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Biomedical subjects

R Holm

Publications and source records attributed to R Holm.

At least 91 records · Page 5Linked to original sources
PubMed1993

p53 abnormalities in different subtypes of human sarcomas.

In this report we examined p53 alterations at the DNA, mRNA, and protein levels on tissue from 39 patients with different subtypes of sarcoma. Loss of heterozygosity for the chromosome 17p region was found in 60, 63, and 33% of 10 informative osteosarcomas, 11 malignant fibrous histiocytomas, and 6 leiomyosarcomas, respectively. In addition, 2 of 10 tumors belonging to a heterogeneous group of soft tissue sarcomas showed loss of heterozygosity. Elevated levels of p53 mRNA were found in six tumors, four had a truncated transcript, and in six patients no mRNA was detected. In most cases, elevated transcript levels were accompanied by overexpression of protein as studied by immunohistochemistry, whereas the presence of truncated transcripts was associated with negative immunostaining. Point mutations in exons 5, 7, or 8 of the TP53 gene were detected in seven tumors. Six of these expressed high levels of mRNA and protein, probably reflecting a point mutation in one of the alleles and loss of the other. Three of the mutations have not previously been described. Taken together, p53 abnormalities were found in approximately 65% of the osteosarcomas, malignant fibrous histiocytomas, and leiomyosarcomas examined and in 30% of the other soft tissue tumors. The results indicate that the TP53 gene is involved in the tumorigenesis of several sarcoma subtypes in a higher fraction of cases than was previously recognized.

Base Sequence↗
PubMed1993

[Transgenic mice as animal model of Cushing's syndrome].

Transgenic mice were generated with the polyoma early region promoter linked to cDNA encoding polyoma large T antigen (PyLT). Light microscopic examination showed up to 5 mm large pituitary adenomas in clinically ill transgenic mice. The tumour cells showed positive ACTH immuno-reactivity. The adrenal glands of clinically ill mice showed an increase in weight and exhibited medullary hyperplasia. These findings were unexpected, and might have been caused by transgene expression in the neuroendocrine cells of the adrenal medulla. Plasma ACTH measurements showed significantly increased levels in clinically ill PyLT-1 transgenic mice.

Adenoma↗
PubMed1993

No germline TP53 mutations detected in familial and bilateral testicular cancer.

Mutations in the TP53 gene are considered to be among the most common genetic alterations in human cancers. Both somatic and germline mutations have been found. Using polymerase chain reaction (PCR), constant denaturant gel electrophoresis (CDGE), and denaturing gradient gel electrophoresis (DGGE), we have examined 32 patients with bilateral and familial germ cell tumors (GCT) and two patients with sporadic GCT for germline mutations within the conserved regions of the gene. In addition, 15 tumors were screened for somatic mutations and analyzed for loss of heterozygosity (LOH) at the TP53 locus. Twelve tumors were analyzed for expression of TP53 via immunohistochemistry. Neither germline nor somatic TP53 mutations were detected. LOH was observed in one of five informative cases. No tumors showed increased expression of TP53 protein. These results indicate that alterations in the TP53 gene are not important for the predisposition to and development of GCT.

Carcinoma in Situ↗
PubMed1993

Immunohistochemical analysis of p53 protein overexpression in normal, premalignant, and malignant tissues of the cervix uteri.

Two hundred and thirty-eight cervical lesions ranging from normal to malignant were examined for overexpression of p53 protein. Whereas p53 protein was identified in 62 per cent of invasive squamous cell carcinomas, 11 per cent of invasive adenocarcinomas, and 7 per cent of squamous cell carcinomas in situ, no staining was found in adenocarcinoma in situ, dysplastic tissue, condyloma, and normal tissue. In 9 per cent of the positive cases of invasive squamous cell carcinomas, 5-50 per cent of the tumour cells were immunoreactive for p53 protein, whereas the other positive specimens were characterized by only rare p53-positive cells. We conclude that in invasive cervical carcinomas widespread overexpression of p53 protein is unusual, but occasional positive nuclei can be found frequently. Furthermore, our results indicate that altered expression of p53 protein may be involved in the progression of cervical carcinomas.

Adenocarcinoma↗
PubMed1993

Genetic alterations of the TP53 gene, p53 protein expression and HPV infection in primary cervical carcinomas.

Primary cervical carcinomas from 92 patients were investigated for genetic alterations in the tumour suppressor gene TP53. Studies of allelic imbalance (AI) were performed by Southern blot analysis and by using two PCR (polymerase chain reaction) polymorphisms within the TP53 gene. AI in the tumour was observed in 22 per cent (11 of 52 informative patients) and was significantly associated with recurrence both in a univariate (P = 0.013) and in a multivariate (P = 0.045) analysis. The DNA samples were subjected to mutation analysis of four of the conserved domains in the TP53 gene, using PCR followed by constant denaturant gel electrophoresis (CDGE). Mutations were observed in 2 of 92 tumours (2 per cent), of which one was a silent mutation and the other a frameshift. Overexpression of the p53 protein was found by immunostaining of sections from formalin-fixed, paraffin-embedded material in 55 per cent (51/92) of the tumours. In 88 per cent (45/51) of these, overexpression was present in less than 5 per cent of the tumour cells. Overexpression was significantly associated with relapse-free survival only in a univariate analysis (P = 0.045). AI of the TP53 locus did not correlate with p53 expression or mutation. The important gene on 17p, responsible for the shorter disease-free survival for patients with AI of TP53, may therefore be another gene closely linked to TP53. In addition, the 92 tumour samples were tested for the presence of human papillomavirus (HPV) types 16 and 18. Fifty-four per cent (50/92) of the samples were positive for HPV 16 using in situ hybridization, and 93 per cent (86/92) using the PCR technique. The numbers for HPV 18 were 15 per cent (14/92) and 23 per cent (21/92), respectively. Twenty-one per cent (19/92) were positive for both HPV 16 and HPV 18, while 4 per cent (4/92) were negative for both HPV 16 and 18. The tumour with the frameshift TP53 mutation was HPV 16-positive, and the four samples negative for HPV 16 and 18 did not contain TP53 mutations within the conserved domains but had elevated p53 protein expression.

Adult↗
PubMed1993

Prognostic significance of TP53 alterations in breast carcinoma.

Constant denaturant gel electrophoresis (CDGE) was used to screen 179 breast carcinomas for mutations in the conserved regions of the TP53 gene (exons 5 through 8). Mutations were found in 35 of 163 primary tumours (21%) and in 5 of 16 metastases (31%) and resided predominantly in exon 7. The majority of the mutations were G:C-->A:T transitions. Immunohistochemistry demonstrated nuclear accumulation of p53 protein in 35 of 162 primary tumours (22%) and in four of 15 metastases (27%). TP53 mutation was strongly associated with nuclear accumulation of p53 protein. In total 42 of 163 primary tumours (26%) and 5 of 16 metastases (31%) were demonstrated to contain TP53 alterations (mutation and/or nuclear protein accumulation). TP53 alteration in primary tumour was significantly associated with the following parameters: positive node status, T status > 1, negative oestrogen receptor status, negative progesterone receptor status, presence of ERBB2 gene amplification, and invasive ductal histology. Furthermore, there were statistically significant associations, independent of other prognostic factors, between TP53 alterations in primary tumour and disease-free and overall survival.

Adult↗
PubMed1993

Squamous cell carcinomas. An immunohistochemical study of cytokeratins and involucrin in primary and metastatic tumours.

The expression of cytokeratins (CK) 1, 4, 5/6, 8, 13, 18, 19 and 20 and involucrin in 42 cases of squamous cell carcinomas from various locations was examined. The tumours expressed CK5/6 in 55%, CK8 in 76%, CK13 in 43% and CK19 in 95% of cases. The CK5/6-positive primary tumours were from uterine cervix, head and neck, lung, skin, oesophagus and urinary bladder, and the CK13-positive primary tumours were from uterine cervix, lung and vulva. Metastatic squamous cell carcinomas from head and neck more frequently expressed CK5/6 and 13, 7/7 (100%) and 6/7 (86%) compared with 3/5 (60%) and 0/5 (0%) in the primary squamous cell carcinomas. Few cases were CK1, CK4 and CK18 immunoreactive. CK20 immunoreactivity was not observed. Involucrin was expressed in 71% of tumours, and most of the involucrin-positive cells were located at the central parts of tumour cell clusters except for one case in which the peripheral cells around tumour cell clusters were positive. Thus, expression of the so-called simple epithelial markers CK8 and CK19 occurs in the majority of squamous cell carcinomas. The absence of CK20 immunoreactivity may be helpful in differential diagnosis.

Carcinoma, Squamous Cell↗
PubMed1993

Overexpression of p53 protein and c-erbB-2 protein in small cell carcinoma of the cervix uteri.

Twenty-eight primary small cell carcinomas of the cervix uteri were examined immunohistochemically for overexpression of p53 protein and c-erbB-2 protein. Twenty-one per cent of the cases showed positive immunostaining for p53 protein, whereas no staining was observed using the antibody against c-erbB-2. Our results indicate that altered expression of p53 protein may be involved in the development of small cell carcinoma of the cervix uteri.

Biomarkers, Tumor↗
PubMed1993

ACTH-producing pituitary tumors in transgenic mice. An ultrastructural and immunoelectron microscopic study.

Ultrastructural and electron microscopic immunohistochemical features of corticotropic pituitary tumors arising in polyoma large T transgenic mice and the corresponding tumor transplants in non-transgenic mice are reported. Spherical, irregular and drop-shaped secretory granules measuring 150-450 nm in diameter, were seen in all tumors. Both in tumors from transgenic mice and in tumor transplants immunoreactivity for adrenocorticotropic hormone (ACTH) and beta-endorphin was expressed in the majority of the secretory granules, whereas growth hormone (GH) immunoreactivity was demonstrated only in a small number of cells in tumors from transgenic mice. In addition, positive immunostaining for neuron-specific enolase (NSE) and synaptophysin was found in the two pituitary tumor transplants tested. The study shows that the pituitary tumors from transgenic mice and their tumor transplants have features similar to human corticotropic pituitary tumors, and may therefore be a valuable model for experimental studies of the tumorigenesis.

Adenoma↗
PubMed1992

P53 mutations in gastric carcinomas.

We carried out an immunohistochemical study and DNA analysis of 30 gastric carcinomas to evaluate p53 overexpression and allelic loss at 17p. The immunohistochemical study demonstrated immunoreactivity for p53 protein in four cases. Allelic loss for the pYNZ22.1 marker was detected in nine cases. In total, ten cases showed immunoreactivity for p53 protein, allelic loss, or both. The study of nine of these cases by constant denaturant gel electrophoresis revealed p53 mutations in three cases. We conclude that the prevalence of mutations of p53 in our series is similar to what has recently been observed in other cases of gastric cancer, but lower than in colon carcinomas.

Alleles↗
PubMed1992

In situ hybridization with nonisotopic probes using different detection systems.

In order to evaluate a sensitive nonisotopic in situ hybridization method for routine work in pathology laboratories, we compared seven different detection systems, using digoxigenin- and biotin-labeled probes. The sensitivity of these methods was tested on four cases of cervical condyloma all known to be positive for HPV 6. Four of these methods gave satisfactory results without any background staining. The single biotin method and the single digoxigenin method were equally sensitive, while the two triple biotin methods, using mouse anti-biotin/anti-mouse IgG/alkaline phosphatase mouse anti-alkaline phosphatase or mouse anti-biotin/alkaline phosphatase anti-mouse IgG/alkaline phosphatase mouse anti-alkaline phosphatase as the detection systems, tremendously improved the sensitivity. The enhanced sensitivity of the nonisotopic in situ hybridization method make it useful in investigation of pathologic tissues.

Biotin↗
PubMed1992

c-erbB-2 expression in primary gastric carcinomas and their metastases.

In an attempt to evaluate the relationship between c-erbB-2 expression and/or gene amplification, DNA ploidy and morphology, wall penetration, lymphatic permeation, and vascular invasion, we studied a series of 87 primary gastric carcinomas and their respective metastases (n = 335) using immunohistochemistry and performed DNA analysis of 30 primary tumors and 10 metastases from eight cases. Flow cytometry of fresh or frozen material was performed in 79 primary tumors. Five out of 87 primary tumors (5.7%) and 17 out of 335 lymph node metastases (5.1%) showed unequivocal membrane immunostaining for c-erbB-2. Seven out of 30 primary tumors (23.3%) showed gene amplification while amplification was identified in four out of 10 metastases (40.0%) from three patients. Eight tumors (9.2%) showed c-erbB-2 protein immunoreactivity, gene amplification, or both. One of these cases showed c-erbB-2 protein immunoreactivity only in the metastatic deposits, while gene amplification could be identified in the primary tumor. Three primary tumors showed gene amplification, but immunoreactive cells could not be identified. In no case was protein overexpression identified in the absence of gene amplification. Five cases with c-erbB-2 expression/amplification were well/moderately differentiated, and all the eight cases with c-erbB-2 expression/amplification disclosed aggressive features. Lymphatic permeation/lymph node metastases were found in all the cases and seven cases showed vascular invasion as well. In one case, there was also a liver metastasis. Two cases were early gastric carcinomas (T1sm) showing lymphatic permeation/nodal metastases and venous invasion. Six cases were aneuploid.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Lectin histochemistry and ultrastructure of medullary carcinoma of the thyroid gland.

Lectin histochemistry and electron microscopy were used to study a series of 13 solid or microacinar medullary carcinomas of the thyroid (MCTs) and compare them with four follicular MCTs and other forms of thyroid cancer. Lectin histochemistry was not found to be of diagnostic value, since the MCT did not display any distinct lectin-binding pattern. This approach demonstrated that all MCTs, irrespective of their histologic appearance, consist of polarized cells, arranged into microfollicles that can be demonstrated readily by electron microscopy. We conclude that all MCTs form follicles, some visible by light microscopy, while others are submicroscopic and apparent only on histochemical staining. Because of the histochemical and ultrastructural similarities between solid MCTs and tumors with a follicular pattern, the latter should not be considered a distinct variant of C-cell neoplasia.

Adult↗
PubMed1989

Null cell adenomas of the pituitary gland. An immunohistochemical study.

Fourteen null cell adenomas of the pituitary gland were examined immunohistochemically with antisera against three general neuroendocrine markers and 22 hormones. All cases showed positive immunostaining for neuron-specific enolase, ten cases for synaptophysin, and six cases expressed chromogranin immunoreactivity. Hormone immunoreactivity was detected in a few cells in ten of the 14 cases studied and the number of hormones demonstrated in each case was one or two. Thyroid-stimulating hormone was detected in five of the 14 cases, gastrin in four, beta-endorphin in two, calcitonin gene related peptide in one, prolactin in one, and follicle-stimulating hormone in one.

Adenoma↗
PubMed1989

Ultrastructural and electron immunohistochemical features of medullary thyroid carcinoma.

An ultrastructural study, both morphological and immunohistochemical, has been carried out on eight thyroglobulin-positive and nine thyroglobulin-negative medullary carcinomas of the thyroid. The morphometric analysis of granule size showed that all tumours contained cells with small granules and cells with medium size granules, whereas eight tumours had additional cells with large granules. The small granules had an electron dense core, while the medium and large sized granules were both pale-cored and dense-cored. The cells with small, medium or large secretory granules were all immunoreactive for calcitonin and CGRP. No ultrastructural differences were observed between thyroglobulin-positive and thyroglobulin-negative cases of medullary carcinoma of the thyroid.

Adult↗