bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression of MicroRNA miR-122 Facilitates an Efficient Replication in Nonhepatic Cells upon Infection with Hepatitis C Virus
Authors: Fukuhara Takasuke , Kambara Hiroto , Shiokawa Mai , Ono Chikako , Katoh Hiroshi , Morita Eiji , Okuzaki Daisuke , Maehara Yoshihiko , Koike Kazuhiko , Matsuura Yoshiharu 
Published: May 2012

ABSTRACT

Hepatitis C virus (HCV) is one of the most common etiologic agents of chronic liver diseases, including liver cirrhosis and hepatocellular carcinoma. In addition, HCV infection is often associated with extrahepatic manifestations (EHM), including mixed cryoglobulinemia and non-Hodgkin's lymphoma. However, the mechanisms of cell tropism of HCV and HCV-induced EHM remain elusive, because
in vitro
propagation of HCV has been limited in the combination of cell culture-adapted HCV (HCVcc) and several hepatic cell lines. Recently, a liver-specific microRNA called miR-122 was shown to facilitate the efficient propagation of HCVcc in several hepatic cell lines. In this study, we evaluated the importance of miR-122 on the replication of HCV in nonhepatic cells. Among the nonhepatic cell lines expressing functional HCV entry receptors, Hec1B cells derived from human uterus exhibited a low level of replication of the HCV genome upon infection with HCVcc. Exogenous expression of miR-122 in several cells facilitates efficient viral replication but not production of infectious particles, probably due to the lack of hepatocytic lipid metabolism. Furthermore, expression of mutant miR-122 carrying a substitution in a seed domain was required for efficient replication of mutant HCVcc carrying complementary substitutions in miR-122-binding sites, suggesting that specific interaction between miR-122 and HCV RNA is essential for the enhancement of viral replication. In conclusion, although miR-122 facilitates efficient viral replication in nonhepatic cells, factors other than miR-122, which are most likely specific to hepatocytes, are required for HCV assembly.
Suppression of Extracellular Signal-Regulated Kinase Activity in Herpes Simplex Virus 1-Infected Cells by the Us3 Protein Kinase
Authors: Chuluunbaatar Uyanga , Roller Richard , Mohr Ian 
Published: May 2012

ABSTRACT
Host mitogen-activated protein kinases (MAPKs) are deregulated by herpes simplex virus 1 (HSV-1). Unlike p38 MAPK and Jun N-terminal protein kinase (JNK), which require ICP27 for their activation early in infection, extracellular signal-regulated kinase (ERK) activity is suppressed by an unknown mechanism. Here, we establish that HSV-1-induced suppression of ERK activity requires viral gene expression, occurs with delayed-early kinetics, and requires the functional virus-encoded Us3 Ser/Thr protein kinase. Finally, Us3 expression in uninfected cells was necessary and sufficient to suppress ERK activity in the absence of any other virus-encoded gene products. This demonstrates that inhibition of ERK activity in HSV-1-infected cells is an intrinsic Us3 function and defines a new role for this alphaherpesvirus Us3 kinase in regulating MAPK activation in infected cells.
A Single Mutation in the Glycophorin A Binding Site of Hepatitis A Virus Enhances Virus Clearance from the Blood and Results in a Lower Fitness Variant
Authors: Costafreda M. Isabel , Ribes Enric , Franch Àngels , Bosch Albert , Pintó Rosa M. 
Published: May 2012

ABSTRACT

Hepatitis A virus (HAV) has previously been reported to bind to human red blood cells through interaction with glycophorin A. Residue K221 of VP1 and the surrounding VP3 residues are involved in such an interaction. This capsid region is specifically recognized by the monoclonal antibody H7C27. A monoclonal antibody-resistant mutant with the mutation G1217D has been isolated. In the present study, the G1217D mutant was characterized physically and biologically in comparison with the parental HM175 43c strain. The G1217D mutant is more sensitive to acid pH and binds more efficiently to human and rat erythrocytes than the parental 43c strain. In a rat model, it is eliminated from serum more rapidly and consequently reaches the liver with a certain delay compared to the parental 43c strain. In competition experiments performed
in vivo
in the rat model, the G1217D mutant was efficiently outcompeted by the parental 43c strain. Only in the presence of antibodies reacting specifically with the parental 43c strain could the G1217D mutant outcompete the parental 43c strain in serum, although the latter still showed a remarkable ability to reach the liver. Altogether, these results indicate that the G1217D mutation induces a low fitness phenotype which could explain the lack of natural antigenic variants of the glycophorin A binding site.
cis
-Acting Determinants of 7SL RNA Packaging by HIV-1
Authors: Keene Sarra E. , Telesnitsky Alice 
Published: May 2012

ABSTRACT

The host noncoding RNA 7SL is highly enriched in the virions of retroviruses. We examined the regions of 7SL that mediate packaging by HIV-1. Both the
Alu
domain and the S domain were sufficient to mediate specific packaging when expressed separately as truncations of 7SL. However, while the
Alu
domain competed with endogenous 7SL for packaging in proportion to Gag, the S domain was packaged additively, implying that the
Alu
and S domains are packaged via separate mechanisms and that the
Alu
domain is packaged by the same mechanism as endogenous 7SL. Further truncations of the
Alu
domain or mutation of the
Alu
domain helix 5c region significantly reduced packaging efficiency, implicating helix 5c as critical for packaging, reinforcing the finding that 7SL packaging is highly selective, and confirming that 7SL is not passively acquired. Surprisingly, when the
Alu
domain was mutated so that it no longer contained a binding site for the SRP protein heterodimer SRP9/14, it was no longer packaged in a competitive manner but instead was packaged additively with endogenous 7SL. These data support a model in which 7SL RNA is packaged via interactions between Gag and a 7SL RNA structure that exists transiently at a discrete stage of SRP biogenesis. Our data further indicate that a secondary “additive” pathway exists that can result in the packaging of certain 7SL derivatives in molar excess to endogenously packaged 7SL.
An evidence based blunt trauma protocol
Authors: van Vugt Raoul , Kool Digna R , Lubeek Satish F K , Dekker Helena M , Brink Monique , Deunk Jaap , Edwards Michael J R 
Published: May 2012

ObjectiveCurrently CT is rapidly implemented in the evaluation of trauma patients. In anticipation of a large international multicentre trial, this study's aim was to evaluate the clinical feasibility of a new diagnostic protocol, used for the primary radiological evaluation in adult blunt high-energy trauma patients, especially for the use of CT.MethodsAn evidence-based flow chart was created with criteria based on trauma mechanism, physical examination and laboratory analyses to indicate appropriateness of conventional radiography (CR), sonography and CT of head, cervical spine and trunk. To evaluate this protocol, the authors prospectively included 81 consecutive patients. Collected data included protocol adherence and number and type of performed CR and CT scans. The authors also determined the time needed to perform radiological investigations, adverse events in the CT room and clinically relevant missed injuries after 1-month clinical follow-up.ResultsThere was 99% adherence to the protocol concerning CT. Seventy-nine patients (98%) received one or more CT scans: 72 (89%) had thoracoabdominal, 78 (96%) cervical spine and 54 (67%) had cranial CT. In 30 patients, one or more CT scans of body regions could be omitted. In 38%, CR was wrongly omitted or performed incorrectly at a variance with the protocol. No major adverse events occurred in the CT room and no clinically relevant injuries were missed.ConclusionsThe authors introduced a diagnostic protocol that seems feasible and safe for the evaluation of adult blunt high-energy trauma patients. Implementation of this protocol has the potential to reduce unnecessary radiological investigations, especially CT scans.
Preventive behaviours against radiation and related factors among general workers after Fukushima's nuclear disasters
Authors: Kanda Hideyuki , Hayakawa Takehito , Koyama Kikuo 
Published: May 2012

BackgroundThe nuclear power plant accidents in Fukushima resulted in a widespread release of radioactive substances in the Fukushima prefecture.AimTo clarify what factors led to precautions among general workers who displayed preventive behaviours against radiation following the nuclear disasters in Fukushima.MethodsDescriptive study of preventive behaviours among general workers 3–5 months following the nuclear disasters. The subjects were 1394 regular workers who took part in radiation seminars conducted by the Fukushima Occupational Health Promotion Center between July and August 2011. Of 1217 responses, 1110 eligible responses were included in this study. This anonymous questionnaire survey was asking for characteristics and questions on preventive behaviours following the nuclear disasters. The authors assessed the contribution of each variable by a logistic regression analysis.ResultsKeeping track of environmental radiation levels and washing hands and gargling were significantly more frequent among female subjects, older age and workers residing up to approximately 80 km away from the power plants. Washing hands and gargling were also related with living with children. Wearing a mask when leaving home and buying bottled water were significantly more often observed with female subjects and workers residing up to 80 km. Refraining from going outdoors was positively associated with workers residing up to 80 km and workers living with children.ConclusionsThese results provide information that may help with the targeting of health information after a nuclear disaster. This may contribute to determining an order of priority when distributing information after a nuclear disaster.
Adequacy of the emergency point-of-care ultrasound core curriculum for the local burden of disease in South Africa
Authors: van Hoving Daniël J , Lamprecht Heinrich H , Stander Melanie , Vallabh Kamil , Fredericks David , Louw Pauline , Müller Monique , Malan Jacques J 
Published: May 2012

ObjectiveThis prospective cross-sectional study assesses the adequacy of the current South African emergency point-of-care ultrasound (EPCUS) core curriculum against the local burden of disease.MethodPatients presenting to five Emergency Centres during July 2011 were eligible for inclusion. Patients under the age of 12, after-hour presentations, missing folders and folders with incomplete notes were excluded. Emergency physicians with EPCUS exposure were responsible for data collection. They were all blinded to the study's aim. Summary statistics describe the proportion of clinical cases and procedures for which EPCUS was used. One investigator assessed the adequacy of the curriculum by matching the clinical indications of each module with the presenting complaint and final diagnosis of each patient. The ultrasound modules were ranked according to the frequency of their clinical indications. κ-Statistics are reported on 10% randomly selected cases to quantify interobserver agreement.ResultsThe study included 2971 patients. Ultrasound assisted with diagnosis in 384 (12.92%) patients and in 34 (1.14%) procedures. A total of 1933 EPCUS procedures were indicated in 1844 (66.07%) patients. The five most frequently indicated modules were pulmonary, musculoskeletal, cardiac, focused assessment with sonography of HIV/tuberculosis co-infection and renal. The interobserver agreement (κ) was 0.602 (95% CI 0.559 to 0.645).ConclusionsThis study was an attempt to ensure an evidence-based approach to assess the adequacy of the EPCUS core curriculum in South Africa. The results illustrate that our local burden of disease may require a change of the current core curriculum.
Cancer Angiogenesis Induced by Kaposi Sarcoma–Associated Herpesvirus Is Mediated by EZH2
Authors: He Meilan , Zhang Wei , Bakken Thomas , Schutten Melissa , Toth Zsolt , Jung Jae U. , Gill Parkash , Cannon Mark , Gao Shou-Jiang 
Published: May 2012

Abstract
EZH2 is a component of the epigenetic regulator PRC2 that suppresses gene expression. Elevated expression of EZH2 is common in human cancers and is associated with tumor progression and poor prognosis. In this study, we show that EZH2 elevation is associated with epigenetic modifications of Kaposi sarcoma–associated herpesvirus (KSHV), an oncogenic virus that promotes the development of Kaposi sarcoma and other malignancies that occur in patients with chronic HIV infections. KSHV induction of EZH2 expression was essential for KSHV-induced angiogenesis. High expression of EZH2 was observed in Kaposi sarcoma tumors. In cell culture, latent KSHV infection upregulated the expression of EZH2 in human endothelial cells through the expression of vFLIP and LANA, two KSHV-latent genes that activate the NF-κB pathway. KSHV-mediated upregulation of EZH2 was required for the induction of Ephrin-B2, an essential proangiogenic factor that drives endothelial cell tubule formation. Taken together, our findings indicate that KSHV regulates the host epigenetic modifier EZH2 to promote angiogenesis. Cancer Res; 72(14); 3582–92. ©2012 AACR.
New Use for an Old Drug: Inhibiting ABCG2 with Sorafenib
Authors: Wei Yinxiang , Ma Yuanfang , Zhao Qing , Ren Zhiguang , Li Yan , Hou Tingjun , Peng Hui 
Published: May 2012

Abstract
Human ABCG2, a member of the ATP-binding cassette transporter superfamily, represents a promising target for sensitizing MDR in cancer chemotherapy. Although lots of ABCG2 inhibitors were identified, none of them has been tested clinically, maybe because of several problems such as toxicity or safety and pharmacokinetic uncertainty of compounds with novel chemical structures. One efficient solution is to rediscover new uses for existing drugs with known pharmacokinetics and safety profiles. Here, we found the new use for sorafenib, which has a dual-mode action by inducing ABCG2 degradation in lysosome in addition to inhibiting its function. Previously, we reported some novel dual-acting ABCG2 inhibitors that showed closer similarity to degradation-induced mechanism of action. On the basis of these ABCG2 inhibitors with diverse chemical structures, we developed a pharmacophore model for identifying the critical pharmacophore features necessary for dual-acting ABCG2 inhibitors. Sorafenib forms impressive alignment with the pharmacophore hypothesis, supporting the argument that sorafenib is a potential ABCG2 inhibitor. This is the first article that sorafenib may be a good candidate for chemosensitizing agent targeting ABCG2-mediated MDR. This study may facilitate the rediscovery of new functions of structurally diverse old drugs and provide a more effective and safe way of sensitizing MDR in cancer chemotherapy. Mol Cancer Ther; 11(8); 1693–702. ©2012 AACR.
Analysis of Gene Expression Regulated by the ETV5 Transcription Factor in OV90 Ovarian Cancer Cells Identifies FOXM1 Overexpression in Ovarian Cancer
Authors: Llauradó Marta , Majem Blanca , Castellví Josep , Cabrera Sílvia , Gil-Moreno Antonio , Reventós Jaume , Ruiz Anna 
Published: May 2012

Abstract
Epithelial ovarian cancer is the most lethal gynecologic malignancy and the fifth leading cause of cancer death in women in the Western world. ETS transcription factors have been implicated in the regulation of gene expression during a variety of biologic processes including cell growth and differentiation. We recently examined the role of the ETS transcription factor ETV5 in epithelial ovarian cancer and described ETV5 as being upregulated in ovarian tumor samples as compared with ovarian tissue controls. In ovarian cancer cells, we showed that ETV5 regulated the expression of cell adhesion molecules, enhancing ovarian cancer cell survival in anchorage-independent conditions and suggesting that it plays a role in ovarian cancer cell dissemination and metastasis into the peritoneal cavity. To understand the role of ETV5 transcription factor during ovarian cancer cell dissemination, we analyzed by gene expression microarray technology those genes whose expression was altered in an ovarian cancer cell line with a stable downregulation of ETV5. The analysis of the genes and signaling pathways under the control of ETV5 in OV90 cells has unraveled new signaling pathways that interact with ETV5, among them the cell-cycle progression and the TGFβ signaling pathway. In addition, we found that the downregulation of ETV5 reduced the expression of the oncogenic transcription factor FOXM1. Consistently, FOXM1 was overexpressed in ovarian tumor samples, and its transcriptional levels increased with ETV5 transcription in ovarian tumor samples. Moreover, FOXM1 expression levels increased with tumor grade, suggesting a role in the progression of ovarian cancer. Mol Cancer Res; 10(7); 914–24. ©2012 AACR.
Acute Hemodynamic Effect of Left Ventricular Endocardial Pacing in Cardiac Resynchronization Therapy
Authors: Padeletti Luigi , Pieragnoli Paolo , Ricciardi Giuseppe , Perrotta Laura , Grifoni Gino , Porciani Maria Cristina , Lionetti Vincenzo , Valsecchi Sergio 
Published: May 2012

Background—
During cardiac resynchronization therapy (CRT) device implantation, the pacing lead is usually positioned in the coronary sinus (CS) to stimulate the left ventricular (LV) epicardium. Transvenous LV endocardial pacing via transseptal puncture has been proposed as an alternative method. In the present study, we evaluated the acute hemodynamic effects of CRT through LV endocardial pacing in heart failure patients by analyzing LV pressure–volume relationships.

Methods and Results—

LV pressure and volume data were determined via conductance catheter during CRT device implantation in 10 patients. In addition to the standard epicardial CS pacing, the following endocardial LV sites were systematically assessed: the site transmural to the CS lead, the LV apex, the septal midwall, the basal lateral free wall, and the midlateral free wall. Four atrioventricular delays were tested. There was a significant improvement of systolic function with CRT in all LV pacing configurations, whereas no differences in systolic or diastolic function were detected between LV epicardial and endocardial transmural sites. The optimal pacing site varied among patients but was rarely related to relatively longer activation delays, as assessed by analyzing endocardial electric activation maps. Nonetheless, positioning the pacing lead at the optimal endocardial LV site in each patient significantly improved LV performance in comparison with conventional CS site stimulation (stroke volume, 83 [79–112] mL versus 73 [62–89] mL;
P
=0.034).

Conclusions—
Pacing at the optimal individual LV endocardial site yields enhanced LV performance in comparison with conventional CS site stimulation. Endocardial LV pacing might constitute an alternative approach to CRT, when CS pacing is not viable.
Off-Pump Coronary Artery Bypass Surgery Is Associated With Worse Arterial and Saphenous Vein Graft Patency and Less Effective Revascularization
Authors: Hattler Brack , Messenger John C. , Shroyer A. Laurie , Collins Joseph F. , Haugen Scott J. , Garcia Joel A. , Baltz Janet H. , Cleveland Joseph C. , Novitzky Dimitri , Grover Frederick L. 
Published: May 2012

Background—
The Department of Veterans Affairs Randomized On/Off Bypass (ROOBY) trial compared clinical and angiographic outcomes in off-pump versus on-pump coronary artery bypass graft (CABG) surgery to ascertain the relative efficacy of the 2 techniques.

Methods and Results—

From February 2002 to May 2007, the ROOBY trial randomized 2203 patients to off-pump versus on-pump CABG. Follow-up angiography was obtained in 685 off-pump (62%) and 685 on-pump (62%) patients. Angiograms were analyzed (blinded to treatment) for FitzGibbon classification (A=widely patent, B=flow limited, O=occluded) and effective revascularization. Effective revascularization was defined as follows: All 3 major coronary territories with significant disease were revascularized by a FitzGibbon A-quality graft to the major diseased artery, and there were no new postanastomotic lesions. Off-pump CABG resulted in lower FitzGibbon A patency rates than on-pump CABG for arterial conduits (85.8% versus 91.4%;
P
=0.003) and saphenous vein grafts (72.7% versus 80.4%;
P
<0.001). Fewer off-pump patients were effectively revascularized (50.1% versus 63.9% on-pump;
P
<0.001). Within each major coronary territory, effective revascularization was worse off pump than on pump (all
P
≤0.001). The 1-year adverse cardiac event rate was 16.4% in patients with ineffective revascularization versus 5.9% in patients with effective revascularization (
P
<0.001).

Conclusions—
Off-pump CABG resulted in significantly lower FitzGibbon A patency for arterial and saphenous vein graft conduits and less effective revascularization than on-pump CABG. At 1 year, patients with less effective revascularization had higher adverse event rates.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00032630.
Reduced Endoglin Activity Limits Cardiac Fibrosis and Improves Survival in Heart Failure
Authors: Kapur Navin K. , Wilson Szuhuei , Yunis Adil A. , Qiao Xiaoying , Mackey Emily , Paruchuri Vikram , Baker Corey , Aronovitz Mark J. , Karumanchi S. Ananth , Letarte Michelle , Kass David A. , Mendelsohn Michael E. , Karas Richard H. 
Published: May 2012

Background—
Heart failure is a major cause of morbidity and mortality worldwide. The ubiquitously expressed cytokine transforming growth factor-β1 (TGFβ1) promotes cardiac fibrosis, an important component of progressive heart failure. Membrane-associated endoglin is a coreceptor for TGFβ1 signaling and has been studied in vascular remodeling and preeclampsia. We hypothesized that reduced endoglin expression may limit cardiac fibrosis in heart failure.

Methods and Results—
We first report that endoglin expression is increased in the left ventricle of human subjects with heart failure and determined that endoglin is required for TGFβ1 signaling in human cardiac fibroblasts using neutralizing antibodies and an siRNA approach. We further identified that reduced endoglin expression attenuates cardiac fibrosis, preserves left ventricular function, and improves survival in a mouse model of pressure-overload–induced heart failure. Prior studies have shown that the extracellular domain of endoglin can be cleaved and released into the circulation as soluble endoglin, which disrupts TGFβ1 signaling in endothelium. We now demonstrate that soluble endoglin limits TGFβ1 signaling and type I collagen synthesis in cardiac fibroblasts and further show that soluble endoglin treatment attenuates cardiac fibrosis in an in vivo model of heart failure.

Conclusion—
Our results identify endoglin as a critical component of TGFβ1 signaling in the cardiac fibroblast and show that targeting endoglin attenuates cardiac fibrosis, thereby providing a potentially novel therapeutic approach for individuals with heart failure.