Background In patients with vitiligo, an increased reactive oxygen species (ROS) level has been proved to be a key player during disease initiation and progression in melanocytes. Nevertheless, ...little is known about the effects of ROS on other cells involved in the aberrant microenvironment, such as keratinocytes and the following immune events. CXCL16 is constitutively expressed in keratinocytes and was recently found to mediate homing of CD8+ T cells in human skin. Objective We sought to explicate the effect of oxidative stress on human keratinocytes and its capacity to drive CD8+ T-cell trafficking through CXCL16 regulation. Methods We first detected putative T-cell skin-homing chemokines and ROS in serum and lesions of patients with vitiligo. The production of candidate chemokines was detected by using quantitative real-time PCR and ELISA in keratinocytes exposed to H2 O2 . Furthermore, the involved mediators were analyzed by using quantitative real-time PCR, Western blotting, ELISA, and immunofluorescence. Next, we tested the chemotactic migration of CD8+ T cells from patients with vitiligo mediated by the CXCL16-CXCR6 pair using the transwell assay. Results CXCL16 expression increased and showed a positive correlation with oxidative stress levels in serum and lesions of patients with vitiligo. The H2 O2 -induced CXCL16 expression was due to the activation of 2 unfolded protein response pathways: kinase RNA (PKR)–like ER kinase–eukaryotic initiation factor 2α and inositol-requiring enzyme 1α–X-box binding protein 1. CXCL16 produced by stressed keratinocytes induced migration of CXCR6+ CD8+ T cells derived from patients with vitiligo. CXCR6+ CD8+ T-cell skin infiltration is accompanied by melanocyte loss in lesions of patients with vitiligo. Conclusion Our study demonstrated that CXCL16-CXCR6 mediates CD8+ T-cell skin trafficking under oxidative stress in patients with vitiligo. The CXCL16 expression in human keratinocytes induced by ROS is, at least in part, caused by unfolded protein response activation.
Abstract Background Large cohort studies provide conflicting evidence regarding the potential for oral macrolide antibiotics to increase the risk of serious cardiac events. Objectives This study ...performed a meta-analysis to examine the link between macrolides and risk of sudden cardiac death (SCD) or ventricular tachyarrhythmias (VTA), cardiovascular death, and death from any cause. Methods We performed a search of published reports by using MEDLINE (January 1, 1966, to April 30, 2015) and EMBASE (January 1, 1980, to April 30, 2015) with no restrictions. Studies that reported relative risk (RR) estimates with 95% confidence intervals (CIs) for the associations of interest were included. Results Thirty-three studies involving 20,779,963 participants were identified. Patients taking macrolides, compared with those who took no macrolides, experienced an increased risk of developing SCD or VTA (RR: 2.42; 95% CI: 1.61 to 3.63), SCD (RR: 2.52; 95% CI: 1.91 to 3.31), and cardiovascular death (RR: 1.31; 95% CI: 1.06 to 1.62). No association was found between macrolides use and all-cause death or any cardiovascular events. The RRs associated with SCD or VTA were 3.40 for azithromycin, 2.16 for clarithromycin, and 3.61 for erythromycin, respectively. RRs for cardiovascular death were 1.54 for azithromycin and 1.48 for clarithromycin. No association was noted between roxithromycin and adverse cardiac outcomes. Treatment with macrolides is associated with an absolute risk increase of 118.1 additional SCDs or VTA, and 38.2 additional cardiovascular deaths per 1 million treatment courses. Conclusions Administration of macrolide antibiotics is associated with increased risk for SCD or VTA and cardiovascular death but not increased all-cause mortality.
Abstract Background Asthmatic inflammation is dominated either by eosinophil and/or neutrophil accumulation in airways. Disposal of these inflammatory cells is the key to disease control. ...Eosinophilic airway inflammation is responsive to corticosteroid treatment, while neutrophilic inflammation is resistant and increases the burden of global health care. Corticosteroid resistant neutrophilic asthma remains mechanistically poorly understood and requires novel effective therapeutic strategies. Objective We thought to explore the underlying mechanisms of airway inflammation persistence as well as corticosteroid resistance, and to investigate a new strategy of effective treatment against corticosteroid-insensitive neutrophilic asthma. Methods Mouse models of either eosinophils-dominated or neutrophils-dominated airway inflammation were used in this study to test corticosteroid sensitivity in vivo and in vitro . We also used vav-Bcl-2 transgenic mice to confirm the importance of granulocytes apoptosis in the clearance of airway inflammation. Finally, Bcl-2 inhibitors ABT-737 or ABT-199 –were tested for their therapeutic effects against eosinophilic or neutrophilic airway inflammation and airway hyperresponsiveness. Results Overexpression of Bcl-2 protein was found to be responsible for persistence of granulocytes in bronchoalveolar lavage fluid following allergic challenge. This was important as allergen-induced airway inflammation aggravated and persisted in vav-Bcl-2 transgenic mice, where nucleated hematopoietic cells were over-expressed with Bcl-2 and resistant to apoptosis. Bcl-2 inhibitors, ABT-737 or ABT-199, play efficient roles in alleviation of either eosinophilic or corticosteroid resistant-neutrophilic airway inflammation, by inducing apoptosis of immune cell, such as eosinophils, neutrophils, Th2, Th17 and dendritic cells. Moreover, these inhibitors were found to be more efficient than steroid to induce granulocytes apoptosis ex vivo from severe asthma patients. Conclusion Apoptosis of inflammatory cells is essential for the clearance of allergen-induced airway inflammation. Bcl-2 inhibitors ABT-737 or ABT-199 may be promising drugs for the treatment against airway inflammation, especially for corticosteroid-insensitive neutrophilic airway inflammation.
Abstract Background Fish consumption may protect against colorectal cancer, but results from observational studies are inconsistent; therefore, a systematic review with a meta-analysis was conducted. ...Methods Relevant studies were identified by a search of MEDLINE and EMBASE databases to May 2011, with no restrictions. Reference lists from retrieved articles also were reviewed. Studies that reported odds ratio (OR) or relative risk estimates with 95% confidence intervals (CIs) for the association between the consumption of fish and the risk of colorectal, colon, or rectal cancer were included. Two authors independently extracted data and assessed study quality. The risk estimate (hazard ratio, relative risk, or OR) of the highest and lowest reported categories of fish intake were extracted from each study and analyzed using a random-effects model. Results Twenty-two prospective cohort and 19 case-control studies on fish consumption and colorectal cancer risk met the inclusion criteria and were included in the meta-analysis. Our analysis found that fish consumption decreased the risk of colorectal cancer by 12% (summary OR, 0.88; 95% CI, 0.80-0.95). The pooled ORs of colorectal cancer for the highest versus lowest fish consumption in case-control studies and cohort studies were 0.83 (95% CI, 0.72-0.95) and 0.93 (95% CI, 0.86-1.01), respectively. There was heterogeneity among case-control studies ( P < .001) but not among cohort studies. A significant inverse association was found between fish intake and rectal cancer (summary OR, 0.79; 95% CI, 0.65-0.97), and there was a modest trend seen between fish consumption and colon cancer (summary OR, 0.96; 95% CI, 0.81-1.14). This study had no publication bias. Conclusion Our findings from this meta-analysis suggest that fish consumption is inversely associated with colorectal cancer.
Objective:
To evaluate whether this conversion rate to resectability could be increased when patients are treated with transarterial chemoembolization and hepatic arterial infusion chemotherapy ...(TACE-HAIC) using oxaliplatin plus fluorouracil/leucovorin.
Background:
Conventional TACE (c-TACE) is a common regimen for initially unresectable hepatocellular carcinoma (HCC), which converts to curative-intent resection in about 10% of those patients. It is urgent need to investigated better regimen for those patients.
Methods:
The data of 83 initially unresectable HCC patients were examined, including 41 patients in the TACE-HAIC group and 42 patients in the c-TACE group. Their response rate, conversion rate to resection, survival outcome, and adverse events were compared.
Results:
The conversion rate was significantly better in the TACE-HAIC group than in the c-TACE group (48.8% vs 9.5%;
P
< 0.001). The TACE-HAIC had marginal superiority in overall response rate as compared to c-TACE (14.6% vs 2.4%;
P
= 0.107 RECIST; 65.9% vs 16.7%;
P
< 0.001 mRECIST, respectively). The median progression-free survival was not available and 9.2 months for the TACE-HAIC and cTACE groups, respectively (hazard rate HR: 0.38; 95% confidence interval CI, 0.20–0.70;
P
= 0.003). The median overall survival was not available and 13.5 months for the TACE-HAIC and c-TACE groups, respectively (HR, 0.63; 95% CI, 0.34–1.17;
P
= 0.132). The 2 groups had similar rates of grade 3/4 adverse events (all
P
> 0.05).
Conclusions:
TACE-HAIC demonstrated a higher conversion rate and progression-free survival benefit than c-TACE and could be considered as a more effective regimen for patients with initially unresectable HCC. Future prospective randomized trials are needed to confirm it.
Background In patients with persistent upper airway inflammation, the number of forkhead box protein 3 (Foxp3)+ regulatory T (Treg) cells is reduced, but the regulation of Foxp3 expression in Treg ...cells is poorly understood. Objective We investigated the interaction between suppressor of cytokine signaling 3 (SOCS3) and Foxp3 expression in the airway mucosa. Methods Expression of SOCS3 and Foxp3 was measured in tissue from patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and control tissue. Coexpression of SOCS3 and Foxp3 was evaluated in PBMCs and in tissue from patients with CRSwNP. We also switched off and overexpressed SOCS3 in tissue from patients with CRSwNP and in pancreatic carcinoma epithelial-like cell line (PANC-1) cells and examined the effect on Foxp3 expression. Results SOCS3 gene and protein expression was upregulated in inflammatory cells in airway mucosa, whereas Foxp3 gene and protein expression was downregulated. Mucosal Treg cells coexpressed both proteins. Switching off the expression of SOCS3 in human airway mucosa resulted in Foxp3 upregulation, whereas inducing it in PANC-1 cells led to Foxp3 downregulation. We also found that phosphorylation of signal transducer and activator of transcription (STAT) 3 was decreased in inflamed mucosa, and we hypothesized that SOCS3 was responsible. Phosphorylation of STAT3 increased on silencing SOCS3 expression in inflamed mucosa and decreased on SOCS3 plasmid transfection in PANC-1 cells. Conclusion For the first time, we demonstrate that SOCS3 and Foxp3 are coexpressed in Treg cells in human nasal mucosa and that SOCS3 negatively regulates Foxp3 expression in human airway mucosa, possibly through phosphorylation of STAT3. Hence SOCS3 could be a potential target for restoring Foxp3 expression in Treg cells in patients with persistent mucosal inflammation.
Summary Chemokine receptor, CXCR3, has been increasingly reported to be involved in tumorigenesis and tumor progression, but limited data are available regarding the expression of CXCR3 in gastric ...cancer (GC). In the present study, the expressions of CXCR3 and its variants were detected in 96 GC and corresponding nontumor gastric tissues by immunohistochemical staining, in 40 freshly frozen GC and nontumor gastric tissues by reverse-transcription polymerase chain reaction and quantitative real-time polymerase chain reaction, and in 10 freshly frozen GC and nontumor gastric tissues by Western blotting. Results revealed that an overexpression of CXCR3 occurs in GC tissues as compared to the nontumor gastric tissues. High level of CXCR3 expression was found to be inversely associated with invasion depth and metastasis ( P = .030 and P = .019, respectively) and directly associated with improved overall survival (log-rank test, P < .001). Furthermore, multivariate analysis showed that high CXCR3 expression acts an independent prognostic factor for GC patients (hazard ratio, 0.379 0.196-0.734; P = .004). The messenger RNA expression of both the CXCR3 variants, CXCR3-A and CXCR3-B, were up-regulated in GC tissues ( P = .006 and P = .002, respectively), although CXCR3-B messenger RNA expression was significantly higher than CXCR3-A, with an average CXCR3-B to CXCR3-A ratio of 1.80. CXCR3-B protein expression was also up-regulated in GC tissues ( P = .023). In conclusion, our study suggested a potential use of CXCR3 overexpression as a prognostic marker for GC and involvement of the up-regulation of CXCR3-B in favorable prognosis of GC patients.
Summary Our aim was to investigate the expression of micro-RNA-200b (miR-200b) and cAMP-responsive element-binding protein 1 (CREB-1) in astrocytoma and its efficacy for predicting outcome. Both ...miR-200b and CREB-1 messenger RNA expression was measured in 122 astrocytomas and 30 nonneoplastic brain specimens by quantitative real-time polymerase chain reaction. Expression of miR-200b was significantly lower in astrocytoma than in nonneoplastic brain ( P < .001), whereas CREB-1 messenger RNA expression was significantly elevated in the tumors ( P < .001). Both miR-200b down-regulation and CREB-1 up-regulation were significantly associated with advanced pathologic grade ( P = .002 and P = .006, respectively). Low miR-200b expression correlated negatively with Karnofsky performance score ( P = .03), and high CREB-1 expression correlated positively with mean tumor diameter ( P = .03). By Kaplan-Meier analysis, low miR-200b, high CREB-1, and coexistence of abnormal miR-200b and CREB-1 expression (low miR-200b/high CREB-1) were predictive of shorter progression-free survival and overall survival in both grade III and grade IV astrocytoma. By multivariate analysis, only low miR-200b/high CREB-1 expression was an independent prognostic factor for poor prognosis in astrocytoma of advanced grade. Both miR-200b and CREB-1 may play important cooperative roles in the progression of human astrocytoma. The efficacy of miR-200b and CREB-1 together as a predictor of prognosis in astrocytoma patients is shown for the first time.
Abstract Background Preexisting cirrhosis usually leads to an inadequate and delayed regeneration of the future liver remnant (FLR) after portal vein embolization (PVE). Bone marrow-derived ...mesenchymal stem cells (BMSC) are promising candidates for therapeutic applications in liver diseases. In this study, the efficacy of autologous BMSCs transplantation to promote FLR regeneration was investigated in a rat cirrhotic model. Methods Autologous BMSCs were expanded and labeled with PKH26, and then were injected immediately into nonembolized lobes after PVE through portal vein in cirrhotic rat. At 7, 14, and 28 d after this, liver weight and Ki-67 labeling index were measured, and blood analysis was performed. Cirrhotic degree of FLR was assessed by hydroxyproline content assay and histopathology. Gene expressions of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), interleukin-10 (IL-10), and matrix metalloproteinase-9 (MMP-9) were detected with real-time reverse transcriptase-polymerase chain reaction. Distribution and hepatocyte differentiation of BMSCs in FLR were determined by confocal microscopy. Results Autologous BMSCs significantly increased the FLR weight ratio to the total liver and the Ki-67 labeling index, and serum albumin levels were significantly higher and total bilirubin levels were significantly lower in the BMSCs group compared with the controls without BMSCs transplantation 14 and 28 d post-PVE. BMSCs significantly decreased the hydroxyproline content and collagen accumulation, up-regulated the expressions of HGF, IL-10, VEGF, and MMP-9 28 d post-PVE, and expressed hepatocyte-specific markers, such as α-fetoprotein, cytokeratin 18, and albumin in a time-dependent manner in FLR. Conclusions Autologous BMSCs can differentiate into hepatocyte and promote FLR regeneration after PVE in cirrhotic liver, which may be through improving local microenvironment by decreasing cirrhosis, up-regulating the gene expressions of VEGF, HGF, IL-10, and MMP-9.
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