No abstract

The transcription factor SOX11 plays an important role in embryonic neurogenesis and tissue remodeling. Recent studies have shown aberrant expression of SOX11 in various types of aggressive B cell neoplasms. In this study, we have analyzed SOX11 transcription levels in 86 patients with diagnosis of chronic lymphocytic leukemia (CLL). Results were correlated with well-known prognostic factors such as immunoglobulin heavy chain variable (IGHV) gene mutational status, cytogenetics risk groups and clinicopathological characteristics of the disease. Overall, 35 % of cases showed SOX11 expression; meanwhile, the remaining 65 % lacked gene expression. The analysis taking into account the IGHV mutational status showed significant differences in SOX11 transcripts levels between mutated (0.004 ± 0.0001) and unmutated CLL patients (0.405 ± 0.011) (p < 0.0001), as well as a positive correlation between SOX11 mRNA expression and the percentage of IGHV homology (p = 0.0001). Furthermore, significantly lower SOX11 mRNA expression was detected in patients with deletion 13q14 as a single alteration (0.016 ± 0.008) than those observed in cases with deletions 11q/17p (0.35 ± 0.017) (p = 0.02). The correlation of gene expression with clinical evolution showed shorter treatment free survival (p = 0.043) and overall survival (p = 0.047) in SOX11 positive patients compared to SOX11 negative cases. Our findings show for the first time an association between SOX11 expression and some CLL poor prognostic factors. These results suggest SOX11 as a possible biomarker that adds new biological information that could contribute to a better understanding of this pathology.

Human embryonic stem cells (hESCs) are self-renewing pluripotent cells that can differentiate to a wide range of specialized cells and hold great promise as models for human development and disease, as well as for drug discovery and cell-replacement therapies. Group B Coxsackie viruses (CVBs) produce acute myocarditis, pancreatitis, non-septic meningitis and encephalitis in neonates, children and young adults. Moreover, CVBs can produce spontaneous miscarriage after early embryo infection. It was reported that hESCs express CVBs receptors and are susceptible to CVB3 infection. Apoptosis is one of the hallmarks of CVBs infection although details regarding CVB3 involvement in the apoptotic processes remain elusive. In order to evaluate the mechanisms of cell death induced by CVB3 in these pluripotent cells, we infected HUES-5 (H5) and WA01 (H1) hESC lines with CVB3. After validating the maintenance of stemness in these hESC lines when grown as confluent monolayers in feeder-free conditions, we analysed several aspects of programmed cell death triggered by CVB3. In all cases, we detected chromatin condensation, DNA fragmentation and caspase-9 and 3 cleavages. Moreover, we observed the presence of cleaved PARP product which was preceded by the appearance of p17, the catalytically active fragment of caspase-3. Mitochondrial function assays revealed a MOI dependent decrease in cell viability at 24 h post-infection (pi). No appreciable modifications in Bcl-2, Bcl-X(L) and Bax protein levels were observed upon CVB3 infection during 5-24 h observation period. However, a marked decrease in pro-apoptotic Bad abundance was detected without changes in its mRNA levels. In this study we found that the hESCs are highly susceptible to CVB3 infection and display elevated apoptosis rates, thus emerging as suitable human non-transformed in vitro models to study CVB3-induced apoptosis and resulting relevant to understand CVBs pathogenesis.

Glioblastomas (GBM), the most prevalent and lethal primary brain tumors, are characterized by high intertumoral heterogeneity, diffuse infiltration, and resistance to conventional therapies. Notably, the ability of tumor cells to invade surrounding tissues is one of their most damaging characteristics, it not only causes resistance to therapies such as surgery and radiotherapy but is ultimately the primary cause of death. Therapies that cause hypoxia (e.g. anti-angiogenic therapies) have been shown to increase invasiveness, leading to resistance to the therapy itself and further complications for the patients. Using patient-derived glioma stem cell lines (GSCL) we have discovered cell lines that display heterogeneous migratory behavior in response to hypoxia. As expected we observed that four GSCLs studied had increased migration in hypoxia. Strikingly, two other cell lines studied showed decreased migration in hypoxia. This unforeseen result reflects the heterogeneous nature of GBM and the difference between these GSCLs could be key to understanding this variable. To delve into the molecular context that could explain these differences we performed an exploratory RNAseq analysis on four of the GSCLs, two that showed hypoxia-induced migration and two with decreased migration in hypoxia, and evaluated genes differentially expressed in hypoxia versus normoxia. We also carried out gene ontology and pathway enrichment analysis to discover molecular and pathway patterns consistent with the migratory behaviors observed in each group of GSCLs. The results show how that a similar migratory response to hypoxia coincides with particular sets of enriched genes and pathways. Specifically, we found NOTCH and WNT signaling pathways upregulated in GSCLs which showed increased migration in hypoxia while the IFN-gamma pathway upregulated in GSCLs with decreased migration in hypoxia. Knowing the individual molecular mechanisms responsible for the migratory behavior could allow for tailor-made therapies that reduce the dissemination of these tumors.