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to the nature of Ti-Ta-Nb-oxides, which are included in the mineral associations that have historically gone by the now outdated name of “wiikites”, there is no unanimity of opinion.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

Reduction of Movement in Neurological Diseases: Effects on Neural Stem Cells Characteristics.

Both astronauts and patients affected by chronic movement-limiting pathologies face impairment in muscle and/or brain performance. Increased patient survival expectations and the expected longer stays in space by astronauts may result in prolonged motor deprivation and consequent pathological effects. Severe movement limitation can influence not only the motor and metabolic systems but also the nervous system, altering neurogenesis and the interaction between motoneurons and muscle cells. Little information is yet available about the effect of prolonged muscle disuse on neural stem cells characteristics. Our in vitro study aims to fill this gap by focusing on the biological and molecular properties of neural stem cells (NSCs). Our analysis shows that NSCs derived from the SVZ of HU mice had shown a reduced proliferation capability and an altered cell cycle. Furthermore, NSCs obtained from HU animals present an incomplete differentiation/maturation. The overall results support the existence of a link between reduction of exercise and muscle disuse and metabolism in the brain and thus represent valuable new information that could clarify how circumstances such as the absence of load and the lack of movement that occurs in people with some neurological diseases, may affect the properties of NSCs and contribute to the negative manifestations of these conditions

Re-establishing apoptosis competence in bone associated cancers via communicative reprogramming induced through notch signaling inhibition

Notch and its ligands on adjacent cells are key mediators of cellular communication during developmental choice in embryonic and adult tissues. This communication is frequently altered in the pathological interaction between cancer cells and healthy cells of the microenvironment due to the aberrant expression of tumor derived Notch receptors or ligands, that results in homotypic or heterotypic Notch signaling activation in tumor cells or surrounding stromal cells. A deadly consequence of this pathological communication is pharmacological resistance that results in patient\u2019s relapse. We will provide a survey of the role of Notch signaling in the bone marrow (BM), a microenvironment with a very high capacity to support several types of cancer, including primary cancers such as osteosarcoma or multiple myeloma and bone metastases from carcinomas. Moreover, in the BM niche several hematological malignancies maintain a reservoir of cancer stem cells, characterized by higher intrinsic drug resistance. Cell\u2013cell communication in BM-tumor interaction triggers signaling pathways by direct contact and paracrine communication through soluble growth factors or extracellular vesicles, which can deliver specific molecules such as mRNAs, miRNAs, proteins, metabolites, etc. enabling tumor cells to reprogram the healthy cells of the microenvironment inducing them to support tumor growth. In this review we will explore how the dysregulated Notch activity contributes to tumor-mediated reprogramming of the BM niche and drug resistance, strengthening the rationale of a Notch-directed therapy to re-establish apoptosis competence in cancer

Reduction of Movement in Neurological Diseases : Effects on Neural Stem Cells Characteristics

Both astronauts and patients affected by chronic movement-limiting pathologies face impairment in muscle and/or brain performance. Increased patient survival expectations and the expected longer stays in space by astronauts may result in prolonged motor deprivation and consequent pathological effects. Severe movement limitation can influence not only the motor and metabolic systems but also the nervous system, altering neurogenesis and the interaction between motoneurons and muscle cells. Little information is yet available about the effect of prolonged muscle disuse on neural stem cells characteristics. Our in vitro study aims to fill this gap by focusing on the biological and molecular properties of neural stem cells (NSCs). Our analysis shows that NSCs derived from the SVZ of HU mice had shown a reduced proliferation capability and an altered cell cycle. Furthermore, NSCs obtained from HU animals present an incomplete differentiation/maturation. The overall results support the existence of a link between reduction of exercise and muscle disuse and metabolism in the brain and thus represent valuable new information that could clarify how circumstances such as the absence of load and the lack of movement that occurs in people with some neurological diseases, may affect the properties of NSCs and contribute to the negative manifestations of these conditions

Expression Pattern and Biological Significance of the lncRNA ST3GAL6-AS1 in Multiple Myeloma

The biological impact of long non-coding RNAs (lncRNAs) in multiple myeloma (MM) is becoming an important aspect of investigation, which may contribute to the understanding of the complex pathobiology of the disease whilst also providing novel potential therapeutic targets. Herein, we investigated the expression pattern and the biological significance of the lncRNA ST3 beta-galactoside alpha-2,3 sialyltransferase 6 antisense RNA 1 (ST3GAL6-AS1) in MM. We documented a high ST3GAL6-AS1 expression level in MM compared to normal plasma cells (PCs) or other hematological malignancies. Transcriptome analyses of MM PCs from patients included in the CoMMpass database indicated a potential involvement of ST3GAL6-AS1 in MAPK signaling and ubiquitin-mediated proteolysis pathways. ST3GAL6-AS1 silencing by LNA-gapmeR antisense oligonucleotides inhibits cell proliferation and triggers apoptosis in MM cell line. Notably, ST3GAL6-AS1 silencing in vitro displayed the down-regulation of the MAPK pathway and protein ubiquitination. These data suggest that ST3GAL6-AS1 deregulation may play a pathogenetic role in MM by affecting both proliferation pathways and circuits fundamental for PC survival. However, ST3GAL6-AS1 expression levels seem not to be significantly associated with clinical outcome and its targeting appears to exert antagonistic effects with proteasome inhibitors used in MM. These findings strongly urge the need for further studies investigating the relevance of ST3GAL6-AS1 in MM

Expression pattern and biological significance of the lncRNA ST3GAL6-AS1 in multiple myeloma

The biological impact of long non-coding RNAs (lncRNAs) in multiple myeloma (MM) is becoming an important aspect of investigation, which may contribute to the understanding of the complex pathobiology of the disease whilst also providing novel potential therapeutic targets. Herein, we investigated the expression pattern and the biological significance of the lncRNA ST3 beta-galactoside alpha-2,3 sialyltransferase 6 antisense RNA 1 (ST3GAL6-AS1) in MM. We documented a high ST3GAL6-AS1 expression level in MM compared to normal plasma cells (PCs) or other hematological malignancies. Transcriptome analyses of MM PCs from patients included in the CoMMpass database indicated a potential involvement of ST3GAL6-AS1 in MAPK signaling and ubiquitin-mediated proteolysis pathways. ST3GAL6-AS1 silencing by LNA-gapmeR antisense oligonucleotides inhibits cell proliferation and triggers apoptosis in MM cell line. Notably, ST3GAL6-AS1 silencing in vitro displayed the down-regulation of the MAPK pathway and protein ubiquitination. These data suggest that ST3GAL6-AS1 deregulation may play a pathogenetic role in MM by affecting both proliferation pathways and circuits fundamental for PC survival. However, ST3GAL6-AS1 expression levels seem not to be significantly associated with clinical outcome and its targeting appears to exert antagonistic effects with proteasome inhibitors used in MM. These findings strongly urge the need for further studies investigating the relevance of ST3GAL6-AS1 in MM

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

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

The Use of L-Menthol in Endoscopic Transpapillary Interventions. Prospective Randomized Dual-Center Study

Aim: to study the effect of L-menthol on duodenal peristalsis, the results of cannulation of the papilla, the effectiveness and safety of endoscopic retrograde transpapillary interventions (ERTI).Materials and methods. A prospective two-center randomized placebo-controlled trial was carried out from January to November 2022 in two centers. The study included 126 patients, 69 (54.8 %) men and 57 (45.2 %) women, mean age — 62.1 ± 1.8 years. The inclusion criteria were age 18–75 years, indications for ERTI, absence of previous endoscopic papillotomy, absence of allergy to menthol, consent to participate in the study. After randomization, the main group (“L”) included 70 patients, the control group — 56. Patients in group “L” were irrigated with 25 mL (160 mg) of L-menthol (Spectavium), patients in the control group — with 25 mL of saline solution. Peristaltic activity was studied before and three minutes after administration of the drug. The intensity of peristalsis was assessed according to a modified Hiki scale: 0 points — complete absence of peristalsis; 1 point — single peristaltic waves; 2 points — intense peristalsis, little amenable to straightening at maximum insufflation; 3 points — pronounced peristalsis.Results. Three minutes post-irrigation, the suppression of peristaltic waves was noted in the experimental group “L”: 0 points — 63 (90 %) patients, 1 point — 6 (8.6 %) patients, compared to the control, with no change in peristalsis (p < 0.05). Successful selective cannulation was achieved in 64 (91.4 %) patients of group “L” and in 41 (73.2 %) — of the control group (p < 0.05). Non-cannulation endoscopic papillotomy had to be used in 6 (8.5 %) cases in group “L” and in 14 (25 %) cases in the control group. In general, successful cannulation was achieved in 100 % of patients in group “L”, and in 94.5 % — in the control group (p < 0.05). The duration of the intervention was significantly reduced in group “L” — 40 ± 2.5 vs. 50.3 ± 3.6 min. Among the complications, only intraoperative bleeding was registered (2 (2.9 %) — group “L”, 5 (8.9 %) — the control group), which was eliminated endoscopically in all cases.Conclusion. The use of L-menthol during ERTI helps to achieve noticeable inhibition of peristalsis, promotes successful cannulation, reduces the intervention time, minimizes the risk of intraoperative complications. Thus, L-menthol has demonstrated its effectiveness and safety, which makes it possible to use it in the arsenal of combating enhanced peristalsis during ERTI

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