Phase I and pharmacokinetic study of brostallicin (PNU-166196), a new DNA minor-groove binder, administered intravenously every 3 weeks to adult patients with metastatic cancer

PURPOSE: Brostallicin (PNU-166196) is a cytotoxic agent that binds to the minor groove of DNA with significant antitumor activity in preclinical studies. This trial was designed to determine the maximum tolerated dose, the toxicity profile, and the pharmacokinetics of Brostallicin in cancer patients. Experimental Design: Patients were treated with escalating doses of Brostallicin ranging from 0.85 to 15 mg/m(2) administered as a 10-min i.v. infusion every 3 weeks. Blood samples for pharmacokinetic analysis were collected during the first and second course, and analyzed by liquid-chromatography with tandem-mass spectrometric detection. RESULTS: Twenty-seven evaluable patients received a total of 73 courses. Grade 4 neutropenia was the only dose-limiting toxicity at 12.5 mg/m(2), whereas grade 4 thrombocytopenia (1 patient) and grade 4 neutropenia (2 patients) were the dose-limiting toxicities at 15 mg/m(2). Other side effects, including thrombocytopenia and nausea, were generally mild. The maximum tolerated dose was defined at 10 mg/m(2). The clearance and terminal half-life of Brostallicin were dose-independent, with mean (+/-SD) values of 9.33 +/- 2.38 liters/h/m(2) and 4.69 +/- 1.88 h, respectively. There was no significant accumulation of Brostallicin with repeated administration. Significant relationships were observed between systemic exposure to Brostallicin and neutrophil counts at nadir. One partial response was observed in a patient with a gastrointestinal stromal tumor. CONCLUSION: Brostallicin was found to be well tolerated, with neutropenia being the principal toxicity. The recommended dose for additional evaluation in this schedule is 10 mg/m(2)

Mechanisms for a nutrient-conserving carbon pump in a seasonally stratified, temperate continental shelf sea

Continental shelf seas may have a significant role in oceanic uptake and storage of carbon dioxide (CO2) from the atmosphere, through a ‘continental shelf pump’ mechanism. The northwest European continental shelf, in particular the Celtic Sea (50°N 8°W), was the target of extensive biogeochemical sampling from March 2014 to September 2015, as part of the UK Shelf Sea Biogeochemistry research programme (UK-SSB). Here, we use the UK-SSB carbonate chemistry and macronutrient measurements to investigate the biogeochemical seasonality in this temperate, seasonally stratified system. Following the onset of stratification, near-surface biological primary production during spring and summer removed dissolved inorganic carbon and nutrients, and a fraction of the sinking particulate organic matter was subsequently remineralised beneath the thermocline. Water column inventories of these variables throughout 1.5 seasonal cycles, corrected for air-sea CO2 exchange and sedimentary denitrification and anammox, isolated the combined effect of net community production (NCP) and remineralisation on the inorganic macronutrient inventories. Overall inorganic inventory changes suggested that a significant fraction (>50%) of the annual NCP of around 3 mol-C m–2 yr–1 appeared to be stored within a long-lived organic matter (OM) pool with a lifetime of several months or more. Moreover, transfers into and out of this pool appeared not to be in steady state over the one full seasonal cycle sampled. Accumulation of such a long-lived and potentially C-rich OM pool is suggested to be at least partially responsible for the estimated net air-to-sea CO2 flux of ∼1.3 mol-C m–2 yr–1 at our study site, while providing a mechanism through which a nutrient-conserving continental shelf pump for CO2 could potentially operate in this and other similar regions

Prototype ATLAS IBL Modules using the FE-I4A Front-End Readout Chip

The ATLAS Collaboration will upgrade its semiconductor pixel tracking detector with a new Insertable B-layer (IBL) between the existing pixel detector and the vacuum pipe of the Large Hadron Collider. The extreme operating conditions at this location have necessitated the development of new radiation hard pixel sensor technologies and a new front-end readout chip, called the FE-I4. Planar pixel sensors and 3D pixel sensors have been investigated to equip this new pixel layer, and prototype modules using the FE-I4A have been fabricated and characterized using 120 GeV pions at the CERN SPS and 4 GeV positrons at DESY, before and after module irradiation. Beam test results are presented, including charge collection efficiency, tracking efficiency and charge sharing.Comment: 45 pages, 30 figures, submitted to JINS

Noncoding deletions reveal a gene that is critical for intestinal function.

Large-scale genome sequencing is poised to provide a substantial increase in the rate of discovery of disease-associated mutations, but the functional interpretation of such mutations remains challenging. Here we show that deletions of a sequence on human chromosome 16 that we term the intestine-critical region (ICR) cause intractable congenital diarrhoea in infants1,2. Reporter assays in transgenic mice show that the ICR contains a regulatory sequence that activates transcription during the development of the gastrointestinal system. Targeted deletion of the ICR in mice caused symptoms that recapitulated the human condition. Transcriptome analysis revealed that an unannotated open reading frame (Percc1) flanks the regulatory sequence, and the expression of this gene was lost in the developing gut of mice that lacked the ICR. Percc1-knockout mice displayed phenotypes similar to those observed upon ICR deletion in mice and patients, whereas an ICR-driven Percc1 transgene was sufficient to rescue the phenotypes found in mice that lacked the ICR. Together, our results identify a gene that is critical for intestinal function and underscore the need for targeted in vivo studies to interpret the growing number of clinical genetic findings that do not affect known protein-coding genes

Multidecadal accumulation of anthropogenic and remineralized dissolved inorganic carbon along the Extended Ellett Line in the northeast Atlantic Ocean

Marine carbonate chemistry measurements have been carried out annually since 2009 during UK research cruises along the Extended Ellett Line (EEL), a hydrographic transect in the northeast Atlantic Ocean. The EEL intersects several water masses that are key to the global thermohaline circulation, and therefore the cruises sample a region in which it is critical to monitor secular physical and biogeochemical changes. We have combined results from these EEL cruises with existing quality-controlled observational data syntheses to produce a hydrographic time series for the EEL from 1981 to 2013. This reveals multidecadal increases in dissolved inorganic carbon (DIC) throughout the water column, with a near-surface maximum rate of 1.80 ± 0.45 µmol kg−1 yr−1. Anthropogenic CO2 accumulation was assessed, using simultaneous changes in apparent oxygen utilization (AOU) and total alkalinity (TA) as proxies for the biogeochemical processes that influence DIC. The stable carbon isotope composition of DIC (δ13CDIC) was also determined and used as an independent test of our method. We calculated a volume-integrated anthropogenic CO2 accumulation rate of 2.8 ± 0.4 mg C m−3 yr−1 along the EEL, which is about double the global mean. The anthropogenic CO2 component accounts for only 31 ± 6% of the total DIC increase. The remainder is derived from increased organic matter remineralization, which we attribute to the lateral redistribution of water masses that accompanies subpolar gyre contraction. Output from a general circulation ecosystem model demonstrates that spatiotemporal heterogeneity in the observations has not significantly biased our multidecadal rate of change calculations and indicates that the EEL observations have been tracking distal changes in the surrounding North Atlantic and Nordic Seas

Multi-ancestry genome-wide association study accounting for gene-psychosocial factor interactions identifies novel loci for blood pressure traits

Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP, taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from five ancestry groups. In the combined meta-analyses of stages 1 and 2, we identified 59 loci (p value < 5e−8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel loci supports a major role for genes implicated in the immune response (PLCL2), synaptic function and neurotransmission (LIN7A and PFIA2), as well as genes previously implicated in neuropsychiatric or stress-related disorders (FSTL5 and CHODL). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

The BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity.

Although the spliceogenic nature of the BRCA2 c.68-7T>A variant has been demonstrated, its association with cancer risk remains ontroversial. In this study, we accurately quantified by real-time PCR and digital PCR the BRCA2 isoforms retaining or missing exon 3. In addition, the combined odds ratio for causality of the variant was estimated using genetic and clinical data, and its associated cancer risk was estimated by case-control analysis in 83,636 individuals. Co-occurrence in trans with pathogenic BRCA2 variants was assessed in 5,382 families. Exon 3 exclusion rate was 4.5-fold higher in variant carriers (13%) than controls (3%), indicating an exclusion rate for the c.68-7T>A allele of approximately 20%. The posterior probability of pathogenicity was 7.44 x 10-115. There was neither evidence for increased risk of breast cancer (OR 1.03; 95% CI 0.86-1.24), nor for a deleterious effect of the variant when co-occurring with pathogenic variants. Our data provide for the first time robust evidence of the non-pathogenicity of the BRCA2 c.68-7T>A. Genetic and quantitative transcript analyses together inform the threshold for the ratio between functional and altered BRCA2 isoforms compatible with normal cell function. These findings might be exploited to assess the relevance for cancer risk of other BRCA2 spliceogenic variants