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Biomedical subjects

Isaac Yaniv

Publications and source records attributed to Isaac Yaniv.

48 records · Page 3Linked to original sources
PubMed2003

High incidence of early cholelithiasis detected by ultrasonography in children and young adults with hereditary spherocytosis.

OBJECTIVES: Retrospective cholecystography studies in adults with hereditary spherocytosis (HS) suggested detectable gallstones in 37% to 43% of patients. Since longitudinal studies using biliary ultrasonography are unavailable, the aim of the present study was to determine the incidence of gallstone disease, as detected by biliary ultrasonography, in children and young adults with HS. As individuals with HS who co-inherit Gilbert syndrome have a greater risk of developing gallstones, uridine diphosphate-glucuronyl transferase (UGT-1A) gene polymorphism was also determined. PATIENTS AND METHODS: The authors retrospectively evaluated 44 patients aged 1.4 to 22 years with HS, 12 (27%) of whom underwent splenectomy. Ultrasonography was performed annually starting at the age of 4 years or at the time of diagnosis, if later. RESULTS: Of the 44 patients, 18 (41%) developed cholelithiasis as demonstrated by gallbladder ultrasonography. In most patients (94%) the test first proved positive at age 4 to 13 years. Patients with HS and Gilbert syndrome tended to be younger at the time of cholelithiasis. CONCLUSIONS: Early cholelithiasis was detected in children and young adults with HS. To identify this complication, the authors recommend early annual biliary ultrasonography in HS children, starting at about 4 years of age. In patients with Gilbert syndrome, closer follow-up may be indicated.

Adolescent↗
PubMed2002

Congenital dyserythropoietic anemia type I is caused by mutations in codanin-1.

Congenital dyserythropoietic anemias (CDAs) constitute a rare group of inherited red-blood-cell disorders associated with dysplastic changes in late erythroid precursors. CDA type I (CDAI [MIM 224120], gene symbol CDAN1) is characterized by erythroid pathological features such as internuclear chromatin bridges, spongy heterochromatin, and invagination of the nuclear membrane, carrying cytoplasmic organelles into the nucleus. A cluster of 45 highly inbred Israeli Bedouin with CDAI enabled the mapping of the CDAN1 disease gene to a 2-Mb interval, now refined to 1.2 Mb, containing 15 candidate genes on human chromosome 15q15 (Tamary et al. 1998). After the characterization and exclusion of 13 of these genes, we identified the CDAN1 gene through 12 different mutations in 9 families with CDAI. This 28-exon gene, which is transcribed ubiquitously into 4738 nt mRNA, was reconstructed on the basis of gene prediction and homology searches. It encodes codanin-1, a putative o-glycosylated protein of 1,226 amino acids, with no obvious transmembrane domains. Codanin-1 has a 150-residue amino-terminal domain with sequence similarity to collagens and two shorter segments that show weak similarities to the microtubule-associated proteins, MAP1B (neuraxin) and synapsin. These findings, and the cellular phenotype, suggest that codanin-1 may be involved in nuclear envelope integrity, conceivably related to microtubule attachments. The specific mechanisms by which codanin-1 underlies normal erythropoiesis remain to be elucidated.

Amino Acid Sequence↗
PubMed2002

Related umbilical cord blood transplantation in patients with thalassemia and sickle cell disease.

Allogeneic bone marrow transplantation (BMT) from HLA-identical siblings is an accepted treatment for both thalassemia and sickle cell disease (SCD). However, it is associated with decided risk of both transplant-related mortality (TRM) and chronic graft-versus-host disease (GVHD). We analyzed 44 patients (median age, 5 years; range, 1-20 years) given an allogeneic related cord blood transplant for either thalassemia (n = 33) or SCD (n = 11). Thirty children were given cyclosporin A (CsA) alone as GVHD prophylaxis, 10 received CsA and methotrexate (MTX), and 4 patients received other combinations of immunosuppressive drugs. The median number of nucleated cells infused was 4.0 x 10(7)/kg (range, 1.2-10 x 10(7)/kg). No patient died and 36 of 44 children remain free of disease, with a median follow-up of 24 months (range, 4-76 months). Only one patient with SCD did not have sustained donor engraftment as compared with 7 of the 33 patients with thalassemia. Three of these 8 patients had sustained donor engraftment after BMT from the same donor. Four patients experienced grade 2 acute GVHD; only 2 of the 36 patients at risk developed limited chronic GVHD. The 2-year probability of event-free survival is 79% and 90% for patients with thalassemia and SCD, respectively. Use of MTX for GVHD prophylaxis was associated with a greater risk of treatment failure. Related CBT for hemoglobinopathies offers a good probability of success and is associated with a low risk of GVHD. Optimization of transplantation strategies could further improve these results.

Acute Disease↗
PubMed2002

Factors influencing outcome and incidence of long-term complications in children who underwent autologous stem cell transplantation for acute myeloid leukemia in first complete remission.

To evaluate factors influencing outcome and incidence of long-term complications, we analyzed, in a retrospective, multicenter study, 387 children who underwent autologous hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML) in first complete remission (CR). Median follow-up time from transplantation was 60 months. Transplantation of bone marrow cells was performed in 318 children, whereas in 60 patients peripheral blood progenitor cells (PBPCs) were used. In multivariate analysis, we investigated the variables influencing probability of hematopoietic recovery, transplantation-related mortality (TRM), relapse, and leukemia-free survival (LFS). We found that use of PBPCs as stem cell sources and use of BCNU (N,N-bis[2-chloroethyl]-N-nitrosourea), amsacrine, VP-16, and cytosine arabinoside (BAVC) as a preparative regimen were associated with faster neutrophil recovery. Infusion of PBPCs, young age of patients, use of BAVCs, and absence of marrow purging predicted an accelerated platelet reconstitution. The 5-year Kaplan-Meier estimates of TRM, relapse, and LFS were 3% +/- 1%, 39% +/- 3% and 60% +/- 3%, respectively. Relapse probability was increased in children given the BAVC regimen, and it was decreased after in vitro purging of hematopoietic progenitors and in children with a French-American-British classification of M3 and a time interval of 170 days or more between CR and HSCT. These 2 latter variables favorably influenced the probability of LFS, which was, by contrast, reduced with the BAVC regimen. Thirty-three percent of patients surviving more than 18 months experienced at least one late sequela; use of total body irradiation was the only predictive factor. The results obtained in this analysis can be of help in designing prospective studies of autologous HSCT in children with AML in first CR.

Adolescent↗
PubMed2002

Distinct cytogenetic pathways of advanced-stage neuroblastoma tumors, detected by spectral karyotyping.

Molecular studies of advanced-stage neuroblastoma (NBL) have revealed a marked genetic heterogeneity. In addition to MYCN amplification and chromosome 1 short-arm deletions/translocations detected by conventional cytogenetics, application of fluorescence in situ hybridization has disclosed a high prevalence of 17q gain, whereas allelotyping and comparative genomic hybridization techniques also have revealed loss of 11q and of other chromosomal material. Using the recently developed technique of spectral karyotyping (SKY), we sought to refine the cytogenetic information, identify hidden recurrent structural chromosomal abnormalities, and compare them to the molecular findings. Thirteen samples of metaphase spreads from 11 patients with advanced-stage NBL were analyzed by SKY. Most of them were found to have complex karyotypes (more than three changes per metaphase) and complex unbalanced rearrangements. Recurrent aberrations leading to 17q gain, deletion of 1p, MYCN amplification, and loss of 11q appeared in 7, 4, 4, and 5 patients, respectively, in simple and complex karyotypes. Chromosome 3 changes and gain of 1q and 7q appeared in 6, 5, and 4 patients, respectively, in complex karyotypes only, reflecting later changes. A strikingly high prevalence of the unbalanced translocation der(11)t(11;17), leading to concomitant 11q loss and 17q gain in 4 patients, delineated a distinct cytogenetic group, none having 1p deletion and/or MYCN amplification. der(11)t(11;17) was associated with complex karyotypes with changes in chromosomes 3 and 7q. The 17q translocations with partners other than 11q were associated with 1p deletion and/or MYCN amplification. The distinct cytogenetic subgroups identified by SKY confirm and extend the recent molecular observations, and suggest that different genes may interact in the der(11)t(11;17) pathway of NBL development and progression.

Adolescent↗
PubMed2002

Expression of p53 gene product and cell proliferation marker Ki-67 in Ewing's sarcoma: correlation with clinical outcome.

Overexpression of tumor suppressor gene p53, cell proliferation nuclear antigen Ki-67, and proto-oncogene HER-2/neu are associated with poor prognosis in some tumors. We studied p53, Ki-67, and HER-2/neu immunohistochemical expression in archival biopsies of 37 patients with Ewing's sarcoma (ES). Patients with ES were treated at four Israeli hospitals between 1982 and 2000. Formalin-fixed paraffin-embedded tissue sections were stained by immunohistochemistry for p53, Ki-67, and HER-2/neu. More than 300 cells were counted on each slide, and the percentage of positively stained nuclei was computed. p53 overexpression was defined as nuclear staining of >2.3% of cells, Ki-67 overexpression as nuclear staining of >8.3% malignant cells. HER-2/neu staining was scored semiquantitatively on a scale of 0 to 4+. Twenty-two of 37 patients are alive and well, with mean follow-up time of 38 months. There was overexpression of p53 in 16 patients (43%) and of Ki-67 in 21 patients (57%). The correlation between p53 and Ki-67 overexpressions was 0.61. We found no overexpression of HER-2/neu. Median relapse-free survival (RFS) was statistically significantly shorter for patients with p53 overexpression (25 months) than for patients with negative staining (>92 months). The prognostic value of p53 overexpression was also significant after adjusting for tumor location and age. Median RFS was shorter for patients with positive Ki-67 staining (40 months) than for patients with negative staining (80 months) but did not reach statistical significance. Our study suggests that p53 is a predictor of RFS in patients with ES. More patients must be studied to assess the validity of this observation.

Adolescent↗
PubMed2002

PAX3/forkhead homolog in rhabdomyosarcoma oncoprotein activates glucose transporter 4 gene expression in vivo and in vitro.

Increased levels of glucose uptake and increased expression of the glucose transporter (GLUT) genes are characteristic features of tumors. In the muscle-derived tumor alveolar rhabdomyosarcoma (ARMS), a chromosomal translocation t(2:13) generates the PAX3/forkhead homolog in rhabdomyosarcoma (FKHR) oncoprotein. In muscle tissues, glucose transport is primarily mediated by GLUT4. However, the mechanisms that regulate GLUT4 gene expression in tumor tissues are largely unknown. Therefore, we evaluated the role of PAX3/FKHR in the regulation of GLUT4 gene expression in muscle tumorigenesis. GLUT4 mRNA and protein were detected in ARMS-derived human biopsies and in ARMS-derived RH30 myoblasts, which both express the PAX3/FKHR chimeric protein, but not in either C2C12 or embryonal rhabdomyosarcoma-derived myoblasts. GLUT4 was functionally active in RH30 cells, because insulin induced a 1.4-fold stimulation of basal 2-deoxyglucose uptake rates. Coexpression of PAX3/FKHR increased basal transcriptional activity from a GLUT4 promoter reporter (GLUT4-P) in C2C12, SaOS-2, and Chinese hamster ovary-K1 cells in a dose-dependent and tissue-specific manner. PAX3/FKHR mutants with deletions in either the homeodomain (DeltaHD) or the FKHR-derived activation domain (DeltaFKHR), or in which the PAX3-derived paired domain (PD) was point-mutated (PD-R56L), were unable to activate GLUT4-P. Progressive 5'-deletion analysis of GLUT4-P further identified a specific region of the promoter, -66/+163 bp, which retained about 65% of the full transactivation effect. EMSA studies established that the PAX3/FKHR protein directly and specifically binds to this region and to a shorter fragment, -4/+36 bp, that contains potential binding sites for HD and PD, but not to a -4/+36-bp fragment whose HD and PD sites have been mutated. Thus, the functional interaction of PAX3/FKHR with GLUT4-P appears to require all of the functional domains of PAX3/FKHR, as well as a -4/+36-bp region within the GLUT4 promoter. Taken together, the data suggest that the GLUT4 gene is a downstream target of PAX3/FKHR and that GLUT4 is aberrantly transactivated by this oncoprotein both in vivo and in vitro.

Animals↗
PubMed2002

The molecular biology of Fanconi anemia.

Fanconi anemia is a rare autosomal recessive disorder characterized clinically by congenital abnormalities, progressive bone marrow failure, and a predisposition to malignancy. FA cells are sensitive to DNA cross-linking agents. Complementation analysis of FA cells using somatic cell fusion has facilitated the identification of eight complementation groups, suggesting that FA is a genetically heterogeneous disorder. Six genes (FANCA, FANCC, FANCD2, FANCE, FANGF, FANCG) have been cloned so far. The majority of affected patients belong to FA group A. Of the 32 unrelated Israeli patients with FA that we studied, 6 carried the FANCC mutations and 15 the FANCA mutations. Among the Jewish patients, ethnic-related mutations were common. Recent cumulative evidence suggests that the FA proteins are repair proteins. FANCC, FANCA and FANCG bind and interact in a protein complex found in the cytoplasm and nucleus of normal cells. FANCD2 exists in two isoforms; the long active form, FANCD2-L, is absent from FA cells of all complementation groups. FANCD2 colocalizes with BRCA1 in nuclear foci, probably as part of a large genomic surveillance complex. Studies using FANCA and FANCC knockout mice suggest that bone marrow precursors express interferon-gamma hypersensitivity and show progressive apoptosis. The definition of the molecular basis of FA in many affected families now enables prenatal diagnosis.

Adolescent↗
PubMed2002

Methotrexate-related neurotoxicity in the treatment of childhood acute lymphoblastic leukemia.

The addition of methotrexate to treatment protocols in children with acute lymphoblastic leukemia has been found beneficial in preventing central nervous system relapse. However, MTX itself may be associated with neurologic morbidities, the most significant of which is leukoencephalopathy. The present study describes the clinical spectrum of leukoencephalopathy, which ranges from a subclinical disease manifested only radiologically to a progressive, devastating encephalopathy. The interaction of MTX with other components of the treatment protocol is discussed, as is the effect of leucovorin. A summary is presented of the metabolic pathways that may be involved in the development of MTX toxicity. Researchers are still seeking a biochemical marker to aid in the determination of the amount of MTX that may be safely administered.

Antimetabolites, Antineoplastic↗
PubMedDate not supplied

Central venous line thrombosis in children and young adults with thalassemia major.

High doses of intravenous deferoxamine via central venous line (CVL) has recently been shown to improve survival in patients with noncompliant thalassemia major (TM). The aim of this retrospective study was to evaluate the extent of CVL-related thrombosis and to determine the presence of prothrombotic factors in children and young patients with TM on such a regimen. Twenty-three patients (median age 13, range 5-25 years) with TM in whom a tunneled CVL was inserted for intensification of iron chelation were evaluated for signs and symptoms of thrombosis and for inherited and acquired risk factors of thrombosis. Mean duration of CVL placement was 37 +/- 31 months (range 6-98 months). Eight patients (35%) had CVL-related thrombosis diagnosed clinically or by echocardiography. Nine patients (39%) had prothrombotic factors, but the thrombosis subgroup did not differ from the other group in age, platelet counts, duration of CVL placement, or the presence of predisposing prothrombotic factors. Based on the high rate of CVL-related thrombosis, routine monitoring is suggested for CVL thrombosis in this population.

Adolescent↗
PubMedDate not supplied

Role of 18F-FDG PET/CT in staging and follow-up of lymphoma in pediatric and young adult patients.

OBJECTIVE: To assess the role of 18F-Fluorodeoxyglucose (18F-FDG) PET/CT in pediatric patients with Hodgkin disease (HD) and non-Hodgkin lymphoma (NHL). MATERIALS AND METHODS: 31 patients, mean age 12.9 +/- 5.1, HD (n = 24), and NHL (n = 7) underwent 18F-FDG PET/CT at diagnosis (n = 31 studies) and later in the course of the disease (n = 75 studies). The findings of PET/CT were correlated with diagnostic CT and clinical follow-up. RESULTS: PET/CT findings resulted in a change of disease staging in 10 patients (32.3%), upstaging in 7 (22.6%) and downstaging in 3 (9.6%). On a lesion analysis, 164 disease sites were detected by PET/CT of which 38 were overlooked by DCT. At mid-treatment, PET was negative in 28 out of 31 patients (90%) with negative predictive value of 96% as all latter patients except for 1, were disease free (mean 15.4 +/- 8.8 months). The positive predictive value of persistent increased 18F-FDG uptake was 100% as 3 patients with latter findings had active disease. On the CT part, 76 residual masses were identified in 22 patients. Increased 18F-FDG uptake was detected in 11 masses in 4 patients who had active disease. Remaining 65 PET negative masses were false positive findings. The positive predictive value of residual CT mass was 14%. CONCLUSIONS: PET/CT is associated with change in staging in approximately 1 out of 3 pediatric patients with HD and NHL. When used for monitoring response to treatment, a negative study is associated with disease-free period, even when residual mass is detected. A positive PET study indicates residual malignant disease.

Adolescent↗