[The Effects of the Hydrogen Sulfide Donor GYY4137 on the Proteasome Pool of Colorectal Cancer Cells].

Cancer cells are characterized by an increased level of metabolism and are highly dependent on the correct functioning of the processes that ensure homeostasis. Reactive sulfur species (RSS) are important molecular modulators of metabolic processes in both healthy and tumor cells. The effect of RSS and, in particular, H2S, on key cellular systems, including the ubiquitin-proteasome system (UPS), which provides the destruction of most intracellular proteins, has been shown. The main components of the UPS are proteasomes, multisubunit protein complexes, within which proteolysis occurs. At the same time, data on the effect of H2S directly on the pool of proteasomes in tumor cells are insufficient. Here, we studied the effect of incubation of SW620B8-mCherry colorectal adenocarcinoma cells expressing a fluorescently labeled proteasome subunit with 50, 100, and 200 µM of the hydrogen sulfide donor GYY4137. The effect of the substance on the proteasome pool was assessed 6, 24, 48, and 72 h after administration. It was shown that the chymotrypsin-like and caspase-like proteasome activity decreases in cells incubated with 200 µM of the GYY4137 for 24 h. This coincided with an increase in the expression of proteasome subunit genes. In lysates of cells incubated with 200 µM GYY4137 for 48 h an increase in the content of the constitutive ß5 subunit was observed and the activity of proteasomes leveled off. Following prolonged incubation with GYY4137 (72h), an increase in the expression levels of some proteasome genes was also observed, although this did not have a significant effect on the activity and subunit composition of proteasomes. Thus, the obtained data indicate the modulation of proteasome activity by the hydrogen sulfide donor and the effect of GYY4137 on transcription and translation of proteasome genes.

[Second-generation long-acting injectable antipsychotics in clinical practice]. / In"ektsionnye antipsikhotiki-prolongi vtoroi generatsii v klinicheskoi praktike.

On the example of 5 clinical cases of paranoid schizophrenia at different stages of the development of the disease, the therapeutic tactics of using drugs from the group of second-generation injectable prolong antipsychotics to solve problems that arise during anti-relapse therapy are shown. The research data substantiating these approaches are presented. Various combination therapy options are discussed, including at the stage of drug replacement and the appointment of a second-generation long-acting injectable antipsychotic.

[Long-term postoperative outcomes in patients with drug-resistant epilepsy]. / Otdalennye rezul'taty khirurgicheskogo lecheniya patsientov s farmakorezistentnymi formami epilepsii.

Epilepsy surgery is effective in 30-82% of patients with drug-resistant epilepsy. However, risk factors of unfavorable outcomes after epilepsy surgery require further study. OBJECTIVE: To evaluate risk factors of favorable and unfavorable long-term postoperative outcomes in patients with drug-resistant epilepsy. MATERIAL AND METHODS: Postoperative outcomes in a large cohort of patients with epilepsy are reported for the first time in the Russian Federation. There were 271 patients with drug-resistant scheduled for surgery. Preoperative examination and surgical treatment were carried out between January 1, 2014 and December 12, 2019 at the Evdokimov Moscow State University of Medicine and Dentistry and Sklifosovsky Research Institute for Emergency Care. We used Engel grading system to assess postoperative outcomes after 12, 24, 48 and 60 months. We distinguished favorable (Engel I-II) and unfavorable (Engel III-IV) outcomes and analyzed the factors influencing postoperative results in these patients. RESULTS: There were 319 surgical procedures in 271 patients (217 primary resections, implantation of vagus nerve stimulator in 31 patients, 9 redo resections and 8 radiosurgical procedures). Focal cortical dysplasia (FCD) was found in 162 (60%) patients, «dual pathology¼ - in 118 (44%) cases. In 12 months after surgery, favorable outcomes (Engel l-II) were observed in 69% of patients (n=148), after 24 months - in 71% (n=127) of patients. Postoperative complications occurred in 6 (1.9%) patients. There was no mortality. The earlier onset of epilepsy (p=0.01), multifocal (p=0.002) and bilateral lesions (p=0.0038) were the most significant risk factors of unfavorable postoperative outcomes. CONCLUSION: Surgical resection is effective approach for drug-resistant epilepsy.

[Resection of S1 root schwannoma with extravertebral retroperitoneal spread via posterior median and laparoscopic approach]. / Odnomomentnoe udalenie nevrinomy pravogo spinnomozgovogo koreshka S1 s ekstravertebral'nym retroperitoneal'nym rasprostraneniem zadnim sredinnym i laparoskopicheskim dostupom (klinicheskoe nablyudenie).

The authors report simultaneous surgical treatment of the right S1 root schwannoma with extravertebral retroperitoneal spread. Well-equipped operating theatre, professional experience and multidisciplinary approach involving neurosurgeons and abdominal surgeons ensure total minimally invasive simultaneous resection of schwannoma via posterior median and laparoscopic approach.

[Analysis of local hemodynamics in complex aneurysms: an effect of the vessel arising from the dome or the neck]. / Issledovanie lokal'noi gemodinamiki v slozhnykh anevrizmakh: vliyanie sosuda, otkhodyashchego ot kupola ili sheiki.

BACKGROUND: Assessment of rupture risk for intracranial aneurysms (IA) is a particular challenge in cases of so-called complex aneurysms due to their variable morphometric characteristics. Arterial branch arising from the dome or the neck of IA is one of the least explored features of complex aneurysms. The methods of computational fluid dynamics may be valuable to determine the influence of arterial branches of IA on local hemodynamics. OBJECTIVE: To analyze local hemodynamics in IA with arterial branch arising from the cupola or the neck depending on the structure of the aneurysm and blood flow rate in the parent vessel. MATERIAL AND METHODS: CT angiography data of 4 patients with IA were estimated in this study. Modifications of the baseline 3D models of the aneurysms resulted 12 patient-specific models included into analysis. Hemodynamic calculations were made by using of ANSYS Workbench 19 software package. RESULTS: Wall shear stress (WSS) was characterized by the most significant variability, especially in case of sidewall aneurysms. Small cross-sectional area of additional branch in relation to the neck of IA was not followed by considerable changes of blood flow patterns inside IA after «virtual¼ removal of the vessel. Otherwise, the intensity of flows was drastically reduced. Simulation of high inlet flows demonstrated substantial variation of WSS in the area of jet. CONCLUSION: Additional arterial branch arising from the dome or the neck of IA significantly influences local hemodynamics. This influence depends on the localization of IA in relation to the parent vessel and the diameter of additional arterial branch.

The comparison of the process of manual and robotic positioning of the electrode performing radiofrequency ablation under the control of a surgical navigation system.

This study is aimed at the comparison of the process of manual and robotic positioning of the electrode performing radiofrequency ablation under the control of a surgical navigation system. The main hypothesis of this experiment was that the use of a collaborative manipulator (KUKA iiwa) will allow to position the active part of the electrode relative to the center of the tumor more accurately and from the first attempt. We also monitor the stability of the electrode's velocity during insertion and consider some advantages in ergonomics using the robotic manipulator. We use three more criteria to compare the surgeon's and robotic performance, unlike other studies, where only the target point's accuracy criterion is observed. The main idea is to examine the movement parameters of the electrode that can lead to potential patient trauma. Sphere-shaped tumor phantoms measuring 8 mm in diameter were filled with contrast and inserted in bovine livers. 10 livers were used for the robotic experiment and an equal quantity for manual surgery. The livers were encased in silicone phantoms designed to imitate the liver position in a real patient's abdominal cavity. Analysis of CT data gave the opportunity to find the entry and the target point for each tumor phantom. This data was loaded into a surgical navigation system that was used to track and record the position of the RF-electrode during the operation for further analysis. The standard deviation of points from the programmed linear trajectory totaled in the average 0.3 mm for the robotic experiment and 2.33 mm for the manual operation with a maximum deviation of 0.55 mm and 7.99 mm respectively. Standard deviation from the target point was 2.69 mm for the collaborative method and 2.49 mm for the manual method. The average velocity was 2.97 mm/s for the manipulator and 3.12 mm/s for the manual method, but the standard deviation of the velocity relative to the value of the average velocity was 0.66 mm/s and 3.05 mm/s respectively. Thus, in two criteria out of three, the manipulator is superior to the surgeon, and equality is established in one. Surgeons also noticed advantages in ergonomics performing the procedure using the manipulator. This experiment was produced as part of the work on the developing of a robotic multifunctional surgical complex. We can confirm the potential advantages of using collaborative robotic manipulators for minimally invasive surgery in case of practice for cancer treatment.

[Outcomes of surgical treatment of patients with pharmacoresistant epilepsy]. / Iskhody khirurgicheskogo lecheniya patsientov s farmakorezistentnymi formami epilepsii.

AIM: To evaluate the results of surgical treatment of patients with pharmacoresistant epilepsy. MATERIAL AND METHODS: Examination and surgical treatment of 61 patients with pharmacoresistant forms of symptomatic epilepsy were performed from 01.01.14 to 01.05.16. RESULTS AND CONCLUSION: The results confirmed the safety and efficacy of the surgical treatment of pharmacoresistant epilepsy. After 12 months, seizures were controlled in 69% of operated patients. The necessity of complex examination of all patients with pharmacoresistant epilepsy to make a decision about possible surgery is shown.

[Operations of revascularization in surgery of cerebrovascular aneurysms].

Surgical revascularization of the brain is one of the most important trends in the development of neurosurgery. Restoration of adequate blood flow through pre- and intracerebral arteries promotes prevention and treatment of ischaemic lesions of the brain in various pathology. The present work was aimed at analysing the experience gained in performing revascularizing operations in patients with cerebral aneurysms at the department of neurosurgery. The authors analysed therapeutic outcomes in a total of 45 patients presenting with giant and complex aneurysms of cerebral arteries and treated from 2009 to 2014. Of the 45 patients with giant and complex aneurysms of cerebral arteries, 31 (68.8%) patients underwent open microsurgical interventions (including 10 patients with the use of different variants of revascularizing operation) and 14 (31.2%) patients were subjected to endovascular exclusion of the aneurysm from the blood flow. It was shown that performing revascularizing operations in patients with complex and giant aneurysms of cerebral arteries makes it possible to compensate circulation in the interested arterial basin and to obtain good functional results.

D-glucuronyl C5-epimerase suppresses small-cell lung cancer cell proliferation in vitro and tumour growth in vivo.

BACKGROUND: D-Glucuronyl C5-epimerase (GLCE) is a key enzyme involved in the biosynthesis of heparan sulphate proteoglycans, which has an important role in cell-cell and cell-matrix interactions and signalling. Decreased GLCE expression in human breast tumours and its anti-proliferative effects in breast cancer cells suggest that it may be a candidate tumour-suppressor gene. The aim of this study was to investigate the involvement of GLCE in lung carcinogenesis. METHODS: D-Glucuronyl C5-epimerase expression in different lung cancer cell lines was determined and the gene was ectopically re-expressed in U2020 small-cell lung cancer cells. Cellular proliferation in vitro and tumour growth in vivo were then examined. RESULTS: Ectopic re-expression of GLCE in U2020 cells did not affect cell viability but did influence morphology. Cellular proliferation in vitro and tumour formation in vivo were both suppressed. These effects were mediated via downregulation of several pro-angiogenic growth factors and their receptors, including VEGF-A, TGFB1, FGFR2, PDGF-A and PDGF-B, and TNFa and its receptors. Expression of matrix metalloproteinase2, MTA1, PLAU, TIMP3, S100A4, SERPINE1 and TWIST1 was also downregulated. CONCLUSION: The anti-tumour effects associated with ectopic GLCE re-expression suggest that it may be a potential tumour-suppressor gene and a possible target for lung cancer diagnosis and treatment.

Epigenetic regulation of the ras effector/tumour suppressor RASSF2 in breast and lung cancer.

RASSF2 is a recently identified member of a class of novel tumour suppressor genes, all containing a ras-association domain. RASSF2 resides at 20p13, a region frequently lost in human cancers. In this report we investigated methylation status of the RASSF2 promoter CpG island in a series of breast, ovarian and non-small cell lung cancers (NSCLC). RASSF2 was frequently methylated in breast tumour cell lines (65%, 13/20) and in primary breast tumours (38%, 15/40). RASSF2 expression could be switched back on in methylated breast tumour cell lines after treatment with 5'-aza-2'deoxycytidine. RASSF2 was also frequently methylated in NSCLC tumours (44%, (22/50). The small number of corresponding normal breast and lung tissue DNA samples analysed were unmethylated. We also did not detect RASSF2 methylation in ovarian tumours (0/17). Furthermore no mutations were found in the coding region of RASSF2 in these ovarian tumours. We identified a highly conserved putative bipartite nuclear localization signal (NLS) and demonstrated that endogenous RASSF2 localized to the nucleus. Mutation of the putative NLS abolished the nuclear localization. RASSF2 suppressed breast tumour cell growth in vitro and in vivo, while the ability of NLS-mutant RASSF2 to suppress growth was much diminished. Hence we demonstrate that RASSF2 has a functional NLS that is important for its tumour suppressor gene function. Our data from this and a previous report indicate that RASSF2 is frequently methylated in colorectal, breast and NSCLC tumours. We have identified RASSF2 as a novel methylation marker for multiple malignancies and it has the potential to be developed into a valuable marker for screening several cancers in parallel using promoter hypermethylation profiles.

Expression of different proteoglycans in human breast tumors.

The composition of proteoglycans and their changes during malignant transformation are important factors influencing adhesive properties and mitotic activity of tumor cells. In this study, expression level of different proteoglycans (decorin, syndecan-1, lumican, glypican-1, and aggrecan) in tumors and normal human breast tissue was investigated. Multiplex RT-PCR data revealed different expression changes for different proteoglycans in human breast tumors--syndecan expression was activated compared to almost no expression in normal breast tissue, expression of decorin and lumican decreased 2-5- and 2-3-fold, respectively, and aggrecan transcription seems to be unaffected. A change of expression level of decorin correlated with expression of D-glucuronyl-C5-epimerase, a key enzyme responsible for the biosynthesis of idurone-containing glycosaminoglycans, possessing antimitotic activity. The results suggest that changes in decorin, lumican, and syndecan-1 expression in tumor tissue could induce a distortion of proteoglycan composition and mitotic activity of cells in human breast tumor.

Proteoglycans and human breast cancer.

Comparative analysis of proteoglycans in the control and tumor tissue of human mammary gland revealed disorders in the biosynthesis of dermatan sulfate proteoglycans in tumor cells. Using the methods of reverse transcription-PCR and Western blotting for the analysis of decorin expression we showed that these disorders were paralleled by reduced expression of the core protein and changes in the structure of proteoglycan carbohydrate chains and could be a cause of malignant degeneration of mammary gland cells.

Dynamical control: comparison of map and continuous-flow approaches.

Continuous and pulsed forms of control of a multistable system are compared directly, both theoretically and numerically, taking as an example the switching of a periodically driven class-B laser between its stable and unstable pulsing regimes. It is shown that continuous control is the more energy efficient. This result is illuminated by making use of the close correspondence that exists between the problems of energy-optimal control and the stability of a steady state.

Spatiotemporal structures in a model with delay and diffusion.

Pattern formation described by differential-difference equations with diffusion is investigated. It is shown that an arbitrarily small diffusion induces space-time turbulence just at the instability threshold of the homogeneous stationary solution. We prove this property by deriving a complex Ginzburg-Landau equation on the basis of normal form analysis. Well above threshold, such turbulent structures give way to synchronized states ordered by spirals and targets. This secondary instability can be understood with an asymptotic method representing the system as a cellular automaton network.

Proteoglycan composition in cell nuclei of mouse hepatoma.

Cell nuclei of mouse hepatoma contain various proteoglycans (PG) which include heparan sulfate proteoglycan (HS-PG), dermatan sulfate proteoglycan (DS-PG), and chondroitin sulfate proteoglycan (CS AC-PG). The latter is not found in cell nuclei of normal mouse liver. Heparan sulfate (HS) and dermatan sulfate (DS) are the main constituents of carbohydrate chains of nuclear proteoglycans of tumor and normal cells, respectively. Changes in the composition of nuclear PG during malignant transformation are discussed considering the concept of their possible involvement in the regulation of cell mitotic activity.