Integrative analyses identify modulators of response to neoadjuvant aromatase inhibitors in patients with early breast cancer

Introduction Aromatase inhibitors (AIs) are a vital component of estrogen receptor positive (ER+) breast cancer treatment. De novo and acquired resistance, however, is common. The aims of this study were to relate patterns of copy number aberrations to molecular and proliferative response to AIs, to study differences in the patterns of copy number aberrations between breast cancer samples pre- and post-AI neoadjuvant therapy, and to identify putative biomarkers for resistance to neoadjuvant AI therapy using an integrative analysis approach. Methods Samples from 84 patients derived from two neoadjuvant AI therapy trials were subjected to copy number profiling by microarray-based comparative genomic hybridisation (aCGH, n = 84), gene expression profiling (n = 47), matched pre- and post-AI aCGH (n = 19 pairs) and Ki67-based AI-response analysis (n = 39). Results Integrative analysis of these datasets identified a set of nine genes that, when amplified, were associated with a poor response to AIs, and were significantly overexpressed when amplified, including CHKA, LRP5 and SAPS3. Functional validation in vitro, using cell lines with and without amplification of these genes (SUM44, MDA-MB134-VI, T47D and MCF7) and a model of acquired AI-resistance (MCF7-LTED) identified CHKA as a gene that when amplified modulates estrogen receptor (ER)-driven proliferation, ER/estrogen response element (ERE) transactivation, expression of ER-regulated genes and phosphorylation of V-AKT murine thymoma viral oncogene homolog 1 (AKT1). Conclusions These data provide a rationale for investigation of the role of CHKA in further models of de novo and acquired resistance to AIs, and provide proof of concept that integrative genomic analyses can identify biologically relevant modulators of AI response

Pseudo-aneurysm of the anterior tibial artery, a rare cause of ankle swelling following a sports injury

BACKGROUND: Ankle pain and swelling following sports injuries are common presenting complaints to the accident and emergency department. Frequently these are diagnosed as musculoskeletal injuries, even when no definitive cause is found. Vascular injuries following trauma are uncommon and are an extremely rare cause of ankle swelling and pain. These injuries may however be limb threatening and are important to diagnose early, in order that appropriate treatment can be delivered. We highlight the steps to diagnosis of these injuries, and methods of managing these injuries. It is important for clinicians to be aware of the potential for this injury in patients with seemingly innocuous trauma from sports injuries, who have significant ankle pain and swelling. CASE PRESENTATION: A young, professional sportsman presented with a swollen, painful ankle after an innocuous hyper-plantar flexion injury whilst playing football, which was initially diagnosed as a ligamentous injury after no bony injury was revealed on X-Ray. He returned 2 days later with a large ulcer at the lateral malleolus and further investigation by duplex ultrasound and transfemoral arteriogram revealed a Pseudo-Aneurysm of the Anterior Tibial Artery. This was initially managed with percutaneous injection of thrombin, and later open surgery to ligate the feeding vessel. The patient recovered fully and was able to return to recreational sport. CONCLUSION: Vascular injuries remain a rare cause of ankle pain and swelling following sports injuries, however it is important to consider these injuries when no definite musculo-skeletal cause is found. Ultrasound duplex and Transfemoral arteriogram are appropriate, sensitive modalities for investigation, and may allow novel treatment to be directed percutaneously. Early diagnosis and intervention are essential for the successful outcome in these patients

DNA barcoding reveals both known and novel taxa in the Albitarsis Group (Anopheles: Nyssorhynchus) of Neotropical malaria vectors

<p>Abstract</p> <p>Background</p> <p>Mosquitoes belonging to the Albitarsis Group (<it>Anopheles</it>: <it>Nyssorhynchus</it>) are of importance as malaria vectors across the Neotropics. The Group currently comprises six known species, and recent studies have indicated further hidden biodiversity within the Group. DNA barcoding has been proposed as a highly useful tool for species recognition, although its discriminatory utility has not been verified in closely related taxa across a wide geographic distribution.</p> <p>Methods</p> <p>DNA barcodes (658 bp of the mtDNA <it>Cytochrome c Oxidase </it>- <it>COI</it>) were generated for 565 <it>An. albitarsis </it>s.l. collected in Argentina, Brazil, Colombia, Paraguay, Trinidad and Venezuela over the past twenty years, including specimens from type series and type localities. Here we test the utility of currently advocated barcoding methodologies, including the Kimura-two-parameter distance model (K2P) and Neighbor-joining analysis (NJ), for determining species delineation within mosquitoes of the Neotropical Albitarsis Group of malaria vectors (<it>Anopheles</it>: <it>Nyssorhynchus</it>), and compare results with Bayesian analysis.</p> <p>Results</p> <p>Species delineation through barcoding analysis and Bayesian phylogenetic analysis, fully concur. Analysis of 565 sequences (302 unique haplotypes) resolved nine NJ tree clusters, with less than 2% intra-node variation. Mean intra-specific variation (K2P) was 0.009 (range 0.002 - 0.014), whereas mean inter-specific divergence were several-fold higher at 0.041 (0.020 - 0.056), supporting the reported "barcoding gap". These results show full support for separate species status of the six known species in the Albitarsis Group (<it>An. albitarsis </it>s.s., <it>An. albitarsis </it>F, <it>An. deaneorum</it>, <it>An. janconnae</it>, <it>An. marajoara </it>and <it>An. oryzalimnetes</it>), and also support species level status for two previously detected lineages - <it>An. albitarsis </it>G &<it>An. albitarsis </it>I (designated herein). In addition, we highlight the presence of a unique mitochondrial lineage close to <it>An. deaneorum </it>and <it>An. marajoara </it>(<it>An. albitarsis </it>H) from Rondônia and Mato Grosso in southwestern Brazil. Further integrated studies are required to confirm the status of this lineage.</p> <p>Conclusions</p> <p>DNA barcoding provides a reliable means of identifying both known and undiscovered biodiversity within the closely related taxa of the Albitarsis Group. We advocate its usage in future studies to elucidate the vector competence and respective distributions of all eight species in the Albitarsis Group and the novel mitochondrial lineage (<it>An. albitarsis </it>H) recovered in this study.</p

Theoretical analysis of the mechanisms of a gender differentiation in the propensity for orthostatic intolerance after spaceflight

<p>Abstract</p> <p>Background</p> <p>A tendency to develop reentry orthostasis after a prolonged exposure to microgravity is a common problem among astronauts. The problem is 5 times more prevalent in female astronauts as compared to their male counterparts. The mechanisms responsible for this gender differentiation are poorly understood despite many detailed and complex investigations directed toward an analysis of the physiologic control systems involved.</p> <p>Methods</p> <p>In this study, a series of computer simulation studies using a mathematical model of cardiovascular functioning were performed to examine the proposed hypothesis that this phenomenon could be explained by basic physical forces acting through the simple common anatomic differences between men and women. In the computer simulations, the circulatory components and hydrostatic gradients of the model were allowed to adapt to the physical constraints of microgravity. After a simulated period of one month, the model was returned to the conditions of earth's gravity and the standard postflight tilt test protocol was performed while the model output depicting the typical vital signs was monitored.</p> <p>Conclusions</p> <p>The analysis demonstrated that a 15% lowering of the longitudinal center of gravity in the anatomic structure of the model was all that was necessary to prevent the physiologic compensatory mechanisms from overcoming the propensity for reentry orthostasis leading to syncope.</p

Commissioning of the vacuum system of the KATRIN Main Spectrometer

The KATRIN experiment will probe the neutrino mass by measuring the beta-electron energy spectrum near the endpoint of tritium beta-decay. An integral energy analysis will be performed by an electro-static spectrometer (Main Spectrometer), an ultra-high vacuum vessel with a length of 23.2 m, a volume of 1240 m^3, and a complex inner electrode system with about 120000 individual parts. The strong magnetic field that guides the beta-electrons is provided by super-conducting solenoids at both ends of the spectrometer. Its influence on turbo-molecular pumps and vacuum gauges had to be considered. A system consisting of 6 turbo-molecular pumps and 3 km of non-evaporable getter strips has been deployed and was tested during the commissioning of the spectrometer. In this paper the configuration, the commissioning with bake-out at 300{\deg}C, and the performance of this system are presented in detail. The vacuum system has to maintain a pressure in the 10^{-11} mbar range. It is demonstrated that the performance of the system is already close to these stringent functional requirements for the KATRIN experiment, which will start at the end of 2016.Comment: submitted for publication in JINST, 39 pages, 15 figure

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

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

Systematic Evaluation of the Teaching Qualities of Obstetrics and Gynecology Faculty: Reliability and Validity of the SETQ Tools

BACKGROUND: The importance of effective clinical teaching for the quality of future patient care is globally understood. Due to recent changes in graduate medical education, new tools are needed to provide faculty with reliable and individualized feedback on their teaching qualities. This study validates two instruments underlying the System for Evaluation of Teaching Qualities (SETQ) aimed at measuring and improving the teaching qualities of obstetrics and gynecology faculty. METHODS AND FINDINGS: This cross-sectional multi-center questionnaire study was set in seven general teaching hospitals and two academic medical centers in the Netherlands. Seventy-seven residents and 114 faculty were invited to complete the SETQ instruments in the duration of one month from September 2008 to September 2009. To assess reliability and validity of the instruments, we used exploratory factor analysis, inter-item correlation, reliability coefficient alpha and inter-scale correlations. We also compared composite scales from factor analysis to global ratings. Finally, the number of residents' evaluations needed per faculty for reliable assessments was calculated. A total of 613 evaluations were completed by 66 residents (85.7% response rate). 99 faculty (86.8% response rate) participated in self-evaluation. Factor analysis yielded five scales with high reliability (Cronbach's alpha for residents' and faculty): learning climate (0.86 and 0.75), professional attitude (0.89 and 0.81), communication of learning goals (0.89 and 0.82), evaluation of residents (0.87 and 0.79) and feedback (0.87 and 0.86). Item-total, inter-scale and scale-global rating correlation coefficients were significant (P<0.01). Four to six residents' evaluations are needed per faculty (reliability coefficient 0.60-0.80). CONCLUSIONS: Both SETQ instruments were found reliable and valid for evaluating teaching qualities of obstetrics and gynecology faculty. Future research should examine improvement of teaching qualities when using SETQ