tbuckley/cabot-search huggingface dataset:
Multiomics insights into the female reproductive aging
Authors: Simin Wei, Weicheng Tang, Dan Chen, Jiaqiang Xiong, Liru Xue, Yun Dai, Yican Guo, Chuqing Wu, Jun Dai, Meng Wu, Shixuan Wang
Journal: Ageing Research Reviews (2024)

The human female reproductive lifespan significantly diminishes with age, leading to decreased fertility, reduced fertility quality and endocrine function disorders. While many aspects of aging in general have been extensively documented, the precise mechanisms governing programmed aging in the female reproductive system remain elusive. Recent advancements in omics technologies and computational capabilities have facilitated the emergence of multiomics deep phenotyping. Through the application and refinement of various high-throughput omics methods, a substantial volume of omics data has been generated, deepening our comprehension of the pathogenesis and molecular underpinnings of reproductive aging. This review highlights current and emerging multiomics approaches for investigating female reproductive aging, encompassing genomics, epigenomics, transcriptomics, proteomics, metabolomics, and microbiomics. We elucidate their influence on fundamental cell biology and translational research in the context of reproductive aging, address the limitations and current challenges associated with multiomics studies, and offer a glimpse into future prospects.
Erratum: “Drinking Water–Associated PFAS and Fluoroethers and Lipid Outcomes in the GenX Exposure Study”
Authors: Emma M. Rosen, Nadine Kotlarz, Detlef R.U. Knappe, C. Suzanne Lea, David N. Collier, David B. Richardson, Jane A. Hoppin
Journal: Environmental Health Perspectives (2024)
Outcomes of High-Grade Immune Checkpoint Inhibitor Hepatitis in Hospitalized and Nonhospitalized Patients
Authors: Michael Li, Danny Wong, Jordan S. Sack, Alexander S. Vogel, F. Stephen Hodi, Lawrence Fong, Jennifer C. Lai, Stephen D. Zucker, Shilpa Grover
Journal: Clinical Gastroenterology and Hepatology (2024)
Gut microbial co-metabolite 2-methylbutyrylcarnitine exacerbates thrombosis via binding to and activating integrin α2β1
Authors: Kan Huang, Zilun Li, Xi He, Jun Dai, Bingding Huang, Yongxia Shi, Dongxiao Fan, Zefeng Zhang, Yunchong Liu, Na Li, Zhongyu Zhang, Jiangyun Peng, Chenshu Liu, Renli Zeng, Zhipeng Cen, Tengyao Wang, Wenchao Yang, Meifeng Cen, Jingyu Li, Shuai Yuan, Lu Zhang, Dandan Hu, Shuxiang Huang, Pin Chen, Peilong Lai, Liyan Lin, Jielu Wen, Zhengde Zhao, Xiuyi Huang, Lining Yuan, Lifang Zhou, Haoliang Wu, Lihua Huang, Kai Feng, Jian Wang, Baolin Liao, Weiping Cai, Xilong Deng, Yueping Li, Jianping Li, Zhongwei Hu, Li Yang, Jiaojiao Li, Youguang Zhuo, Fuchun Zhang, Lin Lin, Yifeng Luo, Wei Zhang, Qianlin Ni, Xiqiang Hong, Guangqi Chang, Yang Zhang, Dongxian Guan, Weikang Cai, Yutong Lu, Fang Li, Li Yan, Meng Ren, Linghua Li, Sifan Chen
Journal: Cell Metabolism (2024)
Development of pluripotent stem cell-derived epidermal organoids that generate effective extracellular vesicles in skin regeneration
Authors: Sojung Kwak, Cho Lok Song, Jinhyuk Lee, Sungyeon Kim, Seungyoon Nam, Young-Jun Park, Jungwoon Lee
Journal: Biomaterials (2024)

Cellular skin substitutes such as epidermal constructs have been developed for various applications, including wound healing and skin regeneration. These cellular models are mostly derived from primary cells such as keratinocytes and fibroblasts in a two-dimensional (2D) state, and further development of three-dimensional (3D) cultured organoids is needed to provide insight into the in vivo epidermal phenotype and physiology. Here, we report the development of epidermal organoids (EpiOs) generated from induced pluripotent stem cells (iPSCs) as a novel epidermal construct and its application as a source of secreted biomolecules recovered by extracellular vesicles (EVs) that can be utilized for cell-free therapy of regenerative medicine. Differentiated iPSC-derived epidermal organoids (iEpiOs) are easily cultured and expanded through multiple organoid passages, while retaining molecular and functional features similar to in vivo epidermis. These mature iEpiOs contain epidermal stem cell the populations and retain the ability to further differentiate into other skin compartment lineages, such as hair follicle stem cells. By closely recapitulating the epidermal structure, iEpiOs are expected to provide a more relevant microenvironment to influence cellular processes and therapeutic response. Indeed, iEpiOs can generate high-performance EVs containing high levels of the angiogenic growth factor VEGF and miRNAs predicted to regulate cellular processes such as proliferation, migration, differentiation, and angiogenesis. These EVs contribute to target cell proliferation, migration, and angiogenesis, providing a promising therapeutic tool for in vivo wound healing. Overall, the newly developed iEpiOs strategy as an organoid-based approach provides a powerful model for studying basic and translational skin research and may also lead to future therapeutic applications using iEpiOs-secreted EVs.
Adjuvanted nanoliposomes displaying six hemagglutinins and neuraminidases as an influenza virus vaccine
Authors: Zachary R. Sia, Jayishnu Roy, Wei-Chiao Huang, Yiting Song, Shiqi Zhou, Yuan Luo, Qinzhe Li, Dominic Arpin, Hilliard L. Kutscher, Joaquin Ortega, Bruce A. Davidson, Jonathan F. Lovell
Journal: Cell Reports Medicine (2024)

Inclusion of defined quantities of the two major surface proteins of influenza virus, hemagglutinin (HA) and neuraminidase (NA), could benefit seasonal influenza vaccines. Recombinant HA and NA multimeric proteins derived from three influenza serotypes, H1N1, H3N2, and type B, are surface displayed on nanoliposomes co-loaded with immunostimulatory adjuvants, generating "hexaplex" particles that are used to immunize mice. Protective immune responses to hexaplex liposomes involve functional antibody elicitation against each included antigen, comparable to vaccination with monovalent antigen particles. When compared to contemporary recombinant or adjuvanted influenza virus vaccines, hexaplex liposomes perform favorably in many areas, including antibody production, T cell activation, protection from lethal virus challenge, and protection following passive sera transfer. Based on these results, hexaplex liposomes warrant further investigation as an adjuvanted recombinant influenza vaccine formulation.
Benralizumab versus Mepolizumab for Eosinophilic Granulomatosis with Polyangiitis
Authors: Michael E Wechsler, Parameswaran Nair, Benjamin Terrier, Bastian Walz, Arnaud Bourdin, David R W Jayne, David J Jackson, Florence Roufosse, Lena Börjesson Sjö, Ying Fan, Maria Jison, Christopher McCrae, Sofia Necander, Anat Shavit, Claire Walton, Peter A Merkel
Journal: New England Journal of Medicine (2024)

BackgroundEosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis characterized by eosinophilic inflammation. Benralizumab, a monoclonal antibody against the interleukin-5α receptor expressed on eosinophils, may be an option for treating EGPA.MethodsWe conducted a multicenter, double-blind, phase 3, randomized, active-controlled noninferiority trial to evaluate the efficacy and safety of benralizumab as compared with mepolizumab. Adults with relapsing or refractory EGPA who were receiving standard care were randomly assigned in a 1:1 ratio to receive benralizumab (30 mg) or mepolizumab (300 mg) subcutaneously every 4 weeks for 52 weeks. The primary end point was remission at weeks 36 and 48 (prespecified noninferiority margin, –25 percentage points). Secondary end points included the accrued duration of remission, time to first relapse, oral glucocorticoid use, eosinophil count, and safety.Download a PDF of the Research Summary.ResultsA total of 140 patients underwent randomization (70 assigned to each group). The adjusted percentage of patients with remission at weeks 36 and 48 was 59% in the benralizumab group and 56% in the mepolizumab group (difference, 3 percentage points; 95% confidence interval [CI], –13 to 18; P=0.73 for superiority), showing noninferiority but not superiority of benralizumab to mepolizumab. The accrued duration of remission and the time to first relapse were similar in the two groups. Complete withdrawal of oral glucocorticoids during weeks 48 through 52 was achieved in 41% of the patients who received benralizumab and 26% of those who received mepolizumab. The mean (±SD) blood eosinophil count at baseline was 306.0±225.0 per microliter in the benralizumab group and 384.9±563.6 per microliter in the mepolizumab group, decreasing to 32.4±40.8 and 71.8±54.4 per microliter, respectively, at week 52. Adverse events were reported in 90% of the patients in the benralizumab group and 96% of those in the mepolizumab group; serious adverse events were reported in 6% and 13%, respectively.ConclusionsBenralizumab was noninferior to mepolizumab for the induction of remission in patients with relapsing or refractory EGPA. (Funded by AstraZeneca; MANDARA ClinicalTrials.gov number, NCT04157348.) Quick Take Benralizumab versus Mepolizumab for EGPA 1m 56s
Optimistic vs Pessimistic Message Framing in Communicating Prognosis to Parents of Very Preterm Infants
Authors: Fiona A. Forth, Florian Hammerle, Jochem König, Michael S. Urschitz, Philipp Neuweiler, Eva Mildenberger, André Kidszun
Journal: JAMA Network Open (2024)

Importance In the neonatal intensive care unit, there is a lack of understanding about how best to communicate the prognosis of a serious complication to parents. Objective To examine parental preferences and the effects of optimistic vs pessimistic message framing when providing prognostic information about a serious complication. Design, Setting, and Participants This crossover randomized clinical trial was conducted at a single German university medical center between June and October 2021. Eligible participants were parents of surviving preterm infants with a birth weight under 1500 g. Data were analyzed between October 2021 and August 2022. Interventions Alternating exposure to 2 scripted video vignettes showing a standardized conversation between a neonatologist and parents, portrayed by professional actors, about the prognosis of a hypothetical very preterm infant with severe intraventricular hemorrhage. The video vignettes differed in the framing of identical numerical outcome estimates as either probability of survival and probability of nonimpairment (optimistic framing) or a risk of death and impaired survival (pessimistic framing). Main Outcomes and Measures The primary outcome was preference odds (ratio of preference for optimistic vs pessimistic framing). Secondary outcomes included state anxiety, perceptions of communication, and recall of numerical estimates. Results Of 220 enrolled parents (142 [64.5%] mothers; mean [SD] age: mothers, 39.1 [5.6] years; fathers, 42.7 [6.9] years), 196 (89.1%) preferred optimistic and 24 (10.1%) preferred pessimistic framing (preference odds, 11.0; 95% CI, 6.28-19.10; P &amp;amp;lt; .001). Preference for optimistic framing was more pronounced when presented second than when presented first (preference odds, 5.41; 95% CI, 1.77-16.48; P = .003). State anxiety scores were similar in both groups at baseline (mean difference, −0.34; −1.18 to 0.49; P = .42) and increased equally after the first video (mean difference, −0.55; 95% CI, −1.79 to 0.69; P = .39). After the second video, state anxiety scores decreased when optimistic framing followed pessimistic framing but remained unchanged when pessimistic framing followed optimistic framing (mean difference, 2.15; 95% CI, 0.91 to 3.39; P &amp;amp;lt; .001). With optimistic framing, participants recalled numerical estimates more accurately for survival (odds ratio, 4.00; 95% CI, 1.64-9.79; P = .002) but not for impairment (odds ratio, 1.50; 95% CI, 0.85-2.63; P = .16). Conclusions and Relevance When given prognostic information about a serious complication, parents of very preterm infants may prefer optimistic framing. Optimistic framing may lead to more realistic expectations for survival, but not for impairment. Trial Registration German Clinical Trials Register (DRKS): DRKS00024466
Severe COVID-19 in Vaccinated Adults With Hematologic Cancers in the Veterans Health Administration
Authors: Sonia T. Anand, Austin D. Vo, Jennifer La, Nhan V. Do, Nathanael R. Fillmore, Mary Brophy, Westyn Branch-Elliman, Paul A. Monach
Journal: JAMA Network Open (2024)

Importance With SARS-CoV-2 transforming into an endemic disease and with antiviral treatments available, it is important to establish which patients remain at risk of severe COVID-19 despite vaccination. Objective To quantify the associations of clinical and demographic variables with odds of severe COVID-19 among patients with hematologic cancers. Design, Setting, and Participants This case-control study included all patients with hematologic malignant neoplasms in the national Veterans Health Administration (VHA) who had documented SARS-CoV-2 infection after vaccination. Groups of patients with severe (cases) vs nonsevere (controls) COVID-19 were compared. Data were collected between January 1, 2020, and April 5, 2023, with data on infection collected between January 1, 2021, and September 30, 2022. All patients with diagnostic codes for hematologic malignant neoplasms who had documented vaccination followed by documented SARS-CoV-2 infection and for whom disease severity could be assessed were included. Data were analyzed from July 28 to December 30, 2023. Exposures Clinical (comorbidities, predominant viral variant, treatment for malignant neoplasm, booster vaccination, and antiviral treatment) and demographic (age and sex) variables shown in prior studies to be associated with higher or lower rates of severe COVID-19. Comorbidities included Alzheimer disease or dementia, chronic kidney disease, chronic obstructive pulmonary disease, diabetes, heart failure, and peripheral vascular disease. Main Outcome and Measures The main outcome was severe COVID-19 compared with nonsevere SARS-CoV-2 infection. Severe COVID-19 was defined as death within 28 days, mechanical ventilation, or hospitalization with use of dexamethasone or evidence of hypoxemia or use of supplemental oxygen. Multivariable logistic regression was used to estimate the associations of demographic and clinical variables with the odds of severe COVID-19, expressed as adjusted odds ratios (aORs) with 95% CIs. Results Among 6122 patients (5844 [95.5%] male, mean [SD] age, 70.89 [11.57] years), 1301 (21.3%) had severe COVID-19. Age (aOR per 1-year increase, 1.05; 95% CI, 1.04-1.06), treatment with antineoplastic or immune-suppressive drugs (eg, in combination with glucocorticoids: aOR, 2.32; 95% CI, 1.93-2.80), and comorbidities (aOR per comorbidity, 1.35; 95% CI, 1.29-1.43) were associated with higher odds of severe disease, whereas booster vaccination was associated with lower odds (aOR, 0.73; 95% CI, 0.62-0.86). After oral antiviral drugs became widely used in March 2022, 20 of 538 patients (3.7%) with SARS-CoV-2 infection during this period had progression to severe COVID-19. Conclusions and Relevance In this case-control study of patients with hematologic cancers, odds of severe COVID-19 remained high through mid-2022 despite vaccination, especially in patients requiring treatment.
Childhood Factors Associated With Unnatural Death Through Midadulthood
Authors: Kimberly B. Roth, Geoffrey Kahn, Carla L. Storr, Holly C. Wilcox
Journal: JAMA Network Open (2024)

Importance Life expectancy is decreasing in the US. Without national efforts to address factors that support policies and programs directed at children living in areas of concentrated poverty, life expectancy will likely continue to decline while costs and suffering associated with unnatural deaths will increase. Objective To identify which childhood factors are associated with death from unnatural causes through midadulthood. Design, Setting, and Participants For this cohort study, longitudinal data on childhood characteristics came from a group-randomized intervention trial implemented in Baltimore City Public Schools, Baltimore, Maryland (baseline 1985-1986; all students entering first grade were selected to participate at age 6 years). Participants were followed up to midadulthood with a National Death Index search through December 31, 2020. Data analysis was performed from February to May 2023. Exposures Exposures included individual factors (ie, sociodemographic characteristics, teacher-reported aggressive behavior, self-reported depression, anxiety, early alcohol and cannabis use, and assaultive violence exposure), family and peer factors (ie, household structure and education level, deviant peer affiliation, and parental monitoring), and neighborhood factors (ie, rates of neighborhood assault and public assistance). Main Outcomes and Measures The main outcome was unnatural death, defined as death due to unintentional injury, suicide, and homicide. A National Death Index search ascertained participants who died by age 41 to 42 years and cause of death. Multivariable Cox proportional hazards models were used to identify whether the exposures were independently associated with future mortality by unnatural causes. Results The initial trial included 2311 children, and longitudinal data were available for 2180 participants (median [IQR] age in first grade, 6.3 [6.0-6.5] years; 1090 female [50.0%]; 1461 Black [67.0%]; 1168 received free or reduced lunch in first grade [53.6%]). A total of 111 male participants (10.2%) and 29 female participants (2.7%) died; among those who died, 96 male participants (86.5%) and 14 female participants (48.3%) died of unnatural causes. Two factors remained significantly associated with mortality from unnatural causes: female sex was associated with reduced risk (hazard ratio, 0.13; 95% CI, 0.08-0.22), and neighborhood public assistance was associated with increased risk (hazard ratio, 1.89; 95% CI, 1.09-3.30). Conclusions and Relevance In this urban population-based cohort study, no modifiable risk factors of mortality at the level of the individual (eg, depression or anxiety and substance use) or the family (eg, household education level) were identified. However, the degree of neighborhood poverty in early childhood was significantly associated with death by unnatural causes in early adulthood, suggesting that economic policies are needed to advance health equity in relation to premature mortality.
Improved Innate Immune Function in Patients with Chronic Lymphocytic Leukemia Treated with Targeted Therapy in Clinical Trials
Authors: Rebecca Svanberg Teglgaard, Hanne Vibeke Marquart, Hans Jakob Hartling, Jakob Thaning Bay, Caspar da Cunha-Bang, Christian Brieghel, Tereza Faitová, Lisbeth Enggaard, Arnon P. Kater, Mark-David Levin, Sabina Kersting, Sisse Rye Ostrowski, Carsten U. Niemann
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Patients with chronic lymphocytic leukemia (CLL) have increased risk of severe infections. Although adaptive immune dysfunction is well described, clinical tools for identifying patients at risk are lacking, warranting investigation of additional immune components. In contrast to chemotherapy, targeted agents could spare or even improve innate immune function. Therefore, we investigated innate immune phenotypes and function in patients with CLL before and during targeted treatment. Experimental Design: Baseline and consecutive blood samples were collected from patients with CLL treated with acalabrutinib (n = 17) or ibrutinib+venetoclax (n = 18) in clinical trials. Innate immune function was assessed by TruCulture, a whole-blood ligand-stimulation assay quantifying cytokine release in response to standardized stimuli. Innate immune phenotypes were characterized by flow cytometry. As a proxy for infections, we mapped antimicrobial use before and during treatment. Results: At baseline, patients with CLL displayed impaired stimulated cytokine responses to the endotoxin lipopolysaccharide (LPS) along with deactivated monocytes, enrichment of myeloid-derived suppressor cells and metamyelocytes, and elevated (unstimulated) proinflammatory cytokines. Two/three cycles of acalabrutinib or ibrutinib normalized LPS-stimulated responses, in parallel with decreased duration of infections. Innate immune profiles and elevated proinflammatory cytokines further normalized during longer-term acalabrutinib or ibrutinib+venetoclax, paralleled by decreased infection frequency. Conclusions: Innate immune impairment and infection susceptibility in patients with CLL were restored in parallel during targeted therapy. Thus, targeted treatment may reduce the risk of infections in CLL, as currently under investigation in the PreVent-ACaLL phase 2 trial of acalabrutinib+venetoclax for high-risk CLL (NCT03868722).
Atrial Fibrillation Symptom Assessment—It’s Us, We’re (Part of) the Problem
Authors: Benjamin A. Steinberg
Journal: JAMA Network Open (2024)

Nobuhiro Ikemura, MD, PhD; Shun Kohsaka, MD; Takehiro Kimura, MD, PhD; Philip G. Jones, MS; Yoshinori Katsumata, MD, PhD; Kojiro Tanimoto, MD, PhD; Ikuko Ueda, PhD; Seiji Takatsuki, MD, PhD; Masaki Ieda, MD, PhD; Paul S. Chan, MD, MSc; John A. Spertus, MD, MPH
Mesothelin CAR T Cells Secreting Anti-FAP/Anti-CD3 Molecules Efficiently Target Pancreatic Adenocarcinoma and its Stroma
Authors: Marc Wehrli, Samantha Guinn, Filippo Birocchi, Adam Kuo, Yi Sun, Rebecca C. Larson, Antonio J. Almazan, Irene Scarfò, Amanda A. Bouffard, Stefanie R. Bailey, Praju Vikas Anekal, Paula Montero Llopis, Linda T. Nieman, Yuhui Song, Katherine H. Xu, Trisha R. Berger, Michael C. Kann, Mark B. Leick, Harrison Silva, Diego Salas-Benito, Tamina Kienka, Korneel Grauwet, Todd D. Armstrong, Rui Zhang, Qingfeng Zhu, Juan Fu, Andrea Schmidts, Felix Korell, Max Jan, Bryan D. Choi, Andrew S. Liss, Genevieve M. Boland, David T. Ting, Richard A. Burkhart, Russell W. Jenkins, Lei Zheng, Elizabeth M. Jaffee, Jacquelyn W. Zimmerman, Marcela V. Maus
Journal: Clinical Cancer Research (2024)

Targeting solid tumors with chimeric antigen receptor (CAR) T cells remains challenging due to heterogenous target antigen expression, antigen escape, and the immunosuppressive tumor microenvironment (TME). Pancreatic cancer is characterized by a thick stroma generated by cancer-associated fibroblasts (CAF), which may contribute to the limited efficacy of mesothelin-directed CAR T cells in early-phase clinical trials. To provide a more favorable TME for CAR T cells to target pancreatic ductal adenocarcinoma (PDAC), we generated T cells with an antimesothelin CAR and a secreted T-cell-engaging molecule (TEAM) that targets CAF through fibroblast activation protein (FAP) and engages T cells through CD3 (termed mesoFAP CAR-TEAM cells).
Cardiorespiratory Fitness and Physical Activity in Pediatric Diabetes
Authors: Hannah Steiman De Visser, Isaak Fast, Nicole Brunton, Edward Arevalo, Nicole Askin, Rasheda Rabbani, Ahmed M. Abou-Setta, Jonathan McGavock
Journal: JAMA Network Open (2024)

It is unclear whether cardiorespiratory fitness (CRF) and physical activity are lower among youths with type 1 diabetes (T1D) and type 2 diabetes (T2D) compared with youths without diabetes.