Экстракорпоральная иммунофармакотерапия

Extracorporal immunophamiacotherapy is a cellular engineer immunocorrection mode allowing to use pharmacologically activated ex corpora cells-regulators of the immune system and corticodistant mediators produces. This way is carried out technically by following manner: leucocytes are extracted from blood with the fractionator and are incubated in the drug solution during some hours, then are washed and reinfused to a patient. This method allows to evacuate a part of lymphocytes from the action media of suppressor factors an d after their activation with drugs to use for the functional activity reparation of the patient immunity. This way provides the sharp reparation of the decreased parameters of the immunity activity up to normal values. In the study, the experimental basing and results of its clinical trials on models of heavy atopic syndrome, Liell’s syndrome, and atopic bronchial asthma treatment.Экстракорпоральная иммупофармакотерапия представляет собой клеточно-инженерный способ иммунокоррекции, позволяющий использовать с целью лечения активированные вне организма (экстракорпорально) фармакологическими препаратами клетки-регуляторы иммунной системы, продуценты кортикодистантных медиаторов. Технически этот прием выполняется следующим образом: с помощью фракционатора клеток крови получают лейкоциты, обрабатывают их лекарственным препаратом (несколько часов), отмывают и реинфузируют пациенту. Метод позволяет вывести часть лимфоцитов из-под действия эндогенных супрессорных факторов и после их активации лекарственными препаратами использовать для восстановления функциональной активности иммунной системы больного. Этот прием обеспечивает быстрое (в течение 1—3 суток) восстановление до нормы значительно сниженных показателей активности иммунитета. В работе приведено экспериментальное обоснование метода и результаты его клинических испытаний на примере лечения тяжелого атопического синдрома , синдрома Лайела, атопической бронхиальной астмы

Walking pathways with positive feedback loops reveal DNA methylation

Background: the search for molecular biomarkers of early-onset colorectal cancer (CRC) is an important but still quite challenging and unsolved task. Detection of CpG methylation in human DNA obtained from blood or stool has been proposed as a promising approach to a noninvasive early diagnosis of CRC. Thousands of abnormally methylated CpG positions in CRC genomes are often located in non-coding parts of genes. Novel bioinformatic methods are thus urgently needed for multi-omics data analysis to reveal causative biomarkers with a potential driver role in early stages of cancer. Methods: we have developed a method for finding potential causal relationships between epigenetic changes (DNA methylations) in gene regulatory regions that affect transcription factor binding sites (TFBS) and gene expression changes. This method also considers the topology of the involved signal transduction pathways and searches for positive feedback loops that may cause the carcinogenic aberrations in gene expression. We call this method 'Walking pathways', since it searches for potential rewiring mechanisms in cancer pathways due to dynamic changes in the DNA methylation status of important gene regulatory regions ('epigenomic walking'). Results: in this paper, we analysed an extensive collection of full genome gene-expression data (RNA-seq) and DNA methylation data of genomic CpG islands (using Illumina methylation arrays) generated from a sample of tumor and normal gut epithelial tissues of 300 patients with colorectal cancer (at different stages of the disease) (data generated in the EU-supported SysCol project). Identification of potential epigenetic biomarkers of DNA methylation was performed using the fully automatic multi-omics analysis web service 'My Genome Enhancer' (MGE) (my-genome-enhancer.com). MGE uses the database on gene regulation TRANSFAC®, the signal transduction pathways database TRANSPATH®, and software that employs AI (artificial intelligence) methods for the analysis of cancer-specific enhancers. Conclusions: the identified biomarkers underwent experimental testing on an independent set of blood samples from patients with colorectal cancer. As a result, using advanced methods of statistics and machine learning, a minimum set of 6 biomarkers was selected, which together achieve the best cancer detection potential. The markers include hypermethylated positions in regulatory regions of the following genes: CALCA, ENO1, MYC, PDX1, TCF7, ZNF43

Glycolysis downregulation is a hallmark of HIV-1 latency and sensitizes infected cells to oxidative stress

HIV-1 infects lymphoid and myeloid cells, which can harbor a latent proviral reservoir responsible for maintaining lifelong infection. Glycolytic metabolism has been identified as a determinant of susceptibility to HIV-1 infection, but its role in the development and maintenance of HIV-1 latency has not been elucidated. By combining transcriptomic, proteomic, and metabolomic analyses, we here show that transition to latent HIV-1 infection downregulates glycolysis, while viral reactivation by conventional stimuli reverts this effect. Decreased glycolytic output in latently infected cells is associated with downregulation of NAD+/NADH. Consequently, infected cells rely on the parallel pentose phosphate pathway and its main product, NADPH, fueling antioxidant pathways maintaining HIV-1 latency. Of note, blocking NADPH downstream effectors, thioredoxin and glutathione, favors HIV-1 reactivation from latency in lymphoid and myeloid cellular models. This provides a “shock and kill effect” decreasing proviral DNA in cells from people living with HIV/AIDS. Overall, our data show that downmodulation of glycolysis is a metabolic signature of HIV-1 latency that can be exploited to target latently infected cells with eradication strategies

Экстракорпоральная иммунофармакотерапия с преднизолоном и цианокобаламином атопической глюкокортикостероидозависимой бронхиальной астмы

Extracorporal Immunopharmacopherapy (EIPT) with Prednisolone and Ciancobalamini (В 12) is a method of the treatment of severe glucocorticosteroid (GCS) — dependent atopic bronchial asthma. •Leucocytes 4—8 billions collected to the collection-bag by means of blood cell separator, incubated with Prednisolone 30 mcg/ml and B12 1 mcg/ml for 3 houres at 37 °C, washed with sodium solution 3 times and then reinfused to patients. A therapeutic effect is isually reached after 3—5 procedures repeated every 3—5 days.We put EIPT into practice for treatment of 20 patients with atopic atshma. All that patients had got GCS-dependence before EIPT and exhibited evedence for remition for 6 to 24 months without sistem GCS after EIPT. Moreover these patients showed decreasment of histamine skin sensitivity and IgE-levels in plasma, elevation of plasma cortisol concentration. These patients mononuclear cells had got high level of histamine liberation activity before EIPT and had decreasment it after treatment.EIPT with Prednisolone and B12 appears to be an effective method for abolishing of GCS-dependence in patients with severe GCS-dependent atopic asthma and preventing severe complications of GCS-treatment.

Mistakes and complications of endodontic treatment and ways to overcome them (literature review)

This review presents an analysis of domestic and foreign literature, which reflects the quality of endodontic treatment of complications of caries, errors and adverse outcomes of treatment in the immediate and long-term periods. Convincingly proved the need for new innovative methods of reuse of endodontic treatment. The expediency of using dental microscopy, and is represented by its effectiveness.В обзоре представлен анализ отечественной и зарубежной специальной литературы, отражающий качество эндодонтического лечения осложнений кариеса, ошибки и неблагоприятные исходы лечения в ближайшие и отдаленные сроки. Убедительно доказана необходимость поиска новых инновационных методов повторного эндодонтического лечения. Обоснована целесообразность использования дентальной микроскопии и представлена ее эффективность

CLU blocks HDACI-mediated killing of neuroblastoma

Clusterin is a ubiquitously expressed glycoprotein with multiple binding partners including IL-6, Ku70, and Bax. Clusterin blocks apoptosis by binding to activated Bax and sequestering it in the cytoplasm, thereby preventing Bax from entering mitochondria, releasing cytochrome c, and triggering apoptosis. Because increased clusterin expression correlates with aggressive behavior in tumors, clusterin inhibition might be beneficial in cancer treatment. Our recent findings indicated that, in neuroblastoma cells, cytoplasmic Bax also binds to Ku70; when Ku70 is acetylated, Bax is released and can initiate cell death. Therefore, increasing Ku70 acetylation, such as by using histone deacetylase inhibitors, may be therapeutically useful in promoting cell death in neuroblastoma tumors. Since clusterin, Bax, and Ku70 form a complex, it seemed likely that clusterin would mediate its anti-apoptotic effects by inhibiting Ku70 acetylation and blocking Bax release. Our results, however, demonstrate that while clusterin level does indeed determine the sensitivity of neuroblastoma cells to histone deacetylase inhibitor-induced cell death, it does so without affecting histone deacetylase-inhibitor-induced Ku70 acetylation. Our results suggest that in neuroblastoma, clusterin exerts its anti-apoptotic effects downstream of Ku70 acetylation, likely by directly blocking Bax activation

Comparison of the clonogenic survival of A549 non-small cell lung adenocarcinoma cells after irradiation with low-dose-rate beta particles and high-dose-rate X-rays

Purpose: Lung cancer is the leading cause of cancer-related death. Among the new modalities to treat cancer, internal radiotherapy seems to be very promising. However, the achievable dose-rate is two orders of magnitude lower than the one used in conventional external radiotherapy, and data has to be collected to evaluate the cell response to highlight the potential effectiveness of low-dose-rate beta particles irradiation. This work investigates the phosphorus beta irradiation ( P) dose response on the clonogenicity of human A549 non-small cell lung adenocarcinoma cells and compares it to high-dose-rate X-irradiations results. Materials and methods: Cell survival was evaluated by a colony forming assay eight days after low-dose-rate P beta irradiations (0.8 Gy/h) and high-dose-rate X-ray irradiations (0.855 Gy/min). Results: Survival curves were obtained for both types of irradiations, and showed hyper-radiosensitivity at very low doses. Radiosensitivity parameters were obtained by using the linear-quadratic and induced-repair models. Conclusions: Comparison with high-dose-rate X-rays shows a similar surviving fraction, confirming the effectiveness of beta particles for tumor sterilization. © 2012 Informa UK, Ltd

(Table 2) Ice rafted debris abundance and accumulation rate, sedimentation rate and dry bulk density of bottom sediments from the Sea of Okhotsk

Oxygen isotope records, radiocarbon AMS data, carbonate and opal stratigraphy, sediment magnetic susceptibility, tephrachronology, and paleontological results were used to obtain detailed sediment stratigraphy and an age model for the studied cores. For studying sea-ice sedimentation an analysis of lithogenic grain number in >0.15 mm grain size fraction of bottom sediments was carried out. For quantitative estimation of intensity ice-rafting debris sedimentation number of IRD particles per sq cm per ka was calculated. Obtained results allowed to plot IRD AR distribution for the first oxygen isotope stage (0-12.5 14C ka, 14C) and for the second stage (12.5-24 14C ka). The first stage was subdivided into the latest deglaciation and the beginning of Holocene (6-12.5 14C ka) (transitive period), when the sea level was changing significantly, and the second part of Holocene (0-6 14C ka), when climate conditions and the sea level were similar to modern estimates. Data clearly show strong increase in ice formation in the glacial Sea of Okhotsk and its extent in the middle part of the sea. Average annual duration of ice coverage during glaciation was longer than that for interglaciation. However the sea ice cover was not continuous all the year round and disappeared in summer time except the far northwestern part of the sea

Finite time thermodynamics: Limiting performance of diffusion engines and membrane systems

In this paper, the limiting performance of membrane systems with inhomogeneous composition is studied within the class of fixed rate processes. The problem of maintaining a nonequilibrium state in such a system using minimal power (separation problem) and the problem of extracting maximal power from such a system (diffusion engine problem) are formulated and solved. Results are obtained for diffusion engines with constant and periodic contact between the working body and the reservoirs. © 2005 American Chemical Society