tbuckley/cabot-search huggingface dataset:
A quantum biochemistry investigation of cancer immunotherapy.
Authors: E.L. Albuquerque, Ana Beatriz M.L.A. Tavares, L.R. da Silva, J.X. Lima-Neto, U.L. Fulco
Journal: Journal of Clinical Oncology (2017)

e14558 Background: Immunotherapy is a procedure to boost the patient's own immune system to fight diseases such as cancer. In some types of cancer, it has been found that the programmed cell death receptor PD-1 impedes the body's immune defenses from functioning at full strength. Therefore drugs, like pembrolizumab, which prevent the interaction between this protein and the T-cells, may be a key tool to avoid the onset of cancer tumors. Methods: The aim of this work is to describe the interaction energies between the protein PD-1 and its drug inhibitor pembrolizumab by using a quantum biochemistry calculations, taking advantage of the X-ray crystal structure of the protein PD-1 in complex with its inhibitor. The protonation state of the drug was obtained using the Marvin Sketch code (Marvin Beans Suite). The optimization procedure was performed using the parametrization tool for organic molecules CHARMM (Chemistry at Harvard Macromolecular Mechanics). Afterwards, simulations within the density functional theory (DFT) framework were carried out by using the Gaussian code to provide a detailed energy profile of the interactions between the inhibitor and the receptor. Results: The interaction energy between each PD-1 molecule and the drug was calculated considering any significant attractive and repulsive drug’s amino acid residues. A searchfor an optimal binding pocket radius was done, looking for no significantvariation in the total binding energy. The converged binding pocket radius was found to be 1.5 nm, comprising a total of 145 amino acids residues displayed in a BIRD (Binding site, Interaction energy and Residues Domain) graphic panel. Although it was observed few repulsive interactions, the attractive ones were predominant, pointing out to a strong inhibition of the programmed cell death receptor. Conclusions: Immunotherapy is ranked nowadays as an important alternative to treat cancer. Among the drugs been tested, those blocking the protein PD-1 and its ligands have been considered an efficient way to trigger the T-cells. In this context, the computational method used in this work is a low cost efficient first step to unveil the drug’s amino-acids residues that play the most important role on the binding affinity of the receptor-ligand complex.
DEPDC5 takes a second hit in familial focal epilepsy
Authors: Matthew P. Anderson
Journal: Journal of Clinical Investigation (2018)

Loss-of-function mutations in a single allele of the gene encoding DEP domain-containing 5 protein (DEPDC5) are commonly linked to familial focal epilepsy with variable foci; however, a subset of patients presents with focal cortical dysplasia that is proposed to result from a second-hit somatic mutation. In this issue of the JCI, Ribierre and colleagues provide several lines of evidence to support second-hit DEPDC5 mutations in this disorder. Moreover, the authors use in vivo, in utero electroporation combined with CRISPR-Cas9 technology to generate a murine model of the disease that recapitulates human manifestations, including cortical dysplasia-like changes, focal seizures, and sudden unexpected death. This study provides important insights into familial focal epilepsy and provides a preclinical model for evaluating potential therapies.
Development of hepatocellular carcinoma following HCV eradication by direct-acting antivirals: Real-life experience from Japanese multicenter cohort
Authors: E. Ogawa, N. Furusyo, N. Hideyuki, K. Dohmen, N. Higashi, K. Takahashi, A. Kawano, K. Azuma, T. Satoh, M. Nakamuta, T. Koyanagi, S. Shimoda, M. Kato, E. Kajiwara, J. Hayashi
Journal: Journal of Hepatology (2018)
Elderly Man With Left Iliac Fossa and Inguinal Pain
Authors: Argyrios Ioannidis, Christos Koutserimpas, Nikolaos Nikitakis
Journal: JAMA Surgery (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 Surgery 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 Surgery journal
Proteomic Analyses of Human Regulatory T Cells Reveal Adaptations in Signaling Pathways that Protect Cellular Identity
Authors: Eloy Cuadrado, Maartje van den Biggelaar, Sander de Kivit, Yi-yen Chen, Manon Slot, Ihsane Doubal, Alexander Meijer, Rene A.W. van Lier, Jannie Borst, Derk Amsen
Journal: Immunity (2018)
Abstract 19399: Failure to Adequately Reduce Tricuspid Valve Size in Hypoplastic Left Heart Syndrome: Tricuspid Valve Repair is an Important Mechanism of Significant Post-Operative Regurgitation
Authors: Kandice Mah, Billie-Jean Martin, Silvia Alvarez, Nassiba Alami Laroussi, Ivan M Rebeyka, Jeffrey Smallhorn, Nee Khoo, Timothy Colen
Journal: Circulation (2016)

Background:  Tricuspid valve regurgitation (TR) is associated with morbidity and mortality in hypoplastic left heart syndrome (HLHS). Successful tricuspid valve repair (TVR) may improve outcomes, however 30-50% of patients develop significant post-operative TR, often requiring further surgery. We sought to determine pre-operative factors associated with development of TR after TVR in HLHS.   Methods:  Twenty-six HLHS patients requiring TVR for TR between 2005 and 2015 were assessed. 2D echocardiography (2DE) was used pre-op and late post-op (> 6 months) to assess TR grade, vena contracta (VC) size and annulus size. Patients were divided into those with ≤ mild TR (group A) and those with ≥ moderate TR (group B) at late post-op. Pre-op 3D echocardiography (3DE) was used to assess mechanism and location of TR. Surgical notes were reviewed for repair details.   Results:  Fourteen patients (54%) had ≤ mild TR (group A) and 12 (46%) had ≥ moderate TR (group B) at late post-op. TVR occurred most commonly with other surgical procedures (2 at Norwood, 8 at Glenn, and 7 at Fontan). On preop 3DE, 13 (52%) had central TR, 7 (28%) had central TR with extension into a commissure, 2 (8%) had anterior-septal TR, and 3 (12%) had mixed commissural TR. The primary mechanism was tethering in 14 (56%) and prolapse in 12 (44%). For surgical repair, 17 (65%) had posterior annuloplasty, 5 (19%) cleft closure, and 4 (16%) other. Types of surgical repair were similar between the 2 groups.  Group A had smaller pre-op 2DE TV annulus Z-score (3.4 vs 5.0, P=0.013) but no difference in pre-op 2DE VC diameter, when compared to group B. Group A pre and post op-comparison showed reduced annulus Z-score (3.4 vs 0.8, P=0.01) and VC diameter (p=0.01), while Group B pre and post op annulus size and VC size showed no reduction. There was no difference between group A and B with respect to TR location or primary mechanism involved. Late post-op VC demonstrated moderate correlation with pre-op TV annulus size (P=0.005; R=0.54) but not with pre-op VC.   Conclusion:  TR after valve repair is common. Larger pre op annulus size is related to post-operative TR. Despite surgical repair aimed at reducing TV annulus size, failure to adequately reduce TV size appears to be a mechanism of persistent significant post-operative regurgitation in HLHS.
The cost-effectiveness of needle and syringe provision in preventing transmission of Hepatitis C virus in people who inject drugs
Authors: Z. Ward, S. Sweeney, L. Platt, L. Guinness, L. Maher, V. Hope, M. Hickman, J. Smith, R. Ayres, I. Hainey, T. Chamberlain, P. Vickerman
Journal: Journal of Hepatology (2018)
Drug Repositioning to Alleviate Systemic Inflammatory Response Syndrome Caused by Gram‐Negative Bacterial Outer Membrane Vesicles
Authors: Ji Hyun Kim, Jaewook Lee, Kyong‐Su Park, Sung‐Wook Hong, Yong Song Gho
Journal: Advanced Healthcare Materials (2018)

Sepsis is characterized by systemic inflammatory response syndrome (SIRS) accompanied with infection. Gram-negative bacteria can evoke sepsis by activating the host immune system, such as the release of IL-6 and TNF-α, through their virulence factors. Outer membrane vesicles (OMVs), nanosized bilayered proteolipids derived from Gram-negative bacteria, harbor various virulence factors and are shown to induce SIRS. Here, drugs are repositioned to alleviate SIRS caused by Gram-negative bacterial OMVs. Using novel OMV-based drug screening systems, a total of 178 commercially available drugs are primarily screened, and a total of 18 repositioned drug candidates are found to effectively block IL-6 and TNF-α production from OMV-stimulated macrophages. After excluding the compounds which are previously known to intervene sepsis or which show cytotoxicity to macrophages, the compounds which show dose-dependency in inhibiting the release of IL-6 and TNF-α by the OMV-stimulated macrophages in vitro and which reduce OMV-induced SIRS in vivo are selected. Salbutamol, a β2 adrenergic receptor agonist, is selected as a novel candidate to alleviate OMV-induced SIRS. This study sheds light on using Gram-negative bacterial OMVs in exploring novel candidate compounds to alleviate inflammatory diseases including sepsis.
Abstract 19040: Different SCARB1 Locus Variants Associate With Hdl-Cholesterol and the Risk of Coronary Artery Disease
Authors: Anna Helgadottir, Patrick Sulem, Gudmundur Thorgeirsson, Isleifur Olafsson, Gudmundur I Eyjolfsson, Olof Sigurdardottir, Unnur Thorsteinsdottir, Daniel F Gudbjartsson, Hilma Holm, Kari Stefansson
Journal: Circulation (2016)

Background and objective:  Scavenger receptor class B type 1 (SR-B1), encoded by the  SCARB1  gene, promotes uptake of cholesterol from circulating HDL and plays a role in reverse cholesterol transport. Genome-wide association studies (GWAS) have identified common variants at the  SCARB1  locus that associate with HDL-C and rare  SCARB1  coding variants have been shown to increase HDL-C. Recently a rare missense variant p.P376L in  SCARB1  that raises HDL-C was reported to increase CAD risk, in contrast to expected cardiovascular protection as observed in epidemiologic studies. GWAS studies have also found common  SCARB1  locus variants that associate with levels of vitamin E and Lp-PLA2 activity, highlighting the complexity of the association signals at this locus. We aim to examine the relationship between HDL-C associating variants at the  SCARB1  locus and the risk of CAD.   Methods and results:  We examined all sequence variants in the  SCARB1  locus identified through whole-genome sequencing of 8,453 Icelanders and subsequently imputed into a large population-based dataset for association with HDL-C (n= 136,672) and CAD (39,904 cases/306,338 controls). Apart from replicating association of two common HDL-C variants we identified the third common variant that independently associates with HDL-C (β= -1.25 mg/dL,  P =1.7x10 -18 ). In addition, we identified two rare missense variants, occurring in the large extracellular loop of the SR-BI protein, that associate with elevated levels of HDL-C (p.G319V: β=11.12 mg/dL,  P =8.0x10 -7  and p.V111M: β=8.25 mg/dL,  P =1.1x10 -6 ). None of the five independent variants that associate with HDL-C at the  SCARB1  locus associate with CAD. However, another intronic  SCARB1  variant, that correlated with markers previously shown to associate with Lp-PLA2 and vitamin E, associates with CAD (OR=1.08,  P =1.9x10 -8 ), but not with HDL-C.   Conclusion:  While rare and common HDL-C associating variants at the  SCARB1  locus do not associate with CAD, a different common variant at the same locus does. This suggests that the CAD associating locus variant mediates its effect through HDL-C independent mechanisms.
Abstract 13226: Shorter Left Ventricular Ejection Time is Associated With Adverse Outcomes in Heart Failure Patients With Reduced Ejection Fraction
Authors: Priyesh A Patel, Matthew Phelan, Michael MacKenzie, Karen Chiswell, Melissa K Van Dyke, Jennifer Tomfohr, Fawaz A Alenezi, Narimon Honarpour, Eric J Velazquez
Journal: Circulation (2016)

Introduction: Worsening heart failure (HF) is thought to be associated with shorter left ventricular ejection time (LVET), but there are limited data describing the relationship between LVET and outcomes. We report the largest study to date describing the association between LVET and outcomes in an ambulatory HF population. Methods: We identified HF patients without significant structural or congenital heart disease who had an outpatient transthoracic echocardiogram (TTE) performed between 8/2008-7/2010 at Duke University Medical Center. We excluded patients with paced or irregular rhythms. All TTE were re-analyzed in triplicate. Multivariable logistic regression was used to evaluate the association between LVET and 1 year outcomes among HF patients with reduced ejection fraction (HFrEF) and patients with preserved ejection fraction (HFpEF). Results: We identified 545 HF patients (171 HFrEF, 374 HFpEF) meeting inclusion criteria. HFrEF patients were younger (median age was 60 (Quartile 1 to Quartile (Q1-Q3) 50-69) vs. 64 (Q1-Q3 53-74), with smaller proportion of females (30.4 vs. 56.4%) and similar ratio of African Americans (35.7 vs. 35.0%). Median EF among patients with HFrEF was 30% (Q1-Q3 25-35%) and with HFpEF was 54% (Q1-Q3 48-58%). There were no statistical differences in medical histories or neurohormonal therapies. Median LVET was shorter (280 vs. 315ms, p&lt;0.001), median pre-ejection period was longer (114 vs. 89ms, p&lt;0.001), and median relaxation time was shorter (351 vs 411ms, p&lt;0.001) among patients with HFrEF versus HFpEF. Death or HF hospitalization occurred in 46/171 HFrEF patients and 44/374 HFpEF patients. After adjustment, longer LVET was associated with lower odds of the composite of 1 year death/1 year HF hospitalization among HFrEF patients, but not among HFpEF (Table). Conclusion: Longer LVET is independently associated with improved outcomes among HFrEF patients supporting a potential role for increasing LVET as a therapeutic target.
Sex-Specific Association of Apolipoprotein E With Cerebrospinal Fluid Levels of Tau
Authors: Timothy J. Hohman, Logan Dumitrescu, Lisa L. Barnes, Madhav Thambisetty, Gary Beecham, Brian Kunkle, Katherine A. Gifford, William S. Bush, Lori B. Chibnik, Shubhabrata Mukherjee, Philip L. De Jager, Walter Kukull, Paul K. Crane, Susan M. Resnick, C. Dirk Keene, Thomas J. Montine, Gerard D. Schellenberg, Jonathan L. Haines, Henrik Zetterberg, Kaj Blennow, Eric B. Larson, Sterling C. Johnson, Marilyn Albert, David A. Bennett, Julie A. Schneider, Angela L. Jefferson
Journal: JAMA Neurology (2018)

The strongest genetic risk factor for Alzheimer disease (AD), the apolipoprotein E (APOE) gene, has a stronger association among women compared with men. Yet limited work has evaluated the association between APOE alleles and markers of AD neuropathology in a sex-specific manner.
TCTAP C-013 Delivery System Stuck in the Coronary Artery Caused by the Stent Balloon Rupture
Authors: Kota Tanaka, Hiroyuki Nagai, Atsunori Okamura, Tomohiro Yamasaki, Akinori Sumiyoshi, Takamasa Tanaka, Kenshi Fujii
Journal: Journal of the American College of Cardiology (2018)
P126The administration of a CD31 agonist peptide exerts a beneficial effect in experimental heart failure with both reduced and preserved ejection fraction
Authors: V Syvannarath, S Delbosc, B Escoubet, M Le Borgne-Moynier, J Khallou-Laschet, M Morvan, G Even, C Journee, A Nicoletti, G Caligiuri
Journal: Cardiovascular Research (2018)
Brief Report: Whole‐Exome Sequencing to Identify Rare Variants and Gene Networks That Increase Susceptibility to Scleroderma in African Americans
Authors: Pravitt Gourh, Elaine F. Remmers, Steven E. Boyden, Theresa Alexander, Nadia D. Morgan, Ami A. Shah, Maureen D. Mayes, Ayo Doumatey, Amy R. Bentley, Daniel Shriner, Robyn T. Domsic, Thomas A. Medsger, Virginia D. Steen, Paula S. Ramos, Richard M. Silver, Benjamin Korman, John Varga, Elena Schiopu, Dinesh Khanna, Vivien Hsu, Jessica K. Gordon, Lesley Ann Saketkoo, Heather Gladue, Brynn Kron, Lindsey A. Criswell, Chris T. Derk, S. Louis Bridges, Victoria K. Shanmugam, Kathleen D. Kolstad, Lorinda Chung, Reem Jan, Elana J. Bernstein, Avram Goldberg, Marcin Trojanowski, Suzanne Kafaja, Kathleen M. Maksimowicz‐McKinnon, James C. Mullikin, Adebowale Adeyemo, Charles Rotimi, Francesco Boin, Daniel L. Kastner, Fredrick M. Wigley
Journal: Arthritis & Rheumatology (2018)

Objective Whole‐exome sequencing ( WES ) studies in systemic sclerosis ( SS c) patients of European American ( EA ) ancestry have identified variants in the ATP 8B4 gene and enrichment of variants in genes in the extracellular matrix ( ECM )–related pathway that increase SS c susceptibility. This study was undertaken to evaluate the association of the ATP 8B4 gene and the ECM ‐related pathway with SS c in a cohort of African American ( AA ) patients. Methods SS c patients of AA ancestry were enrolled from 23 academic centers across the US under the Genome Research in African American Scleroderma Patients consortium. Unrelated AA individuals without serologic evidence of autoimmunity who were enrolled in the Howard University Family Study were used as unaffected controls. Functional variants in genes reported in the 2 WES studies in EA patients with SS c were selected for gene association testing using the optimized sequence kernel association test ( SKAT ‐O) and pathway analysis by Ingenuity Pathway Analysis in 379 patients and 411 controls. Results Principal components analysis demonstrated that the patients and controls had similar ancestral backgrounds, with roughly equal proportions of mean European admixture. Using SKAT ‐O, we examined the association of individual genes that were previously reported in EA patients and none remained significant, including ATP 8B4 ( P = 0.98). However, we confirmed the previously reported association of the ECM ‐related pathway with enrichment of variants within the COL 13A1 , COL 18A1 , COL 22A1 , COL 4A3 , COL 4A4 , COL 5A2 , PROK 1 , and SERPINE 1 genes (corrected P = 1.95 × 10 −4 ). Conclusion In the largest genetic study in AA patients with SS c to date, our findings corroborate the role of functional variants that aggregate in a fibrotic pathway and increase SS c susceptibility.
Variables associated with persistence of elevated ALT after SVR in patients with chronic hepatitis C: Data from the German Hepatitis C-Registry (DHC-R)
Authors: S. Mauss, P. Buggisch, K. Boeker, H. Klinker, T. Müller, R. Guenther, J. Wiegand, M. Cornberg, C. Lange, T. Berg, S. Zeuzem, F. Tacke
Journal: Journal of Hepatology (2018)
Image Gallery: Folliculocystic and collagen hamartoma: a lesser-known presentation of tuberous sclerosis
Authors: A. Bishnoi, S. Tripathy, K. Vinay, D. De, D. Parsad, D. Chatterjee, U.N. Saikia
Journal: British Journal of Dermatology (2018)

Funding sources: none. Conflicts of interest: none declared. Dear Editor, An adolescent girl diagnosed with tuberous sclerosis (TSc) complex presented with a slowly progressive, ill‐defined, doughy, nontender plaque on her left flank, which was studded with comedonal plugs, circumscribed nodules and cysts (a, b). Histopathological examination revealed cysts lined with stratified squamous epithelium (c), which were surrounded by extensive collagenization extending up to the subcutaneous fat (d). A diagnosis of 'folliculocystic and collagen hamartoma' was made, which was in accordance with a previous study by Torrelo et al. that described similar lesions in patients having TSc.1 It is important to recognize this relatively new and rare entity as a part of TSc complex and to study the association further.
Aerobic exercise interventions reduce blood pressure in patients after stroke or transient ischaemic attack: a systematic review and meta-analysis
Authors: Cheng Wang, Jessica Redgrave, Mohsen Shafizadeh, Arshad Majid, Karen Kilner, Ali N Ali
Journal: British Journal of Sports Medicine (2018)

Objective Secondary vascular risk reduction is critical to preventing recurrent stroke. We aimed to evaluate the effect of exercise interventions on vascular risk factors and recurrent ischaemic events after stroke or transient ischaemic attack (TIA). Design Intervention systematic review and meta-analysis. Data sources OVID MEDLINE, PubMed, The Cochrane Library, Web of Science, The National Institute for Health and Care Excellence, TRIP Database, CINAHL, PsycINFO, SCOPUS, UK Clinical Trials Gateway and the China National Knowledge Infrastructure were searched from 1966 to October 2017. Eligibility criteria Randomised controlled trials evaluating aerobic or resistance exercise interventions on vascular risk factors and recurrent ischaemic events among patients with stroke or TIA, compared with control. Results Twenty studies (n=1031) were included. Exercise interventions resulted in significant reductions in systolic blood pressure (SBP) −4.30 mm Hg (95% CI −6.77 to −1.83) and diastolic blood pressure −2.58 mm Hg (95% CI −4.7 to −0.46) compared with control. Reduction in SBP was most pronounced among studies initiating exercise within 6 months of stroke or TIA (−8.46 mm Hg, 95% CI −12.18 to −4.75 vs −2.33 mm Hg, 95% CI −3.94 to −0.72), and in those incorporating an educational component (−7.81 mm Hg, 95% CI −14.34 to −1.28 vs −2.78 mm Hg, 95% CI −4.33 to −1.23). Exercise was also associated with reductions in total cholesterol (−0.27 mmol/L, 95% CI −0.54 to 0.00), but not fasting glucose or body mass index. One trial reported reductions in secondary vascular events with exercise, but was insufficiently powered. Summary Exercise interventions can result in clinically meaningful blood pressure reductions, particularly if initiated early and alongside education.
Recent update of the 2017 Korean Association for the Study of the Liver (KASL) treatment guidelines of chronic hepatitis C: Comparison of guidelines from other continents, 2017 AASLD/IDSA and 2016 EASL
Authors: Jong Eun Yeon
Journal: Clinical and Molecular Hepatology (2018)

The paradigm for the treatment of chronic hepatitis C (CHC) has been changed due to the development of direct acting antivirals (DAAs) of hepatitis C virus (HCV). The high sustained virologic response rate and ease of administration makes the DAAs approach ideal to contribute to the complete eradication of HCV. Currently, treatment options for individual patients vary depending on the genotype or subtype of HCV, presence or absence of liver cirrhosis, previous experience of antiviral treatment or resistance associated substitutions. Because of drug avalilability, cost-effectiveness, preference, compliance and greater possibility of desirable effects and presumed patient-important outcomes may vary between countries, treatment options for individual patients are different. The review focuses on the comparing the current treatment options for CHC in other continents with the 2017 Korea Association for the Study of the Liver guidelines. Keywords: Hepatitis C virus; Direct acting antiviral; Resistance associated substitutions; Genotype; Liver cirrhosis