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{"title":"KRAS mutation status integrated with RNA subtyping improves prognostic modeling in FOLFIRINOX-treated metastatic pancreatic cancer.","authors":"Marjolein F Lansbergen, Mark P G Dings, Jan Koster, Mariette Labots, Emile D Kerver, Anouk Jochems, Marjolein Y V Homs, Judith de Vos-Geelen, Mathijs P Hendriks, Michael W T Tanck, Johanna W Wilmink, Hanneke W M van Laarhoven, Maarten F Bijlsma","doi":"10.1016/j.medj.2025.100601","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100601","url":null,"abstract":"<p><strong>Background: </strong>First-line chemotherapy (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin [FOLFIRINOX]) benefits few patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). Prognostic markers for treatment-related survival are needed. This study validated the added benefit of whole-genome sequencing (WGS) to transcriptome-based classification in modeling FOLFIRINOX-related survival.</p><p><strong>Methods: </strong>Patients with mPDAC planning to start FOLFIRINOX were included in a prospective nationwide cohort. Pretreatment biopsies were submitted to WGS and RNA sequencing. Samples of non-FOLFIRINOX-treated patients were included for exploratory analyses.</p><p><strong>Findings: </strong>WGS was performed in biopsies from 108 FOLFIRINOX-treated patients and 51 non-FOLFIRINOX-treated patients. 12% of the tumors were KRAS wild type. These tumors had more targetable alterations (42% vs. 17%) and were associated with a longer median overall survival (mOS) than KRAS mutant tumors (7.8 months in KRAS mutant vs. 17.7 months in wild-type tumors, p = 0.0024). Transcriptome-based clustering revealed a tumor subgroup showing low classical and basal-like gene expression, enriched for KRAS wild-type status (p < 0.0001), a so-called \"classifier-negative\" subtype. The gene expression of these classifier-negative tumors correlated with neural-like signatures. For patients with a homologous recombination-deficient (HRD) tumor, mOS was not increased (8.0 months in homologous recombination-proficient [HRP] vs. 13.3 months in HRD tumors, p = 0.21).</p><p><strong>Conclusions: </strong>KRAS wild-type tumors are a distinct PDAC subgroup with a better prognosis. Consequently, KRAS status assessment before transcriptome-based subtyping can stratify patients into three prognostic molecular subgroups (KRAS wild type, KRAS mutant classical, and KRAS mutant basal like). This integrative way of classification should be validated prior to incorporation in diagnostic practice.</p><p><strong>Funding: </strong>ZonMw \"Good Use of Medicine\" program (848101012).</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100601"},"PeriodicalIF":12.8,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411010","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":"Toripalimab plus platinum-doublet chemotherapy as perioperative therapy for initially unresectable NSCLC: An open-label, phase 2 trial.","authors":"Liang Zeng, Huan Yan, Wenjuan Jiang, Haoyue Qin, Jiacheng Dai, Yuda Zhang, Shiyou Wei, Shanmei Chen, Li Liu, Yi Xiong, Haiyan Yang, Yizhi Li, Zhan Wang, Li Deng, Qinqin Xu, Ling Peng, Ruiguang Zhang, Chao Fang, Xue Chen, Jun Deng, Jing Wang, Ting Li, Hong Liu, Gao Zhang, Nong Yang, Yongchang Zhang","doi":"10.1016/j.medj.2025.100574","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100574","url":null,"abstract":"<p><strong>Background: </strong>Perioperative treatment with toripalimab combined with chemotherapy was efficacious and safe in resectable stage II-IIIA non-small cell lung cancer (NSCLC); however, little is known about whether this treatment regimen could convert unresectable NSCLC to resectable.</p><p><strong>Methods: </strong>This study enrolled 40 treatment-naive patients with initially unresectable stage IIIA-IIIB NSCLC. Toripalimab (240 mg) and platinum-doublet chemotherapy were administered every 3 weeks for 2-4 cycles. Surgical resection was decided after assessing the efficacy of induction therapy. The primary outcome was the R0 resection rate. The secondary outcomes included safety, overall survival, disease-free survival, event-free survival, objective response rate, major pathological response (MPR), and pathological complete response (pCR). Available baseline tumor biopsy samples were used for molecular biomarker analyses, including bulk RNA sequencing and multiplex immunostaining. This study was registered at ClinicalTrials.gov: NCT04144608.</p><p><strong>Findings: </strong>Of the 40 patients who received induction toripalimab plus chemotherapy, 29 (72.5%) patients received surgery, and all achieved R0 resection (100% R0 rate). Of these patients, 17 (58.6%) achieved MPR, with 10 (34.5%) patients evaluated as pCR. With a median follow-up of 31.8 months (95% confidence interval [CI]: 24.2-39.4), the median event-free survival and overall survival were not reached. Molecular analyses revealed highly expressed gene sets for germinal center B cells (signatures of tertiary lymphoid structure [TLS]) at baseline among patients with pCR compared to patients with non-pCR, suggesting that the TLS status of the patients was associated with the induction of immunotherapy responses.</p><p><strong>Conclusions: </strong>Toripalimab-based induction treatment of initially unresectable NSCLC yielded a high R0 rate and MPR rate, with a good safety profile and encouraging survival outcomes.</p><p><strong>Funding: </strong>This work was funded by the National Natural Science Foundation of China.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100574"},"PeriodicalIF":12.8,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075669","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":"HMPL-306 in relapsed or refractory IDH1- and/or IDH2-mutated acute myeloid leukemia: A phase 1 study.","authors":"Lijuan Hu, Xudong Wei, Weili Zhao, Yu Hu, Juan Li, Yugang Dong, Tiejun Gong, Xuhan Zhang, Yajing Xu, Yu Zhang, Chongyuan Xu, Cheng Zhang, Zhen Cai, Hongmei Jing, Ruihua Mi, Wen Wu, Wenjuan He, Hehua Wang, Qinghua Tang, Zhiping Jiang, Hui Liu, Guo Chen, Jie Sun, Jian Chen, Sai Yan, Huan Yan, Jiaxuan Wangwu, Zeyu Zhong, Linfang Wang, Songhua Fan, Michael Shi, Weiguo Su, Xiaojun Huang","doi":"10.1016/j.medj.2025.100575","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100575","url":null,"abstract":"<p><strong>Background: </strong>HMPL-306 has equally high inhibitory activity against mutated isocitrate dehydrogenases 1 and 2 (mIDH1/2).</p><p><strong>Methods: </strong>This first-in-human, phase 1 dose-escalation/dose-expansion study (this study was registered at ClinicalTrials.gov: NCT04272957) enrolled patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) harboring mIDH1 and/or mIDH2. Patients received 25-250 mg of HMPL-306 orally once daily (QD) in a 28-day treatment cycle. Primary objectives were safety, tolerability, and recommended phase 2 dose (RP2D), and the secondary objective was preliminary efficacy.</p><p><strong>Findings: </strong>A total of 76 patients were enrolled. No dose-limiting toxicities were observed, and the maximum tolerated dose was not reached. RP2D was 250 mg QD for cycle 1 and 150 mg QD from cycle 2 onward. Common (≥10%) grade ≥3 treatment-related adverse events included platelet count decreased, anemia, neutrophil count decreased, and white blood cell count decreased. In patients who received 150 mg, 250 mg, or the RP2D (N = 59), rates of complete remission (CR)+CR with partial hematologic recovery were 34.6% and 36.4% in the mIDH1 (n = 26) and mIDH2 (n = 33) subgroups, respectively, and among these, CR with minimal residual disease negative rates were 77.8% and 50.0%, respectively. The median overall survival was 13.4 months in patients with mIDH1 and 13.1 months in patients with mIDH2.</p><p><strong>Conclusions: </strong>HMPL-306 showed an acceptable safety profile and promising preliminary efficacy. A phase 3, randomized study of HMPL-306 in R/R AML (this study was registered at ClinicalTrials.gov: NCT06387069) has been initiated.</p><p><strong>Funding: </strong>HUTCHMED Limited, National Key Research and Development Program of China, National Natural Science Foundation of China, and Peking University Medicine Fund for world's leading discipline or discipline cluster development.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100575"},"PeriodicalIF":12.8,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075667","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":"Setting \"cold\" tumors on fire: Cancer therapy with live tumor-targeting bacteria.","authors":"Simin Manole, Dinh-Huy Nguyen, Jung-Joon Min, Shibin Zhou, Neil Forbes","doi":"10.1016/j.medj.2024.11.002","DOIUrl":"10.1016/j.medj.2024.11.002","url":null,"abstract":"<p><p>Immunotherapy with checkpoint blockade has shown remarkable efficacy in many patients with a variety of different types of cancer. However, the majority of patients with cancer have yet to benefit from this revolutionary therapy. Studies have shown that checkpoint blockade works best against immune-inflamed tumors characterized by the presence of tumor-infiltrating lymphocytes (TILs). In this review, we summarize studies using live tumor-targeting bacteria to treat cancer and describe various strategies to engineer the tumor-targeting bacteria for maximized immunoregulatory effects. We propose that tumor-localized infections by such engineered bacteria can create an immune microenvironment in favor of a more effective antitumor immunity with or without other therapies, such as immune checkpoint blockade (ICB). Finally, we will briefly outline some exemplary oncology clinical trials involving ICB plus live therapeutic bacteria, with a focus on their ability to modulate antitumor immune responses.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100549"},"PeriodicalIF":12.8,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142847432","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":"Clinical advances of mRNA vaccines for cancer immunotherapy.","authors":"Alexey V Yaremenko, Muhammad Muzamil Khan, Xueyan Zhen, Yan Tang, Wei Tao","doi":"10.1016/j.medj.2024.11.015","DOIUrl":"https://doi.org/10.1016/j.medj.2024.11.015","url":null,"abstract":"<p><p>The development of mRNA vaccines represents a significant advancement in cancer treatment, with more than 120 clinical trials to date demonstrating their potential across various malignancies, including lung, breast, prostate, melanoma, and more challenging cancers such as pancreatic and brain tumors. These vaccines work by encoding tumor-specific antigens and immune-stimulating molecules, effectively activating the immune system to target and eliminate cancer cells. Despite these promising advancements, significant challenges remain, particularly in achieving efficient delivery and precise regulation of the immune response. This review provides a comprehensive overview of recent clinical progress in mRNA cancer vaccines, discusses the innovative strategies being employed to overcome existing hurdles, and explores future directions, including the integration of CRISPR-Cas9 technology and advancements in mRNA design. Our aim is to provide insights into the ongoing research and clinical trials, highlighting the transformative potential of mRNA vaccines in advancing oncology and improving patient outcomes.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"6 1","pages":"100562"},"PeriodicalIF":12.8,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142972400","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":"Heterozygous cis HYDIN mutations cause primary ciliary dyskinesia.","authors":"Randy Suryadinata, Paul Martinello, Vicki Bennett-Wood, Phil Robinson","doi":"10.1016/j.medj.2024.08.007","DOIUrl":"10.1016/j.medj.2024.08.007","url":null,"abstract":"<p><strong>Background: </strong>The product of ciliary gene HYDIN is an integral component for c2b projection within the motile cilia central pair (CP) apparatus. Biallelic mutations of this gene cause primary ciliary dyskinesia (PCD), an uncommon heterogeneous recessive disorder affecting motile cilia, resulting in defective mucociliary clearance that leads to chronic suppurative lung disease.</p><p><strong>Methods: </strong>Nasal brushing samples were collected from two siblings attending the Victorian Diagnostic service for PCD. Nasal airway epithelial cells (NAECs) were cultured before cilia structure and function studies using high-speed video microscopy (HSVM), transmission electron microscopy, and immunofluorescence.</p><p><strong>Findings: </strong>Cultured NAECs from both siblings showed defective cilia beating patterns under HSVM. A confirmatory PCD diagnosis was achieved through immunofluorescence, which showed the loss of HYDIN and the associated protein SPEF2 from the cilia axoneme.</p><p><strong>Conclusions: </strong>This case report details the diagnosis of two siblings who displayed similar defective cilia beating phenotypes seen in patients with PCD bearing recessive HYDIN mutations. Uniquely, both siblings carry two previously unreported HYDIN mutations, which are in the cis position, demonstrating the possibility for disease manifestation without biallelic mutations of ciliary genes.</p><p><strong>Funding: </strong>The authors declare no funding support for this study.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100508"},"PeriodicalIF":12.8,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142355446","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":"Cell-mediated immunotherapy: A new frontier in preventing disease progression and treating drug-resistant cancer.","authors":"Shimon Slavin","doi":"10.1016/j.medj.2024.11.005","DOIUrl":"https://doi.org/10.1016/j.medj.2024.11.005","url":null,"abstract":"<p><p>Although immunotherapy holds significant promise for treating drug-resistant cancers, currently available procedures are rarely curative. A new type of cell-mediated immunotherapy based on anticancer targeting activated mismatched cancer killer cells (ATACK) has demonstrated better efficacy and curative potential in preclinical animal models and in a pilot compassionate clinical study.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"6 1","pages":"100552"},"PeriodicalIF":12.8,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142972399","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":"Tertiary lymphoid structures and cancer immunotherapy: From bench to bedside.","authors":"Florent Peyraud, Jean-Philippe Guegan, Lucile Vanhersecke, Maxime Brunet, Diego Teyssonneau, Lola-Jade Palmieri, Alban Bessede, Antoine Italiano","doi":"10.1016/j.medj.2024.10.023","DOIUrl":"https://doi.org/10.1016/j.medj.2024.10.023","url":null,"abstract":"<p><p>Tertiary lymphoid structures (TLSs) are organized ectopic lymphoid aggregates within the tumor microenvironment that serve as crucial sites for the development of adaptive antitumor cellular and humoral immunity. TLSs have been consistently documented in numerous cancer types, correlating with improved prognosis and enhanced responses to immunotherapy, especially immune-checkpoint blockade (ICB). Given the potential role of TLSs as predictive biomarkers for the efficacy of ICB in cancer patients, the therapeutic manipulation of TLSs is gaining significant attention as a promising avenue for cancer treatment. Herein, we comprehensively review the composition, definition, and detection methods of TLSs in humans. We also discuss the contributions of TLSs to antitumor immunity, their prognostic value in cancer patients, and their association with therapeutic response to ICB-based immunotherapy. Finally, we present preclinical data supporting the potential of therapeutically manipulating TLSs as a promising approach for innovative cancer immunotherapy.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"6 1","pages":"100546"},"PeriodicalIF":12.8,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142972403","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 pretrained frame generative model enables real-time low-dose DSA imaging: An AI system development and multi-center validation study.","authors":"Huangxuan Zhao, Ziyang Xu, Lei Chen, Linxia Wu, Ziwei Cui, Jinqiang Ma, Tao Sun, Yu Lei, Nan Wang, Hongyao Hu, Yiqing Tan, Wei Lu, Wenzhong Yang, Kaibing Liao, Gaojun Teng, Xiaoyun Liang, Yi Li, Congcong Feng, Tong Nie, Xiaoyu Han, Dongqiao Xiang, Charles B L M Majoie, Wim H van Zwam, Aad van der Lugt, P Matthijs van der Sluijs, Theo van Walsum, Yun Feng, Guoli Liu, Yan Huang, Wenyu Liu, Xuefeng Kan, Ruisheng Su, Weihua Zhang, Xinggang Wang, Chuansheng Zheng","doi":"10.1016/j.medj.2024.07.025","DOIUrl":"10.1016/j.medj.2024.07.025","url":null,"abstract":"<p><strong>Background: </strong>Digital subtraction angiography (DSA) devices are commonly used in numerous interventional procedures across various parts of the body, necessitating multiple scans per procedure, which results in significant radiation exposure for both doctors and patients. Inspired by generative artificial intelligence techniques, this study proposes GenDSA, a large-scale pretrained multi-frame generative model-based real-time and low-dose DSA imaging system.</p><p><strong>Methods: </strong>GenDSA was developed to generate 1-, 2-, and 3-frame sequences following each real frame. A large-scale dataset comprising ∼3 million DSA images from 27,117 patients across 10 hospitals was constructed to pretrain, fine-tune, and validate GenDSA. Two other datasets from 25 hospitals were used for evaluation. Objective evaluations included SSIM and PSNR. Five interventional radiologists independently assessed the quality of the generated frames using the Likert scale and visual Turing test. Scoring consistency among the radiologists was measured using the Kendall coefficient of concordance (W). The Fleiss' kappa values were used for inter-rater agreement analysis for visual Turing tests.</p><p><strong>Findings: </strong>Using only one-third of the clinical radiation dose, videos generated by GenDSA were perfectly consistent with real videos. Objective evaluations demonstrated that GenDSA's performance (PSNR = 36.83, SSIM = 0.911, generation time = 0.07 s/frame) surpassed state-of-the-art algorithms. Subjective ratings and statistical results from five doctors indicated no significant difference between real and generated videos. Furthermore, the generated videos were comparable to real videos in overall quality (4.905 vs. 4.935) and lesion assessment (4.825 vs. 4.860).</p><p><strong>Conclusions: </strong>With clear clinical and translational values, the developed GenDSA can significantly reduce radiation damage to both doctors and patients during DSA-guided procedures.</p><p><strong>Funding: </strong>This study was supported by the National Key R&D Program and the National Natural Science Foundation of China.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100497"},"PeriodicalIF":12.8,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142009593","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":"Impact of omega-3 fatty acids on hypertriglyceridemia, lipidomics, and gut microbiome in patients with type 2 diabetes.","authors":"Jieli Lu, Ruixin Liu, Huahui Ren, Shuangyuan Wang, Chunyan Hu, Zhun Shi, Mian Li, Wei Liu, Qin Wan, Qing Su, Qifu Li, Hongting Zheng, Shen Qu, Fangming Yang, Hongyi Ji, Hong Lin, Hongyan Qi, Xueyan Wu, Kui Wu, Yuhong Chen, Yu Xu, Min Xu, Tiange Wang, Jie Zheng, Guang Ning, Ruizhi Zheng, Yufang Bi, Huanzi Zhong, Weiqing Wang","doi":"10.1016/j.medj.2024.07.024","DOIUrl":"10.1016/j.medj.2024.07.024","url":null,"abstract":"<p><strong>Background: </strong>Fish oil (FO), a mixture of omega-3 fatty acids mainly comprising docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), has been recommended for patients with type 2 diabetes (T2D) and hypertriglyceridemia. However, its effects on lipidomic profiles and gut microbiota and the factors influencing triglyceride (TG) reduction remain unclear.</p><p><strong>Methods: </strong>We conducted a 12-week, randomized, double-blind, placebo-controlled trial in 309 Chinese patients with T2D with hypertriglyceridemia (ClinicalTrials.gov: NCT03120299). Participants were randomly assigned (1:1) to receive either 4 g FO or corn oil for 12 weeks. The primary outcome was changes in serum TGs and the lipidomic profile, and the secondary outcome included changes in the gut microbiome and other metabolic variables.</p><p><strong>Findings: </strong>The FO group had significantly better TG reduction (mean [95% confidence interval (CI)]: -1.51 [-2.01, -1.01] mmol/L) compared to the corn oil group (-0.66 [-1.15, -0.16] mmol/L, p = 0.02). FO significantly altered the serum lipid profile by reducing low-unsaturated TG species and increasing those containing DHA or EPA. FO had minor effects on gut microbiota, while baseline microbial features predicted the TG response to FO better than phenotypic or lipidomic features, potentially mediated by specific lipid metabolites. A total of 9 lipid metabolites significantly mediated the link between 4 baseline microbial variables and the TG response to FO supplementation.</p><p><strong>Conclusions: </strong>Our findings demonstrate differential impacts of omega-3 fatty acids on lipidomic and microbial profiles in T2D and highlight the importance of baseline gut microbiota characteristics in predicting the TG-lowering efficacy of FO.</p><p><strong>Funding: </strong>This study was funded by the National Nature Science Foundation.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100496"},"PeriodicalIF":12.8,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142009592","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}