HSMVS: heuristic search for minimum vertex separator on massive graphs.

In graph theory, the problem of finding minimum vertex separator (MVS) is a classic NP-hard problem, and it plays a key role in a number of important applications in practice. The real-world massive graphs are of very large size, which calls for effective approximate methods, especially heuristic search algorithms. In this article, we present a simple yet effective heuristic search algorithm dubbed HSMVS for solving MVS on real-world massive graphs. Our HSMVS algorithm is developed on the basis of an efficient construction procedure and a simple yet effective vertex-selection heuristic. Experimental results on a large number of real-world massive graphs present that HSMVS is able to find much smaller vertex separators than three effective heuristic search algorithms, indicating the effectiveness of HSMVS. Further empirical analyses confirm the effectiveness of the underlying components in our proposed algorithm.

Application of a second opinion ultrasound in Breast Imaging Reporting and Data System 4A cases: can immediate biopsy be avoided?

OBJECTIVE: The probability of malignancy in women who are diagnosed with a Breast Imaging Reporting and Data System (BI-RADS) 4A score is low. Application of a second opinion ultrasound (SOUS), which is low in cost and minimally invasive, may lower the biopsy rate for patients who fall into this category. This study aimed to apply SOUS to patients with a BI-RADS score of 4A and predict the pathological results of a biopsy. METHODS: One hundred seventy-eight patients were analyzed. Univariate and multivariate analyses were performed to screen for predictive factors that are associated with malignancy. Categorical alteration of downgraded, unchanged, or upgraded was made after SOUS results. Changes in category were compared with biopsies to determine their predictive value of benignancy or malignancy. RESULTS: Independent factors associated with malignancy were age (>50 years), tumor size (≥20 mm), margin (not circumscribed), orientation (not parallel), and peripheral location, and an upgraded categorical alteration from SOUS. Downgraded categorical alterations were associated with benignancy. CONCLUSIONS: In BI-RADS 4A cases, a biopsy is recommended when independent factors are associated with malignancy. A downgraded result from an SOUS examination is a protective factor, supporting the likelihood of benignancy in these patients.

Effect of 3D printed polycaprolactone scaffold with a bionic structure on the early stage of fat grafting.

Mature adipocytes are sensitive to stress and hypoxia, which are the two major obstacles in large-volume fat grafting. Bionic scaffolds are considered beneficial for fat grafting; however, their mechanism is still unclear. In this study, polycaprolactone scaffolds were fabricated by a 3D-printing technique and compounded with liposuction fat. They were implanted subcutaneously into nude mice. At different times, gross and histological observations were performed to evaluate the retention rates and histological morphologies. Adipocyte viability, apoptosis, and vascularization were analyzed by special immunostaining. Quantitative polymerase chain reaction was used to detect the variations in hypoxia and inflammation. The results showed that the volume and weight retentions in the scaffold group were higher than those in the fat group with the former exhibiting fewer vacuoles and less fibrosis. In immunostaining, elevated CD31+ capillaries, more perilipin+ adipocytes, and fewer TUNEL+ apoptotic cells were observed in the scaffold group by week 4. The lower expression of HIF-1α indicated the alleviation of hypoxia. In conclusion, the scaffold provided mechanical support to resist skin tension, thereby decreasing the interstitial pressure, and improving substance exchange and vascular ingrowth. In this regard, the scaffold attenuated hypoxia and promoted vascularization, making it a feasible method to increase long-term retention in fat grafting using scaffolds with suitable degradation rates and additional vascular maturation stimulation.

Multiple synchronous anorectal melanomas with different colors: A case report.

BACKGROUND: Anorectal melanoma (AM) is an extremely rare malignant tumor originating from anorectal melanocytes with a poor prognosis. AM has been reported to have a much lower incidence than cutaneous or choroid melanoma, accounting for 0.4%-1.6% of all melanomas. CASE SUMMARY: We report a 76-year-old female patient diagnosed with anorectal malignant melanoma by colonoscopy and biopsy. Intraoperative examination revealed two distinct anorectal tumors, one melanotic and another amelanotic, as well as two pigmented mucosal zones at the dentate line level. Abdominal perineal resection was performed. A pathological report confirmed all four lesions to be melanomas. Postoperatively, we followed an immunotherapy protocol targeting PD-1 (nivolumab). The patient had 24 mo of disease-free follow-up upon completion of nivolumab treatment. CONCLUSION: This is the first reported case presenting coexistence of pigmented and unpigmented AMs in the same patient.

Deguelin exerts anticancer activity of human gastric cancer MGC-803 and MKN-45 cells in vitro.

During the pathogenesis of gastric cancer, Akt signaling is considered as a pivotal inducer of gastric cancer development. Here we report the identification of anticancer activities of deguelin, a natural agent that inhibits Akt signaling. When applied to MGC-803 and MKN-45 cells, deguelin suppressed the proliferation and arrested cell cycle by p21-mediated inhibition of cyclin E. We further present in vitro evidence that deguelin promoted apoptosis of cancer cells by decreasing the phospho-Akt signaling and affecting expression of the apoptosis-associated genes Bax and Bcl-2. Additionally, deguelin was found to suppress the migration and invasion of gastric cancer cells. Taken together, these results indicated that deguelin exerted anticancer activity of human gastric cancer MGC-803 and MKN-45 cells in vitro.

Inhibition effects of total flavonoids from Sculellaria barbata D. Don on human breast carcinoma bone metastasis via downregulating PTHrP pathway.

It is abundantly clear that tumor-derived parathyroid hormone-related protein (PTHrP), receptor activator of nuclear factor-κB ligand (RANKL) and osteoprotegerin (OPG) are central contributors in promoting osteolytic process of breast carcinoma bone metastasis. Forcusing on this molecular basis, the study was undertaken to explore the inhibition effects of total flavonoids from Scutellaria barbata D. Don (TF-SB) on human breast carcinoma bone metastasis. MDA-MB-231 cells and nude mouse models of breast cancer bone metastasis were given TF-SB in different concentrations. The proliferation, migration and invasion potentials of MDA-MB-231 cells were respectively tested. The effects of TF-SB on tumor weights and bone destruction were investigated. The mRNA and protein expression of PTHrP, OPG and RANKL were assessed by qPCR and western blot analysis. In vitro, TF-SB inhibited the proliferation, migration and invasion of MDA-MB-231 cells in a dose-dependent manner. In vivo, TF-SB prevented bone metastasis of breast cancer by decreasing the number of osteoclast cells per field in a dose-dependent manner, but not affecting tumor growth or mouse survival. Molecular analysis revealed that TF-SB controled the secretion of osteolysis-related factors PTHrP and its downstream RANKL/OPG. Together, by controlling the expression of PTHrP and its downstream OPG/RANKL, TF-SB has significant inhibition effects on breast cancer bone metastasis, which indicates a new therapeutic method.

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.

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.

Interfering with CXCR4 expression inhibits proliferation, adhesion and migration of breast cancer MDA-MB-231 cells.

To investigate the effect and mechanism of the CXC chemokine receptor 4 (CXCR4) in the proliferation and migration of breast cancer, a short-hairpin RNA (shRNA) eukaryotic expression vector targeting CXCR4 was constructed, and the impact of such on the proliferation, adhesion and migration of human breast cancer MDA-MB-231 cells was observed. The fragments of CXCR4-shRNA were synthesized and cloned into a pGCsi-U6-Neo-green fluorescent protein vector. The recombinant plasmids were transfected into 293T cells and the most efficacious interfering vector was selected. MDA-MB-231 cells were transfected by liposome assay. The effects of silencing CXCR4 expression by shRNA on the growth, adhesion and migration of MDA-MB-231 cells were determined by Cell Counting Kit-8, cell-matrix adhesion and wound-healing assays. The shRNA eukaryotic expression vectors targeting CXCR4 (CXCR4-shRNA) were successfully constructed and transfected into 293T cells. Quantitative polymerase chain reaction and western blot analysis revealed that the maximum inhibitory rate of CXCR4 expression was 81.3%. CXCR4-shRNA transfection significantly inhibited the proliferation of MDA-MB-231 cells (P<0.05), as well as the adhesion between MDA-MB-231 cells and the extracellular matrix (P<0.05). Furthermore, wound-healing assays demonstrated that the migration distance of MDA-MB-231 cells in the CXCR4-shRNA transfection group was significantly smaller than that in the control plasmid and blank control groups (P<0.01). The CXCR4-shRNA interfering vector specifically inhibited CXCR4 expression, as well as the proliferation, adhesion and migration of MDA-MB-231 cells.

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.

A meta-analysis examining the use of fibrin glue mesh fixation versus suture mesh fixation in open inguinal hernia repair.

BACKGROUND: The aim of this study was to systematically analyze the randomized trials comparing fibrin glue mesh fixation with suture mesh fixation in open inguinal hernia repair. METHODS: Information was collected from a literature search using PubMed, Springer, Cochrane Library database and reference lists. The methodological quality of included publications was evaluated. Statistical analysis was performed using Review Manager Version 5.2.5 software. RESULTS: Nine articles were identified for inclusion: four randomized controlled trials (RCTs) and five prospective observational clinical studies. All the trials were considered to be of fair quality. The results showed that there was a lower incidence of chronic pain (RR 0.42, 95% CI 0.22-0.79, I(2) 11%; p < 0.01), and hematoma/seroma (RR 0.43, 95% CI 0.21-0.87, I(2) 0%; p < 0.05) in the fibrin glue mesh fixation group. However, the results of meta-analysis revealed that the incidence of recurrence or urinary problems between the two procedures were similar. CONCLUSIONS: During the 6-15 months follow-up, fibrin glue mesh fixation is a feasible alternative for mesh fixation with sutures in open inguinal hernia repair. However, the poor quality of the included trials limits the evidence; rigorously designed trials are warranted to confirm this conclusion.

Evaluation of the Wound Healing Potential of Resina Draconis (Dracaena cochinchinensis) in Animal Models.

Resina Draconis (RD) is a type of dragon's blood resin obtained from Dracaena cochinchinensis (Lour.) S.C. Chen (Yunnan, China). It has been used as a medicine since ancient times by many cultures. The ethanolic extract of Resina Draconis (RDEE) was evaluated for its wound-healing activity using excision and incision wound models in rats. Group I, the control group, was treated with ointment base. Group II, which served as a reference standard, was treated with moist exposed burn ointment (MEBO). Group III was treated with RDEE. The parameters observed were percentage of wound contraction, epithelialization period, tensile strength, histopathological studies, microvessel density (MVD), and the expression of vascular endothelial growth factor (VEGF) and transforming growth factor- ß 1 (TGF- ß 1). The group treated with RDEE showed significantly better wound contraction and better skin-breaking strength as compared with the control group. The results of histopathological examination, MVD, and the expression levels of growth factors supported the outcome of the wound models as well. The present study provided a scientific rationale for the traditional use of RD in the management of wounds.

AMP-activated protein kinase (AMPK)/Ulk1-dependent autophagic pathway contributes to C6 ceramide-induced cytotoxic effects in cultured colorectal cancer HT-29 cells.

Colorectal cancer is the second leading cause of cancer-related deaths. Drug resistance and/or off-target toxicity against normal cells limit the effectiveness of current chemotherapies for the treatment of colorectal cancer. In the current study, we studied the potential cytotoxic effects of short-chain and cell-permeable C6 ceramide in cultured colorectal cancer HT-29 cells and focused on the underlying mechanisms. We observed that C6 ceramide-induced HT-29 cell death and growth inhibition in a dose- and time-dependent manner. However, no significant apoptosis was observed in C6 ceramide-treated HT-29 cells. Our data support that autophagy contributed to C6 ceramide-induced cytotoxic effects, as autophagy inhibitors, 3-methyladenine (3-MA) and hydroxychloroquine, inhibited C6 ceramide's effect; however, autophagy activators, everolimus (RAD001) and temsirolimus, mimicked C6 ceramide effects and induced HT-29 cell death. Further, we indentified that AMP-activated protein kinase (AMPK)/Ulk1 signaling was required for autophagy induction by C6 ceramide, and AMPK silencing by a specific short hairpin RNA suppressed C6 ceramide-induced autophagy and cytotoxic effects. Reversely, forced activation of AMPK by its activator AICAR or by genetic manipulation caused autophagic death in HT-29 cells, which was inhibited by 3-MA. Our results suggest that autophagy, but not apoptosis, is a major contributor for C6 ceramide-induced cytotoxic effects in HT-29 cells, and activation of AMPK/Ulk1 is required for the process.

RNAi silencing of the MEKK3 gene promotes TRAIL-induced apoptosis in MCF-7 cells and suppresses the transcriptional activity of NF-κB.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family of cytokines, which can induce apoptotic cell death in a variety of tumor cells or transformed cells, yet, it is relatively non-toxic to most normal cells. Consequently, TRAIL was thought to be a promising agent for cancer therapy. However, recent research reports revealed that many tumors are unresponsive to TRAIL treatment. Apoptotic agents were identified that when used in combination with TRAIL can sensitize tumor cells to TRAIL-mediated apoptosis. It was demonstrated that MEKK3-siRNA sensitized MCF-7 cells to TRAIL cytoxicity. In addition, we investigated the discrepancy of the expression of MEKK3 in breast cancers. It was concluded that elevated MEKK3 expression is found at high frequencies in breast cancer compared to normal breast tissue. Further experiments on the signal machinery showed that MEKK3-siRNA increased the sensitivity of MCF-7 cells to TRAIL by suppressing the transcription activity of NF-κB, and enhancing the caspase-processing to generate executive apoptotic signals. These findings indicate that down-regulation of MEKK3 by siRNA approaches will lead to successful treatment of human breast cancer with TRAIL.

Lymphangiogenesis induced by VEGF-C and VEGF-D promotes metastasis and a poor outcome in breast carcinoma: a retrospective study of 61 cases.

PURPOSE: To evaluate lymphangiogenesis in patients with breast carcinoma, explore the underlying mechanism, and study the relationship between lymphangiogenesis and progression of breast carcinoma. METHODS: Sixty-one cases of breast carcinoma with complete clinical and pathological data were analyzed. Using an anti-podoplanin monoclonal antibody, an immunohistochemical study was made of all specimens to detect lymphatic vessel density (LVD) and to investigate its clinicopathological and prognostic value. VEGF-C and VEGF-D were observed by RT-PCR and immunostaining to investigate their clinicopathological and prognostic values and their relationship with lymphangiogenesis. RESULTS: LVD in breast carcinoma (6.28+/-3.73) was significantly higher than in benign mammary lesions (0.50+/-1.27), P<0.01 and was significantly associated with lymphatic metastasis and high TNM stage, P<0.01. The level of VEGF-C and VEGF-D expression was also significantly higher in breast carcinomas than in benign mammary lesions, P<0.01. LVD increased significantly with higher expression of VEGF-C and VEGF-D, P<0.01. Patients with high expression of VEGF-C and VEGF-D were observed to be more likely to have a bad outcome, P<0.05. CONCLUSIONS: Lymphangiogenesis was significantly associated with lymph node metastasis, high TNM, and poor outcome in breast carcinoma. LVD may serve as a predictor of lymph node metastasis and a prognostic factor in breast carcinoma. VEGF-C and VEGF-D play an important role in lymphangiogenesis making the carcinoma more aggressive and leading to a poor prognosis.

TK gene combined with mIL-2 and mGM-CSF genes in treatment of gastric cancer.

AIM: Cancer gene therapy has received more and more attentions in the recent decade. Various systems of gene therapy for cancer have been developed. One of the most promising choices is the suicide gene. The product of thymidine kinase (TK) gene can convert ganciclovir (GCV) to phosphorylated GCV, which inhibits the synthesis of cell DNA, and then induces the cells to death. Cytokines play an important role in anti-tumor immunity. This experiment was designed to combine the TK gene and mIL-2/mGM-CSF genes to treat gastric cancer, and was expected to produce a marked anti-tumor effect. METHODS: TK gene was constructed into the retroviral vector pLxSN, and the mIL-2 and mGM-CSF genes were inserted into the eukaryotic expressing vector pIRES. The gastric cancer cells were transfected by retroviral serum that was harvested from the package cells. In vitro study, the transfected gastric cancer cells were maintained in the GCV- contained medium, to assay the cell killing effect and bystander effect. In vivo experiment, retroviral serum and cytokines plasmid were transfected into tumor-bearing mice, to observe the changes of tumor volumes and survival of the mice. RESULTS: In vitro experiment, 20 % TK gene transduced cells could cause 70-80 % of total cells to death. In vivo results showed that there was no treatment effect in control group and TK/GCV could inhibit the tumor growth. The strongest anti-tumor effect was shown in TK+mIL-2+mGM-CSF group. The pathologic examination showed necrosis of the cancer in the treated groups. CONCLUSION: TK/GCV can kill tumor cells and inhibit the tumor growth in vivo. IL-2 and GM-CSF strongly enhance the anti-tumor effect. Through the retrovirus and liposome methods, the suicide gene and cytokine genes are all expressed in the tissues.