Cell Reports Medicine最新文献_第8页

Phase 1a study of ESG401, a Trop2 antibody-drug conjugate, in patients with locally advanced/metastatic solid tumors. 对局部晚期/转移性实体瘤患者进行 Trop2 抗体-药物共轭物 ESG401 的 1a 期研究。

IF 11.7 1区医学

Cell Reports Medicine Pub Date : 2024-09-17 Epub Date: 2024-08-30 DOI: 10.1016/j.xcrm.2024.101707

Jiani Wang, Zhongsheng Tong, Yinuo Tan, Yehui Shi, Yun Wu, Qing Zhou, Xiaoyan Xing, Xiaomei Chen, Fuming Qiu, Fei Ma

{"title":"Phase 1a study of ESG401, a Trop2 antibody-drug conjugate, in patients with locally advanced/metastatic solid tumors.","authors":"Jiani Wang, Zhongsheng Tong, Yinuo Tan, Yehui Shi, Yun Wu, Qing Zhou, Xiaoyan Xing, Xiaomei Chen, Fuming Qiu, Fei Ma","doi":"10.1016/j.xcrm.2024.101707","DOIUrl":"10.1016/j.xcrm.2024.101707","url":null,"abstract":"This phase 1a study assesses ESG401 in patients with heavily pretreated locally advanced or metastatic solid tumors, focusing on metastatic breast cancer. Forty patients are enrolled: three experience dose-limiting toxicities, establishing the maximum tolerated dose at 16 mg/kg on days 1, 8, and 15 of a 28-day cycle. The most common grade ≥3 treatment-related adverse events are neutropenia and leukopenia. Among 38 efficacy-evaluable patients, the objective response rate (ORR) is 34.2%, the disease control rate (DCR) is 65.8%, and the clinical benefit rate (CBR) is 50.0% (including stable disease for at least 6 months). The median progression-free survival is 5.1 months, and the median duration of response is 6.3 months. In patients receiving therapeutically relevant doses, the ORR, DCR, and CBR are 40.6%, 75.0%, and 56.3%, respectively. ESG401 demonstrates a favorable safety profile and promising antitumor activity in this heavily treated population. The trial is registered at ClinicalTrials.gov (NCT04892342).","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101707"},"PeriodicalIF":11.7,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11524954/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Proteo-metabolomics and patient tumor slice experiments point to amino acid centrality for rewired mitochondria in fibrolamellar carcinoma. 蛋白质代谢组学和患者肿瘤切片实验表明，氨基酸是纤维乳头状癌线粒体重新配线的核心。

IF 11.7 1区医学

Cell Reports Medicine Pub Date : 2024-09-17 Epub Date: 2024-08-28 DOI: 10.1016/j.xcrm.2024.101699

Donald Long, Marina Chan, Mingqi Han, Zeal Kamdar, Rosanna K Ma, Pei-Yin Tsai, Adam B Francisco, Joeva Barrow, David B Shackelford, Mark Yarchoan, Matthew J McBride, Lukas M Orre, Nathaniel M Vacanti, Taranjit S Gujral, Praveen Sethupathy

{"title":"Proteo-metabolomics and patient tumor slice experiments point to amino acid centrality for rewired mitochondria in fibrolamellar carcinoma.","authors":"Donald Long, Marina Chan, Mingqi Han, Zeal Kamdar, Rosanna K Ma, Pei-Yin Tsai, Adam B Francisco, Joeva Barrow, David B Shackelford, Mark Yarchoan, Matthew J McBride, Lukas M Orre, Nathaniel M Vacanti, Taranjit S Gujral, Praveen Sethupathy","doi":"10.1016/j.xcrm.2024.101699","DOIUrl":"10.1016/j.xcrm.2024.101699","url":null,"abstract":"Fibrolamellar carcinoma (FLC) is a rare, lethal, early-onset liver cancer with a critical need for new therapeutics. The primary driver in FLC is the fusion oncoprotein, DNAJ-PKAc, which remains challenging to target therapeutically. It is critical, therefore, to expand understanding of the FLC molecular landscape to identify druggable pathways/targets. Here, we perform the most comprehensive integrative proteo-metabolomic analysis of FLC. We also conduct nutrient manipulation, respirometry analyses, as well as key loss-of-function assays in FLC tumor tissue slices from patients. We propose a model of cellular energetics in FLC pointing to proline anabolism being mediated by ornithine aminotransferase hyperactivity and ornithine transcarbamylase hypoactivity with serine and glutamine catabolism fueling the process. We highlight FLC's potential dependency on voltage-dependent anion channel (VDAC), a mitochondrial gatekeeper for anions including pyruvate. The metabolic rewiring in FLC that we propose in our model, with an emphasis on mitochondria, can be exploited for therapeutic vulnerabilities.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101699"},"PeriodicalIF":11.7,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11528240/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Risk assessment with gene expression markers in sepsis development. 利用败血症发展过程中的基因表达标记进行风险评估。

IF 11.7 1区医学

Cell Reports Medicine Pub Date : 2024-09-17 Epub Date: 2024-09-03 DOI: 10.1016/j.xcrm.2024.101712

Albert Garcia Lopez, Sascha Schäuble, Tongta Sae-Ong, Bastian Seelbinder, Michael Bauer, Evangelos J Giamarellos-Bourboulis, Mervyn Singer, Roman Lukaszewski, Gianni Panagiotou

{"title":"Risk assessment with gene expression markers in sepsis development.","authors":"Albert Garcia Lopez, Sascha Schäuble, Tongta Sae-Ong, Bastian Seelbinder, Michael Bauer, Evangelos J Giamarellos-Bourboulis, Mervyn Singer, Roman Lukaszewski, Gianni Panagiotou","doi":"10.1016/j.xcrm.2024.101712","DOIUrl":"10.1016/j.xcrm.2024.101712","url":null,"abstract":"Infection is a commonplace, usually self-limiting, condition but can lead to sepsis, a severe life-threatening dysregulated host response. We investigate the individual phenotypic predisposition to developing uncomplicated infection or sepsis in a large cohort of non-infected patients undergoing major elective surgery. Whole-blood RNA sequencing analysis was performed on preoperative samples from 267 patients. These patients developed postoperative infection with (n = 77) or without (n = 49) sepsis, developed non-infectious systemic inflammatory response (n = 31), or had an uncomplicated postoperative course (n = 110). Machine learning classification models built on preoperative transcriptomic signatures predict postoperative outcomes including sepsis with an area under the curve of up to 0.910 (mean 0.855) and sensitivity/specificity up to 0.767/0.804 (mean 0.746/0.769). Our models, confirmed by quantitative reverse-transcription PCR (RT-qPCR), potentially offer a risk prediction tool for the development of postoperative sepsis with implications for patient management. They identify an individual predisposition to developing sepsis that warrants further exploration to better understand the underlying pathophysiology.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101712"},"PeriodicalIF":11.7,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11528229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142131954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Combinatorial targeting of glutamine metabolism and lysosomal-based lipid metabolism effectively suppresses glioblastoma. 针对谷氨酰胺代谢和溶酶体脂质代谢的组合疗法可有效抑制胶质母细胞瘤。

IF 11.7 1区医学

Cell Reports Medicine Pub Date : 2024-09-17 Epub Date: 2024-09-04 DOI: 10.1016/j.xcrm.2024.101706

Yaogang Zhong, Feng Geng, Logan Mazik, Xinmin Yin, Aline Paixao Becker, Shabber Mohammed, Huali Su, Enming Xing, Yongjun Kou, Cheng-Yao Chiang, Yunzhou Fan, Yongchen Guo, Qiang Wang, Pui-Kai Li, Xiaokui Mo, Etienne Lefai, Liqing He, Xiaolin Cheng, Xiang Zhang, Arnab Chakravarti, Deliang Guo

{"title":"Combinatorial targeting of glutamine metabolism and lysosomal-based lipid metabolism effectively suppresses glioblastoma.","authors":"Yaogang Zhong, Feng Geng, Logan Mazik, Xinmin Yin, Aline Paixao Becker, Shabber Mohammed, Huali Su, Enming Xing, Yongjun Kou, Cheng-Yao Chiang, Yunzhou Fan, Yongchen Guo, Qiang Wang, Pui-Kai Li, Xiaokui Mo, Etienne Lefai, Liqing He, Xiaolin Cheng, Xiang Zhang, Arnab Chakravarti, Deliang Guo","doi":"10.1016/j.xcrm.2024.101706","DOIUrl":"10.1016/j.xcrm.2024.101706","url":null,"abstract":"Antipsychotic drugs have been shown to have antitumor effects but have had limited potency in the clinic. Here, we unveil that pimozide inhibits lysosome hydrolytic function to suppress fatty acid and cholesterol release in glioblastoma (GBM), the most lethal brain tumor. Unexpectedly, GBM develops resistance to pimozide by boosting glutamine consumption and lipogenesis. These elevations are driven by SREBP-1, which we find upregulates the expression of ASCT2, a key glutamine transporter. Glutamine, in turn, intensifies SREBP-1 activation through the release of ammonia, creating a feedforward loop that amplifies both glutamine metabolism and lipid synthesis, leading to drug resistance. Disrupting this loop via pharmacological targeting of ASCT2 or glutaminase, in combination with pimozide, induces remarkable mitochondrial damage and oxidative stress, leading to GBM cell death in vitro and in vivo. Our findings underscore the promising therapeutic potential of effectively targeting GBM by combining glutamine metabolism inhibition with lysosome suppression.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101706"},"PeriodicalIF":11.7,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11524980/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Detecting altered hepatic lipid oxidation by MRI in an animal model of MASLD. 通过磁共振成像检测 MASLD 动物模型中肝脏脂质氧化的改变。

IF 11.7 1区医学

Cell Reports Medicine Pub Date : 2024-09-17 Epub Date: 2024-09-05 DOI: 10.1016/j.xcrm.2024.101714

Marc McLeod, Mario C Chang, Anna Rushin, Mukundan Ragavan, Rohit Mahar, Gaurav Sharma, Arshee Badar, Anthony Giacalone, Max E Glanz, Vinay R Malut, Dalton Graham, Nishanth E Sunny, James A Bankson, Kenneth Cusi, Matthew E Merritt

{"title":"Detecting altered hepatic lipid oxidation by MRI in an animal model of MASLD.","authors":"Marc McLeod, Mario C Chang, Anna Rushin, Mukundan Ragavan, Rohit Mahar, Gaurav Sharma, Arshee Badar, Anthony Giacalone, Max E Glanz, Vinay R Malut, Dalton Graham, Nishanth E Sunny, James A Bankson, Kenneth Cusi, Matthew E Merritt","doi":"10.1016/j.xcrm.2024.101714","DOIUrl":"10.1016/j.xcrm.2024.101714","url":null,"abstract":"Metabolic dysfunction-associated steatotic liver disease (MASLD) prevalence is increasing annually and affects over a third of US adults. MASLD can progress to metabolic dysfunction-associated steatohepatitis (MASH), characterized by severe hepatocyte injury, inflammation, and eventual advanced fibrosis or cirrhosis. MASH is predicted to become the primary cause of liver transplant by 2030. Although the etiology of MASLD/MASH is incompletely understood, dysregulated fatty acid oxidation is implicated in disease pathogenesis. Here, we develop a method for estimating hepatic β-oxidation from the metabolism of [D15]octanoate to deuterated water and detection with deuterium magnetic resonance methods. Perfused livers from a mouse model of MASLD reveal dysregulated hepatic β-oxidation, findings that corroborate in vivo imaging. The high-fat-diet-induced MASLD mouse studies indicate that decreased β-oxidative efficiency in the fatty liver could serve as an indicator of MASLD progression. Furthermore, our method provides a clinically translatable imaging approach for determining hepatic β-oxidation efficiency.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101714"},"PeriodicalIF":11.7,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11525016/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Integrating multi-omics to unravel host-microbiome interactions in inflammatory bowel disease 整合多组学揭示炎症性肠病中宿主与微生物组的相互作用

IF 14.3 1区医学

Cell Reports Medicine Pub Date : 2024-09-17 DOI: 10.1016/j.xcrm.2024.101738

Yiran Zhang, John P. Thomas, Tamas Korcsmaros, Lejla Gul

{"title":"Integrating multi-omics to unravel host-microbiome interactions in inflammatory bowel disease","authors":"Yiran Zhang, John P. Thomas, Tamas Korcsmaros, Lejla Gul","doi":"10.1016/j.xcrm.2024.101738","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101738","url":null,"abstract":"The gut microbiome is crucial for nutrient metabolism, immune regulation, and intestinal homeostasis with changes in its composition linked to complex diseases like inflammatory bowel disease (IBD). Although the precise host-microbial mechanisms in disease pathogenesis remain unclear, high-throughput sequencing have opened new ways to unravel the role of interspecies interactions in IBD. Systems biology—a holistic computational framework for modeling complex biological systems—is critical for leveraging multi-omics datasets to identify disease mechanisms. This review highlights the significance of multi-omics data in IBD research and provides an overview of state-of-the-art systems biology resources and computational tools for data integration. We explore gaps, challenges, and future directions in the research field aiming to uncover novel biomarkers and therapeutic targets, ultimately advancing personalized treatment strategies. While focusing on IBD, the proposed approaches are applicable for other complex diseases, like cancer, and neurodegenerative diseases, where the microbiome has also been implicated.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"1 1","pages":""},"PeriodicalIF":14.3,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting NAT10 inhibits osteosarcoma progression via ATF4/ASNS-mediated asparagine biosynthesis 靶向 NAT10 可通过 ATF4/ASNS 介导的天冬酰胺生物合成抑制骨肉瘤进展

IF 14.3 1区医学

Cell Reports Medicine Pub Date : 2024-09-17 DOI: 10.1016/j.xcrm.2024.101728

Yutong Zou, Siyao Guo, Lili Wen, Dongming Lv, Jian Tu, Yan Liao, Weidong Chen, Ziyun Chen, Hongbo Li, Junkai Chen, Jingnan Shen, Xianbiao Xie

{"title":"Targeting NAT10 inhibits osteosarcoma progression via ATF4/ASNS-mediated asparagine biosynthesis","authors":"Yutong Zou, Siyao Guo, Lili Wen, Dongming Lv, Jian Tu, Yan Liao, Weidong Chen, Ziyun Chen, Hongbo Li, Junkai Chen, Jingnan Shen, Xianbiao Xie","doi":"10.1016/j.xcrm.2024.101728","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101728","url":null,"abstract":"Despite advances in treatment, the prognosis of patients with osteosarcoma remains unsatisfactory, and searching for potential targets is imperative. Here, we identify N4-acetylcytidine (ac4C) acetyltransferase 10 (NAT10) as a candidate therapeutic target in osteosarcoma through functional screening. NAT10 overexpression is correlated with a poor prognosis, and NAT10 knockout inhibits osteosarcoma progression. Mechanistically, NAT10 enhances mRNA stability of activating transcription factor 4 (ATF4) through ac4C modification. ATF4 induces the transcription of asparagine synthetase (ASNS), which catalyzes asparagine (Asn) biosynthesis, facilitating osteosarcoma progression. Utilizing virtual screening, we identify paliperidone and AG-401 as potential NAT10 inhibitors, and both inhibitors are found to bind to NAT10 proteins. Inhibiting NAT10 suppresses osteosarcoma progression in vivo. Combined treatment using paliperidone and AG-401 produces synergistic inhibition for osteosarcoma in patient-derived xenograft (PDX) models. Our findings demonstrate that NAT10 facilitates osteosarcoma progression through the ATF4/ASNS/Asn axis, and pharmacological inhibition of NAT10 may be a feasible therapeutic approach for osteosarcoma.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"20 1","pages":""},"PeriodicalIF":14.3,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dietary vitamin B3 supplementation induces the antitumor immunity against liver cancer via biased GPR109A signaling in myeloid cell 膳食中补充维生素 B3 可通过髓系细胞中偏向 GPR109A 的信号传导诱导肝癌抗肿瘤免疫力

IF 14.3 1区医学

Cell Reports Medicine Pub Date : 2024-09-17 DOI: 10.1016/j.xcrm.2024.101718

Yang Yang, Tianduo Pei, Xiaolin Hu, Yu Lu, Yanqiu Huang, Tingya Wan, Chaobao Liu, Fengqian Chen, Bao Guo, Yuemei Hong, Qian Ba, Xiaoguang Li, Hui Wang

{"title":"Dietary vitamin B3 supplementation induces the antitumor immunity against liver cancer via biased GPR109A signaling in myeloid cell","authors":"Yang Yang, Tianduo Pei, Xiaolin Hu, Yu Lu, Yanqiu Huang, Tingya Wan, Chaobao Liu, Fengqian Chen, Bao Guo, Yuemei Hong, Qian Ba, Xiaoguang Li, Hui Wang","doi":"10.1016/j.xcrm.2024.101718","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101718","url":null,"abstract":"The impact of dietary nutrients on tumor immunity remains an area of ongoing investigation, particularly regarding the specific role of vitamins and their mechanism. Here, we demonstrate that vitamin B3 (VB3) induces antitumor immunity against liver cancer through biased GPR109A axis in myeloid cell. Nutritional epidemiology studies suggest that higher VB3 intake reduces liver cancer risk. VB3 supplementation demonstrates antitumor efficacy in multiple mouse models through alleviating the immunosuppressive tumor microenvironment (TME) mediated by tumor-infiltrating myeloid cell, thereby augmenting effectiveness of immunotherapy or targeted therapy in a CD8+ T cell-dependent manner. Mechanically, the TME induces aberrant GPR109A/nuclear factor κB (NF-κB) activation in myeloid cell to shape the immunosuppressive TME. In contrast, VB3 activates β-Arrestin-mediated GPR109A degradation and NF-κB inhibition to suppress the immunosuppressive polarization of myeloid cell, thereby activating the cytotoxic function of CD8+ T cell. Overall, these results expand the understanding of how vitamins regulate the TME, suggesting that dietary VB3 supplementation is an adjunctive treatment for liver cancer.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"31 1","pages":""},"PeriodicalIF":14.3,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Single-cell AI-based detection and prognostic and predictive value of DNA mismatch repair deficiency in colorectal cancer 基于单细胞人工智能的结直肠癌 DNA 错配修复缺陷检测及其预后和预测价值

IF 14.3 1区医学

Cell Reports Medicine Pub Date : 2024-09-17 DOI: 10.1016/j.xcrm.2024.101727

Marta Nowak, Faiz Jabbar, Ann-Katrin Rodewald, Luciana Gneo, Tijana Tomasevic, Andrea Harkin, Tim Iveson, Mark Saunders, Rachel Kerr, Karin Oein, Noori Maka, Jennifer Hay, Joanne Edwards, Ian Tomlinson, Owen Sansom, Caroline Kelly, Francesco Pezzella, David Kerr, Alistair Easton, Enric Domingo, David N. Church

{"title":"Single-cell AI-based detection and prognostic and predictive value of DNA mismatch repair deficiency in colorectal cancer","authors":"Marta Nowak, Faiz Jabbar, Ann-Katrin Rodewald, Luciana Gneo, Tijana Tomasevic, Andrea Harkin, Tim Iveson, Mark Saunders, Rachel Kerr, Karin Oein, Noori Maka, Jennifer Hay, Joanne Edwards, Ian Tomlinson, Owen Sansom, Caroline Kelly, Francesco Pezzella, David Kerr, Alistair Easton, Enric Domingo, David N. Church","doi":"10.1016/j.xcrm.2024.101727","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101727","url":null,"abstract":"Testing for DNA mismatch repair deficiency (MMRd) is recommended for all colorectal cancers (CRCs). Automating this would enable precision medicine, particularly if providing information on etiology not captured by deep learning (DL) methods. We present AIMMeR, an AI-based method for determination of mismatch repair (MMR) protein expression at a single-cell level in routine pathology samples. AIMMeR shows an area under the receiver-operator curve (AUROC) of 0.98, and specificity of ≥75% at 98% sensitivity against pathologist ground truth in stage II/III in two trial cohorts, with positive predictive value of ≥98% for the commonest pattern of somatic MMRd. Lower agreement with microsatellite instability (MSI) testing (AUROC 0.86) reflects discordance between MMR and MSI PCR rather than AIMMeR misclassification. Analysis of the SCOT trial confirms MMRd prognostic value in oxaliplatin-treated patients; while MMRd does not predict differential benefit of chemotherapy duration, it correlates with difference in relapse by regimen (PInteraction = 0.04). AIMMeR may help reduce pathologist workload and streamline diagnostics in CRC.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"7 1","pages":""},"PeriodicalIF":14.3,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The gut-brain axis in depression: Are multi-omics showing the way? 抑郁症的肠脑轴：多组学是否指明了方向？

IF 14.3 1区医学

Cell Reports Medicine Pub Date : 2024-09-17 DOI: 10.1016/j.xcrm.2024.101741

Jane Allyson Foster, Madhukar Hariprasad Trivedi

引用次数: 0