Clinical and translational discovery最新文献

{"title":"CLDN18.2 in pancreatic ductal adenocarcinoma: Biomarker assessment, spatial heterogeneity and therapeutic modality selection","authors":"Ruyu Tan,&nbsp;Zhexin Zhang,&nbsp;Jiaxin Wang,&nbsp;Roland Andersson,&nbsp;Daniel Ansari,&nbsp;Jinfei Chen","doi":"10.1002/ctd2.70202","DOIUrl":"https://doi.org/10.1002/ctd2.70202","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Claudin 18.2 (CLDN18.2) is expressed in a subset of pancreatic ductal adenocarcinomas (PDACs) and is under clinical development as a target for monoclonal antibodies, antibody-drug conjugates, immune-cell engagers, and chimeric antigen receptor (CAR) T-cell therapies. The testing and clinical-development pathways established in gastric and gastroesophageal junction cancers provide a useful reference for PDAC; however, PDAC studies have yet to standardize the antibodies, specimen types, scoring methods, or positivity thresholds used for patient selection. Intratumoral and interlesional heterogeneity, discordance between primary and metastatic sites, and changes in membrane localization limit the ability of a single positive or negative sample to capture the tumor's antigenic state. Therapeutic modalities also differ in their requirements for membrane-antigen coverage, spatial distribution, and the tumor microenvironment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This narrative review draws on peer-reviewed articles, regulatory documents, ClinicalTrials.gov records, and relevant conference abstracts available through 31 July 2026. This review examines the biological basis, pathological assessment, spatial heterogeneity, and therapeutic development of CLDN18.2 in PDAC, with particular emphasis on treatment selection across different expression states.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>At baseline, the percentage of tumor cells with 2+/3+ membranous staining is used to describe antigen coverage, H-score complements this measure by capturing overall expression, and intratumoral and interlesional distribution and specimen representativeness are recorded separately.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings support the selection of monoclonal antibodies, antibody-drug conjugates, immune-cell engagers, and CAR T-cell therapy according to antigen coverage and spatial distribution, as well as treatment sequencing after disease progression.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"6 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70202","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148943120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Factor VIII inhibitors demonstrate type I or type II kinetics in high-titre alloantibodies and autoantibodies","authors":"Cuicui Qiao,&nbsp;Jie Wang,&nbsp;Tiantian Wang,&nbsp;Hehe Wang,&nbsp;Yingfang Pan,&nbsp;Wei Liu,&nbsp;Yan Cheng,&nbsp;Feng Xue,&nbsp;Man-Chiu Poon,&nbsp;Xinsheng Zhang,&nbsp;Yunhai Fang","doi":"10.1002/ctd2.70205","DOIUrl":"https://doi.org/10.1002/ctd2.70205","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>In the past, most references have indicated that inhibitors in inherited haemophilia A (HA) patients had type I reaction kinetics, while inhibitors in acquired haemophilia A (AHA) had type II reaction kinetics. However, researches have also shown that samples from AHA patients exhibit type I kinetics, while inhibitor samples from HA patients may also exhibit type II kinetics.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>To characterise inhibitor kinetics in HA patients and AHA patients in our centre.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Inhibitor measurement was performed using the Bethesda assay, and inhibitor type was classified by kinetic study with dilutions. The recovery of four HA patients with type II inhibitors was tested after FVIII replacement therapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In the 156 HA patients with high-titre inhibitors, 131 patients exhibited type I kinetics and 15 patients exhibited type II kinetics. In the 79 AHA patients with high-titre inhibitors, 21 patients exhibited type I kinetics and 38 patients exhibited type II kinetics. Pharmacokinetic showed that FVIII replacement was effective in four patients with type II kinetic inhibitors.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The inhibitor kinetic type cannot be used by itself determine auto- versus allo-anti-FVIII antibody type. Inhibitors for both HA alloantibodies and AHA autoantibodies may display either type I or type II kinetics. Pharmacokinetic study suggested that patients with type II kinetics may still be treated with higher doses of FVIII replacement therapy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"6 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70205","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148942649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SGLT2i in heart failure: Cardiorenal mechanisms, clinical evidence and translational perspectives","authors":"Jelica Grujic-Milanovic,&nbsp;Jovana Rajkovic,&nbsp;Radmila Novakovic,&nbsp;Javad Sharifi-Rad,&nbsp;Daniela Calina","doi":"10.1002/ctd2.70204","DOIUrl":"https://doi.org/10.1002/ctd2.70204","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Heart failure (HF) remains a major clinical and public health challenge despite advances in guideline-directed therapy. Sodium–glucose cotransporter 2 inhibitors (SGLT2i) have transformed HF management by reducing worsening HF events across the spectrum of left ventricular ejection fraction, irrespective of diabetes status.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This narrative review critically examines the mechanisms, clinical evidence, safety, limitations, and translational perspectives of SGLT2i in HF. MEDLINE/PubMed, EMBASE, Web of Science and Scopus were searched for relevant literature published up to January 2026, supplemented by manual reference screening. Priority was given to randomized clinical trials, systematic reviews, meta-analyses, major mechanistic studies, guidelines and regulatory sources.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Evidence from pivotal trials supports consistent reductions in HF hospitalization and cardiorenal events in HFrEF, HFmrEF and HFpEF. These benefits involve interconnected renal, haemodynamic, metabolic, mitochondrial, anti-inflammatory and intracellular ion-handling pathways. Genetic knockout studies further indicate that some myocardial effects may occur independently of direct SGLT2 inhibition, emphasizing the mechanistic complexity of this drug class. Important uncertainties remain regarding mortality benefits in some HF phenotypes, advanced CKD and other underrepresented populations, long-term implementation and the relative contribution of individual cardioprotective mechanisms. Natural compounds share several potentially complementary biological pathways with SGLT2i; however, evidence for their combined use remains predominantly preclinical, and randomized clinical evidence is lacking.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Overall, SGLT2i are a cornerstone of contemporary HF therapy, but further mechanistic, phenotype-specific, and translational studies are required to optimize their clinical use and establish the safety and potential value of natural compounds as adjunctive strategies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"6 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70204","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148942641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene therapy for hereditary deafness: Progress, challenges and translational implications from OTOF to GJB2","authors":"Jiahui Zhao,&nbsp;Mengzhao Xun,&nbsp;Yu Sun","doi":"10.1002/ctd2.70203","DOIUrl":"https://doi.org/10.1002/ctd2.70203","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Hereditary deafness is a common sensory disorder in infants and children. Gene therapy has achieved major clinical breakthroughs in <i>OTOF</i>-related deafness, establishing proof of concept for treating monogenic hearing loss. In contrast, <i>GJB2</i>-related hearing loss remains more challenging because of its broad cochlear expression, complex supporting-cell targets, developmental involvement, and narrow therapeutic window.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We reviewed recent advances in hereditary deafness gene therapy, focusing on the translational progression from <i>OTOF</i> to <i>GJB2</i>. We summarize early inner-ear gene-therapy efforts, clinical and preclinical developments in <i>OTOF</i>-targeted therapy, and current <i>GJB2</i>-directed strategies, including gene replacement, cell-specific delivery, base editing, pharmacological rescue, and potential in utero intervention.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p><i>OTOF</i> gene therapy has progressed to clinical trials, with dual-adeno-associated-virus strategies producing substantial and durable hearing restoration in patients with DFNB9. Its success is supported by preserved cochlear architecture and efficient inner-hair-cell targeting. <i>GJB2</i> therapy remains at the preclinical or early-clinical stage. Major barriers include the broad distribution of connexin 26-expressing cells, the need for precise supporting-cell targeting, limitations of current disease models, developmental differences between mice and humans, and irreversible cochlear abnormalities before postnatal treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p><i>OTOF</i> provides an important translational framework, but <i>GJB2</i> requires distinct strategies involving precise cochlear delivery, controlled transgene expression, improved models, large-animal validation, and potentially earlier intervention.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"6 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70203","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148942164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computational strategies to address therapeutic resistance in estrogen receptor-positive breast cancer: A narrative review of molecular docking, molecular dynamics simulations, and emerging therapeutic targets","authors":"Emmanuel Ifeanyi Obeagu,&nbsp;Yaregal Asres","doi":"10.1002/ctd2.70195","DOIUrl":"https://doi.org/10.1002/ctd2.70195","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Estrogen receptor-positive (ER+) breast cancer represents the most common molecular subtype of breast cancer and remains highly responsive to endocrine therapy. However, therapeutic efficacy is frequently compromised by acquired or intrinsic endocrine resistance, particularly through ESR1 mutations, altered receptor conformation, co-regulatory mechanisms, and activation of compensatory signaling pathways such as PI3K/AKT/mTOR. Conventional drug-discovery approaches are often slow, resource-intensive, and insufficiently equipped to address the structural and molecular heterogeneity underlying treatment resistance.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Objective&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;This review evaluates the contribution of computationally aided drug discovery, with particular emphasis on molecular docking, molecular dynamics (MD) simulations, and translational clinical targeting, to the development of more effective therapeutic strategies for ER+ breast cancer.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;A narrative review approach was used to synthesize evidence concerning computational drug-design strategies in ER+ breast cancer. Emphasis was placed on studies applying molecular docking to predict ligand receptor interactions and binding modes, MD simulations to evaluate structural stability, conformational dynamics, and ligand persistence, and integrative computational frameworks incorporating genomic, molecular, pharmacological, and clinical information.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Computational approaches have substantially expanded the capacity to identify, characterise, and optimise therapeutic candidates for ER+ breast cancer. Molecular docking enables rapid structural screening and prioritisation of compounds according to predicted receptor interactions and binding configurations, while MD simulations provide complementary information regarding ligand stability, receptor flexibility, conformational transitions, and mutation-associated alterations in ERα behaviour.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The integration of molecular docking, MD simulations, and translational clinical targeting provides a powerful framework for accelerating therapeutic discovery in ER+ breast cancer. Beyond reducing the time and cost associated with conventional drug development, computational approaches enable mechanistically informed targeting of receptor mutations, adaptive signaling networks, and molecular d","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"6 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70195","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148849192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Macrophage lipid efflux regulates the tumour microenvironment in early-stage lung adenocarcinoma","authors":"Yujie Zheng,&nbsp;Yuan Wang,&nbsp;Yalin Wang,&nbsp;Yue Shi,&nbsp;Hui Kong,&nbsp;Shaohua Lu,&nbsp;Yong Zhang,&nbsp;Jie Hu,&nbsp;Jian Zhou,&nbsp;Xiangdong Wang,&nbsp;Meng Xiang,&nbsp;Qiong Liu,&nbsp;Hongyi Xin,&nbsp;Charles A. Powell,&nbsp;Fred R. Hirsch,&nbsp;Chunxue Bai,&nbsp;Yuanlin Song,&nbsp;Jun Yin,&nbsp;Dawei Yang","doi":"10.1002/ctd2.70199","DOIUrl":"https://doi.org/10.1002/ctd2.70199","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Metabolic rewiring influences macrophage functions in tumours. However, metabolic heterogeneity of macrophages in early-stage lung adenocarcinoma (LUAD) has not been fully understood.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Based on single-cell transcriptomic analysis on lung tissues from human subsolid pulmonary nodules and from <i>Kras^G12D</i>and <i>Kras^G12DTgfbr2^−/−</i> mice, we unveiled alterations of macrophage states in LUAD. We applied cell migration and invasion assays to examine effects of ATP binding cassette subfamily A member 1 (ABCA1) in macrophages on tumour progression. In addition, using coculture system, we explored its role in macrophage polarisation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Major macrophage subsets underwent shifts during tumourigenesis, as alveolar macrophages reduced sharply and their interstitial counterparts increased. Of note, tumour-associated macrophages (TAMs) are metabolically rewired, with a subset enhancing lipid efflux predominated in both human and murine tumour. It was characterised by high expression of the lipid transporter, ABCA1. Targeting ABCA1 by its inhibitor probucol suppressed TAM capacity to induce tumour cell migration and invasion. In addition, inhibiting ABCA1 was associated with dampened immunosuppression of TAMs by shifting them to a M1-like phenotype.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We uncovered TAM heterogeneity in early-stage LUAD and proposed ABCA1 as a potential target for metabolic rewiring, which manipulated macrophage polarisation states and its effects on tumour aggressiveness.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"6 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70199","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148849124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune cells in the pathogenesis of abdominal aortic aneurysm: Roles, regulation and targeted interventions","authors":"Junqi Peng,&nbsp;Hanqing Zhang,&nbsp;Yun Wu,&nbsp;Song Chen","doi":"10.1002/ctd2.70200","DOIUrl":"https://doi.org/10.1002/ctd2.70200","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Abdominal aortic aneurysm (AAA) is a lethal degenerative vascular disease with no approved clinical drugs. Immune responses dominate the entire AAA pathological process, and multiple immune cells regulate vascular homeostasis and disease progression via cytokine secretion.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This study systematically reviewed current literature to elaborate the infiltration and functions of macrophages, neutrophils and T cells in AAA, and summarized immune cell phenotypic imbalance and core regulatory mechanisms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We clarified the immune cell interaction network in AAA, generalized updated immune-targeted intervention strategies, and sorted out major controversies in existing related studies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This review highlights immune-mediated AAA pathogenesis and research gaps, providing theoretical support for subsequent AAA basic research and novel immune-targeted drug development.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"6 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70200","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148848663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic profiling reveals conserved stage-associated programs across gastrointestinal adenocarcinomas","authors":"Wynston Jay Abenojar,&nbsp;Ron Jacob Avila,&nbsp;Po-Wei Tsai,&nbsp;Lemmuel Tayo","doi":"10.1002/ctd2.70201","DOIUrl":"https://doi.org/10.1002/ctd2.70201","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Gastrointestinal (GI) adenocarcinomas exhibit substantial molecular heterogeneity despite their shared epithelial origin and anatomical continuity. Whether these anatomically distinct cancers share conserved transcriptomic programs associated with pathological stage remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>This study aimed to identify conserved transcriptomic programs associated with pathological stage across pan-GI adenocarcinomas using an integrated transcriptomic network analysis approach.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods and results</h3>\u0000 \u0000 <p>RNA sequencing data from oesophageal, gastric, colon and rectal adenocarcinomas in The Cancer Genome Atlas were integrated into a stage-stratified pan-GI cohort. Weighted gene co-expression network analysis identified conserved co-expression modules, which were validated through hub gene validation in independent Clinical Proteomic Tumor Analysis Consortium Phase cohorts and module preservation analysis in Gene Expression Omnibus datasets. Functional enrichment, differential expression, miRNA–mRNA regulatory network and survival analyses were subsequently performed. Two conserved co-expression modules remained significantly associated with pathological stage after adjustment for age, sex and primary anatomical site. These modules were enriched for intracellular signalling and extracellular matrix-related pathways and contained seven consistently dysregulated validated hub genes (<i>ZEB1</i>, <i>FERMT2</i>, <i>MPDZ</i>, <i>LRCH2</i>, <i>ZFPM2</i>, <i>GLI3</i> and <i>PDGFRB</i>), together with three candidate regulatory microRNAs (<i>hsa-miR-19a</i>, <i>hsa-miR-19b</i> and <i>hsa-miR-20a</i>).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Pan-GI transcriptomic profiling identified conserved epithelial- and stromal-associated molecular programs shared across anatomically distinct GI adenocarcinomas. These reproducible transcriptomic features provide a systems-level framework for understanding shared disease biology and establish a foundation for future mechanistic studies and stage-informed therapeutic strategies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"6 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70201","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148848664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-invasive biomarkers in biliary atresia: A scoping review of fibrosis assessment, translational readiness and clinical implementation gaps","authors":"Elizabeth Brits,&nbsp;Stephen Brown,&nbsp;Lezelle Botes,&nbsp;Michael Pienaar","doi":"10.1002/ctd2.70196","DOIUrl":"https://doi.org/10.1002/ctd2.70196","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Biliary atresia (BA) is a progressive fibro-inflammatory cholangiopathy in which liver fibrosis influences clinical outcomes. Although liver biopsy remains the reference standard for fibrosis assessment, it is invasive and unsuitable for longitudinal monitoring. Numerous non-invasive biomarkers have been proposed, but their readiness for clinical implementation remains uncertain. This review synthesised evidence on biomarkers associated with histological fibrosis severity in BA and evaluated their translational readiness and clinical utility.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A scoping review was conducted in accordance with the Joanna Briggs Institute methodology and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. MEDLINE and Scopus were searched for human studies published between January 2019 and July 2025. Eligible studies evaluated associations between non-invasive biomarkers and histological liver fibrosis at diagnosis or Kasai portoenterostomy (KPE). Biomarkers were classified by pathobiological mechanism, U.S. Food and Drug Administration (FDA)-National Institutes of Health (NIH) Biomarkers, EndpointS and other Tools (BEST) category and translational readiness level (TRL).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Thirty-eight studies met the inclusion criteria. Most (33/38; 86.8%) reported significant associations with fibrosis severity. Biomarkers were categorised by mechanism (e.g., fibrogenesis, imaging and inflammatory). Serum matrix metalloproteinase-7 (MMP-7) and elastography demonstrated the highest translational maturity, being the only tools supported beyond early validation. Conversely, most molecular, metabolic and inflammatory candidates remain at proof-of-concept or analytical validation stages. Substantial methodological heterogeneity remains regarding thresholds and reference standards.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The challenge in BA biomarker research has shifted from discovery to clinical implementation. While MMP-7 and elastography are the most mature tools, none of them currently serves as a standalone determinant of management. Future progress requires methodological standardisation, multicentre validation and the integration of biomarkers into multimodal clinical decision-making frameworks to meaningfully improve patient care.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"6 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70196","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148807738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correlation of the peripheral blood DNA methylation profile and immune-related adverse events in patients with solid cancer treated with immune checkpoint inhibitors","authors":"Markus Kleinberger,&nbsp;Angelika Martina Starzer,&nbsp;Erwin Tomasich,&nbsp;Julia Maria Berger,&nbsp;Vincent Sunder-Plassmann,&nbsp;Lynn Gottmann,&nbsp;Isabella Solano Henao,&nbsp;Martin Korpan,&nbsp;Josef Fuerst,&nbsp;Nikola Vladic,&nbsp;Cihan Ay,&nbsp;Helmuth Haslacher,&nbsp;Julia Furtner,&nbsp;Matthias Preusser,&nbsp;Gerwin Heller,&nbsp;Anna Sophie Berghoff","doi":"10.1002/ctd2.70156","DOIUrl":"https://doi.org/10.1002/ctd2.70156","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background/Introduction</h3>\u0000 \u0000 <p>Immune-related adverse events (irAEs) remain unpredictable complications of immune checkpoint inhibitor (ICI) therapy. Current biomarkers, such as inflammatory blood parameter lack specificity and clinical robustness. Because DNA methylation reflects stable immune programming and predisposition to autoimmune diseases, blood methylation profiling may offer a tumour-agnostic approach for irAE prediction.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Material &amp; methods</h3>\u0000 \u0000 <p>We analysed baseline leukocyte DNA methylation in a prospectively enrolled real-world cohort of advanced pan-cancer patients treated with ICI in a palliative setting. Genome-wide methylation was profiled using Infinium MethylationEPIC v1.0 BeadChips. Differentially methylated positions (DMPs) were identified by rank-based comparison and tested for Gene Ontology enrichment. Blood-cell deconvolution using EpiDISH was applied to exclude compositional bias.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Among 195 patients (median age 65 years; 34.9% female), 32.8% experienced at least one irAE, most frequently involving thyroid, skin, or lung. Despite globally concordant DNA methylation between groups (<i>ρ</i> = 0.9996), DMP analysis revealed subtle but distinct site-specific differences. A methylation-based classifier discriminated patients who developed irAEs with good accuracy (area under the curve [AUC] 0.831, 95% confidence interval [CI] 0.735–0.927), which remained robust in an internal validation subset (AUC 0.874, 95% CI 0.757–0.992). EpiDISH confirmed no significant variation in immune cell fractions between groups. Functional enrichment of top-ranked DMPs showed significant overrepresentation of neuronal development, cell-cell signalling, and epithelial morphogenesis pathways, networks linked to immune-synapse formation, cytokine signalling, and tissue repair responses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Discussion</h3>\u0000 \u0000 <p>Baseline blood DNA methylation captures systemic immune-developmental states predisposing to irAEs. The enrichment of <b>cell-cell signalling and epithelial morphogenesis</b> pathways suggests an epigenetically encoded predisposition for dysregulated immune-tissue communication. Blood-based methylation profiling thus represents a promising, tumour-agnostic biomarker approach for individualised irAE risk prediction in cancer immunotherapy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"6 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70156","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148753158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}