Study Guide

§1 Define · Necrosis is unprogrammed, passive cell death due to external injury that always triggers an inflammatory response. Apoptosis is programmed, active cell suicide requiring ATP, characterized by cell shrinkage and absence of inflammation.

§2 Mechanism · In necrosis, the loss of membrane integrity leads to calcium influx (the point of no return), enzymatic digestion, and leakage of cellular contents into the interstitium. In contrast, apoptosis proceeds via the intrinsic (mitochondrial) or extrinsic (death receptor) pathways, activating a caspase cascade. This leads to DNA fragmentation and the formation of apoptotic bodies that are quietly cleared by phagocytes.

§3 Clinical + Test · A clinical example of necrosis is a Myocardial Infarction, often diagnosed by elevated Cardiac Troponin. Apoptosis is essential during embryogenesis for digit formation; failure can result in syndactyly.

§1 Define · Acute inflammation is a rapid, short-duration response (minutes to days) to injury or infection. It is characterized by the accumulation of fluid (exudate) and the recruitment of neutrophils.

§2 Mechanism · The vascular phase involves histamine-mediated vasodilation and increased permeability, allowing protein-rich fluid to leak. The cellular phase follows with neutrophil recruitment via a cascade of rolling (selectins), adhesion (integrins/ICAM-1), and transmigration. Chemotactic agents like IL-8 and C5a guide neutrophils to the site of injury to perform phagocytosis and degranulation.

§3 Clinical + Test · Bacterial pneumonia is a classic example, resulting in an exudative pleural effusion. Diagnosis is supported by an elevated C-Reactive Protein (CRP) and leukocytosis with a 'left shift' on a CBC.

§1 Define · Chronic inflammation is a prolonged response (weeks to years) characterized by simultaneous tissue destruction and repair via fibrosis. The dominant cell type is the macrophage, alongside lymphocytes and plasma cells.

§2 Mechanism · Macrophages are polarized into M1 (pro-inflammatory, induced by IFN-gamma) and M2 (anti-inflammatory/repair, induced by IL-4/IL-13). Persistent injury leads to M2-mediated release of TGF-beta, which activates fibroblasts/stellate cells into myofibroblasts. These cells deposit excessive Collagen I, leading to the replacement of functional parenchyma with scar tissue.

§3 Clinical + Test · Liver Cirrhosis is an example of chronic inflammation driving bridging fibrosis. Diagnosis is confirmed via liver biopsy or elastography, with AFP levels monitored to screen for Hepatocellular Carcinoma.

§1 Define · Proto-oncogenes are normal genes that regulate cell growth; when mutated, they become oncogenes. Oncogenes act through dominant gain-of-function mutations, meaning only one mutant allele is required to drive cancer.

§2 Mechanism · Activation occurs via point mutation (RAS), amplification (HER2), or translocation (BCR-ABL). These mutations cause constitutive activation of growth factor receptors or signal transducers like the MAPK/ERK and PI3K/AKT pathways. This leads to continuous transcription of proliferation genes such as MYC, bypassing normal cell cycle checkpoints.

§3 Clinical + Test · Chronic Myeloid Leukemia (CML) is caused by the t(9;22) translocation creating the BCR-ABL fusion protein. Diagnosis is confirmed by FISH for the Philadelphia chromosome, and treatment involves the tyrosine kinase inhibitor Imatinib.

§1 Define · Tumor suppressor genes (TSGs) are 'brakes' on the cell cycle that prevent uncontrolled proliferation. They generally follow Knudson's Two-Hit Hypothesis, acting through recessive loss-of-function mutations where both alleles must be inactivated.

§2 Mechanism · Gatekeepers like p53 and pRb monitor DNA integrity and G1/S transition; p53 induces p21 to cause cell cycle arrest or BAX for apoptosis when damage is severe. Caretakers like BRCA1/2 are involved in DNA repair pathways. Loss of these proteins prevents the cell from arresting in response to damage, allowing the accumulation of further mutations.

§3 Clinical + Test · Retinoblastoma is the classic example of RB1 gene loss; Li-Fraumeni syndrome involves a germline TP53 mutation. Diagnosis is achieved through genetic testing (NGS) for mutations or IHC showing loss of protein expression.

§1 Define · PTEN (Phosphatase and Tensin Homolog) is a major tumor suppressor protein that acts as a Loss-of-Function (LoF) phosphatase to negatively regulate the PI3K/AKT/mTOR survival pathway.

§2 Mechanism · PTEN dephosphorylates PIP3 back into PIP2, thereby antagonizing PI3K activity; its loss leads to constitutive AKT activation. In the tumor microenvironment (TME), PI3K pathway overactivation increases the expression of immunosuppressive cytokines like VEGF and IL-10 while decreasing T-cell infiltration. This molecular imbalance creates a 'cold' tumor phenotype that is resistant to T-cell mediated destruction.

§3 Clinical + Test · A clinical example is PTEN-deficient metastatic melanoma, which often fails to respond to PD-1 inhibitors. The diagnostic test is IHC for loss of PTEN expression or NGS for PTEN deletions, and treatment may involve PI3K inhibitors to restore immune sensitivity.

§1 Define · The metastatic cascade is a complex 7-step process allowing malignant cells to spread from a primary site to distant organs through the blood or lymphatics.

§2 Mechanism · The process begins with local invasion and Epithelial-Mesenchymal Transition (EMT), where E-cadherin is lost and Snail/Twist are upregulated. Cells then undergo intravasation, survive in circulation by coating themselves in platelets to evade NK cells, and eventually arrest at distant capillary beds via selectins. Finally, they extravasate, form micrometastases, and undergo Mesenchymal-Epithelial Transition (MET) to colonize the new tissue and stimulate angiogenesis via VEGF.

§3 Clinical + Test · A clinical example is breast cancer metastasizing to the bone or lungs. TNM staging is used for clinical assessment, while biopsy and CT/PET scans are the primary diagnostic tests to confirm distant spread (M1).

§1 Define · This refers to critical regulatory nodes, such as p53 or pRb, that decide cell fate—arrest, repair, or apoptosis—in response to stress or growth signals.

§2 Mechanism · In the p53 pathway, ATM kinases detect DNA damage and stabilize p53 by preventing MDM2-mediated degradation. Accumulating p53 acts as a transcription factor for p21 (causing G1 arrest via CDK inhibition) or BAX (inducing mitochondrial pore formation and cytochrome c release). If repair fails, the cell crosses the threshold into programmed cell death (apoptosis) to prevent oncogenic transformation.

§3 Clinical + Test · Li-Fraumeni syndrome is a classic clinical example involving germline TP53 mutations. Diagnostic testing is done via NGS for TP53 variants, often showing early-onset multi-organ malignancies.

§1 Define · The genetic roadmap describes the progression of genomic alterations from initial 'driver' mutations to clonal expansion and eventual malignancy.

§2 Mechanism · It typically starts with a gatekeeper mutation, such as the pRb 'two-hit' hypothesis, which removes cell cycle inhibition. This is followed by activation of dominant gain-of-function oncogenes like RAS, which locks the cell in a proliferative state via the MAPK/ERK pathway. Additional mutations in caretaker genes lead to genomic instability, allowing the tumor to acquire 'hallmarks' like replicative immortality and sustained angiogenesis.

§3 Clinical + Test · Sporadic colorectal cancer (the Adenoma-Carcinoma sequence) follows this roadmap, starting with APC loss. Colonoscopy and biopsy followed by NGS or Sanger sequencing for KRAS/BRAF mutations guide the therapeutic use of EGFR inhibitors.

§1 Define · This is the systematic application of precise genetic definitions and diagnostic tiered testing to identify mutation types and inheritance patterns.

§2 Mechanism · The architecture classifies mutations into point mutations, copy number variants (CNVs), or structural rearrangements like translocations. Diagnostic selection depends on resolution: Karyotype for chromosomal scale, CGH-array for micro-level additions/deletions, and NGS for single-base precision. This hierarchy ensures that the correct molecular mechanism (e.g., amorphic vs. hypomorphic alleles) is identified to predict clinical severity.

§3 Clinical + Test · Duchenne Muscular Dystrophy (DMD) illustrates this; MLPA is used to detect the most common exon deletions (CNVs). If MLPA is negative, NGS is the next tier to find rare nonsense or frame-shift point mutations.

§1 Define · DNA organization into chromatin involves the wrapping of double-stranded DNA around histone octamers to form nucleosomes, the functional unit of heredity.

§2 Mechanism · Epigenetic modifications like histone acetylation (via HATs) relax chromatin while DNA methylation (via DNMTs) at CpG islands typically silences gene expression. At the chromosome level, regions like pseudoautosomal regions (PAR1/PAR2) on the X/Y chromosomes allow for homologous recombination and escape X-inactivation. This architecture ensures precise gene dosage and provides a scaffold for replication and transcription.

§3 Clinical + Test · Turner Syndrome (45,X); diagnostic test is Karyotype showing SHOX gene haploinsufficiency due to the lack of the second PAR1 region, resulting in short stature.

§1 Define · Mendelian inheritance describes Autosomal Dominant (AD), Autosomal Recessive (AR), and X-linked patterns, characterized by specific risks of transmission to offspring.

§2 Mechanism · AD disorders often involve gain-of-function or dominant-negative mutations in structural proteins (Fibrillin-1) or receptors (FGFR3). AR disorders typically involve loss-of-function mutations in enzymes or transporters (CFTR), where 50% protein function in carriers is sufficient for health. Incomplete penetrance may hide the phenotype in carriers, whereas variable expressivity leads to differing clinical severity among siblings with the same mutation.

§3 Clinical + Test · Cystic Fibrosis (AR); diagnostic test is Sweat Chloride (>60 mmol/L) or NGS for CFTR delta-F508; managed with CFTR modulators like Trikafta.

§1 Define · Aneuploidy is a numerical chromosomal abnormality involving the gain or loss of a chromosome, typically caused by meiotic non-disjunction.

§2 Mechanism · Failure of homologous chromosomes (Meiosis I) or sister chromatids (Meiosis II) to separate leads to gametes with n+1 or n-1 chromosomes. Following fertilization, the resulting trisomy or monosomy causes gene dosage imbalance, disrupting embryonic signaling and development. Common examples include autosomal trisomies (21, 18, 13) or sex chromosome aneuploidies like Klinefelter (47,XXY).

§3 Clinical + Test · Down Syndrome (Trisomy 21); diagnostic test is G-banded Karyotype; clinical features include intellectual disability and congenital heart defects.

§1 Define · Non-Mendelian inheritance includes parent-of-origin imprinting, unstable trinucleotide repeat expansions (dynamic mutations), and matrilineal mitochondrial DNA transfer.

§2 Mechanism · Imprinting involves epigenetic silencing of one parental allele at the 15q11 region via methylation. Dynamic mutations involve CAG or CGG repeats that expand during gametogenesis (anticipation), leading to gene silencing (Fragile X) or toxic protein gain-of-function (Huntington). Mitochondrial inheritance depends on the transmission of the maternal oocyte's cytoplasm, affecting high-energy demand tissues (muscles, nerves).

§3 Clinical + Test · Prader-Willi Syndrome (loss of paternal 15q11); diagnostic test is DNA Methylation Analysis or FISH for microdeletion.

§1 Define · Diabetes is a chronic metabolic disorder of glucose homeostasis characterized by absolute (Type 1) or relative (Type 2) insulin deficiency.

§2 Mechanism · T1DM involves autoimmune destruction of beta cells by CD8+ T cells and Th1 cytokines (IFN-gamma). T2DM involves insulin resistance and GLUT4 downregulation coupled with AGE formation and RAGE activation, leading to endothelial dysfunction and atherosclerosis. Chronic hyperglycemia triggers the hepatic synthesis of VLDL and promotes systemic inflammation through oxidative stress.

§3 Clinical + Test · Diabetic Foot Gangrene; diagnostic test is HbA1c (>= 6.5%) or anti-GAD65/IA-2 for T1DM; management includes insulin for T1DM or metformin and SGLT2 inhibitors for T2DM.

§1 Define · Physical or functional changes in cells in response to physiological or pathological stress to maintain homeostasis without undergoing death. These include hypertrophy, hyperplasia, atrophy, and metaplasia.

§2 Mechanism · Adaptation occurs via specific signaling pathways: Hypertrophy involves PI3K/AKT and G-protein coupled receptors leading to increased protein synthesis. Metaplasia is a reprogramming of stem cells where one cell type is replaced by another better suited for the stressor, such as squamous metaplasia in bronchi due to smoking. Atrophy involves the ubiquitin-proteasome pathway and autophagy-lysosome systems to reduce cell size and workload.

§3 Clinical + Test · Left ventricular hypertrophy in hypertensive patients; diagnosed via Echocardiography (increased wall thickness). Barrett’s esophagus is a clinical example of intestinal metaplasia diagnosed by endoscopy/biopsy, increasing the risk of esophageal adenocarcinoma.

§1 Define · Nano-sized membrane-bound vesicles (30-150nm) secreted by cells into the extracellular space to facilitate intercellular communication. They carry biological cargo including proteins, lipids, and various RNA species (miRNA, mRNA).

§2 Mechanism · Formed through the inward budding of late endosomal membranes into multivesicular bodies (MVBs), regulated by the ESCRT complex. MVBs then fuse with the plasma membrane to release exosomes into the circulation. In cancer, exosomes from the tumor microenvironment (TME) can reprogram distant cells to form a 'pre-metastatic niche' by delivering oncogenic signals or immunosuppressive factors.

§3 Clinical + Test · Detection of tumor-derived exosomes in blood acts as a 'liquid biopsy' for early cancer detection. Diagnostic tests include ultracentrifugation or NTA (Nanoparticle Tracking Analysis) and ELISA for specific surface markers like CD9, CD63, and CD81.

§1 Define · Cancers whose growth and survival are driven by excessive hormone signaling, typically involving steroid hormones like estrogen or androgens. These are characterized by the expression of specific nuclear receptors (ER, PR, AR).

§2 Mechanism · In breast cancer, estrogen binds to ERα, translocating to the nucleus to act as a transcription factor for Cyclin D1 and MYC, driving the G1-S cell cycle transition. In prostate cancer, DHT binds the Androgen Receptor (AR), which upregulates PSA and pro-survival genes. Chronic stimulation leads to uncontrolled proliferation and eventual resistance via receptor amplification or splice variants.

§3 Clinical + Test · ER+ Breast Cancer diagnosed via Immunohistochemistry (IHC) and treated with Tamoxifen (SERM) or Letrozole (Aromatase Inhibitor). Prostate cancer is monitored via PSA levels and treated with Androgen Deprivation Therapy (ADT) like Leuprolide.

§1 Define · Disorders of the endocrine system resulting from hormone excess (hyperfunction), deficiency (hypofunction), or resistance at the target tissue level. These often involve autoimmune destruction or adenoma-driven secretion.

§2 Mechanism · Cushing’s syndrome involves chronic hypercortisolism; ACTH-secreting pituitary adenomas drive the adrenal cortex to overproduce cortisol through the cAMP/PKA pathway. Conversely, Hashimoto’s thyroiditis involves a loss of self-tolerance where T-cells and anti-TPO antibodies destroy thyrocytes, leading to primary hypothyroidism. These imbalances disrupt the feedback loops of the hypothalamic-pituitary-target organ axes.

§3 Clinical + Test · Hashimoto’s Thyroiditis is diagnosed by elevated TSH and positive anti-TPO titers. Cushing’s Disease is diagnosed via the 24h urine free cortisol test and confirmed with a low-dose dexamethasone suppression test.

§1 Define · A reduction in the total circulating red blood cell mass or hemoglobin concentration, leading to diminished oxygen-carrying capacity. It is classified by morphology (microcytic, normocytic, macrocytic) or mechanism (blood loss, hemolysis, impaired production).

§2 Mechanism · Iron deficiency anemia (microcytic) occurs when low iron stores impair heme synthesis, leading to smaller, pale RBCs. In hemolytic anemias, RBCs are destroyed either intravascularly or in the spleen (extravascularly) by macrophages, releasing LDH and unconjugated bilirubin. Pernicious anemia (megaloblastic) is caused by Vitamin B12 deficiency due to lack of Intrinsic Factor, impairing DNA synthesis and causing nuclear-cytoplasmic dyssynchrony.

§3 Clinical + Test · Sickle Cell Anemia (HBB point mutation, Glu6Val) is diagnosed by Hemoglobin Electrophoresis or NGS. Management includes Hydroxyurea to increase fetal hemoglobin (HbF) or blood transfusions to prevent vaso-occlusive crises.