First performance evaluation of a Multi-layer Thick Gaseous Electron Multiplier with in-built electrode meshes - MM-THGEM

We describe a new micro-pattern gas detector structure comprising a multi-layer hole-type multiplier (M-THGEM) combined with two in-built electrode meshes: the Multi-Mesh THGEM-type multiplier (MM-THGEM). Suitable potential differences applied between the various electrodes provide an efficient collection of ionization electrons within the MM-THGEM holes and a large charge avalanche multiplication between the meshes. Different from conventional hole-type multipliers (e.g. Gas Electron Multipliers - GEMs, Thick Gas Electron Multipliers - THGEMs, etc.), which are characterized by a variable (dipole-like) field strength inside the avalanche gap, electrons in MM-THGEMs are largely multiplied by a strong uniform field established between the two meshes, like in the parallel-plate avalanche geometry. The presence of the two meshes within the holes allows for the trapping of a large fraction of the positive ions that stream back to the drift region. A gas gain above 10^5 has been achieved for single photo-electron detection with a single MM-THGEM in Ar/(10%)CH4 and He/(10%)CO2, at standard conditions for temperature and pressure. When the MM-THGEM is coupled to a conventional THGEM and used as first cascade element, the maximum achievable gains reach values above 10^6 in He/(10%)CO2, while the IBF approaches of 1.5% in the case of optimum detector-bias configuration. This IBF value is several times lower compared to the one obtained by a double GEM/THGEM detector (5-10%), and equivalent to the performance attained by a Micromegas detector.Comment: 11 pages, 8 figures. Submitted to JINS

The revised Brussels-Locarno Sunspot Number (1981-2015)

In 1981, the production of the international Sunspot Number moved from the Z\"{u}rich Observatory to the Royal Observatory of Belgium, marking a very important transition in the history of the Sunspot Number. Those recent decades are particularly important for linking recent modern solar indices and fluxes and the past Sunspot Number series. However, large variations have been recently identified in the scale of the Sunspot Number between 1981 and the present. Here, we reconstruct a new average Sunspot Number series $S_N$ using long-duration stations between 1981 and 2015. We also extend this reconstruction using long-time series from 35 stations over 1945-2015, which includes the 1981 transition. In both reconstructions, we also derive a parallel Group Number series $G_N$. Our results confirm the variable trends of the Locarno pilot station. We also verify the scale of the resulting 1981-2015 correction factor relative to the preceding period 1945--1980. By comparing the new $S_N$ and $G_N$ series, we find that a constant quadratic relation exists between those two indices. This proxy relation leads to a fully constant and cycle-independent $S_N/G_N$ ratio over cycles 19 to 23, with the exception of cycle 24. We find a very good agreement between our reconstructed $G_N$ and the new "backbone" Group Number but inhomogeneities in the original Group Number as well as the $F_{10.7}$ radio flux and the American sunspot number $R_a$. This analysis opens the way to the implementation of a more advanced method for producing the Sunspot Number in the future. In particular, we identify the existence of distinct subsets of observing stations sharing very similar personal k factors, which may be a key element for building a future multi-station reference in place of the past single pilot station.Comment: 33 pages, 23 figures, 2 table

A UV Sensitive Integrated Micromegas with Timepix Readout

This article presents a detector system consisting of three components, a CMOS imaging array, a gaseous-detector structure with a Micromegas layout and a UV-photon sensitive CsI reflective photocathode. All three elements have been monolithically integrated using simple post-processing steps. The Micromegas structure and the CMOS imaging chip are not impacted by the CsI deposition. The detector operated reliably in He/isobutane mixtures and attained charge gains with single photons up to a level of 6 \cdot 10^4. The Timepix CMOS array permitted high resolution imaging of single UV-photons. The system has an MTF50 of 0.4 lp/pixel which corresponds to app. 7 lp/mm.Comment: 4 pages with 8 figures. Submitted to Nucl. Instr. and Meth. A (Elsevier) for proceedings of VCI 2010

Italian family with two independent mutations:3358T/A in BRCA1 and 8756delA in BRCA2 genes.

Hereditary breast/ovarian cancer is a well-characterized clinical entity, largely attributed to the inheritance of BRCA1 or BRCA2 mutations. Among general population, the mutation's frequency of these genes is very low; therefore, the identification of two independent mutations in the same family is a rare event. This study reports the presence of two mutations, one in the BRCA1 and the second in the BRCA2 gene in an Italian Caucasian kindred. This family is composed of more than 250 individuals, spanning through five generations, among which endogamy was a common phenomenon. Considering the tumor spectrum, this family is characterized by a high incidence of different types of cancer. In our study, we considered only three out of seven family units for BRCA1 and BRCA2 analysis. In one of the family units, we found independent mutations of both BRCA genes. The BRCA1 mutation on exon 11 (3358TA) was identified originally in the index case and subsequently in 18 members of this family, whereas the same mutation was not detected in a related family member with male breast cancer. The male breast cancer patient led to the identification, through mutational analysis, of a new BRCA2 mutation (8756delA). This BRCA2 mutation was also found in the male breast cancer patient's daughter. The discovery of the BRCA2 mutation allowed us to alert the patient's daughter who, otherwise, could be falsely reassured since she had a negative BRCA1 test

Induction chemotherapy followed by neoadjuvant chemoradiotherapy and surgery in locally advanced rectal cancer: preliminary results of a phase II study

PURPOSE: To report preliminary results of induction chemotherapy (IC) followed by neoadjuvant chemoradiotherapy (CRT) and surgery in locally advanced rectal cancer (LARC) patients.MATERIALS AND METHODS: This is the preliminary evaluation of a phase II study. Patients with histologically proven rectal adenocarcinoma, stage II-III disease, who met the inclusion criteria, received induction FOLFOXIRI (5-FU, leucovorin, oxaliplatin and irinotecan) regimen in combination with targeted agents followed by CRT and surgery. Analysis of the first 8 patients was required to confirm the treatment feasibility before the accrual of 20 additional patients. RESULTS: The first 8 patients were evaluated. The median follow-up time was 23 months. There were no treatment-related deaths. Trimodality strategy was well tolerated with high compliance and a good level of toxicity. There were no evidence of febrile neutropenia and any grade 4 adverse events were recorded. Three patients had pathologic complete response (pCR) and 1 patient had a nearly pCR (ypT1 ypN0). CONCLUSION: Preliminary results are encouraging. FOLFOXIRI regimen plus targeted agents followed by CRT and surgery seems a safe approach. Longer follow-up and higher number of patients are mandatory to confirm such findings

Contribution of MUTYH variants to male breast cancer risk: results from a multicenter study in Italy

Inherited mutations in BRCA1, and, mainly, BRCA2 genes are associated with increased risk of male breast cancer (MBC). Mutations in PALB2 and CHEK2 genes may also increase MBC risk. Overall, these genes are functionally linked to DNA repair pathways, highlighting the central role of genome maintenance in MBC genetic predisposition. MUTYH is a DNA repair gene whose biallelic germline variants cause MUTYH-associated polyposis (MAP) syndrome. Monoallelic MUTYH variants have been reported in families with both colorectal and breast cancer and there is some evidence on increased breast cancer risk in women with monoallelic variants. In this study, we aimed to investigate whether MUTYH germline variants may contribute to MBC susceptibility. To this aim, we screened the entire coding region of MUTYH in 503 BRCA1/2 mutation negative MBC cases by multigene panel analysis. Moreover, we genotyped selected variants, including p.Tyr179Cys, p.Gly396Asp, p.Arg245His, p.Gly264Trpfs*7, and p.Gln338His, in a total of 560 MBC cases and 1,540 male controls. Biallelic MUTYH pathogenic variants (p.Tyr179Cys/p.Arg241Trp) were identified in one MBC patient with phenotypic manifestation of adenomatous polyposis. Monoallelic pathogenic variants were identified in 14 (2.5%) MBC patients, in particular, p.Tyr179Cys was detected in seven cases, p.Gly396Asp in five cases, p.Arg245His and p.Gly264Trpfs*7 in one case each. The majority of MBC cases with MUTYH pathogenic variants had family history of cancer including breast, colorectal, and gastric cancers. In the case-control study, an association between the variant p.Tyr179Cys and increased MBC risk emerged by multivariate analysis [odds ratio (OR) = 4.54; 95% confidence interval (CI): 1.17-17.58; p = 0.028]. Overall, our study suggests that MUTYH pathogenic variants may have a role in MBC and, in particular, the p.Tyr179Cys variant may be a low/moderate penetrance risk allele for MBC. Moreover, our results suggest that MBC may be part of the tumor spectrum associated with MAP syndrome, with implication in the clinical management of patients and their relatives. Large-scale collaborative studies are needed to validate these findings

A simplified genomic profiling approach predicts outcome in metastatic colorectal cancer

The response of metastatic colorectal cancer (mCRC) to the first-line conventional combination therapy is highly variable, reflecting the elevated heterogeneity of the disease. The genetic alterations underlying this heterogeneity have been thoroughly characterized through omic approaches requiring elevated efforts and costs. In order to translate the knowledge of CRC molecular heterogeneity into a practical clinical approach, we utilized a simplified Next Generation Sequencing (NGS) based platform to screen a cohort of 77 patients treated with first-line conventional therapy. Samples were sequenced using a panel of hotspots and targeted regions of 22 genes commonly involved in CRC. This revealed 51 patients carrying actionable gene mutations, 22 of which carried druggable alterations. These mutations were frequently associated with additional genetic alterations. To take into account this molecular complexity and assisted by an unbiased bioinformatic analysis, we defined three subgroups of patients carrying distinct molecular patterns. We demonstrated these three molecular subgroups are associated with a different response to first-line conventional combination therapies. The best outcome was achieved in patients exclusively carrying mutations on TP53 and/or RAS genes. By contrast, in patients carrying mutations in any of the other genes, alone or associated with mutations of TP53/RAS, the expected response is much worse compared to patients with exclusive TP53/RAS mutations. Additionally, our data indicate that the standard approach has limited efficacy in patients without any mutations in the genes included in the panel. In conclusion, we identified a reliable and easy-to-use approach for a simplified molecular-based stratification of mCRC patients that predicts the efficacy of the first-line conventional combination therapy