Liu H.,Second Military Medical UniversityShanghai |
Shen J.,Second Military Medical UniversityShanghai |
Lu K.,Second Military Medical UniversityShanghai
Biochemical and Biophysical Research Communications | Year: 2017
Limited efficacy of immune checkpoint inhibitors in hepatocellular carcinoma (HCC) was observed in clinical trials, thus prompting investigation into combination therapy. Interleukin-6 (IL-6) has important roles in modeling immune responses in cancers. Here, we hypothesized that IL-6 blockade would enhance antitumor immunity of HCC and synergize with anti-programmed death-1-ligand 1 (PD-L1) checkpoint inhibitor in treating HCC. The sources and immune modulating effects of IL-6 were investigated in HCC models. Combination of anti-IL-6 and anti-PD-L1 was tested in HCC bearing mice. We found that IL-6 is mainly secreted by cancer associated fibroblast (CAFs), but not tumor cells in HCC. High IL-6 expression CAFs could induce strong immunosuppression in HCC microenvironment by recruiting immunosuppressive cells, such as myeloid derived suppressive cells. In addition, high IL-6 expression CAFs also impaired tumor infiltrating T-cell function via upregulating inhibitory immune checkpoints. Using IL-6 blockade could reverse anti-PD-L1 resistance in HCC tumor model. In conclusion, our study indicates that targeted inhibition of IL-6 may enhance the efficacy of anti-PD-L1 in HCC, providing a potential strategy to overcoming anti-PD-L1 resistance in HCC. © 2017
Zhu Y.,Second Military Medical UniversityShanghai |
Zhu Y.,Institute of Medical Mycology |
Pan W.H.,Second Military Medical UniversityShanghai |
Pan W.H.,Institute of Medical Mycology |
And 12 more authors.
International Immunopharmacology | Year: 2015
Abstract The aim of the current study was to investigate the involvement of tryptase and protease-activated receptor-2 (PAR2) in the pathogenesis of itch using a recently developed murine model of atopic dermatitis (AD) elicited by epicutaneous sensitization with ovalbumin (OVA). We also examined whether tacrolimus exerts an antipruritic effect. Epicutaneous sensitization of BALB/c mice with OVA led to a significant increase in the number of scratches. Notably, PAR2 mRNA and protein levels as well as cutaneous levels of tryptase were significantly enhanced in epicutaneously sensitized mice. Pretreatment with the protease inhibitor, leupeptin, PAR2 antibody, and tacrolimus significantly reduced the number of degranulated mast cells and tryptase content, and consequently alleviated scratching behavior. Cetirizine (10 mg/kg) exerted a significant inhibitory effect on the scratching behavior of mice, but did not affect the number of degranulated mast cells and induction of tryptase. Our results collectively suggest that tryptase and PAR2 are involved in OVA allergy-induced scratching behavior. © 2015 Elsevier B.V.
Cao W.,Anticancer, Inc. |
Cao W.,University of California at San Diego |
Cao W.,Second Military Medical UniversityShanghai |
Li L.,Anticancer, Inc. |
And 8 more authors.
Cell Cycle | Year: 2016
We demonstrate in the present study that young host mice rejuvenate aged hair follicles after transplantation. Young mice promote the hair shaft growth of transplanted old hair follicles, as well as young follicles, in contrast to old host mice, which did not support hair-shaft growth from transplanted old or young follicles. Nestin-expressing hair follicle-associated pluripotent (HAP) stem cells of transplanted old and young hair follicles remained active in young host nude mice. In contrast, the nestin-expressing HAP stem cells in young and old hair follicles transplanted to old nude mice were not as active as in young nude host mice. The present study shows that transplanted old hair follicles were rejuvenated by young host mice, suggesting that aging may be reversible. © 2016 Taylor & Francis.
PubMed | Ningxia Medical University, Second Military Medical UniversityShanghai, Shanghai University and Shanghai Municipal Hospital of Traditional Chinese Medicine Shanghai
Type: | Journal: Frontiers in pharmacology | Year: 2016
Propionate is a short chain fatty acid that is abundant as butyrate in the gut and blood. However, propionate has not been studied as extensively as butyrate in the treatment of colitis. The present study was to investigate the effects of sodium propionate on intestinal barrier function, inflammation and oxidative stress in dextran sulfate sodium (DSS)-induced colitis mice. Animals in DSS group received drinking water from 1 to 6 days and DSS [3% (w/v) dissolved in double distilled water] instead of drinking water from 7 to 14 days. Animals in DSS+propionate (DSS+Prop) group were given 1% sodium propionate for 14 consecutive days and supplemented with 3% DSS solution on day 7-14. Intestinal barrier function, proinflammatory factors, oxidative stress, and signal transducer and activator of transcription 3 (STAT3) signaling pathway in the colon were determined. It was found that sodium propionate ameliorated body weight loss, colon-length shortening and colonic damage in colitis mice. Sodium propionate significantly inhibited the increase of FITC-dextran in serum and the decrease of zonula occludens-1 (ZO-1), occludin, and E-cadherin expression in the colonic tissue. It also inhibited the expression of interleukin (IL)-1, IL-6, and tumor necrosis factor- (TNF-) mRNA and phosphorylation of STAT3 in colitis mice markedly, reduced the myeloperoxidase (MPO) level, and increased the superoxide dismutase and catalase level in colon and serum compared with DSS group. Sodium propionate inhibited macrophages with CD68 marker infiltration into the colonic mucosa of colitis mice. These results suggest that oral administration of sodium propionate could ameliorate DSS-induced colitis mainly by improving intestinal barrier function and reducing inflammation and oxidative stress via the STAT3 signaling pathway.
PubMed | Fudan University, Second Military Medical UniversityShanghai and Shanghai University
Type: Journal Article | Journal: American journal of translational research | Year: 2016
Primary glioblastoma always has a fatal outcome despite maximal therapy. Identification and validation of prognostic biomarkers and novel therapeutics will be potentially powerful to transform the care of glioblastoma patients. In this study, we constructed Affymetrix gene microarrays with 14 glioma samples to screen for genes with potential prognostic value by hieratical clustering, and 83 genes including WD-repeat containing protein 1 (WDR1) were filtered out. WDR1 is a major co-factor collaborating with cofilin in actin cytoskeletal dynamics, which may play vital role in glioma proliferation and invasion. Further, The Cancer Genome Atlas (TCGA) database was utilizedto verify the expression of WDR1 and its prognostic implicationin 528 glioblastoma specimens. Survival and correlation analyses showed WDR1 expression was highly expressed and related to the prognosis of glioblastoma and the expression of signal transducer and activator of transcription 3 (STAT3), respectively (p<0.05). Finally, WDR1 expression was detected in our large cohort containing 258 glioma patients (including 100 primary glioblastomas).And univariate and multivariate analyses confirmed that high WDR1 expression was an independent prognostic factor for a shorter progression-free survival (PFS) and overall survival (OS) in primary glioblastoma patients at our center [hazard ratio (HR)=1.844, p=0.005 and HR=2.085, p=0.001, respectively]. Together, WDR1 is significantly over-expressed in primary glioblastoma. High expression of WDR1 can independently predict unfavorable clinical outcome for primary glioblastoma patients. This study identifies a novel prognostic biomarker and a potential therapeutic target for glioblastoma.
PubMed | Shanghai JiaoTong University, Second Military Medical UniversityShanghai and Shanghai University
Type: Journal Article | Journal: American journal of translational research | Year: 2016
Growing evidence indicates that long non-coding RNAs (lncRNAs) play key roles in cancer initiation and progression. However, little is known about the therapeutic significance of lncRNAs in glioma. In this study, we explored the tumorigenic role of a classical lncRNA, FOXD3 antisense RNA 1 (FOXD3-AS1) in glioma. Systemic analysis of the patient specimens and clinical data showed that FOXD3-AS1 was markedly up-regulated in high-grade glioma tissues (WHO grade III-IV) compared with that in low-grade glioma (WHO grade I-II) and normal brain tissues (both P<0.01), and patients with low FOXD3-AS1 expression had grater survival probability. Multivariate regression analysis showed that increased FOXD3-AS1 expression was a significant independent indicator of poor prognosis in glioma patients (P=0.034). To understand the tumorigenic mechanism of FOXD3-AS1, the expression pattern and functional role of FOXD3-AS1 in glioma were detected using real-time PCR and Smart Silencer-mediated knockdown study. In related cell biological assays, we discovered that FOXD3-AS1 knockdown significantly inhibited cell proliferation, induced cell cycle S-phase arrest, and impaired cell migration and invasion in malignant glioma cells. As expected, we also found that the expression of FOXD3-AS1 was positively correlated with FOXD3 mRNA. Knockdown of FOXD3-AS1 reduced the protein level of FOXD3 in cultured U251 and A172 cell lines. These results suggest that FOXD3-AS1 is an oncogenic lncRNA, which may promote the occurrence and development of glioma through transcriptional regulation of FOXD3.
Tang G.,Second Military Medical UniversityShanghai |
Shen X.,Second Military Medical UniversityShanghai |
Lv K.,Second Military Medical UniversityShanghai |
Wu Y.,94Th Hospital Of Chinese Peoples Liberation Army |
And 2 more authors.
Medical Science Monitor | Year: 2015
Background: Circulating microRNA (miRNA) are promising biomarkers for diagnosing and prognosticating numerous diseases. Reports have demonstrated controversial or even contradictory conclusions in studies on circulating microRNA. This study aimed to evaluate the potential bias of using different reference genes for analyzing circulating microRNAs in the same malignant digestive diseases. Material/Methods: We measured plasma concentrations of U6-snRNA, let-7a, miRNA-21, miRNA-106a, miRNA-155, miRNA-219, miRNA-221, and miRNA-16 in patients with hepatocellular carcinoma (HCC), gastric carcinoma (GC), hepatic cirrhosis, hepatitis B, and healthy volunteers using quantitative real-time polymerase chain reaction (qPCR). The GeNorm, Normfinder, BestKeeper, and Comparative DCq algorithms integrated in RefFinder were used to screen the most suitable reference genes from the candidates. The 4 commonly used statistical evaluation software packages provided different results regarding the stability of the candidate reference genes. Results: RefFinder revealed miRNA-106a and miRNA-21 as the most stably expressed reference genes, with comprehensive stability values of 1.189 and 1.861, respectively. U6-snRNA was the most unstable nucleic acid in our data. When 5 normalization strategies were compared using U6-snRNA, serum volume, miRNA-106a, miRNA-21, or the mean value of miRNA-106a and miRNA-21, obvious expression bias was detected in almost all target microRNAs. Intriguingly, all these normalization strategies indicated that circulating miRNA-155 is greatly upregulated in patients with HCC and GC, but downregulated in benign hepatic disease. Conclusions: Single reference genes used without justification in plasma microRNAs produce significant analysis bias or even erroneous results. Circulating miRNA-155 may be a promising non-invasive biomarker for discriminating malignant digestive tumors from the corresponding benign diseases. © Med Sci Monit, 2015.
He D.-W.,Second Military Medical UniversityShanghai |
Yang F.,Second Military Medical UniversityShanghai |
Zhu X.-D.,Second Military Medical UniversityShanghai |
Li J.-F.,Second Military Medical UniversityShanghai
Academic Journal of Second Military Medical University | Year: 2014
To evaluate the value of Dynesys dynamic fixation for treatment of lumbar degenerative disease by comparing with lumbar spinal fusion. Methods The clinical data of 60 patients with lumbar degenerative disease, who were treated inChanghai Hospital from June 2009 to June 2010, were retrospectively analyzed. Twenty-six patients, including 15 males and 11 females, with age ranging 32-56 years (average [42.45 ± 10.12] years), received Dynesys implantation for segments L4-L5 (13 cases) and L5-S1 (13 cases). Thirty-four patients, including 20 males and 14 females, with age ranging 3860 years(average [45.24 ± 12.15] years), received fusion implantation for segments L4-L5 (18 cases) and L5S (16 cases). The following parameters were observed and compared between the two groups: operation time, blood loss, hospital stay, preoperative Oswestry disability index (ODI), ODI at last follow-up, low back and leg pain visual analogue scale (VAS), results of health status questionnaire (SF-36), segmental angulation degree of lumbar spine, and intervertebral height. Results All the 60 patients were followed up for 3-4 years (average [3.2 ± 0.2] years). The operation time and intra-operative blood loss were significantly different between the two groups (P < 0.05), and no difference was found for average hospital days. The ODI, VAS, and SF-36 clinical scores at last follow-up were significantly improved compared with those before operation in the two groups (P < 0.01), with the improvement in Dynesys group being more significant than the fusion group (P < 0.01). The segmental angulation degree of lumbar spine had no noticeable improvement in the two groups at last follow- up, and there were no significant differences between the two groups. There was no intervertebral height loss at the last follow-up in the two groups, and there was no significant difference in intervertebral heights between the two groups. Conclusion Dynesys dynamic lumbar fixation shows no more advantages in terms of radiological results compared with the fusion group. Moreover, fusion fixation is not suggested to have more adjacent segment degeneration (ASD) than Dynesys dynamic lumbar fixation. But clinically Dynesys dynamic lumbar fixation yields a greater improvement, with the advantages of less bleeding and shorter operation time. In middle-aged and elderly patients with degenerative diseases, Dynesys dynamic lumbar fixation is an acceptable choice.
Shen X.-J.,Second Military Medical UniversityShanghai |
Zhang H.,No 411 Hospital Of Navyshanghai |
Tang G.-S.,Second Military Medical UniversityShanghai |
Wang X.-D.,Second Military Medical UniversityShanghai |
And 5 more authors.
International Journal of Biological Sciences | Year: 2015
Stromal fibroblasts play an important role in chronic cancer-related inflammation and the development as well as progression of malignant diseases. However, the difference and relationship between inflammation-associated fibroblasts (IAFs) and cancer-associated fibroblasts (CAFs) are poorly understood. In this study, gastric cancer-associated fibroblasts (GCAFs) and their corresponding inflammation-associated fibroblasts (GIAFs) were isolated from gastric cancer (GC) with chronic gastritis and cultured in vitro. These activated fibroblasts exhibited distinct secretion and tumor-promoting behaviors in vitro. Using proteomics and bioinformatics techniques, caveolin-1 (Cav-1) was identified as a major network-centric protein of a sub-network consisting of 121 differentially expressed proteins between GIAFs and GCAFs. Furthermore, immunohistochemistry in a GC cohort showed significant difference in Cav-1 expression score between GIAFs and GCAFs and among patients with different grades of chronic gastritis. Moreover, silencing of Cav-1 in GIAFs and GCAFs using small interfering RNA increased the production of pro-inflammatory and tumor-enhancing cytokines and chemokines in conditioned mediums that elevated cell proliferation and migration when added to GC cell lines AGS and MKN45 in vitro. In addition, Cav-1 status in GIAFs and GCAFs independently predicted the prognosis of GC. Our findings indicate that Cav-1 loss contributes to the distinct activation statuses of fibroblasts in GC microenvironment and gastritis mucosa, and Cav-1 expression in both GCAFs and GIAFs may serve as a potential biomarker for GC progression. © 2015 Ivyspring International Publisher.
Zhang J.-Q.,Second Military Medical UniversityShanghai |
Sheng J.-G.,Second Military Medical UniversityShanghai |
Diao Z.-P.,Second Military Medical UniversityShanghai |
Zhao L.-L.,Second Military Medical UniversityShanghai |
Zhang H.,Second Military Medical UniversityShanghai
Academic Journal of Second Military Medical University | Year: 2014
Objective To introduce the hydro-dissection technique and its application in ultrasound-guided percutaneous thermal ablation therapy of neck nodular lesions. Methods A total of 1 126 patients suffering from neck nodular diseases received percutaneous thermal therapy using radiofrequency ablation or microwave ablation from May 2005 to April 2013. As a part of the treatment procedure, ultrasound-guided injection of separating liquid was performed into between the target nodules and surrounding structures to form a separating zone prior to ablation. The roles of hydro-dissection technique in improving the safety of puncture route, reducing the thermal injury to normal tissues, and enhancing the curative effects of ablation were analyzed. Results Hydro-dissection technique was successfully performed in as many as fourteen parts related to the thyroids, parathyroids, submandibular glands and lymph nodes. The key points and ultrasonic characteristics of this maneuver were well established and understood. Compared with those not receiving the technique, those receiving the technique had significantly reduced heat damage to lesion-adjacent structures (0.7% vs 15%, P < 0.01) and decreased incomplete ablation rate of the lirst try (0.29% vs 7.4%, P < 0.01). Conclusion Hydro-dissection technique under ultrasound-guidance is easy to perform, has good repeatability and reliable effect; it may serve as a safe and effective supplementary measure for thermal ablation of various neck nodular lesions.