Distribution-based measures of tumor heterogeneity are sensitive to mutation calling and lack strong clinical predictive power.

Mutant allele frequency distributions in cancer samples have been used to estimate intratumoral heterogeneity and its implications for patient survival. However, mutation calls are sensitive to the calling algorithm. It remains unknown whether the relationship of heterogeneity and clinical outcome is robust to these variations. To resolve this question, we studied the robustness of allele frequency distributions to the mutation callers MuTect, SomaticSniper, and VarScan in 4722 cancer samples from The Cancer Genome Atlas. We observed discrepancies among the results, particularly a pronounced difference between allele frequency distributions called by VarScan and SomaticSniper. Survival analysis showed little robust predictive power for heterogeneity as measured by Mutant-Allele Tumor Heterogeneity (MATH) score, with the exception of uterine corpus endometrial carcinoma. However, we found that variations in mutant allele frequencies were mediated by variations in copy number. Our results indicate that the clinical predictions associated with MATH score are primarily caused by copy number aberrations that alter mutant allele frequencies. Finally, we present a mathematical model of linear tumor evolution demonstrating why MATH score is insufficient for distinguishing different scenarios of tumor growth. Our findings elucidate the importance of allele frequency distributions as a measure for tumor heterogeneity and their prognostic role

Pan-cancer classifications of tumor histological images using deep learning

Histopathological images are essential for the diagnosis of cancer type and selection of optimal treatment. However, the current clinical process of manual inspection of images is time consuming and prone to intra- and inter-observer variability. Here we show that key aspects of cancer image analysis can be performed by deep convolutional neural networks (CNNs) across a wide spectrum of cancer types. In particular, we implement CNN architectures based on Google Inception v3 transfer learning to analyze 27815 H&E slides from 23 cohorts in The Cancer Genome Atlas in studies of tumor/normal status, cancer subtype, and mutation status. For 19 solid cancer types we are able to classify tumor/normal status of whole slide images with extremely high AUCs (0.995±0.008). We are also able to classify cancer subtypes within 10 tissue types with AUC values well above random expectations (micro-average 0.87±0.1). We then perform a cross-classification analysis of tumor/normal status across tumor types. We find that classifiers trained on one type are often effective in distinguishing tumor from normal in other cancer types, with the relationships among classifiers matching known cancer tissue relationships. For the more challenging problem of mutational status, we are able to classify TP53 mutations in three cancer types with AUCs from 0.65-0.80 using a fully-trained CNN, and with similar cross-classification accuracy across tissues. These studies demonstrate the power of CNNs for not only classifying histopathological images in diverse cancer types, but also for revealing shared biology between tumors. We have made software available at: https://github.com/javadnoorb/HistCNNFirst author draf

Design Optimization of a Hybrid Trapped Field Magnet Lens (HTFML)

The concept of a hybrid trapped field magnet lens (HTFML) was recently proposed by the authors, which consists of a trapped field magnet (TFM) cylinder exploiting the “vortex pinning effect,” combined with a superconducting bulk magnetic lens exploiting the “diamagnetic shielding effect.” This HTFML can generate, within its bore, a magnetic field higher than the applied magnetic field, even after external field decreases to zero. In this paper, a design optimization of the inner GdBaCuO magnetic lens within the GdBaCuO TFM cylinder was carried out using numerical simulations based on the finite element method, in order to maximize the concentrated magnetic field. The HTFML with an optimized shape and size achieved a concentrated magnetic field of Bc = 5.6 and 12.8 T at the center of the lens for applied magnetic fields of Bapp = 3 and 10 T, respectively. A maximum tensile stress of +135 MPa exists in the outer GdBaCuO TFM cylinder during the magnetizing process for Bapp = 10 T, which exceeds the fracture strength of the bulk. This result suggests that mechanical reinforcement is necessary to avoid mechanical fracture under such high magnetic field conditions

Pulsed Field Magnetization of Single-Grain Bulk YBCO Processed from Graded Precursor Powders

Large, single-grain bulk high-temperature superconducting materials can trap high magnetic fields in comparison with conventional permanent magnets, making them ideal candidates to develop more compact and efficient devices, such as actuators, magnetic levitation systems, flywheel energy storage systems and electric machines. However, macrosegregation of Y-211 inclusions in melt-processed Y-Ba-Cu-O (YBCO) limits the macroscopic critical current density of such bulk superconductors, and hence, the potential trapped field. A new fabrication technique using graded precursor powders has recently been developed by our research group, which results in a more uniform distribution of Y-211 particles, in order to further improve the superconducting properties and trapped field capability of such materials. Large, single-grain bulk high-temperature superconducting materials can trap high magnetic fields in comparison with conventional permanent magnets, making them ideal candidates to develop more compact and efficient devices, such as actuators, magnetic levitation systems, flywheel energy storage systems and electric machines. However, macrosegregation of Y-211 inclusions in melt-processed Y-Ba-Cu-O (YBCO) limits the macroscopic critical current density of such bulk superconductors, and hence, the potential trapped field. A new fabrication technique using graded precursor powders has recently been developed by our research group, which results in a more uniform distribution of Y-211 particles, in order to further improve the superconducting properties and trapped field capability of such materials.M. D. Ainslie would like to acknowledge financial support from a Royal Academy of Engineering Research Fellowship. This work was also supported by a Royal Society International Exchanges Scheme Grant, IE131084. J. Zou would like to acknowledge financial support from Churchill College, the China Scholarship Council and the Cambridge Commonwealth, European and International Trust.This is the author accepted manuscript. The final version is available from IEEE via http://dx.doi.org/10.1109/TASC.2015.250916

Mutations in DNA repair genes are associated with increased neo-antigen load and activated T cell infiltration in lung adenocarcinoma.

Mutations in DNA repair genes lead to increased genomic instability and mutation frequency. These mutations represent potential biomarkers for cancer immunotherapy efficacy, as high tumor mutational burden has been associated with increased neo-antigens and tumor infiltrating lymphocytes. While mismatch repair mutations have successfully predicted response to anti-PD-1 therapy in colorectal and other cancers, they have not yet been tested for lung cancer, and few have investigated genes from other DNA repair pathways. We utilized TCGA samples to comprehensively immunophenotype lung tumors and analyze the links between DNA repair mutations, neo-antigen and total mutational burden, and tumor immune infiltration. Overall, 73% of lung tumors contained infiltration by at least one T cell subset, with high mutational burden tumors containing significantly increased infiltration by activated CD4 and CD8 T cells. Further, mutations in mismatch repair genes, homologous recombination genes, or POLE accurately predicted increased tumor mutational burden, neo-antigen load, and T cell infiltration. Finally, neo-antigen load correlated with expression of M1-polarized macrophage genes, PD-1, PD-L1, IFNγ, GZMB, and FASLG, among other immune-related genes. Overall, after defining the immune infiltrate in lung tumors, we demonstrate the potential value of utilizing gene mutations from multiple DNA repair pathways as biomarkers for lung cancer immunotherapy. Oncotarget 2018; 9(8):7949-796

Fostering bioinformatics education through skill development of professors: Big Genomic Data Skills Training for Professors.

Bioinformatics has become an indispensable part of life science over the past 2 decades. However, bioinformatics education is not well integrated at the undergraduate level, especially in liberal arts colleges and regional universities in the United States. One significant obstacle pointed out by the Network for Integrating Bioinformatics into Life Sciences Education is the lack of faculty in the bioinformatics area. Most current life science professors did not acquire bioinformatics analysis skills during their own training. Consequently, a great number of undergraduate and graduate students do not get the chance to learn bioinformatics or computational biology skills within a structured curriculum during their education. To address this gap, we developed a module-based, week-long short course to train small college and regional university professors with essential bioinformatics skills. The bioinformatics modules were built to be adapted by the professor-trainees afterward and used in their own classes. All the course materials can be accessed at https://github.com/TheJacksonLaboratory/JAXBD2K-ShortCourse

Pulsed-field magnetisation of Y-Ba-Cu-O bulk superconductors fabricated by the infiltration growth technique

Funder: King Abdulaziz City for Science and Technology; doi: http://dx.doi.org/10.13039/501100004919Abstract: Bulk high temperature superconductors based on the rare-earth copper oxides can be used effectively as trapped field magnets capable of generating large magnetic fields. The top-seeded infiltration growth (TSIG) processing technique can provide a more homogeneous microstructure and therefore more uniform superconducting properties than samples grown using conventional melt growth processes. In the present investigation, the properties of bulk, single grain superconductors processed by TSIG and magnetised by the pulsed-field magnetisation technique using a copper-wound solenoid have been studied. A trapped field of ∼3 T has been achieved in a 2-step buffer-assisted TSIG-processed Y-Ba-Cu-O (YBCO) sample at 40 K by magnetising the bulk superconductor completely via a single-pulse magnetisation process. Samples were also subjected to pulsed-field magnetisation at 65 K and by conventional field-cooled magnetisation at 77 K for comparison. Good correlation was observed between the microstructures, critical current densities and trapped field performance of bulk samples fabricated by TSIG and magnetised by pulsed-field and field-cooled magnetisation. The homogeneous distribution of Y2BaCuO5 inclusions within the microstructure of bulk YBCO samples fabricated by the 2-step buffer-assisted TSIG process reduces inhomogeneous flux penetration into the interior of the sample. This, in turn, results in a lower temperature rise of the bulk superconductor during the pulsed-field magnetisation process and a more effective and reliable magnetisation process

Respiratory Inductance Plethysmography to Assess Fatigability during Repetitive Work

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Mutations in DNA repair genes are associated with increased neoantigen burden and a distinct immunophenotype in lung squamous cell carcinoma.

Deficiencies in DNA repair pathways, including mismatch repair (MMR), have been linked to higher tumor mutation burden and improved response to immune checkpoint inhibitors. However, the significance of MMR mutations in lung cancer has not been well characterized, and the relevance of other processes, including homologous recombination (HR) and polymerase epsilon (POLE) activity, remains unclear. Here, we analyzed a dataset of lung squamous cell carcinoma samples from The Cancer Genome Atlas. Variants in DNA repair genes were associated with increased tumor mutation and neoantigen burden, which in turn were linked with greater tumor infiltration by activated T cells. The subset of tumors with DNA repair gene variants but without T cell infiltration exhibited upregulation of TGF-β and Wnt pathway genes, and a combined score incorporating these genes and DNA repair status accurately predicted immune cell infiltration. Finally, high neoantigen burden was positively associated with genes related to cytolytic activity and immune checkpoints. These findings provide evidence that DNA repair pathway defects and immunomodulatory genes together lead to specific immunophenotypes in lung squamous cell carcinoma and could potentially serve as biomarkers for immunotherapy

A simple, reliable and robust reinforcement method for the fabrication of (RE)–Ba–Cu–O bulk superconductors

Abstract: Bulk high temperature superconductors (HTS) based on the rare-earth barium cuprates [(RE)BCO] have the potential to be applied in a variety of engineering and technological applications such as trapped field magnets, rotating electrical machines, magnetic bearings and flywheel energy storage systems. The key materials figure of merit for most practical applications of bulk superconductors is simply the product of the maximum current density that can be supported, which correlates directly with the maximum achievable trapped magnetic field, and the physical length scale over which the current flows. Unfortunately, however, bulk (RE)BCO superconductors exhibit relatively poor mechanical properties due to their inherent ceramic nature. Consequently, the performance of these materials as trapped field magnets is limited significantly by their tensile strength, rather than critical current and size, given that the relatively large Lorentz forces produced in the generation of large magnetic fields can lead to catastrophic mechanical failure. In the present work, we describe a simple, but effective and reliable reinforcement methodology to enhance the mechanical properties of (RE)BCO bulk superconductors by incorporating hybrid SiC fibres consisting of a tungsten core with SiC cladding within the bulk microstructure. An improvement in tensile strength by up to 40% has been achieved via this process and, significantly, without compromising the superconducting performance of the bulk material