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

// ─── PALETTE ──────────────────────────────────────────────────────────────────
const C = {
  navy:      "0D1B2A",   // dominant dark
  teal:      "1B6CA8",   // supporting blue
  cyan:      "4FC3F7",   // accent
  amber:     "F59E0B",   // highlight / warning
  red:       "E53935",   // danger / disease
  lightBg:   "EFF6FF",   // slide background
  white:     "FFFFFF",
  textDark:  "0D1B2A",
  textMid:   "1B3A5C",
  textLight: "90AFC5",
  green:     "2E7D32",
  purple:    "6A1B9A",
  tealDark:  "005B8E",
};

// ─── HELPERS ──────────────────────────────────────────────────────────────────
function darkSlide(slide) {
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}
function lightSlide(slide) {
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function addFooter(slide, num) {
  slide.addText(`Cytokines: Health and Disease  |  Pathology Residency Education  |  Slide ${num}`, {
    x: 0, y: 7.3, w: 13.3, h: 0.22,
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// ═══════════════════════════════════════════════════════════════════════════════
// SLIDE 1 — TITLE
// ═══════════════════════════════════════════════════════════════════════════════
{
  const sl = pres.addSlide();
  darkSlide(sl);

  // left accent stripe
  sl.addShape(pres.ShapeType.rect, { x: 0, y: 0, w: 0.22, h: 7.5, fill: { color: C.teal }, line: { color: C.teal } });
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  sl.addText("CYTOKINES", {
    x: 0.6, y: 1.2, w: 9, h: 1.2,
    fontSize: 54, bold: true, fontFace: "Calibri", color: C.white, charSpacing: 8,
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  });
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  sl.addText([
    { text: "A Comprehensive Overview for Pathology Residents\n", options: { fontSize: 16, color: C.textLight, bold: false } },
    { text: "Mechanisms • Classification • Disease Pathology • Therapeutics", options: { fontSize: 13, color: C.cyan, bold: false, italic: true } },
  ], { x: 0.6, y: 3.65, w: 10, h: 1.2, fontFace: "Calibri" });

  sl.addText("Source: Robbins Pathologic Basis of Disease | Cellular & Molecular Immunology | Harrison's Principles", {
    x: 0.6, y: 6.9, w: 10, h: 0.3, fontSize: 9, color: C.textLight, fontFace: "Calibri",
  });
}

// ═══════════════════════════════════════════════════════════════════════════════
// SLIDE 2 — WHAT ARE CYTOKINES?
// ═══════════════════════════════════════════════════════════════════════════════
{
  const sl = pres.addSlide();
  lightSlide(sl);
  addSlideTitle(sl, "What Are Cytokines?");
  addFooter(sl, 2);

  // definition box
  sl.addShape(pres.ShapeType.rect, { x: 0.4, y: 1.0, w: 12.5, h: 0.9, fill: { color: C.teal }, line: { color: C.teal } });
  sl.addText('"Cytokines are small secreted proteins (typically 8–80 kDa) that mediate and regulate immunity, inflammation, and hematopoiesis."', {
    x: 0.55, y: 1.05, w: 12.2, h: 0.8, fontSize: 14, italic: true, color: C.white, fontFace: "Calibri", valign: "middle",
  });

  // 4 property cards
  const props = [
    { title: "PLEIOTROPIC", icon: "●", desc: "One cytokine acts on multiple cell types with different effects", col: C.teal },
    { title: "REDUNDANT", icon: "●", desc: "Multiple cytokines share overlapping functional activities", col: C.purple },
    { title: "SYNERGISTIC", icon: "●", desc: "Combined effects of two cytokines > sum of individual effects", col: C.green },
    { title: "ANTAGONISTIC", icon: "●", desc: "Some cytokines inhibit the actions of others (e.g., IL-10 vs IL-1)", col: C.red },
  ];
  props.forEach((p, i) => {
    const x = 0.4 + i * 3.15;
    sl.addShape(pres.ShapeType.rect, { x, y: 2.1, w: 3.0, h: 0.4, fill: { color: p.col }, line: { color: p.col } });
    sl.addText(p.title, { x: x + 0.08, y: 2.12, w: 2.84, h: 0.36, fontSize: 12, bold: true, color: C.white, fontFace: "Calibri", margin: 0 });
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    sl.addText(p.desc, { x: x + 0.1, y: 2.56, w: 2.8, h: 0.88, fontSize: 11, color: C.textDark, fontFace: "Calibri", valign: "middle" });
  });

  // Key features
  sl.addText("Key Functional Properties", { x: 0.4, y: 3.7, w: 5, h: 0.35, fontSize: 13, bold: true, color: C.teal, fontFace: "Calibri" });
  const features = [
    "Act in autocrine, paracrine, or endocrine fashion",
    "Signal through specific high-affinity cell-surface receptors",
    "Induce changes in gene expression, protein synthesis, cell proliferation/apoptosis",
    "Effects depend on local concentration and receptor expression",
    "Produced transiently in response to stimuli (not constitutively stored)",
  ];
  sl.addText(features.map((f, i) => ({ text: f, options: { bullet: { code: "25B8" }, breakLine: i < features.length - 1, fontSize: 11.5, color: C.textDark, fontFace: "Calibri", paraSpaceBefore: 5 } })), {
    x: 0.4, y: 4.1, w: 12.5, h: 2.8, valign: "top",
  });
}

// ═══════════════════════════════════════════════════════════════════════════════
// SLIDE 3 — CLASSIFICATION
// ═══════════════════════════════════════════════════════════════════════════════
{
  const sl = pres.addSlide();
  lightSlide(sl);
  addSlideTitle(sl, "Classification of Cytokines");
  addFooter(sl, 3);

  const families = [
    { name: "Interleukins (ILs)", color: C.teal, items: ["IL-1 through IL-38+", "Produced by leukocytes & non-immune cells", "Key roles: fever, T cell activation, B cell differentiation"] },
    { name: "Tumor Necrosis Factors (TNFs)", color: C.red, items: ["TNF-α (main), TNF-β (lymphotoxin)", "Produced by macrophages, T cells", "Septic shock, cachexia, apoptosis induction"] },
    { name: "Interferons (IFNs)", color: C.purple, items: ["Type I: IFN-α, IFN-β (antiviral)", "Type II: IFN-γ (macrophage activation)", "Antiviral, antiproliferative, immunomodulatory"] },
    { name: "Chemokines", color: C.amber, items: ["~50 members (CXC, CC, C, CX3C families)", "Direct leukocyte migration (chemotaxis)", "CXCL8 (IL-8), CCL2 (MCP-1) major examples"] },
    { name: "Colony-Stimulating Factors (CSFs)", color: C.green, items: ["G-CSF, M-CSF, GM-CSF", "Regulate hematopoiesis", "Clinical use: post-chemotherapy neutropenia"] },
    { name: "Growth Factors & Others", color: C.tealDark, items: ["TGF-β: anti-inflammatory, fibrosis", "VEGF: angiogenesis", "IL-17 family: mucosal immunity & autoimmunity"] },
  ];

  families.forEach((fam, i) => {
    const row = Math.floor(i / 3);
    const col = i % 3;
    const x = 0.4 + col * 4.3;
    const y = 1.1 + row * 2.7;
    sl.addShape(pres.ShapeType.roundRect, { x, y, w: 4.1, h: 2.55, fill: { color: C.white }, line: { color: fam.color, width: 2.5 }, rectRadius: 0.1 });
    sl.addShape(pres.ShapeType.rect, { x, y, w: 4.1, h: 0.44, fill: { color: fam.color }, line: { color: fam.color } });
    sl.addText(fam.name, { x: x + 0.1, y: y + 0.05, w: 3.9, h: 0.34, fontSize: 11.5, bold: true, color: C.white, fontFace: "Calibri", margin: 0 });
    const blist = fam.items.map((t, idx) => ({ text: t, options: { bullet: { code: "2022" }, breakLine: idx < fam.items.length - 1, fontSize: 10.5, color: C.textDark, fontFace: "Calibri", paraSpaceBefore: 5 } }));
    sl.addText(blist, { x: x + 0.12, y: y + 0.52, w: 3.86, h: 1.95, valign: "top" });
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}

// ═══════════════════════════════════════════════════════════════════════════════
// SLIDE 4 — CYTOKINE RECEPTORS & SIGNALING
// ═══════════════════════════════════════════════════════════════════════════════
{
  const sl = pres.addSlide();
  lightSlide(sl);
  addSlideTitle(sl, "Cytokine Receptors & Signaling Pathways");
  addFooter(sl, 4);

  // receptor families table
  const headers = ["Receptor Family", "Representative Cytokines", "Signaling Pathway", "Examples"];
  const rows = [
    ["Type I (Hematopoietin)", "IL-2, IL-4, IL-6, IL-7, GM-CSF", "JAK-STAT (STAT3, STAT5)", "IL-6 → STAT3 in acute phase response"],
    ["Type II (Interferon)", "IFN-α/β, IFN-γ, IL-10", "JAK1/TYK2 → STAT1/STAT2", "IFN-γ → STAT1 → macrophage activation"],
    ["TNF Receptor (TNFR)", "TNF-α, TNF-β, FasL, TRAIL", "NF-κB, MAPK, Caspases", "TNFR1 → apoptosis or inflammation"],
    ["IL-1 Receptor Family", "IL-1α/β, IL-18, IL-33", "MyD88 → NF-κB, MAPK", "IL-1R → NF-κB → fever, acute phase"],
    ["Chemokine Receptors", "CXCL8, CCL2, CCL5, CXCL12", "G-protein → PI3K, MAPK", "CXCR4 used by HIV; CCR5 by HIV"],
    ["TGF-β Receptor", "TGF-β1/2/3", "SMAD2/3 → SMAD4 → nucleus", "Fibrosis, Treg induction, immunosuppression"],
  ];
  const colW = [2.6, 2.8, 2.8, 4.0];
  const colX = [0.4, 3.0, 5.8, 8.6];
  // header row
  headers.forEach((h, i) => {
    sl.addShape(pres.ShapeType.rect, { x: colX[i], y: 1.1, w: colW[i], h: 0.42, fill: { color: C.navy }, line: { color: C.navy } });
    sl.addText(h, { x: colX[i] + 0.06, y: 1.12, w: colW[i] - 0.12, h: 0.38, fontSize: 10, bold: true, color: C.white, fontFace: "Calibri", margin: 0 });
  });
  rows.forEach((row, ri) => {
    const bg = ri % 2 === 0 ? "EFF6FF" : C.white;
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      sl.addShape(pres.ShapeType.rect, { x: colX[ci], y: 1.52 + ri * 0.82, w: colW[ci], h: 0.82, fill: { color: bg }, line: { color: "D0E4F5", width: 0.5 } });
      sl.addText(cell, { x: colX[ci] + 0.07, y: 1.55 + ri * 0.82, w: colW[ci] - 0.14, h: 0.76, fontSize: 9.5, color: C.textDark, fontFace: "Calibri", valign: "middle" });
    });
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  sl.addText("Key Concept: JAK inhibitors (tofacitinib, baricitinib) block multiple cytokine pathways simultaneously — major therapeutic implication", {
    x: 0.4, y: 6.6, w: 12.5, h: 0.45, fontSize: 11, italic: true, color: C.teal, bold: true, fontFace: "Calibri",
  });
}

// ═══════════════════════════════════════════════════════════════════════════════
// SLIDE 5 — KEY CYTOKINES: IL-1 & TNF-α
// ═══════════════════════════════════════════════════════════════════════════════
{
  const sl = pres.addSlide();
  lightSlide(sl);
  addSlideTitle(sl, "Key Cytokines I: IL-1 and TNF-α (Proinflammatory Masters)");
  addFooter(sl, 5);

  // IL-1 card
  sl.addShape(pres.ShapeType.roundRect, { x: 0.4, y: 1.05, w: 6.0, h: 5.8, fill: { color: C.white }, line: { color: C.red, width: 2.5 }, rectRadius: 0.1 });
  sl.addShape(pres.ShapeType.rect, { x: 0.4, y: 1.05, w: 6.0, h: 0.48, fill: { color: C.red }, line: { color: C.red } });
  sl.addText("IL-1α / IL-1β", { x: 0.55, y: 1.08, w: 5.7, h: 0.42, fontSize: 15, bold: true, color: C.white, fontFace: "Calibri", margin: 0 });

  sl.addText([
    { text: "Sources: ", options: { bold: true } }, { text: "Macrophages, DCs, endothelium, fibroblasts\n" },
    { text: "Receptor: ", options: { bold: true } }, { text: "IL-1R → MyD88 → NF-κB\n" },
    { text: "Activation: ", options: { bold: true } }, { text: "Inflammasome (NLRP3) cleaves pro-IL-1β → IL-1β\n\n" },
    { text: "LOCAL EFFECTS:\n", options: { bold: true, color: C.red } },
    { text: "• Vasodilation & increased vascular permeability\n• Endothelial activation (ICAM-1, selectins)\n• Neutrophil recruitment\n• Activates macrophages & T cells\n\n" },
    { text: "SYSTEMIC EFFECTS:\n", options: { bold: true, color: C.red } },
    { text: "• Fever (acts on hypothalamus via PGE2)\n• Acute phase response (CRP, fibrinogen ↑)\n• Anorexia, sleep (CNS effects)\n• Hypotension in high doses\n\n" },
    { text: "DISEASE LINKS:\n", options: { bold: true, color: C.red } },
    { text: "• RA, gout (NLRP3 inflammasome)\n• Autoinflammatory syndromes (FMF, CAPS)\n• IL-1β blocking: Canakinumab → ↓ CV events (CANTOS trial)" },
  ], { x: 0.55, y: 1.62, w: 5.7, h: 5.1, fontSize: 10.5, color: C.textDark, fontFace: "Calibri", valign: "top" });

  // TNF-α card
  sl.addShape(pres.ShapeType.roundRect, { x: 6.9, y: 1.05, w: 6.0, h: 5.8, fill: { color: C.white }, line: { color: C.amber, width: 2.5 }, rectRadius: 0.1 });
  sl.addShape(pres.ShapeType.rect, { x: 6.9, y: 1.05, w: 6.0, h: 0.48, fill: { color: C.amber }, line: { color: C.amber } });
  sl.addText("TNF-α (Tumor Necrosis Factor)", { x: 7.05, y: 1.08, w: 5.7, h: 0.42, fontSize: 15, bold: true, color: C.white, fontFace: "Calibri", margin: 0 });

  sl.addText([
    { text: "Sources: ", options: { bold: true } }, { text: "Activated macrophages (primary), T cells, NK cells, mast cells\n" },
    { text: "Receptors: ", options: { bold: true } }, { text: "TNFR1 (ubiquitous), TNFR2 (immune cells) → NF-κB or apoptosis\n" },
    { text: "Form: ", options: { bold: true } }, { text: "Transmembrane precursor cleaved by TACE/ADAM17\n\n" },
    { text: "LOCAL EFFECTS:\n", options: { bold: true, color: C.amber } },
    { text: "• Endothelial activation → leukocyte recruitment\n• Promotes coagulation (procoagulant shift)\n• Tumor cell killing via apoptosis (historical name)\n• Granuloma formation & maintenance\n\n" },
    { text: "SYSTEMIC EFFECTS (HIGH DOSE):\n", options: { bold: true, color: C.amber } },
    { text: "• Fever, acute phase proteins\n• Cachexia (inhibits lipoprotein lipase, increases metabolism)\n• Septic shock (↓ SVR, DIC, multi-organ failure)\n\n" },
    { text: "DISEASE LINKS:\n", options: { bold: true, color: C.amber } },
    { text: "• RA, IBD, psoriasis, ankylosing spondylitis\n• Anti-TNF therapy: Infliximab, Adalimumab, Etanercept\n• TB reactivation risk with anti-TNF treatment" },
  ], { x: 7.05, y: 1.62, w: 5.7, h: 5.1, fontSize: 10.5, color: C.textDark, fontFace: "Calibri", valign: "top" });
}

// ═══════════════════════════════════════════════════════════════════════════════
// SLIDE 6 — KEY CYTOKINES: IL-6, IL-10, IL-12
// ═══════════════════════════════════════════════════════════════════════════════
{
  const sl = pres.addSlide();
  lightSlide(sl);
  addSlideTitle(sl, "Key Cytokines II: IL-6, IL-10, and IL-12");
  addFooter(sl, 6);

  sectionBox(sl, 0.4, 1.05, 4.1, 5.8, "IL-6 — The Versatile Mediator", [
    "Sources: Macrophages, endothelium, fibroblasts, T & B cells",
    "Receptor: IL-6R + gp130 → JAK1/2 → STAT3",
    "",
    "KEY ROLES:",
    "• Hepatic acute phase response (CRP, SAA, fibrinogen, hepcidin)",
    "• B cell differentiation → plasma cells (Ig production)",
    "• Th17 cell differentiation (with TGF-β)",
    "• Neuroinflammation & fever",
    "• Megakaryocyte proliferation (platelet production)",
    "",
    "DISEASE RELEVANCE:",
    "• Castleman disease (IL-6 driven lymphadenopathy)",
    "• Cytokine Release Syndrome (CAR-T therapy)",
    "• COVID-19 severe disease",
    "• RA treatment: Tocilizumab (anti-IL-6R)",
  ], C.teal);

  sectionBox(sl, 4.7, 1.05, 4.1, 5.8, "IL-10 — The Anti-inflammatory Brake", [
    "Sources: Macrophages, Treg cells, B cells, Th2 cells",
    "Receptor: IL-10R1/2 → JAK1/TYK2 → STAT3",
    "",
    "KEY ROLES:",
    "• Inhibits macrophage activation (↓ IL-1, TNF, IL-6, IL-12)",
    "• Suppresses Th1 & Th17 responses",
    "• Promotes regulatory T cell function",
    "• Prevents excessive immunopathology",
    "• Anti-inflammatory in gut mucosa",
    "",
    "DISEASE RELEVANCE:",
    "• IL-10 deficiency → colitis (murine models & IBD)",
    "• IL-10 overproduction → impaired pathogen clearance",
    "• EBV encodes IL-10 homolog (BCRF1) for immune evasion",
    "• IL-10 mutations → early-onset IBD in children",
  ], C.green);

  sectionBox(sl, 9.0, 1.05, 4.1, 5.8, "IL-12 — The Th1 Polarizer", [
    "Sources: Dendritic cells, macrophages (after TLR activation)",
    "Receptor: IL-12Rβ1/β2 → STAT4",
    "",
    "KEY ROLES:",
    "• Master inducer of Th1 differentiation (with IFN-γ)",
    "• Activates NK cells → IFN-γ production",
    "• Bridges innate and adaptive immunity",
    "• Promotes cytotoxic T cell responses",
    "",
    "DISEASE RELEVANCE:",
    "• IL-12/IL-23 axis in autoimmunity (psoriasis, IBD)",
    "• IL-12p40 deficiency → susceptibility to mycobacteria",
    "• Ustekinumab targets IL-12/IL-23 shared p40 subunit",
    "• IL-23 (not IL-12) now considered dominant in Crohn's",
    "• IL-12 used as adjuvant in cancer immunotherapy",
  ], C.purple);
}

// ═══════════════════════════════════════════════════════════════════════════════
// SLIDE 7 — INTERFERONS
// ═══════════════════════════════════════════════════════════════════════════════
{
  const sl = pres.addSlide();
  lightSlide(sl);
  addSlideTitle(sl, "Interferons — Antiviral & Immunomodulatory Sentinels");
  addFooter(sl, 7);

  // Type I block
  sl.addShape(pres.ShapeType.roundRect, { x: 0.4, y: 1.05, w: 8.5, h: 2.85, fill: { color: "E3F2FD" }, line: { color: C.teal, width: 2 }, rectRadius: 0.08 });
  sl.addShape(pres.ShapeType.rect, { x: 0.4, y: 1.05, w: 8.5, h: 0.4, fill: { color: C.teal }, line: { color: C.teal } });
  sl.addText("TYPE I INTERFERONS — IFN-α & IFN-β", { x: 0.55, y: 1.07, w: 8.2, h: 0.36, fontSize: 12, bold: true, color: C.white, fontFace: "Calibri", margin: 0 });
  sl.addText([
    { text: "Triggers: ", options: { bold: true } }, { text: "Viral dsRNA (TLR3), viral ssRNA (TLR7/8), viral DNA (TLR9, cGAS-STING) → IRF3/IRF7 → IFN gene transcription\n" },
    { text: "Signaling: ", options: { bold: true } }, { text: "IFNAR1/2 → JAK1/TYK2 → STAT1/2 + IRF9 → ISGF3 complex → ISG transcription\n" },
    { text: "Effects: ", options: { bold: true } }, { text: "Antiviral state (PKR, Mx, OAS), MHC-I upregulation, NK cell activation, IgG class switching\n" },
    { text: "Disease: ", options: { bold: true } }, { text: "Overactive Type I IFN → Aicardi-Goutières syndrome, SLE (IFN signature). Therapeutic: IFN-β in MS, PEG-IFN-α in HCV/HBV" },
  ], { x: 0.6, y: 1.52, w: 8.2, h: 2.28, fontSize: 10.5, color: C.textDark, fontFace: "Calibri", valign: "top" });

  // Type II block
  sl.addShape(pres.ShapeType.roundRect, { x: 0.4, y: 4.05, w: 8.5, h: 2.85, fill: { color: "F3E5F5" }, line: { color: C.purple, width: 2 }, rectRadius: 0.08 });
  sl.addShape(pres.ShapeType.rect, { x: 0.4, y: 4.05, w: 8.5, h: 0.4, fill: { color: C.purple }, line: { color: C.purple } });
  sl.addText("TYPE II INTERFERON — IFN-γ", { x: 0.55, y: 4.07, w: 8.2, h: 0.36, fontSize: 12, bold: true, color: C.white, fontFace: "Calibri", margin: 0 });
  sl.addText([
    { text: "Sources: ", options: { bold: true } }, { text: "Th1 CD4+ T cells, cytotoxic CD8+ T cells, NK cells\n" },
    { text: "Triggers: ", options: { bold: true } }, { text: "IL-12 + IL-18 (innate), antigen-specific TCR signaling (adaptive)\n" },
    { text: "Signaling: ", options: { bold: true } }, { text: "IFNGR1/2 → JAK1/JAK2 → STAT1 homodimer (GAF) → GAS element transcription\n" },
    { text: "Critical Effects: ", options: { bold: true } }, { text: "Classical macrophage activation (M1 polarization), MHC-I & II upregulation, iNOS → NO production, granuloma formation\n" },
    { text: "Disease: ", options: { bold: true } }, { text: "IFN-γ deficiency/receptor mutations → disseminated mycobacterial & Salmonella infections. Excess → HLH, macrophage activation syndrome. Therapeutic use in CGD" },
  ], { x: 0.6, y: 4.52, w: 8.2, h: 2.28, fontSize: 10.5, color: C.textDark, fontFace: "Calibri", valign: "top" });

  // Type III sidebar
  sl.addShape(pres.ShapeType.roundRect, { x: 9.1, y: 1.05, w: 4.0, h: 5.85, fill: { color: "FFF8E1" }, line: { color: C.amber, width: 2 }, rectRadius: 0.08 });
  sl.addShape(pres.ShapeType.rect, { x: 9.1, y: 1.05, w: 4.0, h: 0.4, fill: { color: C.amber }, line: { color: C.amber } });
  sl.addText("TYPE III — IFN-λ", { x: 9.25, y: 1.07, w: 3.7, h: 0.36, fontSize: 12, bold: true, color: C.white, fontFace: "Calibri", margin: 0 });
  sl.addText([
    { text: "Members: IFN-λ1 (IL-29), IFN-λ2/3 (IL-28A/B)\n\n" },
    { text: "Receptor: IL-10Rβ + IL-28Rα\n(restricted to epithelial cells)\n\n" },
    { text: "Function:\n• Antiviral at mucosal surfaces (respiratory, GI tracts)\n• Less systemic inflammation than Type I\n• Synergizes with Type I IFNs\n\n" },
    { text: "Clinical:\n• Protective in COVID-19 & influenza\n• Investigational therapeutics\n• IL28B polymorphism → HCV clearance predictor\n\n" },
    { text: "Emerging area in respiratory\nviral pathology" },
  ], { x: 9.25, y: 1.52, w: 3.7, h: 5.2, fontSize: 10, color: C.textDark, fontFace: "Calibri", valign: "top" });
}

// ═══════════════════════════════════════════════════════════════════════════════
// SLIDE 8 — CHEMOKINES
// ═══════════════════════════════════════════════════════════════════════════════
{
  const sl = pres.addSlide();
  lightSlide(sl);
  addSlideTitle(sl, "Chemokines — Directing the Traffic of Immune Cells");
  addFooter(sl, 8);

  sl.addText("Chemokines are chemotactic cytokines that direct leukocyte migration. ~50 members; classified by conserved cysteine residue motifs.", {
    x: 0.4, y: 1.0, w: 12.5, h: 0.5, fontSize: 12, color: C.textMid, italic: true, fontFace: "Calibri",
  });

  // families
  const families = [
    { name: "CXC (α-chemokines)", color: C.teal, ex: "CXCL8 (IL-8), CXCL10 (IP-10), CXCL12 (SDF-1)", target: "Neutrophils, T cells, stem cells", note: "CXCL8: acute neutrophil recruitment; CXCL12/CXCR4: HIV co-receptor, stem cell homing" },
    { name: "CC (β-chemokines)", color: C.purple, ex: "CCL2 (MCP-1), CCL3 (MIP-1α), CCL5 (RANTES)", target: "Monocytes, T cells, NK cells, eosinophils", note: "CCL2 drives monocyte/macrophage recruitment in atherosclerosis, IBD; CCR5 = HIV co-receptor" },
    { name: "C (γ-chemokines)", color: C.green, ex: "XCL1 (lymphotactin)", target: "CD8+ T cells, NK cells", note: "Single cysteine; lymphoid tissue homing" },
    { name: "CX3C (δ-chemokines)", color: C.amber, ex: "CX3CL1 (fractalkine)", target: "Monocytes, NK cells, T cells", note: "Unique: membrane-bound form (adhesion) vs soluble form (chemoattraction)" },
  ];
  families.forEach((f, i) => {
    const y = 1.65 + i * 1.38;
    sl.addShape(pres.ShapeType.rect, { x: 0.4, y, w: 2.2, h: 1.2, fill: { color: f.color }, line: { color: f.color } });
    sl.addText(f.name, { x: 0.45, y: y + 0.02, w: 2.1, h: 1.16, fontSize: 11, bold: true, color: C.white, fontFace: "Calibri", valign: "middle", align: "center" });
    sl.addShape(pres.ShapeType.rect, { x: 2.6, y, w: 10.3, h: 1.2, fill: { color: i % 2 === 0 ? "EFF6FF" : C.white }, line: { color: "D0E4F5", width: 0.5 } });
    sl.addText([
      { text: "Key Members: ", options: { bold: true } }, { text: f.ex + "\n" },
      { text: "Targets: ", options: { bold: true } }, { text: f.target + "\n" },
      { text: "Note: ", options: { bold: true, italic: true } }, { text: f.note },
    ], { x: 2.7, y: y + 0.08, w: 10.1, h: 1.04, fontSize: 10.5, color: C.textDark, fontFace: "Calibri", valign: "top" });
  });

  sl.addText("Pathology Pearl: Viruses encode chemokine decoy receptors to evade immunity (e.g., HCMV US28). Chemokine receptor expression on tumor cells influences metastatic tropism.", {
    x: 0.4, y: 7.0, w: 12.5, h: 0.44,
    fontSize: 10.5, italic: true, color: C.teal, fontFace: "Calibri",
  });
}

// ═══════════════════════════════════════════════════════════════════════════════
// SLIDE 9 — THE INFLAMMASOME
// ═══════════════════════════════════════════════════════════════════════════════
{
  const sl = pres.addSlide();
  lightSlide(sl);
  addSlideTitle(sl, "The Inflammasome — Gateway to IL-1β and IL-18");
  addFooter(sl, 9);

  sl.addText("The inflammasome is a cytosolic multiprotein complex that activates Caspase-1, enabling cleavage of pro-IL-1β and pro-IL-18 into active forms, and triggering pyroptosis.", {
    x: 0.4, y: 1.0, w: 12.5, h: 0.55, fontSize: 12, color: C.textMid, fontFace: "Calibri",
  });

  // NLRP3 box
  sl.addShape(pres.ShapeType.roundRect, { x: 0.4, y: 1.65, w: 5.5, h: 5.55, fill: { color: C.white }, line: { color: C.red, width: 2.5 }, rectRadius: 0.1 });
  sl.addShape(pres.ShapeType.rect, { x: 0.4, y: 1.65, w: 5.5, h: 0.44, fill: { color: C.red }, line: { color: C.red } });
  sl.addText("NLRP3 Inflammasome (Best Characterized)", { x: 0.55, y: 1.67, w: 5.2, h: 0.4, fontSize: 12, bold: true, color: C.white, fontFace: "Calibri", margin: 0 });
  sl.addText([
    { text: "Components: NLRP3 sensor + ASC adaptor + Caspase-1\n\n" },
    { text: "SIGNAL 1 (Priming):\n", options: { bold: true } },
    { text: "TLR/NF-κB → upregulates NLRP3 & pro-IL-1β expression\n\n" },
    { text: "SIGNAL 2 (Activation triggers):\n", options: { bold: true } },
    { text: "• Crystalline substances: MSU (gout), CPPD, cholesterol crystals, asbestos, silica\n• ATP (danger signal, P2X7 receptor)\n• K⁺ efflux (pore-forming toxins)\n• Mitochondrial ROS & mtDNA\n• Lysosomal damage\n\n" },
    { text: "OUTCOMES:\n", options: { bold: true } },
    { text: "• Caspase-1 activation\n• IL-1β & IL-18 secretion\n• Gasdermin D cleavage → membrane pores\n• Pyroptotic cell death (lytic, proinflammatory)\n\n" },
    { text: "DISEASE: Gout, pseudogout, atherosclerosis,\ntype 2 diabetes (islet amyloid), Muckle-Wells\nsyndrome, CAPS, NLRP3 gain-of-function diseases" },
  ], { x: 0.55, y: 2.16, w: 5.2, h: 4.9, fontSize: 10.5, color: C.textDark, fontFace: "Calibri", valign: "top" });

  // other inflammasomes
  sl.addShape(pres.ShapeType.roundRect, { x: 6.15, y: 1.65, w: 6.9, h: 2.4, fill: { color: C.white }, line: { color: C.amber, width: 2 }, rectRadius: 0.08 });
  sl.addShape(pres.ShapeType.rect, { x: 6.15, y: 1.65, w: 6.9, h: 0.4, fill: { color: C.amber }, line: { color: C.amber } });
  sl.addText("Other Inflammasome Complexes", { x: 6.3, y: 1.67, w: 6.6, h: 0.36, fontSize: 12, bold: true, color: C.white, fontFace: "Calibri", margin: 0 });
  sl.addText([
    { text: "NLRP1: ", options: { bold: true } }, { text: "Anthrax lethal toxin, MDP → activates Caspase-1, Caspase-5\n" },
    { text: "NLRC4 (IPAF): ", options: { bold: true } }, { text: "Bacterial flagellin, T3SS → Salmonella, Legionella defense\n" },
    { text: "AIM2: ", options: { bold: true } }, { text: "Cytosolic dsDNA (viral/bacterial) → Caspase-1 via ASC\n" },
    { text: "Pyrin: ", options: { bold: true } }, { text: "Rho GTPase inhibition by toxins → activated in FMF" },
  ], { x: 6.3, y: 2.12, w: 6.6, h: 1.85, fontSize: 10.5, color: C.textDark, fontFace: "Calibri", valign: "top" });

  // pyroptosis box
  sl.addShape(pres.ShapeType.roundRect, { x: 6.15, y: 4.15, w: 6.9, h: 3.05, fill: { color: C.white }, line: { color: C.purple, width: 2 }, rectRadius: 0.08 });
  sl.addShape(pres.ShapeType.rect, { x: 6.15, y: 4.15, w: 6.9, h: 0.4, fill: { color: C.purple }, line: { color: C.purple } });
  sl.addText("Pyroptosis vs Apoptosis vs Necrosis", { x: 6.3, y: 4.17, w: 6.6, h: 0.36, fontSize: 12, bold: true, color: C.white, fontFace: "Calibri", margin: 0 });
  const comp = [
    ["Feature", "Pyroptosis", "Apoptosis", "Necrosis"],
    ["Trigger", "Inflammasome/Caspase-1", "Caspase-3/7/9", "Membrane disruption"],
    ["Morphology", "Pores, cell swelling, lysis", "Shrinkage, blebbing, apoptotic bodies", "Swelling, early membrane rupture"],
    ["Inflammation", "Pro-inflammatory (IL-1β, IL-18)", "Anti-inflammatory", "Pro-inflammatory"],
    ["Gasdermin D", "Yes (cleaved)", "No", "No"],
  ];
  comp.forEach((row, ri) => {
    row.forEach((cell, ci) => {
      const cx = 6.15 + ci * 1.73;
      const cy = 4.6 + ri * 0.48;
      const bg = ri === 0 ? C.navy : (ri % 2 === 0 ? "F0F4FF" : C.white);
      sl.addShape(pres.ShapeType.rect, { x: cx, y: cy, w: 1.73, h: 0.48, fill: { color: bg }, line: { color: "C0D0E8", width: 0.5 } });
      sl.addText(cell, { x: cx + 0.04, y: cy + 0.04, w: 1.65, h: 0.4, fontSize: ri === 0 ? 9 : 8.5, bold: ri === 0, color: ri === 0 ? C.white : C.textDark, fontFace: "Calibri", valign: "middle" });
    });
  });
}

// ═══════════════════════════════════════════════════════════════════════════════
// SLIDE 10 — TH1/TH2/TH17/TREG CYTOKINE AXIS
// ═══════════════════════════════════════════════════════════════════════════════
{
  const sl = pres.addSlide();
  lightSlide(sl);
  addSlideTitle(sl, "T Helper Cell Subsets and Their Cytokine Profiles");
  addFooter(sl, 10);

  const subsets = [
    {
      name: "Th1", color: C.teal, drive: "IL-12 + IFN-γ", transcription: "T-bet",
      cytokines: "IFN-γ, IL-2, TNF-α, LT",
      function: "Macrophage activation, CTL induction, intracellular pathogen defense (mycobacteria, Leishmania), granuloma formation",
      disease: "Organ-specific autoimmunity (T1DM, MS, Crohn's), sarcoidosis, contact dermatitis",
    },
    {
      name: "Th2", color: C.amber, drive: "IL-4 (TSLP, IL-25, IL-33)", transcription: "GATA-3",
      cytokines: "IL-4, IL-5, IL-13, IL-10, IL-25",
      function: "IgE class switching (IL-4), eosinophil recruitment (IL-5), mucus production (IL-13), mast cell activation, anti-parasitic",
      disease: "Atopy (asthma, allergic rhinitis, atopic dermatitis), helminth-induced immunopathology, IL-13 in fibrosis",
    },
    {
      name: "Th17", color: C.red, drive: "TGF-β + IL-6 (IL-23 for maintenance)", transcription: "RORγt",
      cytokines: "IL-17A, IL-17F, IL-21, IL-22, GM-CSF",
      function: "Neutrophil recruitment (IL-8 induction), mucosal barrier defense (IL-22), extracellular bacteria & fungi (Candida, Klebsiella)",
      disease: "Psoriasis, RA, ankylosing spondylitis, IBD, MS. IL-17 and IL-23 blockers now first-line in many conditions",
    },
    {
      name: "Treg", color: C.green, drive: "TGF-β + IL-2 (thymus or peripheral)", transcription: "FoxP3",
      cytokines: "IL-10, TGF-β, IL-35",
      function: "Suppress effector T cells, maintain tolerance to self-antigens, prevent autoimmunity, tumor immune evasion, maternal tolerance",
      disease: "FoxP3 mutation → IPEX syndrome (polyendocrinopathy, enteropathy). Reduced in autoimmunity; increased in tumor microenvironment",
    },
  ];
  subsets.forEach((s, i) => {
    const x = 0.4 + i * 3.24;
    sl.addShape(pres.ShapeType.roundRect, { x, y: 1.05, w: 3.1, h: 6.15, fill: { color: C.white }, line: { color: s.color, width: 2.5 }, rectRadius: 0.1 });
    sl.addShape(pres.ShapeType.rect, { x, y: 1.05, w: 3.1, h: 0.5, fill: { color: s.color }, line: { color: s.color } });
    sl.addText(`T${s.name} (${s.transcription})`, { x: x + 0.1, y: 1.07, w: 2.9, h: 0.46, fontSize: 12, bold: true, color: C.white, fontFace: "Calibri", margin: 0 });
    sl.addText([
      { text: "Driven by:\n", options: { bold: true, color: s.color } }, { text: s.drive + "\n\n" },
      { text: "Key Cytokines:\n", options: { bold: true, color: s.color } }, { text: s.cytokines + "\n\n" },
      { text: "Function:\n", options: { bold: true, color: s.color } }, { text: s.function + "\n\n" },
      { text: "Disease:\n", options: { bold: true, color: s.color } }, { text: s.disease },
    ], { x: x + 0.12, y: 1.62, w: 2.86, h: 5.5, fontSize: 9.8, color: C.textDark, fontFace: "Calibri", valign: "top" });
  });
}

// ═══════════════════════════════════════════════════════════════════════════════
// SLIDE 11 — CYTOKINES IN ACUTE INFLAMMATION
// ═══════════════════════════════════════════════════════════════════════════════
{
  const sl = pres.addSlide();
  lightSlide(sl);
  addSlideTitle(sl, "Cytokines in Acute Inflammation — From Stimulus to Response");
  addFooter(sl, 11);

  // timeline arrow
  sl.addShape(pres.ShapeType.rect, { x: 0.4, y: 3.4, w: 12.5, h: 0.12, fill: { color: C.teal }, line: { color: C.teal } });
  sl.addShape(pres.ShapeType.triangle, { x: 12.7, y: 3.22, w: 0.3, h: 0.48, fill: { color: C.teal }, line: { color: C.teal } });
  const steps = [
    { x: 0.4, label: "STIMULUS\n(PAMPs/DAMPs)", sub: "Bacteria, necrosis,\ncrystals, trauma", color: C.navy },
    { x: 2.9, label: "PATTERN\nRECOGNITION", sub: "TLRs, NLRs,\ncGAS-STING", color: C.tealDark },
    { x: 5.4, label: "EARLY CYTOKINES\n(0-2 hrs)", sub: "TNF-α, IL-1β,\nIL-6, CXCL8", color: C.red },
    { x: 7.9, label: "VASCULAR\nCHANGES", sub: "Vasodilation,\npermeability ↑", color: C.purple },
    { x: 10.4, label: "LEUKOCYTE\nRECRUITMENT", sub: "Margination →\nTransmigration", color: C.green },
  ];
  steps.forEach((s, i) => {
    sl.addShape(pres.ShapeType.roundRect, { x: s.x, y: 1.1, w: 2.3, h: 2.1, fill: { color: s.color }, line: { color: s.color }, rectRadius: 0.1 });
    sl.addText(s.label, { x: s.x + 0.1, y: 1.2, w: 2.1, h: 0.9, fontSize: 11, bold: true, color: C.white, fontFace: "Calibri", align: "center", valign: "middle" });
    sl.addText(s.sub, { x: s.x + 0.1, y: 2.15, w: 2.1, h: 0.9, fontSize: 10, color: C.cyan, fontFace: "Calibri", align: "center", valign: "middle" });
    if (i < steps.length - 1) {
      sl.addShape(pres.ShapeType.triangle, { x: s.x + 2.32, y: 1.9, w: 0.25, h: 0.4, fill: { color: C.cyan }, line: { color: C.cyan }, rotate: 90 });
    }
    // connector dot on timeline
    sl.addShape(pres.ShapeType.ellipse, { x: s.x + 0.98, y: 3.34, w: 0.22, h: 0.22, fill: { color: C.navy }, line: { color: C.navy } });
  });

  // local vs systemic
  sl.addShape(pres.ShapeType.roundRect, { x: 0.4, y: 3.75, w: 5.9, h: 3.35, fill: { color: "E8F5E9" }, line: { color: C.green, width: 2 }, rectRadius: 0.08 });
  sl.addShape(pres.ShapeType.rect, { x: 0.4, y: 3.75, w: 5.9, h: 0.4, fill: { color: C.green }, line: { color: C.green } });
  sl.addText("LOCAL Effects (Low Concentration)", { x: 0.55, y: 3.77, w: 5.6, h: 0.36, fontSize: 11, bold: true, color: C.white, fontFace: "Calibri", margin: 0 });
  sl.addText([
    "• Vasodilation → erythema (rubor), warmth (calor)\n",
    "• Vascular permeability → edema (tumor)\n",
    "• Neutrophil & monocyte recruitment\n",
    "• Pain sensitization (dolor) via PGE2, bradykinin\n",
    "• Tissue repair & healing initiation\n",
    "• Loss of function (functio laesa)\n",
    "• Antimicrobial activity (ROS, NO from macrophages)\n",
  ].join(""), { x: 0.55, y: 4.22, w: 5.6, h: 2.75, fontSize: 10.5, color: C.textDark, fontFace: "Calibri", valign: "top" });

  sl.addShape(pres.ShapeType.roundRect, { x: 6.8, y: 3.75, w: 6.1, h: 3.35, fill: { color: "FFEBEE" }, line: { color: C.red, width: 2 }, rectRadius: 0.08 });
  sl.addShape(pres.ShapeType.rect, { x: 6.8, y: 3.75, w: 6.1, h: 0.4, fill: { color: C.red }, line: { color: C.red } });
  sl.addText("SYSTEMIC Effects (High Concentration)", { x: 6.95, y: 3.77, w: 5.8, h: 0.36, fontSize: 11, bold: true, color: C.white, fontFace: "Calibri", margin: 0 });
  sl.addText([
    { text: "FEVER: ", options: { bold: true } }, { text: "IL-1, TNF, IL-6 → hypothalamus → COX-2 → PGE2 → ↑ set point\n" },
    { text: "ACUTE PHASE RESPONSE: ", options: { bold: true } }, { text: "IL-6 + IL-1 → hepatic APR proteins\n" },
    { text: "  ↑ CRP, SAA, fibrinogen, ferritin, complement, hepcidin\n" },
    { text: "  ↓ Albumin, transferrin, pre-albumin (negative reactants)\n" },
    { text: "LEUKOCYTOSIS: ", options: { bold: true } }, { text: "CSFs → bone marrow mobilization; demargination\n" },
    { text: "METABOLIC: ", options: { bold: true } }, { text: "Cachexia, insulin resistance, gluconeogenesis ↑\n" },
    { text: "SHOCK (excess): ", options: { bold: true } }, { text: "Vasodilation, ↓ SVR, DIC, multi-organ failure" },
  ], { x: 6.95, y: 4.22, w: 5.8, h: 2.75, fontSize: 10.5, color: C.textDark, fontFace: "Calibri", valign: "top" });
}

// ═══════════════════════════════════════════════════════════════════════════════
// SLIDE 12 — CYTOKINE STORM
// ═══════════════════════════════════════════════════════════════════════════════
{
  const sl = pres.addSlide();
  darkSlide(sl);

  // red accent stripe top
  sl.addShape(pres.ShapeType.rect, { x: 0, y: 0, w: 13.3, h: 0.25, fill: { color: C.red }, line: { color: C.red } });

  sl.addText("CYTOKINE STORM", {
    x: 0.4, y: 0.35, w: 12.5, h: 0.85,
    fontSize: 38, bold: true, color: C.white, fontFace: "Calibri", charSpacing: 4,
  });
  sl.addText("Dysregulated Systemic Hyperinflammation", {
    x: 0.4, y: 1.22, w: 12.5, h: 0.42, fontSize: 18, color: C.red, italic: true, fontFace: "Calibri",
  });

  const boxes = [
    { title: "Definition & Mechanism", color: C.teal, x: 0.4, y: 1.75, items: [
      "Uncontrolled systemic cytokine release leading to multi-organ dysfunction",
      "Positive feedback loops: cytokines → immune cell activation → more cytokines",
      "Key mediators: IL-6, IL-1β, TNF-α, IL-18, IFN-γ, IL-10, CXCL8",
      "Endothelial injury → vascular leak → ARDS, AKI, DIC",
    ]},
    { title: "Triggers / Etiologies", color: C.amber, x: 0.4, y: 4.0, items: [
      "Infections: severe sepsis, influenza H5N1, COVID-19, EBV, CMV",
      "CAR-T cell therapy & checkpoint inhibitors (irAE)",
      "Hemophagocytic Lymphohistiocytosis (HLH) — primary & secondary",
      "Macrophage Activation Syndrome (MAS/sHLH) in Still's, SLE, AOSD",
      "Hematopoietic SCT (graft-vs-host disease)",
    ]},
    { title: "HLH Criteria (HScore/HLH-2004)", color: C.purple, x: 7.1, y: 1.75, items: [
      "Fever ≥38.5°C + Splenomegaly",
      "Cytopenias ≥2 cell lines",
      "Hypertriglyceridemia and/or hypofibrinogenemia",
      "Hemophagocytosis in bone marrow/spleen/LN",
      "Low/absent NK cell activity",
      "Ferritin ≥500 μg/L (>10,000 very suggestive)",
      "Elevated soluble CD25 (sIL-2Rα) ≥2400 U/mL",
    ]},
    { title: "Treatment Principles", color: C.red, x: 7.1, y: 4.0, items: [
      "Treat underlying cause (antimicrobials, tumor therapy)",
      "HLH: Dexamethasone + Etoposide (HLH-94 protocol)",
      "CAR-T CRS: Tocilizumab (anti-IL-6R) ± dexamethasone",
      "Anakinra (anti-IL-1) for MAS/refractory HLH",
      "Ruxolitinib (JAK1/2 inhibitor) in refractory cases",
      "Emapalumab (anti-IFN-γ) for primary HLH",
    ]},
  ];

  boxes.forEach(b => {
    sl.addShape(pres.ShapeType.roundRect, { x: b.x, y: b.y, w: 6.5, h: 2.0, fill: { color: "111F30" }, line: { color: b.color, width: 2 }, rectRadius: 0.08 });
    sl.addShape(pres.ShapeType.rect, { x: b.x, y: b.y, w: 6.5, h: 0.38, fill: { color: b.color }, line: { color: b.color } });
    sl.addText(b.title, { x: b.x + 0.12, y: b.y + 0.04, w: 6.26, h: 0.3, fontSize: 11, bold: true, color: C.white, fontFace: "Calibri", margin: 0 });
    const items = b.items.map((t, i) => ({ text: t, options: { bullet: { code: "2022" }, breakLine: i < b.items.length - 1, fontSize: 10, color: C.white, fontFace: "Calibri", paraSpaceBefore: 3 } }));
    sl.addText(items, { x: b.x + 0.16, y: b.y + 0.44, w: 6.18, h: 1.48, valign: "top" });
  });

  addFooter(sl, 12);
}

// ═══════════════════════════════════════════════════════════════════════════════
// SLIDE 13 — CYTOKINES IN AUTOIMMUNITY
// ═══════════════════════════════════════════════════════════════════════════════
{
  const sl = pres.addSlide();
  lightSlide(sl);
  addSlideTitle(sl, "Cytokines in Autoimmune and Inflammatory Diseases");
  addFooter(sl, 13);

  const diseases = [
    { name: "Rheumatoid Arthritis", cytokines: "TNF-α ↑↑, IL-1β ↑, IL-6 ↑, IL-17 ↑", mech: "Synovial macrophage/T cell activation → pannus; TNF drives osteoclastogenesis via RANKL", therapy: "Anti-TNF, anti-IL-6R (tocilizumab), anti-IL-17, JAK inhibitors (tofacitinib)", color: C.red },
    { name: "Inflammatory Bowel Disease", cytokines: "IL-12/23 ↑ (Crohn's), IL-13 ↑ (UC), TNF-α ↑, IL-6 ↑", mech: "Dysregulated mucosal immunity; Th1/Th17 in CD; Th2 in UC; IL-23/IL-17 axis dominant", therapy: "Anti-TNF (infliximab), anti-IL-12/23 (ustekinumab), anti-IL-23 (risankizumab)", color: C.amber },
    { name: "Psoriasis", cytokines: "IL-17A ↑↑, IL-23 ↑↑, TNF-α ↑, IL-22 ↑", mech: "pDC → IL-12/23 → Th17 → IL-17 → keratinocyte hyperproliferation; neutrophil recruitment (Munro's microabscesses)", therapy: "Anti-IL-17 (secukinumab, ixekizumab), anti-IL-23 (guselkumab), anti-TNF, anti-IL-12/23", color: C.purple },
    { name: "Systemic Lupus Erythematosus", cytokines: "Type I IFN ↑↑ (IFN signature), IL-6 ↑, BAFF ↑, IL-10 ↑", mech: "Autoantibodies → immune complexes → pDC activation → type I IFN → B cell activation → more autoAbs", therapy: "Hydroxychloroquine, belimumab (anti-BAFF), anifrolumab (anti-IFNAR), voclosporin", color: C.teal },
    { name: "Asthma / Atopy", cytokines: "IL-4 ↑, IL-5 ↑, IL-13 ↑, IL-33 ↑, TSLP ↑", mech: "Th2/ILC2 activation; IL-4 drives IgE; IL-5 → eosinophilia; IL-13 → mucus, AHR, goblet cell metaplasia", therapy: "Anti-IL-5 (mepolizumab), anti-IL-4Rα (dupilumab), anti-IgE (omalizumab), anti-TSLP (tezepelumab)", color: C.green },
    { name: "Ankylosing Spondylitis", cytokines: "IL-17A ↑↑, IL-23 ↑, TNF-α ↑, IL-22 ↑", mech: "HLA-B27 dysregulation of IL-23/17 axis; entheseal inflammation; new bone formation via IL-22/Wnt signaling", therapy: "Anti-IL-17 (secukinumab first-line if anti-TNF fails), NSAIDs, JAK inhibitors", color: C.tealDark },
  ];

  diseases.forEach((d, i) => {
    const row = Math.floor(i / 2);
    const col = i % 2;
    const x = 0.4 + col * 6.5;
    const y = 1.1 + row * 2.1;
    sl.addShape(pres.ShapeType.roundRect, { x, y, w: 6.25, h: 1.95, fill: { color: C.white }, line: { color: d.color, width: 2 }, rectRadius: 0.08 });
    sl.addShape(pres.ShapeType.rect, { x, y, w: 6.25, h: 0.38, fill: { color: d.color }, line: { color: d.color } });
    sl.addText(d.name, { x: x + 0.1, y: y + 0.04, w: 6.05, h: 0.3, fontSize: 11.5, bold: true, color: C.white, fontFace: "Calibri", margin: 0 });
    sl.addText([
      { text: "Cytokines: ", options: { bold: true } }, { text: d.cytokines + "\n" },
      { text: "Mechanism: ", options: { bold: true } }, { text: d.mech + "\n" },
      { text: "Therapy: ", options: { bold: true, color: d.color } }, { text: d.therapy },
    ], { x: x + 0.12, y: y + 0.44, w: 6.01, h: 1.44, fontSize: 9.8, color: C.textDark, fontFace: "Calibri", valign: "top" });
  });
}

// ═══════════════════════════════════════════════════════════════════════════════
// SLIDE 14 — CYTOKINES IN CANCER
// ═══════════════════════════════════════════════════════════════════════════════
{
  const sl = pres.addSlide();
  lightSlide(sl);
  addSlideTitle(sl, "Cytokines in Cancer — Tumor Promotion, Suppression & Immunotherapy");
  addFooter(sl, 14);

  sectionBox(sl, 0.4, 1.05, 5.9, 3.0, "PRO-TUMOR CYTOKINES", [
    "IL-6: Activates STAT3 → anti-apoptosis, proliferation (multiple myeloma, HCC, CRC)",
    "IL-10: Immunosuppressive TME; inhibits DC & T cell function; elevated in NHL",
    "TGF-β: Suppresses CTL & NK cells; promotes Treg expansion & fibrosis in stroma",
    "VEGF (cytokine-like): Tumor angiogenesis; anti-VEGF = bevacizumab",
    "M-CSF/CSF1: Drives M2 macrophage polarization in TME → immune evasion",
    "IL-17: Promotes angiogenesis and tumor progression (context-dependent)",
  ], C.red);

  sectionBox(sl, 6.5, 1.05, 6.4, 3.0, "ANTI-TUMOR CYTOKINES", [
    "IFN-γ: MHC-I upregulation → CTL killing; M1 macrophage activation; antiproliferative",
    "TNF-α: Direct tumor necrosis at high concentrations (historical, isolated limb perfusion)",
    "IL-2: T cell proliferation; CD8+ CTL & NK activation; used in melanoma/RCC (IL-2 therapy)",
    "IL-12: Th1 polarization; NK & CTL activation; cancer vaccine adjuvant",
    "IL-15: NK cell development and maintenance; memory T cell homeostasis",
    "IFN-α: Antiproliferative; used in HCL, CML, KS",
  ], C.green);

  sectionBox(sl, 0.4, 4.25, 5.9, 2.85, "CYTOKINES IN TUMOR MICROENVIRONMENT (TME)", [
    "TME typically immunosuppressive: IL-10, TGF-β, IL-6 dominate",
    "Tumor-associated macrophages (TAM) polarized to M2 by IL-4, IL-13, M-CSF",
    "MDSCs suppress T cells via IL-10, TGF-β, IL-6, arginase",
    "Tregs recruited by CCL22; suppressed via IL-10 and TGF-β",
    "Hypoxia-induced IL-6/STAT3 loop → therapeutic resistance",
    "Hot vs Cold tumors: IFN-γ signature = hot tumor = better response to PD-1 blockade",
  ], C.amber);

  sectionBox(sl, 6.5, 4.25, 6.4, 2.85, "CYTOKINE-BASED CANCER THERAPEUTICS", [
    "Recombinant IL-2: Metastatic melanoma, RCC (capillary leak = major toxicity)",
    "IFN-α2b: Adjuvant melanoma, HCL, follicular lymphoma",
    "Checkpoint inhibitors (PD-1/CTLA-4) → re-activate IFN-γ & cytotoxic programs",
    "CAR-T therapy → CRS (treat with tocilizumab)",
    "IL-15 superagonist (N-803): NK/T cell expansion",
    "Anti-TGF-β: Multiple trials in combination with checkpoint blockade",
  ], C.purple);
}

// ═══════════════════════════════════════════════════════════════════════════════
// SLIDE 15 — CYTOKINES IN INFECTIOUS DISEASE
// ═══════════════════════════════════════════════════════════════════════════════
{
  const sl = pres.addSlide();
  lightSlide(sl);
  addSlideTitle(sl, "Cytokines in Infectious Disease");
  addFooter(sl, 15);

  const data = [
    { pathogen: "Gram-negative bacteria / Sepsis", cytokines: "TNF-α, IL-1β, IL-6, CXCL8, IL-18", outcome: "LPS → macrophage activation → TNF → septic shock; DIC; multi-organ failure", protection: "Early controlled TNF/IL-1 → neutrophil recruitment & pathogen clearance" },
    { pathogen: "Mycobacterium tuberculosis", cytokines: "IFN-γ, TNF-α, IL-12, IL-23", outcome: "IFN-γ/TNF → granuloma containment; IFN-γR/IL-12R defects → disseminated TB", protection: "Th1 response essential; anti-TNF therapy risks TB reactivation" },
    { pathogen: "SARS-CoV-2 / COVID-19", cytokines: "IL-6 ↑↑, IL-10 ↑, TNF ↑, IFN-λ, CXCL10", outcome: "Severe disease: cytokine storm, ARDS, endotheliitis; delayed Type I IFN response", protection: "Early IFN-I response → mild disease; late dysregulated IL-6 → severe" },
    { pathogen: "HIV/AIDS", cytokines: "TNF-α ↑, IL-6 ↑, IL-10 ↑, IFN-α ↑ (chronic)", outcome: "Chronic immune activation → CD4 depletion; IL-10 impairs HIV clearance; viral IL-10 homolog (EBV)", protection: "CXCR4/CCR5 used by HIV as co-receptors; CCR5 Δ32 mutation → resistance" },
    { pathogen: "Helminth infections", cytokines: "IL-4, IL-5, IL-13, IL-33, TSLP", outcome: "Type 2 response; protective expulsion vs pathologic fibrosis (liver, lung)", protection: "IL-5 → eosinophilia; IL-4/13 → smooth muscle contraction, mucus, IgE" },
    { pathogen: "Viral immune evasion", cytokines: "IFN system targeted", outcome: "CMV: IL-10 homolog (UL111A); HCMV: US28 chemokine decoy receptor", protection: "EBV BCRF1 (vIL-10) suppresses macrophages; adenovirus VAI RNA blocks PKR" },
  ];

  const cols = [2.8, 2.5, 3.3, 3.6];
  const colX = [0.4, 3.2, 5.7, 9.0];
  const headers = ["Pathogen", "Key Cytokines", "Pathology", "Protective Role / Note"];
  headers.forEach((h, i) => {
    sl.addShape(pres.ShapeType.rect, { x: colX[i], y: 1.1, w: cols[i], h: 0.4, fill: { color: C.navy }, line: { color: C.navy } });
    sl.addText(h, { x: colX[i] + 0.06, y: 1.12, w: cols[i] - 0.12, h: 0.36, fontSize: 10, bold: true, color: C.white, fontFace: "Calibri", margin: 0 });
  });
  data.forEach((row, ri) => {
    const bg = ri % 2 === 0 ? "EFF6FF" : C.white;
    const cells = [row.pathogen, row.cytokines, row.outcome, row.protection];
    cells.forEach((cell, ci) => {
      sl.addShape(pres.ShapeType.rect, { x: colX[ci], y: 1.5 + ri * 0.9, w: cols[ci], h: 0.9, fill: { color: bg }, line: { color: "D0E4F5", width: 0.5 } });
      sl.addText(cell, { x: colX[ci] + 0.07, y: 1.54 + ri * 0.9, w: cols[ci] - 0.14, h: 0.82, fontSize: 9, color: C.textDark, fontFace: "Calibri", valign: "middle" });
    });
  });
}

// ═══════════════════════════════════════════════════════════════════════════════
// SLIDE 16 — TGF-β & IL-17: FIBROSIS & BARRIER IMMUNITY
// ═══════════════════════════════════════════════════════════════════════════════
{
  const sl = pres.addSlide();
  lightSlide(sl);
  addSlideTitle(sl, "TGF-β and IL-17 — Fibrosis, Barrier Immunity & Autoimmunity");
  addFooter(sl, 16);

  // TGF-β
  sl.addShape(pres.ShapeType.roundRect, { x: 0.4, y: 1.05, w: 6.1, h: 5.9, fill: { color: C.white }, line: { color: C.tealDark, width: 2.5 }, rectRadius: 0.1 });
  sl.addShape(pres.ShapeType.rect, { x: 0.4, y: 1.05, w: 6.1, h: 0.48, fill: { color: C.tealDark }, line: { color: C.tealDark } });
  sl.addText("TGF-β (Transforming Growth Factor-β)", { x: 0.55, y: 1.08, w: 5.8, h: 0.42, fontSize: 13, bold: true, color: C.white, fontFace: "Calibri", margin: 0 });
  sl.addText([
    { text: "Isoforms: ", options: { bold: true } }, { text: "TGF-β1 (immune), TGF-β2 (tissue), TGF-β3 (palatal fusion)\n" },
    { text: "Receptor: ", options: { bold: true } }, { text: "TGFβRI/II → SMAD2/3 → SMAD4 → transcription\n" },
    { text: "Secreted in latent form (LTBP); activated by proteases, ROS, integrins\n\n" },
    { text: "ANTI-INFLAMMATORY ROLES:\n", options: { bold: true, color: C.tealDark } },
    { text: "• Inhibits T cell, B cell, macrophage, NK cell activation\n• Induces Foxp3+ Treg differentiation (with IL-2)\n• Suppresses Th1 and Th2 responses\n• Counter-regulatory during chronic inflammation\n\n" },
    { text: "PRO-FIBROTIC ROLES:\n", options: { bold: true, color: C.tealDark } },
    { text: "• Activates fibroblasts → myofibroblast transformation\n• ↑ Collagen, fibronectin, ECM synthesis\n• ↓ Matrix metalloproteinases (MMP inhibition)\n• Epithelial-to-mesenchymal transition (EMT)\n\n" },
    { text: "DISEASE:\n", options: { bold: true, color: C.tealDark } },
    { text: "• IPF (↑ TGF-β1 in fibrotic foci)\n• Systemic sclerosis (scleroderma)\n• Post-organ transplant fibrosis\n• CKD → glomerulosclerosis, tubular atrophy\n• Camurati-Engelmann disease (TGF-β1 gain of function)\n• Dual role in cancer: tumor suppressor early → promoter late (EMT, immune evasion)\n\n" },
    { text: "Rx: Pirfenidone (IPF, partly via TGF-β), nintedanib, anti-TGF-β trials in SSc/cancer" },
  ], { x: 0.55, y: 1.6, w: 5.8, h: 5.25, fontSize: 10.3, color: C.textDark, fontFace: "Calibri", valign: "top" });

  // IL-17
  sl.addShape(pres.ShapeType.roundRect, { x: 6.9, y: 1.05, w: 6.0, h: 5.9, fill: { color: C.white }, line: { color: C.red, width: 2.5 }, rectRadius: 0.1 });
  sl.addShape(pres.ShapeType.rect, { x: 6.9, y: 1.05, w: 6.0, h: 0.48, fill: { color: C.red }, line: { color: C.red } });
  sl.addText("IL-17 Family — Mucosal Guardian & Autoimmune Driver", { x: 7.05, y: 1.08, w: 5.7, h: 0.42, fontSize: 13, bold: true, color: C.white, fontFace: "Calibri", margin: 0 });
  sl.addText([
    { text: "Members: ", options: { bold: true } }, { text: "IL-17A (main), IL-17B-F, IL-25 (IL-17E)\n" },
    { text: "Sources: ", options: { bold: true } }, { text: "Th17 cells, ILC3, γδ T cells, mast cells, neutrophils\n" },
    { text: "Receptor: ", options: { bold: true } }, { text: "IL-17RA/RC → Act1 → TRAF6 → NF-κB, MAPK, C/EBP\n\n" },
    { text: "PROTECTIVE IMMUNITY:\n", options: { bold: true, color: C.red } },
    { text: "• Extracellular bacteria: Klebsiella, S. aureus, S. pneumoniae\n• Fungal infections: Candida albicans (mucocutaneous)\n• IL-17 deficiency → chronic mucocutaneous candidiasis\n• IL-22 (related Th17 cytokine) → epithelial barrier, antimicrobial peptides\n\n" },
    { text: "AUTOIMMUNE PATHOLOGY:\n", options: { bold: true, color: C.red } },
    { text: "• Psoriasis: IL-17A drives keratinocyte hyperproliferation\n• Ankylosing spondylitis: entheseal IL-17 → osteitis\n• RA: IL-17 + TNF synergy → pannus formation\n• Multiple sclerosis: Th17 cells in CNS infiltrate\n• IBD: Paradoxical worsening with IL-17 blockade\n\n" },
    { text: "THERAPEUTICS:\n", options: { bold: true, color: C.red } },
    { text: "IL-17A blockers: Secukinumab, ixekizumab (psoriasis, AS, PsA)\n" },
    { text: "IL-17RA blocker: Bimekizumab (also blocks IL-17F)\n" },
    { text: "IL-23 blockers: Guselkumab, risankizumab, tildrakizumab\n" },
    { text: "⚠ IBD contraindication: risk of exacerbation" },
  ], { x: 7.05, y: 1.6, w: 5.7, h: 5.25, fontSize: 10.3, color: C.textDark, fontFace: "Calibri", valign: "top" });
}

// ═══════════════════════════════════════════════════════════════════════════════
// SLIDE 17 — CYTOKINE-TARGETED THERAPEUTICS
// ═══════════════════════════════════════════════════════════════════════════════
{
  const sl = pres.addSlide();
  lightSlide(sl);
  addSlideTitle(sl, "Cytokine-Targeted Therapeutics — Biologics & Small Molecules");
  addFooter(sl, 17);

  const drugs = [
    ["Drug (Class)", "Target", "Mechanism", "Indications", "Key Adverse Effects"],
    ["Infliximab / Adalimumab / Golimumab\n(Monoclonal Ab)", "TNF-α", "Neutralize soluble & membrane TNF", "RA, IBD, psoriasis, AS, PsA, JIA, uveitis", "Infections (TB, fungal), demyelination, CHF, lymphoma"],
    ["Etanercept\n(Fc-fusion protein)", "TNF-α/β", "Decoy TNF receptor (TNFR2-Fc)", "RA, psoriasis, AS — NOT for IBD", "Similar to anti-TNF mAbs; less mucosal"],
    ["Tocilizumab\n(Monoclonal Ab)", "IL-6 receptor (IL-6R)", "Blocks IL-6 signaling (soluble + membrane)", "RA, CRS (CAR-T), COVID-19 severe, GCA, Castleman", "Elevated LFTs, dyslipidemia, GI perforation"],
    ["Anakinra\n(IL-1Ra recombinant)", "IL-1R", "Competes with IL-1α/β for receptor binding", "RA, CAPS, Still's disease, MAS, gout (off-label)", "Injection site reactions, infections (short t½)"],
    ["Canakinumab\n(Monoclonal Ab)", "IL-1β", "Directly neutralizes IL-1β", "CAPS, gout, Still's, CANTOS trial (CV)", "Infections, elevated LFTs"],
    ["Secukinumab / Ixekizumab", "IL-17A", "Neutralize IL-17A", "Psoriasis, PsA, AS — avoid in IBD", "Nasopharyngitis, candidiasis, IBD worsening"],
    ["Ustekinumab", "IL-12/23 (p40)", "Blocks both IL-12 and IL-23", "Psoriasis, PsA, Crohn's, UC", "Infections, rare RPLS"],
    ["Dupilumab\n(Monoclonal Ab)", "IL-4Rα (shared IL-4/IL-13)", "Blocks IL-4 and IL-13 signaling", "Atopic dermatitis, asthma, CRSwNP, EoE, PNP", "Conjunctivitis (atopy), injection site"],
    ["Mepolizumab / Benralizumab", "IL-5 / IL-5Rα", "↓ eosinophil production & survival", "Severe eosinophilic asthma, EGPA, HES", "Infections, arthralgia"],
    ["Tofacitinib / Baricitinib / Upadacitinib\n(JAK inhibitors)", "JAK1/2/3 (pan-cytokine)", "Block JAK kinases → ↓ STAT signaling", "RA, PsA, AS, UC, AD, COVID-19 (bari)", "VTE, infections, CV risk, malignancy watch"],
    ["Ruxolitinib\n(JAK1/2 inhibitor)", "JAK1/2", "Broad JAK inhibition", "MF, PV, GVHD, HLH, CRS", "Anemia, infections, reactivation"],
  ];

  const colW2 = [2.6, 1.5, 2.4, 2.9, 3.3];
  const colX2 = [0.4, 3.0, 4.5, 6.9, 9.8];
  drugs.forEach((row, ri) => {
    const bg = ri === 0 ? C.navy : (ri % 2 === 0 ? "EFF6FF" : C.white);
    const isHeader = ri === 0;
    row.forEach((cell, ci) => {
      sl.addShape(pres.ShapeType.rect, { x: colX2[ci], y: 1.1 + ri * 0.555, w: colW2[ci], h: 0.555, fill: { color: bg }, line: { color: "C0D0E8", width: 0.4 } });
      sl.addText(cell, { x: colX2[ci] + 0.05, y: 1.12 + ri * 0.555, w: colW2[ci] - 0.1, h: 0.515, fontSize: isHeader ? 9.5 : 8.8, bold: isHeader, color: isHeader ? C.white : C.textDark, fontFace: "Calibri", valign: "middle" });
    });
  });
}

// ═══════════════════════════════════════════════════════════════════════════════
// SLIDE 18 — SUMMARY & KEY PEARLS
// ═══════════════════════════════════════════════════════════════════════════════
{
  const sl = pres.addSlide();
  darkSlide(sl);

  sl.addShape(pres.ShapeType.rect, { x: 0, y: 0, w: 13.3, h: 0.3, fill: { color: C.cyan }, line: { color: C.cyan } });

  sl.addText("Key Takeaways for the Pathology Resident", {
    x: 0.5, y: 0.4, w: 12.3, h: 0.7, fontSize: 26, bold: true, color: C.white, fontFace: "Calibri",
  });
  sl.addShape(pres.ShapeType.rect, { x: 0.5, y: 1.12, w: 4.0, h: 0.06, fill: { color: C.amber }, line: { color: C.amber } });

  const pearls = [
    { num: "1", text: "Cytokines are context-dependent: the same cytokine (e.g., TNF-α) may be protective in granuloma formation but lethal in septic shock — concentration and tissue context matter.", color: C.teal },
    { num: "2", text: "The IL-6/STAT3 axis drives acute phase response, Th17 polarization, and tumor progression — IL-6 is a unifying thread across many pathological states.", color: C.cyan },
    { num: "3", text: "IFN-γ is the master macrophage activator — defects in the IFN-γ/IL-12 axis lead to susceptibility to intracellular pathogens (mycobacteria, Salmonella).", color: C.amber },
    { num: "4", text: "The NLRP3 inflammasome links 'sterile' crystals (MSU, cholesterol, calcium pyrophosphate) to IL-1β secretion — fundamental to gout, atherosclerosis, and CAPS.", color: C.purple },
    { num: "5", text: "Type I interferon signature in blood is a diagnostic hallmark of SLE — patients with anti-dsDNA antibodies have highest IFN scores and most severe disease.", color: C.green },
    { num: "6", text: "Cytokine Release Syndrome (CRS) — graded by fever, hypotension, hypoxia — is the major toxicity of CAR-T therapy; tocilizumab (anti-IL-6R) is standard treatment.", color: C.red },
    { num: "7", text: "TGF-β is the master fibrosis driver — upregulated in IPF, SSc, renal fibrosis. Its dual role as tumor suppressor (early cancer) and promoter (late cancer/EMT) is a classic pathology concept.", color: C.tealDark },
    { num: "8", text: "JAK inhibitors (tofacitinib, baricitinib, ruxolitinib) target multiple cytokine pathways simultaneously — monitor for VTE, malignancy, and opportunistic infections.", color: C.amber },
  ];

  pearls.forEach((p, i) => {
    const row = Math.floor(i / 2);
    const col = i % 2;
    const x = 0.4 + col * 6.5;
    const y = 1.4 + row * 1.5;
    sl.addShape(pres.ShapeType.roundRect, { x, y, w: 6.25, h: 1.35, fill: { color: "0A1520" }, line: { color: p.color, width: 2 }, rectRadius: 0.08 });
    sl.addShape(pres.ShapeType.ellipse, { x: x + 0.1, y: y + 0.28, w: 0.55, h: 0.55, fill: { color: p.color }, line: { color: p.color } });
    sl.addText(p.num, { x: x + 0.1, y: y + 0.28, w: 0.55, h: 0.55, fontSize: 14, bold: true, color: C.white, fontFace: "Calibri", align: "center", valign: "middle" });
    sl.addText(p.text, { x: x + 0.75, y: y + 0.1, w: 5.4, h: 1.15, fontSize: 10, color: C.white, fontFace: "Calibri", valign: "middle" });
  });

  sl.addText("References: Robbins & Cotran Pathologic Basis of Disease (10e) | Cellular & Molecular Immunology (10e, Abbas et al.) | Harrison's Principles (22e) | Goodman & Gilman's Pharmacological Basis of Therapeutics", {
    x: 0, y: 7.32, w: 13.3, h: 0.22, fontSize: 7.5, color: C.textLight, align: "center", fontFace: "Calibri",
  });
}

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