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Biomedical subjects

Matthias Ebert

Publications and source records attributed to Matthias Ebert.

13 recordsLinked to original sources
PubMed2006

Current treatment approach to locally advanced esophageal cancer: is resection mandatory?

Ongoing controversy surrounds the question of whether locally advanced cancer of the esophagus should be resected or treated with nonsurgical methods. Survival after resection, particularly of patients with squamous cell cancer, remains poor. Results of recent studies suggest that in cases of squamous cell cancer there is no clear survival advantage favoring surgery, but local tumor control is significantly improved after resection. Besides this clinically relevant difference, important issues concerning the design and conduct of the most recent studies have not been investigated carefully and deserve critical discussion. Of particular note is the fact that surgery has not yet been compared with a nonsurgical approach in treating adenocarcinoma of the esophagus. Consequently, surgery remains the standard approach, at least for this cancer subtype. Response to induction chemotherapy and radiation will determine future treatment algorithms, and promising tools for predicting response are currently being investigated.

Algorithms↗
PubMed2005

Up-regulation of cathepsin X in Helicobacter pylori gastritis and gastric cancer.

Recently, we identified increased cathepsin X expression in H. pylori-infected gastric mucosa. Here, we describe further up-regulation in gastric cancer and report on the role of inflammatory cytokines required for cathepsin X up-regulation in H. pylori-infected gastric mucosa, as well as on consequences for cellular invasion. Biopsy specimens were taken from the antrum, corpus and cardia of H. pylori-infected and non-infected patients. Gastric cancer samples were obtained from patients undergoing gastric surgery. Cathepsin X was detected in gastric mucosa by quantitative real-time RT-PCR, western blotting and immunohistochemistry. Induction of cathepsin X expression in epithelial and inflammatory cells caused by H. pylori infection was tested in in vitro contact and non-contact co-cultures of AGS cells and monocytic cells. Patients with H. pylori gastritis showed significantly higher cathepsin X mRNA (2.5-fold) and protein (1.6-fold) expression than H. pylori-negative patients. Cathepsin X was also up-regulated in gastric cancer (3-12-fold) compared to non-neoplastic mucosa. Cathepsin X was predominantly expressed by macrophages in the mucosal stroma and in glands of the antral mucosa. In addition, tumour cells stained for cathepsin X in 26 (68%) patients with gastric carcinoma. In general, staining was significantly more common (20 vs. 6 patients) and more intense (3.55 vs. 0.83) in intestinal type gastric cancer than in the diffuse type. In vitro cell culture experiments revealed that intercellular signalling between pathogenicity island (PAI)-positive H. pylori-infected epithelial cells and macrophages via soluble factors in the culture medium seems to be responsible for increased expression of cathepsin X in monocytes. Using antisense oligonucleotides, cathepsin X up-regulation was directly associated with higher invasiveness in vitro. Although no correlation of cathepsin X expression and TNM stage was found, our study demonstrates that cathepsin X plays a role not only in the chronic inflammation of gastric mucosa but also in the tumourigenesis of gastric cancer.

Adult↗
PubMed2005

Differential expression of individual gamma-protocadherins during mouse brain development.

Three tandemly arrayed protocadherin gene clusters (Pcdh-alpha, -beta, -gamma) comprising more than 50 genes are found in human and mouse. Here, we have investigated the expression and distribution of individual gamma-protocadherins (Pcdhs-gamma) in the developing mouse brain. We find that transfection of Pcdh-gamma genes promotes calcium-dependent cell adhesion in HEK 293 cells. Furthermore, Pcdh-gamma can be recruited to synapses of transfected primary hippocampal neurons. Several individual members of the in total 22 Pcdhs-gamma were chosen to examine the expression of the three subfamilies, Pcdh-gammaA, -gammaB, and -gammaC. These Pcdh-gamma transcripts are expressed all over the brain, with minor regional and cell-type specific differences. Interestingly, a distinct, later onset of expression is observed for Pcdh-gammaC5, a gene located at the end of the Pcdh-gamma cluster. Largely overlapping expression patterns of individual Pcdh-gamma proteins are detected with anti-peptide antibodies. Small differences are observed in the staining of dendritic processes and synapse-rich layers. Our results support the idea that Pcdhs-gamma participate in neuronal differentiation and may be implicated in the fine-tuning of neuronal morphology and synaptogenesis. Cell autonomous regulation of transcription might generate the widespread distribution of individual Pcdhs-gamma in the brain, which is strikingly different from the restricted expression patterns observed for classical cadherins. Thus, a defined set of Pcdhs-gamma may engage in neuronal adhesion and signaling on the cellular level.

Animals↗
PubMed2005

Small-bowel metaplasia arising in the remnant esophagus after esophagojejunostomy--a [corrected] prospective study in patients with a history of total gastrectomy.

OBJECTIVES: The pathogenesis of Barrett's mucosa is incompletely understood. Acidic gastro-esophageal reflux is considered an essential causative factor. The aim of this study was to detect esophageal columnar metaplasia after total gastrectomy with esophagojejunostomy, a condition of enteric, but nonacidic reflux. METHODS: In a prospective study, patients with a history of total gastrectomy and esophagojejunostomy were investigated for the presence of columnar metaplasia in the remnant esophagus. Patients with such history, who were now referred for esophagogastroduodenoscopy, were included during a 2-yr period. Biopsies for histopathology were taken from the anastomosis and any columnar metaplasia of the esophagus. RESULTS: In 8 of 25 patients (32%) with a history of gastrectomy, columnar metaplasia was found in the remnant esophagus, mostly in shape of tongues, partly associated with erosive reflux esophagitis. Histopathology showed a typical small-bowel mucosa, but with some villous atrophy. In a resection specimen, a double-layered muscularis mucosa was present, which proved the metaplastic nature of the intestinal mucosa. Length of the columnar metaplasia correlated with the time interval since surgery. CONCLUSIONS: Esophageal mucosa, if exposed long term to an enteric, but nongastric refluxate, can evolve into a highly differentiated intestinal metaplasia, which resembles small-bowel mucosa. This proves that complete-type intestinal metaplasia may arise not only in the stomach, but also in the esophagus. Esophageal intestinalization seems to reflect adaptation to enteric reflux.

Aged↗
PubMed2005

The disintegrin-metalloproteinases ADAM9, ADAM12, and ADAM15 are upregulated in gastric cancer.

The ADAMs (A disintegrin and metalloproteinase) are a family of cell-surface membrane glycoproteins, whose multidomain structure enables diverse roles in a wide range of cellular processes. Accumulating evidence associates an increased expression of individual ADAM family members with various types of cancer, and we investigated the possible involvement of ADAM9, 12 and 15 in the pathogenesis of gastric cancer (GC). Using immunohistochemistry and quantitative RT-PCR, we examined the transcription and expression pattern of ADAM9, 12, and 15 in GCs and the corresponding non-tumor tissue, and in GC cell lines (AGS, MKN45, MKN28, NCI-N87, KATOIII). All three ADAMs were found to be significantly upregulated in GC compared to non-neoplastic foveolar epithelium, with ADAM12 expression being higher in intestinal- than in diffuse-type tumors. In vitro proliferation assays were used to evaluate the effects of ADAM-specific antibodies on the growth of GC cell lines. The administration of anti-ADAM9 and anti-ADAM15 antibodies inhibited cell growth, whereas anti-ADAM12 enhanced the proliferation of the GC cell lines. ADAM9, 12 and 15 are implicated in the malignant growth of GC cells, perhaps via the interaction with adhesion molecules, or the proteolytic 'shedding' of signaling molecules and the consequent transactivation of their receptors, such as the epithelial growth factor receptor and its ligands. The resultant modulation of the tumor-host interface may contribute to the pathogenesis, development or progression of gastric cancer.

ADAM Proteins↗
PubMed2004

The ectopeptidases CD10, CD13, CD26, and CD143 are upregulated in gastric cancer.

Due to their extracellular orientation, the ectopeptidases CD10, CD13, CD26, and CD143 have numerous functions, including the post-secretory processing of the neuropeptides and peptide hormones involved in the regulation of growth and differentiation in the gastrointestinal tract. We investigated the transcription and expression pattern of these four ectopeptidases in gastric carcinomas (GC), the corresponding non-neoplastic epithelium, a selection of lymph node metastases (LNM), and the MKN28, AGS, NCI-N87, KATO III gastric cancer cell lines. The gastric foveolar epithelium did not express CD10, CD13, or CD143, but the intestinal metaplasia demonstrated strong immunoreactivity at the brush border for all four ectopeptidases. CD10, CD13, and CD143 were significantly up-regulated in GCs and the lymph node metastases, confirming that they are important for the tumor cell biology. However, there is a lack of correlation between expression in intestinal metaplasia and tumor, as well as in tumor and LNM. Cell proliferation assays were performed with MKN28 and AGS, in which inhibition of CD10 significantly reduced the growth of both cell lines, and inhibition of CD13 significantly increased the proliferation of the AGS cells, indicating that the ability to degrade gastrointestinal peptides may play an important role in the pathobiology of gastric cancer.

Adult↗
PubMed2003

Helicobacter pylori infection, vitamin B12 and homocysteine. A review.

It has been suggested that there is an association between Helicobacter pylori infection, reduced cobalamin absorption and cobalamin status and, consequently, elevated homocysteine levels. This would offer an explanation why H. pylori infection is associated with coronary heart disease. To date, more than 25 studies have been published that either deal with H. pylori infection and homocysteine, H. pylori infection and cobalamin status, or both. The design of these studies differs widely in terms of definition of H. pylori status, measuring cobalamin status, selection of study cohorts and geographical study areas. Therefore, results are fairly inconclusive at present and do not suggest a major role of H. pylori infection in the development of cobalamin deficiency and elevated homocysteine levels.

Anemia, Pernicious↗
PubMed2002

Expression of G1 phase cyclins in human gastric cancer and gastric mucosa of first-degree relatives.

The aim of this study was to investigate the expression of D-type cyclins and cyclin E in gastric cancer patients (N = 34), in healthy first-degree relatives of gastric cancer patients (N = 29), and in control subjects (N = 18). Expression of cyclins D1, D2, D3, and E was determined by RT-PCR. Localization of cyclin expression was determined by immunohistochemistry. Expression of cyclins D2, D3, and E was more frequently detected in tumor tissue compared with tumor-free gastric mucosa (P < 0.05) and was associated with the presence of intestinal metaplasia. In contrast, cyclin D1 was frequently expressed in both tumor- and tumor-free tissue. Cyclin D3 expression was more frequently detected in the antrum mucosa of first-degree relatives compared to controls (P < 0.01) and was associated with the presence of Helicobacter pylori. Our data suggest that deregulation of G1 phase cyclins may play a role in gastric carcinogenesis, and may point to the presence of molecular alterations in individuals at an increased risk for gastric cancer.

Aged↗
PubMed2002

Transgenic overexpression of amphiregulin induces a mitogenic response selectively in pancreatic duct cells.

BACKGROUND & AIMS: The epidermal growth factor (EGF) receptor family and the corresponding ligands are frequently overexpressed in pancreatic cancer. To compare the biological effects of transforming growth factor (TGF)-alpha and amphiregulin (AR) on growth and differentiation of the exocrine pancreas, we have generated transgenic mice overexpressing AR under control of the elastase promoter. METHODS: Two independently generated transgenic mouse lines overexpress 50-, 43-, 28-, 26-, and 16-kilodalton AR forms in the pancreas. RESULTS: Morphologic and immunohistochemical examinations suggest that small intralobular duct and centro-acinar cells proliferate in response to AR in these mice. AR transgenic mice display increased Ras, Erk1/2, cyclin D/CDK4, and cyclin E/CDK2 activity and G1/S progression in pancreatic duct cells. In contrast to TGF-alpha transgenic mice, AR neither induced tubular complex formation nor elicited a strong fibrogenic response. AR induced a slight induction of ErbB2 on duct cells, whereas TGF-alpha resulted in overexpression of the EGF receptor in cells within tubular complexes. Furthermore, AR and TGF-alpha displayed different effects on differentiation of isolated acini in vitro comparable to the situation in vivo. CONCLUSIONS: These data suggest that AR induces a mitogenic response selectively in small duct cells through activation of Ras, CDK2, and CDK4, respectively. The closely related EGF receptor ligands, AR and TGF-alpha, display different biological effects when overexpressed in the exocrine pancreas in vivo.

Amphiregulin↗
PubMed2002

Soluble thrombomodulin plasma levels are an early indication of a lethal course in human acute pancreatitis.

BACKGROUND: The potential to predict severe disease and lethality by using plasma soluble thrombomodulin (sTM) and C-reactive protein (CRP) levels in 73 patients with acute pancreatitis was analyzed in a prospective 5-year investigation performed at a single institution. METHODS: According to the Atlanta criteria, pancreatitis was classified as mild in 23 patients and as severe in 50 patients. Blood was collected on days 1, 3, 5, 7, 10, 14, 21, and 28 after the onset of pain and analyzed for sTM and CRP. RESULTS: During the period between days 3 and 10 of acute pancreatitis when most of the admissions occurred, sTM levels at a cutoff of 75 ng/mL on day 3 (sensitivity, 100%; specificity, 77%; positive predictive value, 38%; negative predictive value, 100%) and 71 ng/mL on day 10 (sensitivity, 100%; specificity, 77%; positive predictive value, 41%; negative predictive value, 100%) were predictive of a lethal outcome. With sTM levels, it was not possible to differentiate patients with mild pancreatitis from those with severe pancreatitis (Atlanta classification). In contrast, CRP levels at a cutoff of 113 mg/L on day 3 differentiated severe from mild courses with a diagnostic sensitivity of 84%, a specificity of 60%, a positive predictive value of 78%, and a negative predictive value of 69%. CRP levels at a cutoff of 122 mg/L on day 10 differentiated mild from severe courses (nonsurvivors) with a diagnostic sensitivity of 72%, a specificity of 72%, a positive predictive value of 86%, and a negative predictive value of 53%. In contrast, differentiation of mild forms of acute pancreatitis from severe pancreatitis (survivors) on day 10 was not possible. CONCLUSIONS: CRP is a valuable marker of disease severity in acute pancreatitis especially in the first period of pancreatitis, whereas sTM identifies early those patients with the most severe courses and a high risk of dying (negative predictive value, 100%). Determination of sTM in addition to CRP offers the opportunity of identifying early those patients who require intensive care most urgently. Of course, further investigations of sTM in acute pancreatitis are indicated to confirm our results.

Acute Disease↗
PubMed2002

Parker weights revisited.

The short-scan case in fan-beam computed tomography requires the introduction of a weighting function to handle redundant data. Parker introduced such a weighting function for a scan over pi plus the opening angle of the fan. In this article we derive a general class of weighting functions for arbitrary scan angles between pi plus fan angle and 2pi (over-scan). These weighting functions lead to mathematically exact reconstructions in the continuous case. Parker weights are a special case of a weighting function that belongs to this class. It will be shown that Parker weights are not generally the best choice in terms of noise reduction, especially when there is considerable over-scan. We derive a new weighting function that has a value of 0.5 for most of the redundant data and is smooth at the boundaries.

Algorithms↗