tbuckley/cabot-search huggingface dataset:
Cancer-Associated Fibroblasts Expressing Sulfatase 1 Facilitate VEGFA-Dependent Microenvironmental Remodeling to Support Colorectal Cancer
Authors: Huijuan Wang, Jiaxin Chen, Xiaoyu Chen, Yingqiang Liu, Jiawei Wang, Qing Meng, Huogang Wang, Ying He, Yujia Song, Jingyun Li, Zhenyu Ju, Peng Xiao, Junbin Qian, Zhangfa Song
Journal: Cancer Research (2024)

Abstract Tumor stroma plays a critical role in fostering tumor progression and metastasis. Cancer-associated fibroblasts (CAFs) are a major component of the tumor stroma. Identifying the key molecular determinants for the pro-tumor properties of CAFs could enable the development of more effective treatment strategies. Herein, through analyses of single-cell sequencing data, we identified a population of CAFs expressing high levels of sulfatase 1 (SULF1), which was associated with poor prognosis in colorectal cancer (CRC) patients. CRC models using mice with conditional SULF1 knockout in fibroblasts revealed the tumor-supportive function of SULF1+ CAFs. Mechanistically, SULF1+ CAFs enhanced the release of vascular endothelial growth factor A (VEGFA) from heparan sulfate proteoglycan (HSPG). The increased bioavailability of VEGFA initiated the deposition of extracellular matrix (ECM) and enhanced angiogenesis. In addition, intestinal microbiota-produced butyrate suppressed SULF1 expression in CAFs through its HDAC inhibitory activity. The insufficient butyrate production in CRC patients increased the abundance of SULF1+ CAFs, thereby promoting tumor progression. Importantly, tumor growth inhibition by HDAC inhibition was dependent on SULF1 expression in CAFs, and CRC patients with more SULF1+ CAFs were more responsive to treatment with the HDAC inhibitor chidamide. Collectively, these findings unveil the critical role of SULF1+ CAFs in CRC and provide a strategy to stratify CRC patients for HDAC inhibitor treatment.
Targeting NTRK1 Enhances Immune Checkpoint Inhibitor Efficacy in NTRK1 Wild-type Non-Small Cell Lung Cancer
Authors: Margaret R. Smith, Caroline B. Dixon, Yuezhu Wang, Yin Liu, Ralph D’Agostino, Jimmy Ruiz, George Oliver, Lance D. Miller, Umit Topaloglu, Michael D. Chan, Michael Farris, Jing Su, Kathryn F. Mileham, Dawen Zhao, Wencheng Li, Tammy Sexton, Thomas Lycan, Karen M. Haas, Jason M. Grayson, Fei Xing
Journal: Cancer Research (2024)

Abstract Treatment of non–small cell lung cancer (NSCLC) has drastically changed in recent years owing to the robust anticancer effects of immune checkpoint inhibitors (ICI). However, only 20% of the patients with NSCLC benefit from ICIs, highlighting the need to uncover the mechanisms mediating resistance. By analyzing the overall survival (OS) and mutational profiles of 424 patients with NSCLC who received ICI treatments between 2015 and 2021, we determined that patients carrying a loss-of-function mutation in neurotrophic tyrosine kinase receptor 1 (NTRK1) had a prolonged OS when compared with patients with wild-type NTRK1. Notably, suppression of the NTRK1 pathway by knockdown or entrectinib treatment significantly enhanced ICI efficacy in mouse NSCLC models. Comprehensive T-cell population analyses demonstrated that stem-like CD4+ T cells and effector CD4+ and CD8+ T cells were highly enriched in anti–PD-1–treated mice bearing tumors with decreased NTRK1 signaling. RNA sequencing revealed that suppression of NTRK1 signaling in tumor cells increased complement C3 expression, which enhanced the recruitment of T cells and myeloid cells and stimulated M1-like macrophage polarization in the tumor. Together, this study demonstrates a role for NTRK1 signaling in regulating cross-talk between tumor cells and immune cells in the tumor microenvironment and provides a potential therapeutic approach to overcome immunotherapy resistance in patients with NSCLC with NTRK1 wild-type. Significance: Inhibition of NTRK1 signaling confers sensitivity to immunotherapy by enhancing complement C3-mediated T-cell and macrophage functions, leading to improved responses to immune checkpoint inhibitors in patients with lung cancer with NTRK1 mutations.
Rejuvenation of aged oocyte through exposure to young follicular microenvironment
Authors: HaiYang Wang, Zhongwei Huang, Xingyu Shen, Yaelim Lee, XinJie Song, Chang Shu, Lik Hang Wu, Leroy Sivappiragasam Pakkiri, Poh Leong Lim, Xi Zhang, Chester Lee Drum, Jin Zhu, Rong Li
Journal: Nature Aging (2024)
Airway tryptase levels inform the lack of clinical efficacy of the tryptase inhibitor <scp>MTPS9579A</scp> in asthma
Authors: Horace Rhee, Lindsay M. Henderson, Rebecca N. Bauer, Kit Wong, Tracy L. Staton, David F. Choy, Prajna Banerjee, Victor Poon, Kenta Yoshida, Chen Chen, Keyi Long, Gizette Sperinde, Steven T. Laing, Nicholas S. Jones, Sara B. Glickstein, Parul Dayal, Alice Fong, Ajit Dash, Grazyna Pulka, Brian Leaker, Dave Singh, Peter Bradding
Journal: Allergy (2024)

Abstract Background Tryptase, a mast cell protease, has been identified as a potential therapeutic target in managing patients with refractory asthma. We assessed the efficacy, safety, pharmacokinetics, and pharmacodynamics of MTPS9579A, an anti‐tryptase antibody, in a phase 2a randomized trial for patients with uncontrolled asthma and a phase 1c trial to understand activity within the lower respiratory tract. Methods Phase 2a patients ( n = 134) received 1800 mg MTPS9579A or placebo intravenously every 4 weeks for 48 weeks. The primary endpoint was time to the first composite exacerbation event. Phase 1c patients ( n = 27) received one intravenous dose of 300 or 1800 mg MTPS9579A or placebo. Both trials measured MTPS9579A concentrations and effects on tryptase in serum and nasal lining fluid; phase 1c also analyzed bronchial lining fluid. Results MTPS9579A did not meet the primary endpoint (hazard ratio = 0.90; 95% CI: 0.55–1.47; p = 0.6835); exacerbation rates in the placebo group were low. Serum and nasal MTPS9579A pharmacokinetics and tryptase levels were consistent with data from healthy volunteers. However, in phase 1c patients, compared to nasal levels, MTPS9579A bronchial concentrations were 6.8‐fold lower, and bronchial active and total tryptase levels were higher (119‐fold and 30‐fold, respectively). Pharmacokinetic/pharmacodynamic modeling predicted intravenous doses of 3800 mg every 4 weeks would be necessary to achieve 95% active tryptase inhibition from baseline. Conclusions The MTPS9579A dose tested in the phase 2a study was insufficient to inhibit tryptase in bronchial lining fluid, likely contributing to the observed lack of efficacy.
The Large Language Model GPT-4 Compared to Endocrinologist Responses on Initial Choice of Antidiabetic Medication under Conditions of Clinical Uncertainty
Authors: James H. Flory, Jessica S. Ancker, Scott Y.H. Kim, Gilad Kuperman, Aleksandr Petrov, Andrew Vickers
Journal: Diabetes Care (2024)

OBJECTIVE To explore how the commercially available large language model (LLM) GPT-4 compares to endocrinologists when addressing medical questions when there is uncertainty regarding the best answer. RESEARCH DESIGN AND METHODS This study compared responses from GPT-4 to responses from 31 endocrinologists using hypothetical clinical vignettes focused on diabetes, specifically examining the prescription of metformin versus alternative treatments. The primary outcome was the choice between metformin and other treatments. RESULTS With a simple prompt, GPT-4 chose metformin in 12% (95% CI 7.9–17%) of responses, compared with 31% (95% CI 23–39%) of endocrinologist responses. After modifying the prompt to encourage metformin use, the selection of metformin by GPT-4 increased to 25% (95% CI 22–28%). GPT-4 rarely selected metformin in patients with impaired kidney function, or a history of gastrointestinal distress (2.9% of responses, 95% CI 1.4–5.5%). In contrast, endocrinologists often prescribed metformin even in patients with a history of gastrointestinal distress (21% of responses, 95% CI 12–36%). GPT-4 responses showed low variability on repeated runs except at intermediate levels of kidney function. CONCLUSIONS In clinical scenarios with no single right answer, GPT-4’s responses were reasonable, but differed from endocrinologists’ responses in clinically important ways. Value judgments are needed to determine when these differences should be addressed by adjusting the model. We recommend against reliance on LLM output until it is shown to align not just with clinical guidelines but also with patient and clinician preferences, or it demonstrates improvement in clinical outcomes over standard of care.
Pathophysiology and Treatment of Prediabetes and Type 2 Diabetes in Youth
Authors: Fida Bacha, Tamara S. Hannon, Mustafa Tosur, Julie M. Pike, Ashley Butler, Kalie L. Tommerdahl, Philip S. Zeitler
Journal: Diabetes Care (2024)

Youth-onset type 2 diabetes is a heterogeneous disease with increasing prevalence in relation to increased rates of obesity in children. It has genetic, epigenetic, social, and environmental determinants. Youth-onset type 2 diabetes is alarming given a rapidly progressive course compared with the course of adult-onset disease, early-onset vascular complications, and long-term exposure to hyperglycemia and associated complications. It is often preceded by prediabetes, a disease phase where defects in β-cell function relative to insulin sensitivity emerge. Herein, we review the current understanding of the pathophysiology of prediabetes and type 2 diabetes in youth. We describe the mechanisms underlying insulin resistance, the precipitous decline of β-cell function, and the role of other hormonal abnormalities in the pathogenesis of the disease. We discuss the critical importance of social determinants of health in the predisposition and progression of these conditions and present current management strategies and the advances in therapeutic approaches. These must adapt to meet the unique needs of the individual patient and family. Significant knowledge gaps remain that need to be addressed in future research.
Impaired calcium influx underlies skewed T helper cell differentiation in children with <scp>IgE</scp>‐mediated food allergies
Authors: C. L. Lai, B. Santner‐Nanan, P. J. Maltese, C. K. S. Ong, D. J. Palmer, D. E. Campbell, M. Makrides, M. Gold, R. Nanan, S. L. Prescott, P. S. Hsu
Journal: Allergy (2024)

Reasons for Th2 skewing in IgE-mediated food allergies remains unclear. Clinical observations suggest impaired T cell activation may drive Th2 responses evidenced by increased atopic manifestations in liver transplant patients on tacrolimus (a calcineurin inhibitor). We aimed to assess differentiation potential, T cell activation and calcium influx of naïve CD4+ T cells in children with IgE-mediated food allergies. Peripheral blood mononuclear cells from infants in the Starting Time for Egg Protein (STEP) Trial were analyzed by flow cytometry to assess Th1/Th2/Treg development. Naïve CD4+ T cells from children with and without food allergies were stimulated for 7 days to assess Th1/Th2/Treg transcriptional factors and cytokines. Store operated calcium entry (SOCE) was measured in children with and without food allergies. The effect of tacrolimus on CD4+ T cell differentiation was assessed by treating stimulated naïve CD4+ T cells from healthy volunteers with tacrolimus for 7 days. Egg allergic infants had impaired development of IFNγ+ Th1 cells and FoxP3+ transitional CD4+ T cells compared with non-allergic infants. This parallels reduced T-bet, IFNγ and FoxP3 expression in naïve CD4+ T cells from food allergic children after in vitro culture. SOCE of naïve CD4+ T cells was impaired in food allergic children. Naïve CD4+ T cells treated with tacrolimus had reduced IFNγ, T-bet, and FoxP3, but preserved IL-4 expression. In children with IgE-mediated food allergies, dysregulation of T helper cell development is associated with impaired SOCE, which underlies an intrinsic impairment in Th1 and Treg differentiation. Along with tacrolimus-induced Th2 skewing, this highlights an important role of SOCE/calcineurin pathway in T helper cell differentiation.
Initial Defibrillator Pad Position and Outcomes for Shockable Out-of-Hospital Cardiac Arrest
Authors: Joshua R. Lupton, Craig D. Newgard, David Dennis, Jack Nuttall, Ritu Sahni, Jonathan Jui, Matthew R. Neth, Mohamud R. Daya
Journal: JAMA Network Open (2024)

Importance Ventricular fibrillation (VF) or pulseless ventricular tachycardia (pVT) are the most treatable causes of out-of-hospital cardiac arrest (OHCA). Yet, it remains unknown if defibrillator pad position, placement in the anterior-posterior (AP) or anterior-lateral (AL) locations, impacts patient outcomes in VF or pVT OHCA. Objective To determine the association between initial defibrillator pad placement position and OHCA outcomes for patients presenting with VF or pVT. Design, Setting, and Participants This prospective cohort study included patients with OHCA and VF or pVT treated by a single North American emergency medical services (EMS) agency from July 1, 2019, through June 30, 2023. The study included patients with OHCA treated by a large suburban fire-based EMS agency that covers a population of 550 000. Consecutive patients with an initial EMS-assessed rhythm of VF or pVT receiving EMS defibrillation were included. Pediatric patients (younger than 18 years), interfacility transfers, arrests of obvious traumatic etiology, and patients with preexisting do-not-resuscitate status were excluded. Exposure AP or AL pad placement. Main Outcomes and Measures Return of spontaneous circulation (ROSC) at any time with secondary outcomes of pulses present at emergency department (ED) arrival, survival to hospital admission, survival to hospital discharge, and functional survival at hospital discharge (cerebral performance category score of 2 or less). Measures included adjusted odds ratios (aOR), multivariable logistic regressions, and Fine-Gray competing risks regression. Results A total of 255 patients with OHCA were included (median [IQR] age, 66 [55-74] years; 63 females [24.7%]), with initial pad positioning documented as either AP (158 patients [62.0%]; median [IQR] age, 65 [54-74] years; 37 females [23.4%]) or AL (97 patients [38.0%]; median [IQR] age, 66 [57-74] years; 26 females [26.8%]). Patients with AP placement had higher adjusted odds ratio (aOR) of ROSC at any time (aOR, 2.64 [95% CI, 1.50-4.65]), but not significantly different odds of pulses present at ED arrival (1.34 [95% CI, 0.78-2.30]), survival to hospital admission (1.41 [0.82-2.43]), survival to hospital discharge (1.55 [95% CI, 0.83-2.90]), or functional survival at hospital discharge (1.86 [95% CI, 0.98-3.51]). Competing risk analysis found significantly greater cumulative incidence of ROSC among those at risk with initial AP placement compared with AL (subdistribution hazard ratio, 1.81 [95% CI, 1.23-2.67]; P = .003). Conclusions and Relevance In this cohort study of patients with OHCA and VF or pVT, AP defibrillator pad placement was associated with higher ROSC compared with AL placement.
Anxiety and Depression in Youth With Chronic Pain
Authors: Joanne Dudeney, Rachel V. Aaron, Taylor Hathway, Kavya Bhattiprolu, Madelyne A. Bisby, Lakeya S. McGill, Milena Gandy, Nicole Harte, Blake F. Dear
Journal: JAMA Pediatrics (2024)

Importance For youth with chronic pain, anxiety and depression are reported as consequences of experiencing pain and maintaining factors of ongoing pain and disability. However, prevalence estimates of anxiety and depression remain unclear. Objective To report the prevalence of clinical anxiety and depression for youth with chronic pain and compare symptoms of anxiety and depression between youth with and without chronic pain. Data Sources MEDLINE, PsycINFO, CENTRAL, and Embase from inception to April 30, 2023. Study Selection Included studies that reported prevalence data or symptom scores for anxiety and/or depression in individuals younger than 25 years (mean, ≤18 years) with chronic pain and were published in English. Data Extraction and Synthesis From 9648 nonduplicate records, 801 full-text articles were screened. Screening and data extraction occurred in duplicate. Prevalence was determined using event rate calculations. Between-group symptom differences were calculated using Hedges g . Analyses were conducted using the random-effects model. Reporting bias and Grading of Recommendation, Assessment, Development, and Evaluation assessments were conducted. Main Outcomes and Measures Prevalence of anxiety and depression (based on diagnosis and clinical cutoff scores) and differences in anxiety and depression symptoms. Moderators of prevalence and symptom differences were analyzed when data allowed. Results A total of 79 studies were included with a total sample of 22 956 youth (n = 12 614 with chronic pain). Most youth were female (mean, 74%), with an age range of 4 to 24 (mean [SD], 13.7 [2.10]) years. The prevalence estimate of anxiety diagnoses was 34.6% (95% CI, 24.0%-47.0%) and the portion that exceeded clinical cutoff scores was 23.9% (95% CI, 18.3%-30.6%). The prevalence of depression diagnoses was 12.2% (95% CI, 7.8%-18.7%) and the portion that exceeded clinical cutoff scores was 23.5% (95% CI, 18.7%-29.2%). Youth with chronic pain had greater symptoms of anxiety ( g = 0.61; 95% CI, 0.46-0.77) and depression ( g = 0.74; 95% CI, 0.63-0.85) compared with controls. Sex, age, pain location, and recruitment sample may moderate anxiety and depression. Considerable heterogeneity was reported for all outcomes. Studies had a low reporting bias, and outcomes were moderate to high quality. Conclusions and Relevance The findings of this meta-analysis suggest that 1 in 3 youth with chronic pain meet criteria for anxiety disorder, and 1 in 8 meet criteria for a depressive disorder. This represents a major clinical comorbidity. Moving forward, screening, prevention, and treatment of mental health should be important health care priorities for youth with chronic pain.
Early Newborn Metabolic Patterning and Sudden Infant Death Syndrome
Authors: Scott P. Oltman, Elizabeth E. Rogers, Rebecca J. Baer, Ribka Amsalu, Gretchen Bandoli, Christina D. Chambers, Hyunkeun Cho, John M. Dagle, Kayla L. Karvonen, Stephen F. Kingsmore, Safyer McKenzie-Sampson, Allison Momany, Eric Ontiveros, Liana D. Protopsaltis, Larry Rand, Erica Sanford Kobayashi, Martina A. Steurer, Kelli K. Ryckman, Laura L. Jelliffe-Pawlowski
Journal: JAMA Pediatrics (2024)

Importance Sudden infant death syndrome (SIDS) is a major cause of infant death in the US. Previous research suggests that inborn errors of metabolism may contribute to SIDS, yet the relationship between SIDS and biomarkers of metabolism remains unclear. Objective To evaluate and model the association between routinely measured newborn metabolic markers and SIDS in combination with established risk factors for SIDS. Design, Setting, and Participants This was a case-control study nested within a retrospective cohort using data from the California Office of Statewide Health Planning and Development and the California Department of Public Health. The study population included infants born in California between 2005 and 2011 with full metabolic data collected as part of routine newborn screening (NBS). SIDS cases were matched to controls at a ratio of 1:4 by gestational age and birth weight z score. Matched data were split into training (2/3) and testing (1/3) subsets. Data were analyzed from January 2005 to December 2011. Exposures Metabolites measured by NBS and established risk factors for SIDS. Main Outcomes and Measures The primary outcome was SIDS. Logistic regression was used to evaluate the association between metabolic markers combined with known risk factors and SIDS. Results Of 2 276 578 eligible infants, 354 SIDS (0.016%) cases (mean [SD] gestational age, 38.3 [2.3] weeks; 220 male [62.1%]) and 1416 controls (mean [SD] gestational age, 38.3 [2.3] weeks; 723 male [51.1%]) were identified. In multivariable analysis, 14 NBS metabolites were significantly associated with SIDS in a univariate analysis: 17-hydroxyprogesterone, alanine, methionine, proline, tyrosine, valine, free carnitine, acetyl-L-carnitine, malonyl carnitine, glutarylcarnitine, lauroyl-L-carnitine, dodecenoylcarnitine, 3-hydroxytetradecanoylcarnitine, and linoleoylcarnitine. The area under the receiver operating characteristic curve for a 14-marker SIDS model, which included 8 metabolites, was 0.75 (95% CI, 0.72-0.79) in the training set and was 0.70 (95% CI, 0.65-0.76) in the test set. Of 32 infants in the test set with model-predicted probability greater than 0.5, a total of 20 (62.5%) had SIDS. These infants had 14.4 times the odds (95% CI, 6.0-34.5) of having SIDS compared with those with a model-predicted probability less than 0.1. Conclusions and Relevance Results from this case-control study showed an association between aberrant metabolic analytes at birth and SIDS. These findings suggest that we may be able to identify infants at increased risk for SIDS soon after birth, which could inform further mechanistic research and clinical efforts focused on monitoring and prevention.
Distinct mucosal endotypes as initiators and drivers of rheumatoid arthritis
Authors: V Michael Holers, Kristen M Demoruelle, Jane H Buckner, Eddie A James, Gary S Firestein, William H Robinson, Allen C Steere, Fan Zhang, Jill M Norris, Kristine A Kuhn, Kevin D Deane
Journal: Nature Reviews Rheumatology (2024)
Amygdala Cannabinoid 1 Receptor, Pain Response, and Emotional Numbing in Trauma-Exposed Individuals
Authors: Nachshon Korem, Ansel T. Hillmer, Deepak Cyril D’Souza, Anahita Bassir Nia, Ifat Levy, Robert H. Pietrzak, Ilan Harpaz-Rotem
Journal: JAMA Network Open (2024)

This case-control study assesses associations of amygdala cannabinoid 1 receptor availability with amygdala response to shock-induced pain and severity of emotional numbing symptoms of veterans with posttraumatic stress disorder.
Author Correction: Genetic variants in UNC93B1 predispose to childhood-onset systemic lupus erythematosus
Authors: Mahmoud Al-Azab, Elina Idiiatullina, Ziyang Liu, Meng Lin, Katja Hrovat-Schaale, Huifang Xian, Jianheng Zhu, Mandy Yang, Bingtai Lu, Zhiyao Zhao, Yiyi Liu, Jingjie Chang, Xiaotian Li, Caiqin Guo, Yunfeng Liu, Qi Wu, Jiazhang Chen, Chaoting Lan, Ping Zeng, Jun Cui, Xia Gao, Wenhao Zhou, Yan Zhang, Yuxia Zhang, Seth L Masters
Journal: Nature Immunology (2024)
Machine Learning to Enhance Electronic Detection of Diagnostic Errors
Authors: Andrew J. Zimolzak, Li Wei, Usman Mir, Ashish Gupta, Viralkumar Vaghani, Devika Subramanian, Hardeep Singh
Journal: JAMA Network Open (2024)

This cohort study examines whether machine learning (ML) can enhance the ability of electronic triggers to identify possible missed opportunities in diagnosis.
Lipolysis engages CD36 to promote ZBP1-mediated necroptosis-impairing lung regeneration in COPD
Authors: Jiazhen Wang, Ru Wang, Yicun Li, Jiahui Huang, Yang Liu, Jiayi Wang, Peng Xian, Yuanhang Zhang, Yanmei Yang, Haojian Zhang, Jiansheng Li
Journal: Cell Reports Medicine (2024)