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Gideon Rechavi

Publications and source records attributed to Gideon Rechavi.

87 records · Page 5Linked to original sources
PubMed2003

Genetic predisposition to infectious pathogens: a review of less familiar variants.

The susceptibility and clinical manifestations of infectious diseases in human populations are influenced by a variety of factors, among them host genetics. Obvious examples for the effect of host genetics on predisposition to unique infections are the primary immunodeficiency diseases. Minor gene variants that influence the host immune system are much more common. The iceberg model can be used to illustrate the epidemiology of immunodeficiency states. Accordingly only a few individuals have known and severe recognized primary immunodeficiencies, whereas many more patients have mild immunodeficiencies that may remain undiagnosed and are predisposed to a unique infectious disease. We review some of the less common variants that influence the host defense and predispose to certain infectious agents or change their outcome.

Animals↗
PubMed2002

Human and porcine early kidney precursors as a new source for transplantation.

Kidney transplantation has been one of the major medical advances of the past 30 years. However, tissue availability remains a major obstacle. This can potentially be overcome by the use of undifferentiated or partially developed kidney precursor cells derived from early embryos and fetal tissue. Here, transplantation in mice reveals the earliest gestational time point at which kidney precursor cells, of both human and pig origin, differentiate into functional nephrons and not into other, non-renal professional cell types. Moreover, successful organogenesis is achieved when using the early kidney precursors, but not later-gestation kidneys. The formed, miniature kidneys are functional as evidenced by the dilute urine they produce. In addition, decreased immunogenicity of the transplants of early human and pig kidney precursors compared with adult kidney transplants is demonstrated in vivo. Our data pinpoint a window of human and pig kidney organogenesis that may be optimal for transplantation in humans.

Adult↗
PubMed2002

SKY detection of chromosome rearrangements in two cases of tMDS with a complex karyotype.

In this study, we used spectral karyotyping (SKY) and fluorescence in situ hybridization (FISH) as complementary techniques for the analysis of two therapy-related secondary myelodysplastic syndrome (t-MDS) cases with complex karyotypes, previously analyzed by G-banding. Different types of SKY's cytogenetic contributions include confirmation of G-banding results, identification of partially characterized rearrangements, identification of marker chromosomes unidentified by G-banding, and detection of cryptic reciprocal translocations. In particular, the ability of SKY to clarify a number of markers led to the comprehension of clonal evolution. The common aberration found in these two t-MDS cases was the fragility of chromosome 5 and monosomy of chromosome 18. We clearly present that the use of SKY combined with conventional G-banding analysis and FISH has assisted in the identification of important chromosomal events that may play a key role in the development of t-MDS.

Aged↗
PubMed2002

Combined analysis of morphology and fluorescence in situ hybridization in follow-up of minimal residual disease in a child with Philadelphia-positive acute lymphoblastic leukemia.

The past decade has brought new technologies to the study of minimal residual disease (MRD) in leukemia. Each of them has limitations and is far from being accurate. Recently, a new multiparametric cell scanning system (Duet) was introduced to the field of MRD detection. This system has the advantage of automatically scanning large numbers of cells and performing combined analysis of morphology and fluorescence in situ hybridization (FISH) on the same cell. We used this system to characterize the lineage and degree of maturation of the cells carrying the minor m-BCR/ABL fusion, in a follow-up of an 8-year-old boy with Philadelphia-positive (Ph(+)) acute lymphoblastic leukemia (ALL). The boy was treated using a high-risk protocol and was closely monitored with FISH analysis for cells carrying the m-BCR/ABL fusion. Consecutive analysis along 2.5 years from remission showed 0.2-4.5% m-BCR/ALB(+) cells in the peripheral blood (PB), which is within the accepted background range for this method. The combined analysis found that all the m-BCR/ABL(+) cells were mature lymphocytes. Because mature lymphocytes have a long life span in the circulation, this finding supports the fact that the patient is in remission. Moreover, since mature differentiated cells have a low proliferative capacity, there is a low risk for relapse.

Cell Division↗
PubMed2002

Identification of direct p73 target genes combining DNA microarray and chromatin immunoprecipitation analyses.

The newly discovered p53 family member, p73, has a striking homology to p53 in both sequence and modular structure. Ectopic expression of p73 promotes transcription of p53 target genes and recapitulates the most characterized p53 biological effects such as growth arrest, apoptosis, and differentiation. Unlike p53-deficient mice that develop normally but are subject to spontaneous tumor formation, p73-deficient mice exhibit severe defects in the development of central nervous system and suffer from inflammation but are not prone to tumor development. These phenotypes suggest different biological activities mediated by p53 and p73 that might reflect activation of specific sets of target genes. Here, we have analyzed the gene expression profile of H1299 cells after p73alpha or p53 activation using oligonucleotide microarrays capable of detecting approximately 11,000 mRNA species. Our results indicate that p73alpha and p53 activate both common and distinct groups of genes. We found 141 and 320 genes whose expression is modulated by p73alpha and p53, respectively. p73alpha up-regulates 85 genes, whereas p53 induces 153 genes, of which 27 are in common with p73alpha. Functional classification of these genes reveals that they are involved in many aspects of cell function ranging from cell cycle and apoptosis to DNA repair. Furthermore, we report that some of the up-regulated genes are directly activated by p73alpha or p53.

Base Sequence↗
PubMed2002

GLI3 is not mutated commonly in sporadic medulloblastomas.

BACKGROUND: Medulloblastoma is a malignant, invasive embryonic tumor of the cerebellum. Sonic hedgehog (SHH) is a secreted glycoprotein that has a major role in the developing cerebellum. Activation of the SHH pathway resulting from mutations in the PATCH gene, which is an inhibitor of the pathway, are associated with hereditary and sporadic medulloblastomas. The GLI3 protein is another negative regulator of SHH signaling. The authors hypothesized that mutations in GLI3 may be associated with meduloblastomas. METHODS: The authors describe a patient with hereditary Greig syndrome, which was caused by mutations in GLI3, and medulloblastoma. Another such patient was described in the literature. They also sequenced the GLI3 gene, including all exon-intron boundaries, in an additional 12 sporadic medulloblastomas. RESULTS: The authors detected a new nonsense germline mutation in a child with Greig syndrome and medulloblastoma. This mutation generates a stop codon in position 809 of GLI3 that has been predicted to result in massive truncation of the protein. Several new polymorphisms, but no tumor-associated mutations, were found in sporadic tumors. CONCLUSIONS: Gli3 is mutated rarely in medulloblastoma.

Cerebellar Neoplasms↗
PubMed2002

A positive feedback mechanism in the transcriptional activation of Apaf-1 by p53 and the coactivator Zac-1.

p53 exerts its tumor suppressor effects by activating genes involved in cell growth arrest and programmed cell death. The p53 target genes inducing growth arrest are well defined whereas those inducing apoptosis are not fully characterized. Proapoptotic activity of p53 was shown to involve several genes like Bax, Noxa and Puma, which may function in the release of cytochrome c from the mitochondria. Cytochrome c associates with Apaf-1 and caspase 9 to form the apoptosome. Genetic and cellular data indicate that Apaf-1 deficiency abrogates the apoptotic effect of p53 and substitutes for p53 loss in promoting tumor formation. Here we show that Apaf-1, the mammalian homologue of C. elegans CED4, is a direct target of p53 as demonstrated by gel shift analysis of the target site sequence in the presence of p53 and by Apaf-1 promoter-luciferase assays. We also show that the p53 activation of the Apaf-1 luciferase construct can be enhanced by the putative tumor suppressor gene product, Zac-1, a transcription factor that has previously been shown to inhibit cell proliferation. Furthermore, we demonstrate that Zac-1 is a possible direct target of p53 since the sequence upstream to the first coding exon of Zac-1 contains a p53 recognition site and the luciferase construct containing this region is activated by p53. These results suggests the existence of a tightly controlled self amplifying mechanism of transcriptional activation leading to apoptosis by p53.

Animals↗
PubMed2002

Interphase fluorescence in situ hybridization detection of chromosome 17 and 17q region gains in neuroblastoma: are they secondary events?

Gains of chromosome 17 and 17q region are the most frequent chromosomal abnormalities in neuroblastoma and have been associated with established prognostic indicators. Interphase fluorescence in situ hybridization (FISH) was used to define the status of chromosome 17 in near-triploid (3n) and near-diploid/tetraploid (2n/4n) primary tumors. Gains of chromosome 17 and 17q were detected in 22 and 26 tumors, respectively, in which the ploidy status was determined mainly by the copy number of chromosome 1. Four different types of gains were detected: gain of whole chromosome 17 (+17) and three partial gains (17q11.2 approximately qter, 17q21.1 approximately qter, and 17q21.3 approximately qter). The 17q11.2 approximately qter gains were found in both the 2n/4n and the 3n tumors. Gains of 17q21.1 approximately qter and 17q21.3 approximately qter were found only in the 2n/4n group, and the latter was involved always as a der(22)t(17;22)(q21;q13). A high association was found between chromosome 17 gains and 3n ploidy: +17 was detected in 93% of the 3n group and was not observed in the 2n/4n group. The +17 clone or clones were always present in combination with a clone with normal copies of chromosome 17 and, in the majority, with a +17q11.2 approximately qter clone. We conclude that interphase FISH is a sensitive method for detecting whole and partial chromosome 17 gains in neuroblastoma and can demonstrate the simultaneous presence of several clones with different status of chromosome 17 in 3n neuroblastomas. We suggest that chromosome 17 and 17q gains are not a primary event in the development of neuroblastoma.

Chromosome Aberrations↗
PubMed2002

MAP kinase activation by mu opioid receptor in cord blood CD34(+)CD38(-) cells.

OBJECTIVE: Opioid receptor expression and function traditionally have been studied in neuronal cells and recently in mature lymphoid cells; however, little is known about their possible functions in hematopoietic stem cells (CD34(+) cells). We studied the expression of the mu receptor on CD34(+) cells and assessed the signal transduction cascade it induces. MATERIALS AND METHODS: Mu-receptor expression on cord blood (CB) and peripheral blood (PB) CD34(+) cells was studied by microarrays, immunostaining, and fluorescence-activated cell sorting analysis. Signal transduction by the mu receptor was studied through Western blots and kinase assay of enkephalin-activated CB CD34(+) cells. Apoptotic, differentiation, and proliferation responses following mu-receptor activatioSn were studied by annexin V assay and inverted microscopy. RESULTS: A prominent difference in gene expression, in favor of CB compared to PB CD34(+) cells, was observed in the mu-receptor gene. This receptor was mainly expressed on the CB CD34(+)CD38(-) subpopulation. A MAP kinase signal transduction cascade was shown to be induced through activation of this receptor by enkephalin or morphine. CONCLUSIONS: We showed for the first time that the mu receptor is expressed on immature CB stem cells and that its activation by enkephalin or morphine induces a MAP kinase signal transduction cascade. Because the MAP kinase cascade is known to elicit proliferation and differentiation responses, these findings suggest a possible role of endogenous enkephalins in hematopoietic stem cell proliferation and differentiation and may lead to therapeutic applications of opiates in CB stem cell expansion and neuronal differentiation.

ADP-ribosyl Cyclase↗
PubMed2002

Immature leukemic CD34+CXCR4+ cells from CML patients have lower integrin-dependent migration and adhesion in response to the chemokine SDF-1.

Chronic myelogenous leukemia (CML), a malignant myeloproliferative disorder originating from a pluripotent stem cell expressing the bcr-abl oncogene, is characterized by abnormal release of the expanded, malignant stem cell clone from the bone marrow (BM) into the circulation. Moreover, immature CD34+ CML cells have lower adhesion to stromal cells and fibronectin as well as lower engraftment potential in severe combined immunedeficient (SCID) and nonobese diabetic (NOD)/SCID mice than normal CD34+ cells. We report in this study that leukemic Philadelphia chromosome-positive (Ph+)CD34+ cells from newly diagnosed CML patients that express the chemokine receptor CXCR4 migrate in response to stromal-derived factor-1 (SDF-1). However, normal Ph-CD34+CXCR4+ cells derived from the same patient have significantly higher migration levels toward SDF-1. In contrast to their transwell migration potential, the SDF-1-mediated integrin-dependent polarization and migration of the Ph+CD34+CXCR4+ cells through extracellular matrix-like gels were significantly lower than for normal cells. Concomitantly, binding of these cells to vascular cell adhesion molecule-1 or fibronectin, in the presence of SDF-1, was also substantially lower. These findings suggest a major role for SDF-1-mediated, integrin-dependent BM retention of Ph+CD34+ cells.

Antigens, CD34↗
PubMed2002

Engraftment and differentiation of human metanephroi into functional mature nephrons after transplantation into mice is accompanied by a profile of gene expression similar to normal human kidney development.

Metanephroi, the embryonic precursors of the adult kidney, can be induced in vivo to grow and develop. Despite their potential clinical utility for transplantation, the ability of human metanephroi to differentiate after transplantation into functional mature nephrons is mostly unknown. To address this, 70-d human metanephroi were transplanted into NOD/SCID mice; global gene expression patterns that underlie development of human metanephric transplants were analyzed and compared with normal human kidney development. In addition, functionality of the grafts was assessed by dimercaptosuccinic acid radioisotope scans at different times after transplantation. The results of hybridization to cDNA arrays when RNA was derived from normal human kidneys at 8, 12, 16, and 20 wk gestation demonstrated that a subset of 240 genes changed substantially with time. The induced genes can be classified as cell cycle regulators, transcription and growth factors, and signaling, transport, adhesion, and extracellular matrix molecules. Strikingly, clustering analysis of global gene expression at 2, 6, and 10 wk after metanephric transplantation revealed an expression profile that characterizes normal human kidney development. Moreover, maturation of the transplants was accompanied by an increased uptake of dimercaptosuccinic acid. Nevertheless, expression levels of specific genes were mostly found to be suppressed in the transplants compared with the normal kidneys. These data provide insights into human kidney development and support the possibility of the transplantability of human metanephroi. Understanding of the molecular regulation of the transplanted developing metanephroi might lead to the development of strategies aimed at increasing the levels of specific genes, nephron endowment, and graft function.

Animals↗
PubMed2002

Molecular medicine--an overview.

Advances in the fields of molecular genetics and cell biology are transforming medicine. Discoveries made today in the laboratory are translated at a rapid pace into new diagnostics and therapeutics. The aim of this series of review on different aspects of molecular medicine is to update physicians on new advances at the bench that are likely to impact bedside medicine.

DNA↗
PubMed2002

Stem-cell transplantation for primary immunodeficiencies.

Until further improvement in gene therapy is achieved, stem-cell transplantation is still the main option for cure of patients with primary immunodeficiency diseases. Performing the transplant in early infancy before severe infections and organ damage develop has the highest chance for success. The remarkable progress that has been achieved in understanding these disorders has made it possible to identify most of the genetic abnormalities. This enables an early transplant immediately after birth or even in utero. However, the optimal approach for stem-cell transplantation in children with immunodeficiency has yet to be determined. The non-myeloablative protocols increasingly used in recent years have the potential for immune reconstitution without considerable toxicity, but the experience is still limited. A better understanding of the specific immune dysfunction and the exact degree of residual immunity may enable the tailoring of the most appropriate conditioning regimen for each patient so that engraftment will be ensured with little morbidity.

Hematopoietic Stem Cell Transplantation↗
PubMedDate not supplied

Reduced human germ cell-less (HGCL) expression in azoospermic men with severe germinal cell impairment.

Germ cell-less (GCL) protein is a nuclear envelope protein highly conserved between the mammalian and Drosophila orthologues. In Drosophila, maternal GCL protein is required to establish the germ lineage during embryonic development. In mammals, it is suggested that the GCL function is mainly in spermatogenesis and that it might be related to the ability of mouse GCL to repress transcription. Using reverse transcriptase-polymerase chain reaction analyses, we investigated the role of human GCL (HGCL) in spermatogenesis by studying its expression in the testicular tissue of 67 azoospermic men with normal karyotype and no Y-chromosome microdeletion. Their testicular biopsy specimens underwent meticulous histological and cytological analysis as well as molecular analysis with various markers of spermatogenesis (RBM1, DAZ, and CDY1). The rate of X-Y and 18 chromosome bivalent formation during meiosis was additionally assessed in 22 of these biopsy specimens and correlated to HGCL expression. Expression of HGCL was affected in parallel with the severity of testicular impairment found. Defective sperm motility was associated with the absence of HGCL. Nevertheless, the absence of HGCL expression did not influence the normal process of chromosome bivalent formation in meiosis. Our results suggest that HGCL is not essential for the chromosomal events of meiosis but might be involved in later aspects of spermatogenesis.

Biopsy↗