Systematic Identification of Combinatorial Drivers and Targets in Cancer Cell Lines

There is an urgent need to elicit and validate highly efficacious targets for combinatorial intervention from large scale ongoing molecular characterization efforts of tumors. We established an in silico bioinformatic platform in concert with a high throughput screening platform evaluating 37 novel targeted agents in 669 extensively characterized cancer cell lines reflecting the genomic and tissue-type diversity of human cancers, to systematically identify combinatorial biomarkers of response and co-actionable targets in cancer. Genomic biomarkers discovered in a 141 cell line training set were validated in an independent 359 cell line test set. We identified co-occurring and mutually exclusive genomic events that represent potential drivers and combinatorial targets in cancer. We demonstrate multiple cooperating genomic events that predict sensitivity to drug intervention independent of tumor lineage. The coupling of scalable in silico and biologic high throughput cancer cell line platforms for the identification of co-events in cancer delivers rational combinatorial targets for synthetic lethal approaches with a high potential to pre-empt the emergence of resistance

Development and evaluation of a cancer-related fatigue patient education program: protocol of a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Cancer-related fatigue (CRF) and its impact on patients' quality of life has been an increasing subject of research. However, in Germany there is a lack of evidence-based interventions consistent with the multidimensional character of fatigue. The objective of this study is to develop and evaluate a self-management program for disease-free cancer patients to cope with CRF.</p> <p>Methods</p> <p>Based on evidence extracted from a literature review, a curriculum for the self-management program was elaborated. The curriculum was reviewed and validated by an interdisciplinary expert group and the training-modules will be pretested with a small number of participants and discussed in terms of feasibility and acceptance.</p> <p>To determine the efficacy of the program a randomised controlled trial will be carried out: 300 patients will be recruited from oncological practices in Bremen, Germany, and will be allocated to intervention or control group. The intervention group participates in the program, whereas the control group receives standard care and the opportunity to take part in the program after the end of the follow-up (waiting control group). Primary outcome measure is the level of fatigue, secondary outcome measures are quality of life, depression, anxiety, self-efficacy and physical activity. Data will be collected before randomisation, after intervention, and after a follow-up of 6 months.</p> <p>Discussion</p> <p>Because there are no comparable self-management programs for cancer survivors with fatigue, the development of the curriculum has been complex; therefore, the critical appraisal by the experts was an important step to validate the program and their contributions have been integrated into the curriculum. The experts appreciated the program as filling a gap in outpatient cancer care.</p> <p>If the results of the evaluation prove to be satisfactory, the outpatient care of cancer patients can be broadened and supplemented.</p> <p>Trial Registration</p> <p>ClinicalTrials NCT00552552</p

In participatory budgeting we trust? Fairness, tactics and (in)accessibility in participatory governance

Participatory budgeting (PB) is a significant innovation in democracy and local development. PB provides the opportunity for citizens to engage in processes of deliberation and decision-making upon the allocation of public funds. As new critical discourse emerges surrounding this model of local government spending, a significant area warranting investigation concerns how trust, and indeed mistrust, factor into PB. Through an analysis of interviews with residents and Council staff engaged in PB processes in a county in the north of England, we highlight the ways in which issues of trust can impact on participation in these initiatives, and also strengthen relationships between voting delegates, project teams and local government. This paper argues that increasing the perceived accessibility, and reconsidering the inclusion of mass membership groups in PB, might help to create progressive, effective and trustful participation

A high-performance 8 nV/root Hz 8-channel wearable and wireless system for real-time monitoring of bioelectrical signals

Background: It is widely accepted by the scientific community that bioelectrical signals, which can be used for the identification of neurophysiological biomarkers indicative of a diseased or pathological state, could direct patient treatment towards more effective therapeutic strategies. However, the design and realisation of an instrument that can precisely record weak bioelectrical signals in the presence of strong interference stemming from a noisy clinical environment is one of the most difficult challenges associated with the strategy of monitoring bioelectrical signals for diagnostic purposes. Moreover, since patients often have to cope with the problem of limited mobility being connected to bulky and mains-powered instruments, there is a growing demand for small-sized, high-performance and ambulatory biopotential acquisition systems in the Intensive Care Unit (ICU) and in High-dependency wards. Finally, to the best of our knowledge, there are no commercial, small, battery-powered, wearable and wireless recording-only instruments that claim the capability of recording electrocorticographic (ECoG) signals. Methods: To address this problem, we designed and developed a low-noise (8 nV/√Hz), eight-channel, battery-powered, wearable and wireless instrument (55 × 80 mm2). The performance of the realised instrument was assessed by conducting both ex vivo and in vivo experiments. Results: To provide ex vivo proof-of-function, a wide variety of high-quality bioelectrical signal recordings are reported, including electroencephalographic (EEG), electromyographic (EMG), electrocardiographic (ECG), acceleration signals, and muscle fasciculations. Low-noise in vivo recordings of weak local field potentials (LFPs), which were wirelessly acquired in real time using segmented deep brain stimulation (DBS) electrodes implanted in the thalamus of a non-human primate, are also presented. Conclusions: The combination of desirable features and capabilities of this instrument, namely its small size (~one business card), its enhanced recording capabilities, its increased processing capabilities, its manufacturability (since it was designed using discrete off-the-shelf components), the wide bandwidth it offers (0.5 – 500 Hz) and the plurality of bioelectrical signals it can precisely record, render it a versatile and reliable tool to be utilized in a wide range of applications and environments

Glioblastoma—a moving target

The slow development of effective treatment of glioblastoma is contrasted by the rapidly advancing research on the molecular mechanisms underlying the disease. Amplification and overexpression of receptor tyrosine kinases, particularly EGFR and PDGFRA, are complemented by mutations in the PI3K, RB1, and p53 signaling pathways. In addition to finding effective means to target these pathways, we may take advantage of the recent understanding of the hierarchical structure of tumor cell populations, where the progressive expansion of the tumor relies on a minor subpopulation of glioma stem cells, or glioma-initiating cells. Finding ways to reprogram these cells and block their self-renewal is one of the most important topics for future research