The Identification of Zinc-Finger Protein 433 as a Possible Prognostic Biomarker for Clear-Cell Renal Cell Carcinoma.

Clear-cell renal cell carcinoma (ccRCC) is the most common and aggressive form of all urological cancers, with poor prognosis and high mortality. At late stages, ccRCC is known to be mainly resistant to chemotherapy and radiotherapy. Therefore, it is urgent and necessary to identify biomarkers that can facilitate the early detection of ccRCC in patients. In this study, the levels of transcripts of ccRCC from The Cancer Genome Atlas (TCGA) dataset were used to identify prognostic biomarkers in this disease. Analyzing the data obtained indicated that the KRAB-ZNF protein is significantly suppressed in clear-cell carcinomas. Furthermore, ZNF433 is differentially expressed in ccRCC in a stage- and histological-grade-specific manner. In addition, ZNF433 expression was correlated with metastasis, with greater node involvement associated with lower ZNF433 expression (p < 0.01) and with a more unsatisfactory overall survival outcome (HR, 0.45; 95% CI, 0.33-0.6; p = 8.5 × 10-8). Since ccRCC is characterized by mutations in proteins that alter epigenetic modifications and /or chromatin remodeling, we examined the expression of ZNF433 transcripts in ccRCC with wildtype and mutated forms of BAP1, KDMC5, MTOR, PBRM1, SETD2, and VHL. Analysis revealed that ZNF433 expression was significantly reduced in ccRCC with mutations in the BAP1, SETD2, and KDM5C genes (p < 0.05). In addition, the ZNF433 promoter region was highly methylated, and hypermethylation was significantly associated with mRNA suppression (p < 2.2 × 10-16). In silico analysis of potential ZNF target genes found that the largest group of target genes are involved in cellular metabolic processes, which incidentally are particularly impaired in ccRCC. It was concluded from this study that gene expression of ZNF433 is associated with cancer progression and poorer prognosis, and that ZNF433 behaves in a manner that suggests that it is a prognostic marker and a possible tumor-suppressor gene in clear-cell renal cell carcinoma.

Valproate and sodium butyrate attenuate manganese-decreased locomotor activity and astrocytic glutamate transporters expression in mice.

Manganese (Mn) is an essential trace element, but chronic overexposure to this metal, either environmentally or occupationally may cause manganism, a disease analogous to Parkinson's disease. Inhibitors of histone deacetylases, such as valproic acid (VPA) and sodium butyrate (NaB) exert neuroprotective effects in various animal models of neurological disorders. Thus, the present study investigated whether VPA or NaB prevent Mn-induced neurotoxicity by assessing locomotor activities and expression of astrocytic glutamate transporters, glutamate transporter 1 (GLT-1) and glutamate aspartate transporter (GLAST), in C57BL/6 mice. C57BL/6 mice were pretreated with VPA (200mg/kg, i.p.) or NaB (1200mg/kg, i.p.) prior to intranasal instillation of Mn (30mg/kg) continually for 21days, followed by open-field and rota-rod behavioral tests and analyses of astrocytic glutamate transporters GLT-1 and GLAST protein/mRNA levels. The results showed that Mn significantly decreased locomotor activity as determined by total distance travelled, stereotypic and ambulatory counts. Mn also significantly decreased rota-rod activity reflecting altered motor coordination. Pretreatment with VPA and NaB with Mn reversed the effects of Mn on the locomotor activity and motor coordination. VPA and NaB also attenuated the Mn-induced decrease in GLT-1 and GLAST mRNA and protein levels in the cerebral cortical and cerebellar regions of mice. These results suggest that VPA and NaB exert protective effects against Mn toxicity seem in vitro are also shown in vivo. VPA and NaB pretreatment in mice enhancing astrocytic glutamate transporter GLT-1 expression as well as locomotor activities. Future research endeavors are warranted to determine if the therapeutic potential of VPA and NaB is via common molecular mechanism, namely, inhibition of histone deacetylases.

Racial Differences in Age-Related Variations of Testosterone Levels Among US Males: Potential Implications for Prostate Cancer and Personalized Medication.

AIM: The magnitude of the age-related declines in testosterone rather than levels measured at single point in time may be related to the genesis of prostate cancer (PCa). We examined age-related variations of testosterone levels among black and white males, which may provide important insights into racial disparities in PCa incidence and mortality. METHOD: We analyzed data from the 1999-2004 National Health and Nutritional Examination Survey to compare age-related variations in the testosterone levels of 355 black and 631 white males. RESULT: Overall, between the ages of 12 and 15, black males had lower testosterone levels than white males. Testosterone levels increased rapidly with age and reached higher and earlier peak levels in black males compared to white males at 20-30 years of age. After reaching a peak level, testosterone levels declined earlier in blacks than in whites. Further analyses showed that black males had considerably higher levels of testosterone compared to white males aged 20-39 years after adjusting for covariates, including age, body mass index, cigarette smoking, physical activity, and waist circumference; however, no statistically significant differences were observed between the groups at any other age. CONCLUSION: Our study revealed that testosterone levels in black males decrease substantially with increasing age compared to those in white males. This rapid drop in testosterone levels may contribute to racial disparities in PCa. Our findings also suggest that personalized medication for hormone replacement therapy may be necessary to avoid sudden drops in testosterone levels, particularly for black males.

Comparative proteomic analysis reveals growth inhibition by 3-N-alkyloxyestradiol derivative (SERM) in prostate cancer cells.

BACKGROUND/AIM: In this study we evaluated the proteomic profile of PC-3 cells treated with novel, 3-N-alkyloxyestradiol derivative, 3-[2-diisopropylamino]-ethoxy-D1,3,5 (10)-estrien-17-one (DI) (USPTO #7,687,486). MATERIALS AND METHODS: The growth inhibitory potential of DI was determined by the National Cancer Institute (NCI) Developmental Therapeutics Program. 2-D gel electrophoresis and mass spectrometry were employed to identify differentially expressed proteins after treatment with DI. RESULTS: Growth inhibitory (GI(50)) results showed that DI inhibited the growth of PC-3 and DU-145 cells, at 13.9 µM and 30.8 µM, respectively. Out of the proteins differentially expressed, five were selected for identification with four of those being successfully identified. The identified proteins play a role in protein folding, cell motility, carbohydrate biosynthesis, and carbohydrate degradation. CONCLUSION: Our studies resulted in the identification of targets associated with the glycolytic pathway and cell motility which have been implicated in the development and progression of many cancers.

Clinical cultural competency and knowledge of health disparities among pharmacy students.

OBJECTIVE: To evaluate the level of competency and knowledge about health disparities among third-year doctor of pharmacy (PharmD) students at 2 Florida public colleges of pharmacy and to explore the demographic correlates of these variables. METHODS: A cross-sectional survey study design was used to collect data from participants. RESULTS: The students had low health-disparities knowledge and moderate skills in dealing with sociocultural issues and cross-cultural encounters. Speaking a language(s) other than English and having exposure to cultural-competency instruction were the demographic variables found to be most significantly associated with clinical cultural competency and/or knowledge of health disparities. CONCLUSIONS: Clinical cultural competency and health-disparities instruction may not be adequately incorporated into the pharmacy school curricula in the institutions studied. Relevant education and training are necessary to enhance cultural competency among pharmacy students.