Effect of thinner inhalation on lipid peroxidation and some antioxidant enzymes of people working with paint thinner

Paint thinner is a commonly used industrial solvent with considerable potential for abuse by inhalation. Paint thinner is taken into the body by inhalation or by contact with the skin. Paint thinner is oxidized gradually by cytochrome P450-dependent monooxygenase and consequently free radicals are produced. In the present study we measured plasma malondialdehyde (MDA, a product of lipid peroxidation) levels as an indicator of oxidative damage and activity levels of antioxidant enzymes gluthatione peroxidase (GSH-Px) and superoxide dismutase (SOD) in erythrocytes of a group of people (n = 18) working with paint thinner. The control group was composed of 18 healthy adults. There was a statistically significant (p < 0.001) increase in MDA (2.0+/-0.7 nmol ml(-1)) and GSH-Px (86.5+/-16.6 U g(-1) Hb) activity levels in people working with paint thinner compared with control subjects (MDA: 1.0+/-0.3 nmol ml(-1); GSH-Px: 53.9+/-14.5 U g(-1) Hb). Similarly, there was also an increase (p < 0.05) in the SOD levels (1079+/-214.6 U g(-1) Hb) of people working with paint thinner compared with controls (953.3+/-46.7 U g(-1) Hb). Based on our results, it can be concluded that paint thinner inhalation may increase lipid peroxidation and consequently induce antioxidant enzymes.     

Takayasu's arteritis is associated with HLA-B*52, but not with HLA-B*51, in Turkey

Introduction

HLA-B*51 and HLA-B*52 are two close human leukocyte antigen (HLA) allele groups with minor amino acid differences. However, they are associated with two different vasculitides (HLA-B*51 in Behçet's disease and HLA-B*52 in Takayasu's arteritis (TAK)) and with major clinical and immunological differences. In this study, we aimed to screen a large cohort of TAK patients from Turkey for the presence of HLA-B*51 and HLA-B*52 as susceptibility and severity factors.

Methods

TAK patients (n = 330) followed at a total of 15 centers were included in the study. The mean age of the patients was 37.8 years, and 86% were women. DNA samples from the patients and healthy controls (HC; n = 210) were isolated, and the presence of HLA-B*51 or HLA-B*52 was screened for by using PCR with sequence-specific primers.

Results

We found a significant association of HLA-B*52 with TAK (20.9% vs HC = 6.7%, P = 0.000, OR = 3.7, 95% CI = 2.02 to 6.77). The distribution of HLA-B*51 did not differ between TAK patients and HCs (22.7% vs 24.8%, OR = 0.9, 95% CI = 0.60 to 1.34). The presence of HLA-B*52 decreased in late-onset patients (> 40 years of age; 12.0%, P = 0.024, OR = 0.43, 95% CI = 0.20 to 0.91). Patients with angiographic type I disease with limited aortic involvement also had a lower presence of HLA-B*52 compared to those with all other disease subtypes (13.1% vs 26%, P = 0.005, OR = 0.43, 95% CI = 0.23 to 0.78).

Conclusions

In this study, the previously reported association of TAK with HLA-B*52 in other populations was confirmed in patients from Turkey. The functional relevance of HLA-B*52 in TAK pathogenesis needs to be explored further.     

Optimal pooling for genome re-sequencing with ultra-high-throughput short-read technologies

New generation sequencing technologies offer unique opportunities and challenges for re-sequencing studies. In this article, we focus on re-sequencing experiments using the Solexa technology, based on bacterial artificial chromosome (BAC) clones, and address an experimental design problem. In these specific experiments, approximate coordinates of the BACs on a reference genome are known, and fine-scale differences between the BAC sequences and the reference are of interest. The high-throughput characteristics of the sequencing technology makes it possible to multiplex BAC sequencing experiments by pooling BACs for a cost-effective operation. However, the way BACs are pooled in such re-sequencing experiments has an effect on the downstream analysis of the generated data, mostly due to subsequences common to multiple BACs. The experimental design strategy we develop in this article offers combinatorial solutions based on approximation algorithms for the well-known max n-cut problem and the related max n-section problem on hypergraphs. Our algorithms, when applied to a number of sample cases give more than a 2-fold performance improvement over random partitioning.     

Glucocorticoid effects on angiogenesis are associated with mTOR pathway activity

Glucocorticoids (GC) often are administered during pregnancy, but despite their widespread use in clinical practice, it remains uncertain how GC exposure affects pro-angiogenic factors and their receptors. We investigated the effects of GC on vascular endothelial growth factor (VEGF), placental growth factor (PIGF), vascular endothelial growth factor receptor 1 (VEGFR1) and vascular endothelial growth factor receptor 2 (VEGFR2) protein and mRNA expressions and investigated the possible association of GC with the Akt/mTOR pathway. We incubated human umbilical vein endothelial cells (HUVECs) with a synthetic GC, triamcinolone acetonide (TA). TA administration caused decreased cellular and soluble VEGF and VEGFR1 protein expressions and increased soluble VEGFR2 expression. VEGF, VEGFR1 and VEGFR2 mRNA expressions were altered in a time and dose dependent manner. PIGF protein expression was unaffected by TA treatment, but PIGF mRNA expression decreased in a dose dependent manner after incubation for 48 and 72 h. Phospho-mTOR and phospho-Akt expressions were unaffected. Phospho-p70S6K and phospho-4EBP1 protein expressions and the vascular network forming capacity of HUVECs decreased in a dose dependent manner. We found that GC exert detrimental effects on angiogenesis by altering cellular and soluble angiogenic protein and mRNA levels, and vascular network forming capacities by the Akt/mTOR pathway.     

Evolution of an adenocarcinoma in response to selection by targeted kinase inhibitors

Background

Adenocarcinomas of the tongue are rare and represent the minority (20 to 25%) of salivary gland tumors affecting the tongue. We investigated the utility of massively parallel sequencing to characterize an adenocarcinoma of the tongue, before and after treatment.

Results

In the pre-treatment tumor we identified 7,629 genes within regions of copy number gain. There were 1,078 genes that exhibited increased expression relative to the blood and unrelated tumors and four genes contained somatic protein-coding mutations. Our analysis suggested the tumor cells were driven by the RET oncogene. Genes whose protein products are targeted by the RET inhibitors sunitinib and sorafenib correlated with being amplified and or highly expressed. Consistent with our observations, administration of sunitinib was associated with stable disease lasting 4 months, after which the lung lesions began to grow. Administration of sorafenib and sulindac provided disease stabilization for an additional 3 months after which the cancer progressed and new lesions appeared. A recurring metastasis possessed 7,288 genes within copy number amplicons, 385 genes exhibiting increased expression relative to other tumors and 9 new somatic protein coding mutations. The observed mutations and amplifications were consistent with therapeutic resistance arising through activation of the MAPK and AKT pathways.

Conclusions

We conclude that complete genomic characterization of a rare tumor has the potential to aid in clinical decision making and identifying therapeutic approaches where no established treatment protocols exist. These results also provide direct in vivo genomic evidence for mutational evolution within a tumor under drug selection and potential mechanisms of drug resistance accrual.