BCL-XL ACTIVITY INFLUENCES OUTCOME OF THE MITOTIC ARREST

Microtubule-targeting (MT) drugs taxanes and vinca alkaloids are widely used as chemotherapeutic agents against different tumors for more than 30 years because of their ability to block mitotic progression by disrupting the mitotic spindle and activating the spindle assembly checkpoint (SAC) for a prolonged period of time. However, responses to mitotic arrest are different—some cells die during mitotic arrest, whereas others undergo mitotic slippage and survive becoming able for proliferation. Using normal fibroblasts and several cancer cell types we determined two critical doses, T1 and T2, of mitotic inhibitors (nocodazole, Taxol, and vinorelbine). T1 is the maximal dose cells can tolerate undergoing normal division, and T2 is the minimal mitostatic dose, wherein > 90% of mitotic cells are arrested in mitosis. In all studied cell lines after treatment with mitotic inhibitors in a dose above T2 cells had entered mitosis either die or undergo mitotic slippage. We show that for all three drugs used cell death during mitotic arrest and after slippage proceeded via mitochondriadependent apoptosis. We determined two types of cancer cells: sensitive to mitotic arrest, that is, undergoing death in mitosis (DiM) frequently, and resistant to mitotic arrest, that is, undergoing mitotic slippage followed by prolonged survival. We then determined that inhibition of Bcl-xL, but not other antiapoptotic proteins of the Bcl-2 group that regulate MOMP, make resistant cells susceptible to DiM induced by mitotic inhibitors. Combined treatment with MT drugs and highly specific Bcl-xL inhibitors A-1155643 or A-1331852 allows achieving 100% DiM in a time significantly shorter than maximal duration of mitotic arrest in all types of cultured cells tested. We further examined efficacy of sequential treatment of cultured cells using mitotic inhibitors followed by inhibitors of Bcl-xL anti-apoptotic protein and for the first time show that sensitivity to Bcl-xL inhibitors rapidly declines after mitotic slippage. Thus sequential use of mitotic inhibitors and inhibitors of Bcl-xL anti-apoptotic protein will be efficient only if the Bcl-xL inhibitor will be added before mitotic slippage occurs or soon afterward. The combined treatment proposed might be an efficient approach to anti-cancer therapy

Lambda hyperons produced in central nucleus-nucleus interactions at 4.5 GeV/c momentum per incident nucleon

Transverse momenta and rapidities of Lambda 's produced in central nucleus-nucleus collisions at 4.5 GeV/c·u (C-C,...,O-Pb) were studied and compared with those from inelastic He-Li interactions at the same incident momentum. Polarization of the Lambda hyperons was found to be consistent with zero ( alpha P=-0.06=0.11 for Lambda 's from central collisions). An upper limit of the Lambda -bar / Lambda production ratio was estimated to be less than 4.5 x 10-3. The experiment was performed in a triggered streamer chamber

Peasant settlers and the ‘civilizing mission’ in Russian Turkestan, 1865-1917

This article provides an introduction to one of the lesser-known examples of European settler colonialism, the settlement of European (mainly Russian and Ukrainian) peasants in Southern Central Asia (Turkestan) in the late nineteenth and early twentieth centuries. It establishes the legal background and demographic impact of peasant settlement, and the role played by the state in organising and encouraging it. It explores official attitudes towards the settlers (which were often very negative), and their relations with the local Kazakh and Kyrgyz population. The article adopts a comparative framework, looking at Turkestan alongside Algeria and Southern Africa, and seeking to establish whether paradigms developed in the study of other settler societies (such as the ‘poor white’) are of any relevance in understanding Slavic peasant settlement in Turkestan. It concludes that there are many close parallels with European settlement in other regions with large indigenous populations, but that racial ideology played a much less important role in the Russian case compared to religious divisions and fears of cultural backsliding. This did not prevent relations between settlers and the ‘native’ population deteriorating markedly in the years before the First World War, resulting in large-scale rebellion in 1916

Development of combined technology for rebellious metamorphized polymetallic ores

After study of above mentioned ores material content it was found, that some of them reduce the degree of effective mineral separation by means of flotation. As a result of study of Maleevsky ore energetic parameters made, it was found, that it is possible to use the roentgenoradiometric separation for extraction ores with high platinoid content. The study of thermoelectric properties indicated, that almost all basic ore minerals (except pyrrotine) have both electron and hole conduction, the hole conduction frequently can be found in metamorphizated ores. As distinct of Rydny Altai deposits, where chalcopyrite can have only electron conduction, chalcopyrite of Maleevsky deposit has both electron and hole conduction. It is found, that metal losses in different concentrates are caused by similarity of their electrochemical properties. The study of magnetic properties of zinc concentrates gave the possibility to choose the way of improving their quality by means of magnetic separation. The experiments conducted indicate, that fragmentation class of zinc concentrate does not influence the magnetic fraction distribution, that suppose the possibility of finishing the zinc concentrate in separator magnetic field without pre-classification of size grade. There is a possibility of extracting the magnetic product from zinc concentrate with an output 16.52% operational and content of lead 2.64%; zinc 8.45%; copper 11.73%; iron 33.77%

Comparison of aluminum and manganum concentration in Akmola region, Kazakhstan

The results of seasonal Al and Mn activity on the surface of the atmosphere above the city of Nur-Sultan are shown from October 2016 to January 2017. The technique of sampling aerosols in various fractions and further analysis of the data are described. Together with scientists from the University of Hiroshima (Hiroshima, Japan) and the University of Tsukuba (Tsukuba, Japan), the composition of aerosols in the air of Astana was monitored. The aim of the project was to develop a methodology for sampling aerosols in various fractions and conduct measurements on an ongoing basis. The studies were carried out using a high-volume air sampler and a cascade of impactors that measure the size distribution and the respirable mass fraction of airborne particles of the environment. Fiberglass filters, which are a commonly used material for sample collection, were also used. The data obtained in the study of aerosol samples using a cascade of impactors allowing the selection of aerosols with sizes up to 0.49 μm showed the content of aluminum isotope in the atmosphere of the city. The smaller the clearance gap, the more particles are trapped. On average, aerosols were taken from more than 200 thousand cubic meters of air

Image6_Bcl-xL activity influences outcome of the mitotic arrest.tif

Microtubule-targeting (MT) drugs taxanes and vinca alkaloids are widely used as chemotherapeutic agents against different tumors for more than 30 years because of their ability to block mitotic progression by disrupting the mitotic spindle and activating the spindle assembly checkpoint (SAC) for a prolonged period of time. However, responses to mitotic arrest are different—some cells die during mitotic arrest, whereas others undergo mitotic slippage and survive becoming able for proliferation. Using normal fibroblasts and several cancer cell types we determined two critical doses, T1 and T2, of mitotic inhibitors (nocodazole, Taxol, and vinorelbine). T1 is the maximal dose cells can tolerate undergoing normal division, and T2 is the minimal mitostatic dose, wherein > 90% of mitotic cells are arrested in mitosis. In all studied cell lines after treatment with mitotic inhibitors in a dose above T2 cells had entered mitosis either die or undergo mitotic slippage. We show that for all three drugs used cell death during mitotic arrest and after slippage proceeded via mitochondria-dependent apoptosis. We determined two types of cancer cells: sensitive to mitotic arrest, that is, undergoing death in mitosis (DiM) frequently, and resistant to mitotic arrest, that is, undergoing mitotic slippage followed by prolonged survival. We then determined that inhibition of Bcl-xL, but not other anti-apoptotic proteins of the Bcl-2 group that regulate MOMP, make resistant cells susceptible to DiM induced by mitotic inhibitors. Combined treatment with MT drugs and highly specific Bcl-xL inhibitors A-1155643 or A-1331852 allows achieving 100% DiM in a time significantly shorter than maximal duration of mitotic arrest in all types of cultured cells tested. We further examined efficacy of sequential treatment of cultured cells using mitotic inhibitors followed by inhibitors of Bcl-xL anti-apoptotic protein and for the first time show that sensitivity to Bcl-xL inhibitors rapidly declines after mitotic slippage. Thus sequential use of mitotic inhibitors and inhibitors of Bcl-xL anti-apoptotic protein will be efficient only if the Bcl-xL inhibitor will be added before mitotic slippage occurs or soon afterward. The combined treatment proposed might be an efficient approach to anti-cancer therapy.</p

Image9_Bcl-xL activity influences outcome of the mitotic arrest.tif

Microtubule-targeting (MT) drugs taxanes and vinca alkaloids are widely used as chemotherapeutic agents against different tumors for more than 30 years because of their ability to block mitotic progression by disrupting the mitotic spindle and activating the spindle assembly checkpoint (SAC) for a prolonged period of time. However, responses to mitotic arrest are different—some cells die during mitotic arrest, whereas others undergo mitotic slippage and survive becoming able for proliferation. Using normal fibroblasts and several cancer cell types we determined two critical doses, T1 and T2, of mitotic inhibitors (nocodazole, Taxol, and vinorelbine). T1 is the maximal dose cells can tolerate undergoing normal division, and T2 is the minimal mitostatic dose, wherein > 90% of mitotic cells are arrested in mitosis. In all studied cell lines after treatment with mitotic inhibitors in a dose above T2 cells had entered mitosis either die or undergo mitotic slippage. We show that for all three drugs used cell death during mitotic arrest and after slippage proceeded via mitochondria-dependent apoptosis. We determined two types of cancer cells: sensitive to mitotic arrest, that is, undergoing death in mitosis (DiM) frequently, and resistant to mitotic arrest, that is, undergoing mitotic slippage followed by prolonged survival. We then determined that inhibition of Bcl-xL, but not other anti-apoptotic proteins of the Bcl-2 group that regulate MOMP, make resistant cells susceptible to DiM induced by mitotic inhibitors. Combined treatment with MT drugs and highly specific Bcl-xL inhibitors A-1155643 or A-1331852 allows achieving 100% DiM in a time significantly shorter than maximal duration of mitotic arrest in all types of cultured cells tested. We further examined efficacy of sequential treatment of cultured cells using mitotic inhibitors followed by inhibitors of Bcl-xL anti-apoptotic protein and for the first time show that sensitivity to Bcl-xL inhibitors rapidly declines after mitotic slippage. Thus sequential use of mitotic inhibitors and inhibitors of Bcl-xL anti-apoptotic protein will be efficient only if the Bcl-xL inhibitor will be added before mitotic slippage occurs or soon afterward. The combined treatment proposed might be an efficient approach to anti-cancer therapy.</p