tbuckley/cabot-search huggingface dataset:
Glucagon-Like Peptide-1 Receptor Agonists and Pancreatic Cancer Risk in Patients With Type 2 Diabetes
Authors: Rachel Dankner, Havi Murad, Nirit Agay, Liraz Olmer, Laurence S. Freedman
Journal: JAMA Network Open (2024)

Importance Concerns have been raised that glucagon-like peptide-1 receptor agonists (GLP-1RA) may increase the risk of pancreatic cancer. Objective To investigate the association of GLP-1RA treatment with pancreatic cancer incidence over 9 years of follow-up. Design, Setting, and Participants In this population-based historical cohort study, adult patients (aged 21 to 89 years) with type 2 diabetes insured by Clalit Healthcare Services, the largest state-mandated health organization in Israel, were followed up from 2009, when GLP-1RA became available in Israel, until pancreatic cancer diagnosis, death, reaching age 90 years, or end of follow-up (December 2017). Data were analyzed from June 2022 to November 2023. Exposures Treatment with GLP-1RA was compared with basal insulin. Main Outcome and Measures Pancreatic cancer incidence was compared according to weighted cumulative exposures to GLP-1RA and to basal insulin in a Cox model implemented in discrete time, with time origin at 2 years after diabetes diagnosis, adjusting for confounding. In sensitivity analyses, propensity score–matched pair new-user design and prevalent new-user design were used for the comparison. Because of risk for reverse-causation bias, results in the fifth to seventh year after medication were emphasized. Results During a cumulative follow-up of 3 290 439 person-years of 543 595 adults with a mean (SD) age of 59.9 (12.8) years (277 502 women [51%]) with incident diabetes, 1665 patients received pancreatic cancer diagnoses. In total, 33 377 patients (6.1%) used GLP-1RA and 106 849 (19.7%) used basal insulin. The estimated hazard ratio (HR) for pancreatic cancer associated with incremental use of 1 defined daily dose per day of GLP-1RA compared with basal insulin in the fifth to seventh year previously (all other characteristics, including age, sex, ethnic background, sociodemographic status, baseline body mass index, smoking history, history of pancreatitis, other glucose-lowering medications treatment history, and length of diabetes, being equal) was 0.50 (95% CI, 0.15-1.71). The new-user and prevalent new-user designs showed HRs from the fifth year onwards following initiation of GLP-1RA vs basal insulin of 0.52 (95 % CI, 0.19-1.41) and 0.75 (95 % CI, 0.37-1.53), respectively. Conclusions and Relevance In this historical cohort study of adults with type 2 diabetes, no support for an increased pancreatic cancer incidence over 7 years following start of GLP-1RA treatment was found. However, monitoring for pancreatic cancer risk beyond 7 years following initiation of therapy is still required. Trial Registration ClinicalTrials.gov Identifier: NCT02072902
Aster-B–dependent estradiol synthesis protects female mice from diet-induced obesity
Authors: Xu Xiao, John P. Kennelly, An-Chieh Feng, Lijing Cheng, Beatriz Romartinez-Alonso, Alexander Bedard, Yajing Gao, Liujuan Cui, Stephen G. Young, John W.R. Schwabe, Peter Tontonoz
Journal: Journal of Clinical Investigation (2024)

Aster proteins mediate the nonvesicular transport of cholesterol from the plasma membrane (PM) to the endoplasmic reticulum (ER). However, the importance of nonvesicular sterol movement for physiology and pathophysiology in various tissues is incompletely understood. Here we show that loss of Aster-B leads to diet-induced obesity and insulin resistance in female but not male mice, and that this sex difference is abolished by ovariectomy. We further demonstrate that Aster-B deficiency impairs nonvesicular cholesterol transport from the PM to the ER in ovaries in vivo, leading to hypogonadism and reduced estradiol synthesis. Female Aster-B-deficient mice exhibit reduced locomotor activity and energy expenditure, consistent with established effects of estrogens on systemic metabolism. Administration of exogenous estradiol ameliorates the diet-induced obesity phenotype of Aster-B-deficient female mice. These findings highlight the key role of Aster-B-dependent nonvesicular cholesterol transport in regulating estradiol production and protecting females from obesity.
Air Pollutants and Risk of Parkinson’s Disease among Women in the Sister Study
Authors: Zichun Cao, Yaqun Yuan, Alexandra J. White, Chenxi Li, Zhehui Luo, Aimee A. D’Aloisio, Xuemei Huang, Joel D. Kaufman, Dale P. Sandler, Honglei Chen
Journal: Environmental Health Perspectives (2024)

Air pollutants may contribute to the development of Parkinson’s disease (PD), but empirical evidence is limited and inconsistent.
Emerging Strategies for the Prevention of Immune Toxicities Associated with T cell–Engaging Cancer Therapies
Authors: Andrew Kowalski, Jill Lykon, Benjamin Diamond, David G. Coffey, Marcella Kaddoura, Francesco Maura, James E. Hoffman, Dickran Kazandjian, Ola Landgren
Journal: Blood Cancer Discovery (2024)

Immune-related toxicities including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are common side effects of bispecific antibody and chimeric antigen receptor (CAR) T-cell therapies of hematologic malignancies. As anti-inflammatory therapy (the standard of care) is variably effective in mitigating these toxicities after onset, here we discuss emerging evidence for shifting the strategy from mitigation to prevention.
Publisher Correction: Mechanisms, pathways and strategies for rejuvenation through epigenetic reprogramming
Authors: Andrea Cipriano, Mahdi Moqri, Sun Y. Maybury-Lewis, Ryan Rogers-Hammond, Tineke Anna de Jong, Alexander Parker, Sajede Rasouli, Hans Robert Schöler, David A. Sinclair, Vittorio Sebastiano
Journal: Nature Aging (2024)
Author Correction: Adjuvant nivolumab in resected stage IIB/C melanoma: primary results from the randomized, phase 3 CheckMate 76K trial
Authors: John M. Kirkwood, Michele Del Vecchio, Jeffrey Weber, Christoph Hoeller, Jean-Jacques Grob, Peter Mohr, Carmen Loquai, Caroline Dutriaux, Vanna Chiarion-Sileni, Jacek Mackiewicz, Piotr Rutkowski, Petr Arenberger, Gaelle Quereux, Tarek M. Meniawy, Paolo A. Ascierto, Alexander M. Menzies, Piyush Durani, Maurice Lobo, Federico Campigotto, Brian Gastman, Georgina V. Long
Journal: Nature Medicine (2024)
Meaningful Endpoints for Idiopathic Pulmonary Fibrosis (IPF) Clinical Trials: Emphasis on ‘Feels, Functions, Survives’. Report of a Collaborative Discussion in a Symposium with Direct Engagement from Representatives of Patients, Investigators, the National Institutes of Health, a Patient Advocacy Organization, and a Regulatory Agency
Authors: Ganesh Raghu, Marya Ghazipura, Thomas R. Fleming, Kerri I. Aronson, Jürgen Behr, Kevin K. Brown, Kevin R. Flaherty, Ella A. Kazerooni, Toby M. Maher, Luca Richeldi, Joseph A. Lasky, Jeffrey J. Swigris, Robert Busch, Lili Garrard, Dong-Hyun Ahn, Ji Li, Khalid Puthawala, Gabriela Rodal, Sally Seymour, Nargues Weir, Sonye K. Danoff, Neil Ettinger, Jonathan Goldin, Marilyn K. Glassberg, Leticia Kawano-Dourado, Nasreen Khalil, Lisa Lancaster, David A. Lynch, Yolanda Mageto, Imre Noth, Jessica E. Shore, Marlies Wijsenbeek, Robert Brown, Daniel Grogan, Dorothy Ivey, Patrycja Golinska, Banu Karimi-Shah, Fernando J. Martinez
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

Background: Idiopathic pulmonary fibrosis (IPF) carries significant mortality and unpredictable progression, with limited therapeutic options. Designing trials with patient-meaningful endpoints, enhancing the reliability and interpretability of results, and streamlining the regulatory approval process are of critical importance to advancing clinical care in IPF. Methods: A landmark in-person symposium in June 2023 assembled 43 participants from the US and internationally, including patients with IPF, investigators, and regulatory representatives, to discuss the immediate future of IPF clinical trial endpoints. Patient advocates were central to discussions, which evaluated endpoints according to regulatory standards and the FDA's 'feels, functions, survives' criteria. Results: Three themes emerged: 1) consensus on endpoints mirroring the lived experiences of patients with IPF; 2) consideration of replacing forced vital capacity (FVC) as the primary endpoint, potentially by composite endpoints that include 'feels, functions, survives' measures or FVC as components; 3) support for simplified, user-friendly patient-reported outcomes (PROs) as either components of primary composite endpoints or key secondary endpoints, supplemented by functional tests as secondary endpoints and novel biomarkers as supportive measures (FDA Guidance for Industry (Multiple Endpoints in Clinical Trials) available at: https://www.fda.gov/media/162416/download). Conclusions: This report, detailing the proceedings of this pivotal symposium, suggests a potential turning point in designing future IPF clinical trials more attuned to outcomes meaningful to patients, and documents the collective agreement across multidisciplinary stakeholders on the importance of anchoring IPF trial endpoints on real patient experiences—namely, how they feel, function, and survive. There is considerable optimism that clinical care in IPF will progress through trials focused on patient-centric insights, ultimately guiding transformative treatment strategies to enhance patients' quality of life and survival.
Alport syndrome: A puzzling case of thrombocytopenia and giant unusual platelets in blood smear
Authors: Jon Ocal, Martha Sola‐Visner, Lisa Rimsza
Journal: American Journal of Hematology (2024)

A puzzling case of thrombocytopenia and giant unusual platelets in blood smear reveals a past diagnosis of Alport syndrome in 44-year-old woman with end-stage renal disease and abnormal CBC values. No conflicts to disclose.
Synthetic Polymer Nanoparticles as an Abiotic Artificial Inhibitor of Tyrosinase
Authors: Tong Zhang, Yuan Li, Jing Guo, Weiliang Sun, Yongqin Lv
Journal: Advanced Healthcare Materials (2024)

Abstract An innovative methodology is presented for synthesizing synthetic polymer nanoparticles (TINPs) as potent tyrosinase inhibitors. This inhibition strategy combines the integration of two distinct functionalities, phenol, and phenylboronic acid, within the TINPs structure. The phenyl group mimics the natural monophenol substrate, forming a strong coordination with the catalytic copper ion, significantly inhibiting tyrosinase activity. Additionally, phenylboronic acid interacts with catechol, another tyrosinase substrate, further reducing enzyme efficiency. The shared benzene ring in phenyl and phenylboronic acid enhances binding to tyrosinase's hydrophobic pocket near its copper active site, contributing to potent inhibition. TINPs exhibit exceptional performance, boasting an impressive IC 50 value of 3.5×10 −8 m and an inhibition constant of 9.8×10 −9 m . Validation of the approach is unequivocally demonstrated through the successful inhibition of tyrosinase activity and melanin production, substantiated in both in vitro and in vivo scenarios. The mechanism of TINP inhibition is elucidated through circular dichroism and Fourier transform infrared spectroscopy. This study introduces a versatile design approach for developing abiotic polymer‐based enzyme inhibitors, expanding possibilities in enzyme inhibition research.
<i>QuickStats:</i> Rate of Triplet and Higher-Order Multiple Births,*<sup>,</sup>† by Age of Mother — National Vital Statistics System, United States, 1998 and 2022
Journal: MMWR Morbidity and Mortality Weekly Report (2024)

Support Width OptionsPage wide = 7.5" QuickStats = 5.0" 1½ columns = 4.65" 1 column = 3.
SMAD7 expression in CAR-T cells improves persistence and safety for solid tumors
Authors: Sixin Liang, Rui Zheng, Baile Zuo, Jia Li, Yiyi Wang, Yujie Han, Hao Dong, Xiaojuan Zhao, Yiting Zhang, Pengju Wang, Ruotong Meng, Lintao Jia, Angang Yang, Bo Yan
Journal: Cellular and Molecular Immunology (2024)
Second Nationwide Tuberculosis Outbreak Caused by Bone Allografts Containing Live Cells — United States, 2023
Authors: Jonathan M. Wortham, Maryam B. Haddad, Rebekah J. Stewart, Pallavi Annambhotla, Sridhar V. Basavaraju, Scott A. Nabity, Isabel S. Griffin, Emily McDonald, Elizabeth M. Beshearse, Marissa K. Grossman, Kimberly R. Schildknecht, Helene M. Calvet, Chris E. Keh, Jeffrey M. Percak, Myron Coloma, Tambi Shaw, Peter J. Davidson, Shona R. Smith, Robert P. Dickson, Daniel R. Kaul, Annett R. Gonzalez, Saroj Rai, Gretchen Rodriguez, Sandra Morris, Lisa Y. Armitige, Jessica Stapleton, Michael Lacassagne, Laura R. Young, Kiley Ariail, Heidi Behm, Hannah T. Jordan, Magdalene Spencer, Diana M. Nilsen, Brenda Montoya Denison, Marcos Burgos, Juliet M. Leonard, Erick Cortes, Tyler C. Thacker, Kimberly A. Lehman, Adam J. Langer, Lauren S. Cowan, Angela M. Starks, Philip A. LoBue
Journal: MMWR Morbidity and Mortality Weekly Report (2024)

During July 7-11, 2023, CDC received reports of two patients in different states with a tuberculosis (TB) diagnosis following spinal surgical procedures that used bone allografts containing live cells from the same deceased donor. An outbreak associated with a similar product manufactured by the same tissue establishment (i.e., manufacturer) occurred in 2021. Because of concern that these cases represented a second outbreak, CDC and the Food and Drug Administration worked with the tissue establishment to determine that this product was obtained from a donor different from the one implicated in the 2021 outbreak and learned that the bone allograft product was distributed to 13 health care facilities in seven states. Notifications to all seven states occurred on July 12. As of December 20, 2023, five of 36 surgical bone allograft recipients received laboratory-confirmed TB disease diagnoses; two patients died of TB. Whole-genome sequencing demonstrated close genetic relatedness between positive Mycobacterium tuberculosis cultures from surgical recipients and unused product. Although the bone product had tested negative by nucleic acid amplification testing before distribution, M. tuberculosis culture of unused product was not performed until after the outbreak was recognized. The public health response prevented up to 53 additional surgical procedures using allografts from that donor; additional measures to protect patients from tissue-transmitted M. tuberculosis are urgently needed.
<i>Notes from the Field:</i> Seizures, Hyperthermia, and Myocardial Injury in Three Young Adults Who Consumed Bromazolam Disguised as Alprazolam — Chicago, Illinois, February 2023
Authors: Paul F. Ehlers, Amy Deitche, Leslie M. Wise, Sarah L. Patrick, Alfreda Holloway-Beth, Ross Ellison, Jordan Trecki, Roy Gerona, Michael S. Wahl
Journal: MMWR Morbidity and Mortality Weekly Report (2024)

Bromazolam is a "designer" triazolobenzodiazepine synthesized in 1976 but never approved for therapeutic use (1).Since its first detection in Sweden in 2016, a significant increase has persisted in both the toxicologic identification of bromazolam in combination with fentanyl and its identification in counterfeit benzodiazepine preparations (2).The number of law enforcement seizures in the United States that involved bromazolam increased from no more than three per year during 2016-2018 to 2,142 in 2022, and 2,913 in 2023.*In Illinois, bromazolam-involved † deaths increased from 10 in 2021 to 51 in 2022.§ Although human studies with clinical data are limited, animal models suggest bromazolam acts predominantly as a sedative, similar to other benzodiazepines, and to date, no signal for hyperthermia, myocardial injury, or seizures attributable to bromazolam intoxication exists (3).Although mostly detected alongside fentanyl or other opioids (88%-100% of tested samples), ¶ consumption of bromazolam can be life-threatening even in the absence of other drugs.This report discusses a cluster of three young adult patients who were treated at local emergency departments for hyperthermia, seizures, and myocardial injury after consuming bromazolam disguised as alprazolam.This activity was reviewed by CDC, deemed not research, and was conducted consistent with applicable federal law and CDC policy.*** The National Forensic Laboratory Information System (NFLIS) is an important resource in monitoring illicit drug trafficking, including the diversion of legally manufactured pharmaceuticals into illegal markets.NFLIS-Drug is a comprehensive information system that includes data from forensic laboratories that handle approximately 98% of an estimated 1.5 million distinct annual federal, state, and local drug analysis cases.NFLIS-Drug includes drug chemistry results from completed analyses only.Query date was December 14, 2023; data for 2023 are still being reported.https://www.nflis.deadiversion.usdoj.gov/† A case was categorized as bromazolam-involved if bromazolam was listed as a contributing cause of death on the death certificate in the Illinois Vital Records system.§ https://dph.illinois.gov/data-statistics/vital-statistics.html
Multiregion sampling of de novo metastatic prostate cancer reveals complex polyclonality and augments clinical genotyping
Authors: Evan W. Warner, Kim Van der Eecken, Andrew J. Murtha, Edmond M. Kwan, Cameron Herberts, Joonatan Sipola, Sarah W. S. Ng, Xinyi E. Chen, Nicolette M. Fonseca, Elie Ritch, Elena Schönlau, Cecily Q. Bernales, Gráinne Donnellan, Aslı D. Munzur, Karan Parekh, Kevin Beja, Amanda Wong, Sofie Verbeke, Nicolaas Lumen, Jo Van Dorpe, Bram De Laere, Matti Annala, Gillian Vandekerkhove, Piet Ost, Alexander W. Wyatt
Journal: Nature Cancer (2024)
Microglia enhance post-anesthesia neuronal activity by shielding inhibitory synapses
Authors: Koichiro Haruwaka, Yanlu Ying, Yue Liang, Anthony D. Umpierre, Min-Hee Yi, Vaclav Kremen, Tingjun Chen, Tao Xie, Fangfang Qi, Shunyi Zhao, Jiaying Zheng, Yong U. Liu, Hailong Dong, Gregory A. Worrell, Long-Jun Wu
Journal: Nature Neuroscience (2024)
Randomized open-label trial of semaglutide and dapagliflozin in patients with type 2 diabetes of different pathophysiology
Authors: Chinmay Dwibedi, Ola Ekström, Jasmine Brandt, Martin Adiels, Stefan Franzén, Birgitta Abrahamsson, Anders H. Rosengren
Journal: Nature Metabolism (2024)

The limited understanding of the heterogeneity in the treatment response to antidiabetic drugs contributes to metabolic deterioration and cardiovascular complications
A neural mechanism for conserved value computations integrating information and rewards
Authors: Ethan S. Bromberg-Martin, Yang-Yang Feng, Takaya Ogasawara, J. Kael White, Kaining Zhang, Ilya E. Monosov
Journal: Nature Neuroscience (2024)

Abstract Behavioral and economic theory dictate that we decide between options based on their values. However, humans and animals eagerly seek information about uncertain future rewards, even when this does not provide any objective value. This implies that decisions are made by endowing information with subjective value and integrating it with the value of extrinsic rewards, but the mechanism is unknown. Here, we show that human and monkey value judgements obey strikingly conserved computational principles during multi-attribute decisions trading off information and extrinsic reward. We then identify a neural substrate in a highly conserved ancient structure, the lateral habenula (LHb). LHb neurons signal subjective value, integrating information’s value with extrinsic rewards, and the LHb predicts and causally influences ongoing decisions. Neurons in key input areas to the LHb largely signal components of these computations, not integrated value signals. Thus, our data uncover neural mechanisms of conserved computations underlying decisions to seek information about the future.
Multimodal profiling reveals site-specific adaptation and tissue residency hallmarks of γδ T cells across organs in mice
Authors: Anastasia du Halgouet, Kerstin Bruder, Nina Peltokangas, Aurélie Darbois, David Obwegs, Marion Salou, Robert Thimme, Maike Hofmann, Olivier Lantz, None Sagar
Journal: Nature Immunology (2024)

Abstract γδ T cells perform heterogeneous functions in homeostasis and disease across tissues. However, it is unclear whether these roles correspond to distinct γδ subsets or to a homogeneous population of cells exerting context-dependent functions. Here, by cross-organ multimodal single-cell profiling, we reveal that various mouse tissues harbor unique site-adapted γδ subsets. Epidermal and intestinal intraepithelial γδ T cells are transcriptionally homogeneous and exhibit epigenetic hallmarks of functional diversity. Through parabiosis experiments, we uncovered cellular states associated with cytotoxicity, innate-like rapid interferon-γ production and tissue repair functions displaying tissue residency hallmarks. Notably, our observations add nuance to the link between interleukin-17-producing γδ T cells and tissue residency. Moreover, transcriptional programs associated with tissue-resident γδ T cells are analogous to those of CD8 + tissue-resident memory T cells. Altogether, this study provides a multimodal landscape of tissue-adapted γδ T cells, revealing heterogeneity, lineage relationships and their tissue residency program.
Gene therapy with bidridistrogene xeboparvovec for limb-girdle muscular dystrophy type 2E/R4: phase 1/2 trial results
Authors: Jerry R. Mendell, Eric R. Pozsgai, Sarah Lewis, Danielle A. Griffin, Linda P. Lowes, Lindsay N. Alfano, Kelly J. Lehman, Kathleen Church, Natalie F. Reash, Megan A. Iammarino, Brenna Sabo, Rachael Potter, Sarah Neuhaus, Xiaoxi Li, Herb Stevenson, Louise R. Rodino-Klapac
Journal: Nature Medicine (2024)

Abstract Limb-girdle muscular dystrophy 2E/R4 is caused by mutations in the β-sarcoglycan ( SGCB ) gene, leading to SGCB deficiency and consequent muscle loss. We developed a gene therapy approach based on functional replacement of the deficient SCB protein. Here we report interim results from a first-in-human, open-label, nonrandomized, phase 1/2 trial evaluating the safety and efficacy of bidridistrogene xeboparvovec, an adeno-associated virus-based gene therapy containing a codon-optimized, full-length human SGCB transgene. Patients aged 4–15 years with confirmed SGCB mutations at both alleles received one intravenous infusion of either 1.85 × 10 13 vector genome copies kg − 1 (Cohort 1, n = 3) or 7.41 × 10 13 vector gene copies kg −1 (Cohort 2, n = 3). Primary endpoint was safety, and secondary endpoint was change in SGCB expression in skeletal muscle from baseline to Day 60. We report interim Year 2 results (trial ongoing). The most frequent treatment-related adverse events were vomiting (four of six patients) and gamma-glutamyl transferase increase (three of six patients). Serious adverse events resolved with standard therapies. Robust SGCB expression was observed: Day 60 mean (s.d.) percentage of normal expression 36.2% (2.7%) in Cohort 1 and 62.1% (8.7%) in Cohort 2. Post hoc exploratory analysis showed preliminary motor improvements using the North Star Assessment for Limb-girdle Type Muscular Dystrophies maintained through Year 2. The 2-year safety and efficacy of bidridistrogene xeboparvovec support clinical development advancement. Further studies are necessary to confirm the long-term safety and efficacy of this gene therapy. ClinicalTrials.gov registration: NCT03652259 .
Sotorasib with panitumumab in chemotherapy-refractory KRASG12C-mutated colorectal cancer: a phase 1b trial
Authors: Yasutoshi Kuboki, Marwan Fakih, John Strickler, Rona Yaeger, Toshiki Masuishi, Edward J. Kim, Christine M. Bestvina, Scott Kopetz, Gerald S. Falchook, Corey Langer, John Krauss, Sonam Puri, Panli Cardona, Emily Chan, Tracy Varrieur, Lata Mukundan, Abraham Anderson, Qui Tran, David S. Hong
Journal: Nature Medicine (2024)