Lei-Ming Xu

Value of bevacizumab in treatment of colorectal cancer：A meta-analysis

AIM To assess the efficacy and safety of bevacizumab in the treatment of colorectal cancer. METHODS All randomized controlled trials of bevacizumab for the treatment of colorectal cancer from January 2003 to June 2013 were collected by searching the Cochrane Library, PubMed, Chinese National Knowledge Infrastructure and Wanfang databases. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival, overall response rate and adverse events. Two reviewers extracted data independently. Statistical analyses were performed with Stata 12.0. The degree of bias was assessed using funnel plots for the effect size of OS at the primary endpoint. RESULTS Following the inclusion criteria and exclusion criteria, ten studies comprising 6977 cases were finally included, of which nine were considered to be of high quality (4-7 points) and one of low quality (1-3 points). Our meta-analysis revealed the efficacy of bevacizumab in patients with colorectal cancer in terms of OS (HR = 0.848, 95%CI: 0.747-0.963), progression-free survival (HR = 0.617, 95%CI: 0.530-0.719), and overall response rate (OR = 1.627, 95%CI: 1.199-2.207). Regarding safety, higher rates of grade ≥ 3 hypertension, proteinuria, bleeding, thrombosis, and gastrointestinal perforation were observed in the bevacizumab treatment group (P < 0.05); however, the incidence of serious toxicity was very low. There was no publication bias in the 10 reports included in this meta-analysis. CONCLUSION The clinical application of bevacizumab in colorectal cancer is effective with good safety.

Engineering of lipid prodrug-based, hyaluronic acid-decorated nanostructured lipid carriers platform for 5-fluorouracil and cisplatin combination gastric cancer therapy

Purpose The first-line chemotherapy treatment protocol for gastric cancer is combination chemotherapy of 5-fluorouracil (5-FU) and cisplatin (CDDP). The aim of this study was to engineer prodrug-based nanostructured lipid carriers (NLC) platform for codelivery of 5-FU and CDDP to enhance therapy and decrease toxicity. Methods First, 5-FU-stearic acid lipid conjugate was synthesized by two steps. Second, 5-FU-stearic acid prodrug and CDDP were loaded in NLC. Finally, hyaluronic acid (HA) was coated onto NLC surface. Average size, zeta potential, and drug loading capacity of NLC were evaluated. Human gastric cancer cell line BGC823 (BGC823 cells) was used for the testing of in vitro cytotoxicity assays. In vivo antitumor activity of NLC was evaluated in mice bearing BGC823 cells model. Results HA-coated 5-FU-stearic acid prodrug and CDDP-loaded NLC (HA-FU/C-NLC) showed a synergistic effect in combination therapy and displayed the greatest antitumor activity than all of the free drugs or uncoated NLC in vitro and in vivo. Conclusion This work reveals that HA-coated NLC could be used as a novel carrier to code-liver 5-FU and CDDP for gastric cancer therapy. HA-FU/C-NLC could be a promising targeted and combinational therapy in nanomedicine.

Effects of integrin-targeted photodynamic therapy on pancreatic carcinoma cell.

AIM To investigate the effects of photodynamic therapy with quantum dots-arginine-glycine-aspartic acid (RGD) probe as photosensitizer on the proliferation and apoptosis of pancreatic carcinoma cells. METHODS Construction of quantum dots-RGD probe as photosensitizer for integrin-targeted photodynamic therapy was accomplished. After cells were treated with photodynamic therapy (PDT), the proliferation of SW1990 cells were measured by methyl thiazolyl tetrazolium assay. Morphologic changes, cell cycle retardance and apoptosis were observed under fluoroscope and flow cytometry. The expression of myeloid cell leukemia-1 (Mcl-1), protein kinase B (Akt) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mRNA were detected by reverse transcription-polymerase chain reaction. The amount of reactive oxygen species were also evaluated by fluorescence probe. RESULTS The photodynamic therapy with quantum dots-RGD probe as photosensitizer significantly inhibited cell proliferation (P < 0.01). Apoptotic cells and morphologic changes could be found under optical microscope. The FCM revealed PDT group had more significant cell apoptosis rate compared to control cells (F = 130.617, P < 0.01) and cell cycle G0/G1 and S retardance (P < 0.05) compared to control cells. The expression of Mcl-1 and Akt mRNA were down-regulated, while expression of TRAIL mRNA was up-regulated after cells treated with PDT. PDT group had more significant number of cells producing reactive oxygen species compared to control cells (F = 3262.559, P < 0.01). CONCLUSION The photodynamic therapy with quantum dots-RGD probe as photosensitizer significantly inhibits cell proliferation and increases apoptosis in SW1990 cells.

Antifibrotic effect of N-acetyl-seryl-aspartyl-lysyl-proline on bile duct ligation induced liver fibrosis in rats

AIM To investigate the preventive effect of N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) on bile duct ligation (BDL)-induced liver fibrosis in rats. METHODS Liver fibrosis in rats was induced by BDL and AcSDKP was infused subcutaneously for 2 wk via a osmotic minipump (Alzet 2ML4) immediately after BDL operation. After scarifying, serum and liver specimens were collected. Hematoxylin and eosin staining, Sirius red staining, enzyme linked immunosorbent assay, Western blot or real-time polymerase chain reaction were used to determinate liver functions, histological alterations, collagen deposition, mRNA expression of markers for fibroblasts, transforming growth factor-β1 (TGF-β1) and bone morphogenetic protein-7 (BMP-7). RESULTS When compared to model rats, chronic exogenous AcSDKP infusion suppressed profibrogenic TGF-β1 signaling, α-smooth muscle actin positivity (α-SMA), fibroblast specific protein-1 (FSP-1) staining and collagen gene expression. Col I, Col III, matrix metalloproteinase-2, tissue inhibitors of metalloproteinase-1 and tissue inhibitors of metalloproteinase-2 mRNA expressions were all significantly downregulated by AcSDKP infusion (2.02 ± 1.10 vs. 14.16 ± 6.50, 2.02 ± 0.45 vs. 10.00 ± 3.35, 2.91 ± 0.30 vs. 7.83 ± 1.10, 4.64 ± 1.25 vs. 18.52 ± 7.61, 0.46 ± 0.16 vs. 0.34 ± 0.12, respectively, P < 0.05). Chronic exogenous AcSDKP infusion attenuated BDL-induced liver injury, inflammation and fibrosis. BDL caused a remarkable increase in alanine transaminase, aspartate transaminase, total bilirubin, and prothrombin time, all of which were reduced by AcSDKP infusion. Mast cells, collagen accumulation, α-SMA, TGF-β1, FSP-1 and BMP-7 increased. The histological appearance of liver specimens was also improved. CONCLUSION Infusion of exogenous AcSDKP attenuated BDL-induced fibrosis in the rat liver. Preservation of AcSDKP may be a useful therapeutic approach in the management of liver fibrosis.

Effects of medical adhesives in prevention of complications after endoscopic submucosal dissection.

AIM To evaluate the use of medical adhesive spray in endoscopic submucosal dissection (ESD). METHODS Patients who underwent ESD between January 2009 and June 2012 (n = 173) were enrolled in the prospective randomized study. Two patients undergoing surgery due to severe intraoperative hemorrhage and failed hemostasis were excluded, and the remaining 171 patients were randomly divided into two groups: group A (medical adhesive group, n = 89) and group B (control group, n = 82). In group A, a medical adhesive spray was evenly applied after routine electrocoagulation and hemostasis using hemostatic clip after ESD. Patients in group B only treated with routine wound management. Intraoperative and postoperative data were collected and compared. RESULTS In all 171 patients, ESD was successfully completed. There was no significant difference in the average treatment time between groups A and B (59.4 min vs 55.0 min, respectively). The average length of hospital stay was significantly different between group A and B (8.89 d vs 9.90 d, respectively). The incidence of intraoperative perforation was 10.1% in group A and 9.8% in group B, and was not significantly different between the two groups. In all cases, perforations were successfully managed endoscopically and with conservative treatment. The incidence of postoperative delayed bleeding in group A was significantly lower than that in group B (0.00% vs 4.88%, respectively). CONCLUSION ESD is an effective minimally invasive treatment for gastrointestinal precancerous lesions or early-stage gastrointestinal cancer. Medical adhesive spray is effective in preventing delayed bleeding after ESD, and can thus reduce the average length of hospital stay.

CdSe/ZnS quantum dots induce photodynamic effects and cytotoxicity in pancreatic cancer cells

AIM To investigate the photodynamic effect of CdSe/ZnS quantum dots (QDs) on pancreatic cancer cells and elucidate the probable mechanisms. METHODS The pancreatic cancer cell line SW1990 was treated with different concentrations of CdSe/ZnS QDs (0, 0.5, 1.0, 1.5, 2.0, 2.5 μmol/L), with or without illumination. The viability of SW1990 cells was tested using the Cell Counting Kit-8 (CCK-8) assay. The ultrastructural changes of SW1990 cells were observed by transmission electron microscopy. Apoptosis was detected by nuclear staining and flow cytometry (FCM). Reactive oxygen species (ROS) were measured by dichlorofluorescein diacetate via fluorescence microscopy. Expression of Bax, Bcl-2 and caspase-3 was measured by real-time polymerase chain reaction (PCR) and protein immunoblotting 24 h after SW1990 cells were treated with CdSe/ZnS QDs and illuminated. RESULTS The CCK-8 assay results showed that both CdSe/ZnS QDs with and without illumination suppressed SW1990 cell proliferation. Cell viability was significantly lower when illuminated or with a longer incubation time and a higher light dose. CdSe/ZnS QDs with illumination caused ultrastructural changes in SW1990 cells, such as organelle degeneration and chromatin condensation and aggregation at the periphery of the nucleus. Fluorescence microscopy and FCM showed that CdSe/ZnS QDs (1.5 μmol/L) with illumination increased SW1990 cell apoptosis (53.2%) and ROS generation compared with no illumination. Real-time PCR showed that expression of Bax and caspase-3 was upregulated and Bcl-2 was downregulated. Immunoblotting results were consistent with real-time PCR results. Inhibition of ROS and apoptosis both attenuated QD-photodynamic-therapy-induced cell death. CONCLUSION CdSe/ZnS QDs can be used as a photosensitizer to inhibit SW1990 cell proliferation through ROS generation and apoptotic protein expression regulation.

Effects of arginine–glycine–aspartic acid peptide-conjugated quantum dots-induced photodynamic therapy on pancreatic carcinoma in vivo

Quantum dots (QDs) conjugated with integrin antagonist arginine–glycine–aspartic acid (RGD) peptides (QDs-RGD) are novel nanomaterials with a unique optical property: a high molar extinction coefficient. Previously, we have shown that QDs-RGD demonstrate a photodynamic therapy (PDT) effect as new photosensitizers for the pancreatic cancer cell line SW1990 in vitro. Here, we investigate the application of QDs-RGD in mice bearing pancreatic tumors using PDT. To ensure that more photosensitizers accumulated in tumors, QDs-RGD were injected intratumorally. After selection of an adequate dosage for injection from analyses of biodistribution images captured by an IVIS system, PDT was initiated. Three groups were created according to different PDT procedures. In group 1, mice were injected with QDs-RGD intratumorally, and an optical fiber connected to a laser light was inserted directly into the tumor. Irradiation was sustained for 20 min with a laser light (630 nm) at 100 mW/cm2. In group 2, the laser optical fiber was placed around, and not inserted into, tumors. In group 3, PDT was conducted as in group 1 but without injection of QDs-RGD. After 28 days of observation, tumors on the back of mice in group 1 grew slowly (V/V0 =3.24±0.70) compared with the control groups, whose tumors grew quickly, and the mean V/V0 reached 6.08±0.50 (group 2) and 7.25±0.82 (group 3). Histology of tumor tissues showed more necrotic tissues, more inflammatory cells, and less vascular tissue in the PDT group than those in the control groups. These results suggest that QDs-RGD-mediated PDT, with illumination using an optical fiber inserted directly into the tumor, can inhibit the growth of SW1990 tumors with high efficiency in nude mice.

TM4SF1 Promotes Metastasis of Pancreatic Cancer via Regulating the Expression of DDR1

Transmembrane-4-L-six-family-1(TM4SF1), a four-transmembrane L6 family member, is highly expressed in various pancreatic cancer cell lines and promotes cancer cells metastasis. However, the TM4SF1-associated signaling network in metastasis remains unknown. In the present study, we found that TM4SF1 affected the formation and function of invadopodia. Silencing of TM4SF1 reduced the expression of DDR1 significantly in PANC-1 and AsPC-1 cells. Through double fluorescence immuno-staining and Co-immunoprecipitation, we also found that TM4SF1 colocalized with DDR1 and had an interaction with DDR1. In addition, upregulating the expression of DDR1 rescued the inhibitory effects of cell migration and invasion, the expression of MMP2 and MMP9 and the formation and function of invadopodia when TM4SF1 silenced. In pancreatic cancer tissues, qRT-PCR and scatter plots analysis further determined that TM4SF1 had a correlation with DDR1. Collectively, our study provides a novel regulatory pathway involving TM4SF1, DDR1, MMP2 and MMP9, which promotes the formation and function of invadopodia to support cell migration and invasion in pancreatic cancer.

Easy and Effective Endoscopic Retrieval of Ingested Sharp Foreign Bodies

Abstract: Here we reported two cases of successful removal of accidentally ingested sharp foreign body. The swallowed objects were dentures with clasps which increased the risk of gastroesophageal bleeding or perforation in both cases. After several unsuccessful attempts of removal with normal assistant apparatus, the foreign bodies were eventually retrieved by using modified ship-form semitransparent plastic bags without any complications.

Overexpression of xeroderma pigmentosum group C decreases the chemotherapeutic sensitivity of colorectal carcinoma cells to cisplatin

Xeroderma pigmentosum group C (XPC) is a DNA-damage-recognition gene active at the early stage of DNA repair. XPC also participates in regulation of cell-cycle checkpoint and DNA-damage-induced apoptosis. In the present study, the expression levels of genes involved in nucleotide excision repair (NER) were assessed in human colorectal cancer (CRC) tissue. This analysis revealed that expression of XPC mRNA significantly increased in colorectal carcinoma tissues compared with matched normal controls. Expression of XPC gradually increased along with the degree of progression of CRC. In vitro, an XTT assay demonstrated that small interfering RNA (siRNA) targeting XPC significantly increased the sensitivity of CRC SW480 cells to cisplatin, whereas cells transfected with a XPC-overexpression plasmid became more resistant to cisplatin. Furthermore, flow cytometry revealed that the proportion of apoptotic cells significantly increased in XPC-knockdown cells upon cisplatin treatment. However, the overexpression XPC significantly increased the resistance of cells to cisplatin. In vivo, tumor growth was significantly reduced in tumor-bearing mice when the XPC gene was knocked down. Upregulation of the expression of pro-apoptotic Bcl-associated X and downregulation of the anti-apoptotic B-cell lymphoma 2 proteins was observed in the implanted tumor tissue. In conclusion, XPC serves a key role in chemotherapeutic sensitivity of CRC to cisplatin, meaning that it may be a potential target for chemotherapy of CRC.