General Pathology

Front 1

In response to DNA lesions, what is the role of FOXO1 in response to blocked CDK2 activity?
What is the role of BRCA2?

Back 1

FOXO1 -> prodeath gene expression.
BRCA2 -> DNA repair.
There is a counteraction / balance between FOXO1 and BRCA2.

Hint 1

Science 13 oct 2006 vol 314 no 5797 pp261-262

Front 2

Name the role of ubiquitination in the pathogenesis of:
- anthrax
- Yersiniosis
- many viruses, which encode for E3 Ub ligases

Back 2

- Anthrax toxin triggers ubiquitination of its receptor -> endocytosis -> low pH endosomal compartment -> toxicity of toxin.
- Yersinia produces YopJ -> YoPJ acts as a deubiquitination enzyme -> NF-kappaB activation is prevented.
- E3 Ub ligase (named modulator of immune recognition 1 of KSHV) -> ubiquitination, endocytosis and degradation of MHC class I molecules.

Hint 2

Science 12 Jan 2007 vol 315 no.5809 pp.201-205

Front 3

How does increase in cytosolic calcium lead to pores in the mitochondrial membranes?

Back 3

cytosolic Ca up -> mitochondrial Ca up (because mito membrane potential is maintained) -> mitochondrial permeability transition -> pores (=< 1.5 kDa).

Hint 3

Ann.Rev.Path. vol.1 pp405-434 2006

Front 4

Function of survivin?

Back 4

- member of inhibitor of apoptosis (IAP) gene family; inhibits apoptosis by binding of caspase-9 or blocking of SMAC.
- binds to microtubules of mitotic spindle to maintain a normal bipolar mitotic apparatus.
- expressed during embryonal development, absent in terminally differentiated normal tissues.
- upregulated in several human cancers.

Hint 4

Vet Pathol 41:599-607 (2004)

Front 5

What is the role of phosphatidylserine on cells dying by apoptosis?

Back 5

- PS (normally limited to the inner leaflet of the cell membrane) stimulates macrophage PS receptor (PSR) -> phagocytosis.
- Suppressive pathways that prevent phagocytes from mounting a proinflammatory response. TGFbeta-1 plays a role in this suppression of inflammation.

Hint 5

Science 28 nov 2003 vol 302 p.1516

Front 6

Questions on autophagy:
1. what is TOR kinase?
2. how can autophagy promote cell survival?
3. how can autophagy be activated?
4. how can autophagy be inhibited?
5. how can autophagy prevent cancer?
6. how can autophagy promote cancer?

Back 6

1. an enzyme that senses nutrient status, regulator of cell growth, negative regulator of autophagy-execution proteins.
2. nutrient recycling and housekeeping function.
3. by many signals that activate apoptosis: sphingolipids, death-receptor signalling molecules, serine/threonine death kinases, mitochondrial-associated death proteins.
4. regulators of apoptosis of Bcl-2 family can disarm autophagy-execution proteins such as Beclin 1.
5. 1) death-promoting, 2) prevent DNA damage by housekeeping: removing sources of oxidative stress; 3) negatively regulates growth.
6. through survival of normal cells during nutrient starvation.

Hint 6

Nature 445,745-747, 12 april 2007

Front 7

Name 5 caspase substrates.

Back 7

- nuclear proteins
- transcription factors and cell-cycle regulators
- caspase-sensitive kinases
- cytoskeletal proteins
- proinflammatory cytokines

Hint 7

AJP sep 2006 vol 169 no 3 p.729 (table 2)

Front 8

Explain how apoptosis-inducing factor (AIF) is involved in a form of cell death which follows the morphological pattern of apoptosis but does not involve caspase activation.

Back 8

AIF, a free-radical scavenger oxidoreductase, is normally confined to mitochondria. After mitochondrial injury, AIF translocates into the nucleus to initiate DNase activity.

Hint 8

AJP sep 2006 vol169 no3 p.729

Front 9

How can apoptosis be a result of early phase sepsis?

Back 9

Early phase sepsis: bacteria and their byproducts stimulate macrophages to release pro-apoptotic substances such as TNFalpha, NO, glucocorticoids.
(during sepsis: massive apoptotic loss of lymphocytes; caspase-9/mitochondrial pathway)

Hint 9

EID 2007 feb 13(2):191-8.

Front 10

What is the recently proposed 'trinity' of pathogen receptors cooperating in innate immunity?
Which cytokine is important particulary in respons to viral RNA detection?

Back 10

- NOD-like receptors (bacteria)
- Toll-like receptors (viruses, bacteria, fungi, protozoa)
- RIG-like receptors (viruses)

In response to viral RNA detection: type I interferon production.

Hint 10

Science 314 10 nov 2006 p.935

Front 11

In sepsis, give an example of:
1. excessive cellular activation
2. depressed cellular function
3. too little apoptosis
4. too much apoptosis

Back 11

1. neutrophils: excess toxic products -> damage
2. neutrophil failure to phagocytize and clear invading pathogens
3. neutrophils -> damage
4. lymphocytes -> poor immunity

Hint 11

AJP vol 170 no 5, may 2007

Front 12

In sepsis-induced coagulation in the baboon lung, does the level of TFPI go up or down?
And TF?

Back 12

TFPI down.
TF up.

May explain the coagulation.

Hint 12

AJP vol171 no3 sep 2007

Front 13

Name biological functions of these acute phase proteins:
1. C-reactive protein
2. Serum amyoid-A
3. Haptoglobin
4. Alpha-1-acid glycoprotein
5. Ceruloplasmin

Back 13

1. when bound to bacteria, promotes phagocytosis; induction of cytokines; inhibition of chemotaxis and modulation of neutrophil function.
2. chemotaxis; downregulation of inflammation.
3. antagonist for receptor-ligand activation of immune system; bactericidal.
4. antiinflammatory and immunomodulatory.
5. transport of Cu for wound healing, collagen formation and maturation; protects against oxidants; reduction of neutrophil attachment to endothelium.

Hint 13

Vet Clin Path vol 34 no 2 2005 p.87

Front 14

NF-kB:
1. activation leads to the formation of which products?
2. name 3 activators of NF-kB
3. name an inhibitor of NF-kB

Back 14

1. iNOS, COX-2, IL-8, eotaxin, ICAM-1, VCAM-1, and IkB-alpha (autoreg.).
2. TNFalpha, protein kinase C (PKC), oxidants (H2O2).
3. glucocorticoids

Hint 14

LI 2006 86 867-872

Front 15

Regarding the role of p53 in cardiac hypertrophy:
Draw a figure showing the relationships between cardiac hypertrophy, ischemia, HIF-1, p53, VEGF, angiogenesis and heart failure. Use arrows to indicate positive and negative influences among these factors.

Back 15

See figure.

Hint 15

Nature vol 446 22 march 2007

Front 16

Genome mutations

Back 16

loss or gain of whole chromosomes
-> monosomy or trisomy

Hint 16

Robbins p.147

Front 17

chromosome mutations

Back 17

rearrangement of genetic material

-> visible structural changes in the chromosome

Hint 17

Robbins p.147

Front 18

gene mutations

Back 18

submicroscopic. may result in deletion of a whole gene or a single base

Hint 18

Robbins p. 147/148

Front 19

missense mutation

Back 19

mutation leading to altered meaning of the genetic code (different amino acid)

Hint 19

Robbins p. 147/148

Front 20

conservative missense mutation

Back 20

missense mutation with little change in the function of the protein

Hint 20

Robbins p. 147/148

Front 21

nonconservative missense mutation

Back 21

missense mutation in which the amino acid is replaced with a very different one

Hint 21

Robbins p. 147/148

Front 22

nonsense mutation

Back 22

mutation leading to a stop codon

Hint 22

Robbins p. 147/148

Front 23

How can mutations within noncoding sequences cause deleterious effects?

Back 23

They can be in regulatory sequences and interfere with binding of transcription factors.

Hint 23

Robbins ch5

Front 24

codominance

Back 24

both alleles of a gene pair fully expressed in the heterozygote

Hint 24

Robbins ch5

Front 25

pleiotropism of a gene mutation

Back 25

many end effects

Hint 25

Robbins ch5

Front 26

genetic heterogeneity

Back 26

mutations at several loci produce the same trait

Hint 26

Robbins ch5

Front 27

DNA polymorphism

Back 27

a DNA change that occurs in at least 1% of the population (not causing disease)

Hint 27

Robbins ch5

Front 28

Reduced penetrance of a gene mutation

Back 28

some individuals inherit the mutant gene but are phenotypically normal

Hint 28

Robbins ch5

Front 29

variable expressivity

Back 29

a trait is seen in all individuals carrying the mutant gene but is expressed differently among individuals

Hint 29

Robbins ch5

Front 30

Two major categories of nonenzyme proteins affected in autosomal dominant disorders

Back 30

1. those involved in regulation of complex metabolic pathways that are subject to feedback inhibition (LDL receptor)
2. key structural proteins (collagen, cytoskeletal elements of erythrocyte membrane)

Hint 30

Robbins ch5

Front 31

dominant negative mutant allele

Back 31

mutant allele impairs the function of a normal allele

Hint 31

Robbins ch5

Front 32

inborn errors of metabolism: usual mode of inheritance?

Back 32

autosomal recessive

Hint 32

Robbins ch5

Front 33

hemizygous

Back 33

male with mutant gene on the X chromosome

Hint 33

Robbins ch5

Front 34

1. accumulation of the substrate
2. metabolic block and a decreased amount of end product that may be necessary for normal function
3. failure to inactivate a tissue-damaging substrate

Back 34

Figure 5-7 Scheme of a possible metabolic pathway in which a substrate is converted to an end product by a series of enzyme reactions. M1, M2, products of a minor pathway.
The biochemical consequences of an enzyme defect in such a reaction?

Hint 34

Robbins ch5

Front 35

Name important defects in lysosomal storage diseases, other than lack of lysosomal enzyme.

Back 35

Synthesis of a catalytically inactive protein that cross-reacts immunologically with the normal enzyme. Thus, by immunoassays the enzyme levels appear to be normal.
Defects in post-translational processing of the enzyme protein. Included in this category is a failure to attach the mannose-6-phosphate "marker," the absence of which prevents the enzyme from following its correct path to the lysosome. Instead the enzyme is secreted outside the cell.
Lack of an enzyme activator or protector protein.
Lack of a substrate activator protein. In some instances, proteins that react with the substrate to facilitate its hydrolysis may be missing or defective.
Lack of a transport protein required for egress of the digested material from the lysosomes.

Hint 35

Robbins ch5

Front 36

Describe the synthesis and intracellular transport of lysosomal enzymes.

Back 36

See figure.

Hint 36

R fig 5-11

Front 37

One quarter of canine lymphomas show which aberration of chromosome 13?

Back 37

Trisomy

Hint 37

McG p283

Front 38

A missense mutation has been identified in the Birt-Hogg-Dubé (DBH) gene in German shepherd dogs with which diseases?

Back 38

- hereditary multifocal renal cystadenocarcinoma
- nodular dermatofibrosis

Hint 38

McG p284

Front 39

Which genetic alteration is found in the c-kit gene in canine mast cell tumors?

Back 39

Internal tandem duplication.

Hint 39

McG p.284

Front 40

What is characteristic of DNA methylation in cancer?

Back 40

- overal decrease in 5-methylcytosine in the bulk of the genome (global hypomethylation)
- paradoxal increase in gene-specific methylation of clusters of CpG sites in the promoter and/or exon 1 of genes (CpG islands).

Hint 40

McG p.284

Front 41

In general, does hypermethylation of genes (particular promoter regions) lead to gene activation or silencing?

Back 41

Silencing.
(exception: paradoxical promoter methylation in cancer)

Hint 41

McG p.284

Front 42

Draw the pathogenetic mechanism by which (human) papillomavirus causes neoplasia.

Back 42

See figure (from Robbins)

Hint 42

Robbins

Front 43

How does histone acetylation affect transcription?

Back 43

DNA is wound around histones. The presence of acetyl groups (Ac) on histone tails is associated with relaxed chromatin, which is permissive to gene transcription. Removal of acetyl groups by histone deacetylases results in a closed chromatin configuration that is less permissive to the transcription machinery.

Hint 43

McG p285 fig 6-40

Front 44

How are mature miRNAs made from primary transcripts (pri-miRNAs)?
Name 2 regulatory small noncoding RNAs. name functions and differences between the two.

Back 44

Processed by two RNase III enzymes: Drosha and Dicer.

regulatory small ncRNAs: siRNAs and miRNAs. both have a similar mechanism for gene expression regulation.
siRNAs: often exogenous. from long dsRNAs or long hairpins.
miRNAs: endogenous. from short hairpin precursors. more important. usually target sequences at other loci.

miRNAs are aberrantly expressed in diverse cancers, thought to be both tumor suppressors and oncogenes. This article: aberrant miRNA in hypertrophic heart.
mRNA targets of miRNA are complex, with perfect / imperfect complementarity, and one miRNA may have multiple mRNA targets.

Hint 44

AJP 170:6 june 2007

Front 45

What can be measured in gene expression profiles?
What is array-based comparative genomic hybridization?
What is tissue microarray?

Back 45

mRNA levels across thousands of genes simultaneously.
Array CGH: tumor and normal genomic DNA labeled and compared by hybridization to microarrays comprising DNA probes of defined genome map position. Tumor/normal ratios mapped to reveal amplifications and deletions which drive altered expression of cancer genes.
TMA: cylindrical tissue cores from several hundred different tumor specimens sectioned on one glass slide to measure a single gene's expression across many samples.->also info on cellular location of expression.

Hint 45

AJP 171:2 August 2007

Front 46

Role of transforming growth factor beta in cancer?
In inflammation?
In wound healing?

Back 46

Cancer: TGFbeta suppresses progression of early lesions, but later, cancer cells produce TGFbeta-> metastasis, angiogenesis, immunosuppression.
Anti-inflammatory.
Promotes wound healing.

Contributes to apoptosis control, angiogenesis, wound healing, immune regulation and tumor biology.

Hint 46

LI 2007 1-15

Front 47

miRNAs: how are they made?
2 possible roles microRNAs in tumorigenesis?

Back 47

primary miRNAs (pri-miRNAs) transcribed from miRNA genes by RNA polymerase II, spliced, polyadenylated.
Processed by the RNAase enzyme Drosha to pre-miRNAs.
Transport from nucleus to cytoplasm by Exportin-5, and processed by Dicer (another RNAase III enzyme) -> miRNA:miRNA* hybrids.
Binding to Argonaut-> miRNA* released -> RISC (RNA interference silencing complex).
Deregulation-> transcription miRNA due to altered gene copy number, methylation of promoter, or changes in activity of TFs.
Tumorigenesis:
1. accumulation miRNA that normally regulates tumor suppressor-> underexpression of tumor suppressor.
2. underexpression of miRNA that controls proto-oncogene -> excess product.
And they can themselves be transcriptional targets of oncogenes and tumor suppressor genes.

Hint 47

AJP 2007 171:728-738

Front 48

Name 4 proteasome-independent functions of ubiquitin.
What are similarities between protein ubiquitination and phosphorylation?

Back 48

Regulation of:
- cell division
- differentiation
- signal transduction
- protein trafficking, and quality control.
Both ubiquitination and phosphorylation: proteins are specifically, diversely, and reversibly modified.

Hint 48

Science 12 Jan 2007 vol 315 no.5809 pp.201-205

Front 49

Name functions, outside of the death pathway, where caspases have been implicated.

Back 49

- keratinocyte differentiation
- lens cell differentiation
- erythrocyte differentiation
- platelet formation
- cell fusion
- monocyte differentiation into macrophages and dendritic cells
- clonal expansion of T and B lymphocytes.

Hint 49

AJP sep 2006 vol 169 no 3 p.729