ASTRO Journals' Data Sharing Policy and Recommended Best Practices.

Transparency, openness, and reproducibility are important characteristics in scientific publishing. Although many researchers embrace these characteristics, data sharing has yet to become common practice. Nevertheless, data sharing is becoming an increasingly important topic among societies, publishers, researchers, patient advocates, and funders, especially as it pertains to data from clinical trials. In response, ASTRO developed a data policy and guide to best practices for authors submitting to its journals. ASTRO's data sharing policy is that authors should indicate, in data availability statements, if the data are being shared and if so, how the data may be accessed

Chromatin interaction analysis reveals changes in small chromosome and telomere clustering between epithelial and breast cancer cells

BACKGROUND: Higher-order chromatin structure is often perturbed in cancer and other pathological states. Although several genetic and epigenetic differences have been charted between normal and breast cancer tissues, changes in higher-order chromatin organization during tumorigenesis have not been fully explored. To probe the differences in higher-order chromatin structure between mammary epithelial and breast cancer cells, we performed Hi-C analysis on MCF-10A mammary epithelial and MCF-7 breast cancer cell lines. RESULTS: Our studies reveal that the small, gene-rich chromosomes chr16 through chr22 in the MCF-7 breast cancer genome display decreased interaction frequency with each other compared to the inter-chromosomal interaction frequency in the MCF-10A epithelial cells. Interestingly, this finding is associated with a higher occurrence of open compartments on chr16-22 in MCF-7 cells. Pathway analysis of the MCF-7 up-regulated genes located in altered compartment regions on chr16-22 reveals pathways related to repression of WNT signaling. There are also differences in intra-chromosomal interactions between the cell lines; telomeric and sub-telomeric regions in the MCF-10A cells display more frequent interactions than are observed in the MCF-7 cells. CONCLUSIONS: We show evidence of an intricate relationship between chromosomal organization and gene expression between epithelial and breast cancer cells. Importantly, this work provides a genome-wide view of higher-order chromatin dynamics and a resource for studying higher-order chromatin interactions in two cell lines commonly used to study the progression of breast cancer

SMARCA4 regulates gene expression and higher-order chromatin structure in proliferating mammary epithelial cells

The packaging of DNA into chromatin plays an important role in transcriptional regulation and nuclear processes. Brahma-related gene-1 SMARCA4 (also known as BRG1), the essential ATPase subunit of the mammalian SWI/SNF chromatin remodeling complex, uses the energy from ATP hydrolysis to disrupt nucleosomes at target regions. Although the transcriptional role of SMARCA4 at gene promoters is well-studied, less is known about its role in higher-order genome organization. SMARCA4 knockdown in human mammary epithelial MCF-10A cells resulted in 176 up-regulated genes, including many related to lipid and calcium metabolism, and 1292 down-regulated genes, some of which encode extracellular matrix (ECM) components that can exert mechanical forces and affect nuclear structure. ChIP-seq analysis of SMARCA4 localization and SMARCA4-bound super-enhancers demonstrated extensive binding at intergenic regions. Furthermore, Hi-C analysis showed extensive SMARCA4-mediated alterations in higher-order genome organization at multiple resolutions. First, SMARCA4 knockdown resulted in clustering of intra- and inter-subtelomeric regions, demonstrating a novel role for SMARCA4 in telomere organization. SMARCA4 binding was enriched at topologically associating domain (TAD) boundaries, and SMARCA4 knockdown resulted in weakening of TAD boundary strength. Taken together, these findings provide a dynamic view of SMARCA4-dependent changes in higher-order chromatin organization and gene expression, identifying SMARCA4 as a novel component of chromatin organization

An exploration of parents’ preferences for foot care in juvenile idiopathic arthritis: a possible role for the discrete choice experiment

Background: An increased awareness of patients’ and parents’ care preferences regarding foot care is desirable from a clinical perspective as such information may be utilised to optimise care delivery. The aim of this study was to examine parents’ preferences for, and valuations of foot care and foot-related outcomes in juvenile idiopathic arthritis (JIA).<p></p> Methods: A discrete choice experiment (DCE) incorporating willingness-to-pay (WTP) questions was conducted by surveying 42 parents of children with JIA who were enrolled in a randomised-controlled trial of multidisciplinary foot care at a single UK paediatric rheumatology outpatients department. Attributes explored were: levels of pain; mobility; ability to perform activities of daily living (ADL); waiting time; referral route; and footwear. The DCE was administered at trial baseline. DCE data were analysed using a multinomial-logit-regression model to estimate preferences and relative importance of attributes of foot care. A stated-preference WTP question was presented to estimate parents’ monetary valuation of health and service improvements.<p></p> Results: Every attribute in the DCE was statistically significant (p < 0.01) except that of cost (p = 0.118), suggesting that all attributes, except cost, have an impact on parents’ preferences for foot care for their child. The magnitudes of the coefficients indicate that the strength of preference for each attribute was (in descending order): improved ability to perform ADL, reductions in foot pain, improved mobility, improved ability to wear desired footwear, multidisciplinary foot care route, and reduced waiting time. Parents’ estimated mean annual WTP for a multidisciplinary foot care service was £1,119.05.<p></p> Conclusions: In terms of foot care service provision for children with JIA, parents appear to prefer improvements in health outcomes over non-health outcomes and service process attributes. Cost was relatively less important than other attributes suggesting that it does not appear to impact on parents’ preferences.<p></p&gt

Development and evaluation of an online three-level proton vs photon decision support prototype for head and neck cancer - Comparison of dose, toxicity and cost-effectiveness

AbstractTo quantitatively assess the effectiveness of proton therapy for individual patients, we developed a prototype for an online platform for proton decision support (PRODECIS) comparing photon and proton treatments on dose metric, toxicity and cost-effectiveness levels. An evaluation was performed with 23 head and neck cancer datasets

External validation of a prognostic model incorporating quantitative PET image features in esophageal cancer

Aim Enhanced prognostic models are required to improve risk stratification of patients with oesophageal cancer so treatment decisions can be optimised. The primary aim was to externally validate a published prognostic model incorporating PET image features. Transferability of the model was compared using only clinical variables. Methods This was a Transparent Reporting of a multivariate prediction model for Individual Prognosis Or Diagnosis (TRIPOD) type 3 study. The model was validated against patients treated with neoadjuvant chemoradiotherapy according to the Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS) trial regimen using pre- and post-harmonised image features. The Kaplan–Meier method with log-rank significance tests assessed risk strata discrimination. A Cox proportional hazards model assessed model calibration. Primary outcome was overall survival (OS). Results Between 2010 and 2015, 449 patients were included in the development (n = 302), internal validation (n = 101) and external validation (n = 46) cohorts. No statistically significant difference in OS between patient quartiles was demonstrated in prognostic models incorporating PET image features (X2 = 1.42, df = 3, p = 0.70) or exclusively clinical variables (age, disease stage and treatment; X2 = 1.19, df = 3, p = 0.75). The calibration slope β of both models was not significantly different from unity (p = 0.29 and 0.29, respectively). Risk groups defined using only clinical variables suggested differences in OS, although these were not statistically significant (X2 = 0.71, df = 2, p = 0.70). Conclusion The prognostic model did not enable significant discrimination between the validation risk groups, but a second model with exclusively clinical variables suggested some transferable prognostic ability. PET harmonisation did not significantly change the results of model validation

Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis

Second-generation colon capsule endoscopy compared with colonoscopy

Colon capsule endoscopy (CCE) represents a noninvasive technology that allows visualization of the colon without requiring sedation and air insufflation. A second-generation colon capsule endoscopy system (PillCam Colon 2) (CCE-2) was developed to increase sensitivity for colorectal polyp detection compared with the first-generation system. OBJECTIVE: To assess the feasibility, accuracy, and safety of CCE-2 in a head-to-head comparison with colonoscopy. DESIGN AND SETTING: Prospective, multicenter trial including 8 European sites. PATIENTS: This study involved 117 patients (mean age 60 years). Data from 109 patients were analyzed. INTERVENTION: CCE-2 was prospectively compared with conventional colonoscopy as the criterion standard for the detection of colorectal polyps that are >/=6 mm or masses in a cohort of patients at average or increased risk of colorectal neoplasia. Colonoscopy was independently performed within 10 hours after capsule ingestion or on the next day. MAIN OUTCOME MEASUREMENTS: CCE-2 sensitivity and specificity for detecting patients with polyps >/=6 mm and >/=10 mm were assessed. Capsule-positive but colonoscopy-negative cases were counted as false positive. Capsule excretion rate, level of bowel preparation, and rate of adverse events also were assessed. RESULTS: Per-patient CCE-2 sensitivity for polyps >/=6 mm and >/=10 mm was 84% and 88%, with specificities of 64% and 95%, respectively. All 3 invasive carcinomas were detected by CCE-2. The capsule excretion rate was 88% within 10 hours. Overall colon cleanliness for CCE-2 was adequate in 81% of patients. LIMITATIONS: Not unblinding the CCE-2 results at colonoscopy; heterogenous patient population; nonconsecutive patients. CONCLUSION: In this European, multicenter study, CCE-2 appeared to have a high sensitivity for the detection of clinically relevant polypoid lesions, and it might be considered an adequate tool for colorectal imaging

Building the Future Therapies for Down Syndrome:The Third International Conference of the T21 Research Society

Research focused on Down syndrome has increased in the last several years to advance understanding of the consequences of trisomy 21 (T21) on molecular and cellular processes and, ultimately, on individuals with Down syndrome. The Trisomy 21 Research Society (T21RS) is the premier scientific organization for researchers and clinicians studying Down syndrome. The Third International Conference of T21RS, held June 6-9, 2019, in Barcelona, Spain, brought together 429 scientists, families, and industry representatives to share the latest discoveries on underlying cellular and molecular mechanisms of T21, define cognitive and behavioral challenges and better understand comorbidities associated with Down syndrome, including Alzheimer's disease and leukemia. Presentation of cutting-edge results in neuroscience, neurology, model systems, psychology, cancer, biomarkers and molecular and phar-ma-cological therapeutic approaches demonstrate the compelling interest and continuing advancement in all aspects of understanding and ameliorating conditions associated with T21