Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of European ancestry

Contains fulltext : 167299.pdf (publisher's version ) (Closed access)Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 x 10(-6)), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 x 10(-11)) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 x 10(-10)). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region-the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r(2) = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case-case P </= 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer

Deficient angiogenesis in redox-dead Cys17Ser PKARIα knock-in mice

Angiogenesis is essential for tissue development, wound healing and tissue perfusion, with its dysregulation linked to tumorigenesis, rheumatoid arthritis and heart disease. Here we show that pro-angiogenic stimuli couple to NADPH oxidase-dependent generation of oxidants that catalyse an activating intermolecular-disulphide between regulatory-RIα subunits of protein kinase A (PKA), which stimulates PKA-dependent ERK signalling. This is crucial to blood vessel growth as 'redox-dead' Cys17Ser RIα knock-in mice fully resistant to PKA disulphide-activation have deficient angiogenesis in models of hind limb ischaemia and tumour-implant growth. Disulphide-activation of PKA represents a new therapeutic target in diseases with aberrant angiogenesis.</p

What is the role of routine follow-up for localised limb soft tissue sarcomas? A retrospective analysis of 174 patients

BACKGROUND: There are neither prospective data nor agreement on the optimal routine follow-up procedures in patients treated for soft tissue sarcoma of the limb. METHODS: Data on 174 consecutive patients with a soft tissue sarcoma of the limb undergoing follow-up by oncologists at a single centre from 2003 to 2009 were included in this analysis. The rate and site of recurrence and mode of detection were analysed. Outcome of the patients was assessed. RESULTS: Eighty-two patients (47%) experienced relapse of any type. Isolated local recurrence occurred in 26 patients and local relapse with synchronous pulmonary metastases in five patients. Local recurrences were detected clinically in 30 of these 31 patients; magnetic resonance imaging identified only one local recurrence. Twenty-eight patients developed isolated lung metastases; in nine patients these were amenable to resections, seven of whom are currently free of disease after treatment. Lung metastases were detected by chest x-ray (CXR) in 19 patients, computed tomography scanning in 3 patients, and clinically in 11 patients. Twenty-three patients developed non-pulmonary metastases. More than 80% of relapses occurred in the first 2 years of follow-up; however, later recurrences were also observed. CONCLUSIONS: Routine follow-up CXR can detect lung metastases suitable for surgical resection, although the optimal interval of imaging has yet to be defined. Local relapse is almost always detected by patients or physicians, and routine scanning of the primary site is of doubtful benefit. Patient and physician education to detect local relapse may be helpful. Prospective evaluation of follow-up is recommended