tbuckley/cabot-search huggingface dataset:
Artificial intelligence-enabled ECG for left ventricular diastolic function and filling pressure
Authors: Eunjung Lee, Saki Ito, William R. Miranda, Francisco Lopez-Jimenez, Garvan C. Kane, Samuel J. Asirvatham, Peter A. Noseworthy, Paul A. Friedman, Rickey E. Carter, Barry A. Borlaug, Zachi I. Attia, Jae K. Oh
Journal: npj Digital Medicine (2024)

Abstract Assessment of left ventricular diastolic function plays a major role in the diagnosis and prognosis of cardiac diseases, including heart failure with preserved ejection fraction. We aimed to develop an artificial intelligence (AI)-enabled electrocardiogram (ECG) model to identify echocardiographically determined diastolic dysfunction and increased filling pressure. We trained, validated, and tested an AI-enabled ECG in 98,736, 21,963, and 98,763 patients, respectively, who had an ECG and echocardiographic diastolic function assessment within 14 days with no exclusion criteria. It was also tested in 55,248 patients with indeterminate diastolic function by echocardiography. The model was evaluated using the area under the curve (AUC) of the receiver operating characteristic curve, and its prognostic performance was compared to echocardiography. The AUC for detecting increased filling pressure was 0.911. The AUCs to identify diastolic dysfunction grades ≥1, ≥2, and 3 were 0.847, 0.911, and 0.943, respectively. During a median follow-up of 5.9 years, 20,223 (20.5%) died. Patients with increased filling pressure predicted by AI-ECG had higher mortality than those with normal filling pressure, after adjusting for age, sex, and comorbidities in the test group (hazard ratio (HR) 1.7, 95% CI 1.645–1.757) similar to echocardiography and in the indeterminate group (HR 1.34, 95% CI 1.298–1.383). An AI-enabled ECG identifies increased filling pressure and diastolic function grades with a good prognostic value similar to echocardiography. AI-ECG is a simple and promising tool to enhance the detection of diseases associated with diastolic dysfunction and increased diastolic filling pressure.
Notch2 with retinoic acid license IL-23 expression by intestinal EpCAM+ DCIR2+ cDC2s in mice
Authors: Daiya Ohara, Yusuke Takeuchi, Hitomi Watanabe, Yoonha Lee, Hiroki Mukoyama, Toshiaki Ohteki, Gen Kondoh, Keiji Hirota
Journal: The Journal of Experimental Medicine (2024)

Despite the importance of IL-23 in mucosal host defense and disease pathogenesis, the mechanisms regulating the development of IL-23–producing mononuclear phagocytes remain poorly understood. Here, we employed an Il23aVenus reporter strain to investigate the developmental identity and functional regulation of IL-23–producing cells. We showed that flagellin stimulation or Citrobacter rodentium infection led to robust induction of IL-23–producing EpCAM+ DCIR2+ CD103− cDC2s, termed cDCIL23, which was confined to gut-associated lymphoid tissues, including the mesenteric lymph nodes, cryptopatches, and isolated lymphoid follicles. Furthermore, we demonstrated that Notch2 signaling was crucial for the development of EpCAM+ DCIR2+ cDC2s, and the combination of Notch2 signaling with retinoic acid signaling controlled their terminal differentiation into cDCIL23, supporting a two-step model for the development of gut cDCIL23. Our findings provide fundamental insights into the developmental pathways and cellular dynamics of IL-23–producing cDC2s at steady state and during pathogen infection.
Histone methyltransferase Suv39h1 regulates hepatic stellate cell activation and is targetable in liver fibrosis
Authors: Ming Kong, Junjing Zhou, Aoqi Kang, Yameng Kuai, Huihui Xu, Min Li, Xiulian Miao, Yan Guo, Zhiwen Fan, Yong Xu, Zilong Li
Journal: Gut (2024)

Objective Liver fibrosis is a prelude to a host of end-stage liver diseases. Hepatic stellate cells (HSCs), switching from a quiescent state to myofibroblasts, are the major source for excessive production of extracellular matrix proteins. In the present study, we investigated the role of Suv39h1, a lysine methyltransferase, in HSC-myofibroblast transition and the implication in liver fibrosis. Design HSC-specific or myofibroblast-specific Suv39h1 deletion was achieved by crossbreeding the Suv39h1 f/f mice to the Lrat -Cre mice or the Postn -Cre ERT2 mice. Liver fibrosis was induced by CCl 4 injection or bile duct ligation. Results We report that Suv39h1 expression was universally upregulated during HSC-myofibroblast transition in different cell and animal models of liver fibrosis and in human cirrhotic liver tissues. Consistently, Suv39h1 knockdown blocked HSC-myofibroblast transition in vitro. HSC-specific or myofibroblast-specific deletion of Suv39h1 ameliorated liver fibrosis in mice. More importantly, Suv39h1 inhibition by a small-molecule compound chaetocin dampened HSC-myofibroblast transition in cell culture and mitigated liver fibrosis in mice. Mechanistically, Suv39h1 bound to the promoter of heme oxygenase 1 (HMOX1) and repressed HMOX1 transcription. HMOX1 depletion blunted the effects of Suv39h1 inhibition on HSC-myofibroblast transition in vitro and liver fibrosis in vivo. Transcriptomic analysis revealed that HMOX1 might contribute to HSC-myofibroblast transition by modulating retinol homeostasis. Finally, myofibroblast-specific HMOX1 overexpression attenuated liver fibrosis in both a preventive scheme and a therapeutic scheme. Conclusions Our data demonstrate a previously unrecognised role for Suv39h1 in liver fibrosis and offer proof-of-concept of its targetability in the intervention of cirrhosis.
Multistep tumor genetic evolution and changes in immunogenicity trigger immune-mediated disease eradication in stage IV melanoma: lessons from a single case
Authors: Viviana Vallacchi, Elisabetta Vergani, Mara Cossa, Chiara Gargiuli, Adele Busico, Andrea Devecchi, Matteo Dugo, Laura Bergamaschi, Loris De Cecco, Stefano Cavalieri, Barbara Valeri, Elena Tamborini, Gianfrancesco Gallino, Michele Del Vecchio, Mario Santinami, Marialuisa Sensi, Licia Rivoltini, Lorenza Di Guardo, Monica Rodolfo
Journal: Journal for ImmunoTherapy of Cancer (2024)

Durable remissions are observed in 10%–20% of treated patients with advanced metastatic melanoma but the factors associated with long-term complete clinical responses are largely unknown. Here, we report the molecular characteristics of tumor evolution during disease progression along a 9-year clinical course in a patient with advanced disseminated melanoma who received different treatments, including trametinib, ipilimumab, radiation, vemurafenib, surgical tumor debulking and a second ipilimumab course, ultimately achieving complete long-term disease remission. Longitudinal analyses of therapies-resistant metastatic tumors revealed the effects of different treatments on tumor’s microenvironment and immunogenicity, ultimately creating a milieu favorable to immunotherapy response. Monitoring of the temporal dynamics of T cells by analysis of the T cell receptor (TCR) repertoire in the tumor and peripheral blood during disease evolution indicated that T-cell clones with common TCR rearrangements, present at low levels at baseline, were maintained and expanded after immunotherapy, and that TCR diversity increased. Analysis of genetic, molecular, and cellular components of the tumor depicted a multistep process in which treatment with kinase inhibitors strongly conditioned the immune microenvironment creating an inflamed milieu converting cold into hot tumors, while ipilimumab impacted and increased the TCR repertoire, a requirement for tumor rejection. Since the optimal sequencing of treatment with antibodies targeting immune checkpoints and kinase inhibitors for advanced melanoma is still clinically debated, this case indicates that immunotherapy success is possible even after progression on targeted therapy.
CXCL6 in idiopathic pulmonary fibrosis: a novel mediator in the complex epithelial–mesenchymal crosstalk
Authors: Doumet Georges Helou, Bruno Crestani
Journal: European Respiratory Journal (2024)

<h3>Tweetable abstract</h3> <b>In IPF, CXCL6 is involved as a profibrotic mediator in the complex crosstalk between ectopic epithelial cells and fibroblasts. Elevated levels are linked to high mortality rates, suggesting CXCL6 as a potential biomarker and a new therapeutic target.</b> https://bit.ly/3uNkQe1
Contexts, behavioural mechanisms and outcomes to optimise therapeutic exercise prescription for persistent low back pain: a realist review
Authors: Lianne Wood, Nadine E Foster, Sarah Gerard Dean, Vicky Booth, Jill A Hayden, Andrew Booth
Journal: British Journal of Sports Medicine (2024)

Objective Therapeutic exercises are a core treatment for low back pain (LBP), but it is uncertain how rehabilitative exercise facilitates change in outcomes. Realist reviews explore how the context (C) of certain settings or populations and underlying mechanisms (M) create intended or unintended outcomes (O). Our objective was to explore and understand the behavioural mechanisms by which therapeutic exercise creates change in outcomes of adherence, engagement and clinical outcomes for patients with LBP. Methods This was a realist review reported following the Realist and Meta-narrative Evidence Syntheses: Evolving Standards guidance. We developed initial programme theories, modified with input from a steering group (experts, n=5), stakeholder group (patients and clinicians, n=10) and a scoping search of the published literature (n=37). Subsequently, an information specialist designed and undertook an iterative search strategy, and we refined and tested CMO configurations. Results Of 522 initial papers identified, 75 papers were included to modify and test CMO configurations. We found that the patient–clinician therapeutic consultation builds a foundation of trust and was associated with improved adherence, engagement and clinical outcomes, and that individualised exercise prescription increases motivation to adhere to exercise and thus also impacts clinical outcomes. Provision of support such as timely follow-up and supervision can further facilitate motivation and confidence to improve adherence to therapeutic exercises for LBP. Conclusions Engagement in and adherence to therapeutic exercises for LBP, as well as clinical outcomes, may be optimised using mechanisms of trust, motivation and confidence. These CMO configurations provide a deeper understanding of ways to optimise exercise prescription for patients with LBP.
Sox9 Accelerates Vascular Aging by Regulating Extracellular Matrix Composition and Stiffness
Authors: Maria Faleeva, Sadia Ahmad, Konstantinos Theofilatos, Steven Lynham, Gabriel Watson, Meredith Whitehead, Emilie Marhuenda, Thomas Iskratsch, Susan Cox, Catherine M. Shanahan
Journal: Circulation Research (2024)

Vascular calcification and increased extracellular matrix (ECM) stiffness are hallmarks of vascular aging. Sox9 (SRY-box transcription factor 9) has been implicated in vascular smooth muscle cell (VSMC) osteo/chondrogenic conversion; however, its relationship with aging and calcification has not been studied.
Will inhalational GM-CSF replace whole lung lavage as a treatment for autoimmune pulmonary alveolar proteinosis? Many pole positions, not yet the final winner
Authors: Francesco Bonella, Effrosyni D. Manali, Spyros A. Papiris
Journal: European Respiratory Journal (2024)

<h3>Tweetable abstract</h3> <b>Inhalational GM-CSF, alone or in combination with whole lung lavage, is a promising treatment for autoimmune alveolar proteinosis, as confirmed by the latest clinical trials</b>https://bit.ly/3MV2cHe
mRNA vaccines against SARS-CoV-2 induce divergent antigen-specific T-cell responses in patients with lung cancer
Authors: No-Joon Song, Karthik B Chakravarthy, Hyeongseon Jeon, Chelsea Bolyard, Kelsi Reynolds, Kevin P Weller, Sarah Reisinger, Yi Wang, Anqi Li, Sizun Jiang, Qin Ma, Dan H Barouch, Mark P Rubinstein, Peter G Shields, Eugene M Oltz, Dongjun Chung, Zihai Li
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant is highly transmissible and evades pre-established immunity. Messenger RNA (mRNA) vaccination against ancestral strain spike protein can induce intact T-cell immunity against the Omicron variant, but efficacy of booster vaccination in patients with late-stage lung cancer on immune-modulating agents including anti-programmed cell death protein 1(PD-1)/programmed death-ligand 1 (PD-L1) has not yet been elucidated. Methods We assessed T-cell responses using a modified activation-induced marker assay, coupled with high-dimension flow cytometry analyses. Peripheral blood mononuclear cells (PBMCs) were stimulated with various viral peptides and antigen-specific T-cell responses were evaluated using flow cytometry. Results Booster vaccines induced CD8 + T-cell response against the ancestral SARS-CoV-2 strain and Omicron variant in both non-cancer subjects and patients with lung cancer, but only a marginal induction was detected for CD4 + T cells. Importantly, antigen-specific T cells from patients with lung cancer showed distinct subpopulation dynamics with varying degrees of differentiation compared with non-cancer subjects, with evidence of dysfunction. Notably, female-biased T-cell responses were observed. Conclusion We conclude that patients with lung cancer on immunotherapy show a substantial qualitative deviation from non-cancer subjects in their T-cell response to mRNA vaccines, highlighting the need for heightened protective measures for patients with cancer to minimize the risk of breakthrough infection with the Omicron and other future variants.
Cognitive behavioural therapy sessions approach ineffective for anxiety and depression in COPD: is the door closed for good?
Authors: Abebaw Mengistu Yohannes, Anand S. Iyer, Karin Ferneyhough Hoth, Mark T. Dransfield
Journal: European Respiratory Journal (2024)

<h3>Tweetable abstract</h3> <b>Examining CBT sessions approach in a RCT for treatment of depression and anxiety in patients with COPD is a new advancement. However, a more holistic, collaborative care approach using a dose−response CBT intervention is paramount in future trials.</b>https://bit.ly/47pMBax
Gene therapy encoding cell cycle factors to treat chronic ischemic heart failure in rats
Authors: Riham R E Abouleisa, Xian-Liang Tang, Qinghui Ou, Abou-Bakr M Salama, Amie Woolard, Dana Hammouri, Hania Abdelhafez, Sarah Cayton, Sameeha K Abdulwali, Momo Arai, Israel D Sithu, Daniel J Conklin, Roberto Bolli, Tamer M A Mohamed
Journal: Cardiovascular Research (2024)

Abstract Aims Gene therapies to induce cardiomyocyte (CM) cell cycle re-entry have shown a potential to treat subacute ischaemic heart failure (IHF) but have not been tested in the more relevant setting of chronic IHF. Our group recently showed that polycistronic non-integrating lentivirus encoding Cdk1/CyclinB1 and Cdk4/CyclinD1 (TNNT2-4Fpolycistronic-NIL) is effective in inducing CM cell cycle re-entry and ameliorating subacute IHF models and preventing the subsequent IHF-induced congestions in the liver, kidneys, and lungs in rats and pigs. Here, we aim to test the long-term efficacy of TNNT2-4Fpolycistronic-NIL in a rat model of chronic IHF, a setting that differs pathophysiologically from subacute IHF and has greater clinical relevance. Methods and results Rats were subjected to a 2-h coronary occlusion followed by reperfusion; 4 weeks later, rats were injected intramyocardially with either TNNT2-4Fpolycistronic-NIL or LacZ-NIL. Four months post-viral injection, TNNT2-4Fpolycistronic-NIL–treated rats showed a significant reduction in scar size and a significant improvement in left ventricular (LV) systolic cardiac function but not in the LV dilatation associated with chronic IHF. A mitosis reporter system developed in our lab showed significant induction of CM mitotic activity in TNNT2-4Fpolycistronic-NIL–treated rats. Conclusion This study demonstrates, for the first time, that TNNT2-4Fpolycistronic-NIL gene therapy induces CM cell cycle re-entry in chronic IHF and improves LV function, and that this salubrious effect is sustained for at least 4 months. Given the high prevalence of chronic IHF, these results have significant clinical implications for developing a novel treatment for this deadly disease.
<i>ERJ</i>2024: your journal, my journal, our journal
Authors: Don D. Sin, James D. Chalmers
Journal: European Respiratory Journal (2024)

Our 5-year mission at the European Respiratory Journal ( ERJ ) is to be the best journal in respiratory medicine, to publish outstanding science and to be the "go-to" educational source for you, our readers [1]. To achieve these lofty goals, we have carefully listened to your suggestions, and have made some significant changes and implemented new initiatives in 2023 at the journal (with more to come in 2024). How have we done thus far? There are new changes coming to the ERJ in 2024 <https://bit.ly/484WVp6>
Blood-based colorectal cancer screening in an integrated health system: a randomised trial of patient adherence
Authors: Gloria D Coronado, Charisma L Jenkins, Elizabeth Shuster, Cheryl Johnson, David Amy, Jennifer Cook, Samantha Sahnow, Jamilyn M Zepp, Rajasekhara Mummadi
Journal: Gut (2024)

Objective We evaluated whether people who had not completed a faecal immunochemical test (FIT) for colorectal cancer (CRC) screening would complete a blood-based testing option if offered one during health encounters. Blood-based screening tests for CRC could add to the total number of people screened for CRC by providing another testing alternative. Design Study participants were patients aged 45–75 years at a large, integrated health system who were offered but did not complete an FIT in the prior 3–9 months and were scheduled for a clinical encounter. Individuals were randomised (1:1) to be offered a commercially available CRC blood test (Shield, Guardant Health) versus usual care. We compared 3-month CRC screening proportions in the two groups. Results We randomised 2026 patients; 2004 remained eligible following postrandomisation exclusions (1003 to usual care and 1001 to blood draw offer; mean age: 60, 62% female, 80% non-Hispanic white). Of the 1001 allocated to the blood test group, 924 were recruited following chart-review exclusions; 548 (59.3%) were reached via phone, of which 280 (51.1%) scheduled an appointment with the research team. CRC screening proportions were 17.5 percentage points higher in the blood test group versus usual care (30.5% vs 13.0%; OR 2.94, 95% CI 2.34 to 3.70; p&lt;0.001). Conclusion Among adults who had declined prior CRC screening, the offer of a blood-based screening test boosted CRC screening by 17.5 percentage points over usual care. Further research is needed on how to balance the favourable adherence with lower advanced adenoma detection compared with other available tests. Trial registration number NCT05987709 .
ATP citrate lyase (ACLY)-dependent immunometabolism in mucosal T cells drives experimental colitis in vivo
Authors: Anja Schulz-Kuhnt, Katharina Rühle, Asal Javidmehr, Michael Döbrönti, Jana Biwank, Selina Knittel, Peter Neidlinger, Jannik Leupold, Li-Juan Liu, Mark Dedden, Regina Verena Taudte, Arne Gessner, Martin F Fromm, Dirk Mielenz, Lucas Kreiss, Maximilian J Waldner, Sebastian Schürmann, Oliver Friedrich, Barbara Dietel, Rocío López-Posadas, Christina Plattner, Sebastian Zundler, Christoph Becker, Raja Atreya, Markus F Neurath, Imke Atreya
Journal: Gut (2024)

Objective Mucosal T cells play a major role in inflammatory bowel disease (IBD). However, their immunometabolism during intestinal inflammation is poorly understood. Due to its impact on cellular metabolism and proinflammatory immune cell function, we here focus on the enzyme ATP citrate lyase (ACLY) in mucosal T cell immunometabolism and its relevance for IBD. Design ACLY expression and its immunometabolic impact on colitogenic T cell function were analysed in mucosal T cells from patients with IBD and in two experimental colitis models. Results ACLY was markedly expressed in colon tissue under steady-state conditions but was significantly downregulated in lamina propria mononuclear cells in experimental dextran sodium sulfate-induced colitis and in CD4 + and to a lesser extent in CD8 + T cells infiltrating the inflamed gut in patients with IBD. ACLY-deficient CD4 + T cells showed an impaired capacity to induce intestinal inflammation in a transfer colitis model as compared with wild-type T cells. Assessment of T cell immunometabolism revealed that ACLY deficiency dampened the production of IBD-relevant cytokines and impaired glycolytic ATP production but enriched metabolites involved in the biosynthesis of phospholipids and phosphatidylcholine. Interestingly, the short-chain fatty acid butyrate was identified as a potent suppressor of ACLY expression in T cells, while IL-36α and resolvin E1 induced ACLY levels. In a translational approach, in vivo administration of the butyrate prodrug tributyrin downregulated mucosal infiltration of ACLY high CD4 + T cells and ameliorated chronic colitis. Conclusion ACLY controls mucosal T cell immunometabolism and experimental colitis. Therapeutic modulation of ACLY expression in T cells emerges as a novel strategy to promote the resolution of intestinal inflammation.
Ripretinib versus sunitinib in gastrointestinal stromal tumor: ctDNA biomarker analysis of the phase 3 INTRIGUE trial
Authors: Michael C. Heinrich, Robin L. Jones, Suzanne George, Hans Gelderblom, Patrick Schöffski, Margaret von Mehren, John R. Zalcberg, Yoon-Koo Kang, Albiruni Abdul Razak, Jonathan Trent, Steven Attia, Axel Le Cesne, Brittany L. Siontis, David Goldstein, Kjetil Boye, Cesar Sanchez, Neeltje Steeghs, Piotr Rutkowski, Mihaela Druta, César Serrano, Neeta Somaiah, Ping Chi, William Reichmann, Kam Sprott, Haroun Achour, Matthew L. Sherman, Rodrigo Ruiz-Soto, Jean-Yves Blay, Sebastian Bauer
Journal: Nature Medicine (2024)

Abstract INTRIGUE was an open-label, phase 3 study in adult patients with advanced gastrointestinal stromal tumor who had disease progression on or intolerance to imatinib and who were randomized to once-daily ripretinib 150 mg or sunitinib 50 mg. In the primary analysis, progression-free survival (PFS) with ripretinib was not superior to sunitinib. In clinical and nonclinical studies, ripretinib and sunitinib have demonstrated differential activity based on the exon location of KIT mutations. Therefore, we hypothesized that mutational analysis using circulating tumor DNA (ctDNA) might provide further insight. In this exploratory analysis ( N = 362), baseline peripheral whole blood was analyzed by a 74-gene ctDNA next-generation sequencing–based assay. ctDNA was detected in 280/362 (77%) samples with KIT mutations in 213/362 patients (59%). Imatinib-resistant mutations were found in the KIT ATP-binding pocket (exons 13/14) and activation loop (exons 17/18). Mutational subgroup assessment showed 2 mutually exclusive populations with differential treatment effects. Patients with only KIT exon 11 + 13/14 mutations (ripretinib, n = 21; sunitinib, n = 20) had better PFS with sunitinib versus ripretinib (median, 15.0 versus 4.0 months). Patients with only KIT exon 11 + 17/18 mutations (ripretinib, n = 27; sunitinib, n = 25) had better PFS with ripretinib versus sunitinib (median, 14.2 versus 1.5 months). The results of this exploratory analysis suggest ctDNA sequencing may improve the prediction of the efficacy of single-drug therapies and support further evaluation of ripretinib in patients with KIT exon 11 + 17/18 mutations. ClinicalTrials.gov identifier: NCT03673501.