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PubMed2006

Matrix metalloproteinase-2 and -9 expression correlated with angiogenesis in human adenomyosis.

BACKGROUND: Adenomyosis is an important cause of dysmenorrhea and infertility for women all over the world, however, the pathogenesis has not been completely elucidated. The purpose of the study was to investigate the role of matrix metalloproteinases (MMPs) and their relation to angiogenesis in human adenomyosis. METHODS: Adenomyotic endometrial specimens were removed by hysterectomy from 68 women with adenomyosis. The control group consisted of 26 normal endometrial specimens. Immunohistochemistry was used to demonstrate expression of MMP-2, -9, vascular endothelial growth factor (VEGF) and microvessel density (MVD). Staining intensity was analyzed by computerized image analysis system. RESULTS: In both eutopic and ectopic endometrium of adenomyosis, the expression of MMP-2, -9 as well as VEGF was significantly greater than in normal endometrium (p < 0.05). MVD was higher in ectopic endometrium than eutopic endometrium with or without adenomyosis (p < 0.05). In adenomyosis, a positive correlation was observed between VEGF expression and MMP-2 (p < 0.001, r = 0.583) as well as MMP-9 expression (p = 0.002,r = 0.490). A positive correlation was also found between MVD and MMP-2 (p < 0.001,r = 0.589) or MMP-9 expression (p < 0.001,r = 0.589). CONCLUSION: Our results indicate that the elevation of MMP-2, -9 expression may have an important role in the development of adenomyosis, probably through contributing to invasion of endometrial tissues into the myometrium and angiogenesis in adenomyotic implants.

Adult↗

PubMed2004

Cellular protein and mRNA expression patterns of matrix metalloproteinases-2, -3 and -9 in human breast cancer: correlation with tumour growth.

The expression of matrix metalloproteinases (MMPs) with type IV collagenase activity has been associated with tumour invasion and metastatic potential in experimental models. We studied whether the cellular localization of MMP expression provides useful information on tumour behaviour in human breast cancer. Immunohistochemistry and non-radioisotopic-detected in situ hybridization were used to study protein and mRNA expression profiles for MMPs-2, -3 and -9 in paraffin sections of 70 invasive breast carcinomas. Protein and mRNA expression of the MMPs was observed in tumour as well as in peritumoural stromal cells. MMP protein expression was increased at the invasive border (p < 0.05). Grade 3 carcinomas expressed MMP-2 mRNA in significantly more tumour cells than grade 2 carcinomas (p = 0.006). Ductal carcinomas with an extensive intraductal component were characterized by the lowest percentages of MMPs-2 and -3 mRNA expressing peritumoural stromal cells (p < 0.05). No correlation was observed between MMP protein/mRNA expression and pTNM classification. In conclusion our results indicate that the expression of MMPs is associated with tumour behaviour. The correlation of MMPs-2 and -3 expression in peritumoural stromal cells with tumour type, shown for the first time, suggests that transcriptional regulation of these MMPs in stromal cells is important for the growth pattern of breast cancer.

Breast Neoplasms↗

PubMed1987

New scoring matrix for amino acid residue exchanges based on residue characteristic physical parameters.

Based on residue characteristic physical parameters, a new scoring matrix, called EMPAR, for amino acid exchanges in proteins was obtained. When comparing protein sequences for detecting homologies, the use of this matrix in place of the Dayhoff log-odds matrix yields results that reflect the topological similarities in the proteins. The use of EMPAR is equivalent to the parametric correlates coefficient approach of Ooi and his colleagues. This matrix correlates at 0.63 with the Dayhoff matrix.

Amino Acid Sequence↗

PubMed1999

Semiclassical spectra and diagonal matrix elements by harmonic inversion of cross-correlated periodic orbit sums.

Semiclassical spectra weighted with products of diagonal matrix elements of operators A(alpha), i.e., g(alphaalpha')(E)= summation operator(n) /(E-E(n)), are obtained by harmonic inversion of a cross-correlation signal constructed of classical periodic orbits. The method provides highly resolved semiclassical spectra even in situations of nearly degenerate states, and opens the way to reducing the required signal lengths to shorter than the Heisenberg time. This implies a significant reduction of the number of orbits required for periodic orbit quantization by harmonic inversion.

Journal Article↗

PubMed2005

Expression of cyclooxygenase-2 and matrix metalloproteinase-9 in gastric carcinoma and its correlation with angiogenesis.

OBJECTIVE: To investigate the expression of cyclooxygenase (COX)-2 and matrix metalloproteinase (MMP)-9 in gastric carcinomas, and to correlate this expression with clinicopathological parameters and angiogenesis. METHODS: Ninety-six resected tumor specimens from patients with gastric carcinoma were obtained, and 30 corresponding paracancerous normal tissues were randomly selected as a control. Immunohistochemical staining was used for detecting the expression of COX-2 and MMP-9. Monoclonal antibody against CD34 was used for displaying vascular endothelial cells, and microvascular density (MVD) was calculated by counting of CD34-positive vascular endothelial cells. RESULTS: The positive expression rates of COX-2, MMP-9 and MVD in the cancerous tissue were 80.2%, 74.0%, and 32.5 +/- 8.3, respectively, which were significantly higher than those in the normal tissue (P < 0.01). COX-2, MMP-9 expression rates and MVD in the patients with stages III and IV were 91.4%, 84.5% and 34.9 +/- 8.7, respectively, which were significantly higher than those in the patients with stages I and II (P < 0.01). In addition, the Spearman rank correlation test showed that tumor MVD was closely associated with COX-2 (r = 0.311, P < 0.01) and MMP-9 (r = 0.349, P < 0.01) expressions. CONCLUSIONS: Overexpression of COX-2 and MMP-9 is related to tumor invasion and lymph node metastasis in the gastric carcinoma. These results provide evidence that COX-2 contribute to gastric cancer development by promoting MMP-9 expression and angiogenesis.

Adenocarcinoma↗

PubMed1999

The statistical relationship between connectivity and neural activity in fractionally connected feed-forward networks.

It is desirable to have a statistical description of neuronal connectivity in developing tractable theories on the development of biological neural networks and in designing artificial neural networks. In this paper, we bring out a relationship between the statistics of the input environment, the degree of network connectivity, and the average postsynaptic activity. These relationships are derived using simple neurons whose inputs are only feed-forward, excitatory and whose activity is a linear function of its inputs. In particular, we show that only the empirical mean of the pairwise input correlations, rather than the full matrix of all such correlations, is needed to produce an accurate estimate of the number of inputs necessary to attain a prespecified average postsynaptic activity level. Predictions from this work also include distributional aspects of connectivity and activity as shown by a combination of analysis and simulations.

Computer Simulation↗

PubMed2005

Predictors of renal allograft histologic damage progression.

The objective of this study was to analyze factors that are involved in the progression of renal allograft damage in the first 6 mo after transplantation. Donor and 6-mo protocol biopsies of 83 patients who received a renal transplant were classified using the Chronic Allograft Damage Index (CADI). Histologic changes were compared and correlated to clinical parameters at transplantation, at 6 mo, and annually over 2 yr. All CADI components increased significantly in the 6-mo posttransplantation period, except chronic vascular changes and the percentage of glomerulosclerosis. Total cholesterol and LDL- cholesterol at the time of biopsy correlated positively with mesangial matrix increase, and HDL cholesterol correlated negatively with vascular intima increase. High BP at biopsy was associated with tubular atrophy. Diastolic BP at biopsy correlated with 6-mo CADI (CADI-6). Patients with diastolic BP > or =85 mmHg at biopsy had a higher difference between CADI score in protocol biopsies and CADI score in donor biopsies (DeltaCADI) and higher creatinine at 1 and 2 yr. CADI in donor biopsies (CADI-0) >1 was more frequently found in older (odds ratio [OR], 1.07; 95% confidence interval [CI], 1.01 to 1.14) and nontraumatic dead donors (OR, 3.89; 95% CI, 1.13 to 13.33). CADI-6 >3 was more frequently found in those with CADI-0 >1 (OR, 3.82; 95% CI, 1.19 to 12.21), older donors (OR, 1.05; 95% CI, 1.01 to 1.10), and number of AB mismatches (OR, 2.36; 95% CI, 1.09 to 5.10). CADI-0, CADI-6, and DeltaCADI correlated significantly with serum creatinine at hospital discharge, at 6 mo, and at 2 yr. DeltaCADI was affected by initial percentage of glomerulosclerosis (OR, 1.10; 95% CI, 1.02 to 1.19) and creatinine at hospital discharge (OR, 1.01; 95% CI, 1.00 to 1.02). Donor-related as well as nonimmunologic factors, such as hypertension and dyslipidemia, are associated with increased risk for renal allograft damage progression.

Adolescent↗

PubMed2005

Matrix GLA protein gene polymorphisms: clinical correlates and cardiovascular mortality in chronic kidney disease patients.

BACKGROUND: Increased vascular calcification plays an important role in the pathogenesis of cardiovascular events in chronic kidney disease (CKD) patients. It is the result of an active ossification process counteracted by 'protective' proteins, such as matrix GLA protein (MGP). Polymorphisms of MGP have been identified. METHODS: The aim of this study was to define the distribution of two MGP polymorphisms (-7, -138) in 99 hemodialysis (HD) patients, in 26 patients with CKD stage 3 and in 135 age- and sex-matched healthy controls. Patients were followed up for 12 months to record any cardiovascular deaths. The cause of death was determined by medical doctors, considering the medical history of each patient. The primers were designed with Primer Express software. RESULTS: MGP -138TT homozygotes were more frequent in the HD group versus controls (p = 0.0004). Additionally, the frequency of the T allele was significantly higher in the HD group (p = 0.0006). The frequency of the A allele of MGP-7 was significantly higher both in the HD group (p = 0.033) and in the CKD group (p = 0.0017) versus controls. MGP-7 GG homozygotes were significantly less common in the CKD group than in controls (p = 0.037). Combination -138TT -7AA was significantly more frequent in both CKD patients (p = 0.001) and in HD patients (p = 0.029) than in controls. Seventeen out of 99 HD patients experienced fatal cardiovascular events. Sixteen (94.1%) were -138TT homozygotes and either -7AA homozygotes or -7GA heterozygotes. CONCLUSION: This study suggests that CKD and HD patients have a different distribution of MGP gene polymorphism as compared with the normal population. Altered MGP gene polymorphism may be a negative prognostic factor for the progression to end-stage renal disease and for cardiovascular events in CKD patients.

Aged↗

PubMed2002

Local antilaminin antibody treatment alters the rejection pattern of murine cardiac allografts: correlation between cellular infiltration and extracellular matrix.

BACKGROUND: Emerging data place extracellular matrix (ECM) proteins as important elements in lymphocyte positioning and effector function in alloreactive responses. Using a non-vascularized model of allogeneic heart transplantation in Swiss mice, we have observed a correlation between the cellular infiltration and ECM deposition towards the interior of the graft during the kinetics of rejection. METHODS: To confirm the importance of ECM during the rejection process in this model, we treated the transplanted animals with local injections of antilaminin monoclonal antibody and analyzed, by histology and immunohistochemistry, the grafts on day 15, which corresponds to the peak of cellular infiltration and ECM deposition. RESULTS: The treatment with mAb antilaminin decreased the cellular infiltrate and ECM deposition within the grafts, as compared to controls. Moreover, we found a diminished IFN-gamma, TNF-alpha and IL-2 deposition in the transplant area, and a reduced co-localization of these cytokines with laminin. By contrast, the antilaminin treatment increased tenascin deposition, a molecule with immunosuppressive properties, and also caused an increase in apoptosis of the cellular infiltrate. CONCLUSIONS: These data hallmark the importance of laminin, in distinct aspects concerning the events leading to allograft rejection, and also reinforce this molecule as a potential target for immune intervention in organ transplantation.

Animals↗

PubMedDate not supplied

Serum matrix metalloproteinase-3 and fibrin degradation product levels correlate with clinical disease activity in rheumatoid arthritis.

OBJECTIVE: Plasmin and matrix metalloproteinase-3 (MMP-3) have been linked to articular destruction in rheumatoid arthritis (RA). We compared circulating levels of plasmin-mediated fibrin degradation product (FDP D-dimer) and MMP-3 with traditional parameters of disease activity in RA to determine their clinical utility. MATERIALS AND METHODS: Serum levels of MMP-3 and D-dimer were determined by enzyme-linked immunoassays in 60 patients with RA. Twenty healthy females and 21 patients with systemic lupus erythematosus (SLE) served as controls. RESULTS: MMP-3 (436.8 +/- 474.2 ng/ml) and D-dimer levels (351.2 +/- 296.3 ng/ml) were markedly elevated in the sera from RA patients as compared with healthy controls (43.9 +/- 15.2 ng/ml and 63.0 +/- 64.1 ng/ml, p < 0.0001, respectively). Both levels strongly correlated with each other (r = 0.627, p < 0.0001) and were closely associated with various clinical parameters for the disease activity of RA, including the erythrocyte sedimentation rate (ESR) and the Lansbury's activity index (p < 0.0001). MMP-3 levels were more highly correlated with articular parameters such as the swollen and painful joint counts (r = 0.454, p = 0.0002), whereas D-dimer levels correlated well with C-reactive protein (CRP) levels (r = 0.581, p < 0.0001). In SLE patients, MMP-3 (239.1 +/- 199.6 ng/ml, p < 0.0001) and D-dimer levels (86.9 +/- 85.2 ng/ml, p = 0.0278) were also higher than in healthy controls. Both levels correlated with each other (r = 0.612, p = 0.0025), and were associated with ESR and CRP levels, as was observed in RA patients, but not with most of the other clinical indicators for SLE. CONCLUSIONS: Serum levels of MMP-3 and D-dimer are clinically useful indicators for disease activity in RA. Our results further support the hypothesis that MMP-3 and plasmin may interact in the inflammatory synovial tissues, and thus augment the articular destruction seen in RA. In SLE patients, however, MMP-3 producing cells could be different from in RA patients, and further studies will be required to clarify the pathogenetic mechanism underlying the raised serum levels of MMP-3 and/or D-dimer.

Adult↗

PubMed2003

Expression of cyclooxygenase-2 in renal cell carcinoma: correlation with tumor cell proliferation, apoptosis, angiogenesis, expression of matrix metalloproteinase-2, and survival.

PURPOSE: Cyclooxygenase (COX)-2 plays an important role in tumor cell proliferation, resistance to apoptosis, angiogenesis, and invasion in various malignant tumors. However, the relationships between COX-2 expression and these biological processes, clinicopathological features, and survival rate in patients with renal cell carcinoma are not clear. EXPERIMENTAL DESIGN: Tumor sections surgically removed from 131 patients were examined for COX-2 expression by immunohistochemistry. We also examined Ki-67 labeling index, apoptotic index, microvessel density, and matrix metalloproteinase (MMP)-2 expression, and correlated COX-2 expression with various clinicopathological features and survival. RESULTS: Of 131 sections, 70 (53.4%) were positive for COX-2 expression. COX-2 expression was associated significantly with various clinicopathological features, and correlated with the Ki-67 labeling index, microvessel density, and MMP-2 expression (P < 0.01), but not with the apoptotic index (P = 0.054). COX-2 expression was also identified as an independent risk factor for large tumor size (>7 cm) in multivariate logistic regression model. COX proportional hazards analysis showed that distant metastasis and high T stage were independent prognostic factors [odds ratio (OR), 9.41; 95% confidence interval (CI), 2.16-41.11; P < 0.01 and OR, 5.19; 95% CI, 1.02-26.54; P = 0.048, respectively), whereas COX-2 expression was not (OR, 1.46; 95% CI, 0.24-9.00; P = 0.68). CONCLUSION: COX-2 expression in patients with renal cell carcinoma is associated with several clinicopathological factors, and appeared to play an important role in tumor cell proliferation and MMP-2 expression, but is not a significant prognostic factor.

Adult↗

PubMed1996

Matrix metalloproteinases and tumor invasion: from correlation and causality to the clinic.

Tumor cell invasion is now viewed as dysregulated physiologic invasion. Investigators have started to define the molecular events that are involved in this process. We find that there are many functional similarities with molecular events involved in physiologic process such as angiogenesis and wound healing. Matrix metalloproteinase activity is a common denominator in these pathologic conditions and in normal responses. Studies using endogenous metalloproteinase inhibitors suggest that targeting matrix metalloproteinase activity may prevent tumor cell dissemination. The development and pre-clinical testing of novel, low molecular weight matrix metalloproteinase inhibitors support this concept and suggest that an exciting new era of cancer therapy is on the horizon.

Endopeptidases↗

PubMed2003

Zymographic analysis of latent and activated forms of matrix metalloproteinase-2 and -9 in synovial fluid: correlation to polymorphonuclear leukocyte infiltration and in response to infection.

BACKGROUND: Matrix metalloproteinase-2 and-9 (MMP-2, MMP-9), and gelatinase A and B participate in the degradation of the extracellular matrix proteins in a variety of inflammatory connective tissue diseases including arthritis. METHODS: Synovial fluid was collected by aseptic aspiration from patients with rheumatoid arthritis (RA), osteoarthritis (OA), gout, infected joint, septic arthritis, and systemic lupus erythematosus (SLE). Synovial fluid was subjected to cell count with polymorphonuclear leukocyte (PMN) differential, Gram staining and culture as necessary. MMP-2 and -9 were characterized by substrate gel electrophoresis (gelatin zymography) to resolve latent and activated 'partially proteolyzed' forms. RESULTS: Gelatin zymography revealed that MMP-9 (92, 130, 225 kDa) in synovial fluid was associated with extent of white blood cell infiltration specifically PMNs. In contrast, fibroblast MMP-2 (72 kDa) was present in all synovial fluids irrespective of PMN count. No MMP-9 was detected in the osteoarthritic specimen with low PMN count. Higher PMN count was associated with the presence of activated MMPs, especially in specimens that were confirmed culture positive. Activated synovial fluid MMPs persisted despite resolution of infection. DISCUSSION: Latent and activated MMP-2 and MMP-9 in synovial fluids fluctuate in proportion to PMN infiltration and specifically in response to infection. The presence of activated MMPs post-therapy would suggest that use of specific MMP inhibitors be indicated to eliminate activated MMPs that apparently persist post-infection.

Adult↗

PubMed2006

Estimation of genetic correlations among countries in international dairy sire evaluations with structural models.

The increase in the number of participating countries and the lack of genetic ties between some countries has lead to statistical and computational difficulties in estimating the genetic (co)variance matrix needed for international sire evaluation of milk yield and other traits. Structural models have been proposed to reduce the number of parameters to estimate by exploiting patterns in the genetic correlation matrix. Genetic correlations between countries are described as a simple function of unspecified country characteristics that can be mapped in a space of limited dimensions. Two link functions equal to the exponential of minus the Euclidian distance between the coordinates of two countries and the exponential of minus the square of this Euclidian distance were used for the study on international simulated and field data. On simulated data, it was shown that structural models might allow an easier estimation of genetic correlations close to the border of the parameter space. This is not always possible with an unstructured model. On milk yield data, genetic correlations obtained from 22 countries for structural models based on 2 and 7 dimensions, respectively, were analyzed. Only a structural model with a large number of axes gave reasonable estimates of genetic correlations compared with correlations obtained for an unstructured model: 76.7% of correlations deviated by less than 0.030. Such a model reduces the number of parameters from 231 genetic correlations to 126 coordinates. On foot angle data, large deviations were observed between genetic correlations estimated with an unstructured model and correlations estimated with a structural model, regardless of the number of axes taken into account.

Algorithms↗

PubMed1997

Plasminogen activator and matrix metalloproteinase production and extracellular matrix degradation by rat prostate cancer cells in vitro: correlation with metastatic behavior in vivo.

BACKGROUND: The plasminogen activation (PA) and metalloproteinase (MMP) system are involved in tumor cell migration and invasion. METHODS: The proteolytic activity of cell lines originating from the rat Dunning R-3327 prostate tumor was analyzed by measuring in vitro extracellular matrix degradation, enzyme activity, and mRNA levels of enzymes, inhibitors, and receptors, and compared with their known metastatic behavior in vivo. RESULTS: Only the highly metastatic sublines AT-3, MATLu, and MATLyLu showed a high extracellular matrix degradation mediated by urokinase-type plasminogen activator (u-PA). Relatively high levels of u-PA were present in the aggressive cell lines. u-PA receptor mRNA was produced in all cells, and all but AT-1 produced LDL-receptor-related-protein (LRP) mRNA. t-PA mRNA was only found in HIF and MATLu. In gelatin, zymography lysis was observed at 72 kD and 74-76 kD in MATLu and MATLyLu cells, respectively. MMP-2 mRNA was present in all cell lines except AT-1 and AT-2, and MMP-3 mRNA was present in AT-2, AT-3, and MATLu. CONCLUSIONS: These in vitro experiments show that in different rat prostate cancer sublines, proteolytic activity and u-PA-mediated extracellular matrix degradation correlate with their known metastatic behavior in vivo.

Analysis of Variance↗

PubMed1999

Correlations of eigenvectors for non-Hermitian random-matrix models.

We establish a general relation between the diagonal correlator of eigenvectors and the spectral Green's function for non-Hermitian random-matrix models in the large-N limit. We apply this result to a number of non-Hermitian random-matrix models and show that the outcome is in good agreement with numerical results.

Journal Article↗

PubMed1992

Severe generalised dystonia associated with a mosaic pattern of striatal gliosis.

A mosaic pattern of striatal pathology is described in a male who developed severe generalised dystonia from the age of 10 years, and died at the age of 18 years. There was no family history of dystonia, and extensive investigations during his life failed to identify a cause for the dystonia. The caudate nucleus and putamen showed a network of cell loss and gliosis surrounding islands of preserved striatum. Dorsal parts showed confluent gliosis, and ventral parts were spared. The pattern suggested a correlation with patch-matrix organisation, but there was no correlation with the distribution of calbindin immunoreactive cells, which are present in the matrix of the classical striosome-matrix organisation. The pathological findings were unlike those in status marmoratus, perinatal hypoxia-ischaemia, Huntington's disease, and neuroacanthocytosis, but similar to those reported in a 44-year-old man with predominantly cranial dystonia.

Adolescent↗

PubMed1996

Characteristics of high and low laminin-adherent Dunn osteosarcoma cells selected by adhesiveness to laminin. Correlation between invasiveness through the extracellular matrix and pulmonary metastatic potential.

We investigated the invasiveness through the extracellular matrix and pulmonary metastatic potential in high laminin-adherent [LN(+)] and low laminin-adherent [LN(-)] Dunn oseosarcoma cells selected for adhesiveness to laminin. In the invasion assay using a reconstituted basement membrane (matrigel) in a Boyden chamber, LN(+) cells proved to be more invasive than LN(-) and the parental Dunn cells. Pulmonary metastatic potential was correlated with invasiveness through the matrigel in three cell types. The ability of LN(+) cells to attach to laminin and the matrigel was significantly higher than that of LN(-) or the parental Dunn cells. LN(-) cells showed much lower attachment ability compared to the other cells. There were no significant differences in type IV collagenolysis and cell migration among the three cell types. In LN(+) and the parental Dunn cells, laminin significantly stimulated type IV collagenolytic and migration activities. LN(-) cells showed no significant differences of type IV collagenolysis and cell migration in response to laminin. These findings suggested that the different invasiveness of these cells was associated with the difference in the abilities of cell attachment to laminin and type IV collagenolysis and cell migration activities stimulated by laminin. YIGSR inhibited not only the laminin-mediated cell attachment but also the type IV collagenolysis and cell migration induced by the cell attachment to laminin. The amount of laminin receptor of LN(+) cells was about fourfold that of LN(-) and twofold that of the parental Dunn cells, suggesting the stimulatory effect of laminin on the invasiveness through the matrix is associated with the level of laminin receptor expression in these cells. The present study provides several findings suggesting that laminin has important roles in invasiveness through the extracellular matrix and metastasis formation in Dunn osteosarcoma cells.

Animals↗