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  • 1
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; EXPRESSION ; CELL ; Germany ; human ; DEATH ; CLONING ; GENE-EXPRESSION ; PROTEIN ; SAMPLE ; SAMPLES ; DIFFERENTIATION ; LIGAND ; MECHANISM ; CONTRAST ; mechanisms ; IN-SITU ; NEOPLASIA ; CELL-DEATH ; DECREASE ; RECEPTORS ; SMALL-INTESTINE ; TRAIL ; protein expression ; LACKING ; molecular ; RECOMBINANT ; MOLECULAR-MECHANISM ; VARIANT ; INCREASE ; CELL-SURFACE EXPRESSION ; PH ; regulation ; development ; MOLECULAR-MECHANISMS ; methods ; cell death ; CELIAC-DISEASE ; death receptor ; USA ; LIGAND TRAIL ; HOMEOSTASIS ; INCREASES ; apoptotic ; MUCOSAL ; ACYL-COA-SYNTHETASE-5 ; HUMAN SMALL-INTESTINE ; IMPAIRED EXPRESSION
    Abstract: Background & Aims: The constant renewal of enterocytes along the crypt-villus axis (CVA) of human small intestine is due to cell-inherent changes resulting in the apoptotic cell death of senescent enterocytes. The aim of the present study was to examine underlying molecular mechanisms of the cell death at the villus tip. Methods: Characterization of human acyl-coenzyme A (CoA) synthetase 5 (ACSL5) was performed by cloning, recombinant protein expression, biochemical approaches, and several functional and in situ analyses. Results: Our data show that different amounts of acyl-CoA synthetase 5-full length (ACSL5-fl) and a so far unknown splice variant lacking exon 20 (ACSL5-Delta 20) are found in human enterocytes. In contrast with the splice variant ACSL5-Delta 20, recombinant and purified ACSL5-fl protein is active at a highly alkaline pH. Over expression of ACSL5-fl protein is associated with a decrease of the anti-apoptotic FLIP protein in a ceramide-dependent manner and an increased cell-surface expression of the death receptor TRAIL-RI. Expression analyses revealed that the ACSL5-fl/ACSL5-Delta 20 ratio increases along the CVA, thereby sensitizing ACSL5-fl-dominated cells at the villus tip to the death ligand TRAIL, which is corroborated by functional studies with human small intestinal mucosal samples and an immortalized human small intestinal cell fine. Conclusions: Our results suggest an ACSL5-dependent regulatory mechanism that contributes to the cellular renewal along the CVA in human small intestine. Deregulation of the ACSL5-fl/ACSL5-Delta 20 homeostasis in the maturation and shedding of cells along the CVA might also be of relevance for the development of intestinal neoplasia
    Type of Publication: Journal article published
    PubMed ID: 17681178
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  • 2
    Keywords: brain ; APOPTOSIS ; CELLS ; EXPRESSION ; IN-VITRO ; tumor ; CELL ; Germany ; human ; IN-VIVO ; INHIBITION ; KINASE ; PATHWAY ; VITRO ; PROTEIN ; RNA ; TUMORS ; BIOLOGY ; MOLECULAR-BIOLOGY ; PHOSPHORYLATION ; resistance ; genetics ; CANCER-CELLS ; ONCOGENE ; GLUCOSE ; OVEREXPRESSION ; heredity ; MAP KINASES ; INTEGRIN ACTIVATION ; signaling ; molecular biology ; molecular ; ONCOLOGY ; RE ; BRAIN-TUMORS ; GLIOMA ; GLIOMA-CELLS ; TRANSPORTER ; brain tumors ; LEVEL ; analysis ; PHOSPHOPROTEIN ; ENGLAND ; GLIOBLASTOMA ; ASTROCYTES ; CYTOPLASMIC SEQUESTRATION ; DEATH EFFECTOR DOMAIN ; ERK1/2 ; PEA-15/PED ; PED/PEA-15
    Abstract: PEA-15 ( phosphoprotein enriched in astrocytes 15 kDa) is a death effector domain-containing protein, which is involved in the regulation of apoptotic cell death. Since PEA-15 is highly expressed in cells of glia l origin, we studied the role of PEA-15 in human malignant brain tumors. Immunohistochemical analysis of PEA-15 expression shows strong immunoreactivity in astrocytomas and glioblastomas. Phosphorylation of PEA-15 at Ser(116) is found in vivo in perinecrotic areas in glioblastomas and in vitro after glucose deprivation of glioblastoma cells. Overexpression of PEA-15 induces a marked resistance against glucose deprivation-induced apoptosis, whereas small interfering RNA (siRNA)-mediated downregulation of endogenous PEA-15 results in the sensitization to glucose withdrawal-mediated cell death. This antiapoptotic activity of PEA-15 under low glucose conditions depends on its phosphorylation at Ser116. Moreover, siRNA-mediated knockdown of PEA-15 abolishes the tumorigenicity of U87MG glioblastoma cells in vivo. PEA-15 regulates the level of phosphorylated extracellular-regulated kinase ( ERK) 1/ 2 in glioblastoma cells and the PEA-15-dependent protection from glucose deprivation-induced cell death requires ERK1/2 signaling. PEA-15 transcriptionally upregulates the Glucose Transporter 3, which is abrogated by the inhibition of ERK1/2 phosphorylation. Taken together, our findings suggest that Ser(116)-phosphorylated PEA-15 renders glioma cells resistant to glucose deprivation-mediated cell death as encountered in poor microenvironments, for example in perinecrotic areas of glioblastomas
    Type of Publication: Journal article published
    PubMed ID: 17700518
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  • 3
    Keywords: APOPTOSIS ; CANCER ; THERAPY ; BIOLOGY ; PHOSPHORYLATION ; DEGRADATION ; sensitization ; THERAPIES
    Abstract: Resistance to apoptosis is one reason for the poor response of malignant brain tumors to therapy. The PPARgamma-modulating drug Troglitazone downregulates the anti-apoptotic FLIP protein and sensitizes glioblastoma cells to apoptosis induced by the death ligand TRAIL. To investigate the molecular basis of an experimental combination therapy for malignant gliomas with TRAIL and Troglitazone, we investigated the Troglitazone-induced signaling cascades and the expression of TRAIL receptors and FLIP in malignant gliomas. Troglitazone downregulated the FLIP protein through accelerated ubiquitin/proteasome-dependent degradation, which might be mediated by a Troglitazone-induced increase in reactive oxygen species. Moreover, Troglitazone induced the phosphorylation of the MAP kinase ERK1/2 as well as of the BAD protein. Inhibition of either PPARgamma or MEK1/2 blocked the Troglitazone-mediated phosphorylation of BAD and further increased the synergistic induction of glioma cell death by TRAIL and Troglitazone. Immunohistochemical analysis demonstrated that FLIP and TRAIL-R2 were significantly higher expressed in anaplastic (WHO grade III) than in diffuse (WHO grade II) gliomas. High FLIP and low TRAIL-R2 expression levels were associated with a poor prognosis of patients. Our findings warrant a further pre-clinical evaluation of an experimental anti-glioma therapy with TRAIL and Troglitazone, potentially in conjunction with a MAP kinase inhibitor.
    Type of Publication: Journal article published
    PubMed ID: 19158480
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  • 4
    Keywords: brain ; PEPTIDE ; APOPTOSIS ; CANCER ; CELLS ; GROWTH ; IN-VITRO ; INHIBITOR ; INVASION ; tumor ; TUMOR-CELLS ; CELL ; Germany ; human ; IN-VIVO ; INHIBITION ; KINASE ; VITRO ; VIVO ; DEATH ; DISTINCT ; PROTEIN ; RNA ; TUMORS ; ACTIVATION ; BIOLOGY ; DOWN-REGULATION ; treatment ; CLEAVAGE ; ASSAY ; resistance ; CELL-DEATH ; INDUCED APOPTOSIS ; DECREASE ; STRESS ; RESECTION ; CANCER-CELLS ; MIGRATION ; STRATEGIES ; CONSTITUTIVE ACTIVATION ; CASPASE 8 ; CROSS-TALK ; CD95 ; CASPASE ; INHIBITORS ; signaling ; ONCOLOGY ; RE ; PATTERN ; BRAIN-TUMORS ; GLIOMA ; GLIOMA-CELLS ; MALIGNANT GLIOMAS ; CASPASE-8 ; ASSAYS ; cell death ; PROMOTION ; USA ; caspases ; focal adhesion kinase ; gelsolin ; cancer research ; in vivo ; MOTILITY ; GLIOBLASTOMA ; PROMOTES ; apoptotic ; caspase-3 ; block ; SMALL INTERFERING RNA ; SECONDARY GLIOBLASTOMAS ; CELLULAR-RESISTANCE ; RADIOCHEMOTHERAPY
    Abstract: Glioblastomas, the most malignant of all brain tumors, are characterized by cellular resistance to apoptosis and a highly invasive growth pattern. These factors contribute to the poor response of glioblastomas to radiochemotherapy and prevent their complete neurosurgical resection. However, the driving force behind the distinct motility of glioma cells is only partly understood. Here, we report that in the absence of cellular stress and proapoptotic stimuli, human glioblastoma cells exhibit a constitutive activation of caspases in vivo and in vitro. The inhibition of caspases by various peptide inhibitors decreases the migration of cells in scrape motility assays and the invasiveness of cells in spheroid assays. Similarly, specific small interfering RNA- or antisense-mediated down-regulation of caspase-3 and caspase-8 results in an inhibition of the migratory potential of glioma cells. The constitutive caspase-dependent motility of glioblastoma cells is independent of CD95 activation and it is not mediated by mitogen-activated protein/ extracellular signal-regulated kinase kinase signaling. The basal caspase activity is accompanied by a constant cleavage of the motility-associated gelsolin protein, which may contribute to the caspase-mediated promotion of migration and invasiveness in glioblastoma cells. Our results suggest that the administration of low doses of caspase inhibitors that block glioma cell motility without affecting the execution of apoptotic cell death may be exploited as a novel strategy for the treatment of glioblastomas
    Type of Publication: Journal article published
    PubMed ID: 18171980
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  • 5
  • 6
    Keywords: LUNG-CANCER ; INDUCED APOPTOSIS ; OVARIAN-CANCER ; INTEGRIN ACTIVATION ; GLIOMA-CELLS ; CYTOPLASMIC SEQUESTRATION ; DEATH EFFECTOR DOMAIN ; CANCER STEM-CELLS ; ERK MAP KINASE ; DIFFERENTIAL DISPLAY
    Abstract: The PEA-15/PED (phosphoprotein enriched in astrocytes 15 kD/phosphoprotein enriched in diabetes) protein is a multifunctional phosphoprotein involved in various signaling pathways which determine survival, proliferation, and migration of cancer cells. Here, we investigated the expression and cellular functions of PEA-15 in colorectal carcinoma (CRC). PEA-15 is expressed in the majority of human CRC, predominantly in well differentiated tumor areas. A tissue microarray analysis of 1262 human CRC specimens from the DACHS study showed that PEA-15 expression is significantly associated with a low pT stadium as defined by limited invasion into the bowel wall. Moreover, patients with PEA-15-positive CRC exhibited a significantly longer tumor-specific survival time. To investigate the functional relevance of PEA-15 expression on a cellular level, we over-expressed PEA-15 in several CRC cell lines. Increased expression of PEA-15 resulted in a strong inhibition of clonogenicity, proliferation, and invasiveness of CRC cells. These effects were associated with a PEA-15-dependent down-regulation of integrin alpha v beta 5 as well as with elevated levels of the phosphorylated MAP kinase ERK1/2. Moreover, expression of PEA-15 resulted in significant protection from cell death induced by cytotoxic drugs (5-FU, cisplatin), by the death ligand TRAIL, or by serum withdrawal. In conclusron, the PEA-15 protein regulates invasiveness, proliferation, and apoptosis resistance in CRC cells. PEA-15 might play an important role in chemoresistance, progression and metastasis in CRC.
    Type of Publication: Journal article published
    PubMed ID: 23481023
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  • 7
    ISSN: 1432-1041
    Keywords: Smoking ; Omeprazole ; Cytochrome P4501A ; UDP-glucuronosyltransferase ; duodenal biopsies
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Drug-metabolizing enzymes were investigated in duodenal biopsy specimens. Cytochrome P4501A (CYP1A) activity was determined by measuring 7-ethoxyresorufin O-deethylase (EROD) activity in biopsies from 20 smokers (3–30 cigarettes per day), 21 nonsmokers, and 10 nonsmokers receiving omeprazole treatment (20–60 mg/day for at least 1 week). Omeprazole is known to act as a polycyclic aromatic hydrocarbon (PAH)-type inducer in humans. EROD activity was found to be significantly induced in smokers and omeprazole-treated patients, with medians of 2.1 and 1.1 pmol· min−1·mg protein−1, respectively, compared with 0.5 pmol·min−1·mg protein−1 in nonsmokers. Immunoblot analysis substantiated that EROD activity was correlated with CYP1A protein. In contrast, UDP-glucuronosyltransferase (UGT) activity towards 4-methylumbelliferone (an overlapping substrate of several constitutive and inducible UGTs) was not significantly affected. The results demonstrate CYP1A induction by omeprazole and by constituents of cigarette smoke in the human duodenum and support the utility of duodenal biopsies to monitor CYP1A induction by PAH-type inducers.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1433-7339
    Keywords: Percutaneous endoscopic gastrostomy (PEG) ; Abdominal wall metastasis ; Complication
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Percutaneous endoscopic gastrostomy (PEG) has become a widely used method for nutritional support, particularly in patients with advanced head and neck carcinomas. Since the method is easy and widely established it is necessary to assess possible complications, even rare ones. In this paper we report on two patients with vaccination metastasis following PEG insertion. Both patients had advanced squamous cell carcinoma of the head and neck or the upper esophagus. In three patients previous bougienage was performed, because of considerable stenosis of the pharynx and/or esophagus. Fast-growing metastases were found at the site of PEG insertion, with and without involvement of the gastric wall. In neither case was abdominal wall metastasis the cause of death. There is a small but definite risk of tumor seeding into the abdominal wall after PEG insertion for obstructive malignant tumors. The clinical impact of this finding, however, is still undefined and needs further investigation.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Der Chirurg 71 (2000), S. 1307-1326 
    ISSN: 1433-0385
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Unter Endoskopie verstehen wir die Beobachtung der inneren Körperoberflächen, von Körperhöhlen und Hohlorganen mit optischen Instrumenten, die durch die natürlichen Öffnungen oder perkutan in den Körper eingebracht werden. Aus historischen und praktischen Gründen unterscheidet man entsprechend den verwendeten Instrumenten die “starre” von der “flexiblen” Endoskopie. Beide Untersuchungstechniken dienten initial der Diagnostik, schon bald konnten jedoch durch Entwicklung entsprechender Instrumente therapeutische Interventionen vorgenommen werden. Für die flexible Endoskopie – stärker als für die starren Endoskope – ist dies ein anhaltender dynamischer Prozess, der ständig neue Perspektiven und therapeutische Ansätze eröffnet. Die interventionell-operative Endoskopie hat sich damit zu einem weiteren Schwerpunkt in der Chirurgie und zu einem Pendant der (vornehmlich mit starrem Instrumentarium ausgeführten) minimal-invasiven Chirurgie entwickelt. Die technologische Entwicklung lässt erwarten, dass sich beide Bereiche in Zukunft mehr und mehr ergänzen und durchdringen.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1432-2307
    Keywords: Perimembranous GN ; Glomerular lesions ; Interstitium ; Interstitial fibrosis ; Renal insufficiency
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Morphometric investigations in 40 patients suffering from perimembranous glomerulonephritis at different stages showed that there is no certain relationship between the severity of glomerular lesions and the serum creatinine level. In 19 cases in stages I–III, with serum creatinine level less than 1.2 mg/100 ml on biopsy, the renal interstitium was less enlarged than in 21 cases in the same stages, but with serum creatinine level higher than 2 mg/100 ml. There is a significant positive correlation between the relative interstitial volume and the level of serum creatinine. The best congruence was demonstrated in the lin/log-plotting indicating that our values correlate best with an exponential function. We therefore conclude that in perimembranous glomerulonephritis, generally considered to be a glomerular disease, functional impairment cannot be explained by the glomerular lesions alone; interstitial changes have also to be taken into account as a cause of renal insufficiency. The following hypothesis is proposed; that the increase in renal interstitium and possible shrinking of collagen fibres may lead to a narrowing of intertubular capillaries. This may result in slowing of glomerular blood flow and may lead to renal insufficiency.
    Type of Medium: Electronic Resource
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