bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human Cytomegalovirus Interleukin-10 Polarizes Monocytes toward a Deactivated M2c Phenotype To Repress Host Immune Responses
Authors: Avdic Selmir , Cao John Z. , McSharry Brian P. , Clancy Leighton E. , Brown Rebecca , Steain Megan , Gottlieb David J. , Abendroth Allison , Slobedman Barry 
Published: July 2013

ABSTRACTSeveral human cytomegalovirus (HCMV) genes encode products that modulate cellular functions in a manner likely to enhance viral pathogenesis. This includesUL111A, which encodes homologs of human interleukin-10 (hIL-10). Depending upon signals received, monocytes and macrophages become polarized to either classically activated (M1 proinflammatory) or alternatively activated (M2 anti-inflammatory) subsets. Skewing of polarization toward an M2 subset may benefit the virus by limiting the proinflammatory responses to infection, and so we determined whether HCMV-encoded viral IL-10 influenced monocyte polarization. Recombinant viral IL-10 protein polarized CD14+monocytes toward an anti-inflammatory M2 subset with an M2c phenotype, as demonstrated by high expression of CD163 and CD14 and suppression of major histocompatibility complex (MHC) class II. Significantly, in the context of productive HCMV infection, viral IL-10 produced by infected cells polarized uninfected monocytes toward an M2c phenotype. We also assessed the impact of viral IL-10 on heme oxygenase 1 (HO-1), which is an enzyme linked with suppression of inflammatory responses. Polarization of monocytes by viral IL-10 resulted in upregulation of HO-1, and inhibition of HO-1 function resulted in a loss of capacity of viral IL-10 to suppress tumor necrosis factor alpha (TNF-α) and IL-1β, implicating HO-1 in viral IL-10-induced suppression of proinflammatory cytokines by M2c monocytes. In addition, a functional consequence of monocytes polarized with viral IL-10 was a decreased capacity to activate CD4+T cells. This study identifies a novel role for viral IL-10 in driving M2c polarization, which may limit virus clearance by restricting proinflammatory and CD4+T cell responses at sites of infection.
Mammalian Adaptation in the PB2 Gene of Avian H5N1 Influenza Virus
Authors: Min Ji-Young , Santos Celia , Fitch Adam , Twaddle Alan , Toyoda Yoshiko , DePasse Jay V. , Ghedin Elodie , Subbarao Kanta 
Published: July 2013

ABSTRACT
The substitution of glutamic acid (E) for lysine (K) at position 627 of the PB2 protein of avian H5N1 viruses has been identified as a virulence and host range determinant for infection of mammals. Here, we report that the E-to-K host-adaptive mutation in the PB2 gene appeared from day 4 and 5 along the respiratory tracts of mice and was complete by day 6 postinoculation. This mutation correlated with efficient replication of the virus in mice.
Fematrin-1 Is Involved in Fetomaternal Cell-to-Cell Fusion in Bovinae Placenta and Has Contributed to Diversity of Ruminant Placentation
Authors: Nakaya Yuki , Koshi Katsuo , Nakagawa So , Hashizume Kazuyoshi , Miyazawa Takayuki 
Published: July 2013

ABSTRACT

During placentation, mammals employ different strategies for nourishing and supporting fetuses. Members of the Bovidae family, consisting of cloven-hoofed ruminants, utilize multiple maternal attachment points on the placenta, known as cotyledons, and hybrid cells, named trinucleate cells or syncytial plaques, made up of a fusion of fetal trophoblasts and maternal endometrial cells to provide essential hormones and maintain long gestation periods. These hybrid cells are unique to the Bovidae, as fetomaternal borders are clearly separated by syncytiotrophoblasts or epithelial cells in the placenta of other mammals. Recently, it was reported that Syncytin-Rum1 was inserted into ruminant genomes, including cattle and sheep, and was possibly involved in fetomaternal cell-to-cell fusion in both species. However, Syncytin-Rum1 alone is insufficient to explain the morphological diversity of the fetomaternal hybrids between Bovinae and Caprinae (i.e., trinucleate cells in Bovinae and syncytial plaques in Caprinae). Here we report that the bovine endogenous retrovirus K1 (BERV-K1) envelope, which we term Fematrin-1, was specifically expressed in binucleated trophoblasts throughout gestation in cattle and induced fusion with bovine endometrial cells
in vitro
at a significantly higher level than Syncytin-Rum1 under physiological conditions.
Fematrin-1
was found to be integrated into intron 18 of FAT tumor suppressor homolog 2 (
FAT2
) about 18.3 to 25.4 million years ago and has been subject to purifying selection through the evolution of Bovinae. Phylogenetically,
Fematrin-1
is distinct from
Syncytin
genes found in other mammalian species that form syncytiotrophoblasts. Our results suggest that the newly acquired endogenous retroelement has contributed to generating placentation diversity through ruminant evolution.
Phenotypic and Functional Characterization of Circulating Polyomavirus BK VP1-Specific CD8
+
T Cells in Healthy Adults
Authors: van Aalderen Michiel C. , Remmerswaal Ester B. M. , Heutinck Kirstin M. , ten Brinke Anja , Pircher Hanspeter , van Lier René A. W. , ten Berge Ineke J. M. 
Published: July 2013

ABSTRACT

The human polyomavirus BK virus (BKV) establishes a latent and asymptomatic infection in the majority of the population. In immunocompromised individuals, the virus frequently (re)activates and may cause severe disease such as interstitial nephritis and hemorrhagic cystitis. Currently, the therapeutic options are limited to reconstitution of the antiviral immune response. T cells are particularly important for controlling this virus, and T cell therapies may provide a highly specific and effective mode of treatment. However, little is known about the phenotype and function of BKV-specific T cells in healthy individuals. Using tetrameric BKV peptide-HLA-A02 complexes, we determined the presence, phenotype, and functional characteristics of circulating BKV VP1-specific CD8
+
T cells in 5 healthy individuals. We show that these cells are present in low frequencies in the circulation and that they have a resting CD45RA
−
CD27
+
memory and predominantly CCR7
−
CD127
+
KLRG1
+
CD49d
hi
CXCR3
hi
T-bet
int
Eomesodermin
lo
phenotype. Furthermore, their direct cytotoxic capacity seems to be limited, since they do not readily express granzyme B and express only little granzyme K. We compared these cells to circulating CD8
+
T cells specific for cytomegalovirus (CMV), Epstein-Barr virus (EBV), and influenza virus (Flu) in the same donors and show that BKV-specific T cells have a phenotype that is distinct from that of CMV- and EBV-specific T cells. Lastly, we show that BKV-specific T cells are polyfunctional since they are able to rapidly express interleukin-2 (IL-2), gamma interferon (IFN-γ), tumor necrosis factor α, and also, to a much lower extent, MIP-1β and CD107a.
Determinants of workplace injury among Thai Cohort Study participants
Authors: Berecki-Gisolf Janneke , Tawatsupa Benjawan , McClure Roderick , Seubsman Sam-ang , Sleigh Adrian 
Published: July 2013

ObjectivesTo explore individual determinants of workplace injury among Thai workers.DesignCross-sectional analysis of a large national cohort.SettingThailand.ParticipantsThai Cohort Study participants who responded to the 2009 follow-up survey were included if they reported doing paid work or being self-employed (n=51 751).Outcome measuresSelf-reported injury incidence over the past 12 months was calculated. Multivariate logistic regression models were used to test associations between individual determinants and self-reported workplace injury.ResultsWorkplace injuries were reported by 1317 study participants (2.5%); the incidence was 34 (95% CI 32 to 36)/1000 worker-years for men, and 18 (17–20) for women. Among men working ≥41 h and earning <10 000 Baht, the injury rate was four times higher compared with men working <11 h and earning ≥20 001 Baht; differences in injury rates were less pronounced in women. Multivariate modelling showed that working ≥49 h/week (23%) and working for ≤10 000 Bath/month (37%) were associated with workplace injury. The increase in injury risk with increased working hours did not exceed the risk expected from increased exposure.ConclusionsReductions in occupational injury rates could be achieved by limiting working hours to 48/week. Particularly for Thai low wage earners and those with longer workdays, there is a need for effective injury preventive programmes.
A structured judgement method to enhance mortality case note review: development and evaluation
Authors: Hutchinson Allen , Coster Joanne E , Cooper Katy L , Pearson Michael , McIntosh Aileen , Bath Peter A 
Published: July 2013

BackgroundCase note review remains a prime means of retrospectively assessing quality of care. This study examines a new implicit judgement method, combining structured reviewer comments with quality of care scores, to assess care of people who die in hospital.MethodsUsing 1566 case notes from 20 English hospitals, 40 physicians each reviewed 30–40 case notes, writing structured judgement-based comments on care provided within three phases of care, and on care overall, and scoring quality of care from 1 (unsatisfactory) to 6 (very best care). Quality of care comments on 119 people who died (7.6% of the cohort) were analysed independently by two researchers to investigate how well reviewers provided structured short judgement notes on quality of care, together with appropriate care scores. Consistency between explanatory textual data and related scores was explored, using overall care score to group cases.ResultsPhysician reviewers made informative, clinical judgement-based comments across all phases of care and usually provided a coherent quality of care score relating to each phase. The majority of comments (83%) were explicit judgements. About a fifth of patients were considered to have received less than satisfactory care, often experiencing a series of adverse events.ConclusionsA combination of implicit judgement, explicit explanatory comment and related quality of care scores can be used effectively to review the spectrum of care provided for people who die in hospital. The method can be used to quickly evaluate deaths so that lessons can be learned about both poor and high quality care.
Home and work neighbourhood environments in relation to body mass index: the Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Moore Kari , Diez Roux Ana V , Auchincloss Amy , Evenson Kelly R , Kaufman Joel , Mujahid Mahasin , Williams Kayleen 
Published: July 2013

BackgroundLittle is known about the neighbourhood characteristics of workplaces, the extent to which they are independently and synergistically correlated with residential environments, and their impact on health.MethodsThis study investigated cross-sectional relationships between home and workplace neighbourhood environments with body mass index (BMI) in 1503 working participants of the Multi-Ethnic Study of Atherosclerosis with mean age 59.6 (SD=7.4). Neighbourhood features were socioeconomic status (SES), social environment (aesthetic quality, safety and social cohesion) and physical environment (walking environment, recreational facilities and food stores) derived from census data, locational data on businesses and survey data. Paired t tests and correlations compared environments overall and by distance between locations. Cross-classified multilevel models estimated associations with BMI.ResultsHome neighbourhoods had more favourable social environments while workplaces had more favourable SES and physical environments. Workplace and home measures were correlated (0.39–0.70), and differences between home and workplaces were larger as distance increased. Associations between BMI and neighbourhood SES and recreational facilities were stronger for home environment (p≤0.05) but did not significantly differ for healthy food, safety or social cohesion. Healthy food availability at home and work appeared to act synergistically (interaction p=0.01).ConclusionsConsideration of workplace environment may enhance our understanding of how place affects BMI.
Werner Syndrome Helicase Has a Critical Role in DNA Damage Responses in the Absence of a Functional Fanconi Anemia Pathway
Authors: Aggarwal Monika , Banerjee Taraswi , Sommers Joshua A. , Iannascoli Chiara , Pichierri Pietro , Shoemaker Robert H. , Brosh Robert M. 
Published: July 2013

Abstract
Werner syndrome is genetically linked to mutations in WRN that encodes a DNA helicase-nuclease believed to operate at stalled replication forks. Using a newly identified small-molecule inhibitor of WRN helicase (NSC 617145), we investigated the role of WRN in the interstrand cross-link (ICL) response in cells derived from patients with Fanconi anemia, a hereditary disorder characterized by bone marrow failure and cancer. In FA-D2−/− cells, NSC 617145 acted synergistically with very low concentrations of mitomycin C to inhibit proliferation in a WRN-dependent manner and induce double-strand breaks (DSB) and chromosomal abnormalities. Under these conditions, ataxia–telangiectasia mutated activation and accumulation of DNA-dependent protein kinase, catalytic subunit pS2056 foci suggested an increased number of DSBs processed by nonhomologous end-joining (NHEJ). Rad51 foci were also elevated in FA-D2−/− cells exposed to NSC 617145 and mitomycin C, suggesting that WRN helicase inhibition interferes with later steps of homologous recombination at ICL-induced DSBs. Thus, when the Fanconi anemia pathway is defective, WRN helicase inhibition perturbs the normal ICL response, leading to NHEJ activation. Potential implication for treatment of Fanconi anemia–deficient tumors by their sensitization to DNA cross-linking agents is discussed. Cancer Res; 73(17); 5497–507. ©2013 AACR.
Molecular Pathways: Inflammation-Associated Nitric-Oxide Production as a Cancer-Supporting Redox Mechanism and a Potential Therapeutic Target
Authors: Grimm Elizabeth A. , Sikora Andrew G. , Ekmekcioglu Suhendan 
Published: July 2013

Abstract
It is widely accepted that many cancers express features of inflammation, driven by both microenvironmental cells and factors, and the intrinsic production of inflammation-associated mediators from malignant cells themselves. Inflammation results in intracellular oxidative stress with the ultimate biochemical oxidants composed of reactive nitrogens and oxygens. Although the role of inflammation in carcinogensis is well accepted, we now present data showing that inflammatory processes are also active in the maintenance phase of many aggressive forms of cancer. The oxidative stress of inflammation is proposed to drive a continuous process of DNA adducts and crosslinks, as well as posttranslational modifications to lipids and proteins that we argue support growth and survival. In this perspective, we introduce data on the emerging science of inflammation-driven posttranslational modifications on proteins responsible for driving growth, angiogenesis, immunosuppression, and inhibition of apoptosis. Examples include data from human melanoma, breast, head and neck, lung, and colon cancers. Fortunately, numerous antioxidant agents are clinically available, and we further propose that the pharmacologic attenuation of these inflammatory processes, particularly the reactive nitrogen species, will restore the cancer cells to an apoptosis-permissive and growth-inhibitory state. Our mouse model data using an arginine antagonist that prevents enzymatic production of nitric oxide directly supports this view. We contend that selected antioxidants be considered as part of the cancer treatment approach, as they are likely to provide a novel and mechanistically justified addition for therapeutic benefit. Clin Cancer Res; 19(20); 5557–63. ©2013 AACR.
Tumor-Infiltrating Lymphocytes in Glioblastoma Are Associated with Specific Genomic Alterations and Related to Transcriptional Class
Authors: Rutledge W. Caleb , Kong Jun , Gao Jingjing , Gutman David A. , Cooper Lee A.D. , Appin Christina , Park Yuna , Scarpace Lisa , Mikkelsen Tom , Cohen Mark L. , Aldape Kenneth D. , McLendon Roger E. , Lehman Norman L. , Miller C. Ryan , Schniederjan Matthew J. , Brennan Cameron W. , Saltz Joel H. , Moreno Carlos S. , Brat Daniel J. 
Published: July 2013

Abstract
Purpose: Tumor-infiltrating lymphocytes (TIL) have prognostic significance in many cancers, yet their roles in glioblastoma have not been fully defined. We hypothesized that TILs in glioblastoma are associated with molecular alterations, histologies, and survival.
Experimental Design: We used data from The Cancer Genome Atlas (TCGA) to investigate molecular, histologic, and clinical correlates of TILs in glioblastomas. Lymphocytes were categorized as absent, present, or abundant in histopathologic images from 171 TCGA glioblastomas. Associations were examined between lymphocytes and histologic features, mutations, copy number alterations, CpG island methylator phenotype, transcriptional class, and survival. We validated histologic findings using CD3G gene expression.
Results: We found a positive correlation between TILs and glioblastomas with gemistocytes, sarcomatous cells, epithelioid cells, and giant cells. Lymphocytes were enriched in the mesenchymal transcriptional class and strongly associated with mutations in NF1 and RB1. These mutations are frequent in the mesenchymal class and characteristic of gemistocytic, sarcomatous, epithelioid, and giant cell histologies. Conversely, TILs were rare in glioblastomas with small cells and oligodendroglioma components. Lymphocytes were depleted in the classical transcriptional class and in EGF receptor (EGFR)-amplified and homozygous PTEN-deleted glioblastomas. These alterations are characteristic of glioblastomas with small cells and glioblastomas of the classical transcriptional class. No association with survival was shown.
Conclusions: TILs were enriched in glioblastomas of the mesenchymal class, strongly associated with mutations in NF1 and RB1 and typical of histologies characterized by these mutations. Conversely, TILs were depleted in the classical class, EGFR-amplified, and homozygous PTEN-deleted tumors and rare in histologies characterized by these alterations. Clin Cancer Res; 19(18); 4951–60. ©2013 AACR.
A Randomized Pilot Trial of Dietary Modification for the Chemoprevention of Noninvasive Bladder Cancer: The Dietary Intervention in Bladder Cancer Study
Authors: Parsons J. Kellogg , Pierce John P. , Natarajan Loki , Newman Vicky A. , Barbier Leslie , Mohler James , Rock Cheryl L. , Heath Dennis D. , Guru Khurshid , Jameson Michael B. , Li Hongying , Mirheydar Hossein , Holmes Michael A. , Marshall James 
Published: July 2013

Abstract
Epidemiological data suggest robust associations of high vegetable intake with decreased risks of bladder cancer incidence and mortality, but translational prevention studies have yet to be conducted. We designed and tested a novel intervention to increase vegetable intake in patients with noninvasive bladder cancer. We randomized 48 patients aged 50 to 80 years with biopsy-proven noninvasive (Ta, T1, or carcinoma in situ) urothelial cell carcinoma to telephone- and Skype-based dietary counseling or a control condition that provided print materials only. The intervention behavioral goals promoted seven daily vegetable servings, with at least two of these as cruciferous vegetables. Outcome variables were self-reported diet and plasma carotenoid and 24-hour urinary isothiocyanate (ITC) concentrations. We used two-sample t tests to assess between-group differences at 6-month follow-up. After 6 months, intervention patients had higher daily intakes of vegetable juice (P = 0.02), total vegetables (P = 0.02), and cruciferous vegetables (P = 0.07); lower daily intakes of energy (P = 0.007), fat (P = 0.002) and energy from fat (P = 0.06); and higher plasma α-carotene concentrations (P = 0.03). Self-reported cruciferous vegetable intake correlated with urinary ITC concentrations at baseline (P &lt; 0.001) and at 6 months (P = 0.03). Although urinary ITC concentrations increased in the intervention group and decreased in the control group, these changes did not attain between-group significance (P = 0.32). In patients with noninvasive bladder cancer, our novel intervention induced diet changes associated with protective effects against bladder cancer. These data show the feasibility of implementing therapeutic dietary modifications to prevent recurrent and progressive bladder cancer. Cancer Prev Res; 6(9); 971–8. ©2013 AACR.
Rictor in Perivascular Adipose Tissue Controls Vascular Function by Regulating Inflammatory Molecule Expression
Authors: Bhattacharya Indranil , Drägert Katja , Albert Verena , Contassot Emmanuel , Damjanović Marlen , Hagiwara Asami , Zimmerli Lukas , Humar Rok , Hall Michael N. , Battegay Edouard J. , Haas Elvira 
Published: July 2013

Objective—
Perivascular adipose tissue (PVAT) wraps blood vessels and modulates vasoreactivity by secretion of vasoactive molecules. Mammalian target of rapamycin complex 2 (mTORC2) has been shown to control inflammation and is expressed in adipose tissue. In this study, we investigated whether adipose-specific deletion of rictor and thereby inactivation of mTORC2 in PVAT may modulate vascular function by increasing inflammation in PVAT.

Approach and Results—

Rictor, an essential mTORC2 component, was deleted specifically in mouse adipose tissue (rictor
ad−/−
). Phosphorylation of mTORC2 downstream target Akt at Serine 473 was reduced in PVAT from rictor
ad−/−
mice but unaffected in aortic tissue. Ex vivo functional analysis of thoracic aortae revealed increased contractions and impaired dilation in rings with PVAT from rictor
ad−/−
mice. Adipose rictor knockout increased gene expression and protein release of interleukin-6, macrophage inflammatory protein-1α, and tumor necrosis factor-α in PVAT as shown by quantitative real-time polymerase chain reaction and Bioplex analysis for the cytokines in the conditioned media, respectively. Moreover, gene and protein expression of inducible nitric oxide synthase was upregulated without affecting macrophage infiltration in PVAT from rictor
ad−/−
mice. Inhibition of inducible nitric oxide synthase normalized vascular reactivity in aortic rings from rictor
ad−/−
mice with no effect in rictor
fl/fl
mice. Interestingly, in perivascular and epididymal adipose depots, high-fat diet feeding induced downregulation of rictor gene expression.

Conclusions—
Here, we identify mTORC2 as a critical regulator of PVAT-directed protection of normal vascular tone. Modulation of mTORC2 activity in adipose tissue may be a potential therapeutic approach for inflammation-related vascular damage.