An epidemiologic study of early biologic effects of benzene in Chinese workers.

Benzene is a recognized hematotoxin and leukemogen, but its mechanisms of action in humans are still uncertain. To provide insight into these processes, we carried out a cross-sectional study of 44 healthy workers currently exposed to benzene (median 8-hr time-weighted average; 31 ppm), and unexposed controls in Shanghai, China. Here we provide an overview of the study results on peripheral blood cells levels and somatic cell mutation frequency measured by the glycophorin A (GPA) gene loss assay and report on peripheral cytokine levels. All peripheral blood cells levels (i.e., total white blood cells, absolute lymphocyte count, platelets, red blood cells, and hemoglobin) were decreased among exposed workers compared to controls, with the exception of the red blood cell mean corpuscular volume, which was higher among exposed subjects. In contrast, peripheral cytokine levels (interleukin-3, interleukin-6, erythropoietin, granulocyte colony-stimulating factor, tissue necrosis factor-alpha) in a subset of the most highly exposed workers (n = 11) were similar to values in controls (n = 11), suggesting that benzene does not affect these growth factor levels in peripheral blood. The GPA assay measures stem cell or precursor erythroid cell mutations expressed in peripheral red blood cells of MN heterozygous subjects, identifying NN variants, which result from loss of the GPA M allele and duplication of the N allele, and N phi variants, which arise from gene inactivation. The NN (but not N phi) GPA variant cell frequency was elevated in the exposed workers compared with controls (mean +/- SD, 13.9 +/- 8.4 mutants per million cells versus 7.4 +/- 5.2 per million cells, (respectively; p = 0.0002), suggesting that benzene produces gene-duplicating but not gene-inactivating mutations at the GPA locus in bone marrow cells of exposed humans. These findings, combined with ongoing analyses of benzene macromolecular adducts and chromosomal aberrations, will provide an opportunity to comprehensively evaluate a wide range of early biologic effects associated with benzene exposure in humans

The Functional DRD3 Ser9Gly Polymorphism (rs6280) Is Pleiotropic, Affecting Reward as Well as Movement

Abnormalities of motivation and behavior in the context of reward are a fundamental component of addiction and mood disorders. Here we test the effect of a functional missense mutation in the dopamine 3 receptor (DRD3) gene (ser9gly, rs6280) on reward-associated dopamine (DA) release in the striatum. Twenty-six healthy controls (HCs) and 10 unmedicated subjects with major depressive disorder (MDD) completed two positron emission tomography (PET) scans with [11C]raclopride using the bolus plus constant infusion method. On one occasion subjects completed a sensorimotor task (control condition) and on another occasion subjects completed a gambling task (reward condition). A linear regression analysis controlling for age, sex, diagnosis, and self-reported anhedonia indicated that during receipt of unpredictable monetary reward the glycine allele was associated with a greater reduction in D2/3 receptor binding (i.e., increased reward-related DA release) in the middle (anterior) caudate (p<0.01) and the ventral striatum (p<0.05). The possible functional effect of the ser9gly polymorphism on DA release is consistent with previous work demonstrating that the glycine allele yields D3 autoreceptors that have a higher affinity for DA and display more robust intracellular signaling. Preclinical evidence indicates that chronic stress and aversive stimulation induce activation of the DA system, raising the possibility that the glycine allele, by virtue of its facilitatory effect on striatal DA release, increases susceptibility to hyperdopaminergic responses that have previously been associated with stress, addiction, and psychosis

Body optimization approach of sedan structure for improving small overlap impact rating

Small overlap accidents of sedans often result in severe injuries. In this article, a crashworthiness design method, including engine-room energy management, suspension safety design and passenger compartment enhancement, was evaluated to improve the small overlap rating based on finite element simulation. Longitudinal reinforcement and shotgun redesign techniques were proposed to increase energy-absorption and decrease the impact force that transferred to the passenger compartment. The response surface methodology was utilized to propose the optimal passenger compartment parameters in order to reduce intrusion. The evaluation of the sedan structure performance was conducted by comparing simulated intrusion results with the rating guidelines of the Insurance Institute for Highway Safety (IIHS). The optimal results indicated that the intrusion was decreased by an average of 58.64%, with a minimum percentage of 44.98% around footrest area, and the measurement points for intrusion was upgraded to good. The proposed crashworthiness design approach is effective in vehicle structure optimization for better small overlap impact performanc

Mechanism of endothelial progenitor cell recruitment into neo-vessels in adjacent non-tumor tissues in hepatocellular carcinoma

Abstract Background We investigated the distribution and clinical significance of mobilized endothelial progenitor cells (EPCs) in hepatocellular carcinoma (HCC). We found that many more EPCs were recruited to nonmalignant liver tissue (especially into adjacent non-tumor tissues (AT)) than to tumor vessels. These results suggest that the mechanism underlying the recruitment of EPCs into microvessels in AT merits further investigation Methods Angiogenic factors were detected in three tissue microarrays comprising normal liver, paired tumor tissue (TT) and AT from 105 patients (who had undergone hepatectomy for HCC) using immunohistochemistry. Also, the number of EPCs (positive for Sca-1, Flk-1 and c-Kit) in the blood and liver of cirrhotic mice were determined by flow cytometry and immunohistochemistry. The distribution of these labeled EPCs in tumor and non-tumor tissues was then studied. Results The results from the tissue microarrays showed that the expression levels of VEGF-A, bFGF, TGF-β, MCP-1, TSP-1, MMP-9, TIMP-2, and endostatin were significantly higher in AT than in either normal liver or TT (p Conclusions Both liver cirrhosis and HCC led to increased expression of pro-angiogenic factors, which resulted in the recruitment of EPCs into AT. Also, EPCs were mobilized, recruited and homed to cirrhotic liver. The unique pathology of HCC coupled with liver cirrhosis may, therefore, be associated with the distribution and function of EPCs.</p

Biocleavable Polycationic Micelles as Highly Efficient Gene Delivery Vectors

An amphiphilic disulfide-containing polyamidoamine was synthesized by Michael-type polyaddition reaction of piperazine to equimolar N, N′-bis(acryloyl)cystamine with 90% yield. The polycationic micelles (198 nm, 32.5 mV), prepared from the amphiphilic polyamidoamine by dialysis method, can condense foreign plasmid DNA to form nanosized polycationic micelles/DNA polyelectrolyte complexes with positive charges, which transfected 293T cells with high efficiency. Under optimized conditions, the transfection efficiencies of polycationic micelles/DNA complexes are comparable to, or even higher than that of commercially available branched PEI (Mw 25 kDa)

Pollen and Phytoliths from Fired Ancient Potsherds as Potential Indicators for Deciphering Past Vegetation and Climate in Turpan, Xinjiang, NW China

It is demonstrated that palynomorphs can occur in fired ancient potsherds when the firing temperature was under 350°C. Pollen and phytoliths recovered from incompletely fired and fully fired potsherds (ca. 2700 yrs BP) from the Yanghai Tombs, Turpan, Xinjiang, NW China can be used as potential indicators for reconstructing past vegetation and corresponding climate in the area. The results show a higher rate of recovery of pollen and phytoliths from incompletely fired potsherds than from fully fired ones. Charred phytoliths recovered from both fully fired and incompletely fired potsherds prove that degree and condition of firing result in a permanent change in phytolith color. The palynological data, together with previous data of macrobotanical remains from the Yanghai Tombs, suggest that temperate vegetation and arid climatic conditions dominated in the area ca. 2700 yrs BP

LRP16 Integrates into NF-κB Transcriptional Complex and Is Required for Its Functional Activation

BACKGROUND: Nuclear factor κB (NF-κB)-mediated pathways have been widely implicated in cell survival, development and tumor progression. Although the molecular events of determining NF-κB translocation from cytoplasm to nucleus have been extensively documented, the regulatory mechanisms of NF-κB activity inside the nucleus are still poorly understood. Being a special member of macro domain proteins, LRP16 was previously identified as a coactivator of both estrogen receptor and androgen receptor, and as an interactor of NF-κB coactivator UXT. Here, we investigated the regulatory role of LRP16 on NF-κB activation. METHODOLOGY: GST pull-down and coimmunoprecipitation (CoIP) assays assessed protein-protein interactions. The functional activity of NF-κB was assessed by luciferase assays, changes in expression of its target genes, and its DNA binding ability. Annexin V staining and flow cytometry analysis were used to evaluate cell apoptosis. Immunohistochemical staining of LRP16 and enzyme-linked immunosorbent assay-based evaluation of active NF-κB were performed on primary human gastric carcinoma samples. RESULTS: We demonstrate that LRP16 integrates into NF-κB transcriptional complex through associating with its p65 component. RNA interference knockdown of the endogenous LRP16 in cells leads to impaired NF-κB activity and significantly attenuated NF-κB-dependent gene expression. Mechanistic analysis revealed that knockdown of LRP16 did not affect tumor necrosis factor α (TNF-α)-induced nuclear translocation of NF-κB, but blunted the formation or stabilization of functional NF-κB/p300/CREB-binding protein transcription complex in the nucleus. In addition, knockdown of LRP16 also sensitizes cells to apoptosis induced by TNF-α. Finally, a positive link between LRP16 expression intensity in nuclei of tumor cells and NF-κB activity was preliminarily established in human gastric carcinoma specimens. CONCLUSIONS: Our findings not only indicate that LRP16 is a crucial regulator for NF-κB activation inside the nucleus, but also suggest that LRP16 may be an important contributor to the aberrant activation of NF-κB in tumors

Asthma susceptible genes in Chinese population: A meta-analysis

<p>Abstract</p> <p>Background</p> <p>Published data regarding the associations between genetic variants and asthma risk in Chinese population were inconclusive. The aim of this study was to investigate asthma susceptible genes in Chinese population.</p> <p>Methods</p> <p>The authors conducted 18 meta-analyzes for 18 polymorphisms in 13 genes from eighty-two publications.</p> <p>Results</p> <p>Seven polymorphisms were found being associated with risk of asthma, namely: <it>A Disintegrin and Metalloprotease 33 </it>(<it>ADAM33</it>) T1-C/T (odds ratio [OR] = 6.07, 95% confidence interval [CI]: 2.69-13.73), <it>Angiotensin-Converting Enzyme </it>(<it>ACE</it>) D/I (OR = 3.85, 95%CI: 2.49-5.94), <it>High-affinity IgE receptor β chain </it>(<it>FcεRIβ</it>) -6843G/A (OR = 1.49, 95%CI: 1.01-2.22), <it>Interleukin 13</it>(<it>IL-13</it>) -1923C/T (OR = 2.99, 95%CI: 2.12-4.24), <it>IL-13 </it>-2044A/G (OR = 1.49, 95%CI: 1.07-2.08), <it>Regulated upon Activation, Normal T cell Expressed and Secreted </it>(<it>RANTES</it>) -28C/G (OR = 1.64, 95%CI: 1.09-2.46), <it>Tumor Necrosis Factor-α </it>(<it>TNF-α</it>) -308G/A(OR = 1.42, 95%CI: 1.09, 1.85). After subgroup analysis by age, the <it>ACE </it>D/I, <it>β2-Adrenergic Receptor </it>(<it>β2-AR</it>) -79G/C, <it>TNF-α </it>-308G/A, <it>Interleukin 4 receptor</it>(<it>IL-4R</it>) -1902G/A and <it>IL-13 </it>-1923C/T polymorphisms were found significantly associated with asthma risk in Chinese children. In addition, the <it>ACE </it>D/I, <it>FcεRIβ </it>-6843G/A, <it>TNF-α </it>-308G/A, <it>IL-13 </it>-1923C/T and <it>IL-13 </it>-2044A/G polymorphisms were associated with asthma risk in Chinese adults.</p> <p>Conclusion</p> <p><it>ADAM33, FcεRIβ, RANTES, TNF-α, ACE, β2-AR, IL-4R </it>and <it>IL-13 </it>genes could be proposed as asthma susceptible genes in Chinese population. Given the limited number of studies, more data are required to validate these associations.</p