Search

The incidence of prostate cancer has increased in Japan recently and is developing into a life-threatening disease for many Japanese men. This is a result of several convergent factors including the adoption of a Western lifestyle, the widespread use of prostate-specific antigen (PSA) testing, and an increased population of advanced years in Japanese men. Although there is much information to date relating to molecular events underlying the etiology of prostate cancer, it is still unclear as to how and when these genetic alterations occur in each step of tumorigenesis. One fruitful area of investigation has been in the analysis of chromosomal abnormalities commonly observed in prostate cancer. However, no single candidate gene has been definitely identified in cancer initiation and/or progression; in addition, less research has been devoted to understanding the molecular events that underlie tumor histogenesis in terms of likely precursor lesions, such as prostatic intraepithelial neoplasia (PIN). This article reviews the current knowledge of the molecular pathology of prostate cancer, including its histogenesis, genetic and epigenetic alterations, and hereditary factors. [ABSTRACT FROM AUTHOR]

To characterize genetic alterations occurring in renal tumorigenesis, EHEN-induced renal cell tumors were examined using restriction landmark genomic scanning (RLGS) analysis, an electrophoretic separation technique that detects gene amplifications and deletions. Comparison of DNAs from tumor against those from corresponding nontumorous kidney and/or EHEN-treated kidney without development of renal tumors yielded specific alterations in terms of both amplified and reduced DNA spots. Two amplified spots were detected only in renal cell tumors and an additional four spots were frequent in EHEN-treated kidneys. One reduced spot was common to all tumor samples, and another was frequently detected in the tumors analyzed but not in EHEN-treated kidneys. A subset of the altered spots thus appeared to be specific for EHEN-induced renal tumorigenesis. [ABSTRACT FROM AUTHOR]

Prognostic factors for low-grade astrocytomas have been proposed, but optimal treatment remains controversial. Eighty-eight consecutive adult patients with supratentorial low-grade astrocytomas were retrospectively reviewed to determine specific factors influencing outcome. All underwent craniotomy (43 radical resections, 45 nonradical resections). Sex, age at diagnosis, preoperative Karnofsky performance status (KPS), tumor location, estimated extent of resection, radiation, chemotherapy, histological type, p53 status, MIB-1 staining and the apoptotic index were assessed as parameters for prognostic significance. KPS (p = 0.03), tumor location (p < 0.001), extent of surgical resection (p < 0.001) and radiotherapy (p = 0.01) were significantly assoicated with longer survival rates by univariate analysis. Multivariate analysis also showed a significant correlation between radiation therapy after surgical removal and survival time (p < 0.001). p53 status was not of importance in determining the necessity for radiotherapy. Radical surgical removal is the most important factor in the management of low-grade astrocytomas. Radiation therapy appears to be effective in improving the prognosis regardless of the extent of surgical resection or the p53 status.Copyright © 2000 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Midkine (MK) is a growth/differentiation factor frequently expressed at high levels in some types of human malignancies. To investigate whether MK is a useful marker in prostate carcinogenesis, immunohistochemical analysis was performed on samples of both latent and clinical prostate cancers of various stages, as well as on specimens of normal gland and prostatic intraepithelial neoplasia (PIN). Of the 80 clinical cancers examined, 69 specimens (86.3%) were immunoreactive for MK, with metastatic lesions generally showing higher expression than the corresponding primaries; normal prostate tissues were negative or showed only weak staining. Midkine was also detected in 12 of 15 latent cancers (80%) and in 12 of 16 cases of PIN (75%). In sections of whole prostate, MK showed variable expression through tumorous sections, probably in reflection of heterogeneous cell populations. The results demonstrate the possible value of MK as a marker for early and latent disease, as well as for more advanced clinical stages of prostate cancer. [ABSTRACT FROM AUTHOR]

The expression of pepsinogen II (PG II), an aspartyl proteinase usually involved in the digestion of proteins in the stomach, was immunohistochemically investigated in conjunction with androgen (AR) and estrogen receptor (ER) status in prostate adenocarcinomas. Of a total of 38 samples obtained from radical prostatectomies, 23 tumors (60.5%) were positive for PG II and there was a significant positive correlation to the expression of AR but not to ER. Cells positive for PG II were localized mainly to the peripheral zones of tumorous glands which, in normal prostate, are negative, and in areas also expressing AR. In addition, a significant correlation between AR and ER was detected in the prostate carcinomas examined, which suggests a hormone-dependent status. On the basis of these results, PG II expression might be closely related to hormonal alterations associated with the development of prostate tumors. [ABSTRACT FROM AUTHOR]

Examines the tumor metastasis suppressor gene in paraffin-embedded normal, hyperplastic and neoplastic prostate carcinoma cell lines. Visualization of cells by immunochemistry; Immunoreactivity of the membrane antigen in cell lines; Details on the pretreatment with trypsin enhanced immunoreactivity.

Focal segmental glomerulosclerosis (FSGS) is a commonly occurring cause of steroid-resistant nephrotic syndrome and frequently progresses to renal failure. Podocyte epithelial-mesenchymal transition (EMT) is thought to induce podocyte detachment in glomerular diseases, and severe degeneration and shedding of glomerular podocytes plays a major role in the progression of FSGS. We showed that fibroblast specific protein 1 (FSP1), an EMT marker, is strongly expressed in podocytes of FSGS patients, but the significance of podocyte expression of FSP1 to the pathophysiology of FSGS remained unclear. Here, we investigated FSP1 expression in podocytes from mice with adriamycin (ADR)-induced nephropathy, a murine model of FSGS. The number of FSP1-positive (FSP1+) podocytes was increased in ADR-treated mice and positively correlated with the degree of proteinuria and glomerulosclerosis in ADR-treated mice. ADR-induced FSGS and the attendant proteinuria were significantly ameliorated in FSP1 knockout mice as compared to wild type mice. These findings indicate that podocyte expression of FSP1 plays a crucial role in the pathogenesis of FSGS, which makes FSP1 a potential target for treatment of FSGS. • FSP1 expression was detected in podocytes from ADR-treated FSGS mice. • FSP1+ podocyte counts increased with progression of FSGS in mice. • FSP1 gene deficiency ameliorated the progression of FSGS in mice. • FSP1 may be a promising novel therapeutic target for FSGS. [ABSTRACT FROM AUTHOR]

The effects of pretreatment with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) on the acute and long-term effects of methamphetamine on striatal dopamine were evaluated in BALB/c mice. Four subcutaneous injections of a non-toxic dose of MPTP (8 mg/kg, at 2 hr intervals) were followed three days later by a toxic regimen of methamphetamine (four injections of 4 mg/kg, at 2 hr intervals) and mice were sacrificed immediately or three days later. Control mice received saline in place of the MPTP or methamphetamine and mice were observed for acute changes in body temperature, self-injurious behaviour, and striatal dopamine metabolites, or long-term changes in striatal dopamine levels, tyrosine hydroxylase immunoreactivity and glial fibrillary acidic protein. It was observed that pretreatment with MPTP protected mice against the acute increase in body temperature caused by the methamphetamine but, at the same time, delayed the occurrence of self-injurious behaviour following the repeated injections of methamphetamine. Likewise, pretreatment with MPTP attenuated the long-term depletion of striatal dopamine induced by the methamphetamine as well as the large increase in glial fibrillary acidic protein and the reduction in tyrosine hydroxylase immunoreactivity. The MPTP-treatment itself did not alter any of these neurotoxic markers. Finally, the acute decrease in 3,4-dihydroxyphenyacetic acid levels and increased ratio of 3-methoxytyramine/dopamine observed 60 min. after a single injection of methamphetamine (4 mg/kg) were also attenuated in MPTP-treated mice. These results are discussed in the context of the hypothesis that the low-dose treatment with MPTP may modify exchange diffusion across the striatal cell membrane thereby altering the acute and long-lasting effects of methamphetamine. [ABSTRACT FROM AUTHOR]

We previously demonstrated using restriction landmark genomic scanning-based 2-dimensional genome electrophoresis method decreased results of 16 primary hepatocellular carcinomas (HCCs) revealed reduction of intensity of 60 NotI-landmark spots, and increase in five spots that were frequently observed in HCCs. Most frequently decreased spot (14/16 HCCs) was identified to it corresponds to a gene encoding SSI-1, a JAK-binding protein (SSI-1/SOCS-1/JAB) that regulated the JAK/STAT signal transduction pathway. This signaling pathway is important for relaying signals from various cytokines outside the cell to the inside. Expression level of SOCS-1 messenger RNA was markedly suppressed in 50% of HCCs (4/8). Loss of heterozygosity at the SSI-1 gene, was found in all cases with aberrant expression. Methylation analysis of the CpG-rich regions of SSI-1 gene revealed hypermethylation of these regions. In an additional series of methylation analysis using 30 HCCs, 16 (53%) showed hypermethylation of the gene. These results indicate that the SSI-1 gene is silenced in a substantial portion of HCC though the combined mechanisms of methylation of either 5′ or exon CpG rich regions and by a chromosomal loss of the remaining allele. [Copyright &y& Elsevier]

We investigated the relationship between Neutrophil-to-lymphocyte ratio (NLR) and the quantities of neutrophil elastase, CD3, Foxp3, and CD204 in tumor-infiltrating cells and circulating cytokines (IL-2, -6, -8, 17a, and TGF-β) in muscle-invasive bladder cancer. IL-6 and IL-8 levels showed a significant correlation with NLR in blood and Foxp3+ cells around the tumor. After co-culture of peripheral blood cells with bladder cancer cell lines, the induction of regulatory T cell (Treg) was higher in T24 whose IL-6 and IL-8 levels were higher. High NLR correlates with increased IL-6 and IL-8 and Treg expression. [ABSTRACT FROM AUTHOR]

Objective: To estimate the phenotypic characterization of fibrotic process in adenomyosis occurring at the inner or the outer myometrium. Methods: Eight cases of adenomyosis occurring at the inner myometrium (Subtype I) and 10 cases of adenomyosis occurring at the outer myometrium (Subtype II), and 10 normal counterparts were used in this study. A immunohistochemical study for smooth muscle cells (SMCs) was performed using cytoskeletal proteins, Type I and III collagen, TGF-β and its signaling molecules. Results: An increased expression of Type I collagen was observed in the extracellular matrix of adenomyotic foci. In normal uteri, immunostaining of SMC differentiation marker proteins (Desmin, Smoothelin, Myosin heavy chain (MHC)) were absent or only found in low numbers at the inner myometrium, while all of these marker proteins were clearly stained at the outer myometrium. In both types of adenomyotic foci, Desmin, Smoothelin, and MHC commonly showed a negative staining at the adjacent area to the glands. A significant staining of Non-muscle myosin IIB, TGF-β, and phosphorylated TGF-β type I receptors were found only at the SMCs of Subtype II adenomyosis. The Smad3/2 ratio of Subtype II adenomyosis was significantly higher than that of Subtype I. Conclusions: The inner myometrium of normal uteri was composed of undifferentiated phenotypes of SMCs, while the outer myometrium was composed of terminally differentiated SMCs. Various fibrotic processes have been suggested in the development of uterine adenomyosis. Distinct expression patterns of fibrosis related proteins have been shown to be implicated with differences in the subtypes of adenomyosis. [ABSTRACT FROM AUTHOR]

Background: To assess the trends in risk classification and primary therapy of Japanese prostate cancer patients who were diagnosed between 2004 and 2012.Methods: A total of 7768 patients who were newly diagnosed with prostate cancer at Nara Medical University and its 23 affiliated hospitals between 2004 and 2012 were enrolled. The trends in risk classification and primary therapy in 2004-2006 (prior period), 2007-2009 (middle period), and 2010-2012 (latter period) were compared.Results: The proportion of high-risk and worse patients significantly decreased in the latter period compared to the prior period (p < 0.001), while that of intermediate-risk patients significantly increased over the years (p < 0.001). The proportion of primary androgen deprivation therapy (PADT) was 50% in the prior period, 40% in the middle period, and 30% in the latter period, respectively. The proportions of radiation therapy and active surveillance significantly increased. The proportion of radical prostatectomy remained similar over these periods (30%). The primary therapy was significantly different between the three periods (p < 0.001).Conclusions: High-risk patients significantly decreased in the latter period. The use of PADT also significantly decreased, while radiation therapy and active surveillance significantly increased over these periods. [ABSTRACT FROM AUTHOR]

Objective: The present study evaluated the clinical relevance of an integrative preoperative assessment of inflammation-, nutrition-, and muscle-based markers for patients with muscle-invasive bladder cancer (MIBC) undergoing curative radical cystectomy (RC). Methods: The analysis enrolled 117 patients and the variables included age, body mass index (BMI), neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, platelet-to-lymphocyte ratio, modified Glasgow Prognostic Score (mGPS), prognostic nutritional index (PNI), Controlling Nutritional Status score, psoas muscle index (PMI), and peak expiratory flow (PEF). The correlations among the variables were evaluated and their prognostic values after RC were tested. Results: Three inflammation markers (ratios of blood cell counts) were positively correlated (p < 0.0001). The PNI and the BMI were positively correlated (p = 0.04), although they were inversely correlated with the three inflammation markers (p < 0.0001). Age was not significantly correlated with the inflammation markers and PMI, although older age was associated with lower PNI and lower PEF. The disease-specific survival was independently predicted by T4 tumor, positive N status, and decreased PNI. Overall survival was independently predicted by T4 tumor, mGPS, and pretreatment sarcopenia status. Conclusions: The inflammation-, nutrition-, and muscle-based markers would be useful risk assessment tools for MIBC. [ABSTRACT FROM AUTHOR]

Background: To compare the PSA value at the last follow-up of patients who underwent prostate low-dose rate brachytherapy (LDR-BT) with that of patients who underwent intensity-modulated radiation therapy (IMRT).Methods: A total of 610 prostate cancer patients (cT1c-3bN0M0) were enrolled, and 445 of them underwent LDR-BT, while 165 received IMRT (74-76 Gy). The median follow-up period of these two groups was 75 months (LDR-BT) and 78 months (IMRT), respectively. We also evaluated the biochemical recurrence (BCR)-free rate using two definitions (Phoenix definition and PSA ≥ 0.2 ng/mL).Results: The percentage of patients who achieved PSA < 0.2 ng/mL at the last follow-up was 77.5% in the LDR-BT group and 49.7% in the IMRT group (p < 0.001). Among patients with a normal testosterone level at the last follow-up, the percentage of those who achieved PSA < 0.2 ng/mL at the last follow-up was 79.2% in the LDR-BT group and 32.1% in the IMRT group (p < 0.001). The 5-year BCR-free rate by the Phoenix definition in the IMRT and LDR-BT groups was 89.5 and 95.0% (p < 0.001), respectively. On the other hand, the 5-year BCR-free rate using the definition of PSA ≥ 0.2 ng/mL was 59.1 and 80.1% in the IMRT and LDR-BT groups, respectively (p < 0.001).Conclusions: The PSA value at the last follow-up of LDR-BT was significantly lower than that of IMRT, and this result was particularly marked in patients with a normal testosterone level at the last follow-up. [ABSTRACT FROM AUTHOR]

Objectives To investigate the effect of bacillus Calmette-Guérin maintenance therapy on patients with intermediate- and high-risk non-muscle-invasive bladder cancer receiving aggressive complete transurethral resection of bladder tumors standardized by well-trained surgeons. Methods A total of 95 patients were prospectively enrolled. Patients were diagnosed with multiple or recurrent non-muscle-invasive bladder cancer (Ta and T1), or with carcinoma in situ after complete transurethral resection of bladder tumors. Patients with Ta or T1 tumors without carcinoma in situ received six bacillus Calmette-Guérin instillations as induction therapy. Those with carcinoma in situ underwent eight bacillus Calmette-Guérin instillations as induction therapy. The patients were randomized into maintenance and non-maintenance groups. The maintenance group received intravesical bacillus Calmette-Guérin instillations once a week for 3 weeks at 3, 6, 12 and 18 months after bacillus Calmette-Guérin instillation. The primary end-point was recurrence-free survival. Results A total of 88 patients were evaluated. The average follow-up period was 48.3 ± 19.0 months. Five-year recurrence-free survival rates for the maintenance and non-maintenance groups were 80.1% and 79.3%, respectively. Five-year progression-free survival rates of the maintenance and non-maintenance groups were 92.4% and 85.3%, respectively. Recurrence- and progression-free survival rates did not significantly increase in the maintenance group compared with that in the non-maintenance group. Conclusions Bacillus Calmette-Guérin maintenance therapy did not improve recurrence- and progression-free survival rates after the initial complete transurethral resection of bladder tumors compared with that after bacillus Calmette-Guérin induction therapy alone. [ABSTRACT FROM AUTHOR]

Background: To elucidate the optimal number of prostate biopsy cores using a nomogram allocating 6-12 biopsy cores, the number generally used in daily practice, based on age and prostate volume (PV). Methods: We enrolled 936 patients who received an initial prostate biopsy from April 2006 to January 2009. A number of 6-12 biopsy cores was allocated based on age and PV Nara Urological Research and Treatment Group (NURTG) nomogram. To elucidate the predictive parameters of cancer detection in patients with a prostate specific antigen (PSA) value in the gray zone, univariate and multivariate logistic regression analysis were carried out. Results: The total cancer detection rate and the cancer detection rate in the PSA gray zone (4.1-10.0 ng/mL) were 48.0 and 37.6 %, respectively. The cancer detection rates in the gray zone stratified by patient age of ≤59, 60-64, 65-69, 70-74, 75-79, and ≥80 years were 28.4, 35.0, 26.9, 37.9, 45.7, and 54.8 %, respectively. The significant predictive parameters of cancer detection in the gray zone were age, volume biopsy ratio (VBR: PV divided by number of biopsy cores), PSA density (PSAD), digital rectal examination findings, and transrectal ultrasound findings in univariate analyses. Finally, age, VBR, and PSAD were independent parameters to predict cancer detection in the gray zone. The adverse event profile was acceptable. Conclusions: Our present study revealed that the cancer detection rate using the NURTG nomogram allocating 6-12 biopsy cores, the number generally used in daily practice, based on age and PV, could provide similar efficacy as previous studies involving more biopsy cores. In older patients the number of biopsy cores could be reduced. [ABSTRACT FROM AUTHOR]

Background: A new molecular marker of carcinoma in the urinary bladder is needed as a diagnostic tool or as a therapeutic target. Potential markers include microRNAs (miRNAs), which are short, low molecular weight RNAs 19-24 nt long that regulate genes associated with cell proliferation, differentiation, and development in various cancers. In this study, we investigated the molecular mechanisms by which miR-145 promotes survival of urothelial carcinoma cells and differentiation into multiple lineages. We found miR-145 to regulate expression of syndecan-1, a heparin sulfate proteoglycan. Methods: Cell proliferation in the human urothelial carcinoma cell lines T24 and KU7 was assessed by MTS assay. Cellular senescence and apoptosis were measured by senescence-associated β-galactosidase (SA-β-gal) and TUNEL assay, respectively. Quantitative RT-PCR was used to measure mRNA expression of various genes, including syndecan-1, stem cell factors, and markers of differentiation into squamous, glandular, or neuroendocrine cells. Results: Overexpression of miR-145 induced cell senescence, and thus significantly inhibited cell proliferation in T24 and KU7 cells. Syndecan-1 expression diminished, whereas stem cell markers such as SOX2, NANOG, OCT4, and E2F3 increased. miR-145 also up-regulated markers of differentiation into squamous (p63, TP63, and CK5), glandular (MUC-1, MUC-2, and MUC-5 AC), and neuroendocrine cells (NSE and UCHL-1). Finally, expression of miR-145 was down-regulated in high-grade urothelial carcinomas, but not in low-grade tumors. Conclusions: Results indicate that miR-145 suppresses syndecan-1 and, by this mechanism, up-regulates stem cell factors and induces cell senescence and differentiation. We propose that miR-145 may confer stem cell-like properties on urothelial carcinoma cells and thus facilitate differentiation into multiple cell types. [ABSTRACT FROM AUTHOR]

Background and purpose The aim of this study was to evaluate chronologic changes in lower urinary tract symptoms (LUTS), health-related (HR) quality of life (QOL), and disease-specific QOL during the first 12 months after salvage radiotherapy (SRT) for biochemical recurrence of prostate cancer in patients who underwent radical prostatectomy. Materials and methods In 81 patients who received SRT (70 Gy/35fr/7 weeks), International Prostate Symptom Score (IPSS), 36-Item Short Form scores, and UCLA-Prostate Cancer Index (UCLA-PCI) were recorded before, during, and immediately after SRT, and 1–12 months after the completion of SRT. Results The total IPSS and storage symptom-related sum were significantly increased following initiation of SRT, and returned to the baseline 6 months after SRT. For three of eight domains of HRQOL, and the physical component summary score showed transient deterioration in the period between completion of SRT and 1 month following SRT. The UCLA-PCI for urinary function/bother and bowel function/bother was affected until 1–6 months after SRT. Conclusions This is the first report to concurrently evaluate detailed chronologic changes in LUTS and QOL in patients who received SRT. Knowledge of changes in LUTS and QOL outcomes associated with SRT may influence treatment recommendations and enable patients to make better-informed decisions. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are short (19–24 nt), low molecular weight RNAs that play important roles in the regulation of target genes associated with cell proliferation, differentiation, and development, by binding to the 3′-untranslated region of the target mRNAs. In this study, we examined the expression of miRNA-126 (miR-126) and miR-149 in prostate cancer, and investigated the molecular mechanisms by which they affect syndecan-1 in prostate cancer. Functional analysis of miR-126 and miR-149 was conducted in the prostate cancer cell lines, PC3, Du145, and LNCaP. The expression levels of SOX2, NANOG, Oct4, miR-126 and miR-149 were evaluated by quantitative RT-PCR. After silencing syndecan-1, miR-126, and/or miR-149 in the PC3 cells, cell proliferation, senescence, and p21 induction were assessed using the MTS assay, senescence-associated β -galactosidase (SA- β -Gal) assay, and immunocytochemistry, respectively. Compared to the Du145 and LNCaP cells, PC3 cells exhibited higher expression of syndecan-1. When syndecan-1 was silenced, the PC3 cells showed reduced expression of miR-126 and miR-149 most effectively. Suppression of miR-126 and/or miR-149 significantly inhibited cell growth via p21 induction and subsequently, induced senescence. The mRNA expression levels of SOX2, NANOG, and Oct4 were significantly increased in response to the silencing of miR-126 and/or miR-149. Our results suggest that miR-126 and miR-149 are associated with the expression of syndecan-1 in prostate cancer cells. These miRNAs promote cell proliferation by suppressing SOX2, NANOG, and Oct4. The regulation of these factors by miR-126 and miR-149 is essential for syndecan-1-mediated development of androgen-refractory prostate cancer. [ABSTRACT FROM AUTHOR]

Background To evaluate the effect of two different alpha-1 adrenoceptor antagonists on lower urinary tract symptoms in patients who underwent LDR-brachytherapy. Methods A total of 141 patients who had been clinically diagnosed with localized prostate cancer and underwent LDR-brachytherapy between were enrolled. Patients were randomized and allocated to two groups (silodosin 8 mg vs. naftopidil 75 mg). The primary endpoint was a change in the international prostate symptom score (IPSS) at 3 months after seed implantation. Secondary endpoints included the recovery rate of IPSS at 12 months after seed implantation, the change in IPSS and overactive bladder symptom score, uroflowmetric parameters, and frequency volume chart (FVC). To determine independent variables that can predict IPSS recovery, logistic regression analysis was carried out. Results The mean change in the IPSS at 3 months after seed implantation in both groups was ⊿10.6 (naftopidil) and ⊿10.4 (silodosin), respectively. There was not a significant difference between the two groups (p=0.728). An increase in urinary frequency and a decrease in total urinated volume and mean voided volume were observed in FVC for 12 months after seed implantation. Multivariate analysis revealed that the urethral dose (UD30) was an independent predictive parameter of IPSS recovery. Patients with UD30 < 200Gy showed a higher recovery rate of IPSS at 12 months after seed implantation. Conclusion There was no significant difference of serial change in IPSS between silodosin and naftopidil during the first year after seed implantation. A lower dose on the urethra was an independent predictor of IPSS recovery at 12 months after seed implantation. [ABSTRACT FROM AUTHOR]

Objective. To examine the role played by E-selectin in bystander IgM-mediated modification of glomerular lesions in experimental lupus nephritis. Methods. Experimental lupus SCID mice were induced by an intraperitoneal injection of clone 7B6.8, which was derived from a MRL/lpr mouse and shown to induce wire-loop type glomerular lesions. Mice were subsequently administered clone Sp6, a non-nephritogenic IgM antibody- producing hybridoma. E-selectin expression was then evaluated in glomeruli showing histopathological conversion of lesions from wire-loop-like to a cell-proliferative form. We also investigated the effects of a circulating soluble form of E-selectin (sE-selectin) on the modification of glomerular lesions in this lupus model. Results. In experimental lupus mice, glomerular E-selectin expression significantly increased during the conversion from wire-loop-like glomerular lesions to a cell-proliferative type mediated by a non-nephritogenic bystander IgM antibody in presence of a nephritogenic antibody. Intraglomerular infiltration of CD68 + macrophages correlated significantly with the glomerular level of E-selectin expression. In addition, overexpression of circulating sE-selectin significantly suppressed conversion to cell-proliferative glomerular lesions and glomerular macrophage infiltration in these lupus model mice. Conclusions. The histopathological modification of lupus nephritis by non-nephritogenic bystander IgM antibodies is associated in part with glomerular E-selectin expression. [ABSTRACT FROM AUTHOR]

In order to study multiple contiguous prostate cancer lesions, we constructed computer-assisted, three-dimensional models of multifocal prostate cancer specimens obtained by radical prostatectomy. We then examined the genetic heterogeneity among the specimens by DNA microarray analysis. Cancer foci with high Gleason patterns were found to occur de novo, whereas those with low Gleason patterns occurred contiguously with cancers of low Gleason patterns. Three-dimensional analysis showed that distinct, noncontiguous cancerous foci were genetically independent and multicentric. In contrast some contiguous multifocal lesions had the same genetic origin. [ABSTRACT FROM AUTHOR]

BACKGROUND Herpesvirus entry mediator (HVEM) is known to regulate immune response and to be expressed in several human malignancies. However, to the authors's knowledge, the precise role of HVEM in human cancer biology remains unknown. The objective of the current study was to clarify the clinical significance of HVEM in human esophageal squamous cell carcinoma as well as its in vivo functions. METHODS HVEM expression was evaluated in 103 patients with esophageal squamous cell carcinoma to explore its clinical relevance and prognostic value. The functions of HVEM in tumors were analyzed in vitro and in vivo using the small interfering RNA (siRNA) silencing technique. RESULTS HVEM expression was found to be significantly correlated with depth of tumor invasion and lymph node metastasis. Furthermore, it was found to be inversely correlated with tumor-infiltrating CD4+, CD8+, and CD45RO+ lymphocytes. It is important to note that HVEM status was identified as an independent prognostic marker. HVEM gene silencing significantly inhibited cancer cell proliferation in vitro and cancer growth in vivo. This antitumor effect was associated with reduced cell proliferation activity. The effect was also correlated with the induction of CD8+ cells and upregulation of local immune response. CONCLUSIONS HVEM plays a critical role in both tumor progression and the evasion of host antitumor immune responses, possibly through direct and indirect mechanisms. Therefore, HVEM may be a promising therapeutic target for human esophageal cancer. Cancer 2014;120:808-817. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

Renal α-Klotho (α-KL) plays a fundamental role as a co-receptor for fibroblast growth factor 23 (FGF23), a phosphaturic hormone and regulator of 1,25(OH)2 vitamin D3 (1,25VitD3). Disruption of FGF23-α-KL signaling is thought to be an early hallmark of chronic kidney disease (CKD) involving reduced renal α-KL expression and a reciprocal rise in serum FGF23. It remains unclear, however, whether the rise in FGF23 is related to the loss of renal α-KL. We evaluated α-KL expression in renal biopsy samples and measured levels of several parameters of mineral metabolism, as well as soluble α-KL (sKL), in serum and urinary samples from CKD patients (n = 236). We found that although renal α-KL levels were significantly reduced and serum FGF23 levels were significantly elevated in early and intermediate CKD, serum phosphate levels remained within the normal range. Multiple regression analysis showed that the increases in FGF23 were significantly associated with reduced renal function and elevated serum phosphate, but were not associated with loss of renal α-KL. Moreover, despite falling renal α-KL levels, the increase in FGF23 enhanced urinary fractional excretion of phosphate and reduced serum 1,25VitD3 levels in early and intermediate CKD, though not in advanced CKD. Serum sKL levels also fell significantly over the course of CKD, and renal α-KL was a significant independent determinant of sKL. These results demonstrate that FGF23 levels rise to compensate for renal failure-related phosphate retention in early and intermediate CKD. This enables FGF23-α-KL signaling and a neutral phosphate balance to be maintained despite the reduction in α-KL. In advanced CKD, however, renal α-KL declines further. This disrupts FGF23 signaling, and serum phosphate levels significantly increase, stimulating greater FGF23 secretion. Our results also suggest the serum sKL concentration may be a useful marker of renal α-KL expression levels. [ABSTRACT FROM AUTHOR]

Spindle cell hemangioma is a rare benign tumor characterized by cavernous blood vessels and spindle cell proliferation. It typically arises in the subcutis of the distal extremities, particularly in the hand. Spindle cell hemangioma of periosteal origin is extremely rare, and our extensive literature search did not find any reports of this condition. We report here a case of spindle cell hemangioma of periosteal origin arising from the right fibula of a 49-year-old woman. Pathological examination of a needle biopsy specimen indicated the possibility of low-grade spindle cell sarcoma, and the patient underwent resection of the fibular diaphysis with a wide margin. Subsequent examination of the surgical specimen revealed a diagnosis of periosteal spindle cell hemangioma. Follow-up examination at 10 months showed no evidence of local recurrence or metastasis. A large tissue sample was required for definitive diagnosis in this case. Spindle cell hemangioma behaves in a benign fashion, but recurrence occurs in about 60% of cases. Excision of the fibula was a reasonable course of management in this case because these patients usually maintain good function. Reports of additional cases will be required to determine the most appropriate treatment for this tumor. [ABSTRACT FROM AUTHOR]

Objective: To assess whether the phosphorylated Fas-associated death domain protein (FADD) at 194 serine (p-FADD) is valuable as a marker of biochemical recurrence in hormone-naive patients who had undergone radical prostatectomy. Materials and Methods: We used radical prostatectomy specimens from 106 patients. None of the patients had received neoadjuvant or adjuvant therapy. The percentage of positive p-FADD cells (nuclear staining) was immunohistochemically evaluated. The correlation between FADD phosphorylation and the clinicopathologic parameters was assessed. The correlation between the biochemical recurrence-free rate and the p-FADD expression level was analyzed using the Kaplan-Meier method. Results: Overall, 39 patients developed biochemical recurrence. We investigated the expression of p-FADD in 106 patients with prostate cancer using immunohistochemistry. We compared our findings with the clinicopathologic parameters, including the follow-up data. Patients with a greater positive p-FADD rate had a significantly lower biochemical recurrence rate than those with a lower positive p-FADD rate (P < .001). A significant inverse correlation was found between the positive p-FADD rate and the Gleason score. Conclusion: A low expression of p-FADD could be a predictor of biochemical recurrence in hormone-naive patients who have undergone radical prostatectomy. [ABSTRACT FROM AUTHOR]

Background: To compare the periodical incidence rates of genitourinary (GU) and gastrointestinal (GI) toxicity in patients who underwent prostate low-dose-rate brachytherapy between the monotherapy group (seed implantation alone) and the boost group (in combination with external beam radiation therapy (EBRT)). Methods: A total of 218 patients with a median follow-up of 42.5 months were enrolled. The patients were divided into 2 groups by treatment modality, namely, the monotherapy group (155 patients) and the boost group (63 patients). The periodical incidence rates of GU and GI toxicity were separately evaluated and compared between the monotherapy group and the boost group using the National Cancer Institute - Common Terminology Criteria for Adverse Events, version 3.0. To elucidate an independent factor among clinical and postdosimetric parameters to predict grade 2 or higher GU and GI toxicity in the acute and late phases, univariate and multivariate logistic regression analyses were carried out. Results: Of all patients, 78.0% showed acute GU toxicity, and 7.8% showed acute GI toxicity, while 63.8% showed late GU toxicity, and 21.1% showed late GI toxicity. The incidence rates of late GU and GI toxicity were significantly higher in the boost group. Multivariate analysis showed that the International Prostate Symptom Score (IPSS) before seed implantation was a significant parameter to predict acute GU toxicity, while there were no significant predictive parameters for acute GI toxicity. On the other hand, combination with EBRT was a significant predictive parameter for late GU toxicity, and rectal volume (mL) receiving 100% of the prescribed dose (R100) was a significant predictive parameter for late GI toxicity. Conclusions: The boost group showed higher incidence rates of both GU and GI toxicity. Higher IPSS before seed implantation, combination with EBRT and a higher R100 were significant predictors for acute GU, late GU and late GI toxicity. [ABSTRACT FROM AUTHOR]

Background: To assess the trends of risk classification and primary therapy in Japanese patients who were diagnosed with prostate cancer between 2004-2006 and 2007-2009.Methods: A total of 4752 patients who were newly diagnosed with prostate cancer at Nara Medical University and its 23 affiliated hospitals between 2004 and 2009 were enrolled. The differences in risk classification and primary therapy were compared in patients who were newly diagnosed between 2004-2006 (prior period) and 2007-2009 (latter period).Results: The proportion of patients with a high or greater risk significantly decreased in the latter period compared to the prior period (p < 0.001). The proportion of primary androgen deprivation therapy (PADT) was 50% in the prior period, and 40% in the latter period. On the other hand, the proportion of radiation therapy was 14% in the prior period, but 24% in the latter period. The proportion of radical prostatectomy was the same in the two periods (30%). The primary therapy was significantly different between the two periods (p < 0.001).Conclusions: Higher risk patients significantly decreased in the latter period compared to the prior period. The use of PADT also significantly decreased in the latter period. However, there were still higher risk patients in Japan, and the use of PADT was still common in patients with localized prostate cancer or locally advanced prostate cancer in Japan. [ABSTRACT FROM AUTHOR]

The PCA-1/ALKBH3 gene implicated in DNA repair is expressed in several human malignancies but its precise contributions to cancer remain mainly unknown. In this study, we have determined its functions and clinical importance in pancreatic cancer. PCA-1/ALKBH3 functions in proliferation, apoptosis and angiogenesis were evaluated in human pancreatic cancer cells in vitro and in vivo. Further, PCA-1/ALKBH3 expression in 116 patients with pancreatic cancer was evaluated by immunohistochemistry. siRNA-mediated silencing of PCA-1/ALKBH3 expression induced apoptosis and suppressed cell proliferation. Conversely, overexpression of PCA-1/ALKBH3 increased anchorage-independent growth and invasiveness. In addition, PCA-1/ALKBH3 silencing downregulated VEGF expression and inhibited angiogenesis in vivo. Furthermore, immunohistochemical analysis showed that PCA-1/ALKBH3 expression was abundant in pancreatic cancer tissues, where it correlated with advanced tumor status, pathological stage and VEGF intensity. Importantly, patients with low positivity of PCA-1/ALKBH3 expression had improved postoperative prognosis compared with those with high positivity. Our results establish PCA-1/ALKBH3 as important gene in pancreatic cancer with potential utility as a therapeutic target in this fatal disease. [ABSTRACT FROM AUTHOR]

Hypercalciuria is one of the early manifestations of diabetic nephropathy. We explored here the role of α-Klotho, a protein expressed predominantly in distal convoluted tubules that has a role in calcium reabsorption. We studied 31 patients with early diabetic nephropathy and compared them with 31 patients with IgA nephropathy and 7 with minimal change disease. Renal α-Klotho expression was significantly lower and urinary calcium excretion (UCa/UCr) significantly higher in diabetic nephropathy than in IgA nephropathy or minimal change disease. Multiple regression analyses indicated that α-Klotho mRNA was inversely correlated with calcium excretion. We next measured these parameters in a mouse model of streptozotocin (STZ)-induced diabetic nephropathy, characterized by glomerular hyperfiltration, as seen in early diabetic nephropathy. We also confirmed a reduction of renal α-Klotho mRNA down to almost 50% and enhanced calcium excretion in mice with STZ-induced diabetic nephropathy in comparison with nondiabetic mice. Hypercalciuria was exacerbated in heterozygous α-Klotho knockout mice in comparison with wild-type mice, each with STZ-induced diabetic nephropathy. Thus, α-Klotho expression was decreased in distal convoluted tubules in diabetic nephropathy in humans and mice. Renal loss of α-Klotho may affect urinary calcium excretion in early diabetic nephropathy. [ABSTRACT FROM AUTHOR]

In this report, we describe a case of phyllodes tumor of the prostate with a high value of prostate-specific antigen (PSA). A 47-year-old man with symptoms of hematospermia presented with a steadily elevated serum PSA value of 60.76 ng/mL (normal range, <4 ng/mL). A needle biopsy revealed atypical stromal cells without any evidence of malignancy. After radical prostatectomy, the tumor measured 2.9 cm in diameter and consisted of a single nodule composed of irregular, elongated epithelial ducts and atypical stromal cells with enlarged, occasionally multinucleated, pleomorphic, or hyperchromatic nuclei. Immunohistochemistry showed that the atypical stromal cells were positive for vimentin, androgen receptor, estrogen receptor, progesterone, and 5α-reductase, but negative for MIB-1, PSA, SMA, p53, desmin, CD34, c-kit, CD10, S-100, and EGFR. Excess PSA might be secreted by hyperplastic luminal cells driven by 5α-reductase-positive stromal and epithelial cells. Array-comparative genomic hybridization (array CGH) for genomic alterations revealed a gain of 11p13, which includes the WT1 gene, and a loss of 1p36.23 and 12p12.1. After surgery, the serum PSA value rapidly decreased to within the normal range; no recurrence or distant metastasis was noted after 2 years of follow up. [ABSTRACT FROM AUTHOR]

Abstract: The aim of the study: The present study was conducted to assess the effects of intraperitoneal administration of n-propyl gallate (PG) on hippocampal neuronal survival after forebrain ischemia. Methods: Forty male Sprague-Dawley rats were randomly assigned to one of 6 groups. Animals in the PG-I-10, PG-I-8 and PG-S groups received intraperitoneal injection of PG (100mg/kg) 72, 48, 24h and 30min before severe (10min) or moderate (8min) ischemia or sham operation, respectively, while animals in the V-I-10, V-I-8 and V-S groups received the vehicle (10% DMSO) in the same manner. Forebrain ischemia was produced by bilateral carotid occlusion combined with hypotension (35mmHg) under isoflurane anesthesia. Animals were killed 7 days after reperfusion. Histological assessments were performed using hematoxylin and eosin staining. In separate groups of animals that received PG or vehicle, m-RNA levels of hypoxia-inducible factor 1α (HIF-1α), erythropoietin (EPO) and vascular endothelial growth factor (VEGF) were measured using the reverse transcription-PCR protocol. Results: The number of normal neurons was significantly higher in the PG-I-8 group compared with that in the V-I-8 group, whereas it was similar between the PG-I-10 and V-I-10 groups. Animals that received PG had significantly higher levels of HIF-1α, EPO and VEGF expression compared with those that received vehicle. Conclusion: The results indicated that intraperitoneal administration of PG may have neuroprotective effects in a model of moderate, but not severe, forebrain ischemia in rats. [Copyright &y& Elsevier]

Purpose. The purpose of this study is to investigate whether the clinicopathological biopsy findings can predict the oncological outcome in patients who undergo radical prostatectomy. Materials and Methods. Between January 1997 and March 2006, 255 patients with clinically localized adenocarcinoma of the prostate (clinical T1-3N0M0) who had undergone retropubic radical prostatectomy were enrolled in this study. None of the patients received neoadjuvant or adjuvant therapy. Clinicopathological parameters were assessed to determine a predictive parameter of biochemical recurrence. Results. Of the total 255 patients, 77 showed biochemical recurrence during the follow-up period. The estimated 5-year overall survival, 5-year cause-specific survival, and 5-year biochemical recurrence-free survival rates were 97.7%, 99.5%, and 67.3%, respectively. Multivariate analysis using the Cox proportional hazards model showed that calculated cancer volume was an independent predictor among the preoperative clinicopathological parameters (P < 0.05). SVI and PSM were independent predictors among the postoperative parameters (SVI; P < 0.001, PSM; P = 0.049). Among the significant preoperative and postoperative parameters, calculated cancer volume remained an independent predictive parameter inmultivariate analysis (P < 0.01). Conclusions. Tumor volume, as calculated by preoperative parameters, is an independent predictor of biochemical recurrence in patients who had undergone radical prostatectomy. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to evaluate the oncological outcomes in patients who underwent radical prostatectomy in various risk groups. Methods: The subjects were 468 patients with clinically localized or locally advanced adenocarcinoma of the prostate (T1-3N0M0) who underwent retropubic radical prostatectomy with/without neoadjuvant and/or adjuvant therapy at Nara Medical University and its affiliated hospitals between January 1997 and December 2006. All patients were stratified by D'Amico risk classification. The independent predictor of biochemical recurrence was determined in each risk group. Results: Of all 468 patients, 171 patients showed biochemical recurrence during a mean follow-up period of 53 months. The 5-year estimated biochemical recurrence-free survival rates in the low, intermediate, and high-risk groups were 77.3, 71.3, and 46.3%, respectively. The multivariate analysis using Cox's proportional hazard model showed that patient age in the low-risk group, seminal vesicle involvement in the intermediate-risk group, and prostate-specific antigen value at diagnosis, surgical Gleason score, percent positive core, and perineural invasion in the high-risk group were independent predictors of biochemical recurrence. Conclusions: The high-risk patients showed a significant higher biochemical recurrence than the low- and intermediate-risk patients. The independent predictor of biochemical recurrence was different in each risk group. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is known to have pivotal roles in various inflammatory processes. The TWEAK receptor, fibroblast growth factor-inducible 14 (Fn14), has various unique functions under physiological and pathological conditions; however, the therapeutic potential of its direct targeting remains unknown. Here, we found that Fn14 expression was highly upregulated in ischemic renal tissues and tubular epithelial cells of patient biopsies and experimental animal models of renal injury. To clarify the function of Fn14 in ischemia reperfusion injury, we coincubated renal tubular cells with ITEM-2, an anti-Fn14 blocking monoclonal antibody, and found that it inhibited the production of proinflammatory cytokines and chemokines after injury. Furthermore, Fn14 blockade downregulated the local expression of several proinflammatory mediators, reduced accumulation of neutrophils and macrophages in ischemic tissues, and inhibited tubular cell apoptosis. Importantly, Fn14 blockade attenuated the development of chronic fibrosis after ischemia reperfusion injury and significantly prolonged the survival of lethally injured mice. Thus, we conclude that Fn14 is a critical mediator in the pathogenesis of ischemia reperfusion injury. [ABSTRACT FROM AUTHOR]

Protein O-phosphorylation often occurs reciprocally with O-GlcNAc modification and represents a regulatory principle for proteins. O-phosphorylation of serine by glycogen synthase kinase-3β on Snail1, a transcriptional repressor of E-cadherin and a key regulator of the epithelial-mesenchymal transition (EMT) programme, results in its proteasomal degradation. We show that by suppressing O-phosphorylation-mediated degradation, O-GlcNAc at serine112 stabilizes Snail1 and thus increases its repressor function, which in turn attenuates E-cadherin mRNA expression. Hyperglycaemic condition enhances O-GlcNAc modification and initiates EMT by transcriptional suppression of E-cadherin through Snail1. Thus, dynamic reciprocal O-phosphorylation and O-GlcNAc modification of Snail1 constitute a molecular link between cellular glucose metabolism and the control of EMT. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: The purpose of this study was to prospectively assess the variations in health-related quality of life (HR-QoL) in patients who underwent low–dose rate prostate brachytherapy using iodine-125 seed source during the first year after seed implantation. Methods and Materials: Between July 2004 and December 2006, 109 patients underwent low–dose rate brachytherapy. The Medical Outcomes study 36-Item Short Form; the University of California, Los Angeles-Prostate Cancer Index; and the International Index of Erectile Function-5 were evaluated before and at 1, 3, 6, and 12 months after seed implantation. Results: In Medical Outcomes study 36-Item Short Form analyses and the HR-QoL scores were well preserved during the first year after seed implantation. In the University of California, Los Angeles-Prostate Cancer Index analyses, the urinary function and bother scores showed significant decrease during 6 months after seed implantation. The bowel function and bother scores showed significant decrease at 3 months after seed implantation. The sexual function score showed significant decrease at 3, 6, and 12 months after seed implantation, whereas the sexual bother score showed no change during the first year. The International Index of Erectile Function-5 score dramatically decreased at 1, 3, 6, and 12 months after seed implantation. Conclusions: The general HR-QoL in the patients who underwent seed implantation was well preserved during the first year after seed implantation, whereas the urinary, bowel, and sexual function and bother scores showed transient deterioration during the first year after seed implantation. Especially, sexual function showed significant deterioration in Japanese men after seed implantation. [ABSTRACT FROM AUTHOR]

Abstract: The two-vein occlusion (2VO) model is known to be useful for ischemic penumbra studies in vivo. It was applied here to examine sequential changes of regional cerebral blood flow (CBF) and cerebral venous infarction in normal (Long–Evans Tokushima Otsuka, LETO) and diabetic (Otsuka Long–Evans Tokushima Fatty, OLETF) rats. The aim of our study was to examine and compare the ischemic pathogenesis related to regional changes in cerebral blood flow (CBF) induced with 2VO in diabetic OLETF and non-diabetic LETO rats. Two cortical veins were occluded photochemically by using rose bengal dye in 10 OLETF and 10 LETO rats. All animals were killed with perfusion fixation at 48 h after 2VO. Bax and Bcl-2 staining was performed along with the terminal deoxynucleotidyl transderase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay to examine the relationship to single-cell death. Smooth muscle actin and Van Gieson''s elastic staining were done for assessment of thickening of the vessel walls. Not only the volume of cerebral cortex affected by 2VO-induced venous infarction was increased in diabetic OLETF rats, but we also observed significantly reduced CBF at 90 min after 2VO, coupled with increased apoptosis in and around ischemic lesions. Morphologically, OLETF rats demonstrated marked thickening of the walls in the small cerebral vessels with perivascular fibrosis, indicating more severe cerebral microvascular atherosclerotic changes as compared to their non-diabetic LETO counterparts. The OLETF rat thus appears to be an excellent animal model for studying the diabetic enhancement of venous ischemia induced by 2VO. [Copyright &y& Elsevier]

Objectives: To evaluate the chronologic changes in the International Prostate Symptom Score (IPSS), uroflowmetric parameters, and prostate volume (PV) in patients who received low-dose-rate brachytherapy. Methods: Between July 2004 and December 2006, 110 patients received low-dose-rate brachytherapy. Of the 110 patients, 82 were treated with seed implantation alone and 28 with combined external beam radiotherapy. The IPSS, uroflowmetric parameters, and PV were evaluated before seed implantation and at 1, 3, 6, and 12 months after seed implantation. Results: The mean IPSS showed a significant increase at 1 and 6 months after seed implantation and had returned to baseline 12 months later. The maximal flow rate, voided volume, and postvoid residual urine volume showed transient deterioration at 1 and 6 months after seed implantation and had returned to the baseline 12 months later. The mean PV compared with the baseline PV showed a significant 3.8-cm decrease (11.2%) at 12 months after implantation. The patients who did not receive neoadjuvant hormonal therapy had a 5.9-cm decrease in PV (20.2%) 12 months later. In contrast, those who received neoadjuvant hormonal therapy had no change in PV after seed implantation. Conclusions: This is the first report to evaluate the chronologic changes in subjective parameters (IPSS) and objective parameters (uroflowmetry) and PV, concurrently. The changes in subjective parameters correlated with the changes in objective parameters during the first 12 months after seed implantation. The change in the PV was different after seed implantation in patients with or without neoadjuvant hormonal therapy. [Copyright &y& Elsevier]

Objectives: To assess our initial experience in the treatment of localized prostate cancer using low-dose-rate brachytherapy (LDR-brachytherapy) with iodine-125. Methods: One-hundred consecutive patients received LDR-brachytherapy between July 2004 and October 2006. Seventy-six patients were treated with seed implantation alone, whereas 24 patients were treated with a combination of brachytherapy and external beam radiotherapy. The minimal percentage of the dose received by 90% of the prostate gland (%D90), the percentage prostate volume receiving 100% of the prescribed minimal peripheral dose (V100), and the operation time were compared among every 10 consecutive patients. Results: The means of %D90 and V100 were 109.6% and 93.4%, respectively. When compared with the first 10 patients, both D90 and V100 showed significant improvement in the following 10 consecutive patients. Similarly, the mean operation time decreased significantly according to the accumulated number of patients. Conclusions: Our initial experience with the first 100 cases suggests that LDR-brachytherapy needs accumulation of many more patients to obtain high-quality post-implant dosimetric outcomes. [ABSTRACT FROM AUTHOR]

Although the delta-opioid agonist SNC80 has been shown to attenuate hind-limb motor function and gray matter injury in normothermic rats subjected to spinal cord ischemia (SCI), its effects on white matter injury remain undetermined. In the present study, we investigated whether SNC80 could attenuate white matter injury in normothermic and mildly hypothermic rats. Forty rats were randomly allocated to one of following five groups: vehicle or SNC80 with 10 min of SCI at 38°C (V-38-10m or SNC-38-10m, respectively), vehicle or SNC80 with 22 min of SCI at 35°C (V-35-22m or SNC-35-22m, respectively), or sham. SNC80 or vehicle was intrathecally administered 15 min before SCI. Forty-eight hours after reperfusion, the white matter injury was evaluated by the extent of vacuolation. The percent area of vacuolation in the ventral white matter was significantly lower in the SNC-38-10m and SNC-35-22m groups compared with that in the V-38-10m and V-35-22m groups, respectively ( P < 0.05). The results indicate that intrathecal treatment with the delta-opioid agonist SNC80 can attenuate the ventral white matter injury following SCI in rats under normothermic and mildly hypothermic conditions. [ABSTRACT FROM AUTHOR]

Abstract: Background: ALS exclusively involves motor neurons, however, accumulating evidence suggests involvement of sympathetic neurons, as in other diseases including Parkinson''s disease and multiple system atrophy. In these diseases increased risk of sudden cardiac arrest is established, while that in ALS remains uncertain. Methods: The authors retrospectively studied 12 pathologically confirmed sporadic ALS patients who received no assisted ventilation. Among them, two patients died of sudden cardiac arrest. Changes in QTc interval and dispersion, indices of sympathetic activities obtainable by routine electrocardiograms, were evaluated at the early stage and the terminal stage. Pathologically, intermediolateral nucleus (IML) sympathetic neurons in the upper thoracic cord were examined. Results: The QTc intervals and dispersion were significantly increased at the terminal stage compared with that at the early stage (p <0.01). The numbers of IML neurons were significantly lower in ALS patients than in controls (p =0.017), and had linear inverse correlation with the rate of increases in maximum QTc interval and QTc dispersion (p =0.01, r =−0.915 and p =0.02, r =−0.884). Notably, two patients with sudden cardiac arrest showed longer QTc interval, larger QTc dispersion, and lower number of IML neurons than most of others. Conclusions: Patients with ALS had reduced sympathetic activities at the terminal stage of disease, presumably due to neuronal loss in IML, which may increase risk of sudden cardiac arrest. Thus, prolonged QTc intervals and increased QTc dispersion may suggest an increased risk of sudden death in ALS, as in other neurodegenerative diseases. [Copyright &y& Elsevier]

Abstract: It has been reported that delta opioid agonists can have neuroprotective efficacy in the central nervous system. This study was conducted to test the hypothesis that a delta opioid receptor (DOR) agonist, [d-Ala2, d-Leu5] enkephalin (DADLE), can improve neuron survival against experimental forebrain ischemia in rats. Using male rats (n =125), intraperitoneal injection of DADLE (0, 0.25, 1, 4, 16mgkg−1) was performed 30min before ischemia. Ten minutes interval forebrain ischemia was provided by the bilateral carotid occlusion combined with hypotension (35mmHg) under isoflurane (1.5%) anesthesia. All animals were neurologically and histologically evaluated after a recovery period of 1 week. As histological evaluation, percentages of ischemic neurons in the CA1, CA3, dentate gyrus (DG) were measured. During the recovery period, 27 rats died because of apparent upper airway obstruction, seizure, or unidentified causes. There were no differences in the motor activity score among the groups. Ten minutes forebrain ischemia induced approximately 75, 20, and 10% neuronal death in the CA1, CA3, and DG, respectively. Any doses of DADLE did not attenuate neuronal injury in the hippocampus after ischemia. Pre-ischemic treatment of DORs agonism with DADLE did not provide any neuroprotection to the hippocampus in rats subjected to forebrain ischemia. [Copyright &y& Elsevier]

The Otsuka Long-Evans Tokushima fatty rat is an animal model of Type 2 diabetes mellitus (DM), which is characterized by diastolic dysfunction associated with decreased sarcoplasmic reticulum Ca2+-ATPase (SERCA2a). The aim of this study was to examine whether gene transfer of SERCA2a can influence coronary blood flow and cardiomyocyte diameter in this model. DM rats were injected with adenovirus carrying SERCA2a (DM+SERCA) or β-galactosidase gene (DM+βGal). Coronary blood flow was measured in cross-circulated excised hearts 3 days after infection. Although in all groups coronary blood flow remained unchanged even if left ventricular (LV) volume or intracoronary Ca2+ infusion was increased, the DM+SERCA group showed a sustained increase in coronary blood flow compared with the other groups. This result suggests that the sustained high coronary blood flow is a specific response in SERCA2a-overexpressed hearts. Although the LV weight-to-body weight ratio (LVIBW) and cardiomyocyte diameter were higher in the DM and DM+βGal groups than in the non-DM group, in the DM+SERCA group, these measurements were restored to non-DM size. The percentages of collagen area in the three DM groups was significantly higher than results shown in non-DM rats, and there were no significant differences in collagen area percentage among the three DM groups. These results suggest that a lowered LV/BW by SERCA2a overexpression is due mainly to reduced size of cardiomyocytes without any changes in collagen area percentage. In conclusion, in DM failing hearts, SERCA2a gene transfer can increase coronary blood flow and reduce cardiomyocyte size without reduction in collagen production. [ABSTRACT FROM AUTHOR]

We successfully established cynomolgus monkey embryonic stem (cES) cell lines expressing enhanced green fluorescent protein (GFP) by introducing a GFP-encoding gene under cytomegalovirus immediate early enhancer (CMVIE) promoter regulation into cES cells. The cells maintained the ability of in vitro differentiation toward ectodermal, mesodermal, and endodermal lineages, and produced teratomas composed of tissues derived from the three embryonic germ layers when transplanted into severe combined immunodeficient disease mice. GFP expression was also observed in the differentiated cells. These GFP-expressing cES cell lines are considered useful for basic research, including cell transplantation. [Copyright &y& Elsevier]