tbuckley/cabot-search huggingface dataset:
Abstract 405: Unprocessed ProBNP Secretion is Regulated by miR30-GALNTs Axis Dependent O-glycosylation in the Pathological Myocardium
Authors: Yasuaki Nakagawa, Koichiro Kuwahara, Toshio Nishikimi, Hideyuki Kinoshita, Chinatsu Yamada, Hideaki Inazumi, Kazuwa Nakao, Takeshi Kimura
Journal: Circulation Research (2016)

Background: It has been reported that biological inactive pro-brain natriuretic peptide(proBNP), precursor peptide of bioactive BNP, is increased in patients with heart failure, as well as mature BNP-32. However, underlying mechanisms of increased plasma proBNP levels in heart failure remain unclear. Methods: We used the conventional BNP assay system, which detects both proBNP and BNP-32, and our recently developed specific human proBNP assay system. We assessed cardiac production of proBNP and BNP(=proBNP+BNP-32) in patients with heart failure. To elucidate the molecular mechanisms underlying the processing and secretion of proBNP, we generated lentivirus vectors carrying several mutations in glycosylation sites of human proBNP. We evaluated the proBNP/BNP ratio, as an efficacy of processing of proBNP to BNP-32. Results: In coronary sinus, plasma proBNP/BNP ratios were significantly elevated in heart failure patients in accordance with the disease severity. In conditioned medium of cultured ventricular myocytes expressing wild type human proBNP, proBNP/BNP ratio was 37%, while in those of myocytes expressing glycosylation-resistant mutant of proBNP, proBNP/BNP ratio was only 3%, demonstrating the essential contribution of glycosylation to the secretion of proBNP. Among 7 glycosylation sites, we found that glycosylation of Thr48 and Thr71 in proBNP is critical for the secretion of proBNP from ventricular myocytes by attenuating proBNP processing. GalNAc-transferase(GALNT) is the largest glycosyltransferase enyme family, which controll O-glycosylasion. We identified GALNT 1 and 2 mediated the glycosylation-regulated increase in cardiac proBNP secretion by screening with siRNAs. Indeed, GALNT1 and 2-expression was increased in FCS-treated ventricular myocytes and failing hearts. We further found that GALNT1 and 2 expression is suppressed by miR-30 family, and that miR-30s expression is decreased in FCS-treated ventricular myocytes and failing hearts. Conclusions: We have elucidated novel molecular pathways that miR-30-GALNTs axis-mediated O -glycosylation in proBNP contributes to increased proportion of proBNP among secreted BNP in the pathological myocardium.
Abstract 17863: Renal Function and Coronary Artery Disease Progression in Patients with Acute Coronary Syndrome
Authors: Tatsuya Nakachi, Kazuki Fukui, Takeshi Nakagawa, Yasuo Ohkusu, Kazuhiro Muto, Shingo Kato, Yuka Kusakawa, Nao Ishii, Masami Kosuge, Kazuo Kimura
Journal: Circulation (2011)

Background: Renal dysfunction is a powerful predictor of adverse outcomes in acute coronary syndrome (ACS); however, its underlying mechanism has not been fully elucidated. Although renal dysfunction has been shown to be associated with the severity of coronary artery disease (CAD), the relation between renal function and CAD progression remains unclear. Methods: We studied 209 patients with ACS who underwent percutaneous coronary intervention (PCI) for culprit lesion during initial hospitalization. All patients underwent serial coronary angiograms (CAGs) immediately before PCI, and at 8 + 3 months and 60 + 10 months after presentation. Coronary disease progression (CP) was defined as an increase &gt; 15 % in stenosis severity of lesion in nonculprit artery between 2 serial CAGs. Estimated glomerular filtration rate (eGFR), cardiac-specific troponin T and lipid profiles were measured on initial admission. Patients were divided into tertiles according to eGFR at initial admission: the lower [T1; eGFR 54 + 9 mL/min/1.73m 2 , n=70], the middle [T2; eGFR 71 + 6 mL/min/1.73m 2 , n=69], and the upper tertile [T3; eGFR 102 + 20 mL/min/1.73m 2 , n=70]. Results: There were no differences in gender, coronary risk factors, lipid profiles, positive-troponin T, follow-up periods and medications in the 3 groups. In T1,T2, and T3, ages were 68 + 7, 63 + 10, and 60 + 11 years (p&lt;0.001). The rate of multivessel disease were 71, 55, and 51 % (p=0.047). The rate of CP between first and second CAGs was highest in T1 (41%), followed by T2 (24%), and lowest in T3 (21%) (p=0.046). The rate of CP between second and final CAGs was highest in T1 (49%, 31%, and 30% in T1, T2, and T3, respectively; p=0.033). Multivariate analysis revealed that T1 (OR 2.82, 95% CI 1.12 to 6.64, p=0.018) and age &gt; 65 years (OR 2.68, 95% CI 1.08 to 6.64, p=0.033) were independently associated with the presence of both of CP between each of 2 serial CAGs. Conclusions: In patients with ACS, renal function is associated with not only the severity of CAD but also continuous CAD progression. These findings may partly explain adverse outcomes in patients with renal dysfunction.
Accuracy of MRI, mammography (MG), and 2D and 3D ultrasound (2DUS/3DUS) in determining the pathologic tumor response after neoadjuvant chemotherapy (NACT) in breast cancer patients.
Authors: Markus Hahn, Katja C. Siegmann, Christoph Meisner, Ann-Katrin Steinhoff, Valerie Hattermann, Tanja N. Fehm, Andreas D. Hartkopf, Markus Wallwiener, Ulrich Vogel, Diethelm Wallwiener
Journal: Journal of Clinical Oncology (2012)

1067 Background: The pathological tumor response in patients with locally advanced breast cancer to NACT is essential for survival and for surgical strategies. Therapy monitoring based on German recommendations is routinely performed by clinical examination, MG and 2DUS. The clinical value of MRI and 3DUS has not been established yet. The aim of the study was to determine the accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) between the different imaging techniques in predicting postoperative histological tumor response after NACT. Methods: Patients with primary breast cancer (cT1-T4, cN0-1, M0) undergoing neoadjuvant chemotherapy between 2005 and 2010 were eligible for this prospective trial. The response was measured by MRI, MG, 2DUS and 3DUS for complete or partial remission versus stable disease after the last cycle of treatment and compared with the final pathological response. Patients with progressive disease were excluded from the study. Statistical analysis was done by calculating the accuracy of each imaging technique and the size difference between imaging and histological tumor size. Sensitivity, specificity, PPV and NPV were calculated for complete or partial pathological response. The study was approved by the local ethic committee (BCD001 194/2004). Results: 103 patients with the mean age of 47.7 (range 24.5 – 71.4) years were evaluated. The accuracy was 0.680 (95%CI: 0.580 -0.768) for MRI, 0.563 (95%CI: 0.453-0.669) for MG, 0.724 (95%CI: 0.618 -0.815) for 2DUS and 0.710 (95%CI: 0.588-0.813) for 3DUS. Sensitivity, specificity, PPV and NPV were 78%, 47%, 75% and 52% for MRI, 61%, 45%, 69% and 36% for MG, 93%, 23%, 74% and 60% for 2DUS, 94%, 19%, 73% and 57% for 3DUS. The mean (standard deviation) size difference was -1.8 mm (14.8) on MRI, 1.5 mm (26.0) on MG, -9.1mm (19.1) on 2DUS and for the volume difference -6916mm3 (15831) on 3DUS. Conclusions: The data suggest that 2DUS is sufficient in predicting tumor response between NACT treatment. MRI and MG are more accurate the 2DUS in predicting the tumor size for surgical planning.
Abstract 1386: Safety and tolerability of guadecitabine (SGI-110) plus cisplatin in patients with platinum refractory germ cell tumors (GCT): A phase 1 study
Authors: Costantine Albany, Neda S. Hashemi, Fang Fang, James Lowder, Lawrence Einhorn, Kenneth Nephew
Journal: Cancer Research (2018)

Abstract BACKGROUND: Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine and deoxyguanosine resistant to degradation by cytidine deaminase. Germ cell tumor including platinum-resistant embryonal carcinoma cells lines are extremely sensitive to hypomethylating agents and low dose decitabine can restore cisplatin sensitivity in cell lines. We aimed to assess the safety and clinical activity of guadecitabine in combination with cisplatin in patients with platinum-refractory GCT. METHODS: In this open-label, phase 1 study, patients with GCT refractory to or had relapsed after platinum-based treatment were treated with subcutaneous (SQ) guadecitabine, once-daily for 5 consecutive days, followed by cisplatin on day 8 in a 28-day treatment cycle. A modified toxicity probability interval (mTPI) dose-escalation design was used in which we treated patients with guadecitabine doses of 30-45 mg/m2 plus cisplatin 100 mg/m2 up to 6 cycles until progression or intolerable toxicity. The primary objective was to assess safety and tolerability of guadecitabine in combination with cisplatin, determine the maximum tolerated and identify the recommended phase 2 dose of guadecitabine. Safety analyses included all patients who received at least one dose of guadecitabine. Pharmacodynamic analyses to determine the biologically effective dose included all patients for whom samples were available. This study is registered with ClinicalTrials.gov, number NCT02429466. FINDINGS: Between 2015 and 2017, we enrolled and treated 10 patients. Grade 3 or 4 adverse events were febrile neutropenia, thrombocytopenia, anemia, and diarrhea. The most common serious adverse events were febrile neutropenia and thrombocytopenia. Guadecitabine 45 mg/m2 was associated with prolonged SAE and felt to be unsafe to continue. The maximum tolerated dose was 30 mg/m2 daily × 5. Two patients achieved a complete response to treatment lasting more than 6 months. INTERPRETATION: Guadecitabine SQ at 30 mg/m2 daily × 5 is well tolerated and is clinically and biologically active in patients with platinum-refractory GCT. The study is still ongoing. Citation Format: Costantine Albany, Neda S. Hashemi, Fang Fang, James Lowder, Lawrence Einhorn, Kenneth Nephew. Safety and tolerability of guadecitabine (SGI-110) plus cisplatin in patients with platinum refractory germ cell tumors (GCT): A phase 1 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1386.
Abstract 289: Improved Disease Modeling Reveals 9p21 Risk Allele Regulates Connexins to Induce Arrhythmic Phenotypes
Authors: Aditya Kumar, Stephanie Thomas, Kirsten Wong, Valentina Lo Sardo, Daniel Cheah, Kevin Tenerelli, William Ferguson, Eric Topol, Kristin Baldwin, Adam Engler
Journal: Circulation Research (2017)

Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) in the non-coding 9p21 gene locus associated with increased risk of coronary artery disease (CAD) and myocardial infarction (MI). In addition, SNP correlations with sudden and arrhythmic death, even after accounting for patient and family history for CAD and MI, suggest an altered cardiac remodeling response. However, little is known about a possible cardiac phenotype as studies have largely focused on its effect on CAD and have trouble describing regulation with non-coding loci. Using induced pluripotent stem cell-derived CMs from patients that are homozygous risk/risk (R/R) and non-risk/non-risk (N/N) for 9p21 SNPs, we assessed cardiomyocyte (CM) function when cultured on hydrogels capable of mimicking the fibrotic stiffening associated with disease post-heart attack, i.e. stiffening from 10 kiloPascals (kPa) to 50 kPa. While all CMs independent of genotype beat synchronously on soft matrices, R/R CMs cultured on dynamically stiffened hydrogels exhibited asynchronous contractions versus N/N CMs in the same conditions. Dynamic stiffening reduced connexin 43 expression and gap junction assembly in R/R CMs but not N/N CMs. To eliminate patient-to-patient variability, we created an isogenic line by deleting the 9p21 locus from a R/R patient, i.e. R/R KO. R/R KO CMs maintained synchronous contractions and organized connexin 43 junctions after stiffening. The 9p21 locus suppresses the activity of the cell cycle regulator CDKN2A. p16, a protein produced by CDKN2A, prevents JNK phosphorylation (p-JNK), which in turn reduces gap junction expression in CMs and contributes to the development of arrhythmias in rabbit myocardium in response to stress. We observed that treatment with the p-JNK antagonist SP600125 after stiffening restored synchronous contractions and organized gap junction assembly to R/R CM. As a non-coding locus, 9p21 appears to repress connexin transcription, but only when the niche is stiffened as in disease. These data are the first to demonstrate that disease-specific niche remodeling can differentially affect CM function depending on SNPs within a non-coding locus.
Argentinian senators reject bill to legalise abortion
Authors: Claudia Collucci
Journal: BMJ (2018)

Argentina’s Senate has rejected a bill to legalise abortion in the first 14 weeks of pregnancy by 38 votes to 31.

After a session that lasted 17 hours, senators voted against the bill that had already been approved by the lower house. There were celebrations among those who opposed the bill, while pro-choice senators said that they would keep fighting for a change in the law.

Argentine president Mauricio Macri said that he would sign the bill if it was approved by the Senate, despite his personal misgivings.

One of the last people to speak in the debate was former president Cristina Kirchner (2007 to 2015), who was against abortion during her tenure, but who said she had changed her mind. “Today, I think …
Abstract 15944: Comparative Vascular Responses After Implantation of Everolimus-Eluting Bioresorbable Vascular Scaffolds in a Diabetic Atherosclerotic Porcine Coronary Arterial Model: A Longitudinal Histology Study
Authors: Mie Kurata, Nienke S van Ditzhuijzen, Mieke van den Heuvel, Oana Sorop, Richard van Duin, Ilona Krabbendam-Peters, Rorry van Haeren, Patrick W Serruys, Richard Rapoza, Felix Zijlstra, Dirk J Duncker, Evelyn S Regar, Heleen M van Beusekom
Journal: Circulation (2013)

Background: The outcome of patients with diabetes mellitus (DM) after revascularization is usually worse compared to non-DM (NDM) patients. Vascular tissue alterations following implantation of everolimus-eluting bioresorbable vascular scaffold (Absorb BVS) have been reported in a healthy swine coronary model. However, it is not known how DM and atherosclerosis affect this response. We therefore investigated the vascular response to Absorb BVS in a porcine coronary model of streptozotocin (STZ)-induced DM and a high cholesterol diet. Method: Of 15 farm-bred swine, 8 swine received 140 mg/kg STZ to induce DM. Two weeks after stable induction of DM, a high cholesterol diet was introduced (8 DM, 7 NDM). Nine months later, Absorb BVS (3.0x18 mm) were randomly implanted in the coronary arteries under guidance of quantitative coronary angiography (QCA). Histological analysis was performed on 5 scaffolds at 3 months (DM n=3, NDM n=2) and 10 scaffolds at 6months (DM n=5, NDM n=5). Analyses included neointimal thi...
Abstract 16504: Human Gene Profiling Reveals Contribution of Tissue Plasminogen Activator to Intimal Thickening of the Ductus Arteriosus
Authors: Junichi Saito, Utako Yokoyama, Munetaka Masuda, Toshihide Asou, Yoshihiro Ishikawa
Journal: Circulation (2016)

Introduction: Intimal thickening (IT) formation is required to lead complete closure of the ductus arteriosus (DA). The initial step of intimal thickening is disruption of the internal elastic lami...
Relationship between IDH1 mutation status and magnetic resonance imaging features in WHO grade II and III oligodendroglial tumors.
Authors: Frederique Toulgoat, Pierre Paul Arrigoni, Delphine Loussouarn, Christophe Leux, Jean-Sebastien Frenel, Marc G. Denis, Anne-Gaelle Le loupp, Maud Aumont, Mario Campone, Stephane Martin, Hubert Desal
Journal: Journal of Clinical Oncology (2012)

2082 Background: In gliomas, relationship between radiological characteristics and several biomarkers was the subject of numerous publications. Mutations in the isocitrate dehydrogenase 1 (IDH1) gene have been identified recently to play a key role in these tumors occuring in up to 75% of low-grade diffuse (WHO grade II) and anaplastic (WHO grade III) astrocytic, oligodendroglial and mixed oligodendroglial neoplasms. However, the correlation with magnetic resonance imaging (MRI) features has been little studied. Methods: Patients treated for WHO grade II and III oligodendroglial tumors between 2005 and 2011 were retrospectively identified. Each case has been reviewed by the same neuropathologist. IDH1 and IDH2 mutations were available. Preoperative MRI, including T1 weighted, T2 weighted, T1 contrast enhanced, FLAIR, T2* weighted, diffusion weighted (ADC ratio), perfusion weighted (CBV ratio) and MR spectroscopy, were analyzed by two radiologists blinded from molecular data. Logistic regression analysis and Fisher’s test were used to develop predictive models of genetic profile from imaging. Results: Sixty eight patients, WHO grade II (n= 37) and grade III (n=31) patients were identified. Mean age at diagnosis was 46 years; ratio male/female was 40/28. IDH1 mutations were identified in 42 patients (62 %), IDH2 in 4 patients (6 %). Analysis of tumor location, size, borders, morphological aspect, and signal did not shown any significant difference between IDH1 mutated group and IDH1 non mutated group neither in grade II nor in grade III oligodendroglial tumors. In the same way, MR spectroscopy (Choline/NAA ratio and detection of lipid and lactate) was not relevant to discern the two groups. As well, ADC ratio (1,5 versus 1,4; p=0,35) and CBV ratio (3,4 versus 4,2; p= 0,46) did not reveal any difference between mutated group and non mutated group. Conclusions: In our study, IDH1 mutations were not correlated with MRI features available during routine MRI. Nevertheless, recent studies suggest the ability of MR spectroscopy to detect 2-hydroxyglutarate as an MRI marker of IDH1 mutated tumors, which encourage carrying on research in molecular imaging.
Circulating Levels of Secretory Type II Phospholipase A2 Predict Coronary Events in Patients with Coronary Artery Disease
Authors: KiyotakaKugiyama, YasutakaOta, KeijiTakazoe, YasushiMoriyama, HiroakiKawano, YujiMiyao, TomohiroSakamoto, HirofumiSoejima, HisaoOgawa, HidekiDoi, SeigoSugiyama, HirofumiYasue
Journal: Circulation (1999)

Background—The circulating levels of secretory nonpancreatic type II phospholipase A2 (sPLA2) are increased in various chronic inflammatory diseases and the increase in the levels correlates with the disease severity. sPLA2 may possibly play a role in atherogenesis and is highly expressed in atherosclerotic arterial walls that are known to have inflammatory features. Thus, this study prospectively examined whether circulating levels of sPLA2 may have a significant risk and prognostic values in patients with coronary artery disease (CAD). Methods and Results—Plasma levels of sPLA2 were measured in 142 patients with CAD and in 93 control subjects by a radioimmunoassay. The sPLA2 levels had a significant and positive relations with serum levels of C-reactive protein, a marker of systemic inflammation, and with the number of the traditional coronary risk factors associated with individuals. Multivariate logistic regression analysis showed that higher levels of sPLA2 (>246 ng/dL; 75th percentile of sPLA2 distr...
Angiotensin II Induces LOX-1, the Human Endothelial Receptor for Oxidized Low-Density Lipoprotein
Authors: HenningMorawietz, UweRueckschloss, BerndNiemann, NicoleDuerrschmidt, JanGalle, KavousHakim, Hans-ReinhardZerkowski, TatsuyaSawamura, JuergenHoltz
Journal: Circulation (1999)

Background—Oxidatively modified LDL (oxLDL) plays an important role in the development of atherosclerosis. OxLDL effects, eg, foam cell formation, are mediated in part by the classic scavenger receptor, whereas other effects may involve the recently cloned endothelial oxLDL receptor, LOX-1 (lectinlike oxLDL receptor-1), which is distinct from macrophage scavenger receptors. Because the regulation of LOX-1 must still be defined, we investigated whether LOX-1 is regulated by the potentially proatherosclerotic stimulant angiotensin II (Ang II). Methods and Results—Using competitive reverse transcription–polymerase chain reaction (RT-PCR), we quantified mRNA expression of LOX-1 in primary cultures of human umbilical vein endothelial cells (HUVECs). After treatment with Ang II for 3 hours (1 nmol/L to 1 μmol/L), LOX-1 mRNA was concentration-dependently induced (from 6.9±1.4 to 23.1±5.5 relative units [RU] by 1 μmol/L Ang II; P<0.05). The angiotensin II type 1 (AT1) receptor antagonist losartan prevented this i...
Abstract 17538: Baseline High Sensitivity Cardiac Troponin-T Can Identify Reversible Myocardial Ischemia Even in the Presence of LV Systolic Dysfunction
Authors: Muhammad A Nadir, Sushma Rekhraj, Ellie Dow, John Davidson, Norman Kennedy, Allan D Struthers
Journal: Circulation (2012)

Background: Detectable levels of cardiac troponin-T by high sensitivity assay (hs-TnT) are elevated by both ischaemia and LV systolic dysfunction (LVSD) but it is unknown whether hs-TnT could be a ...
Positive and Negative Inotropic Effects of dl-Sotalol and d-Sotalol in Failing and Nonfailing Human Myocardium Under Physiological Experimental Conditions
Authors: ChristianHolubarsch, RalfSchneider, BurkertPieske, ThorstenRuf, GerdHasenfuss, GustavFraedrich, HerbertPosival, HanjörgJust
Journal: Circulation (1995)

Background dl-Sotalol has class III antiarrhythmic activity through prolongation of the repolarization phase of the action potential as well as β-adrenoceptor–blocking properties. Although the former effect was found to exert positive inotropic effects in animal experimental studies, the latter may be detrimental in heart failure due to negative inotropism. In contrast to dl-sotalol, d-sotalol is suggested to exert only positive inotropic effects, which were never tested in isolated human myocardium. Methods and Results Therefore, we investigated the effects of racemic dl-sotalol and its enantiomer d-sotalol in human right atrial muscle strip preparations and in left ventricular muscle strip preparations from nonfailing and end-stage failing human hearts. dl-sotalol and d-sotalol significantly (P<.01) increased peak developed force in atrial preparations by 14.0±3.4% and 16.7±3.8%, respectively, but had no effect in ventricular myocardium. In nonfailing ventricular myocardium, both dl-sotalol and d-sotalo...
Glycogen Synthase Kinase 3 Inhibition Slows Mitochondrial Adenine Nucleotide Transport and Regulates Voltage-Dependent Anion Channel Phosphorylation
Authors: SamarjitDas, ReneeWong, NishadiRajapakse, ElizabethMurphy, CharlesSteenbergen
Journal: Circulation Research (2008)

Inhibition of glycogen synthase kinase (GSK)-3 reduces ischemia/reperfusion injury by mechanisms that involve the mitochondria. The goal of this study was to explore possible molecular targets and mechanistic basis of this cardioprotective effect. In perfused rat hearts, treatment with GSK inhibitors before ischemia significantly improved recovery of function. To assess the effect of GSK inhibitors on mitochondrial function under ischemic conditions, mitochondria were isolated from rat hearts perfused with GSK inhibitors and were treated with uncoupler or cyanide or were made anoxic. GSK inhibition slowed ATP consumption under these conditions, which could be attributable to inhibition of ATP entry into the mitochondria through the voltage-dependent anion channel (VDAC) and/or adenine nucleotide transporter (ANT) or to inhibition of the F1F0-ATPase. To determine the site of the inhibitory effect on ATP consumption, we measured the conversion of ADP to AMP by adenylate kinase located in the intermembrane s...