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The role of the epithelial cell adhesion molecule EpCAM in cancer progression remains largely unclear. High expression of EpCAM in primary tumors is often associated with more aggressive phenotypes and EpCAM is the prime epithelial antigen in use to isolate circulating tumor cells (CTCs) and characterize disseminated tumor cells (DTCs). However, reduced expression of EpCAM was associated with epithelial-to-mesenchymal transition (EMT) and reports on a lack of EpCAM on CTCs emerged. These contradictory observations might reflect a context-dependent adaption of EpCAM expression during metastatic progression. To test this, EpCAM expression was monitored in esophageal cancer at different sites of early systemic disease. Although most of the primary esophageal tumors expressed high levels of EpCAM, the majority of DTCs in bone marrow lacked EpCAM. In vitro , downregulation of EpCAM expression at the plasma membrane was observed in migrating and invading cells, and was associated with a partial loss of the epithelial phenotype and with significantly decreased proliferation. Accordingly, induction of EMT through the action of TGFβ resulted in substantial loss of EpCAM cell surface expression on esophageal cancer cells. Knock-down or natural loss of EpCAM recapitulated these effects as it reduced proliferation while enhancing migration and invasion of cancer cells. Importantly, expression of EpCAM on DTCs was significantly associated with the occurrence of lymph node metastases and with significantly decreased overall survival of esophageal cancer patients. We validated this observation by showing that high expression of EpCAM promoted tumor outgrowth after xenotransplantation of esophageal carcinoma cells. The present data disclose a dynamic expression of EpCAM throughout tumor progression, where EpCAM high phenotypes correlate with proliferative stages, whereas EpCAM low/negative phenotypes associated with migration, invasion and dissemination. Thus, differing expression levels of EpCAM must be taken into consideration for therapeutic approaches and during clinical retrieval of disseminated tumor cells.

Input data for applications that run in cloud computing centres can be stored at distant repositories, often with multiple copies of the popular data stored at many sites. Locating and retrieving the remote data can be challenging, and we believe that federating the storage can address this problem. A federation would locate the closest copy of the data on the basis of GeoIP information. Currently we are using the dynamic data federation Dynafed, a software solution developed by CERN IT. Dynafed supports several industry standards for connection protocols like Amazon's S3, Microsoft's Azure, as well as WebDAV and HTTP. Dynafed functions as an abstraction layer under which protocol-dependent authentication details are hidden from the user, requiring the user to only provide an X509 certificate. We have setup an instance of Dynafed and integrated it into the ATLAS data distribution management system. We report on the challenges faced during the installation and integration. We have tested ATLAS analysis jobs submitted by the PanDA production system and we report on our first experiences with its operation.

The estimated relative cancer risk may be 15 fold higher than in the general population 1 and appears to be particularly high in women (20 fold) because of an increased risk of development of breast cancer and gynaecological malignancies. 2 Germline mutations in the STK11/LKB1 gene on 19p13.3 are found in 30-70% of PJS cases, depending on the screening method, with considerable uncharacterised genetic heterogeneity remaining in this syndrome. 3, 4 The disease causing gene has been identified by two independent groups. 5, 6 Human STK11 encodes a serine/threonine protein kinase that is highly homologous to the mouse protein Lkb1 and the Xenopus kinase XEEK1, 7, 8 and is expressed in all human tissues. 9 The kinase domain of the human 433 amino acid protein is localised between residues 49 and 309, 7 and shows homology to the conserved catalytic core of the kinase domain common to both serine/threonine and tyrosine protein kinase family members. 10 Most mutations found in PJS patients are small deletions/insertions or single base substitutions leading to an abnormal truncated/kinase inactive protein. PJS is a cancer predisposing disorder; however, cancer risk may vary. [...]we studied whether specific STK11 mutations may confer a lower or higher cancer risk in PJS patients by examining the site and type of mutations with regard to cancer frequency and cancer type.

The distributed cloud using the CloudScheduler VM provisioning service is one of the longest running systems for HEP workloads. It has run millions of jobs for ATLAS and Belle II over the past few years using private and commercial clouds around the world. Our goal is to scale the distributed cloud to the 10,000-core level, with the ability to run any type of application (low I/O, high I/O and high memory) on any cloud. To achieve this goal, we have been implementing changes that utilize context-aware computing designs that are currently employed in the mobile communication industry. Context-awareness makes use of real-time and archived data to respond to user or system requirements. In our distributed cloud, we have many opportunistic clouds with no local HEP services, software or storage repositories. A context-aware design significantly improves the reliability and performance of our system by locating the nearest location of the required services. We describe how we are collecting and managing contextual information from our workload management systems, the clouds, the virtual machines and our services. This information is used not only to monitor the system but also to carry out automated corrective actions. We are incrementally adding new alerting and response services to our distributed cloud. This will enable us to scale the number of clouds and virtual machines. Further, a context-aware design will enable us to run analysis or high I/O application on opportunistic clouds. We envisage an open-source HTTP data federation (for example, the DynaFed system at CERN) as a service that would provide us access to existing storage elements used by the HEP experiments.

To understand the functional significance of RNA processing for the expression of plastome-encoded photosynthesis genes, we investigated the nuclear mutation hcf107 of Arabidopsis. The mutation is represented by two alleles, both of which lead to a defective photosystem II (PSII). In vivo protein labeling, in vitro phosphorylation, and immunoblot experiments revealed that the psbB gene product (CP47) and an 8-kD phosphoprotein, the psbH gene product (PsbH), are absent in mutant plants. PsbH and PsbB are essential requirements for PSII assembly in photosynthetic eukaryotes, and their absence in hcf107 is consistent with the PSII-less mutant phenotype. RNA gel blot hybridizations showed that the hcf107 mutation specifically impairs the accumulation of some but not all oligocistronic psbH transcripts that are released from the pentacistronic psbB-psbT-psbH-petB-petD precursor RNA by intergenic endonucleolytic cleavage. In contrast, neither the levels nor the sizes of psbB-containing RNAs are affected. S1 nuclease protection analyses revealed that psbH RNAs are lacking only where psbH is the leading cistron and that they are processed at position -45 in the 5′ leader segment of psbH. These data and additional experiments with the cytochrome b6f complex mutant hcf152, which is defective in 3′ psbH processing, suggest that only those psbH-containing transcripts that are processed at their -45 5′ ends can be translated. Secondary structure analysis of the 5′ psbH leader predicted the formation of stable stem loops in the nonprocessed transcripts, which are unfolded by processing at the -45 site. We propose that this unfolding of the psbH leader segment as a result of RNA processing is essential for the translation of the psbH reading frame. We suggest further that HCF107 has dual functions: it is involved in intercistronic processing of the psbH 5′ untranslated region or the stabilization of 5′ processed psbH RNAs, and concomitantly, it is required for the synthesis of CP47.

Small changes in the radiation budget at the earth's surface can lead to large climatological responses when persistent over time. With the increasing debate on anthropogenic influences on climatic processes during the 1980s the need for accurate radiometric measurements with higher temporal resolution was identified, and it was determined that the existing measurement networks did not have the resolution or accuracy required to meet this need. In 1988 the WMO therefore proposed the establishment of a new international Baseline Surface Radiation Network (BSRN), which should collect and centrally archive high-quality ground-based radiation measurements in 1 min resolution. BSRN began its work in 1992 with 9 stations; currently (status 2018-01-01), the network comprises 59 stations (delivering data to the archive) and 9 candidates (stations recently accepted into the network with data forthcoming to the archive) distributed over all continents and oceanic environments. The BSRN database is the World Radiation Monitoring Center (WRMC). It is hosted at the Alfred Wegener Institute (AWI) in Bremerhaven, Germany, and now offers more than 10 300 months of data from the years 1992 to 2017. All data are available at https://doi.org/10.1594/PANGAEA.880000 free of charge.

The limited sensitivity of circulating tumor cell (CTC) detection in pancreatic adenocarcinoma (PDAC) stems from their extremely low concentration in the whole circulating blood, necessitating enhanced detection methodologies. This study sought to amplify assay-sensitivity by employing diagnostic leukapheresis (DLA) to screen large blood volumes. Sixty patients were subjected to DLA, with a median processed blood volume of ~ 2.8 L and approximately 5% of the resulting DLA-product analyzed using CellSearch (CS). Notably, DLA significantly increased CS-CTC detection to 44% in M0-patients and 74% in M1-patients, yielding a 60-fold increase in CS-CTC enumeration. DLA also provided sufficient CS-CTCs for genomic profiling, thereby delivering additional genomic information compared to tissue biopsy samples. DLA CS-CTCs exhibited a pronounced negative prognostic impact on overall survival (OS), evidenced by a reduction in OS from 28.6 to 8.5 months (univariate: p = 0.002; multivariable: p = 0.043). Additionally, a marked enhancement in sensitivity was achieved (by around 3-4-times) compared to peripheral blood (PB) samples, with positive predictive values for OS being preserved at around 90%. Prognostic relevance of CS-CTCs in PDAC was further validated in PB-samples from 228 PDAC patients, consolidating the established association between CTC-presence and reduced OS (8.5 vs. 19.0 months, p < 0.001). In conclusion, DLA-derived CS-CTCs may serve as a viable tool for identifying high-risk PDAC-patients and aiding the optimization of multimodal treatment strategies. Moreover, DLA enables comprehensive diagnostic profiling by providing ample CTC material, reinforcing its utility as a reliable liquid-biopsy approach. This high-volume liquid-biopsy strategy presents a potential pathway for enhancing clinical management in this malignancy.