bluuebunny/crossref_metadata_2025_split huggingface dataset:
Complete Genome Sequence of the Genotype 4 Hepatitis E Virus Strain Prevalent in Swine in Jiangsu Province, China, Reveals a Close Relationship with That from the Human Population in This Area
Authors: Wang Hua , He Yilin , Shen Quan , Wang Xiaochun , Yang Shixing , Cui Li , Ren Liping , Sun Guangming , Hua Xiuguo , Shao Shihe , Zhang Wen 
Published: July 2012

ABSTRACT
Hepatitis E virus (HEV) is a zoonotic pathogen of which several species of animal were reported as reservoirs. Swine stands out as the major reservoir for HEV infection in humans, as suggested by the close genetic relationship of swine and human viruses. In a previous study, we sequenced the complete genome of a human genotype 4 HEV strain (HM439284) that is prevalent in Jiangsu Province, China. Here we report the complete genome of one genotype 4 HEV strain which is prevalent in swine herds in Jiangsu Province. Phylogenetic analysis indicated that the swine HEV strain in the present study has high sequence homology (>92%) with the genotype 4 HEV strains prevalent in the human population of Jiangsu Province. These results suggested that the genotype 4 HEV strain in the present study is involved in cross-species transmission between swine and humans in this area.
Complete Genome Sequence of Bluetongue Virus Serotype 9: Implications for Serotyping
Authors: Rao Pavuluri Panduranga , Reddy Yella Narasimha , Hegde Nagendra R. 
Published: July 2012

ABSTRACT
The second complete genome of bluetongue virus serotype 9 (BTV-9) is presented in this report. The sequence analysis points to continued circulation in India of a mixed topotype virus apparently belonging to the BTV-9 serotype, and it raises questions about approaches for serotyping bluetongue viruses.
PanM, an Acetyl-Coenzyme A Sensor Required for Maturation of
l
-Aspartate Decarboxylase (PanD)
Authors: Stuecker Tara N. , Tucker Alex C. , Escalante-Semerena Jorge C. 
Published: July 2012

ABSTRACT

Coenzyme A (CoA) is essential for cellular chemistry in all forms of life. The pantothenate moiety of CoA is generated from the condensation of pantoate and β-alanine. β-Alanine is formed by decarboxylation of
l
-aspartate catalyzed by PanD, a pyruvoyl enzyme that is synthesized by the cell as an inactive precursor (pro-PanD). Maturation of pro-PanD into PanD occurs via a self-cleavage event at residue Ser25, which forms the catalytic pyruvoyl moiety. We recently reported that
Salmonella enterica
PanM was necessary for pro-PanD maturation, both
in vitro
and
in vivo
. Notably, PanM is annotated as a Gcn5-like
N
-acetyltransferase (GNAT), which suggested that lysine acetylation might be part of the mechanism of maturation. Here we show that PanM lacks acetyltransferase activity and that acetyl-CoA stimulates its activity. Results of experiments with nonhydrolyzable ethyl-CoA and genetically encoded acetyl-lysine-containing PanD support the conclusion that PanM-dependent pro-PanD maturation does not involve an acetyl transfer event. We also show that CoA binding to PanM is needed for
in vivo
activity and that disruption of CoA binding prevents PanM from interacting with PanD. We conclude that PanM is a GNAT homologue that lost its acetyltransferase activity and evolved a new function as an acetyl-CoA sensor that can trigger the maturation of pro-PanD.

IMPORTANCE
Nε-lysine acetylation is increasingly being recognized as a widespread and important form of posttranslational regulation in bacteria. The acetyltransferases that catalyze these reactions are poorly characterized in bacteria. Based on annotation, most bacterial genomes contain several acetyltransferases, but the physiological roles of only a handful have been determined. Notably, a subset of putative acetyltransferases lack residues that are critical for activity in most biochemically characterized acetyltransferases. We show that one such putative acetyltransferase, PanM (formerly YhhK), lacks acetyltransferase activity but functions instead as an acetyl-coenzyme A (CoA) sensor. This work establishes the possibility that, like PanM, other putative acetyltransferases may have evolved new functions while retaining the ability to sense acetyl-CoA.
The impact of a novel franchise clinic network on access to medicines and vaccinations in Kenya: a cross-sectional study
Authors: Berk Justin , Adhvaryu Achyuta 
Published: July 2012

ObjectivesTo study the impact of a new franchise health clinic model (The HealthStore Foundation's CFWShops) on access to vaccinations and treatment for acute illnesses in a nationally representative sample of children in Kenya.DesignThe authors used multivariate linear and count regressions to examine associations between receipt of vaccinations or treatment and proximity to a franchise health clinic, adjusting for individual, household and clinic attributes as well as region fixed effects.SettingDemographic and Health Survey data from Kenya, 2008–2009.Participants6079 Kenyan children younger than 5 years, of whom 2310 reported recent acute illness.Main outcome measuresOutcomes for all children were number of polio doses received, number of DPT doses received, receipt of BCG vaccine, receipt of measles vaccine and number of total vaccinations received. Outcomes for acutely ill children were receipt of any medical treatment, treatment for fever, treatment for malaria and treatments specifically stocked by CFWShops.ResultsChildren living within 30 km of a CFWShop received 0.129 (p=0.017) and 0.113 (p=0.025) more DPT and polio doses, respectively; and 0.285 more total vaccinations (p=0.023). Among acutely ill children, CFWShop proximity was associated with significant increases in the probabilities of receiving any medical treatment (0.142; p<0.001), treatment for fever (0.117; p=0.007) and treatments specifically stocked by CFWShops (0.064; p=0.015). Use of CFWShop services was not significantly different for lower-income vis-a-vis higher-income households.ConclusionsThe franchise health clinic model could substantially increase access to essential vaccinations and treatments in low-income countries. Moreover, the model's benefits may accrue to lesser- and higher-income households alike.
Long-term follow-up of cortisol awakening response in patients treated for stress-related exhaustion
Authors: Sjörs Anna , Ljung Thomas , Jonsdottir Ingibjörg H 
Published: July 2012

ObjectivesStudies on hypothalamus–pituitary–adrenal (HPA) axis activity in stress-related exhaustion and burnout have revealed incongruent results, and few longitudinal studies on clinical populations have been performed. This study was designed to investigate differences in HPA axis activity between patients with stress-related exhaustion and healthy controls and to investigate longitudinal changes in HPA axis activity in the patient group as they entered a multimodal treatment programme.DesignHPA axis activity was assessed through the cortisol awakening response (CAR). Salivary cortisol was sampled at awakening and after 15 min. Follow-up measurements were performed in the patient group after 3, 6, 12 and 18 months.SettingAn outpatient clinic specialising in stress-related illness.ParticipantsPatients with clinically diagnosed stress-related exhaustion (n=162) and healthy controls (n=79).Primary and secondary outcome measuresThe primary measure was CAR measured as the difference between the two salivary cortisol samples. Changes in CAR during follow-up were related to changes in symptoms of burnout, depression and anxiety.ResultsPatients showed similar CAR as the controls and their CAR did not change significantly during treatment. No association was found between CAR and symptom development during treatment.ConclusionsThe authors conclude that CAR does not seem to discriminate clinically defined patients with exhaustion from healthy controls and it appears not to change during treatment. CAR, measured as salivary cortisol, at awakening and after 15 min, is thus not a valid marker for stress-related exhaustion.
Return to pre-injury health status and function 12 months after hospitalisation for sport and active recreation related orthopaedic injury
Authors: Andrew Nadine Elizabeth , Wolfe Rory , Cameron Peter , Richardson Martin , Page Richard , Bucknill Andrew , Gabbe Belinda J 
Published: July 2012

BackgroundHospitalised sport and active recreation injuries can have serious long-term consequences. Despite this, few studies have examined the long-term outcomes of these injuries. The purpose of this study was to establish whether patients hospitalised with orthopaedic sport and active recreation injuries, have returned to their pre-injury levels of health status and function, 12 months post injury and identify factors associated with poor outcomes. The present work was a cohort study with retrospective assessment of pre-injury status and prospective assessment of outcome at 12 months post injury.MethodsAdults with orthopaedic sport and active recreation injuries, captured by the Victorian Orthopaedic Trauma Outcomes Registry were recruited to the study. Pre-injury and 12-month outcomes were assessed using the 36-item Short Form Health Survey (SF-36) and the extended Glasgow Outcome Scale. Differences in pre-injury and post-injury SF-36 scores were examined and demographic, injury, hospital and physical activity variables were assessed for associations with outcome using multivariate linear regression.ResultsOf the 324 participants 98% were followed-up at 12 months post injury. At 12 months, participants reported a mean 7.0-point reduction in physical health (95% CI 5.8 to 7.8) and a 2.5-point reduction in mental health (95% CI 1.2 to 3.0), with 58% (95% CI 52.6% to 63.4%) reporting reduced function. Sporting group (p=0.001), Injury Severity Score >15 (p=0.007) and high pre-injury vigorous activity levels (p=0.04), were related to poorer physical health outcomes.ConclusionsAt 12 months post injury, most participants reported large reductions in physical health and reduced function. This information is important for furthering our understanding of the burden of sport and active recreation injury and setting priorities for treatment and rehabilitation.
ATP-Citrate Lyase: A Key Player in Cancer Metabolism
Authors: Zaidi Nousheen , Swinnen Johannes V. , Smans Karine 
Published: July 2012

Abstract
ATP-citrate lyase (ACLY) is a cytosolic enzyme that catalyzes the generation of acetyl CoA from citrate. Acetyl CoA is a vital building block for the endogenous biosynthesis of fatty acids and cholesterol and is involved in isoprenoid-based protein modifications. Acetyl CoA is also required for acetylation reactions that modify proteins, such as histone acetylation. ACLY is upregulated or activated in several types of cancers, and its inhibition is known to induce proliferation arrest in cancer cells both in vitro and in vivo. The present review highlights current knowledge about the role of ACLY in cancer cells, with special reference to the different pathways that are linked by ACLY. Cancer Res; 72(15); 3709–14. ©2012 AACR.
AT13148 Is a Novel, Oral Multi-AGC Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity
Authors: Yap Timothy A. , Walton Mike I. , Grimshaw Kyla M. , te Poele Robert H. , Eve Paul D. , Valenti Melanie R. , de Haven Brandon Alexis K. , Martins Vanessa , Zetterlund Anna , Heaton Simon P. , Heinzmann Kathrin , Jones Paul S. , Feltell Ruth E. , Reule Matthias , Woodhead Steven J. , Davies Thomas G. , Lyons John F. , Raynaud Florence I. , Eccles Suzanne A. , Workman Paul , Thompson Neil T. , Garrett Michelle D. 
Published: July 2012

Abstract
Purpose: Deregulated phosphatidylinositol 3-kinase pathway signaling through AGC kinases including AKT, p70S6 kinase, PKA, SGK and Rho kinase is a key driver of multiple cancers. The simultaneous inhibition of multiple AGC kinases may increase antitumor activity and minimize clinical resistance compared with a single pathway component.
Experimental Design: We investigated the detailed pharmacology and antitumor activity of the novel clinical drug candidate AT13148, an oral ATP-competitive multi-AGC kinase inhibitor. Gene expression microarray studies were undertaken to characterize the molecular mechanisms of action of AT13148.
Results: AT13148 caused substantial blockade of AKT, p70S6K, PKA, ROCK, and SGK substrate phosphorylation and induced apoptosis in a concentration and time-dependent manner in cancer cells with clinically relevant genetic defects in vitro and in vivo. Antitumor efficacy in HER2-positive, PIK3CA-mutant BT474 breast, PTEN-deficient PC3 human prostate cancer, and PTEN-deficient MES-SA uterine tumor xenografts was shown. We show for the first time that induction of AKT phosphorylation at serine 473 by AT13148, as reported for other ATP-competitive inhibitors of AKT, is not a therapeutically relevant reactivation step. Gene expression studies showed that AT13148 has a predominant effect on apoptosis genes, whereas the selective AKT inhibitor CCT128930 modulates cell-cycle genes. Induction of upstream regulators including IRS2 and PIK3IP1 as a result of compensatory feedback loops was observed.
Conclusions: The clinical candidate AT13148 is a novel oral multi-AGC kinase inhibitor with potent pharmacodynamic and antitumor activity, which shows a distinct mechanism of action from other AKT inhibitors. AT13148 will now be assessed in a first-in-human phase I trial. Clin Cancer Res; 18(14); 3912–23. ©2012 AACR.
An In Vivo Immunotherapy Screen of Costimulatory Molecules Identifies Fc-OX40L as a Potent Reagent for the Treatment of Established Murine Gliomas
Authors: Murphy Katherine A. , Lechner Melissa G. , Popescu Flavia E. , Bedi Jessica , Decker Stacy A. , Hu Peisheng , Erickson Jami R. , O'Sullivan M. Gerard , Swier Lauryn , Salazar Andres M. , Olin Michael R. , Epstein Alan L. , Ohlfest John R. 
Published: July 2012

Abstract
Purpose: We tested the combination of a tumor lysate vaccine with a panel of costimulatory molecules to identify an immunotherapeutic approach capable of curing established murine gliomas.
Experimental Design: Glioma-bearing mice were primed with a tumor lysate vaccine, followed by systemic administration of the following costimulatory ligands: OX40L, CD80, 4-1BBL, and GITRL, which were fused to the Fc portion of human immunoglobulin. Lymphocytes and mRNA were purified from the brain tumor site for immune monitoring studies. Numerous variations of the vaccine and Fc-OX40L regimen were tested alone or in combination with temozolomide.
Results: Lysate vaccinations combined with Fc-OX40L led to the best overall survival, yielding cure rates of 50% to 100% depending on the timing, regimen, and combination with temozolomide. Cured mice that were rechallenged with glioma cells rejected the challenge, showing immunologic memory. Lymphocytes isolated from the draining lymph nodes of vaccine/Fc-OX40L–treated mice had superior tumoricidal function relative to all other groups. Vaccine/Fc-OX40L–treated mice exhibited a significant increase in proliferation of brain-infiltrating CD4 and CD8 T cells, as indicated by Ki67 staining. Fc-OX40L had single-agent activity in transplanted and spontaneous glioma models, and the pattern of inflammatory gene expression in the tumor predicted the degree of therapeutic response.
Conclusions: These data show that Fc-OX40L has unique and potent activity against experimental gliomas and warrants further testing. Clin Cancer Res; 18(17); 4657–68. ©2012 AACR.
First Evidence of Sphingosine 1-Phosphate Lyase Protein Expression and Activity Downregulation in Human Neoplasm: Implication for Resistance to Therapeutics in Prostate Cancer
Authors: Brizuela Leyre , Ader Isabelle , Mazerolles Catherine , Bocquet Magalie , Malavaud Bernard , Cuvillier Olivier 
Published: July 2012

Abstract
This is the first report of sphingosine 1-phosphate lyase (SPL) protein expression and enzymatic activity in human neoplasm. This enzyme drives irreversible degradation of sphingosine 1-phosphate (S1P), a bioactive lipid associated with resistance to therapeutics in various cancers, including prostate adenocarcinoma. In fresh human prostatectomy specimens, a remarkable decrease in SPL enzymatic activity was found in tumor samples, as compared with normal adjacent tissues. A significant relationship between loss of SPL expression and higher Gleason score was confirmed in tissue microarray (TMA) analysis. Moreover, SPL protein expression and activity were inversely correlated with those of sphingosine kinase-1 (SphK1), the enzyme producing S1P. SPL and SphK1 expressions were independently predictive of aggressive cancer on TMA, supporting the relevance of S1P in prostate cancer. In human C4-2B and PC-3 cell lines, silencing SPL enhanced survival after irradiation or chemotherapy by decreasing expression of proteins involved in sensing and repairing DNA damage or apoptosis, respectively. In contrast, enforced expression of SPL sensitized cancer cells to irradiation or docetaxel by tilting the ceramide/S1P balance toward cell death. Interestingly, the S1P degradation products failed to sensitize to chemo- and radiotherapy, supporting the crucial role of ceramide/S1P balance in cancer. Of note, the combination of SPL enforced expression with a SphK1 silencing strategy by further decreasing S1P content made prostate cancer cells even more sensitive to anticancer therapies, suggesting that a dual strategy aimed at stimulating SPL, and inhibiting SphK1 could represent a future approach to sensitize cancer cells to cancer treatments. Mol Cancer Ther; 11(9); 1841–51. ©2012 AACR.
Cell Intrinsic Role of COX-2 in Pancreatic Cancer Development
Authors: Hill Reginald , Li Yunfeng , Tran Linh M. , Dry Sarah , Calvopina Joseph Hargan , Garcia Alejandro , Kim Christine , Wang Ying , Donahue Timothy R. , Herschman Harvey R. , Wu Hong 
Published: July 2012

Abstract
COX-2 is upregulated in pancreatic ductal adenocarcinomas (PDAC). However, how COX-2 promotes PDAC development is unclear. While previous studies have evaluated the efficacy of COX-2 inhibition via the use of nonsteroidal anti-inflammatory drugs (NSAID) or the COX-2 inhibitor celecoxib in PDAC models, none have addressed the cell intrinsic versus microenvironment roles of COX-2 in modulating PDAC initiation and progression. We tested the cell intrinsic role of COX-2 in PDAC progression using both loss-of-function and gain-of-function approaches. Cox-2 deletion in Pdx1+ pancreatic progenitor cells significantly delays the development of PDAC in mice with K-ras activation and Pten haploinsufficiency. Conversely, COX-2 overexpression promotes early onset and progression of PDAC in the K-ras mouse model. Loss of PTEN function is a critical factor in determining lethal PDAC onset and overall survival. Mechanistically, COX-2 overexpression increases p-AKT levels in the precursor lesions of Pdx1+; K-rasG12D/+; Ptenlox/+ mice in the absence of Pten LOH. In contrast, Cox-2 deletion in the same setting diminishes p-AKT levels and delays cancer progression. These data suggest an important cell intrinsic role for COX-2 in tumor initiation and progression through activation of the PI3K/AKT pathway. PDAC that is independent of intrinsic COX-2 expression eventually develops with decreased FKBP5 and increased GRP78 expression, two alternate pathways leading to AKT activation. Together, these results support a cell intrinsic role for COX-2 in PDAC development and suggest that while anti-COX-2 therapy may delay the development and progression of PDAC, mechanisms known to increase chemoresistance through AKT activation must also be overcome. Mol Cancer Ther; 11(10); 2127–37. ©2012 AACR.
SLC45A3-ELK4 Chimera in Prostate Cancer: Spotlight on cis-Splicing
Authors: Kumar-Sinha Chandan , Kalyana-Sundaram Shanker , Chinnaiyan Arul M. 
Published: July 2012

Abstract
Summary: Using a series of detailed experiments, Zhang and colleagues establish that the prostate cancer RNA chimera SLC45A3-ELK4 is generated by cis-splicing between the 2 adjacent genes and does not involve DNA rearrangements or trans-splicing. The chimera expression is induced by androgen treatment likely by overcoming the read-through block imposed by the intergenic CCCTC insulators bound by CCCTC-binding factor repressor protein. The chimeric transcript, but not wild-type ELK4, is shown to augment prostate cancer cell proliferation. Cancer Discov; 2(7); 582–5. ©2012 AACR.
Commentary on Zhang et al., p. 598.
Association between cardiovascular disease risk factors and occurrence of venous thromboembolism
Authors: Lutsey Pamela L. , Bell Elizabeth J. , Gornik Heather , Cushman Mary , Heckbert Susan R. , Rosamond Wayne D. , Folsom Aaron R. , Wattanakit Keattiyoat 
Published: July 2012

SummaryApart from obesity, it remains controversial whether atherosclerosis and its cardiovascular risk disease (CVD) factors are associated with risk of venous thromboembolism (VTE). Using data from the Atherosclerosis Risk in Communities study (ARIC), we evaluated associations between CVD risk factors and incident VTE in a cohort of 15,340 participants who were free a history of VTE and/or anticoagulant use on enrolment. The CVD risk factors were updated during the follow-up period. Over a mean follow-up time of 15.5 years (237,375 person-years), 468 participants had VTE events. Adjusting for demographic variables and body mass index (BMI), current smokers were at greater risk [HR of 1.44 (95% CI: 1.12–1.86)] compared to non-smokers. There was a positive monotonic association between BMI and VTE risk. Individuals with a BMI ≥35 kg/m2 had a HR for VTE of 3.09 (95%CI: 2.26–4.23) compared to those with normal BMI (<25 kg/m2). Greater physical activity was associated with lower VTE risk in a demographic adjusted model; however, this association became non-significant following adjustment for BMI. Alcohol intake, diabetes, hypertension, high-density lipoprotein and low-density lipoprotein cholesterol, and triglycerides were not associated with VTE risk. In conclusion, among the well-established CVD risk factors, only current smoking and obesity were independently associated with VTE risk in this large cohort where risk factors were updated serially during follow-up. This finding corroborates that the pathogenesis of venous disease differs from that of atherosclerotic disease.
The urokinase receptor (CD87) represents a central mediator of growth factor-induced endothelial cell migration
Authors: Poettler Marina , Unseld Matthias , Mihaly-Bison Judit , Uhrin Pavel , Koban Florian , Binder Bernd R. , Zielinski Christoph C. , Prager Gerald W. 
Published: July 2012

SummaryAngiogenesis, the sprouting of blood vessels form pre-existing vasculature after injury or in neoplastic diseases, is initiated by growth factor-induced endothelial cell migration. Recently, the major angiogenic growth factor VEGF165 has become the target of therapeutic interventions. However, this approach has been clinically proven to be of limited efficacy, which might be due to the fact that tumour angiogenesis is not only induced by VEGF, but also by a variety of other growth factors. Thus, the identification of a common downstream mediator of growth-factor-induced endothelial cell migration is mandatory to effectively interfere with (tumour-) angiogenesis. We found that the urokinase-type plas-minogen activator (uPA)-system, which affects proteolytic as well as adhesive capacities, represents an essential regulatory mechanism in growth factor-induced endothelial cell migration and invasion. This mechanism was not limited to VEGF165, but mediated pro-angiogenic endothelial cell behaviour induced by various growth factors. Thus, VEGF165, VEGF-E, FGF-2, EGF as well as HGF induced a PI3k-dependent activation of pro-uPA when bound to uPAR, which led to an increase in cell surface fibrinolytic activity. As a consequence, uPAR became internalised and redistributed via LDLR-proteins. Interference with these events led to a reduced migratory response of endothelial cells towards VEGF in vitro as well as endothelial cell invasion in vivo. These data give first evidence that the uPA-system, which represents the only level-of-evidence-1 cancer biomarker system for prognosis and/or prediction in node negative breast cancer, might directly affect (tumour-) angiogenesis.