tbuckley/cabot-search huggingface dataset:
Preadipocyte IL-13/IL-13Rα1 signaling regulates beige adipogenesis through modulation of PPARγ activity
Authors: Alexandra R Yesian, Mayer M Chalom, Nelson H Knudsen, Alec L Hyde, Jean Personnaz, Hyunjii Cho, Yae-Huei Liou, Kyle A Starost, Chia-Wei Lee, Dong-Yan Tsai, Hsing-Wei Ho, Jr-Shiuan Lin, Jun Li, Frank B Hu, Alexander S Banks, Chih-Hao Lee
Journal: Journal of Clinical Investigation (2025)

Type 2 innate lymphoid cells (ILC2) regulate the proliferation of preadipocytes that give rise to beige adipocytes. Whether and how ILC2 downstream Th2 cytokines control beige adipogenesis remain unclear. We employed cell systems and genetic models to examine the mechanism through which interleukin-13 (IL-13), an ILC2-derived Th2 cytokine, controls beige adipocyte differentiation. IL-13 priming in preadipocytes drives beige adipogenesis by upregulating beige-promoting metabolic programs, including mitochondrial oxidative metabolism and PPARγ-related pathways. The latter is mediated by increased expression and activity of PPARγ through IL-13 receptor α1 (IL-13Rα1) downstream effectors, STAT6 and p38 MAPK, respectively. Il13 knockout (Il13KO) or preadipocyte Il13ra1 knockout (Il13ra1KO) mice are refractory to cold- or β-3 adrenergic agonist-induced beiging in inguinal white adipose tissue, whereas Il4 knockout mice show no defects in beige adipogenesis. Il13KO and Il13ra1KO mouse models exhibit increased body weight/fat mass and dysregulated glucose metabolism but have a mild cold intolerant phenotype, likely due to their intact brown adipocyte recruitment. We also find that genetic variants of human IL13RA1 are associated with body mass index and type 2 diabetes. These results suggest that IL-13 signaling-regulated beige adipocyte function may play a predominant role in modulating metabolic homeostasis rather than in thermoregulation.
Multimarker assessment of B cell and plasma cell subsets and their prognostic role in the colorectal cancer microenvironment
Authors: Onni Sirkiä, Henna Karjalainen, Hanna Elomaa, Sara A. Väyrynen, Anne Tuomisto, Päivi Sirniö, Ville K. Äijälä, Vilja V. Tapiainen, Meeri Kastinen, Erkki-Ville Wirta, Olli Helminen, Sanna Meriläinen, Jukka Rintala, Juha Saarnio, Tero Rautio, Toni T. Seppälä, Markus J. Mäkinen, Jukka-Pekka Mecklin, Jan Böhm, Maarit Ahtiainen, Juha P. Väyrynen
Journal: Clinical Cancer Research (2025)

Abstract Purpose: While the association between cytotoxic T lymphocytes and favorable prognosis in colorectal cancer is well established, the prognostic significance of B lymphocytes remain more ambiguous. This study aimed to assess the characteristics and significance of various B cell and plasma cell subsets in colorectal tumors. Experimental Design: We designed a seven-plex immunohistochemistry assay, combined with machine learning-based image analysis, to identify various B cell and plasma cell populations and applied it to study a cohort of 912 colorectal tumors. We assessed the prognostic significance of B cell and plasma cell densities using Kaplan-Meier estimators and Cox regression models. Additionally, we designed a more clinically applicable three-plex assay, which we used to study B cell and plasma cell densities in a separate validation cohort of 737 patients. Results: High plasma cell density in the center of the tumor was associated with longer cancer-specific survival independent of disease stage, mismatch repair status, T cell densities, and other covariates. In the study cohort, multivariable HR for high (vs. low) plasma cell density was 0.48 (95% CI 0.32–0.72, Ptrend = 0.0005), while the corresponding HR in the validation cohort was 0.37 (95% CI 0.21–0.65, Ptrend = 0.0003). Of the specific subsets, IgG1–IgG2– plasma cells showed the strongest association with improved survival. High B cell densities were not independently associated with better prognosis. Conclusions: Plasma cell densities in the center of the tumor represent a relevant tumor immune biomarker in colorectal cancer, complementing the T cell density measurements.
Azacitidine, Venetoclax and Magrolimab in Newly Diagnosed and Relapsed Refractory Acute Myeloid Leukemia: Phase 1b/2 Study and Correlative Analysis
Authors: Naval Daver, Jayastu Senapati, Hagop M. Kantarjian, Bofei Wang, Patrick K. Reville, Sanam Loghavi, Musa Yilmaz, Courtney D. DiNardo, Tapan M. Kadia, Mhd Yousuf Yassouf, Abhishek Maiti, Sankalp Arora, Guillermo Montalban Bravo, Guilin Tang, Gautam Borthakur, Koji Sasaki, Naveen Pemmaraju, Joie Alvarez, Graciela M. Nogueras Gonzalez, Jing Ning, Ghayas C. Issa, Marina Konopleva, Michael Andreeff, Farhad Ravandi, Guillermo Garcia-Manero, Hussein A. Abbas
Journal: Clinical Cancer Research (2025)

Abstract Purpose: Magrolimab is a monoclonal antibody directed against macrophage checkpoint CD47 on myeloid leukemia cells that was pre-clinically synergistic with azacitidine-venetoclax, warranting further clinical evaluation. Patients and Methods: In this phase 1b/2 study the triplet combination of azacitidine, venetoclax and magrolimab was evaluated in adult patients with frontline (ineligible for intensive chemotherapy) and relapsed/refractory AML. Azacitidine was dosed at 75mg/m2 for 7 days, venetoclax at 400 mg/day for 28 days, and magrolimab (recommended phase 2 dose [RP2D]) as follows: 1 mg/kg dose on days 1 and 4, 15 mg/kg on day 8, 30 mg/kg on day 11, 15 and 22 (cycle 1), followed by 30 mg/kg weekly for cycle 2, then 30 mg/kg every 2 weeks cycle 3 and beyond. The primary endpoint was RP2D for phase 1b and rates of composite complete response (CRc) in phase 2. Results: The frontline cohort included 54 patients (median age 70.1 years); 35 (64.8%) were TP53 mutated (TP53mut). CRc was attained in 34 patients (63%); 49% in TP53mut and 90% in the TP53 wild-type patients. At a median follow-up of 27.9 months, the median event free survival (EFS) and overall survival (OS) was 6.6 months and 9.8 months respectively; for TP53mut patients the median EFS and OS was 5.9 and 7.6 months, while for TP53 wild type it was 9.6 months and 13 months respectively. CRc in the relapsed/refractory cohort (n=52) was 29% and median OS was 3.9 months. The regimen was well tolerated; infections were the most common ≥ grade 3 adverse event (75.4%) with no immune toxicities or deaths related to therapy. scRNAseq was performed on 27 longitudinal samples from 11 TP53mut patients (8 responders). Gene set enrichment analysis revealed enrichment of IFNγ and TNFα signaling in non-responders at baseline, while erythroid differentiation was associated with resistance. Patients at relapse also showed up-regulated CD47 expression and elevated leukemia regeneration score. Conclusions: The triplet regimen was safe but did not lead to promising survival outcomes.
Tolebrutinib in Nonrelapsing Secondary Progressive Multiple Sclerosis
Authors: Robert J. Fox, Amit Bar-Or, Anthony Traboulsee, Celia Oreja-Guevara, Gavin Giovannoni, Patrick Vermersch, Sana Syed, Ye Li, Wendy S. Vargas, Timothy J. Turner, Erik Wallstroem, Daniel S. Reich
Journal: New England Journal of Medicine (2025)

Throughout the course of multiple sclerosis, gradually progressive neurologic impairment can occur, which has been called disability accrual. Current disease-modifying therapies for multiple sclerosis have limited effects on disability accrual unrelated to relapses, which is thought to be partially caused by chronic, nonresolving neuroinflammation within the central nervous system. Tolebrutinib is an oral, brain-penetrant Bruton's tyrosine kinase inhibitor that targets myeloid cells (including microglia) and B cells in both the periphery and central nervous system. There are no approved treatments for nonrelapsing secondary progressive multiple sclerosis. In a phase 3, double-blind, placebo-controlled, event-driven trial, we randomly assigned participants with nonrelapsing secondary progressive multiple sclerosis, in a 2:1 ratio, to receive tolebrutinib (60 mg once daily) or matching placebo. The primary end point was confirmed disability progression that was sustained for at least 6 months, assessed in a time-to-event analysis. A total of 1131 participants underwent randomization: 754 were assigned to receive tolebrutinib and 377 to receive placebo. The median follow-up was 133 weeks. A smaller percentage of participants in the tolebrutinib group than in the placebo group had confirmed disability progression sustained for at least 6 months (22.6% vs. 30.7%; hazard ratio, 0.69; 95% confidence interval, 0.55 to 0.88; P = 0.003). Serious adverse events occurred in 15.0% of the participants in the tolebrutinib group and in 10.4% of those in the placebo group. A total of 4.0% of the participants in the tolebrutinib group and 1.6% of those in the placebo group had increases in alanine aminotransferase levels to more than 3 times the upper limit of the normal range. In participants with nonrelapsing secondary progressive multiple sclerosis, the risk of disability progression was lower among those who received treatment with tolebrutinib than among those who received placebo. (Funded by Sanofi; HERCULES ClinicalTrials.gov number, NCT04411641.).
Outcomes in Patients Undergoing TAVR Planning with Contrast-Enhanced CT vs Noncontrast CT and CMR
Authors: Besir Besir, Judah Rajendran, Shivabalan Kathavarayan Ramu, Maryam Muhammad Ali Majeed-Saidan, Aditya Mantha, Rishi Puri, Grant W. Reed, James Yun, Amar Krishnaswamy, Serge C. Harb, Samir R. Kapadia
Journal: JACC. Cardiovascular imaging (2025)
Tolebrutinib versus Teriflunomide in Relapsing Multiple Sclerosis
Authors: Jiwon Oh, Douglas L. Arnold, Bruce A.C. Cree, Carolina Ionete, Ho Jin Kim, Maria Pia Sormani, Sana Syed, Yixin Chen, Christina R. Maxwell, Patrick Benoit, Timothy J. Turner, Erik Wallstroem, Heinz Wiendl
Journal: New England Journal of Medicine (2025)

Tolebrutinib is an oral, brain-penetrant, and bioactive Bruton's tyrosine kinase inhibitor that modulates peripheral inflammation and persistent immune activation within the central nervous system, including disease-associated microglia and B cells. More data are needed on its efficacy and safety in treating relapsing multiple sclerosis. In two phase 3, double-blind, double-dummy, event-driven trials (GEMINI 1 and GEMINI 2), participants with relapsing multiple sclerosis were randomly assigned in a 1:1 ratio to receive tolebrutinib (60 mg once daily) or teriflunomide (14 mg once daily), each with matching placebo. The primary end point was the annualized relapse rate. The key secondary end point was confirmed worsening of disability that was sustained for at least 6 months, which was assessed in a time-to-event analysis that was pooled across trials. A total of 974 participants were enrolled in GEMINI 1, and 899 were enrolled in GEMINI 2. The median follow-up was 139 weeks. The annualized relapse rate in the tolebrutinib and teriflunomide groups was 0.13 and 0.12, respectively, in GEMINI 1 (rate ratio, 1.06; 95% confidence interval [CI], 0.81 to 1.39; P = 0.67) and 0.11 and 0.11, respectively, in GEMINI 2 (rate ratio, 1.00; 95% CI, 0.75 to 1.32; P = 0.98). The pooled percentage of participants with confirmed disability worsening sustained for at least 6 months was 8.3% with tolebrutinib and 11.3% with teriflunomide (hazard ratio, 0.71; 95% CI, 0.53 to 0.95; no formal hypothesis testing was conducted owing to the prespecified hierarchical testing plan, and the width of the confidence interval is not adjusted for multiple testing). The percentage of participants who had adverse events was similar in the two treatment groups, although the percentage with minor bleeding was higher in the tolebrutinib group than in the teriflunomide group (petechiae occurred in 4.5% vs. 0.3%, and heavy menses in 2.6% vs. 1.0%). Tolebrutinib was not superior to teriflunomide in decreasing annualized relapse rates among participants with relapsing multiple sclerosis. (Funded by Sanofi; GEMINI 1 and GEMINI 2 ClinicalTrials.gov numbers, NCT04410978 and NCT04410991, respectively.).
A theoretical perspective on the role of sleep in borderline personality disorder: From causative factor to treatment target
Authors: Shanna van Trigt, Tanja van der Zweerde, Eus J W van Someren, Annemieke van Straten, Hein J F van Marle
Journal: Sleep Medicine Reviews (2025)

Sleep plays a crucial role in emotion regulation. Disturbed sleep is therefore increasingly seen as a potential causal factor for the development and maintenance of affective psychiatric disorders. This may hold especially for borderline personality disorder (BPD), a core emotion dysregulation disorder. Although BPD is strongly associated with sleep disturbances such as insomnia, nightmares and circadian dysrhythmia, research into the role of sleep in BPD remains sparse. In this narrative review, we outline a putative vicious cycle of reciprocal exacerbation of disturbed sleep and emotion dysregulation in BPD, that sheds light on BPD pathophysiology and opens up new avenues for sleep-based treatments. We discuss emotional dysregulation as the base of BPD as well as the observed sleep disturbances in BPD. Based on existing theories of sleep's role in emotion regulation and memory, we then propose several behavioral and neurobiological pathways by which inherent sleep disturbances in BPD may hamper adaptive overnight emotional processing. This likely results in sustained emotional states and associated sleep-disruptive behavior, which in turn negatively impact sleep. We end by proposing a sleep-based research agenda for BPD to further detail the causative role of disturbed sleep in BPD and test the effectiveness of novel sleep-based treatment strategies.
Incidence and prevalence of asthma, chronic obstructive pulmonary disease and interstitial lung disease between 2004 and 2023: harmonised analyses of longitudinal cohorts across England, Wales, South-East Scotland and Northern Ireland
Authors: Hannah Whittaker, Adriana Kramer Fiala Machado, Sara Hatam, Sarah Cook, Sean Scully, Hywel Turner T Evans, Thomas Bolton, Constantinos Kallis, John Busby, Liam G Heaney, Aziz Sheikh, Jennifer K Quint
Journal: Thorax (2025)

Background We describe the epidemiology of asthma, chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) from 2004 to 2023 in England, Wales, Scotland and Northern Ireland (NI) using a harmonised approach. Methods Data from the National Health Service England (NHSE), Clinical Practice Research Datalink Aurum in England, Secure Anonymised Information Linkage Databank in Wales, DataLoch in South-East Scotland and the Honest Broker Service in NI were used. A harmonised approach to COPD, asthma and ILD case definitions, study designs and study populations across the four nations was performed. Age-sex-standardised incidence rates and point prevalence were calculated between 2004 and 2023 depending on data availability. Logistic and negative binomial regression compared incidence and prevalence rates between the start and end of each study period. Linear extrapolation projected incidence rates between 2020 and 2023 to illustrate how observed and projected rates differed. Results Incidence rates were lower in 2019 versus 2005 for asthma (England: incidence rate ratio 0.89, 95% CI 0.88 to 0.90; Wales: 0.66, 0.65 to 0.68; Scotland: 0.67, 0.64 to 0.71; NI: 0.84, 0.81 to 0.86), COPD (England: 0.83, 0.82 to 0.85; Wales: 0.67, 0.65 to 0.69) and higher for ILD (England: 3.27, 3.05 to 3.50; Wales: 1.39, 1.27 to 1.53; Scotland: 1.63, 1.36 to 1.95; NI: 3.03, 2.47 to 3.72). In NHSE, the incidence of asthma was similar in June 2023 versus November 2019, but lower for COPD and higher for ILD. Prevalence of asthma in 2019 in England, Wales, Scotland and NI was 9.7%, 15.9%, 13.2% and 7.0%, respectively, for COPD 4.5%, 5.1%, 4.4% and 3.0%, and for ILD 0.4%, 0.5%, 0.6% and 0.3%. Projected incidence rates were 2.8, 3.4 and 1.8 times lower for asthma, COPD and ILD compared with observed rates at the height of the pandemic. Interpretation Asthma, COPD and ILD affect over 10 million people across the four nations, and a substantial number of diagnoses were missed during the pandemic.
Steatotic liver disease classification is dynamic, affecting clinical trial eligibility and subclass-specific treatments
Authors: Mads Israelsen, Katrine Holtz Thorhauge, Peter Andersen, Stine Johansen, Helle Lindholm Schnefeld, Katrine Tolstrup Bech, Johanne Kragh Hansen, Nikolaj Torp, Ellen Lyngbeck Jensen, Emil Deleuran Hansen, Ida Ziegler Spedtsberg, Ida Falk Villesen, Camilla Dalby Hansen, Torben Hansen, Katrine Prier Lindvig, Maja Thiele, Aleksander Krag
Journal: Clinical Gastroenterology and Hepatology (2025)

Steatotic liver disease (SLD) includes the subclasses metabolic-dysfunction associated steatotic liver disease (MASLD), metabolic and alcohol-related liver disease (MetALD) and alcohol-related liver disease (ALD). We investigated the robustness of the SLD diagnoses after two years. We performed a prospective cohort study among individuals from the general population and individuals at risk of SLD. Participants were classified according to the diagnostic criteria of the SLD nomenclature at baseline and after 2 years. We included 1042 participants, mean age was 57 (±10) years, 663 were male (64%) and 379 (36%) female and 70 (7%) had advanced fibrosis. At baseline, 595 (57%) had SLD, hereof 371 (62%) met the criteria for MASLD, 140 (24%) for MetALD and 83 (14%) for ALD, and 1 (<1%) were classified as cryptogenic SLD. Median time between the baseline and follow up visit was 25 months (IQR 24-31). Overall, 399 (38%) of the 1042 participants changed SLD classification from baseline to follow-up. In the group without SLD at baseline, 25% had SLD at follow-up. In comparison, 38% with MASLD at baseline were classified differently at follow-up, while 62% and 69% of participants with baseline MetALD and ALD were classified differently at follow-up. The primary reasons for changing classification were that individuals no longer met the criteria for having SLD or had altered their alcohol intake. SLD and the subclassification hereof is highly dynamic, especially driven by changes in alcohol use and hepatic steatosis. This affects eligibility for clinical trials and clinical management of patients with SLD.
Correction to “Impact of vaccination with third generation modified vaccinia Ankara and sexual behaviour on mpox incidence in men who have sex with men: analysis among participants of the ANRS-174 DOXYVAC trial” [The Lancet Regional Health—Europe 45, October 2024, 101020]
Authors: Jade Ghosn, Lambert Assoumou, Moussa Ouattara, Emma Rubenstein, Gilles Pialoux, Christine Katlama, Laure Surgers, Claudine Duvivier, Juliette Pavie, Jean-Paul Viard, Michèle Algarte-Genin, Severine Gibowski, Manon Ollivier, Dominique Costagliola, Jean-Michel Molina
Journal: The Lancet Regional Health - Europe (2025)
Real-world treatment patterns for teclistamab and talquetamab in multiple myeloma (MM): experience from 609 patients
Authors: Farheen Chunara, Chris Lugo, Kristen Osinski, Mansi R Shah, Nishi Shah, Jessica Kent, Ghulam Rehman Mohyuddin, Sabarinath Venniyil Radhakrishnan, Gurbakhash Kaur, Rajshekhar Chakraborty, Rahul Banerjee, Leo Rasche, Carolina Schinke, Anita D'Souza, Aniko Szabo, Meera Mohan
Journal: Blood Cancer Journal (2025)
Quantification of carotid artery plaque and peri-vascular adipose tissue attenuation on computed tomography
Authors: Beth Whittington, Viswan Thiagarajah, Evangelos Tzolos, Jakub Kaczynski, Caelan Taggart, Alex Vesey, Damini Dey, Rachael O Forsythe, Andrew Tambyraja, Edwin J R van Beek, Marc R Dweck, David E Newby, Michelle C Williams
Journal:  (2025)

Abstract Introduction Quantitative assessment of carotid artery plaque on computed tomography (CT) may identify high-risk phenotypes associated with culprit lesions and subsequent ischaemic stroke or transient ischaemic attack. Methods Carotid CT angiography was performed in 48 patients with acute ischaemic stroke or transient ischaemic attack within 21 days. Quantitative plaque assessment was performed in the proximal 6 cm of the internal and external carotid artery, distal 6 cm of the common carotid artery, and residual common carotid artery. Semi-automated quantification included assessment of non-calcified, calcified, low-attenuation and total plaque, area and diameter stenosis and peri-vascular adipose tissue attenuation. Results In 48 patients (mean age 71±11 years, 67% male), 96 vessels were assessed with 30 (31%) identified as culprit vessels. Culprit internal carotid arteries had greater area (83 (65,94) versus 64 (55, 77 %) and diameter (56 (39,74) versus 32 (21,48)%) stenosis, and more non-calcified (563 [413, 965] versus 428 [283,649] mm3, p=0.04), low-attenuation (33.7 [6.9, 72.4] versus 16.3 [3.35, 54.3]] mm3, p=0.01) and total (699 [455, 1057] versus 492 [311, 809], p=0.04) plaque. There was no difference in calcified plaque or peri-vascular adipose tissue attenuation between culprit and non-culprit internal carotid arteries. There were no differences in quantitative plaque or peri-vascular adipose tissue attenuation in the external carotid artery or common carotid artery. Conclusion Carotid atherosclerotic plaque characteristics are the principal features associated with culprit plaques with little or no demonstrable relationship with calcified plaque or increased peri-vascular adipose tissue attenuation.
Evaluating the performance of common reference laboratory tests for acute dengue diagnosis: a systematic review and meta-analysis of RT-PCR, NS1 ELISA, and IgM ELISA
Authors: Kamla Pillay, Suzanne H Keddie, Elizabeth Fitchett, Cassandra Akinde, Oliver Bärenbold, John Bradley, Jane Falconer, Ruth H Keogh, Zhia Ning Lim, Behrouz Nezafat Maldonado, Laura Maynard-Smith, Ellen Sugrue, Okuda Taylor, Heidi Hopkins, Audrey Dubot-Pérès
Journal: The Lancet Microbe (2025)

Dengue fever is listed among the top ten global health threats by WHO. Prompt identification of dengue virus can guide clinical management and outbreak response, yet laboratory diagnosis is complex, costly, and lacks consensus on performance evaluation. This systematic review aims to provide reliable diagnostic accuracy estimates in order to inform global guidance and evaluate novel rapid diagnostic tests. In this systematic review and meta-analysis, we searched nine literature databases on Feb 16, 2021, for reports on five common reference tests for dengue infection: NS1 ELISA, IgM ELISA, IgG ELISA, RT-PCR, and viral neutralisation test. Articles were included if they reported primary data from more than five participants to complete 2×2 tables comparing one of these tests (on human serum) with any comparator. Diagnostic accuracy was estimated using Bayesian random-effect meta-analysis, which does not require a gold-standard comparator. Risk of bias was assessed using QUADAS-2. This review is registered with PROSPERO (CRD42022341552). Data were extracted from 161 articles, allowing analysis of multiple timeframes for three tests of interest. Pooled sensitivities of RT-PCR (0-4 days after symptom onset), NS1 ELISA (0-4 days), and IgM ELISA (1-7 days) were 95% (95% credible interval 77-99), 90% (68-98), and 71% (57-84), respectively. The corresponding pooled estimates of specificity were 89% (60-98), 93% (71-99), and 91% (82-95). A subanalysis of only studies at low risk of bias demonstrated similar estimates. IgM ELISA shows poor diagnostic accuracy early in the symptom course. NS1 ELISA shows similar diagnostic accuracy to RT-PCR, which has important implications for global public health policy, given its relatively low cost and accessibility. None.