tbuckley/cabot-search huggingface dataset:
Early Ezetimibe Initiation After Myocardial Infarction Protects Against Later Cardiovascular Outcomes in the SWEDEHEART Registry
Authors: Margret Leosdottir, Jessica Schubert, Julia Brandts, Stefan Gustafsson, Thomas Cars, Johan Sundström, Tomas Jernberg, Kausik K Ray, Emil Hagström
Journal: Journal of the American College of Cardiology (2025)

Combination lipid-lowering therapy (LLT) after myocardial infarction (MI) achieves lower low-density lipoprotein cholesterol (LDL-C) levels and better cardiovascular outcomes vs statin monotherapy. As a result, global guidelines recommend lower LDL-C but, paradoxically, advise treatment through a stepwise approach. Yet the need for combination therapy is inevitable as <20% of patients achieve goals with statins alone. Whether combining ezetimibe with a statin early vs late after MI results in better outcomes is unknown. In this study, the authors sought to assess the impact of delayed treatment escalation on outcomes by comparing early vs late oral combination LLT (statins plus ezetimibe) in patients with MI. LLT-naïve patients (SWEDEHEART registry) hospitalized for MI (2015-2022) and discharged on statins were included. Using clone-censor-weight and Cox proportional hazards models, we compared differences in risks of MACE (death, MI, stroke), components of MACE, and cardiovascular death between patients with ezetimibe added to statins ≤12 weeks after discharge as reference (early combination therapy), from 13 weeks to 16 months (late combination therapy), or not at all. Of 35,826 patients (median age 65.1 years, 26.0% women), 6,040 (16.9%) received ezetimibe early, 6,495 (18.1%) ezetimibe late, and 23,291 (65.0%) received no ezetimibe. High-intensity statin use was ≥98% in all groups. Over a median 3.96 years (Q1-Q3: 2.15-5.81 years), 2,570 patients had MACE (440 cardiovascular deaths). One-year MACE incidences were 1.79 (early), 2.58 (late), and 4.03 (none) per 100 patient-years. Compared with early combination therapy, weighted risk differences in MACE for late combination therapy at 1, 2, and 3 years were 0.6% (95% CI: 0.1%-1.1%; P < 0.01), 1.1% (95% CI: 0.3%-2.0%; P < 0.01), and 0.7% (95% CI: -0.2% to 1.3%; P = 0.18), and 3-year HR was 1.14 (95% CI: 0.95-1.41). For those receiving no ezetimibe, risk differences were 0.7% (95% CI: 0.2%-1.3%), 1.6% (95% CI: 0.8%-2.5%), and 1.9% (95% CI: 0.8%-3.1%; P for all <0.01; 3-year HR: 1.29 [95% CI: 1.12-1.55]). Similar differences in risk of cardiovascular death at 3 years were observed (HRs vs early: late: 1.64 [95% CI: 1.15-2.63]; none: 1.83 [95% CI: 1.35-2.69]). MI care pathways should implement early combination therapy with statins and ezetimibe as standard care, because delaying use of combination LLT or using high-intensity statin monotherapy is associated with avoidable harm.
Systematic identification of disease-causing promoter and untranslated region variants in 8040 undiagnosed individuals with rare disease
Authors: Alexandra C Martin-Geary, Alexander J M Blakes, Ruebena Dawes, Scott D Findlay, Jenny Lord, Shan Dong, Susan Walker, Jonathan Talbot-Martin, Nechama Wieder, Elston N D'Souza, Maria Fernandes, Sarah Hilton, Nayana Lahiri, Christopher Campbell, Sarah Jenkinson, Christian G E L DeGoede, Emily R Anderson, Toby Candler, Helen Firth, Christopher B Burge, Stephan J Sanders, Jamie Ellingford, Diana Baralle, Siddharth Banka, Nicola Whiffin
Journal: Genome Medicine (2025)

Abstract Background Both promoters and untranslated regions (UTRs) have critical regulatory roles, yet variants in these regions are largely excluded from clinical genetic testing due to difficulty in interpreting pathogenicity. The extent to which these regions may harbour diagnoses for individuals with rare disease is currently unknown. Methods We present a framework for the identification and annotation of potentially deleterious proximal promoter and UTR variants in known dominant disease genes. We use this framework to annotate de novo variants (DNVs) in 8040 undiagnosed individuals in the Genomics England 100,000 genomes project, which were subject to strict region-based filtering, clinical review, and validation studies where possible. In addition, we performed region and variant annotation-based burden testing in 7862 unrelated probands against matched unaffected controls. Results We prioritised eleven DNVs and identified an additional variant overlapping one of the eleven. Ten of these twelve variants (82%) are in genes that are a strong match to the individual’s phenotype and six had not previously been identified. Through burden testing, we did not observe a significant enrichment of potentially deleterious promoter and/or UTR variants in individuals with rare disease collectively across any of our region or variant annotations. Conclusions Whilst screening promoters and UTRs can uncover additional diagnoses for individuals with rare disease, including these regions in diagnostic pipelines is not likely to dramatically increase diagnostic yield. Nevertheless, we provide a framework to aid identification of these variants.
Loss-of-Function in APOC3 and Protection Against Aortic Valve Disease
Authors: Jérôme Bourgault, Anders Berg Wulff, Ursula Houessou, Hasanga D Manikpurage, Marie-Annick Clavel, Philippe Pibarot, Yohan Bossé, Patrick Mathieu, Anne Tybjærg-Hansen, Sébastien Thériault, Pia R Kamstrup, Benoit J Arsenault
Journal: Journal of the American College of Cardiology (2025)
Empowering integrative and collaborative exploration of single-cell and spatial multimodal data with SGS genome browser
Authors: Tingting Xia, Jiahe Sun, Yongjiang Luo, Hailong Guo, Yudi Mao, Ling Xu, Fang Lu, Yi Wang
Journal: Cell Genomics (2025)

Recent advancements in single-cell and spatial omics technologies have generated a large amount of complex, high-dimensional data, which poses significant challenges to visualization tools. We introduce SGS (single-cell and spatial genomics system), a user-friendly, collaborative, and versatile browser designed for visualizing single-cell and spatial multimodal data. SGS excels in the integrative visualization of complex multimodal data, offering an innovative genome browser, flexible visualization modes, and 3D spatially resolved transcriptomics (SRT) data visualization capabilities. Notably, SGS empowers users with advanced capabilities for comparative visualization through features like scCompare, scMultiView, and the dual-chromosome mode. It supports a variety of data formats and is compatible with established analysis tools, enabling collaborative data exploration and visualization without programming. Overall, SGS is a comprehensive browser that enables researchers to unlock novel insights from multimodal data.
Enhanced interpretation of immune cell phenotype and function through a rhesus macaque single-cell atlas
Authors: Eisa Mahyari, Gregory J Boggy, G W McElfresh, Maanasa Kaza, Sebastian Benjamin, Benjamin Varco-Merth, Sohita Ojha, Shana Feltham, William Goodwin, Candice Nkoy, Derick Duell, Andrea Selseth, Tyler Bennett, Aaron Barber-Axthelm, Jeremy V Smedley, Caralyn S Labriola, Michael K Axthelm, R Keith Reeves, Afam A Okoye, Scott G Hansen, Louis J Picker, Benjamin N Bimber
Journal: Cell Genomics (2025)

Single-cell RNA sequencing (scRNA-seq) allows cell classification using genome-wide transcriptional state; however, high-dimensional transcriptomic profiles, and the unsupervised analyses employed to interpret them, provide a systematically different view of biology than well-established functional/lineage definitions of immunocytes. Understanding these differences and limits is essential for accurate interpretation of these rich data. We present the Rhesus Immune Reference Atlas (RIRA), the first immune-focused macaque single-cell multi-tissue atlas. We contrasted transcriptional profiles against immune lineages, using surface protein and marker genes as ground truth. While the pattern of clustering can align with cell type, this is not always true. Especially within T and natural killer (NK) cells, many functionally distinct subsets lack defining markers, and strong shared expression programs, such as cytotoxicity, result in systematic intermingling by unsupervised clustering. We identified gene programs with high discriminatory/diagnostic value, including multi-gene signatures that model T/NK cell maturation. Directly measuring these diagnostic programs complements unsupervised analyses.
Personalized neoadjuvant chemotherapy for gastrointestinal cancers – shaping imprecision to be precise
Authors: Dan Høgdall, Jakob V. Schou, Julia Johanna Almer. Bromann, Jesper B. Andersen, Colm J. O'Rourke
Journal: Clinical Cancer Research (2025)

Abstract Neoadjuvant chemotherapy can down-size or down-stage tumors, minimize post-surgical recurrence risk, or even replace surgery when deployed appropriately for patients with gastrointestinal cancers. However, accomplishing these goals is rate-limited by all-comer treatment protocols, median arm-based comparisons in clinical trials, and the persisting omission of precision approaches for cytotoxic agents. Despite heterogeneity in benefit from standard-of-care regimens, mounting biological data support the presence of actionable sensitivities or potentially targetable dependencies in most tumors. Conceptually, such tumor vulnerabilities could be a gamechanger. In treatment-resistant malignancies (biliary tract cancer, pancreatic ductal adenocarcinoma), individualized neoadjuvant treatment may increase the curative surgery frequencies that currently only occur in a minority of patients. For more treatment-sensitive gastrointestinal cancers, tailored chemotherapy strategies might reduce the need for high-intensity regimens, minimize post-surgical morbidity and allow dose de-escalation for selected patients without compromising oncological outcomes. Personalizing chemotherapy strategies remains inferential from comparing outcomes of molecularly distinct patients receiving a single treatment, or unselected patients (with comparable baseline characteristics) on different regimens. We discuss the critical importance of harnessing tumor biology to develop and implement predictive signatures for personalized neoadjuvant chemotherapy (alone or in combination with other modalities). This includes exploiting transcriptomics to retrospectively understand the molecular basis of treatment outcomes from patient biopsies, identifying existing agents to replace or supplement current standard-of-care for those unlikely to respond, and matching novel preclinical treatments to potential responder patients. Deploying mechanistically distinct cytotoxic regimens against gastrointestinal tumors with unique predispositions for DNA damage tolerance is a necessity for boosting neoadjuvant outcomes.
Tailoring an intravenously injectable oncolytic virus for augmenting radiotherapy
Authors: Chen Xu, Liting Chen, Guangna Liu, Jiaqi Xu, Wei Lv, Xiaoyu Gao, Peijun Xu, Ming Tang, Yaohe Wang, Xiao Zhao, Guangjun Nie, Keman Cheng, Funan Liu
Journal: Cell Reports Medicine (2025)

Oncolytic viruses (OVs) combined with radiotherapy (RT) show promise but are limited by challenges such as poor intravenous delivery and insufficient RT-induced DNA damage. In this study, an oncolytic adenovirus (AD) formulation, RadioOnco (AD@PSSP), is developed to improve delivery, infectivity, immune response, and RT efficacy. The multifunctional polyethylenimine (PEI)-selenium-polyethylene glycol (PEG) (PSSP) enhances intravenous delivery, shields the virus from rapid clearance, and enables targeted delivery to tumor sites after RT. The exposed PEI enhances the infectivity of AD through electrostatic interactions, thereby increasing DNA damage after RT by inhibiting the expression of DNA repair proteins, such as CHEK1 and CDK1. Furthermore, AD-PEI captures and delivers RT-induced tumor-released antigens to lymph nodes, activating robust anti-tumor immune responses. Animal model data demonstrate that RadioOnco overcomes RT resistance, targets distant metastases, and promotes long-term immunity, addressing metastasis and recurrence. In summary, this intravenously injectable OV enhances RT synergy through surface modification with multifunctional materials.
Acute exposure to high-fat diet impairs ILC3 functions and gut homeostasis
Authors: Le Xiong, Shanti Diwakarla, Roxanne Chatzis, Olivia Artaiz, Matthew Macowan, Shengbo Zhang, Alexandra Garnham, Pooranee K Morgan, Natalie A Mellett, Peter J Meikle, Graeme I Lancaster, Benjamin J Marsland, Stephen L Nutt, Cyril Seillet
Journal: Immunity (2025)

Prolonged exposure to a high-fat diet (HFD) exacerbates intestinal disease pathology, yet the early events preceding the development of gut inflammation remain poorly understood. Here, we show that within 48 h, HFD impairs intestinal group 3 innate lymphoid cells (ILC3s) and their capacity to produce interleukin-22 (IL-22), critical for maintaining gut homeostasis. This loss of function was associated with rapid dysbiosis, increased gut permeability, and reduced production of antimicrobial peptides, mucus, and tight-junction proteins. While saturated fatty acids metabolized through oxidation impaired ILC3 function, unsaturated fatty acids sustained IL-22 secretion by ILC3s through the formation of lipid droplets using diacylglycerol O-acyltransferase (DGAT) enzymes. Upon inflammation, saturated fatty acids impaired IL-22 production by ILC3s and increased the susceptibility of the gut to injury. Our findings reveal the differential acute impact of saturated and unsaturated fatty acids on gut homeostasis through distinct metabolic pathways in ILC3s.
Primate thalamic nuclei select abstract rules and shape prefrontal dynamics
Authors: Jessica M Phillips, Mohsen Afrasiabi, Niranjan A Kambi, Michelle J Redinbaugh, Summer Steely, Emily R Johnson, Xi Cheng, Maath Fayyad, Sounak Mohanta, Asia Carís, Charles B Mikell, Sima Mofakham, Yuri B Saalmann
Journal: Neuron (2025)
Neoadjuvant chemotherapy and surgery versus surgery for organ preservation of T3 and T4a nasal and paranasal sinus squamous cell carcinoma (NPNSCC) ECOG-ACRIN EA3163
Authors: Nabil F. Saba, Yael Flamand, Derrick T. Lin, Christine H. Chung, Mark W. McDonald, Styliani Flampouri, Saad A. Khan, Carl H. Snyderman, Ehab Y. Hanna, Ivan H. El-Sayed, Clementino A. Solares, Christopher H. Le, Maged Ghaly, Peter H. Hwang, Dong M. Shin, Rita S. Axelrod, Chukwuemeka V. Ikpeazu, Douglas R. Adkins, Fenghai Duan, Marc Cohen, Michael A. Samuels, Paul L. Swiecicki, Rathan M. Subramaniam, A. Bapsi Chakravarthy, Barbara A. Burtness
Journal: Clinical Cancer Research (2025)

Abstract Purpose: Neoadjuvant chemotherapy for structure preservation (SP) in nasal and paranasal sinus squamous cell carcinoma (NPNSCC) has been described in single-institution but not randomized studies. EA3163 was a randomized study investigating whether cytoreductive neoadjuvant chemotherapy would improve SP or overall survival (OS). Patients and Methods: Patients with T3/T4a and select T4b NPNSCC requiring orbital or base of skull (BOS) resection were randomized to surgery (Arm A), versus surgery preceded by docetaxel/cisplatin x3 cycles (Arm B). Degree of anticipated SP (orbit and BOS) was required preoperatively and post-chemotherapy. SP was noted at surgery. Co-primary objectives were SP rate (orbit/BOS) and OS. 82 patients needed to be accrued for 81% power with 0.1 one-sided alpha using Fisher’s exact test for SP rate and 83% with 0.1 one-sided alpha using log-rank test for OS. Results: Among 23 evaluable patients, overall SP rate was 30%: 15% in Arm A (N=2/13, 95%CI: 1.9-45.4%), 50% in Arm B (N=5/10, 95%CI: 18.7-81.3%) (p=0.17). Among 18 patients with pathologic T3/T4a disease, overall SP rate was 39%: 18% in Arm A (N=2/11, 95%CI: 2.3-51.8%), 71% in Arm B (N=5/7, 95%CI: 29.0-96.3%) (p=0.049). Orbit and BOS-specific preservation rates were 38% (95%CI: 8.5-75.5%) vs 83% (95%CI: 35.9-99.6%), and 33% (95%CI: 9.9-65.1%) vs 67% (95%CI: 29.9-92.5%) in Arm A vs B, respectively. The most common grade ≥3 toxicities included mucositis, anemia, nausea and lymphopenia (all &amp;gt;10%). No grade 5 events were reported. Conclusions: These results support neoadjuvant chemotherapy as an effective intervention for SP in T3/T4a NPNSCC and deserve further evaluation.
A Prospective Study Consortium for the Discovery and Validation of Early Detection Markers for Ovarian Cancer (“PREDICT”) – Baseline findings for CA125
Authors: Rudolf Kaaks, Victoria Cooley, Trasias Mukama, Lauren R. Teras, Alpa V. Patel, Giovanna Masala, Marta Crous-Bou, Holly R. Harris, Hilde Langseth, Heljä-Marja Surcel, Nicolas Wentzensen, Kathryn Terry, Naoko Sasamoto, Shelley Tworoger, Renée Turzanski. Fortner
Journal: Clinical Cancer Research (2025)

Abstract Purpose: Epithelial ovarian cancer (EOC) is a lethal malignancy. CA125, the “best” available marker for detecting EOC, has insufficient sensitivity and specificity for earlier-stage disease and is not a meaningful screening tool, motivating the search for further biomarkers. Cancer biomarker discovery is enhanced by “omics” technologies. Discovery studies for EOC biomarkers should be conducted in pre-diagnosis blood samples from prospective cohorts to maximize likelihood of identifying markers that can detect disease before usual diagnosis and in earlier disease stage, while reducing methodologic biases. Experimental Design: Individual cohorts with pre-diagnosis blood samples have insufficient sample size for such studies. thus, we established “PREDICT” (“Prospective Early Detection Consortium for Ovarian Cancer")—a collaboration of nine prospective studies—to assemble a sufficient number of EOC cases with blood samples collected ≤18 months before diagnosis plus controls. The 457 cases and 1,687 controls have circulating CA125 measured using a clinical assay. Results: The discrimination capacity for single CA125 measurements in samples collected &amp;lt;6 months prior to diagnosis was high (area under the curve (AUC), PREDICT overall=0.92; range across cohorts of non-pregnant individuals=0.89–0.98), and declined with extended time between blood collection and diagnosis. Between-cohort variability in CA125 levels and predictive performance was observed. Conclusions: Ongoing investigations in PREDICT are evaluating the early detection potential of tumor-associated autoantibodies and microRNAs, using CA125 as a benchmark. PREDICT is a well-characterized resource for identifying and validating detection markers for EOC that may then be used in multi-modal screening, as a complement to CA125 and combined with imaging.
Oral gepotidacin for the treatment of uncomplicated urogenital gonorrhoea (EAGLE-1): a phase 3 randomised, open-label, non-inferiority, multicentre study
Authors: Jonathan D C Ross, Janet Wilson, Kimberly A Workowski, Stephanie N Taylor, David A Lewis, Sally Gatsi, William Flight, Nicole E Scangarella-Oman, Charles Jakielaszek, Dan Lythgoe, Marcy Powell, Salim Janmohamed, Judith Absalon, Caroline Perry
Journal: The Lancet (2025)
Global Transcriptional Complexity of Estrogen Receptor Low Positive Breast Cancers in a Prospective Swedish Population-based SCAN-B Cohort
Authors: Siker Kimbung, Srinivas Veerla, Kadum Muhammad, Anna Ehinger, Johan Vallon-Christersson, Martin Malmberg, Niklas Loman
Journal: Clinical Cancer Research (2025)

Abstract Purpose: There is uncertainty whether ER-low tumors with a 1-10% immunohistochemical staining of nuclei represent a distinct molecular biological entity of BC, posing significant challenges for their clinical management and developing novel therapies. We aimed to elucidate ER-low tumor biology. Experimental Design: We analyzed primary tumors included in a Swedish population-based SCAN-B BC cohort, 2% (n=174) of which were classified ER-low. Transcriptional patterns, tumor inflammatory infiltration and prognosis were compared between ER-low versus ER-negative (ER-neg; 0%) and ER-positive (ER-pos; &amp;gt;10%) tumors. Results: The transcriptomes of ER-low and ER-neg tumors remarkably overlapped; displaying predominantly non-luminal PAM50 subtypes and down-regulated ER signaling. All TNBC molecular subtypes were represented within ER-low/HER2-negative BC. Unsupervised clustering algorithms failed to segregate ER-low/HER2-negative from TNBC tumors and only 2 genes were significantly differentially expressed above 1.5 fold-difference between the groups. However, borderline ER-low tumors (with exactly10% ER) were mostly assigned labels associated with luminal disease biology suggesting possible endocrine responsiveness. Lymphocyte infiltration was comparable between ER-low and ER-neg but was significantly higher relative to ER-pos tumors. Within ER-low/HER2-negative disease, HR-positivity and low/intermediate PAM50 ROR score inferred from RNAseq data and lymphocyte fraction ≥30%, were respectively associated with better prognosis. Conclusions: ER-low/HER2-negative is not a distinct BC molecular biological entity but an integral part of TNBC deserving similar treatments. Nonetheless, a few borderline cases with moderately active ER-signaling can potentially respond to ET. HR-related signatures and TILs may stratify ER-low/HER2-negative tumors according to risk for recurrence. The true benefit of ET in ER-low BC requires prospective investigation.
Clinical Context Shapes the Relationship Between Genomic Alterations and Response to AR Inhibitors and Chemotherapy in Metastatic Prostate Cancer
Authors: Kalpit Shah, Matthew H. Secrest, Wei Zhou, Shu Wang, Dan Canter, Yuxiang Zhang, Dexter Jin, Ethan Sokol, Malgorzata Nowicka, Armande Ang Houle, Ciara Metcalfe, Steven Gendreau, Carsten Schröder, Matthew Wongchenko, Gerhardt Attard
Journal: Clinical Cancer Research (2025)

Abstract Purpose: Many preclinical hypotheses, including reciprocal feedback activation between AR-PI3K pathway in PTEN loss and ASI-induced “BRCAness” regardless of BRCA1/2 status, have struggled to translate into clinical benefit for metastatic prostate cancer patients. This gap in translatability, particularly in mCRPC, may stem from a limited understanding of prostate cancer evolution. A key challenge is how early-stage tumor genetics correlate with mCRPC. By examining clinical, genomic, and molecular changes over time, we aim to refine clinical trial design. Experimental Design: Using a comprehensive dataset from electronic health records (EHR) with genomic profiling, we observed a shift in the prognostic value of biomarkers from mHSPC to mCRPC. Additionally, genomic and transcriptomic analyses of primary tumors from the IPATential150 trial and mCRPC samples from the SU2C cohort examined the changing AR-PI3K signaling correlation. Results: PI3K-AKT pathway alterations lost their prognostic significance in later stages. While AR and PI3K-AKT signaling were inversely correlated in primary tumors, this relationship was disrupted in mCRPC, independent of PIK3CA/AKT1/PTEN status. We identified broad transcriptional rewiring associated with AR signaling, increasing tumor heterogeneity. Improving understanding of early-stage disease, we identified a high-risk mHSPC subset enriched for AR alterations. Additionally, in a subset of patients, AR ligand-binding domain mutations preceded amplification, potentially leading to preferential amplification of the mutant AR form. Conclusions: Our findings underscore the dynamic nature of prostate tumor biology and emphasize the need for translational research to validate preclinical hypotheses in clinically relevant settings, ultimately improving trial design and therapeutic strategies.