bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stimulus Duration and Response Time Independently Influence the Kinetics of Lytic Cycle Reactivation of Epstein-Barr Virus
Authors: Countryman Jill , Gradoville Lyndle , Bhaduri-McIntosh Sumita , Ye Jianjiang , Heston Lee , Himmelfarb Sarah , Shedd Duane , Miller George 
Published: August 2009

ABSTRACT
Epstein-Barr virus (EBV) can be reactivated from latency into the lytic cycle by many stimuli believed to operate by different mechanisms. Cell lines containing EBV differ in their responses to inducing stimuli, yet all stimuli require de novo protein synthesis (44). A crucial step preliminary to identifying these proteins and determining when they are required is to measure the duration of stimulus and response time needed for activation of expression of EBV BRLF1 and BZLF1, the earliest viral indicators of reactivation. Here we show, with four EBV-containing cell lines that respond to different inducing agents, that stimuli that are effective at reactivating EBV can be divided into two main groups. The histone deacetylase inhibitors sodium butyrate and trichostatin A require a relatively long period of exposure, from 2 to 4 h or longer. Phorbol esters, anti-immunoglobulin G (anti-IgG), and, surprisingly, 5-aza-2′-deoxycytidine require short exposures of 15 min or less. The cell/virus background influences the response time. Expression of the EBV BZLF1 and BRLF1 genes can be detected before 2 h in Akata cells treated with anti-IgG, but both long- and short-duration stimuli required 4 or more hr to activate BZLF1 and BRLF1 expression in HH514-16, Raji, or B95-8 cells. Thus, stimulus duration and response time are independent variables. Neither stimulus duration nor response time can be predicted by the number of cells activated into the lytic cycle. These experiments shed new light on the earliest events leading to lytic cycle reactivation of EBV.
Probing the Spatial Organization of Measles Virus Fusion Complexes
Authors: Paal Tanja , Brindley Melinda A. , St. Clair Courtney , Prussia Andrew , Gaus Dominika , Krumm Stefanie A. , Snyder James P. , Plemper Richard K. 
Published: August 2009

ABSTRACT
The spatial organization of metastable paramyxovirus fusion (F) and attachment glycoprotein hetero-oligomers is largely unknown. To further elucidate the organization of functional fusion complexes of measles virus (MeV), an archetype of the paramyxovirus family, we subjected central predictions of alternative docking models to experimental testing using three distinct approaches. Carbohydrate shielding through engineered N-glycans indicates close proximity of a membrane-distal, but not membrane-proximal, section of the MeV attachment (H) protein stalk domain to F. Directed mutagenesis of this section identified residues 111, 114, and 118 as modulators of avidity of glycoprotein interactions and determinants of F triggering. Stalk-length variation through deletion or insertion of HR elements at positions flanking this section demonstrates that the location of the stalk segment containing these residues cannot be altered in functional fusion complexes. In contrast, increasing the distance between the H head domains harboring the receptor binding sites and this section through insertion of structurally rigid α-helical domains with a pitch of up to approximately 75 Å downstream of stalk position 118 partially maintains functionality in transient expression assays and supports efficient growth of recombinant virions. In aggregate, these findings argue against specific protein-protein contacts between the H head and F head domains but instead support a docking model that is characterized by short-range contacts between the prefusion F head and the attachment protein stalk, possibly involving H residues 111, 114, and 118, and extension of the head domain of the attachment protein above prefusion F.
Vaccinia Virus K1L and C7L Inhibit Antiviral Activities Induced by Type I Interferons
Authors: Meng Xiangzhi , Jiang Canhua , Arsenio Janilyn , Dick Kevin , Cao Jingxin , Xiang Yan 
Published: August 2009

ABSTRACTCellular tropism of vaccinia virus (VACV) is regulated by host range genes, including K1L, C7L, and E3L. While E3L is known to support viral replication by antagonizing interferon (IFN) effectors, including PKR, the exact functions of K1L and C7L are unclear. Here, we show that K1L and C7L can also inhibit antiviral effectors induced by type I IFN. In human Huh7 and MCF-7 cells, a VACV mutant lacking both K1L and C7L (vK1L−C7L−) replicated as efficiently as wild-type (WT) VACV, even in the presence of IFN. However, pretreating the cells with type I IFN, while having very little effect on WT VACV, blocked the replication of vK1L−C7L−at the step of intermediate viral gene translation. Restoring either K1L or C7L to vK1L−C7L−fully restored the IFN resistance phenotype. The deletion of K1L and C7L from VACV did not affect the ability of the virus to inhibit IFN signaling or its ability to inhibit the phosphorylation of PKR and the α subunit of eukaryotic initiation factor 2, indicating that K1L and C7L function by antagonizing an IFN effector(s) but with a mechanism that is different from those of IFN antagonists previously identified for VACV. Mutations of K1L that inactivate the host range function also rendered K1L unable to antagonize IFN, suggesting that K1L supports VACV replication in mammalian cells by antagonizing the same antiviral factor(s) that is induced by IFN in Huh7 cells.
Cross Talk among the Glycoproteins Involved in Herpes Simplex Virus Entry and Fusion: the Interaction between gB and gH/gL Does Not Necessarily Require gD
Authors: Avitabile Elisa , Forghieri Cristina , Campadelli-Fiume Gabriella 
Published: August 2009

ABSTRACT
The gD, gB, and gH/gL glycoprotein quartet constitutes the basic apparatus for herpes simplex virus (HSV) entry into the cell and fusion. gD serves as a receptor binding glycoprotein and trigger of fusion. The conserved gB and gH/gL execute fusion. Central to understanding HSV entry/fusion has become the dissection of how the four glycoproteins engage in cross talk. While the independent interactions of gD with gB and gD with gH/gL have been documented, less is known of the interaction of gB with gH/gL. So far, this interaction has been detected only in the presence of gD by means of a split green fluorescent protein complementation assay. Here, we show that gB interacts with gH/gL in the absence of gD. The gB-gH/gL complex was best detected with a form of gB in which the endocytosis and phosphorylation motif have been deleted; this form of gB persists in the membranes of the exocytic pathway and is not endocytosed. The gB-gH/gL interaction was detected both in whole transfected cells by means of a split yellow fluorescent protein complementation assay and, biochemically, by a pull-down assay. Results with a panel of chimeric forms of gB, in which portions of the glycoprotein bracketed by consecutive cysteines were replaced with the corresponding portions from human herpesvirus 8 gB, favor the view that gB carries multiple sites for interaction with gH/gL, and one of these sites is located in the pleckstrin-like domain 1 carrying the bipartite fusion loop.
Analysis of Human Cytomegalovirus-Encoded MicroRNA Activity during Infection
Authors: Stern-Ginossar Noam , Saleh Niveen , Goldberg Miri D. , Prichard Mark , Wolf Dana G. , Mandelboim Ofer 
Published: August 2009

ABSTRACT
MicroRNAs (miRNAs) are expressed in a wide variety of organisms, ranging from plants to animals, and are key posttranscriptional regulators of gene expression. Virally encoded miRNAs are unique in that they could potentially target both viral and host genes. Indeed, we have previously demonstrated that a human cytomegalovirus (HCMV)-encoded miRNA, miR-UL112, downregulates the expression of a host immune gene, MICB. Remarkably, it was shown that the same miRNA also downregulates immediate-early viral genes and that its ectopic expression resulted in reduced viral replication and viral titers. The targets for most of the viral miRNAs, and hence their functions, are still unknown. Here we demonstrate that miR-UL112 also targets the UL114 gene, and we present evidence that the reduction of UL114 by miR-UL112 reduces its activity as uracil DNA glycosylase but only minimally affects virus growth. In addition, we show that two additional HCMV-encoded miRNAs, miR-US25-1 and miR-US25-2, reduce the viral replication and DNA synthesis not only of HCMV but also of other viruses, suggesting that these two miRNAs target cellular genes that are essential for virus growth. Thus, we suggest that in addition to miR-UL112, two additional HCMV miRNAs control the life cycle of the virus.
A Conserved Proline between Domains II and III of Hepatitis C Virus NS5A Influences both RNA Replication and Virus Assembly
Authors: Hughes Mair , Gretton Sarah , Shelton Holly , Brown David D. , McCormick Christopher J. , Angus Allan G. N. , Patel Arvind H. , Griffin Stephen , Harris Mark 
Published: August 2009

ABSTRACT
We previously demonstrated that two closely spaced polyproline motifs, with the consensus sequence Pro-X-X-Pro-X-Lys/Arg, located between residues 343 to 356 of NS5A, mediated interactions with cellular SH3 domains. The N-terminal motif (termed PP2.1) is only conserved in genotype 1 isolates, whereas the C-terminal motif (PP2.2) is conserved throughout all hepatitis C virus (HCV) isolates, although this motif was shown to be dispensable for replication of the genotype 1b subgenomic replicon. In order to investigate the potential role of these motifs in the viral life cycle, we have undertaken a detailed mutagenic analysis of these proline residues in the context of both genotype 1b (FK5.1) or 2a subgenomic replicons and the genotype 2a infectious clone, JFH-1. We show that the PP2.2 motif is dispensable for RNA replication of all subgenomic replicons and, furthermore, is not required for virus production in JFH-1. In contrast, the PP2.1 motif is only required for genotype 1b RNA replication. Mutation of proline 346 within PP2.1 to alanine dramatically attenuated genotype 1b replicon replication in three distinct genetic backgrounds, but the corresponding proline 342 was not required for replication of the JFH-1 subgenomic replicon. However, the P342A mutation resulted in both a delay to virus release and a modest (up to 10-fold) reduction in virus production. These data point to critical roles for these proline residues at multiple stages in the HCV life cycle; however, they also caution against extrapolation of data from culture-adapted replicons to infectious virus.
Detection of Circulating Tumor Cells in Peripheral Blood of Patients with Renal Cell Carcinoma Correlates with Prognosis
Authors: Bluemke Karen , Bilkenroth Udo , Meye Axel , Fuessel Susanne , Lautenschlaeger Christine , Goebel Steffen , Melchior Andres , Heynemann Hans , Fornara Paolo , Taubert Helge 
Published: August 2009

Abstract
Purpose: The aim of this study was to evaluate the clinical relevance of the presence of disseminated tumor cells in peripheral blood (so-called circulating tumor cells) for renal cell carcinoma patients.
Methods: Two hundred thirty-three peripheral blood samples from 154 renal cell carcinoma patients were investigated for the presence of disseminated tumor cells by autoMACS technique and immunocytochemical staining of cytokeratin. The frequency of circulating tumor cells was analyzed statistically for correlation with relevant clinical data.
Results: Two kinds of tumor cells were detected: those with expression of cytokeratin 8/18 (CK+) and cells without a detectable cytokeratin expression, which we called large blue-stained cells with a tumorlike morphology. After following the CD45 autoMACS depletion protocol, we identified circulating tumor cells in 96 (41%) of 233 peripheral blood samples, which originated from 81 (53%) of 154 renal cell carcinoma patients. A significant correlation between the detection of circulating tumor cells and positive lymph node status (P &lt; 0.001; χ2 test) and the presence of synchronous metastases at the time of primary tumor resection (P = 0.014; χ2 test) was found. In a multivariate Cox's regression hazard model, presence of CK+ circulating tumor cells was significantly correlated with poor overall survival for renal cell carcinoma patients (relative risk, 2.3; P = 0.048).
Conclusions: The presence of circulating tumor cells correlated to lymph node status and presence of synchronous metastases in renal cell carcinoma. It is important to evaluate CK+ and blue-stained tumor cells together to determine the role of circulating tumor cells in tumor behavior and disease progression. Detection of CK+ circulating tumor cells in peripheral blood is a significant and independent prognostic factor for renal cell carcinoma.(Cancer Epidemiol Biomarkers Prev 2009;18(8):2190–4)
Plasma Levels of B Vitamins and Colorectal Cancer Risk: The Multiethnic Cohort Study
Authors: Le Marchand Loïc , White Kami K. , Nomura Abraham M.Y. , Wilkens Lynne R. , Selhub Jacob S. , Tiirikainen Maarit , Goodman Marc T. , Murphy Suzanne P. , Henderson Brian E. , Kolonel Laurence N. 
Published: August 2009

AbstractB vitamins, such as folate, vitamin B6, and vitamin B12, play an important role as coenzymes in one-carbon metabolism and may affect colorectal cancer risk. We aimed to comprehensively investigate the relationships of plasma folate, pyridoxal-5′-phosphate (PLP, the active form of vitamin B6), vitamin B12, methylmalonic acid, homocysteine, and cysteine with colorectal cancer risk, accounting for suspected modifiers (alcohol intake, MTHFR C677T genotype, and plasma C-reactive protein) and potential confounders. We conducted a case-control study nested within the Multiethnic Cohort study and analyzed prospectively collected blood samples from 224 incident colorectal cancer cases and 411 controls matched on age, sex, race/ethnicity, study site, date/time of blood draw, and hours of fasting. We found an inverse association between plasma PLP levels and colorectal cancer, with odds ratios (95% confidence intervals) for increasing quartiles of 1.00, 0.84 (0.51-1.40), 0.62 (0.37-1.03), and 0.49 (0.29-0.83), with P trend = 0.009. This association was not explained by an association with plasma folate, seemed to be stronger at low levels of alcohol intake and among individuals with the MTHFR 677TT genotype, and was independent of plasma C-reactive protein levels. An inverse association with plasma folate was also observed among individuals with a low level of alcohol intake. These data suggest an independent role for vitamin B6 in reducing colorectal cancer risk. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2195–201)
Maternal Immunoglobulin E and Childhood Leukemia
Authors: Chang Jeffrey S. , Buffler Patricia A. , Metayer Catherine , Chokkalingam Anand P. , Patoka Joe , Kronish Daniel , Wiemels Joseph L. 
Published: August 2009

Abstract
Childhood leukemia, particularly acute lymphoblastic leukemia (ALL), has long been hypothesized to be affected by abnormal immune responses to microbial challenges stemming from a lack of immune modulation in early childhood. Studies of allergies suggest that a child's immune development may be modulated by maternal immune status. We conducted a study to explore the relationship between maternal immunoglobulin E (IgE) and childhood leukemia and to investigate whether maternal immune status can influence childhood leukemia risk. Serum total and specific IgE (respiratory and food) were measured in biological mothers of 352 children (193 healthy controls and 159 leukemia cases, including 139 ALL cases) ages &lt;8 years who were enrolled in the Northern California Childhood Leukemia Study. Odds ratios associated with maternal IgE were calculated using unconditional logistic regression adjusted for child's age, sex, race/ethnicity, and annual household income. A positive association between childhood leukemia or ALL and elevated levels of maternal serum total IgE was observed, especially among Hispanics. In addition, a positive association was observed between childhood leukemia or ALL and maternal respiratory or food IgE status. These results suggest that maternal immune function may play a crucial role in the etiology of childhood leukemia, although additional studies need to be conducted to confirm the results of this study and provide a perspective on mechanisms.(Cancer Epidemiol Biomarkers Prev 2009;18(8):2221–7)
The Use of Herbal Preparations to Alleviate Climacteric Disorders and Risk of Postmenopausal Breast Cancer in a German Case-Control Study
Authors: Obi Nadia , Chang-Claude Jenny , Berger Jürgen , Braendle Wilhelm , Slanger Tracy , Schmidt Martina , Steindorf Karen , Ahrens Wolfgang , Flesch-Janys Dieter 
Published: August 2009

AbstractBackground:The use of herbal preparations (HEP) to alleviate climacteric disorders is expected to increase as women seek alternatives to menopausal hormone therapy to avoid the associated breast cancer risk. Data are sparse on the long-term effects of HEP containing phytoestrogens and black cohosh on breast cancer risk.Methods: Within a German case-control study, associations between patterns of HEP use and incident breast cancer were investigated in 10,121 postmenopausal women (3,464 cases, 6,657 controls). Information on HEP use was collected in face-to-face interviews supported by a list of brand names. Multivariate logistic and polytomous regression analyses were done.Findings: Ever use of HEP (9.9%) was inversely associated with invasive breast cancer [odds ratio (OR), 0.74; 95% confidence interval (CI), 0.63-0.87] in a dose-dependent manner (OR, 0.96 per year of use; P = 0.03). Classes of HEP did not differ significantly (Pheterogeneity = 0.81). Risks for invasive ductal (OR, 0.72; 95% CI, 0.60-0.87) and combined lobular/mixed/tubular tumors (OR, 0.76; 95% CI, 0.58-1.01) were similarly reduced by any HEP use but not for in situ carcinomas (1.34; 95% CI, 0.86-2.09). There were no substantial differences in associations of HEP use by estrogen receptor status (ER+ OR, 0.74; 95% CI, 0.62-0.89; ER− OR, 0.68, 95% CI, 0.50-0.93) and progesterone receptor status of the tumor.Interpretation: Our findings support the hypothesis that HEP use protects from invasive breast cancer in postmenopausal women. Among conceivable modes of action, those independent of estrogen receptor–mediated pathways seem to be involved (i.e., cytotoxicity, apoptosis). (Cancer Epidemiol Biomarkers Prev 2009;18(8):2207–13)
Breast Cancer Receptor Status: Do Results from a Centralized Pathology Laboratory Agree with SEER Registry Reports?
Authors: Ma Huiyan , Wang Yaping , Sullivan-Halley Jane , Weiss Linda , Burkman Ronald T. , Simon Michael S. , Malone Kathleen E. , Strom Brian L. , Ursin Giske , Marchbanks Polly A. , McDonald Jill A. , Spirtas Robert , Press Michael F. , Bernstein Leslie 
Published: August 2009

AbstractWe investigated the extent to which estrogen receptor (ER) and progesterone receptor (PR) status results from a centralized pathology laboratory agree with ER and PR results from community pathology laboratories reported to two Surveillance, Epidemiology and End Results (SEER) registries (Los Angeles County and Detroit) and whether statistical estimates for the association between reproductive factors and breast cancer receptor subtypes differ by the source of data. The agreement between the centralized laboratory and SEER registry classifications was substantial for ER (κ = 0.70) and nearly so for PR status (κ = 0.60). Among the four subtypes defined by joint ER and PR status, the agreement between the two sources was substantial for the two major breast cancer subtypes (ER−/PR−, κ = 0.69; ER+/PR+, κ = 0.62) and poor for the two rarer subtypes (ER+/PR−, κ = 0.30; ER−/PR+, κ = 0.05). Estimates for the association between reproductive factors (number of full-term pregnancies, age at first full-term pregnancy, and duration of breastfeeding) and the two major subtypes (ER+/PR+ and ER−/PR−) differed minimally between the two sources of data. For example, parous women with at least four full-term pregnancies had 40% lower risk for ER+/PR+ breast cancer than women who had never been pregnant [centralized laboratory, odds ratio, 0.60 (95% confidence interval, 0.39-0.92); SEER, odds ratio, 0.57 (95% confidence interval, 0.38-0.85)]; no association was observed for ER−/PR− breast cancer (both Ptrend &gt; 0.30). Our results suggest that conclusions based on SEER registry data are reasonably reliable for ER+/PR+ and ER−/PR− subtypes. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2214–20)
Circulating Estrogen Metabolites and Risk for Breast Cancer in Premenopausal Women
Authors: Arslan Alan A. , Shore Roy E. , Afanasyeva Yelena , Koenig Karen L. , Toniolo Paolo , Zeleniuch-Jacquotte Anne 
Published: August 2009

Abstract
Background: It has been proposed that a shift toward 2-hydroxyestrone from 16α-hydroxyestrone metabolic pathway may be inversely associated with breast cancer risk because 2-hydroxyestrone is thought to be less genotoxic and estrogenic than 16α-hydroxyestrone.
Methods: We examined the associations of invasive breast cancer risk with circulating 2-hydroxyestrone, 16α-hydroxyestrone, and the 2-hydroxyestrone:16α-hydroxyestrone ratio in a case-control study on premenopausal women nested within a prospective cohort the New York University Women's Health Study. The serum levels of 2-hydroxyestrone and 16α-hydroxyestrone were measured in 377 incident premenopausal breast cancer cases and 377 premenopausal controls, who were matched on age at enrollment, number and dates of blood donations, and day and phase of menstrual cycle.
Results: Overall, no significant associations were observed between breast cancer risk and serum levels of 2-hydroxyestrone, 16α-hydroxyestrone, or their ratio. The 2-hydroxyestrone:16α-hydroxyestrone ratio was positively associated with risk for estrogen receptor–positive breast cancer in the analyses controlling for matching factors. However, the association was attenuated and not significant after adjustment for potential confounders (odds ratio for the highest versus the lowest quartile, 2.15; 95% CI, 0.88-5.27; Ptrend = 0.09).
Conclusions: The results of the current study do not support the hypothesis that a metabolic shift from 16α-hydroxyestrone toward 2-hydroxyestrone in premenopausal women is associated with reduced risk for breast cancer. The association between the 2-hydroxy:16α-hydroxyestrone ratio and estrogen receptor–positive breast cancer needs to be explored in future studies. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2273–9)