New 5-Hydroxycoumarin-Based Tyrosyl-DNA Phosphodiesterase I Inhibitors Sensitize Tumor Cell Line to Topotecan.

Tyrosyl-DNA-phosphodiesterase 1 (TDP1) is an important enzyme in the DNA repair system. The ability of the enzyme to repair DNA damage induced by a topoisomerase 1 poison such as the anticancer drug topotecan makes TDP1 a promising target for complex antitumor therapy. In this work, a set of new 5-hydroxycoumarin derivatives containing monoterpene moieties was synthesized. It was shown that most of the conjugates synthesized demonstrated high inhibitory properties against TDP1 with an IC50 in low micromolar or nanomolar ranges. Geraniol derivative 33a was the most potent inhibitor with IC50 130 nM. Docking the ligands to TDP1 predicted a good fit with the catalytic pocket blocking access to it. The conjugates used in non-toxic concentration increased cytotoxicity of topotecan against HeLa cancer cell line but not against conditionally normal HEK 293A cells. Thus, a new structural series of TDP1 inhibitors, which are able to sensitize cancer cells to the topotecan cytotoxic effect has been discovered.

Disinfection of Virtual Reality Devices in Health Care Settings: In Vitro Assessment and Survey Study.

BACKGROUND: Virtual reality (VR) devices are increasingly used in health care settings. The use among patients has the potential to unintentionally transmit pathogens between patients and hospital staff. No standard operating procedure for disinfection exists to ensure safe use between patients. OBJECTIVE: This study aims to determine the efficacy of disinfectants on VR devices in order to ensure safe use in health care settings. METHODS: Three types of bacteria were inoculated onto porous and nonporous surfaces of 2 VR devices: the Meta Oculus Quest and Meta Oculus Quest 2. Disinfection was performed using either isopropyl alcohol or alcohol-free quaternary ammonium wipes. A quantitative culture was used to assess the adequacy of disinfection. A survey was separately sent out to VR device technicians at other pediatric health care institutes to compare the methods of disinfection and how they were established. RESULTS: Both products achieved adequate disinfection of the treated surfaces; however, a greater log-kill was achieved on nonporous surfaces than on the porous surfaces. Alcohol performed better than quaternary ammonium on porous surfaces. The survey respondents reported a wide variability in disinfection processes with only 1 person reporting an established standard operating procedure. CONCLUSIONS: Disinfection can be achieved through the use of either isopropyl alcohol or quaternary ammonium products. Porous surfaces showed lesser log-kill rates than the nonporous surfaces, indicating that the use of an added barrier may be of benefit and should be a point of future research. Given the variability in the disinfection process across health care systems, a standard operating procedure is proposed.

'How was it for you?' - GP trainees' experiences of a novel practice swap.

Newly-qualified General Practitioners (GPs) are underprepared for the challenges of working as independent GPs. This study describes a practice swap - an innovative experiential learning opportunity to increase confidence amongst final year GP trainees for the challenges of future work. The effectiveness of the practice swap was evaluated across two separate GP training areas using questionnaires for GP trainees, practice managers, educational supervisors and newly-qualified GPs. In addition, GP trainees were interviewed in focus groups. The results demonstrated the positive educational value of the practice swap. GP trainees reported increased confidence in the ability to work as independent GPs specifically as a locum doctor, improved Information Technology (IT) competence, clinical knowledge and time keeping. The practice swap helped to inform the trainees on future career choices. Practice swapping has become one of the building blocks of a wider programme to equip newly-qualified GPs for the numerous challenges of being a GP, with a series of workshops on self-employment, job applications, practice management and IT training. The arrangements and benefits of practice swapping are transferrable to other GP Training Schemes across the UK and possibly internationally.

What do General Practitioners think of written reflection? A focus group study.

BACKGROUND: Written reflection has become a key part of evidence for assessment for General Practitioners (GPs) and GP Specialist Trainees (GPSTs), as it is thought to enhance the reflective process and demonstrate on-going learning. However, the educational value of mandatory reflection has been questioned, and there is little evidence on the acceptability of written reflection to clinicians. AIM: To explore the views of GPs and GPSTs on the use of written reflection in the MRCGP and NHS appraisal. DESIGN AND SETTING: A qualitative approach with GPs and GPSTs from the South of England. METHOD: Three focus group discussions with 11 GPs and 14 GPSTs. Thematic analysis was used on the coded texts. RESULTS: There were diverse views on the value of written reflection. Some participants with particular learning styles found it useful; some viewed it as a 'tick-box' exercise and as a game. Some questioned its value as a tool for quality improvement. Its use may have opportunity costs on clinical work, other learning and leisure time. CONCLUSION: Written reflection produced strong feelings among participants. Research is needed to gauge how commonly these feelings are held, to allow informed decisions on the place of written reflection in education and assessment.

Preclinical evaluation of statins as a treatment for ovarian cancer.

OBJECTIVE: To evaluate the potential for statins to treat ovarian cancer. METHODS: The sensitivity of 7 ovarian cancer cell lines to either statins or statins combined with either carboplatin or paclitaxel was assessed using monolayer cultures. Sensitivity to simvastatin was also evaluated in ovarian cancer spheroids. The kinetics of cell death induced by simvastatin was evaluated by measuring Trypan Blue exclusion. Autophagy induced by simvastatin was assessed by measuring LC3-II, p62 or Rab7 by immunoblotting or immunocytochemistry. RESULTS: All statins except pravastatin demonstrated single agent activity against monolayers (IC50=1-35 µM) and spheroids (IC50=1-13 µM). This was mediated by HMG-CoAR inhibition, because either mevalonate or geranylgeraniol prevented the cytotoxic effects of simvastatin. Continuous exposure for 4 days was necessary to cause cell death. Simvastatin caused accumulation of p62 but loss of Rab7, suggesting inhibition of autophagosome trafficking. Accumulation of LC3-II was also observed, even in the presence of bafilomycin, suggesting additional stimulation of an earlier step in autophagy. Knockdown of the key autophagy regulator Atg5 caused a modest increase in the sensitivity of Ovcar-8 cells to simvastatin. Finally, additive or mild antagonist effects were observed when simvastatin was combined simultaneously with either carboplatin or paclitaxel, but when cells were exposed to simvastatin prior to carboplatin, profound antagonism was observed. CONCLUSIONS: These observations suggest that clinical trials of statins in ovarian cancer should evaluate high doses and schedules that ensure continual inhibition of HMG-CoAR. Simvastatin has conflicting effects on the autophagy pathway and this may contribute to its cytotoxic activity.

Chain length impact on the retro Diels-Alder mediated release of gemcitabine from hybrid nanoparticles towards pancreatic cancer therapy.

Previously reported gold coated iron oxide nanoparticles (Au-IONP's) have demonstrated their effectiveness as drug delivery vehicles for gemcitabine conjugated to a thermally labile Diels-Alder linker containing a chain of 4 carbon atoms (TTLD4) for the treatment of pancreatic cancer. Heat generated via laser irradiation of Au-IONPs facilitated retro Diels-Alder mediated release in a burst release profile where approximately half of all total release over 180 min occurred within the first 5 min. Two analogues of TTLD4, which differ only in linker chain length (TTLD3 & TTLD6) were synthesised and conjugated to Au-IONP's. Heat-mediated release of gemcitabine at 45 °C over 180 min from these formulations was confirmed to be based on linker length, which was 94%, 76% and 45% for TTLD3, TTLD4 and TTLD6, respectively. Drug loading of the Diels-Alder linkers in a 5:1 Drug/Au-IONP w/w ratio appears to favour those containing an even number of carbons TTLD4 (76%) & TTLD6 (57%) over TTLD3 (25%), possibly due to the linker likely being positioned perpendicular to the Au-IONP surface because of the 120 °C-C bond.

Animosity, antagonism, and avatars: teaching conflict management in second life.

Conflict exists in all health care organizations and may take many forms, including lateral or horizontal violence. The Essentials of Baccalaureate Nursing Education identified the development of conflict resolution strategies as core knowledge required of the bachelor's of science in nursing generalist. However, learning the art of conflict management takes both time and practice. With competition for clinical space increasing, class time in short supply, and traditional clinical opportunities for teaching conflict management lacking, a virtual approach to teaching conflict resolution was explored through the use of Second Life®. The project presented here explored students' perceptions of this unique approach to learning conflict management and sought to examine the effectiveness of this teaching method.

Thermally reactive N-(2-hydroxypropyl)methacrylamide (HPMA) amphiphiles for drug solubilisation.

Thermally active polymers, can respond structurally to temperature changes, making them interesting as potential drug delivery vehicles. Polymers of N-(3-aminopropyl) methacrylamide hydrochloride (APMA) are cationic with primary amine groups in their structure, which have been explored in biomedical applications via post-polymerisation modifications. In this work, we synthesised amphiphilic APMA monomers using hydrophobic pendant groups via conjugation onto their primary amine group. The pendant groups chosen in this study were palmitoyl, dansyl and cholesteryl moieties. The amphiphilic monomers were subsequently copolymerized with N-(2-hydroxypropyl)methacrylamide (HPMA) using varied monomer feed ratios resulting in a thermo-responsive system. The ability of the resultant aggregates in aqueous solution to encapsulate and liberate model drugs (e.g., propofol, griseofulvin and prednisolone) was then determined. Our data showed that the HPMA based formulations were capable of loading the model drug molecules inside their lipophilic core; HPMA-co-(APMA-Dansyl 2%) exhibited the largest drug encapsulation ability. Subsequently, poly(ethylene glycol) (PEG) was incorporated into the intrinsic polymer structure. This resulted in a more rapid drug release profile, whereby 100% of griseofulvin and prednisolone were liberated after only 4 h, which was only 5% and 10% before the PEG inclusion, respectively. Similarly, propofol showed 70% liberation from the polymer aggregate after 24 h, compared with only 30% liberation pre-PEGylation. These studies give an insight into the potential of the HMPA based amphiphiles as thermally responsive cargo carrier/release systems which could be exploited in the delivery of poorly soluble drugs.

Investigation into the Use of Microfluidics in the Manufacture of Metallic Gold-Coated Iron Oxide Hybrid Nanoparticles.

Hybrid iron oxide-gold nanoparticles are of increasing interest for applications in nanomedicine, photonics, energy storage, etc. However, they are often difficult to synthesise without experience or 'know-how'. Additionally, standard protocols do not allow for scale up, and this is significantly hindering their future potential. In this study, we seek to determine whether microfluidics could be used as a new manufacturing process to reliably produce hybrid nanoparticles with the line of sight to their continuous manufacture and scaleup. Using a Precision Nano NanoAssemblr Benchtop® system, we were able to perform the intermediate coating steps required in order to construct hybrid nanoparticles around 60 nm in size with similar chemical and physical properties to those synthesised in the laboratory using standard processes, with Fe/Au ratios of 1:0.6 (standard) and 1:0.7 (microfluidics), indicating that the process was suitable for their manufacture with optimisation required in order to configure a continuous manufacturing plant.

Effect of Poly(allylamine) Molecular Weight on Drug Loading and Release Abilities of Nano-Aggregates for Potential in Cancer Nanomedicine.

Poly(allylamine) graft polymers have been shown to hold potential as drug delivery vehicles and complexation agents for biological molecules such as insulin. The nanoparticles formed upon aggregation or complexation allow for enhanced cellular trafficking resulting in enhanced efficacy. Multiple reports have shown the ease of synthesis and reliability of these graft polymers, however, little investigation into the effect of the molecular weight of the homopolymer poly(allylamine) has been carried out. In this work we synthesized a range of oxadiazole grafted poly(allylamine) derivatives of varied molecular weight (15, 17.5, 120 & 900 kDa) set at a 5% polymer:oxadiazole mole grafting. The effect of molecular weight on the size, critical aggregation concentration and drug loading/release was evaluated in model drugs before loading the optimal formulation with doxorubicin and carrying out a preliminary cytotoxicity study. In line with other cationic polymers, the larger poly(allylamine) amphiphilic derivatives resulted in greater drug loading, however, the particle size increased whilst drug loading dramatically decreased, which for cancer nanomedicine could be a barrier for pharmaceutical use.

Application of Nanoparticle Technologies in the Combat against Anti-Microbial Resistance.

Anti-microbial resistance is a growing problem that has impacted the world and brought about the beginning of the end for the old generation of antibiotics. Increasingly, more antibiotics are being prescribed unnecessarily and this reckless practice has resulted in increased resistance towards these drugs, rendering them useless against infection. Nanotechnology presents a potential answer to anti-microbial resistance, which could stimulate innovation and create a new generation of antibiotic treatments for future medicines. Preserving existing antibiotic activity through novel formulation into or onto nanotechnologies can increase clinical longevity of action against infection. Additionally, the unique physiochemical properties of nanoparticles can provide new anti-bacterial modes of action which can also be explored. Simply concentrating on antibiotic prescribing habits will not resolve the issue but rather mitigate it. Thus, new scientific approaches through the development of novel antibiotics and formulations is required in order to employ a new generation of therapies to combat anti-microbial resistance.

Stimuli Responsive Polymeric Systems for Cancer Therapy.

Nanoscale polymers systems have dominated the revolution of drug delivery advancement. Their potential in the fight against cancer is unrivalled with other technologies. Their functionality increase, targeting ability and stimuli responsive nature have led to a major boom in research focus. This review article concentrates on the use of these smart polymers in cancer therapy. Nanotechnologies have shown potential as drug carriers leading to increased drug efficacy and penetration. Multifunctional smart carriers which can release their payload upon an external or internal trigger such as pH or temperature are proving to be major frontrunners in the development of effective strategies to overcome this disease with minimal patient side effects.

Dual Acting Polymeric Nano-Aggregates for Liver Cancer Therapy.

Liver cancer treatments are often hindered by poor drug physicochemical properties, hence there is a need for improvement in order to increase patient survival and outlook. Combination therapies have been studied in order to evaluate whether increased overall efficacy can be achieved. This study reports the combined treatment of liver cancer cells with a combination treatment of chemotherapeutic agent paclitaxel and pro-apoptotic protein cytochrome C. In order to administer both agents in a single formulation, a poly(allylamine)-based amphiphile has been fabricated with the incorporation of a hybrid iron oxide-gold nanoparticle into its structure. Here, the insoluble paclitaxel becomes incorporated into the hydrophobic core of the self-assemblies formed in an aqueous environment (256 nm), while the cytochrome C attaches irreversibly onto the hybrid nanoparticle surface via gold-thiol dative covalent binding. The self-assemblies were capable of solubilising up to 0.698 mg/mL of paclitaxel (700-fold improvement) with 0.012 mg/mL of cytochrome C also attached onto the hybrid iron oxide-gold nanoparticles (HNPs) within the hydrophobic core. The formulation was tested on a panel of liver cancer cells and cytotoxicity was measured. The findings suggested that indeed a significant improvement in combined therapy (33-fold) was observed when compared with free drug, which was double the enhancement observed after polymer encapsulation without the cytochrome C in hepatocellular carcinoma (Huh-7D12) cells. Most excitingly, the polymeric nanoparticles did result in improved cellular toxicity in human endothelian liver cancer (SK-hep1) cells, which proved completely resistant to the free drug.

A Novel PAA Derivative with Enhanced Drug Efficacy in Pancreatic Cancer Cell Lines.

Nanoparticles have been shown to be effective drug carriers in cancer therapy. Pancreatic cancer forms dense tumours which are often resistant to drug molecules. In order to overcome such multidrug resistance, new drug entities, novel delivery systems and combination therapy strategies are being explored. In this paper, we report the design and synthesis of a poly(allylamine)-based amphiphile modified with hydrophobic naphthalimido pendant groups. Bisnaphthalimide compounds have been shown to possess anticancer activity. The potential of this polymer to encapsulate, solubilize and enhance drug (5-fluorouricil and bis-(naphthalimidopropyl)-diaminooctane) cytotoxicity in BxPC-3 cells was evaluated. Our studies showed that the insoluble drugs could be formulated up to 4.3 mg mL-1 and 2.4 mg mL-1 inside the amphiphiles, respectively. Additionally, the novel poly(allylamine)-naphthalimide carrier resulted in an amplification of cytotoxic effect with drug treatment after 24 h, and was capable of reduction of 50% cell population at concentrations as low as 3 µg mL-1.

Combined Effect of Anticancer Agents and Cytochrome C Decorated Hybrid Nanoparticles for Liver Cancer Therapy.

Hepatocellular carcinoma is an aggressive form of liver cancer that displays minimal symptoms until its late stages. Unfortunately, patient prognosis still remains poor with only 10% of patients surviving more than five years after diagnosis. Current chemotherapies alone are not offering efficient treatment, hence alternative therapeutic approaches are urgently required. In this work, we highlight the potential of combination of treatment of hepatocellular carcinoma with existing chemotherapies in combination with pro-apoptotic factor cytochrome C. In order to allow cytochrome C to cross the cellular membrane and become internalized, it has been immobilised onto the surface of hybrid iron oxide-gold nanoparticles. This novel approach has been tested in vitro on HepG2, Huh-7D and SK-hep-1 cell lines in order to elucidate potential as a possible alternative therapy with greater efficacy. The data from our studies show consistently that combining treatment of clinically used anticancer agents (doxorubicin, paclitaxel, oxaliplatin, vinblastine and vincristine) significantly increases the levels of apoptosis within the cell lines, which leads to cellular death. Hence, this combined approach may hold promise for future treatment regimes.

Nanotechnologies in Pancreatic Cancer Therapy.

Pancreatic cancer has been classified as a cancer of unmet need. After diagnosis the patient prognosis is dismal with few surviving over 5 years. Treatment regimes are highly patient variable and often the patients are too sick to undergo surgical resection or chemotherapy. These chemotherapies are not effective often because patients are diagnosed at late stages and tumour metastasis has occurred. Nanotechnology can be used in order to formulate potent anticancer agents to improve their physicochemical properties such as poor aqueous solubility or prolong circulation times after administration resulting in improved efficacy. Studies have reported the use of nanotechnologies to improve the efficacy of gemcitabine (the current first line treatment) as well as investigating the potential of using other drug molecules which have previously shown promise but were unable to be utilised due to the inability to administer through appropriate routes-often related to solubility. Of the nanotechnologies reported, many can offer site specific targeting to the site of action as well as a plethora of other multifunctional properties such as image guidance and controlled release. This review focuses on the use of the major nanotechnologies both under pre-clinical development and those which have recently been approved for use in pancreatic cancer therapy.

Thermally triggered theranostics for pancreatic cancer therapy.

Hybrid iron oxide-gold nanoparticles (HNPs) show the ability to bind drugs onto their surface with a triggered release at elevated temperatures. The iron oxide core allows for diagnostic imaging whilst heating of the gold shell upon laser irradiation reverses drug binding. This study exploits the reversible binding of novel polyamine based drugs in order to provide a specific and effective method for pancreatic cancer treatment. Here we used a novel bisnaphthalamido (BNIP) based drug series. Our hybrid nanoparticles (50 nm) showed the ability to load drugs onto their surface (3 : 1 : 0.25, drug : Fe : Au). By exploiting the surface-to-drug electrostatic interaction of a range of BNIP agents, heat triggered drug release was achieved. A 12-fold reduction in IC50 after 24 h in vitro and a 5-fold reduction of tumour retardation in vivo compared with free drug in pancreatic models after treatment were achieved with the HNP-formulation and laser irradiation. This heat activated system could provide a key platform for future therapeutic strategies.

Diels Alder-mediated release of gemcitabine from hybrid nanoparticles for enhanced pancreatic cancer therapy.

Hybrid nanoparticles (HNPs) have shown huge potential as drug delivery vehicles for pancreatic cancer. Currently, the first line treatment, gemcitabine, is only effective in 23.8% of patients. To improve this, a thermally activated system was developed by introducing a linker between HNPs and gemcitabine. Whereby, heat generation resulting from laser irradiation of the HNPs promoted linker breakdown resulting in prodrug liberation. In vitro evaluation in pancreatic adenocarcinoma cells, showed the prodrug was 4.3 times less cytotoxic than gemcitabine, but exhibited 11-fold improvement in cellular uptake. Heat activation of the formulation led to a 56% rise in cytotoxicity causing it to outperform gemcitabine by 26%. In vivo the formulation outperformed free gemcitabine with a 62% reduction in tumor weight in pancreatic xenografts. This HNP formulation is the first of its kind and has displayed superior anti-cancer activity as compared to the current first line drug gemcitabine after heat mediated controlled release.

Becoming a general practice trainer: experience of higher preparatory training.

WHAT IS ALREADY KNOWN IN THIS AREA • Basic training courts for general; practice trainers; do not always meet the demands for the level of 'professionalition' expected. • Many regions now run university-accredited teaching bourses, some of which advocate compulsion. WHAT THIS WORK ADDS • This work has shown that a mandatory course is generally accepted by participants. • Organisational infrastructure needs to be efficient. SUGGESTIONS FOR FUTURE RESEARCH • The effects on trainer recruitment need to be monitored and studied. • The effects on further individual continuing professional development in terms of following this initial course towards a diploma or higher degree.

Women in senior post-graduate medicine career roles in the UK: a qualitative study.

OBJECTIVES: This qualitative study sought to elicit the views, experiences, career journeys and aspirations of women in senior post-graduate medical education roles to identify steps needed to help support career progression. DESIGN: In-depth semi-structured telephone interviews. SETTING: UK. PARTICIPANTS: Purposive sample of 12 women in a variety of senior leadership roles in post-graduate medical education in the UK. MAIN OUTCOME MEASURES: Self reported motivating influences, factors that helped and hindered progress, key branch points, and key educational factors and social support impacting on participants' career in postgraduate medicine. RESULTS: Respondents often reported that career journeys were serendipitous, rather than planned, formal or well structured. Senior women leaders reported having a high internal locus of control, with very high levels of commitment to the NHS. All reported significant levels of drive, although the majority indicated that they were not ambitious in the sense of a strong drive for money, prestige, recognition or power. They perceived that there was an under-representation of women in senior leadership positions and that high-quality female mentorship was particularly important in redressing this imbalance. Social support, such a spouse or other significant family member, was particularly valued as reaffirming and supporting women's chosen career ambition. Factors that were considered to have hindered career progression included low self-confidence and self-efficacy, the so-called glass ceiling and perceived self-limiting cultural influences. Factors indirectly linked to gender such as part-time versus working full time were reportedly influential in being overlooked for senior leadership roles. Implications of these findings are discussed in the paper. CONCLUSION: Social support, mentorship and role modelling are all perceived as highly important in redressing perceived gender imbalances in careers in post-graduate medical education.