tbuckley/cabot-search huggingface dataset:
Predictors of the efficacy of His bundle pacing in patients with a prolonged PR interval: A stratified analysis of the HOPE‐HF randomized controlled trial
Authors: Daniel Keene, Nandita Kaza, Divya Srinivasan, Nadine Ali, Mark Tanner, Paul Foley, Badri Chandrasekaran, Philip Moore, Shaumik Adhya, Norman Qureshi, Amal Muthumala, Rebecca Lane, Aldo Rinaldi, Sharad Agarwal, Francisco Leyva, Jonathan Behar, Sukh Bassi, Andre Ng, Paul Scott, Rachana Prasad, Jon Swinburn, Joseph Tomson, Amarjit Sethi, Jaymin Shah, Phang Boon Lim, Andreas Kyriacou, Dewi Thomas, Jenny Chuen, Ravi Kamdar, Prapa Kanagaratnam, Myril Mariveles, Nicholas Johnson, Emanuela Falaschetti, James P. Howard, Ahran Arnold, John G.F. Cleland, Darrel P. Francis, Zachary Whinnett, Matthew Shun‐Shin
Journal: European Journal of Heart Failure (2024)

Abstract Aims The randomized, double‐blind, placebo‐controlled HOPE‐HF trial assessed the benefit of atrio‐ventricular (AV) delay optimization delivered using His bundle pacing. It recruited patients with left ventricular ejection fraction ≤40%, PR interval ≥200 ms, and baseline QRS ≤140 ms or right bundle branch block. Overall, there was no significant increase in peak oxygen uptake (VO 2 max) but there was significant improvement in heart failure specific quality of life. In this pre‐specified secondary analysis, we evaluated the impact of baseline PR interval, echocardiographic E‐A fusion, and the magnitude of acute high‐precision haemodynamic response to pacing, on outcomes. Methods and results All 167 randomized participants underwent measurement of PR interval, acute haemodynamic response at optimized AV delay, and assessment of presence of E‐A fusion. We tested the impact of these baseline parameters using a Bayesian ordinal model on VO 2 max, quality of life and activity measures. There was strong evidence of a beneficial interaction between the baseline acute haemodynamic response and the blinded benefit of pacing for VO 2 (Pr 99.9%), Minnesota Living With Heart Failure (MLWHF) (Pr 99.8%), MLWHF physical limitation score (Pr 98.9%), EQ‐5D visual analogue scale (Pr 99.6%), and exercise time (Pr 99.4%). The baseline PR interval and the presence of baseline E‐A fusion did not have this reliable ability to predict the clinical benefit of pacing over placebo across multiple endpoints. Conclusions In the HOPE‐HF trial, the acute haemodynamic response to pacing reliably identified patients who obtained clinical benefit. Patients with a long PR interval (≥200 ms) and left ventricular impairment who obtained acute haemodynamic improvement with AV‐optimized His bundle pacing were likely to obtain clinical benefit, consistent across multiple endpoints. Importantly, this gradation can be reliably tested for before randomization, but does require high‐precision AV‐optimized haemodynamic assessment to be performed.
Extra-domain A containing fibronectin in pulmonary hypertension and treatment effects of a function-blocking antibody
Authors: Isabell Singerer, Laura Tempel, Katja Gruen, Judith Heiß, Clara Gutte, Mattia Matasci, Andrea Schrepper, Reinhard Bauer, Alexander Berndt, Christian Jung, P Christian Schulze, Dario Neri, Marcus Franz
Journal: Cardiovascular Research (2024)

Abstract Aims Pulmonary vascular and right ventricular (RV) remodelling processes are important for development and progression of pulmonary hypertension (PH). The current study analysed the functional role of the extra domain A-containing fibronectin (ED-A+ Fn) for the development of PH by comparing ED-A+ Fn knockout (KO) and wild-type (WT) mice as well as the effects of an antibody-based therapeutic approach in a model of monocrotaline (MCT)-induced PH, which will be validated in a model of Sugen 5416/hypoxia-induced PH. Methods and results PH was induced using MCT (PH mice). Sixty-nine mice were divided into the following groups: sham-treated controls (WT: n = 7; KO: n = 7), PH mice without specific treatment (WT: n = 12; KO: n = 10), PH mice treated with a dual endothelin receptor antagonist (macitentan; WT: n = 6; KO: n = 11), WT PH mice treated with the F8 antibody, specifically recognizing ED-A+ Fn, (n = 8), and WT PH mice treated with an antibody of irrelevant antigen specificity (KSF, n = 8). Compared to controls, WT_PH mice showed a significant elevation of the RV systolic pressure (P = 0.04) and RV functional impairment including increased basal RV (P = 0.016) diameter or tricuspid annular plane systolic excursion (P = 0.008). In contrast, KO PH did not show such effects compared to controls (P = n.s.). In WT_PH mice treated with F8, haemodynamic and echocardiographic parameters were significantly improved compared to untreated WT_PH mice or those treated with the KSF antibody (P &amp;lt; 0.05). On the microscopic level, KO_PH mice showed significantly less tissue damage compared to the WT_PH mice (P = 0.008). Furthermore, lung tissue damage could significantly be reduced after F8 treatment (P = 0.04). Additionally, these findings could be verified in the Sugen 5416/hypoxia mouse model, in which F8 significantly improved echocardiographic, haemodynamic, and histologic parameters. Conclusion ED-A+ Fn is of crucial importance for PH pathogenesis representing a promising therapeutic target in PH. We here show a novel therapeutic approach using antibody-mediated functional blockade of ED-A+ Fn capable of attenuating and partially reversing PH-associated tissue remodelling.
Neuro-immune crosstalk in hematopoiesis, inflammation, and repair
Authors: Damilola Emmanuel Akinyemi, Raphael Chevre, Oliver Soehnlein
Journal: Trends in Immunology (2024)

Innate immune cells are primary effectors during host defense and in sterile inflammation. Their production in the bone marrow is tightly regulated by growth and niche factors, and their activity at sites of inflammation is orchestrated by a network of alarmins and cytokines. Yet, recent work highlights a significant role of the peripheral nervous system in these processes. Sympathetic neural pathways play a key role in regulating blood cell homeostasis, and sensory neural pathways mediate pro- or anti-inflammatory signaling in a tissue-specific manner. Here, we review emerging evidence of the fine titration of hematopoiesis, leukocyte trafficking, and tissue repair via neuro-immune crosstalk, and how its derailment can accelerate chronic inflammation, as in atherosclerosis.
Proteomic screening identifies PF4/Cxcl4 as a critical driver of myelofibrosis
Authors: Daniele Capitanio, Francesca R Calledda, Vittorio Abbonante, Daniele Cattaneo, Manuela Moriggi, Bartalucci Niccolò, Cristina Bucelli, Delfina Tosi, Umberto Gianelli, Alessandro Maria Vannucchi, Alessandra Iurlo, Cecilia Gelfi, Alessandra Balduini, Alessandro Malara
Journal: Leukemia (2024)
Catheter‐based ablation to improve outcomes in patients with atrial fibrillation and heart failure with preserved ejection fraction: Rationale and design of the <scp>CABA</scp>‐<scp>HFPEF</scp>‐<scp>DZHK27</scp> trial
Authors: Abdul S. Parwani, Stefan Kääb, Tim Friede, Roland Richard Tilz, Johann Bauersachs, Norbert Frey, Gerhard Hindricks, Thorsten Lewalter, Michiel Rienstra, Andreas Rillig, Daniel Scherr, Daniel Steven, Paulus Kirchhof, Burkert Pieske
Journal: European Journal of Heart Failure (2024)

Abstract Aims Atrial fibrillation (AF) is common in heart failure (HF) and negatively impacts outcomes. The role of ablation‐based rhythm control in patients with AF and HF with preserved (HFpEF) or mildly reduced ejection fraction (HFmrEF) is not known. The CABA‐HFPEF‐DZHK27 (CAtheter‐Based Ablation of atrial fibrillation compared to conventional treatment in patients with Heart Failure with Preserved Ejection Fraction) trial will determine whether early catheter ablation for AF can prevent adverse cardiovascular outcomes in patients with HFpEF or HFmrEF. Methods CABA‐HFPEF‐DZHK27 (NCT05508256) is an investigator‐initiated, prospective, randomized, open, interventional multicentre strategy trial with blinded outcome assessment. Approximately 1548 patients with paroxysmal or persistent AF diagnosed within 24 months prior to enrolment and HFpEF or HFmrEF will be randomized to early catheter ablation within 4 weeks after randomization or to usual care. All patients receive anticoagulation, rate control, and HF management according to current guideline recommendations. Usual care can include rhythm control in symptomatic patients. Patients will be followed until the end of the trial for the primary outcome, a composite of cardiovascular death, stroke, and total unplanned hospitalizations for HF or acute coronary syndrome. The safety outcome comprises complications of catheter ablation and death. The trial is powered for a rate ratio of 0.75 (two‐sided alpha = 0.05, 1‐beta = 0.8). Conclusion CABA‐HFPEF‐DZHK27 will define the role of systematic and early catheter ablation in patients with AF and HFpEF or HFmrEF.
Maternal obesogenic diet operates at the tumor cell of origin to increase incidence and decrease latency of neurofibromatosis type 1 optic pathway glioma
Authors: Ambrose Chan, Kailong Zhang, Gemma Martin, Sabiha Bano, Jit Chatterjee, Sarvika Mahto, Avery Wang, David H Gutmann, Nicole M Brossier
Journal: Neuro-Oncology (2024)

Pediatric low-grade glioma incidence has been rising in the United States, mirroring the rising rates of pediatric and maternal obesity. Recently, children of obese mothers were demonstrated to develop brain tumors at higher rates. Importantly, obesity in the United States is largely driven by diet, given the prevalence of high-fat and high-sugar (HFHS) food choices. Since high-fat diet exposure can increase embryonic neuroglial progenitor cell (NPC) proliferation, the potential cells of origin for a low-grade glioma, we hypothesized that in utero exposure to an obesogenic diet would modify pediatric brain penetrance and latency by affecting the tumor cell of origin.
Unusual cause of retroperitoneal leak in a patient undergoing peritoneal dialysis
Authors: Nicolas A.D. Bergeron, Alexandre Candellier, Mathieu Rousseau-Gagnon, Fabrice Mac-Way
Journal: Kidney International (2024)

A 63-year-old woman who had been on continuous cycling peritoneal dialysis (PD) for 24 months for end-stage kidney disease due to a homozygous required for meiotic nuclear division 1 homolog (RMND1) mutation was evaluated for a 3-kg weight gain and reduced dialysate effluent in less than a week. RMND1 mutation is a mitochondriopathy also leading to myopathy, leukopenia, ovarian insufficiency, and sensorineural hearing loss. Use of higher concentrations of dextrose solutions was unable to restore dry weight. Physical examination results were unremarkable, except for slight bilateral ankle edema. Notably, there was no evidence of cutaneous fluid accumulation over the abdomen and lumbar region. Biochemistry values were as usual. Peritoneal membrane permeability test did not suggest a membrane failure. Computed tomography scan with intraperitoneal contrast injection showed unusual dialysate leakage in the right anterior and posterior pararenal space (Figure 1a). The patient was temporarily transferred to hemodialysis. After 6 weeks, continuous cycling PD was progressively resumed over a 4-week period to the prior parameters. Computed tomography scan peritoneography performed 1 week and 1 month after PD restart did not reveal any leakage, and PD exchanges have been proceeding normally since then (Figure 1b). Dialysate leaks are common complications of PD but rarely manifest as retroperitoneal leakage in patients undergoing continuous cycling PD. As the patient was practicing physical exercises regularly, we suspect that abrupt increases in intra-abdominal pressure may have contributed to the occurrence of a communication between the parietal peritoneum and pararenal space. No association has yet been described between mitochondriopathy and peritoneal abnormalities. This case highlights the utility of computed tomography scan peritoneography for revealing dialysate leaks and the need to carefully investigate the possibility of retroperitoneal leak in patients undergoing PD. Finally, the occurrence of retroperitoneal leak should not discourage clinicians from resuming PD. All the authors declared no competing interests.
Challenges to identifying risk versus protective factors in Alzheimer’s disease
Authors: Chiara Pappalettera, Claudia Carrarini, Stefano Cappa, Naike Caraglia, Maria Cotelli, Camillo Marra, Daniela Perani, Alberto Redolfi, Patrizia Spadin, Fabrizio Tagliavini, Nicola Vanacore, Fabrizio Vecchio, Paolo Maria Rossini
Journal: Nature Medicine (2024)
Profiling protein–protein interactions to predict the efficacy of B-cell-lymphoma-2-homology-3 mimetics for acute myeloid leukaemia
Authors: Changju Chun, Ja Min Byun, Minkwon Cha, Hongwon Lee, Byungsan Choi, Hyunwoo Kim, Saem Hong, Yunseo Lee, Hayoung Park, Youngil Koh, Tae-Young Yoon
Journal: Nature Biomedical Engineering (2024)

Abstract B-cell-lymphoma-2 (BCL2) homology-3 (BH3) mimetics are inhibitors of protein–protein interactions (PPIs) that saturate anti-apoptotic proteins in the BCL2 family to induce apoptosis in cancer cells. Despite the success of the BH3-mimetic ABT-199 for the treatment of haematological malignancies, only a fraction of patients respond to the drug and most patients eventually develop resistance to it. Here we show that the efficacy of ABT-199 can be predicted by profiling the rewired status of the PPI network of the BCL2 family via single-molecule pull-down and co-immunoprecipitation to quantify more than 20 types of PPI from a total of only 1.2 × 10 6 cells per sample. By comparing the obtained multidimensional data with BH3-mimetic efficacies determined ex vivo, we constructed a model for predicting the efficacy of ABT-199 that designates two complexes of the BCL2 protein family as the primary mediators of drug effectiveness and resistance, and applied it to prospectively assist therapeutic decision-making for patients with acute myeloid leukaemia. The characterization of PPI complexes in clinical specimens opens up opportunities for individualized protein-complex-targeting therapies.
Radiotherapy-triggered reduction of platinum-based chemotherapeutic prodrugs in tumours
Authors: Qunfeng Fu, Shuren Zhang, Siyong Shen, Zhi Gu, Junyi Chen, Dongfan Song, Pengwei Sun, Chunhong Wang, Zhibin Guo, Yunlong Xiao, Yi Qin Gao, Zijian Guo, Zhibo Liu
Journal: Nature Biomedical Engineering (2024)
Reply to: Challenges to identifying risk versus protective factors in Alzheimer’s disease
Authors: Juan Fortea, Lídia Vaqué-Alcázar, Jordi Pegueroles, Daniel Alcolea, Olivia Belbin, Oriol Dols-Icardo, Laura Videla, Juan Domingo Gispert, Marc Suárez-Calvet, Sterling C Johnson, Reisa Sperling, Alexandre Bejanin, Alberto Lleó, Víctor Montal
Journal: Nature Medicine (2024)
Gα13 restricts nutrient driven proliferation in mucosal germinal centers
Authors: Hang T. Nguyen, Moyi Li, Rahul Vadakath, Keirstin A. Henke, Tam C. Tran, Huifang Li, Maryam Yamadi, Sriranjani Darbha, Yandan Yang, Juraj Kabat, Anne R. Albright, Enoc Granados Centeno, James D. Phelan, Sandrine Roulland, Da Wei Huang, Michael C. Kelly, Ryan M. Young, Stefania Pittaluga, Simone Difilippantonio, Jagan R. Muppidi
Journal: Nature Immunology (2024)

Abstract Germinal centers (GCs) that form in mucosal sites are exposed to gut-derived factors that have the potential to influence homeostasis independent of antigen receptor-driven selective processes. The G-protein Gα13 confines B cells to the GC and limits the development of GC-derived lymphoma. We discovered that Gα13-deficiency fuels the GC reaction via increased mTORC1 signaling and Myc protein expression specifically in the mesenteric lymph node (mLN). The competitive advantage of Gα13-deficient GC B cells (GCBs) in mLN was not dependent on T cell help or gut microbiota. Instead, Gα13-deficient GCBs were selectively dependent on dietary nutrients likely due to greater access to gut lymphatics. Specifically, we found that diet-derived glutamine supported proliferation and Myc expression in Gα13-deficient GCBs in the mLN. Thus, GC confinement limits the effects of dietary glutamine on GC dynamics in mucosal tissues. Gα13 pathway mutations coopt these processes to promote the gut tropism of aggressive lymphoma.
Disseminated tuberculosis is associated with impaired T cell immunity mediated by non-canonical NF-κB pathway
Authors: Jing Jiang, Zhihong Cao, Binyu Li, Xihui Ma, Xianping Deng, Bingfen Yang, Yanhua Liu, Fei Zhai, Xiaoxing Cheng
Journal: Journal of Infection (2024)

The mechanism that leads to disseminated tuberculosis in HIV-negative patients is still largely unknown. T cell subsets and signaling pathways that were associated with disseminated tuberculosis were investigated.
In chronic spontaneous urticaria, increased Galectin‐9 expression on basophils and eosinophils is linked to high disease activity, endotype‐specific markers, and response to omalizumab treatment
Authors: Jiang Ji, Minhui Tang, Yue Zhao, Chuqiao Zhang, Yu Shen, Bin Zhou, Cuiping Liu, Marcus Maurer, Qingqing Jiao
Journal: Allergy (2024)

Abstract Background Galectin‐9 (Gal‐9) has been implicated in allergic and autoimmune diseases, but its role and relevance in chronic spontaneous urticaria (CSU) are unclear. Objectives To characterize the role and relevance of Gal‐9 in the pathogenesis of CSU. Methods We assessed 60 CSU patients for their expression of Gal‐9 on circulating eosinophils and basophils as well as T cell expression of the Gal‐9 receptor TIM‐3, compared them with 26 healthy controls (HCs), and explored possible links with disease features including disease activity (urticaria activity score, UAS), total IgE, basophil activation test (BAT), and response to omalizumab treatment. We also investigated potential drivers of Gal‐9 expression by eosinophils and basophils. Results Our CSU patients had markedly increased rates of circulating Gal‐9 + eosinophils and basophils and high numbers of lesional Gal‐9 + cells. High rates of blood Gal‐9 + eosinophils/basophils were linked to high disease activity, IgE levels, and BAT negativity. Serum levels of TNF‐α were positively correlated with circulating Gal‐9 + eosinophils/basophils, and TNF‐α markedly upregulated Gal‐9 on eosinophils. CSU patients who responded to omalizumab treatment had more Gal‐9 + eosinophils/basophils than non‐responders, and omalizumab reduced blood levels of Gal‐9 + eosinophils/basophils in responders. Gal‐9 + eosinophils/basophils were negatively correlated with TIM‐3 + T H 17 cells. Conclusion Our findings demonstrate a previously unrecognized involvement of the Gal‐9/TIM‐3 pathway in the pathogenesis CSU and call for studies that explore its relevance.
Non-coding variants impact cis-regulatory coordination in a cell type-specific manner
Authors: Olga Pushkarev, Guido van Mierlo, Judith Franziska Kribelbauer, Wouter Saelens, Vincent Gardeux, Bart Deplancke
Journal: Genome biology (2024)

Abstract Background Interactions among cis -regulatory elements (CREs) play a crucial role in gene regulation. Various approaches have been developed to map these interactions genome-wide, including those relying on interindividual epigenomic variation to identify groups of covariable regulatory elements, referred to as chromatin modules (CMs). While CM mapping allows to investigate the relationship between chromatin modularity and gene expression, the computational principles used for CM identification vary in their application and outcomes. Results We comprehensively evaluate and streamline existing CM mapping tools and present guidelines for optimal utilization of epigenome data from a diverse population of individuals to assess regulatory coordination across the human genome. We showcase the effectiveness of our recommended practices by analyzing distinct cell types and demonstrate cell type specificity of CRE interactions in CMs and their relevance for gene expression. Integration of genotype information revealed that many non-coding disease-associated variants affect the activity of CMs in a cell type-specific manner by affecting the binding of cell type-specific transcription factors. We provide example cases that illustrate in detail how CMs can be used to deconstruct GWAS loci, assess variable expression of cell surface receptors in immune cells, and reveal how genetic variation can impact the expression of prognostic markers in chronic lymphocytic leukemia. Conclusions Our study presents an optimal strategy for CM mapping and reveals how CMs capture the coordination of CREs and its impact on gene expression. Non-coding genetic variants can disrupt this coordination, and we highlight how this may lead to disease predisposition in a cell type-specific manner.
Leveraging neighborhood representations of single-cell data to achieve sensitive DE testing with miloDE
Authors: Alsu Missarova, Emma Dann, Leah Rosen, Rahul Satija, John Marioni
Journal: Genome biology (2024)

Single-cell RNA-sequencing enables testing for differential expression (DE) between conditions at a cell type level. While powerful, one of the limitations of such approaches is that the sensitivity of DE testing is dictated by the sensitivity of clustering, which is often suboptimal. To overcome this, we present miloDE-a cluster-free framework for DE testing (available as an open-source R package). We illustrate the performance of miloDE on both simulated and real data. Using miloDE, we identify a transient hemogenic endothelia-like state in mouse embryos lacking Tal1 and detect distinct programs during macrophage activation in idiopathic pulmonary fibrosis.
Single-cell decoding of drug induced transcriptomic reprogramming in triple negative breast cancers
Authors: Farhia Kabeer, Hoa Tran, Mirela Andronescu, Gurdeep Singh, Hakwoo Lee, Sohrab Salehi, Beixi Wang, Justina Biele, Jazmine Brimhall, David Gee, Viviana Cerda, Ciara O'Flanagan, Teresa Algara, Takako Kono, Sean Beatty, Elena Zaikova, Daniel Lai, Eric Lee, Richard Moore, Andrew J Mungall, Marc J Williams, Andrew Roth, Kieran R Campbell, Sohrab P Shah, Samuel Aparicio
Journal: Genome biology (2024)

Abstract Background The encoding of cell intrinsic drug resistance states in breast cancer reflects the contributions of genomic and non-genomic variations and requires accurate estimation of clonal fitness from co-measurement of transcriptomic and genomic data. Somatic copy number (CN) variation is the dominant mutational mechanism leading to transcriptional variation and notably contributes to platinum chemotherapy resistance cell states. Here, we deploy time series measurements of triple negative breast cancer (TNBC) single-cell transcriptomes, along with co-measured single-cell CN fitness, identifying genomic and transcriptomic mechanisms in drug-associated transcriptional cell states. Results We present scRNA-seq data (53,641 filtered cells) from serial passaging TNBC patient-derived xenograft (PDX) experiments spanning 2.5 years, matched with genomic single-cell CN data from the same samples. Our findings reveal distinct clonal responses within TNBC tumors exposed to platinum. Clones with high drug fitness undergo clonal sweeps and show subtle transcriptional reversion, while those with weak fitness exhibit dynamic transcription upon drug withdrawal. Pathway analysis highlights convergence on epithelial-mesenchymal transition and cytokine signaling, associated with resistance. Furthermore, pseudotime analysis demonstrates hysteresis in transcriptional reversion, indicating generation of new intermediate transcriptional states upon platinum exposure. Conclusions Within a polyclonal tumor, clones with strong genotype-associated fitness under platinum remained fixed, minimizing transcriptional reversion upon drug withdrawal. Conversely, clones with weaker fitness display non-genomic transcriptional plasticity. This suggests CN-associated and CN-independent transcriptional states could both contribute to platinum resistance. The dominance of genomic or non-genomic mechanisms within polyclonal tumors has implications for drug sensitivity, restoration, and re-treatment strategies.