tbuckley/cabot-search huggingface dataset:
Early Notch signals from fibroblastic reticular cells program effector CD8+ T cell differentiation
Authors: Dave Maurice De Sousa, Eric Perkey, Laure Le Corre, Salix Boulet, Daniela Gómez Atria, Anneka Allman, Frédéric Duval, Jean-François Daudelin, Joshua D. Brandstadter, Katlyn Lederer, Sarah Mezrag, Livia Odagiu, Myriam Ennajimi, Marion Sarrias, Hélène Decaluwe, Ute Koch, Freddy Radtke, Burkhard Ludewig, Christian W. Siebel, Ivan Maillard, Nathalie Labrecque
Journal: The Journal of Experimental Medicine (2025)

A better understanding of the mechanisms regulating CD8+ T cell differentiation is essential to develop new strategies to fight infections and cancer. Using genetic mouse models and blocking antibodies, we uncovered cellular and molecular mechanisms by which Notch signaling favors the efficient generation of effector CD8+ T cells. Fibroblastic reticular cells from secondary lymphoid organs, but not dendritic cells, were the dominant source of Notch signals in T cells via Delta-like1/4 ligands within the first 3 days of immune responses to vaccination or infection. Using transcriptional and epigenetic studies, we identified a unique Notch-driven T cell-specific signature. Early Notch signals were associated with chromatin opening in regions occupied by bZIP transcription factors, specifically BATF, known to be important for CD8+ T cell differentiation. Overall, we show that fibroblastic reticular cell niches control the ultimate molecular and functional fate of CD8+ T cells after vaccination or infection through the delivery of early Notch signals.
Histopathological and molecular characteristics of IDH-wildtype glioblastoma without contrast enhancement: implications for clinical outcomes
Authors: Martha Foltyn-Dumitru, Rouzbeh Banan, Marianne Schell, Mustafa Ahmed Mahmutoglu, Tobias Kessler, Wolfgang Wick, Gianluca Brugnara, Martin Bendszus, Felix Sahm, Philipp Vollmuth
Journal: Neuro-Oncology (2025)

Glioblastoma (GB) heterogeneity poses substantial challenges for diagnosis and treatment. IDH-wildtype GB may lack contrast enhancement on MRI and exhibit a "low-grade radiologic appearance" (non-CE GB), a phenomenon with unclear clinical implications. This study investigates the histopathological and molecular differences and survival outcomes between contrast-enhancing (CE) and non-CE GB. This retrospective study at Heidelberg University Hospital analyzed 457 IDH-wildtype GB cases (09/2009-01/2021). Contrast enhancement on preoperative MRI was volumetrically assessed, classifying tumors as non-CE/CE GB using a 1 cm³ cut-off. Molecular and histopathological features, including microvascular proliferation, necrosis, and overall survival (OS), were compared between the groups. Of the initial cohort, 352 (77%) patients met the inclusion criteria, with 44 (12.5%) non-CE and 308 (87.5%) CE GB. The histopathological assessment revealed that non-CE GB was less likely to present traditional hallmarks of glioblastoma, such as microvascular proliferation (39% vs. 94%) and necrosis (25% vs. 92%) (p<0.001). In the non-CE group, 24 patients (55%) were diagnosed as molecular-GB, compared to only 8 patients (3%) in the CE group (p < 0.001). A significant difference was observed in Ki-67 levels, with non-CE GBs having a lower mean Ki-67 index of 18 ± 12% compared to 26 ± 13% in CE tumors (p<0.001). The median OS was 27.2 months (95%CI 19.8-NA) for non-CE and 14.7 months (95% CI, 13.2-17.1) for CE GB (p=0.0049). IDH-wildtype GBs without contrast enhancement are often diagnosed based on molecular criteria due to less frequent histopathological hallmarks and are associated with prolonged OS.
How can Africa sustain its HIV response amid US aid cuts?
Authors: Wilbroad Mutale, Aggrey Semeere, Elizabeth A Bukusi, Dike Ojji, Francois Venter, Thomas Odeny, Roma Chilengi, Mosepele Mosepele, Elvin Geng, Izukanji Sikazwe, Samuel Bosomprah, Llyod Mulenga, Fred Simitala
Journal: The Lancet HIV (2025)
Riluzole in Combination with mFOLFOX6 and Bevacizumab in Treating Patients with Metastatic Colorectal Cancer: A Phase 1 Clinical Trial
Authors: Chunjie Li, Anne M. Noonan, John Hays, Sameek Roychowdhury, Pannaga Malalur, Rifat Elkhatib, Ashish Manne, Arjun Mittra, Shafia Rahman, Liwei Yan, Kasey Hill, Nicole Abbott, Mitch Phelps, Joo Young Na, Beiyuan Liang, Hayden Storts, Misbah Khan, Evan H. Zhang, Wayne Miles, Vedat Yildiz, Lai Wei, Jing J. Wang, Ning Jin
Journal: Clinical Cancer Research (2025)

Abstract BACKGROUND: Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the US. 5-fluorouracil (5-FU)-based chemotherapies in combination with targeted agents remain the standard of care in patients with metastatic or locally advanced disease. New treatment strategies are needed for metastatic CRC patients with microsatellite stable disease. Preclinical studies showed that riluzole, an oral medicine for amyotrophic lateral sclerosis, inhibits glutamate release and synergizes with 5-FU to reduce cell viability in CRC cell lines. METHODS: In this single-arm, phase 1 trial of riluzole in combination with mFOLFOX6/bevacizumab for patients with metastatic CRC, the riluzole dose started at 50 mg twice daily, escalating to 100 mg twice daily or de-escalating to 50 mg once daily. Patients received riluzole for 16 weeks in combination with mFOLOFX6/bevacizumab for 8 cycles. Patients then either continued mFOLFOX6/bevacizumab or switched therapy. RESULTS: Twelve of the 14 patients enrolled were evaluable. All patients previously received FOLFOX, and 5 patients (41.7%) showed disease resistance to it. Two patients obtained partial responses, 9 had stable disease, and 1 had progressive disease. The objective response rate was 16.7%, and the disease control rate was 91.7%. The median duration of response was 4.9 months (95% CI 1.6-9.8). Median progression-free survival and overall survival were 4.89 and 12.98 months, respectively. CONCLUSION: Our study showed that riluzole plus mFOLFOX6/bevacizumab is well tolerated in patients with metastatic CRC and may have clinical activity in patients whose disease is resistant to FOLFOX.
The non-artemisinin antimalarial drugs under development: a review
Authors: Dearie Glory Okwu, Rella Zoleko Manego, Stephan Duparc, Peter Gottfried Kremsner, Michael Ramharter, Ghyslain Mombo-Ngoma
Journal: Clinical Microbiology and Infection (2025)

In 2022, malaria caused approximately 249 million cases and 608000 deaths, primarily in Africa. Current treatments target asexual blood-stage parasites, gametocytes, and liver hypnozoites. Standard guidelines recommend a 3-day course of artemisinin-based combination therapies as first-line treatment of uncomplicated malaria and parenteral artesunate for severe malaria. However, emergence of partial resistance to artemisinin derivatives threatens the treatment efficacy, highlighting the urgent need for novel antimalarial drugs. This review summarizes recent progress in the clinical development of antimalarials particularly non-artemisinin compounds under target product profile (TPP)-1. Data were gathered from the medicines for malaria venture (MMV) portfolio and clinical trial databases between 2020 and 2024. Sixteen clinical trials were reviewed, including safety and efficacy studies involving healthy volunteers, experimentally infected volunteers, asymptomatic P. falciparum carriers, and malaria patients. Six trials evaluated the safety and tolerability of MMV533, ZY19489, INE963, GSK701/MMV367, and intravenous KAE609 in healthy volunteers. Efficacy trials involving experimentally infected volunteers assessed ZY19489 and GSK701/MMV367, while studies on asymptomatic carriers tested ZY19489/ferroquine and cabamiquine/pyronaridine. Trials on malaria patients investigated combinations of ganaplacide/lumefantrine-SDF, cabamiquine/pyronaridine, both oral and intravenous cipargamin, and INE963. Although attrition remains a possibility, several promising candidate drugs with novel modes of action are advancing through clinical development. Many are expected to become available for treating uncomplicated and severe malaria within the next decade. These new antimalarials could significantly enhance malaria treatment, reduce resistance, and support global health effort toward malaria control, elimination, and, potentially, eradication.
Safety of pertussis vaccination in pregnancy and effectiveness in infants: A Danish national cohort study 2019-2023
Authors: Helene Kildegaard, Andreas Jensen, Peter H S Andersen, Tine Dalby, Mie Agermose Gram, Øjvind Lidegaard, Lone Graff Stensballe
Journal: Clinical Microbiology and Infection (2025)

Recent surges in pertussis spread have renewed focus on pertussis vaccination strategies. Denmark implemented pertussis vaccination during pregnancy in 2019 to protect infants under three months. This nationwide study assessed the real-world safety and effectiveness of acellular pertussis vaccination during pregnancy. Using nationwide Danish registers, we included all pregnancies beyond 24 gestational weeks and all liveborn children from November 1, 2019, to June 1, 2023, with follow-up until December 31, 2023. Maternal safety outcomes included hypertension, preeclampsia, chorioamnionitis, preterm birth, and stillbirth. Infant safety outcomes included neonatal mortality, neonatal intensive care unit admission and sepsis. Vaccine effectiveness was evaluated against laboratory-confirmed pertussis and related hospital contacts. For maternal safety, vaccinated individuals were matched 1:1 to unvaccinated individuals based on gestational days, calendar week and region. Infant outcomes were assessed among the cohort of all liveborn children with follow-up until 3 months of age. Analyses were adjusted for a range of demographic, socioeconomic and medical characteristics. Among 50,851 vaccinated and 50,851 unvaccinated individuals during pregnancy, initial analyses showed an increased risk of hypertension and preeclampsia following pertussis vaccination. However, after adjusting for influenza and Covid-19 vaccination during pregnancy, pertussis vaccination was not associated with increased risks of any maternal safety outcomes including hypertension (incidence rate ratio (IRR) 0.98, 0.94-1.02), mild preeclampsia (0.97, 0.92-1.02), and severe preeclampsia or HELLP syndrome (0.95, 0.86-1.05). Among 215,974 liveborn children, 108,350 were exposed to the vaccine. Vaccination was not associated with adverse infant outcomes and yielded a 72% (42%-87%) effectiveness against laboratory-confirmed pertussis (9 vs. 32 events). Pertussis vaccination in pregnancy was effective in preventing infant pertussis and was not associated with adverse pregnancy or infant outcomes. Future studies should, however, examine whether other vaccines or the administration of multiple vaccines during pregnancy pose an increased maternal risk of hypertensive disorders in pregnancy.
Interaction between stromal cells and tumor cells promotes the GCB-DLBCL cell survival via CD40/RANK-KDM6B-NF-κB axis
Authors: Dandan Liu, Haohao Zhang, Yiwang Zhang, Liping Xiao, Jingyao Wang, Shiyan Liao, Hongrui Chen, Huilian Wu, Yiming Hu, Yuhang Jiang, Qi Wang, Cuifeng Li, Pengfei Chen, Yu Zhan, Lingling Li, Ningxia Xie, Deji Ye, Donglin Sun, Yingyong Hou, Yufang Shi, Yongzhong Liu, Jiang Zhu, Wei Li, Chunkui Shao, Xiaoren Zhang
Journal: Molecular Therapy (2025)
Bcor loss promotes Richter transformation of chronic lymphocytic leukemia associated with Notch1 activation in mice
Authors: Chiara Rompietti, Francesco Maria Adamo, Daniele Sorcini, Filomena De Falco, Arianna Stella, Giovanni Martino, Barbara Bigerna, Erica Dorillo, Estevão Carlos Silva Barcelos, Angela Esposito, Clelia Geraci, Roberta Arcaleni, Jessica Bordini, Lydia Scarfò, Emanuela Rosati, Paolo Ghia, Brunangelo Falini, Paolo Sportoletti
Journal: Leukemia (2025)

Abstract Richter’s transformation (RT) is an aggressive lymphoma occurring upon progression from chronic lymphocytic leukemia (CLL). Despite advances in deciphering the RT genetic architecture, the mechanisms driving this disease remain unknown. BCOR disruptive mutations were found in CLL and frequently associated with NOTCH1 aberrations, a common feature in CLL and RT. We engineered mice to knock-out Bcor in B and CLL cells of Eμ- TCL1 mice. Bcor loss resulted in alterations of the B cell compartment and favored CLL transformation into an aggressive lymphoma with reduced survival in Eμ- TCL1 mice. RNA-sequencing demonstrated a molecular signature reminiscent of human RT and implied the involvement of the T cell tumour microenvironment in the disease onset. Bcor deficiency was associated with Notch1 activation in splenic CD19 + CD5+ cells to accelerate Eμ -TCL1 mice lymphoproliferation. Notch1 inhibition progressively reduced circulating CD19+ CD5+ and RT cells infiltrating the spleen of diseased mice with concomitant reduction of PD-1 expressing T cells and improved survival. Our data demonstrated an interplay between the tumour suppressor activity of Bcor and Notch1 in RT pathogenesis with potential for tumour targeting. This model represented a new platform to uncover promising alternatives for this incurable tumour.
Long-read sequencing identifies copy-specific markers of SMN gene conversion in spinal muscular atrophy
Authors: M. M. Zwartkruis, M. G. Elferink, D. Gommers, I. Signoria, L. Blasco-Pérez, M. Costa-Roger, J. van der Sel, I. J. Renkens, J. W. Green, J. V. Kortooms, C. Vermeulen, R. Straver, H. W. M. van Deutekom, J. H. Veldink, F. Asselman, E. F. Tizzano, R. I. Wadman, W. L. van der Pol, G. W. van Haaften, E. J. N. Groen
Journal: Genome Medicine (2025)

The complex 2 Mb survival motor neuron (SMN) locus on chromosome 5q13, including the spinal muscular atrophy (SMA)-causing gene SMN1 and modifier SMN2, remains incompletely resolved due to numerous segmental duplications. Variation in SMN2 copy number, presumably influenced by SMN1 to SMN2 gene conversion, affects disease severity, though SMN2 copy number alone has insufficient prognostic value due to limited genotype–phenotype correlations. With advancements in newborn screening and SMN-targeted therapies, identifying genetic markers to predict disease progression and treatment response is crucial. Progress has thus far been limited by methodological constraints. To address this, we developed HapSMA, a method to perform polyploid phasing of the SMN locus to enable copy-specific analysis of SMN and its surrounding genes. We used HapSMA on publicly available Oxford Nanopore Technologies (ONT) sequencing data of 29 healthy controls and performed long-read, targeted ONT sequencing of the SMN locus of 31 patients with SMA. In healthy controls, we identified single nucleotide variants (SNVs) specific to SMN1 and SMN2 haplotypes that could serve as gene conversion markers. Broad phasing including the NAIP gene allowed for a more complete view of SMN locus variation. Genetic variation in SMN2 haplotypes was larger in SMA patients. Forty-two percent of SMN2 haplotypes of SMA patients showed varying SMN1 to SMN2 gene conversion breakpoints, serving as direct evidence of gene conversion as a common genetic characteristic in SMA and highlighting the importance of inclusion of SMA patients when investigating the SMN locus. Our findings illustrate that both methodological advances and the analysis of patient samples are required to advance our understanding of complex genetic loci and address critical clinical challenges.
Structural insights into the binding modes of lanreotide and pasireotide with somatostatin receptor 1
Authors: Zicheng Zeng, Qiwen Liao, Shiyi Gan, Xinyu Li, Tiantian Xiong, Lezhi Xu, Dan Li, Yunlu Jiang, Jing Chen, Richard Ye, Yang Du, Thiansze Wong
Journal: Acta Pharmaceutica Sinica B (2025)
The Modern Role of Basal Insulin in Advancing Therapy in People With Type 2 Diabetes
Authors: Geremia B. Bolli, Philip D. Home, Francesca Porcellati, Matthew C. Riddle, Hertzel C. Gerstein, Paola Lucidi, Carmine G. Fanelli, David R. Owens
Journal: Diabetes Care (2025)

Insulin deficiency, often aggravated by insulin resistance, results in type 2 diabetes mellitus (T2DM). With the availability of glucagon-like peptide 1 receptor agonists and sodium–glucose cotransporter 2 inhibitors, basal insulin (BI) therapy is no longer the first-line option after lifestyle modification plus oral agents is insufficient. In contrast to BI, the newer medications require minor titration, lower hyperglycemia in a glucose-dependent manner, and reduce body weight. Importantly, the newer agents reduce cardiorenal events in the short term. Nonetheless, insulin therapy continues to play a key role in control of hyperglycemia and therefore long-term prevention of vascular complications. Its use is essential in many circumstances, including metabolic emergencies, new diabetes onset, latent autoimmune diabetes (LADA), pregnancy, and when other agents are less desirable due to comorbidities. BI is needed in the frequent condition of failure of other therapies to keep HbA1c to target and/or intolerance of them. There are several advantages to the combination of BI with the newer medications given their different but complementary mechanisms of action, primarily, the lower dose of each, improving adherence and outcomes while decreasing the side effects. Multiple choices for single or combination use can better meet the variety of clinical phenotypes in the heterogeneous T2DM population, using the tenets of precision medicine.
Characteristics and Antibiotic Preferences of US Adults Reporting Frequent Use vs No Use of Antibiotics
Authors: Alistair Thorpe, Rachael A. Lee, Angela Fagerlin, Valerie M. Vaughn, Julia E. Szymczak
Journal: JAMA Network Open (2025)

This survey study compares demographic characteristics, beliefs, and antibiotic preferences of US adults who frequently use antibiotics with those who have not used antibiotics over the past year.
Rethinking a “Successful” Ablation
Authors: Edward Chu
Journal: JAMA Network Open (2025)

Tomoya Iwawaki, MD; Satoshi Yanagisawa, MD, PhD; Yasuya Inden, MD, PhD; Kei Hiramatsu, MD; Ryota Yamauchi, MD; Kiichi Miyamae, MD; Hiroyuki Miyazawa, MD; Takayuki Goto, MD; Shun Kondo, MD; Masaya Tachi, MD; Masafumi Shimojo, MD; Yukiomi Tsuji, MD, PhD; Toyoaki Murohara, MD, PhD
Liver Transplant and Surgical Site Infections—Developing a Deeper Understanding
Authors: Grace B. DeMarco, Rebecca N. Kumar
Journal: JAMA Network Open (2025)

Peter W. Schreiber, MD; Linard D. Hoessly, PhD; Katia Boggian, MD; Dionysios Neofytos, MD, MPH; Christian van Delden, MD; Adrian Egli, MD, PhD; Michael Dickenmann, MD; Cédric Hirzel, MD; Oriol Manuel, MD, MER; Michael Koller, MD; Simona Rossi, PhD; Vanessa Banz, MD, PhD; Philippe Compagnon, MD, PhD; Philipp Dutkowski, MD; Andreas E. Kremer, MD, PhD, MHBA; Annalisa Berzigotti, MD, PhD; Julien Vionnet, MD; Nicolas Goossens, MD; David Semela, MD, PhD; Patrizia Künzler-Heule, PhD; Christine Bernsmeier, MD, PhD; Stefan P. Kuster, MD, MSc, eMBA; Susanne Stampf, PhD; Nicolas J. Mueller, MD; Swiss Transplant Cohort Study; Patrizia Amico; Adrian Bachofner; Vanessa Banz; Sonja Beckmann; Guido Beldi; Christoph Berger; Ekaterine Berishvili; Annalisa Berzigotti; Isabelle Binet; Pierre-Yves Bochud; Sanda Branca; Anne Cairoli; Emmanuelle Catana; Yves Chalandon; Sabina De Geest; Sophie De Seigneux; Joëlle L Dreifuss; Michel Duchosal; Thomas Fehr; Sylvie Ferrari-Lacraz; Jaromil Frossard; Déla Golshayan; Nicolas Goossens; Fadi Haidar; Dominik Heim; Christoph Hess; Sven Hillinger; Hans H Hirsch; Patricia Hirt; Linard Hoessly; Günther Hofbauer; Uyen Huynh-Do; Nina Khanna; Michael Koller; Andreas Kremer; Thorsten Krueger; Christian Kuhn; Bettina Laesser; Frédéric Lamoth; Roger Lehmann; Alexander Leichtle; Oriol Manuel; Hans-Peter Marti; Michele Martinelli; Valérie McLin; Katell Mellac; Aurélia Mercay; Karin Mettler; Nicolas Müller; Ulrike Müller-Arndt; Mirjam Nägeli; Graziano Oldani; Manuel Pascual; Rosemarie Pazeller; Klara Posfay-Barbe; David Reineke; Juliane Rick; Simona Rossi; Fabian Rössler; Silvia Rothlin; Frank Ruschitzka; Thomas Schachtner; Stefan Schaub; Dominik Schneidawind; Macé Schuurmans; Simon Schwab; Thierry Sengstag; Frederico Simonetta; Jürg Steiger; Guido Stirniman; Ueli Stürzinger; Christian Van Delden; Jean-Pierre Venetz; Jean Villard; Julien Vionnet; Caroline Wehmeier; Madeleine Wick; Markus Wilhelm; Patrick Yerly
Association Between Diabetes and Anemia: Evidence From NHANES and the UK Biobank
Authors: Danyang Wang, Jedidiah I. Morton, Agus Salim, Jonathan E. Shaw, Dianna J. Magliano
Journal: Diabetes Care (2025)

OBJECTIVE To explore the association between diabetes and anemia. RESEARCH DESIGN AND METHODS We included 9,026 and 389,616 participants from the U.S. National Health and Nutrition Examination Surveys and the UK Biobank study (UKB), respectively. Multivariable logistic regression was used to examine the cross-sectional association of diabetes with anemia, as defined by hemoglobin measurement. For the UKB follow-up, multivariable Cox proportional hazards regression was performed to estimate hazard ratios (HRs) and 95% CIs of incident anemia, as defined by hemoglobin levels or diagnosis records, in relation to diabetes. We further assessed the impact of inflammation, renal dysfunction, and medication use on this association in both populations. RESULTS Among White people aged 40–69 years in the U.S. and U.K., the adjusted odds of study participants with diagnosed diabetes also having anemia was two to four times higher than in those with normal glycemia. Over a median follow-up of 13.6 years in the UKB, 42,354 people developed anemia. The adjusted HRs for incident anemia comparing diagnosed diabetes with normal glycemia were 3.05 (95% CI 2.90–3.21) for iron deficiency anemia, 3.02 (95% CI 2.51–3.63) for anemia of chronic disease, and 4.88 (95% CI 4.23–5.63) for vitamin B12 deficiency anemia. Further adjustment for inflammation, renal dysfunction, and medication use partially attenuated these associations, but they remained strong and significant. CONCLUSIONS Diabetes was associated with several major types of anemia. Further studies are warranted to identify the mechanisms.
Presymptomatic Awareness of <i>BRCA1/BRCA2</i> Status and Outcomes in Women With Ovarian Cancer
Authors: Shunit Armon, Adi Hollander, Yakir Segev, Ora Rosengarten, Ariela Tomer, Ephrat Levy-Lahad, Rachel Michaelson-Cohen
Journal: JAMA Network Open (2025)

This cohort study examines the association between patients’ prediagnosis awareness of their genetic risk for ovarian cancer and cancer outcomes.