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Biomedical subjects

J Kopolovic

Publications and source records attributed to J Kopolovic.

At least 19 recordsLinked to original sources
PubMed1998

Rates of Jewish ancestral mutations in BRCA1 and BRCA2 in borderline ovarian tumors.

BACKGROUND: Germline mutations in the BRCA1 and BRCA2 genes are known to be associated with an increased risk of breast and epithelial ovarian cancers. Two specific mutations, 185delAG-BRCA1 and 6174delT-BRCA2, have been detected in a substantial proportion (20%-60%) of unselected Ashkenazi Jewish patients--i.e., Jewish patients of Eastern/Northern European descent--with invasive ovarian cancer and in a measurable proportion (2%) of the general Ashkenazi Jewish population. However, uncertainty exists concerning the heritable basis of borderline ovarian tumors and whether these tumors represent an early form of ultimately invasive disease. To gain insight into these issues, we determined the rates of 185delAG-BRCA1 and 6174delT-BRCA2 mutations in patients with borderline ovarian tumors. METHODS: Analysis of 185delAG-BRCA1 and 6174delT-BRCA2 germline mutations was performed by use of a heteroduplex formation assay in samples from 46 consecutive patients with borderline ovarian tumors and 59 consecutive patients with invasive epithelial ovarian cancers. Forty-eight samples were also analyzed by restriction enzyme analysis for the presence of the 5382insC-BRCA1 mutation, a mutation detected in 2.2% of Ashkenazi Jewish patients with breast, but not ovarian, cancer. RESULTS: One (2.2%) of the 46 patient with borderline tumors was identified as a carrier of the 185delAG-BRCA1 mutation, and no patients were found to carry the 6174delT-BRCA2 mutation. Nineteen (32%) of the 59 patients with invasive ovarian cancer were found to carry one of these two mutations; 17 carried 185delAG-BRCA1 and two carried 6174delT-BRCA2 (chi2 test with continuity correction, P = .00028). None of the patients analyzed for 5382insC-BRCA1 were found to carry the mutation. In one high-risk family that included 185delAG-BRCA1 carriers, a single patient with stage IIIc borderline ovarian tumor did not carry the mutation. CONCLUSIONS: Invasive epithelial and borderline ovarian tumors appear to differ in their genetic predisposition and in the molecular mechanisms underlying their genesis.

Female↗
PubMed1998

Borderline tumors of the ovary: fertility treatment, conservative management, and pregnancy outcome.

BACKGROUND: Ovarian tumors of borderline malignancy have a less aggressive behavior and tend to occur at a younger age than their invasive counterparts. The role and extent of fertility-sparing conservative treatments is under continuous evaluation. METHODS: The current study was a retrospective review of 82 patients with confirmed borderline tumors diagnosed over a 25-year period, with special focus on fertility-associated issues. RESULTS: Follow-up was available for 96% of the patients, for a total of 357 women-years of follow-up. Thirty-nine patients underwent conservative management. Of these, only three patients had a contralateral recurrence. Two of the three again opted for conservative management and were without evidence of disease at last follow-up. Seventeen patients did benefit from contralateral ovarian dissection either by cystectomy or oophorectomy because of contralateral benign or borderline disease. Eleven patients had received or were scheduled to receive ovulation induction. Five patients were diagnosed during the evaluation, and another two were diagnosed so soon after the initiation of ovulation induction that a causative relationship appeared to be unlikely. Six patients were diagnosed during ongoing pregnancies. Twenty-two pregnancies were achieved in 15 patients after conservative treatment. No influence of the disease or its treatment on the pregnancy (or vice versa) was observed during a mean follow-up of 69 months. CONCLUSIONS: Data are accumulating that indicate conservative fertility-sparing disease management is adequate treatment for patients with borderline tumors. Available data indicate that in these patients fertility, pregnancy outcome, and survival remain excellent.

Adenocarcinoma, Mucinous↗
PubMed1998

Expression of matrix proteins in uterine cervical neoplasia using immunohistochemistry.

OBJECTIVE: Neoplastic cells of various tumors are capable of modifying extracellular matrix, and can reduce basement membrane components and express matrix proteins and mRNA. Findings in cervical cancer cells have been consistent concerning their ability to reduce basement membrane, but there is a lack of consensus concerning the expression of matrix proteins in the neoplastic cells. We have investigated the expression of matrix proteins in the subepithelial basement membrane, in blood vessels and in the epithelial cells using immunohistochemistry. STUDY DESIGN: A total of 49 cases, including normal cervix, Cervical Intraepithelial Neoplastia (CIN) grades, I, II and III, and invasive squamous cell carcinoma, were stained for fibronectin (FN), laminin (LN) and collagen IV (C IV) and analyzed by immunohistochemistry. Subepithelial and peritumoral basement membrane staining for C IV was scored as 0, 1, 2 or 3 (0, absent; 1, weak and discontinuous; 2, weak or discontinuous; 3, strong and diffuse). Vascular basement membrane staining by all three markers was interpreted as positive or negative. Staining of normal epithelium, CIN lesions and invasive carcinoma cells was evaluated with all three markers. RESULTS: Subepithelial basement membrane staining was graded as score = 3 in all normal cervices, in contrast to 9/10, 2/10, 1/10 and 0/9 cases of CIN I, CIN, II, CIN III and invasive carcinoma, respectively. Remaining cases showed variable degrees of basement membrane loss. In 6/10 CIN III cases and 8/9 carcinomas, staining was absent (score = 0). Blood vessels stained positive for FN, LN and C IV in all cases studied. Epithelial cells were LN-positive in only one case of CIN II and FN-positive in only two cases of CIN III. Conversely, 3/9 carcinomas were LN-positive, 6/9 were FN-positive and 2/9 were C IV-positive, including two cases positive for all three markers. Staining pattern was cytoplasmic, mainly in the periphery to tumor islands. CONCLUSIONS: Invasive squamous cell carcinomas of the cervix are capable of expressing matrix proteins that are usually absent in normal squamous cervical cells or preinvasive lesions. Secretion or degradation of these proteins could facilitate tumor invasion of stroma and vessels. In addition, basement membrane dissolution becomes pronounced in CIN II-III lesions, being complete in most invasive carcinomas, probably reflecting the ability of pre-invasive neoplastic cells to degrade basement membrane components with metalloproteases.

Basement Membrane↗
PubMed1998

Immunohistochemical analysis of rasGTPase activating protein (rasGAP) in prostate cancer.

The ras protooncogene plays a key role in the signal transduction cascade of activated growth factors, and is known to be activated or overexpressed in multiple tumor types, including prostate cancer. rasGTPase activating protein (rasGAP), a major downregulator of ras activity, has been shown to be underexpressed in human trophoblastic tumors, and presumably acts as a tumor suppressor gene product in these neoplasms. To assess the role that rasGAP plays in the development of prostate cancer, we performed immunohistochemical analyses with anti rasGAP antibodies of 125 human prostate tumors from Israel. Staining results were correlated with Gleason grade. In the majority of tumors (99/125-79%) there was either no staining or the tumor and surrounding benign glands had a similar pattern of staining. In up to 16% of the tumors, cytoplasmic, tumor-specific loss of expression was noted, presumably indicative of the role of rasGAP as a tumor suppressor gene. Unexpectedly, in up to 21% of the tumors, nuclear staining was demonstrated, and in about 20% of these, there was an accompanying loss of expression in the non neoplastic cytoplasm. Neither cytoplasmic nor nuclear staining correlated with Gleason grade. These findings of nuclear staining by anti-rasGAP are intriguing, since it is the first time that nuclear translocation of rasGAP is demonstrated, which might indicate that in this subset of tumors, rasGAP acts as a direct acting oncogene. The data indicate that rasGAP may play a dual regulatory role in prostate proliferation and that nuclear expression of it may be associated with malignant transformation of these cells.

Adenocarcinoma↗
PubMed1998

Ulex Europaeus lectin and anti-CD31 staining in squamous cell carcinoma of the uterine cervix: potential prognostic markers.

Seventy-five squamous cell carcinomas of the uterine cervix and 10 controls were stained for Ulex Europaeus lectin 1 (UEA-1) and anti-CD31, and the results were analyzed with respect to patient age, clinical stage, tumor grade, and survival during a follow-up period of 1 to 13 years. The patients' mean age at the time of diagnosis was 47.8 years (range, 27 to 83). Seventeen patients died of disease, 2 had disease recurrence, and 51 patients remained free of disease; 5 patients were lost to follow-up. Twenty-eight cases (37.3%) showed focal membranous staining for UEA-1 and 9 cases (12%) showed a diffuse pattern; 38 cases (50.7%) were UEA-1 negative. Poor survival was related to diffuse membranous UEA-1 immunoreactivity (p = 0.02), age (p = 0.014), grade (p = 0.02), and stage (p = 0.0002). CD31-positive neoplastic cells displayed a cytoplasmic pattern. Fifteen cases (20%) had diffuse staining and another 15 (20%) stained focally; 45 cases (60%) were CD31-negative. The adjacent nonneoplastic epithelium and all 10 controls were uniformly negative for CD31. Variable staining of the endocervical epithelium and weak or negative staining of ectocervical epithelium for UEA-1 were observed. However, the epithelium in all controls was negative for UEA-1. Poor survival was related to both focal and diffuse staining for CD31 (p = 0.01 and p = 0.03, respectively). Staining by both UEA-1 and anti-CD31 retained its correlation with survival after exclusion of stage la tumors.

Adult↗
PubMed1998

CD44 expression in normal adrenal tissue and adrenal tumours.

BACKGROUND: CD44 is a cell surface glycoprotein found on many normal cells, mainly lymphoid and epithelial. Normal cells usually express standard CD44 (CD44-S), whereas malignant tumours may express CD44 variant isoforms (CD44-V). CD44 expression has been described for neural crest derivatives. Characterisation of differences in CD44 expression may help in the diagnosis and differentiation of distinct adrenal tumours. AIMS: To examine CD44 expression in different layers of cortical cortex, in adrenal medulla, and in adrenal tumours. METHODS: CD44-S and CD44-V6 expression were studied in 12 cases of adrenal cortical adenoma, 3 of adrenal cortical carcinoma, 10 of pheochromocytoma, and 4 normal adrenal glands. RESULTS: CD44-V6 staining showed cytoplasmic expression in normal adrenal cortex and in cortical adenomas and carcinomas. Pheochromocytomas also showed CD44-V6 expression but in 5 of the 10 cases it was sparse, focal, and sometimes perinuclear. Strong membranous staining for CD44-S was observed in normal adrenal medulla. Analysis of CD44-S expression revealed differences between cortical adrenal tumours and pheochromocytomas. Ten of 12 cortical adenomas and 2 of 3 cortical carcinoma cells showed weak to moderate cytoplasmic staining, but all cases of pheochromocytoma had strong membranous staining. CONCLUSIONS: Membranous CD44-S staining may help to distinguish pheochromocytoma from adrenal cortical adenoma.

Adrenal Cortex↗
PubMed1998

CD44 expression in uterine cervical intraepithelial neoplasia and squamous cell carcinoma: an immunohistochemical study.

CD44 is an integral membrane glycoprotein, functioning as the receptor for hyaluronic acid. CD44 is expressed on epithelial, mesenchymal, lymphoid, and glial cells. CD44 distribution, pattern of staining, and isoform types are altered in neoplastic conditions, including cervical dysplasia and carcinoma. We have studied CD44 expression by immunohistochemistry in 49 patients with cervical intraepithelial neoplasia (CIN) I, II, III invasive squamous cell carcinoma of the uterine cervix and controls. Only membranous staining was considered positive. Diffuse membranous staining was observed in all controls and CIN I cases, but only in 7/10, 3/10, and 4/9 cases of CIN II, CIN III and squamous cell carcinoma, respectively. The remaining cases showed either complete lack of staining, only focal membranous staining or only diffuse inconsistent (weak/cytoplasmic/fragmented) staining. Three invasive carcinomas showed both areas of membranous staining and areas of inconsistent staining in the same section. No correlation was observed between tumor grade and CD44 pattern of staining. Human papillomavirus (HPV) was found in 24/29 high-grade intraepithelial lesions and carcinomas. HPV expression did not correlate with CD44 staining. In conclusion, CD44 expression was found to be reduced in more than 50% of high-grade intraepithelial neoplastic lesions and invasive carcinomas. This might be associated with the loss of cellular adhesion characteristics of pre-invasive and invasive lesions. HPV presence did not seem to influence CD44 expression.

Carcinoma, Squamous Cell↗
PubMed1998

Expression of rasGTPase activating protein in basal cell carcinoma of the skin.

The ras proto-oncogene, a key component in the signal transduction cascade of activated growth factors, is involved in multiple tumor types, including basal cell carcinoma (BCC). rasGTPase activating protein (rasGAP), is a dual function protein in the ras signaling pathway, i.e., it downregulates activated ras via its catalytic domain, and it also participates in the downstream effector signaling pathway by mediating protein-protein interaction. Missense mutations presumably leading to rasGAP activation were previously detected in this gene, in a subset of BCCs. To assess the role of rasP21 and rasGAP in BCC tumorigenesis, we performed an immunohistochemical analysis of 48 BCCs, of which 45 were of the circumscribed variant (indolent-growth tumors) and the remaining 3 (2 morpheaform, 1 infiltrative), were aggressive-growth variants. rasGAP overexpression was demonstrated in 7 of 48 BCC cases, i.e., in 4 (8.8%) of 45 indolent-growth cases and in all of the 3 aggressive-growth cases. We detected tumor-specific reduction of rasP21 levels in 5 (11.1%) of 45 cases. There was no overlap between the tumors displaying rasGAP and rasP21 alternations and a high proliferation index, as assessed by Ki-67 staining, except for one case of aggressive-growth variant. We conclude that rasGAP overexpression is associated with BCC tumorigenesis in a ras-independent manner, is not reflective of the proliferation status of the tumor, and is more characteristic of aggressive-growth BCCs.

Biomarkers, Tumor↗
PubMed1997

DAP kinase links the control of apoptosis to metastasis.

DAP kinase is a new type of calcium/calmodulin-dependent enzyme that phosphorylates serine/threonine residues on proteins. Its structure contains ankyrin repeats and the 'death' domain, and it is associated with the cell cytoskeleton. The gene encoding DAP kinase was initially isolated as a positive mediator of apoptosis induced by interferon-gamma, by using a strategy of functional cloning. We have now tested whether this gene has tumour-suppressive activity. We found that lung carcinoma clones, characterized by their highly aggressive metastatic behaviour and originating from two independent murine lung tumours, did not express DAP kinase, in contrast to their low-metastatic counterparts. Restoration of DAP kinase to physiological levels in high-metastatic Lewis carcinoma cells suppressed their ability to form lung metastases after intravenous injection into syngeneic mice, and delayed local tumour growth in a foreign 'microenvironment' Conversely, in vivo selection of rare lung lesions following injection into syngeneic mice of low-metastatic Lewis carcinoma cells or of DAP kinase transfectants, was associated with loss of DAP kinase expression. In situ TUNEL staining of tumour sections revealed that DAP kinase expression from the transgene raised the incidence of apoptosis in vivo. DAP-kinase transfectants also showed increased sensitivity in vitro to apoptotic stimuli, of the sort encountered by metastasizing cells at different stages of malignancy. We propose that loss of DAP kinase expression provides a unique mechanism that links suppression of apoptosis to metastasis.

Animals↗
PubMed1997

[Pulmonary alveolar microlithiasis presenting with prolonged cough].

A 40-year-old man had been followed in the pulmonary clinic for prolonged cough. Chest X-ray showed bilateral diffuse interstitial infiltrates with accentuation toward the bases. CT-scan demonstrated a fine diffuse reticulonodular pattern. Transbronchial lung biopsy showed pulmonary alveolar microlithiasis, a rare disease characterized by the presence of concentric calcifications within the pulmonary alveoli. This is the second case of the disease reported in Israel.

Adult↗
PubMed1997

Inflammatory response in cervical intraepithelial neoplasia and squamous cell carcinoma of the uterine cervix.

Leukocytic infiltrates are a morphologic feature of most solid tumors, including uterine cervical intraepithelial neoplasia (CIN) and invasive carcinoma. We have studied 50 cases of CIN I, CIN II, CIN III, invasive carcinoma and normal controls in order to evaluate the inflammatory response. Two markers--CD68, a macrophage-specific marker, and ICAM-1, present on leukocytes, blood vessels and epithelial cells--were employed. Results have demonstrated similar inflammatory cell counts in normal, CIN II and CIN III lesions by both markers, and lower counts for CIN I. Invasive carcinomas demonstrated a statistically significant increase in infiltrate density by both CD68 (p < 0.002) and ICAM-1 (p < 0.05). Macrophage density by either marker did not correlate with Human Papillomavirus (HPV) presence, specific type, or evidence of co-infection with several types. We conclude that the inflammatory response to cervical intraepithelial-neoplasia is inadequate. The elevated cell counts in invasive carcinomas may reflect a reaction towards invasion rather than tumor-specific immune response. Depression of inflammation in CIN I lesions may be associated with active viral replication in these lesions.

Antigens, CD↗
PubMed1997

Angiogenesis in uterine cervical intraepithelial neoplasia and squamous cell carcinoma: an immunohistochemical study.

Changes in vascular patterns aid in the colposcopic diagnosis of cervical neoplasia. We have studied vessels in 50 cases of normal cervix, cervical intraepithelial neoplasia (CIN I, II, III), and invasive carcinoma by two markers, Von-Willebrand factor (VWF) and ulex europaeus lectin I. With both markers, an increase in microvessel counts parallel to neoplastic progression was seen, with highest counts observed in CIN III. Average counts for ulex lectin and VWF increased from approximately 6 vessels per field in normal cervices to 15 vessels per field in CIN III. For each diagnostic group, comparable numbers of vessels were stained by both markers, with a slight preponderance of VWF in invasive carcinomas and of ulex lectin in noninvasive lesions. No correlation was found between microvessel count and human papilloma virus (HPV) by in situ hybridization. We conclude that enhanced microvessel density occurs in cervical neoplasia. The vessels are mostly blood vessels, not lymphatics. Therefore, the role of enhanced microvessel density in tumor spread remains to be proven.

Carcinoma, Squamous Cell↗
PubMed1997

Characterization of smoking-induced nasopharyngeal lymphoid hyperplasia.

The frequency of smoking-induced nasopharyngeal lymphoid hyperplasia in heavy smokers and its potential clinical implications are still unknown. Precise criteria to differentiate this entity from other types of nasopharyngeal lymphoid hyperplasia are needed. A prospective clinicopathological study of smoking-induced nasopharyngeal lymphoid hyperplasia was conducted in 17 heavy smokers. Ten nonsmoking patients, five of them with chronic sinusitis, three with adult-onset adenoid hypertrophy, and two children with adenoidal hypertrophy served as a control group. Both in smokers and in nonsmokers, lymphocytic infiltration of the mucosa was characterized immunohistochemically as T cells. In smokers, semithin (1 micron) sections revealed deformed and migrating cytotoxic lymphocytes in the nasopharyngeal mucosa. The lymphocytes were attached to epithelial, ciliated, and goblet cells, resulting in cell damage. Transmission electron microscopy of biopsies from smokers revealed emperipolesis, characterized by mucosal invasion and epithelial cell damage by an unusual population of migrating T lymphocytes that penetrate them. These findings confirm a direct effect of smoking on the nasopharyngeal lymphoid tissue, which forms part of the immune system. It is concluded that the diagnostic evaluation and therapeutic approach of heavy smokers with otological and airway symptoms should be based on thorough endoscopic examination of the nasopharynx. When the diagnosis is not clear-cut, selective tele-endoscopic biopsy and electron microscopic examination are recommended. This entity should be added to the list of known clinical manifestations of the smoking habit.

Adenoids↗
PubMed1997

The use of porphyrins for eradication of Staphylococcus aureus in burn wound infections.

The assessment of deuteroporphyrin-hemin complex as an agent for the treatment of burn wounds infected with a multiple-drug resistant strain of Staphylococcus aureus was performed. The effect of the porphyrin on the survival of the infectious bacteria was first assayed in culture, and later tested as well in a burned infected animal model. The addition of deuteroporphyrin and hemin, separately or together (as a complex) to a growing culture of S. aureus was monitored during 8 hours. It was found that deuteroporphyrin alone was strongly bactericidal only after photosensitization. On the other hand, hemin alone was moderately bactericidal but light independent. A combination of both deuteroporphyrin and hemin was extremely potent even in the dark and did not require illumination to eradicate the bacteria. The in vivo experiments by application of the above porphyrins in combination to infected burn wounds in guinea pigs was an effective way to reduce dramatically the contaminating S. aureus. Reduction of more than 99% of the viable bacteria was noted after the porphyrin mixture was dropped on the eschar or injected into the eschar, an effect that lasted for up to 24 hours. The deuteroporphyrin-hemin complex may be suggested as a new bactericidal treatment of S. aureus infected burns since it was found to be a potent and promising anti-Staphylococcal agent.

Administration, Topical↗
PubMed1997

Atherosclerosis in LDL-receptor knockout mice is accelerated by immunization with anticardiolipin antibodies.

Atherosclerosis is a process initiated by accumulation of macrophages in distinct areas of endothelial cell damage and uptake of large amounts of lipids. Recently, it has been shown that the immune system plays an active part in the progression of the atherosclerotic plaque although its precise role has not yet been elucidated. Anticardiolipin antibodies (aCL) are generally found in the sera of patients with the antiphospholipid syndrome (APS) and are associated with a prothrombotic state. Several authors have demonstrated that aCL can activate platelets and endothelial cells as well as increase oxidized low density lipoprotein (LDL) uptake by macrophages. In the present study we sought to assess the effect of immunization with aCL (Ab1, leading to the production of mouse aCL-Ab3) on the progression of atherosclerosis. Two groups of 8-weeks old female LDL-receptor knockout mice (n = 13 per group) were immunized with IgG purified from the serum of an APS patient or with normal human IgG, respectively. The aCL immunized mice developed high titres of 'self' aCL (detected using the standard aCL ELISA) as compared with the normal human IgG immunized mice, whereas no differences were noted between both study groups with respect to the serum lipid levels. The extent of fatty streak formation was significantly higher in the aCL immunized mice in comparison with the human IgG injected mice (mean aortic lesion size of 5308 +/- 471 microns2 vs 1027 +/- 184 microns2, respectively, P < 0.01). The immunohistochemical analysis of the atherosclerotic plaques from both mouse groups did not display differences in cellular composition. The results of the study show that mouse aCL induced by immunization with human aCL from an APS patient enhance atherogenesis in LDL-RKO mice and imply that these antibodies may play a role in atherosclerosis development in patients with the APS.

Animals↗
PubMed1996

Increased insulin-like growth factor binding protein-2 (IGFBP-2) gene expression and protein production lead to high IGFBP-2 content in malignant ovarian cyst fluid.

Expression of insulin-like growth factor-I (IGF-I), its receptor and IGF-binding proteins (IGFBPs) by ovarian cancer cells and its mitogenic effect on these cells in vitro, suggest that IGF-I may have a role in regulation of human ovarian cancer. We have recently shown IGFBP-2 to be markedly elevated in malignant ovarian cyst fluid in vivo. To identify the origin of increased IGFBP-2 in these cyst fluids, the gene expression and protein content of IGFBP-2 were investigated in 14 malignant and four benign epithelial ovarian neoplasms. IGFBP-2 mRNA was detected in all ovarian specimens and was 2- to 30-fold higher in malignant than in benign neoplasms. Within the malignant tissues IGFBP-2 mRNA levels correlated with the aggressiveness of the tumour and were higher in invasive tumours than in those with borderline pathology. Southern blot analysis revealed no amplification of IGFBP-2 gene in the DNA samples from ovarian tumours regardless of their nature. IGFBP-2 was the major binding protein in tissue extracts, as measured by both Western ligand blotting and immunoblotting, and was significantly higher in malignant than in benign neoplasms. These findings were further supported by immunohistochemical detection of IGFBP-2 in tumour sections. Our data suggest that increased local production by the tumour in vivo is responsible for the increased IGFBP-2 levels in the cyst fluid bathing the ovarian malignancy. This may represent an autocrine regulatory mechanism for IGF-I proliferative effect of ovarian cancer.

Blotting, Northern↗