Necroptosis, a form of programmed cell death, initiates a series of biological responses and further culminates in necroinflammatory processes, consequently limiting the efficacy of cytokine antagonists in treating inflammatory diseases. To address this issue, DNAzyme R3-Dz specifically targeting receptor-interacting protein kinase 3 (RIP3) mRNA, a necrosome component, has been successfully developed and studied to elucidate the mechanism in cleaving its target mRNA. Then a polyamidoamine (PAMAM) derivative was constructed through the modification of nucleobase analog (termed AP) to achieve the R3-Dz delivery to macrophages. The AP/R3-Dz nanoparticles effectively downregulated the RIP3 expression, leading to subsequent decrease in the levels of reactive oxygen species (ROS) and damage-associated molecular patterns (DAMPs), ultimately inhibiting the necroinflammatory processes mediated by the NOD-like receptor family pyrin domain-containing 3 (NLRP3). Finally, AP/R3-Dz nanoparticles and their combination with the NLRP3 inhibitor MCC950 suppressed the necrotic phenotype and ameliorated the disease progression in diverse models, including gouty arthritis, autoimmune hepatitis and rheumatoid arthritis. In summary, the AP/R3-Dz nanoparticles in combination with MCC950 have been demonstrated to achieve the intervention in necroptosis and inflammation by dual disruption of the intricate feedback loop of necroinflammation and thus have promising potential in the treatment of inflammatory diseases.

Objective:To assess the diagnostic and prognostic value of lymphocyte subtyping for invasive candidiasis infection (ICI) in critically ill patients with non-neutropenic sepsis.Methods:A prospective observational cohort study was performed at Peking Union Medical College Hospital (PUMCH), 377 patients with non-neutropenic sepsis admitted to Department of Critical Care Medicine from January 2017 to November 2019 were enrolled. There were 9.0% (34/377) patients diagnosed as ICI. Vital signs, supportive care therapy and microbiological specimens were collected. Peripheral blood lymphocyte subtypes, serum globulin, complements, inflammatory factors such as interleukin(IL)-6, IL-8, IL-10 and tumor necrosis factor were detected within 24 hours after sepsis was diagnosed. The receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value and prognostic significance of immunological indicators for ICI. Multiple logistic regression was used to analyze the independent risk factors for ICI. Kaplan-Meier analysis was used to analyze survival.Results:The acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ) score was 17.0 (13.0, 21.0) in all 377 patients. The sequential organ failure score (SOFA) was 11.0 (8.0, 13.0), and the 28-day mortality rate was 27.6% (104/377). Peripheral blood CD8 +absolute T lymphocyte count≤177 cells/μl, CD28 +CD8 +T-cell count≤81 cells/μl and 1, 3-β-D-glucan (BDG) ≥88.20 ng/L were closely correlated with the diagnosis of ICI (AUC=0.793,95 %CI 0.749-0.833, P<0.000 1;AUC=0.892,95 %CI 0.856-0.921, P<0.000 1;AUC=0.761, 95 %CI 0.715-0.803, P<0.000 1, respectively), with sensitivity of diagnosis 94.12%, 100.00%, and 88.24%; the specificity of diagnosis 81.34%, 62.39%, 63.56% respectively. Multivariate logistic regression analysis identified CD8 +T-cell count≤139 cells/μl ( OR=7.463, 95 %CI 1.300-42.831, P=0.024) and CD28 +CD8 +T-cell counts≤52 cells/μl ( OR=57.494, 95 %CI 3.986-829.359, P=0.003) as independent risk factors for higher mortality. Kaplan-Meier survival analysis suggested that CD8 +T-cell count ≤139 cells/μl ( P=0.0159) and CD28 +CD8 +T-cell count≤52 cells/μl ( P=0.000 1) were associated with higher mortality within 28 days (68.8%, 91.7%). Conclusions:Low CD28 +CD8 +T cell count in peripheral blood is closely related to the development and clinical outcome of ICI in sepsis patients, which could be used as an effective indicator for the diagnosis and prognosis prediction of ICI.

Objective To study the efficacy and safety of endoscopic submucosal dissection ( ESD ) for colorectal neuroendocrine tumor .Methods Clinical data of 43 cases of colorectal neuroendocrine tumor receiving ESD therapy from Sep .2010 to Feb.2014 were retrospectively analyzed , and the safety and efficacy were evalua-ted.Results All the 43 cases received ESD therapy , among whom 2(4.65%)cases developed delayed bleeding and recovered after endoscopic treatment .No perforation was found .4 cases had high fever and recovered after antibiotic treatment.One case(2.33%)of recurrence was found by colonoscopy 1 year later, and underwent sur-gery.The other 42 cases were followed up for 6 months to 2 years, during which no recurrence or metastasis was found.Conclusion ESD is a simple, safe and effective modality for colorectal neuroendocrine tumor .