Small interfering RNA silencing of interleukin-6 in mesenchymal stromal cells inhibits multiple myeloma cell growth

Studies demonstrated that mesenchymal stromal cells (MSC) from bone marrow stroma produced high concentration of interleukin-6 (IL-6) that promoted multiple myeloma cell growth. In view of the failure of IL-6 monoclonal antibody therapy to demonstrate substantial clinical responses in early clinical trials, more effective methods are needed in order to disrupt the favourable microenvironment provided by the bone marrow stroma. In this study, we evaluated the short interfering RNA (siRNA)-mediated silencing of IL-6 in MSC and the efficacy of these genetically modified MSC, with IL-6 suppression, on inhibition of U266 multiple myeloma cell growth. IL-6 mRNA and protein were significantly suppressed by 72 h post IL-6 siRNA transfection without affecting the biological properties of MSC. Here we show significant inhibition of cell growth and IL-6 production in U266 cells co-cultured with MSC transfected with IL-6 siRNA when compared to U266 cells co-cultured with control MSC. We also show that the tumour volume and mitotic index of tumours in nude mice co-injected with U266 and MSC transfected with IL-6 siRNA were significantly reduced compared to tumours of mice co-injected with control MSC. Our results suggest potential use of RNA interference mediated therapy for multiple myeloma

Synthesis and antitrypanosomal activities of novel pyridylchalcones

Collaboration with the London School of Hygiene and Tropical Medicine. The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.A library of novel pyridylchalcones were synthesised and screened against Trypanosoma brucei rhodesiense. Eight were shown to have good activity with the most potent 8 having an IC50 value of 0.29 M. Cytotoxicity testing with human KB cells showed a good selectivity profile for this compound with a selectivity index of 47. Little activity was seen when the library was tested against Leishmania donovani. In conclusion, pyridylchalcones are promising leads in the development of novel compounds for the treatment of human African trypanosomiasis (HAT)

An Evaluation of the Performance of Five Burnout Screening Tools: A Multicentre Study in Anaesthesiology, Intensive Care, and Ancillary Staff.

Burnout is an important occupational hazard and early detection is paramount in preventing negative sequelae in physicians, patients, and healthcare systems. Several screening tools have been developed to replace lengthy diagnostic tools for large-scale screening, however, comprehensive head-to-head evaluation for performance and accuracy are lacking. The primary objective of this study was to compare the diagnostic performance of five burnout screening tools, including a novel rapid burnout screening tool (RBST). This was a cross-sectional study involving 493 hospital staff (anaesthesiology and intensive care doctors, nurses, and ancillary staff) at the COVID-19 frontline across four hospitals in Singapore between December 2020 and April 2021. The Maslach Burnout Inventory-Human Services Survey (MBI-HSS) was used as the reference standard. Five burnout screening tools, the single-item MBI measure of burnout (SI-MBI), dual-item MBI (DI-MBI), abbreviated MBI (aMBI), Single Item Burnout Question (SIBOQ), and the RBST, were administered via a 36-item online survey. Tools were administered simultaneously and responses were anonymised. Burnout prevalence was 19.9%. The RBST and the SI-MBI had the two highest accuracies (87.8% and 81.9% respectively) and AUROC scores (0.86, 95% CI: 0.83-0.89 and 0.86, 95% CI: 0.82-0.89 respectively). However, the accuracy of the RBST was significantly higher than the SI-MBI (p < 0.0001), and it had the highest positive likelihood ratio (+LR = 7.59, 95% CI 5.65-10.21). Brief screening tools detect burnout albeit with a wide range of accuracy. This can strain support services and resources. The RBST is a free screening tool that can detect burnout with a high degree of accuracy

The synthesis of chalcones as anticancer prodrugs and their bioactivation in CYP1 expressing breast cancer cells

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI linkAbstract: Background: Although the expression levels of many P450s differ between tumour and corresponding normal tissue, CYP1B1 is one of the few CYP subfamilies which is significantly and consistently overexpressed in tumours. CYP1B1 has been shown to be active within tumours and is capable of metabolising a structurally diverse range of anticancer drugs. Because of this, and its role in the activation of procarcinogens, CYP1B1 is seen as an important target for anticancer drug development. Objectives: To synthesise a series of chalcone derivatives based on the chemopreventative agent DMU-135 and investigate their antiproliferative activities in human breast cancer cell lines which express CYP1B1 and CYP1A1. Method: A series of chalcones were synthesised in yields of 43-94% using the Claisen-Schmidt condensation reaction. These were screened using a MTT assay against a panel of breast cancer cell lines which have been characterised for CYP1 expression. Results: A number of derivatives showed promising antiproliferative activities in human breast cancer cell lines which express CYP1B1 and CYP1A1, while showing significantly lower toxicity towards a non-tumour breast cell line with no CYP expression. Experiments using the CYP1 inhibitors acacetin and -naphthoflavone provided supporting evidence for the involvement of CYP1 enzymes in the bioactivation of these compounds. Conclusions: Chalcones show promise as anticancer agents with evidence suggesting that CYP1 activation of these compounds may be involved

2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: executive summary.

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withdrawn 2017 hrs ehra ecas aphrs solaece expert consensus statement on catheter and surgical ablation of atrial fibrillation

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2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: executive summary.

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Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

The effects of stock market and interest rates on credit default swaps.

In this paper, we studied the effects of stock market and interest rates on credit default swaps (CDS), taking time series effect into consideration. Results showed substantial evidence that time series effect was distorting to our study. Without regarding time series effect, there were no consistent correlations amongst CDS and equity indices. On the contrary, with time series effect accounted for, there appeared a possible structural relationship amongst CDS and equity indices. On the explanatory power aspects, without regarding time series effect, the equity indices had lower explanatory power than T-bill rates on the CDS spreads. With time series effect accounted for, the explanatory power order was reversed. Lastly, we found that CDS indices categorized themselves into asset backed and non-asset backed based on their relation to different equity indices. However, with the time series effect accounted for, the CDS indices categorized themselves into U.S. market based and non U.S. market based instead.BUSINES