tbuckley/cabot-search huggingface dataset:
Intratumoral heterogeneity of oxygen metabolism and neovascularization uncovers 2 survival-relevant subgroups of IDH1 wild-type glioblastoma
Authors: Andreas Stadlbauer, Max Zimmermann, Arnd Doerfler, Stefan Oberndorfer, Michael Buchfelder, Roland Coras, Melitta Kitzwögerer, Karl Roessler
Journal: Neuro-Oncology (2018)

Abstract Background The intratumoral heterogeneity of oxygen metabolism in combination with variable patterns of neovascularization (NV) as well as reprogramming of energy metabolism affects the landscape of tumor microenvironments (TMEs) in glioblastoma. Knowledge of the hypoxic and perivascular niches within the TME is essential for understanding treatment failure. Methods Fifty-two patients with untreated glioblastoma (isocitrate dehydrogenase 1 wild type [IDH1wt]) were examined with a physiological MRI protocol including a multiparametric quantitative blood oxygen level dependent (qBOLD) approach and vascular architecture mapping (VAM). Imaging biomarker information about oxygen metabolism (mitochondrial oxygen tension) and neovascularization (microvascular density and type) were fused for classification of 6 different TMEs: necrosis, hypoxia with/without neovascularization, oxidative phosphorylation (OxPhos), and glycolysis with/without neovascularization. Association of the different TME volume fractions with progression-free survival (PFS) was assessed using Kaplan–Meier analysis and Cox proportional hazards models. Results A common spatial structure of TMEs was detected: central necrosis surrounded by tumor hypoxia (with defective and functional neovasculature) and different TMEs with a predominance of OxPhos and glycolysis for energy production, respectively. The percentage of the different TMEs on the total tumor volume uncovered 2 clearly different subtypes of glioblastoma IDH1wt: a glycolytic dominated phenotype with predominantly functional neovasculature and a necrotic/hypoxic dominated phenotype with approximately 50% of defective neovasculature. Patients with a necrotic/hypoxic dominated phenotype showed significantly shorter PFS (P = 0.035). Conclusions Our non-invasive mapping approach allows for classification of the TME and detection of tumor-supportive niches in glioblastoma which may be helpful for both clinical patient management and research.
Interleukin 2 Promotes Hepatic Regulatory T Cell Responses and Protects From Biliary Fibrosis in Murine Sclerosing Cholangitis
Authors: Amy E. Taylor, Alexandra N. Carey, Ramesh Kudira, Celine S. Lages, Tiffany Shi, Simon Lam, Rebekah Karns, Julia Simmons, Kumar Shanmukhappa, Maha Almanan, Claire A. Chougnet, Alexander G. Miethke
Journal: Hepatology (2018)

In the multidrug resistance protein 2 (Mdr2) ‐/‐ mouse model, low phospholipid bile instigates biliary epithelial injury, sterile inflammation, and fibrosis, thereby recapitulating disease mechanisms implicated in biliary atresia (BA) and primary sclerosing cholangitis. We hypothesize that T lymphocytes contribute to the biliary injury and fibrosis in murine sclerosing cholangitis (SC) and that they are susceptible to suppression by regulatory T cells (Tregs). In juvenile Mdr2 ‐/‐ mice, intrahepatic CD8+ lymphocytes were expanded, and contraction of intrahepatic Tregs coincided with rising serum alanine transferase and alkaline phosphatase (ALP) levels between days 14‐30 of life. Antibody‐mediated depletion of intrahepatic CD8+ lymphocytes during that time reduced ALP levels and the expression of osteopontin (Opn), a pro‐fibrogenic cytokine. Depletion of intrahepatic Tregs with anti‐CD25 antibody between days 7‐30 increased intrahepatic CD8+ T cells, Opn expression, and fibrosis. Conversely, expansion of intrahepatic Tregs with interleukin 2/anti‐interleukin 2 immune complexes (IL‐2c) downregulated hepatic expression of Opn and Tnf, reduced frequency of intrahepatic CD8+ lymphocytes, and diminished biliary injury and fibrosis. Treatment with IL‐2c upregulated hepatic Treg expression of CD39, an ectonucleotidase capable of hydrolyzing pro‐inflammatory adenosine triphosphate. In vitro, Tregs expressing CD39 suppressed the proliferation of hepatic CD8+ lymphocytes from Mdr2 ‐/‐ mice more efficiently than those lacking CD39. In infants with BA, infiltration of interlobular bile ducts with CD8+ cells was associated with biliary expression of Opn and its transcription was negatively correlated with mRNA expression of Treg‐associated genes. Conclusion: Hepatic CD8+ T lymphocytes drive biliary injury and fibrosis in murine SC. Their proliferation is controlled by hepatic Tregs through the purinergic pathway, which is responsive to IL‐2c, suggesting that Treg‐directed low‐dose Il‐2 treatment may be considered as therapy for SC.
Clinical and virological predictors of response after antiviral therapy interruption in HBeAg-negative chronic hepatitits B
Authors: S. Lens, M. García-López, Z. Mariño, M. Bonacci, S. Rodríguez-Tajes, E. Perpiñan, F. Rodríguez-Frías, B. Testoni, G. Koutsoudakis, M.B. Ferret, F. Zoulim, Sofía Pérez del Pulgar, X. Forns
Journal: Journal of Hepatology (2018)
Abstract 9671: Molecular Dynamics and Calcium Binding Studies on Troponin Mutations Causing Dilated Cardiomyopathy
Authors: Steffen Lindert, Andy McCammon
Journal: Circulation (2013)

Troponin (Tn), part of the thin filament in cardiomyocytes, plays an important role in calcium signaling events in cardiac muscle contraction. It acts as a Ca2+-dependent switch, activating and deactivating the myofilament leading to contraction and relaxation of the muscle cell. The most common form of heart muscle disease, dilated cardiomyopathy (DCM), is characterized by dilatation of the heart and impaired systolic function of the left or both ventricles. Several Tn mutations that cause DCM have been reported. We used microsecond timescale molecular dynamics (MD) simulations to elucidate the molecular action of three troponin C (TnC) DCM mutations - D75Y, E59D and G159D - with particular focus on calculating the free energy difference between the open and closed states of the TnC as well as average times between opening events. We found free energy differences between the open and closed states of ~8 kcal/mol for the wildtype system. While G159D causes a significant increase in the free energy difference (by ~4 kcal/mol), D75Y does not change the free energy difference significantly, and E59D even causes a ~2 kcal/mol drop in the free energy difference. This finding illustrates nicely that the opening propensity of the TnC hydrophobic patch is only one possible mechanism by which DCM mutations can influence the contractility in cardiomyocytes. Both G159D and E59D use this mechanism. D75Y, however, does not influence TnI binding but rather impacts Ca2+-binding affinity, which can also be observed in our Brownian Dynamics simulations of calcium association.
Sphingolipids as targets for inhalation treatment of cystic fibrosis
Authors: Katrin Anne Becker, Joachim Riethmüller, Aaron P. Seitz, Aaron Gardner, Ryan Boudreau, Markus Kamler, Burkhard Kleuser, Edward Schuchman, Charles C. Caldwell, Michael J. Edwards, Heike Grassmé, Malcolm Brodlie, Erich Gulbins
Journal: Advanced Drug Delivery Reviews (2018)
Unexpected findings from a large Asian HCV real life study
Authors: S.G. Lim, W.W. Phyo, S. Shah, K.M. Win, S.S. Hamid, T. Piratvisuth, S.S. Tan, Y.Y. Dan, Y.M. Lee, T. Ahmed, W.L. Yang, K.P. Chen, M. Kamat, M. Wadhawan, K. Madan, R. Mehta, A. Shukla, P. Dhore, C.E. Eapen, P. Abraham, S. Tyagi, A. Koshy, H.B. Aung, W. Jafri, S. Abid, F.A.Q. Arisar, T. Tanwandee, T.P. Yin, H.P. Tee, R.B.H.M. Said, K.L. Goh, S.H. Ho, R. Mohamed, N.A. Bakar
Journal: Journal of Hepatology (2018)
Abstract 18993: Statins Reduce Thoracic Aortic Aneurysm Growth in Marfan Syndrome Mice via Inhibition of the RAS Induced ERK Signaling Pathway
Authors: Mamoru Arakawa, Tiffany K Koyano, Tetsuya Sato, Young-Nam Youn, Kiril Penov, Albert J Pedroza, Andrew J Connoly, Hideo Adachi, Michael Fischbein
Journal: Circulation (2015)

Rationale: Aortic root aneurysm formation and subsequent dissection remain the major cause of death in patients with Marfan syndrome (MFS). HMG-CoA reductase inhibitors (statins) have been reported to reduce aneurysm growth in MFS mouse models, although the mechanism is unknown. In addition to reducing cholesterol, statins block both farneslyation and geranylgeranylation, which participate in membrane bound G-protein signaling, including Ras. The Ras signaling pathway (via ERK) has been shown to be important in MFS aneurysm formation. Objective: Systematically dissect the prenylation pathway to better define the mechanism behind the beneficial effect of statins on aneurysm reduction in MFS and anticipate this will help elucidate the pathophysiology of aneurysm formation. Method and results: Fbn1 C1039G/+ mice (4 week old) were treated subcutaneously with either (a) Pravastatin (PS) (HMG-Co Reductase inhibitor) (100 mg/kg per day); (b) Manumycin A (MA) (FPT inhibitor) (2.5 mg/kg/every other day); (c) Perillyl Alcohol (PA) (GGPT-1 and -2 inhibitor) (5.0 mg/kg/every other day); or (d) vehicle control Fbn1 C1039G/+ mice from age 4-8 weeks. PS and MA significantly reduced aneurysm growth compared to vehicle control (PS:1.57 ± 0.03 mm; MA: 1.55 ± 0.06 mm; vehicle: 1.77 ± 0.05 mm, respectively: p &lt; 0.05). There was no significant difference between PS and MA treated groups. In contrast, PA did not significantly decrease aneurysm size (PA: 1.81 ± 0.06 mm). Elastin staining illustrated reduced elastin breakdown in MA treated mice compared to vehicle control treated groups (MA: 2.2 ± 0.3, vehicle: 4.2 ± 0.6, respectively: p &lt; 0.05). After identifying that the Ras pathway is important, we measured the relative expression of pRaf-1 and pErk1/2, downstream enzymes in transforming growth factor- β (TGF-β) signaling pathway with Western blot. Although elevated in control Marfan mice, both pRaf-1 and pErk 1/2 were significantly reduced in MA treated mice, corresponding with a reduction in aneurysm growth (pRaf-1: MA: 5.1 ± 1.3, vehicle: 8.8 ± 0.8, p = 0.08, pErk1/2: MA: 2.3 ± 0.1, vehicle: 3.2 ± 0.1, p &lt; 0.05, respectively). Conclusion: Statins reduce aortic aneurysm growth in Fbn1 C1039G/+ Marfan mice by decreasing both Ras activation and downstream ERK signaling.
Mechanisms of action of cortisol in steatotic and non-steatotic livers subjected to partial hepatectomy with vascular occlusion
Authors: E. Bujaldon, María E. Cornide-Petronio, E. Negrete-Sánchez, C.G. Ávalos De León, A.I. Álvarez-Mercado, J. Gulfo, Mónica Jiménez-Castro, F. Rotondo, J. Gracia-Sancho, C. Peralta
Journal: Journal of Hepatology (2018)
Top-Down Systematic Approach to Interpretation of FDG-PET for Dementia
Authors: David M. Sawyer, Phillip H. Kuo
Journal: Clinical Nuclear Medicine (2018)

Dementia is an important cause of morbidity and mortality worldwide and encompasses a very heterogenous group of disease processes. Positron emission tomography (PET) of the brain using fluorodeoxyglucose (FDG) is a useful modality for differentiating types of dementia. Because FDG does not bind to pathologic proteins, FDG-PET requires that the reader recognize characteristic patterns of glucose hypometabolism to identify pathology. These patterns have been documented in the literature for both primary neurodegenerative disorders and secondary causes of dementia. This article presents an algorithm for organizing these findings and systematically applying them to interpret FDG-PET brain imaging for dementia.
Strong correlation of hepatitis B virus prevalence among Mongolian adults 40 to 65 years old of age with HCC mortality rate: A result from the national general hepatitis screening program
Authors: U. Baatarsuren, M. Myanganbayar, S. Narankhuu, E. Enkhbayar, A. Imashkhan, O.-E. Battulga, B. Surenpurev, U. Dagva, O. Oidosambuu, A. Enkhbat, D. Boldbaatar, B. Dashtseren, M. Budeebazar, G. Jargalsaikhan, B. Rinchindorj, D. Zulkhuu, P. Bat-Ulzii, O. Lkhagva-Ochir, M. Enkhbat, Z. Davaadorj, B. Dendev, A. Dagvadorj, A. Murdorj, Z. Genden, D. Yagaanbuyant, A. Bungert, N. Dashdorj, N. Naranjargal
Journal: Journal of Hepatology (2018)
A Learning Collaborative Approach Increases Specificity of Diagnosis of Acute Liver Failure in Pediatric Patients
Authors: Michael R. Narkewicz, Simon Horslen, Regina M. Hardison, Benjamin L. Shneider, Norberto Rodriguez-Baez, Estella M. Alonso, Vicky L. Ng, Mike A. Leonis, Kathleen M. Loomes, David A. Rudnick, Philip Rosenthal, Rene Romero, Girish C. Subbarao, Ruosha Li, Steven H. Belle, Robert H. Squires, Robert H. Squires, Kathryn Bukauskas, Madeline Schulte, Michael R. Narkewicz, Michelle Hite, Kathleen M. Loomes, Elizabeth B. Rand, David Piccoli, Deborah Kawchak, Christa Seidman, Rene Romero, Saul Karpen, Liezl de la Cruz-Tracy, Vicky Ng, Kelsey Hunt, Girish C. Subbarao, Ann Klipsch, Sarah Munson, Estella M. Alonso, Lisa Sorenson, Susan Kelly, Katie Neighbors, Philip Rosenthal, Shannon Fleck, Mike A. Leonis, John Bucuvalas, Tracie Horning, Norberto Rodriguez Baez, Shirley Montanye, Margaret Cowie, Simon P. Horslen, Karen Murray, Melissa Young, Heather Nielson, Jani Klein, David A. Rudnick, Ross W. Shepherd, Kathy Harris, Saul J. Karpen, Alejandro De La Torre, Dominic Dell Olio, Deirdre Kelly, Carla Lloyd, Steven J. Lobritto, Sumerah Bakhsh, Maureen Jonas, Scott A. Elifoson, Roshan Raza, Kathleen B. Schwarz, Wikrom W. Karnsakul, Mary Kay Alford, Anil Dhawan, Emer Fitzpatrick, Benjamin L. Shneider, Nanda N. Kerkar, Brandy Haydel, Sreevidya Narayanappa, M. James Lopez, Victoria Shieck, Edward Doo, Averell H. Sherker, Steven H. Belle
Journal: Clinical Gastroenterology and Hepatology (2018)
Opioid epidemic leads to surge in US organ donors, study shows
Authors: Ingrid Torjesen
Journal: BMJ (2018)

The US epidemic of drug overdose deaths in recent years has corresponded with a dramatic increase in use of donor organs from this group, a study has shown.

Outcomes in recipients of such organs are not inferior to those in patients who received organs donated after trauma or medical death, said the study report, published in the Annals of Internal Medicine .1

The authors noted that concern about increased infection risk behaviours among overdose death donors (ODDs) leads to many organs being discarded. But they said that the use of more of these organs should be considered, including those from donors infected with hepatitis C virus, given the numbers of patients on waiting lists for organs.

The study looked at transplants involving 138 565 deceased …
DNA methyltransferase expression in triple-negative breast cancer predicts sensitivity to decitabine
Authors: Jia Yu, Bo Qin, Ann M. Moyer, Somaira Nowsheen, Tongzheng Liu, Sisi Qin, Yongxian Zhuang, Duan Liu, Shijia W. Lu, Krishna R. Kalari, Daniel W. Visscher, John A. Copland, Sarah A. McLaughlin, Alvaro Moreno-Aspitia, Donald W. Northfelt, Richard J. Gray, Zhenkun Lou, Vera J. Suman, Richard Weinshilboum, Judy C. Boughey, Matthew P. Goetz, Liewei Wang
Journal: Journal of Clinical Investigation (2018)

Triple-negative breast cancer (TNBC) is a heterogeneous disease with poor prognosis that lacks targeted therapies, especially in patients with chemotherapy-resistant disease. Since DNA methylation-induced silencing of tumor suppressors is common in cancer, reversal of promoter DNA hypermethylation by 5-aza-2'-deoxycytidine (decitabine), an FDA-approved DNA methyltransferase (DNMT) inhibitor, has proven effective in treating hematological neoplasms. However, its antitumor effect varies in solid tumors, stressing the importance of identifying biomarkers predictive of therapeutic response. Here, we focused on the identification of biomarkers to select decitabine-sensitive TNBC through increasing our understanding of the mechanism of decitabine action. We showed that protein levels of DNMTs correlated with response to decitabine in patient-derived xenograft (PDX) organoids originating from chemotherapy-sensitive and -resistant TNBCs, suggesting DNMT levels as potential biomarkers of response. Furthermore, all 3 methytransferases, DNMT1, DNMT3A, and DNMT3B, were degraded following low-concentration, long-term decitabine treatment both in vitro and in vivo. The DNMT proteins could be ubiquitinated by the E3 ligase, TNF receptor-associated factor 6 (TRAF6), leading to lysosome-dependent protein degradation. Depletion of TRAF6 blocked decitabine-induced DNMT degradation, conferring resistance to decitabine. Our study suggests a potential mechanism of regulating DNMT protein degradation and DNMT levels as response biomarkers for DNMT inhibitors in TNBCs.
Physical preparation of the football player with an intramuscular hamstring tendon tear: clinical perspective with video demonstrations
Authors: Matt Taberner, Daniel Dylan Cohen
Journal: British Journal of Sports Medicine (2018)

Hamstring strain injuries (HSIs) are common injuries in professional sport and the musculotendinous junction the most frequently injured site.1 2 MRI proves that the tendon extends into the muscle belly and has increased awareness of the intramuscular tendon injury.3 Some argue that this subtype of HSI may require surgical repair. Currently, there is no consensus on intramuscular tendon injury management; there is agreement that players are at an increased risk of re-injury on return to play (RTP).3 4 Evidence suggests that clinical decision-making, based on achieving functional goals, is an essential element of successful rehabilitation.4 

In this video-supported education review with a strong clinical slant, I outline the rehabilitation of an English Premier League footballer who suffered a proximal hamstring intramuscular tendon injury during competition. The conceptual goal was to mechanically load the muscle–tendon unit hoping to improve tensile strength, elastic stiffness and cross-sectional area. Adequate high and maximal speed running exposure and objective neuromuscular performance data informed progression through rehabilitation and RTP. The player returned to competition in 120 days and remained injury free 13 months later.

During rehabilitation following initial physiotherapy care, isometric hamstring exercises were prescribed, beginning with single-leg heel drives (figure 1), progressing to unloaded, then loaded bilateral isometric hip extension holds (online supplementary video 1), then single-leg hip extension holds (online supplementary video 2) emphasising pelvic control before adding dynamic perturbations (online supplementary video 3). These high-intensity isometric exercises, using maximal voluntary contractions (~3–5 s) in cluster sets (ie, 5×5–3–5 s) were included with the theoretical aim of providing cyclic high-strain magnitudes postulated to increase …
Maximal exercise capacity in patients with obstructive sleep apnoea syndrome: a systematic review and meta-analysis
Authors: Monique Mendelson, Mathieu Marillier, Sébastien Bailly, Patrice Flore, Jean-Christian Borel, Isabelle Vivodtzev, Stéphane Doutreleau, Renaud Tamisier, Jean-Louis Pépin, Samuel Verges
Journal: European Respiratory Journal (2018)

Maximal aerobic capacity is a strong health predictor and peak oxygen consumption ( V ′ O 2 peak ) is considered a reflection of total body health. No systematic reviews or meta-analyses to date have synthesised the existing data regarding V ′ O 2 peak in patients with obstructive sleep apnoea (OSA). A systematic review of English and French articles using PubMed/MEDLINE and Embase included studies assessing V ′ O 2 peak in OSA patients either in mL·kg −1 ·min −1 compared with controls or in % predicted. Two independent reviewers analysed the studies, extracted the data and assessed the quality of evidence. Mean V ′ O 2 peak expressed in mL·kg −1 ·min −1 was significantly lower in patients with OSA than in controls (mean difference −2.7 mL·kg −1 ·min −1 ; p&lt;0.001; n=850). This reduction in V ′ O 2 peak was found to be larger in non-obese patients (body mass index &lt;30 kg·m −2 ). Mean V ′ O 2 peak % pred was 89.9% in OSA patients (n=643). OSA patients have reduced maximal aerobic capacity, which can be associated with increased cardiovascular risks and reduced survival in certain patient subgroups. Maximal exercise testing can be useful to characterise functional limitation and to evaluate health status in OSA patients.
Molecular and Functional Neuroscience in Immunity
Authors: Valentin A. Pavlov, Sangeeta S. Chavan, Kevin J. Tracey
Journal: Annual Review of Immunology (2018)

The nervous system regulates immunity and inflammation. The molecular detection of pathogen fragments, cytokines, and other immune molecules by sensory neurons generates immunoregulatory responses through efferent autonomic neuron signaling. The functional organization of this neural control is based on principles of reflex regulation. Reflexes involving the vagus nerve and other nerves have been therapeutically explored in models of inflammatory and autoimmune conditions, and recently in clinical settings. The brain integrates neuro-immune communication, and brain function is altered in diseases characterized by peripheral immune dysregulation and inflammation. Here we review the anatomical and molecular basis of the neural interface with immunity, focusing on peripheral neural control of immune functions and the role of the brain in the model of the immunological homunculus. Clinical advances stemming from this knowledge within the framework of bioelectronic medicine are also briefly outlined.
Written Exposure Therapy vs Cognitive Processing Therapy
Authors: Candice M. Monson, Kathleen M. Chard, Leslie A. Morland
Journal: JAMA Psychiatry (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 Psychiatry 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 Psychiatry journal
Pro: continuous positive airway pressure and cardiovascular prevention
Authors: Miguel Angel Martinez-Garcia, Francisco Campos-Rodriguez, Shahrokh Javaheri, David Gozal
Journal: European Respiratory Journal (2018)

In the clinical realm, the highest degree of evidence driving practice guidelines originates from randomised controlled trials (RCTs) and meta-analysis of RCTs. For practice changes to occur, adequate RCT methodology and optimal sample size, as well as accurate definition of primary objectives and patient selection, are paramount, along with satisfactory adherence to the targeted intervention in a high proportion of the participants. Critically, the results of any of such trials can only apply to the targeted population and cannot be extrapolated to alternative groups, even if they suffer from the same disease [1]. Furthermore, if controversial findings emerge between previous basic and clinical studies, a cogent explanation for such discrepancies would be required to identify future study directions. The methodological limitations of the current RCTs on the CPAP effect on cardiovascular protection do not support a change in our clinical practice <http://ow.ly/V11730ieGYk>
Role of human forkhead box P3 in early thymic maturation and peripheral T-cell homeostasis
Authors: Francesca R. Santoni de Sio, Laura Passerini, Silvia Restelli, Maria Maddalena Valente, Aleksandar Pramov, Maria Elena Maccari, Francesca Sanvito, Maria Grazia Roncarolo, Matthew Porteus, Rosa Bacchetta
Journal: Journal of Allergy and Clinical Immunology (2018)