• Microstructural imaging of the human brain with a 'super-scanner': 10 key advantages of ultra-strong gradients for diffusion MRI

  Jones, DK; Alexander, DC; Bowtell, R; Cercignani, M; Dell'Acqua, F; McHugh, Damien J; Miller, KL; Palombo, M; Parker, Geoff JM; Rudrapatna, US; Tax, CMW; Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology, Cardiff University, Maindy Road, Cardiff (2018)

  The key component of a microstructural diffusion MRI 'super-scanner' is a dedicated high-strength gradient system that enables stronger diffusion weightings per unit time compared to conventional gradient designs. This can, in turn, drastically shorten the time needed for diffusion encoding, increase the signal-to-noise ratio, and facilitate measurements at shorter diffusion times. This review, written from the perspective of the UK National Facility for In Vivo MR Imaging of Human Tissue Microstructure, an initiative to establish a shared 300 mT/m-gradient facility amongst the microstructural imaging community, describes ten advantages of ultra-strong gradients for microstructural imaging. Specifically, we will discuss how the increase of the accessible measurement space compared to a lower-gradient systems (in terms of ?, b-value, and TE) can accelerate developments in the areas of 1) axon diameter distribution mapping; 2) microstructural parameter estimation; 3) mapping micro-vs macroscopic anisotropy features with gradient waveforms beyond a single pair of pulsed-gradients; 4) multi-contrast experiments, e.g. diffusion-relaxometry; 5) tractography and high-resolution imaging in vivo and 6) post mortem; 7) diffusion-weighted spectroscopy of metabolites other than water; 8) tumour characterisation; 9) functional diffusion MRI; and 10) quality enhancement of images acquired on lower-gradient systems. We finally discuss practical barriers in the use of ultra-strong gradients, and provide an outlook on the next generation of 'super-scanners'.
• Mutation pattern analysis reveals polygenic mini-drivers associated with relapse after surgery in lung adenocarcinoma

  Bennett, Laura; Howell, Matthew; Memon, Danish; Smowton, Christopher; Zhou, Cong; Miller, Crispin J; RNA Biology Group, CRUK Manchester Institute, The University of Manchester, Alderley Park, Manchester, SK10 4TG, UK (2018)

  The genomic lesions found in malignant tumours exhibit a striking degree of heterogeneity. Many tumours lack a known driver mutation, and their genetic basis is unclear. By mapping the somatic mutations identified in primary lung adenocarcinomas onto an independent coexpression network derived from normal tissue, we identify a critical gene network enriched for metastasis-associated genes. While individual genes within this module were rarely mutated, a significant accumulation of mutations within this geneset was predictive of relapse in lung cancer patients that have undergone surgery. Since it is the density of mutations within this module that is informative, rather than the status of any individual gene, these data are in keeping with a 'mini-driver' model of tumorigenesis in which multiple mutations, each with a weak effect, combine to form a polygenic driver with sufficient power to significantly alter cell behaviour and ultimately patient outcome. These polygenic mini-drivers therefore provide a means by which heterogeneous mutation patterns can generate the consistent hallmark changes in phenotype observed across tumours.
• Curvature delays growth-induced wrinkling

  Jia, F; Pearce, Simon P; Goriely, A; School of Manufacturing Science and Engineering, Southwest University of Science and Technology, Sichuan 621010, China (2018)

  Wrinkling patterns can be induced by the growth of a thin elastic film over a soft elastic substrate. While there is a good understanding of how this pattern is initiated on a flat geometry, wrinkling patterns over a curved surface are more complicated. Here, we consider this phenomenon within the framework of large deformation morphoelasticity by investigating surface wrinkling of a growing thin elastic film bonded to a large elastic cylinder. The system has two important dimensionless parameters: the ratio ? of the film thickness by the cylinder radius and the relative stiffness of the two layers ?. Depending on the values of ? and ? we identify four different regimes for which we find the critical growth and wrinkling mode number. By combining asymptotic methods with numerical computations we determine the effect of the curvature on the bifurcation and establish that it always induces a delay at the bifurcation: Larger growth is needed on a curved surface to induce the same wrinkling instability. These results are crucial to understand pattern formation on surface with varying curvatures.
• What Do the Guidelines Say for Metastatic Prostate Cancer Starting Androgen Deprivation Therapy? National Comprehensive Cancer Network, European Society for Medical Oncology, and European Association of Urology recommendations

  Yu, EY; Gillessen, Silke; Mottet, N; Department of Medicine, Division of Oncology, University of Washington, Seattle, WA, USA; (2018)

  Clinical trial data forms the foundation of how we treat men with metastatic prostate cancer who are initiating therapy. However, clinical trial data does not answer everything; hence, good clinical practice, pragmatism, and occasionally extrapolation drives how we manage these patients. Fortunately, multiple international guideline committees meet regularly and offer clinical guidance. In this mini-review, we focus on the United States National Comprehensive Cancer Network, European Society for Medical Oncology, and European Association of Urology (EAU) recommendations for the initial treatment of metastatic prostate cancer.
• The p38alpha Stress Kinase Suppresses Aneuploidy Tolerance by Inhibiting Hif-1alpha

  Simoes-Sousa, Susana; Littler, Samantha; Thompson, Sarah L; Minshall, Paul; Whalley, Helen J; Bakker, B; Belkot, Klaudyna,; Moralli, D; Bronder, Daniel; Tighe, Anthony; Spierings, DCJ; Bah, Nourdine; Graham, Joshua; Nelson, Louisa; Green, CM; Foijer, F; Townsend, Paul A; Taylor, Stephen S; Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Cancer Research Centre, Wilmslow Road, Manchester M20 4QL (2018)

  Deviating from the normal karyotype dramatically changes gene dosage, in turn decreasing the robustness of biological networks. Consequently, aneuploidy is poorly tolerated by normal somatic cells and acts as a barrier to transformation. Paradoxically, however, karyotype heterogeneity drives tumor evolution and the emergence of therapeutic drug resistance. To better understand how cancer cells tolerate aneuploidy, we focused on the p38 stress response kinase. We show here that p38-deficient cells upregulate glycolysis and avoid post-mitotic apoptosis, leading to the emergence of aneuploid subclones. We also show that p38 deficiency upregulates the hypoxia-inducible transcription factor Hif-1? and that inhibiting Hif-1? restores apoptosis in p38-deficent cells. Because hypoxia and aneuploidy are both barriers to tumor progression, the ability of Hif-1? to promote cell survival following chromosome missegregation raises the possibility that aneuploidy tolerance coevolves with adaptation to hypoxia.

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