Dynamics of host immune responses and a potential function of Trem2hi interstitial macrophages in Pneumocystis pneumonia.

BACKGROUND: Pneumocystis pneumonia (PCP) is a life-threatening opportunistic fungal infection with a high mortality rate in immunocompromised patients, ranging from 20 to 80%. However, current understanding of the variation in host immune response against Pneumocystis across different timepoints is limited. METHODS: In this study, we conducted a time-resolved single-cell RNA sequencing analysis of CD45+ cells sorted from lung tissues of mice infected with Pneumocystis. The dynamically changes of the number, transcriptome and interaction of multiply immune cell subsets in the process of Pneumocystis pneumonia were identified according to bioinformatic analysis. Then, the accumulation of Trem2hi interstitial macrophages after Pneumocystis infection was verified by flow cytometry and immunofluorescence. We also investigate the role of Trem2 in resolving the Pneumocystis infection by depletion of Trem2 in mouse models. RESULTS: Our results characterized the CD45+ cell composition of lung in mice infected with Pneumocystis from 0 to 5 weeks, which revealed a dramatic reconstitution of myeloid compartments and an emergence of PCP-associated macrophage (PAM) following Pneumocystis infection. PAM was marked by the high expression of Trem2. We also predicted that PAMs were differentiated from Ly6C+ monocytes and interacted with effector CD4+ T cell subsets via multiple ligand and receptor pairs. Furthermore, we determine the surface markers of PAMs and validated the presence and expansion of Trem2hi interstitial macrophages in PCP by flow cytometry. PAMs secreted abundant pro-inflammation cytokines, including IL-6, TNF-α, GM-CSF, and IP-10. Moreover, PAMs inhibited the proliferation of T cells, and depletion of Trem2 in mouse lead to reduced fungal burden and decreased lung injury in PCP. CONCLUSION: Our study delineated the dynamic transcriptional changes in immune cells and suggests a role for PAMs in PCP, providing a framework for further investigation into PCP's cellular and molecular basis, which could provide a resource for further discovery of novel therapeutic targets.

Prognostic biomarkers of malignant patients with pleural effusion: a systematic review and meta-analysis.

BACKGROUND: Pleural effusion is a common clinical problem in patients with cancer. We aimed to summarize all the known prognostic indicators of malignant pleural effusion. METHODS: We did a systematic review and meta-analysis with a systematic literature search. All prospective or retrospective cohort studies that estimated the prognostic factors of malignant pleural effusion were enrolled. Mantel-Haenszel method was used to calculate the pooled hazard ratio (HR) and 95% confidence interval (CI). RESULTS: Eventually, we identified 82 studies with a total of 10,748 patients that met our inclusion criteria. The LENT score showed a good prognostic value (HR 1.97, 95% CI 1.67-2.31) so did the LENT score item. In addition, clinical parameters like stage (HR 1.68, 95% CI 1.25-2.25), distant metastasis (HR 1.62, 95% CI 1.38-1.89), EGFR mutation (HR 0.65, 95% CI 0.56-0.74), serum biological parameters like hemoglobin (HR 1.56, 95% CI 1.17-2.06), albumin (HR 1.71, 95% CI 1.25-2.34), C-reaction protein (HR 1.84, 95% CI 1.49-2.29), VEGF (HR 1.70, 95% CI 1.18-2.43) and pleural effusion biological parameters like PH (HR 1.95, 95% CI 1.46-2.60), glucose (HR 1.75, 95% CI 1.18-2.61), VEGF (HR 1.99, 95% CI 1.67-2.37), and survivin (HR 2.90, 95% CI 1.17-7.20) are also prognostic factors for malignant pleural effusion. CONCLUSIONS: For malignant pleural effusion, LENT score and its items are valuable prognostic biomarkers, so do the clinical parameters like stage, distant metastasis, EGFR mutation, the serum biological parameters like hemoglobin, albumin, C-reaction protein, VEGF and the pleural effusion biological parameters like PH, glucose, VEGF and survivin.

TSAd Plays a Major Role in Myo9b-Mediated Suppression of Malignant Pleural Effusion by Regulating TH1/TH17 Cell Response.

Emerging evidence indicates that Myo9b is a cancer metastasis-related protein and functions in a variety of immune-related diseases. However, it is not clear whether and how Myo9b functions in malignant pleural effusion (MPE). In this study, our data showed that Myo9b expression levels correlated with lung cancer pleural metastasis, and nucleated cells in MPE from either patients or mice expressed a lower level of Myo9b than those in the corresponding blood. Myo9b deficiency in cancer cells suppressed MPE development via inhibition of migration. Myo9b deficiency in mice suppressed MPE development by decreasing TH1 cells and increasing TH17 cells. CD4+ naive T cells isolated from Myo9b-/- mouse spleens exhibited less TH1 cell differentiation and more TH17 cell differentiation in vitro. mRNA sequencing of nucleated cells showed that T cell-specific adaptor protein (TSAd) was downregulated in Myo9b-/- mouse MPE, and enrichment of the H3K27me3 mark in the TSAd promoter region was found in the Myo9b-/- group. Naive T cells purified from wild type mouse spleens transfected with TSAd-specific small interfering RNAs (siRNAs) also showed less TH1 cell differentiation and more TH17 cell differentiation than those from the siRNA control group. Furthermore, downregulation of TSAd in mice using cholesterol-conjugated TSAd-specific siRNA suppressed MPE development, decreased TH1 cells, and increased TH17 cells in MPE in vivo. Taken together, Myo9b deficiency suppresses MPE development not only by suppressing pleural cancer metastasis but also by regulating TH1/TH17 cell response via a TSAd-dependent pathway. This work suggests Myo9b and TSAd as novel candidates for future basic and clinical investigations of cancer.

IL-10 promotes malignant pleural effusion by regulating TH 1 response via an miR-7116-5p/GPR55/ERK pathway in mice.

IL-10, produced by a wide variety of cells, is a highly pleiotropic cytokine that plays a critical role in the control of immune responses. However, its regulatory activity in tumor immunity remains poorly understood. In this study, we report that IL-10 deficiency robustly suppressed the formation of malignant pleural effusion (MPE) and significantly enhanced miR-7116-5p expression in pleural CD4+ T cells. We demonstrated that miR-7116-5p suppressed IL-10-mediated MPE formation by inhibiting pleural vascular permeability as well as tumor angiogenesis and tumor growth. IL-10 promoted MPE formation by suppressing miR-7116-5p that enhances TH 1 response. We identified G protein-coupled receptor 55 (GPR55) as a potential target of miR-7116-5p, and miR-7116-5p promoted TH 1 cell function by downregulating GPR55. Moreover, GPR55 promoted MPE formation by inhibiting TH 1 cell expansion through the ERK phosphorylation pathway. These results uncover an IL-10-mediated pathway controlling TH 1 cells and demonstrate a central role for miR-7116-5p/GPR55/ERK signaling in the physiological regulation of IL-10-driven pro-malignant responses.

PD-1 Deficiency Promotes Macrophage Activation and T-Helper Cell Type 1/T-Helper Cell Type 17 Response in Pneumocystis Pneumonia.

Pneumocystis is an unusual, opportunistic fungal pathogen capable of causing Pneumocystis pneumonia (PCP) in immunocompromised hosts. Although PCP was discovered >100 years ago, its pathogenesis remains unclear. The inhibitory receptor PD-1 (programmed death 1), a negative regulator of activated T cells, has been reported to take part in tumor escape, immune tolerance, and infection immunity. In this study, we examined the role of the PD-1/PD-L1 (programmed death-ligand 1) pathway in patients with PCP and in mice. The expression levels of PD-1/PD-L1 in patients with PCP and in mice were measured by real-time PCR and flow cytometry. The effects of PD-1 deficiency are demonstrated using wild-type and PD-1-/- mice. Our data show that Pneumocystis infection promotes PD-1/PD-L1 expression; PD-1 deficiency enhances the phagocytic function of macrophages and the pulmonary T-helper cell type 1 (Th1)/Th17 response, which might contribute to Pneumocystis clearance; and PD-1 deficiency affects the polarization of macrophages. PCP mice treated with anti-PD-1 antibody showed improved pulmonary clearance of Pneumocystis. Collectively, our results demonstrate that the PD-1/PD-L1 pathway plays a role in regulating the innate and adaptive immune responses, suggesting that manipulation of this pathway may constitute an immunotherapeutic strategy for PCP.

IL-10 promotes malignant pleural effusion in mice by regulating TH 1- and TH 17-cell differentiation and migration.

The role of IL-10 in malignant pleural effusion (MPE) remains unknown. By using murine MPE models, we observed that an increase in pleural IL-10 was a significant predictor of increased risk of death. We noted that TH 1- and TH 17-cell content in MPE was higher in IL-10-/- mice than in WT mice, and IL-10 deficiency promoted differentiation into TH 1 but not into TH 17 cells. A higher fraction of TH 1 and TH 17 cells in the MPE of IL-10-/- mice expressed CXCR3 compared with WT mice. We also demonstrated that Lewis lung cancer and colon adenocarcinoma cells secreted large amounts of CXCL10, a ligand of CXCR3, which induced the migration of TH 1 and TH 17 cells into the MPE, and IFN-γ could promote this signaling cascade. Furthermore, intrapleural injection of mice with CXCL10-deficient tumor cells led to decreased TH 1- and TH 17-cell content in MPE, increased MPE volume, and reduced survival of MPE-bearing mice. Taken together, we demonstrated that IL-10 deficiency promoted T-cell differentiation into TH 1 cells and upregulated the CXCR3-CXCL10 signaling pathway that recruits TH 1 and TH 17 cells into MPE, ultimately resulting in decreased MPE formation and longer survival time of mice-bearing MPE.

Influence of age on the diagnostic accuracy of soluble biomarkers for tuberculous pleural effusion: a post hoc analysis.

BACKGROUND: Accurately diagnosing pleural effusion is a frequent and significant problem in clinical practice. Combining pleural biomarkers with patients' age may be a valuable method for diagnosing TPE. We sought to evaluate the influence of age on diagnostic values of pleural adenosine deaminase (ADA), interferon-gamma (IFN-γ), and interleukin 27 (IL-27) for tuberculous pleural effusion (TPE). METHODS: Two hundred seventy-four consecutive adult patients with pleural effusion were selected from Beijing and Wuhan between January 1, 2014 and June 30, 2015, and their pleural fluid concentrations of ADA, IFN-γ, and IL-27 were tested. Biomarker performance was analyzed by standard receiver operating characteristic (ROC) curves according to different ages. RESULTS: Data from the Beijing cohort showed that ADA, IFN-γ, and IL-27 could all accurately diagnose TPE in young patients (≤ 40 years of age). With a cutoff of 21.4 U/L, the area under the curve (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of ADA for diagnosing TPE were 1.000 (95% confidence interval: 0.884-1.000), 100.0, 100.0%, 100.0, and 100.0, respectively. In older patients (> 40 years of age), IL-27 and IFN-γ were excellent biomarkers for discriminating TPE versus non-TPE cases. With a cutoff of 591.4 ng/L, the AUC, sensitivity, specificity, PPV, and NPV of IL-27 for diagnosing TPE were 0.976 (95% confidence interval: 0.932-0.995), 96.3, 99.0%, 96.3, and 99.0, respectively. Similar diagnostic accuracy among the three pleural biomarkers was validated in the Wuhan cohort. CONCLUSIONS: Among young patients, ADA is reliable for diagnosing TPE. Conversely, in older patients, IL-27 and IFN-γ are excellent biomarkers to differentiate TPE versus non-TPE cases.

IL-10-producing B cells regulate Th1/Th17-cell immune responses in Pneumocystis pneumonia.

Pneumocystis pneumonia (PCP) is a common opportunistic infectious disease that is prevalent in immunosuppressed hosts. Accumulating evidence shows that B cells play an important role in infectious diseases. In the present study, the immune regulatory role of mature B cells in host defense to Pneumocystis was evaluated. Pneumocystis infection resulted in a decrease in B cells in patients and mice, and the Pneumocystis burden in B cell-deficient mice also progressively increased from weeks 1 to 7 after infection. The clearance of Pneumocystis was delayed in B cell-activating factor receptor (BAFF-R)-deficient mice (BAFF-R-/- mice), which had few B cells and Pneumocystis-specific IgG and IgM antibodies, compared with clearance in wild-type (WT) mice. There were fewer effector CD4+ T cells and higher percentages of T helper (Th)1/Th17 cells in BAFF-R-/- mice than in WT mice. Adoptive transfer of naive B cells, mRNA sequencing, and IL-1ß neutralization experiments indicated that IL-1ß is a likely determinant of the IL-10-producing B cell-mediated suppression of Th1/Th17-cell immune responses in BAFF-R-/- PCP mice. Our data indicated that B cells play a vital role in the regulation of Th cells in response to Pneumocystis infection.

Activated naïve B cells promote development of malignant pleural effusion by differential regulation of TH1 and TH17 response.

Inflammatory signaling networks between tumor cells and immune cells contribute to the development of malignant pleural effusion (MPE). B cells have been found in MPE; however, little is known about their roles there. In the present study, by using mouse MPE models, we noted that although the total B cells in MPE were decreased as compared with the corresponding blood and spleen, the percentage of activated naïve B cells expressing higher levels of CD80, CD86, myosin heavy chain-II, CD44, CD69, and programmed cell death-ligand 1 (PD-L1) molecules were increased in wild-type mouse MPE. Compared with wild-type mice, decreased T helper (TH)1 cells and increased TH17 cells were present in B cell-deficient mouse MPE, which paralleled to the reduced MPE volume and longer survival time. Adoptive transfer of activated naïve B cells into B cell-deficient mice was able to increase TH1 cells and decrease TH17 cells in MPE and shorten the survival of mice bearing MPE. Furthermore, we demonstrated that activated naïve B cells inhibited TH17-cell expansion via the PD-1/PD-L1 pathway and promoted naïve CD4+ T-cell differentiation into TH1/TH17 cells through secreting IL-27/IL-6 independent of the PD-1/PD-L1 pathway. Collectively, our data uncovered a mechanism by which naïve B cells promote MPE formation by regulating TH1/TH17 cell responses, making these B cells an attractive target for therapeutic intervention in the fight against cancer.

Diagnostic accuracy of interleukin 27 for tuberculous pleural effusion: two prospective studies and one meta-analysis.

BACKGROUND: Accurate differentiating diagnosis is essential for choosing treatment for exudative pleural effusions. OBJECTIVE: To establish the diagnostic accuracy of interleukin 27 for tuberculous pleural effusion (TPE). METHODS: First, the concentrations of pleural interleukin 27, interferon-gamma and adenosine deaminase were compared between 51 patients with TPE and 103 with non-TPEs (Beijing cohort), and their diagnostic values were evaluated. These were further verified in another independent population (Wuhan cohort, n=120). In the second part of the study, we performed a meta-analysis. RESULTS: With a cut-off value of 591.4 ng/L in the Beijing cohort, the area under the curve, sensitivity, specificity, positive predictive value and negative predictive value of interleukin 27 to diagnose TPE were 0.983 (95% CI 0.947 to 0.997), 96.1% (86.5% to 99.5%), 99.0% (94.7% to 100%), 98.0 (89.4 to 99.9) and 98.1 (93.3 to 99.8), respectively. Excellent diagnostic accuracy of interleukin 27 was also found in the Wuhan cohort and was further confirmed in the meta-analysis. The diagnostic performance of interleukin 27 was comparable to that of interferon-gamma and was more accurate than that of adenosine deaminase. Since the post-test probability of a negative result was always <0.1%, a negative test was considered to exclude TPE in all tuberculosis prevalence settings. CONCLUSIONS: Interleukin 27 can be used to diagnose TPE in a high prevalence setting, and a negative result can also be reliably used to rule out TPE in all prevalence settings.

Transcriptomic Analysis Reveals Significant B Lymphocyte Suppression in Corticosteroid-Treated Hosts with Pneumocystis Pneumonia.

Pneumocystis pneumonia (PCP) is an opportunistic, infectious disease that is prevalent in immunosuppressed hosts. Corticosteroid treatment is the most significant risk factor for patients with PCP who are human immunodeficiency virus negative, although little is known about how corticosteroids alter the host defense against Pneumocystis infection. In the present study, we used transcriptome analysis to examine the immune response in the lungs of corticosteroid-treated PCP mice. The results showed down-regulation in the genes related to both native immunity, such as antigen processing and presentation, inflammatory response, and phagocytosis, as well as B and T lymphocyte immunity. The repression of gene expression, corresponding to B cell immunity, including B cell signaling, homeostasis, and Ig production, was prominent. The finding was confirmed by quantitative PCR of mouse lungs and the peripheral blood of patients with PCP. Flow cytometry also revealed a significant depletion of B cells in corticosteroid-treated PCP mice. Our study has highlighted that corticosteroid treatment suppresses the B cell immunity in the PCP host, which is likely one of the main reasons that corticosteroid treatment may stimulate PCP development.

Immune Regulation of Toll-Like Receptor 2 Engagement on CD4+ T Cells in Murine Models of Malignant Pleural Effusion.

Toll-like receptor (TLR) 2 has a well-known role in sensing multiple ligands that include microbial products, endotoxin, and some extracellular matrix molecules; however, its role in the development of malignant pleural effusion (MPE) remains unknown. We performed the present study to explore the impact of TLR2 signaling on the development of MPE and to define the underlying mechanisms by which TLR2 works. Development of MPE was compared between TLR2-/- and wild-type (WT) mice. The effect of TLR2 on differentiation of T helper type 17 (Th17), Th9, and Th2 cells in MPE was explored. The mechanisms of TLR2 on survival of mice bearing MPE were also investigated. MPE volume in TLR2-/- mice was lower than that in WT mice, and the survival of TLR2-/- mice bearing MPE was longer than that of WT mice. TLR2 deficiency increased, and TLR2 activation decreased, Th17 cells in MPE, whereas TLR2 signaling showed the contrary effects on Th2 cells. Th9 cells were increased in MPE of TLR2-/- mice but were not influenced by TLR2 signaling. Intraperitoneal injection of anti-IL-17 monoclonal antibody (mAb), anti-IL-9 mAb, or recombinant mouse IL-4 accelerated the death of TLR2-/- mice bearing MPE, and intraperitoneal injection anti-IL-17 mAb in TLR2-/- mice was associated with a significantly shorter survival time than in WT mice. We have demonstrated, for the first time, that TLR2 signaling promotes the development of MPE and accelerates the death of mice bearing MPE by directly suppressing Th17 cell differentiation and directly promoting Th2 cell differentiation, and also by indirectly suppressing Th9 cell differentiation via an IL-17-dependent mechanism.

Germline variation in the 3'-untranslated region of the POU2AF1 gene is associated with susceptibility to lymphoma.

Genetic variations in certain genes may alter the susceptibility to lymphoma. We searched electronic databases and selected candidate single-nucleotide polymorphisms (SNPs) located within 3'-untranslated regions (3'-UTRs) that might affect miRNA-binding ability in the 50 most dysregulated genes in lymphoma for further study. We found that rs1042752-located in the 3'-UTR of POU2AF1, which plays a vital role in lymphomagenesis-was significantly associated with lymphoma risk in a case-control study with 793 patients and 939 controls. Compared with individuals with the rs1042752TT genotype, those with the rs1042752CC genotype had a higher risk of lymphoma (OR = 2.14, 95% CI: 1.55-2.95, P < 0.001), even in stratified analysis for non-Hodgkin lymphoma (OR = 4.58, 95% CI: 2.38-8.81, P < 0.001), B-cell lymphoma (OR = 4.89, 95% CI: 2.46-9.73, P < 0.001), T-cell lymphoma (OR = 4.20, 95% CI: 1.76-10.05, P = 0.001), and Hodgkin lymphoma (OR = 3.62, 95% CI: 1.25-10.46, P = 0.018). Similar results were also observed in a recessive genetic model. Database findings suggested that rs1042752 might affect the interaction of POU2AF1 mRNA with hsa-miR-633. Functional assays confirmed that rs1042752C altered the binding site of hsa-miR-633 and increased POU2AF1 expression in Ramos, HuT 102, and Jurkat E6-1 cell lines. These findings demonstrate for the first time that functional polymorphism in the 3'-UTR of POU2AF1 is associated with susceptibility, and that SNP interaction with hsa-miR-633 affects gene expression and increases the risk of lymphoma.

Evidence of associations of APOBEC3B gene deletion with susceptibility to persistent HBV infection and hepatocellular carcinoma.

APOBEC3s are a family of cytidine deaminases involved in innate cellular immunity against virus including hepatitis B virus (HBV). A germline deletion across APOBEC3A and APOBEC3B (A3B) genes results in complete removal of the A3B coding region and destroys A3B expression. To determine whether this deletion affects susceptibility to HBV infection and HBV-related hepatocellular carcinoma (HCC), A3B genotypes were analyzed in 1124 individuals with HCC, 510 individuals with persistent HBV infection and 826 healthy controls and the association was estimated by odds ratio (OR) and 95% confidence interval (CI) computed by logistic regression. We also examined the effects of A3B on HBV genome hypermutation and replication in HCC cells. We observed a significantly higher frequency of the A3B deletion allele in persistent HBV carriers (33.3%; P = 0.0015) and HCC patients (37.9%; P = 1.28 × 10(-11)) compared with that in controls (27.5%). An increased risk for persistent HBV infection (OR = 1.35, 95% CI: 1.03-1.77) and HCC development (OR = 1.90, 95% CI: 1.58-2.28) was associated with at least one A3B deletion allele (+/- or -/- genotype) compared with the +/+ genotype. Transfection of A3B in HepG2 cells caused a substantial reduction of HBV RNA levels and G → A hypermutation in the HBV genome. Interestingly, a cytidine deaminase null mutant of A3B (E255A) also inhibited HBV RNA production although it was unable to edit HBV. These results suggest that the deletion of A3B attenuates HBV clearance, which in turn may result in persistent HBV infection and increased risk for developing HCC. Further studies are needed to verify our findings.

Toll-like receptor 4 signaling inhibits malignant pleural effusion by altering Th1/Th17 responses.

Toll-like receptor 4 (TLR4) is involved in multiple malignancies; however, the role of TLR4 in the pathogenesis of malignant pleural effusion (MPE) remains unknown. The objectives of this study were to explore the impact of TLR4 signaling on the development of MPE in a murine model and to define the underline mechanisms by which TLR works. Development of MPE as well as proliferation and angiogenesis of pleural tumor were determined in TLR4(-/-) and wild type mice. Differentiation of Th1 and Th17 cells as well as their signal transductions was explored. The effects of TLR4 signaling on survival of mice bearing MPE were also investigated. Compared with wild type mice, Th1 cells were augmented, and Th17 cells were suppressed in MPE from TLR4(-/-) mice. The in vitro experiments showed that TLR4 deficiency promoted Th1 cell differentiation via enhancing STAT1 pathway and inhibited Th17 cell differentiation via suppressing STAT3 pathway. TLR4 deficiency promoted MPE formation and, thus, accelerated the death of mice bearing MPE, whereas intraperitoneal injection of anti-IFN-γ mAb or recombinant mouse IL-17 protein into TLR4(-/-) mice was associated with improved survival. Our data provides the first definitive evidence of a role for TLR4 signaling in protective immunity in the development of MPE. Our findings also demonstrate that TLR4 deficiency promotes MPE formation and accelerates mouse death by enhancing Th1 and suppressing Th17 response.

Recruitment of IL-27-Producing CD4(+) T Cells and Effect of IL-27 on Pleural Mesothelial Cells in Tuberculous Pleurisy.

BACKGROUND: The numbers of IL-27-producing CD4(+) T cells and the concentration of soluble IL-27 have been found to be increased in tuberculous pleural effusion (TPE). The objective of the present study was to explore the mechanism by which IL-27(+)CD4(+) T cells are recruited into the pleural space, and to explore the impact of IL-27 on pleural mesothelial cells (PMCs). METHODS: The expression profiles of chemokine receptor (CCR) were determined by flow cytometry. The chemoattractant activity of chemokines CCL20 and CCL22 for IL-27(+)CD4(+) T cells in vitro was observed. Effects of IL-27 on wound healing, proliferation and apoptosis of PMCs were also investigated. RESULTS: IL-27(+)CD4(+) T cells in TPE expressed high level of CCR6, medium level of CCR4, and low levels of CCR2, CCR3, CCR5, CCR7, CCR10, and CXCR3. Recruitment of IL-27(+)CD4(+) T cells into TPE could be induced by pleural CCL20 and CCL22. By activating STAT3 signaling, IL-27 significantly improved wound healing and promoted proliferation of PMCs, and completely prevented apoptosis of PMCs induced by IFN-γ. CONCLUSIONS: After being recruited into pleural space by CCL20 or/and CCL22, these pleural IL-27-producing CD4(+) T cells may play important roles in tuberculosis immunity by affecting PMC functions.

Gallic acid can play a chondroprotective role against AGE-induced osteoarthritis progression.

BACKGROUND: Advanced glycation end products (AGEs) are a group of stable covalent compounds generated by proteins, lipids, other macromolecules and sugar through a series of non-enzymatic reactions. As reported, AGEs can cause widespread pathophysiological responses through activation of AGE receptors (RAGEs) on the cell surface, and play an important role in the pathogenesis of osteoarthritis (OA). We hypothesized that the antioxidant and anti-glycan agent gallic acid (GA) can work against the effects of AGEs and can be used as a potential drug for the cure of OA. METHODS: The present study first explored the negative functions of AGEs via AGE-treated chondrocytes isolated form rabbits. Then, we observed the protective role of GA in AGE-treated chondrocytes by measuring the reactive oxygen species (ROS), superoxide dismutase (SOD), collagen II, aggrecan, nitric oxide synthase (iNOs) and cyclooxygenase-2 (COX-2) in vitro. Finally, the changes in a cartilage lesion in a rabbit model of knee osteoarthritis was observed. RESULTS: Exposure of chondrocytes to AGEs resulted in a reduction of ROS, SOD, collagen II and aggrecan, and an increase in iNOs and COX-2, which means exposure promoted OA lesions in a clinical setting. When AGE-treated chondrocytes were pretreated with GA, there were no significant changes in these key components compared to the normal chondrocytes. In vivo study showed cartilage degradation was reduced by GA as compared to the vehicle group. CONCLUSION: The results of this study confirmed the chondroprotective role of GA and provide a potential drug for the relief of OA.

A genome wide association study of genetic loci that influence tumour biomarkers cancer antigen 19-9, carcinoembryonic antigen and α fetoprotein and their associations with cancer risk.

OBJECTIVE: Tumour biomarkers are used as indicators for cancer screening and as predictors for therapeutic responses and prognoses in cancer patients. We aimed to identify genetic loci that influence concentrations of cancer antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA) and α fetoprotein (AFP), and investigated the associations between the significant single nucleotide polymorphisms (SNPs) with risks of oesophageal squamous cell (OSCC), pancreatic and hepatocellular cancers. DESIGN: We carried out a genome wide association study on plasma CA19-9, CEA and AFP concentrations in 3451 healthy Han Chinese and validated the results in 10 326 individuals. Significant SNPs were further investigated in three case control studies (2031 OSCC cases and 2044 controls; 981 pancreatic cancer cases and 1991 controls; and 348 hepatocellular cancer cases and 359 controls). RESULTS: The analyses showed association peaks on three genetic loci for CA19-9 (FUT6-FUT3 at 19p13.3, FUT2-CA11 at 19q13.3 and B3GNT3 at 19p13.1; p=1.16×10(-13)-3.30×10(-290)); four for CEA (ABO at 9q34.2, FUT6 at 19p13.3, FUT2 at 19q13.3 and FAM3B at 21q22.3; p=3.33×10(-22)-5.81×10(-209)); and two for AFP (AFP at 4q11-q13 and HISPPD2A at 15q15.3; p=3.27×10(-18) and 1.28×10(-14)). These explained 17.14% of the variations in CA19-9, 8.95% in CEA and 0.57% in AFP concentrations. Significant ABO variants were also associated with risk of OSCC and pancreatic cancers, and AFP variants with risk of hepatocellular cancer (p<0.05). CONCLUSIONS: This study identified several loci associated with CA19-9, CEA and AFP concentrations. The ABO variants were associated with risk of OSCC and pancreatic cancers and AFP variants with risk of hepatocellular cancer.

Different role of tumor necrosis factor-α polymorphism in non-Hodgkin lymphomas among Caucasian and Asian populations: a meta-analysis.

Tumor necrosis factor-α (TNF-α) is an immunoregulatory cytokine involved in B- and T-cell function, and also plays an important role in inflammation and cancer. TNF-α-308G>A has been associated with constitutively elevated TNF-α expression. Several studies have reported the association between the TNF-α-308G>A polymorphism and non-Hodgkin lymphomas (NHL) risk, however, results are still inconsistent. To solve these conflicts, we conducted the first meta-analysis to assess the effect of TNF-α-308G>A polymorphism on the risk of NHL and various subtypes (additive model) including 10,619 cases and 12,977 controls in Caucasian and Asian populations. Our meta-analysis indicated that TNF-α-308G>A polymorphism is not associated with NHL risk when pooling all studies together (OR=1.06, 95% CI: 0.92-1.23, p=0.413). In stratified analyses, we found TNF-α-308A allele was significantly associated with higher risk of NHL, B-cell lymphomas (BCL), T-cell lymphomas (TCL) and diffuse large B-cell lymphomas (DLBCL) in Caucasians (OR=1.22, 95% CI: 1.06-1.40, p=0.007; OR=1.18, 95% CI: 1.03-1.34, p=0.014; OR=1.20, 95% CI: 1.01-1.42, p=0.040; OR=1.21, 95% CI: 1.11-1.32, p<0.001, respectively). Interestingly, it was associated with decreased risk of NHL, BCL and DLBCL in Asians (OR=0.75, 95% CI: 0.66-0.86, p<0.001; OR=0.70, 95% CI: 0.52-0.94, p=0.018; OR=0.70, 95% CI: 0.57-0.86, p=0.001). These findings also suggest TNF-α might play a distinct role in pathogenesis of NHL in different populations.

Risk of genome-wide association study-identified genetic variants for non-Hodgkin lymphoma in a Chinese population.

Recent genome-wide association studies have identified 15 single nucleotide polymorphisms (SNPs) associated with non-Hodgkin lymphoma (NHL) and its subtypes. Because the incidence and subtype portion of NHL between the Chinese population and Caucasian populations are substantially different, we assessed the associations of these SNPs with NHL risk in a case-control study consisting of 792 cases and 1542 controls derived from the Chinese population. Odds ratios (OR) and 95% confidence intervals (CI) were computed by logistic regression. False-positive report probability was also assessed for significant findings. We found that the allele frequencies of the 15 SNPs in our study population significantly differed from those in Caucasian populations, with rs13397985, rs735665 and rs11083846 being extremely rare in Chinese. Only two variants (rs872071 in IRF4 and rs2647012 in HLA class II) were significantly associated with NHL risk in Chinese, with the ORs of 1.20 (95% CI, 1.05-1.38; P = 0.009) and 1.20 (95% CI, 1.03-1.39; P = 0.018) for per allele of rs872071 and rs2647012, respectively, calculated using an additive model. These results indicate a substantial different genetic background for susceptibility to NHL among the different ethnic populations.