PubMed Health⌕ Search

Biomedical subjects

M van de Rijn

Publications and source records attributed to M van de Rijn.

At least 19 recordsLinked to original sources
PubMed2006

Upregulation of histidine decarboxylase expression in superficial cortical nephrons during pregnancy in mice and women.

Mechanisms regulating pregnancy-induced changes in renal function are incompletely understood. Few candidate genes have been identified and data suggest that alternate mechanisms remain to be elucidated. Our objective was to screen thousands of genes expressed in kidneys from mice throughout gestation to identify possible key regulators of renal function during pregnancy. Mouse complementary DNA microarrays were used to screen for differences in expression during pregnancy in C57BL/6 mice. Interesting candidate genes whose expression varied with pregnancy were further analyzed by reverse transcription-PCR and Northern blot. Expression was localized by in situ hybridization and immunohistochemistry. Follow-up immunohistochemical analyses in archival human kidney sections from the fetus, non-pregnant, and pregnant women were also performed. Histidine decarboxylase (HDC), the enzyme that synthesizes histamine, was markedly upregulated in the mouse kidney during pregnancy. HDC expression localized to proximal tubule cells of fetal and adult mice. Females showed strong expression in the juxtamedullary zone before pregnancy and upregulation in the superficial cortical zone (SCZ) by mid-gestation. Histamine colocalized with HDC. Male mice showed only low HDC expression. Similar expression patterns were observed in human kidneys. Our results show that HDC expression and histamine production are increased in the SCZ during pregnancy. If histamine acts as a vasodilator, we speculate that increasing production in the SCZ may increase renal blood flow to this zone and recruit superficial cortical nephrons during pregnancy.

Adolescent↗
PubMed2006

The role of microarray technologies in the study of soft tissue tumours.

Array technologies (gene array, tissue microarray and others) are being used in a growing number of research projects involving soft tissue tumours. Gene array techniques allow for measurements of RNA expression levels or gene copy number changes for a large number of genes in a single specimen. A complementary technique, tissue microarrays, allows for the measurement of expression of a single gene in a large number of specimens. These techniques and similar ones have created a fundamentally new approach to the investigation of soft tissue tumours. This review addresses some of the advantages, problems, and solutions to those problems that come with these technologies.

Cluster Analysis↗
PubMed2004

Applications of microarrays to histopathology.

High-throughput microarray technologies have the potential to impact significantly on the practice of histopathology over the coming years. Global gene expression profiling allows for a systematic search of all human genes for novel diagnostic and prognostic markers and for potential therapeutic targets. Likewise, gene copy number changes can be determined on a gene-by-gene basis using microarrays. Tissue microarrays are an efficient method to extend and validate the findings obtained from the initial 'discovery' phase of the research, done using cDNA microarrays. In addition, tissue microarrays can be used for quality assurance for immunohistochemical and in situ hybridization procedures. In this review we give a brief overview of microarray technology and research uses, and discuss potential applications of microarrays in the practice of diagnostic histopathology.

Animals↗
PubMed2003

[Novel approaches; improved diagnosis and therapy with DNA microarrays. I. Technology and data analysis].

With DNA microarrays it will be possible to refine diagnostics and treatment with the use of genome wide information on a patient's sample. Microarrays are currently applied to unravel gene functions, pathogenetic mechanisms, metabolic routes and the effects of drugs on these, to refine diagnostic classifications and prognostic indexes, and to find new targets for therapy. With genotyping it will be possible to generate risk profiles for certain diseases and to assess the likelihood of a given drug-related side effect. Furthermore, it may accelerate research of mutations in genes for which the normal DNA sequences are already known. The basic principle of DNA microarrays is that thousands of different DNA sequences, each specific for a given gene, are immobilised on a solid surface (for example a microscope slide), arranged in a known order, and are hybridised with a solution of labelled DNA or RNA molecules. The DNA or RNA molecules under investigation bind to complementary base pairs on the slide, and permit us to measure the amount of labelled DNA or RNA hybridised to each gene sequence. Sophisticated software is used to analyse the large amount of data generated. The ultimate aim is to group genes with similar expression patterns across all samples, and then group samples accordingly. Conventional biological or biochemical techniques are required to validate the data obtained with microarrays, and to verify whether the observed associations among genes are biologically relevant.

Diagnostic Techniques and Procedures↗
PubMed2003

[Novel approaches; improved diagnostics and therapeutics with DNA microarrays. II. Applications].

The most important (future) applications of DNA microarrays in medicine are based on three different molecular analyses: gene expression analysis, genotyping with a specific type of microarray (single nucleotide polymorphism chip (SNP chip)), and DNA sequencing to search for a well-known mutation in a certain gene. With gene expression analysis one can obtain a 'molecular signature' of a tissue by allowing tissue RNA to react with a DNA microarray. This information may help to refine disease classifications, to guide the choice of therapy and to find new therapeutic targets. Genotyping utilizes genomic DNA that, after digestion, reacts with a SNP chip to obtain an individual SNP pattern. An SNP is a change of a single base pair within a gene sequence that can sometimes influence the function of the gene product. SNPs are considered to be variations in the genome and should be distinguished from mutations. These variations can for instance provide information about the probability of a certain disease, or the effectiveness or side effect of a certain drug. Sequencing well characterized genes to search for mutations is used to screen for genetic abnormalities. This process can be accelerated with the aid of oligonucleotide arrays. With this tool an individual's risk of developing certain forms of cancer or monogenetic diseases can be estimated.

Diagnostic Techniques and Procedures↗
PubMed2001

Diversity of gene expression in adenocarcinoma of the lung.

The global gene expression profiles for 67 human lung tumors representing 56 patients were examined by using 24,000-element cDNA microarrays. Subdivision of the tumors based on gene expression patterns faithfully recapitulated morphological classification of the tumors into squamous, large cell, small cell, and adenocarcinoma. The gene expression patterns made possible the subclassification of adenocarcinoma into subgroups that correlated with the degree of tumor differentiation as well as patient survival. Gene expression analysis thus promises to extend and refine standard pathologic analysis.

Adenocarcinoma↗
PubMed2001

Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications.

The purpose of this study was to classify breast carcinomas based on variations in gene expression patterns derived from cDNA microarrays and to correlate tumor characteristics to clinical outcome. A total of 85 cDNA microarray experiments representing 78 cancers, three fibroadenomas, and four normal breast tissues were analyzed by hierarchical clustering. As reported previously, the cancers could be classified into a basal epithelial-like group, an ERBB2-overexpressing group and a normal breast-like group based on variations in gene expression. A novel finding was that the previously characterized luminal epithelial/estrogen receptor-positive group could be divided into at least two subgroups, each with a distinctive expression profile. These subtypes proved to be reasonably robust by clustering using two different gene sets: first, a set of 456 cDNA clones previously selected to reflect intrinsic properties of the tumors and, second, a gene set that highly correlated with patient outcome. Survival analyses on a subcohort of patients with locally advanced breast cancer uniformly treated in a prospective study showed significantly different outcomes for the patients belonging to the various groups, including a poor prognosis for the basal-like subtype and a significant difference in outcome for the two estrogen receptor-positive groups.

Algorithms↗
PubMed2001

Towards a novel classification of human malignancies based on gene expression patterns.

As a result of progress on the human genome project, approximately 19 000 genes have been identified and tens of thousands more tentatively identified as partial fragments of genes termed expressed sequence tags (ESTs). Most of these genes are only partially characterized and the functions of the vast majority are as yet unknown. It is likely that many genes that might be useful for diagnosis and/or prognostication of human malignancies have yet to be recognized. The advent of cDNA microarray technology now allows the efficient measurement of expression for almost every gene in the human genome in a single overnight hybridization experiment. This genomic scale approach has begun to reveal novel molecular-based sub-classes of tumours in breast carcinoma, colon carcinoma, lymphoma, leukaemia, and melanoma. In several instances, gene microarray analysis has already identified genes that appear to be useful for predicting clinical behaviour. This review discusses some recent findings using gene microarray technology and describes how this and related technologies are likely to contribute to the emergence of novel molecular classifications of human malignancies.

Breast Neoplasms↗
PubMed2001

Orbital hemangiopericytoma and solitary fibrous tumor: a morphologic continuum.

Solitary fibrous tumors (SFT) and hemangiopericytomas (HPC) are soft tissue tumors with known histologic and immunohistochemical overlap. A series of these tumors located in the orbit were analyzed in order to determine whether they could be re-classified based on currently recognized histologic criteria. Ten orbital spindle cell lesions, all of which were positive for CD34 antigen, were examined. Diagnostic criteria for SFT included a cytologically bland spindle cell lesion with variable cellularity and focal dense collagenization with diffuse, strong CD34 reactivity, while the criteria for HPC required a more monotonous cellular proliferation without significant variability in cellularity, a "staghorn" vascular pattern, minimal collagenization, and focal or absent CD34 staining. Tumors with typical histologic and immunohistochemical features of HPC or SFT were diagnosed as HPC and SFT, respectively. Those tumors with histologic or antigenic profiles not classic for HPC or SFT were defined as 'indeterminate.' Three lesions were classified as SFT and 1 tumor was diagnosed as HPC through use of the above-cited histologic criteria. All lesions showed positive staining of tumor cells with CD34 antigen in varying amounts and were negative for cytokeratin AE1-3, epithelial membrane antigen, CD68, and Factor XIIIa. One solitary fibrous tumor focally stained for S-100 protein and 1 hemangiopericytoma was focally positive for HHF-35. Of the 10 analyzed tumors, 6 were classified as 'indeterminate.' Furthermore, 1 lesion whose primary histology was that of an SFT recurred 9 years later with an appearance consistent with an 'indeterminate' lesion. Our results call into question the present histologic separation of HPC and SFT in the orbit. As in other sites, including deep soft tissue, these data suggest that SFT and HPC are 2 lesions whose morphologic features are best interpreted to exist along a continuum, rather than 2 lesions with distinctly defined histopathology.

Adult↗
PubMed2000

Molecular portraits of human breast tumours.

Human breast tumours are diverse in their natural history and in their responsiveness to treatments. Variation in transcriptional programs accounts for much of the biological diversity of human cells and tumours. In each cell, signal transduction and regulatory systems transduce information from the cell's identity to its environmental status, thereby controlling the level of expression of every gene in the genome. Here we have characterized variation in gene expression patterns in a set of 65 surgical specimens of human breast tumours from 42 different individuals, using complementary DNA microarrays representing 8,102 human genes. These patterns provided a distinctive molecular portrait of each tumour. Twenty of the tumours were sampled twice, before and after a 16-week course of doxorubicin chemotherapy, and two tumours were paired with a lymph node metastasis from the same patient. Gene expression patterns in two tumour samples from the same individual were almost always more similar to each other than either was to any other sample. Sets of co-expressed genes were identified for which variation in messenger RNA levels could be related to specific features of physiological variation. The tumours could be classified into subtypes distinguished by pervasive differences in their gene expression patterns.

Breast Neoplasms↗
PubMed2000

CD40L, but not CD40, is required for allergen-induced bronchial hyperresponsiveness in mice.

Asthma is characterized by immunoglobulin (Ig) E production, infiltration of the respiratory mucosa by eosinophils (EOSs) and mononuclear cells, and bronchial hyperresponsiveness (BHR). Interaction of CD40 on B cells and antigen presenting cells, with its ligand (CD40L) expressed transiently on activated T cells, is known to augment both T cell-driven inflammation and humoral immune responses, especially IgE production. Considering both the prominent role of inflammation in asthma and the association of the disease with IgE, we hypothesized that CD40-CD40L interactions would be important in pathogenesis. To test this hypothesis, we subjected wild-type (WT) mice and animals lacking either CD40 or CD40L to repeated inhalation of Aspergillus fumigatus (Af ) antigen. Af-treated WT mice displayed elevated IgE levels, bronchoalveolar lavage and pulmonary tissue eosinophilic inflammation, and BHR. IgE production was markedly suppressed in both the CD40 -/- and CD40L -/- strains. However, pulmonary inflammation did not appear to be inhibited by either of these mutations. Paradoxically, development of BHR was prevented by the lack of CD40L but not by the absence of CD40. We conclude that CD40/CD40L interactions, although critical in the induction of IgE responses to inhaled allergen, are not required for the induction of EOS-predominant inflammation. CD40L, but not CD40, is necessary for the development of allergen-induced BHR.

Allergens↗
PubMed2000

Peripheral T-cell lymphoma complicated by a proliferation of large B cells.

We studied 14 cases that showed a morphologic appearance of peripheral T-cell lymphoma and contained substantial numbers of CD20+ large B cells. In all but 2 cases, the CD20+ large cells showed a mix of kappa and lambda light chain expression. Two cases showed a focal predominance of kappa expression. In situ hybridization using the EBER1 probe for detection of Epstein-Barr virus (EBV) RNA was performed on every case. EBV RNA was present in 10 cases. Of 8 cases with EBV RNA stained by immunohistochemistry for the latent membrane protein of EBV, 6 were positive. Double-labeling immunohistochemistry and in situ hybridization confirmed that EBV was present in the large B cells. Polymerase chain reaction (PCR) analysis showed a clonal rearrangement of the T-cell receptor (TCR)-gamma chain gene in 12 of 13 cases tested. One additional case showed a clonal rearrangement of the TCR-beta chain gene by Southern blot hybridization. PCR analysis showed a clonal immunoglobulin gene rearrangement in 5 cases, a suggestion of a clonal rearrangement in 1, an oligoclonal pattern in 4, and a polyclonal pattern in 4. The finding of large B and T cells may result in a misdiagnosis of a reactive process or of T-cell-rich B-cell lymphoma. The presence of EBV in some cases could cause further confusion with the reactive T- and B-immunoblastic proliferation of infectious mononucleosis.

Adult↗
PubMed1999

Distinctive gene expression patterns in human mammary epithelial cells and breast cancers.

cDNA microarrays and a clustering algorithm were used to identify patterns of gene expression in human mammary epithelial cells growing in culture and in primary human breast tumors. Clusters of coexpressed genes identified through manipulations of mammary epithelial cells in vitro also showed consistent patterns of variation in expression among breast tumor samples. By using immunohistochemistry with antibodies against proteins encoded by a particular gene in a cluster, the identity of the cell type within the tumor specimen that contributed the observed gene expression pattern could be determined. Clusters of genes with coherent expression patterns in cultured cells and in the breast tumors samples could be related to specific features of biological variation among the samples. Two such clusters were found to have patterns that correlated with variation in cell proliferation rates and with activation of the IFN-regulated signal transduction pathway, respectively. Clusters of genes expressed by stromal cells and lymphocytes in the breast tumors also were identified in this analysis. These results support the feasibility and usefulness of this systematic approach to studying variation in gene expression patterns in human cancers as a means to dissect and classify solid tumors.

Algorithms↗
PubMed1999

Detection of a variant SYT-SSX1 fusion in a case of predominantly epithelioid synovial sarcoma.

BACKGROUND: The translocation t(X;18)(p11.2;q11.2) characterizes synovial sarcoma, fusing the SYT gene at 18q11.2 to either SSX1 or SSX2 at Xp11.2. The usual chimeric product fuses SYT codon 379 to SSX1 or SSX2 codon 111. To date only three variant fusions have been identified. A predominantly epithelioid synovial sarcoma that expressed a novel variant of the SYT-SSX1 fusion is described. METHODS AND RESULTS: The current case was tested for the SYT-SSX fusion by reverse transcriptase polymerase chain reaction (PCR) followed by sequencing of the PCR product. Analysis revealed a 673 bp SYT-SSX1 chimeric product characterized by a novel junction of SYT codon 379 to SSX1 codon 83 with a 6 bp insertion at the fusion junction. CONCLUSION: As the number of reported variations of the SYT-SSX chimeric fusion increases in synovial sarcoma, the mechanics of the translocation machinery and the functional significance of these chimeric fusions will be better understood.

Abdominal Pain↗
PubMed1999

Absence of SYT-SSX fusion products in soft tissue tumors other than synovial sarcoma.

The chromosomal translocation t(X;18), which generates SYT-SSX1 and SYT-SSX2 fusion products, is a sensitive marker for synovial sarcoma; most synovial sarcomas test positive for this marker. However, few studies have addressed the presence of t(X;18) or its fusion products in spindle cell sarcomas in the differential diagnosis of synovial sarcoma. We studied the presence of the SYT-SSX fusion products with reverse transcriptase polymerase chain reaction on frozen tissue samples of 24 synovial sarcomas and 24 other spindle cell sarcomas, including 12 malignant peripheral nerve sheath tumors. In cases histopathologically diagnosed as synovial sarcoma, SYT-SSX fusion products were detected in 21 of 24 (87%) lesions. No evidence of these fusions was found in 12 malignant peripheral nerve sheath tumors, 2 hemangiopericytomas, 3 leiomyosarcomas, 2 fibrosarcomas, 1 poorly differentiated sarcoma (malignant fibrous histiocytoma), 1 sarcoma with rhabdoid features, and 2 sarcomas not otherwise specified. One lesion with histologic, immunohistologic, and ultrastructural features indeterminate for a diagnosis of synovial sarcoma or malignant peripheral nerve sheath tumor was studied and was positive for SYT-SSX1. The SYT-SSX fusion products appear specific for synovial sarcoma and are not seen in other spindle cell lesions in its differential diagnosis.

Adult↗
PubMed1999

Poorly differentiated synovial sarcoma: an analysis of clinical, pathologic, and molecular genetic features.

Poorly differentiated synovial sarcoma is a variant of synovial sarcoma in which the tumor cells lack the bland spindle cell appearance of the usual type monophasic synovial sarcoma. Although poorly differentiated synovial sarcoma has been recognized as an entity for many years, no series addressing the clinicopathologic features of this variant have appeared. We describe the histologic, immunohistologic, and molecular findings of a series of 20 poorly differentiated synovial sarcomas. Three types of poorly differentiated synovial sarcoma can be recognized: a large cell epithelioid variant, a small cell variant, and a high-grade spindle cell variant. Epithelial membrane antigen reactivity was seen in 95% of cases, and reactivity for cytokeratin was seen in 42%. The S100 antigen was expressed in 63% of cases. Electron microscopic findings in poorly differentiated synovial sarcoma parallel those found in usual type synovial sarcoma. In 10 cases, material was available for molecular studies; 9 of 10 cases showed the presence of t(X;18) or the associated fusion gene product. These data indicate that poorly differentiated synovial sarcoma is a lesion that shares immunologic, ultrastructural, and molecular characteristics with the usual synovial sarcoma. Follow-up data were available in 16 patients with a mean follow-up of 39 months. Eight patients died with a mean survival time of 33 months. Poorly differentiated synovial sarcoma is a variant of synovial sarcoma that may be associated with a poor prognosis.

Adolescent↗
PubMed1999

A population based, case control study of non-Hodgkin's lymphoma in patients with rheumatoid arthritis.

OBJECTIVE: Epstein-Barr virus (EBV) associated lymphoproliferative disorders (LPD) similar to those that occur in immunosuppressed solid organ recipients have been reported in patients with rheumatoid arthritis (RA). These LPD cause significant morbidity and/or mortality in a state of sustained immunosuppression, but may spontaneously regress if immunocompetence is restored. We determined the population based frequency of EBV associated LPD relative to all non-Hodgkin's lymphomas (NHL) that occur in the general population of patients with RA. METHODS: Forty-two case patients with NHL and RA and 49 control patients with NHL and no RA were identified in a population based, case control study of NHL that occurred in a 6 county Northern California area during the years 1988-94. The lymphoma tissue specimens were reviewed and the diagnosis of NHL was confirmed. In addition, the specimens were analyzed for NHL grade, histologic subtype, histopathologic features associated with immunosuppression, immunophenotype, and the presence of EBV genome in the tumor cells. RESULTS: No significant differences were identified between NHL in the RA case group and the control group (no RA) with respect to any variables investigated. One patient (2%) in the case group and one (2%) in the control group developed LPD containing EBV. CONCLUSION: Our findings reveal that EBV associated lymphomas represent only a small fraction of all NHL in the general RA patient population. EBV associated LPD should be recognized when they occur because they require a special approach to patient management. However, these data indicate that the majority of NHL that occurs in patients with RA is probably coincidental with RA and not the result of significant immunosuppression.

Adult↗