Xiaochen Zhang

Introduction: This meta-analysis aimed to evaluate the efficacy and safety of Lenvatinib plus transarterial chemoembolization with or without programmed death-1 inhibitors (PD-1 inhibitors) in the treatment of intermediate or advanced hepatocellular carcinoma (HCC).Materials and Methods: Four databases (Pubmed, Embase, Web of Science, and Cochrane Library) were searched for studies comparing lenvatinib plus transarterial chemoembolization with PD-1 inhibitors (TACE-L-P) versus Lenvatinib plus transarterial chemoembolization (TACE-L) for intermediate or advanced HCC. Meta-analyses were conducted for progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and Grade ≥ 3 treatment-related adverse events (Grade ≥ 3 AEs).Results: The meta-analysis comprised 19 retrospective cohort studies, including of 2002 patients diagnosed with intermediate or advanced HCC. In this cohort, 1011 individuals were administered TACE-L-P, while 991 patients received TACE-L. In comparison to TACE-L, TACE-L-P demonstrated a superior ORR [odds ratio (OR) = 2.38, 95% confidence interval (CI) 1.98 ~ 2.87, P < 0.00001] and DCR (OR = 3.22, 95% CI, 2.32 ~ 4.45, P < 0.00001). TACE-L-P showed superior efficacy compared to TACE-L regarding PFS (HR: 0.56, 95%CI 0.50 to 0.62, P<0.0001) and OS (HR: 0.70, 95%CI 0.60 to 0.80, P<0.0001). Regarding safety, the incidence of Grade ≥ 3 AEs was more prevalent in the TACE-L-P group compared to the TACE-L group (OR=1.58, 95% CI: 1.27 ~ 1.97, P<0.0001).Conclusions: The present meta-analysis present a comparison of the efficacy and safety of TACE-L-P against TACE-L for intermediate or advanced HCC. TACE-L-P enhanced ORR, DCR, PFS, and OS relative to TACE-L. Furthermore, the improved efficacy of TACE-L-P was correlated with a rise in the incidence of Grade ≥ 3 AEs.Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024590414, identifier CRD42024590414.

Introduction: The combination of PD-1/PD-L1 inhibitor with CTLA-4 inhibitor for advanced non-small cell lung cancer(NSCLC) is presently a significant area of research, however its clinical application remains contentious. This meta-analysis aimed to assess the efficacy and safety of first-line PD-1/PD-L1 inhibitor in combination with CTLA-4 inhibitor (CP) in the treatment of patients with advanced NSCLC.Methods: A systemic search was conducted in four databases (PubMed, Cochrane library, Embase, and Web of Science) from their establishment until January 17, 2024, for randomized controlled trials that investigated the use of the first-line PD-1/PD-L1 inhibitor plus CTLA-4 inhibitor in patients with advanced NSCLC. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were subjected to meta-analyses.Results: Totally 7 eligible randomized controlled trials including 4682 people were included. Two comparative analyses were performed: CP versus chemotherapy, CP versus PD-1/PD-L1 inhibitor (P). Compared with the chemotherapy group, CP improved OS (HR: 0.84, 95% CI: 0.75-0.94, p<0.05) but not PFS (HR: 0.94, 95%CI: 0.73-1.20, p = 0.63) or ORR (OR: 1.16, 95% CI: 0.79-1.71, p = 0.45). In terms of toxicity, CP had slightly fewer any AEs compared to chemotherapy (RR: 0.94, 95% CI: 0.91-0.97; p<0.05). Compared to the P group, there was no significant difference in OS (MD: -0,25, 95% CI: -2.47-1.98, p = 0.83), PFS (MD: -0.91, 95% CI: -3.19-1.36, p = 0.43), and ORR (OR:1.05, 95% CI. 0.80-1.36, p = 0.73). Subgroup analysis revealed that CP provided superior OS compared with P in patients with PD-L1 expression < 1%.Conclusion: CP was a feasible and safe first-line therapy for patients with advanced NSCLC. Specifically, CP may function as a therapeutic alternative for individuals with low or negative PD-L1 expression, resulting in enhanced long-term outcomes compared to chemotherapy or P. Further randomized controlled trials with prolonged follow-up periods are necessary to validate these results, particularly focusing on efficacy in patients with differing PD-L1 expression levels, to improve the stratified implementation of immunotherapy.Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024621116, identifier CRD42024621116.

Epilepsy (EP) is a neurological disorder characterized by abnormal, sudden neuronal discharges. Seizures increase extracellular glutamate levels, causing excitotoxic damage. Glutamate transporter type 1 (GLT-1) and its human homologue excitatory amino acid transporter-2 (EAAT2) clear 95% of extracellular glutamate. Studies on neurodegenerative diseases suggest that trichostatin A (TSA), a broad-spectrum histone deacetylase (HDAC) inhibitor, can increase GLT-1/EAAT2 transcription. However, the precise mechanism by which TSA modulates GLT-1/EAAT2 levels remains unclear. This research demonstrated that TSA increases GLT-1/EAAT2 expression through histone acetylation, exerting substantial antiepileptic effects. Our results identify a promising therapeutic strategy for EP involving the modulation of glutamate transporters to mitigate seizures. Future research should explore the specific mechanisms underlying the effects of TSA and its potential clinical applications. Acute and chronic EP models were induced using kainic acid (KA) to assess the effects of TSA on the seizure threshold and frequency. Electrophysiological recordings of the hippocampus were used to evaluate the impact of TSA on neuronal excitability. RNA-Seq was used to analyse changes in glutamate transporter-related gene expression. Western blot analysis and qRT‒PCR were used to assess the influence of TSA on HDAC expression. To validate the role of GLT-1/EAAT2 in the antiepileptic effects of TSA, the impact of the GLT-1/EAAT2 inhibitor dihydrokainic acid (DHK) on the effects of TSA was assessed. Glutamate release was measured, and microdialysis was used to determine the glutamate content in the cerebrospinal fluid. Finally, metabolomics analysis was used to explore changes in amino acid levels in the hippocampus following TSA treatment to further confirm the antiepileptic potential of TSA. TSA effectively inhibited seizures in both acute and chronic models. It reduced the amplitude of excitatory postsynaptic currents (PSCs) and the frequency of spontaneous excitatory PSCs in the hippocampus without affecting inhibitory PSCs. Transcriptome analysis was used to identify glutamate transmission-related targets and revealed significant upregulation of the GLT-1 and EAAT2 genes in the hippocampus, which was confirmed by qRT‒PCR and Western blotting. Acetylation-induced upregulation of GLT-1/EAAT2 was observed, and inhibition of these transporters by DHK reduced the seizure-mitigating effects of TSA, underscoring the role of GLT-1/EAAT2 in clearing glutamate and its contribution to the observed antiepileptic effects of TSA. Our findings highlight the crucial role of GLT-1/EAAT2 in mediating the impact of TSA on glutamatergic transmission and seizure activity. These insights pave the way for the development of novel therapeutic approaches for EP involving the modulation of glutamate transporters.