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FOM > Exam 5 > Flashcards

Exam 5 Flashcards

1
Q

Intrinsic apoptosis

A

Initiated by perturbations of the extracellular or intracellular microenvironment, demarcated by MOMP, and precipitated by executioner caspases, mainly C3 

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2
Q

Extrinsic apoptosis

A

Initiated by perturbations of the extra cellular microenvironment detected by plasma membrane receptors, propagated by C8, and precipitated by executioner caspases, mainly C3

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3
Q

Autophagy-dependent cell death

A

Mechanistically depends on the autophagic machinery

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4
Q

Necroptosis

A

Triggered by perturbations of extracellular or intracellular homeostasis that critically depends on MLKL, RIPK3, and kinase activity of RIPK1

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5
Q

Ferroptosis

A

Initiated by oxidative perturbations of the intracellular microenvironment that is under control by glutathione peroxidase (GPX4), can be inhibited by iron chelators or lipophilic antioxidants

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6
Q

Caspase target MST1

A

Chromatin condensation

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7
Q

Caspase target ICAD (inhibitor of a DNase)

A

DNA cleavage

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8
Q

Caspase target Lamins

A

Nuclear envelope breakdown

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9
Q

Caspase target Rho Kinase

A

Actin cytoskeleton disruption

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10
Q

Caspase target cell-cell and cell-ECM adhesion junctions

A

Cell rounding and deattachment (blebbing)

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11
Q

Caspase target golgi and ER proteins

A

Fragmentation of organelles

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12
Q

Caspase target eIFs

A

Translation arrest

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13
Q

Caspase triggering externalization of phosphatidyl serine

A

“Eat me” to phagocytic white blood cells

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14
Q

How does membrane blebbing occur?

A

Process of ROCK (Rho-associated kinase) leads to actin bundle contraction and membrane blebbing

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15
Q

How does chromatin condensation occur?

A

Proteolysis of the protein kinase MST1 releases an active fragment that phosphorylates histamine 2B and promotes condensation

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16
Q

Initiator Caspases

A

C 9, 2, 8, 10

Activated in protein complexes, the nature is site-dependent (Close together perpetuates signals Causing DISCs assemble a plasma membrane receptors, and PIDDosomes appear to interact with mitotic machinery)

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17
Q

Effector caspases

A

C 3, 7, 6

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18
Q

Apoptosome

A

A protein complex that activates C9

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19
Q

DISC

A

Death inducing signaling complex (activates C8 and C10) 

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20
Q

PIDDosome

A

A Caspase-activating protein complex that includes p53 induced death domain protein (activates C2)

Mitotic spindle problems involving kinetochores and spindle poles activate C2 which activates PIDDosomes —> hydrolyze Mdm2 —> inducing p53 activity 

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21
Q

Extrinsic pathway of Caspase activation

A

Death ligand binds to death receptor, FasL to Fas, Which creates the DISC Intracellularly: includes scaffolding which can then bind and activate C8  —> C3 —> apoptosis

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22
Q

Intrinsic pathway of Caspase activation

A

Involves damage or stress, which is transmitted to the mitochondria, resulting in MOMP and release of cytochrome C —> set a currency forms a complex with a PAF1 and C9 (apoptosome) —> Activates C9 —> C3

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23
Q

Inhibit MOMP and suppress apoptosis

A

• Bcl-2
• Bcl-xL

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24
Q

Promote MOMP and promote apoptosis

A

• Bax
• BAK

BH1,2,3 protein

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25
Q

Inhibit Bcl-2 and Bcl-xL and promote apoptosis

A

• Bid, Bad
• Puma, Noxa

BH3-only protein

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26
Q

IAPS: Inhibitor of apoptosis proteins

A

Bind to caspases and directly inhibit their proteolytic activity

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27
Q

Smac/Diablo

A

Released by mitochondria after MOMP, these proteins can inhibit IAPs 

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28
Q

AIF: Apoptosis inducing factor

A

A nucleus that is released by mitochondrial MOMP that can translocate the nucleus and cleave DNA, resulting in cell death, independent of caspases

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29
Q

ER stress transduced into apoptotic response

A

Activate C12 —> C9 —> Rest of Caspase cascade

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30
Q

DNA damage transduced into apoptotic response

A

• Damage detected by ATM/ATR kinases
•  activates Chk1/2 —> Stabilizes p53
• p53 Target Bax, which promotes MOMP, cytochrome C release, formation of apoptosomes leading to apoptosis

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31
Q

What keeps Bcl-2 free from inhibition by proapoptotic Bcl-2 family members?

A

PKB/Akt regulated by PI3K

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32
Q

Autophagy

A

Provides bulk degradation and recycling of cytoplasmic components in lysosomes promoting cell health and survival

When in excess, this compromises the cytoplasm and activates apoptosis 

• Beclin1, PI3K, Atg

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33
Q

AMPK responding to metabolic conditions

A

Promotes autophagy both by inhibiting mTOR and activating ULK1

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34
Q

Beclin-PI3K-Atg Complex

A

Receives input from mTOR (inhibits complex)

Receives input from AMPK (activates complex) 

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35
Q

Bcl-2 functioning as a switch between apoptosis and controlled autophagy

A

• binds and inhibits Beclin1, thereby restraining autophagy— if Phosphorylated by jnk, Beclin1 is free and autophagy occurs

• when bound to Beclin1, it is not bound to Bak/BAX, promoting apoptosis

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36
Q

Necroptosis

A

C8 inhibited by FLIP/pathogens -> increases RIPK1/3 -> increases MLKL (penetrates membrane w 4 alpha-helices, cell swelling) -> increases necroptosis

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37
Q

Necroptosis and PAMP/DAMP

A

Necroptosis releases PAMPs and DAMPs (Pathogen/damage associated molecular patterns), that active the inflammatory response

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38
Q

Ferroptosis

A

decrease GPX4, increase accumulation of ROS. Lipid peroxidation in the associated rupture of cellular membranes is a hallmark of ferroptosis

• occurs with age in Lipofuscin granules, Fenton rxns

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39
Q

(1) death receptor signaling at the plasma membrane
(2) Extensive DNA or organelle damage
(3) Malformed mitotic spindles was compromised function

A

(1) DISCs
(2) apoptosomes (cyt C, APAF1, C9)
(3) PIDDosomes

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40
Q

Increasing bax-mediated pore formation in mitochondrial outer membrane is most likely to result in the assembly of

A

Apoptosomes

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41
Q

A dying sell displaying an unusually large number of lysosomes is most likely undergoing:

A

Autophagy

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42
Q

Increasing the expression of which of the following proteins would be expected to make a cell more resistant to apoptosis?

A

Bcl-2

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43
Q

Cells can shift from an apoptotic response to a necroptotic response if _______ is inactivated by _________.

A

Caspase 8 , viral proteins (pathogens) 

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44
Q

What would be expected to facilitate MOMP and promote apoptosis?

A

Extrinsic pathway activation leading to the production of t-Bid from BID with the consequent activation of the intrinsic pathway

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45
Q

Protein that functions in transducing DNA damage into either cell cycle arrest or an apoptotic response, depending on the severity of the damage in the overall cell state

A

p53

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46
Q

Selection bias: Berkson Bias

A

Also known as collider bias, Study population selected from a hospital that can lead to spurious negative associations

Strategy to reduce bias: choice of comparison group

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47
Q

Selection bias: healthy worker effect

A

Study population is healthier than the general population

Strategy to reduce bias: study design, choice of comparison group

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48
Q

Selection bias: nonresponse bias

A

People who choose to participate are different in meaningful ways from people who choose to not participate

Strategy to reduce bias: study design

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49
Q

Recall bias

A

Awareness of disorder/disease causes people to recall potential exposures differently

Strategy to reduce bias: study design

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50
Q

Measurement bias

A

Differential versus non-differential

Hawthorne effect: participants change their behavior because they know they’re being observed

Strategies to reduce bias: choice of comparison group, use standard/validated tests/procedures, regular calibration of equipment, training of study staff

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51
Q

Procedure bias

A

Participants in different groups are not treated the same

Strategy to reduce bias: masked study design

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52
Q

Observer expectancy bias

A

Researchers preconceived ideas of results influence measurement, documentation, statisical analyses

Strategies to reduce bias: masked study design, independent statistical analyses

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53
Q

Confounding bias

A

Risk factor is related to both exposure and health outcomes, but is not casually related (Ex. Use of cod liver oil is positively associated with age related hearing loss)

Strategies to reduce bias call study design, replication studies

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54
Q

Lead-time bias

A

Early detection is confused with increased survival time

Strategies to reduce bias: study design

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55
Q

Survivor bias

A

A.k.a. incidence prevalence bias

Strategies to reduce bias: limit analysis to incident cases

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56
Q

Publication bias

A

Studies were statistically significant results are more likely to be pushed, as are those documenting a novel finding

Strategies to reduce bias: measure existence with Donald lots, include novel sources to identify data for meta-analyses 

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57
Q

Example of a common genetic polymorphism

A

Rh system: (+) and (-)

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58
Q

Alpha1-antitrypsin (ZZ)

A

Major serum protein that inhibits proteolytic enzymes, major target is leukocyte elastase which can damage lung connective tissue if not down regulated— Early onset emphysema 

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59
Q

Ecogenetics

A

Genetic variation in susceptibility to environmental agents

Examples: fair complexion and UV light, ADH deficiency and alcohol, G6PD deficiency and fava beans

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60
Q

Heterozygous advantage

A

A deleterious allele that is maintained in a population because it increases reproductive fitness when it is heterozygous — Ex. Sickle cell

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61
Q

 Hardy Weinberg law

A

1.) there is no appreciable rate of new mutation
2.) Individuals with all genotypes are equally capable of mating and passing on their genes— no selection against any particular genotype
3.) No significant immigration of individuals from a population with allele frequencies very different from the endogenous population

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62
Q

Hardy Weinberg equation

A

p^2 + 2pq + q^2

p^2: probability of AA genotype
q^2: probability of aa genotype
pq: heterozygous

p= 1-q

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63
Q

Importance of Hardy Weinberg disequilibrium

A

When alleles at a locus are not in HW equilibrium this can indicate that a particular allele is associated with a disease— fatal/ doesn’t show up as frequently in a community

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64
Q

Mendelian diseases

A

Primary single gene diseases, the disruption of a single gene

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65
Q

The most common functional protein change mutation

A

Loss of function— Miss sense, nonsense, frameshift, deletions, insertions

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66
Q

Gain of function mutations

A

Increase gene dosage/proteins function

Ex. Down syndrome, achondroplasia

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67
Q

Allelic heterogeneity

A

Different alleles of the same gene/locus causing very disease severity

— PKU

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68
Q

Locus heterogeneity 

A

Mutations in different genes/locus is can yield a similar clinical phenotype 

— hyperphenylalaninemia 

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69
Q

Modifier genes

A

People with the same mutation can present dramatically different phenotypes due to the presence of modifier genes

Ex: ApoE4 frequency increasing neurological and neurodegenerative disorders

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70
Q

Example of enzyme defect

A

PAH gene and the disease PKU— Also an example of defect that occurs in one tissue (liver, kidney) but where the phenotype is manifest elsewhere (brain)

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71
Q

Defects in lysosomal storage

A

Leads to increased tissue mass and is a common cause of neurodegeneration and CNS problems

Example: Tay-Sachs disease buildup of GM2 gangliosides sphingolipids in the retina lysosomes

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72
Q

Defects in protein trafficking

A

I-cell disease: autosomal recessive lysosomal storage disease caused by a defect in proteins trafficking, acid hydrolases which are required are not properly modified with glycoproteins

Acid hydrolases get sent out of the cell instead of to the lysosomes

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73
Q

Defect in cofactor metabolism example

A

Alpha 1-AT : Involved in the breakdown of various proteases that can damage lung tissue if not regulated. (Interaction with environmental factors like cigarette smoke) 

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74
Q

Defect in receptor proteins example

A

Hypercholesterolemia: LDLR defect, causes cardiovascular disease

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75
Q

Defect in transport examples

A

Cystic fibrosis, delta F508, Mutation of a chloride channel, affects lungs and exocrine pancreas

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76
Q

Defects in structural proteins example

A

DMD: X-linked recessive disease caused by a mutation in the dystrophin gene

Female carrier: elevated creatine kinase levels, no clinical manifestation

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77
Q

Triple repeat expansion disorders

A

Huntington’s, fragile X, Friedreich ataxia, myotonic dystrophy 1 and 2

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78
Q

Mitochondrial genetic bottleneck

A

The restriction and subsequent amplification of mtDNA during oogenesis: mosaicism/heteroplasmy

Mothers with a high proportion of mutant mtDNA are more likely to have clinically affected offspring

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79
Q

Complex genetic diseases

A

Do not demonstrate a simple Mendelian pattern of inheritance, often demonstrate familial aggregation, inheritance is more common among the close relatives of a proband, more likely in MZ versus DZ twins

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80
Q

Human characteristics which show a continuous normal distribution

A

• blood pressure
• dermatoglyphics
• head circumference
• height
• IQ
• skin color 

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81
Q

Four characteristics of inheritance of complex diseases

A

1.) no simple Mendelian pattern of inheritance
2.) Familial aggregation
3.) Environmental factors
4.) More common among close relatives of the proband 

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82
Q

Relative risk ratio

A

Prevalence of the disease in the relatives of an infected person
___________________________________
Prevalence of the disease in the general population

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83
Q

Odds ratio

A

OR=1 would show complete lack of association

OR>1 A higher risk of an outcome

OR<1 Lower risk of an outcome

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84
Q

Examples of recurrence risks and relative risk ratios

A

Schizophrenia, bipolar disorder, coronary artery disease, MI, Alzheimer’s disease

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85
Q

Approaches to identifying genes underlying complex diseases

A

1.) Test a candidate gene for variance in a disease population

2.) map a gene in a family/families with history of disease

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86
Q

Quantitative trait loci (QTLs) 

A

Complex disease genes identified often have quantitative affects

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87
Q

Physical mapping of disease genes

A

Actual sequence and physical location on a chromosome are being looked at

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88
Q

Genetic mapping for disease genes

A

Based on the following a phenotypic trait in the families, indicates the relative position of genes (as identified by their function) as shown by linkage analysis

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89
Q

Linkage analysis

A

Uses statistics to determine whether to genes, loci or the markers they are based on, are likely to live near one another. Estimated by the frequency that they are transmitted together

Two genetic loci are linked if they are transmitted together from parent to offspring more often than expected under independent inheritance

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90
Q

Recombination frequency

A

RF > 50% means two genes are unlinked

RF < 50% means two genes are linked

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91
Q

Mendel’s first law

A

The principle of segregation: the two members of a gene pair segregate from each other in the formation of gametes. Half of the gametes carry one allele, and the other half carry the other allele

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92
Q

Mendel’s second law

A

The principle of independent assortment: genes for different traits assort independently of one another in the formation of gametes. —unlinked 

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93
Q

A disease locus can be mapped by:

A

Following its co-transmission with known chromosomal markers (Without knowledge of the actual gene)

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94
Q

LOD scores

A

Logarithm of the odds: odds ratio is expressed as the log10 of this ratio

— this is the likelihood of data if loci are linked

LOD of 3+ : 1000:1 odds favor of linkage (not random)

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95
Q

Association analysis

A

Start with a candidate gene, suspect that a defect or polymorphism is responsible and then look into families and or population to determine if people with a disease are statistically more likely to carry a particular rotation or polymorphism

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96
Q

Steps in mapping a complex disease gene

A

• linkage analysis/prior knowledge
• Genomic analysis, association analysis to determine the correspondence
•  alternative strategy: SNP chips
• Follow up with bio chemical and molecular analysis/animal models

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97
Q

Calpain-10 (CAPN10)

A

A type two diabetes gene, found by linkage analysis of Mexican American family

— Is not a polymorphic marker, is actually the disease. Assisting protease that interferes with insulin secretion and glucose uptake

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98
Q

Sib-pair analysis

A

Uses small families and asks whether affected siblings share specific gene alleles had a frequency higher than expected by random chance

 Comparing identical by descent (IBD) to identical by state (IBS)

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99
Q

Identical by descent

A

Siblings have the same allele from the same parent

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100
Q

Identical by state

A

Siblings have the same allele, regardless of what parent it came from

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101
Q

Hirschsprung disease and Sib-Pairs

A

55/67 shared three polymorphic markers at three different genes

The other 12 shared at least two of the three polymorphic markers

— RET gene malfunction 

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102
Q

Sources of one-carbon units

A

Serine, glycine, histidine, formaldehyde, formate

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103
Q

Regulation of the one-carbon pool

A

FH4 delegating a C — formyl <—> methylene <—> methyl

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104
Q

Folate

A

• Vitamin precursor of FH4
• found in leafy green vegetables, liver, legumes, yeast, fortified flour
• has glutamic acid tail

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105
Q

Major form of folate in the blood

A

Reduced N5-methyl tetrahydrofolate from the intestinal epithelial cells

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106
Q

PCFT

A

Proton (H+) coupled folate transporter encoded on the SLC46A1 gene on enterocytes and hepatocytes

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107
Q

Hereditary folate malabsorption

A

An inherited mutation in the proton coupled folate transporter causing a functional folate deficiency despite adequate folate in the diet: no absorption 

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108
Q

What is a folate deficiency associated with before and during pregnancy?

A

Spina bifida, neural tube defects

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109
Q

Folate to FH4

A

Folate —dihydrofolate reductase—> dihydrofolate — dihydrofolate reductase—> tetrahydrofolate

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110
Q

What drugs target dihydrofolate reductase?

A

Methotrexate colon cancer, rheumatoid arthritis

Trimethoprim: antibacterial

Pyrimethamine: antimalarial

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111
Q

How is formate formed?

A

The degradation of tryptophan— Formate is one source of carbon for the “one carbon pool”

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112
Q

Redox of formate/tetrahydrofolate 

A

FH4 + formate —> N10- formyl <—> N5,N10-methenyl <—> N5,N10-methylene —> N5-methyl

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113
Q

Forminotransferase deficiency

A

FIGLU accumulation (from FH4 + histidine —> 5-formimino + glutamate) characterized by Megaloblastic anemia and mental retardation

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114
Q

Serine and the one carbon pool

A

Serine is the most important contributor to the one carbon pool. It forms N5,10- methylenetetrahydrofolate when it donates its carbon to FH4 using PLP as a cofactor

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115
Q

Sources of products of the one carbon pool

A

Serine, glycine, Choline, Histidine, tryptophan

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116
Q

Two forms of B12 in the body

A

Methylcobalamin

Adenosylcobalamin 

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117
Q

Methylcobalamin reaction:

A

Donation of a methyl to homocystine to make methionine

— Methylcobalamin is consumed in the process

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118
Q

Adenosylcobalamin reaction:

A

Catalyzes the isomerization of a methyl group in converting methylmalonyl CoA to succinylacetone CoA 

— catabolism of branched chain an odd chain length fatty acids, isoleucine, valine
— Adenosylcobalamin not consumed in the reaction

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119
Q

How B12 enters the body

A

1.) binds to R binder proteins in the stomach
2.) R binders get digested, B12 then binds to intrinsic factor
3.) Intrinsic factor B12 complex is taken up by intestinal epithelial cells and transported into the blood
— Transcobalamin II is the protein used
4.) B12 get stored in the liver complex with Cubillin

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120
Q

B12 deficiency

A

• Causes pernicious anemia, megaloblastic anemia plus neurological problems
• caused from dietary deficiency, loss of function of intrinsic factor, transcobalamin II, or cubillin 

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121
Q

What is S – adenosylhomocystine used for?

A

SAM — A methyl donor for many biosynthetic and regulatory enzymes, and it must be regenerated with carbon that comes from N5-methyltetrahydrofolate

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122
Q

Methotrexate

A

Targets dihydrofolate reductase,

FH2 —x—> FH4

Folate deficiency leads to decrease in nucleotide production. Use against cancer, because those cells require deoxynucleotides for rapid cell division

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123
Q

5–fluorouracil

A

A uracil analog that inhibits thymidylate synthase. Is a suicide inhibitor

dUMP—x—> dTMP

Folate deficiency leads to decrease in nucleotide production. Use against cancer, because those cells require deoxynucleotides for rapid cell division

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124
Q

Hyperhomocystinemia

A

Accumulation of homocystine because it cannot be converted to methionine by B12 (Methylcobalamin)

This can also be caused by a vitamin B6 deficiency, because the homocysteine cannot convert to cysteine 

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125
Q

Betaine

A

This is the bodies second pathway to turn homocysteine to methionine. It is a metal donor

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126
Q

The buildup of homocysteine affects: 

A

• PNS & CNS deficiencies
• atherosclerosis
• Osteoporosis
— Interferes with collagen maturation 

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127
Q

Methylmalonyl CoA mutase activity lost (Adenosylcobalamin def) causes:

A

Inappropriate synthesis causing branched chain fatty acids rather than unbranched. These branched fatty acids compromise the membrane structure

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128
Q

Methyl trap hypothesis

A

The only metabolic fate of N5-methyl FH4 is to lose its methyl to cobalamin. In a dietary or functional deficiency, folate becomes trapped as N5-methyl FH4, unable to participate in other one carbon transfers

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129
Q

Clinical features of cobalamin deficiency

A

Megaloblastic Anemia, sore tongue, auto immune gastritis, numbness and ataxia

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130
Q

Severe osteoporosis and young patient should always suggest the possibility of what?

A

Homocystinuria

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131
Q

The two main processes of tissue repair

A

1.) regeneration: restoration of normal cells

2.) Scarring/fibrosis: deposition of connective tissue

Ultimate repair is usually a combination of both

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132
Q

Mechanisms of regeneration of tissue

A

1.) proliferation of differentiated cells that survive injury and have ability to proliferate (ex. Liver)

2.) Tissue stem cells produce new and differentiated cells (ex. Skin, GI)

— Regeneration typically requires intact supporting structures

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133
Q

Mechanism of scarring/fibrosis of tissue

A

1.) injured area is patched with connective/fibrous tissue. Occurs when cells are not capable of regeneration, or supporting structures are too severely damaged

2.) functional cells are replaced by connective tissue, which provides structure but does not provide function

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134
Q

Three classes of tissues that can be repaired

A

1.) labile, constantly dividing tissue
2.) Stable tissue
3.) Permanent tissue

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135
Q

Labile, constantly dividing tissue

A

• Constant overturn fed by stem cells and proliferation of mature cells
• Occurs in the lung, skin, G.I. tract, and hematopoietic
• surface of the epithelia 

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136
Q

Types of labile cells

A

• Type two pneumocyte in the lung
• basal cell in the skin
• Crypt cells in the G.I. tract
• CD34+ cells

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137
Q

Stable tissue

A

• made of quiescent cells (G0)
• Capable of proliferating when tissue is injured or lost
— In solid tissues: liver, kidney pancreas
— in connective tissue: endothelium, smooth muscle, fibroblasts

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138
Q

Permanent tissue

A

• cells are terminally differentiated and cannot proliferate
• This includes most neurons, cardiac, and skeletal muscle
• Repair is almost entirely scarring/fibrosis

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139
Q

Regeneration after injury is driven by:

A

Growth factors derived from:
• Active macrophages at the side of injury (most common)
• Platelets
• Epithelial cells
• Stromal cells (Fibroblasts)
• Sequestered pool in extracellular matrix

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140
Q

Heparan sulfate

A

An extra cellular matrix signaler for tissue damage 

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141
Q

Phase 1 of scarring/fibrosis repair

A

Inflammatory (days 1-3)
• Cellular mediators: platelets, neutrophils, macrophages
• Actions: acute inflammatory responses

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142
Q

Phase 2 of scarring/fibrosis repair

A

Proliferative (day 3-weeks)
• Cellular mediators: fibroblasts, myofibroblasts, endothelial cells, epithelial cells, macrophages
• actions: establishment of granulation tissue, angiogenesis, epithelial cell proliferation, type III collagen deposition

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143
Q

Phase 3 of scarring/fibrosis repair

A

Remodeling (1 week- months)
• Cellular mediators: fibroblasts
• Actions: type III collagen deposition replaced by type I collagen (stiffer, less elastic) 

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144
Q

Granulation tissue

A

Many new blood vessels, fibroblasts, and chronic inflammation including numerous macrophages

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145
Q

Angiogenesis: action of VEGF

A

Vascular endothelial growth factor:

• Stimulates both migration and proliferation of endothelial cells
• Promotes vasodilation by stimulating the production of NO
• Contributes to the formation of vascular lumen

(Important for healing) 

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146
Q

Angiogenesis growth factors

A

FGF, TGF-beta, VEGF,

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147
Q

Fibrosis growth factors

A

TGF-beta, PDGF

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148
Q

Vascular remodeling and smooth muscle migration growth factor

A

PDGF

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149
Q

Cell proliferation and regeneration growth factor

A

EGF

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150
Q

Central role of the macrophage

A

M1: clearing offending agents and dead tissue

M2:
• Provide growth factors causing the proliferation of various cells
• Secrete cytokines that stimulate fibroblasts to proliferate and deposit connective tissue in ECM

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151
Q

Temporally regulated

A

Initially, the macrophages are classically activated (M1), but are gradually replaced by alternately activated type (M2)

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152
Q

TGF-beta

A

• produced by cells in granulation tissue
• Stimulus fibroblast migration and proliferation
• Increases synthesis of collagen and fibronectin
• decreases degradation of ECM
• Has anti-inflammatory properties

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153
Q

Clinical factors that can impede repair

A

INFECTION, diabetes, nutritional deficiencies, medication/steroids, mechanical stress, ischemia/poor perfusion, foreign material, injury type and extent, injury location

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154
Q

First intention wound

A

A suture surgical incision with tightly apposed edges

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155
Q

Second intention wound

A

A wide open wound, which leads to more inflammation, more granulation tissue, increased risk of infection, large scar

myofibroblastic contraction plays a major role in wound closing

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156
Q

Wound strength

A

At one week: wound is about 10% as strong as normal skin

After two months: maximum strength is achieved, still only 75% of the original tissue strength

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157
Q

Hypertrophic scar

A

Raised, limited to boundaries of original wound, tends to regress overtime, parallel collagen I bundles as in normal scar

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158
Q

Keloid scar

A

Markedly raised, expands beyond the boundaries of the original wound, contains bright eosinophillic collagen bundles that are disorganized

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159
Q

Scar contracture

A

Failure to make a scar, the fibroblasts pull the skin back together and it pulls too tightly

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160
Q

Leak channels:

A

Always open, help maintain resting membrane potential, permeate K more than Na

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161
Q

Voltage gated channels

A

Activated by membrane potential: Na, Ca, K, Cl channels 

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162
Q

Extracellular ligand activated channels

A

Regulated by ligands (neurotransmitters), glutamate, GABA, and glycine receptor channels

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163
Q

Intracellular ligand gated ion channels

A

Activated by Ca2+, ATP, cyclic AMP and GMP, often activated indirectly by GPCRs including CFTR and ABC transporters

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164
Q

Thermos sensitive channels

A

Regulated by temperature and pain, TRP channels

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165
Q

Mechano-sensory and volume regulated channels

A

Activated by touch, hearing, cardiovascular regulation, sensing of gravity, and osmotic stress

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166
Q

Light gated channels

A

Used for Optogenetics

Channelrhodopsin: blue light (Na+,K+)
Halorhodopsin: yellow light (Cl-)

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167
Q

Types of gated ion channels

A

1.) Confirmational change in one region
2.) General structural change
3.) Blocking particle (AA)
4.) ligand gated
5.) Phosphorylation gated
6.) Voltage gated
7.) Stress or pressure gated (Cytoskeleton)

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168
Q

Mechanisms for channel inactivation

A

1.) change in membrane potential
2.) Calcium binding
3.) Dephosphorylation

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169
Q

Which channel type is the most diverse?

A

K+

— they can be sensitive to depolarization, hyper polarization, pH, and change in intracellular Ca2+ 

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170
Q

Equilibrium of K+

A

-58mV

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171
Q

The action potential

A

Na channel
1.) resting potential, leak K channel, -60mV
2.) Rising phase, opening Na channels
3.) Overshoot phase, Na close, K open
4.) Falling phase, K opens maximally
5.) Under shoot phase: refractory because K is slow to close

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172
Q

Action potential of cardiac muscle

A

0.) Rapid influx Na+ through open fast Na+ channels
1.) Transient K channels open and K efflux returns TMP to 0mV
2.) inflow of Ca2+ through L-type Ca2+ channels is electrically balanced by K efflux through delayed rectifier K channels
3.) Ca2+ channels close but delayed rectifier K channels remain open and return TMP to -90mV
4.) Na+, Ca2+ channels closed, open K rectifier channels keep TMP stable at -90mV

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173
Q

Long QT syndrome

A

Loss of K channels, dangerous because no recovery before another spike

Symptoms: torsades de pointes, syncope, seizures, sudden death

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174
Q

Purines are constructed by:

A

Adding atoms from formyltetrahydrofolate, glutamine, glycine, aspartate, and CO2 sequentially to PRPP

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175
Q

Pyrimidines are constructed by:

A

Building the orotate base from aspartame, CO2, and glutamine. The base is then transferred to PRPP and further modified to cytosine, thymidine, or uracil

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176
Q

PRPP

A

An activated ribose sugar created by transfer of pyrophosphate to ribose-5-phosphate by PRPP synthetase (KEY REGULATORY STEP!)

PRPP synthetase is allosterically inhibited by purine diphosphonucleosides (GDP, ADP)

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177
Q

IMP is synthesized by

A

N10-formyl FH4 (twice)

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178
Q

IMP + aspartate + GTP

A

AMP (+ fumarate)—>ADP—>dADP—>dATP—>DNA

Or

AMP—>ADP—> ATP—> RNA

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179
Q

IMP + glutamine + ATP

A

XMP—> GMP—> GDP—> GTP —> RNA

or

XMP—> GMP—> GDP—> dGDP—> dGTP—> DNA

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180
Q

Ribonucleotide reductase uses what as substrates?

A

Nucleotide diphosphate (ADP, GDP)

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181
Q

Purine salvage: free bases to nucleotides and back

A

Converting free bases to nucleotides, using APRT & HGPRT (Phosphoribosyltransferases that add ribose form PRPP)

Hypoxanthine (HGPRT)—> IMP
Guanine (HGPRT)—> GMP
Adenine (APRT)—> AMP

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182
Q

Purine salvage: Nucleosides to nucleotides

A

Purine nucleoside phosphorylase removes ribose, leaving the free base

Inosine—> hypoxanthine
Guanosine—> guanine

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183
Q

Purine salvage: Adenosine kinase

A

Adenosine can be converted to AMP directly through phosphorylation by adenosine kinase 

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184
Q

Gout

A

Precipitation of uric acid in distal joints. Caused by purine degradation leading to hyperuricemia

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185
Q

CPS II

A

Uses glutamine as an amine donor to form carbamoyl phosphate (Same product as CPS I, doesn’t use ammonia) It is allosterically inhibited by UTP and activated by PRPP

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186
Q

Thymidine synthase

A

Uses dUMP as a substrate, so dUDP has to be the phosphorylated before it can be methylated to dTMP. dTMP Is then phosphorylated twice to make dTTP, a substrate for DNA synthesis

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187
Q

PRPP synthetase superactivity

A

Inhibited by ADP, and GDP normally. Super activity loses inhibition

X-linked condition seen only in males, symptoms are due to increased purine production and increase uric acid

— Crystalluria, urinary stones, gout


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188
Q

ADA-SCID

A

Severe combined immunodeficiency resulting from adenosine deaminase deficiency (ADA— Normally removes amine group from adenosine in salvage pathway)

Leads to an accumulation of adenosine and 2-deoxyadenosine in the blood. Toxic to developing lymphocytes

— Requires hemopoietic stem cell transfer

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189
Q

PNP-SCID

A

Combined immunodeficiency resulting from purine nucleotide phosphorylase deficiency

— Requires hemopoietic stem cell transfer

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190
Q

Lesch Nyhan Syndrome

A

X-linked, results in Deficiency in hypoxanthine- guanine phosphoribolsyltransferase

He’s Got Purine Recycling Trouble (HGPRT deficiency)

Symptoms: self injury, uric acid in the urine, mental retardation, dystonia, recurrent vomiting, renal failure 

191
Q

Allopurinol

A

Drug aimed at reducing uric acid

Treatment for gout (Suicide inhibitor of xanthine oxidase), and renal failure


192
Q

Capacitation

A

A set of biochemical changes in the sperm that occur after about 5 to 6 hours of residency in the female reproductive tract

193
Q

Normal site of fertilization

A

Ampulla

194
Q

What happens during capacitation?

A

• cholesterol efflux from plasma membrane
• Membrane hyperpolarization
• Increased cytosolic pH
• unmasking of cell surface receptors that bind the sperm to the egg
• Ca2+ and HCO3- enter the sperm and activate adenylyl cyclase —> increase cAMP —> tyrosine phosphorylation of many proteins 

195
Q

Acrosomal reaction

A

Necessary for sperm egg fusion to occur
• Vigorous swimming leading to penetration of the follicle cell layer
• Sperm plasma member associated proteins binding to ZP3 —> Activating sperm plasma membrane Na/H transporters —> opens Ca2+ channels • The calcium influx triggers exocytosis of the acrosomal vesicle, liberating its contents (Hydrolytic enzymes, that digest an opening through the Zona) 

196
Q

Sperm egg fusion

A

Izumo1 On sperm and Juno on egg

197
Q

Once sperm egg fusion occurs:

A

PLC-zeta Enters the egg, cleaving PI(4,5)BP into IP3 and DAG, initiating a calcium spike in the egg cytoplasm 

198
Q

What are the three reactions triggered in the egg once PLC-zeta enters?

A

1.) triggers cortical granule exocytosis
2.) Stimulates the completion of meiosis II (and 2nd polar body forms)
3.) Activates the first mitotic cell signal and development of the zygote 

199
Q

The fertilization induced calcium signaling is:

A

A profoundly important event that triggers sets of events that will culminate into an activated zygote

200
Q

The Zona reaction

A

The calcium induced cortical granules digest ZP2 and alter ZP3, there by inhibiting the passage of more sperm

Also sheds Juno

201
Q

Metaphase II arrest

A

LH —> increased Emi2 —> inhibits APC/C —> M2 arrest

202
Q

Completion of meiosis II

A

Increased Ca2+ —> inhibits Emi2 —> increases APC/C —> proteolysis of cyclin B and inhibition of M-CDK activity

203
Q

Pronuclei

A

The nuclear envelopes form around each set of parental chromosomes

204
Q

The zygote centrosome is formed from:

A

The sperm basal body and some maternal pericentriolar material

205
Q

What degenerates and disappears from the sperm in the first cell cycle?

A

The sperm axoneme microtubules and mitochondria

206
Q

Formation of the male pronucleus includes remodeling where

A

Protamines are exchanged for maternal histones

207
Q

Causes of female infertility

A

• Physical damage to the uterus or fallopian tubes
• deficits in ovulation

208
Q

Causes of male infertility

A

• Failure of emmission
• retrograde ejaculation
• varicocoele
• Oligospermia (reduced sperm #)
•Asthenospermia (reduced motility)
• tetrazoospermia (wrong morphology)

209
Q

ART: assisted reproduction techniques

A

Eggs are obtained by hormone-based super ovulation protocols, and collected by physically rupturing the follicles with an ultrasound guided catheter and subsequent aspiration. Eggs are flushed into a Petri plate with appropriate buffer

210
Q

GIFT: gamete intra-fallopian transfer

A

Collection of 1 to 4 eggs, and 100,000 sperm placed directly into an ovaduct

211
Q

ZIFT: zygote intra-fallopian transfer

A

Collected eggs and sperm are combined in a petri dish and allowed to undergo fertilization, fertilized zygote are placed in the oviduct

212
Q

IVF – ET: in vitro fertilization embryo transfer

A

Eggs and sperm are combined in a petri dish and allowed to undergo fertilization. Embryos then placed into the fallopian tube or uterus. Main difference from ZIFT is that the fertilized egg is allowed to develop for a longer period of time

213
Q

SUZI: subzonal insemination

A

2 to 10 sperm are injected with a micro pipette directly into the peri-vitelline space of the oocyte. Fertilization is monitored and zygote/embryo replaced in uterus or fallopian tube
— sometimes uses zonal drilling: acid digestion of Zona to allow sperm access to egg surface

214
Q

ICSI: Intracytoplasmic sperm injection

A

A single sperm is placed into a micro pipette and micro injected directly into the egg cytoplasm. Zygote/embryo transferred back to uterus/fallopian tube

— Most commonly performed procedure

215
Q

Two fundamental differences of meiosis from mitosis

A

1.) One S-phase followed by two M-phases

2.) pairing of homologous chromosomes in prophase one: homologs find each other in prophase and form cohesins 

216
Q

To mechanisms to promote genetic variability in meiosis

A

1.) homologous recombination (crossing over)

2.) Independent assortment

217
Q

Homologous recombination

A

• occurs in prophase of meiosis I
• Synapsis: Homologous chromosome pairs find each other the other formation of synaptonemal complexes
• recombination nodules formed between chromatids of different homologs (2-3 spots)

218
Q

Chiasma

A

Where reciprocal splicing occurs during crossover

219
Q

Independent assortment

A

Which replicated homolog (M1) or daughter chromatid (M2) faces which spindle pole in meitotic cells is random

220
Q

Pairing of homologous chromosomes in meiotic prophase I

A

• Dyein associate with cytoplasmic portion of KASH5 and binds to microtubules
• adapter proteins bind chromosome telomeres in the nuclear portion of SUN1
• Microtubule motor based motility pulls the telomeres together to form bouquets— Facilitating pairing of homologs 

221
Q

Shugoshin

A

Protects the centromeric cohesions from being digested by separase in M1

Shugoshin is dislodged from daughters chromatids allowing separase to destroy cohesin, in anaphase II of M2

222
Q

Nondisjunction

A

Failure of chromosomes to separate normally in anaphase. can occur in meiosis I or II

This can cause monosomies/trisomies (downs 21, Edward 18, and patau 13) 

223
Q

XY nondisjunction

A

The most common type of paternal nondisjunction event

224
Q

Progression of gametogenesis

A

Primordial germ cells—> Spermatogonia and oogonia—> primary spermatocytes and oocytes—> M1 —> secondary spermatocytes and oocytes —>

Males: M2 —> haploid spermatids —> spermatozoa

Females: arrest in M2 , ovum until fertilized

225
Q

When does imprinting occur?

A

PGCs become detectable at the fourth week of embryonic development. As they differentiate into oogonia and spermatogonia, DNA methylation occurs: which is imprinting

226
Q

Supporting cells of spermatogenesis

A

Sertoli cells

227
Q

Transformation of spermatogonia to spermatids into spermatozoa

A
  • production of haploid spermatids by meiosis
  • Morphological transformation of spermatids into spermatozoa by Formation of an acrosomal vesicle, elaboration of a flagellum, replacement of histones in sperm chromatin with protamines (condense DNA into sperm head) 
228
Q

Protamines

A

Small, arginine-rich proteins that replace histones late in spermatogenesis. This allows for greater compaction of DNA to form the small, dense head of the sperm. It also removes histone epigenetic marks 

229
Q

Oogenesis

A

In fetal development: PGCs —> M1, arrest prophase I (primary oocytes) —> puberty, M1 resumed —> M2: arrested in metaphase II until fertilization

230
Q

RA and Stra8 signaling

A

Females: retinoic acid + Stra8 in fetal ovary regulates a number of genes involved in driving oogonia into meiosis

Males: RA is rapidly metabolized in the testes until puberty, then RA and Stra8 rapidly accumulates driving spermatogonia into meiosis

231
Q

Regulation of mitotic arrests during oogenesis meiosis I

A

Follicle gap junctions —> High cAMP —> PKA —> activating phosphorylation of Wee1 —> inhibitory phosphorylation of M-CDK —> arrests oocyte in prophase I

Mid cycle increase in LH —> decreases cGMP and cAMP —> increases Mos kinase —> increases M-CDK —> completion of M1

232
Q

Regulation of mitotic arrests during oogenesis meiosis II

A

Increase LH —> increases Emi2 —> inhibits APC/C —> arrests in metaphase II

fertilization —> increased Ca2+ —> inhibits Emi2 —> increases APC/C —> proteolysis of Cyclin B and inhibition of M-CDK —> M2 completion

233
Q

The main components of the cell complex released during ovulation

A

Secondary oocyte arrested in metaphase II, a daughter polar body, surrounding layers of ECM (zona pellucida) , and follicle cells (corona radiata)

234
Q

 Early development events by week

A

Week 1: cleavage and implantation
Week 2: Bilaminar disc formation and delamination
Week 3: gastrulation, neurulation, somitogenesis
Week 4: embryo rolling and folding, establishment of the adult body plan

235
Q

The four processes used to make multicellular organisms

A

1.) cell proliferation
2.) cell specialization
3.) cell interactions
4.) Cell movements

236
Q

Cleavage

A

Cell divisions resulting in a loosely adherent ball of cells, called a morula

237
Q

Compaction— Initial cell differentiation

A

Flattening of cells against each other, due to formation of cell-cell junctions

— as this occurs, the outer cells envelop a core of inner cells. The outer cells give rise to the trophoblast, inner cells give rise to the inner cell mass (embryo)

238
Q

Hatching

A

Escape from the Zona Pellucida— The ZP serves as a barrier to implantation, and must be discarded prior to blastocyst attachment to the uterine epithelium

239
Q

Normal implantation site

A

The superior and posterior wall of the uterus

Abnormal includes: abdominal cavity, ovary, uterine tube, or too close to the cervix

240
Q

Placenta previa

A

Occurs when implantation occurs low in the uterus, and the placenta subsequently covers part or all of the cervix. It can result in bleeding in the second half of pregnancy, and growth restriction of the fetus

241
Q

Syncytiotrophoblast

A

Expansion of the trophoblast, forms a multinucleated mass which overlays the cellular trophoblast

242
Q

Cytotrophoblast

A

Once the cellular trophoblast is over laid by the syncytiotrophoblast, the inside becomes the cytotrophoblast

243
Q

Hypoblast

A

Differentiates and separates the inner cell mass (embryoblast), from the blastocyst cavity

244
Q

Primitive streak

A

Created from epiblast cells, it begins caudally, identifying cranial, coral, left, right embryo axes 

Downward dive: endoderm
Partially downward dive: Mesoderm
Top layer: ectoderm (overlying epiblast 

245
Q

Notochord

A

Extends downward through the primitive node and then cranially in the mesoderm

Supporting structure for the embryo, a source of midline signals that pattern surrounding tissues

246
Q

Ectoderm derivatives

A

Epidermis, hair, nails, cutaneous, memory glands, central and peripheral nervous system

247
Q

Mesoderm derivatives

A

Paraxial: Muscles of the head, trunk, limbs, axial skeleton, dermis, connective tissue
Intermediate: urogenital system, including gonads
Lateral: serous membranes of pleura, pericardium, and peritoneum, connective tissue and muscle of viscera, heart, blood cells

248
Q

Endoderm

A

Epithelium of lung, bladder and G.I. tract, glands associated with G.I. tract, including liver and pancreas

249
Q

Sacrococcygeal teratoma

A

Develops at the base of the coccyx in the developing fetus, derives from pluripotent cells from the primitive streak

250
Q

Neurulation in the third week

A

Ectoderm thickens to form neural plate —> fold to form neural groove —> Neural crest cells invade the underlying mesoderm —> folds fuse to form neural tube

251
Q

Failure of the neural tube closure at the cranial and

A

Anencephaly

252
Q

Failure of the neural tube closure at the caudal end

A

Rachischisis (spina bifida)

253
Q

Neural crest derivatives

A
  • spinal, autonomic, and cranial nerve ganglia
  • Schwann cells
  • meninges
  • Melanocytes
  • Adrenal medulla
  • Craniofacial muscles and skeleton
254
Q

Lateral plate mesoderm

A

Splanchnic: ventral wing
Somatic: dorsal wing
Extraembryonic: continuity of wings on yolk sac and amnion 

255
Q

Intermediate mesoderm

A

Kidney, gonads

256
Q

Paraxial mesoderm 

A

Head

Somite: sclerotome, myotome, dermatome 

257
Q

Somite derivatives

A

Sclerotome: Vertebrae, ribs, rib cartilage
Myotome: musculature of the back, ribs, and limbs
Dermatome: dermis of the back

258
Q

Spina bifida

A

Wnt and Shh signaling errors: failure of the bilateral dorsal sclerotome to completely encircle the spinal cord leaving a gap on the dorsal side

259
Q

Blood and blood vessel formation

A

Blood islands + peripheral cells —> primitive vasculature and endothelium

Cardio genie mesoderm—> forms toward cranial end and rolls caudally during embryo folding

260
Q

Transfers embryo rolling and cephalocaudal embryo folding

A

Converts the body plan from disc-like to tubular

Re-organize the cranial end, positions the heart, forms the foregut, midgut and hindgut

261
Q

How does citrate leave the mitochondria?

A

Citrate/Malate antiporter to create either oxaloacetate or acetyl CoA

262
Q

Glycolysis from citrate

A

Citrate lyase (forms OAA from citrate), malate dehydrogenase (forms Malate from OAA) , malic enzyme, NADP+ (pyruvate from Malate)

263
Q

The pyruvate/Malate cycle has two functions in lipogenesis

A

1.) transports acetyl Coa away from the mitochondria to the cytosol

2.) Malic enzyme generates NADPH to power fatty acid synthesis

264
Q

Fatty acid synthase (FAS) consumes what?

A

NADPH generated in the cytosol by the PPP and malic enzyme 

265
Q

Acetyl CoA —> Malonyl CoA 

A

Acetyl CoA carboxylase + CO2 + ATP

Activated by citrate, xylulose-5-p, insulin

Inhibited by palmitoyl CoA, phosphorylation by AMPK/PKA 

266
Q

Rate limiting step in fatty acids synthesis

A

Acetyl CoA carboxylase. It is regulated in multiple ways

267
Q

Inhibition of CPT1

A

Malonyl CoA inhibits CPT1, this stops beta oxidation of fatty acids while fatty acid synthesis is occurring

268
Q

Fatty acid synthesis reaction sequence

A

Bond formation, reduction, dehydration, reduction

269
Q

Electron acceptor for the creation of carbon carbon double bonds by fatty acyl CoA desaturase

A

O2. Energy for this comes from NADH —> H2O

270
Q

Precursor of prostaglandins

A

Arachidonic acid. 20 carbons with 4 points of unsaturation. Must be obtained from the diet because we cannot synthesize double bonds near the omega carbon like it has

271
Q

Fatty acids are packaged as

A

Triacylglycerides, glycerophospholipids, ether phospholipids, sphingolipids

272
Q

Glycerol 3-phosphate in the liver

A

Glycerol (from Lipolysis) + ATP—Glycerol kinase—> glycerol 3-phosphate

Only liver cells express glycerol kinase

273
Q

Glycerol 3-phosphate in the adipose tissue

A

Glucose—>DHAP + NADH —> glycerol 3-phosphate

(Glycolysis coupling)

274
Q

VLDL

A

Very low density lipoprotein, delivers fatty acids to adipose tissue to store fatty acids as triacylglycerol

Lipoprotein lipase, LPL, is an enzyme on endothelial cells activated by apoC2 that cleaves off FAs to reduce the VLDL —> IDL —> LDL

275
Q

Glycerophospholipid

A

2 FAs and a phosphate head group on a glycerol backbone

Mainly used in cell membranes, but are also constituents of Lipoproteins, bile, and lung surfactant

276
Q

Etherlipid (plasmogen)

A

1 FA, 1 phosphate head group, 1 ether-linked hydrocarbon tail on a glycerol backbone

277
Q

Sphingomyelin: lung surfactant

A

1 FA, 1 phosphate choline group on a sphingosine backbone

278
Q

Glycolipids

A

1 FA, 1 carbohydrate group on a sphingosine backbone

279
Q

Common glycerophosphates

A

Phosphatidylcholine
Phosphatidylethanolamine
Phosphatidylserine
Phosphatidylinositol biphosphate

280
Q

Glycerophospholipids formed similarly to triacylglycerols

A

Phosphatidic acid is dephosphorylated to diacylglycerol. Then the head group bound to a nucleotide (CDP) is added to glycerol backbone.

Ex. Phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine

281
Q

Glycerophospholipids formed other ways:

A

Bonding phosphatidic acid to a nucleotide, then exchanging the nucleotide for a head group

Ex. Phosphatidylinositol, Cardiolipin, phosphatidylglycerol

282
Q

Sphingolipids

A

Use ceramide instead of glycerol for their backbone. Ceramide is derived from serine and Palmitoyl CoA (sphingosine)

283
Q

Cerebrosides

A

Ceramide plus either glucose or galactose

284
Q

Globosides

A

Two or more sugar is attached to a ceramide

285
Q

Gangliosides

A

Have two or more sugars, plus NANA

286
Q

Major lung surfactant

A

Dipalmatoylphosphatidylcholine: The major component of lung surfactant, required to prevent alveolar collapse

Sphingomyelin is another lung surfactant. The ratio of sphingomyelin to phosphatidylcholine in amniotic fluid is an indicator of gestational progress

287
Q

Totipotent

A

Able to give rise to all embryonic and extraembryonic (triphoblasts) cells

This includes the zygote and early blastomeres

288
Q

Pluripotent

A

Able to give rise to cells representative of all three germ layers, but not trophoblast or other extra embryonic cells

This includes the inner cell mass cells

289
Q

Multipotent

A

Can give rise to a number of different cell types, but not as many as pluripotent cells. Limited to one germ layer

290
Q

Unipotent

A

Only able to give rise to a single type of differentiated cell

291
Q

Cell fate of the embryo is not determined until:

A

After the inner mass cells and early epiblast stages

292
Q

Committed cells

A

Cells gain a general type of identity, but the precise cell type is not yet defined, and can be modulated by environmental signals

293
Q

Determined cells

A

The type of cell is defined, and further development is independent of environmental signals

294
Q

Waddington’s model of self fate determination

A

Like a marble rolling down a landscape that separates into different grooves: initial major groups would be trophoblast versus inner cell mass, next would be epiblast versus hypoblast, and then ectoderm, mesoderm, or endoderm. Cells acquire specific fates as they roll down and enter different grooves

295
Q

Asymmetrical cell division

A

Specific factors are partitioned unequally among daughter cells during cell division. This results in the assignment of different fates as daughter cells are produced

Mosaicism 

296
Q

Induction

A

Cells are initially the same, but can be separately influenced by other cells or other types of environmental signals. Cells are not born different, but instead become different by receiving distinct environmental signals. Regulative pattern of development (most common) 

297
Q

How do you cells become different from one another during early development?

A

1.) cell signaling, select activation of transcriptional regulators via cell signaling pathways

2.) Epigenetic modification of chromatin

298
Q

Morphogens

A

Signals that alter a cell’s fate in the process of induction 

299
Q

Instructive cell signaling behavior

A

Cell a gives A signal, causing specifications and differentiation of cell B

300
Q

Permissive cell signaling behavior

A

Cell B already specified, but a signal from cell A allows differentiation to proceed

301
Q

Most embryonic inductions are mediated by:

A

Secreted signaling factors. Example: inductive, gradient, antagonist, cascade, combinatorial, lateral signaling 

302
Q

Gradient signaling

A

Different concentrations of a single morphogen can generate different cell types

303
Q

An example of sequential induction

A

Eye development: optic vesicle —> FGF8 released to form lens (only ectoderm can respond due to expression of Pax6)

Morphogen: FGF8
Inducer: optic vesicle
Pax6: renders ectoderm in head “competent” to respond

304
Q

Major signaling pathways involved in induction:

A

• RTKs
• TGF-beta
• Wnt
• Hedgehog
• Notch

305
Q

Two mechanisms that direct Cell’s decisions and “lock” them in

A
  1. Stabilization of cell signaling pathways
  2. Epigenetic modification of gene expression
306
Q

DNA methylation

A

• responsible for epigenetic regulation of chromatin activity
• DNMTs methylate DNA. DNMT1 copies methylation patterns during cell division, making epigenetic pattering heritable
• ex: imprinting in pre-primordial germ cells and X chromosome in activation 

307
Q

Histone modifications

A

• responsible for epigenetic regulation of chromatin activity
• Activating modifications found at active promoters, and are negatively associated with DNA methylation
• ex. repressive modifications, trithorax complex proteins, Polycomb complex proteins

308
Q

Hydatiform mole

A

Instead of forming a normal placenta, the trophoblast forms of mass of cysts. These are a manifestation of imprinting, caused by an under representation of the maternal genome

309
Q

Maternal imprinting:

A

Favors the development of the embryo

310
Q

Paternal imprinting

A

Favors the development of the trophoblast

311
Q

Two global genomic DNA methylation events in the human life cycle

A
  1. Associated with the gain of totipotency by the zygote and blastomeres
  2. Associated with PGC‘s as they “wipe the slate clean” prior to the application of sex specific imprints 
312
Q

Major early developmental sell differentiation events

A
  1. Trophoblast vs inner cell mass
  2. Formation of epiblast and hypoblast
  3. Formation of ectoderm, mesoderm, and endoderm
  4. Information of body axes (Dorsal/ventral, cranial/caudal, left/right)
313
Q

Inner cell mass or trophoblast?

A

Asymmetric division —> increase CDX2 in outer cells —> Inhibition of hippo pathway —> Increasing yap —> Increasing CDX2 expression —> inhibits Oct4/NANOG/Sox2 which become restricted to inner cell mass—> inhibition of CDX2 in inner cell mass 

314
Q

CDX2

A

Trophoblast differentiation, asymmetric cell divisions initially concentrate CDX2 in outer cells

315
Q

Oct4/NANOG/Sox2

A

Define inner cells and are associated with the maintenance of pluripotency

316
Q

Epiblast or hypoblast?

A

ICM Express both NANOG and Gata6—> ICM variably express FGFR2, lots of FGFR2 —> ERK signaling —> increases Gata6

Gata6: differentiation into hypoblast (primitive endoderm)
NANOG: maintains pluripotency and promotes epiblast

317
Q

Creating the cranio-caudal axis

A

• Hox genes (A,B,C,D), Homeobox genes
• Retinoic acid regulates Hox expression
• RA in the primitive node, the longer cells stay there the more posterior they will become
• RA can be teratogenic in pregnancy

318
Q

Dorsal ventral axis— Neural tube

A

• notochord—> ventral floor plate—> Shh
• dorsal roof plate —> BMP
• Neural cell differentiation in the neural tube is instructed by opposing gradient of BMP and Shh, which result in differential expression of transcription factors 

319
Q

Left right asymmetry

A

Arises from the ability of the primitive node cilia to concentrate Nodal on the left side of the embryo resulting in the regional activation of transcription factors such as Pitx2
• driven by dynein 
Nodal—> Pitx2 and Lefty
Lefty—> inhibits Nodal

320
Q

Humoral mediated immunity

A

• Antibody mediated
• B lymphocytes
• Antibodies circulating in serum
• Primary defense against extracellular pathogens, extracellular bacteria, circulating viruses

321
Q

B cell maturation stages

A

1.) in the bone marrow, antigen independent, stem cell to pre-B cells, creates IgM

2.) in lymphoid tissue, antigen dependent, B cells migrate into follicles, form germinal centers (GC), IgM and IgD—> plasma cell 

322
Q

Self tolerance of B cells

A
  1. Receptor editing: replacement of self reactive receptor with non-self reactive receptor
  2. Clonal deletion: elimination of self reactive B cell clones
  3. Clonal anergy: An antigen specific hyporesponsiveness, does not respond
323
Q

Clonal selection

A

Epitopes: the specific molecular target of which a complementary antibody binds
Immunoglobins: B cells surface acting as antigen binding sites, binding causes proliferation of clone daughter cells

324
Q

Mono clonal antibody response

A

One antibody binds to a singular, specific epitope on an antigen. This is the most specific antibody response

325
Q

Polyclonal antibody response

A

A combination of more than one antibody, each specific for a different Epitope and varying affinities (group of things)

326
Q

Germinal center zones

A

Dark zone: proliferating cells (centroblasts) undergo somatic hyper mutation

Light zone: Hypermutated resting B cells (centrocytes) and follicular dendritic cells

Mantle zone: mutated B cells and Tfh cells stimulation by Tfh —> plasma or memory cell transformation

327
Q

Chemokines

A

Family of proteins orchestrating the migration of B cells from the dark zone to the light zone (reversible too)

328
Q

The reason for so many mechanisms to prevent self reactive B cells 

A

B cells Express IgM, which can trigger non-specific antibody response such as TLRs and the complement cascade —> destroy all self cells

Ex. Lupus, celiac, rheumatoid arthritis

329
Q

Structure of antibody

A

Y: heavy chain with a hinge region, and an FC region (constant/crystalline)

II: Attachments on the outside of the two Y arms, light chain, contain the Fab, and the antigen binding sites

330
Q

Somatic hypermutation

A

The process of generating a larger repertoire of antibodies with diverse specificities via mutation of the V region DNA (not germline) 

331
Q

Primary infection antibody response

A
  1. IgM: very rapid, short-lived

Isotype switching

  1. IgG: Longer, sustained, secondary recall
332
Q

Antibody affinity

A

The strength of an interaction between a specific epitope and an individual antibody antigen binding site.

High affinity antibody will bind a greater amount of antigen in a shorter period of time

333
Q

Antibody Avidity

A

The overall strength of an antibody antigen complex across all binding sites

Dependent on:
1.) Affinity Cohen of the antibody for an epitope
2.) Valency: number of binding sites of both antibody and antigen
3.) Structural arrangements: of interacting regions of antibody and antigen 

334
Q

IgD

A

• no isotypes
• Monomer
• Antigen receptor on B cells not previously exposed to antigen
• Basophils and mast cells

335
Q

IgE

A

• no isotypes
• Monomer
• Parasitic worm protection via activation of eosinophils — histamine

336
Q

IgG

A

• IgG - 1,2,3,4 isotypes
• monomer
• Antibody-based immunity
• Opsonization, complement activation, antibody dependent cell cytotoxicity, neonatal immunity
• Passive immunity to baby from pregnant mom, short-lived

337
Q

IgA

A

• IgA- 1,2 isotypes
• Dimer most commonly, can be monomer or trimer
• mucosal immunity— Good, respiratory tract, urogenital tract, saliva, tears
• breast milk —> passive to baby 

338
Q

IgM

A

• no isotypes
• Pentamer
• Naïve B cell antigen receptors
• The first produced, complement activation
• associated with cold autoimmune hemolytic anemia

339
Q

The diverse roles of natural IgM 

A

• pathogen neutralization
• complement activation
• Antigen recruitment to secondary lymphoid organs
• Antibody dependent cell mediated cytotoxicity
• Apoptotic cell phagocytosis
• controlling inflammation
• Prevent auto immunity
• Immune regulation and homeostasis

340
Q

Neutralization: isotypes

A

IgM, IgA, IgG1,2,3,4

341
Q

Opsonization: isotypes 

A

IgM, IgA, IgG1,3,4

342
Q

Sensitization for killing by NK cells (ADCC) 

A

IgG1, 3

343
Q

Sensitization of mast cells

A

IgE, IgG1,3

344
Q

Activate complement system

A

IgM, IgA, IgG1,2,3

345
Q

The goal of mechanisms are current and secondary lymphoid tissues

A
  1. Antibody secretion
  2. Isotype switching
  3. Affinity maturation
  4. Memory B cell 
346
Q

B cell functions

A
  1. Antibody production
  2. Neuronal survival and differentiation
  3. Immunosuppression
  4. Inflammation
  5. Memory
  6. Antigen presenting
347
Q

T cell independent mechanisms of B cell activation

A

• pattern recognition receptors
• Complement pathways
• neutralization
• Opsonization
• Antibody dependent cellular cytotoxicity (ADCC)

— Mainly IgM, low affinity antibodies, short-lived plasma cells

348
Q

Opsonization

A

Antibodies coding the surface of a pathogen act as opsonins. These opsonins change the charge of the cell walls to help drive phagocytosis creates (+) infected cell to bind (-) phagocyte 

349
Q

Where are complement receptors expressed for B cells

A

Follicular and marginal zone

350
Q

T cell dependent B cell activation

A

• Activated helper T cell expresses CD40L, secretes cytokines
• B cells are activated by CD40 engagement, cytokines
• causes B cell proliferation and differentiation

351
Q

Live attenuated vaccine

A

Pathogen rendered non-pathogenic with transient growth in host
Pros: cellular and humoral, strong, lifelong
Cons: no use for pregnancy and immuno compromised
Ex Adenovirus, polio, MMR, smallpox, InfluA 

352
Q

Killed or inactivated vaccine

A

Epitope structure of antigen surface. inactivated via heat or chemicals
Pros: Safe
Cons: mostly humeral, boosters needed
Ex: Have a comma rabies, IM influenza, polio

353
Q

Subunit, recombinant, polysaccharide, and conjugate vaccine

A

Use specific antigens to best stimulate response
Pros: target specific epitopes of antigen
Conns: expensive, weaker immune response
Ex: HPV, HPV, streptococcus pneumonia, herpes zoster

354
Q

Toxoid vaccine

A

Denatured bacterial toxin with receptor binding site
Pros: protects against bacterial toxins, antibody response without causing disease
Cons: boosters needed
Ex: Diphtheria

355
Q

MRNA vaccine

A

Lipid nano particle delivers mRNA, cells synthesize for proteins
Pros: cellular and humoral, high efficacy, safe in pregnancy
Cons: local transient systemic inflammation, myocarditis
Ex: Covid vaccine 

356
Q

Risk factors for cancers

A

• 70% of cancers arise initially from environmental causes such as smoking, diet, obesity, viral infection

• Regardless of the initiating factor, all cancers involve multiple genetic and epigenetic changes that occur in a sequence overtime (aging = more cancer)

• Cancer arises from a clone of transformed cells, Gene-gene, gene-environment, modifier genes

357
Q

Neoplasia

A

A disease process associated with uncontrolled cellular proliferation leading to a mass, or tumor (neoplasm)

358
Q

The most common aggressive cancer, largely incurable

A

Metastatic solid tumors
— Defined by acquisition of genetic changes that permit invasion, evasion, and translocation

359
Q

Carcinoma

A

Epithelial: intestine, breast, lungs

360
Q

Hemopoietic and lymphoid

A

Leukemias and lymphomas

361
Q

Sarcomas

A

Mesenchymal origin: bone, muscle, connective tissue

362
Q

Most cancers are thought to arise in:

A

A stem cell tumor precursor. Cancer comes from transformed stem cell, differentiated cell does not have the potency

363
Q

How neoplastic cells evade cellular constraints on growth and proliferation

A

• Independence from cell cycle regulation
• Independence from external growth signals
• Evasion of cell death
• Non-detection by the immune system
• avoidance of cellular senescence
• Disabling DNA repair mechanisms
• Capacity for angiogenesis


364
Q

Clonal evolution hypothesis

A

Every tumor cell is equally capable of initiating neoplastic growth. Genetic and epigenetic changes occur over time, and with a selective advantage they will allow individual clones of cells to outcompete other cells and expand

365
Q

The cancer stem cell hypothesis

A

Growth and progression of many cancers are driven by small sub populations of CSC‘s

Tumors contain a cell hierarchy in which a minority of SCs could self-renew and be able to regenerate a timer

366
Q

Inherited cancer

A

Mendelian inherited: every cell in your body carries the mutation, you just need one hit/mutation

Results:
— Multiple tumors
— bilateral
— Early onset

367
Q

Sporadic cancer

A

Most common, requires two hits/mutations to silence/mutate both alleles

Results:
— Single tumors
— Unilateral
— Later onset

368
Q

Oncogene mutations

A

Turn on a stimulatory pathway and leave it stuck in the on position (gas— broken accelerator)

Examples: sis, Ret, Abl, K-Ras2, Myc, telomerase,Blc2

369
Q

Tumor suppressor genes

A

Control aberrant cell growth, Considered the brakes

Examples: RB1, TP53, APC, VHL, BRCA1/BRCA2, MLH1/MSH2

370
Q

Modes of action of the P 53 tumor suppressor

A

Activators: hyperproliferative signals, DNA damage, telomere shortening, hypoxia

Results: cell cycle arrest, senescence, apoptosis

371
Q

What contributes to tumorigenesis?

A

Increased cell division, decreased apoptosis, and tumor microenvironment

372
Q

Knudson’s two hit hypothesis and LOH

A

Almost all tumor suppressor genes act recessively at the cellular level: All function of the tumor suppressor gene must be lost

Loss of the second allele is called loss of heterozygosity

Inherited cancers considered autosomal dominant because the germline mutation is invariably followed by loss of the wild type of oil in a subset of cells

Dominant of the level of the organism but recessive at the level of the cell

373
Q

Ways to lose the good copy of the tumor suppressor gene

A

(LOH: 2nd event)

Nondisjunction causing chromosome loss, chromosome loss then chromosome duplication, mitotic recombination, gene conversion, deletion, point mutation

374
Q

Small scale: microinstability (MIN)

A

Arises from defects in mismatch repair or nuclear excision repair. Defects include MMR mutations that caused microsatellite expansions

375
Q

Large scale: chromosomal instability (CIN) 

A

Arises downstream of defects in DNA damage checkpoints, genes that control chromatin condensation, chromatid separation, and genes that control mitotic events

376
Q

Detection of a microunstable cancer is done by:

A

PCR amplification of select microsatellite regions in the genome. Tumors show extra PCR bands due to a failure to repair expansion or retraction of DNA repeat regions

377
Q

A classic example of a tumor suppressor gene for colorectal cancer

A

APC, mutations of APC are rate limiting in about 85% of colorectal cancer. Two hits needed

APC regulates cellular level of beta-catenin, When not regulated it moves into the nucleus and uncontrolled expression of proliferation genes occurs

FAP: Familial adenomatous polyposis Inherited form of CRC, Mutant copy of APC —bad

378
Q

Gleevec (imatinib)

A

Drug that targets the activity of the fusion of protein and halts CML (inhibits BRC 9-22 mutation activities)

—Must take the drug for life

379
Q

Example of splitting diseases

A

Classification of diffuse large B cell lymphoma (DLBCL)

• consists of two distinct cancers, 40% of patients respond to chemotherapy R-CHOP
— Germinal Center B-cell DLBCL (good outcome) vs. activated B-cell-like DLBCL (poor outcome)

380
Q

Cholesterol is synthesized:

A

From Acetyl CoA in the cytosol or taken up from the diet

381
Q

Cholesterol functions:

A
  • membranes
  • lipoprotein particles
  • bile acids
  • steroid hormones
    -vitamin D
382
Q

Four stages of cholesterol synthesis

A

1.) Three Acetyl CoA make mevalonate (6C)
2.) mevalonate converted to isoprene (5C)
3.) six isoprenes condense to form squalene (30C)
4.) squalene is cyclized and converted to cholesterol ( 27C)

383
Q

Key regulatory enzyme in cholesterol synthesis

A

beta-hydroxy-beta-methylglutaryl CoA reductase (HMG CoA reductase)

384
Q

Statins target ____ for ______

A

HMG CoA reductase; managing high cholesterol

385
Q

Transcriptional regulation of HMG CoA reductase

A

High cholesterol: SREBP sequestered in intracellular membranes with SCAP. Promotes proteolysis of HMG CoA reductase

Low cholesterol: SCAP leaves the DNA binding domain of SCREBP, which then translocates to the nucleus to increase activity of HMG CoA reductase

386
Q

Regulatory phosphorylation of HMG CoA

A

Fasted/low energy: HMG CoA reductase is (P) by AMPK (AMPK activated by AMP and sterols)

Insulin/Fed: promotes cholesterol synthesis by activating phosphatases that dephosphorylate HMG CoA reductase

387
Q

Farnesyl pyrophosphate

A

FP–> squalene –> cholesterol

FP –> ubiquinone

FP –> Dolichol (glycosylation in the ER)

388
Q

The main source of cholesterol synthesis

A

Liver. Can export cholesterol in the form of: cholesterol esters in VLDL particles into the blood, and bile acids into the lumen of the gut

Glucose –> glycerol-3-P + FA CoA –> TG –> VLDL–> interacts with LPL –> TG –> FA

389
Q

The rate limiting step in bile acid synthesis is:

A

7-alpha-hydroxylase (high levels of bile acids inhibit this step). This step also uses energy from NADPH

390
Q

Bile acids as detergents

A

Bile acids are used to break down fats in the body. They become better detergents by oxidation of their side chains (3-alpha, 7-alpha, 12-alpha), and by forming conjugates with either taurine or glycine.

391
Q

Secondary bile salts

A

Recycled bile acids that have lost their 7-alpha-hydroxyl group from gut bacteria breakdown. 95% of bile salts are recycled, they must have the 3-alpha-hydroxyl “ reuptake tag” otherwise they are excreted in feces

392
Q

Nascent chylomicrons

A

Store dietary fat and cholesterol in an immature form with ApoB48, they enter the lymph and then the blood. In the blood they uptake ApoCII and ApoE to become mature chylomicrons.

ApoCII activates lipoprotein lipase (LPL)

393
Q

The largest and least dense of the lipoprotein particles

A

Chylomicrons

394
Q

Funtion of Bile salts in the gut

A

Gallbladder–> breakdown of TGs –> FA + 2-MG –> into nascent chylomicrons and reform into TG

395
Q

Lecithin cholesterol acyl transferase

A

Within HDL particles, this enzyme allows cholesterol to be picked up by HDL and be trapped within the particle for reverse cholesterol transport to the liver from the blood.

396
Q

Two functions of HDL particles:

A

1.) give ApoCII to nascent chylomicrons and immature VLDL particles
2.) Reverse cholesterol transport

397
Q

VLDL contains

A

ApoB100, ApoE, and ApoCII

ApoB100 and ApoB48 are the same gene, changed by mRNA editing of a C–>U initiating a stop codon via APOBEC-1

398
Q

VLDL and HDL swap:

A

HDL gives cholesterol esters to VLDL

VLDL gives TGs to HDL (return to liver)

399
Q

Macrophages as scavengers

A

uptake oxidized LDL to create foamy cells when overabundance or when LDL receptors are mutated/inhibited

400
Q

Steroid hormones derived from cholesterol

A
  • glucocorticoids (cortisol, mobilize stored fuels)
  • mineralcorticoids (Aldosterone, fluid + salt balance)
  • androgens (testosterone, male dev)
  • estrogens (estradiol, female dev)
  • progestins (progesterone, pregnancy + female dev)
401
Q

Difficulty with production of cortisol will create:

A

increased testosterone, and estradiol (slower)

402
Q

Cortisol synthesis

A

Hypothalamus –> CRH –> ACTH in anterior pituitary –> cortisol synthesis from adrenal gland —> inhibits CRH and ACTH

403
Q

Calcium homeostasis

A

Low Ca2+ –> PTH –> PTH1R –> increase CYP27B1 –> Ca2+ reabsorption from kidney

Low Ca2+ –> PTH –> PTH1R –> 25(OH)D –> calcitriol –> increased VDR –> Ca2+ reabsorption from the intestine

Low Ca2+ –> PTH –> PTH1R –> bone resorption and Ca2+ release

404
Q

Three steps of vitamin D synthesis

A

1.) skin, sunlight (UV)
2.) liver, 25-hydroxylase
3.) Kidney, PTH-1-alpha-hydroxylase

Creates 1,25-dihyroxycholecalciferol (Calcitriol) - most active form of vitamin D

405
Q

Mutation in the LDL receptor

A

Familial hypercholesterolemia– can lead to atherosclerotic plaques under the endothelial layer of blood vessels

406
Q

Congenital adrenal hyperplasia

A

mutations in steroid hormone biosynthesis genes leading to increased androgens and decreased aldosterone and cortisol.

Symptoms: salt wasting, hirsutism, virilization, short stature, high androgens, high ACTH

407
Q

Fungi types

A

1.) yeast, single cellular-budding/nuclear fission reproduction– psuedohyphae

2.) mold, chains growing together, hyphae with septates or smooth

408
Q

Dimorphic fungal cell

A

can occur as mold OR yeast, can switch between the two

409
Q

Fungi characteristics

A

ALL: heterotrophic: cannot produce food on their own
MOST: saprobes: obtain food from dead and decaying cells
SOME: obtain food from living plants and animals

410
Q

Sporangiospore

A

Spore bearing sac, all spores are released at the same time–reproductive

411
Q

Conidia

A

no sac-like structure around the spores, growing in cilia-like formations, one-a few spores pop off the top of the chain when ready–reproductive

412
Q

Types of Conidiospores

A

1.) Coccidioides: release arthrospores
2.) Candid albicans: release Chlamydospores and/or blastospores
3.) Aspergillus: release phialospores
4.) Microsporum: release microconidia and macroconidia
5.) porospores

413
Q

Superficial tissue involvement fungal infections

A

1.) Malassezia furfur
2.) Microsporum, trichophyton, epidermophyton
3.) Candida albicans

414
Q

Systemic involvement fungal infections

A

Lung, lung and skin
1.) Coccidioides immitis dermatitidis, blastomyces, histoplasma capsulatum, cryptoccus neoformans
2.) paracoccidioides brasiliensis

415
Q

Helminths

A

Roundworm: nematodes: ingestion, fecal pollution, close contact, meat, larva burrowing, fly bite, water containing cyclops

Flatworm: Trematodes/Cestodes: fresh water containing larva stage, pork, fish

416
Q

Protozoa life cycle

A

Trophozyte (all)–> cyst (some, resting dormant phase)–> Trophozyte reformation

417
Q

Pathogenic protozoa

A

Classified by how they move:
1.) Amoeboid (entamoeba, naegleria)
2.) ciliated (balantidium)
3.) flagellated (giardia, trichomonas vag, trypanosoma, leishmania)
4.) nonmotile (plasmodium, toxoplasma, cryptosporidium, cyclospora)

418
Q

Reduviid bug

A

Example of infection cycle of Trypanosome: infects this bug which can infect humans and animals via bite

419
Q

Type I hypersensitivity: immediate

A

IgE, CD4+, Th2 cells, histamine release and inflammation

Mech: mast cells, eosinophils leading to vasoactive amines, lipids, proteolytic enzymes, cytokines: IL-4, 5, 13

420
Q

Type II hypersensitivity: Antibody mediated

A

IgM, IgG against cell surface or extracellular matrix proteins

Mech: Cell destruction (opsonization, complement, ADCC), and Inflammation (cellular dysfunction:antibodies block or activate signaling)

421
Q

Type III hypersensitivity: Immune complex mediated

A

Circulating antigen:antibody complexes (large, hard to break down)- isotypes

Mech: Complement, neutrophils, lysozymes

422
Q

Type IV hypersensitivity: Delayed, T-cell mediated

A

CD4+, Th1, 17, CD8+, cytotoxic T lymphocytes– 48-72hrs

Mech: CD4+ Th cytokine mediated inflammation, macrophage, neutrophil, direct target cell killing (CD8+ and CTLs)

423
Q

Examples of Type I hypersensitivity

A

Atopy: atopic allergy to common environmental substances (dust mites, pollen, etc)

Anaphylaxis: Food, drugs, bee stings

424
Q

Examples of Type II hypersensitivity

A

Blood transfusions (ABO and Rh +/-) including hemolytic anemia, thrombocytopenia, and hemolytic diseases of the newborn

425
Q

Goodpasture syndrome (type II)

A

rare fetal autoimmune disease mediated by anti-glomerular basement membrane antibodies that target alpha-3 chains of type IV collagen in kidney and lungs

426
Q

Acute rheumatic fever (type II)

A

Following strep infection, lectin complement pathway activated, binding antibody to heart cells causing rheumatic heart disease

427
Q

Grave’s Diease (type II)

A

antibodies against thyrotropin receptor–hyperthyroidism (opthalmopathy)

428
Q

Myasthenia Gravis (type II)

A

Antibodies attack acetylcholine receptor (AChr) affecting skeletal muscles and neuromuscular signal transmission

429
Q

Serum sickness (type III)

A

antibodies to foreign antigens form complexes that travel around the body and deposit randomly: complement reaction

430
Q

Systemic lupus erythematosus (type III)

A

autoantibodies to FNA, nucleoproteins, cytoplasmic antigens, leukocyte antigens, clotting factors, etc

431
Q

Rheumatoid arthritis (type III)

A

autoantibodies to self IgG molecules

432
Q

Examples of Type IV hypersensitivity

A

Delayed-type hypersensitivity: proteins (venom, TB)

Contact hypersensitivity: haptens (metal, poison ivy)

Gluten-sensitive enteropathy: Celiac, alpha-gliadin

433
Q

Hallmark feature of Type IV hypersensitivity

A

Granulomas (macrophage accumulations, multinucleated giant cells, and lymphocytes)

434
Q

The TB test is an example of:

A

Type IV hypersensitivity (T-cell mediated)

435
Q

Contact dermatitis (type IV)

A

Urushiol + self antigens –> neoantigen that recruits cytokines, chemokines, leukocytes, Langerhans cells present to memory CTLS to result in direct killing, mast cells and basophils recruited

436
Q

Multiple Sclerosis (type IV)

A

demyelinating disease of the CNS, forming demyelinating plaques
1.) initiating events
2.) Th1 (IFN-gamma), or Th17 (IL-17/IL-22)
3.) T cells, B cells, monocytes, and macrophages cross the BBB
4.) presentation of myelin antigen to immune cells
5.) CD4+, CD8+ destruction of myelin via complement system or ADCC

437
Q

Type I Diabetes Mellitus (type IV)

A

destruction of beta-islets of Langerhans in the pancreas leading to insulin deficiency

438
Q

Inflammatory Bowel Disease (type IV)

A

Ulcerative colitis or Chron’s
– Dysfunctional immune response to commensal organisms (Th1 and Th17)

439
Q

Celiac Disease (type IV)

A

anti-gliadin response –> T-cell, plasma cell, macrophage infiltration –> villi destruction –> diarrhea, dehydration, malabsorption

440
Q

Neoplasia

A

An uncontrolled, monoclonal proliferation of cells

441
Q

Neoplasm

A

 A combination of neoplastic cells(Parenchyma) and supporting stroma (blood vessels and connective tissue, which are not neoplastic)

442
Q

Benign neoplasm

A

Remains at the site of origin, usually amenable to surgical removal

443
Q

Malignant neoplasm

A

Invades surrounding tissues and has the capacity to spread to distant sites (metastasis) 

444
Q

-oma

A

Benign neoplasm of mesenchymal origin

445
Q

Sarcoma

A

Malignant neoplasm of mesenchymal tissue origin

446
Q

Benign neoplasm of epithelial origin

A

• adenoma: glandular tissue
• Papilloma: fingerlike or warty projections
• Cystadenoma: glandular tissue and forming large cysts

447
Q

Carcinomas

A

Malignant tumors of epithelial origin

448
Q

Leukemias/lymphomas

A

Malignant neoplasms of blood forming cells

449
Q

Differentiation

A

How much a neoplasm resembles the tissue of origin

450
Q

Anaplasia

A

Lack of differentiation, malignant neoplasms often are in a plastic, benign neoplasms are not

451
Q

Pleomorphism

A

The degree to which cells within a neoplasm differ from each other

Malignancies are more pleomorphic then benign neoplasms 

452
Q

Dysplasia

A

Refers to a pre-malignant pleomorphic state

453
Q

Invasion

A

Ability of a neoplasm to breach normal barriers (penetrating basement membrane) and survive in new environments

454
Q

Metastasis

A

Spreading to distance sites

Mechanisms:
1.) seeding of body cavities
2.) lymphatic (carcinomas)
3.) hematogenous/hepatocellular carcinoma/thyroid follicular carcinoma 

455
Q

Synaptophysin and chromogranin stain

A

Target Neuroendocrine cells

Ex: Small cell carcinoma of the lung, carcinoid tumors

456
Q

Cytokeratin stain

A

Targets epithelial cells

Ex: Carcinomas

457
Q

Desmin stain

A

Targets muscles

Ex: leiomyoma, rhabdomyosarcoma

458
Q

GFAP stains

A

Target neuroglia

Ex: astrocytoma, glioblastoma

459
Q

Neurofilament stains

A

Targets neurons

Ex: neuroblastoma, neuroma

460
Q

PSA stains

A

Target prostate epithelium

Ex: adenocarinoma of the prostate

461
Q

S-100 stains

A

Targets neural crest cells

Ex: melanocytes and neural tumors

462
Q

TRAP stains

A

Target tartrate-resistant acid phosphatase

Ex: hairy cell leukemia

463
Q

Vimentin

A

Targets mesenchymal cells

Ex: sarcomas

464
Q

Cachexia

A

A hyper catabolic state with muscle loss, often debilitating and fatal. Comes from the production of inflammatory mediators and hormones that can be produced/activated by tumors

465
Q

Paraneoplastic syndrome

A

Tumors develop signs and symptoms that are not related to their anatomic location, and are due to the production of substances acting at a distance

466
Q

Incidence versus deaths of cancer

A

Incidence: most common is CRC, breast

Deaths: most common is lungs and bronchus

467
Q

Oncogenes

A

Mutated genes that cause excessive growth, independent of external cues. These are gain of function, behave in a dominant fashion (only one allele needs to be mutated) 

468
Q

Tumor suppressor genes

A

Mutation of genes that inhibit cell proliferation normally, loss of growth inhibition. Loss of function, behaving in a recessive fashion (requiring mutation of both alleles)

469
Q

Hallmarks of cancer

A

1.) self-sufficiency in growth signals
2.) insensitivity to growth inhibitory signals
3.) Altered cellular metabolism
4.) evasion of apoptosis
5.) Immortality, telomerase
6.) angiogenesis
7.) Invasion and metastasis
8.) avoiding host immune response
9.) Enabling of inflammation, prolong regeneration; more cellular division

470
Q

Warburg effect

A

Cancer cells show market activation of glycolysis, with less use of mitochondrial oxidative phosphorylation— this helps create substrates for biosynthesis needed for growth and proliferation

471
Q

Immune checkpoint inhibitors

A

Tumor and CTL binding at the TCR and peptide MHC leads to cytotoxic granules being released to kill the tumor if anti-PD1 and anti-PD1 ligand is available (The tumor can’t secondary bind to the CTL and inhibit it’s “not self” recognition)

472
Q

 Grading of malignancies

A

Higher grades occur when the tumor lacks differentiation, have a high mitotic rate, and have more nuclear pleomorphism

473
Q

Staging of malignancies

A

Measuring the degree of localization or spread, TNM (Tumor, lymph nodes status, metastasis) 

FOM (5 decks)

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