Biomedical subjects

Rajiv Dhir

Publications and source records attributed to Rajiv Dhir.

42 records · Page 3Linked to original sources

PubMed2002

Gene expression analysis of prostate cancers.

Prostate cancer is a biologically heterogeneous disease with considerable variation in clinical aggressiveness. The behavior of prostate cancer can be considered a direct or indirect result of aberrant alterations of gene expression in prostate epithelial cells. Identification of the patterns of gene-expression alterations that are related to the aggressiveness of prostate cancers will greatly assist the development of tools for early detection of prostate cancers with poor clinical outcome and identification of targets for future therapeutic intervention. To detect the patterns of gene-expression alterations of prostate cancers, we performed a comprehensive gene-expression analysis on 30 prostate tissues of various levels of invasiveness (ranging from those confined to the organ to distant metastases) and Gleason grades (combined scores 4-9), using the Affymetrix chip set Hu35k (A-D) and U95a. Following three sequential selection screens, we identified 84 largely novel genes and expressed sequence tag (EST) sequences whose expression levels were altered significantly in prostate cancer samples compared with control normal tissues. In addition, the expression levels of a group of 12 genes and EST sequences was found to be altered significantly in aggressive type of prostate cancers but not in organ-confined prostate cancers. Cluster analysis using the 84-gene list showed that the highly aggressive prostate cancers contained gene-expression patterns that were distinct from organ-confined prostate cancers.

Cluster Analysis↗

PubMed2002

Selective activation of members of the signal transducers and activators of transcription family in prostate carcinoma.

PURPOSE: Cytokines, hormones and growth factors use signal transducers and activators of transcription (STAT) signaling pathways to control various biological responses, including development, differentiation, cell proliferation and survival. Constitutive activation of STATs has been found in a wide variety of human tumors. In this study we examined the activity of STATs in primary human prostate tissues. MATERIALS AND METHODS: STAT activity was determined in 104 human primary prostate tissues, including 42 tumors, 42 matched normal prostates adjacent to tumors and 20 normal prostates from donors without cancer by electromobility shift assay. RESULTS: Significant levels of activated Stat4 and Stat6 were detected in primary prostate tissues. However, little or no expression of active Stat1, Stat2 or Stat5 was detected in primary prostate tissues. Significantly higher levels of constitutive Stat6 activity were found in prostate carcinomas compared with levels in normal tissue adjacent to tumors and normal prostates from donors without prostate cancer. There was no significant difference in Stat6 activity in normal prostate tissues adjacent to tumors and normal prostates from donors without prostate cancer. The levels of Stat4 activity varied but failed to yield statistically significant differences among tumors, matched normal prostates adjacent to tumors and normal prostates from donors without cancer. CONCLUSIONS: We have previously shown that Stat3 is activated in prostate cancer. The results of the current study demonstrate that in addition to Stat3, Stat6 is selectively activated in prostate cancer.

Adult↗

PubMed2002

High prevalence of screening-detected prostate cancer among Afro-Caribbeans: the Tobago Prostate Cancer Survey.

Risk for prostate cancer is high among African Americans. We hypothesized that risk for prostate cancer is also high in other populations of African descent. Our objective was to determine the screening-detected prevalence of prostate cancer in the predominantly Afro-Caribbean population on the island of Tobago. Male residents, ages 40-79 years, were invited to participate in a population-based screening for prostate cancer using serum prostate-specific antigen (PSA) and digital rectal exam (DRE). Men with elevated PSA (>or=4 ng/ml) or abnormal DRE were offered an ultrasound-guided sextant biopsy of the prostate gland. Men (2484), ages 40-79 years, underwent prostate cancer screening between September 1997 and June 2001. Mean age was 55.9, SD was 10.6 years, and median was 54 years. Mean serum PSA was 14.8 ng/ml, SD was 376 [excluding 4 values >or= 2 SD above the mean (1,112, 1,317, 1,818, and 18,330 ng/ml) mean PSA was 5.5 ng/ml and SD was 29.6], and median PSA was 1.2 ng/ml. Elevated PSA and/or abnormal DRE were observed in 31% (759 of 2484) overall, and in age groups 40-49 (87 of 843, 10%), 50-59 (201 of 729, 28%), 60-69 (262 of 584, 45%), and 70-79 (209 of 328, 64%). Of 681 men biopsied, 259 (38%, or 10% of the 2484 screened) were diagnosed with prostate cancer. Age-specific rates of screening detected prostate cancer were: 1%, ages 40-79 years; 7%, ages 50-59 years; 18%, ages 60-69 years; and 28%, ages 70-79 years. These screening results indicate a very high screening-detected prevalence of prostate cancer in this population of West African descent. These data support the hypothesis that populations of African descent share genetic and/or lifestyle factors that contribute to their elevated risk for prostate cancer.

Adult↗

PubMed2002

Prostate cancer risk is three-fold higher among men, aged 50-64, of African descent compared with men of Asian-Indian descent in Trinidad and Tobago.

OBJECTIVE: To test the hypothesis that the screening-detected prevalence of prostate cancer is higher among men of African descent than among men of Asian-Indian descent living in Trinidad & Tobago. DESIGN: Population-based prostate cancer screening study among men aged 50-64. SETTING: Caribbean islands of Trinidad and Tobago. PARTICIPANTS: Tobago, population-based sample of 1196 male residents of African descent; Trinidad, 173 agricultural workers of Asian-Indian descent. INTERVENTIONS: Serum prostate specific antigen (PSA, Abbot AxSYM) and digital rectal exam (DRE) were used to screen men for prostate cancer. Men with elevated PSA (> or = 4 ng/mL) and/or abnormal DRE were offered an ultrasound guided sextant biopsy of the prostate gland. MAIN OUTCOME MEASURES: Prevalence of abnormal screen; prevalence of prostate cancer. RESULTS: Elevated PSA and/or abnormal DRE were observed in 29% (348/1196) of Afro-Tobagonian men. Three hundred sixteen men underwent biopsies. Screening-detected prostate cancer prevalence was: 4.9% (23/468) for those aged 50-55; 7.7% (28/366) for those aged 55-59; and 13.3% (48/362) for those aged 60-64 years. Screening was abnormal in 18% (31/173) of Asian-Indian men; 25 underwent biopsies. Prostate cancer prevalence in Asian Indian men was: 1.6% (1/63) for those aged 50-54; 1.4% (1/71) for those aged 55-59; and 5.1% (2/39) for those aged 60-64 years. Mantel-Haenszel age-adjusted rate ratio was 3.4, 95% CI 1.3-9.0. CONCLUSIONS: This study establishes a high prevalence of screening-detected prostate cancer among Afro-Tobagonians compared with Indo-Trinidadians. Comparison of candidate genes, environmental, and lifestyle factors between these populations may identify factors that increase risk for, or provide protection against, prostate cancer.

Africa↗

PubMedDate not supplied

Androgen regulation of JM-27 is associated with the diseased prostate.

Despite intense research efforts, the etiology of prostatic hyperplasia associated with both benign prostatic hyperplasia (BPH) and prostate cancer remains poorly understood. Our previous studies using array technology identified JM-27 as a transcript that is dramatically up-regulated in the prostates of patients with symptomatic BPH and in normal, adjacent prostatic regions of patients with prostate cancer. In the present study, using an extended sample set, we show a correlation between the messenger RNA and protein expression of JM-27. To investigate the possible functions of this gene, its expression in the rat prostate was examined by immunoblot analysis using a polyclonal antibody specific to human JM-27. This antibody reacts with 2 rat polypeptides of 17 kd and 27 kd in size. Whereas the 27-kd form of the JM-27 protein found in human prostate is selectively expressed in the dorsolateral lobes of the rat prostate, the 17-kd form is expressed only in the ventral lobe. Expression of both forms of this protein appears to be androgen-regulated. There is a time-dependent decrease in expression of the protein products in the ventral and dorsolateral lobes of the rat prostate after castration. Administration of exogenous testosterone in castrated animals maintains protein expression in both lobes. Androgens are believed to play a central role in prostate growth and development, and therefore, it is tempting to speculate that JM-27, an androgen-regulated gene, may be involved in prostatic growth regulation. Further studies are underway to evaluate such a function for JM-27 in prostatic diseases.

Animals↗

PubMedDate not supplied

Lack of toxicity of EGFR antisense gene therapy.

PURPOSE: EGFR is overexpressed in many human cancer cells, including head and neck squamous cell carcinoma (HNSCC). We have previously shown that elevated EGFR levels in the primary HNSCC tumor are associated with decreased survival. Reduction of EGFR tumor expression levels using an antisense EGFR sequence under the control of the U6 small nuclear RNA promoter abrogates tumor growth in a head and neck xenograft model. In support of a phase I clinical trial of an EGFR antisense gene-liposome complex administered to HNSCC patients, we conducted a series of studies to evaluate the safety of intralesional injections of EGFR liposomal antisense gene therapy in normal mice. METHODS: Three dose tiers were examined including the starting DNA-lipid dose for the clinical trial. RESULTS: Tissues and blood were harvested from mice treated with the liposome-mediated gene therapy and control mice at several time points for analysis. In this dosing range, administration of the antisense EGFR DNA-liposome complex had no apparent adverse effect on renal, hepatic and hematologic parameters studied. No major organ pathologic changes were observed. CONCLUSIONS: These results suggest that the toxicity of intralesional EGFR antisense DNA plus liposomes is restricted to a self-limited inflammation at the injection site, and may be well-tolerated in the clinical setting. EGFR antisense gene therapy was reviewed by the Recombinant DNA Advisory Committee and the Food and Drug Administration, and a phase I clinical trial is currently underway in patients with advanced HNSCC.

Animals↗