Unraveling the contribution of ectoenzymes to myeloma life and survival in the bone marrow niche

The bone marrow provides a protected environment for generating a vast array of cell types. Bones are thus a dynamic source of structural components and soluble factors used either locally or at a distance from their site of production. We discuss the role of ectoenzymes in the bone niche where human myeloma grows. Selected ectoenzymes have been tested for their ability to promote production of substrates involved in signaling, synthesis of growth factors and hormones, and modulation of the immune response. Because of the difficulty of simultaneously tracking all these activities, we narrow our focus to events potentially influencing synthesis of adenosine (ADO), an important regulator of multiple biological functions, including local immunological tolerance. Our working hypothesis, to be discussed and partially tested herein, is that CD38, and likely BST1/CD157-both NAD(+) -consuming enzymes, are active in the myeloma niche and lead a discontinuous chain of ectoenzymes whose final products are exploited by the neoplastic plasma cell as part of its local survival strategy. Coadjuvant ectoenzymes include PC-1/CD203a, CD39, and CD73, which control the production of ADO. Results discussed here and from ongoing experiments indicate that the myeloma niche hosts the canonical, as well as alternative, pathways of ADO generation. Other possibilities are presented and discussed

A Comprehensive Characterization of Mitochondrial DNA Mutations in Glioblastoma Multiforme

Glioblastoma Multiforme (GBM) is the most malignant brain cancer in adults, with a poor prognosis, whose molecular stratification still represents a challenge in pathology and clinics. On the other hand, mitochondrial DNA (mtDNA) mutations have been found in most tumors as modifiers of the bioenergetics state, albeit in GBM a characterization of the mtDNA status is lacking to date. Here, a large characterization of the burden of mtDNA mutations in GBM samples was performed. First, investigation of tumor-specific vs. non tumor-specific mutations was carried out with the MToolBox bioinformatics pipeline by analyzing 46 matched tumor/blood samples, from whole genome or whole exome sequencing datasets obtained from The Cancer Genome Atlas (TCGA) consortium. Additionally, the entire mtDNA sequence was obtained in a dataset of 104 fresh-frozen GBM samples. Mitochondrial mutations with potential pathogenic interest were prioritized based on heteroplasmic fraction, nucleotide variability, and in silico prediction of pathogenicity. A preliminary biochemical analysis of the activity of mitochondrial respiratory complexes was also performed on fresh-frozen GBM samples. Although a high number of mutations were detected, we report that the large majority of them do not pass the prioritization filters. Therefore, a relatively limited burden of pathogenic mutations is indeed carried by GBM, which did not appear to determine a general impairment of the respiratory chain

Unruptured Aneurysms Italian Study (UAIS) background and method

Treatment of unruptured cerebral aneurysms still represents an unsettled question in neurosurgical and neuroradiological communities. Although nowadays the indication for treatment have become relatively clear, indeed uncertainity remains for what concerns the proper treatment modality (surgical or endovascular) in terms of both the risk and the mid and long-term efficacy of the two procedures. The "Unruptured Aneurysms Italian Study" is a cooperative prospective study which aims to delineate the "State of the Art" in a nation based population. It has been designed: 1) to depict the nationwide modality of treatment of Unruptured Aneurysms, 2) to assess in the most objective way the overall treatment-related mortality and morbidity as well as the surgical and endovascular risk in the respective patient populations (it is not a surgical versus endovascular study) and 3) to asses the efficacy of the different procedures in the mid and long term periods. The study started on June 2003 and to June 2006, 637 patients have been enrolled. The study will end when the 1000th patient is enrolled