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This report describes the diagnosis, clinical signs, and laboratory and histopathological findings of a canine renal cystadenocarcinoma and nodular dermatofibrosis. A 10-year-old entire female half-breed German Shepherd Dog x Rottweiler was brought to a veterinary clinic with hematuria and was non-responsive to the treatment with ciprofloxacin and prednisone. Erythrogram showed a normocytic normochromic anemia. Serum biochemical analysis revealed mildly elevated aspartate aminotransferase activity and high level of symmetric dimethylarginine. Data acquired during physical examination, abdominal sonography and X-ray evaluation allowed for the presumptive diagnosis of renal cystadenocarcinoma and nodular dermatofibrosis, which was confirmed by kidney histopathology. Symmetric dimethylarginine serum level is useful with evaluating and staging of the chronic kidney disease in dogs affected by renal cystadenocarcinoma and nodular dermatofibrosis.

BackgroundRenal cell carcinoma (RCC) comprises five major molecular and histological subtypes. The Birt–Hogg–Dubé (BHD) syndrome is a hereditary human cancer syndrome that predisposes affected individuals to develop renal carcinoma of nearly all subtypes, in addition to benign fibrofolliculomas, and pulmonary and renal cysts. BHD is caused by loss-of-function mutations in the folliculin (FLCN) protein. The molecular function of FLCN is still largely unknown; opposite and conflicting evidence of the role of FLCN in mammalian target of rapamycin signalling/phosphorylated ribosomal protein S6 (p-S6) activation had recently been reported.Results and MethodsHere, the expression pattern of murine Flcn was described, and it was observed that homozygous disruption of Flcn results in embryonic lethality early during development. Importantly, heterozygous animals manifest early preneoplastic kidney lesions, devoid of Flcn expression, that progress towards malignancy, including cystopapillary adenomas. A bona fide tumour suppressor activity of FLCN was confirmed by nude mouse xenograft assays of two human RCC cell lines with either diminished or re-expressed FLCN. It was observed that loss of FLCN expression leads to context-dependent effects on S6 activation. Indeed, solid tumours and normal kidneys show decreased p-S6 upon diminished FLCN expression. Conversely, p-S6 is found to be elevated or absent in FLCN-negative renal cysts.ConclusionIn accordance with clinical data showing distinct renal malignancies arising in BHD patients, in this study FLCN is shown as a general tumour suppressor in the kidney.

Canine hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis (RCND) is a rare, naturally occurring inherited cancer syndrome observed in dogs. Genetic linkage analysis of an RCND-informative pedigree has identified a linkage group flanking RCND (CHP14-C05.377-C05.414-FH2383-C05.771-[RCND-CPH18]-C02608-GLUT4-T P53-ZuBeCa6-AHT141-FH2140-FH2594) thus localizing the disease to a small region of canine chromosome 5. The closest marker, C02608, is linked to RCND with a recombination fraction (θ) of 0.016, supported by a logarithm of odds score of 16.7. C02608 and the adjacent linked markers map to a region of the canine genome corresponding to portions of human chromosomes 1p and 17p. A combination of linkage analysis and direct sequencing eliminate several likely candidate genes, including tuberous sclerosis 1 and 2 genes (TSC1 and TSC2) and the tumor suppressor gene TP53. These data suggest that RCND may be caused by a previously unidentified tumor suppressor gene and highlight the potential for canine genetics in the study of human disease predisposition.

Since the initial report, other cases have been described. 2- 13 The cutaneous manifestations of BHD, which typically appear during the third or fourth decade of life, have been associated with renal carcinoma, 2, 5 spontaneous pneumothorax, 2, 6 and colonic polyps. 3, 4 Toro et al 2 recently reported three extended kindreds in whom renal neoplasms and BHD segregated together. BHD and this group of German Shepherd dogs share many features in common: autosomal dominant inheritance, renal cysts and tumours, and a dense collagen deposition in the skin. [...]German Shepherd dogs with RCND may be a good animal model for BHD.

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