Increased phosphorylation of eIF2α in chronic myeloid leukemia cells stimulates secretion of matrix modifying enzymes.

Recent studies underscore the role of the microenvironment in therapy resistance of chronic myeloid leukemia (CML) cells and leukemia progression. We previously showed that sustained mild activation of endoplasmic reticulum (ER) stress in CML cells supports their survival and resistance to chemotherapy. We now demonstrate, using dominant negative non-phosphorylable mutant of eukaryotic initiation factor 2 α subunit (eIF2α), that phosphorylation of eIF2α (eIF2α-P), which is a hallmark of ER stress in CML cells, substantially enhances their invasive potential and modifies their ability to secrete extracellular components, including the matrix-modifying enzymes cathepsins and matrix metalloproteinases. These changes are dependent on the induction of activating transcription factor-4 (ATF4) and facilitate extracellular matrix degradation by CML cells. Conditioned media from CML cells with constitutive activation of the eIF2α-P/ATF4 pathway induces invasiveness of bone marrow stromal fibroblasts, suggesting that eIF2α-P may be important for extracellular matrix remodeling and thus leukemia cells-stroma interactions. Our data show that activation of stress response in CML cells may contribute to the disruption of bone marrow niche components by cancer cells and in this way support CML progression.

[Hazardous substances and detrimental conditions at the workplace]. / Czynniki szkodliwe wystepujace w srodowisku pracy.

UNLABELLED: An artificially created working environment, conditioned by technological processes, puts people in circumstances unparalleled in the place of living. Working conditions exert an influence on the employee's health, thus affecting health status of the whole society. Risks occurring on the working stands may result from the presence of physical, chemical and biological agents. Their vicinity devastates the harmony of man's co-operation with the environment, activates defence mechanisms and enforces an introduction of protection systems. The target of this research was to estimate a sugar factory employees' exposure to the detrimental agents occurring in their place of work. The research was conducted in one of Lublin sugar factories and it involved an estimation of working conditions via a measurement of such physical agent parameters as microclimate, dust density, noise volume, light intensity and exposure to carbon oxide. The results of sanitary-epidemic services' inquiry into the issue were also included here. The estimation of the joint influence of the microclimatic elements in the working environment was made with the measures of temperature, humidity and air circulation were taken into account. The WBGT factor ranged from 18.80 degrees to 31.73 degrees and frequently stayed out of the limits of the thermal comfort. The measuring of the dust density showed an exceeding of the binding quotas on single working stands only. The highest weight average was 17 mg/m3. A comparison of these results with the findings of the previous years surveys shows a constant decrease in dust density. The most considerable bias from the binding quotas was noted while measuring noise level. The noise volume on some stands reached from 98 dB to 109 dB, which, taking into account the eight-hour working day, gave an average exposure level within the boundaries of 82 dB to 98 dB. CONCLUSIONS: 1. The presence of detrimental agents in working environment should lead to permanent monitoring of risks. 2. It is purposeful to undertake various preventive actions in order to minimalise effects to the employees.

Diffprot - software for non-parametric statistical analysis of differential proteomics data.

Mass spectrometry-based global proteomics experiments generate large sets of data that can be converted into useful information only with an appropriate statistical approach. We present Diffprot - a software tool for statistical analysis of MS-derived quantitative data. With implemented resampling-based statistical test and local variance estimate, Diffprot allows to draw significant results from small scale experiments and effectively eliminates false positive results. To demonstrate the advantages of this software, we performed two spike-in tests with complex biological matrices, one label-free and one based on iTRAQ quantification; in addition, we performed an iTRAQ experiment on bacterial samples. In the spike-in tests, protein ratios were estimated and were in good agreement with theoretical values; statistical significance was assigned to spiked proteins and single or no false positive results were obtained with Diffprot. We compared the performance of Diffprot with other statistical tests - widely used t-test and non-parametric Wilcoxon test. In contrast to Diffprot, both generated many false positive hits in the spike-in experiment. This proved the superiority of the resampling-based method in terms of specificity, making Diffprot a rational choice for small scale high-throughput experiments, when the need to control the false positive rate is particularly pressing.