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

Показатели кислородного статуса как маркеры дисфункции почек у новорожденных в критическом состоянии

Objective: to study whether the use of donor blood components can be reduced in patients with baseline anemia during endo-prosthetic replacement of the hip joint. Subjects and methods. The trial was carried out in 262 patients, including 233 patients who had normal preoperative hemoglobin levels and 29 were found to have anemia that was perioperatively corrected using erythropoiesis stimulants (Eprex® (Silag AG, Switzerland)). The patients with normal hemoglobin levels were operated on under normotensive spinal anesthesia (SA) (n=129) and spinal anesthesia with moderate controlled intraoperative hypotension during infusion of microdoses of adrenaline (n=104). All the patients with baseline anemia were operated on under SA with moderate controlled intraoperative hypotension. Results. Preoperative hemopoiesis stimulation in patients with anemia caused a significant increase in hemoglobin and red blood cells in the preoperative period. The volume of intraoperative, drainage, and total blood losses under SA in patients with intraoperative moderate hypotension was significantly lower than that in those with normotensive SA. Throughout the hospitalization, hemotransfusions during erythropoiesis stimulation were needed in 17% of the patients with baseline anemia, in 7% of those with normal preoperative hemoglobin levels, operated on under SA with moderate intraoperative hypotension, and in 40% of those operated on under normotensive SA. Conclusion. The use of erythropoiesis stimulants during preoperative preparation of patients with baseline anemia makes it possible to substantially elevate hemoglobin before surgery and to avoid its considerable postoperative decrease. That of SA with moderate controlled hypotension during endoprosthetic replacement of the hip joint results in the volume of perioperative blood loss, which permits avoidance of packed donor red blood cells in the majority of patients with preoperative anemia during its correction with erythropoiesis stimulants. Key words: endoprosthetic replacement of the hip joint, erythro-poiesis stimulants, spinal anesthesia, blood loss, blood transfusion.Исследование посвящено вопросам патогенеза и ранней диагностики дисфункции почек у недоношенных новорожденных с низкой и экстремально низкой массой тела (ЭНМТ). Цель исследования . Изучение особенностей механизмов развития острой почечной недостаточности (ОПН) у новорожденных с низкой и экстремально низкой массой тела и использование анализа показателей кислородного статуса как метода ранней диагностики ОПН у новорожденных. Материал и методы. В исследование было включено 172 новорожденных ребенка с массой тела при рождении от 800 до 1500 г. Всем детям ежедневно проводилось исследование показателей газового состава и кислотно-основного состояния крови, а также кислородного статуса с анализом всех показателей, отражающих наличие тканевой гипоксии. Результаты исследования. Существенных различий при анализе показателей кислородного статуса в зависимости от массы тела ребенка выявлено не было. Было продемонстрировано, что развитие дисфункции почек и ОПН у новорожденных с низкой и ЭНМТ чаще всего обусловлено прогрессированием респираторной недостаточности и тканевой гипоксии, что свидетельствует о вторичном характере поражения почек в структуре синдрома полиорганной недостаточности. Выявлено, что наличие отеков имеет прямую корреляционную связь с фракцией физиологического шунта и индексом оксигенации и обратную умеренную корреляцию с напряжением кислорода в крови и респираторным индексом. Кроме этого, выявлена обратная корреляционная связь между концентрацией лактата в сыворотке крови и объемом диуреза за сутки. Темп почасового диуреза имеет прямую корреляционную связь с респираторным индексом и обратную — с индексом оксигенации. Заключение. Дисфункция почек и острая почечная недостаточность у новорожденных в структуре синдрома полиорганной дисфункции носит вторичный характер и тесно связана с прогрессированием респираторной недостаточности, о чем свидетельствуют показатели кислородного статуса, которые могут быть использованы для прогнозирования и ранней диагностики ОПН у новорожденных с низкой и ЭНМТ. Ключевые слова: острая почечная недостаточность, дисфункция почек, новорожденные, низкая и экстремально низкая масса тела, гипоксия, кислородный статус, синдром полиорганной дисфункции

Results of a Joint Epizootiological Survey of Transboundary Natural Plague Foci of the Russian Federation and Potentially Focal Territories of the Republic of Kazakhstan in 2019–2022

Consolidation of the efforts in implementation of epidemiological surveillance and control over plague and other dangerous natural-focal infections is an essential aspect in ensuring epidemiological well-being as regards particularly dangerous infectious diseases in the territory of natural plague foci and potentially focal territories located within the borders of the Russian Federation and the Republic of Kazakhstan. The aim of the work was to carry out a joint epizootiological survey of the transboundary territories of the Volga-Ural sandy natural plague focus and the territory of the East Kazakhstan region of the Republic of Kazakhstan (RK) potentially focal for plague over the period of 2019–2022. Materials and methods. Samples of field materials, collected during the epizootiological survey of the territory of Kazakhstan, were studied using bacteriological, molecular-genetic, and immune-serological methods. Results and discussion. We have obtained the current evidence on the spatial-biocenotic structure, the circulation of pathogens of dangerous natural-focal infectious diseases in the transboundary territories of Eastern and Western Kazakhstan. It has been established that the conditions that contribute to the possibility of human infection with plague and other dangerous infectious diseases in case of the aggravation of epizootic situation in the foci or importation of the pathogens into the territory are in place

Oxygen Status Parameters as Markers of Renal Dysfunction in Neonatal Infants with Critical Status

Objective: to study whether the use of donor blood components can be reduced in patients with baseline anemia during endo-prosthetic replacement of the hip joint. Subjects and methods. The trial was carried out in 262 patients, including 233 patients who had normal preoperative hemoglobin levels and 29 were found to have anemia that was perioperatively corrected using erythropoiesis stimulants (Eprex® (Silag AG, Switzerland)). The patients with normal hemoglobin levels were operated on under normotensive spinal anesthesia (SA) (n=129) and spinal anesthesia with moderate controlled intraoperative hypotension during infusion of microdoses of adrenaline (n=104). All the patients with baseline anemia were operated on under SA with moderate controlled intraoperative hypotension. Results. Preoperative hemopoiesis stimulation in patients with anemia caused a significant increase in hemoglobin and red blood cells in the preoperative period. The volume of intraoperative, drainage, and total blood losses under SA in patients with intraoperative moderate hypotension was significantly lower than that in those with normotensive SA. Throughout the hospitalization, hemotransfusions during erythropoiesis stimulation were needed in 17% of the patients with baseline anemia, in 7% of those with normal preoperative hemoglobin levels, operated on under SA with moderate intraoperative hypotension, and in 40% of those operated on under normotensive SA. Conclusion. The use of erythropoiesis stimulants during preoperative preparation of patients with baseline anemia makes it possible to substantially elevate hemoglobin before surgery and to avoid its considerable postoperative decrease. That of SA with moderate controlled hypotension during endoprosthetic replacement of the hip joint results in the volume of perioperative blood loss, which permits avoidance of packed donor red blood cells in the majority of patients with preoperative anemia during its correction with erythropoiesis stimulants. Key words: endoprosthetic replacement of the hip joint, erythro-poiesis stimulants, spinal anesthesia, blood loss, blood transfusion

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

Image7_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

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

Image4_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

DataSheet1_Bcl-xL activity influences outcome of the mitotic arrest.pdf

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