bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hepatitis C Virus Variants with Decreased Sensitivity to Direct-Acting Antivirals (DAAs) Were Rarely Observed in DAA-Naive Patients prior to Treatment
Authors: Bartels Doug J. , Sullivan James C. , Zhang Eileen Z. , Tigges Ann M. , Dorrian Jennifer L. , De Meyer Sandra , Takemoto Darin , Dondero Elizabeth , Kwong Ann D. , Picchio Gaston , Kieffer Tara L. 
Published: November 2012

ABSTRACT

The prevalence of naturally occurring hepatitis C virus (HCV) variants that are less sensitive to direct-acting antiviral (DAA) inhibitors has not been fully characterized. We used population sequence analysis to assess the frequency of such variants in plasma samples from 3,447 DAA-naive patients with genotype 1 HCV. In general, HCV variants with lower-level resistance (3- to 25-fold increased 50% inhibitor concentration [IC
50
]) to telaprevir were observed as the dominant species in 0 to 3% of patients, depending on the specific variant, whereas higher-level resistant variants (>25-fold-increased IC
50
) were not observed. Specific variants resistant to NS5A inhibitors were predominant in up to 6% of patients. Most variants resistant to nucleo(s/t)ide active-site NS5B polymerase inhibitors were not observed, whereas variants resistant to non-nucleoside allosteric inhibitors were observed in up to 18% of patients. The presence of DAA-resistant variants in NS5A, NS5B, or NS3 (including telaprevir-resistant variants), in baseline samples of treatment-naive patients receiving a telaprevir-based regimen in phase 3 studies did not affect the sustained viral response (SVR). Treatment-naive patients with viral populations containing the telaprevir-resistant variants NS3 V36M, T54S, or R155K at baseline achieved a 74% SVR rate, whereas patients with no resistant variants detected prior to treatment achieved a 76% SVR rate. The effect of specific resistant variant frequency on response to various DAA treatments in different patient populations, including interferon nonresponders, should be further studied.
Oligomeric Properties of Adeno-Associated Virus Rep68 Reflect Its Multifunctionality
Authors: Zarate-Perez Francisco , Mansilla-Soto Jorge , Bardelli Martino , Burgner John W. , Villamil-Jarauta Maria , Kekilli Demet , Samso Monserrat , Linden R. Michael , Escalante Carlos R. 
Published: November 2012

ABSTRACT

The adeno-associated virus (AAV) encodes four regulatory proteins called Rep. The large AAV Rep proteins Rep68 and Rep78 are essential factors required in almost every step of the viral life cycle. Structurally, they share two domains: a modified version of the AAA
+
domain that characterizes the SF3 family of helicases and an N-terminal domain that binds DNA specifically. The combination of these two domains imparts extraordinary multifunctionality to work as initiators of DNA replication and regulators of transcription, in addition to their essential role during site-specific integration. Although most members of the SF3 family form hexameric rings
in vitro
, the oligomeric nature of Rep68 is unclear due to its propensity to aggregate in solution. We report here a comprehensive study to determine the oligomeric character of Rep68 using a combination of methods that includes sedimentation velocity ultracentrifugation, electron microscopy, and hydrodynamic modeling. We have determined that residue Cys151 induces Rep68 to aggregate
in vitro
. We show that Rep68 displays a concentration-dependent dynamic oligomeric behavior characterized by the presence of two populations: one with monomers and dimers in slow equilibrium and a second one consisting of a mixture of multiple-ring structures of seven and eight members. The presence of either ATP or ADP induces formation of larger complexes formed by the stacking of multiple rings. Taken together, our results support the idea of a Rep68 molecule that exhibits the flexible oligomeric behavior needed to perform the wide range of functions occurring during the AAV life cycle.
The Hemagglutinin Protein of Highly Pathogenic H5N1 Influenza Viruses Overcomes an Early Block in the Replication Cycle To Promote Productive Replication in Macrophages
Authors: Cline Troy D. , Karlsson Erik A. , Seufzer Bradley J. , Schultz-Cherry Stacey 
Published: November 2012

ABSTRACT
Macrophages are known to be one of the first lines of defense against influenza virus infection. However, they may also contribute to severe disease caused by the highly pathogenic avian (HPAI) H5N1 influenza viruses. One reason for this may be the ability of certain influenza virus strains to productively replicate in macrophages. However, studies investigating the productive replication of influenza viruses in macrophages have been contradictory, and the results may depend on both the type of macrophages used and the specific viral strain. In this work, we investigated the ability of H1 to H16 viruses to productively replicate in primary murine alveolar macrophages and RAW264.7 macrophages. We show that only a subset of HPAI H5N1 viruses, those that cause high morbidity and mortality in mammals, can productively replicate in macrophages, as measured by the release of newly synthesized virus particles into the cell supernatant. Mechanistically, we found that these H5 strains can overcome a block early in the viral life cycle leading to efficient nuclear entry, viral transcription, translation, and ultimately replication. Studies with reassortant viruses demonstrated that expression of the hemagglutinin gene from an H5N1 virus rescued replication of H1N1 influenza virus in macrophages. This study is the first to characterize H5N1 influenza viruses as the only subtype of influenza virus capable of productive replication in macrophages and establishes the viral gene that is required for this characteristic. The ability to productively replicate in macrophages is unique to H5N1 influenza viruses and may contribute to their increased pathogenesis.
Histone Deacetylase Inhibitor AR-42 Differentially Affects Cell-cycle Transit in Meningeal and Meningioma Cells, Potently Inhibiting NF2-Deficient Meningioma Growth
Authors: Burns Sarah S. , Akhmametyeva Elena M. , Oblinger Janet L. , Bush Matthew L. , Huang Jie , Senner Volker , Chen Ching-Shih , Jacob Abraham , Welling D. Bradley , Chang Long-Sheng 
Published: November 2012

Abstract
Meningiomas constitute about 34% of primary intracranial tumors and are associated with increased mortality in patients with neurofibromatosis type 2 (NF2). To evaluate potential medical therapies for these tumors, we have established a quantifiable orthotopic model for NF2-deficient meningiomas. We showed that telomerase-immortalized Ben-Men-1 benign meningioma cells harbored a single nucleotide deletion in NF2 exon 7 and did not express the NF2 protein, merlin. We also showed that AR-42, a pan-histone deacetylase inhibitor, inhibited proliferation of both Ben-Men-1 and normal meningeal cells by increasing expression of p16INK4A, p21CIP1/WAF1, and p27KIP1. In addition, AR-42 increased proapoptotic Bim expression and decreased anti-apoptotic BclXL levels. However, AR-42 predominantly arrested Ben-Men-1 cells at G2–M whereas it induced cell-cycle arrest at G1 in meningeal cells. Consistently, AR-42 substantially decreased the levels of cyclin D1, E, and A, and proliferating cell nuclear antigen in meningeal cells while significantly reducing the expression of cyclin B, important for progression through G2, in Ben-Men-1 cells. In addition, AR-42 decreased Aurora A and B expression. To compare the in vivo efficacies of AR-42 and AR-12, a PDK1 inhibitor, we generated and used luciferase-expressing Ben-Men-1-LucB cells to establish intracranial xenografts that grew over time. While AR-12 treatment moderately slowed tumor growth, AR-42 caused regression of Ben-Men-1-LucB tumors. Importantly, AR-42–treated tumors showed minimal regrowth when xenograft-bearing mice were switched to normal diet. Together, these results suggest that AR-42 is a potential therapy for meningiomas. The differential effect of AR-42 on cell-cycle progression of normal meningeal and meningioma cells may have implications for why AR-42 is well-tolerated while it potently inhibits tumor growth. Cancer Res; 73(2); 792–803. ©2012 AACR.
Brachytherapy Using Injectable Seeds That Are Self-Assembled from Genetically Encoded Polypeptides In Situ
Authors: Liu Wenge , McDaniel Jonathan , Li Xinghai , Asai Daisuke , Quiroz Felipe Garcia , Schaal Jeffery , Park Ji Sun , Zalutsky Michael , Chilkoti Ashutosh 
Published: November 2012

Abstract
Brachytherapy is a common clinical technique involving implantation of sealed radioactive “seeds” within a tumor to selectively irradiate the tumor mass while minimizing systemic toxicity. To mitigate the disadvantages associated with complex surgical implantation and subsequent device removal procedures, we have developed an alternative approach using a genetically encoded peptide polymer solution composed of a thermally responsive elastin-like polypeptide (ELP) radiolabeled with 131I that self-assembles into radionuclide seeds upon intratumoral injection. The formation of these nontoxic and biodegradable polymer seeds led to prolonged intratumoral retention (∼85% ID/tumor 7 days postinjection) of the radionuclide, elicited a tumor growth delay in 100% of the tumors in two human xenografts (FaDu and PC-3), and cured more than 67% of tumor-bearing animals after a single administration of labeled ELP. These results suggest that in situ self-assembly of biodegradable and injectable radionuclide-containing polypeptide seeds could be a promising therapeutic alternative to conventional brachytherapy. Cancer Res; 72(22); 5956–65. ©2012 AACR.
Prospective Study of Helicobacter pylori Biomarkers for Gastric Cancer Risk among Chinese Men
Authors: Epplein Meira , Zheng Wei , Xiang Yong-Bing , Peek Richard M. , Li Honglan , Correa Pelayo , Gao Jing , Michel Angelika , Pawlita Michael , Cai Qiuyin , Shu Xiao-Ou 
Published: November 2012

Abstract
Background:Helicobacter pylori is the leading risk factor for gastric cancer, yet only a fraction of infected individuals ever develop neoplasia.
Methods: To identify potential predictive biomarkers, we assessed the association of 15 antibodies to H. pylori proteins and gastric cancer in a nested case–control study. Blood levels of antibodies were assessed using multiplex serology for 226 incident cases and 451 matched controls from the Shanghai Men's Health Study. ORs and 95% confidence intervals (CI) were calculated using conditional logistic regression.
Results: Seropositivity to four (Omp, HP0305, HyuA, and HpaA) proteins was associated with a 1.5- to 3-fold increased risk for gastric cancer. When excluding cases diagnosed within 2 years of study enrollment, seropositivity to two additional proteins (CagA and VacA) showed significant associations with risk. Compared with individuals with three or fewer seropositive results to the six virulent proteins identified in this population, individuals with four to five seropositive results were at a 2-fold increased risk (OR, 2.08; 95% CI, 1.31–3.30) and individuals seropositive to all six proteins had a 3.5-fold increase in risk (OR, 3.49; 95% CI, 2.00–6.11) for gastric cancer. Among individuals diagnosed at least 2 years after study enrollment, these associations were even stronger (ORs, 2.79 and 4.16, respectively).
Conclusions: Increasing number of seropositives to six H. pylori proteins may be a risk marker for distal gastric cancer in China.
Impact: In a population with a 90% prevalence of CagA-positive H. pylori infection, assessment of additional virulent H. pylori proteins might better identify individuals at high risk for gastric cancer. Cancer Epidemiol Biomarkers Prev; 21(12); 2185–92. ©2012 AACR.
Associations between Arsenic Exposure and Global Posttranslational Histone Modifications among Adults in Bangladesh
Authors: Chervona Yana , Hall Megan N. , Arita Adriana , Wu Fen , Sun Hong , Tseng Hsiang-Chi , Ali Eunus , Uddin Mohammad Nasir , Liu Xinhua , Zoroddu Maria Antonietta , Gamble Mary V. , Costa Max 
Published: November 2012

AbstractBackground: Exposure to arsenic (As) is associated with an increased risk of several cancers as well as cardiovascular disease, and childhood neuro-developmental deficits. Arsenic compounds are weakly mutagenic, alter gene expression and posttranslational histone modifications (PTHMs) in vitro.Methods: Water and urinary As concentrations as well as global levels of histone 3 lysine 9 di-methylation and acetylation (H3K9me2 and H3K9ac), histone 3 lysine 27 tri-methylation and acetylation (H3K27me3 and H3K27ac), histone 3 lysine 18 acetylation (H3K18ac), and histone 3 lysine 4 trimethylation (H3K4me3) were measured in peripheral blood mononuclear cells (PBMC) from a subset of participants (N = 40) of a folate clinical trial in Bangladesh (FACT study).Results: Total urinary As (uAs) was positively correlated with H3K9me2 (r = 0.36, P = 0.02) and inversely with H3K9ac (r = −0.47, P = 0.002). The associations between As and other PTHMs differed in a gender-dependent manner. Water As (wAs) was positively correlated with H3K4me3 (r = 0.45, P = 0.05) and H3K27me3 (r = 0.50, P = 0.03) among females and negatively correlated among males (H3K4me3: r = −0.44, P = 0.05; H3K27me3: r = −0.34, P = 0.14). Conversely, wAs was inversely associated with H3K27ac among females (r = −0.44, P = 0.05) and positively associated among males (r = 0.29, P = 0.21). A similar pattern was observed for H3K18ac (females: r = −0.22, P = 0.36; males: r = 0.27, P = 0.24).Conclusion: Exposure to As is associated with alterations of global PTHMs; gender-specific patterns of association were observed between As exposure and several histone marks.Impact: These findings contribute to the growing body of evidence linking As exposure to epigenetic dysregulation, which may play a role in the pathogenesis of As toxicity. Cancer Epidemiol Biomarkers Prev; 21(12); 2252–60. ©2012 AACR.
Urinary Concentrations of Estrogens and Estrogen Metabolites and Smoking in Caucasian Women
Authors: Gu Fangyi , Caporaso Neil E. , Schairer Catherine , Fortner Renee T. , Xu Xia , Hankinson Susan E. , Eliassen A. Heather , Ziegler Regina G. 
Published: November 2012

Abstract
Background: Smoking has been hypothesized to decrease biosynthesis of parent estrogens (estradiol and estrone) and increase their metabolism by 2-hydroxylation. However, comprehensive studies of smoking and estrogen metabolism by 2-, 4-, or 16-hydroxylation are sparse.
Methods: Fifteen urinary estrogens and estrogen metabolites (jointly called EM) were measured by liquid chromatography/tandem mass spectrometry (LC/MS-MS) in luteal phase urine samples collected during 1996 to 1999 from 603 premenopausal women in the Nurses' Health Study II (NHSII; 35 current, 140 former, and 428 never smokers). We calculated geometric means and percentage differences of individual EM (pmol/mg creatinine), metabolic pathway groups, and pathway ratios, by smoking status and cigarettes per day (CPD).
Results: Total EM and parent estrogens were nonsignificantly lower in current compared with never smokers, with estradiol significant (Pmultivariate = 0.02). We observed nonsignificantly lower 16-pathway EM (P = 0.08) and higher 4-pathway EM (P = 0.25) and similar 2-pathway EM in current versus never smokers. EM measures among former smokers were similar to never smokers. Increasing CPD was significantly associated with lower 16-pathway EM (P-trend = 0.04) and higher 4-pathway EM (P-trend = 0.05). Increasing CPD was significantly positively associated with the ratios of 2- and 4-pathway to parent estrogens (P-trend = 0.01 and 0.002), 2- and 4-pathway to 16-pathway (P-trend = 0.02 and 0.003), and catechols to methylated catechols (P-trend = 0.02).
Conclusions: As hypothesized, we observed lower urinary levels of total EM and parent estrogens in active smokers. Our results also suggest smoking is associated with altered estrogen metabolism, specifically increased 2- and 4-hydroxylation, decreased 16-hydroxylation, and decreased catechol methylation.
Impact: Our study suggests how smoking might influence estrogen-related cancers and conditions. Cancer Epidemiol Biomarkers Prev; 22(1); 58–68. ©2012 AACR.
Postdiagnosis Alcohol Consumption and Breast Cancer Prognosis in the After Breast Cancer Pooling Project
Authors: Kwan Marilyn L. , Chen Wendy Y. , Flatt Shirley W. , Weltzien Erin K. , Nechuta Sarah J. , Poole Elizabeth M. , Holmes Michelle D. , Patterson Ruth E. , Shu Xiao Ou , Pierce John P. , Caan Bette J. 
Published: November 2012

Abstract
Background: Alcohol consumption is an established risk factor for incident breast cancer. However, its role in breast cancer prognosis remains unclear.
Methods: We conducted an investigation of postdiagnosis alcohol consumption with recurrence and mortality among 9,329 breast cancer patients in the After Breast Cancer Pooling Project. Women were diagnosed from 1990 to 2006 with AJCC Stage I-III breast tumors from three prospective US cohorts. Alcohol intake was assessed at cohort entry (mean 2.1 years postdiagnosis) using a food frequency questionnaire. HR and 95% confidence intervals (CI) were estimated using delayed entry Cox proportional hazards models with adjustment for known prognostic factors.
Results: After a mean follow-up of 10.3 years, 1,646 recurrences and 1,543 deaths were ascertained. 5,422 women (58%) were considered drinkers (≥0.36 g/day of alcohol, ≥0.25 drinks/week) with a median of 5.3 g/day. Overall, compared with nondrinking, regular alcohol intake (≥6.0 g/day) was not associated with risk of recurrence (HR for 6 to less than 12 g/day, 1.03; 95% CI, 0.86–1.24; HR for 12 to less than 24 g/day, 1.12; 95% CI, 0.93–1.34; HR for ≥24 g/day, 1.04; 95% CI, 0.84–1.31). However, risk varied significantly by menopausal status (P for interaction &lt; 0.05). Postmenopausal women who regularly consumed alcohol (≥6.0 g/day) had increased risk of recurrence (HR, 1.19; 95% CI, 1.01–1.40). Alcohol intake was not associated with mortality.
Conclusions: Regular alcohol consumption was not associated with breast cancer recurrence and total mortality overall, yet recurrence risk was only elevated in postmenopausal women.
Impact: The association between alcohol intake and recurrence may depend on menopausal status at breast cancer diagnosis. Cancer Epidemiol Biomarkers Prev; 22(1); 32–41. ©2012 AACR.
Variation in Genes Related to Obesity, Weight, and Weight Change and Risk of Contralateral Breast Cancer in the WECARE Study Population
Authors: Brooks Jennifer D. , Bernstein Leslie , Teraoka Sharon N. , Knight Julia A. , Mellemkjær Lene , John Esther M. , Malone Kathleen E. , Reiner Anne S. , Lynch Charles F. , Concannon Patrick , Haile Robert W. , Bernstein Jonine L. ,   for the WECARE Study Collaborative Group
Published: November 2012

Abstract
Background: Body mass index (BMI), a known breast cancer risk factor, could influence breast risk through mechanistic pathways related to sex hormones, insulin resistance, chronic inflammation, and altered levels of adipose-derived hormones. Results from studies of the relationship between BMI and second primary breast cancer have been mixed. To explore the relationship between BMI and asynchronous contralateral breast cancer (CBC), we examined whether variants in genes related to obesity, weight, and weight change are associated with CBC risk.
Methods: Variants in 20 genes [182 single-nucleotide polymorphisms (SNP)] involved in adipose tissue metabolism, energy balance, insulin resistance, and inflammation, as well as those identified through genome-wide association studies (GWAS) of BMI and type II-diabetes were evaluated. We examined the association between variants in these genes and the risk of CBC among Caucasian participants [643 cases with CBC and 1,271 controls with unilateral breast cancer (UBC)] in the population-based Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study using conditional logistic regression.
Results: After adjustment for multiple comparisons, no statistically significant associations between any variant and CBC risk were seen. Stratification by menopausal or estrogen receptor (ER) status did not alter these findings.
Conclusion: Among women with early-onset disease who survive a first breast cancer diagnosis, there was no association between variation in obesity-related genes and risk of CBC.
Impact: Genetic variants in genes related to obesity are not likely to strongly influence subsequent risk of developing a second primary breast cancer. Cancer Epidemiol Biomarkers Prev; 21(12); 2261–7. ©2012 AACR.
Metabolic Gene Remodeling and Mitochondrial Dysfunction in Failing Right Ventricular Hypertrophy Secondary to Pulmonary Arterial Hypertension
Authors: Gomez-Arroyo Jose , Mizuno Shiro , Szczepanek Karol , Van Tassell Benjamin , Natarajan Ramesh , dos Remedios Cristobal G. , Drake Jennifer I. , Farkas Laszlo , Kraskauskas Donatas , Wijesinghe Dayanjan S. , Chalfant Charles E. , Bigbee John , Abbate Antonio , Lesnefsky Edward J. , Bogaard Harm J. , Voelkel Norbert F. 
Published: November 2012

Background—
Right ventricular (RV) dysfunction (RVD) is the most frequent cause of death in patients with pulmonary arterial hypertension. Although abnormal energy substrate use has been implicated in the development of chronic left heart failure, data describing such metabolic remodeling in RVD remain incomplete. Thus, we sought to characterize metabolic gene expression changes and mitochondrial dysfunction in functional and dysfunctional RV hypertrophy.

Methods and Results—
Two different rat models of RV hypertrophy were studied. The model of RVD (SU5416/hypoxia) exhibited a significantly decreased gene expression of peroxisome proliferator-activated receptor-γ coactivator-1α, peroxisome proliferator-activated receptor-α and estrogen-related receptor-α. The expression of multiple peroxisome proliferator-activated receptor-γ coactivator-1α target genes required for fatty acid oxidation was similarly decreased. Decreased peroxisome proliferator-activated receptor-γ coactivator-1α expression was also associated with a net loss of mitochondrial protein and oxidative capacity. Reduced mitochondrial number was associated with a downregulation of transcription factor A, mitochondrial, and other genes required for mitochondrial biogenesis. Electron microscopy demonstrated that, in RVD tissue, mitochondria had abnormal shape and size. Lastly, respirometric analysis demonstrated that mitochondria isolated from RVD tissue had a significantly reduced ADP-stimulated (state 3) rate for complex I. Conversely, functional RV hypertrophy in the pulmonary artery banding model showed normal expression of peroxisome proliferator-activated receptor-γ coactivator-1α, whereas the expression of fatty acid oxidation genes was either preserved or unregulated. Moreover, pulmonary artery banding-RV tissue exhibited preserved transcription factor A mitochondrial expression and mitochondrial respiration despite elevated RV pressure-overload.

Conclusions—
Right ventricular dysfunction, but not functional RV hypertrophy in rats, demonstrates a gene expression profile compatible with a multilevel impairment of fatty acid metabolism and significant mitochondrial dysfunction, partially independent of chronic pressure-overload.