Structure of Active Sites of Fe-N-C Nano-Catalysts for Alkaline Exchange Membrane Fuel Cells.

Platinum group metal-free (PGM-free) catalysts based on transition metal-nitrogen-carbon nanomaterials have been studied by a combination of ex situ and in situ synchrotron X-ray spectroscopy techniques; high-resolution Transmission Electron Microscope (TEM); Mößbauer spectroscopy combined with electrochemical methods and Density Functional Theory (DFT) modeling/theoretical approaches. The main objective of this study was to correlate the HO2- generation with the chemical nature and surface availability of active sites in iron-nitrogen-carbon (Fe-N-C) catalysts derived by sacrificial support method (SSM). These nanomaterials present a carbonaceous matrix with nitrogen-doped sites and atomically dispersed and; in some cases; iron and nanoparticles embedded in the carbonaceous matrix. Fe-N-C oxygen reduction reaction electrocatalysts were synthesized by varying several synthetic parameters to obtain nanomaterials with different composition and morphology. Combining spectroscopy, microscopy and electrochemical reactivity allowed the building of structure-to-properties correlations which demonstrate the contributions of these moieties to the catalyst activity, and mechanistically assign the active sites to individual reaction steps. Associated with Fe-Nx motive and the presence of Fe metallic particles in the electrocatalysts showed the clear differences in the variation of composition; processing and treatment conditions of SSM. From the results of material characterization; catalytic activity and theoretical studies; Fe metallic particles (coated with carbon) are main contributors into the HO2- generation.

Substrate dependence of Pt4 electronic properties.

We show through first-principles calculations that the electronic properties of Pt4 clusters can be tuned by adsorption on substrates with different electronic valence characters. Pt clusters exhibit a metallic character on γ-Al2O3(111) and insulator properties on CaZrO3(001). The noted difference indicates the role of the electronic valence states of the substrate atoms that directly bond with Pt.

A theoretical study of the reactivity of Cu2O(111) surfaces: the case of NO dissociation.

We compare the electronic properties of Cu(111) and Cu(2)O(111) surfaces in relation to the dissociation of NO using first principles calculations within density functional theory. We note a well-defined three-fold site on both O- and Cu-terminated Cu(2)O surfaces which is verified as the active site for the adsorption and dissociation of NO. The interaction of Cu with O atoms results in the forward shifting of the local density of states and formation of unoccupied states above the Fermi level, compared to the fully occupied d band of pure Cu. These results give valuable insights in the realization of a catalyst without precious metal for the dissociation of NO.

Nitrogen monoxide adsorption on Pt4 clusters coated on gamma-Al2O3 (111) surface.

The nitrogen monoxide (NO) adsorption on platinum tetramer (Pt4) clusters supported on gamma alumina (gamma-Al2O3) with surface index (111) was investigated by using ab-initio calculation based on density functional theory. The Pt4 geometries used in this study are tetrahedron and planar rhombus. The adsorption of Pt4 on gamma-Al2O3 (111) surface in tetrahedron configuration is energetically more favorable as compared to that of the planar rhombus. However, it was found that NO molecule adheres strongly to Pt4 with planar configuration on gamma-Al2O3(111) surface. In addition, the NO adsorption calculation on the isolated Pt4 clusters also shows similar preference to planar configuration. The local density of states (LDOS) reveals that the difference in reactivity comes from the different hybridization strengths between the electronic states of nitrogen atom and those of platinum tetramers. The results are in good agreement with the experiments which show similar tendency for CO and N2O reactivity to gas-phase platinum clusters.

Phase-II study of docetaxel, estramustine phosphate, and carboplatin in patients with hormone-refractory prostate cancer.

OBJECTIVES: To determine the safety and efficacy of combination chemotherapy with docetaxel (DTX), estramustine phosphate (EMP), and carboplatin (CBDCA) in patients with hormone-refractory prostate cancer (HRPC). METHODS: This study included a total of 40 HRPC patients. We evaluated the activity of the following schedule: weekly DTX 30 mg/m(2) iv, daily EMP 10mg/kg po, and CBDCA AUC=6 iv on day 1 of a every 4-wk cycle. Treatment was continued until disease progression or excessive toxicity. RESULTS: All patients were assessable for response. A median of six consecutive cycles was administered per patient. Levels of prostate-specific antigen decreased by more than 50% in 95.0% of the patients. Consumption of medication for cancer-induced pain was reduced in 84.6%. Partial response was attained in 66.7% of measurable lesions. Of patients with bone metastasis, 8.3% demonstrated partial response. With a median follow-up of 11.4 mo, the median time to progression was 12.0 mo, and the median overall survival time was 26.6 mo. The predominant toxicities were grade-3 or -4 anemia in 32.5% of the patients, leukopenia in 20.0%, and thrombocytopenia in 17.5%. However, all toxicity was temporary and reversible with dose reduction or temporary cessation of chemotherapeutic agents. There were no therapy-related deaths. CONCLUSIONS: Combination chemotherapy with DTX/EMP/CBDCA was found to have significant clinical activity with an acceptable toxicity profile in HRPC patients. More suitable selection of patients may be beneficial in terms of improved overall survival in the future.

Usefulness of an immunochromatographical assay, PSA Rapid Test as a primary screening test for prostate cancer.

BACKGROUND: The recent rapid increase of mass screening for prostate cancer by measuring PSA in Japan will increase the economic burden to the healthcare system. PSA Rapid Test (PRT) is a simple inexpensive test. The usefulness of PRT as a primary screening test for prostate cancer was evaluated. METHODS: When we conducted educational lectures for prostate cancer in our city, screening for prostate cancer using PRT was offered to the male participants. The results of the tests were handed to participants in writing at the end of the lectures. When the results were judged as positive, letters of referral to our institute were enclosed. RESULTS: One hundred and fourteen (18.6%) of 614 men were judged as positive by PRT. Of the 114 men with positive PRT, 73 (64%) visited our institution. Finally, 37 men underwent a transrectal prostate biopsy and a diagnosis of prostate cancer was made in 21 men (3.4% of all participants). The total costs for the PSA tests in this study were summed to be approximately $2,300, while they would be approximately $9,200 if all participants had undergone screening using the conventional quantitative method from the outset. CONCLUSION: PRT is a low-cost method to detect patients with prostate cancer. We believe the PRT is useful as an initial screening test for detecting prostate cancer and that the combination of the PRT and more precise quantitative testing would be a reasonable way to reduce the cost and achieve high detection rate.

Epigenetic inactivation of Wnt inhibitory factor-1 plays an important role in bladder cancer through aberrant canonical Wnt/beta-catenin signaling pathway.

PURPOSE: Aberrant activation of the Wingless-type (Wnt) pathway plays a significant role in the pathogenesis of several human cancers. Wnt inhibitory factor-1 (Wif-1) was identified as one of the secreted antagonists that can bind Wnt protein. We hypothesize that Wif-1 plays an important role in bladder cancer pathogenesis. EXPERIMENTAL DESIGN: To test this hypothesis, epigenetic and genetic pathways involved in the Wif-1 gene modulation and expression of Wnt/beta-catenin-related genes were analyzed in 4 bladder tumor cell lines and 54 bladder tumor and matched normal bladder mucosa. RESULTS: Wif-1 mRNA expression was significantly enhanced after 5-aza-2'-deoxycytidine treatment in bladder tumor cell lines. Wif-1 promoter methylation level was significantly higher and Wif-1 mRNA expression was significantly lower in bladder tumor samples than in bladder mucosa samples. In the total bladder tumor and bladder mucosa samples, an inverse correlation was found between promoter methylation and Wif-1 mRNA transcript levels. However, loss-of-heterozygosity at chromosome 12q14.3 close to the Wif-1 gene loci was a rare event (3.7%). Nuclear accumulation of beta-catenin was significantly more frequent in bladder tumor than in bladder mucosa and inversely correlated with Wif-1 expression. In addition, known targets of the canonical Wnt/beta-catenin signaling pathway, such as c-myc and cyclin D1, were up-regulated in bladder tumor compared with bladder mucosa, and this up-regulation was associated with reduced Wif-1 expression at both mRNA and protein levels. Furthermore, transfection of Wif-1 small interfering RNA into bladder tumor cells expressing Wif-1 mRNA transcripts had increased levels of c-myc and cyclin D1 and accelerated cell growth. CONCLUSION: This is the first report showing that CpG hypermethylation of the Wif-1 promoter is a frequent event in bladder tumor and may contribute to pathogenesis of bladder cancer through aberrant canonical Wnt/beta-catenin signaling pathway. The present study elucidates novel pathways that are involved in the pathogenesis of bladder cancer.

Health related quality of life after orthotopic neobladder construction and its comparison with normative values in the Japanese population.

PURPOSE: We report the difference in quality of life (QOL) between patients with an orthotopic neobladder and normative values in the age matched Japanese population. MATERIALS AND METHODS: Between November 1996 and June 2003, 75 patients underwent orthotopic neobladder construction at our institution, of whom 47 males and 9 females were enrolled in this study. A total of 19 patients were excluded because of death or insufficient followup (less than 6 months). Two types of questionnaire, namely the RAND 36-Item Health Survey, version 2 and the Functional Assessment of Cancer Therapy-Bladder Cancer, were mailed to all 56 patients. The 48 patients (86%) who returned the completed forms were included in our analysis. Postoperative QOL was compared with age matched normative values in the control Japanese population. RESULTS: Overall there was no significant difference in any scale between patients with a neobladder and the age matched control Japanese population. The patient bodily pain score in the seventh decade of life and the role-physical score in those older than 70 years were better than age matched normative values in the Japanese population (p < 0.005 and p < 0.05, respectively). Male patients in the seventh decade of life were more likely to have better QOL in the physical functioning, role-physical and role-emotional subscales in addition to the bodily pain subscale compared to age matched control values (p < 0.05, < 0.05, < 0.001 and < 0.001, respectively). Likewise in male patients older than 70 years role-physical scores remained better than age matched normative values in the Japanese population (p < 0.01). Further analysis of bladder cancer related QOL showed that patients followed more than 24 months were more likely to have a lower incontinence score than those followed less than 24 months (p < 0.05). In addition, the continence related QOL change alone did not affect any health related QOL scales, as analyzed by RAND 36-Intem Health Survey. CONCLUSIONS: Our study shows that there is no essential difference in health related QOL between patients with a neobladder and the age matched Japanese control population. The current results provide some primary evidence to help in decision making and eliminate potential anxiety about worse QOL after cystectomy.

CpG methylation at promoter site -140 inactivates TGFbeta2 receptor gene in prostate cancer.

BACKGROUND: The action of transforming growth factor beta (TGF-beta) is mediated through type 1 (TbetaRI) and type 2 (TbetaRII) receptors. Prostate cancer cells are often resistant to TGF-beta signaling due to loss of TbetaRII expression. The authors of the current study hypothesized that CpG methylation of the TbetaRII promoter at the Sp1 binding site -140 mediates this loss of TbetaRII expression in prostate cancer. METHODS: Sixty-seven prostate cancer (PC) samples, 8 benign prostatic hyperplasia (BPH) samples, and 4 prostate cancer cell lines (DUPro, LNCaP, ND-1 and PC-3) were analyzed for 1) TbetaRII mRNA expression by semiquantitative RT-PCR, 2) TbetaRII protein expression by immunohistochemistry, and 3) TGFbetaRII promoter methylation at CpG site -140 by methylation specific PCR and bisulfite DNA sequencing. Prostate cancer cell lines were treated with the demethylating agent 5aza2'deoxycytidine to determine if TbetaRII gene expression could be increased by blocking promoter methylation. RESULTS: mRNA and protein expression of TbetaRII was lower in the PC samples than in the BPH samples. CpG methylation at site -140 was higher in PC than in BPH (P < 0.01). Promoter methylation was inversely correlated with TbetaRII mRNA expression in the PC and BPH samples (P < 0.0001). PC3, ND1, and DUPro TbetaRII mRNA expression increased following treatment of cells with 5-aza-2'-deoxycytidine. CONCLUSION: CpG methylation of the TbetaRII promoter at CPG site -140 leads to functional loss of the TbetaRII gene in prostate cancer. Treatment with 5-aza-2' deoxycytidine can restore gene expression. The current study results report the first association between prostate cancer and loss of the TGF- beta signaling pathway by TbetaRII DNA promoter methylation.

Docetaxel-based chemotherapy as second-line treatment for paclitaxel-based chemotherapy-resistant hormone-refractory prostate cancer: a pilot study.

OBJECTIVES: To examine docetaxel (DTX)-based chemotherapy in paclitaxel (PTX)-based chemotherapy-resistant hormone-refractory prostate cancer (HRPC) to investigate the activity and degree of toxicity in a pilot study. We have previously reported on the effectiveness of combination chemotherapy with PTX, estramustine (EMP), and carboplatin against HRPC. Although many patients with HRPC initially responded to this PTX/EMP-based combination chemotherapy, most finally progressed to PTX-resistant status within a mean of less than 1 year. DTX is an inhibitor of microtubule depolymerization like PTX and has demonstrated activity against PTX-resistant metastatic tumors. METHODS: The subjects were 15 patients with HRPC who displayed disease progression while receiving PTX/EMP/carboplatin combination chemotherapy. The patients were treated with intravenous DTX 30 mg/m2 weekly, oral EMP 10 mg/kg daily, and intravenous carboplatin (dosed to an area under the curve of 6) on day 1 of every 4-week cycle. Treatment was continued until disease progression or excessive toxicity. RESULTS: Each patient received a median of eight consecutive cycles. The prostate-specific antigen level decreased by 50% or more in 33.3% of patients and by 90% or more in 13.3%. The median follow-up was 49.6 weeks, with median time to progression of 25.0 weeks and median overall survival of 54.0 weeks. One patient died of interstitial pneumonitis. One patient developed secondary osteomyelodysplastic syndrome. The major severe toxicities were grade 3 or 4 anemia in 66.7% of patients, leukopenia in 26.7%, and thrombocytopenia in 40.0%. CONCLUSIONS: The results of our study have shown that DTX is comparatively active for heavily pretreated patients with PTX-resistant HRPC. However, given the significant toxicities and small subject population, well-designed Phase I-II trials of the improved regimen are warranted.

Blockade of paclitaxel-induced thymidine phosphorylase expression can accelerate apoptosis in human prostate cancer cells.

Recently, survival benefit by chemotherapy using paclitaxel (PTX) and the induction of thymidine phosphorylase (TP) by PTX have been reported in several solid tumors. On the other hand, TP confers antiapoptotic effect on tumor cells through inhibition of caspase-8 activation in vitro. On the basis of these previous observations, we hypothesized that (a) TP can be induced after PTX treatment in human prostate cancer (PC) and (b) blockade of PTX-induced TP expression can enhance the apoptotic processes in human PC cells. PTX was used to find TP expression in all eight hormone-refractory PC cases after chemotherapy; however, cleaved caspase-8 was not expressed after chemotherapy in the six hormone-refractory PC cases with strong TP expression. In PC cell lines (PC-3, DU 145, and LNCaP), TP expression after PTX treatment was clearly up-regulated in a dose-dependent manner. Cell viability of PC cell lines treated with PTX and TP antisense was significantly reduced in a time-dependent and dose-dependent manner compared with the PTX treatment alone. Likewise, apoptotic index of PC cells treated with PTX and TP antisense was significantly increased in comparison with PTX alone. After complete blockade of PTX-induced TP translation by TP antisense transfection, cleaved form of caspase-3 and poly(ADP-ribose) polymerase was increased, and this exaggeration of apoptosis also ran parallel with caspase-8 activation in a PTX dose-dependent manner. However, in PC cell lines treated with TP antisense alone, neither caspase-3 nor poly(ADP-ribose) polymerase was cleaved despite caspase-8 activation. These results indicate that PTX-induced TP up-regulation is associated with decreased caspase-8 activation. This study is the first report showing that blockade of PTX-induced TP expression could exaggerate the processing of apoptosis in PC cells treated with PTX. Our results provide preclinical evidence that TP could be a new molecular target for enhancing the potency of PTX-mediated apoptosis in PC cells.

Expression of the survivin gene in prostate cancer: correlation with clinicopathological characteristics, proliferative activity and apoptosis.

PURPOSE: Although survivin expression has been reported in prostate cancer, the clinical significance of survivin expression remains unclear. To clarify the clinical significance of survivin in prostate cancer we examined survivin mRNA levels in prostate cancer tissues, and correlated these levels with parameters including the clinicopathological characteristics of patients and proliferation and apoptosis levels within prostate cancer tissues. MATERIALS AND METHODS: Cancer and matched control tissues were obtained from the prostates of 150 patients who were treated with radical prostatectomy between July 1998 and December 2002. Of the 150 samples, RNA could be extracted and pathological confirmation obtained from 82 prostate cancer and 80 normal prostate samples. Polymerase chain reaction studies were performed using primers for the survivin gene with the G3PDH gene serving as control. Preoperative prostate specific antigen doubling time (PSA-DT) could be calculated for 50 patients by linear regression analysis. Immunohistochemical staining was used to study expression of proliferating cell nuclear antigen as an index of proliferative activity and single stranded DNA as an index of apoptosis. RESULTS: Of 82 prostate cancer samples 68 (82.9%) and 47 (58.8%) of 80 control samples exhibited detectable levels of survivin mRNA. In the 65 cases in which RNA could be extracted from prostate cancer and matched control samples, the mean level of survivin expression +/- SE in prostate cancer was significantly higher than that found in control tissues (0.079 +/- 0.017 vs 0.025 +/- 0.005, p = 0.003). The survivin expression in cancers with a short PSA-DT (less than 2 years) was significantly higher than those with a moderate PSA-DT (2 to 4 years, p <0.05) or long PSA-DT (greater than 4 years, p <0.05). In the 82 cases with prostate cancer, survivin expression was significantly higher in cancers with a high pathological T stage (p <0.05), positive lymph node metastasis (p = 0.002), positive vessel invasion (p = 0.03), positive surgical margin (p = 0.02) and high Gleason score (p <0.05). A positive correlation was present between survivin expression and proliferative activity (p = 0.005). A nonsignificant inverse association was found between survivin expression and apoptosis of prostate cancer cells (p = 0.06). CONCLUSIONS: These results suggest that the degree of survivin expression is related to the progression and aggressiveness of prostate cancer.

The role of thymidine phosphorylase (TP) mRNA expression in angiogenesis of prostate cancer.

BACKGROUND: Thymidine phosphorylase (TP) is associated with tumor angiogenesis. The aim of this study was to investigate the role of TP mRNA expression in the angiogenesis of prostate cancer (PC). MATERIALS AND METHODS: Prostatic tissues were obtained from 37 patients who underwent radical prostatectomy. TP and TP mRNA expression was assessed by immunohistochemistry and RT-PCR, respectively. Vascular endothelial growth factor (VEGF) expression, microvessel density (MVD) and blood flow were studied as markers of angiogenesis. RESULTS: The level of TP mRNA expression significantly correlated with the TP expression level, MVD and Gleason score in a group where TP expression was predominantly localized to stromal cells rather than malignant cells within the tumor. It also correlated with VEGF expression and blood flow, but not with clinical findings including T category and serum PSA level. CONCLUSION: This study suggests that the overexpression of TP mRNA by stromal cells within tumors plays an important role in tumor angiogenesis of PC.

Traumatic rhabdomyolysis resulting from continuous compression in the exaggerated lithotomy position for radical perineal prostatectomy.

This report demonstrates a case of rhabdomyolysis as a result of the exaggerated lithotomy position during radical perineal prostatectomy. The pathogenesis, diagnosis, management, and preventive measures of rhabdomyolysis are also reviewed.

Combination chemotherapy with paclitaxel, estramustine and carboplatin for hormone refractory prostate cancer.

PURPOSE: The activity of estramustine phosphate is synergistic with paclitaxel against hormone refractory prostate cancer. Moreover, the single agent activity of carboplatin has demonstrated a 17% response rate in measurable disease. Therefore, we conducted a prospective trial to establish more effective chemotherapy consisting of paclitaxel, estramustine phosphate and carboplatin for hormone refractory prostate cancer. MATERIALS AND METHODS: The study included 32 patients with hormone refractory prostate cancer. Prior chemotherapy was accepted. Patients were treated with 100 mg./m.2 paclitaxel intravenously weekly, 10 mg./kg. estramustine phosphate orally daily and carboplatin intravenously to an area under the curve of 6 on day 1 of every 4-week cycle. Treatment was continued until disease progression or excessive toxicity. RESULTS: Of the 32 patients 30 were assessable for response. A median of 7 consecutive cycles was administered per patient. Ten patients had received prior cytotoxic chemotherapy. Levels of prostate specific antigen decreased by greater than 50% in 100% of patients and by greater than 90% in 56.7%. Partial response was obtained in 61.1% of measurable lesions. Consumption of medication for cancer induced pain was reduced in 89.5% of patients. Tumor volume reduction and/or antitumor therapeutic effects were exhibited in 81.0% of patients with positive biopsy. At a median followup of 48 weeks median time to progression was 48 weeks and median overall survival was 95 weeks. Two patients suffered myocardial infarction and hepatic insufficiency, respectively, and discontinued treatment during the first cycle. Major toxicities were grade 3 or 4 anemia in 59.4% of patients, leukopenia in 37.5%, thrombocytopenia in 28.1% and neuropathy in 12.5%. However, all toxicity was temporary and reversible with dose reduction or temporary cessation of chemotherapeutic agents. CONCLUSIONS: Paclitaxel, estramustine phosphate and carboplatin chemotherapy was extremely effective for hormone refractory prostate cancer. Although hematological and neurotoxicity were modest, this therapy may be more manageable with lower doses.