Yan Gu

Comparison of Two Porcine-Derived Materials for Repairing Abdominal Wall Defects in Rats

Objective The purpose of this study was to compare the mechanical properties, host responses and incorporation of porcine small intestine submucosa (PSIS) and porcine acellular dermal matrix (PADM) in a rat model of abdominal wall defect repair. Materials and Methods Prior to implantation, PSIS and PADM were prepared and evaluated in terms of structure and mechanical properties. Full-thickness abdominal wall defects were created in 50 Sprague-Dawley rats, and were repaired using either PSIS or PADM. Rats were sacrificed 1, 2, 4, 8 and 12 weeks post-repair and examined for herniation, infection, adhesions, contraction, and changes in the thickness and strength of the tissues incorporated at the defect sites. Histopathology and immunohistochemistry were performed to analyze inflammatory responses, collagen deposition and vascularization. Results PADM showed more dense collagen deposition and stronger mechanical properties than PSIS prior to implantation (P<0.01). However, the mechanical properties observed after integration with the surrounding native tissues was similar for PADM and PSIS. Both PADM and PSIS showed significant contraction by week 12. However, PADM tissue induced less adhesion and increased in thickness more slowly, and showed less infiltration by foreign giant cells, polymorphonuclear cells, and mononuclear cells. Improved remodeling of host tissue was observed after PSIS implantation, which was apparent from the orientation of bands of fibrous connective tissue, intermixed with newly formed blood vessels by Week 12. Conclusion PSIS showed weaker mechanical properties prior to implantation. However, after implantation PSIS induced more pronounced host responses and showed better incorporation into host tissues than PADM.

The Prognosis of Breast Cancer Patients after Mastectomy and Immediate Breast Reconstruction: A Meta-Analysis

Background An increasing number of patients with breast cancer are being offered immediate breast reconstruction (IBR). The aim of this study was to analyze the impact of IBR on the prognosis of patients with breast cancer. Methods We searched the electronic databases of Medline (Pubmed), ISI Web of Knowledge, Embase, and Google Scholar databases for studies reporting the overall recurrence, disease-free survival (DFS), and overall survival (OS) of patients after mastectomy only and mastectomy with IBR. With these data, we conducted a meta-analysis of the clinical outcomes. Results Fourteen studies, including 3641 cases and 9462 controls, matched our criteria. Relevant information was extracted from these 14 studies. There was no significant heterogeneity (P for Q-statistic > 0.10 and I2 < 25%). Patients who underwent IBR showed no increased risk of overall recurrence of breast cancer (RR = 0.89; 95% confidence interval [CI]: 0.75, 1.04; P = 0.14). Furthermore, patients receiving IBR had similar DFS (RR = 1.04; 95%CI: 0.99, 1.08); P = 0.10) and OS (RR = 1.02; 95%CI: 0.99, 1.05; P = 0.24)) as those of control patients. Conclusion This meta-analysis provides evidence that IBR does not have an adverse effect on prognosis. These data suggest that IBR is an appropriate and safe choice for patients with breast cancer.

Carbon nanotubes as VEGF carriers to improve the early vascularization of porcine small intestinal submucosa in abdominal wall defect repair.

Insufficient early vascularization in biological meshes, resulting in limited host tissue incorporation, is thought to be the primary cause for the failure of abdominal wall defect repair after implantation. The sustained release of exogenous angiogenic factors from a biocompatible nanomaterial might be a way to overcome this limitation. In the study reported here, multiwalled carbon nanotubes (MWNT) were functionalized by plasma polymerization to deliver vascular endothelial growth factor165 (VEGF165). The novel VEGF165-controlled released system was incorporated into porcine small intestinal submucosa (PSIS) to construct a composite scaffold. Scaffolds incorporating varying amounts of VEGF165-loaded functionalized MWNT were characterized in vitro. At 5 weight percent MWNT, the scaffolds exhibited optimal properties and were implanted in rats to repair abdominal wall defects. PSIS scaffolds incorporating VEGF165-loaded MWNT (VEGF–MWNT–PSIS) contributed to early vascularization from 2–12 weeks postimplantation and obtained more effective collagen deposition and exhibited improved tensile strength at 24 weeks postimplantation compared to PSIS or PSIS scaffolds, incorporating MWNT without VEGF165 loading (MWNT–PSIS).

Erastin Disrupts Mitochondrial Permeability Transition Pore (mPTP) and Induces Apoptotic Death of Colorectal Cancer Cells.

We here evaluated the potential anti-colorectal cancer activity by erastin, a voltage-dependent anion channel (VDAC)-binding compound. Our in vitro studies showed that erastin exerted potent cytotoxic effects against multiple human colorectal cancer cell lines, possibly via inducing oxidative stress and caspase-9 dependent cell apoptosis. Further, mitochondrial permeability transition pore (mPTP) opening was observed in erastin-treated cancer cells, which was evidenced by VDAC-1 and cyclophilin-D (Cyp-D) association, mitochondrial depolarization, and cytochrome C release. Caspase inhibitors, the ROS scavenger MnTBAP, and mPTP blockers (sanglifehrin A, cyclosporin A and bongkrekic acid), as well as shRNA-mediated knockdown of VDAC-1, all significantly attenuated erastin-induced cytotoxicity and apoptosis in colorectal cancer cells. On the other hand, over-expression of VDAC-1 augmented erastin-induced ROS production, mPTP opening, and colorectal cancer cell apoptosis. In vivo studies showed that intraperitoneal injection of erastin at well-tolerated doses dramatically inhibited HT-29 xenograft growth in severe combined immunodeficient (SCID) mice. Together, these results demonstrate that erastin is cytotoxic and pro-apoptotic to colorectal cancer cells. Erastin may be further investigated as a novel anti-colorectal cancer agent.

Repair of Abdominal Wall Defects In Vitro and In Vivo Using VEGF Sustained-Release Multi-Walled Carbon Nanotubes (MWNT) Composite Scaffolds

Objective Porcine acellular dermal matrices (ADM) have been widely used in experimental and clinical research for abdominal wall repair. Compared to porcine small intestinal submucosa (SIS), the effect of these matrices on the regenerative capacity of blood vessels is still not ideal. Multi-walled carbon nanotubes (MWNTs) can more effectively transport VEGF to cells or tissues because of their large specific surface area and interior cavity. In this study, we explored the safety and efficacy of implanted VEGF-loaded MWNT composite scaffolds in vitro and vivo to repair abdominal wall defects. Materials and Methods VEGF-loaded MWNTs were prepared by a modified plasma polymerization treatment. Four composite scaffolds were evaluated for cytotoxicity, proliferation, and release dynamics. We created 3 cm×4 cm abdominal wall defects in 43 Sprague-Dawley rats. After implantation times of 2, 4, 8, and 12 weeks, the scaffolds and the surrounding tissues were collected and examined by gross inspection, biomechanical testing, and histological examination. Results A 5–10 nm poly(lactic-co-glycolic acid) (PLGA) film was evenly distributed on MWNTs. The 3% MWNT composite group showed lower cytotoxicity and appropriate release performance, and it was thus tested in vivo. In rats with the 3% composite implanted, host cells were prevented from migrating to the ADM at 2 weeks, vascularization was established more rapidly at 12 weeks, and the values for both the maximum load and the elastic modulus were significantly lower than in the ADM-alone group (p<0.01). Histological staining revealed that the MWNT was still not completely eliminated 12 weeks after implantation. Conclusion MWNTs were able to carry VEGF to cells or tissues, and the 3% MWNT composite material showed lower cytotoxicity and had an appropriate release performance, which prompted faster vascularization of the ADM than other scaffolds. Nevertheless, the MWNTs induced harmful effects that should be carefully considered in biomedical studies.

Sulfatase 2 promotes breast cancer progression through regulating some tumor-related factors

In previous studies Sulf2 has been evidenced to play an important role in tumor progression through editing sulfate moieties on heparan sulfate proteoglycans (HSPGs) and modulating heparin binding growth factors. However, the role of Sulf2 in breast cancer progression is still poorly understood. In the present study, we hypothesized that Sulf2 promoted breast cancer progression. Two different breast cancer cell lines, MCF-7 and MDA-MB-231, were chosen for this study because of high and low Sulf2 expression levels. We also altered their Sulf2 expression by establishing Sulf2 knockdown and overexpressing breast cancer cell lines MCF-7 shSulf2 and MDA-MB-231 Sulf2. To evaluate the functions of Sulf2, cell proliferation, apoptosis, cell cycle, invasion, mobility and adhesion of these cell lines were measured in vitro, and xenograft formation, invasion and metastasis ability were examined in vivo. Furthermore, expression of related genes were screened and were certified in these cell lines. We found that Sulf2 increased breast cancer proliferation, invasion, mobility and adhesion both in vitro and in vivo. Sulf2 also decreased cisplatin inducing breast cancer apoptosis without affecting the cell cycle. Sulf2 upregulated c-fos induced growth factor (FIGF) and nuclear receptor subfamily 4 group A member 3 (NR4A3) expression and downregulated the cluster of differentiation 82 (CD82) and platelet-derived growth factor C (PDGFC) expression in breast cancer. Our data confirmed that Sulf2 promoted breast cancer progression and regulated the expression of tumor-related genes in breast cancer.

Comparison of Porcine Small Intestinal Submucosa versus Polypropylene in Open Inguinal Hernia Repair: A Systematic Review and Meta-Analysis

Background A systematic review and meta-analysis was performed in randomized controlled trials (RCTs) to compare porcine small intestinal submucosa (SIS) with polypropylene in open inguinal hernia repair. Method Electronic databases MEDLINE, Embase, and the Cochrane Library were used to compare patient outcomes for the two groups via meta-analysis. Result A total of 3 randomized controlled trials encompassing 200 patients were included in the meta-analysis. There was no significant difference in recurrence (P = 0.16), hematomas (P = 0.06), postoperative pain within 30 days (P = 0.45), or postoperative pain after 1 year (P = 0.12) between the 2 groups. The incidence of discomfort was significantly lower (P = 0.0006) in the SIS group. However, the SIS group experienced a significantly higher incidence of seroma (P = 0.03). Conclusions Compared to polypropylene, using SIS in open inguinal hernia repair is associated with a lower incidence of discomfort and a higher incidence of seroma. However, well-designed larger RCT studies with a longer follow-up period are needed to confirm these findings.

Small Activating RNA Restores the Activity of the Tumor Suppressor HIC-1 on Breast Cancer

HIC-1 is a gene that is hypermethylated in cancer, and commonly downregulated in human breast cancer. However, the precise mechanisms and molecular pathways regulated by HIC-1 remain unclear. We assessed HIC-1 expression on a tissue microarray containing 80 cases of breast cancer. We also analyzed its biological function by restoring HIC-1 expression using 5-aza-2′ deoxycytidine (5-CdR) and small-activating RNAs for the reversal of HIC-1 tumor suppressive effects on MCF-7 and MDA-MB-231 cell lines. An Agilent Q44h global expressing microarray was probed after restoring the expression of HIC-1. Data demonstrated that HIC-1 expression was reduced significantly in breast cancer tissues. HIC-1 immunohistochemistry resulted in mean staining scores in cancer tissue and normal ductal epithelia of 3.54 and 8.2, respectively (p<0.01). 5-CdR partially reversed HIC-1 expression, and modulated cell growth and apoptosis. dsHIC1-2998, an saRNA, showed activating efficacy in breast cancer cells. A group of differentially expressed genes were characterized by cDNA microarray. Upon saRNA treatment, genes upregulated included those involved in immune activation, cell cycle interference, the induction of apoptosis, anti-metastasis, and cell differentiation. Downregulated genes included oncogenes and those that play roles in cell invasion, cell growth, and cell division. Our findings may provide valuable resources not only for gene functional studies, but also for potential clinical applications to develop novel drug targets.

Reactivation of HIC‑1 gene by saRNA inhibits clonogenicity and invasiveness in breast cancer cells

Hypermethylated in cancer 1 (HIC-1) is a tumor suppressor gene, which is epigenetically silenced in breast cancer. It is known that the loss of HIC-1, caused by promoter hypermethylation, is associated with tumor aggression and poor survival in breast carcinoma. It has been shown that small activating RNA (saRNA) targeting promoter sequences may induce gene re-expression. In the current study, saRNA was used to restore HIC-1 expression, and the effects on colony formation, invasiveness and the cell cycle in breast cancer cells were explored. dsHIC1-2998, an saRNA, exhibited activating efficacy on MCF-7 and MDA-MB-231 cancer cell lines. A clonogenicity assay showed that evident colony inhibition was induced via saRNA-mediated re-expression of HIC-1 in the two cancer cell lines. Reactivation of HIC-1 significantly inhibited cell migration and invasion, resulting in G0/G1 cell cycle arrest in these cell lines. These findings suggest that HIC-1 may be a potential target in gene therapy for the treatment of breast cancer. saRNA may function as a therapeutic option for upregulating tumor suppressor genes in breast cancer.

Expressing Status and Correlation of ARID1A and Histone H2B on Breast Cancer

ARID1A is one of the important cancer-related genes and regulates transcription of certain genes by altering chromatin structure. Inactivated mutations and decreased expression of ARID1A gene have been reported in several kinds of cancer. Histone H2B is a major component of chromatin and encoded by HIST1H2BE. The goal of the study is to evaluate expressing status of ARID1A and H2B as well as their correlation on breast cancer. Gene expression profiles of ARID1A and H2B on Oncomine database are analyzed. Tissue microarray of breast cancer was used for examination of ARID1A and H2B expression by immunohistochemistry. As a result, the disagreement of ARID1A expression was found, while HIST1H2BE expression is elevated in 4 out of 5 datasets on Oncomine database. There were 15 cases (20%) of breast cancers that were positive for ARID1A. Fifty-eight out of 75 cases of breast cancer (77.3%) were highly expressed for H2B protein and 17 cases (22.7%) were low expressed for H2B protein. All cases with ARID1A expression are overlapped with H2B high expression. Among 15 cases with ARID1A and H2B coexpression, 13 are invasive ductal carcinoma and 2 are mucinous carcinoma. Our results indicate that ARID1A gene may be involved in carcinogenesis of some subtypes of breast cancer.