bluuebunny/crossref_metadata_2025_split huggingface dataset:
Suppression of HIV-1 Infection by APOBEC3 Proteins in Primary Human CD4
+
T Cells Is Associated with Inhibition of Processive Reverse Transcription as Well as Excessive Cytidine Deamination
Authors: Gillick Kieran , Pollpeter Darja , Phalora Prabhjeet , Kim Eun-Young , Wolinsky Steven M. , Malim Michael H. 
Published: November 2012

ABSTRACT

The Vif protein of human immunodeficiency virus type 1 (HIV-1) promotes viral replication by downregulation of the cell-encoded, antiviral APOBEC3 proteins. These proteins exert their suppressive effects through the inhibition of viral reverse transcription as well as the induction of cytidine deamination within nascent viral cDNA. Importantly, these two effects have not been characterized in detail in human CD4
+
T cells, leading to controversies over their possible contributions to viral inhibition in the natural cell targets of HIV-1 replication. Here we use wild-type and Vif-deficient viruses derived from the CD4
+
T cells of multiple donors to examine the consequences of APOBEC3 protein function at natural levels of expression. We demonstrate that APOBEC3 proteins impart a profound deficiency to reverse transcription from the initial stages of cDNA synthesis, as well as excessive cytidine deamination (hypermutation) of the DNAs that are synthesized. Experiments using viruses from transfected cells and a novel method for mapping the 3′ termini of cDNAs indicate that the inhibition of reverse transcription is not limited to a few specific sites, arguing that APOBEC3 proteins impede enzymatic processivity. Detailed analyses of mutation spectra in viral cDNA strongly imply that one particular APOBEC3 protein, APOBEC3G, provides the bulk of the antiviral phenotype in CD4
+
T cells, with the effects of APOBEC3F and APOBEC3D being less significant. Taken together, we conclude that the dual mechanisms of action of APOBEC3 proteins combine to deliver more effective restriction of HIV-1 than either function would by itself.
Multiple Gag Domains Contribute to Selective Recruitment of Murine Leukemia Virus (MLV) Env to MLV Virions
Authors: Gregory Devon A. , Lyddon Terri D. , Johnson Marc C. 
Published: November 2012

ABSTRACT
Retroviruses, like all enveloped viruses, must incorporate viral glycoproteins to form infectious particles. Interactions between the glycoprotein cytoplasmic tail and the matrix domain of Gag are thought to direct recruitment of glycoproteins to native virions for many retroviruses. However, retroviruses can also incorporate glycoproteins from other viruses to form infectious virions known as pseudotyped particles. The glycoprotein murine leukemia virus (MLV) Env can readily form pseudotyped particles with many retroviruses, suggesting a generic mechanism for recruitment. Here, we sought to identify which components of Gag, particularly the matrix domain, contribute to recruitment of MLV Env into retroviral particles. Unexpectedly, we discovered that the matrix domain of HIV-1 Gag is dispensable for generic recruitment, since it could be replaced with a nonviral membrane-binding domain without blocking active incorporation of MLV Env into HIV virions. However, MLV Env preferentially assembles with MLV virions. When MLV and HIV particles are produced from the same cell, MLV Env is packaged almost exclusively by MLV particles, thus preventing incorporation into HIV particles. Surprisingly, the matrix domain of MLV Gag is not required for this selectivity, since MLV Gag containing the matrix domain from HIV is still able to outcompete HIV particles for MLV Env. Although MLV Gag is sufficient for selective incorporation to occur, no single Gag domain dictates the selectivity. Our findings indicate that Env recruitment is more complex than previously believed and that Gag assembly/budding sites have fundamental properties that affect glycoprotein incorporation.
Assessment of simple risk markers for early mortality among HIV-infected patients in Guinea-Bissau: a cohort study
Authors: Oliveira Inés , Andersen Andreas , Furtado Alcino , Medina Candida , da Silva David , da Silva Zacarias J , Aaby Peter , Laursen Alex Lund , Wejse Christian , Eugen-Olsen Jesper ,   for the Bissau HIV cohort study group
Published: November 2012

BackgroundDecisions about when to start an antiretroviral therapy (ART) are normally based on CD4 cell counts and viral load (VL). However, these measurements require equipment beyond the capacity of most laboratories in low-income and middle-income settings. Thus, there is an urgent need to identify and test simple markers to guide the optimal time for starting and for monitoring the effect of ART in developing countries.Objectives(1) To evaluate anthropometric measurements and measurement of plasma-soluble form of the urokinase plasminogen activator receptor (suPAR) levels as potential risk factors for early mortality among HIV-infected patients; (2) to assess whether these markers could help identify patients to whom ART should be prioritised and (3) to determine if these markers may add information to CD4 cell count when VL is not available.DesignAn observational study.SettingThe largest ART centre in Bissau, Guinea-Bissau.Participants1083 ART-naïve HIV-infected patients.Outcome measuresAssociations between baseline anthropometric measurements, CD4 cell counts, plasma suPAR levels and survival were examined using Cox proportional hazards models.ResultsLow body mass index (BMI≤18.5 kg/m2), low mid-upper-arm-circumference (MUAC≤250 mm), low CD4 cell count (≤350 cells/μl) and high suPAR plasma levels (>5.3 ng/ml) were independent predictors of death. Furthermore, mortality among patients with low CD4 cell count, low MUAC or low BMI was concentrated in the highest suPAR quartile.ConclusionsIrrespective of ART initiation and baseline CD4 count, MUAC and suPAR plasma levels were independent predictors of early mortality in this urban cohort. These markers could be useful in identifying patients at the highest risk of short-term mortality and may aid triage for ART when CD4 cell count is not available or when there is shortness of antiretroviral drugs.
How might the London 2012 Olympics influence health and the determinants of health? Local newspaper analysis of pre-Games pathways and impacts
Authors: Selvanayagam Marinie , Thompson Claire , Taylor Stephanie J C , Cummins Steven , Bourke Liam 
Published: November 2012

ObjectivesTo conduct a content analysis of pre-Games local media coverage of the potential impact on health and the determinants of health in Newham, the site of the Olympic Park.DesignLocal newspaper content analysis.SettingOlympic park host site of the London Borough of Newham.Outcome measuresMedia coverage of employment, physical activity and well-being.ResultsThree hundred and 51 articles meeting the inclusion criteria were included in the analysis. The overwhelming majority of the articles took a positive perspective on the Olympic Games being hosted in Newham with less than 10% (32/351) addressing potential adverse effects. The frequency of articles reporting on both employment and well-being increased significantly over time (p=0.002 and p=0.006, respectively). A non-significant increasing trend was observed for physical activity (p=0.146). New employment opportunities and the promotion of physical activity in young people were the pathways most frequently reported in the local media. However, much less attention is devoted to understanding the uncertainties about how much of these new opportunities will directly improve the determinants of health in the Newham population.ConclusionsPre-Games reporting on the impact on health and the determinants of health increased over time in the London Borough of Newham, and is overwhelmingly positive. However, specific uncertainties around the true nature of its impact on local employment and physical activity were articulated. Further evaluation of the tangible impacts on population health, and the determinants of health and health inequalities from the London 2012 Olympics, is required.
Efficacy of multimodal, systematic non-surgical treatment of knee osteoarthritis for patients not eligible for a total knee replacement: a study protocol of a randomised controlled trial
Authors: Skou Soren Thorgaard , Roos Ewa M , Laursen Mogens Berg , Rathleff Michael Skovdal , Arendt-Nielsen Lars , Simonsen Ole , Rasmussen Sten 
Published: November 2012

IntroductionIt is recommended that non-operative treatment of knee osteoarthritis (KOA) should be individually tailored and include multiple treatment modalities. Despite these recommendations, no one has yet investigated the efficacy of combining several non-surgical treatment modalities in a randomised controlled study. The purpose of this randomised controlled study is to examine if an optimised, combined non-surgical treatment programme results in greater improvements in pain, function and quality of life in comparison with usual care in patients with KOA who are not eligible for total knee arthroplasty (TKA).Methods and analysisThis study will include 100 consecutive patients from the North Denmark Region not eligible for TKA with radiographic KOA (K-L grade ≥1) and mean pain during the previous week of ≤60 mm (0–100). The participants will be randomised to receive either a 12-week non-surgical treatment programme consisting of patient education, exercise, diet, insoles, paracetamol and/or NSAIDs or usual care (two information leaflets containing information on KOA and advice regarding the above non-surgical treatment). The primary outcome will be the change from baseline to 12 months on the self-report questionnaire Knee Injury and Osteoarthritis Outcome Score (KOOS)4defined as the average score for the subscale scores for pain, symptoms, activities of daily living and quality of life. Secondary outcomes include the five individual KOOS subscale scores, pain on a 100 mm Visual Analogue Scale, EQ-5D, self-efficacy, pain pressure thresholds, postural control and isometric knee flexion and knee extension strength.Ethics and disseminationThis study was approved by the local Ethics Committee of The North Denmark Region (N-20110085) and the protocol conforms to the principles of the Declaration of Helsinki. Data collection will be completed by April 2014. Publications will be ready for submission in the summer of 2014.Trial registration numberThis study is registered withhttp://clinicaltrials.gov(NCT01535001).
A Preclinical Mouse Model of Invasive Lobular Breast Cancer Metastasis
Authors: Doornebal Chris W. , Klarenbeek Sjoerd , Braumuller Tanya M. , Klijn Christiaan N. , Ciampricotti Metamia , Hau Cheei-Sing , Hollmann Markus W. , Jonkers Jos , de Visser Karin E. 
Published: November 2012

Abstract
Metastatic disease accounts for more than 90% of cancer-related deaths, but the development of effective antimetastatic agents has been hampered by the paucity of clinically relevant preclinical models of human metastatic disease. Here, we report the development of a mouse model of spontaneous breast cancer metastasis, which recapitulates key events in its formation and clinical course. Specifically, using the conditional K14cre;Cdh1F/F;Trp53F/F model of de novo mammary tumor formation, we orthotopically transplanted invasive lobular carcinoma (mILC) fragments into mammary glands of wild-type syngeneic hosts. Once primary tumors were established in recipient mice, we mimicked the clinical course of treatment by conducting a mastectomy. After surgery, recipient mice succumbed to widespread overt metastatic disease in lymph nodes, lungs, and gastrointestinal tract. Genomic profiling of paired mammary tumors and distant metastases showed that our model provides a unique tool to further explore the biology of metastatic disease. Neoadjuvant and adjuvant intervention studies using standard-of-care chemotherapeutics showed the value of this model in determining therapeutic agents that can target early- and late-stage metastatic disease. In obtaining a more accurate preclinical model of metastatic lobular breast cancer, our work offers advances supporting the development of more effective treatment strategies for metastatic disease. Cancer Res; 73(1); 353–63. ©2012 AACR.
Targeting Truncated Retinoid X Receptor-α by CF31 Induces TNF-α–Dependent Apoptosis
Authors: Wang Guang-Hui , Jiang Fu-Quan , Duan Ying-Hui , Zeng Zhi-Ping , Chen Fan , Dai Yi , Chen Jie-Bo , Liu Jin-Xing , Liu Jie , Zhou Hu , Chen Hai-Feng , Zeng Jin-Zhang , Su Ying , Yao Xin-Sheng , Zhang Xiao-Kun 
Published: November 2012

Abstract
A truncated version of retinoid X receptor-α, tRXR-α, promotes cancer cell survival by activating the phosphoinositide 3-kinase (PI3K)/AKT pathway. However, targeting the tRXR-α–mediated survival pathway for cancer treatment remains to be explored. We report here our identification of a new natural product molecule, CF31, a xanthone isolated from Cratoxylum formosum ssp. pruniflorum, and the biologic evaluation of its regulation of the tRXR-α–mediated PI3K/AKT pathway. CF31 binds RXR-α and its binding results in inhibition of RXR-α transactivation. Through RXR-α mutational analysis and computational studies, we show that Arg316 of RXR-α, known to form salt bridges with certain RXR-α ligands, such as 9-cis-retinoic acid (9-cis-RA), is not required for the antagonist effect of CF31, showing a distinct binding mode. Evaluation of several CF31 analogs suggests that the antagonist effect is mainly attributed to an interference with Leu451 of helix H12 in RXR-α. CF31 is a potent inhibitor of AKT activation in various cancer cell lines. When combined with TNF-α, it suppresses TNF-α activation of AKT by inhibiting TNF-α–induced tRXR-α interaction with the p85α regulatory subunit of PI3K. CF31 inhibition of TNF-α activation of AKT also results in TNF-α–dependent activation of caspase-8 and apoptosis. Together, our results show that CF31 is an effective converter of TNF-α signaling from survival to death by targeting tRXR-α in a unique mode and suggest that identification of a natural product that targets an RXR-mediated cell survival pathway that regulates PI3K/AKT may offer a new therapeutic strategy to kill cancer cells. Cancer Res; 73(1); 307–18. ©2012 AACR.
Reduced Overall and Event-Free Survival among Colon Cancer Patients Using Dual System Care
Authors: Tarlov Elizabeth , Lee Todd A. , Weichle Thomas W. , Durazo-Arvizu Ramon , Zhang Qiuying , Perrin Ruth , Bentrem David , Hynes Denise M. 
Published: November 2012

Abstract
Background: Many veterans have dual Veterans Administration (VA) and Medicare healthcare coverage. We compared 3-year overall and cancer event-free survival (EFS) among patients with nonmetastatic colon cancer who obtained substantial portions of their care in both systems and those whose care was obtained predominantly in the VA or in the Medicare fee-for-service system.
Methods: We conducted a retrospective observational cohort study of patients older than 65 years with stages I to III colon cancer diagnosed from 1999 to 2001 in VA and non-VA facilities. Dual use of VA and non-VA colon cancer care was categorized as predominantly VA use, dual use, or predominantly non-VA use. Extended Cox regression models evaluated associations between survival and dual use.
Results: VA and non-VA users (all stages) had reduced hazard of dying compared with dual users [e.g., for stage I, VA HR 0.40, 95% confidence interval (CI): 0.28–0.56; non-VA HR 0.54, 95% CI: 0.38–0.78). For EFS, stage I findings were similar (VA HR 0.47, 95% CI: 0.35–0.62; non-VA HR 0.64, 95% CI: 0.47–0.86). Stage II and III VA users, but not non-VA users, had improved EFS (stage II: VA HR 0.74, 95% CI: 0.56–0.97; non-VA HR 0.92, 95% CI: 0.69–1.22; stage III: VA HR 0.73, 95% CI: 0.56–0.94; non-VA HR 0.81, 95% CI: 0.62–1.06).
Conclusions: Improved survival among VA and non-VA compared with dual users raises questions about coordination of care and unmet needs.
Impact: Additional study is needed to understand why these differences exist, why patients use both systems, and how systems may be improved to yield better outcomes in this population. Cancer Epidemiol Biomarkers Prev; 21(12); 2231–41. ©2012 AACR.
Common Obesity-Related Genetic Variants and Papillary Thyroid Cancer Risk
Authors: Kitahara Cari M. , Neta Gila , Pfeiffer Ruth M. , Kwon Deukwoo , Xu Li , Freedman Neal D. , Hutchinson Amy A. , Chanock Stephen J. , Sturgis Erich M. , Sigurdson Alice J. , Brenner Alina V. 
Published: November 2012

Abstract
Background: Epidemiologic studies have shown consistent associations between obesity and increased thyroid cancer risk, but, to date, no studies have investigated the relationship between thyroid cancer risk and obesity-related single-nucleotide polymorphisms (SNP).
Methods: We evaluated 575 tag SNPs in 23 obesity-related gene regions in a case–control study of 341 incident papillary thyroid cancer (PTC) cases and 444 controls of European ancestry. Logistic regression models, adjusted for attained age, year of birth, and sex were used to calculate ORs and 95% confidence intervals (CI) with SNP genotypes, coded as 0, 1, and 2 and modeled continuously to calculate Ptrend.
Results: Nine of 10 top-ranking SNPs (Ptrend &lt; 0.01) were located in the FTO (fat mass and obesity associated) gene region, whereas the other was located in INSR (insulin receptor). None of the associations were significant after correcting for multiple testing.
Conclusions: Our data do not support an important role of obesity-related genetic polymorphisms in determining the risk of PTC.
Impact: Factors other than selected genetic polymorphisms may be responsible for the observed associations between obesity and increased PTC risk. Cancer Epidemiol Biomarkers Prev; 21(12); 2268–71. ©2012 AACR.
Gender Difference in Systemic Oxidative Stress and Antioxidant Capacity in Current and Former Heavy Smokers
Authors: Hakim Iman A. , Harris Robin , Garland Linda , Cordova Catherine A. , Mikhael Dalia M. , Sherry Chow H-H. 
Published: November 2012

Abstract
Background: Several studies suggested that women may be more susceptible to oxidative damage induced by cigarette smoking, but the role of smoking status and antioxidant capacity in gender difference in susceptibility to oxidative damage has not been well studied.
Methods: We conducted a cross-sectional analysis of the baseline data from 146 current and former heavy smokers enrolled in a chemoprevention trial to determine the gender difference in oxidative damage and antioxidant capacity. Oxidative DNA and lipid damage were assessed by urinary 8-hydroxy-2′-deoxyguanosine (8OHdG) and 8-isoprostaglandin F2α (8-iso-PGF2α), respectively. The erythrocyte antioxidant enzymes and serum fat-soluble antioxidants were measured to assess antioxidant capacity.
Results: Female smokers had significantly greater levels of 8OHdG and 8-iso-PGF2α than males but the gender difference was only significant in current smokers. No gender difference was noted in erythrocyte antioxidant enzymes, although female current smokers had significantly lower or a trend for lower antioxidant enzymes. Female smokers had higher serum β-carotene than males. Biomarkers of oxidative damage did not correlate significantly with the antioxidant enzymes. Urinary 8OHdG did not correlate significantly with fat-soluble antioxidants. Inverse correlations were observed between urinary 8-iso-PGF2α and several serum carotenoids.
Conclusion: Female current smokers have a greater extent of oxidative damage despite having higher serum levels of fat-soluble antioxidants. Lower erythrocyte antioxidant enzymes in female current smokers may contribute to the greater extent of oxidative damage.
Impact: The study may help identify appropriate high-risk populations for interventions that attenuate oxidative damage and appropriate biomarkers for clinical studies in smokers. Cancer Epidemiol Biomarkers Prev; 21(12); 2193–200. ©2012 AACR.
HPV Vaccination among Adolescent Females from Appalachia: Implications for Cervical Cancer Disparities
Authors: Reiter Paul L. , Katz Mira L. , Paskett Electra D. 
Published: November 2012

Abstract
Background: Appalachia is a geographic region with high cervical cancer incidence and mortality rates, yet little is known about human papillomavirus (HPV) vaccination in this region. We determined HPV vaccine coverage among adolescent females from Appalachia, made comparisons to non-Appalachian females, and examined how coverage differs across subregions within Appalachia.
Methods: We analyzed data from the National Immunization Survey-Teen 2008–2010 for adolescent females ages 13–17 (n = 1,951, Appalachian females and n = 25,468, non-Appalachian females). We examined HPV vaccine initiation (receipt of at least one dose), completion (receipt of at least three doses), and follow-through (completion among initiators). Analyses used weighted logistic regression.
Results: HPV vaccine initiation [Appalachian = 40.8% vs. non-Appalachian = 43.6%; OR, 0.92; 95% confidence interval (CI), 0.79–1.07] and completion (Appalachian = 27.7% vs. non-Appalachian = 25.3%; OR, 1.12; 95% CI, 0.95–1.32) were similar between Appalachian and non-Appalachian females. HPV vaccine follow-through was higher among Appalachian females than non-Appalachian females (67.8% vs. 58.1%; OR, 1.36; 95% CI, 1.07–1.72). Vaccination outcomes tended to be higher in the Northern (completion and follow-through) and South Central (follow-through) subregions of Appalachia compared with non-Appalachian United States. Conversely, vaccination outcomes tended to be lower in the Central (initiation and completion) and Southern (initiation and completion) subregions.
Conclusions: In general, HPV vaccination in Appalachia is mostly similar to the rest of the United States. However, vaccination is lagging in regions of Appalachia where cervical cancer incidence and mortality rates are highest.
Impact: Current cervical cancer disparities could potentially worsen if HPV vaccine coverage is not improved in regions of Appalachia with low HPV vaccine coverage. Cancer Epidemiol Biomarkers Prev; 21(12); 2220–30. ©2012 AACR.
Age-Dependent Associations between Androgenetic Alopecia and Prostate Cancer Risk
Authors: Muller David C. , Giles Graham G. , Sinclair Rod , Hopper John L. , English Dallas R. , Severi Gianluca 
Published: November 2012

AbstractBackground: Both prostate cancer and androgenetic alopecia are strongly age-related conditions that are considered to be androgen dependent, but studies of the relationship between them have yielded inconsistent results. We aimed to assess whether androgenetic alopecia at ages 20 and 40 years are associated with risk of prostate cancer.Methods: At a follow-up of the Melbourne Collaborative Cohort Study, men were asked to assess their hair pattern at ages 20 and 40 years relative to eight categories in showcards. Cases were men notified to the Victorian Cancer Registry with prostate cancer diagnosed between cohort enrollment (1990–1994) and follow-up attendance (2003–2009). Flexible parametric survival models were used to estimate age-varying HRs and predicted cumulative probabilities of prostate cancer by androgenetic alopecia categories.Results: Of 9,448 men that attended follow-up and provided data on androgenetic alopecia, we identified 476 prostate cancer cases during a median follow-up of 11 years four months. Cumulative probability of prostate cancer was greater at all ages up to 76 years, for men with vertex versus no androgenetic alopecia at age of 40 years. At age of 76 years, the estimated probabilities converged to 0.15. Vertex androgenetic alopecia at 40 years was also associated with younger age of diagnosis for prostate cancer cases.Conclusions: Vertex androgenetic alopecia at age of 40 years might be a marker of increased risk of early-onset prostate cancer.Impact: If confirmed, these results suggest that the apparently conflicting findings of previous studies might be explained by failure to adequately model the age-varying nature of the association between androgenetic alopecia and prostate cancer. Cancer Epidemiol Biomarkers Prev; 22(2); 209–15. ©2012 AACR.