Search

BOOK REVIEW:Christianity and fear. Life without burden, guilt and horror of the unknown. - Oscar Pfister. M: EXMO, 2019 .-- 544 p.ISBN: 978-5-04-095202-1; 777.00 RUB *, Рецензия на книгу:Христианство и страх.Жизнь без бремени, вины и ужаса перед неизвестностью. – Оскар Пфистер. М: ЭКСМО, 2019. – 544 стр. ISBN: 978-5-04-095202-1; 777.00 RUB

Doxorubicin is a well-known antitumor drug that is not employed for chemotherapy of brain tumors. Indeed, doxorubicin does not penetrate across the blood-brain barrier in therapeutic concentrations.To study the antitumor effect of doxorubicin combined with nitrosorbide on intracranial experimental glioblastoma 101/8 in rats.Male Wistar rats (Combination of doxorubicin and nitrosorbide significantly increased survival (57% and 155%, respectively) and slowed down tumor growth (16±12 and 8±6 mmNitric oxide donor nitrosorbide considerably potentiated the antitumor effect of doxorubicin against intracranial 101/8 glioblastoma in rats.Противоопухолевое действие доксорубицина в отношении глиобластом проявляется при внутриопухолевом введении, однако при внутривенном введении препарат неэффективен, поскольку не проникает в мозг в терапевтических концентрациях.Оценить влияние широко применяемого в клинике донора NO изосорбида динитрата на эффективность доксорубицина в отношении экспериментальной глиобластомы крысы 101/8 (тканевый штамм), схожей по своим гистологическим характеристикам с глиобластомой человека.Самцам крыс Вистар с имплантированной глиобластомой крысы 101/8 (По сравнению с монотерапией доксорубицином совместное введение изосорбида динитрата и доксорубицина позволило значительно увеличить продолжительность жизни животных (57% и 155% соответственно) и ингибировать рост опухоли (16±12 и 8±6 ммДонор оксида азота изосорбида динитрат потенцирует противоопухолевый эффект доксорубицина в отношении интракраниальной глиобластомы крысы 101/8.

Terahertz (THz) technology holds strong potential for the intraoperative label-free diagnosis of brain gliomas, aimed at ensuring their gross-total resection. Nevertheless, it is still far from clinical applications due to the limited knowledge about the THz-wave-brain tissue interactions. In this work, rat glioma model 101.8 was studied

Terahertz (THz) technology holds strong potential for the intraoperative label-free diagnosis of brain gliomas, aimed at ensuring their gross-total resection. Nevertheless, it is still far from clinical applications due to the limited knowledge about the THz-wave–brain tissue interactions. In this work, rat glioma model 101.8 was studied ex vivo using both the THz pulsed spectroscopy and the 0.15λ-resolution THz solid immersion microscopy (λ is a free-space wavelength). The considered homograft model mimics glioblastoma, possesses heterogeneous character, unclear margins, and microvascularity. Using the THz spectroscopy, effective THz optical properties of brain tissues were studied, as averaged within the diffraction-limited beam spot. Thus measured THz optical properties revealed a persistent difference between intact tissues and a tumor, along with fluctuations of the tissue response over the rat brain. The observed THz microscopic images showed heterogeneous character of brain tissues at the scale posed by the THz wavelengths, which is due to the distinct response of white and gray matters, the presence of different neurovascular structures, as well as due to the necrotic debris and hemorrhage in a tumor. Such heterogeneities might significantly complicate delineation of tumor margins during the intraoperative THz neurodiagnosis. The presented results for the first time pose the problem of studying the inhomogeneity of brain tissues that causes scattering of THz waves, as well as the urgent need to use the radiation transfer theory for describing the THz-wave — tissue interactions.

The effects of 16α, 17α -cyclohexanodihydroprogesterone, the structural analogues of the closest progesterone metabolites (4,5-dihy-droprogesterones) on the uterine tissues of intact, impregnated, and pseudopregnant rats has demonstrated that they cause uterine epithelial destruction. This effect does not affect the rate and completeness of fetal implantation, but it may play a role during labor, by facilitating fetal rejection. Earlier studies have indicated that the above analogues of the metabolites of progesterone eliminate the latter-induced oxytocin receptor blockade and cause myometrial destruction in pseudopregnant animals. These facts suggest that by accumulating by the end of pregnancy, the natural progesterone metabolites (4.5-dihydroprogesterones) can act as trigger compounds - "labor hormones".Изучение влияния 16α,17α-циклогексанодигидропрогестеронов, структурных аналогов ближайших метаболитов прогестерона (4,5-дигидропрогестеронов), на ткани матки интактных, оплодотворенных и псевдобеременных крыс показало, что они вызывают деструкцию эпителия матки. Этот эффект не сказывается на скорости и полноте имплантации зародыша, но может играть роль в процессе родов, облегчая отторжение плода. Ранее нами было показано, что указанные аналоги метаболитов прогестерона снимают блокировку последним рецептора окситоцина и вызывают деструкцию миометрия псевдобеременных животных. Эти факты позволяют высказать предположение о том, что природные метаболиты прогестерона - 4,5 дигидропрогестероны, накапливаясь к концу беременности, могут играть роль пусковых соединений - "гормонов родов".

Brain delivery of drugs by nanoparticles is a promising strategy that could open up new possibilities for the chemotherapy of brain tumors. As demonstrated in previous studies, the loading of doxorubicin in poly(lactide-co-glycolide) nanoparticles coated with poloxamer 188 (Dox-PLGA) enabled the brain delivery of this cytostatic that normally cannot penetrate across the blood-brain barrier in free form. The Dox-PLGA nanoparticles produced a very considerable anti-tumor effect against the intracranial 101.8 glioblastoma in rats, thus representing a promising candidate for the chemotherapy of brain tumors that warrants clinical evaluation. The objective of the present study, therefore, was the optimization of the Dox-PLGA formulation and the development of a pilot scale manufacturing process. Optimization of the preparation procedure involved the alteration of the technological parameters such as replacement of the particle stabilizer PVA 30–70 kDa with a presumably safer low molecular mass PVA 9–10 kDa as well as the modification of the external emulsion medium and the homogenization conditions. The optimized procedure enabled an increase of the encapsulation efficiency from 66% to >90% and reduction of the nanoparticle size from 250 nm to 110 nm thus enabling the sterilization by membrane filtration. The pilot scale process was characterized by an excellent reproducibility with very low inter-batch variations. The in vitro hematotoxicity of the nanoparticles was negligible at therapeutically relevant concentrations. The anti-tumor efficacy of the optimized formulation and the ability of the nanoparticles to penetrate into the intracranial tumor and normal brain tissue were confirmed by in vivo experiments.

The complexity of software grows every year, and while there are many programming techniques and new languages that accommodate the need to provide high abstractions, still many languages that require attention to low-level details are in use as of yet In order to avoid tedious debugging which needs time that could be spent on dealing with high-level logic, static analysis of source code can be used to more efficiently find common problems. We have studied the process of creation of algorithms for static analysis tools by building a simple value range analysis mechanism, that is, a way to detect some cases of integers not matching a predicate involving arithmetic and comparison operations. This algorithm provides means to detect possible division by zero and integer overflow and is easily extended to find cases of out-of-bounds addressing of containers. While there is a multitude of value range analysis mechanisms that are more sophisticated by orders of magnitude, the works in which they are presented focus on the properties of the resulting tools such as estimated amount of false positives, performance, memory usage, or soundness. We, on the other hand, are going to present the process of extension of static analysis algorithm from ground up. An ad hoc programming language is developed in multiple stages to separate the creation of algorithm from numerous details of its implementation which would necessarily arise were we to build it on a real-world language.

Targeted drug delivery for brain tumor treatment is one of the important objectives in nanomedicine. Human glioblastoma is the most frequent and aggressive type of brain tumors. The preferential expression of membrane protein connexin 43 (Cx43) and brain-specific anion transporter (BSAT1) in the tumor and peritumoral area is a key component for targeted drug delivery. The purpose of this study was to design cisplatin-loaded nanogels conjugated with monoclonal antibodies to Cx43 and BSAT1 for treatment of intracranial gliomas 101/8. MRI volumetric analysis of tumor-bearing rats indicated significantly reduced tumor volume with cisplatin-loaded targeted-nanogel treatment compared to other formulations. The median survival of rats treated with targeted nanogels conjugated with specific mAbs against extracellular loops of Cx43 and BSAT1 were 27 and 26.6 days higher than that in control group, respectively. For the first time we demonstrated the efficiency of mAb-targeted cisplatin-loaded nanogels in the experimental model of glioma 101/8. This approach could facilitate the development of new drug delivery systems for the treatment of gliomas.

The aim of the investigation was to evaluate the performance of multimodal OCT (MM OCT) for differential diagnostics of normal and diseased brain tissue using an experimental model of glioblastoma. Materials and Methods. The spectral domain MM OCT device developed at the Institute of Applied Physics of the Russian Academy of Sciences (Nizhny Novgorod, Russia) was used for the study. It provides two modes of investigation: cross-polarization OCT (CP OCT) and microangiographic OCT (MA OCT). The instrument features the following characteristics: rate of information gathering — 20,000 A-scans per second; wavelength — 1.3 μm; shot size — ~4×2 mm; lateral resolution — 20 μm; axial resolution — 10–15 μm. The OCT investigation was performed on an experimental 101.8 rat brain glioblastoma tumor model inoculated and maintained in the Research Institute of Human Morphology. To evaluate the signal parameters typical of the tumor and of normal brain tissue, CP OCT and MA OCT images were compared with histological specimens (stained with hematoxylin and eosin). Analysis of the MA OCT images was performed on the basis of comparison with the findings of ZOOM-microscopy. Results. The model of the rat 101.8 glioblastoma helped to identify links between CP OCT images of areas of brain tissue and their morphological structure. We performed a comparative evaluation of the signals from the glial tumor and from normal brain tissue. MA OCT allowed the visualization of the blood vessels both in the tumor and in the normal brain tissues, revealing changes in the form and sizes typical of the tumor vessels. Conclusion. ММ OCT is an innovative technology with potential for use in intraoperational diagnoses of glial tumors of the brain. The ability to combine several modes of investigation enables information to be obtained simultaneously about the structure of the tissues and about any peculiarities of the structure of the different elements of their microvascular network.

Progress in the surgery of infiltratively growing gliomas is closely related to intraoperative diagnostics. Currently the most promising methods of optical imaging in the field of intraoperative identification of glioma boundaries and of grade of tumor are those providing high spatial resolution, such as optical coherence tomography (OCT) and multiphoton tomography (MPT). Nevertheless, for routine clinical use, evidence-based criteria are required. In this work the results of parallel ex vivo analysis of specimens of different grades of gliomas and of peritumoral areas obtained through the use of MPT and cross-polarization OCT (CP OCT) are compared with simultaneous histological descriptions and are presented in order to reveal the usefulness of each method in neurooncology.

Glioblastomas belong to the most aggressive human cancers with short survival times. Due to the blood-brain barrier, they are mostly inaccessible to traditional chemotherapy. We have recently shown that doxorubicin bound to polysorbate-coated nanoparticles crossed the intact blood-brain barrier, thus reaching therapeutic concentrations in the brain. Here, we investigated the therapeutic potential of this formulation of doxorubicin in vivo using an animal model created by implantation of 101/8 glioblastoma tumor in rat brains. Groups of 5-8 glioblastoma-bearing rats (total n = 151) were subjected to 3 cycles of 1.5-2.5 mg/kg body weight of doxorubicin in different formulations, including doxorubicin bound to polysorbate-coated nanoparticles. The animals were analyzed for survival (% median increase of survival time, Kaplan-Meier). Preliminary histology including immunocytochemistry (glial fibrillary acidic protein, ezrin, proliferation and apoptosis) was also performed. Rats treated with doxorubicin bound to polysorbate-coated nanoparticles had significantly higher survival times compared with all other groups. Over 20% of the animals in this group showed a long-term remission. Preliminary histology confirmed lower tumor sizes and lower values for proliferation and apoptosis in this group. All groups of animals treated with polysorbate-containing formulations also had a slight inflammatory reaction to the tumor. There was no indication of neurotoxicity. Additionally, binding to nanoparticles may reduce the systemic toxicity of doxorubicin. This study showed that therapy with doxorubicin bound to nanoparticles offers a therapeutic potential for the treatment of human glioblastoma.

Рассмотрена возможность применения относительного изменения электрокожного сопротивления (ЭКС) в зависимости от навязанного режима работы в дифференциации индивидуальных двигательных способностей легкоатлетов. = The possibility of using the relative change in electric resistance (ECS) depending on the operating mode imposed in the differentiation of individual motor abilities of athletes.

Polysorbate 80-coated poly(butyl cyanoacrylate) nanoparticles (NP) were shown to enable the transport of a number of drugs including the anti-tumour antibiotic doxorubicin (DOX) across the blood-brain barrier (BBB) to the brain after intravenous administration and to considerably reduce the growth of brain tumours in rats. The objective of the present study was to evaluate the acute toxicity of DOX associated with polysorbate 80-coated NP in healthy rats and to establish a therapeutic dose range for this formulation in rats with intracranially implanted 101/8 glioblastoma. Single intravenous administration of empty poly(butyl cyanoacrylate) NP in the dose range 100-400 mg/kg did not cause mortality within the period of observation. NP also did not affect body weight or weight of internal organs. Association of DOX with poly(butyl cyanoacrylate) NP did not produce significant changes of quantitative parameters of acute toxicity of the anti-tumour agent. Likewise, the presence of polysorbate 80 in the formulations was not associated with changes in toxicity compared with free or nanoparticulate drug. Dose regimen of 3x1.5 mg/kg on days 2, 5, 8 after tumour implantation did not cause drug-induced mortality. The results in tumour-bearing rats were similar to those in healthy rats. These results demonstrate that the toxicity of DOX bound to NP was similar or even lower than that of free DOX.

Glioblastomas belong to the most devastating cancer diseases. For this reason, polysorbate 80 (Tween 80)-coated poly(isohexyl cyanoacrylate) (PIHCA) (Monorex) nanoparticles loaded with doxorubicin were developed and tested for their use for the treatment of glioblastomas. The preparation of the nanoparticles resulted in spherical particles with high doxorubicin loading. The physico-chemical properties and the release of doxorubicin from the PIHCA-nanoparticles were analysed, and the influence on cell viability of the rat glioblastoma 101/8-cell line was investigated. In vitro, the empty nanoparticles did not show any toxicity, and the anti-cancer effects of the drug-loaded nanoparticles were increased in comparison to doxorubicin solution, represented by IC(50) values. The in vivo efficacy was then tested in intracranially glioblastoma 101/8-bearing rats. Rats were treated with 3 × 1.5mg/kg doxorubicin and were sacrificed 18 days after tumour transplantation. Histological and immunohistochemical analyses were carried out to assess the efficacy of the nanoparticles. Tumour size, proliferation activity, vessel density, necrotic areas, and expression of glial fibrillary acidic protein demonstrated that doxorubicin-loaded PIHCA-nanoparticles were much more efficient than the free drug. The results suggest that poly(isohexyl cyanoacrylate) nanoparticles hold great promise for the non-invasive therapy of human glioblastomas.

BACKGROUND: Chemotherapy of glioblastoma is largely ineffective as the blood-brain barrier (BBB) prevents entry of most anticancer agents into the brain. For an efficient treatment of glioblastomas it is necessary to deliver anti-cancer drugs across the intact BBB. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles coated with poloxamer 188 hold great promise as drug carriers for brain delivery after their intravenous injection. In the present study the anti-tumour efficacy of the surfactant-coated doxorubicin-loaded PLGA nanoparticles against rat glioblastoma 101/8 was investigated using histological and immunohistochemical methods. METHODOLOGY: The particles were prepared by a high-pressure solvent evaporation technique using 1% polyvinylalcohol (PLGA/PVA) or human serum albumin (PLGA/HSA) as stabilizers. Additionally, lecithin-containing PLGA/HSA particles (Dox-Lecithin-PLGA/HSA) were prepared. For evaluation of the antitumour efficacy the glioblastoma-bearing rats were treated intravenously with the doxorubicin-loaded nanoparticles coated with poloxamer 188 using the following treatment regimen: 3 × 2.5 mg/kg on day 2, 5 and 8 after tumour implantation; doxorubicin and poloxamer 188 solutions were used as controls. On day 18, the rats were sacrificed and the antitumour effect was determined by measurement of tumour size, necrotic areas, proliferation index, and expression of GFAP and VEGF as well as Isolectin B4, a marker for the vessel density. CONCLUSION: The results reveal a considerable anti-tumour effect of the doxorubicin-loaded nanoparticles. The overall best results were observed for Dox-Lecithin-PLGA/HSA. These data demonstrate that the poloxamer 188-coated PLGA nanoparticles enable delivery of doxorubicin across the blood-brain barrier in the therapeutically effective concentrations.

The objective of this study was to investigate the therapeutic effects of doxorubicin bound to polysorbate-coated nanoparticles that had previously been shown to significantly enhance survival in the ortho-topic rat 101/8 glioblastoma model. Tumor-bearing animals were subjected to chemotherapy using doxorubicin in solution (Dox-sol) or doxorubicin bound to polysorbate 80-coated poly(butyl cyanoacrylate) nanoparticles (Dox-np) injected intravenously on Days 2, 5 and 8 post tumor implantation. The antitumor effect was assessed on Days 10, 14 and 18 post tumor implantation. Tumors showed signs of malignancy including invasion of brain tissue, brisk mitotic activity, microvascular proliferation, necrosis and increased proliferation resembling human glioblastoma. Dox-np produced a considerably more pronounced antitumor effect exhibited as a reduced tumor size, lower proliferation, and a decreased necrotic area compared to Dox-sol and to untreated control groups. A drastic effect of Dox-np on vascularization indicated an antiangiogenic mode of action.

Poly(n-butyl cyanoacrylate) nanoparticles coated with polysorbate-80 can enable the transport of bound drugs across the blood-brain barrier (BBB) after i.v. injection. In the present study the influence of different formulation parameters on the anti-tumoural effects of doxorubicin nanoparticles against glioblastoma 101/8 was investigated. The manufacturing parameters of poly(alkyl cyanoacrylate) doxorubicin-loaded nanoparticles were optimized concerning drug loading. The nanoparticles were coated with different surfactants and injected intravenously on days 2, 5 and 8 after intra-cranial implantation of glioblastoma 101/8 to rats. The survival times of all doxorubicin containing preparations, including a doxorubicin solution, increased the survival times significantly compared to untreated tumour-bearing rats. The most pronounced increase in survival was obtained with the poly(n-butyl cyanoacrylate) doxorubicin-loaded nanoparticles coated with polysorbate 80 and 35% of these animals survived for over 180 days (termination of the experiments). The other nanoparticle preparations yielded lower survival times. Poly(n-butyl cyanoacrylate) doxorubicin-loaded nanoparticles coated with polysorbate 80-coated proved to be very efficient against glioblastoma 101/8. The data suggest that the interaction of nanoparticles with the blood after injection as well as the enhanced permeability and retention effect (EPR effect) contributed differently to the anti-tumoural efficacy depending on nanoparticle formulation and surface properties.

It was recently shown that doxorubicin (DOX) bound to polysorbate-coated nanoparticles (NP) crossed the intact blood-brain barrier (BBB), and thus reached therapeutic concentrations in the brain. Here, we investigated the biodistribution in the brain and in the body of poly(butyl-2-cyano[3-(14)C]acrylate) NP ([(14)C]-PBCA NP), polysorbate 80 (PS 80)-coated [(14)C]-PBCA NP, DOX-loaded [(14)C]-PBCA NP in glioblastoma 101/8-bearing rats after i.v. injection. The biodistribution profiles and brain concentrations of radiolabeled NP were determined by radioactivity counting after i.v. administration in rats. Changes in BBB permeability after tumour inoculation were assessed by i.v. injection of Evans Blue solution. The accumulation of NP in the tumour site and in the contralateral hemisphere in glioblastoma bearing-rats probably was augmented by the enhanced permeability and retention effect (EPR effect) that may have been becoming instrumental due to the impaired BBB on the NP delivery into the brain. The uptake of the NP by the organs of the reticuloendothelial system (RES) was reduced after PS 80-coating, but the addition of DOX increased again the concentration of NP in the RES.