Block Two (Pathogenesis & Microbiology) Study Guide PDF

UICOM BLOCK TWO STUDY GUIDE PATHOGENESIS & MICROBIOLOGY Open access study guides for medical school preclinical curriculum By Ryan Parnell TO SUPPORT OPEN ACCESS LEARNING AND ACCESS THE GUIDES FOR FREE https://www.patreon.com/ryanparnell OPEN ACCESS P...

UICOM BLOCK TWO STUDY GUIDE PATHOGENESIS & MICROBIOLOGY Open access study guides for medical school preclinical curriculum By Ryan Parnell TO SUPPORT OPEN ACCESS LEARNING AND ACCESS THE GUIDES FOR FREE https://www.patreon.com/ryanparnell OPEN ACCESS PRE-CLINICAL STUDY GUIDES: Body Systems & Homeostasis (65 pages) Pathogenesis & Microbiology (90 pages) Musculoskeletal, Skin, Connective Tissue Study Guide (90 pages) Cardiology Study Guide (69 pages) Respiratory Study Guide (50 pages) Renal Study Guide (39 pages) Gastrointestinal Study Guide (60 pages) Neurology / Psychiatry Study Guide (125 pages) Endocrine Study Guide (39 pages) Reproduction Study Guide (44 pages) Biostatistics / Epidemiology Study Guide (10 pages) Physical Exam Maneuvers Study Guide (13 pages) TO SUPPORT OPEN ACCESS LEARNING AND ACCESS THE GUIDES FOR FREE https://www.patreon.com/ryanparnell Please share this document with any medical school classmates! Block 2 - Week 1 Fate of Amino Acids: Urea Cycle (Independent Learning) Aminotransferases: ​first step of amino acid breakdown,​ ​NH​4​+​ is extremely toxic (especially in neural tissue) so it must be “carried” through the body until it is converted to urea Block 2 - Week 1 Glutamate / Glutamine: ​interconversion between these forms is used to carry NH​4​+​ to the liver Urea Cycle: ​conversion of ammonia → urea for excretion, occurs exclusively in the liver Primary Hyperammonemia: ​defects in urea cycle enzymes or transporters Block 2 - Week 1 Secondary Hyperammonemia: ​inhibited by substrate deficiencies / enzyme inhibition Presentation of Hyperammonemia: ​severe cases will present 24-72 hours after birth Increased blood glutamine concentration, decreased blood urea nitrogen (BUN) Mild cases = agitation, headache, vomiting, lethargy, confusion Severe cases = seizures, ataxia, encephalopathy, coma Hyperammonemia lower glutamate (excitatory neurotransmitter) levels (shunted to glutamine via glutamine synthetase reaction) → reduced CNS activity One Carbon Metabolism (Independent Learning) Folate (Vitamin B​9​): ​found in nuts, lentils, chickpeas, leafy greens, synthetically “fortified” food Deficiency = megaloblastic anemia, neural tube defects, commonly seen in alcoholics Cobalamin (Vitamin B​12​): ​produced by bacteria, found in meat products Deficiency = secondary folate deficiency (methyl trap hypothesis), megaloblastic anemia + irreversible neurological symptoms Block 2 - Week 1 One-Carbon Metabolic Pathways: Folate Cycle: THF facilitates transfer of one-carbon groups required for synthesis of purines, thymidine (dTMP, used in DNA synthesis), glycine, methionine, and S-adenosylmethionine (SAM) FIGLU in urine after histidine ingestion is a diagnostic sign of folate deficiency Folate deficiency impairs cell division in rapidly growing cells ○ ↓ dTMP, ↓ DNA synthesis, ↓ purines, ↑ dUMP, ↑ fragmentation of DNA ○ Megaloblastic anemia (defective DNA synthesis ) + hypersegmented neutrophils ○ Glossitis → swollen and glossy tongue due to damaged papilla Methotrexate = competitive inhibitor of DHFR, used for cancer/inflammation ○ Supplemented with N​5​-formyl-THF → “leucovorin rescue” Methionine Cycle: Connected to folate cycle via methionine synthase (requires Vit. B12 cofactor) S-Adenosylmethionine (SAM) = methyl-group donor in synthesis of many compounds ○ Hormone / phospholipid synthesis, DNA methylation, etc Transsulfuration Pathway: Homocystine is not reabsorbed by kidneys → metabolism of homocysteine is essential to maintain homeostasis Classic Homocystinuria = CBS deficiency, most common cause of homocystinuria ○ Characterized by thromboembolism + displacement of lens (treated w/ B6) Block 2 - Week 1 Diabetes Pathophysiology (Independent Learning) Anatomy of Glucose Regulation: Islets of Langerhans = alpha (glucagon) + beta (insulin) endocrine glands in pancreas ○ Other types: delta (somatostatin) + PP cells (pancreatic polypeptide) ○ Receives neural input form adrenergic and cholinergic innervation Liver = glycogen storage, glycogenolysis (stabilization of blood glucose) Muscle = disposes 80% of glucose load (stored as glycogen) Fat Tissue = triglyceride synthesis (glycerol backbone + FA precursors from glucose) GLUT2 = insulin independent glucose transporter in liver / pancreas GLUT4 = insulin dependent glucose transporter in muscle / adipose Mechanisms of Glucose Regulation: Beta Islet Cells: uptake glucose via GLUT2 → glucokinase cell sensor activates ATP production → ATP sensitive K​+​ channels close, leading to depolarization → intracellular voltage-gated Ca​2+ channels open → Ca​2+​ induces vesicle fusion and insulin release Incretins: GIP (from proximal GI tract K cells) and GLP-1 (from distal GI tract L cells) are GI hormones that induce insulin secretion (~50%) ○ Metabolized by dipeptidyl dipeptidases (DPPs) → DPP-4 is a major drug target Glucocorticoids: produced by adrenal gland, enhance protein catabolism + increase gluconeogenesis via transcription alteration (cortisol, epinephrine, etc.) Hormonal Regulation of Metabolism: Diabetes: ​~8% of population affected, leading cause of renal disease, blindness, amputations Classical triad: polyuria (large volumes dilute urine), polydipsia (abnormal thirst), and polyphagia (extreme hunger) → combination of polyphagia + weight loss Block 2 - Week 1 Type I vs Type II Diabetes: Type 1 Diabetes and Ketoacidosis: ​complete lack of insulin + increased counter-regulatory hormones (glucagon, epinephrine) leads to total dysregulation Unregulated FA oxidation → Malonyl-CoA usually regulates carnitine transport, but it is completely depleted due to lack of FA synthesis Hormone sensitive lipase is activated by glucagon → massive increase in acetyl-CoA is shunted into ketone bodies → rapid and severe ketogenesis Pathophysiology of Hyperglycemia: AGE-RAGE Binding​ → advanced glycation end products (AGE) lead to activation of inflammatory cells Protein​ ​Kinase C Activation​ → PKC leads to cytokine secretion + transcription alterations Oxidative Stress​ → increased glucose → sorbitol conversion leads to sorbitol build-up + depletion of NADPH (cannot protect cells against oxidative stress) Hexosamine Pathway Activation​ → leads to enhanced expression of plasminogen activator inhibitor + TGFβ → exacerbates end organ damage Macrovascular Pathology​ → these physiological changes favor formation of lesions, leading to atherosclerosis (increases risk for stroke, heart attack, etc) Microvascular Pathology​ → hyaline arteriosclerosis (increases risk for neuropathy, retinopathy, nephropathy) Renal Disease​ → hyaline arteriosclerosis of efferent arteriole + nodular glomerulosclerosis (Kimmelstiel-Wilson lesion) are classic markers for diabetes Retinopathy​ → microaneurysms / vascular leakage (early-stage) or hemorrhage / retinal detachment (late stage) Peripheral Neuropathy​ → loss of sensory function in peripheral nerves Block 2 - Week 1 Mono/Disaccharides and Pentose Phosphate Pathway Disorders of Fructose + Galactose Metabolism: Block 2 - Week 1 Pentose Phosphate Pathway: ​occurs in cytosol of all cell types (independent of mitochondria) NADPH Functions: ​reductive, formed via PPP ​or​ malic enzyme (requires mitochondria) Block 2 - Week 1 Polyol Pathway: ​conversion of glucose → fructose (main energy source for spermatozoa) Aldolase Reducase: converts glucose → sorbitol and galactose → galactitol Sorbitol / galactitol accumulation leads to ​cataracts​, ​peripheral​ n ​ europathy​, and microvascular problems associated with ​diabetic​ ​neuropathy ○ Glucose uptake in peripheral nerves is not dependent on insulin → high blood glucose in diabetes leads to high nerve glucose → increased sorbitol ○ Aldolase reductase activity depletes NADPH → increased oxidative stress Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency: ​glutathione can’t neutralize H​2​O​2 Without G6PD, RBCs cannot produce NADPH → hemolytic anemia (die from ox. stress) ○ RBCs present with bite cells + heinz bodies → disulfide linked aggregates of Hb Most common enzyme deficiency (​X-linked​, 7% of world population, 2% of USA) ○ Affected individuals have increased resistance to falciparum malaria ○ Geographic distribution (tropical Africa / Asia / Middle East) follows sickle cell Precipitating factors for hemolytic anemia in G6PD deficiency: ○ Oxidant Drugs (AAA) → antibiotics (sulfa drugs), antimalarials, antipyretics ○ Favism → ingestion of fava bean purine glycoside (react w/ reduced glutathione) ○ Infection → inflammatory response increases ROS (induces oxidative damage) ○ Neonatal Jaundice → increased production of bilirubin (heme degradation) Fate of Amino Acids: Carbon Skeleton Digestive Enzymes: Block 2 - Week 1 Amino Acid Metabolism: Block 2 - Week 1 Amino Acid Metabolism Disorders: Block 2 - Week 1 Glycogen Synthesis, Degradation, and Related Disorders Block 2 - Week 1 Hormonal Regulation of Glycogen: Glycogen Storage Diseases: ​autosomal recessive Block 2 - Week 1 Vitamins, Cofactors and Their Metabolism Protein-Energy Malnutrition (PEM): Marasmus: caloric deficiency → muscle wasting + fat emaciation + anemia Kwashiorkor: protein deficiency → edema + hypoalbuminemia + anemia Secondary PEM: marasmus-like (chronic illness) or kwashiorkor-like (protein malabsorption) Vitamins: Vitamin D Synthesis: Block 2 - Week 1 Lipid Synthesis and Transport Fatty Acid Synthesis: ​occurs in cytoplasm / liver, high-energy state (acetyl-CoA, ATP) Triacylglycerol / Phospholipid Synthesis: ​occurs in liver / intestine / adipose tissue Block 2 - Week 1 Lipoproteins: Block 2 - Week 2 Gram Positive Algorithm: Block 2 - Week 2 Gram Positive Bacteria - Staphylococcus​: Block 2 - Week 2 Gram Positive Bacteria - Streptococcus​: Block 2 - Week 2 Gram Positive Bacteria - Streptococcus​: Block 2 - Week 2 Gram Positive Bacteria - Anaerobic Bacilli​: Block 2 - Week 2 Gram Positive Bacteria - Aerobic Bacilli​: Block 2 - Week 2 Gram Positive Bacteria - Branching, Filamentous Rods​: Block 2 - Week 2 Gram Negative Algorithm​: Block 2 - Week 2 Gram Negative Bacteria - Bacilli​: Block 2 - Week 2 Gram Negative Bacteria - Diplococci​: Block 2 - Week 2 Gram-Negative Bacteria - Other​: Block 2 - Week 2 DNA Viruses​: Block 2 - Week 2 DNA Viruses - Herpesviruses​: Block 2 - Week 2 DNA Viruses - Herpesviruses​: Block 2 - Week 2 RNA Viruses​: Block 2 - Week 2 RNA Viruses​: Block 2 - Week 2 Mycobacteria​: Block 2 - Week 2 Antimicrobial Resistance​: Intrinsic Resistance: ​natural characteristic of organism, encoded by chromosomes Acquired Resistance: ​mutation of existing DNA or plasmid uptake (more likely in gram negative than gram positive) Decreased permeability (porin channels, permeability barrier) Inactivating enzymes (beta-lactamases, acetyltransferases) Active efflux pumps Altered target sites (PBPs, DNA gyrase, ribosomes, RNA polymerase) Extended-Spectrum Beta-Lactamases (ESBL): ​treated with carbapenems Carbapenem-Resistant Enterobacteriaceae (CRE): ​treated with colistin, polymyxin B, aminoglycosides Block 2 - Week 2 Antimicrobials​: Block 2 - Week 2 Antimicrobials​: Block 2 - Week 3 Parasitic Infections: Protozoa: ​unicellular eukaryotes, easy to see under microscope Trophozoites → feeding form, vulnerable to environmental conditions Cysts → durable form, found in nature (feces → water → infection) Block 2 - Week 3 Parasitic Infections:​ Block 2 - Week 3 Parasitic Infections: Block 2 - Week 3 Helminths​: Block 2 - Week 3 Spirochetes: Block 2 - Week 3 Zoonotic Infections: Block 2 - Week 3 Zoonotic Infections: Block 2 - Week 3 Fungal Infections: Block 2 - Week 3 Fungal Infections: Block 2 - Week 3 Fungal Infections: Block 2 - Week 3 Block 2 - Week 4 Immunosuppressive Drugs (Independent Learning)​: Block 2 - Week 4 Core Case: Hypersensitivity (I, II, III, IV): Block 2 - Week 4 Congenital Immunodeficiencies: Block 2 - Week 4 HIV/AIDS Pathogenesis: Block 2 - Week 4 Immune Regulation of Inflammation: Complement System: ​cascade of enzymatic reactions for pathogen destruction Peripheral Tolerance: ​mechanisms for halting immune response outside of lymphoid organs Block 2 - Week 4 Core Case: Opportunistic Infections in HIV/AIDS: Block 2 - Week 4 Block 2 - Week 4 Core Case: Pharmacological Interventions & AIDS Patient Awareness: Block 2 - Week 5 Treatment of Anemia (Independent Learning​) Hematopoiesis: ​blood cell production in bone marrow (requires iron, B​12​, folate, growth factors) Anemia: ​deficiency in functional erythrocytes Block 2 - Week 5 Pharmacological Treatment of Anemia: Amyloidosis (Independent Learning) Amyloidosis: ​pathologic aggregate of amyloid proteins (> 20 types of proteins) Block 2 - Week 5 Heme Synthesis Block 2 - Week 5 Heme Degradation Block 2 - Week 5 Eicosanoids​: ​20-carbon molecules (PG, TX, LT) derived from ω3 and ω6 fatty acids Block 2 - Week 5 Reactive Leukocytosis Block 2 - Week 5 Mechanisms of Injury, Necrosis, and Apoptosis Block 2 - Week 5 Mechanisms of Injury, Necrosis, and Apoptosis (cont.) Ischemia: ​deprivation of oxygen + nutrients → decreased ATP, leading to… ↓ Na​+​/ K​+ ​pump activity = loss of membrane potentials → swelling Lack of protein / lipid / carbohydrate synthesis Lactic acidosis → alters enzyme activity via pH change Increased cytosolic Ca​2+​ → membrane / nuclear / mitochondrial damage Ribosomal detachment via reduction in protein synthesis Reperfusion Injury: ​restored blood flow leads to excess reactive oxygen species (ROS ) Overwhelming of cellular scavenging mechanisms (Vit E, Vit C, catalase, glutathione) Lipid peroxidation (membrane damage) Protein / DNA oxidation (misfolding, mutations) Cell Adaptations: Hypertrophy: ↑ cell size (due to increased work) Hyperplasia: ↑ cell number (due to growth factors) Atrophy: ↓ cell size (due to decreased work / disuse) Metaplasia: change in cell type (reprogramming of stem cells due to irritant or injury) ○ ALWAYS PATHOLOGIC Dysplasia: pre-neoplastic change of disordered growth or congenital maldevelopment Neoplasia: unregulated proliferation of cells Cellular Accumulations: Triglycerides: reversible change, occurs in liver / heart / muscles Lipofuscin: polymers of lipid complexed to protein, pigment associated with aging Hemosiderin: storage form of iron, leads to golden brown pigment in cells Anthracosis: carbon particles, found in pulmonary macrophages Tissue Calcification: ​deposit of calcium salts in tissues Cellular Senescence: ​cell aging leads to increased mutations + shortened telomeres P53 Checkpoint: identifies short telomeres and induces apoptosis Mitotic Catastrophe: premature entry into mitosis leads to cell death Block 2 - Week 5 Mechanisms of Inflammation Leukocyte Activity in Inflammation: Inflammation Terminology: Serous​: cell poor, protein poor exudate Fibrinous​: protein rich with fibrin, neutrophils, vascular damage Purulent​ / ​Suppurative​: cell rich, protein rich with many neutrophils Ulcerative​: ulceration of epithelial surface Block 2 - Week 5 Systemic Inflammatory Response: ​locally produced cytokines enter bloodstream TNF + IL-1 + IL-6 reach CNS → release of PGE​2​ → increase of temperature set-point in hypothalamus IL-1 + IL-6 act on liver to induce production of acute phase proteins ○ ↑ ESR, C-reactive protein, SAA, transferrin, fibrinogen, ceruloplasmin ○ ↓ albumin, transferrin, transthyretin, retinol binding protein TNF + IL-1 + IL-6 act on bone marrow to induce production of leukocytes ○ Left shift will occur (greater % of band cells compared to neutrophils) Dysregulated Systemic Inflammation: Sepsis: life-threatening inflammation secondary to infection (ARDS, DIC) Systemic Inflammatory Response Syndrome: dysregulated inflammation secondary to another pro-inflammatory process (autoimmunity, pancreatitis, vasculitis) Chronic Inflammation: ​tissue destruction + repair occurring simultaneously Common Causes: prolonged infection (type IV HS), autoimmune disease Carried out by mononuclear cells → macrophages, T and B cells, plasma cells Usually associated with fibrosis (look for macrophages + fibroblasts on histology) Block 2 - Week 5 Mechanisms of Tissue Repair, Regeneration and Wound Healing Labile Tissues: ​continuously dividing, easily regenerate Stable Tissues: ​minimal replicate, may proliferate in response to injury (liver, kidney, pancreas) Permanent Tissues: ​cannot significantly regenerate (neurons, cardiac myocytes) Scar Formation: 1. Angiogenesis ​→ new blood vessel growth a. Vascular Endothelial Growth Factor (VEGF): stimulates angiogenesis b. Fibroblast Growth Factor (FGF): chemotactic for fibroblasts + stimulates angiogenesis 2. Fibroblast Activation ​→ lay down fibrous tissue a. Fibroblasts: secrete type III collagen + fibronectin at injury sites b. TGF-β: stimulates collagen production + anti-inflammatory effects c. Platelet Derived Growth Factor (PDGF): stimulates fibroblasts d. Granulation Tissue: 3-5 days after injury, composed of collagen + new blood vessels 3. Scar Maturation ​→ production of stronger, stable scar tissue (m a. Myofibroblasts: fibroblasts with contractile proteins, contract wound (pull edges together) b. Metalloproteinases: zinc-containing enzyme, breakdown type III collagen c. Lysyl Oxidase: copper-dependent enzyme, crosslinks collagen Cutaneous Wound Healing: First Intention: ​tissue surfaces approximated (closed together via sutures / staples) ○ Epithelial regeneration is main mechanism of healing Second Intention: ​too large to approximate edges → large scar Keloid: ​raised scars caused by excessive healing / scar (beyond borders of original wound) Contain type I and III disorganized collagen, treated with corticosteroids + 5-FU Hypertrophic Scars: ​excessive scar formation (remain within wound borders) Type III parallel collagen Mechanisms of Edema and Hemorrhage Edema: ​accumulation of excess interstitial fluid Transudate​: protein-poor fluid accumulation (non-inflammatory, ↑ hydrostatic pressure) Exudate​: protein-rich fluid accumulation (inflammatory / infection) ○ Due to lymphatic obstruction + inflammation / infection Hydrothorax​: fluid accumulation in the chest (thoracic effusion) Ascites​: fluid accumulation in abdominal cavity (abdominal effusion) Anasarca​: body wide fluid accumulation (non-inflammatory) Hyperemia:​ active meditator driven arteriolar dilation feeding more blood to injury tissue → increased hydrostatic pressure → edema + redness Congestion​: passive meditator driven process of venous dilation reducing outflow of blood → increased hydrostatic pressure → edema + redness (i.e. nutmeg liver) Hemorrhage: ​extravasation of blood from vessels (vessel damage or defective clot formation) Block 2 - Week 5 Introduction to Transfusion Medicine ABO Blood Group: ​carbohydrate with naturally occuring antibodies against non-host antigens Rh Blood Group: ​transmembrane proteins w/ > 50 antigens (C, c, D, E, e) D antigen is highly immunogenic → most important Rh antigen ○ Rh Positive = contain D antigen (83% of caucasians, 98% of asians) ○ Rh Negative = does not contain D antigen, may develop anti-D Abs (IgGs) Newborn Hemolytic Disease: RhD- mother with RhD+ fetus leads to maternal anti-D Abs ○ First pregnancy: mother exposed to D+ RBCS during delivery → develops anti-D IgG ○ Second pregnancy: maternal anti-D IgG crosses placenta → attacks fetus Mild = hemolytic anemia, severe = hydrops fetalis Anti-D immune globulin is given to D- women in third trimester Direct Antiglobulin Test (DAT): ​Coombs Test, used to determine if RBCs have been coated ​in vivo​ with antibodies or complement (Coombs reagent = anti-human IgG + anti-human C3) Transfusion Medicine: Blood Products: Packed RBCs → RBCs w/o plasma, minimizes transfusion volume Platelets → mismatch is less common (do not express Rh or HLA class II) Fresh Frozen Plasma (FPP) → used for clotting disorders Cryoprecipitate → contains lots of fibrinogen (used for massive bleeding) Block 2 - Week 5 Complications of Transfusions Acute Hemolytic Transfusion Reaction (AHTR): Immune-mediated lysis of transfused RBCs (due to pre-formed antibodies, type II HSR) ○ anti-A and anti-B antibodies have high titer / avidity → activate complement Life-threatening → fever, chills, DIC, elevated bilirubin (dark urine / jaundice) Caused by transfusion of wrong blood product (due to clerical / procedural error) Delayed Hemolytic Transfusion Reaction (DHTR): Extravascular hemolysis of transfused RBCs due to immune response to alloantigen Mild reaction → mild fever, jaundice, decrease in hemoglobin Treatment → transfusion of compatible RBC lacking inciting antigen (crossmatch) Anaphylactic Transfusion Reaction: Antibody to donor plasma proteins (type I HSR to IgA, C4, haptoglobin, etc) ○ Commonly occurs in IgA deficient individuals reacting to transfused IgA Transfusion Related Acute Lung Injury (TRALI): Sudden hypoxemia during transfusion → neutrophil activation → pulmonary edema Severe symptoms → acute, hypoxemia, bilateral chest infiltrates, no atrial hypertension ○ #1 cause of transfusion related death Transfusion Associated Circulatory Overload (TACO): Rapid transfusion of large volume → hypervolemia → dyspnea, hypertension High-risk patients: renal insufficiency, cardiac impairment Diffuse, bilateral infiltrates on chest x-ray No fever + hypertension are signs of TACO (differentiated from TRALI) Febrile Non-Hemolytic Transfusion Reaction (FNHTR): Fever, chills, rigors caused by cytokines in blood products (especially IL-1) Leukoreduction → reduction of cytokines in donor blood products Septic Transfusion Reaction: Bacterial contamination (greater risk in platelets = room temp storage) RBCs → Yersinia enterocolitica, Serratia liquefaciens Platelets → staphylococcus, enterobacteria, streptococcus Block 2 - Week 6 Purine and Pyrimidine Metabolism Block 2 - Week 6 Block 2 - Week 6 Block 2 - Week 6 Genetic Mechanisms of Cancer Tumor​ ​Suppressor​ ​Genes​: suppress cancerous characteristics Requires ​two​ ​inactivation​ ​events​ to cause complete loss-of-function ○ Sporadic Cancer → two somatic inactivation events ○ Hereditary Cancer → one germline mutation, one somatic inactivation (↑ odds) Maintain correct chromosome structure/number, DNA repair proteins, cell cycle regulators Proto-Oncogenes​: favor cancerous characteristics Requires ​one​ ​activation​ e ​ vent​ to promote cancer formation Promote cell growth / proliferation, control growth-promoting gene expression, inhibit apoptosis Block 2 - Week 6 Inactivation Events: ​lead to loss-of-function in tumor suppressor genes Local Inactivation → gene mutations, transcriptional silencing, chromosome loss Loss of Heterozygosity → loss of normal allele in heterozygous chromosome allows defective allele to clinically manifest Activation Events: ​leads to activation of proto-oncogenes → oncogenes Block 2 - Week 6 Hereditary Cancers: ​inheritance of germline mutation in tumor suppressor gene Only one “hit” is required for cancer proliferation → massively increased likelihood Multiple tumors, bilateral occurrence, and early onset are typical of hereditary cancer ○ Multiple affected generations / relatives (>3 members on same side), rare cases In pedigree, cancer will show ​autosomal dominant ​pattern ○ Demonstrates ​reduced​ ​penetrance​ → some members will not obtain second “hit” ○ Demonstrates ​variable​ ​expressivity​ → different types of cancer will manifest Block 2 - Week 6 Pathology Lab: Cancer Formation, Progression, and Carcinogenesis Carcinogenesis: ​sub-lethal alteration of DNA / epigenetics resulting in unregulated growth Genetic: activation of oncogenes, deletion of tumor suppressors Environmental: direct (alter DNA without metabolism) + indirect (alter DNA after metabolism) ○ Direct Carcinogens​: alkylating / acylating agent ○ Indirect Carcinogens: ​polycyclic hydrocarbons, aromatic amines, aflatoxins, etc Radiation: low energy (UV, pyrimidine dimers) + high energy (X-rays / CT, DNA mutations) Infectious Diseases: HPV, EBV, Hep B, HHV-8 Tumor Characteristics: Dysregulation of Growth Control: ​growth stimulation + loss of growth inhibition ○ Altered growth factors / cell cycle regulation / receptor signaling Angiogenesis: ​induction of vessel growth, required to reach size > 2 mm ○ Activated by hypoxia → mediated by HIF / VEGF Altered Metabolism: ​switch to Warburg effect (aerobic glycolysis) ○ Glycolysis provides carbon units as “building blocks” required for cell replication Unlimited Ability to Replicate: ​“immortal” cells via evasion of senescence ○ Mutated P53 → eliminates cell cycle arrest / senescence / apoptosis ○ Upregulated Telomerase → maintains telomere length, evading senescence Evasion of Apoptosis: ​avoid destruction by immune system ○ Follicular Lymphoma: (14,18) translocation → excess BCL2 (anti-apoptosis) ○ Mutated TP53 → loss-of-function of BAX / Puma → cannot initiate apoptosis ○ Decreased FAS / CD95 expression → avoids apoptosis Mass Lesion: ​space-occupying + destruction of surrounding tissue Block 2 - Week 6 Biomarkers of Cancer: ​may suggest neoplasm, but biopsy is necessary for definitive diagnosis Other clinical signs of cancer include… Mass effect lesions (depends on tumor location) Unexplained weight loss / fever / fatigue Unusual bleeding / regenerative anemia Hematuria / oral leukoplakia Non-healing wounds Aging demographic with family history Paraneoplastic syndrome Cancer Cachexia:​ tissue wasting due to ↑ catabolism ○ mediated by TNF / other macrophage cytokines Paraneoplastic Syndromes: ​caused by hormones / cytokines produced by tumor / immune response against the tumor (commonly endocrine effects, see examples below) Tumor Nomenclature: Sarcomas: ​malignant tumors arising from solid ​mesenchymal​ tissues (fat / bone / muscle) ○ Hematogenous​ ​Spread​ (liver + lungs are common sites of hematogenous spread) Carcinomas: ​malignant tumors arising from ​epithelial​ tissue (ectoderm / mesoderm / endoderm) ○ Lymphatic​ ​Spread​: majority of carcinomas ○ Hematogenous Spread: renal cell, hepatocellular, follicular thyroid, choriocarcinoma ○ Seeding of Body Cavities: ovarian carcinoma Teratomas: ​tumors with cells from multiple germ layers (ectoderm / endoderm / mesoderm) ○ Arise from germ cells in ovaries and testes Parenchyma: ​transformed / neoplastic cells Stroma: ​host-derived, non-neoplastic connective tissue + blood vessels + inflammatory cells Block 2 - Week 6 Tumor Characteristics: Tumor Grading: ​degree of differentiation via tissue biopsy analysis by pathologist (I, II, III, IV) ○ Well-differentiated = resembles parent tissue → lower grade, better prognosis ○ Poorly differentiated = does not resemble parent tissue → higher grade, worse prognosis Tumor Staging: ​size and degree of tumor spread via radiology / imaging (key prognostic factor) ○ TNM Staging System:​ T = size (T1-T4), N = lymph node spread (N0-N3), M = metastases (M0/1) Tumor Histology: Tumor Immunohistochemistry: Block 2 - Week 6 Antineoplastics Skipper’s Log-Kill Hypothesis: ​given dose of drug kills fixed ​percentage​ of tumor cells Anticancer drugs act with ​first-order kinetics ​(kill fixed percentage regardless of tumor size) Each ​log-kill​ reduces cancer cell population by one order of magnitude Cell Cycle-Nonspecific (CCNS) Drugs: ​act on cells in cell cycle + G​0​ phase Cell Cycle-Specific (CCS) Drugs: ​act on cells in cell cycle only Block 2 - Week 6 Block 2 - Week 6 Block 2 - Week 6 Introduction to Anatomy Block 2 - Week 7 Hypocoagulation (Bleeding) / Hypercoagulation (Clotting) Disorders Primary Hemostasis:​ activation of platelets to seal damage blood vessels Secondary Hemostasis:​ formation of cross-linked fibrin by activated coagulation factor Block 2 - Week 7 Block 2 - Week 7 Overview of Neoplastic WBC Disorders Block 2 - Week 7 Acute Leukemia: Neoplastic proliferation of ​blasts​ (​>20% in bone marrow​) Blasts “crowds out” normal hematopoiesis → acute presentation of ​anemia / pancytopenia Blasts enter bloodstream, resulting in ​high levels of WBCs in peripheral blood Myelodysplastic Syndrome: ​abnormal myeloid progenitors leads to ineffective hematopoiesis Peripheral Blood: ​pancytopenia​, < 20% blasts, dysplastic granulocytes Bone Marrow: ​hypercellular / dysplasia​, < 20% blasts, biopsy is used for diagnosis Associated with ​environmental factors ​(radiation, chemotherapy) ~40% of patients will​ progress to AML (​ once blasts > 20%) Block 2 - Week 7 Chronic Leukemias: ​slower onset, does not involve blasts Myeloproliferative Disorders: Hematopoietic neoplasms → ↑ peripheral cell counts (granulocytes, platelets, RBCs, etc.) Often associated with ​JAK2 mutation ​(↑ tyrosine phosphorylation = hypersensitivity to cytokines) Block 2 - Week 7 Plasma Cell Disorders: Overproduction of monoclonal immunoglobulins (​Ig)​ due to plasma cell disorder Identified via ​M spike ​on serum protein electrophoresis (​SPEP​) Lymphomas: Malignancies of lymphocytes, commonly present as ​enlarged, painless lymph node Accompanied by ​“B” symptoms ​(systemic release of cytokines → fever, chills, night sweats) Diagnosis is made via ​malignant lymphocytes p ​ resent in ​tissue biopsy Block 2 - Week 7 Hodgkin Lymphoma Subtypes: Block 2 - Week 7 Non-Hodgkin Lymphomas: B and T cell malignancies, lead to obliteration of lymph node architecture B cells = majority of malignancies, found in ​follicles​ of lymph node T cells = minority of malignancies, found in ​paracortex ​of lymph node Lymphadenopathy (LAD): ​enlarged lymph nodes Painful LAD ​is associated with acute infection Painless LAD ​is associated with chronic inflammation, metastatic carcinoma, or lymphoma ○ Follicles = rheumatoid arthritis and early HIV (B cells) ○ Paracortex = viral infection (T cells) ○ Sinus histiocytes = lymph node draining tissue with cancer Block 2 - Evidence-Based Medicine Block 2 - Radiology Independent Learning Introduction to X-Ray Imaging Introduction to CT and PET/CT (Independent Learning): Block 2 - Radiology Independent Learning Introduction to Ultrasonography Introduction to MRI Block 2 - Radiology Independent Learning Introduction to Nuclear Medicine Radiation Exposure and Appropriateness of Medical Imaging