tbuckley/cabot-search huggingface dataset:
Rax-dependent PKR activation is required for host anti-viral defense after vesicular stomatitis virus infection
Authors: Richard L. Bennett, William L. Blalock, Sue A. Moyer, W. Stratford May
Journal: Cancer Research (2006)

4450  The interferon-inducible dsRNA-dependent kinase PKR has been well studied as a component of host anti-viral defense. In this context, PKR is activated by dsRNA byproducts produced during viral infection to phosphorylate the alpha subunit of eukaryotic initiation factor 2 (eIF2alpha) and stop de novo protein synthesis. In previous studies we discovered and characterized Rax, which to date is the only identified cellular PKR activator. Rax is also a dsRNA binding protein, yet the role of Rax in host antiviral defense is not clear. Now we report that the level of Rax expression in murine embryonic fibroblast (MEF) cells directly affects resistance to infection by vesicular stomatitis virus (VSV). Knock-down of Rax expression in MEF cells by 80% using siRNA prevents virus-induced PKR activation and eIF2alpha phosphorylation. Consequently, cells with reduced Rax display in creased VSV protein synthesis and viral titers >1000 fold higher than control cells 24 hours after infection. In contrast, expression of exogenous Rax in MEF cells promotes PKR activation and eIF2alpha phosphorylation upon VSV infection and inhibits viral protein production resulting in decreased viral titer after infection compared to control cells. Interestingly, both lowering and increasing Rax expression enhanced cell death after infection with VSV. We propose that increased Rax expression promotes enhanced PKR activity and apoptosis while reduced Rax expression results in failure to activate PKR and increases cell death due to increased viral production following infection with VSV. Taken together, our findings indicate that Rax-dependent PKR activation is required for proper cellular host defense to infection by VSV. This may indicate that the Rax-PKR signaling axis has a necessary role to inhibit viral induced cellular transformation.
Understanding the relationship between general intelligence and socio-cognitive abilities in humans
Authors: Pablo Fernández-Berrocal, Rosario Cabello, María José Gutiérrez-Cobo
Journal: Behavioral and Brain Sciences (2017)

Abstract Burkart et al. consider that the relationship between general intelligence and socio-cognitive abilities is poorly understood in animals and humans. We examine this conclusion in the perspective of an already substantial evidence base on the relationship among general intelligence, theory of mind, and emotional intelligence. We propose a link between general intelligence and socio-cognitive abilities within humans.
Abstract 14766: Pulmonary Vein Isolation Alone is Not Superior to Amiodarone for the Treatment of Persistent Atrial Fibrillation in Patients With Congestive Heart Failure and an Implanted Device: Results From the AATAC Randomized Trial
Authors: Luigi Di Biase, Prasant Mohanty, Sanghamitra Mohanty, Pasquale Santangeli, Chintan Trivedi, Dhanujaya Lakkireddy, Madhu Reddy, Pierre Jais, Sakis Themistoclakis, Antonio Dello Russo, Michela Casella, Gemma Pelargonio, Maria Lucia Narducci, Robert Schweikert, Petr Neuzil, Javierr Sanchez, Rodney Horton, Salwa Beheiry, Richard Hongo, Steven Hao, Antonio Rossillo, Giovanni Forleo, Claudio Tondo, J. David Burkhardt, Michelle Haïssaguerre, Andrea Natale
Journal: Circulation (2015)

Introduction: The best treatment option for the management of patients (pts) with heart failure (HF) and persistent AF is unknown. The AATAC trial showed that catheter ablation (CA) is superior to Amiodarone in achieving freedom from AF at follow up. In this analysis we present the outcome sorted by type of AF procedure. Methods: AATAC was a randomized multicenter study. Pts with persistent AF, dual chamber ICD or CRTD, NYHA II-III and LV EF &lt;40% within the last 6 months were randomly assigned (1:1 ratio) to undergo CA for AF (group 1=102 pts) or receive AMIO, (group 2=101 pts). Recurrence of AF was the primary end point. Based on operator’s choice patients could undergo pulmonary vein isolation alone (PVI) or PVI plus posterior wall plus non PV trigger ablation (PVI+PW+NPV) as detected by high dosage of isoproterenol. Results: PVI was performed in 22 patients undergoing ablation, while PVI+PW+NPV ablation was performed in 80 patients. Baseline characteristics were not different between the groups. At 26±8 months follow-up, the success rates in PVI, PVI+PW+NPV, and AMIO groups were 8 [36.4%] and 63 [78.8%] and 34 (34.0%) respectively, p&lt;0.001 (figure). Patients receiving PVI+PW+NPV ablation, showed significantly higher success than those with PVI alone or amiodarone (p &lt;0.001). The outcome in the PVI alone group was not different from AMIO group (p= 0.67). No patient was lost to follow-up during the study period. At the time of analysis, all recurrence-free patients had completed ≥6 month follow-up. Conclusion: This randomized study shows that PVI alone has a low success rate similar to Amiodarone when compared to PVI plus posterior wall plus non pv trigger in patients with heart failure and persistent AF.
Abstract P312: Tracheal Instillation of Diesel Exhaust Particles Exacerbates Myocardial Ischaemia and Reperfusion Injury in Rats
Authors: Sarah Robertson, Ashleigh L Thomson, Catherine A Shaw, Mark R Miller, David E Newby, Patrick W Hadoke, Gillian A Gray
Journal: Circulation Research (2011)

Episodes of increased air pollution are associated with higher cardiovascular mortality. The adverse effects of air pollution have been attributed to particulate matter, especially ultrafine particles. This study addresses the hypothesis that ultrafine diesel exhaust particles (DEP) exacerbate myocardial ischaemia reperfusion (I/R) injury secondary to induction of a systemic inflammatory response. Wistar rats (n=5–6/group) received DEP (0.5 mg) or saline vehicle by intratracheal instillation. 6h later I/R was induced either in vivo or ex vivo in isolated buffer perfused hearts. Lung inflammation was confirmed 6h after DEP instillation by increased levels of neutrophils, total protein and IL-6 in bronchoalveolar lavage fluid. However, there was no evidence for systemic inflammation as assessed by plasma cytokine levels (IL-6, TNF-α, and CRP) or by neutrophil priming (CD11b expression) or activation (CD62L expression). In vivo , systolic blood pressure was significantly higher in DEP-instilled rats (129 ± 7 mmHg) than in saline controls (92 ± 3 mmHg, P&lt;0.01), consistent with increased autonomic activation. Arrhythmias occurred intermittently after induction of ischaemia (in total 8.2±1.2 s in the saline group) and were more prevalent in DEP-instilled rats (32.9±5.0s, P&lt;0.001). Fatal arrhythmias occurred in 60% of rats receiving DEP but not at all in saline controls. Following reperfusion, infarct size (extent of triphenyltetrazolium chloride staining) was significantly increased after DEP (34.7 ± 1.2% left ventricle) vs saline-instilled (10.3 ± 1.2%, P&lt;0.001). Infarct size was similarly potentiated in hearts isolated from DEP instilled rats and perfused ex-vivo . Histological examination confirmed the absence of inflammatory infiltrate in hearts prior to I/R. Prior exposure to pollution in vivo thus renders the heart more vulnerable to I/R injury, either in situ in the body or ex vivo when the heart is isolated from systemic mediators and cells. Systemic inflammation does not appear to be necessary for this ‘priming’ effect of DEP. The role of autonomic activation in promoting cardiac arrythmia in vivo after DEP instillation and in determining the ability of the heart to withstand subsequent I/R injury merits further investigation.
Therapeutic Targeting of the CBP/p300 Bromodomain Blocks the Growth of Castration-Resistant Prostate Cancer
Authors: Lingyan Jin, Jesse Garcia, Emily Chan, Cecile de la Cruz, Ehud Segal, Mark Merchant, Samir Kharbanda, Ryan Raisner, Peter M. Haverty, Zora Modrusan, Justin Ly, Edna Choo, Susan Kaufman, Maureen H. Beresini, F. Anthony Romero, Steven Magnuson, Karen E. Gascoigne
Journal: Cancer Research (2017)

Resistance invariably develops to antiandrogen therapies used to treat newly diagnosed prostate cancers, but effective treatments for castration-resistant disease remain elusive. Here, we report that the transcriptional coactivator CBP/p300 is required to maintain the growth of castration-resistant prostate cancer. To exploit this vulnerability, we developed a novel small-molecule inhibitor of the CBP/p300 bromodomain that blocks prostate cancer growth in vitro and in vivo Molecular dissection of the consequences of drug treatment revealed a critical role for CBP/p300 in histone acetylation required for the transcriptional activity of the androgen receptor and its target gene expression. Our findings offer a preclinical proof of concept for small-molecule therapies to target the CBP/p300 bromodomain as a strategy to treat castration-resistant prostate cancer. Cancer Res; 77(20); 5564-75. ©2017 AACR.
DLC-1 exerts its suppressive effect through the specific inhibition of Cdc42-mediated cell growth promotion in human NCI-H358 lung adenocarcinoma cell line
Authors: Bao-Zhu Yuan, Amy M. Jefferson, Steven H. Reynolds
Journal: Cancer Research (2004)

1878   The DLC-1 functions as a tumor suppressor gene in human non-small cell lung carcinoma (NSCLC) and contains three functional domains, which are the sterile alpha motif (SAM), the RhoGTPase activating (GAP) and the steroidogenic acute regulatory-related lipid-transfer (START) domain. RhoA and Cdc42, among the members of Rho GTPase subfamily, were suspected to be the targets of the GAP domain of DLC-1. To determine the involvement of DLC-1’s three functional domains in the suppression of NSCLC cell growth, we performed gene transfection studies using different mutations of DLC-1, which are the deletions of one of the three functional DLC-1 domains, or a point mutation at codon 667, 714 or 718 in the GAP domain, and using NCI-H358, a human NSCLC cell line without intrinsic expression of DLC-1, as the host cell to test the effect of different DLC-1 mutations on tumor cell growth. It was shown that deletion of either the GAP or START domains, but not the SAM domain, significantly reduced the suppressive effect of wild type DLC-1 on  in vitro  cell growth as well as on  in vivo  tumorigenicity. Among three point mutations, R718E mutation eliminated the function of wild type DLC-1 in cell growth inhibition, whereas K667E and K714E mutations exhibited smaller effects. To determine the specific target of DLC-1’s GAP domain, a secondary DNA transfection study using RhoA, RhoA-G14V (constitutively activated) and RhoA-T19N (dominant negative) cDNAs, or Cdc42, Cdc42-G12V (constitutively activated) and Cdc42-T17N (dominant negative) cDNAs was performed using different mutated DLC-1 transfected NCI-H358 as host cells and employing a colony formation assay to test the effect of secondary transfection on tumor cell growth. New findings in this study were: 1) Cdc42 or RhoA-T19N promoted growth of parental NCI-H358 cells, but RhoA or Cdc42-T17N dramatically inhibited cell growth; 2) DLC-1 inhibited both Cdc42 and RhoA-T19N in cell growth; 3) SAM domain deletion significantly enhanced inhibitory effect of DLC-1 on Cdc42; 4) GAP domain deletion and point mutations significantly reduced the inhibitory effect of DLC-1 on Cdc42; 5) START domain deletion reduced the inhibitory effect on RhoA-T19N. Taken together, these data suggest that both the GAP and START domains, but not the SAM domain, are directly involved in DLC-1-mediated inhibition of tumor cell growth. RhoA acts as an inhibitory regulator, while Cdc42 behaves as a promoting element in tumor cell growth. The DLC-1 operates as a tumor suppressor gene in NCI-H358 cell line through specifically inhibiting Cdc42 with its RhoGAP domain and enhancing RhoA’s inhibitory effect with its START domain.
PTU-076 The “getting fit” project in nottingham: a comparison of haemoglobin levels as measured by oc sensor and hm jack in two week wait referrals
Authors: CJ Chapman, A Banerjea, O Ng, A Barke, A Duffin, K Dale, J Allen, RF Logan
Journal: Gut (2017)

Introduction  NICE guidance (NG12), published in 2015, on indications for urgent referral for possible colorectal cancer (CRC) included the use of faecal occult blood tests (FOB). We report here our early experience of using two different FIT kits in the two week wait (2WW) pathway.  Method  In September 2016 FIT was incorporated into Nottingham’s straight to test (STT) pathway. FIT kits from 2 different manufacturers were posted to patients referred on the 2WW pathway without rectal bleeding with instructions for use. Patients were asked to complete both kits and sample faecal material from the same bowel motion. All returned kits were analysed according to manufacturer’s protocols (EIKEN OC-Sensor and Alpha HM Jack) and results expressed in µg Hb/g faeces. Statistical analyses were undertaken on GraphPad Prism 3.0. Data on patients who returned kits between 6/9/16 and 10/2/17 are included in this report.  Results  So far 348/441 (79%) individuals within the 2WW pathway have returned samples, with 334 individuals returning two analysable samples. Mean time to return was 7 days, with ~95% returned within 14 days. FIT results for OC sensor and HM Jack are shown in the Table. Linear regression analysis of 310 pairs of samples (with values  14 CRCs were identified in the 2WW cohort. Eleven of these cancers had values>150 µg Hb/g faeces in at least 1 test (10 in both tests). The other 3 (21%) had values between 3 and 25µgHb/g in both tests. These CRCs were all right sided cancers in patients with anaemia at the time of referral.  Using a cut off of 10 µg/g for OC sensor, or 7 µg/g for HM Jack, 2 of these cancers would have been missed, depending on the test used. Although rare, levels of faecal Hb were observed to vary as much as 100x within the same bowel motion with 3 individuals having Hb levels 100 µg/g in the other.  Conclusion  Our experience shows that FIT sent by post can be introduced into symptomatic pathways with a high and rapid return rate. With either FIT a value of >150 µg/g has a high predictive value for CRC but even at the proposed 10 µg/g threshold with a single FIT 21% would go undetected.  Finally differences in in levels of Hb within the same individual bowel motion may be due to differences in distribution of blood within a single faecal sample, highlighting the importance of repeat testing for individuals whose symptoms persist.  Disclosure of Interest  None Declared
Epigenetic regulation of hepatitis B virus covalently closed circular DNA: Implications for epigenetic therapy against chronic hepatitis B
Authors: Xupeng Hong, Elena S. Kim, Haitao Guo
Journal: Hepatology (2017)

Hepatitis B virus (HBV) infection represents a significant public health burden worldwide. Although current therapeutics manage to control the disease progression, lifelong treatment and surveillance are required because drug resistance develops during treatment and reactivations frequently occur following medication cessation. Thus, the occurrence of hepatocellular carcinoma is decreased, but not eliminated. One major reason for failure of HBV treatment is the inability to eradicate or inactivate the viral covalently closed circular DNA (cccDNA), which is a stable episomal form of the viral genome decorated with host histones and nonhistone proteins. Accumulating evidence suggests that epigenetic modifications of cccDNA contribute to viral replication and the outcome of chronic HBV infection. Here, we summarize current progress on HBV epigenetics research and the therapeutic implications for chronic HBV infection by learning from the epigenetic therapies for cancer and other viral diseases, which may open a new venue to cure chronic hepatitis B. (Hepatology 2017;66:2066-2077).
Gambogic acid mediates transferrin receptor-1 phosphorylation leading to jnk-dependant apoptosis
Authors: Jinlong Jian, Jonathan Eckard, Xi Huang
Journal: Cancer Research (2008)

3399  Transferrin receptor 1 (TfR1) is a ubiquitous type II membrane receptor with 63aa in the N-terminal cytoplasmic region. TfR1 is highly expressed in proliferating normal cells and cancer cells but not quiescent cells. Overexpression of TfR1 in highly proliferating cells and cancer cells is thought to be a result of the increased requirement of iron uptake necessary for cell growth. Recently, our study has shown that total iron content, measured by atomic absorption, is comparable among various types of cells expressing different levels of TfR1. These results suggest that TfR1 may have other functions because TfR1 gene expression could be independent of iron status. In the present study, we have tested a hypothesis that, in addition to its known function of iron transport through transferrin, TfR1 is a signaling molecule that plays a role in cell survival and apoptosis. Using gambogic acid (GA), an apoptosis inducer and recently identified TfR1 ligand, we have found that GA induced tyrosine phosphorylation of TfR1 protein, most likely in theY20 position of the cytoplasmic region, in primary normal human epidermal keratinocytes and breast cancer MDA-MB-231 cells. On the contrary, the iron transport protein transferrin and inorganic iron did not induce tyrosine phosphorylation of TfR1. Furthermore, GA, but not transferrin, activated the JNK and p38 signal pathways and cell apoptosis. The JNK kinase inhibitor SP600125 partially blocked GA-induced apoptosis and caspase-3 and -8 cleavages. Upon GA treatment, Src was activated exerting its anti-apoptotic effect and the Src inhibitor PP2 promoted GA-induce apoptosis and JNK activation. Our results indicate that in addition to iron transport, TfR1 may play a role in regulating cell survival and apoptosis. This work is supported by R21 CA132684.
Epigenome-Wide Association Study Identifies Cardiac Gene Patterning and a Novel Class of Biomarkers for Heart Failure
Authors: Benjamin Meder, Jan Haas, Farbod Sedaghat-Hamedani, Elham Kayvanpour, Karen Frese, Alan Lai, Rouven Nietsch, Christina Scheiner, Stefan Mester, Diana Martins Bordalo, Ali Amr, Carsten Dietrich, Dietmar Pils, Dominik Siede, Hauke Hund, Andrea Bauer, Daniel Benjamin Holzer, Arjang Ruhparwar, Matthias Mueller-Hennessen, Dieter Weichenhan, Christoph Plass, Tanja Weis, Johannes Backs, Maximilian Wuerstle, Andreas Keller, Hugo A. Katus, Andreas E. Posch
Journal: Circulation (2017)

Biochemical DNA modification resembles a crucial regulatory layer among genetic information, environmental factors, and the transcriptome. To identify epigenetic susceptibility regions and novel biomarkers linked to myocardial dysfunction and heart failure, we performed the first multi-omics study in myocardial tissue and blood of patients with dilated cardiomyopathy and controls.Infinium human methylation 450 was used for high-density epigenome-wide mapping of DNA methylation in left-ventricular biopsies and whole peripheral blood of living probands. RNA deep sequencing was performed on the same samples in parallel. Whole-genome sequencing of all patients allowed exclusion of promiscuous genotype-induced methylation calls.In the screening stage, we detected 59 epigenetic loci that are significantly associated with dilated cardiomyopathy (false discovery corrected P≤0.05), with 3 of them reaching epigenome-wide significance at P≤5×10-8. Twenty-seven (46%) of these loci could be replicated in independent cohorts, underlining the role of epigenetic regulation of key cardiac transcription regulators. Using a staged multi-omics study design, we link a subset of 517 epigenetic loci with dilated cardiomyopathy and cardiac gene expression. Furthermore, we identified distinct epigenetic methylation patterns that are conserved across tissues, rendering these CpGs novel epigenetic biomarkers for heart failure.The present study provides to our knowledge the first epigenome-wide association study in living patients with heart failure using a multi-omics approach.
Hazards of Neurological Nomenclature
Authors: Rahul S. Desikan, A. James Barkovich
Journal: JAMA Neurology (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Neurology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Neurology journal
Abstract 17603: Transgenic Overexpression of Alanine-glyoxylate Aminotransferase 2 in Mice Lowers Asymmetric Dimethylarginine and Improves Vasomotor Function
Authors: Roman N Rodionov, Dmitrii Burdin, Silke Brilloff, Vladimir Todorov, Natalia Jarzebska, Jens Martens-Lobenhoffer, Anton Demyanov, Karl Hilgers, Nada Cordasic, Johannes Jacobi, Renke Maas, Anja Hofmann, Henning Morawietz, Stefanie M Bode-Böger, Christian P Hugo, Bernd Hohenstein, Norbert Weiss
Journal: Circulation (2015)

Background: ADMA (asymmetric dimethylarginine), an inhibitor of nitric oxide synthase, has been shown to be associated with the risk of cardiovascular diseases. There are two known pathways for ADMA catabolism: hydrolysis to citrulline by dimethylarginine dimethylaminohydrolases (DDAH) and transamination by alanine-glyoxylate aminotransferase 2 (AGXT2) with formation of asymmetric dimethylguanidino valeric acid (ADGV). In contrast to the first pathway, the second one is poorly characterized. The goal of our study was to test the hypothesis that transgenic overexpression of AGXT2 would lead to lowering of systemic levels of ADMA and improvement of vasomotor function. Results: We generated transgenic mice (TG) with ubiquitous overexpression of AGXT2 under control of the chicken beta actin (CAG) promoter. qPCR and Western Blot were used to confirm the ubiquitous expression of the transgene. We did not observe and developmental or phenotypic abnormalities in the TG animals. Biochemical data were generated using HPLC-MS/MS. AGXT2 TG mice had ADMA plasma levels decreased by 15% (p&lt;0.05), whereas ADGV plasma levels were 6 times higher in comparison with wild-types (p&lt;0.001). Lung and heart of TG animals exhibited 2 times lower tissue ADMA content in comparison with controls (p&lt;0.05). Isolated aortic rings were used to estimate endothelium-dependent and -independent relaxation in response to acetylcholine (Ach) and sodium nitroprusside (SNP), respectively. Aortas from AGXT2 TG mice demonstrated an increase in maximal response to ACh (p&lt;0.05). There was a similar relaxation in response to SNP in both groups. We did not observe any differences in mean arterial blood pressure measured by telemetry between the wild type and AGXT2 TG mice. Conclusion: In the current study we were able to demonstrate that upregulation of AGXT2 leads to lowering of ADMA levels and improvement in endothelial-dependent relaxation in vivo. AGXT2 thereby may be a potential drug target for long-term reduction of systemic ADMA levels in cardiovascular pathologies. This is especially important, because all the efforts to develop ADMA-lowering interventions by means of upregulation of DDAH have not been successful so far.