Expression of nodal signalling components in cycling human endometrium and in endometrial cancer

<p>Abstract</p> <p>Background</p> <p>The human endometrium is unique in its capacity to remodel constantly throughout adult reproductive life. Although the processes of tissue damage and breakdown in the endometrium have been well studied, little is known of how endometrial regeneration is achieved after menstruation. Nodal, a member of the transforming growth factor-beta superfamily, regulates the processes of pattern formation and differentiation that occur during early embryo development.</p> <p>Methods</p> <p>In this study, the expression of Nodal, Cripto (co-receptor) and Lefty A (antagonist) was examined by RT-PCR and immunohistochemistry across the menstrual cycle and in endometrial carcinomas.</p> <p>Results</p> <p>Nodal and Cripto were found to be expressed at high levels in both stromal and epithelial cells during the proliferative phase of the menstrual cycle. Although immunoreactivity for both proteins in surface and glandular epithelium was maintained at relatively steady-state levels across the cycle, their expression was significantly decreased within the stromal compartment by the mid-secretory phase. Lefty expression, as has previously been reported, was primarily restricted to glandular epithelium and surrounding stroma during the late secretory and menstrual phases. In line with recent studies that have shown that Nodal pathway activity is upregulated in many human cancers, we found that Nodal and Cripto immunoreactivity increased dramatically in the transition from histologic Grade 1 to histologic Grades 2 and 3 endometrial carcinomas. Strikingly, Lefty expression was low or absent in all cancer tissues.</p> <p>Conclusion</p> <p>The expression of Nodal in normal and malignant endometrial cells that lack Lefty strongly supports an important role for this embryonic morphogen in the tissue remodelling events that occur across the menstrual cycle and in tumourogenesis.</p

Movements and Inferred Foraging by Bowhead Whales in the Canadian Beaufort Sea during August and September, 2006–12

Each spring, most bowhead whales of the Bering-Chukchi-Beaufort (BCB) population migrate to the southeast Beaufort Sea and summer in Canadian waters. In August and September, they form aggregations, which are known to occur mainly in the shallow, shelf waters when oceanographic conditions promote concentration of their zooplankton prey. The movements of individual bowheads while they occupy these late summer habitats are less well known; our knowledge is based on photographic evidence and limited tagging studies conducted from 1982 to 2000. In this study, 85% (17) of the 20 satellite-tagged whales that could have spent some time in the Canadian portion of the Beaufort Sea during late summer 2006 to 2012 spent all or part of August and September there. We analyzed location data for 16 whales, using a two-state switching correlated random walk (CRW) behavioural model, and classified locations in the Canadian waters as associated with lingering behaviour (inferred foraging) or directed travel. We found that these whales spent the greatest proportion of their time lingering (59%), followed by traveling (22%), and transitioning between lingering and traveling (19%). Using only lingering locations for these tagged whales in all study years pooled, we calculated kernel densities and defined five areas within the 75% density contour as aggregation areas. Together, the five aggregation areas we defined comprised 25 341 km2, 14.1% of the total area used by these tagged whales in Canadian waters during August and September of the deployment years. Three aggregation areas were located in shallow waters of the Beaufort Sea Shelf and were used almost exclusively by immature tagged whales in our sample. Two other aggregation areas were observed, one in Darnley Bay and one in Viscount Melville Sound in the Canadian Arctic Archipelago. Each of these was used by one mature whale. Tagged whales were observed to use one or two aggregation areas in a single season, and rarely more. The proportion of lingering time spent in each aggregation area was highly variable among individuals. The largest aggregation area (10 877 km2), located over the Beaufort Shelf north of the Tuktoyaktuk Peninsula (5 – 52 m depth), was used by 13 of the 16 tagged whales, almost exclusively by the immature whales, including three of four that were tracked in two consecutive summers. The Beaufort Shelf overall (and possibly the Tuktoyaktuk Shelf, including the Outer Shelf, in particular) was especially important for immature bowhead whales, while mature whales used habitats beyond the Beaufort Shelf during late summer. Findings may be important to inform both decisions on management and mitigative actions relating to bowhead whale use of the Beaufort Shelf and studies that aim to improve our understanding of the prey base of BCB bowhead whales in the Canadian Beaufort Sea region.Tous les printemps, la plupart des baleines boréales de la population de Béring-Tchouktches-Beaufort (BCB) migrent vers le sud-est de la mer de Beaufort et passent l’été dans les eaux canadiennes. En août et en septembre, elles forment des agrégations, principalement dans les eaux de plateau peu profondes lorsque les conditions océanographiques favorisent la concentration du zooplancton, qui leur sert de proie. Individuellement, les déplacements des baleines boréales qui occupent ces habitats en fin d’été sont moins connus. Nos connaissances sont fondées sur des preuves photographiques ainsi que sur des études de marquage restreint réalisées entre 1982 et 2000. Dans le cadre de la présente étude, 85 % (17) des 20 baleines pistées par satellite qui auraient pu passer du temps dans la partie canadienne de la mer de Beaufort vers la fin de l’été de 2006 à 2012 y ont passé les mois d’août et de septembre, en totalité ou en partie. Nous avons analysé les données de localisation de16 baleines à l’aide d’un modèle de comportement de marche aléatoire corrélée à commutation binaire, et classé les localisations dans les eaux canadiennes comme relevant d’un comportement de traînage (présupposition de comportement d’alimentation) ou comme relevant de déplacements orientés. Nous avons constaté que ces baleines passaient la plus grande partie de leur temps à traîner (59 %), à se déplacer (22 %), et à faire la transition entre traîner et se déplacer (19 %). En n’utilisant que les localisations de traînage des baleines pistées pour toutes les années à l’étude, nous avons calculé les noyaux de densité et défini cinq zones à l’intérieur du contour de la densité de 75 % à titre de zones d’agrégation. Ensemble, les cinq zones d’agrégation que nous avons définies s’étendent sur 25 341 km2, soit 14,1 % de la zone totale utilisée par ces baleines pistées dans les eaux canadiennes en août et en septembre des années de déploiement. Trois zones d’agrégation étaient situées dans les eaux peu profondes du plateau de la mer de Beaufort, et ces zones étaient principalement utilisées par les baleines immatures pistées dans notre échantillon. Deux autres agrégations ont été observées, une dans la baie Darnley et l’autre dans le détroit du Vicomte de Melville situés dans la partie canadienne de l’archipel Arctique. Chacun de ces endroits était utilisé par une baleine adulte. Des baleines pistées ont été aperçues dans une ou deux zones d’agrégation au cours d’une même saison, rarement plus. La proportion du temps passé à traîner dans chaque zone d’agrégation variait beaucoup d’un individu à l’autre. La plus grande zone d’agrégation (10 877 km2), située sur le plateau de la mer de Beaufort au nord de la péninsule de Tuktoyaktuk (d’une profondeur de 5 à 52 m), était utilisée par 13 des 16 baleines pistées, presque toujours des baleines immatures, dont trois sur quatre ont été repérées pendant deux étés consécutifs. Dans l’ensemble, le plateau de la mer de Beaufort (et peut-être le plateau de Tuktoyaktuk, y compris la zone externe du plateau, en particulier) revêtait une importance particulière pour les baleines boréales immatures, tandis que les baleines adultes se servaient des habitats situés au-delà du plateau de la mer de Beaufort vers la fin de l’été. Ces constatations pourraient jouer un rôle important quand vient le temps d’éclairer tant les décisions en matière de gestion et de mesures d’atténuation se rapportant à l’utilisation que fait la baleine boréale du plateau de la mer de Beaufort que les études visant à améliorer notre compréhension de la composition des proies des baleines boréales de BCB dans la région canadienne de la mer de Beaufort

A Fully Integrated Real-Time Detection, Diagnosis, and Control of Community Diarrheal Disease Clusters and Outbreaks (the INTEGRATE Project):Protocol for an Enhanced Surveillance System

BACKGROUND:Diarrheal disease, which affects 1 in 4 people in the United Kingdom annually, is the most common cause of outbreaks in community and health care settings. Traditional surveillance methods tend to detect point-source outbreaks of diarrhea and vomiting; they are less effective at identifying low-level and intermittent food supply contamination. Furthermore, it can take up to 9 weeks for infections to be confirmed, reducing slow-burn outbreak recognition, potentially impacting hundreds or thousands of people over wide geographical areas. There is a need to address fundamental problems in traditional diarrheal disease surveillance because of underreporting and subsequent unconfirmed infection by patients and general practitioners (GPs); varying submission practices and selective testing of samples in laboratories; limitations in traditional microbiological diagnostics, meaning that the timeliness of sample testing and etiology of most cases remains unknown; and poorly integrated human and animal surveillance systems, meaning that identification of zoonoses is delayed or missed. OBJECTIVE:This study aims to detect anomalous patterns in the incidence of gastrointestinal disease in the (human) community; to target sampling; to test traditional diagnostic methods against rapid, modern, and sensitive molecular and genomic microbiology methods that identify and characterize responsible pathogens rapidly and more completely; and to determine the cost-effectiveness of rapid, modern, sensitive molecular and genomic microbiology methods. METHODS:Syndromic surveillance will be used to aid identification of anomalous patterns in microbiological events based on temporal associations, demographic similarities among patients and animals, and changes in trends in acute gastroenteritis cases using a point process statistical model. Stool samples will be obtained from patients' consulting GPs, to improve the timeliness of cluster detection and characterize the pathogens responsible, allowing health protection professionals to investigate and control outbreaks quickly, limiting their size and impact. The cost-effectiveness of the proposed system will be examined using formal cost-utility analysis to inform decisions on national implementation. RESULTS:The project commenced on April 1, 2013. Favorable approval was obtained from the Research Ethics Committee on June 15, 2015, and the first patient was recruited on October 13, 2015, with 1407 patients recruited and samples processed using traditional laboratory techniques as of March 2017. CONCLUSIONS:The overall aim of this study is to create a new One Health paradigm for detecting and investigating diarrhea and vomiting in the community in near-real time, shifting from passive human surveillance and management of laboratory-confirmed infection toward an integrated, interdisciplinary enhanced surveillance system including management of people with symptoms. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID):DERR1-10.2196/13941

Maize Cultivar Performance under Diverse Organic Production Systems

Maize (Zea mays L.) performance can vary widely between different production systems. The need for high-performing hybrids for organic systems with wide adaptation to various macroenvironments is becoming increasingly important. The goal of this study was to characterize inbred lines developed by distinct breeding programs for their combining ability and hybrid yield performance across diverse organic environments. Parent lines were selected from five different breeding programs to give a sample of publically available germplasm with potential for use in organic production systems with expired plant variety protection (Ex-PVP) and current commercial inbreds as benchmarks. A North Carolina Design II mating design was used to produce all possible cross combinations between seven lines designated as males and seven lines designated as females. A significantly positive general combining ability for the female inbred UHF134 suggests that it performs well in hybrid combination. Significant general combining ability was not observed for any male inbred line in this study. Several significantly positive specific combining abilities suggest that nonadditive genetic effects play an important role in determining yield in this germplasm. Further analysis revealed that hybrids containing either an Ex-PVP line or a commercial inbred line were on average superior to hybrids containing only inbreds developed by the cooperators of this study. This demonstrates the utility of testing inbreds from diverse sources when developing hybrids for organic production systems

Convergence of Cells from the Progenitor Fraction of Adult Olfactory Bulb Tissue to Remyelinating Glia in Demyelinating Spinal Cord Lesions

Progenitor cells isolated from adult brain tissue are important tools for experimental studies of remyelination. Cells harvested from neurogenic regions in the adult brain such as the subependymal zone have demonstrated remyelination potential. Multipotent cells from the progenitor fraction have been isolated from the adult olfactory bulb (OB) but their potential to remyelinate has not been studied. cell bodies adjacent to and surrounding peripheral-type myelin rings.We report that neural cells from the progenitor fraction of the adult rat OB grown in monolayers can be expanded for several passages in culture and that upon transplantation into a demyelinated spinal cord lesion provide extensive remyelination without ectopic neuronal differentiation

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