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191 Cards in this Set
- Front
- Back
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Is the lactating mammary gland an example of:
• Hyperplasia • Metaplasia • Hypertrophy • Dysplasia ? |
Hyperplasia
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Is psoriasis an example of:
• Hyperplasia • Metaplasia • Hypertrophy • Dysplasia ? |
Hyperplasia
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Is the obesity an example of:
• Hyperplasia • Metaplasia • Hypertrophy • Dysplasia ? |
Trick question: it’s an example of both hyperplasia and hypertrophy.
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What is metaplasia?
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Metaplasia is the change in differentiation from one cell type to another, reversible.
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What is dysplasia?
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Dysplasia is an abnormal hyperplasia, with a propensity to malignant change, sometimes reversible.
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What is the cellular change that occurs in smoker’s lung?
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Smoker’s lung is an example of squamous metaplasia where there’s a change from respiratory epithelium from stratified columnar cells to squamous epithelial cells.
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What’s the cellular change that occurs in Barrett’s esophagus?
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Barrett’s esophagus is an example of metaplastic change of the esophageal stratified squamous epithelium to intestinal epithelium due to chronic heart burn and/or alcoholism. The peptic acid injury leads to ulceration, which leads to chronic inflammation, which causes a change in stem cell commitment to intestinal epithelia as opposed to stratified squamous epithelium.
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When looking at an H&E slide that differs from normal in that there’s more pink/eosinophilic staining, what could that mean?
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If the tissue is more pink, the nuclei have dropped out and died.
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When looking at an H&E slide that differs from normal in that there’s more blue/basophilic staining, what could that mean?
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If it’s more blue, then it’s usually inflamed, or it’s undergoing dysplasia or malignant transformation.
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What’s necessary to convert the pancreas into soap?
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FFA+Ca+high pH
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What is reperfusion injury, and how does it occur?
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Reperfusion injury occurs when quasi-perfused areas during ischemia are reperfused; they can generate free radicals as a result of the reoxygenation.
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What is the extrinsic pathway of apoptosis?
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The extrinsic pathway occurs when lymphocytes release peptide factors like TNF and FasL that bind to the surface receptors of cells and trigger death in a signaling cascade that ends with caspases.
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What is the intrinsic pathway of apoptosis?
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In the intrinsic pathway of apoptosis, there’s an intrinsic mechanism of sensing damage to the cell at the level of DNA and/or mitochondria. P53 activates the intrinsic pathway by upregulating pro-apoptotic members of the BCL2 family of proteins like PUMA and BAX. BAX releases cyt c from mitochondria, which activates caspase 9
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What are hallmark differences between apoptosis and necrosis?
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see image
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What is the pathological mechanism in alpha1-antitrypsin deficiency?
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Alpha 1-antitrypsin (A1AT) is produced in the liver, and one of its functions is to protect the lungs from neutrophil elastase, an enzyme that can disrupt connective tissue. Alpha 1-antitrypsin deficiency (α1-antitrypsin deficiency, A1AD or simply Alpha-1) is a genetic disorder that causes defective production of alpha 1-antitrypsin (A1AT), leading to decreased A1AT activity in the blood and lungs, and deposition of excessive abnormal A1AT protein in liver cells.
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What causes the discoloration in hematoma (extravasation of blood into the extracellular space)?
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Color is due to heme/porphyrin rings liberated into surrounding tissues and processed into bilirubin with different colors
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What is the pathological mechanism of gout?
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Gout is the hyposecretion of uric acid from the kidney.
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What causes dystrophic calcification?
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Negative charges/high pH in damaged or dead tissue (in particular mitochondria) serve as nidus for calcium deposition results in tissue being “entombed” in shell of calcium
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Which cells are continuously dividing?
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• Skin
• GI mucosa • Respiratory epithelium • Bone marrow |
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Which cells are conditionally dividing?
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• Hepatocytes
• Pancreatic acinar cells • Kidney • Endocrine cells |
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Which cells in the human body are typically non-dividing?
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• Adult neurons
• adult cardiac myocytes • Adult skeletal muscle cells |
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Why does it make sense that the daughter cell from stem cell division gets the new DNA?
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It makes telelogic sense that the stem “mother” cell receives that DNA which is least likely to be damaged (DNA damage is most likely to occur during replication).
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Is HGF mitogenic (induces cell proliferation), motogenic (induces motility/scattering), or morphogenic (induces morphological patterns)?
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HGF is mitogenic (induces cell proliferation), motogenic (induces motility/scattering), AND morphogenic (induces morphological patterns). It is all three.
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What cells produce HGF?
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HGF is produced by Ito cells in the liver.
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Is hyperplasia reversible or not?
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Hyperplasia is reversible.
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Obesity in the child/adult is due to hyperplasia or hypertrophy?
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Adult-hypertrophy
Child-hyperplasia |
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What are pathologic causes of apoptosis?
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• DNA damage (triggers p53-mediated pathway)
• Misfolded protein accumulation • Infections (most notably viruses) • Immune-related (cytotoxic T cells) |
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How does inhibition or activation of Bcl-2 affect apoptosis?
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Inhibition of Bcl-2 activity leads to increased apoptosis; increased Bcl-2 activity causes inhibition of apoptosis.
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What insults cause fatty liver?
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• Hypoxia
• Alcohol • Malnutrition • Toxic and chemical insults |
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What are causes of non-alcoholic steatohepatitis?
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• Obesity
• Diabetes • Syndrome X • Metabolic disturbances in fatty acid oxidation |
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What are the two intertwined processes central to cellular aging?
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1) Decreased cellular proliferation (“senescence”)
2) Increased genetic and metabolic damage |
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Which cells have telomerases?
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Germ cells and stem cells
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Is the basement membrane still intact in dysplasia?
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The basement membrane is still intact in dysplasia.
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Which type of cancers typically use hematogenous spread?
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Sarcomas typically use hematogenous spread, but carcinomas can as well.
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Do malignant neoplasms always arise from dysplasia?
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Malignant neoplasms may or may not arise from dysplasia.
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Can a benign neoplasm progress to a malignant neoplasm?
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Benign neoplasms usually do not progress to malignant neoplasms. Case in which they do: benign metastatic parotid tumors.
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In tumor nomenclature, what does the prefix “chondro-“ refer to?
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Chondro-cartilage tumor
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What does “well-differentiated” mean in reference to tumors?
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Well-differentiated means that it resembles and has nearly the same function as the tissue that it’s from. Conversely, poorly differentiated tumors lose cell architecture and function.
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Which 4 categories do malignant tumors generally fall into?
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1. Carcinoma
2. Sarcoma (mesenchymal derivation – fat, muscle, bone) 3. Lymphoma 4. Melanoma |
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What characteristics define whether or not a tumor is benign or malignant?
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1) Differentiation
2) Rate of growth 3) Invasiveness, and 4) Metastasis define whether or not a tumor is benign or malignant. |
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What does pleomorphism mean?
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Pleomorphism refers to variation in cellular size and shape.
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Which type of tumor, benign or malignant, grows as expansile nodules without infiltration of adjacent tissue, often surrounded by a fibrous capsule?
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Benign tumors grow as expansile nodules without infiltration of adjacent tissue, often surrounded by a fibrous capsule.
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Metastasis is the defining quality of what type of tumor?
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Metastasis is the defining quality of malignant tumors.
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Lymphatic spread is classically associated with what type of tumors?
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Lymphatic spread is classically associated with carcinomas, whereas hematogenous spread is classically associated with sarcomas.
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Which organs are the most typical sites for metastatic spread?
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Liver and lungs are most frequent secondarily involved sites.
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What is the difference between a mutagen and a carcinogen?
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A mutagen is something that causes a mutation in an organism's genetic code (DNA). Mutations can be neutral, beneficial, or harmful (although they are rarely beneficial.) A carcinogen causes a mutation that leads to cancer, which is obviously a harmful type of mutation. So, a carcinogen is a type of mutagen that specifically leads to cancer.
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What is the difference between a direct and an indirect carcinogen?
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Direct carcinogens are already electrophilic (have a net positive charge), whereas indirect carcinogens must be metabolized into an electrophilic form to have their carcinogenic effect (i.e., bind to nucleophilic targets).
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What percentage of cancers are environmentally induced?
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80-90% of cancers are estimated to be environmentally induced and thus are of a somatic nature.
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What are examples of direct-acting carcinogens?
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• Nitrogen mustard
• Chlorambucil • Melphalan • Cancer chemotherapeutic agents (ironically enough; they’re double-edged swords) |
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What is an important indirect-acting carcinogen that is widely prevalent during the summertime?
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Polycyclic aromatic hydrocarbons are indirect-acting carcinogens produced by incomplete combustion of organic materials and present in chimney soot, charcoal grilled meats, auto exhaust, cigarette smoke, etc.
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What indirectly acting carcinogen is present in America’s favorite drink, beer?
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Nitrosamines are indirectly acting carcinogens present in pickled fish and beer. They’re implicated in GI cancers, specifically stomach cancer.
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Which indirect carcinogen was used as a drug and commonly appears on the boards?
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Diethylstilbestrol is a carcinogen that was used in the 1950’s to prevent premature labor in pregnant women.
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What test is used to determine mutagenicity?
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The Ames test determines mutagenicity; most mutagens are carcinogens.
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What is “promotion” in the context of the process of carcinogenesis?
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Promotion is the process by which an initiated cell is selected for and proliferates/divides to form premalignant/dysplastic neoplasm or lesion. It is characterized by repetitive treatments or events in tissue containing initiated cells. Initially, at least, it is reversible.
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What are some examples of promoters in human cancers?
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• Cigarettes (both an initiator and a promoter)
• UV (both an initiator and a promoter) • Asbestos (acts as an initiator and a promoter) • Hormones • Viral infection • High fat diet |
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What is progression in the context of carcinogenesis?
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Progression is the process by which neoplastic or dysplastic cells progress to malignant cells with invasive potential (carcinoma in situ). The genetic changes that occur in progression involve alterations in genes that encode cell adhesion proteins (enabling cells to diassociate from one another and spread). Molecules in angiogenesis and enzymes that promote the metabolism/degradation of ECM materials (to enable the cell to invade through tissues) are also a part of the process.
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Aflatoxin-exposed generation of HCC has a specific mutation associated with it. What is that mutation?
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In aflatoxin-exposed generation of HCC, there’s a p53 gene with a characteristic G->T mutation in codon 249.
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What is the initiating event for the cervical dysplasia-carcinoma sequence?
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The initiating event for the cervical dysplasia-carcinoma sequence is integration of HPV DNA with the host DNA.
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What is the most common type of skin cancer?
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Basal cell carcinoma is the most common type of skin cancer.
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What are the ABCDEs of melanoma?
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• Asymmetry
• B – Irregular border • Color Change • Diameter • Evolution |
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What key mutation is involved in the carcinogenesis of melanoma?
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BRAF!
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What specific type of cancer was induced by the Chernobyl incident?
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A unique type of thyroid cancer was incited by the Chernobyl incident in children. The specific molecular change was a fusion between the RET and PTC3 genes,and it was a solid variant of papillary thyroid cancer. Remember: Chernobyl, radiation, solid variant of papillary thyroid carcinoma in children, characterized by RET/PTC3 fusions…
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What is the mechanism of carcinogenesis from asbestos?
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Asbestos generates free radicals which induces chronic inflammation/injury.
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The majority of neoplasms are epithelial in origin. Why is that?
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1) Epithelium is the first line of defense, covering surfaces exposed to the environment (skin, GI tract, respiratory tract, vagina, urethra, etc.
2) Epithelium exhibits increased cell proliferation 3) Epithelium has more drug metabolizing enzymes |
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What are characteristics of anaplasia?
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Anaplasia, lack of differentiation is marked by:
1) Pleomorphism 2) Abnormal nuclear morphology with abundant DNA and hyperchromatic staining 3) Abnormal nuclear to cytoplasmic ratio; large nucleoli 4) Abnormal and abundant mitoses, bizarre mitotic figures sometimes producing tripolar or multipolar spindles 5) Loss of polarity, w/ disturbed orientation and growth in disorganized fashion |
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What is a way to measure DNA synthesis?
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DNA synthesis is measured by IHC staining for proliferating cell nuclear antigen (PCNA), a 261-amino acid non-histone polypeptide localized in the nucleus and associated with cell proliferation. Other ways:
• H3-thymidine incorporation w/ autoradiography or scintillation counts • Visualizing bromodeoxyuridine nuclear incorporation with IHC • Flow cytometry |
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What’s an example of a carcinoma that invades the surrounding tissues but does not metastasize?
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Basal cell carcinoma invades the surrounding tissues but rarely metastasizes.
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The degradation of what important organ/structural lining is important for invasion?
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The degradation of basement membrane (BM) is required for local invasion of the tumor cells.
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How does beta-catenin plays a role in wound healing?
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Beta-catenin binds the cytoplasmic tail of E-cadherin, a cell-surface protein that maintainis intercellular adhesiveness. Loss of cell-cell contact, such as in a wound or injury to the epithelium, disrupts the interaction between E-cadherin and beta-catenin and allows beta-catenin to travel to the nucleus and stimulate proliferation.
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Which MMPs play an active role in tumor invasion?
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MMP-2 and MMP-9 appear to play an active role in tumor invasion; they’re associated with poor prognosis.
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Is fatty liver reversible?
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Fatty liver is reversible
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What is the mechanism of hepatic steatosis?
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In hepatic steatosis, there’s altered fatty acid metabolism such that there’s either an increased production or decreased degradation of fatty acids.
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What are Mallory bodies?
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Mallory bodies are tangled intermediate filaments that have become glycosylated and nonfunctional and form precipitates in the liver of those with alcoholic liver disease. Incidentally, they are also ubiquitinated proteins that do not find the proteasume and accumulate forming cytoplasmic inclusion bodies.
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What happens during the unfolded protein response (non-ERAD pathway)?
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Receptors sit on the surface of the ER and work through chaperone proteins which serve as sensors for unfolded proteins (e.g., BiP). Some have kinases that work through signaling pathways. Others have transcription factors that go to the nucleus and takes care of business.
Fast negative feedback: They can send a signal to ER and ribosomes to stop making protein (fast response). OR Slow negative feedback: TFs can alter gene expression for less proteins. |
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What happens during the unfolded protein response (ERAD pathway)?
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ERAD (endoplasmic reticulum-assocaited protein degradation) pathway: targeted degradation of the protein in the proteasome via ubiquitination.
If ERAD senses that the cell has gotten irreversibly denatured (e.g., when you burn yourself), it will trigger apoptosis. |
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What is lipofuscin?
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Lipofuscin is a yellow-brown insoluble pigment that is composed of lipid-containing breakdown products of lysosomal digestion. It's composed of lipids and phospholipids in complex with protein. It accumulates normally during the wear and tear/aging of cells. It is a telltale sign of free radical injury and lipid peroxidation.
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What causes nutmeg liver?
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In nutmeg liver, there’s a transient accumulation of hemosiderin. This causes an accumulation of iron as the RBCs rupture in the liver as a consequence of stasis.
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What is the mechanism of hemochromatosis?
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Hemochromatosis occurs due to an improper functioning of iron sensing in the liver, which leads to the accumulation of iron in the liver. If untreated, the ionic iron in the liver can cause free radical generation which leads to hepatocyte death and subsequently cirrhosis.
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What are Psammoma bodies?
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Psammoma bodies occur in the process of the calcification of dying tumor cells. As the cells die, they dispose negative charge, and Ca++ deposits. It’s characteristic of papillary thyroid CA and meningioma.
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What is myositis ossificans?
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Myositis ossificans is an aberrant response to trauma whereby instead of making new cells or forming scars, damaged cells have calcium deposited.
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Which helper cell suppresses CD4 activity?
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Th2
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Which genetic haplotype has a higher incidence of SLE?
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HLA-B8
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Which hypersensitivity occurs in autoimmune disorders?
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Hypersensitivity II. When there’s a complex formed between antibody and antigen, and it goes into the body, that’s hypersensitivity III
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What causes the protrusion of eyes in Graves?
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Attack of tissue behind the eye (retro-orbital tissue)band causes mucoid degradation of retrobulbar tissue (muscle and fatty tissue). Degradation->Water accumulation->eyeball becomes prominent
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What is the mechanism of pathogenesis in vitamin B12 deficiency?
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Normal: B12 binds to R-binder (rapid binding proteins that come from salivary fluid) and forms a complex which carries it from stomach into duodenum. At the same time gastric parietal cells secrete a protein called intrinsic factor (IF)
In duodenum, complex of R-B12 is split and B12 is free. In distal part of duodenum, B12 binds IF which goes to the ileum where there’s an IF receptor and gets absorbed and then transported by a protein called transcobalamin to the liver. Transcobalamin is needed for folate synthesis and DNA maturation. Pathogenesis: 1) Blocking auto-antibody won’t allow B-12 complex, so B-12 cannot be absorbed. 2) 2nd situation: binding antibody inteferes with absorption of IF receptor complex. In either case, there’s less B12, and RBCs cannot mature coming out of the bone marrow. |
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What two antigens are diagnostic for SLE?
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If a pt has both dsDNA and Smith, there’s a 99% chance of SLE
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What is Raynaud’s phenomenon, and what causes it?
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Pallar and cyanosis of fingers in cold. Multiple mechanisms involved in its causation, including vasculitis and increased plasma endothelin levels.
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Which drugs can induce lupus?
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• Procainamide
• Hydralazine • Dephenylhydantoin • Antihistone antibodies |
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What is the auto-antibody important in Progressive Systemic Sclerosis (PSS)?
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ScL-70: Anti-DNA Topoisomerase I
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Which diseases causes “fish mouth appearance” and claw-like deformities?
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Progressive Systemic Sclerosis (PSS). TGF-beta and PDGF bind to promoter regions and cause excessive production of collagen; the skin thickens (scleroderma), and it’s not very elastic, because collagen isn’t very elastic
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What happens to the lungs in Progressive Systemic Sclerosis (PSS)?
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The deposition of the collagen into the tissue causes the trapping of air inside alveoli, since they cannot collapse. This gives a bubbly honeycomb appearance and induces pulmonary HTN, which can cause right CHF.
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What happens to the kidney arteries in Progressive Systemic Sclerosis (PSS)?
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The deposition of collagen causes a concentric lamination of the renal artery, which lowers the blood supply to the kidney->ischemic kidney->activation of RAAS->increase in systemic blood pressure due to retention of sodium->systemic HTN.
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What happens to the esophagus in Progressive Systemic Sclerosis (PSS)?
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The esophagus becomes rigid, and patients have malabsoprtion syndrome.
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What are the most important diagnostic markers for SLE?
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Smith and anti-dsDNA
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What are criteria determinant for membranous lupus?
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To call it membranous lupus, you must have deposits in subendothelial region as well as mesangial region.
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What is CREST syndrome?
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see slide
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What are the two most defining characteristics of Sjrogen’s Syndrome?
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• Dryness of the mouth (xerostomia)
• Dryness/irritation of the eyes (keraconjunctivitis) |
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What are the implications of speckled fluorescence?
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Speckled fluorescence could indicate either the presence of Smith antibodies (SLE) or Mixed Connective Tissue disease.
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What 3 things are necessary to call a diagnosis of Wegener’s granulomatosis?
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see slide
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What is the difference between C-ANCA and P-ANCA?
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P-ANCA is myeloperoxidase present in the granules of the polymorphonuclear leukocytes. C-ANCA is anti-proteinase 3 present in the cytoplasm of PMNs.
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If C-ANCA is positive and P-ANCA is negative, what is a feasible diagnosis?
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Wegener’s granulomatosis
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Does Amyloidosis involve inflammation?
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Amyloidosis doesn’t involve any inflammatory process, but it causes mechanical problems.
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What are the two most common fibrillary proteins in amyloidosis?
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AA and AL are the two most common fibrillary proteins in amyloidosis. Mostly (75% of the time) it’s AL.
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What are dangerous consequences for amyloid deposits in the myocardium?
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Amyloid deposits in the myocardia can cause arrhythmias that could only be cured via heart transplant.
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What are the different deposition patterns for amyloid in the spleen?
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Amyloid could be deposited around the arterioles (Sago) or in between the arterioles (Lardaceous)
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What are some different means for diagnosing amyloidosis, once you have the biopsy specimen?
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• Congo red stain
• Birefringence • Definitively diagnostic: appearance of 8-10 nm criss-crossing fibrils seen on SEM. |
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What are defining characteristics of nephrotic syndrome?
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see slide
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What is Bence Jones proteinuria?
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Amyloid light chains (AL) come out in the urine.
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Describe the work up with a patient with amyloidosis:
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see slide
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What 3 diseases is mixed connective tissue disease seemingly a combination of?
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1) SLE
2) Systemic Sclerosis 3) Polymyositis |
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Which of the following patterns of immunofluorescence is highly specific for SLE?
* Homogeneous * Peripheral * Speckled * Nucleolar |
Peripheral is highly specific for SLE
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What is the crithidia luciliae test?
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The crucidia luciliae test is a protozoan in which kinetoplast staining indicates the presence of anti-dsDNA antibodies.
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What are characteristics of the diffuse proliferative form of lupus glomerulonephritis?
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severe form, karyorrhexis (the destructive fragmentation of the nucleus of a dying cell), PMNs influx, crescents, wire loops, hematoxylin bodies, thumb prints-like elements in subendothelial deposits, proteinuria & hematuria (nephritic state)
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What are characteristics of membranous nephritis form of lupus glomerulonephritis?
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thickened basement membranes (GBMs), subepithelial and mesangial deposits containing IgG and C3, patients are usually heavily proteinuric (nephrotic state)
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Which connective tissue disorder has a high incidence of B-cell lymphoma?
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Sjrogen's Syndrome has a 40 times higher incidence of B cell lymphoma than normal.
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Are oncogenes, tumor suppressor genes dominant or recessive?
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Oncogenes are dominant, tumor suppressor genes are recessive.
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What is the role of RET in carcinogenesis?
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RET protooncogene is associated with the dominantly inherited MEN (multiple endocrine neoplasm syndrome) type IIA and IIB, familial medullary thyroid carcinoma and Hirschsprung disease. For MEN IIA has mutations in RET in the extracellular domain (associated with medullary thyroid carcinomas, and adrenal and parathyroid tumors), whereas MEN IIB has mutations in RET in the cytoplasmic domain (associated with thyroid and adrenal tumors).
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What is the role of c-kit in carcinogenesis?
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c-kit is a cytokine receptor tyrosine kinase and a protooncogene that, when overexpressed, can lead to cancer (associated with GI stromal tumors as well as others). Normally, c-kit signalling plays a role in cell survival, proliferation, and differentiation.
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What is the most common abnormality of dominant oncogenes in human tumors?
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Mutation of the ras oncogene is the most common abnormality of dominant oncogenes in human tumors. Most mutations involve codons 12, 59, 61. 90% of pancreatic adenocarcinomas have ras mutations.
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What are all the oncogenes that we discussed in lecture?
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Ras, myc, c-kit, RET, ERB-B2 (HER2/neu),
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What are the 2 important checkpoints in the cell cycle as far as molecular carcinogenesis, and what mediates arrest in the cell cycle in the Rb-propagated carcinogenesis?
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G1/S; cell cycle arrest mediated through p53 by a cell cycle inhibitor
G2/M; cell cycle arrest mediated by both p53 dependent and independent mechanisms |
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Which 4 regulators of the cell cycle are dysregulated in most human tumors?
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Cyclin D, CDK4, RB, and p16INK4a
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What percentage of tumors have a mutated p53 gene, and what is p53’s major function, as related to carcinogenesis?
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>50% of tumors have a p53 mutation. P53 acts to initiate apoptosis in response to DNA damage; it is also involved in the regulation of apoptosis. Furthermore, since radiation and chemotherapy act by inducing apoptosis, tumors with mutated p53 are relatively resistant.
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What gene is mutated in adenomatous polyposis?
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The APC gene, located on chromosome 5q21, is mutated in adenomatous polyposis.
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Can you describe the pathogenesis in Rb-generated tumors?
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The Rb gene (located on chromosome 13q14), is lost or mutated from the germ line in the classic paradigm of the two-hit hypothesis development of retinoblastoma. This leads to a genetic predisposition to the development of retinoblastoma (and less frequently osteosarcomas).
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In what disease is BCL-2 overexpressed?
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BCL-2 (an anti-apoptotic gene) is overexpressed in B-cell follicular lymphomas.
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What is a mechanism of immune system evasion mediated by tumors?
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Tumors cover themselves with platelets which are from the host and thus are able to evade the immune system.
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What is CD44, and what does it do?
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CD44 is a cell surface glycoprotein receptor that functions in adhesion, cell-cell interactions, and migration. It is an adhesion molecule that helps with targeting (?) of tumor cells and telling them where to go.
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What are the 3 types of DNA repair mechanisms?
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• Mismatch repair
• Nucleotide excision repair • Recombination repair |
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What is HNPCC?
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HNPCC is the hereditary nonpolyposis cancer syndrome, a condition of the colon that results from defects in DNA mismatch repair genes.
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What is the genetic deficiency that leads to xeroderma pigmentosum?
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Xeroderma pigmentosum, a condition prone to the development of skin caner, results from defects of the nucleotide excision repair pathway.
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What is the major mechanism genetic repair mechanism by which familial breast cancer develops?
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DNA Homologous recombination repair dysfunction. BRCA1 and BRCA2 in particular are genes that participate in the process of homologous recombination of DNA repair.
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Besides familial breast cancer, what other disorders are caused by defects in DNA repair by homologous recombination?
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• Bloom syndrome
• Fanconi anemia • Ataxia-telangiectasia (caused by a mutation of the ATM gene) |
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What are examples of chromosomal translocations causing cancer?
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• A chromosomal translocation between 8 and 14 where c-myc is moved to 14 and put under promotion of Ig (resulting in increased myc) occurs in Burkitt’s lymphoma.
• In CML, there’s a fusion of bcr and abl from chromosomes 9 and 22. |
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What were examples of gene amplification that occur as another mechanism of oncogene activation?
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• ERB-B2
• N-MYC |
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Besides structural changes like mutations, what’s another way tumor suppressor genes may be inactivated?
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Methylation (see also, genomic imprinting—hypermethylation of genes such that only one copy of alleles is active, and the copy is from one parent; can lead to cancer).
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How do you define “caretaker genes?”
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They are genes that do not directly control tumor growth but affect genomic stability. This is contrasted with “gatekeeper genes” like p53 and other tumor suppressors and includes oncogenes.
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Can you describe the mechanism of carcinogenesis in the adenoma-carcinoma sequence?
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1. Individual is born with one mutant APC allele ->increased likelihood of developing colon cancer/”first hit”
2. Second hit acquired somehow, and loss of normal APC gene 3. Mutation in oncogene K-RAS 4. Other mutations inactivate tumor suppressors (e.g., p53, SMAD2/SMAD4), leading to carcinoma 5. Additional mutations occur |
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Do low grade dysplasias tend to be monoclonal or polyclonal?
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Low grade dysplasias tend to be polyclonal and high grade dysplasia tends to be clonal
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What is desmoplasia?
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Desmoplasia is the growth of connective tissue or stroma/fibrosis in response to a malignant tumors (emphasis on the response aspect of it)
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Which HPVs are the high risk types? Low risk types?
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• 6,11 = low risk
a. Cutaneous (verruca vulgaris) b. genital warts (condyloma acuminatum) • 16, 18 = high risk (viral DNA can integrate into host genome) a. Can cause squamous dysplasia and cancer b. Cervix, anus, oropharynx |
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What are the molecular mechanisms of carcinogenesis in the induction of cancer by HPV?
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E6 accelerates proteolytic degradation of p53, and E7 binds RB and releases E2F (transcription factor that promotes cell cycle) from RB, which promotes cells to enter cell cycle. Uncontrolled cell proliferation + accumulation of DNA damage -> progression to dysplasia and cancer.
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What is LMP1, and what does it do?
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LMP1 sends signal to cells in the context of an EBV viral infection, causing them to proliferate and expand->B cell lymphoma.
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During Paintal’s second lecture, we were given examples of tumors that secrete hormones. What cancers were they, and what were the hormones secreted?
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• small cell carcinomas -> ACTH and ADH->cortisol production and Cushing’s syndrome
• Squamous cell carcinoma -> PTHrp |
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What 3 hematologic effects are important causes of illness/death in cancer patients?
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• Infection/Immunosuppression
– Chemotherapy, malnutration induced – Cytokine milieu • Thrombosis/Bleeding – Inflammatory milieu (activates endothelium, platelets) – Secreted factors (Tissue factor, cancer procoagulant) • Anemia – Inflammatory milieu – Chemotherapy induced |
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What are the top 3 cancers in men and women by INCIDENCE?
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Men
1. Prostate 2. Lung 3. Colon Women 1. Breast 2. Lung 3. Colon |
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What are the top 3 causes of cancer deaths in men and women?
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Men
1. Lung 2. Prostate 3. Colon Women 1. Lung 2. Breast 3. Colon |
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What are the fetal antigens and their corresponding cancers?
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• Alpha-fetoprotein (AFP) –
o HCC • Carcinoembryonic antigen (CEA) – o colonic adenocarcinoma, o pancreatic carcinoma, o pulmonary tumors • Prostate Specific Antigen (PSA) – o prostate cancer, o BPH, o Prostatitis • Human Chorionic Gonadotrophin (HCG) o Embryonal carcinoma of the testis |
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How can heart failure lead to edema?
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Heart failure can lead to decreased renal blood flow->activation of RAAS->retention of Na+ and H2O-> increased blood volume->edema
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Compare and contrast the fluid in edema from increased hydrostatic pressure as opposed to inflammatory edema.
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Edema from increased hydrostatic pressure is transudate with little protein content(<3g/dL; specific gravity >1.015), whereas inflammatory edema is exudate, rich in protein content (>3g/dL; specific gravity >1.015).
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What is embolism, and what is the usual source of embolisms?
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Embolism – the movement and lodging of an obstruction in the vascular system. Thrombi are the usual source of emboli.
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What’s the most common cause of infarction?
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Thrombotic or embolic arterial occlusion cause most (~99%) infarcts.
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What’s the most common cause of septic shock?
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Currently, most septic shock is triggered by gram(+) bacterial infections.
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What determines the differentiated fate of the residing stem cell population?
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The tissue microenvironment determines the differentiated fate of the residing stem cell population.
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What are the 1 in 10 rules regarding chronic heart burn?
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1 in 10 with severe chronic heart burn will develop Barrett’s esophagus, and 1 in 10 with Barrett’s esophagus will develop adenocarcinomas of the esophagus.
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What are 4 underlying mechanisms of necrosis?
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The four causes of necrosis all involve the cell membrane in one way or another and all kind of interlinked:
1) ATP depletion (Na+/K+ pumps don’t work well)->Ca++ influx; body can’t deal with free radicals generated (body makes a lot of free radicals in neutrophils which is important in management of infectious disease). 2) ROS, damage to macromolecules (e.g., protein, RNA, DNA). Can break down lipid, which induces pores in the membrane and causes greater influx of Ca++ 3) Disruption of Ca++ homeostasis: influx of Ca++ can cause plasma membrane damage 4) Membrane damage: plasma membrane, organelles: |
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What are some useful roles of apoptosis?
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• Tissue remodeling in developing embryo
• Elimination of virus-infected cells • Killing of inflammatory cells at immune privileged sites (eye) • Removal of DNA damaged cells & transformed cells • Removal of activated T cells at the end of immune response |
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What is coagulative necrosis?
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Coagulative necrosis is a form of cell death most commonly encountered after severe acute cell injury from ischemia or due to exposure to toxic agents (chemicals/poisons/toxins). The necrotic foci appear pale, opaque and drier than surrounding normal tissue. Although nuclei may be absent, cell outlines and cytoplasm are still discernible; necrotic tissue eventually undergoes digestion/liquefaction and removal by PMNs and later by macrophages. Most commonly occurs in heart, kidney, spleen, brain.
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What is liquefaction necrosis?
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Liquefaction necrosis is a form of coagulative necrosis where the necrotic area is rapidly liquefied due to extensive lysis. The necrotic area is soft, and the center becomes liquefied as a result of the release and activation of hydrolytic enzymes from lysosomes of infiltrating leukocytes; as necrotic tissue is digested, a cyst filled with cellular debris and fluid may be formed. It most commonly occurs in the brain after ischemic injury from arterial occlusion, severe cerebral trauma or bacterial infections of brain.
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What is caseous necrosis?
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Caseous necrosis is a form of necrosis characterized by whitish-gray foci, sharply demarcated from surrounding non-necrotic tissue. It appears soft, granular, friable, reminiscent of dry cheese, hence the name caseous. Slowly, the center undergoes liquefaction, and granuloma formation is a hallmark of this type of necrosis.
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What is fat necrosis?
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Fat necrosis is almost exclusively found in adipose tissue contiguous to the pancreas and more rarely at distant sites. It is the result of leakage of lipase and other hydrolytic enzymes from acutely injured acinar cells of the pancreas. The foci of necrosis are yellowish white and soft, becoming white and acquire the consistency of chalk within a week or so after formation. Saponification occurs which leads to hypocalcemia and tetany.
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What is gangrenous necrosis?
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Gangrenous necrosis is not necessarily a different type of necrosis. It is characteristic of the soft tissue of lower limbs that have been compromised by protracted hypoxia and ischemia, where the extent of vascular occlusion is global; leukocytes cannot migrate to the areas of coagulation necrosis, and it is not digested and removed and becomes desiccated and mummified (dry gangrene). If overlying skin is devitalized, bacteria and/or leukocytes will enter the area of necrosis and extensive liquefaction may ensue (wet gangrene).
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What is the Hayflick limit?
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The Hayflick limit is a phenomenon observed in human cells where after 50 rounds of cell division, most cells either stop or dramatically slow down cell cycle progression. Cells that are maintained in culture after they reach the Hayflick limit either ultimately die (the majority) or undergo malignant transformation, a phenomenon known as cell crises.
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What are telomeres?
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Telomeres are short, repeated sequences of DNA (TTAGGG) that cap the end of each chromosome. They are essential for DNA replication from the lagging strand. As somatic cells replicate, the terminal repeat(s) are not replicated, and thus with each division the telomere is shortened.
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What are Hurthle cells?
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Hurthle cells are degenerated thyroid epithelial cells, hallmarks of the Hashimoto’s disease process.
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What 3 types of auto-antibodies can induce pernicious anemia (which is actually megaloblastic anemia)?
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1) Antibodies can block the binding of B12 to IF
2) Antibodies can block the secretion of IF by gastric parietal cells 3) Antibodies can interfere with the absorption of the IF receptor complex |
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If they took a patient biopsy and tested for the presence of SLE using immunofluorescence, would they use direct or indirect immunofluorescence?
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If they do tissue biopsy, they use direct immunofluorescence, whereas if they use serum, it’s indirect
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What are characteristics of the nephrotic state?
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• Proteinuria > 3.0 gms/24 hour
• Serum albumin < 3.0 gm/dl • Serum cholesterol > 300 mg/dl • Lipiduria • Edema |
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What are characteristics of the nephritic state?
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• Hematuria
• Proteinuria • Azotemia (Increased Cr and BUN) • Oliguria (less urine formation) • HTN • Edema |
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Where do immune complexes deposit in membranous nephritis syndrome of SLE?
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You get subepithelial and mesangial immune complex deposits in the membranous nephritis syndrome of SLE.
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Where do immune complexes deposit in the diffuse proliferative syndrome of SLE?
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You get subendothelial deposits in the diffuse proliferative syndrome of SLE.
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What is an isograft?
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Isograft- transplantation between genetically identical individuals
(e.g. monozygotic twins). |
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What is an orthotopic transplantation?
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Orthotopic transplantation-transplantation of an organ to its normal anatomic position (e.g., liver and heart).
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What is an allograft?
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An allograft is a transplantation between genetically disparate individuals (most common type of transplantation).
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What are the signs of liver transplant rejection?
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Indicators of acute allograft rejection:
Clinical: fever, anorexia, ascites, and back and upper quadrant pain Decreased bile output Biochemical: elevated serum bilirubin, alkaline phosphatase and transaminases Biopsy: portal inflammation (lymphocytes, EOSINOPHILS, neutrophils) bile duct damage (ductulitis) and endothelialitis Indicators of chronic rejection: The overall chronic rejection rate is about 5-10% Clinical: jaundice Biochemical: elevated bilirubin and alkaline phosphatase Biopsy: BILE DUCT LOSS (irreversible), obliterative arteriopathy (subintimal fibrosis and foam cell accumulation) and portal fibrosis |
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In ischemic heart disease why and when heart transplant indicated?
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Indications for adult transplantation:
1. Advanced symptomatic heart failure (cardiomyopathies secondary to ischemia or idiopathic) 2. Cardiogenic shock or low output state 3. Recurrent symptomatic life-threatening ventricular arrhythmias 4. Refractory angina pectoris |
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What antibodies would you look for for Mixed Connective Tissue Disease?
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High titers of anti-Ribonucleoprotein Abs
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What antibodies would you look for for polymyositis/Dermatomyositis?
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Invariably, you would find Abs to myoglobin & tRNA synthetase (Jo-1). There would also be C2 deficiency.
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How do viral infections cause cancer?
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1. Long term infection causes chronic inflammation which results in cell/DNA damage, turnover, proliferation.
2. Many viruses replicate by dysregulating the cell cycle and promoting host cell proliferation. |
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Which type of edema is associated with right-sided heart failure versus left-sided heart failure?
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Pitting edema -> right sided hair failure
Pulmonary edema -> left-sided heart failure |
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What is Starling’s hypothesis?
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Starling’s hypothesis is that edema results from hydrostatic versus plasma colloid osmotic pressure forces that drive fluid out of the intravascular space.
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What is the cause of periorbital edema in nephrotic syndrome?
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Periorbital edema is caused by albuminemia in nephrotic syndrome.
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What is myxedema?
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Myxedema is a special form of edema characterized by the accumulation of hydrophilic mucopolysaccharides which retain water in the connective tissue. It occurs in chronic hypothyroidism in an older child or adult, and it is NOT of the pitting type. When you apply physical pressure to this welling, displacement of fluid does not occur.
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What are examples of exudates?
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Examples of exudates include:
Pleuritis and pleural effusion Inflammatory edema in bronchopneumonia Infected ascites Pericardial effusion following infarction or inflammation and spinal fluid in bacterial meningitis Pus |
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What are causes of petechiae?
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Petechiae could be due to congestion or low platelet count
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What are the lines of Zahn?
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Lines of Zahn are the alternating layering of pale platelet and fibrin deposits with darker red cell rich layers.
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What is paradoxical embolus?
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A paradoxical embolus arises in the venous circulation or the right side of the heart, right ventricle, or atrium and travels to the systemic circulation of the brain, kidney, or spleen. Normally an embolus form the right should go to lungs and cause pulmonary infarct. In paradoxical embolus, there’s usually a right to left shunt (an atrial septal defect or patent foramen ovale), through which the thrombus formed in the venous circulation gains entry into the arterial circulation.
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What is Disseminated Intravascular Coagulation (DIC)?
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Disseminated Intravascular Coagulation (DIC) = the sudden or insidious onset of widespread fibrin thrombi in the microcirculation. DIC is not a primary disease but a potential complication of any condition associated with widespread activation of thrombin.
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Where do pulmonary emboli come from?
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PEs come from DVTs (>95%). Fragmented thrombi from DVTs are carried through progressively Larger channels and the right side of the heart before slamming into the pulmonary arterial vasculature.
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What’s the difference between white infarcts and red infarcts?
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White infarcts: Infarcts resulting from arterial occlusions in organs without a dual blood supply
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What is the cause of cardiogenic shock?
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Cardiogenic shock results from low cardiac output due to myocardial pump failure. This can be due to intrinsic myocardial damage (infarction), ventricular arrhythmias, extrinsic compression (cardiac tamponade), or outflow obstruction (e.g., pulmonary embolism).
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