bluuebunny/crossref_metadata_2025_split huggingface dataset:
Foot-and-Mouth Disease Virus Nonstructural Protein 2C Interacts with Beclin1, Modulating Virus Replication
Authors: Gladue D. P. , O'Donnell V. , Baker-Branstetter R. , Holinka L. G. , Pacheco J. M. , Fernandez-Sainz I. , Lu Z. , Brocchi E. , Baxt B. , Piccone M. E. , Rodriguez L. , Borca M. V. 
Published: August 2012

ABSTRACT

Foot-and-mouth disease virus (FMDV), the causative agent of foot-and-mouth disease, is an
Apthovirus
within the
Picornaviridae
family. Replication of the virus occurs in association with replication complexes that are formed by host cell membrane rearrangements. The largest viral protein in the replication complex, 2C, is thought to have multiple roles during virus replication. However, studies examining the function of FMDV 2C have been rather limited. To better understand the role of 2C in the process of virus replication, we used a yeast two-hybrid approach to identify host proteins that interact with 2C. We report here that cellular Beclin1 is a specific host binding partner for 2C. Beclin1 is a regulator of the autophagy pathway, a metabolic pathway required for efficient FMDV replication. The 2C-Beclin1 interaction was further confirmed by coimmunoprecipitation and confocal microscopy to actually occur in FMDV-infected cells. Overexpression of either Beclin1 or Bcl-2, another important autophagy factor, strongly affects virus yield in cell culture. The fusion of lysosomes to autophagosomes containing viral proteins is not seen during FMDV infection, a process that is stimulated by Beclin1; however, in FMDV-infected cells overexpressing Beclin1 this fusion occurs, suggesting that 2C would bind to Beclin1 to prevent the fusion of lysosomes to autophagosomes, allowing for virus survival. Using reverse genetics, we demonstrate here that modifications to the amino acids in 2C that are critical for interaction with Beclin1 are also critical for virus growth. These results suggest that interaction between FMDV 2C and host protein Beclin1 could be essential for virus replication.
Epitope Mapping of Broadly Neutralizing HIV-2 Human Monoclonal Antibodies
Authors: Kong Rui , Li Hui , Georgiev Ivelin , Changela Anita , Bibollet-Ruche Frederic , Decker Julie M. , Rowland-Jones Sarah L. , Jaye Assan , Guan Yongjun , Lewis George K. , Langedijk Johannes P. M. , Hahn Beatrice H. , Kwong Peter D. , Robinson James E. , Shaw George M. 
Published: August 2012

ABSTRACT

Recent studies have shown that natural infection by HIV-2 leads to the elicitation of high titers of broadly neutralizing antibodies (NAbs) against primary HIV-2 strains (T. I. de Silva, et al., J. Virol. 86:930–946, 2012; R. Kong, et al., J. Virol. 86:947–960, 2012; G. Ozkaya Sahin, et al., J. Virol. 86:961–971, 2012). Here, we describe the envelope (Env) binding and neutralization properties of 15 anti-HIV-2 human monoclonal antibodies (MAbs), 14 of which were newly generated from 9 chronically infected subjects. All 15 MAbs bound specifically to HIV-2 gp120 monomers and neutralized heterologous primary virus strains HIV-2
7312A
and HIV-2
ST
. Ten of 15 MAbs neutralized a third heterologous primary virus strain, HIV-2
UC1
. The median 50% inhibitory concentrations (IC
50
s) for these MAbs were surprisingly low, ranging from 0.007 to 0.028 μg/ml. Competitive Env binding studies revealed three MAb competition groups: CG-I, CG-II, and CG-III. Using peptide scanning, site-directed mutagenesis, chimeric Env constructions, and single-cycle virus neutralization assays, we mapped the epitope of CG-I antibodies to a linear region in variable loop 3 (V3), the epitope of CG-II antibodies to a conformational region centered on the carboxy terminus of V4, and the epitope(s) of CG-III antibodies to conformational regions associated with CD4- and coreceptor-binding sites. HIV-2 Env is thus highly immunogenic
in vivo
and elicits antibodies having diverse epitope specificities, high potency, and wide breadth. In contrast to the HIV-1 Env trimer, which is generally well shielded from antibody binding and neutralization, HIV-2 is surprisingly vulnerable to broadly reactive NAbs. The availability of 15 human MAbs targeting diverse HIV-2 Env epitopes can facilitate comparative studies of HIV/SIV Env structure, function, antigenicity, and immunogenicity.
Developing temporal hydroecological perspectives to inform stewardship of a northern floodplain landscape subject to multiple stressors: paleolimnological investigations of the Peace–Athabasca Delta
Authors: Wolfe Brent B. , Hall Roland I. , Edwards Thomas W.D. , Johnston John W. 
Published: August 2012

Effective stewardship of ecologically-significant floodplain landscapes requires knowledge of the relative roles of natural processes and upstream human activities on environmental flows. In these landscapes, hydroecological conditions that develop from potentially competing drivers, such as climate change and industrial development, tend to be expressed at spatial and temporal scales that are often inadequately captured by existing monitoring datasets. Consequently, perceived cause–effect relations may be misunderstood, conflict can escalate among stakeholders, and effectiveness of surveillance systems, policies, and governance may be impaired. This is the context for the Peace–Athabasca Delta (PAD), an internationally-recognized water-rich floodplain landscape located in northern Alberta (Canada) that has been subject to multiple stressors. Here we synthesize evidence from paleolimnological records that have fostered an unparalled window into the natural history of this landscape. Over the past 12 years, we have assembled numerous decadal- to multicentennial-long records of hydrological and ecological variability, including an exceptionally detailed chronicle of Peace River flood frequency and magnitude spanning ~600 years. These efforts recently culminated in a 5200-year reconstruction of Lake Athabasca water-level history. Results have provided the foundation to identify drivers of landscape change and generate insight into the delta’s dynamic and ongoing evolution. Contrary to widespread perceptions that hydroelectric regulation of the Peace River since the late 1960s has reduced the frequency of ice-jam floods and lowered floodplain lake-water levels, results indicate that climate variability exerts the overwhelming influence on the delivery of water to the PAD. We show that impending climate-driven freshwater scarcity of a scale unprecedented in our collective societal memory now poses a significant threat to the ecological integrity of this world-renowned landscape and a major challenge to water resource managers. Also, we propose a hydroecological monitoring program, built upon the knowledge gained from our extensive process studies and paleoenvironmental research, to inform effective ongoing stewardship of the delta.
Biomarkers of Response to Akt Inhibitor MK-2206 in Breast Cancer
Authors: Sangai Takafumi , Akcakanat Argun , Chen Huiqin , Tarco Emily , Wu Yun , Do Kim-Anh , Miller Todd W. , Arteaga Carlos L. , Mills Gordon B. , Gonzalez-Angulo Ana Maria , Meric-Bernstam Funda 
Published: August 2012

AbstractPurpose: We tested the hypothesis that allosteric Akt inhibitor MK-2206 inhibits tumor growth, and that PTEN/PIK3CA mutations confer MK-2206 sensitivity.Experimental Design: MK-2206 effects on cell signaling were assessed in vitro and in vivo. Its antitumor efficacy was assessed in vitro in a panel of cancer cell lines with differing PIK3CA and PTEN status. Its in vivo efficacy was tested as a single agent and in combination with paclitaxel.Results: MK-2206 inhibited Akt signaling and cell-cycle progression, and increased apoptosis in a dose-dependent manner in breast cancer cell lines. Cell lines with PTEN or PIK3CA mutations were significantly more sensitive to MK-2206; however, several lines with PTEN/PIK3CA mutations were MK-2206 resistant. siRNA knockdown of PTEN in breast cancer cells increased Akt phosphorylation concordant with increased MK-2206 sensitivity. Stable transfection of PIK3CA E545K or H1047R mutant plasmids into normal-like MCF10A breast cells enhanced MK-2206 sensitivity. Cell lines that were less sensitive to MK-2206 had lower ratios of Akt1/Akt2 and had less growth inhibition with Akt siRNA knockdown. In PTEN-mutant ZR75-1 breast cancer xenografts, MK-2206 treatment inhibited Akt signaling, cell proliferation, and tumor growth. In vitro, MK-2206 showed a synergistic interaction with paclitaxel in MK-2206–sensitive cell lines, and this combination had significantly greater antitumor efficacy than either agent alone in vivo.Conclusions: MK-2206 has antitumor activity alone and in combination with chemotherapy. This activity may be greater in tumors with PTEN loss or PIK3CA mutation, providing a strategy for patient enrichment in clinical trials. Clin Cancer Res; 18(20); 5816–28. ©2012 AACR.
Novel Tumor Subgroups of Urothelial Carcinoma of the Bladder Defined by Integrated Genomic Analysis
Authors: Hurst Carolyn D. , Platt Fiona M. , Taylor Claire F. , Knowles Margaret A. 
Published: August 2012

AbstractPurpose: There is a need for improved subclassification of urothelial carcinoma (UC) at diagnosis. A major aim of this study was to search for novel genomic subgroups.Experimental design: We assessed 160 tumors for genome-wide copy number alterations and mutation in genes implicated in UC. These comprised all tumor grades and stages and included 49 high-grade stage T1 (T1G3) tumors.Results: Our findings point to the existence of genomic subclasses of the “gold-standard” grade/stage groups. The T1G3 tumors separated into 3 major subgroups that differed with respect to the type and number of copy number events and to FGFR3 and TP53 mutation status. We also identified novel regions of copy number alteration, uncovered relationships between molecular events, and elucidated relationships between molecular events and clinico-pathologic features. FGFR3 mutant tumors were more chromosomally stable than their wild-type counterparts and a mutually exclusive relationship between FGFR3 mutation and overrepresentation of 8q was observed in non-muscle-invasive tumors. In muscle-invasive (MI) tumors, metastasis was positively associated with losses of regions on 10q (including PTEN), 16q and 22q, and gains on 10p, 11q, 12p, 19p, and 19q. Concomitant copy number alterations positively associated with TP53 mutation in MI tumors were losses on 16p, 2q, 4q, 11p, 10q, 13q, 14q, 16q, and 19p, and gains on 1p, 8q, 10q, and 12q. Significant complexity was revealed in events affecting chromosome 9.Conclusions: These findings may lead to improved biologic understanding and the development of prognostic biomarkers. Novel regions of copy number alteration may reveal potential therapeutic targets. Clin Cancer Res; 18(21); 5865–77. ©2012 AACR.
Selective Targeting of Interferon γ to Stromal Fibroblasts and Pericytes as a Novel Therapeutic Approach to Inhibit Angiogenesis and Tumor Growth
Authors: Bansal Ruchi , Tomar Tushar , Östman Arne , Poelstra Klaas , Prakash Jai 
Published: August 2012

Abstract
New approaches to block the function of tumor stromal cells such as cancer-associated fibroblasts and pericytes is an emerging field in cancer therapeutics as these cells play a crucial role in promoting angiogenesis and tumor growth via paracrine signals. Because of immunomodulatory and other antitumor activities, IFNγ, a pleiotropic cytokine, has been used as an anticancer agent in clinical trials. Unfortunately only modest beneficial effects, but severe side effects, were seen. In this study, we delivered IFNγ to stromal fibroblasts and pericytes, considering its direct antifibrotic activity, using our platelet-derived growth factor-beta receptor (PDGFβR)-binding carrier (pPB-HSA), as these cells abundantly express PDGFβR. We chemically conjugated IFNγ to pPB-HSA using a heterobifunctional PEG linker. In vitro in NIH3T3 fibroblasts, pPB-HSA-IFNγ conjugate activated IFNγ-signaling (pSTAT1α) and inhibited their activation and migration. Furthermore, pPB-HSA-IFNγ inhibited fibroblasts-induced tube formation of H5V endothelial cells. In vivo in B16 tumor-bearing mice, pPB-HSA-IFNγ rapidly accumulated in tumor stroma and pericytes and significantly inhibited the tumor growth while untargeted IFNγ and pPB-HSA carrier were ineffective. These antitumor effects of pPB-HSA-IFNγ were attributed to the inhibition of tumor vascularization, as shown with α-SMA and CD-31 staining. Moreover, pPB-HSA-IFNγ induced MHC-II expression specifically in tumors compared with untargeted IFNγ, indicating the specificity of this approach. This study thus shows the impact of drug targeting to tumor stromal cells in cancer therapy as well as provides new opportunities to use cytokines for therapeutic application. Mol Cancer Ther; 11(11); 2419–28. ©2012 AACR.
Smoking Induces Epithelial-to-Mesenchymal Transition in Non–Small Cell Lung Cancer through HDAC-Mediated Downregulation of E-Cadherin
Authors: Nagathihalli Nagaraj S. , Massion Pierre P. , Gonzalez Adriana L. , Lu Pengcheng , Datta Pran K. 
Published: August 2012

Abstract
Epidemiological studies have shown that most cases of lung cancers (85%–90%) are directly attributable to tobacco smoking. Although association between cigarette smoking and lung cancer is well documented, surprisingly little is known about the molecular mechanisms of how smoking is involved in epithelial-to-mesenchymal transition (EMT) through epigenetic changes. Here, we show that lung cancer patients with a smoking history have low E-cadherin levels and loss of E-cadherin is a poor prognostic factor in smokers. Moreover, the downregulation of E-cadherin correlates with the number of pack years. In an attempt to determine the role of long-term cigarette smoking on EMT, we observed that treatment of lung cell lines with cigarette smoke condensate (CSC) induces EMT through downregulation of epithelial markers, including E-cadherin and upregulation of mesenchymal markers. CSC decreases E-cadherin expression at the transcriptional level through upregulation of LEF1 and Slug, and knockdown of these two proteins increases E-cadherin expression. Importantly, chromatin immunoprecipitation assays suggest that LEF-1 and Slug binding to E-cadherin promoter is important for CSC-mediated downregulation of E-cadherin. The histone deacetylase (HDAC) inhibitor MS-275 reverses CSC-induced EMT, migration, and invasion through the restoration of E-cadherin expression. These results suggest that recruitment of HDACs by transcriptional repressors LEF-1 and Slug is responsible for E-cadherin suppression and EMT in cigarette smokers and provide a potential drug target toward the treatment of lung cancer. Mol Cancer Ther; 11(11); 2362–72. ©2012 AACR.
Voice Symptoms in Patients with Autoimmune Disease
Authors: Liu Zi Wei , Masterson Liam M. , Srouji Ibrahim A. , Musonda Patrick , Scott David G. I. 
Published: August 2012

ObjectiveTo assess the prevalence and severity of voice symptoms in individuals with a diagnosis of autoimmune disease.Study DesignCross‐sectional survey.SettingStudy participants were recruited from a rheumatology tertiary referral clinic at Norfolk and Norwich University Hospital.Subjects and MethodsA cross‐sectional questionnaire analyzing 109 patients with autoimmune disease (rheumatoid arthritis, seronegative spondyloarthritis, connective tissue disease) and a control group of 41 patients with non‐autoimmune disease (osteoarthritis/osteoporosis). Main outcome measures were the Voice Handicap Index–10 (VHI‐10), xerostomia scale, acid reflux inquiry, and anxiety/depression scale.ResultsPatients with autoimmune disease were more likely to experience voice symptoms as assessed by the VHI‐10 questionnaire (P =. 0035). Subgroup analysis showed autoimmune patients were more likely to report voice symptoms regardless of whether they were on a disease‐modifying antirheumatic drug (DMARD; P =. 0010) or non‐DMARD (P =. 017), suggesting autoimmune disease may be an independent risk factor from pharmacotherapy. Xerostomia was more common in an autoimmune population compared with the control group (P =. 02). A positive correlation between xerostomia and VHI‐10 scores was found for the DMARD group (Spearman rank coefficient = 0.49, P <. 001). No significant difference in acid reflux inquiry (P =. 44) or the anxiety/depression scale (P =. 36) was found when comparing the autoimmune and control groups.ConclusionPatients with autoimmune disease have increased likelihood of voice symptoms when compared with a control population with non‐autoimmune disease. Further prospective studies to elucidate the cause of voice disorder would be valuable.
Genotoxicity and oxidative stress in chromium-exposed tannery workers in North India
Authors: Ambreen Khushboo , Khan Faizan Haider , Bhadauria Smrati , Kumar Sudhir 
Published: August 2012

Trivalent chromium (Cr) is an environmental contaminant, which is extensively used in tanning industries throughout the world and causes various forms of health hazards in tannery workers. Therefore, a cross-sectional study design was used to evaluate the DNA damage and oxidative stress condition in tannery workers exposed to Cr in North India. The study population comprised 100 male tanners in the exposed group and 100 healthy males (no history of Cr exposure) in the comparable control group. Baseline characteristics including age, smoking, alcohol consumption habits and duration of exposure were recorded via interviewing the subjects. Blood Cr level (measured by atomic absorption spectrophotometry), DNA damage (measured by comet assay) and oxidative stress parameters (malondialdehyde (MDA), glutathione (GSH) and superoxide dismutase (SOD)) were estimated in both the groups. As a result of statistical analysis, exposed group showed significantly higher level of Cr ( p < 0.0001), DNA damage ( p < 0.0001), MDA ( p < 0.0001), SOD ( p < 0.05) and lower level of GSH ( p < 0.001) when compared with controls. Smoking, alcohol consumption habits and age had no significant effect ( p > 0.05) on DNA damage and oxidative stress parameters in both the groups. In simple and multiple correlation analysis, DNA damage and oxidative stress parameters showed significant correlation with Cr level and duration of exposure in exposed group. The findings of the present study revealed that chronic occupational exposure to trivalent Cr may cause DNA damage and oxidative stress in tannery workers.
Self-reported sleep problems, but not fatigue, lead to decline in sustained attention in MS patients
Authors: Lehmann Pia , Eling Paul , Kastrup Andreas , Grothues Oliver , Hildebrandt Helmut 
Published: August 2012

Objective: According to the compensation theory, fatigue in MS results from efforts to compensate for a reduction in capacity due to demyelination or neurodegeneration. Recently, it has been argued that fatigue may result from poor sleep. Both explanations predict a worsening of fatigue and a cognitive decline during sustained attention tasks (higher fatigability). Method: We compared MS patients with and without self-reported cognitive fatigue, in three sessions with a two-back working memory task, registering hits and response latencies as well as changes in fatigue. In the two breaks between the sessions, either a video instruction to relax or a stimulating video was presented. Subsequently, patients were divided into those with and those without self-reported sleep problems and the analyses were repeated. Results: Patients with fatigue performed worse than healthy controls, irrespective of task duration and type of video during the break. The task-related increase of fatigue also did not differ between the groups and no differential effect of the videos was observed in the MS patients with fatigue. In contrast, patients with sleep problems did show a performance decline as predicted by the compensation theory. Conclusion: MS patients with fatigue were impaired in working memory, but did not show greater fatigability, whereas MS participants with self-reported sleep problems showed fatigability, which could be improved with a restorative rest period. Our data therefore do not support the compensation theory of fatigue, and we argue that sleep problems and fatigue in MS patients differ with respect to their functional consequences.
An update on the use of ambrisentan in pulmonary arterial hypertension
Authors: D’Alto Michele 
Published: August 2012

The development of effective oral treatments that are capable of modulating the activity of endothelin receptor 1 (ET-1) represents a significant milestone in the field of pulmonary arterial hypertension (PAH). Randomized clinical trials confirm that endothelin receptor antagonist (ERA) treatments confer significant improvements on important clinical endpoints, such as exercise capacity, functional class, quality of life and pulmonary hemodynamics. Moreover, ERAs may prevent or delay clinical worsening and retard disease progression. Ambrisentan is a propanoic acid-based ERA, showing preferential affinity for the type A ET-1 over the type B receptor. It provides another valuable, effective treatment option in PAH. Two large, randomized-placebo controlled trials demonstrated the efficacy of ambrisentan in PAH at improving exercise tolerance as measured by the 6 min walk distance. Additional secondary measures of improvement including time to clinical worsening, survival, functional class, quality of life and hemodynamic variables have been reported in clinical trials. A favorably low incidence of aminotransferase elevation indicating lower hepatic toxicity than other ERAs has been observed. Ambrisentan can be safely administered with warfarin or sildenafil without the need for dose adjustment of either therapy. A once daily oral medication with relatively few side effects is an attractive option, especially as the use of therapies in combination continues to increase. Long-term data and hemodynamic data confirm the benefits can be compared with other ERAs with fewer drug–drug interactions and a better liver safety profile.
The human GFI136N variant induces epigenetic changes at the Hoxa9 locus and accelerates K-RAS driven myeloproliferative disorder in mice
Authors: Khandanpour Cyrus , Krongold Joseph , Schütte Judith , Bouwman Frederique , Vassen Lothar , Gaudreau Marie-Claude , Chen Riyan , Calero-Nieto Fernando J. , Diamanti Evangelia , Hannah Rebecca , Meyer Sara E. , Grimes H. Leighton , van der Reijden Bert A. , Jansen Joop H. , Patel Chandrashekhar V. , Peeters Justine K. , Löwenberg Bob , Dührsen Ulrich , Göttgens Bertie , Möröy Tarik 
Published: August 2012

AbstractThe coding single nucleotide polymorphism GFI136N in the human gene growth factor independence 1 (GFI1) is present in 3%-7% of whites and increases the risk for acute myeloid leukemia (AML) by 60%. We show here that GFI136N, in contrast to GFI136S, lacks the ability to bind to the Gfi1 target gene that encodes the leukemia-associated transcription factor Hoxa9 and fails to initiate histone modifications that regulate HoxA9 expression. Consistent with this, AML patients heterozygous for the GFI136N variant show increased HOXA9 expression compared with normal controls. Using ChipSeq, we demonstrate that GFI136N specific epigenetic changes are also present in other genes involved in the development of AML. Moreover, granulomonocytic progenitors, a bone marrow subset from which AML can arise in humans and mice, show a proliferative expansion in the presence of the GFI136N variant. In addition, granulomonocytic progenitors carrying the GFI136N variant allele have altered gene expression patterns and differ in their ability to grow after transplantation. Finally, GFI136N can accelerate a K-RAS driven fatal myeloproliferative disease in mice. Our data suggest that the presence of a GFI136N variant allele induces a preleukemic state in myeloid precursors by deregulating the expression of Hoxa9 and other AML-related genes.