Репозиторий Университета

© 2021, The Author(s). Background: CARs are simulated receptors containing an extracellular single-chain variable fragment (scFv), a transmembrane domain, as well as an intracellular region of immunoreceptor tyrosine-based activation motifs (ITAMs) in association with a co-stimulatory signal. Main body: Chimeric antigen receptor (CAR) T cells are genetically engineered T cells to express a receptor for the recognition of the particular surface marker that has given rise to advances in the treatment of blood disorders. The CAR T cells obtain supra-physiological properties and conduct as “living drugs” presenting both immediate and steady effects after expression in T cells surface. But, their efficacy in solid tumor treatment has not yet been supported. The pivotal challenges in the field of solid tumor CAR T cell therapy can be summarized in three major parts: recognition, trafficking, and surviving in the tumor. On the other hand, the immunosuppressive tumor microenvironment (TME) interferes with T cell activity in terms of differentiation and exhaustion, and as a result of the combined use of CARs and checkpoint blockade, as well as the suppression of other inhibitor factors in the microenvironment, very promising results were obtained from the reduction of T cell exhaustion. Conclusion: Nowadays, identifying and defeating the mechanisms associated with CAR T cell dysfunction is crucial to establish CAR T cells that can proliferate and lyse tumor cells severely. In this review, we discuss the CAR signaling and efficacy T in solid tumors and evaluate the most significant barriers in this process and describe the most novel therapeutic methods aiming to the acquirement of the promising therapeutic outcome in non-hematologic malignancies.

© 2021, The Author(s). Background: CARs are simulated receptors containing an extracellular single-chain variable fragment (scFv), a transmembrane domain, as well as an intracellular region of immunoreceptor tyrosine-based activation motifs (ITAMs) in association with a co-stimulatory signal. Main body: Chimeric antigen receptor (CAR) T cells are genetically engineered T cells to express a receptor for the recognition of the particular surface marker that has given rise to advances in the treatment of blood disorders. The CAR T cells obtain supra-physiological properties and conduct as “living drugs” presenting both immediate and steady effects after expression in T cells surface. But, their efficacy in solid tumor treatment has not yet been supported. The pivotal challenges in the field of solid tumor CAR T cell therapy can be summarized in three major parts: recognition, trafficking, and surviving in the tumor. On the other hand, the immunosuppressive tumor microenvironment (TME) interferes with T cell activity in terms of differentiation and exhaustion, and as a result of the combined use of CARs and checkpoint blockade, as well as the suppression of other inhibitor factors in the microenvironment, very promising results were obtained from the reduction of T cell exhaustion. Conclusion: Nowadays, identifying and defeating the mechanisms associated with CAR T cell dysfunction is crucial to establish CAR T cells that can proliferate and lyse tumor cells severely. In this review, we discuss the CAR signaling and efficacy T in solid tumors and evaluate the most significant barriers in this process and describe the most novel therapeutic methods aiming to the acquirement of the promising therapeutic outcome in non-hematologic malignancies.

© 2021, The Author(s). A crosstalk established between tumor microenvironment and tumor cells leads to contribution or inhibition of tumor progression. Mesenchymal stem cells (MSCs) are critical cells that fundamentally participate in modulation of the tumor microenvironment, and have been reported to be able to regulate and determine the final destination of tumor cell. Conflicting functions have been attributed to the activity of MSCs in the tumor microenvironment; they can confer a tumorigenic or anti-tumor potential to the tumor cells. Nonetheless, MSCs have been associated with a potential to modulate the tumor microenvironment in favouring the suppression of cancer cells, and promising results have been reported from the preclinical as well as clinical studies. Among the favourable behaviours of MSCs, are releasing mediators (like exosomes) and their natural migrative potential to tumor sites, allowing efficient drug delivering and, thereby, efficient targeting of migrating tumor cells. Additionally, angiogenesis of tumor tissue has been characterized as a key feature of tumors for growth and metastasis. Upon introduction of first anti-angiogenic therapy by a monoclonal antibody, attentions have been drawn toward manipulation of angiogenesis as an attractive strategy for cancer therapy. After that, a wide effort has been put on improving the approaches for cancer therapy through interfering with tumor angiogenesis. In this article, we attempted to have an overview on recent findings with respect to promising potential of MSCs in cancer therapy and had emphasis on the implementing MSCs to improve them against the suppression of angiogenesis in tumor tissue, hence, impeding the tumor progression.

© 2021, The Author(s). A crosstalk established between tumor microenvironment and tumor cells leads to contribution or inhibition of tumor progression. Mesenchymal stem cells (MSCs) are critical cells that fundamentally participate in modulation of the tumor microenvironment, and have been reported to be able to regulate and determine the final destination of tumor cell. Conflicting functions have been attributed to the activity of MSCs in the tumor microenvironment; they can confer a tumorigenic or anti-tumor potential to the tumor cells. Nonetheless, MSCs have been associated with a potential to modulate the tumor microenvironment in favouring the suppression of cancer cells, and promising results have been reported from the preclinical as well as clinical studies. Among the favourable behaviours of MSCs, are releasing mediators (like exosomes) and their natural migrative potential to tumor sites, allowing efficient drug delivering and, thereby, efficient targeting of migrating tumor cells. Additionally, angiogenesis of tumor tissue has been characterized as a key feature of tumors for growth and metastasis. Upon introduction of first anti-angiogenic therapy by a monoclonal antibody, attentions have been drawn toward manipulation of angiogenesis as an attractive strategy for cancer therapy. After that, a wide effort has been put on improving the approaches for cancer therapy through interfering with tumor angiogenesis. In this article, we attempted to have an overview on recent findings with respect to promising potential of MSCs in cancer therapy and had emphasis on the implementing MSCs to improve them against the suppression of angiogenesis in tumor tissue, hence, impeding the tumor progression.

The family of Tribbles proteins play many critical nonenzymatic roles and regulate a wide range of key signaling pathways. Tribbles homolog 2 (Trib2) is a pseudo serine/threonine kinase that functions as a scaffold or adaptor in various physiological and pathological processes. Trib2 can interact with E3 ubiquitin ligases and control protein stability of downstream effectors. This protein is induced by mitogens and enhances the propagation of several cancer cells, including myeloid leukemia, liver, lung, skin, bone, brain, and pancreatic. Thus, Trib2 can be a predictive and valuable biomarker for the diagnosis and treatment of cancer. Recent studies have illustrated that Trib2 plays a major role in cell fate determination of stem cells. Stem cells have the capacity to self-renew and differentiate into specific cell types. Stem cells are important sources for cell-based regenerative medicine and drug screening. Trib2 has been found to increase the self-renewal ability of embryonic stem cells, the reprogramming efficiency of somatic cells, and chondrogenesis. In this review, we will focus on the recent advances of Trib2 function in tumorigenesis and stem cell fate decisions. [MediaObject not available: see fulltext.]

Objective: The current scientific research direction is development of drugs with a targeted effect on malignant tumors. One of the promising groups is indolocarbazoles and their derivatives, which can initiate various tumor cell death pathways. Russian scientists from N. N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russian Federation has developed a new experimental drug form of the original compound LCS 1269 with cytotoxic and antiangiogenic properties, blocking vasculogenic mimicry in tumor. The study aim is the experimental drug form LCS 1269 antitumor activity on models of transplantable mouse tumors B-16 melanoma and Lewis epidermoid lung carcinoma (LLC) with different routes and modes of administration. Material and methods: Female F1 hybrid mice (C Bl/  x DBA/2) and male and female linear mice C BL/  were used for management of tumor strains. Mice were obtained from N. N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russian Federation vivarium. The antitumor effect was assessed by tumor growth inhibition (TGI) and increase of treated animal’s life span (ILS) compared to the control. Results: The experimental drug form showed high antitumor activity when administered intravenously once at doses of 100 and 120 mg/kg (TGI = 98–82% and TGI = 95–77%, respectively, ILS = 24%, p < 0.05) on melanoma B-16 mice. On LLC mice, the experimental drug form showed that the intravenous administration route was effective in the range of doses from 60 to 80 mg/kg with a 5 day administration regimen with an interval of 24 h. A dose of 70 mg/kg had maximum effect at the level of TGI = 96–77% (p < 0.05) with its retention for 20 days after the end of treatment. Conclusion: The studies have shown that the new compound LCS 1269 in the original drug form, has a pronounced antitumor activity and significantly reduces the volume of tumor mass both on melanoma B-16 and on LLC. It allows us to recommend continue the search for sensitivity of animal transplantable tumors to LCS 1269. 57 6 57 6

Objective: The current scientific research direction is development of drugs with a targeted effect on malignant tumors. One of the promising groups is indolocarbazoles and their derivatives, which can initiate various tumor cell death pathways. Russian scientists from N. N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russian Federation has developed a new experimental drug form of the original compound LCS 1269 with cytotoxic and antiangiogenic properties, blocking vasculogenic mimicry in tumor. The study aim is the experimental drug form LCS 1269 antitumor activity on models of transplantable mouse tumors B-16 melanoma and Lewis epidermoid lung carcinoma (LLC) with different routes and modes of administration. Material and methods: Female F1 hybrid mice (C Bl/  x DBA/2) and male and female linear mice C BL/  were used for management of tumor strains. Mice were obtained from N. N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russian Federation vivarium. The antitumor effect was assessed by tumor growth inhibition (TGI) and increase of treated animal’s life span (ILS) compared to the control. Results: The experimental drug form showed high antitumor activity when administered intravenously once at doses of 100 and 120 mg/kg (TGI = 98–82% and TGI = 95–77%, respectively, ILS = 24%, p < 0.05) on melanoma B-16 mice. On LLC mice, the experimental drug form showed that the intravenous administration route was effective in the range of doses from 60 to 80 mg/kg with a 5 day administration regimen with an interval of 24 h. A dose of 70 mg/kg had maximum effect at the level of TGI = 96–77% (p < 0.05) with its retention for 20 days after the end of treatment. Conclusion: The studies have shown that the new compound LCS 1269 in the original drug form, has a pronounced antitumor activity and significantly reduces the volume of tumor mass both on melanoma B-16 and on LLC. It allows us to recommend continue the search for sensitivity of animal transplantable tumors to LCS 1269. 57 6 57 6

© 2021 Spandidos Publications. All rights reserved. Malignant melanomas within the eye present different types of metabolic and metastatic behavior. Uveal melanoma (UM) affects a quarter of a million individuals in the USA; however, the molecular pathogenesis is not well understood. Although UV radiation is a risk factor in cutaneous melanomas, it is not crucial for UM progression. Apart from chromosomal abnormalities, numerous major tumorigenic signaling pathways, including the PI3K/Akt, MAPK/ERK, Ras-association domain family 1 isoform A and Yes-associated protein/transcriptional co-activator with PDZ-binding motif signaling pathways, are associated with intraocular tumors. The present review describes the current insights regarding these signaling pathways that regulate the cell cycle and apoptosis, and could be used as potential targets for the treatment of UMs.

© 2020 Elsevier B.V. Brain metastases manifest the advanced stage of breast cancer disease with poor prognosis for patient survival. Recent reports demonstrate that some therapeutic agents can activate the expression of several breast cancer-associated genes, whose products are involved in the onset and development of brain metastases. In this study, we discovered a functional link between KISS1 and E-cadherin that could be observed in both primary brain metastatic lesions and paired cell lines, such as parental CN34TGL and MDA-MB-231 and their respective brain metastatic subclones CN34Brm2Ctgl and MDA-MB-231Br. Remarkably, expression of KISS1 and E-cadherin genes consistently showed an inverse correlation in all of the above cell/tissue types. While E-cadherin expression was strongly upregulated in metastatic clones isolated from blood and brain, the levels of this protein in parental MDA-MB-231 cell line was low. Furthermore, E-cadherin upregulation can be artificially induced in MDA-MB-231Br and CN34Brm2Ctgl cell populations by knocking down KISS1 expression directly or through overexpressing the miR345 mimic. In the aggregate, our data suggest that the tumor microenvironment, which controls breast cancer spreading via miR345-regulated KISS1 expression, might modulate metastatic spreading by a mechanism(s) involving upregulation of E-cadherin production.

© Springer Science+Business Media, LLC, part of Springer Nature 2020. We describe here the Oncobox method for scoring efficiencies of anticancer target drugs (ATDs) using high throughput gene expression data. The method rationale, design, and validation are given along with the examples of its practical applications in biomedicine. The method is based on the analysis of intracellular molecular pathways activation and measuring expressions of molecular target genes for every ATD under consideration. Using Oncobox method requires collection of normal (control) expression profiles and annotated databases of molecular pathways and drug target genes. Both microarray and RNA sequencing profiles are acceptable, although the latter type of data prevails in the most recent applications of this technique.

© 2019 Wiley Periodicals, Inc. Introduction: Sarcomas of the mandible are extremely rare tumors, with osteosarcoma being the most common, followed by Ewing's sarcoma. Materials and methods: A retrospective review of the clinical records, imaging studies, and pathology slides of patients with sarcoma of the mandible at a Tertiary Care Cancer Center from 1998 to 2014 was undertaken. The impact of neoadjuvant chemotherapy and postoperative radiotherapy with or without chemotherapy was studied, and factors impacting upon local control and disease-specific survival were analyzed. Results: Twenty-two patients were treated over the study period, comprising of 15 males and seven females. External swelling, intraoral growth, or facial numbness were the presenting symptoms. Eighteen patients had osteosarcoma and four had the Ewing's sarcoma. Nine patients received neoadjuvant chemotherapy. All but one patient underwent surgery. Eleven had negative margins, with 90% recurrence-free survival at 3 years, compared to 10 with positive or close margins, leading to 67% recurrence-free survival. None of the patients receiving neoadjuvant chemotherapy developed recurrence and all were alive at 3 years. The impact of postoperative radiotherapy or adjuvant chemotherapy was not statistically significant. Conclusions: Wide surgical resection with negative margins remains the hallmark of surgical treatment.

© 2018 by the authors. Licensee MDPI, Basel, Switzerland. Sequential courses of anticancer target therapy lead to selection of drug-resistant cells, which results in continuous decrease of clinical response. Here we present a new approach for predicting effective combinations of target drugs, which act in a synergistic manner. Synergistic combinations of drugs may prevent or postpone acquired resistance, thus increasing treatment efficiency. We cultured human ovarian carcinoma SKOV-3 and neuroblastoma NGP-127 cancer cell lines in the presence of Tyrosine Kinase Inhibitors (Pazopanib, Sorafenib, and Sunitinib) and Rapalogues (Temsirolimus and Everolimus) for four months and obtained cell lines demonstrating increased drug resistance. We investigated gene expression profiles of intact and resistant cells by microarrays and analyzed alterations in 378 cancer-related signaling pathways using the bioinformatical platform Oncobox. This revealed numerous pathways linked with development of drug resistant phenotypes. Our approach is based on targeting proteins involved in as many as possible signaling pathways upregulated in resistant cells. We tested 13 combinations of drugs and/or selective inhibitors predicted by Oncobox and 10 random combinations. Synergy scores for Oncobox predictions were significantly higher than for randomly selected drug combinations. Thus, the proposed approach significantly outperforms random selection of drugs and can be adopted to enhance discovery of new synergistic combinations of anticancer target drugs.

© 2018, © 2018 Taylor  &  Francis. A library of 29 2-amino-6-sulfanylpyridine-3,5-dicarbonitriles functionalized with a pyridoxine moiety was synthesized using a three-component one-pot reaction of aldehyde derivative of pyridoxine, malononitrile, and thiophenol. The obtained bipyridine structures were converted into methylpyridinium salts. Several compounds demonstrated expressed antibacterial activity with MICs (minimum inhibitory concentrations) in the range of 0.5–4 µg/mL against the three studied Gram-positive strains and 8–64 µg/mL against the Gram-negative E. coli strain, which was comparable or better than the activity of the reference antimicrobial agents. At the same time, all the synthesized compounds were inactive against the Gram-negative P. aeruginosa. Several compounds also demonstrated high cytotoxic activity against the studied tumor cells, but without selectivity for the normal HSF (human foreskin fibroblast) cells. Despite the preliminary character of the performed biological studies, the obtained results make the obtained structural chemotype a promising starting point for the design of physiologically active compounds.

© 2018 The Author(s). Introduction: Due to the beginning of the use of immunophenotypic and cytogenetic techniques, new nosological forms of lymphoproliferative diseases have appeared over the past few decades. According to the WHO classification (2008), today there are more than 50 known lymphoproliferative diseases. Case Presentation: We present the case of a 51-year-old man with lymphoproliferative syndrome. Our patient underwent morphological and immunohistochemical investigations of biopsy materials from the right inguinal lymph node. The morphological picture was characteristic for small cell lymphoma. Immunophenotypically, tumor proliferate cells expressed CD20, CD76b, CD5, and cyclin D, and the tumor immunophenotype matched mantle cell lymphoma. Discussion: At the present stage of the development of medicine, the diagnosis of lymphoproliferative diseases is based on the clinical picture of the disease with the definition of localization and characteristics of the tumor process, morphological study of tumor tissue and cells, and immunophenotypic and/or cytogenetic analyses are mandatory to determine the final diagnosis.

© 2018 Vitebsk State Medical University. All rights reserved. Primary-multifocal malignant tumors hold a specific place in oncology. Present case report describes the combination of two neoplastic processes with different anatomic localization, the analogues to which have not been found either in the domestic literature or foreign sources. The article presents the case of a synchronous primary-multiple malignant neoplasm - malignant tumor from the membranes of the peripheral nerves of the nasal cavity with expansion into the right maxillary sinus, the cells of the ethmoidal sinus т2bN0M0 and moderately differentiated adenocarcinoma of the sigmoid colon т4аN0M0. Physical examination and positron emission tomography combined with the computed tomography confirmed a hypervascular tumor of the posterior cells of the ethmoidal sinus and a nasal cavity without hypermetabolism and the circular tumor of the sigmoid colon with hypermetabolism. Taking into account the primary-multiple character of the lesion and the clinic of intestinal obstruction, a tactic of the treatment was a combined surgery - the removal of the neoplasm of the nasal cavity with resection of the right maxillary sinus with microsurgical technique and a reconstructive-plastic component using a coronary access, laparotomy, resection of the sigmoid colon, lymphadenectomy. The chosen treatment allowed eliminating both of the tumors in a short time and moving on to a further stage of treatment. The patient is under the supervision, there is no recurrence of the disease at the moment.

© 2018 Kapeleris, Kulasinghe, Warkiani, Vela, Kenny, O'Byrne and Punyadeera. Lung cancer affects over 1. 8 million people worldwide and is the leading cause of cancer related mortality globally. Currently, diagnosis of lung cancer involves a combination of imaging and invasive biopsies to confirm histopathology. Non-invasive diagnostic techniques under investigation include "liquid biopsies" through a simple blood draw to develop predictive and prognostic biomarkers. A better understanding of circulating tumor cell (CTC) dissemination mechanisms offers promising potential for the development of techniques to assist in the diagnosis of lung cancer. Enumeration and characterization of CTCs has the potential to act as a prognostic biomarker and to identify novel drug targets for a precision medicine approach to lung cancer care. This review will focus on the current status of CTCs and their potential diagnostic and prognostic utility in this setting.

© 2018 IEEE. We demonstrate a wavelet-domain denoising technique for imaging of human brain malignant tissues by optical coherence tomography. It allows for reducing the scattering noise and retaining signal artifacts for each tissue type, including malignant glioma and meningioma.

© 2018 IEEE. In our work, we have performed in vitro terahertz (THz) measurements of gelatin-embedded malignant human brain gliomas using the THz pulsed spectroscopy. The gelatin embedding yields sustain the THz response of tissues close to that of the freshly-excised ones for a long time after the resection. We have observed significant differences between the THz responses of normal and pathological tissues of the brain, which highlights a potential of the THz technology in label-free intraoperative neurodiagnosis of tumors.

© 2018 IEEE. Modern progress in terahertz (THz) diagnostics of malignancies, including non-invasive, least-invasive and intraoperative techniques is briefly discussed. Special attention is paid to intraoperative diagnosis of brain tumors, which is a rapidly developing field nowadays. We discuss our recent results in this research field, which are associated with (i) in vitro studies the THz dielectric response of gelatin-embedded human brain tumors (including gliomas and meningiomas featuring different grades), (ii) analysis an ability for differentiation between normal and pathological tissues of the brain relying on the methods of THz spectroscopy and imaging, and, finally, (iii) development of novel THz instrumentation for the intraoperative detection of margins of tumors in order to guarantee its gross total resection.

© 2018 Elsevier B.V. Over the last decade, autophagy has emerged as one of the critical cellular systems that control homeostasis. Besides management of normal homeostatic processes, autophagy can also be induced by tissue damage stress or by rapidly progressing tumors. During tumor progression, autophagy mediates a cellular reaction to the changes inside and outside of cells, which leads to tumor adaptation. Even though the regulation of autophagy seems universal and is a well-described process, its dysregulation and role in glioma progression remain an important topic of investigation. In this review, we summarize recent evidence of autophagy regulation in brain tumor tissues and possible interconnection between signaling pathways that govern cellular responses. This perspective may help to assess the qualitative differences and various outcomes in response to autophagy stimulation.