Biomedical subjects
Publications and source records attributed to B Mayr.
Ninety canine and 101 feline tumours of various types were investigated for gene mutations in the coding regions of the metastasis-associated gene S100A4 (mts1). No gene mutations were present in the analysed genomic area. A widespread histidine/tyrosine polymorphism was detected in codon 17 of S100A4.
Tumour suppressor p53 is critical in a broad panel of tumour types in human, mouse and other mammals. Regions of the promoter and exon 1 play an important role in expression of p53. In the present study, the DNA sequences of promoter and exon 1 regions of four domestic animal species (dog, cat, horse and cattle) are determined and compared with experimental rodents (mouse, rat and hamster) and man. A broad panel of tumour types have been investigated for mutations in this regulatory area in 90 canine, 136 feline, 25 equine and 10 bovine patients. No mutation was detected in any of the tumours analysed.
A region from exon 4 to 8 of the tumour suppressor gene p53 was analysed in 60 feline tumours (30 fibrosarcomas, seven malignant histiocytomas, three lymphosarcomas, five basal cell tumours, five squamous cell carcinomas, two adenocarcinomas of tubular skin glands, one undifferentiated carcinoma of the skin, seven mammary carcinomas). Missense mutations were detected in two fibrosarcomas, one malignant fibrous histiocytoma, the undifferentiated carcinoma of the skin and one mammary carcinoma. One nonsense mutation was detected in one fibrosarcoma and one deletion/frameshift-mutation was observed in one squamous cell carcinoma.
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Controlled expression of cloned PhiX174 gene E in Gram-negative bacteria results in lysis of the bacteria by formation of an E-specific transmembrane tunnel structure built through the cell envelope complex. Bacterial ghosts from a variety of bacteria are used as non-living candidate vaccines. In the recombinant ghost system, foreign proteins are attached on the inside of the inner membrane as fusions with specific anchor sequences. Ghosts have a sealed periplasmic space and the export of proteins into this space vastly extends the capacity of ghosts or recombinant ghosts to function as carriers of foreign antigens. In addition, S-layer proteins forming shell-like self assembly structures can be expressed in candidate vaccine strains prior to E-mediated lysis. Such recombinant S-layer proteins carrying foreign epitopes further extend the possibilities of ghosts as carriers of foreign epitopes. As ghosts have inherent adjuvant properties, they can be used as adjuvants in combination with subunit vaccines. Subunits or other ligands can also be coupled to matrixes like dextran which are used to fill the internal lumen of ghosts. Oral, aerogenic or parenteral immunization of experimental animals with recombinant ghosts induced specific humoral and cellular immune responses against bacterial and target components including protective mucosal immunity. The most relevant advantage of recombinant bacterial ghosts as immunogens is that no inactivation procedures that denature relevant immunogenic determinants are employed in this production. This fact explains the superior quality of ghosts when compared to other inactivated vaccines. The endotoxic component of the outer membrane does not limit the use of ghosts as vaccine candidates but triggers the release of several potent immunoregulatory cytokines. As carriers, there is no limitation in the size of foreign antigens that can be inserted in the membrane and the capacity of all spaces including the membranes, peri-plasma and internal lumen of the ghosts can be fully utilized. This extended recombinant ghost system represents a new strategy for adjuvant free combination vaccines.
INTRODUCTION: Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy. Although the clinical course is usually rather benign, a subset of tumors is more aggressive. The ret/PTC oncogene was found only in PTC, with varying frequencies of up to 30%. Recently, two new variants of ret/PTC could be identified in post-Chernobyl PTCs, which raised the possibility that the prevalence of ret/PTC in non-radiation-induced PTCs might be higher than previously described. Normal thyroid cells do not express wild-type ret, but there is evidence that ret activation from any cause, including wild-type ret, occurs in more than a half of papillary tumors. METHODS: We used reverse transcription polymerase chain reaction and sequencing to examine wild-type ret and all five forms of ret/PTC known today in 99 PTCs from Hannover, Dusseldorf, Halle and Regensburg. Our method could also detect other variants within the known breakpoint regions. The presence of the ret tyrosine-kinase domain was examined by immunohistochemistry. RESULTS: Seven PTC1-positive tumors and one PTC3-positive tumor (8%), but none with the new variants or other variants of PTC1, 2 or 3 could be detected. Of 43 tumors examined, 20 showed expression of wild-type ret mRNA and staining of ret protein located predominantly to the cell membrane. CONCLUSION: Variants of ret/PTC do not substantially contribute to non-radiation-related ret/PTC-positive tumors, and the prevalence of ret/PTC in Germany is low in contrast to the high rate of wild-type ret expression. Thus, expression of wild-type ret should be examined for pathogenic, prognostic and possible therapeutic implications.
Exons 4 to 8 of the tumour suppressor gene p53 were analysed in 25 skin and 25 mammary tumours of 50 dogs. A 1 bp deletion (ACC-->AC) was detected in codon 89 in exon 4 in a squamous cell carcinoma. A missense mutation CGC-->CAC (arginine-->histidine) was present in codon 162 in exon 5 in a mammary adenocarcinoma. Moreover, a silent mutation occurred in codon 103 (serine) of exon 4 in a mammary adenoma. The somatic nature of the three mutations was demonstrated.
Mammary carcinomas of six feline patients were subjected to karyotypic analysis. A broad variation in the numerical and structural alterations was evident. None the less, several repeatedly occurring alterations were observed.
Serum calcitonin screening has recently been found to be a useful supplement to fine-needle aspiration biopsy, ultrasound and radionuclide imaging in the evaluation of thyroid nodules. We describe a case where introduction of routine calcitonin screening in nodular thyroid disease led to the detection of a family with medullary thyroid carcinoma. The benefits and problems of basal and stimulated serum calcitonin testing and ret-proto-oncogene mutation studies are exemplified and we discuss the appropriate use and interpretation of these tests. We conclude that routine basal serum calcitonin measurement in nodular thyroid disease and thoughtful use of ret-mutation analysis is cost-effective in detecting medullary thyroid carcinoma and multiple endocrine neoplasia type II.
We have determined the canine and feline N-, K-, and H-ras gene sequences from position +23 to +270 covering exons I and II which contain the mutational hot spot codons 12, 13, and 61. The results were used to assess the degree of similarity between ras gene DNA regions containing the critical domains affected in neoplastic disorders in different mammalian species. The comparative analyses performed included human, canine, feline, murine, rattine, and, whenever possible, bovine, leporine (rabbit), porcelline (guinea pig), and mesocricetine (hamster) ras gene sequences within the region of interest. Comparison of feline and canine nucleotide sequences with the corresponding regions in human DNA revealed a sequence similarity greater than 85% to the human sequence. Contemporaneous analysis of previously published ras DNA sequences from other mammalian species showed a similar degree of homology to human DNA. Most nucleotide differences observed represented synonymous changes without effect on the amino acid sequence of the respective proteins. For assessment of the phylogenetic evolution of ras gene family, a maximum parsimony dendrogram based on multiple sequence alignment of the common region of exons I and II in the N-, K-, and H-ras genes was constructed. Interestingly, a higher substitution rate among the H-ras genes became apparent, indicating accelerated sequence evolution within this particular clade. The most parsimonious tree clearly shows that the duplications giving rise to the three ras genes must have occurred before the mammalian radiation.
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Four mesenchymal neoplasms (two malignant fibroblastic histiocytomas, one fibrosarcoma, one fibroma) were investigated cytogenetically. Although no specific alterations were present, the frequent nonrandom involvement of chromosome E1 became clearly evident. Karyotypic alterations involving unrelated clonal changes were also present in the fibroma.
Twenty feline neoplasms were sequenced in the region from exons 5 to 8 for the presence of tumour suppressor gene p53 mutations. In a spindle cell sarcoma of the bladder, a missense mutation (codon 164 AAG-->GAG, lysine-->glutamic acid) in exon 5 was detected. In a pleomorphic sarcoma, a 23 bp deletion involving the splicing junction between intron 5 and exon 6 was observed. In a fibrosarcoma, a 6 bp deletion of p53 covering 2 bp of exon 7 and 4 bp of intron 7, including the splicing junction, was found. The study demonstrates three new p53 mutations in different types of sarcomas in cats.
Ret/PTC oncogene has been described with a frequency of 2.5-30% in papillary thyroid carcinomas. We examined the expression of ret/PTC in 99 German papillary thyroid carcinomas, including two recently described new variants of ret/PTC3 and identified eight ret/PTC-positive tumours (8%) but none with the new variants.
A case of basal cell carcinoma in a 10-year-old spaniel dog was analysed cytogenetically. A reciprocal translocation t(10;35) was detectable.
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OBJECTIVE: To identify mutations in canine mammary tumors. ANIMALS: 10 tumor-bearing dogs. PROCEDURE: Culture of neoplastic cells originating from mammary tumors was performed, and trypsin-G banding was used for cytogenetic investigations. The same tumors were subjected to molecular genetic screening by use of DNA extraction, polymerase chain reaction, DNA elution, and DNA sequencing for ras oncogenes and the p53 tumor suppressor gene. RESULTS: A broad spectrum of chromosome aberrations was observed, including trisomies, reciprocal translocations, and structural and numerical X-chromosome alterations and deletions. Molecular genetic analysis revealed a tumor suppressor p53 gene mutation in codon 249 of exon 7 in one instance. Interestingly, analyzed mammary tumors were free of mutations in N-ras, K-ras and H-ras, exons 1 and 2. CONCLUSIONS: Chromosome alterations are wide-spread in canine mammary tumors, but no ras family mutations were detected in tumors from these 10 dogs. CLINICAL RELEVANCE: Knowledge about chromosome, oncogene, and tumor suppressor gene damage could be helpful for diagnosis and prognosis of neoplastic diseases in dogs.