Dihydropyrimidinase and β-ureidopropionase gene variation and severe fluoropyrimidine-related toxicity

AIMS To assess the association of DPYS and UPB1 genetic variation, encoding the catabolic enzymes downstream of dihydropyrimidine dehydrogenase, with early-onset toxicity from fluoropyrimidine-based chemotherapy. PATIENTS & METHODS The coding and exon-flanking regions of both genes were sequenced in a discovery subset (164 patients). Candidate variants were genotyped in the full cohort of 514 patients. RESULTS & CONCLUSIONS Novel rare deleterious variants in DPYS (c.253C > T and c.1217G > A) were detected once each in toxicity cases and may explain the occurrence of severe toxicity in individual patients, and associations of common variants in DPYS (c.1-1T > C: padjusted = 0.003; OR = 2.53; 95% CI: 1.39-4.62, and c.265-58T > C: padjusted = 0.039; OR = 0.61; 95% CI: 0.38-0.97) with 5-fluorouracil toxicity were replicated.

Genetic Resistance Determinants, In Vitro Time-Kill Curve Analysis and Pharmacodynamic Functions for the Novel Topoisomerase II Inhibitor ETX0914 (AZD0914) in Neisseria gonorrhoeae.

Resistance in Neisseria gonorrhoeae to all available therapeutic antimicrobials has emerged and new efficacious drugs for treatment of gonorrhea are essential. The topoisomerase II inhibitor ETX0914 (also known as AZD0914) is a new spiropyrimidinetrione antimicrobial that has different mechanisms of action from all previous and current gonorrhea treatment options. In this study, the N. gonorrhoeae resistance determinants for ETX0914 were further described and the effects of ETX0914 on the growth of N. gonorrhoeae (ETX0914 wild type, single step selected resistant mutants, and efflux pump mutants) were examined in a novel in vitro time-kill curve analysis to estimate pharmacodynamic parameters of the new antimicrobial. For comparison, ciprofloxacin, azithromycin, ceftriaxone, and tetracycline were also examined (separately and in combination with ETX0914). ETX0914 was rapidly bactericidal for all wild type strains and had similar pharmacodynamic properties to ciprofloxacin. All selected resistant mutants contained mutations in amino acid codons D429 or K450 of GyrB and inactivation of the MtrCDE efflux pump fully restored the susceptibility to ETX0914. ETX0914 alone and in combination with azithromycin and ceftriaxone was highly effective against N. gonorrhoeae and synergistic interaction with ciprofloxacin, particularly for ETX0914-resistant mutants, was found. ETX0914, monotherapy or in combination with azithromycin (to cover additional sexually transmitted infections), should be considered for phase III clinical trials and future gonorrhea treatment.

Retinal slit lamp video mosaicking

Purpose To this day, the slit lamp remains the first tool used by an ophthalmologist to examine patient eyes. Imaging of the retina poses, however, a variety of problems, namely a shallow depth of focus, reflections from the optical system, a small field of view and non-uniform illumination. For ophthalmologists, the use of slit lamp images for documentation and analysis purposes, however, remains extremely challenging due to large image artifacts. For this reason, we propose an automatic retinal slit lamp video mosaicking, which enlarges the field of view and reduces amount of noise and reflections, thus enhancing image quality. Methods Our method is composed of three parts: (i) viable content segmentation, (ii) global registration and (iii) image blending. Frame content is segmented using gradient boosting with custom pixel-wise features. Speeded-up robust features are used for finding pair-wise translations between frames with robust random sample consensus estimation and graph-based simultaneous localization and mapping for global bundle adjustment. Foreground-aware blending based on feathering merges video frames into comprehensive mosaics. Results Foreground is segmented successfully with an area under the curve of the receiver operating characteristic curve of 0.9557. Mosaicking results and state-of-the-art methods were compared and rated by ophthalmologists showing a strong preference for a large field of view provided by our method. Conclusions The proposed method for global registration of retinal slit lamp images of the retina into comprehensive mosaics improves over state-of-the-art methods and is preferred qualitatively.

THE NATURAL AND ORTHOGONAL INTERACTION (NOIA) MODELS FOR QUANTITATIVE TRAITS (QTs) AND COMPLEX DISEASES

My dissertation focuses on developing methods for gene-gene/environment interactions and imprinting effect detections for human complex diseases and quantitative traits. It includes three sections: (1) generalizing the Natural and Orthogonal interaction (NOIA) model for the coding technique originally developed for gene-gene (GxG) interaction and also to reduced models; (2) developing a novel statistical approach that allows for modeling gene-environment (GxE) interactions influencing disease risk, and (3) developing a statistical approach for modeling genetic variants displaying parent-of-origin effects (POEs), such as imprinting. In the past decade, genetic researchers have identified a large number of causal variants for human genetic diseases and traits by single-locus analysis, and interaction has now become a hot topic in the effort to search for the complex network between multiple genes or environmental exposures contributing to the outcome. Epistasis, also known as gene-gene interaction is the departure from additive genetic effects from several genes to a trait, which means that the same alleles of one gene could display different genetic effects under different genetic backgrounds. In this study, we propose to implement the NOIA model for association studies along with interaction for human complex traits and diseases. We compare the performance of the new statistical models we developed and the usual functional model by both simulation study and real data analysis. Both simulation and real data analysis revealed higher power of the NOIA GxG interaction model for detecting both main genetic effects and interaction effects. Through application on a melanoma dataset, we confirmed the previously identified significant regions for melanoma risk at 15q13.1, 16q24.3 and 9p21.3. We also identified potential interactions with these significant regions that contribute to melanoma risk. Based on the NOIA model, we developed a novel statistical approach that allows us to model effects from a genetic factor and binary environmental exposure that are jointly influencing disease risk. Both simulation and real data analyses revealed higher power of the NOIA model for detecting both main genetic effects and interaction effects for both quantitative and binary traits. We also found that estimates of the parameters from logistic regression for binary traits are no longer statistically uncorrelated under the alternative model when there is an association. Applying our novel approach to a lung cancer dataset, we confirmed four SNPs in 5p15 and 15q25 region to be significantly associated with lung cancer risk in Caucasians population: rs2736100, rs402710, rs16969968 and rs8034191. We also validated that rs16969968 and rs8034191 in 15q25 region are significantly interacting with smoking in Caucasian population. Our approach identified the potential interactions of SNP rs2256543 in 6p21 with smoking on contributing to lung cancer risk. Genetic imprinting is the most well-known cause for parent-of-origin effect (POE) whereby a gene is differentially expressed depending on the parental origin of the same alleles. Genetic imprinting affects several human disorders, including diabetes, breast cancer, alcoholism, and obesity. This phenomenon has been shown to be important for normal embryonic development in mammals. Traditional association approaches ignore this important genetic phenomenon. In this study, we propose a NOIA framework for a single locus association study that estimates both main allelic effects and POEs. We develop statistical (Stat-POE) and functional (Func-POE) models, and demonstrate conditions for orthogonality of the Stat-POE model. We conducted simulations for both quantitative and qualitative traits to evaluate the performance of the statistical and functional models with different levels of POEs. Our results showed that the newly proposed Stat-POE model, which ensures orthogonality of variance components if Hardy-Weinberg Equilibrium (HWE) or equal minor and major allele frequencies is satisfied, had greater power for detecting the main allelic additive effect than a Func-POE model, which codes according to allelic substitutions, for both quantitative and qualitative traits. The power for detecting the POE was the same for the Stat-POE and Func-POE models under HWE for quantitative traits.

Una nueva metodología... : el piano, en el sendero de la educación a distancia

Fil: Furgiuele, Ana. Universidad Nacional de Cuyo. Facultad de Artes y Diseño

Horizontal profiles of longwave and shortwave radiation components over sea ice near Barrow, Alaska during the 2011 melt

An integrated instrument package for measuring and understanding the surface radiation budget of sea ice is presented, along with results from its first deployment. The setup simultaneously measures broadband fluxes of upwelling and downwelling terrestrial and solar radiation (four components separately), spectral fluxes of incident and reflected solar radiation, and supporting data such as air temperature and humidity, surface temperature, and location (GPS), in addition to photographing the sky and observed surface during each measurement. The instruments are mounted on a small sled, allowing measurements of the radiation budget to be made at many locations in the study area to see the effect of small-scale surface processes on the large-scale radiation budget. Such observations have many applications, from calibration and validation of remote sensing products to improving our understanding of surface processes that affect atmosphere-snow-ice interactions and drive feedbacks, ultimately leading to the potential to improve climate modelling of ice-covered regions of the ocean. The photographs, spectral data, and other observations allow for improved analysis of the broadband data. An example of this is shown by using the observations made during a partly cloudy day, which show erratic variations due to passing clouds, and creating a careful estimate of what the radiation budget along the observed line would have been under uniform sky conditions, clear or overcast. Other data from the setup's first deployment, in June 2011 on fast ice near Point Barrow, Alaska, are also shown; these illustrate the rapid changes of the radiation budget during a cold period that led to refreezing and new snow well into the melt season.