Photodynamic therapy with mTHPC and polyethylene glycol-derived mTHPC: a comparative study on human tumour xenografts

The photosensitizing properties of m-tetrahydroxyphenylchlorin (mTHPC) and polyethylene glycol-derivatized mTHPC (pegylated mTHPC) were compared in nude mice bearing human malignant mesothelioma, squamous cell carcinoma and adenocarcinoma xenografts. Laser light (20 J/cm2) at 652 nm was delivered to the tumour (surface irradiance) and to an equal-sized area of the hind leg of the animals after i.p. administration of 0.1 mg/kg body weight mTHPC and an equimolar dose of pegylated mTHPC, respectively. The extent of tumour necrosis and normal tissue injury was assessed by histology. Both mTHPC and pegylated mTHPC catalyse photosensitized necrosis in mesothelioma xenografts at drug-light intervals of 1–4 days. The onset of action of pegylated mTHPC seemed slower but significantly exceeds that of mTHPC by days 3 and 4 with the greatest difference being noted at day 4. Pegylated mTHPC also induced significantly larger photonecrosis than mTHPC in squamous cell xenografts but not in adenocarcinoma at day 4, where mTHPC showed greatest activity. The degree of necrosis induced by pegylated mTHPC was the same for all three xenografts. mTHPC led to necrosis of skin and underlying muscle at a drug-light interval of 1 day but minor histological changes only at drug-light intervals from 2–4 days. In contrast, pegylated mTHPC did not result in histologically detectable changes in normal tissues under the same treatment conditions at any drug-light interval assessed. In this study, pegylated mTHPC had advantages as a photosensitizer compared to mTHPC

Stress field sensitivity analysis in a sedimentary sequence of the Alpine foreland, Northern Switzerland

The stress field at depth is a relevant parameter for the design of subsurface constructions and reservoir management. Yet the distortion of the regional stress field due to local-scale features such as sedimentary and tectonic structures or topography is often poorly constrained. We conduct a stress sensitivity analysis using 3-D numerical geomechanical modelling with an elasto-plastic material law to explore the impact of such site specific features on the stress field in a sedimentary sequence of the Swiss Alpine foreland. The model\u27s dimensions are 14 km × 14 km × 3 km and it contains ten units with different mechanical properties, intersected by two regional fault zones. An initial stress state is established involving a semi-empirical relationship between the ratio of horizontal to vertical stress and the overconsolidation ratio of argillaceous sediments. The model results indicate that local topography can affect the stress field significantly to depths greater than the relief contrasts at the surface, especially in conjunction with horizontal tectonic loading. The complexity and frictional properties of faults are also relevant. The greatest variability of the stress field arises across the different sedimentary units. Stress magnitudes and stress anisotropy are much larger in stiffer formations such as massive limestones than in softer argillaceous formations. The stiffer formations essentially carry the load of the far-field forces and are therefore more sensitive to changes of the boundary conditions. This general characteristic of stress distribution in the stiff and soft formations is broadly maintained also with progressive loading towards the plastic limit. The stress field in argillaceous sediments within a stack of formations with strongly contrasting mechanical properties like in the Alpine foreland appears to be relatively insensitive to changes in the tectonic boundary conditions and is largely controlled by the maximum stiffness contrast with respect to the load-bearing formations

Influence of operating parameters on the biodegradation of steroid estrogens and nonylphenolic compounds during biological wastewater treatment processes

This document is the unedited author's version of a Submitted Work that was subsequently accepted for publication in Environmental Science & Technology, copyright © American Chemical Society after peer review. To access the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/es901612v.This study investigated operational factors influencing the removal of steroid estrogens and nonylphenolic compounds in two sewage treatment works, one a nitrifying/denitrifying activated sludge plant and the other a nitrifying/denitrifying activated sludge plant with phosphorus removal. Removal efficiencies of >90% for steroid estrogens and for longer chain nonylphenol ethoxylates (NP4−12EO) were observed at both works, which had equal sludge ages of 13 days. However, the biological activity in terms of milligrams of estrogen removed per day per tonne of biomass was found to be 50−60% more efficient in the nitrifying/denitrifying activated sludge works compared to the works which additionally incorporated phosphorus removal. A temperature reduction of 6 °C had no impact on the removal of free estrogens, but removal of the conjugated estrone-3-sulfate was reduced by 20%. The apparent biomass sorption (LogKp) values were greater in the nitrifying/denitrifying works than those in the nitrifying/denitrifying works with phosphorus removal for both steroid estrogens and nonylphenolic compounds possibly indicating a different cell surface structure and therefore microbial population. The difference in biological activity (mg tonne−1 d−1) identified in this study, of up to seven times, suggests that there is the potential for enhancing the removal of estrogens and nonylphenols if more detailed knowledge of the factors responsible for these differences can be identified and maximized, thus potentially improving the quality of receiving waters.Public Utilities Board (Singapore), Anglian Water Ltd, Severn Trent Water Ltd, Thames Water Utilities Ltd, United Utilities 393 Plc and Yorkshire Water Services

A critical review of the formation of mono- and dicarboxylated metabolic intermediates of alkylphenol polyethoxylates during wastewater treatment and their environmental significance

This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ 2010 Taylor & Francis.Alkylphenoxyacetic acids, the metabolic biodegradation products of alkylphenol ethoxylates, are commonly found in wastewaters and sewage effluents. These persistent hydrophilic derivatives possess intrinsic estrogenic activity, which can mimic natural hormones. Their concentrations increase through the sewage treatment works as a result of biodegradation and biotransformation, and when discharged can disrupt endocrine function in fish. These acidic metabolites represent the dominant alkylphenolic compounds found in wastewater effluent and their presence is cause for concern as, potentially, through further biotransformation and biodegradation, they can act as sources of nonylphenol, which is toxic and estrogenic. The authors aim to assess the mechanisms of formation as well as elimination of alkylphenoxyacetic acids within conventional sewage treatment works with the emphasis on the activated sludge process. In addition, they evaluate the various factors influencing their degradation and formation in laboratory scale and full-scale systems. The environmental implications of these compounds are considered, as is the need for tertiary treatment processes for their removal

Rapid disease progression in a patient with mismatch repair-deficient and cortisol secreting adrenocortical carcinoma treated with pembrolizumab

Context: Metastatic adrenocortical carcinoma (ACC) is an aggressive malignancy with a poor prognosis and limited therapeutic options. A subset of ACC is due to Lynch syndrome, an inherited tumour syndrome resulting from germline mutations in mismatch repair (MMR) genes. It has been demonstrated that several cancers characterised by MMR-deficiency are sensitive to immune checkpoint inhibitors that target PD-1. Here, we provide the first report of PD-1 blockade by pembrolizumab in a patient with Lynch syndrome and progressive cortisol-secreting metastatic ACC. Case report: A 58-year old female with known Lynch syndrome who presented with severe Cushing’s syndrome was diagnosed with a cortisol-secreting ACC. Three months following surgical resection and adjuvant mitotane therapy the patient developed metastatic disease and persistent hypercortisolaemia. She commenced pembrolizumab, but her second cycle was delayed due to a transient transaminitis. Computed tomography performed after twelve weeks and 2 cycles of pembrolizumab administration revealed significant disease progression and treatment was discontinued. Seven weeks later, the patient became jaundiced and died rapidly with fulminant liver failure. Conclusion: Treatment of MMR-deficient cortisol-secreting ACC with pembrolizumab may be ineffective due to supra-physiological levels of circulating corticosteroids, which may in turn mask severe drug-induced organ damage

Smart homes and their users:a systematic analysis and key challenges

Published research on smart homes and their users is growing exponentially, yet a clear understanding of who these users are and how they might use smart home technologies is missing from a field being overwhelmingly pushed by technology developers. Through a systematic analysis of peer-reviewed literature on smart homes and their users, this paper takes stock of the dominant research themes and the linkages and disconnects between them. Key findings within each of nine themes are analysed, grouped into three: (1) views of the smart home-functional, instrumental, socio-technical; (2) users and the use of the smart home-prospective users, interactions and decisions, using technologies in the home; and (3) challenges for realising the smart home-hardware and software, design, domestication. These themes are integrated into an organising framework for future research that identifies the presence or absence of cross-cutting relationships between different understandings of smart homes and their users. The usefulness of the organising framework is illustrated in relation to two major concerns-privacy and control-that have been narrowly interpreted to date, precluding deeper insights and potential solutions. Future research on smart homes and their users can benefit by exploring and developing cross-cutting relationships between the research themes identified

Use of biobehavioral interventions in children undergoing surgery and associated patient-reported outcomes

Background: Biobehavioral interventions including relaxation, distraction, and mindfulness meditation exercises have been shown to decrease perioperative stress, anxiety, and pain. Our aims were to 1) quantify pediatric surgical patient-reported pre-operative exposure to and post-operative use of biobehavioral interventions; 2) understand barriers and facilitators to incorporation of biobehavioral interventions into clinical practice; and 3) evaluate associated patient-reported outcomes. Methods: We conducted an embedded mixed-methods study with a quantitative focus. Data were collected as part of the 18-hospital ENhanced Recovery In CHildren Undergoing Surgery (ENRICH-US) clinical trial for children, ages 10–18 years, undergoing elective gastrointestinal surgery. Patients/caregivers were surveyed about preoperative exposure to and postoperative use of biobehavioral interventions. Four semi-structured group interviews with 20 pediatric surgery providers were conducted. Outcomes included pain-related functional disability, health-related quality of life (HRQoL), and perioperative nervousness. Results: 41 % (n = 67) of 164 enrolled patients/caregivers reported preoperative exposure to and 71 % (n = 117) reported postoperative use of a biobehavioral intervention(s). Barriers to incorporation of biobehavioral interventions included lack of standardized workflows, clinician knowledge, and resources. Potential facilitators included media and peer-counseling. After adjusting for individual and hospital characteristics, those who reported using a biobehavioral intervention(s) were 70 % less likely to report worsened postoperative nervousness (95 % CI 0.10–0.91; p = 0.03). Reported use of a biobehavioral intervention(s) was not found to be associated with pain-related functional disability or HRQoL. Conclusions: Use of a biobehavioral intervention(s) may stabilize postoperative nervousness of children undergoing surgery. There is a need for redesign of clinical workflows and clinician training to facilitate integration of biobehavioral interventions.</p

Exploring the development of a cultural care framework for European caring science

The aim of this paper is to discuss the development of a cultural care framework that seeks to inform and embrace the philosophical ideals of caring science. Following a review of the literature that identified a lack of evidence of an explicit relationship between caring science and cultural care, a number of well-established transcultural care frameworks were reviewed. Our purpose was to select one that would resonate with underpinning philosophical values of caring science and that drew on criteria generated by the European Academy of Caring Science members. A modified framework based on the work of Giger and Davidhizar was developed as it embraced many of the values such as humanism that are core to caring science practice. The proposed caring science framework integrates determinants of cultural lifeworld-led care and seeks to provide clear directions for humanizing the care of individuals. The framework is offered to open up debate and act as a platform for further academic enquiry