tbuckley/cabot-search huggingface dataset:
Glomerular Function and Structural Integrity Depend on Hyaluronan Synthesis by Glomerular Endothelium
Authors: Bernard M. van den Berg, Gangqi Wang, Margien G. S. Boels, M. Cristina Avramut, Erik Jansen, Wendy M. P. J. Sol, Franck Lebrin, Anton Jan van Zonneveld, Eelco J. P. de Koning, Hans Vink, Hermann-Josef Gröne, Peter Carmeliet, Johan van der Vlag, Ton J. Rabelink
Journal: Journal of the American Society of Nephrology (2019)

A glycocalyx envelope consisting of proteoglycans and adhering proteins covers endothelial cells, both the luminal and abluminal surface. We previously demonstrated that short-term loss of integrity of the luminal glycocalyx layer resulted in perturbed glomerular filtration barrier function.To explore the role of the glycocalyx layer of the endothelial extracellular matrix in renal function, we generated mice with an endothelium-specific and inducible deletion of hyaluronan synthase 2 (Has2), the enzyme that produces hyaluronan, the main structural component of the endothelial glycocalyx layer. We also investigated the presence of endothelial hyaluronan in human kidney tissue from patients with varying degrees of diabetic nephropathy.Endothelial deletion of Has2 in adult mice led to substantial loss of the glycocalyx structure, and analysis of their kidneys and kidney function showed vascular destabilization, characterized by mesangiolysis, capillary ballooning, and albuminuria. This process develops over time into glomerular capillary rarefaction and glomerulosclerosis, recapitulating the phenotype of progressive human diabetic nephropathy. Using a hyaluronan-specific probe, we found loss of glomerular endothelial hyaluronan in association with lesion formation in tissue from patients with diabetic nephropathy. We also demonstrated that loss of hyaluronan, which harbors a specific binding site for angiopoietin and a key regulator of endothelial quiescence and maintenance of EC barrier function results in disturbed angiopoietin 1 Tie2.Endothelial loss of hyaluronan results in disturbed glomerular endothelial stabilization. Glomerular endothelial hyaluronan is a previously unrecognized key component of the extracelluar matrix that is required for glomerular structure and function and lost in diabetic nephropathy.
Kaposi sarcoma–associated herpesvirus miRNAs suppress CASTOR1-mediated mTORC1 inhibition to promote tumorigenesis
Authors: Tingting Li, Enguo Ju, Shou-Jiang Gao
Journal: Journal of Clinical Investigation (2019)

Cytosolic arginine sensor for mTORC1 subunits 1 and 2 (CASTOR1 and CASTOR2) inhibit the mammalian target of rapamycin complex 1 (mTORC1) upon arginine deprivation. mTORC1 regulates cell proliferation, survival, and metabolism and is often dysregulated in cancers, indicating that cancer cells may regulate CASTOR1 and CASTOR2 to control mTORC1 signaling and promote tumorigenesis. mTORC1 is the most effective therapeutic target of Kaposi sarcoma, which is caused by infection with the Kaposi sarcoma-associated herpesvirus (KSHV). Hence, KSHV-induced cellular transformation is a suitable model for investigating mTORC1 regulation in cancer cells. Currently, the mechanism of KSHV activation of mTORC1 in KSHV-induced cancers remains unclear. We showed that KSHV suppressed CASTOR1 and CASTOR2 expression to activate the mTORC1 pathway. CASTOR1 or CASTOR2 overexpression and mTOR inhibitors abolished cell proliferation and colony formation in soft agar of KSHV-transformed cells by attenuating mTORC1 activation. Furthermore, the KSHV-encoded miRNA miR-K4-5p, and probably miR-K1-5p, directly targeted CASTOR1 to inhibit its expression. Knockdown of miR-K1-5p and -K4-5p restored CASTOR1 expression and thereby attenuated mTORC1 activation. Overexpression of CASTOR1 or CASTOR2 and mTOR inhibitors abolished the activation of mTORC1 and growth transformation induced by pre-miR-K1 and -K4. Our results define the mechanism of KSHV activation of the mTORC1 pathway and establish the scientific basis for targeting this pathway to treat KSHV-associated cancers.
Gambling: health experts investigate scale of harm
Authors: Adrian O’Dowd
Journal: BMJ (2019)

Public health experts are investigating the harm caused by gambling to allow better targeted support for problem gamblers, peers have been told.

Knowledge about the scale of harm from gambling in the UK is limited, government officials told peers on 16 July, during the first evidence session of the House of Lords select committee on the social and economic impact of the gambling industry.

Peers asked witnesses why accurate estimates of the extent of the problem seemed to be lacking, noting a 2016 report from the Institute for Public Policy Research,1 which had estimated that the cost of problem gambling could be anything from …
Quality and Safety in Healthcare, Part LVII
Authors: Jay A. Harolds
Journal: Clinical Nuclear Medicine (2019)

Abstract Problems with healthcare organizations frequently result in burnout. Teams are very important not only to decrease burnout, but also to increase wellness and joy in healthcare, by changing the organization for the better. These organizational improvements, and teamwork itself, not only make life better for the workers, but also promote efficiency for the institution, increase quality and safety for patients and workers, and stimulate collaboration among the workers.
The transcription factor Sox11 is highly specific overexpressed in human malignant gliomas
Authors: Bernd Weigle, Reinhard Ebner, Sandra Schwind, Gabriele Schackert, Hans K. Schackert, Ernst P. Rieber
Journal: Cancer Research (2005)

2366  Malignant glioma comprises the majority of primary human brain tumors with 16,800 new cases reported each year in the US. Despite optimization of local therapies, such as surgery and radio/chemotherapy and the development of aggressive multimodality therapies, the median survival time of only 40 to 60 weeks for patients with glioblastoma multiforme (GBM) has not substantially changed during the last decade. Although rarely metastasizing in areas outside the central nervous system (CNS), recurrence of GBM at or adjacent to the site of origin is a major drawback being responsible for the poor outcome. Failure to treat locally recurrent tumors is thought to be due to tumor infiltration into the surrounding neural tissue which impedes complete surgical resection. Thus, control of infiltrating tumor cells is the aim of many approaches exploring the potential of targeted immunotherapy, either antibody- or cell-mediated. The identification of potential target structures highly overexpressed in brain tumors is a crucial prerequisite for the activation of the immune defense against malignant glioma cells. In order to identify new brain tumor-specific genes, we screened an Affymetrix DNA chip-based expression database and found the Pit-Oct-Unc (POU) cooperating transcription factor SOX11 to be highly overexpressed in GBM and other malignant gliomas. SOX11 belongs to a group of developmentally regulated transcription factors and is known to be crucially involved in brain development. Analysis of the expression pattern of SOX11 in different normal adult and fetal tissues by multiple tissue dot blot and by a highly sensitive quantitative PCR assay confirmed the selective overexpression of SOX11 in fetal brain tissue. Examination of tissue specimens obtained from malignant gliomas and from normal brain by quantitative real time PCR revealed upregulation of SOX11 in almost all tumor samples as compared to the pooled normal brain. Seventy-five per cent of the tumor samples showed a 5- to more than 600-fold overexpression. We conclude that, after downregulation of SOX11 in the adult brain, its expression is reactivated during tumorigenesis and that SOX11 therefore represents a promising novel molecular target for adjuvant therapy of malignant gliomas.
The Ketogenic Diet for Obesity and Diabetes—Enthusiasm Outpaces Evidence
Authors: Shivam Joshi, Robert J. Ostfeld, Michelle McMacken
Journal: JAMA Internal Medicine (2019)

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 Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast 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 Internal Medicine journal
Diabetes Increases Risk of Gastric Cancer After <i>Helicobacter pylori</i> Eradication: A Territory-Wide Study With Propensity Score Analysis
Authors: Ka Shing Cheung, Esther W. Chan, Lijia Chen, Wai Kay Seto, Ian C.K. Wong, Wai K. Leung
Journal: Diabetes Care (2019)

Whether diabetes mellitus (DM) increases risk of gastric cancer (GC) remains controversial because of inadequate adjustments for important risk factors, including Helicobacter pylori (HP) infection status, concomitant medication use, and cancer site. We investigated whether type 2 DM increased risk of GC in patients after they received treatment for HP infection.This was a territory-wide cohort study of patients aged ≥45 years who had received clarithromycin-based triple therapy for HP infection between 2003 and 2012 in Hong Kong. Data were retrieved from a public electronic health database. Observation started from receipt of therapy for HP infection to GC diagnosis, death, or the end of the study (December 2015). Exclusion criteria included type 1 DM, GC diagnosed within the 1st year of HP therapy, prior GC or gastrectomy, and retreatment for HP infection. The adjusted hazard ratio (aHR) of GC with type 2 DM was calculated by using a Cox model that adjusted for 20 covariates (age, sex, comorbidities, and medications) through propensity score regression.During a median follow-up of 7.1 years (interquartile range 4.8-9.3 years), 153 of 46,460 patients (0.33%) developed GC at a median age of 72.4 years. Type 2 DM was associated with an increased risk of GC (aHR 1.73 [95% CI 1.08-2.79]). Stratified analysis showed an increase in risk for cardia cancer only (aHR 3.40 [95% CI 1.45-7.97]) and in those with suboptimal DM control (time-weighted mean HbA1c ≥6.0% [42 mmol/mol]; aHR 1.68 [95% CI 1.07-2.63]).Type 2 DM is associated with an increased risk of GC among patients in whom HP was eradicated, in particular gastric cardia cancer and in those with suboptimal DM control.
Controlled Trial of Two Incremental Milk-Feeding Rates in Preterm Infants
Authors: Jon Dorling, Jane Abbott, Janet Berrington, Beth Bosiak, Ursula Bowler, Elaine Boyle, Nicholas Embleton, Oliver Hewer, Samantha Johnson, Edmund Juszczak, Alison Leaf, Louise Linsell, Kenny McCormick, William McGuire, Omar Omar, Christopher Partlett, Mehali Patel, Tracy Roberts, Ben Stenson, John Townend
Journal: New England Journal of Medicine (2019)

Observational data have shown that slow advancement of enteral feeding volumes in preterm infants is associated with a reduced risk of necrotizing enterocolitis but an increased risk of late-onset sepsis. However, data from randomized trials are limited.We randomly assigned very preterm or very-low-birth-weight infants to daily milk increments of 30 ml per kilogram of body weight (faster increment) or 18 ml per kilogram (slower increment) until reaching full feeding volumes. The primary outcome was survival without moderate or severe neurodevelopmental disability at 24 months. Secondary outcomes included components of the primary outcome, confirmed or suspected late-onset sepsis, necrotizing enterocolitis, and cerebral palsy.Among 2804 infants who underwent randomization, the primary outcome could be assessed in 1224 (87.4%) assigned to the faster increment and 1246 (88.7%) assigned to the slower increment. Survival without moderate or severe neurodevelopmental disability at 24 months occurred in 802 of 1224 infants (65.5%) assigned to the faster increment and 848 of 1246 (68.1%) assigned to the slower increment (adjusted risk ratio, 0.96; 95% confidence interval [CI], 0.92 to 1.01; P = 0.16). Late-onset sepsis occurred in 414 of 1389 infants (29.8%) in the faster-increment group and 434 of 1397 (31.1%) in the slower-increment group (adjusted risk ratio, 0.96; 95% CI, 0.86 to 1.07). Necrotizing enterocolitis occurred in 70 of 1394 infants (5.0%) in the faster-increment group and 78 of 1399 (5.6%) in the slower-increment group (adjusted risk ratio, 0.88; 95% CI, 0.68 to 1.16).There was no significant difference in survival without moderate or severe neurodevelopmental disability at 24 months in very preterm or very-low-birth-weight infants with a strategy of advancing milk feeding volumes in daily increments of 30 ml per kilogram as compared with 18 ml per kilogram. (Funded by the Health Technology Assessment Programme of the National Institute for Health Research; SIFT Current Controlled Trials number, ISRCTN76463425.).
Abstract 13216: Nlrp3 Inflammasome-Primed Neutrophils Amplify Granulopoiesis Following Myocardial Injury
Authors: Prabhakara R Nagareddy, Gopalkrishna Sreejit, Baskaran Athmanathan, Ashish Dhyani, Rahul Annabathula, Susan S Smyth, Enzo Porrello, Ahmed Abdel-Latif, Andrew J Murphy
Journal: Circulation (2018)

Ischemic myocardial damage triggers granulopoiesis resulting in heightened production and recruitment of neutrophils to the ischemic heart. However, little is known about the myocardial molecular d...
Pembrolizumab alone or with chemotherapy for PD-L1 positive NSCLC: A network meta-analysis of randomized trials.
Authors: Mark Doherty, Seanthel Delos Santos, Amanda Putri Rahmadian, Louis Everest, Kelvin K. Chan
Journal: Journal of Clinical Oncology (2019)

9087 Background: Pembrolizumab (P) has replaced chemotherapy (C) as first-line treatment for advanced non-small cell lung cancer (NSCLC) with tumor PD-L1 expression &gt; / = 50%. Among PD-L1 unselected patients, P+C is superior to C alone. This network meta-analysis compared P alone with P+C in patients with &gt; / = 50% PD-L1 positive NSCLC. Methods: An indirect network was constructed to compare P and P+C through the control arms of the Keynote 024, 189 and 407 (PD-L1 &gt; / = 50% subgroup) trials. Baseline characteristics and chemotherapy outcomes were examined for heterogeneity. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and toxicities including immune-related adverse events (irAE) were extracted from trial results. Toxicity results were unavailable for the PD-L1 &gt; / = 50% subgroups of KN 189 &amp; 407, so overall study results were used. Survival outcomes are expressed as hazard ratios (HRs) or restricted mean survival time (RMST) ratios, and toxicity and ORR as risk difference (RD). Results: 507 patients were included: 154 on P, 430 on C and 483 on P+C. Patient characteristics across trials were similar in age, sex, performance status and smoking history. All trials had similar chemotherapy outcomes (PFS 6, 4.9, 4.8 mos) suggesting similar populations. Network meta-analysis showed no difference between P+C and C alone in OS (HR 0.85, 95%CI 0.45-1.59, p = 0.60) or PFS (HR 0.73, 95%CI 0.48-1.1, p = 0.13), but P+C was associated with higher ORR (+16.9%, 95%CI 0.7-33%, p = 0.04). RMST analysis suggested fewer early PFS events with P+C (0-6 mo RMST ratio 1.25, RMST difference 1.02 mo, p = 0.002), with the difference disappearing at 1 year (0-12 mo RMST ratio 1.16, p = 0.07). No difference in RMST for OS was found. Overall toxicities, hematologic and grade 3-5 toxicities were higher with P+C compared with P alone (table). Conclusions: Among patients with &gt; / = 50% PD-L1 positive NSCLC, P+C did not improve OS or PFS compared with P alone, but was associated with higher ORR. RMST analysis suggested fewer early progression events using P+C. [Table: see text]
Engineering nanoparticles to locally activate T cells in the tumor microenvironment
Authors: Dangge Wang, Tingting Wang, Haijun Yu, Bing Feng, Lei Zhou, Fangyuan Zhou, Bo Hou, Hanwu Zhang, Min Luo, Yaping Li
Journal: Science Immunology (2019)

Immunological tolerance of tumors is characterized by insufficient infiltration of cytotoxic T lymphocytes (CTLs) and immunosuppressive microenvironment of tumor. Tumor resistance to immune checkpoint inhibitors due to immunological tolerance is an ongoing challenge for current immune checkpoint blockade (ICB) therapy. Here, we report the development of tumor microenvironment-activatable anti-PDL1 antibody (αPDL1) nanoparticles for combination immunotherapy designed to overcome immunological tolerance of tumors. Combination of αPDL1 nanoparticle treatment with near-infrared (NIR) laser irradiation-triggered activation of photosensitizer indocyanine green induces the generation of reactive oxygen species, which promotes the intratumoral infiltration of CTLs and sensitizes the tumors to PDL1 blockade therapy. We showed that the combination of antibody nanoparticles and NIR laser irradiation effectively suppressed tumor growth and metastasis to the lung and lymph nodes in mouse models. The nanoplatform that uses the antibody nanoparticle alone both for immune stimulation and PDL1 inhibition could be readily adapted to other immune checkpoint inhibitors for improved ICB therapy.
Standards for Studies of Neurological Prognostication in Comatose Survivors of Cardiac Arrest: A Scientific Statement From the American Heart Association
Authors: Romergryko G. Geocadin, Clifton W. Callaway, Ericka L. Fink, Eyal Golan, David M. Greer, Nerissa U. Ko, Eddy Lang, Daniel J. Licht, Bradley S. Marino, Norma D. McNair, Mary Ann Peberdy, Sarah M. Perman, Daniel B. Sims, Jasmeet Soar, Claudio Sandroni
Journal: Circulation (2019)

Significant improvements have been achieved in cardiac arrest resuscitation and postarrest resuscitation care, but mortality remains high. Most of the poor outcomes and deaths of cardiac arrest survivors have been attributed to widespread brain injury. This brain injury, commonly manifested as a comatose state, is a marker of poor outcome and a major basis for unfavorable neurological prognostication. Accurate prognostication is important to avoid pursuing futile treatments when poor outcome is inevitable but also to avoid an inappropriate withdrawal of life-sustaining treatment in patients who may otherwise have a chance of achieving meaningful neurological recovery. Inaccurate neurological prognostication leading to withdrawal of life-sustaining treatment and deaths may significantly bias clinical studies, leading to failure in detecting the true study outcomes. The American Heart Association Emergency Cardiovascular Care Science Subcommittee organized a writing group composed of adult and pediatric experts from neurology, cardiology, emergency medicine, intensive care medicine, and nursing to review existing neurological prognostication studies, the practice of neurological prognostication, and withdrawal of life-sustaining treatment. The writing group determined that the overall quality of existing neurological prognostication studies is low. As a consequence, the degree of confidence in the predictors and the subsequent outcomes is also low. Therefore, the writing group suggests that neurological prognostication parameters need to be approached as index tests based on relevant neurological functions that are directly related to the functional outcome and contribute to the quality of life of cardiac arrest survivors. Suggestions to improve the quality of adult and pediatric neurological prognostication studies are provided.
Comprehensive genomic profiling (CGP) defines the genomic landscape of colorectal cancer (CRC) in individuals of African ancestry
Authors: P. Myer, J. Lee, R. Madison, J. Newberg, J. Ross, J. Chung, L. Albacker, B. Alexander, V. Miller, A. Schrock, E. Mitchell, G. Frampton, S. Ali
Journal: Annals of Oncology (2019)
The epigenetic regulator SIRT6 protects the liver from alcohol-induced tissue injury by reducing oxidative stress in mice
Authors: Hyeong Geug Kim, Menghao Huang, Yue Xin, Yang Zhang, Xinge Zhang, Gaihong Wang, Sheng Liu, Jun Wan, Ali Reza Ahmadi, Zhaoli Sun, Suthat Liangpunsakul, Xiwen Xiong, Xiaocheng Charlie Dong
Journal: Journal of Hepatology (2019)
Role of antibiotic use, plasma citrulline and blood microbiome in advanced non-small cell lung cancer patients treated with nivolumab
Authors: Julia Ouaknine Krief, Pierre Helly de Tauriers, Coraline Dumenil, Nathalie Neveux, Jennifer Dumoulin, Violaine Giraud, Sylvie Labrune, Julie Tisserand, Catherine Julie, Jean-François Emile, Thierry Chinet, Etienne Giroux Leprieur
Journal: Journal for ImmunoTherapy of Cancer (2019)

Recent data suggested a role of gut microbiota and antibiotic use on immune checkpoint inhibitors efficacy. We aimed to evaluate the impact of early use of antibiotic (EUA), blood microbiome and plasmatic citrulline (marker of the intestinal barrier) on nivolumab efficacy in non-small cell lung cancer (NSCLC).We included all consecutive patients with advanced NSCLC treated with nivolumab in our Department between 2014 and 2017. Blood microbiome was analyzed at month (M) M0 and M2. Citrulline rates were evaluated at M0, M2, M4 and M6.Seventy-two patients were included (EUA in 42%). Overall survival (OS) was longer without EUA (median 13.4 months) than with EUA (5.1 months, p = 0.03). Thirty-five patients (49%) had plasma samples available. High citrulline rate (≥20 μM) at M0 was associated with tumor response (p = 0.084) and clinical benefit (nivolumab > 6 months) (p = 0.002). Median progression-free survival (PFS) was 7.9 months (high citrulline) vs 1.6 months (low citrulline) (p < 0.0001), and median OS were respectively non reached vs 2.2 months (p < 0.0001). Patients with EUA had lower median citrulline rates at M0: 21 μM (IQR 15.0-30.8) vs 32 μM (IQR 24.0-42.0) without EUA (p = 0.044). The presence of specific bacterial DNA in blood at M0 was associated with response and clinical benefit (Peptostreptococcae, Paludibaculum, Lewinella) or with tumor progression (Gemmatimonadaceae). Multivariate analyses on PFS and OS confirmed the prognostic role of citrulline and blood microbiome.EUA is associated with shorter OS with nivolumab and lower citrulline rates. Plasma citrulline and blood microbiome appear to be promising predictive factors of nivolumab efficacy.