1.

Cell Membrane Composition

●​ Lipid bilayer: Amphiphilic lipids (phospholipids, sphingolipids)​

○​ Polar head: Faces outside (hydrophilic)​

○​ Hydrophobic tails: Face inside (lipophilic core)​

●​ Proteins: Integral & Peripheral​

●​ Other lipids: Cholesterol​

●​ Carbohydrates: Glycoproteins & Glycolipids → form Glycocalyx​

Key functions:

●​ Semipermeable barrier​

●​ Maintains fluidity (lateral movement of lipids/proteins)​

●​ Cell recognition, protection, and immune differentiation​

2. Membrane Proteins

Type Location Function Example/Note

Integral Partially or fully Transport, Na⁺/K⁺ pump

embedded receptors (transmembrane),
beta-barrel channels
Periphe Loosely attached via Enzymes, Digestive enzymes on
ral H-bonds or signaling intestinal cells
electrostatics

Shapes:

●​ α-helix → receptors​

●​ Helical bundle → transporters, enzymes​

●​ β-barrel → channels​

3. Glycoproteins & Glycocalyx

●​ Glycoproteins: Cell recognition​

●​ Glycocalyx: Protective, antigenic, prevents dehydration, differentiates

RBC blood groups​

4. Membrane Fluidity Regulators

Component Effect

Phospholipi Short chains → more fluid; Unsaturated → more fluid

d

Carbohydra Hydrophilic, attract water

tes
Proteins Hydrophilic regions interact with cytosol; hydrophobic with
tails

Cholesterol Stabilizes membrane; High temp → reduces fluidity, Low

temp → prevents clustering

5. Membrane Transport
A. Passive Transport (No ATP)

1.​ Simple diffusion: Small/lipophilic molecules (O₂, CO₂)​

2.​ Osmosis: Water movement via semi-permeable membrane​

3.​ Facilitated diffusion: Large/charged molecules via proteins​

○​ Ion channels: Voltage-gated, ligand-gated​

○​ Aquaporins: Water channels​

B. Active Transport (ATP required)

1.​ Primary: Direct ATP hydrolysis → e.g., Na⁺/K⁺ pump (3 Na⁺ out, 2 K⁺ in)​

2.​ Secondary: Uses electrochemical gradient​

○​ Uniport: 1 molecule down conc. gradient​

○​ Symport: 2 molecules same direction​

○​ Antiport: 2 molecules opposite directions​

Transporters: Specific, can be inhibited competitively/non-competitively

6. Clinical Significance
●​ Cystic fibrosis: CFTR mutation → Cl⁻ transport fails → thick mucus →
lung infections, pancreatic enzyme blockage​

●​ Cellular processes: Nutrient uptake, waste excretion, signal

transduction​

Chromosomes & Chromatin

1.​ Chromosomes are the condensed form of chromatin, which is uncoiled DNA in the
nucleus.​

2.​ During mitosis, each daughter cell receives identical chromosomes.​

MCQ focus: Difference between chromatin and chromosomes; mitotic outcome.

Cell Cycle & Interphase

1.​ Interphase has three stages: G1 (cell growth), S (DNA replication), G2 (preparation for
mitosis, error checking).​

2.​ Cells can enter G0, a resting phase, if they are not dividing.​

MCQ focus: Functions of G1, S, G2, and G0; checkpoints during interphase.

Mitotic Phase

1.​ Prophase: Chromatin condenses into sister chromatids; mitotic spindle forms.​
 2.​ Prometaphase: Nuclear envelope breaks down; microtubules attach to kinetochores.​

3.​ Metaphase: Chromosomes align at the metaphase plate.​

4.​ Anaphase: Sister chromatids separate and move to opposite poles.​

5.​ Telophase: Nuclear envelope reforms; chromatin decondenses.​

6.​ Cytokinesis: Cleavage furrow forms and divides the cytoplasm into two cells.​

MCQ focus: Stages of mitosis; order of events; spindle and kinetochore roles.

Checkpoints & Regulation

1.​ Checkpoints monitor:​

○​ G1/S: Is the cell large enough?​

○​ G2/M: Is DNA replicated?​

○​ Metaphase: Are chromosomes aligned properly?​

2.​ Positive growth signals: Polypeptide hormones, growth factors, and cytokines.​

MCQ focus: Function of checkpoints; examples of growth factors (PDGF, IL-2, IGF).

Regulatory Proteins

1.​ Cyclins: Proteins synthesized and degraded cyclically in the cell cycle.​

2.​ Cyclin-dependent kinases (Cdks): Enzymes activated when bound to cyclins.​

○​ Cdk1-Cyclin B: G2 → M​

○​ Cdk2-Cyclin A/E: Initiates DNA synthesis in S phase​

○​ Cdk4/6-Cyclin D: G1/S progression​

 3.​ MPF (M-phase promoting factor): Complex of Cdk1 and Cyclin B that triggers mitosis.​

MCQ focus: Cdk-cyclin combinations; function of MPF; role of regulatory proteins in cell cycle
progression.

Diseases from Mitosis Errors

1.​ Cancer arises from uncontrolled cell division due to loss of tumor suppressors like p53,
pRb, PTEN.​

2.​ Cancer cells ignore density-dependent inhibition and divide excessively.​

MCQ focus: Causes of cancer related to mitotic regulation.

Meiosis

1.​ Meiosis occurs in reproductive organs (gametogenesis).​

○​ Spermatogenesis produces sperm in males.​

○​ Oogenesis produces ova in females.​

2.​ Meiosis reduces chromosome number by half and produces four haploid cells.​

3.​ Meiosis I: Homologous chromosomes separate.​

○​ Prophase I stages: Leptotene, Zygotene, Pachytene (crossing over), Diplotene,

Diakinesis​

○​ Metaphase I: Homologous chromosomes align at metaphase plate.​

○​ Anaphase I: Homologs separate; sister chromatids remain attached.​

MCQ focus: Difference between meiosis I and II; stages and events in prophase I; significance
of crossing over and independent assortment.
Holliday Model

1.​ Crossing over involves strand invasion and formation of Holliday junctions.​

2.​ Resolution produces:​

○​ N1: Splice (crossover) products – genetic material rearranged​

○​ N2: Patch (non-crossover) products – small hybrid region​

MCQ focus: Steps of Holliday junction formation and resolution; outcomes (crossover vs
non-crossover).

Significance of Meiosis

1.​ Maintains chromosome number in offspring.​

2.​ Introduces genetic variation through independent assortment (metaphase I) and

crossing over (prophase I).​

MCQ focus: Functions and importance of meiosis.

Diseases from Meiosis Errors

1.​ Meiotic nondisjunction can lead to trisomies, such as Down syndrome (trisomy 21).​

MCQ focus: Examples of nondisjunction disorders; difference between mitotic and meiotic
errors.

3) Resting Membrane Potential & Action Potential

1.​ Resting Membrane Potential (RMP) is typically around -70 mV. It is negative because
the membrane is more permeable to K⁺ than Na⁺, allowing K⁺ to leak out, while
negatively charged proteins and phosphate ions remain inside.​

2.​ Action Potential (AP) is a sudden reversal of membrane polarity caused by a stimulus.
AP is essential for nerve impulse transmission, muscle contraction, and activation of
 glands.​

3.​ The development of AP involves depolarization (Na⁺ influx), repolarization (K⁺ efflux),
refractory period (preventing immediate re-firing), and hyperpolarization (membrane
temporarily more negative than RMP).​

4.​ The size of an AP does not change; only the frequency can vary with the intensity of
the stimulus.​

5.​ Myelin sheath increases the speed of AP conduction via saltatory conduction. Schwann
cells form the sheath in the PNS, and oligodendrocytes in the CNS.​

Graded Potentials

1.​ Graded potentials are local changes in membrane potential confined to a small region of
the membrane.​

2.​ Types include receptor potential, synaptic potential, and pacemaker potential.​

3.​ Unlike APs, graded potentials vary in magnitude and can summate.​

Skeletal Muscle

1.​ Slow-twitch (Type I) fibers contract slowly, have a high oxidative capacity, more
mitochondria, better blood supply, and are resistant to fatigue.​

2.​ Fast-twitch (Type II) fibers contract rapidly, have low oxidative capacity, fewer
mitochondria, less blood supply, and fatigue more quickly.​

3.​ Exercise effects: Hypertrophy increases muscle size, while atrophy decreases it.​

Smooth Muscle

1.​ Smooth muscle cells are spindle-shaped, lack troponin, and contract when myosin is
phosphorylated.​

2.​ Actin filaments attach to dense bodies, and contraction draws dense bodies together.​

3.​ Two types:​

 ○​ Multi-unit: Each cell independently innervated; found in iris, blood vessels;
contraction is neurogenic.​

○​ Single-unit: Cells connected via gap junctions; contract as a syncytium; has

myogenic tone and rhythmic contraction.​

Cardiac Muscle

1.​ Cardiac muscle cells (cardiomyocytes) are smaller than skeletal muscle, contain a single
nucleus, many mitochondria, and rely on aerobic metabolism.​

2.​ Intercalated discs (desmosomes and gap junctions) allow rapid ion diffusion and
synchronized contraction.​

3.​ Two populations:​

○​ Working myocardial cells: Responsible for contraction and pumping.​

○​ Conducting tissue: Non-contractile, generates and conducts impulses

(automaticity).​

4.​ Properties: Automaticity, excitability, conductivity, contractility.​

Pacemaker Action Potential

1.​ Phase 4: Spontaneous depolarization due to gradual Na⁺ influx.​

2.​ Phase 0: Rapid depolarization (upstroke).​

3.​ Phase 3: Repolarization to around -60 mV.​

Resting Membrane & Action Potential

1.​ The resting membrane potential (RMP) is typically -70 mV, which occurs because the
membrane is more permeable to K⁺ than Na⁺, and due to the presence of non-diffusible
anions inside the cell.​

2.​ The sodium-potassium pump maintains RMP by moving 3 Na⁺ out and 2 K⁺ in, working
continuously.​
 3.​ An action potential (AP) is a sudden reversal of membrane polarity, important for impulse
transmission, muscle contraction, and glandular activation.​

4.​ AP develops when the membrane reaches threshold (-55 mV), Na⁺ channels open
(depolarisation), followed by K⁺ channel opening (repolarisation), and ends with a
refractory period and hyperpolarisation.​

5.​ The frequency of action potentials increases with stimulus intensity; the size of AP
remains constant.​

6.​ Myelination speeds up AP conduction via saltatory conduction; in PNS, Schwann cells
form myelin, and in CNS, oligodendrocytes do.​

7.​ Graded potentials are localized changes in membrane potential, unlike APs which are
all-or-none.​

Skeletal, Smooth, and Cardiac Muscle

1.​ Skeletal muscle fibers can be slow-twitch (high oxidative, fatigue-resistant) or fast-twitch
(low oxidative, faster contraction, fatigue quickly).​

2.​ Smooth muscle is spindle-shaped, lacks troponin, and contracts via dense bodies
drawing actin filaments together.​

3.​ Smooth muscle can be single-unit (syncytial, myogenic tone) or multi-unit (neurogenic,
individual contraction).​

4.​ Cardiac muscle cells (cardiomyocytes) are smaller, single-nucleated, highly aerobic,
connected by intercalated discs, and form a functional syncytium.​

5.​ Cardiac muscle exhibits automaticity, excitability, conductivity, and contractility; working
myocardial cells contract, while conducting tissue generates impulses.​

6.​ Pacemaker AP phases: Phase 4 (spontaneous depolarisation), Phase 0 (depolarisation),

Phase 3 (repolarisation).​

7.​ Exercise induces hypertrophy (increase in muscle size) or atrophy (decrease in muscle
size).​
Synapse & Neuronal Communication

1.​ Neurons communicate via electrical signals and neurotransmitters; chemical synapses
have a synaptic delay, while electrical synapses use gap junctions for direct ion flow.​

2.​ Post-synaptic activation occurs via ionotropic (ligand-gated) or metabotropic (second

messenger) receptors.​

3.​ Excitatory post-synaptic potentials (EPSPs) depolarize the post-synaptic neuron (e.g.,
cholinergic synapse).​

4.​ Inhibitory post-synaptic potentials (IPSPs) hyperpolarize the post-synaptic neuron (e.g.,
GABAergic synapse).​

5.​ Convergence is when multiple pre-synaptic neurons affect one post-synaptic neuron;
divergence is when one pre-synaptic neuron affects many post-synaptic neurons.​

Reflex Arc

1.​ Somatic reflexes activate skeletal muscle (e.g., stretch reflex, deep tendon reflex,
withdrawal reflex); autonomic reflexes activate smooth/cardiac muscle or glands (e.g.,
heart rate adjustment).​

2.​ Stretch reflex is monosynaptic and ipsilateral: muscle spindle detects stretch, sensory
neuron synapses directly on alpha motor neuron, causing contraction.​

3.​ Deep tendon reflex and withdrawal reflex are polysynaptic and ipsilateral; cross-extensor
reflex is polysynaptic and contralateral.​

4.​ Reflex circuits may be maintained by reverberating circuits for repetitive output.​

5.​ Golgi tendon organs monitor tendon tension; muscle spindles detect muscle length and
mediate stretch reflexes.

Important Notes (High-Yield)

Cellular Adaptation

●​ Atrophy: ↓ cell size & number; caused by ↓ workload, loss of innervation, ↓ blood supply,
aging.​
 ●​ Hypertrophy: ↑ cell size; due to ↑ functional demand, hormones, growth factors.​

●​ Hyperplasia: ↑ cell number; hormone or growth factor-induced.​

●​ Metaplasia: Replacement of one cell type with another; may lead to cancer.​

●​ Anaplasia: Loss of cellular differentiation; associated with malignancy.​

Causes of Cell Injury

●​ Hypoxia / Ischemia – e.g., blocked arteries, lung disease, anemia​

●​ Toxins – e.g., cigarette smoke, CO, ethanol, drugs​

●​ Infections – virus, bacteria, fungi, parasites​

●​ Immune reactions – autoimmune, allergies​

●​ Genetic abnormalities – chromosomal mutations, congenital disorders​

●​ Nutritional imbalances – deficiency/excess​

●​ Physical agents – trauma, extreme temperatures, radiation, shock​

Reversible Cell Injury

●​ Cellular swelling: ATP ↓ → ion pumps fail → Na⁺/Ca²⁺ influx → water enters →
organelle swelling.​

●​ Fatty change: lipid accumulation in hepatocytes; reversible; may cause organ

enlargement.​

Necrosis (Irreversible “Accidental” Cell Death)

●​ Cytoplasmic changes: ↑ eosinophilia, vacuolization​

 ●​ Nuclear changes: Pyknosis (shrink), Karyorrhexis (fragment), Karyolysis (dissolve)​

●​ Fates: Digestion by enzymes or dystrophic calcification​

Types of Necrosis:

1.​ Coagulative: Firm tissue; infarcts in solid organs (except brain)​

2.​ Liquefactive: Tissue digested → viscous liquid; CNS hypoxic death​

3.​ Gangrenous: Dry (ischemia) vs wet (bacterial infection)​

4.​ Caseous: Granular, amorphous; TB infection​

5.​ Fat: Focal fat destruction; pancreatitis, trauma​

6.​ Fibrinoid: Antigen-antibody deposits in vessel walls; vasculitis, transplant rejection​

Apoptosis (Regulated Cell Death)

●​ Physiologic causes: Development, tissue turnover, elimination of self-reactive

lymphocytes​

●​ Pathologic causes: DNA damage, misfolded proteins, infection​

●​ Mechani[Link]

○​ Extrinsic: Fas ligand → Fas receptor → caspase activation​

○​ Intrinsic: Mitochondrial cytochrome c release; balance of Bcl-2 family proteins​

●​ Morphology: Cell shrinkage, chromatin condensation, apoptotic bodies​

Acute Inflammation
Definition:

●​ Rapid response of vascularized tissues to infection or tissue damage​

 ●​ Brings leukocytes, plasma proteins to site → eliminates offending agents → initiates
tissue repair​

Causes:

1.​ Infection (bacteria, viruses, fungi, parasites)​

2.​ Tissue necrosis (ischemia, trauma, chemicals, burns)​

3.​ Foreign bodies​

4.​ Immune reactions (hypersensitivity, autoimmune disease)​

Cardinal signs (Celsus + Virchow):

1.​ Redness (Rubor) – vasodilation​

2.​ Heat (Calor) – increased blood flow​

3.​ Swelling (Tumor) – exudation​

4.​ Pain (Dolor) – chemical mediators (bradykinin, prostaglandins)​

5.​ Loss of function (Functio laesa) – swelling/pain​

Vascular Events

1.​ Vasodilation – increased blood flow → redness & heat​

2.​ Increased permeability – plasma proteins & leukocytes exit circulation →

edema/exudate​

3.​ Exudate vs Transudate:​

○​ Exudate: high protein, due to inflammation​

○​ Transudate: low protein, due to hydrostatic/osmotic imbalance​

Lymphatic response:
 ●​ Drain excess fluid & debris → lymphangitis/lymphadenitis​

●​ Enlarged nodes, follicular hyperplasia, more lymphocytes/macrophages​

Cellular Events

Neutrophil Extravasation:

1.​ Margination – leukocytes move to vessel periphery​

2.​ Rolling – weak interactions with endothelium​

3.​ Adhesion – firm attachment​

4.​ Diapedesis – transmigration through vessel wall​

5.​ Migration – chemotaxis to injury site​

Phagocytosis:

1.​ Recognition​

2.​ Engulfment → phagosome​

3.​ Fusion with lysosome → phagolysosome​

4.​ Degradation/killing​

Neutrophils vs Macrophages:

●​ Neutrophils: early response, short-lived​

●​ Macrophages: later response, cleanup & repair​

Mediators of Inflammation
 1.​ Cell-derived: mast cells, leukocytes, platelets, endothelial cells​

2.​ Plasma-derived: liver-produced proteins (complement, kinins)​

3.​ Prostaglandins: pain, fever, vasodilation, leukocyte chemotaxis (inhibited by NSAIDs)​

4.​ Short-lived, regulate each other​

Morphological Patterns

1.​ Serous: Clear fluid, e.g., skin blisters, burns​

2.​ Fibrinous: Fibrin exudate on serous membranes, e.g., pericarditis​

3.​ Suppurative/Purulent: Pus, abscess formation, neutrophil-rich​

4.​ Ulcer: Excavation of surface due to necrosis, e.g., peptic ulcer​

Outcomes of Acute Inflammation

1.​ Complete resolution – tissue returns to normal​

2.​ Abscess formation – localized pus​

3.​ Progression to chronic inflammation – persistent stimulus​

4.​ Scarring/Fibrosis – if tissue repair follows damage

Chronic Inflammation – Key Points

Definition

●​ Prolonged inflammation where tissue injury, inflammation, and repair coexist.​

●​ May follow acute inflammation or arise insidiously without acute signs.​

Causes

1.​ Persistent infections: e.g., mycobacteria, fungi, certain viruses → granulomatous

inflammation.​

2.​ Hypersensitivity diseases: Autoimmune (e.g., rheumatoid arthritis) or allergic (e.g.,

asthma).​

3.​ Prolonged exposure to toxic agents: Exogenous (silica) or endogenous (cholesterol in

atherosclerosis).​

Morphological Features

1.​ Mononuclear cell infiltration (macrophages, lymphocytes, plasma cells).​

2.​ Tissue destruction.​

3.​ Attempted healing: angiogenesis, fibrosis.​

Key Cells

●​ Macrophages: Dominant; phagocytosis, cytokine release, tissue repair.​

●​ Lymphocytes: CD4+ T cells promote inflammation; B cells for antibody production.​

●​ Eosinophils: Fight parasites, IgE-mediated reactions.​

●​ Mast cells: Release histamine, prostaglandins in allergic reactions.​

●​ Neutrophils: Present in chronic inflammation, phagocytosis, last for months.​

Systemic Effects

●​ Acute phase response: Fever, leukocytosis, increased acute phase proteins (CRP,
fibrinogen, SAA).​
 ●​ Other: Increased pulse/BP, shivering, malaise, sometimes DIC in severe infection.​

Granulomatous Inflammation

●​ Collection of activated macrophages (epithelioid cells), multinucleated giant cells, T

lymphocytes.​

●​ Types:​

1.​ Immune granulomas: Persistent T-cell response; often caseous (e.g., TB).​

2.​ Foreign body granulomas: Inert material, noncaseating (e.g., sutures, Crohn’s
disease).​

●​ Morphology: Activated macrophages, lymphocyte collar, possible fibrosis during healing.​

Healing and Repair

Definitions
●​ Healing: Replacement of injured cells by fibrous tissue (scar formation).​

○​ Examples: Myocardial infarction, stomach ulcer, surgical incision.​

●​ Regeneration: Replacement of injured cells by cells of the same type.​

○​ Requires intact basement membrane.​

○​ Examples: Skin, oral mucosa, liver (if mild injury).​

Tissue Regeneration
●​ Controlled by biochemical factors released in response to injury or trauma.​
 ●​ Maintains balance between stimulatory and inhibitory signals:​

○​ Shortens cell cycle​

○​ Decreases cell loss​

Cellular Proliferation Potential

1.​ Labile cells: Constantly dividing (epithelia, oral cavity, GI tract)​

2.​ Stable cells: Usually G0, low division; can proliferate when stimulated (liver, kidney,
pancreas)​

3.​ Permanent cells: Irreversible injury leads to scar (neurons, myocardium, skeletal
muscle)​

Intercellular Signaling

●​ Autocrine: Cell responds to its own factors (e.g., liver regeneration)​

●​ Paracrine: Cell responds to nearby cells (e.g., wound healing)​

●​ Endocrine: Cell responds to distant factors via blood (hormones)​

Growth Factors

●​ Polypeptides that stimulate proliferation, migration, differentiation, and remodeling.​

1.​ Epidermal growth factor (EGF): Keratinocytes, fibroblasts​

2.​ Vascular endothelial growth factor (VEGF): Angiogenesis​

3.​ Transforming growth factor (TGF): Fibrogenesis​

4.​ Platelet-derived growth factor (PDGF): Migration & proliferation of fibroblasts, smooth
muscle, monocytes​

Extracellular Matrix (ECM)

 ●​ Provides structural support, adhesion, and reservoir for growth factors.​

●​ Must remain intact for parenchymal healing.​

Components:

1.​ Collagen – structural protein, scar formation if damaged​

2.​ Adhesive glycoproteins – laminin, fibronectin, integrins (bind ECM & cells)​

3.​ Proteoglycans & hyaluronic acid – influence ECM permeability & structure​

Stages of Wound Healing

1.​ Hemostasis: Blood clot formation​

2.​ Inflammation: Neutrophils & macrophages remove debris​

3.​ Proliferation: Fibroblasts proliferate, granulation tissue forms​

4.​ Remodeling: Collagen deposition & scar formation​

8 Steps of Tissue Healing:

1.​ Inflammation induction​

2.​ Removal of dead tissue​

3.​ Migration & proliferation of connective tissue cells​

4.​ Angiogenesis & granulation tissue formation​

5.​ ECM synthesis & collagen deposition​

6.​ Tissue remodeling​

7.​ Wound contraction​

 8.​ Acquisition of tensile strength​

Granulation Tissue
●​ Pink, soft, bleeds easily​

●​ Composed of new blood vessels and fibroblasts​

●​ Angiogenesis: Budding of pre-existing vessels → endothelial migration, proliferation,

maturation​

Fibrosis (Fibroplasia)
●​ Proliferation of fibroblasts and ECM deposition within granulation tissue​

●​ Scar remodeling: Strengthened by metalloproteinases (interstitial collagenases,

gelatinases, stromelysins)​

●​ Debris cleared by phagocytosis​

Healing by Primary Intention

●​ Minimal tissue loss; wound edges approximated.​

●​ Timeline:​

○​ 24h: Neutrophils, basal membrane mitoses​

○​ 1–2d: Basal epithelial cells grow along wound​

○​ 3d: Macrophages enter; granulation tissue forms​

○​ 5d: Collagen bridges wound; epidermis restored​

 ○​ Week 2: Collagen accumulates; blanching occurs​

○​ 1 month: Connective tissue matured; epidermis intact​

○​ 6–8 months: Tensile strength 70–80%​

Healing by Secondary Intention

●​ Large tissue defects or purulent infection prevent direct approximation​

●​ Wound closes via granulation tissue formation and scar tissue remodeling​

Factors Influencing Healing

Local

●​ Wound size & site​

●​ Infection & foreign material​

●​ Blood supply​

●​ Excess movement​

●​ Radiation exposure​

●​ Locally applied drugs​

Systemic

●​ Age​

●​ Nutritional deficiency (Vitamin C, zinc)​

●​ Metabolic diseases (diabetes, renal failure)​

 ●​ Catabolic states (malignancy)​

●​ Drugs​

●​ Circulatory disorders (atherosclerosis)​

Complications of Wound Healing

1.​ Inadequate scar formation:​

○​ Wound dehiscence (gaping)​

○​ Ulceration (diabetic neuropathy)​

2.​ Hypertrophic scar / Keloid:​

○​ Excess collagen & fibroblast proliferation​

○​ Hypertrophic: confined to wound edges​

○​ Keloid: extends beyond wound boundaries​

3.​ Exuberant granulation tissue​

4.​ Wound contracture: Excess myofibroblast proliferation (burn victims)​

5.​ Delayed wound healing / chronic wounds – “DID NOT HEAL”​

○​ Drugs, Infection, Diabetes, Nutritional deficiency, Oxygen, Toxins,

Hypo-/hyperthermia, Excess tension, Acidosis, Local anesthetics

Medical Microbiology Notes

Definition
●​ Study of microbes (bacteria, fungi, viruses, parasites) that cause human infectious
disease.​
 ●​ Includes prions (infectious proteins) and parasites (protozoa, helminths, ectoparasites).​

Classification of Microbes
Bacteria

●​ Single-celled, prokaryotic, no nucleus.​

●​ Cell wall: peptidoglycan; may have fimbriae, pili, flagella.​

●​ Gram staining:​

○​ Gram-positive: thick peptidoglycan.​

○​ Gram-negative: phospholipid bilayer + LPS (endotoxin).​

○​ Acid-fast: high glycolic acid; resists Gram stain.​

●​ Shapes:​

○​ Cocci: circular​

○​ Bacilli: rod-shaped​

○​ Spiral/Helical: spirochetes​

Common Examples

●​ Gram-positive cocci: Staphylococcus aureus, Streptococcus pyogenes, Streptococcus

pneumoniae​

●​ Gram-negative cocci: Neisseria gonorrhoeae, Neisseria meningitidis​

●​ Gram-positive bacilli: Clostridium tetani, Bacillus cereus​

●​ Gram-negative bacilli: E. coli, Haemophilus influenzae, Helicobacter pylori,

Campylobacter jejuni​

●​ Spirochaetes: Treponema pallidum (syphilis), Borrelia burgdorferi (Lyme)​

Atypical bacteria mnemonic:​
“THESE ATYPICAL MICROBES USUALLY LACK COLOUR BECAUSE MICROBES
BARELY EAT RAMEN”

●​ Treponema, Anaplasmosis, Mycoplasma, Ureaplasma, Leptospira/Legionella,

Chlamydia, Bartonella, Mycobacteria, Borrelia, Ehrlichia, Rickettsia​

Special notes:

●​ Chlamydia: STI, trachoma​

●​ Rickettsia: tick/lice transmitted; typhus, RMSF​

●​ Acid-fast bacteria: Mycobacterium tuberculosis, M. leprae​

●​ Mycoplasma: no cell wall, resistant to antibiotics​

Fungi

●​ Eukaryotic, with nucleus; cell wall: mannan, chitin, glucans. Membrane: ergosterol.​

●​ Dimorphic: yeast ↔ filamentous (hyphae) depending on environment.​

●​ Reproduction:​

○​ Yeast: budding, binary fission​

○​ Filamentous fungi: hyphal extension​

●​ Pathogenic fungi:​

○​ Candida albicans – oral/vaginal candidiasis​

○​ Aspergillus – lung infections​

○​ Dermatophytes – ringworm​

●​ Types:​

○​ Superficial: skin, nail, hair (Tinea)​

 ○​ Subcutaneous: trauma → Sporothrix schenckii​

○​ Systemic: lungs → multiple organs​

○​ Opportunistic: immunocompromised hosts​

Viruses

●​ Non-living outside host; require host machinery.​

●​ Components: DNA/RNA genome, capsid, sometimes envelope.​

●​ Replication: attachment → entry → genome replication → assembly → release​

●​ Bacteriophages: lytic vs lysogenic cycles​

●​ Retrovirus: RNA → DNA via reverse transcriptase​

●​ Prions: infectious proteins causing spongiform encephalopathies​

Virus classification:

●​ DNA vs RNA, ss vs ds, enveloped vs non-enveloped, capsid symmetry

(icosahedral/helical/complex)​

Examples:

●​ ssDNA: Parvovirus, Papillomavirus​

●​ ssRNA (+): Picornavirus, Flavivirus, Coronavirus​

●​ ssRNA (-): Rhabdovirus, Filovirus, Orthomyxovirus​

●​ dsRNA: Reovirus​

Parasites
 ●​ Protozoa: unicellular eukaryotes, binary fission; some multiple life stages​

○​ Amoebae: Entamoeba histolytica – amoebiasis​

○​ Flagellates: Giardia lamblia – giardiasis​

○​ Sporozoans: Plasmodium spp – malaria​

●​ Helminths: multicellular worms​

○​ Cestodes (tapeworms): Taenia spp​

○​ Nematodes (roundworms): Ascaris, Hookworms​

○​ Trematodes (flukes): Schistosoma, Clonorchis​

●​ Ectoparasites: mosquitoes, ticks, mites, fleas, lice – vectors for multiple infections​

Key Clinical Associations

●​ Bacteria: infections ranging from pneumonia to food poisoning​

●​ Fungi: superficial, subcutaneous, systemic, opportunistic infections​

●​ Viruses: from mild respiratory infections to cancers and neurodegenerative disorders

(prions)​

●​ Parasites: gastrointestinal, systemic, blood-borne diseases​

Pathogenic Mechanisms of
Microorganisms
Key Terms
 ●​ Pathogenicity: Ability of a microorganism to cause disease.​

●​ Transmissibility: Ability to transfer from one host to another.​

●​ Infectivity: Ability to breach a host’s defense.​

●​ Invasiveness: Spread from initial site to other tissues (lymphatics, bloodstream, direct
extension, nerves).​

●​ Virulence: Measure of severity of disease caused.​

○​ LD50: Dose that kills 50% of hosts.​

○​ ID50: Dose that infects 50% of hosts.​

Virulence Determinants
1.​ Adhesion factors: Pili, fimbriae​

2.​ Capsules: Avoid host immune destruction​

3.​ Cell wall components: LPS (endotoxin) → fever, hypotension, septic shock​

4.​ Exotoxins: Secreted polypeptides → host cell damage, highly antigenic​

5.​ Extracellular enzymes: Protease, lipase, collagenase, hyaluronidase, leukocidins,

hemolysins​

Pathogenicity Spectrum
Course of Infection:

1.​ Incubation period: Exposure to first symptom​

2.​ Subclinical infection: No early symptoms, may remain asymptomatic​

 3.​ Clinical infection: Typical disease signs​

4.​ Recovery: Tissue heals, symptoms resolve​

5.​ Carrier state: Host appears healthy but can transmit infection​

Infection Process
1.​ Entry: Skin, inhalation, ingestion​

2.​ Colonization: Attachment to host tissue/cells​

3.​ Multiplication: Evades host defenses​

4.​ Damage: Host tissue injury​

Modes of Transmission
1.​ Direct contact: Sexual contact, transplacental (Syphilis, Gonorrhea, Flu)​

2.​ Indirect contact: Contaminated water, food, instruments (Vibrio cholerae, Salmonella,
Hepatitis A/E)​

3.​ Aerosol: Airborne bacteria & viruses (TB, Diphtheria, Influenza, Measles, Varicella)​

4.​ Vector: Arthropods (Mosquito – dengue, Wuchereria; Flies – Trypanosoma; Ticks –

Rickettsia, Yersinia pestis)​

5.​ Zoonoses: Animal-to-human diseases​

○​ Avian: Chlamydia psittaci, H5N1​

○​ Mammalian: Yersinia pestis, Bacillus anthracis, Rabies virus, H1N1​

Duration of Infection
●​ Acute: Rapid onset, short course​

●​ Chronic: Slow progression, may persist​

●​ Latent: Dormant, no active symptoms

Enzymes – Key Points

Structure & Function

●​ Proteins made of amino acids, usually globular.​

●​ Active site binds specific substrate → enzyme-substrate (ES) complex.​

●​ Functions:​

○​ Lower activation energy (Ea)​

○​ Increase reaction rate​

○​ Stabilize transition state​

Models of ES Interaction

1.​ Lock-and-key: Active site fits substrate perfectly.​

2.​ Induced fit: Active site molds around substrate for better fit.​

Activation Energy

●​ Enzymes provide alternate pathway → lower Ea.​

●​ Higher affinity for transition state than product → product dissociates easily.​

Factors Affecting Enzyme Activity

 ●​ Temperature: ↑ activity with temp, too high → denaturation.​

●​ pH: Optimal pH varies per enzyme.​

●​ Substrate concentration: ↑ rate until saturation (Vmax).​

Michaelis-Menten Kinetics

●​ Km: Substrate concentration at ½ Vmax; lower Km → higher enzyme affinity.​

●​ Vmax: Maximum reaction rate when enzyme saturated.​

●​ Graph: Initially linear (1st order), plateaus at saturation (0 order).​

Enzyme Regulation

1.​ Inhibition​

○​ Irreversible: Covalent, permanent binding.​

○​ Reversible: Non-covalent, can dissociate.​

■​ Competitive, non-competitive, uncompetitive​

2.​ Cofactors & Coenzymes: Non-protein helpers, often vitamins.​

3.​ Feedback inhibition: Product inhibits enzyme.​

4.​ Feedback repression: Product blocks enzyme synthesis at DNA level.​

5.​ Covalent modification: Phosphate groups alter activity.​

Hormones – Key Points

Definition

●​ Chemical messengers secreted into blood → target organs.​

●​ Functions: Growth, metabolism, reproduction, cognition, temperature & thirst regulation.​

Classification by Signaling
Type Action

Paracrine Neighboring cells

Autocrine Same cell (self)

Endocrine Distant cells via bloodstream

Classification by Solubility

●​ Lipophilic: Diffuse into cells → bind intracellular receptors → gene transcription

(Steroid, Thyroid)​

●​ Hydrophilic: Bind membrane receptors → activate second messengers (Peptide,

Amine)​

Hormone Types

1.​ Steroid hormones​

○​ Derived from cholesterol (e.g., testosterone, progesterone)​

○​ Lipophilic, intracellular receptor​

2.​ Peptide hormones​

○​ Amino acid chains, bind cell surface → second messengers (cAMP, Ca²⁺)​

○​ Example: Insulin​

■​ Binds receptor → IRS-1 → PI3K → GLUT4 → glucose uptake​

 ○​ Example: Glucagon​

■​ Binds G-protein receptor → PKA → glycogenolysis & gluconeogenesis​

3.​ Amine hormones​

○​ Derived from a single amino acid (e.g., phenylalanine derivatives)​

Quick Notes

●​ Enzyme activity = highly dependent on environment and substrate.​

●​ Hormones = specific, regulated, and classified by action, solubility, and chemical

nature.​

●​ Steroid vs peptide hormones: steroid = slow but long-lasting, peptide = fast but
short-acting.

✅ Nucleotide Structure, Metabolism &

DNA Replication — Condensed Notes

1. Nucleosides & Nucleotides — Basic Structure

Nucleotide = Base + Sugar + Phosphate

●​ Bond: 3’–5’ phosphodiester bond​

Nucleoside = Base + Sugar

●​ Bond: N-glycosidic bond​

Nitrogenous Bases
 1.​ Purines (2 rings) – Adenine, Guanine​

2.​ Pyrimidines (1 ring) – Cytosine, Thymine, Uracil​

Base pairing:

●​ A–T = 2 H-bonds​

●​ G–C = 3 H-bonds (stronger → ↑melting point)​

Pentose sugars

●​ Ribose (RNA)​

●​ Deoxyribose (DNA)​

Phosphates

●​ Can have 1, 2, or 3 phosphates → AMP, ADP, ATP​

2. Functions of Nucleotides
●​ Building blocks of DNA & RNA​

●​ Energy (ATP, GTP)​

●​ Coenzymes (NAD+, FAD, CoA)​

●​ Signalling (cAMP, cGMP)​

●​ Activator molecules (UDP-glucose)​

●​ Allosteric regulators​
3. De novo Synthesis of Nucleotides
Purine synthesis
Sources of atoms:

●​ Glutamine, Glycine, Aspartate, CO₂, formyl-THF​

Main steps:

1.​ Ribose-5-P → PRPP​

2.​ PRPP → IMP​

3.​ IMP → AMP & GMP​

4.​ → ATP/GTP → RNA​

5.​ Reduction → dATP/dGTP → DNA​

Drugs:

●​ Methotrexate inhibits dihydrofolate reductase → ↓THF → ↓purine synthesis​

●​ Anti-cancer drug (but affects all dividing cells)​

Pyrimidine synthesis
Steps:

1.​ Glutamine + CO₂ → Carbamoyl phosphate​

2.​ → Orotic acid​

3.​ Orotic acid + PRPP → UMP​

4.​ UMP → UTP → CTP​

 5.​ CTP → dCTP​

6.​ dUMP → dTMP (via thymidylate synthase)​

Drug:

●​ 5-fluorouracil (5-FU) inhibits thymidylate synthase​

Formation of deoxyribonucleotides
●​ Enzyme: Ribonucleotide reductase​

●​ Converts NDP → dNDP using NADPH​

4. Salvage Pathways
●​ Reuse purine/pyrimidine bases → saves energy​

●​ Enzyme: HGPRT​

5. Degradation of Nucleotides
Purines
Adenosine → Inosine → Hypoxanthine → Xanthine → Uric acid​
(Enzyme: xanthine oxidase)

Disorders

1. Gout
 ●​ ↑Uric acid → crystals in joints​

●​ Treatment: Allopurinol (inhibits xanthine oxidase)​

2. Lesch-Nyhan syndrome

●​ HGPRT deficiency​

●​ ↑Uric acid + self-mutilation + mental retardation​

3. ADA deficiency

●​ Toxic dATP builds up → SCID​

Pyrimidines
●​ Converted to β-alanine / β-aminoisobutyrate + CO₂ + NH₃​

Disorder

Hereditary orotic aciduria

●​ Defect in converting orotate → UMP​

●​ Symptoms: growth failure, megaloblastic anemia​

●​ Treatment: give uridine​

6. DNA Structure
●​ Double helix​
 ●​ Complementary & antiparallel (5’→3’ and 3’→5’)​

●​ Chromatin = DNA + histones​

○​ Euchromatin = active​

○​ Heterochromatin = inactive​

Telomeres

●​ TTAGGG repeats​

●​ Maintain chromosome ends​

●​ Shorten with age​

●​ Telomerase active in germ/stem cells and cancer cells​

7. DNA Replication (Semi-Conservative)

Key enzymes
●​ Helicase – unwinds DNA​

●​ SSB proteins – prevent re-annealing​

●​ Topoisomerase – removes supercoils​

●​ Primase – makes RNA primer​

●​ DNA Pol III – major synthesis + proofreading​

●​ DNA Pol I – removes RNA primer, fills gap​

●​ Ligase – joins Okazaki fragments​

Leading strand: continuous

Lagging strand: discontinuous (Okazaki fragments)

8. DNA Repair Mechanisms

1. Base Excision Repair

●​ Fixes small, non-bulky damage​

2. Mismatch Repair

●​ Fixes replication errors (post-replication)​

3. Nucleotide Excision Repair

●​ Removes bulky lesions e.g. thymine dimers​

●​ Defect → Xeroderma pigmentosum

1. DNA Transcription (Eukaryotes)

Key Concepts
●​ DNA → RNA by RNA polymerase​

●​ Occurs in nucleus​

●​ Uses exons (coding) & introns (non-coding)​

Promoters
●​ TATA box, CCAAT, GC box​

●​ Recognised by general transcription factors (TFII A, B, D, E, F, H)​

 ○​ TFIID binds promoter​

○​ TFIIF brings RNA Pol II​

○​ TFIIH unwinds DNA (helicase)​

Eukaryotic RNA Polymerases

1.​ RNA Pol I → rRNA (28S, 18S, 5.8S)​

2.​ RNA Pol II → mRNA + snRNA​

3.​ RNA Pol III → tRNA, 5S rRNA​

Stages
1.​ Initiation​

○​ Transcription factors + RNA Pol II bind promoter​

○​ DNA unwinds → transcription bubble​

2.​ Elongation​

○​ RNA strand grows 5’ → 3’​

3.​ Termination​

○​ Signals polyadenylation​

2. Post-Transcriptional Processing
1. 5' Capping
●​ Adds 7-methylguanosine​
 ●​ Protects RNA, helps export, aids translation start​

2. Splicing
●​ Introns removed, exons joined​

●​ Done by spliceosome​

●​ Allows alternative splicing → different proteins from same gene​

3. Polyadenylation
●​ AAUAAA signal​

●​ Adds ~200 A’s to 3’ end​

●​ Increases stability & translation​

3. Genetic Code — Features

1.​ Triplet codons​

2.​ Non-overlapping​

3.​ Has start (AUG) & stop codons​

4.​ Degenerate — multiple codons = same AA​

5.​ Read in fixed reading frame​

6.​ mRNA 5’→3’ corresponds to protein N→C terminus​

4. Translation (Protein Synthesis)
Occurs in cytoplasm on ribosomes.

Ribosomes
●​ Eukaryotic: 40S + 60S = 80S​

tRNA Charging
●​ Done by aminoacyl-tRNA synthetase​

●​ Ensures correct amino acid attaches to tRNA​

Initiation
1.​ eIF2 + GTP + Met-tRNA = ternary complex​

2.​ Joins with 40S → 43S complex​

3.​ Attaches to mRNA​

4.​ Scans for AUG in Kozak sequence​

Elongation
●​ tRNAs bring amino acids into ribosome​

●​ Peptide chain grows in A → P → E sites​

Termination
 ●​ Stop codon recognised by release factors​

●​ GTP-dependent release​

5. Post-Translational Modifications
1.​ Trimming — removing extra peptides​

2.​ Phosphorylation (Ser, Thr, Tyr)​

3.​ Hydroxylation (Pro, Lys) — e.g., collagen​

4.​ Carboxylation — Vitamin K dependent​

5.​ Glycosylation (N-linked, O-linked)​

6.​ Lipid addition (membrane anchoring)​

7.​ Protein folding​

○​ Chaperones: Hsp60, Hsp70​

6. Gene Expression Regulation

Prokaryotes
●​ Operons (lac, trp)​

Eukaryotes
●​ Enhancers (↑ transcription)​
 ●​ Silencers (↓ transcription)​

●​ Regulated by transcription factors​

●​ Translation regulated by eIF2 phosphorylation​

7. Reverse Transcriptase
●​ RNA → DNA​

●​ Used in viruses (HIV)​

●​ Used in labs to create cDNA​

●​ No proofreading → high mutation rate​

8. Antibiotics that Affect Protein Synthesis

Antibiotic Action

Streptomycin Binds 30S → blocks initiation

Tetracycline Blocks tRNA binding at A-site

Puromycin Causes premature chain

termination

Chloramphenicol Inhibits peptidyl transferase (50S)

Clindamycin/Erythromycin Block translocation (50S)

📌 Population Genetics — Important

Notes
1. Natural Selection & Genetic Variation
Population

A group of interbreeding individuals of the same species living in the same place and time.

Gene pool

All alleles carried by all individuals in the population.

Genetic variation is important because:

1.​ Allows adaptation to changing environments​

2.​ Increases biodiversity​

3.​ Helps populations survive diseases, climate change, etc.​

How variation arises

●​ Mutation​

●​ Migration​

●​ Genetic recombination​

●​ Natural selection​

●​ Genetic drift​

2. Hardy-Weinberg Law
Purpose

Predicts allele and genotype frequencies in a stable population.

Equation

p² + 2pq + q² = 1

●​ p² = frequency of homozygous dominant​

●​ 2pq = heterozygous carriers​

●​ q² = homozygous recessive (affected)​

●​ p + q = 1​

Conditions

Population must have:

1.​ Large population​

2.​ Random mating​

3.​ No mutation​

4.​ No migration​

5.​ No natural selection​

👉 If any condition is broken → allele frequencies change.

Example

If disease incidence (aa) = 1/1000 → q² = 1/1000 → q = √(1/1000)​

Used to estimate carrier frequency (2pq).

3. Factors Causing Changes in Genotype

Frequency
1. Mutation
 ●​ Creates new alleles​

●​ Usually rare, but essential for variation​

2. Migration (gene flow)

●​ Movement of individuals into or out of a population​

●​ Introduces or removes alleles​

3. Natural Selection

Organisms with favourable traits survive & produce more offspring.

Types of natural selection

1.​ Stabilising selection​

○​ Favors the intermediate trait​

○​ Reduces extremes​

○​ Example: human birth weight​

2.​ Directional selection​

○​ Favors one extreme​

○​ Shifts allele frequency in one direction​

○​ Example: antibiotic resistance​

4. Genetic Drift

Random change in allele frequency, especially in small populations.

a. Bottleneck effect

●​ Population drastically reduced​

●​ Loss of genetic variation​

●​ Example: natural disasters​

b. Founder effect

●​ Small group starts a new population​

●​ Reduced variation​

●​ Example: isolated island groups​

5. Non-random mating

●​ Mating based on preference or relatedness​

●​ Examples: inbreeding, consanguinity​

●​ Increases homozygosity → more recessive genetic disorders​

4. Mutation vs Polymorphism (brief –

detailed in another lecture)
Mutation

●​ Rare​

●​ Often harmful​

●​ May cause disease​

Polymorphism

●​ Common (>1% of population)​

●​ Usually harmless​

●​ Contributes to normal differences (height, eye color)​

2. Human Evolution
●​ Evolution: change in allele frequencies over generations​

●​ Human evolution: gradual change in the lineage leading to Homo sapiens​

●​ Key stages:​

○​ Early primates → Australopithecus → Homo habilis → Homo erectus → Homo

sapiens​

●​ Traits evolving in humans:​

○​ Bipedalism​

○​ Larger brain size​

○​ Reduced jaw size​

○​ Complex tools and culture​

3. Mechanisms of Speciation
●​ Speciation: formation of new species​

●​ Types:​

○​ Allopatric speciation: geographic isolation → reproductive isolation​

○​ Sympatric speciation: same area, but behavioral or ecological isolation​

 ○​ Parapatric speciation: adjacent populations with limited gene flow​

○​ Peripatric speciation: small population isolated at edge of main population​

●​ Key factors:​

○​ Natural selection​

○​ Genetic drift​

○​ Mutations​

○​ Reproductive isolation​

4. Evidence for Human Evolution

1.​ Fossil records: skulls, bones showing brain expansion & bipedalism​

2.​ Comparative anatomy: similar bone structure with primates​

3.​ Molecular biology: DNA similarity with chimpanzees (~98–99%)​

4.​ Embryology: similar early developmental stages in vertebrates​

5.​ Archaeology: tools, fire use, cave paintings​

5. Factors Influencing Speciation

●​ Geography: mountains, rivers, islands​

●​ Behavior: mating rituals, vocalizations​

●​ Ecology: habitat, diet, competition​

●​ Genetics: mutations, chromosomal changes​

📝 Quick Summary Table
Concept Key Points

Human evolution Change over generations in Homo sapiens

lineage

Speciation Formation of new species

Allopatric Geographic isolation

Sympatric Same area, reproductive isolation

Evidence Fossils, DNA, anatomy, embryology, archaeology

Mendelian Inheritance of Disease

Mendel’s Laws

1.​ Law of Segregation​

○​ Each individual has 2 alleles per gene.​

○​ Alleles segregate during gamete formation → each gamete carries 1 allele.​

○​ Explains monohybrid crosses.​

2.​ Law of Independent Assortment​

○​ Alleles of different genes assort independently.​

○​ Explains dihybrid crosses → 9:3:3:1 ratio.​

Exceptions to Mendel’s Laws

●​ Codominance: Both alleles expressed (e.g., AB blood group)​

●​ Incomplete dominance: Heterozygous phenotype intermediate (1:2:1)​

 ●​ Multiple alleles: More than 2 alleles exist, but only 2 per individual​

●​ Linkage: Genes on same chromosome do not assort independently​

●​ Non-nuclear inheritance: Mitochondrial genes​

Patterns of Inheritance
Autosomal

1.​ Dominant​

○​ Single copy → disease expressed​

○​ No carriers, 1:1 normal:affected​

○​ Examples: Brachydactyly, Marfan syndrome, Huntington’s disease​

2.​ Recessive​

○​ Two copies → disease expressed​

○​ Heterozygotes = carriers​

○​ Examples: Albinism, Cystic fibrosis, Tay-Sachs disease​

Sex-Linked

1.​ X-linked Recessive​

○​ Males affected; females can be carriers​

○​ Examples: Hemophilia, Color blindness, Duchenne Muscular Dystrophy​

2.​ Y-linked​

○​ Only males affected, father → son​

○​ Examples: Hypertrichosis of ears, XYY syndrome​

Mitochondrial

●​ Maternal inheritance only​

●​ Examples: MELAS, Leber’s hereditary optic neuropathy​

Monogenic vs Polygenic/Multifactorial Diseases

Feature Monogenic Polygenic/Multifactorial

Gene involvement Single gene Multiple genes

Mendelian pattern Yes No

Phenotype Usually discrete Quantitative/continuous (height, BP)

(present/absent)

Environmental Usually minimal Often significant

effect

Examples Cystic fibrosis, Huntington’s Diabetes, Hypertension, Schizophrenia,

disease Cleft lip

Polygenic Inheritance

●​ Many genes at different loci​

●​ Environment has little/no effect​

●​ Quantitative traits → continuous distribution​

●​ Example: Height, Intelligence, Skin colour​

Multifactorial Inheritance

●​ Genes + environment​

●​ Additive effect of multiple loci​

●​ Common in congenital malformations & chronic diseases​

 ●​ Examples: Cleft lip, Diabetes, CHD, Asthma, Neural tube defects

Single-Gene vs Polygenic Diseases

Feature Single-Gene Disorder Polygenic / Complex
Disease

Genetic cause Mutation in one gene Variants in multiple genes

Effect on phenotype Large effect Moderate effect per gene

Inheritance Mendelian (AD, AR, X/Y-linked) Non-Mendelian, unclear

Frequency Rare Common

Environmental influence Minimal Often major influence

Predictability of offspring High Low

Polygenic Traits
●​ Continuous / Quantitative: Traits show a range of phenotypes (e.g., height, blood
pressure). Often normally distributed.​

●​ Discontinuous / Dichotomous: Traits show yes/no outcome (e.g., disease threshold).

Liability determined by genetic + environmental factors.​

Recurrence risk:

●​ Risk of disease in relatives increases with more affected family members.​

Reasons for commonality:

1.​ High mutation rate​

2.​ Late-onset (after reproductive age)​

3.​ Selective advantage for carriers (e.g., thrifty gene hypothesis in type II diabetes)​
Genetic Variation
●​ Variations in DNA can be:​

○​ Harmless (phenotype unchanged)​

○​ Harmful (disease-causing)​

○​ Latent (manifest under specific conditions)​

Single-Nucleotide Polymorphism (SNP)

●​ Definition: Single base change in DNA sequence present in >1% of the population.​

○​ <1% → considered mutation​

●​ Location: Coding or non-coding regions (mostly non-coding)​

●​ Effect:​

○​ Coding SNPs → may alter protein​

○​ Non-coding SNPs → may serve as genetic markers​

●​ Importance:​

○​ Identify genetic predisposition to diseases​

○​ Predict drug response and personalized therapy​

○​ Each individual has a unique SNP profile​

Example of SNP Relevance

●​ Type II diabetes: Polygenic disease with major environmental influence​

○​ SNPs in genes related to insulin, glucose metabolism, and leptin can modify risk​
 ○​ Environmental factors (diet, exercise) interact with SNPs to determine disease
onset

Early Embryonic Development – Notes

1. Gametogenesis

Spermatogenesis (Male)

●​ Location: Seminiferous tubules of testes​

●​ Process: Primordial germ cell → Spermatogonium → Primary spermatocyte →

Secondary spermatocyte → Spermatid → Spermatozoa​

●​ Hormones:​

○​ GnRH → stimulates anterior pituitary → LH & FSH​

○​ LH → Leydig cells → Testosterone​

○​ FSH → Sertoli cells → Androgen-binding protein (ABP) + Inhibin​

●​ Sertoli cells: Nourish sperm, support maturation​

●​ Spermiogenesis: Formation of acrosome, condensation of nucleus, tail formation,

cytoplasm shedding​

Oogenesis (Female)

●​ Location: Ovaries​

●​ Process: Primordial germ cell → Oogonia → Primary oocyte → Secondary oocyte →

Ovum​

●​ Meiotic arrest: Primary oocyte arrests at diplotene of prophase I until puberty; secondary
oocyte arrests at metaphase II until fertilisation​

●​ Hormones:​

○​ FSH → Follicular cells → Estrogen → Prepares endometrium​

○​ LH → Luteal cells → Progesterone → Maintains endometrium​

 ●​ Ovulation: Release of secondary oocyte from Graafian follicle​

●​ Corpus luteum: Produces progesterone & estrogen, supports early pregnancy​

2. Fertilisation

Prerequisites:

1.​ Capacitation – Removal of glycoproteins from sperm head → hypermotility​

2.​ Acrosomal reaction – Sperm enzymes penetrate zona pellucida​

3.​ Fast block to polyspermy – Sodium influx → membrane depolarisation​

4.​ Slow block to polyspermy – Cortical reaction → zona hardening​

Steps:

1.​ Penetration of corona radiata​

2.​ Penetration of zona pellucida​

3.​ Fusion of sperm and oocyte membranes​

4.​ Completion of meiosis II → formation of zygote​

3. Cleavage & Blastocyst Formation

●​ Cleavage: Rapid mitotic division of zygote → blastomeres → morula (16+ cells)​

●​ Blastulation: Morula → Blastocyst​

○​ Outer cell mass → Trophoblast → Cytotrophoblast + Syncytiotrophoblast​

○​ Inner cell mass → Embryoblast → Epiblast + Hypoblast​

●​ Implantation: Blastocyst embeds into endometrium (fundus)​

 ○​ Syncytiotrophoblast secretes hCG → maintains corpus luteum​

●​ Abnormal implantation: Ectopic pregnancy, Hydatidiform mole​

4. Bilaminar & Trilaminar Germ Discs

Bilaminar disc (Week 2):

●​ Epiblast → dorsal layer​

●​ Hypoblast → ventral layer​

●​ Amniotic cavity (AC) above epiblast, yolk sac (YS) below hypoblast​

Gastrulation (Week 3):

●​ Formation of primitive streak and primitive groove​

●​ Epiblast cells migrate:​

○​ Replace hypoblast → Endoderm​

○​ Form layer between epiblast & hypoblast → Mesoderm​

○​ Remaining epiblast → Ectoderm​

●​ Mesoderm derivatives:​

○​ Paraxial → Somites → Muscle, axial skeleton, dermis​

○​ Intermediate → Kidneys, gonads​

○​ Lateral plate → Splanchnic → GI, heart; Somatic → body wall​

5. Notochord & Neurulation

●​ Notochord: Formed by cells migrating through primitive pit​

 ○​ Lies beneath ectoderm, above endoderm​

○​ Functions: Induces neural plate, forms nucleus pulposus in adult​

●​ Neurulation: Neural plate → Neural folds → Neural tube (CNS)​

○​ Neural crest cells → PNS, sensory ganglia, melanocytes, craniofacial structures​

●​ Neuropores:​

○​ Anterior → brain; Posterior → spinal cord​

○​ Folate necessary for closure​

○​ Defects:​

■​ Anterior → Anencephaly, Encephalocele​

■​ Posterior → Spina bifida​

6. Germ Layer Derivatives

Germ Derivatives
Layer

Ectoderm CNS, PNS, epidermis, hair, nails, pituitary, mammary/sweat glands, enamel,
sensory epithelium (eye, ear, nose)

Mesoderm Paraxial: muscles, axial skeleton, dermis

Intermediate: kidneys, gonads
Lateral: heart, GI muscular/connective, pleura/pericardium/peritoneum

Endoderm GI & respiratory epithelium, liver, pancreas, thyroid, parathyroid, bladder

epithelium, tympanic cavity lining

Placodes:

●​ Otic → Ear​

●​ Optic → Lens of eye

Growth Hormone & IGF-I – Notes
1. Synthesis and Structure

●​ GH (Somatotrophin): Major growth-regulating hormone, 191 amino acids, MW 22 kDa,

2 disulfide bonds​

●​ Produced by somatotrophs in anterior pituitary​

●​ Similar AA sequence to prolactin and chorionic somatomammotropin →

growth-promoting & lactogenic effects​

2. GH Receptor

●​ MW: 70 kDa​

●​ GH binds → dimerisation of receptor → activation of JAK2 tyrosine kinase​

●​ Signalling pathways:​

1.​ STAT proteins → gene transcription​

2.​ MAP kinase​

3.​ PI3 kinase​

4.​ PLC → DAG → PKC​

3. Regulation of GH Secretion

●​ Hypothalamic control:​

○​ GHRH → stimulates GH​

○​ GHIH (Somatostatin) → inhibits GH (also from pancreatic D cells)​

●​ Feedback: High GH → ↑GHIH, ↓GHRH​

 ●​ Other factors:​

○​ Glucose ↑ → GH ↓; Hypoglycemia → GH ↑​

○​ Amino acids ↑ → GH ↑​

○​ Fatty acids ↑ → GH ↓​

○​ Stress & sleep rhythms also modulate GH​

4. Physiological & Biochemical Actions

Growth

●​ GH stimulates growth indirectly via IGFs​

○​ IGF-I (Somatomedin C):​

■​ Liver-derived, acts on epiphyseal plates → linear bone growth​

■​ Enhances sulfate incorporation into cartilage​

○​ IGF-II: Plasma levels ~2x IGF-I, binds to membrane receptors​

Protein Metabolism

●​ ↑ Amino acid uptake in muscle​

●​ ↑ RNA & DNA synthesis​

Carbohydrate Metabolism

●​ Antagonises insulin → ↑ gluconeogenesis, ↓ tissue glucose uptake​

●​ ↑ hepatic glycogen synthesis​

●​ Chronic excess → risk of diabetes​

Lipid Metabolism
 ●​ Stimulates lipolysis → ↑ free fatty acids (FA) & glycerol​

●​ FA oxidized → acetyl-CoA → ketone bodies​

●​ Conserves glucose​

Mineral Metabolism

●​ ↑ Calcium, phosphate, magnesium retention​

●​ ↑ Na⁺, K⁺, Cl⁻ retention​

Energy Metabolism

●​ Muscle & adipose: FA used preferentially for energy​

●​ Glucose & AA oxidation decreased​

●​ AA used for protein synthesis​

Prolactin-like Effects

●​ GH binds lactogenic receptors → stimulates mammary glands, lactogenesis​

5. Disorders of GH Secretion

Hyposecretion

●​ Infancy: Growth failure​

●​ Children: Dwarfism – responds to recombinant GH therapy​

●​ Laron-type dwarf: GH receptor defect → low IGF-I​

●​ Pygmies: Post-receptor defect​

●​ GH fails to rise after hypoglycemia​

Hypersecretion
 ●​ Usually due to pituitary tumour​

●​ Children: Gigantism (before epiphyseal closure)​

●​ Adults: Acromegaly (after epiphyseal closure)​

○​ Facial & acral changes (jaw, nose, hands, feet)​

●​ Diagnostic test: GH levels + oral glucose tolerance test (GH fails to suppress)

Hypothalamo-Hypophyseal Axis & Pituitary Gland

Anterior Pituitary (Adenohypophysis)

●​ Secretes trophic hormones: GH, FSH, LH, TSH, ACTH, prolactin​

●​ Secretion is pulsatile and under feedback control from hypothalamus and target
organs.​

●​ Diseases: Excess → hormone hypersecretion syndromes; Deficiency → inherited or

acquired.​

Posterior Pituitary (Neurohypophysis)

●​ Stores ADH (vasopressin) and oxytocin from hypothalamic neurons.​

●​ ADH: Concentrates urine, retains water, vasoconstriction → ↑BP​

●​ Oxytocin: Stimulates milk ejection postpartum​

ADH Disorders
1. SIADH (ADH Excess)

●​ Low urine volume, high urine concentration​

●​ Plasma volume ↑, hyponatremia​

 ●​ Causes: Brain injury, infections, hypothyroidism, malignancy (small-cell lung CA), drugs
(SSRIs, carbamazepine)​

●​ Symptoms: Headache, confusion, nausea, coma​

2. Diabetes Insipidus (ADH Deficiency)

●​ High urine volume, low urine concentration​

●​ Types:​

○​ Central (Cranial) DI: ↓ADH production​

○​ Nephrogenic DI: Kidney resistance to ADH (V2 receptor or aquaporin defects)​

●​ Symptoms: Polyuria, polydipsia, enuresis, nocturia​

●​ Diagnosis:​

○​ 24h urine output & osmolarity​

○​ Water deprivation test​

○​ Desmopressin (DDAVP) test to differentiate central vs nephrogenic​

Growth Hormone (GH)

Physiology

●​ Produced by somatotropes of anterior pituitary​

●​ Stimulated by GHRH, inhibited by somatostatin​

●​ Influenced by glucose, amino acids, fatty acids, stress, sleep​

Actions

●​ Growth: via IGF-I → bone, cartilage, soft tissue​

 ●​ Protein: ↑AA uptake, ↑RNA/DNA synthesis​

●​ Carbohydrate: Antagonizes insulin → ↑gluconeogenesis, ↓glucose uptake​

●​ Lipid: ↑lipolysis → free FA used as energy​

●​ Mineral: Positive Ca²⁺, Mg²⁺, PO₄³⁻ balance​

Disorders

●​ Hyposecretion:​

○​ Infancy → dwarfism​

○​ Laron dwarf → GH receptor defect​

○​ Pygmies → post-receptor defect​

●​ Hypersecretion:​

○​ Gigantism: before epiphyseal plate closure​

○​ Acromegaly: after epiphyseal closure​

Hormonal Dysfunction Types

●​ Primary: Target gland disorder​

●​ Secondary: Pituitary disorder​

●​ Tertiary: Hypothalamic disorder​

Evaluation of Pituitary Disorders

GH Deficiency
 ●​ Dynamic/Provocative Tests: Insulin tolerance (hypoglycemia), stress, glucagon, sleep,
GHRH​

●​ Interpretation: ↑GH → sufficient reserve; no ↑GH → deficiency​

GH Excess (Gigantism/Acromegaly)

●​ Static Test: Serum IGF-I​

●​ Suppression Test: Oral glucose tolerance test​

○​ Normal: glucose suppresses GH​

○​ Acromegaly: failure to suppress​

Hyperprolactinemia

●​ ↑Prolactin → galactorrhea, hypogonadism (amenorrhea, infertility)​

●​ Test: Basal prolactin, neuroimaging; dynamic tests not helpful​

Panhypopituitarism

●​ Loss of multiple anterior pituitary hormones (GH, LH, FSH, ACTH, TSH)​

●​ Causes: infarction, trauma, tumor, iatrogenic, infiltrative​

●​ Tests: Sequential stimulation tests (GHRH, GnRH, CRH)​

Neoplasia & Tumours

Key Definitions

●​ Normal cell: No atypia, pleomorphism, or dysplasia​

●​ Neoplasia: Excessive, uncontrolled cell proliferation​

●​ Tumour: Abnormal tissue growth causing swelling​

 ●​ Benign: Localized, slow-growing, non-invasive​

●​ Malignant: Invasive, fast-growing, metastasizes​

Special terms:

●​ Adenoma: Benign glandular tumour​

●​ Carcinoma: Malignant epithelial tumour​

●​ Sarcoma: Malignant mesenchymal tumour​

●​ Hamartoma: Benign, normal tissue but disorganized​

●​ Choristoma: Normal tissue in abnormal location​

●​ Dysplasia: Disordered arrangement of cells (precursor lesion)​

●​ Carcinoma in situ: Severe, irreversible dysplasia​

●​ Metastasis: Spread to distant organs​

Non-Neoplastic vs Neoplastic Proliferation

Feature Non-Neoplastic Neoplastic

Control Controlled, reversible Uncontrolled,

irreversible

Polyclonal/Monoclonal Polyclonal Monoclonal

Growth Hypertrophy, hyperplasia, metaplasia, Benign or malignant

dysplasia

Benign Tumours
●​ Slow-growing, capsulated, non-invasive​
 ●​ Do not metastasize​

●​ Well-differentiated​

●​ Few mitoses, normal nuclear-cytoplasm ratio (1:4)​

●​ Naming: Suffix “-oma”​

Examples

●​ Fibroma, osteoma, chondroma, lipoma, adenoma, papilloma​

Malignant Tumours
●​ Fast-growing, unencapsulated, invasive​

●​ Metastasize via lymph, blood, or seeding​

●​ Well to poorly differentiated, often anaplastic​

●​ Many mitoses, hyperchromatic nuclei, high N:C ratio (1:1)​

●​ Naming:​

○​ Epithelial: Carcinoma (adenocarcinoma for glandular)​

○​ Mesenchymal: Sarcoma​

Examples

●​ Fibrosarcoma, osteosarcoma, chondrosarcoma, liposarcoma, adenocarcinoma,

squamous cell carcinoma​

Molecular Basis of Cancer

 ●​ DNA damage → failure to repair → mutation → uncontrolled proliferation​

●​ Key genes:​

1.​ Proto-oncogenes → oncogenes (growth-promoting)​

2.​ Tumour suppressor genes (loss → cancer)​

3.​ Apoptosis-regulating genes (failure → cell survival)​

Carcinogenesis steps:

1.​ Initiation – DNA damage​

2.​ Promotion – proliferation of damaged cells​

3.​ Latency – time between promotion and progression​

4.​ Progression – malignant transformation​

Hallmarks of malignant cells:

●​ Sustained growth signals​

●​ Evade growth suppressors​

●​ Genome instability​

●​ Resist apoptosis​

●​ Angiogenesis​

●​ Invasion & metastasis​

●​ Avoid immune detection​

Tumour Progression & Metastasis

Metastasis Pathways
 1.​ Seeding: Body cavities (e.g., colon → peritoneum)​

2.​ Lymphatic spread: Carcinomas​

3.​ Hematogenous spread: Sarcomas​

Metastatic Cascade

1.​ Intravasation – tumour cells enter vessels​

2.​ Tumour cell embolus – tumour + platelets/lymphocytes​

3.​ Extravasation – exit vessel & invade tissue​

Enzymes:

●​ Matrix metalloproteinases (MMPs): degrade ECM, basement membrane → invasion &

angiogenesis​

Nomenclature Summary
Tissue Benign Malignant

Fibrous Fibroma Fibrosarcoma

Bone Osteoma Osteosarcoma

Cartilage Chondroma Chondrosarcoma

Fat Lipoma Liposarcoma

Glandular Adenoma Adenocarcinoma

Squamous/Transitiona Papilloma Squamous/Transitional Cell Carcinoma

l

Exceptions:

●​ Leukemia – malignant blood cancer​

 ●​ Lymphoma – malignant lymphoid tumour​

●​ Glioma – benign/malignant glial tumour​

●​ Hepatoma – adenoma or carcinoma​

●​ Melanoma – malignant skin tumour​

●​ Seminoma – malignant testicular tumour​

●​ Teratomas – from germ layers, can be benign or malignant

Carcinogenesis and Carcinogenic Agents

Learning Outcomes

1.​ Understand physical, chemical, and biological causes of cancer.​

2.​ Understand molecular basis of oncogenesis.​

Characteristics of Malignant Cells (Hallmarks of Cancer)

●​ Sustained proliferative signalling → continuous growth​

●​ Evade growth suppressors → ignore cell cycle checkpoints​

●​ Resist cell death → limit apoptosis​

●​ Enable replicative immortality → telomerase activation​

●​ Induce angiogenesis → blood supply for growth​

●​ Activate invasion & metastasis → spread to other tissues​

●​ Genome instability & mutations → mutator phenotype​

●​ Deregulate cellular energetics → increased glycolysis​

 ●​ Tumour-promoting inflammation​

●​ Avoid immune destruction​

Tumour Genetics
●​ Proto-oncogenes → normal genes; when activated → oncogenes → uncontrolled
growth​

●​ Tumour suppressor genes (TSG) → inhibit cell growth; both alleles must be inactivated
to cause hyperproliferation (e.g., p53)​

●​ Genes regulating apoptosis → mutations prevent programmed cell death​

Principles of Carcinogenesis
1.​ Initiation → DNA mutation (from chemical, radiation, viral exposure)​

2.​ Promotion → non-tumorigenic agents induce proliferation (reversible)​

3.​ Transformation → neoplastic conversion​

4.​ Progression → accumulation of mutations → malignancy​

Carcinogenic Agents
1. Chemical Carcinogens

●​ Pro-carcinogens require metabolic activation​

●​ Examples: benzene, aflatoxin B, nitrosamines, vinyl chloride​

●​ Mechanism: Initiation → Promotion → Transformation​

 ●​ Promotion is reversible; initiator + promoter sequence matters​

2. Ionizing Radiation

●​ Includes X-rays, gamma rays, alpha/beta particles, neutrons​

●​ Mechanism:​

○​ Direct DNA damage → mutations & translocations​

○​ Indirect via free radicals from water​

●​ Target organs: bone marrow (leukemia), thyroid (cancer in children), lung (radon
exposure)​

3. UV Radiation

●​ Induces pyrimidine dimers → DNA mutations​

●​ Major risk: squamous cell carcinoma, basal cell carcinoma, melanoma​

●​ Fair-skinned individuals at higher risk​

●​ Basal cell carcinoma rarely metastasizes​

4. Oncogenic Microbes

●​ Viruses:​

○​ HPV 16 & 18 → cervical carcinoma​

○​ EBV → Burkitt lymphoma, nasopharyngeal carcinoma​

○​ HBV/HCV → hepatocellular carcinoma​

○​ KSHV → Kaposi sarcoma​

○​ HTLV → adult T-cell leukemia​

●​ Bacteria:​
 ○​ H. pylori → stomach cancer​

Mechanisms of Carcinogenesis
1.​ Growth promotion:​

○​ Overexpression of growth factors/receptors (e.g., EGF, Ras) → gain-of-function

mutations​

2.​ Loss of tumour suppressor gene function:​

○​ Cells escape growth inhibition → loss of adhesion, basement membrane invasion​

3.​ Limitation of apoptosis:​

○​ Overexpression of anti-apoptotic genes (e.g., Bcl-2) prevents cell death​

Key Concepts
●​ Malignant transformation = multi-step process of DNA damage → mutation → clonal
expansion → invasion & metastasis​

●​ Oncogenesis = molecular/cellular changes leading to uncontrolled cell proliferation​

●​ Chemical/radiation/biological agents can initiate or promote cancer

Clinical Aspects of Neoplasia

Learning Outcomes

1.​ Recognize clinical features of benign & malignant tumours​

2.​ Understand paraneoplastic syndromes​

3.​ Know common paraneoplastic syndromes in malignancy​

 4.​ Discuss laboratory investigations, grading, staging, and diagnosis​

Host Factors Affecting Tumour Growth

●​ Blood supply: Tumours secrete angiogenic factors (e.g., FGF)​

●​ Hormones: Hormone-sensitive tumours grow faster with excess hormones​

●​ Immune response: Host immunity vs tumour evasion​

Tumour-Host Interactions
1. Local Effects

●​ Tumour impingement: Pressure on organs​

○​ Pituitary adenoma → optic nerve​

○​ Pancreatic carcinoma → bile duct​

○​ Esophageal carcinoma → lumen obstruction​

●​ Ulceration/Bleeding:​

○​ Colon cancer → blood in stool​

○​ Gastric cancer → vomiting blood​

○​ Renal cell carcinoma → hematuria​

●​ Infection (obstruction):​

○​ Lung carcinoma → pneumonia​

○​ Cervical carcinoma → urinary infections​

 ●​ Rupture/Infarction:​

○​ Ovarian, hepatic, adrenal, metastatic melanoma​

2. Cancer Cachexia

●​ Weight loss >20%, weakness, anorexia, anaemia​

●​ Caused by:​

○​ Increased metabolism​

○​ Hypothalamic effects​

○​ TNF-α from macrophages​

3. Paraneoplastic Syndromes

●​ Effects of hormones or bioactive factors from tumours​

●​ Occurs in ~10–15% of patients​

●​ May be earliest sign of hidden tumour​

●​ Common syndromes: anaemia, hypercoagulability, hypercalcemia, cachexia​

Examples:

Tumour Type Syndrome Mediator

Small cell lung Cushing ACTH/ACTH-like

Bronchial carcinoid, pancreatic Carcinoid Serotonin, bradykinin

Renal carcinoma, HCC Polycythaemia Erythropoietin

SCC lung, breast Hypercalcemia PTHrP, TGF-α, TNF, IL-1

Tumour Diagnosis
Clinical & Radiological

●​ History & examination​

●​ Procedures: Endoscopy, laparoscopy​

●​ Imaging: X-ray, US, CT, MRI​

Morphological

●​ Cytology: Pap smear, FNAC​

●​ Biopsy: Histopathology, molecular markers​

Grading & Staging

●​ Grading: Cell differentiation & aggressiveness​

●​ Staging (TNM):​

○​ T: Tumour size​

○​ N: Lymph node involvement​

○​ M: Metastasis presence​

Diagnostic Methods
●​ Histology: H&E slides, FFPE, gene arrays​

●​ Immunohistochemistry (IHC): Tumour subclassification, differentiation​

●​ Molecular: PCR, FISH, flow cytometry​

●​ Biochemical assays: Tumour markers​

Examples of Tumour Markers
Marker Associated Tumour Notes

PSA Prostate carcinoma Organ-specific, not cancer-specific

α-Fetoprotein HCC, embryonal tumours Also in congenital abnormalities

(AFP)

CEA Colorectal, pancreatic Monitoring disease, not primary

carcinoma diagnosis

Histologic Progression Example: Breast Cancer

Normal → Florid proliferation → ADH (Atypical Ductal Hyperplasia) → DCIS (Ductal Carcinoma
in situ) → Invasive carcinoma

Clinical Aspects of Neoplasia

Host Factors Affecting Tumour Growth

1.​ Blood supply – Tumours secrete angiogenic factors (e.g., FGF).​

2.​ Hormones – Hormone-dependent tumours grow faster with more hormone.​

3.​ Immunology – Balance between host immune response and tumour resistance.​

Tumour-Host Interactions

1.​ Local Effects​

○​ Impingement: Pituitary adenoma → optic nerve; Pancreatic carcinoma → bile

duct​

○​ Ulceration/Bleeding: Colon → stool; Gastric → vomit; Renal → urine​

 ○​ Infection: Blocked bronchi → pneumonia; Blocked ureters → UTI​

○​ Rupture/Infarction: Ovary, liver, adrenal, melanoma metastases​

2.​ Cancer Cachexia​

○​ Weakness, anorexia, anaemia, >20% weight loss​

○​ Mediated by hypothalamus & TNF-α​

3.​ Paraneoplastic Syndromes​

○​ Hormones/factors secreted by tumours (10–15% of patients)​

○​ Examples:​

■​ Small cell lung cancer → Cushing’s (ACTH)​

■​ Bronchial carcinoid/pancreas → Carcinoid syndrome (serotonin,

bradykinin)​

■​ Renal/HCC → Polycythaemia (EPO)​

■​ SCC lung/breast → Hypercalcemia (PTHrP, TGF-α, TNF, IL-1)​

Diagnosis of Tumours

1.​ Clinical & Radiology​

○​ History, examination, endoscopy, laparoscopy​

○​ Imaging: X-ray, USG, CT, MRI​

2.​ Morphological Methods​

○​ Cytology (Pap smear, FNAC)​

○​ Biopsy (Histopathology, molecular markers)​

Grading vs Staging

●​ Grading: Differentiation of tumour cells; predicts aggressiveness​

●​ Staging: Extent of spread; TNM system​

○​ T: Tumour size​

○​ N: Lymph node involvement​

○​ M: Metastasis​

Laboratory & Molecular Diagnosis

●​ Histology: H&E staining, FFPE, gene arrays​

●​ Immunohistochemistry (IHC): Tumour differentiation, mitotic rate​

●​ Flow cytometry: Cell surface proteins, DNA content​

●​ FISH: Identify genetic abnormalities, sub-classify tumours​

●​ Tumour markers: PSA, AFP, CEA – used for screening, prognosis, follow-up​

Immune Surveillance & Tumour-Host

Reactions
Immune Surveillance

●​ Detects & destroys early tumour cells​

●​ Cells involved: CD4+ Th1, CD8+ CTLs, NK cells​

●​ Cytokines: IFN-γ inhibits tumour growth & angiogenesis​

Immune Evasion by Tumours

1.​ Loss/mutation of MHC → no antigen presentation​

2.​ Secretion of immunosuppressive cytokines (TGF-β, IL-10)​

3.​ Expression of inhibitory surface proteins​

Evidence of Immune Response

●​ Immune responses to tumour antigens: mutated oncogenes, tumour suppressor genes,

oncofetal antigens (AFP, CEA), altered glycoproteins​

●​ Lymphocytes infiltrate tumours​

●​ Some tumours regress spontaneously​

Tumour Immunoediting

Three Phases:

1.​ Elimination: Immune cells destroy tumour; IFN-γ inhibits growth​

2.​ Equilibrium: Dormant tumour cells persist; Th1, IL-12, IFN-γ maintain control​

3.​ Escape: Tumour evades immune system; progresses & metastasizes​

Methods of Escape:

●​ Antigenic modulation​

●​ Low immunogenicity (down-regulate MHC I)​

●​ Tumour-induced immunosuppression​
Tumour Markers

●​ Purpose: Screening, differential diagnosis, staging, monitoring recurrence​

●​ Types: Diagnostic, prognostic, predictive, DNA/protein markers​

●​ Examples:​

○​ Hormones/Enzymes: AFP → HCC, PSA → prostate carcinoma​

○​ Oncofetal Antigens: CEA → colorectal/pancreatic carcinoma​

●​ Lab Tests: ELISA, Flow cytometry, FISH, Karyotyping, IHC