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1.  Male circumcision and the incidence and clearance of genital human papillomavirus (HPV) infection in men: the HPV Infection in men (HIM) cohort study 
Background
Reported associations of male circumcision (MC) with human papillomavirus (HPV) infection in men have been inconsistent.
Methods
4,033 healthy men were examined every six months for a median of 17.5 months. In each study visit, exfoliated cell specimens from the coronal sulcus/glans penis, penile shaft, and scrotum were collected and combined into one sample per person for HPV DNA detection. Samples were tested for 37 HPV types. Cox proportional hazards models were used to evaluate the association between MC and the incidence and clearance of HPV infections and specific genotypes.
Results
The overall incidence of new HPV infections did not differ by MC status (for any HPV, adjusted hazard ratio (aHR) 1.08, 95% confidence interval (CI) 0.91-1.27). However, incidence was significantly lower among circumcised versus uncircumcised men for HPV types 58 (p = 0.01), 68 (p < 0.001), 42 (p = 0.01), 61 (p < 0.001), 71 (p < 0.001), 81 (p = 0.04), and IS39 (p = 0.01), and higher for HPV types 39 (p = 0.01) and 51 (p = 0.02). Despite the lack of an overall association in the risk of HPV clearance by MC (for any HPV, aHR 0.95, 95% CI 0.88-1.02), median times to clearance were significantly shorter among circumcised than uncircumcised men for HPV types 33 (p = 0.02) and 64 (p = 0.04), and longer for HPV types 6 (p < 0.001), 16 (p < 0.001), and 51 (p = 0.02).
Conclusions
MC is not associated with the incidence and clearance of genital HPV detection, except for certain HPV types. The use of a single combined sample from the penis and scrotum for HPV DNA detection likely limited our ability to identify a true effect of MC at the distal penis.
doi:10.1186/1471-2334-14-75
PMCID: PMC3925013  PMID: 24517172
Male circumcision; Genital; HPV; Incidence; Clearance
2.  TRM: A Powerful Two-stage Machine Learning Approach for Identifying SNP-SNP Interactions 
Annals of human genetics  2011;76(1):53-62.
SUMMARY
Studies have shown that interactions of single nucleotide polymorphism (SNP) may play an important role for understanding causes of complex disease. Machine learning approaches provide useful features to explore interactions more effectively and efficiently. We have proposed an integrated method that combines two machine learning methods - Random Forests (RF) and Multivariate Adaptive Regression Splines (MARS) - to identify a subset of important SNPs and detect interaction patterns. In this two-stage RF-MARS (TRM) approach, RF is first applied to detect a predictive subset of SNPs, and then MARS is used to identify the interaction patterns among the selected SNPs. We evaluated the TRM performances in four models: three causal models with one two-way interaction and one null model. RF variable selection was based on out-of-bag classification error rate (OOB) and variable important spectrum (IS). First, we compared the selection of important variable of RF and MARS. Our results support that RFOOB had better performance than MARS and RFIS in detecting important variables. We also evaluated the true positive rate and false positive rate of identifying interaction patterns in TRM and MARS. This study demonstrates that TRMOOB, which is RFOOB plus MARS, has combined the strengths of RF and MARS in identifying SNP-SNP interaction patterns in a scenario of 100 candidate SNPs. TRMOOB had greater true positive rate and lower false positive rate compared with MARS, particularly for searching interactions with a strong association with the outcome. Therefore the use of TRMOOB is favored for exploring SNP-SNP interactions in a large-scale genetic variation study.
doi:10.1111/j.1469-1809.2011.00692.x
PMCID: PMC3243917  PMID: 22150548
polymorphism; interaction; machine learning
3.  Who tended to continue smoking after cancer diagnosis: the national health and nutrition examination survey 1999–2008 
BMC Public Health  2012;12:784.
Background
It has been estimated that there are approximately 12 million cancer survivors in the United States. Continued smoking after a cancer diagnosis is linked to adverse effects among cancer survivors on overall survival, treatment effectiveness, and quality of life. Little is known about who is more likely to quit smoking after his/her cancer diagnosis. The objective of this study is to evaluate factors associated with smoking cessation in cancer survivors, which to date has not been well studied.
Method
The National Health and Nutrition Examination Survey (NHANES) 1999–2008 surveys were used in this study. A total of 2,374 cancer survivors aged 20 and over with valid smoking status in the NHANES 99–08 survey were included in this study. Among them, 566 cancer survivors who regularly smoked at the time of their cancer diagnosis were included in the analyses.
Results
Around 50.6% of cancer survivors smoked regularly prior to their cancer diagnosis and only 36.1% of them quit smoking after their cancer diagnosis. Racial disparity was observed in smoking cessation among cancer survivors. Hispanics (OR = 0.23, 95% CI = 0.10-0.57) were less likely to quit smoking than Whites after their cancer diagnosis.
Conclusion
Two-thirds of cancer survivors continued smoking after cancer diagnosis. Our study observed that the high risk group of continued smokers among cancer survivors is made up of those who are female, younger, Hispanic, with longer smoking history, underweight or with normal weight and without smoking-related cancer. These findings suggest that smoking cessation for cancer survivors should target on the high risk subgroups.
doi:10.1186/1471-2458-12-784
PMCID: PMC3528617  PMID: 22974404
Cancer survivor; Tobacco control; Disparity
4.  Race and prevalence of human papillomavirus infection among men residing in Brazil, Mexico, and the United States 
HPV causes anal, penile and oropharyngeal cancers in men. Genital HPV prevalence in men appears to vary by world region with men residing in Asia having among the lowest prevalence. Unfortunately, there is little information on prevalence of HPV infection in men by race. The purpose of this study was to examine HPV prevalence by race across three countries. 3,909 men ages 18–70 years enrolled in an ongoing prospective cohort study of the natural history of HPV in men (The HIM Study) were included in the analysis. Participants completed risk factor questionnaires and samples were taken from the penile epithelium and scrotum for HPV detection. HPV testing of the combined DNA extract was conducted using PCR and genotyping. Asian/Pacific Islanders had the lowest HPV prevalence of 42.2% compared to Blacks (66.2%), and Whites (71.5%). The Asian/Pacific Islander race was strongly protective in univariate analysis (prevalence ratio(PR)= 0.59; 95% confidence interval(CI):0.48 – 0.74) and multivariate analysis for any HPV infection (PR= 0.65; 95% CI:0.52 – 0.8). Stratified analysis by lifetime number of female partners also showed strong inverse associations with the Asian/Pacific Islander race. We consistently observed the lowest prevalence of HPV infection among Asian/Pacific Islanders with moderate inverse associations even after various adjustments for potential confounding factors. Unmeasured behavioral factors, sexual mixing with low risk women, and/or race-specific differences in the frequency of germline variations among immune regulating genes may underlie these associations. Further studies among Asian populations that incorporate measures of immuno-genetics are needed to understand this phenomenon.
doi:10.1002/ijc.27397
PMCID: PMC3458422  PMID: 22161806
5.  Polymorphisms in Drug Metabolism Genes, Smoking, and p53 Mutations in Breast Cancer 
Molecular carcinogenesis  2008;47(2):88-99.
Polymorphisms in phase I and phase II enzymes may enhance the occurrence of mutations at critical tumor suppressor genes, such as p53, and increase breast cancer risk by either increasing the activation or detoxification of carcinogens and/or endogenous estrogens. We analyzed polymorphisms in CYP1B1, GSTM1, GSTT1, and GSTP1 and p53 mutations in 323 breast tumor samples. Approximately 11% of patients exhibited mutations in p53. Women with mutations had a significantly younger age of diagnosis (P = 0.01) and a greater incidence of tumors classified as stage II or higher (P = 0.002). More women with mutations had a history of smoking (55%) compared to women without mutations (39%). Although none of the genotypes alone were associated with p53 mutations, positive smoking history was associated with p53 mutations in women with the GSTM1 null allele [OR = 3.54; 95% CI = 0.97–12.90 P = 0.06] compared to women with the wild-type genotype and smoking history [OR = 0.62, 95% CI = 0.19–2.07], although this association did not reach statistical significance. To test for gene–gene interactions, our exploratory analysis in the Caucasian cases suggested that individuals with the combined GSTP1 105 VV, CYP1B1 432 LV/VV, and GSTM1 positive genotype were more likely to harbor mutations in p53 [OR = 4.94; 95% CI = 1.11–22.06]. Our results suggest that gene–smoking and gene–gene interactions may impact the prevalence of p53 mutations in breast tumors. Elucidating the etiology of breast cancer as a consequence of common genetic polymorphisms and the genotoxic effects of smoking will enable us to improve the design of prevention strategies, such as lifestyle modifications, in genetically susceptible subpopulations.
doi:10.1002/mc.20365
PMCID: PMC3722359  PMID: 17683074
breast cancer; p53; polymorphisms; drug metabolism
6.  Genital Human Papillomavirus (HPV) Concordance in Heterosexual Couples 
The Journal of Infectious Diseases  2012;206(2):202-211.
Background. Few studies have assessed genital human papillomavirus (HPV) concordance and factors associated with concordance among asymptomatic heterosexual couples.
Methods. Genotyping for HPV was conducted with male and female sex partners aged 18–70 years from Tampa, Florida. Eligibility included no history of HPV-associated disease. Type-specific positive concordance (partners with ≥1 genotype in common) and negative concordance (neither partner had HPV) were assessed for 88 couples. Factors associated with concordance were assessed with Fisher exact tests and tests for trend.
Results. Couples reported engaging in sexual intercourse for a median of 1.7 years (range, 0.1–49 years), and 75% reported being in the same monogamous relationship for the past 6 months. Almost 1 in 4 couples had type-specific positive concordance, and 35% had negative concordance for all types tested, for a total concordance of 59%. Concordance was not associated with monogamy. Type-specific positive concordance was associated with an increasing difference in partners’ lifetime number of sex partners and inversely associated with an increasing difference in age. Negative concordance was inversely associated with both the couple's sum of lifetime number of sex partners and the difference in the partners’ lifetime number of sex partners.
Conclusions. Genital HPV concordance was common. Viral infectiousness and number of sex partners may help explain concordance among heterosexual partners.
doi:10.1093/infdis/jis327
PMCID: PMC3490693  PMID: 22539815
7.  Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31 
Permuth-Wey, Jennifer | Lawrenson, Kate | Shen, Howard C. | Velkova, Aneliya | Tyrer, Jonathan P. | Chen, Zhihua | Lin, Hui-Yi | Chen, Y. Ann | Tsai, Ya-Yu | Qu, Xiaotao | Ramus, Susan J. | Karevan, Rod | Lee, Janet | Lee, Nathan | Larson, Melissa C. | Aben, Katja K. | Anton-Culver, Hoda | Antonenkova, Natalia | Antoniou, Antonis | Armasu, Sebastian M. | Bacot, François | Baglietto, Laura | Bandera, Elisa V. | Barnholtz-Sloan, Jill | Beckmann, Matthias W. | Birrer, Michael J. | Bloom, Greg | Bogdanova, Natalia | Brinton, Louise A. | Brooks-Wilson, Angela | Brown, Robert | Butzow, Ralf | Cai, Qiuyin | Campbell, Ian | Chang-Claude, Jenny | Chanock, Stephen | Chenevix-Trench, Georgia | Cheng, Jin Q. | Cicek, Mine S. | Coetzee, Gerhard A. | Cook, Linda S. | Couch, Fergus J. | Cramer, Daniel W. | Cunningham, Julie M. | Dansonka-Mieszkowska, Agnieszka | Despierre, Evelyn | Doherty, Jennifer A | Dörk, Thilo | du Bois, Andreas | Dürst, Matthias | Easton, Douglas F | Eccles, Diana | Edwards, Robert | Ekici, Arif B. | Fasching, Peter A. | Fenstermacher, David A. | Flanagan, James M. | Garcia-Closas, Montserrat | Gentry-Maharaj, Aleksandra | Giles, Graham G. | Glasspool, Rosalind M. | Gonzalez-Bosquet, Jesus | Goodman, Marc T. | Gore, Martin | Górski, Bohdan | Gronwald, Jacek | Hall, Per | Halle, Mari K. | Harter, Philipp | Heitz, Florian | Hillemanns, Peter | Hoatlin, Maureen | Høgdall, Claus K. | Høgdall, Estrid | Hosono, Satoyo | Jakubowska, Anna | Jensen, Allan | Jim, Heather | Kalli, Kimberly R. | Karlan, Beth Y. | Kaye, Stanley B. | Kelemen, Linda E. | Kiemeney, Lambertus A. | Kikkawa, Fumitaka | Konecny, Gottfried E. | Krakstad, Camilla | Kjaer, Susanne Krüger | Kupryjanczyk, Jolanta | Lambrechts, Diether | Lambrechts, Sandrina | Lancaster, Johnathan M. | Le, Nhu D. | Leminen, Arto | Levine, Douglas A. | Liang, Dong | Lim, Boon Kiong | Lin, Jie | Lissowska, Jolanta | Lu, Karen H. | Lubiński, Jan | Lurie, Galina | Massuger, Leon F.A.G. | Matsuo, Keitaro | McGuire, Valerie | McLaughlin, John R | Menon, Usha | Modugno, Francesmary | Moysich, Kirsten B. | Nakanishi, Toru | Narod, Steven A. | Nedergaard, Lotte | Ness, Roberta B. | Nevanlinna, Heli | Nickels, Stefan | Noushmehr, Houtan | Odunsi, Kunle | Olson, Sara H. | Orlow, Irene | Paul, James | Pearce, Celeste L | Pejovic, Tanja | Pelttari, Liisa M. | Pike, Malcolm C. | Poole, Elizabeth M. | Raska, Paola | Renner, Stefan P. | Risch, Harvey A. | Rodriguez-Rodriguez, Lorna | Rossing, Mary Anne | Rudolph, Anja | Runnebaum, Ingo B. | Rzepecka, Iwona K. | Salvesen, Helga B. | Schwaab, Ira | Severi, Gianluca | Shridhar, Vijayalakshmi | Shu, Xiao-Ou | Shvetsov, Yurii B. | Sieh, Weiva | Song, Honglin | Southey, Melissa C. | Spiewankiewicz, Beata | Stram, Daniel | Sutphen, Rebecca | Teo, Soo-Hwang | Terry, Kathryn L. | Tessier, Daniel C. | Thompson, Pamela J. | Tworoger, Shelley S. | van Altena, Anne M. | Vergote, Ignace | Vierkant, Robert A. | Vincent, Daniel | Vitonis, Allison F. | Wang-Gohrke, Shan | Weber, Rachel Palmieri | Wentzensen, Nicolas | Whittemore, Alice S. | Wik, Elisabeth | Wilkens, Lynne R. | Winterhoff, Boris | Woo, Yin Ling | Wu, Anna H. | Xiang, Yong-Bing | Yang, Hannah P. | Zheng, Wei | Ziogas, Argyrios | Zulkifli, Famida | Phelan, Catherine M. | Iversen, Edwin | Schildkraut, Joellen M. | Berchuck, Andrew | Fridley, Brooke L. | Goode, Ellen L. | Pharoah, Paul D. P. | Monteiro, Alvaro N.A. | Sellers, Thomas A. | Gayther, Simon A.
Nature communications  2013;4:1627.
Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3′ untranslated region at putative microRNA (miRNA) binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA binding site single nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene-environment Study. We identify several miRSNPs associated with invasive serous EOC risk (OR=1.12, P=10−8) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion (P=10−10). Variation at 17q21.31 associates with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. An integrated molecular analysis in this region provides evidence for ARHGAP27 and PLEKHM1 as candidate EOC susceptibility genes.
doi:10.1038/ncomms2613
PMCID: PMC3709460  PMID: 23535648
8.  Underutilization of the AIDS Drug Assistance Program: Associated Factors and Policy Implications 
Health Services Research  2011;46(3):982-995.
Background
The AIDS Drug Assistance Program (ADAP) provides antiretroviral medications to low-income individuals with HIV infection.
Methods
A prospective cohort study of ADAP utilization, measured using medication possession ratio (MPR), was conducted during the 2008 calendar year at the University of Alabama at Birmingham 1917 HIV Clinic. Multivariable ordinal logistic regression evaluated factors associated with ADAP utilization.
Results
Among 245 patients, MPR quartiles (Q) were the following: Q1<69 percent, Q2 = 69–83 percent, Q3 = 84–93 percent, Q4>93 percent. In ordinal logistic regression, younger age (OR = 0.59 per 10 years; 95 percent CI = 0.44–0.79), nonwhite males (2.18; 1.18–4.04), lower CD4 count (2.79 for <200 cells/mm3; 1.44–5.43), and a history of alcohol abuse (2.11; 1.02–4.37) were associated with poor ADAP utilization.
Conclusions
One quarter of ADAP enrollees had MPR below 69 percent, a level well below that associated with optimal HIV treatment outcomes, indicating a need for programmatic interventions to improve ADAP utilization.
doi:10.1111/j.1475-6773.2010.01223.x
PMCID: PMC3097412  PMID: 21210795
HIV; adherence; public health
9.  SNP-SNP Interaction Network in Angiogenesis Genes Associated with Prostate Cancer Aggressiveness 
PLoS ONE  2013;8(4):e59688.
Angiogenesis has been shown to be associated with prostate cancer development. The majority of prostate cancer studies focused on individual single nucleotide polymorphisms (SNPs) while SNP-SNP interactions are suggested having a great impact on unveiling the underlying mechanism of complex disease. Using 1,151 prostate cancer patients in the Cancer Genetic Markers of Susceptibility (CGEMS) dataset, 2,651 SNPs in the angiogenesis genes associated with prostate cancer aggressiveness were evaluated. SNP-SNP interactions were primarily assessed using the two-stage Random Forests plus Multivariate Adaptive Regression Splines (TRM) approach in the CGEMS group, and were then re-evaluated in the Moffitt group with 1,040 patients. For the identified gene pairs, cross-evaluation was applied to evaluate SNP interactions in both study groups. Five SNP-SNP interactions in three gene pairs (MMP16+ ROBO1, MMP16+ CSF1, and MMP16+ EGFR) were identified to be associated with aggressive prostate cancer in both groups. Three pairs of SNPs (rs1477908+ rs1387665, rs1467251+ rs7625555, and rs1824717+ rs7625555) were in MMP16 and ROBO1, one pair (rs2176771+ rs333970) in MMP16 and CSF1, and one pair (rs1401862+ rs6964705) in MMP16 and EGFR. The results suggest that MMP16 may play an important role in prostate cancer aggressiveness. By integrating our novel findings and available biomedical literature, a hypothetical gene interaction network was proposed. This network demonstrates that our identified SNP-SNP interactions are biologically relevant and shows that EGFR may be the hub for the interactions. The findings provide valuable information to identify genotype combinations at risk of developing aggressive prostate cancer and improve understanding on the genetic etiology of angiogenesis associated with prostate cancer aggressiveness.
doi:10.1371/journal.pone.0059688
PMCID: PMC3618555  PMID: 23593148
10.  Heat shock proteins HSP27 and HSP70 are present in the skin and are important mediators of allergic contact hypersensitivity 
Proteomic analysis of murine skin has shown that a variety of heat shock proteins (HSPs) are constitutively expressed in the skin. Using murine allergic contact hypersensitivity as a model, we investigated the role of two heat shock proteins – HSP27 and HSP70 – in the induction of cutaneous cell-mediated immune responses. Immunohistochemical examination of skin specimens showed that HSP27 was present in the epidermis and HSP70 was present in both the epidermis and dermis. Inhibition of HSP27 and HSP70 produced a reduction in the DNFB contact hypersensitivity response and resulted in the induction of antigen specific unresponsiveness. Treatment of dendritic cell cultures with recombinant HSP27 caused in the upregulation of IL-1β, TNF-α, IL-6, IL-12p70 and IL-12p40 but not IL-23p19, which was inhibited when antibodies to HSP27 were added. DNFB conjugated dendritic cells that had been treated with HSP27 had an increased capacity to initiate contact hypersensitivity responses compared to control dendritic cells. This augmented capacity required TLR4 signaling because neither cytokine production by dendritic cells nor the increased induction of contact hypersensitivity responses occurred in TLR4 deficient C3H/HeJ mice. Our findings indicate that a cascade of events occurs following initial interaction of hapten with the skin that includes increased activity of heat shock proteins, their interaction with TLR4 and, in turn, increased production of cytokines that are known to enhance antigen presentation by T-cells. The results suggest that heat shock proteins form a link between adaptive and innate immunity during the early stages of contact hypersensitivity.
PMCID: PMC3573708  PMID: 19109201
HSP27; HSP70; Contact Hypersensitivity; 1-Fluoro-2,4-dinitrobenzene (DNFB); Toll-like receptor (TLR)
11.  Six-Month Incidence, Persistence, and Factors Associated With Persistence of Anal Human Papillomavirus in Men: The HPV in Men Study 
The Journal of Infectious Diseases  2011;204(11):1711-1722.
Background. Although there are limited numbers of incidence and persistence estimates for anal human papillomavirus (HPV) in women and in men who have sex with men (MSM), there are no such reports for men who have sex with women (MSW).
Methods. Genotyping was performed on anal samples from men, aged 18–70, from São Paulo, Brazil; Cuernavaca, Mexico; and Tampa, Florida, who provided specimens at enrollment and the 6-month visit of a 4-year prospective study. Eligibility included no history of genital warts or human immunodeficiency virus. A total of 954 MSW and 156 MSM provided evaluable specimens at both visits. Persistence was defined as type-specific infection at each visit.
Results. Incident anal infection was common among both MSM and MSW but generally higher for MSM for HPV groups and specific genotypes. A total of 5.1% of MSM and 0.0% of MSW had a persistent HPV-16 infection at the 6-month visit. Cigarette smoking among MSM and age among MSW were associated with persistent infection with any HPV genotype.
Conclusions. Although anal HPV infection is commonly acquired by both MSW and MSM, incident events and persistence occurred more often among MSM. Cigarette smoking is a modifiable risk factor that may contribute to HPV persistence among MSM.
doi:10.1093/infdis/jir637
PMCID: PMC3203231  PMID: 21964400
12.  Protein expressions and genetic variations of SLC5A8 in prostate cancer risk and aggressiveness 
Urology  2011;78(4):971.e1-971.e9.
OBJECTIVES
Previous studies suggest that SLC5A8 may function as a tumor suppressor gene whose silencing by epigenetic changes may contribute to carcinogenesis. To understand a role in prostate cancer risk and aggressiveness, we investigated expression in prostate tumor and single nucleotide polymorphisms (SNPs) of SLC5A8.
METHODS
We constructed tissue microarrays (TMAs) from 183 prostate tumor tissues, 43 adjacent non-neoplastic tissues from the same prostate cancer patients, and 13 tissues from patients with benign prostatic hyperplasia (BPH) or prostate intraepithelial neoplasia (PIN). A semi-quantitative assessment of SLC5A8 protein expression was determined as the product of immuno-stain intensity and percentage of cells stained. In addition, we compared the frequencies of four SNPs (rs164365, rs1709189, rs1399236, and rs1681096) in SLC5A8 between 668 prostate cancer cases and 385 controls.
RESULTS
SLC5A8 expression was significantly higher in tumor tissues than in paired non-neoplastic tissues (p<0.0001). In the Moffitt samples, we observed a borderline moderate risk increase in individuals with a genotype containing at least one ‘A’ allele of rs164365 (OR=1.35, 95%=1.00–1.80), especially among tall individuals (≥70 inches) (OR=1.80, 95%=1.20–2.68). However, these results were not confirmed in the CGEMS population.
Conclusions
These data suggest that expression pattern of SLC5A8 may be used as a diagnostic biomarker, and a larger study is required to assess the importance of SLC5A8 SNPs in prostate cancer.
doi:10.1016/j.urology.2011.04.055
PMCID: PMC3190039  PMID: 21802122
Prostate cancer; SLC5A8; tissue microarray; polymorphism
13.  The Role of Toxicity-Related Regimen Changes in the Development of Antiretroviral Resistance 
Abstract
In an effort to evaluate factors associated with the development of antiretroviral (ARV) resistance, we assessed the prevalence of toxicity-related regimen changes and modeled its association to the subsequent development of ARV resistance in a cohort of treatment-naive individuals initiating ARV therapy (ART). A retrospective analysis of patients initiating ART was conducted at the UAB 1917 Clinic from 1 January 2000 to 30 September 2007. Cox proportional hazards models were fit to identify factors associated with the development of resistance to ≥1 ARV drug class. Among 462 eligible participants, 14% (n=64) developed ARV resistance. Individuals with ≥1 toxicity-related regimen change (HR=3.94, 95% CI=1.09–14.21), initiating ART containing ddI or d4T (4.12, 1.19–14.26), and from a minority race (2.91, 1.16–7.28) had increased risk of developing resistance. Achieving virologic suppression within 12 months of ART initiation (0.10, 0.05–0.20) and higher pretreatment CD4 count (0.85 per 50 cells/mm3, 0.75–0.96) were associated with decreased hazards of resistance. Changes in ART due to drug intolerance were associated with the subsequent development of ARV resistance. Understanding the role of ARV drug selection and other factors associated with the emergence of ARV resistance will help inform interventions to improve patient care and ensure long-term treatment success.
doi:10.1089/aid.2010.0291
PMCID: PMC3192056  PMID: 21342052
14.  MicroRNA Processing and Binding Site Polymorphisms are not Replicated in the Ovarian Cancer Association Consortium 
Background
Single nucleotide polymorphisms (SNPs) in microRNA-related genes have been associated with epithelial ovarian cancer (EOC) risk in two reports, yet associated alleles may be inconsistent across studies.
Methods
We conducted a pooled analysis of previously-identified SNPs by combining genotype data from 3,973 invasive EOC cases and 3,276 controls from the Ovarian Cancer Association Consortium. We also conducted imputation to obtain dense coverage of genes and comparable genotype data for all studies. In total, 226 SNPs within 15 kilobases of 4 miRNA biogenesis genes (DDX20, DROSHA, GEMIN4, and XPO5) and 23 SNPs located within putative miRNA binding sites of 6 genes (CAV1, COL18A1, E2F2, IL1R1, KRAS, and UGT2A3) were genotyped or imputed and analyzed in the entire dataset.
Results
After adjustment for European ancestry, no overall association was observed between any of the analyzed SNPs and EOC risk.
Conclusions
Common variants in these evaluated genes do not appear to be strongly associated with EOC risk.
Impact
This analysis suggests earlier associations between EOC risk and SNPs in these genes may have been chance findings, possibly confounded by population admixture. To more adequately evaluate the relationship between genetic variants and cancer risk, large sample sizes are needed, adjustment for population stratification should be performed, and use of imputed SNP data should be considered.
doi:10.1158/1055-9965.EPI-11-0397
PMCID: PMC3153581  PMID: 21636674
miRNA processing; binding sites; inherited susceptibility; ovarian cancer; genetic variants
15.  LIN28B polymorphisms influence susceptibility to epithelial ovarian cancer 
Cancer research  2011;71(11):3896-3903.
Defective miRNA biogenesis contributes to the development and progression of epithelial ovarian cancer (EOC). In this study, we examined the hypothesis that single nucleotide polymorphisms (SNPs) in miRNA biogenesis genes may influence EOC risk. In an initial investigation, 318 SNPs in 18 genes were evaluated among 1,815 EOC cases and 1,900 controls, followed up by a replicative joint meta-analysis of data from an additional 2,172 cases and 3,052 controls. Of 23 SNPs from 9 genes associated with risk (empirical P<0.05) in the initial investigation, the meta-analysis replicated 6 SNPs from the DROSHA, FMR1, LIN28, and LIN28B genes, including rs12194974 (G>A), a SNP in a putative transcription factor binding site in the LIN28B promoter region (summary OR=0.90, 95% CI: 0.82–0.98; P=0.015) which has been recently implicated in age of menarche and other phenotypes. Consistent with reports that LIN28B over-expression in EOC contributes to tumorigenesis by repressing tumor suppressor let-7 expression, we provide data from luciferase reporter assays and quantitative RT-PCR to suggest that the inverse association among rs12194974 A allele carriers may be due to reduced LIN28B expression. Our findings suggest that variants in LIN28B and possibly other miRNA biogenesis genes may influence EOC susceptibility.
doi:10.1158/0008-5472.CAN-10-4167
PMCID: PMC3107389  PMID: 21482675
miRNA processing; inherited susceptibility; ovarian cancer; genetic variants
16.  Rhein Induces Apoptosis in Human Breast Cancer Cells 
Human breast cancers cells overexpressing HER2/neu are more aggressive tumors with poor prognosis, and resistance to chemotherapy. This study investigates antiproliferation effects of anthraquinone derivatives of rhubarb root on human breast cancer cells. Of 7 anthraquinone derivatives, only rhein showed antiproliferative and apoptotic effects on both HER2-overexpressing MCF-7 (MCF-7/HER2) and control vector MCF-7 (MCF-7/VEC) cells. Rhein induced dose- and time-dependent manners increase in caspase-9-mediated apoptosis correlating with activation of ROS-mediated activation of NF-κB- and p53-signaling pathways in both cell types. Therefore, this study highlighted rhein as processing anti-proliferative activity against HER2 overexpression or HER2-basal expression in breast cancer cells and playing important roles in apoptotic induction of human breast cancer cells.
doi:10.1155/2012/952504
PMCID: PMC3189565  PMID: 22007260
17.  The Potential Utility of Curcumin in the Treatment of HER-2-Overexpressed Breast Cancer: An In Vitro and In Vivo Comparison Study with Herceptin 
HER-2 is an important oncoprotein overexpressed in about 15–25% of breast cancers. We hypothesized that the ability of curcumin to downregulate HER-2 oncoprotein and inhibit the signal transduction pathway of PI3K/Akt, MAPK, and NF-κB activation may be important in the treatment of HER-2-overexpressed breast cancer. To examine the effect of curcumin on breast cancer cells, MCF-7, MDA-MB-231, MCF-10A, BT-474, and SK-BR-3-hr (a herceptin resistant strain from SK-BR-3) cells were used for in vitro analysis. The in vivo effect of curcumin on HER-2-overexpressed breast cancer was investigated with the HER-2-overexpressed BT-474 xenograft model. Cell growth, cell cycle change, the antimobility effect, signal transduction, and xenograft volume analysis between groups treated with herceptin and/or curcumin were tested. Curcumin decreased the cell growth of various breast cancer cell lines (MCF-7, MDA-MB-231, MCF-10A, BT-474, and SK-BR-3-hr). In Western blot analysis, the phosphorylation of Akt, MAPK, and expression of NF-κB were reduced in BT-474 cells, but not in SK-BR-3-hr cells, after treatment with herceptin. When treated with curcumin, the HER-2 oncoprotein, phosphorylation of Akt, MAPK and expression of NF-κB were decreased in both BT-474 and SK-BR-3-hr cells. In the BT-474 xenograft model, though not as much as herceptin, curcumin did effectively decrease the tumor size. The combination of curcumin with herceptin was not better than herceptin alone; however, the combination of taxol and curcumin had an antitumor effect comparable with taxol and herceptin. The results suggested that curcumin has potential as a treatment for HER-2-overexpressed breast cancer.
doi:10.1155/2012/486568
PMCID: PMC3162976  PMID: 21876713
18.  Effect of Supplementation of Tanshinone IIA and Sodium Tanshinone IIA Sulfonate on the Anticancer Effect of Epirubicin: An In Vitro Study 
Tanshinone IIA (Tan IIA) and sodium tanshinone IIA sulfonate (STS) were found to have protective effects on cardiomyocyte against adriamycin-induced damage and may be used clinically. It is unclear whether the supplementation of STS or Tan IIA would affect the anticancer activity of anthracycline. To evaluate the effect of Tan IIA or STS on the anticancer of epirubicin, the cell viability, apoptosis, Akt expression, and uptake of epirubicin after supplementation of Tan IIA or STS in the epirubicin-treated BT-20 cells were measured and compared. Tan IIA inhibited BT-20 cell growth and induced apoptosis in a time- and dose-dependent manner. When Tan IIA was used with epirubicin, an increase of BT-20 cells apoptosis was accompanied by the decreasing phosphorylation of Akt. STS had no effect on the cell viability of BT-20 cells. However, when used with epirubicin, STS decreased the epirubicin-induced cytotoxicity and apoptosis in BT-20 cells. The antagonistic effect of STS on epirubicin-induced cytotoxicity in BT-20 cells occurred concomitantly with the reduced epirubicin uptake and the increased phosphorylation of Akt. STS decreased the uptake of epirubicin in BT-20 cells and blocked epirubicin-induced apoptosis through activation of Akt.
doi:10.1155/2011/841564
PMCID: PMC3118485  PMID: 21716682
19.  Chemoprevention of Nonmelanoma Skin Cancer With Celecoxib: A Randomized, Double-Blind, Placebo-Controlled Trial 
Background
Preclinical studies indicate that the enzyme cyclooxygenase 2 plays an important role in ultraviolet-induced skin cancers. We evaluated the efficacy and safety of celecoxib, a cyclooxygenase 2 inhibitor, as a chemopreventive agent for actinic keratoses, the premalignant precursor of nonmelanoma skin cancers, and for nonmelanoma skin cancers, including cutaneous squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs).
Methods
A double-blind placebo-controlled randomized trial involving 240 subjects aged 37–87 years with 10–40 actinic keratoses was conducted at eight US academic medical centers. Patients were randomly assigned to receive 200 mg of celecoxib or placebo administered orally twice daily for 9 months. Subjects were evaluated at 3, 6, 9 (ie, completion of treatment), and 11 months after randomization. The primary endpoint was the number of new actinic keratoses at the 9-month visit as a percentage of the number at the time of randomization. In an intent-to-treat analysis, the incidence of actinic keratoses was compared between the two groups using t tests. In exploratory analyses, we evaluated the number of nonmelanoma skin cancers combined and SCCs and BCCs separately per patient at 11 months after randomization using Poisson regression, after adjustment for patient characteristics and time on study. The numbers of adverse events in the two treatment arms were compared using χ2 or Fisher exact tests. All statistical tests were two-sided.
Results
There was no difference in the incidence of actinic keratoses between the two groups at 9 months after randomization. However, at 11 months after randomization, there were fewer nonmelanoma skin cancers in the celecoxib arm than in the placebo arm (mean cumulative tumor number per patient 0.14 vs 0.35; rate ratio [RR] = .43, 95% confidence interval [CI] = 0.24 to 0.75; P = .003). After adjusting for age, sex, Fitzpatrick skin type, history of actinic keratosis at randomization, nonmelanoma skin cancer history, and patient time on study, the number of nonmelanoma skin cancers was lower in the celecoxib arm than in the placebo arm (RR = 0.41, 95% CI = 0.23 to 0.72, P = .002) as were the numbers of BCCs (RR = 0.40, 95% CI = 0.18 to 0.93, P = .032) and SCCs (RR = 0.42, 95% CI = 0.19 to 0.93, P = .032). Serious and cardiovascular adverse events were similar in the two groups.
Conclusions
Celecoxib may be effective for prevention of SCCs and BCCs in individuals who have extensive actinic damage and are at high risk for development of nonmelanoma skin cancers.
doi:10.1093/jnci/djq442
PMCID: PMC3001966  PMID: 21115882
20.  Canaries in the coal mine: a cross-species analysis of the plurality of obesity epidemics 
A dramatic rise in obesity has occurred among humans within the last several decades. Little is known about whether similar increases in obesity have occurred in animals inhabiting human-influenced environments. We examined samples collectively consisting of over 20 000 animals from 24 populations (12 divided separately into males and females) of animals representing eight species living with or around humans in industrialized societies. In all populations, the estimated coefficient for the trend of body weight over time was positive (i.e. increasing). The probability of all trends being in the same direction by chance is 1.2 × 10−7. Surprisingly, we find that over the past several decades, average mid-life body weights have risen among primates and rodents living in research colonies, as well as among feral rodents and domestic dogs and cats. The consistency of these findings among animals living in varying environments, suggests the intriguing possibility that the aetiology of increasing body weight may involve several as-of-yet unidentified and/or poorly understood factors (e.g. viral pathogens, epigenetic factors). This finding may eventually enhance the discovery and fuller elucidation of other factors that have contributed to the recent rise in obesity rates.
doi:10.1098/rspb.2010.1890
PMCID: PMC3081766  PMID: 21106594
obesity; animals; epigenetic
21.  14-3-3τ Regulates Ubiquitin-Independent Proteasomal Degradation of p21, a Novel Mechanism of p21 Downregulation in Breast Cancer▿ †  
Molecular and Cellular Biology  2010;30(6):1508-1527.
14-3-3 proteins regulate many cellular functions, including proliferation. However, the detailed mechanisms by which they control the cell cycle remain to be fully elucidated. We report that one of the 14-3-3 isoforms, 14-3-3τ, is required for the G1/S transition through its role in ubiquitin-independent proteasomal degradation of p21. 14-3-3τ binds to p21, MDM2, and the C8 subunit of the 20S proteasome in G1 phase and facilitates proteasomal targeting of p21. This function of 14-3-3τ may be deregulated in cancer. The overexpression of 14-3-3τ is frequently found in primary human breast cancer and correlates with lower levels of p21 and shorter patient survival. Tenascin-C, an extracellular matrix protein involved in tumor initiation and progression and a known 14-3-3τ inducer, decreases p21 and abrogates adriamycin-induced G1/S arrest. It has been known that p21 is required for a proper tamoxifen response in breast cancer. We show that the overexpression of 14-3-3τ inhibits tamoxifen-induced p21 induction and growth arrest in MCF7 cells. Together, the findings of our studies strongly suggest a novel oncogenic role of 14-3-3τ by downregulating p21 in breast cancer. Therefore, 14-3-3τ may be a potential therapeutic target in breast cancer.
doi:10.1128/MCB.01335-09
PMCID: PMC2832502  PMID: 20086099
22.  Cytokine genetic polymorphisms and prostate cancer aggressiveness 
Carcinogenesis  2009;30(8):1358-1362.
Prostate cancer (PCa) is one of the most common cancers in the world. Inflammation has been described as a risk factor for PCa and depends on the production of cytokines in response to tissue damage or the presence of stimuli that induces cellular stress. Interindividual variation in cytokine production is partially controlled by single-nucleotide polymorphisms (SNPs) that have been associated with differential production of cytokines. We have recently showed that SNP–SNP interactions of cytokine genes are associated with PCa risk. However, little is known about the association of cytokine SNPs and PCa aggressiveness. In this study, we evaluated the association of 15 SNPs in five cytokine genes and aggressiveness of PCa in African- and Caucasian-American individuals. Caucasian Americans with the genotypes IL10−1082GG or IL1B+3954TT had 2.31-fold [95% confidence interval (CI) = 1.13–4.72] and 3.11 (95% CI = 1.20–8.06)-fold risk, respectively, of developing aggressive PCa, as compared with individuals without those genotypes. We did not find any associations in the African-American group. Using Multivariate Adaptive Regression Splines modeling for exploratory SNP–SNP interactions, our results showed that more aggressive PCa in Caucasians Americans is associated with the CT genotype at IL8−47 [odds ratios (OR) = 3.50; 95% CI = 1.13–10.88] or combined genotypes of IL1B−511CC and IL10−1082GG (OR = 3.38; 95% CI = 1.70–6.71). Unfortunately, the same analysis could not be performed in the African-Americans due to limited number of individuals. With limited sample size, the results from this study suggest that SNPs in cytokine genes may be associated with PCa aggressiveness. More extensive studies are warranted to validate our findings.
doi:10.1093/carcin/bgp124
PMCID: PMC2718072  PMID: 19474090
23.  Parametric Modeling of Localized Melanoma Prognosis and Outcome 
This investigation explored the most suitable parametric model for melanoma prognosis and compared it with the Cox model. Cox-Snell residuals and survival function plots were applied to assess the generalized gamma (GG) model was the best fit parametric model for the data. The GG model is a powerful alternative to the Cox model in prognostic modeling. The GG model offers an advantage of explicit and flexible individualized hazard functions over the Cox model, and provides a clinically useful risk assessment over time to aid clinicians in formulating patient treatment and follow-up plans and for clinical trial design and analysis.
doi:10.1080/10543400902964175
PMCID: PMC2831414  PMID: 20183437
Accelerated Failure Time Models; Melanoma Survival Data; Mortality; Generalized Gamma Distribution; Parametric Models; Cox Model
24.  The Therapeutic Implications of Timely Linkage and Early Retention in HIV Care 
AIDS patient care and STDs  2009;23(1):41-49.
Following HIV diagnosis, linkage to outpatient treatment, antiretroviral initiation, and longitudinal retention in care represent the foundation for successful treatment. While prior studies have evaluated these processes in isolation, a systematic evaluation of successive steps in the same cohort of patients has not yet been performed. To ensure optimal long-term outcomes, a better understanding of the interplay of these processes is needed. Therefore, a retrospective cohort study of patients initiating outpatient care at the University of Alabama at Birmingham 1917 HIV/AIDS Clinic between January 2000 and December 2005 was undertaken. Multivariable models determined factors associated with: late diagnosis/linkage to care (initial CD4 < 350 cells/mm3), timely antiretroviral initiation, and retention across the first two years of care. Delayed linkage was observed in two-thirds of the overall sample (n = 567) and was associated with older age (odds ratio [OR] 1.31 per 10 years; 95% confidence interval [CI] = 1.06-1.62) and African American race (OR = 2.45; 95% CI = 1.60-3.74). Attending all clinic visits (hazard ratio [HR] = 6.45; 95% CI = 4.47-9.31) and lower initial CD4 counts led to earlier antiretroviral initiation. Worse retention in the first 2 years was associated with younger age (OR = 0.68 per 10 years; 95% CI = 0.56-0.83), higher baseline CD4 count, and substance abuse (OR = 1.78; 95% CI = 1.16-2.73). Interventions to improve timely HIV diagnosis and linkage to care should focus on older patients and African Americans while efforts to improve retention should address younger patients, those with higher baseline CD4 counts, and substance abuse. Missed clinic visits represent an important obstacle to the timely initiation of antiretroviral therapy. These data inform development of interventions to improve linkage and retention in HIV care, an emerging area of growing importance.
doi:10.1089/apc.2008.0132
PMCID: PMC2733237  PMID: 19055408
25.  The Therapeutic Implications of Timely Linkage and Early Retention in HIV Care 
AIDS Patient Care and STDs  2009;23(1):41-49.
Following HIV diagnosis, linkage to outpatient treatment, antiretroviral initiation, and longitudinal retention in care represent the foundation for successful treatment. While prior studies have evaluated these processes in isolation, a systematic evaluation of successive steps in the same cohort of patients has not yet been performed. To ensure optimal long-term outcomes, a better understanding of the interplay of these processes is needed. Therefore, a retrospective cohort study of patients initiating outpatient care at the University of Alabama at Birmingham 1917 HIV/AIDS Clinic between January 2000 and December 2005 was undertaken. Multivariable models determined factors associated with: late diagnosis/linkage to care (initial CD4 < 350 cells/mm3), timely antiretroviral initiation, and retention across the first two years of care. Delayed linkage was observed in two-thirds of the overall sample (n = 567) and was associated with older age (odds ratio [OR] = 1.31 per 10 years; 95% confidence interval [CI] = 1.06–1.62) and African American race (OR = 2.45; 95% CI = 1.60–3.74). Attending all clinic visits (hazard ratio [HR] = 6.45; 95% CI = 4.47–9.31) and lower initial CD4 counts led to earlier antiretroviral initiation. Worse retention in the first 2 years was associated with younger age (OR = 0.68 per 10 years; 95% CI = 0.56–0.83), higher baseline CD4 count, and substance abuse (OR = 1.78; 95% CI = 1.16–2.73). Interventions to improve timely HIV diagnosis and linkage to care should focus on older patients and African Americans while efforts to improve retention should address younger patients, those with higher baseline CD4 counts, and substance abuse. Missed clinic visits represent an important obstacle to the timely initiation of antiretroviral therapy. These data inform development of interventions to improve linkage and retention in HIV care, an emerging area of growing importance.
doi:10.1089/apc.2008.0132
PMCID: PMC2733237  PMID: 19055408

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