Репозиторий Университета

© 2020, LLC Science and Innovations. Pancreatic cancer (PC) is one of the most fatal types of oncological disease in the world and is an extremely aggressive cancer with a poor prognosis. The objective of this review was to analyze the domestic data of the incidence of PC in the Russian Federation and to analyze the protocols that are used for the management of this group of patients in Russian clinical centers. For the analysis of the literature sources, the data in the elibrary.ru database published in the period from 2015 to 2019 were used. The methodology that was used in each study was examined in order to ensure its reliability, and these data were selected as potential sources of evidence for the preparation of national recommendations. The study results influence the level of evidence assigned to the publication. Updates to the national recommendations are conducted at least once every three years, and these updates depend on new information about the diagnosis and management of patients with PC.

© 2020, LLC Science and Innovations. Pancreatic cancer (PC) is one of the most fatal types of oncological disease in the world and is an extremely aggressive cancer with a poor prognosis. The objective of this review was to analyze the domestic data of the incidence of PC in the Russian Federation and to analyze the protocols that are used for the management of this group of patients in Russian clinical centers. For the analysis of the literature sources, the data in the elibrary.ru database published in the period from 2015 to 2019 were used. The methodology that was used in each study was examined in order to ensure its reliability, and these data were selected as potential sources of evidence for the preparation of national recommendations. The study results influence the level of evidence assigned to the publication. Updates to the national recommendations are conducted at least once every three years, and these updates depend on new information about the diagnosis and management of patients with PC.

Recently, mesenchymal stem/stromal cells (MSCs) and their widespread biomedical applications have attracted great consideration from the scientific community around the world. However, reports have shown that the main populations of the transplanted MSCs are trapped in the liver, spleen, and lung upon administration, highlighting the importance of the development of cell-free therapies. Concerning rising evidence suggesting that the beneficial effects of MSC therapy are closely linked to MSC-released components, predominantly MSC-derived exosomes, the development of an MSC-based cell-free approach is of paramount importance. The exosomes are nano-sized (30–100 nm) lipid bilayer membrane vesicles, which are typically released by MSCs and are found in different body fluids. They include various bioactive molecules, such as messenger RNA (mRNA), microRNAs, proteins, and bioactive lipids, thus showing pronounced therapeutic competence for tissues recovery through the maintenance of their endogenous stem cells, the enhancement of regenerative phenotypic traits, inhibition of apoptosis concomitant with immune modulation, and stimulation of the angiogenesis. Conversely, the specific roles of MSC exosomes in the treatment of various tumors remain challenging. The development and clinical application of novel MSC-based cell-free strategies can be supported by better understanding their mechanisms, classifying the subpopulation of exosomes, enhancing the conditions of cell culture and isolation, and increasing the production of exosomes along with engineering exosomes to deliver drugs and therapeutic molecules to the target sites. In the current review, we deliver a brief overview of MSC-derived exosome biogenesis, composition, and isolation methods and discuss recent investigation regarding the therapeutic potential of MSC exosomes in regenerative medicine accompanied by their double-edged sword role in cancer.

© 2020 The Author(s) Patients with cancer undergoing chemotherapy are at risk of thrombocytopenia. The co-incidence of cancer-associated venous thromboembolism (VTE) and thrombocytopenia is a frequent complication in patients with cancer. Especially in certain tumour entities at high VTE risk, chemotherapeutic agents with myelosuppressive effects are part of the standard of care. The management of cancer-associated VTE in the setting of chemotherapy-induced thrombocytopenia is challenging, in the absence of evidence from high-quality studies. Thrombocytopenia is associated with both increased risk of recurrent VTE and risk of bleeding during anticoagulation. In this case-based concise review, we aimed at summarizing available literature and expert consensus guidance on the treatment of cancer-associated VTE in patients with chemotherapy-induced thrombocytopenia.

© 2020 Immunotherapy methods using potential tumor microenvironment modulators have elicited durable therapeutic responses in cancer treatment. Immune checkpoint molecule programmed cell death-ligand 1 (PD-L1) and oncogenic transcription factor STAT3 (signal transducer and activator of transcription-3) assigned as inhibitory targets of our study and particular delivery system designed to deliver small interfering RNAs (siRNAs) to silence the targeted genes. Generated trimethyl chitosan (TMC) and thiolated chitosan (TC) nanoparticles (NPs) conjugated with HIV-1-derived TAT peptide and HA (hyaluronic acid) exhibited eligible physicochemical characteristics, notable siRNA encapsulation, serum stability, non-toxicity, controlled siRNA release, and extensive cellular uptake by cancer cells. Dual inhibition with STAT3/PD-L1 siRNA-loaded HA-TAT-TMC-TC NPs led to promising results, including significant downregulation of PD-L1 and STAT3 genes, striking suppressive effects on proliferation, migration, and angiogenesis of breast and melanoma cancer cell lines, and restrained tumor growth in vivo. These findings infer the capability of HA-TAT-TMC-TC NPs containing STAT3/PD-L1 siRNAs as a novel tumor-suppressive candidate in cancer treatment.

© 2020 The Authors. International Journal of Cancer published by John Wiley  &  Sons Ltd on behalf of Union for International Cancer Control. Androgen deprivation therapy (ADT) remains a key approach in the treatment of prostate cancer (PCa). However, PCa inevitably relapses and becomes ADT resistant. Besides androgens, there is evidence that thyroid hormone thyroxine (T4) and its active form 3,5,3′-triiodo-L-thyronine (T3) are involved in the progression of PCa. Epidemiologic evidences show a higher incidence of PCa in men with elevated thyroid hormone levels. The thyroid hormone binding protein μ-Crystallin (CRYM) mediates intracellular thyroid hormone action by sequestering T3 and blocks its binding to cognate receptors (TRα/TRβ) in target tissues. We show in our study that low CRYM expression levels in PCa patients are associated with early biochemical recurrence and poor prognosis. Moreover, we found a disease stage-specific expression of CRYM in PCa. CRYM counteracted thyroid and androgen signaling and blocked intracellular choline uptake. CRYM inversely correlated with [18F]fluoromethylcholine (FMC) levels in positron emission tomography/magnetic resonance imaging of PCa patients. Our data suggest CRYM as a novel antagonist of T3- and androgen-mediated signaling in PCa. The role of CRYM could therefore be an essential control mechanism for the prevention of aggressive PCa growth.

© 2020 The Authors. International Journal of Cancer published by John Wiley  &  Sons Ltd on behalf of Union for International Cancer Control. Androgen deprivation therapy (ADT) remains a key approach in the treatment of prostate cancer (PCa). However, PCa inevitably relapses and becomes ADT resistant. Besides androgens, there is evidence that thyroid hormone thyroxine (T4) and its active form 3,5,3′-triiodo-L-thyronine (T3) are involved in the progression of PCa. Epidemiologic evidences show a higher incidence of PCa in men with elevated thyroid hormone levels. The thyroid hormone binding protein μ-Crystallin (CRYM) mediates intracellular thyroid hormone action by sequestering T3 and blocks its binding to cognate receptors (TRα/TRβ) in target tissues. We show in our study that low CRYM expression levels in PCa patients are associated with early biochemical recurrence and poor prognosis. Moreover, we found a disease stage-specific expression of CRYM in PCa. CRYM counteracted thyroid and androgen signaling and blocked intracellular choline uptake. CRYM inversely correlated with [18F]fluoromethylcholine (FMC) levels in positron emission tomography/magnetic resonance imaging of PCa patients. Our data suggest CRYM as a novel antagonist of T3- and androgen-mediated signaling in PCa. The role of CRYM could therefore be an essential control mechanism for the prevention of aggressive PCa growth.

© 2020 Elsevier B.V. Bioactive compounds from endophytic fungi exhibit diverse biological activities which include anticancer effect. Capitalising on the abundance of unexplored endophytes that reside within marine plants, this study assessed the anticancer potential of ethyl acetate endophytic fungal extracts (i.e. MBFT Tip 2.1, MBL 1.2, MBS 3.2, MKS 3 and MKS 3.1) derived from leaves, stem and fruits of marine plants that grow along Morib Beach, Malaysia. For identification of endophytic fungi, EF 4/ EF 3 and ITS 1/ ITS 4 PCR primer pairs were used to amplify the fungal 18S rDNA sequence and ITS region sequence, respectively. The resultant sequences were subjected to similarity search via the NCBI GenBank database. High-performance thin layer chromatography (HPTLC) hyphenated with bioassays was used to characterise the extracts in terms of their phytochemical profiles and bioactivity. Microchemical derivatisation was used to assess polyphenolic and phytosterol/ terpenoid content whereas biochemical derivatisation was used to establish antioxidant activities and α-amylase enzyme inhibition. The sulforhodamine B (SRB) assay was used to assess the anticancer effect of the extracts against HCT116 (a human colorectal cancer cell line). The present results indicated MBS 3.2 (Penicillium decumbens) as the most potent extract against HCT116 (IC50 = 0.16 μg/mL), approximately 3-times more potent than 5-flurouracil (IC50 = 0.46 μg/mL). Stepwise multiple regression method suggests that the anticancer effect of MBS 3.2 could be associated with high polyphenolic content and antioxidant potential. Nonlinear regression analysis confirmed that low to moderate α-amylase inhibition exhibits maximum anticancer activity. Current findings warrant further in-depth mechanistic studies.

© 2020, Springer Science+Business Media, LLC, part of Springer Nature. Label-free characterization of cell subpopulations is a very promising biomedical approach. Nowadays, there are several label-free methods based on different physical properties such as size, density, stiffness, etc. allowing the characterization of biological objects. However, fluorescence properties are the most suitable feature for the label-free study of tissue and cells. Understanding the autofluorescence level peculiarities of normal and pathological / live and dead cells can become a helpful tool for cells’ metabolic activity, viability evaluation, and diagnostics of a number of diseases. In this study, we applied a series of mouse cell lines (RAW 264.7 - macrophages, L929 - fibroblasts, C2C12 – myoblasts, and B16-F10 – melanoma) to compare cell autofluorescence of live and dead cells under 488 nm laser excitation and found the difference between their autofluorescence depending on a cell state and type.

© 2020 Elsevier Inc. Peroxidase nanoenzymes exhibit a specific affinity toward substrates, thereby demonstrating application potential for realizing the colorimetric immunoassays of hydrogen peroxide (H2O2), which can be further used as a probe for imaging cancer cells. To enhance the intrinsic peroxidase activity of molybdenum sulfide (MoS2) nanomaterials, gold (Au) nanoparticles with an average diameter of approximately 2.1 nm were modified on a MoS2/carbon surface (denoted as MoS2/C-Au600) via ascorbic acid reduction. MoS2/C-Au600 can oxidize 3,3′,5,5′-tetramethylbenzidine (TMB) to generate a blue oxidation product in the presence of H2O2; this product exhibits peroxidase-like activities, superior to those of most existing MoS2-based nanoenzymes. Furthermore, MoS2/C-Au600 exhibits a high detection capability for H2O2 in the range of 1 × 10−5 to 2 × 10−4 mol/L (R2 = 0.99), and the lowest detection limit is 1.82 µmol/L in a sodium acetate and acetic acid buffer solution. Steady state kinetics studies indicate that the catalytic mechanism is consistent with the ping-pong mechanism. Given its strong absorption peak at 652 nm in the visible region, MoS2/C-Au600 can be used to image cancer cells due to the enhanced permeability and retention effect. Our findings demonstrate that the synergistic electronic coupling between multiple components can enhance the peroxidase activity, which can facilitate the development of an effective, facile, and reliable method to perform colorimetric immunoassays of H2O2 and cancer cells.

© 2020 Epithelial-to-mesenchymal transition (EMT) is an essential molecular and cellular process that is part of normal embryogenesis and wound healing, and also has a ubiquitous role in various types of carcinoma and glioblastoma. EMT is activated and regulated by specific microenvironmental endogenous triggers and a complex network of signalling pathways. These mostly include epigenetic events that affect protein translation-controlling factors and proteases, altogether orchestrated by the switching on and off of oncogenes and tumour-suppressor genes in cancer cells. The hallmark of cancer-linked EMT is that the process is incomplete, as it is opposed by the reverse process of mesenchymal-to-epithelial transition, which results in a hybrid epithelial/mesenchymal phenotype that shows notable cell plasticity. This is a characteristic of cancer stem cells (CSCs), and it is of the utmost importance in their niche microenvironment, where it governs CSC migratory and invasive properties, thereby creating metastatic CSCs. These cells have high resistance to therapeutic treatments, in particular in glioblastoma.

© 2020 Elsevier Ltd Background: A beneficial impact of robotic proctectomy on circumferential resection margin (CRM) is expected due to the robot's articulating instruments in the pelvis. There are however concerns about a negative impact on the quality of total mesorectal excision (TME) due to the lack of tactile feedback. The aim of this study was to assess whether surgeons' learning curve impacted CRM and TME quality. Methods: In a multicenter study, individual patient data of robotic proctectomy for resectable rectal cancer were pooled. Patients were stratified into two phases of surgeons’ learning curve. Cumulative sum (CUSUM) analysis was used to determine the transition from learning phase (LP) to plateau phase (PP), which were compared. CRM was microscopically measured in mm by pathologists. TME quality was classified by pathologists as complete, nearly complete or incomplete. T-test and Chi-squared tests were used to compare continuous and categorical variables, respectively. Results: 235 patients underwent robotic proctectomy by five surgeons. 83 LP patients were comparable to 152 PP patients for age (p = 0.20), gender (67.5% vs. 65.1% males; p = 0.72), BMI (p = 0.82), cancer stage (p = 0.36), neoadjuvant chemoradiation (p = 0.13), distance of tumor from anal verge (5.8 ± 4.4 vs. 5.5 ± 3.3; p = 0.56). CRM did not differ (7.7 ± 11.4 mm vs. 8.4 ± 10.3 mm; p = 0.62). The rate of complete TME quality was significantly improved in PP patients as compared to LP patients (73.5% vs. 92.1%; p < 0.001). Conclusion: While learning had no impact on circumferential resection margins, the quality of TME significantly improved during surgeons’ plateau phase as compared to their learning phase.

© 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.

© 2020 Elsevier B.V. Cancer cells continuously secrete inflammatory biomolecules which play significant roles in disease progression and tumor metastasis toward secondary sites. Despite recent efforts to capture cancer cells' intercellular secretion heterogeneity using microfluidics, the challenges in operation of these systems as well as the complexity of designing a biosensing assay for long-term and real-time measurement of single cell secretions have become grand research barriers. Here, we present a new capillary-based microfluidic biosensing approach to easily and reliably capture ~500 single cells inside isolated dead-end nanoliter compartments using simple pipette injection, and quantify their individual secretion dynamics at the single cell resolution over a long period of culture (~16 h). We first present a detailed investigation of the fluid mechanics underlying the formation of nanoliter compartments in the microfluidic system. Based on the measurement of single cell capture efficiency, we employ a one-step FRET-based biosensor which monitors the single cancer cells' protease activity. The sensor reports the fluorescent signal as a product of amino acid chain cleavage and reduction in its quenching capability. Using the single cell protease secretion data, we identified modes of cell secretion dynamics in our cell sample. While most of the cells had low secretion levels, two other smaller and more aggressive secretion dynamics were cells with secretion modes that include sharp spikes or slow but progressive trend. The method presented here overcomes the difficulties associated with performing single cell secretion assays, enabling a feasible and reliable technique for high throughput measurement of metabolic activities in cancer cells.

© 2020 Elsevier B.V. Cancer cells continuously secrete inflammatory biomolecules which play significant roles in disease progression and tumor metastasis toward secondary sites. Despite recent efforts to capture cancer cells' intercellular secretion heterogeneity using microfluidics, the challenges in operation of these systems as well as the complexity of designing a biosensing assay for long-term and real-time measurement of single cell secretions have become grand research barriers. Here, we present a new capillary-based microfluidic biosensing approach to easily and reliably capture ~500 single cells inside isolated dead-end nanoliter compartments using simple pipette injection, and quantify their individual secretion dynamics at the single cell resolution over a long period of culture (~16 h). We first present a detailed investigation of the fluid mechanics underlying the formation of nanoliter compartments in the microfluidic system. Based on the measurement of single cell capture efficiency, we employ a one-step FRET-based biosensor which monitors the single cancer cells' protease activity. The sensor reports the fluorescent signal as a product of amino acid chain cleavage and reduction in its quenching capability. Using the single cell protease secretion data, we identified modes of cell secretion dynamics in our cell sample. While most of the cells had low secretion levels, two other smaller and more aggressive secretion dynamics were cells with secretion modes that include sharp spikes or slow but progressive trend. The method presented here overcomes the difficulties associated with performing single cell secretion assays, enabling a feasible and reliable technique for high throughput measurement of metabolic activities in cancer cells.

© 2020 The Authors Background: Haemostatic activation and hypercoagulability are frequently observed in patients with metastatic colorectal cancer (mCRC), increase risk of venous thromboembolism (VTE) and have been implicated in tumour proliferation and progression. To date, the association of haemostatic biomarkers with oncologic outcomes including overall survival (OS), progression free survival (PFS) and disease control rate (DCR) is incompletely understood. Methods: Within the framework of the Vienna Cancer and Thrombosis Study, a prospective observational cohort study, we conducted an exploratory analysis to investigate the association of six known biomarkers of haemostasis with oncologic outcomes in 99 patients with mCRC prior to chemotherapy initiation. Results: Patients with high levels of factor VIII activity (FVIII), D-dimer, prothrombin fragment 1 + 2 (F1 + 2) and fibrinogen (defined as levels >75th percentile) had significantly shorter median OS than patients with lower levels. Elevation of four biomarkers was associated with mortality in multivariable analysis, adjusting for age, sex, number of metastatic sites and VTE (hazard ratio [95% CI] for death per doubling of levels: FVIII: 2.06 [1.28–3.30]; sP-selectin: 1.55 [1.07–2.24]; D-dimer: 1.40 [1.18–1.65]; F1 + 2: 1.64 [1.10–2.46]). Patients with elevated levels had numerically shorter median PFS across all markers and disease control rate (DCR) was significantly smaller in those with high levels of FVIII and F1 + 2 (adjusted odds ratio [95% CI] for DCR per doubling of levels: 0.23 [0.09–0.62] and 0.36 [0.16–0.82]) compared to patients with lower levels. Conclusion: Specific elevated haemostatic biomarkers are associated with higher mortality and partially with worse response to chemotherapy in patients with mCRC.

© 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.

© Springer Science+Business Media, LLC, part of Springer Nature 2020. Intracellular molecular pathways (IMPs) control all major events in the living cell. IMPs are considered hotspots in biomedical sciences and thousands of IMPs have been discovered for humans and model organisms. Knowledge of IMPs activation is essential for understanding biological functions and differences between the biological objects at the molecular level. Here we describe the Oncobox system for accurate quantitative scoring activities of up to several thousand molecular pathways based on high throughput molecular data. Although initially designed for gene expression and mainly RNA sequencing data, Oncobox is now also applicable for quantitative proteomics, microRNA and transcription factor binding sites mapping data. The Oncobox system includes modules of gene expression data harmonization, aggregation and comparison and a recursive algorithm for automatic annotation of molecular pathways. The universal rationale of Oncobox enables scoring of signaling, metabolic, cytoskeleton, immunity, DNA repair, and other pathways in a multitude of biological objects. The Oncobox system can be helpful to all those working in the fields of genetics, biochemistry, interactomics, and big data analytics in molecular biomedicine.

© Springer Science+Business Media, LLC, part of Springer Nature 2020. DNA mutations govern cancer development. Cancer mutation profiles vary dramatically among the individuals. In some cases, they may serve as the predictors of disease progression and response to therapies. However, the biomarker potential of cancer mutations can be dramatically (several orders of magnitude) enhanced by applying molecular pathway-based approach. We developed Oncobox system for calculation of pathway instability (PI) values for the molecular pathways that are aggregated mutation frequencies of the pathway members normalized on gene lengths and on number of genes in the pathway. PI scores can be effective biomarkers in different types of comparisons, for example, as the cancer type biomarkers and as the predictors of tumor response to target therapies. The latter option is implemented using mutation drug score (MDS) values, which algorithmically rank the drugs capacity of interfering with the mutated molecular pathways. Here, describe the mathematical basis and algorithms for PI and MDS values calculation, validation and implementation. The example analysis is provided encompassing 5956 human tumor mutation profiles of 15 cancer types from The Cancer Genome Atlas (TCGA) project, that totally make 2,316,670 mutations in 19,872 genes and 1748 molecular pathways, thus enabling ranking of 128 clinically approved target drugs. Our results evidence that the Oncobox PI and MDS approaches are highly useful for basic and applied aspects of molecular oncology and pharmacology research.

© 2019 Elsevier Inc. Hyponatremia has been associated with an increased risk of demise in several malignancies. The aim of the current study was to evaluate its prognostic value in patients with castration-resistant prostate cancer. In 186 patients planned for docetaxel chemotherapy, we detected an association between hyponatremia and decreased survival (P = .04). We suggest conducting further well-designed studies including full workup of hyponatremia.