cd /home/daytona/workspace/attachments/d3da3433-5073-4e88-b3fb-a7814739edbb && p…

wc -l /home/daytona/workspace/manuscript_extracted.md && grep -n "^##\|^\*\*\[" …

grep -n "underline\|^\*\*" /home/daytona/workspace/manuscript_extracted.md | hea…

proteoglycans oral squamous cell carcinoma

/home/daytona/workspace

mkdir -p /home/daytona/workspace/revised-manuscript && ls /home/daytona/skills/d…

~/revised-manuscript/build.js

const {
  Document, Packer, Paragraph, TextRun, HeadingLevel,
  AlignmentType, UnderlineType, BorderStyle, PageBreak
} = require('docx');
const fs = require('fs');

// ─── helpers ────────────────────────────────────────────────────────────────
const heading1 = (text) => new Paragraph({
  text,
  heading: HeadingLevel.HEADING_1,
  spacing: { before: 320, after: 120 },
});

const heading2 = (text) => new Paragraph({
  text,
  heading: HeadingLevel.HEADING_2,
  spacing: { before: 240, after: 80 },
});

const para = (runs, opts = {}) => new Paragraph({
  children: Array.isArray(runs) ? runs : [new TextRun({ text: runs, font: 'Times New Roman', size: 24 })],
  spacing: { before: 100, after: 100, line: 360 },
  alignment: AlignmentType.JUSTIFIED,
  ...opts,
});

const boldRun = (t) => new TextRun({ text: t, bold: true, font: 'Times New Roman', size: 24 });
const normalRun = (t) => new TextRun({ text: t, font: 'Times New Roman', size: 24 });
const italicRun = (t) => new TextRun({ text: t, italics: true, font: 'Times New Roman', size: 24 });
const superRun = (t) => new TextRun({ text: t, superScript: true, font: 'Times New Roman', size: 20 });

// ─── DOCUMENT SECTIONS ───────────────────────────────────────────────────────

const children = [

  // ── TITLE ──────────────────────────────────────────────────────────────────
  new Paragraph({
    children: [new TextRun({
      text: 'ROLE OF PROTEOGLYCANS IN THE INITIATION AND PROGRESSION OF ORAL SQUAMOUS CELL CARCINOMA',
      bold: true, allCaps: true, font: 'Times New Roman', size: 28
    })],
    alignment: AlignmentType.CENTER,
    spacing: { before: 0, after: 240 },
  }),

  // ── ABSTRACT ───────────────────────────────────────────────────────────────
  heading1('ABSTRACT'),

  para([
    boldRun('Background: '),
    normalRun('Oral squamous cell carcinoma (OSCC) accounts for 90–95% of all oral malignancies and continues to carry a poor prognosis despite multimodal treatment. The extracellular matrix (ECM), particularly its proteoglycan constituents, is now recognised as an active driver of tumour initiation and progression rather than a passive structural scaffold.'),
  ]),
  para([
    boldRun('Objective: '),
    normalRun('This narrative review summarises current evidence on the structural biology, molecular signalling mechanisms, clinicopathological significance, and translational potential of proteoglycans in OSCC, with coverage of perlecan, agrin, syndecan-1, glypicans, versican, decorin, biglycan, lumican, fibromodulin, PRELP, SPOCK1, and chondroitin sulphate proteoglycan 4 (CSPG4).'),
  ]),
  para([
    boldRun('Methods: '),
    normalRun('A comprehensive literature search was conducted across PubMed, Scopus, and Web of Science using the terms "proteoglycans", "glycosaminoglycans", "oral squamous cell carcinoma", "tumour microenvironment", and related mesh terms. Peer-reviewed original articles, reviews, and book chapters published up to April 2026 were included.'),
  ]),
  para([
    boldRun('Results: '),
    normalRun('Proteoglycans exhibit context-dependent roles as tumour suppressors or promoters by modulating epithelial–mesenchymal transition, angiogenesis, matrix remodelling, immune evasion, and therapeutic resistance. Aberrant proteoglycan expression correlates with tumour grade, lymph node metastasis, and patient survival in OSCC. Several proteoglycans, including syndecan-1, decorin, and versican, show promise as diagnostic biomarkers and therapeutic targets.'),
  ]),
  para([
    boldRun('Conclusion: '),
    normalRun('Proteoglycans are integral regulators of OSCC pathobiology. Elucidating their molecular mechanisms across disease stages and anatomical subsites may open new avenues for biomarker development and ECM-targeted therapy in OSCC.'),
  ]),
  para([boldRun('Keywords: '), normalRun('proteoglycans; oral squamous cell carcinoma; extracellular matrix; tumour microenvironment; glycosaminoglycans; biomarkers')]),

  // ── INTRODUCTION ───────────────────────────────────────────────────────────
  heading1('1. INTRODUCTION'),

  para('Oral squamous cell carcinoma (OSCC) is the most prevalent malignancy of the oral cavity, comprising approximately 90–95% of all oral cancers. It predominantly affects the tongue, floor of the mouth, buccal mucosa, and gingiva, with strong aetiological associations with tobacco use, areca nut chewing, alcohol consumption, and human papillomavirus infection — risk factors that are particularly prevalent in South and Southeast Asian populations, where OSCC incidence remains disproportionately high. [8,9]'),

  para('Despite advances in surgery, radiotherapy, chemotherapy, and targeted molecular therapy, the five-year survival rate for OSCC has remained at approximately 50–60% over the past three decades. This stagnation in prognosis is attributable not solely to delayed clinical presentation but also to aggressive local invasion, cervical lymph node metastasis, high rates of locoregional recurrence, and resistance to therapy. Emerging evidence indicates that these features are driven not merely by intrinsic genetic alterations in tumour cells but also by complex bidirectional interactions between tumour cells and the surrounding tumour microenvironment (TME). [8,9]'),

  para('The TME comprises tumour cells, cancer-associated fibroblasts, endothelial cells, immune effector and suppressor cells, inflammatory mediators, and the extracellular matrix (ECM). Once considered an inert structural scaffold, the ECM is now established as a biologically active compartment that governs tissue architecture, mechanotransduction, growth factor bioavailability, cell adhesion, migration, proliferation, differentiation, angiogenesis, and intracellular signalling. The composition and organisation of the ECM are dynamically remodelled during malignant transformation, with these changes directly influencing tumour aggressiveness and treatment susceptibility. [8,9,4]'),

  para('Among ECM constituents, proteoglycans have attracted considerable research attention as pivotal regulators of both tissue homeostasis and tumour biology. Proteoglycans are structurally diverse macromolecules in which a core protein carries one or more covalently attached glycosaminoglycan (GAG) chains. Their extraordinary diversity — arising from variations in core protein identity, GAG chain class, chain length, sulphation density, and epimerisation — confers the capacity to interact with a broad spectrum of growth factors, cytokines, morphogens, matrix proteins, and cell-surface receptors. [1,2,5]'),

  para('Depending on their molecular identity and tissue context, proteoglycans may act as tumour suppressors or tumour promoters. They regulate epithelial–mesenchymal transition (EMT), angiogenesis, tumour invasion, metastatic dissemination, immune evasion, and responsiveness to chemotherapy and radiotherapy. In OSCC specifically, aberrant expression of proteoglycans including perlecan, agrin, syndecan-1, glypicans (GPC1, GPC3, GPC5), versican, decorin, biglycan, lumican, fibromodulin, PRELP, SPOCK1, and CSPG4 has been documented across precancerous lesions and invasive carcinomas, with clinicopathological correlations extending to tumour grade, lymphovascular invasion, lymph node status, and survival outcomes. [8,10,11,12,13]'),

  para('Despite a growing body of individual studies, current knowledge remains fragmented, with most investigations addressing single proteoglycans in isolation and lacking integration across structural biology, signalling mechanisms, and clinical implications. The present review addresses this gap by providing a synthesised account of the role of proteoglycans in the initiation and progression of OSCC, with particular emphasis on molecular mechanisms, clinicopathological significance, and translational opportunities.'),

  // ── CLASSIFICATION AND STRUCTURE ───────────────────────────────────────────
  heading1('2. CLASSIFICATION AND STRUCTURE OF PROTEOGLYCANS'),

  para('Proteoglycans form a heterogeneous superfamily of glycoconjugates distributed throughout the ECM, basement membrane, pericellular matrix, cell surface, and intracellular compartments. Although they constitute a quantitatively minor fraction of total ECM mass, their structural and signalling contributions are indispensable to tissue organisation, intercellular communication, and physiological homeostasis. [1,2]'),

  para('The defining structural feature of a proteoglycan is the covalent attachment of one or more GAG chains to a core protein via a conserved tetrasaccharide linker sequence (glucuronic acid–galactose–galactose–xylose). The biological behaviour of any individual proteoglycan is determined by the identity of its core protein together with the class, number, length, sulphation pattern, and epimerisation of its GAG chains, collectively generating a degree of structural diversity that far exceeds that achievable by protein sequence variation alone. [1,2,5]'),

  para('GAGs are long, unbranched, negatively charged polysaccharides composed of repeating disaccharide units. Based on their monosaccharide composition and sulphation chemistry, they are classified into heparan sulphate (HS), chondroitin sulphate (CS), dermatan sulphate (DS), keratan sulphate (KS), and hyaluronan. With the exception of hyaluronan — which circulates as a free polysaccharide and signals primarily through CD44 and RHAMM receptors — all other GAG classes are covalently linked to core proteins. The specific pattern and density of sulphation along GAG chains determines their affinity for extracellular ligands and, consequently, the scope of signalling pathways they modulate. [1,2,5]'),

  para('Based on their principal cellular localisation, proteoglycans are classified into four broad groups:'),

  para([
    boldRun('(i) Intracellular proteoglycans: '),
    normalRun('Exemplified by serglycin, which is stored in secretory granules of haematopoietic cells and mast cells, and is involved in inflammatory mediator packaging and release.'),
  ]),
  para([
    boldRun('(ii) Cell-surface proteoglycans: '),
    normalRun('Principally represented by the syndecan family (SDC1–4) and glypican family (GPC1–6). Syndecans are transmembrane heparan sulphate proteoglycans that function as co-receptors for receptor tyrosine kinases, integrins, and growth factors. Glypicans are glycosylphosphatidylinositol (GPI)-anchored HS proteoglycans that regulate Wnt, Hedgehog, FGF, and BMP signalling. Both families modulate receptor clustering, ligand gradients, and intracellular signal transduction.'),
  ]),
  para([
    boldRun('(iii) Basement membrane and pericellular proteoglycans: '),
    normalRun('Perlecan, agrin, and type XVIII collagen are key members of this group. Perlecan is the dominant HS proteoglycan of basement membranes, contributing to structural integrity while simultaneously sequestering and releasing angiogenic growth factors such as FGF-2 and VEGF. Agrin, also a basement membrane HS proteoglycan, participates in acetylcholine receptor clustering and has more recently been implicated in tumour stroma organisation.'),
  ]),
  para([
    boldRun('(iv) Extracellular matrix proteoglycans: '),
    normalRun('This group encompasses two major families — the hyalectans (versican, aggrecan, neurocan, brevican) and the small leucine-rich proteoglycans (SLRPs; decorin, biglycan, lumican, fibromodulin, PRELP, keratocan). Versican, a large CS proteoglycan, regulates cell proliferation and migration through interactions with hyaluronan and cell-surface receptors including CD44 and EGFR. The SLRP family members interact with collagen fibrils to regulate matrix assembly and also engage pattern recognition receptors such as TLR2 and TLR4 to modulate innate immune signalling and the inflammatory tumour microenvironment.'),
  ]),

  para('Recent molecular and structural studies have further broadened this classification. SPOCK1 (testican-1/SPARC/osteonectin, CWCV and kazal-like domains proteoglycan 1) is a secreted HS/CS proteoglycan that regulates matrix metalloproteinase activity and has been identified as a promoter of cancer cell stemness and invasion. CSPG4 (chondroitin sulphate proteoglycan 4, also known as NG2), a transmembrane CS proteoglycan, has emerged as a marker of aggressive squamous cell carcinoma phenotypes, enhancing EGFR and integrin signalling to drive proliferation and invasion. [1,2,3,4,5]'),

  para('The structural diversity and multivalent signalling capacity of proteoglycans provide the molecular basis for their context-dependent roles in cancer. Alterations in proteoglycan expression, GAG chain composition, or receptor interactions disrupt ECM homeostasis, remodel the tumour microenvironment, and activate pro-tumourigenic signalling cascades. A thorough understanding of these structural and functional properties is therefore the necessary foundation for interpreting the specific contributions of individual proteoglycans to OSCC pathogenesis. [2,3,4,5]'),

  // ── CONCLUSION ─────────────────────────────────────────────────────────────
  heading1('3. CONCLUSION AND FUTURE DIRECTIONS'),

  para('The evidence reviewed in this paper establishes proteoglycans as multifaceted regulators of OSCC pathobiology. Their contributions span the full continuum of tumour development, from early epithelial dysplasia through to invasive carcinoma, lymph node metastasis, and therapeutic resistance. The dual tumour-suppressive and tumour-promoting functions of individual proteoglycans are not contradictory but rather reflect the extraordinary sensitivity of proteoglycan biology to molecular context, cell type, disease stage, and the specific composition of the surrounding ECM and TME.'),

  para('Several clinically significant patterns have emerged from current literature. Loss of decorin expression or its nuclear mislocalisation correlates with dysplastic progression and invasive behaviour. Syndecan-1 shedding from the tumour cell surface and its accumulation in the stromal compartment associates with lymphovascular invasion and poor prognosis. Elevated perlecan and agrin expression in neoplastic stroma correlates with basement membrane disruption and depth of invasion. Overexpression of SPOCK1 and versican has been linked to EMT and metastatic potential, while CSPG4 upregulation marks an aggressive, proliferative tumour phenotype.'),

  para('Despite these advances, several gaps limit translational progress. Most available data are derived from immunohistochemical or single-cell in vitro studies, with limited prospective validation of proteoglycans as independent prognostic biomarkers in large OSCC cohorts. The influence of site-specific anatomical and microenvironmental differences — such as between tongue, buccal mucosa, and floor of mouth — on proteoglycan expression profiles remains insufficiently characterised. The interplay between risk-factor-driven molecular alterations (tobacco, areca nut, HPV) and proteoglycan regulation represents another underexplored domain with direct relevance to OSCC prevention and early detection.'),

  para('From a therapeutic standpoint, ECM-targeted strategies exploiting proteoglycan biology hold real promise. Decorin and endorepellin (a bioactive perlecan fragment) have demonstrated antiangiogenic and anti-tumour activity in preclinical models. Syndecan-1 and CSPG4 are being explored as targets for antibody-drug conjugates and CAR-T cell approaches. Future research should prioritise the systematic profiling of the proteoglycan expression landscape across OSCC subsites and clinical stages, integration of proteoglycan data into multimodal biomarker panels for early diagnosis and risk stratification, and the development of ECM-directed therapeutics suitable for clinical translation in OSCC.'),

  // ── DECLARATIONS ───────────────────────────────────────────────────────────
  heading1('DECLARATIONS'),

  heading2('Conflict of Interest'),
  para('The authors declare no conflict of interest.'),

  heading2('Funding'),
  para('This review received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.'),

  heading2('Author Contributions'),
  para('All authors contributed to conceptualisation, literature search, writing, and critical revision of the manuscript. All authors approved the final version for submission.'),

  heading2('Ethics Approval'),
  para('Not applicable. This manuscript is a narrative review of previously published literature and does not involve human participants or animal subjects.'),

  // ── REFERENCES ─────────────────────────────────────────────────────────────
  heading1('REFERENCES'),

  ...[
    '1. Iozzo RV, Schaefer L. Proteoglycan form and function: a comprehensive nomenclature of proteoglycans. Matrix Biol. 2015;42:11–55. doi:10.1016/j.matbio.2015.02.003.',
    '2. Theocharis AD, Skandalis SS, Tzanakakis GN, Karamanos NK. Proteoglycans in health and disease: novel roles for proteoglycans in malignancy and their pharmacological targeting. FEBS J. 2010;277(19):3904–3923. doi:10.1111/j.1742-4658.2010.07800.x.',
    '3. Neill T, Schaefer L, Iozzo RV. Decoding the matrix: instructive roles of proteoglycan receptors. Biochemistry. 2015;54(30):4583–4598. doi:10.1021/acs.biochem.5b00653.',
    '4. De Pasquale V, Pavone LM. Heparan sulfate proteoglycan signaling in tumor microenvironment. Int J Mol Sci. 2020;21(18):6588. doi:10.3390/ijms21186588.',
    '5. Peres GB, Peres ATC, Campos NSP, Suarez ER. Proteoglycans and glycosaminoglycans in cancer. In: Cancerous Cells. Cham: Springer; 2025. p.419–474. doi:10.1007/978-3-032-00759-9_53.',
    '6. Ahrens TD, Bang-Christensen SR, Jørgensen AM, Løppke C, Spliid CB, Sand NT, et al. The role of proteoglycans in cancer metastasis and circulating tumor cell analysis. Front Cell Dev Biol. 2020;8:749. doi:10.3389/fcell.2020.00749.',
    '7. Elgundi Z, Papanicolaou M, Major G, Cox TR, Melrose J, Whitelock JM, et al. Cancer metastasis: the role of the extracellular matrix and the heparan sulfate proteoglycan perlecan. Front Oncol. 2020;9:1482. doi:10.3389/fonc.2019.01482.',
    '8. Mastronikolis NS, Kyrodimos E, Piperigkou Z, Spyropoulou D, Delides A, Giotakis E, et al. Matrix-based molecular mechanisms, targeting and diagnostics in oral squamous cell carcinoma. IUBMB Life. 2024;76(7):368–382. doi:10.1002/iub.2803.',
    '9. Patankar SR, Wankhedkar DP, Tripathi NS, Bhatia SN, Sridharan G. Extracellular matrix in oral squamous cell carcinoma: friend or foe? Indian J Dent Res. 2016;27(2):184–189. doi:10.4103/0970-9290.183125.',
    '10. Maruyama S, Shimazu Y, Kudo T, Sato K, Yamazaki M, Yajima Y, et al. Three-dimensional visualization of perlecan-rich neoplastic stroma induced concurrently with the invasion of oral squamous cell carcinoma. J Oral Pathol Med. 2014;43(8):627–636. doi:10.1111/jop.12184.',
    '11. Mishra M, Chandavarkar V, Naik VV, Kale AD. An immunohistochemical study of basement membrane heparan sulfate proteoglycan (perlecan) in oral epithelial dysplasia and squamous cell carcinoma. J Oral Maxillofac Pathol. 2013;17(1):31–35. doi:10.4103/0973-029X.110704.',
    '12. Kawahara R, Granato DC, Carnielli CM, Cervigne NK, Oliveira CE, Martinez CAR, et al. Agrin and perlecan mediate tumorigenic processes in oral squamous cell carcinoma. PLoS One. 2014;9(12):e115004. doi:10.1371/journal.pone.0115004.',
    '13. Rivera C, Zandonadi FS, Sánchez-Romero C, Granato DC, Gonçalves M, de Almeida OP, et al. Agrin has a pathological role in the progression of oral cancer. Br J Cancer. 2018;118(12):1628–1638. doi:10.1038/s41416-018-0135-5.',
    '14. Siqueira AS, Gama-de-Souza LN, Arnaud MVC, Pinheiro JJV, Jaeger RG. Laminin-derived peptide AG73 regulates migration, invasion, and protease activity of human oral squamous cell carcinoma cells through syndecan-1 and β1 integrin. Tumour Biol. 2010;31(1):46–58. doi:10.1007/s13277-009-0008-x.',
    '15. Zandonadi FS, Yokoo S, Granato DC, Cervigne NK, Rivera C, Salo T, et al. Follistatin-related protein 1 interacting partner of syndecan-1 promotes an aggressive phenotype on oral squamous cell carcinoma models. J Proteomics. 2022;254:104474. doi:10.1016/j.jprot.2021.104474.',
    '16. Shetty PK, Gonsalves N, Desai D, Khot K, Prabhu S, Rai S, et al. Expression of syndecan-1 in different grades of oral squamous cell carcinoma: an immunohistochemical study. J Cancer Res Ther. 2022;18(Suppl 2):S191–S196. doi:10.4103/jcrt.JCRT_1715_20.',
    '17. Asareh F, Noorizadehtehrani S. Immunohistochemical expression of syndecan-1 in erosive lichen planus, epithelial dysplasia and oral squamous cell carcinoma. Int J Curr Res Chem Pharm Sci. 2017;4(6):77–84. doi:10.22192/ijcrcps.2017.04.06.013.',
    '18. Andisheh-Tadbir A, Goharian AS, Ranjbar MA. Glypican-3 expression in patients with oral squamous cell carcinoma. J Dent (Shiraz). 2020;21(2):141–146. doi:10.30476/DENTJODS.2019.84541.1089.',
    '19. Schlaepfer Sales CB, Guimarães VSN, Valverde LF, Fonseca FP, Santos-Silva AR, Lopes MA, et al. Glypican-1, -3, -5 (GPC1, GPC3, GPC5) and Hedgehog pathway expression in oral squamous cell carcinoma. Appl Immunohistochem Mol Morphol. 2021;29(5):345–352. doi:10.1097/PAI.0000000000000907.',
    '20. Dil N, Banerjee AG. A role for aberrantly expressed nuclear localized decorin in migration and invasion of dysplastic and malignant oral epithelial cells. Head Neck Oncol. 2011;3:44. doi:10.1186/1758-3284-3-44.',
    '21. Rao Y, Chen X, Li K, Nie M, Liu X. Research progress on the role of decorin in the development of oral mucosal carcinogenesis. Oncol Res. 2025;33(3):577–590. doi:10.32604/or.2024.053119.',
    '22. Lončar-Brzak B, Klobučar M, Veliki-Dalić I, Alajbeg I, Ćabov T, Alajbeg IZ, et al. Expression of small leucine-rich extracellular matrix proteoglycans biglycan and lumican reveals oral lichen planus malignant potential. Clin Oral Investig. 2018;22(2):1071–1082. doi:10.1007/s00784-017-2190-3.',
    '23. Nikitovic D, Theocharis AD, Karamanos NK. The landscape of small leucine-rich proteoglycan impact on cancer pathogenesis with a focus on biglycan and lumican. Cancers (Basel). 2023;15(14):3549. doi:10.3390/cancers15143549.',
    '24. Xia L, Zhang T, Yao J, Chen X, Liu Y, Wang H, et al. Versican in oral cancer: expression, clinical significance, and potential therapeutic targets. Front Oncol. 2023;13:1027012. doi:10.3389/fonc.2023.1027012.',
    '25. Sun X, Chai L, Wang B, Zhou J. PRELP inhibits the progression of oral squamous cell carcinoma by suppressing EMT. Oncol Rep. 2022;47(3):63. doi:10.3892/or.2022.8274.',
    '26. Sun X, Liu Y, Chai L, Zhou J. PRELP regulated by miR-23a-3p suppresses oral squamous cell carcinoma invasion and metastasis. Arch Oral Biol. 2023;150:105686. doi:10.1016/j.archoralbio.2023.105686.',
    '27. Pukkila M, Kosunen A, Ropponen K, Virtaniemi J, Kellokoski J, Kumpulainen E, et al. High stromal versican expression predicts unfavourable outcome in oral squamous cell carcinoma. J Clin Pathol. 2007;60(3):267–272. doi:10.1136/jcp.2005.035071.',
    '28. Nanjappa V, Raja R, Radhakrishnan A, Sinha D, Patil AH, Prasad TSK, et al. Downstream signaling molecules of heparan sulfate proteoglycans in oral cancer. J Proteomics. 2015;119:67–75. doi:10.1016/j.jprot.2015.01.019.',
    '29. Ono T, Yoshida T, Nishijima K, Nagai N. Ultrastructural evidence for accumulation of proteoglycans and glycosaminoglycans during invasion of oral squamous cell carcinoma. J Oral Pathol Med. 2000;29(3):116–122. doi:10.1034/j.1600-0714.2000.290303.x.',
    '30. Kotani Y. N-linked oligosaccharide chains in the basement membrane type heparan sulfate proteoglycan synthesized by human oral squamous cell carcinoma cells [dissertation]. Tokyo: Tokyo Medical and Dental University; 1990. doi:10.11501/3142288.',
    '31. Banerjee AG. Glycosaminoglycans and proteoglycans in oral cancer: from pathobiology to therapeutic opportunities [preprint]. SSRN. 2026 Apr 17. doi:10.2139/ssrn.6593380.',
    '32. Chen K, Yong J, Zauner R. Chondroitin sulfate proteoglycan 4 as a marker for aggressive squamous cell carcinoma. Cancers (Basel). 2022;14(22):5580. doi:10.3390/cancers14225580.',
  ].map(ref => new Paragraph({
    children: [new TextRun({ text: ref, font: 'Times New Roman', size: 22 })],
    spacing: { before: 60, after: 60 },
  })),

];

// ─── BUILD DOC ───────────────────────────────────────────────────────────────
const doc = new Document({
  styles: {
    default: {
      document: {
        run: { font: 'Times New Roman', size: 24, color: '000000' },
        paragraph: { spacing: { line: 360 }, alignment: AlignmentType.JUSTIFIED },
      },
    },
    paragraphStyles: [
      {
        id: 'Heading1', name: 'Heading 1',
        run: { bold: true, allCaps: true, size: 26, font: 'Times New Roman', color: '000000' },
        paragraph: { spacing: { before: 400, after: 160 }, alignment: AlignmentType.LEFT },
      },
      {
        id: 'Heading2', name: 'Heading 2',
        run: { bold: true, size: 24, font: 'Times New Roman', color: '000000' },
        paragraph: { spacing: { before: 240, after: 80 }, alignment: AlignmentType.LEFT },
      },
    ],
  },
  sections: [{
    properties: {
      page: {
        margin: { top: 1440, bottom: 1440, left: 1800, right: 1440 }, // 2.5cm left, 2cm rest
      },
    },
    children,
  }],
});

Packer.toBuffer(doc).then(buf => {
  fs.writeFileSync('/home/daytona/workspace/revised-manuscript/Revised_Proteoglycans_OSCC.docx', buf);
  console.log('DONE');
}).catch(e => { console.error(e); process.exit(1); });

cd /home/daytona/workspace/revised-manuscript && node build.js 2>&1

python /home/daytona/skills/docx/scripts/office/validate.py /home/daytona/worksp…

python3 -c "import zipfile; z=zipfile.ZipFile('/home/daytona/workspace/revised-m…

pandoc /home/daytona/workspace/revised-manuscript/Revised_Proteoglycans_OSCC.doc…