Bertha Hidalgo

Short-cycle structured intermittent treatment of chronic HIV infection with highly active antiretroviral therapy: Effects on virologic, immunologic, and toxicity parameters

Although continuous highly active antiretroviral therapy (HAART) is effective for many HIV-infected patients, it can be toxic and prohibitive in cost. By decreasing the total amount of time patients receive medications, intermittent HAART could reduce toxicity and cost. Therefore, we initiated a pilot study in which 10 HIV-infected individuals receiving effective therapy that resulted in levels of HIV RNA <50 copies per ml of plasma and CD4+ T cell counts >300 cells per mm3 of whole blood received repeated cycles of 7 days on HAART followed by 7 days off of HAART. Patients maintained suppression of plasma viremia for 32–68 weeks. There was no significant increase in HIV proviral DNA or replication-competent HIV in peripheral CD4+ T cells or HIV RNA in peripheral blood or lymph node mononuclear cells. There was no significant change in CD4+ T cell counts, no significant increase in CD4+ or CD8+ T cells expressing activation markers or producing IFN-γ in response to HIV, no increase in CD4+ T cell proliferation to p24 antigen, and no evidence for the development of resistance to HAART medications. There was a significant decrease in serum cholesterol and triglyceride levels. Thus, in this proof-of-concept study, short-cycle intermittent HAART maintained suppression of plasma viremia as well as HIV replication in reservoir sites while preserving CD4+ T cell counts. In addition, there was a decrease in serum cholesterol and triglyceride levels. Intermittent therapy may be an important strategy to reduce cost and toxicity for HIV-infected individuals.

Epigenome-Wide Association Study of Fasting Measures of Glucose, Insulin, and HOMA-IR in the Genetics of Lipid Lowering Drugs and Diet Network Study

Known genetic susceptibility loci for type 2 diabetes (T2D) explain only a small proportion of heritable T2D risk. We hypothesize that DNA methylation patterns may contribute to variation in diabetes-related risk factors, and this epigenetic variation across the genome can contribute to the missing heritability in T2D and related metabolic traits. We conducted an epigenome-wide association study for fasting glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) among 837 nondiabetic participants in the Genetics of Lipid Lowering Drugs and Diet Network study, divided into discovery (N = 544) and replication (N = 293) stages. Cytosine guanine dinucleotide (CpG) methylation at ∼470,000 CpG sites was assayed in CD4+ T cells using the Illumina Infinium HumanMethylation 450 Beadchip. We fit a mixed model with the methylation status of each CpG as the dependent variable, adjusting for age, sex, study site, and T-cell purity as fixed-effects and family structure as a random-effect. A Bonferroni corrected P value of 1.1 × 10−7 was considered significant in the discovery stage. Significant associations were tested in the replication stage using identical models. Methylation of a CpG site in ABCG1 on chromosome 21 was significantly associated with insulin (P = 1.83 × 10−7) and HOMA-IR (P = 1.60 × 10−9). Another site in the same gene was significant for HOMA-IR and of borderline significance for insulin (P = 1.29 × 10−7 and P = 3.36 × 10−6, respectively). Associations with the top two signals replicated for insulin and HOMA-IR (P = 5.75 × 10−3 and P = 3.35 × 10−2, respectively). Our findings suggest that methylation of a CpG site within ABCG1 is associated with fasting insulin and merits further evaluation as a novel disease risk marker.

Pilot Study of the Effects of Intermittent Interleukin-2 on Human Immunodeficiency Virus (HIV)–Specific Immune Responses in Patients Treated during Recently Acquired HIV Infection

Highly active antiretroviral therapy (HAART) initiated during acute human immunodeficiency virus (HIV) infection may preserve HIV-specific CD4+ T cell responses that are thought to enhance HIV-specific CD8+ T cell function. The present pilot study was designed to determine whether preserved HIV-specific immune responses are augmented by the administration of the immunomodulatory agent interleukin (IL)-2. Nine persons recently (<6 months) infected with HIV were randomized to receive HAART alone or HAART plus 3 cycles of intermittent IL-2 during a 12-month period. Although HAART plus IL-2 significantly increased counts of total and naive CD4+ T cells, compared with HAART alone, there was no increase in CD4+ or CD8+ HIV-specific immune responses. In addition, adjuvant IL-2 therapy did not reduce the pool of HIV-infected resting CD4+ T cells. Thus, although intermittent IL-2 plus HAART quantitatively increased CD4+ T cells, this increase was not selective for HIV-specific CD4+ or CD8+ T cell responses in recently infected persons.

Evaluation of initial CD4+ T cell counts in individuals with newly diagnosed human immunodeficiency virus infection, by sex and race, in urban settings

The CD4+ T cell count is an important determinant of disease stage and prognosis in human immunodeficiency virus (HIV)-infected individuals. This study evaluated the CD4+ T cell counts in individuals at the time of diagnosis of HIV infection at 4 community clinics in large urban settings with relatively high frequencies of HIV infection. Of 2223 individuals, 57% and 36% had CD4+ T cell counts < 350 and < 200 cells/mm(3), respectively, at the time of diagnosis. There were no clear differences by sex or race. Enhanced educational efforts regarding the importance of HIV testing for at-risk individuals across sex and race strata in community settings may be important for early identification of individuals with HIV infection. This in turn could impact efforts to reduce transmission, and it could impact the prognosis for patients who receive antiretroviral therapy.

Epigenome-wide study identifies novel methylation loci associated with body mass index and waist circumference

To conduct an epigenome‐wide analysis of DNA methylation and obesity traits.

Development of a Theory-Based (PEN-3 and Health Belief Model), Culturally Relevant Intervention on Cervical Cancer Prevention Among Latina Immigrants Using Intervention Mapping

The development of efficacious theory-based, culturally relevant interventions to promote cervical cancer prevention among underserved populations is crucial to the elimination of cancer disparities. The purpose of this article is to describe the development of a theory-based, culturally relevant intervention focusing on primary (sexual risk reduction) and secondary (Pap smear) prevention of cervical cancer among Latina immigrants using intervention mapping (IM). The PEN-3 and Health Belief Model provided theoretical guidance for the intervention development and implementation. IM provides a logical five-step framework in intervention development: delineating proximal program objectives, selecting theory-based intervention methods and strategies, developing a program plan, planning for adoption in implementation, and creating evaluation plans and instruments. We first conducted an extensive literature review and qualitatively examined the sociocultural factors associated with primary and secondary prevention of cervical cancer. We then proceeded to quantitatively validate the qualitative findings, which led to development matrices linking the theoretical constructs with intervention objectives and strategies as well as evaluation. IM was a helpful tool in the development of a theory-based, culturally relevant intervention addressing primary and secondary prevention among Latina immigrants.

Genetic Characterization of Rebounding Human Immunodeficiency Virus Type 1 in Plasma during Multiple Interruptions of Highly Active Antiretroviral Therapy

ABSTRACT Various strategies of interrupting highly active antiretroviral therapy (HAART) are being investigated for the treatment of human immunodeficiency virus (HIV) infection. Interruptions of greater than 2 weeks frequently result in rebound of plasma HIV RNA. In order to discern changes in the viral population that might occur during cycles of treatment interruption, we evaluated the homology of HIV-1 envelope gene sequences over time in 12 patients who received four to seven cycles of 4 weeks off HAART followed by 8 weeks on HAART by using the heteroduplex tracking assay and novel statistical tools. HIV populations in 9 of 12 patients diverged from those found in the first cycle in at least one subsequent cycle. The substantial genetic changes noted in HIV env did not correlate with increased or decreased log changes in levels of plasma HIV RNA (P > 0.5). Thus, genetic changes in HIV env itself did not contribute in a systematic way to changes in levels of plasma viremia from cycle to cycle of treatment interruption. In addition, the data suggest that there may be multiple compartments contributing to the rebound of plasma viremia and to viral diversity from cycle to cycle of intermittent therapy.

Effect of Niclosamide on Basal-like Breast Cancers

Basal-like breast cancers (BLBC) are poorly differentiated and display aggressive clinical behavior. These tumors become resistant to cytotoxic agents, and tumor relapse has been attributed to the presence of cancer stem cells (CSC). One of the pathways involved in CSC regulation is the Wnt/β-catenin signaling pathway. LRP6, a Wnt ligand receptor, is one of the critical elements of this pathway and could potentially be an excellent therapeutic target. Niclosamide has been shown to inhibit the Wnt/β-catenin signaling pathway by causing degradation of LRP6. TRA-8, a monoclonal antibody specific to TRAIL death receptor 5, is cytotoxic to BLBC cell lines and their CSC-enriched populations. The goal of this study was to examine whether niclosamide is cytotoxic to BLBCs, specifically the CSC population, and if in combination with TRA-8 could produce increased cytotoxicity. Aldehyde dehydrogenase (ALDH) is a known marker of CSCs. By testing BLBC cells for ALDH expression by flow cytometry, we were able to isolate a nonadherent population of cells that have high ALDH expression. Niclosamide showed cytotoxicity against these nonadherent ALDH-expressing cells in addition to adherent cells from four BLBC cell lines: 2LMP, SUM159, HCC1187, and HCC1143. Niclosamide treatment produced reduced levels of LRP6 and β-catenin, which is a downstream Wnt/β-catenin signaling protein. The combination of TRA-8 and niclosamide produced additive cytotoxicity and a reduction in Wnt/β-catenin activity. Niclosamide in combination with TRA-8 suppressed growth of 2LMP orthotopic tumor xenografts. These results suggest that niclosamide or congeners of this agent may be useful for the treatment of BLBC. Mol Cancer Ther; 13(4); 800–11. ©2014 AACR.

Association of DNA Methylation at CPT1A Locus with Metabolic Syndrome in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study

In this study, we conducted an epigenome-wide association study of metabolic syndrome (MetS) among 846 participants of European descent in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN). DNA was isolated from CD4+ T cells and methylation at ~470,000 cytosine-phosphate-guanine dinucleotide (CpG) pairs was assayed using the Illumina Infinium HumanMethylation450 BeadChip. We modeled the percentage methylation at individual CpGs as a function of MetS using linear mixed models. A Bonferroni-corrected P-value of 1.1 x 10−7 was considered significant. Methylation at two CpG sites in CPT1A on chromosome 11 was significantly associated with MetS (P for cg00574958 = 2.6x10-14 and P for cg17058475 = 1.2x10-9). Significant associations were replicated in both European and African ancestry participants of the Bogalusa Heart Study. Our findings suggest that methylation in CPT1A is a promising epigenetic marker for MetS risk which could become useful as a treatment target in the future.

Dietary interventions and quality of life: a systematic review of the literature.

OBJECTIVE To systematically review the literature to examine whether there has been adequate assessment of the effects of dietary intervention on quality of life (QOL) independent of weight loss, assess which instruments are being used to measure nutrition-related QOL, identify gaps in the literature, and suggest future directions. DESIGN Systematic review guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement. RESULTS A total of 24 studies were eligible for inclusion. The Short Form-36 Health Survey was the most widely used instrument to assess QOL. Other disease-specific instruments were used. Several different dietary approaches (eg, low carbohydrate, low calorie, low fat, combinations) were recommended. Across studies, QOL generally improved after participating in behavioral weight loss interventions, but findings revealed a lack of evidence to definitively determine whether reported changes in QOL were a result of weight loss or independent of it. CONCLUSIONS AND IMPLICATIONS It is important to consider how making broad dietary recommendations for all individuals might affect overall QOL in both positive and negative directions when considering factors other than weight loss and health improvement. If dietary interventions are adversely affecting QOL in other domains (eg, social, economic) and this relationship is not being detected or reported by current research practices, barriers for successful and sustainable dietary changes may not be fully understood.