bluuebunny/crossref_metadata_2025_split huggingface dataset:
Herpes Simplex Virus 2 (HSV-2) Prevents Dendritic Cell Maturation, Induces Apoptosis, and Triggers Release of Proinflammatory Cytokines: Potential Links to HSV-HIV Synergy
Authors: Stefanidou Martha , Ramos Irene , Mas Casullo Veronica , Trépanier Janie B. , Rosenbaum Sara , Fernandez-Sesma Ana , Herold Betsy C. 
Published: November 2012

ABSTRACT
Herpes simplex virus 2 (HSV-2) may cause frequent recurrences, highlighting its ability to evade host defense. This study tested the hypothesis that HSV-2 interferes with dendritic cell (DC) function as an escape mechanism, which may contribute to enhanced HIV replication in coinfected populations. Immature monocyte-derived human DCs were exposed to live or UV-inactivated HSV-2 or lipopolysaccharide. Little or no increase in the maturation marker CD83 was observed in response to HSV-2 and HSV-2 exposed DCs were impaired in their ability to present antigen (influenza) to T cells. Exposure to UV-inactivated virus stimulated a modest, but significant increase in CD83, suggesting that viral gene expression contributes to the block in DC maturation. The functional impairment of HSV-2-exposed DCs could be partially attributed to the induction of apoptosis. Live and inactivated HSV-2 triggered an increase in the number of early and late apoptotic cells in both the infected and bystander cell populations; apoptosis was associated with a decrease in cellular FLICE-inhibitory protein (c-FLIP). Paradoxically, HSV-2 induced Akt phosphorylation, which typically promotes DC maturation and survival. Despite these aberrant responses, live and inactivated HSV-2 induced the release of cytokines into culture supernatants, which were sufficient to activate HIV-1 replication in latently infected U1 cells. Together, these findings suggest that in the presence of overt or subclinical HSV-2, the function of mucosal DCs would be impaired. These responses may allow HSV to escape immune surveillance but may also promote HIV infection and contribute to the epidemiological link between HIV and HSV.
Expansion of Monocytic Myeloid-Derived Suppressor Cells Dampens T Cell Function in HIV-1-Seropositive Individuals
Authors: Qin Aiping , Cai Weiping , Pan Ting , Wu Kang , Yang Qiong , Wang Nina , Liu Yufeng , Yan Dehong , Hu Fengyu , Guo Pengle , Chen Xiaoping , Chen Ling , Zhang Hui , Tang Xiaoping , Zhou Jie 
Published: November 2012

ABSTRACT

T lymphocyte dysfunction contributes to human immunodeficiency virus type 1 (HIV-1) disease progression by impairing antivirus cellular immunity. However, the mechanisms of HIV-1 infection-mediated T cell dysfunction are not completely understood. Here, we provide evidence that expansion of monocytic myeloid-derived suppressor cells (M-MDSCs) suppressed T cell function in HIV-1-infected individuals. We observed a dramatic elevation of M-MDSCs (HLA-DR
−/low
CD11b
+
CD33
+/high
CD14
+
CD15
−
cells) in the peripheral blood of HIV-1-seropositive subjects (
n
= 61) compared with healthy controls (
n
= 51), despite efficacious antiretroviral therapy for nearly 2 years. The elevated M-MDSC frequency in HIV-1
+
subjects correlated with prognostic HIV-1 disease markers, including the HIV-1 load (
r
= 0.5957;
P
< 0.0001), CD4
+
T cell loss (
r
= −0.5312;
P
< 0.0001), and activated T cells (
r
= 0.4421;
P
= 0.0004). Functional studies showed that M-MDSCs from HIV-1
+
subjects suppressed T cell responses in both HIV-1-specific and antigen-nonspecific manners; this effect was dependent on the induction of arginase 1 and required direct cell-cell contact. Further investigations revealed that direct HIV-1 infection or culture with HIV-1-derived Tat protein significantly enhanced human MDSC generation
in vitro
, and MDSCs from healthy donors could be directly infected by HIV-1 to facilitate HIV-1 replication and transmission, indicating that a positive-feedback loop between HIV-1 infection and MDSC expansion existed. In summary, our studies revealed a novel mechanism of T cell dysfunction in HIV-1-infected individuals and suggested that targeting MDSCs may be a promising strategy for HIV-1 immunotherapy.
Acetylation of Conserved Lysines in Bovine Papillomavirus E2 by p300
Authors: Quinlan Edward J. , Culleton Sara P. , Wu Shwu-Yuan , Chiang Cheng-Ming , Androphy Elliot J. 
Published: November 2012

ABSTRACT

The p300, CBP, and pCAF lysine acetyltransferase (KAT) proteins have been reported to physically interact with bovine (BPV) and human (HPV) papillomavirus E2 proteins. While overexpression of these KAT proteins enhances E2-dependent transcription, the mechanism has not been determined. Using RNA interference (RNAi) to deplete these factors, we demonstrated that E2 transcriptional activity requires physiological levels of p300, CBP, and pCAF. Each protein appears to have a unique function in E2-dependent transcription, since overexpression of one KAT failed to compensate for RNAi knockdown of another KAT. Using an
in vitro
acetylation assay, we identified highly conserved lysines that are targeted by p300 for acetylation. The conservative changes of lysines at positions 111 and 112 to arginine were of particular interest. The K111R and the K111R/K112R mutants showed reduced transcriptional activity that was not responsive to p300 overexpression, while the K112R mutant retained activity. p300 and CBP were detected at the viral promoter; however, pCAF was not. We propose a model by which E2 transcriptional activity is controlled by p300-mediated acetylation of lysine 111. This model represents a novel mechanism regulating papillomavirus gene expression.
Novel Mutations in gB and gH Circumvent the Requirement for Known gD Receptors in Herpes Simplex Virus 1 Entry and Cell-to-Cell Spread
Authors: Uchida Hiroaki , Chan Janet , Shrivastava Indira , Reinhart Bonnie , Grandi Paola , Glorioso Joseph C. , Cohen Justus B. 
Published: November 2012

ABSTRACT
Both entry and cell-to-cell spread of herpes simplex virus (HSV) involve a cascade of cooperative interactions among the essential glycoproteins D, B, and H/L (gD, gB, and gH/gL, respectively) initiated by the binding of gD to a cognate HSV entry receptor. We previously reported that a variant (D285N/A549T) of glycoprotein B (gB:NT) enabled primary virus entry into cells that were devoid of typical HSV entry receptors. Here, we compared the activities of the gB:NT variant with those of a newly selected variant of glycoprotein H (gH:KV) and a frequently coselected gB variant (gB:S668N). In combination, gH:KV and gB:S668N enabled primary virus entry into cells that lacked established HSV entry receptors as efficiently as did gB:NT, but separately, each variant enabled only limited entry. Remarkably, gH:KV uniquely facilitated secondary virus spread between cells that lacked canonical entry receptors. Transient expression of the four essential entry glycoproteins revealed that gH:KV, but not gB:NT, induced fusion between cells lacking the standard receptors. Because the involvement of gD remained essential for virus spread and cell fusion, we propose that gH:KV mimics a transition state of gH that responds efficiently to weak signals from gD to reach the active state. Computational modeling of the structures of wild-type gH and gH:KV revealed relatively subtle differences that may have accounted for our experimental findings. Our study shows that (i) the dependence of HSV-1 entry and spread on specific gD receptors can be reduced by sequence changes in the downstream effectors gB and gH, and (ii) the relative roles of gB and gH are different in entry and spread.
Transcriptional Response of Mucoid Pseudomonas aeruginosa to Human Respiratory Mucus
Authors: Cattoir V. , Narasimhan G. , Skurnik D. , Aschard H. , Roux D. , Ramphal R. , Jyot J. , Lory S. 
Published: November 2012

ABSTRACTAdaptation of bacterial pathogens to a host can lead to the selection and accumulation of specific mutations in their genomes with profound effects on the overall physiology and virulence of the organisms. The opportunistic pathogenPseudomonas aeruginosais capable of colonizing the respiratory tract of individuals with cystic fibrosis (CF), where it undergoes evolution to optimize survival as a persistent chronic human colonizer. The transcriptome of a host-adapted, alginate-overproducing isolate from a CF patient was determined following growth of the bacteria in the presence of human respiratory mucus. This stable mucoid strain responded to a number of regulatory inputs from the mucus, resulting in an unexpected repression of alginate production. Mucus in the medium also induced the production of catalases and additional peroxide-detoxifying enzymes and caused reorganization of pathways of energy generation. A specific antibacterial type VI secretion system was also induced in mucus-grown cells. Finally, a group of small regulatory RNAs was identified and a fraction of these were mucus regulated. This report provides a snapshot of responses in a pathogen adapted to a human host through assimilation of regulatory signals from tissues, optimizing its long-term survival potential.IMPORTANCEThe basis for chronic colonization of patients with cystic fibrosis (CF) by the opportunistic pathogenPseudomonas aeruginosacontinues to represent a challenging problem for basic scientists and clinicians. In this study, the host-adapted, alginate-overproducingPseudomonas aeruginosa2192 strain was used to assess the changes in its transcript levels following growth in respiratory CF mucus. Several significant and unexpected discoveries were made: (i) although the alginate overproduction in strain 2192 was caused by a stable mutation, a mucus-derived signal caused reduction in the transcript levels of alginate biosynthetic genes; (ii) mucus activated the expression of the type VI secretion system, a mechanism for killing of other bacteria in a mixed population; (iii) expression of a number of genes involved in respiration was altered; and (iv) several small regulatory RNAs were identified, some being mucus regulated. This work highlights the strong influence of the host environment in shaping bacterial survival strategies.
Antibiotic-Mediated Selection of Quorum-Sensing-Negative Staphylococcus aureus
Authors: Paulander Wilhelm , Nissen Varming Anders , Bæk Kristoffer T. , Haaber Jakob , Frees Dorte , Ingmer Hanne 
Published: November 2012

ABSTRACT

Staphylococcus aureus
is a human commensal that at times turns into a serious bacterial pathogen causing life-threatening infections. For the delicate control of virulence,
S. aureus
employs the
agr
quorum-sensing system that, via the intracellular effector molecule RNAIII, regulates virulence gene expression. We demonstrate that the presence of the
agr
locus imposes a fitness cost on
S. aureus
that is mediated by the expression of RNAIII. Further, we show that exposure to sublethal levels of the antibiotics ciprofloxacin, mupirocin, and rifampin, each targeting separate cellular functions, markedly increases the
agr
-mediated fitness cost by inducing the expression of RNAIII. Thus, the extensive use of antibiotics in hospitals may explain why
agr
-negative variants are frequently isolated from hospital-acquired
S. aureus
infections but rarely found among community-acquired
S. aureus
strains. Importantly,
agr
deficiency correlates with increased duration of and mortality due to bacteremia during antibiotic treatment and with a higher frequency of glycopeptide resistance than in
agr
-carrying strains. Our results provide an explanation for the frequent isolation of
agr
-defective strains from hospital-acquired
S. aureus
infections and suggest that the adaptability of
S. aureus
to antibiotics involves the
agr
locus.

IMPORTANCE
Staphylococcus aureus
is the most frequently isolated pathogen in intensive care units and a common cause of nosocomial infections, resulting in a high degree of morbidity and mortality. Surprisingly, a large fraction (15 to 60%) of hospital-isolated
S. aureus
strains are
agr
defective and lack the main quorum-sensing-controlled virulence regulatory system. This is a problem, as
agr
-defective strains are associated with a mortality level in bacteremic infections and a probability of glycopeptide resistance greater than those of other strains. We show here that
agr
-negative strains have a fitness advantage over
agr
-positive strains in the presence of sublethal concentrations of some antibiotics and that the fitness defect of
agr
-positive cells is caused by antibiotic-mediated expression of the
agr
effector molecule RNAIII. These results offer an explanation of the frequent isolation of
agr
-defective
S. aureus
strains in hospitals and will influence how we treat
S. aureus
infections.
Which Risk Model to Use? Clinical Implications of the ACS MRI Screening Guidelines
Authors: Ozanne Elissa M. , Drohan Brian , Bosinoff Phil , Semine Alan , Jellinek Michael , Cronin Claire , Millham Frederick , Dowd Dana , Rourke Taryn , Block Caroline , Hughes Kevin S. 
Published: November 2012

Abstract
The American Cancer Society (ACS) guidelines define the appropriate use of MRI as an adjunct to mammography for breast cancer screening. Three risk assessment models are recommended to determine if women are at sufficient risk to warrant the use of this expensive screening tool, however, the real-world application of these models has not been explored. We sought to understand how these models behave in a community setting for women undergoing mammography screening. We conducted a retrospective analysis of 5,894 women, who received mammography screening at a community hospital and assessed their eligibility for MRI according to the ACS guidelines. Of the 5,894 women, 342 (5.8%) were eligible for MRI, but we found significant differences in the number of eligible women identified by each model. Our results indicate that these models identify very different populations, implying that the ACS guidelines deserve further development and consideration. Cancer Epidemiol Biomarkers Prev; 22(1); 146–9. ©2012 AACR.
Influence of Quercetin-Rich Food Intake on microRNA Expression in Lung Cancer Tissues
Authors: Lam Tram K. , Shao Stephanie , Zhao Yingdong , Marincola Francesco , Pesatori Angela , Bertazzi Pier Alberto , Caporaso Neil E. , Wang Ena , Landi Maria Teresa 
Published: November 2012

Abstract
Background: Epidemiologic studies have reported that frequent consumption of quercetin-rich foods is inversely associated with lung cancer incidence. A quercetin-rich diet might modulate microRNA (miR) expression; however, this mechanism has not been fully examined.
Methods: miR expression data were measured by a custom-made array in formalin-fixed paraffin-embedded tissue samples from 264 lung cancer cases (144 adenocarcinomas and 120 squamous cell carcinomas). Intake of quercetin-rich foods was derived from a food-frequency questionnaire. In individual-miR–based analyses, we compared the expression of miRs (n = 198) between lung cancer cases consuming high versus low quercetin-rich food intake using multivariate ANOVA tests. In family-miR–based analyses, we used Functional Class Scoring (FCS) to assess differential effect on biologically functional miR families. We accounted for multiple testing using 10,000 global permutations (significance at Pglobal &lt; 0.10). All multivariate analyses were conducted separately by histology and by smoking status (former and current smokers).
Results: Family-based analyses showed that a quercetin-rich diet differentiated miR expression profiles of the tumor suppressor let-7 family among adenocarcinomas (PFCS &lt; 0.001). Other significantly differentiated miR families included carcinogenesis-related miR-146, miR-26, and miR-17 (PFCS &lt; 0.05). In individual-based analyses, we found that among former and current smokers with adenocarcinoma, 33 miRs were observed to be differentiated between highest and lowest quercetin-rich food consumers (23 expected by chance; Pglobal = 0.047).
Conclusions: We observed differential expression of key biologically functional miRs between high versus low consumers of quercetin-rich foods in adenocarcinoma cases.
Impact: Our findings provide preliminary evidence on the mechanism underlying quercetin-related lung carcinogenesis. Cancer Epidemiol Biomarkers Prev; 21(12); 2176–84. ©2012 AACR.
The Heritability of Mammographic Breast Density and Circulating Sex-Hormone Levels: Two Independent Breast Cancer Risk Factors
Authors: Varghese Jajini S. , Smith Paula L. , Folkerd Elizabeth , Brown Judith , Leyland Jean , Audley Tina , Warren Ruth M.L. , Dowsett Mitchell , Easton Douglas F. , Thompson Deborah J. 
Published: November 2012

AbstractBackground: Mammographic breast density and endogenous sex-hormone levels are both strong risk factors for breast cancer. This study investigated whether there is evidence for a shared genetic basis between these risk factors.Methods: Using data on 1,286 women from 617 families, we estimated the heritabilities of serum estradiol, testosterone, and sex-hormone binding globulin (SHBG) levels and of three measures of breast density (dense area, nondense area, and percentage density). We tested for associations between hormone levels and density measures and estimated the genetic and environmental correlations between pairs of traits using variance and covariance components models and pedigree-based maximum likelihood methods.Results: We found no significant associations between estradiol, testosterone, or SHBG levels and any of the three density measures, after adjusting for body mass index (BMI).The estimated heritabilities were 63%, 66%, and 65% for square root–transformed adjusted percentage density, dense area, and nondense area, respectively, and 40%, 25%, and 58% for log-transformed–adjusted estradiol, testosterone, and SHBG. We found no evidence of a shared genetic basis between any hormone levels and any measure of density, after adjusting for BMI. The negative genetic correlation between dense and nondense areas remained significant even after adjustment for BMI and other covariates (ρ = −0.34; SE = 0.08; P = 0.0005).Conclusions: Breast density and sex hormones can be considered as independent sets of traits.Impact: Breast density and sex hormones can be used as intermediate phenotypes in the search for breast cancer susceptibility loci. Cancer Epidemiol Biomarkers Prev; 21(12); 2167–75. ©2012 AACR.
Prospective Study on Physical Activity and Risk of In Situ Breast Cancer
Authors: Steindorf Karen , Ritte Rebecca , Tjonneland Anne , Johnsen Nina Føns , Overvad Kim , Østergaard Jane Nautrup , Clavel-Chapelon Françoise , Fournier Agnès , Dossus Laure , Lukanova Annekatrin , Chang-Claude Jenny , Boeing Heiner , Wientzek Angelika , Trichopoulou Antonia , Karapetyan Tina , Trichopoulos Dimitrios , Masala Giovanna , Krogh Vittorio , Mattiello Amalia , Tumino Rosario , Polidoro Silvia , Quirós José Ramón , Travier Noémie , Sánchez María-José , Navarro Carmen , Ardanaz Eva , Amiano Pilar , Bueno-de-Mesquita H. Bas , van Duijnhoven Fränzel J.B. , Monninkhof Evelyn , May Anne M. , Khaw Kay-Tee , Wareham Nick , Key Tim J. , Travis Ruth C. , Borch Kristin Benjaminsen , Fedirko Veronika , Rinaldi Sabina , Romieu Isabelle , Wark Petra A. , Norat Teresa , Riboli Elio , Kaaks Rudolf 
Published: November 2012

Abstract
Background: Physical activity has been identified as protective factor for invasive breast cancer risk, whereas comparable studies on in situ carcinoma are rare.
Methods: The study included data from 283,827 women of the multinational European Prospective Investigation into C7ancer and Nutrition (EPIC)-cohort study. Detailed information on different types of physical activity conducted during the prior year, such as occupational, recreational, and household activity, as well as on important cofactors, was assessed at baseline. Adjusted HRs for in situ breast cancer were estimated by Cox proportional hazards models.
Results: During a median follow-up period of 11.7 years, 1,059 incidents of breast carcinoma in situ were identified. In crude and adjusted multivariable models, no associations were found for occupational, household, and recreational physical activity. Furthermore, total physical activity was not associated with risk of in situ breast cancer. Comparing moderately inactive, moderately active, and active participants with inactive study participants resulted in adjusted HRs of 0.99 [95% confidence interval (CI), 0.83–1.19], 0.99 (95% CI, 0.82–1.20), and 1.07 (95% CI, 0.81–1.40), respectively (P value of trend test: 0.788). No inverse associations were found in any substrata defined by age at diagnosis or body mass index (BMI) status.
Conclusions: In this large prospective study, we did not find any evidence of an association between physical activity and in situ breast cancer risk. If not by chance, the contrast between our results for carcinoma in situ and the recognized inverse association for invasive breast cancer suggests that physical activity may have stronger effects on proliferation and late stage carcinogenesis. Cancer Epidemiol Biomarkers Prev; 21(12); 2209–19. ©2012 AACR.
Increased Formation of Monocyte-Platelet Aggregates in Ischemic Heart Failure
Authors: Wrigley Benjamin J. , Shantsila Eduard , Tapp Luke D. , Lip Gregory Y.H. 
Published: November 2012

Background—
Cross-talk between monocytes and platelets is reflected by the formation of monocyte-platelet aggregates (MPAs). It is not known whether MPAs are affected in heart failure (HF), and we examined differences in patients with acute HF (AHF), stable HF (SHF), stable coronary artery disease (CAD) without HF, and healthy controls (HCs).

Methods and Results—

MPAs were analyzed by flow cytometry for the 3 monocyte subsets (CD14++CD16-CCR2+ [Mon1], CD14++CD16+CCR2+ [Mon2] and CD14+CD16++CCR2– [Mon3]) in patients with AHF (n=51), SHF (n=42), stable CAD (n=44), and HCs (n=40). Counts of total MPA and MPAs associated with Mon1 and Mon2 were significantly higher in AHF compared with SHF, CAD, and HCs (
P
<0.001 for all). The proportion of Mon1 aggregated with platelets was increased in AHF compared with SHF (
P
=0.033), CAD (
P
<0.001), and HCs (
P
<0.001). A higher percentage of Mon3 aggregated with platelets was also seen in AHF compared with SHF (
P
=0.012) and HCs (
P
<0.001) but not compared with CAD (
P
=0.647). MPAs associated with Mon2 were significantly lower in patients who experienced adverse clinical outcomes of death or rehospitalization compared with those who remained free of events (
P
=0.03). Mon2 count remained an independent negative predictor of combined death and rehospitalization after adjustment for age, left ventricular ejection fraction, creatinine, and brain natriuretic peptide (hazard ratio, 0.58 [95% CI, 0.34–0.98];
P
=0.043).

Conclusions—
MPA formation in patients with both acute and stable HF is increased and seems to be confined to monocytes from Mon1 and Mon2 subsets. MPAs associated with Mon2 seem to be negatively predictive of a worse prognosis in AHF.