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N6-methyladenosine (m6A) is a common transcriptomic modification in cancer. Recently, it has been found to be involved in the regulation of non-small cell lung cancer (NSCLC) formation and metastasis. Interleukin 37 (IL-37) plays a crucial protective role in lung cancer. In our previous studies, we found that IL-37 is a potential novel tumor suppressor by inhibiting IL-6 expression to suppress STAT3 activation and decreasing epithelial-to-mesenchymal transition. Moreover, we found that treatment of IL-37 in lung cancer cells induced widespread and dynamic RNA m6A methylation. The effects of RNA m6A methylation of IL-37 treatment require further study. However, the functions of RNA m6A methylation of IL-37 treatment still await elucidation. Using MeRIP-seq and RNA-seq, we uncovered a unique m6A methylation profile in the treatment of IL-37 on the A549 cell line. We also showed the expression of m6A writers METTL3, METTL14, and WTAP and erasers ALKBH5 and FTO in A549 cells and lung cancer tissues after the treatment of IL-37. This study showed that IL-37 could lead to changes in m6A methylation level and related molecule expression level in A546 cells and may downregulate the proliferation by inhibiting Wnt5a/5b pathway in A549 cells. We conclude that IL-37 suppresses tumor growth through regulation of RNA m6A methylation in lung cancer cells.

Parkinson's disease (PD) is a progressive and degenerative disorder of the central nervous system, characterized by the loss of dopaminergic neurons and muscular rigidity. Treatment with propofol (2,6‑diisopropylphenol) has been observed to attenuate oxidative stress injury via inhibition of programmed cell death. Results from the present study indicate that propofol treatment attenuates 1‑methyl‑4‑phenylpyridinium (MPP+)‑induced oxidative stress, which was demonstrated by increased levels of reactive oxygen species, 4‑hydroxy‑2‑nonenal and protein carbonyls. Furthermore, it was demonstrated that propofol may ameliorate MPP+‑induced mitochondrial dysfunction by increasing the level of ATP and the mitochondrial membrane potential. MTT and lactate dehydrogenase assays indicated that propofol treatment reduces cell vulnerability to MPP+‑induced insult. Propofol was also observed to prevent apoptotic signals by reducing the ratio of Bcl‑2‑associated X protein to B‑cell lymphoma 2, reducing the expression level of cleaved caspase‑3 and attenuating cytochrome c release. Thus, propofol may present as a novel therapeutic strategy for the treatment of PD.

Purpose. To identify the somatic mutated genes for optimal targets of non-small-cell lung cancer after resistance to osimertinib treatment. Patients and Methods. Study patients all had advanced lung adenocarcinoma and acquired resistance to osimertinib as a second- or third-line treatment. These patients had harboring EGFR T790M mutation before osimertinib treatment, which was confirmed by Amplification Refractory Mutation System (ARMS) PCR or Next-Generation Sequencing (NGS). After resistance to osimertinib treatment, tumor tissue was collected by core needle biopsy. DNA was extracted from 15 × 5 um sliced section of formalin-fixed paraffin-embedded (FFPE) material and NGS was done. The genetic changes were analyzed. Results. A total of 9 Chinese patients were studied, 5 females and 4 males, age 51–89 years. After progression with osimertinib treatment, core needle biopsy was performed and next-generation sequencing was performed. Nine patients had harboring 62 point mutations, 2 altered gene copies, 2 amplifications, and 1 EML4-ALK gene fusion. No MET or HER2 amplification was found in this cohort study. Nine patients still maintained initial EGFR 19 del or L858R activating mutations, while 7 of them kept EGFR T790M mutations. Among the 7 patients, 5 had secondary EGFR C797S and/or C797G mutations, which all happened in the same allele with T790M mutation. All patients were treated with targets therapies, chemotherapy, or best supportive care (BSC) in accordance with NGS genetic results and patients’ performance status; 7 of them are still alive and 2 of them died of disease progression at last follow-up. Conclusions. EGFR C797S/G mutation and the same one presented on the same allele with EGFR T790M mutation were the most common mutation feature and played a key role in resistance to osimertinib in Chinese patients with NSCLC. Tumor cells losing T790M mutation and maintaining EGFR activating mutation might benefit from first-generation EGFR-TKI treatment.

To compare the efficacy and toxicity of osimertinib versus docetaxel-bevacizumab as third-line treatment in EGFR T790M mutated NSCLC.In this phase 3, open-label, three-center study, we randomly assigned (1:1) previously treated with TKI-chemotherapy or chemotherapy-TKI recurrent or metastatic advanced non-squamous lung cancer patients into two groups. These patients had acquired EGFR T790M resistance mutation confirmed by tumor tissues or serum. One group received oral osimertinib (80 mg/day) and the other group received intravenous infusion docetaxel (75 mg/mA total of 147 patients were treated. Among them, 74 were enrolled in the osimertinib group and 73 were in the docetaxel-bevacizumab group. The median progression-free survival was 10.20 months in the osimertinib group versus 2.95 months in the docetaxel-bevacizumab group (hazard ratio 0.23; 95% confidence interval [CI], 0.12-0.38; P 0.001). The overall response rate in the osimertinib group was significantly better than in the docetaxel-bevacizumab group (61.6%; 95% CI, 55.5-67.7 versus 8.3%; 95% CI, 1.3-15.3; p 0.001). Because all the progressed patients in the docetaxel-bevacizumab group crossed over to the osimertinib group, there was no significant difference in the median OS between two groups at the time of last follow-up (hazard ratio 0.79; 95% CI, 0.38-1.61; P = .551). The main grade 3 or 4 toxic effects were diarrhea (2.7%) and interstitial lung disease (1.4%) in the osimertinib group and alopecia (15.3%), anorexia (12.5%), neutropenia (9.7%) and nausea (8.3%) in the docetaxel-bevacizumab group.Osimertinib had higher response rate, longer PFS and milder side effects than docetaxel-bevacizumab in third-line therapy in patients with EGFR T790 M positive advanced NSCLC.

// Zuomin Yin 1 , Botao Yu 1 , Weisheng Liu 1 and Ketao Lan 1 1 Department of Chest Pain Center, The Affiliated Central Hospital of Qingdao University, Qingdao, Shandong Province, China Correspondence to: Ketao Lan, email: ketaolan123@126.com Keywords: blood transfusion, myocardial infarction, mortality, meta-analysis Received: June 13, 2017 Accepted: June 29, 2017 Published: July 12, 2017 ABSTRACT Background: Several observational and preclinical studies have shown that blood transfusion may modify the mortality of patients with myocardial infarction (MI). The aim of this meta-analysis is to evaluate the recent evidence on the effectiveness of blood transfusion for all-cause mortality in patients with MI. Materials and Methods: PUBMED, EMBASE and the Cochrane central register of controlled trials were searched up to June 2016 by two independent investigators. Studies were considered eligible if they recruited adult MI patients and reported hazard ratio (HR) for all-cause mortality comparing those who received blood transfusion with those who did not receive blood transfusion. We abstracted and calculated pooled HRs using a random-effects model. Results: From 4277 unique reports, we identified 17 studies including 260811 patients with 11 studies examining short-term (in hospital/30-day) all-cause mortality and 9 studies examining long-term (more than 30 days) all-cause mortality. Meta-analysis demonstrated that patients treated with blood transfusion had increased short-term all-cause mortality (HR, 2.39, 95% CI 1.81 to 3.15) compared with those without blood transfusion treatment. Similar findings were observed by subgroup analyses. We also find significant association between blood transfusion and long-term all-cause mortality (HR 1.90, 95% CI 1.40 to 2.58) for MI patients. Conclusions: In patients with MI, blood transfusion treatment is associated with patient short-term and long-term all-cause mortality. However, further large-scale prospective studies are needed to establish its validity of this association.

Background Prognosis of metastatic pancreatic adenocarcinoma is gloomy. To elicit a chemotherapy regimen with higher efficiency and with lower toxicities is critical important. Methods This was a one arm, phase 2, three-center study. Enrolled patients were histological or pathologically confirmed; treatment naive metastatic pancreatic adenocarcinoma. Enrolled patients were 18 years or older, with at least one measurable lesion and performance status between 0-2 with ECOG score. Irrinotecan 165 mg/m2 and oxaliplatin 85 mg/m2 were administered intravenous infusion on days 1, and S1 40 mg/m2 was administered orally on day 1-14, every 21 day a cycle until progressive disease or intolerable toxicities or patient death. The primary endpoint was overall survival and the second endpoints were progression-free survival and toxicities. Results A total of 41 patients were enrolled, median age was 59 year-old. There were 18 men and 23 women. The median progression-free survival was 4.33 (95% CI: 2.83-5.88) and median overall survival was 11.00 (95% CI: 9.16-12.84). There were 38 patients validated for efficiency evaluation. There was no complete response, the partial response rate, stable disease and progression disease was 42.11% (16/38), 31.58% (12/38) and 26.32% (10/38) respectively. The most common adverse effect was mild to moderate nausea, vomiting, neutropenia and thrombocytopenia. The 3/4 degree neutropenia and thrombocytopenia were 29.27% (12/41) and 12.20% (5/41) respectively. Conclusions Irinotecan combined with oxaliplatin and S1 was effective in metastatic pancreatic adenocarcinoma; its toxicities were mild to moderate and tolerable. Furthermore, patients to enrol the study is needed. Clinical trial identification NCT03726021. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

e20080 Background: 4-6 cycles platinum and etoposide (EP) or platinum and irinotecan (IP) chemotherapy is the mainstay treatment for the extensive-stage small-cell lung cancer (SCLC); but the role of maintenance treatment is not fully understood. This study compared the efficacy and toxicities of 4-6 cycles EP or IP chemotherapy treatment followed by S-1 maintenance treatment or placebo control. Methods: In this phase 2, open-label, three-center preliminary study, patients who reached complete response (CR), partial response (PR) or stable disease (SD) after 4-6 cycles of EP or IP therapy were randomly assigned (1:1) with a minimization procedure. One group received oral S-1 25mg/mg2 twice a day as maintenance treatment until disease progression or unacceptable toxic effects. The other group was received placebo and routine follow-up. The primary end point of this study was progression-free survival (PFS) and the secondary end points were response rates, toxicities and overall survival (OS). This trial was registered with ClinicalTrials.gov, number NCT03769935. Results: A total of 89 patients were enrolled, of whom 45 received S-1 maintenance therapy and 44 received placebo. The median PFS was 6.35 months in the S-1 group, as compared with 5.98 months in the placebo group (hazard ratio for progression in the S-1 group, 1.057; 95% confidence interval [CI], 0.656-1.707; P = 0.820). The median OS was 10.82 months in the S-1 group, as compared with 10.09 months in the placebo group (hazard ratio for death in the S-1 group, 0.860; 95% CI, 0.374-1.617; P = 0.905). Tumor regression rate influenced patients’ survival. The PFS was 7.2 months and 5.3 months (p = 0.015), and OS was 12.9 months and 10.9 months (p = 0.042) in patients with CR or PR compared to in patients with SD after induction chemotherapy respectively. The adverse events were mild to moderate skin rash and acne, diarrhea, alopecia, dry skin and fatigue; which were mainly induced by induction chemotherapy and S-1 administration. Conclusions: S-1 maintenance treatment for extensive-stage SCLC had acceptable toxicities; however, there was no significant difference in PFS or OS statistically. Further research with novel agents in the maintenance setting is warranted. Clinical trial information: NCT03769935.

Background: Delayed immune reconstitution is an important risk factor for increased susceptibility to fungal pathogens. However, little is known about the association between the recovery of CD4+T cell subsets and invasion fungal infections (IFIs) in patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The aim of the study was to analyze the immune reconstitution characteristics of CD4+T cell subsets and their association with the incidence of IFIs over the first 3 months after allo-HSCT. Methods: Fifty-three patients were included, 13 with IFIs. We assessed CD4+T cell subsets and the mRNA expression of specific transcription factors T-bet, GATA3, RORγt, and Foxp3 in peripheral blood mononuclear cells over three time points. The serum levels of IFN-γ, IL-6, IL-10, and TGF-β were detected using the enzyme-linked immunosorbent assay. Results: CD4+T cell subsets increased progressively in non-IFI patients after allo-HSCT. In IFI patients, Th17 cell counts were significantly decreased compared to non-IFI patients at 3 months after allo-HSCT. IFI patients showed the lower ratios of RORγt/GATA3 and RORγt/Foxp3 compared with non-IFI patients. In addition, we observed increased levels of IFN-γ and IL-10 in IFI patients after allo-HSCT. In the multivariate analysis, the occurrence of IFIs was independently associated with the incidence of IFIs. Finally, we observed a lower CD4:CD8 ratio in IFI patients and its association with Th17 cells. Conclusions: These findings supported that Th17 cells may be involved in the immune pathology of IFIs after allo-HSCT.

Acute graft-versus-host disease (aGVHD) is associated with an immune dysregulation usually mediated by T lymphocytes. Recently, IL-17-producing T cells including Th17 and Tc17 cells have been implicated in immune-related diseases. However, their roles in aGVHD remain uncertain. In the study, we analyzed IL-17-producing cell recovery and association with the occurrence of aGVHD. While Th17 cells steadily recovered, Tc17 cell numbers remained unaltered during the first 3months after transplantation. Occurrence of aGVHD was correlated with increased level of Tc17 cells at the second months after allo-SCT. Interestingly, Tc17 cells were negatively associated with CD4+CD25+FOXP3+ regulatory T (Treg) cells, which was an important prognostic predictor in patients with aGVHD. In addition, we found that Tc17 numbers increased as the increased concentrations of TGF-β and IL-6, which are known to drive Th17 polarization. These finding supported that Tc17 subset is involved in the immunopathology of aGVHD. Blocking the abnormally increased number of Tc17 may be a reasonable therapeutic strategy for aGVHD.

9017 Background: Osimertinib, an oral irreversible EGFR tyrosine kinase inhibitor, had promising results in patients with EGFR T790M resistance mutation of non-small-cell lung cancer (NSCLC). This study compared efficacy and toxicities of osimertinib versus docetaxel -bevacizumab as third-line treatment in EGFR T790M mutated NSCLC. Methods: In this phase 3, open-label, three-center study, we randomly assigned previously treated with TKI-chemotherapy or chemotherapy-TKI recurrent or metastatic advanced non-squamous lung cancer patients who had acquired EGFR T790M resistance mutation confirmed by tumor tissues or serum genetic test. Patients were randomly assigned in a ratio of 1:1 to receive oral osimertinib (80mg/day) or receive intravenous infusion docetaxel (75mg/m2) and bevacizumab (7.5mg/kg) until disease progression or unacceptable toxic effects. Docetaxel -bevacizumab group patients might crossover to osimertinib group after disease progression. The primary end-point of this study was progression-free survival and the secondary end-point were response rates, toxicities and OS. Results: A total of 147 patients were treated. Among them, 74 enrolled in the osimertinib group and 73 in the docetaxel-bevacizumab group. The median progression-free survival was 10.20 months and 2.95 months in the osimertinib group and docetaxel -bevacizumab group respectively (Hazard ratio 0.23; 95% confidence interval, 0.12 to 0.38; P < 0.0001). The overall response rate and disease control rate was 61.6% or 87.6% in osimertinib group 8.3% or 43.0% in docetaxel-bevacizumab group respectively. The median overall survival time was not reached. The main grade 3 or 4 toxic effects were diarrhea (2.7%) and interstitial lung disease (1.2%) in the osimertinib group and alopecia (15.1%), anorexia (12.3%), neutropenia (9.6%) and nausea (8.6%) in docetaxel -bevacizumab group. Conclusions: Response rate and progression-free survival of osimertinib group were superior to docetaxel-bevacizumab group in third-line treatment of EGFR T790M positive NSCLC. There was no survival difference between patients with EGFR 19 Del-T790M mutation and EGFR L858R-T790M mutation. Clinical trial information: NCT02959749.

To explore the efficacy and safty of sorafenib in Child-Pugh class B to class C hepatocellular carcinoma (HCC).In this three-center open-label study from November 2011 to May 2013, we randomly assigned 189 patients with advanced Child-Pugh class B or C HCC patients into two groups, one group with 95 patient to receive sorafenib (400 mg a time, twice a day) and the other group with 94 patients to receive best supportive care. The primary end points were progression-free survival and overall survival.The median progression-free survival was 2.2 months and 1.9 months in the sorafenib group and best supportive care group respectively (Hazard ratio in the sorafenib group, 0.55; 95% confidence interval, 0.40-0.75; P=0.002). The median overall survival was 4.0 months and 3.5 months in the sorafenib group and best supportive care group respectively (Hazard ratio in the sorafenib group, 0.48; 95% confidence interval, 0.35-0.68; P0.001). The main adverse effect of sorafenib was rash and acne of the skin (in 51.7% patients). The incidences of severe rash, diarrhea, and dry skin were 5.6%, 5.6%, and 2.2% in the sorafenib group. One patient reached partial response in the sorafenib group.Sorafenib is safe in patients with liver function impaired advanced HCC. It is effective in terms of progression-free survival and overall survival compared with best supportive care. Liver functions are the important predictive factors.