Gifts to Minors

Gifts to Minor

KRAS driven expression signature has prognostic power superior to mutation status in non-small cell lung cancer

KRAS is the most frequently mutated oncogene in non-small cell lung cancer (NSCLC). However, the prognostic role of KRAS mutation status in NSCLC still remains controversial. We hypothesize that the expression changes of genes affected by KRAS mutation status will have the most prominent effect and could be used as a prognostic signature in lung cancer. We divided NSCLC patients with mutation and RNA-seq data into KRAS mutated and wild type groups. Mann-Whitney test was used to identify genes showing altered expression between these cohorts. Mean expression of the top five genes was designated as a "transcriptomic fingerprint" of the mutation. We evaluated the effect of this signature on clinical outcome in 2,437 NSCLC patients using univariate and multivariate Cox regression analysis. Mutation of KRAS was most common in adenocarcinoma. Mutation status and KRAS expression were not correlated to prognosis. The transcriptomic fingerprint of KRAS include FOXRED2, KRAS, TOP1, PEX3 and ABL2. The KRAS signature had a high prognostic power. Similar results were achieved when using the second and third set of strongest genes. Moreover, all cutoff values delivered significant prognostic power (p < 0.01). The KRAS signature also remained significant (p < 0.01) in a multivariate analysis including age, gender, smoking history and tumor stage. We generated a "surrogate signature" of KRAS mutation status in NSCLC patients by computationally linking genotype and gene expression. We show that secondary effects of a mutation can have a higher prognostic relevance than the primary genetic alteration itself

Evidence for the existence of powder sub-populations in micronized materials : Aerodynamic size-fractions of aerosolized powders possess distinct physicochemical properties

This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.Purpose: To investigate the agglomeration behaviour of the fine ( 12.8 µm) particle fractions of salmeterol xinafoate (SX) and fluticasone propionate (FP) by isolating aerodynamic size fractions and characterising their physicochemical and re-dispersal properties. Methods: Aerodynamic fractionation was conducted using the Next Generation Impactor (NGI). Re-crystallized control particles, unfractionated and fractionated materials were characterized for particle size, morphology, crystallinity and surface energy. Re-dispersal of the particles was assessed using dry dispersion laser diffraction and NGI analysis. Results: Aerosolized SX and FP particles deposited in the NGI as agglomerates of consistent particle/agglomerate morphology. SX particles depositing on Stages 3 and 5 had higher total surface energy than unfractionated SX, with Stage 5 particles showing the greatest surface energy heterogeneity. FP fractions had comparable surface energy distributions and bulk crystallinity but differences in surface chemistry. SX fractions demonstrated higher bulk disorder than unfractionated and re-crystallized particles. Upon aerosolization, the fractions differed in their intrinsic emission and dispersion into a fine particle fraction (< 5.0 µm). Conclusions: Micronized powders consisted of sub-populations of particles displaying distinct physicochemical and powder dispersal properties compared to the unfractionated bulk material. This may have implications for the efficiency of inhaled drug deliveryPeer reviewe

The Complete Spectrum of Yeast Chromosome Instability Genes Identifies Candidate CIN Cancer Genes and Functional Roles for ASTRA Complex Components

Chromosome instability (CIN) is observed in most solid tumors and is linked to somatic mutations in genome integrity maintenance genes. The spectrum of mutations that cause CIN is only partly known and it is not possible to predict a priori all pathways whose disruption might lead to CIN. To address this issue, we generated a catalogue of CIN genes and pathways by screening ∼2,000 reduction-of-function alleles for 90% of essential genes in Saccharomyces cerevisiae. Integrating this with published CIN phenotypes for other yeast genes generated a systematic CIN gene dataset comprised of 692 genes. Enriched gene ontology terms defined cellular CIN pathways that, together with sequence orthologs, created a list of human CIN candidate genes, which we cross-referenced to published somatic mutation databases revealing hundreds of mutated CIN candidate genes. Characterization of some poorly characterized CIN genes revealed short telomeres in mutants of the ASTRA/TTT components TTI1 and ASA1. High-throughput phenotypic profiling links ASA1 to TTT (Tel2-Tti1-Tti2) complex function and to TORC1 signaling via Tor1p stability, consistent with the role of TTT in PI3-kinase related kinase biogenesis. The comprehensive CIN gene list presented here in principle comprises all conserved eukaryotic genome integrity pathways. Deriving human CIN candidate genes from the list allows direct cross-referencing with tumor mutational data and thus candidate mutations potentially driving CIN in tumors. Overall, the CIN gene spectrum reveals new chromosome biology and will help us to understand CIN phenotypes in human disease

Evolvement of Uniformity and Volatility in the Stressed Global Financial Village

Background: In the current era of strong worldwide market couplings the global financial village became highly prone to systemic collapses, events that can rapidly sweep throughout the entire village. Methodology/Principal Findings: We present a new methodology to assess and quantify inter-market relations. The approach is based on the correlations between the market index, the index volatility, the market Index Cohesive Force and the meta-correlations (correlations between the intra-correlations.) We investigated the relations between six important world markets—U.S., U.K., Germany, Japan, China and India—from January 2000 until December 2010. We found that while the developed ‘‘western’’ markets (U.S., U.K., Germany) are highly correlated, the interdependencies between these markets and the developing ‘‘eastern’’ markets (India and China) are volatile and with noticeable maxima at times of global world events. The Japanese market switches ‘‘identity’’—it switches between periods of high meta-correlations with the ‘‘western’’ markets and periods when it behaves more similarly to the ‘‘eastern’’ markets. Conclusions/Significance: The methodological framework presented here provides a way to quantify the evolvement of interdependencies in the global market, evaluate a world financial network and quantify changes in the world inter market relations. Such changes can be used as precursors to the agitation of the global financial village. Hence, the new approach can help to develop a sensitive ‘‘financial seismograph’’ to detect early signs of global financial crises so they can be treated before they develop into worldwide event

Review article: MHD wave propagation near coronal null points of magnetic fields

We present a comprehensive review of MHD wave behaviour in the neighbourhood of coronal null points: locations where the magnetic field, and hence the local Alfven speed, is zero. The behaviour of all three MHD wave modes, i.e. the Alfven wave and the fast and slow magnetoacoustic waves, has been investigated in the neighbourhood of 2D, 2.5D and (to a certain extent) 3D magnetic null points, for a variety of assumptions, configurations and geometries. In general, it is found that the fast magnetoacoustic wave behaviour is dictated by the Alfven-speed profile. In a $\beta=0$ plasma, the fast wave is focused towards the null point by a refraction effect and all the wave energy, and thus current density, accumulates close to the null point. Thus, null points will be locations for preferential heating by fast waves. Independently, the Alfven wave is found to propagate along magnetic fieldlines and is confined to the fieldlines it is generated on. As the wave approaches the null point, it spreads out due to the diverging fieldlines. Eventually, the Alfven wave accumulates along the separatrices (in 2D) or along the spine or fan-plane (in 3D). Hence, Alfven wave energy will be preferentially dissipated at these locations. It is clear that the magnetic field plays a fundamental role in the propagation and properties of MHD waves in the neighbourhood of coronal null points. This topic is a fundamental plasma process and results so far have also lead to critical insights into reconnection, mode-coupling, quasi-periodic pulsations and phase-mixing.Comment: 34 pages, 5 figures, invited review in Space Science Reviews => Note this is a 2011 paper, not a 2010 pape

The Role of Appearance in Adolescents’ Experiences of Neurofibromatosis Type 1: A Survey of Young People and Parents

© 2016, National Society of Genetic Counselors, Inc. Neurofibromatosis type 1 (NF1) is a genetic condition which can result in varying degrees of visible difference (disfigurement). Adolescence is a time when appearance concerns become more salient for many young people and is acknowledged as a particularly challenging time for individuals with NF1. There is currently little research into the psychosocial impact of the appearance changes associated with NF1 during this stage of life. In order to address this, surveys of young people with NF1 aged 14–24years (n=73), and parents of young people with NF1 (n=55) were developed following interview studies with these groups. The surveys included the Perceived Stigma Questionnaire, Social Comfort Questionnaire, Body Esteem Scale (appearance subscale) and the Subjective Happiness Scale. Young people and parents identified appearance as central to young peoples’ experience of NF1, however no significant difference was found on measures of body esteem, happiness, stigma or social comfort between those young people who reported their NF1 was noticeable to others and those who reported it was not. Findings from the parent survey indicated that their reports of greater perceived noticeability did relate to greater perceived stigma and lower levels of social comfort. Findings highlight the importance of attending to young people’s concerns around appearance in general and managing the possibility of future appearance changes, rather than the current noticeability of NF1

Impact of vaccination on the association of COVID-19 with cardiovascular diseases:An OpenSAFELY cohort study

Infection with SARS-CoV-2 is associated with an increased risk of arterial and venous thrombotic events, but the implications of vaccination for this increased risk are uncertain. With the approval of NHS England, we quantified associations between COVID-19 diagnosis and cardiovascular diseases in different vaccination and variant eras using linked electronic health records for ~40% of the English population. We defined a 'pre-vaccination' cohort (18,210,937 people) in the wild-type/Alpha variant eras (January 2020-June 2021), and 'vaccinated' and 'unvaccinated' cohorts (13,572,399 and 3,161,485 people respectively) in the Delta variant era (June-December 2021). We showed that the incidence of each arterial thrombotic, venous thrombotic and other cardiovascular outcomes was substantially elevated during weeks 1-4 after COVID-19, compared with before or without COVID-19, but less markedly elevated in time periods beyond week 4. Hazard ratios were higher after hospitalised than non-hospitalised COVID-19 and higher in the pre-vaccination and unvaccinated cohorts than the vaccinated cohort. COVID-19 vaccination reduces the risk of cardiovascular events after COVID-19 infection. People who had COVID-19 before or without being vaccinated are at higher risk of cardiovascular events for at least two years.</p