Irinotecan pathway genotype analysis to predict pharmacokinetics

PURPOSE: The purpose was to explore the relationships between irinotecan disposition and allelic variants of genes coding for adenosine triphosphate binding cassette transporters and enzymes of putative relevance for irinotecan. EXPERIMENTAL DESIGN: Irinotecan was administered to 65 cancer patients as a 90-min infusion (dose, 200-350 mg/m(2)), and pharmacokinetic data were obtained during the first cycle. All patients were genotyped for variants in genes encoding MDR1 P-glycoprotein (ABCB1), multidrug resistance-associated proteins MRP-1 (ABCC1) and MRP-2 (canalicular multispecific organic anion transporter; ABCC2), breast cancer resistance protein (ABCG2), carboxylesterases (CES1, CES2), cytochrome p450 isozymes (CYP3A4, CYP3A5), UDP glucuronosyltransferase (UGT1A1), and a DNA-repair enzyme (XRCC1), which was included as a nonmechanistic control. RESULTS: Eighteen genetic variants were found in nine genes of putative importance for irinotecan disposition. The homozygous T allele of the ABCB1 1236C>T polymorphism was associated with significantly increased exposure to irinotecan (P = 0.038) and its active metabolite SN-38 (P = 0.031). Pharmacokinetic parameters were not related to any of the other multiple variant genotypes, possibly because of the low allele frequency. The extent of SN-38 glucuronidation was slightly impaired in homozygous variants of UGT1A1*28, although differences were not statistically significant (P = 0.22). CONCLUSIONS: It is concluded that genotyping for ABCB1 1236C>T may be one of the factors assisting with dose optimization of irinotecan chemotherapy in cancer patients. Additional investigation is required to confirm these findings in a larger population and to assess relationships between irinotecan disposition and the rare variant genotypes, especially in other ethnic groups

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

Open data from the third observing run of LIGO, Virgo, KAGRA, and GEO

The global network of gravitational-wave observatories now includes five detectors, namely LIGO Hanford, LIGO Livingston, Virgo, KAGRA, and GEO 600. These detectors collected data during their third observing run, O3, composed of three phases: O3a starting in 2019 April and lasting six months, O3b starting in 2019 November and lasting five months, and O3GK starting in 2020 April and lasting two weeks. In this paper we describe these data and various other science products that can be freely accessed through the Gravitational Wave Open Science Center at https://gwosc.org. The main data set, consisting of the gravitational-wave strain time series that contains the astrophysical signals, is released together with supporting data useful for their analysis and documentation, tutorials, as well as analysis software packages

Strong base catalysts for fine chemical synthesis: relating reaction energetics to base strength

The aldol condensation of acetone to mesityl oxide (MO) and its subsequent hydrogenation to methyl isobutyl ketone (MIBK) has been studied relative to the base strength measured by CO2 temperature programmed desorption (TPD). The activation energy for the hydrogenation to MIBK correlates to base strength of the catalysts. A mechanism has been proposed and an understanding of the CO2adsorption and TPD has also been developed

Molecular analyses of Pythium irregulare isolates from grapevines in South Africa suggest a single variable species

The Pythium irregulare species complex is the most common and widespread Pythium spp. associated with grapevines in South Africa. This species complex has been subdivided into several morphological and phylogenetic species that are all highly similar at the sequence level [internal transcribed spacer (ITS) and cytochrome c oxidase (cox) regions]. The complex includes Pythium regulare and Pythium cylindrosporum, which are morphologically distinct, and P. irregulare sensu stricto (s.s.) and Pythium cryptoirregulare, which are morphologically similar. The aim of the current study was to determine whether 50 South African grapevine P. irregulare isolates represented more than one phylogenetically distinct species. The isolates were characterised using nuclear (ITS and β-tubulin) and mitochondrial (cox1 and cox2) gene region phylogenies and two isozyme loci [glucose-6-phosphate isomerase (Gpi) and malate dehydrogenase (Mdh-1)]. Some of the gene sequence data were difficult to interpret phylogenetically, since some isolates contained two or more polymorphic ITS copies within the same isolate (intra-isolate variation) that clustered into different ITS sub-clades, i.e. the P. irregulare s.s. and P. cryptoirregulare sub-clades. The molecular data furthermore only revealed the presence of one phylogenetic species, P. irregulare. Morphological analyses of a subset of the isolates confirmed that the isolates were P. irregulare, and further showed that the P. cylindrosporum ex-type strain formed typical P. irregulare oogonia, and not the previously reported distinct elongated oogonia. Some of the molecular analyses suggested the occurrence of outcrossing events and possibly the formation of aneuploids or polyploids since (i) the nuclear and mitochondrial gene data sets were incongruent, (ii) polymorphic ITS copies were present within the same isolate, (iii) heterozygosities were observed in the β-tubulin gene and Gpi and Mdh-1 loci in some isolates and (iv) more than two β-tubulin alleles were detected in some isolates. Altogether, the data suggest that P. irregulare, P. cryptoirregulare, P. cylindrosporum, and possibly P. regulare should be synonimised under the name P. irregulare. © 2011 The British Mycological Society