Quantitative evaluation of RASSF1A methylation in the non-lesional, regenerative and neoplastic liver

BACKGROUND: Epigenetic changes during ageing and their relationship with cancer are under the focus of intense research. RASSF1A and NORE1A are novel genes acting in concert in the proapoptotic pathway of the RAS signalling. While NORE1A has not been previously investigated in the human liver, recent reports have suggested that RASSF1A is frequently epigenetically methylated not only in HCC but also in the cirrhotic liver. METHODS: To address whether epigenetic changes take place in connection to age and/or to the underlying disease, we investigated RASSF1A and NORE1A gene promoter methylation by conventional methylation specific PCR and Real-Time MSP in a series of hepatitic and non-hepatitic livers harboring regenerative/hyperplastic (cirrhosis/focal nodular hyperplasia), dysplastic (large regenerative, low and high grade dysplastic nodules) and neoplastic (hepatocellular adenoma and carcinoma) growths. RESULTS: In the hepatitic liver (chronic hepatitic/cirrhosis, hepatocellular nodules and HCC) we found widespread RASSF1A gene promoter methylation with a methylation index that increased from regenerative conditions (cirrhosis) to hepatocellular nodules (p < 0.01) to HCC (p < 0.001). In the non-hepatitic liver a consistent pattern of gene methylation was also found in both lesional (focal nodular hyperplasia and hepatocellular adenoma) and non-lesional tissue. Specifically, hepatocellular adenomas (HA) showed a methylation index significantly higher than that detected in focal nodular hyperplasia (FNH) (p < 0.01) and in non-lesional tissue (p < 0.001). In non-lesional liver also the methylation index gradually increased by ageing (p = 0.002), suggesting a progressive spreading of methylated cells over time. As opposed to RASSF1A gene promoter methylation, NORE1A gene was never found epigenetically alterated in both hepatitic and non-hepatitic liver. CONCLUSION: We have shown that in non-lesional, regenerative and neoplastic liver the RASSF1A gene is increasingly methylated, that this condition takes place as an age-related phenomenon and that the early setting and spreading over time of an epigenetically methylated hepatocyte subpopulation, might be related to liver tumorigenesis

Mobilization of Hematopoietic Stem Cells with Lenograstim in Healthy Donors: Efficacy and Safety Analysis According to Donor Age

n/

Toward a better definition of EPCAM deletions in Lynch Syndrome: Report of new variants in Italy and the associated molecular phenotype

BackgroundInherited epimutations of Mismatch Repair (MMR) genes are responsible for Lynch Syndrome (LS) in a small, but well defined, subset of patients. Methylation of the MSH2 promoter consequent to the deletion of the upstream EPCAM gene is found in about 1%-3% of the LS patients and represents a classical secondary, constitutional and tissue-specific epimutation. Several different EPCAM deletions have been reported worldwide, for the most part representing private variants caused by an Alu-mediated recombination.Methods712 patients with suspected LS were tested for MMR mutation in our Institute. EPCAM deletions were detected by multiplex ligation-dependent probe amplification (MLPA) and then defined by Long-Range polymerase chain reaction (PCR)/Sanger sequencing. A comprehensive molecular characterization of colorectal cancer (CRC) tissues was carried out by immunohistochemistry of MMR proteins, Microsatellite Instability (MSI) assay, methylation specific MLPA and transcript analyses. In addition, somatic deletions and/or variants were investigated by MLPA and next generation sequencing (NGS).ResultsAn EPCAM deletion was found in five unrelated probands in Italy: variants c.556-490_*8438del and c.858+1193_*5826del are novel; c.859-1430_*2033del and c.859-670_*530del were previously reported. All probands were affected by CRC at young age; tumors showed MSI and abnormal MSH2/MSH6 proteins expression. MSH2 promoter methylation, as well as aberrant in-frame or out-of-frame EPCAM/MSH2 fusion transcripts, were detected in CRCs and normal mucosae.ConclusionAn EPCAM deletion was the causative variant in about 2% of our institutional series of 224 LS patients, consistent with previously estimated frequencies. Early age and multiple CRCs was the main clinical feature of this subset of patients

Nab-paclitaxel/gemcitabine combination is more effective than gemcitabine alone in locally advanced, unresectable pancreatic cancer - A GISCAD phase II randomized trial

The role of combination chemotherapy has not yet been established in unresectable locally advanced pancreatic cancer (LAPC) lacking dedicated randomized trials

AVIATR - Aerial Vehicle for In-situ and Airborne Titan Reconnaissance A Titan Airplane Mission Concept

We describe a mission concept for a stand-alone Titan airplane mission: Aerial Vehicle for In-situ and Airborne Titan Reconnaissance (AVIATR). With independent delivery and direct-to-Earth communications, AVIATR could contribute to Titan science either alone or as part of a sustained Titan Exploration Program. As a focused mission, AVIATR as we have envisioned it would concentrate on the science that an airplane can do best: exploration of Titan's global diversity. We focus on surface geology/hydrology and lower-atmospheric structure and dynamics. With a carefully chosen set of seven instruments-2 near-IR cameras, 1 near-IR spectrometer, a RADAR altimeter, an atmospheric structure suite, a haze sensor, and a raindrop detector-AVIATR could accomplish a significant subset of the scientific objectives of the aerial element of flagship studies. The AVIATR spacecraft stack is composed of a Space Vehicle (SV) for cruise, an Entry Vehicle (EV) for entry and descent, and the Air Vehicle (AV) to fly in Titan's atmosphere. Using an Earth-Jupiter gravity assist trajectory delivers the spacecraft to Titan in 7.5 years, after which the AVIATR AV would operate for a 1-Earth-year nominal mission. We propose a novel 'gravity battery' climb-then-glide strategy to store energy for optimal use during telecommunications sessions. We would optimize our science by using the flexibility of the airplane platform, generating context data and stereo pairs by flying and banking the AV instead of using gimbaled cameras. AVIATR would climb up to 14 km altitude and descend down to 3.5 km altitude once per Earth day, allowing for repeated atmospheric structure and wind measurements all over the globe. An initial Team-X run at JPL priced the AVIATR mission at FY10 $715M based on the rules stipulated in the recent Discovery announcement of opportunity. Hence we find that a standalone Titan airplane mission can achieve important science building on Cassini's discoveries and can likely do so within a New Frontiers budget

Non-functioning pituitary adenoma database: a useful resource to improve the clinical management of pituitary tumors

Objective: The long-term outcome of non-functioning pituitary adenoma (NFPA) patients is not clearly established, probably due to the low annual incidence and prolonged natural history of these rare tumors. The aim of this study was to evaluate clinical data at presentation and long-term post-surgery and radiotherapy outcome in a cohort of patients with NFPA. Design and methods: A computerized database was developed using Access 2000 software (Microsoft Corporation, 1999). Retrospective registration of 295 NFPA patients was performed in seven Endocrinological Centers of North West Italy. Data were analyzed by STATA software. Results: The main presenting symptoms were visual defects (67.8%) and headache (41.4%) and the most frequent pituitary deficit was hypogonadism (43.3%), since almost all tumors were macroadenomas (96.5%). Surgery was the first choice treatment (98% of patients) and total debulking was achieved in 35.5%. Radiotherapy was performed as adjuvant therapy after surgery in 41% of patients. At the follow-up, recurrence occurred in 19.2% of patients without post-surgical residual tumor after 7.5 ± 2.6 years, regrowth in 58.4% of patients with post-surgical remnant after 5.3 ± 4.0 years and residue enlargement in 18.4% of patients post-surgically treated with radiotherapy after 8.1 ± 7.3 years. Conclusions: Our database indicates that the goal of a definitive surgical cure has been achieved during the last decade in a low percentage of patients with NFPA. This tumor database may help to reduce the delay between symptom onset and diagnosis, to assess prognostic parameters for the follow-up of patients with different risk of recurrence and to define the efficacy and safety of different treatments and their association with mortality/morbidity

Andean evolution of the Aluminé fold and thrust belt, Northern Patagonian Andes (38º30’-40º30’S)

The study of the retroarc area between 38º30’ and 40º30’S allowed us to define and characterize the different stages that led to its present configuration, and to understand the real extent and relative importance of each deformational phase and how they interrelate trough the history of the region. The analysis of the Tertiary synorogenic deposits, and its relationship with the main structural features of the area, together with the ages obtained for the cretaceous - paleogene volcanic sequences, and the determination of a structural control in their emplacement, allowed us to define the main contractional phases that affected this segment.Fil: Garcia Morabito, Ezequiel. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ramos, Victor Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Estudios Andinos "Don Pablo Groeber". Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Estudios Andinos "Don Pablo Groeber"; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; ArgentinaInternational Colloquium on Latin American Earth SciencesHeidelbergAlemaniaGermany Research Foundatio