Автоматизированная система дозирования сырья на суточных силосах производства каменной ваты

Предпосылкой для разработки системы автоматизации послужили недостатки систем дозирования сырья в металлургических, химических и перерабатывающих отраслях производств, на основе тарельчатых и шнековых питателей, в виде неточности взвешиваемой величины дозируемых компонентов, в связи с чем, предлагается разработка автоматизированной системы дозирования на основе вибрационных дозаторов с частотным регулированием работы приводов. Разработанная автоматизированная система позволит повысить точность дозируемых материалов, а также увеличит производительность системы, что в положительную сторону отразится на технико-экономических показателях производства.The prerequisite for the development of the automation system was the shortcomings of the dosing systems of raw materials in the metallurgical, chemical and processing industries, based on plate and screw feeders, in the form of inaccuracy of the weighed quantity of the dosed components, and therefore, it is proposed to develop an automated dosing system based on vibration dispensers with a frequency regulation of the drives. The developed automated system will improve the accuracy of the dosed materials, as well as increase the performance of the system, which will positively affect the technical and economic indicators of production

Distinct transcriptional changes in non-small cell lung cancer patients associated with multi-antigenic RNActive® CV9201 immunotherapy

ABSTRACT We recently completed a phase I/IIa trial of RNActive® CV9201, a novel mRNA-based therapeutic vaccine targeting five tumor-associated antigens in non-small cell lung cancer (NSCLC) patients. The aim of the study presented here was to comprehensively analyze changes in peripheral blood during the vaccination period and to generate hypotheses facilitating the identification of potential biomarkers correlating with differential clinical outcomes post RNActive® immunotherapy. We performed whole-genome expression profiling in a subgroup of 22 stage IV NSCLC patients before and after initiation of treatment with CV9201. Utilizing an analytic approach based on blood transcriptional modules (BTMs), a previously described, sensitive tool for blood transcriptome data analysis, patients segregated into two major clusters based on transcriptional changes post RNActive® treatment. The first group of patients was characterized by the upregulation of an expression signature associated with myeloid cells and inflammation, whereas the other group exhibited an expression signature associated with T and NK cells. Patients with an enrichment of T and NK cell modules after treatment compared to baseline exhibited significantly longer progression-free and overall survival compared to patients with an upregulation of myeloid cell and inflammatory modules. Notably, these gene expression signatures were mutually exclusive and inversely correlated. Furthermore, our findings correlated with phenotypic data derived by flow cytometry as well as the neutrophil-to-lymphocyte ratio. Our study thus demonstrates non-overlapping, distinct transcriptional profiles correlating with survival warranting further validation for the development of biomarker candidates for mRNA-based immunotherapy

Phase Ib evaluation of a self-adjuvanted protamine formulated mRNA-based active cancer immunotherapy, BI1361849 (CV9202), combined with local radiation treatment in patients with stage IV non-small cell lung cancer

Background: Preclinical studies demonstrate synergism between cancer immunotherapy and local radiation, enhancing anti-tumor effects and promoting immune responses. BI1361849 (CV9202) is an active cancer immunotherapeutic comprising protamine-formulated, sequence-optimized mRNA encoding six non-small cell lung cancer (NSCLC)-associated antigens (NY-ESO-1, MAGE-C1, MAGE-C2, survivin, 5T4, and MUC-1), intended to induce targeted immune responses. Methods: We describe a phase Ib clinical trial evaluating treatment with BI1361849 combined with local radiation in 26 stage IV NSCLC patients with partial response (PR)/stable disease (SD) after standard first-line therapy. Patients were stratified into three strata (1: non-squamous NSCLC, no epidermal growth factor receptor (EGFR) mutation, PR/SD after ≥4 cycles of platinum- and pemetrexed-based treatment [n = 16]; 2: squamous NSCLC, PR/SD after ≥4 cycles of platinum-based and non-platinum compound treatment [n = 8]; 3: non-squamous NSCLC, EGFR mutation, PR/SD after ≥3 and ≤ 6 months EGFR-tyrosine kinase inhibitor (TKI) treatment [n = 2]). Patients received intradermal BI1361849, local radiation (4 × 5 Gy), then BI1361849 until disease progression. Strata 1 and 3 also had maintenance pemetrexed or continued EGFR-TKI therapy, respectively. The primary endpoint was evaluation of safety; secondary objectives included assessment of clinical efficacy (every 6 weeks during treatment) and of immune response (on Days 1 [baseline], 19 and 61). Results: Study treatment was well tolerated; injection site reactions and flu-like symptoms were the most common BI1361849-related adverse events. Three patients had grade 3 BI1361849-related adverse events (fatigue, pyrexia); there was one grade 3 radiation-related event (dysphagia). In comparison to baseline, immunomonitoring revealed increased BI1361849 antigen-specific immune responses in the majority of patients (84%), whereby antigen-specific antibody levels were increased in 80% and functional T cells in 40% of patients, and involvement of multiple antigen specificities was evident in 52% of patients. One patient had a partial response in combination with pemetrexed maintenance, and 46.2% achieved stable disease as best overall response. Best overall response was SD in 57.7% for target lesions. Conclusion: The results support further investigation of mRNA-based immunotherapy in NSCLC including combinations with immune checkpoint inhibitors. Trial registration: ClinicalTrials.gov, Identifier: NCT01915524

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Studies on the synthesis and transport of endogenous sphingomyelin in BHK-21 cells

The synthesis and intracellular transport of sphingomyelin in BHK-21 cells has been studied in the presence of brefeldin A (BFA) and monensin which are inhibitors of vesicular transport through the Golgi apparatus. Both drugs inhibit delivery of newly synthesised sphingomyelin to the cell surface, albeit by different mechanisms. BFA increases overall synthesis of sphingomyelin, but prevents vesicular transport of newly synthesised sphingomyelin to the trans Golgi network and the cell surface. Monensin seems to specifically inhibit synthesis of plasma membrane sphingomyelin by blocking vesicular transport of ceramide past the medial-Golgi. Ceramide can be produced at the plasma membrane by degradation of surface sphingomyelin by an extracellular sphingomyelinase. In untreated cells this ceramide is almost completely utilised for the resynthesis of plasma membrane sphingomyelin. Neither BFA nor monensin interfere with resynthesis of sphingomyelin from plasma membrane ceramide. However, resynthesis of sphingomyelin is largely prevented in mitotic and ATP-depleted cells in which endocytosis and vesicular transport are suppressed. These findings are conceptualised by a model which assumes in contrast to the prevailing orthodoxy, that the major site for the synthesis of plasma membrane sphingomyelin is not in the cis-lmedial-Go\gi, but distal to the trans-Golgi in an endosomal compartment on the plasma membrane recycling pathway. The depletion of plasma membrane sphingomyelin by either drug or sphingomyelinase treatment causes an increased esterification of cholesterol and, in the case of BFA, a decrease of cholesterol synthesis. These observations are consistent with the previous findings that cholesterol synthesis and esterification processes in cells are influenced by the plasma membrane content of sphingomyelin. It is suggested that the correct balance between plasma membrane cholesterol and sphingomyelin is created at the putative endosomal site of sphingomyelin synthesis after delivery of newly synthesised cholesterol to this site

The role of transsignalling via the agonistic soluble IL-6 receptor in human diseases

AbstractThe activation of cells that do not express the membrane bound interleukin-6 6 receptor (IL-6R) by IL-6 and the soluble IL-6 receptor (sIL-6R) is termed transsignalling. Transsignalling may be an pathogenetic factor in human diseases as diverse as multiple myeloma (MM), Castleman's disease, prostate carcinoma, Crohn's disease, systemic sclerosis, Still's disease, osteoporosis and cardiovascular diseases. IL-6 and sIL-6R may directly or indirectly enhance their own production on endothelial or bone marrow stromal cells. Positive feedback autocrine loops thus created in affected organs may either cause or maintain disease progression. In autoimmune or vasculitic disease, the ability of the IL-6/sIL-6R complex to inhibit apoptosis of autoreactive T-cells may be central to the development of tissue specific autoimmunity. The anti-apoptotic effect of the IL-6/sIL-6R complex may be involved in tumour genesis and resistance to chemotherapy.Only in rare cases, where counterregulation has failed, there is a notable systemic effect of IL-6/sIL-6R. Appropriate animal models are necessary to establish the pathogenetic role of the IL-6/sIL-6R complex. A specific treatment option for diseases influenced by the sIL-6R could be based on gp130–Fc, a soluble gp130 (sgp130) linked to the Fc-fragment of IgG1. gp130–Fc has shown efficacy in vivo in animal models of Crohn's disease