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Biomedical subjects

C S Cooper

Publications and source records attributed to C S Cooper.

At least 19 recordsLinked to original sources
PubMed1992

Preparation and in vitro and in vivo evaluation of quinolones with selective activity against gram-positive organisms.

A series of quinolones were prepared which contained oximes or substituted oximes as replacements for the amine substituents normally found on the pyrrolidine or piperidine fragments of quinolone antibacterial agents. These substituents led to compounds that had selective activity against Gram-positive organisms. These compounds showed in vivo activity against Staphylococcus aureus. Only compound 29 had in vivo activity against Streptococcus pneumoniae.

4-Quinolones↗
PubMed1992

The impact of iatrogenic urothelial trauma on urinary levels of transforming growth factor-alpha.

Growth factors are important regulators of epithelial cell biology. We postulated that iatrogenic bladder manipulations may alter urinary growth factor levels and thereby influence both normal and neoplastic urothelium. Using a rat model we studied the effects of various types of urothelial injury, corresponding to bladder catheterization, cystoscopy, fulguration, and chronic indwelling catheterization (Groups B, C, D, and E respectively) on levels of urinary transforming growth factor-alpha (uTGFa). Urine samples collected circa the time of transurethral bladder manipulation were analyzed for protein, creatinine (Cr), and TGFa. Results in experimental groups were compared to control values (group A). Peak concentrations of uTGFa uniformly occurred on the day of surgery and represented 176%, 196%, 726%, 461% and 916% increases relative to pre-operative values in groups A, B, C, D and E respectively. Total uTGFa (nM/mg. Cr) was maximal on experimental day 0 in groups A, B, C, D and day 2 in group E (102%, 114%, 227%, 290% and 976% change from baseline respectively). Compared to control, levels of uTFGFa were significantly elevated on day 0 in the fulguration group, and day 0 and 2 in the chronic catheterization animals (p less than .05). Nonsignificant elevations of uTGFa relative to control were based in all groups through day 7. The chronic catheterization levels remained significantly elevated, compared to control, over the duration of the study (ANOVA, p less than .05). Urinary protein levels correlated with the severity of the injury and showed a strong positive correlation with uTGFa (p = .0001). This study demonstrated a clear impact of iatrogenic urothelial trauma on urinary levels of TGFa.

Animals↗
PubMed1992

Increased expression and mutation of p53 in choroidal melanoma.

Using CM-1 antibody directed against the human p53 protein, high levels of mutant p53 protein expression were found in 12 out of 18 malignant choroidal melanomas. In contrast, we failed to observe elevated p53 expression, indicating the absence of p53 mutation in seven choroidal naevi, a potentially premalignant condition that can progress to form malignant melanoma. For two choroidal melanomas, we demonstrated that high levels of p53 protein were accompanied by exon 7 mutations. The mutations were found at codon 238, TGT-->TTT and codon 253, ACC-->AGC. These observations suggest that acquisition of abnormalities of the p53 gene may be an important step in the development of malignant melanoma.

Animals↗
PubMed1992

Localization of the synovial sarcoma t(X;18)(p11.2;q11.2) breakpoint by fluorescence in situ hybridization.

A high proportion of synovial sarcomas contain a chromosome translocation t(X;18)(p11.2;q11.2). We have previously used somatic cell hybrids derived from an established cell line, SS255, to map the X chromosome breakpoint to the interval flanked by the markers DXS14 and DXS146. In this study we have examined these hybrids with thirteen additional markers located at Xp11.3-Xcen, by Southern hybridization. Based on these results we have delimited the breakpoint as follows Xpter-DXS228-(UBE1-OATL1-TIMP-DXS226 )-(DXS255-TFE3-ELK1-DXS146)-OATL2- X;18-(DXS14-DXS422-DXS423-DXS674-DXS679)-+ ++Xcen. Confirmation of the breakpoint location has been obtained by analysis of two synovial sarcoma cell lines, SS255 and HA2243, using fluorescence in situ hybridization. A 350kb YAC probe spanning the DXS423 locus hybridized only to the derivative X chromosome, showing that it maps proximal to the breakpoint. Two YAC probes of 300kb and 450kb, containing the OATL2 locus, hybridized to both derivative chromosomes, indicating that these YACs span the translocation breakpoint. Similar results were obtained with both cell lines. The identification of YACs that span the t(X;18) breakpoint now facilitates a strategy for cloning candidate genes from this precisely defined region.

Animals↗
PubMed1992

The human tpr gene encodes a protein of 2094 amino acids that has extensive coiled-coil regions and an acidic C-terminal domain.

We recently provided evidence that the human tpr gene encodes a 726 amino acid protein (designated tpr-S) and identified an alternatively spliced transcript that encodes a larger tpr protein with an extended C-terminal domain. In this study, through isolation and sequencing of tpr cDNA clones, we have established that this alternatively spliced transcript encodes a protein of 2094 amino acids (designated tpr-L). The larger tpr protein is predicted to have extensive regions of alpha-helix and several stretches of a heptad repeat that is characteristic of proteins adopting a coiled-coil conformation. Furthermore the carboxy domain of this protein is very rich in acidic residues and exhibits homology (58-80%) to the acidic regions of several nuclear proteins, including the Drosophila engrailed protein, Escherichia coli RNA polymerase sigma subunit and nucleolin. To gain additional insight into the function of tpr we examined the expression of tpr transcripts in tissues from adult rat. The highest levels of tpr transcripts were observed in testis, lung, thymus and spleen.

Amino Acid Sequence↗
PubMed1992

Nucleotide sequence analysis of human tpr cDNA clones.

In this study we have characterized cDNA clones corresponding to a gene, called tpr, that has been implicated in the activation of the met and raf proto-oncogenes. Sequencing of tpr clones isolated from an HT1080 human fibrosarcoma cell line cDNA library identified an open reading frame (ORF) of 726 amino acids. In addition we have established that alternative splicing can result in the deletion of a 30 bp sequence that spans the translation termination site of this ORF. This modification generates mRNAs encoding a tpr protein that has an extended C-terminal domain. The 726 amino acid tpr protein is predicted to have extensive regions of alpha-helix and has three stretches of a heptad repeat motif that is characteristic of proteins adopting a coiled-coil conformation. The tpr protein exhibits weak homology (28-39%) to the alpha-helical domains of several proteins including tropomyosin, spectrin, laminin B1, the Drosophila glued protein and the tail region of myosin heavy chain.

Amino Acid Sequence↗
PubMed1991

A case of cerebellar medulloblastoma with a single chromosome abnormality.

In the few published karyotypes of human medulloblastoma, multiple chromosome abnormalities have usually been demonstrated. We report a case of medulloblastoma in which only a single structural alteration was observed, namely an unbalanced translocation between chromosomes 1 and 6 resulting in partial 1q trisomy and partial 6q mónosomy. This finding may help define genomic regions that are of importance in development of medulloblastoma.

Cerebellar Neoplasms↗
PubMed1991

The role of non-ras transforming genes in chemical carcinogenesis.

DNA transfection experiments using the NIH 3T3 mouse fibroblast cell line have demonstrated that chemically induced tumors and chemically transformed cell lines frequently contain dominant transforming genes. Although many of the genes detected using the NIH 3T3 transfection-transformation assay are activated versions of H-ras, K-ras, and N-ras, in some experimental systems activated forms of genes such as met and neu that are unrelated to ras have been observed. The activated met gene was originally detected in a human cell line that had been transformed by exposure to N-methyl-N'-nitro-N-nitrosoguanidine. Subsequent studies demonstrated that the met proto-oncogene encodes a novel growth factor receptor and that gene activation involves the production of a chimeric gene in which the regions of met encoding the extracellular and transmembrane domains of the receptor are replaced by the 5'-region of an unrelated gene called trp. The activated neu gene was detected in tumors of the nervous system that arose in mice following transplacental exposure to N-ethyl-N-nitrosourea. The neu gene also encodes a novel growth factor receptor but, in contrast to met, its activation involves a single T:A----A:T point mutation in the region of the neu gene encoding the receptor transmembrane domain. The presence of genetic alterations in chemically induced malignancies has also been assessed in cytogenetic studies and by Southern analysis of DNA from neoplastic cells.(ABSTRACT TRUNCATED AT 250 WORDS)

3T3 Cells↗
PubMed1991

Detection of transforming genes by transfection of DNA from primary soft-tissue tumours.

A series of adult soft-tissue tumours were screened for the presence of activated oncogenes by transfecting tumour DNA into NIH3T3 mouse fibroblasts. In these studies an activated K-ras gene that contained a mutation at the second position of codon 12 (GGT----GAT) was found in a leiomyosarcoma. In addition, following transfection of DNA from a liposarcoma, we identified an activated gene that failed to hybridize to probes prepared from 10 known human oncogenes (K-ras, H-ras, N-ras, ret, met, trk, mas, dbl, raf and hst) that have previously been detected in DNA transfection experiments. BamHI-BamHI fragments of this activated gene of 3.5 and 8.5 kb were cloned from NIH3T3 secondary transfectants using a probe that detects the human alu family of highly repetitive DNA sequences. Repeat-free subclones of these BamHI fragments were used to map this gene to human chromosome 19 (p13.2-q13.3). Our studies also demonstrate that a subclone from one of the BamHI fragments detects a 3.0 kb transcript in primary and secondary transfectants.

3T3 Cells↗
PubMed1990

Chemical induction of thymomas in AKR mice: interaction of chemical carcinogens and endogenous murine leukemia viruses. Comparison of N-methyl-N-nitrosourea and methyl methanesulphonate.

The time course of development of thymic lymphoma, which occurs spontaneously in mice of the AKR strain, is accelerated by the methylating agents N-methyl-N-nitrosourea (MNU) and methyl methanesulphonate (MMS). Since MNU is a potent mutagen inducing G----A transition mutations and MMS a relatively weak mutagen, it was of interest to examine the genetic alterations associated with each class of the chemically induced tumors and to compare these alterations with those found in the spontaneous tumors. The same spectrum of genetic alterations was found for MMS-induced and spontaneous thymomas. Both showed rearrangements of c-myc and Pim-1 genes that appeared to result from integration of recombinant mink cytopathic focus-forming (MCF) proviruses but failed to reveal evidence for activation of ras oncogenes, either by DNA transfection experiments or by hybridization of DNA to specific oligonucleotide probes. Some alteration in c-myc and Pim-1 genes were also found in MNU-induced tumors, but, mainly, these involved integration of ecotropic-like rather than recombinant MCF viruses. Furthermore, MNU-induced tumors frequently (in 24% of thymomas) contained G----A transition mutations, activating the Ki-ras oncogene at codon 12 position 2. Another feature that distinguishes the MNU-induced tumors from those occurring in untreated and MMS-treated mice was the consistently high level of c-myc mRNA that occurred in the absence of c-myc gene rearrangement. Taken together, the data indicate that the mechanisms of development of tumors following treatment with MNU and MMS are distinct, and that the effect of MMS is probably to speed up the process of viral leukemogenesis.

Animals↗
PubMed1990

The synthesis and antibacterial activities of quinolones containing five- and six-membered heterocyclic substituents at the 7-position.

A series of 6-fluoro-7-substituted-1-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acids were prepared. The substituents at the 7-position included five- and six-membered heterocyclic rings such as oxazoline and oxazine as well as five-membered heteroaromatic rings such as oxazoles and imidazoles. The structure--activity relationships (SAR) of these compounds indicated that oxazole substituents containing a 2-methyl group had the greatest in vitro potency. The compounds showed greater in vitro antibacterial activity against Gram-positive organisms than against Gram-negative organisms.

4-Quinolones↗
PubMed1990

The effect of social support on adolescent mothers' styles of parent-child interaction as measured on three separate occasions.

The purpose of this study was to determine the effect of social support on parent-child interaction in a group of 19 adolescent mothers. The subjects participated in a 20-week model demonstration program in which they worked in a preschool classroom with skilled caregivers who modeled facilitative styles of interacting with young children. Each subject was videotaped while interacting with a 1- to 2-year-old child upon entering the program, midway through the program, and at the end. Results showed that girls who were 16 years or older significantly increased their frequency of using responsive, engaging, and elaborative styles of behavior. Those under age 16 did not show significant changes in these three behaviors. Overall, subjects significantly increased the duration of time they spent observing the child's play behavior.

Adolescent↗
PubMed1989

Detection of point mutations in N-ras and K-ras genes of human embryonal rhabdomyosarcomas using oligonucleotide probes and the polymerase chain reaction.

Previous studies have demonstrated that genes of the ras family (H, K, and N) can be activated by point mutations at codons 12, 13, and 61. In the present study we have used oligonucleotide probes corresponding to these regions to assess the role of ras gene mutations in the genesis of human rhabdomyosarcoma. To increase the sensitivity of this method the appropriate regions of the three ras genes were first amplified using the polymerase chain reaction. The results show that 35% (5/14) embryonal rhabdomyosarcomas investigated contain mutations in the N-ras or K-ras genes. Thus ras gene mutation is implicated in the development of mesenchymal and embryonal tumors in addition to its previously documented role in epithelial and hematological neoplasia.

Adolescent↗
PubMed1989

Cytogenetic abnormalities in human ependymomas.

The karyotypes of 4 human ependymomas have been determined. In one ependymoma, translocations involving chromosomes 9, 17 and 22 were observed together with the loss of the normal chromosome 17. A second ependymoma had many chromosomal alterations that included a translocation between chromosomes 1 and 2 and re-arrangements involving chromosome 17. No major consistent alterations were detected in the remaining 2 cases. Our karyotypes do not resemble the few previously published karyotypes of ependymomas, but had features, such as the alterations involving chromosome 17, that were similar to those of other brain tumours in children.

Brain Neoplasms↗
PubMed1989

Tyrosine kinase receptor indistinguishable from the c-met protein.

Growth factor receptors with protein tyrosine kinase activity are central to the control of proliferation of both normal and malignant cells. Using anti-phosphotyrosine antibodies, we have previously identified a transmembrane glycoprotein with abnormally high protein tyrosine kinase activity in a human gastric tumour cell line (GTL-16). Electrophoresis under non-reducing conditions revealed that this kinase (relative molecular mass 145,000 (145 K)) is disulphide-linked to a 50K chain in an alpha beta-complex of 190K (p190). From its novel two-chain structure, we deduced that p190 was the prototype of a new class of tyrosine kinase receptors. We now show that p190 is indistinguishable from the protein encoded by the c-met proto-oncogene and that the alpha beta-subunit structure is conserved in other human cell lines. We also show that the high level of p190 found in the GTL-16 cell line is accompanied by amplification and overexpression of c-met. This provides the first example of a functional alteration of c-met in a human tumour cell line.

Cell Line↗