Assessment of adherence to at-home oral anti-infective therapy among paediatric patients discharged from a Quebec hospital.

OBJECTIVES: Non-adherence to anti-infective therapy contributes to treatment failure and the emergence of bacterial resistance. This study aimed to assess at-home adherence, by paediatric patients, to oral anti-infective (OAI) therapy prescribed for treatment of acute infections and to explore the factors contributing to non-adherence. METHODS: This prospective descriptive study involved French-speaking patients under 16 years of age who were discharged with one or more OAIs prescribed for home administration for a maximum of 30 days. Telephone surveys were used to assess overall adherence, which consisted of primary adherence (patient's ability to procure the medication) and secondary adherence (patient's ability to take the treatment as prescribed). RESULTS: Overall, 51.7% (30/58) of patients were adherent to OAI therapy, with 100% primary adherence (n=69/69) and 51.7% secondary adherence (n=30/58). On average, patients took 98% of the total number of doses prescribed, and non-adherence was related mostly to not following medication administration schedules (63.3% of patients followed the exact schedule). Indeed, the adherence rate for patients taking one or two doses per day was twice the rate for patients taking more than two doses per day (81.8% vs 44.7%, p=0.043). CONCLUSIONS: Half of the paediatric patients treated for acute infections were non-adherent to OAI therapy at home. Interventions are needed to improve this situation.

Design and Development of an Escape Game as a Knowledge Transfer Tool in Preparation for an Accreditation Visit in a Health Care Facility.

Background: Knowledge transfer helps health care staff to be competent, well informed, and up to date. It also contributes to adherence to standards and best practices. Objectives: To design, implement, and evaluate an escape game based on a selection of Accreditation Canada required organizational practices (ROPs). Methods: This prospective descriptive study involved nurses and pharmacists in a health care centre. An escape game based on 6 ROPs was designed. The game was played by teams of participants in a patient room within the centre, with each game lasting 25 minutes. Participants' satisfaction with various aspects of their experience was assessed. Results: A total of 200 people (52 teams) participated in the escape game. About half of the teams (n = 28) completed the game within the allotted time (average completion time 20 minutes, 53 seconds; standard deviation [SD] 2 minutes, 45 seconds). On average, 1.32 (SD 0.88) clues were provided to successful teams and 1.88 (SD 0.95) to unsuccessful teams. Participants were very satisfied with their experience. However, members of unsuccessful teams had significantly lower agreement that the escape game was relevant to their practice and that it was an effective method of communication. Conclusions: An escape game based on a selection of ROPs was successfully implemented as part of the hospital's preparation for an accreditation visit. Use of an escape game as a knowledge transfer tool was appreciated by the staff.

Contexte: La transmission des connaissances aide le personnel de la santé à être compétent, bien informé et à jour. Elle contribue également au respect des normes et des meilleures pratiques. Objectifs: Concevoir, mettre en œuvre et évaluer un jeu d'évasion basé sur une sélection de pratiques organisationnelles requises (POR) d'Agrément Canada. Méthodes: Des infirmiers et des pharmaciens d'un centre de santé ont participé à cette étude prospective descriptive. Un jeu d'évasion basé sur 6 POR a été conçu. Des équipes de participants y ont joué dans une chambre de patient au sein du centre, chaque partie durant 25 minutes. La satisfaction des participants à l'égard de divers aspects de leur expérience a été évaluée. Résultats: Au total, 200 personnes (52 équipes) y ont participé. Environ la moitié des équipes (n = 28) ont terminé le jeu dans le temps imparti (temps moyen d'achèvement 20 minutes, 53 secondes ; écart type [ET] 2 minutes, 45 secondes). En moyenne, 1,32 indice (ET 0,88) a été remis aux équipes qui l'ont réussi et 1,88 (ET 0,95) aux équipes qui ont échoué. Les participants étaient très satisfaits de leur expérience. Cependant, les membres des équipes ayant échoué étaient significativement moins d'accord sur le fait que le jeu d'évasion était pertinent pour l'exercice de leur profession et qu'il s'agissait d'une méthode de communication efficace. Conclusions: Un jeu d'évasion basé sur une sélection de POR a été mis en place avec succès dans le cadre de la préparation de l'hôpital à une visite d'agrément. L'utilisation d'un jeu d'évasion comme outil de transmission des connaissances a été reçue de manière positive par le personnel.

A Descriptive Chemical Composition of Concentrated Bud Macerates through an Optimized SPE-HPLC-UV-MS2 Method-Application to Alnus glutinosa, Ribes nigrum, Rosa canina, Rosmarinus officinalis and Tilia tomentosa.

Concentrated bud macerates (CBMs) are obtained from meristematic tissues such as buds and young shoots by maceration in a solvent composed of glycerin, water and ethanol (1/1/1/, v/v). Their traditional utilization in gemmotherapy has gained interest in the past years, and the knowledge of their chemical characterization can provide commercial arguments, particularly to secure their quality control. Therefore, an optimized method for phytochemical analysis including glycerol removal by a preliminary solid phase extraction (SPE) followed by compound identification using high performance liquid chromatography coupled with ultra-violet and tandem mass detectors (HPLC-UV-MS2) was developed. This method was applied on 5 CBMs obtained from Alnus glutinosa, Ribesnigrum, Rosmarinus officinalis, Rosa canina and Tilia tomentosa in order to determinate their chemical composition. Their antioxidant effects were also investigated by radical scavenging activity assays (DPPH and ORAC). Glycerol removal improved the resolution of HPLC chemical profiles and allowed us to perform TLC antioxidant screening. Our approach permitted the identification of 57 compounds distributed in eight major classes, three of them being common to all macerates including nucleosides, phenolic acids and glycosylated flavonoids. Quantification of the later class as a rutin equivalent (RE) showed a great disparity between Rosa canina macerate (809 mg RE/L), and the other ones (from 175 to 470 mg RE/L). DPPH and ORAC assays confirmed the great activity of Rosa canina (4857 and 6479 µmol TE/g of dry matter, respectively). Finally, phytochemical and antioxidant analysis of CBMs strengthened their phytomedicinal interest in the gemmotherapy field.

Revisiting the Molecular Interactions between the Tumor Protein TCTP and the Drugs Sertraline/Thioridazine.

TCTP protein is a pharmacological target in cancer and TCTP inhibitors such as sertraline have been evaluated in clinical trials. The direct interaction of TCTP with the drugs sertraline and thioridazine has been reported in vitro by SPR experiments to be in the ∼30-50 µM Kd range (Amson et al. Nature Med 2012), supporting a TCTP-dependent mode of action of the drugs on tumor cells. However, the molecular details of the interaction remain elusive although they are crucial to improve the efforts of on-going medicinal chemistry. In addition, TCTP can be phosphorylated by the Plk-1 kinase, which is indicative of poor prognosis in several cancers. The impact of phosphorylation on TCTP structure/dynamics and binding with therapeutical ligands remains unexplored. Here, we combined NMR, TSA, SPR, BLI and ITC techniques to probe the molecular interactions between TCTP with the drugs sertraline and thioridazine. We reveal that drug binding is much weaker than reported with an apparent ∼mM Kd and leads to protein destabilization that obscured the analysis of the published SPR data. We further demonstrate by NMR and SAXS that TCTP S46 phosphorylation does not promote tighter interaction between TCTP and sertraline. Accordingly, we question the supported model in which sertraline and thioridazine directly interact with isolated TCTP in tumor cells and discuss alternative modes of action for the drugs in light of current literature.

Reversing Reactivity: Stereoselective Desulfurative 1,2-trans-O-Glycosylation of Anomeric Thiosugars with Carboxylic Acids under Copper or Cobalt Catalysis.

We have discovered a new mode of reactivity of 1-thiosugars in the presence of Cu(II) or Co(II) for a stereoselective O-glycosylation reaction. The process involves the use of a catalytic amount of Cu(acac)2 or Co(acac)2 and Ag2CO3 as an oxidant in α,α,α-trifluorotoluene. Moreover, this protocol turned out to have a broad scope, allowing the preparation of a wide range of complex substituted O-glycoside esters in good to excellent yields with an exclusive 1,2-trans-selectivity. The late-stage modification of pharmaceuticals by this method was also demonstrated. To obtain a closer insight into the reaction mechanism, cyclic voltammetry was performed.

Conformité du circuit du médicament dans les unités de soins et les cliniques externes : étude observationnelle transversale au sein d'un établissement universitaire de 500 lits.

BACKGROUND: In the hospital setting, the medication-use system is complex, having more than 50 steps. To assess the compliance of the study organization's medication-use system with established criteria, an annual audit process was developed. OBJECTIVES: The primary objective was to describe the compliance of certain steps in the medication-use system (mainly medication management) in care units and outpatient clinics of a mother and child university hospital centre. The secondary objective was to compare the current results with those of previous audits. METHODS: This cross-sectional descriptive observational study was carried out in summer 2018 in patient care units (n = 34) and outpatient clinics (n = 28) of the study hospital. Data were collected according to an audit matrix. RESULTS: In 2018, the rate of compliance with audit criteria varied between 32% and 100% for the patient care units. Relative to the previous year, the compliance rate remained unchanged for 30 criteria and worsened for 4 criteria. For 35% of the criteria (12/34), compliance was greater than 85%. In 2018, the rate of compliance with audit criteria varied between 0% and 100% for the outpatient clinics. The compliance rate increased for one criterion, remained unchanged for 21 criteria, and worsened for 2 criteria. For 32% of the criteria (9/28), compliance was more than 85%. Thirty-five recommendations were made to the pharmacy and nursing care committee, and a personalized report was sent to managers. CONCLUSIONS: This cross-sectional descriptive observational study reports the degree to which the medication-use system complies with medication management criteria, mainly in patient care units and outpatients' clinics. This original approach from the Pharmacy Department led to the formulation of 35 recommendations to the pharmacy and nursing care committee, which helped to improve the safety of the medication-use system in patient care units and outpatient clinics.

Needlestack: an ultra-sensitive variant caller for multi-sample next generation sequencing data.

The emergence of next-generation sequencing (NGS) has revolutionized the way of reaching a genome sequence, with the promise of potentially providing a comprehensive characterization of DNA variations. Nevertheless, detecting somatic mutations is still a difficult problem, in particular when trying to identify low abundance mutations, such as subclonal mutations, tumour-derived alterations in body fluids or somatic mutations from histological normal tissue. The main challenge is to precisely distinguish between sequencing artefacts and true mutations, particularly when the latter are so rare they reach similar abundance levels as artefacts. Here, we present needlestack, a highly sensitive variant caller, which directly learns from the data the level of systematic sequencing errors to accurately call mutations. Needlestack is based on the idea that the sequencing error rate can be dynamically estimated from analysing multiple samples together. We show that the sequencing error rate varies across alterations, illustrating the need to precisely estimate it. We evaluate the performance of needlestack for various types of variations, and we show that needlestack is robust among positions and outperforms existing state-of-the-art method for low abundance mutations. Needlestack, along with its source code is freely available on the GitHub platform: https://github.com/IARCbioinfo/needlestack.

Utilisation des jeux d'évasion en santé : une revue de littérature.

BACKGROUND: Many different teaching strategies are used to promote learning in an academic or professional environment. Among these can be noted the emergence of simulation, based on the concept of escape games. OBJECTIVE: To identify methodologies relating to the use, design, and implementation of escape games in health care. DATA SOURCES: The Pubmed, Embase, and CINAHL databases were searched up to December 3, 2018. STUDY SELECTION: All studies focusing on the design or development of escape games in the health care field (published in English or French) were included. DATA EXTRACTION: For each study, the country, target population, design, development, method of evaluation, and results were extracted for analysis. DATA SYNTHESIS: Seven poster abstracts and 9 published articles were included. Twelve escape games were developed in the United States. They were used in medicine (n = 5), pharmacy (n = 4), nursing (n = 4) and other fields (n = 3), mainly within academic teaching contexts (n = 12) but also in professional settings (n = 4). Their goals were to improve knowledge (n = 8), to increase participants' interest and motivation regarding a specific topic (n = 2), and to improve cohesion and communication within a team (n = 2). Ten of the escape games described in the articles were based on a clinical scenario. Ten of the research teams held debriefings with participants, and one did not; 5 articles did not report information about debriefing. CONCLUSIONS: Few data exist concerning the use of escape games in the health care setting, and it is too early to judge the efficiency of this approach to learning. However, growing interest justifies systematic monitoring of the literature to follow the evolution of such strategies and to better understand their place in health care education.

Correction: Immuno-related polymorphisms and cervical cancer risk: The IARC multicentric case-control study.

[This corrects the article DOI: 10.1371/journal.pone.0177775.].

Genome-wide association study identifies multiple risk loci for renal cell carcinoma.

Previous genome-wide association studies (GWAS) have identified six risk loci for renal cell carcinoma (RCC). We conducted a meta-analysis of two new scans of 5,198 cases and 7,331 controls together with four existing scans, totalling 10,784 cases and 20,406 controls of European ancestry. Twenty-four loci were tested in an additional 3,182 cases and 6,301 controls. We confirm the six known RCC risk loci and identify seven new loci at 1p32.3 (rs4381241, P=3.1 × 10-10), 3p22.1 (rs67311347, P=2.5 × 10-8), 3q26.2 (rs10936602, P=8.8 × 10-9), 8p21.3 (rs2241261, P=5.8 × 10-9), 10q24.33-q25.1 (rs11813268, P=3.9 × 10-8), 11q22.3 (rs74911261, P=2.1 × 10-10) and 14q24.2 (rs4903064, P=2.2 × 10-24). Expression quantitative trait analyses suggest plausible candidate genes at these regions that may contribute to RCC susceptibility.

Immuno-related polymorphisms and cervical cancer risk: The IARC multicentric case-control study.

A small proportion of women who are exposed to infection with human-papillomavirus (HPV) develop cervical cancer (CC). Genetic factors may affect the risk of progression from HPV infection to cervical precancer and cancer. We used samples from the International Agency for Research on Cancer (IARC) multicentric case-control study to evaluate the association of selected genetic variants with CC. Overall, 790 CC cases and 717 controls from Algeria, Morocco, India and Thailand were included. Cervical exfoliated cells were obtained from control women and cervical exfoliated cells or biopsy specimens from cases. HPV-positivity was determined using a general primer GP5+/6+ mediated PCR. Unconditional logistic regression was used to estimate odds ratios (OR) and corresponding 95% confidence intervals (CI) of host genotypes with CC risk, using the homozygous wild type genotype as the referent category and adjusting by age and study centre. The association of polymorphisms with the risk of high-risk HPV-positivity among controls was also evaluated. A statistically significant association was observed between single nucleotide polymorphism (SNP) CHR6 rs2844511 and CC risk: the OR for carriers of the GA or GG genotypes was 0.70 (95% CI: 0.43-1.14) and 0.61 (95% CI: 0.38-0.98), respectively, relative to carriers of AA genotype (p-value for trend 0.03). We also observed associations of borderline significance with the TIPARP rs2665390 polymorphism, which was previously found to be associated with ovarian and breast cancer, and with the EXOC1 rs13117307 polymorphism, which has been linked to cervical cancer in a large study in a Chinese population. We confirmed the association between CC and the rs2844511 polymorphism previously identified in a GWAS study in a Swedish population. The major histocompatibility region of chromosome 6, or perhaps other SNPs in linkage disequilibrium, may be involved in CC onset.

Genome-wide association analyses identify new susceptibility loci for oral cavity and pharyngeal cancer.

We conducted a genome-wide association study of oral cavity and pharyngeal cancer in 6,034 cases and 6,585 controls from Europe, North America and South America. We detected eight significantly associated loci (P < 5 × 10-8), seven of which are new for these cancer sites. Oral and pharyngeal cancers combined were associated with loci at 6p21.32 (rs3828805, HLA-DQB1), 10q26.13 (rs201982221, LHPP) and 11p15.4 (rs1453414, OR52N2-TRIM5). Oral cancer was associated with two new regions, 2p23.3 (rs6547741, GPN1) and 9q34.12 (rs928674, LAMC3), and with known cancer-related loci-9p21.3 (rs8181047, CDKN2B-AS1) and 5p15.33 (rs10462706, CLPTM1L). Oropharyngeal cancer associations were limited to the human leukocyte antigen (HLA) region, and classical HLA allele imputation showed a protective association with the class II haplotype HLA-DRB1*1301-HLA-DQA1*0103-HLA-DQB1*0603 (odds ratio (OR) = 0.59, P = 2.7 × 10-9). Stratified analyses on a subgroup of oropharyngeal cases with information available on human papillomavirus (HPV) status indicated that this association was considerably stronger in HPV-positive (OR = 0.23, P = 1.6 × 10-6) than in HPV-negative (OR = 0.75, P = 0.16) cancers.

Stereoretentive Copper-Catalyzed Directed Thioglycosylation of C(sp2 )-H Bonds of Benzamides.

An efficient thioglycosylation of C(sp2 )-H bonds with thiosugars has been established for the first time. Using only Cu(OAc)2 ⋅H2 O as a catalyst and Ag2 CO3 as an additive in DMSO, the protocol proved to have broad scope, and a variety of complex thioglycosides have been prepared in good yields with exclusive ß-selectivity.

A Novel Risk Locus at 6p21.3 for Epstein-Barr Virus-Positive Hodgkin Lymphoma.

BACKGROUND: A proportion of the genetic variants involved in susceptibility to Hodgkin lymphoma differ by the tumor's Epstein-Barr virus (EBV) status, particularly within the MHC region. METHODS: We have conducted an SNP imputation study of the MHC region, considering tumor EBV status in 1,200 classical Hodgkin lymphoma (cHL) cases and 5,726 control subjects of European origin. Notable findings were genotyped in an independent study population of 468 cHL cases and 551 controls. RESULTS: We identified and subsequently replicated a novel association between a common genetic variant rs6457715 and cHL. Although strongly associated with EBV-positive cHL [OR, 2.33; 95% confidence interval (CI), 1.83-2.97; P = 7 × 10(-12)], there was little evidence for association between rs6457715 and the EBV-negative subgroup of cHL (OR, 1.06; 95% CI, 0.92-1.21), indicating that this association was specific to the EBV-positive subgroup (Phet < P = 10(-8)). Furthermore, the association was limited to EBV-positive cHL subgroups within mixed cell (MCHL) and nodular sclerosis subtypes (NSHL), suggesting that the association is independent of histologic subtype of cHL. CONCLUSIONS: rs6457715, located near the HLA-DPB1 gene, is associated with EBV-positive cHL and suggests this region as a novel susceptibility locus for cHL. IMPACT: This expands the number of genetic variants that are associated with cHL and provides additional evidence for a critical and specific role of EBV in the etiology of this disease.

A rare truncating BRCA2 variant and genetic susceptibility to upper aerodigestive tract cancer.

Deleterious BRCA2 genetic variants markedly increase risk of developing breast cancer. A rare truncating BRCA2 genetic variant, rs11571833 (K3326X), has been associated with a 2.5-fold risk of lung squamous cell carcinoma but only a modest 26% increase in breast cancer risk. We analyzed the association between BRCA2 SNP rs11571833 and upper aerodigestive tract (UADT) cancer risk with multivariable unconditional logistic regression adjusted by sex and combinations of study and country for 5942 UADT squamous cell carcinoma case patients and 8086 control patients from nine different studies. All statistical tests were two-sided. rs11571833 was associated with UADT cancers (odds ratio = 2.53, 95% confidence interval = 1.89 to 3.38, P = 3x10(-10)) and was present in European, Latin American, and Indian populations but extremely rare in Japanese populations. The association appeared more apparent in smokers (current or former) compared with never smokers (P het = .026). A robust association between a truncating BRCA2 variant and UADT cancer risk suggests that treatment strategies orientated towards BRCA2 mutations may warrant further investigation in UADT tumors.

The 12p13.33/RAD52 locus and genetic susceptibility to squamous cell cancers of upper aerodigestive tract.

Genetic variants located within the 12p13.33/RAD52 locus have been associated with lung squamous cell carcinoma (LUSC). Here, within 5,947 UADT cancers and 7,789 controls from 9 different studies, we found rs10849605, a common intronic variant in RAD52, to be also associated with upper aerodigestive tract (UADT) squamous cell carcinoma cases (OR = 1.09, 95% CI: 1.04-1.15, p = 6x10(-4)). We additionally identified rs10849605 as a RAD52 cis-eQTL inUADT(p = 1x10(-3)) and LUSC (p = 9x10(-4)) tumours, with the UADT/LUSC risk allele correlated with increased RAD52 expression levels. The 12p13.33 locus, encompassing rs10849605/RAD52, was identified as a significant somatic focal copy number amplification in UADT(n = 374, q-value = 0.075) and LUSC (n = 464, q-value = 0.007) tumors and correlated with higher RAD52 tumor expression levels (p = 6x10(-48) and p = 3x10(-29) in UADT and LUSC, respectively). In combination, these results implicate increased RAD52 expression in both genetic susceptibility and tumorigenesis of UADT and LUSC tumors.

A systematic investigation of the contribution of genetic variation within the MHC region to HPV seropositivity.

High-risk mucosal types of human papillomavirus (HPV) cause anogenital and oropharyngeal cancers, whereas cutaneous types (e.g. HPV8 and 77) are suspected to be involved in non-melanoma skin cancer. The antibody response to HPVs is a key determinant of protective immunity, but not all infected individuals seroconvert. Genetic variability of the host may have large impact on seroconversion. A previous genome-wide association study (GWAS) has identified a susceptibility locus (rs41270488) for HPV8 seropositivity within the major histocompatibility complex (MHC) region. To further study this locus, we imputed alleles at classical leukocyte antigen (HLA) loci using HLA*IMP:02 with a reference panel from the HapMap Project and the 1958 Birth Cohort, and conducted an integrated analysis among 4811 central European subjects to assess the contribution of classical HLA alleles and gene copy number variation (CNV) at the hypervariable DRB locus within the MHC region to HPV seropositivity at both the individual HPV type level and the phylogenetic species level. Our study provides evidence that the association noted between rs41270488 and HPV8 seropositivity is driven by two independent variants, namely DQB1*0301 [odds ratio (OR) = 1.51, 95% confidence interval (CI) = 1.36-1.68, P = 1.0 × 10(-14)] and DRB1*1101 (OR = 1.89, 95%CI = 1.57-2.28, P = 1.5 × 10(-11)) within the HLA class II region. Additionally, we identified two correlated alleles DRB1*0701 (OR = 1.67, 95%CI = 1.41-1.98, P = 2.6 × 10(-9)) and DQA1*0201 (OR = 1.67, 95%CI = 1.38-1.93, P = 1.7 × 10(-8)), to be associated with HPV77 seropositivity. Comparable results were observed through imputation using SNP2HLA with another reference panel from the Type 1 diabetes Genetics Consortium. This study provides support for an important role of HLA class II alleles in antibody response to HPV infection.

Genetic variants in nicotine addiction and alcohol metabolism genes, oral cancer risk and the propensity to smoke and drink alcohol: a replication study in India.

BACKGROUND: Genetic variants in nicotinic acetylcholine receptor and alcohol metabolism genes have been associated with propensity to smoke tobacco and drink alcohol, respectively, and also implicated in genetic susceptibility to head and neck cancer. In addition to smoking and alcohol, tobacco chewing is an important oral cancer risk factor in India. It is not known if these genetic variants influence propensity or oral cancer susceptibility in the context of this distinct etiology. METHODS: We examined 639 oral and pharyngeal cancer cases and 791 controls from two case-control studies conducted in India. We investigated six variants known to influence nicotine addiction or alcohol metabolism, including rs16969968 (CHRNA5), rs578776 (CHRNA3), rs1229984 (ADH1B), rs698 (ADH1C), rs1573496 (ADH7), and rs4767364 (ALDH2). RESULTS: The CHRN variants were associated with the number of chewing events per day, including in those who chewed tobacco but never smoked (P =  0.003, P =  0.01 for rs16969968 and rs578776 respectively). Presence of the variant allele contributed to approximately 13% difference in chewing frequency compared to non-carriers. While no association was observed between rs16969968 and oral cancer risk (OR =  1.01, 95% CI =  0.83- 1.22), rs578776 was modestly associated with a 16% decreased risk of oral cancer (OR =  0.84, 95% CI =  0.72- 0.98). There was little evidence for association between polymorphisms in genes encoding alcohol metabolism and oral cancer in this population. CONCLUSION: The association between rs16969968 and number of chewing events implies that the effect on smoking propensity conferred by this gene variant extends to the use of smokeless tobacco.

Association between TP53 R249S mutation and polymorphisms in TP53 intron 1 in hepatocellular carcinoma.

Over 100 single nucleotide polymorphisms (SNP) are validated in the TP53 tumor suppressor gene. They define haplotypes, which may differ in their activities. Therefore, mutation in cancer may occur at different rates depending upon haplotypes. However, these associations may be masked by differences in mutations types and causes of mutagenesis. We have analyzed the associations between 19 SNPs spanning the TP53 locus and a single specific aflatoxin-induced TP53 mutation (R249S) in 85 in hepatocellular carcinoma cases and 132 controls from Thailand. An association with R249S mutation (P = 0.007) was observed for a combination of two SNPs (rs17882227 and rs8064946) in a linkage disequilibrium block extending from upstream of exon 1 to the first half of intron 1. This domain contains two coding sequences overlapping with TP53 (WRAP53 and Hp53int1) suggesting that sequences in TP53 intron 1 encode transcripts that may modulate R249S mutation rate in HCC.

Tobacco consumption and genetic susceptibility to nasopharyngeal carcinoma (NPC) in Thailand.

BACKGROUND: The incidence of nasopharyngeal carcinoma (NPC) varies substantially worldwide, with an endemic pocket in Southeast Asia. METHOD: We assessed lifestyle and genetic factors in relation to NPC risk among 681 NPC cases and 1,078 controls from Thailand. Evaluated lifestyle factors included traditionally preserved foods, tobacco smoking, betel quid chewing, and alcohol consumption. Genetic factors included six variants implicated in a previous a genome-wide association study (GWAS) of NPC and three variants residing near the CHRNA3 and TERT genes that were linked to lung cancer risk in Asian populations. Odds ratios (OR) and 95 % confidence intervals (95 % CI) were estimated using unconditional logistic regression. RESULTS: Frequent consumption of fermented vegetables was associated with increased NPC risk (OR of consumption ≥weekly vs. ≤rare 1.78, 95 % CI 1.24-2.55, p (trend) = 0.005), as was tobacco smoking (p (trend) < 0.001), former and current smokers displaying OR of 1.57 (95 % CI 1.10-2.30) and 2.00 (95 % CI 1.48-2.71) compared to never smokers, respectively. Four out of six genetic variants implicated in the recent NPC GWAS were associated with NPC risk (p (trend) ≤ 0.03), as well as two variants (rs402710 and rs2736098) on the TERT locus at 5p15.33 (p = 0.004 and p = 0.04, respectively). CONCLUSIONS: These results strengthen our previous observation that tobacco smoking is an important risk factor of NPC in this population. Four out of six genetic variants identified in a recent NPC GWAS were confirmed, and the association noted with variants on 5p15.33 suggests that this locus is involved in NPC susceptibility, representing a novel finding in NPC epidemiology.