RAGE mediates S100A4-induced cell motility via MAPK/ERK and hypoxia signaling and is a prognostic biomarker for human colorectal cancer metastasis

Survival of colorectal cancer patients is strongly dependent on development of distant metastases. S100A4 is a prognostic biomarker and inducer for colorectal cancer metastasis. Besides exerting intracellular functions, S100A4 is secreted extracellularly. The receptor for advanced glycation end products (RAGE) is one of its interaction partners. The impact of the S100A4-RAGE interaction for cell motility and metastasis formation in colorectal cancer has not been elucidated so far. Here we demonstrate the RAGE-dependent increase in migratory and invasive capabilities of colorectal cancer cells via binding to extracellular S100A4. We show the direct interaction of S100A4 and RAGE, leading to hyperactivated MAPK/ERK and hypoxia signaling. The S100A4-RAGE axis increased cell migration (P<0.005) and invasion (P<0.005), which was counteracted with recombinant soluble RAGE and RAGE-specific antibodies. In colorectal cancer patients, not distantly metastasized at surgery, high RAGE expression in primary tumors correlated with metachronous metastasis, reduced overall (P=0.022) and metastasis-free survival (P=0.021). In summary, interaction of S100A4-RAGE mediates S100A4-induced colorectal cancer cell motility. RAGE by itself represents a biomarker for prognosis of colorectal cancer. Thus, therapeutic approaches targeting RAGE or intervening in S100A4-RAGE-dependent signaling early in tumor progression might represent alternative strategies restricting S100A4-induced colorectal cancer metastasis

Combination of Wnt/β-catenin targets S100A4 and DKK1 improves prognosis of human colorectal cancer

Metastasis is directly linked to colorectal cancer (CRC) patient survival. Wnt signaling through β-catenin plays a key role. Metastasis-inducing S100A4 is a Wnt/β-catenin target gene and a prognostic biomarker for CRC and other cancer types. We aimed to identify S100A4-dependent expression alterations to better understand CRC progression and metastasis for improved patient survival. S100A4-induced transcriptome arrays, confirmatory studies in isogenic CRC cell lines with defined β-catenin genotypes, and functional metastasis studies were performed. S100A4-regulated transcriptome examination revealed the transcriptional cross-regulation of metastasis-inducing S100A4 with Wnt pathway antagonist Dickkopf-1 (DKK1). S100A4 overexpression down-regulated DKK1, S100A4 knock-down increased DKK1. Recombinant DKK1 reduced S100A4 expression and S100A4-mediated cell migration. In xenografted mice, systemic S100A4-shRNA application increased intratumoral DKK1. The inverse correlation of S100A4 and DKK1 was confirmed in five independent publicly available CRC expression datasets. Combinatorial analysis of S100A4 and DKK1 in two additional independent CRC patient cohorts improved prognosis of overall and metastasis-free survival. The newly discovered transcriptional cross-regulation of Wnt target S100A4 and Wnt antagonist DKK1 is predominated by an S100A4-induced Wnt signaling feedback loop, increasing cell motility and metastasis risk. S100A4 and DKK1 combination improves the identification of CRC patients at high risk

Waste walnut shell valorization to iron loaded biochar and its application to arsenic removal

Iron loaded biochar (ILB) was prepared from waste walnut shell by microwave pyrolysis and its application for arsenic removal was attempted. The ILB was characterized using X-ray diffraction, scanning electron microscopy and BET Surface area analyzer. The adsorption isotherm of As (V) in ILB covering a temperature range of 25 to 45 °C, as well as the kinetics of adsorption at 25 °C were experimentally generated. The adsorption isotherms were modeled using Langmuir and Freundlich isotherm models, while the kinetics of adsorption was modeled using the pseudo-first-order, pseudo-second-order kinetic models, and intra particle diffusion model. The ILB had a surface area of 418 m2/g with iron present in the form of hematite (Fe2O3) and magnetite (Fe3O4). The arsenic adsorption isotherm matches well with Langmuir isotherm model with a monolayer adsorption capacity of 1.91 mg/g at 25 °C. The adsorption capacity of As (V) well compares with other porous adsorbents widely reported in literature, supporting its application as a cost effective adsorbent

Integriertes, intelligentes Video-Endoskopie-System in Mikrosystemtechnik -ENDOSKOP Schlussbericht

1. Goal of the project: The miniaturisation of a 3-CCD video system for use in medical endoscopy is demanded because the superior resolution and the more natural colour reproduction in comparison to the 1-CCD technology is of significant importance in endoscopic diagnosis. In addition the features autofocus and motorised zoom will considerably comfort the handling of the camera. 2. Method: Use of micromechanical components for drive substitution. Miniaturised zoom lens system by the aid of purposeful calculation. Use of high-grade materials. 3. Result: Production of an endoscopic camerahead as a prototype with integrated autofocus function and motorised zoom. 4. Possible Intention of use: The main field of application will be the medical endoscopic surgery and diagnosis, especially at operation scene without a camera assistant. Other possible use is in the combination with an automatic tracing system which keeps the endoscope always in the region of interest, in technical endoscopy and in quality control systems. (orig.)SIGLEAvailable from TIB Hannover: DtF QN1(84,33) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Bildung und Forschung (BMBF), Bonn (Germany)DEGerman

Berichte aus dem Projekt Arbeitsmarkt Bremen

UuStB Koeln(38)-850106446 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Prognostic value of MACC1 and proficient mismatch repair status for recurrence risk prediction in stage II colon cancer patients: the BIOGRID studies

Background: We assessed the novel MACC1 gene to further stratify stage II colon cancer patients with proficient mismatch repair (pMMR). Patients and methods: Four cohorts with 596 patients were analyzed: Charite 1 discovery cohort was assayed for MACC1 mRNA expression and MMR in cryo-preserved tumors. Charite 2 comparison cohort was used to translate MACC1 qRT-PCR analyses to FFPE samples. In the BIOGRID 1 training cohort MACC1 mRNA levels were related to MACC1 protein levels from immunohistochemistry in FFPE sections; also analyzed for MMR. Chemotherapy-naive pMMR patients were stratified by MACC1 mRNA and protein expression to establish risk groups based on recurrence-free survival (RFS). Risk stratification from BIOGRID 1 was confirmed in the BIOGRID 2 validation cohort. Pooled BIOGRID datasets produced a best effect-size estimate. Results: In BIOGRID 1, using qRT-PCR and immunohistochemistry for MACC1 detection, pMMR/MACC1-low patients had a lower recurrence probability versus pMMR/MACC1-high patients (5-year RFS of 92% and 67% versus 100% and 68%, respectively). In BIOGRID 2, longer RFS was confirmed for pMMR/MACC1-low versus pMMR/MACC1-high patients (5-year RFS of 100% versus 90%, respectively). In the pooled dataset, 6.5% of patients were pMMR/MACC1-low with no disease recurrence, resulting in a 17% higher 5-year RFS (95% CI (12.6-21.3%)) versus pMMR/MACC1-high patients (P=0.037). Outcomes were similar for pMMR/MACC1-low and deficient MMR (dMMR) patients (5-year RFS of 100% and 96%, respectively). Conclusions: MACC1 E xpression stratifies colon cancer patients with unfavorable pMMR status. Stage II colon cancer patients with pMMR/MACC1-low tumors have a similar favorable prognosis to those with dMMR with potential implications for the role of adjuvant therapy

A link between inflammation and metastasis:serum amyloid A1 and A3 induce metastasis, and are targets of metastasis-inducing S100A4

S100A4 is implicated in metastasis and chronic inflammation, but its function remains uncertain. Here we establish an S100A4-dependent link between inflammation and metastatic tumor progression. We found that the acute-phase response proteins serum amyloid A (SAA) 1 and SAA3 are transcriptional targets of S100A4 via Toll-like receptor 4 (TLR4)/nuclear factor-{kappa}B signaling. SAA proteins stimulated the transcription of RANTES (regulated upon activation normal T-cell expressed and presumably secreted), G-CSF (granulocyte-colony-stimulating factor) and MMP2 (matrix metalloproteinase 2), MMP3, MMP9 and MMP13. We have also shown for the first time that SAA stimulate their own transcription as well as that of proinflammatory S100A8 and S100A9 proteins. Moreover, they strongly enhanced tumor cell adhesion to fibronectin, and stimulated migration and invasion of human and mouse tumor cells. Intravenously injected S100A4 protein induced expression of SAA proteins and cytokines in an organ-specific manner. In a breast cancer animal model, ectopic expression of SAA1 or SAA3 in tumor cells potently promoted widespread metastasis formation accompanied by a massive infiltration of immune cells. Furthermore, coordinate expression of S100A4 and SAA in tumor samples from colorectal carcinoma patients significantly correlated with reduced overall survival. These data show that SAA proteins are effectors for the metastasis-promoting functions of S100A4, and serve as a link between inflammation and tumor progression