| 1. |
- Bryukhovetskiy, Igor, et al.
(författare)
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Personalized therapy and stem cell transplantation for pro-inflammatory modulation of cancer stem cells microenvironment in glioblastoma : Review
- 2020
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Ingår i: NOVEL THERAPEUTIC ADVANCES IN GLIOBLASTOMA. - LONDON ENGLAND : Elsevier. - 9780128211144 ; , s. 67-98
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Bokkapitel (refereegranskat)abstract
- Glioblastoma multiforme (GBM) is one of the most aggressive types of brain tumor in humans. The prognosis for patients with GBM is unfavorable and treatment is largely ineffective, where modern treatment regimens typically increase survival by 15 months. GBM relapse and progression are associated with cancer stem cells (CSCs). The present review provides a critical analysis of the primary reasons underlying the lack of effectiveness of modern CSC management methods. An emphasis is placed on the role of the blood-brain barrier in the development of treatment resistance. The existing methods for increasing the efficiency of antitumor genotoxic therapy are also described, and a strategy for personalized regulation of CSC based on post-genome technologies is suggested. The hypothesis that GBM cells employ a special mechanism for DNA repair based on their interactions with normal stem cells, is presented and the function of the tumor microenvironment in fulfilling the antitumor potential of normal stem cells is explained. Additionally, the mechanisms by which cancer stem cells regulate glioblastoma progression and recurrence are described based on novel biomedical technologies.
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| 2. |
- Bryukhovetskiy, Igor, et al.
(författare)
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Transforming growth factor-beta mimics the key proteome properties of CD133- differentiated and CD133+ cancer stem cells in glioblastoma
- 2020
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Ingår i: Novel therapeutic advances in glioblastoma. - : Elsevier BV. - 9780128211144 ; , s. 219-242
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Bokkapitel (refereegranskat)abstract
- Glioblastoma multiforme is the most aggressive type of primary brain tumor in humans. Its invasive growth is associated with cluster of differentiation (CD)133 cancer stem cells (CSCs) and CD133(-) differentiated glioblastoma cells (DGCs) with aggressive phenotype, which are developed under the influence of transforming growth factor (TGF)-beta. The present study aimed to compare the proteomes of CD133 CSCs and CD133(-) DGCs stimulated by TGF-beta, as well as the expression levels of the main proteins responsible for activating the signaling pathway of receptor interactions with the extracellular matrix (ECM). The U87MG GBM cell line was used in this study. CSCs were extracted from gliomaspheres through magnetic-activated cell sorting based on the expression of CD133 (CD133); CD133(-) DCGs served as a control. CD133(-) DGCs of the U87-MG cell line were treated with 10ng/mL TGF-beta 1, and cell proliferation and migration were analyzed via real-time quantitative microscopy. High-performance liquid chromatography mass spectrometry was used for proteome analysis. The results revealed 589 proteins with significantly changes in expression among CD133 CSCs compared with those in CD133(-) DGCs (P < 0.05). Bioinformatics analysis allowed to attribute 134 differentially expressed proteins to 15 signaling pathways; among these proteins, 14 were involved in signaling cascades associated with the interaction between CSCs and the ECM, and were upregulated > twofold, while four proteins activated this signaling cascade. TGF-beta-stimulation increased the mobility, suppressed the proliferation and transformed the proteome profile of CD133(-) DGCs. Were identified 13 key proteins that activate the signaling pathway of receptor interaction with the ECM and three proteins activating this signaling pathway in CD133(-) DGCs which had the same values as those of CD133 CSCs. In conclusion, TGF-beta increased the expression of proteins that activate the signaling pathway of receptor interaction with the ECM in CD133(-) DGCs to the level of those in CD133 CSCs.
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| 3. |
- Lyakhova, Irina, et al.
(författare)
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3-Bromofascaplysin is a prospective chemical compound for developing new chemotherapy agents in glioblastoma treatment
- 2020
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Ingår i: Novel therapeutic advances in glioblastoma. - : Elsevier BV. - 9780128211144 ; , s. 325-343
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Bokkapitel (refereegranskat)abstract
- Glioblastoma (GB) is one of the most aggressive human brain tumors. The prognosis is unfavorable, its treatment is relatively ineffective, and the median survival is about 15months. Medication development with new chemical compounds is one of the ways to solve the problem of current treatment inefficiency. This study is focused on the group of chemical substances, based on pentacyclic system of 12H-pyrido[1,2-a:3,4-b] diindole, and the most well-known part of this group is fascaplysin, first extracted from the sponge Fascaplysinopsis spp. We have synthesized a series of the following fascaplysin derivatives: 7-phenylfascaplysin, 3-chlorofascaplysin, 3-bromofascaplysin, 9-bromofascaplysin. The paper is aimed at analyzing the cytotoxic effect of these compounds on GB cells. Materials and methods. The study used rat glioma C6 cell line (ATCC (R); cat no CCL-107), U-87MG cell line (ATCC; cat no. HTB-14T) and human glioblastoma T98-G cells (ATCC (R) CRL-1690T). Cell culture method, experimental pharmacological trials and.-radiation in vitro, as well as flow cytofluorometry were used in the study. Results: Cytotoxic effect of the tested compounds is stronger than the effect of unsubstituted fascaplysin, and appears to be dose-dependent and time-dependent. 3-bromofascaplysin is more efficient for cancer cells elimination, and by the end of the experiment the amount of living cancer cells in G(0) phase remained at its lowest. Cytotoxic effect of 3-bromofascaplysin on glioblastoma T98-G cells is inferior to that of TMZ, and in case of preliminary radiation treatment of cancer cells with 48Gy the effect of the compound matches the TMZ treatment results. Conclusion: 3-Bromofascaplysin is a prospective chemical compound for development of new anti-cancer chemotherapeutic agents.
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| 4. |
- Lyakhova, Irina, et al.
(författare)
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Alkaloids of fascaplysin are promising chemotherapeutic agents for the treatment of glioblastoma : Review
- 2020
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Ingår i: NOVEL THERAPEUTIC ADVANCES IN GLIOBLASTOMA. - LONDON ENGLAND : Elsevier. - 9780128211144 ; , s. 299-324
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Bokkapitel (refereegranskat)abstract
- Glioblastoma is one of the most aggressive human brain tumors. Even following all the modern protocols of complex treatment, the median patient survival typically does not exceed 15 months. This review analyzes the main reasons for glioblastoma resistance to therapy, as well as attempts at categorizing the main approaches to increasing chemotherapy efficiency. Special emphasis is placed on the specific group of compounds, known as marine alkaloids and their synthetic derivatives exerting a general antitumor effect on glioblastoma cells. The unique mechanisms of marine alkaloid influence on the tumor cells prompt considering them as a promising basis for creating new chemotherapeutic agents for glioblastoma treatment.
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| 5. |
- Sharma, Hari Shanker, et al.
(författare)
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Pathophysiology of blood-brain barrier in brain tumor. : Novel therapeutic advances using nanomedicine
- 2020
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Ingår i: Novel Therapeutic Advances In Glioblastoma. - LONDON ENGLAND : Elsevier. - 9780128211144 ; , s. 1-66
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Bokkapitel (refereegranskat)abstract
- Glioblastoma Multiforme (GBM) is one the most common intracranial tumors discovered by Burns (1800) and Abernethy (1804) based on gross morphology of the autopsied material and referred to as "medullary sarcoma" and later "fungus medullare" (Abernethy, 1804; Burns, 1800). Virchow in 1863 was the first German pathologist using histomorphological techniques discovered that GBM is a tumor of glial origin. Virchow (1863/65) also then used the term Glioma for the first time and classified as low-grade glioma and high-grade glioma very similar to that of today according to World health organization (WHO) classification (Jellinger, 1978; Virchow, 1863/65). After almost >50 years of this discovery, Baily and Cushing (1926) based on modern neuropathological tools provide the classification of gliomas that is still valid today (Baily & Cushing, 1926). Although, our knowledge about development of gliomas has advanced through development of modern cellular and molecular biological tools (Gately, McLachlan, Dowling, & Philip, 2017; Omuro & DeAngelis, 2013), therapeutic advancement of GBM still requires lot of efforts for the benefit of patients. This review summarizes new developments on pathophysiological aspects of GBM and novel therapeutic strategies to enhance quality of life of patients. These novel therapeutic approaches rely on enhanced penetration of drug therapy into the tumor tissues by use of nanomedicine for both the diagnostic and therapeutic purposes, referred to as "theranostic nanomedicine" (Alphandery, 2020; Zhao, van Straten, Broekman, Preat, & Schiffelers, 2020). Although, the blood-brain barrier (BBB) is fenestrated around the periphery of the tumor tissues, the BBB is still tight within the deeper tissues of the tumor. Thus, drug delivery is a challenge for gliomas and requires new therapeutic advances (Zhao et al., 2020). Associated edema development around tumor tissues is another factor hindering therapeutic effects (Liu, Mei, & Lin, 2013). These factors are discussed in details using novel therapeutic advances in gliomas.
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| 6. |
- Shevchenko, Valeriy, et al.
(författare)
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Molecular determinants of the interaction between glioblastoma CD133(+) cancer stem cells and the extracellular matrix
- 2020
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Ingår i: NOVEL THERAPEUTIC ADVANCES IN GLIOBLASTOMA. - LONDON ENGLAND : Elsevier. - 9780128211144 ; , s. 155-169
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Bokkapitel (refereegranskat)abstract
- Glioblastoma multiforme (GBM) is the most common primary tumor of the human brain. It is characterized by invasive growth and strong resistance to treatment, and the median survival time of patients is 15 months. The invasive growth of this tumor type is associated with tumor cells with an aggressive phenotype, while its treatment resistance is attributed to cancer stem cells (CSCs). It remains unclear if CSCs have a more invasive nature than differentiated glioblastoma cells (DGCs), and what contribution CSCs make to the aggressive phenotype of GBM. Interaction with the extracellular matrix (ECM) is a key factor in the development of invasion. The aim of the present study was to compare the expression levels of signaling pathway proteins involved in interaction of receptors with the ECM in CSCs and DGCs. The U-87MG GBM cell line was used in the present study CSCs were extracted from gliomaspheres through magnetic-activated cell sorting based on the expression of cluster of differentiation 133 (CD133); CD133-negative DCGs were used as a control. HPLC and mass spectrometry were also used, and biological and molecular functions, signaling pathways and protein-protein interactions were analyzed using publicly available databases. Increased expression levels of the following 10 proteins involved in interaction with the ECM were identified in CSCs, compared with expression levels in DGCs: COL6A1, COL6A3, FN1, ITGA2, ITGA5, ITGAV, ITGB1, ITGB3, LAMB1 and LAMC1. The proteome of CSCs was observed to have >2-fold higher expression of these key proteins, when compared with the DGC proteome. Increased expression levels of four proteins (FERMT2, LOXL2, HDAC2 and FBN1) involved in activating signaling in response to receptor interaction with the ECM was also observed, indicating that CSCs may have highly invasive nature. LOXL2 expression level was >9-fold higher in CSCs compared to DGCs, suggesting that this protein may have potential as an marker for CSCs and as a target for this cell type in GBM.
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| 7. |
- Shevchenko, Valeriy, et al.
(författare)
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Proteins of Wnt signaling pathway in cancer stem cells of human glioblastoma
- 2020
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Ingår i: NOVEL THERAPEUTIC ADVANCES IN GLIOBLASTOMA. - LONDON ENGLAND : Elsevier. - 9780128211144 ; , s. 185-200
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Bokkapitel (refereegranskat)abstract
- Rationale: Glioblastoma multiforme (GBM) is the most aggressive primary glial brain tumor. The prognosis for GBM patients is not favorable, with the median survival time being 15 months. Its treatment resistance is associated with GBM cell population having cancer stem cells (CSCs). Wnt/beta-catenin signaling pathway is a strategically important molecular mechanism, providing proliferation of stem cells of all types. This study compares the expression levels of signaling pathway proteins in CD133(+) CSCs and CD133 (-) differentiated glioblastoma cells (DGCs). Materials and methods: the present study used U-87MG cells of human glioblastoma, the material was tested for mycoplasma contamination. High-performance liquid chromatography (HPLC) mass spectrometry was used for proteome analysis. Biological and molecular functions, signaling pathways and protein-protein interactions were analyzed using free-access databases: PubMed, PANTHER, Gene Ontology, Swiss-Prot and KEGG. Protein-protein interactions (PPIs) were analyzed using the STRING database (version 10). Results: There were identified 589 proteins with significantly changed expression in CD133+ CSCs, as compared with CD133-DGCs (P < 0.05). Bioinformatics analysis allowed to attribute 134 differentially expressed proteins to 16 signaling pathways. A significant increase in expression of eight Wnt signaling pathway proteins (APC, CSNK1E, CSNK1A, CSNK2A2, CSNK2B, CTNNB1, DVL1, RUVBL) was detected, as well as four proteins of the non-canonical Wnt pathway-RHOA, ROCK2, RAC2, DAAM1. Special attention should be paid to beta-catenin (CTNNB1) with more than 13.98-fold increase of expression in CSCs and Disheveled-associated activator of morphogenesis 1 (DAAM1) with 6.15-fold higher upregulation level. Conclusion: proteins of Wnt/beta-catenin signaling cascade are a prospective target for regulating CSCs activity.
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| 8. |
- Zaitsev, Sergei, et al.
(författare)
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Pro-inflammatory modification of cancer cells microsurroundings increases the survival rates for rats with low differentiated malignant glioma of brain
- 2020
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Ingår i: NOVEL THERAPEUTIC ADVANCES IN GLIOBLASTOMA. - LONDON ENGLAND : Elsevier. - 9780128211144 ; , s. 253-279
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Bokkapitel (refereegranskat)abstract
- Rationale: Glioblastoma multiforme (GBM) is one of the most aggressive human brain tumors. The prognosis is unfavorable with a median survival of 15 months. GBM aggressive nature is associated with a special phenotype of cancer cells that develops because of the transforming growth factor beta (TGF-beta). The study was aimed at providing experimental justification in vivo of a possibility to suppress TGF-beta production in a tumor via pro-inflammatory modification of cancer cell microenvironment, using CD45+ mononuclear cells of the red bone marrow. Materials and methods: The experiment used animals with transplanted C6 glioma. The animals were divided into 4 groups: (I) control (N = 60); (II) group of rats (N = 30) that received granulocyte colony-stimulating factor (G-CSF) to recruit CD45+ bone marrow mononuclear cells into their systemic circulation (G-CSF group); (III) group of rats (N = 30) that received pro-inflammatory therapy to trigger systemic inflammatory reaction by injecting bacterial lipopolysaccharides (LPS) and interferon-gamma (IFN gamma); (IV) rats (N = 30), stimulated with G-CSF, followed by pro-inflammatory therapy. Stereotaxic modeling of a brain tumor in experimental animals, as well as a combination of morphological, immunocytochemical analyses and immunosorbent assay were used. Results: TGF-beta 1 production in the tumor tissue resulted being inversely proportional to the intensity of proliferation processes and directly proportional to the size of necrosis areas, peaking on the 28th day of the experiment. Stimulation of experimental animals with G-CSF recruits CD45+ mononuclear stem and progenitor cells into the systemic circulation of experimental animals with C6 glioma, accompanied by intensification of microglial proliferation in the tumor and infiltration of the tumor tissue with microglial cells. Pro-inflammatory therapy against G-CSF stimulation results in polarization of microglia/macrophages population together with intensified antigen presentation, lower production of TGF-beta and IL10, increased synthesis of pro-inflammatory cytokines TNF alpha and IL1 in the tumor lesion and adjacent brain matter, remodeling of tumor matrix and higher survival rates for the experimental animals. Conclusions: Pro-inflammatory inflammatory modification of cancer cell microenvironment suppresses TGF beta production in a tumor and increases survival rates of the rats with transplanted poorly differentiated malignant brain glioma.
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| 9. |
- Bryukhovetskiy, Andrey S., et al.
(författare)
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Human mind has microwave electromagnetic nature and can be recorded and processed
- 2020
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Ingår i: Neuropharmacology of Neuroprotection. - : ELSEVIER. - 9780128208137 ; , s. 439-463
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Bokkapitel (refereegranskat)abstract
- Introduction: In 2014 and 2015 Professor of neurology Andrey Bryukhovetskiy published a novel theory of the information-commutation organization of the human brain in Russia, China and the USA. The theory posits the hypothesis that the higher nervous activity (cognitive, intellectual, mnestic) of the humans and their mind are material and have microwave electromagnetic nature. The theory perceives the human mind as a result of dynamic extracortical information-commutation relations of the super-positions of the electromagnetic waves of ultra high frequency emitted by different areas of the human brain in the inter-membrane cerebrospinal fluid space of the human head at a certain period of time. The inter-membrane cerebrospinal fluid space of the human head (the space between the dura, arachnoid and pia mater filled with the cerebrospinal fluid) of about 10mm size, has all morphological attributes to realize the holography. It is a universal natural bioprocessor for processing, analysis and synthesis of the input data and their record or reproduction on the pia as on the biological holographic membrane. The theory suggested that the processes of the mind can be recorded and digitalized with the last generation contemporary microwave receptors of the UHF band. Goal: The goal is to experimentally test the theory of the information-commutation organization of the human brain, particularly, the postulate that the human mind has material, and, namely, electromagnetic nature represented by the microwave bioelectric activity; it must be detected, recorded and statistically processed, i.e. its existence must be confirmed. Methods: On their own initiative, the team of mathematicians, radioengineers and neurologists performed the non-invasive research of the electromagnetic radiation of human brain in the broad frequency range varying from 850MHz to 26.5GHz with the last generation specialized measuring equipment with high sensitivity and recording speed, specialized measuring antennas and low noise amplifying equipment in the anechoic chamber of the 1st class of protection according to the Russian system of certification GOST R 50414-92. Results: The previously unknown microwave electromagnetic radiation of the EHF/UHF range (from 1.5GHz to 4.5GHz) with signal strength of -130dBm .. -100dBm (1e(-15) .. 1e(-13) W) are discovered. The detected electromagnetic waves have zonal variations in the different areas of the human head and are absent in other areas of the human body. The method of recording of the microwave electromagnetic activity of the human brain is patented in the Russian Federation. The microwave electromagnetic activity of the brain is billion-fold different from the bioelectric activity recorded by the encephalography. Conclusion: Discovery of the phenomenon of the microwave radiation of the human brain provides evidence to the idea that thinking and mind are material. This phenomenon has the potential to become a new informational channel of the diagnostics of the functional and pathological state of the higher nervous activity of the human brain. It can provide the basis for the development of the equipment for real-time analysis of the microwave bioelectric activity of the brain in norm and pathology, for objective early diagnostics of the functional and emotional conditions as well as of the psychiatric disorders at the preclinical stage, for the biocontrol of the human brain and the artificial simulators of the human brain. It also can provide the foundation for new systems of the artificial intellect, brain-computer interface and systems of the closed-loop biomanagement of the damaged brain.
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| 10. |
- Bryukhovetskiy, Andrey S., et al.
(författare)
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Is the ALS a motor neuron disease or a hematopoietic stem cell disease?
- 2020
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Ingår i: Neuropharmacology of Neuroprotection. - : ELSEVIER. - 9780128208137 ; , s. 381-396
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Bokkapitel (refereegranskat)abstract
- Introduction. Amyotrophic lateral sclerosis (ALS) is also known as motor neuron disease (MND) or Lou Gehrig's disease. It is a fatal neurodegenerative disease the cause of which is not clear. The effective therapy is absent. ALS is diagnosed through clinical examination and neurophysiologic tests. Clinically, the symptoms manifest when about 80% of motor neurons are dead. Materials and methods. The hematopoietic stem cells are isolated through administration of the granulocyte colony-stimulating factor from three groups: group 1 of 62 ALS cases, group 2 of 54 ALS-free healthy donors and group 3 of 6 ALS-free ALS-family members. The expression of HLA-DR, CD38, CD117, CD13, CD33, CD56, Thy-1, CD45, CD10, CD71 was assessed in 86 samples of HSCs in ALS group, 61 samples of HSCs in healthy group and 6 samples from ALS-free ALS-family members by the multiparameter flow cytometry. Results. The obtained immunophenotypic profiles of HSCs membrane antigens of the ALS group significantly differ from the ALS-free group, while the immunophenotypic profiles of HSCs membrane antigens of the ALS-family members group are close to the ALS group. Discussion. We suppose that the ALS onset as the disease of HSCs and manifests in the genome and proteome of the HSCs. Such immunophenotypic profiling might permit identification of ALS-specific immune insufficiency and become a tool for early diagnostics of the ALS before clinical manifestation of the disease. New options of the updated therapy of ALS might be developed or corrected considering this new evidence. Conclusion. Further research with larger samples and deeper examination is required.
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