const pptxgen = require("pptxgenjs");

const pres = new pptxgen();
pres.layout = "LAYOUT_16x9";
pres.title = "Cytokines: Health and Disease";
pres.author = "Pathology Residency Education";

// ─── COLOUR PALETTE ───────────────────────────────────────────────
const C = {
  bg:       "0D1B2A",   // deep navy  (dominant bg)
  bgAlt:    "132438",   // slightly lighter navy
  bgLight:  "1A3050",   // card bg
  accent:   "4FC3F7",   // sky-blue accent
  accent2:  "EF9A9A",   // soft coral (pro-inflammatory)
  accent3:  "A5D6A7",   // soft green  (anti-inflammatory)
  accent4:  "FFE082",   // amber (therapeutic)
  white:    "FFFFFF",
  grey:     "B0BEC5",
  dark:     "0D1B2A",
};

// ─── HELPER FUNCTIONS ─────────────────────────────────────────────
function titleSlide(title, subtitle) {
  const s = pres.addSlide();
  s.addShape(pres.ShapeType.rect, { x: 0, y: 0, w: "100%", h: "100%", fill: { color: C.bg } });
  // accent stripe
  s.addShape(pres.ShapeType.rect, { x: 0, y: 4.8, w: "100%", h: 0.08, fill: { color: C.accent } });
  s.addText(title, {
    x: 0.6, y: 1.4, w: 8.8, h: 1.8,
    fontSize: 44, bold: true, color: C.white, align: "center",
    fontFace: "Calibri Light",
  });
  s.addText(subtitle, {
    x: 0.6, y: 3.3, w: 8.8, h: 0.8,
    fontSize: 20, color: C.accent, align: "center", fontFace: "Calibri",
  });
  s.addText("Pathology Residency | June 2026", {
    x: 0.6, y: 4.9, w: 8.8, h: 0.4,
    fontSize: 13, color: C.grey, align: "center", fontFace: "Calibri",
  });
  return s;
}

function sectionDivider(title, subtitle = "") {
  const s = pres.addSlide();
  s.addShape(pres.ShapeType.rect, { x: 0, y: 0, w: "100%", h: "100%", fill: { color: C.bg } });
  s.addShape(pres.ShapeType.rect, { x: 0, y: 0, w: 0.18, h: "100%", fill: { color: C.accent } });
  s.addText(title, {
    x: 0.5, y: 1.8, w: 9.0, h: 1.2,
    fontSize: 36, bold: true, color: C.white, fontFace: "Calibri Light",
  });
  if (subtitle) {
    s.addText(subtitle, {
      x: 0.5, y: 3.15, w: 9.0, h: 0.6,
      fontSize: 18, color: C.accent, fontFace: "Calibri",
    });
  }
  return s;
}

function contentSlide(heading, bullets, opts = {}) {
  const s = pres.addSlide();
  // Background
  s.addShape(pres.ShapeType.rect, { x: 0, y: 0, w: "100%", h: "100%", fill: { color: C.bg } });
  // Header bar
  s.addShape(pres.ShapeType.rect, { x: 0, y: 0, w: "100%", h: 0.78, fill: { color: C.bgAlt } });
  s.addShape(pres.ShapeType.rect, { x: 0, y: 0.78, w: "100%", h: 0.04, fill: { color: C.accent } });
  s.addText(heading, {
    x: 0.35, y: 0.05, w: 9.3, h: 0.65,
    fontSize: 22, bold: true, color: C.accent, fontFace: "Calibri", margin: 0,
  });

  const bulletItems = bullets.map((b, i) => {
    if (typeof b === "string") {
      return { text: b, options: { bullet: { type: "bullet" }, breakLine: i < bullets.length - 1, color: C.white, fontSize: 17, fontFace: "Calibri" } };
    }
    // object with text + sub
    const items = [{ text: b.text, options: { bullet: { type: "bullet" }, breakLine: true, color: C.white, fontSize: 17, bold: b.bold || false, fontFace: "Calibri" } }];
    if (b.sub) {
      b.sub.forEach((ss, si) => {
        items.push({ text: ss, options: { bullet: { indent: 30 }, breakLine: si < b.sub.length - 1 || i < bullets.length - 1, color: C.grey, fontSize: 15, fontFace: "Calibri" } });
      });
    }
    return items;
  }).flat();

  s.addText(bulletItems, {
    x: 0.35, y: 0.95, w: opts.w || 9.3, h: opts.h || 4.4,
    valign: "top",
  });
  if (opts.source) {
    s.addText(opts.source, { x: 0.35, y: 5.3, w: 9.3, h: 0.25, fontSize: 10, color: C.grey, fontFace: "Calibri", italic: true });
  }
  return s;
}

function twoColSlide(heading, leftTitle, leftBullets, rightTitle, rightBullets, leftColor = C.accent2, rightColor = C.accent3) {
  const s = pres.addSlide();
  s.addShape(pres.ShapeType.rect, { x: 0, y: 0, w: "100%", h: "100%", fill: { color: C.bg } });
  s.addShape(pres.ShapeType.rect, { x: 0, y: 0, w: "100%", h: 0.78, fill: { color: C.bgAlt } });
  s.addShape(pres.ShapeType.rect, { x: 0, y: 0.78, w: "100%", h: 0.04, fill: { color: C.accent } });
  s.addText(heading, { x: 0.35, y: 0.05, w: 9.3, h: 0.65, fontSize: 22, bold: true, color: C.accent, fontFace: "Calibri", margin: 0 });

  // Left card
  s.addShape(pres.ShapeType.roundRect, { x: 0.25, y: 0.95, w: 4.5, h: 4.5, rectRadius: 0.08, fill: { color: C.bgLight }, line: { color: leftColor, width: 2 } });
  s.addText(leftTitle, { x: 0.35, y: 1.05, w: 4.3, h: 0.45, fontSize: 14, bold: true, color: leftColor, fontFace: "Calibri", margin: 0 });
  s.addText(leftBullets.map((b, i) => ({ text: b, options: { bullet: { type: "bullet" }, breakLine: i < leftBullets.length - 1, color: C.white, fontSize: 14, fontFace: "Calibri" } })),
    { x: 0.35, y: 1.55, w: 4.3, h: 3.7, valign: "top" });

  // Right card
  s.addShape(pres.ShapeType.roundRect, { x: 5.1, y: 0.95, w: 4.5, h: 4.5, rectRadius: 0.08, fill: { color: C.bgLight }, line: { color: rightColor, width: 2 } });
  s.addText(rightTitle, { x: 5.2, y: 1.05, w: 4.3, h: 0.45, fontSize: 14, bold: true, color: rightColor, fontFace: "Calibri", margin: 0 });
  s.addText(rightBullets.map((b, i) => ({ text: b, options: { bullet: { type: "bullet" }, breakLine: i < rightBullets.length - 1, color: C.white, fontSize: 14, fontFace: "Calibri" } })),
    { x: 5.2, y: 1.55, w: 4.3, h: 3.7, valign: "top" });
  return s;
}

function tableSlide(heading, headers, rows, colW) {
  const s = pres.addSlide();
  s.addShape(pres.ShapeType.rect, { x: 0, y: 0, w: "100%", h: "100%", fill: { color: C.bg } });
  s.addShape(pres.ShapeType.rect, { x: 0, y: 0, w: "100%", h: 0.78, fill: { color: C.bgAlt } });
  s.addShape(pres.ShapeType.rect, { x: 0, y: 0.78, w: "100%", h: 0.04, fill: { color: C.accent } });
  s.addText(heading, { x: 0.35, y: 0.05, w: 9.3, h: 0.65, fontSize: 22, bold: true, color: C.accent, fontFace: "Calibri", margin: 0 });

  const tableData = [];
  tableData.push(headers.map(h => ({ text: h, options: { bold: true, color: C.dark, fill: { color: C.accent }, fontSize: 13, fontFace: "Calibri", align: "center" } })));
  rows.forEach((row, ri) => {
    tableData.push(row.map(cell => ({ text: cell, options: { color: C.white, fill: { color: ri % 2 === 0 ? C.bgLight : C.bg }, fontSize: 12, fontFace: "Calibri" } })));
  });

  s.addTable(tableData, { x: 0.3, y: 0.92, w: 9.4, colW: colW, rowH: 0.42, border: { color: C.bgLight } });
  return s;
}

// ════════════════════════════════════════════════════════════════
// SLIDE 1 — Title
// ════════════════════════════════════════════════════════════════
titleSlide(
  "CYTOKINES: HEALTH AND DISEASE",
  "Structure • Classification • Mechanisms • Pathology • Therapeutics"
);

// ════════════════════════════════════════════════════════════════
// SLIDE 2 — Learning Objectives
// ════════════════════════════════════════════════════════════════
contentSlide("Learning Objectives", [
  "Define cytokines and distinguish them from hormones and growth factors",
  "Classify the major cytokine families with key members",
  "Describe cytokine signalling pathways (JAK-STAT, NF-κB, MAPK)",
  "Explain roles of pro-inflammatory vs. anti-inflammatory cytokines",
  "Link cytokine dysregulation to specific diseases: sepsis, autoimmune disorders, malignancy",
  "Identify cytokines as diagnostic biomarkers and therapeutic targets",
], { source: "Source: Robbins & Kumar Basic Pathology; Henry's Clinical Diagnosis & Management" });

// ════════════════════════════════════════════════════════════════
// SECTION 1 — INTRODUCTION
// ════════════════════════════════════════════════════════════════
sectionDivider("SECTION 1", "Introduction to Cytokines");

// SLIDE 3 — What are Cytokines?
contentSlide("What Are Cytokines?", [
  { text: "Definition", bold: true, sub: [
    "Soluble proteins / glycoproteins released by cells to facilitate inter-cellular communication",
    "Coordinate innate & adaptive immune responses, inflammation, hematopoiesis, and tissue repair",
    "Act at picomolar–femtomolar concentrations (extraordinarily potent)",
  ]},
  { text: "Modes of action", bold: true, sub: [
    "Autocrine — act on the producing cell itself",
    "Paracrine — act on nearby cells",
    "Endocrine — act at distant sites via circulation (rare, high-dose states e.g. sepsis)",
  ]},
  { text: "Distinguishing features", bold: true, sub: [
    "Pleiotropic: one cytokine → multiple effects on different cell types",
    "Redundant: multiple cytokines share overlapping functions",
    "Synergistic or antagonistic interactions common",
  ]},
], { source: "Source: Henry's Clinical Diagnosis & Management by Laboratory Methods; Robbins Pathology" });

// SLIDE 4 — Cytokine Families Overview (table)
tableSlide(
  "Cytokine Families — Overview",
  ["Family", "Key Members", "Primary Role"],
  [
    ["Interleukins (ILs)", "IL-1, IL-2, IL-4, IL-6, IL-10, IL-12, IL-17", "Immune cell communication"],
    ["Tumor Necrosis Factor (TNF)", "TNF-α, TNF-β (LT-α)", "Inflammation, apoptosis, cachexia"],
    ["Interferons (IFNs)", "IFN-α, IFN-β (Type I); IFN-γ (Type II)", "Antiviral defense, macrophage activation"],
    ["Colony-Stimulating Factors", "G-CSF, GM-CSF, M-CSF, IL-3", "Hematopoiesis, myeloid differentiation"],
    ["Chemokines", "IL-8 (CXCL8), RANTES, MCP-1", "Leukocyte chemotaxis & trafficking"],
    ["Transforming Growth Factor-β", "TGF-β1, TGF-β2, TGF-β3", "Immune suppression, fibrosis"],
    ["Adipokines", "Leptin, adiponectin, resistin", "Metabolism–immunity interface"],
  ],
  [2.6, 3.8, 3.0],
);

// ════════════════════════════════════════════════════════════════
// SECTION 2 — SIGNALLING
// ════════════════════════════════════════════════════════════════
sectionDivider("SECTION 2", "Cytokine Signalling Pathways");

// SLIDE 5 — JAK-STAT Pathway
contentSlide("JAK-STAT Signalling Pathway", [
  { text: "Most cytokines signal through receptor-associated JAKs (Janus kinases)", bold: true },
  { text: "Steps", bold: true, sub: [
    "1. Cytokine binds receptor → receptor dimerisation / oligomerisation",
    "2. JAK trans-phosphorylation → receptor phosphorylation",
    "3. STAT proteins recruited → phosphorylated by JAKs",
    "4. Phospho-STATs dimerize → translocate to nucleus → gene transcription",
  ]},
  { text: "Key JAK-STAT associations", bold: true, sub: [
    "IFN-α/β → JAK1/TYK2 → STAT1/STAT2 (antiviral genes, ISGs)",
    "IFN-γ → JAK1/JAK2 → STAT1 (macrophage activation)",
    "IL-6 → JAK1/JAK2 → STAT3 (acute-phase proteins, oncogenesis)",
    "IL-4/IL-13 → JAK1/JAK3 → STAT6 (Th2 / allergic responses)",
    "IL-2 → JAK1/JAK3 → STAT5 (T-cell proliferation)",
  ]},
  { text: "Negative regulation: SOCS proteins (suppressors of cytokine signalling)", bold: false },
], { source: "Source: Robbins Pathology; Goodman & Gilman's Pharmacological Basis of Therapeutics" });

// SLIDE 6 — NF-κB & MAPK Pathways
twoColSlide(
  "NF-κB and MAPK Signalling",
  "NF-κB Pathway",
  [
    "Activated by: TNF-α, IL-1β, LPS (TLR4), ROS",
    "IKK complex phosphorylates IκB → proteasomal degradation",
    "Free NF-κB (p50/p65) translocates to nucleus",
    "Induces: IL-1β, IL-6, IL-8, COX-2, iNOS, anti-apoptotic genes",
    "Master regulator of inflammatory gene expression",
    "Dysregulation → chronic inflammation, cancer (NF-κB constitutively active in many lymphomas)",
  ],
  "MAPK Cascade",
  [
    "Activated by: growth factors, cytokines, cellular stress",
    "Key cascades: ERK1/2, p38 MAPK, JNK",
    "p38 MAPK: induced by IL-1, TNF → stabilises pro-inflammatory mRNAs",
    "JNK: activated by TNF, IL-1 → AP-1 transcription factor",
    "Roles: cell proliferation, differentiation, apoptosis, cytokine production",
    "Therapeutic target: p38 MAPK inhibitors (clinical trials for RA)",
  ],
  C.accent2,
  C.accent,
);

// ════════════════════════════════════════════════════════════════
// SECTION 3 — PRO-INFLAMMATORY
// ════════════════════════════════════════════════════════════════
sectionDivider("SECTION 3", "Pro-Inflammatory Cytokines");

// SLIDE 7 — TNF-α
contentSlide("TNF-α — Tumor Necrosis Factor-alpha", [
  { text: "Sources", bold: true, sub: ["Activated macrophages (primary), T lymphocytes, mast cells, NK cells"] },
  { text: "Key actions in inflammation", bold: true, sub: [
    "Endothelial activation: upregulates E-selectin, P-selectin, ICAM-1 → leukocyte adhesion",
    "Stimulates neutrophil and macrophage microbicidal activity",
    "Induces IL-1, IL-6, chemokines, prostaglandins (amplification loop)",
    "Systemic: fever, acute-phase response (with IL-1 and IL-6)",
  ]},
  { text: "Pathological roles", bold: true, sub: [
    "At high concentrations (sepsis): vasodilation, reduced cardiac contractility → hypotension, shock",
    "Sustained production → cachexia (lipid/protein mobilization, anorexia) in chronic infection & cancer",
    "Granuloma maintenance in tuberculosis and sarcoidosis",
  ]},
  { text: "Therapeutic relevance", bold: true, sub: [
    "Anti-TNF biologics (infliximab, adalimumab, etanercept) highly effective in RA, psoriasis, IBD",
    "Risk: reactivation of latent TB — screen before initiating therapy",
  ]},
], { source: "Source: Robbins & Kumar Basic Pathology, p.54–56" });

// SLIDE 8 — IL-1β
contentSlide("IL-1β — Interleukin-1 Beta", [
  { text: "Sources", bold: true, sub: ["Activated macrophages, dendritic cells, epithelial cells, monocytes"] },
  { text: "Unique feature: Inflammasome-dependent activation", bold: true, sub: [
    "Pro-IL-1β is cleaved by caspase-1 within the NLRP3 (or other) inflammasome complex",
    "Inflammasome triggers: urate crystals (gout), cholesterol crystals (atherosclerosis), amyloid-β",
  ]},
  { text: "Key actions", bold: true, sub: [
    "Endothelial activation and leukocyte recruitment (with TNF)",
    "Stimulates fibroblast collagen synthesis → synovial hyperplasia",
    "Induces Th17 responses → amplifies neutrophil recruitment",
    "Fever (endogenous pyrogen) and acute-phase response",
  ]},
  { text: "Disease relevance", bold: true, sub: [
    "IBD, rheumatoid arthritis, psoriasis (IL-1 dysregulation)",
    "Autoinflammatory syndromes (familial Mediterranean fever, Muckle-Wells)",
    "IL-1 antagonist (anakinra) effective in autoinflammatory diseases",
  ]},
], { source: "Source: Robbins Pathology; Henry's Clinical Diagnosis & Management" });

// SLIDE 9 — IL-6, IL-17
twoColSlide(
  "IL-6 and IL-17 in Inflammation",
  "IL-6",
  [
    "Sources: macrophages, T cells, endothelial & stromal cells",
    "Signals via JAK1/JAK2 → STAT3",
    "Acute-phase: induces CRP, fibrinogen, serum amyloid A (liver)",
    "Stimulates hepatic acute-phase protein production",
    "Drives Th17 differentiation (with TGF-β)",
    "Disease: RA, Castleman disease, cytokine release syndrome",
    "Elevated in COVID-19 severe disease",
    "Therapy: tocilizumab (IL-6R blockade) — RA, CRS",
  ],
  "IL-17A",
  [
    "Sources: Th17 cells, ILC3, γδ T cells",
    "Potent inducer of neutrophil recruitment (via IL-8/CXCL8)",
    "Stimulates epithelial cells to produce defensins, antimicrobials",
    "Disease: psoriasis, ankylosing spondylitis, IBD, MS, RA",
    "Links adaptive (Th17) and innate (neutrophil) immunity",
    "Therapeutic targets: secukinumab (IL-17A), ixekizumab",
    "IL-23 (upstream driver of Th17) targeted by guselkumab, risankizumab",
  ],
  C.accent2,
  C.accent,
);

// SLIDE 10 — Chemokines
contentSlide("Chemokines — The Navigation System", [
  { text: "Definition", bold: true, sub: [
    "Small (8–10 kDa) chemoattractant cytokines; ~40 members, >20 receptors",
    "Named by cysteine motif: CXC (α), CC (β), C (γ), CX3C (δ) families",
  ]},
  { text: "Functions", bold: true, sub: [
    "Inflammation: bind proteoglycans on endothelium → create concentration gradient",
    "Stimulate leukocyte integrin activation → firm adhesion and transmigration",
    "Direct cell migration (chemotaxis) to sites of injury/infection",
    "Homeostatic chemokines: organize lymph node architecture (T vs. B cell zones)",
  ]},
  { text: "Pathologically important chemokines", bold: true, sub: [
    "IL-8 (CXCL8): neutrophil chemoattractant; elevated in sepsis, pneumonia",
    "MCP-1 (CCL2): monocyte/macrophage recruiter; atherosclerosis, fibrosis",
    "RANTES (CCL5): T-cell, eosinophil recruiter; asthma, HIV co-receptor",
    "CXCL12 (SDF-1): bone marrow stem cell homing; implicated in cancer metastasis",
  ]},
], { source: "Source: Robbins Pathology, p.57" });

// ════════════════════════════════════════════════════════════════
// SECTION 4 — ANTI-INFLAMMATORY
// ════════════════════════════════════════════════════════════════
sectionDivider("SECTION 4", "Anti-Inflammatory & Regulatory Cytokines");

// SLIDE 11 — Anti-inflammatory cytokines
contentSlide("Anti-Inflammatory Cytokines", [
  { text: "IL-10", bold: true, sub: [
    "Produced by: Tregs, macrophages (M2), B cells, mast cells",
    "Potent suppressor: inhibits macrophage activation, reduces TNF, IL-1, IL-12 production",
    "Critical for preventing excessive inflammation and autoimmunity",
    "IL-10 deficiency → spontaneous colitis (mouse models); protective in IBD",
  ]},
  { text: "TGF-β (Transforming Growth Factor-beta)", bold: true, sub: [
    "Produced by Tregs, macrophages, platelets, most tissue cells",
    "Suppresses T-cell proliferation and macrophage activation",
    "Drives fibrosis: stimulates fibroblast collagen synthesis (wound healing & pathological scarring)",
    "Promotes Treg differentiation (with IL-2) and Th17 differentiation (with IL-6)",
  ]},
  { text: "IL-4 & IL-13", bold: true, sub: [
    "Th2 cytokines; suppress Th1/Th17 inflammation",
    "Drive alternatively activated (M2) macrophage phenotype",
    "Promote IgE class switching → allergy/asthma pathogenesis",
    "IL-4Rα targeted by dupilumab (atopic dermatitis, asthma)",
  ]},
], { source: "Source: Robbins Pathology; Roitt's Essential Immunology" });

// ════════════════════════════════════════════════════════════════
// SECTION 5 — SYSTEMIC REACTIONS
// ════════════════════════════════════════════════════════════════
sectionDivider("SECTION 5", "Systemic Cytokine Effects & the Acute-Phase Response");

// SLIDE 12 — Acute Phase Response
contentSlide("Acute-Phase Response (APR)", [
  { text: "Key cytokine drivers: IL-6 > IL-1β > TNF-α", bold: true },
  { text: "Systemic effects", bold: true, sub: [
    "FEVER: cytokines induce PGE₂ in hypothalamus → raises thermostat set-point",
    "Liver: ↑ CRP, fibrinogen, serum amyloid A, complement proteins, hepcidin",
    "Liver: ↓ albumin, transferrin (negative acute-phase proteins)",
    "Bone marrow: stimulates leukocytosis (G-CSF, GM-CSF from activated stroma)",
    "Adrenal gland: IL-1/TNF → corticotropin-releasing hormone → cortisol (counter-regulatory)",
    "Brain: somnolence, anorexia, malaise (sickness behaviour)",
  ]},
  { text: "Laboratory correlates", bold: true, sub: [
    "CRP: acute-phase protein, half-life 19h — reliable marker of active inflammation",
    "ESR: rises due to fibrinogen-induced erythrocyte rouleaux formation",
    "Procalcitonin (PCT): induced by bacterial infection; distinguishes bacterial from viral",
    "Ferritin: acute-phase reactant; markedly elevated in hemophagocytic syndrome",
  ]},
], { source: "Source: Robbins & Kumar Basic Pathology; Henry's Clinical Diagnosis" });

// SLIDE 13 — Cytokine Storm & SIRS
contentSlide("Cytokine Storm / SIRS (Systemic Inflammatory Response Syndrome)", [
  { text: "Pathophysiology", bold: true, sub: [
    "Massive dysregulated systemic cytokine release → organ dysfunction",
    "TNF-α & IL-1: peripheral vasodilation, endothelial injury, increased permeability",
    "IL-6: amplifies APR, drives coagulopathy",
    "IL-8: pulmonary neutrophil recruitment → ARDS",
    "High TNF: dilates blood vessels + reduces myocardial contractility → septic shock",
  ]},
  { text: "Clinical conditions", bold: true, sub: [
    "Sepsis: gram-negative LPS triggers massive TLR4 → TNF, IL-1, IL-6 cascade",
    "Hemophagocytic Lymphohistiocytosis (HLH): IFN-γ, IL-18, IL-12 storm",
    "CAR-T cell therapy / immunotherapy-associated CRS: IL-6 dominant",
    "COVID-19 severe disease: IL-6, IL-10, IP-10, MCP-1 cytokine storm",
    "Macrophage Activation Syndrome (MAS): overlap with HLH; IL-18 very high",
  ]},
  { text: "Therapy targets", bold: true, sub: [
    "Tocilizumab (IL-6R): CAR-T CRS, COVID-19 severe cases",
    "Anakinra (IL-1Ra): HLH, MAS, autoinflammatory",
    "Emapalumab (anti-IFN-γ): primary HLH",
  ]},
], { source: "Source: Robbins Pathology; Henry's Clinical Diagnosis; Medical Microbiology 9e" });

// ════════════════════════════════════════════════════════════════
// SECTION 6 — CYTOKINES IN DISEASE
// ════════════════════════════════════════════════════════════════
sectionDivider("SECTION 6", "Cytokines in Disease Pathogenesis");

// SLIDE 14 — Autoimmune Diseases
tableSlide(
  "Cytokine Dysregulation in Autoimmune Diseases",
  ["Disease", "Key Cytokines Dysregulated", "Pathological Role"],
  [
    ["Rheumatoid Arthritis", "TNF-α, IL-1β, IL-6, IL-17", "Synovitis, bone/cartilage erosion, systemic inflammation"],
    ["Systemic Lupus (SLE)", "IFN-α (Type I IFN signature), IL-6, IL-10", "B-cell hyperactivation, immune complex deposition"],
    ["Psoriasis", "IL-17A, IL-23, TNF-α", "Keratinocyte hyperproliferation, skin plaques"],
    ["IBD (Crohn's / UC)", "IL-1, IL-6, IL-12, IL-23, IL-17", "Mucosal barrier disruption, granuloma formation"],
    ["Multiple Sclerosis", "IFN-β (protective), IL-17, TNF", "Demyelination, BBB disruption"],
    ["Ankylosing Spondylitis", "IL-17A, IL-23, TNF-α", "New bone formation, spinal fusion, enthesitis"],
    ["Sjögren Syndrome", "Type I IFN, IL-6", "Salivary/lacrimal gland destruction"],
  ],
  [2.5, 3.2, 3.7],
);

// SLIDE 15 — Cytokines & Cancer
contentSlide("Cytokines in Cancer Biology", [
  { text: "Tumour-promoting cytokines", bold: true, sub: [
    "IL-6 / STAT3 axis: promotes tumour cell survival, proliferation, angiogenesis; constitutively active in colon, breast, multiple myeloma",
    "TNF-α: can act as tumour promoter via NF-κB — promotes invasion, angiogenesis, immune evasion",
    "TGF-β: dual role — suppresses early tumours; promotes metastasis in advanced disease (EMT)",
    "VEGF (growth factor / cytokine-like): tumour angiogenesis → bevacizumab target",
  ]},
  { text: "Tumour-suppressing cytokines", bold: true, sub: [
    "IFN-γ: enhances NK and CTL cytotoxicity; upregulates MHC I on tumour cells",
    "IL-12: promotes Th1 and NK responses against tumour; basis for tumour immunotherapy",
    "TNF-α (paradoxically): can induce tumour apoptosis in some contexts",
  ]},
  { text: "Cytokines & myeloproliferative neoplasms", bold: true, sub: [
    "JAK2 V617F mutation (PV, ET, MF) → constitutive JAK-STAT activation",
    "IL-8 and other chemokines: tumour cell migration, metastatic niche formation",
  ]},
], { source: "Source: Henry's Clinical Diagnosis & Management; Robbins Pathology" });

// SLIDE 16 — Infectious Disease
contentSlide("Cytokines in Infectious Disease", [
  { text: "Innate immune cytokines (first responders)", bold: true, sub: [
    "Type I IFNs (IFN-α/β): secreted by plasmacytoid DCs → antiviral state, ISG induction",
    "IL-12 & IL-18: produced by macrophages/DCs → induce IFN-γ from NK and T cells",
    "IL-8 (CXCL8): neutrophil recruitment to site of bacterial infection",
  ]},
  { text: "Protective Th1 responses", bold: true, sub: [
    "IFN-γ: macrophage activation → oxidative burst → intracellular killing (mycobacteria, Listeria)",
    "IL-2: T-cell expansion and survival",
    "IL-12: drives Th1 differentiation — critical for anti-mycobacterial immunity",
  ]},
  { text: "Viral exploitation of cytokine pathways", bold: true, sub: [
    "Many viruses encode IFN-antagonist proteins to evade Type I IFN responses",
    "Cytokine storm in influenza A (H5N1): IFN-γ, TNF → ARDS, multi-organ failure",
    "HIV: uses CXCR4 (CXCL12 receptor) or CCR5 (RANTES receptor) as co-receptors for cell entry",
  ]},
], { source: "Source: Medical Microbiology 9e; Robbins Pathology" });

// SLIDE 17 — Cytokines in Fibrosis & Tissue Repair
contentSlide("Cytokines in Tissue Repair and Fibrosis", [
  { text: "Phase 1 — Haemostasis & acute inflammation", bold: true, sub: [
    "Platelet-derived PDGF, TGF-β: growth factors for fibroblast recruitment",
    "TNF, IL-1: activate endothelium and recruit leukocytes",
  ]},
  { text: "Phase 2 — Proliferation", bold: true, sub: [
    "IL-4, IL-13, TGF-β: promote M2 macrophage polarisation (pro-fibrotic phenotype)",
    "TGF-β1: master fibrosis cytokine → myofibroblast differentiation, collagen I/III synthesis",
    "PDGF & IGF-1: fibroblast mitogen",
  ]},
  { text: "Phase 3 — Remodelling", bold: true, sub: [
    "MMPs (metalloproteinases) regulated by cytokine balance",
    "TGF-β promotes TIMP production → reduced MMP activity → excess collagen",
    "Pathological fibrosis: liver cirrhosis, IPF, systemic sclerosis (scleroderma), renal fibrosis",
  ]},
  { text: "Emerging therapeutic targets", bold: true, sub: [
    "Nintedanib / pirfenidone (anti-fibrotic in IPF): modify TGF-β downstream signalling",
    "IL-13 inhibition: under investigation in IPF (tralokinumab, cendakimab)",
  ]},
]);

// ════════════════════════════════════════════════════════════════
// SECTION 7 — DIAGNOSTIC & THERAPEUTIC
// ════════════════════════════════════════════════════════════════
sectionDivider("SECTION 7", "Cytokines as Biomarkers & Therapeutic Targets");

// SLIDE 18 — Lab measurement
contentSlide("Cytokine Measurement in Clinical Practice", [
  { text: "Bioassays — gold standard but impractical", bold: true, sub: [
    "Cell-based assays measure biological activity; time-consuming and costly",
  ]},
  { text: "ELISA (Enzyme-Linked Immunosorbent Assay)", bold: true, sub: [
    "Most widely used; kits available for IL-1α/β, IL-4, IL-5, IL-6, IL-10, IFN-γ, TNF-α",
    "Single analyte; well-established; used clinically",
  ]},
  { text: "Multiplex / bead-based assays (Luminex, electrochemiluminescence)", bold: true, sub: [
    "Simultaneously measure 20–50+ cytokines from a single low-volume sample",
    "High sensitivity; used in research and increasingly in clinical cytokine storm assessment",
  ]},
  { text: "Clinically used cytokine-related biomarkers", bold: true, sub: [
    "IL-6: COVID-19 severity, CRS, Castleman disease",
    "IL-18 / ferritin: HLH / MAS diagnosis (sHLH score)",
    "IFN-γ (QuantiFERON): latent TB screening",
    "PCT (procalcitonin): bacterial sepsis (induced by bacterial cytokine cascade)",
    "IL-2R (sCD25): lymphoma, HLH activity marker",
  ]},
], { source: "Source: Henry's Clinical Diagnosis & Management by Laboratory Methods" });

// SLIDE 19 — Therapeutic Targeting
tableSlide(
  "Cytokine-Targeted Therapies — Key Biologics",
  ["Drug / Class", "Target", "Indications"],
  [
    ["Infliximab, Adalimumab, Etanercept", "TNF-α", "RA, psoriasis, IBD, AS, JIA"],
    ["Tocilizumab, Sarilumab", "IL-6 receptor (IL-6R)", "RA, CRS (CAR-T), COVID-19"],
    ["Anakinra", "IL-1Ra (IL-1 receptor antagonist)", "RA, HLH, MAS, autoinflammatory"],
    ["Canakinumab", "IL-1β", "Gout flares, CAPS, TRAPS, HIDS"],
    ["Secukinumab, Ixekizumab", "IL-17A", "Psoriasis, AS, PsA"],
    ["Guselkumab, Risankizumab", "IL-23 (p19 subunit)", "Psoriasis, PsA, IBD"],
    ["Dupilumab", "IL-4Rα (IL-4 & IL-13)", "Atopic dermatitis, asthma, CRS"],
    ["Ruxolitinib, Baricitinib", "JAK1/JAK2 inhibitor", "RA, myelofibrosis, alopecia areata"],
    ["Emapalumab", "IFN-γ", "Primary HLH"],
    ["Ustekinumab", "IL-12/23 (p40 subunit)", "Psoriasis, CD, UC"],
  ],
  [3.5, 2.8, 2.9],
);

// ════════════════════════════════════════════════════════════════
// SLIDE 20 — Summary Schematic (text-based)
// ════════════════════════════════════════════════════════════════
contentSlide("Summary: The Cytokine Network", [
  { text: "Trigger → innate recognition (TLR, NLR, CLR, RLR)", bold: true },
  { text: "Early cytokines (TNF, IL-1β, IL-6, Type I IFN)", bold: true, sub: [
    "→ Endothelial activation, leukocyte recruitment, fever, APR",
  ]},
  { text: "Adaptive arm cytokines (IL-12→IFN-γ, IL-4, IL-17, IL-2)", bold: true, sub: [
    "→ Th1/Th2/Th17/Treg differentiation; immunological memory",
  ]},
  { text: "Resolution (IL-10, TGF-β, IL-4)", bold: true, sub: [
    "→ Dampen inflammation; wound repair and fibrosis",
  ]},
  { text: "Dysregulation outcomes", bold: true, sub: [
    "Excess pro-inflammatory: sepsis/shock, ARDS, CRS, HLH",
    "Chronic imbalance: autoimmune disease (RA, SLE, IBD, psoriasis)",
    "Oncogenic: IL-6/STAT3, JAK2-mutation driven MPN",
    "Fibrotic: TGF-β driven IPF, cirrhosis, scleroderma",
  ]},
], { source: "Source: Robbins & Kumar Basic Pathology; Henry's Clinical Diagnosis & Management" });

// ════════════════════════════════════════════════════════════════
// SLIDE 21 — Key Take-home Messages
// ════════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  s.addShape(pres.ShapeType.rect, { x: 0, y: 0, w: "100%", h: "100%", fill: { color: C.bg } });
  s.addShape(pres.ShapeType.rect, { x: 0, y: 0, w: "100%", h: 0.78, fill: { color: C.bgAlt } });
  s.addShape(pres.ShapeType.rect, { x: 0, y: 0.78, w: "100%", h: 0.04, fill: { color: C.accent } });
  s.addText("Key Take-Home Messages for the Pathologist", { x: 0.35, y: 0.05, w: 9.3, h: 0.65, fontSize: 22, bold: true, color: C.accent, fontFace: "Calibri", margin: 0 });

  const msgs = [
    ["1", "Cytokines are pleiotropic & redundant — no single cytokine tells the whole story.", C.accent2],
    ["2", "TNF-α + IL-1β + IL-6 = the triad driving acute inflammation, fever, and APR.", C.accent],
    ["3", "JAK-STAT is the dominant signalling axis — constitutive STAT3 → lymphoma/cancer.", C.accent3],
    ["4", "Cytokine storms (sepsis, HLH, CRS) share a common pathway of uncontrolled amplification.", C.accent2],
    ["5", "Th17 / IL-17 / IL-23 axis is the backbone of inflammatory skin, gut, and joint disease.", C.accent],
    ["6", "TGF-β is the master fibrosis mediator — critical in IPF, cirrhosis, scleroderma.", C.accent3],
    ["7", "JAK inhibitors and anti-cytokine biologics have transformed management of autoimmune & haematologic disease.", C.accent4],
  ];

  msgs.forEach(([num, text, color], i) => {
    const y = 0.95 + i * 0.63;
    s.addShape(pres.ShapeType.roundRect, { x: 0.25, y: y, w: 0.45, h: 0.45, rectRadius: 0.1, fill: { color: color } });
    s.addText(num, { x: 0.25, y: y, w: 0.45, h: 0.45, fontSize: 15, bold: true, color: C.dark, align: "center", valign: "middle", fontFace: "Calibri", margin: 0 });
    s.addText(text, { x: 0.80, y: y + 0.03, w: 8.9, h: 0.42, fontSize: 15, color: C.white, fontFace: "Calibri", valign: "middle" });
  });
}

// ════════════════════════════════════════════════════════════════
// SLIDE 22 — References
// ════════════════════════════════════════════════════════════════
contentSlide("References", [
  "Kumar V, Abbas AK, Aster JC. Robbins & Kumar Basic Pathology, 10th ed. Elsevier, 2023. [Chapter 2: Inflammation & Repair; Chapter 5: Immunity]",
  "McPherson RA, Pincus MR. Henry's Clinical Diagnosis and Management by Laboratory Methods, 23rd ed. Elsevier, 2021. [Chapter 49: Cytokines & Adhesion Molecules]",
  "Roitt IM, Delves PJ, Martin SJ, Burton DR. Roitt's Essential Immunology, 13th ed. Wiley-Blackwell, 2017.",
  "Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th ed. McGraw-Hill, 2023.",
  "Brocker C, Thompson D, Matsumoto A, et al. Evolutionary divergence and functions of the human interleukin (IL) gene family. Hum Genomics 2010;5:30–55.",
  "Akdis M, Burgler S, Crameri R, et al. Interleukins, from 1 to 37, and interferon-γ: receptors, functions, and roles in diseases. J Allergy Clin Immunol 2011;127:701–721.",
  "Dinarello CA. Overview of the IL-1 family in innate inflammation and acquired immunity. Immunol Rev 2018;281:8–27.",
]);

// ════════════════════════════════════════════════════════════════
// WRITE FILE
// ════════════════════════════════════════════════════════════════
pres.writeFile({ fileName: "/home/daytona/workspace/cytokines-ppt/Cytokines_Health_and_Disease.pptx" })
  .then(() => console.log("DONE: /home/daytona/workspace/cytokines-ppt/Cytokines_Health_and_Disease.pptx"))
  .catch(e => { console.error("ERROR:", e); process.exit(1); });

Successfully replaced 1 instance(s) of the string in '/home/daytona/workspace/cytokines-ppt/build.js'