LncRNA SNHG16 Inhibits Intracellular M. tuberculosis Growth Involving Cathelicidin Pathway, Autophagy, and Effector Cytokines Production.

Long noncoding small nucleolar RNA (LncRNA) host gene 16 (SNHG16) is associated with certain diseases, including cancers. However, its role and mechanism in Mycobacterium tuberculosis (Mtb) infection remain unclear. Here, we demonstrated that SNHG16 expression levels were suppressed in peripheral blood mononuclear cells (PBMCs) and CD14+ monocytes of tuberculosis (TB) patients. SNHG16 was up-regulated by acute Mtb infection of PBMCs from healthy control (HC) subjects. Such TB suppression of SNHG16 was consistent with an immunosuppressive-like state driven by IL-10 signaling as seen in TB patients. Notably, SNHG16 limited Mtb growth in macrophages/monocytes through autophagy and vitamin D receptor (VDR)-dependent cathelicidin (CAMP) antimicrobial pathways. Concurrently, SNHG16 was highly expressed in lymphocytes, including CD8+ and Vγ2 Vδ2 T-cell subsets in HCs. SNHG16 overexpression in lymphocytes allowed them to control Mtb infection in macrophages, and SNHG16 epigenetically increased the expression of anti-Mtb effector cytokines in lymphocytes by developing more accessible chromatin states in gene loci encoding IFN-γ, TNF-α, and Granzyme B. Furthermore, the adoptive transfer of SNHG16-overexpressing human PBMCs into Mtb-infected SCID mice conferred protective immunity against Mtb infection. Thus, SNHG16 drove the induction of pleiotropic effector functions that inhibited intracellular Mtb growth in vitro and in vivo, serving as an immunotherapy target in TB.

Two-pronged microenvironmental modulation of metal-oxidase cascade catalysis and metabolic intervention for synergistic tumor immunotherapy.

Immunotherapy is an emerging treatment modality for tumors after surgery, radiotherapy, and chemotherapy. Despite the potential for eliminating primary tumor cells and depressing cancer metastasis, immunotherapy has huge challenges including low tumor immunogenicity and undesirable immunosuppressive tumor microenvironment (TME). Herein, the two-pronged microenvironmental modulation nanoplatform is developed to overcome these limitations. Specifically, hollow mesoporous MnO2 (HM) nanoparticles with pH responsive property are prepared and modified with glucose oxidase (GOX) by amide bond, which are further loaded with a potent glutaminase inhibitor CB839 to obtain HM-GOX/CB839. Under the low pH values in TME, HM was disintegrated, thereby releasing Mn2+, GOX and CB839. On the one hand, Mn2+ can convert H2O2 that increased by GOX catalysis in tumors into highly toxic hydroxyl radicals (•OH) and further induce immunogenic cell death (ICD) through the metal-oxidase cascade catalytic reaction, enhancing immunogenicity. On the other hand, GOX and CB839 can block glycolytic and glutamine metabolism pathways, respectively, which effectively reduce the number of immunosuppressive cells and reshape TME, improving anti-tumor immune efficacy. It is demonstrated that HM-GOX/CB839 can effectively activate the body's immunity and inhibit tumor growth and metastasis, providing a potential strategy for comprehensive tumor therapy. STATEMENT OF SIGNIFICANCE: Integrated microenvironmental modulation of metal-oxidase cascade catalysis and metabolic intervention offers a potential avenue for tumor immunotherapy. Under this premise, we constructed a two-pronged microenvironmental modulation nanoplatform (HM-GOX/CB839). On the one hand, the metal oxidase cascade could catalyze the generation of hydroxyl radicals (•OH) and induce immunogenic cell death (ICD), enhancing immunogenicity; on the other hand, metabolic intervention reprogrammed tumor microenvironment to relieve immunosuppression and thereby enhancing anti-tumor immune response. The resulting data demonstrated that HM-GOX/CB839 effectively inhibited tumor growth and metastasis, providing therapeutic potential for cancer immunotherapy.

Synthesis, Antifungal Activity, 3D-QSAR and Controlled Release on Hydrotalcite Study of Longifolene-Derived Diphenyl Ether Carboxylic Acid Compounds.

Twenty-two novel longifolene-derived diphenyl ether-carboxylic acid compounds 7a-7v were synthesized from renewable biomass resources longifolene, and their structures were confirmed by FT-IR, 1H NMR, 13C NMR, and HRMS. The preliminary evaluation of in vitro antifungal activity displayed that compound 7b presented inhibition rates of 85.9%, 82.7%, 82.7%, and 81.4% against Alternaria solani, Cercospora arachidicola, Rhizoctonia solani, and Physalospora piricola, respectively, and compound 7l possessed inhibition rates of 80.7%, 80.4%, and 80.3% against R. solani, C. arachidicola, P. piricola, respectively, exhibiting excellent and broad-spectrum antifungal activities. Besides, compounds 7f and 7a showed significant antifungal activities with inhibition rates of 81.2% and 80.7% against A.solani, respectively. Meanwhile, a reasonable and effective 3D-QSAR mode (r2 = 0.996, q2 = 0.572) has been established by the CoMFA method. Furthermore, the drug-loading complexes 7b/MgAl-LDH were prepared and characterized. Their pH-responsive controlled-release behavior was investigated as well. As a result, complex 7b/MgAl-LDH-2 exhibited excellent controlled-releasing performance in the water/ethanol (10:1, v:v) and under a pH of 5.7.

Characterization difference of typical KL1, KL2 and ST11-KL64 hypervirulent and carbapenem-resistant Klebsiella pneumoniae.

Almost all the formation of hypervirulent and carbapenem-resistant Klebsiella pneumoniae follow two major patterns: KL1/KL2 hvKP strains acquire carbapenem-resistance plasmids (CR-hvKP), and carbapenem-resistant Klebsiella pneumoniae (CRKP) strains obtain virulence plasmids (hv-CRKP). These two patterns may pose different phenotypes. In this study, three typical resistance and hypervirulent K. pneumoniae (KL1, KL2, and ST11-KL64), isolating from poor prognosis patients, were selected. Compared with ST11-KL64 hv-CRKP, KL1/KL2 hypervirulent lineages harbor significantly fewer resistance determinants and exhibited lower-level resistance to antibiotics. Notably, though the blaKPC gene could be detected in all these isolates, KL1/KL2 hvKP strain did not exhibit corresponding high-level carbapenem resistance. Unlike the resistance features, we did not observe significant virulence differences between the three strains. The ST11-KL64 hv-CRKP (1403) in this study, showed similar mucoviscosity, siderophores production, and biofilm production compared with KL1 and KL2 hvKP. Moreover, the hypervirulent of ST11-KL64 hvKP also verified with the human lung epithelial cells infection and G. mellonella infection models. Moreover, we found the pLVPK-like virulence plasmid and IncF blaKPC-2 plasmid was crucial for the formation of hypervirulent and carbapenem-resistant K. pneumoniae. The conservation of origin of transfer site (oriT) in these virulence and blaKPC-2 plasmids, indicated the virulence plasmids could transfer to CRKP with the help of blaKPC-2 plasmids. The co-existence of virulence plasmid and blaKPC-2 plasmid facilitate the formation of ST11-KL64 hv-CPKP, which then become nosocomial epidemic under the antibiotic stress. The ST11-KL64 hv-CPKP may poses a substantial threat to healthcare networks, urgent measures were needed to prevent further dissemination in nosocomial settings.

The Value of Rivaroxaban Combined with Ticagrelor in Antithrombotic Therapy after PCI in Patients with Nonvalvular Atrial Fibrillation with Acute Coronary Syndrome.

Objective: Based on a retrospective cohort study, to investigate the value of rivaroxaban combined with ticagrelor in antithrombotic therapy after PCI in patients with nonvalvular atrial fibrillation with acute coronary syndrome. Methods: A total of 60 patients from January 2019 to May 2021 accepted therapy with antithrombotic therapy after PCI. The patients treated with ticagrelor were set as the control group, and those given rivaroxaban combined with ticagrelor were set as the research group. The curative effect, myocardial level, TIMI blood flow grade, platelet aggregation rate, and the incidence of cardiovascular events were taken from the comparisons. Results: The research group's therapeutic impact was superior to the control group's therapeutic impact, and the value was higher. After treatment, the myocardial levels of the two groups decreased, and the levels of troponin I, creatine kinase isoenzyme, and hypersensitive C-reactive protein in the research group were greatly less than those in the control group, and the difference was statistically significant (P < 0.05). After operation, the TIMI blood flow classification in the experimental group was better than that in the control group, and the difference was statistically significant (P < 0.05). The experimental group's platelet aggregation incidence was considerably lower than the control group's platelet aggregation incidence at 0.5 and 2 hours following surgery, and the difference was statistically significant (P < 0.05). The incidence of acute myocardial infarction, cardiogenic death, and intractable angina pectoris in the research group was significantly lower than that in the control group. Conclusion: Rivaroxaban combined with ticagrelor in the treatment of nonvalvular atrial fibrillation with acute coronary syndrome after percutaneous coronary intervention; the TIMI blood flow grade is better than ticagrelor, which is of great significance to reduce mortality and has high safety in clinical application.

Engineering controllable oxygen vacancy defects in iron hydroxide oxide immobilized on reduced graphene oxide for boosting visible light-driven photo-Fenton-like oxidation.

Visible light-driven photo-Fenton-like technology is a promising advanced oxidation process for water remediation, while the construction of effective synergetic system remains a great challenge. Herein, iron hydroxide oxide (α-FeOOH) with controllable oxygen vacancy defects were engineered on reduced graphene oxide (rGO) nanosheets (named as OVs-FeOOH/rGO) through an in-situ redox method for boosting visible light-driven photo-Fenton-like oxidation. By adjusting the pH environment to modulate the redox reaction kinetics between graphene oxide (GO) and ferrous salt precursors, the oxygen vacancy concentration in α-FeOOH could be precisely controlled. With optimized oxygen vacancy defects obtained at pH 5, the OVs-FeOOH/rGO displayed superior photo-Fenton-like performance for Rhodamine B degradation (99% within 40 mins, rate constant of 0.2278 mg-1 L min-1) with low H2O2 dosage (5 mM), standing out among the reported photo-Fenton-like catalysts. The catalyst also showed excellent reusability, general applicability, and tolerance ability of realistic environmental conditions, which demonstrates great potential for practical applications. The results reveal that moderate oxygen vacancy defects can not only strengthen absorption of visible light and organic pollutants, but also promote the charge transfer to simultaneously accelerate the photogenerated electron-hole separation and Fe(III)/Fe(II) Fenton cycle, leading to the remarkable photo-Fenton-like oxidation performance. This work sheds light on the controllable synthesis and mechanism of oxygen vacancy defects to develop efficient photo-Fenton-like catalysts for wastewater treatment.

Twice-daily vs higher-dose once-daily thoracic radiotherapy for limited-disease small-cell lung cancer: A PRISMA-compliant meta-analysis.

INTRODUCTION: The optimal dose and fractionation of thoracic radiotherapy (RT) for limited-disease small-cell lung cancer (LD-SCLC) remain controversial. This meta-analysis was performed to compare the efficacy and RT toxicity between twice-daily thoracic RT (45 Gy with 1.5 Gy twice daily) and higher-dose once-daily RT (60-72 Gy with 1.8 Gy/2 Gy once daily) administered with chemotherapy in LD-SCLC patients. METHODS: PubMed, EMBASE, Web of Science, and the Cochrane Library were searched up to March 19, 2020 for studies that compared twice-daily thoracic RT (45 Gy with 1.5 Gy twice daily over 3 weeks) with higher-dose once-daily RT (60-72 Gy with 1.8 Gy/2 Gy once daily over 6-8 weeks) in LD-SCLC patients. RESULTS: Five studies involving 13,726 patients were included in this analysis. Compared with the once-daily thoracic RT group, the 1-year overall survival (OS) rate (P < .001), the 2-year OS rate (P < .001), the 5-year OS rate (P < .001), the mOS (P < .001), and the 1-year LRFS rate (P = .048) were significantly improved in the twice-daily RT group. The toxic effects of RT (esophagitis: P = .293; pneumonitis: P = .103) were similar in both groups. CONCLUSION: Compared with the higher-dose once-daily regimen, the twice-daily thoracic radiotherapy regimen improved efficacy but did not increase RT toxicity in LD-SCLC patients.

Hypofractionated radiation therapy with versus without immune checkpoint inhibitors in patients with brain metastases: A meta-analysis.

INTRODUCTION: The efficacy and safety of hypofractionated radiation therapy (HFRT) combined with immune checkpoint inhibitors (ICIs) in patients with brain metastases (BM) remain controversial. This meta-analysis was performed to compare the efficacy and safety of HFRT with and without ICIs in BM patients. MATERIALS AND METHODS: PubMed, Embase, and Cochrane Library were searched up to 25 December 2018 for studies that compared the efficacy and safety of HFRT with and without ICIs in BM patients. RESULTS: Twenty-four studies involving 2,365 patients were included in this analysis. Compared with those of HFRT without ICIs, the 6-month locoregional recurrence-free survival (LRFS) rate (P = 0.002), 6-month overall survival (OS) rate (P = 0.001), 1-year OS rate (P = 0.001), 2-year OS rate (P = 0.007), and median OS (mOS) (P < 0.001) were significantly improved in combined HFRT and ICI treatment. A trend toward improved 1-year LRFS rate (P = 0.392) and 3-year OS rate (P = 0.266) for the ICI arm was observed compared with the non-ICI arm, although there was no statistically significant difference between the two arms. No significant difference in toxicity was found between the two arms (radionecrosis: P = 0.361; BM hemorrhage: P = 0.738). CONCLUSIONS: Compared with HFRT without ICIs, the combination of these two therapies improved efficacy but did not increase toxicity in patients with BM.

Bevacizumab and risk of intracranial hemorrhage in patients with brain metastases: a meta-analysis.

Administration of bevacizumab to patients with brain metastases (BM) is controversial due to concerns about the increased risk of intracranial hemorrhage (ICH). This meta-analysis assessed whether the risk of ICH increases in BM patients receiving treatments that contain bevacizumab versus without. PubMed, Embase, Cochrane Library and annual meeting abstracts of the American Society of Clinical Oncology up to 13 November 2016 were searched for studies that referred to ICH complications due to bevacizumab in patients with BM. Eight studies involving 8713 patients were included in this analysis. Compared with the control arm without bevacizumab, the bevacizumab treatment arm did not exhibit a significant increase in ICH [odds ratio (OR) 1.20; 95% confidence intervals (CI) 0.69-2.09; P = 0.53]. Subgroup analyses with retrospective studies showed a similar result, although subgroup analyses with prospective studies failed. This meta-analysis revealed that bevacizumab does not significantly increase the risk of ICH in solid tumor patients with BM.