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2.
Mol Pathol ; 56(4): 218-25, 2003 Aug.
Article in English | MEDLINE | ID: mdl-12890743

ABSTRACT

BACKGROUND: The E-cadherin-catenin adhesion complex is crucial for intercellular adhesiveness and maintenance of tissue architecture. Its impairment is associated with poorly differentiated phenotype and increased invasiveness of carcinomas. AIMS: To evaluate E-cadherin, beta catenin, gamma catenin, and ezrin expression and its relation to histopathological features of primary and metastatic Wilms's tumours. METHODS: Immunohistochemistry was used to determine the expression and cellular distribution of E-cadherin, beta catenin, gamma catenin, and ezrin in primary and metastatic Wilms's tumours. Western blotting was used to determine polypeptide size and expression of E-cadherin and beta catenin in Wilms's tumours compared with normal kidney. RESULTS: Moderate expression of E-cadherin was found mainly in cytoplasm and occasionally cell membranes of dysplastic tubules, whereas low expression was seen in cytoplasm of blastemal cells. Primary and metastatic tumours showed moderate to high beta catenin expression in blastemal and epithelial cells, with predominantly membranous and cytoplasmic staining. Occasional nuclear staining was noted in metastatic tumours. Low to high gamma catenin and ezrin expression was seen in cytoplasm of blastemal and epithelial cells of primary and metastatic tumours. Higher amounts of 92 kDa beta catenin were detected in tumours than in normal kidney. Low expression of 120 kDa E-cadherin was seen in moderately differentiated tumours, whereas expression was lacking in poorly differentiated tumours. CONCLUSIONS: Compared with primary tumours, metastatic tumours showed lower expression of E-cadherin and gamma catenin, with nuclear staining for beta catenin. Low E-cadherin was associated with poorly differentiated tumours. These results suggest that abnormal expression of adhesion proteins correlates with the invasive and metastatic phenotype in Wilms's tumours.


Subject(s)
Biomarkers, Tumor/analysis , Cadherins/analysis , Cytoskeletal Proteins/analysis , Kidney Neoplasms/metabolism , Trans-Activators/analysis , Wilms Tumor/metabolism , Wilms Tumor/secondary , Analysis of Variance , Blotting, Western/methods , Child , Child, Preschool , Desmoplakins , Female , Humans , Immunohistochemistry/methods , Infant , Kidney Neoplasms/pathology , Male , Phosphoproteins/analysis , Wilms Tumor/pathology , beta Catenin , gamma Catenin
3.
Nat Genet ; 23(1): 94-8, 1999 Sep.
Article in English | MEDLINE | ID: mdl-10471507

ABSTRACT

Members of the CCN (for CTGF, cyr61/cef10, nov) gene family encode cysteine-rich secreted proteins with roles in cell growth and differentiation. Cell-specific and tissue-specific differences in the expression and function of different CCN family members suggest they have non-redundant roles. Using a positional-candidate approach, we found that mutations in the CCN family member WISP3 are associated with the autosomal recessive skeletal disorder progressive pseudorheumatoid dysplasia (PPD; MIM 208230). PPD is an autosomal recessive disorder that may be initially misdiagnosed as juvenile rheumatoid arthritis. Its population incidence has been estimated at 1 per million in the United Kingdom, but it is likely to be higher in the Middle East and Gulf States. Affected individuals are asymptomatic in early childhood. Signs and symptoms of disease typically develop between three and eight years of age. Clinically and radiographically, patients experience continued cartilage loss and destructive bone changes as they age, in several instances necessitating joint replacement surgery by the third decade of life. Extraskeletal manifestations have not been reported in PPD. Cartilage appears to be the primary affected tissue, and in one patient, a biopsy of the iliac crest revealed abnormal nests of chondrocytes and loss of normal cell columnar organization in growth zones. We have identified nine different WISP3 mutations in unrelated, affected individuals, indicating that the gene is essential for normal post-natal skeletal growth and cartilage homeostasis.


Subject(s)
Growth Substances/genetics , Immediate-Early Proteins , Intercellular Signaling Peptides and Proteins , Mutation , Oncogene Proteins , Osteochondrodysplasias/genetics , Adolescent , Bone and Bones/physiology , CCN Intercellular Signaling Proteins , Cartilage/growth & development , Cartilage/physiology , Chromosomes, Human, Pair 6 , Connective Tissue Growth Factor , Hand/diagnostic imaging , Haplotypes , Humans , Intracellular Signaling Peptides and Proteins , Male , Molecular Sequence Data , Nephroblastoma Overexpressed Protein , Osteochondrodysplasias/diagnostic imaging , Proto-Oncogene Proteins , Radiography
4.
Genet Test ; 3(4): 329-33, 1999.
Article in English | MEDLINE | ID: mdl-10627939

ABSTRACT

Progressive pseudorheumatoid dysplasia is a skeletal genetic disorder affecting primarily the articular cartilage, causing joint stiffness and leading to a crippling status. More than two-thirds of the reported patients belong to Arab and Mediterranean populations. The disease locus has been mapped to chromosome 6q22 in a region of 12.9 cM using a Jordanian family. We examined two additional families, one Jordanian and one Palestinian, to test for homogeneity of the disorder and the presence of a common haplotype, to fine map the disorder, and to use all the information to derive a tool for heterozygote identification. The two families showed linkage to the same previously reported locus, thus suggesting homogeneity, but they did not share a common haplotype. They also provided information that refined the genetic region for the disease locus to 2.1 cM with three microsatellite markers. The absence of a common haplotype indicates that no common ancestor mutations were inherited by our patients. Genotyping for the three-marker haplotype showed that it can be used as a heterozygote identification tool.


Subject(s)
Chromosomes, Human, Pair 6 , Genetic Linkage , Osteochondrodysplasias/genetics , Adolescent , Adult , Child , Child, Preschool , Female , Haplotypes , Heterozygote , Humans , Jordan , Male , Microsatellite Repeats , Pedigree
5.
Eur J Hum Genet ; 6(3): 251-6, 1998.
Article in English | MEDLINE | ID: mdl-9781029

ABSTRACT

Progressive pseudorheumatoid dysplasia is an autosomal recessive skeletal dysplasia with radiographic changes in the spine similar to Spondyleopiphyseal dysplasia tarda and clinical, though not radiographic resemblance to rheumatoid arthritis. About two-thirds of the reported patients are of Arabic and Mediterranean origin which reflects the relative high incidence in this population. We performed homozygosity mapping utilising the DNA pooling approach to map progressive pseudorheumatoid dysplasia to a chromosomal region on the long arm of chromosome 6. We examined a possible candidate gene in the same region of linkage, namely COL10A1, for alterations in this disorder. We did not identify any mutations in our family, but did not totally exclude COL10A1 gene from being the disease-causing gene.


Subject(s)
Chromosomes, Human, Pair 6 , Collagen/genetics , Osteochondrodysplasias/genetics , Base Sequence , Chromosome Mapping , DNA Primers , Female , Genetic Linkage , Homozygote , Humans , Male , Pedigree
6.
Am J Pathol ; 152(6): 1563-75, 1998 Jun.
Article in English | MEDLINE | ID: mdl-9626060

ABSTRACT

We previously established that the expression of the human nov gene (novH) was altered in Wilms' tumors and that levels of novH and WT1 mRNA were inversely correlated in individual Wilms' tumors. Insofar as novH has been shown to be a target for WT1 regulation, novH might play an important role during normal nephrogenesis and in the development of Wilms' tumors. We now show that during normal nephrogenesis novH protein is tightly associated with differentiation of glomerular podocytes. NovH expression is not restricted to renal differentiation but is also detected in endothelium and neural tissue of the kidney. Our results establish that alteration of novH expression in sporadic and heritable Wilms' tumors is associated with dysregulated expression of both novH mRNA and protein. In general, the highest novH expression was noted in the Wilms' tumor, genitourinary anomalies, aniridia, and mental retardation (WAGR)-associated Wilms' tumors. Expression in the Denys-Drash syndrome (DDS)-associated Wilms' tumors fell within the variable spectrum observed in sporadic Wilms' tumor cases. As in developing kidney podocytes, novH protein was also prominent in the abnormal hypoplastic podocytes from DDS cases and in kidney podocytes adjoining Wilms' tumors. In Wilms' tumors exhibiting heterotypic differentiation, novH protein was expressed at high levels in tumor-derived striated muscle and at lower levels in tumor-derived cartilage. These observations taken together indicate that novH may represent both a marker of podocytic differentiation in kidney and a marker of heterotypic mesenchymal differentiation in Wilms' tumors. In addition, absence or very low levels of WT1 are correlated with higher novH expression, and its variable expression in cases with mutant WT1 (sporadic and DDS) suggests that the potential activation and repression transcriptional functions possessed by WT1 are likely dependent on the specific mutation incurred.


Subject(s)
Gene Expression Regulation , Growth Substances/metabolism , Immediate-Early Proteins/metabolism , Intercellular Signaling Peptides and Proteins , Kidney/metabolism , Wilms Tumor/metabolism , Animals , Blotting, Western , Cells, Cultured , Connective Tissue Growth Factor , Dogs , Glycosylation , Growth Substances/chemistry , Humans , Immediate-Early Proteins/chemistry , Immunohistochemistry , In Situ Hybridization , Kidney/growth & development , Nephroblastoma Overexpressed Protein , RNA, Messenger/analysis , Time Factors
7.
In Vitro Cell Dev Biol Anim ; 32(8): 496-504, 1996 Sep.
Article in English | MEDLINE | ID: mdl-8889604

ABSTRACT

The temporal and spatial expression patterns of the Wilms tumor gene, WT1, were studied during the organogenesis of the mouse kidney in vitro. In situ hybridization and immunocytochemistry localized cellular expression of WT1 in whole kidney organ cultures to the induced metanephric mesenchyme and developing podocytes. Organ cultures were further characterized immunocytochemically with antibodies that specifically labeled the different tubular epithelial components and supporting mesenchyme of the developing nephrons. In organ cultures, the WT1 expression pattern could be visualized in induced metanephric mesenchyme and entire cell cohorts of differentiating podocytes. Expression of WT1 and cell specific markers were retained in short-term monolayer cultures of dissociated kidneys. The development of the metanephric kidney in vitro involves a highly restricted temporal and spatial cellular expression pattern of WT1 which closely follows that observed in tissue sections from gestational kidney isolated during organogenesis in the mouse.


Subject(s)
DNA-Binding Proteins/biosynthesis , Gene Expression Regulation, Developmental , Genes, Wilms Tumor , Kidney/embryology , Nephrons/embryology , Transcription Factors/biosynthesis , Animals , Immunohistochemistry , In Situ Hybridization , Kidney/cytology , Kidney/metabolism , Mice , Nephrons/cytology , Organ Culture Techniques , RNA, Messenger/analysis , RNA, Messenger/biosynthesis , Transcription, Genetic , WT1 Proteins , Zinc Fingers
9.
Ann Pharm Fr ; 47(6): 383-93, 1989.
Article in French | MEDLINE | ID: mdl-2488252

ABSTRACT

In this paper the authors have studied the structure-parasitic activity relationships through the Chemical Abstracts data base which groups together the works published in this field for the last twenty years. With mathematical methods of multidimensional data reduction using a computer it has been possible to validate the classification of human parasites on the base of their sensitivity to chemical families. The specificity of the pharmacochemical relationships was described through two factorial maps. This work shows that it is possible to find new chemical series with potential parasitic activity.


Subject(s)
Anthelmintics/classification , Anti-Infective Agents/classification , Antiprotozoal Agents/classification , Parasites/classification , Animals , Anthelmintics/pharmacology , Anti-Infective Agents/pharmacology , Antiprotozoal Agents/pharmacology , Bibliometrics , Information Systems , Parasites/drug effects , Structure-Activity Relationship
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