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Biomedical subjects

Joel B Nelson

Publications and source records attributed to Joel B Nelson.

At least 19 recordsLinked to original sources
PubMed2007

Correlation between risk factors for vascular disease and the American Urological Association Symptom Score.

OBJECTIVE: To evaluate the correlation between risk factors for vascular disease and the American Urological Association Symptom Score (AUA-SS), by comparing the presence of these risk factors with the degree of lower urinary tract symptoms (LUTS). PATIENTS AND METHODS: We retrospectively reviewed the medical history, AUA-SS, and prostate volume of men who had a radical prostatectomy. The degree of LUTS in men with and without risk factors for cardiovascular disease was compared. RESULTS: The mean AUA-SS was 7.2 for the entire cohort, 5.6 in men with no risk factors, and 7.9 in men with at least one risk factor (P < 0.05). In men with one to four risk factors, the mean AUA-SS was 6.9, 7.9, 10.7, and 19.5, respectively. There was no correlation between the AUA-SS and prostate size in the entire cohort or among any groups. CONCLUSIONS: Men with risk factors for vascular disease are more likely to have a higher AUA-SS than men without these risk factors. These findings suggest the possibility of an association between vascular disease and the development and severity of LUTS in men.

Adult↗
PubMed2006

Quality of life as a potential predictor for morbidity and mortality in patients with metastatic hormone-refractory prostate cancer.

BACKGROUND: The association between HRQL measures with outcomes in patients with metastatic hormone-refractory prostate cancer (HRPC) is unclear. METHODS: Baseline and 12-week HRQL was collected using the European Organization for Research and Treatment of Cancer (EORTC QLQ-C30) and the Functional Assessment of Cancer Therapy - Prostate (FACT-P). Outcomes included: (1) survival; (2) time to disease progression and (3) time to bone pain. Cox proportional hazards regression models were used. The relative predictive performance of each HRQL instrument and domain was compared. RESULTS: Baseline HRQL scores and 12-week change scores > the median were significant predictors of all clinical outcomes but varied by domain. For example, the hazard of death for a change in FACT-P Grand Total Score > median was 49% of the hazard for a change < or = the median. Including baseline or 12-week change in HRQL resulted in improvement in prediction performance. CONCLUSIONS: Patients with better baseline HRQL have better predicted survival, time to disease progression and pain prognosis than those with worse HRQL. In addition, the 12-week change in HRQL appears to improve predictive accuracy for most clinical outcomes. It appears that greater deterioration in HRQL is prognostic for rapid disease progression.

Aged↗
PubMed2006

Endothelin-1 promotes cell survival in renal cell carcinoma through the ET(A) receptor.

Endothelin-1 (ET-1) is a potent vasoconstrictor that has been shown to significantly impact many benign and malignant tissues by signaling through its two cognate receptors: ET(A) and ET(B). As ET-1 has a role in both normal and diseased kidney, we initiated studies to investigate endothelin axis expression and function in renal cell carcinoma (RCC). In this study, relatively high levels of ET-1 were detected in all six human RCC cell lines investigated. RT-PCR and Southern analyses revealed that all six RCC cell lines expressed ET(A) receptor mRNA, while 3/6 cell lines also expressed ET(B) mRNA. High affinity ET-1 binding occurred in all but one RCC cell line and quantitative RT-PCR demonstrated ET(A) mRNA expression in all six cell lines. Methylation of the ET(B) promoter (EDNRB) in 4/6 RCC cell lines was observed, suggesting a mechanism for repressed ET(B) expression. Moreover, methylation occurred in 32/48 of renal tumors and in 27/55 of histologically normal adjacent tissue samples studied, while no methylation was evident in any normal tissue isolated from nephrectomy or at autopsy. Functionally, ET-1 significantly inhibited paclitaxel-induced apoptosis in RCC cells through binding ET(A) with the ET-1 signaling mediated via the PI3-kinase/Akt pathway. Collectively, these data support the therapeutic targeting of the ET(A) receptor as a novel treatment strategy for RCC.

Androstadienes↗
PubMed2006

Endothelin receptor A blockade enhances taxane effects in prostate cancer.

Endothelin (ET) 1 is important in the growth of prostate cancer cells through the activation of the endothelin A (ET(A)) receptor. ET receptor blockade is a new therapeutic target in treating advanced prostate cancer. This study investigates the impact of the combination of the ET(A) antagonist atrasentan (ABT-627) and taxane chemotherapy on prostate cancer cell survival in vitro and on the delay of prostate cancer in a xenograft mouse model. In vitro, PPC-1 cells transfected with an ET(A)-overexpressing vector were treated with ABT-627, paclitaxel/docetaxel, or both. Clonogenic viability and cell death assays were used to determine cell survival and apoptosis, respectively. ABT-627 and docetaxel combination treatment was used in vivo to treat mice with established ET(A)-overexpressing PPC-1 xenograft tumors, and tumor growth rates were assessed. Cell proliferation and vascularity were determined with Ki-67 and CD31 staining, respectively. Cells treated with combination therapy had significantly fewer viable cells and more programmed cell death than cells given monotherapy. Xenograft tumor growth rates were significantly lower in mice treated with combination therapy than in animals given a single agent. Ki-67 immunostaining demonstrated significantly fewer proliferative cells following combination therapy than following monotherapy. This study demonstrates ABT-627 to have additive antitumor effects when used in combination with taxane drugs both in vitro and in vivo.

Animals↗
PubMed2005

Bone loss after initiation of androgen deprivation therapy in patients with prostate cancer.

CONTEXT: Although androgen deprivation therapy (ADT) for prostate cancer is associated with bone loss, little is known about when this bone loss occurs. OBJECTIVE: We postulated that men on ADT would experience the greatest bone loss acutely after initiation of ADT. DESIGN AND SETTING: We conducted a 12-month prospective study at an academic medical center. PATIENTS OR OTHER PARTICIPANTS: We studied 152 men with prostate cancer (30 with acute ADT, < 6 months; 50 with chronic ADT, > or = 6 months; and 72 with no ADT) and 43 healthy age-matched controls. MAIN OUTCOME MEASURES: We assessed bone mineral density (BMD) of the hip, wrist, total body, and spine; body composition; and markers of bone turnover. RESULTS: After 12 months, men receiving acute ADT had a significant reduction in BMD of 2.5 +/- 0.6% at the total hip, 2.4 +/- 1.0% at the trochanter, 2.6 +/- 0.5% at the total radius, 3.3 +/- 0.5% at the total body, and 4.0 +/- 1.5% at the posteroanterior spine (all P < 0.05). Men with chronic ADT had a 2.0 +/- 0.6% reduction in BMD at the total radius (P < 0.05). Healthy controls and men with prostate cancer not receiving ADT had no significant reduction in BMD. Both use and duration of ADT were associated with change in bone mass at the hip (P < 0.05). Men receiving acute ADT had a 10.4 +/- 1.7% increase in total body fat and a 3.5 +/- 0.5% reduction in total body lean mass at 12 months, whereas body composition did not change in men with prostate cancer on chronic ADT or in healthy controls (P < 0.05). Markers of bone formation and resorption were elevated in men receiving acute ADT after 6 and 12 months compared with the other men with prostate cancer and controls (P < 0.05). Men in the highest tertile of bone turnover markers at 6 months had the greatest loss of bone density at 12 months. CONCLUSIONS: Men with prostate cancer who are initiating ADT have a 5- to 10-fold increased loss of bone density at multiple skeletal sites compared with either healthy controls or men with prostate cancer who are not on ADT, placing them at increased risk of fracture. Bone loss is maximal in the first year after initiation of ADT, suggesting initiation of early preventive therapy.

Aged↗
PubMed2005

Role of endothelin axis in progression to aggressive phenotype of prostate adenocarcinoma.

BACKGROUND: Mitogenic and anti-apoptotic actions of endothelin-1 (ET-1) are mediated through endothelin A (ET(A)) receptors. We investigated endothelin receptor expression in increasingly aggressive phenotype and in vivo effects of combination therapy using ET(A) antagonist with paclitaxel. METHODS: Dunning prostate cancer cells ranged in aggressiveness from non-tumorigenic G, to tumorigenic, non-metastatic AT-1, and to tumorigenic and metastatic MLL. Binding assays were performed alongside Q-PCR to assess receptor density. MLL xenografts were treated with vehicle, atrasentan, paclitaxel, and paclitaxel+atrasentan. RESULTS: Saturation binding assays demonstrated endothelin receptor density of MLL and AT-1 cells seven- and threefold higher than G cells, respectively. Q-PCR showed 9- and 4.5-fold greater ET(A) mRNA expression in MLL and AT-1 than G cells, respectively and no endothelin receptor B (ET(B)) expression. Combination therapy had significant effect on reduction of tumor volume than paclitaxel or atrasentan alone. CONCLUSIONS: ET(A) expression increases in aggressive prostate carcinoma. ET(A) blockade combined with paclitaxel may reduce tumor growth in advanced prostate carcinoma.

Adenocarcinoma↗
PubMed2005

Perineural invasion in prostate cancer biopsies is not associated with higher rates of positive surgical margins.

PURPOSE: High rates of extracapsular tumor extension have been reported with biopsy perineural invasion (PNI), leading some to advocate routine resection of the ipsilateral neurovascular bundle (NVB) with radical retropubic prostatectomy (RRP) to assure negative surgical margins. The contemporary rates of extracapsular tumor extension (ECE) and margin status associated with biopsy PNI were investigated. MATERIALS AND METHODS: The prostate needle biopsies, RRP specimens, and operative reports of 452 consecutive patients undergoing RRP by a single surgeon were reviewed to determine the presence of PNI invasion, presence of ECE, margin status, and preservation of NVB. Patients were excluded from the analysis if they underwent preoperative hormonal ablation or if their original biopsy was not reviewed by the pathologists at our institution. Both univariate and multivariate analyses were performed to determine the effect of PNI on extracapsular extension, the likelihood of performing a bilateral nerve-sparing technique, and the result of a positive surgical margin. RESULTS: In the 402 evaluable cases, based on multivariate models PNI showed only a marginal association with positive surgical margin (+SM) (P = 0.10) and bilateral nerve-sparing (B-NS) (P = 0.07), but was significantly associated with organ confinement (P = 0.03). The odds ratio (OR) of PNI for +SM, although not statistically significant, was 0.36. Although showing a higher level of statistical significance, PNI for OC had an odds ratio of 0.50. Similarly, the odds ratio was 0.54 for B-NS. CONCLUSIONS: Although biopsy PNI alone was associated with a higher probability of ECE, it is not predictive of bilateral nerve-sparing technique or a positive surgical margin in an individual patient.

Adult↗
PubMed2005

Caspase-dependent apoptosis induction by phenethyl isothiocyanate, a cruciferous vegetable-derived cancer chemopreventive agent, is mediated by Bak and Bax.

PURPOSE: The present study was undertaken to gain insights into the molecular mechanism of apoptosis induction by phenethyl isothiocyanate (PEITC) using prostate cancer cell lines derived from transgenic adenocarcinoma mouse prostate (TRAMP) mice (TRAMP-C1 and TRAMP-C2). EXPERIMENTAL DESIGN AND RESULTS: The viability of TRAMP-C1 and TRAMP-C2 cells was reduced significantly in the presence of PEITC in a concentration-dependent manner as determined by sulforhodamine B and trypan blue dye exclusion assays. Treatment of TRAMP-derived cells with PEITC revealed features characteristic of apoptosis induction, including appearance of subdiploid cells (determined by flow cytometry), cytoplasmic histone-associated DNA fragmentation (determined by an ELISA assay), and cleavage of caspase-3 (determined by immunoblotting). The PEITC-induced apoptosis in TRAMP-derived cells was associated with a marked increase in the level of proapoptotic protein Bak and/or a decrease in the levels of antiapoptotic protein Mcl-1 or Bcl-xL and disruption of mitochondrial membrane potential. The SV40 immortalized mouse embryonic fibroblasts derived from Bak and Bax double knockout mice were significantly more resistant to PEITC-induced DNA fragmentation compared with wild-type or Bak-/- mouse embryonic fibroblasts. The PEITC-induced apoptosis in both cell lines was significantly attenuated in the presence of caspase inhibitors zVAD-fmk, zLEHD-fmk, and zIETD-fmk. Oral administration of PEITC (9 or 12 micromol PEITC/d, Monday-Friday) significantly retarded growth of TRAMP-C1 xenografts in nude mice without causing weight loss or any other side effects. CONCLUSION: The results of the present study indicate that caspase-dependent apoptosis by PEITC is mediated by Bak and Bax proteins.

Adenocarcinoma↗
PubMed2005

Endothelin receptor antagonists.

Hormone refractory prostate cancer remains true to its middle name: it is largely refractory to attempts to delay its progression. New targets and new therapies are demanded. Through a review of the available literature on endothelin and several preclinical observations, the endothelin axis has emerged as one such target. In phase II and III clinical trials of atrasentan, a potent and selective endothelin receptor A subtype (ET(A)) antagonist, disease progression was delayed in some men. This well tolerated, oral agent may help convert advanced prostate cancer to a more chronic disease. This review will discuss the endothelin axis, preclinical rationale and some of the available clinical trial data on this promising new approach.

Apoptosis↗
PubMed2005

Future therapies in hormone-refractory prostate cancer.

Hormone-refractory prostate cancer (HRPC) remains true to its name: it is largely refractory to attempts to delay its progression. Although the number of men presenting with metastatic prostate cancer has decreased significantly over the last several years, the death rate for those men is essentially unchanged. To alter the currently inevitable progression of HRPC to death, new targets and new therapies are needed. This article reviews investigational therapies directed against standard targets (eg, the hypothalamic-pituitary-gonadal axis) as well as novel targets (eg, the endothelin axis).

Antibodies, Monoclonal↗
PubMed2005

Improvement in erectile dysfunction after neurotrophic factor gene therapy in diabetic rats.

PURPOSE: Erectile dysfunction (ED) is a common but difficult to treat complication of diabetes mellitus (DM). We have previously reported herpes simplex virus (HSV) vector mediated delivery of nerve growth factor into the bladder to treat diabetic cystopathy and neurotrophin-3 (NT3) gene transfer for pyridoxine treatment. Nerve growth factor and NT3 are neurotrophic factors that may protect nerves from mechanical and metabolic damage. We investigated the effects of HSV mediated delivery of NT3 for the treatment of diabetic ED. MATERIALS AND METHODS: Male Sprague-Dawley rats weighing 300 to 400 gm were injected with 65 mg/kg streptozotocin to induce DM. After 4 weeks 20 microl containing 5 x 10 pfu replication defective HSV vector expressing lacZ (6 rats) or NT3 (6) were injected directly into the cavernous nerve sheath with a 30 gauge needle. Four weeks later the animals underwent measurement of intracavernous pressure under electrical stimulation (20 Hz, 0.5 millisecond and 10 V) of the cavernous nerve. Staining for lacZ and neuronal nitric oxide synthase in the major pelvic ganglia was also performed. RESULTS: beta-Galactosidase staining revealed lacZ positive neurons in the major pelvic ganglia. Maximal intracavernous pressure induced by electrical stimulation showed statistically significant mean values +/- SEM of 15.1 +/- 2.1 and 43.8 +/- 11.1 cm H2O in the lacZ and NT3 vector injected groups, respectively (p = 0.03). The mean number of neuronal nitric oxide synthase positive neurons per section in the NT3 group was significantly higher than that in the lacZ control group at 3.33 +/- 0.23 and 0.64 +/- 0.14 neurons per high power field, respectively (p < 0.001). CONCLUSIONS: We report that gene therapy for the treatment of diabetic ED is feasible with HSV vectors. NT3 gene therapy may be applicable for the treatment of ED induced by DM.

Animals↗
PubMed2005

Caspase-dependent apoptosis induction by guggulsterone, a constituent of Ayurvedic medicinal plant Commiphora mukul, in PC-3 human prostate cancer cells is mediated by Bax and Bak.

The present study was undertaken to gain insights into the molecular mechanism of cell death (apoptosis) by guggulsterone, a constituent of Ayurvedic medicinal plant Commiphora mukul, using PC-3 human prostate cancer cells as a model. The viability of PC-3 cells, but not a normal prostate epithelial cell line (PrEC), was reduced significantly on treatment with guggulsterone in a concentration-dependent manner. Guggulsterone-mediated suppression of PC-3 cell proliferation was not due to perturbation in cell cycle progression but caused by apoptosis induction characterized by appearance of subdiploid cells and cytoplasmic histone-associated DNA fragmentation. Guggulsterone-induced apoptosis was associated with induction of multidomain proapoptotic Bcl-2 family members Bax and Bak. Interestingly, the expression of antiapoptotic proteins Bcl-2 and Bcl-xL was initially increased in guggulsterone-treated PC-3 cells but declined markedly following a 16- to 24-hour treatment with guggulsterone. Ectopic expression of Bcl-2 in PC-3 cells failed to confer significant protection against guggulsterone-induced cell death. On the other hand, SV40 immortalized mouse embryonic fibroblasts derived from Bax-Bak double knockout mice were significantly more resistant to guggulsterone-induced cell killing compared with wild-type cells. Guggulsterone treatment resulted in cleavage (activation) of caspase-9, caspase-8, and caspase-3, and guggulsterone-induced cell death was significantly attenuated in the presence of general caspase inhibitor as well as specific inhibitors of caspase-9 and caspase-8. In conclusion, the present study indicates that caspase-dependent apoptosis by guggulsterone is mediated in part by Bax and Bak.

Animals↗
PubMed2005

Endothelin-1 inhibits apoptosis in prostate cancer.

Endothelin-1 (ET-1), produced by the prostate epithelia, likely plays an important role in the progression of prostate cancer. ET-1 can bind two receptor subtypes; generally, binding of the endothelin receptor A (ET(A)) induces a survival pathway, whereas binding of the endothelin receptor B (ET(B)) mediates clearance of circulating ET-1 as well as promotes apoptosis. In prostate carcinoma, hypermethylation of the ET(B) promoter results in repression of ET(B) expression, thereby eliminating the negative growth response that ET-1 binding elicits through this receptor. Therefore, activation of ET(A) exclusively provides a pathway for survival advantage. Our current studies examine the mechanisms by which activation of the ET(A) may allow growth/survival. ET-1 treatment of prostate tumor cells significantly decreased paclitaxel-induced apoptosis through activation of the ET(A) subtype. The anti-apoptotic effects of ET-1 are mediated, at least in part, through the Bcl-2 family. Although no significant changes in Bcl-2 expression occurred with ET-1 treatment, the pro-apoptotic family members Bad, Bax, and Bak all decreased significantly. Further analysis of the survival pathway demonstrated that phosphorylation of Akt occurs with ET-1 treatment in a time- and dose-dependent manner through phosphatidyinositol 3-kinase activation. These data support the combination of ET(A) antagonists and apoptosis-inducing therapies for prostate cancer treatment.

Annexin A5↗
PubMed2004

Endothelin A receptor blockade does not alter PSA secretion in prostate cancer cell lines.

BACKGROUND: Some men treated with atrasentan (ABT-627), an endothelin A (ETA) receptor inhibitor, had declines in their serum PSA levels. It is our hypothesis that this decrease is due to anti-tumoral activity and not a reduction in PSA secretion at the cellular level. METHODS: Two PSA secreting prostate cancer cell lines (LAPC4 and LNCaP) were treated with atrasentan and an ETB receptor antagonist (A192621) in varying concentrations (10(-6)-10(-10) M) and PSA levels were measured in the culture media. RESULTS: LNCaP and LAPC4 cells both express ETA receptors. Neither the ETA or ETB antagonist altered PSA secretion, while addition of DHT, a positive control, produced a marked increase in PSA secretion. CONCLUSIONS: Blockade of the ETA receptor does not affect the secretion of PSA in prostate cancer cell lines.

Atrasentan↗
PubMed2004

Function and survival of dendritic cells depend on endothelin-1 and endothelin receptor autocrine loops.

The biologic effects of endothelin-1 (ET-1) are not limited to its potent vasoconstricting activity. The endothelin receptors, ETA and ETB, have differential tissue and functional distributions. Here we showed that dendritic cells (DCs), the major antigen-presenting cells in the adaptive limb of the immune system, produce large amounts of ET-1 and significantly increase the expression of endothelin receptors upon maturation. Selective blockade of the ETA receptor significantly reduced expression of the mature DC marker CD83, decreased the production of the immunostimulatory cytokine interleukin-12, down-regulated DC ability to stimulate T cells, and promoted DC apoptosis. Selective ETB receptor blockade, on the other hand, resulted in increased expression of CD83 and improved DC survival. Therefore, ET-1/ETA/ETB autocrine/paracrine loops on DCs appear to be essential for the normal maturation and function of human DCs, presenting a unique target for immunomodulatory therapies.

Annexin A5↗
PubMed2004

Delayed intraoperative hydration limits blood loss during radical retropubic prostatectomy.

OBJECTIVES: To evaluate the effects of limiting hydration during prostate mobilization on intraoperative blood loss. METHODS: The patient records of 519 consecutive men undergoing radical retropubic prostatectomy by a single surgeon from January 2000 through April 2003 were reviewed. In the initial 328 cases, intravenous fluids were not limited throughout the case (constant hydration group). In the next 189 cases, intravenous fluids were limited to a target of 1500 mL during prostate dissection (delayed hydration group). After the prostate was removed, hydration was brisk for an additional target of 3500 mL. The patient characteristics, perioperative events, and postoperative recovery were evaluated. RESULTS: Delayed hydration resulted in a statistically significant reduction in estimated blood loss compared with the constant hydration group, averaging 700 mL versus 965 mL, respectively. The immediate postoperative hematocrit values were also significantly greater in the delayed hydration group (31.5%) than in the constant hydration group (30.2%). Furthermore, the delayed hydration group had significantly fewer cases of blood loss greater than 1500 mL and fewer patients needed intraoperative transfusions. No statistically significant difference was found in total intravenous fluids given and no increased morbidity occurred with delayed hydration. CONCLUSIONS: Delayed hydration appears to reduce blood loss during radical retropubic prostatectomy. In the hemodynamically stable patient, limiting intravenous fluids before complete dissection of the prostate is feasible without increasing morbidity.

Adenocarcinoma↗