Interaction of metal phthalocyanines with carbon zigzag and armchair nanotubes with different diameters

Quantum-chemical calculations of the association of metal free, cobalt, copper and zinc phthalocyanines (MPc) with carbon zigzag and armchair nanotubes (CNTs) with diameters in the range of 7–14 Å were carried out by the DFT method with the use of BH van der Waals density functional and DZP atomic basis set. It was shown that interaction energy between the phthalocyanine molecules and the CNTs, as a whole, increases with an increase of the diameter of carbon nanotubes. However, in the case of CNT(n,0) the energy reaches its maximal value at n = 16 or 17 depending on the central metal atom and phthalocyanine orientation on the carbon nanotubes surface. Up to diameter of 10.5 Å of the CNTs, stronger binding of the considered MPc macrocyclic molecules is observed with carbon armchair nanotubes. However, in the case of higher diameters the phthalocyanines are associated more strongly with the zigzag CNTs

Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.

BACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. METHODS: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. RESULTS: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. CONCLUSIONS: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function

Un examen actualizado de la percepción de las barreras para la implementación de la farmacogenómica y la utilidad de los pares fármaco/gen en América Latina y el Caribe

La farmacogenómica (PGx) se considera un campo emergente en los países en desarrollo. La investigación sobre PGx en la región de América Latina y el Caribe (ALC) sigue siendo escasa, con información limitada en algunas poblaciones. Por lo tanto, las extrapolaciones son complicadas, especialmente en poblaciones mixtas. En este trabajo, revisamos y analizamos el conocimiento farmacogenómico entre la comunidad científica y clínica de ALC y examinamos las barreras para la aplicación clínica. Realizamos una búsqueda de publicaciones y ensayos clínicos en este campo en todo el mundo y evaluamos la contribución de ALC. A continuación, realizamos una encuesta regional estructurada que evaluó una lista de 14 barreras potenciales para la aplicación clínica de biomarcadores en función de su importancia. Además, se analizó una lista emparejada de 54 genes/fármacos para determinar una asociación entre los biomarcadores y la respuesta a la medicina genómica. Esta encuesta se comparó con una encuesta anterior realizada en 2014 para evaluar el progreso en la región. Los resultados de la búsqueda indicaron que los países de América Latina y el Caribe han contribuido con el 3,44% del total de publicaciones y el 2,45% de los ensayos clínicos relacionados con PGx en todo el mundo hasta el momento. Un total de 106 profesionales de 17 países respondieron a la encuesta. Se identificaron seis grandes grupos de obstáculos. A pesar de los continuos esfuerzos de la región en la última década, la principal barrera para la implementación de PGx en ALC sigue siendo la misma, la "necesidad de directrices, procesos y protocolos para la aplicación clínica de la farmacogenética/farmacogenómica". Las cuestiones de coste-eficacia se consideran factores críticos en la región. Los puntos relacionados con la reticencia de los clínicos son actualmente menos relevantes. Según los resultados de la encuesta, los pares gen/fármaco mejor clasificados (96%-99%) y percibidos como importantes fueron CYP2D6/tamoxifeno, CYP3A5/tacrolimus, CYP2D6/opioides, DPYD/fluoropirimidinas, TMPT/tiopurinas, CYP2D6/antidepresivos tricíclicos, CYP2C19/antidepresivos tricíclicos, NUDT15/tiopurinas, CYP2B6/efavirenz y CYP2C19/clopidogrel. En conclusión, aunque la contribución global de los países de ALC sigue siendo baja en el campo del PGx, se ha observado una mejora relevante en la región. La percepción de la utilidad de las pruebas PGx en la comunidad biomédica ha cambiado drásticamente, aumentando la concienciación entre los médicos, lo que sugiere un futuro prometedor en las aplicaciones clínicas de PGx en ALC.Pharmacogenomics (PGx) is considered an emergent field in developing countries. Research on PGx in the Latin American and the Caribbean (LAC) region remains scarce, with limited information in some populations. Thus, extrapolations are complicated, especially in mixed populations. In this paper, we reviewed and analyzed pharmacogenomic knowledge among the LAC scientific and clinical community and examined barriers to clinical application. We performed a search for publications and clinical trials in the field worldwide and evaluated the contribution of LAC. Next, we conducted a regional structured survey that evaluated a list of 14 potential barriers to the clinical implementation of biomarkers based on their importance. In addition, a paired list of 54 genes/drugs was analyzed to determine an association between biomarkers and response to genomic medicine. This survey was compared to a previous survey performed in 2014 to assess progress in the region. The search results indicated that Latin American and Caribbean countries have contributed 3.44% of the total publications and 2.45% of the PGx-related clinical trials worldwide thus far. A total of 106 professionals from 17 countries answered the survey. Six major groups of barriers were identified. Despite the region’s continuous efforts in the last decade, the primary barrier to PGx implementation in LAC remains the same, the “need for guidelines, processes, and protocols for the clinical application of pharmacogenetics/pharmacogenomics”. Cost-effectiveness issues are considered critical factors in the region. Items related to the reluctance of clinicians are currently less relevant. Based on the survey results, the highest ranked (96%–99%) gene/drug pairs perceived as important were CYP2D6/tamoxifen, CYP3A5/tacrolimus, CYP2D6/opioids, DPYD/fluoropyrimidines, TMPT/thiopurines, CYP2D6/tricyclic antidepressants, CYP2C19/tricyclic antidepressants, NUDT15/thiopurines, CYP2B6/efavirenz, and CYP2C19/clopidogrel. In conclusion, although the global contribution of LAC countries remains low in the PGx field, a relevant improvement has been observed in the region. The perception of the usefulness of PGx tests in biomedical community has drastically changed, raising awareness among physicians, which suggests a promising future in the clinical applications of PGx in LAC

An Updated Examination of the Perception of Barriers for Pharmacogenomics Implementation and the Usefulness of Drug/Gene Pairs in Latin America and the Caribbean

Pharmacogenomics (PGx) is considered an emergent field in developing countries. Research on PGx in the Latin American and the Caribbean (LAC) region remains scarce, with limited information in some populations. Thus, extrapolations are complicated, especially in mixed populations. In this paper, we reviewed and analyzed pharmacogenomic knowledge among the LAC scientific and clinical community and examined barriers to clinical application. We performed a search for publications and clinical trials in the field worldwide and evaluated the contribution of LAC. Next, we conducted a regional structured survey that evaluated a list of 14 potential barriers to the clinical implementation of biomarkers based on their importance. In addition, a paired list of 54 genes/drugs was analyzed to determine an association between biomarkers and response to genomic medicine. This survey was compared to a previous survey performed in 2014 to assess progress in the region. The search results indicated that Latin American and Caribbean countries have contributed 3.44% of the total publications and 2.45% of the PGx-related clinical trials worldwide thus far. A total of 106 professionals from 17 countries answered the survey. Six major groups of barriers were identified. Despite the region’s continuous efforts in the last decade, the primary barrier to PGx implementation in LAC remains the same, the “need for guidelines, processes, and protocols for the clinical application of pharmacogenetics/pharmacogenomics”. Cost-effectiveness issues are considered critical factors in the region. Items related to the reluctance of clinicians are currently less relevant. Based on the survey results, the highest ranked (96%–99%) gene/drug pairs perceived as important were CYP2D6/tamoxifen, CYP3A5/tacrolimus, CYP2D6/opioids, DPYD/fluoropyrimidines, TMPT/thiopurines, CYP2D6/tricyclic antidepressants, CYP2C19/tricyclic antidepressants, NUDT15/thiopurines, CYP2B6/efavirenz, and CYP2C19/clopidogrel. In conclusion, although the global contribution of LAC countries remains low in the PGx field, a relevant improvement has been observed in the region. The perception of the usefulness of PGx tests in biomedical community has drastically changed, raising awareness among physicians, which suggests a promising future in the clinical applications of PGx in LAC

A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America

Background: Genetic counselling and testing for Lynch syndrome (LS) have recently been introduced in several Latin America countries. We aimed to characterize the clinical, molecular and mismatch repair (MMR) variants spectrum of patients with suspected LS in Latin America. Methods: Eleven LS hereditary cancer registries and 34 published LS databases were used to identify unrelated families that fulfilled the Amsterdam II (AMSII) criteria and/or the Bethesda guidelines or suggestive of a dominant colorectal (CRC) inheritance syndrome. Results: We performed a thorough investigation of 15 countries and identified 6 countries where germline genetic testing for LS is available and 3 countries where tumor testing is used in the LS diagnosis. The spectrum of pathogenic MMR variants included MLH1 up to 54%, MSH2 up to 43%, MSH6 up to 10%, PMS2 up to 3% and EPCAM up to 0.8%. The Latin America MMR spectrum is broad with a total of 220 different variants which 80% were private and 20% were recurrent. Frequent regions included exons 11 of MLH1 (15%), exon 3 and 7 of MSH2 (17 and 15%, respectively), exon 4 of MSH6 (65%), exons 11 and 13 of PMS2 (31% and 23%, respectively). Sixteen international founder variants in MLH1, MSH2 and MSH6 were identified and 41 (19%) variants have not previously been reported, thus representing novel genetic variants in the MMR genes. The AMSII criteria was the most used clinical criteria to identify pathogenic MMR carriers although microsatellite instability, immunohistochemistry and family history are still the primary methods in several countries where no genetic testing for LS is available yet. Conclusion: The Latin America LS pathogenic MMR variants spectrum included new variants, frequently altered genetic regions and potential founder effects, emphasizing the relevance implementing Lynch syndrome genetic testing and counseling in all of Latin America countries.Radium Hospital Foundation (Oslo, Norway) in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript, Helse Sør-Øst (Norway) in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript, the French Association Recherche contre le Cancer (ARC) in the analysis, and interpretation of data, the Groupement des Entreprises Françaises dans la Lutte contre le Cancer (Gefluc) in the analysis, and interpretation of data, the Association Nationale de la Recherche et de la Technologie (ANRT, CIFRE PhD fellowship to H.T.) in the analysis, and interpretation of data and by the OpenHealth Institute in the analysis, and interpretation of data. Barretos Cancer Hospital received financial support by FINEP-CT-INFRA (02/2010)info:eu-repo/semantics/publishedVersio

Large-Scale Genome-Wide Association Studies and Meta-Analyses of Longitudinal Change in Adult Lung Function

BackgroundGenome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.MethodsWe performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.ResultsThe overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10-7). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10-8) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively.ConclusionsIn this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function

Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function

Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV1), and its ratio to forced vital capacity (FEV1/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV1 and FEV1/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P JMA = 5.00×10−11), HLA-DQB1 and HLA-DQA2 (smallest P JMA = 4.35×10−9), and KCNJ2 and SOX9 (smallest P JMA = 1.28×10−8) were associated with FEV1/FVC or FEV1 in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects

Genome-wide association analysis identifies six new loci associated with forced vital capacity

Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10−8) with FVC in or near EFEMP1, BMP6, MIR129-2–HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease

European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.</p