Cincinnati Veteran Affairs Medical Center

Cincinnati, OH, United States

Cincinnati Veteran Affairs Medical Center

Cincinnati, OH, United States

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Ho S.-M.,Center for Environmental Genetics | Ho S.-M.,University of Cincinnati | Ho S.-M.,Cincinnati Veteran Affairs Medical Center | Leung Y.-K.,Center for Environmental Genetics | And 2 more authors.
Molecular and Cellular Endocrinology | Year: 2013

Estrogen receptor β (ERβ) and its isoforms have different putative functions and expression patterns in prostate cancer. Current studies on 5'-most exons, 0K and 0N, show that their respective promoters are actively involved in transcription. These data, however, do not explain why ERβ isoforms are differentially expressed in normal and cancerous tissues, since 0K and 0N transcripts are detectable in clinical specimens. Various combinations of 5' untranslated exons, termed exon 0Xs, associate with promoter 0K only and exon 0Xs accommodate upstream open reading frames (uORFs) reducing protein expression. Moreover, ERβ1, 2, and 5 are transcriptionally linked to promoter 0K; exon 0Xs are spliced only into ERβ2 and ERβ5 transcripts, suggesting that their expressions are regulated post-transcriptionally by exon 0Xs. This study reveals that expression of ERβ1 is regulated primarily at the transcriptional level, whereas that of ERβ2 and ERβ5 is controlled by the interplay between transcriptional and post-transcriptional regulation. © 2013 Elsevier Ireland Ltd.


Howard T.D.,Center for Genomics and Personalized Medicine Research | Ho S.-M.,University of Cincinnati | Ho S.-M.,Cincinnati Veteran Affairs Medical Center | Chen J.,University of Cincinnati | And 4 more authors.
PLoS ONE | Year: 2011

Nutritional interventions are important alternatives for reducing the prevalence of many chronic diseases. Soy is a good source of protein that contains isoflavones, including genistein and daidzein, and may alter the risk of obesity, Type 2 diabetes, osteoporosis, cardiovascular disease, and reproductive cancers. We have shown previously in nonhuman primates that soy protein containing isoflavones leads to improved body weight, insulin sensitivity, lipid profiles, and atherosclerosis compared to protein without soy isoflavones (casein), and does not increase the risk of cancer. Since genistein has been shown to alter DNA methylation, we compared the methylation profiles of cynomolgus monkeys, from multiple tissues, eating two high-fat, typical American diets (TAD) with similar macronutrient contents, with or without soy protein. DNA methylation status was successfully determined for 80.6% of the probes in at least one tissue using Illumina's HumanMethylation27 BeadChip. Overall methylation increased in liver and muscle tissue when monkeys switched from the TAD-soy to the TAD-casein diets. Genes involved in epigenetic processes, specifically homeobox genes (HOXA5, HOXA11, and HOXB1), and ABCG5 were among those that changed between diets. These data support the use of the HumanMethylation27 BeadChip in cynomolgus monkeys and identify epigenetic changes associated with dietary interventions with soy protein that may potentially affect the etiology of complex diseases. © 2011 Howard et al.


Cholerton B.A.,Geriatric Research | Cholerton B.A.,University of Washington | Zabetian C.P.,Geriatric Research | Zabetian C.P.,Parkinsons Disease Research | And 23 more authors.
Movement Disorders | Year: 2014

Mild cognitive impairment in Parkinson's disease (PD-MCI) is common and increases the risk for dementia. Establishing distinct PD-MCI cognitive subtypes could be valuable for eventually predicting those most likely to convert to dementia. However, the study of PD-MCI subtypes has not yielded consistent results among cohorts. To determine whether there are distinct cognitive subtypes among participants diagnosed with PD-MCI in the Pacific Northwest Udall Center Clinical Consortium, we cognitively subtyped 95 patients with PD-MCI, using the Movement Disorders Society Task Force diagnostic guidelines. Psychometric test scores were then subjected to principle components factor analysis to determine whether similar cognitive subgroups could be identified using statistical methodology. Multiple-domain PD-MCI was diagnosed in 95% of the sample, and a range of cognitive impairments were noted. Factor analysis yielded seven factors and demonstrated overlap of phonemic verbal fluency on two factors, as well as the loading of verbal fluency on the same factor as a visuospatial measure; however, these factors did not partition the sample into distinct cognitive subtypes. Separation of cognitive subtypes based on the current PD-MCI criteria, or via statistical methods, may not provide sufficient information to describe distinct PD groups. Future efforts to validate the PD-MCI criteria and identify combinations of genetic or other risk factors for cognitive impairment are warranted. © 2014 International Parkinson and Movement Disorder Society.


Brumm S.,Cincinnati Veteran Affairs Medical Center | Theisen K.,Xavier University | Falciglia M.,Cincinnati Veteran Affairs Medical Center | Falciglia M.,University of Cincinnati
Diabetes Educator | Year: 2016

Purpose: The purpose of the study was to evaluate a diabetes transition care program in a population of veterans with diabetes by calculating 30-day readmission rates and assessing glycemic control. Methods: Hospitalized patients with poorly controlled diabetes were identified to participate in the diabetes transition care program. The program included follow-up through a postdischarge telephone call by the diabetes educator, with an opportunity for a face-to-face clinic visit. A retrospective before-and-after study design was used. Analysis included calculating the readmission rate and the pre- and postintervention A1C rates to evaluate the intervention. Results: Of the 40 participants, 100% completed the intervention. All 40 participants received a postdischarge telephone call as follow-up, with 20% presenting for a face-to-face visit. The 30-day readmission rate for the cohort was 10%, in comparison to 14.3% for patients who did not receive the intervention but were otherwise comparable. For those who had repeat A1C measurements conducted 2 to 8 months after time of enrollment in the program (n = 33), average A1C declined −2.2%, from 11.3% (100 mmol/mol) to 9.1% (76 mmol/mol). Conclusions: Diabetes-specific transition of care for those with complex psychiatric, medical, and social needs was feasible, with good outcomes in hospital readmission rates and glycemic control, when executed by an adult nurse practitioner who was the inpatient diabetes educator. © 2016, © 2016 The Author(s).


Lam H.-M.,University of Cincinnati | Suresh Babu C.V.,University of Cincinnati | Wang J.,University of Cincinnati | Yuan Y.,University of Cincinnati | And 4 more authors.
Molecular and Cellular Endocrinology | Year: 2012

Multiple phosphorylation sites on the human estrogen receptor (hER)α were identified and shown to influence mammary carcinogenesis. In contrast, functional phosphorylation sites of hERβ have yet to be experimentally identified and validated. Here, using mass spectrometry, we uncovered three serines (S75, S87, and S105) in the N-terminus of hERβ as targets of ERK1/2 and p38 kinases. We raised a specific antibody against phosphorylated S105 (pS105) and demonstrated that this site was endogenously phosphorylated in MDA-MB-231 and BT-474 cells. A phospho-mimetic mutant generated from hERβ1 was found to exhibit higher transactivation activity than hERβ1. Ectopic expression of this mutant inhibited cell migration and invasion, but did not affect cell growth and cell-cycle progression in these cell models. In breast cancer specimens, pS105-hERβ immunoreactivity was detected with a higher prevalence and intensity than that of hERβ1. These results underscore the functional importance of the first experimentally identified hERβ-phosphorylation site in breast cancer. © 2012 Elsevier Ireland Ltd.


Zafar M.A.,University of Cincinnati | Zafar M.A.,Cincinnati Veteran Affairs Medical Center | Droege C.,University of Cincinnati | Foertsch M.,University of Cincinnati | And 2 more authors.
Expert Opinion on Investigational Drugs | Year: 2014

Introduction: For the last two decades, long-acting β agonists (LABAs) have been a cornerstone in the management of chronic obstructive pulmonary disease (COPD). They relax airway smooth muscle and augment expiratory airflow, which reduces hyperinflation and improves dyspnea, functional capacity and quality of life. In recent years, Indacaterol, a LABA with an ultra-long duration of action (ultra-LABA), which only requires once-daily dosing, was approved by the FDA. The clinical efficacy of indacaterol is comparable, and, in some aspects better, than the currently available LABAs. Areas covered: This article reviews the pharmacological properties, clinical efficacy, safety and potential role of the ultra-LABAs in COPD management. Expert opinion: Ultra-LABAs are effective bronchodilators with a prolonged duration of action. By decreasing dosing frequency, ultra-LABAs potentially may improve respiratory medication adherence, which is associated with better survival and less healthcare utilization. In addition to their salubrious benefits, β agonists may produce untoward effects. Increased mortality and hospitalizations among patients with left ventricular heart failure, who were treated with β agonists, has caused concern about their use in patients with COPD and heart disease. Further experience and testing will determine the optimal role of ultra-LABAs in the management of COPD. © Informa UK, Ltd.


Tang W.-Y.,University of Cincinnati | Levin L.,University of Cincinnati | Talaska G.,University of Cincinnati | Cheung Y.Y.,University of Cincinnati | And 6 more authors.
Environmental Health Perspectives | Year: 2012

Background: Maternal factors are implicated in the onset of childhood asthma. Differentiation of naïve CD4+ T lymphocytes into pro-allergic T-helper 2 cells induces interleukin (IL)4 expression and inhibits interferon (IFN)γ expression accompanied by concordant methylation changes in the promoters of these genes. However, it has yet to be established whether maternal exposure to polycyclic aromatic hydrocarbons (PAHs) can alter these gene promoters epigenetically during fetal development. Objectives: In this study we sought to elucidate the relationship between maternal PAH exposure and promoter methylation status of IFNγ and IL4. Methods: We assessed the effects of benzo[a]pyrene (BaP), a representative airborne PAH, on the methylation status of the IFNγ and IL4 promoters in Jurkat cells and two lung adenocarcinoma cell lines, and on gene expression. In addition, we evaluated methylation status of the IFNγ promoter in cord white blood cells from 53 participants in the Columbia Center for Children's Environmental Health cohort. Maternal PAH exposure was estimated by personal air monitoring during pregnancy. Results: In vitro exposure of the cell models to low, noncytotoxic doses (0.1 and 1 nM) of BaP elicited increased promoter hypermethylation and reduced expression of IFNγ, but not IL4. IFNγ promoter methylation in cord white blood cells was associated with maternal PAH exposure in the cohort study subsample. Conclusion: Consistent with the results for the cell lines, maternal exposure to PAHs was associated with hypermethylation of IFNγ in cord blood DNA from cohort children. These findings support a potential role of epigenetics in fetal reprogramming by PAH-induced environmental diseases.


Lee M.-T.,University of Cincinnati | Ho S.-M.,University of Cincinnati | Ho S.-M.,Cincinnati Veteran Affairs Medical Center | Tarapore P.,University of Cincinnati | And 2 more authors.
Neoplasia (United States) | Year: 2013

Alternative splicing of estrogen receptor β (ERβ) yields five isoforms, but their functions remain elusive. ERβ isoform5 (ERβ5) has been positively correlated with better prognosis and longer survival of patients with breast cancer (BCa) in various clinical studies. In this study, we investigated the inhibitory role of ERβ5 in BCa cells. Although ERβ5 does not reduce proliferation of BCa cell lines MCF-7 and MDA-MB-231, its ectopic expression significantly decreases their survival by sensitizing them to doxorubicin- or cisplatin-induced apoptosis through the intrinsic apoptotic pathway. Moreover, we discovered Bcl2L12, which belongs to the Bcl-2 family regulating apoptosis, to be a specific interacting partner of ERβ5, but not ERβ1 or ERα, in an estradiol-independent manner. Knockdown of Bcl2L12 enhanced doxorubicin- or cisplatin-induced apoptosis, and this process was further promoted by ectopic expression of ERβ5. Whereas Bcl2L12 was previously shown to inhibit apoptosis through binding to caspase 7, such interaction is reduced in the presence of ERβ5, suggesting a mechanism by which ERβ5 sensitizes cells to apoptosis. In conclusion, ERβ5 interacts with Bcl2L12 and functions in a novel estrogen-independent molecular pathway that promotes chemotherapeutic agent-induced in vitro apoptosis of BCa cell lines. © 2013 Neoplasia Press, Inc. All rights reserved.


Govindarajah V.,University of Cincinnati | Leung Y.-K.,University of Cincinnati | Leung Y.-K.,Cincinnati Cancer Center | Ying J.,University of Cincinnati | And 6 more authors.
Journal of Nutritional Biochemistry | Year: 2016

Human studies suggest that high-fat diets (HFDs) increase the risk of breast cancer. The 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary carcinogenesis rat model is commonly used to evaluate the effects of lifestyle factors such as HFD on mammary tumor risk. Past studies focused primarily on the effects of continuous maternal exposure on the risk of offspring at the end of puberty (PND50). We assessed the effects of prenatal HFD exposure on cancer susceptibility in prepubertal mammary glands and identified key gene networks associated with such disruption. During pregnancy, dams were fed AIN-93G-based diets with isocaloric high olive oil, butterfat or safflower oil. The control group received AIN-93G. Female offspring were treated with DMBA on PND21. However, a significant increase in tumor volume and a trend of shortened tumor latency were observed in rats with HFD exposure against the controls (P=.048 and P=.067, respectively). Large-volume tumors harbored carcinoma in situ. Transcriptome profiling identified 43 differentially expressed genes in the mammary glands of the HFBUTTER group as compared with control. Rapid hormone signaling was the most dysregulated pathway. The diet also induced aberrant expression of Dnmt3a, Mbd1 and Mbd3, consistent with potential epigenetic disruption. Collectively, these findings provide the first evidence supporting susceptibility of prepubertal mammary glands to DMBA-induced tumorigenesis that can be modulated by dietary fat that involves aberrant gene expression and likely epigenetic dysregulation. © 2015 Elsevier Inc.


Leung Y.-K.,University of Cincinnati | Chan Q.K.-Y.,Chinese University of Hong Kong | Ng C.-F.,Chinese University of Hong Kong | Ma F.M.-T.,Chinese University of Hong Kong | And 6 more authors.
PLoS ONE | Year: 2014

Fulvestrant (ICI-182,780) has recently been shown to effectively suppress prostate cancer cell growth in vitro and in vivo. But it is unclear whether microRNAs play a role in regulating oncogene expression in fulvestrant-treated prostate cancer. Here, this study reports hsa-miR-765 as the first fulvestrant-driven, ERβ-regulated miRNA exhibiting significant tumor suppressor activities like fulvestrant, against prostate cancer cell growth via blockage of cell-cycle progression at the G2/M transition, and cell migration and invasion possibly via reduction of filopodia/intense stress-fiber formation. Fulvestrant was shown to upregulate hsa-miR-765 expression through recruitment of ERβ to the 5′-regulatory-region of hsa-miR-765. HMGA1, an oncogenic protein in prostate cancer, was identified as a downstream target of hsa-miR-765 and fulvestrant in cell-based experiments and a clinical study. Both the antiestrogen and the hsa-miR-765 mimic suppressed HMGA1 protein expression. In a neo-adjuvant study, levels of hsa-miR-765 were increased and HMGA1 expression was almost completely lost in prostate cancer specimens from patients treated with a single dose (250 mg) of fulvestrant 28 days before prostatectomy. These findings reveal a novel fulvestrant signaling cascade involving ERβ-mediated transcriptional upregulation of hsa-miR-765 that suppresses HMGA1 protein expression as part of the mechanism underlying the tumor suppressor action of fulvestrant in prostate cancer. © 2014 Leung et al.

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