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2.  Strontium ranelate in fracture healing and joint pain improvement in a rheumatoid arthritis patient 
Rheumatoid arthritis is a chronic inflammatory disease characterized by cartilage and bone destruction leading to functional disability. Patients with rheumatoid arthritis also are inclined to have lower bone density and to develop osteoporosis, a condition that leaves them more prone to fractures. With improper care, these incapacitated patients can develop increased morbidity and mortality. Strontium ranelate, currently prescribed for osteoporosis, can be especially helpful in rheumatoid arthritis by strengthening bone quality, reducing fracture risks, and promoting fracture healing. We report a 62-year-old woman with rheumatoid arthritis who suffered a periprosthetic fracture of the femur. After five months of treatment with systemic administration of strontium ranelate, she achieved pain-free ambulation and near union of the aforementioned fracture. In addition, she reported a significant improvement of her polyarthralgia, so that she could stop taking analgesics for her underlying condition in the second month of strontium ranelate therapy. Given this unexpected result, we propose that besides its already known pharmacological effects, strontium ranelate could have an additional benefit in improving polyarthralgia in rheumatoid arthritis patients.
PMCID: PMC3917586  PMID: 24554934
strontium ranelate; rheumatoid arthritis; joint pain; fracture healing
3.  The Impact of Self-Identified Race on Epidemiologic Studies of Gene Expression 
Genetic epidemiology  2011;35(2):93-101.
Although population differences in gene expression have been established, the impact on differential gene expression studies in large populations is not well understood. We describe the effect of self-reported race on a gene expression study of lung function in asthma. We generated gene expression profiles for 254 young adults (205 non-Hispanic whites and 49 African Americans) with asthma on whom concurrent total RNA derived from peripheral blood CD4+ lymphocytes and lung function measurements were obtained. We identified four principal components that explained 62% of the variance in gene expression. The dominant principal component, which explained 29% of the total variance in gene expression, was strongly associated with self-identified race (P<10−16). The impact of these racial differences was observed when we performed differential gene expression analysis of lung function. Using multivariate linear models, we tested whether gene expression was associated with a quantitative measure of lung function: pre-bronchodilator forced expiratory volume in one second (FEV1). Though unadjusted linear models of FEV1 identified several genes strongly correlated with lung function, these correlations were due to racial differences in the distribution of both FEV1 and gene expression, and were no longer statistically significant following adjustment for self-identified race. These results suggest that self-identified race is a critical confounding covariate in epidemiologic studies of gene expression and that, similar to genetic studies, careful consideration of self-identified race in gene expression profiling studies is needed to avoid spurious association.
PMCID: PMC3718033  PMID: 21254216
ancestry; gene expression; population stratification; self-identified race
4.  Mapping of numerous disease-associated expression polymorphisms in primary peripheral blood CD4+ lymphocytes 
Human Molecular Genetics  2010;19(23):4745-4757.
Genome-wide association studies of human gene expression promise to identify functional regulatory genetic variation that contributes to phenotypic diversity. However, it is unclear how useful this approach will be for the identification of disease-susceptibility variants. We generated gene expression profiles for 22 184 mRNA transcripts using RNA derived from peripheral blood CD4+ lymphocytes, and genome-wide genotype data for 516 512 autosomal markers in 200 subjects. We screened for cis-acting variants by testing variants mapping within 50 kb of expressed transcripts for association with transcript abundance using generalized linear models. Significant associations were identified for 1585 genes at a false discovery rate of 0.05 (corresponding to P-values ranging from 1 × 10−91 to 7 × 10−4). Importantly, we identified evidence of regulatory variation for 119 previously mapped disease genes, including 24 examples where the variant with the strongest evidence of disease-association demonstrates strong association with specific transcript abundance. The prevalence of cis-acting variants among disease-associated genes was 63% higher than the genome-wide rate in our data set (P = 6.41 × 10−6), and although many of the implicated loci were associated with immune-related diseases (including asthma, connective tissue disorders and inflammatory bowel disease), associations with genes implicated in non-immune-related diseases including lipid profiles, anthropomorphic measurements, cancer and neurologic disease were also observed. Genetic variants that confer inter-individual differences in gene expression represent an important subset of variants that contribute to disease susceptibility. Population-based integrative genetic approaches can help identify such variation and enhance our understanding of the genetic basis of complex traits.
PMCID: PMC2972694  PMID: 20833654
5.  TBX3 over-expression causes mammary gland hyperplasia and increases mammary stem-like cells in an inducible transgenic mouse model 
The T-box transcription factor TBX3 is necessary for early embryonic development and for the normal development of the mammary gland. Homozygous mutations, in mice, are embryonic lethal while heterozygous mutations result in perturbed mammary gland development. In humans, mutations that result in the haploinsufficiency of TBX3 causes Ulnar Mammary Syndrome (UMS) characterized by mammary gland hypoplasia as well as other congenital defects. In addition to its role in mammary gland development, various studies have also supported a role for Tbx3 in breast cancer development. TBX3 is over-expressed in various breast cancer cell lines as well as cancer tissue and has been found to contribute to breast cancer cell migration. Previous studies have suggested that TBX3 contributes to cancer development by its ability to bypass senescence by repressing the expression of p14ARF-tumor suppressor. Although many studies have shown that a dysregulation of TBX3 expression may contribute to cancer progression, no direct evidence shows TBX3 causes breast cancer.
In this study, we created doxycycline inducible double transgenic mice (MMTV-rtTA;tet-myc-TBX3-IRES-Luciferase) to test whether TBX3 over-expression can induce tumor formation within the mammary gland. Although over-expression of TBX3, alone, did not induce tumor formation it did promote accelerated mammary gland development by increasing mammary epithelial cell proliferation. We also show that TBX3 directly binds to and represses NFκBIB, an inhibitor of the NF-κB pathway known to play a role in regulating cell proliferation. Lastly, we also show that the over-expression of TBX3 is associated with an increase in mammary stem-like cells.
Overall, our data suggests that over-expression of TBX3 may contribute to breast cancer development by promoting accelerated mammary gland development through the inhibition of the NF-κB pathway and stimulation of both mammary epithelial cell and stem-like cell proliferation.
PMCID: PMC3217876  PMID: 22039763
6.  Evidence-Based Intervention to Reduce Access Barriers to Cervical Cancer Screening Among Underserved Chinese American Women 
Journal of Women's Health  2010;19(3):463-469.
The primary objective of the present study was to evaluate the effects of a community-based pilot intervention that combined cervical cancer education with patient navigation on cervical cancer screening behaviors among Chinese American women residing in New York City.
Chinese women (n = 134) who had not had a Pap test within the previous 12 months were recruited from four Asian community-based organizations (CBOs). Women from two of the CBOs received the intervention (n = 80) consisting of education, interaction with a Chinese physician, and navigation assistance, including help in identifying and accessing free or low-cost screening services. The control group (n = 54) received education delivered by Chinese community health educators and written materials on general health and cancer screening, including cervical cancer, the Pap test, and information about sites that provided free screening. Study assessments were obtained in-person at baseline and postintervention. Screening behavior was self-reported at 12-month postintervention and verified by medical staff.
In the 12-month interval following the program, screening rates were significantly higher in the intervention group (70%) compared to the control group (11.1%). Hierarchical logistic regression analyses indicated that screening behavior was associated with older age (OR = 1.08, 95% CI = 1.01–1.15, p < .05). In addition, women with poorer English language fluency (OR = 0.30, 95% CI = 0.10–0.89, p < .05) and who did not have health insurance were less likely to obtain screening (OR = 0.15, 95% CI = 0.02–0.96, p < .05). Among health beliefs, greater perceived severity of disease was positively associated with screening behavior (OR = 4.26, 95% CI = 1.01-18.04, p < .05).
Community-based programs that provide combined education and patient navigation may be effective in overcoming the extensive linguistic and access barriers to screening faced by Chinese American women.
PMCID: PMC2867551  PMID: 20156089
7.  The effect of a culturally tailored smoking cessation for Chinese American smokers 
Nicotine & Tobacco Research  2009;11(12):1448-1457.
Tobacco use is a serious public health problem among low-income Chinese Americans with limited English proficiency. Chinese men are at high risk for smoking-related morbidity and mortality. We tested the feasibility of a culturally and linguistically sensitive smoking intervention program with combined counseling and pharmacological components for Chinese smokers in New York City; identified factors and techniques that enhance the administration and appropriateness of the intervention program; and examined the overall impact of this program on quit attempts, quit rates, and overall smoking reduction.
We were guided by the transtheoretical model and used an adapted motivational interviewing (MI) approach. The study involved a randomized sample with pretreatment assessment and multiple follow-up measures. Eligible participants (N = 122) were randomly assigned to intervention (4 individualized counselor-led MI sessions and nicotine replacement therapy [NRT]) or control groups (4 general health education sessions, self-help materials, and NRT).
Quit rate at 6 months in the intervention group was 67% versus 32% for the control group, indicating minimal relapse and a highly successful intervention program. Increase in self-efficacy and decease in pros of smoking from baseline to 6-month follow-up were positively associated with smoking cessation. The number of cigarette smoked at baseline was inversely related to smoking cessation. Results indicate that a combined intensive behavioral counseling and pharmacological intervention can reduce smoking substantially.
The results of this pilot will be used as a basis for a large-scale randomized trial of an intervention with combined culturally and linguistically sensitive MI and NRT components for Chinese and other Asian ethnic groups.
PMCID: PMC2784492  PMID: 19915080
8.  A new nonhydrolyzable reactive cGMP analogue, (Rp)-Guanosine-3′, 5′-cyclic-S-(4-bromo-2, 3-dioxobutyl)monophosphorothioate, which targets the cGMP binding site of human platelet PDE3A 
Bioorganic chemistry  2008;36(3):141-147.
The amino acids involved in substrate (cAMP) binding to human platelet cGMP-inhibited cAMP phosphodiesterase (PDE3A) are identified. Less is known about the inhibitor (cGMP) binding site. We have now synthesized a nonhydrolyzable reactive cGMP analog, Rp-guanosine-3′, 5′-cyclic-S-(4-bromo-2, 3-dioxobutyl)monophosphorothioate (Rp-cGMPS-BDB). Rp-cGMPS-BDB irreversibly inactivates PDE3A (KI = 43.4 ± 7.2 μM and kcart = 0.007 ± 0.0006 min−1). The effectiveness of protectants in decreasing the rate of inactivation by Rp-cGMPS-BDB is: Rp-cGMPS (Kd = 72 μM) > Sp-cGMPS (124), Sp-cAMPS (182) > GMP (1517), Rp-cAMPS (3762), AMP (4370 μM). NAD+, neither a substrate nor an inhibitor of PDE3A, does not protect. Nonhydrolyzable cGMP analogs exhibit greater affinity than the cAMP analogs. These results indicate that Rp-cGMPS-BDB targets favorably the cGMP binding site consistent with a docking model of PDE3A-Rp-cGMPS-BDB active site. We conclude that Rp-cGMPS-BDB is an effective active site-directed affinity label for PDE3A with potential for other cGMP-dependent enzymes.
PMCID: PMC2516375  PMID: 18394675
Affinity label; Rp-cGMPS-BDB; Human platelets; Phosphodiesterase; PDE3A

Results 1-8 (8)