Single nucleotide polymorphisms of ABCC5 and ABCG1 transporter genes correlate to irinotecan-associated gastrointestinal toxicity in colorectal cancer patients: a DMET microarray profiling study.

Abstract Recent findings have disclosed the role of UDP-glucuronosyltransferase (UGT) 1A1*28 on the haematological toxicity induced by irinotecan (CPT-11), a drug commonly used in the treatment of metastatic colorectal cancer (mCRC). We investigated the pharmacogenomic profile of irinotecan-induced gastrointestinal (GI) toxicity by the novel drug-metabolizing enzyme and transporter (DMET) microarray genotyping platform. Twenty-six mCRC patients who had undergone to irinotecan-based chemotherapy were enrolled in a case (patients experiencing > grade 3 gastrointestinal, (GI) toxicity) - control (matched patients without GI toxicity) study. A statistically significant difference of SNP genotype distribution was found in the case versus control group. The homozygous genotype C/C in the (rs562) ABCC5 gene occurred in 6/9 patients with GI toxicity versus 1/17 patients without GI toxicity (P=0.0022). The homozygous genotype G/G in the (rs425215) ABCG1 was found in 7/9 patients with GI toxicity versus 4/17 patients without GI toxicity (P=0.0135). The heterozygous genotype G/A in the 388G>A (rs2306283) OATP1B1/SLCO1B1 was found in 3/9 patients with grade > 3 GI toxicity versus 14/17 patients without GI toxicity (P=0.0277). DNA extracted from peripheral blood cells was genotyped by DMET Plus chip on Affymetrix array system. Genotype association was calculated by Fisher's exact test (two tailed) and relevant SNPs were further analyzed by direct sequencing. We have identified 3 SNPs mapping in ABCG1, ABCC5 and OATP1B1/SLCO1B1 transporter genes associated with GI toxicity induced by irinotecan in mCRC patients expanding the available knowledge of irinogenomics. The DMET microarray platform is an emerging technology for easy identification of new genetic variants for personalized medicine

Garlic consumption in relation to colorectal cancer risk and to alterations of blood bacterial DNA

PURPOSE: Garlic consumption has been inversely associated to intestinal adenoma (IA) and colorectal cancer (CRC) risk, although evidence is not consistent. Gut microbiota has been implied in CRC pathogenesis and is also influenced by garlic consumption. We analyzed whether dietary garlic influence CRC risk and bacterial DNA in blood. METHODS: We conducted a case-control study in Italy involving 100 incident CRC cases, 100 IA and 100 healthy controls matched by center, sex and age. We used a validated food frequency questionnaire to assess dietary habits and garlic consumption. Blood bacterial DNA profile was estimated using qPCR and16S rRNA gene profiling. We derived odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) of IA and CRC according to garlic consumption from multiple conditional logistic regression. We used Mann-Whitney and chi-square tests to evaluate taxa differences in abundance and prevalence. RESULTS: The OR of CRC for medium/high versus low/null garlic consumption was 0.27 (95% CI = 0.11-0.66). Differences in garlic consumption were found for selected blood bacterial taxa. Medium/high garlic consumption was associated to an increase of Corynebacteriales order, Nocardiaceae family and Rhodococcus genus, and to a decrease of Family XI and Finegoldia genus. CONCLUSIONS: The study adds data on the protective effect of dietary garlic on CRC risk. Moreover, it supports evidence of a translocation of bacterial material to bloodstream and corroborates the hypothesis of a diet-microbiota axis as a mechanism behind the role of garlic in CRC prevention

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Datalog with existential quantifiers: an optimal trade-off between expressiveness and scalability

Dottorato di Ricerca in Matematica ed Informatica, Ciclo XXV, a.a. 2011-2012Ontologies and rules play a central role in the development of the Semantic Web. Recent research in this context focuses especially on highly scalable formalisms for the Web of Data, which may highly benefit from exploiting database technologies. In particular, Datalog∃ is the natural extension of Datalog, allowing existentially quantified variables in rule heads. This language is highly expressive and enables easy and powerful knowledge-modeling, but the presence of existentially quantified variables makes reasoning over Datalog∃ undecidable, in the general case. The results in this thesis enable powerful, yet decidable and efficient reasoning (query answering) on top of Datalog∃ programs. On the theoretical side, we define the class of parsimonious Datalog∃ programs, and show that it allows of decidable and efficiently-computable reasoning. Unfortunately, we can demonstrate that recognizing parsimony is undecidable. However, we single out Shy, an easily recognizable fragment of parsimonious programs, that significantly extends both Datalog and Linear Datalog∃. Moreover, we show that Shy preserves the same (data and combined) complexity of query answering over Datalog, although the addition of existential quantifiers. On the practical side, we implement a bottom-up evaluation strategy for Shy programs inside the DLV system, enhancing the computation by a number of optimization techniques. The resulting system is called DLV∃– a powerful system for answering conjunctive queries over Shy programs, which is profitably applicable to ontology-based query answering. Moreover, we design a rewriting method extending the well-known Magic-Sets technique to any Datalog∃ program. We demonstrate that our rewriting method preserves query equivalence on Datalog∃, and can be safely applied to Shy programs. We therefore incorporate the Magic- Sets method in DLV∃. Finally, we carry out an experimental analysis assessing the positive impact of Magic-Sets on DLV∃, and the effectiveness of the enhanced DLV∃ system compared to a number of state-of-the-art systems for ontologybased query answering.Università della Calabri

The ASP system DLV2

We introduce DLV2, a new Answer Set Programming (ASP) system. DLV2 combines I-DLV, a fully-compliant ASP-Core-2 grounder, with the well-assessed solver wasp. Input programs may be enriched by annotations and directives that customize heuristics of the system and extend its solving capabilities. An empirical analysis conducted on benchmarks from past ASP competitions shows that DLV2 outperforms the old DLV system and is close to the state-of-the-art ASP system clingo