Med最新文献

{"title":"Resectability redefined: Lessons from quadruple therapy in HCC.","authors":"Nan Jiang, Bin-Yan Zhong","doi":"10.1016/j.medj.2026.101136","DOIUrl":"10.1016/j.medj.2026.101136","url":null,"abstract":"<p><p>Qiu et al. report a phase II trial (PLATIC) evaluating sintilimab, lenvatinib, and transarterial chemoembolization combined with hepatic arterial infusion chemotherapy (TACE-HAIC) as conversion therapy for unresectable hepatocellular carcinoma (uHCC).¹ While these results represent a substantial advance in conversion therapy, they also raise critical questions about how to optimally integrate locoregional and systemic therapies.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"7 6","pages":"101136"},"PeriodicalIF":11.8,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148240400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First human decedent model of orthotopic multi-organ xenotransplantation: Whole liver and bilateral kidneys from a six-gene-edited pig.","authors":"Jixiang Liao, Sanqi An, Jianhui Dong, ShihJung Li, Jianhui Li, Lei Dong, Ziyang Luo, Liugen Lan, Ning Wen, Jihua Wu, Jiqiu Wen, Zhiying Lei, Dongge Yang, Haibin Li, Minghu Li, Yan Mo, Luying Chen, Zhao Gao, Xuyang Liu, Haisong Qin, Xiang Wang, Yajing Chen, Wenli Yin, Bihui Huang, Wenxing Li, Gabriel Oniscu, Wenshi Jiang, Dengke Pan, Zhengxin Wang, Zhijun Zhu, Jinzhen Cai, Haitao Li, Juntao Gao, Xiaocong Kuang, Xuyong Sun","doi":"10.1016/j.medj.2026.101148","DOIUrl":"10.1016/j.medj.2026.101148","url":null,"abstract":"<p><strong>Background: </strong>We report orthotopic combined whole-liver and bilateral-kidney xenotransplantation (xeno-CLKT) from a six-gene-edited pig into a 53-year-old human decedent recipient.</p><p><strong>Methods: </strong>After simultaneous implantation and reperfusion, graft function was monitored for nearly 5 days using continuous clinical assessments. Host responses were further characterized with single-cell RNA sequencing, proteomics, and metabolomics of blood and graft tissues collected before and after transplantation.</p><p><strong>Findings: </strong>All grafts maintained basic physiological function throughout the observation period, with no evidence of hyperacute rejection. Early post-transplant immune analysis showed expansion of S100A12⁺ neutrophils, which emerged as central hubs in inferred intercellular communication networks. Systems-level metabolomic profiling indicated that post-transplant metabolic patterns remained positively correlated with the recipient's pre-transplant baseline, with generally higher magnitudes.</p><p><strong>Conclusions: </strong>This study provides initial evidence for the feasibility of pig-to-human orthotopic whole-liver plus bilateral-kidney transplantation and identifies early immune and metabolic features that may inform perioperative management and future clinical translation.</p><p><strong>Funding: </strong>The research was supported by the Guangxi Key Research and Development Program (AB24010059), the Shenzhen Medical Research Fund (SMAF) (B2302008), and the Guangdong Province Guangdong-Shenzhen Joint Key Project (2023B1515120083).</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"101148"},"PeriodicalIF":13.3,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148057292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expansion of NKG2A⁺CD8⁺ T cells with regulatory signatures distinguish individuals living with HIV-2 from those with HIV-1.","authors":"Aurelio Orta Resendiz, Caroline Petitdemange, Marie Lazzerini, Béatrice Jacquelin, Emma Beaumont, Federico Perdomo-Celis, Assia Samri, Olivier Lambotte, Laurence Meyer, Cecile Goujard, Florence Damond, Diane Descamps, Charlotte Charpentier, Jade Ghosn, Nicolas Huot, Michaela Müller-Trutwin","doi":"10.1016/j.medj.2026.101143","DOIUrl":"10.1016/j.medj.2026.101143","url":null,"abstract":"<p><strong>Background: </strong>NKG2A⁺CD8⁺ T cells are unconventional T cells described in the context of various diseases. However, their role remains poorly understood. People living with HIV-2 (PLWH2), unlike people living with HIV-1 (PLWH1), exhibit minimal intestinal inflammation despite continuous viral replication in the absence of antiretroviral treatment, but the mechanisms underlying this protection are unknown.</p><p><strong>Methods: </strong>We characterized NKG2A⁺ and NKG2C⁺ CD8⁺ T cells from PLWH1 and PLWH2 with distinctive clinical phenotypes using spectral flow cytometry. Their functional response was evaluated using target cells, polyclonal T cell receptor activation, and cytokine stimulations. Cellular and plasma markers of gut mucosal integrity, T cell activation, and systemic inflammation were quantified.</p><p><strong>Findings: </strong>NKG2A⁺ and NKG2C⁺ CD8⁺ T cells demonstrated stronger responsiveness to stimulation than conventional CD8⁺ T cells. NKG2A⁺CD8⁺ T cells frequently expressed regulatory molecules, homing receptors, and interleukin-22 (IL-22). The frequencies of NKG2A⁺ and NKG2C⁺ CD8⁺ T cells were increased in PLWH2 compared to PLWH1. They more frequently expressed DNAM-1 (CD226), CCR5, and CD49d. NKG2A⁺CD8⁺ T cells from PLWH2 correlated with gut integrity (CD4⁺ T helper 17/regulatory T cell ratio) and reduced chronic immune activation. PLWH2 displayed lower levels of plasma biomarkers of inflammation, gut integrity, and IL-23, but higher levels of IL-15 compared to PLWH1. IL-15 promoted the functional activity of NKG2A⁺CD8⁺ T cells and enhanced their expression of CD39 and DNAM-1.</p><p><strong>Conclusions: </strong>Our findings suggest that NKG2A⁺CD8⁺ T cells contribute to the maintenance of gut homeostasis and low systemic inflammation in PLWH2.</p><p><strong>Funding: </strong>This work was funded by Sidaction, ANRS-MIE, Institut Pasteur, and the MESRI (France).</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"101143"},"PeriodicalIF":11.8,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147960452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diabetic retinal disease: Five trials to watch.","authors":"Hannah Khan, Aamir A Aziz, Arshad M Khanani, Sobha Sivaprasad","doi":"10.1016/j.medj.2026.101144","DOIUrl":"10.1016/j.medj.2026.101144","url":null,"abstract":"<p><p>Diabetic retinal disease remains a leading cause of vision loss, with current treatment limited by frequent injections and poor adherence. Ongoing clinical trials are evaluating topical therapies, sustained delivery systems, and gene therapy as alternatives to current gold standard treatments. The field is shifting toward earlier, more personalized, and more durable disease-modifying strategies.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"7 6","pages":"101144"},"PeriodicalIF":13.3,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148240392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neoadjuvant mFOLFOXIRI with or without cadonilimab versus mFOLFOX6 in locally advanced colorectal cancer: A randomized phase 2 trial (OPTICAL-2).","authors":"Jianwei Zhang, Sifan Qi, Huabin Hu, Xiaosheng He, Liang Huang, Jiaming Zhou, Hui Wang, Xiaojian Wu, Liang Kang, Meijin Huang, Zhen He, Huaiming Wang, Dianke Chen, Xiaohui Zhai, Xiaoyu Xie, Jiayu Ling, Yan Zhang, Jiancong Hu, Shanshan Li, Zehua Wu, Tao Yang, Runkai Cai, Yue Cai, Lixing Zhong, Weiwei Li, Lishuo Shi, Chao Wang, Yan Huang, Yandong Zhao, Wuteng Cao, Ge Qin, Yanhong Deng","doi":"10.1016/j.medj.2026.101141","DOIUrl":"10.1016/j.medj.2026.101141","url":null,"abstract":"<p><strong>Background: </strong>The efficacy of neoadjuvant chemotherapy combined with dual immune checkpoint blockade in proficient mismatch repair/microsatellite-stable (pMMR/MSS) locally advanced colorectal cancer (LACRC) remains uncertain.</p><p><strong>Methods: </strong>In this open-label, randomized phase 2 trial (ClinicalTrials.gov: NCT05571644), eligible patients were randomly assigned (1:1:1) to receive 6 cycles of neoadjuvant mFOLFOXIRI plus cadonilimab, mFOLFOXIRI, or mFOLFOX6, followed by surgery and adjuvant chemotherapy. The primary endpoint was pathological complete response (pCR) in the intention-to-treat population. Secondary endpoints included major pathological response (MPR), safety, locoregional recurrence, disease-free survival, and overall survival.</p><p><strong>Findings: </strong>Between July 2023 and August 2024, 123 patients were randomly assigned (41 per group). Neoadjuvant mFOLFOXIRI plus cadonilimab significantly improved pCR compared with mFOLFOX6 (26.8% versus 9.8%; odds ratio [OR], 3.4; 95% confidence interval [CI], 1.04 to 13.24; p = 0.046), whereas mFOLFOXIRI alone did not (14.6% versus 9.8%; OR, 1.6; 95% CI, 0.4 to 6.7; p = 0.50). MPR rates were 68.3%, 46.3%, and 43.9%, respectively, and were significantly higher with mFOLFOXIRI plus cadonilimab than with mFOLFOX6 (p = 0.026). Downstaging to ypStage 0-I occurred in 66%, 45%, and 41% of patients in the three groups, respectively, and was significantly higher in the mFOLFOXIRI plus cadonilimab group (p = 0.027). Grade ≥3 adverse events were manageable, with liver enzyme elevation and neutropenia being the most common.</p><p><strong>Conclusions: </strong>Neoadjuvant mFOLFOXIRI plus cadonilimab significantly improved pCR compared with mFOLFOX6 in LACRC, with a manageable safety profile, supporting further investigation.</p><p><strong>Funding: </strong>This work was funded by the National Science Fund for Distinguished Young Scholars (82425045) and the National Natural Science Foundation of China (82272800).</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"101141"},"PeriodicalIF":13.3,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147942775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mapping the genomic landscape of MASLD: A framework for molecular subtyping and precision hepatology.","authors":"Carlos José Pirola, Silvia Sookoian","doi":"10.1016/j.medj.2026.101131","DOIUrl":"10.1016/j.medj.2026.101131","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is not merely a hepatic manifestation of systemic metabolic dysregulation, but a central node and active determinant of multi-organ derangement. As a primary cause of cirrhosis and hepatocellular carcinoma, the progression to metabolic dysfunction-associated steatohepatitis (MASH) represents a critical prognostic threshold. The pathogenesis of MASLD reflects a complex genomic architecture arising from the interplay of rare high-penetrance variants, common genetic risk loci, and extrinsic modifiers. While Mendelian drivers illuminate fundamental pathways in intermediary metabolism and cellular stress, common variants account for the interindividual heterogeneity in fibrosis severity. Epigenetic modifications, mitochondrial dynamics, and host-microbiota interactions functionally bridge environmental exposures and host genomic risk. These converging biological layers-environmental clues, including microbial metabolites, to the host epigenome-establish a framework for precision risk stratification and the development of genotype-directed therapeutics tailored to specific molecular subtypes.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"101131"},"PeriodicalIF":11.8,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147821665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"National- and state-level burdens of substance use disorders in the USA, 1990-2023, with forecasts up to 2050: Global Burden of Disease Study 2023.","authors":"","doi":"10.1016/j.medj.2026.101139","DOIUrl":"10.1016/j.medj.2026.101139","url":null,"abstract":"<p><strong>Background: </strong>While the United States of America (USA) faces a substantial substance use disorder (SUD) burden on a global scale, relatively little is known about the current trends and future trajectories at both national and state levels.</p><p><strong>Methods: </strong>Using the Global Burden of Disease Study 2023, we examined estimates of prevalence and disability-adjusted life years (DALYs) for SUDs in the USA, including alcohol use disorders (AUDs) and drug use disorders (DUDs), across all 50 states and Washington, DC, from 1990 to 2023 and forecasted trends to 2050.</p><p><strong>Findings: </strong>In 2023, the USA had the highest age-standardized prevalence of SUDs across the globe. Overall, age-standardized SUD prevalence increased from 4,664.6 (95% uncertainty interval, 4,076.4-5,333.3) estimated rates per 100,000 people in 1990 to 6,430.1 (5,871.7-7,056.3) per 100,000 people in 2023, representing an increase of 37.9%. At the state level in 2023, broader geographical variations were observed in terms of estimated age-standardized DALYs for SUDs. At both the national and state levels, the age-standardized prevalence and burden of DUDs have outpaced and surpassed the increase in AUDs over time. By 2050, if existing trends continue, the age-standardized prevalence of SUDs is projected to rise to 8,956.0 (7,478.8-10,118.4) per 100,000 people, driven primarily by increasing age-standardized prevalence of DUDs, while age-standardized prevalence of AUDs is predicted to increase slightly.</p><p><strong>Conclusion: </strong>These findings suggest that current interventions have been insufficient to curb the SUD crisis. Without urgent, evidence-based reforms, the SUD burden will continue to increase and deepen health disparities across the USA.</p><p><strong>Funding: </strong>This work was funded by the Gates Foundation.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"7 6","pages":"101139"},"PeriodicalIF":13.3,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148240373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Large-scale quantitative metabolomics and mass spectrometry imaging define the metabolic atlas in human acute type A aortic dissection.","authors":"Xiaozheng Zhou, Peirong Lin, Ying Ma, Yanru Duan, Lin Zheng, Jiyuan Luo, Florian Osmanaj, Kun Hua, Junming Zhu, Xiubin Yang, Yunhui Du, Yingyuan Lu, Zhiyong Du","doi":"10.1016/j.medj.2026.101078","DOIUrl":"10.1016/j.medj.2026.101078","url":null,"abstract":"<p><strong>Background: </strong>Acute type A aortic dissection (ATAAD) is the most frequent acute aortic disease with high mortality. To date, a comprehensive metabolic characterization of the human ATAAD ascending aorta remains elusive.</p><p><strong>Methods: </strong>We used large-scale targeted metabolomics on ascending aortas obtained from patients with ATAAD, patients with ascending thoracic aortic aneurysm (ATAA), and healthy donors to quantify the 1,349 metabolites. By integrating with transcriptomics and mass spectrometry imaging (MSI) analysis, we further visualized the spatial distribution of the key ATAAD-altered metabolic network.</p><p><strong>Findings: </strong>Quantitative profiling revealed distinct hydrophilic metabolite and glycerophospholipid profiles in ascending aortas from patients with ATAAD (n = 20), which remarkably differed from those in patients with ATAA (n = 20) and healthy controls (n = 20). Various metabolites in purine, pyrimidine, and amino acid metabolic pathways were found to be specifically and significantly altered in the ascending aorta of ATAAD. MSI analysis indicated that those differentiated metabolites were mainly enriched in the tunica media and intima. Two key ATAAD-altered metabolites-hypoxanthine and pyroglutamic acid-were selected as proof-of-concept candidates. In a prospective ATAAD cohort (n = 196), circulating levels of both metabolites correlated positively with adverse clinical outcomes. Functional studies confirmed they promote aortic dissection by impairing vascular smooth muscle and endothelial cell functions.</p><p><strong>Conclusions: </strong>Our study presents the first large-scale quantitative and spatial metabolic atlas of the human ATAAD ascending aorta, highlighting key metabolic disturbances with potential as risk markers and therapeutic targets for acute aortic diseases.</p><p><strong>Funding: </strong>This work was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project and the Beijing Natural Science Foundation.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"101078"},"PeriodicalIF":13.3,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147575650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"T cell exhaustion in bi- and trispecific T cell engager therapy in hematologic malignancies: Mechanisms and implications.","authors":"Amelie Muth, Alessandra Holzem, Anne-Sophie Neumann, Veit L Buecklein, Marion Subklewe, Nora Philipp","doi":"10.1016/j.medj.2026.101031","DOIUrl":"10.1016/j.medj.2026.101031","url":null,"abstract":"<p><p>T cell engagers (TCEs) have revolutionized the treatment of hematologic malignancies, with eight approved bispecific constructs and numerous bi- and trispecific TCEs currently in clinical trials. However, despite their clinical success, lack of response and high relapse rates remain major challenges. T cell exhaustion has emerged as an important mechanism of resistance to TCE therapy. Characterizing the T cell pool in patients prior to and during TCE therapy is warranted (1) to identify patients who will benefit most from TCE therapy and (2) to develop strategies to circumvent exhaustion during treatment to improve patient outcomes. We here review the current evidence of pre-existing and acquired T cell exhaustion during TCE therapy in patients with hematologic malignancies. We furthermore review state-of-the-art (pre)clinical strategies aimed at ameliorating exhaustion and reinvigorating T cell function.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"101031"},"PeriodicalIF":13.3,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147322294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CTHRC1⁺ fibroblasts in intestinal fibrosis in Crohn's disease: A done deal?","authors":"Meiqi Yang, Zhanju Liu","doi":"10.1016/j.medj.2026.101102","DOIUrl":"10.1016/j.medj.2026.101102","url":null,"abstract":"<p><p>CTHRC1⁺ fibroblasts are identified as a key player in creeping fat-driven intestinal fibrosis in Crohn's disease. Bauer-Rowe et al. mapped the spatial and transcriptional landscape of fibroblasts, revealing how creeping fat contributes to intestinal fibrosis in Crohn's disease through mechanosensitive signaling pathways.¹.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"7 5","pages":"101102"},"PeriodicalIF":13.3,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147864549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}