On the identification of Ti-Ta-Nb-oxides in “wiikites” from Karelia

Purpose. With respect to the nature of Ti-Ta-Nb-oxides, which are included in the mineral associations that have historically gone by the now outdated name of “wiikites”, there is no unanimity of opinion. The main difficulty in identifying them is associated with the complexity of their chemical composition, their metamict structure and the substantial changes in their initial mineral form due to the effects of natural weathering. The aim of this work is the development of methodology to identify Ti-Ta-Nb-oxides corresponding to the mineral formulas AB2O6 and A2B2O7. Methods. The methodology developed in the work includes two experimental approaches: 1) electron probe microanalysis of phases revealed through use of the SEM-BSE method. Based on the resulting data, a hypothesis about the nature of the Ti-Ta-Nb-oxides in a number of wiikite samples is proposed. 2) XRD analysis of those phases that are formed in the course of thermal annealing of samples from 200 to 1000°C. Based on the resulting data here, the previous hypotheses are either accepted or rejected for each sample. Findings. Using this methodology, three “wiikite” samples were analyzed (the experimental codes were Wk-2, Wk-3 and Wk-7). The Ti-Ta-Nb-oxides in two of these wiikites (Wk-2 and Wk-3) were preliminarily determined to be hydroxyyttropyrochlore and hydroxycalciobetafite, respectively. In the third sample (Wk-7), the Ti-Ta-Nb-oxide was classified as polycrase. The results of XRD phase analysis of the annealed samples were compatible with the primary hypotheses that hydroxycalciobetafite and polycrase were the initial minerals in “wiikites” 3 and 7, respectively. Originality. The paper considers the issue of the chemical conditions necessary for the recovery of the original Ti-Ta-Nb-oxide during recrystallization of the metamict structures. This is a problem that has not been substantively addressed in the literature. Also for the first time experimentally proved the existence of the polycrase in “wiikites”. Practical implications. Completed work expands our knowledge of the mineral composition of the granitic pegmatites of the Baltic shield and the possibility of their use both for research purposes and for needs of national economy.Мета. Розробка методології ідентифікації Ti-Ta-Nb-оксидів складного хімічного складу з метаміктною структурою, що відповідають мінеральним формулами АВ2О6 та А2В2О7. Методика. Для розробки методології ідентифікації у роботі використано два експериментальних підходи: 1) рентген-спектральний мікроаналіз фаз, виявлених методом скануючої електронної мікроскопії зразків у назад відображених електронах. На основі отриманих результатів висунута гіпотеза щодо природи Ti-Ta-Nb-оксидів. 2) рентген-дифракційний аналіз фаз, що утворюються в процесі термічного відпалу зразків від 200 до 1000°С. На основі отриманих результатів для кожного зразка первинна гіпотеза приймалася або відкидалася. Результати. З використанням даної методики були вивчені три зразки “віікітів” (шифри зразків: Wk-2, Wk-3 і Wk-7). Наявність Ti-Ta-Nb-оксидів попередньо визначено e двох зразках (Wk-2 і Wk-3) відповідно, як гідроксііттропірохлор та гідроксікальціобетафіт. У третьому зразку (Wk-7) Ti-Ta-Nb діагностований як полікраз. Результати рентген-дифракційного аналізу відпалених зразків підтвердили гіпотези про те, що початковими мінералами у Wk-3 і Wk-7 були гідроксікальціобетафіт і полікраз відповідно. Наукова новизна. Визначено хімічні умови, необхідні для утворення початкового Тi-Ta-Nb під час рекристалізації метаміктної структури, що раніше не розглядалось у відповідній тематичній науковій літературі. Вперше експериментально виявлено присутність у “віікітах” полікраза. Практична значимість. Отримані результати розширюють й доповнюють знання щодо мінерального складу гранітних пегматитів Балтійського щита та надають можливість їх використання в дослідницьких цілях і потребах народного господарства.Цель. Разработка методологии идентификации Ti-Ta-Nb-оксидов сложного химического состава с метамиктной структурой, соответствующих минеральным формулам АВ2О6 и А2В2О7. Методика. Для разработки методологии идентификации в работе использовано два экспериментальных подхода: 1) рентген-спектральный микроанализ фаз, выявленных методом сканирующей электронной микроскопии образцов в обратно отраженных электронах. На основе полученных результатов выдвинута гипотеза о природе Ti-Ta-Nb-оксидов. 2) рентген-дифракционный анализ фаз, образующихся в процессе термического отжига образцов от 200 до 1000°С. На основе полученных результатов для каждого образца первоначальная гипотеза принималась или отвергалась. Результаты. С использованием данной методики были изучены три образца “виикитов” (шифры образцов: Wk-2, Wk-3 и Wk-7). Наличие Ti-Ta-Nb-оксидов предварительно определено в двух образцах (Wk-2 и Wk-3) соответственно, как гидроксииттропирохлор и гидроксикальциобетафит. В третьем образце (Wk-7) Ti-Ta-Nb диагностирован как поликраз. Результаты рентген-дифракционного анализа отожженных образцов подтвердили гипотезы о том, что первоначальными минералами в Wk-3 и Wk-7 были гидроксикальциобетафит и поликраз соответственно. Научная новизна. Определены химические условия, необходимые для образования первоначального Тi-Ta-Nb во время рекристаллизации метамиктной структуры, что ранее не рассматривалось в соответствующих тематических научных литературе. Впервые экспериментально выявлено присутствие в “виикитах” поликраза. Практическая значимость. Полученные результаты расширяют и дополняют знания о минеральном составе гранитных пегматитов Балтийского щита и дают возможности их использования в исследовательских целях и нуждах народного хозяйства.The study was conducted using equipment of the Center of X-ray Diffraction Studies and the Center for Microscopy and Microanalysis of the Research Park at Saint Petersburg State University, as well as the analytical laboratory of OJSC MMC Norilsk Nickel in Saint Petersburg

Emotional Leadership: The Relationship of Level of Education and Emotional Intelligence

The article proposes the formulation of the problem of the correlation of the level and direction of education with emotional intelligence and leadership potential. Leadership is seen as the ability to influence individuals and groups to achieve company’s goals, based on emotional intelligence. The conceptual basis of the study of emotional leadership is proposed as the basis for the success of an organization at all levels and the need for leadership development. The basic approaches for understanding emotional intelligence and its basic models are given. The author describes the relevance of the research topic for the modern world. The results of an empirical study are presented, during which interconnections of three main components were established: emotional intelligence, educational level and leadership potential. The necessity of modern educational programs of managerial education for managers is substantiated. The prospect of further research on the problem of the development of emotional leadership is determined

Prevalence of certain forms of obstetric pathology and incidence of their implementation at pregnant women with infertility history

The article presents data on the frequency prediction of pregnancy in women with a history of infertility, complications of pregnancy and labor. The study showed a higher frequency of the projected implementation obstetric pathologies in women with impaired reproductive function, hence the need to improve the quality of medical care provided since the preparation for pregnancy

Outbreak of West Nile virus infection, Volgograd Region, Russia, 1999.

From July 25 to October 1, 1999, 826 patients were admitted to Volgograd Region, Russia, hospitals with acute aseptic meningoencephalitis, meningitis, or fever consistent with arboviral infection. Of 84 cases of meningoencephalitis, 40 were fatal. Fourteen brain specimens were positive in reverse transcriptase-polymerase chain reaction assays, confirming the presence of West Nile/Kunjin virus

Notch signaling deregulation in multiple myeloma : a rational molecular target

Despite recent therapeutic advances, multiple myeloma (MM) is still an incurable neoplasia due to intrinsic or acquired resistance to therapy. Myeloma cell localization in the bone marrow milieu allows direct interactions between tumor cells and non-tumor bone marrow cells which promote neoplastic cell growth, survival, bone disease, acquisition of drug resistance and consequent relapse. Twenty percent of MM patients are at high-risk of treatment failure as defined by tumor markers or presentation as plasma cell leukemia. Cumulative evidences indicate a key role of Notch signaling in multiple myeloma onset and progression. Unlike other Notch-related malignancies, where the majority of patients carry gain-of-function mutations in Notch pathway members, in MM cell Notch signaling is aberrantly activated due to an increased expression of Notch receptors and ligands; notably, this also results in the activation of Notch signaling in surrounding stromal cells which contributes to myeloma cell proliferation, survival and migration, as well as to bone disease and intrinsic and acquired pharmacological resistance. Here we review the last findings on the mechanisms and the effects of Notch signaling dysregulation in MM and provide a rationale for a therapeutic strategy aiming at inhibiting Notch signaling, along with a complete overview on the currently available Notch-directed approaches

Notch pathway promotes multiple myeloma cell IL-6 independence

Background Multiple myeloma (MM) is a malignant plasma cells (PC) disorder accounting for approximately 10% of hematologic cancers. Even though advanced chemotherapeutic regimens have increased the median time of survival to 5 years after diagnosis, myeloma remains incurable. Once immortalized, the survival and proliferation of myeloma cells strictly depend on a complex interaction with the bone marrow (BM) microenvironment, which is mediated both by adhesion molecules and production of several cytokines, especially interleukin-6 (IL-6). Following MM progression, at the stage of plasma cell leukemia, the malignant PC acquires autonomous proliferative ability, becomes indipendent on growth factors like IL-6 and is no longer confined in the BM. Several recent evidences point to a possible role for Notch signaling in mediating critical events in MM progression. The Notch pathway is highly conserved and plays a crucial role in cell-fate decision, tissue patterning and morphogenesis. Recently, Notch receptors and ligands have been shown to be upregulated during MM progression and their signaling positively regulates cell proliferation, drug resistance and BM infiltration. Aims The ability of Notch signaling to regulate proliferation and survival pathways (i.e. NF-kB, AKT, Myc, and the same IL-6) prompted us to study if its up-regulation during MM progression may play a role in the acquirement of IL-6 independence. To this end we used two opposite approaches. Specifically, we verified if Notch signaling upregulation in IL-6 dependent cell lines promotes their independence and assessed if, upon Notch inihibition, IL-6 independent MM cell lines lost self-sufficient proliferation. Methods Cell culture and cell growth analysis: HMCL CMA03, INA-6 and XG-1 were maintained in complete RPMI-1640 medium supplemented with 10% V/V FBS and IL-6 10, 2.5 or 1 ng/mL, respectivetly. OPM2, CMA03/06 and U266 cell lines were cultured in the same conditions without IL-6 addition. The number and viability of cells were assessed by means of trypan blue exclusion assay. The Notch inihibitor, DAPT, was added to the medium at the final concentration of 50mM. Soluble Jagged1 was used at 5mg/mL. Flow cytometry analysis: Apoptosys analysis was perfomed by AnnexinV-FITC/Propidium Iodide staining. Cell cycle analysis was performed by Propidium Iodide staining. Real time-PCR: Quantitative PCR reactions were carried out using the Maxima\u2122 SYBR Green/ROX qPCR Master Mix. Results To evaluate if Notch pathway upregulation is involved in the development of IL-6 independence in MM cells, we activated the Notch signaling in three MM cell lines, CMA03, INA-6 and XG-1, strictly dependent on IL-6. At this purpose, MM cells were cultured with the soluble form of the Notch ligand Jagged1. We demonstrated that Jagged1 stimulation partially rescued the reduced cell growth due to IL-6 withdrawal. On the other hand, three different IL-6 independent cell lines, CMA03/06, OPM2 and U266, treated with a gamma-secretase inhibitor (DAPT) which causes Notch pathway blockade, displayed a significant decrease in cell growth. Remarkably, this effect could be reverted by the addition of IL-6 in the culture medium. The mechanisms underlying Notch-IL-6 crosstalking was partially investigated. Preliminary results indicate that Notch signalling is required for MM cell autonomous IL-6 production. Summay/Conclusion The present results suggest that Notch pathway activation may contribute to the transition from IL-6-dependent to IL-6-independent MM cell growth. Furthermore, the inhibition of the Notch patwhay may lead to a decrease in MM cells proliferation in part due to the reduction of IL-6 expression. Even though studies are necessary to identify further mechanisms of IL-6 independence possibly involving other Notch downstrem pathways, these preliminary results support the rationale for a Notch-directed approach in plasma cell dyscrasias

Multiple myeloma exploits Jagged1 and Jagged2 to promote intrinsic and bone marrow-dependent drug resistance

Multiple myeloma is still incurable due to an intrinsic aggressiveness or, more frequently, to the interactions of malignant plasma cells with bone marrow microenvironment. Myeloma cells educate bone marrow cells to support neoplastic cell growth, survival, acquisition of drug resistance resulting in disease relapse. Myeloma microenvironment is characterized by Notch signaling hyperactivation due to the increased expression of Notch1 and 2 and the ligands Jagged1 and 2 in tumor cells. Notch activation influences myeloma cell biology and promotes the reprogramming of bone marrow stromal cells. In this work we demonstrate, by in vitro, ex vivo and using a zebrafish multiple myeloma model, that Jagged inhibition causes a decrease in both myeloma-intrinsic and stromal cell-induced resistance to currently used drugs, i.e. bortezomib, lenalidomide and melphalan. The molecular mechanism of drug resistance involves the chemokine system CXCR4/SDF1\u3b1. Myeloma cell-derived Jagged ligands trigger Notch activity in bone marrow stromal cells. These, in turn, secrete higher levels of SDF1\u3b1 in the bone marrow microenvironment increasing CXCR4 activation in myeloma cells, which is further potentiated by the concomitant increased expression of this receptor induced by Notch activation. Consistently with the augmented pharmacological resistance, SDF1\u3b1 boosts the expression of BCL2, Survivin and ABCC1. These results indicate that a Jagged-tailored approach may contribute to disrupting the pharmacological resistance due to intrinsic myeloma cell features or to the pathological interplay with bone marrow stromal cells and, conceivably, improve patients' response to standard-of-care therapies

Bone marrow-mediated drug resistance is promoted by Jagged-induced Notch signaling in multiple myeloma

BACKGROUND Multiple myeloma (MM) is an hematologic tumor caused by the accumulation of malignant plasma cells in the bone marrow (BM). The dysregulated expression of two Notch ligands, Jagged1 and Jagged2, hyperactivates the Notch pathway both in MM cells and in BM stromal cell (BMSC). Several Notch downstream mediators are involved in MM cell survival and proliferation, i.e. IL6, SDF1\u3b1, CXCR4, NF-kB, VEGF and IGF. Although treatments with new drugs, such as alkylating agents, proteasome inhibitors and immunomodulatory agents, increased patients\u2019survival, MM remains incurable, principally due to the development of endogenous or BM-mediated drug resistance (DR). Therefore it is crucial to find new therapeutic targets. The aim of this study was to investigate the role of Notch signaling in endogenous and BMSC-promoted DR in MM. MATERIAL AND METHODS U266 and OPM2 cell lines were maintained in complete RPMI-1640 medium. The BMSC lines NIH3T3 (murine) and HS5 (human) were maintained in complete DMEM medium. MM cells were cultured alone or on a BMSC monolayer for 24h, and subsequently treated with Mitoxantrone, Bortezomib, Melphalan or the vehicle in the presence or the absence of the CXCR4 antagonist AMD3100 for additional 24 hours. BMSCs were previously stained with PKH26 (Sigma-Aldrich) to discriminate them from MM by flow cytometry. Apoptosis was determined by Annexin V-FITC staining. qRT-PCR reactions were carried out in a 7500 Fast Real-time PCR system (Applied Biosystems) using the Maxima\u2122 SYBR Green/ROX qPCR Master Mix (ThermoScientific Inc) using murine or human primer sets to discriminate the source of the RNA molecules. Silencing of Jagged1 and 2 was obtained by transient expression of specific siRNAs (Stealth Select RNAi siRNA system, Life Technologies). RESULTS The possible role of Notch withdrawal in DR was investigated by silencing Jagged 1 and 2 ligands in MM cell lines OPM-2 and U266. Results showed an increased sensitivity to Bortezomib, Mitoxantrone and Melphalan associated to a decrease in the expression of SDF1\u3b1, CXCR4, Bcl-XL, Bcl-2, Survivin and ABCC1. When co-cultured with murine and human BMSCs, MM cells showed increased DR due to: i) increased expression of anti-apoptotic genes in MM cells, i.e. Bcl-XL, Bcl-2, Survivin and ABCC1; ii) BMSC release of soluble mediators relevant to MM cells, i.e. SDF1\u3b1 and VEGF. We suggest that these effects may be driven by the reciprocal activation of Notch signaling observed in both cell types and consistently we demonstrated that DR may be significantly reduced by silencing Jagged1 and 2 in MM cells. Finally, the evidence that CXCR4 blockade significantly reduced MM cells resistance to Bortezomib induced by BMCSs, indicates that CXCR4/SDF1\u3b1 chemokine axis is a key mediator of Notch in MM-associated DR. CONCLUSION The evidence that Jagged1/2 silencing affects endogenous and BMSC-induced DR in MM cells supports the use of a Jagged-targeted approach in MM therapy alone or in combination with common drugs

The role of notch pathway in multiple myeloma progression toward IL-6 independence

Introduction Multiple myeloma (MM) is a heamotologic malignancy characterized by proliferation of neoplastic plasma cells in the bone marrow (BM). Initially, myeloma cells strictly depend on BM, which supports tumor progression through adhesion molecules and soluble mediators as interleukin-6 (IL-6). Later, at the stage of plasma cell leukemia, MM cells acquire mutations resulting in proliferation indipendent from environmental factors such as IL-6. Recently, Notch signaling has been shown to be upregulated during MM progression and to positively regulate cell proliferation, drug resistance and BM infiltration. The aim of this study is to evaluate if Notch signalling plays a role in the acquirement of IL-6 independence. Methods The human MM cell lines CMA03, INA-6 and XG1 were maintained in RPMI-1640 medium supplemented with IL-6 (respectivetly at 10, 2.5 and 1ng/ml). CMA03/06, OPM2 and U266 were maintened in the same condition withouth IL-6. The murine fibroblasts NIH3T3 were used as BMSC mimic and maintained in DMEM. Viable cells were counted by trypan blue exclusion assay. Notch inhibition was obtained by using the &3-secretase inhibitor DAPT at 50mM, soluble Jagged1 was used at 5mg/ml. qRT-PCR reactions were performed by Maxima\u2122 SYBR GreenqPCR Master Mix. Silencing of Jagged1 and 2 was obtained by transient expression of specific siRNAs (Select RNAiTM siRNA system, Invitrogen). Results The global expression analysis of the MM model of IL-6 independence acquisistion represented by CMA03 and CMA03/06 cell line (Verdelli et al. Genes Chromosomes Cancer, 2014), indicated that Notch pathway activation may contribute to the IL-6 independence in MM by inducing proliferative signals. Accordingly, we showed here that the activation of Notch signaling, induced by stimulation with soluble Jagged1 ligand, partially rescued IL-6 dependency in XG1 cells. Otherwise, Notch signaling inhibition obtained with DAPT in three different IL-6-indipendent MM cell lines (CMA03/06, OPM2 and U266) resulted in a significant decrease of cell growth which could be reverted by IL-6. This confirms that Notch and IL-6 are complementary in activating MM cell proliferation. Of note, Notch withdrawal induced by Jagged1/2 silencing, decreased IL-6 expression in OPM2 and U266 cell lines. This suggests that Notch-directed IL-6 regulation might have a biological significance in those MM cell lines which express high IL-6 levels. More frequently, BM stromal cells represent the main source of IL-6 for those MM cells which do not display an autonomous production. Results from co-culture systems indicate that surface Jagged expressed on MM cell lines induced Notch-directed IL-6 production in stromal cells. This effect was reverted by silencing Jagged1/2 in MM cells. Conclusions These results suggest that Notch pathway activation may contribute to the transition from IL-6-dependent to IL-6-independent cell growth, and that its inhibition may result in decreased cell proliferation

First Use of Superpulsed Fibre Thulium Laser-Based Contact Stone Ablation in Common Bile and Main Pancreatic Ducts

Aim. A clinical demonstration of the feasibility of novel superpulsed thulium fibre laser in contact intraductal lithotripsy in patients with choledocholithiasis and pancreatic lithiasis.Key points. We describe two clinically successful ablations of large biliary and pancreatic calculi using a FiberLase U2 superpulse fibre thulium laser appliance (IRE-Polus, Russia) during oral transpapillary cholangiopancreaticoscopy in patients with technically unfeasible conventional minimally invasive treatment for choledocho- and pancreatic lithiasis. A 72-yo patient was urgently admitted with acute mechanical jaundice, cholangitis and a history of endoscopic papillosphincterotomy (EPST) and bilioduodenal stenting with a plastic implant for technically impractical lithotripsy and lithoextraction. An ineffective extracorporeal lithotripsy attempt was followed on day 3 by a second retrograde intervention and endoscopic contact laser lithotripsy controlled in oral transpapillary cholangioscopy with FiberLase U2. A 50-yo patient was admitted with clinical signs of chronic calculous pancreatitis and a history of EPST, pancreatic ductotomy and plastic pancreatic stenting. The first endoscopy stage comprised the encrusted pancreatic stent removal, retrograde pancreaticography, pancreatic ductotomy, narrowed terminal Wirsung’s duct bougienage with mechanical dilators and additional balloon-assisted dilation of the excision area and pancreatic stricture. Mechanical intraductal lithotripsy was unsuccessful. Contact lithotripsy with a novel superpulsed fibre thulium laser has been rendered. The technique presented ensures a complete sanation of the duct at no mucosal damage.Conclusion. We present the fully successful first national and world experience of the superpulsed fibre thulium laser application in contact lithotripsy of large calculi in common bile and main pancreatic ducts