Evaluating predictive pharmacogenetic signatures of adverse events in colorectal cancer patients treated with fluoropyrimidines

The potential clinical utility of genetic markers associated with response to fluoropyrimidine treatment in colorectal cancer patients remains controversial despite extensive study. Our aim was to test the clinical validity of both novel and previously identified markers of adverse events in a broad clinical setting. We have conducted an observational pharmacogenetic study of early adverse events in a cohort study of 254 colorectal cancer patients treated with 5-fluorouracil or capecitabine. Sixteen variants of nine key folate (pharmacodynamic) and drug metabolising (pharmacokinetic) enzymes have been analysed as individual markers and/or signatures of markers. We found a significant association between TYMP S471L (rs11479) and early dose modifications and/or severe adverse events (adjusted OR = 2.02 [1.03; 4.00], p = 0.042, adjusted OR = 2.70 [1.23; 5.92], p = 0.01 respectively). There was also a significant association between these phenotypes and a signature of DPYD mutations (Adjusted OR = 3.96 [1.17; 13.33], p = 0.03, adjusted OR = 6.76 [1.99; 22.96], p = 0.002 respectively). We did not identify any significant associations between the individual candidate pharmacodynamic markers and toxicity. If a predictive test for early adverse events analysed the TYMP and DPYD variants as a signature, the sensitivity would be 45.5 %, with a positive predictive value of just 33.9 % and thus poor clinical validity. Most studies to date have been under-powered to consider multiple pharmacokinetic and pharmacodynamic variants simultaneously but this and similar individualised data sets could be pooled in meta-analyses to resolve uncertainties about the potential clinical utility of these markers

Large introns in relation to alternative splicing and gene evolution: a case study of Drosophila bruno-3

Background: Alternative splicing (AS) of maturing mRNA can generate structurally and functionally distinct transcripts from the same gene. Recent bioinformatic analyses of available genome databases inferred a positive correlation between intron length and AS. To study the interplay between intron length and AS empirically and in more detail, we analyzed the diversity of alternatively spliced transcripts (ASTs) in the Drosophila RNA-binding Bruno-3 (Bru-3) gene. This gene was known to encode thirteen exons separated by introns of diverse sizes, ranging from 71 to 41,973 nucleotides in D. melanogaster. Although Bru-3's structure is expected to be conducive to AS, only two ASTs of this gene were previously described. Results: Cloning of RT-PCR products of the entire ORF from four species representing three diverged Drosophila lineages provided an evolutionary perspective, high sensitivity, and long-range contiguity of splice choices currently unattainable by high-throughput methods. Consequently, we identified three new exons, a new exon fragment and thirty-three previously unknown ASTs of Bru-3. All exon-skipping events in the gene were mapped to the exons surrounded by introns of at least 800 nucleotides, whereas exons split by introns of less than 250 nucleotides were always spliced contiguously in mRNA. Cases of exon loss and creation during Bru-3 evolution in Drosophila were also localized within large introns. Notably, we identified a true de novo exon gain: exon 8 was created along the lineage of the obscura group from intronic sequence between cryptic splice sites conserved among all Drosophila species surveyed. Exon 8 was included in mature mRNA by the species representing all the major branches of the obscura group. To our knowledge, the origin of exon 8 is the first documented case of exonization of intronic sequence outside vertebrates. Conclusion: We found that large introns can promote AS via exon-skipping and exon turnover during evolution likely due to frequent errors in their removal from maturing mRNA. Large introns could be a reservoir of genetic diversity, because they have a greater number of mutable sites than short introns. Taken together, gene structure can constrain and/or promote gene evolution

Sex-specific relevance of diabetes to occlusive vascular and other mortality : a collaborative meta-analysis of individual data from 980 793 adults from 68 prospective studies

Background: Several studies have shown that diabetes confers a higher relative risk of vascular mortality among women than among men, but whether this increased relative risk in women exists across age groups and within defined levels of other risk factors is uncertain. We aimed to determine whether differences in established risk factors, such as blood pressure, BMI, smoking, and cholesterol, explain the higher relative risks of vascular mortality among women than among men. Methods: In our meta-analysis, we obtained individual participant-level data from studies included in the Prospective Studies Collaboration and the Asia Pacific Cohort Studies Collaboration that had obtained baseline information on age, sex, diabetes, total cholesterol, blood pressure, tobacco use, height, and weight. Data on causes of death were obtained from medical death certificates. We used Cox regression models to assess the relevance of diabetes (any type) to occlusive vascular mortality (ischaemic heart disease, ischaemic stroke, or other atherosclerotic deaths) by age, sex, and other major vascular risk factors, and to assess whether the associations of blood pressure, total cholesterol, and body-mass index (BMI) to occlusive vascular mortality are modified by diabetes. Findings: Individual participant-level data were analysed from 980793 adults. During 9 center dot 8 million person-years of follow-up, among participants aged between 35 and 89 years, 19686 (25 center dot 6%) of 76965 deaths were attributed to occlusive vascular disease. After controlling for major vascular risk factors, diabetes roughly doubled occlusive vascular mortality risk among men (death rate ratio [RR] 2 center dot 10, 95% CI 1 center dot 97-2 center dot 24) and tripled risk among women (3 center dot 00, 2 center dot 71-3 center dot 33; x(2) test for heterogeneity p<0 center dot 0001). For both sexes combined, the occlusive vascular death RRs were higher in younger individuals (aged 35-59 years: 2 center dot 60, 2 center dot 30-2 center dot 94) than in older individuals (aged 70-89 years: 2 center dot 01, 1 center dot 85-2 center dot 19; p=0 center dot 0001 for trend across age groups), and, across age groups, the death RRs were higher among women than among men. Therefore, women aged 35-59 years had the highest death RR across all age and sex groups (5 center dot 55, 4 center dot 15-7 center dot 44). However, since underlying confounder-adjusted occlusive vascular mortality rates at any age were higher in men than in women, the adjusted absolute excess occlusive vascular mortality associated with diabetes was similar for men and women. At ages 35-59 years, the excess absolute risk was 0 center dot 05% (95% CI 0 center dot 03-0 center dot 07) per year in women compared with 0 center dot 08% (0 center dot 05-0 center dot 10) per year in men; the corresponding excess at ages 70-89 years was 1 center dot 08% (0 center dot 84-1 center dot 3 2) per year in women and 0 center dot 91% (0 center dot 77-1 center dot 05) per year in men. Total cholesterol, blood pressure, and BMI each showed continuous log-linear associations with occlusive vascular mortality that were similar among individuals with and without diabetes across both sexes. Interpretation: Independent of other major vascular risk factors, diabetes substantially increased vascular risk in both men and women. Lifestyle changes to reduce smoking and obesity and use of cost-effective drugs that target major vascular risks (eg, statins and antihypertensive drugs) are important in both men and women with diabetes, but might not reduce the relative excess risk of occlusive vascular disease in women with diabetes, which remains unexplained

Tuning fresh: radiation through rewiring of central metabolism in streamlined bacteria

Most free-living planktonic cells are streamlined and in spite of their limitations in functional flexibility, their vast populations have radiated into a wide range of aquatic habitats. Here we compared the metabolic potential of subgroups in the Alphaproteobacteria lineage SAR11 adapted to marine and freshwater habitats. Our results suggest that the successful leap from marine to freshwaters in SAR11 was accompanied by a loss of several carbon degradation pathways and a rewiring of the central metabolism. Examples for these are C1 and methylated compounds degradation pathways, the Entner–Doudouroff pathway, the glyoxylate shunt and anapleuretic carbon fixation being absent from the freshwater genomes. Evolutionary reconstructions further suggest that the metabolic modules making up these important freshwater metabolic traits were already present in the gene pool of ancestral marine SAR11 populations. The loss of the glyoxylate shunt had already occurred in the common ancestor of the freshwater subgroup and its closest marine relatives, suggesting that the adaptation to freshwater was a gradual process. Furthermore, our results indicate rapid evolution of TRAP transporters in the freshwater clade involved in the uptake of low molecular weight carboxylic acids. We propose that such gradual tuning of metabolic pathways and transporters toward locally available organic substrates is linked to the formation of subgroups within the SAR11 clade and that this process was critical for the freshwater clade to find and fix an adaptive phenotype.This work was supported by the Swedish Research Council (Grant Numbers 2012-4592 to AE and 2012-3892 to SB) and the Communiy Sequencing Programme of the US Department of Energy Joint Genome Institute. The work conducted by the US Department of Energy Joint Genome Institute, a DOE Office of Science User Facility, is supported under Contract No. DE-AC02-05CH11231

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Single- versus two- layer intestinal anastomosis: a meta-analysis of randomized controlled trials

BACKGROUND: To compare single- with two- layer intestinal anastomosis after intestinal resection: a meta-analysis of randomized controlled trials. METHODS: Randomized controlled trials comparing single- with two-layer intestinal anastomosis were identified using a systematic search of Medline, Embase and the Cochrane Library Databases covering articles published from 1966 to 2004. Outcome of primary interest was postoperative leak. A risk ratio for trial outcomes and weighted pooled estimates for data were calculated. A fixed-effect model weighted using Mantel-Haenszel methods and a random-effect model using DerSimonian-Laird methods were employed. RESULTS: Six trials were analyzed, comprising 670 participants (single-layer group, n = 299; two-layer group, n = 371). Data on leaks were available from all included studies. Combined risk ratio using DerSimonian-Laird methods was 0.91 (95% CI = 0.49 to 1.69), and indicated no significant difference. Inter-study heterogeneity was significant (χ(2 )= 10.5, d.f. = 5, p = 0.06). CONCLUSION: No evidence was found that two-layer intestinal anastomosis leads to fewer post-operative leaks than single layer. Considering duration of the anastomosis procedure and medical expenses, single-layer intestinal anastomosis appears to represent the optimal choice for most surgical situations

Screening for adulticidal bioactivity of South African plants against Anopheles arabiensis

<p>Abstract</p> <p>Background</p> <p>This study was conducted to evaluate whether a selection of South African ethnomedicinal plants included in this study displayed insecticidal properties when screened against adult stages of the mosquito.</p> <p>Methods</p> <p>381 crude extracts of 80 plant taxa in 42 families were sprayed onto ceramic tiles and screened using the cone bio-assay method for insecticide efficacy testing. Blood-fed, female <it>Anopheles arabiensis </it>mosquitoes were exposed to the treated tiles for a period of sixty minutes. Mosquito mortality was monitored for twenty-four hours.</p> <p>Results</p> <p>Of all the extracts analysed, the highest activity was observed in <it>Ptaeroxylon obliquum </it>(Ptaeroxylaceae) and <it>Pittosporum viridiflorum </it>(Pittosporaceae), a single extract from each, exhibiting more than 50% mortality. A large proportion (81.63%) of the extracts tested displayed low levels of mosquitocidal activity. The remainder of the extracts (17.85%) exhibited no bioactivity (0% mortality).</p> <p>Conclusions</p> <p>The screening results have shown that in accordance with WHO standards, none of the crude extracts tested had exhibited greater than 60% mortality against the adult stages of the malaria vector <it>Anopheles arabiensis</it>.</p

Modelling a Historic Oil-Tank Fire Allows an Estimation of the Sensitivity of the Infrared Receptors in Pyrophilous Melanophila Beetles

Pyrophilous jewel beetles of the genus Melanophila approach forest fires and there is considerable evidence that these beetles can detect fires from great distances of more than 60 km. Because Melanophila beetles are equipped with infrared receptors and are also attracted by hot surfaces it can be concluded that these infrared receptors are used for fire detection

Contact metamorphism associated to the Penamacor - Monsanto granitic intrusion (Central Portugal): geochemical, isotopic and mineralogical features

Contact metamorphism related to Variscan and late-Variscan granitic plutons in the Iberian Peninsula is superimposed on medium-grade regional metamorphism, making it often difficult to evaluate per se the thermal effects due to those intrusions and explaining the paucity of scientific literature on the subject. An exhaustive set of geochemical, isotopic and mineralogical data on the contact-zone metasediments hosting the Penamacor-Monsanto granite (Central Iberian Zone, Portugal) provides a significant contribution to the characterization of low- to intermediate-grade contact metamorphism in geological contexts formerly affected by regional metamorphism. The metasediments hosting the Penamacor-Monsanto pluton belong to the extensive detrital sequence of the ante-Ordovician Schist-Greywacke Complex. Bulk geochemistry, oxygen isotope data and crystal-chemistry of key minerals from those contact-zone and neighbouring metasediments have made it possible to infer metamorphic conditions on the contact zone of this granitic intrusion, and to distinguish them from late boron-metasomatism at the exocontact. Mineral paragenesis (muscovite + biotite + chlorite quartz plagioclase cordierite, in spotted-schists; biotite + chlorite quartz plagioclase ( cordierite), in hornfelses) and the composition of these coexisting mineral phases indicate that most of the contact rocks reached the biotite zone (or even the cordierite zone, in some cases), equivalent to upper greenschist – lower amphibolite metamorphic grade. The relatively narrow range of O-isotope temperatures estimated for the crystallization of the marginal granites (550-625ºC) explains the absence of significant effects of thermal flow anisotropy on the contact-zone rocks. Besides, textural, paragenetic, mineralogical, isotopic and geochemical nuances observed in hornfelses and spotted-schists seem mainly related to the local host-rock heterogeneities, rather than to thermal effects. The relatively low temperatures estimated for granitoid emplacement and their restricted isotopic and mineralogical impacts on the metasedimentary host-rocks account for the narrow metamorphic aureole associated with the Penamacor-Monsanto pluton, and suggest this massif may correspond to the outcropping tip of a larger granitic intrusion at depth.Las intrusions graníticas Varíscicas y tardivaríscicas de la Península Ibérica dieron lugar a un metamorfsmo de contacto que afecta a un encajante previamente sometido a un metamorfsmo regional de grado medio, lo que difculta separar los efectos térmicos de aquellos regionales, y explica la escasez de estudios sobre el mismo. El estudio detallado de la zona de contacto entre el Granito de Penamacor-Monsanto (Zona Centro-Ibérica; Portugal) y su encajante metasedimentario mediante técnicas geoquímicas, mineralógicas e isotópicas supone una notable contribución al conocimiento y caracterización del metamorfsmo de contacto de grados bajos a intermedios en contextos geológicos previamente afectados por metamorfsmo regional. El encajante metasedimentario del Plutón de Penamacor-Monsanto es parte de la amplia secuencia detrítica ante-Ordovícia conocida como Complejo Esquisto-Grawackico. Datos geoquímicos de roca total y cristaloquímicos de los minerales más característicos, y relaciones isotópicas de oxígeno en la zona de contacto y metasedimentos aledaños permiten inferir las condiciones metamórfcas en la zona de contacto de dicha intrusión, y diferenciarla de aquella afectada por metasomatismo tardío por B. La paragénesis mineral (muscovita + biotita + clorita ± cuarzo ± plagioclasa ± cordierita en los esquistos moteados; biotita + clorita ± cuarzo ± plagiclasa (± cordierita) en corneanas) y la composición de las fases minerales coexistentes indican que la mayoría de rocas del contacto alcanzaron la zona de la biotita (e incluso, en algunos casos, aquella de la cordierita), equivalente a la parte alta del grado metamórfco de los esquistos verdes, o a la parte baja de las anfbolitas. El rango relativamente pequeño de temperaturas de cristalización de los granitos marginales (550-625°C), calculado mediante isótopos de oxígeno, explica la carencia de anisotropías térmicas signifcativas en las rocas del contacto. Las sutiles diferencias texturales, paragenéticas, mineralógicas, isotópicas y geoquímicas en esquistos moteados y corneanas parecen relacionadas con heterogeneidades locales de los encajantes, y no con efectos térmicos diferenciados. Las temperaturas relativamente bajas estimadas durante la intrusión del granito de Penamacor-Monsanto, y el limitado efecto mineralógico e isotópico sobre el encajante metasedimentario, dan lugar a una aureola de contacto estrecha, y sugieren que este macizo puede corresponder al techo de una intrusión mayor en profundidad.Funding was provided by FCT—Fundação para a Ciên cia e Tecnologia, through project METMOB (PTDC/CTE-GIX/116204/2009