Characterization of Cucurbitacin-Inspired Estrone Analogues as Novel Inhibitors of Human ATP- Binding Cassette Proteins (ABCB1 and ABCC1)

ATP-binding cassette (ABC) transporters are a large class of integral membrane proteins that contribute to key physiological functions in all organisms by utilizing ATP binding and hydrolysis to transport diverse substrates across membrane barriers. P-glycoprotein (P-gp/ ABCB1) and Multidrug Resistance protein 1 (MRP1/ABCC1) are widely reported ABC transporters associated with multidrug resistance in cancer. Multidrug resistance (MDR) mediated by P-gp and MRP1 is responsible for treatment failures of many metastatic cancers as a result of reduced accumulation, bioavailability and diminished potency of anticancer drugs. Currently, known P-gp and MRP1 inhibitors are limited due to toxicity, lack of selectivity and low therapeutic benefit which necessitates the investigation of novel compounds with improved potency and specificity. In this study, we investigated the inhibition potential of newly synthesized cucurbitacin-inspired estrone analogs (CIEAs) on P-gp and MRP1 mediated MDR. Utilizing a high content fluorescence-based transport activity assay initially developed in our lab, a library of 81 CIEAs were screened to identify inhibitors for P-gp and MRP1 proteins. The screening assay identified eight P-gp inhibitors using calcein-AM as a fluorescent reporter. A total of six MRP1 inhibitors were identified using doxorubicin and calcein red orange as fluorescent reporters. The inhibitory effect of the identified compounds on P-gp and MRP1 activity were confirmed using established cell-based functional assays. The identified inhibitors significantly increased the accumulation of P-gp substrate, calcein-AM and MRP1 substrates, doxorubicin and calcein red orange. Interestingly, the identified inhibitors demonstrated selective sensitization of P-gp and MRP1 overexpressing cancer cell lines towards different anticancer drugs. On the other hand, the identified inhibitors did not alter protein levels of both P-gp and MRP1. Furthermore, our in silico and FRET-based spectroscopic studies showed that the inhibitor compounds directly interact with P-gp and MRP1 proteins. Together, our findings demonstrated that CIEAs are promising drug candidates for further development into therapeutic agents against P-gp and MRP1-mediated multidrug resistance in cancer

The law applicable to liability arising from the use of selfdriving cars in the wake of the Fourth Industrial Revolution : a global comparative analysis

Abstract: This study explores the liability associated with the use of autonomous vehicles. With the increase in efforts by automobile industries to manufacture driverless cars, the issue of liability occupies the front seat of the discussion. A major benefit of autonomous and connected vehicles is their potential to ameliorate, if not eradicate, avoidable accidents on roads. Currently, it is estimated that 90% of road accidents are caused by human error. The epoch of driverless vehicles, where the narrative will drastically change, is upon us. This means a shift away from human liability to machine liability, since these technologies have in-built algorithms to ensure autonomous decisions by the vehicle. Product liability becomes crucial in the wake of driverless cars. The gradual and ultimate shift of liability from the traditional human driver to the machine ‘driver’ coupled with the cross-border sale of driverless vehicles provide justification for scholarly attention. Accidents may now be attributed to technological error and not human mistake. Conflict of law issues become central in instances where manufacturers and users live in different parts of the world...LL.M. (International Commercial Law

Solar and tray-drying methods and physicochemical properties of sweetpotato starch

Two drying methods were investigated to determine if drying is possible without affecting the quality of starch. The drying methods were solar dryer (53-55 °C) and electrically powered tray dryer (60 °C). The physicochemical properties of starch from five sweetpotato were evaluated after dehydration using the two methods. The results showed that drying methodshad effect on some physicochemical properties of sweetpotato starch. The tray-dried starches had higher moisture, ash, viscosity, and L* values. The swelling power and solubility values for tray-dried starches were significantly different from solar-dried ones, except for the tray-dried “Sauti” starch. Although the water binding capacity and amylase content were higher in solar-dried starches relative to tray-dried starches, statistically therewas no significant difference(

WHAT NUTRITION INFORMATION ARE DIETITIANS USING WITH THEIR PATIENTS WHO HAVE TYPE 2 DIABETES?

Introduction Dietitians offer specialist evidence-based dietary advice to their patients. Dietary advice for people with type 2 diabetes (T2DM) including written nutrition information (NI) is a key component of the management plan. The aim of the project was to investigate the NI used by dietitians with people with T2DM. Methods An online ad hoc questionnaire exploring whether dietitians produced NI, whether they have had training in the production, any patient involvement in the production, other sources of NIs, factors affecting choice of NIs used and the provision of NIs to other healthcare professionals (HCPs) was developed and pre-piloted. Individual dietitians and departments with dietitians who were working with people with T2DM across England were emailed a link to an online questionnaire. Data were analysed using descriptive statistics and thematic analysis. Ethics approval was obtained from the University of Hertfordshire. Results All 93 respondents used NIs in their consultations. The main sources were a national diabetes charity and a national provider of nutrition information. The main reason given for their use was that the information met the needs of patients. Two thirds of respondents also used NIs produced by their own departments. However almost 40% reported not having any training in the production of NIs and only 10% involved patients in their development. Over 80% of respondents also supplied HCPs with information; nurses and GPs being the main recipients. Conclusions, discussion and/or practical application Dietitians are using evidence-based information and in ensuring HCPs who work with people with T2DM have access to appropriate resources. However their lack of access to training in the development of NIs and in involving patients may limit the effectiveness of resources developed by their own departments. Dietitians could benefit from training in the development of NIs and should be encouraged to involve patients in the development process.Peer reviewe

Analytical Parametric Model Used to Study the Influence of Electrostatic Force on Surface Coverage During Electrospinning of Polymer Fibers

Electrospinning (ES) can readily produce polymer fibers with cross-sectional dimensions ranging from tens of nanometers to tens of microns. Qualitative estimates of surface area coverage are rather intuitive. However, quantitative analytical and numerical methods for predicting surface coverage during ES have not been covered in sufficient depth to be applied in the design of novel materials, surfaces, and devices from ES fibers. This article presents a modeling approach to ES surface coverage where an analytical model is derived for use in quantitative prediction of surface coverage of ES fibers. The analytical model is used to predict the diameter of circular deposition areas of constant field strength and constant electrostatic force. Experimental results of polyvinyl alcohol fibers are reported and compared to numerical models to supplement the analytical model derived. The analytical model provides scientists and engineers a method for estimating surface area coverage. Both applied voltage and capillary-to-collection-plate separation are treated as independent variables for the analysis. The electric field produced by the ES process was modeled using COMSOL Multiphysics software to determine a correlation between the applied field strength and the size of the deposition area of the ES fibers. MATLAB scripts were utilized to combine the numerical COMSOL results with derived analytical equations. Experimental results reinforce the parametric trends produced via modeling and lend credibility to the use of modeling techniques for the qualitative prediction of surface area coverage from ES. (Copyright: 2014 American Vacuum Society.

Evaluating a palliative care education programme for domiciliary care workers

Background: Many domiciliary care workers have reported low confidence and isolation when delivering end of life care in patients’ homes. Project Extension for Community Healthcare Outcomes (ECHO) is an initiative that has demonstrated success in increasing confidence and knowledge of end of life care in UK nursing home and community hospice workers, but it has not been evaluated with domiciliary care workers. Aim: To test the acceptability of Project ECHO to domiciliary care workers as a means of increasing their knowledge of, and confidence in, delivering palliative care, and its effectiveness in reducing their isolation by developing a community of practice. Method: A service evaluation, involving one domiciliary care agency delivering care in the community, was conducted from May 2018 to April 2019. The participants were 25 home care workers who were employed by the agency. Participants were invited to attend an event at which gaps in their knowledge were identified, and a curriculum of learning on the Project ECHO programme was developed. The learning involved 12 educational sessions over 12 months, with each session teaching a different component of palliative care. Questionnaires were completed by the participants before and after the educational sessions to assess their effect. In addition, a focus group was conducted with four of the participants. Results: Comparison of the questionnaires completed before and after participating in the education sessions revealed an increase in self-reported knowledge across all 12 topics of the curriculum and an increase in confidence in seven of the 12 topics. However, attendance across the 12 sessions was variable, with no more than nine being attended by any one participant. Conclusion: Palliative care education for domiciliary care staff using ECHO methodology was well received, relevant and accessible, and may have the potential to improve self-assessed knowledge and confidence. However, finding an ideal time for as many staff to attend as possible may be challenging

The Global Threat of Counterfeit Drugs: Why Industry and Governments Must Communicate the Dangers

The production of substandard and fake drugs is a vast and underreported problem, particularly affecting poorer countries. Cockburn and colleagues argue that the pharmaceutical industry and governments must both take actio

Emergency department presentations in palliative care patients : a retrospective cohort study

Objectives: To map the patient journey for individuals known to palliative care presenting to the emergency department (ED). Methods: A linked dataset from the CUREd database and palliative care services in a region in the North of England was used. The study describes day and time of presentations, events occurring in the ED, mode of leaving the department and length of hospital admissions for presentations occurring within 90 days of a contact with palliative care. Findings were compared with the wider population in the CUREd database. Results: A significant proportion of individuals known to palliative care (29.4%) presented to the ED. Presentations typically occurred in working hours. Most presented by ambulance (84.4%) and were admitted to hospital (75.1%); these observations persisted across age groups. Most presentations involved investigations (88.5%) and/or treatment (84.1%). Conclusions: Palliative patients exhibit significant use of the ED; some have the potential to benefit from attendances, but there is a minority for whom ED is unlikely to have improved their care. Advance care planning and communication between services are important for empowering those who stand to benefit from ED, while ensuring appropriate care is planned for those who prefer to avoid presenting

Cost-effectiveness of cenobamate for focal seizures in people with drug-resistant epilepsy

OBJECTIVES: To estimate the cost-effectiveness of add-on cenobamate in the UK when used to treat drug-resistant focal seizures in adults who are not adequately controlled with at least two prior antiseizure medication, including at least one used adjunctively. METHODS: We estimated the cost per quality-adjusted life-year (QALY) for cenobamate compared to brivaracetam, eslicarbazepine, lacosamide and perampanel in the UK National Health Service over a lifetime time horizon. We used a Markov cohort structure to determine response to treatment, using pooled data from three long-term studies of cenobamate. A network meta-analysis informed the likelihood of response to therapy with brivaracetam, eslicarbazepine, lacosamide and perampanel relative to cenobamate. Once individuals discontinued treatment, they transitioned to subsequent treatment health states, including other antiseizure medicines, surgery, and vagus nerve stimulation. Costs included treatment, administration, routine monitoring, event management and adverse events. Published evidence and expert opinion informed the likelihood of response to subsequent treatments, associated adverse events, and costs. Utility data was based on short-form, six dimensions utility. Discounting was applied at 3.5% per annum as per National Institute for Health and Care Excellence guidance. Uncertainty was explored through deterministic and probabilistic sensitivity analyses. RESULTS: In the base case, cenobamate led to cost savings of £51,967 (compared to brivaracetam), £21,080 (compared to eslicarbazepine), £33,619 (compared to lacosamide), and £28,296 (compared to perampanel) and increased QALYs of 1.047 (compared to brivaracetam), 0.598 (compared to eslicarbazepine), 0.776 (compared to lacosamide), and 0.703 (compared to perampanel) per individual over a lifetime time horizon. Cenobamate also dominated the four drugs across most sensitivity analyses. Differences were due to reduced seizure frequency with cenobamate relative to comparators. SIGNIFICANCE: Cenobamate improved QALYs and was less costly than brivaracetam, eslicarbazepine, lacosamide and perampanel. Therefore, cenobamate may be considered as a cost-effective adjunctive antiseizure medication for people with drug-resistant focal seizures