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Biomedical subjects

D Heckel

Publications and source records attributed to D Heckel.

15 recordsLinked to original sources
PubMed1999

Caudate size in first-episode neuroleptic-naive schizophrenic patients measured using an artificial neural network.

BACKGROUND: Structural brain imaging studies have demonstrated an increase in caudate volume in schizophrenic patients medicated with typical neuroleptics and a volume decrease following treatment with atypical neuroleptics. The measurement of striatal volume in patients who have never been treated with neuroleptics may indicate whether these changes are superimposed on intrinsic basal ganglia pathology in schizophrenia or are solely neuroleptic-induced. METHODS: We studied 36 first-episode, neuroleptic-naive schizophrenic patients and 43 control subjects using an artificial neural network (ANN) to identify and measure the caudate nucleus. The resulting volumes were analyzed using an ANCOVA controlling for intracranial volume, age, gender, and socioeconomic status. RESULTS: The mean volume difference between the caudate nuclei of patients and control subjects was .297 mL, the caudate nuclei of the patients being smaller than those of controls. When we covaried for intracranial volume, this was a statistically significant difference in caudate volume (n = 79; df = 1,75; F = 4.18; p > .04). CONCLUSIONS: Caudate nuclei of neuroleptic naive schizophrenic patients are significantly smaller than those of controls. This suggests that patients suffering from schizophrenia may have intrinsic pathology of the caudate nucleus, in addition to the pathology observed as a consequence of chronic neuroleptic treatment.

Adult↗
PubMed1999

Role of amplified genes in the production of autoantibodies.

A variety of previously published studies have shown the presence of autoantibodies directed against oncogenic proteins in the sera of patients with tumors. Generally the underlying genetic aberration responsible for the induction of an immune response directed against an abnormal protein is unknown. In our studies we analyzed the role of gene amplification in the production of autoantibodies in squamous cell lung carcinoma. We screened a cDNA expression library with autologous patient serum and characterized the isolated cDNA clones encoding tumor expressed antigens termed LCEA (lung carcinoma expressed antigens). As determined by sequence analysis, the 35 identified cDNA clones represent 19 different genes of both known and unknown function. The spectrum of different clones were mapped by polymerase chain reaction (PCR) and fluorescence in-situ hybridization, showing that a majority are located on chromosome 3, which is frequently affected by chromosomal abnormalities in lung cancer. Gene amplification of 14 genes was analyzed by comparative PCR. Nine genes (65% of all analyzed genes) were found to be amplified; furthermore, most of them are also overrepresented in the pool of cDNA clones, suggesting an overexpression in the corresponding tumor. These results strongly suggest that gene amplification is one possible mechanism for the expression of immunoreactive antigens in squamous cell lung carcinoma.

Antigens, Neoplasm↗
PubMed1999

Expression analysis of genes at 3q26-q27 involved in frequent amplification in squamous cell lung carcinoma.

Gene amplifications are known to occur frequently in lung cancer. Recently, we identified gene amplifications at 3q26 in squamous cell lung carcinoma (SCC) using reverse chromosome painting. Here, our aim was to analyse the expression of genes which map within the amplified chromosomal region. The genes which were selected for their known function and their potential involvement in tumour development included the genes for ribosomal protein L22 (RPL22), butyrylcholinesterase (BCHE), glucose transporter 2 (SLC2A2), transferrin receptor (TFRC), thrombopoietin (THPO) and the phosphatidylinositol-3 kinase catalytic alpha polypeptide (PIK3CA). While five genes were expressed in the majority of the 17 samples of SCC, the gene for the glucose transporter 2 (SLC2A2) was expressed in only three cases, excluding SLC2A2 as the target gene of the amplification unit. For a subset of tumours, we determined the amplification status of the six genes. The TFRC, PIK3CA, BCHE, THPO and SLC2A2 genes were amplified in several cases, whereas the RPL22 gene was amplified in only one case. The combined amplification and expression data of this and our previous studies indicate that the amplified region at 3q26 contains several genes that are transcribed in SCC, providing the possibility that several amplified and functionally important genes at 3q26 may be involved in the pathogenesis of SCC.

Blotting, Southern↗
PubMed1999

Quantitative in vivo measurement of gyrification in the human brain: changes associated with aging.

Clinical observation suggests that the aging process affects gyrification, with the brain appearing more 'atrophic' with increasing age. Empirical studies of tissue type indicate that gray matter volume decreases with age while cerebrospinal fluid increases. Quantitative changes in cortical surface characteristics such as sulcal and gyral shape have not been measured, however, due to difficulties in developing a method that separates abutting gyral crowns and opens up the sulci -- the 'problem of buried cortex'. We describe a quantitative method for measuring brain surface characteristics that is reliable and valid. This method is used to define the gyral and sulcal characteristics of atrophic and non-atrophic brains and to examine changes that occur with aging in a sample of 148 normal individuals from a broad age range. The shape of gyri and sulci change significantly over time, with the gyri becoming more sharply and steeply curved, while the sulci become more flattened and less curved. Cortical thickness also decreases over time. Cortical thinning progresses more rapidly in males than in females. The progression of these changes appears to be relatively stable during midlife and to begin to progress some time during the fourth decade. Measurements of sulcal and gyral shape may be useful in studying the mechanisms of both neurodevelopmental and neurodegenerative changes that occur during brain maturation and aging.

Adolescent↗
PubMed1999

Measurement of brain structures with artificial neural networks: two- and three-dimensional applications.

PURPOSE: To evaluate the ability of an artificial neural network (ANN) to identify brain structures. This ANN was applied to postprocessed magnetic resonance (MR) images to segment various brain structures in both two- and three-dimensional applications. MATERIALS AND METHODS: An ANN was designed that learned from experience to define the corpus callosum, whole brain, caudate, and putamen. Manual segmentation was used as a training set for the ANN. The ANN was trained on two-thirds of the manually segmented images and was tested on the remaining one-third. The reliability of the ANN was compared against manual segmentations by two technicians. RESULTS: The ANN was able to identify the brain structures as readily and as well as did the two technicians. Reliability of the ANN compared with the technicians was 0.96 for the corpus callosum, 0.95 for the whole brain, 0.86 (right) and 0.93 (left) for the caudate, and 0.71 (right) and 0.88 (left) for the putamen. CONCLUSION: The ANN was able to identify the structures used in this study as well as did the two technicians. The ANN could do this much more rapidly and without rater drift. Several other cortical and subcortical structures could also be readily identified with this method.

Adult↗
PubMed1999

Five novel immunogenic antigens in meningioma: cloning, expression analysis, and chromosomal mapping.

Tumorigenesis of meningioma has been associated with chromosome 22, most notably the NF2 gene, but additional genes have been implicated in meningioma development. Here, we report the identification of five novel immunogenic antigens expressed in meningioma. An expression library was generated from a meningioma that retained both copies of chromosome 22. Screening with autologous patient serum identified seven cDNA clones that were indicated by antigen-antibody complexes. The clones were sequenced, and sequence comparison revealed that the seven clones represent five different genes, providing evidence that meningiomas express a spectrum of immunoreactive antigens, which were termed meningioma expressed antigens (MGEAs). One gene was identical with the connective tissue growth factor, one gene was in part homologous to an Alzheimer disease-associated gene, and a third gene was in part identical to Homo sapiens molybdenum cofactor biosynthesis proteins A and C mRNA. One gene was partially homologous to previously reported cDNA sequences of unknown function, and the fifth gene showed no significant homologies to sequences deposited in databases. Using somatic hybrid mapping, three genes were localized on chromosome 6, and two genes were localized on chromosomes 3 and 17, respectively. To distinguish the MGEAs from the so-called natural autoantigenes, we also screened the library with 12 sera from individuals without obvious disease. The clones identified by reactivity with normal sera were completely different from the clones identified by screening the same meningioma expression library with serum from the patient bearing the tumor. These data suggest that the newly identified MGEA genes may be useful for diagnosis and possibly therapy of meningioma.

Algorithms↗
PubMed1998

An efficient procedure for permutation tests in imaging research.

Recent interest in hypothesis testing on functional imaging data has spurred the development of several statistical techniques. The purpose of this paper is to provide a method to reduce the computational intensity associated with randomization tests of positron emission tomography imaging data. We discuss the advantages and disadvantages of traditional distributional hypothesis testing versus the advantages and disadvantages of randomization tests. A method for reducing the computational intensity of randomization uses a conjunction of updating and sequenching and results in significantly reduced processing. The running times of randomization methods are compared.

Algorithms↗
PubMed1998

Novel immunogenic antigen homologous to hyaluronidase in meningioma.

By screening a meningioma expression library with autologous serum we identified four cDNA clones representing a novel gene with striking homology to Caenorhabditis elegans hyaluronidase as indicated by BLASTP analysis. In humans hyaluronidase has been implicated in cancer development and three human genes are known to encode proteins with hyaluronidase activity. None of the human genes, however, showed any homology at the nucleotide or amino acid sequence level to the newly isolated antigen we termed meningioma expressed antigen 5 (MGEA5). Somatic cell hybrid mapping and fluorescence in situ hybridization mapped the gene for MGEA5 to chromosomal band 10q24.1-q24.3. Reverse transcription (RT)-PCR and northern blot hybridization revealed expression of the gene encoding MGEA5 in several meningioma and additional human tissues. Expression analysis also indicated an alternative splicing event giving rise to a shorter and altered transcript termed MGEA5s. The expression of MGEA5 and MGEA5s as fusion proteins revealed an approximate molecular weight of 92 and 54 kDa, respectively. Using heterologous sera we found antibodies against MGEA5s in five out of 23 meningioma patients, whereas no immune reaction was detected in 12 control sera from healthy individuals. Confirmation of hyaluronidase activity was independently achieved by turbidometric analysis and a gel matrix assay. A model for involvement of the novel hyaluronidase gene in meningioma development is proposed.

Acetylglucosaminidase↗
PubMed1997

Amplification of the genes BCHE and SLC2A2 in 40% of squamous cell carcinoma of the lung.

Gene amplification is a common genetic change in human cancer cells. Previously, we provided the first evidence for gene amplification at chromosome band 3q26 in squamous cell lung carcinoma. In this study, the following analyses were performed: (a) we evaluated biopsies and paraffin-embedded tissues of 16 additional squamous cell lung carcinomas for gene amplification using reverse chromosome painting. Of the 16 tumors, 3 tumors showed an amplification of the entire long arm of chromosome 3, and 3 tumors showed various amplifications on 3q, all of which involved chromosome band 3q26; (b) we tested eight genes encompassing region 3q25-qter in two different tumors to identify amplified genes on chromosome 3q. The genes SI, BCHE, and SLC2A2 were amplified in both tumors; and (c) we analyzed 15 additional paraffin-embedded tissues to determine the amplification frequency of these genes. Of the 15 squamous cell lung carcinomas, 6 showed amplification for at least 1 of the genes, with BCHE and SLC2A2 as the genes most frequently amplified. Together, our reverse chromosome painting data and our PCR analysis indicate gene amplification at 3q26 in 40% of all squamous cell lung carcinomas with BCHE and SLC2A2 as possible target genes of the amplification unit in squamous cell lung carcinoma.

Blotting, Southern↗
PubMed1997

Identification of an amplified gene cluster in glioma including two novel amplified genes isolated by exon trapping.

Gene amplification, which occurs in more than 50% of malignant gliomas, is considered to play a pivotal role in tumorigenesis. There are, however, few studies aimed toward the isolation of novel genes from amplified sequences. Previously, we reported amplification of the protooncogene MET (hepatocyte growth factor receptor; 7q31) in more than 20% of glioblastomas. For an approximate size estimation of the amplification unit we analyzed three glioblastomas all of which carried an amplified MET gene, by Southern blot analysis and/or competitive polymerase chain reaction using eight DNA markers. Although the extent of the amplified domain varied, the close vicinity of the MET gene was the only region consistently amplified in these glioblastomas. A yeast artificial chromosome (YAC) contig of 900 kb was refined spanning the amplified region flanking the MET gene. The YAC inserts were subcloned into 59 cosmids, which were used for exon trapping. Eight sequences were identical to parts of the genes MET and CAPZA2 (human actin capping protein alpha-subunit). Two newly identified exons and the CAPZA2 exons were amplified in tumor TX3095, which retains an amplified MET gene. The new exons were localized close to MET and CAPZA2. Characterization of the clones, which were termed glioma-amplified sequence (GAS)7-1 and GAS7-2, showed an open reading frame and a different expression pattern in multiple human tissues. This study reports the identification of a cluster of amplified genes including two novel genes in a region amplified in more than 20% of glioblastomas.

Actin Capping Proteins↗
PubMed1997

Translation initiation factor eIF-4gamma is encoded by an amplified gene and induces an immune response in squamous cell lung carcinoma.

Amplification of cellular oncogenes is an important mechanism of altered gene expression in human cancers. Using comparative genomic hybridization we recently identified an amplification at 3q26.1-q26.3 in 30% of squamous cell carcinomas of the lung. A variety of methods including microdissection-mediated procedures permit cloning of genes encoded within amplified domains but do not directly lead to the identification of biologically relevant genes. In this study, we have circumvented this problem by combining an immunological and molecular genetic approach to analyze squamous cell lung carcinoma. To identify both amplified and tumor relevant genes, we generated a cDNA expression library from a tumor with the 3q amplification and hybridized the expressed recombinant polypeptides with the autologous serum. Of 400000 cDNA clones we identified 17 antigens which induce an immune response in a patient with squamous cell lung carcinoma. While most clones represent individual genes sequence analysis revealed that four of the 17 cDNAs are nearly identical with the eukaryotic translation initiation factor (eIF)-4gamma recently assigned on 3q. We demonstrated that the gene for eIF-4gamma was amplified within 3q26-q27 in independent squamous cell lung carcinomas. In this study, we report the identification of several antigens which elicit an immune response in a squamous cell lung carcinoma patient including eIF-4gamma. eIF-4gamma is encoded by an amplified gene and possibly plays a crucial part in the development of squamous cell lung carcinoma.

Base Sequence↗
PubMed1997

Cloning of a novel transcription factor-like gene amplified in human glioma including astrocytoma grade I.

Gene amplification, which is generally considered to occur late in tumor development, is a common feature of high grade glioma. Up until now, there have been no reports on amplification in astrocytoma grade I. In this study, we report cloning and sequencing of a cDNA termed glioma-amplified sequence (GAS41) which was identified recently in a glioblastoma cell line by microdissection-mediated cDNA capture. This technique is tailored to isolate amplified genes from human tumors. An increased copy number of GAS41 was found in glioblastoma multiforme and astrocytoma III, and at a high frequency in astrocytoma grades I and II. Sequence comparison indicates a high homology between the GAS41 protein, the yeast and human AF-9 and the human ENL proteins. Both AF-9 and ENL belong to a new class of transcription factors, indicating that GAS41 might also represent a transcription factor. With GAS41 being the first gene found with increased copy number in low grade glioma, this study provides the first evidence that gene amplification can occur in early tumor development.

Amino Acid Sequence↗
PubMed1997

cDNA cloning and chromosomal mapping of a predicted coiled-coil proline-rich protein immunogenic in meningioma patients.

There is increasing evidence that tumor expressed genes induce immune responses in cancer patients. To identify meningioma expressed antigens, we established a meningioma expression library which was screened with autologous serum. Out of 20 positive cDNA clones eight share high sequence homologies as determined by sequence analysis. These eight clones can be grouped into three classes which differ in length and which are characterized by specific sequence variations. The longest open reading frame was found to be 2412 bp encoding an immunoreactive antigen termed meningioma expressed antigen 6 (MEA6). Using five sequence specific primer pairs, somatic hybrid panel mapping revealed locations of the three classes on several human chromosomes including chromosomes 2, 3, 6, 7, 9, 13 and 14. The mapping results were confirmed by fluorescence in situ hybridization. RT-PCR showed consistent expression of all classes in several meningiomas and additional tissues using the same set of primer pairs as for chromosomal mapping. The expression data were confirmed by northern blot analysis. For the predicted amino acid sequence BLASTX revealed a homology to a human C219-reactive peptide which was previously isolated by an antibody directed against p-glycoprotein. Sequence properties of the MEA protein include an acidic activation domain, a proline-rich region and two coiled-coil domains indicating protein binding and activation functions.

Amino Acid Sequence↗
PubMed1996

Tests for comparing images based on randomization and permutation methods.

Tests comparing image sets can play a critical role in PET research, providing a yes-no answer to the question "Are two image sets different?" The statistical goal is to determine how often observed differences would occur by chance alone. We examined randomization methods to provide several omnibus test for PET images and compared these tests with two currently used methods. In the first series of analyses, normally distributed image data were simulated fulfilling the requirements of standard statistical tests. These analyses generated power estimates and compared the various test statistics under optimal conditions. Varying whether the standard deviations were local or pooled estimates provided an assessment of a distinguishing feature between the SPM and Montreal methods. In a second series of analyses, we more closely simulated current PET acquisition and analysis techniques. Finally, PET images from normal subjects were used as an example of randomization. Randomization proved to be a highly flexible and powerful statistical procedure. Furthermore, the randomization test does not require extensive and unrealistic statistical assumptions made by standard procedures currently in use.

Computer Simulation↗