tbuckley/cabot-search huggingface dataset:
Extended-Infusion β-Lactam Therapy, Mortality, and Subsequent Antibiotic Resistance Among Hospitalized Adults With Gram-Negative Bloodstream Infections
Authors: Sara M. Karaba, Sara E. Cosgrove, Jae Hyoung Lee, Suiyini Fiawoo, Emily L. Heil, Katelyn S. Quartuccio, Katherine C. Shihadeh, Pranita D. Tamma
Journal: JAMA Network Open (2024)

Importance Current evidence is conflicting for associations of extended-infusion β-lactam (EI-BL) therapy with clinical outcomes. Objective To investigate the association of EI-BL therapy with survival, adverse events, and emergence of antibiotic resistance in adults with gram-negative bloodstream infections (GN-BSI). Design, Setting, and Participants This cohort study of consecutive adults with GN-BSI admitted to 24 United States hospitals between January 1, 2019, and December 31, 2019, receiving EI-BL were compared with adults with GN-BSI receiving the same agents as intermittent infusion β-lactam (II-BL; ≤1-hour infusions). Statistical analysis was performed from January to October 2023. Exposures EI-BL (ie, ≥3-hour infusion). Main Outcomes and Measures EI-BL and II-BL groups underwent 1:3 nearest-neighbor propensity score matching (PSM) without replacement. Multivariable regression was applied to the PSM cohort to investigate outcomes, all censored at day 90. The primary outcome was mortality; secondary outcomes included antibiotic adverse events and emergence of resistance (≥4-fold increase in the minimum inhibitory concentration of the β-lactam used to treat the index GN-BSI). Results Among the 4861 patients included, 2547 (52.4%) were male; and the median (IQR) age was 67 (55-77) years. There were 352 patients in the EI-BL 1:3 PSM group, and 1056 patients in the II-BL 1:3 PSM group. Among 1408 PSM patients, 373 (26.5%) died by day 90. The odds of mortality were lower in the EI-BL group (adjusted odds ratio [aOR], 0.71 [95% CI, 0.52-0.97]). In a stratified analysis, a survival benefit was only identified in patients with severe illness or elevated minimum inhibitory concentrations (ie, in the intermediate range for the antibiotic administered). There were increased odds of catheter complications (aOR, 3.14 [95% CI, 1.66-5.96]) and antibiotic discontinuation because of adverse events (eg, acute kidney injury, cytopenias, seizures) in the EI-BL group (aOR, 3.66 [95% CI, 1.68-7.95]). Emergence of resistance was similar in the EI-BL and II-BL groups at 2.9% vs 7.2%, respectively ( P = .35). Conclusions and Relevance In this cohort study of patients with GN-BSI, EI-BL therapy was associated with reduced mortality for patients with severe illness or those infected with nonsusceptible organisms; potential advantages in other groups remain unclear and need to be balanced with potential adverse events. The subsequent emergence of resistance warrants investigation in a larger cohort.
Gender-Affirming Hormone Treatment and Metabolic Syndrome Among Transgender Veterans
Authors: Leila Hashemi, Andriana Marijic Buljubasic, Matthew J. Budoff, Laurel A. Copeland, Nicholas J. Jackson, Guneet K. Jasuja, Jeffery Gornbein, Karen Reue
Journal: JAMA Network Open (2024)

Gender-affirming hormone treatment (GAHT) is a common therapy for transgender individuals to reduce gender dysphoria and improve quality of life. Clarifying the long-term effects of GAHT remains a priority in transgender health research.
Pan-cancer mapping of single CD8+ T cell profiles reveals a TCF1:CXCR6 axis regulating CD28 co-stimulation and anti-tumor immunity
Authors: Katherine Tooley, Livnat Jerby, Giulia Escobar, S. Harsha Krovi, Davide Mangani, Gitanjali Dandekar, Hanning Cheng, Asaf Madi, Ella Goldschmidt, Conner Lambden, Rajesh K. Krishnan, Orit Rozenblatt-Rosen, Aviv Regev, Ana C. Anderson
Journal: Cell Reports Medicine (2024)
Mono-methylation of lysine 27 at histone 3 confers lifelong susceptibility to stress
Authors: Angélica Torres-Berrío, Molly Estill, Vishwendra Patel, Aarthi Ramakrishnan, Hope Kronman, Angélica Minier-Toribio, Orna Issler, Caleb J. Browne, Eric M. Parise, Yentl Y. van der Zee, Deena M. Walker, Freddyson J. Martínez-Rivera, Casey K. Lardner, Romain Durand-de Cuttoli, Scott J. Russo, Li Shen, Simone Sidoli, Eric J. Nestler
Journal: Neuron (2024)
Human plasma cells engineered to secrete bispecifics drive effective in vivo leukemia killing
Authors: Tyler F Hill, Parnal Narvekar, Gregory D Asher, Jasmine N Edelstein, Nathan D Camp, Annaiz Grimm, Kerri R Thomas, Michael D Leiken, Katherine M Molloy, Peter J Cook, Sean P Arlauckas, Richard A Morgan, Sarah K Tasian, David J Rawlings, Richard G James
Journal: Molecular Therapy (2024)
Dietary fiber alleviates alcoholic liver injury via Bacteroides acidifaciens and subsequent ammonia detoxification
Authors: Haiyuan Shen, Liangliang Zhou, Hao Zhang, Yuanru Yang, Ling Jiang, Dongqing Wu, Hang Shu, Hejiao Zhang, Linxi Xie, Kaichen Zhou, Chen Cheng, Lei Yang, Jiali Jiang, Siya Wang, Yiran Han, Jiayi Zhu, Long Xu, Zhihua Liu, Hua Wang, Shi Yin
Journal: Cell Host & Microbe (2024)
Cellular and circuit architecture of the lateral septum for reward processing
Authors: Gaowei Chen, Shishi Lai, Shaolei Jiang, Fengling Li, Kaige Sun, Xiaocong Wu, Kuikui Zhou, Yutong Liu, Xiaofei Deng, Zijun Chen, Fang Xu, Yu Xu, Kunhua Wang, Gang Cao, Fuqiang Xu, Guo-Qiang Bi, Yingjie Zhu
Journal: Neuron (2024)
Housing Status and Acute Care Use After Cancer Diagnosis
Authors: Hannah Decker, Sara Colom, Dave Graham-Squire, Elizabeth Wick, Margot B. Kushel, Maria Raven, Hemal K. Kanzaria
Journal: JAMA Network Open (2024)

This cohort study examines housing status and acute care use after a cancer diagnosis among individuals treated at a public hospital in San Francisco, California.
Proteomic predictors of individualized nutrient-specific insulin secretion in health and disease
Authors: Jelena Kolic, WenQing Grace Sun, Haoning Howard Cen, Jessica D. Ewald, Jason C. Rogalski, Shugo Sasaki, Han Sun, Varsha Rajesh, Yi Han Xia, Renata Moravcova, Søs Skovsø, Aliya F. Spigelman, Jocelyn E. Manning Fox, James Lyon, Leanne Beet, Jianguo Xia, Francis C. Lynn, Anna L. Gloyn, Leonard J. Foster, Patrick E. MacDonald, James D. Johnson
Journal: Cell Metabolism (2024)

Population-level variation and mechanisms behind insulin secretion in response to carbohydrate, protein, and fat remain uncharacterized. We defined prototypical insulin secretion responses to three macronutrients in islets from 140 cadaveric donors, including those with type 2 diabetes. The majority of donors' islets exhibited the highest insulin response to glucose, moderate response to amino acid, and minimal response to fatty acid. However, 9% of donors' islets had amino acid responses, and 8% had fatty acid responses that were larger than their glucose-stimulated insulin responses. We leveraged this heterogeneity and used multi-omics to identify molecular correlates of nutrient responsiveness, as well as proteins and mRNAs altered in type 2 diabetes. We also examined nutrient-stimulated insulin release from stem cell-derived islets and observed responsiveness to fat but not carbohydrate or protein-potentially a hallmark of immaturity. Understanding the diversity of insulin responses to carbohydrate, protein, and fat lays the groundwork for personalized nutrition.
Thermal facial image analyses reveal quantitative hallmarks of aging and metabolic diseases
Authors: Zhengqing Yu, Yong Zhou, Kehang Mao, Bo Pang, Kai Wang, Tang Jin, Haonan Zheng, Haotian Zhai, Yiyang Wang, Xiaohan Xu, Hongxiao Liu, Yi Wang, Jing-Dong J Han
Journal: Cell Metabolism (2024)
The activity of early-life gene regulatory elements is hijacked in aging through pervasive AP-1-linked chromatin opening
Authors: Ralph Patrick, Marina Naval-Sanchez, Nikita Deshpande, Yifei Huang, Jingyu Zhang, Xiaoli Chen, Ying Yang, Kanupriya Tiwari, Mohammadhossein Esmaeili, Minh Tran, Amin R. Mohamed, Binxu Wang, Di Xia, Jun Ma, Jacqueline Bayliss, Kahlia Wong, Michael L. Hun, Xuan Sun, Benjamin Cao, Denny L. Cottle, Tara Catterall, Hila Barzilai-Tutsch, Robin-Lee Troskie, Zhian Chen, Andrea F. Wise, Sheetal Saini, Ye Mon Soe, Snehlata Kumari, Matthew J. Sweet, Helen E. Thomas, Ian M. Smyth, Anne L. Fletcher, Konstantin Knoblich, Matthew J. Watt, Majid Alhomrani, Walaa Alsanie, Kylie M. Quinn, Tobias D. Merson, Ann P. Chidgey, Sharon D. Ricardo, Di Yu, Thierry Jardé, Seth W. Cheetham, Christophe Marcelle, Susan K. Nilsson, Quan Nguyen, Melanie D. White, Christian M. Nefzger
Journal: Cell Metabolism (2024)

A mechanistic connection between aging and development is largely unexplored. Through profiling age-related chromatin and transcriptional changes across 22 murine cell types, analyzed alongside previous mouse and human organismal maturation datasets, we uncovered a transcription factor binding site (TFBS) signature common to both processes. Early-life candidate cis-regulatory elements (cCREs), progressively losing accessibility during maturation and aging, are enriched for cell-type identity TFBSs. Conversely, cCREs gaining accessibility throughout life have a lower abundance of cell identity TFBSs but elevated activator protein 1 (AP-1) levels. We implicate TF redistribution toward these AP-1 TFBS-rich cCREs, in synergy with mild downregulation of cell identity TFs, as driving early-life cCRE accessibility loss and altering developmental and metabolic gene expression. Such remodeling can be triggered by elevating AP-1 or depleting repressive H3K27me3. We propose that AP-1-linked chromatin opening drives organismal maturation by disrupting cell identity TFBS-rich cCREs, thereby reprogramming transcriptome and cell function, a mechanism hijacked in aging through ongoing chromatin opening.
E-Cigarette Use and Lung Cancer Screening Uptake
Authors: Qian Wang, Changchuan Jiang, Melinda L. Hsu, Juan Wisnivesky, Afshin Dowlati, Paolo Boffetta, Chung Yin Kong
Journal: JAMA Network Open (2024)

This cross-sectional study examines e-cigarette use and lung cancer screening uptake among individuals in the US.
A novel STING variant triggers endothelial toxicity and SAVI disease
Authors: Erika Valeri, Sara Breggion, Federica Barzaghi, Monah Abou Alezz, Giovanni Crivicich, Isabel Pagani, Federico Forneris, Claudia Sartirana, Matteo Costantini, Stefania Costi, Achille Marino, Eleonora Chiarotto, Davide Colavito, Rolando Cimaz, Ivan Merelli, Elisa Vicenzi, Alessandro Aiuti, Anna Kajaste-Rudnitski
Journal: The Journal of Experimental Medicine (2024)

Gain-of-function mutations in STING cause STING-associated vasculopathy with onset in infancy (SAVI) characterized by early-onset systemic inflammation, skin vasculopathy, and interstitial lung disease. Here, we report and characterize a novel STING variant (F269S) identified in a SAVI patient. Single-cell transcriptomics of patient bone marrow revealed spontaneous activation of interferon (IFN) and inflammatory pathways across cell types and a striking prevalence of circulating naïve T cells was observed. Inducible STING F269S expression conferred enhanced signaling through ligand-independent translocation of the protein to the Golgi, protecting cells from viral infections but preventing their efficient immune priming. Additionally, endothelial cell activation was promoted and further exacerbated by cytokine secretion by SAVI immune cells, resulting in inflammation and endothelial damage. Our findings identify STING F269S mutation as a novel pathogenic variant causing SAVI, highlight the importance of the crosstalk between endothelial and immune cells in the context of lung disease, and contribute to a better understanding of how aberrant STING activation can cause pathology.
Biochemical hallmarks-targeting antineoplastic nanotherapeutics
Authors: Jing Han, He Dong, Tianyi Zhu, Qi Wei, Yongheng Wang, Yun Wang, Yu Lv, Haoran Mu, Shandeng Huang, Ke Zeng, Jing Xu, Jianxun Ding
Journal: Bioactive Materials (2024)

Tumor microenvironments (TMEs) have received increasing attention in recent years as they play pivotal roles in tumorigenesis, progression, metastases, and resistance to the traditional modalities of cancer therapy like chemotherapy. With the rapid development of nanotechnology, effective antineoplastic nanotherapeutics targeting the aberrant hallmarks of TMEs have been proposed. The appropriate design and fabrication endow nanomedicines with the abilities for active targeting, TMEs-responsiveness, and optimization of physicochemical properties of tumors, thereby overcoming transport barriers and significantly improving antineoplastic therapeutic benefits. This review begins with the origins and characteristics of TMEs and discusses the latest strategies for modulating the TMEs by focusing on the regulation of biochemical microenvironments, such as tumor acidosis, hypoxia, and dysregulated metabolism. Finally, this review summarizes the challenges in the development of smart anti-cancer nanotherapeutics for TME modulation and examines the promising strategies for combination therapies with traditional treatments for further clinical translation.
MMP9 and CCL18 associate with chronic urticaria while type I, IV, and VI collagens change with omalizumab treatment
Authors: Ewa A. Bartko, Maiken Mellergaard, Solveig S. Groen, Signe Holm Nielsen, Jesper Elberling, Aase Handberg, Lars K. Poulsen, Lars H. Blom, Bettina M. Jensen
Journal: Allergy (2024)

Data S1. Data S2. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Central nervous system multiple myeloma: A real‐world multi‐institutional study of the Greek Myeloma Study Group
Authors: Eirini Katodritou, Dimitra Dalampira, Sosana Delimpasi, Ioannis Ntanasis‐Stathopoulos, Fryni Karaolidou, Annita‐Ioanna Gkioka, Vasiliki Labropoulou, Emmanouil Spanoudakis, Theodora Triantafyllou, Maria Kotsopoulou, Eyrydiki Michalis, Chrysanthi Vadikolia, Theodosia Papadopoulou, Aggeliki Sevastoudi, Michael Michael, Aikaterini Daiou, Aikaterini Pentidou, Ioannis Kostopoulos, Vasiliki Palaska, Maria Gavriatopoulou, Marie‐Christine Kyrtsonis, Evgenia Verrou, Efstathios Kastritis, Meletios‐Athanasios Dimopoulos, Evangelos Terpos
Journal: American Journal of Hematology (2024)

Abstract Central nervous system (CNS) involvement is a rare and aggressive complication of multiple myeloma (MM). We identified 54/4352 MM patients (1.2%), who developed CNS‐MM between 2000 and 2022. A matched‐control group of MM patients without CNS‐MM was used for comparisons. Median age was 63 years. Median time to CNS‐MM was 28 months; 6/54 experienced CNS‐MM at MM diagnosis. Abnormal lactate dehydrogenase (LDH), high‐risk cytogenetics, and extramedullary involvement (EMI), that is, soft tissue plasmacytomas and/or plasma cell leukemia (PCL), were more frequent in CNS‐MM versus controls ( p &lt; .05); 13/54 had PCL at CNS‐MM. The majority had leptomeningeal infiltration (LMI) (66%); 26% had CNS‐MM without systemic myeloma; EMI was the strongest predictor for CNS‐MM (OR: 6.3). Median overall survival (OS) of CNS‐MM patients versus controls was 43 months (95% CI: 32–54) versus 60 months (95% CI: 38–82) ( p &lt; .001); treatment of CNS‐MM included mainly bortezomib/thalidomide/chemotherapy whereas 20% received novel drugs/immunotherapy combinations; 28 patients underwent cerebrospinal fluid infusions; EMI was the strongest negative predictor for post CNS‐MM OS ( p = .005; HR: 2.9). Treatment after 2016 predicted significantly for OS ( p = .002; HR: 0.27). Median post CNS‐MM OS was 4 months (95% CI: 2.6–5.4); in patients treated after 2016 median OS was 12 months. In conclusion, we have demonstrated in this large real‐world series that survival of CNS‐MM remains poor; however, there is a positive impact of treatment after 2016, related to the efficacy of modern anti‐myeloma therapy; EMI significantly increases the probability to develop CNS‐MM and the risk of post CNS‐MM death, indicating a potential need for CNS prophylaxis for those patients.
Hydroxyurea to prevent brain injury in children with sickle cell disease (<scp>HU</scp> Prevent)—A randomized, placebo‐controlled phase <scp>II</scp> feasibility/pilot study
Authors: James F. Casella, Dana K. Furstenau, Robert J. Adams, Donald J. Brambilla, Jeffrey D. Lebensburger, James J. Fehr, Lori C. Jordan, Allison A. King, Rebecca N. Ichord, Robert C. McKinstry, Michael A. Kraut, Dennis W. Shaw, Desiree A. White, Donna A. Whyte‐Stewart, Radhika Avadhani, Emily A. Barron‐Casella, Alicia D. Cannon, Cyd K. Eaton, Kristin A. Riekert, Joanne E. Shay, Cynthia A. Smith‐Seidel, Diane C. Weiss, Noeleen D. Ostapkovich, Krista Vermillion, Kevin E. Treine, Claire E. Kingsbury, John J. Strouse, Richard E. Thompson, Daniel F. Hanley
Journal: American Journal of Hematology (2024)

Central nervous system (CNS) injury is common in sickle cell disease (SCD) and occurs early in life. Hydroxyurea is safe and efficacious for treatment of SCD, but high-quality evidence from randomized trials to estimate its neuroprotective effect is scant. HU Prevent was a randomized (1:1), double-blind, phase II feasibility/pilot trial of dose-escalated hydroxyurea vs. placebo for the primary prevention of CNS injury in children with HbSS or HbS-β
An expedited screening platform for the discovery of anti-ageing compounds in vitro and in vivo
Authors: Celia Lujan, Eleanor Jane Tyler, Simone Ecker, Amy Philomena Webster, Eleanor Rachel Stead, Victoria Eugenia Martinez-Miguel, Deborah Milligan, James Charles Garbe, Martha Ruskin Stampfer, Stephan Beck, Robert Lowe, Cleo Lucinda Bishop, Ivana Bjedov
Journal: Genome Medicine (2024)

Abstract Background Restraining or slowing ageing hallmarks at the cellular level have been proposed as a route to increased organismal lifespan and healthspan. Consequently, there is great interest in anti-ageing drug discovery. However, this currently requires laborious and lengthy longevity analysis. Here, we present a novel screening readout for the expedited discovery of compounds that restrain ageing of cell populations in vitro and enable extension of in vivo lifespan. Methods Using Illumina methylation arrays, we monitored DNA methylation changes accompanying long-term passaging of adult primary human cells in culture. This enabled us to develop, test, and validate the CellPopAge Clock, an epigenetic clock with underlying algorithm, unique among existing epigenetic clocks for its design to detect anti-ageing compounds in vitro. Additionally, we measured markers of senescence and performed longevity experiments in vivo in Drosophila , to further validate our approach to discover novel anti-ageing compounds. Finally, we bench mark our epigenetic clock with other available epigenetic clocks to consolidate its usefulness and specialisation for primary cells in culture. Results We developed a novel epigenetic clock, the CellPopAge Clock, to accurately monitor the age of a population of adult human primary cells. We find that the CellPopAge Clock can detect decelerated passage-based ageing of human primary cells treated with rapamycin or trametinib, well-established longevity drugs. We then utilise the CellPopAge Clock as a screening tool for the identification of compounds which decelerate ageing of cell populations, uncovering novel anti-ageing drugs, torin2 and dactolisib (BEZ-235). We demonstrate that delayed epigenetic ageing in human primary cells treated with anti-ageing compounds is accompanied by a reduction in senescence and ageing biomarkers. Finally, we extend our screening platform in vivo by taking advantage of a specially formulated holidic medium for increased drug bioavailability in Drosophila . We show that the novel anti-ageing drugs, torin2 and dactolisib (BEZ-235), increase longevity in vivo. Conclusions Our method expands the scope of CpG methylation profiling to accurately and rapidly detecting anti-ageing potential of drugs using human cells in vitro, and in vivo, providing a novel accelerated discovery platform to test sought after anti-ageing compounds and geroprotectors.
Targeting exhausted cytotoxic T cells through <scp>CTLA</scp>‐4 inhibition promotes elimination of neoplastic cells in human myelofibrosis xenografts
Authors: Lara Tavernari, Sebastiano Rontauroli, Ruggiero Norfo, Margherita Mirabile, Monica Maccaferri, Barbara Mora, Elena Genovese, Sandra Parenti, Chiara Carretta, Elisa Bianchi, Matteo Bertesi, Francesca Pedrazzi, Elena Tenedini, Silvia Martinelli, Maria Teresa Bochicchio, Paola Guglielmelli, Leonardo Potenza, Alessandro Lucchesi, Francesco Passamonti, Enrico Tagliafico, Mario Luppi, Alessandro Maria Vannucchi, Rossella Manfredini
Journal: American Journal of Hematology (2024)

Abstract Myeloproliferative neoplasms represent a group of clonal hematopoietic disorders of which myelofibrosis (MF) is the most aggressive. In the context of myeloid neoplasms, there is a growing recognition of the dysregulation of immune response and T‐cell function as significant contributors to disease progression and immune evasion. We investigated cytotoxic T‐cell exhaustion in MF to restore immune response against malignant cells. Increased expression of inhibitory receptors like CTLA‐4 was observed on cytotoxic T cells from MF patients together with a reduced secretion of IFNɣ and TNFɑ. CTLA‐4 ligands CD80 and CD86 were increased on MF granulocytes and monocytes highlighting a possible role for myeloid cells in suppressing T‐cell activation in MF patients. Unlike healthy donors, the activation of cytotoxic T cells from MF patients was attenuated in the presence of myeloid cells and restored when T cells were cultured alone or treated with anti‐CTLA‐4. Moreover, anti‐CTLA‐4 treatment promoted elimination of neoplastic monocytes and granulocytes in a co‐culture system with cytotoxic T cells. To test CTLA‐4 inhibition in vivo , patient‐derived xenografts were generated by transplanting MF CD34+ cells and by infusing homologous T cells in NSGS mice. CTLA‐4 blockade reduced human myeloid chimerism and led to T‐cell expansion in spleen and bone marrow. Overall, these findings shed light on T‐cell dysfunction in MF and suggest that CTLA‐4 blockade can boost the cytotoxic T cell‐mediated immune response against tumor cells.
Pan-cancer profiling of tumor-infiltrating natural killer cells through transcriptional reference mapping
Authors: Herman Netskar, Aline Pfefferle, Jodie P. Goodridge, Ebba Sohlberg, Olli Dufva, Sarah A. Teichmann, Demi Brownlie, Jakob Michaëlsson, Nicole Marquardt, Trevor Clancy, Amir Horowitz, Karl-Johan Malmberg
Journal: Nature Immunology (2024)

The functional diversity of natural killer (NK) cell repertoires stems from differentiation, homeostatic, receptor-ligand interactions and adaptive-like responses to viral infections. In the present study, we generated a single-cell transcriptional reference map of healthy human blood- and tissue-derived NK cells, with temporal resolution and fate-specific expression of gene-regulatory networks defining NK cell differentiation. Transfer learning facilitated incorporation of tumor-infiltrating NK cell transcriptomes (39 datasets, 7 solid tumors, 427 patients) into the reference map to analyze tumor microenvironment (TME)-induced perturbations. Of the six functionally distinct NK cell states identified, a dysfunctional stressed CD56