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Lin D.-C.,Cedars Sinai Medical Center | Lin D.-C.,National University of Singapore | Hao J.-J.,Peking Union Medical College | Nagata Y.,University of Tokyo | And 24 more authors.
Nature Genetics | Year: 2014

Esophageal squamous cell carcinoma (ESCC) is prevalent worldwide and particularly common in certain regions of Asia. Here we report the whole-exome or targeted deep sequencing of 139 paired ESCC cases, and analysis of somatic copy number variations (SCNV) of over 180 ESCCs. We identified previously uncharacterized mutated genes such as FAT1, FAT2, ZNF750 and KMT2D, in addition to those already known (TP53, PIK3CA and NOTCH1). Further SCNV evaluation, immunohistochemistry and biological analysis suggested their functional relevance in ESCC. Notably, RTK-MAPK-PI3K pathways, cell cycle and epigenetic regulation are frequently dysregulated by multiple molecular mechanisms in this cancer. Our approaches also uncovered many druggable candidates, and XPO1 was further explored as a therapeutic target because it showed both gene mutation and protein overexpression. Our integrated study unmasks a number of novel genetic lesions in ESCC and provides an important molecular foundation for understanding esophageal tumors and developing therapeutic targets. © 2014 Nature America, Inc. All rights reserved.


Fan X.,Sun Yat Sen University | Lin T.,Sun Yat Sen University | Xu K.,Sun Yat Sen University | Yin Z.,Sun Yat sen Memorial Hospital | And 3 more authors.
European Urology | Year: 2012

Context: Laparoendoscopic single-site (LESS) surgery has increasingly been used to perform radical, partial, simple, or donor nephrectomy to reduce the morbidity and scarring associated with surgical intervention. Studies comparing LESS nephrectomy (LESS-N) and conventional laparoscopic nephrectomy (CL-N) have reported conflicting results. Objective: To assess the current evidence regarding the efficiency, safety, and potential advantages of LESS-N compared with CL-N. Evidence acquisition: We comprehensively searched PubMed, Embase, and the Cochrane Library and performed a systematic review and cumulative meta-analysis of all randomized controlled trials (RCTs) and retrospective comparative studies assessing the two techniques. Evidence synthesis: Two RCTs and 25 retrospective studies including a total of 1094 cases were identified. Although LESS-N was associated with a longer operative time (weighted mean difference [WMD]: 9.87 min; 95% confidence interval [CI], 3.37-16.38; p = 0.003) and a higher conversion rate (6% compared with 0.3%; odds ratio: 4.83; 95% CI, 1.87-12.45; p = 0.001), patients in this group might benefit from less postoperative pain (WMD: -0.48; 95% CI, -0.95 to -0.02; p = 0.04), lower analgesic requirement (WMD: -4.78 mg; 95% CI, -8.59 to -0.97; p = 0.01), shorter hospital stay (WMD: -0.32 d; 95% CI, -0.55 to -0.09; p = 0.007), shorter recovery time (WMD: -5.08 d; 95% CI, -8.49 to -1.68; p = 0.003), and better cosmetic outcome (WMD: 1.07; 95% CI, 0.67-1.48; p < 0.00001). Perioperative complications, estimated blood loss, warm ischemia time, and postoperative serum creatinine levels of graft recipients did not differ significantly between techniques. Conclusions: LESS-N offers a safe and efficient alternative to CL-N with less pain, shorter recovery time, and better cosmetic outcome. Given the inherent limitations of the included studies, future well-designed RCTs are awaited to confirm and update the findings of this analysis. © 2012 European Association of Urology.


Hu J.,Sun Yat Sen University | Wang P.,Sun Yat Sen University | Wang P.,Sun Yat Sen Memorial Hospital | Zhang W.,Sun Yat Sen University
Arthropod Structure and Development | Year: 2015

In this study, we report that two types of embryos, normal and pseudogerm, are generated from a single egg of the polyembryonic larval endoparasitoid Macrocentrus cingulum (Braconidae). M. cingulum larvae develop in the host hemocoel, emerging from the host to pupate. After egg cleavage and embryo proliferation dozens of normal embryos and thousands of pseudogerms are generated in the host larva. The difference between normal embryos and pseudogerms is that the former develop into larvae while the latter do not. The primordium that develops in normal embryos is surrounded by an extraembryonic membrane that originates from the syncytium. Pseudogerms in contrast consist only of a syncytium containing many large nuclei and are continuously generated during embryonic development. Both pseudogerms and early embryos possess dense microvilli that function to absorb nutrients from the host. After eclosion wasp larvae produced from normal embryos feed on pseudogerms. Therefore, two types of embryos originating from the same egg serve different functions. These results contribute to our understanding of the development of polyembryonic parasitoids. © 2015 Elsevier Ltd.


Xiang Q.,Sun Yat Sen University | Chen W.,Southern Medical University | Ren M.,Sun Yat sen Memorial Hospital | Wang J.,Sun Yat Sen University | And 5 more authors.
Clinical Cancer Research | Year: 2014

Purpose: MET signaling has been suggested a potential role in hepatocellular carcinoma (HCC) and associated with prometastasis during antiangiogenesis therapy. We investigated the potential association between MET expression and therapeutic response to sorafenib in patients with HCC. Antitumor effects of cabozantinib, a dual inhibitor of MET and VEGFR2, were examined in cultured HCC cells as well as in vivo models. Experimental Design: Total MET and phosphorylated MET (p-MET) were measured in 29 resected HCC specimens, and correlated with response to sorafenib as postoperative adjuvant therapy. In the second set of experiments using cultured HCC cells, and mouse xenograft and metastatic models, effects of cabozantinib were examined. Results: High level of p-MET in resected HCC specimens was associated with resistance to adjuvant sorafenib therapy. In cultured HCC cells that expressed p-MET, cabozantinib inhibited the activity of MET and its downstream effectors, leading to G1-phase arrest. Cabozantinib inhibited tumor growth in p-MET-positive and p-MET-negative HCC by decreasing angiogenesis, inhibiting proliferation, and promoting apoptosis, but it exhibited more profound efficacy in p-MET-positive HCC xenografts. Cabozantinib blocked the hepatocyte growth factor (HGF)-stimulated MET pathway and inhibited the migration and invasion of the HCC cells. Notably, cabozantinib reduced the number of metastatic lesions in the lung and liver in the experimental metastatic mouse model. Conclusions: Patients with HCC with high level of p-MET are associated with resistance to adjuvant sorafenib treatment. The dual blockade of VEGFR2 and MET by cabozantinib has significant antitumor activities in HCC, and the activation of MET in HCC may be a promising efficacy-predicting biomarker. ©2014 AACR.


Hong G.-B.,Fifth Affiliated Hospital | Hong G.-B.,Sun Yat sen Memorial Hospital | Zhou J.-X.,Sun Yat sen Memorial Hospital | Yuan R.-X.,Sun Yat Sen University
International Journal of Nanomedicine | Year: 2012

Targeted delivery of contrast agents is a highly desirable strategy for enhancing diagnostic efficiency and reducing side effects and toxicity. Water-soluble and tumor-targeting superparamagnetic iron oxide nanoparticles (SPIONs) were synthesized by loading hydrophobic SPIONs into micelles assembled from an amphiphilic block copolymer poly(ethylene glycol)-poly(ε-caprolactone) (PEG-PCL) bearing folate in the distal ends of PEG chains. Compared to the water-soluble SPIONs obtained by small molecular surfactant coating, ultrasmall SPION encapsulation with PEG-PCL micelles (PEG-PCL-SPIONs) simultaneously increases transverse (r2) and decreases longitudinal (r1) magnetic resonance (MR) relaxivities of water proton in micelle solution, leading to a notably high r2/r1 ratio up to 78, which makes the PEG-PCL-SPIONs a highly sensitive MR imaging (MRI) T2 contrast agent. The mean size of folate-attached SPION micelles (Fa-PEG-PCL-SPIONs) is 44 ± 3 nm on average, ideal for in vivo MRI applications in which long circulation is greatly determined by small particle size and is highly desirable. Prussian blue staining of BEL-7402 cells over-expressing folate receptors, after incubation with micelle-containing medium, demonstrated that folate functionalization of the magnetic particles significantly enhanced their cell uptake. The potential of Fa-PEG-PCL-SPIONs as a potent MRI probe for in vivo tumor detection was assessed. At 3 hours after intravenous injection of the Fa-PEG-PCL-SPION solution into mice bearing subcutaneous xenografts of human BEL-7402 hepatoma, a 41.2% signal intensity decrease was detected in the T2-weighted MR images of the tumor, indicating the efficient accumulation of Fa-PEG-PCL-SPIONs in the tumor tissue. © 2012 Hong et al, publisher and licensee Dove Medical Press Ltd.


Zhu Y.,Sun Yat Sen University | Yu F.,Sun Yat Sen University | Jiao Y.,Sun Yat Sen University | Feng J.,Sun Yat Sen University | And 7 more authors.
Clinical Cancer Research | Year: 2011

Purpose: Tumor-initiating cells are resistant to chemotherapy, but how microRNAs play a role in regulating drug resistance of breast tumor-initiating cells (BT-IC) needs to be clarified. Experimental Design: Lentivirus-mediated miR-128 transduction was done in BT-ICs, enriched by mammosphere cultures or CD44 +CD24 - fluorescence-activated cell sorting. Apoptosis and DNA damage were determined upon treatment with doxorubicin. Expression of miR-128 in breast cancer tissues was examined by in situ hybridization and correlated with breast tumor response to neoadjuvant chemotherapy and patient survival. Results: MiR-128 was significantly reduced in chemoresistant BT-ICs enriched from breast cancer cell lines and primary breast tumors (P < 0.01), accompanied by an overexpression of Bmi-1 and ABCC5, which were identified as targets of miR-128. Ectopic expression of miR-128 reduced the protein levels of Bmi-1 and ABCC5 in BT-ICs, along with decreased cell viability (P < 0.001) and increased apoptosis (P < 0.001) and DNA damage (P < 0.001) in the presence of doxorubicin. Reduced miR-128 expression in breast tumor tissues was associated with chemotherapeutic resistance (P < 0.001) and poor survival of breast cancer patients (P < 0.05; n = 57). Conclusions: Reduction in miR-128 leading to Bmi-1 and ABCC5 overexpression is a stem cell-like feature of BT-ICs, which contributes to chemotherapeutic resistance in breast cancers. Ectopic expression of miR-128 sensitizes BT-ICs to the proapoptotic and DNA-damaging effects of doxorubicin, indicating therapeutic potential. ©2011 AACR.


He W.,Sun Yat sen Memorial Hospital | Cai Q.,Sun Yat Sen University | Sun F.,Tongji University | Sun F.,Shanghai Tenth Peoples Hospital | And 8 more authors.
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2013

Objectives: The human genome encodes many long intergenic noncoding RNAs (lincRNAs). However, their biological functions, molecular mechanisms and prognostic values associated with bladder cancer remain to be elucidated. Here we investigated a lincRNA termed linc-UBC1 (Up-regulated in bladder cancer 1) and evaluated its prognostic value in bladder cancer patients. Materials and methods: Expression of linc-UBC1 was evaluated by quantitative reverse transcription PCR (qRT-PCR) in 102 bladder cancer tissue samples and normal adjacent tissues. The functions of linc-UBC1 on cell proliferation, migration, invasion, colony formation, tumorigenicity and metastatic potential were evaluated by knockdown strategy in vitro and in vivo. RNA immunoprecipitation (RIP) was performed to confirm that linc-UBC1 physically associates with EZH2 and SUZ12, core components of polycomb repressive complex 2 (PRC2). Chromatin immunoprecipitation (ChIP) was conducted to examine histone modification status. Results: qRT-PCR confirmed that linc-UBC1 expression is up-regulated in 60 cases (58.8%) in bladder cancer tissues compared with normal adjacent tissues, and its overexpression correlates with lymph node metastasis and poor survival. Further functional analysis demonstrated that knockdown of linc-UBC1 attenuates bladder cancer cell proliferation, motility, invasion, colony formation ability, tumorigenicity and metastatic potential. Importantly, the inhibitory effect of linc-UBC1 on cell proliferation was also observed in primary bladder cancer cells obtained from patients. RIP and ChIP assay confirmed that linc-UBC1 physically associates with PRC2 complex and regulates histone modification status of target genes. Conclusions: Frequently overexpressed linc-UBC1 physically associates with PRC2 complex, and acts as a negative prognostic factor for lymph node metastasis and survival in bladder cancer. © 2013 Elsevier B.V.


Wang H.,Sun Yat sen Memorial Hospital
Nan fang yi ke da xue xue bao = Journal of Southern Medical University | Year: 2013

To investigate the expression of enhancer of zeste homolog 2 (EZH2) in esophageal squamous cell carcinoma and its association with the prognosis of postoperative patients. Surgical specimens were obtained from 102 patients with esophageal squamous cell carcinoma undergoing radical resection in our hospital from 1996 to 2006. Immunochemistry was employed to examine EZH2 protein expressions in the specimens, including 102 carcinoma tissue specimens, 30 adjacent tissue specimens and 30 normal esophageal tissue specimens. The expression levels of EZH2 were analyzed in relation to the clinicopathological parameters of the patients including gender, age, tumor differentiation, TNM, and lymph node metastasis. The postoperative patients were followed up to analyze the association of EZH2 expression with the clinical outcomes. The esophageal squamous cell carcinoma tissue showed a higher EZH2 expression than the adjacent and normal esophageal tissues. EZH2 expression was higher in poorly differentiated carcinoma than in well differentiated tissue, and also higher in cases with lymph node metastasis than those without; the expression was higher in TNM stage II/III patients than in stage I patients but lower than in stage IV patients. The patients with low EZH2 expression was found to have a longer survival time than those with high EZH2 expression (P<0.05). EZH2 plays an important role in the differentiation and metastasis of esophageal squamous cell carcinoma, and a high EZH2 expression is associated with a poor outcome in the the postoperative patients.


BACKGROUND: Subtrochanteric femoral shortening osteotomy is a crucial procedure to prevent nerve injury in total hip arthroplasty for severe developmental dysplasia of the hip. Transverse osteotomy was first applied, and other modified methods have also been reported. Each has its own advantages and limitations, but no definitive conclusions regarding differences in outcomes have been reached to date.METHODS: We therefore performed a comprehensive meta-analysis to compare the outcomes of different approaches. 37 studies (795 hips) were included in the final analysis. Meta-analysis, subgroup analysis and meta-regression were performed.RESULTS: Meta-analysis and subgroup analysis showed no significant difference between transverse and modified method. This is further confirmed by meta-regression. Method of osteotomy was found to be not associated with nonunion rate (P = 0.472), as well as other post-operative outcomes including nerve palsy (P = 0.240), dislocation (P = 0.735), revision (P = 0.653) and Harris hip score improvement (P = 0.562). In addition, western countries (P = 0.010) and duration of follow-up more than 5 years (P = 0.014) were associated with higher revision rate.CONCLUSIONS: Transverse osteotomy and modified osteotomy appear to be equivalent in terms of nonunion, safety and efficacy. Transverse osteotomy may be recommended, due to its simplicity and convenience in adjusting the anteversion angle. Well-designed and large-sample-size randomized controlled trials are expected to confirm and update the findings of this analysis.


Chen B.,SUN Yat sen Memorial Hospital
Zhonghua er bi yan hou tou jing wai ke za zhi = Chinese journal of otorhinolaryngology head and neck surgery | Year: 2011

To evaluate the value of narrow band imaging (NBI) endoscopy in the diagnosis of nasopharyngeal lesions. Between December 2009 and April 2010, a total of 124 patients with nasopharyngeal lesions were examined with electronic nasopharyngolaryngoscope equipped with the white light mode and NBI mode. The biopsies of nasopharyngeal lesions were done in all patients. The characteristics of morphologies of mucosa and mucosal superficial vessels of each lesion under NBI mode were evaluated. Of all cases, there were 1 of papilloma, 87 of lymphoid follicular hyperplasia and chronic inflammation, 11 of nasopharyngeal cysts, and 25 of nasopharyngeal carcinoma. According to the pathological results, the morphologies of nasopharyngeal lesions under NBI mode were quite different. The color depth of the mucosa could be divided into four types: light red (+), dark red (++), prunosus (+++), and blue or blue black (++++). Under NBI, the color depths were (+) in papilloma, (++) in nasopharyngeal cysts, and (+++) in lymphoid follicular hyperplasia and chronic inflammation, without abnormal vessels. The color depths were (+++)-(++++) in nasopharyngeal cancer, with abnormal vessels. NBI has a potential ability to predict pathological results of nasopharyngeal lesions.

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