tbuckley/cabot-search huggingface dataset:
Abstract 411: Discovery and Cardioprotective Effects of the First Non-peptide Agonists of Prokineticin Receptor-1
Authors: Canan G Nebigil, Adeline Gasser, Simone Brogi, Andrea Tafi, Hitoshi Kurose, Laurent Désaubry
Journal: Circulation Research (2015)

Prokineticins are angiogenic hormones that activate two G protein-coupled receptors: PKR1 and PKR2. PKR1 has emerged as a critical mediator of cardiovascular homeostasis and cardioprotection. Identification of non-peptide PKR1 agonists that contribute to myocardial repair and collateral vessel growth hold promises for treatment of heart diseases. Through a combination of in silico studies, medicinal chemistry, and pharmacological profiling approaches, we designed, synthesized, and characterized the first PKR1 agonists, demonstrating their cardioprotective activity against myocardial infarction (MI) in mice. Based on high throughput docking protocol, 250,000 compounds were computationally screened for putative PKR1 agonistic activity, using a homology model, and 10 virtual hits were pharmacologically evaluated. One hit internalizes PKR1, increases calcium release and activates ERK and Akt kinases. Among the 30 derivatives of the hit compound, the most potent derivative, IS20, was confirmed for its selectivity and specificity through genetic gain- and loss-of-function of PKR1. Importantly, IS20 prevented cardiac lesion formation and improved cardiac function after MI in mice, promoting proliferation of cardiac progenitor cells and neovasculogenesis. The preclinical investigation of the first PKR1 agonists provides a novel approach to promote cardiac neovasculogenesis after MI.
Sarcopenia in hiding: The risk and consequence of underestimating muscle dysfunction in nonalcoholic steatohepatitis
Authors: Rahima A. Bhanji, Praveena Narayanan, Alina M. Allen, Harmeet Malhi, Kymberly D. Watt
Journal: Hepatology (2017)

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Up to one third of individuals with NAFLD will develop nonalcoholic steatohepatitis (NASH), which is associated with progression to cirrhosis and is rapidly becoming the leading indication for liver transplantation. Sarcopenia is defined as a progressive and generalized loss of skeletal muscle mass, strength, and function. It is observed in up to 60% of patients with end‐stage liver disease and portends a poor prognosis. Recent studies have shown that sarcopenia is a novel risk factor for developing NAFLD. Pathophysiological mechanisms relating sarcopenia and NASH may include insulin resistance (IR) and increased inflammation. IR leads to accumulation of triglycerides in both muscle tissue and the liver. It also exacerbates proteolysis and leads to muscle depletion. Chronic inflammation leads to liver injury and progression of fibrosis. The inflammatory milieu also stimulates protein catabolism. Viewing skeletal muscle as an endocrine organ that secretes various salutary myokines may help us understand its role in the development of steatosis. A better understanding of the pathophysiology will aid in developing physical and pharmacological therapeutic interventions. In this review, we will explore the complex inter‐relationships between sarcopenia and NASH. We will discuss the impact of sarcopenia in patients with NASH and therapeutic options for the management of sarcopenia. (H epatology 2017;66:2055–2065)
ULTRASONOGRAPHIC CHANGES OF UPPER EXTREMITY TENDONS IN RECREATIONAL BADMINTON PLAYERS: THE EFFECT OF HAND DOMINANCE AND COMPARISON WITH CLINICAL FINDINGS
Authors: Jin Park, Young-Hee Lee, In Deok Kong, Tae-jun Park, Jae Seung Chang, Taeho Kim, Hi Chan Lee
Journal: British Journal of Sports Medicine (2017)

Background Shoulder and elbow injuries have been reported to constitute a sizeable percentage of injuries in overhead sports, including badminton. Since badminton requires repetitive, high-speed overhead motions putting high loads on the upper extremity joints, the badminton players frequently complain of pain and decreased function of shoulders and elbows. Objective The study evaluated the ultrasound abnormalities of selected shoulder and elbow tendons in recreational badminton players and investigated their correlation with hand dominance and clinical symptoms. Design This pilot study was designed as a cross-sectional research. Setting &amp; Participants Forty-nine badminton players participating in recreational badminton clubs were invited to Wonju Sports Training Center from March to June 2016. Interventions (or Assessment of Risk Factors) The subjects underwent clinical and US examinations, both in dominant and non-dominant arms. The ultrasound assessments were performed by two residents of rehabilitation medicine. Main Outcome Measurements This study evaluated any correlation between the presence of US abnormalities of supraspinatus, long head of biceps, ECRB and hand dominance as well as clinical symptoms. Results Among 26 players with shoulder/elbow lesions in ultrasound, 8 (31%) players were asymptomatic while 18 (69%) players had pain in dominant arm. The relationship between the presence of shoulder/elbow lesions and current pain showed no significance (p=0.255, 0.91, 0.9). Supraspinatus partial tear/calcifications were observed in 8 dominant vs 1 non-dominant shoulders (odds ratio=2.462, p=0.628), long head of biceps partial tears/calcifications in 3 dominant vs 1 non-dominant shoulders (odds ratio=0.667, p=0.6), and lateral epicondyle fluid collection/partial tears in 10 dominant vs 3 non-dominant elbows (odds ratio=0.606, p=0.5). Conclusions Although ultrasound abnormalities involving supraspinatus, biceps, lateral epicondyle showed an overall tendency of higher prevalence in the dominant arm, the result did not show significant differences according to hand dominance or clinical symptoms. Further studies with larger number of subjects are needed in the future.
The actin-binding protein profilin 2 is a novel regulator of iron homeostasis
Authors: Sara Luscieti, Bruno Galy, Lucia Gutierrez, Michael Reinke, Jorge Couso, Maya Shvartsman, Antonio Di Pascale, Walter Witke, Matthias W. Hentze, Pietro Pilo Boyl, Mayka Sanchez
Journal: Blood (2017)
Abstract 266: Novel Sites of Angiotension II Type 1 Receptor are Identified for Direct Activation by Mechanical Stretch Independent of Angiotension II
Authors: Hui Gong, Guoliang Jiang, Chunjie Yang, Shijun Wang, Zhidan Chen, Guoping Zhang, Yunzeng Zou
Journal: Circulation Research (2014)

The angiotensin II type 1 receptor (AT1R) has a crucial role in cardiac hypertrophy induced by pressure overload. In the previous study, we found a novel mechanism for mechanical stress-induced AT1R activation without the involvement of Ang II. However, few reports focus on how AT1R senses mechanical stress and translates it into biochemical signals inside the cells to induce cardiomyocyte hypertrophy. Here, we constructed different site-directed mutagenesis of AT1R and transfected them to COS7 cells and ATG–/– (Angiotensinogen knockout) cardiomyocytes, respectively, to observe the activation of downstream signaling to identify functional site of AT1R. The results showed AT1R-WT, AT1R-K199Q, AT1R-L212F,AT1R-Q257A and AT1R-C289A plasmids or adenovirus were overexpressed at high level in plasma membrane of COS7 or cardiomyocytes respectively. There was no obvious difference in subcellular expression of wt-AT1R and all the mut-AT1Rs. The further study revealed that Ang II-induced-phosphorylation of ERK, Jak2 and the redistribution of Gαq11 were dramatically decreased in COS7 cells expressing AT1R-K199Q or AT1R-Q257A, while these effects induced by mechanical stretch were greatly suppressed in COS7 cells expressing AT1R-L212F,AT1R-Q257A or AT1R-C289A compared to these in COS7 cells expressing AT1R-WT. We then transfected the adenovirus of wt-AT1R or different mut-AT1Rs to ATG–/– cardiomyocytes to exclude the influence of endogenous Ang II. The results were consistent with these results in COS7 cells. Moreover, ATG–/– cardiomyocytes overexpressing AT1R-K199Q or AT1R-Q257A parlty abolished hypertrophic response induce by Ang II, while the cardiomyocytes overexpressing AT1R-L212F,AT1R-Q257A or AT1R-C289A greatly inhibited the hypertrophic response induced by mechanical stretch. The present study indicated that Leu212, Gln257 and Cys289 are critical sites for AT1R activation by mechanical stretch without Ang II but Lys199 and Gln257 play important role in AT1R activation with Ang II.
Development and Mechanism of Small Activating RNA Targeting CEBPA, a Novel Therapeutic in Clinical Trials for Liver Cancer
Authors: Jon Voutila, Vikash Reebye, Thomas C. Roberts, Pantelitsa Protopapa, Pinelopi Andrikakou, David C. Blakey, Robert Habib, Hans Huber, Pal Saetrom, John J. Rossi, Nagy A. Habib
Journal: Molecular Therapy (2017)

Small activating RNAs (saRNAs) are short double-stranded oligonucleotides that selectively increase gene transcription. Here, we describe the development of an saRNA that upregulates the transcription factor CCATT/enhancer binding protein alpha (CEBPA), investigate its mode of action, and describe its development into a clinical candidate. A bioinformatically directed nucleotide walk around the CEBPA gene identified an saRNA sequence that upregulates CEBPA mRNA 2.5-fold in human hepatocellular carcinoma cells. A nuclear run-on assay confirmed that this upregulation is a transcriptionally driven process. Mechanistic experiments demonstrate that Argonaute-2 (Ago2) is required for saRNA activity, with the guide strand of the saRNA shown to be associated with Ago2 and localized at the CEBPA genomic locus using RNA chromatin immunoprecipitation (ChIP) assays. The data support a sequence-specific on-target saRNA activity that leads to enhanced CEBPA mRNA transcription. Chemical modifications were introduced in the saRNA duplex to prevent activation of the innate immunity. This modified saRNA retains activation of CEBPA mRNA and downstream targets and inhibits growth of liver cancer cell lines in vitro. This novel drug has been encapsulated in a liposomal formulation for liver delivery, is currently in a phase I clinical trial for patients with liver cancer, and represents the first human study of an saRNA therapeutic.
Mueller Maneuver Stress Echocardiography for Evaluation of Exercise Capacity in Healthy Subjects and Patients with Nonischemic Cardiomyopathy
Authors: Onoue Takeshi, Fukuda Shota, Hayashi Atsushi, Kado Yuichiro, Nagata Yasufumi, Otani Kyoko, Takeuchi Masaaki, Otsuji Yutaka
Journal: Circulation (2016)
Immediate, Complete, and Sustained Inhibition of C5 with ALXN1210 Reduces Complement-Mediated Hemolysis in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH): Interim Analysis of a Dose-Escalation Study
Authors: Jong-Wook Lee, Eric Scott Bachman, Rasha Aguzzi, Jun Ho Jang, Jin Seok Kim, Scott T. Rottinghaus, Lori Shafner, Jeff Szer
Journal: Blood (2016)
Household survey of HIV incidence in Rwanda: a national observational cohort study
Authors: Sabin Nsanzimana, Eric Remera, Steve Kanters, Augustin Mulindabigwi, Amitabh B Suthar, Jean Paul Uwizihiwe, Mutagoma Mwumvaneza, Edward J Mills, Heiner C Bucher
Journal: The Lancet HIV (2017)
Private hospital launches legal challenge against NHS trust that employed rogue breast surgeon
Authors: Tom Moberly
Journal: BMJ (2017)

A private hospital company where the rogue surgeon Ian Paterson worked has launched a legal challenge against an NHS trust to determine whether the trust’s duty of care covered the surgeon’s private practice.

A trial is due to start in the High Court on 30 October 2017 to determine whether the Heart of England NHS Foundation Trust had a legal duty of care that extended to Paterson’s non-NHS patients. The case is being brought by Spire Healthcare, where Paterson conducted much of his private practice.

A spokeswoman for the trust …
ポリエチレンイミングラフト化酸化メソ多孔質炭素ナノスフェアにより達成された光熱併用遺伝子治療【Powered by NICT】
Authors: Meng Ying, Wang Shanshan, Li Chengyi, Qian Min, Yan Xueying, Yao Shuangchao, Peng Xiyue, Wang Yi, Huang Rongqin
Journal: Biomaterials (2016)
Audit de la pratique de la Gastrostomie Percutanée Endoscopique (GPE) dans un Service d’Hépato-gastro-entérologie de CHU
Authors: M Le Rhun, F Noly, E Coron, A Biron, D Darmaun, S Bruley des Varannes, JP Galmiche
Journal: Endoscopy (2004)

Introduction: La gastrostomie percutanée endoscopique (GPE) permet de maintenir une alimentation entérale en cas de trouble prolongé de la déglutition. Les grandes séries de patients ainsi traités sont peu nombreuses. Le but de cette étude était de déterminer le suivi et les complications de ce mode d’alimentation à l’aide d’un cahier d’observation standardisé accompagnant le patient, et rempli prospectivement. Patients et Méthodes: De 1996 à 2001, 490 GPE (234 premières poses, 256 renouvellements) ont été posées dans notre service par 23 opérateurs différents. Les patients (âge 60 ans, extrêmes: 13–94; sex ratio 1) étaient adressés par un service hospitalier (80%) ou un centre de convalescence (15%). L’indication était une cause neurologique 8 fois sur 10 (AVC 43%, affection dégénérative 31%) ou une cause locale. Les sondes (BARD® 80%, calibre 20 F) étaient posées sous anesthésie locale après soins de bouche, désinfection cutanée et antibiothérapie IV (90%). Le changement de sonde (nouvelle sonde 85%, bouton 15%), par traction percutanée sans anesthésie, a été nécessaire chez 41% des patients (moyenne: 2,8 changements, extrêmes: 1–14), en moyenne 7 mois après la pose. Il était motivé principalement par un vieillissement prématuré de la sonde (42%) ou par un changement systématiquement recommandé (39%). Résultats: Au cours du suivi, 61% des patients sont décédés (médiane de survie après la pose: 10 mois, extrêmes: 1 j-72 mois). Les complications graves liées à la sonde ont été exceptionnelles (0,6%, 3 décès par pneumothorax, péritonite et inhalation). Les complications mineures ont été fréquentes (24% des premières poses, sepsis 1 fois sur 2, douleurs 1 fois sur 4), de survenue précoce (90% lors du 1er mois) et rapidement résolutives (seuls 2 sepsis locaux ont nécessité le retrait de la sonde). Aucune complication n’est survenue lors du changement de sonde. La morbidité est restée stable durant toute la période de l’étude. Une alimentation orale normale a pu être reprise définitivement par 34 patients (16%). Conclusion: La GPE est une technique sûre, rapide à maîtriser, dont les complications essentiellement infectieuses et mineures sont simples à prendre en charge.
アルビノラットにおける硝子体内ドラッグデリバリーシステムとしてのポリエステルアミド(PEA)とポリエステル(PLGA)ミクロスフェアの評価【Powered by NICT】
Authors: Peters Tobias, Kim Seong-Woo, Castro Vinicius, Stingl Krunoslav, Strasser Torsten, Bolz Sylvia, Schraermeyer Ulrich, Mihov George, Zong MengMeng, Andres-Guerrero Vanessa, Herrero Vanrell Rocio, A Dias Aylvin, R Cameron Neil, Zrenner Eberhart
Journal: Biomaterials (2017)
PET/CT in an 8-Year-Old Girl With Epstein-Barr Virus–Associated Smooth Muscle Tumor
Authors: Ishan Garg, Maria J. Baladron Zanetti, Saba Yasir, Ajit H. Goenka, Ayse T. Kendi
Journal: Clinical Nuclear Medicine (2017)

Epstein-Barr virus-associated smooth muscle tumor is a rare indolent neoplasm, which can occur in unusual locations. It has been reported in immunosuppressed individuals in only 3 settings: posttransplant, human immunodeficiency virus infection, and primary immunodeficiency. Here, we present CT, MRI, and F-FDG PET/CT findings of Epstein-Barr virus-associated smooth muscle tumor in an 8-year-old girl with primary immunodeficiency and metachronous adrenal involvement.
Le parc d’endoscopes français est-il vieillissant?
Authors: J Lapuelle, JM Canard, D Sautereau, JC Letard, JP Arpurt, C Boustiere, J Boyer, J Escourrou, M Greff, R Laugier, B Marchetti, B Napoléon, L Palazzo, B Vedrenne
Journal: Endoscopy (2004)

Introduction: Le parc d’endoscopes français qui se compose de 13 à 15000 appareils reste relativement mal connu particulièrement en ce qui concerne sa vétusté. Le but de cette étude est d’essayer d’apprécier l’ancienneté des gastroscopes et des coloscopes qui composent le parc français. Patients et Méthodes: Entre le 30 juin et le 1er octobre 2003 une enquête sur l’état du parc d’endoscopes a été pratiquée auprès de l’ensemble des hépatogastro-entérologues exerçant en France. Il a été ainsi adressé à chaque praticien deux fiches distinctes, l’une relative aux gastroscopes et l’autre aux coloscopes, à remplir par une seule personne au sein des établissements de soins et des cabinets de groupe. Cette fiche demandait le nombre d’endoscopes en service, l’année d’achat, la marque, le modèle et le numéro d’identification. Ces données renvoyées par courrier, télécopie ou en ligne sur le site Web ont ensuite été saisies ou importées dans un même classeur MicrosoftExcel pour traitement informatique. Les fiches incomplètes et les doublons ont été éliminés. Résultats (Tableau 1). 425 centres représentant 1819 gastroscopes et 2026 coloscopes ont été inclus dans une étude brute en première approche. Il en ressort notamment que plus de la moitié du parc (53,6% des gastroscopes et 56,84% des coloscopes) a moins de 5 ans et en particulier que plus de 20%(22,12% des gastroscopes et 20,57% des coloscopes) est très récent (2002 et 2003) mais aussi qu’une part non négligeable (8,04% des gastroscopes et 10,8% des coloscopes) date de plus de 10 ans. Conclusion: Cette étude montre un vieillissement du parc d’endoscopes car 40% ont un âge supérieur à 5 ans. Ceci est dû à un taux de renouvellementannuel insuffisant de 12%. A l’heure de l’étude du coût de la pratique ceci pourrait être pénalisant pour les gastro-entérologues.
AODTH-001 Snare tip assisted resection (star) of colorectal lesions – a novel technique
Authors: J Frost, A Kurup, R Dawson, C Hall, S Hebbar
Journal: Endoscopy (2017)

<h3>Introduction</h3> Endoscopic submucosal dissection (ESD) can be a highly effective technique for the en-bloc removal of complex colorectal lesions, but is technically challenging and associated with a higher incidence of adverse events. In light of this, hybrid knife assisted resection (KAR)<sup>1</sup> method has been previously described. We describe a novel technique of snare tip assisted resection (STAR), its indications for use, and our observed outcomes so far. <h3>Method</h3> All data was recorded prospectively from June 2014 to February 2017. All procedures were performed by a single endoscopist. 'Complex' colorectal lesions were defined as those with features suggestive of early malignancy, recurrent lesions, scarred lesions from previous incomplete resection, and for lesions identified in patients with colitis. STAR was also used to assist snare resection of polyps with flat components. Lesions are lifted with a standard EMR solution. The tip of a stiff spiral snare is advanced by 1–2 mm, and using endocut current a deep submucosal incision is made and subsequently extended circumferentially via a tapping technique. The snare is then opened and engaged within the groove in order to complete the resection. <h3>Results</h3> STAR resection was used for 51 lesions amongst 50 patients. Lesion size varied from 0.5–7 cm (mean 2.6 cm). Of the 51 lesions, two thirds (34) were felt to have endoscopic features suggestive of early malignancy. Using the STAR technique, en-bloc resection was successful in 19/34 (56%). Upon histological analysis, cancer was identified in 11 (32%) specimens and focal high grade dysplasia in another 8 (24%). Of the cancerous lesions, 9 had complete endoscopic resection, of which 4 had a curative sm1R0 resection requiring no further treatment. Using STAR technique, 10 scarred lesions and 7 lesions with flat components were also resected. At present 1 year follow up data is available for 19 patients and 3–6 month data in 12, and reveals no residual or recurrent lesion occurrence to date. Three patients had adverse events: 2 patients had bleeding complications (one required embolization therapy) and 1 patient had a delayed perforation necessitating surgery. Overall, the significant complication rate was 5.8% <h3>Conclusion</h3> STAR is a novel technique and this is the first ever Western reported case series. We would suggest that when adopted by endoscopists with significant experience in EMR/ESD, STAR is an effective, inexpensive, and alternative technique for the management of selective complex colorectal lesions. <h3>Reference</h3> . Bhattacharyya R, et al. KAR of large and refractory colonic polyps at a Western centre: Feasibility, safety and efficacy study to guide future practice. <i>UEG Journal</i>. 2016;4(3):466–473. <h3>Disclosure of Interest</h3> None Declared
Metabolic and immune effects of immunotherapy with proinsulin peptide in human new-onset type 1 diabetes
Authors: Mohammad Alhadj Ali, Yuk-Fun Liu, Sefina Arif, Danijela Tatovic, Hina Shariff, Vivienne B. Gibson, Norkhairin Yusuf, Roman Baptista, Martin Eichmann, Nedyalko Petrov, Susanne Heck, Jennie H. M. Yang, Timothy I. M. Tree, Irma Pujol-Autonell, Lorraine Yeo, Lucas Baumard, Rachel Stenson, Alex Howell, Alison Clark, Zoe Boult, Jake Powrie, Laura Adams, Florence S. Wong, Stephen Luzio, Gareth Dunseath, Kate Green, Alison O’Keefe, Graham Bayly, Natasha Thorogood, Robert Andrews, Nicola Leech, Frank Joseph, Sunil Nair, Susan Seal, HoYee Cheung, Craig Beam, Robert Hills, Mark Peakman, Colin M. Dayan
Journal: Science Translational Medicine (2017)

Immunotherapy using short immunogenic peptides of disease-related autoantigens restores immune tolerance in preclinical disease models. We studied safety and mechanistic effects of injecting human leukocyte antigen-DR4(DRB1*0401)-restricted immunodominant proinsulin peptide intradermally every 2 or 4 weeks for 6 months in newly diagnosed type 1 diabetes patients. Treatment was well tolerated with no systemic or local hypersensitivity. Placebo subjects showed a significant decline in stimulated C-peptide (measuring insulin reserve) at 3, 6, 9, and 12 months versus baseline, whereas no significant change was seen in the 4-weekly peptide group at these time points or the 2-weekly group at 3, 6, and 9 months. The placebo group's daily insulin use increased by 50% over 12 months but remained unchanged in the intervention groups. C-peptide retention in treated subjects was associated with proinsulin-stimulated interleukin-10 production, increased FoxP3 expression by regulatory T cells, low baseline levels of activated β cell-specific CD8 T cells, and favorable β cell stress markers (proinsulin/C-peptide ratio). Thus, proinsulin peptide immunotherapy is safe, does not accelerate decline in β cell function, and is associated with antigen-specific and nonspecific immune modulation.
Is Weekend-Only Physical Activity Enough to Compensate for a Sedentary Lifestyle?
Authors: Michael Huen Sum Lam, Paul H. Lee, Ka Yiu Lee
Journal: JAMA Internal Medicine (2017)

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