Prognostic impact of reduced connexin43 expression and gap junction coupling of neoplastic stromal cells in giant cell tumor of bone

Missense mutations of the GJA1 gene encoding the gap junction channel protein connexin43 (Cx43) cause bone malformations resulting in oculodentodigital dysplasia (ODDD), while GJA1 null and ODDD mutant mice develop osteopenia. In this study we investigated Cx43 expression and channel functions in giant cell tumor of bone (GCTB), a locally aggressive osteolytic lesion with uncertain progression. Cx43 protein levels assessed by immunohistochemistry were correlated with GCTB cell types, clinico-radiological stages and progression free survival in tissue microarrays of 89 primary and 34 recurrent GCTB cases. Cx43 expression, phosphorylation, subcellular distribution and gap junction coupling was also investigated and compared between cultured neoplastic GCTB stromal cells and bone marow stromal cells or HDFa fibroblasts as a control. In GCTB tissues, most Cx43 was produced by CD163 negative neoplastic stromal cells and less by CD163 positive reactive monocytes/macrophages or by giant cells. Significantly less Cx43 was detected in alpha-smooth muscle actin positive than alpha-smooth muscle actin negative stromal cells and in osteoclast-rich tumor nests than in the adjacent reactive stroma. Progressively reduced Cx43 production in GCTB was significantly linked to advanced clinico-radiological stages and worse progression free survival. In neoplastic GCTB stromal cell cultures most Cx43 protein was localized in the paranuclear-Golgi region, while it was concentrated in the cell membranes both in bone marrow stromal cells and HDFa fibroblasts. In Western blots, alkaline phosphatase sensitive bands, linked to serine residues (Ser369, Ser372 or Ser373) detected in control cells, were missing in GCTB stromal cells. Defective cell membrane localization of Cx43 channels was in line with the significantly reduced transfer of the 622 Da fluorescing calcein dye between GCTB stromal cells. Our results show that significant downregulation of Cx43 expression and gap junction coupling in neoplastic stromal cells are associated with the clinical progression and worse prognosis in GCTB

Two men printing bundles of railway tickets, New South Wales, ca. 1930 [picture].

Title devised from accompanying information where available.; Part of the: Fairfax archive of glass plate negatives.; Fairfax number: 3074.; Also available online at: http://nla.gov.au/nla.pic-vn6217043; Acquired from Fairfax Media, 2012

Iranian Version of the Quality of Life in Adult Cancer Survivors (QLACS) Questionnaire: Examining Face and Content Validity, Exploratory Factor Analysis and Reliability

Background: Quality of life among cancer patients after diagnosis and treatment steps is an important factor in preventing further cancer complications. Thus, appropriate tools to evaluate the quality of life among this group are required. Quality of life in Adult Cancer Survivors (QLACS) questionnaire is a suitable tool which evaluates different aspects of life among cancer survivors. Objectives: This study evaluated the Persian version of the QLACS questionnaire among Iranian short-survivors of breast cancer by assessing its validity and reliability. Methods: The QLACS was translated to Persian for this study. The questionnaire�s face and content validity were assessed by a panel of experts by the impact score, content validity ratio, and index methods. In the next step, the questionnaire was filled out by 150 women with breast cancer who were diagnosed 1.5-5 years before this study. Explanatory factor analysis was performed to assess factors. Reliability was evaluated using Cronbach�s alpha. Results: Overall, 37 items were selected for explanatory factor analysis that had an impact score of more than 1.5, content validity ratio (CVR) more than 0.99, and a suitable content validity index (CVI). In factor analysis, 10 factors were extracted via varimax rota-tion, accounting for 75.8 of the total variance. Cronbach�s alpha of all the factors was more than 0.7, that was similar to the original questionnaire. Conclusions: We conclude that the Persian version of the QLACS questionnaire has optimal properties for the assessment of quality of life among Iranian short-survivors of breast cancer

Intercalated disc in failing hearts from patients with dilated cardiomyopathy: Its role in the depressed left ventricular function

Alterations in myocardial structure and reduced cardiomyocyte adhesions have been previously described in dilated cardiomyopathy (DCM). We studied the transcriptome of cell adhesion molecules in these patients and their relationships with left ventricular (LV) function decay. We also visualized the intercalated disc (ID) structure and organization. The transcriptomic profile of 23 explanted LV samples was analyzed using RNA-sequencing (13 DCM, 10 control [CNT]), focusing on cell adhesion genes. Electron microscopy analysis to visualize ID structural differences and immunohistochemistry experiments of ID proteins was also performed. RT-qPCR and western blot experiments were carried out on ID components. We found 29 differentially expressed genes, most of all, constituents of the ID structure. We found that the expression of GJA3, DSP and CTNNA3 was directly associated with LV ejection fraction (r = 0.741, P = 0.004; r = 0.674, P = 0.011 and r = 0.565, P = 0.044, respectively), LV systolic (P = 0.003, P = 0.003, P = 0.028, respectively) and diastolic dimensions (P = 0.006, P = 0.001, P = 0.025, respectively). Electron microscopy micrographs showed a reduced ID convolution index and immunogold labeling of connexin 46 (GJA gene), desmoplakin (DSP gene) and catenin α-3 (CTNNA3 gene) proteins in DCM patients. Moreover, we observed that protein and mRNA levels analyzed by RT-qPCR of these ID components were diminished in DCM group. In conclusion, we report significant gene and protein expression changes and found that the ID components GJA3, DSP and CTNNA3 were highly related to LV function. Microscopic observations indicated that ID is structurally compromised in these patients. These findings give new data for understanding the ventricular depression that characterizes DCM, opening new therapeutic perspectives for these critically diseased patients