Epithelial-to-Mesenchymal Transition in Pancreatic Ductal Adenocarcinoma and Pancreatic Tumor Cell Lines: The Role of Neutrophils and Neutrophil-Derived Elastase

Pancreatic ductal adenocarcinoma (PDAC) is frequently associated with fibrosis and a prominent inflammatory infiltrate in the desmoplastic stroma. Moreover, in PDAC, an epithelial-to-mesenchymal transition (EMT) is observed. To explore a possible connection between the infiltrating cells, particularly the polymorphonuclear neutrophils (PMN) and the tumor cell transition, biopsies of patients with PDAC (n=115) were analysed with regard to PMN infiltration and nuclear expression of β-catenin and of ZEB1, well-established indicators of EMT. In biopsies with a dense PMN infiltrate, a nuclear accumulation of β-catenin and of ZEB1 was observed. To address the question whether PMN could induce EMT, they were isolated from healthy donors and were cocultivated with pancreatic tumor cells grown as monolayers. Rapid dyshesion of the tumor cells was seen, most likely due to an elastase-mediated degradation of E-cadherin. In parallel, the transcription factor TWIST was upregulated, β-catenin translocated into the nucleus, ZEB1 appeared in the nucleus, and keratins were downregulated. EMT was also induced when the tumor cells were grown under conditions preventing attachment to the culture plates. Here, also in the absence of elastase, E-cadherin was downmodulated. PMN as well as prevention of adhesion induced EMT also in liver cancer cell line. In conclusion, PMN via elastase induce EMT in vitro, most likely due to the loss of cell-to-cell contact. Because in pancreatic cancers the transition to a mesenchymal phenotype coincides with the PMN infiltrate, a contribution of the inflammatory response to the induction of EMT and—by implication—to tumor progression is possible

Imaging features of fibrolamellar hepatocellular carcinoma in gadoxetic acid-enhanced MRI

Background: Fibrolamellar hepatocellular carcinoma (FLC) is a rare malignancy occurring in young patients without cirrhosis. Objectives of our study were to analyze contrast material uptake in hepatobiliary phase imaging (HBP) in gadoxetic acid-enhanced liver MRI in patients with FLC and to characterize imaging features in sequence techniques other than HBP. Methods: In this retrospective study on histology-proven FLC, contrast material uptake in HBP was quantitatively assessed by calculating the corrected FLC enhancement index (CEI) using mean signal intensities of FLC and lumbar muscle on pre-contrast imaging and HBP, respectively. Moreover, enhancement patterns in dynamic contrast-enhanced MRI and relative signal intensities compared with background liver parenchyma were determined by two radiologists in consensus for HBP, diffusion-weighted imaging using high b-values (DWI), and T2 and T1 weighted pre-contrast imaging. Results: In 6 of 13 patients with FLC gadoxetic acid-enhanced liver MRI was available. The CEI suggested presence of HBP contrast material uptake in all FLCs. A mean CEI of 1.35 indicated FLC signal increase of 35% in HBP compared with pre-contrast imaging. All FLCs were hypointense in HBP compared with background liver parenchyma. Three of 6 FLCs had arterial hyperenhancement and venous wash-out. In DWI and T2 weighted imaging, 5 of 6 FLCs were hyperintense. In T1 weighted imaging, 5 of 6 FLCs were hypointense. Conclusion: Hepatobiliary uptake of gadoxetic acid was quantitatively measurable in all FLCs investigated in our study. The observation of hypointensity of FLCs in HBP compared with background liver parenchyma emphasizes the role of gadoxetic acid-enhanced liver MRI for non-invasive diagnosis of FLC and its importance in the diagnostic work-up of indeterminate liver lesions

Human Mesenchymal Stromal Cells Resolve Lipid Load in High Fat Diet-Induced Non-Alcoholic Steatohepatitis in Mice by Mitochondria Donation

Mesenchymal stromal cells (MSC) increasingly emerge as an option to ameliorate non-alcoholic steatohepatitis (NASH), a serious disease, which untreated may progress to liver cirrhosis and cancer. Before clinical translation, the mode of action of MSC needs to be established. Here, we established NASH in an immune-deficient mouse model by feeding a high fat diet. Human bone-marrow-derived MSC were delivered to the liver via intrasplenic transplantation. As verified by biochemical and image analyses, human mesenchymal stromal cells improved high-fat-diet-induced NASH in the mouse liver by decreasing hepatic lipid content and inflammation, as well as by restoring tissue homeostasis. MSC-mediated changes in gene expression indicated the switch from lipid storage to lipid utilization. It was obvious that host mouse hepatocytes harbored human mitochondria. Thus, it is feasible that resolution of NASH in mouse livers involved the donation of human mitochondria to the mouse hepatocytes. Therefore, human MSC might provide oxidative capacity for lipid breakdown followed by restoration of metabolic and tissue homeostasis

Evaluation of the modified HTK solution in pancreas transplantationdAn experimental model

One of the great challenges in pancreas transplantation is the ischemia reperfusion injury. It is mentioned that free oxygen and/or nitrogen radicals play a prominent role in this phase. To minimize this problem, a modified histidineetryptophan eketoglutarate (HTK) solution that contains modified antioxidants has been developed. Our aim was to evaluate this solution in improving the viability of the pancreas in comparison with standard HTK and University of Wisconsin (UW) solutions in a porcine model of pancreas transplantation

The behaviour of political parties and MPs in the parliaments of the Weimar Republic

Copyright @ 2012 The Authors. This is the author's accepted manuscript. The final published article is available from the link below.Analysing the roll-call votes of the MPs of the Weimar Republic we find: (1) that party competition in the Weimar parliaments can be structured along two dimensions: an economic left–right and a pro-/anti-democratic. Remarkably, this is stable throughout the entire lifespan of the Republic and not just in the later years and despite the varying content of votes across the lifespan of the Republic, and (2) that nearly all parties were troubled by intra-party divisions, though, in particular, the national socialists and communists became homogeneous in the final years of the Republic.Zukunftskolleg, University of Konstan

Molecular testing for the clinical diagnosis of fibrolamellar carcinoma.

Fibrolamellar carcinoma has a distinctive morphology and immunophenotype, including cytokeratin 7 and CD68 co-expression. Despite the distinct findings, accurate diagnosis of fibrolamellar carcinoma continues to be a challenge. Recently, fibrolamellar carcinomas were found to harbor a characteristic somatic gene fusion, DNAJB1-PRKACA. A break-apart fluorescence in situ hybridization (FISH) assay was designed to detect this fusion event and to examine its diagnostic performance in a large, multicenter, multinational study. Cases initially classified as fibrolamellar carcinoma based on histological features were reviewed from 124 patients. Upon central review, 104 of the 124 cases were classified histologically as typical of fibrolamellar carcinoma, 12 cases as 'possible fibrolamellar carcinoma' and 8 cases as 'unlikely to be fibrolamellar carcinoma'. PRKACA FISH was positive for rearrangement in 102 of 103 (99%) typical fibrolamellar carcinomas, 9 of 12 'possible fibrolamellar carcinomas' and 0 of 8 cases 'unlikely to be fibrolamellar carcinomas'. Within the morphologically typical group of fibrolamellar carcinomas, two tumors with unusual FISH patterns were also identified. Both cases had the fusion gene DNAJB1-PRKACA, but one also had amplification of the fusion gene and one had heterozygous deletion of the normal PRKACA locus. In addition, 88 conventional hepatocellular carcinomas were evaluated with PRKACA FISH and all were negative. These findings demonstrate that FISH for the PRKACA rearrangement is a clinically useful tool to confirm the diagnosis of fibrolamellar carcinoma, with high sensitivity and specificity. A diagnosis of fibrolamellar carcinoma is more accurate when based on morphology plus confirmatory testing than when based on morphology alone

Nuclear pore component Nup98 is a potential tumor suppressor and regulates posttranscriptional expression of select p53 target genes

The p53 tumor suppressor utilizes multiple mechanisms to selectively regulate its myriad target genes, which in turn mediate diverse cellular processes. Here, using conventional and single-molecule mRNA analyses, we demonstrate that the nucleoporin Nup98 is required for full expression of p21, a key effector of the p53 pathway, but not several other p53 target genes. Nup98 regulates p21 mRNA levels by a posttranscriptional mechanism in which a complex containing Nup98 and the p21 mRNA 3\u27UTR protects p21 mRNA from degradation by the exosome. An in silico approach revealed another p53 target (14-3-3sigma) to be similarly regulated by Nup98. The expression of Nup98 is reduced in murine and human hepatocellular carcinomas (HCCs) and correlates with p21 expression in HCC patients. Our study elucidates a previously unrecognized function of wild-type Nup98 in regulating select p53 target genes that is distinct from the well-characterized oncogenic properties of Nup98 fusion proteins

Cenozoic evolution of Asian climate and sources of Pacific seawater Pb and Nd derived from eolian dust of sediment core LL44‐GPC3

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95692/1/palo954.pd

Source and possible tectonic driver for Jurassic–Cretaceous gold deposits in the West Qinling Orogen, China

The West Qinling Orogen (WQO) in Central China Orogenic Belt contains numerous metasedimentary rock-hosted gold deposits (>2000 t Au), which mainly formed during two pulses: one previously recognized in the Late Triassic to Early Jurassic (T3–J1) and one only recently identified in the Late Jurassic to Early Cretaceous (J3–K1). Few studies have focused on the origin and geotectonic setting of the J3–K1 gold deposits. Textural relationships, LA-ICP-MS trace element and sulfur isotope compositions of pyrites in hydrothermally altered T3 dykes within the J3–K1 Daqiao deposit were used to constrain relative timing relationships between mineralization and pyrite growth in the dykes, and to characterize the source of ore fluid. These results are integrated with an overview of the regional geodynamic setting, to advance understanding of the tectonic driver for J3–K1 hydrothermal gold systems. Pyrite in breccia- and dyke-hosted gold ores at Daqiao have similar chemical and isotopic compositions and are considered to be representative of J3–K1 gold deposits in WQO. Co/Ni and sulfur isotope ratios suggest that ore fluids were derived from underlying Paleozoic Ni- and Se-rich carbonaceous sedimentary rocks. The geochemical data do not support the involvement of magmatic fluids. However, in the EQO (East Qinling Orogen), J3–K1 deposits are genetically related to magmatism. Gold mineralization in WQO is contemporaneous with magmatic deposits in the EQO and both are mainly controlled by NE- and EW-trending structures produced by changes in plate motion of the Paleo-Pacific plate as it was subducted beneath the Eurasian continent. We therefore infer that the J3–K1 structural regime facilitated the ascent of magma in the EQO and metamorphic fluids in the WQO with consequent differences in the character of contemporaneous ore deposits. If this is correct, then the far-field effects of subduction along the eastern margin of NE Asia extended 1000's of km into the continental interior