The role of apoptosis repressor with a CARD domain (ARC) in the therapeutic resistance of renal cell carcinoma (RCC): the crucial role of ARC in the inhibition of extrinsic and intrinsic apoptotic signalling

Background: Renal cell carcinomas (RCCs) display broad resistance against conventional radio- and chemotherapies, which is due at least in part to impairments in both extrinsic and intrinsic apoptotic pathways. One important anti-apoptotic factor that is strongly overexpressed in RCCs and known to inhibit both apoptotic pathways is ARC (apoptosis repressor with a CARD domain). Methods: Expression and subcellular distribution of ARC in RCC tissue samples and RCC cell lines were determined by immunohistochemistry and fluorescent immunohistochemistry, respectively. Extrinsic and intrinsic apoptosis signalling were induced by TRAIL (TNF-related apoptosis-inducing ligand), ABT-263 or topotecan. ARC knock-down was performed in clearCa-12 cells using lentiviral transduction of pGIPZ. shRNAmir constructs. Extrinsic respectively intrinsic apoptosis were induced by TRAIL (TNF-related apoptosis-inducing ligand), ABT263 or topotecan. Potential synergistic effects were tested by pre-treatment with topotecan and subsequent treatment with ABT263. Activation of different caspases and mitochondrial depolarisation (JC-1 staining) were analysed by flow cytometry. Protein expression of Bcl-2 family members and ARC in RCC cell lines was measured by Western blotting. Statistical analysis was performed by Student’s t-test. Results: Regarding the extrinsic pathway, ARC knockdown strongly enhanced TRAIL-induced apoptosis by increasing the activation level of caspase-8. Regarding the intrinsic pathway, ARC, which was only weakly expressed in the nuclei of RCCs in vivo, exerted its anti-apoptotic effect by impairing mitochondrial activation rather than inhibiting p53. Topotecan- and ABT-263-induced apoptosis was strongly enhanced following ARC knockdown in RCC cell lines. In addition, topotecan pre-treatment enhanced ABT-263-induced apoptosis and this effect was amplified in ARC-knockdown cells. Conclusion: Taken together, our results are the first to demonstrate the importance of ARC protein in the inhibition of both the extrinsic and intrinsic pathways of apoptosis in RCCs. In this context, ARC cooperates with anti-apoptotic Bcl-2 family members to exert its strong anti-apoptotic effects and is therefore an important factor not only in the therapeutic resistance but also in future therapy strategies (i.e., Bcl-2 inhibitors) in RCC. In sum, targeting of ARC may enhance the therapeutic response in combination therapy protocols

Разработка эффективных центраторов обсадной колонны

Основной целью работы является разработка эффективных центраторов обсадной колонны. Для выполнения поставленной цели рассмотрены основные решаемые задачи: 1 Провести обзор сортамента центраторов обсадных колонн различных производителей. 2 Провести патентный обзор центраторов обсадных колонн. 3 Провести анализ, существующих центраторов и разработать эффективный центратор обсадной колонны, лишенный недостатков, выделенных в анализе. Также выполнены разделы "Социальная ответственность" и "Производственный менеджмент, ресурсоэффективность и ресурсосбережение".The main goal of the work is to develop efficient casing centralizers. To accomplish this goal, the main tasks are addressed: 1 Review the range of casing centralizers from different manufacturers. 2 Conduct a patent review of casing centralizers. 3 Carry out an analysis of existing centralizers and develop an effective casing centering device that is free from the weaknesses highlighted in the analysis. Also the sections "Social Responsibility" and "Production Management, Resource Efficiency and Resource Saving"

Research of molybdenum carbide by raman spectroscopy

Molybdenum carbides crystalline phases are well-known polymorphs with useful technological applications including sensors, electronics, and catalysis. According to Mo-C known phase diagram, several polymorphs can exist under ambient conditions. One of the promising synthesis techniques is DC arc plasma. Nowadays, recent trends focus on the non-vacuum arcing procedure in ambient conditions which is possible due to carbon monoxide generation during the synthesis process. This phenomenon as a result of graphite electrodes usage can prevent the oxidation of the synthesis products. As an advantage of this method should be noted the possible cost benefits through the lower energy consumption, also the productivity can be increased by our approach. In this contribution, the arc plasma method is investigated for the crystalline molybdenum carbides synthesis. According to the X-ray diffraction results, the Mo2C and Mo1.2C0.8 crystalline phases were synthesized. Raman spectroscopy confirms the presence and high crystallinity of these MoC phases. This work shows an inexpensive and promising way to obtain molybdenum carbides with potential in optoelectronics, environmental, and energy applications

Nucleolin as activator of TCF7L2 in human hematopoietic stem/progenitor cells

The accumulation of somatic mutations in hematopoietic stem cells during aging, leading to clonal expansion, is linked to a higher risk of cardiovascular mortality and hematologic malignancies. Clinically, clonal hematopoiesis is associated with a pro-inflammatory phenotype of hematopoietic cells and their progeny, inflammatory conditions and a poor outcome for patients with hematologic neoplasms and solid tumors. Here, we review the relevance and complications of clonal hematopoiesis for the treatment of hematologic malignancies with cell therapeutic approaches. In autologous and allogeneic hematopoietic stem cell transplantation native hematopoietic and immune effector cells of clonal origin are transferred, which may affect outcome of the procedure. In chimeric antigen receptor modified T-cell therapy, the effectiveness may be altered by preexisting somatic mutations in genetically modified effector cells or by unmodified bystander cells harboring clonal hematopoiesis. Registry studies and carefully designed prospective trials will be required to assess the relative roles of donor- and recipient-derived individual clonal events for autologous and allogeneic cell therapies and to incorporate novel insights into therapeutic strategies

За кадры. 1968. № 30 (1303)

Ленин и наука / Г. ЯловскаяПамяти Ильича / Р. ГорскаяПленум комитета ВЛКСМ / В. ВалеринОтчеты и выборы / Р. СергееваПариж, улица Мари-Роз. Здесь жил и работал Ленин / Р. Городнева, Ю. ЗагромовДобрая память / М. СамаревРассказывают фотографии / А. КлапоухФотоинформацияВерность / П. АнфимоваПо ленинским заветам / В. ФедоровК 150-летию со дня рождения Карла МарксаНа приз газеты "За кадры"Закрытие сезона / Б. ПлотниковНа ковре борцы / Ю. Тележки

PIDDosome Expression and the Role of Caspase-2 Activation for Chemotherapy-Induced Apoptosis in RCCs

Background: The importance of caspase-2 activation for mediating apoptosis in cancer is not clear and seems to differ between different tumour types. Furthermore, only few data have been obtained concerning the expression of caspase-2, which can be alternatively spliced into caspase-2L and caspase-2S, and the other PIDDosome members PIDD and RAIDD in human tumours in vivo. We, therefore, investigated their expression in renal cell carcinomas (RCCs) of the clear cell type in vivo and analysed the role of caspase-2 in chemotherapy-induced apoptosis in RCCs in vitro

HA14-1 is Able to Reconstitute the Impaired Mitochondrial Pathway of Apoptosis in Renal Cell Carcinoma Cell Lines

Renal cell carcinomas (RCCs) exhibit a marked resistance towards apoptosis. Although most apoptotic stimuli converge at the level of the mitochondria, little is known about the mitochondrial apoptosis pathway in renal cell carcinomas. The aim of the present study, therefore, was to investigate the functionality of the mitochondrial apoptosis pathway in renal cell carcinoma cell lines by exposure to TRAIL, etoposide, HA14-1 and betulinic acid activating the mitochondria by different mechanisms. Sensitivity to TRAIL-induced apoptosis correlated with cleavage of the initiator caspase-8, but the mitochondrial apoptosis pathway was not induced. Similarly, etoposide and betulinic acid could not induce mitochondrial damage. In contrast, HA14-1 was able to activate mitochondrial apoptosis, thereby demonstrating functionally inducible signalling pathways downstream of the mitochondria. The intactness of the pathways upstream of the mitochondria was shown by pretreatment of TRAIL-sensitive cell lines with HA14-1, which could reconstitute TRAIL-induced mitochondrial damage and resulted in a synergistic apoptosis induction