Development of a molecular technique for microsatellite instability for use in colon cancer

El Cáncer Colorrectal (CCR) es la segun-da causa de muerte por cáncer en Argentina, con más de 11.000 nuevos casos por año. Entre el 3 y el 8% de los casos son producidos por mutaciones heredables. El síndrome más común es el Síndrome de Lynch o Cán-cer Colorrectal Hereditario no Polipósico (CCHNP). Los pacientes afectados tienen un riesgo superior al 80% de desarrollar cáncer de colon y en mujeres, el riesgo de cáncer de endometrio es de 60%. También se encuentra incrementado el riesgo de padecer cáncer de estómago, ovario, intestino delgado, vías biliares y riñón. La patogé-nesis del CCHNP se relaciona con fallas en el sistema de reparación del ADN que lleva a la acumulación de muta-ciones de nucleótido único y cambios en la longitud de secuencias repetitivas, fenómeno conocido como Inesta-bilidad de Microsatélites (MSI). Alta Inestabilidad de mi-crosatélites (MSI-High) se presenta en más del 85% de casos de CCHNP. Además, puede detectarse en el 10-15% de los casos de CCR no asociados a CCHNP debido a metilación de los genes de las enzimas de reparación del ADN. Los tumores colorrectales con MSI tienen carac-terísticas histológicas definidas, mejor pronóstico que los tumores sin MSI y diferente respuesta a la quimioterapia. El descubrimiento de MSI en CCR ha incrementado el co-nocimiento de la diversidad de los CCR y colabora en el diagnóstico, tratamiento y asesoramiento genético. Objetivo: diseñar una técnica molecular para el análisis de MSI de bajo costo y adecuar los algoritmos para me-jorar el diagnóstico de Síndrome de Lynch en la región

Improvement of cardiometabolic markers after fish oil intervention in young Mexican adults and the role of PPARα L162V and PPARγ2 P12A

Polyunsaturated fatty acids (PUFA) contained in fish oil (FO) are ligands for peroxisome proliferator-activated receptors (PPAR) that may induce changes in cardiometabolic markers. Variation in PPAR genes may influence the beneficial responses linked to FO supplementation in young adults. The study aimed to analyze the effect of FO supplementation on glucose metabolism, circulating lipids and inflammation according to PPARα L162V and PPARγ2 P12A genotypes in young Mexican adults. 191 young, non-smoking subjects between 18 and 40 years were included in a one-arm study. Participants were supplemented with 2.7 g/day of EPA+DHA, during six weeks. Dietary analysis, body composition measurements and indicators for glucose metabolism, circulating lipids, and markers for inflammation were analyzed before and after intervention. An overall decrease in triglycerides (TG) and an increase in HS-ω3 index were observed in all subjects [-4.1 mg/dL, (SD:±51.7), P=.02 and 2.6%, (SD:±1.2), P\u3c.001 respectively]. Mean fasting insulin and glycated hemoglobin (HbA1c%) were significantly decreased in all subjects [-0.547mlU/L, (SD:±10.29), P=.034 and-0.07%, (SD:±0.3), P\u3c.001 respectively], whereas there was no change in body composition, fasting glucose, adiponectin and inflammatory markers. Subjects carrying the minor alleles of PPARα L162V and PPARγ2 P12A had higher responses in reduction of TG and fasting insulin respectively. Interestingly, doses below 2.7 g/day (1.8 g/day) were sufficient to induce a significant reduction in fasting insulin and HbA1c% from baseline (P=.019 and P\u3c.001). The observed responses in triglycerides and fasting insulin in the Mexican population give further evidence of the importance of FO supplementation in young people as an early step towards the prevention of cardiometabolic disease. Trial registration: ClinicalTrials.gov NCT02296385

Historic sampling of a vanishing beast: Population structure and diversity in the Black Rhinoceros

The black rhinoceros (Diceros bicornis L.) is a critically endangered species historically distributed across sub-Saharan Africa. Hunting and habitat disturbance have diminished both its numbers and distribution since the 19th century, but a poaching crisis in the late 20th century drove them to the brink of extinction. Genetic and genomic assessments can greatly increase our knowledge of the species and inform management strategies. However, when a species has been severely reduced, with the extirpation and artificial admixture of several populations, it is extremely challenging to obtain an accurate understanding of historic population structure and evolutionary history from extant samples. Therefore, we generated and analyzed whole genomes from 63 black rhinoceros museum specimens collected between 1775 and 1981. Results showed that the black rhinoceros could be genetically structured into six major historic populations (Central Africa, East Africa, Northwestern Africa, Northeastern Africa, Ruvuma, and Southern Africa) within which were nested four further subpopulations (Maasailand, southwestern, eastern rift, and northern rift), largely mirroring geography, with a punctuated north–south cline. However, we detected varying degrees of admixture among groups and found that several geographical barriers, most prominently the Zambezi River, drove population discontinuities. Genomic diversity was high in the middle of the range and decayed toward the periphery. This comprehensive historic portrait also allowed us to ascertain the ancestry of 20 resequenced genomes from extant populations. Lastly, using insights gained from this unique temporal data set, we suggest management strategies, some of which require urgent implementation, for the conservation of the remaining black rhinoceros diversity

Functional Variant in the Autophagy-Related 5 Gene Promotor is Associated with Childhood Asthma

Rationale and Objective: Autophagy is a cellular process directed at eliminating or recycling cellular proteins. Recently, the autophagy pathway has been implicated in immune dysfunction, the pathogenesis of inflammatory disorders, and response to viral infection. Associations between two genes in the autophagy pathway, ATG5 and ATG7, with childhood asthma were investigated. Methods: Using genetic and experimental approaches, we examined the association of 13 HapMap-derived tagging SNPs in ATG5 and ATG7 with childhood asthma in 312 asthmatic and 246 non-allergic control children. We confirmed our findings by using independent cohorts and imputation analysis. Finally, we evaluated the functional relevance of a disease associated SNP. Measurements and Main Results: We demonstrated that ATG5 single nucleotide polymorphisms rs12201458 and rs510432 were associated with asthma (p = 0.00085 and 0.0025, respectively). In three independent cohorts, additional variants in ATG5 in the same LD block were associated with asthma (p,0.05). We found that rs510432 was functionally relevant and conferred significantly increased promotor activity. Furthermore, Atg5 expression was increased in nasal epithelium of acute asthmatics compared to stable asthmatics and non-asthmatic controls. Conclusion: Genetic variants in ATG5, including a functional promotor variant, are associated with childhood asthma. Thes

Measurement of the cross-section for b-jets produced in association with a Z boson at root s=7 TeV with the ATLAS detector ATLAS Collaboration

A measurement is presented of the inclusive cross-section for b-jet production in association with a Z boson in pp collisions at a centre-of-mass energy of root s = 7 TeV. The analysis uses the data sample collected by the ATLAS experiment in 2010, corresponding to an integrated luminosity of approximately 36 pb(-1). The event selection requires a Z boson decaying into high P-T electrons or muons, and at least one b-jet, identified by its displaced vertex, with transverse momentum p(T) > 25 GeV and rapidity vertical bar y vertical bar < 2.1. After subtraction of background processes, the yield is extracted from the vertex mass distribution of the candidate b-jets. The ratio of this cross-section to the inclusive Z cross-section (the average number of b-jets per Z event) is also measured. Both results are found to be in good agreement with perturbative QCD predictions at next-to-leading order

An epigenome-wide association study of total serum immunoglobulin E concentration

Immunoglobulin E (IgE) is a central mediator of allergic (atopic) inflammation. Therapies directed against IgE can alleviate hay fever and allergic asthma. Genetic association studies have not yet identified novel therapeutic targets or pathways underlying IgE regulation. We therefore surveyed epigenetic associations between serum IgE concentrations and methylation at loci concentrated in CpG islands genome wide in 95 nuclear pedigrees, using DNA from peripheral blood leukocytes. We validated positive results in additional families and in subjects from the general population. Here we show replicated associations-with a meta-analysis false discovery rate less than 10(-4)-between IgE and low methylation at 36 loci. Genes annotated to these loci encode known eosinophil products, and also implicate phospholipid inflammatory mediators, specific transcription factors and mitochondrial proteins. We confirmed that methylation at these loci differed significantly in isolated eosinophils from subjects with and without asthma and high IgE levels. The top three loci accounted for 13% of IgE variation in the primary subject panel, explaining the tenfold higher variance found compared with that derived from large single-nucleotide polymorphism genome-wide association studies. This study identifies novel therapeutic targets and biomarkers for patient stratification for allergic diseases

Search for new phenomena in high-mass final states with a photon and a jet from pp collisions at root s=13 TeV with the ATLAS detector

A search is performed for new phenomena in events having a photon with high transverse momentum and a jet collected in 36.7 fb−1 of proton–proton collisions at a centre-of-mass energy of s√ = 13 TeV recorded with the ATLAS detector at the Large Hadron Collider. The invariant mass distribution of the leading photon and jet is examined to look for the resonant production of new particles or the presence of new high-mass states beyond the Standard Model. No significant deviation from the background-only hypothesis is observed and cross-section limits for generic Gaussian-shaped resonances are extracted. Excited quarks hypothesized in quark compositeness models and high-mass states predicted in quantum black hole models with extra dimensions are also examined in the analysis. The observed data exclude, at 95% confidence level, the mass range below 5.3 TeV for excited quarks and 7.1 TeV (4.4 TeV) for quantum black holes in the Arkani-Hamed–Dimopoulos–Dvali (Randall–Sundrum) model with six (one) extra dimensions

Allele-specific transcription of the asthma-associated PHD finger protein 11 gene (PHF11) modulated by octamer-binding transcription factor 1 (Oct-1).

BACKGROUND: Asthma is a common, chronic inflammatory airway disease of major public health importance with multiple genetic determinants. Previously, we found by positional cloning that PHD finger protein 11 (PHF11) on chromosome 13q14 modifies serum immunoglobulin E (IgE) concentrations and asthma susceptibility. No coding variants in PHF11 were identified. OBJECTIVE: Here we investigate the 3 single nucleotide polymorphisms (SNPs) in this gene most significantly associated with total serum IgE levels--rs3765526, rs9526569, and rs1046295--for a role in transcription factor binding. METHODS: We used electrophoretic mobility shift assays to examine the effect of the 3 SNPs on transcription factor binding in 3 cell lines relevant to asthma pathogenesis. Relative preferential expression of alleles was investigated by using the allelotyping method. RESULTS: Electrophoretic mobility shift assays show that rs1046295 modulates allele-specific binding by the octamer-binding transcription factor 1 (Oct-1). Analysis of the relative expression levels of the 2 alleles of this SNP in heterozygous individuals showed a modest, but highly significant (P = 6.5 × 10(-16)), preferential expression of the A allele consistent with a functional role for rs1046295. CONCLUSION: These results suggest a mechanism by which rs1046295 may act as a regulatory variant modulating transcription at this locus and altering asthma susceptibility

Impact of maternal characteristics on human milk oligosaccharide composition over the first 4 months of lactation in a cohort of healthy European mothers

Human milk oligosaccharide (HMO) composition varies among lactating mothers and changes during the course of lactation period. Interindividual variation is largely driven by fucosyltransferase (FUT2 and FUT3) polymorphisms resulting in 4 distinct milk groups. Little is known regarding whether maternal physiological status contributes to HMO variability. We characterized the trajectories of 20 major HMOs and explored whether maternal pre-pregnancy body mass index (ppBMI), mode of delivery, or parity may affect milk HMO composition. Using longitudinal breastmilk samples from healthy mothers (n = 290) across 7 European countries, we characterized HMO composion and employed mixed linear models to explore associations of maternal characteristics with individual HMOs. We observed HMO-specific temporal trajectories and milk group dependencies. We observed relatively small but significant differences in HMO concentrations based on maternal ppBMI, mode of delivery and parity. Our findings suggest that HMO composition to be regulated time-dependently by an enzyme as well as substrate availability and that ppBMI, mode of delivery, and parity may influence maternal physiology to affect glycosylation marginally within the initital period of lactation. Our observational study is the largest European standardized and longitudinal (up to 4 months) milk collection study assessing HMO concentrations and basic maternal characteristics. Time of lactation and milk groups had the biggest impact on HMO variation. Future studies need to elucidate these observations and assess the physiological significance for the breastfed infant

Human milk oligosaccharides, infant growth, and adiposity over the first 4 months of lactation

Background: The relationship between human milk oligosaccharides (HMOs) and infant growth and adiposity is not fully understood and comprehensive studies are missing from the current literature. Methods: We screened and recruited 370 healthy, pregnant women and their infants from seven European countries. Breastmilk samples were collected using standardized procedures at six time points over 4 months, as were infant parameters. Correlations and associations between HMO area under the curve, anthropometric data, and fat mass at 4 months were tested. Results: Lacto-N-neotetraose had a negative correlation with the change in length (rs = 120.18, P = 0.02). Sialyllacto-N-tetraose c (LSTc) had a positive correlation with weight for length (rs = 0.19, P = 0.015). Infants at the 25th upper percentile were fed milk higher in 3\u2032-sialyllactose and LSTc (P = 0.017 and P = 0.006, respectively) compared to the lower 25th percentile of the weight-for-length z-score gain over 4 months of lactation. No significant associations between growth and body composition and Lewis or secretor-dependent HMOs like 2\u2032-fucosyllactose were identified. Conclusions: Changes in the HMO composition of breastmilk during the first 4 months appear to have little influence on infant growth and body composition in this cohort of healthy mothers and infants. Impact: Modest associations exist between individual HMO and infant growth outcomes at least in healthy growing populations.Our study provides a comprehensive investigation of associations between all major HMO and infant growth and adiposity including several time points. Certain groups of HMOs, like the sialylated, may be associated with adiposity during the first months of lactation.HMO may modulate the risk of future metabolic disease. Future population studies need to address the role of specific groups of HMOs in the context of health and disease to understand the long-term impact