Tiotropium resulted in a higher FEV than placebo at 24 months and ameliorated the annual decline in the FEV after bronchodilator use in patients with COPD of GOLD stage 1 or 2. (Funded by Boehringer Ingelheim and others; Tie-COPD ClinicalTrials.gov number, NCT01455129 .).

Little is known about the functions of Toll-like receptor 2 (TLR2) and TLR4 in innate/acquired responses to Schistosoma japonicum. Through in vivo study, the contributions of TLR2 and TLR4 to host immune responses during S. japonicum infection were investigated. Early infection experiments showed higher protein and mRNA levels of IL-12, IFN-γ and IL-4 in dermal tissues and retroauricular draining lymph nodes respectively in TLR2(-/-) mice on day four post-infection and opposite changes in TLR4(-/-) mice. In the acute infection with S. japonicum for 6 weeks, TLR2(-/-) mice manifested lower egg burden as well as the enhancement of T cell activation and upregulated expression of some cytotoxic genes, as assayed by Th1/Th2 cytokine secretion and DNA microarray analysis. Also, the opposite parasitological and immunological effects were observed in TLR4(-/-) mice. These results demonstrate that during S. japonicum infection, TLR2 and TLR4 might direct distinct adaptive immune responses since the early stage, which may lead to different infection outcomes.

Background Hepatocellular carcinoma (HCC) remains one of the most common malignant neoplasms. Lysophosphatidylcholine acyltransferase 1 (LPCAT1) plays a key role in the lipid remodelling and is correlated with various neoplasms. Nonetheless, the biological functions and molecular mechanisms of LPCAT1 underlying HCC remain obscure. Methods In the present study, we investigated the role of LPCAT1 in the progression of HCC. In-house RT-qPCR, tissue microarrays, and immunohistochemistry were performed to detect the expression levels and the clinical value of LPCAT1 in HCC. External datasets were downloaded to confirm the results. Proliferation, migration, invasiveness, cell cycle, and apoptosis assays were conducted to reveal the biological effects LPCAT1 has on SMMC-7721 and Huh7 cells. HCC differentially expressed genes and LPCAT1 co-expressed genes were identified to explore the molecular mechanisms underlying HCC progression. Results LPCAT1 showed upregulated expression in 3715 HCC specimens as opposed to 3105 non-tumour specimens. Additionally, LPCAT1 might be an independent prognostic factor for HCC. LPCAT1-knockout hampered cellular proliferation, migration, and metastasis in SMMC-7721 and Huh7 cells. More importantly, the cell cycle and chemical carcinogenesis were the two most enriched signalling pathways. Conclusions The present study demonstrated that increased LPCAT1 correlated with poor prognosis in HCC patients and fuelled HCC progression by promoting cellular growth, migration, and metastasis.

Background Hepatocellular carcinoma (HCC) causes a heavy disease burden worldwide. Cell division cycle 45 (Cdc45) and its encoding gene ( CDC45 ) have been studied for a long time, but their expression patterns and roles in liver carcinogenesis and advanced HCC deterioration are still incompletely understood. This study integrated tissue microarray and bioinformatics analyses to explore the expression and clinical value of CDC45 and Cdc45 in HCC. Material/Methods In HCC, the expression and relationships with clinic-pathological parameters of CDC45 and Cdc45 were investigated by integrating the RNA-sequencing data, downloaded from The Cancer Genome Atlas and Oncomine databases, and tissue microarray with immunohistochemistry staining. Co-expressed genes and genetic alterations of CDC45 separately obtained from Oncomine and cBioPortal databases were identified to shed light on the potential mechanisms of CDC45 in HCC. Results CDC45 and Cdc45 were both overexpressed in HCC tissues, and the CDC45 level progressively increased from stage I to III. The survival outcomes of the group with high CDC45 expression were significantly worse compared with the group with low expression. Amplification and deep deletion were 2 major significant alteration types in HCC patients, and the outcomes were worse in patients with altered versus unaltered CDC45 . NUDT1 , E2F1 , CCNE2 , MCM5 , and CENPM were identified as the most significantly co-expressed genes. Conclusions CDC45 and Cdc45 were both upregulated in HCC, and increased expression levels and genetic alternations of CDC45 were correlated with worse prognosis in HCC patients. CDC45 may promote HCC by co-expressing with NUDT1 , E2F1 , CCNE2 , MCM5 , and CENPM .

Background Previous studies showed that soluble IL-2Rα is an important marker of cellular immune activation and might be a marker of treatment efficacy for children with brucellosis. However, data regarding adult patients with brucellosis were unknown. The aim of study was to explore the potential role of serum sIL-2Rα evaluating treatment responses in adult patients with brucellosis, and T cell immune status was also examined. Methods During January 2016–April 2017, 30 patients with acute brucellosis from the Third People’s Hospital of Linfen in Shanxi Province and Beijing Di Tan Hospital, and 28 healthy controls were included in this study. Peripheral blood samples were collected before and after six weeks of antibiotic treatment. Serum sIL-2Rα levels were measured by enzyme-linked immunosorbent assay, and the percentage of Th1, Th2, Tc1, Tc2, and Tregs was detected by flow cytometry after intracellular staining for cytokines (interferon-γ and interleukin-4) and Foxp3 in T lymphocytes from peripheral blood. The obtained data were analyzed with Wilcoxon ranked sum tests for paired values, Mann-Whitney U-tests for comparisons between patients and healthy controls, and Spearman rank tests for correlation analyses. Results Serum sIL-2Rα levels were significantly higher in patients than in controls ( P = 0.001). A significant decline was observed in patients after the cessation of treatment ( P < 0.001) and return to normal ( P > 0.05). Th1, Tc1, Th2, and Tc2 cell frequencies were higher in patients than in healthy subjects ( P < 0.05), while the Th1/Th2 and Tc1/Tc2 ratios were significantly lower ( P = 0.0305 and 0.0005, respectively) and returned to normal levels after treatment. In patients with acute brucellosis, serum sIL-2Rα levels were negatively correlated with the Th1/Th2 ratio ( r = − 0.478, P = 0.028), Tc1/Tc2 ratio ( r = − 0.677, P = 0.001), and Tc1 percentage ( r = − 0.516, P = 0.017). Serum sIL-2Rα and Tc2 percentages were positively correlated ( r = 0.442, P = 0.045). Conclusions Based on the correlations with Th1/Th2 and Tc1/Tc2 ratios, serum sIL-2Rα levels may reflect the immune response status. sIL-2Rα may be a marker for therapeutic efficacy in acute brucellosis.

Background The immunoregulatory functions of regulatory T cells (Tregs) in the development and progression of some chronic infectious diseases are mediated by immune checkpoint molecules and immunosuppressive cytokines. However, little is known about the immunosuppressive functions of Tregs in human brucellosis, which is a major burden in low-income countries. In this study, expressions of immune checkpoint molecules and Treg-related cytokines in patients with acute and chronic Brucella infection were evaluated to explore their impact at different stages of infection. Methods Forty patients with acute brucellosis and 19 patients with chronic brucellosis admitted to the Third People’s Hospital of Linfen in Shanxi Province between August 2016 and November 2017 were enrolled. Serum and peripheral blood mononuclear cells were isolated from patients before antibiotic treatment and from 30 healthy subjects. The frequency of Tregs (CD4+ CD25+ FoxP3+ T cells) and expression of CTLA-4, GITR, and PD-1 on Treg cells were detected by flow cytometry. Levels of Treg-related cytokines, including IL-35, TGF-β1, and IL-10, were measured by customised multiplex cytokine assays using the Luminex platform. Results The frequency of Tregs was higher in chronic patients than in healthy controls (P = 0.026) and acute patients (P = 0.042); The frequency of CTLA-4+ Tregs in chronic patients was significantly higher than that in healthy controls (P = 0.011). The frequencies of GITR+ and PD-1+ Tregs were significantly higher in acute and chronic patients than in healthy controls (P < 0.05), with no significant difference between the acute and chronic groups (all P > 0.05). Serum TGF-β1 levels were higher in chronic patients (P = 0.029) and serum IL-10 levels were higher in acute patients (P = 0.033) than in healthy controls. We detected weak correlations between serum TGF-β1 levels and the frequencies of Tregs (R = 0.309, P = 0.031) and CTLA-4+ Tregs (R = 0.302, P = 0.035). Conclusions Treg cell immunity is involved in the chronicity of Brucella infection and indicates the implication of Tregs in the prognosis of brucellosis. CTLA-4 and TGF-β1 may contribute to Tregs-mediated immunosuppression in the chronic infection stage of a Brucella infection.

Background Acid phosphatase type 6 (ACP6) is a mitochondrial lipid phosphate phosphatase that played a role in regulating lipid metabolism and there is still blank in the clinico-pathological significance and functional roles of ACP6 in human cancers. No investigations have been conducted on ACP6 in hepatocellular carcinoma (HCC) up to date. Methods Herein, we appraised the clinico-pathological significance of ACP6 in HCC via organizing expression profiles from globally multi-center microarrays and RNA-seq datasets. The molecular basis of ACP6 in HCC was explored through multidimensional analysis. We also carried out in vitro and in vivo experiment on nude mice to investigate the effect of knocking down ACP6 expression on biological functions of HCC cells, and to evaluate the expression variance of ACP6 in xenograft of HCC tissues before and after the treatment of NC. Results ACP6 displayed significant overexpression in HCC samples (standard mean difference (SMD) = 0.69, 95% confidence interval (CI) = 0.56–0.83) and up-regulated ACP6 performed well in screening HCC samples from non-cancer liver samples. ACP6 expression was also remarkably correlated with clinical progression and worse overall survival of HCC patients. There were close links between ACP6 expression and immune cells including B cells, CD8 + T cells and naive CD4 + T cells. Co-expressed genes of ACP6 mainly participated in pathways including cytokine-cytokine receptor interaction, glucocorticoid receptor pathway and NABA proteoglycans. The proliferation and migration rate of HCC cells transfected with ACP6 siRNA was significantly suppressed compared with those transfected with negative control siRNA. ACP6 expression was significantly inhibited by nitidine chloride (NC) in xenograft HCC tissues. Conclusions ACP6 expression may serve as novel clinical biomarker indicating the clinical development of HCC and ACP6 might be potential target of anti-cancer effect by NC in HCC.

Introduction: Soluble CD163 (sCD163) and soluble CD14 (sCD14) levels, monocyte/macrophage activation markers, are elevated in patient serum during Brucella infection. The aim of this study was to measure serum sCD163 and sCD14 levels during treatment for acute brucellosis to determine whether they can be used to monitor treatment efficacy. Methodology: Blood samples were collected from 30 patients with acute brucellosis (disease duration < 8 weeks) before and after 6 weeks of antibiotic therapy as well as from a comparison group of 28 healthy control individuals. Serum sCD163 and sCD14 levels were measured with specific, sandwich enzyme-linked immunosorbent assays. The clinical data and routine indices including C-reactive protein (CRP), erythrocyte sedimentation rates (ESR), as well as white cell counts (WBC) were also studied. Results: Both serum sCD163 and sCD14 levels were significantly higher in patients with acute brucellosis than in healthy controls (p < 0.0001). A significant decline was observed in patients after cessation of treatment (p < 0.001), which still be significantly higher than that in healthy controls (p < 0.001). In additional, serum sCD163 levels were positively correlated with sCD14 levels; both of which were positively associated with CRP levels. However, neither sCD163 nor sCD14 levels were correlated with ESR or WBC. Conclusions: The decline in sCD163 and sCD14 levels following antibiotic therapy may be used as a marker to assess therapeutic efficacy following treatment of acute brucellosis.