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Xu J.,Renji Hospital | Li Z.,Vrije Universiteit Brussel | Wang J.,Renji Hospital | Chen H.,Renji Hospital | And 3 more authors.
Translational Oncology | Year: 2014

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor commonly inactivated in glioblastoma multiforme (GBM), but the prognostic significance of PTEN remains controversial. Here, we demon- strate significant prognostic value of combined PTEN mutation and expression for the survival of patients with GBM on the basis of analysis of large-scale cancer genomic data. PTEN nonsense mutations associated with significantly shorter disease-free survival and overexpression of PTEN protein linked to shorter disease-free and overall survival of patients with GBM. PTEN nonsense mutations correlated with decreased p53 and Gata3 protein levels and increased genomic instability in human GBM tissues. Expression of nonsense PTEN mutant decreased p53 and Gata3 levels, producing increased DNA damage both in vitro and in vivo. Mice carrying xenograft tumors with nonsense PTEN mutant displayed significantly shorter survival. Our data demonstrated the prognostic value of combined PTEN mutation and protein expression for patients with GBM and highlighted distinct biologic effects of nonsense and missense mutations of PTEN. © 2014 Neoplasia Press. All rights reserved.


Weng Y.-R.,Renji Hospital | Weng Y.-R.,Shanghai JiaoTong University | Cui Y.,Renji Hospital | Cui Y.,Shanghai JiaoTong University | And 3 more authors.
Molecular Cancer Research | Year: 2012

The structural proteins cytokeratin 18 (CK18) and its coexpressed complementary partner CK8 are expressed in a variety of adult epithelial organs and may play a role in carcinogenesis. In this study, we focused on the biological functions of CK18, which is thought to modulate intracellular signaling and operates in conjunction with various related proteins. CK18 may affect carcinogenesis through several signaling pathways, including the phosphoinositide 3-kinase (PI3K)/Akt, Wnt, and extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) signaling pathways. CK18 acts as an identical target of Akt in the PI3K/Akt pathway and of ERK1/2 in the ERK MAPK pathway, and regulation of CK18 by Wnt is involved in Akt activation. Finally, we discuss the importance of gaining a more complete understanding of the expression of CK18 during carcinogenesis, and suggest potential clinical applications of that understanding. ©2012 AACR.


Yang W.-S.,Shanghai JiaoTong University | Yang W.-S.,Renji Hospital | Va P.,New England College | Wong M.-Y.,Hong Kong University of Science and Technology | And 4 more authors.
American Journal of Clinical Nutrition | Year: 2011

Background: Although several in vitro and animal in vivo studies have suggested that soy or soy isoflavones may exert inhibitory effects on lung carcinogenesis, epidemiologic studies have reported inconclusive results on the association between soy intake and lung cancer. Objective: The aim of this meta-analysis was to investigate whether an association exists between soy and lung cancer in epidemiologic studies. Design: We searched PubMed, EMBASE, and the Cochrane Library from their inception to February 2011 for both case-control and cohort studies that assessed soy consumption and lung cancer risk. Study-specific risk estimates were combined by using fixedeffect or random-effect models. Results: A total of 11 epidemiologic studies that consisted of 8 case-control and 3 prospective cohort studies were included. A significantly inverse association was shown between soy intake and lung cancer with an overall RR of 0.77 (95% CI: 0.65, 0.92). Findings were slightly different when analyses were restricted to 5 high-quality studies (RR: 0.70; 95% CI: 0.45, 0.99). In a subgroup meta-analysis, a statistically significant protective effect of soy consumption was observed in women (RR: 0.79; 95% CI: 0.67, 0.93), never smokers (RR: 0.62; 95% CI: 0.51, 0.76), and Asian populations (RR: 0.86; 95% CI: 0.74, 0.98). Conclusions: Our findings indicate that the consumption of soy food is associated with lower lung cancer risk. Because of different methods used to assess soy consumption across studies, more well-designed cohort studies or intervention studies that use unified measures of soy intake are needed to fully characterize such an association. © 2011 American Society for Nutrition.


Sun X.,Shanghai JiaoTong University | Mao Y.,Shanghai JiaoTong University | Wang J.,Shanghai JiaoTong University | Zu L.,Shanghai JiaoTong University | And 8 more authors.
Oncogene | Year: 2014

Cancer-associated fibroblasts (CAFs) have been implicated in the development of resistance to anticancer drugs; however, the role and mechanism underlying CAFs in luminal breast cancer (BrCA) tamoxifen resistance are unclear. We found that stromal fibroblasts isolated from the central or peripheral area of BrCA have similar CAF phenotype and activity. In vitro and in vivo experiments showed that CAFs derived from clinical-luminal BrCAs induce tamoxifen resistance through decreasing estrogen receptor-α (ER-α) level when cultured with luminal BrCA cell lines MCF7 and T47D. CAFs promoted tamoxifen resistance through interleukin-6 (IL-6) secretion, which activates Janus kinase/signal transducers and activators of transcription (JAK/STAT3) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways in tumor cells, followed by induction of epithelial-mesenchymal transition and upregulation of E3 ubiquitin ligase anaphase-promoting complex 10 activity, which targeted ER-α degradation through the ubiquitin-proteasome pathway. Inhibition of proteasome activity, IL-6 activity or either the JAK/STAT3 or PI3K/AKT pathways markedly reduced CAF-induced tamoxifen resistance. In xenograft experiments of CAFs mixed with MCF7 cells, CAF-specific IL-6 knockdown inhibited tumorigenesis and restored tamoxifen sensitivity. These findings indicate that CAFs mediate tamoxifen resistance through IL-6-induced degradation of ER-α in luminal BrCAs.Oncogene advance online publication, 9 June 2014; doi:10.1038/onc.2014.158.


Xue H.,Shanghai JiaoTong University | Wang Y.-C.,Shanghai JiaoTong University | Lin B.,Fudan University | An J.,Shanghai JiaoTong University | And 3 more authors.
PLoS ONE | Year: 2012

We aimed to explore the role of IL-10 -592 A/C SNP in the susceptibility to gastric cancer through a systematic review and meta-analysis. Each initially included article was scored for quality appraisal. 17 studies were eligible for the meta-analysis. We adopted the most probably appropriate genetic model (recessive model). Potential sources of heterogeneity were sought out via subgroup and sensitivity analyses, and publication biases were estimated. IL-10-592 AA genotype is associated with the reduced risk of developing gastric cancer among Asians and even apparently observed among Asians high quality subgroup, suggesting IL-10-592 AA genotype may seem to be more protective from overall gastric cancer in Asian populations. IL-10-592 AA genotype is also associated with the overall reduced gastric cancer susceptibility in persons with H. pylori infection compared with controls without H. pylori infection, suggesting IL-10-592 AA genotype may seem to be more protective from overall gastric cancer susceptibility in persons infected with H. pylori. IL-10-592 AA genotype is not associated with either pathologic subtypes (intestinal or diffuse) or anatomic subtypes (non-cardia or cardia) of gastric cancer susceptibility. Genotyping methods like direct sequencing should be highly advocated to be conducted in future well-designed high quality studies among different ethnicities or populations. © 2012 Xue et al.


Findlay J.Y.,Mayo Medical School | Wen D.,Renji Hospital | Mandell M.S.,University of Colorado at Denver
Current Opinion in Organ Transplantation | Year: 2010

PURPOSE OF REVIEW: Cardiovascular disease has emerged as a leading cause of perioperative morbidity and mortality in renal and liver transplant patients. There is no consensus on how to diagnose cardiac disease in transplant patients. Further, there is significant disagreement in the literature regarding the use of routine screening methods to detect disease. This review will explore published observations on cardiac complications in renal and liver transplant patients to try and determine why investigators hold such divergent opinions. RECENT FINDINGS: The prevalence of cardiac disease is greater in renal and liver transplant patients than in the general public. Complications of cardiac disease play a large role in early mortality and graft loss in the postoperative period. While the presence of risk factors seems to predict coronary disease in renal disease, these factors do not perform as well in liver disease. Noninvasive stress testing for coronary artery disease seems to have low sensitivity in both transplant populations. However, the measurement of cardiac troponin seems to be of some value in predicting early mortality. SUMMARY: Physicians have not identified an effective yet cost-effective way to screen transplant patients for cardiac disease. Therefore, the first step in creating widely accepted protocols demand that physicians decide what predictive power that screening tests should have in this unique population © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins..


Guan H.-B.,Shenyang University | Wu L.,Center for Clinical and Translational Science | Wu Q.-J.,Renji Hospital | Zhu J.,University of Minnesota | Gong T.,Shenyang University
PLoS ONE | Year: 2014

Background: Previous epidemiologic studies have reported inconsistent results between parity and pancreatic cancer (PC) risk. To our knowledge, a comprehensive and quantitative assessment of this association has not been conducted. Methods: Relevant published studies of parity and PC were identified using MEDLINE (PubMed) and Web of Science databases until November 2013. Two authors (H-BG and LW) independently assessed eligibility and extracted data. Eleven prospective and 11 case-control studies reported relative risk (RR) estimates and 95% confidence intervals (CIs) of PC associated with parity. Fixed- and random-effects models were used to estimate the summary RR depending on the heterogeneity of effects. Results: The summary RR for PC comparing the highest versus lowest parity was 0.86 (95% CI: 0.73-1.02; Q = 50.49, P<0.001, I2 = 58.4%). Significant inverse associations were also observed in the studies that adjusted for cigarette smoking (RR = 0.81; 95% CI: 0.68-0.98), Type 2 diabetes mellitus (RR = 0.83; 95% CI: 0.75-0.93), and those that included all confounders or important risk factors (RR = 0.85; 95% CI: 0.76-0.96). Additionally, in the dose-response analysis, the summary RR for per one live birth was 0.97 (95% CI: 0.94-1.01; Q = 62.83, P<0.001, I2 = 69.8%), which also indicated a borderline statistically significant inverse effect of parity on PC risk. No evidence of publication bias and significant heterogeneity between subgroups were detected by meta-regression analyses. Conclusion: In summary, these findings suggest that higher parity is associated with a decreased risk of PC. Future large consortia or pooled studies are warranted to fully adjust for potential confounders to confirm this association. © 2014 Guan et al.


Jiang X.-G.,Renji Hospital | Lin Y.,Renji Hospital | Li Y.-S.,Renji Hospital
European Review for Medical and Pharmacological Sciences | Year: 2014

BACKGROUND: The causes of post-stroke depression (PSD) were complex, and it is hard to identify the consistent risk factors because the correlation may change along with time. AIM: To study the prevalence and multiple correlation factors of PSD in acute stroke patients. PATIENTS AND METHODS: The patients within over 2-6 weeks after stroke were collected and divided into depression group, depressive symptom group, and control group according to the Hamilton Depression Rating Scale for Depression. The NIH (National Institute of Health) Stroke Scale, the Barthel index (BI), the Instrumental Activities of Daily Living (IADL), and the Mini-Mental State Examination (MMSE) were respectively used to evaluate the neurologic impairment, Ability of Daily Life, and cognitive function of patients. RESULTS: PSD was associated with lower incomes (p < 0.05), but not associated with education level, medical insurance, and nature of the acute stroke (p > 0.05). The lesion location in the left hemisphere of the brain had a higher morbidity than that in the right hemisphere or both sides. There was a significant difference in the incidence of PSD between multifocal lesions and single lesion (p < 0.01). CONCLUSIONS: Lower income, cognitive dysfunctions, poor activities of daily life, poor social support, and history of hypertension and previous stroke were risk factors for the acute stroke patients to get depression. Stroke survivors with left hemisphere of the brain and more lesions (> 2) have more chance to get the PSD.


Chen X.-X.,Friedrich - Alexander - University, Erlangen - Nuremberg | Chen X.-X.,Renji Hospital | Baum W.,Friedrich - Alexander - University, Erlangen - Nuremberg | Dwyer D.,Amgen Inc. | And 6 more authors.
Annals of the Rheumatic Diseases | Year: 2013

Objective To test whether inhibition of sclerostin by a targeted monoclonal antibody (Scl-Ab) protects from bone and cartilage damage in inflammatory arthritis. Sclerostin is a potent inhibitor of bone formation and may be responsible for the low level of bone repair in patients with rheumatoid arthritis. Methods Human tumour necrosis factor transgenic mice (hTNFtg mice) developing inflammatory arthritis and local and bone loss were administered either vehicle, anti-TNF antibody, Scl-Ab, or a combination of both agents. Inflammation, systemic and periarticular bone loss, bone erosion and cartilage damage were evaluated at baseline (week 8) and after 3 weeks of treatment by clinical assessment, micro-CT and histology. Results Scl-Ab did not affect joint swelling or synovitis. Systemic bone loss in the spine and periarticular bone loss in the proximal tibia were completely blocked and partially reversed by inhibition of sclerostin but not by inhibition of TNF. Moreover, Scl-Ab completely arrested the progression of bone erosion in hTNFtg mice and in combination with TNF inhibition even led to significant regression of cortical bone erosions. Protective effects of Scl-Ab were also observed for the articular cartilage. Conclusions These data suggest that sclerostin inhibition is a powerful tool to enhance bone repair in inflammatory arthritis.


Wu B.,Renji Hospital | Chen H.,Renji Hospital | Shen J.,Renji Hospital | Ye M.,Renji Hospital
Clinical Therapeutics | Year: 2011

Background: Adding rh-endostatin to standard platinum-based chemotherapy may significantly improve progression-free and overall survival in patients with advanced non-small cell lung cancer (NSCLC), but the cost-effectiveness of this practice is unclear. Objective: The purpose of this cost-effectiveness analysis was to estimate the effects of adding rh-endostatin to standard chemotherapy in patients with advanced NSCLC on health and economic outcomes in China. Methods: A semi-Markov model was constructed to track 3-week patient transitions between 3 health states: progression-free survival, progressed survival, and death. Probabilities were derived mainly from the results of a pivotal Phase III trial assessing the addition of rh-endostatin to standard first-line chemotherapy with vinorelbine-cisplatin in patients with advanced NSCLC. Costs were estimated from the perspective of the Chinese health care system, and the analysis was run over a 10-year time horizon. The primary outcome was the incremental cost-effectiveness ratio (ICER) of adding rh-endostatin at a willingness-to-pay (WTP) threshold of 3 × the per-capita gross domestic product (GDP) per quality-adjusted life-year (QALY) gained. One-way and probabilistic sensitivity analyses were performed. Results: According to the model, treatment with rh-endostatin plus standard chemotherapy would increase overall survival by 0.63 years and 0.35 QALYs per patient compared with standard chemotherapy, at an additional cost of $8402.60. The ICER for adding rh-endostatin to chemotherapy was $24,454.25/QALY gained (at a 3% discounted rate). On 1-way sensitivity analysis, the utility value of progression-free survival was the most influential factor on the results, followed by the cost of rh-endostatin. On probabilistic sensitivity analysis, the probabilities of cost-effectiveness varied by region due to discrepant per-capita GDPs in China. Modeling to extrapolate clinical survival beyond trial completion was the main limitation. Conclusion: The findings from the present analysis suggest that the addition of rh-endostatin to standard first-line chemotherapy is unlikely to be cost-effective. However, at a high WTP, rh-endostatin might be a cost-effective treatment option. © 2011 Elsevier HS Journals, Inc..

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