RESUMO
BACKGROUND: Immune checkpoint inhibitor therapy for non-small cell lung cancer is widely used in clinical practice. However, there has not been a systematic statistical proof of the efficacy of PD-1 inhibitors in patients with advanced cancer. This meta-analysis aims to evaluate its efficacy and related influencing factors, so as to provide a basis for clinical diagnosis and treatment. OBJECTIVE: To assess the effectiveness and safety of programmed death-1 (PD-1)/PD ligand 1 (PD-L1) inhibitors versus chemotherapy as second-line or late-line treatment for patients with advanced non-small-cell lung cancer (NSCLC) via a systematic review of published randomized controlled trials (RCTs). METHODS: Studies were identified through PubMed, EMBASE, and Cochrane Library electronic databases. RevMan 5.3.5 was used to analyze the data extracted from all eligible studies. RESULTS: All 4122 eligible patients from 8 RCTs were included in this study. The meta-analysis showed that PD-1/PD-L1 inhibitors could significantly improve overall survival (hazards ratio [HR] 0.71, 95% confidence interval [CI] 0.66-0.77, Pâ<â.001), progression-free survival (HR 0.88, 95%CI 0.81-0.94, Pâ=â.01), and objective response rate (HR 2.03, 95%CI 1.66-2.49, Pâ<â.001) compared with chemotherapy drugs. The incidence of side effects of any grade (HR 0.34, 95%CI 0.29-0.39, Pâ<â.001) or grades 3 to 5 (HR 0.15, 95%CI 0.10-0.23, Pâ<â.001) consistently showed that PD-1/PD-L1 inhibitors were safer than chemotherapy. Furthermore, subgroup analysis based on tumor proportion score or pathology classification revealed that PD-1/PD-L1 inhibitors significantly improved overall survival compared with chemotherapy. CONCLUSION: As a second-line or late-line treatment, PD-1/PD-L1 inhibitors are safer and more effective than chemotherapy in patients with advanced NSCLC.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Adolescente , Adulto , Antígeno B7-H1/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Adulto JovemRESUMO
Merlin is a versatile tumor suppressor protein encoded by the NF2 gene. Several lines of evidence suggest that Merlin exerts its tumor suppressor activity, at least in part, by forming an inhibitory complex with cluster of differentiation 44 (CD44). Consistently, numerous NF2 mutations in cancer patients are predicted to perturb the interaction of Merlin with CD44. We hypothesized that disruption of the Merlin-CD44 complex through loss of Merlin, unleashes putative tumor- or metastasis-promoting functions of CD44. To evaluate the relevance of the Merlin-CD44 interaction in vivo, we compared tumor growth and progression in Cd44-positive and Cd44-negative Nf2-mutant mice. Heterozygous Nf2-mutant mice were prone to developing highly metastatic osteosarcomas. Importantly, while the absence of the Cd44 gene had no effect on the frequency of primary osteosarcoma development, it strongly diminished osteosarcoma metastasis formation in the Nf2-mutant mice. In vitro assays identified transendothelial migration as the most prominent cellular phenotype dependent on CD44. Adhesion to endothelial cells was blocked by interfering with integrin α4ß1 (very late antigen-4, VLA-4) on osteosarcoma cells and CD44 upregulated levels of integrin VLA-4 ß1 subunit. Among other putative functions of CD44, which may contribute to the metastatic behavior, the passage through the endothelial cells also appears to be critical in vivo, as CD44 significantly promoted formation of lung metastasis upon intravenous injection of osteosarcoma cells into immunocompromised mice. Altogether, our results strongly suggest that CD44 plays a metastasis-promoting role in the absence of Merlin.
Assuntos
Neoplasias Ósseas/genética , Receptores de Hialuronatos/metabolismo , Neoplasias Pulmonares/genética , Neurofibromina 2/genética , Osteossarcoma/genética , Animais , Neoplasias Ósseas/patologia , Osso e Ossos/patologia , Adesão Celular/genética , Linhagem Celular Tumoral/transplante , Proliferação de Células/genética , Modelos Animais de Doenças , Progressão da Doença , Humanos , Receptores de Hialuronatos/genética , Pulmão/patologia , Neoplasias Pulmonares/secundário , Masculino , Camundongos , Camundongos Knockout , Osteossarcoma/secundárioRESUMO
Parkinson's disease (PD) is the second most common late-age onset neurodegenerative disease. Except for the symptomatic alleviating treatment, no disease modifying therapy is currently available. In this study, we investigated the potential neuroprotective role of hydroxytyrosol (HT), a major phenolic compound present in olive oil, against dopaminergic cell death. We found that HT effectively protected dopaminergic SH-SY5Y cells against dopamine (DA) and 6-hydroxydopamine (6-OHDA) induced cell death, but had no apparent effect on 1-methyl-4-phenylpyridinium (MPP(+))-induced cytotoxicity. Furthermore, we have shown that HT efficiently induced the expression of phase II detoxifying enzymes, including NAD(P)H quinone oxidoreductase 1 (NQO1). Using an NQO1 inhibitor, we revealed that increased NQO1 expression contributed to the protective effect of HT against dopaminergic cell death. Together, our findings suggest that HT has a protective effect against DA- and 6-OHDA-induced dopaminergic cell death, supporting the beneficial effect of olive oil in preventing DA-metabolism related dopaminergic neuron dysfunction.