tbuckley/cabot-search huggingface dataset:
Discovery of BBO-8520, a first-in-class direct and covalent dual inhibitor of GTP-bound (ON) and GDP-bound (OFF) KRASG12C
Authors: Anna E. Maciag, James P. Stice, Bin Wang, Alok K. Sharma, Albert H. Chan, Ken Lin, Devansh Singh, Marcin Dyba, Yue Yang, Saman Setoodeh, Brian P. Smith, Jin Hyun Ju, Stevan Jeknic, Dana Rabara, Zuhui Zhang, Erik K. Larsen, Dominic Esposito, John-Paul Denson, Michela Ranieri, Mary Meynardie, Sadaf Mehdizadeh, Patrick A. Alexander, Maria Abreu Blanco, David M. Turner, Rui Xu, Felice C. Lightstone, Kwok-Kin Wong, Andrew G. Stephen, Keshi Wang, Dhirendra K. Simanshu, Kerstin W. Sinkevicius, Dwight V. Nissley, Eli Wallace, Frank McCormick, Pedro J. Beltran
Journal: Cancer Discovery (2024)

Approved inhibitors of KRASG12C prevent oncogenic activation by sequestering the inactive, GDP-bound (OFF) form rather than directly binding and inhibiting the active, GTP-bound (ON) form. This approach provides no direct target coverage of the active protein. Expectedly, adaptive resistance to KRASG12C (OFF)-only inhibitors is observed in association with increased expression and activity of KRASG12C(ON). To provide optimal KRASG12C target coverage, we have developed BBO-8520, a first-in-class, direct dual inhibitor of KRASG12C(ON) and (OFF) forms. BBO-8520 binds in the Switch-II/Helix3 pocket, covalently modifies the target cysteine, and disables effector binding to KRASG12C(ON). BBO-8520 exhibits potent signaling inhibition in growth factor-activated states, in which current (OFF)-only inhibitors demonstrate little measurable activity. In vivo, BBO-8520 demonstrates rapid target engagement and inhibition of signaling, resulting in durable tumor regression in multiple models, including those resistant to KRASG12C(OFF)-only inhibitors. BBO-8520 is in phase 1 clinical trials in patients with KRASG12C non-small cell lung cancer. Significance: BBO-8520 is a first-in-class direct, small molecule covalent dual inhibitor that engages KRASG12C in the active (ON) and inactive (OFF) conformations. BBO-8520 represents a novel mechanism of action that allows for optimal target coverage and delays the emergence of adaptive resistance seen with (OFF)-only inhibitors in the clinic. See related commentary by Zhou and Westover, p. 455.
Association of Tailpipe-Related and Nontailpipe–Related Air Pollution Exposure with Cognitive Decline in the Chicago Health and Aging Project
Authors: Ryan M. Andrews, Sara D. Adar, Adam A. Szpiro, Joel D. Kaufman, Cami N. Christopher, Todd L. Beck, Klodian Dhana, Robert S. Wilson, Kumar B. Rajan, Denis Evans, Jennifer Weuve
Journal: Environmental Health Perspectives (2024)

Evidence suggests that long-term exposure to air pollution may increase the risk of dementia and related cognitive outcomes. A major source of air pollution is automotive traffic, which is modifiable by technological and regulatory interventions.
Dynamics of Histoplasma fungal load in people living with HIV with disseminated histoplasmosis under treatment with liposomal amphotericin B
Authors: Aude Sturny-Leclère, Elodie Da Silva, Cassia S M Godoy, Renata B A Soares, Terezinha do Menino Jesus Silva Leitão, Lisandra Serra Damasceno, Monica B Bay, Marineide Melo, Daiane Dalla Lana, Larissa R Silva, Dennis Israelski, Diego R Falci, Alessandro C Pasqualotto, Alexandre Alanio
Journal: Clinical Microbiology and Infection (2024)
Tailoring Osteoimmunity and Hemostasis Using 3D-Printed Nano-Photocatalytic Bactericidal Scaffold for Augmented Bone Regeneration
Authors: Sayan Deb Dutta, Jin Hexiu, Md Moniruzzaman, Tejal V Patil, Rumi Acharya, Jong Sung Kim, Ki-Taek Lim
Journal: Biomaterials (2024)
Prevalence of Life Stressors and Posttraumatic Stress Disorder Among Women in Iceland
Authors: Edda Bjork Thordardottir, Huan Song, Qing Shen, Andri Bjornsson, Hildur Yr Hilmarsdottir, Berglind Guðmundsdottir, Engilbert Sigurdsson, Gunnar Tómasson, Harpa Rúnarsdóttir, Donghao Lu, Filip K. Arnberg, Jóhanna Jakobsdóttir, Fang Fang, Thor Aspelund, Arna Hauksdóttir, Unnur Anna Valdimarsdóttir
Journal: JAMA Network Open (2024)

Importance Comprehensive data on the prevalence of various life stressors and their role in posttraumatic stress disorder (PTSD) among women are lacking. Objective To determine the prevalence of a broad range of life stressors and their association with PTSD in a large nationally representative cohort of women. Design, Setting, and Participants This cross-sectional analysis used data from the population-based Stress-And-Gene-Analysis, which invited women in Iceland to complete an online survey from March 1, 2018, to July 1, 2019. Participants were a nationally representative sample of women 18 to 69 years of age. This analysis was conducted from January 21, 2022, to September 13, 2024. Exposures History of 23 life stressors assessed with the Life Events Checklist for the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) ( DSM-5) and additional survey questions. Main Outcomes and Measures The main outcome was probable PTSD during the past month assessed for the worst life stressor experienced as evaluated with the PTSD Checklist for DSM-5 . Modified Poisson log-linear models were used to assess prevalence ratios (PRs) of PTSD by type of life stressor, adjusting for multiple covariates, including number of life stressors and time since the worst life stressor. Results Overall, 28 199 women participated in the study (mean [SD] age, 43.8 [13.7] years). The prevalence of life stressors varied substantially, ranging from 3.3% for war or armed conflict–related events to 66.4% for unwanted sexual experiences. The overall prevalence of probable PTSD was 15.9% and varied substantially across life stressor types. The highest prevalence of probable PTSD was for sexual assault (1427 of 3872 [36.9%]) and lowest for natural disasters (15 of 456 [3.3%]). Interpersonal trauma, specifically sexual assault (adjusted PR [APR], 6.66 [95% CI, 4.01-11.04]), other unwanted sexual experience (APR, 4.33 [95% CI, 2.53-7.42]), and physical assault (APR, 4.44 [95% CI, 2.63-7.49]) were associated with the highest prevalence increase of probable PTSD compared with natural disasters as the reference category. Conclusions and Relevance This cross-sectional study of 28 199 women in Iceland, which ranks highest globally in gender equality, found that sexual and physical assaults were among the most common life stressors reported and were associated with the highest prevalence of probable PTSD. The propensity of such trauma to result in PTSD calls for widespread societal efforts to prevent sexual and physical violence and reduce gender-based disparities in mental health.
Outpatient Oral Doxycycline Therapy for Ocular Syphilis
Authors: Yicheng K. Bao, Jodi Hwang, Christopher Long, Kusha Davar, Nahel Kapadia, Brad Spellberg, Brandon Wong, Narsing Rao, Brian C. Toy
Journal: JAMA Network Open (2024)

This cohort study compares the outcomes of oral doxycycline therapy with those of intravenous penicillin therapy among patients with ocular syphilis.
Cardiovascular Health Score and Atherosclerotic Cardiovascular Disease in the Million Veteran Program
Authors: Xuan-Mai T. Nguyen, Yanping Li, Yusi Gong, Serena Houghton, Yuk-Lam Ho, Mary Pyatt, Timothy Treu, Ruifeng Li, Kitan Akinosho, Sridharan Raghavan, David R. Gagnon, John Michael Gaziano, Peter W. F. Wilson, Kelly Cho
Journal: JAMA Network Open (2024)

Importance The American Heart Association proposed Life’s Essential 8 (LE8) as an enhanced measurement tool for cardiovascular health. Objective To examine the association of LE8 with risk of atherosclerotic cardiovascular disease (ASCVD) incidence and prognosis in veterans. Design, Setting, and Participants This was a prospective cohort study of US veterans enrolled in the Department of Veterans Affairs (VA) Million Veteran Program (MVP) between 2011 and 2022. Data were analyzed from 2023 to 2024. Exposure LE8 score ranged from 0 to 100, with higher score indicating better cardiovascular health. Main Outcomes and Measures The primary outcome was total ASCVD incidence in veterans without baseline ASCVD, and the secondary outcome was incidence of a major adverse cardiovascular event (MACE) among veterans with and without ASCVD at baseline. Results A total of 413 052 veterans (mean [SD] age, 65.8 [12.1] years; 378 162 [91.6%] male) were included. Based on 1.7 million person-years of follow-up of 279 868 veterans without any ASCVD at baseline, 45 067 veterans had an ASCVD event during follow-up. Total LE8 score and each component LE8 factor score was associated with incident ASCVD in an inverse, linear, dose-response manner. For veterans without prior ASCVD, those with an LE8 score between 80 and 100 had lower risk of ASCVD compared with those with an LE8 score of 0 to 49 (adjusted hazard ratio [aHR], 0.36 [95% CI, 0.35-0.38]). Similarly, risk of MACE was significantly lower among veterans with an LE8 score of 80 to 100 regardless of baseline ASCVD status (with ASCVD: aHR, 0.52 [95% CI, 0.48-0.56]; without ASCVD: aHR, 0.14 [95% CI, 0.13-0.15]) compared with those with ASCVD and an LE8 score of 0 to 49. Conclusions and Relevance In this cohort study of US veterans, higher LE8 scores were associated with significantly lower ASCVD incidence risk and lower likelihood of developing adverse cardiovascular events regardless of ASCVD status at baseline. These results support the utility of LE8 for health promotion and ASCVD prevention.
Market of First Launch for High-Risk Therapeutic Medical Devices
Authors: Kushal T. Kadakia, Christina Lalani, Daniel B. Kramer, Hibiki Orui, Robert W. Yeh
Journal: JAMA Network Open (2024)

This cross-sectional study examines the marketing history of high-risk medical devices launched first in the international market or the US, including specialty, time from US Food and Drug Administration Review to launch, and recall history.
Cholesterol, Triglyceride, and Glucose Levels Across Birth Cohorts in the US
Authors: Xiaoning Huang, Lucia C. Petito, Nilay S. Shah, Donald M. Lloyd-Jones, Sadiya S. Khan, Natalie A. Cameron
Journal: JAMA Network Open (2024)

Importance Population mean levels of total cholesterol and fasting triglycerides have decreased substantially in the US in recent decades, but improvements in cardiometabolic health may have slowed among younger cohorts. Conversely, prevalence of diabetes (types 1 and 2) and obesity has increased, especially among adults younger than 65 years. It is unclear how trends in cholesterol, triglyceride, and glucose levels have changed across different birth cohorts and whether adverse trends in obesity are associated with these patterns. Objective To quantify national trends in total cholesterol, fasting triglyceride, and fasting glucose levels among cohorts born between 1920 and 1999 and examine the potential association of these patterns with body mass index (BMI). Design, Setting, and Participants This serial cross-sectional study used National Health and Nutrition Examination Survey (NHANES) data from the 1999-2000 to 2017-2020 cycles. Data were analyzed between November 1, 2023, and July 31, 2024. Participants included nonpregnant and noninstitutionalized US adults 18 years or older, born between 1920 and 1999, who had data collected from 1999 to 2020. Exposure Eight 10-year birth cohorts (from 1920 to 1999). Main Outcomes and Measures Total cholesterol, fasting triglyceride, and fasting glucose levels and BMI. Quantile regression models reported average marginal effects to quantify mean change in cardiometabolic outcome measures per decade of birth years. Parametric regression models estimated the association of birth cohort with outcomes, assessing BMI as the mediator. Results Of 52 006 participants weighted to represent 264 664 915 US adults, weighted median age was 46 (IQR, 33-60) years and 50.6% were women. For the 50th percentile of measures, mean difference per 1-decade younger birth cohort was −7.1 (95% CI, −8.2 to −6.1) mg/dL for total cholesterol level, −13.1 (95% CI, −15.1 to −11.1) mg/dL for fasting triglyceride level, and 2.7 (95% CI, 2.3-3.1) mg/dL for fasting glucose level. BMI appeared to attenuate the associations between birth cohort and lipid levels and enhanced the associations between birth cohort and fasting glucose levels. However, up to 80% of the associations between birth cohorts and cardiometabolic outcomes were not mediated through BMI. Conclusions and Relevance In this cross-sectional study of 52 006 participants representing 264 664 915 US adults, population-level improvements in total cholesterol and triglyceride levels decelerated and adverse trends in glucose levels accelerated in more recent birth cohorts, which was partially mediated by concurrent increases in BMI. Public health initiatives that target antecedent health behaviors are needed to improve cardiometabolic health across generations.
Metformin Treatment With or Without Mediterranean Diet for the Prevention of Age-Related Diseases in People With Metabolic Syndrome: The MeMeMe Randomized Trial
Authors: Patrizia Pasanisi, Andreina Oliverio, Ivan Baldassari, Eleonora Bruno, Elisabetta Venturelli, Manuela Bellegotti, Giuliana Gargano, Daniele Morelli, Antonio Bognanni, Marta Rigoni, Paola Muti, Franco Berrino
Journal: Diabetes Care (2024)

OBJECTIVE The Metformin and Dietary Restriction to Prevent Age-Related Morbid Events in People With Metabolic Syndrome (MeMeMe) trial tested whether 1,700 mg/day metformin (MET) with or without a Mediterranean diet (MedDiet) intervention could reduce the cumulative incidence of major noncommunicable diseases in people with metabolic syndrome. RESEARCH DESIGN AND METHODS A total of 1,442 participants were randomly assigned to one of four interventions: 1) MET (1,700 mg/day) plus MedDiet intervention (MET+MedDiet); 2) placebo plus MedDiet intervention; 3) MET (1,700 mg/day) alone; and 4) placebo alone. Participants were followed up for 3 years on average. The primary outcome was the cumulative incidence of major noncommunicable diseases (including type 2 diabetes, cardiovascular diseases, and cancer). Secondary outcomes were the incidence of type 2 diabetes and the changing prevalence of metabolic syndrome. RESULTS The crude incidence of the major noncommunicable diseases was 6.7 cases per 100 person-years in the MET+MedDiet group, 6.9 in the MET alone group, 13.3 in the placebo plus MedDiet group, and 11.3 in the placebo group. The differences were fully explained by the reduction of type 2 diabetes, which was 80% and 92% lower in the MET and MET+MedDiet groups, respectively, compared with placebo. CONCLUSIONS The use of 1,700 mg/day MET is effective to prevent diabetes in people selected on the basis of metabolic syndrome.
Outcome of Cerebral Vasculopathy and Cognitive Performances 10 Years Post-Enrollment in the Drepagreffe Trial Comparing Allogeneic Stem Cell Transplantation to Standard-Care in Children with Sickle Cell Anemia and History of Abnormal Cerebral Velocities
Authors: Françoise Bernaudin, Suzanne Verlhac, Elisabeth Ducros-Miralles, Cecile Arnaud, Isabelle Genty, Marie Petras, Catherine Paillard, Thuret Isabelle, Annie Kamdem, Corinne Pondarré, Giovanna Cannas, Christelle Chantalat-Auger, Gonzalo De Luna, Benoit Meunier, Nadia Firah, Sophie Pertuisel, Corinne Guitton, Laure Joseph, Florence Missud, Claire Pluchart, Monique Elmaleh, Benedicte Neven, Marie Angoso, Pierre Frange, Karima Yakouben, Bénédicte Bruno, Nathalie Dhédin, Jean-Hugues Dalle, Regis Peffault de Latour, Catherine Belozertseva, Camille Jung
Journal: Blood (2024)
Author Correction: Multivariate analysis of 1.5 million people identifies genetic associations with traits related to self-regulation and addiction
Authors: Richard Karlsson Linnér, Travis T. Mallard, Peter B. Barr, Sandra Sanchez-Roige, James W. Madole, Morgan N. Driver, Holly E. Poore, Ronald de Vlaming, Andrew D. Grotzinger, Jorim J. Tielbeek, Emma C. Johnson, Mengzhen Liu, Sara Brin Rosenthal, Trey Ideker, Hang Zhou, Rachel L. Kember, Joëlle A. Pasman, Karin J. H. Verweij, Dajiang J. Liu, Scott Vrieze, Bernice Porjesz, Victor Hesselbrock, Tatiana M. Foroud, Arpana Agrawal, Howard J. Edenberg, John I. Nurnberger Jr, Yunlong Liu, Samuel Kuperman, John Kramer, Jacquelyn L. Meyer, Chella Kamarajan, Ashwini K. Pandey, Laura Bierut, John Rice, Kathleen K. Bucholz, Marc A. Schuckit, Jay Tischfield, Andrew Brooks, Ronald P. Hart, Laura Almasy, Danielle M. Dick, Jessica E. Salvatore, Allison Goate, Manav Kapoor, Paul Slesinger, Denise M. Scott, Lance Bauer, Leah Wetherill, Xiaoling Xuei, Dongbing Lai, Sean J. O’Connor, Martin H. Plawecki, Spencer Lourens, Laura Acion, Grace Chan, David B. Chorlian, Jian Zhang, Sivan Kinreich, Gayathri Pandey, Michael J. Chao, Andrey P. Anokhin, Vivia V. McCutcheon, Scott Saccone, Fazil Aliev, Peter B. Barr, Hemin Chin, Abbas Parsian, Henry R. Kranzler, Joel Gelernter, Kathleen Mullan Harris, Elliot M. Tucker-Drob, Irwin D. Waldman, Abraham A. Palmer, K. Paige Harden, Philipp D. Koellinger, Danielle M. Dick
Journal: Nature Neuroscience (2024)
Identification of Hepatic-like Erythropoietin with Enhanced Activity As a New Cause of Hereditary and Acquired Erythrocytosis
Authors: Laurent Martin, Darko Maric, Salam Idriss, Marine Delamare, Amandine Le Roy, Nada Maaziz, Amandine Caillaud, Karim Si-Tayeb, Florence Robriquet, Marion Lenglet, Lucie Erceau, Christine Bellanné-Chantelot, Isabelle Plo, Bernard Aral, Céline Garrec, Fabrice Airaud, Clara Gianfermi, Vincent Antunes, Anna Keppner, Sarah Mathilda Vincent, Alexis Desfontaine, Nina Modé, Fabien Laporte, Anne Gaignerie, Caroline Chariau, Isabelle Leray, Coline Rogue, Laurent David, Richard Redon, Stephane Bezieau, Lamisse Mansour, Frederic Galacteros, Thibault Maillet, Marlène Pasquet, Pierre Cougoul, Anne-Marie Nloga, Claude Gardin, Corinne Guitton, Viviane Dubruille, Vannina Giacobbi-Milet, Thierry Leblanc, Zuhre Kaya, Denis Semama, Chloe James, Serge Carillo, Marlène Ochmann, Anders Waage, Erwan Mortier, Mike Maillasson, Agnès Quéméner, Holger Cario, Radek C. Skoda, Yaël Zermati, David Hoogewijs, Alexandre Marchand, Francois Girodon, Betty Gardie
Journal: Blood (2024)
Lack of Benefit of Autologous Hematopoietic Cell Transplantation (auto-HCT) in Mantle Cell Lymphoma (MCL) Patients (pts) in First Complete Remission (CR) with Undetectable Minimal Residual Disease (uMRD): Initial Report from the ECOG-ACRIN EA4151 Phase 3 Randomized Trial
Authors: Timothy S. Fenske, Xin Victoria Wang, Brian G. Till, Kristie A. Blum, Matthew Lunning, Hillard M. Lazarus, Paul A.S. Fishkin, Lale Kostakoglu Shields, David W. Scott, Ann S. LaCasce, Patrick B. Johnston, Amanda F. Cashen, Leslie L. Popplewell, Robert M. Dean, Nausheen Ahmed, Nirav N. Shah, Nina D. Wagner-Johnston, Boyu Hu, Bhagirathbhai R. Dholaria, Richard F. Little, Jonathan W. Friedberg, John P. Leonard, Brad S. Kahl
Journal: Blood (2024)
Tafasitamab Plus Lenalidomide and Rituximab for Relapsed or Refractory Follicular Lymphoma: Results from a Phase 3 Study (inMIND)
Authors: Laurie H. Sehn, Stefano Luminari, Christian W. Scholz, Kai Hübel, Antonio Salar, Shankara Paneesha, Bjorn E Wahlin, Panayiotis Panayiotidis, Hui-Peng Lee, Ana Jiménez Ubieto, Juan-Manuel Sancho, Tae Min Kim, Eva Domingo Domenech, Takahiro Kumode, Christina Poh, Catherine Thieblemont, Dries Deeren, Edwin de Wit, Michael Arbushites, Marie-Laure Casadebaig, Marek Trneny
Journal: Blood (2024)
Extended Treatment of Venous Thromboembolism with Reduced- Vs Full-Dose Direct Oral Anticoagulants in Patients at High Risk of Recurrence
Authors: Francis Couturaud, Olivier Sanchez, Nicolas Meneveau, Laurent Bertoletti, Gilles Pernod, Isabelle Mahe, Emilie Presles, Philippe Girard, Cécile Tromeur, Patrick Mismetti, Silvy Laporte, Christophe Leroyer
Journal: Blood (2024)
Emerging debates and resolutions in brown adipose tissue research
Authors: Aaron M Cypess, Barbara Cannon, Jan Nedergaard, Lawrence Kazak, Douglas C Chang, Jonathan Krakoff, Yu-Hua Tseng, Camilla Schéele, Jeremie Boucher, Natasa Petrovic, Denis P Blondin, André C Carpentier, Kirsi A Virtanen, Sander Kooijman, Patrick C N Rensen, Cheryl Cero, Shingo Kajimura
Journal: Cell Metabolism (2024)
Elevated IL-22 as a result of stress-induced gut leakage suppresses septal neuron activation to ameliorate anxiety-like behavior
Authors: Mengyu Xia, Junmei Lu, Jiabin Lan, Teng Teng, Rani Shiao, Hongbin Sun, Zheyu Jin, Xueer Liu, Jie Wang, Hongyan Wu, Changchun Wang, Han Yi, Qingqing Qi, Jixi Li, Marc Schneeberger, Wei Shen, Boxun Lu, Lei Chen, Anoj Ilanges, Xinyu Zhou, Xiaofei Yu
Journal: Immunity (2024)
Unraveling bidirectional evolution of unstable mitochondrial DNA mutations in hepatocellular carcinoma at single-cell resolution
Authors: Kaixiang Zhou, Zhenni Wang, Wenjie Guo, Fanfan Xie, Qing Yuan, Shanshan Guo, Huanqin Zhang, Yang Liu, Xiwen Gu, Wenjie Song, Xu Guo, Jinliang Xing
Journal: Hepatology (2024)

Background and Aims: Somatic mutations in mitochondrial DNA (mtDNA) are abundant in HCC and directly affect metabolic homeostasis and tumor progression. The mixed population of mutant and wild-type mtDNA alleles within a cell, termed heteroplasmy, can vary from cell-to-cell and orchestrate tumorigenesis. However, the systematic evolutionary dynamics of somatic mtDNA mutations in HCC tissues remain to be delineated at single-cell resolution. Approach and Results: We established the single-cell capture-based mtDNA sequencing approach for accurately detecting somatic mtDNA mutations at single-cell resolution. Based on single-cell capture-based mtDNA sequencing, the single-cell somatic mtDNA mutational landscape, intratumor heterogeneity (ITH), and spatiotemporal clonal evolution were systematically investigated in 1641 single cells from 11 patients with HCC and 528 single cells from 2 patient-derived xenografts mouse models. Our data revealed the presence of 2 distinct categories of mtDNA mutation at single-cell resolution, including stable mutations exhibiting similar heteroplasmy levels and unstable mutations exhibiting remarkable cell-to-cell variability of heteroplasmy levels. Furthermore, the proportion of unstable mtDNA mutations was positively associated with the ITH of patients with HCC, with high ITH reflecting the proliferative and aggressive clinicopathological features of HCC cells. In addition, reconstruction of the evolutionary history classified HCC evolution patterns as linear or branched. Notably, spatiotemporal lineage tracing in patient-derived xenograft mouse models and multifocal lesions revealed bidirectional evolution of unstable mtDNA mutations during HCC progression. Conclusions: Our study unravels the landscape of single-cell somatic mtDNA mutations in HCC tissues and reveals the bidirectional evolution of unstable mtDNA mutations, with potential implications for HCC stratification and therapeutic intervention.