tbuckley/cabot-search huggingface dataset:
PDE4 and mAKAPβ are nodal organizers of β2-ARs nuclear PKA signalling in cardiac myocytes
Authors: Ibrahim Bedioune, Florence Lefebvre, Patrick Lechêne, Audrey Varin, Valérie Domergue, Michael S Kapiloff, Rodolphe Fischmeister, Grégoire Vandecasteele
Journal: Cardiovascular Research (2018)

β1- and β2-adrenergic receptors (β-ARs) produce different acute contractile effects on the heart partly because they impact on different cytosolic pools of cAMP-dependent protein kinase (PKA). They also exert different effects on gene expression but the underlying mechanisms remain unknown. The aim of this study was to understand the mechanisms by which β1- and β2-ARs regulate nuclear PKA activity in cardiomyocytes. We used cytoplasmic and nuclear targeted biosensors to examine cAMP signals and PKA activity in adult rat ventricular myocytes upon selective β1- or β2-ARs stimulation. Both β1- and β2-AR stimulation increased cAMP and activated PKA in the cytoplasm. Although the two receptors also increased cAMP in the nucleus, only β1-ARs increased nuclear PKA activity and up-regulated the PKA target gene and pro-apoptotic factor, inducible cAMP early repressor (ICER). Inhibition of phosphodiesterase (PDE)4, but not Gi, PDE3, GRK2 nor caveolae disruption disclosed nuclear PKA activation and ICER induction by β2-ARs. Both nuclear and cytoplasmic PKI prevented nuclear PKA activation and ICER induction by β1-ARs, indicating that PKA activation outside the nucleus is required for subsequent nuclear PKA activation and ICER mRNA expression. Cytoplasmic PKI also blocked ICER induction by β2-AR stimulation (with concomitant PDE4 inhibition). However, in this case nuclear PKI decreased ICER up-regulation by only 30%, indicating that other mechanisms are involved. Down-regulation of mAKAPβ partially inhibited nuclear PKA activation upon β1-AR stimulation, and drastically decreased nuclear PKA activation upon β2-AR stimulation in the presence of PDE4 inhibition. β1- and β2-ARs differentially regulate nuclear PKA activity and ICER expression in cardiomyocytes. PDE4 insulates a mAKAPβ-targeted PKA pool at the nuclear envelope that prevents nuclear PKA activation upon β2-AR stimulation.
Serum and urine extracellular vesicles contain mRNA biomarkers for primary sclerosing cholangitis (PSC) and cholangiocarcinoma (CCA)
Authors: A. Arbelaiz, A. Lapitz, M. Krawczyk, Á. Santos-Laso, J.L. Lavin, M.J. Perugorria, R. Jimenez-Aguero, A. Lacasta, C. Ibarra, A. Sanchez-Campos, J.P. Jimeno, E. Gonzalez, F. Lammert, M. Marzioni, R. Macias, J. Marin, T.H. Karlsen, J. Falcon-Perez, A. María Aransay, L. Bujanda, Jesús Banales
Journal: Journal of Hepatology (2018)
P451The endocardial expression of ADGRG6 (Gpr126) is necessary for survival in mouse and sufficient to drive trabeculation in zebrafish
Authors: G Musa, S Srivastava, F B Engel
Journal: Cardiovascular Research (2018)

wall displacement (Wd) in a function of EV and FP, deformation factor (Df) and divergent factor (Divf)).Results: There was about 21% difference in spatial deformation for gelatine sealed ePTFE and 25% in Dacron prostheses compared to iliac arteries.In contrast, ePTFE presented about 2.4-fold increase of stiffness compared to iliac arteries.The highest Dd was observed for the iliac arteries (0.8360.016mm-1.4860.008mm)and Dacron (0.7960.016mm-1.4360.011mm).In contrast, the smallest Dd was for ring enforced ePTFE (0.2660.007mm-0.5360.008mm)and ePTFE (0.4160.012mm-0.6560.008mm),while the highest Wd was observed for Dacron (7.4760.180mm-12.5660.102mm).Similar trend was observed for the iliac arteries.In contrast, bio prostheses showed about 43% and 56% lower Wd for gelatin sealed ePTFE (3.8660.038mm-7.9560.033mm)and Omniflow II (2.4660.032mm-6.9660.028mm).The smallest Wd was observed for ePTFE.Also, for the vessels with low Dd and Wd higher value of Df was observed.The highest Df was showed for ePTFE (1.0060.052-0.2160.003,where DDd¼0.2460.01mmand DWd¼2.6960.03mm;p<0.05), while the lowest Df was observed for ring enforced ePTFE (0.0660.001-0.0560.001,where DDd¼0.2760.01mmand DWd¼3.5260.03mm;p<0.05) and Dacron (0.1160.001-0.1060.001,where DDd¼0.6460.01mmand DWd¼5.0960.03mm;p<0.05).Finally, Divf indicated the highest association between gelatin sealed ePTFE and iliac arteries and the lowest with ePTFE.Conclusion: Using ACM in which EV and FP can be varied independently, we have shown different mechanical responses of synthetic, biosynthetic and vascular grafts.Both Dacron and bio prostheses act similarly to human iliac arteries.These observations may be useful to further our understanding of the mechanical behaviour of vascular grafts and to explore new approaches towards improving their patency rates in future.
Activity and selectivity cliffs for DPP‐IV inhibitors: Lessons we can learn from SAR studies and their application to virtual screening
Authors: María José Ojeda‐Montes, Aleix Gimeno, Sarah Tomas‐Hernández, Adrià Cereto‐Massagué, Raúl Beltrán‐Debón, Cristina Valls, Miquel Mulero, Gerard Pujadas, Santiago Garcia‐Vallvé
Journal: Medicinal Research Reviews (2018)

Abstract The inhibition of dipeptidyl peptidase‐IV (DPP‐IV) has emerged over the last decade as one of the most effective treatments for type 2 diabetes mellitus, and consequently (a) 11 DPP‐IV inhibitors have been on the market since 2006 (three in 2015), and (b) 74 noncovalent complexes involving human DPP‐IV and drug‐like inhibitors are available at the Protein Data Bank (PDB). The present review aims to (a) explain the most important activity cliffs for DPP‐IV noncovalent inhibition according to the binding site structure of DPP‐IV, (b) explain the most important selectivity cliffs for DPP‐IV noncovalent inhibition in comparison with other related enzymes (i.e., DPP8 and DPP9), and (c) use the information deriving from this activity/selectivity cliff analysis to suggest how virtual screening protocols might be improved to favor the early identification of potent and selective DPP‐IV inhibitors in molecular databases (because they have not succeeded in identifying selective DPP‐IV inhibitors with IC 50 ≤ 100 nM). All these goals are achieved with the help of available homology models for DPP8 and DPP9 and an analysis of the structure–activity studies used to develop the noncovalent inhibitors that form part of some of the complexes with human DPP‐IV available at the PDB.
Combined [18F]-Fluoroethylcholine PET/CT and 99mTc–Macroaggregated Albumin SPECT/CT Predict Survival in Patients With Intermediate-Stage Hepatocellular Carcinoma
Authors: Markus Hartenbach, Stefan Weber, Magdalena Pilz, Sabrina Hartenbach, Mathias J. Zacherl, Philipp M. Paprottka, Reinhold Tiling, Peter Bartenstein, Marcus Hacker, Alexander R. Haug, Nathalie L. Albert
Journal: Clinical Nuclear Medicine (2018)

The aim of this study was to retrospectively analyze the prognostic value of combined Tc-macroaggregated albumin (MAA) SPECT/CT and [F]-fluoroethylcholine (FEC) PET/CT before radioembolization for survival of patients with intermediate-stage hepatocellular carcinoma.Twenty-four patients with known hepatocellular carcinoma Barcelona Clinic Liver Cancer stage B were eligible for this analysis. All patients were scheduled for radioembolization and received a pretherapeutic [F]FEC PET/CT scan as well as Tc-MAA SPECT/CT for hepatopulmonary shunting. Laboratory and semiquantitative PET parameters and morphologic and metabolic (intersection) volumes of MAA and FEC were evaluated. Spearman correlation with overall survival, receiver operating curve analyses, univariate and multivariate Cox regression, and Kaplan-Meier-analysis was applied.All patients (5 female/19 male) are deceased within the observational period. Median survival was 395 days (±51 days; range, 23-1122 days). The percentage of hypervascularized metabolically active tumor volume (vascularized tumor ratio; defined as high MAA and FEC uptake) correlated significantly with survival. Vascularized tumor ratio was a significant predictor in univariate and multivariate analyses (P = 0.026; hazard ratio, 11.65; 95% confidence interval, 1.62-83.73; P = 0.015). Statistical significance was not reached by all other variables in multivariate analysis. Receiver operating curve analysis for 1-year survival revealed an area under the curve of 0.77 (P = 0.024) for vascularized tumor ratio. At a cutoff value of 9%, sensitivity, specificity, and positive and negative prediction were 83%, 67%, and 71% and 80% (P = 0.036). Patients with a higher tumor vascularization had a median survival of 274 ± 80 versus 585 ± 284 days (P = 0.015).Hepatocellular carcinoma with high vascularization in metabolic active areas as assessed by combined FEC PET/CT and Tc-MAA SPECT/CT represents an unfavorable subgroup with reduced overall survival after radioembolization.
Abstract 545: Preclinical development of a bispecific antibody-trap selectively targeting CD47 and CD20 for the treatment of B cell lineage cancer
Authors: Wenzhi Tian, Song Li, Dianze Chen, Guangjun Liang, Li Zhang, Wei Zhang, Xiaoping Tu, Liang Peng, Jie Weng, Gui Zhao, Dandan Liu, Huiqin Guo, Chunmei Yang, Ruliang Zhang
Journal: Cancer Research (2019)

Abstract Tumor cells over expressing CD47 can evade immune surveillance through delivering a “Don’t eat me” signal to macrophages. Developing CD47-targeted modalities has been a hot pursue in the pharmaceutical industry. However due to the ubiquitous expression of CD47 in normal tissues, especially in red blood cells (RBC), severe antigenic sink as well as hemotoxicity including anemia set up a higher bar for this particular targeted therapy development. To overcome these hurdles, we have developed a bispecific recombinant antibody-trap, IMM0306, designed to simultaneously target CD47 and CD20 on B cells but avoid binding to human RBCs. Extensive in vitro characterization demonstrated that IMM0306 binds to both CD47 and CD20 with affinity 3-8 folds lower than either single-targeted molecule, but has strong pro-phagocytosis activity over CD47-positive target cells, and even stronger ADCC activity than Rituximab. Intriguingly, IMM0306 has no binding activity at all toward human RBCs, albeit much lower binding activity toward monkey RBCs. Treatment of tumor-implanted SCID mice with IMM0306 significantly inhibited tumor growth and led to eradication of the tumor cells from 5 out of 8 mice, which is much more effective than Rituximab and than co-administration of Rituximab and SIRPα-Fc (IMM01), although profound synergistic effect has been observed for the co-administration. Preclinical study in non-human primates demonstrated a favorable pharmacokinetic profile with no obvious hemotoxicity following single as well as multiple administrations at different dosage. Our study suggests that antibody-trap like IMM0306 might be an ideal approach for CD47-targeted immunotherapy development since selective avoidance of RBC mediated antigen-sink as well as anemia could be achieved along with the robust anti-tumor activity. Citation Format: Wenzhi Tian, Song Li, Dianze Chen, Guangjun Liang, Li Zhang, Wei Zhang, Xiaoping Tu, Liang Peng, Jie Weng, Gui Zhao, Dandan Liu, Huiqin Guo, Chunmei Yang, Ruliang Zhang. Preclinical development of a bispecific antibody-trap selectively targeting CD47 and CD20 for the treatment of B cell lineage cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 545.
Common Variant Burden Contributes to the Familial Aggregation of Migraine in 1,589 Families
Authors: Padhraig Gormley, Mitja I. Kurki, Marjo Eveliina Hiekkala, Kumar Veerapen, Paavo Häppölä, Adele A. Mitchell, Dennis Lal, Priit Palta, Ida Surakka, Mari Anneli Kaunisto, Eija Hämäläinen, Salli Vepsäläinen, Hannele Havanka, Hanna Harno, Matti Ilmavirta, Markku Nissilä, Erkki Säkö, Marja-Liisa Sumelahti, Jarmo Liukkonen, Matti Sillanpää, Liisa Metsähonkala, Seppo Koskinen, Terho Lehtimäki, Olli Raitakari, Minna Männikkö, Caroline Ran, Andrea Carmine Belin, Pekka Jousilahti, Verneri Anttila, Veikko Salomaa, Ville Artto, Markus Färkkilä, Heiko Runz, Mark J. Daly, Benjamin M. Neale, Samuli Ripatti, Mikko Kallela, Maija Wessman, Aarno Palotie, Michelle Agee, Babak Alipanahi, Adam Auton, Robert K. Bell, Katarzyna Bryc, Sarah L. Elson, Pierre Fontanillas, Nicholas A. Furlotte, Karen E. Huber, Aaron Kleinman, Nadia K. Litterman, Jennifer C. McCreight, Matthew H. McIntyre, Joanna L. Mountain, Carrie A.M. Northover, Steven J. Pitts, J. Fah Sathirapongsasuti, Olga V. Sazonova, Janie F. Shelton, Suyash Shringarpure, Chao Tian, Joyce Y. Tung, Vladimir Vacic, Catherine H. Wilson, Verneri Anttila, Ville Artto, Andrea Carmine Belin, Dorret I. Boomsma, Sigrid Børte, Daniel I. Chasman, Lynn Cherkas, Anne Francke Christensen, Bru Cormand, Ester Cuenca-Leon, George Davey-Smith, Martin Dichgans, Cornelia van Duijn, Tonu Esko, Ann-Louise Esserlind, Michel D. Ferrari, Rune R. Frants, Tobias Freilinger, Nick Furlotte, Padhraig Gormley, Lyn Griffiths, Eija Hamalainen, Thomas Folkmann Hansen, Marjo Hiekkala, M Arfan Ikram, Andres Ingason, Marjo-Riitta Järvelin, Risto Kajanne, Mikko Kallela, Jaakko Kaprio, Mari Kaunisto, Christian Kubisch, Mitja Kurki, Tobias Kurth, Lenore Launer, Terho Lehtimaki, Davor Lessel, Lannie Ligthart, Nadia Litterman, Arn van den Maagdenberg, Alfons Macaya, Rainer Malik, Massimo Mangino, George McMahon, Bertram Muller-Myhsok, Benjamin M. Neale, Carrie Northover, Dale R. Nyholt, Jes Olesen, Aarno Palotie, Priit Palta, Linda Pedersen, Nancy Pedersen, Danielle Posthuma, Patricia Pozo-Rosich, Alice Pressman, Lydia Quaye, Olli Raitakari, Markus Schürks, Celia Sintas, Kari Stefansson, Hreinn Stefansson, Stacy Steinberg, David Strachan, Gisela Terwindt, Marta Vila-Pueyo, Maija Wessman, Bendik S. Winsvold, William Wrenthal, Huiying Zhao, John-Anker Zwart
Journal: Neuron (2018)
Abstract 19576: Identification of a Novel Signaling Pathway for S1P Mediated Cardioprotection
Authors: Sunny Y Xiang, Kunfu Ouyang, Alan V Smrcka, Ju Chen, Joan Heller Brown
Journal: Circulation (2012)

Background — Recently, we demonstrated that activation of the small GTPase RhoA in cardiomyocytes induces striking protection against ischemia/reperfusion (I/R) injury. The GPCR agonist, sphingosine 1-phosphate (S1P), well known for its profound protective effects on I/R injury, activates RhoA. Here we asked whether S1P protects cardiomyocytes through RhoA signaling and further characterized the mechanism and downstream targets responsible. Methods and Results — We determined that stimulation of the isolated perfused mouse heart with S1P activates RhoA and protein kinase D (PKD). Phospholipase Cε (PLCε) is a newly identified RhoA target. Genetic deletion of PLCε fully abolishes PKD activation by S1P and blocks S1P mediated protection from I/R injury. Cardioprotection by S1P is also abolished in PKD1 -/- (KO) mice. We used the neonatal rat ventricular myocytes (NRVMs) model to confirm these findings and further elucidate molecular mechanisms. S1P elicits robust activation of PKD in NRVMs through effects on RhoA (blocked with C3) and PLCε (blocked with siRNA). PKD is required for S1P mediated protection against H 2 O 2 induced cell death implicating PKD as a pro-survival target of S1P/RhoA/PLCε signaling. We further identified the PKD substrate Slingshot 1L (SSH1L) as an S1P target that is regulated through PKD mediated phosphorylation. Importantly, regulation of SSH1L by S1P reduces translocation of Cofilin2, an SSH1L substrate, to the mitochondrion in response to H 2 O 2 . In addition, we demonstrate that Cofilin2 co-IPs with the pro-death protein Bax and that mitochondrial translocation of Bax is inhibited through this pathway by S1P. Finally, we demonstrate that S1P significantly reduces translocation of Cofilin2 and Bax to mitochondria, in parallel with its ability to protect the isolated heart against I/R injury. Conclusion — These studies reveal previously unknown mechanisms through which GPCR agonists that activate RhoA induces cardioprotection. In addition they define multiple new molecular players (PLCε, PKD, SSH1L and Cofilin2) that converge at the level of the mitochondrion to protect cardiomyocytes from oxidative stress.
Differentiation of acute icteric autoimmune hepatitis from idiosyncratic drug-induced liver injury by histological and biochemical criteria
Authors: M. Sebode, U. Drebber, H.-P. Dienes, T. Krech, S.A. Weidemann, E. Vettorazzi, A. Lohse, C. Schramm
Journal: Journal of Hepatology (2018)
NS5A resistance patterns and treatment outcomes in DAA-naive genotype 1a chronic hepatitis C patients with and without baseline resistance-associated substitutions
Authors: J. Dietz, J. Vermehren, S. Susser, K.-H. Peiffer, T. Welzel, K. Wursthorn, J. Petersen, H. Klinker, J.S.Z. Wiesch, H. Hinrichsen, T. Discher, L. Reinhardt, S. Mauss, M. Mueller-Schilling, C. Niederau, C. Neumann-Haefelin, R. Thimme, C. Berg, S. Zeuzem, C. Sarrazin
Journal: Journal of Hepatology (2018)
Cheap alcohol disappears from shelves in Scotland as minimum unit price starts
Authors: Bryan Christie
Journal: BMJ (2018)

Bottles and cans of cheap alcohol can no longer be bought in supermarkets and shops across Scotland, as health professionals celebrate the long awaited arrival of minimum unit pricing.

After a six year legal battle with the drinks industry,123456 Scotland has become one of the first countries in the world to introduce a minimum price for a unit of alcohol in a move that campaigners want to see replicated in other parts of the UK.

Although Scotland is being congratulated for its …
P86Stimulation of endogenous glutathione synthesis prevent postreperfusion NOS uncoupling, oxidative nitrosative stress and cardiodynamic disturbances in rats
Authors: R A Fedichkina, Y V Goshovska, V F Sagach
Journal: Cardiovascular Research (2018)

Background: The insufficient regenerative capacity of the adult human heart represents a great therapeutic challenge, and treatments that could promote regeneration are urgently needed.The mammalian hearts lose their intrinsic regenerative capacity within the first week of postnatal life.This coincides with a metabolic switch in cardiomyocytes, in which the energy production converts from glycolysis to lipid oxidation.More detailed understanding of the metabolic changes and regulation of cardiomyocyte cell cycle withdrawal is required for the development of regenerative therapies.Purpose: The aim of this work was to elucidate the metabolic changes occurring in the murine heart in the early postnatal period in order to identify potential new drug targets for the development of cardiac regeneration-inducing therapies.Methods: Ventricular tissue samples from C57/Bl6 mouse pups at postnatal days 1, 4, 9 and 23 (P1, P4, P9 and P23, respectively) were analysed using genome-wide RNA sequencing, quantitative shotgun proteomics (LC-MS/MS) and global metabolomics (LC-MS, GCxGC-MS).RNA sequencing was performed from one set of tissue samples (Set 2, n¼3 pooled samples per group, each from 3 hearts) while proteomics and metabolomics analyses were carried out with two separate sets of tissue samples (Sets 1 and 2; individual hearts analysed separately, n¼5-15 for each group in both sets).Differential expression analysis was carried out and changes were considered significant when FDR-corrected p<0.01.For RNA sequencing and metabolomics, a fold change limit of 1.5 was also applied.Fuzzy clustering, gene set enrichment analysis and KEGG pathway analysis were performed to identify correlative changes in RNA, protein and metabolite data.Results: The multiomics analysis identifies a number of metabolic pathways with significant and correlative changes on all levels (mRNA, protein, metabolites) within the early postnatal period.These include previously reported changes in energy metabolism, down-regulation of glycolytic pathways and up-regulation of fatty acid oxidation, as well as metabolic pathways, whose role in cardiac maturation and regeneration has not been reported.Several examples of interesting metabolic pathways that are time-wise associated with the postnatal loss of regenerative capacity of the murine heart will be presented.These may represent attractive therapeutic targets for heart failure.Conclusions: Combining RNA sequencing with proteomics and metabolomics provides a powerful tool for understanding changes in metabolic pathways and for the identification of novel drug targets.The present study provides the first resource of combined transcriptomics, proteomics and metabolomics data from the early postnatal hearts associated with the loss of regenerative potential.
Prenatal antibiotic exposure and childhood asthma: a population-based study
Authors: Keely Loewen, Barret Monchka, Salaheddin M. Mahmud, Geert 't Jong, Meghan B. Azad
Journal: European Respiratory Journal (2018)

Antibiotic use during infancy alters gut microbiota and immune development and is associated with an increased risk of childhood asthma. The impact of prenatal antibiotic exposure is unclear. We sought to characterise the association between prenatal antibiotic exposure and childhood asthma. We performed a population-based cohort study using prescription records, hospitalisation records and physician billing claims from 213 661 mother–child dyads born in Manitoba, Canada between 1996 and 2012. Associations were determined using Cox regression, adjusting for maternal asthma, postnatal antibiotics and other potential confounders. Sensitivity analyses evaluated maternal antibiotic use before and after pregnancy. 36.8% of children were exposed prenatally to antibiotics and 10.1% developed asthma. Prenatal antibiotic exposure was associated with an increased risk of asthma (adjusted hazard ratio (aHR) 1.23, 95% CI 1.20–1.27). There was an apparent dose response (aHR 1.15, 95% CI 1.11–1.18 for one course; aHR 1.26, 95% CI 1.21–1.32 for two courses; and aHR 1.51, 95% CI 1.44–1.59 for three or more courses). Maternal antibiotic use during 9 months before pregnancy (aHR 1.27, 95% CI 1.24–1.31) and 9 months postpartum (aHR 1.32, 95% CI 1.28–1.36) were similarly associated with asthma. Prenatal antibiotic exposure was associated with a dose-dependent increase in asthma risk. However, similar associations were observed for maternal antibiotic use before and after pregnancy, suggesting the association is either not directly causal, or not specific to pregnancy.
P517Autocrine angiotensin II-signaling in FGF23-induced Ca2+-mediated hypertrophy in ventricular cardiomyocytes
Authors: K N Mhatre, P Wakula, E Bisping, B Pieske, F Heinzel
Journal: Cardiovascular Research (2018)

resulted in reduced leukocyte infiltration in both the ischaemic and non-ischaemic myocardium and preservation of LV wall thickness after three weeks.Conclusions: PC-mAb treatment attenuates the post-ischemic inflammatory response, leading to a reduction in adverse cardiac remodeling and preservation of cardiac function in hypercholesterolemic ApoE*3-Leiden mice.Therefore, PC-mAb therapy is considered as a therapeutic approach against MI-R injury.
Reduction in the incidence of hepatitis C-related decompensated cirrhosis associated with national scale-up of direct-acting antiviral therapies targeting patients with advanced liver fibrosis
Authors: S. Hutchinson, H. Valerio, J. Dillon, R. Fox, H. Innes, A. Weir, S. Barclay, S. Mcdonald, N. Kennedy, A. Fraser, A. Stanley, P. Bramley, P. Hayes, D. Goldberg
Journal: Journal of Hepatology (2018)