Pub Date : 2024-08-20DOI: 10.1016/j.xcrm.2024.101705
Ronald M Galiwango, Brenda Okech, Daniel E Park, Lane Buchanan, Zhongtian Shao, Bernard Bagaya, Juliet Mpendo, Vineet Joag, Sergey Yegorov, Annet Nanvubya, Victoria M Biribawa, Teddy Namatovu, Charles Kato, Barbara Kawoozo, Ali Ssetaala, Moses Muwanga, Maliha Aziz, Tony Pham, Sanja Huibner, Aaron A R Tobian, Cindy M Liu, Jessica L Prodger, Rupert Kaul
Within the penile microbiome, bacteria associated with seroconversion, immunology, and cells (BASIC species) enhance HIV susceptibility in heterosexual uncircumcised men by inducing foreskin inflammation and HIV target cell recruitment. This phase 1/2 clinical trial randomizes HIV-uninfected Ugandan men (n = 125) to either oral tinidazole, topical metronidazole, topical clindamycin, or topical hydrogen peroxide to define impact on ex vivo foreskin HIV susceptibility, penile immunology, and BASIC species density. Antimicrobials are well tolerated, and 116 (93%) participants complete the protocol. Topical metronidazole and oral tinidazole reduce the inner foreskin tissue density of HIV-susceptible CD4+ T cells (predefined primary endpoint). Antimicrobials also have varying but substantial effects on reducing prepuce inflammation and BASIC species density, reducing density of foreskin T cell subsets, and increasing foreskin epithelial integrity. Immune alterations correlate strongly with changes in the abundance of BASIC species. Clinical interventions targeting the penile microbiota, particularly topical metronidazole, may reduce HIV susceptibility in uncircumcised men.
在阴茎微生物组中,与血清转换、免疫学和细胞相关的细菌(BASIC 菌种)通过诱导包皮炎症和 HIV 靶细胞招募,提高了未接受包皮环切术的异性恋男性对 HIV 的易感性。这项 1 / 2 期临床试验对未感染 HIV 的乌干达男性(n = 125)随机进行口服替硝唑、外用甲硝唑、外用克林霉素或外用过氧化氢治疗,以确定对体内外包皮 HIV 易感性、阴茎免疫学和 BASIC 细胞密度的影响。抗菌药的耐受性良好,116 人(93%)完成了治疗方案。外用甲硝唑和口服替硝唑可降低包皮内组织中易感染艾滋病病毒的 CD4+ T 细胞密度(预定的主要终点)。抗菌药物对减少包皮炎症和 BASIC 菌种密度、降低包皮 T 细胞亚群密度和增加包皮上皮完整性也有不同但实质性的作用。免疫改变与 BASIC 物种丰度的变化密切相关。针对阴茎微生物群的临床干预措施,尤其是外用甲硝唑,可能会降低未行包皮环切术男性对艾滋病毒的易感性。
{"title":"Impact of antimicrobials on penile HIV susceptibility and immunology in uncircumcised men: A randomized phase 1/2 clinical trial.","authors":"Ronald M Galiwango, Brenda Okech, Daniel E Park, Lane Buchanan, Zhongtian Shao, Bernard Bagaya, Juliet Mpendo, Vineet Joag, Sergey Yegorov, Annet Nanvubya, Victoria M Biribawa, Teddy Namatovu, Charles Kato, Barbara Kawoozo, Ali Ssetaala, Moses Muwanga, Maliha Aziz, Tony Pham, Sanja Huibner, Aaron A R Tobian, Cindy M Liu, Jessica L Prodger, Rupert Kaul","doi":"10.1016/j.xcrm.2024.101705","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101705","url":null,"abstract":"<p><p>Within the penile microbiome, bacteria associated with seroconversion, immunology, and cells (BASIC species) enhance HIV susceptibility in heterosexual uncircumcised men by inducing foreskin inflammation and HIV target cell recruitment. This phase 1/2 clinical trial randomizes HIV-uninfected Ugandan men (n = 125) to either oral tinidazole, topical metronidazole, topical clindamycin, or topical hydrogen peroxide to define impact on ex vivo foreskin HIV susceptibility, penile immunology, and BASIC species density. Antimicrobials are well tolerated, and 116 (93%) participants complete the protocol. Topical metronidazole and oral tinidazole reduce the inner foreskin tissue density of HIV-susceptible CD4<sup>+</sup> T cells (predefined primary endpoint). Antimicrobials also have varying but substantial effects on reducing prepuce inflammation and BASIC species density, reducing density of foreskin T cell subsets, and increasing foreskin epithelial integrity. Immune alterations correlate strongly with changes in the abundance of BASIC species. Clinical interventions targeting the penile microbiota, particularly topical metronidazole, may reduce HIV susceptibility in uncircumcised men.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104787","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}
Levites et al. demonstrate that mouse models of Alzheimer disease (AD), exhibiting amyloid-beta (Αβ) plaque formation, share Αβ responsome proteins with humans. Their work underscores the value of these models in studying Αβ aggregation, cellular vulnerability, and early-stage AD pathology.
{"title":"A core proteome profile unites mouse models and patients in Alzheimer disease.","authors":"Grigoria Tsaka, Frederic Rousseau, Joost Schymkowitz","doi":"10.1016/j.xcrm.2024.101683","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101683","url":null,"abstract":"<p><p>Levites et al. demonstrate that mouse models of Alzheimer disease (AD), exhibiting amyloid-beta (Αβ) plaque formation, share Αβ responsome proteins with humans. Their work underscores the value of these models in studying Αβ aggregation, cellular vulnerability, and early-stage AD pathology.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016486","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}
Pub Date : 2024-08-20Epub Date: 2024-07-24DOI: 10.1016/j.xcrm.2024.101658
Jiying Cheng, Min Li, Edyta Motta, Deivi Barci, Wangyang Song, Ding Zhou, Gen Li, Sihan Zhu, Anru Yang, Brian D Vaillant, Axel Imhof, Ignasi Forné, Sabine Spiegl-Kreinecker, Nu Zhang, Hiroshi Katayama, Krishna P L Bhat, Charlotte Flüh, Roland E Kälin, Rainer Glass
The DNA damage response (DDR) and the blood-tumor barrier (BTB) restrict chemotherapeutic success for primary brain tumors like glioblastomas (GBMs). Coherently, GBMs almost invariably relapse with fatal outcomes. Here, we show that the interaction of GBM and myeloid cells simultaneously induces chemoresistance on the genetic and vascular levels by activating GP130 receptor signaling, which can be addressed therapeutically. We provide data from transcriptomic and immunohistochemical screens with human brain material and pharmacological experiments with a humanized organotypic GBM model, proteomics, transcriptomics, and cell-based assays and report that nanomolar concentrations of the signaling peptide humanin promote temozolomide (TMZ) resistance through DDR activation. GBM mouse models recapitulating intratumoral humanin release show accelerated BTB formation. GP130 blockade attenuates both DDR activity and BTB formation, resulting in improved preclinical chemotherapeutic efficacy. Altogether, we describe an overarching mechanism for TMZ resistance and outline a translatable strategy with predictive markers to improve chemotherapy for GBMs.
{"title":"Myeloid cells coordinately induce glioma cell-intrinsic and cell-extrinsic pathways for chemoresistance via GP130 signaling.","authors":"Jiying Cheng, Min Li, Edyta Motta, Deivi Barci, Wangyang Song, Ding Zhou, Gen Li, Sihan Zhu, Anru Yang, Brian D Vaillant, Axel Imhof, Ignasi Forné, Sabine Spiegl-Kreinecker, Nu Zhang, Hiroshi Katayama, Krishna P L Bhat, Charlotte Flüh, Roland E Kälin, Rainer Glass","doi":"10.1016/j.xcrm.2024.101658","DOIUrl":"10.1016/j.xcrm.2024.101658","url":null,"abstract":"<p><p>The DNA damage response (DDR) and the blood-tumor barrier (BTB) restrict chemotherapeutic success for primary brain tumors like glioblastomas (GBMs). Coherently, GBMs almost invariably relapse with fatal outcomes. Here, we show that the interaction of GBM and myeloid cells simultaneously induces chemoresistance on the genetic and vascular levels by activating GP130 receptor signaling, which can be addressed therapeutically. We provide data from transcriptomic and immunohistochemical screens with human brain material and pharmacological experiments with a humanized organotypic GBM model, proteomics, transcriptomics, and cell-based assays and report that nanomolar concentrations of the signaling peptide humanin promote temozolomide (TMZ) resistance through DDR activation. GBM mouse models recapitulating intratumoral humanin release show accelerated BTB formation. GP130 blockade attenuates both DDR activity and BTB formation, resulting in improved preclinical chemotherapeutic efficacy. Altogether, we describe an overarching mechanism for TMZ resistance and outline a translatable strategy with predictive markers to improve chemotherapy for GBMs.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141757345","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}
Pub Date : 2024-08-20Epub Date: 2024-08-08DOI: 10.1016/j.xcrm.2024.101680
Francesca Fagiani, Edoardo Pedrini, Stefano Taverna, Elena Brambilla, Valentina Murtaj, Paola Podini, Francesca Ruffini, Erica Butti, Clarissa Braccia, Annapaola Andolfo, Roberta Magliozzi, Lena Smirnova, Tanja Kuhlmann, Angelo Quattrini, Peter A Calabresi, Daniel S Reich, Gianvito Martino, Paola Panina-Bordignon, Martina Absinta
The role of central nervous system (CNS) glia in sustaining self-autonomous inflammation and driving clinical progression in multiple sclerosis (MS) is gaining scientific interest. We applied a single transcription factor (SOX10)-based protocol to accelerate oligodendrocyte differentiation from human induced pluripotent stem cell (hiPSC)-derived neural precursor cells, generating self-organizing forebrain organoids. These organoids include neurons, astrocytes, oligodendroglia, and hiPSC-derived microglia to achieve immunocompetence. Over 8 weeks, organoids reproducibly generated mature CNS cell types, exhibiting single-cell transcriptional profiles similar to the adult human brain. Exposed to inflamed cerebrospinal fluid (CSF) from patients with MS, organoids properly mimic macroglia-microglia neurodegenerative phenotypes and intercellular communication seen in chronic active MS. Oligodendrocyte vulnerability emerged by day 6 post-MS-CSF exposure, with nearly 50% reduction. Temporally resolved organoid data support and expand on the role of soluble CSF mediators in sustaining downstream events leading to oligodendrocyte death and inflammatory neurodegeneration. Such findings support the implementation of this organoid model for drug screening to halt inflammatory neurodegeneration.
{"title":"A glia-enriched stem cell 3D model of the human brain mimics the glial-immune neurodegenerative phenotypes of multiple sclerosis.","authors":"Francesca Fagiani, Edoardo Pedrini, Stefano Taverna, Elena Brambilla, Valentina Murtaj, Paola Podini, Francesca Ruffini, Erica Butti, Clarissa Braccia, Annapaola Andolfo, Roberta Magliozzi, Lena Smirnova, Tanja Kuhlmann, Angelo Quattrini, Peter A Calabresi, Daniel S Reich, Gianvito Martino, Paola Panina-Bordignon, Martina Absinta","doi":"10.1016/j.xcrm.2024.101680","DOIUrl":"10.1016/j.xcrm.2024.101680","url":null,"abstract":"<p><p>The role of central nervous system (CNS) glia in sustaining self-autonomous inflammation and driving clinical progression in multiple sclerosis (MS) is gaining scientific interest. We applied a single transcription factor (SOX10)-based protocol to accelerate oligodendrocyte differentiation from human induced pluripotent stem cell (hiPSC)-derived neural precursor cells, generating self-organizing forebrain organoids. These organoids include neurons, astrocytes, oligodendroglia, and hiPSC-derived microglia to achieve immunocompetence. Over 8 weeks, organoids reproducibly generated mature CNS cell types, exhibiting single-cell transcriptional profiles similar to the adult human brain. Exposed to inflamed cerebrospinal fluid (CSF) from patients with MS, organoids properly mimic macroglia-microglia neurodegenerative phenotypes and intercellular communication seen in chronic active MS. Oligodendrocyte vulnerability emerged by day 6 post-MS-CSF exposure, with nearly 50% reduction. Temporally resolved organoid data support and expand on the role of soluble CSF mediators in sustaining downstream events leading to oligodendrocyte death and inflammatory neurodegeneration. Such findings support the implementation of this organoid model for drug screening to halt inflammatory neurodegeneration.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141912016","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}
Pub Date : 2024-08-20DOI: 10.1016/j.xcrm.2024.101679
Rui Sun, Jun A, Haolan Yu, Yan Wang, Miaoxia He, Lingling Tan, Honghan Cheng, Jili Zhang, Yingrui Wang, Xiaochen Sun, Mengge Lyu, Min Qu, Lingling Huang, Zijian Li, Wenhui Zhang, Kunpeng Ma, Zhenyang Dong, Weigang Ge, Yun Zhang, Xuan Ding, Bo Yang, Jianguo Hou, Chuanliang Xu, Linhui Wang, Yi Zhu, Tiannan Guo, Xu Gao, Chenghua Yang
Prostate cancer (PCa) is the most common malignant tumor in men. Currently, there are few prognosis indicators for predicting PCa outcomes and guiding treatments. Here, we perform comprehensive proteomic profiling of 918 tissue specimens from 306 Chinese patients with PCa using data-independent acquisition mass spectrometry (DIA-MS). We identify over 10,000 proteins and define three molecular subtypes of PCa with significant clinical and proteomic differences. We develop a 16-protein panel that effectively predicts biochemical recurrence (BCR) for patients with PCa, which is validated in six published datasets and one additional 99-biopsy-sample cohort by targeted proteomics. Interestingly, this 16-protein panel effectively predicts BCR across different International Society of Urological Pathology (ISUP) grades and pathological stages and outperforms the D'Amico risk classification system in BCR prediction. Furthermore, double knockout of NUDT5 and SEPTIN8, two components from the 16-protein panel, significantly suppresses the PCa cells to proliferate, invade, and migrate, suggesting the combination of NUDT5 and SEPTIN8 may provide new approaches for PCa treatment.
{"title":"Proteomic landscape profiling of primary prostate cancer reveals a 16-protein panel for prognosis prediction.","authors":"Rui Sun, Jun A, Haolan Yu, Yan Wang, Miaoxia He, Lingling Tan, Honghan Cheng, Jili Zhang, Yingrui Wang, Xiaochen Sun, Mengge Lyu, Min Qu, Lingling Huang, Zijian Li, Wenhui Zhang, Kunpeng Ma, Zhenyang Dong, Weigang Ge, Yun Zhang, Xuan Ding, Bo Yang, Jianguo Hou, Chuanliang Xu, Linhui Wang, Yi Zhu, Tiannan Guo, Xu Gao, Chenghua Yang","doi":"10.1016/j.xcrm.2024.101679","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101679","url":null,"abstract":"<p><p>Prostate cancer (PCa) is the most common malignant tumor in men. Currently, there are few prognosis indicators for predicting PCa outcomes and guiding treatments. Here, we perform comprehensive proteomic profiling of 918 tissue specimens from 306 Chinese patients with PCa using data-independent acquisition mass spectrometry (DIA-MS). We identify over 10,000 proteins and define three molecular subtypes of PCa with significant clinical and proteomic differences. We develop a 16-protein panel that effectively predicts biochemical recurrence (BCR) for patients with PCa, which is validated in six published datasets and one additional 99-biopsy-sample cohort by targeted proteomics. Interestingly, this 16-protein panel effectively predicts BCR across different International Society of Urological Pathology (ISUP) grades and pathological stages and outperforms the D'Amico risk classification system in BCR prediction. Furthermore, double knockout of NUDT5 and SEPTIN8, two components from the 16-protein panel, significantly suppresses the PCa cells to proliferate, invade, and migrate, suggesting the combination of NUDT5 and SEPTIN8 may provide new approaches for PCa treatment.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016492","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}
Hyperuricemic nephropathy (HN) is a global metabolic disorder characterized by uric acid (UA) metabolism dysfunction, resulting in hyperuricemia (HUA) and tubulointerstitial fibrosis (TIF). Sodium-dependent glucose transporter 2 inhibitor, dapagliflozin, has shown potential in reducing serum UA levels in patients with chronic kidney disease (CKD), though its protective effects against HN remain uncertain. This study investigates the functional, pathological, and molecular changes in HN through histological, biochemical, and transcriptomic analyses in patients, HN mice, and UA-stimulated HK-2 cells. Findings indicate UA-induced tubular dysfunction and fibrotic activation, which dapagliflozin significantly mitigates. Transcriptomic analysis identifies estrogen-related receptor α (ERRα), a downregulated transcription factor in HN. ERRα knockin mice and ERRα-overexpressed HK-2 cells demonstrate UA resistance, while ERRα inhibition exacerbates UA effects. Dapagliflozin targets ERRα, activating the ERRα-organic anion transporter 1 (OAT1) axis to enhance UA excretion and reduce TIF. Furthermore, dapagliflozin ameliorates renal fibrosis in non-HN CKD models, underscoring the therapeutic significance of the ERRα-OAT1 axis in HN and CKD.
{"title":"The SGLT2 inhibitor dapagliflozin ameliorates renal fibrosis in hyperuricemic nephropathy.","authors":"Hongtu Hu, Weiwei Li, Yiqun Hao, Zhuan Peng, Zhengping Zou, Jiali Wei, Ying Zhou, Wei Liang, Yun Cao","doi":"10.1016/j.xcrm.2024.101690","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101690","url":null,"abstract":"<p><p>Hyperuricemic nephropathy (HN) is a global metabolic disorder characterized by uric acid (UA) metabolism dysfunction, resulting in hyperuricemia (HUA) and tubulointerstitial fibrosis (TIF). Sodium-dependent glucose transporter 2 inhibitor, dapagliflozin, has shown potential in reducing serum UA levels in patients with chronic kidney disease (CKD), though its protective effects against HN remain uncertain. This study investigates the functional, pathological, and molecular changes in HN through histological, biochemical, and transcriptomic analyses in patients, HN mice, and UA-stimulated HK-2 cells. Findings indicate UA-induced tubular dysfunction and fibrotic activation, which dapagliflozin significantly mitigates. Transcriptomic analysis identifies estrogen-related receptor α (ERRα), a downregulated transcription factor in HN. ERRα knockin mice and ERRα-overexpressed HK-2 cells demonstrate UA resistance, while ERRα inhibition exacerbates UA effects. Dapagliflozin targets ERRα, activating the ERRα-organic anion transporter 1 (OAT1) axis to enhance UA excretion and reduce TIF. Furthermore, dapagliflozin ameliorates renal fibrosis in non-HN CKD models, underscoring the therapeutic significance of the ERRα-OAT1 axis in HN and CKD.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016497","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}
Pub Date : 2024-08-20Epub Date: 2024-08-09DOI: 10.1016/j.xcrm.2024.101681
H Ceren Ates, Abdallah Alshanawani, Stefan Hagel, Menino O Cotta, Jason A Roberts, Can Dincer, Cihan Ates
Clinical studies investigating the benefits of beta-lactam therapeutic drug monitoring (TDM) among critically ill patients are hindered by small patient groups, variability between studies, patient heterogeneity, and inadequate use of TDM. Accordingly, definitive conclusions regarding the efficacy of TDM remain elusive. To address these challenges, we propose an innovative approach that leverages data-driven methods to unveil the concealed connections between therapy effectiveness and patient data, collected through a randomized controlled trial (DRKS00011159; 10th October 2016). Our findings reveal that machine learning algorithms can successfully identify informative features that distinguish between healthy and sick states. These hold promise as potential markers for disease classification and severity stratification, as well as offering a continuous and data-driven "multidimensional" Sequential Organ Failure Assessment (SOFA) score. The positive impact of TDM on patient recovery rates is demonstrated by unraveling the intricate connections between therapy effectiveness and clinically relevant data via machine learning.
{"title":"Unraveling the impact of therapeutic drug monitoring via machine learning for patients with sepsis.","authors":"H Ceren Ates, Abdallah Alshanawani, Stefan Hagel, Menino O Cotta, Jason A Roberts, Can Dincer, Cihan Ates","doi":"10.1016/j.xcrm.2024.101681","DOIUrl":"10.1016/j.xcrm.2024.101681","url":null,"abstract":"<p><p>Clinical studies investigating the benefits of beta-lactam therapeutic drug monitoring (TDM) among critically ill patients are hindered by small patient groups, variability between studies, patient heterogeneity, and inadequate use of TDM. Accordingly, definitive conclusions regarding the efficacy of TDM remain elusive. To address these challenges, we propose an innovative approach that leverages data-driven methods to unveil the concealed connections between therapy effectiveness and patient data, collected through a randomized controlled trial (DRKS00011159; 10th October 2016). Our findings reveal that machine learning algorithms can successfully identify informative features that distinguish between healthy and sick states. These hold promise as potential markers for disease classification and severity stratification, as well as offering a continuous and data-driven \"multidimensional\" Sequential Organ Failure Assessment (SOFA) score. The positive impact of TDM on patient recovery rates is demonstrated by unraveling the intricate connections between therapy effectiveness and clinically relevant data via machine learning.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141912018","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}
Pub Date : 2024-08-20DOI: 10.1016/j.xcrm.2024.101687
Daniel J Vis, Patricia Jaaks, Nanne Aben, Elizabeth A Coker, Syd Barthorpe, Alexandra Beck, Caitlin Hall, James Hall, Howard Lightfoot, Ermira Lleshi, Tatiana Mironenko, Laura Richardson, Charlotte Tolley, Mathew J Garnett, Lodewyk F A Wessels
Combining drugs can enhance their clinical efficacy, but the number of possible combinations and inter-tumor heterogeneity make identifying effective combinations challenging, while existing approaches often overlook clinically relevant activity. We screen one of the largest cell line panels (N = 757) with 51 clinically relevant combinations and identify responses at the level of individual cell lines and tissue populations. We establish three response classes to model cellular effects beyond monotherapy: synergy, Bliss additivity, and independent drug action (IDA). Synergy is rare (11% of responses) and frequently efficacious (>50% viability reduction), whereas Bliss and IDA are more frequent but less frequently efficacious. We introduce "efficacious combination benefit" (ECB) to describe high-efficacy responses classified as either synergy, Bliss, or IDA. We identify ECB biomarkers in vitro and show that ECB predicts response in patient-derived xenografts better than synergy alone. Our work here provides a valuable resource and framework for preclinical evaluation and the development of combination treatments.
联合用药可以提高药物的临床疗效,但可能的联合用药数量和肿瘤间的异质性使得确定有效的联合用药具有挑战性,而现有的方法往往忽略了临床相关的活性。我们用 51 种临床相关组合筛选了最大的细胞系面板之一(N = 757),并确定了单个细胞系和组织群水平的反应。我们建立了三个反应类别,以模拟单药治疗以外的细胞效应:协同作用、布利斯加成作用和独立药物作用(IDA)。协同作用很少见(占反应的 11%),但经常有效(存活率降低 >50%),而 Bliss 和 IDA 更常见,但疗效较差。我们引入了 "高效联合效益"(ECB)来描述被归类为协同作用、Bliss 或 IDA 的高效反应。我们在体外确定了 ECB 的生物标志物,并证明 ECB 比单独的协同作用更能预测患者衍生异种移植物的反应。我们在此开展的工作为临床前评估和开发联合疗法提供了宝贵的资源和框架。
{"title":"A pan-cancer screen identifies drug combination benefit in cancer cell lines at the individual and population level.","authors":"Daniel J Vis, Patricia Jaaks, Nanne Aben, Elizabeth A Coker, Syd Barthorpe, Alexandra Beck, Caitlin Hall, James Hall, Howard Lightfoot, Ermira Lleshi, Tatiana Mironenko, Laura Richardson, Charlotte Tolley, Mathew J Garnett, Lodewyk F A Wessels","doi":"10.1016/j.xcrm.2024.101687","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101687","url":null,"abstract":"<p><p>Combining drugs can enhance their clinical efficacy, but the number of possible combinations and inter-tumor heterogeneity make identifying effective combinations challenging, while existing approaches often overlook clinically relevant activity. We screen one of the largest cell line panels (N = 757) with 51 clinically relevant combinations and identify responses at the level of individual cell lines and tissue populations. We establish three response classes to model cellular effects beyond monotherapy: synergy, Bliss additivity, and independent drug action (IDA). Synergy is rare (11% of responses) and frequently efficacious (>50% viability reduction), whereas Bliss and IDA are more frequent but less frequently efficacious. We introduce \"efficacious combination benefit\" (ECB) to describe high-efficacy responses classified as either synergy, Bliss, or IDA. We identify ECB biomarkers in vitro and show that ECB predicts response in patient-derived xenografts better than synergy alone. Our work here provides a valuable resource and framework for preclinical evaluation and the development of combination treatments.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016487","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}
Pub Date : 2024-08-20DOI: 10.1016/j.xcrm.2024.101688
Jie Zheng, Jieli Lu, Jiying Qi, Qian Yang, Huiling Zhao, Haoyu Liu, Zhihe Chen, Lanhui Huang, Youqiong Ye, Min Xu, Yu Xu, Tiange Wang, Mian Li, Zhiyun Zhao, Ruizhi Zheng, Shuangyuan Wang, Hong Lin, Chunyan Hu, Celine Sze Ling Chui, Shiu Lun Au Yeung, Shan Luo, Olympia Dimopoulou, Padraig Dixon, Sean Harrison, Yi Liu, Jamie Robinson, James Yarmolinsky, Philip Haycock, Jinqiu Yuan, Sarah Lewis, Zhongshang Yuan, Tom R Gaunt, George Davey Smith, Guang Ning, Richard M Martin, Bin Cui, Weiqing Wang, Yufang Bi
We evaluated the effect of sodium-glucose cotransporter 2 (SGLT2) inhibition on prostate cancer by evidence triangulation. Using Mendelian randomization, we found that genetically proxied SGLT2 inhibition reduced the risk of overall (odds ratio = 0.56, 95% confidence interval [CI] = 0.38 to 0.82; 79,148 prostate cancer cases and 61,106 controls), advanced, and early-onset prostate cancer. Using electronic healthcare data (nSGLT2i = 24,155; nDPP4i = 24,155), we found that the use of SGLT2 inhibitors was associated with a 23% reduced risk of prostate cancer (hazard ratio = 0.77, 95% CI = 0.61 to 0.99) in men with diabetes. Using data from two prospective cohorts (n4C = 57,779; nUK_Biobank = 165,430), we found little evidence to support the association of HbA1c with prostate cancer, implying a non-glycemic effect of SGLT2 inhibition on prostate cancer. In summary, this study provides multiple layers of evidence to support the beneficial effect of SGLT2 inhibition on reducing prostate cancer risk. Future trials are warranted to investigate whether SGLT2 inhibitors can be recommended for prostate cancer prevention.
{"title":"The effect of SGLT2 inhibition on prostate cancer: Mendelian randomization and observational analysis using electronic healthcare and cohort data.","authors":"Jie Zheng, Jieli Lu, Jiying Qi, Qian Yang, Huiling Zhao, Haoyu Liu, Zhihe Chen, Lanhui Huang, Youqiong Ye, Min Xu, Yu Xu, Tiange Wang, Mian Li, Zhiyun Zhao, Ruizhi Zheng, Shuangyuan Wang, Hong Lin, Chunyan Hu, Celine Sze Ling Chui, Shiu Lun Au Yeung, Shan Luo, Olympia Dimopoulou, Padraig Dixon, Sean Harrison, Yi Liu, Jamie Robinson, James Yarmolinsky, Philip Haycock, Jinqiu Yuan, Sarah Lewis, Zhongshang Yuan, Tom R Gaunt, George Davey Smith, Guang Ning, Richard M Martin, Bin Cui, Weiqing Wang, Yufang Bi","doi":"10.1016/j.xcrm.2024.101688","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101688","url":null,"abstract":"<p><p>We evaluated the effect of sodium-glucose cotransporter 2 (SGLT2) inhibition on prostate cancer by evidence triangulation. Using Mendelian randomization, we found that genetically proxied SGLT2 inhibition reduced the risk of overall (odds ratio = 0.56, 95% confidence interval [CI] = 0.38 to 0.82; 79,148 prostate cancer cases and 61,106 controls), advanced, and early-onset prostate cancer. Using electronic healthcare data (n<sub>SGLT2i</sub> = 24,155; n<sub>DPP4i</sub> = 24,155), we found that the use of SGLT2 inhibitors was associated with a 23% reduced risk of prostate cancer (hazard ratio = 0.77, 95% CI = 0.61 to 0.99) in men with diabetes. Using data from two prospective cohorts (n<sub>4C</sub> = 57,779; n<sub>UK_Biobank</sub> = 165,430), we found little evidence to support the association of HbA<sub>1c</sub> with prostate cancer, implying a non-glycemic effect of SGLT2 inhibition on prostate cancer. In summary, this study provides multiple layers of evidence to support the beneficial effect of SGLT2 inhibition on reducing prostate cancer risk. Future trials are warranted to investigate whether SGLT2 inhibitors can be recommended for prostate cancer prevention.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016496","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}
Sirtuin 1 (SIRT1) is a histone deacetylase and plays diverse functions in various physiological events, from development to lifespan regulation. Here, in Parkinson's disease (PD) model mice, we demonstrated that SIRT1 ameliorates parkinsonism, while SIRT1 knockdown further aggravates PD phenotypes. Mechanistically, SIRT1 interacts with and deacetylates pyruvate kinase M2 (PKM2) at K135 and K206, thus leading to reduced PKM2 enzyme activity and lactate production, which eventually results in decreased glial activation in the brain. Administration of lactate in the brain recapitulates PD-like phenotypes. Furthermore, increased expression of PKM2 worsens PD symptoms, and, on the contrary, inhibition of PKM2 by shikonin or PKM2-IN-1 alleviates parkinsonism in mice. Collectively, our data indicate that excessive lactate in the brain might be involved in the progression of PD. By improving lactate homeostasis, SIRT1, together with PKM2, are likely drug targets for developing agents for the treatment of neurodegeneration in PD.
{"title":"SIRT1 improves lactate homeostasis in the brain to alleviate parkinsonism via deacetylation and inhibition of PKM2.","authors":"Bolin Lian, Jing Zhang, Xiang Yin, Jiayan Wang, Li Li, Qianqian Ju, Yuejun Wang, Yuhui Jiang, Xiaoyu Liu, Yu Chen, Xin Tang, Cheng Sun","doi":"10.1016/j.xcrm.2024.101684","DOIUrl":"10.1016/j.xcrm.2024.101684","url":null,"abstract":"<p><p>Sirtuin 1 (SIRT1) is a histone deacetylase and plays diverse functions in various physiological events, from development to lifespan regulation. Here, in Parkinson's disease (PD) model mice, we demonstrated that SIRT1 ameliorates parkinsonism, while SIRT1 knockdown further aggravates PD phenotypes. Mechanistically, SIRT1 interacts with and deacetylates pyruvate kinase M2 (PKM2) at K135 and K206, thus leading to reduced PKM2 enzyme activity and lactate production, which eventually results in decreased glial activation in the brain. Administration of lactate in the brain recapitulates PD-like phenotypes. Furthermore, increased expression of PKM2 worsens PD symptoms, and, on the contrary, inhibition of PKM2 by shikonin or PKM2-IN-1 alleviates parkinsonism in mice. Collectively, our data indicate that excessive lactate in the brain might be involved in the progression of PD. By improving lactate homeostasis, SIRT1, together with PKM2, are likely drug targets for developing agents for the treatment of neurodegeneration in PD.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916191","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}