Chemotherapy-induced apoptosis in hepatocellular carcinoma involves the p53 family and is mediatedviathe extrinsic and the intrinsic pathway

We investigated the downstream mechanisms by which chemotherapeutic drugs elicit apoptosis in hepatocellular carcinoma (HCC). Genomic signatures of HCC cell lines treated with different chemotherapeutic drugs were obtained. Analyses of apoptosis pathways were performed and RNA interference was used to evaluate the role of the p53 family. Endogenous p53, p63 and p73 were upregulated in response to DNA damage by chemotherapeutic drugs. Blocking p53 family function led to chemoresistance in HCC. Stimulation and blocking experiments of the CD95-, the TNF- and the TRAIL-receptor systems revealed that cytotoxic drugs, via the p53 family members as transactivators, can trigger expression of each o…

Nanosession: Spin Tunneling Systems

Investigating spintronics thin film systems with synchrotron radiation

Abstract Spintronics is a research field involving a wide variety of different magnetic materials. Synchrotron radiation in the VUV and soft X-ray regime is ideally suited to investigate the relationships between magnetic properties and electronic structure of spintronics thin film stacks. Complex layered structures and nanomagnets are the main building blocks for current and future spintronics applications. In this contribution we describe the study of spintronics model systems with respect to the static and dynamic behavior with an emphasis on interfaces.

Electronic structure of EuO spin filter tunnel contacts directly on silicon

We present an electronic structure study of a magnetic oxide/ semiconductor model system, EuO on silicon, which is dedicated for efficient spin injection and spin detection in silicon-based spintronics devices. A combined electronic structure analysis of Eu core levels and valence bands using hard X-ray photoemission spectroscopy was performed to quantify the nearly ideal stoichiometry of EuO “spin filter” tunnel barriers directly on silicon, and the absence of silicon oxide at the EuO/Si interface. These results provide evidence for the successful integration of a magnetic oxide tunnel barrier with silicon, paving the way for the future integration of magnetic oxides into functional spintr…

Cyclooxygenase-2 inhibition induces apoptosis signaling via death receptors and mitochondria in hepatocellular carcinoma.

AbstractInhibition of cyclooxygenase (COX)-2 elicits chemopreventive and therapeutic effects in solid tumors that are coupled with the induction of apoptosis in tumor cells. We investigated the mechanisms by which COX-2 inhibition induces apoptosis in hepatocellular carcinoma (HCC) cells. COX-2 inhibition triggered expression of the CD95, tumor necrosis factor (TNF)-R, and TNF-related apoptosis-inducing ligand (TRAIL)-R1 and TRAIL-R2 death receptors. Addition of the respective specific ligands further increased apoptosis, indicating that COX-2 inhibition induced the expression of functional death receptors. Overexpression of a dominant-negative Fas-associated death domain mutant reduced COX…

Genome-wide association study of PR interval.

The electrocardiographic PR interval reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation (AF). To identify underlying common genetic variation, we meta-analyzed genome-wide association results for PR interval from seven community-based studies of European-ancestry individuals in the CHARGE consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N=28,517). Statistically significant loci (P<5×10-8) were tested for association with AF (N=5,741 cases). We identified nine loci associated with PR interval. At chromosome 3p22.2, we observed two independent associations in voltage gated sodium channel genes SCN10A and SCN5…

Genome-Wide Association Studies of the PR Interval in African Americans.

The PR interval on the electrocardiogram reflects atrial and atrioventricular nodal conduction time. The PR interval is heritable, provides important information about arrhythmia risk, and has been suggested to differ among human races. Genome-wide association (GWA) studies have identified common genetic determinants of the PR interval in individuals of European and Asian ancestry, but there is a general paucity of GWA studies in individuals of African ancestry. We performed GWA studies in African American individuals from four cohorts (n = 6,247) to identify genetic variants associated with PR interval duration. Genotyping was performed using the Affymetrix 6.0 microarray. Imputation was p…

ΔNp73β is oncogenic in hepatocellular carcinoma by blocking apoptosis signaling via death receptors and mitochondria

p73 belongs to the p53 family of transcription factors known to regulate cell cycle and apoptosis. The Trp73 gene has two promoters that drive the expression of two major p73 isoform subfamilies: TA and ΔN. In general, TAp73 isoforms show proapoptotic activities, whereas members of the N-terminally truncated (ΔN) p73 subfamily that lack the transactivation domain show antiapoptotic functions. We found that upregulation of ΔNp73 in hepatocellular carcinoma (HCC) correlated with reduced survival. Here, we investigated the molecular mechanisms accounting for the oncogenic role of ΔNp73 in HCC.ΔNp73β can directly interfere with the transcriptional activation function of the TA (containing the t…

CellMinerHCC: a microarray-based expression database for hepatocellular carcinoma cell lines.

Background & Aims Therapeutic options for hepatocellular carcinoma (HCC) still remain limited. Development of gene targeted therapies is a promising option. A better understanding of the underlying molecular biology is gained in in vitro experiments. However, even with targeted manipulation of gene expression varying treatment responses were observed in diverse HCC cell lines. Therefore, information on gene expression profiles of various HCC cell lines may be crucial to experimental designs. To generate a publicly available database containing microarray expression profiles of diverse HCC cell lines. Methods Microarray data were analyzed using an individually scripted R program package. Dat…

Mcl-1 is an anti-apoptotic factor for human hepatocellular carcinoma

Defects in apoptosis signaling in hepatocytes contribute to tumorigenesis in hepatocellular carcinoma (HCC). In addition, treatment with chemotherapeutic drugs is often ineffective in HCC patients due to the apoptosis resistance of cancer cells. Anti-apoptotic members of the Bcl-2 family, including myeloid cell leukemia-1 (Mcl-1), which regulate intrinsic apoptosis induction at the mito-chondrial level, are often overexpressed in human cancer, and are implicated with disease grade and prognosis. Yet, little is known about the role of Mcl-1 in HCC. In this study, we analyzed the relevance of Mcl-1 expression for the apop-tosis resistance of human HCC. Mcl-1 protein expression was considerabl…

Chemical stability of the magnetic oxide EuO directly on silicon observed by hard x-ray photoemission spectroscopy

We present a detailed study of the electronic structure and chemical state of high-quality stoichiometric EuO and O-rich ${\mathrm{Eu}}_{1}{\mathrm{O}}_{1+x}$ thin films grown directly on silicon without any buffer layer using hard x-ray photoemission spectroscopy (HAXPES). We determine the EuO oxidation state from a consistent quantitative peak analysis of $4f$ valence band and $3d$ core-level spectra. The results prove that nearly ideal, stoichiometric, and homogeneous EuO thin films can be grown on silicon, with a uniform depth distribution of divalent Eu cations. Furthermore, we identify the chemical stability of the EuO/silicon interface from Si $2p$ core-level photoemission. This work…