tbuckley/cabot-search huggingface dataset:
Use paracetamol for most acute sore throats, says NICE
Authors: Zosia Kmietowicz
Journal: BMJ (2018)

Doctors should not prescribe antibiotics for most cases of acute sore throat, including pharyngitis and tonsillitis, says guidance from the National Institute for Health and Care Excellence.1

The guidance, which has been produced together with Public Health England, quotes research from 2014 which found that 60% of patients who attend general practice with a sore throat walk …
Abstract 13411: Outcomes Associated With Warfarin Time in Therapeutic Range among Veterans With Nonvalvular Atrial Fibrillation in the US, 2005-2015
Authors: Shuqian Liu, Xiaoyan Li, Qian Shi, Melissa Hamilton, Keith Friend, Yingnan Zhao, Ruslan Horblyuk, Shalini Hede, Lizheng Shi
Journal: Circulation (2016)

Introduction: This study evaluated the relationship between quality of warfarin control and clinical outcomes among US veterans with nonvalvular atrial fibrillation (NVAF). Hypothesis: Poor quality of warfarin control (time in therapeutic range (TTR) &lt;65%) is associated with reduced effectiveness and safety. Methods: Using the US Veterans Affairs electronic medical records database, patients with NVAF who newly initiated warfarin from 1/1/2005-12/31/2015 were grouped into two cohorts based on TTR &lt;65% or ≥65%. TTR was computed from international normalized ratio test results comprehensively recorded in the database. Clinical outcomes assessed in the study were stroke/systemic embolism (SE), hemorrhagic stroke, ischemic stroke, and major bleeding, defined based on hospitalization with those conditions as primary diagnosis, as well as all-cause mortality. Patients were followed from warfarin initiation to the first occurrence of an outcome or censoring. For each outcome, unadjusted and adjusted hazard ratios (HR and aHR) between two cohorts were estimated, with the latter from propensity score weighting-adjusted time-varying Cox proportional hazard regression stratified by CHA 2 DS 2 -VAS C score (≥2 or not), controlling for setting of warfarin initiation, baseline patient demographic and clinical characteristics, and use of co-medications. Results: A total of 127,385 patients with NVAF (mean age (SD): 71.3 (9.8) years, 99% male) with a median of 1.4 follow-up years (IQR: 3.3) were included. Mean TTR was 51%. TTR&lt;65% was observed in 65% of patients. Mean CHA 2 DS 2 -VAS C score (SD) was 2.9 (1.5) in low TTR cohort and 2.7 (1.4) in high TTR cohort. Low TTR cohort (with mean TTR as 38%) had significantly higher risk for assessed outcomes compared with high TTR cohort (with mean TTR as 77%) (Table). Conclusions: In the study, the observed quality of warfarin control among US veterans with NVAF was suboptimal and associated with elevated risk of adverse clinical outcomes.
Vigilance-Associated Gamma Oscillations Coordinate the Ensemble Activity of Basolateral Amygdala Neurons
Authors: Alon Amir, Drew B. Headley, Seung-Chan Lee, Darrell Haufler, Denis Paré
Journal: Neuron (2018)

Principal basolateral amygdala (BL) neurons profoundly influence motivated behaviors, yet few of them are activated by emotionally valenced stimuli. Here, we show that a likely explanation for this paradox is the synchronizing influence of the high-gamma rhythm. High-gamma (75–95 Hz) entrained BL firing more strongly than all other rhythms. It was most pronounced during states of increased vigilance, when rats were apprehensive. Relative to behavioral states, high-gamma produced minor changes in firing rates yet dramatic increases in synchrony. Moreover, connected pairs of cells showed similarly high levels of entrainment and synchronization. Unexpectedly, prefrontal- and accumbens-projecting cells, respectively, showed high and low entrainment by high-gamma, indicating that this rhythm differentially synchronizes the activity of BL neurons projecting to specific sites. Overall, our findings suggest that individual BL neurons encode information not only by changing their firing rates, but also by synchronizing their collective activity, amplifying their impact on target structures.
Functional activity of maternal and cord antibodies elicited by an investigational group B Streptococcus trivalent glycoconjugate vaccine in pregnant women
Authors: Monica Fabbrini, Fabio Rigat, Giovanna Tuscano, Emiliano Chiarot, Gilbert Donders, Roland Devlieger, Sara Filippini, Elisabetta Frigimelica, Pietro Forte, Frederick Wittke, Scott A. Halperin, Karen Slobod, Guido Grandi, Immaculada Margarit
Journal: Journal of Infection (2018)
Abstract 13093: The Inducible Nuclear Protein IκBζ Plays a Pivotal Role in the Transition From Adaptive to Maladaptive Cardiac Hypertrophy During Pressure Overload
Authors: Yasutomi Higashikuni, Daiju Fukuda, Masataka Sata, Issei Komuro
Journal: Circulation (2014)

Background: Inflammation has been implicated in the pathophysiology of both adaptive and maladaptive cardiac hypertrophy in response to pressure overload. However, it remains unclear how chronic inflammation contributes to the transition from adaptive to maladaptive cardiac hypertrophy. Interleukin-1β (IL-1β) has been shown to induce Akt phosphorylation, which plays an important role in cardiac adaptive response to pressure overload, whereas chronic IL-6 signaling has been reported to inhibit Akt phosphorylation through induction of suppressor of cytokine signaling (SOCS) 3. IκBζ, encoded by the NFKBIZ gene, is an inducible nuclear protein which regulates the transition from IL-1β expression to IL-6 expression in the NF-κB system. This study was performed to clarify the role of IκBζ in pressure overload-induced cardiac hypertrophy. Methods and Results: Pressure overload was induced in Nfkbiz +/+ and Nfkbiz +/- mice by transverse aortic constriction (TAC). In Nfkbiz +/+ mice, TAC-operated hearts showed adaptive cardiac hypertrophy until 2 weeks after the operation, whereas at 4 weeks after TAC, impaired systolic function with left ventricular dilatation was observed (n=10). TAC-operated Nfkbiz +/- hearts showed similar adaptive cardiac hypertrophy to TAC-operated Nfkbiz +/+ hearts until 2 weeks after the operation (n=10). However, at 4 weeks after TAC, Nfkbiz +/- hearts showed preserved systolic function with attenuated LV dilatation compared with Nfkbiz +/+ hearts. Real time PCR revealed that IL-1β mRNA expression levels were higher in Nfkbiz +/- hearts than in Nfkbiz +/+ hearts at 4 weeks after TAC (n=5), whereas mRNA expression levels of IL-6 and SOCS3 were higher in Nfkbiz +/+ hearts that in Nfkbiz +/- hearts. Western blot analysis demonstrated that Akt phosphorylation levels were higher in Nfkbiz +/- hearts that in Nfkbiz +/+ hearts at 4 weeks after TAC. Conclusions: Our results suggest that IκBζ plays a pivotal role in the transition from adaptive to maladaptive cardiac hypertrophy during pressure overload, possibly in part, through the regulation of proinflammatory cytokine expression pattern in the heart tissue, which may regulate Akt phosphorylation levels. Thus, IκBζ may be a novel therapeutic target for treating heart failure.
Abstract 19058: STEMI Patients Presenting to Non PCI Capable Hospitals in New York State: Treatment Strategies and 30-Day Mortality
Authors: Alice K Jacobs, Peter Berger, Gary D Walford, Yifeng Wu, Edward L Hannan
Journal: Circulation (2016)

Background: Most of what is known about patients (pts) with STEMI is derived from the minority of hospitals voluntary reporting in national registries, primarily those undergoing PCI. Less is known...
Targeting the Senescence-Overriding Cooperative Activity of Structurally Unrelated H3K9 Demethylases in Melanoma
Authors: Yong Yu, Kolja Schleich, Bin Yue, Sujuan Ji, Philipp Lohneis, Kristel Kemper, Mark R. Silvis, Nouar Qutob, Ellen van Rooijen, Melanie Werner-Klein, Lianjie Li, Dhriti Dhawan, Svenja Meierjohann, Maurice Reimann, Abdel Elkahloun, Steffi Treitschke, Bernd Dörken, Christian Speck, Frédérick A. Mallette, Leonard I. Zon, Sheri L. Holmen, Daniel S. Peeper, Yardena Samuels, Clemens A. Schmitt, Soyoung Lee
Journal: Cancer Cell (2018)
Chemotherapy (CT) of solid tumors and reactivation of latent viral infections (VI).
Authors: Tatyana A. Zykova, Liubov Yu Vladimirova, Natalya A Abramova, Irina L Popova, Natalya Mikhailovna Tikhanovskaya, Ludmila A. Ryadinskaya
Journal: Journal of Clinical Oncology (2016)

e14002 Background: Clinical manifestations of herpesvirus infections are often non-specific and is a problem to differentiate it from the reactions to CT. The study was performed to analyze immunological markers of infections induced by HSV 1.2, CMV, EBV, HHV6 and HHV8 activation of during the CT of solid tumors. Methods: The patients who was received CT for histologically verified metastatic solid tumors was recruited in the study. Blood samples were collected before and after CT. Antibodies to viral proteins were determined by ELISA: IgM and IgG to HSV1.2, CMV, EBV, HHV6, HHV8. Results: 29 patients were recruited: with colorectal cancer (CRC) - 27.6%(8), breast cancer (BC) - 24.1%(7), laryngeal cancer (LC) - 34.5%(10), other tumors -13.8% (4). All patients received CT, 51.7% (15) – combined with targeted therapy. CT-induced eosinophilia was in 13.8%(4) pts, lymphocytosis - 6.8%(2), leukopenia 2Gr - 17.2%(5). 13.8%(4) pts had subfebrile temperature. Study of paired sera demonstrated markers of active VI in 58.6%(17) of patients after CT. Reactivation of latent HSV 1.2 was found in 17.2%(5), CMV in 17.2%(5), EBV in 31.0%(9), HHV6 in 27.6%(8). Concurrent reactivation of several VI was registered in 31.0 (9)%. CT-induced reactivation of VI was most frequent in BC - 85.7%(6) than in CRC - 50.0%(4) and LC - 40.0%(4), p < 0.05. Pts with BC had reactivation of HHV6 in 57.1%, with CRC - HSV1.2 (37.5%) and HHV6 (37.5%), with LC - HSV1.2(30.0%). 12 pts (41.4%) had markers of active VI but their clinical manifestations were not observed. HSV1.2-induced viral infection was the most frequent. Conclusions: Results of the study demonstrate the significance of CT in the reactivation of latent VI. The full range of markers for the timely identification of reactivation of herpes viruses and administration of adequate antiviral therapy is necessary to use during the CT of solid tumors.
STAT3-enhancing germline mutations contribute to tumor-extrinsic immune evasion
Authors: Daniel Kogan, Alexander Grabner, Christopher Yanucil, Christian Faul, Vijay Kumar Ulaganathan
Journal: Journal of Clinical Investigation (2018)

Immune evasion and the suppression of antitumor responses during cancer progression are considered hallmarks of cancer and are typically attributed to tumor-derived factors. Although the molecular basis for the crosstalk between tumor and immune cells is an area of active investigation, whether host-specific germline variants can dictate immunosuppressive mechanisms has remained a challenge to address. A commonly occurring germline mutation (c.1162G>A/rs351855 G/A) in the FGFR4 (CD334) gene enhances signal transducer and activator of transcription 3 (STAT3) signaling and is associated with poor prognosis and accelerated progression of multiple cancer types. Here, using rs351855 SNP-knockin transgenic mice and Fgfr4-knockout mice, we reveal the genotype-specific gain of immunological function of suppressing the CD8/CD4+FOXP3+CD25+ regulatory T cell ratio in vivo. Furthermore, using knockin transgenic mouse models for lung and breast cancers, we establish the host-specific, tumor-extrinsic functions of STAT3-enhancing germline variants in impeding the tumor infiltration of CD8 T cells. Thus, STAT3-enhancing germline receptor variants contribute to immune evasion through their pleiotropic functions in immune cells.
DNA methylation mapping identifies gene regulatory effects in patients with systemic lupus erythematosus
Authors: Juliana Imgenberg-Kreuz, Jonas Carlsson Almlöf, Dag Leonard, Andrei Alexsson, Gunnel Nordmark, Maija-Leena Eloranta, Solbritt Rantapää-Dahlqvist, Anders A Bengtsson, Andreas Jönsen, Leonid Padyukov, Iva Gunnarsson, Elisabet Svenungsson, Christopher Sjöwall, Lars Rönnblom, Ann-Christine Syvänen, Johanna K Sandling
Journal: Annals of the Rheumatic Diseases (2018)

Objectives Systemic lupus erythematosus (SLE) is a chronic autoimmune condition with heterogeneous presentation and complex aetiology where DNA methylation changes are emerging as a contributing factor. In order to discover novel epigenetic associations and investigate their relationship to genetic risk for SLE, we analysed DNA methylation profiles in a large collection of patients with SLE and healthy individuals. Methods DNA extracted from blood from 548 patients with SLE and 587 healthy controls were analysed on the Illumina HumanMethylation 450 k BeadChip, which targets 485 000 CpG sites across the genome. Single nucleotide polymorphism (SNP) genotype data for 196 524 SNPs on the Illumina ImmunoChip from the same individuals were utilised for methylation quantitative trait loci ( cis -meQTLs) analyses. Results We identified and replicated differentially methylated CpGs (DMCs) in SLE at 7245 CpG sites in the genome. The largest methylation differences were observed at type I interferon-regulated genes which exhibited decreased methylation in SLE. We mapped cis -meQTLs and identified genetic regulation of methylation levels at 466 of the DMCs in SLE. The meQTLs for DMCs in SLE were enriched for genetic association to SLE, and included seven SLE genome-wide association study (GWAS) loci: PTPRC (CD45), MHC-class III , UHRF1BP1 , IRF5 , IRF7 , IKZF3 and UBE2L3 . In addition, we observed association between genotype and variance of methylation at 20 DMCs in SLE, including at the HLA-DQB2 locus. Conclusions Our results suggest that several of the genetic risk variants for SLE may exert their influence on the phenotype through alteration of DNA methylation levels at regulatory regions of target genes.
Integrated molecular profiling of juvenile myelomonocytic leukemia
Authors: Norihiro Murakami, Yusuke Okuno, Kenichi Yoshida, Yuichi Shiraishi, Genta Nagae, Kyogo Suzuki, Atsushi Narita, Hirotoshi Sakaguchi, Nozomu Kawashima, Xinan Wang, Yinyan Xu, Kenichi Chiba, Hiroko Tanaka, Asahito Hama, Masashi Sanada, Masafumi Ito, Masashi Hirayama, Arata Watanabe, Toshihide Ueno, Seiji Kojima, Hiroyuki Aburatani, Hiroyuki Mano, Satoru Miyano, Seishi Ogawa, Yoshiyuki Takahashi, Hideki Muramatsu
Journal: Blood (2018)
Single Intramuscular Injection of AAV-shRNA Reduces DNM2 and Prevents Myotubular Myopathy in Mice
Authors: Hichem Tasfaout, Valentina M. Lionello, Christine Kretz, Pascale Koebel, Nadia Messaddeq, Deborah Bitz, Jocelyn Laporte, Belinda S. Cowling
Journal: Molecular Therapy (2018)

Myotubular myopathy, or X-linked centronuclear myopathy, is a severe muscle disorder representing a significant burden for patients and their families. It is clinically characterized by neonatal and severe muscle weakness and atrophy. Mutations in the myotubularin (MTM1) gene cause myotubular myopathy, and no specific curative treatment is available. We previously found that dynamin 2 (DNM2) is upregulated in both Mtm1 knockout and patient muscle samples, whereas its reduction through antisense oligonucleotides rescues the clinical and histopathological features of this myopathy in mice. Here, we propose a novel approach targeting Dnm2 mRNA. We screened and validated in vitro and in vivo several short hairpin RNA (shRNA) sequences that efficiently target Dnm2 mRNA. A single intramuscular injection of AAV-shDnm2 resulted in long-term reduction of DNM2 protein level and restored muscle force, mass, histology, and myofiber ultrastructure and prevented molecular defects linked to the disease. Our results demonstrate a robust DNM2 knockdown and provide an alternative strategy based on reduction of DNM2 to treat myotubular myopathy. Myotubular myopathy, or X-linked centronuclear myopathy, is a severe muscle disorder representing a significant burden for patients and their families. It is clinically characterized by neonatal and severe muscle weakness and atrophy. Mutations in the myotubularin (MTM1) gene cause myotubular myopathy, and no specific curative treatment is available. We previously found that dynamin 2 (DNM2) is upregulated in both Mtm1 knockout and patient muscle samples, whereas its reduction through antisense oligonucleotides rescues the clinical and histopathological features of this myopathy in mice. Here, we propose a novel approach targeting Dnm2 mRNA. We screened and validated in vitro and in vivo several short hairpin RNA (shRNA) sequences that efficiently target Dnm2 mRNA. A single intramuscular injection of AAV-shDnm2 resulted in long-term reduction of DNM2 protein level and restored muscle force, mass, histology, and myofiber ultrastructure and prevented molecular defects linked to the disease. Our results demonstrate a robust DNM2 knockdown and provide an alternative strategy based on reduction of DNM2 to treat myotubular myopathy.
Under-dilated TIPS Associate With Efficacy and Reduced Encephalopathy in a Prospective, Non-randomized Study of Patients With Cirrhosis
Authors: Filippo Schepis, Francesco Vizzutti, Guadalupe Garcia-Tsao, Guido Marzocchi, Luigi Rega, Nicola De Maria, Tommaso Di Maira, Stefano Gitto, Cristian Caporali, Stefano Colopi, Mario De Santis, Umberto Arena, Antonio Rampoldi, Aldo Airoldi, Alessandro Cannavale, Fabrizio Fanelli, Cristina Mosconi, Matteo Renzulli, Roberto Agazzi, Roberto Nani, Pietro Quaretti, Ilaria Fiorina, Lorenzo Moramarco, Roberto Miraglia, Angelo Luca, Raffaele Bruno, Stefano Fagiuoli, Rita Golfieri, Pietro Torricelli, Fabrizio Di Benedetto, Luca Saverio Belli, Federico Banchelli, Giacomo Laffi, Fabio Marra, Erica Villa
Journal: Clinical Gastroenterology and Hepatology (2018)
Dynamic lumen obstructing angulation in advanced sigmoid-type achalasia successfully treated by additional proximal curve myotomy
Authors: Stefan Seewald, Tiing Ang, Michael Patak, Karl Yu Kim Teng, Haruhiro Inoue
Journal: Endoscopy (2018)

Peroral endoscopy myotomy (POEM) is now well accepted as primary treatment for achalasia [1] [2] [3]. It is also effective after failed Heller myotomy [4] and can be repeated when symptoms recur [5].
PABA-NO, a nitric oxide releasing prodrug, is a potent inducer of protein glutathionylation
Authors: Danyelle M. Townsend, Farit Fazliyev, Victoria J. Findlay, Joseph E. Saavedra, Larry K. Keefer, Kenneth D. Tew
Journal: Cancer Research (2004)

5316  Glutathionylation is emerging as an important post-translational modification that has been shown to alter the function and stability of a variety of proteins. Glutathionylation occurs through disulfide bond formation between glutathione (GSH) and available cysteine residues. In response to oxidative and nitrative stress, such modifications can alter the characteristics of a spectrum of proteins. PABA-NO is novel prodrug that liberates nitric oxide (NO) following glutathione S-transferase (GST) activation. We have shown that PABA-NO has selective activity in tumor cells expressing GST and potent in vivo efficacy in ovarian cancer xenografts. The mechanism by which PABA-NO elicits the cytotoxic effects is not understood. We do know, however, that once NO is released it can combine with GSH to form GSNO, a potent stimulator of protein glutathionylation that can lead to activation of death response pathways. To evaluate the biological impact of protein modification via PABA-NO, we have utilized monoclonal antibodies directed against glutathionylated cysteine residues. One and two dimensional gel analysis confirms that treatment of NIH3T3 and HL60 cells with PABA-NO results in a time and dose-dependent glutathionylation of greater than 50 proteins within 5 minutes. The toxicity of PABA-NO is decreased in NIH3T3 cells overexpressing MRP1 (3T3-MRP1) and HL60 cells made resistant to adriamycin (HL60-ADR). HL60-ADR cells overexpress MRP1. A significant dose and time dependent delay in glutathionylation occurs in these cells. We propose that MRP1 facilitates the efflux of a metabolite of PABA-NO that leads to glutathionylation and ultimately cytotoxicity. Using purified recombinant JNK, we show that PABA-NO induces glutathionylation of JNK in vitro. Through peptide digestion and mass spectral analysis, we are analyzing the residues in JNK that are modified by PABA-NO treatment.
Ezh2 and Runx1 Mutations Collaborate to Initiate Lympho-Myeloid Leukemia in Early Thymic Progenitors
Authors: Christopher A.G. Booth, Nikolaos Barkas, Wen Hao Neo, Hanane Boukarabila, Elizabeth J. Soilleux, George Giotopoulos, Noushin Farnoud, Alice Giustacchini, Neil Ashley, Joana Carrelha, Lauren Jamieson, Deborah Atkinson, Tiphaine Bouriez-Jones, Rab K. Prinjha, Thomas A. Milne, David T. Teachey, Elli Papaemmanuil, Brian J.P. Huntly, Sten Eirik W. Jacobsen, Adam J. Mead
Journal: Cancer Cell (2018)
Abstract 14828: Comparison of Expression Profiling of the Vascular Endothelium in Patients With Heart Failure and in Healthy Subjects Using a Novel Methodology: Human Endothelial Sampling Coupled With Microarray Analysis
Authors: Paolo C Colombo, Duygu Onat, Ante Harxhi, Yacki Hayashi, Ka Yuk Wong, Panos Papapanou, Nir Uriel, Ulrich P Jorde, Ryan T Demmer
Journal: Circulation (2013)

Background:  In heart failure (HF), veins are chronically exposed to higher levels of endovascular pressure and of circulating pro-inflammatory mediators, which might contribute to a modified endothelial cell (EC) phenotype. We studied gene expression signatures in venous ECs collected from HF patients and compared to those from healthy subjects to gain insights into the pathobiology of the venous endothelium in HF patients.   Methods:  29 symptomatic (NYHA Class II-III) out-patients with compensated HF (28% female, aged 50±12 years) and 16 healthy subjects (31% female, aged 38±9 years) were studied. ECs were collected from arm veins using endovascular wires. Magnetic beads coated with EC specific antibodies were used for EC separation; amplified mRNA was analyzed by Affymetrix HG-U133 Plus 2.0 Microarray. mRNA data were normalized and differential gene expression between HF patients and controls was studied using generalized linear regression models. A false discovery rate (FDR) of 5% was used to determine statistical significance. Signaling Pathway Impact Analysis (SPIA) identified possible biological pathways impacted in the vascular endothelium of HF patients.   Results:  No adverse events were observed. Peripheral venous pressure in HF patients was 8±3mmHg vs. 5±2 mmHg in healthy subjects (p   Conclusion:  We provide the first comparison of venous EC gene expression between HF patients and healthy controls. A large number of genes and signaling pathways of possible relevance to HF were differentially expressed among HF patents. These data can help generate novel insights into the pathobiology of endothelial dysfunction in HF by identifying yet unrecognized biologic pathways for more focused study.
Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons
Authors: Yingxiao Shi, Shaoyu Lin, Kim A Staats, Yichen Li, Wen-Hsuan Chang, Shu-Ting Hung, Eric Hendricks, Gabriel R Linares, Yaoming Wang, Esther Y Son, Xinmei Wen, Kassandra Kisler, Brent Wilkinson, Louise Menendez, Tohru Sugawara, Phillip Woolwine, Mickey Huang, Michael J Cowan, Brandon Ge, Nicole Koutsodendris, Kaitlin P Sandor, Jacob Komberg, Vamshidhar R Vangoor, Ketharini Senthilkumar, Valerie Hennes, Carina Seah, Amy R Nelson, Tze-Yuan Cheng, Shih-Jong J Lee, Paul R August, Jason A Chen, Nicholas Wisniewski, Victor Hanson-Smith, T Grant Belgard, Alice Zhang, Marcelo Coba, Chris Grunseich, Michael E Ward, Leonard H van den Berg, R Jeroen Pasterkamp, Davide Trotti, Berislav V Zlokovic, Justin K Ichida
Journal: Nature Medicine (2018)