bluuebunny/crossref_metadata_2025_split huggingface dataset:
Viperin, MTAP44, and Protein Kinase R Contribute to the Interferon-Induced Inhibition of Bunyamwera Orthobunyavirus Replication
Authors: Carlton-Smith Charles , Elliott Richard M. 
Published: August 2012

ABSTRACT

The first line of defense against viral infection is the interferon (IFN) response, which culminates in the expression of hundreds of proteins with presumed antiviral activity, and must be overcome by a virus for successful replication. The nonstructural NSs protein is the primary IFN antagonist encoded by Bunyamwera virus (BUNV), the prototype of the
Orthobunyavirus
genus and the family
Bunyaviridae
. The NSs protein interferes with RNA polymerase II-mediated transcription, thereby inhibiting cellular mRNA production, including IFN mRNAs. A recombinant virus, rBUNdelNSs, that is unable to express the NSs protein does not inhibit cellular transcription and is a strong IFN inducer. We report here that cells stimulated into the antiviral state by IFN-β treatment were protected against wild-type BUNV and rBUNdelNSs infection but addition of IFN-β after infection had little effect on the replication cycle of either virus. By screening a panel of cell lines that overexpressed individual IFN-stimulated genes, we found that protein kinase R (PKR), MTAP44, and particularly viperin appreciably restricted BUNV replication. The enzymatic activities of PKR and viperin were required for their inhibitory activities. Taken together, our data show that the restriction of BUNV replication mediated by IFN is an accumulated effect of at least three IFN-stimulated genes that probably act on different stages of the viral replication cycle.
Broadly Neutralizing Immune Responses against Hepatitis C Virus Induced by Vectored Measles Viruses and a Recombinant Envelope Protein Booster
Authors: Reyes-del Valle Jorge , de la Fuente Cynthia , Turner Mallory A. , Springfeld Christoph , Apte-Sengupta Swapna , Frenzke Marie E. , Forest Amelie , Whidby Jillian , Marcotrigiano Joseph , Rice Charles M. , Cattaneo Roberto 
Published: August 2012

ABSTRACT
Hepatitis C virus (HCV) infection remains a serious public health problem worldwide. Treatments are limited, and no preventive vaccine is available. Toward developing an HCV vaccine, we engineered two recombinant measles viruses (MVs) expressing structural proteins from the prototypic HCV subtype 1a strain H77. One virus directs the synthesis of the HCV capsid (C) protein and envelope glycoproteins (E1 and E2), which fold properly and form a heterodimer. The other virus expresses the E1 and E2 glycoproteins separately, with each one fused to the cytoplasmic tail of the MV fusion protein. Although these hybrid glycoproteins were transported to the plasma membrane, they were not incorporated into MV particles. Immunization of MV-susceptible, genetically modified mice with either vector induced neutralizing antibodies to MV and HCV. A boost with soluble E2 protein enhanced titers of neutralizing antibody against the homologous HCV envelope. In animals primed with MV expressing properly folded HCV C-E1-E2, boosting also induced cross-neutralizating antibodies against two heterologous HCV strains. These results show that recombinant MVs retain the ability to induce MV-specific humoral immunity while also eliciting HCV neutralizing antibodies, and that anti-HCV immunity can be boosted with a single dose of purified E2 protein. The use of MV vectors could have advantages for pediatric HCV vaccination.
Full-Length HIV-1 Immunogens Induce Greater Magnitude and Comparable Breadth of T Lymphocyte Responses to Conserved HIV-1 Regions Compared with Conserved-Region-Only HIV-1 Immunogens in Rhesus Monkeys
Authors: Stephenson Kathryn E. , SanMiguel Adam , Simmons Nathaniel L. , Smith Kaitlin , Lewis Mark G. , Szinger James J. , Korber Bette , Barouch Dan H. 
Published: August 2012

ABSTRACT

A global HIV-1 vaccine will likely need to induce immune responses against conserved HIV-1 regions to contend with the profound genetic diversity of HIV-1. Here we evaluated the capacity of immunogens consisting of only highly conserved HIV-1 sequences that are aimed at focusing cellular immune responses on these potentially critical regions. We assessed in rhesus monkeys the breadth and magnitude of T lymphocyte responses elicited by adenovirus vectors expressing either full-length HIV-1 Gag/Pol/Env immunogens or concatenated immunogens consisting of only highly conserved HIV-1 sequences. Surprisingly, we found that the full-length immunogens induced comparable breadth (
P
= 1.0) and greater magnitude (
P
= 0.01) of CD8
+
T lymphocyte responses against conserved HIV-1 regions compared with the conserved-region-only immunogens. Moreover, the full-length immunogens induced a 5-fold increased total breadth of HIV-1-specific T lymphocyte responses compared with the conserved-region-only immunogens (
P
= 0.007). These results suggest that full-length HIV-1 immunogens elicit a substantially increased magnitude and breadth of cellular immune responses compared with conserved-region-only HIV-1 immunogens, including greater magnitude and comparable breadth of responses against conserved sequences.
Specific Dietary Oligosaccharides Increase Th1 Responses in a Mouse Respiratory Syncytial Virus Infection Model
Authors: Schijf Marcel A. , Kruijsen Debby , Bastiaans Jacqueline , Coenjaerts Frank E. J. , Garssen Johan , van Bleek Grada M. , van't Land Belinda 
Published: August 2012

ABSTRACT

Breast feeding reduces the risk of developing severe respiratory syncytial virus (RSV) infections in infants. In addition to maternal antibodies, other immune-modulating factors in human milk contribute to this protection. Specific dietary prebiotic oligosaccharides, similar to oligosaccharides present in human milk, were evaluated in a C57BL/6 mouse RSV infection model. During primary RSV infection, increased numbers of RSV-specific CD4
+
T cells producing gamma interferon (IFN-γ) were found in the lungs at days 8 to 10 postinfection in mice receiving diet containing short-chain galactooligosacharides, long-chain fructooligosaccharides, and pectin-derived acidic oligosaccharides (termed scGOS/lcFOS/pAOS). In a Th2-skewed formalin-inactivated (FI)-RSV vaccination model, the prebiotic diet reduced RSV-specific Th2 cytokine (interleukin-4 [IL-4], IL-5, and IL-13)-producing CD4
+
T cells in the lung and the magnitude of airway eosinophilia at day 4 and 6 after infection. This was accompanied by a decreased influx of inflammatory dendritic cells (CD11b
+
/CD11c
+
) and increased numbers of IFN-γ-producing CD4
+
and CD8
+
T cells at day 8 after viral challenge. These findings suggest that specific dietary oligosaccharides can influence trafficking and/or effector functions of innate immune, CD4
+
, and CD8
+
T cell subsets in the lungs of RSV-infected mice. In our models, scGOS/lcFOS/pAOS had no effect on weight but increased viral clearance in FI-RSV-vaccinated mice 8 days after infection. The increased systemic Th1 responses potentiated by scGOS/lcFOS/pAOS might contribute to an accelerated Th1/Th2 shift of the neonatal immune system, which might favor protective immunity against viral infections with a high attack rate in early infancy, such as RSV.
Potential role of tRNAs in wheat and Lolium mitochondrial rps7 transcript processing
Authors: Byers Evan , Bonen Linda 
Published: August 2012

The wheat mitochondrial gene for ribosomal protein S7 exhibits multiple transcripts that share the same 3′ terminus but range in overall length from 3.4 to 0.7 kb because of 5′end-maturation events. The longest detectable precursor RNA maps precisely to the 3′ end of a chloroplast-origin tRNA-Phe gene, consistent with it providing signals for endonucleolytic cleavage. Steady-state levels of precursor RNAs were seen to be lower in seedlings than in germinating embryos, although the degree of editing within untranslated regions (UTRs) was higher in seedlings. In another grass, Lolium multiflorum Lam., rps7 displays transcripts of 1.3 and 0.7 kb, and although the distal 5′ UTRs are unrelated in sequence to those of wheat, the 5′ terminus of the longer transcript also maps to a tRNA gene, in this case the native mitochondrial-type tRNA-Ser. Our findings illustrate the plasticity of plant mitochondrial transcriptional units and the recruitment of chloroplast-origin sequences for the expression of mitochondrial genes.
JUST.ASK — A MULTI-PRONGED APPROACH TO QUESTION ANSWERING
Authors: MENDES ANA CRISTINA , COHEUR LUÍSA , SILVA JOÃO , RODRIGUES HUGO 
Published: August 2012

In the last decades, several research areas experienced key improvements due to the appearance of numerous tools made available to the scientific community. For instance, Moses plays an important role in recent developments in machine translation and Lucene is, with no doubt, a widespread tool in information retrieval. The existence of these systems allows an easy development of baselines and, therefore, researchers can focus on improving preliminary results, instead of spending time in developing software from scratch. In addition, the existence of appropriate test collections leads to a straightforward comparison of systems and of their specific components. In this paper we describe Just.Ask, a multi-pronged approach to open-domain question answering. Just.Ask combines rule- with machine learning-based components and implements several state-of-the-art strategies in question answering. Also, it has a flexible architecture that allows for further extensions. Moreover, in this paper we report a detailed evaluation of each one of Just.Ask components. The evaluation is split into two parts: in the first one, we use a manually built test collection — the GoldWebQA — that intends to evaluate Just.Ask performance when the information source in use is the Web, without having to deal with its constant changes; in the second one, we use a set of questions gathered from the TREC evaluation forum, having a closed text collection, locally indexed and stored, as information source. Therefore, this paper contributes with a benchmark for research on question answering, since both Just.Ask and the GoldWebQA corpus are freely available for the scientific community.
Clusterin Mediates TGF-β–Induced Epithelial–Mesenchymal Transition and Metastasis via Twist1 in Prostate Cancer Cells
Authors: Shiota Masaki , Zardan Anousheh , Takeuchi Ario , Kumano Masafumi , Beraldi Eliana , Naito Seiji , Zoubeidi Amina , Gleave Martin E. 
Published: August 2012

Abstract
TGF-β promotes epithelial–mesenchymal transition (EMT) and induces clusterin (CLU) expression, linking these genes to cancer metastasis. CLU is a pleiotropic molecular chaperone that confers survival and proliferative advantage to cancer cells. However, the molecular mechanisms by which TGF-β regulates CLU expression and CLU affects metastasis remain unknown. In this study, we report that the transcription factor Twist1 mediates TGF-β–induced CLU expression. By binding to E-boxes in the distal promoter region of CLU gene, Twist1 regulated basal and TGF-β–induced CLU transcription. In addition, CLU reduction reduced TGF-β induction of the mesenchymal markers, N-cadherin and fibronectin, thereby inhibiting the migratory and invasive properties induced by TGF-β. Targeted inhibition of CLU also suppressed metastasis in an in vivo model. Taken together, our findings indicate that CLU is an important mediator of TGF-β–induced EMT, and suggest that CLU suppression may represent a promising therapeutic option for suppressing prostate cancer metastatic progression. Cancer Res; 72(20); 5261–72. ©2012 AACR.
Vaccination with mRNA-Electroporated Dendritic Cells Induces Robust Tumor Antigen-Specific CD4+ and CD8+ T Cells Responses in Stage III and IV Melanoma Patients
Authors: Aarntzen Erik H. J. G. , Schreibelt Gerty , Bol Kalijn , Lesterhuis W. Joost , Croockewit Alexandra J. , de Wilt Johannes H. W. , van Rossum Michelle M. , Blokx Willeke A. M. , Jacobs Joannes F. M. , Duiveman-de Boer Tjitske , Schuurhuis Danita H. , Mus Roel , Thielemans Kris , de Vries I. Jolanda M. , Figdor Carl G. , Punt Cornelis J. A. , Adema Gosse J. 
Published: August 2012

AbstractPurpose: Electroporation of dendritic cells (DC) with mRNA encoding tumor-associated antigens (TAA) has multiple advantages compared to peptide loading. We investigated the immunologic and clinical responses to vaccination with mRNA-electroporated DC in stage III and IV melanoma patients.Experimental design: Twenty-six stage III HLA*02:01 melanoma patients scheduled for radical lymph node dissection (stage III) and 19 melanoma patients with irresectable locoregional or distant metastatic disease (referred to as stage IV) were included. Monocyte-derived DC, electroporated with mRNA encoding gp100 and tyrosinase, were pulsed with keyhole limpet hemocyanin and administered intranodally. TAA-specific T-cell responses were monitored in blood and skin-test infiltrating lymphocyte (SKIL) cultures.Results: Comparable numbers of vaccine-induced CD8+ and/or CD4+ TAA-specific T-cell responses were detected in SKIL cultures; 17/26 stage III patients and 11/19 stage IV patients. Strikingly, in this population, TAA-specific CD8+ T cells that recognize multiple epitopes and produce elevated levels of IFNγ upon antigenic challenge in vitro, were significantly more often observed in stage III patients; 15/17 versus 3/11 stage IV patients, P = 0.0033. In stage IV patients, one mixed and one partial response were documented. The presence or absence of IFNγ-producing TAA-specific CD8+ T cells in stage IV patients was associated with marked difference in median overall survival of 24.1 months versus 11.0 months, respectively.Conclusion: Vaccination with mRNA-electroporated DC induces a broad repertoire of IFNγ producing TAA-specific CD8+ and CD4+ T-cell responses, particularly in stage III melanoma patients. Clin Cancer Res; 18(19); 5460–70. ©2012 AACR.
Clinicopathologic Features and Long-term Outcomes of NUT Midline Carcinoma
Authors: Bauer Daniel E. , Mitchell Chelsey M. , Strait Kelly M. , Lathan Christopher S. , Stelow Edward B. , Lüer Sonja C. , Muhammed Somala , Evans Andrew G. , Sholl Lynette M. , Rosai Juan , Giraldi Eugenia , Oakley Richard P. , Rodriguez-Galindo Carlos , London Wendy B. , Sallan Stephen E. , Bradner James E. , French Christopher A. 
Published: August 2012

AbstractPurpose: NUT midline carcinoma (NMC) is a poorly differentiated squamous cancer characterized by rearrangement of the NUT gene. Research advances have provided opportunities for targeted therapy in NMC, yet the clinical features of this rare disease have not been systematically characterized. We report on a large population of such patients to identify the disease characteristics and treatments, correlate them with outcome, and to consider clinical recommendations.Experimental Design: A clinical database was established using retrospective demographic and outcomes data available on all known cases of NMC. Questionnaires were completed by treating physicians. Pathologic, demographic, and clinical variables were assessed for 63 patients, the largest cohort of patients with NMC studied to date. Outcome data from 54 patients were available for survival analyses.Results: The diagnosis of NMC has increased annually since 2007. Since 2009, there has been an observed increase in the age at diagnosis (P &lt; 0.05). Geographic distribution of patients with NMC has been concentrated in the United States (n = 41, 65%). The median overall survival for patients with NMC was 6.7 months. The 2-year progression-free survival (PFS) was 9% with a 95% confidence interval (CI) of 1% to 17% [1-year PFS 15% (5–24%) and 2-year overall survival (OS) was 19% with a 95% CI of 7%–31% (1-year OS: 30% (27–34%)]. Multivariate analysis suggested that extent of surgical resection and initial radiotherapy were independent predictors of PFS and OS. Notably, no chemotherapeutic regimen was associated with improved outcome.Conclusions: NMC portends a poor prognosis among all squamous cell neoplasms and seems to be frequently unrecognized. The finding that conventional chemotherapy has been inadequate indicates a pressing need for the development of targeted therapeutics. Intensive local therapies such as gross total resection and radiotherapy might be associated with enhanced survival. Clin Cancer Res; 18(20); 5773–9. ©2012 AACR.
Response to Erlotinib in Patients with EGFR Mutant Advanced Non–Small Cell Lung Cancers with a Squamous or Squamous-like Component
Authors: Paik Paul K. , Varghese Anna M. , Sima Camelia S. , Moreira Andre L. , Ladanyi Marc , Kris Mark G. , Rekhtman Natasha 
Published: August 2012

Abstract
We previously reported that although EGFR mutations are not a feature of pure squamous cell carcinomas (SCC) of the lung, these mutations do occur in adenosquamous carcinomas (AD-SCC) and in rare solid adenocarcinomas, both of which can mimic SCC in small samples. Here we present an expanded series of these cases with a focus on sensitivity to erlotinib. The study included 13 patients with EGFR mutant lung carcinomas, which after detailed pathologic review were classified as AD-SCC (n = 11) or solid adenocarcinoma (n = 2). The majority received a diagnosis of SCC in at least 1 sample. All patients were treated with erlotinib. Eight of 11 patients with AD-SCC were evaluable for response. Their overall response rate was 88% (7/8; 95% CI, 47% to 99%). One of 2 solid adenocarcinoma patients responded to erlotinib. As a group, median progression-free survival was 12 months (95% CI, 8 to not reached); median overall survival was 29 months (95% CI, 27 to not reached). In conclusion, EGFR mutant AD-SCC and solid adenocarcinoma show a response to erlotinib that is comparable to that seen in patients with conventional adenocarcinoma. These tumors can mimic SCC in small samples. We propose an approach to increase the capture of these rare histology patients for EGFR mutation testing. Mol Cancer Ther; 11(11); 2535–40. ©2012 AACR.
Revisiting the Complexity of the Ovarian Cancer Microenvironment—Clinical Implications for Treatment Strategies
Authors: Musrap Natasha , Diamandis Eleftherios P. 
Published: August 2012

AbstractEpithelial ovarian cancer (EOC) is the leading cause of death among gynecological malignancies in North American women. Given that EOC encompasses a broad class of tumors consisting of a variety of different histologic and molecular subtypes, which generates genetically and etiologically distinct tumors, several challenges arise during treatment of patients with this disease. Overlaying this complexity is the contribution of supporting cells, particularly stromal components such as fibroblasts and immune infiltrates that collectively create a microenvironment that promotes and enhances cancer progression. A notable example is the induction of angiogenesis, which occurs through the secretion of pro-angiogenic factors by both tumor and tumor-associated cells. The recent development of angiogenic inhibitors targeting tumor vasculature, which have been shown to improve patient outcome when combined with standard therapy, has launched a paradigm shift on how cancer patients should be treated. It is evident that future clinical practices will focus on the incorporation of therapies that antagonize the protumoral effects of such microenvironment contributors. Herein, an overview of the varying tumor–host interactions that influence tumor behavior will be discussed, in addition to the recent efforts undertaken to target these interactions and their potential to revolutionize EOC patient care. Mol Cancer Res; 10(10); 1254–64. ©2012 AACR.
Identification of Luminal Breast Cancers That Establish a Tumor-Supportive Macroenvironment Defined by Proangiogenic Platelets and Bone Marrow–Derived Cells
Authors: Kuznetsov Hanna S. , Marsh Timothy , Markens Beth A. , Castaño Zafira , Greene-Colozzi April , Hay Samantha A. , Brown Victoria E. , Richardson Andrea L. , Signoretti Sabina , Battinelli Elisabeth M. , McAllister Sandra S. 
Published: August 2012

Abstract
Breast cancer recurrence rates vary following treatment, suggesting that tumor cells disseminate early from primary sites but remain indolent indefinitely before progressing to symptomatic disease. The reasons why some indolent disseminated tumors erupt into overt disease are unknown. We discovered a novel process by which certain luminal breast cancer (LBC) cells and patient tumor specimens (LBC “instigators”) establish a systemic macroenvironment that supports outgrowth of otherwise-indolent disseminated tumors (“responders”). Instigating LBCs secrete cytokines that are absorbed by platelets, which are recruited to responding tumor sites where they aid vessel formation. Instigator-activated bone marrow cells enrich responding tumor cell expression of CD24, an adhesion molecule for platelets, and provide a source of VEGF receptor 2+ tumor vessel cells. This cascade results in growth of responder adenocarcinomas and is abolished when platelet activation is inhibited by aspirin. These findings highlight the macroenvironment as an important component of disease progression that can be exploited therapeutically.
Significance: Currently, processes that mediate progression of otherwise indolent tumors are not well understood, making it difficult to accurately predict which cancer patients are likely to relapse. Our findings highlight the macroenvironment as an important component of disease progression that can be exploited to more accurately identify patients who would benefit from adjuvant therapy. Cancer Discov; 2(12); 1150–65. ©2012 AACR.
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Childhood Air Pollutant Exposure and Carotid Artery Intima-Media Thickness in Young Adults
Authors: Breton Carrie V. , Wang Xinhui , Mack Wendy J. , Berhane Kiros , Lopez Milena , Islam Talat S. , Feng Mei , Lurmann Fred , McConnell Rob , Hodis Howard N. , Künzli Nino , Avol Ed 
Published: August 2012

Background—
Exposure to ambient air pollutants increases risk for cardiovascular health outcomes in adults. The contribution of childhood air pollutant exposure to cardiovascular health has not been thoroughly evaluated.

Methods and Results—

The Testing Responses on Youth study consists of 861 college students recruited from the University of Southern California in 2007 to 2009. Participants attended 1 study visit during which blood pressure, heart rate, and carotid artery intima-media thickness (CIMT) were assessed. Self-administered questionnaires collected information about health and sociodemographic characteristics, and a 12-hour fasting blood sample was drawn for lipid and biomarker analyses. Residential addresses were geocoded and used to assign cumulative air pollutant exposure estimates based on data derived from the U.S. Environmental Protection Agency's Air Quality System database. The associations between CIMT and air pollutants were assessed using linear regression analysis. Mean CIMT was 603 μm (±54 SD). A 2 standard deviation (SD) increase in childhood (aged 0–5 years) or elementary school (aged 6–12 years) O
3
exposure was associated with a 7.8-μm (95% confidence interval, −0.3–15.9) or 10.1-μm (95% confidence interval, 1.8–18.5) higher CIMT, respectively. Lifetime exposure to O
3
showed similar but nonsignificant associations. No associations were observed for PM
2.5
, PM
10
, or NO
2
, although adjustment for these pollutants strengthened the childhood O
3
associations.

Conclusions—

Childhood exposure to O
3
may be a novel risk factor for CIMT in a healthy population of college students. Regulation of air pollutants and efforts that focus on limiting childhood exposures continue to be important public health goals.