IL-37 Confers Anti-Tumor Activity by Regulation of m6A Methylation.

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.

Osimertinib compared docetaxel-bevacizumab as third-line treatment in EGFR T790M mutated non-small-cell lung cancer.

OBJECTIVE: To compare the efficacy and toxicity 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 (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/m2) and bevacizumab (7.5 mg/kg) every 21 days until disease progression, unacceptable toxic effects or patient death. The primary endpoint of this study was progression-free survival (PFS) and the secondary endpoints were response rates, toxicities and overall survival (OS). This trial was registered with ClinicalTrials.gov, number NCT02959749. RESULTS: A 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. CONCLUSIONS: 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.

Mutational Profiling of Non-Small-Cell Lung Cancer Resistant to Osimertinib Using Next-Generation Sequencing in Chinese Patients.

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.

Decreased levels of Th17 cells are associated with invasion fungal infections after allogeneic hematopoietic stem cell transplantation.

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-ß 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.

Blood transfusion and mortality in myocardial infarction: an updated meta-analysis.

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.

[Significance of Thl7/Treg Ratio in aGVHD Occurence after Allo-HSCT].

OBJECTIVE: To explore the relationship between Th17 and Treg levels and aGVHD occurence in patients after allo-HSCT. METHODS: Thirty-nine patients received allo-HSCT were divided into 2 groups: aGVHD group(17 cases) and non-aGVHD group (22 cases). For aGVHD group, the peripheral blood was collected before aGVHD occurence, in occurence and after aGVHD improvement; for non-aGVHD group, the peripheral blood was collected after 1, 2 and 3 months of transplantation. In addition, 16 healthy donors were used as controls, their peripheral blood was collected before mobilization. The Th17 and Treg counts as well as Th17/Treg ratio were detected by flow cytometry. RESULTS: Among patients with aGVHD after transplantation, the Th17 count increased, and the Treg count decreased, the Th17/Treg ratio increased before aGVHD occurence, as compared with the patients without aGVHD(P<0.05); but after aGVHD occurence, the Th17 count decreased, Treg count increated, and the Th17/Treg ratio decreased as compared with that before aGVHD occurence (P<0.05). After aGVHD was improved, the Th17/Treg ratio decreased as compared with level before aGVHD occurence (P<0.05). After aGVHD was improved, the Th17/Treg ratio was no statistical different from healthy donors (P>0.05). Among patients without aGVHD after transplantation, the Th17/Treg ratio at 2 and 3 months after transplantation was no statistical different from that of healthy donos(P>0.05). CONCLUSION: The Th17 and Treg levels recoverel showly after transplantation, but the Th17/Treg ratio recoveres after 2 months in the patients after transplantation. The Th17 cells may initiate aGVHD; when aGVHD happened, the Treg level increases, which may regulate the aGVHD ontcome through inhibiting the Th17 cells. The detection of Th17/Treg ratio after transplantation can predict the occurence and outcome of aGVHD.

Correlation of Tc17 cells at early stages after allogeneic hematopoietic stem cell transplantation with acute graft-versus-host disease.

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-ß 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.

Propofol protects against the neurotoxicity of 1­methyl­4­phenylpyridinium.

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 (2,6­diisopropylphenol) has been observed to attenuate oxidative stress injury via inhibition of programmed cell death. Results from the present study indicate that propofol treatment attenuates 1­methyl­4­phenylpyridinium (MPP+)­induced oxidative stress, which was demonstrated by increased levels of reactive oxygen species, 4­hydroxy­2­nonenal 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 Bcl­2­associated X protein to B­cell lymphoma 2, reducing the expression level of cleaved caspase­3 and attenuating cytochrome c release. Thus, propofol may present as a novel therapeutic strategy for the treatment of PD.

Sorafenib in liver function impaired advanced hepatocellular carcinoma.

OBJECTIVE: To explore the efficacy and safty of sorafenib in Child-Pugh class B to class C hepatocellular carcinoma (HCC). METHODS: 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. RESULTS: 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; P<0.001). 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. CONCLUSIONS: 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.