tbuckley/cabot-search huggingface dataset:
Elafibranor improves diet-induced nonalcoholic steatohepatitis associated with heart failure with preserved ejection fraction in Golden Syrian hamsters
Authors: François Briand, Julie Maupoint, Emmanuel Brousseau, Natalia Breyner, Mélanie Bouchet, Clément Costard, Thierry Leste-Lasserre, Mathieu Petitjean, Li Chen, Audrey Chabrat, Virgile Richard, Rémy Burcelin, Caroline Dubroca, Thierry Sulpice
Journal: Metabolism (2021)

Cardiovascular disease is the leading cause of deaths in nonalcoholic steatohepatitis (NASH) patients. Mouse models, while widely used for drug development, do not fully replicate human NASH nor integrate the associated cardiac dysfunction, i.e. heart failure with preserved ejection fraction (HFpEF). To overcome these limitations, we established a nutritional hamster model developing both NASH and HFpEF. We then evaluated the effects of the dual peroxisome proliferator activated receptor alpha/delta agonist elafibranor developed for the treatment of NASH patients.Male Golden Syrian hamsters were fed for 10 to 20 weeks with a free choice diet, which presents hamsters with a choice between control chow diet with normal drinking water or a high fat/high cholesterol diet with 10% fructose enriched drinking water. Biochemistry, histology and echocardiography analysis were performed to characterize NASH and HFpEF. Once the model was validated, elafibranor was evaluated at 15 mg/kg/day orally QD for 5 weeks.Hamsters fed a free choice diet for up to 20 weeks developed NASH, including hepatocyte ballooning (as confirmed with cytokeratin-18 immunostaining), bridging fibrosis, and a severe diastolic dysfunction with restrictive profile, but preserved ejection fraction. Elafibranor resolved NASH, with significant reduction in ballooning and fibrosis scores, and improved diastolic dysfunction with significant reduction in E/A and E/E' ratios.Our data demonstrate that the free choice diet induced NASH hamster model replicates the human phenotype and will be useful for validating novel drug candidates for the treatment of NASH and associated HFpEF.
A robust platform for expansion and genome editing of primary human natural killer cells
Authors: Rih-Sheng Huang, Min-Chi Lai, Hsin-An Shih, Steven Lin
Journal: The Journal of Experimental Medicine (2021)

Genome editing is a powerful technique for delineating complex signaling circuitry and enhancing the functionality of immune cells for immunotherapy. Natural killer (NK) cells are potent immune effectors against cell malignancy, but they are challenging to modify genetically by conventional methods due to the toxicity of DNA when introduced into cells coupled with limited transfection and transduction efficiency. Here, we describe an integrated platform that streamlines feeder-free ex vivo expansion of cryopreserved primary human NK cells and nonviral genome editing by the nucleofection of CRISPR-Cas9 ribonucleoproteins (Cas9 RNPs). The optimized Cas9 nucleofection protocol allows efficient and multiplex gene knockout in NK cells while preserving high cell viability and negligible off-target effects. Cointroduction of a DNA template also enables in-frame gene knock-in of an HA affinity tag and a gfp reporter across multiple loci. This work demonstrates the advantages and flexibility of working with cryopreserved NK cells as potential off-the-shelf engineered therapeutic agents.
Cytomegalovirus kinetics after hematopoietic cell transplantation reveal peak titers with differential impact on mortality, relapse and immune reconstitution
Authors: Saskia Leserer, Evren Bayraktar, Mirko Trilling, Rashit Bogdanov, Esteban Arrieta‐Bolaños, Nikolaos Tsachakis‐Mück, Pietro Crivello, Michael Koldehoff, Fabienne Maaßen, Rudolf Stefan Ross, Katharina Fleischhauer, Dietrich W. Beelen, Amin T. Turki
Journal: American Journal of Hematology (2021)

Abstract Even in the era of PCR‐based monitoring, prophylaxis, and preemptive therapy, Cytomegalovirus (CMV) viremia remains a relevant cause of non‐relapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT). However, studies using binary analysis (presence/absence of CMV) reported contradicting data for NRM, overall survival and leukemia relapse. Here, we analyzed CMV replication kinetics in 11 508 whole blood PCR samples of 705 patients with HCT between 2012 and 2017. Using two independent models based on CMV peak titers and on the time point of first CMV reactivation, we stratified patients into risk cohorts. Each cohort had distinct cellular immune reconstitution profiles and differentiated for relevant clinical outcomes. Patients with high CMV peak titers had significantly reduced overall survival (HR 2.13, 95% CI 1.53–2.96; p &lt; .0001), due to high NRM. Early impaired T cell reconstitution was a risk factor for high CMV peak titers, however relevant CMV viremia also related to boosted T cell reconstitution. Importantly, intermediate CMV peak titers associated with a significantly reduced relapse probability (HR 0.53, 95% CI 0.31–0.91; p = .022). In short, CMV kinetics models distinguished relevant clinical outcome cohorts beyond the R+ serostatus with distinct immune reconstitution patterns and resolve in part contradicting results of previous studies exclusively focused on the presence or absence of CMV.
Reduction in dipyridamole-induced single-photon emission computed tomography myocardial defect size by beta-blockers: Time to re-examine the patient preparation protocol for pharmacologic stress testing**Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Myron C Gerson
Journal: Journal of the American College of Cardiology (2003)
Synbindin restrains proinflammatory macrophage activation against microbiota and mucosal inflammation during colitis
Authors: Luoyan Ai, Yimeng Ren, Mingming Zhu, Shiyuan Lu, Yun Qian, Zhaofei Chen, Antao Xu
Journal: Gut (2021)

As a canonical membrane tethering factor, the function of synbindin has been expanding and indicated in immune response. Here, we investigated the role of synbindin in the regulation of toll-like receptor 4 (TLR4) signalling and macrophage response to microbiota during colitis.Three distinct mouse models allowing global, myeloid-specific or intestinal epithelial cell-specific synbindin heterozygous deletion were constructed and applied to reveal the function of synbindin during dextran sodium sulfate (DSS) colitis. Effects of synbindin on TLR4 signalling and macrophage activation in response to bacterial lipopolysaccharide (LPS) or Fusobacterium nucleatum were evaluated. The colocalisation and interaction between synbindin and Rab7b were determined by immunofluorescence and coimmunoprecipitation. Synbindin expression in circulating monocytes and intestinal mucosal macrophages of patients with active IBD was detected.Global synbindin haploinsufficiency greatly exacerbated DSS-induced intestinal inflammation. The increased susceptibility to DSS was abolished by gut microbiota depletion, while phenocopied by specific synbindin heterozygous deletion in myeloid cells rather than intestinal epithelial cells. Profoundly aberrant proinflammatory gene signatures and excessive TLR4 signalling were observed in macrophages with synbindin interference in response to bacterial LPS or Fusobacterium nucleatum. Synbindin was significantly increased in intestinal mucosal macrophages and circulating monocytes from both mice with DSS colitis and patients with active IBD. Interleukin 23 and granulocyte-macrophage colony-stimulating factor were identified to induce synbindin expression. Mechanistic characterisation indicated that synbindin colocalised and directly interacted with Rab7b, which coordinated the endosomal degradation pathway of TLR4 for signalling termination.Synbindin was a key regulator of TLR4 signalling and restrained the proinflammatory macrophage activation against microbiota during colitis.
Targeting the NTRK Fusion Gene in Pancreatic Acinar Cell Carcinoma: A Case Report and Review of the Literature
Authors: Medhavi Gupta, Christopher Sherrow, Maghan E. Krone, Edik M. Blais, Michael J. Pishvaian, Emanuel F. Petricoin, Lynn M. Matrisian, Patricia DeArbeloa, Gary Gregory, Alyson Brown, Olivia Zalewski, Gillian Prinzing, Charles Roche, Kazunori Kanehira, Sarbajit Mukherjee, Renuka Iyer, Christos Fountzilas
Journal: Journal of the National Comprehensive Cancer Network (2021)

Pancreatic acinar cell carcinoma (PACC) is a rare pancreatic exocrine malignancy. Compared with the more common pancreatic ductal adenocarcinoma (PDAC), PACC is more common in younger White men, has earlier stages and a lower mean age (56 vs 70 years) at the time of presentation, and has a better prognosis. In addition to differences in demographic, histologic, and clinical characteristics, PACC has a genomic profile distinct from PDAC, with only rare mutations in TP53, KRAS, and p16 that are commonly found in PDAC. This case report presents a man aged 81 years who presented with a pancreatic body mass with peripancreatic lymph node enlargement. Biopsy of the mass showed acinar cell carcinoma. The patient underwent upfront surgical resection, followed by one cycle of adjuvant gemcitabine, with stoppage of therapy due to poor tolerance. Lower-dose gemcitabine was reintroduced after disease progression 6 months later. Nab-paclitaxel was added to gemcitabine after 6 cycles because of a continued increase in the size of peripancreatic lymph nodes. Combination chemotherapy was stopped after 4 cycles because of further disease progression with new liver metastasis. Molecular testing showed the presence of an SEL1L-NTRK1 fusion. Targeted therapy was started with the oral neurotrophic tropomyosin receptor kinase (NTRK) inhibitor larotrectinib at a dosage of 100 mg twice daily. At the time of writing, the patient has been on therapy for 13 months with an exceptional radiographic response and has not experienced any grade 3 adverse effects. To our knowledge, this is the first clinical report of an NTRK gene fusion in a patient with PACC. This case study highlights the significance of tumor molecular profiling in patients with pancreatic tumors, especially rare histologies.
OA05.03 Tepotinib in Patients with Advanced NSCLC with MET Exon 14 (METex14) Skipping: Overall Efficacy Results from VISION Cohort A
Authors: J. Mazieres, P. Paik, E. Felip, R. Veillon, H. Sakai, A. Cortot, S. Viteri, M. Garassino, J. Van Meerbeeck, J. Raskin, M. Thomas, M. Morise, B.C. Cho, P. Conte, R. Bruns, T. Demuth, K.M. Schumacher, X. Le
Journal: Journal of Thoracic Oncology (2021)
Public Concern About Violence, Firearms, and the COVID-19 Pandemic in California
Authors: Nicole Kravitz-Wirtz, Amanda Aubel, Julia Schleimer, Rocco Pallin, Garen Wintemute
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Violence is a significant public health problem that has become entwined with the coronavirus disease 2019 (COVID-19) pandemic. <h3>Objective</h3> To describe individuals' concerns regarding violence in the context of the pandemic, experiences of pandemic-related unfair treatment, prevalence of and reasons for firearm acquisition, and changes in firearm storage practices due to the pandemic. <h3>Design, Setting, and Participants</h3> This survey study used data from the 2020 California Safety and Well-being Survey, a probability-based internet survey of California adults conducted from July 14 to 27, 2020. Respondents came from the Ipsos KnowledgePanel, an online research panel with members selected using address-based sampling methods. Responses were weighted to be representative of the adult population of California. <h3>Main Outcomes and Measures</h3> Topics included worry about violence for oneself before and during the pandemic; concern about violence for someone else due to a pandemic-related loss; experiences of unfair treatment attributed to the pandemic; firearm and ammunition acquisition due to the pandemic; and changes in firearm storage practices due to the pandemic. <h3>Results</h3> Of 5018 invited panel members, 2870 completed the survey (completion rate, 57%). Among respondents (52.3% [95% CI, 49.5%-55.0%] women; mean [SD] age, 47.9 [16.9] years; 41.9% [95% CI, 39.3%-44.6%] White individuals), self-reported worry about violence for oneself was significantly higher during the pandemic for all violence types except mass shootings, ranging from a 2.8 percentage point increase for robbery (from 65.5% [95% CI, 62.8%-68.0%] to 68.2% [95% CI, 65.6%-70.7%];<i>P</i> = .008) to a 5.6 percentage point increase for stray bullet shootings (from 44.5% [95% CI, 41.7%-47.3%] to 50.0% [47.3%-52.8%];<i>P</i> &lt; .001). The percentage of respondents concerned that someone they know might intentionally harm themselves was 13.1% (95% CI, 11.5%-15.3%). Of those, 7.5% (95% CI, 4.5%-12.2%) said it was because the other person had experienced a pandemic-related loss. An estimated 110 000 individuals (2.4% [95% CI, 1.1%-5.0%] of firearm owners in the state) acquired a firearm due to the pandemic, including 47 000 new owners (43.0% [95% CI, 14.8%-76.6%] of those who had acquired a firearm). Of owners who stored at least 1 firearm in the least secure way, 6.7% (95% CI, 2.7%-15.6%) said they had adopted this unsecure storage practice in response to the pandemic. <h3>Conclusions and Relevance</h3> In this analysis of findings from the 2020 California Safety and Well-being Survey, the COVID-19 pandemic was associated with increases in self-reported worry about violence for oneself and others, increased firearm acquisition, and changes in firearm storage practices. Given the impulsive nature of many types of violence, short-term crisis interventions may be critical for reducing violence-related harm.
Circular RNAs in body fluids as cancer biomarkers: the new frontier of liquid biopsies
Authors: Sumeng Wang, Ke Zhang, Shanyue Tan, Junyi Xin, Qianyu Yuan, Huanhuan Xu, Xian Xu, Qi Liang, David C. Christiani, Meilin Wang, Lingxiang Liu, Mulong Du
Journal: Molecular Cancer (2021)

Abstract Cancer is a leading cause of death worldwide, particularly because of its high mortality rate in patients who are diagnosed at late stages. Conventional biomarkers originating from blood are widely used for cancer diagnosis, but their low sensitivity and specificity limit their widespread application in cancer screening among the general population. Currently, emerging studies are exploiting novel, highly-accurate biomarkers in human body fluids that are obtainable through minimally invasive techniques, which is defined as liquid biopsy. Circular RNAs (circRNAs) are a newly discovered class of noncoding RNAs generated mainly by pre-mRNA splicing. Following the rapid development of high-throughput transcriptome analysis techniques, numerous circRNAs have been recognized to exist stably and at high levels in body fluids, including plasma, serum, exosomes, and urine. CircRNA expression patterns exhibit distinctly differences between patients with cancer and healthy controls, suggesting that circRNAs in body fluids potentially represent novel biomarkers for monitoring cancer development and progression. In this study, we summarized the expression of circRNAs in body fluids in a pan-cancer dataset and characterized their clinical applications in liquid biopsy for cancer diagnosis and prognosis. In addition, a user-friendly web interface was developed to visualize each circRNA in fluids ( https://mulongdu.shinyapps.io/circrnas_in_fluids/ ).
Inhibition of CD24 by siRNA or monoclonal antibodies is a novel therapeutic modality for suppressing cancer cell growth in vitro and in vivo
Authors: Eyal Sagiv, Diana Kazanov, Nadir Arber
Journal: Cancer Research (2007)

5264  Aim: To identify novel oncogenes in colorectal cancer (CRC) carcinogenesis and set them as a target for cancer treatment using MAB and siRNA.   Background: We had found, through gene expression arrays that CD24 is an important oncogene in the gut, expressed in rat enterocytes following Ras transformation and reverted to normal expression following short and long exposures to Cox-2 inhibitors. As a novel oncogene encoding for a membrane receptor we targeted it for treatment.  Methods: 1. As a validation of the results and for human patients, immunohistochemistry was performed on 398 biological samples from the GI tract (normal, polyps and adenocarcinomas). 2. The response of six cancer cell lines to three anti-CD24 monoclonal antibodies (MAB) ± combination with standard chemotherapeutic agents (doxorubicin, paclitaxel and 5-fluorouracil) was tested using methylene-blue assay. HT29 (107 cells), which express high level of CD24, were injected subcutaneously into nude mice (n=20); anti-CD24 MAB were injected to the tail-vein twice weekly when tumor volume was 0.1 ml. 3. HT29 cells were stably transfected with two siRNA expression vectors, pSUPER, encoding for molecules align to two regions of the CD24 mRNA or to non-coding RNA (vector control). Cell growth was examined by in-vitro growth curves and in-vivo by subcutaneous injection to nude mice. Results: CD24 was expressed in 90.7% of adenomas and 86.3% of CRC. Very low expression was seen in normal epithelium (16.6%). All cancer cells demonstrated significant growth inhibition (up to 90%) in response to MAB therapy, according to their CD24 expression levels, in a dose and time dependent manners. These results were repetitive for three different antibodies. Cancer cells not bearing CD24 were not inhibited, nor did the control antibody induce growth inhibition. Growth inhibition was augmented by the addition of the 3 classic chemotherapies. In vivo, tumor burden was significantly smaller in MAB treated mice (figure is very impressive). CD24 was markedly down regulated in the siRNA-expressing HT29 derivatives. The growth of the siRNA clones was slower. Conclusions: CD24 is a putative new oncogene that is overexpressed in GI malignancies, already at an early stage of carcinogenesis. It is a potential useful target for early intervention in the prevention and treatment of cancer.
Multicentre, prospective, randomised study comparing the diagnostic yield of colon capsule endoscopy versus CT colonography in a screening population (the TOPAZ study)
Authors: Brooks D Cash, Mark R Fleisher, Steven Fern, Elizabeth Rajan, Robyn Haithcock, David M Kastenberg, David Pound, Neofytos P Papageorgiou, Ignacio Fernández-Urién, Ira J Schmelkin, Douglas K Rex
Journal: Gut (2020)

Objective Colon capsule endoscopy (CCE) has shown promise for colorectal neoplasia detection compared with optical colonoscopy (OC), but has not been compared with other screening tests in average risk screening patients. Design Patients 50 to 75 years of age (African Americans, 45–75 years) were randomised to CCE or CT colonography (CTC) and subsequent blinded OC. The primary endpoint was diagnostic yield of polyps ≥6 mm with CCE or CTC. Secondary endpoints included accuracy for size and histology, examination completeness, number/proportion of subjects with polyps and adenomas ≥6 mm and ≥10 mm, subject satisfaction and safety. Results From 320 enrolled subjects, data from 286 (89.4%) were evaluable. The proportion of subjects with any polyp ≥6 mm confirmed by OC was 31.6% for CCE versus 8.6% for CTC (pPr non-inferiority and superiority=0.999). The diagnostic yield of polyps ≥10 mm was 13.5% with CCE versus 6.3% with CTC (pPr non-inferiority=0.9954). The sensitivity and specificity of CCE for polyps ≥6 mm was 79.2% and 96.3% while that of CTC was 26.8% and 98.9%. The sensitivity and specificity of CCE for polyps ≥10 mm was 85.7% and 98.2% compared with 50% and 99.1% for CTC. Both tests were well tolerated/safe. Conclusion CCE was superior to CTC for detection of polyps ≥6 mm and non-inferior for identification of polyps ≥10 mm. CCE should be considered comparable or superior to CTC as a colorectal neoplasia screening test, although neither test is as effective as OC. Trial registration number ClinicalTrials.gov no: NCT02754661 .
ACC/AHA 2002 guideline update for exercise testing: summary article
Authors: Raymond J Gibbons, Gary J Balady, J Timothy Bricker, Bernard R Chaitman, Gerald F Fletcher, Victor F Froelicher, Daniel B Mark, Ben D McCallister, Aryan N Mooss, Michael G O’Reilly, William L Winters, Raymond J Gibbons, Elliott M Antman, Joseph S Alpert, David P Faxon, Valentin Fuster, Gabriel Gregoratos, Loren F Hiratzka, Alice K Jacobs, Richard O Russell, Sidney C Smith
Journal: Journal of the American College of Cardiology (2002)
Longitudinal Analysis of Mental Disorder Burden Among Elderly Patients With Gastrointestinal Malignancies
Authors: Jeremy P. Harris, Mehr Kashyap, Jessi N. Humphreys, Daniel T. Chang, Erqi L. Pollom
Journal: Journal of the National Comprehensive Cancer Network (2021)

Patients with cancer are at high risk for having mental disorders, resulting in widespread psychosocial screening efforts. However, there is a need for population-based and longitudinal studies of mental disorders among patients who have gastrointestinal cancer and particular among elderly patients.We used the SEER-Medicare database to identify patients aged ≥65 years with colorectal, pancreatic, gastric, hepatic/biliary, esophageal, or anal cancer. Earlier (12 months before or up to 6 months after cancer diagnosis) and subsequent mental disorder diagnoses were identified.Of 112,283 patients, prevalence of an earlier mental disorder was 21%, 23%, 20%, 20%, 19%, and 26% for colorectal, pancreatic, gastric, hepatic/biliary, esophageal, and anal cancer, respectively. An increased odds of an earlier mental disorder was associated with pancreatic cancer (odds ratio [OR], 1.17; 95% CI, 1.11-1.23), esophageal cancer (OR, 1.10; 95% CI, 1.02-1.18), and anal cancer (OR, 1.17; 95% CI, 1.05-1.30) compared with colorectal cancer and with having regional versus local disease (OR, 1.09; 95% CI, 1.06-1.13). The cumulative incidence of a subsequent mental disorder at 5 years was 19%, 16%, 14%, 13%, 12%, and 10% for patients with anal, colorectal, esophageal, gastric, hepatic/biliary, and pancreatic cancer, respectively. There was an association with having regional disease (hazard ratio [HR], 1.08; 95% CI, 1.04-1.12) or distant disease (HR, 1.36; 95% CI, 1.28-1.45) compared with local disease and the development of a mental disorder. Although the development of a subsequent mental disorder was more common among patients with advanced cancers, there continued to be a significant number of patients with earlier-stage disease at risk.This study suggests a larger role for incorporating psychiatric symptom screening and management throughout oncologic care.
Efficacy and safety of nintedanib in patients with systemic sclerosis-associated interstitial lung disease treated with mycophenolate: a subgroup analysis of the SENSCIS trial
Authors: Kristin B Highland, Oliver Distler, Masataka Kuwana, Yannick Allanore, Shervin Assassi, Arata Azuma, Arnaud Bourdin, Christopher P Denton, Jörg H W Distler, Anna Maria Hoffmann-Vold, Dinesh Khanna, Maureen D Mayes, Ganesh Raghu, Madelon C Vonk, Martina Gahlemann, Emmanuelle Clerisme-Beaty, Mannaig Girard, Susanne Stowasser, Donald Zoz, Toby M Maher
Journal: The Lancet Respiratory Medicine (2021)
Matt Morgan: The hospital bed is broken
Authors: Matt Morgan
Journal: BMJ (2021)

As I am driving to work, the local radio headlines tell me that our hospital has over 30 empty beds in the intensive care unit. Strange, that—as it was a struggle for us to care for any new critically ill patients yesterday. Staff sickness, combined with covid-19, and on top of the usual demands of day-to-day life, meant that it was a tough shift. Still, something major must have happened in the 12 hours since I left, as we now apparently have more empty beds than funded beds. Soon, however, the illusion is shattered. In fact, that illusion …