Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Physiotherapy students' perspectives of online e-learning for interdisciplinary management of chronic health conditions: A qualitative study

© 2016 Gardner et al. Background: To qualitatively explore physiotherapy students' perceptions of online e-learning for chronic disease management using a previously developed, innovative and interactive, evidence-based, e-learning package: Rheumatoid Arthritis for Physiotherapists e-Learning (RAP-eL). Methods: Physiotherapy students participated in three focus groups in Perth, Western Australia. Purposive sampling was employed to ensure maximum heterogeneity across age, gender and educational background. To explore students' perspectives on the advantages and disadvantages of online e-learning, ways to enhance e-learning, and information/learning gaps in relation to interdisciplinary management of chronic health conditions, a semi-structured interview schedule was developed. Verbatim transcripts were analysed using inductive methods within a grounded theory approach to derive key themes. Results: Twenty-three students (78 % female; 39 % with previous tertiary qualification) of mean (SD) age 23 (3.6) years participated. Students expressed a preference for a combination of both online e-learning and lecture-style learning formats for chronic disease management, citing flexibility to work at one's own pace and time, and access to comprehensive information as advantages of e-learning learning. Personal interaction and ability to clarify information immediately were considered advantages of lecture-style formats. Perceived knowledge gaps included practical application of interdisciplinary approaches to chronic disease management and developing and implementing physiotherapy management plans for people with chronic health conditions. Conclusions: Physiotherapy students preferred multi-modal and blended formats for learning about chronic disease management. This study highlights the need for further development of practically-oriented knowledge and skills related to interdisciplinary care for people with chronic conditions among physiotherapy students. While RAP-eL focuses on rheumatoid arthritis, the principles of learning apply to the broader context of chronic disease management

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Remarkable muscles, remarkable locomotion in desert-dwelling wildebeest

Large mammals that live in arid and/or desert environments can cope with seasonal and local variations in rainfall, food and climate1 by moving long distances, often without reliable water or food en route. The capacity of an animal for this long-distance travel is substantially dependent on the rate of energy utilization and thus heat production during locomotion—the cost of transport2,3,4. The terrestrial cost of transport is much higher than for flying (7.5 times) and swimming (20 times)4. Terrestrial migrants are usually large1,2,3 with anatomical specializations for economical locomotion5,6,7,8,9, because the cost of transport reduces with increasing size and limb length5,6,7. Here we used GPS-tracking collars10 with movement and environmental sensors to show that blue wildebeest (Connochaetes taurinus, 220 kg) that live in a hot arid environment in Northern Botswana walked up to 80 km over five days without drinking. They predominantly travelled during the day and locomotion appeared to be unaffected by temperature and humidity, although some behavioural thermoregulation was apparent. We measured power and efficiency of work production (mechanical work and heat production) during cyclic contractions of intact muscle biopsies from the forelimb flexor carpi ulnaris of wildebeest and domestic cows (Bos taurus, 760 kg), a comparable but relatively sedentary ruminant. The energetic costs of isometric contraction (activation and force generation) in wildebeest and cows were similar to published values for smaller mammals. Wildebeest muscle was substantially more efficient (62.6%) than the same muscle from much larger cows (41.8%) and comparable measurements that were obtained from smaller mammals (mouse (34%)11 and rabbit (27%)). We used the direct energetic measurements on intact muscle fibres to model the contribution of high working efficiency of wildebeest muscle to minimizing thermoregulatory challenges during their long migrations under hot arid conditions

Functional immune responses against SARS-CoV-2 variants of concern after fourth COVID-19 vaccine dose or infection in patients with blood cancer

Summary Patients with blood cancer continue to have a greater risk of inadequate immune responses following three COVID-19 vaccine doses and risk of severe COVID-19 disease. In the context of the CAPTURE study (NCT03226886) we report immune responses in 80 patients with blood cancer who received a fourth dose of BNT162b2. We measured neutralising antibody titres (NAbT) using a live virus microneutralization assay against wild-type (WT), Delta, Omicron BA.1 and BA.2 and T cell responses against WT and Omicron BA.1 using an activation-induced marker (AIM) assay. The proportion of patients with detectable NAb titres and T cell responses after the fourth vaccine dose increases compared to those after the third vaccine dose. Patients who received B cell-depleting therapies within 12 months before vaccination have the greatest risk of not having detectable NAbT. In addition, we report immune responses in 57 patients with breakthrough infections after vaccination

Determining relative bulk viscosity of kilometre-scale crustal units using field observations and numerical modelling

Though the rheology of kilometre-scale polymineralic rock units is crucial for reliable large-scale, geotectonic models, this information is difficult to obtain. In geotectonic models, a layer is defined as an entity at the kilometre scale, even though it is heterogeneous at the millimetre to metre scale. Here, we use the shape characteristics of the boundaries between rock units to derive the relative bulk viscosity of those units at the kilometre scale. We examine the shape of a vertically oriented ultramafic, harzburgitic-lherzolitic unit, which developed a kilometre-scale pinch and swell structure at mid-crustal conditions (~ 600 °C, ~ 8.5 kbar), in the Anita Shear Zone, New Zealand. The ultramafic layer is embedded between a typical polymineralic paragneiss to the west, and a feldspar-quartz-hornblende orthogneiss, to the east. Notably, the boundaries on either side of the ultramafic layer give the ultramafics an asymmetric shape. Microstructural analysis shows that deformation was dominated by dislocation creep (n = 3). Based on the inferred rheological behaviour from the field, a series of numerical simulations are performed. Relative and absolute values are derived for bulk viscosity of the rock units by comparing boundary tortuosity difference measured on the field example and the numerical series. Our analysis shows that during deformation at mid-crustal conditions, paragneisses can be ~ 30 times less viscous than an ultramafic unit, whereas orthogneisses have intermediate viscosity, ~ 3 times greater than the paragneisses. If we assume a strain rate of 10⁻ ¹⁴ s⁻ ¹ the ultramafic, orthogneiss and paragneiss have syn-deformational viscosities of 3 × 10²², 2.3 × 10²¹ and 9.4 × 10²⁰ Pa s, respectively. Our study shows pinch and swell structures are useful as a gauge to assess relative bulk viscosity of rock units based on shape characteristics at the kilometre scale and in non-Newtonian flow regimes, even where heterogeneity occurs within the units at the outcrop scale

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure