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Biomedical subjects

A Karasik

Publications and source records attributed to A Karasik.

At least 19 recordsLinked to original sources
PubMed2001

Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Multiple outcomes of raloxifene evaluation.

Raloxifene, a selective estrogen receptor modulator approved for the prevention and treatment of postmenopausal osteoporosis, has shown a significant reduction in breast cancer incidence after 3 years in this placebo-controlled, randomized clinical trial in postmenopausal women with osteoporosis. This article includes results from an additional annual mammogram at 4 years and represents 3,004 additional patient-years of follow-up in this trial. Breast cancers were ascertained through annual screening mammograms and adjudicated by an independent oncology review board. A total of 7,705 women were enrolled in the 4-year trial; 2,576 received placebo, 2,557 raloxifene 60 mg/day, and 2,572 raloxifene 120 mg/day. Women were a mean of 66.5-years old at trial entry, 19 years postmenopause, and osteoporotic (low bone mineral density and/or prevalent vertebral fractures). As of 1 November 1999, 61 invasive breast cancers had been reported and were confirmed by the adjudication board, resulting in a 72% risk reduction with raloxifene (relative risk (RR) 0.28, 95% confidence interval (CI) 0.17, 0.46). These data indicate that 93 osteoporotic women would need to be treated with raloxifene for 4 years to prevent one case of invasive breast cancer. Raloxifene reduced the risk of estrogen receptor-positive invasive breast cancer by 84% (RR 0.16, 95% CI 0.09, 0.30). Raloxifene was generally safe and well-tolerated, however, thromboembolic disease occurred more frequently with raloxifene compared with placebo (p=0.003). We conclude that raloxifene continues to reduce the risk of breast cancer in women with osteoporosis after 4 years of treatment, through prevention of new cancers or suppression of subclinical tumors, or both. Additional randomized clinical trials continue to evaluate this effect in postmenopausal women with osteoporosis, at risk for cardiovascular disease, and at high risk for breast cancer.

Aged↗
PubMed2001

Activation of the insulin-like growth factor 1 signaling pathway by the antiapoptotic agents aurintricarboxylic acid and evans blue.

Aurintricarboxylic acid (ATA), an endonuclease inhibitor, prevents the death of a variety of cell types in culture. Previously we have shown that ATA, similar to insulin-like growth factor I (IGF-I), protected MCF-7 cells against apoptotic death induced by the protein synthesis inhibitor cycloheximide. Here we show that ATA and a polysulfonated aromatic compound, Evans blue (EB), similar to IGF-I, promote survival and increase proliferation of MCF-7 cells in serum-free culture medium. This may suggest a common signaling pathway shared by the aromatic polyanions and IGF-I. Therefore, the ability of these aromatic compounds to activate the signal transduction pathway of IGF-I was examined. We found that ATA and EB mimicked the IGF-I effect on tyrosine phosphorylation of the IGF-I receptor (IGF-IR) and its major substrates, insulin receptor substrate-1 (IRS-1) and IRS-2; induced the association of these substrates with phosphatidylinositol 3-kinase and Grb2; and activated Akt kinase and p42/p44 mitogen-activated protein kinases. ATA and EB competed for IGF-I binding to the IGF-IR. ATA was found to be selective for the IGF-IR, whereas EB also activated the insulin receptor. Upon fractionation of commercial ATA by size exclusion chromatography, we found that fractions that enhanced the intensity of tyrosyl-phosphorylated IRS-1/IRS-2 also increased the survival of MCF-7 cells in the presence of cycloheximide, whereas fractions devoid of IRS phosphorylation activity had no survival ability. Taken together, these results suggest that the survival/proliferation-promoting effects of ATA and EB in MCF-7 cells are transduced via the IGF-IR signaling pathway.

3T3 Cells↗
PubMed2000

Implantation of rat insulinoma cell line into cyclosporine treated rats. Effect of the in vivo environment on beta-cell specific gene expression.

BACKGROUND: Transplantation of engineered beta cell-derived lines is a promising modality for cell-based therapy of diabetes mellitus. The in vivo environment and antirejection and other medications may have significant effects on the differentiation and proliferation of the transplanted beta cells, thus affecting their function. The effect of the in vivo environment on expression of genes encoding proteins involved in insulin production, secretion, and glucose sensing were analyzed in the RIN 104638 cell line. METHODS: RIN 104638 cells, were used for s.c. implantation in cyclosporine treated rats and for parallel in vitro culture. The differential expression of the insulin, PDX-1, GLUT-2, and glucokinase genes were assessed by quantitative reverse transcription polymerase chain reaction. RESULTS: The in vivo environment of cyclosporine-treated rats, preserved most of the differentiated characteristics of the implanted cells. Insulin and glucokinase gene expression were maintained at high levels, although GLUT-2 expression decreased. This was in contrast to the substantial decrease of all the three genes expression when cultured in vitro. Cyclosporine treatment reduced insulin and GLUT-2 gene expression in in vitro culture. CONCLUSIONS: Beta cell implantation in cyclosporine-treated rats induces alteration in expression of genes pivotal to insulin production and secretion and the glucose sensing abilities. The normal in vivo environment improves the implanted b cell function by increasing the insulin gene expression and content. Furthermore, it reverses some of the dedifferentiating changes caused by the in vitro culture. This may have a positive effect on the therapeutic efficiency of this cell line.

Actins↗
PubMed2000

Mutation analysis of the MEN1 gene in Israeli patients with MEN1 and familial isolated hyperprolactinemia.

Multiple endocrine neoplasia type 1 (MEN-1) is characterized by hyperfunction and tumor formation of the parathyroids, anterior pituitary and endocrine pancreas. We carried out exon-specific, PCR-based DNA sequencing of the coding exons of the MEN1 gene in 8 Israeli MEN1 patients: 4 familial and 4 sporadic. We similarly analyzed Israeli families with a unique phenotype of isolated hyperprolactinemia (HPRL). Four mutations were detected in 4 MEN1 patients: C to T alteration at nucleotide 2608 resulting in R108X, and three intronic insertions/deletions (a 13 basepair (bp) deletion and a 1 bp insertion both in intron 1, and a 2 bp insertion in intron 3) leading to exonic frame shifts as they encompass the splice junctions. An additional patient exhibited a compound mutation: a G to T change at position 7614 resulting in E463X, and insertion/deletion of 9 bp at position 7622-7630 resulting in EAE466-468X. Haplotype analysis showed no segregation of phenotype with 11q13 markers in 4 familial HPRL, and no men 1 germline mutations were detected in three representative individuals, from 3 families. Our results confirm that men 1 gene germline mutations occur in the majority of patients with clinically diagnosed MEN1, and that familial HPRL is a genetically distinct disorder.

Adolescent↗
PubMed2000

Hypopituitarism following closed head injury.

We describe four young patients (age 19-34 years) with hypopituitarism following closed head injury. The diagnosis was made by demonstration of low basal pituitary hormone levels and dynamic tests showing low pituitary reserve. The time interval between the injury and diagnosis of hypopituitarism was between three weeks and two months demonstrating the difficulty and complexity of making this diagnosis. Three of our patients (all patients suffering from anterior pituitary hormone deficiency) had ACTH deficiency, a condition which may be life threatening if left undiagnosed; these patients also demonstrated central hypothyroidism. Hypogonadotrophic hypogonadism occurred in three of the patients and was treated with hormonal replacement. Diabetes insipidus was the only insult in one of our patients, accompanied other hormonal deficits in two, and did not appear at all in another patient. Information about skull damage was available for three of the patients, and included skull base and facial bone fractures, probably reflecting the extent of injury necessary to cause hypopituitarism. All patients regained normal lives with adequate hormonal replacement therapy.

Adrenocorticotropic Hormone↗
PubMed2000

Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia.

Insulin gene expression is restricted to islet beta cells of the mammalian pancreas through specific control mechanisms mediated in part by specific transcription factors. The protein encoded by the pancreatic and duodenal homeobox gene 1 (PDX-1) is central in regulating pancreatic development and islet cell function. PDX-1 regulates insulin gene expression and is involved in islet cell-specific expression of various genes. Involvement of PDX-1 in islet-cell differentiation and function has been demonstrated mainly by 'loss-of-function' studies. We used a 'gain-of-function' approach to test whether PDX-1 could endow a non-islet tissue with pancreatic beta-cell characteristics in vivo. Recombinant-adenovirus-mediated gene transfer of PDX-1 to the livers of BALB/C and C57BL/6 mice activated expression of the endogenous, otherwise silent, genes for mouse insulin 1 and 2 and prohormone convertase 1/3 (PC 1/3). Expression of PDX-1 resulted in a substantial increase in hepatic immunoreactive insulin content and an increase of 300% in plasma immunoreactive insulin levels, compared with that in mice treated with control adenovirus. Hepatic immunoreactive insulin induced by PDX-1 was processed to mature mouse insulin 1 and 2 and was biologically active; it ameliorated hyperglycemia in diabetic mice treated with streptozotocin. These data indicate the capacity of PDX-1 to reprogram extrapancreatic tissue towards a beta-cell phenotype, may provide a valuable approach for generating 'self' surrogate beta cells, suitable for replacing impaired islet-cell function in diabetics.

Adenoviridae↗
PubMed1999

Common origin of the I1307K APC polymorphism in Ashkenazi and non-Ashkenazi Jews.

A common germline missense mutation within the APC gene, I1307K, has recently been described in Ashkenazi Jews. We detected this polymorphism in two non-Ashkenazi Jewish women using denaturing gradient gel electrophoresis (DGGE), and hypothesized that in Jewish individuals it might not be restricted to Ashkenazim, and actually reflect a common ancestral polymorphism. To test this notion we performed allelic pattern determination using APC-linked markers in these two women and in nine Ashkenazi carrier controls. The pattern of the intragenic markers, as well as a single downstream marker 30-70 Kb from the APC gene was identical in all individuals, regardless of ethnic origin. We conclude that the I1307K polymorphism in Jewish individuals, is not restricted to Ashkenazim and probably reflects a founder mutation.

Female↗
PubMed1999

Increase in PDX-1 levels suppresses insulin gene expression in RIN 1046-38 cells.

RIN1046-38 cells (RIN-38) exhibit a passage-dependent reduction in both basal and glucose-regulated insulin secretion, accompanied by decreased insulin content. In an attempt to explain the mechanism of the gradual decrease in insulin production in cultured cells, we analyzed the insulin promoter activity and the levels of an important trans-activator of the insulin gene, PDX-1, as a function of aging in culture. We demonstrate that the decrease in insulin content and secretion is reflected in decreased promoter activity and is associated with a decrease in E47 and BETA2 nuclear factors, but with a paradoxical 3-fold increase in PDX-1 protein levels. To dissect the effect of increased PDX-1 from the decrease in the additional transcription factors on insulin promoter activity, we overexpressed PDX-1 protein in low passage RIN-38 cells by recombinant adenovirus technology. PDX-1 overexpression did not reduce E47 and BETA2 levels, but was sufficient to suppress rat insulin promoter activity in a dose-dependent manner. The fact that PDX-1 levels participate in trans-activation of insulin promoter activity was demonstrated in HIT-T15 cells. Treating HIT-T15 cells with 1-2 multiplicity of infection of AdCMV-PDX-1 increased rat insulin promoter activity, whereas higher doses repressed insulin promoter activity in these cells as in RIN-38 cells. Our data demonstrate that PDX-1 regulates transcription of the insulin gene in a dose-dependent manner. Depending on its nuclear dosage and the levels of additional cooperating transcription factors, PDX-1 may act as an activator or a repressor of insulin gene expression, such that low as well as high doses may be deleterious to insulin production.

Adenoviridae↗
PubMed1998

The development of the foetal thyroid: in utero ultrasonographic measurements.

OBJECTIVE: The early recognition of potentially treatable thyroid disease in the foetus frequently depends on the detection of abnormal growth of the foetal thyroid gland. We have therefore established nomograms for foetal thyroid transverse width and circumference from 14 weeks of gestation until term, using transvaginal and transabdominal high-resolution ultrasound techniques. DESIGN: A prospective, cross-sectional study of 193 normal singleton pregnancies was performed. MEASUREMENTS: Thyroid size was measured by transvaginal ultrasonography between 14 and 17 weeks, and by abdominal ultrasound from 18 to 37 weeks of gestation. RESULTS: Data was accurately obtained for 193 foetuses. The mean +/- SD thyroid width and circumference were 11.7 +/- 4.1 mm (95% confidence interval 11.1-12.3) and 39.5 +/- 14.1 mm (95% confidence interval 37.4-41.6), respectively. Thyroid size as a function of gestational age was expressed by the regression equations: thyroid width (mm) = -3.94 + 0.68 x gestational age (weeks), and thyroid circumference (mm) = -1.38 + 0.23 x gestational age (weeks). The correlation coefficients, r = 0.91 and r = 0.93, for thyroid width and circumference, respectively, were found to be highly statistically significant (p < 0.0001). The normal mean of thyroid width and circumference for each week of gestational age and the 95% prediction limits were defined. CONCLUSIONS: The present data offer normative measurements of the foetal thyroid that may facilitate the prenatal diagnosis of foetal goitre and make early administration of in utero treatment possible.

Cross-Sectional Studies↗
PubMed1998

The STOP-NIDDM Trial: an international study on the efficacy of an alpha-glucosidase inhibitor to prevent type 2 diabetes in a population with impaired glucose tolerance: rationale, design, and preliminary screening data. Study to Prevent Non-Insulin-Dependent Diabetes Mellitus.

OBJECTIVE: To describe the rationale and design, and to discuss the preliminary screening data, of the Study to Prevent NIDDM (STOP-NIDDM Trial), an international study on the efficacy of the alpha-glucosidase inhibitor acarbose in preventing or delaying the development of type 2 diabetes in a population with impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS: A total of 1,418 subjects diagnosed with IGT according to the World Health Organization's criteria and having a fasting plasma glucose concentration > or =5.6 mmol/L were randomized in a double-blind fashion to receive either acarbose (100 mg t.i.d.) or placebo for a predictive median follow-up period of 3.9 years. The primary outcome is the development of type 2 diabetes diagnosed using a 75-g oral glucose tolerance test according to the new criteria. The secondary outcomes are changes in blood pressure, lipid profile, insulin sensitivity, cardiovascular events, and morphometric profile. RESULTS: Screening was performed in a high-risk population. As of 1 March 1997, 4,424 subjects had been screened, and data were available for 3,919 (88.5%) subjects. Of these subjects, 1,200 (30.6%) had glucose intolerance. Of the subjects with glucose intolerance, 521 (13.3%) had previously undetected type 2 diabetes, and 679 (17.3%) had IGT. Of the IGT population, 412 (60.7%) subjects were eligible for the study This population had the following characteristics: the mean age was 54.8 years, 52% of the subjects were female, 53% had more than one risk factor for type 2 diabetes, >90% had a family history of diabetes, 78.2% had a BMI > or =27 kg/m2, 47.5% had high blood pressure, 51.2% had dyslipidemia, and 22.8% of the women had a history of gestational diabetes. CONCLUSIONS: Screening of a high-risk population yields one eligible subject per every 10 volunteers screened. This study should definitely answer the question of whether acarbose can prevent or delay the progression of IGT to type 2 diabetes mellitus.

Acarbose↗
PubMed1997

A molecular basis for insulin resistance. Elevated serine/threonine phosphorylation of IRS-1 and IRS-2 inhibits their binding to the juxtamembrane region of the insulin receptor and impairs their ability to undergo insulin-induced tyrosine phosphorylation.

Tumor necrosis factor alpha (TNFalpha) or chronic hyperinsulinemia that induce insulin resistance trigger increased Ser/Thr phosphorylation of the insulin receptor (IR) and of its major insulin receptor substrates, IRS-1 and IRS-2. To unravel the molecular basis for this uncoupling in insulin signaling, we undertook to study the interaction of Ser/Thr-phosphorylated IRS-1 and IRS-2 with the insulin receptor. We could demonstrate that, similar to IRS-1, IRS-2 also interacts with the juxtamembrane (JM) domain (amino acids 943-984) but not with the carboxyl-terminal region (amino acids 1245-1331) of IR expressed in bacteria as His6 fusion peptides. Moreover, incubation of rat hepatoma Fao cells with TNFalpha, bacterial sphingomyelinase, or other Ser(P)/Thr(P)-elevating agents reduced insulin-induced Tyr phosphorylation of IRS-1 and IRS-2, markedly elevated their Ser(P)/Thr(P) levels, and significantly reduced their ability to interact with the JM region of IR. Withdrawal of TNFalpha for periods as short as 30 min reversed its inhibitory effects on IR-IRS interactions. Similar inhibitory effects were obtained when Fao cells were subjected to prolonged (20-60 min) pretreatment with insulin. Incubation of the cell extracts with alkaline phosphatase reversed the inhibitory effects of insulin. These findings suggest that insulin resistance is associated with enhanced Ser/Thr phosphorylation of IRS-1 and IRS-2, which impairs their interaction with the JM region of IR. Such impaired interactions abolish the ability of IRS-1 and IRS-2 to undergo insulin-induced Tyr phosphorylation and further propagate the insulin receptor signal. Moreover, the reversibility of the TNFalpha effects and the ability to mimic its action by exogenously added sphingomyelinase argue against the involvement of a proteolytic cascade in mediating the acute inhibitory effects of TNFalpha on insulin action.

Animals↗
PubMed1997

Phosphorylation of A 27-kDa protein correlates with survival of protein-synthesis-inhibited MCF-7 cells.

Previously, we have shown that IGF-1, the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) and aurintricarboxylic acid (ATA) protected MCF-7 cells against death induced by the protein synthesis inhibitor cycloheximide (CHX). We proposed that phosphorylation of a putative cellular proteins(s) may be involved in this survival mechanism. In the present study we investigated the ability of several agents to induce phosphorylation of cellular proteins and correlated this ability to their survival effect. We found that TPA, ATA, and IGF-1 increased the degree of phosphorylation of a 27-kDa protein in a dose- and time-dependent manner in CHX-treated MCF-7 cells. The ED50 values observed were 25 ng/ml, 40 micrograms/ml and 15 ng/ml for TPA, ATA, and IGF-1, respectively. The effect was measured upon 10 min of cell treatment with each agent; it reached maximum at 60 min and thereafter decreased continuously to control levels. The 27-kDa protein was found in the cytosolic fraction as a phosphorylated serine residue. Further characterization with two-dimensional electrophoresis indicated that the 27-kDa phosphorylated serine residue. Further characterization with two-dimensional electrophoresis indicated that the 27-kDa phosphoprotein was resolved into two isoforms with pI 5.7 and 5.9. Such characteristics were observed for the small molecular weight heat shock protein HSP27. Indeed, a single band of 27 kDa was detected immunologically with rabbit polyclonal anti-human HSP27. The inactive phorbol ester alpha TPA, epidermal growth factor (EGF), and 8-bromoadenosine 3'5'-cyclic monophosphate (Br-cAMP) did not increase phosphorylation of the 27-kDa protein. Cell survival was measured by exposure of the CHX-pretreated cells to increasing concentrations of the various agents for 60 min, followed by a further incubation for 48 h in the presence of CHX only. TPA, ATA, and IGF-1 were found to enhance cell survival, whereas alpha-TPA, EGF and Br-cAMP did not. Our results indicate a correlation between phosphorylation of a 27-kDa protein, probably HSP27, and enhanced cell survival, suggesting a role for this phosphoprotein in the survival mechanism.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1997

Long-term effects of insulin-like growth factor (IGF)-I on serum IGF-I, IGF-binding protein-3 and acid labile subunit in Laron syndrome patients with normal growth hormone binding protein.

A minority of patients with Laron syndrome have normal serum GH binding protein (GHBP), indicating that the defect is elsewhere than in the extracellular domain of the GH receptor. We have evaluated the effect of long-term IGF-I treatment on serum IGF-binding protein (IGFBP)-3 and the acid-labile subunit (ALS) in three sibling with Laron syndrome caused by a GH post-receptor defect and with normal GHBP. The children (a boy aged 3 years, a girl aged 4 years and a boy aged 10 years) were treated by daily s.c. injection of IGF-I in a dose of 150 micrograms/kg. IGFBP-3 was measured by RIA and Western ligand blotting, ALS by RIA. Based values of IGFBP-3 and ALS were low. During IGF-I treatment, the IGFBP-3 concentrations in the girl gradually increased, whereas in the boys there was a 60% decrease during the first week, followed by gradual increase towards baseline. The ALS concentrations followed a similar pattern. We conclude that IGF-I treatment induces and initial suppression and then an increase in the IGFBP-3 and ALS concentrations, confirming data from animal experiments that IGFBP-3 synthesis is not solely under GH control. The differences in responsiveness between the female and male siblings may reflect genetic differences, or lower circulating concentrations of IGF-I in the boys compared with the girl.

Carrier Proteins↗
PubMed1997

A pituitary mass and hypopituitarism: improvement after corticosteroid therapy.

Lymphocytic hypophysitis of the anterior pituitary is a rare autoimmune disease, invariably diagnosed either by surgical biopsy of the adenohypophysis or at autopsy. The current report describes the rapid development of hypopituitarism in a 42-year-old nulliparous woman with a large sellar mass, who did not undergo pituitary surgery. Transient regression of the sellar mass and partial improvement of the hypopituitarism was induced by treatment with corticoids. We suggest that the diagnosis of lymphocytic hypophysitis can be established clinically and that conservative treatment with corticoids should be considered prior to surgical intervention.

Adult↗
PubMed1996

Sphingomyelinase and ceramide suppress insulin-induced tyrosine phosphorylation of the insulin receptor substrate-1.

The sphingomyelin pathway is a newly described signal transduction pathway mediating the action of several cytokines including tumor necrosis factor-alpha (TNF). TNF was recently shown to interfere with insulin-induced tyrosine phosphorylation of the insulin receptor substrate-1 (IRS-1). In this work we examined the possible effect of direct activation of the sphingomyelin pathway on insulin-induced tyrosine phosphorylation of IRS-1. Incubation of the insulin-sensitive rat hepatoma Fao cells with bacterial sphingomyelinase (SMase) that causes membrane hydrolysis of sphingomyelin led to a time- and dose-dependent decrease in insulin-induced tyrosine phosphorylation of IRS-1. The effect was apparent after 10 min of incubation and with a dose of 10 milliunits/ml SMase. It was not associated with a decrease in insulin receptor autophosphorylation. In addition, SMase treatment interrupted the association of the 85-kDa catalytic subunit of phosphatidylinositol 3-kinase with IRS-1. A similar impact on IRS-1 tyrosine phosphorylation was observed after addition of cell-permeable ceramide analogs (C2 and C6). Comparable changes in IRS-1 tyrosine phosphorylation and electrophoretic mobility were found after exposure of cells to either TNF, SMase, or ceramide. Our findings suggest that TNF may utilize the sphingomyelin pathway in its effect on the insulin-stimulated tyrosine phosphorylation of IRS-1.

Animals↗
PubMed1996

Necrobiosis lipoidica and diabetic control revisited.

Necrobiosis lipoidica diabeticorum is a rare skin disorder, usually considered a marker for diabetes mellitus. More than half of the patients with necrobiosis lipoidica diabeticorum have diabetes mellitus, but less than one per cent of diabetes mellitus patients have necrobiosis lipoidica diabeticorum. In the diabetes and dermatology literature, we find the position that there is no effect of glucose control on either the appearance of necrobiosis lipoidica diabeticorum or the clinical course of the lesion. We base our challenge to this position on a critical review of the original data. And conclude on the contrary, that necrobiosis lipoidica diabeticorum is usually associated with poor glucose control and that tighter glucose control, as currently practised, might improve or prevent the disorder.

Blood Glucose↗
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↗