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pres.layout = "LAYOUT_16x9";
pres.title = "Cytokines: Health and Disease";
pres.author = "Pathology Resident Lecture";

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// ════════════════════════════════════════════════════════════════
// SLIDE 1 – TITLE
// ════════════════════════════════════════════════════════════════
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// ════════════════════════════════════════════════════════════════
// SLIDE 2 – LEARNING OBJECTIVES
// ════════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
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  slideTitle(s, "Learning Objectives");
  const items = [
    "Define cytokines and classify the major cytokine families (TNF, IL, IFN, CSF, chemokines)",
    "Understand cytokine receptors and key signaling pathways (JAK-STAT, NF-κB, MAPK)",
    "Describe the role of cytokines in acute and chronic inflammation",
    "Explain how cytokine dysregulation drives autoimmune disease, cancer, and cytokine storm",
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  footerNote(s, "Sources: Robbins & Cotran Pathologic Basis of Disease; Henry's Clinical Diagnosis & Management; Cellular and Molecular Immunology (Abbas); Roitt's Essential Immunology");
}

// ════════════════════════════════════════════════════════════════
// SLIDE 3 – WHAT ARE CYTOKINES?
// ════════════════════════════════════════════════════════════════
{
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  slideTitle(s, "What Are Cytokines?", "Pleiotropic protein mediators of immune and inflammatory responses");

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  s.addText("The term cytokine encompasses: lymphokines · monokines · interleukins · colony-stimulating factors · interferons · TNF family · chemokines · adipokines", {
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  footerNote(s, "Henry's Clinical Diagnosis & Management by Laboratory Methods, 7e (Table 49.1)");
}

// ════════════════════════════════════════════════════════════════
// SLIDE 4 – CLASSIFICATION OF CYTOKINE FAMILIES
// ════════════════════════════════════════════════════════════════
{
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  slideTitle(s, "Classification of Cytokine Families");

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  footerNote(s, "Henry's 7e; Cellular and Molecular Immunology (Abbas 10e); Roitt's Essential Immunology 14e");
}

// ════════════════════════════════════════════════════════════════
// SLIDE 5 – CYTOKINE RECEPTORS & SIGNALING
// ════════════════════════════════════════════════════════════════
{
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  slideTitle(s, "Cytokine Receptors & Signaling Pathways");

  const receptors = [
    { name: "Class I (Hematopoietin)", examples: "IL-2, IL-4, IL-6, G-CSF, GM-CSF receptors", pathway: "JAK-STAT", color: C.accent },
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    { name: "Immunoglobulin Superfamily", examples: "IL-1R, IL-18R, M-CSF-R", pathway: "NF-κB, MAPK", color: C.orange },
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// ════════════════════════════════════════════════════════════════
// SLIDE 6 – CYTOKINES IN ACUTE INFLAMMATION
// ════════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  darkBg(s);
  slideTitle(s, "Cytokines in Acute Inflammation", "Based on Robbins & Cotran Table 3.7");

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    ["IL-6", "Macrophages, endothelium, T cells", "Acute phase proteins (CRP, fibrinogen); promotes B cell differentiation; fever"],
    ["Chemokines", "Macrophages, endothelium, T cells, mast cells", "Recruit leukocytes to inflammation sites; regulate leukocyte migration in tissues"],
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  footerNote(s, "Robbins & Cotran Pathologic Basis of Disease, 10e – Chapter 3 (Table 3.7)");
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// ════════════════════════════════════════════════════════════════
// SLIDE 7 – CYTOKINES IN CHRONIC INFLAMMATION
// ════════════════════════════════════════════════════════════════
{
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  slideTitle(s, "Cytokines in Chronic Inflammation");

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    { cytokine: "IL-17", source: "Th17 T cells", action: "Recruits neutrophils and monocytes to chronic inflammation sites; key in autoimmune diseases", color: C.orange },
    { cytokine: "TGF-β", source: "T regs, macrophages, platelets", action: "Anti-inflammatory; promotes fibrosis; drives Treg differentiation; inhibits effector T cells", color: C.green },
    { cytokine: "IL-10", source: "Macrophages, T regs", action: "Anti-inflammatory; suppresses macrophage and DC activation; maintains homeostasis", color: C.yellow },
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  footerNote(s, "Robbins & Cotran, 10e – Chapter 3; Cellular and Molecular Immunology (Abbas 10e)");
}

// ════════════════════════════════════════════════════════════════
// SLIDE 8 – TH1 / TH2 / TH17 / TREG CYTOKINE BALANCE
// ════════════════════════════════════════════════════════════════
{
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  slideTitle(s, "T Helper Cell Subsets & Cytokine Balance");

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    {
      name: "Th17",
      polarizing: "TGF-β + IL-6, IL-23",
      master: "RORγt",
      produces: "IL-17A/F, IL-22, IL-21",
      role: "Extracellular pathogens (fungi, bacteria); IBD, RA, psoriasis",
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    {
      name: "Treg",
      polarizing: "TGF-β, IL-2",
      master: "FoxP3",
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      role: "Suppresses autoimmunity; maintains peripheral tolerance; limits inflammation",
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  footerNote(s, "Roitt's Essential Immunology 14e; Cellular and Molecular Immunology, Abbas 10e");
}

// ════════════════════════════════════════════════════════════════
// SLIDE 9 – CYTOKINE STORM
// ════════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  darkBg(s);
  slideTitle(s, "Cytokine Storm", "Pathological amplification of the cytokine response");

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  s.addText(
    "\"TNF, IL-6, and IL-1 are the principal cytokine mediators of sepsis, but IFN-γ and IL-12 may also contribute. This early burst of large amounts of cytokines is sometimes called a cytokine storm.\" — Cellular & Molecular Immunology",
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  const causes = [
    { title: "Bacterial Sepsis", detail: "LPS triggers massive TNF-α, IL-1, IL-6 release from macrophages; vascular collapse, DIC, multi-organ failure" },
    { title: "Viral Infection", detail: "SARS-CoV-2, influenza: plasmacytoid DC → IFN storm; TNF, IL-6 surges; endothelial injury, coagulopathy" },
    { title: "Macrophage Activation Syndrome (MAS)", detail: "Fulminant cytokine storm: fever, DIC, hepatobiliary dysfunction, cytopenias, hyperferritinemia" },
    { title: "CAR-T / Immunotherapy", detail: "T cell activation → massive IL-6, IFN-γ release; clinical syndrome managed with tocilizumab" },
  ];

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    s.addText(c.detail, { x: x + 0.1, y: y + 0.35, w: 4.3, h: 1.0, fontSize: 10.5, color: C.light, fontFace: "Calibri", margin: 0 });
  });

  footerNote(s, "Cellular & Molecular Immunology (Abbas); Medical Microbiology 9e; Goldman-Cecil Medicine 2025; Harrison's Principles 22e");
}

// ════════════════════════════════════════════════════════════════
// SLIDE 10 – CYTOKINES IN AUTOIMMUNE DISEASE
// ════════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  darkBg(s);
  slideTitle(s, "Cytokines in Autoimmune Disease");

  s.addText(
    "Under homeostatic conditions, proinflammatory cytokine responses are balanced by anti-inflammatory responses. Persistent challenge or immune dysregulation leads to chronic inflammatory disease. (Henry's 7e)",
    { x: 0.4, y: 1.25, w: 9.2, h: 0.55, fontSize: 11.5, color: C.light, fontFace: "Calibri", italic: true, fill: { color: C.cardBg }, margin: [4, 8, 4, 8] }
  );

  const diseases = [
    { disease: "Rheumatoid Arthritis", cytokines: "TNF-α ↑, IL-1β ↑, IL-6 ↑, IL-17A ↑, IL-18 ↑", targets: "Anti-TNF (etanercept, infliximab), anti-IL-6R (tocilizumab), anakinra" },
    { disease: "Systemic Lupus Erythematosus", cytokines: "IFN-α ↑ (type I IFN signature), IL-6 ↑, BLyS ↑; IL-10 dysregulated", targets: "Belimumab (anti-BLyS), anifrolumab (anti-IFNAR)" },
    { disease: "IBD (Crohn's/UC)", cytokines: "TNF-α ↑, IL-1β ↑, IL-6 ↑, IL-12/23 ↑, IL-17A ↑", targets: "Anti-TNF (infliximab), anti-IL-12/23 (ustekinumab), anti-IL-17" },
    { disease: "Psoriasis", cytokines: "IL-17A ↑↑, IL-23 ↑, IL-22 ↑, TNF-α ↑", targets: "Anti-IL-17 (secukinumab, ixekizumab), anti-IL-23 (guselkumab, risankizumab)" },
    { disease: "Multiple Sclerosis", cytokines: "IFN-γ ↑, IL-17A ↑, IL-6 ↑; IL-10 reduced in lesions", targets: "IFN-β therapy, natalizumab, ozanimod" },
  ];

  const cols = ["Disease", "Key Cytokines Elevated", "Therapeutic Targets"];
  const cx = [0.3, 2.95, 6.5];
  const cw = [2.55, 3.45, 3.0];
  cols.forEach((c, i) => {
    s.addShape(pres.ShapeType.rect, { x: cx[i], y: 1.88, w: cw[i], h: 0.32, fill: { color: C.midBlue }, line: { color: C.accent, width: 0.5 } });
    s.addText(c, { x: cx[i] + 0.06, y: 1.88, w: cw[i] - 0.1, h: 0.32, fontSize: 11, bold: true, color: C.teal, fontFace: "Calibri", valign: "middle", margin: 0 });
  });

  diseases.forEach((d, ri) => {
    const y = 2.2 + ri * 0.61;
    const rowBg = ri % 2 === 0 ? C.cardBg : C.navy;
    const vals = [d.disease, d.cytokines, d.targets];
    vals.forEach((v, ci) => {
      s.addShape(pres.ShapeType.rect, { x: cx[ci], y, w: cw[ci], h: 0.59, fill: { color: rowBg }, line: { color: C.midBlue, width: 0.5 } });
      s.addText(v, { x: cx[ci] + 0.06, y: y + 0.04, w: cw[ci] - 0.1, h: 0.51, fontSize: ci === 0 ? 11 : 10, bold: ci === 0, color: ci === 0 ? C.yellow : C.light, fontFace: "Calibri", valign: "middle", margin: 0 });
    });
  });

  footerNote(s, "Henry's 7e; Roitt's 14e; Robbins & Cotran 10e");
}

// ════════════════════════════════════════════════════════════════
// SLIDE 11 – CYTOKINES IN CANCER
// ════════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  darkBg(s);
  slideTitle(s, "Cytokines in Cancer", "Dual role: tumor suppression vs. tumor promotion");

  // Two column layout
  // Tumor promoting
  s.addShape(pres.ShapeType.rect, { x: 0.3, y: 1.25, w: 4.45, h: 0.38, fill: { color: C.red }, line: { type: "none" } });
  s.addText("TUMOR PROMOTING", { x: 0.3, y: 1.25, w: 4.45, h: 0.38, fontSize: 13, bold: true, color: C.white, fontFace: "Calibri", align: "center", valign: "middle", margin: 0 });
  s.addShape(pres.ShapeType.rect, { x: 0.3, y: 1.63, w: 4.45, h: 3.4, fill: { color: C.cardBg }, line: { color: C.red, width: 1 } });
  const promoting = [
    "TNF-α: NF-κB activation → anti-apoptotic genes, tumor survival",
    "IL-6: JAK-STAT3 → proliferation; Castleman disease; promotes multiple myeloma growth",
    "IL-10: Immunosuppressive in tumor microenvironment; limits antitumor CTL responses",
    "TGF-β: Suppresses tumor immunity; promotes EMT and metastasis",
    "VEGF (cytokine-like): Angiogenesis driven by IL-6, TNF-α stimulation",
    "IL-17: Promotes angiogenesis; links chronic inflammation to cancer (CRC, NSCLC)",
  ];
  const ptArr = promoting.map((p, i) => ({ text: p, options: { bullet: { indent: 10 }, breakLine: i < promoting.length - 1, color: C.light } }));
  s.addText(ptArr, { x: 0.4, y: 1.68, w: 4.25, h: 3.3, fontSize: 10.5, fontFace: "Calibri", valign: "top", margin: 0 });

  // Tumor suppressing
  s.addShape(pres.ShapeType.rect, { x: 5.25, y: 1.25, w: 4.45, h: 0.38, fill: { color: C.green }, line: { type: "none" } });
  s.addText("TUMOR SUPPRESSING / THERAPY", { x: 5.25, y: 1.25, w: 4.45, h: 0.38, fontSize: 13, bold: true, color: C.white, fontFace: "Calibri", align: "center", valign: "middle", margin: 0 });
  s.addShape(pres.ShapeType.rect, { x: 5.25, y: 1.63, w: 4.45, h: 3.4, fill: { color: C.cardBg }, line: { color: C.green, width: 1 } });
  const suppressing = [
    "IFN-α: Approved for melanoma, lymphoma, CML, Kaposi sarcoma — inhibits proliferation, ↑MHC-I",
    "IL-2 (high-dose): ~10% response in melanoma/RCC; stimulates CD8+ CTLs and NK cells",
    "IFN-γ: Macrophage activation; antitumor in animal models; ↑MHC-I → CTL susceptibility",
    "IL-12: Activates NK cells + CTLs; anti-angiogenic via IFN-γ; immunotherapy research",
    "GM-CSF: Used post-chemotherapy; enhances DC accumulation in tumors (TVEC contains GM-CSF gene)",
    "G-CSF / G-CSF analogs: Reduce febrile neutropenia after chemotherapy",
  ];
  const stArr = suppressing.map((p, i) => ({ text: p, options: { bullet: { indent: 10 }, breakLine: i < suppressing.length - 1, color: C.light } }));
  s.addText(stArr, { x: 5.35, y: 1.68, w: 4.25, h: 3.3, fontSize: 10.5, fontFace: "Calibri", valign: "top", margin: 0 });

  footerNote(s, "Cellular & Molecular Immunology (Abbas 10e) – Chapter 15; Henry's 7e; Robbins & Cotran 10e");
}

// ════════════════════════════════════════════════════════════════
// SLIDE 12 – KEY INDIVIDUAL CYTOKINES: TNF, IL-1, IL-6
// ════════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  darkBg(s);
  slideTitle(s, "Key Cytokines in Depth: TNF-α · IL-1 · IL-6");

  const cytokines = [
    {
      name: "TNF-α",
      color: C.red,
      source: "Macrophages, DC, mast cells, T cells",
      receptor: "TNFR1 (ubiquitous), TNFR2",
      pathway: "NF-κB, caspase-dependent apoptosis",
      actions: [
        "↑ Endothelial adhesion molecules (ICAM-1, E-selectin, VCAM-1)",
        "Fever, weight loss (cachexia), hypotension",
        "Acute phase response",
        "Promotes neutrophil and monocyte recruitment",
        "High levels → septic shock, DIC",
      ],
      disease: "Sepsis, RA, IBD, Crohn's, cachexia",
    },
    {
      name: "IL-1β",
      color: C.orange,
      source: "Macrophages, DC, epithelial cells",
      receptor: "IL-1R1 (signal) / IL-1R2 (decoy), IL-1RA (antagonist)",
      pathway: "NF-κB, MAPK via MyD88/IRAK",
      actions: [
        "Potent fever induction (hypothalamic PGE2)",
        "Endothelial activation; promotes vascular permeability",
        "Stimulates IL-6 and IL-8 production",
        "Activates T cells and B cells",
        "Drives inflammasome in gout (IL-1β cleaved by caspase-1)",
      ],
      disease: "Gout, Still's disease, NLRP3 inflammasomopathies, RA",
    },
    {
      name: "IL-6",
      color: C.teal,
      source: "Macrophages, endothelium, fibroblasts, T cells",
      receptor: "IL-6R (soluble + membrane bound) / gp130",
      pathway: "JAK1/2 → STAT3 (primary); MAPK",
      actions: [
        "Major driver of acute phase response (CRP, SAA, fibrinogen ↑)",
        "Hepatocyte stimulation → CRP production (biomarker use)",
        "Promotes B cell differentiation → antibody production",
        "Elevated in COVID-19, Castleman disease, myeloma",
        "Tocilizumab targets IL-6R (RA, cytokine storm)",
      ],
      disease: "Multiple myeloma, Castleman disease, RA, sepsis, COVID-19",
    },
  ];

  cytokines.forEach((cy, i) => {
    const x = 0.22 + i * 3.2;
    s.addShape(pres.ShapeType.rect, { x, y: 1.2, w: 3.08, h: 0.38, fill: { color: cy.color }, line: { type: "none" } });
    s.addText(cy.name, { x, y: 1.2, w: 3.08, h: 0.38, fontSize: 16, bold: true, color: C.white, fontFace: "Calibri", align: "center", valign: "middle", margin: 0 });
    s.addShape(pres.ShapeType.rect, { x, y: 1.58, w: 3.08, h: 3.82, fill: { color: C.cardBg }, line: { color: cy.color, width: 1 } });

    const fields = [
      ["Source", cy.source],
      ["Receptor", cy.receptor],
      ["Pathway", cy.pathway],
      ["Disease", cy.disease],
    ];
    let yOff = 1.62;
    fields.forEach(([label, val]) => {
      s.addText(label + ": ", { x: x + 0.1, y: yOff, w: 0.75, h: 0.28, fontSize: 9, bold: true, color: cy.color, fontFace: "Calibri", margin: 0 });
      s.addText(val, { x: x + 0.85, y: yOff, w: 2.1, h: 0.28, fontSize: 9, color: C.light, fontFace: "Calibri", margin: 0 });
      yOff += 0.28;
    });
    yOff += 0.06;
    s.addText("Key Actions:", { x: x + 0.1, y: yOff, w: 2.9, h: 0.22, fontSize: 9, bold: true, color: cy.color, fontFace: "Calibri", margin: 0 });
    yOff += 0.2;
    const actArr = cy.actions.map((a, ai) => ({ text: a, options: { bullet: { indent: 8 }, breakLine: ai < cy.actions.length - 1, color: C.light } }));
    s.addText(actArr, { x: x + 0.1, y: yOff, w: 2.9, h: 2.2, fontSize: 9, fontFace: "Calibri", valign: "top", margin: 0 });
  });

  footerNote(s, "Robbins & Cotran 10e (Chapter 3); Henry's 7e; Cellular & Molecular Immunology (Abbas 10e)");
}

// ════════════════════════════════════════════════════════════════
// SLIDE 13 – INTERFERONS & CHEMOKINES
// ════════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  darkBg(s);
  slideTitle(s, "Interferons & Chemokines");

  // Interferons
  s.addShape(pres.ShapeType.rect, { x: 0.3, y: 1.22, w: 4.55, h: 0.35, fill: { color: C.teal }, line: { type: "none" } });
  s.addText("INTERFERONS", { x: 0.3, y: 1.22, w: 4.55, h: 0.35, fontSize: 13, bold: true, color: C.white, fontFace: "Calibri", align: "center", valign: "middle", margin: 0 });

  const ifnRows = [
    { type: "Type I  IFN-α/β", detail: "Antiviral defense; produced by plasmacytoid DCs; ↑MHC-I; used in hepatitis, hairy cell leukemia, melanoma" },
    { type: "Type II  IFN-γ", detail: "Macrophage activator; promotes Th1; upregulates MHC-I and II; key in tuberculosis, intracellular pathogens" },
    { type: "Type III  IFN-λ", detail: "Mucosal antiviral immunity; acts at epithelial barriers; limits spread of respiratory viruses" },
    { type: "IFN-α therapy", detail: "Approved: melanoma, CML, HCV, hairy cell leukemia, Kaposi sarcoma; inhibits proliferation + ↑NK killing" },
  ];
  ifnRows.forEach((r, i) => {
    const y = 1.57 + i * 0.88;
    const bg = i % 2 === 0 ? C.cardBg : C.navy;
    s.addShape(pres.ShapeType.rect, { x: 0.3, y, w: 4.55, h: 0.84, fill: { color: bg }, line: { color: C.teal, width: 0.5 } });
    s.addText(r.type, { x: 0.4, y: y + 0.04, w: 4.35, h: 0.26, fontSize: 11, bold: true, color: C.teal, fontFace: "Calibri", margin: 0 });
    s.addText(r.detail, { x: 0.4, y: y + 0.3, w: 4.35, h: 0.5, fontSize: 10, color: C.light, fontFace: "Calibri", margin: 0 });
  });

  // Chemokines
  s.addShape(pres.ShapeType.rect, { x: 5.2, y: 1.22, w: 4.55, h: 0.35, fill: { color: C.orange }, line: { type: "none" } });
  s.addText("CHEMOKINES", { x: 5.2, y: 1.22, w: 4.55, h: 0.35, fontSize: 13, bold: true, color: C.white, fontFace: "Calibri", align: "center", valign: "middle", margin: 0 });

  const chemRows = [
    { type: "CXC (α-chemokines)", detail: "CXCL8 (IL-8): neutrophil chemotaxis; CXCL9/10/11: recruit Th1/CTLs via CXCR3; CXCL12/SDF-1: B cell & stem cell homing" },
    { type: "CC (β-chemokines)", detail: "CCL2 (MCP-1): monocyte recruitment; CCL5 (RANTES): T cell and eosinophil attraction; CCL11: eosinophils in allergy" },
    { type: "CX3C & XC", detail: "Fractalkine (CX3CL1): tethers monocytes to endothelium; Lymphotactin (XCL1): attracts CD8+ T cells" },
    { type: "Disease Relevance", detail: "HIV uses CCR5/CXCR4 as co-receptors; maraviroc (CCR5 antagonist) as antiretroviral; CXCR4 in bone marrow niche" },
  ];
  chemRows.forEach((r, i) => {
    const y = 1.57 + i * 0.88;
    const bg = i % 2 === 0 ? C.cardBg : C.navy;
    s.addShape(pres.ShapeType.rect, { x: 5.2, y, w: 4.55, h: 0.84, fill: { color: bg }, line: { color: C.orange, width: 0.5 } });
    s.addText(r.type, { x: 5.3, y: y + 0.04, w: 4.35, h: 0.26, fontSize: 11, bold: true, color: C.orange, fontFace: "Calibri", margin: 0 });
    s.addText(r.detail, { x: 5.3, y: y + 0.3, w: 4.35, h: 0.5, fontSize: 10, color: C.light, fontFace: "Calibri", margin: 0 });
  });

  footerNote(s, "Cellular & Molecular Immunology (Abbas); Robbins & Cotran 10e; Roitt's 14e");
}

// ════════════════════════════════════════════════════════════════
// SLIDE 14 – ANTI-CYTOKINE THERAPEUTICS
// ════════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  darkBg(s);
  slideTitle(s, "Anti-Cytokine Therapeutics & Cytokine Therapy", "Biologics and recombinant cytokines in clinical use");

  const drugs = [
    { drug: "Infliximab / Adalimumab / Etanercept", target: "TNF-α", indication: "RA, Crohn's, UC, ankylosing spondylitis, psoriasis", type: "Anti-cytokine", color: C.red },
    { drug: "Tocilizumab / Sarilumab", target: "IL-6 receptor", indication: "RA, GCA, cytokine storm (COVID-19, CAR-T toxicity)", type: "Anti-cytokine", color: C.teal },
    { drug: "Anakinra / Canakinumab", target: "IL-1R / IL-1β", indication: "Gout, Still's disease, CAPS, pericarditis, MAS/sepsis", type: "Anti-cytokine", color: C.orange },
    { drug: "Secukinumab / Ixekizumab", target: "IL-17A", indication: "Psoriasis, PsA, ankylosing spondylitis", type: "Anti-cytokine", color: C.accent },
    { drug: "Ustekinumab", target: "IL-12/IL-23 (p40)", indication: "Crohn's disease, UC, psoriasis, PsA", type: "Anti-cytokine", color: C.green },
    { drug: "IL-2 (high dose)", target: "IL-2 (agonist)", indication: "Melanoma, RCC — ~10% response; vascular leak limits use", type: "Cytokine therapy", color: C.yellow },
    { drug: "IFN-α (pegylated)", target: "IFN-α (agonist)", indication: "HCV, HBV, hairy cell leukemia, melanoma, CML, Kaposi sarcoma", type: "Cytokine therapy", color: C.yellow },
    { drug: "G-CSF (filgrastim) / GM-CSF", target: "CSF receptor", indication: "Post-chemotherapy neutropenia; stem cell mobilization", type: "Cytokine therapy", color: C.green },
  ];

  // Table
  const cols = ["Drug / Agent", "Target", "Indication", "Type"];
  const cx = [0.2, 3.15, 5.8, 8.95];
  const cw = [2.85, 2.55, 3.05, 0.9];
  cols.forEach((c, i) => {
    s.addShape(pres.ShapeType.rect, { x: cx[i], y: 1.22, w: cw[i], h: 0.32, fill: { color: C.midBlue }, line: { color: C.accent, width: 0.5 } });
    s.addText(c, { x: cx[i] + 0.05, y: 1.22, w: cw[i] - 0.08, h: 0.32, fontSize: 11, bold: true, color: C.teal, fontFace: "Calibri", valign: "middle", margin: 0 });
  });

  drugs.forEach((d, ri) => {
    const y = 1.54 + ri * 0.5;
    const rowBg = ri % 2 === 0 ? C.cardBg : C.navy;
    const vals = [d.drug, d.target, d.indication, d.type];
    vals.forEach((v, ci) => {
      s.addShape(pres.ShapeType.rect, { x: cx[ci], y, w: cw[ci], h: 0.48, fill: { color: rowBg }, line: { color: C.midBlue, width: 0.5 } });
      s.addText(v, {
        x: cx[ci] + 0.05, y: y + 0.04, w: cw[ci] - 0.08, h: 0.4,
        fontSize: ci === 3 ? 8.5 : 9.5, color: ci === 0 ? C.yellow : ci === 3 ? d.color : C.light,
        bold: ci === 0 || ci === 3,
        fontFace: "Calibri", valign: "middle", margin: 0,
      });
    });
  });

  footerNote(s, "Cellular & Molecular Immunology (Abbas 10e); Goodman & Gilman's Pharmacology; Robbins & Cotran 10e");
}

// ════════════════════════════════════════════════════════════════
// SLIDE 15 – JAK INHIBITORS & CYTOKINE ASSAYS
// ════════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  darkBg(s);
  slideTitle(s, "JAK Inhibitors & Cytokine Lab Measurement");

  // Left: JAKi
  s.addShape(pres.ShapeType.rect, { x: 0.3, y: 1.22, w: 4.5, h: 0.35, fill: { color: C.accent }, line: { type: "none" } });
  s.addText("JAK INHIBITORS (JAKi)", { x: 0.3, y: 1.22, w: 4.5, h: 0.35, fontSize: 13, bold: true, color: C.white, fontFace: "Calibri", align: "center", valign: "middle", margin: 0 });
  s.addShape(pres.ShapeType.rect, { x: 0.3, y: 1.57, w: 4.5, h: 3.78, fill: { color: C.cardBg }, line: { color: C.accent, width: 1 } });
  const jakiContent = [
    "Block JAK1, JAK2, JAK3, TYK2 — block downstream STAT activation",
    "Oral small-molecule drugs; broad cytokine signal suppression",
    "",
    "Tofacitinib (JAK1/3) — RA, UC, psoriatic arthritis",
    "Baricitinib (JAK1/2) — RA, alopecia areata, COVID-19",
    "Ruxolitinib (JAK1/2) — myelofibrosis, polycythemia vera, GVHD",
    "Upadacitinib (JAK1 selective) — RA, IBD, atopic dermatitis",
    "",
    "Side effects: ↑infection risk, reactivation of TB/herpes zoster",
    "JAK2 mutations (V617F) in myeloproliferative neoplasms — diagnostic marker",
    "γc receptor mutations → SCID (X-linked SCID via JAK3 deficiency)",
  ];
  const jakArr = jakiContent.map((t, i) => ({
    text: t,
    options: t === "" ? { breakLine: true } : { bullet: { indent: 10 }, breakLine: i < jakiContent.length - 1, color: C.light },
  }));
  s.addText(jakArr, { x: 0.4, y: 1.61, w: 4.3, h: 3.68, fontSize: 10.5, fontFace: "Calibri", valign: "top", margin: 0 });

  // Right: Cytokine Assays
  s.addShape(pres.ShapeType.rect, { x: 5.2, y: 1.22, w: 4.5, h: 0.35, fill: { color: C.green }, line: { type: "none" } });
  s.addText("CYTOKINE LAB MEASUREMENT", { x: 5.2, y: 1.22, w: 4.5, h: 0.35, fontSize: 13, bold: true, color: C.white, fontFace: "Calibri", align: "center", valign: "middle", margin: 0 });
  s.addShape(pres.ShapeType.rect, { x: 5.2, y: 1.57, w: 4.5, h: 3.78, fill: { color: C.cardBg }, line: { color: C.green, width: 1 } });

  const assayContent = [
    "ELISA: Gold standard for quantitative measurement of individual cytokines (IL-1α/β, IL-4, IL-5, IL-6, IL-10, IFN-γ, TNF-α)",
    "",
    "Multiplex assays (Luminex, electrochemiluminescence): Measure panels of 20–40 cytokines simultaneously; low volume; high sensitivity",
    "",
    "Bioassays: Historically gold standard; time-consuming; not routine clinical use",
    "",
    "Clinical uses:",
    "  • Ferritin + IL-18 + sIL-2R in MAS / HLH diagnosis",
    "  • IL-6 monitoring in CAR-T cytokine syndrome",
    "  • IFN-γ release assays (QuantiFERON) for TB",
    "  • Elevated IL-6 in COVID-19 — prognostic marker",
  ];
  const assayArr = assayContent.map((t, i) => ({
    text: t,
    options: t === "" ? { breakLine: true } : { bullet: { indent: t.startsWith("  ") ? 20 : 10 }, breakLine: i < assayContent.length - 1, color: C.light },
  }));
  s.addText(assayArr, { x: 5.3, y: 1.61, w: 4.3, h: 3.68, fontSize: 10.5, fontFace: "Calibri", valign: "top", margin: 0 });

  footerNote(s, "Henry's Clinical Diagnosis & Management 7e; Goodman & Gilman's Pharmacology 14e");
}

// ════════════════════════════════════════════════════════════════
// SLIDE 16 – CYTOKINES IN PATHOLOGY PRACTICE
// ════════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  darkBg(s);
  slideTitle(s, "Cytokines in Pathology Practice", "Recognizing cytokine-mediated tissue changes");

  const topics = [
    {
      title: "Granuloma Formation",
      color: C.teal,
      detail: "IFN-γ activates macrophages → epithelioid cell transformation → granuloma. IL-12 drives Th1 responses upstream. TNF-α essential for granuloma maintenance (anti-TNF → TB reactivation risk).",
    },
    {
      title: "Acute Phase Response",
      color: C.orange,
      detail: "IL-6, IL-1, TNF-α signal hepatocytes → CRP, SAA, fibrinogen ↑; albumin, transferrin ↓. CRP rise on histology workup signals active inflammation. Serum amyloid A → AA amyloidosis in chronic inflammation.",
    },
    {
      title: "Tissue Fibrosis",
      color: C.accent,
      detail: "TGF-β1: master pro-fibrotic cytokine → myofibroblast activation → collagen deposition. PDGF, IL-13 contribute. Seen in hepatic cirrhosis, IPF, post-inflammatory scars.",
    },
    {
      title: "Tumor Microenvironment",
      color: C.red,
      detail: "IL-10, TGF-β → immunosuppressive TME → T cell exhaustion. IL-6/STAT3 → tumor cell survival. M2 macrophage polarization by IL-4, IL-10, IL-13 → poor anti-tumor immunity.",
    },
    {
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      detail: "Extreme cytokine storm: IFN-γ, IL-18, IL-6, TNF-α. Histology: hemophagocytosis in marrow/liver. Ferritin >10,000 ng/mL diagnostic clue. Treated with etoposide, dexamethasone, IL-1R antagonist.",
    },
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    },
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// ════════════════════════════════════════════════════════════════
// SLIDE 17 – SUMMARY: CYTOKINES AT A GLANCE
// ════════════════════════════════════════════════════════════════
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    ["IL-1β", "Fever / Inflammasome", "Anakinra, Canakinumab"],
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    ["IFN-γ", "Macrophage Activation / Granuloma", "Emapalumab (anti-IFN-γ for HLH)"],
    ["IL-12/23", "Th1/Th17 differentiation", "Ustekinumab"],
    ["IL-17A", "Neutrophilic Inflammation / Psoriasis", "Secukinumab, Ixekizumab"],
    ["TGF-β", "Fibrosis / Immune suppression", "Pirfenidone (fibrosis); research targets"],
    ["IL-10", "Anti-inflammatory / Tolerance", "Deficiency → IBD; preclinical agonists"],
    ["IFN-α/β", "Antiviral / Type I IFN signature (SLE)", "Pegylated IFN-α; anifrolumab"],
    ["CSFs", "Hematopoiesis / Myeloid support", "G-CSF (filgrastim); GM-CSF (sargramostim)"],
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// ════════════════════════════════════════════════════════════════
// SLIDE 18 – CLOSING / THANK YOU
// ════════════════════════════════════════════════════════════════
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    "Cytokines are pleiotropic, redundant protein mediators active at picomolar concentrations — context and combinations determine effects",
    "JAK-STAT is the primary signaling cascade; NF-κB and MAPK also critical; SOCS proteins provide negative feedback",
    "TNF-α, IL-1β, IL-6 are the master mediators of acute inflammation and sepsis",
    "T helper subsets (Th1/Th2/Th17/Treg) are defined by their cytokine profiles and transcription factors",
    "Cytokine dysregulation drives autoimmunity, cancer, fibrosis, and potentially life-threatening cytokine storm",
    "Anti-cytokine biologics and JAK inhibitors have transformed treatment of RA, IBD, psoriasis, and lymphoma",
    "Pathologists must recognize cytokine-mediated tissue changes: granulomas (IFN-γ), fibrosis (TGF-β), hemophagocytosis (IFN-γ storm)",
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// ── Write file ─────────────────────────────────────────────────
pres.writeFile({ fileName: "/home/daytona/workspace/cytokines-ppt/Cytokines_Health_and_Disease.pptx" })
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  .catch(err => { console.error(err); process.exit(1); });

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