tbuckley/cabot-search huggingface dataset:
Selective regulation of IFN-γ and IL-4 co-producing unconventional T cells by purinergic signaling
Authors: Calvin Xu, Andreas Obers, Minyi Qin, Alice Brandli, Joelyn Wong, Xin Huang, Allison Clatch, Aly Fayed, Graham Starkey, Rohit D’Costa, Claire L. Gordon, Jeffrey Y.W. Mak, David P. Fairlie, Lynette Beattie, Laura K. Mackay, Dale I. Godfrey, Hui-Fern Koay
Journal: The Journal of Experimental Medicine (2024)

Unconventional T cells, including mucosal-associated invariant T (MAIT), natural killer T (NKT), and gamma-delta T (γδT) cells, comprise distinct T-bet+, IFN-γ+ and RORγt+, IL-17+ subsets which play differential roles in health and disease. NKT1 cells are susceptible to ARTC2-mediated P2X7 receptor (P2RX7) activation, but the effects on other unconventional T-cell types are unknown. Here, we show that MAIT, γδT, and NKT cells express P2RX7 and are sensitive to P2RX7-mediated cell death. Mouse peripheral T-bet+ MAIT1, γδT1, and NKT1 cells, especially in liver, co-express ARTC2 and P2RX7. These markers could be further upregulated upon exposure to retinoic acid. Blocking ARTC2 or inhibiting P2RX7 protected MAIT1, γδT1, and NKT1 cells from cell death, enhanced their survival in vivo, and increased the number of IFN-γ-secreting cells without affecting IL-17 production. Importantly, this revealed the existence of IFN-γ and IL-4 co-producing unconventional T-cell populations normally lost upon isolation due to ARTC2/P2RX7-induced death. Administering extracellular NAD in vivo activated this pathway, depleting P2RX7-sensitive unconventional T cells. Our study reveals ARTC2/P2RX7 as a common regulatory axis modulating the unconventional T-cell compartment, affecting the viability of IFN-γ- and IL-4-producing T cells, offering important insights to facilitate future studies into how these cells can be regulated in health and disease.
Longitudinal multimodal profiling of IDH-wildtype glioblastoma reveals the molecular evolution and cellular phenotypes underlying prognostically different treatment responses
Authors: Calixto-Hope G Lucas, Nadeem N Al-Adli, Jacob S Young, Rohit Gupta, Ramin A Morshed, Jasper Wu, Ajay Ravindranathan, Anny Shai, Nancy Ann Oberheim Bush, Jennie W Taylor, John de Groot, Javier E Villanueva-Meyer, Melike Pekmezci, Arie Perry, Andrew W Bollen, Philip V Theodosopoulos, Manish K Aghi, Edward F Chang, Shawn L Hervey-Jumper, David R Raleigh, Annette M Molinaro, Joseph F Costello, Aaron A Diaz, Jennifer L Clarke, Nicholas A Butowski, Joanna J Phillips, Susan M Chang, Mitchel S Berger, David A Solomon
Journal: Neuro-Oncology (2024)

Abstract Background Despite recent advances in the biology of IDH-wildtype glioblastoma, it remains a devastating disease with median survival of less than 2 years. However, the molecular underpinnings of the heterogeneous response to the current standard-of-care treatment regimen consisting of maximal safe resection, adjuvant radiation, and chemotherapy with temozolomide remain unknown. Methods Comprehensive histopathologic, genomic, and epigenomic evaluation of paired initial and recurrent glioblastoma specimens from 106 patients was performed to investigate the molecular evolution and cellular phenotypes underlying differential treatment responses. Results While TERT promoter mutation and CDKN2A homozygous deletion were early events during gliomagenesis shared by initial and recurrent tumors, most other recurrent genetic alterations (eg, EGFR, PTEN, and NF1) were commonly private to initial or recurrent tumors indicating acquisition later during clonal evolution. Furthermore, glioblastomas exhibited heterogeneous epigenomic evolution with subsets becoming more globally hypermethylated, hypomethylated, or remaining stable. Glioblastoma that underwent sarcomatous transformation had shorter interval to recurrence and were significantly enriched in NF1, TP53, and RB1 alterations and the mesenchymal epigenetic class. Patients who developed somatic hypermutation following temozolomide treatment had significantly longer interval to disease recurrence and prolonged overall survival, and increased methylation at 4 specific CpG sites in the promoter region of MGMT was significantly associated with this development of hypermutation. Finally, an epigenomic evolution signature incorporating change in DNA methylation levels across 347 critical CpG sites was developed that significantly correlated with clinical outcomes. Conclusions Glioblastoma undergoes heterogeneous genetic, epigenetic, and cellular evolution that underlies prognostically different treatment responses.
Metastasis development in non-muscle-invasive bladder cancer
Authors: Michael Leyderman, Thenappan Chandrasekar, Petros Grivas, Roger Li, Seetharam Bhat, Alina Basnet, Oleg Shapiro, Joseph Jacob, Michael A. Daneshvar, Eyal Kord, Gennady Bratslavsky, Hanan Goldberg
Journal: Nature Reviews Urology (2024)
Elevated risk of lung cancer among asian American females who have never smoked: an emerging cancer disparity
Authors: Scarlett Lin Gomez, Mindy DeRouen, Moon S Chen, Heather Wakelee, Jeffrey B Velotta, Lori C Sakoda, Salma Shariff-Marco, Peggy Reynolds, Iona Cheng
Journal: JNCI Journal of the National Cancer Institute (2024)

Abstract Lung cancer is a leading cause of cancer mortality for most ethnic groups of Asian American females, including Chinese, Korean, Japanese, and Vietnamese Americans, a striking pattern given the exceedingly low prevalence of smoking among Asian American females in the general population. Recent research demonstrates that among Asian American females diagnosed with lung cancer, the vast majority of patients have never smoked, as high as &amp;gt; 80% among Chinese and Asian Indian American females. Despite declining rates in lung cancer overall in the United States, rates among Asian American females who have never smoked appear to be increasing. This Commentary articulates extant knowledge, based on studies in Asia, of a range of risk factors such as a family history of lung cancer, history of lung diseases including tuberculosis and chronic obstructive pulmonary diseases, exposure to cooking fumes and second-hand smoke, and various putative risk factors. Unique mutational profiles at the tumor level, including higher prevalence of EGFR mutations among Asian populations, highlight the importance of tumor genomic testing of newly-diagnosed patients. Additional research is essential, given the high burden of disease among Asian American females who have never smoked, and limited knowledge regarding contributing risk factors specific to Asian American females, as the risk factors identified in Asians living in Asia may not apply.
Drug Survival and Safety of Biosimilars Compared with Originator Adalimumab for Psoriasis: A Multinational Cohort Study
Authors: Duc Binh Phan, Hugo Jourdain, Miguel Angel Descalzo-Gallego, Alicia González-Quesada, Mahmoud Zureik, Raquel Rivera-Díaz, Antonio Sahuquillo-Torralba, Mark Lunt, Ignacio Garcia-Doval, Emilie Sbidian, Richard B Warren, Zenas Z N Yiu
Journal: British Journal of Dermatology (2024)

Abstract Background The lack of evidence from routine clinical settings has limited the widespread adoption of adalimumab biosimilars for the treatment of psoriasis. Objectives To compare the drug survival and safety of adalimumab biosimilars with Humira® in psoriasis. Methods We conducted a prevalent new-user cohort study using data from the French National Health Data System (SNDS), the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR) and the Spanish Registry of Systemic Therapy in Psoriasis (BIOBADADERM). Adalimumab-naïve patients initiating adalimumab biosimilars (new users) were compared with Humira new users. Patients switching from Humira to biosimilars (switchers) were compared with those who continued Humira treatment. Patients were matched 1 : 1 based on previous adalimumab exposure time to create equal-sized cohorts of biosimilar and Humira users. Co-primary outcomes included drug discontinuation and serious adverse events (SAEs). Hazard ratios (HRs) were calculated using Cox proportional hazard models. Meta-analyses using random-effect models were performed to combine results from the three databases. Results In total, 7387 biosimilar new users and 3654 switchers were matched and compared with Humira users. No differences in all-cause discontinuation were found between biosimilar and Humira new users [HR 0.99, 95% confidence interval (CI) 0.94–1.04]. Switching from Humira to biosimilars was associated with a higher discontinuation rate than remaining on Humira (HR 1.35, 95% CI 1.19–1.52). Similar results were observed for discontinuation due to ineffectiveness or adverse events. Risks of SAEs were similar between biosimilar new users and Humira new users [incidence rate ratio (IRR) 0.91, 95% CI 0.80–1.05] or between switchers and continuous Humira users (IRR 0.92, 95% CI 0.83–1.01). Conclusions Adalimumab biosimilars can be considered viable alternatives to Humira for new patients, with comparable effectiveness and safety. However, owing to the higher likelihood of discontinuation, patients who switch from Humira to biosimilars may require closer monitoring and support.
First Cycle Toxicity and Survival in Patients with Rare Cancers Treated with Checkpoint Inhibitors
Authors: Megan Othus, Sandip P Patel, Young Kwang Chae, Eliana Dietrich, Howard Streicher, Elad Sharon, Razelle Kurzrock
Journal: JNCI Journal of the National Cancer Institute (2024)

Abstract Background Associations between immune-related adverse events from checkpoint inhibitor therapy and outcomes have been previously evaluated, with most prior research finding a positive association between toxicity and survival. This prior research has generally reported on more common tumor types. We use a unique data resource of a federally funded basket trial (NCT02834013) for patients with rare cancers (n = 684) to evaluate associations between immune-related adverse events and overall survival and progression-free survival (PFS). Methods Patients were treated with nivolumab and ipilimumab; the trial was opened at more than 1000 sites. Landmark Cox regression models were used to assess first cycle immune-related adverse event associations with PFS and overall survival. Results We found that grade 1-2 treatment-related immune-related adverse events in the first cycle of therapy were associated with longer overall survival (multivariable hazard ratio [HR] = 0.61, 95% confidence interval [CI] = 0.49 to 0.75; P &amp;lt; .001) compared with no treatment-related immune-related adverse event, while grade 3-4 immune-related adverse events were associated with shorter overall survival (HR = 1.41, 95% CI = 1.04 to 1.90; P = .025). Similar but weaker associations were observed with PFS and grade 1-2 treatment-related immune-related adverse events (HR = 0.83, 95% CI = 0.67 to 1.01; P = .067) and grade 3-4 (HR = 1.35, 95% CI = 1.02 to 1.78; P = .037) compared with no treatment-related immune-related adverse events. Grade 1-2 dermatologic toxicity was associated with improved overall survival compared with other grade 1-2 toxicities (HR = 0.67, 95% CI = 0.52 to 0.85; P = .002). There was no statistically significant overall survival difference between patients with grade 1-2 fatigue, gastrointestinal, metabolic, hepatic, endocrine, and thyroid toxicities vs other grade 1-2 toxicities. Conclusion In this large cohort of patients with rare tumors receiving checkpoint inhibitor therapy, grade of immune-related adverse event in the first cycle was predictive for survival.
Halving premature death and improving quality of life at all ages: cross-country analyses of past trends and future directions
Authors: Ole F Norheim, Angela Y Chang, Sarah Bolongaita, Mariana Barraza-Lloréns, Ayodamope Fawole, Lia Tadesse Gebremedhin, Eduardo González-Pier, Prabhat Jha, Emily K Johnson, Omar Karlsson, Mizan Kiros, Sarah Lewington, Wenhui Mao, Osondu Ogbuoji, Muhammad Pate, Jennifer L Sargent, Xuyang Tang, David Watkins, Gavin Yamey, Dean T Jamison, Richard Peto
Journal: The Lancet (2024)

Although death in old age is unavoidable, premature death-defined here as death before age 70 years-is not. To assess whether halving premature mortality by 2050 is feasible, we examined the large variation in premature death rates before age 70 years and trends over the past 50 years (1970-2019), covering ten world regions and the 30 most-populous nations. This analysis was undertaken in conjunction with the third report of The Lancet Commission on Investing in Health: Global Health 2050: the path to halving premature death by mid-century.
Endometriosis and uterine fibroids and risk of premature mortality: prospective cohort study
Authors: Yi-Xin Wang, Leslie V Farland, Audrey J Gaskins, Siwen Wang, Kathryn L Terry, Kathryn M Rexrode, Janet W Rich-Edwards, Rulla Tamimi, Jorge E Chavarro, Stacey A Missmer
Journal: BMJ (2024)

Abstract Objective To prospectively assess the effect of endometriosis and uterine fibroids on the long term risk of premature mortality (younger than 70 years). Design Prospective cohort study Setting The Nurses’ Health Study II, United States (1989-2019). Participants 110 091 women aged 25-42 years in 1989 without a history of hysterectomy before endometriosis or fibroids diagnosis, cardiovascular diseases, or cancer. Main outcome measures Hazard ratios (estimated by Cox proportional hazards models) for total and cause specific premature mortality according to laparoscopically confirmed endometriosis or ultrasound or hysterectomy confirmed uterine fibroids reported in biennial questionnaires. Results 4356 premature deaths were recorded during 2 994 354 person years of follow-up (27.2 years per person), including 1459 from cancer, 304 from cardiovascular diseases, and 90 from respiratory diseases. The crude incidence of all cause premature mortality for women with and without laparoscopically confirmed endometriosis was 2.01 and 1.40 per 1000 person years, respectively. In age adjusted models, laparoscopically confirmed endometriosis was associated with a hazard ratio of 1.19 (95% confidence interval 1.09 to 1.30) for premature death; these models were strengthened after also adjusting for potential confounders including behavioral factors (1.31, 1.20 to 1.44). Cause specific mortality analyses showed that the association was largely driven by mortality from senility and ill-defined diseases (1.80, 1.19 to 2.73), non-malignant respiratory diseases (1.95, 1.11 to 3.41), diseases of the nervous system and sense organs (2.50, 1.40 to 4.44), and malignant neoplasm of gynecological organs (2.76, 1.79 to 4.26). Ultrasound or hysterectomy confirmed uterine fibroids were not associated with all cause premature mortality (1.03, 0.95 to 1.11), but were associated with a greater risk of mortality from malignant neoplasm of gynecological organs (2.32, 1.59 to 3.40) in cause specific mortality analyses. The risk of mortality caused by cardiovascular and respiratory diseases varied according to joint categories of endometriosis and uterine fibroids, with an increased risk of all cause premature mortality among women reporting both endometriosis and uterine fibroids. Conclusion Women with a history of endometriosis and uterine fibroids might have an increased long term risk of premature mortality extending beyond their reproductive lifespan. These conditions were also associated with an increased risk of death due to gynecological cancers. Endometriosis was associated with a greater risk of non-cancer mortality. These findings highlight the importance for primary care providers to consider these gynecological disorders in their assessment of women's health.
Regulation of disease-associated microglia in the optic nerve by lipoxin B4 and ocular hypertension
Authors: Shubham Maurya, Maggie Lin, Shruthi Karnam, Tanirika Singh, Matangi Kumar, Emily Ward, Jeremy Sivak, John G. Flanagan, Karsten Gronert
Journal: Molecular Neurodegeneration (2024)

Abstract Background The resident astrocyte-retinal ganglion cell (RGC) lipoxin circuit is impaired during retinal stress, which includes ocular hypertension-induced neuropathy. Lipoxin B 4 produced by homeostatic astrocytes directly acts on RGCs to increase survival and function in ocular hypertension-induced neuropathy. RGC death in the retina and axonal degeneration in the optic nerve are driven by the complex interactions between microglia and macroglia. Whether LXB 4 neuroprotective actions include regulation of other cell types in the retina and/or optic nerve is an important knowledge gap. Methods Cellular targets and signaling of LXB 4 in the retina were defined by single-cell RNA sequencing. Retinal neurodegeneration was induced by injecting silicone oil into the anterior chamber of mouse eyes, which induced sustained and stable ocular hypertension. Morphological characterization of microglia populations in the retina and optic nerve was established by MorphOMICs and pseudotime trajectory analyses. The pathways and mechanisms of action of LXB 4 in the optic nerve were investigated using bulk RNA sequencing. Transcriptomics data was validated by qPCR and immunohistochemistry. Differences between experimental groups were assessed by Student’s t-test and one-way ANOVA. Results Single-cell transcriptomics identified microglia as a primary target for LXB 4 in the healthy retina. LXB 4 downregulated genes that drive microglia environmental sensing and reactivity responses. Analysis of microglial function revealed that ocular hypertension induced distinct, temporally defined, and dynamic phenotypes in the retina and, unexpectedly, in the distal myelinated optic nerve. Microglial expression of CD74, a marker of disease-associated microglia in the brain, was only induced in a unique population of optic nerve microglia, but not in the retina. Genetic deletion of lipoxin formation correlated with the presence of a CD74 optic nerve microglia population in normotensive eyes, while LXB 4 treatment during ocular hypertension shifted optic nerve microglia toward a homeostatic morphology and non-reactive state and downregulated the expression of CD74. Furthermore, we identified a correlation between CD74 and phospho-phosphoinositide 3-kinases (p-PI3K) expression levels in the optic nerve, which was reduced by LXB 4 treatment. Conclusion We identified early and dynamic changes in the microglia functional phenotype, reactivity, and induction of a unique CD74 microglia population in the distal optic nerve as key features of ocular hypertension-induced neurodegeneration. Our findings establish microglia regulation as a novel LXB 4 target in the retina and optic nerve. LXB 4 maintenance of a homeostatic optic nerve microglia phenotype and inhibition of a disease-associated phenotype are potential neuroprotective mechanisms for the resident LXB 4 pathway.
Evidence-based Guidelines for Keratorefractive Lenticule Extraction Surgery
Authors: Yan Wang, Lixin Xie, Ke Yao, Walter Sekundo, Jorge L Alió, Jod S Mehta, Sanjay Goel, Ahmed Elmassry, Julie Schallhorn, Tatiana Shilova, Huazheng Cao, Lulu Xu, Xuan Chen, Fengju Zhang, Ji Bai, Wenfang Zhang, Qin Liu, Xingtao Zhou, Yueguo Chen, Zheng Wang, Vishal Jhanji, Kehu Yang
Journal: Ophthalmology (2024)
A pan-family screen of nuclear receptors in immunocytes reveals ligand-dependent inflammasome control
Authors: Yutao Wang, Yanbo Zhang, Kyungsub Kim, Jichang Han, Daniel Okin, Zhaozhao Jiang, Liang Yang, Arum Subramaniam, Terry K Means, Frank O Nestlé, Katherine A Fitzgerald, Gwendalyn J Randolph, Cammie F Lesser, Jonathan C Kagan, Diane Mathis, Christophe Benoist
Journal: Immunity (2024)
Machine Learning-Based Prediction of Death and Hospitalization in Patients With Implantable Cardioverter Defibrillators
Authors: Lindsey Rosman, Rachel Lampert, Kaicheng Wang, Anil K Gehi, James Dziura, Elena Salmoirago-Blotcher, Cynthia Brandt, Samuel F Sears, Matthew Burg
Journal: Journal of the American College of Cardiology (2024)
Advanced Imaging Assessment of the Impact of Tricuspid Regurgitation on Cardiac Remodeling
Authors: João L Cavalcante, Markus Scherer, Miho Fukui, Stamatios Lerakis, Serge Harb, Amit Pursnani, Jonathan G Schwartz, Samir Kapadia, Mark J Ricciardi, Omar Khalique, Susheel Kodali, Dipan Shah, Steven H Little, Nishant Sekaran, Brian Whisenant, Peter Flueckiger, Pradeep Yadav, Abbas Emaminia, Wayne Batchelor, Peter Kellman, Zexu Lin, Phillip M Trusty, Rebecca T Hahn, David Adams, Paul Sorajja
Journal: Journal of the American College of Cardiology (2024)
Anatomic and Physiologic Repair of Congenitally Corrected Transposition of the Great Arteries
Authors: Kirolos A Jacob, Jürgen Hörer, Viktor Hraska, Valirie N Agbor, Saniyé Duchateau, Abraham van Wijk, David J Barron, Paul H Schoof
Journal: Journal of the American College of Cardiology (2024)
Similar Weaning Success Rate with High-Intensity and Sham Inspiratory Muscle Training: A Randomized Controlled Trial (IMweanT)
Authors: Marine Van Hollebeke, Diego Poddighe, Mariana Hoffman, Beatrix Clerckx, Jan Muller, Zafeiris Louvaris, Greet Hermans, Rik Gosselink, Daniel Langer
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

Inspiratory muscle training (IMT) improves respiratory muscle function in patients with weaning difficulties. IMT protocols involve performing daily sets of breaths against external loads. However, the impact of IMT on weaning outcomes while incorporating sham control interventions remains unclear.
Author Correction: Brca1 haploinsufficiency promotes early tumor onset and epigenetic alterations in a mouse model of hereditary breast cancer
Authors: Carman Man-Chung Li, Alyssa Cordes, Michael U. J. Oliphant, S. Aidan Quinn, Mayura Thomas, Laura M. Selfors, Francesca Silvestri, Nomeda Girnius, Gianmarco Rinaldi, Jason J. Zoeller, Hana Shapiro, Christina Tsiobikas, Kushali P. Gupta, Shailja Pathania, Aviv Regev, Cigall Kadoch, Senthil K. Muthuswamy, Joan S. Brugge
Journal: Nature Genetics (2024)
Editorial Expression of Concern: Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells
Authors: Angela Nebbioso, Nicole Clarke, Emilie Voltz, Emmanuelle Germain, Concetta Ambrosino, Paola Bontempo, Rosana Alvarez, Ettore M. Schiavone, Felicetto Ferrara, Francesco Bresciani, Alessandro Weisz, Angel R. de Lera, Hinrich Gronemeyer, Lucia Altucci
Journal: Nature Medicine (2024)
R(+) Propranolol decreases lipid accumulation in haemangioma-derived stem cells
Authors: Jerry Wei Heng Tan, Jill Wylie-Sears, Caroline T Seebauer, John B Mulliken, Mathias Francois, Annegret Holm, Joyce Bischoff
Journal: British Journal of Dermatology (2024)

Infantile hemangioma (IH), often treated with propranolol, is a benign vascular tumor that undergoes a spontaneous involution to a fibrofatty residuum. We investigated how R(+) propranolol, the non-beta blocker enantiomer of racemic propranolol, affects lipid accumulation and adipogenesis in IH. This was motivated by our previous work showing R(+) propranolol can block blood vessel formation in a pre-clinical model of IH. Our findings suggest a novel regulatory role for the R(+) propranolol in modulating lipid accumulation in HemSC. This highlights a novel role of R(+) propranolol in the involuting phase of IH and a strategy to reduce fibrofatty residua in IH.