Disagreement in risk groups for metastatic renal cancer.

In patients with metastatic renal cell carcinoma, risk stratification according to the Memorial Sloan-Kettering Cancer Center or the International Metastatic Renal Cell Carcinoma Database Consortium classification systems is a crucial part of clinical assessment and essential for guiding management. New research has now demonstrated that disagreement in risk-group classification is common and prognostically relevant

Functional analysis of a putative membrane-bound endo-β-1,4-glucanase from Panicum virgatum

Cellulose is the most abundant carbohydrate in the world and is degraded by the synergistic action of multiple enzymes. One large family of enzymes capable of hydrolyzing cellulose is glycoside hydrolase family 9 (GH9), which includes several endoglucanases. Recent research into the molecular biology of plants has revealed certain genes coding for endo-β-1,4-glucanases (EGases). The EGases in plants are primarily functional during cell elongation through wall stress relaxation. GH9 enzymes have been found in insects, bacteria, oomycetes, and fungi. In insects, EGases enable the organism to digest cellulose; in fungi, EGases are suspected to play an important role in obtaining nutrition for the fungi and may be associated with defense mechanisms. In these systems, EGases play an important role in breaking the internal bonds of cellulose resulting in a disruption of the crystalline structure. EGases are able to cleave cellulose at the β-1,4 linkages in the cellulose chain with a net inversion of anomeric configuration. A putative EGase from switchgrass (Panicum virgatum) was isolated from leaf cDNA. This gene of interest was cloned into Escherichia coli via the pET160 expression system. Selection by antibiotic resistance confirmed transformation of E. coli. Protein expression was detected via SDS-PAGE and tested to confirm cellulose lysing. The optimal pH and temperature were determined using 3,5-Dinitrosalycilic acid (DNSA) assay at different pH and temperature settings measuring reduced sugars released. Functionality in plants was determined through a gene rescue experiment using Arabidopsis thaliana mutants known to be deficient in putative EGase homologs. Switchgrass containing an overexpression of the EGase was compared to wildtype switchgrass via histology and microscopy. The confirmation of a functional EGase from switchgrass may aid in the development of switchgrass transformants with an amorphous cellulose structure, thereby reducing the amount of resources required during biofuel refinery

A qualitative exploration of key stakeholders’ views and perceptions in relation to organisational change for the implementation of polypharmacy management in Oman.

Polypharmacy contributes to patient non-adherence and increases medication harm. Barriers to implementation prevent desired outcomes when addressing inappropriate polypharmacy at organisational levels and there is a need for theory-based strategies for change management. The objective of this study was to explore the views and perceptions of key stakeholders in relation to organisational change for the development and implementation of a polypharmacy management healthcare strategy in Oman. Qualitative face to face interviews started in March 2022 with key stakeholders in Oman Ministry of Health (MOH) including leaders from practice of Medical, pharmacy and nursing as well as academic leaders from school of medicine, pharmacy and nursing. The interview schedule developed based on a scoping review, Kotter's first three steps of leading change and grounded in the consolidated Framework for Implementation Research (CIFR). Interviews were digitally recorded, transcribed, and analysed independently by at least two researchers using CFIR as a coding framework. Ethics approval was in place prior to data generation. Identified themes related to views and perceptions of key stakeholders in relation to the topic area. To date, ten interviews have been conducted with directors of medical (n=2), pharmacy (2) and nursing practice (1), academic healthcare leaders (3), a healthcare policy developer (1) and patient safety leader (1). Additional interviews are planned and will continue until data saturation. Emerging themes show that participants have views that polypharmacy is a burden on healthcare services and there is a need for organisational change in relation to polypharmacy management. Perceptions of reported organisational level barriers were; fragmentation of care, lack of systems for coordination among healthcare providers, absence of electronic link between the government and private sector, lack of sense of urgency among leaders regarding the polypharmacy and shortage of pharmacists. Facilitators were; the presence of well-developed electronic health system and leadership support. There is a need for for organisational change in relation to polypharmacy management in Oman. Further research is needed to obtain consensus of Omani stakeholders on the plan for a strategic framework for organisational change in relation to polypharmacy management

Implementation frameworks for polypharmacy management within healthcare organisations: a scoping review.

Several guidelines support polypharmacy management in individual patients. More organisational-level focus is needed on the use of implementation frameworks. The aim of this scoping review was to characterise the peer-reviewed literature on implementation frameworks, focussing on barriers and facilitators to implementation at organisational level in the context of polypharmacy management. A scoping review protocol was devised, supporting retrieval of studies published in English, reporting from any sector of practice. Medline, International Pharmaceutical Abstracts, Cumulative Index of Nursing and Allied Health Literature and Business Source Complete were searched to January 2022 using Medical Subject Headings including: 'polypharmacy', 'deprescriptions', 'strategic planning' and 'organizational innovation'. A narrative approach to data synthesis was applied. Searching, data extraction and synthesis were undertaken independently by two reviewers. After screening 797 records, eight papers remained. Two were descriptive, outlining details of specific initiatives; six used qualitative methods to explore determinants for implementation, including barriers and enablers. Barriers at the organisation level included: poor organisational culture with a lack of sense of urgency and national plans, resource availability and communication issues including patient information and at transitions of care. Organisational facilitators included availability of government funding and regulatory environment promoting patient safety, a national emphasis on quality of care for older adults, co-ordinated national efforts and local evidence. Limited literature focusses on the use of implementation frameworks at organisational levels. This review highlights the need for further work on implementation frameworks in this context to help achieve effective organisational change

Epidemiology and screening for renal cancer.

PURPOSE: The widespread use of abdominal imaging has affected the epidemiology of renal cell carcinoma (RCC). Despite this, over 25% of individuals with RCC have evidence of metastases at presentation. Screening for RCC has the potential to downstage the disease. METHODS: We performed a literature review on the epidemiology of RCC and evidence base regarding screening. Furthermore, contemporary RCC epidemiology data was obtained for the United Kingdom and trends in age-standardised rates of incidence and mortality were analysed by annual percentage change statistics and joinpoint regression. RESULTS: The incidence of RCC in the UK increased by 3.1% annually from 1993 through 2014. Urinary dipstick is an inadequate screening tool due to low sensitivity and specificity. It is unlikely that CT would be recommended for population screening due to cost, radiation dose and increased potential for other incidental findings. Screening ultrasound has a sensitivity and specificity of 82-83% and 98-99%, respectively; however, accuracy is dependent on tumour size. No clinically validated urinary nor serum biomarkers have been identified. Major barriers to population screening include the relatively low prevalence of the disease, the potential for false positives and over-diagnosis of slow-growing RCCs. Individual patient risk-stratification based on a combination of risk factors may improve screening efficiency and minimise harms by identifying a group at high risk of RCC. CONCLUSION: The incidence of RCC is increasing. The optimal screening modality and target population remain to be elucidated. An analysis of the benefits and harms of screening for patients and society is warranted

Measuring the effects of fractionated radiation therapy in a 3D prostate cancer model system using SERS nanosensors.

Multicellular tumour spheroids (MTS) are three-dimensional cell cultures that possess their own microenvironments and provide a more meaningful model of tumour biology than monolayer cultures. As a result, MTS are becoming increasingly used as tumor models when measuring the efficiency of therapies. Monitoring the viability of live MTS is complicated by their 3D nature and conventional approaches such as fluorescence often require fixation and sectioning. In this paper we detail the use of Surface Enhanced Raman Spectroscopy (SERS) to measure the viability of MTS grown from prostate cancer (PC3) cells. Our results show that we can monitor loss of viability by measuring pH and redox potential in MTS and furthermore we demonstrate that SERS can be used to measure the effects of fractionation of a dose of radiotherapy in a way that has potential to inform treatment planning.EaStCHEM, NHS Lothian, Jamie King Cancer Research FundThis is the final version of the article. It first appeared from the Royal Society of Chemistry via http://dx.doi.org/10.1039/C6AN01032

The Egg Surface LDL Receptor Repeat-Containing Proteins EGG-1 and EGG-2 Are Required for Fertilization in Caenorhabditis elegans

SummaryThe molecular machinery that mediates sperm-egg interactions at fertilization is largely unknown. We identify two partially redundant egg surface LDL receptor repeat-containing proteins (EGG-1 and EGG-2) that are required for Caenorhabditis elegans fertility in hermaphrodites, but not males. Wild-type sperm cannot enter the morphologically normal oocytes produced by hermaphrodites that lack egg-1 and egg-2 function despite direct gamete contact. Furthermore, we find that levels of meiotic maturation/ovulation and sperm migratory behavior are altered in egg-1 mutants. These observations suggest an unexpected regulatory link between fertilization and other events necessary for reproductive success. egg-1 and egg-2 are the result of a gene duplication in the nematode lineage leading to C. elegans. The two closely related species C. briggsae and C. remanei encode only a single egg-1/egg-2 homolog that is required for hermaphrodite/female fertility. In addition to being the first identified egg components of the nematode fertilization machinery, the egg-1 and egg-2 gene duplication could be vital with regards to maximizing C. elegans fecundity and understanding the evolutionary differentiation of molecular function and speciation

Risk score predicts high-grade prostate cancer in DNA-methylation positive, histopathologically negative biopsies.

BACKGROUND: Prostate cancer (PCa) diagnosis is challenging because efforts for effective, timely treatment of men with significant cancer typically result in over-diagnosis and repeat biopsies. The presence or absence of epigenetic aberrations, more specifically DNA-methylation of GSTP1, RASSF1, and APC in histopathologically negative prostate core biopsies has resulted in an increased negative predictive value (NPV) of ∼90% and thus could lead to a reduction of unnecessary repeat biopsies. Here, it is investigated whether, in methylation-positive men, DNA-methylation intensities could help to identify those men harboring high-grade (Gleason score ≥7) PCa, resulting in an improved positive predictive value. METHODS: Two cohorts, consisting of men with histopathologically negative index biopsies, followed by a positive or negative repeat biopsy, were combined. EpiScore, a methylation intensity algorithm was developed in methylation-positive men, using area under the curve of the receiver operating characteristic as metric for performance. Next, a risk score was developed combining EpiScore with traditional clinical risk factors to further improve the identification of high-grade (Gleason Score ≥7) cancer. RESULTS: Compared to other risk factors, detection of DNA-methylation in histopathologically negative biopsies was the most significant and important predictor of high-grade cancer, resulting in a NPV of 96%. In methylation-positive men, EpiScore was significantly higher for those with high-grade cancer detected upon repeat biopsy, compared to those with either no or low-grade cancer. The risk score resulted in further improvement of patient risk stratification and was a significantly better predictor compared to currently used metrics as PSA and the prostate cancer prevention trial (PCPT) risk calculator (RC). A decision curve analysis indicated strong clinical utility for the risk score as decision-making tool for repeat biopsy. CONCLUSIONS: Low DNA-methylation levels in PCa-negative biopsies led to a NPV of 96% for high-grade cancer. The risk score, comprising DNA-methylation intensity and traditional clinical risk factors, improved the identification of men with high-grade cancer, with a maximum avoidance of unnecessary repeat biopsies. This risk score resulted in better patient risk stratification and significantly outperformed current risk prediction models such as PCPTRC and PSA. The risk score could help to identify patients with histopathologically negative biopsies harboring high-grade PCa. Prostate 76:1078-1087, 2016. © 2016 The Authors. The Prostate Published by Wiley Periodicals, Inc.MDxHealthThis is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Wiley