Michelangelo Marasco, Dinesh Kumar, Tessa Seale, Santiago Garcia Borrego, Esther Kaplun, Ilinca Aricescu, Soren Cole, Besnik Qeriqi, Juan Qiu, Xiaoping Chen, Amber Bahr, Deborah Fidele, Marco H Hofmann, Daniel Gerlach, Fabio Savarese, Taha Merghoub, Jedd D Wolchok, Zhan Yao, Elisa de Stanchina, David Solit, Sandra Misale, Neal Rosen
{"title":"Concurrent SOS1 and MEK suppression inhibits signaling and growth of NF1-null melanoma.","authors":"Michelangelo Marasco, Dinesh Kumar, Tessa Seale, Santiago Garcia Borrego, Esther Kaplun, Ilinca Aricescu, Soren Cole, Besnik Qeriqi, Juan Qiu, Xiaoping Chen, Amber Bahr, Deborah Fidele, Marco H Hofmann, Daniel Gerlach, Fabio Savarese, Taha Merghoub, Jedd D Wolchok, Zhan Yao, Elisa de Stanchina, David Solit, Sandra Misale, Neal Rosen","doi":"10.1016/j.xcrm.2024.101818","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101818","url":null,"abstract":"<p><p>Neurofibromin (NF1) is a negative regulator of RAS signaling, frequently mutated in cancer. NF1-mutant melanoma is a highly malignant tumor for which targeted therapies are lacking. Here, we use biochemical and pharmacological assays on patient-derived models and isogenic cell lines to identify potential pharmacologic targets, revealing that NF1-null melanomas are dependent on RAS activation and that MEK inhibition relieves ERK-dependent negative feedback, increasing RAS signaling. MEK inhibition with avutometinib abrogates the adaptive rebound in ERK signaling, but the antitumor effects are limited. However, concurrent inhibition of MEK and SOS1 abrogates ERK activation, induces cell death, and suppresses tumor growth. In contrast to the NF1-deficient setting, concurrent SOS1 and SOS2 depletion is required to completely inhibit RAS signaling in NF1 wild-type cells. In sum, our data provide a mechanistic rationale for enhancing the therapeutic efficacy of MEK inhibitors by exploiting the lower residual SOS activity in NF1-null tumor cells.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101818"},"PeriodicalIF":11.7,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142563507","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}
{"title":"Bifidobacteria with indole-3-lactic acid-producing capacity exhibit psychobiotic potential via reducing neuroinflammation.","authors":"Xin Qian, Qing Li, Huiyue Zhu, Ying Chen, Guopeng Lin, Hao Zhang, Wei Chen, Gang Wang, Peijun Tian","doi":"10.1016/j.xcrm.2024.101798","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101798","url":null,"abstract":"<p><p>The escalating global prevalence of depression demands effective therapeutic strategies, with psychobiotics emerging as a promising solution. However, the molecular mechanisms governing the neurobehavioral impact of psychobiotics remain elusive. This study reveals a significant reduction in hippocampal indole-3-lactic acid (ILA) levels in depressed mice, which is ameliorated by the psychobiotic Bifidobacterium breve. In both human subjects and mice, the ILA increase in the circulatory system results from bifidobacteria supplementation. Further investigation identifies the key aromatic lactate dehydrogenase (Aldh) gene and pathway in bifidobacteria responsible for ILA production. Importantly, the antidepressant effects are nullified in the Aldh mutants compared to the wild-type strain. At the bifidobacteria species level, those with Aldh exhibit heightened antidepressant effects. Finally, this study emphasizes the antidepressant efficacy of psychobiotic-derived ILA, potentially mediated by aryl hydrocarbon receptor (AhR) signaling activation to alleviate neuroinflammation. This study unveils the molecular and genetic foundations of psychobiotics' antidepressant effects, offering insights for microbial therapies targeting mood disorders.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101798"},"PeriodicalIF":11.7,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543969","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}
{"title":"Lnc-H19-derived protein shapes the immunosuppressive microenvironment of glioblastoma.","authors":"Junju Chen, Yixin Gao, Jian Zhong, Xujia Wu, Zhaojie Leng, Ming Liu, Yesheng Wang, Yuan Wang, Xuesong Yang, Nunu Huang, Feizhe Xiao, Maolei Zhang, Xuesong Liu, Nu Zhang","doi":"10.1016/j.xcrm.2024.101806","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101806","url":null,"abstract":"<p><p>The immunosuppressive tumor microenvironment (TME) is a prominent feature of glioblastoma (GBM), the most lethal primary brain cancer resistant to current immunotherapies. The mechanisms underlying GBM-TME remain to be explored. We report that long non-coding RNA (LncRNA) H19 encodes an immune-related protein called H19-IRP. Functionally separated from H19 RNA, H19-IRP promotes GBM immunosuppression by binding to the CCL2 and Galectin-9 promoters and activating their transcription, thereby recruiting myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), leading to T cell exhaustion and an immunosuppressive GBM-TME. H19-IRP, overexpressed in clinical GBM samples, acts as a tumor-associated antigen (TAA) presented by major histocompatibility complex class I (MHC-I). A circular RNA vaccine targeting H19-IRP (circH19-vac) triggers a potent cytotoxic T cell response against GBM and inhibits GBM growth. Our results highlight the unrevealed function of H19-IRP in creating immunosuppressive GBM-TME by recruiting MDSCs and TAMs, supporting the idea of targeting H19-IRP with cancer vaccine for GBM treatment.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101806"},"PeriodicalIF":11.7,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557271","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}
{"title":"Effect of remote ischemic preconditioning on cerebral circulation time in severe carotid artery stenosis: Results from the RIC-CCT trial.","authors":"Quan-Ying Liu, Yu Cui, Wei Li, Jing Qiu, Thanh N Nguyen, Hui-Sheng Chen","doi":"10.1016/j.xcrm.2024.101796","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101796","url":null,"abstract":"<p><p>In patients with severe internal carotid artery stenosis (sICAS), cerebral circulation time (CCT) is associated with cerebral hyperperfusion syndrome. This study aims to investigate the effect of remote ischemic preconditioning (RIC) on CCT in patients with sICAS. Patients are randomly assigned to the RIC group (RIC twice daily, for 2-4 days before carotid artery stenting [CAS] as an adjunct to standard medical therapy) and the control group. The results show that RIC produces a significant decrease in CCT of the stenosis side (sCCT) from baseline to pre-CAS, and the occurrence of contrast staining on brain computed tomography (CT) is lower in RIC versus control group after CAS. In addition, significant changes in some serum biomarkers suggest that anti-neuroinflammation, anti-oxidative stress, protecting endothelial injury, and improving cerebral autoregulation may be associated with the effect of RIC. These findings provide supporting evidence that RIC can modulate cerebral circulation in patients with sICAS. This study was registered at ClinicalTrials.gov (NCT05451030).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101796"},"PeriodicalIF":11.7,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543970","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}
Lin Li, Rui Li, Qingying Tian, Yaogan Luo, Ruyi Li, Xiaoyu Lin, Yunjing Ou, Tianyu Guo, Xue Chen, An Pan, JoAnn E Manson, Gang Liu
{"title":"Effects of healthy low-carbohydrate diet and time-restricted eating on weight and gut microbiome in adults with overweight or obesity: Feeding RCT.","authors":"Lin Li, Rui Li, Qingying Tian, Yaogan Luo, Ruyi Li, Xiaoyu Lin, Yunjing Ou, Tianyu Guo, Xue Chen, An Pan, JoAnn E Manson, Gang Liu","doi":"10.1016/j.xcrm.2024.101801","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101801","url":null,"abstract":"<p><p>The effect of a healthy low-carbohydrate diet (HLCD) and time-restricted eating (TRE), alone or in combination, on body weight and gut microbiome beyond caloric restriction remains unclear. In this 12-week two-by-two factorial randomized trial with a 28-week follow-up among 96 participants with overweight or obesity, isocaloric-restricted feeding yields significant weight loss, ranging from 2.57 to 4.11 kg across different groups. Beyond caloric restriction, HLCD and TRE lead to additional reduction in body mass index. HLCD results in additional fat mass loss while TRE yields more lean mass loss. Additionally, HLCD leads to decreased fecal branched-chain amino acids, and TRE tends to yield an increased abundance of probiotic species involved in synthesizing short-chain fatty acids. Moreover, the effect of HLCD on reducing fat mass is sustained during the post-intervention follow-up. Overall, HLCD and TRE are effective in weight management and yield profound gut microbiome and metabolome alteration beyond caloric restriction. This study was registered at ChiCTR.org.cn (ChiCTR2200056363).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101801"},"PeriodicalIF":11.7,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496031","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}
Anna S Huang, Ralf D Wimmer, Norman H Lam, Bin A Wang, Sahil Suresh, Maxwell J Roeske, Burkhard Pleger, Michael M Halassa, Neil D Woodward
{"title":"A prefrontal thalamocortical readout for conflict-related executive dysfunction in schizophrenia.","authors":"Anna S Huang, Ralf D Wimmer, Norman H Lam, Bin A Wang, Sahil Suresh, Maxwell J Roeske, Burkhard Pleger, Michael M Halassa, Neil D Woodward","doi":"10.1016/j.xcrm.2024.101802","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101802","url":null,"abstract":"<p><p>Executive dysfunction is a prominent feature of schizophrenia and may drive core symptoms. Dorsolateral prefrontal cortex (dlPFC) deficits have been linked to schizophrenia executive dysfunction, but mechanistic details critical for treatment development remain unclear. Here, capitalizing on recent animal circuit studies, we develop a task predicted to engage human dlPFC and its interactions with the mediodorsal thalamus (MD). We find that individuals with schizophrenia exhibit selective performance deficits when attention is guided by conflicting cues. Task performance correlates with lateralized MD-dlPFC functional connectivity, identifying a neural readout that predicts susceptibility to conflict during working memory in a larger independent schizophrenia cohort. In healthy subjects performing a probabilistic reversal task, this MD-dlPFC network predicts switching behavior. Overall, our three independent experiments introduce putative biomarkers for executive function in schizophrenia and highlight animal circuit studies as inspiration for the development of clinically relevant readouts.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101802"},"PeriodicalIF":11.7,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602559","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}
{"title":"Intra-channel bi-epitopic crosslinking unleashes ultrapotent antibodies targeting Na<sub>V</sub>1.7 for pain alleviation.","authors":"Yaning Zhang, Yanchao Ding, Ziyan Zeng, Rui Zhu, Peiyuan Zheng, Shilong Fan, Qingjuan Cao, Hang Chen, Weishuai Ren, Mengling Wu, Luyao Wang, Juanjuan Du","doi":"10.1016/j.xcrm.2024.101800","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101800","url":null,"abstract":"<p><p>Crucial for cell activities, ion channels are key drug discovery targets. Although small-molecule and peptide modulators dominate ion channel drug discovery, antibodies are emerging as an alternative modality. However, challenges persist in generating potent antibodies, especially for channels with limited extracellular epitopes. We herein present a bi-epitopic crosslinking strategy to overcome these challenges, focusing on Na<sub>V</sub>1.7, a potential analgesic target. Aiming to crosslink two non-overlapping epitopes on voltage-sensing domains II and IV, we construct bispecific antibodies and ligand-antibody conjugates. Enhanced affinity and potency are observed in comparison to the monospecific controls. Among them, a ligand-antibody conjugate (1080-PEG<sub>7</sub>-ACDTB) displays a two-orders-of-magnitude improvement in potency (IC<sub>50</sub> of 0.06 ± 0.01 nM) and over 1,000-fold selectivity for Na<sub>V</sub>1.7. Additionally, this conjugate demonstrates robust analgesic effects in mouse pain models. Our study introduces an approach to developing effective antibodies against Na<sub>V</sub>1.7, thereby initiating a promising direction for the advancement of pain therapeutics.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101800"},"PeriodicalIF":11.7,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496033","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}
Shen Li, Bo Tao, Jijun Wan, Enca Montecino-Rodriguez, Ping Wang, Feiyang Ma, Baiming Sun, Yiqian Gu, Sivakumar Ramadoss, Lianjiu Su, Qihao Sun, Johanna Ten Hoeve, Linsey Stiles, Jeffrey Collins, R Michael van Dam, Mikayla Tamboline, Richard Taschereau, Orian Shirihai, Douglas B Kitchen, Matteo Pellegrini, Thomas Graeber, Kenneth Dorshkind, Shili Xu, Arjun Deb
{"title":"A humanized monoclonal antibody targeting an ectonucleotidase rescues cardiac metabolism and heart function after myocardial infarction.","authors":"Shen Li, Bo Tao, Jijun Wan, Enca Montecino-Rodriguez, Ping Wang, Feiyang Ma, Baiming Sun, Yiqian Gu, Sivakumar Ramadoss, Lianjiu Su, Qihao Sun, Johanna Ten Hoeve, Linsey Stiles, Jeffrey Collins, R Michael van Dam, Mikayla Tamboline, Richard Taschereau, Orian Shirihai, Douglas B Kitchen, Matteo Pellegrini, Thomas Graeber, Kenneth Dorshkind, Shili Xu, Arjun Deb","doi":"10.1016/j.xcrm.2024.101795","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101795","url":null,"abstract":"<p><p>Myocardial infarction (MI) results in aberrant cardiac metabolism, but no therapeutics have been designed to target cardiac metabolism to enhance heart repair. We engineer a humanized monoclonal antibody against the ectonucleotidase ENPP1 (hENPP1mAb) that targets metabolic crosstalk in the infarcted heart. In mice expressing human ENPP1, systemic administration of hENPP1mAb metabolically reprograms myocytes and non-myocytes and leads to a significant rescue of post-MI heart dysfunction. Using metabolomics, single-nuclear transcriptomics, and cellular respiration studies, we show that the administration of the hENPP1mAb induces organ-wide metabolic and transcriptional reprogramming of the heart that enhances myocyte cellular respiration and decreases cell death and fibrosis in the infarcted heart. Biodistribution and safety studies showed specific organ-wide distribution with the antibody being well tolerated. In humanized animals, with drug clearance kinetics similar to humans, we demonstrate that a single \"shot\" of the hENPP1mAb after MI is sufficient to rescue cardiac dysfunction.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101795"},"PeriodicalIF":11.7,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496028","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}
{"title":"A dual-STING-activating nanosystem expands cancer immunotherapeutic temporal window.","authors":"Jian Wang, Xiaohu Wang, Qingqing Xiong, Shan Gao, Shihao Wang, Siqi Zhu, Shuting Xiang, Mingxi Li, Haitang Xie, Suxin Li","doi":"10.1016/j.xcrm.2024.101797","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101797","url":null,"abstract":"<p><p>Stimulator of interferon genes (STING) is a promising antitumor target via bridging innate and adaptive immunity, yet the transient nature of immune signal transduction renders small-molecule agonists susceptible to short time effectiveness. Here, we report a dual-STING-activating micelle system (D-SAM) to dynamically program STING kinetics. Mechanistically, the natural ligand cGAMP encapsulated in D-SAM initiates STING signaling, while the pH-sensitive polymeric agonist PC7A disassembled from micelle shell buffers lysosomal protons and retards STING degradation. This prolonged STING activity facilitates dendritic cell (DC) antigen presentation and extends cytotoxic T lymphocyte priming. D-SAM improves efficacy over single soluble or delivered agonists against established, metastatic, and recurring murine tumors. Specific depletion of STING in DCs or blockade of CD8<sup>+</sup> T cell infiltration abrogates therapeutic effects. The feasibility of immune modulation is further validated in resected human patient tissues. This work underscores the temporal rhythm of STING as crucial for mounting a potent and enduring antitumor immune response.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101797"},"PeriodicalIF":11.7,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496027","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}
Jonathan Wickel, Ulf Schnetzke, Anne Sayer-Klink, Jenny Rinke, Dominic Borie, Diana Dudziak, Andreas Hochhaus, Lukas Heger, Christian Geis
{"title":"Anti-CD19 CAR-T cells are effective in severe idiopathic Lambert-Eaton myasthenic syndrome.","authors":"Jonathan Wickel, Ulf Schnetzke, Anne Sayer-Klink, Jenny Rinke, Dominic Borie, Diana Dudziak, Andreas Hochhaus, Lukas Heger, Christian Geis","doi":"10.1016/j.xcrm.2024.101794","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101794","url":null,"abstract":"<p><p>Lambert-Eaton myasthenic syndrome (LEMS) is an autoantibody-mediated disease of the neuromuscular junction characterized by muscular weakness. Autoantibodies to presynaptic P/Q-type voltage-gated calcium channels (VGCCs) induce defective neuromuscular function. In severe cases, current immunosuppressive and immunomodulatory treatment strategies are often insufficient. First reports show beneficial effects of anti-CD19 chimeric antigen receptor (CAR)-T cell therapy in patients with autoantibody-mediated myasthenia gravis. We report a patient with isolated idiopathic LEMS treated with autologous anti-CD19-CAR-T cells. In this patient, CAR-T infusion leads to expansion of predominantly CD4<sup>+</sup> CAR-T cells with a terminally differentiated effector memory cells re-expressing CD45RA (TEMRA)-like phenotype indicating cytotoxic capabilities and subsequent B cell depletion. VGCC antibody titers decrease, resulting in a clinical improvement of LEMS symptoms, e.g., 8-fold increase in walking distance. The patient does not show relevant side effects except for cytokine release syndrome grade 2 and intermittent neutropenia suggesting that anti-CD19 CAR-T cell therapy may be a treatment option in patients with LEMS.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101794"},"PeriodicalIF":11.7,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496029","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}
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