Optimization of Invasion-Specific Effects of Betulin Derivatives on Prostate Cancer Cells through Lead Development

The anti-invasive and anti-proliferative effects of betulins and abietane derivatives was systematically tested using an organotypic model system of advanced, castration-resistant prostate cancers. A preliminary screen of the initial set of 93 compounds was performed in two-dimensional (2D) growth conditions using non-transformed prostate epithelial cells (EP156T), an androgen-sensitive prostate cancer cell line (LNCaP), and the castration-resistant, highly invasive cell line PC-3. The 25 most promising compounds were all betulin derivatives. These were selected for a focused secondary screen in three-dimensional (3D) growth conditions, with the goal to identify the most effective and specific anti-invasive compounds. Additional sensitivity and cytotoxicity tests were then performed using an extended cell line panel. The effects of these compounds on cell cycle progression, mitosis, proliferation and unspecific cytotoxicity, versus their ability to specifically interfere with cell motility and tumor cell invasion was addressed. To identify potential mechanisms of action and likely compound targets, multiplex profiling of compound effects on a panel of 43 human protein kinases was performed. These target de-convolution studies, combined with the phenotypic analyses of multicellular organoids in 3D models, revealed specific inhibition of AKT signaling linked to effects on the organization of the actin cytoskeleton as the most likely driver of altered cell morphology and motility.</p

A Pilot Study of IL-2Rα Blockade during Lymphopenia Depletes Regulatory T-cells and Correlates with Enhanced Immunity in Patients with Glioblastoma

Preclinical studies in mice have demonstrated that the prophylactic depletion of immunosuppressive regulatory T-cells (T(Regs)) through targeting the high affinity interleukin-2 (IL-2) receptor (IL-2Rα/CD25) can enhance anti-tumor immunotherapy. However, therapeutic approaches are complicated by the inadvertent inhibition of IL-2Rα expressing anti-tumor effector T-cells.To determine if changes in the cytokine milieu during lymphopenia may engender differential signaling requirements that would enable unarmed anti-IL-2Rα monoclonal antibody (MAbs) to selectively deplete T(Regs) while permitting vaccine-stimulated immune responses.A randomized placebo-controlled pilot study was undertaken to examine the ability of the anti-IL-2Rα MAb daclizumab, given at the time of epidermal growth factor receptor variant III (EGFRvIII) targeted peptide vaccination, to safely and selectively deplete T(Regs) in patients with glioblastoma (GBM) treated with lymphodepleting temozolomide (TMZ).Daclizumab treatment (n = 3) was well-tolerated with no symptoms of autoimmune toxicity and resulted in a significant reduction in the frequency of circulating CD4+Foxp3+ TRegs in comparison to saline controls (n = 3)( p = 0.0464). A significant (p<0.0001) inverse correlation between the frequency of TRegs and the level of EGFRvIII specific humoral responses suggests the depletion of TRegs may be linked to increased vaccine-stimulated humoral immunity. These data suggest this approach deserves further study.ClinicalTrials.gov NCT00626015

Width and string tension of the flux tube in SU(2) lattice gauge theory at high temperature

Chagdaa S, Galsandorj E, Laermann E, Purev B. Width and string tension of the flux tube in SU(2) lattice gauge theory at high temperature. Journal of Physics G: Nuclear and Particle Physics. 2017;45(2): 025002

Interaction of PP2A catalytic subunit with Rb2/p130 is required for all-trans retinoic acid suppression of ovarian carcinoma cell growth.

All-trans retinoic acid (ATRA) treatment causes CAOV3 ovarian carcinoma cells to growth arrest in the G0/G1 phase and to elevate the level of Rb2/p130 protein. PP2A, a serine/threonine phosphatase, binds and dephosphorylates Rb2/p130, thereby increasing the half-life of Rb2/p130 in the cell. In order to further characterize the interaction between Rb2/p130 and PP2A upon ATRA treatment, we examined the posttranslational modification of PP2A. ATRA treatment leads to hypophosphorylation of PP2A catalytic subunit (PP2Ac) that correlates with increased PP2A activity. In addition, the N-terminus of PP2Ac binds directly to NLS sequences located in the C-terminus of Rb2/p130. Furthermore, CAOV3 cells transfected with a truncated Rb2/p130 construct consisting of only the wt C-terminus grew more aggressively and were less sensitive to ATRA treatment when compared to parental CAOV3 cells. In contrast, CAOV3 cells transfected with a truncated Rb2/p130 construct consisting of only the C-terminus in which the NLS sites were mutated and which could not interact with PP2A, were as sensitive to ATRA treatment as parental CAOV3 cells. These studies suggest that ATRA treatment suppresses the growth of CAOV3 cells via a novel posttranscriptional mechanism involving PP2A

Characterization of clinical grade CD19 chimeric antigen receptor T cells produced using automated CliniMACS prodigy system

Wei Zhang,1 Kimberly R Jordan,2 Brian Schulte,3 Enkhtsetseg Purev1 1Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; 2Division of Immunology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; 3Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA Background: Chimeric antigen receptor (CAR) T-cell therapy is highly effective for treating acute lymphoblastic leukemia and non-Hodgkin&rsquo;s lymphoma with high rate complete responses. However, the broad clinical application of CAR T-cell therapy has been challenging, largely due to the lack of widespread ability to produce and high cost of CAR T-cell products using traditional methods of production. Automated cell processing in a closed system has emerged as a potential method to increase the feasibility of producing CAR T cells locally at academic centers due to its minimal reliance on experienced labor, thereby making the process less expensive and more consistent than traditional methods of production. Method: In this study, we describe the successful production of clinical grade CD19 CAR T cells using the Miltenyi CliniMACS Prodigy Automated Cell Processor at University of Colorado Anschutz Medical Campus in a rapid manner with a high frequent CD19 CAR expression. Results: The final CAR T-cell product is highly active, low in immune suppression, and absent in exhaustion. Full panel cytokine assays also showed elevated production of Th1 cytokines upon IL-2 stimulation when specifically killing CD19+ target cells.Conclusion: These results demonstrate the feasibility of producing CAR T cells locally in a university hospital setting using automated cell processor for future clinical applications. Keywords: automated decentralized cell production, CD19, chimeric antigen receptor, immunophenotype, activation status, cytokine pane

Modelling of Escherichia coli O157:H7 growth at various storage temperatures on beef treated with electrolyzed oxidizing water

a b s t r a c t The influence of storage temperature (4, 10, 15, 20, 25, and 30°C) on the growth of Escherichia coli O157:H7 in beef untreated (control) and treated by acidic electrolyzed oxidizing water (AcEOW) or slightly acidic electrolyzed oxidizing water (SAcEOW) was examined. A Baranyi model was employed to describe growth parameters such as specific growth rate (SGR) and lag time (LT) as a function of storage temperature. SGR increased and LT declined with rising temperatures in all samples. There were no significant differences between the SGR and LT values obtained from beef treated with AcEOW or SAc-EOW. Secondary models were established for SGR and LT to evaluate the effects of storage temperature on the growth kinetics of E. coli O157:H7 in treated and untreated beef. Mathematical evaluation was carried out to validate the performance of the developed models

Цветовые обозначения в топонимии Монголии: типологический аспект

Рукопись поступила в редакцию 11.04.2022. Рукопись принята к печати 11.11.2022.Received on 11 April 2022. Accepted on 11 November 2022.Топонимия является важным источником информации о восприятии и концептуализации человеком физического пространства, что делает топонимы исключительно важным материалом для когнитивных наук. Данная статья стремится расширить междисциплинарные исследования в области топономастики путем изучения закономерностей использования цветообозначений как составных элементов географических названий. Материал исследования извлечен из базы данных, включающей 214 805 топонимов, относящихся к территории Монголии. Из этого массива по определенному алгоритму были отобраны топонимы, содержащие цветовые обозначения — как основные, так и дополнительные, после чего результаты сопоставлялись с предшествующими работами по топонимии других стран и регионов. Основные результаты исследования можно свести к следующим трем наблюдениям. 1. Наиболее частотные указания на цвета, встречающиеся в монгольской топонимии (а именно ‘черный’, ‘белый’ и ‘красный’), идентичны цветовым обозначениям, которые чаще всего встречаются в топонимии других территорий, если судить по имеющимся в научной литературе данным. Этот феномен требует объяснения, основывающегося на универсальных когнитивных механизмах цветового восприятия и, соответственно, развития цветовой терминологии. 2. Цветообозначения чаще встречаются в топонимии степных и пустынных районов Монголии, а не в топонимии областей с континентальным климатом, что может быть объяснено особенностями ландшафта этих двух географических зон и универсальными когнитивными механизмами топономинации. Вместе с тем было выяснено, что независимо от региона и ландшафтно-климатических особенностей местности в топонимии Монголии используется единый набор цветовых терминов. 3. В типологическом отношении топонимия Монголии обнаруживает культурно- специфическую особенность, связанную с широким использованием цветовых терминов, изначально предназначенных для описания оттенков шерсти животных, что может объясняться влиянием кочевого образа жизни и скотоводства на культуру монголов и на систему цветовой терминологии. Изучение цветообозначений как элементов географических названий расширяет наше понимание когнитивных механизмов номинации географических объектов и по-своему дополняет когнитивные исследования в области восприятия и концептуализации цвета.With their implications for human perception and conceptualization of the physical environment, place names have been largely analyzed from a cognitive perspective. This article aims to extend such cross-disciplinary studies by investigating the use of color terms in place names. The authors use a large-scale database of 214,805 toponyms of Mongolia to identify place names that feature color terms, both basic and non-basic, and compare them with previous literature on the toponymy of other countries and languages. Our results can be summed up in three major findings. (1) The most frequently attested color terms in Mongolian toponymy (namely, ‘black,’ ‘white,’ and ‘red’) prove to be identical to the most salient “toponymic colors” in other territories and cultures as can be seen from the analysis of previous research. The phenomenon of similar behavior of color terms in place names across different languages and cultures requires an explanation based on the universal cognitive mechanisms of color perception and development of color terminology. (2) Color terms are more frequently found in the toponymy of desert and steppe areas of Mongolia than in continental climate areas, which can be explained by the topographic properties of these two zones and universal cognitive mechanisms of place naming. Along with that, it was found that all Mongolian place names feature a unified set of color terms regardless of the region and topographic environment. (3) Against the typological background, Mongolian toponyms appear to be culture-specific in that they largely feature animal coat colors, as nomadic lifestyle and stock-raising have always been an essential part of the culture and, in the past, had a major impact on the color terminology of Mongolians. Such onomastic investigation into place names with color terms helps broaden our understanding of the cognitive mechanisms of place naming in different cultures and contributes to the color studies in cognitive sciences.Авторы выражают искреннюю благодарность Радвану Энхбаяру и Пурэву Жаймайну, которые любезно поделились разработанной ими базой данных топонимии Монголии. Исследование выполнено в рамках гранта Р2018-3622 Монгольского государственного университета.The authors sincerely thank Ravdan Enkhbayar and Purev Jaimai for kindly sharing the database of Mongolian toponyms. This study was supported by the National University of Mongolia (grant number P2018-3622)