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Kang R.,Aarhus University Hospital | Kang R.,Jiangsu Province Hospital on Integration of Chinese and Western Medicine | Svend Le D.Q.,University of Aarhus | Li H.,Aarhus University Hospital | And 4 more authors.
Journal of Materials Chemistry B | Year: 2013

Repairing annulus fibrosus (AF) defects is one of the most challenging topics in intervertebral disc disease treatment research. The highly oriented native structure offers mechanical functionality to the spine, however manufacturing scaffolds with such a structure still presents a challenge for tissue engineering. Here, a three-dimensional (3D) multi-lamellar scaffold with hierarchically aligned nano- and micro-fibers for AF tissue engineering was successfully developed. Aligned polycaprolactone (PCL) nano-fiber sheets, which were fabricated by electrospinning, were inserted into fused-deposit-modeling (FDM) micro-fibers to build a layer-by-layer structure, with the thickness of each layer being 0.7 mm and the angle of fiber alignment in each adjacent layer being 60°. Human mesenchymal stem cells (hMSCs) were used for in vitro compatibility studies. The architecture of the scaffold was characterized by scanning electron microscopy (SEM). Uniaxial tensile testing showed closed mechanical properties of the scaffold to native AF tissue. The XTT cell viability and DNA quantification of the cells on the multi-lamellar scaffold were found to be significantly higher than the FDM scaffolds without nano-fibers. Confocal microscopy demonstrated that the cells spread evenly on the surface of the electrospun sheet and oriented along the nano-fiber direction. This 3D multi-lamellar scaffold has the advantages of stability from the FDM micro-fibers, and unique characteristics from the aligned electrospun nano-fibers, such as mimicking the extracellular matrix (ECM), and an ultrahigh surface area for improved hMSC attachment, proliferation and contact guidance of cell morphology. The newly designed scaffold mimics the native structure of AF and has a great potential as a substrate for the regeneration of AF. © 2013 The Royal Society of Chemistry.


Kang R.,University of Aarhus | Kang R.,Jiangsu Province Hospital on Integration of Chinese and Western Medicine | Li H.,University of Aarhus | Rickers K.,University of Aarhus | And 3 more authors.
European Spine Journal | Year: 2015

Purpose: To investigate whether exogenous tumor necrosis factor-α (TNF-α) will initiate a degenerative process in intervertebral disc in vivo. Methods: Exogenous TNF-α in dosages of 50 and 100 ng in 50 μL Dulbecco’s Modified Essential Medium (DMEM) was injected into porcine lumbar discs; a third disc was injected only with 50 μL DMEM as a control. Magnetic resonance imaging (MRI) yielding T1- and T2-weighted images, T2-mapping, and post-contrast T1 images was performed and histology was studied as well. Results: After 3 months, a significant decrease in T2 value calculated from T2-mapping MRI was observed in the annulus and nucleus of both groups injected with TNF-α along with a slight decrease in disc height and nucleus volumes in comparison to the control discs. No obvious visual differences among the groups were observed in the normal T1- and T2-weighted MRI images. Post-contrast T1 MRI showed increased annulus enhancement in both TNF-α-injected groups compared to the control discs, while no enhancement difference was observed in the nucleus. Histological analysis showed degenerative changes with annulus fissure, cell cluster, nucleus matrix loss, vascularization and interleukin-1β expression in the outer annulus of both TNF-α-injected discs, while no degenerative changes were observed in the control discs. Conclusions: Intradiscal injection of exogenous TNF-α caused early stage disc degeneration in a porcine model. It may thus support the hypothesis of exogenic TNF-α being an important early pathogenetic factor in disc degeneration. © 2015, Springer-Verlag Berlin Heidelberg.


Tang W.,Nanjing Medical University | Tang W.,Jiangsu Province Hospital on Integration of Chinese and Western Medicine | Jiang Y.,Nanjing Medical University | Mu X.,Nanjing Medical University | And 4 more authors.
Cellular Signalling | Year: 2014

The activation of homeobox A10 (HOXA10) has been proved to be an important event in epithelial ovarian carcinogenesis, yet its regulation in epithelial ovarian cancer (EOC) is still not fully understood. Here, we aimed to reveal the mechanism that a predicted target miRNA regulates HOXA10 expression and the association of its expression with progression of EOC. Here, by using computer-assisted algorithms from PicTar, TargetScan, and miRBase, we identified that the predicted target miRNA of HOXA10 was miR-135a. MiR-135a expression in EOC tissues and controls was measured with quantitative RT-PCR. The role of miR-135a and HOXA10 in the growth and survival of several EOC cell lines was determined with several in vitro approaches. We found that miR-135a expression was downregulated in an EOC patient cohort. Also, patients with low miR-135a expression had shorter overall survival and progression-free survival durations than those with high expression. Functional analysis of three EOC-derived cell lines (SKOV-3, HEY, and OVCAR-3) demonstrated that miR-135a directly regulated HOXA10 expression by targeting its 3'-UTR. Inhibition of HOXA10 expression with miR-135a mimics and HOXA10 siRNA consistently resulted in cell apoptosis with concomitant enhancement of caspase-3, increase of p53 expression and reduction of Bcl-2 expression, and also suppressed cell growth and adhesion. These findings suggest that ubiquitous loss of miR-135a expression is a critical mechanism for the overexpression of HOXA10 in EOC cells, which is implicated in epithelial ovarian carcinogenesis. Furthermore, miR-135a may be predictive of EOC prognosis. © 2014.


Xu S.,St Hedwig Hospital | Xu S.,Jiangsu Province Hospital on Integration of Chinese and Western Medicine | Chen G.,St Hedwig Hospital | Peng W.,St Hedwig Hospital | And 2 more authors.
Journal of Endocrinology | Year: 2013

Benign and malignant thyroid nodules are more prevalent in females than in males. Experimental data suggest that the proliferative effect of oestrogen rather than polymorphisms is responsible for this gender difference. This study analysed whether both differentiated thyroid cells and thyroid stem and progenitor cells are targets of oestrogen action. In thyroid stem/progenitor cells derived from nodular goitres, the ability of 17β-oestradiol (E2) to induce the formation of thyrospheres and the expression of oestrogen receptors (ERs) and the effect of E2 on the growth and expression of markers of stem cells and thyroid differentiation (TSH receptor, thyroperoxidase, thyroglobulin and sodium iodide symporter (NIS)) were analysed. E2 induced thyrosphere formation, albeit to a lower extent than other growth factors. Thyroid stem and progenitor cells expressed ERα (ESR1) and ERβ (ESR2) with eight times higher expression levels of ERα mRNA compared with the differentiated thyrocytes. E2 was a potent stimulator of the growth of thyroid stem/progenitor cells. In contrast, TSH-induced differentiation of progenitor cells, in particular, the expression of NIS, was significantly inhibited by E2. In conclusion, oestrogen stimulated the growth and simultaneously inhibited the differentiation of thyroid nodule-derived stem/progenitor cells. From these data and based on the concept of cellular heterogeneity, we hypothesize a supportive role of oestrogen in the propagation of thyroid stem/progenitor cells leading to the selection of a progeny of growth-prone cells with a decreased differentiation. These cells may be the origin of hypofunctioning or non-functioning thyroid nodules in females. © 2013 Society for Endocrinology.


Chen G.,St Hedwig Hospital | Xu S.,St Hedwig Hospital | Xu S.,Jiangsu Province Hospital on Integration of Chinese and Western Medicine | Renko K.,University Medicine | Derwahl M.,St Hedwig Hospital
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Context: Hyperinsulinemia and insulin resistance are the major reasons for a higher prevalence of several cancer entities in type 2 diabetes mellitus and obesity. Metformin exerts a growth-inhibitory effect by reducing hyperinsulinemia and by a direct cellular action. Objective: We investigated the effect of metformin on growth of differentiated human thyroid cells, anaplastic thyroid carcinoma cells, a doxorubicin-resistant thyroid carcinoma cell line, and thyroid cancer stem cells. Design:Theantimitogenic effect of metforminwasstudied in thyroid cells derivedfromgoitersand in thyroid carcinoma cell lines by analysis of cell growth, cell cycle progression, and apoptosis. Furthermore, the influence of pretreatment with insulin or with chemotherapeutic agents on metformin-induced growth inhibition was investigated in thyroid carcinoma cells, in a doxorubicin- resistant thyroid carcinoma cell line, and in derived carcinoma stem cells. Results: Metformin showed an antimitogenic effect by inhibition of cell cycle progression and induction of apoptosis. In addition, metformin antagonized the growth-stimulatory effect of insulin, inhibited clonal cell growth, reduced thyroid cancer sphere formation, and potentiated the antimitogenic effect of chemotherapeutic agents such as doxorubicin and cisplatin on undifferentiated thyroid carcinoma cells. Remarkably, the antiproliferative effect of metformin was even found in a doxorubicin-resistant thyroid carcinoma cell line. The growth-inhibitory effect of metformin was, however, not restricted to differentiated thyroid cells and undifferentiated thyroid carcinoma cells but was also demonstrated in thyroid carcinoma cancer stem cells. Conclusions: Metformin markedly diminished growth stimulation by insulin and showed an additive antimitogenic effect to chemotherapeutics agents. Therefore, our results suggest this drug as adjuvant treatment for thyroid cancer in type 2 diabetic patients. Copyright © 2012 by The Endocrine Society.


Luo Y.,Nanjing University | Luo Y.,Jiangsu Province Hospital on Integration of Chinese and Western Medicine | Sun Z.,Nanjing University | Li Y.,Jiangsu Province Institute of Traditional Chinese Medicine | And 3 more authors.
Oncology Reports | Year: 2013

In the present study, we investigated the antitumor activity of caudatin in the human hepatoma cell line SMMC-7721 by analysis of cell viability, cell cycle distribution, apoptosis and metastasis. The results showed that caudatin impaired the cell viability and inhibited the growth of SMMC-7721 cells in a time- and dose-dependent manner and resulted in cell cycle arrest in the G2 phase. In addition, SMMC-7721 cells, treated with caudatin exhibited typical characteristics of apoptosis. Furthermore, caudatin treatment resulted in a decrease in β-catenin and GSK3β in SMMC-7721 cells, with a concomitant reduction in metastatic capability and expression of Wnt signaling pathway targeted genes including cox-2, mmp-2 and mmp-9. Our findings revealed that caudatin inhibits human hepatoma cell growth and metastasis by targeting the GSK3β/β-catenin pathway and suppressing VEGF production.


Liu P.,Nanjing University | Duan J.,Nanjing University | Wang P.,Jiangsu Province Hospital on Integration of Chinese and Western Medicine | Qian D.,Nanjing University | And 5 more authors.
Molecular BioSystems | Year: 2013

Primary dysmenorrhea (PDM), a common clinical endocrine disorder affecting young women, is associated with endocrinopathy and metabolic abnormalities. Although some physiological and pathological function parameters have been investigated, little information about the changes of small metabolites in biofluids has been reported, which may cause poor diagnosis and treatment for PDM. The Xiang-Fu-Si-Wu Formula (XFSWF) is a Chinese herbal formula used to treat PDM for hundreds of years. The aim of this study was to establish the metabolic profile of PDM and investigate the action mechanism of XFSWF effect. In this cross-sectional study of 25 patients with PDM and 12 healthy controls, contents of small molecular endogenous metabolites in blood plasma and urine samples were measured by ultra performance liquid chromatography (UPLC) coupled with quadrupole-time-of-flight mass spectrometry (QTOF/MS) and triple quadrupole mass spectrometry (QqQ/MS) based techniques and analyzed by multivariate statistical methods. The levels of LPCs including lypso (16:1), lysoPC(20:4), lysoPC(18:2), lysoPC(16:0), lysoPC(18:1), lysoPC(10:1), estrone, 17-hydroxyprogesterone, myristoylglycine and palmitoylglycine increased significantly (p < 0.05) in PDM, while the levels of phytosphingosine, dihydrocortisol and sphingosine decreased significantly (p < 0.05) compared with the healthy controls. These significant perturbations are involved in glycerophospholipid metabolism and sphingolipid metabolism, as well as steroid hormone biosynthesis. The metabolic deviations recovered to the normal level after XFSWF intervention. The results demonstrated that biofluids metabonomics was a powerful tool in clinical diagnosis and treatment of PDM for providing information on changes in metabolites and neural, endocrinal and immune pathways. XFSWF can be used for the treatment of PDM cases, especially for those adolescents who do not desire a contraceptive method, to reduce the risk of secondary dysmenorrhea. © 2013 The Royal Society of Chemistry.


Huang X.-E.,Nanjing Medical University | Wei G.-L.,Jiangsu Province Hospital on Integration of Chinese and Western Medicine | Huo J.-G.,Jiangsu Province Hospital on Integration of Chinese and Western Medicine | Wang X.-N.,Jiangsu Province Hospital on Integration of Chinese and Western Medicine | And 5 more authors.
Asian Pacific Journal of Cancer Prevention | Year: 2013

Aims: To explore efficacy and side effects of intrapleural or intraperitoneal lobaplatin for treating patients with malignant pleural or peritoneal effusions. Methods: Patients in Jiangsu Cancer Hospital and Research Institute with cytologically confirmed solid tumors complicated with malignant pleural effusion or ascites were enrolled into this study. Lobaplatin (20-30 mg/m2su) was intrapleurally or intraperitoneally infused for patients with malignant pleural effusion or ascites. Results: From 2012 to 2013, intrapleural or intraperitonea lobaplatin was administered for patients with colorectal or uterus cancer who were previous treated for malignant pleural effusion or ascites. Partial response was achieved for them. Main side effects were nausea/vomiting, and bone marrow suppression. No treatment related deaths occurred. Conclusion: Intrapleural or intraperitoneal infusion of lobaplatin is a safe treatment for patients with malignant pleural effusion or ascites, and the treatment efficacy is encouraging.


Wei G.-L.,Nanjing Medical University | Wei G.-L.,Jiangsu Province Hospital on Integration of Chinese and Western Medicine | Huang X.-E.,Nanjing Medical University | Huo J.-G.,Jiangsu Province Hospital on Integration of Chinese and Western Medicine | And 2 more authors.
Asian Pacific Journal of Cancer Prevention | Year: 2013

Purpose: This study was to determine the efficacy and safety of pemetrexed based chemotherapy in treating patients with metastatic gastric cancer who failed to respond to first and (or) second line chemotherapy. Patients and Methods: Metastatic gastric cancer patients who failed first and (or) second line chemotherapy, were enrolled. All patients were recruited from Jiangsu Cancer Hospital & Research Institute, and were treated with pemetrexed 500 mg/m2 (intravenous; on day 1), and a platinum (or irinotecan) every 3 weeks until disease progression, or intolerable toxicity. Evaluation on efficacy was conducted after two cycles of chemotherapy using the Response Evaluation Criteria for Solid Tumors. Toxicity was recorded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. Results: From Jun 2011 to May 2013, 23 patients were enrolled. All eligible 23 patients completed at least 2 cycles of chemotherapy with pemetrexed based chemotherapy, and were evaluable. Their median age was 55 years (range 40 to 78 years). Seventeen patients were male and 6 female. Three patients (13%) achieved partial response, five patients (22%) stable, 15 patients (65%) with disease progression, and none with complete response. Grade 2 neutrophil suppression occurred in 4.3%, grade 3 in 13% of patients, and no grade 4 was reported. Thrombocytopenia was encountered as follows: 4.3% grade 2, 4.3% grade 3 and 4.3% grade 4. Incidence of anemia was 34.8% in grade 2, 8.7% grade 3 and 0% grade 4. Only 4.3% of patients required packed red blood cell infusion. Elevated transaminase were 4.3% in grade 2 and 0% in grade 3 or 4. Other toxicity included oral mucositis. Conclusions: Pemetrexed based chemotherapy is mildly effective in treating patients with metastatic gastric cancer with tolerable toxicity.


Liu K.,Nanjing Medical University | Qian T.,Jiangsu Province Hospital on Integration of Chinese and Western Medicine | Tang L.,Nanjing Medical University | Wang J.,Nanjing Medical University | And 2 more authors.
World Journal of Surgical Oncology | Year: 2012

Background: MicroRNA let-7i has been proven to be down-regulated in many human malignancies and correlated with tumor progression and anticancer drug resistance. Our study aims to characterize the contribution of miRNA let-7i to the initiation and malignant progression of locally advanced gastric cancer (LAGC), and evaluate its possible value in neoadjuvant chemotherapeutic efficacy prediction.Methods: Eighty-six previously untreated LAGC patients who underwent preoperative chemotherapy and radical resection were included in our study. Let-7i expression was examined for pairs of cancer tissues and corresponding normal adjacent tissues (NATs), using quantitative RT-PCR. The relationship of let-7i level to clinicopathological characteristics, pathologic tumor regression grades after chemotherapy, and overall survival (OS) was also investigated.Results: Let-7i was significantly down-regulated in most tumor tissues (78/86: 91%) compared with paired NATs (P < 0.001), and low levels of let-7i were significantly correlated with local invasion, lymphatic metastasis, and poor pathologic tumor response. Multivariate Cox regression analysis revealed that low let-7i expression was an unfavorable prognostic factor of OS (hazard ratio (HR) = 2.316, P =0.024) independently of other clinicopathological factors, including tumor node metastasis (TNM) stage (HR = 3.226, P = 0.013), depth of infiltration (HR = 4.167, P < 0.001), and lymph node status (HR = 2.245, P = 0.037).Conclusions: These findings indicate that let-7i may be a good candidate for use a therapeutic target and a potential tissue marker for the prediction of chemotherapeutic sensitivity and prognosis in LAGC patients. © 2012 Liu et al.; licensee BioMed Central Ltd.

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