Targeting APT2 improves MAVS palmitoylation and antiviral innate immunity.

Innate immunity serves as the primary defense against viral and microbial infections in humans. The precise influence of cellular metabolites, especially fatty acids, on antiviral innate immunity remains largely elusive. Here, through screening a metabolite library, palmitic acid (PA) has been identified as a key modulator of antiviral infections in human cells. Mechanistically, PA induces mitochondrial antiviral signaling protein (MAVS) palmitoylation, aggregation, and subsequent activation, thereby enhancing the innate immune response. The palmitoyl-transferase ZDHHC24 catalyzes MAVS palmitoylation, thereby boosting the TBK1-IRF3-interferon (IFN) pathway, particularly under conditions of PA stimulation or high-fat-diet-fed mouse models, leading to antiviral immune responses. Additionally, APT2 de-palmitoylates MAVS, thus inhibiting antiviral signaling, suggesting that its inhibitors, such as ML349, effectively reverse MAVS activation in response to antiviral infections. These findings underscore the critical role of PA in regulating antiviral innate immunity through MAVS palmitoylation and provide strategies for enhancing PA intake or targeting APT2 for combating viral infections.

Prognostic model and ceRNA network of m7G- and radiosensitivity-related genes in hepatocellular carcinoma.

Background: Radiotherapy is an effective treatment for hepatocellular carcinoma (HCC). Recent studies indicated that N7-methylguanosine (m7G)-associated genes are involved in radioresistance and prognosis of HCC. However, the prognostic value and underlying mechanism of m7G-and radiosensitivity-associated genes are still lacking. Methods: The related statistics of HCC were downloaded from The Cancer Genome Atlas (TCGA). M7G- and radiosensitivity-associated genes were screened and evaluated using correlation, differential, univariate, and multivariate analysis. The least absolute shrinkage and selection operator (LASSO) algorithm was used to establish a prognostic model. Prognostic efficacy, functional analysis, immune cell infiltration,and drug sensitivity of the prognostic model were assessed. The ceRNA network was predicted and evaluated through the StarBase database, correlation analysis, expression analysis, and survival analysis. Result: METTL1, EIF3D, NCBP2, and WDR4 participated in prognosis model construction. The favorable prediction efficiency has been verified in both the training and verification sets. Different risk groups have differences in prognosis outcome, function analysis, immune cell infiltration, and drug sensitivity. NCBP2 can be used to predict the prognosis and has excellent potential in immunotherapy. A prognostic ceRNA network based on the NCBP2/miR-122-5p axis was established. Conclusion: The prognosis model of m7G- and radiosensitivity-related genes is constructed, and widely used in clinical prognosis, immunotherapy, and drug therapy. NCBP2, as a hub gene, may be a prognostic biomarker for HCC and is related to immunotherapy. Establishing the NCBP2/miR-122-5p axis helps study the mechanism of ceRNA and provides new ideas for finding a new candidate biomarker.

Comparison of tube shunt implantation and trabeculectomy for glaucoma: a systematic review and meta-analysis.

OBJECTIVE: To compare the efficacy and safety of tube shunt implantation with trabeculectomy in the treatment of patients with glaucoma. METHODS: A systematic literature search was performed for studies comparing tube with trabeculectomy in patients with glaucoma (final search date: 27 February 2022). Comparisons between tube and trabeculectomy were grouped by the type of tube (Ahmed, Baerveldt, Ex-PRESS and XEN). The primary endpoints included intraocular pressure (IOP), IOP reduction (IOPR), IOPR percentage (IOPR%), complete success rate (CSR), qualified success rate (QSR) and adverse events (AEs). RESULTS: Forty-nine studies were included in this meta-analysis and presented data for 3795 eyes (Ahmed: 670, Baerveldt: 561, Ex-PRESS: 473, XEN: 199, trabeculectomy: 1892). Ahmed and Ex-PRESS were similar to trabeculectomy in terms of IOP outcomes and success rate (Ahmed vs trabeculectomy: IOPR%: mean difference (MD)=1.34 (-5.35, 8.02), p=0.69; Ex-PRESS vs trabeculectomy: IOPR%: MD=0.12 (-3.07, 3.31), p=0.94). The IOP outcomes for Baerveldt were worse than those for trabeculectomy (IOPR%: MD=-7.51 (-10.68, -4.35), p<0.00001), but the QSR was higher. No significant difference was shown for the CSR. XEN was worse than trabeculectomy in terms of IOP outcomes (IOPR%: MD=-7.87 (-13.55, -2.18), p=0.007), while the success rate was similar. Ahmed and Ex-PRESS had a lower incidence of AEs than trabeculectomy. Baerveldt had a lower incidence of bleb leakage/wound leakage, hyphaema and hypotonic maculopathy than trabeculectomy but a higher incidence of concurrent cataracts, diplopia/strabismus and tube erosion. The incidence of AEs was similar for the XEN and trabeculectomy procedures. CONCLUSION: Compared with trabeculectomy, both Ahmed and Ex-PRESS appear to be associated with similar ocular hypotensive effects and lower incidences of AEs. However, Baerveldt and XEN cannot achieve sufficient reductions in IOP outcomes similar to those of trabeculectomy. PROSPERO REGISTRATION NUMBER: CRD42021257852.

Preoperative hypoalbuminemia in patients undergoing cardiac surgery: a meta-analysis.

The preoperative serum albumin level has been shown to be associated with adverse postoperative complications, meaning that hypoalbuminemia may also be a risk factor. We performed a meta-analysis to evaluate the association of serum albumin levels with survival and complication rates after cardiac surgery. Relevant articles were identified through seven databases. Twenty studies with 22553 patients (hypoalbuminemia group, n = 9903; normal group, n = 12650) who underwent cardiac surgery met the inclusion criteria after screening. The primary outcomes were that hypoalbuminemia was significantly correlated with serious long-term all-cause mortality (hazard ratio [HR]: 1.95 [1.54-2.48]; P < 0.00001) and increased mortality (risk ratio [RR] = 1.91 [1.61-2.27], P < 0.00001). Hypoalbuminemic patients with cardiopathy were more likely to suffer postoperative complications (bleeding, infections, renal injury, and others) than those whose serum albumin levels were normal. Furthermore, hypoalbuminemia increased the time in the intensive-care unit (ICU) (mean difference [MD] = 1.18 [0.49-1.87], P = 0.0008), length of hospital stay (LOS) (MD = 3.34, 95% CI: 1.88-4.80, P < 0.00001), and cardiopulmonary bypass time (CPB) (MD = 12.40 [1.13-23.66], P = 0.03). Hypoalbuminemia in patients undergoing cardiac surgery appears to have a poor all-cause mortality or increased risk of complications. Adjusted perioperative serum albumin levels and treatment strategies for this high-risk population have the potential to improve the survival.

The Effect of Vitamin D Supplementation in Children With Asthma: A Meta-Analysis.

Background: An increasing number of studies have suggested that vitamin D can be used to treat childhood asthma, but its clinical effects are still unclear. We conducted this meta-analysis to examine the latest estimates of the effectiveness and safety of using vitamin D to treat childhood asthma. Methods: The PubMed, The Cochrane Library, ScienceDirect, Embase, Scopus, Ovid MEDLINE, Web of Science, and Google Scholar databases were searched for randomized controlled trials (RCTs) describing vitamin D supplementation interventions for asthmatic children. Asthma exacerbation, vitamin D levels, the predicted percentage of forced expiratory volume in the first second (FEV1%) and adverse effects (AEs) were analyzed as the main outcome measures. Results: After screening, eight RCTs with 738 children were included. Compared with placebos, vitamin D supplementation had a stronger effect on serum vitamin D levels [mean difference (MD) = 13.51 (4.24, 22.79), p = 0.004]. The pooled results indicated that no significant changes were found between the groups in asthma control, as measured by adopting the following indicators: asthma exacerbation [risk ratio (RR) = 0.92 (0.68, 1.25), p = 0.60]; Childhood Asthma Control Test (CACT) scores [MD = 0.15 (-0.43, 0.74), p = 0.61]; hospitalizations for asthma exacerbation [RR = 1.20 (0.48, 2.96), p = 0.70]; acute care visits [RR = 1.13 (0.77, 1.65), p = 0.63]; steroid use [RR = 1.03 (0.41, 2.57), p = 0.95]; and fractional exhaled nitric oxide (FeNO) [MD =-3.95 (-22.87, 14.97), p = 0.68]. However, vitamin D supplementation might reduce the FEV1% [MD = -4.77 (-9.35, -0.19), p = 0.04] and the percentage of predicted forced vital capacity (FVC%) [MD =-5.01 (-9.99, -0.02), p = 0.05] in patients. Subgroup analysis revealed no difference in AEs between the two groups. Conclusions: Vitamin D supplementation significantly increased patients' serum vitamin D levels, but it had no benefit for asthma control. However, vitamin D supplementation might reduce patients' lung function. It is essential to systemically search for more large-scale, rigorous, and well-designed RCTs to fully confirm these conclusions. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021288838, PROSPERO CRD42021288838.

Efficacy and safety of empagliflozin at different doses in patients with type 2 diabetes mellitus: A network meta-analysis based on randomized controlled trials.

WHAT IS KNOWN AND OBJECTIVE: As an oral hypoglycaemic drug that significantly reduces cardiovascular risk, empagliflozin is often used in patients with type 2 diabetes mellitus (T2DM). However, the dosage and administration of empagliflozin are still controversial clinically. To determine the most appropriate dose, we performed this network meta-analysis. METHODS: We identified randomized controlled trials (RCTs) about empagliflozin from eight databases. We analysed the pharmacodynamics, adverse effects (AEs), and pharmacokinetics of empagliflozin at different doses. RESULTS: We identified 8264 articles, of which 23 RCTs with 10518 patients were included. Regarding haemoglobin A1c (HbA1c) and fasting plasma glucose (FPG), high-daily doses (10, 25, 50 mg) were significantly better than low doses (1, 2.5, 5 mg). For total AEs, there was a dose-response trend in which safety decreased with increasing doses. According to SUCRA sequencing, the order for lowering HbA1c was 25 > 50 > 10 > 5 > 1 mg, for lowering FPG was 50 > 25 > 10 > 5 > 2.5 > 1 mg and for safety was 1> 5 > 10 > 25> 2.5 > 50 mg. When considering HbA1c, FPG and total AEs, we performed a hierarchical cluster analysis and network meta-analysis to find that 25 mg performed best among different doses, which was more significant after long-term use (≥ 12 weeks). Pharmacokinetic parameters exhibited significant dose-response relationships. WHAT IS NEW AND CONCLUSION: High-daily doses (10, 25, 50 mg) had better efficacy than low doses (1, 2.5, 5 mg). When considering HbA1c, FPG and total AEs, 25 mg performed best among the different doses in patients with T2DM.

The efficacy and toxicity of maintenance therapy with bevacizumab plus pemetrexed versus bevacizumab/pemetrexed alone for stage IIIB/IV nonsquamous non-small cell lung cancer: A meta-analysis of randomized controlled trials.

WHAT IS KNOWN AND OBJECTIVE: Whether maintenance therapy with bevacizumab (Bev) + pemetrexed (Pem) can achieve greater clinical benefits than Bev or Pem alone for stage IIIB/IV nonsquamous non-small cell lung cancer (NSCLC) remains unclear. We assessed the antitumour effect and toxicity of maintenance Bev+Pem versus maintenance with single-agent Bev/Pem in this meta-analysis. METHODS: Appropriate randomized controlled trials (RCTs) were screened using electronic databases (Google Scholar, PubMed, Embase, Scopus, ScienceDirect, Ovid MEDLINE, Cochrane and Web of Science). The endpoints were progression-free survival (PFS), overall survival (OS) and adverse events (AEs). RESULTS AND DISCUSSION: We included six RCTs that contained 2,447 patients receiving induction therapy with platinum-based combination therapies. The maintenance therapy Bev+Pem group had prolonged PFS (HR = 0.74, 95% CI 0.69-0.80, p < 0.00001) and OS (HR = 0.91, 95% CI 0.83-0.99, p = 0.02) compared with the Bev/Pem group. Moreover, we further analysed the PFS rate (PFSR) and OS rate (OSR) and found that the Bev+Pem group exhibited improved PFSR-0.5y, PFSR-1y, PFSR-1.5y, PFSR-2y and OS-2y, with preferable trends in OS-1y, OS-3y and OS-4y compared with the Bev/Pem single-agent maintenance therapy. In addition, subgroup analyses indicated that the Bev+Pem group had greater PFS and OS among patients aged <65 years, patients with an Eastern Cooperative Oncology Group (ECOG) score of 0, and patients who never smoked. Regarding adverse events (AEs), the Bev+Pem group exhibited an increased occurrence of anaemia, fatigue, thrombocytopenia and anorexia. WHAT IS NEW AND CONCLUSION: For stage IIIB/IV nonsquamous NSCLC patients, maintenance therapy with Bev+Pem offers an increased survival outcome (PFS, OS) compared with monotherapy. However, the increased incidence of AEs should not be neglected.

The benefits and risks of pembrolizumab in combination with chemotherapy as first-line therapy in small-cell lung cancer: a single-arm meta-analysis of noncomparative clinical studies and randomized control trials.

BACKGROUND: Although pembrolizumab has shown clinical benefit in patients with small-cell lung cancer (SCLC), its actual efficacy in combination with a conventional chemotherapy drug has not been determined. We performed this study to discern the efficacy and risk of pembrolizumab in combination with chemotherapy as first-line therapy in SCLC patients. METHODS: We systematically searched the PubMed, ScienceDirect, Cochrane Library, Scopus, Ovid MEDLINE, Embase, Web of Science, and Google Scholar databases for relevant studies. The main outcomes were overall survival (OS) and progression-free survival (PFS). RESULTS: We identified 2980 articles and included 6 studies (5 were noncomparative open-label studies and 1 was a randomized controlled trial [RCT]) involving 396 patients in our meta-analysis. The pooled median OS (mOS) was 9.6 months (95% CI, 8.0-11.2), and the pooled median PFS (mPFS) was 4.2 months (95% CI, 2.2-6.1). The 1-year overall survival rate (OSR-1y) and 6-month progression-free survival rate (PFSR-6m) were 45.1% (95% CI, 33-57.2%) and 41.6% (95% CI, 24.3-59%), respectively. The objective response rate (ORR) was 38.8% (95% CI, 11.9-65.67%), disease control rate (DCR) was 69.30% (95% CI, 51.6-87.0%), complete response (CR) was 2.20% (95% CI, 0.8-3.7%), partial response (PR) was 34.70% (95% CI, 7.8-61.5%), and stable disease (SD) was 20.90% (95% CI, 9.1-32.6%). The grade 3-4 adverse effect (AE) rate was 20.88% (95% CI, 1.22-54.85%). The most common AEs were neutropenia (90.16%), anemia (53.21%), dysphagia (41.96%), platelet count decrease (34.87%), and esophagitis (32.89%); severe AEs included neutropenia, respiratory failure, pneumonitis, acute coronary syndrome, and colitis/intestinal ischemia. CONCLUSIONS: The combination of pembrolizumab with conventional chemotherapy is an effective therapeutic schedule with acceptable and manageable efficacy and toxicity in patients with SCLC. More high-quality and well-designed RCTs with large sample sizes are warranted to further validate our findings.

Topotecan plus Platinum-Based Chemotherapy versus Etoposide plus Platinum-Based Chemotherapy for Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Whether topotecan plus platinum-based chemotherapy (TP) can achieve better results than etoposide plus platinum-based chemotherapy (EP) for small-cell lung cancer (SCLC) treatment is still controversial in clinical applications. We compared the effectiveness and toxicity of TP versus EP in this meta-analysis. METHODS: We searched PubMed, ScienceDirect, Cochrane Library, Scopus, Ovid MEDLINE, Embase, Web of Science, and Google Scholar databases for completeness one by one to find articles that met the conditions. Overall survival (OS) and progression-free survival (PFS) were analyzed as primary endpoints, and the objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were analyzed as secondary endpoints. RESULTS: In total, 2,480 articles were retrieved, and 6 randomized controlled trials (RCTs) contained results based on 1,924 patients. EP suggested conspicuously better OS (hazard ratio [HR]: 1.24 [1.02, 1.50], p = 0.03) and PFS (HR: 1.39 [1.17, 1.64], p = 0.0001) in SCLC treatment than TP, and ORR (54.1% vs. 60.2%, risk ratio [RR]: 0.77 [0.57, 1.06], p = 0.11), and DCR (74.9% vs. 84.4%, RR: 0.89 [0.79, 1.00], p = 0.06) tended to favor EP. Subgroup analysis of subsistence showed that EP had prominent benefit in the following subgroups: Asian, median age > 60, first-line treatment, ECOG 0-2, intravenous topotecan, and cisplatin. AEs illustrated that EP had conspicuously more anemia and alopecia than TP. CONCLUSIONS: Compared with TP, EP was noticeably better in OS and PFS, but EP was toxic in terms of anemia and alopecia. More multicenter, better planned RCTs are needed.

The benefits and risks of CTLA4 inhibitor plus PD1/PDL1 inhibitor in stage IIIB/IV non-small cell lung cancer: A systematic analysis and meta-analysis based on randomized controlled trials.

WHAT IS KNOWN AND OBJECTIVE: Although immune checkpoint inhibitors (ICIs) have shown clinical benefit for patients with non-small cell lung cancer (NSCLC), the efficacy of the combination of ICIs targeting different pathways is still unclear. We performed this meta-analysis to explore the efficacy of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor plus programmed cell death 1 receptor (PD-1)/programmed cell death receptor ligand 1 (PD-L1) inhibitor therapy (CP) for NSCLC IIIB/IV patients. METHODS: We systematically searched the main databases for relevant studies. The main outcomes were overall survival (OS) and progression-free survival (PFS). RESULTS AND DISCUSSION: We identified 3526 articles, including 5 randomized controlled trials (RCTs) (4377 patients), in our meta-analysis. We conducted two comparisons of CP versus chemotherapy or PD1/PDL1 inhibitor (P). Compared with chemotherapy, CP was more effective, with better OS (hazard ratio [HR]: 0.77, 95% CI [confidence interval]: 0.66-0.91; p = 0.001), better PFS (HR: 0.77, 95% CI: 0.70-0.85; p < 0.00001) and comparable objective response rate (ORR) (risk ratio [RR]: 1.27, 95% CI: 0.98-1.65; p = 0.07); in terms of toxicity, CP was comparable to chemotherapy across all-grade adverse events (AEs) (RR: 0.87, 95% CI: 0.73-1.03; p = 0.11) and grade 3-5 AEs (RR: 0.85, 95% CI: 0.63-1.14; p = 0.27). Compared with P, CP had no superiority in efficacy in terms of the OS (HR: 1.04, 95%CI: 0.86-1.24; p=0.70), PFS (HR: 0.95, 95%CI: 0.75-1.22; p = 0.70) and the ORR (RR: 1.07, 95% CI: 0.95-1.21; p = 0.27) but CP was more effective than P when PD-L1 expression was <1% (RR: 0.77,95%CI: 0.60-0.98; p = 0.04); in terms of toxicity, CP was associated with increased all-grade AEs (RR:1.07, 95% CI: 0.97-1.19; p = 0.18) and grade 3-5 AEs (RR:1.58, 95% CI: 1.21-2.07; p = 0.0008). WHAT IS NEW AND CONCLUSION: CP is a beneficial therapeutic schedule with longer PFS and OS than chemotherapy and has an acceptable, manageable grade 3-4 AE rate in IIIB/IV NSCLC. However, compared with P, CP results in better OS only in patients with PD-L1 expression <1%.

Silencing UCHL3 enhances radio-sensitivity of non-small cell lung cancer cells by inhibiting DNA repair.

UCHL3 belongs to the UCH family and is involved in multiple biological processes. However, the biological functions and underlying mechanisms of action of UCHL3 in radio-sensitivity of non-small cell lung cancer (NSCLC) remain unknown. Here, we reported that the expression of UCHL3 was significantly up-regulated in NSCLC tissues and cell lines, and associated with poor prognosis of NSCLC patients. The expression of UCHL3 of NSCLC cells was increased after exposure to ionizing radiation (IR). Moreover, we found that knockdown of UCHL3 enhanced the radio-sensitivity of NSCLC cells both in vitro and in vivo. Furthermore, γH2AX foci staining and Western blot analysis showed that knockdown of UCHL3 increased IR-induced DNA damage. Knockdown of UCHL3 in NSCLC cells decreased homologous recombination (HR) repair efficiency and RAD51 foci formation. Collectively, our study revealed that knockdown of UCHL3 enhanced the radio-sensitivity of NSCLC cells and increased IR-induced DNA damage via impairing HR repair.

Use of dexamethasone and a 5-HT3 receptor antagonist with or without aprepitant to prevent chemotherapy-induced nausea and vomiting among patients with lung cancer who are treated with platinum-based chemotherapy: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Researchers have not clearly determined whether adding aprepitant (ADH) to dexamethasone and one 5-HT3 receptor antagonist (DH) is clinically effective at preventing chemotherapy-induced nausea and vomiting (CINV) among patients with lung cancer (LC) treated with platinum-based chemotherapy (PBC). Therefore, we conducted a meta-analysis to examine the efficacy and safety of ADH and DH. METHODS: We searched the PubMed, ScienceDirect, Cochrane Library, and Scopus databases, among others, for relevant studies. The primary outcomes were the complete response (CR) and the no nausea rate (NNR). The secondary endpoints were the number of patients who needed rescue antiemetic treatment (RAT), adverse events (AEs), and the Functional Living Index Emesis (FLIE) score. RESULTS: We initially screened 2,118 articles; ultimately, four randomized controlled trials (RCTs) with 518 patients were included. The ADH group had a superior overall CR [risk ratio (RR): 1.16 (1.06, 1.27), P=0.002] and a lower number of patients who needed RAT [RR: 0.44 (0.29, 0.65), P<0.0001]. The ADH group also had a better overall NNR [RR: 1.11 (0.97, 1.26), P=0.12] and delayed CR [RR: 1.12 (0.97, 1.31), P=0.13]. No significant differences were observed in acute CR, acute NNR, or delayed NNR. In the subgroup analysis of the overall CR and NNR, ADH was superior in certain clinical characteristics (China, cisplatin-based chemotherapy, 2nd-generation 5-HT3 receptor antagonist, ADC <50%, and Eastern Cooperative Oncology Group (ECOG) score of 0-2). No significant differences in the AEs characterized as hematological or nonhematological toxicity were observed between the groups. CONCLUSIONS: Compared with DH, ADH appears to be superior at preventing CINV and achieving a better CR among patients with LC treated with PBC.

Long noncoding RNA LINC00520 accelerates lung adenocarcinoma progression via miR-1252-5p/FOXR2 pathway.

It has been corroborated that long noncoding RNA (lncRNA) played fundamental function in various human malignancies development including lung adenocarcinoma (lung ADC). In our study, LINC00520 roles in lung ADC tumorigenesis were explored. We found that LINC00520 level was elevated in lung ADC tissues and cell lines. Besides, the LINC00520 expression had a negative connection with miR-1252-5p level in lung ADC tissues. Additionally, our results demonstrated the reciprocal repression influence between LINC00520 and miR-1252-5p. Moreover, luciferase reporter assays, RIP (RNA-binding protein immunoprecipitation) and pull down assays revealed that miR-1252-5p regulated LINC00520 in RISC-dependent. Furthermore, knockdown of LINC00520 inhibited lung ADC cells proliferation, migration and invasion, while co-transfection with a miR-1252-5p inhibitor inverted these influences. Additionally, the findings also demonstrated that FOXR2 was a target of miR-1252-5p; thus, LINC00520 could regulate FOXR2 level. Moreover, LINC00520 silencing suppressed the tumor growth of lung ADC in vivo. In summary, our data indicated that LINC00520 may act as a ceRNA to modulated FOXR2 level by sponging miR-1252-5p, which might bring a potential and effective biomarker to lung ADC treatment.