tbuckley/cabot-search huggingface dataset:
Phosphorylation of Acetyl-CoA Carboxylase by AMPK Reduces Renal Fibrosis and Is Essential for the Anti-Fibrotic Effect of Metformin
Authors: Mardiana Lee, Marina Katerelos, Kurt Gleich, Sandra Galic, Bruce E. Kemp, Peter F. Mount, David A. Power
Journal: Journal of the American Society of Nephrology (2018)

Background Expression of genes regulating fatty acid metabolism is reduced in tubular epithelial cells from kidneys with tubulointerstitial fibrosis (TIF), thus decreasing the energy produced by fatty acid oxidation (FAO). Acetyl-CoA carboxylase (ACC), a target for the energy-sensing AMP-activating protein kinase (AMPK), is the major controller of the rate of FAO within cells. Metformin has a well described antifibrotic effect, and increases phosphorylation of ACC by AMPK, thereby increasing FAO. Methods We evaluated phosphorylation of ACC in cell and mouse nephropathy models, as well as the effects of metformin administration in mice with and without mutations that reduce ACC phosphorylation. Results Reduced phosphorylation of ACC on the AMPK site Ser79 occurred in both tubular epithelial cells treated with folate to mimic cellular injury and in wild-type (WT) mice after induction of the folic acid nephropathy model. When this effect was exaggerated in mice with knock-in (KI) Ser to Ala mutations of the phosphorylation sites in ACC, lipid accumulation and fibrosis increased significantly compared with WT. The effect of ACC phosphorylation on fibrosis was confirmed in the unilateral ureteric obstruction model, which showed significantly increased lipid accumulation and fibrosis in the KI mice. Metformin use was associated with significantly reduced fibrosis and lipid accumulation in WT mice. In contrast, in the KI mice, the drug was associated with worsened fibrosis. Conclusions These data indicate that reduced phosphorylation of ACC after renal injury contributes to the development of TIF, and that phosphorylation of ACC is required for metformin’s antifibrotic action in the kidney.
High-Intensity Interval Exercise Effectively Improves Cardiac Function in Patients With Type 2 Diabetes Mellitus and Diastolic Dysfunction
Authors: Siri M. Hollekim-Strand, Marit R. Bjørgaas, Grethe Albrektsen, Arnt E. Tjønna, Ulrik Wisløff, Charlotte B. Ingul
Journal: Journal of the American College of Cardiology (2014)
Healthcare resource utilization and costs associated with incremental systemic corticosteroid exposure in asthma
Authors: Jaco Voorham, Xiao Xu, David B. Price, Sarowar Golam, Jill Davis, Joanna Zhi Jie Ling, Marjan Kerkhof, Mandy Ow, Trung N. Tran
Journal: Allergy (2018)

Although systemic corticosteroid (SCS) treatment, irrespective of duration or dosage, is associated with adverse outcomes for patients with asthma, the longitudinal effects of this treatment on adverse outcomes, healthcare resource utilization (HCRU), and healthcare costs are unknown.We identified patients initiating intermittent or long-term SCS who were diagnosed with active asthma from UK general practice with linked secondary care data. Control (non-SCS) patients were matched by sex and index date with those initiating SCS. Minimum baseline period was 1 year prior to index date; minimum follow-up duration was 2 years post-index date. Cumulative incidence of SCS-associated adverse outcomes and associated HCRU and costs were compared between SCS and non-SCS patient groups and among average SCS daily exposure categories. Associations between exposure and annualized HCRU and costs were assessed, adjusted for confounders.Analyses included 9413 matched pairs. Median (interquartile range) follow up was as follows: SCS group: 7.1 (4.1-11.8) years; control group: 6.4 (3.8-10.0) years. Greater SCS dosages were correlated with greater cumulative incidence. For example, patients with type 2 diabetes receiving an average daily dosage of ≥7.5 mg had a 15-year cumulative incidence (37.5%) that was 1.5-5 times greater than those receiving lower dosages. HCRU and costs increased annually for SCS patients but not for non-SCS patients. Increases in all-cause adverse outcome (excluding asthma)-associated HCRU and costs were dose-dependent.Over the long term, adverse outcomes associated with SCS initiation were relatively frequent and costly, with a positive dosage-response relationship with SCS exposure.
Importance of Intelligence and Emotional Intelligence for Physicians
Authors: Sarah K. Shore, Sandeford J. Schaeffer, Jack W. Tsao
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 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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
Child carriers of antibiotic warning
Authors: Zosia Kmietowicz
Journal: BMJ (2018)

Robin Hiley

Schoolchildren across the UK are being encouraged to take up the fight against antibiotic misuse through the medium of song.

“This is amazing” is how one 9 year old described his participation in the musical The Mould that Changed the World , which premiered at the Science Museum’s IMAX theatre in London earlier this month.

The show …
Resección endoscópica mucosa “Underwater” versus resección endoscópica mucosa convencional para el tratamiento de lesiones colorrectales planas: estudio prospectivo no aleatorizado
Authors: J Rodríguez Sánchez Sánchez, E De La Santa Belda, P Olivencia Palomar, R Salmoral Luque, J Olmedo Camacho
Journal: Endoscopy (2017)

La resección endoscópica mucosa “UnderWater” (UREM) es una variante de la REM tradicional descrita en 2012. Se basa en la realización de la resección en inmersión en agua con el colapso completo de la luz colónica. El efecto de flotación de la mucosa hace no necesaria la formación de habón submucoso y permite a priori, resecciones en bloque de mayor tamaño. A pesar de estas teóricas ventajas no existen estudios comparativos prospectivos con la REM estándar.
Hgf/Met activation mediates resistance to BRAF inhibition in murine anaplastic thyroid cancers
Authors: Jeffrey A. Knauf, Kathleen A. Luckett, Kuen-Yuan Chen, Francesca Voza, Nicholas D. Socci, Ronald Ghossein, James A. Fagin
Journal: Journal of Clinical Investigation (2018)

Anaplastic thyroid carcinomas (ATCs) have a high prevalence of BRAF and TP53 mutations. A trial of vemurafenib in nonmelanoma BRAFV600E-mutant cancers showed significant, although short-lived, responses in ATCs, indicating that these virulent tumors remain addicted to BRAF despite their high mutation burden. To explore the mechanisms mediating acquired resistance to BRAF blockade, we generated mice with thyroid-specific deletion of p53 and dox-dependent expression of BRAFV600E, 50% of which developed ATCs after dox treatment. Upon dox withdrawal there was complete regression in all mice, although recurrences were later detected in 85% of animals. The relapsed tumors had elevated MAPK transcriptional output, and retained responses to the MEK/RAF inhibitor CH5126766 in vivo and in vitro. Whole-exome sequencing identified recurrent focal amplifications of chromosome 6, with a minimal region of overlap that included Met. Met-amplified recurrences overexpressed the receptor as well as its ligand Hgf. Growth, signaling, and viability of Met-amplified tumor cells were suppressed in vitro and in vivo by the Met kinase inhibitors PF-04217903 and crizotinib, whereas primary ATCs and Met-diploid relapses were resistant. Hence, recurrences are the rule after BRAF suppression in murine ATCs, most commonly due to activation of HGF/MET signaling, which generates exquisite dependency to MET kinase inhibitors.
Seeing the Light after 25 Years of Retinal Gene Therapy
Authors: Ivana Trapani, Alberto Auricchio
Journal: Trends in Molecular Medicine (2018)

HighlightsThe first FDA-approved gene therapy product for an inherited disease is an adeno-associated virus (AAV)-based vector for a form of blindness.Clinical development of gene therapy for dozens of rare and common retinal diseases is ongoing, although improvements will be required to broaden the success of retinal gene therapy to a growing number of conditions.Transduction of the retina from the vitreous and delivery of genes larger than 5kb are long-standing goals of the field, for which promising results have been recently obtained in animal models.The recent evolution of designer nucleases, including CRISPR/Cas9, allows to edit toxic gain-of-function mutations even in terminally differentiated neurons.Therapeutic approaches which are independent of the underlying mutations are being developed that are based on delivery of either neurotrophic factors to slow down retinal degeneration or optogenetic molecules to sensitize neurons to light.AbstractThe retina has been at the forefront of translational gene therapy. Proof-of-concept that gene therapy could restore vision in a large animal led to the initiation of the first successful clinical trials and, in turn, to the recent approval of the first gene therapy product for an ocular disease. As dozens of clinical trials of retinal gene therapy have begun, new challenges are identified, which include delivery of large genes, counteracting gain-of-function mutations, and safe and effective gene transfer to diseased retinas. Advancements in vector design, improvements of delivery routes, and selection of optimal timing for intervention will contribute to extend the initial success of retinal gene therapy to an increasing number of inherited blinding conditions.
Importance of both increasing physical activity and reducing sitting time
Authors: Hannah Arem, Charles E Matthews
Journal: British Journal of Sports Medicine (2018)

Ekelund and colleagues should be commended for developing this valuable pooled resource1 to estimate the amount of physical activity needed to minimise excess mortality risk from sedentary time. Here we comment primarily on the cancer outcomes for the report published in BJSM 2 and more broadly on the public health implications of this research.

Research examining the adverse effects of sitting time on cancer risk and mortality is relatively recent. This study examines the potential for physical activity to modify adverse effects of too much sitting on cancer mortality and demonstrates that high TV-viewing time may be associated with increased cancer mortality unless very high activity levels are achieved (≥35.5 Metabolic Equivalent of Task (MET)-hour/week). The authors rightly note that studying overall cancer mortality may obscure differences in associations by specific cancer sites. Cancer includes hundreds of diseases with distinct aetiologies, and investigation of total cancer mortality is expected to produce relatively weak associations. For instance, we previously reported that high physical activity was associated with 11% lower overall cancer mortality, but risk estimates were 2–3 times stronger for site-specific cancer death.3 

The …
ENDOSCOPIC SUBMUCOSAL DISSECTION OF MALIGNANT NON-PEDUNCULATED COLORECTAL LESIONS
Authors: CF Frimand Rönnow, J Elebro, E Toth, H Thorlacius
Journal: Endoscopy (2018)

Endoscopic submucosal dissection (ESD) is an established method for en bloc resection of large non-pedunculated colorectal lesions in Asia but dissemination of ESD in Western countries is limited. The aim of this study was to evaluate the role of ESD in the management of malignant non-pedunculated colorectal lesions in a European center.
Rendimiento de las solicitudes de gastroscopia de alta sospecha de enfermedad grave desde atención primaria
Authors: C De Zárraga Mata, G Thomás Salom, Á Brotons García, A Vilella Martorell, C Garau Colom, ÁL Maura Oliver, A Puy Guillén, C Dolz Abadía
Journal: Endoscopy (2017)

Las peticiones de gastroscopia desde Atención Primaria a la Unidad de Endoscopia del Hospital Son Llàtzer (Palma de Mallorca) desde 2014 están restingidas a la solicitud de gastroscopia por alta sospecha de enfermedad grave. Los criterios explicitados en la petición para la solicitud de la misma son la presencia de anemia con sangre oculta en heces positiva y síntomas digestivos altos, disfagia progresiva o prueba de imagen patológica. Estas solicitudes se priorizan al resto de pruebas endoscópicas solicitadas en nuestro centro.
<i>ERCC2</i> Helicase Domain Mutations Confer Nucleotide Excision Repair Deficiency and Drive Cisplatin Sensitivity in Muscle-Invasive Bladder Cancer
Authors: Qiang Li, Alexis W. Damish, Zoë Frazier, David Liu, Elizaveta Reznichenko, Atanas Kamburov, Andrew Bell, Huiyong Zhao, Emmet J. Jordan, S. Paul Gao, Jennifer Ma, Philip H. Abbosh, Joaquim Bellmunt, Elizabeth R. Plimack, Jean-Bernard Lazaro, David B. Solit, Dean Bajorin, Jonathan E. Rosenberg, Alan D. D'Andrea, Nadeem Riaz, Eliezer M. Van Allen, Gopa Iyer, Kent W. Mouw
Journal: Clinical Cancer Research (2018)

Abstract Purpose: DNA-damaging agents comprise the backbone of systemic treatment for many tumor types; however, few reliable predictive biomarkers are available to guide use of these agents. In muscle-invasive bladder cancer (MIBC), cisplatin-based chemotherapy improves survival, yet response varies widely among patients. Here, we sought to define the role of the nucleotide excision repair (NER) gene ERCC2 as a biomarker predictive of response to cisplatin in MIBC. Experimental Design: Somatic missense mutations in ERCC2 are associated with improved response to cisplatin-based chemotherapy; however, clinically identified ERCC2 mutations are distributed throughout the gene, and the impact of individual ERCC2 variants on NER capacity and cisplatin sensitivity is unknown. We developed a microscopy-based NER assay to profile ERCC2 mutations observed retrospectively in prior studies and prospectively within the context of an institution-wide tumor profiling initiative. In addition, we created the first ERCC2-deficient bladder cancer preclinical model for studying the impact of ERCC2 loss of function. Results: We used our functional assay to test the NER capacity of clinically observed ERCC2 mutations and found that most ERCC2 helicase domain mutations cannot support NER. Furthermore, we show that introducing an ERCC2 mutation into a bladder cancer cell line abrogates NER activity and is sufficient to drive cisplatin sensitivity in an orthotopic xenograft model. Conclusions: Our data support a direct role for ERCC2 mutations in driving cisplatin response, define the functional landscape of ERCC2 mutations in bladder cancer, and provide an opportunity to apply combined genomic and functional approaches to prospectively guide therapy decisions in bladder cancer. See related commentary by Grivas, p. 907
Abstract 518: Factors Contributing to Ventricular Arrhythmias After Skeletal Myoblast Transplantation
Authors: Steven R Coppen, Satsuki Fukushima, Anabel Varela-Carver, Kenichi Yamahara, Leanne E Felkin, Alexander Ermakov, Magdi H Yacoub, Ken Suzuki
Journal: Circulation (2006)
Experiencia con el sistema endoscópico overstitch en un hospital público terciario
Authors: A Campos Ruiz, P Aranzabal Aguilar, I Ganchegui Aguirre, L Urtasun Arlegui, AB Fernandez Laso, I Azagra De Miguel, I Gorroño Zamalloa, M Álvarez Rubio, A Orive Calzada
Journal: Endoscopy (2017)

Overstitch es un sistema aprobado en 2008 por la FDA para la realización de suturas endoscópicas transmurales y la aproximación de tejidos blandos.
ENDOSCOPIC TREATMENT FOR POST-OPERATIVE BENIGN BILIARY STRICTURE
Authors: D Paikos, I Moschos, G Sofianidis, M Gianarakis, G Kouklakis
Journal: Endoscopy (2018)

Post-operative benign biliary strictures (BBSs) is a very serious problem. The aim of the study is to evaluate the efficiency of endoscopic therapy during the early postoperative period (< 30 days).
Características fenotípicas y seguimiento endoscópico tras resección de cáncer colorrectal en población joven
Authors: Á Cañete Ruiz, J Arribas Anta, D Rueda, S Tapial, C Narvaez, A Vivas, JC Marín Gabriel, JB Díaz Tasende, G Castellano Tortajada, J Perea García
Journal: Endoscopy (2017)

El Cáncer colorrectal en jóvenes (CCRJ, < 45 años) podría ser un grupo caracterizable dentro del espectro de pacientes con CCR.
Health Barriers and Patterns of Gastric Cancer Care in Rural Central American Resource-Limited Settings
Authors: Dagoberto Estevez-Ordonez, Eleazar E. Montalvan-Sanchez, Rochelle E. Wong, Daniela M. Montalvan-Sanchez, Aida A. Rodriguez-Murillo, Ricardo L. Dominguez, Douglas R. Morgan
Journal: JAMA Oncology (2018)

diagnosis.In fact, consistent with other studies of survivors from treatment for primary gastrointestinal tract tumors, 2,3 prognosis improves over time.There are some open-source data sets of cancer survival prediction calculators that have been developed to facilitate pragmatic discussions between patients and clinicians pertaining to conditional survival for select solid tumors. 4 As these outcome tools are refined to include individualized patient-level "-omic" information, nextgeneration outcome prediction tools have the potential to be more accurate in estimating outcome for cancer survivors.
Sex differences in Alzheimer disease — the gateway to precision medicine
Authors: Maria Teresa Ferretti, Maria Florencia Iulita, Enrica Cavedo, Patrizia Andrea Chiesa, Annemarie Schumacher Dimech, Antonella Santuccione Chadha, Francesca Baracchi, Hélène Girouard, Sabina Misoch, Ezio Giacobini, Herman Depypere, Harald Hampel
Journal: Nature Reviews Neurology (2018)
EVALUATING THE COMBINATION OF WIRE ASSISTED CANNULATION AND PURE-CUT SPHINCTEROTOMY DURING THERAPEUTIC ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY: A PROSPECTIVE CASE SERIES STUDY
Authors: F Obide, H Matieeg
Journal: Endoscopy (2018)

Post Endoscopic retrograde cholangiopancreatography pancreatitis (PEP) is a well-known complication of endoscopic retrograde cholangiopancreatography (ERCP) (Bilbao et al., 1976; Freeman, 2012), ranging from biochemical rise of amylase to severe fatal necrotising pancreatitis (Talukdar, 2016). Since pancreatitis is a preventable complication, technical optimisation at pre, intra and post procedural levels should be carried out to reduce the risk (Kahaleh et al., 2012). Trying to implement the best approach to lower the risk of pancreatitis, combination of wire assisted cannulation and pure-cut sphincterotomy technique were adopted, since each of these techniques is individually proven to be associated with lower risk of pancreatitis.
Safety and efficacy of adalimumab in arthritis patients previously treated with another biologic agent
Authors: N Feltelius, M Fored, P Blomqvist, L Bertilsson, P Geborek, L T Jacobsson, S Lindblad, J Lysholm, Solbritt Rantapää-Dahlqvist, T Saxne, K Klintberg, M Rutting, L Klareskog
Journal: Annals of the Rheumatic Diseases (2004)

Safety and efficacy of adalimumab in arthritis patients previously treated with another biologic agent
Abstract 14434: Oxidized Low Density Lipoprotein Elevates the Pro-osteogenic Activity in Human Aortic Valve Interstitial Cells via Innate Immune Receptors
Authors: Qingchun Zeng, Lihua Ao, David Fullerton, Charles Dinarello, Xianzhong Meng
Journal: Circulation (2016)

Calcific aortic valve disease (CAVD) is a chronic pathological process involving inflammation, fibrosis and calcification. Pharmacological intervention for prevention of CAVD progression remains unavailable. Calcified aortic valves display higher levels of oxidized low-density lipoprotein (oxLDL), and oxLDL has the potential to interact with Toll-like receptors (TLRs). Interleukin (IL)-37 is an anti-inflammatory cytokine and has been shown to inhibit TLR4-mediated inflammatory responses. We tested the  hypotheses  that oxLDL induces the osteogenic responses in human aortic valve interstitial cells (AVICs) via TLRs and that IL-37 suppresses the responses and may have therapeutic potential for suppression of CAVD progression.   Methods and Results:  Human AVICs from normal valves were treated with oxLDL (20-80 μg/ml) for 72 hours in vitro. OxLDL up-regulated the expression of bone morphogenetic protein-2 (BMP-2) and alkaline phosphatase (ALP) in a dose-dependent fashion. Further, oxLDL induced NF-κB and ERK1/2 phosphorylation through a mechanism involving TLR 2 and TLR4, but not LOX-1. Inhibition of NF-κB or ERK1/2 reduced the effect of oxLDL on BMP-2 and ALP expression. Treatment with recombinant IL-37 suppressed oxLDL-induced NF-κB and ERK1/2 phosphorylation, resulting in marked reductions in BMP-2 and ALP levels, ALP activity and calcium deposit formation. To determine the effect of IL-37 on aortic valve lesions  in vivo,  we fed wild-type and IL-37 transgenic mice with a high fat diet for 8 weeks. Feeding wild-type mice with the high fat diet resulted in aortic valve thickening and expression of BMP-2 that are associated with accumulation of oxLDL in aortic valve leaflets. Transgenic expression of IL-37 prevented aortic valve thickening and BMP-2 expression caused by the high fat diet.   Conclusions:  The results of this study show that oxLDL elevates the pro-osteogenic activity in human AVICs by activation of NF-κB and ERK1/2 through TLR2 and TLR4. IL-37 suppresses oxLDL-induced osteogenic responses in human AVICs and attenuate aortic valve thickening caused by a high fat diet in mice. These findings reveal a novel mechanism of CAVD pathogenesis and indicate that IL-37 has therapeutic potential for suppression of CAVD pathogenesis.
Emerging Targeted Therapy for Tumors with <i>NTRK</i> Fusion Proteins
Authors: Ed S. Kheder, David S. Hong
Journal: Clinical Cancer Research (2018)

The oncogenesis-promoting role of chromosomal rearrangements for several hematologic and solid malignancies is well recognized. However, identifying targetable, actionable, and druggable chromosomal rearrangements remains a challenge. Targeting gene fusions and chromosomal rearrangements is an effective strategy in treating gene rearrangement-driven tumors. The NTRK (Neurotrophic Tyrosine Receptor Kinase) gene family encodes three tropomyosin-related kinase (TRK) receptors that preserve central and peripheral nervous system development and function. NTRK genes, similar to other genes, are subject to alterations, including fusions. Preclinical studies have demonstrated that TRK fusion proteins promote oncogenesis by mediating constitutive cell proliferation and survival. Several clinical trials have estimated the safety and efficacy of TRK fusion kinase receptor inhibitors and have demonstrated encouraging antitumor activity in patients with NTRK-rearranged malignancies. Specifically, larotrectinib and entrectinib have emerged as potent, safe, and promising TRK inhibitors. Herein, we discuss the potential oncogenic characteristics of TRK fusion proteins in various malignancies and highlight ongoing clinical trials of kinase inhibitors targeting them.
RISK FACTORS RELATED TO THE DEVELOPMENT OF PREMALIGNANT LESIONS OF THE COLONIC MUCOSA. CONTRIBUTIONS TO EARLY DIAGNOSIS, CUBA 2002 – 2015
Authors: F Neri Piñol Jiménez
Journal: Endoscopy (2018)

Current scientific evidence confirms that high levels of AB in the intestinal lumen, vesicular lithiasis and being cholecystectomized is associated with inflammatory, premalignant and malignant lesions of the colon.