Biomedical subjects

P O Berberat

Publications and source records attributed to P O Berberat.

11 recordsLinked to original sources

PubMed2006

The ECM proteoglycan decorin links desmoplasia and inflammation in chronic pancreatitis.

BACKGROUND: Recurrent inflammation in chronic pancreatitis (CP) is not well understood. AIMS: To investigate whether decorin, an extracellular matrix (ECM) proteoglycan with macrophage modulating activity, is a pathogenic factor allowing diseased pancreatic stroma to sustain inflammation by affecting the cytokine profile of accumulating inflammatory cells. METHODS: Decorin was examined in 18 donors and 32 patients with CP by quantitative reverse transcription polymerase chain reaction (QRT-PCR), western blotting, and immunohistochemistry of pancreatic specimens. QRT-PCR was used to assess cytokine expression in donor peripheral blood mononuclear cells (PBMC), exposed or not to decorin in vitro, and to compare it with the cytokine profile of circulating and resident mononuclear cells (MNC) of patients with CP. RESULTS: In CP, desmoplasia is associated with overexpression of decorin in the growing ECM and enlarged pancreatic nerves. In culture, exposure of MNC to decorin stimulated expression of the MNC recruiting chemokine MCP-1. In biopsies, MNC infiltrates in decorin rich CP tissue showed a 300-fold upregulation of MCP-1 compared with decorin free peripheral blood, whereas no difference was found in basal MCP-1 expression in PBMC of patients versus donors. This effect was specific for MCP1-other inflammatory cytokines, such as interleukin 1beta and tumour necrosis factor alpha, were not affected. CONCLUSION: Decorin is a molecular marker of desmoplasia in CP, and excessive decorin may allow fibrotic masses to nourish and protract inflammation by deregulating the process of MNC accumulation and activation. These data provide a molecular basis for surgical resection of diseased tissue as a treatment option in CP.

Adolescent↗

PubMed2004

RUNX3 expression in primary and metastatic pancreatic cancer.

AIM: Runx transcription factors are important regulators of lineage specific gene expression, cell proliferation, and differentiation. Runx3 expression is lost in a high proportion of gastric cancers, suggesting a tumour suppressive role in this malignancy. This study investigates the expression and localisation of Runx3 in pancreatic tissues. METHODS: Quantitative polymerase chain reaction was used to measure Runx3 mRNA. Immunohistochemistry was carried out to localise Runx3 in normal pancreatic tissues, and in primary and metastatic pancreatic ductal adenocarcinoma (PDAC). Basal and transforming growth factor beta1 (TGFbeta1) induced Runx3 expression was analysed in cultured pancreatic cancer cell lines. RESULTS: Runx3 expression was low to absent in normal pancreatic tissues, but increased in a third of cancer tissues. Runx3 was present only in islets in normal pancreas, whereas in pancreatic cancers, Runx3 was detected in the cancer cells of seven of 24 samples analysed. In addition, it was expressed by lymphocytes in six of the 16 cases with lymphocyte infiltration. In pancreatic cancer cell lines, Runx3 mRNA was present in Colo-357 and T3M4 cells, but was low to absent in the other cell lines tested. TGFbeta1 repressed Runx3 mRNA expressed in Colo-357 cells, and had no effect on Runx3 expression in the other pancreatic cancer cell lines. CONCLUSION: Runx3 expression is restricted to islets in the normal pancreas. In contrast, a considerable proportion of pancreatic tumours express Runx3, and its expression is localised in the tumour cells and in the infiltrating lymphocytes. Thus, Runx3 might play a role in the pathogenesis of PDAC.

Adenocarcinoma↗

PubMed2003

Heavy chain ferritin acts as an antiapoptotic gene that protects livers from ischemia reperfusion injury.

Heme oxygenase-1 (HO-1) is induced under a variety of pro-oxidant conditions such as those associated with ischemia-reperfusion injury (IRI) of transplanted organs. HO-1 cleaves the heme porphyrin ring releasing Fe2+, which induces the expression of the Fe2+ sequestering protein ferritin. By limiting the ability of Fe2+ to participate in the generation of free radicals through the Fenton reaction, ferritin acts as an anti-oxidant. We have previously shown that HO-1 protects transplanted organs from IRI. We have linked this protective effect with the anti-apoptotic action of HO-1. Whether the iron-binding properties of ferritin contributed to the protective effect of HO-1 was not clear. We now report that recombinant adenovirus mediated overexpression of the ferritin heavy chain (H-ferritin) gene protects rat livers from IRI and prevents hepatocellular damage upon transplantation into syngeneic recipients. The protective effect of H-ferritin is associated with the inhibition of endothelial cell and hepatocyte apoptosis in vivo. H-ferritin protects cultured endothelial cells from apoptosis induced by a variety of stimuli. These findings unveil the anti-apoptotic function of H-ferritin and suggest that H-ferritin can be used in a therapeutic manner to prevent liver IRI and thus maximize the organ donor pool used for transplantation.

Adenoviridae↗

PubMed2001

Identification of disease-specific genes in chronic pancreatitis using DNA array technology.

OBJECTIVE: To use DNA arrays to analyze the differential gene expression patterns in the normal pancreas and in pancreatic diseases. SUMMARY BACKGROUND DATA: Genome-wide gene expression analysis will provide new insights into gene function and cause of disease. METHODS: RNA was extracted from eight normal pancreatic specimens, eight specimens with chronic pancreatitis (CP), and eight pancreatic cancer (PCa) tissues. Poly A(+) RNA was purified, reverse-transcribed, and converted into cRNA using biotinylated nucleotides. The HuGeneFL DNA array containing 5,600 full-length human genes was used for analysis. RESULTS: First, normal pancreatic tissues were analyzed in comparison with a panel of other normal tissues (colon, liver, prostate, lung, lymph node). This analysis revealed 11 signature genes that were selectively expressed in the pancreas (e.g., pancreatic elastase-IIA). Comparison of the expression of 5,600 genes between the normal pancreas, CP, and PCa specimens showed that the expression of 34 genes was decreased in CP tissues compared with normal pancreatic tissues, and that the expression of all of these genes was simultaneously decreased in PCa. In addition, the expression of 157 genes was increased in CP tissues compared with the normal pancreas. Of those, 152 genes were simultaneously increased in PCa. Thus, only 5 of 5,600 genes were significantly overexpressed in CP compared with both normal pancreas and PCa. CONCLUSIONS: The majority of alterations observed in CP are present in PCa, and the number of genes whose expression is selectively deregulated in CP is surprisingly small. These results may provide new insight into the pathobiology of CP and help identify certain molecular alterations that might serve as targets for new diagnostic tools and disease-specific therapy.

Adult↗

PubMed2001

Comparative analysis of galectins in primary tumors and tumor metastasis in human pancreatic cancer.

Galectins are galactoside-binding proteins that exhibit an important function in tumor progression by promoting cancer cell invasion and metastasis formation. Using Northern blotting and Western blotting analysis, in situ hybridization (ISH), and immunohistochemistry (IHC), we studied galectin-1 and galectin-3 in tissue samples of 33 primary pancreatic cancers and in tumor metastases in comparison to 28 normal pancreases. Furthermore, the molecular findings were correlated with the clinical and histopathological parameters of the patients. Northern blotting and Western blotting analysis showed significantly higher galectin-1 and galectin-3 mRNA and protein levels in pancreatic cancer samples than in normal controls. For galectin-1, no ISH signals and immunoreactivity were observed in acinar or ductal cells in the normal pancreas and in pancreatic cancer cells, whereas fibroblasts and extracellular matrix cells around the cancer mass exhibited strong mRNA signals and immunoreactivity. Galectin-3 mRNA signals and immunoreactivity were strongly present in most pancreatic cancer cells, whereas in the normal controls only faint ISH and IHC signals were seen in some ductal cells. Metastatic pancreatic cancer cells exhibited moderate to strong galectin-3 immunoreactivity but were negative for galectin-1. No relationship between the galectin-1 and galectin-3 mRNA levels and the tumor stage or between the IHC staining score and the tumor stage was found. However, galectin-1 mRNA levels and the IHC staining score were significantly higher in poorly differentiated tumors compared with well/moderately differentiated tumors, whereas for galectin 3 no differences were found. The expression pattern of galectin-1 and galectin-3 in pancreatic cancer tissues indicates that galectin-1 plays a role in the desmoplastic reaction that occurrs around pancreatic cancer cells, whereas galectin-3 appears to be involved in cancer cell proliferation. High levels of galectin-3 in metastatic cancer cells suggest an impact on metastasis formation.

Adenocarcinoma↗

PubMed2000

Chronic pancreatitis--new pathophysiological concepts.

The pathophysiology of chronic pancreatitis has been a controversial topic of discussion for decades. None of the concepts proposed up until now have been able to elucidate the course of the disease in a conclusive matter. However, with the growth of new techniques in cell and molecular biology and the ability to create genetically modified cell systems and animals, many new and potentially important mechanisms have been discovered in recent years. This article will review these new pathophysiological aspects in chronic pancreatitis, which include growth factor overexpression, inflammatory mediator activation, deregulated immune response and altered nerve growth with specific neuroimmune interactions.

Animals↗

PubMed2000

Pancreatic cancer--new aspects of molecular biology research.

Pancreatic ductal adenocarcinoma (PDAC) presently has an incidence of approximately 8 to 10 cases per 100,000 citizens in European countries, and the incidence has been increasing throughout the last decades. Approximately 30,000 patients die every year from PDAC in Western Europe and most of the newly diagnosed patients present with an already unresectable tumor stage. Self-sufficiency in growth signals, insensitivity to antigrowth signals, and evasion of apoptosis are hallmarks of malignant growth. In PDAC a variety of growth factors are expressed at increased levels. For example, the concomitant presence of the EGF-receptor and its ligands EGF, TGF-alpha, and/or amphiregulin is associated with enhanced tumor aggressiveness and shorter survival periods following tumor resection. In addition, PDACs often exhibit alterations in growth inhibitory pathways such as Smad4 mutations and Smad6 and Smad7 overexpression, and evade apoptosis through p53 mutations and aberrant expression of apoptosis regulating genes such as members of the Bcl family. Taken together, the abundance of growth promoting factors and the disturbance of growth inhibitory and apoptotic pathways give pancreatic cancer cells a distinct growth advantage which clinically results in rapid tumor progression and poor survival prognosis.

Apoptosis↗

PubMed2000

Galectin-1 and galectin-3 in chronic pancreatitis.

Galectin-1 and galectin-3 have important functions in cell-cell interactions, cell adhesion to extracellular matrix, the organization of extracellular matrix, and tissue remodeling. To assess their potential role in chronic pancreatitis (CP), we examined their expression by Northern blot analysis, in situ hybridization, immunohistochemistry, and Western blot analysis in normal and CP pancreatic tissues. Northern blot analysis revealed a 4.5-fold increase of galectin-1 mRNA (p < 0.01) and a 3.8-fold increase of galectin-3 mRNA (p < 0.01) in CP samples compared with normal controls. In situ hybridization analysis of normal pancreas indicated low abundance of galectin-1 mRNA in fibroblasts, whereas galectin-3 mRNA was moderately present in ductal cells. CP samples exhibited moderate to intense galectin-1 mRNA signals in fibroblasts, whereas galectin-3 mRNA signals were intense in the cells of ductular complexes and weak in the degenerating acinar cells. In addition, intense galectin-1 and galectin-3 mRNA signals were present in nerves of normal and CP samples. Immunohistochemistry showed a distribution pattern of galectin-1 and galectin-3 similar to that described for in situ hybridization. Relative quantification of galectin-1 and galectin-3 protein by immunoblotting revealed an increase of 3.2-fold and 3.0-fold, respectively, in CP compared with normal controls. There was a significant correlation between galectin-1 and fibrosis and between galectin-3 and fibrosis and the density of ductular complexes. Up-regulation of galectin-1 in fibroblasts and galectin-3 in ductular complexes suggests a role of these lectins in tissue remodeling in CP. Galectin-1 might participate in ECM changes, whereas galectin-3 seems to be involved in both ECM changes and ductular complex formation.

Adult↗

PubMed1999

Prevention and treatment of complications in pancreatic cancer surgery.

Pancreatic cancer is the fourth leading cause of death from malignant disease in Western industrialized countries. It is a devastating disease with a very poor prognosis and has a death rate roughly equal to its incidence rate. As this tumor is resistant to all medical treatment options, such as radio- and chemotherapy, radical surgical resection is the only chance of cure so far. Significant advances have been made over the past decades in pancreaticoduodenectomy, which is the standard operation in patients with pancreatic head cancer or periampullary cancer. In specialized centers the operative mortality has fallen under 5%. However, the postoperative complication rates after this demanding procedure are still between 30 and 40%. Complications are mainly due to the technical difficulty of performing a safe and proper anastomosis between the stomach or small bowel and the soft pancreas. This article reviews the treatment of the complications most frequently occurring after pancreatic cancer surgery, such as leakage of pancreatic anastomosis, pancreatic fistula, abscess and hemorrhage. Furthermore, we discuss the management of these complications and how complications following pancreatic surgery can be prevented.

Abdominal Abscess↗

PubMed1999

The role of octreotide in the prevention of complications following pancreatic resection.

Postoperative complications following major pancreatic surgery are mainly due to the difficulties of performing a safe and proper anastomosis between the stomach or small bowel and the pancreas. Continuous pancreatic juice secretion and the often soft structure of the pancreatic parenchyma are major risk factors. The present paper summarizes the results of six previously published, placebo-controlled, double-blind trials and one open randomized trial analyzing the efficacy of octreotide in preventing postoperative complications in patients who undergo major pancreatic surgery. Patients were given either octreotide (3x100-150 microg subcutaneously/day) or a placebo perioperatively for 5-7 days starting at least 1 h before operation. The patients were monitored postoperatively for typical postoperative complications such as: leakage of the anastomosis, pancreatic fistula, abscess, fluid collection, shock, sepsis, pulmonary insufficiency, renal insufficiency, bleeding, postoperative pancreatitis, and death. Six of the seven studies showed significantly fewer postoperative complications in the octreotide group in comparison with the placebo group (p<0.05). The effectiveness of octreotide was most apparent in the prevention of secretion-related complications such as fistula, fluid collection and leakage of the anastomosis. These studies demonstrated that inhibition of perioperative pancreatic secretion is a viable treatment concept in patients undergoing major pancreatic surgery. The perioperative and prophylactic application of octreotide in patients who undergo major pancreatic resection reduces the postoperative complication rate significantly.

Humans↗

PubMedDate not supplied

What should be the standard operation in chronic pancreatitis: Whipple or duodenum-preserving pancreatic head resection?

Surgical options in the treatment of chronic pancreatitis have undergone both development and controversial discussion in the past decades. Operations such as the classical and pylorus-preserving Whipple resections are more and more being replaced by operations such as the duodenum-preserving pancreatic head resection, which preserves extrapancreatic organs like the stomach, the duodenum and the extrapancreatic bile duct. The latter operation preserves a normal food passage and glucose metabolism after surgical intervention. In addition, the duodenum-preserving pancreatic head resection provides long-term pain relief and reduction in up to 90% of chronic pancreatitis patients, as well as a general improvement in quality of life. This article will summarize and compare the surgical options in the treatment of chronic pancreatitis and will provide arguments why the duodenum-preserving pancreatic head resection should replace the classical and the pylorus-preserving Whipple resections as the standard surgical procedure used to treat chronic pancreatitis-related complications.

Chronic Disease↗