Quantification of HER2 heterogeneity in breast cancer-implications for identification of sub-dominant clones for personalised treatment

Breast cancer is a heterogeneous disease, at both an inter- and intra-tumoural level. Appreciating heterogeneity through the application of biomarkers and molecular signatures adds complexity to tumour taxonomy but is key to personalising diagnosis, treatment and prognosis. The extent to which heterogeneity exists, and its interpretation remains a challenge to pathologists. Using HER2 as an exemplar, we have developed a simple reproducible heterogeneity index. Cell-to-cell HER2 heterogeneity was extensive in a proportion of both reported 'amplified' and 'non-amplified' cases. The highest levels of heterogeneity objectively identified occurred in borderline categories and higher ratio non-amplified cases. A case with particularly striking heterogeneity was analysed further with an array of biomarkers in order to assign a molecular diagnosis. Broad biological complexity was evident. In essence, interpretation, depending on the area of tumour sampled, could have been one of three distinct phenotypes, each of which would infer different therapeutic interventions. Therefore, we recommend that heterogeneity is assessed and taken into account when determining treatment options.

Assessing the effect of reducing agents on the selective catalytic reduction of NOx over Ag/Al2O3 catalysts

The selective catalytic reduction (SCR) of NOx in the presence of different reducing agents over Ag/Al2O3 prepared by wet impregnation was investigated by probing catalyst activity and using NMR relaxation time analysis to probe the strength of surface interaction of the various reducing agent species and water. The results reveal that the strength of surface interaction of the reducing agent relative to water, the latter present in engine exhausts as a fuel combustion product and, in addition, produced during the SCR reaction, plays an important role in determining catalyst performance. Reducing agents with weak strength of interaction with the catalyst surface, such as hydrocarbons, show poorer catalytic performance than reducing agents with a higher strength of interaction, such as alcohols. This is attributed to the greater ability of oxygenated species to compete with water in terms of surface interaction with the catalyst surface, hence reducing the inhibiting effect of water molecules blocking catalyst sites. The results support the observations of earlier work in that the light off-temperature and maximum NOx conversion and temperature at which that occurs are sensitive to the reducing agent present during reaction, and the proposal that improved catalyst performance is caused by increased adsorption strength of the reducing agent, relative to water, at the catalyst surface. Importantly, the NMR relaxation time analysis approach to characterising the strength of adsorption more readily describes the trends in catalytic behaviour than does a straightforward consideration of the polarity (i.e., relative permittivity) of the reducing agents studied here. In summary, this paper describes a simple approach to characterising the interaction energy of water and reducing agent so as to aid the selection of reducing agent and catalyst to be used in SCR conversions.

Embracing an integromic approach to tissue biomarker research in cancer: Perspectives and lessons learned

Modern approaches to biomedical research and diagnostics targeted towards precision medicine are generating ‘big data’ across a range of high-throughput experimental and analytical platforms. Integrative analysis of this rich clinical, pathological, molecular and imaging data represents one of the greatest bottlenecks in biomarker discovery research in cancer and other diseases. Following on from the publication of our successful framework for multimodal data amalgamation and integrative analysis, Pathology Integromics in Cancer (PICan), this article will explore the essential elements of assembling an integromics framework from a more detailed perspective. PICan, built around a relational database storing curated multimodal data, is the research tool sitting at the heart of our interdisciplinary efforts to streamline biomarker discovery and validation. While recognizing that every institution has a unique set of priorities and challenges, we will use our experiences with PICan as a case study and starting point, rationalizing the design choices we made within the context of our local infrastructure and specific needs, but also highlighting alternative approaches that may better suit other programmes of research and discovery. Along the way, we stress that integromics is not just a set of tools, but rather a cohesive paradigm for how modern bioinformatics can be enhanced. Successful implementation of an integromics framework is a collaborative team effort that is built with an eye to the future and greatly accelerates the processes of biomarker discovery, validation and translation into clinical practice.

Beneficial effect of a polyphenol-rich diet on cardiovascular risk: a randomised control trial

OBJECTIVES: There is previous epidemiological evidence that intake of polyphenol-rich foods has been associated with reduced cardiovascular disease risk. We aimed to investigate the effect of increasing dietary polyphenol intake on microvascular function in hypertensive participants.

METHODS: All participants completed a 4-week run-in phase, consuming <2 portions of fruit and vegetables (F&V) daily and avoiding berries and dark chocolate. Subjects were then randomised to continue with the low-polyphenol diet for 8 weeks or to consume a high-polyphenol diet of six portions F&V (including one portion of berries/day and 50 g of dark chocolate). Endothelium-dependent (acetylcholine, ACh) and endothelium-independent (sodium nitroprusside) vasodilator responses were assessed by venous occlusion plethysmography. Compliance with the intervention was measured using food diaries and biochemical markers.

RESULTS: Final analysis of the primary endpoint was conducted on 92 participants. Between-group comparison of change in maximum % response to ACh revealed a significant improvement in the high-polyphenol group (p=0.02). There was a significantly larger increase in vitamin C, carotenoids and epicatechin in the high-polyphenol group (between-group difference p<0.001; p<0.001; p=0.008, respectively).

CONCLUSIONS: This study has shown that increasing the polyphenol content of the diet via consumption of F&V, berries and dark chocolate results in a significant improvement in an established marker of cardiovascular risk in hypertensive participants.

Systematic review of tools to measure outcomes for young children with autism spectrum disorder

BACKGROUND: The needs of children with autism spectrum disorder (ASD) are complex and this is reflected in the number and diversity of outcomes assessed and measurement tools used to collect evidence about children's progress. Relevant outcomes include improvement in core ASD impairments, such as communication, social awareness, sensory sensitivities and repetitiveness; skills such as social functioning and play; participation outcomes such as social inclusion; and parent and family impact.

OBJECTIVES: To examine the measurement properties of tools used to measure progress and outcomes in children with ASD up to the age of 6 years. To identify outcome areas regarded as important by people with ASD and parents.

METHODS: The MeASURe (Measurement in Autism Spectrum disorder Under Review) research collaboration included ASD experts and review methodologists. We undertook systematic review of tools used in ASD early intervention and observational studies from 1992 to 2013; systematic review, using the COSMIN checklist (Consensus-based Standards for the selection of health Measurement Instruments) of papers addressing the measurement properties of identified tools in children with ASD; and synthesis of evidence and gaps. The review design and process was informed throughout by consultation with stakeholders including parents, young people with ASD, clinicians and researchers.

RESULTS: The conceptual framework developed for the review was drawn from the International Classification of Functioning, Disability and Health, including the domains 'Impairments', 'Activity Level Indicators', 'Participation', and 'Family Measures'. In review 1, 10,154 papers were sifted - 3091 by full text - and data extracted from 184; in total, 131 tools were identified, excluding observational coding, study-specific measures and those not in English. In review 2, 2665 papers were sifted and data concerning measurement properties of 57 (43%) tools were extracted from 128 papers. Evidence for the measurement properties of the reviewed tools was combined with information about their accessibility and presentation. Twelve tools were identified as having the strongest supporting evidence, the majority measuring autism characteristics and problem behaviour. The patchy evidence and limited scope of outcomes measured mean these tools do not constitute a 'recommended battery' for use. In particular, there is little evidence that the identified tools would be good at detecting change in intervention studies. The obvious gaps in available outcome measurement include well-being and participation outcomes for children, and family quality-of-life outcomes, domains particularly valued by our informants (young people with ASD and parents).

CONCLUSIONS: This is the first systematic review of the quality and appropriateness of tools designed to monitor progress and outcomes of young children with ASD. Although it was not possible to recommend fully robust tools at this stage, the review consolidates what is known about the field and will act as a benchmark for future developments. With input from parents and other stakeholders, recommendations are made about priority targets for research.

FUTURE WORK: Priorities include development of a tool to measure child quality of life in ASD, and validation of a potential primary outcome tool for trials of early social communication intervention.

STUDY REGISTRATION: This study is registered as PROSPERO CRD42012002223.

FUNDING: The National Institute for Health Research Health Technology Assessment programme.