Search PubMed⌕ Search

Biomedical subjects

John A Petros

Publications and source records attributed to John A Petros.

At least 19 recordsLinked to original sources
PubMed2006

Oxidative stress induces ADAM9 protein expression in human prostate cancer cells.

The ADAM (a disintegrin and metalloprotease) family is a group of transmembrane proteins containing cell adhesive and proteolytic functional domains. Microarray analysis detected elevated ADAM9 during the transition of human LNCaP prostate cancer cells from an androgen-dependent to an androgen-independent and metastatic state. Using a prostate tissue array (N = 200), the levels of ADAM9 protein expression were also elevated in malignant as compared with benign prostate tissues. ADAM9 protein expression was found in 43% of benign glands with light staining and 87% of malignant glands with increasing intensity of staining. We found that ADAM9 mRNA and protein expressions were elevated on exposure of human prostate cancer cells to stress conditions such as cell crowding, hypoxia, and hydrogen peroxide. We uncovered an ADAM9-like protein, which is predominantly induced together with the ADAM9 protein by a brief exposure of prostate cancer cells to hydrogen peroxide. Induction of ADAM9 protein in LNCaP or C4-2 cells can be completely abrogated by the administration of an antioxidant, ebselen, or genetic transfer of a hydrogen peroxide degradative enzyme, catalase, suggesting that reactive oxygen species (ROS) are a common mediator. The induction of ADAM9 by stress can be inhibited by both actinomycin D and cycloheximide through increased gene transcription and protein synthesis. In conclusion, intracellular ROS and/or hydrogen peroxide, generated by cell stress, regulate ADAM9 expression. ADAM9 could be responsible for supporting prostate cancer cell survival and progression. By decreasing ADAM9 expression, we observed apoptotic cell death in prostate cancer cells.

ADAM Proteins↗
PubMed2006

Human beta-defensin-1, a potential chromosome 8p tumor suppressor: control of transcription and induction of apoptosis in renal cell carcinoma.

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.

Apoptosis↗
PubMed2006

The value of digital rectal examination as a predictor of prostate cancer diagnosis among United States Veterans referred for prostate biopsy.

BACKGROUND: As digital rectal examination (DRE) remains an essential part of a routine physical examination, it is important to understand its diagnostic value in different circumstances. AIM: To quantify sensitivity, specificity and predictive value of DRE as a predictor of biopsy-confirmed prostate cancer in the US Veteran population. METHODS: The study group included 628 consecutive patients who underwent transrectal biopsy for suspected prostate cancer due to abnormal digital examination of the prostate, elevated serum prostate specific antigen (PSA) or both. The DRE results reported in this study are documented during physical examinations that were performed after referral for biopsy. The relation between DRE results and positive biopsy was examined while taking into consideration demographic and clinical patient characteristics. RESULTS: Among men with normal PSA the adjusted odds ratio (OR) reflecting the association between abnormal DRE and positive prostate biopsy was 0.53 with a 95% confidence interval (CI) from 0.27 to 1.06. In the presence of a moderately elevated (4.1-10 ng/mL) PSA, the OR was 1.07 (0.72-1.60). When serum PSA exceeded 10 ng/mL, the OR was 2.15 (1.12-4.43). The positive predictive value of an abnormal DRE varied widely from as high as 81% to as low as 14% depending on the other patient characteristics. DISCUSSION: These results indicate that DRE results are most informative when evaluated in conjunction with other clinical and demographic information.

Adult↗
PubMed2006

Radical prostatectomy for clinical T4 prostate cancer.

BACKGROUND: Occasionally, patients with clinical T4 (cT4) prostate cancer undergo surgery. Published data on outcomes after radical prostatectomy (RP) in patients with such advanced stage disease and on the impact of adjuvant radiation therapy (RT) and hormone therapy (HT) are nonexistent. METHODS: Data from the Surveillance Epidemiology and End Results (SEER) data base were reviewed for the 7-year period from 1995 to 2001. Specifically, data were analyzed for 1093 patients with cT4, lymph node-negative or lymph node-positive, M0 prostate cancer without distant lymph node involvement or a history of other cancer. Using follow-up data through 2002, postdiagnosis survival was examined in 5 treatment groups: radical prostatectomy (RP) either alone or in combination with other therapy, radiation therapy (RT) alone, hormone therapy (HT) alone, RT plus HT, and no treatment (NT). All results were expressed as 1-year, 3-year, and 5-year observed survival and corresponding relative survival. Mortality across treatment categories was compared by using a Cox proportionate hazards model controlling for age, year of diagnosis, race, tumor grade, regional lymph node involvement, clinical tumor extension, and SEER registry. RESULTS: Observed and relative survival rates were lowest among patients who received NT and highest among patients who underwent RP. Adding adjuvant RT or HT to RP conferred no survival benefit. Multivariate survival analyses revealed a significant increase in mortality among HT-only patients and among patients who received NT compared with patients who underwent RP. The differences in survival among treatment types were most pronounced in a relatively small group of patients who had positive regional lymph node extension. In all other patients, the results suggested a modest (but not significant) improvement in survival after RT plus HT. CONCLUSIONS: SEER data revealed that patients who underwent RP for cT4 prostate cancer had increased survival compared with patients who received RT alone or HT alone and had a survival comparable to that of patients who received RT plus HT. The benefit of RP appears to be limited to a relatively small subset of patients who have regional lymph node extension.

Aged↗
PubMed2006

North American white mitochondrial haplogroups in prostate and renal cancer.

PURPOSE: While the mitochondrion is known to be a key mediator of apoptosis, there has been little inquiry into the inheritance pattern of mitochondria in patients with cancer. We compared the mtDNA haplotype in patients with prostate and renal cancer to that in controls to determine if there is an association between mitochondrial genotype and cancer. MATERIALS AND METHODS: Haplotyping was performed using polymerase chain reaction/digest identification of key polymorphic sites in the mitochondrial genome. A total of 121 and 221 white men with renal and prostate cancer, respectively, were identified following pathological confirmation of cancer, while 246 white controls were selected randomly from a bank of cadaveric organ donor DNA. Statistical analysis was performed and ORs were calculated. RESULTS: Mitochondrial haplogroup U was a highly significant risk factor for prostate and renal cancer vs controls (16.74% and 20.66% vs 9.35%, Fisher's exact test p = 0.019 and 0.005, respectively). The association remained statistically significant in renal cancer even after Bonferroni adjustment for multiple comparisons. Haplogroup U carried an OR of 1.95 for prostate cancer and an OR of 2.52 for renal cancer. CONCLUSIONS: The inheritance of mitochondrial haplogroup U is associated with an approximately 2-fold increased risk of prostate cancer and 2.5-fold increased risk of renal cancer in white North American individuals. Therefore, individuals with this mitochondrial haplotype are in a high risk group. Because mitochondrial haplogroup U is found in 9.35% of the white United States population, there are more than 20 million individuals in this high risk group.

Adolescent↗
PubMed2005

Increased Nox1 and hydrogen peroxide in prostate cancer.

BACKGROUND: Reactive oxygen species (ROS) are emerging as candidate mediators of growth and angiogenesis in cancer. Increased ROS often correlates with cell growth, e.g., Ras-transformed cells and cells treated with growth factors. While non-transformed cells respond to growth factors/cytokines with the regulated production of ROS, tumor cells in culture frequently overproduce H(2)O(2). We propose that NADPH oxidases (Nox) account for increased levels of ROS in some cancers. Previously, transfection of Nox1 into a prostate cancer cell line dramatically enhanced tumor growth (Arbiser et al.: PNAS 99:715-720, 2001). METHODS: Using immunohistochemistry, immunofluorescence, dihydroethidium staining, and Flow cytometry, we investigated the correlation between Nox1 and ROS in prostate cancer. RESULTS: Here, we demonstrate that human prostate tumors show increased H(2)O(2) levels. Furthermore, 80% of human prostate tumor samples show markedly increased Nox1 protein levels and increased mRNA levels. In addition, a series of cell lines developed from LNCaP prostate cancer cells that demonstrate increasing tumor and metastatic potential, show increased Nox1 and a parallel increase in H(2)O(2) levels. CONCLUSIONS: The results illustrate that human prostate cancer frequently show both increased H(2)O(2) and Nox1, and that in an animal model system increased Nox1/H(2)O(2) correlates with increased tumorigenicity.

Animals↗
PubMed2005

mtDNA mutations increase tumorigenicity in prostate cancer.

Mutations in the mtDNA have been found to fulfill all of the criteria expected for pathogenic mutations causing prostate cancer. Focusing on the cytochrome oxidase subunit I (COI) gene, we found that 11-12% of all prostate cancer patients harbored COI mutations that altered conserved amino acids (mean conservation index=83%), whereas <2% of no-cancer controls and 7.8% of the general population had COI mutations, the latter altering less conserved amino acids (conservation index=71%). Four conserved prostate cancer COI mutations were found in multiple independent patients on different mtDNA backgrounds. Three other tumors contained heteroplasmic COI mutations, one of which created a stop codon. This latter tumor also contained a germ-line ATP6 mutation. Thus, both germ-line and somatic mtDNA mutations contribute to prostate cancer. Many tumors have been found to produce increased reactive oxygen species (ROS), and mtDNA mutations that inhibit oxidative phosphorylation can increase ROS production and thus contribute to tumorigenicity. To determine whether mutant tumors had increased ROS and tumor growth rates, we introduced the pathogenic mtDNA ATP6 T8993G mutation into the PC3 prostate cancer cell line through cybrid transfer and tested for tumor growth in nude mice. The resulting mutant (T8993G) cybrids were found to generate tumors that were 7 times larger than the wild-type (T8993T) cybrids, whereas the wild-type cybrids barely grew in the mice. The mutant tumors also generated significantly more ROS. Therefore, mtDNA mutations do play an important role in the etiology of prostate cancer.

Adenosine Triphosphatases↗
PubMed2005

Loss of HOXC6 expression induces apoptosis in prostate cancer cells.

We have performed whole genome expression profiling of 28 patient prostate tumor samples and 12 normal prostate samples and identified 55 upregulated and 60 downregulated genes significantly changed in prostate tumor samples compared to normal prostate tissues. Among the members of the upregulated gene set was the developmental transcription factor Homeobox C6 (HOXC6). Silencing of HOXC6 expression using small-interfering RNA (siRNA) resulted in decreased proliferation rates for both androgen-dependent LnCaP cells and the LnCaP-derived androgen-independent C4-2 cell line. Flow cytometry and immunoblotting for the caspase-cleaved form of poly-ADP ribose polymerase (PARP) determined that the decrease in cell numbers was due to increased apoptosis. To validate the specificity of the siRNA-induced apoptosis, LnCaP cells were cotransfected with siRNA specific to the HOXC6 3'UTR and a mammalian expression vector containing the HOXC6 open reading frame, but lacking the 3'UTR. Overexpression of HOXC6 rescued the LnCaP cells from HOXC6 siRNA-induced apoptosis, and increased growth of control GFP siRNA-transfected cells. Expression profiling of HOXC6 siRNA transfections and HOXC6 overexpression identified neutral endopeptidase (NEP) and insulin-like growth factor binding protein-3 (IGFBP-3) as potential proapoptotic repression targets of HOXC6. Our data suggest that HOXC6 may be a novel potential therapeutic target for prostate cancer.

Apoptosis↗
PubMed2005

In vivo molecular and cellular imaging with quantum dots.

Quantum dots (QDs), tiny light-emitting particles on the nanometer scale, are emerging as a new class of fluorescent probe for in vivo biomolecular and cellular imaging. In comparison with organic dyes and fluorescent proteins, QDs have unique optical and electronic properties: size-tunable light emission, improved signal brightness, resistance against photobleaching, and simultaneous excitation of multiple fluorescence colors. Recent advances have led to the development of multifunctional nanoparticle probes that are very bright and stable under complex in vivo conditions. A new structural design involves encapsulating luminescent QDs with amphiphilic block copolymers and linking the polymer coating to tumor-targeting ligands and drug delivery functionalities. Polymer-encapsulated QDs are essentially nontoxic to cells and animals, but their long-term in vivo toxicity and degradation need more careful study. Bioconjugated QDs have raised new possibilities for ultrasensitive and multiplexed imaging of molecular targets in living cells, animal models and possibly in humans.

Animals↗
PubMed2005

Role of transrectal ultrasonography in diagnosis and treatment of retained Foley catheter.

Retention of Foley balloon in the bladder or urethra is a troublesome complication that presents a challenge to the urologist. We describe a complicated case of Foley catheter balloon retention (and trauma) within the urethra in an orthopedic patient undergoing hemiarthroplasty. The Foley balloon failed to deflate with standard methods. We used transrectal ultrasonography to successfully diagnose and manage the case.

Aged↗
PubMed2005

Molecular classification of renal tumors by gene expression profiling.

Renal tumor classification is important because histopathological subtypes are associated with distinct clinical behavior. However, diagnosis is difficult because tumor subtypes have overlapping microscopic characteristics. Therefore, ancillary methods are needed to optimize classification. We used oligonucleotide microarrays to analyze 31 adult renal tumors, including clear cell renal cell carcinoma (RCC), papillary RCC, chromophobe RCC, oncocytoma, and angiomyolipoma. Expression profiles correlated with histopathology; unsupervised algorithms clustered 30 of 31 tumors according to appropriate diagnostic subtypes while supervised analyses identified significant, subtype-specific expression markers. Clear cell RCC overexpressed proximal nephron, angiogenic, and immune response genes, chromophobe RCC oncocytoma overexpressed distal nephron and oxidative phosphorylation genes, papillary RCC overexpressed serine protease inhibitors, and extracellular matrix products, and angiomyolipoma overexpressed muscle developmental, lipid biosynthetic, melanocytic, and distinct angiogenic factors. Quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry of formalin-fixed renal tumors confirmed overexpression of proximal nephron markers (megalin/low-density lipoprotein-related protein 2, alpha-methylacyl CoA racemase) in clear cell and papillary RCC and distal nephron markers (beta-defensin 1, claudin 7) in chromophobe RCC/oncocytoma. In summary, renal tumor subtypes were classified by distinct gene expression profiles, illustrating tumor pathobiology and translating into novel molecular bioassays using fixed tissue.

Gene Expression Profiling↗
PubMed2005

Epididymal sparing bilateral simple orchiectomy with epididymoplasty: preservation of esthetics and body image.

PURPOSE: We report the surgical technique and results of epididymal sparing bilateral simple orchiectomy as an esthetic alternative to standard bilateral simple orchiectomy and luteinizing hormone releasing hormone (LH-RH) agonist injection therapy in patients with prostate cancer. MATERIALS AND METHODS: The study included 91 consecutive epididymal sparing bilateral simple orchiectomy (BSO) procedures that were performed at the Atlanta Veterans Affairs Medical Center during a 25-month period. All patients had pathologically confirmed prostate cancer. A total of 52 patients (57.1%) were receiving LH-RH agonist therapy prior to the procedure and the remaining 39 (42.9%) were not. All procedures were performed in an outpatient clinic setting using spermatic cord anesthesia block as the only method of anesthesia. In the 52 patients who were on LH-RH agonist therapy prior to the procedure the overall impression/satisfaction with the procedure was evaluated using a questionnaire. RESULTS: All 91 procedures were performed at the urology outpatient clinic using local anesthesia. Mean patient age was 74.2 years (range 44 to 86). Mean serum prostate specific antigen was 58.9 ng/ml. The mean time required to perform the spermatic cord anesthesia block was 3.9 minutes (range 2 to 6) and the volume of anesthetic solution was 18.9 ml per case (range 10 to 32). Despite significant difference in testicular size between patients receiving and not receiving LH/RH agonists there were no differences in anesthesia time or anesthetic volume (3.9 and 3.9 minutes, p = 0.97, and 18.6 and 19.4 ml, respectively, p = 0.47). Mean operative time for BSO excluding anesthesia time was 36.9 minutes (range 18 to 70). Mean operative time was similar in patients receiving and not receiving LH-RH agonists (36.2 and 37.8 minutes, respectively, p = 0.39). The procedure was well tolerated, as judged by the mean intraoperative pain score during BSO of 0.2 (range 0 to 3). The majority of patients (76 or 83.5%) were pain-free during the procedure. Pain scores were similar in patients who were and were not receiving LH-RH agonists during BSO (p = 0.97). There were no adverse events. Followup data were available on 26 of the 52 patients who were receiving LH-RH agonist therapy prior to the procedure. Of them 96.2% were satisfied with the results and 84.6% preferred the procedure over medical castration therapy with LH-RH agonist therapy. CONCLUSIONS: Epididymal sparing bilateral simple orchiectomy is a simple and safe procedure that can be conveniently performed in an outpatient clinic setting using pure local anesthesia. Preservation of the epididymis and subsequent epididymoplasty is effective for maintaining the esthetic appearance of the scrotum and patient satisfaction. The procedure offers patients the convenience of 1-time surgical therapy over lifelong medical injection therapy at a significantly lower cost and without significantly compromising the esthetic appearance of the scrotum.

Adult↗
PubMed2005

Endoscopic enucleation of leiomyoma of the bladder.

A case of benign leiomyoma of the urinary bladder was discovered incidentally and treated successfully with endoscopic enucleation. We describe the technique of this new surgical approach and discuss its advantages. We recommend this minimally invasive approach over open surgical resection.

Cystoscopy↗
PubMed2004

Surgical margin and Gleason score as predictors of postoperative recurrence in prostate cancer with or without chromosome 8p allelic imbalance.

BACKGROUND: Identification of prostate cancer patients at risk for postoperative disease recurrence is an important clinical issue. Existing pathological markers can predict disease recurrence only to a certain extent, and there is a need for more accurate predictors. METHODS: Using "counting alleles," a novel experimental method, we determined allelic status of chromosome 8p in 107 prostatectomy specimens. Statistical analyses examined the association between pathologic predictors (Gleason score, stage, surgical margin, etc.) and cancer recurrence in patients with and without 8p allelic imbalance (8p AI). RESULTS: 8p AI cancers were more likely to recur in the presence of a positive surgical margin, whereas recurrence of 8p retaining tumors was associated with the Gleason score, but not with the surgical margin. CONCLUSIONS: Our findings suggest that chromosome 8p allelic status affects the predictive value of "traditional" markers of prostate cancer recurrence. If confirmed by larger studies, these results may have important clinical implications.

Age Factors↗
PubMed2004

PrLZ, a novel prostate-specific and androgen-responsive gene of the TPD52 family, amplified in chromosome 8q21.1 and overexpressed in human prostate cancer.

We report a previously unrecognized prostate-specific protein, PrLZ (prostate leucine zipper), a new member of the Tumor Protein D52 (TPD52) family. The gene for PrLZ was localized at chromosome 8q21.1, a locus most frequently amplified in human prostate cancer. Multiple tissue analyses demonstrated PrLZ predominantly in the prostate gland. Although its expression was enhanced by androgens in androgen receptor-expressing cells, PrLZ was detected in all of the human prostate cancer cell lines, regardless of androgen receptor status. Monoclonal anti-PrLZ antibodies were produced and intense immunohistochemical staining of PrLZ was observed in prostate epithelial cells in intraepithelial neoplasia and prostate cancer, whereas lower-level staining was detected in normal and benign epithelial components of the prostate gland. As the only prostate-specific gene identified in the most frequently amplified genomic region in prostate cancer, PrLZ may be the link between chromosome 8q amplification and malignant transformation of the prostate epithelia.

Androgens↗