Biomedical subjects

Iris Goldberg

Publications and source records attributed to Iris Goldberg.

At least 37 records · Page 2Linked to original sources

PubMed2003

Tyrphostin AG-556 reduces myocardial infarct size and improves cardiac performance in the rat.

TNF-alpha is a proinflammatory cytokine, abundantly expressed after myocardial infarction. It has been suggested that it exhibits myocardial suppressive and cytotoxic effects. AG-556 is a tyrosine kinase inhibitor synthesized based on its ability to reduce TNF-alpha production and cell toxicity, and to improve experimental models mediated by TNF-alpha (i.e., peritontitis and experimental autoimmune encephalomyelitis). Daily, for 7 days, rats were injected ip with either AG-556 dissolved in DMSO or with the control vehicle. Infarct size was determined in the hearts as well as in fibrous scar formation. Cardiac TNF-alpha expression was evaluated by ELISA and immunohistochemistry. Functional hemodynamic parameters were evaluated employing echocardiography prior to sacrifice. AG-556 treatment reduced MI size at 7 days with a parallel effect on fibrous tissue formation. TNF-alpha production by splenocytes was reduced upon AG-556 treatment, whereas no differences were evident between the groups with regard to myocardial cytokine expression. AG-556 attenuated the decrease in fractional shortening at the expense of preserving end systolic diameter. AG-556 has proven beneficial in reducing myocardial infarct size and attenuated consequent hemodynamic deterioration in the rat model. If reconfirmed, AG-556 may be of potential clinical use in post-MI patients.

Animals↗

PubMed2003

Immunity to heat shock protein 65--an additional determinant in intimal thickening.

Inflammation occurring consequent to vessel injury is thought to play an important role in atherosclerosis and restenosis. Autoimmunity to HSP65 has been shown to accelerate early atherogenesis in rabbits and mice, whereas in humans epidemiological data support this contention. In the current study, we explored the possibility of HSP65 influencing the extent of neointimal growth in the rat carotid injury model. Rats were either immunized with recombinant mycobacterial HSP65, heat killed preparation of Mycobacterium tuberculosis (MT), or with PBS, all emulsified in incomplete Freund's adjuvant. Animals were boosted with a similar protocol 3 weeks following the primary immunization and 2 weeks later carotid injury was applied in all animals by balloon inflation. Upon sacrifice 2 weeks later, sera were obtained for measurement of anti-HSP65 antibodies by ELISA, splenocytes were assessed for proliferative response to in vitro priming with HSP65, and carotid arteries were removed for evaluation of neointimal growth. Rats immunized with HSP65 exhibited a brisk and sustained humoral immune response to HSP65, and cellular immunity was also evident by thymidine uptake to splenocytes primed with the respective protein. Neointimal/medial ratio was significantly increased in HSP65 immunized rats, in comparison with MT injected and control animals. In conclusion, immunity to HSP65 can play a role in accelerating restenosis following arterial injury. These results should be further investigated in humans as they may provide a possible link between infections and restenosis/accelerated arteriosclerosis.

Animals↗

PubMed2003

AlphaV- and beta1-integrin subunits are commonly expressed in malignant effusions from ovarian carcinoma patients.

OBJECTIVE: The objective was to study expression of alphav- and beta1-integrin subunits in effusions, primary tumors, and solid metastases of ovarian carcinoma patients, as well as to evaluate its potential association with previously studied metastasis-associated molecules and clinicopathologic parameters. METHODS: Sections from 121 malignant effusions and 30 corresponding primary and metastatic lesions were evaluated for protein expression of the alphav- and beta1-integrin subunits using immunohistochemistry (IHC). A subset of effusions was additionally studied using immunoblotting (IB) and flow cytometry (FCM). mRNA in situ hybridization (ISH) was performed in 58 effusions and 30 biopsies. RESULTS: Protein expression of alphav- and beta1-integrin subunits was detected in carcinoma cells in 116/121 (96%) and 113/121 (93%) effusions, respectively. alphav protein expression was limited to carcinoma cells. IB and FCM confirmed IHC results. mRNA for alphav- and beta1-integrin subunits was detected in carcinoma cells in 37/58 (64%) and 33/58 (57%) effusions, respectively. Both protein and mRNA expression were higher in peritoneal effusions, significantly for alphav mRNA (P = 0.042) and beta1 protein (P = 0.023). beta1 protein expression in effusions was more frequently detected in better-differentiated tumors (P = 0.006). alphav-integrin subunit expression correlated with that of the previously studied matrix metalloproteinase-9 (MMP-9) (P = 0.006) and the MMP inducer EMMPRIN (P = 0.001). Expression of beta1-integrin subunit showed an association with that of EMMPRIN (P = 0.029), basic fibroblast growth factor (P < 0.001), and the MMP inhibitor TIMP-2 (P = 0.025). In carcinoma cells of solid lesions, alphav protein was uniformly present, while beta1 expression was limited to 15/30 (50%) specimens. As in effusions, protein expression of alphav subunit was cancer-specific, while beta1 protein was detected also in stromal fibroblasts and endothelial cells. CONCLUSIONS: The alphav- and beta1-integrin subunits are frequently expressed in ovarian carcinoma cells in effusions, and the alphav-integrin subunit is a powerful diagnostic marker for carcinoma cells. The reduced expression of the beta1-integrin subunit in solid lesions may be attributed to the role of other subunits at these stages, such as the beta3 subunit as part of the alphavbeta3-vitronectin receptor. The high expression of integrin subunits with a role of binding mesothelium, invasion, and angiogenesis in carcinoma cells in both peritoneal and pleural effusions suggests that cells at both sites have metastatic potential.

Adult↗

PubMed2003

Coordinated expression of integrin subunits, matrix metalloproteinases (MMP), angiogenic genes and Ets transcription factors in advanced-stage ovarian carcinoma: a possible activation pathway?

The events that mediate tumor progression in ovarian carcinoma are poorly understood to date. This review summarizes our results studying metastasis-associated molecules in advanced-stage ovarian carcinomas, details the co-expression of mRNA of these genes, and discusses their prognostic role. Fifty-five primary and metastatic FIGO stage III-IV ovarian carcinomas were analyzed for the expression of alpha v and beta1 integrin subunits, the matrix metalloproteinases MMP-2, MMP-9, and MT1-MMP, the MMP inhibitor TIMP-2, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), interleukin-8 (IL-8), PEA3 and Ets-1 using mRNA in situ hybridization. Tumor and adjacent stromal cell expression was scored. The association between integrin subunit expression and the expression of MMP, TIMP-2, angiogenic genes, PEA3 and Ets-1 was statistically analyzed. Alpha v integrin subunit mRNA expression in carcinoma cells showed significant association with that of MMP-2 and IL-8 in this cellular compartment, while the presence of beta1 integrin subunit mRNA showed similar association with that of PEA3, Ets-1, IL-8, bFGF and MMP-2. Expression of beta1 integrin subunit mRNA in stromal cells was associated with that of TIMP-2 and Ets-1 in this compartment. In addition, significant intercellular associations were found between alpha v integrin subunit mRNA expression in carcinoma cells and stromal cell expression of Ets-1, as well as between stromal cell expression of alpha v integrin subunit and labeling for IL-8 in carcinoma cells. The presence of beta1 integrin subunit mRNA in carcinoma cells showed a significant association with that of Ets-1, IL-8 and bFGF in stromal cells, while the presence of beta1 integrin subunit mRNA in stromal cells was associated with tumor PEA3 mRNA expression. To the best of our knowledge, this is the first evidence for coordinated autocrine and paracrine expression of members of these four families of metastasis-associated genes in human cancer. The results of this analysis support experimental data regarding cross-talk between carcinoma cells and peritumoral fibroblasts. They also suggest the existence of a putative activation sequence of metastatic genes, involving the beta1 (and possibly alpha v) integrin subunits, IL-8, PEA3, Ets-1 and MMP in ovarian carcinoma.

Adenocarcinoma, Mucinous↗

PubMed2003

EMMPRIN (extracellular matrix metalloproteinase inducer) is a novel marker of poor outcome in serous ovarian carcinoma.

EMMPRIN is a member of the immunoglobulin superfamily of adhesion molecules and has a role in the activation of several matrix metalloproteinases (MMP). The objective of this study was to investigate the expression of EMMPRIN in effusions, primary and metastatic tumors of serous ovarian carcinoma patients, as well as to evaluate its association with clinicopathologic parameters and with MMP and integrin expression. Eighty effusions and eighty-three solid lesions were evaluated for expression of EMMPRIN mRNA using in situ hybridization (ISH). Protein expression was studied in 75 effusions and 55 biopsies using immunohistochemistry (IHC). EMMPRIN mRNA and protein were detected in carcinoma cells in 63/80 (79%) and 64/75 (85%) effusions, respectively. Expression was similar in peritoneal and pleural effusions. EMMPRIN was co-expressed with MMP-1 (P < 0.001), MMP-9 (P = 0.006) and the alphav (P = 0.013) and beta1 (P = 0.029) integrin subunits. In solid lesions, EMMPRIN localized most often to tumor cells (51/83 using ISH, 51/55 using IHC), but was also expressed in stromal and endothelial cells in approximately one third of the cases. EMMPRIN mRNA expression in tumor cells was most frequent in peritoneal metastases (P = 0.03). EMMPRIN expression in carcinoma cells of solid tumors showed an association with that of MMP-9 (P = 0.018), while labeling of stromal cells showed co-localization with the beta1 integrin subunit (P = 0.043). In survival analysis, EMMPRIN protein expression in stromal cells of primary tumors (P = 0.012) and in endothelial cells of all solid tumors (P = 0.023) correlated with poor survival. In conclusion, EMMPRIN is a novel prognostic marker in ovarian carcinoma, and is co-expressed with other metastasis-associated molecules in this malignancy. The identical phenotype of carcinoma cells in pleural and peritoneal effusions provides further evidence to our theory that cells at these sites share similar genotypic and phenotypic profiles.

Adult↗

PubMed2003

Immunohistochemical analyses of colon cancer in I1307K APC mutation carriers compared with noncarriers.

The I1307K APC germline mutation is associated with an increased risk to colorectal cancer (CRC). Whether and to what extent the somatic features and the molecular pathways of cancer development in mutation carriers differ from colorectal cancer in noncarriers remains unknown. To gain insight into this issue, 52 Israeli patients with CRC, 24 of whom were I1307K APC mutation carriers, were analyzed. The expression pattern of genes known to be involved in the pathogenesis of sporadic CRC was assessed immunohistochemically: E-cadherin, beta-catenin, deleted in colon cancer (DCC), and p53. In addition, tumors were genotyped for somatic activating mutations in Ki-ras oncogene. Mutation carriers and noncarriers were comparable in age at diagnosis (64.3 +/- 10.1 years for carriers and 60.8 +/- 14.1 years for noncarriers), tumor location in the colon, and disease stages. Tumors of I1307K mutation carriers displayed positive p53 immunostaining and loss of beta-catenin, E-cadherin, and DCC expression more often compared with noncarriers, although none of these differences reached statistical significance. Mutation frequencies in the Ki-ras gene were similar in both groups. In conclusion, the molecular pathways in CRC in I1307K APC mutation carriers are seemingly similar to those of sporadic cases, but a larger study is clearly needed.

Case-Control Studies↗

PubMed2003

Expression of the 67 kDa laminin receptor and the alpha6 integrin subunit in serous ovarian carcinoma.

The aim of this study was to analyze the expression of two laminin receptors, the 67 kDa laminin receptor (LBP) precursor and the alpha6 integrin subunit, in effusions and solid tumors of patients diagnosed with serous ovarian carcinoma and to evaluate their predictive role. Eighty-eight effusions and one hundred sixteen primary (= forty-one) and metastatic (= seventy-five) ovarian carcinomas were evaluated for expression of the above-mentioned mRNAs using in situ hybridization (ISH). LBP protein expression was studied in 24 effusions and 43 solid tumors using immunohistochemistry (IHC). Alpha6 integrin subunit protein expression was studied in 27 effusions using flow cytometry (FCM). Expression of LBP mRNA was frequently detected in both carcinoma (92 of 116 cases, 79%) and stromal (79 of 116 cases, 68%) cells in solid tumors. Expression was still higher in cancer cells in effusions (85 of 88 specimens, 96%). In contrast, alpha6 integrin subunit was less frequently detected in both solid tumors (33 of 116; 28% in carcinoma cells, 23 of 116; 20% in stromal cells) and effusions (36 of 88; 41%). LBP protein expression was found in 19 of 24 (79%) effusions and 40 of 43 (93%) solid tumors, and was higher in effusions of patients who received chemotherapy prior to tapping (P = 0.024). FCM showed protein expression of the alpha6 integrin subunit in 17 of 27 (63%) effusions. Expression of the alpha6 integrin subunit mRNA in tumor cells of solid lesions was significantly lower in solid tumors of FIGO stage-IV patients compared to those of patients diagnosed with stage-III-disease (P = 0.004), and its absence predicted significantly shorter overall survival (OS) in univariate analysis (P = 0.018). Absence of alpha6 integrin subunit protein expression using FCM predicted median OS of 12 months compared to 26 months for patients with tumors expressing the protein, although this finding did not reach significance (P = 0.27). In conclusion, as opposed to previous reports, both mRNA and protein expression of the alpha6 integrin subunit do not appear to be down-regulated in effusions compared to solid tumors. Loss of alpha6 integrin subunit mRNA (and possibly protein) expression is a novel prognostic marker in advanced-stage ovarian carcinoma. LBP mRNA and protein expression is independent of that of the alpha6 integrin subunit in both solid tumors and effusions of serous ovarian carcinoma.

Ascitic Fluid↗

PubMed2003

PEA3 is the second Ets family transcription factor involved in tumor progression in ovarian carcinoma.

PURPOSE: The purpose of this study was to analyze the possible correlation between PEA3 mRNA expression and survival in advanced-stage ovarian carcinomas, studying two patient groups with extremely different disease outcome. EXPERIMENTAL DESIGN: Sections from 61 primary ovarian carcinomas and metastatic lesions from 36 patients diagnosed with advanced-stage ovarian carcinoma [International Federation of Gynecologists and Obstetricians (FIGO) stages III-IV] were evaluated for expression of PEA3 using mRNA in situ hybridization. Patients were divided into long-term (n = 16) and short-term (n = 20) survivors. RESULTS: The mean values for disease-free survival and overall survival were 119 and 137 months for long-term survivors, as compared with 4 and 22 months for short-term survivors, respectively. Expression of PEA3 mRNA was detected in carcinoma cells and stromal cells in 56 of 61 lesions (92%) and 54 of 61 lesions (89%), respectively. Intense stromal expression was detected only in the vicinity of grade 2-3 tumors (P = 0.04). PEA3 expression in stromal cells showed a significant association with matrix metalloproteinase 2 mRNA expression in carcinoma cells (P = 0.022). PEA3 expression in carcinoma cells showed an association with mRNA expression of the beta(1) integrin subunit in the same compartment (P = 0.039). It was also associated with mRNA expression of beta(1) integrin subunit (P = 0.012), basic fibroblast growth factor (P = 0.036), and the matrix metalloproteinase inducer EMMPRIN (P = 0.038) in stromal cells. PEA3 mRNA was detected more often in both carcinoma and stromal cells in tumors of short-term survivors (P = 0.021 for stromal cells). In univariate survival analysis, PEA3 expression in stromal cells correlated with both shorter disease-free survival (P = 0.019) and overall survival (P = 0.029), whereas tumor cell expression predicted poor overall survival (P = 0.049). PEA3 mRNA expression in stromal cells emerged as an independent predictor of poor outcome in multivariate survival analysis, in which all molecules previously studied in this patient cohort were included (P = 0.015). CONCLUSIONS: To the best of our knowledge, this is the first evidence associating PEA3 mRNA expression and poor survival in human epithelial malignancy. PEA3 is thus a novel prognostic marker in advanced-stage ovarian carcinoma. The association between PEA3 mRNA expression and the expression of the beta(1) integrin subunit, basic fibroblast growth factor, and EMMPRIN, first documented in our patient cohort, points to the central role of this transcription factor in tumor progression in ovarian carcinoma.

Adult↗

PubMed2002

Functional inhibition of Ras by S-trans,trans-farnesyl thiosalicylic acid attenuates atherosclerosis in apolipoprotein E knockout mice.

BACKGROUND: Atherosclerosis is a multifactorial disorder involving inflammatory processes. These responses are associated with robust activation of signaling cascades by diverse cell surface receptors in a variety of cell types. The processes that are involved in atherosclerosis would likely require intact Ras pathways, which play a key role in the control of cell growth, differentiation, and apoptosis. METHODS AND RESULTS: We examined whether the Ras inhibitor farnesyl thiosalicylic acid (FTS) can suppress atherogenesis in the apolipoprotein E-deficient mouse model. Mice were treated with FTS or a control regimen 3 times weekly for 6 weeks and fed a normal chow diet. Two additional groups included FTS-treated and control-treated mice that were fed a high-fat diet for 10 weeks. FTS reduced both fatty streaks and advanced lesions compared with the control treatment. Ras inhibition in vivo was evidenced by the reduced content of the active form of Ras (Ras-GTP) in aortas of FTS-treated mice. Splenocytes from the FTS-treated versus control mice exhibited reduced proliferation to oxidized LDL (OxLDL) but not to concanavalin A. IgG anti-OxLDL antibody levels were reduced in FTS-treated mice compared with controls. Whereas no effect of FTS was evident on plaque T lymphocyte and macrophage content, lesional vascular cell adhesion molecule-1 and nuclear factor-kappaB expression were considerably reduced compared with controls. CONCLUSIONS: FTS suppressed atherosclerotic plaques in apolipoprotein E-deficient mice, providing a useful tool for research in atherosclerosis.

Animals↗

PubMed2002

The prognostic value of metalloproteinases and angiogenic factors in ovarian carcinoma.

The objective of this study was to analyze the correlation between matrix metalloproteinases (MMPs) and angiogenic genes and survival in advanced-stage ovarian carcinomas. Primary and metastatic ovarian carcinomas from patients diagnosed with FIGO stage III-IV disease and followed up to 20 years were studied using mRNA in situ hybridization (ISH). Expression of MMP-2, MMP-9, membrane-type 1-MMP (MT1-MMP), the MMP inhibitor TIMP-2, vascular endothelial growth factor (VEGF), interleukin-8 (IL-8) and basic fibroblast growth factor (bFGF) was studied. MMP-2, MMP-9 and TIMP-2 mRNA was detected in both tumor and stromal cells, while MT1-MMP was largely confined to tumor cells. In univariate analysis of primary tumors, TIMP-2 and MMP-9 mRNA expression correlated with poor outcome. In metastatic lesions, mRNA expression of TIMP-2, MMP-2, and MT1-MMP correlated with poor survival. In a multivariate analysis of primary tumors, TIMP-2 expression in stromal cells (P=0.006) and MMP-9 expression in tumor cells (P=0.011) retained their predictive value. Intense expression of bFGF mRNA and weak expression of IL-8 mRNA was detected in both stromal and tumor cells in most cases, while VEGF mRNA expression was limited to a few cases. Angiogenic mRNA expression showed no correlation with disease outcome in survival analysis (P>0.05). We conclude that bFGF is the major angiogenic factor expressed in ovarian carcinoma at the mRNA level. MMP-2, MMP-9, MT1-MMP and TIMP-2 are valid markers of poor survival in advanced-stage ovarian carcinoma.

Adult↗

PubMed2002

Interleukin-8 and vascular endothelial growth factor mRNA and protein levels are down-regulated in ovarian carcinoma cells in serous effusions.

Angiogenic factors are involved in tumor growth and spread. The aim of this study was to evaluate the expression of angiogenesis-related genes in malignant serous effusions of patients with advanced-stage (FIGO stage III and IV) ovarian carcinoma. In addition, to compare the results for carcinoma cells in effusions with corresponding primary tumors and metastatic lesions, and analyze their prognostic role. Sections from 66 effusions and 90 primary and metastatic lesions from 62 ovarian and primary peritoneal carcinoma patients, were evaluated for expression of basic fibroblast factor (bFGF), interleukin-8 (IL-8), and vascular endothelial growth factor (VEGF) using mRNA in situ hybridization (ISH). Protein expression was evaluated in a subset of specimens using immunohistochemistry (IHC). ISH results were correlated with clinical parameters. In both effusions and solid tumors, bFGF mRNA was the most commonly expressed factor (93% of effusions and 95% of solid tumors) followed by IL-8, while VEGF was expressed in a minority of the specimens (P < 0.001 for bFGF vs. IL-8 and VEGF). In solid tumors, angiogenic mRNA expression was seen in both tumor and stromal cells in the majority of positive cases. ISH results did not differ in primary and metastatic tumors. However, carcinoma cells in effusions showed down-regulated expression of VEGF, when compared with both primary tumors (P = 0.029) and metastases (P = 0.015). IL-8 showed a similar down-regulation in effusions, when compared with metastases (P = 0.005). IHC showed excellent agreement with mRNA findings on protein level. In the study of clinico-pathologic parameters, IL-8 mRNA expression in effusions was associated with higher tumor grade (P = 0.044). Angiogenic gene expression in effusions showed no correlation with patient age, previous treatment, residual tumor size, FIGO stage or disease outcome in survival analysis (P > 0.05). Peritoneal and pleural effusions showed similar expression patterns. In conclusion, bFGF is the major angiogenic factor expressed in ovarian carcinoma at the mRNA level. It is highly expressed in both solid tumors and serous effusions, while IL-8 and VEGF are down regulated in carcinoma cells in effusions, possibly due to the lack of interaction with stromal cells. mRNA expression of VEGF, bFGF, and IL-8 does not appear to be a predictor of disease outcome in advanced-stage ovarian carcinoma. Carcinoma cells in pleural and peritoneal effusions show a similar metastatic expression profile, in agreement with our previous findings, supporting the true metastatic nature of ovarian carcinoma cells in ascites.

Ascitic Fluid↗

PubMed2002

Lentigo maligna and superficial spreading melanoma are different in their in situ phase: an immunohistochemical study.

Clinical and pathologic observations have prompted the categorization of malignant melanoma into 4 subtypes. Although some authorities challenge the value of this classification, nevertheless it is generally accepted that lentigo maligna (LM), or melanoma on sun-damaged skin, has a different biological behavior than so-called superficial spreading melanoma (SSM), at least in the early stage of its evolution. To characterize some aspects of this different behavior, the in situ phase of SSM and LM was studied using immunohistochemical methods. Seventeen cases of SSM in situ and 13 cases of LM were chosen for the study. All cases qualified with strict histologic criteria. Sections from these lesions were stained with antibodies against HMB-45 antigen, basic fibroblast growth factor (bFGF), proliferating cell nuclear antigen (PCNA), and factor VIII. Semiquantitative analysis was performed. Cases classified as either LM or SSM corresponded well to the epidemiologic and clinical characteristics as described in the literature; that is, LM appeared in older patients and occurred mostly on the face, whereas SSM occurred mostly on the trunk and lower limbs. Although no difference in HMB-45 stain was observed, melanoctyes of SSM showed greater proliferative activity, as reflected by PCNA stain (P < 0.02) and higher levels of bFGF (P < 0.001), than melanocytes of LM. More blood vessels were counted under SSM than under LM (P < 0.05). These results are in accordance with the biological behavior of SSM and LM, that is, the longer in situ phase of the latter. bFGF is both a growth factor for melanocytes and an angiogentic factor. The differences in PCNA, a proliferation marker, and blood vessel count may be related to the bFGF effect. Thus this study reveals some of the biological differences between LM and SSM. Location and sun exposure habits may contribute to these differences, which already exist in the in situ phase.

Aged↗

PubMed2002

Different beta-catenin immunoexpression in carcinoid tumors of the appendix in comparison to other gastrointestinal carcinoid tumors.

Carcinoid tumor of the appendix is an endocrine tumor that is histologically similar to, but biologically less aggressive than carcinoids arising from other parts of the gastrointestinal tract. In this study, we examined E-cadherin, beta-catenin, DCC, p53 and Ki67 immunoexpression in cases of carcinoid of the appendix and made a comparison with non-appendiceal carcinoid tumors. Nine cases of appendiceal carcinoid and 11 biopsies of carcinoid of other parts of the gastrointestinal tract, five cases of the small intestine and six of the stomach were immunohistochemically evaluated for Ki67, p53, DCC, E-cadherin and beta-catenin. Two main patterns of beta-catenin staining were observed. The first pattern was characterized as membranous and cytoplasmic, and was seen mainly in the peripheral cells of the nests. The second pattern was diffuse, predominantly membranous. Most (five of seven) appendiceal carcinoids and only three of 11 non-appendiceal cases showed the first staining pattern (p < 0.05). Immunoexpression of E-cadherin and DCC was similar in both groups. p53 and Ki-67 immunostaining revealed stronger nuclear positivity in the non-appendiceal carcinoid tumors (statistically not significant). We found a pattern of beta-catenin immunostaining in typical carcinoid tumors of the appendix that was different from the pattern seen in non-appendiceal carcinoid tumors. This alteration suggests that carcinoid of the appendix may represent a different subtype of carcinoid tumors with different immunohistochemical and biological behavior.

Adult↗

PubMed2002

Elevated insulin-like growth factor-1 and insulin-like growth factor binding protein-2 in malignant pleural effusion.

Insulin-like growth factor-1 (IGF-1) and its binding proteins (IGFBPs) are produced by many tissues and are present in serum and other biological fluids. Alterations in sera of IGF-1 and 2 and IGFBPs were demonstrated in patients with malignancy, infection and other diseases causing pleural effusion. In this study the IGF-1 and IGFBP-2 content and the specific electrophoretic patterns of IGFBPs in samples of sera and pleural effusions of 25 patients with malignancy, infection and congestive heart failure were investigated. IGF-1 levels in exudative effusions of malignant solid tumors were significantly higher [(mean +/- SD), 20.9+/-7.5 nmol/L, n = 9] than in lymphoma (11.0+/-5.2 nmol/L, n = 5; p < 0.05), infection (11.4+/-6.5 nmol/L, n = 6; p < 0.05) and transudative effusion of congestive heart failure (4.3+/-3.3 nmol/L, n = 5; p < 0.02). IGFBP-2 was markedly increased in effusions of malignant solid tumors (2.14+/-0.82 mg/L, n = 9) compared with exudates of lymphoma, infection and transudates (1.10+/-0.70, 1.22+/-0.32 and 0.93+/-0.52 nmol/L, respectively, p < 0.05). Moreover, in effusion of solid tumors, IGFBP-2 levels were higher than those in corresponding sera, which suggests local production of this binding protein. The demonstration of IGFBP-2 in solid tumor cells by immunohistochemistry further supports this possibility. This work demonstrates the existence of the IGF-1/IGFBP system in pleural fluids from different etiologies and implies possible use of IGF-1 and IGFBP-2 as a potential marker of malignant effusions.

Adult↗

PubMed2002

Efficacy of IVIG affinity-purified anti-double-stranded DNA anti-idiotypic antibodies in the treatment of an experimental murine model of systemic lupus erythematosus.

Since the idiotypic network is an important mechanism for controlling the immune repertoire, we tested anti-idiotypic modulation employing concentrated specific natural polyclonal anti-double-stranded (ds) DNA anti-idiotypic antibodies obtained from a commercial IVIG in the treatment of experimental systemic lupus erythematosus (SLE). Specific natural polyclonal anti-dsDNA anti-idiotypic antibodies (IVIG-ID) were affinity purified from IVIG on an anti-dsDNA-Sepharose column constructed from anti-dsDNA idiotypes (ID) affinity purified from 55 patients with active SLE. NZB/W F(1) mice were treated i.v. with 3 weekly injections of IVIG-ID (2 mg/kg/injection) or regular IVIG (400 mg/kg/injection) both before (age 8 weeks) and after developing anti-dsDNA antibodies at the age of 21-22 weeks. The IVIG-ID-treated mice showed a decline in the titer of anti-dsDNA antibodies during the treatment, reaching maximum suppression 1 week after the last injection. A significant difference in the proteinuria level in the IVIG-ID-treated group compared to the control group was observed. Immunohistology showed different patterns of IgG deposition, with mesangial and capillary wall deposits in controls and in the IVIG-treated group, but only mesangial deposits in the IVIG-ID-treated group. The survival time of the IVIG-ID-treated group was longer than the IVIG-treated group. Treatment with concentrated specific anti-dsDNA anti-ID prepared from commercial IVIG is more effective in suppressing the humoral reaction and clinical signs of SLE than native IVIG. These results point to the considerable regulatory role of anti-ID in the mechanism of action of IVIG in SLE.

Animals↗

PubMed2002

Bacterial induction of autoantibodies to beta2-glycoprotein-I accounts for the infectious etiology of antiphospholipid syndrome.

The antiphospholipid syndrome (APS) is characterized by the presence of pathogenic autoantibodies against beta2-glycoprotein-I (beta2GPI). The factors causing production of anti-beta2GPI remain unidentified, but an association with infectious agents has been reported. Recently, we identified a hexapeptide (TLRVYK) that is recognized specifically by a pathogenic anti-beta2GPI mAb. In the present study we evaluated the APS-related pathogenic potential of microbial pathogens carrying sequences related to this hexapeptide. Mice immunized with a panel of microbial preparations were studied for the development of anti-beta2GPI autoantibodies. IgG specific to the TLRVYK peptide were affinity purified from the immunized mice and passively infused intravenously into naive mice at day 0 of pregnancy. APS parameters were evaluated in the infused mice on day 15 of pregnancy. Following immunization, high titers of antipeptide [TLRVYK] anti-beta2GPI Ab's were observed in mice immunized with Haemophilus influenzae, Neisseria gonorrhoeae, or tetanus toxoid. The specificity of binding to the corresponding target molecules was confirmed by competition and immunoblot assays. Naive mice infused with the affinity-purified antipeptide Ab's had significant thrombocytopenia, prolonged activated partial thromboplastin time and elevated percentage of fetal loss, similar to a control group of mice immunized with a pathogenic anti-beta2GPI mAb. Our study establishes a mechanism of molecular mimicry in experimental APS, demonstrating that bacterial peptides homologous with beta2GPI induce pathogenic anti-beta2GPI Ab's along with APS manifestations.

Animals↗

PubMed2002

Caveolin-1 expression in ovarian carcinoma is MDR1 independent.

We studied the role of caveolin-1 in tumor progression and prognosis in serous ovarian carcinoma and the association between caveolin-1 and MDR1 expression. The study involved immunohistochemical analysis for caveolin-1 and P-glycoprotein (P-gp) expression in 75 effusions and 90 solid lesions from ovarian and primary peritoneal carcinoma; in situ hybridization for MDR1 messenger RNA (mRNA) expression in 62 effusions and all 90 tumors; and reverse transcription-polymerase chain reaction (RT-PCR) for caveolin-1 mRNA expression in 23 effusions. Immunohistochemical analysis localized caveolin-1 to the cell membrane in 43 effusions and 24 tumors. P-gp membrane expression was detected in 14 effusions and 11 tumors; MDR1 mRNA, in 20 effusions and 30 tumors. Caveolin-1 mRNA was expressed in 19 effusions. Caveolin-1 protein expression showed no association with that of P-gp protein or MDR1 mRNA. The expression of all markers was similar in carcinoma cells in pleural and peritoneal effusions. Caveolin-1 is a novel diagnostic marker for effusions; expression is moderately elevated in tumor cells in effusions, possibly owing to altered signal transduction and metabolism in cancer cells at this site. Expression seems MDR1 independent.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2002

Effect of basic fibroblast growth factor on left ventricular geometry in rats subjected to coronary occlusion and reperfusion.

BACKGROUND: Previous studies have demonstrated myocardial salvage by basic fibroblast growth factor administration following chronic myocardial ischemia or acute myocardial infarction. OBJECTIVES: To study the effect of bFGF on left ventricular morphometry following coronary occlusion and reperfusion episode in rats. METHODS: bFGF (0.5 mg) or placebo was continuously administered for a period of one week using an implanted osmotic pump. Animals were sacrificed 6 weeks after surgery and myocardial cross-sections were stained with Massontrichrome and with anti-proliferating cell nuclear antigen antibody. RESULTS: LV area, LV cavity diameter, LV cavity/wall thickness ratio, and injury size were unchanged compared with control animals. Proliferating endothelial cells were significantly more abundant in injured compared with normal myocardium, but with no differences between animals treated or not treated with bFGF. CONCLUSIONS: One week of systemic bFGF administration following coronary occlusion and reperfusion had no additional effect on LV geometry or cellular proliferation in rats.

Angiogenesis Inducing Agents↗