New CUORICINO Results On the Way to CUORE

CUORE is a 0.75 ton experiment to search for neutrinoless double beta decay of Te130 using 988 TeO2 bolometers. It aims at reaching a sensitivity on the effective neutrino mass of the order of few tens of meV. CUORICINO, a single CUORE tower running since 2003, plays an important role as a stand alone experiment and for developing the future CUORE setup. Present results already achieved and studies that are underway are here presented and discussed

Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen

The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.Peer reviewe

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8–13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05–6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50–75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life. Funding Pfizer, Amgen, Merck Sharp & Dohme, Sanofi–Aventis, Daiichi Sankyo, and Regeneron

Search for β+/EC double beta decay of 120Te

We present a search for β+/EC double beta decay of 120Te performed with the CUORICINO experiment, an array of TeO2 cryogenic bolometers. After collecting 0.0573 kg · y of 120Te, we see no evidence of a signal and therefore set the following limits on the half-life: T1/20ν>1.9·1021 y at 90% C.L. for the 0ν mode and T1/22ν>7.6·1019 y at 90% C.L. for the 2ν mode. These results improve the existing limits by almost three orders of magnitude (four in the case of 0ν mode). © 2011 Published by Elsevier B.V

Search for double-β decay of 130Te to the first 0+ excited state of 130Xe with the CUORICINO experiment bolometer array

The CUORICINO experiment was an array of 62 TeO2 single-crystal bolometers with a total 130Te mass of 11.3kg. The experiment finished in 2008 after more than 3 yr of active operating time. Searches for both 0ν and 2ν double-β decay to the first excited 0+ state in 130Xe were performed by studying different coincidence scenarios. The analysis was based on data representing a total exposure of N(130Te)•t=9.5×1025yr. No evidence for a signal was found. The resulting lower limits on the half-lives are T122ν(130Te→130Xe*)>1. 3×1023yr (90% C.L.), and T120ν(130Te →130Xe*)>9.4×1023yr (90% CL). ©2012 American Physical Society