cancer

97
Q

Gain of fn mutations: MYC TFs, RAS (KRAS), RAF (BRAF), FGR1 amplification

Loss of fn mutations: TP53, RB1

A

Lung cancer

98
Q

Weight loss, anorexia, shortness of breath, cough w/ blood, chest and shoulder pain, tobacco smoke exposure, occupational exposure, paraneoplastic and obstructive symptoms

Tachypnea, hypoxemia, hemoptysis, decreased breath sounds, clubbing, paraneoplastic and obstructive signs
Chest x-ray, CT cancer, bronchoscopy, biopsy

Staging, resection, chemotherapy, radiation, precision therapy to mutation

A

Lung cancer

99
Q

Asymptomatic, gastroesophageal reflux disease (GERD)- cough, regurgitant symptoms, chest pain, heartburn, hoarseness; dysphagia, obesity and smoking

10-15% of US adults with GERD, 5.6% adults with Barrett’s, 50-60 years old peak age, men> female (3:1)

A

Barrett’s Esophagus

100
Q

Transient lower esophageal sphincter relaxation (reflux occurs) → GERD → inflammation and cellular stress → intestinal metaplasia → dysplasia → cancer
Esophageal epithelium exposure gastric secretions: bile acids, acidic pH, enzyme exposure (gastric, pancreatic)

A

Barrett’s Esophagus

101
Q

No specific symptoms, look for GERD (heartburn, dyspepsia, chronic cough or hoarseness, brackish taste in mouth, dysphagia, temporal association w/ foods) family history

Elevated BMI, dental erosions, wheezing
Endoscopy, biopsy
Risk factor modification, Proton Pump Inhibitors (PPI), surveillance, endoscopic ablation

A

Barrett’s Esophagus

102
Q

What is the role of cyclins and CDKs in the progression of cell division cycle?

A

controls the cell-cycle progression via phosphorylation of the target genes, such as tumor suppressor protein retinoblastoma (Rb), leads to progression in S phase

103
Q

What are the 3 fates of cells in the G0 phase?

A

1) Permanent G0, regenerate from stem cells (neurons, skeletal cardiac muscle, RBCs)
2) G0 stable; can reenter G1 (hepatocytes, lymphocytes, PCT, periostea cells)
3) Never in G0, divide rapidly like cancer cells w/ short G1 (bone marrow, gut epithelium, skin, hair follicles, germ cells)

104
Q

How does the retinoblastoma protein regulate the cell cycle? How is it activated? What is role of the E2F, p21 and p16?

A

Rb is a TSG that regulates the progression from G1/S phase in the cell cycle. When cell is ready to replicate DNA, Rb activates CDKs which phosphorylates Rb and releases transcription factor E2F. E2F then activates S phase/ DNA synthesis. p21 and p16 are CDKIs that inhibit cyclins

105
Q

What are the CDKs and cyclin pairs in each phase?

A

cyclin D + CDK 4/6- G1/S phase
cyclin E + CDK2- G1/S phase
cyclin A+ CDK2- S phase
cyclin B+ CDK1- G2 and M phase

106
Q

How is the abundance of CDKIs regulated?

A
107
Q

What regulates the p53?

A

phosphorylation by ATM (Ser/Thr kinase) TSG

108
Q

How does the p53 decide on the fate of the cell for cell cycle arrest or apoptosis?

A

by the extent of DNA damage, if DNA damage is beyond repair (sensed by BAD/BID/BIM) it will undergo apoptosis

109
Q

Which pathway of apoptosis is activated if p53 finds that DNA damage is beyond repair?

A

Sensed by BAD/BID/BIM, BLC-2 (anti-apoptotic) suppression –> BAX/BAK (OMM channel) induction –> apoptosis (intrinsic, cytochrome c, APAF-1, caspase 9/3, DNase)

110
Q

How do germline mutation, aflatoxin, and HPV alter p53 to cause cancer?

A

Germline mutation (Li-Fraumeni syndrome) and Aflatoxin inhibits p53. HPV 16 makes E6 which inhibits p53

111
Q

What is Li-Fraumeni syndrome? How does the loss of heterozygosity affect the progression of germline mutation and sporadic mutation of the p53 gene?

A

Li-Fraumeni syndrome- SBLA (sarcoma, breast, leukemia, and adrenal). Already born with “1st hit” so more susceptible to developing “2nd hit”

112
Q

What is role of p53 in gene transcription? How do the pathways of p53 activation differ under the conditions of DNA damage and oncogene activation?

A

p53 is a transcription factor that suppresses tumor growth. DNA damage –> cell cycle arrest in G1 for repair. Oncogene will activate p53 (phosphorylated) –> gene transcription

113
Q

How do anticancer drugs relate to the cell cycle? Which drugs are cell cycle non-specific?

A

Anticancer drugs inhibit the cell cycle. Cell cycle non specific drugs- alkylating agents, antibiotics, nitrosoureas, platinum

114
Q

Why is combination chemotherapy more effective to treat cancer?

A

targets all dividing cells from all sides, by using different mechanisms of drugs, it decreases the likelihood that resistant cancer cells will develop

115
Q

What are the side effects of MTX and pemetrexed? What is the mechanism of rescue of normal cells by leucovorin?

A

Side effects- *myelosuppression, *nephrotoxicity, *hepatotoxicity
Rescue for all side effects- LECOVORIN (formyl terrahydrofolate) accumulated more readily by normal cells than by neoplastic cells. Giving this after cancer drug results in rescue of normal cells

116
Q

What is selective toxicity? Why do TMP and pyrimethamine do not cause toxicity in the humans like MTX although all of them inhibit DHFR?

A

The aim of antimicrobial therapy is to kill or inhibit the infecting organism without damaging the host. They do not inhibit human DHFR

117
Q

What is tumor lysis syndrome? Which drug is used to prevent this side effect of cancer chemotherapy

A

oncologic emergency that is caused by massive tumor cell lysis with the release of large amounts of potassium, phosphate, and nucleic acids into the systemic circulation; ALLOPURINOL

118
Q

What is the MoA of 5-FU?

A

metabolites 5-fluorodeoxyuridine monophoase (5-FdUMP, “fraudulent”, can’t be converted to dTMP) inhibits thymidylate synthetase

119
Q

How do you treat hemorrhagic cystitis caused by cyclophosphamide/ ifosphamide?

A

N-ACETYLCYSTEINE/ MESNA (Na-2-mercepatoethane sulfonate). they form a non toxic compound with acrolein
fluid intake

120
Q

What are the major side effects of doxorubicin and bleomycin? How do you treat iron-mediated ROS toxicity?

A

Doxorubicin- myelosuppresion, cardiac damage*, nausea and vomiting
Bleomycin- pulmonary fibrosis
Iron-mediated ROS toxicity: DEXRAZOXANE

121
Q

What do the topoisomerases I & II do to help with the replication and transcription?

A

Topoisomerase I- breaks and reseals ss-DNA
Topoisomerase II- breaks and reseals ds-DNA

122
Q

How do irinotecan and etoposide work?

A

Irinotecan—> SN-38 (glucuronidation by UGT1A1 –> bile excretion) (topoisomerase I)

Etoposide- topoisomerase II breaks and reseals ds-DNA

123
Q

What is the MoA of cisplatin?

A

Platinum compound, intra- and inter- strand linking

124
Q

How do the taxane drugs differ from vinca alkaloids by their action on microtubules?

A

taxanes bind at a different site than the vinca alkaloids and cause inhibition of mitosis by prevention of degradation of microtubules, rather than prevention of their assembly

125
Q

What are the signs of neuropathy with vincristine?

A

suppression of deep tendon reflexes early sign, paresthesia hands and toes, cranial nerve damage (hoarseness, facial palsies, or jaw pain)

126
Q

What is reciprocal translocation? How does it generate the Ph chromosome? Which disease is caused by the BCR-ABL fusion protein? What is the mechanism of disease and what is its Rx?

A

occur when part of one chromosome is exchanged with another; The Philadelphia chromosome is a reciprocal translocation involving chromosomes 9 and 22 that is commonly identified in chronic myelogenous leukemia (CML). The break points of the translocation create a fusion of two genes: ABL1 on chromosome 9 and BCR on chromosome 22.
Mechanism: inhibition of tyrosine kinase activity
Rx: Imatinib

127
Q

Why can a VEGF blocking drug block tumor growth? What is BEVACIZUMAB?

A

VEGF receptors that promote angiogenesis; Bevacizumab- recombinant humanized monoclonal antibody against VEGF, Indication- metastatic, age related macular degeneration

128
Q

What is the MoA of rituximab, cetuximab and trastuzumab?

A

Rituximab- binds to CD20 antigen on > 90% of non-Hodgkin lymphoma cells and on normal B lymphocytes

Cetuzimab- EGFR blocker

Trastuzumab- binds to HER2/neu receptor (RTK of human EGFR2)

129
Q

What are the mechanisms of resistance to chemotherapy?

A

*increase efflux (p-glycoprotein; MDR), increase metabolism of drugs, increase DNA repair, altered checkpoints (cell cycle and immune), altered molecular targets, decrease apoptosis, decrease influx, vesicular sequestration

130
Q

Why do chemotherapeutic agents cause myelosuppression, alopecia, nausea, vomiting, sterility, and carcinogenicity?

A

Chemotherapy is killing dividing cells including normal dividing cells like in bone marrow, gut epithelium, skin, hair follicles, germ cells

131
Q

What is the programmed death pathway? How do cancer cells evade immune surveillance?

A

apoptosis; cancer cells make PD-1 ligands that will keep the normal immune pathway blocked and shut down the immune system

132
Q

What is the MoA of nivolumab, pembrolizumab, and ipilimumab?

A

Nivolumab and Pembrolizumab- anti-PD-1, binds PD-1 (ligands made by cancer cells, helps keep immune cells from attacking nonharmful cells in the body)

Ipilimumab- anti-CTLA-4, blocks a critical negative regulator of the antitumor T-cell response.

133
Q

from Streptomyces, active in G2 phase. iron catalyzed free radical formation and DNA strand breakage

Hodgkin and Non-Hodgkin lymphoma, testicular cancer. Part of ABVD regimen (Adriamycin) for Hodgkin

pulmonary fibrosis

A

Bleomycin

134
Q

antibiotics obtained from Streptomyces, idarubicin and mitoxantrone are semisynthetic anthracycline compounds. ROS, Inhibition of Topoisomerase II**, intercalation of DNA, DNA strand break.

breast cancer, bladder and ovarian, Hodgkin disease

myelosuppression, Cardiac damage**, nausea and vomiting. **Rx of ROS-mediated toxicity: Iron chelation w/ Dexrazoxane (binds Fe2+ to prevent ROS toxicity)

A

Doxorubicin and Daunorubicin

135
Q

inactive until metabolized in liver by CYP450

breast cancer, Hodgkin, non-Hodgkin, leukemia, neuroblastoma, retinoblastoma, osteogenic sarcoma, Wilms tumor

alopecia, bone marrow depression, nausea, vomiting, sterility, Hemorrhagic cystitis by acrolein (Rx- fluid intake and N-acetylcysteine/MESNA)

A

Cyclophosphamide

136
Q

platinum compound, intra and inter-strand linking. During S phase –> unpaired strands –> susceptible alkylation. alkylation of guanine N7 –> base excision –> strand break or pairing of alkylated G with Thymine instead of Cytosine, and substitution of GC by AT. this results in a block at G2 –> **apoptosis **

testicular cancer, other germ tumors, ovarian cancer, bladder, lung, sarcoma, cervical, endometrial, gastric, breast, head and neck cancers

nausea and vomiting, nephrotoxicity, toxicity, peripheral neuropathy, hypomagnesemia and K+ wasting

A

Cisplatin

137
Q

Chronic Myeloid Leukemia (CML): reciprocal translocation t(9;22) (q34;q11) from breakpoint cluster region (BCR) gene on chromosome 22 with tyrosine kinase sequence of Abelson (ABL) gene on chromosome 9 = elongates chromosome 9 and shortened chromosome 22 (Philadephia (Ph) Chromosome) AND = chimeric fusion protein pBCR-ABLE has a constitutive active tyrosine kinase activity

Inhibition of tyrosine kinase activity

CML; gastro-intestinal tumor

A

Imatinib

138
Q

inhibits tyrosine kinase domian of EGFR

NSCL; pancreatic cancer in combination with GEMCITABINE (2-deoxycytidine analog antimetaboliite that inhibits DNA polymerase

A

Erlotinib and Geftinib

139
Q

inhibits RTK, including VEGF and PDGF receptors that promote angiogenesis

renal cell carcinoma

A

Sorafenib and Sunitinib

140
Q

V600 mutation in BRAF gene leads to constitutive activation of B-Raf kinase

melanoma

A

Dabrafenib

141
Q

–> SN-38 (glucuronidation by UGT1A1 –> bile excretion). synthetic analogs with greater activity and less toxicity TOPOISOMERASE I

Colorectal cancer, lymphomas, breast, cervical, gastric, lung

myelosuppression, diarrhea

A

Irinotecan

142
Q

renal excretion. synthetic analogs with greater activity and less toxicity TOPOSIOMERASE I

glioma, sarcoma, lung, ovarian tumors

myelosuppression

A

Topotecan

143
Q

TOPISOMERASE II- breaks and reseals dsDNA

testicular, carcinoma, lung cancer, and non-Hodgkin lymphoma

synergy with platinum compounds (CISPLATIN)

A

Etoposide (2 sides)

144
Q

recombinant humanized monoclonal antibody against VEGF

metastatic colorectal cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, age related macular degeneration

A

Bevacizumab

145
Q

EGFR blocker. monoclonal antibody immunotherapy

colon cancer

acne like rash

A

Cetuximab

146
Q

binds to CD50 antigen on > 90% of non-Hodgkin lymphoma cells and on normal B lymphocytes. monoclonal antibody immunotherapy

refractory B-cell Non- Hodgkin lymphoma

A

Rituximab

147
Q

binds to HER2/ neu receptor (RTK of Human EGFR2). monoclonal antibody immunotherapy (“Trust HER”)

metastatic breast cancer (Trastuzumab + Doxorubicin + Paclitaxel). bystander effect. Trastuzumab + Emtansine (microtubule disruptor- 34%, Trastuzumab + Deruxtecan (topo I inhibitor- 76%)- linker cleavage by tumor cells release membrane permeable Deruxtecan, this allows low HER2+ neighboring cells to be killed (bystander effect). combination also approved bot HER2+ gastric cancer

A

Trastuzumab

148
Q

Freezes microtubules in the polymerized state (spindle poison). prevent depolymerization. mitosis inhibition by microtubule stabilization. from Taxus spp. bark tree

NSCLC, ovarian cancer (Carboplatin + Paclitaxel= Rx of choice), metastatic breast cancer. DOCETAXEL for metastatic breast and NSCLC

Neurotoxic, myelosuppression, alopecia

A

Paclitaxel

149
Q

mitosis inhibition by microtubule disruption. prevent depolymerization

ALL, CLL, non-Hodgkin lymphoma

Neurotoxic peripheral neuropathy (sensory and motor). suppression of deep tendon reflexes early sign. Paraesthesia hands and toes. Cranial nerve damage: hoarseness, facial palsies, or jaw pain. Autonomic neuropathies: orthostatic hypotension, abdominal pain, constipation. No myelosuppression (No L in )

A

Vincristine (from periwinkle plant)

150
Q

mitosis inhibition by microtubule disruption. prevent depolymerization

ABVD regimen for Hodgkin disease and breast cancer

Myelosuppression (L in Vinblastine; but no neurotoxicity)

A

Vinblastine (from periwinkle plant)

151
Q

vinblastine derivatives: NSCLC. breast, ovarian

A

Vinorelbine

152
Q

what is the most efficient bactericidal system in neutrophils

A

the H2O2 myeloperoxidase (MPO) halide system

153
Q

what comes in after 24 hours of infection, first line of defense

A

neutrophils

154
Q

what comes in after 48 hours of infection

A

macrophages

155
Q

what causes defects in leukocyte adhesion, impaired adhesion and migration through endothelium, and presents with lots of infections that cannot heal

A

Polymorphism Leukocyte Dysfunction Syndrome (genetic)

156
Q

what are the 4 types of acute inflammation cells

A

serous, fibrinous, purulent (pus), ulcer

157
Q

what are the 5 types of necrosis

A

coagulative (red and dead)
liquefactive
gangrenous
caseous (cheese-like)
fat (often due to sports trauma)

158
Q

what disease is a genetic deficiency, where engulfment of bacteria does not induce an oxygen-dependent killing mechanism, so the macrophage stays and adds up –> granuloma

A

Chronic Granulomatous Disease

159
Q

Type I hypersensitivity disease

A

antigen (smallest)
ex) anaphylactic shock- cannot breathe bc soft tissue in larynx swells

160
Q

Type II hypersensitivity disease

A

antibodies, directed towards antigen

161
Q

Type III hypersensitivity disease

A

antibody + antigen

162
Q

Type IV hypersensitivity disease

A

cells (biggest), mediated by T-lymphocytes

163
Q

ball of macrophages surrounded by lymphocytes

A

granuloma

164
Q

what is the most common cell stress where tissue decreases in size due to disuse, seen with brain in Alzheimers

A

atrophy

165
Q

what is abnormal metabolism after cell stress, example is steatosis (fat storage) after drinking alcohol

A

intracellular storage

166
Q

what is an increase in size of cell after cell stress, due to growth factors (myc), example is uterus getting bigger after birth?

A

hypertrophy

167
Q

what is an increase in number of cells in a tissue, example is in breast during pregnancy; example arteriole due to hypertension

A

hyperplasia

168
Q

what is a reversible change from one normal tissue to another to better cope with extracellular environment
ex) columnar to squamous transformative zone, survey here for cervical cancer

A

metaplasia

169
Q

what is it called when a cancer is confined to an epithelium and restricted to growth in BM, pre cancer, irreversible

A

dysplasia
leads to neoplasia

170
Q

what is the most common gene mutation in colon cancer

A

APC gene

171
Q

receptors with intrinsic tyrosine kinase activity that activate transcription factors through these growth promoting genes (3)

A

MYC, FOS, JUN

172
Q

growth promoting genes that regulate the cell cycle, defects produce oncogenes which lead to uncontrollable cells growth
ex) MYC, FOS, JUN, Ras, ERB2

A

proto-oncogenes

173
Q

growth inhibiting genes, regulate cell cycle, recessive oncogenes (2 hits)
ex) Rb, p53

A

tumor suppressor genes (TSG)

174
Q

genes involved in apoptosis, inactivation of these leads to uncontrollable cell growth

A

BCL-2, p53

175
Q

which apoptosis determining gene is the only one found in mitochondria

A

BCL-2

176
Q

___ binds to CDK4 and hypo/hyper phosphorylates Rb forming ON/OFF switch

A

cyclin D

177
Q

How does HPV cause cervical cancer?

A

HPV makes E6 and E7
E6 inhibits p53 (inhibits response to cell stress)
E7 inhibits Rb (inhibits protein that prevents cell division)

178
Q

Cell death that is IRREVERSIBLE with membrane/organelle rupturing, pathologic, and cell size enlarged

A

necrosis

179
Q

cell death that is physiologic, involves Bcl2 p53 upregulates Bax, Bad, Bak, cell size is reduces

A

apoptosis

180
Q

name the cells that come in during tissue repair and time stamp (4)

A

neutrophils (24 hours)
macrophages (48 hours)
granulation (7 days)
fibrosis/ scar (weeks)

181
Q

what is it called when you have Ca2+ in blood vessel and makes the heart bigger and will kill you

A

Calcific aortic valvular stenosis

182
Q

What is the MoA for the antibiotic Azithromycin

A

binds to 50S and blocks peptidyl transferase AND amino acid translocation

183
Q

What is the MoA of Puromycin

A

aminoacyl tRNA analog, binds A site and acts as a peptidyl acceptor, ABORTING ELONGATION

184
Q

Describe competitive inhibition and an example

A

Vmax= same, Km= increase (right), binds to same site as enzyme
ex) Provostatin- has similar structure to HMG-CoA in the HMG-CoA reductase active site in cholesterol synthesis

185
Q

Describe noncompetitive inhibition and an example

A

Vmax= decrease, Km= same; different binding site reduces amount of enzyme active

ex) Lead- inhibits Heme synthesis leading to anemia

186
Q

Describe uncompetitive inhibition and an example

A

Vmax= decrease, Km= decrease; bind only to formed ES complex (rare)

ex) mycophenolate- inhibits IMP dehydrogenase for nucleotide synthesis and prevents transplant rejection by inhibiting B and T cells (sugar and synthesize base)

187
Q

Describe irreversible inhibition and an example

A

Vmax= decrease, Km= same; reacts covalently with amino acid residue

ex) Organophosphorous insecticides and nerve gasses- inhibits acetylcholinesterase –> inactivates AcH
muscarinic cholinergic receptors (SLUDGE)- treat w/ Atropine
nicotinic cholinergic receptors (diaphragm paralysis)- intubate

188
Q

mending NON BULKY DNA lesions like alkylated and oxidized base pairs
8-oxo-G binds A instead of C
non bulky DNA ex) AP site
excision of base by GLYCOSYLASE
MUTYH associated polyps (MAP)
NTHL1 associated polyps (NAP)

A

base excision repair (BER)

189
Q

microsatellite instability ex) telomeres
recognition by MSH6 and MSH2, PMS2 and MLH1 bind, removal w/ Exo 1 (5’ –> 3’), resynthesis and ligation
Lynch Syndrome (HNPCC)- mutation in MSH2, MLH1, increased lifetime risk of colon cancer

A

mismatch repair (MMR)

190
Q

bulky adduct detection
generated by UV light, cisplatin, cigarette smoke, or Aflatoxin
Xeroderma Pigmentosum, Cockayne Syndrome, Combined XP-CS, COPS syndrome, XFE progeroid syndrome
removal of the damaged bases occurs on only one strand of DNA

A

nucleotide excision repair (NER)

191
Q

happens in G1 when no sister chromatid is needed and ends protected from resection before joining, no homology required, more error prone

A

non homologous end joining

192
Q

less error-prone, no loss of nucleotides
BRCA 1/2 interacts with RAD51 mutation
5’ –> 3’ resection, holiday junction

A

homologous recombination