The cytokine-dependent MUTZ-3 cell line as an in vitro model for the screening of contact sensitizers

Langerhans cells (LC) are key mediators of contact allergenicity in the skin. However, no in vitro methods exist which are based on the activation process of LC to predict the sensitization potential of chemicals. In this study, we have evaluated the performances of MUTZ-3, a cytokine-dependent human monocytic cell line, in its response to sensitizers. First, we compared undifferentiated MUTZ-3 cells with several standard human cells such as THP-1, KG-1, HL-60, K-562, and U-937 in their response to the strong sensitizer DNCB and the irritant SDS by monitoring the expression levels of HLA-DR, CD54, and CD86 by flow cytometry. Only MUTZ-3 and THP-1 cells show a strong and specific response to sensitizer, while other cell lines showed very variable responses. Then, we tested MUTZ-3 cells against a wider panel of sensitizers and irritants on a broader spectrum of cell surface markers (HLA-DR, CD40, CD54, CD80, CD86, B7-H1, B7-H2, B7-DC). Of these markers, CD86 proved to be the most reliable since it detected all sensitizers, including benzocaine, a classical false negative in local lymph node assay (LLNA) but not irritants. We confirmed the MUTZ-3 response to DNCB by real-time PCR analysis. Taken together, our data suggest that undifferentiated MUTZ-3 cells may represent a valuable in vitro model for the screening of potential sensitizers.     

The genetics of multiple sclerosis: an up-to-date review

Multiple sclerosis (MS) is a prevalent inflammatory disease of the central nervous system that often leads to disability in young adults. Treatment options are limited and often only partly effective. The disease is likely caused by a complex interaction between multiple genes and environmental factors, leading to inflammatory-mediated central nervous system deterioration. A series of genomic studies have confirmed a central role for the immune system in the development of MS, including genetic association studies that have now dramatically expanded the roster of MS susceptibility genes beyond the longstanding human leukocyte antigen (HLA) association in MS first identified nearly 40 years ago. Advances in technology together with novel models for collaboration across research groups have enabled the discovery of more than 50 non-HLA genetic risk factors associated with MS. However, with a large proportion of the disease heritability still unaccounted for, current studies are now geared towards identification of causal alleles, associated pathways, epigenetic mechanisms, and gene-environment interactions. This article reviews recent efforts in addressing the genetics of MS and the challenges posed by an ever increasing amount of analyzable data, which is spearheading development of novel statistical methods necessary to cope with such complexity.     

Measurement of left mainstem bronchus using multiplane CT reconstructions and relationship between patient characteristics or tracheal diameters and left bronchial diameters

STUDY OBJECTIVES: To measure the tracheal diameters (TDs) [transverse (Tr) TD, and anteroposterior (AP) TD] and left main bronchus diameters (LBDs) [Tr and AP] using multiplane CT scan reconstructions with a tridimensional correction of the declination. To evaluate the relationship between clinical variables and CT scan diameters of the tracheobronchial tree. To aid in the selection of a double-lumen tube of appropriate size. DESIGN: Prospective observational study. SETTING: Private and university hospitals. PATIENTS: A total of 206 patients (105 women and 101 men) undergoing a CT scan for medical investigations or preoperative evaluation. INTERVENTION: No intervention. MEASUREMENTS AND RESULTS: TDs and LBDs are greater in men (p < 0.001). The Tr-TD is smaller than AP-TD for men (p < 0.001). The Tr-LBD is greater than AP-LBD in both sexes (p < 0.001). In men, height, Tr-TD, and AP-TD are predictive factors for Tr-LBD, while Tr-TD and AP-TD are the only predictive factors for AP-LBD. In women, Tr-TD and AP-TD are the only predictive factors for Tr-LBD and AP-LBD. The smallest LBD (ie, the lesser of the Tr-LBD or the AP-LBD [called the smallest LBD]) is the Tr-LBD in 25.2% of the cases. The mean (+/- SD) ratio of the smallest LBD/Tr-TD is 0.70 +/- 0.14 for men and 0.65 +/- 0.12 for women. The estimated (Est) LBD is calculated using this ratio. The mean value for Est-LBD minus the smallest LBD is 1.6 +/- 1.3 mm, and this difference is < 1 mm in 40% of male patients and 39% of female patients. CONCLUSIONS: In conclusion, the left main bronchus is most often elliptic, and the smallest LBD cannot be accurately evaluated using patient characteristics or a ratio from TD.     

Epigenetic mechanisms of lung carcinogenesis involve differentially methylated CpG sites beyond those associated with smoking

European Journal of Epidemiology - Smoking-related epigenetic changes have been linked to lung cancer, but the contribution of epigenetic alterations unrelated to smoking remains unclear. We sought...     

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Genome-wide associations studies have repeatedly identified the major histocompatibility complex genomic region (6p21.3) as key in immune pathologies. Researchers have also aimed to extend the biological interpretation of associations by focusing directly on human leukocyte antigen (HLA) polymorphisms and their combination as haplotypes. To circumvent the effort and high costs of HLA typing, statistical solutions have been developed to infer HLA alleles from single-nucleotide polymorphism (SNP) genotyping data. Though HLA imputation methods have been developed, no unified effort has yet been undertaken to share large and diverse imputation models, or to improve methods. By training the HIBAG software on SNP + HLA data generated by the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) to create reference panels, we highlighted the importance of (a) the number of individuals in reference panels, with a twofold increase in accuracy (from 10 to 100 individuals) and (b) the number of SNPs, with a 1.5-fold increase in accuracy (from 500 to 24,504 SNPs). Results showed improved accuracy with CAAPA compared to the African American models available in HIBAG, highlighting the need for precise population-matching. The SNP-HLA Reference Consortium is an international endeavor to gather data, enhance HLA imputation and broaden access to highly accurate imputation models for the immunogenomics community.     

Circulating concentrations of B group vitamins and urothelial cell carcinoma

B-group vitamins, as components of the one carbon metabolism pathway, are involved in DNA synthesis, repair and methylation. Our aim was to investigate associations between circulating plasma levels of B vitamins and urothelial cell carcinoma (UCC). We conducted a nested case–control study of UCC within the Melbourne Collaborative Cohort Study. B vitamins were measured in pre-diagnostic plasma samples. Conditional logistic regression was used to estimate odds ratios (OR) for UCC risk associated with circulating B vitamins in 363 matched cases and controls. In a case-only analysis (N = 390), hazard ratios (HR) for overall survival associated with plasma B vitamins were estimated using Cox regression. There were no strong associations between UCC risk and pre-diagnostic levels of plasma B vitamins. No heterogeneity in UCC risk was observed by subtype (invasive or superficial), sex, smoking status or alcohol intake. There was no heterogeneity by country of birth for most B vitamins, except for folate (p-homogeneity = 0.03). In UCC cases, there were no strong associations between plasma B vitamins and overall survival. We found no associations between pre-diagnostic plasma concentrations of B-group vitamins and UCC risk or survival.