Human beta-defensin-1 (hBD-1) is a candidate tumor suppressor gene located on chromosome 8p23. Previously, we showed that cancer-specific loss of hBD-1 was found in 90% of renal clear cell carcinomas and in 82% of prostate cancers. To investigate the possible mechanisms of decreased gene expression and determine the function of hBD-1 protein in urological cancers, we sequenced hBD-1 gene coding regions in prostatic and renal cancer samples. We then analyzed the frequency distribution of promoter polymorphisms and determined the effect of these base changes on transcriptional activity of the hBD-1 promoter. A polymorphism at -688 bases upstream of the ATG start codon affects hBD-1 promoter activity, leading to a rate of reporter gene transcription that is 40% to 50% lower than the wild-type sequence when tested in either DU145 or TSU-Pr1 cell lines. In addition, a polymorphism at -44 bases was shown to enhance transcription up to 2.3 times more than the wild-type sequence in the same cell lines. In addition, three novel hBD-1 promoter mutations were found in renal and prostate cancer clinical samples. An iso-5-aza-2'-deoxycytidine treatment was effective in transcription up-regulation in DU145, suggesting a possible upstream methylation-dependent effect. Synthetic hBD-1 peptide inhibited bladder cancer cell TSU-Pr1 proliferation. Overexpression of the hBD-1 gene in renal cancer cells SW156 resulted in caspase-3-mediated apoptosis. These data support the hypothesis that hBD-1 is a potential tumor suppressor gene for urological cancers. Promoter point mutations may be responsible for cancer-specific loss of hDB-1 expression.
Background: Metabolic Syndrome (MetSyn) is one of the strongest predictors of type 2 diabetes (DM2) and cardiovascular disease (CVD). It is associated with a 4- to 10-fold increased risk of DM2 and a 2- to 3-fold increased risk of CVD. Low income and minority women have some of the highest rates of MetSyn. This study examines the effect of a unique, community based, primary prevention program on the rates of MetSyn and health habits. Methods: Sixty-four low income and minority women were enrolled in the HAPPY (Health Awareness and Primary Prevention in Your neighborhood) Heart Program in an eastern suburb of Boston. Over these 2 years, patients were evaluated by an interdisciplinary medical team: their primary physician, cardiologist, nutritionist, physical therapist, and health coach. The rate of MetSyn was measured at baseline, year 1, and year 2. Comparisons were made either using the paired t test for normally distributed variables or the Wilcoxon Sign test for non-normal variables. Results: The rate of MetSyn fell from 64.7% at baseline to 34.9% at year 1 (p=0.01) and 28.2% at year 2 (p<0.001). This was driven by increases in high-density lipoprotein (HDL-C) (p<0.001) and decreases in blood pressure (p=0.05). Fasting blood glucose trended down, but the hemoglobin A1c (HbA1c) reached significance (decreasing from 6 to 5.8, p<0.01). Nutrition and exercise habits trended toward improvement. There were significant decreases in anxiety (p<0.001), depression (p=0.006) and stress (p=0.002). Conclusion: This lifestyle intervention program is effective at decreasing MetSyn in a socioeconomically disadvantaged, largely minority, female population. This program also decreases anxiety, stress, and depression among participants.
2900 Introduction and Objective: Beta defensin-1 (DEFB1) is a candidate tumor suppressor gene located on chromosome 8p. Cancer-specific loss of DEFB1 expression is found in 90% of clear cell carcinomas (Laboratory Investigation 83:501, 2003). While this gene resides in one of the areas of 8p frequently deleted in renal cancer there has been little work done to determine whether the protein is functional in tumor suppression. The objective of this project was to determine if beta defensin-1 protein inhibits renal cancer cell growth. Methods: Full length DEFB1 cDNA was cloned in pcDNA 3.1 (Invitrogen) for transient transfection of the human renal cell carcinoma cell line SW156. Mature and properly reduced protein was synthesized in solid phase for direct addition to cell cultures. Vector expression was monitored by RT-PCR and western analysis of DEFB1 RNA and protein respectively. Apoptosis was monitored by western analysis of poly(ADP-ribose) polymerase (PARP) cleavage and microscopy for detection of apoptotic bodies and cell viability. Results: The addition of synthetic DEFB1 peptide to tumor cells in culture resulted in modest but consistent growth inhibition compared to control peptide. Transient transfection with over expression of DEFB1 in renal cell carcinoma cell lines resulted in near complete cell death while vector control transfections remained viable under the same conditions. Transfected cells produced DEFB1 protein that appeared in the culture medium prior to cell death. While vector control cells failed to exhibit PARP cleavage, a time dependent increase in PARP cleavage was observed in DEFB1 transfected cells that correlated with the appearance of apoptotic bodies and cell death. Conclusions: Beta defensin-1 induces apoptotic cell death in human renal cell carcinoma. This gene is frequently deleted and resides on chromosome 8p within the area of minimal deletion overlap previously identified in loss of heterozygosity studies as likely to contain a common tumor suppressor gene. DEFB1 protein is absent or severely underexpressed in 90% of clinical cases of renal cell carcinoma. Thus, DEFB1 remains a strong candidate as a new tumor suppressor gene and exhibits functional tumor suppression in vitro.
Background: Metabolic Syndrome (MetSyn), a composite of waist circumference, blood pressure, triglycerides, HDL and insulin sensitivity, is one of the strongest predictors of type 2 diabetes (DM) and cardiovascular disease (CVD). It is associated with a 4-10 fold increased risk of DM and a 2-3 fold increased risk of CVD. Low income and minority women have some of the highest rates of MetSyn. This study examines the effect of a community based, primary prevention program on the rates of MetSyn in this population. Methods: 64 low income and minority women, with at least two preexisting risk factors, were enrolled in the HAPPY (Health Awareness and Primary Prevention in Your neighborhood) Heart Program in a suburb of Boston. Over this 2 year period, patients were evaluated by an interdisciplinary medical team: their primary physician, cardiologist, nutritionist, physical therapist and health coach. The rate of MetSyn was measured at baseline, year 1 and 2. Comparisons were made either using the paired t test for normally distributed variables or the Wilcoxon Sign test for non-normal variables. Results: We examined the 5 components of the MetSyn individually and the overall MetSyn score (see table). The increase in HDL from baseline to year 1 was not significant, but by year 2, the average HDL had increased from 44.5 to 49.3 (p<0.001). Similarly, by year 2, we observed a decrease of 6.8 mmHg in systolic blood pressure (p=0.05). Finally, by year 2, the average decrease in HbA1c was 0.2 (p<0.001). From baseline to year 1, the average MetSyn score decreased by 0.33 (p=0.017) and by year 2, the improvements were sustained and improved, with an average reduction in score of 0.63 (p<0.001). Conclusion: Our results demonstrate that a comprehensive, lifestyle intervention program is effective at decreasing MetSyn in a high risk minority female population. These improvements may take at least two years to become evident; however, when shepherded by a community based, interdisciplinary team, not only are the improvements significant, they are sustained.
Vulnerable populations are more likely to access medical care than visit a dentist. We introduced a dental team into a student-faculty collaborative clinic that serves a low-income Latino population. Documentation of oral exam findings rose from 11.88% to 50.50% in the year following integration of dental students into the clinic.
