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1.  Challenges faced by healthcare providers offering infant feeding counseling to HIV-positive women in sub-Saharan Africa: A review of current research 
AIDS care  2014;27(1):17-24.
Exclusive breastfeeding (EBF) has been identified as the optimal nutrition and critical behavior in attaining human immunodeficiency virus (HIV)-free infant survival in resource-limited settings. Healthcare providers (HCPs) in clinic- and community-settings throughout sub-Saharan Africa (sSA) provide infant feeding counseling. However, rates of EBF at 6 months of age are suboptimal. Healthcare providers (HCPs) are uniquely positioned to educate HIV-positive mothers and provide support by addressing known barriers to EBF. However, limited evidence exists on the experiences faced by HCPs in providing counseling on infant feeding to HIV-positive women. Our objective is to describe experiences faced by HCPs when delivering infant feeding counseling in the context of HIV in program settings in sSA. We searched a range of electronic databases, including PubMed, CINAHL, and PsycINFO from January 1990 to February 2013, in addition to hand-searching, cross-reference searching and personal communications. The search was limited to publications in English. Empirical studies of HCP experiences providing infant feeding counseling in prevention of mother-to-child transmission of HIV (PMTCT) programs in sSA were selected. We identified 10 peer-reviewed articles reporting HCP challenges in infant feeding counseling that met inclusion criteria. Articles included qualitative, cross-sectional and mixed-method studies, and cumulatively reported 31 challenges faced by HCPs. Among the challenges identified, the most commonly reported were personal beliefs held by the HCPs toward infant feeding in the context of HIV, contradictory messages, staff workload, directive counseling styles, and a lack of practical strategies to offer mothers, often leading to improvised counseling approaches. Counseling strategies need to be developed that are relevant, meaningful and responsive to the needs of both HCPs and mothers.
PMCID: PMC4221439  PMID: 25208096
healthcare providers; systematic review; PMTCT; vertical transmission; exclusive breastfeeding
2.  Kaposi Sarcoma–Associated Herpesvirus (KSHV) Seroprevalence in Population-Based Samples of African Children: Evidence for At Least 2 Patterns of KSHV Transmission 
The Journal of infectious diseases  2009;200(3):430-438.
Kaposi sarcoma–associated herpesvirus (KSHV) infection is endemic among adult populations in Africa. A prevailing view is that childhood transmission is primarily responsible for the high seroprevalence of KSHV among adults that is observed throughout the continent. However, few studies have directly examined children, particularly in locations where KS is not commonly endemic.
Participants were children aged 1.5−8.9 years, including 427 children from a population-based sample in South Africa, 422 from a population-based sample in Uganda, and 567 from a clinic-based sample in Uganda. All serum specimens were tested by the same laboratory for KSHV antibodies with use of 2 enzyme immunoassays (against K8.1 and ORF65) and 1 immunofluorescence assay.
KSHV seroprevalence was 7.5%−9.0% among South African children and was not associated with age. In contrast, in the Ugandan population-based sample, KSHV seroprevalence increased from 10% among 2-year-old children to 30.6% among 8-year-old children (Ptrend < .001). In the Ugandan clinic-based sample, seroprevalence increased from 9.3% among 2-year-old children to 36.4% among 8-year-old children (Ptrend < .001).
Two distinct relationships between age and KSHV infection among children imply that KSHV transmission among children is not uniform throughout Africa and is therefore not always responsible for the high seroprevalence observed in adults. There are at least 2 patterns of KSHV transmission in Africa.
PMCID: PMC3975590  PMID: 19534596
3.  Use of Saliva as a Lubricant in Anal Sexual Practices Among Homosexual Men 
Compared with other sexually active adults, men who have sex with men (MSM) are more frequently infected with several pathogens including cytomegalovirus, hepatitis B virus, and Kaposi sarcoma-associated herpesvirus. Because one common element between these organisms is their presence in saliva, we evaluated saliva exposure among MSM in a heretofore relatively unrecognized route—via use of saliva as a lubricant in anal sex.
MSM in a San Francisco population–based cohort were interviewed regarding use of saliva by the insertive partner as a lubricant in various anal sexual practices.
Among 283 MSM, 87% used saliva as a lubricant in insertive or receptive penile–anal intercourse or fingering/fisting at some point during their lifetime; 31%–47% did so, depending upon the act, in the prior 6 months. Saliva use as a lubricant was more common among younger men and among HIV-infected men when with HIV-infected partners. Even among MSM following safe sex guidelines by avoiding unprotected penile–anal intercourse, 26% had anal exposure to saliva via use as a lubricant.
Among MSM, use of saliva as a lubricant is a common, but not ubiquitous, practice in anal sex. The findings provide the rationale for formal investigation of whether saliva use in this way contributes to transmission of saliva-borne pathogens in MSM.
PMCID: PMC3975591  PMID: 19131893
homosexual; saliva; lubricant; anal intercourse
4.  Constitutively-active androgen receptor variants function independently of the HSP90 chaperone but do not confer resistance to HSP90 inhibitors 
Oncotarget  2013;4(5):691-704.
The development of lethal, castration resistant prostate cancer is associated with adaptive changes to the androgen receptor (AR), including the emergence of mutant receptors and truncated, constitutively active AR variants. AR relies on the molecular chaperone HSP90 for its function in both normal and malignant prostate cells, but the requirement for HSP90 in environments with aberrant AR expression is largely unknown. Here, we investigated the efficacy of three HSP90 inhibitors, 17-AAG, HSP990 and AUY922, against clinically-relevant AR missense mutants and truncated variants. HSP90 inhibition effectively suppressed the signaling of wild-type AR and all AR missense mutants tested. By contrast, two truncated AR variants, AR-V7 and ARv567es, exhibited marked resistance to HSP90 inhibitors. Supporting this observation, nuclear localization of the truncated AR variants was not affected by HSP90 inhibition and AR variant:HSP90 complexes could not be detected in prostate cancer cells. Interestingly, HSP90 inhibition resulted in accumulation of AR-V7 and ARv567es in both cell lines and human tumor explants. Despite the apparent independence of AR variants from HSP90 and their treatment-associated induction, the growth of cell lines with endogenous or enforced expression of AR-V7 or ARv567es remained highly sensitive to AUY922. This study demonstrates that functional AR variant signaling does not confer resistance to HSP90 inhibition, yields insight into the interaction between AR and HSP90 and provides further impetus for the clinical application of HSP90 inhibitors in advanced prostate cancer.
PMCID: PMC3742830  PMID: 23674566
Androgen receptor; variant; HSP90; HSP90 inhibitor; prostate cancer
5.  Human Herpesvirus 8 Infection in Children and Adults in a Population-based Study in Rural Uganda 
The Journal of Infectious Diseases  2011;203(5):625-634.
(See the editorial commentary by Mbulaiteye an Goedert, on pages 575–7.)
Background. Human herpesvirus 8 (HHV-8) infection is endemic in sub-Saharan Africa. We examined sociodemographic, behavioral, and biological factors associated with HHV-8 infection in children and adults to determine HHV-8 seroprevalence and potential routes of transmission.
Methods. Participants were 1383 children and 1477 adults from a population-based sample in a rural community in Uganda. Serum samples were tested for HHV-8 antibodies with use of an enzyme immunoassay against K8.1.
Results. HHV-8 seroprevalence increased from 16% among children aged 1.5–2 years to 32% among children aged 10–13 years (P <.001) and from 37% among participants aged 14–19 years to 49% among adults aged ≥50 years (P <.05). HHV-8 seropositivity in children was independently associated with residing with a seropositive parent (P < .001) and residing with ≥1 other seropositive child aged <14 years (P < .001). History of sharing food and/or sauce plates was marginally associated with HHV-8 infection in children (P = .05). Among 1404 participants aged ≥15 years , there was no association between correlates of sexual behavior (eg, number of lifetime sex partners and HIV infection) and HHV-8 seropositivity (P > .10).
Conclusions. Our data suggest that HHV-8 is acquired primarily through horizontal transmission in childhood from intrafamilial contacts and that transmission continues into adulthood potentially through nonsexual routes.
PMCID: PMC3071279  PMID: 21273188
6.  Shamba Maisha: Pilot agricultural intervention for food security and HIV health outcomes in Kenya: design, methods, baseline results and process evaluation of a cluster-randomized controlled trial 
SpringerPlus  2015;4:122.
Despite advances in treatment of people living with HIV, morbidity and mortality remains unacceptably high in sub-Saharan Africa, largely due to parallel epidemics of poverty and food insecurity.
We conducted a pilot cluster randomized controlled trial (RCT) of a multisectoral agricultural and microfinance intervention (entitled Shamba Maisha) designed to improve food security, household wealth, HIV clinical outcomes and women’s empowerment. The intervention was carried out at two HIV clinics in Kenya, one randomized to the intervention arm and one to the control arm. HIV-infected patients >18 years, on antiretroviral therapy, with moderate/severe food insecurity and/or body mass index (BMI) <18.5, and access to land and surface water were eligible for enrollment. The intervention included: 1) a microfinance loan (~$150) to purchase the farming commodities, 2) a micro-irrigation pump, seeds, and fertilizer, and 3) trainings in sustainable agricultural practices and financial literacy. Enrollment of 140 participants took four months, and the screening-to-enrollment ratio was similar between arms. We followed participants for 12 months and conducted structured questionnaires. We also conducted a process evaluation with participants and stakeholders 3–5 months after study start and at study end.
Baseline results revealed that participants at the two sites were similar in age, gender and marital status. A greater proportion of participants at the intervention site had a low BMI in comparison to participants at the control site (18% vs. 7%, p = 0.054). While median CD4 count was similar between arms, a greater proportion of participants enrolled at the intervention arm had a detectable HIV viral load compared with control participants (49% vs. 28%, respectively, p < 0.010). Process evaluation findings suggested that Shamba Maisha had high acceptability in recruitment, delivered strong agricultural and financial training, and led to labor saving due to use of the water pump. Implementation challenges included participant concerns about repaying loans, agricultural challenges due to weather patterns, and a challenging partnership with the microfinance institution. We expect the results from this pilot study to provide useful data on the impacts of livelihood interventions and will help in the design of a definitive cluster RCT.
Trial registration
This trial is registered at, NCT01548599.
Electronic supplementary material
The online version of this article (doi:10.1186/s40064-015-0886-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4429425  PMID: 25992307
HIV; Food insecurity; Microfinance; Agriculture; Livelihoods; Intervention
7.  Double Disclosure Bind: Complexities of communicating an HIV diagnosis in the context of unintended pregnancy in Durban, South Africa 
AIDS and behavior  2014;18(0 1):10.1007/s10461-013-0521-1.
PMCID: PMC3823675  PMID: 23722975
PMTCT; HIV Disclosure; unintended pregnancy; South Africa
8.  Cross-cultural adaptation of instruments assessing breastfeeding determinants: a multi-step approach 
Cross-cultural adaptation is a necessary process to effectively use existing instruments in other cultural and language settings. The process of cross-culturally adapting, including translation, of existing instruments is considered a critical set to establishing a meaningful instrument for use in another setting. Using a multi-step approach is considered best practice in achieving cultural and semantic equivalence of the adapted version. We aimed to ensure the content validity of our instruments in the cultural context of KwaZulu-Natal, South Africa.
The Iowa Infant Feeding Attitudes Scale, Breastfeeding Self-Efficacy Scale-Short Form and additional items comprise our consolidated instrument, which was cross-culturally adapted utilizing a multi-step approach during August 2012. Cross-cultural adaptation was achieved through steps to maintain content validity and attain semantic equivalence in the target version. Specifically, Lynn’s recommendation to apply an item-level content validity index score was followed. The revised instrument was translated and back-translated. To ensure semantic equivalence, Brislin’s back-translation approach was utilized followed by the committee review to address any discrepancies that emerged from translation.
Our consolidated instrument was adapted to be culturally relevant and translated to yield more reliable and valid results for use in our larger research study to measure infant feeding determinants effectively in our target cultural context.
Undertaking rigorous steps to effectively ensure cross-cultural adaptation increases our confidence that the conclusions we make based on our self-report instrument(s) will be stronger. In this way, our aim to achieve strong cross-cultural adaptation of our consolidated instruments was achieved while also providing a clear framework for other researchers choosing to utilize existing instruments for work in other cultural, geographic and population settings.
PMCID: PMC4185181  PMID: 25285151
Breastfeeding; Cross-cultural adaptation; Translation; Scale development; Content validity; Breastfeeding scales
9.  Dual roles of PARP-1 promote cancer growth and progression 
Cancer discovery  2012;2(12):1134-1149.
Poly(ADP-ribose) polymerase-1 (PARP-1) is an abundant nuclear enzyme that modifies substrates by poly(ADP-ribose)-ylation. PARP-1 has well-described functions in DNA damage repair, and also functions as a context-specific regulator of transcription factors. Using multiple models, data demonstrate that PARP-1 elicits pro-tumorigenic effects in androgen receptor (AR)-positive prostate cancer (PCa) cells, both in the presence and absence of genotoxic insult. Mechanistically, PARP-1 is recruited to sites of AR function, therein promoting AR occupancy and AR function. It was further confirmed in genetically-defined systems that PARP-1 supports AR transcriptional function, and that in models of advanced PCa, PARP-1 enzymatic activity is enhanced, further linking PARP-1 to AR activity and disease progression. In vivo analyses demonstrate that PARP-1 activity is required for AR function in xenograft tumors, as well as tumor cell growth in vivo and generation and maintenance of castration-resistance. Finally, in a novel explant system of primary human tumors, targeting PARP-1 potently suppresses tumor cell proliferation. Collectively, these studies identify novel functions of PARP-1 in promoting disease progression, and ultimately suggest that the dual functions of PARP-1 can be targeted in human PCa to suppress tumor growth and progression to castration-resistance.
PMCID: PMC3519969  PMID: 22993403
prostate cancer; androgen receptor; PARP-1; PARP inhibitor; DNA damage
10.  HIV-Infected Adolescent Mothers and Their Infants: Low Coverage of HIV Services and High Risk of HIV Transmission in KwaZulu-Natal, South Africa 
PLoS ONE  2013;8(9):e74568.
Rates of pregnancy and HIV infection are high among South African adolescents, yet little is known about rates of mother-to-child transmission of HIV (MTCT) in this group. We report a comparison of the characteristics of adolescent mothers and adult mothers, including HIV prevalence and MTCT rates.
We examined patterns of health service utilization during the antenatal and early postnatal period, HIV prevalence and MTCT amongst adolescent (<20-years-old) and adult (20 to 39-years-old) mothers with infants aged ≤16 weeks attending immunization clinics in six districts of KwaZulu-Natal between May 2008 and April 2009.
Interviews were conducted with 19,093 mothers aged between 12 and 39 years whose infants were aged ≤16 weeks. Most mothers had attended antenatal care four or more times during their last pregnancy (80.3%), and reported having an HIV test (98.2%). A greater proportion of HIV-infected adult mothers, compared to adolescent mothers, reported themselves as HIV-positive (41.2% vs. 15.9%, p<0.0001), reported having a CD4 count taken during their pregnancy (81.0% vs. 66.5%, p<0.0001), and having received the CD4 count result (84.4% vs. 75.7%, p<0.0001). Significantly fewer adolescent mothers received the recommended PMTCT regimen. HIV antibody was detected in 40.4% of 7,800 infants aged 4–8 weeks tested for HIV, indicating HIV exposure. This was higher among infants of adult mothers (47.4%) compared to adolescent mothers (17.9%, p<0.0001). The MTCT rate at 4–8 weeks of age was significantly higher amongst infants of adolescent mothers compared to adult mothers (35/325 [10.8%] vs. 185/2,800 [6.1%], OR 1.7, 95% CI 1.2–2.4).
Despite high levels of antenatal clinic attendance among pregnant adolescents in KwaZulu-Natal, the MTCT risk is higher among infants of HIV-infected adolescent mothers compared to adult mothers. Access to adolescent-friendly family planning and PMTCT services should be prioritised for this vulnerable group.
PMCID: PMC3779214  PMID: 24073215
11.  Therapeutic response to CDK4/6 inhibition in breast cancer defined by ex vivo analyses of human tumors 
Cell Cycle  2012;11(14):2756-2761.
To model the heterogeneity of breast cancer as observed in the clinic, we employed an ex vivo model of breast tumor tissue. This methodology maintained the histological integrity of the tumor tissue in unselected breast cancers, and importantly, the explants retained key molecular markers that are currently used to guide breast cancer treatment (e.g., ER and Her2 status). The primary tumors displayed the expected wide range of positivity for the proliferation marker Ki67, and a strong positive correlation between the Ki67 indices of the primary and corresponding explanted tumor tissues was observed. Collectively, these findings indicate that multiple facets of tumor pathophysiology are recapitulated in this ex vivo model. To interrogate the potential of this preclinical model to inform determinants of therapeutic response, we investigated the cytostatic response to the CDK4/6 inhibitor, PD-0332991. This inhibitor was highly effective at suppressing proliferation in approximately 85% of cases, irrespective of ER or HER2 status. However, 15% of cases were completely resistant to PD-0332991. Marker analyses in both the primary tumor tissue and the corresponding explant revealed that cases resistant to CDK4/6 inhibition lacked the RB-tumor suppressor. These studies provide important insights into the spectrum of breast tumors that could be treated with CDK4/6 inhibitors, and defines functional determinants of response analogous to those identified through neoadjuvant studies.
PMCID: PMC3409015  PMID: 22767154
ER; PD0332991; breast cancer; cell cycle; ex vivo
12.  Ski-interacting protein (SKIP) interacts with androgen receptor in the nucleus and modulates androgen-dependent transcription 
BMC Biochemistry  2013;14:10.
The androgen receptor (AR) is a member of the nuclear receptor (NR) superfamily of ligand-inducible DNA transcription factors, and is the major mediator of male sexual development, prostate growth and the pathogenesis of prostate cancer. Cell and gene specific regulation by the AR is determined by availability of and interaction with sets of key accessory cofactors. Ski-interacting protein (SKIP; SNW1, NCOA62) is a cofactor shown to interact with several NRs and a diverse range of other transcription factors. Interestingly, SKIP as part of the spliceosome is thought to link mRNA splicing with transcription. SKIP has not been previously shown to interact with the AR.
The aim of this study was to investigate whether SKIP interacts with the AR and modulates AR-dependent transcription. Here, we show by co-immunoprecipitation experiments that SKIP is in a complex with the AR. Moreover, SKIP increased 5α-dihydrotestosterone (DHT) induced N-terminal/C-terminal AR interaction from 12-fold to almost 300-fold in a two-hybrid assay, and enhanced AR ligand-independent AF-1 transactivation. SKIP augmented ligand- and AR-dependent transactivation in PC3 prostate cancer cells. Live-cell imaging revealed a fast (half-time=129 s) translocation of AR from the cytoplasm to the nucleus upon DHT-stimulation. Förster resonance energy transfer (FRET) experiments suggest a direct AR-SKIP interaction in the nucleus upon translocation.
Our results suggest that SKIP interacts with AR in the nucleus and enhances AR-dependent transactivation and N/C-interaction supporting a role for SKIP as an AR co-factor.
PMCID: PMC3668167  PMID: 23566155
13.  A retrospective study of Human Immunodeficiency Virus transmission, mortality and loss to follow-up among infants in the first 18 months of life in a prevention of mother-to-child transmission programme in an urban hospital in KwaZulu-Natal, South Africa 
BMC Pediatrics  2012;12:146.
Follow up of Human Immunodeficiency Virus (HIV)-exposed infants is an important component of Prevention of Mother-to-Child Transmission (PMTCT) programmes in order to ascertain infant outcomes post delivery. We determined HIV transmission, mortality and loss to follow-up (LTFU) of HIV-exposed infants attending a postnatal clinic in an urban hospital in Durban, South Africa.
We conducted a retrospective cohort study of infants born to women in the PMTCT programme at McCord Hospital, where mothers paid a fee for service. Data were abstracted from patient records for live-born infants delivered between 1 May 2008 and 31 May 2009. The infants’ LTFU status and age was based on the date of the last visit. HIV transmission was calculated as a proportion of infants followed and tested at six weeks. Mortality rates were analyzed using Kaplan-Meier (K-M), with censoring on 15 January 2010, LTFU or death.
Of 260 infants, 155 (59.6%) remained in care at McCord beyond 28 weeks: one died at < 28 days, three died between one to six months; 34 were LTFU within seven days, 60 were LTFU by six months. K-M mortality rate: 1.7% at six months (95% confidence interval (CI): 0.6% to 4.3%). Of 220 (83%) infants tested for HIV at six weeks, six (2.7%, 95% CI: 1.1% to 5.8%) were HIV-infected. In Cox regression analysis, late antenatal attendance (≥ 28 weeks gestation) relative to attending in the first trimester was a predictor for infant LTFU (adjusted hazards ratio = 2.3; 95% CI: 1.0 to 5.1; p = 0.044).
This urban PMTCT programme achieved low transmission rates at six weeks, but LTFU in the first six months limited our ability to examine HIV transmission up to 18 months and determinants of mortality. The LTFU of infants born to women who attended antenatal care at 28 weeks gestation or later emphasizes the need to identify late antenatal attendees for follow up care to educate and support them regarding the importance of follow up care for themselves and their infants.
PMCID: PMC3468389  PMID: 22963527
HIV-exposed infants; LTFU; Prevention-of-Mother-to-Child Transmission; Postnatal clinic
14.  Corepressor effect on androgen receptor activity varies with the length of the CAG encoded polyglutamine repeat and is dependent on receptor/corepressor ratio in prostate cancer cells 
The response of prostate cells to androgens reflects a combination of androgen receptor (AR) transactivation and transrepression, but how these two processes differ mechanistically and influence prostate cancer risk and disease outcome remain elusive. Given recent interest in targeting AR transrepressive processes, a better understanding of AR/corepressor interaction and responses is warranted. Here, we used transactivation and interaction assays with wild-type and mutant ARs, and deletion AR fragments, to dissect the relationship between AR and the corepressor, silencing mediator for retinoic acid and thyroid hormone receptors (SMRT). We additionally tested how these processes are influenced by AR agonist and antagonist ligands, as well as by variation in the polyglutamine tract in the AR amino terminal domain (NTD), which is encoded by a polymorphic CAG repeat in the gene. SMRT was recruited to the AR ligand binding domain by agonist ligand, and as determined by the effect of strategic mutations in activation function 2 (AF-2), requires a precise conformation of that domain. A distinct region of SMRT also mediated interaction with the AR-NTD via the transactivation unit 5 (TAU5; residues 315–538) region. The degree to which SMRT was able to repress AR increased from 17% to 56% as the AR polyglutamine repeat length was increased from 9 to 42 residues, but critically this effect could be abolished by increasing the SMRT:AR molar ratio. These data suggest that the the extent to which the CAG encoded polyglutamine repeat influences AR activity represents a balance between corepressor and coactivator occupancy of the same ligand-dependent and independent AR interaction surfaces. Changes in the homeostatic relationship of AR to these molecules, including SMRT, may explain the variable penetrance of the CAG repeat and the loss of AR signalling flexibility in prostate cancer progression.
PMCID: PMC3314496  PMID: 21664238
androgen receptor; polyglutamine; corepressor; SMRT; NCoR; prostate cancer risk; N/C interaction
15.  Substantial Regional Differences in Human Herpesvirus 8 Seroprevalence in Sub-Saharan Africa: Insights on the Origin of the “KS Belt” 
Equatorial Africa has among the highest incidences of Kaposi’s sarcoma (KS) in the world, thus earning the name “KS Belt.” This was the case even prior to the HIV . To date, there is no clear evidence that HHV-8 seroprevalence is higher in this region, but interpretation of the available literature is tempered by differences in serologic assays used across studies. We examined representatively sampled ambulatory adults in Uganda, which is in the “KS Belt”, and in Zimbabwe and South Africa which are outside the Belt, for HHV-8 antibodies. All serologic assays were uniformly performed in the same reference laboratory by the same personnel. In the base-case serologic algorithm, seropositivity was defined by reactivity in an immunofluorescence assay or in two enzyme immunoassays. A total of 2375 participants were examined. In Uganda, HHV-8 seroprevalence was high early in adulthood (35.5% by age 21) without significant change thereafter. In contrast, HHV-8 seroprevalence early in adulthood was lower in Zimbabwe and South Africa (13.7% and 10.8%, respectively), but increased with age. After age adjustment, Ugandans had 3.24-fold greater odds of being HHV-8-infected than South Africans (p<0.001) and 2.22-fold greater odds than Zimbabweans (p<0.001). Inferences were unchanged using all other serologic algorithms evaluated. In conclusion, HHV-8 infection is substantially more common in Uganda than in Zimbabwe and South Africa. These findings help explain the high KS incidence in the “KS Belt” and underscore the importance of a uniform approach to HHV-8 antibody testing.
PMCID: PMC2895015  PMID: 20143397
16.  GSTP1 DNA Methylation and Expression Status Is Indicative of 5-aza-2′-Deoxycytidine Efficacy in Human Prostate Cancer Cells 
PLoS ONE  2011;6(9):e25634.
DNA methylation plays an important role in carcinogenesis and the reversibility of this epigenetic modification makes it a potential therapeutic target. To date, DNA methyltransferase inhibitors (DNMTi) have not demonstrated clinical efficacy in prostate cancer, with one of the major obstacles being the inability to monitor drug activity during the trial. Given the high frequency and specificity of GSTP1 DNA methylation in prostate cancer, we investigated whether GSTP1 is a useful marker of DNMTi treatment efficacy. LNCaP prostate cancer cells were treated with 5-aza-2′-deoxycytidine (5-aza-CdR) either with a single high dose (5–20 µM), every alternate day (0.1–10 µM) or daily (0.005–2.5 µM). A daily treatment regimen with 5-aza-CdR was optimal, with significant suppression of cell proliferation achieved with doses of 0.05 µM or greater (p<0.0001) and induction of cell death from 0.5 µM (p<0.0001). In contrast, treatment with a single high dose of 20 µM 5-aza-CdR inhibited cell proliferation but was not able to induce cell death. Demethylation of GSTP1 was observed with doses of 5-aza-CdR that induced significant suppression of cell proliferation (≥0.05 µM). Re-expression of the GSTP1 protein was observed only at doses of 5-aza-CdR (≥0.5 µM) associated with induction of cell death. Treatment of LNCaP cells with a more stable DNMTi, Zebularine required at least a 100-fold higher dose (≥50 µM) to inhibit proliferation and was less potent in inducing cell death, which corresponded to a lack of GSTP1 protein re-expression. We have shown that GSTP1 DNA methylation and protein expression status is correlated with DNMTi treatment response in prostate cancer cells. Since GSTP1 is methylated in nearly all prostate cancers, our results warrant its testing as a marker of epigenetic therapy response in future clinical trials. We conclude that the DNA methylation and protein expression status of GSTP1 are good indicators of DNMTi efficacy.
PMCID: PMC3182253  PMID: 21980513
17.  Uncoupling of Hormone-dependence from chaperone-dependence in the L701H mutation of the androgen receptor 
The mechanisms underlying androgen receptor (AR)-mediated progression of prostate cancer following androgen ablation have yet to be fully determined. On this basis we screened naturally occurring mutants of human AR for hormone independent activity using a yeast model system. An initial screen of 43 different mutants revealed that ARs having a Leu701His mutation (ARL701H) exhibited hormone-independent activation of a lacZ reporter gene. The ARL701H mutant bound dihydrotestosterone to a similar extent as did wild type AR, although its ability to be induced by hormone for transactivation was reduced substantially. Subsequent studies focused on the dependence of ARL701H on molecular chaperones for folding to the active state. We found that ARL701H was highly dependent on Hsp90 for its hormone independent activation, suggesting that this chaperone functions in ARL701H folding. However, the mutant did not respond specifically to increased levels of FKBP52, suggesting that this chaperone functions at the hormone-dependent activation stage in the folding process. Further studies of ARL701H in PC3 cells suggested that this mutant is prohibited from hormone-independent transactivation in mammalian cells. However, basal expression of a reporter gene by ARL701H was not impaired by the presence of 17-allylamino-17-demethoxygeldanamycin as was wild type AR, suggesting differential interactions of these receptors with molecular chaperones in animal cells.
PMCID: PMC1904484  PMID: 17336451
18.  Food Insufficiency Is Associated with High-Risk Sexual Behavior among Women in Botswana and Swaziland 
PLoS Medicine  2007;4(10):e260.
Both food insufficiency and HIV infection are major public health problems in sub-Saharan Africa, yet the impact of food insufficiency on HIV risk behavior has not been systematically investigated. We tested the hypothesis that food insufficiency is associated with HIV transmission behavior.
Methods and Findings
We studied the association between food insufficiency (not having enough food to eat over the previous 12 months) and inconsistent condom use, sex exchange, and other measures of risky sex in a cross-sectional population-based study of 1,255 adults in Botswana and 796 adults in Swaziland using a stratified two-stage probability design. Associations were examined using multivariable logistic regression analyses, clustered by country and stratified by gender. Food insufficiency was reported by 32% of women and 22% of men over the previous 12 months. Among 1,050 women in both countries, after controlling for respondent characteristics including income and education, HIV knowledge, and alcohol use, food insufficiency was associated with inconsistent condom use with a nonprimary partner (adjusted odds ratio [AOR] 1.73, 95% confidence interval [CI] 1.27–2.36), sex exchange (AOR 1.84, 95% CI 1.74–1.93), intergenerational sexual relationships (AOR 1.46, 95% CI 1.03–2.08), and lack of control in sexual relationships (AOR 1.68, 95% CI 1.24–2.28). Associations between food insufficiency and risky sex were much attenuated among men.
Food insufficiency is an important risk factor for increased sexual risk-taking among women in Botswana and Swaziland. Targeted food assistance and income generation programs in conjunction with efforts to enhance women's legal and social rights may play an important role in decreasing HIV transmission risk for women.
In a cross-sectional study, Sheri Weiser and colleagues found that food insufficiency was an important risk factor for increased sexual risk-taking in women in Botswana and Swaziland.
Editors' Summary
For people in sub-Saharan Africa, insufficient food for their daily needs and infection with the human immunodeficiency virus (HIV; the cause of acquired immunodeficiency syndrome or AIDS) are inextricably linked and major causes of illness and death. By reducing the number of healthy adults in the region, HIV/AIDS has decreased food production so fewer people have secure access to sufficient food for a healthy life—many are subject to “food insecurity.” Because good nutrition is essential for a strong immune system, food insecurity increases the likelihood that people exposed to HIV become infected with the virus and reduces their ability to remain healthy after infection. Consequently, more people succumb to HIV/AIDS and food insecurity increases. To break this vicious cycle, UNAIDS (the Joint United Nations Programme on HIV/AIDS) and other international bodies have suggested a move towards integrated food security programs and HIV/AIDS prevention and treatment programs wherever possible.
Why Was This Study Done?
Integrated food and HIV/AIDS programs might also be beneficial for another reason. HIV is usually spread through unprotected sex with an infected partner and it is thought that a lack of food increases sexual risk taking, particularly among poor women. These women have little control over food supplies but are expected to feed their children and other members of the household (such as elders). To do this, they may sell sex or become sexually involved with men of a different generation, both of which put them at risk of HIV. In addition, they are rarely able to demand that their partners use condoms or to control when they have sex. In this study, the researchers have examined how food insufficiency affects sexual risk taking among men and women in Swaziland and Botswana. These two countries have the highest HIV infection rates in the world—one in three adults in Swaziland and one in four in Botswana are infected—and in both countries many people are extremely poor.
What Did the Researchers Do and Find?
The researchers interviewed more than 2,000 randomly selected adults from Botswana and Swaziland using a standard questionnaire. This included general questions about the participants (for example, age and marital status) and questions about food insufficiency (defined as not having had enough food to eat over the previous 12 months) and risky sexual behaviors—for example, sex exchange (selling or paying for sex) and inconsistent condom use—over the same period. Nearly one in three women and one in four men reported food insufficiency. After allowing for variables such as education and income, women in both countries who reported food insufficiency were nearly twice as likely to have used condoms inconsistently with a non-regular partner or to have sold sex as women who had had sufficient food. They were also more likely to have had intergenerational sexual relationships and to report a lack of control in sexual relationships. Among men, food insufficiency was weakly associated with inconsistent condom use but not with other risky sexual behaviors.
What Do These Findings Mean?
Food insufficiency is associated with multiple (often interdependent) risky sexual practices among women in Botswana and Swaziland. These results may not hold for other countries and may be limited by the definition of food insufficiency used in the study and by participants failing to remember or report all instances of risky behavior or food insufficiency that occurred during the previous year. Nevertheless, the findings strongly suggest that protecting and promoting access to food may decrease vulnerability of women in sub-Saharan Africa to HIV infection. Improved food security might be achieved through targeted food assistance and by supporting women's subsistence farming and other means of food production. Such programs would also need to enhance women's legal and social rights so that they have more control over food supplies as well as their sexual lives.
Additional Information.
Please access these Web sites via the online version of this summary at
The Food and Agriculture Organization of the United Nations Special Programme for Food Security (in several languages)
HIV InSite, comprehensive and up-to-date information on all aspects of HIV/AIDS from the University of California San Francisco
UNAIDS (Joint United Nations Programme on HIV/AIDS) fact sheet on nutrition, food security, and HIV/AIDS
HIV and AIDS in Swaziland and Botswana, information provided by Avert, an international AIDS charity
The IMAGE Study, an example of a research initiative that is investigating the potential role of poverty alleviation and women's empowerment in reducing HIV incidence in South Africa
PMCID: PMC2039764  PMID: 17958460

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