Raddeanin A Improves the Therapeutic Effect of Osimertinib in NSCLC by Accelerating ROS/NLRP3-mediated Pyroptosis.

BACKGROUND: Osimertinib (Osm) is the preferred treatment for non-small cell lung cancer (NSCLC) patients with the epidermal growth factor receptor (EGFR) T790M mutation. Nevertheless, the resistance of NSCLC cells to Osm will eventually develop, which remains the biggest obstacle to treating such diseases. Raddeanin A (RA) exhibits a potent anti-tumor effect on various types of cancer cells. In this study, we aimed to investigate whether RA suppresses NSCLC growth and increases the therapeutic effect of Osm. METHODS: The effects of RA on inhibiting NSCLC cell viability and proliferation were tested using cell counting kit 8 (CCK-8) and EdU assay. The roles of RA in improving the anti-tumor effect of Osm were tested with CCK-8 and colony formation assays. The roles of RA in regulating reactive oxygen species (ROS)/NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3)-mediated pyroptosis were assessed using quantitative real- time PCR (qRT-PCR) and western blotting analysis. RESULTS: RA treatment decreased A549 and H1975 cell viability in a dose- and time-dependent way. RA inhibited NSCLC cell proliferation and tumor growth in vivo. Mechanistically, RA induced ROS overgeneration and resulted in subsequent NLRP3-mediated pyroptosis. In particular, combination treatment with Osm and RA reduced cell viability and clonogenic growth capacity more efficiently than Osm mono treatment in A549 and H1975 cells. Combination treatment also promoted NLRP3-mediated pyroptosis more efficiently than Osm mono treatment. CONCLUSION: RA inhibited the NSCLC growth and increased the anti-tumor role of Osm in NSCLC by facilitating ROS/NLRP3-mediated pyroptosis. These results suggested that combination therapy with RA and Osm might be an effective strategy to treat Osm-resistant NSCLC.

Down-regulated NEDD4L facilitates tumor progression through activating Notch signaling in lung adenocarcinoma.

Neural precursor cell expressed developmentally down-regulated 4-like protein (NEDD4L), an E3 ubiquitin ligase, exerts an important role in diverse biological processes including development, tumorigenesis, and tumor progression. Although the role of NEDD4L in the pathogenesis of lung adenocarcinoma (LUAD) has been described, the mechanism by which NEDD4L promotes LUAD progression remains poorly understood. In the study, the correlation between NEDD4L level and clinical outcome in LUAD patients was analysed using the data from The Cancer Genome Atlas (TCGA) database. NEDD4L expression in LUAD cell lines and tissue samples was assessed through quantitative real-time PCR (qRT-PCR). The biological function of NEDD4L on regulating LUAD cell proliferation was tested with Cell Counting Kit-8 (CCK-8) assay in vitro, and mouse xenograft tumor model in vivo. We found that NEDD4L expression was significantly decreased in LUAD tissues and cell lines. Lower expression of NEDD4L exhibited a significantly poorer overall survival. Functionally, NEDD4L knockdown in H1299 cells accelerated cell growth, whereas NEDD4L overexpression in A549 cells repressed cell proliferation. NEDD4L overexpression also inhibited tumor xenograft growth in vivo. Mechanistically, NEDD4L decreased the protein stability of notch receptor 2 (Notch2) through facilitating its ubiquitination and degradation by ubiquitin-proteasome system. Consequently, NEDD4L negatively regulated Notch signaling activation in LUAD cells, and RO4929097 (a Notch inhibitor) treatment effectively repressed the effect of NEDD4L knockdown on LUAD cell proliferation. Taken together, these results demonstrate that down-regulated NEDD4L facilitates LUAD progression by activating Notch signaling, and NEDD4L may be a promising target to treat LUAD.

Characteristics, Prognostic Factors, and Survival of Patients with NK/T-Cell Lymphoma of Non-upper Aerodigestive Tract: A 17-Year Single-Center Experience.

PURPOSE: The extranodal natural killer (NK)/T-cell lymphoma (NKTCL) of non-upper aerodigestive tract (NUAT) was found to have clinical heterogeneity compared with NKTCL of the upper aerodigestive tract (UAT) in small scale studies. We conducted this study in a much larger cohort to analyze the clinical characteristics, prognostic factors, treatment modality, and clinical outcomes of patients with NUAT-NKTCL. MATERIALS AND METHODS: From January 2001 to December 2017, a total of 757 NKTCL patients were identified and included in this study, including 92 NUAT-NKTCL patients (12.2%) and 665 UAT-NKTCL patients (87.8%). RESULTS: NUAT-NKTCL patients had relatively poorer performance status, more unfavorable prognostic factors, and more advanced stage, compared with UAT-NKTCL patients. The 5-year overall survival (OS) was 34.7% for NUAT-NKTCL, which was significantly worse than UAT-NKTCL (64.2%, p<0.001). The median OS duration was 30.9 months for NUAT-NKTCL. Multivariate analysis showed that presence with B symptoms and elevated serum lactate dehydrogenase independently predicted worse OS. International prognostic index score and prognostic index of natural killer lymphoma score still had prognostic values in NUAT-NKTCL, while the Ann Arbor system could not accurately predict the OS. CONCLUSION: NUAT-NKTCL is a distinctive subtype of NKTCL in many aspects. Patients with NUAT-NKTCL have relatively poorer performance status, more unfavorable prognostic factors, more advanced stage, and poorer prognosis.

Efficacy and safety of cisplatin-based versus nedaplatin-based regimens for the treatment of metastatic/recurrent and advanced esophageal squamous cell carcinoma: a systematic review and meta-analysis.

Cisplatin and nedaplatin show significant antitumor activity and have been widely used for esophageal squamous cell carcinoma (ESCC). However, it is still unclear whether the efficacy and safety of nedaplatin-based regimens are comparable to those of cisplatin-based regimens in patients with metastatic/recurrent or advanced ESCC. Therefore, we conducted a systematic review and meta-analysis to compare the efficacy and safety of these two regimens for the treatment of metastatic/recurrent and advanced ESCC. We systematically searched Pubmed, Web of Science, and the Cochrane Database, as well as abstracts presented at conferences (all up to January 2015), for randomized-controlled and nonrandomized clinical trials that compared cisplatin-based and nedaplatin-based regimens in patients with metastatic/recurrent or advanced ESCC. Data were extracted from the original studies by two independent reviewers. This meta-analysis was performed using Review Manager (RevMan) Version 5.3 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014) software. Ten eligible trials, including 598 patients diagnosed with metastatic/recurrent or advanced ESCC, were included in our analysis. Our results demonstrated that the nedaplatin-based regimens were comparable to the cisplatin-based regimens in terms of overall survival (OS) (hazard ratio, HR: 1.22, 95% confidence interval, CI: 0.86-1.74, p = 0.26) and overall response rate (ORR) (risk ratio, RR: 0.92, 95% CI: 0.77-1.10, p = 0.37) and generated fewer grade 3 and 4 side effects including nausea (RR: 3.41, 95% CI: 1.67-6.96, p < 0.001) and vomiting (RR: 3.62, 95% CI: 1.77-7.40, p < 0.001) and fewer grade 1 and 2 adverse events including nausea (RR: 1.54, 95% CI: 1.23-1.93, p < 0.001), vomiting (RR: 1.76, 95% CI: 1.76-2.30, p < 0.001), peripheral neuropathy (RR: 1.75, 95% CI: 1.08-2.84, p = 0.02) and renal dysfunction (creatinine) (RR: 3.28, 95% CI: 1.37-7.84, p = 0.008). This systematic review and meta-analysis indicated that the efficacy of nedaplatin-based regimens was comparable to that of cisplatin-based regimens for patients with metastatic/recurrent or advanced ESCC, and that nedaplatin-based regimens were associated with less toxicity and better tolerability. However, this study was a meta-analysis of previously released data; therefore, there is a potential publication bias and heterogeneity among the included trials. Future, well-designed RCTs with large cohorts are warranted.

A triplet chemotherapy regimen of cisplatin, fluorouracil and paclitaxel for locoregionally recurrent nasopharyngeal carcinoma cases contraindicated for re-irradiation/surgery.

OBJECTIVE: Salvage treatment for locoregionally recurrent nasopharyngeal carcinoma remains a significant challenge. The present study was conducted to evaluate the efficacy, toxicity and prognostic factors of a triplet chemotherapy regimen involving cisplatin, fluorouracil and paclitaxel (TPF) for locoregionally recurrent nasopharyngeal carcinoma (NPC) cases contraindicated for re-irradiation/surgery. METHODS: Patients with locoregionally recurrent NPC unsuitable for re-irradiation/surgery were treated with TPF therapy. The chemotherapy drugs were administered as follows: 135 mg/m(2) paclitaxel on day 1, 25 mg/m(2)/day cisplatin on days 1-3, followed by continuously infused intravenous fluorouracil for 120 h at a variable dosage from 600 to 800 mg/m(2)/day, depending on prior radiation. RESULTS: Twenty-seven patients were enrolled. The overall response was 66.7%. The median progression-free survival (PFS) and overall survival (OS) were 8.5 and 27.2 months, respectively. Toxicity was mild to moderate. Neutropenia and leukopenia were the primary grade 3-4 chemotherapy toxicities. 6 patients who regained the potential for re-radiotherapy or surgery showed significantly better outcomes than those treated with chemotherapy alone (median PFS: 20.8 vs. 7.1 months, P = 0.005; median OS: 54.2 vs. 20.6 months, P = 0.021). CONCLUSION: TPF triplet chemotherapy showed a high response rate for locoregionally recurrent NPC with an acceptable toxicity profile.

Inhibition of MiR-155 suppresses cell migration in nasopharyngeal carcinoma through targeting ZDHHC2.

Overexpression of miR-155 in nasopharygeal carcinoma (NPC) is partly driven by Epstein-Bar virus infection. However the role of miR-155 in NPC oncogenesis is unclear. This study showed that miR-155 inhibitor could inhibit the cell migration in NPC cell lines. ZDHHC2 was identified as a direct target of miR-155 and downregulation of ZDHHC2 prompted cell migration in NPC. Furthermore, reduced ZDHHC2 expression was associated significantly with metastasis and poor survival of NPC patients. Collectively, inhibition of miR-155 suppresses cell migration in NPC through targeting ZDHHC2. The potential of miR-155 and ZDHHC2 as therapeutic targets in NPC should be further investigated.

Reduced expression of ZDHHC2 is associated with lymph node metastasis and poor prognosis in gastric adenocarcinoma.

BACKGROUND: Zinc finger, DHHC-type containing 2 (ZDHHC2), originally named as reduced expression associated with metastasis protein (REAM), has been proposed as a putative tumor/metastasis suppressor gene and is often aberrantly decreased in human cancers. However ZDHHC2 expression pattern and its clinical significance have not yet been investigated in gastric adenocarcinoma. METHODOLOGY/PRINCIPAL FINDINGS: Quantitative Real-Time PCR (qRT-PCR) and immunostaining were performed to detect ZDHHC2 expression in gastric adenocarcinoma, and then the correlation between ZDHHC2 expression and clinicpathologic parameters, and patient survival was analyzed. Compared to the adjacent normal tissues, ZDHHC2 expression was significantly reduced in gastric tumor tissues as shown by qRT-PCR and immunostaining. Low expression of ZDHHC2 was observed in 44.7% (211/472) of gastric adenocarcinoma patients, and was associated significantly with lymph node metastasis (p<0.001) and histological grade (p<0.001). Multivariate Cox regression analysis indicated that ZDHHC2 expression had a significant, independent predictive value for survival of gastric cancer patients (HR = 0.627, p = 0.001). CONCLUSIONS/SIGNIFICANCE: Our data suggest that reduced ZDHHC2 expression is associated with lymph node metastasis and independently predicts an unfavorable prognosis in gastric adenocarcinoma patients.

Neuroprotective effects of resveratrol on ischemic injury mediated by modulating the release of neurotransmitter and neuromodulator in rats.

The present study was carried out to elucidate the neuroprotective effect and influence of resveratrol on the extracellular levels of neurotransmitter and neuromodulator during ischemia/reperfusion in rats. Male rats were divided into three groups: sham operation, ischemia treatment, and ischemia combined with resveratrol treatment (resveratrol-treated group, 30 mg/kg intraperitoneally for 7 days). Cerebral ischemia was induced by using the model of middle cerebral artery occlusion. The dialysates in hypothalamus were obtained by brain microdialysis technique. The levels of sixteen amino acids and amines in microdialysate were monitored by capillary electrophoresis analysis. This study shows that the ischemic infarcts were significantly reduced and neurological functions were improved in resveratrol-treated group compared to ischemia group. The analysis results demonstrate that chronic treatment with resveratrol remarkably reduced the release of excitatory neurotransmitter glutamate, aspartate and neuromodulator d-Serine during ischemia and reperfusion; and significantly increased the basal extracellular levels of inhibitory neurotransmitter gamma-amino-n-butyric acid, glycine and taurine. Chronic treatment with resveratrol also ameliorated O-phosphoethanolamine levels and excitotoxic index during ischemia and reperfusion. This study provides the first in vivo evidence that resveratrol could exert neuroprotective effect against ischemia injury by modulating the release of multiple neurotransmitters and neuromodulators during ischemia/reperfusion.