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Biomedical subjects

I Goldberg

Publications and source records attributed to I Goldberg.

At least 127 records · Page 7Linked to original sources
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

The cloning and characterization of a murine secretory leukocyte protease inhibitor cDNA.

Human secretory leukocyte protease inhibitor (hSLPI) is produced by epithelial cells at mucosal surfaces, where it regulates both the neutrophil-mediated inflammation that characterizes inflammatory diseases, and pathogens themselves via both antiprotease and "defensin-like" activities. Additionally, hSLPI may regulate other processes such as cutaneous desquamation and placental invasiveness. To better understand the primary physiologic roles of SLPI, it will be important to establish a genetically tractable animal model, the most attractive candidate being the mouse. In this report, the cloning and characterization of murine (m) SLPI is described. mSLPI is encoded by a single copy gene, and appears structurally highly similar to hSLPI. At the same time, significant differences between mSLPI and hSLPI are presented, notably a difference in expression pattern, and a structural difference in the protease binding site that correlates with a difference in the spectrum of protease inhibiton. Such species-specific evolution of this protease inhibitor is notable given that species-specific structure-function differences have previously been reported for the alpha-1 antitrypsin family.

Amino Acid Sequence↗
PubMed1997

Overexpression of cytosolic malate dehydrogenase (MDH2) causes overproduction of specific organic acids in Saccharomyces cerevisiae.

Saccharomyces cerevisiae accumulates L-malic acid through a cytosolic pathway starting from pyruvic acid and involving the enzymes pyruvate carboxylase and malate dehydrogenase. In the present study, the role of malate dehydrogenase in the cytosolic pathway was studied. Overexpression of cytosolic malate dehydrogenase (MDH2) under either the strong inducible GAL10 or the constitutive PGK promoter causes a 6- to 16-fold increase in cytosolic MDH activity in growth and production media and up to 3.7-fold increase in L-malic acid accumulation in the production medium. The high apparent Km of MDH2 for L-malic acid (11.8 mM) indicates a low affinity of the enzyme for this acid, which is consistent with the cytosolic function in the enzyme and differs from the previously published Km of the mitochondrial enzyme (MDH1, 0.28 mM). Under conditions of MDH2 overexpression, pyruvate carboxylase appears to be a limiting factor, thus providing a system for further metabolic engineering of L-malic acid production. The overexpression of MDH2 activity also causes an evaluation in the accumulation of fumaric acid and citric acid. Accumulation of fumaric acid is presumably caused by high intracellular L-malic acid concentrations and the activity of the cytosolic fumarase. The accumulation of citric acid may suggest the intriguing possibility that cytosolic L-malic acid is a direct precursor of citric acid in yeast.

Citric Acid↗
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

Differential cytokine regulation of complement proteins in human glomerular epithelial cells.

We have previously shown in inbred strains of mice which naturally develop systemic lupus erythematosus that kidney C3, C2, C4 and factor B gene expression increases coincidently with the occurrence of glomerulonephritis, suggesting that local tissue complement gene expression could contribute to the pathogenesis of immune complex injury. In this study, we investigated the synthesis of complement proteins in glomerular epithelial cells (GECs) and its regulation. Using biosynthetic labelling, immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis, we demonstrated that GECs synthesized C1r, C1s, C1 inhibitor, C3, C2 and factor B. Interferon-gamma induced increases in the synthesis of all these proteins. Both factor B and C3 proteins were increased following addition of either IL-1beta, IL-6 or TNF-alpha to GEC cultures; however, these cytokines did not increase either C2, C1r, C1s or C1-inhibitor biosynthesis. Lipopolysaccharide affected the biosynthesis of these proteins in a similar way. A semiquantitative analysis of the mRNA expression of some of these proteins by reverse-transcriptase polymerase chain reaction showed that these cytokine effects were pretranslational as there was enhancement of factor B mRNA expression by IL-1, TNF-alpha, IFN-gamma, IL-6 and endotoxin, but only IFN-gamma enhanced C1-inhibitor and C4 mRNA expression. These results may be of significance in the immunopathogenesis of glomerulonephritis, where it is likely that local complement production in GECs is independently regulated by cytokines, derived from resident glomerular mesangial cells or infiltrating monocyte/macrophages and T cells.

Animals↗
PubMed1996

Pathogenic role of anti-endothelial cell antibodies in vasculitis. An idiotypic experimental model.

Idiotypic manipulation of naive mice has previously been used for induction of systemic autoimmune diseases (e.g., antiphospholipid syndrome, systemic lupus erythematosus, and Wegener's granulomatosis). The aim of this study focused on the utilization of this technique to induce the production of anti-endothelial cells Abs (AECA) and autoimmune vasculitis in a murine model. AECA were derived from a Wegener's granulomatosis patient's plasma. IgG was purified by absorption on a proteinase-3 affinity column resulting in the depletion of anti-neutrophil cytoplasmic Ab activity. The absorbed IgG fraction displayed a high titer of AECA as evidenced by a cyto-ELISA against unfixed human umbilical vein endothelial cells. BALB/c mice were actively immunized with the purified AECA. Three months after a boost injection with the human AECA, mice developed endogenous AECA (AB), but not Abs to proteinase-3, cardiolipin, or DNA. Histologic examination of lungs and kidneys revealed both lymphoid cell infiltration surrounding arterioles and venules; as well as deposition of Igs at the outer part of blood vessel walls. This experimental animal model of vasculitis, a product of our method of idiotypic manipulation, provides the first direct proof for the pathogenicity of AECA.

Animals↗
PubMed1996

The safety of topical beta-blockers in glaucoma treatment.

While adverse effects are uncommon in patients who are otherwise fit and well, doctors should be aware of the implications of the systemic effects of these drugs, particularly the non-selective types, and particularly in the elderly.

Adrenergic beta-Antagonists↗
PubMed1996

The cytosolic pathway of L-malic acid synthesis in Saccharomyces cerevisiae: the role of fumarase.

Saccharomyces cerevisiae accumulates L-malic acid but not only minute amounts of fumaric acid. A 13C-nuclear magnetic resonance study following the label from glucose to L-malic acid indicates that the L-malic acid is synthesized from pyruvic acid via oxaloacetic acid. From this, and from previously published studies, we conclude that a cytosolic reductive pathway leading from pyruvic acid via oxaloacetic acid to L-malic acid is responsible for the L-malic acid production in yeast. The non-production of fumaric acid can be explained by the conclusion that, in the cell, cytosolic fumarase catalyzes the conversion of fumaric acid to L-malic but not the reverse. This conclusion is based on the following findings. (a) The cytosolic enzyme exhibits a 17-fold higher affinity towards fumaric acid than towards L-malic acid; the Km for L-malic acid is very high indicating that L-malic acid is not an in vivo substrate of the enzyme. (b) Overexpression of cytosolic fumarase does not cause accumulation of fumaric acid (but rather more L-malic acid). (c) According to 13C NMR studies there is no interconversion of cytosolic L-malic and fumaric acids.

Carbonyl Cyanide m-Chlorophenyl Hydrazone↗
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↗
PubMed1996

Lipid metabolism.

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Carrier Proteins↗
PubMed1996

Standards.

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Australia↗
PubMed1996

Activated protein C resistance--low incidence in glaucomatous optic disc haemorrhage and central retinal vein occlusion.

PURPOSE: Activated protein C (APC) resistance has recently been reported as conferring a sevenfold increase in the risk of venous thrombosis. It is linked to a genetic mutation in the factor V gene which occurs commonly (about 2% to 4% of the community have the mutation). Glaucoma patients with nerve fibre layer (NFL) haemorrhages on the optic disc and patients with central retinal vein occlusion (CRVO) were tested for APC resistance to determine if there was an association. METHODS: Twenty-three patients with glaucomatous NFL haemorrhages and 23 patients with CRVO were tested. The CRVO cases included 11 with relatively young age of onset (mean 45.1 +/- 6.9 years) without conventional vascular risk factors. Eighty randomly selected Red Cross blood donor samples and 33 staff members were tested as controls. Clotting times with and without exogenous APC were recorded and an APC ratio determined. Cases with APC resistance were tested to confirm that they had the factor V Leiden gene. RESULTS: No cases of APC resistance were identified in the glaucoma patients and only one of the younger CRVO patients tested positive, but four of 113 controls tested positive. The difference in prevalence between groups is not significant. The mean APC ratios for the three groups were very similar: NFL haemorrhages 5.46(+/- 1.62), CRVO 5.70(+/- 1.56), controls 5.34 ( +/- 1.19) p > 0.5. CONCLUSION: There was not clear association detected between glaucomatous NFL haemorrhages or CRVO and APC resistance in this sample of patients. This negative finding is important due its known association with venous thrombosis elsewhere in the body.

Adult↗
PubMed1996

Libman-Sacks endocarditis in the antiphospholipid syndrome: immunopathologic findings in deformed heart valves.

OBJECTIVE: To examine the potential immunologic mechanism and involvement of antiphospholipid antibodies in the pathogenesis of heart valve lesions in patients with the antiphospholipid syndrome (APS). METHODS: Immunoperoxidase and immunofluorescence staining methods were used to evaluate 13 heart valve specimens derived from eight patients with the APS, either primary or secondary to systemic lupus erythematosus. Primary antibodies to human immunoglobulins, complement components, serum albumin and a monoclonal anti-idiotypic antibody to human anticardiolipin antibodies (aCL) were employed. Various tissue specimens from a patient with the APS as well as deformed and normal valves from subjects without the APS were used as controls. RESULTS: Linear subendothelial deposition consisting of immunoglobulins with complement components but not of a non-specific serum protein was found in deformed valves from patients with the APS. None of the control valves or tissues disclosed similar deposition. The same pattern and location of staining was obtained by the anti-idiotypic antibody to aCL. A significant amount of IgG immunoglobulins that bound to cardiolipin was eluted from a valve of a patient with secondary APS. CONCLUSION: Deposits of immunoglobulins including aCL, and of complement components, are common in affected valves of patients with primary and secondary APS. Such deposits may be involved in the pathogenesis of valvular lesions.

Adult↗