Yulian Wu

HUMAN BONE MARROW MESENCHYMAL STEM CELLS DIFFERENTIATE INTO INSULIN-PRODUCING CELLS UPON MICROENVIRONMENTAL MANIPULATION IN VITRO

It was recently reported that pluripotent mesenchymal stem cells (MSCs) in rodent bone marrow (BM) have the capacity to generate insulin-producing cells (IPCs) in vitro. However, little is known about this capacity in human BM-MSCs. We developed a nongenetic method to induce human BM-MSCs to transdifferentiate into IPCs both phenotypically and functionally. BM-MSCs from 12 human donors were sequentially cultured in specially defined conditions. Their differentiation extent toward beta-cell phenotype was evaluated systemically. Specifically, after induction human BM-MSCs formed spheroid islet-like clusters containing IPCs, which was further confirmed by dithizone (DTZ) staining and electron microscopy. These IPCs expressed multiple genes related to the development or function of pancreatic beta cells (including NKX6.1, ISL-1, Beta2/Neurod, Glut2, Pax6, nestin, PDX-1, ngn3, insulin and glucagon). The coexpression of insulin and c-peptide was observed in IPCs by immunofluorescence. Moreover, they were able to release insulin in a glucose-dependent manner and ameliorate the diabetic conditions of streptozotocin (STZ)-treated nude mice. These results indicate that human BM-MSCs might be an available candidate to overcome limitations of islet transplantation.

Carbon nanotube-based magnetic-fluorescent nanohybrids as highly efficient contrast agents for multimodal cellular imaging

We developed a simple and novel layer-by-layer (LBL) assembly in combination with covalent connection strategy for the synthesis of multifunctional carbon nanotubes (CNTs)-based magnetic-fluorescent nanohybrids as multimodal cellular imaging agents for detecting human embryonic kidney (HEK) 293T cells via magnetic resonance (MRI) and confocal fluorescence imaging. Superparamagnetic iron oxide nanoparticles (SPIO) and near-infrared fluorescent CdTe quantum dots (QDs) were covalently coupled on the surface of CNTs in sequence via LBL assembly. It was indicated that the SPIO layer acted not only as a contrast agent for MRI, but also as a spacer between CdTe QDs and CNTs for prohibiting fluorescence quenching of QDs on the surface of the CNTs. The multifunctional CNT-based magnetic-fluorescent nanohybrids showed an enhanced MRI signal as contrast agent for detecting 293T cells in comparison with the pure SPIO. This is due to the magnetic coupling between the orderly arrayed SPIO, the function of CNTs for lowering the transverse relaxation and the ability of CNTs for penetrating into cells. Moreover, the multifunctional CNT-based magnetic-fluorescent nanohybrids exhibited the higher intracellular labeling efficiency due to the ability of CNTs for penetrating into cells in comparison with pure SPIO-CdTe nanoparticles.

Elevated levels of plasma fibrinogen in patients with pancreatic cancer: possible role of a distant metastasis predictor.

Objectives: Although changes of plasma fibrinogen have been documented in limited pancreatic malignant tumors, a relationship between plasma fibrinogen and pancreatic cancer in a large-scale clinical study has not been shown. Methods: Preoperative plasma levels of fibrinogen were retrospectively analyzed in 133 pancreatic cancer and 38 pancreatic benign tumor patients. Results: Plasma fibrinogen in pancreatic cancer patients were significantly higher than those with benign pancreatic tumor (3.99 ± 1.01 vs 2.62 ± 0.65; P < 0.001). The percentage of hyperfibrinogenemia (>4.20 g/L) in pancreatic cancer was 41.1%, and no positive results were obtained in benign pancreatic disease. Plasma fibrinogen levels were increased in pancreatic cancer with advanced tumor stage. Accompanied with the progression of tumor stage, there was an increase in the percentage of positivity of hyperfibrinogenemia in pancreatic cancer. There were markedly higher levels of plasma fibrinogen in the distant-metastasis group than in the no-distant-metastasis group (4.41 ± 0.84 vs 3.76 ± 1.04; P < 0.01). Univariate and multivariate analysis revealed that high plasma fibrinogen levels (>4.20 g/L) were positively associated with distant metastasis of pancreatic cancer. Conclusions: Plasma fibrinogen levels had a positive relationship with tumor stage of pancreatic cancer. Increased preoperative plasma fibrinogen levels might be a useful predictor for distant metastasis in human pancreatic cancer.

Neoadjuvant therapy for patients with borderline resectable pancreatic cancer: A systematic review and meta-analysis of response and resection percentages

BACKGROUND We systematically reviewed and performed a meta-analysis of the available data regarding neoadjuvant chemo- and/or radiotherapy with special emphasis on tumor response/progression rates, toxicities, and clinical benefit, i.e. resection probabilities and survival estimates. METHODS AND FINDINGS Trials were identified by searching PUBMED, MEDLINE, and the Cochrane Central Register of Controlled Trials from 1966 to Feb 2015. A total of 18 studies (n = 959) were analyzed. the estimated fraction of patients with complete response was 2.8% (CI 0.8-4.7%) and with partial response 28.7% (CI 18.9%-38.5%). Stable disease was averaged to 45.9% (CI 32.9%-58.9%) in all patients and tumor progression under therapy occurred by estimation in 16.9% (CI 10.2%-23.6%) of the patients. The weighted frequency of those who underwent resection was 65.3% (CI 54.2%-76.5%), and the proportion of R0 resection amounted to 57.4% (CI 48.2%-66.5%). The weighted mean of median survival amounted to 17.9 months (range: 14.7-21.2 months) for the overall cohort of patients, 25.9 months (range: 21.1-30.7 months) for those who were resected, and 11.9 months (range: 10.4-13.5 months) for unresected patients. CONCLUSIONS The resection and R0 resection rates in the group of borderline resectable tumor patients after neoadjuvant therapy are similar to the resectable tumor patients, much higher than those in unresectable tumor patients. The survival estimates of borderline resectable tumor patients after neoadjuvant therapy were similar to resectable tumor patients. Patients with borderline resectable pancreatic cancer should be included in neoadjuvant protocols and subsequently be reevaluated for resection. How to find chemo-responsiveness before neoadjuvant chemotherapy so as to give individualized treatment is still an important issue.

Labeling transplanted mice islet with polyvinylpyrrolidone coated superparamagnetic iron oxide nanoparticles for in vivo detection by magnetic resonance imaging

Superparamagnetic iron oxide nanoparticles (SPIO) are emerging as a novel probe for noninvasive cell tracking with magnetic resonance imaging (MRI) and have potential wide usage in medical research. In this study, we have developed a method using high-temperature hydrolysis of chelate metal alkoxide complexes to synthesize polyvinylpyrrolidone coated iron oxide nanoparticles (PVP-SPIO), as a biocompatible magnetic agent that can efficiently label mice islet beta-cells. The size, crystal structure and magnetic properties of the as-synthesized nanoparticles have been characterized. The newly synthesized PVP-SPIO with high stability, crystallinity and saturation magnetization can be efficiently internalized into beta-cells, without affecting viability and function. The imaging of 100 PVP-SPIO-labeled mice islets in the syngeneic renal subcapsular model of transplantation under a clinical 3.0 T MR imager showed high spatial resolution in vivo. These results indicated the great potential application of the PVP-SPIO as an MRI contrast agent for monitoring transplanted islet grafts in the clinical management of diabetes in the near future.

Delta like ligand 4 induces impaired chemo-drug delivery and enhanced chemoresistance in pancreatic cancer.

The stubborn chemoresistance of pancreatic ductal adenocarcinoma (PDA) is simultaneously influenced by tumor parenchymal and stromal factors, and the ctritical role of Notch ligand Delta-like 4 (DLL4) in the regulation of tumor malignancies has been observed. DLL4 positive expression ratio between duct cells from clinical tumor and adjacent tissues was statistically significant, and the overactivation of DLL4/Notch pathway enhanced the phenotype of EMT and cancer stem cell, even can induce multi-chemoresistance in vitro. Notably, the accompanied defective angiogenesis directly induced inefficient chemo-drug delivery in vivo. Collectively, overexpressed DLL4 on neoplastic cells can enhance chemoresistance through angiogenesis-dependent/independent mechanisms in PDA.

DJ-1, a novel biomarker and a selected target gene for overcoming chemoresistance in pancreatic cancer.

PurposeAberrant expression of DJ-1 has been proven to be associated with tumorigenesis in many carcinomas. However, its role in pancreatic cancer is unknown. The aims of this study were to investigate whether the serum DJ-1 might be a potential biomarker for pancreatic cancer and to determine the biologic function of DJ-1 expression in gemcitabine-induced chemoresistance of pancreatic cancer.MethodsThe serum level of DJ-1 was higher in 128 pancreatic cancer patients compared with 62 healthy controls by ELISA. To determine the effect of DJ-1 on pancreatic tumor chemoresistance, a siRNA-targeting DJ-1 was synthesized and a stably transfected cell line with DJ-1 over-expression was constructed. The mechanism of tumor chemoresistance was assessed by multiple methods, such as MTT assay, real-time PCR, Western blot and flow cytometry.ResultsThe serum level of DJ-1 was higher in pancreatic cancer patients than healthy controls, and it has the relationship with tumor differentiation in pancreatic cancer. Down-regulation of DJ-1 enhanced gemcitabine-induced apoptosis in three pancreatic cancer cell lines. On the contrary, over-expression of DJ-1 desensitized the MIA PaCa-2 to the induction of apoptosis by gemcitabine.ConclusionsOur results suggest that the serum level of DJ-1 may be a potential biomarker for pancreatic cancer, and that DJ-1 plays critical roles in the pancreatic tumor chemoresistance, supporting the development of chemotherapeutic approaches targeting this oncogene.

Magnetodielectric effects of Y3Fe5−xTixO12+x/2 ceramics

Dielectric, magnetic, and magnetodielectric properties of Y3Fe5−xTixO12+x/2 (x = 0, 0.1, 0.2) ceramics were investigated. Ti substitution induces a low temperature dielectric relaxation which comes from the charge carrier hopping between Ti3+ and Ti4+. The Maxwell-Wagner effect related dielectric relaxation becomes weak as the content of Ti increases. The extrinsic effect and intrinsic effect play a dominant role on the magnetodielectric effects for x = 0 at f < 500 kHz and f ≥ 500 kHz, respectively. The contribution of the extrinsic effects to magnetodielectric (MD) effect decreases and the contribution of the intrinsic effects to MD effect increases with increasing Ti amount.

Inhibition of autophagy promotes metastasis and glycolysis by inducing ROS in gastric cancer cells

Autophagy defect has been shown to be correlated with malignant phenotype and poor prognosis of human cancers, however, the detailed mechanisms remain obscure. In this study, we investigated the biological changes induced by autophagy inhibition in gastric cancer. We showed that inhibition of autophagy in gastric cancer cells promotes epithelial-mesenchymal transition (EMT) and metastasis, alters metabolic phenotype from mitochondrial oxidative phosphorylation to aerobic glycolysis and converts cell phenotype toward malignant, which maybe further contribute to chemoresistance and poor prognosis of gastric cancer. We also identified that the EMT and metabolism alterations induced by autophagy inhibition were dependent on ROS-NF-κB-HIF-1α pathway. More importantly, scavenging of ROS by the antioxidant N-acetylcysteine (NAC) attenuated activation of NF-κB and HIF-1α in autophagy-deficient gastric cancer cells, and autophagy inhibition induced metastasis and glycolysis were also diminished by NAC in vivo. Taken together, our findings suggested that autophagy defect promotes metastasis and glycolysis of gastric cancer, and antioxidants could be used to improve disease outcome for gastric cancer patients with autophagy defect.

One-Pot Synthesis of Biocompatible CdSe/CdS Quantum Dots and Their Applications as Fluorescent Biological Labels

We developed a novel one-pot polyol approach for the synthesis of biocompatible CdSe quantum dots (QDs) using poly(acrylic acid) (PAA) as a capping ligand at 240°C. The morphological and structural characterization confirmed the formation of biocompatible and monodisperse CdSe QDs with several nanometers in size. The encapsulation of CdS thin layers on the surface of CdSe QDs (CdSe/CdS core–shell QDs) was used for passivating the defect emission (650 nm) and enhancing the fluorescent quantum yields up to 30% of band-to-band emission (530–600 nm). Moreover, the PL emission peak of CdSe/CdS core–shell QDs could be tuned from 530 to 600 nm by the size of CdSe core. The as-prepared CdSe/CdS core–shell QDs with small size, well water solubility, good monodispersity, and bright PL emission showed high performance as fluorescent cell labels in vitro. The viability of QDs-labeled 293T cells was evaluated using a 3-(4,5-dimethylthiazol)-2-diphenyltertrazolium bromide (MTT) assay. The results showed the satisfactory (>80%) biocompatibility of as-synthesized PAA-capped QDs at the Cd concentration of 15 μg/ml.