Inhibition of MACC1-induced metastasis in esophageal and gastric adenocarcinomas

Esophageal and Gastric Adenocarcinomas (AGE/S) are characterized by early metastasis and poor survival. MACC1 (Metastasis Associated in Colon Cancer 1) acts in colon cancer as a metastasis inducer and is linked to reduced survival. This project illuminates the role and potential for the inhibition of MACC1 in AGE/S. Using 266 of 360 TMAs and survival data of AGE/S patients, we confirm the value of MACC1 as an independent negative prognostic marker in AGE/S patients. MACC1 gene expression is correlated with survival and morphological characteristics. In vitro analysis of lentivirally MACC1-manipulated subclones of FLO-1 and OE33 showed enhanced migration induced by MACC1 in both cell line models, which could be inhibited by the MEK1 inhibitor selumetinib. In vivo, the efficacy of selumetinib on tumor growths and metastases of MACC1-overexpressing FLO-1 cells xenografted intrasplenically in NOG mice was tested. Mice with high-MACC1-expressing cells developed faster and larger distant metastases. Treatment with selumetinib led to a significant reduction in metastasis exclusively in the MACC1-positive xenografts. MACC1 is an enhancer of tumor aggressiveness and a predictor of poor survival in AGE/S. This effect can be inhibited by selumetinib

S100A4 is a strong negative prognostic marker and potential therapeutic target in adenocarcinoma of the stomach and esophagus

Deregulated Wnt-signaling is a key mechanism driving metastasis in adenocarcinoma of the gastroesophageal junction and stomach (AGE/S). The oncogene S100A4 was identified as a Wnt-signaling target gene and is known to promote metastasis. In this project, we illuminate the role of S100A4 for metastases development and disease prognosis of AGE/S. Five gastric cancer cell lines were assessed for S100A4 expression. Two cell lines with endogenous high S100A4 expression were used for functional phenotyping including analysis of proliferation and migration after stable S100A4 knock-down. The prognostic value of S100A4 was evaluated by analyzing the S100A4 expression of tissue microarrays with samples of 277 patients with AGE/S. S100A4 knock-down induced lower migration in FLO1 and NCI-N87 cells. Treatment with niclosamide in these cells led to partial inhibition of S100A4 and to reduced migration. Patients with high S100A4 expression showed lower 5-year overall and disease-specific survival. In addition, a larger share of patients in the S100A4 high expressing group suffered from metachronous metastasis. This study identifies S100A4 as a negative prognostic marker for patients with AGE/S. The strong correlation between S100A4 expression, metastases development and patient survival might open opportunities to use S100A4 to improve the prognosis of these patients and as a therapeutic target for intervention in this tumor entity

Classification and Characteristics of Electronic Payment Systems

Electronic commerce and electronic business greatly need new payment systems that will support their further development. To better understand problems and perspectives of the electronic payment systems this article describes a classification and different characteristic aspects of payment systems

Repositioning of drugs for intervention in tumor progression and metastasis: Old drugs for new targets

The increasing unraveling of the molecular basis of cancer offers manifold novel options for intervention strategies. However, the discovery and development of new drugs for potential clinical applications is a tremendously time-consuming and costly process. Translating a novel lead candidate compound into an approved clinical drug takes often more than a decade, and the success rate is very low due to versatile efforts including defining its pharmacokinetics, pharmacodynamics, side effects as well as lack of sufficient efficacy. Thus, strategies are needed to minimize time and costs, while maximizing success rates. A very attractive strategy for novel cancer therapeutic options is the repositioning of already approved drugs. These medicines, approved for the treatment of non-malignant disorders, have already passed some early costs and time, have been tested in humans and are ready for clinical trials as anti-cancer drugs. Here we discuss the repositioning of nonsteroidal anti-inflammatory drugs (NSAID), statins, anti-psychotic drugs, anti-helminthic drugs and vitamin D as anti-tumor agents. We focus on their novel actions and potential for inhibition of cancer growth and metastasis by interfering with target molecules and pathways, which drive these malignant processes. Furthermore, important pre-clinical and clinical data are reviewed herein, which elucidate their therapeutic mechanisms which enable their repositioning for cancer therapy and disruption of metastasis

Holocene development and anthropogenic disturbance of a shallow lake system in Central Ireland recorded by diatoms

Three cores from two connected lakes in Central Ireland (Lough Kinale and Derragh Lough) were investigated using diatom analysis to establish the Holocene development of the lacustrine system, any local variations within the lakes and any anthropogenic influences. The study area was situated in a lowland location and the lakes were shallow, unstratified and interconnected. Litho-and bio-stratigraphical analyses of the lake cores and deposits beneath a mire separating the two lakes showed the changing spatial configuration of the lake system in the early Holocene and the separation of the initial lake into three basins (cf. lacustrine cells) and finally into two interlinked lakes. The evolution of the lake system is conceptualised as the development of distinct lacustrine cells, and its sediments have recorded changes in the physical (geography, depth and sedimentation) and chemical (water chemistry) properties of the lakes inferred through diatom analyses. The longest sequence, from the early Holocene, records fluctuating lake levels and these are correlated with geomorphological mapping and surveying of palaeoshorelines. The diatom assemblages of the upper 2 m of the three cores, covering approximately the last 2000–3000 radiocarbon years show considerable difference in trophic status and life-form categories. This is related to the location of the cores in the lake and also the distance from human settlement with particular reference to proximity to crannog (artificial island) construction and use. The most central core from the deepest part of Lough Kinale has the least representation of the human settlement and agricultural activity in the catchment and on the fringes of the lake, whereas the core taken from the edge of a crannog is able to identify when construction and use of the crannog occurred. The local nature of the palaeoecological response to human activity due to incomplete water mixing has the advantage of allowing the lake sediment cores to be used to determine spatially discrete settlement patterns

The Role of Internet of Services (IoS) on Industry 4.0 Through the Service Oriented Architecture (SOA)

Part 1: Lean and Green ManufacturingInternational audienceMany different concepts and approaches have been seen for an Industry 4.0 achievement. In the attempt of merging the theory to the practice, there are gaps to determine which concept or technology suits best the productive chain and what is really a pre-requisite to classify it as Industry 4.0. On scientific and empirical literature about this subject, the Internet of Services, IoS, has been mentioned as an important pillar for Industry 4.0, coupled with Internet of Things (IoT) and Cyber-physical systems (CPS). While IoT and CPS as well as their link with Industry 4.0 are detailed in many researches, a deeper understanding on the Internet of Services and its contribution for this scenario is still missing. This paper aims to fill this gap gathering concepts about the Internet of Services, how it is composed and what would be its role on the manufacturing environment. Through a deeper understanding about the origin of the term Internet of Services, there is an important concept that may explain how the Industry 4.0 operates in a business and technological perspective: the concept of SOA - Service Oriented Architecture

Immunohistochemical analysis of Bcl-2, nuclear S100A4, MITF and Ki67 for risk stratification of early-stage melanoma - a combined IHC score for melanoma risk stratification

BACKGROUND AND OBJECTIVES: Overall survival (OS) in patients with early-stage malignant melanoma differs. To date, there are no established prognostic markers. We aimed to contribute to a better understanding of potential prognostic immunohistochemical markers for risk stratification. PATIENTS AND METHODS: 161 surgically resected early-stage malignant melanomas (stage pT1 and pT2) were analyzed for expression of 20 different proteins using immunohistochemistry. The results were correlated with OS. The cohort was randomly split into a discovery and a validation cohort. RESULTS: High Bcl-2 expression, high nuclear S100A4 expression as well as a Ki67 proliferation index of ≥ 20 % were associated with shorter OS. Strong MITF immunoreactivity was a predictor for favorable prognosis. A combination of these four markers resulted in a multi-marker score with significant prognostic value in multivariate survival analysis (HR: 3.704; 95 % CI 1.484 to 9.246; p = 0.005). Furthermore, the score was able to differentiate a low-risk group with excellent OS rates (five-year survival rate: 100 %), an intermediate-risk group (five-year survival rate: 81.8 %) and a high-risk group (five-year survival rate: 52.6 %). The prognostic value was confirmed within the validation cohort. CONCLUSIONS: Combined immunohistochemical analysis of Bcl-2, nuclear S100A4, Ki67 and MITF could contribute to better risk stratification of early-stage malignant melanoma patients