HOPX functions as a tumour suppressor in head and neck cancer.

Head and neck squamous cell carcinoma (HNSCC) is generalized term that encompasses a diverse group of cancers that includes tumours of the oral cavity (OSCC), oropharynx (OPSCC) and nasopharynx (NPC). Genetic alterations that are common to all HNSCC types are likely to be important for squamous carcinogenesis. In this study, we have investigated the role of the homeodomain-only homeobox gene, HOPX, in the pathogenesis of HNSCC. We show that HOPX mRNA levels are reduced in OSCC and NPC cell lines and tissues and there is a general reduction of HOPX protein expression in these tumours and OPSCCs. HOPX promoter methylation was observed in a subset of HNSCCs and was associated with a worse overall survival in HPV negative tumours. RNAseq analysis of OSCC cells transfected with HOPX revealed a widespread deregulation of the transcription of genes related to epithelial homeostasis and ectopic over-expression of HOPX in OSCC and NPC cells inhibited cell proliferation, plating efficiency and migration, and enhanced sensitivity to UVA-induced apoptosis. Our results demonstrate that HOPX functions as a tumour suppressor in HNSCC and suggest a central role for HOPX in suppressing epithelial carcinogenesis

The effectiveness of schemes that refine referrals between primary and secondary care - the UK experience with glaucoma referrals: the Health Innovation & Education Cluster (HIEC) Glaucoma Pathways Project

Objectives: A comparison of glaucoma referral refinement schemes (GRRS) in the UK during a time period of considerable change in national policy and guidance. Design: Retrospective multisite review. Setting: The outcomes of clinical examinations by optometrists with a specialist interest in glaucoma (OSIs) were compared with optometrists with no specialist interest in glaucoma (non-OSIs). Data from Huntingdon and Nottingham assessed non-OSI findings, while Manchester and Gloucestershire reviewed OSI findings. Participants: 1086 patients. 434 patients were from Huntingdon, 179 from Manchester, 204 from Gloucestershire and 269 from Nottingham. Results: The first-visit discharge rate (FVDR) for all time periods for OSIs was 14.1% compared with 36.1% from non-OSIs (difference 22%, CI 16.9% to 26.7%; p<0.001). The FVDR increased after the April 2009 National Institute for Health and Clinical Excellence (NICE) glaucoma guidelines compared with pre-NICE, which was particularly evident when pre-NICE was compared with the current practice time period (OSIs 6.2–17.2%, difference 11%, CI −24.7% to 4.3%; p=0.18, non-OSIs 29.2–43.9%, difference 14.7%, CI −27.8% to −0.30%; p=0.03). Elevated intraocular pressure (IOP) was the commonest reason for referral for OSIs and non-OSIs, 28.7% and 36.1%, respectively, of total referrals. The proportion of referrals for elevated IOP increased from 10.9% pre-NICE to 28.0% post-NICE for OSIs, and from 19% to 45.1% for non-OSIs. Conclusions: In terms of ‘demand management’, OSIs can reduce FVDR of patients reviewed in secondary care; however, in terms of ‘patient safety’ this study also shows that overemphasis on IOP as a criterion for referral is having an adverse effect on both the non-OSIs and indeed the OSIs ability to detect glaucomatous optic nerve features. It is recommended that referral letters from non-OSIs be stratified for risk, directing high-risk patients straight to secondary care, and low-risk patients to OSIs

Development and application of the Demands for Population Health Interventions (Depth) framework for categorising the agentic demands of population health interventions

Background: The ‘agentic demand’ of population health interventions (PHIs) refers to the capacity, resources and freedom to act that interventions demand of their recipients to benefit, which have a socio-economical pattern. Highly agentic interventions, e.g. information campaigns, rely on recipients noticing and responding to the intervention and thus might affect intervention effectiveness and equity. The absence of an adequate framework to classify agentic demands limits the fields’ ability to systematically explore these associations. Methods: We systematically developed the Demands for Population Health Interventions (Depth) framework using an iterative approach: (1) Developing the Depth framework by systematically identifying examples of PHIs aiming to promote healthier diets and physical activity, coding of intervention actors and actions and synthesising the data to develop the framework; (2) Testing the Depth framework in online workshops with academic and policy experts and a quantitative reliability assessment. We applied the final framework in a proof-of-concept review, extracting studies from three existing equity focused systematic reviews on framework category, overall effectiveness and differential socioeconomic effects and visualised the findings in Harvest Plots. Results: The Depth framework identifies three constructs influencing agentic demand: exposure - initial contact with intervention (2 levels), mechanism of action - how the intervention enables or discourages behaviour (5 levels), and engagement - recipient response (2 levels). When combined, these constructs form a matrix of twenty possible classifications. In the proof-of-concept review, we classified all components of 31 interventions according to the Depth framework. Intervention components were concentrated in a small number of Depth classifications; Depth classification appeared to be related to intervention equity but not effectiveness. Conclusions: This framework holds potential for future research, policy and practice, facilitating the design, selection and evaluation of interventions and evidence synthesis

Extraction of Accurate Biomolecular Parameters from Single-Molecule Force Spectroscopy Experiments

The atomic force microscope (AFM) is able to manipulate biomolecules and their complexes with exquisite force sensitivity and distance resolution. This capability, complemented by theoretical models, has greatly improved our understanding of the determinants of mechanical strength in proteins and revealed the diverse effects of directional forces on the energy landscape of biomolecules. In unbinding experiments, the interacting partners are usually immobilized on their respective substrates via extensible linkers. These linkers affect both the force and contour length (Lc) of the complex at rupture. Surprisingly, while the former effect is well understood, the latter is largely neglected, leading to incorrect estimations of Lc, a parameter that is often used as evidence for the detection of specific interactions and remodeling events and for the inference of interaction regions. To address this problem, a model that predicts contour length measurements from single-molecule forced-dissociation experiments is presented that considers attachment position on the AFM tip, geometric effects, and polymer dynamics of the linkers. Modeled data are compared with measured contour length distributions from several different experimental systems, revealing that current methods underestimate contour lengths. The model enables nonspecific interactions to be identified unequivocally, allows accurate determination of Lc, and, by comparing experimental and modeled distributions, enables partial unfolding events before rupture to be identified unequivocally

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

The false negative rate and the role for virtual review in a nationally evaluated glaucoma referral refinement scheme

Purpose: To establish the safety of the CHANGES glaucoma referral refinement scheme (GRRS). Methods: The CHANGES scheme risk stratifies glaucoma referrals, with low risk referrals seen by a community based specialist optometrist (OSI) while high risk referrals are referred directly to the hospital. In this study, those patients discharged by the OSI were reviewed by the consultant ophthalmologist to establish a ‘false negative’ rate (Study 1). Virtual review of optic disc photographs was carried out both by a hospital‐based specialist optometrist as well as the consultant ophthalmologist (Study 2). Results: None of these 34 discharged patients seen by the consultant were found to have glaucoma or started on treatment to lower the intra‐ocular pressure. Five of the 34 (15%) were classified as ‘glaucoma suspect’ based on the appearance of the optic disc and offered a follow‐up appointment. Virtual review by both the consultant and optometrist had a sensitivity of 80%, whilst the false positive rate for the optometrist was 3.4%, and 32% for the consultant (p < 0.05). Conclusions: The false negative rate of the OSIs in the CHANGES scheme was 15%, however there were no patients where glaucoma was missed. Virtual review in experienced hands can be as effective as clinical review by a consultant, and is a valid method to ensure glaucoma is not missed in GRRS. The CHANGES scheme, which includes virtual review, is effective at reducing referrals to the hospital whilst not compromising patient safety

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Not AvailableBlack clam (Villorita cyprinoides) (Gray, 1825) is a bivalve mollusc and majority of its fishery is contributed by Vembanad lake of Kerala. Edible meat has to be separated from calcareous shells of black clam after cooking and the separation of meat from shells is a very difficult task for clam processors. Traditionally, black clam processors rely on indigenous methods for meat-shell separation using devices that lack a standard design, and do not follow any steps to assure the quality of the produce. No food quality standard parameters are adopted while considering the materials used for fabrication resulting in unhygienic handling and processing of clam meat. As a result of the unhygienic handling and processing, the product is often of an inferior quality. In this context, a modified model of indigenous meat-shell separator machine to handle bulk quantities of clams was designed and fabricated. The improved model has continuous mode of operation and the trials using this model demonstrated that it can handle 300 kg clam shells per hour with a meat-shell separation efficiency of 95%. It was found to be efficient, cost effective, ergonomic, and durable and also which conforms to the food safety regulatory requirements. This improved model has the potential to reduce the drudgery of clam processing and can encourage members of the rural communities to take up clam processing hygienically.Not Availabl