Gene expression profiling identifies inflammation and angiogenesis as distinguishing features of canine hemangiosarcoma

<p>Abstract</p> <p>Background</p> <p>The etiology of hemangiosarcoma remains incompletely understood. Its common occurrence in dogs suggests predisposing factors favor its development in this species. These factors could represent a constellation of heritable characteristics that promote transformation events and/or facilitate the establishment of a microenvironment that is conducive for survival of malignant blood vessel-forming cells. The hypothesis for this study was that characteristic molecular features distinguish hemangiosarcoma from non-malignant endothelial cells, and that such features are informative for the etiology of this disease.</p> <p>Methods</p> <p>We first investigated mutations of VHL and Ras family genes that might drive hemangiosarcoma by sequencing tumor DNA and mRNA (cDNA). Protein expression was examined using immunostaining. Next, we evaluated genome-wide gene expression profiling using the Affymetrix Canine 2.0 platform as a global approach to test the hypothesis. Data were evaluated using routine bioinformatics and validation was done using quantitative real time RT-PCR.</p> <p>Results</p> <p>Each of 10 tumor and four non-tumor samples analyzed had wild type sequences for these genes. At the genome wide level, hemangiosarcoma cells clustered separately from non-malignant endothelial cells based on a robust signature that included genes involved in inflammation, angiogenesis, adhesion, invasion, metabolism, cell cycle, signaling, and patterning. This signature did not simply reflect a cancer-associated angiogenic phenotype, as it also distinguished hemangiosarcoma from non-endothelial, moderately to highly angiogenic bone marrow-derived tumors (lymphoma, leukemia, osteosarcoma).</p> <p>Conclusions</p> <p>The data show that inflammation and angiogenesis are important processes in the pathogenesis of vascular tumors, but a definitive ontogeny of the cells that give rise to these tumors remains to be established. The data do not yet distinguish whether functional or ontogenetic plasticity creates this phenotype, although they suggest that cells which give rise to hemangiosarcoma modulate their microenvironment to promote tumor growth and survival. We propose that the frequent occurrence of canine hemangiosarcoma in defined dog breeds, as well as its similarity to homologous tumors in humans, offers unique models to solve the dilemma of stem cell plasticity and whether angiogenic endothelial cells and hematopoietic cells originate from a single cell or from distinct progenitor cells.</p

Synergistic growth inhibition by Iressa and Rapamycin is modulated by VHL mutations in renal cell carcinoma

Epidermal growth factor receptor (EGFR) and tumour growth factor alpha (TGFα) are frequently overexpressed in renal cell carcinoma (RCC) yet responses to single-agent EGFR inhibitors are uncommon. Although von Hippel–Lindau (VHL) mutations are predominant, RCC also develops in individuals with tuberous sclerosis (TSC). Tuberous sclerosis mutations activate mammalian target of rapamycin (mTOR) and biochemically resemble VHL alterations. We found that RCC cell lines expressed EGFR mRNA in the near-absence of other ErbB family members. Combined EGFR and mTOR inhibition synergistically impaired growth in a VHL-dependent manner. Iressa blocked ERK1/2 phosphorylation specifically in wt-VHL cells, whereas rapamycin inhibited phospho-RPS6 and 4E-BP1 irrespective of VHL. In contrast, phospho-AKT was resistant to these agents and MYC translation initiation (polysome binding) was similarly unaffected unless AKT was inhibited. Primary RCCs vs cell lines contained similar amounts of phospho-ERK1/2, much higher levels of ErbB-3, less phospho-AKT, and no evidence of phospho-RPS6, suggesting that mTOR activity was reduced. A subset of tumours and cell lines expressed elevated eIF4E in the absence of upstream activation. Despite similar amounts of EGFR mRNA, cell lines (vs tumours) overexpressed EGFR protein. In the paired cell lines, PRC3 and WT8, EGFR protein was elevated post-transcriptionally in the VHL mutant and EGF-stimulated phosphorylation was prolonged. We propose that combined EGFR and mTOR inhibitors may be useful in the subset of RCCs with wt-VHL. However, apparent differences between primary tumours and cell lines require further investigation

Postpartum psychiatric disorders

Pregnancy is a complex and vulnerable period that presents a number of challenges to women, including the development of postpartum psychiatric disorders (PPDs). These disorders can include postpartum depression and anxiety, which are relatively common, and the rare but more severe postpartum psychosis. In addition, other PPDs can include obsessive–compulsive disorder, post-traumatic stress disorder and eating disorders. The aetiology of PPDs is a complex interaction of psychological, social and biological factors, in addition to genetic and environmental factors. The goals of treating postpartum mental illness are reducing maternal symptoms and supporting maternal–child and family functioning. Women and their families should receive psychoeducation about the illness, including evidence-based discussions about the risks and benefits of each treatment option. Developing effective strategies in global settings that allow the delivery of targeted therapies to women with different clinical phenotypes and severities of PPDs is essential

Genetic diversity and structure in the Philippine Rafflesia lagascae complex (Rafflesiaceae) inform its taxonomic delimitation and conservation

Rafflesia lagascaeis a rare endo-holoparasitic species with a disjunct distribution on Luzon Island. It is morphologically very similar to R. manillana from nearby Samar. This study aims to contribute to the taxonomy and conservation of R. lagascae and R. manillana (i.e. the R. lagascae complex) by resolving their patterns of genetic diversity and structure. The results of analyses of a microsatellite data set indicate that despite their frequently extremely small sizes and geographic isolation, Rafflesia populations display moderate genetic diversity and do not show evidence of pronounced inbreeding. Most populations appear to have limited gene flow among them. Patterns of genetic diversity of staminate and pistillate Rafflesia flowers growing on the same Tetrastigma host plants indicate that the R. lagascae complex is monoecious and that host plants are regularly infected by multiple Rafflesia plants. PCoA and Bayesian cluster analyses show that the complex is composed of three genetically isolated taxa. One of these constitutes R. manillana, supporting the morphology-based hypothesis that it is taxonomically distinct from R. lagascae. The second taxon in this complex is composed of a morphologically cryptic R. lagascae population from Mt. Labo, which is genetically distinct from all remaining R. lagascae populations that were studied and that form the third taxon. We recommend that these three taxa are managed as different conservation entities

Computed tomographic features of incomplete ossification of the canine humeral condyle

Objectives - To describe computed tomographic (CT) features of canine elbows with incomplete ossification of the humeral condyle (IOHC) and investigate co-existing incongruence in the elbow joint. Study Design - Case control study. Animals - Dogs with IOHC (n=20; 38 elbows) and 25 normal elbows. Methods - Elbows with IOHC and normal elbows were assessed by CT. Standardized dorsal and sagittal reconstructions were created at 3 levels using image analysis software to obtain single measurements of the humero-radial and humero-ulnar joint spaces. On dorsal plane reconstructions, joint space measurements were obtained at the center point of the humero-radial and humero-ulnar articulations. Joint incongruity was defined as the difference between the humero-radial and the humero-ulnar joint spaces. Results - Nineteen dogs (95%), all Spaniel breeds, had either bilateral IOHC demonstrable as a saw-toothed intercondylar complete or incomplete hypoattenuating defect with hyperattenuating margins, or IOHC with contralateral humeral condylar fracture (HCF). Joint incongruity values for IOHC were compared with those of normal elbows. Significant differences were noted at the levels of the medial coronoid apex (P &lt;.0001) and base (P &lt;.004) indicative of humero-ulnar incongruence. Evidence of medial coronoid disease in 10 elbows (26%) and degenerative joint disease in 30 elbows (79%) was also found. Conclusions - Presence of elbow incongruence may be an underlying factor in failure of ossification centers to fuse leading to IOHC. Clinical Relevance - IOHC is clearly defined by CT, and it should be considered in larger Spaniel breeds, with a chronic forelimb lameness or HCF