TRIM3 attenuates cytokine storm caused by Dabie bandavirus via promoting Toll-like receptor 3 degradation.

Background: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease that was caused by the Dabie bandavirus (DBV), and it has become a global public health threat. Cytokine storm is considered to be an important pathogenesis of critical SFTS. Tripartite motif-containing 3 (TRIM3), as a member of the TRIM protein family, may contribute to the regulation of the immune and inflammatory responses after viral infection. However, whether TRIM3 plays a major role in the pathogenesis of SFTS has not yet been investigated. Methods: TRIM3 mRNA levels were detected in PBMCs between 29 SFTS patients and 29 healthy controls by qRT-PCR. We established the pathogenic IFNAR-/- SFTS mouse model successfully by inoculating subcutaneously with DBV and testing the expression levels of TRIM3 mRNA and protein by qRT-PCR and immunofluorescence in the livers, spleens, lungs, and kidneys. TRIM3OE THP-1 cells and peritoneal macrophages extracted from TRIM3-/- mice were infected with DBV. The effect of TRIM3 on cytokines was detected by qRT-PCR and ELISA. Then we examined Toll-like receptor 3 (TLR3) and protein phosphorylation in the MAPK pathway after DBV infection using Western blot. Flow cytometry was used to verify TLR3 expression on peripheral blood monocytes in SFTS patients. We further explored the interaction between TRIM3 and TLR3 using CO-IP and Western blot. Results: Compared to healthy controls, TRIM3 mRNA expression in PBMCs is decreased in SFTS patients, especially in severe cases. TRIM3 mRNA and protein were synchronously reduced in the livers, spleens, lungs, and kidney tissues of the IFNAR-/- SFTS mice model. In the DBV-infected cell model, TRIM3 overexpression can inhibit the DBV-induced release of IL-1ß, IL-6, and TNF-α, the expression of TLR3, and protein phosphorylation in the MAPK pathway, which plays an anti-inflammatory role, while TRIM3 deficiency exacerbates the pro-inflammatory effects. We further found that TRIM3 can promote TLR3 degradation through K48-linked ubiquitination. Conclusion: TRIM3 can inhibit the production of cytokines by regulating the degradation of TLR3 through K48-linked ubiquitination, which can be a therapeutic target for improving the prognosis of SFTS.

Evaluation of the efficacy, safety and influencing factors of concomitant and sequential administration of viral respiratory infectious disease vaccines: a systematic review and meta-analysis.

Background: There is no clear conclusion on the immunogenicity and adverse events of concomitant administration the viral respiratory infectious disease vaccines. We aimed to evaluate the impact of concomitant administering viral respiratory infectious disease vaccines on efficiencies, safety and influencing factors. Methods: This meta-analysis included studies from PubMed, Embase, Cochrane Central Register of Clinical Trials, Web of Science, WHO COVID-19 Research, and ClinicalTrials.gov databases. Randomized controlled trials of the adult participants concomitant administered with viral respiratory infectious disease vaccine and other vaccines were included. The main outcomes were the seroconversion rate and seroprotection rate of each vaccine. Used the Mantel-Haenszel fixed effects method as the main analysis to estimate the pooled RRs and the corresponding 95% confidence intervals. The risk of bias for each trial was assessed using the Cochrane Handbook for Systematic Reviews of Interventions, while evidence certainty was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation system. Results: A total of 21 studies comprising 14060 participants with two types of vaccines were retained for the meta-analysis. Concomitant immunization reduced the geometric mean titer (RR: 0.858, 95% CI: (0.785 to 0.939)) and the geometric mean fold rise (0.754 (0.629 to 0.902)) in the SARS-COV-2 vaccine group but increased the seroconversion rate (1.033 (1.0002 to 1.067)) in the seasonal influenza vaccine group. Concomitant administration were influenced by the type of vaccine, adjuvant content, booster immunization, and age and gender of the recipient. Conclusion: This meta-analysis suggested that the short-term protection and safety of concomitant administered were effective. Appropriate adjuvants, health promotion and counselling and booster vaccines could improve the efficiency and safety of Concomitant vaccination. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022343709.

Cyclophilin A causes severe fever with thrombocytopenia syndrome virus-induced cytokine storm by regulating mitogen-activated protein kinase pathway.

Introduction: Severe fever with thrombocytopenia syndrome (SFTS) has become a global threat to public health since its first report in China in 2009. However, the pathogenesis of SFTS virus (SFTSV) in humans remains unclear. Also, there are no effective therapeutics for SFTS. Cyclophilin A (CyPA) regulates protein folding and trafficking involved in various viral infectious diseases, but its role in SFTSV infection has not been elucidated. Methods: We detected plasma CyPA levels in 29 healthy subjects and 30 SFTS patients by ELISA. In THP-1 cells and normal human peripheral blood mononuclear cells (PBMCs), SFTSV-induced extracellular CyPA (eCyPA) was also detected by ELISA. In THP-1, the effects of CyPA on Mitogen-activated protein kinase (MAPK) pathway and NF-κB were determined by Western blot. We validated the interaction between CypA and CD147 by human recombinant CyPA (hrCyPA) and the CD147 inhibitor. Effects of CyPA inhibitor Cyclosporine A (CsA) on cytokines and SFTSV replication in THP-1 cells was also detected. 8-week-old Interferon-α/ß Receptor (IFNAR) knockout (IFNAR-/-) C57BL/6 mice were divided into mock group, 106TCID50 SFTSV (Untreated) group and 106TCID50 SFTSV+CsA (CsA-treated) group. The changes of body weight, animal behavior and survival time of each group were recorded. Blood samples were collected from tail vein regularly. After death, the liver, spleen, lung, kidney and brain were collected for pathological HE staining and SFTSV-NP immunohistochemical staining. Results: Compared to healthy subjects and SFTS patients in the febrile phase of the disease, plasma CyPA levels in SFTS patients at the multi-organ dysfunction (MOD) phase showed significantly elevated (P < 0.01). Extracellular CyPA activates the MAPK pathway by binding to CD147 in THP-1 infected with SFTSV. CsA inhibits the pro-inflammatory and promoting replication effects of CyPA after SFTSV infection in vitro. In vivo, CsA can prolong the survival time and delay the weight loss of SFTSV mice. CsA reduces multi-organ dysfunction in IFNAR-/- mice infected with SFTSV. Discussion: Our results indicate that CyPA is associated with SFTSV-induced cytokine storm, which can be a potential target for SFTS therapy.

Applications of diffusion tensor imaging integrated with neuronavigation to prevent visual damage during tumor resection in the optic radiation area.

Background: Intracranial tumors involving the temporo-occipital lobe often compress or destroy the optic radiation (OpR), resulting in decreased visual function. The aim of this study is to explore the value of diffusion tensor imaging (DTI) tractography integrated with neuronavigation to prevent visual damage when resecting tumors involving the OpR and find potential factors affecting patients' visual function and quality of life (QOL). Methods: Our study is a cross-sectional study that included 28 patients with intracranial tumors in close morphological relationship with the OpR recruited between January 2020 and February 2022. The surgical incision and approach were preoperatively designed and adjusted according to the DTI tractography results and visual function scores. All patients underwent examinations of visual acuity (VA) and visual field index (VFI) and completed visual function and QOL scales at admission and 2 months after discharge. Logistic regression and linear regression analysis were conducted to evaluate clinical factors potentially affecting pre/postoperative OpR morphology, VA, VFI, visual function, and QOL. Results: Lesion size was the main factor found to affect visual function (ß = -0.74, 95%CI: -1.12~-0.36, P = 0.05), VA (left: ß = -0.11, 95%CI: -0.14~-0.08, P < 0.001; right: ß = -0.15, 95%CI: -0.17~-0.13, P < 0.001), and VFI (left: ß = -0.11, 95%CI: -0.14~-0.08, P < 0.001; right: ß = -0.14, 95%CI: -0.16~-0.12, P < 0.001). Lesion size, edema, and involvement of the lateral ventricle temporal horn were factors affecting OpR morphology and QOL. The 28 patients showed significantly improved VA, VFI, visual function, and QOL results (P < 0.05) 2 months after discharge. Conclusions: Combining DTI of OpR mapping and microscopic-based neuronavigation aided precise mapping and thus preservation of visual function in patients undergoing tumor resection. Potential clinical factors affecting patients' visual function and QOL scores were identified which are useful for assessing a patient's condition and predicting prognosis.

Evaluation of the Therapeutic Effect of Antibiotics on Scrub Typhus: A Systematic Review and Network Meta-Analysis.

Background: To explore the efficacy and safety of drugs in patients with scrub typhus. Methods: For this systematic review and network meta-analysis, we searched PubMed, Embase, Web of Science, Cochrane Central Register of Clinical Trials, China National Knowledge Infrastructure (CNKI), and Wanfang data (WF) up to December 2021. All randomized controlled trials (RCTs) of antibiotics used to treat scrub typhus were included without language or date restrictions. The overall effectiveness was evaluated from 4 perspectives: cure rate (CR), defervescence time (DT), gastrointestinal symptoms-adverse events (GS-AD), and abnormal blood count-adverse events (ABC-AD). The quality of evidence was evaluated using the Cochrane Risk of Bias tool and GRADE system. Results: Sixteen studies involving 1,582 patients were included to evaluate 7 drugs, namely, azithromycin, doxycycline, chloramphenicol, tetracycline, rifampin, moxifloxacin, and telithromycin. In this network meta-analysis, rifampicin (82%) and chloramphenicol (65%) were more effective in terms of CR, and moxifloxacin (3%) from the quinolone family was the worst. Azithromycin caused the fewest events in terms of ABC-AD. No differences were found in this network meta-analysis (NMA) in terms of DT and GS-AD. Conclusions: Rifampicin was associated with the highest CR benefit and the lowest risk of DT when used to treat patients with scrub typhus, except in areas where tuberculosis (TB) was endemic. Azithromycin was found to be better in CR and was associated with a lower probability of GS-AD and ABC-AD; therefore, it may be considered to treat pregnant women and children. Moxifloxacin had a much lower CR than other drugs and is, therefore, not recommended for the management of scrub typhus. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42021287837.

Efficacy and Safety of Pharmacological and Physical Therapies for Bell's Palsy: A Bayesian Network Meta-Analysis.

Objective: The objective was to comprehensively assess the efficacy and safety of all pharmacological and physical treatments (short-term, ≤ 1 month) for patients with acute Bell's palsy. Methods: The electronic databases PubMed, Web of Science, Embase, Cochrane Library, and CNKI were searched for the randomized controlled trials comparing two or more regimens in patients with the Bell's palsy to be included in a Bayesian network meta-analysis. Odds ratios and CIs for the primary outcome of the House-Brackmann scale and secondary outcomes of sequelae (synkinesis and crocodile tears) and adverse events were obtained and subgroup analyses of steroids and antivirals were conducted. Results: A total of 26 studies representing 3,609 patients having undergone 15 treatments matched our eligibility criteria. For facial recovery, acupuncture plus electrical stimulation, steroid plus antiviral plus Kabat treatment, and steroid plus antiviral plus electrical stimulation were the top three options based on analysis of the treatment ranking (probability = 84, 80, and 77%, respectively). Steroid plus antiviral plus electrical stimulation had the lowest rate of sequelae but were more likely to lead to mild adverse events. Subgroup analysis revealed that methylprednisolone and acyclovir were likely to be the preferred option. Conclusions: This network meta-analysis indicated that combined therapies, especially steroid plus antiviral plus Kabat treatment, were associated with a better facial function recovery outcome than single therapy. Other physical therapies, such as acupuncture plus electrical stimulation, may be a good alternative for people with systemic disease or allergies. More high-quality trials of physical regimens are needed in the future. Systematic Review Registration: Our registered PROSPERO number is CRD42021275486 and detailed information can be found at https://www.crd.york.ac.uk/PROSPERO/.

Identification of Key Biomarkers and Immune Infiltration in Sporadic Vestibular Schwannoma Basing Transcriptome-Wide Profiling.

BACKGROUND: Vestibular schwannoma is a common intracranial tumor, with 95% of the cases being sporadic vestibular schwannoma (SVS). The purpose of this study was identifying genes responsible for inflammation in SVS and clarifying its underlying immune mechanisms. METHODS: Transcriptional sequencing datasets (GSE141801 and GSE108237) from the Gene Expression Omnibus database were used in this study. The candidate modules closely related to SVS and hub genes were screened out by weighted gene coexpression network analysis. Τhe sensitivity and specificity of the hub genes for SVS prediction were evaluated by receiver operating characteristic curve analysis. The CIBERSORT algorithm was subsequently applied to analyze the immune infiltration between SVS and controls. Finally, biological signaling pathways involved in the hub genes were identified via gene set enrichment analysis. RESULTS: A total of 39 significantly enriched in myelination and collagen-containing extracellular matrix DEGs were identified at the screening step. Three hub genes (MAPK8IP1, SLC36A2, and OR2AT4) were identified, which mainly enriched in pathways of melanogenesis, GnRH, and calcium signaling pathways. Compared with normal nerves, SVS tissue contained a higher proportion of T cells, monocytes, and activated dendritic cells, whereas proportions of M2 macrophages were lower. CONCLUSIONS: The integrated analysis revealed the pattern of immune cell infiltration in SVS and provided a crucial molecular foundation to enhance understanding of SVS. Hub genes MAPK8IP1, SLC36A2, and OR2AT4 are potential biomarkers and therapeutic targets to facilitate the accurate diagnosis, prognosis, and therapy of SVS.

Integrated Analysis of Transcriptome and Differential Methylation of Neurofibromatosis Type 2 Vestibular Schwannomas.

BACKGROUND: Vestibular schwannoma is the third most common benign intracranial tumor that can occur sporadically or be associated with neurofibromatosis type 2 (neurofibromatosis type 2 vestibular schwannoma [NF2-VS]). The aim of this study is to provide a comprehensive bioinformatic analysis of methylated-differentially expressed genes (MDEGs) in NF2-VS. METHODS: Transcriptional sequencing datasets (GSE141801 and GSE108524) and gene methylation microarrays (GSE56598) from the Gene Expression Omnibus database were used to identify and analyze MDEGs in NF2-VS. A protein-protein interaction (PPI) network was built, and the hub genes and modules were identified. Finally, potential pharmacotherapy targeting MDEGs were extracted for NF2-VS. RESULTS: A total of 57 hypermethylation-low expression genes and 88 hypomethylation-high expression genes were identified. Pathways associated with aberrantly MDEGs included P13K-AKT, MAPK, and Ras, which were also involved in NF2-VS. Six hub genes (EGFR, CCND1, CD53, CSF1R, PLAU, and FGFR1) were identified from the PPI network. Modification of the aforementioned genes altered cell-to-cell communication, response to stimulus, cellular regulation, and membrane and protein bindings. Thirty drugs targeting these pathways were selected based on the hub genes. CONCLUSIONS: Analysis of MDEGs may enrich the understanding of the molecular mechanisms of NF2-VS pathogenesis and lay the groundwork for potential biomarkers and therapeutic targets for NF2-VS.

Efficacy and Safety of First-Line Treatment Strategies for Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: A Bayesian Network Meta-Analysis.

BACKGROUND: Targeted therapies have led to significant improvement in the management and prognosis of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). We performed a network meta-analysis of frontline treatment options of ALK-positive NSCLC to provide clinical guidance. METHODS: PubMed, Embase, ClinicalTrials.gov, and international conference databases were searched to identify relevant trials from inception to June 30, 2021. Phase III randomized controlled trials (RCTs) comparing treatments for patients with ALK-positive advanced NSCLC in the first-line setting were included in a Bayesian network meta-analysis. Eligible studies reported at least one of the following clinical outcomes: progression-free survival (PFS), overall survival (OS), risk of the central nervous system (CNS) progression, adverse events (AEs) of grade (G) 3 or higher (G3 AEs), or serious AEs (SAEs). Hazard ratios (HRs) and CI for primary outcome of PFS and secondary outcome of OS and risk of CNS progression were obtained. A multivariate, consistency model, fixed-effects analysis was used in the network meta-analysis. Data on G3 AEs and SAEs were abstracted and meta-analyzed. Risk of bias (RoB) was assessed using the Cochrane Collaboration's tool. RESULTS: Nine RCTs comprising 2,484 patients were included with seven treatments: alectinib, brigatinib, ceritinib, crizotinib, ensartinib, lorlatinib, and chemotherapy. Compared with chemotherapy, ALK-tyrosine kinase inhibitors (TKIs) significantly prolong PFS and reduced risk of CNS progression except for ceritinib. Lorlatinib appears superior at reducing risk of CNS progression. None of the ALK-TKIs have a significantly prolonged OS as compared with chemotherapy. Lorlatinib increases the risk of G3 AEs as compared with alectinib (odds ratio 4.26 [95% CrI 1.22 to 15.53]), while alectinib caused the fewest G3 AEs. CONCLUSIONS: Lorlatinib is associated with the highest PFS benefit and lowest risk of CNS progression benefits for patients with advanced ALK-positive NSCLC, compared with other first-line treatments, but with higher toxicity. The implementation of a newer generation of ALK-TKIs in the first-line treatment of ALK-positive NSCLC into current clinical practice is evolving rapidly.

Reliability and toxicity of bevacizumab for neurofibromatosis type 2-related vestibular schwannomas: A systematic review and meta-analysis.

BACKGROUND: The anti-angiogenic agent bevacizumab is currently the only drug used clinically for neurofibromatosis type 2-related vestibular schwannomas (NF2-VS). Though benefits have been demonstrated in several cases, the standardized dosage remains unclear. OBJECTIVE: Our meta-analysis was performed to systematically and comprehensively investigate the reliability and toxicity of bevacizumab in the treatment of NF2-VS, with particular emphasis on the impact of dosage. METHODS: The literature search was conducted for studies providing data on patients treated with bevacizumab for NF2-VS across PubMed, Embase, and Cochrane Library until December 31, 2020. Two reviewers extracted the incidence rate of results independently. Then we calculated and pooled unadjusted incidence rate with 95% CIs for each study. The subgroups analyzed were conducted. RESULTS: Fourteen citations (prospective or retrospective observational cohort studies) were eligible based on data from a total of 247 patients with NF2 and 332 related VSs. The pooled results showed that the radiographic response rate (RRR) was 30% [95% CI (20%-42%)], the hearing response rate (HRR) was 32% [95% CI (21%-45%)]. The incidence of major complications was: hypertension 29% [95% CI (23%-35%)], proteinuria 30% [95% CI (18%-44%)], menstrual disorders 44% [95% CI (16%-73%)], hemorrhage 14% [95% CI (4%-26%)], grade3/4 events 12% [95% CI (4%-22%)]. CONCLUSIONS: Nearly one-third of NF2-VS patients may benefit significantly from bevacizumab due to hearing improvement and tumor reduction. Menstrual disorders were the most common adverse events. The high-dose regimen didn't show better efficacy, but results varied considerably according to age.