tbuckley/cabot-search huggingface dataset:
Maternal consumption of a fermented diet protects offspring against intestinal inflammation by regulating the gut microbiota
Authors: Cheng Wang, Siyu Wei, Bojing Liu, Fengqin Wang, Zeqing Lu, Mingliang Jin, Yizhen Wang
Journal: Gut Microbes (2022)

The neonatal intestinal tract is immature and can be easily infected by pathogens causing inflammation. Maternal diet manipulation is a promising nutritional strategy to enhance the gut health of offspring. A fermented diet is a gut microbiota targeting diet containing live probiotics and their metabolites, which benefit the gut and overall health host. However, it remains unclear how a maternal fermented diet (MFD) affects neonatal intestinal inflammation. Here, in vivo and in vitro models together with multi-omics analysis were applied to investigate the impacts and the underlying mechanism through which an MFD prevents from gut inflammation in neonates. An MFD remarkably improved the performance of both sows and piglets and significantly altered the gut microbiome and milk metabolome of sows. In addition, the MFD significantly accelerated the maturation of the gut microbiota of neonates and increased the abundance of gut Lactobacillus and the microbial functions of amino acid-related enzymes and glucose metabolism on the weaning day. Notably, the MFD reduced susceptibility to colonic inflammation in offspring. The fecal microbiota of sows was then transplanted into mouse dams and it was found that the mouse dams and pups in the MFD group alleviated the LPS-induced decrease in gut Lactobacillus abundance and barrier injury. Milk L-glutamine (GLN) and gut Lactobacillus reuteri (LR) were found as two of the main MFD-induced sow effectors that contributed to the gut health of piglets. The properties of LR and GLN in modulating gut microbiota and alleviating colonic inflammation by inhibiting the phosphorylation of p38 and JNK activation of Caspase 3 were further verified. These findings provide the first data revealing that an MFD drives neonate gut microbiota development and ameliorates the colonic inflammation by regulating the gut microbiota. This fundamental evidence might provide references for modulating maternal nutrition to enhance early-life gut health and prevent gut inflammation.
A village doctor-led multifaceted intervention for blood pressure control in rural China: an open, cluster randomised trial
Authors: Yingxian Sun, Jianjun Mu, Dao Wen Wang, Nanxiang Ouyang, Liying Xing, Xiaofan Guo, Chunxia Zhao, Guocheng Ren, Ning Ye, Ying Zhou, Jun Wang, Zhao Li, Guozhe Sun, Ruihai Yang, Chung-Shiuan Chen, Jiang He, Chang Wang, Lixia Qiao, Chuning Shi, Xingang Zhang, Songyue Liu, Zihan Chen, Wei Miao, Pengyu Zhang, Zihao Fan, Nan Ye, Linlin Zhang, Danxi Geng, Shu Zhang, Qiyu Li, Qiying Qin, Canru Liu, Xiaoyu Zheng, Tao Wang, Li Jing, Boqiang Zhang, Qun Sun, Yu Yan, Yueyuan Liao, Qiong Ma, Chao Chu, Yue Sun, Dan Wang, Ling Zhou, Heng Ye, Haoran Wei, Hao Liu, Zhaoqing Sun, Liqiang Zheng, Yanli Chen, Ye Chang, Mohan Jiang, Hongmei Yang, Shasha Yu, Wenna Li, Ning Wang, Chunwei Wu, Lufan Sun, Zhi Du, Yan Li, Nan Gao, Xinchi Liu, Ying Wang, Mingang Huang, Yufang Zhou, Lingrui Meng, Jiawen Zhang, Zhen Huang, Huihui Chen, Yuxian Huang, Lingmin Sun, Xin Zhong, Hanmin Wang, Xinyan Hou, Huan Han, Baohui Jin, Hua He
Journal: The Lancet (2022)
Adapted to Survive: Targeting Cancer Cells with BH3 Mimetics
Authors: Joan Montero, Rizwan Haq
Journal: Cancer Discovery (2022)

Abstract A hallmark of cancer is cell death evasion, underlying suboptimal responses to chemotherapy, targeted agents, and immunotherapies. The approval of the antiapoptotic BCL2 antagonist venetoclax has finally validated the potential of targeting apoptotic pathways in patients with cancer. Nevertheless, pharmacologic modulators of cell death have shown markedly varied responses in preclinical and clinical studies. Here, we review emerging concepts in the use of this class of therapies. Building on these observations, we propose that treatment-induced changes in apoptotic dependency, rather than pretreatment dependencies, will need to be recognized and targeted to realize the precise deployment of these new pharmacologic agents. Significance: Targeting antiapoptotic family members has proven efficacious and tolerable in some cancers, but responses are infrequent, particularly for patients with solid tumors. Biomarkers to aid patient selection have been lacking. Precision functional approaches that overcome adaptive resistance to these compounds could drive durable responses to chemotherapy, targeted therapy, and immunotherapies.
PET2 response associated with survival in newly diagnosed diffuse large B-cell lymphoma: results of two independent prospective cohorts
Authors: Sanjal H. Desai, Levi Pederson, Betsy LaPlant, Raphael Mwangi, Matthew Maurer, Jason R. Young, William R. Macon, Rebecca L. King, Yucai Wang, James R. Cerhan, Andrew Feldman, David J. Inwards, Ivana Micallef, Patrick Johnston, Luis F. Porrata, Stephen M. Ansell, Thomas M. Habermann, Thomas E. Witzig, Grzegorz S. Nowakowski
Journal: Blood Cancer Journal (2022)

Abstract Studies evaluating Positron Emission Tomography scan after 2 cycles of chemotherapy (PET2) in newly diagnosed diffuse large B cell lymphoma (DLBCL) are heterogeneous in patient characteristics, treatments and have conflicting results. Here we report association of PET2 with outcomes in two large independent prospective cohorts of newly diagnosed DLBCL pts treated with two RCHOP-based regimens. The discovery cohort consisted of pts enrolled in single arm phase 2 MC078E study of lenalidomide with RCHOP (R2CHOP). The validation cohort consisted of RCHOP-treated pts from the Molecular Epidemiology Resource (MER) cohort. Pts who received 3-6 cycles of therapy and had PET2 were included in the study. Patients who progressed on PET2 were excluded. Revised response criteria 2007 were used to define PET2 response PET2 positive (PET2 + ) pts had inferior EFS [24-month EFS 45.5% vs 87.9%, HR 4.0, CI 95 (2.1–7.9), p &lt; 0.0001) with a trend towards lower OS [24-months OS 77% vs 94.8%, HR 2.0, CI 95 (0.9–4.8), P = 0.1] than PET2 negative (PET2−) pts in MC078E cohort. PET2 + pts had an inferior EFS (24 month EFS 48.7% vs 81.6%, HR 2.9, CI 95 2.0–4.2, p &lt; 0.0001) and OS (24-month OS 68.6% vs 88.1%, HR 2.3, CI 95 : 1.5–3.5, p &lt; 0.0001) in the MER cohort. These results were consistent regardless of age, sex and in the subgroup of advanced stage and high-risk international prognostic index (IPI). For MER, PET2 + pts also had higher odds of positive end of treatment PET (OR: 17.3 (CI 95 7.9–37.7), p &lt; 0.001). PET2 is an early predictor DLBCL pts at high risk of progression and death in two independent prospective cohorts. PET2-guided risk-adapted strategies may improve outcomes, and should be explored in clinical trials.
Treatment of Out-of-Hospital Cardiac Arrest
Authors: Jean Baptiste Lascarrou, Graham Nichol
Journal: JAMA Cardiology (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Cardiology journal
Predictors of primary prevention implantable cardioverter‐defibrillator use in heart failure with reduced ejection fraction: impact of the predicted risk of sudden cardiac death and all‐cause mortality
Authors: Benedikt Schrage, Lars H. Lund, Lina Benson, Ulf Dahlström, Ramin Shadman, Cecilia Linde, Frieder Braunschweig, Wayne C. Levy, Gianluigi Savarese
Journal: European Journal of Heart Failure (2022)

Use of implantable cardioverter-defibrillators (ICD) for primary prevention of sudden cardiac death (SCD) in heart failure with reduced ejection fraction (HFrEF) is limited. We aimed to investigate barriers to ICD use in HFrEF while considering the predicted risk of mortality and SCD.Patients from the SwedeHF registered in 2011-2018 and with an indication for primary prevention ICD were analysed. The Seattle Proportional Risk and Seattle Heart Failure Models were used to predict the proportional SCD and all-cause mortality risk, respectively. A multivariable logistic regression model was fitted to identify independent predictors of ICD use/non-use; Cox regression models to evaluate the interaction between predicted SCD/mortality risk and ICD use for mortality. Of 13 475 patients, only 15.5% had an ICD. Those with higher predicted proportional SCD risk (>45%) had an ∼80% higher likelihood to have an ICD. Other predictors of non-use were follow-up in primary versus specialty care, higher comorbidity burden and lower socioeconomic status. ICD use was associated with lower mortality only in patients with higher predicted SCD and lower mortality risk (34% and 37% relative risk reduction for 3-year all-cause and cardiovascular mortality, respectively). In this subgroup of patients, underuse of ICD was 81.8%.In a contemporary registry, only 15.5% of patients with an indication for primary prevention ICD received the device. While a high predicted proportional SCD risk was appropriately linked to ICD use, the lack of specialized follow-up, higher comorbidity burden, and lower socioeconomic status were major unjustified impediments to implementation. Our findings suggest areas for improving ICD use for primary prevention of SCD in clinical practice.
Volume-Outcome Associations for Parathyroid Surgery in England
Authors: William K. Gray, Annakan V. Navaratnam, Jamie Day, John A. H. Wass, Tim W. R. Briggs, Mark Lansdown
Journal: JAMA Surgery (2022)

Previous studies have suggested an association between surgical volume and patient outcomes for parathyroid surgery. However, most previous studies are relatively small and the literature is dominated by studies form the US, which might not be readily generalizable to other settings.To investigate volume-outcome associations for parathyroid surgery in England.Cohort study that included all National Health Service hospital trusts in England with secondary analysis of administrative data using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10). Participants included all adult, elective hospital admissions for parathyroid surgery without a diagnosis of multiple endocrine neoplasia, parathyroid cancer, or kidney disease over a 5-year period (April 2014-March 2019 inclusive).The number of procedures conducted in the year prior to the index procedure by each surgeon and each hospital trust.Repeat parathyroid surgery within 1 year of the index procedure.This study included data for 17 494 participants who underwent parathyroidectomies conducted across 125 hospital trusts. The median (IQR) age of patients was 62 (53-71) years, and 13 826 were female (79.0%). Across the period, the number of surgeons conducting parathyroid surgery changed little (280 in 2014-2015 and 2018-2019), although the number of procedures conducted rose from 3331 to 3848 per annum. Repeat parathyroid surgery at 1 year was significantly associated with surgeon volume (odds ratio [OR], 0.99; 95% CI, 0.98-0.99), but not trust volume, in the previous 12 months. Extended length of stay (OR, 0.98; 95% CI, 0.98-0.99), hypoparathyroidism/calcium disorder (OR, 1.0; 95% CI, 0.99-1.0), and postprocedural complications (OR, 0.99; 95% CI, 0.99-1.0) were also associated with lower surgeon volume.In this cohort study, higher surgeon annual volume was associated with decreased rates of repeat parathyroid surgery. A minimum volume threshold of 20 procedures per annum should improve patient outcomes, although possible negative effects on access to services should be monitored.
Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma
Authors: Hussein A. Tawbi, Dirk Schadendorf, Evan J. Lipson, Paolo A. Ascierto, Luis Matamala, Erika Castillo Gutiérrez, Piotr Rutkowski, Helen J. Gogas, Christopher D. Lao, Juliana Janoski De Menezes, Stéphane Dalle, Ana Arance, Jean-Jacques Grob, Shivani Srivastava, Mena Abaskharoun, Melissa Hamilton, Sarah Keidel, Katy L. Simonsen, Anne Marie Sobiesk, Bin Li, F. Stephen Hodi, Georgina V. Long
Journal: New England Journal of Medicine (2022)

Lymphocyte-activation gene 3 (LAG-3) and programmed death 1 (PD-1) are distinct inhibitory immune checkpoints that contribute to T-cell exhaustion. The combination of relatlimab, a LAG-3-blocking antibody, and nivolumab, a PD-1-blocking antibody, has been shown to be safe and to have antitumor activity in patients with previously treated melanoma, but the safety and activity in patients with previously untreated melanoma need investigation.In this phase 2-3, global, double-blind, randomized trial, we evaluated relatlimab and nivolumab as a fixed-dose combination as compared with nivolumab alone when administered intravenously every 4 weeks to patients with previously untreated metastatic or unresectable melanoma. The primary end point was progression-free survival as assessed by blinded independent central review.The median progression-free survival was 10.1 months (95% confidence interval [CI], 6.4 to 15.7) with relatlimab-nivolumab as compared with 4.6 months (95% CI, 3.4 to 5.6) with nivolumab (hazard ratio for progression or death, 0.75 [95% CI, 0.62 to 0.92]; P = 0.006 by the log-rank test). Progression-free survival at 12 months was 47.7% (95% CI, 41.8 to 53.2) with relatlimab-nivolumab as compared with 36.0% (95% CI, 30.5 to 41.6) with nivolumab. Progression-free survival across key subgroups favored relatlimab-nivolumab over nivolumab. Grade 3 or 4 treatment-related adverse events occurred in 18.9% of patients in the relatlimab-nivolumab group and in 9.7% of patients in the nivolumab group.The inhibition of two immune checkpoints, LAG-3 and PD-1, provided a greater benefit with regard to progression-free survival than inhibition of PD-1 alone in patients with previously untreated metastatic or unresectable melanoma. Relatlimab and nivolumab in combination showed no new safety signals. (Funded by Bristol Myers Squibb; RELATIVITY-047 ClinicalTrials.gov number, NCT03470922.).
Single-Cell Analysis Unveils the Role of the Tumor Immune Microenvironment and Notch Signaling in Dormant Minimal Residual Disease
Authors: Mahnaz Janghorban, Yuchen Yang, Na Zhao, Clark Hamor, Tuan M. Nguyen, Xiang H.-F. Zhang, Jeffrey M. Rosen
Journal: Cancer Research (2021)

Tumor dormancy is a stage in which residual cancer cells remain inactive, but regrowth of dormant cancer cells contributes to recurrence. The complex ecosystem in cancer that promotes cell survival and the factors that eventually overcome growth constraints and result in proliferation remain to be fully elucidated. Doing so may provide new insights and help identify novel strategies to prolong cancer dormancy and prevent disease recurrence. To dissect the molecular pathways and the microenvironments involved in regulation of dormancy, we utilized a novel immunocompetent transgenic model to study minimal residual disease and relapse. This model revealed a significant reorganization of cancer cell structures, stroma, and immune cells, with cancer cells showing dormant cell signatures. Single-cell RNA sequencing uncovered remodeling of myeloid and lymphoid compartments. In addition, the Jagged-1/Notch signaling pathway was shown to regulate many aspects of tumorigenesis, including stem cell development, epithelial-to-mesenchymal transition, and immune cell homeostasis during minimal residual disease. Treatment with an anti-Jagged-1 antibody inhibited the Jagged-1/Notch signaling pathway in tumor cells and the microenvironment, delaying tumor recurrence. These findings uncover a cascade of regulatory changes in the microenvironment during dormancy and identify a therapeutic strategy to undercut these changes.
Computational and Functional Analyses of HER2 Mutations Reveal Allosteric Activation Mechanisms and Altered Pharmacologic Effects
Authors: Noboru Ishiyama, Matthew O'Connor, Andrei Salomatov, Darlene Romashko, Shalabh Thakur, Ahmet Mentes, Julia F. Hopkins, Garrett M. Frampton, Lee A. Albacker, Anna Kohlmann, Christopher Roberts, Elizabeth Buck
Journal: Cancer Research (2022)

Abstract Amplification of HER2 can drive the proliferation of cancer cells, and several inhibitors of HER2 have been successfully developed. Recent advances in next-generation sequencing now reveal that HER2 is subject to mutation, with over 2,000 unique variants observed in human cancers. Several examples of oncogenic HER2 mutations have been described, and these primarily occur at allosteric sites outside the ATP-binding site. To identify the full spectrum of oncogenic HER2 driver mutations aside from a few well-studied mutations, we developed mutation-allostery-pharmacology (MAP), an in silico prediction algorithm based on machine learning. By applying this computational approach to 820 single-nucleotide variants, a list of 222 known and potential driver mutations was produced. Of these 222 mutations, 111 were screened by Ba/F3-retrovirus proliferation assays; 37 HER2 mutations were experimentally determined to be driver mutations, comprising 15 previously characterized and 22 newly identified oncogenic mutations. These oncogenic mutations mostly affected allosteric sites in the extracellular domain (ECD), transmembrane domain, and kinase domain of HER2, with only a single mutation in the HER2 orthosteric ATP site. Covalent homodimerization was established as a common mechanism of activation among HER2 ECD allosteric mutations, including the most prevalent HER2 mutation, S310F. Furthermore, HER2 allosteric mutants with enhanced covalent homodimerization were characterized by altered pharmacology that reduces the activity of existing anti-HER2 agents, including the mAb trastuzumab and the tyrosine kinase inhibitor lapatinib. Overall, the MAP-scoring and functional validation analyses provided new insights into the oncogenic activity and therapeutic targeting of HER2 mutations in cancer. Significance: This study identified new oncogenic HER2 allosteric mutations, including ECD mutations that share covalent dimerization as a mechanism of oncogenicity, suggesting the need for novel inhibitors to treat HER2-mutant cancers.
Evaluation of Trends in Alcohol Use Disorder–Related Mortality in the US Before and During the COVID-19 Pandemic
Authors: Yee Hui Yeo, Xinyuan He, Peng-Sheng Ting, Jian Zu, Christopher V. Almario, Brennan M. R. Spiegel, Fanpu Ji
Journal: JAMA Network Open (2022)

attributable to indirect effects of the pandemic such as stay-at-home policies and reduced medical and social resources for patients with AUD.Our study is limited by potential misclassification bias in death certificate data.However, AUD is typically underrecognized, and we would expect such factors to result in lower observed death rates.Our findings suggest that the pandemic may have had a disproportionate association with AUD-related deaths and subgroups with high vulnerability and that tailored strategies are needed for AUD prevention and intervention to combat this public health crisis.
Comparative Genetic Analysis of Psoriatic Arthritis and Psoriasis for the Discovery of Genetic Risk Factors and Risk Prediction Modeling
Authors: Mehreen Soomro, Michael Stadler, Nick Dand, James Bluett, Deepak Jadon, Farideh Jalali‐najafabadi, Michael Duckworth, Pauline Ho, Helena Marzo‐Ortega, Philip S. Helliwell, Anthony W. Ryan, David Kane, Eleanor Korendowych, Michael A. Simpson, Jonathan Packham, Ross McManus, Cem Gabay, Céline Lamacchia, Michael J. Nissen, Matthew A. Brown, Suzanne M. M. Verstappen, Tjeerd Van Staa, Jonathan N. Barker, Catherine H. Smith, Oliver FitzGerald, Neil McHugh, Richard B. Warren, John Bowes, Anne Barton
Journal: Arthritis & Rheumatology (2022)

Psoriatic arthritis (PsA) has a strong genetic component, and the identification of genetic risk factors could help identify the ~30% of psoriasis patients at high risk of developing PsA. Our objectives were to identify genetic risk factors and pathways that differentiate PsA from cutaneous-only psoriasis (PsC) and to evaluate the performance of PsA risk prediction models.Genome-wide meta-analyses were conducted separately for 5,065 patients with PsA and 21,286 healthy controls and separately for 4,340 patients with PsA and 6,431 patients with PsC. The heritability of PsA was calculated as a single-nucleotide polymorphism (SNP)-based heritability estimate (h2SNP ) and biologic pathways that differentiate PsA from PsC were identified using Priority Index software. The generalizability of previously published PsA risk prediction pipelines was explored, and a risk prediction model was developed with external validation.We identified a novel genome-wide significant susceptibility locus for the development of PsA on chromosome 22q11 (rs5754467; P = 1.61 × 10-9 ), and key pathways that differentiate PsA from PsC, including NF-κB signaling (adjusted P = 1.4 × 10-45 ) and Wnt signaling (adjusted P = 9.5 × 10-58 ). The heritability of PsA in this cohort was found to be moderate (h2SNP = 0.63), which was similar to the heritability of PsC (h2SNP = 0.61). We observed modest performance of published classification pipelines (maximum area under the curve 0.61), with similar performance of a risk model derived using the current data.Key biologic pathways associated with the development of PsA were identified, but the investigation of risk classification revealed modest utility in the available data sets, possibly because many of the PsC patients included in the present study were receiving treatments that are also effective in PsA. Future predictive models of PsA should be tested in PsC patients recruited from primary care.
Associating Violence With Schizophrenia—Risks and Biases—Reply
Authors: Daniel Whiting, John R. Geddes, Seena Fazel
Journal: JAMA Psychiatry (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Psychiatry HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Psychiatry journal