Pub Date : 2023-11-03DOI: 10.1038/s41591-023-02650-8
Bertrand Routy, John G. Lenehan, Wilson H. Miller Jr, Rahima Jamal, Meriem Messaoudene, Brendan A. Daisley, Cecilia Hes, Kait F. Al, Laura Martinez-Gili, Michal Punčochář, Scott Ernst, Diane Logan, Karl Belanger, Khashayar Esfahani, Corentin Richard, Marina Ninkov, Gianmarco Piccinno, Federica Armanini, Federica Pinto, Mithunah Krishnamoorthy, Rene Figueredo, Pamela Thebault, Panteleimon Takis, Jamie Magrill, LeeAnn Ramsay, Lisa Derosa, Julian R. Marchesi, Seema Nair Parvathy, Arielle Elkrief, Ian R. Watson, Rejean Lapointe, Nicola Segata, S.M. Mansour Haeryfar, Benjamin H. Mullish, Michael S. Silverman, Jeremy P. Burton, Saman Maleki Vareki
{"title":"Author Correction: Fecal microbiota transplantation plus anti-PD-1 immunotherapy in advanced melanoma: a phase I trial","authors":"Bertrand Routy, John G. Lenehan, Wilson H. Miller Jr, Rahima Jamal, Meriem Messaoudene, Brendan A. Daisley, Cecilia Hes, Kait F. Al, Laura Martinez-Gili, Michal Punčochář, Scott Ernst, Diane Logan, Karl Belanger, Khashayar Esfahani, Corentin Richard, Marina Ninkov, Gianmarco Piccinno, Federica Armanini, Federica Pinto, Mithunah Krishnamoorthy, Rene Figueredo, Pamela Thebault, Panteleimon Takis, Jamie Magrill, LeeAnn Ramsay, Lisa Derosa, Julian R. Marchesi, Seema Nair Parvathy, Arielle Elkrief, Ian R. Watson, Rejean Lapointe, Nicola Segata, S.M. Mansour Haeryfar, Benjamin H. Mullish, Michael S. Silverman, Jeremy P. Burton, Saman Maleki Vareki","doi":"10.1038/s41591-023-02650-8","DOIUrl":"10.1038/s41591-023-02650-8","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"30 2","pages":"604-604"},"PeriodicalIF":82.9,"publicationDate":"2023-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41591-023-02650-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71483963","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}
Pub Date : 2023-11-02DOI: 10.1038/s41591-023-02599-8
Liron Zahavi, Amit Lavon, Lee Reicher, Saar Shoer, Anastasia Godneva, Sigal Leviatan, Michal Rein, Omer Weissbrod, Adina Weinberger, Eran Segal
Genome-wide association studies (GWASs) have provided numerous associations between human single-nucleotide polymorphisms (SNPs) and health traits. Likewise, metagenome-wide association studies (MWASs) between bacterial SNPs and human traits can suggest mechanistic links, but very few such studies have been done thus far. In this study, we devised an MWAS framework to detect SNPs and associate them with host phenotypes systematically. We recruited and obtained gut metagenomic samples from a cohort of 7,190 healthy individuals and discovered 1,358 statistically significant associations between a bacterial SNP and host body mass index (BMI), from which we distilled 40 independent associations. Most of these associations were unexplained by diet, medications or physical exercise, and 17 replicated in a geographically independent cohort. We uncovered BMI-associated SNPs in 27 bacterial species, and 12 of them showed no association by standard relative abundance analysis. We revealed a BMI association of an SNP in a potentially inflammatory pathway of Bilophila wadsworthia as well as of a group of SNPs in a region coding for energy metabolism functions in a Faecalibacterium prausnitzii genome. Our results demonstrate the importance of considering nucleotide-level diversity in microbiome studies and pave the way toward improved understanding of interpersonal microbiome differences and their potential health implications. A new framework for linking metagenomic data on the gut microbiome to human traits uncovers bacterial SNPs that associate with BMI in geographically independent cohorts.
{"title":"Bacterial SNPs in the human gut microbiome associate with host BMI","authors":"Liron Zahavi, Amit Lavon, Lee Reicher, Saar Shoer, Anastasia Godneva, Sigal Leviatan, Michal Rein, Omer Weissbrod, Adina Weinberger, Eran Segal","doi":"10.1038/s41591-023-02599-8","DOIUrl":"10.1038/s41591-023-02599-8","url":null,"abstract":"Genome-wide association studies (GWASs) have provided numerous associations between human single-nucleotide polymorphisms (SNPs) and health traits. Likewise, metagenome-wide association studies (MWASs) between bacterial SNPs and human traits can suggest mechanistic links, but very few such studies have been done thus far. In this study, we devised an MWAS framework to detect SNPs and associate them with host phenotypes systematically. We recruited and obtained gut metagenomic samples from a cohort of 7,190 healthy individuals and discovered 1,358 statistically significant associations between a bacterial SNP and host body mass index (BMI), from which we distilled 40 independent associations. Most of these associations were unexplained by diet, medications or physical exercise, and 17 replicated in a geographically independent cohort. We uncovered BMI-associated SNPs in 27 bacterial species, and 12 of them showed no association by standard relative abundance analysis. We revealed a BMI association of an SNP in a potentially inflammatory pathway of Bilophila wadsworthia as well as of a group of SNPs in a region coding for energy metabolism functions in a Faecalibacterium prausnitzii genome. Our results demonstrate the importance of considering nucleotide-level diversity in microbiome studies and pave the way toward improved understanding of interpersonal microbiome differences and their potential health implications. A new framework for linking metagenomic data on the gut microbiome to human traits uncovers bacterial SNPs that associate with BMI in geographically independent cohorts.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"29 11","pages":"2785-2792"},"PeriodicalIF":82.9,"publicationDate":"2023-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71425159","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 : 2023-11-02DOI: 10.1038/s41591-023-02632-w
Ken Mautner, Michael Gottschalk, Scott D. Boden, Alison Akard, Won C. Bae, Lora Black, Blake Boggess, Paramita Chatterjee, Christine B. Chung, Kirk A. Easley, Greg Gibson, Josh Hackel, Katie Jensen, Linda Kippner, Chad Kurtenbach, Joanne Kurtzberg, R. Amadeus Mason, Benjamin Noonan, Krishnendu Roy, Verle Valentine, Carolyn Yeago, Hicham Drissi
Various types of cellular injection have become a popular and costly treatment option for patients with knee osteoarthritis despite a paucity of literature establishing relative efficacy to each other or corticosteroid injections. Here we aimed to identify the safety and efficacy of cell injections from autologous bone marrow aspirate concentrate, autologous adipose stromal vascular fraction and allogeneic human umbilical cord tissue-derived mesenchymal stromal cells, in comparison to corticosteroid injection (CSI). The study was a phase 2/3, four-arm parallel, multicenter, single-blind, randomized, controlled clinical trial with 480 patients with a diagnosis of knee osteoarthritis (Kellgren–Lawrence II–IV). Participants were randomized to the three different arms with a 3:1 distribution. Arm 1: autologous bone marrow aspirate concentrate (n = 120), CSI (n = 40); arm 2: umbilical cord tissue-derived mesenchymal stromal cells (n = 120), CSI (n = 40); arm 3: stromal vascular fraction (n = 120), CSI (n = 40). The co-primary endpoints were the visual analog scale pain score and Knee injury and Osteoarthritis Outcome Score pain score at 12 months versus baseline. Analyses of our primary endpoints, with 440 patients, revealed that at 1 year post injection, none of the three orthobiologic injections was superior to another, or to the CSI control. In addition, none of the four groups showed a significant change in magnetic resonance imaging osteoarthritis score compared to baseline. No procedure-related serious adverse events were reported during the study period. In summary, this study shows that at 1 year post injection, there was no superior orthobiologic as compared to CSI for knee osteoarthritis. ClinicalTrials.gov Identifier: NCT03818737 The multicenter phase 3 trial of stem cell therapy for osteoarthritis (MILES) for knee pain revealed that cell therapies showed no significant difference in knee pain outcomes, compared to corticosteroid injections, 1 year following treatment.
{"title":"Cell-based versus corticosteroid injections for knee pain in osteoarthritis: a randomized phase 3 trial","authors":"Ken Mautner, Michael Gottschalk, Scott D. Boden, Alison Akard, Won C. Bae, Lora Black, Blake Boggess, Paramita Chatterjee, Christine B. Chung, Kirk A. Easley, Greg Gibson, Josh Hackel, Katie Jensen, Linda Kippner, Chad Kurtenbach, Joanne Kurtzberg, R. Amadeus Mason, Benjamin Noonan, Krishnendu Roy, Verle Valentine, Carolyn Yeago, Hicham Drissi","doi":"10.1038/s41591-023-02632-w","DOIUrl":"10.1038/s41591-023-02632-w","url":null,"abstract":"Various types of cellular injection have become a popular and costly treatment option for patients with knee osteoarthritis despite a paucity of literature establishing relative efficacy to each other or corticosteroid injections. Here we aimed to identify the safety and efficacy of cell injections from autologous bone marrow aspirate concentrate, autologous adipose stromal vascular fraction and allogeneic human umbilical cord tissue-derived mesenchymal stromal cells, in comparison to corticosteroid injection (CSI). The study was a phase 2/3, four-arm parallel, multicenter, single-blind, randomized, controlled clinical trial with 480 patients with a diagnosis of knee osteoarthritis (Kellgren–Lawrence II–IV). Participants were randomized to the three different arms with a 3:1 distribution. Arm 1: autologous bone marrow aspirate concentrate (n = 120), CSI (n = 40); arm 2: umbilical cord tissue-derived mesenchymal stromal cells (n = 120), CSI (n = 40); arm 3: stromal vascular fraction (n = 120), CSI (n = 40). The co-primary endpoints were the visual analog scale pain score and Knee injury and Osteoarthritis Outcome Score pain score at 12 months versus baseline. Analyses of our primary endpoints, with 440 patients, revealed that at 1 year post injection, none of the three orthobiologic injections was superior to another, or to the CSI control. In addition, none of the four groups showed a significant change in magnetic resonance imaging osteoarthritis score compared to baseline. No procedure-related serious adverse events were reported during the study period. In summary, this study shows that at 1 year post injection, there was no superior orthobiologic as compared to CSI for knee osteoarthritis. ClinicalTrials.gov Identifier: NCT03818737 The multicenter phase 3 trial of stem cell therapy for osteoarthritis (MILES) for knee pain revealed that cell therapies showed no significant difference in knee pain outcomes, compared to corticosteroid injections, 1 year following treatment.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"29 12","pages":"3120-3126"},"PeriodicalIF":82.9,"publicationDate":"2023-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10719084/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71425160","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}
Pub Date : 2023-11-02DOI: 10.1038/s41591-023-02663-3
Daniel K. Wilton, Kevin Mastro, Molly D. Heller, Frederick W. Gergits, Carly Rose Willing, Jaclyn B. Fahey, Arnaud Frouin, Anthony Daggett, Xiaofeng Gu, Yejin A. Kim, Richard L. M. Faull, Suman Jayadev, Ted Yednock, X. William Yang, Beth Stevens
{"title":"Author Correction: Microglia and complement mediate early corticostriatal synapse loss and cognitive dysfunction in Huntington’s disease","authors":"Daniel K. Wilton, Kevin Mastro, Molly D. Heller, Frederick W. Gergits, Carly Rose Willing, Jaclyn B. Fahey, Arnaud Frouin, Anthony Daggett, Xiaofeng Gu, Yejin A. Kim, Richard L. M. Faull, Suman Jayadev, Ted Yednock, X. William Yang, Beth Stevens","doi":"10.1038/s41591-023-02663-3","DOIUrl":"10.1038/s41591-023-02663-3","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"29 11","pages":"2958-2958"},"PeriodicalIF":82.9,"publicationDate":"2023-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10667092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71425158","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}
Pub Date : 2023-11-01DOI: 10.1038/s41591-023-02674-0
Carlos K. H. Wong, Kristy T. K. Lau, Matthew S. H. Chung, Ivan C. H. Au, Ka Wang Cheung, Eric H. Y. Lau, Yasmin Daoud, Benjamin J. Cowling, Gabriel M. Leung
To date, there is a lack of randomized trial data examining the use of the antiviral nirmatrelvir/ritonavir in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected pregnant persons. This target trial emulation study aimed to address this gap by evaluating the use of nirmatrelvir/ritonavir in nonhospitalized pregnant women with symptomatic SARS-CoV-2 Omicron variant infection. Among patients diagnosed between 16 March 2022 and 5 February 2023, exposure was defined as outpatient nirmatrelvir/ritonavir treatment within 5 days of symptom onset or coronavirus disease 2019 (COVID-19) diagnosis. Primary outcomes were maternal morbidity and mortality index (MMMI), all-cause maternal death and COVID-19-related hospitalization, while secondary outcomes were individual components of MMMI, preterm birth, stillbirth, neonatal death and cesarean section. One-to-ten propensity-score matching was conducted between nirmatrelvir/ritonavir users and nonusers, followed by cloning, censoring and weighting. Overall, 211 pregnant women on nirmatrelvir/ritonavir and 1,998 nonusers were included. Nirmatrelvir/ritonavir treatment was associated with reduced 28-day MMMI risk (absolute risk reduction (ARR) = 1.47%, 95% confidence interval (CI) = 0.21–2.34%) but not 28-days COVID-19-related hospitalization (ARR = −0.09%, 95% CI = −1.08% to 0.71%). Nirmatrelvir/ritonavir treatment was also associated with reduced risks of cesarean section (ARR = 1.58%, 95% CI = 0.85–2.39%) and preterm birth (ARR = 2.70%, 95% CI = 0.98–5.31%). No events of maternal or neonatal death or stillbirth were recorded. The findings suggest that nirmatrelvir/ritonavir is an effective treatment in symptomatic pregnant women with SARS-CoV-2 Omicron variant infection. Analysis of electronic health records of nirmatrelvir/ritonavir use in pregnant women shows that the treatment is associated with a lower risk of pregnancy-related adverse outcomes, including maternal morbidity, premature birth and cesarean section.
{"title":"Nirmatrelvir/ritonavir use in pregnant women with SARS-CoV-2 Omicron infection: a target trial emulation","authors":"Carlos K. H. Wong, Kristy T. K. Lau, Matthew S. H. Chung, Ivan C. H. Au, Ka Wang Cheung, Eric H. Y. Lau, Yasmin Daoud, Benjamin J. Cowling, Gabriel M. Leung","doi":"10.1038/s41591-023-02674-0","DOIUrl":"10.1038/s41591-023-02674-0","url":null,"abstract":"To date, there is a lack of randomized trial data examining the use of the antiviral nirmatrelvir/ritonavir in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected pregnant persons. This target trial emulation study aimed to address this gap by evaluating the use of nirmatrelvir/ritonavir in nonhospitalized pregnant women with symptomatic SARS-CoV-2 Omicron variant infection. Among patients diagnosed between 16 March 2022 and 5 February 2023, exposure was defined as outpatient nirmatrelvir/ritonavir treatment within 5 days of symptom onset or coronavirus disease 2019 (COVID-19) diagnosis. Primary outcomes were maternal morbidity and mortality index (MMMI), all-cause maternal death and COVID-19-related hospitalization, while secondary outcomes were individual components of MMMI, preterm birth, stillbirth, neonatal death and cesarean section. One-to-ten propensity-score matching was conducted between nirmatrelvir/ritonavir users and nonusers, followed by cloning, censoring and weighting. Overall, 211 pregnant women on nirmatrelvir/ritonavir and 1,998 nonusers were included. Nirmatrelvir/ritonavir treatment was associated with reduced 28-day MMMI risk (absolute risk reduction (ARR) = 1.47%, 95% confidence interval (CI) = 0.21–2.34%) but not 28-days COVID-19-related hospitalization (ARR = −0.09%, 95% CI = −1.08% to 0.71%). Nirmatrelvir/ritonavir treatment was also associated with reduced risks of cesarean section (ARR = 1.58%, 95% CI = 0.85–2.39%) and preterm birth (ARR = 2.70%, 95% CI = 0.98–5.31%). No events of maternal or neonatal death or stillbirth were recorded. The findings suggest that nirmatrelvir/ritonavir is an effective treatment in symptomatic pregnant women with SARS-CoV-2 Omicron variant infection. Analysis of electronic health records of nirmatrelvir/ritonavir use in pregnant women shows that the treatment is associated with a lower risk of pregnancy-related adverse outcomes, including maternal morbidity, premature birth and cesarean section.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"30 1","pages":"112-116"},"PeriodicalIF":82.9,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71425161","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 : 2023-10-31DOI: 10.1038/d41591-023-00094-8
A machine-learning diagnosis tool, based on low-cost sequencing, can assist decision-making during brain surgeries.
一种基于低成本测序的机器学习诊断工具可以在脑部手术期间帮助做出决策。
{"title":"AI aids brain tumor surgery","authors":"","doi":"10.1038/d41591-023-00094-8","DOIUrl":"https://doi.org/10.1038/d41591-023-00094-8","url":null,"abstract":"A machine-learning diagnosis tool, based on low-cost sequencing, can assist decision-making during brain surgeries.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"7 10","pages":""},"PeriodicalIF":82.9,"publicationDate":"2023-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71417403","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 : 2023-10-30DOI: 10.1038/s41591-023-02602-2
Timothy J. Kendall, Maria Jimenez-Ramos, Frances Turner, Prakash Ramachandran, Jessica Minnier, Michael D. McColgan, Masood Alam, Harriet Ellis, Donald R. Dunbar, Gabriele Kohnen, Prakash Konanahalli, Karin A. Oien, Lucia Bandiera, Filippo Menolascina, Anna Juncker-Jensen, Douglas Alexander, Charlie Mayor, Indra Neil Guha, Jonathan A. Fallowfield
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the commonest cause of chronic liver disease worldwide and represents an unmet precision medicine challenge. We established a retrospective national cohort of 940 histologically defined patients (55.4% men, 44.6% women; median body mass index 31.3; 32% with type 2 diabetes) covering the complete MASLD severity spectrum, and created a secure, searchable, open resource (SteatoSITE). In 668 cases and 39 controls, we generated hepatic bulk RNA sequencing data and performed differential gene expression and pathway analysis, including exploration of gender-specific differences. A web-based gene browser was also developed. We integrated histopathological assessments, transcriptomic data and 5.67 million days of time-stamped longitudinal electronic health record data to define disease-stage-specific gene expression signatures, pathogenic hepatic cell subpopulations and master regulator networks associated with adverse outcomes in MASLD. We constructed a 15-gene transcriptional risk score to predict future hepatic decompensation events (area under the receiver operating characteristic curve 0.86, 0.81 and 0.83 for 1-, 3- and 5-year risk, respectively). Additionally, thyroid hormone receptor beta regulon activity was identified as a critical suppressor of disease progression. SteatoSITE supports rational biomarker and drug development and facilitates precision medicine approaches for patients with MASLD. SteatoSITE is an open resource that integrates histopathologic assessments, transcriptomic data and longitudinal electronic health records for a cohort of 940 patients with metabolic dysfunction-associated steatotic liver disease.
{"title":"An integrated gene-to-outcome multimodal database for metabolic dysfunction-associated steatotic liver disease","authors":"Timothy J. Kendall, Maria Jimenez-Ramos, Frances Turner, Prakash Ramachandran, Jessica Minnier, Michael D. McColgan, Masood Alam, Harriet Ellis, Donald R. Dunbar, Gabriele Kohnen, Prakash Konanahalli, Karin A. Oien, Lucia Bandiera, Filippo Menolascina, Anna Juncker-Jensen, Douglas Alexander, Charlie Mayor, Indra Neil Guha, Jonathan A. Fallowfield","doi":"10.1038/s41591-023-02602-2","DOIUrl":"10.1038/s41591-023-02602-2","url":null,"abstract":"Metabolic dysfunction-associated steatotic liver disease (MASLD) is the commonest cause of chronic liver disease worldwide and represents an unmet precision medicine challenge. We established a retrospective national cohort of 940 histologically defined patients (55.4% men, 44.6% women; median body mass index 31.3; 32% with type 2 diabetes) covering the complete MASLD severity spectrum, and created a secure, searchable, open resource (SteatoSITE). In 668 cases and 39 controls, we generated hepatic bulk RNA sequencing data and performed differential gene expression and pathway analysis, including exploration of gender-specific differences. A web-based gene browser was also developed. We integrated histopathological assessments, transcriptomic data and 5.67 million days of time-stamped longitudinal electronic health record data to define disease-stage-specific gene expression signatures, pathogenic hepatic cell subpopulations and master regulator networks associated with adverse outcomes in MASLD. We constructed a 15-gene transcriptional risk score to predict future hepatic decompensation events (area under the receiver operating characteristic curve 0.86, 0.81 and 0.83 for 1-, 3- and 5-year risk, respectively). Additionally, thyroid hormone receptor beta regulon activity was identified as a critical suppressor of disease progression. SteatoSITE supports rational biomarker and drug development and facilitates precision medicine approaches for patients with MASLD. SteatoSITE is an open resource that integrates histopathologic assessments, transcriptomic data and longitudinal electronic health records for a cohort of 940 patients with metabolic dysfunction-associated steatotic liver disease.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"29 11","pages":"2939-2953"},"PeriodicalIF":82.9,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10667096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71413175","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}
Pub Date : 2023-10-30DOI: 10.1038/d41591-023-00093-9
Karen O'Leary
{"title":"A little knowledge can be a dangerous thing.","authors":"Karen O'Leary","doi":"10.1038/d41591-023-00093-9","DOIUrl":"https://doi.org/10.1038/d41591-023-00093-9","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":82.9,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71413174","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 : 2023-10-30DOI: 10.1038/s41591-023-02660-6
Julie Stein Deutsch, Ashley Cimino-Mathews, Elizabeth Thompson, Mariano Provencio, Patrick M. Forde, Jonathan Spicer, Nicolas Girard, Daphne Wang, Robert A. Anders, Edward Gabrielson, Peter Illei, Jaroslaw Jedrych, Ludmila Danilova, Joel Sunshine, Keith M. Kerr, Mia Tran, Judith Bushong, Junliang Cai, Vipul Devas, Jaclyn Neely, David Balli, Tricia R. Cottrell, Alex S. Baras, Janis M. Taube
Neoadjuvant immunotherapy plus chemotherapy improves event-free survival (EFS) and pathologic complete response (0% residual viable tumor (RVT) in primary tumor (PT) and lymph nodes (LNs)), and is approved for treatment of resectable lung cancer. Pathologic response assessment after neoadjuvant therapy is the potential analog to radiographic response for advanced disease. However, %RVT thresholds beyond pathologic complete response and major pathologic response (≤10% RVT) have not been explored. Pathologic response was prospectively assessed in the randomized, phase 3 CheckMate 816 trial (NCT02998528), which evaluated neoadjuvant nivolumab (anti-programmed death protein 1) plus chemotherapy in patients with resectable lung cancer. RVT, regression and necrosis were quantified (0–100%) in PT and LNs using a pan-tumor scoring system and tested for association with EFS in a prespecified exploratory analysis. Regardless of LN involvement, EFS improved with 0% versus >0% RVT-PT (hazard ratio = 0.18). RVT-PT predicted EFS for nivolumab plus chemotherapy (area under the curve = 0.74); 2-year EFS rates were 90%, 60%, 57% and 39% for patients with 0–5%, >5–30%, >30–80% and >80% RVT, respectively. Each 1% RVT associated with a 0.017 hazard ratio increase for EFS. Combining pathologic response from PT and LNs helped differentiate outcomes. When compared with radiographic response and circulating tumor DNA clearance, %RVT best approximated EFS. These findings support pathologic response as an emerging survival surrogate. Further assessment of the full spectrum of %RVT in lung cancer and other tumor types is warranted. ClinicalTrials.gov registration: NCT02998528 . Analysis of the phase 3 CheckMate 816 trial shows that the depth of pathologic response as assessed by percent residual viable tumor is correlated with event-free survival following neoadjuvant immunotherapy plus chemotherapy, supporting pathologic response as a biomarker of survival.
{"title":"Association between pathologic response and survival after neoadjuvant therapy in lung cancer","authors":"Julie Stein Deutsch, Ashley Cimino-Mathews, Elizabeth Thompson, Mariano Provencio, Patrick M. Forde, Jonathan Spicer, Nicolas Girard, Daphne Wang, Robert A. Anders, Edward Gabrielson, Peter Illei, Jaroslaw Jedrych, Ludmila Danilova, Joel Sunshine, Keith M. Kerr, Mia Tran, Judith Bushong, Junliang Cai, Vipul Devas, Jaclyn Neely, David Balli, Tricia R. Cottrell, Alex S. Baras, Janis M. Taube","doi":"10.1038/s41591-023-02660-6","DOIUrl":"10.1038/s41591-023-02660-6","url":null,"abstract":"Neoadjuvant immunotherapy plus chemotherapy improves event-free survival (EFS) and pathologic complete response (0% residual viable tumor (RVT) in primary tumor (PT) and lymph nodes (LNs)), and is approved for treatment of resectable lung cancer. Pathologic response assessment after neoadjuvant therapy is the potential analog to radiographic response for advanced disease. However, %RVT thresholds beyond pathologic complete response and major pathologic response (≤10% RVT) have not been explored. Pathologic response was prospectively assessed in the randomized, phase 3 CheckMate 816 trial (NCT02998528), which evaluated neoadjuvant nivolumab (anti-programmed death protein 1) plus chemotherapy in patients with resectable lung cancer. RVT, regression and necrosis were quantified (0–100%) in PT and LNs using a pan-tumor scoring system and tested for association with EFS in a prespecified exploratory analysis. Regardless of LN involvement, EFS improved with 0% versus >0% RVT-PT (hazard ratio = 0.18). RVT-PT predicted EFS for nivolumab plus chemotherapy (area under the curve = 0.74); 2-year EFS rates were 90%, 60%, 57% and 39% for patients with 0–5%, >5–30%, >30–80% and >80% RVT, respectively. Each 1% RVT associated with a 0.017 hazard ratio increase for EFS. Combining pathologic response from PT and LNs helped differentiate outcomes. When compared with radiographic response and circulating tumor DNA clearance, %RVT best approximated EFS. These findings support pathologic response as an emerging survival surrogate. Further assessment of the full spectrum of %RVT in lung cancer and other tumor types is warranted. ClinicalTrials.gov registration: NCT02998528 . Analysis of the phase 3 CheckMate 816 trial shows that the depth of pathologic response as assessed by percent residual viable tumor is correlated with event-free survival following neoadjuvant immunotherapy plus chemotherapy, supporting pathologic response as a biomarker of survival.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"30 1","pages":"218-228"},"PeriodicalIF":82.9,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10803255/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71413176","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}
Pub Date : 2023-10-26DOI: 10.1038/s41591-023-02591-2
Charlotte Fenioux, Baptiste Abbar, Samia Boussouar, Marie Bretagne, John R. Power, Javid J. Moslehi, Paul Gougis, Damien Amelin, Agnès Dechartres, Lorenz H. Lehmann, Pierre-Yves Courand, Jennifer Cautela, Joachim Alexandre, Adrien Procureur, Antoine Rozes, Sarah Leonard-Louis, Juan Qin, International ICI-Myocarditis Registry, Rémi Cheynier, Benedicte Charmeteau-De Muylder, Alban Redheuil, Florence Tubach, Jacques Cadranel, Audrey Milon, Stéphane Ederhy, Thomas Similowski, Douglas B. Johnson, Ian Pizzo, Toniemarie Catalan, Olivier Benveniste, Salim S. Hayek, Yves Allenbach, Michelle Rosenzwajg, Charles Dolladille, Joe-Elie Salem
Immune checkpoint inhibitors (ICI) have transformed the therapeutic landscape in oncology. However, ICI can induce uncommon life-threatening autoimmune T-cell-mediated myotoxicities, including myocarditis and myositis. The thymus plays a critical role in T cell maturation. Here we demonstrate that thymic alterations are associated with increased incidence and severity of ICI myotoxicities. First, using the international pharmacovigilance database VigiBase, the Assistance Publique Hôpitaux de Paris–Sorbonne University data warehouse (Paris, France) and a meta-analysis of clinical trials, we show that ICI treatment of thymic epithelial tumors (TET, and particularly thymoma) was more frequently associated with ICI myotoxicities than other ICI-treated cancers. Second, in an international ICI myocarditis registry, we established that myocarditis occurred earlier after ICI initiation in patients with TET (including active or prior history of TET) compared to other cancers and was more severe in terms of life-threatening arrythmias and concurrent myositis, leading to respiratory muscle failure and death. Lastly, we show that presence of anti-acetylcholine-receptor antibodies (a biological proxy of thymic-associated autoimmunity) was more prevalent in patients with ICI myocarditis than in ICI-treated control patients. Altogether, our results highlight that thymic alterations are associated with incidence and seriousness of ICI myotoxicities. Clinico-radio-biological workup evaluating the thymus may help in predicting ICI myotoxicities. Thymic epithelial tumors are associated with increased risk of immune checkpoint inhibitor (ICI)-induced myotoxicities, and the presence of anti-acetylcholine-receptor antibodies has the potential to serve as a biomarker for ICI-induced myocarditis in patients with cancer.
{"title":"Thymus alterations and susceptibility to immune checkpoint inhibitor myocarditis","authors":"Charlotte Fenioux, Baptiste Abbar, Samia Boussouar, Marie Bretagne, John R. Power, Javid J. Moslehi, Paul Gougis, Damien Amelin, Agnès Dechartres, Lorenz H. Lehmann, Pierre-Yves Courand, Jennifer Cautela, Joachim Alexandre, Adrien Procureur, Antoine Rozes, Sarah Leonard-Louis, Juan Qin, International ICI-Myocarditis Registry, Rémi Cheynier, Benedicte Charmeteau-De Muylder, Alban Redheuil, Florence Tubach, Jacques Cadranel, Audrey Milon, Stéphane Ederhy, Thomas Similowski, Douglas B. Johnson, Ian Pizzo, Toniemarie Catalan, Olivier Benveniste, Salim S. Hayek, Yves Allenbach, Michelle Rosenzwajg, Charles Dolladille, Joe-Elie Salem","doi":"10.1038/s41591-023-02591-2","DOIUrl":"10.1038/s41591-023-02591-2","url":null,"abstract":"Immune checkpoint inhibitors (ICI) have transformed the therapeutic landscape in oncology. However, ICI can induce uncommon life-threatening autoimmune T-cell-mediated myotoxicities, including myocarditis and myositis. The thymus plays a critical role in T cell maturation. Here we demonstrate that thymic alterations are associated with increased incidence and severity of ICI myotoxicities. First, using the international pharmacovigilance database VigiBase, the Assistance Publique Hôpitaux de Paris–Sorbonne University data warehouse (Paris, France) and a meta-analysis of clinical trials, we show that ICI treatment of thymic epithelial tumors (TET, and particularly thymoma) was more frequently associated with ICI myotoxicities than other ICI-treated cancers. Second, in an international ICI myocarditis registry, we established that myocarditis occurred earlier after ICI initiation in patients with TET (including active or prior history of TET) compared to other cancers and was more severe in terms of life-threatening arrythmias and concurrent myositis, leading to respiratory muscle failure and death. Lastly, we show that presence of anti-acetylcholine-receptor antibodies (a biological proxy of thymic-associated autoimmunity) was more prevalent in patients with ICI myocarditis than in ICI-treated control patients. Altogether, our results highlight that thymic alterations are associated with incidence and seriousness of ICI myotoxicities. Clinico-radio-biological workup evaluating the thymus may help in predicting ICI myotoxicities. Thymic epithelial tumors are associated with increased risk of immune checkpoint inhibitor (ICI)-induced myotoxicities, and the presence of anti-acetylcholine-receptor antibodies has the potential to serve as a biomarker for ICI-induced myocarditis in patients with cancer.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"29 12","pages":"3100-3110"},"PeriodicalIF":82.9,"publicationDate":"2023-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54230245","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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