bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cytomegalovirus Replication in Semen Is Associated with Higher Levels of Proviral HIV DNA and CD4
+
T Cell Activation during Antiretroviral Treatment
Authors: Gianella Sara , Massanella Marta , Richman Douglas D. , Little Susan J. , Spina Celsa A. , Vargas Milenka V. , Lada Steven M. , Daar Eric S. , Dube Michael P. , Haubrich Richard H. , Morris Sheldon R. , Smith Davey M. ,   the California Collaborative Treatment Group 592 Team
Published: May 2014

ABSTRACT

Asymptomatic cytomegalovirus (CMV) replication occurs frequently in the genital tract in untreated HIV-infected men and is associated with increased immune activation and HIV disease progression. To determine the connections between CMV-associated immune activation and the size of the viral reservoir, we evaluated the interactions between (i) asymptomatic seminal CMV replication, (ii) levels of T cell activation and proliferation in blood, and (iii) the size and transcriptional activity of the HIV DNA reservoir in blood from 53 HIV-infected men on long-term antiretroviral therapy (ART) with suppressed HIV RNA in blood plasma. We found that asymptomatic CMV shedding in semen was associated with significantly higher levels of proliferating and activated CD4
+
T cells in blood (
P
< 0.01). Subjects with detectable CMV in semen had approximately five times higher average levels of HIV DNA in blood CD4
+
T cells than subjects with no CMV. There was also a trend for CMV shedders to have increased cellular (multiply spliced) HIV RNA transcription (
P
= 0.068) compared to participants without CMV, but it is unclear if this transcription pattern is associated with residual HIV replication. In multivariate analysis, the presence of seminal plasma CMV (
P
= 0.04), detectable 2-long terminal repeat (2-LTR), and lower nadir CD4
+
(
P
< 0.01) were independent predictors of higher levels of proviral HIV DNA in blood. Interventions aimed at reducing seminal CMV and associated immune activation may be important for HIV curative strategies. Future studies of anti-CMV therapeutics will help to establish causality and determine the mechanisms underlying these described associations.

IMPORTANCE
Almost all individuals infected with HIV are also infected with cytomegalovirus (CMV), and the replication dynamics of the two viruses likely influence each other. This study investigated interactions between asymptomatic CMV replication within the male genital tract, levels of inflammation in blood, and the size of the HIV DNA reservoir in 53 HIV-infected men on long-term antiretroviral therapy (ART) with suppressed HIV RNA in blood plasma. In support of our primary hypothesis, shedding of CMV DNA in semen was associated with increased activation and proliferation of T cells in blood and also significantly higher levels of HIV DNA in blood cells. These results suggest that CMV reactivation might play a role in the maintenance of the HIV DNA reservoir during suppressive ART and that it could be a target of pharmacologic intervention in future studies.
Careers in Virology: Public Health Opportunities for Early-Career Basic Scientists
Authors: Kilianski Andy 
Published: May 2014

ABSTRACT
Undergraduate, graduate, and postdoctoral scientists trained as virologists can play critical roles in public health, such as in health science policy, epidemiology, and national defense. Despite a need for basic science backgrounds within these fields, finding entry-level careers can be challenging. Volunteer opportunities are a great way for scientists to experience public health careers while still in school, and this article describes volunteering with the Medical Reserve Corps and outlines unique postgraduate opportunities for early-career virologists.
Exceptionally Potent Neutralization of Middle East Respiratory Syndrome Coronavirus by Human Monoclonal Antibodies
Authors: Ying Tianlei , Du Lanying , Ju Tina W. , Prabakaran Ponraj , Lau Candy C. Y. , Lu Lu , Liu Qi , Wang Lili , Feng Yang , Wang Yanping , Zheng Bo-Jian , Yuen Kwok-Yung , Jiang Shibo , Dimitrov Dimiter S. 
Published: May 2014

ABSTRACT

The recently discovered Middle East respiratory syndrome coronavirus (MERS-CoV) continues to infect humans, with high mortality. Specific, highly effective therapeutics and vaccines against the MERS-CoV are urgently needed to save human lives and address the pandemic concerns. We identified three human monoclonal antibodies (MAbs), m336, m337, and m338, targeting the receptor (CD26/DPP4) binding domain (RBD) of the MERS-CoV spike glycoprotein from a very large naïve-antibody library (containing ∼10
11
antibodies). They bound with high affinity: equilibrium dissociation constants for the three MAbs were equal to 4.2, 9.3, and 15 nM, respectively, as measured by Biacore for Fabs binding to RBD. The avidity for IgG1 m336, m337, and m338 was even higher: 99, 820, and 560 pM, respectively. The antibodies bound to overlapping epitopes that overlap the receptor binding site on the RBD as suggested by competition experiments and further supported by site-directed mutagenesis of the RBD and a docking model of the m336-RBD complex. The highest-affinity MAb, m336, neutralized both pseudotyped and live MERS-CoV with exceptional potency, 50% neutralization at 0.005 and 0.07 μg/ml, respectively, likely by competing with DPP4 for binding to the S glycoprotein. The exceptionally high neutralization activity of these antibodies and especially m336 suggests that they have great potential for prophylaxis and therapy of MERS-CoV infection in humans and as a tool for development of vaccine immunogens. The rapid identification (within several weeks) of potent MAbs suggests a possibility to use the new large antibody library and related methodology for a quick response to the public threat resulting from emerging coronaviruses.

IMPORTANCE
A novel human coronavirus, the Middle East respiratory syndrome coronavirus (MERS-CoV), was found to infect humans with a high mortality rate in 2012, just 1 decade after the appearance of the first highly pathogenic coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV). There are no effective therapeutics available. It is highly desirable to find an approach for rapidly developing potent therapeutics against MERS-CoV, which not only can be implemented for MERS treatment but also can help to develop a platform strategy to combat future emerging coronaviruses. We report here the identification of human monoclonal antibodies (MAbs) from a large nonimmune antibody library that target MERS-CoV. One of the antibodies, m336, neutralized the virus with exceptional potency. It therefore may have great potential as a candidate therapeutic and as a reagent to facilitate the development of vaccines against MERS-CoV.
Roles of Humidity and Temperature in Shaping Influenza Seasonality
Authors: Lowen Anice C. , Steel John 
Published: May 2014

ABSTRACTExperimental studies in guinea pigs demonstrated that influenza virus transmission is strongly modulated by temperature and humidity. A number of epidemiological studies have followed up on these findings and revealed robust associations between influenza incidence in temperate regions and local conditions of humidity and temperature, offering a long-awaited explanation for the wintertime seasonality of influenza in these locales. Despite recent progress, important questions remain as to the mechanism(s) by which humidity and/or temperature affects transmission.
‘It’s on your conscience all the time’: a systematic review of qualitative studies examining views on obesity among young people aged 12–18 years in the UK
Authors: Rees Rebecca W , Caird Jenny , Dickson Kelly , Vigurs Carol , Thomas James 
Published: May 2014

ObjectiveTo explore the perspectives of young people in the UK on obesity, body size, shape and weight.DesignSystematic review of qualitative studies using thematic synthesis.Data sourcesSensitive searches of 18 electronic databases from 1997 to February 2010 supplemented by grey literature searches.Study selectionStudies produced since 1997 using qualitative methods to collect perspectives of people aged 12–18 years in the UK, reporting methods for data collection or analysis. Studies of people with eating disorders and those rated low in reliability and usefulness were excluded.ResultsSearches identified 30 studies involving over 1400 young people from a range of contexts. Young people of all sizes placed considerable emphasis on personal responsibility, and on the social, rather than health implications of being overweight. Young people with experience of obesity described severe, unrelenting, size-related abuse and isolation. Regardless of their own size, young people were judgemental of individuals who were overweight, but those with experience of obesity described an environment that contained multiple barriers to weight loss. Only one study asked young people directly what might support them to have a healthy body size. Study findings were configured under three main themes, labelled with quotes from included studies: general perceptions of size and society's responses (‘It's on your conscience all the time’); the experiences of young people who were overweight (‘If I had the choice I wouldn't be this size’) and these larger young people's experiences of trying to loose weight and suggestions for action (‘Make sure, even when it's hard, you've got people there’).ConclusionsThe perspectives of young people in the UK, when synthesised across the spectrum of body sizes, paint a picture of a stigmatising and abusive social world. Research and policy need to engage young people actively so as to address the social implications of obesity.
Quality of life, support and smoking in advanced lung cancer patients: a qualitative study
Authors: Rowland C , Danson S J , Rowe R , Merrick H , Woll P J , Hatton M Q , Wadsley J , Ellis S , Crabtree C , Horsman J M , Eiser C 
Published: May 2014

BackgroundLung cancer is the most common cancer and smoking is the principal cause. Due to poor survival rates, symptom palliation and promotion of health-related quality of life (HRQoL) are primary outcomes for lung cancer patients. Given the established relationship between smoking and lung cancer, patients who have smoked may feel stigmatised or guilty after diagnosis, and more pessimistic about their illness and likely outcomes. This may have adverse implications for HRQoL.ObjectivesWe explored HRQoL and support experiences among newly diagnosed patients with advanced lung cancer.DesignSemistructured interviews were conducted with nine patients and analysed using interpretative phenomenological analysis.ResultsPatients described the physical, emotional and social impact of disease on HRQoL. Fear of compromising their immune system and adjusting to new relationship roles had a wide-ranging effect on patients’ HRQoL. Patients acknowledged links between lung cancer and smoking but some continued to smoke. They were sensitive to the opinions of medical staff about smoking especially those who continued to smoke or recently quit.ConclusionsWe conclude that staff should give clearer advice about the adverse implications of continued smoking. We discuss the potential value of diagnosis as a teachable moment for promoting smoking cessation among patients and family members.
Radiological and clinical features of vein of Galen malformations
Authors: Chow Maggie L , Cooke Daniel L , Fullerton Heather J , Amans Matthew R , Narvid Jared , Dowd Christopher F , Higashida Randall T , Halbach Van V , Hetts Steven W 
Published: May 2014

BackgroundVein of Galen malformations (VOGMs) are rare and complex congenital arteriovenous fistulas. The clinical and radiological features of VOGMs and their relation to clinical outcomes are not fully characterized.ObjectiveTo examine the clinical and radiological features of VOGMs and the predictors of outcome in patients.MethodsWe retrospectively reviewed the available imaging and medical records of all patients with VOGMs treated at the University of California, San Francisco between 1986 and 2013. Radiological and clinical features were identified. We applied the modified Rankin Scale to determine functional outcome by chart review. Predictors of outcome were assessed by χ2analyses.ResultsForty-one cases were confirmed as VOGM. Most patients (78%) had been diagnosed with VOGM in the first year of life. Age at treatment was bimodally distributed, with predominantly urgent embolization at <10 days of age and elective embolization after 1 year of age. Patients commonly presented with hydrocephalus (65.9%) and congestive heart failure (61.0%). Mixed-type (31.7%) VOGM was more common in our cohort than purely mural (29.3%) or choroidal (26.8%) types. The most common feeding arteries were the choroidal and posterior cerebral arteries. Transarterial embolization with coils was the most common technique used to treat VOGMs at our institution. Functional outcome was normal or only mildly disabled in 50% of the cases at last follow-up (median=3 years, range=0–23 years). Younger age at first diagnosis, congestive heart failure, and seizures were predictive of adverse clinical outcome. The survival rate in our sample was 78.0% and complete thrombosis of the VOGM was achieved in 62.5% of patients.ConclusionsVOGMs continue to be challenging to treat and manage. Nonetheless, endovascular approaches to treatment are continuing to be refined and improved, with increasing success. The neurodevelopmental outcomes of affected children whose VOGMs are treated may be good in many cases.
Risk factors associated with high bulk milk antibody levels to common pathogens in UK dairies
Authors: Williams D. , Winden S. V. 
Published: May 2014

Infectious diseases pose a severe economic burden on the UK dairy industry. This study used bulk milk antibody levels in 1088 UK dairy herds to estimate the current UK prevalence of bovine viral diarrhoea virus (BVDV), bovine herpes virus 1 (BHV‐1) and Leptospira hardjo. Questionnaires collected under the DairyCheck scheme (MSD Animal Health) were used concurrently to gather information on farm demographics and management practices. The prevalence of active BVDV infection was 58.6 per cent, of historic BVDV exposure was 88.6 per cent, of BHV‐1 infection was 69.2 per cent and of L hardjo was 71.9 per cent. An increasing herd size and the purchasing of replacement cattle were risk factors for the presence of all three agents. Year‐round calving was associated with a 1.9 times increased risk for having BVDV (P<0.005). The presence of a bull was associated with a 1.5 times increased risk for having BHV‐1 (P<0.005). When compared with previous results, this study indicates a slight fall in the prevalence of BVDV within the UK dairy herd; however, BHV‐1 and L hardjo levels appear to have remained constant. This study shows that herds purchasing cattle are at greater risk of infectious agents being present and therefore, if possible, a closed herd system should be implemented.
Regional groundwater flow modelling of the confined aquifers below the Boom Clay in NE Belgium
Authors: Vandersteen K. , Gedeon M. , Marivoet J. , Wouters L. 
Published: May 2014

Abstract
For more than 35 years, SCK•CEN has been investigating the possibility of high-level radioactive waste disposal in the Boom Clay in northeastern Belgium. This research, defined in the long-term management programme for high and medium long-lived waste of ONDRAF/NIRAS, includes the regional hydrogeological modelling of the aquifer systems surrounding the Boom Clay. In this paper, the most recent update of the Deep Aquifer Pumping model (DAP) is described, which is capable of quantifying the regional groundwater flow in the complex confined aquifers lying below the Boom Clay in NE Belgium. The DAP model was successfully calibrated using an automated inverse optimization algorithm and is able to reproduce satisfactorily the general trends in the observed groundwater heads. This model can be used as a tool for planning future characterization efforts and reducing the predictive model uncertainty.
GSSPs, global stratigraphy and correlation
Authors: Smith Alan G. , Barry Tiffany , Bown Paul , Cope John , Gale Andy , Gibbard Philip , Gregory John , Hounslow Mark , Kemp David , Knox Robert , Marshall John , Oates Michael , Rawson Peter , Powell John , Waters Colin 
Published: May 2014

Abstract
Procedures used to define an international chronostratigraphic stage boundary and to locate and ratify a Global Boundary Stratotype Section and Point (GSSP) are outlined. A majority of current GSSPs use biostratigraphic data as primary markers with no reference to any physico-chemical markers, despite the International Subcommission on Stratigraphic Classification (ISSC) suggestion that such markers should be included if possible. It is argued that such definitions will not produce the high-precision Phanerozoic time scale necessary to understand such phenomena as pre-Pleistocene ice ages and global climate change. It is strongly recommended that all GSSPs should have physico-chemical markers as an integral part of their guiding criteria, and where such markers cannot be found, the GSSP should be relocated.
The methods and approach embodied in oceanic stratigraphy – coring, logging, analysing and archiving of drill sites by numerous experts using a wide range of methods – could usefully serve as a scientific model for the analysis and archiving of GSSPs, all of which are on the present-day continents. The incorporation of many more stratigraphic sections into GSSP studies, the application of physico-chemical methods, and the replacement of old U–Pb dates by newer CA-TIMS U–Pb dates, together with the use of constrained optimization (CONOP) programs that produce a calendar of events from many sections, should lead to much more precise timescales for pre-Cenozoic time than are currently available.
Mesenchymal Stem Cells from Human Fat Engineered to Secrete BMP4 Are Nononcogenic, Suppress Brain Cancer, and Prolong Survival
Authors: Li Qian , Wijesekera Olindi , Salas Sussan J. , Wang Joanna Y. , Zhu Mingxin , Aprhys Colette , Chaichana Kaisorn L. , Chesler David A. , Zhang Hao , Smith Christopher L. , Guerrero-Cazares Hugo , Levchenko Andre , Quinones-Hinojosa Alfredo 
Published: May 2014

Abstract
Purpose: Glioblastoma is the most common adult primary malignant intracranial cancer. It is associated with poor outcomes because of its invasiveness and resistance to multimodal therapies. Human adipose-derived mesenchymal stem cells (hAMSC) are a potential treatment because of their tumor tropism, ease of isolation, and ability to be engineered. In addition, bone morphogenetic protein 4 (BMP4) has tumor-suppressive effects on glioblastoma and glioblastoma brain tumor–initiating cells (BTIC), but is difficult to deliver to brain tumors. We sought to engineer BMP4-secreting hAMSCs (hAMSCs-BMP4) and evaluate their therapeutic potential on glioblastoma.
Experimental Design: The reciprocal effects of hAMSCs on primary human BTIC proliferation, differentiation, and migration were evaluated in vitro. The safety of hAMSC use was evaluated in vivo by intracranial coinjections of hAMSCs and BTICs in nude mice. The therapeutic effects of hAMSCs and hAMSCs-BMP4 on the proliferation and migration of glioblastoma cells as well as the differentiation of BTICs, and survival of glioblastoma-bearing mice were evaluated by intracardiac injection of these cells into an in vivo intracranial glioblastoma murine model.
Results: hAMSCs-BMP4 targeted both the glioblastoma tumor bulk and migratory glioblastoma cells, as well as induced differentiation of BTICs, decreased proliferation, and reduced the migratory capacity of glioblastomas in vitro and in vivo. In addition, hAMSCs-BMP4 significantly prolonged survival in a murine model of glioblastoma. We also demonstrate that the use of hAMSCs in vivo is safe.
Conclusions: Both unmodified and engineered hAMSCs are nononcogenic and effective against glioblastoma, and hAMSCs-BMP4 are a promising cell-based treatment option for glioblastoma. Clin Cancer Res; 20(9); 2375–87. ©2014 AACR.
Molecular Pathways: Resistance to Kinase Inhibitors and Implications for Therapeutic Strategies
Authors: Lovly Christine M. , Shaw Alice T. 
Published: May 2014

Abstract
The development of targeted therapies has revolutionized the treatment of cancer patients. The identification of “druggable” oncogenic kinases and the creation of small-molecule inhibitors designed to specifically target these mutant kinases have become an important therapeutic paradigm across several different malignancies. Often these inhibitors induce dramatic clinical responses in molecularly defined cohorts. However, resistance to such targeted therapies is an inevitable consequence of this therapeutic approach. Resistance can be either primary (de novo) or acquired. Mechanisms leading to primary resistance may be categorized as tumor intrinsic factors or as patient/drug-specific factors. Acquired resistance may be mediated by target gene modification, activation of “bypass tracks” that serve as compensatory signaling loops, or histologic transformation. This brief review is a snapshot of the complex problem of therapeutic resistance, with a focus on resistance to kinase inhibitors in EGF receptor mutant and ALK rearranged non–small cell lung cancer, BRAF-mutant melanoma, and BCR-ABL–positive chronic myeloid leukemia. We describe specific mechanisms of primary and acquired resistance and then review emerging strategies to delay or overcome drug resistance. Clin Cancer Res; 20(9); 2249–56. ©2014 AACR.
Differential Expression of Stress and Immune Response Pathway Transcripts and miRNAs in Normal Human Endothelial Cells Subjected to Fractionated or Single-Dose Radiation
Authors: Palayoor Sanjeewani T. , John-Aryankalayil Molykutty , Makinde Adeola Y. , Falduto Michael T. , Magnuson Scott R. , Coleman C. Norman 
Published: May 2014

Abstract
Although modern radiotherapy technologies can precisely deliver higher doses of radiation to tumors, thus, reducing overall radiation exposure to normal tissues, moderate dose, and normal tissue toxicity still remains a significant limitation. The present study profiled the global effects on transcript and miR expression in human coronary artery endothelial cells using single-dose irradiation (SD, 10 Gy) or multifractionated irradiation (MF, 2 Gy × 5) regimens. Longitudinal time points were collected after an SD or final dose of MF irradiation for analysis using Agilent Human Gene Expression and miRNA microarray platforms. Compared with SD, the exposure to MF resulted in robust transcript and miR expression changes in terms of the number and magnitude. For data analysis, statistically significant mRNAs (2-fold) and miRs (1.5-fold) were processed by Ingenuity Pathway Analysis to uncover miRs associated with target transcripts from several cellular pathways after irradiation. Interestingly, MF radiation induced a cohort of mRNAs and miRs that coordinate the induction of immune response pathway under tight regulation. In addition, mRNAs and miRs associated with DNA replication, recombination and repair, apoptosis, cardiovascular events, and angiogenesis were revealed.
Implications: Radiation-induced alterations in stress and immune response genes in endothelial cells contribute to changes in normal tissue and tumor microenvironment, and affect the outcome of radiotherapy. Mol Cancer Res; 12(7); 1002–15. ©2014 AACR.