Phase I trial of intravesical Suramin in recurrent superficial transitional cell bladder carcinoma

Suramin is an antitrypanosomal agent with antineoplastic activity, but with serious systemic side effects. We administered Suramin intravesically to determine a concentration with low toxicity but with evidence of a pharmacodynamic effect, to recommend a dose level for phase II trials. This was an open-labelled, nonrandomised dose-escalation phase I study. In all, 12 patients with a history of recurrent superficial bladder cancer were grouped into four dose levels (10–150 mg ml−1 in 60 ml saline). Six catheter instillations at weekly intervals were used. Cystoscopy and biopsy were performed before and 3 months after the start of treatment. Suramin was assayed using high-performance liquid chromatography, vascular endothelial growth factor (VEGF) using ELISA (enzyme-linked immunosorbent assay), and urinary protein profile using surface-enhanced laser desorption ionisation mass spectroscopy (SELDI). Minimal systemic absorption of Suramin was found at the highest dose of 150 mg ml−1. Urinary VEGF was affected by Suramin at doses above 50 mg ml−1, corresponding to the estimated threshold of saturation of Suramin binding to urine albumin. SELDI showed a specific disappearance of urinary protein peaks during treatment. Intravesical Suramin shows lack of toxicity and low systemic absorption. The results of this phase I trial support expanded clinical trials of efficacy at a dose of 100 mg ml−1 intravesically

Hyperbaric oxygen therapy for painful bladder syndrome/interstitial cystitis resistant to conventional treatments: long-term results of a case series in Japan

<p>Abstract</p> <p>Background</p> <p>There is no confirmed strategy for treating painful bladder syndrome/interstitial cystitis (PBS/IC) with unclear etiology. Therefore, a pilot study was carried out to evaluate the efficacy and safety of hyperbaric oxygen (HBO) therapy in treatment-resistant PBS/IC patients.</p> <p>Methods</p> <p>HBO treatment (2.0 ATA for 60 minutes/day × 5 days/week for 2 or 4 weeks) was performed on 11 patients with severe symptoms that had not been improved by previous therapy regimens between December 2004 and July 2009.</p> <p>Results</p> <p>Seven of the 11 patients demonstrated persistent improvement in symptoms during the 12 months after HBO treatment. These responders demonstrated a decrease in the pelvic pain scale and urgency scale from 7.7 ± 1.0 and, 6.6 ± 0.9 to 3.4 ± 2.5 and 4.3 ± 2.4 after 12 months, respectively (p < 0.05). The total score of the interstitial cystitis symptom index and 24-hour urinary frequency demonstrated a significant sustained decrease from the baseline. Two responders, who received an additional course of HBO 12 and 13 months after initial treatment, respectively, did not suffer impairment for more than two years. There was one case of transient eustachian tube dysfunction and three cases of reversible exudative otitis media as a consequence of HBO treatment.</p> <p>Conclusions</p> <p>HBO is a potent treatment for PBS/IC patients resistant to conventional therapy. It was well tolerated and provided maintained amelioration of pain, urgency and urinary frequency for at least 12 months.</p

Comparison of hypoxia transcriptome in vitro with in vivo gene expression in human bladder cancer

Hypoxia-inducible genes have been linked to the aggressive phenotype of cancer. However, nearly all work on hypoxia-regulated genes has been conducted in vitro on cell lines. We investigated the hypoxia transcriptome in primary human bladder cancer using cDNA microarrays to compare genes induced by hypoxia in vitro in bladder cancer cell line EJ28 with genes upregulated in 39 bladder tumour specimens (27 superficial and 12 invasive). We correlated array mRNA fold changes with carbonic anhydrase 9 (CA IX) staining of tumours as a surrogate marker of hypoxia. Of 6000 genes, 32 were hypoxia inducible in vitro more than two-fold, five of which were novel, including lactate transporter SLC16A3 and RNAse 4. Eight of 32 hypoxia-inducible genes in vitro were also upregulated on the vivo array. Vascular endothelial growth factor mRNA was upregulated two-fold by hypoxia and 2–18-fold in 31 out of 39 tumours. Glucose transporter 1 was also upregulated on both arrays mRNA, and fold changes on the in vivo array significantly correlated with CA IX staining of tumours (P=0.008). However, insulin-like growth factor binding protein 3 mRNA was the most strongly differentially expressed gene in both arrays and this confirmed its upregulation in urine of bladder cancer patients (n=157, P<0.01). This study defines genes suitable for an in vivo hypoxia ‘profile', shows the heterogeneity of the hypoxia response and describes new hypoxia-regulated genes

Co-expression of RON and MET is a prognostic indicator for patients with transitional-cell carcinoma of the bladder

Recepteur d'Origine Nantais (RON) is a distinct receptor tyrosine kinase in the c-met proto-oncogene family. We examined the mutational and expression patterns of RON in eight human uroepithelial cell lines. Biological effects of RON overexpression on cancer cells were investigated in vitro, and the prognostic significance of RON and/or c-met protein (MET) expression was analysed in a bladder cancer cohort (n=183). There was no evidence of mutation in the kinase domain of RON. Overexpression of RON using an inducible Tet-off system induced increased cell proliferation, motility, and antiapoptosis. Immunohistochemical analysis showed that RON was overexpressed in 60 cases (32.8%) of primary tumours, with 14 (23.3%) showing a high level of expression. Recepteur d'Origine Nantais expression was positively associated with histological grading, larger size, nonpapillary contour, and tumour stage (all P<0.01). In addition, MET was overexpressed in 82 cases (44.8%). Co-expressed RON and MET was significantly associated with decreased overall survival (P=0.005) or metastasis-free survival (P=0.01) in 35 cases (19.1%). Recepteur d'Origine Nantais-associated signalling may play an important role in the progression of human bladder cancer. Evaluation of RON and MET expression status may identify a subset of bladder-cancer patients who require more intensive treatment

Cooperative stimulation of vascular endothelial growth factor expression by hypoxia and reactive oxygen species: the effect of targeting vascular endothelial growth factor and oxidative stress in an orthotopic xenograft model of bladder carcinoma

Elevated thymidine phosphorylase has been shown to correlate with increased angiogenesis and poor prognosis in many cancers including transitional cell carcinoma of the bladder. In vitro studies have demonstrated that thymidine phosphorylase activity causes cellular oxidative stress and increases secretion of vascular endothelial growth factor. In this study, we show that thymidine phosphorylase activity also augments levels of the hypoxia-inducible factor-1α during in vitro hypoxia, and that thymidine phosphorylase activity and hypoxia act in concert to increase vascular endothelial growth factor (VEGF) secretion. We also demonstrate that thymidine phosphorylase overexpression confers tumorigenicity on an orthotopically implanted transitional cell carcinoma cell line. Administration of the antioxidant N-acetylcysteine together with a blocking anti-VEGF antibody abrogates the increase in tumorigenicity. Our results support the increased efficacy of combination approaches to antiangiogenic therapy

Loss of Hairless Confers Susceptibility to UVB-Induced Tumorigenesis via Disruption of NF-kappaB Signaling

In order to model squamous cell carcinoma development in vivo, researchers have long preferred hairless mouse models such as SKH-1 mice that have traditionally been classified as ‘wild-type’ mice irrespective of the genetic factors underlying their hairless phenotype. The work presented here shows that mutations in the Hairless (Hr) gene not only result in the hairless phenotype of the SKH-1 and Hr−/− mouse lines but also cause aberrant activation of NFκB and its downstream effectors. We show that in the epidermis, Hr is an early UVB response gene that regulates NFκB activation and thereby controls cellular responses to irradiation. Therefore, when Hr expression is decreased in Hr mutant animals there is a corresponding increase in NFκB activity that is augmented by UVB irradiation. This constitutive activation of NFκB in the Hr mutant epidermis leads to the stimulation a large variety of downstream effectors including the cell cycle regulators cyclin D1 and cyclin E, the anti-apoptosis protein Bcl-2, and the pro-inflammatory protein Cox-2. Therefore, Hr loss results in a state of uncontrolled epidermal proliferation that promotes tumor development, and Hr mutant mice should no longer be considered merely hairless 'wild-type' mice. Instead, Hr is a crucial UVB response gene and its loss creates a permissive environment that potentiates increased tumorigenesis

SETDB1 Is Involved in Postembryonic DNA Methylation and Gene Silencing in Drosophila

DNA methylation is fundamental for the stability and activity of genomes. Drosophila melanogaster and vertebrates establish a global DNA methylation pattern of their genome during early embryogenesis. Large-scale analyses of DNA methylation patterns have uncovered revealed that DNA methylation patterns are dynamic rather than static and change in a gene-specific fashion during development and in diseased cells. However, the factors and mechanisms involved in dynamic, postembryonic DNA methylation remain unclear. Methylation of lysine 9 in histone H3 (H3-K9) by members of the Su(var)3–9 family of histone methyltransferases (HMTs) triggers embryonic DNA methylation in Arthropods and Chordates. Here, we demonstrate that Drosophila SETDB1 (dSETDB1) can mediate DNA methylation and silencing of genes and retrotransposons. We found that dSETDB1 tri-methylates H3-K9 and binds methylated CpA motifs. Tri-methylation of H3-K9 by dSETDB1 mediates recruitment of DNA methyltransferase 2 (Dnmt2) and Su(var)205, the Drosophila ortholog of mammalian “Heterochromatin Protein 1”, to target genes for dSETDB1. By enlisting Dnmt2 and Su(var)205, dSETDB1 triggers DNA methylation and silencing of genes and retrotransposons in Drosophila cells. DSETDB1 is involved in postembryonic DNA methylation and silencing of Rt1b{} retrotransposons and the tumor suppressor gene retinoblastoma family protein 1 (Rb) in imaginal discs. Collectively, our findings implicate dSETDB1 in postembryonic DNA methylation, provide a model for silencing of the tumor suppressor Rb, and uncover a role for cell type-specific DNA methylation in Drosophila development

Association between XPF Polymorphisms and Cancer Risk: A Meta-Analysis

Background: Xeroderma pigmentosum complementation group F (XPF or ERCC4) plays a key role in DNA repair that protects against genetic instability and carcinogenesis. A series of epidemiological studies have examined associations between XPF polymorphisms and cancer risk, but the findings remain inconclusive. Methodology/Principal Findings: In this meta-analysis of 47,639 cancer cases and 51,915 controls, by searching three electronic databases (i.e., MEDLINE, EMBASE and CNKI), we summarized 43 case-control studies from 29 publications on four commonly studied polymorphisms of XPF (i.e., rs1800067, rs1799801, rs2020955 and rs744154), and we did not find statistical evidence of any significant association with overall cancer risk. However, in stratification analyses, we found a significant association of XPF-rs1799801 with a reduced cancer risk in Caucasian populations (4,845 cases and 5,556 controls; recessive model: OR = 0.87, 95% CI = 0.76–1.00, P = 0.049, P = 0.723 for heterogeneity test, I2 = 0). Further genotype-phenotype correlation analysis showed that the homozygous variant CC genotype carriers had higher XPF expression levels than that of the TT genotype carriers (Student’s t test for a recessive model: P = 0.046). No publication bias was found by using the funnel plot and Egger’s test. Conclusion: This meta-analysis suggests a lack of statistical evidence for the association between the four XPF SNPs and overall risk of cancers. However, XPF-rs1799801 may be associated with cancer risk in Caucasian populations, which needs to be further validated in single large, well-designed prospective studies

An ethic of connectedness: enacting moral school leadership through people and programs

As educators, we grapple with a myriad of dilemmas and often have difficulty resolving issues that relate to curriculum and instruction, funding, facilities and supervision, to name a few. Depending on the leader(s), a variety of ethics come in to play when making decisions. The ethic of connectedness refers to community building and welfare as central to moral thought and practice (Bradley, 2007). Responsibility to community building and welfare begins in the schools and must be an acculturated practice within the schools so future generations possess the knowledge, skills and dispositions that ensure a connectedness to their society (Marzano et al., 2005; Barth 2006; Collinson et al., 2006). This article will explore the importance of an ethic of connectedness to effective school leadership and the experience of a Pennsylvania school district in nurturing and building a connectedness within the school community.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

Vitamin D exposure and Risk of Breast Cancer: a meta-analysis

The relationship between vitamin D and breast cancer is still controversial. The present meta-analysis examines the effects of the 25(OH)D, 1,25(OH)2D and vitamin D intake on breast cancer risk. For this purpose, a PubMed, Scopus and Web of Science-databases search was conducted including all papers published with the keywords "breast cancer" and "vitamin D" with at least one reported relative risk (RR) or odds ratio (OR). In total sixty eight studies published between 1998 and 2018 were analyzed. Information about type of study, hormonal receptors and menopausal status was retrieved. Pooled OR or RR were estimated by weighting individual OR/RR by the inverse of their variance Our study showed a protective effect between 25 (OH) D and breast cancer in both cohort studies (RR?=?0.85, 95%CI:0.74-0.98) and case-control studies (OR?=?0.65, 95%CI: 0.56-0.76). However, analyzing by menopausal status, the protective vitamin D - breast cancer association persisted only in the premenopausal group (OR?=?0.67, 95%CI: 0.49-0.92) when restricting the analysis to nested case-control studies. No significant association was found for vitamin D intake or 1,25(OH)2D. CONCLUSION: This systematic review suggests a protective relationship between circulating vitamin D (measured as 25(OH) D) and breast cancer development in premenopausal women