Diazoxide Post-conditioning Activates the HIF-1/HRE Pathway to Induce Myocardial Protection in Hypoxic/Reoxygenated Cardiomyocytes

Background: Previous studies have shown that diazoxide can protect against myocardial ischemia-reperfusion injury (MIRI). The intranuclear hypoxia-inducible factor-1 (HIF-1)/hypoxia-response element (HRE) pathway has been shown to withstand cellular damage caused by MIRI. It remains unclear whether diazoxide post-conditioning is correlated with the HIF-1/HRE pathway in protective effect on cardiomyocytes.Methods: An isolated cardiomyocyte model of hypoxia-reoxygenation injury was established. Prior to reoxygenation, cardiomyocytes underwent post-conditioning treatment by diazoxide, and 5-hydroxydecanoate (5-HD), N-(2-mercaptopropionyl)-glycine (MPG), or dimethyloxallyl glycine (DMOG) followed by diazoxide. At the end of reoxygenation, ultrastructural morphology; mitochondrial membrane potential; interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), reactive oxygen species (ROS), and HIF-1α levels; and downstream gene mRNA and protein levels were analyzed to elucidate the protective mechanism of diazoxide post-conditioning.Results: Diazoxide post-conditioning enabled activation of the HIF-1/HRE pathway to induce myocardial protection. When the mitoKATP channel was inhibited and ROS cleared, the diazoxide effect was eliminated. DMOG was able to reverse the effect of ROS absence to restore the diazoxide effect. MitoKATP and ROS in the early reoxygenation phase were key to activation of the HIF-1/HRE pathway.Conclusion: Diazoxide post-conditioning promotes opening of the mitoKATP channel to generate a moderate ROS level that activates the HIF-1/HRE pathway and subsequently induces myocardial protection.

Prototype Automation of Air Conditioning Treatment in the Grinding Area Aneka Cocoa Based on IoT

A good work environment will affect the level of productivity of workers in a company. The operation of the refrigeration machine in the cocoa powder grinding area is very important in production. The indicators for the operation of the cooling machine are dust density, ambient temperature and wind speed. With control on the indicator will increase efficiency. In this study, the indicator is controlled with a GP2Y1010AUF0F dust sensor, a DHT22 temperature sensor, a DS18B20 sensor, and a wind speed sensor as sensor inputs. Furthermore, the sensor will be processed by the Node M CU ESP826 module. System output will be displayed on LED and android. The results of this study indicate the accuracy of the dust sensor is 96.12%, the DHT22 temperature sensor is 99.80%, the DS18B20 temperature sensor is 99.57% and the speed sensor is 95.89%. In this prototype, we can monitor the temperature of the air velocity of dust particles in the engine and the temperature of the engine cooler together and closely monitored.

Ruxolitinib Therapy during Hematopoietic Cell Transplantation for Myelofibrosis

Background :The beneficial effects of JAK 1/2 inhibitors (JAKi) ruxolitinib in MF patients have led to control of disease related symptoms,but ruxolitinib has been limited by their inability to deplete the malignant stem cell clones. Allogeneic hematopoietic cell transplantation (HCT) is currently the only treatment with proven curative potential for myelofibrosis (MF). Previous research suggested pre-HCT ruxolitinib may improve post-HCT outcome because of ruxolitinib accelerate engraftment, improve graft function, decrease the risk and severity of graft-versus-host disease (GVHD). However,HCT in PMF with higher non-relapse mortality (NRM),In the present study, we aimed to prospectively assess the effects of Rux therapy during HCT period(NCT04526223). Objective Preliminarily investigate the safety and efficacy of ruxolitinib in myelofibrosis patients during the peri-transplantation period. Method: To prospectively analyze the clinical data of 26 patients with myelofibrosis who were used DAC bridge BF as conditioning treatment and treated with ruxolitinib(5mg bid +6d to +60d) during the peri-transplantation period. Results: 26 patients were eligible if they had primary myelofibrosis (PMF) as defined by the 2008 World Health Organization classification or secondary MF as defined by the IWG for Myeloproliferative Neoplasms Research and Treatment criteria and met the criteria for Intermediate-1 (Int-1), Int-2, or high-risk disease by the DIPSS scoring system at the time of enrollment. Patients consenting to treatment with Rux for at least 8 weeks prior to HCT and could receive Rux (5mg bid +6d to +60d) during the peri-transplantation period. DAC bridge BF as Myeloablative regiment, There have been no episodes of cytokine release syndrome and all patients achieved sustained engraftment. Neutrophil reconstitution was obtained in 26 patients with a median time of 15 (10 to 31) d; platelet reconstitution was obtained in 26 patients with a median time of 26(12 to 68) d. Acute GVHD occurred in 26 patients (46.15%) , of which 1(3.8%) were ш°; chronic GVHD occurred in 9 patients (34.6%), 1 patients with extensive chronic GVHD. There patients relapsed and two patients died because of resistance to alvage treatment . With a median follow-up 336 (70-993) days，no patient died of non-relapse mortality (NRM)., overall survival is 92.3% (95% CI: 0.73, 0.97) and DFS is 88.5% (95% CI: 0.63, 0.96) at1 year post-HCT. Conclusion: This study demonstrates that Ruxolitinib therapy during HCT is well tolerated and suggests that during-HCT Rux may improve post-HCT outcome. Keywords: Ruxolitinib;Hematopoietic Cell Transplantation;Myelofibrosis Disclosures No relevant conflicts of interest to declare.

Evaluation of thermo-mechanical and microbial-facilitated processing on the chemical composition of soybean meal

A laboratory experiment was conducted to examine the effects of microbial fermentation using Bacillus subtilis and Aspergillus oryzae on the chemical composition of a commercial soybean meal (SBM). Five quadruplicate samples of SBM were subjected to four treatments with one batch serves as a control. The treatments were steam conditioning treatment (P1) where the other three groups were further fermented with B. subtilis (P2), A. oryzae (P3), and the combination of B. subtilis + A. oryzae (P4). The results showed that bacterial and fungal inoculation increased crude protein (CP) content when compared to control (p<0.05). In addition, fiber fractions including neutral detergent fiber (NDF) and acid detergent fiber (ADF) were concomitantly decreased with fermentation (p<0.05). In this study, no significant difference was observed on CP and NDF content with heating treatment (P1, p>0.05). However, this treatment decreased ADF content (p<0.05). Ether extract (EE), ash, non-fibrous carbohydrates (NFC), and total phosphorus contents were not affected by the treatments. To conclude, fermentation either with bacterial or fungal inoculants was effective to improve the chemical composition of SBM as indicated by increasing CP and decreasing fiber contents of SBM.

Longitudinal Tear Protein Changes Correlate with Ocular Chronic GVHD Development in Allogeneic Hematopoietic Stem Cell Transplant Patients

Ocular graft-versus-host disease (oGVHD) is a manifestation of chronic GVHD, frequently occurring in patients after allogeneic hematopoietic stem cell transplant (HSCT). We analyzed tear protein changes before and after allogeneic HSCT, and correlated their levels with the oGVHD development. This retrospective study included 102 patients, and data were recorded before the conditioning treatment, and after 3 to 6 months postoperatively. Tear protein analysis was performed with the Agilent-2100 Bioanalyzer on individual tears sampled by aspiration. Total protein (TP), Lysozyme-C (LYS-C), Lactoferrin (LACTO), Lipocalin-1 (LIPOC-1), Transferrin (TRANSF), Albumin (ALB), and Zinc-alpha-2-glycoprotein (ZAG-2) levels were retrieved and statistically analyzed. Following HSCT forty-three patients developed oGVHD. TP, LACTO, LYS-C, and ZAG-2 levels significantly decreased post-HSCT as compared to pre HSCT levels. In univariate analysis, TP, LACTO, and ZAG-2 decrease was associated with an increased development of oGVHD (OR = 4.49; 95% CI, 1.9 to 10.5; p < 0.001; OR = 3.08; 95% CI 1.3 to 7.6; p = 0.01; OR = 11.1; 95% CI 2.7 to 46.6; p < 0.001, respectively). TRANSF post-HSCT levels significantly increased (OR 15.7; 95% CI, 4.1 to 52.2; p = 0.0001). No pre-post-HSCT changes were shown in ALB and LIPOC-1 levels. Data suggest that TP content, LACTO, TRANSF, and ZAG-2 pre-post changes might be significant predictors of oGVHD development.

Factors That Influence Compliance to Long-Term Remote Ischemic Conditioning Treatment in Patients With Ischemic Stroke

Objectives: To investigate the treatment compliance of patients with ischemic stroke to remote ischemic conditioning (RIC) and to determine the factors that influence compliance.Methods: We conducted a retrospective study of patients with ischemic stroke who were treated with RIC. Treatment compliance was determined and analyzed in patients who had received 1 year of RIC training. Factors that influenced patient compliance were also determined using univariate and multivariate regression analyses.Results: Between March 2017 and February 2018, 91 patients were recruited into this study. The mean (±SD) age was 57.98 ± 10.76 years, and 78 (85.7%) patients were male. The baseline Kolcaba comfort scale of patients with good compliance scores were higher than those with poor compliance. The scores of the four dimensions in the scale and the total score are as follows: physiological dimensions, 15.0 (12.0,17.0) vs 17.0 (13.0,19.0); psychological dimensions, 30.0 (25.0,34.0) vs 31.0 (27.0,35.0); sociological dimensions, 20.0 (18.0,24.0) vs 21.0 (18.0,23.0); environmental dimensions, 19.0 (12.0,24.0) vs 20.0 (17.0,22.0); and total points, 82.0 (69.0,94.0) vs 91.0 (78.0,98.0). the differences between the groups were significant (p &lt; 0.05), except for the sociological dimensions. A history of hypertension, number of follow-ups, and the physiological, psychological, and environmental dimensions of the comfort scale were related to patient compliance, out of which the number of follow-ups (Adjusted OR = 2.498, 95% confidence interval (CI) 1.257–4.964) and the physiological discomfort (Adjusted OR = 1.128, 95% CI 1.029–1.236) independently influenced compliance (p &lt; 0.05).Conclusion: In patients with ischemic cerebrovascular disease who were treated with RIC, the number of follow-up visits and physiological discomfort associated with RIC treatment independently influenced patient compliance. Further studies are needed to investigate the RIC protocols and their corresponding nursing models.

Conditioning treatment with CD27 Ab enhances expansion and antitumor activity of adoptively transferred T cells in mice

Cyclophosphamide plus fludarabine (C/F) are currently used to improve the expansion and effectiveness of adoptive cell therapy (ACT). However, these chemotherapeutics cause pan-leukopenia and adverse events, suggesting that safer and more effective conditioning treatments are needed to improve ACT outcomes. Previously, we reported that varlilumab, a CD27-targeting antibody, mediates Treg -preferential T cell depletion, CD8-T cell dominant costimulation, and systemic immune activation in hCD27 transgenic mice and cancer patients. We reasoned that the activities induced by varlilumab may provide an effective conditioning regimen for ACT. Varlilumab pretreatment of hCD27+/+mCD27 − /− mice resulted in prominent proliferation of transferred T cells isolated from wild-type mice. These studies uncovered a critical role for CD27 signaling for the expansion of transferred T cells, as transfer of T cells from CD27 deficient mice or treatment with a CD70 blocking antibody greatly reduced their proliferation. In this model, varlilumab depletes endogenous hCD27+/+ T cells and blocks their subsequent access to CD70, allowing for more CD70 costimulation available to the mCD27+/+ transferred T cells. CD27-targeted depletion led to a greater expansion of transferred T cells compared to C/F conditioning and resulted in longer median survival and more cures than C/F conditioning in the E.G7 tumor model receiving OT-I cell therapy. We propose that translation of this work could be achieved through engineering of T cells for ACT to abrogate varlilumab binding but preserve CD70 ligation. Thus, varlilumab could be an option to chemotherapy as a conditioning regimen for ACT.

IL-15 mediated expansion of rare durable memory T cells following adoptive cellular therapy

BackgroundSynovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) are ideal solid tumors for the development of adoptive cellular therapy (ACT) targeting NY-ESO-1, as a high frequency of tumors homogeneously express this cancer-testes antigen. Data from early phase clinical trials have shown antitumor activity after the adoptive transfer of NY-ESO-1–specific T cells. In these studies, persistence of NY-ESO-1 specific T cells is highly correlated with response to ACT, but patients often continue to have detectable transferred cells in their peripheral blood following progression.MethodWe performed a phase I clinical trial evaluating the safety of NY-ESO-1–specific endogenous T cells (ETC) following cyclophosphamide conditioning. Peripheral blood mononuclear cells (PBMCs) from treated patients were evaluated by flow cytometry and gene expression analysis as well as through ex vivo culture assays with and without IL-15.ResultsFour patients were treated in a cohort using ETC targeting NY-ESO-1 following cyclophosphamide conditioning. Treatment was well tolerated without significant toxicity, but all patients ultimately had disease progression. In two of four patients, we obtained post-treatment tumor tissue and in both, NY-ESO-1 antigen was retained despite clear detectable persisting NY-ESO-1–specific T cells in the peripheral blood. Despite a memory phenotype, these persisting cells lacked markers of proliferation or activation. However, in ex vivo culture assays, they could be induced to proliferate and kill tumor using IL-15. These results were also seen in PBMCs from two patients who received gene-engineered T-cell receptor–based products at other centers.ConclusionsETC targeting NY-ESO-1 with single-agent cyclophosphamide alone conditioning was well tolerated in patients with SS and those with MRCL. IL-15 can induce proliferation and activity in persisting NY-ESO-1–specific T cells even in patients with disease progression following ACT. These results support future work evaluating whether IL-15 could be incorporated into ACT trials post-infusion or at the time of progression.

Performance improvements of a short glass fiber-reinforced PA66 composite

A plate used in a medium voltage switch, made by a 25 wt% glass fiber-reinforced polyamide 66 composite filled with flame-retardant red phosphorus (RP) (PA66-GF25 FR (RP)), was injection molded. To satisfy the relatively high dimensional accuracy requirement, a “supporting mold” was used to compensate for the difference between the transverse and longitudinal linear shrinkage of the PA66-GF25 FR (RP). To reduce the internal residual stress caused by the “supporting mold,” hygrothermal conditioning treatments, including boiling water bath at 90–100°C and re-drying at 110°C, were used. To determine the effects of boiling water bath and re-drying on the dimensional accuracy and mechanical properties of the product, three treatment routes were applied. It was found that the route in which the boiling water bath is applied after the “supporting mold” is preferred to ensure the dimensional accuracies and the mechanical properties as a whole. Using a boiling water bath as a hygrothermal conditioning treatment can improve the mechanical properties and increase the dimensional accuracy of the product. In addition, by using the preferred route, re-drying can further improve the tensile, bending, and even impact strength.