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Biomedical subjects

S Schwartz

Publications and source records attributed to S Schwartz.

At least 145 records · Page 8Linked to original sources
PubMed1999

CD82 (KAI1), a member of the tetraspan family, is expressed on early haemopoietic progenitor cells and up-regulated in distinct human leukaemias.

CD82 (KAI1) is a member of the tetraspan transmembrane protein family which has been cloned from lymphoblastoid variant cell lines. However, a role for CD82 in early normal and malignant haemopoiesis has not yet been characterized. We studied the CD82 expression in 33 normal donor samples and 98 leukaemias by fluorescence activated cell sorting (FACS) and reverse transcriptase polymerase chain reaction (RT-PCR). We demonstrated that CD82 was moderately expressed in the vast majority of normal granulocytes and monocytes. In contrast, only about one third of the peripheral blood lymphocytes were weakly CD82 positive (CD82+). Interestingly, judgement of the CD82 transcription and expression in various leukaemias revealed that CD82 was overexpressed in chronic myeloid leukaemia (CML) patients in accelerated or blastic phase (CML-AP/BP) as well as in acute myeloid leukaemia (AML) and chronic lymphocytic leukaemia (CLL) patients. Analysis of AML patients with CD34+/CD82+ blasts prompted us to expand our studies on haemopoietic CD34+ progenitor cells. Intriguingly, 84-95% of the CD34+ cells isolated from healthy bone marrow, cord blood or peripheral blood were highly CD82+. CD82 was abundantly expressed on primitive as well as on committed haemopoietic progenitor cells. After in vitro induction of myeloid differentiation in CD34+ peripheral blood progenitor cells (PBPC), the expression of CD82 decreased to levels similar to those found on peripheral blood granulocytes. These observations suggest for the first time a role for CD82 in normal and malignant haemopoiesis.

Antigens, CD↗
PubMed1999

Carboxypeptidase G2 rescue in a 79 year-old patient with cranial lymphoma after high-dose methotrexate induced acute renal failure.

A 79 year-old female patient presented with immunoblastic B-cell lymphoma of the ethmoidal sinuses and destruction of the anterior cranial fossa. After 3 cycles of high-dose methorexate (HD-MTX) MTX serum level remained elevated and creatinine serum levels raised. The patient received Carboxypeptidase G2 (CPG2) intravenously. Within one hour the MTX serum level decreased to <1 micromol/l as determined by high pressure liquid chromatography (HPLC). The patient recovered without significant toxicity and attained a long lasting ongoing (>14 months) complete remission. In this case we were able to demonstrate that rescue from HD-MT nephrotoxicity by CPG2 is also safe and effective in patients with advanced age with impaired renal function. With the help of CPG2, sufficient and potentially curative therapy with HD-MTX may also be provided to patients with a high risk of renal failure.

Acute Kidney Injury↗
PubMed1999

Chromosome breakage in the Prader-Willi and Angelman syndromes involves recombination between large, transcribed repeats at proximal and distal breakpoints.

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct neurobehavioral disorders that most often arise from a 4-Mb deletion of chromosome 15q11-q13 during paternal or maternal gametogenesis, respectively. At a de novo frequency of approximately.67-1/10,000 births, these deletions represent a common structural chromosome change in the human genome. To elucidate the mechanism underlying these events, we characterized the regions that contain two proximal breakpoint clusters and a distal cluster. Novel DNA sequences potentially associated with the breakpoints were positionally cloned from YACs within or near these regions. Analyses of rodent-human somatic-cell hybrids, YAC contigs, and FISH of normal or rearranged chromosomes 15 identified duplicated sequences (the END repeats) at or near the breakpoints. The END-repeat units are derived from large genomic duplications of a novel gene (HERC2), many copies of which are transcriptionally active in germline tissues. One of five PWS/AS patients analyzed to date has an identifiable, rearranged HERC2 transcript derived from the deletion event. We postulate that the END repeats flanking 15q11-q13 mediate homologous recombination resulting in deletion. Furthermore, we propose that active transcription of these repeats in male and female germ cells may facilitate the homologous recombination process.

Angelman Syndrome↗
PubMed1999

Chromosome breakage hotspots and delineation of the critical region for the 9p-deletion syndrome.

The clinical features of the 9p-deletion syndrome include dysmorphic facial features (trigonocephaly, midface hypoplasia, upward-slanting palpebral fissures, and a long philtrum) and mental retardation. The majority of these patients appear to have similar cytogenetic breakpoints in 9p22, but some cases show phenotypic heterogeneity. To define the breakpoints of the deleted chromosomes, we studied 24 patients with a deletion of 9p, by high-resolution cytogenetics, FISH with 19 YACs, and PCR using 25 different sequence-tagged sites. Of 10 different breakpoints identified, 9 were localized within an approximately 5-Mb region, in 9p22-p23, that encompasses the interval between D9S1869 (telomeric) and D9S162 (centromeric). Eight unrelated patients had a breakpoint (group 1) in the same interval, between D9S274 (948h1) and D9S285 (767f2), suggesting a chromosome-breakage hotspot. Among 12 patients, seven different breakpoints (groups 3-9) were localized to a 2-Mb genomic region between D9S1709 and D9S162, which identified a breakpoint-cluster region. The critical region for the 9p-deletion syndrome maps to a 4-6-Mb region in 9p22-p23. The results from this study have provided insight into both the heterogeneous nature of the breakage in this deletion syndrome and the resultant phenotype-karyotype correlations.

Abnormalities, Multiple↗
PubMed1999

Poly(C)-binding protein interacts with the hepatitis C virus 5' untranslated region.

We have investigated whether poly(C)-binding protein (PCBP)-1 and PCBP-2 interact with the hepatitis C virus (HCV) 5' untranslated region. Our results demonstrate that glutathione S-transferase (GST)-PCBP-1 and GST-PCBP-2 fusion proteins bind specifically to the HCV 5' untranslated region. An antiserum raised against PCBP-2 induced a supershift after incubation with RNA-protein complexes formed between proteins in a HeLa cell cytoplasmic extract and the HCV 5' untranslated region, indicating that this interaction occurs intracellularly. The complete internal ribosome entry site was necessary for efficient binding, suggesting that maintenance of the secondary structure was necessary for recognition of the binding site by the PCBPs.

5' Untranslated Regions↗
PubMed1999

The inhibitory activity of the AU-rich RNA element in the human papillomavirus type 1 late 3' untranslated region correlates with its affinity for the elav-like HuR protein.

A 57-nucleotide adenosine- and uridine-rich RNA instability element in the human papillomavirus type 1 late 3' untranslated region termed h1ARE has previously been shown to interact specifically with three nuclear proteins that failed to bind to an inactive mutant RNA. Two of those were identified as the heterogeneous ribonucleoproteins C1 and C2, whereas the third, a 38-kDa, poly(U) binding protein (p38), remained unidentified. Here we show that partially purified p38 reacts with a monoclonal antibody raised against the recently identified elav-like HuR protein, indicating that p38 is the HuR protein. Indeed, recombinant glutathione S-transferase (GST)-HuR protein binds specifically to sites within the h1ARE. Determination of the apparent Kd value of GST-HuR for the h1ARE and the inactive mutant thereof revealed that GST-HuR bound with a more than 50-fold-higher affinity to the wild-type sequence. Therefore, the binding affinity of GST-HuR for the wild-type and mutant h1AREs correlates with their inhibitory activities in transfected cells, strongly suggesting that the HuR protein is involved in the posttranscriptional regulation of human papillomavirus type 1 late-gene expression.

3' Untranslated Regions↗
PubMed1999

A future for epidemiology?

This paper considers ways of thinking about causes and prevention that could guide epidemiology beyond the present era. Discontent with modern epidemiology, in the face of its substantial achievements, is taken as a sign that the guiding principles of the discipline warrant reconsideration. To begin this task, current practices are placed within an historical perspective, in a review of the dominant ideas of successive eras in epidemiology. Then the premises and constraints of the present era of chronic disease epidemiology, with its risk factor paradigm, are specified. Finally, elements of a causal paradigm for an emerging era are proposed. This paradigm encourages thinking about causes at multiple levels of organization and within the historical context of both societies and individuals. The proposed approach aims to preserve and build on the contributions of past eras, as well as the present one.

Epidemiology↗
PubMed1999

DNA-plasmids of HIV-1 induce systemic and mucosal immune responses.

DNA-based immunization has been shown to induce protective immunity against several microbial pathogens including HIV-1. Several routes of DNA vaccination have been exploited. However, the properties of the immune responses seem to differ with the different routes used for DNA delivery, ultimately affecting the outcome of experimental challenge. We measured the primary immune response following one vaccination. This report presents differences associated with three different DNA delivery routes: intramuscular injection, intranasal application, and gene-gun based immunization. Induction of systemic humoral immune responses was achieved most efficiently by either intranasal or gene-gun mediated immunization, followed by intramuscular injection. Mucosal IgA was reproducibly induced by intranasal instillation of the DNA, and found in lung washings, faeces, and vaginal washings. Cytotoxic T cells were not induced by a single immunization, but were observed after three immunizations using intramuscular injections.

AIDS Vaccines↗
PubMed1999

The right answer for the wrong question: consequences of type III error for public health research.

OBJECTIVES: This study examined the impact of assessing the causes of interindividual variation within a population when the research question of interest is about causes of differences between populations or time periods. This discrepancy between the research focus and the research question is referred to as a type III error, one that provides the right answer for the wrong question. METHODS: Homelessness, obesity, and infant mortality were used to illustrate different consequences of type III errors. These different consequences depend on the relationships between the causes of within- and between-group variation. CONCLUSIONS: The causes of inter-individual variation and the causes of variation between populations and time periods may be distinct. The problem of examining invariant causes deserves attention.

Causality↗
PubMed1999

Expression of the C-kit receptor (CD117) is a feature of almost all subtypes of de novo acute myeloblastic leukemia (AML), including cytogenetically good-risk AML, and lacks prognostic significance.

Because of conflicting reports on the prognosis of patients with c-kit receptor positive AML and lacking correlations with cytogenetic analyses, we prospectively evaluated the c-kit receptor expression in 917 AML patients (750 adult patients; 167 children) using flow cytometry and compared the results to the immunophenotype, morphological and cytogenetic findings as well as clinical outcome. Expression of the c-kit receptor was present in 63% of all AML investigated. Among these an immature immunophenotype was more frequent and 30% had a CD34+/CD15- and 37% a CD34+/CD14- phenotype, whereas only 9% and 10% showed these phenotypes in the c-kit receptor negative group, respectively. C-kit receptor expression ranged average in M0 and M1 subtypes (69% versus 70%) but was less pronounced among M5 subtypes (21%). Results of karyotyping were available in 280 patients. C-kit receptor expression occurred in 37 of 42 (88%) patients with favorable cytogenetic abnormalities such as t(8;21), t(15;17) or inv(16) which exceeded the expression rate in patients with intermediate risk, poor risk or other abnormalities. Information about the clinical outcome was available in 228 patients treated according to the protocols of two German multicenter trials (AML-BFM, AMLCG). We found no difference of CR-rate or event-free survival (EFS) in adults with or without c-kit receptor expression. Children with c-kit receptor negative AML had a lower CR-rate and EFS, but also a lower median age and a higher frequency of M5 subtype as compared to children with c-kit receptor expression. In conclusion, analysis of c-kit receptor expression may help to identify phenotypically immature AML but fails to identify myeloid differentiation of leukemic blasts in approximately one third of patients. We found no evidence of an adverse prognosis in AML patients with c-kit receptor expression. Analysis for c-kit receptor expression does not appear to add information to established prognostic parameters in AML.

Adolescent↗
PubMed1999

Gains of the relative genomic content of erbB-1 and erbB-2 in prostate carcinoma and their association with metastasis.

Prostate carcinoma (PC) is the second leading cause of cancer death in men in the western world. Although the role of oncogenes and growth factors in prostate carcinoma is still unclear, overexpression of the epidermal growth factor receptor (erbB-1) and the proto-oncogene erbB-2 have been reported in prostate tumors, and erbB-2 related to poor prognosis and distant metastasis. Recent allelotyping studies in prostate cancer have shown chromosomal gains in 7p and 17q, regions where erbB-1 and erbB-2 are localized respectively, although no direct evidence of an increased gene copy number of either erbB-1 or erbB-2 has been reported. To address this question, we analyzed 20 benign prostatic hyperplasia (BPH) samples and 36 samples of metastatic and non-metastatic PC by means of semiquantitative PCR. Thus, 64% (11/17) and 52% (10/19) of metastatic and non-metastatic tumors respectively showed gains of the relative genomic content of erbB-1 and an association of erbB-1 with prostate cancer but not with metastasis. Additionally, 41% (7/17) of metastatic samples showed gains of erbB-2 genomic content, suggesting an association of erbB-2 with metastasis and poor prognosis (p<0.005). No gains of erbB-1 or erbB-2 genomic content were detected in the BPH samples.

Aged↗
PubMed1999

Analysis of ovarian borderline tumors using comparative genomic hybridization and fluorescence in situ hybridization.

It is unclear whether ovarian borderline tumors (tumors of low malignant potential) are independent entities or whether they are part of a continuum of tumor progression that culminates in ovarian carcinoma. Little is known about genetic abnormalities in borderline tumors because of the difficulty of growing them in culture for chromosome studies, and because the low ratio of tumor to nontumor cells can interfere with molecular genetic examination. To circumvent these problems, we performed comparative genomic hybridization (CGH) on 10 serous borderline tumors from nine patients, using microdissection to enrich the samples for tumor DNA and reduce contamination from stromal and inflammatory cells. CGH analysis revealed that three of the tumors had detectable chromosomal imbalances, whereas seven were in a balanced state. In those tumors with imbalances, the number of abnormalities ranged from 3-6 per tumor. Additional studies by fluorescence in situ hybridization (FISH) on disaggregated nuclei confirmed the imbalances detected by CGH, revealed one tumor to be hypertriploid, and indicated that the remaining tumors were diploid and in a balanced state. All abnormalities observed in the aneuploid cases are consistent with chromosomal aberrations previously reported for ovarian carinomas, providing further evidence that some borderline tumors are part of a continuum of tumor progression. These results also suggest that there may be different mechanisms leading to borderline tumor formation, including one associated with multiple chromosomal imbalances, and others that do not involve imbalances detectable by CGH. Genes Chromosomes Cancer 25:307-315, 1999.

Adult↗
PubMed1999

Second-trimester maternal serum analyte levels associated with fetal trisomy 13.

The aim of this study was to determine whether pregnancies affected by fetal trisomy 13 are associated with second-trimester maternal serum analyte levels different from those typical of the unaffected population. Pregnancies with trisomy 13 were identified through cytogenetics laboratories. Those which had second-trimester maternal serum screening analyte measurements were further evaluated. Maternal serum analyte levels for each case and five matched controls were statistically analysed by matched ranked-sum analysis. 28 cases of fetal trisomy 13 were identified. The median AFP, uE3 and hCG levels were 1.35 MoM, 0.71 MoM and 0.90 MoM, respectively. Only uE3 levels were statistically different (p < 0.01) from those for the unaffected population. These data suggest that second-trimester maternal serum AFP, uE3 and hCG levels are not useful in detecting fetal trisomy 13 and protocols already existing for Down syndrome or trisomy 18 screening will not detect the majority of cases of this aneuploidy.

Adolescent↗
PubMed1998

Reduced mitochondrial DNA transcription in senescent rat heart.

We studied the effect of senescence on mitochondrial DNA (mtDNA) transcription with an in organello system using intact isolated rat heart mitochondria. A comparison of the electrophoretic patterns of mtDNA transcription products in young, adult and senescent rats showed an age-related reduction in newly-synthesized mitochondrial RNAs that reflects a decrease in the synthesis rate. These results correlate with the enzyme activities of the oxidative phosphorylation complexes I and IV, that are partially encoded by the mitochondrial genome. In addition, an age-related increase in the protein carbonyl content of the mitochondrial membranes was observed in senescent mitochondria suggesting an accumulation of mitochondrial oxidative damage. This reduction in the mtDNA transcriptional rate in the heart of senescent animals suggests that this could be one of the molecular bases underlying senescence of the myocardium.

Aging↗