Int6 reduction activates stromal fibroblasts to enhance transforming activity in breast epithelial cells

Background: The INT6 gene was first discovered as a site of integration in mouse mammary tumors by the mouse mammary tumor virus; however, INT6's role in the development of human breast cancer remains largely unknown. By gene silencing, we have previously shown that repressing INT6 promotes transforming activity in untransformed human mammary epithelial cells. In the present study, guided by microarray data of human tumors, we have discovered a role of Int6 in stromal fibroblasts. Results: We searched microarray databases of human tumors to assess Int6's role in breast cancer. While INT6 expression levels, as expected, were lower in breast tumors than in adjacent normal breast tissue samples, INT6 expression levels were also substantially lower in tumor stroma. By immunohistochemistry, we determined that the low levels of INT6 mRNA observed in the microarray databases most likely occurs in stromal fibroblasts, because far fewer fibroblasts in the tumor tissue showed detectable levels of the Int6 protein. To directly investigate the effects of Int6 repression on fibroblasts, we silenced INT6 expression in immortalized human mammary fibroblasts (HMFs). When these INT6-repressed HMFs were co-cultured with breast cancer cells, the abilities of the latter to form colonies in soft agar and to invade were enhanced. We analyzed INT6-repressed HMFs and found an increase in the levels of a key carcinoma-associated fibroblast (CAF) marker, smooth muscle actin. Furthermore, like CAFs, these INT6-repressed HMFs secreted more stromal cell-derived factor 1 (SDF-1), and the addition of an SDF-1 antagonist attenuated the INT6-repressed HMFs' ability to enhance soft agar colony formation when co-cultured with cancer cells. These INT6-repressed HMFs also expressed high levels of mesenchymal markers such as vimentin and N-cadherin. Intriguingly, when mesenchymal stem cells (MSCs) were induced to form CAFs, Int6 levels were reduced. Conclusion: These data suggest that besides enhancing transforming activity in epithelial cells, INT6 repression can also induce fibroblasts, and possibly MSCs as well, via mesenchymal-mesenchymal transitions to promote the formation of CAFs, leading to a proinvasive microenvironment for tumorigenesis

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Improving weak lensing mass map reconstructions using Gaussian and sparsity priors: Application to DES SV

Mapping the underlying density field, including non-visible dark matter, using weak gravitational lensing measurements is now a standard tool in cosmology. Due to its importance to the science results of current and upcoming surveys, the quality of the convergence reconstruction methods should be well understood. We compare three methods: Kaiser–Squires (KS), Wiener filter, and Glimpse. Kaiser–Squires is a direct inversion, not accounting for survey masks or noise. The Wiener filter is well-motivated for Gaussian density fields in a Bayesian framework. Glimpse uses sparsity, aiming to reconstruct non-linearities in the density field. We compare these methods with several tests using public Dark Energy Survey (DES) Science Verification (SV) data and realistic DES simulations. The Wiener filter and Glimpse offer substantial improvements over smoothed Kaiser–Squires with a range of metrics. Both the Wiener filter and Glimpse convergence reconstructions show a 12 per cent improvement in Pearson correlation with the underlying truth from simulations. To compare the mapping methods’ abilities to find mass peaks, we measure the difference between peak counts from simulated ΛCDM shear catalogues and catalogues with no mass fluctuations (a standard data vector when inferring cosmology from peak statistics); the maximum signal-to-noise of these peak statistics is increased by a factor of 3.5 for the Wiener filter and 9 for Glimpse. With simulations, we measure the reconstruction of the harmonic phases; the phase residuals’ concentration is improved 17 per cent by Glimpse and 18 per cent by the Wiener filter. The correlationbetween reconstructions from data and foreground redMaPPer clusters is increased 18 per cent by the Wiener filter and 32 per cent by Glimpse.ISSN:0035-8711ISSN:1365-2966ISSN:1365-871

Measurement of the mass of the Z boson and the energy calibration of LEP

In 1985 the French government created a unique circuit for the dissemination of doctoral theses: References went to a national database “Téléthèses” whereas the documents were distributed to the university libraries in microform. In the era of the electronic document this French network of deposit of and access to doctoral theses is changing. How do you discover and locate a French thesis today, how do you get hold of a paper copy and how do you access the full electronic text? What are the catalogues and databases referencing theses since the disappearance of “Téléthèses”? Where are the archives, and are they open? What is the legal environment that rules the emerging structures and tools? This paper presents national plans on referencing and archiving doctoral theses coordinated by the government as well as some initiatives for creating full text archives. These initiatives come from universities as well as from research institutions and learned societies. “Téléthèses” records have been integrated in a union catalogue of French university libraries SUDOC. University of Lyon-2 and INSA Lyon developed procedures and tools covering the entire production chain from writing to the final access in an archive: “Cyberthèses” and “Cither”. The CNRS Centre for Direct Scientific Communication at Lyon (CCSD) maintains an archive (“TEL”) with about 2000 theses in all disciplines. Another repository for theses in engineering, economics and management called “Pastel” is proposed by the Paris Institute of Technology (ParisTech), a consortium of 10 engineering and commercial schools of the Paris region