The Pathology of Adrenocortical Hyperfunction and the In Vitro Biosynthesis of Adrenal Androgens

Abstract Not Provided

Space-use and sociability are not related to public-information use in ninespine sticklebacks

There has been much recent interest in both public information use, and the evolutionary origins and ecological consequences of animal personalities but surprisingly little integration of these two fields. Personality traits may impact upon the extent to which individuals respond to public information in a number of different ways. As a first step towards addressing some of these questions, in this study, we asked whether personality traits predicted public information use in ninespine sticklebacks (Pungitius pungitius). Over a 33-day period, subjects were scored twice for a number of behavioural traits, including measures of activity, exploration and shoaling tendency, and were exposed multiple times to a public information use foraging task, in which they were required to select the richer of two prey patches based upon the foraging success of two demonstrator groups. The repeatable (r=0.38–0.58) behavioural traits were reduced to two principle components describing space use and sociability. Neither of these was found to be related to either of two measures of public information use. While the personality traits that we considered did not co-vary with public information use in this species, they may well indirectly affect opportunity for exposure to public information, and this is an obvious avenue for further research.PostprintPeer reviewe

Experience shapes social information use in foraging fish

Funding: This work was funded by the Natural Environment Research Council (NE/D010365/1) to K.N.L.Many species of animal use social information, and in a variety of different contexts, but it is not clear to what degree their ability to do this depends upon their prior experience of the association between the behaviour of others and reward. We addressed this question in an experiment in which two stickleback species (Gasterosteus aculeatus and Pungitius pungitius) were exposed to a novel feeding task and then tested under a range of conditions. Using a fully-factorial training design, fish were either fed from the surface or the bottom of their tank, and at the same time were exposed to conspecifics feeding from the surface or bottom. At test, we showed that in order to be able to use demonstrator behaviour to anticipate the presence of food at the surface, test subjects needed first to have prior experience of both: sticklebacks responded to the behaviour of conspecifics that were feeding at the surface by rising higher in the water column themselves, but, crucially, they only did this if they had prior experience both of finding food at the water surface and of seeing others feed there. Moreover, they only displayed this response in the presence of feeding conspecifics, but not when the demonstrators were not feeding or were absent. The role of prior experience and learning in social information use is surprisingly understudied. We suggest that such work is vital if we are to understand the level at which natural selection operates in shaping social information use and social learning.PostprintPeer reviewe

Social information use and social learning in non-grouping fishes

Funding: NERC (NE/D010365/1) and European Research Council advanced grants (EVOCULTURE 232823).Although it is natural to expect that group-living animals will utilize social learning, the expectation for non-grouping species is less clear. Only a few studies have explored the relationship between sociality and social learning. Here we presented 4 non-grouping fish species, fifteenspine sticklebacks (Spinachia spinachia), bullhead sculpins (Cottus gobio), stone loach (Barbatula barbatula) and juvenile European flounders (Platichthys flesus) with social information provided by groups of a shoal-forming heterospecific, the threespine stickleback (Gasterosteus aculeatus). Using a binary choice procedure we allowed individual test subjects to select between simulated prey patches. Although the test subjects could not sample the patches directly they were able to use information generated by the heterospecific demonstrators to select the “richer” of the 2 patches. For comparison we also recorded social information use in 2 shoaling species, threespine, and ninespine sticklebacks (Pungitius pungitius). We saw evidence of social information use and social learning in all 6 species, with no differences seen between social and non-grouping species. We argue that social learning is not likely to be restricted to group-living species, since many solitary species too are regularly exposed to social stimuli from both conspecifics and heterospecifics, and can benefit from using social information. We suggest that researchers have much to learn about the sensory, perceptive, and cognitive mechanisms underlying social learning, and the extent to which these vary (if at all) between grouping and non-grouping species.PostprintPeer reviewe

Identification of differentially expressed sense and antisense transcript pairs in breast epithelial tissues

Background: More than 20% of human transcripts have naturally occurring antisense products (or natural antisense transcripts – NATs), some of which may play a key role in a range of human diseases. To date, several databases of in silico defined human sense-antisense (SAS) pairs have appeared, however no study has focused on differential expression of SAS pairs in breast tissue. We therefore investigated the expression levels of sense and antisense transcripts in normal and malignant human breast epithelia using the Affymetrix HG-U133 Plus 2.0 and Almac Diagnostics Breast Cancer DSA microarray technologies as well as massively parallel signature sequencing (MPSS) data. Results: The expression of more than 2500 antisense transcripts were detected in normal breast duct luminal cells and in primary breast tumors substantially enriched for their epithelial cell content by DSA microarray. Expression of 431 NATs were confirmed by either of the other two technologies. A corresponding sense transcript could be identified on DSA for 257 antisense transcripts. Of these SAS pairs, 163 have not been previously reported. A positive correlation of differential expression between normal and malignant breast samples was observed for most SAS pairs. Orientation specific RT-QPCR of selected SAS pairs validated their expression in several breast cancer cell lines and solid breast tumours. Conclusion: Disease-focused and antisense enriched microarray platforms (such as Breast Cancer DSA) confirm the assumption that antisense transcription in the human breast is more prevalent than previously anticipated. Expression of a proportion of these NATs has already been confirmed by other technologies while the true existence of the remaining ones has to be validated. Nevertheless, future studies will reveal whether the relative abundances of antisense and sense transcripts have regulatory influences on the translation of these mRNAs

Expression of Cancer/Testis genes in ductal carcinoma in situ and benign lesions of the breast

ABSTRACT: Cancer/testis (CT) genes represent a unique class of genes, which are expressed by germ cells, normally silenced in somatic cells, but activated in various cancers. CT proteins can elicit spontaneous immune responses in cancer patients and this feature makes them attractive targets for immunotherapy-based approaches. We have previously reported that CTs are relatively commonly expressed in estrogen receptor (ER) negative, high risk carcinomas. In this study, we examined the expression of selected CT genes in ductal carcinoma in situ (DCIS), lobular carcinoma in situ (LCIS) and benign proliferative lesions of the breast. ER negative DCIS were found to be associated with significant CT gene expression together with HER2 positivity and a marked stromal immune respons

Multiple Cancer/Testis Antigens Are Preferentially Expressed in Hormone-Receptor Negative and High-Grade Breast Cancers

BACKGROUND: Cancer/testis (CT) antigens are protein antigens normally expressed only in germ cells of testis, and yet are expressed in a proportion of a wide variety of human cancers. CT antigens can elicit spontaneous immune responses in cancer patients with CT-positive cancers, and CT antigen-based therapeutic cancer vaccine trials are ongoing for "CT-rich" tumors. Although some previous studies found breast cancer to be "CT-poor", our recent analysis identified increased CT mRNA transcripts in the ER-negative subset of breast cancer. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we performed a comprehensive immunohistochemical study to investigate the protein expression of eight CT genes in 454 invasive ductal carcinomas, including 225 ER/PR/HER2-negative (triple-negative) carcinomas. We found significantly more frequent expression of all eight CT antigens in ER-negative cancers, and five of them--MAGEA, CT7, NY-ESO-1, CT10 and CT45, were expressed in 12-24% of ER-negative cancers, versus 2-6% of ER-positive cancers (p<0.001 to 0.003). In comparison, GAGE, SAGE1 and NXF2 were only expressed in 3-5% of ER-negative and 0-2% of ER-positive cancers. ER-negative cancers were also more likely to simultaneously co-express multiple CT antigens, with 27% (34/125) of ER-negative, CT-positive tumors expressing three or more CT antigens. HER2 status had no consistent effect on CT expression, and triple-negative carcinomas showed similar frequencies of MAGEA and NY-ESO-1 expression as ER-negative/HER2-positive carcinomas. More frequent CT expression was also found in tumors with higher nuclear grade (p<0.001 to p = 0.01) and larger in size (>2 cm). CONCLUSIONS/SIGNIFICANCE: CT antigens are preferentially expressed in hormone receptor-negative and high-grade breast cancer. Considering the limited treatment options for ER/PR/HER2 triple-negative breast cancer, the potential of CT-based immunotherapy should be explored

Dissecting the transcriptional networks underlying breast cancer: NR4A1 reduces the migration of normal and breast cancer cell lines

Introduction: Breast cancer currently accounts for more than one-quarter of all female cancers and, despite the great progress in treatment observed in the past few years, the need for identification of new gene targets that can be used for diagnosis, prognosis and therapy is evident. A previous study identified the transcription factor NR4A1 as a gene upregulated in primary breast cancer compared with normal tissue by microarray analysis and sequencing technologies. The purpose of the study was to identify the role of NR4A1 in normal mammary epithelial and breast cancer cell biology.Methods: NR4A1 expression in breast tumours was assessed by semiquantitative and real-time PCR using RNA from normal and tumour samples or breast cancer cell lines. Immunohistochemistry on tissue microarrays was performed to check NR4A1 protein expression in breast tumours. MCF-10A and 226L normal mammary epithelial cells as well as the tumour lines PMC42, ZR-75-1 and MDA-MB-231 were transduced with full-length NR4A1, and the ability of NR4A1-overexpressing cells to migrate was tested using scratch wound or transwell migration assays. Proliferation was measured using the MTT and BrdU assays, while apoptosis was determined by the Annexin V assay. The ability of the cells to adhere to extracellular matrix was tested by adhesion assays and integrin cell surface expression was measured by flow cytometry. Activation of the FAK as well as ERK1/2 and PI3K pathways was checked by western blotting.Results: Breast tissue microarray analysis showed NR4A1 expression in primary tumours, which was reduced in higher grade and metastatic tumours. Ectopic expression of NR4A1 in MCF-10A, 226L, PMC42 and ZR-75-1 cells led to reduced ability of the cells to migrate, while no differences were observed in their proliferation and apoptotic index. NR4A1 expression altered the ability of the MCF-10A cells to adhere to the extracellular matrix and affected cell surface expression of integrins.Conclusions: NR4A1 acts as an antimigratory factor in two normal mammary epithelial and two breast cancer cell lines tested. It is therefore possible that NR4A1 acts as an antimigratory factor in breast tumours, and further studies should be conducted to understand the mechanisms involved

Internet-based interventions for the secondary prevention of coronary heart disease

Background The Internet could provide a means of delivering secondary prevention programmes to people with coronary heart disease (CHD). Objectives To determine the effectiveness of Internet-based interventions targeting lifestyle changes and medicines management for the secondary prevention of CHD. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, in December 2014. We also searched six other databases in October 2014, and three trials registers in January 2015 together with reference checking and handsearching to identify additional studies. Selection criteria Randomised controlled trials (RCTs) evaluating Internet-delivered secondary prevention interventions aimed at people with CHD. Data collection and analysis Two review authors independently assessed risk of bias and extracted data according to the Cochrane Handbook for Systematic Reviews of Interventions. We assessed evidence quality using the GRADE approach and presented this in a 'Summary of findings' table