HAVE WE REACHED PEAK DESIGN THINKING? Are we entering a new paradigm for how it is used within practice and business?

Design Thinking has gained recognition as an acclaimed process for generating innovative, human centred solutions at a social and business level. It has also gained notoriety amongst many designers, who claim that its success as an exported element of the design process has resulted in its commodification, and led to it becoming a diluted series of processes that lack criticality. As design disciplines and the role of designers continue to evolve, we should reflect on design thinking’s original context and understand its progression into a non-design world. Our hypothesis is that design thinking has reached a ‘peak’ in contemporary practice, and as the term 'design' is further adapted and conformed to suit a business function, this conversational will elicit a constructive debate on the future of design thinking and its positioning within design and non-design industries. Has Design Thinking’s commodification and consumption as a step by step road map to innovation reduced it to a mainstream approach? Can we use the undoubted successes of design thinking as a catalyst for future design research? It is anticipated that through analysis and discussion, this conversation will inform the conceptualisation of enhanced methodological frameworks that aim to support innovation across divergent industry practices

Phenological Parameters Estimation Tool

The Phenological Parameters Estimation Tool (PPET) is a set of algorithms implemented in MATLAB that estimates key vegetative phenological parameters. For a given year, the PPET software package takes in temporally processed vegetation index data (3D spatio-temporal arrays) generated by the time series product tool (TSPT) and outputs spatial grids (2D arrays) of vegetation phenological parameters. As a precursor to PPET, the TSPT uses quality information for each pixel of each date to remove bad or suspect data, and then interpolates and digitally fills data voids in the time series to produce a continuous, smoothed vegetation index product. During processing, the TSPT displays NDVI (Normalized Difference Vegetation Index) time series plots and images from the temporally processed pixels. Both the TSPT and PPET currently use moderate resolution imaging spectroradiometer (MODIS) satellite multispectral data as a default, but each software package is modifiable and could be used with any high-temporal-rate remote sensing data collection system that is capable of producing vegetation indices. Raw MODIS data from the Aqua and Terra satellites is processed using the TSPT to generate a filtered time series data product. The PPET then uses the TSPT output to generate phenological parameters for desired locations. PPET output data tiles are mosaicked into a Conterminous United States (CONUS) data layer using ERDAS IMAGINE, or equivalent software package. Mosaics of the vegetation phenology data products are then reprojected to the desired map projection using ERDAS IMAGIN

Variation in histone configurations correlates with gene expression across nine inbred strains of mice.

The diversity outbred (DO) mice and their inbred founders are widely used models of human disease. However, although the genetic diversity of these mice has been well documented, their epigenetic diversity has not. Epigenetic modifications, such as histone modifications and DNA methylation, are important regulators of gene expression, and as such are a critical mechanistic link between genotype and phenotype. Therefore, creating a map of epigenetic modifications in the DO mice and their founders is an important step toward understanding mechanisms of gene regulation and the link to disease in this widely used resource. To this end, we performed a strain survey of epigenetic modifications in hepatocytes of the DO founders. We surveyed four histone modifications (H3K4me1, H3K4me3, H3K27me3, and H3K27ac), and DNA methylation. We used ChromHMM to identify 14 chromatin states, each of which represented a distinct combination of the four histone modifications. We found that the epigenetic landscape was highly variable across the DO founders and was associated with variation in gene expression across strains. We found that epigenetic state imputed into a population of DO mice recapitulated the association with gene expression seen in the founders suggesting that both histone modifications and DNA methylation are highly heritable mechanisms of gene expression regulation. We illustrate how DO gene expression can be aligned with inbred epigenetic states to identify putative cis-regulatory regions. Finally, we provide a data resource that documents strain-specific variation in chromatin state and DNA methylation in hepatocytes across nine widely used strains of laboratory mice

Phase I trial of WEE1 inhibition with chemotherapy and radiotherapy as adjuvant treatment, and a window of opportunity trial with cisplatin in patients with head and neck cancer: the WISTERIA trial protocol.

INTRODUCTION:Patients with head and neck squamous cell carcinoma with locally advanced disease often require multimodality treatment with surgery, radiotherapy and/or chemotherapy. Adjuvant radiotherapy with concurrent chemotherapy is offered to patients with high-risk pathological features postsurgery. While cure rates are improved, overall survival remains suboptimal and treatment has a significant negative impact on quality of life.Cell cycle checkpoint kinase inhibition is a promising method to selectively potentiate the therapeutic effects of chemoradiation. Our hypothesis is that combining chemoradiation with a WEE1 inhibitor will affect the biological response to DNA damage caused by cisplatin and radiation, thereby enhancing clinical outcomes, without increased toxicity. This trial explores the associated effect of WEE1 kinase inhibitor adavosertib (AZD1775). METHODS AND ANALYSIS:This phase I dose-finding, open-label, multicentre trial aims to determine the highest safe dose of AZD1775 in combination with cisplatin chemotherapy preoperatively (group A) as a window of opportunity trial, and in combination with postoperative cisplatin-based chemoradiation (group B).Modified time-to-event continual reassessment method will determine the recommended dose, recruiting up to 21 patients per group. Primary outcomes are recommended doses with predefined target dose-limiting toxicity probabilities of 25% monitored up to 42 days (group A), and 30% monitored up to 12 weeks (group B). Secondary outcomes are disease-free survival times (groups A and B). Exploratory objectives are evaluation of pharmacodynamic (PD) effects, identification and correlation of potential biomarkers with PD markers of DNA damage, determine rate of resection status and surgical complications for group A; and quality of life in group B. ETHICS AND DISSEMINATION:Research Ethics Committee, Edgbaston, West Midlands (REC reference 16/WM/0501) initial approval received on 18/01/2017. Results will be disseminated via peer-reviewed publication and presentation at international conferences. TRIAL REGISTRATION NUMBER:ISRCTN76291951 and NCT03028766

Protection of innate immunity by C5aR antagonist in septic mice

Innate immune functions are known to be compromised during sepsis, often with lethal consequences. There is also evidence in rats that sepsis is associated with excessive complement activation and generation of the potent anaphylatoxin C5a. In the presence of a cyclic peptide antagonist (C5aRa) to the C5a receptor (C5aR), the binding of murine 125Iâ C5a to murine neutrophils was reduced, the in vitro chemotactic responses of mouse neutrophils to mouse C5a were markedly diminished, the acquired defect in hydrogen peroxide (H2O2) production of C5aâ exposed neutrophils was reversed, and the lung permeability index (extravascular leakage of albumin) in mice after intrapulmonary deposition of IgG immune complexes was markedly diminished. Mice that developed sepsis after cecal ligation/puncture (CLP) and were treated with C5aRa had greatly improved survival rates. These data suggest that C5aRa interferes with neutrophil responses to C5a, preventing C5aâ induced compromise of innate immunity during sepsis, with greatly improved survival rates after CLP.â Huberâ Lang, M. S., Riedeman, N. C., Sarma, J. V., Younkin, E. M., McGuire, S. R., Laudes, I. J., Lu, K. T., Guo, R.â F., Neff, T. A., Padgaonkar, V. A., Lambris, J. D., Spruce, L., Mastellos, D., Zetoune, F. S., Ward, P. A. Protection of innate immunity by C5aR antagonist in septic mice. FASEB J. 16, 1567â 1574 (2002)Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154360/1/fsb2fj020209com.pd

Ultra-low DNA input into whole genome methylation assays and detection of oncogenic methylation and copy number variants in circulating tumour DNA

Background: Abnormal CpG methylation in cancer is ubiquitous and generally detected in tumour specimens using a variety of techniques at a resolution encompassing single CpG loci to genome wide coverage. Analysis of samples with very low DNA inputs, such as formalin fixed (FFPE) biopsy specimens from clinical trials or circulating tumour DNA is challenging at the genome-wide level because of lack of available input. We present the results of low input experiments into the Illumina Infinium HD methylation assay on FFPE specimens and ctDNA samples. Methods: For all experiments, the Infinium HD assay for methylation was used. In total, forty-eight FFPE specimens were used at varying concentrations (lowest input 50 ng); eighteen blood derived specimens (lowest input 10 ng) and six matched ctDNA input (lowest input 10 ng)/fresh tumour specimens (lowest input 250 ng) were processed. Downstream analysis was performed in R/Bioconductor for quality control metrics and differential methylation analysis as well as copy number calls. Results: Correlation coefficients for CpG methylation were high at the probe level averaged R2 = 0.99 for blood derived samples and R2 > 0.96 for the FFPE samples. When matched ctDNA/fresh tumour samples were compared, R2 > 0.91 between the two. Results of differential methylation analysis did not vary significantly by DNA input in either the blood or FFPE groups. There were differences seen in the ctDNA group as compared to their paired tumour sample, possibly because of enrichment for tumour material without contaminating normal. Copy number variants observed in the tumour were generally also seen in the paired ctDNA sample with good concordance via DQ plot. Conclusions: The Illumina Infinium HD methylation assay can robustly detect methylation across a range of sample types, including ctDNA, down to an input of 10 ng. It can also reliably detect oncogenic methylation changes and copy number variants in ctDNA. These findings demonstrate that these samples can now be accessed by methylation array technology, allowing analysis of these important sample types

The Clinical Utility of Cell-Free DNA Measurement in Differentiated Thyroid Cancer::A Systematic Review

BackgroundCell-free DNA (cfDNA) can be detected in the circulation of healthy individuals, but is found in higher concentrations in cancer patients. Furthermore, mutations in tumor cells can be identified in circulating DNA fragments. This has been the subject of significant interest in the field of cancer research, but little has been published in thyroid cancer.ObjectivesTo assess all available evidence on the use of circulating cfDNA in the diagnosis, management and surveillance of patients with differentiated thyroid cancer, and collate it into a systematic review to guide future research.MethodsA comprehensive literature search on the measurement of cfDNA in thyroid cancer was undertaken, and results from relevant studies collated into a systematic review.ResultsNine studies were identified, with varying methodologies and findings. Key techniques and findings are summarized.ConclusionThere is limited but promising evidence that somatic mutations in thyroid cancer can be detected in circulating cfDNA and are associated with more advanced disease. Further research is required to develop a clinically useful tool based on cfDNA to improve the management of thyroid cancers

Determining the neurotransmitter concentration profile at active synapses

Establishing the temporal and concentration profiles of neurotransmitters during synaptic release is an essential step towards understanding the basic properties of inter-neuronal communication in the central nervous system. A variety of ingenious attempts has been made to gain insights into this process, but the general inaccessibility of central synapses, intrinsic limitations of the techniques used, and natural variety of different synaptic environments have hindered a comprehensive description of this fundamental phenomenon. Here, we describe a number of experimental and theoretical findings that has been instrumental for advancing our knowledge of various features of neurotransmitter release, as well as newly developed tools that could overcome some limits of traditional pharmacological approaches and bring new impetus to the description of the complex mechanisms of synaptic transmission