Blockage of NOX2/MAPK/NF- κ

Acute energy failure is one of the critical factors contributing to the pathogenic mechanisms of retinal ischemia. Our previous study demonstrated that glucose deprivation can lead to a caspase-dependent cell death of photoreceptors. The aim of this study was to decipher the upstream signal pathway in glucose deprivation- (GD-) induced cell death. We mimicked acute energy failure by using glucose deprivation in photoreceptor cells (661W cells). GD-induced oxidative stress was evaluated by measuring ROS with the DCFH-DA assay and HO-1 expression by Western blot analysis. The activation of NOX2/MAPK/NF-κB signal was assessed by Western blot and immunohistochemical assays. The roles of these signals in GD-induced cell death were measured by using their specific inhibitors. Inhibition of Rac-1 and NOX2 suppressed GD-induced oxidative stress and protected photoreceptors against GD-induced cell death. NOX2 was an upstream signal in the caspase-dependent cell death cascade, yet the downstream MAPK pathways were activated and blocking MAPK signals rescued 661W cells from GD-induced death. In addition, GD caused the activation of NF-κB signal and inhibiting NF-κB significantly protected 661W cells. These observations may provide insights for treating retinal ischemic diseases and protecting retinal neurons from ischemia-induced cell death

Interim estimates of divergence date and vaccine strain match of human influenza A(H3N2) virus from systematic influenza surveillance (2010–2015) in Hangzhou, southeast of China

SummaryObjectivesIn the post-pandemic period 2010–2015, seasonal influenza A(H3N2) virus predominated in Hangzhou, southeast of China, with an increased activity and semi-annual seasons. This study utilized HA virus gene segment sequences to analyze the divergence date and vaccine strain match of human influenza A(H3N2) virus from systematic influenza surveillance in Hangzhou.MethodsVirological and serological analyses of 124 representative A(H3N2) viruses from prospective studies of systematic surveillance samples were conducted to quantify the genetic and antigenic characteristics and their vaccine strain match.ResultsBayesian phylogenetic inference showed that two separate subgroups 3C.3 and 3C.2 probably diverged from group 3C in early 2012 and then evolved into groups 3C.3a and 3C.2a, respectively, in the 2014/15 influenza season. Furthermore, high amino acid substitution rates of the HA1 subunit were found in A(H3N2) group 3C.2a variants, indicating that increased antigenic drift of A(H3N2) group 3C.2a virus is associated with a vaccine mismatch to the 2015/16 vaccine reference strain Switzerland/9715293/2013 (group 3C.3a).ConclusionsA portion of the group 3C.2a isolates are not covered by the current A(H3N2) vaccine strain. These findings offer insights into the emergence of group 3C.2a variants with epidemic potential in the imminent influenza seasons

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

Cardiac H2S Generation Is Reduced in Ageing Diabetic Mice

Aims. To examine whether hydrogen sulfide (H2S) generation changed in ageing diabetic mouse hearts. Results. Compared to mice that were fed tap water only, mice that were fed 30% fructose solution for 15 months exhibited typical characteristics of a severe diabetic phenotype with cardiac hypertrophy, fibrosis, and dysfunction. H2S levels in plasma, heart tissues, and urine were significantly reduced in these mice as compared to those in controls. The expression of the H2S-generating enzymes, cystathionine γ-lyase and 3-mercaptopyruvate sulfurtransferase, was significantly decreased in the hearts of fructose-fed mice, whereas cystathionine-β-synthase levels were significantly increased. Conclusion. Our results suggest that this ageing diabetic mouse model developed diabetic cardiomyopathy and that H2S levels were reduced in the diabetic heart due to alterations in three H2S-producing enzymes, which may be involved in the pathogenesis of diabetic cardiomyopathy

Improving clinical judgment by simulation: a randomized trial and validation of the Lasater clinical judgment rubric in Chinese

Abstract Background The development and assessment of clinical judgment ability are essential in nursing education. The Lasater Clinical Judgment Rubric (LCJR) was shown to be valid in evaluating nursing students’ learning outcomes and skills in western cultures but has not been validated in mainland China. This study aimed to compare a simulation-teaching model with a traditional teaching method in enhancing the clinical judgment ability of nursing undergraduate students and to validate the Chinese version of the Lasater Clinical Judgment Rubric (C-LCJR). Methods Four classes of nursing students (n = 157) at Hubei University of Chinese Medicine, China, were randomly assigned to two control and two experimental classes. The experimental classes were taught using simulation teaching with standardized patients, while the control classes were taught using traditional teaching methods. At the end of the experiment, students in both kinds of classes evaluated their clinical judgment using the C-LCJR. Teachers also rated the students but without knowing who had received the simulation teaching. Confirmatory factor analysis and a Multiple Indicators Multiple Causes (MIMIC) model with Bayesian estimation was fit to the rating data to investigate measurement properties and experimental effects. Results Compared to the control classes, students in the experimental classes performed better in all subdomains of C-LCJR (noticing, interpreting, responding, and reflecting). The measurement properties of the C-LCJR were found to be satisfactory with high factor loadings and reliabilities and no bias from age, gender, and raters. Conclusions The simulation teaching model is more effective than the traditional (non-simulation-based) teaching method in improving clinical judgment of Chinese nursing students. The C-LCJR is a valid and reliable instrument for measuring clinical judgment in nursing students in China

Anti-Larval and Anti-Algal Natural Products from Marine Microorganisms as Sources of Anti-Biofilm Agents

Bacteria growing inside biofilms are more resistant to hostile environments, conventional antibiotics, and mechanical stresses than their planktonic counterparts. It is estimated that more than 80% of microbial infections in human patients are biofilm-based, and biofouling induced by the biofilms of some bacteria causes serious ecological and economic problems throughout the world. Therefore, exploring highly effective anti-biofilm compounds has become an urgent demand for the medical and marine industries. Marine microorganisms, a well-documented and prolific source of natural products, provide an array of structurally distinct secondary metabolites with diverse biological activities. However, up to date, only a handful of anti-biofilm natural products derived from marine microorganisms have been reported. Meanwhile, it is worth noting that some promising antifouling (AF) compounds from marine microbes, particularly those that inhibit settlement of fouling invertebrate larvae and algal spores, can be considered as potential anti-biofilm agents owing to the well-known knowledge of the correlations between biofilm formation and the biofouling process of fouling organisms. In this review, a total of 112 anti-biofilm, anti-larval, and anti-algal natural products from marine microbes and 26 of their synthetic analogues are highlighted from 2000 to 2021. These compounds are introduced based on their microbial origins, and then categorized into the following different structural groups: fatty acids, butenolides, terpenoids, steroids, phenols, phenyl ethers, polyketides, alkaloids, flavonoids, amines, nucleosides, and peptides. The preliminary structure-activity relationships (SAR) of some important compounds are also briefly discussed. Finally, current challenges and future research perspectives are proposed based on opinions from many previous reviews

The application of China Infectious Diseases Automated-alert and Response System in Zhejiang province, 2012

OBJECTIVE: To analyze and evaluate the application of China Infectious Diseases Automated-alert and Response System(CIDARS)in Zhejiang province.METHODS: Data through the monitoring program in 2012 was analyzed descriptively and compared with the incidence data in the same period as well information related to public health emergency events.RESULTS: A total of 14 292 signals were generated on 28 kinds of infectious diseases in the system, in Zhejiang province. 100% of the signals had been responded and the median time to response was 0.81 hours. 123 signals (0.86%)were preliminarily verified as suspected outbreaks and 33 outbreaks were finally confirmed by further field investigation, with a positive ratio of 0.23% . Information related to regional distribution showed significant differences which reflecting a positive correlation between the numbers of diseases and the time of early-warning(r = 0. 97, P &lt; 0.01). Distribution of information related to different types of diseases was also significantly different, showing a positive correlation between the prevalent strength of the disease and the amount of information in a specific area(r = 0.80, P &lt; 0.01).CONCLUSION: CIDARS had a good performance which could be used to assist the local public health institutions on early detection of possible outbreaks at the early stage. However, the effectiveness was different for different regions and diseases.</p