Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Targeted disruption of exchange protein directly activated by cAMP 1 in mice leads to altered glucose homeostasis

published_or_final_versionAnatomyMasterMaster of Philosoph

Roles of hypoxia-inducible microRNA-210 in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most prevalent human malignancy and the third leading cause of cancer deaths in the world. MicroRNAs (miRNA) are conserved, small noncoding RNA molecules that regulate gene expression of protein-coding gene posttranscriptionally. Dysregulation of miRNA is implicated in many human malignancies including HCC, yet little is known regarding the regulatory mechanisms of these small noncoding RNAs. Hypoxia is a prevalent! tumor microenvironment in HCC because of its rapid growth often to large size and plays a key role in modulating tumor aggressiveness. In the present study, we investigated the effects of hypoxia on microRNA expression in human HCCs, identified and characterized hypoxia-inducible microRNAs that are important for the development of aggressive phenotypes. To initialize the study, we examined the miRNA expression profiles with TaqMan human microRNA Low-Density Array and identified a panel of microRNAs differentially expressed in HCC cells under hypoxic conditions. We observed that miR-210 was consistently upregulated by hypoxia in a total of 7 different HCC cell lines, via a HIF1α-dependent mechanism. In human HCCs, miRL210 overexpression significantly correlated with poorer overall and disease-free survival of patients, as well as aggressive pathologic features, including advanced tumor stages of HCC and the presence of venous invasion. These findings established miRL210 as a surrogate marker of aggressive HCC with high metastatic potential. In most human malignancies, cancer metastasis contributes to about 90% of cancer-related mortality. Given the correlation of miR-210 levels with poorer patient survival and aggressive clinical features of HCC, we then characterized the metastatic role of miRL210 by functional assays in the second part of the study. The findings from in vitro and in vivo experiments using both gain- and loss-of-function approaches led us to conclude that the hypoxic induction of miRL210 enhanced metastatic potential of HCC cells. The pro-metastatic effect of miRL210 was attributed, at least partly, to the downregulation of TIMP2 by hypoxia, through a feedback loop circuit consisting of HIF1α, miRL210, and HIF3α. The impact of miR-210 on HCC metastasis was not the only scope of this study since hypoxia has long been recognized as a major obstacle in chemotherapy. Given that activation of the HIF1α-miR-210 axis was frequently observed in hypoxic HCC cells, in the last part of the study we also investigated whether hypoxic induction of miRL210 promoted cell survival against cytotoxic treatments, including cisplatin and 5-flurouracil. Here, we demonstrated that induction of HIF1α-miR-210 axis conferred chemoresistance to HCC cells under hypoxic conditions, and inhibition of miR-210 re-sensitized HCC cells to these cytotoxic drugs. Mechanistically, we also revealed that RAD52 was a direct functional target of miRL210 that linked hypoxia to chemoresistance in HCC cells. The overall findings of this study have enriched our understanding of miR-210 as a mediator of hypoxic responses in HCC, in particular metastasis and chemoresistance. We have highlighted the clinical significance of this microRNA by showing that miR-210 can serve not only as a prognostic marker for HCC progression, but also as a mediator for the hypoxic tumor microenvironment to modulate tumor aggressiveness.published_or_final_versionPathologyDoctoralDoctor of Philosoph

TCGA whole-transcriptome sequencing data reveals significantly dysregulated genes and signaling pathways in hepatocellular carcinoma

© 2015, Higher Education Press and Springer-Verlag Berlin Heidelberg. This study systematically evaluates the TCGA whole-transcriptome sequencing data of hepatocellular carcinoma (HCC) by comparing the global gene expression profiles between tumors and their corresponding nontumorous liver tissue. Based on the differential gene expression analysis, we identified a number of novel dysregulated genes, in addition to those previously reported. Top-listing upregulated (CENPF and FOXM1) and downregulated (CLEC4G, CRHBP, and CLEC1B) genes were successfully validated using qPCR on our cohort of 65 pairs of human HCCs. Further examination for the mechanistic overview by subjecting significantly upregulated and downregulated genes to gene set enrichment analysis showed that different cellular pathways were involved. This study provides useful information on the transcriptomic landscape and molecular mechanism of hepatocarcinogenesis for development of new biomarkers and further in-depth characterization.Link_to_subscribed_fulltex

Down-regulation of TIMP2 by HIF-1α/miR-210/HIF-3α regulatory feedback circuit enhances cancer metastasis in hepatocellular carcinoma

© 2016 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases. Cancer metastasis is a multistep process that involves a series of tumor-stromal interaction, including extracellular matrix (ECM) remodeling, which requires a concerted action of multiple proteolytic enzymes and their endogenous inhibitors. This study investigated the role of tissue inhibitor of metalloproteinases (TIMP) 2 in the context of hepatocellular carcinoma (HCC) metastasis. We found that TIMP2 was the most significantly down-regulated member among the TIMP family in human HCCs. Moreover, TIMP2 underexpression was frequent (41.8%; 23 of 55) in human HCCs and was significantly associated with liver invasion and poorer survival outcomes of HCC patients. Furthermore, stable silencing of TIMP2 in HCC cell lines enhanced cell invasive ability and ECM degradation associated with formation of invadopodia-like feature, suggesting that TIMP2 is a negative regulator of HCC metastasis. Using an orthotopic tumor xenograft model, we demonstrated that e ctopic expression of TIMP2 open reading frame in the highly metastatic HCC cell line, MHCC-97L, significantly reduced HCC progression as well as pulmonary metastasis. Mechanistically, TIMP2 suppression, in a hypoxic environment, was induced through a regulatory feedback circuit consisting of hypoxia-inducible factor (HIF) 1 alpha, microRNA-210 (miR-210), and HIF-3α. Conclusion: TIMP2 is frequently down-regulated in human HCCs and its down-regulation is associated with aggressive tumor behavior and poorer patient outcome. Its suppression is under the regulation of a novel feedback circuit consisting of HIF-1α/miR-210/HIF-3α. TIMP2 is an important regulator of ECM degradation and HCC metastasis. (Hepatology 2016;64:473-487).Link_to_subscribed_fulltex

Development and validation of risk prediction models for COVID-19 positivity in a hospital setting

ObjectivesTo develop: (1) two validated risk prediction models for coronavirus disease-2019 (COVID-19) positivity using readily available parameters in a general hospital setting; (2) nomograms and probabilities to allow clinical utilisation.MethodsPatients with and without COVID-19 were included from 4 Hong Kong hospitals. The database was randomly split into 2:1: for model development database (n = 895) and validation database (n = 435). Multivariable logistic regression was utilised for model creation and validated with the Hosmer-Lemeshow (H-L) test and calibration plot. Nomograms and probabilities set at 0.1, 0.2, 0.4 and 0.6 were calculated to determine sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV).ResultsA total of 1330 patients (mean age 58.2 ± 24.5 years; 50.7% males; 296 COVID-19 positive) were recruited. The first prediction model developed had age, total white blood cell count, chest x-ray appearances and contact history as significant predictors (AUC = 0.911 [CI = 0.880-0.941]). The second model developed has the same variables except contact history (AUC = 0.880 [CI = 0.844-0.916]). Both were externally validated on the H-L test (p = 0.781 and 0.155, respectively) and calibration plot. Models were converted to nomograms. Lower probabilities give higher sensitivity and NPV; higher probabilities give higher specificity and PPV.ConclusionTwo simple-to-use validated nomograms were developed with excellent AUCs based on readily available parameters and can be considered for clinical utilisation

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field