Biomedical subjects

Martin Wagner

Publications and source records attributed to Martin Wagner.

60 records · Page 4Linked to original sources

PubMed2002

Stat3 and NF-kappaB activation prevents apoptosis in pancreatic carcinogenesis.

BACKGROUND & AIMS: Human pancreatic adenocarcinoma has an overall poor prognosis. Therapeutic efforts are often ineffective because of late diagnosis and a high degree of chemoresistance. Overexpression of transforming growth factor alpha in the pancreas of transgenic mice causes the formation of premalignant ductal lesions and the development of invasive ductal adenocarcinoma. The aim of the present study was to explore regulation of proapoptotic and antiapoptotic signals during pancreatic tumor development in mice. METHODS: EL-TGFalpha-hGH transgenic mice crossbred to p53-deficient mice develop ductal pancreatic adenocarcinoma resembling the human disease. During the multistep carcinogenesis up-regulation of Bcl-x(L) is evident early and persists throughout tumorigenesis as detected by Real Time PCR, Western blot analysis, and immunofluorescence. RESULTS: Up-regulation of Bcl-x(L) is evident early in tumor development and persists throughout tumorigenesis. The transcription factors Stat3 and NF-kappaB induce increased Bcl-x(L) expression in the premalignant lesions and tumor cells. Inhibition of either transcription factor alone leads to Bcl-x(L) down-regulation in transient transfection assays. Functional analysis shows that blocking of both Stat3 and NF-kappaB together induces programmed cell death in murine pancreatic tumor cells. CONCLUSIONS: These findings indicate that apoptosis resistance precedes formation of invasive pancreatic cancer. Therefore, combined inhibition of Stat3 and NF-kappaB might represent a novel strategy for tumor prevention and therapy.

Animals↗

PubMed2002

Early treatment with erythropoietin beta ameliorates anemia and reduces transfusion requirements in infants with birth weights below 1000 g.

OBJECTIVE: To investigate whether recombinant erythropoietin (rhEPO) reduces the need for transfusion in extremely low birth weight (ELBW) infants (birth weight 500-999 g) and to determine the optimal time for treatment. METHODS: In a blinded multicenter trial, 219 ELBW infants were randomized on day 3 to one of 3 groups: early rhEPO group (rhEPO from the first week for 9 weeks, n = 74), late rhEPO group (rhEPO from the fourth week for 6 weeks, n = 74), or control group (no rhEPO, n = 71). All infants received enteral iron (3-9 mg/kg/day) from the first week. The rhEPO beta dose was 750 IU/kg/week. Success was defined as no transfusion and hematocrit levels never below 30%. RESULTS: Success rate was 13% in the early rhEPO group, 11% in the late rhEPO group, and 4% in the control group (P =.026 for early rhEPO versus control group). Median transfusion volume was 0.4 versus 0.5 versus 0.7 mL/kg/day (P =.02) and median donor exposure was 1.0 versus 1.0 versus 2.0 (P =.05) in the early rhEPO group, the late rhEPO group, and the control group, respectively. Infection risk was not increased and weight gain was not delayed with rhEPO beta. CONCLUSION: Early rhEPO beta treatment effectively reduces the need for transfusion in ELBW infants.

Anemia, Neonatal↗

PubMed2002

Loss of the zymogen granule protein syncollin affects pancreatic protein synthesis and transport but not secretion.

Syncollin is a small protein that is abundantly expressed in pancreatic acinar cells and that is tightly associated with the lumenal side of the zymogen granule membrane. To shed light on the hitherto unknown function of syncollin, we have generated syncollin-deficient mice. The mice are viable and show a normal pancreatic morphology as well as normal release kinetics in response to secretagogue stimulation. Although syncollin is highly enriched in zymogen granules, no change was found in the overall protein content and in the levels of chymotrypsin, trypsin, and amylase. However, syncollin-deficient mice reacted to caerulein hyperstimulation with a more severe pancreatitis. Furthermore, the rates of both protein synthesis and intracellular transport of secretory proteins were reduced. We conclude that syncollin plays a role in maturation and/or concentration of zymogens in zymogen granules.

Amino Acid Sequence↗

PubMedDate not supplied

Role of nuclear receptors in the adaptive response to bile acids and cholestasis: pathogenetic and therapeutic considerations.

Cholestasis results in intrahepatic accumulation of cytotoxic bile acids which cause liver injury ultimately leading to biliary fibrosis and cirrhosis. Cholestatic liver damage is counteracted by a variety of intrinsic hepatoprotective mechanisms. Such defense mechanisms include repression of hepatic bile acid uptake and de novo bile acid synthesis. Furthermore, phase I and II bile acid detoxification is induced rendering bile acids more hydrophilic. In addition to "orthograde" export via canalicular export systems, these compounds are also excreted via basolateral "alternative" export systems into the systemic circulation followed by renal elimination. Passive glomerular filtration of hydrophilic bile acids, active renal tubular secretion, and repression of tubular bile acid reabsorption facilitate renal bile acid elimination during cholestasis. The underlying molecular mechanisms are mediated mainly at a transcriptional level via a complex network involving nuclear receptors and other transcription factors. So far, the farnesoid X receptor FXR, pregnane X receptor PXR, and vitamin D receptor VDR have been identified as nuclear receptors for bile acids. However, the intrinsic adaptive response to bile acids cannot fully prevent liver injury in cholestasis. Therefore, additional therapeutic strategies such as targeted activation of nuclear receptors are needed to enhance the hepatic defense against toxic bile acids.

Adaptation, Biological↗

PubMedDate not supplied

[Molecular characterization of Listeria monocytogenes and the significance for food hygiene].

Research on the pathogen Listeria monocytogenes is a key issue both for the clinical and the food microbiologist owing to the unique pathway of infection and the exposure of humans via contaminated foods. Although, in Austria, the incidence of listeriosis is about 870-fold lower than the incidence for Salmonella infection, the food law manages both foodborne pathogens with a comparable stringency. The current risk management is based on the assumption that environmental L. monocytogenes isolates, from which the pool of "foodborne" isolates is recruited, are of similar pathogenicity compared to clinical and outbreak isolates. This verdict became doubted in the recent years. Characterization of L. monocytogenes by virulence gene sequencing, virulence studies in vivo and in vitro and by molecular typing was considerably stimulating the discussion on virulence variability in L. monocytogenes. This article provides insights in the value of epidemiological follow-up studies by presenting a typing study on 15 cases of listeriosis observed in a district hospital in Turkey. Furthermore results from typing L. monocytogenes either by virulence gene sequencing, mismatch amplification mutation assay or by pulsed field gel electrophoresis are discussed. The close interaction of molecular microbiology with food microbiology both in applied and basic science is currently creating a new discipline of molecular food microbiology. We are convinced that veterinary medicine will contribute to this exiting development in a fruitful way.

Animals↗

PubMedDate not supplied

Transcriptional regulation of hepatobiliary transport systems in health and disease: implications for a rationale approach to the treatment of intrahepatic cholestasis.

Hepatobiliary transport systems mediate hepatic uptake and biliary excretion of bile acids, bilirubin and other biliary constituents. Hereditary or acquired defects of these transporters may cause or maintain cholestasis and jaundice under various clinical conditions including progressive familial intrahepatic cholestasis (PFIC) 1-3 or its milder forms, benign recurrent intrahepatic cholestasis (BRIC) 1 and 2 , Dubin-Johnson syndrome, drug and inflammation-induced cholestasis and intrahepatic cholestasis of pregnancy. Moreover, induction of alternative efflux pumps for bile acids/bilirubin and phase I/II detoxifying enzymes may counteract hepatic accumulation of potentially toxic biliary constituents in cholestasis by providing alternative escape routes. Transcriptional and post-transcriptional regulation of hepatobiliary transporters in health and disease is mediated by multiple factors such as bile acids, proinflammatory cytokines, drugs and hormones. Ligand-activated nuclear receptors (NR) and hepatocyte-enriched transcription factors play a critical role in transcriptional transporter regulation. Many hepatobiliary transporter alterations in cholestatic liver disease can now be explained by ligand binding of accumulating cholephiles to NRs. Moreover, NR-mediated actions may be targeted by pharmacological ligands. Understanding the transcriptional mechanisms leading to transporter changes therefore not only represents a key for understanding the pathophysiology of the cholestatic liver disease, but also represents a prerequisite for designing novel therapeutic strategies.

Animals↗