Therapeutic targeting of CBP/β-catenin signaling reduces cancer stem-like population and synergistically suppresses growth of EBV-positive nasopharyngeal carcinoma cells with cisplatin

Nasopharyngeal carcinoma (NPC) is an EBV-associated epithelial malignancy prevalent in southern China. Presence of treatment-resistant cancer stem cells (CSC) may associate with tumor relapse and metastasis in NPC. ICG-001 is a specific CBP/β-catenin antagonist that can block CBP/β-catenin-mediated transcription of stem cell associated genes and enhance p300/β-catenin-mediated transcription, thereby reducing the CSC-like population via forced differentiation. In this study, we aimed to evaluate the effect of ICG-001 on the CSC-like population, and the combination effect of ICG-001 with cisplatin in the C666-1 EBV-positive NPC cells. Results showed that ICG-001 inhibited C666-1 cell growth and reduced expression of CSC-associated proteins with altered expression of epithelial-mesenchymal transition (EMT) markers. ICG-001 also inhibited C666-1 tumor sphere formation, accompanied with reduced SOX2 hi /CD44 hi CSC-like population. ICG-001 was also found to restore the expression of a tumor suppressive microRNA-145 (miR-145). Ectopic expression of miR-145 effectively repressed SOX2 protein expression and inhibited tumor sphere formation. Combination of ICG-001 with cisplatin synergistically suppressed in vitro growth of C666-1 cells and significantly suppressed growth of NPC xenografts. These results suggested that therapeutically targeting of the CBP/β-catenin signaling pathway with ICG-001 can effectively reduce the CSC-like population and combination with cisplatin can effectively suppress the growth of NPC.link_to_OA_fulltex

Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe

Global variation in anastomosis and end colostomy formation following left-sided colorectal resection

Background End colostomy rates following colorectal resection vary across institutions in high-income settings, being influenced by patient, disease, surgeon and system factors. This study aimed to assess global variation in end colostomy rates after left-sided colorectal resection. Methods This study comprised an analysis of GlobalSurg-1 and -2 international, prospective, observational cohort studies (2014, 2016), including consecutive adult patients undergoing elective or emergency left-sided colorectal resection within discrete 2-week windows. Countries were grouped into high-, middle- and low-income tertiles according to the United Nations Human Development Index (HDI). Factors associated with colostomy formation versus primary anastomosis were explored using a multilevel, multivariable logistic regression model. Results In total, 1635 patients from 242 hospitals in 57 countries undergoing left-sided colorectal resection were included: 113 (6·9 per cent) from low-HDI, 254 (15·5 per cent) from middle-HDI and 1268 (77·6 per cent) from high-HDI countries. There was a higher proportion of patients with perforated disease (57·5, 40·9 and 35·4 per cent; P < 0·001) and subsequent use of end colostomy (52·2, 24·8 and 18·9 per cent; P < 0·001) in low- compared with middle- and high-HDI settings. The association with colostomy use in low-HDI settings persisted (odds ratio (OR) 3·20, 95 per cent c.i. 1·35 to 7·57; P = 0·008) after risk adjustment for malignant disease (OR 2·34, 1·65 to 3·32; P < 0·001), emergency surgery (OR 4·08, 2·73 to 6·10; P < 0·001), time to operation at least 48 h (OR 1·99, 1·28 to 3·09; P = 0·002) and disease perforation (OR 4·00, 2·81 to 5·69; P < 0·001). Conclusion Global differences existed in the proportion of patients receiving end stomas after left-sided colorectal resection based on income, which went beyond case mix alone

Acid dulls the senses: impaired locomotion and foraging performance in a marine mollusc

Abstract not availableJonathan Y. S. Leung, Bayden D. Russell, Sean D. Connell, Jenny C. Y. Ng, Mavis M. Y. L

On the spatial behaviors of local mass transfer coefficients over idealized two-dimensional urban street canyons

ASI 1: Urban Climate for Human Comfort, 5-6 Dec 2011 ; ASI 2: Urban Climate and Air Pollution, 7-8 Dec 2011 ; ASI 3: Climate Change and Urban Design , 9-10 Dec 201

Claudin-10 enhanced metastatic potential in hepatocellular carcinoma with MMP activation and modified expression profile of other claudin family members

Background: Claudins, a group of integral membrane proteins, are important components of tight junctions. Increasing evidence shows that claudins are differentially regulated in a variety of malignancies and involved in cancer progression. Previously, we demonstrated that downregulation of CLDN-10 in hepatocellular carcinoma (HCC) is associated with prolonged disease-free survival after curative surgery. The biological function of CLDN-10 in carcinogenesis is lacking. The aim of the current study is to evaluate the biological function of CLDN-10 in HCC by functional assays. Material and Methods: CLDN-10 was overexpressed in Hep3B, an HCC cell line with low invasive ability and siRNA-mediated knockdown of CLDN- 10 was performed in a highly invasive HCC cell line, HLE. The effect on invasion, migration, proliferation and survival was then investigated by in vitro function assays. MMP levels were evaluated by gelatin zymography. Expressions of MT1-MMP and claudin family members were examined by semi-quantitative RT-PCR and Western blotting. Results: Functional studies demonstrated that increased expression of CLDN-10 enhanced the metastatic potential of HCC by promoting cancer cell survival, motility and invasiveness. More importantly, in the CLDN- 10 transfectants, there was increase in mRNA transcription and protein expression of MT1-MMP, a protease shown to promote intrahepatic metastasis in HCC in our earlier study. In addition, CLDN-1, -2 and -4 was up-regulated in CLDN-10 overexpression transfectants, indicating that the expression of claudin family members in cancer cells might affect each other. On the contrary, CLDN-10 siRNA strongly inhibited invasion, MMP2 and MT1-MMP expression. These findings highlighted that CLDN- 10 promotes metastatic potential in HCC by enhancing invasion through up-regulation of MT1-MMP and MMP2 expression. Conclusion: CLDN-10 is important for MMP activation, HCC invasion and migration. It also modifies the claudin family expression profile. These findings underline the contributions of CLDN-10 in HCC progression.link_to_OA_fulltex