CD38 and ZAP-70 are functionally linked and mark CLL cells with high migratory potential

AbstractOur interest in chronic lymphocytic leukemia (CLL) derives primarily from the exploitation of human diseases as strategic models for defining the in vivo biological roles of CD38. Using this model, we showed that CD38 triggers robust proliferation/survival signals modulated through the interactions with the CD31 ligand expressed by nurselike cells and by the stromal/endothelial components. By analyzing a cohort of 56 patients with clinically and molecularly characterized CLL, we show that (1) patients with CD38+/ZAP-70+ are characterized by enhanced migration toward Stromal derived factor-1α (SDF-1α)/CXCL12; (2) CD38 ligation leads to tyrosine phosphorylation of ZAP-70, showing that these markers are functionally linked; (3) ZAP-70 represents a limiting factor for the CD38 pathway in the CLL context, as shown by studying CD38-mediated signal transduction in 26 molecularly characterized patients; and (4) the CLL subgroup of patients defined on the basis of migratory potential is marked by a specific genetic signature, with a significant number of differentially expressed genes being involved in cell-cell interactions and movement. Altogether, the results of this work provide biological evidence for why the combined analysis of CD38 and ZAP-70 expression as determined in several clinical trials results in more dependable identification of patients with CLL who have aggressive disease

Germline NGS targeted analysis in adult patients with sporadic adrenocortical carcinoma

Background: Adrenocortical carcinoma (ACC) is a rare cancer that arises sporadically or due to hereditary syndromes. Data on germline variants (GVs) in sporadic ACC are limited. Our aim was to characterize GVs of genes potentially related to adrenal diseases in 150 adult patients with sporadic ACC. Methods: This was a retrospective analysis of stage I-IV ACC patients with sporadic ACC from two reference centers for ACC in Italy. Patients were included in the analysis if they had confirmed diagnosis of ACC, a frozen peripheral blood sample and complete clinical and follow-up data. Next generation sequencing technology was used to analyze the prevalence of GVs in a custom panel of 17 genes belonging to either cancer-predisposition genes or adrenocortical-differentiation genes categories. Results: We identified 18 GVs based on their frequency, enrichment and predicted functional characteristics. We found six pathogenic (P) or likely pathogenic (LP) variants in ARMC5, CTNNB1, MSH2, PDE11A and TP53 genes; and twelve variants lacking evidence of pathogenicity. New unique P/LP variants were identified in TP53 (p.G105D) and, for the first time, in ARMC5 (p.P731R). The presence of P/LP GVs was associated with reduced survival outcomes and had a significant and independent impact on both progression-free survival and overall survival. Conclusions: GVs were present in 6.7 % of patients with sporadic ACC, and we identified novel variants of ARMC5 and TP53. These findings may improve understanding of ACC pathogenesis and enable genetic counseling of patients and their families

p63 is an alternative p53 repressor in melanoma that confers chemoresistance and a poor prognosis.

The role of apoptosis in melanoma pathogenesis and chemoresistance is poorly characterized. Mutations in TP53 occur infrequently, yet the TP53 apoptotic pathway is often abrogated. This may result from alterations in TP53 family members, including the TP53 homologue TP63. Here we demonstrate that TP63 has an antiapoptotic role in melanoma and is responsible for mediating chemoresistance. Although p63 was not expressed in primary melanocytes, up-regulation of p63 mRNA and protein was observed in melanoma cell lines and clinical samples, providing the first evidence of significant p63 expression in this lineage. Upon genotoxic stress, endogenous p63 isoforms were stabilized in both nuclear and mitochondrial subcellular compartments. Our data provide evidence of a physiological interaction between p63 with p53 whereby translocation of p63 to the mitochondria occurred through a codependent process with p53, whereas accumulation of p53 in the nucleus was prevented by p63. Using RNA interference technology, both isoforms of p63 (TA and ΔNp63) were demonstrated to confer chemoresistance, revealing a novel oncogenic role for p63 in melanoma cells. Furthermore, expression of p63 in both primary and metastatic melanoma clinical samples significantly correlated with melanoma-specific deaths in these patients. Ultimately, these observations provide a possible explanation for abrogation of the p53-mediated apoptotic pathway in melanoma, implicating novel approaches aimed at sensitizing melanoma to therapeutic agents

RENDIMENTO DE CARCAÇA E QUALIDADE DE CARNE DE CODORNAS MACHO PARA POSTURA

Tendo-se o objetivo de avaliar o desempenho, o rendimento de carcaça e a composição química da carne de codornas japonesas macho submetidas a diferentes níveis de energia e proteína na dieta, 216 codornas foram distribuídas em nove tratamentos, quatro repetições e seis aves por parcela. Aos 38 dias de idade as aves foram distribuídas em delineamento inteiramente casualizado, em esquema fatorial 3 x 3, sendo três níveis de energia (2.600, 2.800 e 3.000 kcal EM/kg) e três níveis de proteína (16, 18 e 20%), constituindo as rações experimentais fornecidas até 56 dias de idade. Os resultados mostraram que a matéria seca original foi significativamente mais elevada na carne das aves submetidas ao tratamento contendo 2.600 kcal EM/kg de ração seguida pela carne das aves alimentadas com 3.000 kcal EM/kg. A quantidade de lipídios totais também foi maior na carne das aves alimentadas com rações contendo 2.600 e 3.000 kcal EM/kg de ração. Não houve influência dos níveis de energia e proteína das dietas nos parâmetros de desempenho e qualidade de carne. Conclui-se que os menores níveis de energia e de proteína na dieta não afetaram o desempenho, o rendimento de carcaça e a composição química da carne de codornas machos para postura

An\ue1lise faun\uedstica de Braconidae (Hymenoptera) em tr\ueas \ue1reas de mata nativa do Estado do Paran\ue1, Brasil

The material studied comes from three of the several natural environments which still occur in Paraná State. The samples were collected during the project PROFAUPAR, developed by Departamento de Zoologia, Universidade Federal do Paraná. The selected sites were: Antonina (in the coastal plain), São José dos Pinhais (in the coastal mountain range) and Telêmaco Borba (in the second plateau). During one year of the project, 2,106 specimens of Braconidae were collected with light trap. These wasps represented 21 subfamilies and 1,966 specimens were identified in 85 genera. Hormiinae, Rogadinae, Microgastrinae, Alysiinae, Doryctinae and Meteorinae were the most frequent subfamilies. Indices of diversity and evenness were used to discuss richness and dominance of genera in each locality. Statistical analyses indicated that the asymptote of actual genera richness have been approached only to Antonina and Telêmaco Borba