tbuckley/cabot-search huggingface dataset:
MAIT cells are chronically activated in patients with autoimmune liver disease and promote profibrogenic hepatic stellate cell activation
Authors: Katrin Böttcher, Krista Rombouts, Francesca Saffioti, Davide Roccarina, Matteo Rosselli, Andrew Hall, TuVinh Luong, Emmanuel A. Tsochatzis, Douglas Thorburn, Massimo Pinzani
Journal: Hepatology (2018)

Autoimmune liver diseases (AILDs) are chronic liver pathologies characterized by fibrosis and cirrhosis due to immune-mediated liver damage. In this study, we addressed the question whether mucosal-associated invariant T (MAIT) cells, innate-like T cells, are functionally altered in patients with AILD and whether MAIT cells can promote liver fibrosis through activation of hepatic stellate cells (HSCs). We analyzed the phenotype and function of MAIT cells from AILD patients and healthy controls by multicolor flow cytometry and investigated the interaction between human MAIT cells and primary human hepatic stellate cells (hHSCs). We show that MAIT cells are significantly decreased in peripheral blood and liver tissue of patients with AILD. Notably, MAIT cell frequency tended to decrease with increasing fibrosis stage. MAIT cells from AILD patients showed signs of exhaustion, such as impaired interferon-γ (IFN-γ) production and high ex vivo expression of the activation and exhaustion markers CD38, HLA-DR, and CTLA-4. Mechanistically, this exhausted state could be induced by repetitive stimulation of MAIT cells with the cytokines interleukin (IL)-12 and IL-18, leading to decreased IFN-γ and increased exhaustion marker expression. Of note, repetitive stimulation with IL-12 further resulted in expression of the profibrogenic cytokine IL-17A by otherwise exhausted MAIT cells. Accordingly, MAIT cells from both healthy controls and AILD patients were able to induce an activated, proinflammatory and profibrogenic phenotype in hHSCs in vitro that was partly mediated by IL-17.Our data provide evidence that MAIT cells in AILD patients have evolved towards an exhausted, profibrogenic phenotype and can contribute to the development of HSC-mediated liver fibrosis. These findings reveal a cellular and molecular pathway for fibrosis development in AILD that could be exploited for antifibrotic therapy. (Hepatology 2018;68:172-186).
Nearly 15% of US HIV Infections Undiagnosed in 2015
Authors: Rita Rubin
Journal: JAMA (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Role of TNFSF11 and Group 2 Innate Lymphoid Cells in Type 2 Inflammation in Chronic Rhinosinusitis with Nasal Polyps
Authors: Noriko Ogasawara, Julie A. Poposki, Aiko I. Klingler, Bruce K. Tan, Kathryn E. Hulse, Whitney W. Stevens, Anju T. Peters, Leslie C. Grammer, Robert P. Schleimer, Kevin C. Welch, Stephanie S. Smith, David B. Conley, Joseph R. Raviv, Pejman Soroosh, Tetsuo Himi, Robert C. Kern, Atsushi Kato
Journal: Journal of Allergy and Clinical Immunology (2018)
A Practical Guide to Estimating the Heritability of Pathogen Traits
Authors: Venelin Mitov, Tanja Stadler
Journal: Molecular Biology and Evolution (2017)

Pathogen traits, such as the virulence of an infection, can vary significantly between patients. A major challenge is to measure the extent to which genetic differences between infecting strains explain the observed variation of the trait. This is quantified by the trait's broad-sense heritability, H2. A recent discrepancy between estimates of the heritability of HIV-virulence has opened a debate on the estimators' accuracy. Here, we show that the discrepancy originates from model limitations and important lifecycle differences between sexually reproducing organisms and transmittable pathogens. In particular, current quantitative genetics methods, such as donor-recipient regression of surveyed serodiscordant couples and the phylogenetic mixed model (PMM), are prone to underestimate H2, because they neglect or do not fit to the loss of resemblance between transmission partners caused by within-host evolution. In a phylogenetic analysis of 8,483 HIV patients from the United Kingdom, we show that the phenotypic correlation between transmission partners decays with the amount of within-host evolution of the virus. We reproduce this pattern in toy-model simulations and show that a phylogenetic Ornstein-Uhlenbeck model (POUMM) outperforms the PMM in capturing this correlation pattern and in quantifying H2. In particular, we show that POUMM outperforms PMM even in simulations without selection-as it captures the mentioned correlation pattern-which has not been appreciated until now. By cross-validating the POUMM estimates with ANOVA on closest phylogenetic pairs, we obtain H2 ≈ 0.2, meaning ∼20% of the variation in HIV-virulence is explained by the virus genome both for European and African data.
Updated efficacy of avelumab in patients with previously treated metastatic Merkel cell carcinoma after ≥1 year of follow-up: JAVELIN Merkel 200, a phase 2 clinical trial
Authors: Howard L. Kaufman, Jeffery S. Russell, Omid Hamid, Shailender Bhatia, Patrick Terheyden, Sandra P. D’Angelo, Kent C. Shih, Céleste Lebbé, Michele Milella, Isaac Brownell, Karl D. Lewis, Jochen H. Lorch, Anja von Heydebreck, Meliessa Hennessy, Paul Nghiem
Journal: Journal for ImmunoTherapy of Cancer (2018)

Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer associated with poor survival outcomes in patients with distant metastatic disease (mMCC). In an initial analysis from JAVELIN Merkel 200, a phase 2, prospective, open-label, single-arm trial in mMCC, avelumab-a human anti-programmed death-ligand 1 (PD-L1) monoclonal antibody-showed promising efficacy and a safety profile that was generally manageable and tolerable. Here, we report the efficacy of avelumab after ≥1 year of follow-up in patients with distant mMCC that had progressed following prior chemotherapy for metastatic disease. Patients received avelumab 10 mg/kg by 1-h intravenous infusion every 2 weeks until confirmed disease progression, unacceptable toxicity, or withdrawal. The primary endpoint was best overall response. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Patients (N = 88) were followed for a minimum of 12 months. The confirmed objective response rate was 33.0% (95% CI, 23.3%-43.8%; complete response: 11.4%). An estimated 74% of responses lasted ≥1 year, and 72.4% of responses were ongoing at data cutoff. Responses were durable, with the median DOR not yet reached (95% CI, 18.0 months-not estimable), and PFS was prolonged; 1-year PFS and OS rates were 30% (95% CI, 21%-41%) and 52% (95% CI, 41%-62%), respectively. Median OS was 12.9 months (95% CI, 7.5-not estimable). Subgroup analyses suggested a higher probability of response in patients receiving fewer prior lines of systemic therapy, with a lower baseline disease burden, and with PD-L1-positive tumors; however, durable responses occurred irrespective of baseline factors, including tumor Merkel cell polyomavirus status. With longer follow-up, avelumab continues to show durable responses and promising survival outcomes in patients with distant mMCC whose disease had progressed after chemotherapy. Clinicaltrials.gov identifier: NCT02155647.
NKp46 Receptor-Mediated Interferon-γ Production by Natural Killer Cells Increases Fibronectin 1 to Alter Tumor Architecture and Control Metastasis
Authors: Ariella Glasner, Assi Levi, Jonatan Enk, Batya Isaacson, Sergey Viukov, Shari Orlanski, Alon Scope, Tzahi Neuman, Claes D. Enk, Jacob H. Hanna, Veronika Sexl, Stipan Jonjic, Barbara Seliger, Laurence Zitvogel, Ofer Mandelboim
Journal: Immunity (2018)
Dietary flavonoid fisetin induces apoptosis, down regulates COX2 and suppresses Wnt signaling pathway in HT29 colon cancer cells
Authors: Yewseok Suh, Hasan Mukhtar
Journal: Cancer Research (2008)

3047  Colorectal cancer is one of the common malignancy and represents the third leading cause of cancer deaths in both men and women in the U.S. The Wnt pathway has long been suggested to play a crucial role in colorectal cancer. It is well known that the genetic predisposition such as mutations of APC (adenomatous polyposis coli) or beta-catenin results in uncontrolled proliferation of intestinal epithelial cells through the constitutively active Wnt signaling pathway. Overexpression of COX-2 has been frequently observed in colon tumors. Many studies have implicated that PGE2 (prostaglandin E2), the metabolite of COX-2 enzyme, is a potent mitogen and contributes to colon cancer development via stimulating the growth through Wnt pathway. Recent studies show that selective COX-2 inhibitors possess great potential as chemopreventive agents for colon cancer. Fisetin, 3,39,49,7-tetrahydroxyflavone, is a naturally occurring flavonoid commonly found in various vegetables and fruits such as onion, cucumber, apple, persimmon and strawberry. It has been reported that fisetin induces cell cycle arrest via inhibiting cyclin dependent kinases in HT29 human colon cancer cell line. We found that the treatment of HT29 cells with fisetin (0 ~ 120 μM) resulted in induction of apoptosis in a dose-dependent manner as assayed using dUTP-FITC labeled FACS analysis, annexin-V-Fluorescein and propidium iodide immunofluorescent staining, and by assessing the cleavage of PARP (polyADP ribosyl polymerase) and caspase 3 using western blot analysis. Fisetin treatment down regulated the mRNA and protein expression of COX-2 without affecting COX-1. Decreased expression of COX-2 protein following fisetin treatment was also confirmed by immunofluorescent imaging of cells stained with Alexa Fluor-594 conjugated COX-2 antibody and DAPI. Treatment of fisetin also decreased the promoter activity of COX-2 and the transcriptional activity of T cell factor (TCF)/beta-catenin as assessed by luciferase assay using corresponding reporter plasmids. In further experiments, we found that fisetin treatment of cells resulted in an increase in the cytoplasmic level of phospho-beta-catenin with a concomitant decrease in nuclear level of nonphospho-beta-catenin as assessed by western blot analysis. As expected, the expression of cyclin D1, the most well known target of beta-catenin pathway, was down regulated in fisetin treated cells. Fisetin treatment of cells also inhibited the formation of colonies when assessed in the semi solid agar gel. On an average, fisetin (120 μM) treated cells formed only 37 colonies compared to 138 colonies formed by control cells over the 4 weeks of incubation. Taken together, fisetin can induce apoptosis and suppress the growth of colon cancer cells via inhibiting COX-2 and Wnt signaling pathway. Fisetin could be a useful agent for prevention and treatment of colon cancer.
PD2/PAF1 at the Crossroads of the Cancer Network
Authors: Saswati Karmakar, Parama Dey, Arokia P. Vaz, Sukesh R. Bhaumik, Moorthy P. Ponnusamy, Surinder K. Batra
Journal: Cancer Research (2018)

Pancreatic differentiation 2 (PD2)/RNA polymerase II-associated factor 1 (PAF1) is the core subunit of the human PAF1 complex (PAF1C) that regulates the promoter-proximal pausing of RNA polymerase II as well as transcription elongation and mRNA processing and coordinates events in mRNA stability and quality control. As an integral part of its transcription-regulatory function, PD2/PAF1 plays a role in posttranslational histone covalent modifications as well as regulates expression of critical genes of the cell-cycle machinery. PD2/PAF1 alone, and as a part of PAF1C, provides distinct roles in the maintenance of self-renewal of embryonic stem cells and cancer stem cells, and in lineage differentiation. Thus, PD2/PAF1 malfunction or its altered abundance is likely to affect normal cellular functions, leading to disease states. Indeed, PD2/PAF1 is found to be upregulated in poorly differentiated pancreatic cancer cells and has the capacity for neoplastic transformation when ectopically expressed in mouse fibroblast cells. Likewise, PD2/PAF1 is upregulated in pancreatic and ovarian cancer stem cells. Here, we concisely describe multifaceted roles of PD2/PAF1 associated with oncogenic transformation and implicate PD2/PAF1 as an attractive target for therapeutic development to combat malignancy. Cancer Res; 78(2); 313-9. ©2018 AACR.
Many smokers overestimate e-cigarette risks, MPs hear
Authors: Gareth Iacobucci
Journal: BMJ (2018)

Many smokers are overestimating the risks associated with e-cigarettes because of a “misrepresentation” of current evidence, experts have told MPs.

Paul Aveyard, coordinating editor of the Cochrane Tobacco Addiction Group, told the House of Commons science and technology committee that he was concerned because half of smokers believed e-cigarettes to be as harmful as conventional cigarettes.

“That’s really a terrible misrepresentation of what we know already,” said Aveyard, giving evidence to the committee’s inquiry into e-cigarettes on 9 January.

Jamie Brown, deputy director of University College London’s tobacco and alcohol research group, told the committee …
RARE-35. DABRAFENIB IN PATIENTS WITH RECURRENT, BRAF V600E MUTATED MALIGNANT GLIOMA AND LEPTOMENINGEAL DISEASE
Authors: Michael Burger, Michael Ronellenfitsch, Nadja Lorenz, Marlies Wagner, Martin Voss, David Capper, Theophilos Tzaridis, Ulrich Herrlinger, Joachim Steinbach, Gabriele Stoffels, Karl-Josef Langen, Christian Brandts, Christian Senft, Patrick Harter, Oliver Baehr
Journal: Neuro-Oncology (2017)

BRAF V600E mutations occur frequently in malignant melanoma but are rare in most glioma subtypes. Besides more benign brain tumors, like ganglioglioma, dysembryoblastic neuroepithelial tumours and supratentorial pilocytic astrocytomas, only pleomorphic xanthoastrocytomas (50-78%) and epitheloid glioblastoma (50%) regularly exhibit BRAF mutations. Here we report on three patients with recurrent malignant gliomas harbouring a BRAF V600E mutation. All patients presented with markedly disseminated leptomeningeal disease at recurrence and had progressed after radiotherapy and chemotherapy. Therefore, estimated life expectancy at recurrence was a few weeks. All three patients received dabrafenib as a single agent and all showed a complete or nearly complete response. Treatment is ongoing and patients are stable since 27 months, 7 months and 3 months. One patient showed a dramatic radiologic and clinical response no more than one week after start of treatment. We were able to generate an ex vivo tumor cell culture from CSF in one patient. Treatment of this cell culture with dabrafenib results in reduced cell densitiy and inhibition of ERK phosphorylation in vitro. To date, this is the first series on adult patients with BRAF-mutated malignant glioma and leptomeningeal dissemination treated with dabrafenib monotherapy. All patients showed a dramatic response with one patient showing an ongoing response for more than two years.
Global Overview of the Transnational Alliance for Regenerative Therapies in Cardiovascular Syndromes (TACTICS) Recommendations
Authors: Francisco Fernández-Avilés, Ricardo Sanz-Ruiz, Andreu M. Climent, Lina Badimon, Roberto Bolli, Dominique Charron, Valentin Fuster, Stefan Janssens, Jens Kastrup, Hyo-Soo Kim, Thomas F. Lüscher, John F. Martin, Philippe Menasché, Fausto J. Pinto, Robert D. Simari, Gregg W. Stone, Andre Terzic, James T. Willerson, Joseph C. Wu
Journal: Circulation Research (2018)
PTU-024 Utilisation of classifications for colonic polyps in four districts of united kingdom
Authors: T Mahmood, SA Ahmad, Y Jamali, Z zulfukar
Journal: Gut (2017)

Introduction  The four recommended classifications of polyps are Paris, Kudo, Showa and Histological. Based on these the endoscopist can risk stratify polyps for dysplasia and neoplasia. This study evaluates the utilisation of these classifications by trained endoscopists upon detecting colonic polyps at four district hospitals in the United Kingdom.  Method  All patients who had a polyp detected at flexible sigmoidoscopy or colonoscopy over six months in four sample district hospitals of United Kingdom were retrospectively identified. Total of 979 cases were recruited. Endoscopists of all seniority level were included in the study The reports were reviewed either electronically or manually. Data was tabulated for seniority of the endoscopist, polyp description, polyp characterisation, and utilisation of the four classifications. As the four district hospitals participating in the study are managed by the same NHS Trust, ethics approval was granted through clinical governance and audit department.  Results  Our study showed that at least 20% reports did not have adequate polyp description and did not use Paris classification. It was worst for Kudo classification which was not used in 95.3% reports. Showa classification was not used at all. More than half of the recruited procedures were reported by Consultants (665). Others were reported by Associate Specialists or Registrars (248) or Nurse Endoscopists (66). There was no variation in utilisation of polyp classifications based on level of seniority of the endoscopist. The study did not analyse whether the endoscopist was aware of the polyp classifications.  Conclusion  This study has shown lack of adequate utilisation of the four recommended classifications of colonoc polyps in four district hospitals of United Kingdom regardless of the seniority of the endoscopist. These classifications help in risk stratifying for dysplasia and cancer. It is therefore important to recognise this aspect for quality in colonoscopy and flexible sigmoidoscopy. There can be many reasons for not using the classifications including; lack of awareness, disagreement with validation of the classifications, time constraints etc. Further studies are warranted to look at the causes for lack of compliance and impact on risk stratification for dysplasia or cancer.  References  Kuipers EJ, Rosch T, Bretthauer M: Colorectal cancer screening-optimising current strategies and new directions. Nat Rev Clin Oncol. 2013, 10 (3): 130–142. 10.1038/nrclinonc.2013.12.  Editorial: Trouble in Paris (Classification): Polyp Morphology Is in The Eye of The Beholder. The American Journal of Gastroenterology 110, 188–191 (January 2015) | doi:10.1038/ajg.2014.411  Kudo S, Tamura S, Nakajima T, Yamano H, Kusaka H, Watanabe H. Diagnosis of colorectal tumorous lesions by magnifying endoscopy. Gastrointest Endosc. 1996;44:8–14  Disclosure of Interest  None Declared
Changes in Hospital–Physician Affiliations in U.S. Hospitals
Authors: Russell L. Bedsole
Journal: Annals of Internal Medicine (2018)

Letters16 January 2018Changes in Hospital–Physician Affiliations in U.S. HospitalsRussell L. Bedsole, MDRussell L. Bedsole, MDWiregrass Clinics Internal Medicine Associates, Dothan, Alabama (R.L.B.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L17-0685 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:I read Scott and colleagues' (1) article with interest. I am an internist in a small private group founded in our community more than 30 years ago. Our practice will soon become employed by the local hospital. Such a paradigm shift is due largely to financial concerns, including rising overhead, diminishing insurance payments, and radically expanding documentation requirements and the associated costs of electronic health records (EHRs). I firmly believe that private practices are a dying breed unless a complete overhaul of physician compensation is undertaken on a national level. Whether a change is possible or even ...Reference1. Scott KW, Orav EJ, Cutler DM, Jha AK. Changes in hospital–physician affiliations in U.S. hospitals and their effect on quality of care. Ann Intern Med. 2017;166:1-8. [PMID: 27654704]. doi:10.7326/M16-0125 LinkGoogle Scholar Author, Article, and Disclosure InformationAffiliations: Wiregrass Clinics Internal Medicine Associates, Dothan, Alabama (R.L.B.)Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L17-0685. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoChanges in Hospital–Physician Affiliations in U.S. Hospitals and Their Effect on Quality of Care Kirstin W. Scott , E. John Orav , David M. Cutler , and Ashish K. Jha Changes in Hospital–Physician Affiliations in U.S. Hospitals Kirstin W. Scott , E. John Orav , David M. Cutler , and Ashish K. Jha Changes in Hospital–Physician Affiliations in U.S. Hospitals Alan R. Ertle Changes in Hospital–Physician Affiliations in U.S. Hospitals Edward Ringel Metrics 16 January 2018Volume 168, Issue 2Page: 155KeywordsDisclosureElectronic medical recordsHealth careHealth care policy ePublished: 16 January 2018 Issue Published: 16 January 2018 Copyright & PermissionsCopyright © 2018 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Balloon pulmonary angioplasty in sarcoid-related pulmonary hypertension
Authors: Jelco Tramper, Esther J. Nossent, Rutger J. Lely, Frans H. Krouwels, Lilian J. Meijboom, Anton Vonk Noordegraaf
Journal: European Respiratory Journal (2018)

A 43-year-old, never-smoking, African-American female was referred to our outpatient clinic for progressive dyspnoea. She had a medical history of sarcoidosis with lymph-node, pulmonary, skin and ocular involvement. Diagnosis was based on a previously conducted chest high-resolution computed tomography (CT) that showed bilateral hilar and mediastinal lymphadenopathy containing calcifications and multiple small lung nodules with peri-lymphatic distribution along the pleura and fissures A histological analysis of biopsy specimens from a lymph node located in the left side of the neck revealed large granulomas with multinucleated foreign body giant cells without necrosis. Microbiological cultures were negative. Extrapulmonary manifestations consisted of anterior uveitis and several cutaneous lesions and the reason for initiating corticosteroid therapy, which ameliorated the sarcoidosis . After discontinuation of corticosteroid therapy, the patient's condition deteriorated and she developed progressive dyspnoea (New York Heart Association (NYHA) functional class 3). Thoracic CT showed bilateral pleural and pericardial effusion. There were no signs of pulmonary fibrosis or cardial signs of pulmonary hypertension (PH). Analysis of the pleural fluid showed exudation with lymphocytosis. An infectious cause was excluded. Balloon pulmonary angioplasty can be a successful treatment option in pulmonary hypertension due to sarcoidosis <http://ow.ly/ul4w30h4GVW>