Synthesis and Evaluation of Conjugates of Novel TLR7 Inert Ligands as Self-Adjuvanting Immunopotentiators

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Hematological Evidence of Occupational Exposure to Chemicals and Other Factors among Auto-Repair Workers in Rawalpindi,Pakistan

Objectives

Occupational exposure to aromatic solvents causes many serious health hazards to workers, especially if an ambient environment increases the exposure during routine working hours. This study was conducted on two related groups, i.e., automobile mechanics (MCs) and automobile spray painters (PNs), with an effort to analyze effects of chemical exposure on hematological parameters, keeping a focus on environmental parameters and workers’ personal behavioral characteristics that could be held responsible for increasing exposure risk.

Methods

A preliminary survey of various chemicals used in these places was done, and 78 blood samples were collected from three groups (control, n = 24; mechanics, n = 25; painters, n = 29). Demographic features of workers were recorded through a short questionnaire.

Results

Results showed that mean red blood cell (RBC) count was lower both in MCs [t(51) = 2.38, p < 0.021, r = 0.32] and in PNs [t(47) = 2.12, p < 0.03, r = 0.29], whereas mean hemoglobin (Hb) was significantly lower in MCs [t(51) = 2.5, p = 0.017, r = 0.33]. Combined data for exposed groups for smokers (SMs) versus nonsmokers (NSs) showed that SMs had a significantly lower number (RBC count: t(52) = 2.28, p < 0.027, r = 0.25; Hb count: t(52) = 2.71, p < 0.009, r = 0.30] of these parameters than NSs, even compared to the control group. Moreover, logistic regression results showed that smoking is a significant predictor of reduction in RBC and Hb counts, besides occupational exposure and work experience to a little extent among exposed workers. Mean white blood cell count [t(47) = 2.63, p < 0.01, r=0.35], mean corpuscle volume [t(47)= –2.82, p = 0.007, r = 0.29], and packed cell volume [t(47)= –2.28, p = 0.027, r = 31] were higher exclusively in painters, which could be related to exposure to benzene in addition to isocyanate.

Conclusion

It appeared that workplace exposure may be complex due to interaction of multiple factors and PNs face much more exposure to isocyanate and aromatic solvents than MCs, which had significant effects on their hematopoiesis. Smoking enhances exposure risk manifolds, and among MCs it showed combined effects along with occupational exposure. There is a need to create awareness among these workers to adopt self-safety measures during routine tasks and also of a separate study to elucidate actual occupational exposure among them, eliminating confounding factors.     

The novel anthraquinone derivative IMP1338 induces death of human cancer cells by p53-independent S and G2/M cell cycle arrest

To identify novel small molecules that induce selective cancer cell death, we screened a chemical library containing 1040 compounds in HT29 colon cancer and CCD18-Co normal colon cells, using a phenotypic cell-based viability assay system with the Cell Counting Kit-8 (CCK-8). We discovered a novel anthraquinone derivative, N-(4-[{(9,10-dioxo-9,10-dihydro-1-anthracenyl)sulfonyl}amino]phenyl)-N-methylacetamide (IMP1338), which was cytotoxic against the human colon cancer cells tested. The MTT cell viability assay showed that treatment with IMP1338 selectively inhibited HCT116, HCT116 p53^−/−, HT29, and A549 cancer cell proliferation compared to that of Beas2B normal epithelial cells. To elucidate the cellular mechanism underlying the cytotoxicity of IMP1338, we examined the effect of IMP1338 on the cell cycle distribution and death of cancer cells. IMP1338 treatment significantly arrested the cell cycle at S and G2/M phases by DNA damage and led to apoptotic cell death, which was determined using FACS analysis with Annexin V/PI double staining. Furthermore, IMP1338 increased caspase-3 cleavage in wild-type p53, p53 knockout HCT116, and HT29 cells as determined using immunoblotting. In addition, IMP1338 markedly induced the phosphorylation of histone H2AX and Chk1 in both cell lines while the combination of 5-fluorouracil (5-FU) and radiation inhibited the viability of HCT116, HCT116 p53^−/−, and HT29 cells compared to 5-FU or radiation alone. Our findings indicated that IMP1338 induced p53-independent cell death through S and G2/M phase arrest as well as DNA damage. These results provide a basis for future investigations assessing the promising anticancer properties of IMP1338.     

Echocardiographic evaluation of cardiac function in paediatric oncology patients treated with or without anthracycline

Using Doppler echocardiography, we studied the left ventricular systolic and diastolic function in 124 healthy control children (group C), 110 oncology patients who had received anthracycline (group A), and 76 oncology patients who had received chemotherapy not including anthracycline (group N), at rest and after supine bicycle exercise. The mean dosage of anthracycline that group A patients received was 219 ± 95 mg/m². Impaired systolic function was detected in 29% of the patients in group A and 4% in group N. Figures for impaired diastolic function for group A and N were 27% and 28% respectively. Abnormal diastolic function was detected more frequently in the first two years after chemotherapy in both groups. Four parameters measured at rest appeared to be specifically abnormal in group A but not in group N. These were ejection fraction, fractional shortening, rate-corrected velocity of circumferential fiber shortening (VCFC) and left ventricle peak systolic wall stress (LVWS). After exercise more parameters were abnormal in group N patients when compared to normal children, but abnormalities of VCFC and LVWS remained specific for group A. In conclusion, abnormalities of diastolic function were common among paediatric oncology patients no matter whether they had received anthracycline treatment or not. Abnormalities of systolic function were more specific to anthracycline toxicity. VCFC and LVWS were the most sensitive measurements for differentiating group N patients from group A patients.     

Dual targeting of microtubule and topoisomerase II by α-carboline derivative YCH337 for tumor proliferation and growth inhibition

Both microtubule and topoisomerase II (Top2) are important anticancer targets and their respective inhibitors are widely used in combination for cancer therapy. However, some combinations could be mutually antagonistic and drug resistance further limits their therapeutic efficacy. Here we report YCH337, a novel α-carboline derivative that targets both microtubule and Top2, eliciting tumor proliferation and growth inhibition and overcoming drug resistance. YCH337 inhibited microtubule polymerization by binding to the colchicine site and subsequently led to mitotic arrest. It also suppressed Top2 and caused DNA double-strand breaks. It disrupted microtubule more potently than Top2. YCH337 induced reversible mitotic arrest at low concentrations but persistent DNA damage. YCH337 caused intrinsic and extrinsic apoptosis and decreased MCL-1, cIAP1 and XIAP proteins. In this aspect, YCH337 behaved differently from the combination of vincristine and etoposide. YCH337 inhibited proliferation of tumor cells with an averaged IC₅₀ of 0.3 μM. It significantly suppressed the growth of HT-29 xenografts in nude mice too. Importantly, YCH337 nearly equally killed different-mechanism-mediated resistant tumor cells and corresponding parent cells. Together with the novelty of its chemical structure, YCH337 could serve as a promising lead for drug development and a prototype for a dual microtubule/Top2 targeting strategy for cancer therapy.     

TRANSVAC research infrastructure – Results and lessons learned from the European network of vaccine research and development

TRANSVAC was a collaborative infrastructure project aimed at enhancing European translational vaccine research and training. The objective of this four year project (2009–2013), funded under the European Commission's (EC) seventh framework programme (FP7), was to support European collaboration in the vaccine field, principally through the provision of transnational access (TNA) to critical vaccine research and development (R&D) infrastructures, as well as by improving and harmonising the services provided by these infrastructures through joint research activities (JRA). The project successfully provided all available services to advance 29 projects and, through engaging all vaccine stakeholders, successfully laid down the blueprint for the implementation of a permanent research infrastructure for early vaccine R&D in Europe.     

Combretastatin A-4氨基糖类衍生物CPU-XT-008抑制血管内皮细胞增殖的分子机制

以人脐静脉内皮细胞(HUVEC)为模拟肿瘤血管内皮细胞的实验模型,研究combretastatin A-4(CA-4)的氨基糖类衍生物CPU-XT-008对HUVEC的增殖、周期分布、微管蛋白聚合以及关键周期调控蛋白表达的影响。采用MTT法检测CPU-XT-008对HUVEC增殖的影响;采用流式细胞仪检测CPU-XT-008对HUVEC周期分布的影响;采用免疫荧光染色检测CPU-XT-008对HUVEC凋亡及β-tubulin微管蛋白的聚合变化;采用Western blot检测CPU-XT-008对周期蛋白Cyclin B1,Cdc2和微管蛋白β-tubulin的影响。结果表明,CPU-XT-008能以微管蛋白为靶点抑制β-tubulin微管蛋白聚合,通过上调HUVEC的细胞周期蛋白Cyclin B1水平表达,下调细胞周期依赖性激酶Cdc2蛋白水平的表达从而引发细胞G₂/M期阻滞,抑制细胞增殖并诱导细胞凋亡。     

居室装修后室内空气中苯的来源分析

[目的]了解居室装修后室内空气中苯的污染来源和控制措施. [方法]选择新装修居室40户,分为5个组(每组8户),按聚氨脂漆用量的多少及使用人造板材填充家具分为高、低用量组及家具填充组和2个对照组,按照GB 50325-2010《民用建筑工程室内环境污染控制规范》方法测定苯的浓度. [结果]聚氨脂漆高用量组苯浓度为0.076～1.04 mg/m3;低用量组苯浓度为0.009～0.239 mg/m3;家具填充组苯浓度为0.051～0.143 mg/m3,与对照组比较,差异具有统计学意义(P＜0.05). [结论]居室装修中苯污染与聚氨脂漆的用量及质量、家具的填充量有关,控制漆类产品的用量和质量、家具填充量和家具环保程度是预防装修中苯污染的主要措施.     

Response to incremental doses of dobutamine early after reperfusion is predictive of the degree of myocardial salvage in dogs with experimental acute myocardial infarction

OBJECTIVES

We sought to determine whether the inotropic response to dobutamine might be useful for estimating the extent of viable myocardium soon after reperfusion.

BACKGROUND

Early identification of viable myocardium in the presence of severe left ventricular dysfunction after reperfusion is important for clinical decision making.

METHODS

Nine open-chest dogs had left anterior descending coronary artery occlusion for 40 to 180 min, followed by gradual reperfusion. The systolic thickening response to incremental dobutamine doses was measured with ultrasonic crystals and regional flow by microspheres.

RESULTS

Dogs were divided into two groups based on triphenyl tetralozium chloride infarct size (group 1: 9.3 ± 3.0% risk area; group 2: 51.1 ± 4.8%). In group 2 dogs with larger infarcts, regional flow during peak dobutamine was lower than it was in group 1 in endocardial (1.15 ± 0.22 vs. 2.64 ± 0.33 mL·min⁻¹·g⁻¹) and midwall (1.47 ± 0.32 vs. 2.92 ± 0.36 mL·min⁻¹·g⁻¹) layers, and endocardial flow in group 2 failed to increase from baseline (0.96 ± 0.07 vs. 1.15 ± 0.22 mL·min⁻¹·g⁻¹). Group 1 dogs demonstrated a dose dependent increase in systolic thickening with dobutamine versus a blunted response in group 2. The inotropic response to only 10 μg·kg⁻¹·min⁻¹ of dobutamine was predictive of the degree of myocardial salvage.

CONCLUSIONS

In the early postischemic stunning phase of reperfusion, the inotropic response to dobutamine is predictive of the degree of myocardial salvage and ultimate infarct size. The ability to distinguish between stunned versus necrotic myocardium early after reperfusion was most likely due to the presence of subendocardial flow reserve during dobutamine in dogs with predominantly salvaged myocardium.