Search Results - (Author, Cooperation:T. Kirchner)

2014-09-02

Nature Publishing Group (NPG)

0028-0836

1476-4687

Biology

Chemistry and Pharmacology

Medicine

Natural Sciences in General

Physics

Animals ; Anti-Bacterial Agents/pharmacology ; Butyrates/pharmacology ; Carcinogenesis/*drug effects ; Diet, High-Fat/*adverse effects ; Dietary Fats/*adverse effects ; Disease Progression ; Dysbiosis/*chemically induced/*microbiology ; Intestinal Mucosa/immunology ; Intestinal Neoplasms/chemically induced/*microbiology ; Intestines/drug effects/microbiology ; Mice ; *Obesity/chemically induced/microbiology ; Prebiotics

2018-04-14

The American Association for Cancer Research (AACR)

1078-0432

1557-3265

Medicine

2018-05-09

The American Society for Pharmacology and Experimental Therapeutics

0022-3565

1521-0103

Medicine

2018-06-05

Rockefeller University Press

0022-1007

1540-9538

Medicine

Solid Tumors

1365-2559

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Aims : Bone marrow is the major site of B-cell generation in humans. While in early childhood a high number of B-cell precursors is found in the bone marrow, only very few such cells are usually detectable in adult bone marrow. To assess the number of immature B cells present after haematopoietic cell transplantation the number of terminal deoxynucleotidyl transferase (TdT)-positive cells in regenerating bone marrow of adult patients was analysed.Methods and results : Bone marrow biopsy specimens were analysed from patients after allogeneic bone marrow transplantation (BMT; n = 14) or stem cell transplantation (SCT; n = 25) and autologous BMT (n = 9). Specimens from 11 untransplanted adult patients and 11 infants were also studied, as negative and positive controls, respectively. Immunohistochemistry was performed on paraffin-embedded bone marrow biopsy sections using TdT as a marker of lymphoid progenitors. Immunoreactivity for CD79a, CD20 and CD10 was used to confirm their B-cell origin. Using computer-assisted automated image analysis we quantitatively assessed the TdT+ cells present. We found a significant increase in the numbers of B-cell precursors in the bone marrow after allogeneic and autologous BMT/SCT compared with adult controls (P = 0.022). To analyse this in detail, we followed some patients after allogeneic BMT/SCT for up to 1445 days, when a marked B-cell increase was still detectable. However, the median number of TdT+ B cells after BMT/SCT was significantly lower than the number of equivalent B cells in infantile bone marrow biopsy specimens (P 〈 0.001).Conclusions : Bone marrow of adult patients after BMT/SCT is capable of initiating vigorous precursor B-cell generation, which is not seen in untransplanted adults. However, the increase of immature B cells was variable in our study. Only in two young adult patients did it reach the magnitude of B-cell generation seen in infantile bone marrow where immunocompetent B cells are produced normally. A marked increase in number of immature B cells post-transplant may mimic B-cell acute lymphoblastic leukaemia (B-ALL). This is a potential problem in patients transplanted for B-ALL itself. Since reactive and neoplastic B-cell precursors share the same immunophenotype in paraffin-embedded tissue, additional tools, particularly molecular techniques, may have to be employed to establish the correct diagnosis.

Electronic Resource

1365-2559

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

A multifocal lymphoepithelioma-like carcinoma and a low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT-type) were found simultaneously in the stomach of a 65-year-old patient. Carcinoma and lymphoma were intimately associated forming complexes resembling lymphoepithelial lesions at the primary gastric site and in lymph node metastases. The two tumours had developed on a background of severe chronic-atrophic gastritis of the mucosa of antrum and fundus. Autoantibodies to normal gastric glandular tissue could be demonstrated in the patient’s sera. Using non-radioactive in situ hybridization (ISH), Epstein-Barr virus (EBV) sequences were detected in virtually all carcinoma cells but neither in the non-neoplastic mucosa nor in the lymphoma. These findings suggest that a focal EBV infection occurred early in the development of the carcinoma followed by a subsequent clonal expansion of the EBV-containing tumour cells. A neoplastic transformation in MALT-type lymphoma is not EBV-related but might be triggered by altered immune mechanisms.

Electronic Resource

1365-2559

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Electronic Resource

1365-2559

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

A histogenetic classification of thymic epithelial neoplasms proposed by Müller-Hermelink and co-workers has been shown by a number of recent studies to be of clinical and prognostic value. Reproducibility is an important criterion for the acceptance of any new classification for general diagnostic use. The reproducibility of this classification was tested on 51 cases of thymic epithelial neoplasia, by comparing results obtained by pathologists working from published criteria only with those results obtained by the pathologists who developed the classification. In 78% of cases there was complete concordance of results. Analysis of the 22% discordant cases showed that this discordance was due to a degree of subjectivity in determining cut-off points between categories adjacent to each other in the morphological spectrum of thymic epithelial neoplasia (medullary v. mixed, cortical v. well-differentiated thymic carcinoma). In terms of the important clinical distinction between benign (medullary and mixed) thymomas and those with more aggressive biological behaviour (cortical types and well-differentiated thymic carcinoma), the degree of reproducibility was 96%. The high degree of reproducibility of this histogenetic classification of thymic epithelial neoplasms should facilitate its acceptance and use in routine diagnostic pathology.

Electronic Resource

1365-2559

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Aims: De-differentiated chondrosarcoma is characterized by the presence of two distinct chondroid and nonchondroid tumour portions. The aim of our study was to investigate the distribution of extracellular matrix components in this tumour entity and thus to shed light on its histogenetic origin.〈section xml:id="abs1-1"〉〈title type="main"〉Methods and resultsHistochemical and immunohistochemical analyses were performed for collagen subtypes I, II, III and VI and cartilage proteoglycans in three samples of de-differentiated as well as conventional chondrosarcomas (various grades). In the chondroid tumour areas of de-differentiated chondrosarcoma, typical cartilage matrix components could be detected similar to chondroid areas of grade 1 and 2 conventional chondrosarcomas. In contrast, the tumour matrix of the nonchondroid portions of de-differentiated chondrosarcomas contained matrix molecules which are typical for fibroblastic tissue. This matrix composition was not identical with less differentiated (nonchondroid) areas of grade 2 and 3 conventional chondrosarcomas.〈section xml:id="abs1-2"〉〈title type="main"〉ConclusionsOur results confirm the chondroid nature of the differentiated portion of de-differentiated chondrosarcoma and indicate a nonchondrocytic nature of the nonchondroid portion. De-differentiated chondrosarcoma should not be considered as a ‘de’-differentiated chondrosarcoma (grade 4 neoplasm), but as a tumour entity showing two types of mesenchymal differentiation.

Electronic Resource

1365-2036

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Aim : To study the efficacy of three pantoprazole-based triple therapy regimens for the eradication of Helicobacter pylori infection and gastric ulcer healing.Methods : In an open, multi-centre, randomized study, 519 H. pylori-positive patients with active gastric ulcer were randomized to receive pantoprazole (40 mg) (P) and two of three antibiotics: clarithromycin (500 mg) (C), metronidazole (500 mg) (M) or amoxicillin (1000 mg) (A). Triple therapy (PAC, PCM, PAM) was administered twice daily for 7 days, followed by pantoprazole until the ulcer had healed. Antrum and corpus biopsies were taken to determine the pattern of gastritis, to assess the H. pylori status and to determine the strain susceptibility to antibiotics, and from the ulcer margins and base to exclude malignancy. Scores based on the Sydney system were used to categorize the gastritis phenotypically.Results : The H. pylori eradication rates for the per protocol (intention-to-treat) analysis were 89% (67%) for PAC, 83% (68%) for PCM and 76% (60%) for PAM, with a significant difference between PAC and PAM. Healing rates after 4 weeks were 91% for PAM, 90% for PCM and 88% for PAC (per protocol analysis). The eradication rates were lower in patients in whom strains resistant to any antibiotic used in the triple therapies were detected. Successful eradication [odds ratio, 5.2 (3.3; 8.3)] and the ulcer size (〈 15 mm) were significant predictors for healing after 4 weeks. The regimens showed a comparable safety profile and compliance.Conclusions : Pantoprazole-based triple therapies are effective in the eradication of H. pylori infection in gastric ulcer patients, as reported in previous similar sized studies in duodenal ulcer patients. Successful eradication and an ulcer size of 〈 15 mm are the best predictors of gastric ulcer healing after 4 weeks.

Electronic Resource

0370-2693

Elsevier Journal Backfiles on ScienceDirect 1907 - 2002

Physics

Electronic Resource

0370-2693

Elsevier Journal Backfiles on ScienceDirect 1907 - 2002

Physics

Electronic Resource

1365-2559

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Electronic Resource

1530-0358

Beta-catenin ; Immunohistochemistry ; Metastasis ; Predictive value ; Prognosis ; Rectal cancer ; Tumor marker

Springer Online Journal Archives 1860-2000

Medicine

Abstract PURPOSE: Adenomatous polyposis coli protein, glycogen synthetase kinase-3-beta, T cell transcription factor/lymphoid enhancer-binding factor, and beta-catenin modulate cell differentiation and proliferation via the expression of effector genes. It has recently been postulated that betacatenin is a potent oncogene of sporadic colorectal carcinogenesis and a prognostic tumor marker. Our aim was to investigate whether the nuclear overexpression of betacatenin, possibly caused by mutations in exon 3 of betacatenin (CTNNB1), is correlated with distant metastatic spread or disease-free survival in rectal carcinoma. METHODS: Immunohistochemical analysis was performed with an anti-beta-catenin-monoclonal antibody on paraffin sections of two groups of patients (n=2 × 77) with rectal carcinoma curatively treated by surgery alone. The patients selected were all free of local disease, to exclude surgical influence. Patient groups were matched for age, gender, International Union Against Cancer stage, and year of operation (1982 to 1991) and differed only in subsequent metachronous distant metastatic spread. Follow-up was prospective (median, 9.6 years). Three staining patterns were defined: membranous (normal), diffuse cytoplasmic (pathologic), and intense nuclear staining (pathologic). When intense nuclear staining was defined, the specimen was microdissected. Then, DNA was isolated, polymerase chain reaction-amplified, and sequenced to detect mutations in exon 3. RESULTS: Nuclear overexpression of beta-catenin correlated neither with distant metastatic spread (chisquared, 0.37;P=0.79) nor with disease-free survival (log-rank with trend,P=0.62). No mutations were found in the area of the serine/threonine-kinase glycogen synthetase kinase-3-beta-phosphorylation site in exon 3 (CTNNB1) of beta-catenin. CONCLUSION: Although beta-catenin seems to play an important role in early colorectal carcinogenesis, its value as a prognostic marker is questionable. It must be assumed that metastatic ability is determined by other factors than the disturbance of the beta-catenin T cell transcription factor/lymphoid enhancer-binding factor cascade and that other mechanisms might cause the observed nuclear translocation of beta-catenin.

Electronic Resource

1434-3940

Schlüsselwörter Bone Morphogenetic Protein-4 ; Osteoinduktion ; Chondroneogenese ; Klonierung ; E. coli ; Key words Bone Morphogenetic Protein-4 ; Osteoinduction ; Cloning

Springer Online Journal Archives 1860-2000

Medicine

Summary BMP-4 is physiologically present in low concentrations in human bone matrix. So far the protein has only been produced in small quantities by expression in mammalian cell cultures. In this study we investigated the biological activity of E. coli-expressed BMP-4. In vitro neonatal rat muscle tissue was incubated together with BMP-4 during 4 h, followed by an incubation period of 14 days on cellulose acetate membranes in BMP-free medium. The addition of 0.4 μg BMP-4 induced cartilage formation in 1/8 samples while 4 μg BMP-4 showed chondroneogenesis in 2/10 samples. When the BMP-4 concentration was increased to 40 μg, new cartilage formation was seen in 5/7 samples. In vivo BMP-4 was implanted intramuscularly for 3 weeks in ICR mice. Amounts of 10 μg rhBMP-4 and more (up to 100 μg) constantly induced heterotopic ossicle formation. BMP-4 was also combined with a collagen carrier and implanted for 2 and 4 weeks in the abdominal muscle of SD rats. While 0.4 μg BMP-4 showed no bone or cartilage formation, the amount of 40 μg BMP-4 showed new heterotopic cartilage formation, followed by endochondral ossification in almost all samples. The results prove that E. coli-expressed BMP-4 possesses the same inductive properties as mammalian-cell-expressed BMP-4.

Zusammenfassung BMP-4 ist in geringer Konzentration ein physiologischer Bestandteil der humanen Knochenmatrix. Bisher ist das Protein nur in kleinen Mengen in Säugetierzellkulturen exprimiert worden. Der Artikel untersucht die biologische Aktivität von E.-coli-exprimiertem BMP-4. In vitro wurde neonatales Rattenmuskelgewebe für 4 h mit BMP-4 inkubiert, gefolgt von einer 14tägigen Inkubation auf Zelluloseazetatmembranen in BMP-freiem Medium. Die Zugabe von 0,4 μg BMP-4 induzierte in 1/8 Ansätzen eine Knorpelbildung, während 4 μg BMP-4 in 2/10 Proben eine Chondroneogenese zeigten. Eine Erhöhung der BMP-4-Konzentration auf 40 μg ergab in 5/7 Ansätzen eine Knorpelinduktion. In vivo wurde BMP-4 i.m. für 3 Wochen in ICR-Mäuse implantiert. Implantate mit 10–100 μg BMP-4 induzierten reproduzierbar eine heterotope Ossikelbildung. BMP-4 wurde in weiteren Versuchen an eine Kollagenmatrix gekoppelt und für 2 bzw. 4 Wochen in die Bauchwandmuskulatur von SD-Ratten implantiert. Während 0,4 μg BMP-4 keine Knorpel- oder Knochenbildung zeigten, induzierten 40 μg BMP-4 in fast allen Implantaten eine heterotope Knorpelbildung mit nachfolgender enchondraler Ossifikation. Die Ergebnisse beweisen, daß E.-coli-exprimiertes BMP-4 dieselben induktiven Eigenschaften aufweist, wie BMP-4, welches in Säugetierzellen exprimiert wurde.

Electronic Resource

1434-3940

Schlüsselwörter EHBMP-2 ; BMP-2 ; BMP-Analog ; Osteoinduktion ; Rekonstruktive Chirurgie ; Key words EHBMP-2 ; BMP-mutant ; Osteoinduction ; Reconstructive surgery

Springer Online Journal Archives 1860-2000

Medicine

Summary For the first time a non natural BMP-variant (EHBMP-2) with osteoinductive properties was produced by expression in E. coli through specific mutation of the amino acid sequence. The substitution of 12 N-terminal amino acids by a nonsense sequence results in a neglectible affinity of EHBMP-2 to the extracellular matrix. In vitro EHBMP-2 induces dose-dependent cartilage formation in neonatal muscle tissue. Single intramuscular implantation in mice results in the formation of an ossicle with functional active bone marrow. The size of the ossicle depends on the amount of implanted EHBMP-2 and can significantly be increased by the combination with a collagen carrier. The largest bone formation is observed after injection of EHBMP-2 containing collagen suspensions. In rats a stronger osteoinductive activity can be achieved by coupling of EHBMP-2 to collagen discs than by coupling natural BMP-2 to the same collagen carrier. Critical size defects in rats’ mandibular angels can be restored by the combination of granular collagenous bone matrix (ICBM) with EHBMP-2. Further investigations have to show whether the altered pharmacokinetics of EHBMP-2 has advantages regarding its therapeutical use and tissue-engineering.

Zusammenfassung Durch die gezielte Mutation der Aminosäuresequenz ist es erstmalig gelungen, ein nicht natürliches BMP-Analog (EHBMP-2) mit osteoinduktiven Eigenschaften gentechnisch durch Expression in E.-coli-Bakterien herzustellen. Der Ersatz von 12 N-terminalen Aminosäuren des BMP-2-Moleküls durch eine Nonsense-Sequenz führt zu einer nicht mehr meßbaren Affinität von EHBMP-2 zur extrazellulären Matrix. In vitro induziert EHBMP-2 dosisabhängig die Knorpelbildung in neonatalem Muskelgewebe. Die alleinige i.m. Implantation in Mäuse führt zur Bildung eines Ossikels mit funktionell aktivem Knochenmarkanteil. Die Größe des Ossikels wird durch die Menge an implantiertem EHBMP-2 beeinflußt und kann durch die Kombination von EHBMP-2 mit Kollagen signifikant gesteigert werden. Die größte Knochenneubildung wird nach der Injektion von EHBMP-2-haltigen Kollagensuspensionen beobachtet. In Ratten kann durch die Koppelung von EHBMP-2 an Kollagenscheiben eine stärkere osteoinduktive Aktivität in der Muskulatur erzielt werden als durch die Koppelung von natürlichem BMP-2 an denselben Kollagenträger. In Kombination mit pulverförmiger kollagener Knochenmatrix (ICBM) gelingt die knöcherne Konsolidierung von „critical size defects“ im Kieferwinkel von Ratten durch EHBMP-2. Weitere Untersuchungen müssen zeigen, inwiefern die veränderte Pharmakokinetik von EHBMP-2 Vorteile beim therapeutischen und gewebetechnolgischen Einsatz bietet.

Electronic Resource

0165-4608

Elsevier Journal Backfiles on ScienceDirect 1907 - 2002

Medicine

Electronic Resource

0090-6980

Elsevier Journal Backfiles on ScienceDirect 1907 - 2002

Medicine

Electronic Resource

1432-2307

Helicobacter pylori ; Gastritis ; Host response ; Autoimmunity

Springer Online Journal Archives 1860-2000

Medicine

Abstract Colonization of human gastric mucosa with Helicobacter pylori leads to chronic active gastritis and induces the occurrence of an acquired mucosa-associated lymphoid tissue (MALT) in the stomach. This remodelling of the gastric mucosa together with chronic antigen persistence may induce autoimmune reactions. The aim of this study was to investigate humoral autoimmune reactions to human gastric mucosa in H. pylori gastritis and their clinical relevance. Sera from patients with dyspeptic symptoms were tested for presence of IgG immunoglobulins against H. pylori. Gastric infection with H. pylori and alterations of gastric mucosa were demonstrated by histological examination of gastric biopsy specimens. All sera were tested for reactivity against human gastric mucosa by immunohistochemistry. Two different in-situ binding sites of antigastric autoantibodies were observed. Binding to canalicular structures within parietal cells was significantly correlated with antibodies to H. pylori, elevated basal gastrin levels and atrophy of gastric corpus glands. Our data indicate that autoimmune reactions to antigens in the human gastric mucosa occur in H. pylori gastritis and that they may play a role in the pathogenesis of the disease.

Electronic Resource

1434-3940

Schlüsselwörter BMP-2 ; mrhBMP-2x ; BMP-Träger ; Osteoinduktion ; Rekonstruktive Chirurgie ; Key words BMP-2 ; BMP Carrier ; Osteoinduction ; Reconstructive surgery

Springer Online Journal Archives 1860-2000

Medicine

Summary The extent of BMP-induced new bone formation is mainly determined by the number of mesenchymal target cells in the recipient bed as well as by the biological half-life of the BMP molecules within the tissue. While the number of inducible cells is determined by the age and vascularization of the tissue, the retention time of the BMP molecules can be influenced. One possibility is the coupling of BMPs to suitable carriers, which significantly increases the osteoinductive effect. The reason for this is the physical binding of BMPs to the carrier material, which delays the resorption of the proteins. Other factors are the composition of the carrier materials, their structural stability, and possible dislocations of carrier particles. The local tissue concentration of BMPs can also be increased by an enhanced binding of the proteins to the extracellular matrix. A BMP-2 mutant (BMP-2xa) was produced by the specific modification of the amino acid sequence using recombinant technologies. BMP-2xa induces heterotopic bone formation at significantly lower concentrations than natural BMP-2. Furthermore, BMP-2xa-induced bone tissue possesses a higher bone density.

Zusammenfassung Das Ausmaß der BMP-induzierten Knochenneubildung wird in erster Linie durch die Anzahl der mesenchymalen Zielzellen im Implantatlager sowie durch die Halbwertszeit der BMP-Moleküle im Gewebe bestimmt. Während die induzierbare Zellzahl durch das Lebensalter und die Vaskularisation des Gewebes vorgegeben ist, kann die Verweildauer der BMP-Moleküle im Gewebe beeinflusst werden. Eine Möglichkeit besteht in der Kopplung der BMPs an geeignete Trägermaterialien, wodurch die osteoinduktive Wirkung signifikant gesteigert wird. Verantwortlich hierfür ist die physikalische Bindung der BMPs an das Trägermaterial, durch welche die Resorption der Proteine verzögert wird. Weitere Faktoren stellen die Materialzusammensetzung der Trägermaterialien, deren Formkonstanz sowie eine eventuelle Dislokation von Trägerpartikeln dar. Die lokale Gewebekonzentration der BMPs kann daneben auch durch eine verstärkte Bindung der Proteine an die extrazelluläre Matrix erhöht werden. Durch die gezielte Modifikation der Aminosäuresequenz wurde gentechnisch eine BMP-2-Mutante (BMP-2x a ) hergestellt, welche bei signifikant niedrigerer Konzentration gegenüber dem natürlichen BMP-2 eine heterotope Knochenbildung induziert. Das durch diese BMP-Mutante gebildete Knochengewebe zeichnet sich außerdem durch eine höhere Knochendichte aus.

Electronic Resource