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Biomedical subjects

G Johnen

Publications and source records attributed to G Johnen.

16 recordsLinked to original sources
PubMed2006

[Differential diagnosis of preneoplastic lesions of the pleura and of early mesothelioma: immunohistochemical and morphological findings].

The morphological diagnosis of small mesothelial lesions in pleural biopsies is gaining importance in view of more aggressive, multimodal therapeutic options and of medicolegal aspects if a malignant mesothelioma is diagnosed. We present a light microscopically and immunohistochemically based morphological classification for the planning of further clinical follow-up procedures. A reactive mesothelial hyperplasia heals without scars. Mesothelial inclusions in pleuritic scars are common in recurrent pleuritis and must not be confused with an epithelioid component of a desmoplastic mesothelioma. In case of atypical mesothelial proliferations, further diagnostic procedures have to be performed to obtain a clear diagnosis of malignancy. Mesothelioma in situ is the first morphological step in neoplastic mesothelial changes, also with regard to medicolegal aspects for the unambiguous diagnosis of a mesothelioma. Early infiltrative growth is characteristic of so called early mesothelioma. A useful immunohistochemical panel for the differential diagnosis consists of anti-cytokeratin, Ck 5/6, calretinin, EMA and MiB-1, whereas the immunohistochemical detection of telomerase is not helpful.

Biomarkers, Tumor↗
PubMed2005

[Comparison of chromosomal defects in primary tumor and metastases by comparative genomic hybridization (CGH)].

Molecular methods can complement the classical methods in pathology like macroscopic, histological and immunohistochemical examinations.Comparative genomic hybridization is a cytogenetic method to screen for gains and losses of chromosomal material in tumor cells. This method allows defect studies of archival paraffin-embedded and formalin-fixed tumor material. CGH can detect gains and losses of chromosomal material that are at least 10 to 20 megabases in size. This genome-wide screening method allows to study the cytogenetic relationship between differently located tumors of a patient. To answer the question if these different tumors are metastases of the primary lung tumor or independent primary tumors CGH analysis is a supplementary method that introduces new prospectives.

Chromosome Aberrations↗
PubMed2005

[Myoepithelioma of soft tissue -- case report with clinicopathologic, ultrastructural, and cytogenetic findings].

The case of a soft tissue myoepithelioma is presented including clinicopathologic, ultrastructural, and genetic findings. A 30-year-old male patient suffered from a soft tissue tumor within the deep soft tissues of the right lower leg measuring 13.2 x 8.2 x 9 cm. Histologically, the lesion was diagnosed as a myoepithelioma displaying a lobulated architecture with cords and nests of epithelioid and spindle cells without cytologic atypia lying within a fibromyxoid and partly chondroid matrix; immunohistochemistry was positive for pancytokeratin, S100-protein, calponin and partly for GFAP and EMA. Ultrastructural analysis revealed glycogen deposits and cell-membrane-associated plaque structures, whereas true myofilaments could not be identified (with immunohistochemistry being negative for actin). Using comparative genomic hybridization (CGH), a gain of chromosome Y was detected. A loss on 17p could not be detected unambiguously. However, based on the low resolution of CGH a small loss cannot be excluded. The patient was free of disease 25 months following complete tumor resection. Myoepitheliomas/mixed tumors of deep soft tissue represent rare soft tissue lesions that may reach a considerable size and may mimic other soft tissue tumors or sarcomas. Based on a local relapse rate of approximately 20% according to the literature, a complete resection with thorough follow-up should be recommended.

Adult↗
PubMed2004

Challenges to environmental toxicology and epidemiology: where do we stand and which way do we go?

Modern toxicology investigates a wide array of both old and new health hazards. Priority setting is needed to select agents for research from the plethora of exposure circumstances. The changing societies and a growing fraction of the aged have to be taken into consideration. A precise exposure assessment is of importance for risk estimation and regulation. Toxicology contributes to the exploration of pathomechanisms to specify the exposure metrics for risk estimation. Combined effects of co-existing agents are not yet sufficiently understood. Animal experiments allow a separate administration of agents which can not be disentangled by epidemiological means, but their value is limited for low exposure levels in many of today's settings. As an experimental science, toxicology has to keep pace with the rapidly growing knowledge about the language of the genome and the changing paradigms in cancer development. During the pioneer era of assembling a working draft of the human genome, toxicogenomics has been developed. Gene and pathway complexity have to be considered when investigating gene-environment interactions. For a best conduct of studies, modern toxicology needs a close liaison with many other disciplines like epidemiology and bioinformatics.

Animals↗
PubMed2004

[A rare case of a neuroendocrine carcinoma of the esophagus. Intermediate between a well-differentiated neuroendocrine carcinoma and a low-differentiated neuroendocrine carcinoma].

We report a rare case of a neuroendocrine carcinoma located in the esophagus of a 62-year-old male patient. The initial diagnosis of a "small-cell tumor" was based on biopsy. Our diagnosis was based on the histomorphological examination of the resected material. Diagnostic criteria were the characteristic solid or clustered growth patterns, monomorphic cell nuclei, lack of necrosis, immunohistochemical detection of neuroendocrine markers like chromogranin, synaptophysin and neuron-specific enolase (NSE) as well as detection of cytoplasmic neuroendocrine granules by electron microscopy. In addition, we found an increased prolific activity by staining with Ki67 antigen. 30% of the cell nuclei displayed a positive reaction. Focal invasion of blood vessels was also detected. With 17 different chromosomal imbalances, comparative genomic hybridization (CGH) revealed a malignant tumor stage that was not visible at the microscopic level. According to the new WHO classification of neuroendocrine tumors the described tumor was identified as an intermediate between a well-differentiated neuroendocrine carcinoma and a low-differentiated neuroendocrine carcinoma.

Biomarkers↗
PubMed2004

Interstitial lung disease in a baby with a de novo mutation in the SFTPC gene.

Mutations in the surfactant protein C gene (SFTPC) were recently reported in patients with interstitial lung disease. In a 13-month-old infant with severe respiratory insufficiency, a lung biopsy elicited combined histological patterns of nonspecific interstitial pneumonia and pulmonary alveolar proteinosis. Immunohistochemical and biochemical analyses showed an intra-alveolar accumulation of surfactant protein (SP)-A, precursors of SP-B, mature SP-B, aberrantly processed proSP-C, as well as mono- and dimeric SP-C. Sequencing of genomic DNA detected a de novo heterozygous missense mutation of the SFTPC gene (g.1286T>C) resulting in a substitution of threonine for isoleucine (173T) in the C-terminal propeptide. At the ultrastructural level, abnormal transport vesicles were detected in type-II pneumocytes. Fusion proteins, consisting of enhanced green fluorescent protein and wild-type or mutant proSP-C, were used to evaluate protein trafficking in vitro. In contrast to wild-type proSP-C, mutant proSP-C was routed to early endosomes when transfected into A549 epithelial cells. In contrast to previously reported mutations, the 173T represents a new class of surfactant protein C gene mutations, which is marked by a distinct trafficking, processing, palmitoylation, and secretion of the mutant and wild-type surfactant protein C. This report heralds the emerging diversity of phenotypes associated with the expression of mutant surfactant C proteins.

Base Sequence↗
PubMed2004

Surfactant proteins in pulmonary alveolar proteinosis in adults.

Pulmonary alveolar proteinosis (PAP) is a rare disorder characterised histologically by an intra-alveolar accumulation of fine granular eosinophilic and periodic acid-Schiff positive material. In a retrospective study, the composition of the intra-alveolarly accumulated material of adult patients with PAP was analysed by means of immunohistochemistry and Western blotting. In patients with PAP, the current authors found an intra-alveolar accumulation of surfactant protein (SP)-A, precursors of SP-B, SP-B, variable amounts of mono-, di-, and oligomeric SP-C forms, as well as SP-D. Only in one patient was a precursor of SP-C detected. By means of immuno-electron microscopy, the current authors identified not only transport vesicles labelled for precursors of SP-B and SP-C, but also transport vesicles containing either precursors of SP-B or SP-C in type-II pneumocytes in normal human lungs. It is concluded that pulmonary alveolar proteinosis in adults is characterised by an intra-alveolar accumulation of surfactant protein A, precursors of surfactant protein B, and surfactant proteins B, C and D. The current data provide evidence that not only an impairment of surfactant clearance by alveolar macrophages, but also an abnormal secretion of transport vesicles containing precursors of surfactant protein B (but not surfactant protein C) and an insufficient palmitoylation of surfactant protein C, which may lead to the formation of di- and oligomeric surfactant protein C forms, play a role in the pathogenesis of pulmonary alveolar proteinosis.

Adult↗
PubMed2003

[CGH findings in neuroendocrine tumours of the lung].

According to the 1999 World Health Organisation classification of lung tumors, the classification of neuroendocrine (NE) tumors is solely based on light-microscopic features. Typical and atypical carcinoid tumors are distinguished from large cell (LCNEC) and small cell neuroendocrine carcinomas (SCLC). We used comparative genomic hybridization (CGH) on 50 samples to investigate the cytogenetic relationships between NE tumors. On average, carcinoid tumors showed markedly fewer chromosomal imbalances (1.8/case, 23 cases) than LCNEC (13.3/case, 17 cases) or SCLC (17/case, 10 cases). The frequency of amplicons increased accordingly. Typical carcinoid tumors exhibited significant defects on chromosomes 11 and 13 only. Interestingly, only the frequency of losses on chromosome arm 11q was very similar for all three tumor entities (about 30%). In conclusion, the CGH results support the classification of typical carcinoid tumors as a separate entity in clear distinction from the NE carcinomas.

Carcinoma, Large Cell↗
PubMed2000

[Pathology and molecular biology of lung cancer].

Therapy and prognosis of lung cancer depend crucially on tumor size, tumor stage, and the histomorphological tumor type at the time of primary diagnosis. A tumor weighing only 1 g and barely detectable by clinical examination consists of about 1 x 10(9) tumor cells. The primary histological diagnosis is generally based on small biopsies 1-2 mm in diameter, which allow the assessment of only a few up to some hundred tumor cells in a section of 4 microns. Until 20 years ago light microscopic and histochemical investigations were the basis for sophisticated morphological tumor diagnosis. In recent years electron microscopy, immunohistochemistry, cytometry, and molecular biology have extended our knowledge of the complex tumor biology, with the range of phenotypes and genotypes indicating enormous tumor heterogeneity. The value, expressiveness, and prognostic importance of these laborious and expensive techniques must be examined in studies, keeping in mind new aspects of tumor classification. Histological and cytological findings are still the decisive basis for the primary diagnosis of the pathologist in any given case.

Biopsy↗
PubMed2000

Benign solitary fibrous tumour of the thigh: morphological, chromosomal and differential diagnostic aspects.

Solitary fibrous tumours (SFTs) are rare and usually benign neoplasms of mesenchymal origin that are often found in the visceral pleura (fibrous pleural tumour, FPT) or other serosal surfaces. They have also been found in soft tissues. We report the case of an SFT localised in the thigh of an 86-year-old woman. The tumour specimen was examined morphologically, immunohistochemically and molecular genetically, using comparative genomic hybridisation (CGH). The latter detects unbalanced chromosomal alterations in human neoplasms by competitive nucleic acid hybridisation and consecutive computer image analysis. The tumour consists of fibroblast-like cells, arranged in a typical "patternless pattern". Immunohistochemically, the tumour stained positively for vimentin, CD34, CD99, and focally for actin and desmin. No reaction occurred with keratin or S100 protein antibodies. CGH detected a single loss on chromosome 13q.

Aged↗
PubMed2000

Patterns of chromosomal imbalances in benign solitary fibrous tumours of the pleura.

Solitary fibrous tumours (SFTs) of the pleura, in contrast to malignant mesothelioma, occur independently of previous asbestos exposure. They are benign tumours, but may recur if the stalk to the adjacent pleural or lung tissue remains in situ during surgical removal. The molecular pathology of SFTs is largely unknown. We used comparative genomic hybridisation (CGH) to characterise 12 localised SFTs and 12 predominantly sarcomatoid mesotheliomas. Fifty-eight percent of the investigated SFTs did not show any chromosomal imbalances. The most frequent defects were losses on chromosome arms 13q (33%), 4q and 21q (17% each). Significant gains were seen at chromosome 8 and at 15q in two cases each. There was no correlation between tumour size and molecular pathology findings. In contrast, 75% of the mesotheliomas carried chromosomal defects. On average, the mesotheliomas showed over three times as many defects per tumour as the SFTs. Localisation of several frequent losses and gains were similar to those of the SFTs. Therefore, in individual cases, a clear distinction between SFTs and sarcomatoid mesotheliomas is not possible based on CGH analysis alone. Further molecular characterisation of this rare tumour entity will be necessary to elucidate possible genes involved in early tumorigenesis.

Aged↗
PubMed2000

Severe chromosomal aberrations in pleural mesotheliomas with unusual mesodermal features. Comparative genomic hybridization evidence for a mesothelioma subgroup.

Malignant mesotheliomas are tumors known for their extensive heterogeneity. Apart from the three classical patterns, predominantly epithelioid, sarcomatoid, and biphasic, some rare variants do exist. In some cases, one can find uncommon additional mesodermal tumor components. These tumors have previously been called "mesodermomas" and, like regular mesotheliomas, are usually associated with a previous asbestos exposure. We examined eight cases of mesodermomas by light microscopy, immunohistochemistry and comparative genomic hybridization (CGH). Besides biphasic and epithelioid areas, unusual epithelial, chondroid, osseous, or even angioblastic elements may be found to varying degrees. Immunohistochemical analysis shows similar staining results as with regular mesotheliomas. CGH reveals a high number of chromosomal imbalances (16.5 per case; range, 11-27). In 10 classical biphasic mesotheliomas that served as a control, defects of comparable number and severity could not be detected (8 per case; range, 2-16). The most frequent defects of mesodermomas (losses on 1p, 4pq, 9p, 13q, 14q, and gains on 1q and 15q), however, could also be found in mesotheliomas of the classical type. Thus, our results support the classification of the so-called mesodermomas as a separate tumor subgroup while maintaining the relationship to the classical mesotheliomas. Therefore, we propose to use the term mesodermoma for this subgroup.

Aged↗
PubMed1997

Studies on the enzymatic and transcriptional activity of the dimerization cofactor for hepatocyte nuclear factor 1.

The relationship between the enzymatic and the transcriptional activity of the bifunctional protein pterin-4a-carbinolamine dehydratase/dimerization cofactor for hepatocyte nuclear factor 1 (DCoH) has been elucidated by site-directed mutagenesis. DCoH dimers harbor a binding site for hepatocyte nuclear factor 1 (HNF1), two active centers that bind pterins, and a saddle-shaped surface that resembles nucleic acid binding domains. Two domains of the protein have been selectively targeted to determine if a change in one activity affects the other. No strong correlation has been found, supporting the idea that carbinolamine dehydratase activity is not required for HNF1 binding in vitro or transcriptional coactivation in vivo. Double mutations in the active center, however, influence the in vivo transcriptional activity but not HNF1 binding. This finding suggests that some active center residues also are used during transcription, possibly for binding of another (macro)molecule. Several mutations in the saddle led to a surprising increase in transcription, therefore linking this domain to transcriptional regulation as well. The transcriptional function of DCoH therefore is composed of two parts, HNF1 binding and another contributing effect that involves the active site and, indirectly, the saddle.

Animals↗
PubMed1997

Expression of 4alpha-carbinolamine dehydratase in human epidermal keratinocytes.

4alpha-Carbinolamine dehydratase is a bifunctional protein involved in the regeneration of tetrahydrobiopterin during the hydroxylation of the aromatic amino acids. It is also a dimerization cofactor of HNF1 and therefore is believed to function as part of the hepatic gene transcription system. In view of the recent discoveries that the distribution and developmental pattern of the dehydratase do not correlate strictly with those of the aromatic amino acid hydroxylases and HNF1, the hypothesis that the dehydratase may have other unknown functions has been put forward. In the present paper, we demonstrate unambiguously that human epidermal keratinocytes express detectable levels of this protein as indicated by enzyme assay, immunoprecipitation, Western blot, and RT-PCR. Its complete coding sequence has been cloned and was found to be identical with the human liver counterpart. The possible function of the dehydratase in skin is discussed.

Blotting, Western↗
PubMed1995

Characterization of the wild-type form of 4a-carbinolamine dehydratase and two naturally occurring mutants associated with hyperphenylalaninemia.

The characterization of 4a-carbinolamine dehydratase with the enzymatically synthesized natural substrate revealed non-Michaelis-Menten kinetics. A Hill coefficient of 1.8 indicates that the dehydratase exists as a multisubunit enzyme that shows cooperativity. A mild form of hyperphenylalaninemia with high 7-biopterin levels has been linked to mutations in the human 4a-carbinolamine dehydratase gene. We have now cloned and expressed two mutant forms of the protein based on a patient's DNA sequences. The kinetic parameters of the mutant C82R reveal a 60% decrease in Vmax but no change in Km (approximately 5 microM), suggesting that the cysteine residue is not involved in substrate binding. Its replacement by arginine possibly causes a conformational change in the active center. Like the wild-type enzyme, this mutant is heat stable and forms a tetramer. The susceptibility to proteolysis of C82R, however, is markedly increased in vitro compared with the wild-type protein. We have also observed a decrease in the expression levels of C82R protein in transfected mammalian cells, which could be due to proteolytic instability. The 18-amino acid-truncated mutant GLu-87--> termination could not be completely purified and characterized due to minute levels of expression and its extremely low solubility as a fusion protein. No dehydratase activity was detected in crude extracts from transformed bacteria or transfected mammalian cells. Considering the decrease in specific activity and stability of the mutants, we conclude that the patient probably has less than 10% residual dehydratase activity, which could be responsible for the mild hyperphenylalaninemia and the high 7-biopterin levels.

Amino Acid Metabolism, Inborn Errors↗