The Journal of Physical Chemistry 最新文献

{"title":"High-throughput identification of repurposable neuroactive drugs with potent anti-glioblastoma activity","authors":"Sohyon Lee, Tobias Weiss, Marcel Bühler, Julien Mena, Zuzanna Lottenbach, Rebekka Wegmann, Miaomiao Sun, Michel Bihl, Bartłomiej Augustynek, Sven P. Baumann, Sandra Goetze, Audrey van Drogen, Patrick G. A. Pedrioli, David Penton, Yasmin Festl, Alicia Buck, Daniel Kirschenbaum, Anna M. Zeitlberger, Marian C. Neidert, Flavio Vasella, Elisabeth J. Rushing, Bernd Wollscheid, Matthias A. Hediger, Michael Weller, Berend Snijder","doi":"10.1038/s41591-024-03224-y","DOIUrl":"10.1038/s41591-024-03224-y","url":null,"abstract":"Glioblastoma, the most aggressive primary brain cancer, has a dismal prognosis, yet systemic treatment is limited to DNA-alkylating chemotherapies. New therapeutic strategies may emerge from exploring neurodevelopmental and neurophysiological vulnerabilities of glioblastoma. To this end, we systematically screened repurposable neuroactive drugs in glioblastoma patient surgery material using a clinically concordant and single-cell resolved platform. Profiling more than 2,500 ex vivo drug responses across 27 patients and 132 drugs identified class-diverse neuroactive drugs with potent anti-glioblastoma efficacy that were validated across model systems. Interpretable molecular machine learning of drug–target networks revealed neuroactive convergence on AP-1/BTG-driven glioblastoma suppression, enabling expanded in silico screening of more than 1 million compounds with high patient validation accuracy. Deep multimodal profiling confirmed Ca2+-driven AP-1/BTG-pathway induction as a neuro-oncological glioblastoma vulnerability, epitomized by the anti-depressant vortioxetine synergizing with current standard-of-care chemotherapies in vivo. These findings establish an actionable framework for glioblastoma treatment rooted in its neural etiology. A single-cell ex vivo screening of repurposable drugs in glioblastoma and machine learning of drug–target networks show that anti-tumor neuroactive drugs converge on the AP-1/BTG pathway, based on which prediction models and experimental in vivo and in silico validation identify the anti-depressant vortioxetine as a potential therapeutic agent.","PeriodicalId":58,"journal":{"name":"The Journal of Physical Chemistry ","volume":"30 11","pages":"3196-3208"},"PeriodicalIF":58.7,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41591-024-03224-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142275956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Echocardiographic screening for heart failure and optimization of the care pathway for individuals with pacemakers: a randomized controlled trial","authors":"Maria F. Paton, John Gierula, Haqeel A. Jamil, Sam Straw, Judith E. Lowry, Rowena Byrom, Thomas A. Slater, Alasdair M. Fellows, Richard G. Gillott, Hemant Chumun, Paul Smith, Richard M. Cubbon, Deborah D. Stocken, Mark T. Kearney, Klaus K. Witte","doi":"10.1038/s41591-024-03265-3","DOIUrl":"10.1038/s41591-024-03265-3","url":null,"abstract":"Individuals with pacemakers are at increased risk of left ventricular systolic dysfunction (LVSD). Whether screening for and optimizing the medical management of LVSD in these individuals can improve clinical outcomes is unknown. In the present study, in a multicenter controlled trial (OPT-PACE), we randomized 1,201 patients (717 men) with a pacemaker to echocardiography screening or usual care. In the screening arm, LVSD was detected in 201 of 600 (34%) patients, who then received management in either primary care or a specialist heart failure (HF) and devices clinic. The primary outcome of the trial was the difference in a composite of time to first HF hospitalization or death. Over 31 months (interquartile range = 30–40 months), the primary outcome occurred in 106 of 600 (18%) patients receiving echocardiography screening, which was not significantly different compared with the occurrence of the primary outcome in 115 of 601 (19%) patients receiving the usual care (hazard ratio = 0.89; 95% confidence interval = 0.69, 1.17). In a prespecified, nonrandomized, exploratory analysis, patients with LVSD managed by the specialist clinic experienced the primary outcome event less frequently than those managed in primary care. The results of this trial indicate that echocardiography screening commonly identifies LVSD in individuals with pacemakers but alone does not alter outcomes. ClinicalTrials.gov registration: NCT01819662 . For individuals with pacemakers, a care pathway that includes echocardiographic screening to detect signs of heart failure did not improve cardiac outcomes, but patients flagged as having impaired heart function who were managed by a specialized heart failure clinic benefited, as compared to those managed by primary care physicians.","PeriodicalId":58,"journal":{"name":"The Journal of Physical Chemistry ","volume":"30 11","pages":"3303-3309"},"PeriodicalIF":58.7,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41591-024-03265-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"siRNA therapy lowers triglycerides in patients with rare condition","authors":"","doi":"10.1038/d41591-024-00070-w","DOIUrl":"https://doi.org/10.1038/d41591-024-00070-w","url":null,"abstract":"Plozasiran reduced triglyceride levels by 80% and lowered the risk of pancreatitis in patients with persistent chylomicronemia, with or without a genetic diagnosis.","PeriodicalId":58,"journal":{"name":"The Journal of Physical Chemistry ","volume":"39 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245706","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":"Human outbreaks of a novel reassortant Oropouche virus in the Brazilian Amazon region","authors":"Felipe Gomes Naveca, Tatiana Amaral Pires de Almeida, Victor Souza, Valdinete Nascimento, Dejanane Silva, Fernanda Nascimento, Matilde Mejía, Yasmin Silva de Oliveira, Luisa Rocha, Natana Xavier, Janis Lopes, Rodrigo Maito, Cátia Meneses, Tatyana Amorim, Luciana Fé, Fernanda Sindeaux Camelo, Samyly Coutinho de Aguiar Silva, Alexsandro Xavier de Melo, Leíse Gomes Fernandes, Marco Aurélio Almeida de Oliveira, Ana Ruth Arcanjo, Guilherme Araújo, Walter André Júnior, Renata Lia Coragem de Carvalho, Rosiane Rodrigues, Stella Albuquerque, Cristiane Mattos, Ciciléia Silva, Aline Linhares, Taynã Rodrigues, Francy Mariscal, Márcia Andréa Morais, Mayra Marinho Presibella, Nelson Fernando Quallio Marques, Anne Paiva, Karina Ribeiro, Deusilene Vieira, Jackson Alves da Silva Queiroz, Ana Maísa Passos-Silva, Lígia Abdalla, João Hugo Santos, Regina Maria Pinto de Figueiredo, Ana Cecília Ribeiro Cruz, Livia Neves Casseb, Jannifer Oliveira Chiang, Livia Vinhal Frutuoso, Agata Rossi, Lucas Freitas, Túlio de Lima Campos, Gabriel Luz Wallau, Emerson Moreira, Roberto Dias Lins Neto, Laura W. Alexander, Yining Sun, Ana Maria Bispo de Filippis, Tiago Gräf, Ighor Arantes, Ana I. Bento, Edson Delatorre, Gonzalo Bello","doi":"10.1038/s41591-024-03300-3","DOIUrl":"https://doi.org/10.1038/s41591-024-03300-3","url":null,"abstract":"<p>The Brazilian western Amazon is experiencing its largest laboratory-confirmed Oropouche virus (OROV) outbreak, with more than 6,300 reported cases between 2022 and 2024. Here, we sequenced and analyzed 382 OROV genomes from human samples collected in Amazonas, Acre, Rondônia, and Roraima states, between August 2022 and February 2024, to uncover the origin and genetic evolution of OROV in the current outbreak. Genomic analyses revealed that the upsurge of OROV cases in the Brazilian Amazon coincides with spread of a novel reassortant lineage containing the M segment of viruses detected in the eastern Amazon region (2009-2018) and the L and S segments of viruses detected in Peru, Colombia, and Ecuador (2008-2021). The novel reassortant likely emerged in the Amazonas state between 2010 and 2014 and spread through long-range dispersion events during the second half of the 2010s. Phylodynamics reconstructions showed that the current OROV spread was mainly driven by short-range (&lt; 2 km) movements consistent with the flight range of vectors. Nevertheless, a substantial proportion (22%) of long-range (&gt; 10 km) OROV migrations were also detected, consistent with viral dispersion by humans. Our data provides a view of the unprecedented spread and evolution of OROV in Brazilian western Amazon region.</p>","PeriodicalId":58,"journal":{"name":"The Journal of Physical Chemistry ","volume":"186 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236144","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":"Navigating treatment combinations in small-cell lung cancer","authors":"Ning Li,&nbsp;Si-Yu Wang","doi":"10.1038/s41591-024-03255-5","DOIUrl":"10.1038/s41591-024-03255-5","url":null,"abstract":"The ETER701 trial demonstrates that a four-drug regimen, involving the addition of anti-angiogenesis therapy to immuno-chemotherapy, improves survival outcomes for extensive-stage small-cell lung cancer — but is more indeed better when it comes to treating this intractable disease?","PeriodicalId":58,"journal":{"name":"The Journal of Physical Chemistry ","volume":"30 10","pages":"2731-2732"},"PeriodicalIF":58.7,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236149","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":"Improving primary healthcare with generative AI","authors":"Winnie Yip","doi":"10.1038/s41591-024-03257-3","DOIUrl":"10.1038/s41591-024-03257-3","url":null,"abstract":"Studies in China show how large language models can improve primary healthcare systems, but equitably scaling this technology will require attention to rural, low-resource settings and the companion policies that support its implementation.","PeriodicalId":58,"journal":{"name":"The Journal of Physical Chemistry ","volume":"30 10","pages":"2727-2728"},"PeriodicalIF":58.7,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236142","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":"Countering the impact of the climate crisis on health will require data","authors":"","doi":"10.1038/s41591-024-03276-0","DOIUrl":"10.1038/s41591-024-03276-0","url":null,"abstract":"As drastically rising global temperatures threaten the health and wellbeing of populations, solutions that drive policy action must be based on scientific evidence of which strategies work in different scenarios.","PeriodicalId":58,"journal":{"name":"The Journal of Physical Chemistry ","volume":"30 9","pages":"2379-2379"},"PeriodicalIF":58.7,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41591-024-03276-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Data-driven risk stratification and precision management of pulmonary nodules detected on chest computed tomography","authors":"Chengdi Wang,&nbsp;Jun Shao,&nbsp;Yichu He,&nbsp;Jiaojiao Wu,&nbsp;Xingting Liu,&nbsp;Liuqing Yang,&nbsp;Ying Wei,&nbsp;Xiang Sean Zhou,&nbsp;Yiqiang Zhan,&nbsp;Feng Shi,&nbsp;Dinggang Shen,&nbsp;Weimin Li","doi":"10.1038/s41591-024-03211-3","DOIUrl":"10.1038/s41591-024-03211-3","url":null,"abstract":"The widespread implementation of low-dose computed tomography (LDCT) in lung cancer screening has led to the increasing detection of pulmonary nodules. However, precisely evaluating the malignancy risk of pulmonary nodules remains a formidable challenge. Here we propose a triage-driven Chinese Lung Nodules Reporting and Data System (C-Lung-RADS) utilizing a medical checkup cohort of 45,064 cases. The system was operated in a stepwise fashion, initially distinguishing low-, mid-, high- and extremely high-risk nodules based on their size and density. Subsequently, it progressively integrated imaging information, demographic characteristics and follow-up data to pinpoint suspicious malignant nodules and refine the risk scale. The multidimensional system achieved a state-of-the-art performance with an area under the curve (AUC) of 0.918 (95% confidence interval (CI) 0.918–0.919) on the internal testing dataset, outperforming the single-dimensional approach (AUC of 0.881, 95% CI 0.880–0.882). Moreover, C-Lung-RADS exhibited a superior sensitivity compared with Lung-RADS v2022 (87.1% versus 63.3%) in an independent cohort, which was screened using mobile computed tomography scanners to broaden screening accessibility in resource-constrained settings. With its foundation in precise risk stratification and tailored management, this system has minimized unnecessary invasive procedures for low-risk cases and recommended prompt intervention for extremely high-risk nodules to avert diagnostic delays. This approach has the potential to enhance the decision-making paradigm and facilitate a more efficient diagnosis of lung cancer during routine checkups as well as screening scenarios. Trained on a cohort of 45,064 cases and validated on data acquired from mobile computed tomography scanners deployed in rural China, a lung cancer screening deep learning model is shown to outperform existing lung cancer risk scores.","PeriodicalId":58,"journal":{"name":"The Journal of Physical Chemistry ","volume":"30 11","pages":"3184-3195"},"PeriodicalIF":58.7,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41591-024-03211-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exposure to extreme heat increases perinatal mortality in sub-Saharan Africa","authors":"","doi":"10.1038/s41591-024-03251-9","DOIUrl":"10.1038/s41591-024-03251-9","url":null,"abstract":"Extreme heat events are expected to become more frequent because of climate change. Our analysis of almost 140,000 births across 16 hospitals in four countries in sub-Saharan Africa indicates 34% higher odds of perinatal mortality (stillbirth or death up to 24 hours after birth) if extreme heat occurred in the week preceding childbirth.","PeriodicalId":58,"journal":{"name":"The Journal of Physical Chemistry ","volume":"30 11","pages":"3065-3066"},"PeriodicalIF":58.7,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236146","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":"Targeted therapy guided by circulating tumor DNA analysis in advanced gastrointestinal tumors","authors":"Yoshiaki Nakamura, Hiroshi Ozaki, Makoto Ueno, Yoshito Komatsu, Satoshi Yuki, Taito Esaki, Hiroya Taniguchi, Yu Sunakawa, Kensei Yamaguchi, Ken Kato, Tadamichi Denda, Tomohiro Nishina, Naoki Takahashi, Taroh Satoh, Hisateru Yasui, Hironaga Satake, Eiji Oki, Takeshi Kato, Takashi Ohta, Nobuhisa Matsuhashi, Masahiro Goto, Naohiro Okano, Koushiro Ohtsubo, Kentaro Yamazaki, Riu Yamashita, Naoko Iida, Mihoko Yuasa, Hideaki Bando, Takayuki Yoshino","doi":"10.1038/s41591-024-03244-8","DOIUrl":"https://doi.org/10.1038/s41591-024-03244-8","url":null,"abstract":"<p>Although comprehensive genomic profiling has become standard in oncology for advanced solid tumors, the full potential of circulating tumor DNA (ctDNA)-based profiling in capturing tumor heterogeneity and guiding therapy selection remains underexploited, marked by a scarcity of evidence on its clinical impact and the assessment of intratumoral heterogeneity. The GOZILA study, a nationwide, prospective observational ctDNA profiling study, previously demonstrated higher clinical trial enrollment rates using liquid biopsy compared with tissue screening. This updated analysis of 4,037 patients further delineates the clinical utility of ctDNA profiling in advanced solid tumors, showcasing a significant enhancement in patient outcomes with a 24% match rate for targeted therapy. Patients treated with matched targeted therapy based on ctDNA profiling demonstrated significantly improved overall survival compared with those receiving unmatched therapy (hazard ratio, 0.54). Notably, biomarker clonality and adjusted plasma copy number were identified as predictors of therapeutic efficacy, reinforcing the value of ctDNA in reflecting tumor heterogeneity for precise treatment decisions. These new insights into the relationship between ctDNA characteristics and treatment outcomes advance our understanding beyond the initial enrollment benefits. Our findings advocate for the broader adoption of ctDNA-guided treatment, signifying an advancement in precision oncology and improving survival outcomes in advanced solid tumors.</p>","PeriodicalId":58,"journal":{"name":"The Journal of Physical Chemistry ","volume":"14 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234483","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}