Histone-Related Genes Are Hypermethylated in Lung Cancer and Hypermethylated HIST1H4F Could Serve as a Pan-Cancer Biomarker.

Lung cancer is the leading cause of cancer-related deaths worldwide. Cytologic examination is the current "gold standard" for lung cancer diagnosis, however, this has low sensitivity. Here, we identified a typical methylation signature of histone genes in lung cancer by whole-genome DNA methylation analysis, which was validated by The Cancer Genome Atlas (TCGA) lung cancer cohort (n = 907) and was further confirmed in 265 bronchoalveolar lavage fluid samples with specificity and sensitivity of 96.7% and 87.0%, respectively. More importantly, HIST1H4F was universally hypermethylated in all 17 tumor types from TCGA datasets (n = 7,344), which was further validated in nine different types of cancer (n = 243). These results demonstrate that HIST1H4F can function as a universal-cancer-only methylation (UCOM) marker, which may aid in understanding general tumorigenesis and improve screening for early cancer diagnosis. SIGNIFICANCE: These findings identify a new biomarker for cancer detection and show that hypermethylation of histone-related genes seems to persist across cancers.

Particulate matter disrupts airway epithelial barrier via oxidative stress to promote Pseudomonas aeruginosa infection.

BACKGROUND: Airborne particulate matter (PM) is associated with increasing susceptibility to respiratory bacterial infection. Tight junctions (TJs) are protein complexes that form airway epithelial barrier against infection. This study aimed to investigate the effects of PM on the airway TJs in response to infection. METHODS: The cytotoxicity of PM to BEAS-2B was evaluated. The reactive oxygen species (ROS) production was measured by the flow cytometry. Colony forming units (CFUs) assay and confocal microscopy were utilized to evaluate the number of bacteria. Immunofluorescence and western blot assay were conducted to detect the expressions of TJs proteins. Animal models were used to investigate the role of TJs in PM-induced lung injury upon bacterial infection. RESULTS: In vitro, PM decreased cell viability, increased ROS production, and increased the number of intracellular bacteria accompanying by the degradation of TJs. N-acetylcysteine (NAC) significantly reversed the PM-induced bacterial invasion and PM-induced disruption of TJs. In vivo, PM increases bacteria-infected lung injury, lung bacteria burden and blood bacterial dissemination, which was closely correlated to the degradation of TJs. CONCLUSIONS: PM disrupts TJs via oxidative stress to promote bacterial infection.

Better therapeutic potential of bone marrow-derived mesenchymal stem cells compared with chorionic villi-derived mesenchymal stem cells in airway injury model.

Aim: To determine the efficiency of mesenchymal stem cells (MSCs) of different sources on airway epithelial cells regeneration and track where and to what extent transplanted MSCs home to injured tissues. Materials & methods: We performed DiO-labeled human bone marrow-derived MSCs (hBMSCs) or human chorionic villi-derived MSCs transplantation studies using naphthalene-induced airway injury animal models. Results: Compared with human chorionic villi-derived MSCs, hBMSCs facilitated airway epithelium regeneration faster and better from day 5 after transplantation; moreover, more transplanted hBMSCs distributed in injured lung tissues at the early stage of postinjury, which was mediated by C-X-C motif chemokine ligand 12. Conclusion: hBMSCs possessed better potential of migration to the damaged lung and promoting the repair of the injured airway epithelium.

Lung-Resident Mesenchymal Stem Cells Promote Repair of LPS-Induced Acute Lung Injury via Regulating the Balance of Regulatory T cells and Th17 cells.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are associated with high morbidity and mortality. Mesenchymal stem cells (MSCs) have been shown to improve ALI, and the imbalance of regulatory T cells (Tregs) and Th17 cells is associated with mortality in ALI/ARDS patients. However, whether administration of lung-resident MSC (LRMSC) improves lung injury and regulates the balance of Tregs and Th17 cells remains unknown. An ALI animal model was induced by LPS, and PBS or LRMSC were administered via tail vein after 4 h. LRMSC were subsequently detected in the lungs by a live imaging system (Berthold LB983, Germany). Lung morphology; lung wet-to-dry weight ratio; and total protein concentration, inflammatory cells, and cytokines in bronchoalveolar lavage fluid (BALF) and plasma were determined. The percentage of Tregs in lung and spleen, and of Th17 cells in lung and blood, were also evaluated. The results showed that LRMSC not only attenuated histopathological damage but also mediated the downregulation of lung wet-to-dry weight ratio and the reduction of total protein concentration and inflammatory cells in BALF. LRMSC also decreased inflammatory cytokines in both BALF and plasma and increased KGF-2 and surfactant protein C (SPC) expression in the lung. Flow cytometry revealed the upregulation of Tregs and the downregulation of Th17 cells, and the increase in the ratio of Tregs and Th17 cells. The live imaging system showed that LRMSC migrated to and were retained in the injured area. In conclusion, the results indicated that administration of LRMSC attenuates LPS-induced ALI via upregulating the balance of Tregs and Th17 cells.

Recovery from acute lung injury can be regulated via modulation of regulatory T cells and Th17 cells.

Acute lung injury (ALI) is a severe inflammatory disease, for which no specific treatment exists. The decreased ratio of regulatory T cells (CD4+ CD25+ FoxP3 Tregs) and Th17 cells is implicated in ALI and inflammation. We here investigated whether maintaining the balance of CD4+ CD25+ Foxp3+ Tregs and Th17 cells can alleviate lung injury. For CD4+ CD25+ FoxP3 Treg depletion, 200 µg of an anti-CD25 antibody was administered intraperitoneally per mouse on days -3 and -1 before lipopolysaccharide (LPS) instillation. And 150 µg of TGF-ß was administered intraperitoneally per mouse on day 0 after LPS instillation. To down-regulate of Th17 cells, 200 µg per mouse of isotype, IL-17 or IL-22 antibodies were injected intraperitoneally into mice at days 0 after LPS instillation. We detected lung morphology; lung wet-to-dry weight ratio; protein concentration, the count of total cells, neutrophils and macrophages, and cytokines in bronchoalveolar lavage fluid (BALF). And we also evaluated the percentage of CD4+ CD25+ Foxp3+ Tregs in lung, and Th17 cells in lung. CD4+ CD25+ Foxp3+ Tregs depletion via anti-CD25 treatment or TGF-ß neutralization delayed recovery of ALI. The prolonged inflammation was mainly dominated by neutrophils, macrophages and Th17 cells. Furthermore, inhibition of Th17 cells via monoclonal antibodies against IL-17 and IL-22 alleviated ALI inflammation by inhibiting the recruitment of neutrophils and macrophages, increasing the number of CD4+ CD25+ Foxp3+ Tregs. Our findings support a critical role for CD4+ CD25+ Foxp3+ Tregs in regulating from ALI pathophysiology, and a potential therapeutic role for the inhibition of Th17 cells in ALI treatment. These findings provide a rationale for treating patients with ALI by modulating CD4+ CD25+ Foxp3+ Tregs and Th17 cells.

Direct factor Xa inhibition attenuates acute lung injury progression via modulation of the PAR-2/NF-κB signaling pathway.

The role of coagulation in acute lung injury (ALI) remains unclear. As factor Xa-dependent protease-activated receptor 2 (PAR-2) is reported to be an important target in blood coagulation and other processes, an inhibitor of factor Xa, rivaroxaban, was tested in vivo in C57BL/6 mice with ALI induced by intratracheal injections of lipopolysaccharide (LPS) and in vitro in LPS-stimulated human umbilical vein endothelial cells. Plasma concentrations and coagulation indices were measured in mice fed normal chow or chow containing rivaroxaban (0.2 or 0.4 mg/g) for 10 days. The rivaroxaban-treated mice had significantly reduced neutrophil sequestration with preservation of the lung tissue architecture compared with that in the untreated controls. The levels of tumor necrosis factor alpha, interleukin 1 beta, and interleukin 6, as well as total protein and Evans blue concentrations, were all significantly reduced in bronchoalveolar lavage fluid from mice treated with rivaroxaban. Rivaroxaban treatment also ameliorated the LPS-induced PAR-2 increase and nuclear factor kappa B (NF-κB) activation. In vitro, cells treated with rivaroxaban had higher cell viability with an attenuation of LPS-induced increases in membrane permeability and proinflammatory cytokine levels, as well as reduced apoptosis. Furthermore, rivaroxaban inhibited the phosphorylation of TAK1 and p65. These data show that rivaroxaban attenuates ALI and inflammation by inhibiting the PAR-2/NF-κB signaling pathway.

Neutrophil-to-lymphocyte ratio as a prognostic marker in acute respiratory distress syndrome patients: a retrospective study.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is the leading cause of high mortality in intensive care units (ICUs) worldwide. An effective marker for prognosis in ARDS is particularly important given the absence of effective treatment strategies aside from small tidal volume ventilation. Previous studies identified an association between the neutrophil-to-lymphocyte ratio (NLR) and prognosis in critical patients. In this study, we explored the prognostic and predictive value of the NLR in ARDS patients. METHODS: We retrospectively included 275 ARDS patients treated at a single institute from 2008 to 2015. After excluding patients with chronic lung disease, acute myocardial infarction and missing data, 247 patients were ultimately included in the analysis. Clinical characteristics and experimental test data, including the NLR, were collected from medical records at 24 hours after the ARDS diagnosis. Independent prognostic factors were determined by multivariate Cox regression analysis. Subgroup stratification was performed according to different factors, and the continuous factors were divided according to the median values. RESULTS: The NLR in survivors was significantly lower than that in non-survivors (P<0.001). We took the median NLR value as the cut-off point and further divided all patients into a high NLR group (NLR >14) and a low NLR group (NLR ≤14). We found that an NLR >14 was associated with a shorter overall survival (OS) (P=0.005). In the multivariate Cox regression model, we further identified an NLR >14 as an independent prognostic factor for OS [hazard ratio (HR) 1.532, (95% CI, 1.095-2.143), P=0.013]. Subgroup analysis showed that the prognostic value of the NLR was higher in hypertensive patients (P=0.009) and in patients with low red blood cell specific volume (P=0.013), high sodium (P=0.002) and high creatinine levels (P=0.017). CONCLUSIONS: The NLR is potentially a predictive prognostic biomarker in ARDS patients.

Protective Effect of Rituximab in Chronic Graft-Versus-Host Disease Occurrence in Allogeneic Transplant patients with Epstein Barr Virus Viremia.

B cells are involved in chronic graft-versus-host disease (cGVHD) pathogenesis, and Rituximab may have a therapeutic effect on cGVHD in allogeneic hematopoietic stem cell transplantation (allo-HSCT) patients. Herein, we retrospectively evaluated the prophylactic effect of Rituximab on cGVHD in a group of Chinese allo-HSCT patients. A total of 102 patients, who suffered Epstein Barr virus (EBV) viremia within 100 days after allo-HSCT, were included in this study. Fifty patients received Rituximab (375 mg/m2 weekly) for EBV viremia, while fifty-two patients did not receive Rituximab. A competing risk model was adopted to compare cumulative incidence of cGVHD, cumulative incidence of relapse (CIR) and transplantation-related mortality (TRM) between two groups. Cumulative incidence of cGVHD in the Rituximab group was lower than in controls (P = 0.0579). Multivariate analyses confirmed that Rituximab was an independent factor for the reduction of cumulative cGVHD incidence (P = 0.0069). No significant difference was observed in CIR (P = 0.39) or TRM (P = 0.48) between two groups and 2-year OS and DFS were comparable (OS, P = 0.667; DFS, P = 0.571). Administration of Rituximab in the early post-transplantation phase may protect against cGVHD in allo-HSCT patients without increasing CIR or TRM.