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Biomedical subjects

G Jay

Publications and source records attributed to G Jay.

At least 37 records · Page 2Linked to original sources
PubMed1996

Regulation of transforming growth factor-beta 1 expression by the hepatitis B virus (HBV) X transactivator. Role in HBV pathogenesis.

TGF-beta 1 has been implicated in the pathogenesis of liver disease. The high frequency of detection of the hepatitis B virus X (HBx) antigen in liver cells from patients with chronic hepatitis, cirrhosis, and liver cancer suggested that expression of HBx and TGF-beta 1 may be associated. To test this possibility, we examined the expression of TGF-beta 1 in the liver of transgenic mice expressing the HBx gene. We show that the patterns of expression of TGF-beta 1 and Hbx protein are similar in these mice and that HBx activates transcription of the TGF-beta 1 gene in transfected hepatoma cells. The cis-acting element within the TGF-beta 1 gene that is responsive to regulation by Hbx is the binding site for the Egr family of transcription factors. We further show that the Egr-1 protein associates with the HBx protein, allowing HBx to participate in the transcriptional regulation of immediate-early genes. Our results suggest that expression of Hbx might induce expression of TGF-beta 1 in the early stages of infection and raise the possibility that TGF-beta 1 may play a role in hepatitis B virus pathogenesis.

Amino Acid Sequence↗
PubMed1996

Repression of the NF1 gene by Tax may expain the development of neurofibromas in human T-lymphotropic virus type 1 transgenic mice.

In familial neurofibromatosis type 1 (NF1), individuals with a germ line-transmitted NF1 mutation develop multiple neurofibromas. To explain the observation that transgenic mice expressing the human T-lymphotropic virus type 1 (HTLV-1) tax gene under the control of the viral regulatory element also develop multiple neurofibromas, we demonstrate that the Tax trans-regulator can functionally repress NF1 gene expression through a cis-acting element located immediately upstream of its transcriptional start site, thereby allowing the development of benign neurofibromas without the need for direct mutations in NF1. We propose that such a mechanism would suffice to epigenetically alter NF1 gene expression. The fact that transgenic animals have localized rather than diffuse neurofibroma formation, however, suggests that additional genetic or epigenetic events may be required for neurofibroma formation.

3T3 Cells↗
PubMed1995

The Alzheimer's A beta peptide induces neurodegeneration and apoptotic cell death in transgenic mice.

To test whether the hypothesis that the Alzheimer's A beta peptide is neurotoxic, we introduced a transgene into mice to direct expression of this peptide to neurons. We show that the transgene is expressed in brain regions which are severely affected in Alzheimer's disease resulting in extensive neuronal degeneration. Morphological and biochemical evidence indicates that the eventual death of these cells occurs by apoptosis. Coincident with the cell degeneration and cell death is the presence of a striking reactive gliosis. Over 50% of the transgenic mice die by 12 months of age, half the normal life span of control mice. These data show that A beta is neurotoxic in vivo and suggest that apoptosis may be responsible for the accompanying neuronal loss, the principal underlying cellular feature of Alzheimer's disease.

Alzheimer Disease↗
PubMed1995

Functional inactivation but not structural mutation of p53 causes liver cancer.

Structural mutations in the p53 gene are seen in virtually every form of human cancer. To determine whether such mutations are important for initiating tumorigenesis, we have been studying hepatocellular carcinoma, in which most cases are associated with chronic hepatitis B virus infections. Using a transgenic mouse model where expression of a single HBV gene product, the HBx protein, induces progressive changes in the liver, we show that tumour development correlates precisely with p53 binding to HBx in the cytoplasm and complete blockage of p53 entry into the nucleus. Analysis of tumour cell DNA shows no evidence for p53 mutation, except in advanced tumours where a small proportion of cells may have acquired specific base substitutions. Our results suggest that genetic changes in p53 are late events which may contribute to tumour progression.

Animals↗
PubMed1994

Stepwise immortalization and transformation of adult human prostate epithelial cells by a combination of HPV-18 and v-Ki-ras.

Recent investigations have shown the presence of ras gene mutations and human papillomavirus (HPV) DNA in prostate carcinomas. In the present study, secondary adult human prostatic epithelial cells, upon transfection with a plasmid containing the entire HPV-18 genome, acquired an indefinite life-span in culture but did not undergo malignant conversion. Subsequent infection of these immortalized cells with the Kirsten murine sarcoma virus, which contains an activated Ki-ras oncogene, induced morphological transformation that led to the acquisition of neoplastic properties. These findings demonstrate the malignant transformation of adult human prostate epithelial cells in culture by a combination of viral oncogenes and the successive roles of HPV infection and Ki-ras activation in a multistep process responsible for prostate carcinogenesis.

Adult↗
PubMed1994

Evolving concepts in molecular pathology.

During the last decade, an understanding of the causes of many human diseases has progressed rapidly, in large measure because of the development of technologies that allow us to identify the genes that are involved. Identification of a gene that is suspected to play an important role in a particular disease opens up a whole new dimension of research to understand the molecular events that underlie the cause of that disorder. A crucial step in this process is often the development of an animal model of the disease. Again, the last decade has seen rapid advances in our ability to create such models, particularly in mice. Technologies that allow for the addition, alteration, or elimination of individual genes from the genome to create a transgenic mouse are now routine. The advantages of having a transgenic mouse model of a human disease are many. These animals often provide the first unequivocal proof that a particular gene is responsible for causing the pathological changes that occur with disease. They also can provide a system to carefully dissect the successive events that lead to the disease state, and can provide a custom-designed whole animal system to test potential therapies to treat and eventually cure the disease. Most important, new concepts relating to gene expression and gene function in disease often emerge from such transgenic studies. This review will illustrate several examples in which transgenic animals have contributed significantly to the evolution of concepts of the underlying mechanisms of human disease.

Amyotrophic Lateral Sclerosis↗
PubMed1994

Transgenic mouse models of human gastric and hepatic carcinomas.

The development of human cancer is a complex process which has been difficult to define in vivo. The use of animal models of human cancer may prove useful in elucidating the mechanisms associated with malignant transformation. Transgenic mice with either the adenovirus 12 (Ad12) E1a/E1b genes or the human hepatitis B virus (HBV) HBx gene were developed. Expression of these viral genes resulted in the development of malignant tumors in restricted tissues; in the case of the HBx transgenic mice, hepatocellular carcinomas and in the E1a/E1b transgenic mice, gastric carcinomas. With the E1a/E1b transgenic mice, tumors were found to arise near the junction between the squamous and columnar epithelia, as found in several human cancers, including cervical and esophageal carcinomas, and thus appear to be an ideal animal model for determining why the squamocolumnar junction is such a hot spot for the development of human tumors of epithelial derivation. The HBx transgenic mice showed progressive changes in the liver, beginning with preneoplastic lesions, through benign adenomas, and finally to malignant carcinomas. These mice appear particularly suited for defining epigenetic rather than genetic events underlying the progression of human cancers. These transgenic models address two fundamental observations which are becoming increasingly important for our understanding of the mechanism of carcinogenesis.

Animals↗
PubMed1993

Tumors in hepatobiliary tract and pancreatic islet tissues of transgenic mice harboring gastrin simian virus 40 large tumor antigen fusion gene.

Gastrin is expressed in the gastric antrum and in fetal pancreatic islets but not in adult islets. We have now identified the hepatobiliary tract as another, previously unknown, potential site of gastrin gene expression. Two human gastrin simian virus 40 large tumor antigen (SV40 T antigen) fusion genes containing 1.5 kb of 5' flanking sequence and 10.5 kb that included 5.5 kb upstream, 1.5 kb downstream, and the entire transcribed region were used to generate transgenic mice. Analysis of several transgenic lines, derived from both fusion genes, revealed development of transmissible hepatobiliary tract tumors and pancreatic islet cell tumors. Analysis of each of the tumor cells demonstrates expression of SV40 T antigen but no expression of gastrin. Of the two fusion genes, only the 10.5-kb sequence induces hyperplasia of gastrin-producing cells in the antrum. Analysis of these cells demonstrates expression of SV40 T antigen and gastrin, suggesting that the 10.5-kb sequence is sufficient for gastrin cell hyperplasia in the antrum. These data raise the possibility that gastrin is transiently expressed in the hepatobiliary tract.

Adenoma, Islet Cell↗
PubMed1993

A transgenic model of transactivation by the Tax protein of HTLV-I.

The human T-lymphotropic virus type I (HTLV-I) Tax protein is a transcriptional regulatory protein that has been suggested to play a causal role in the development of several HTLV-I-associated diseases. Tax regulates expression of its own LTR and of certain cellular promoters perhaps by usurping the function of the host transcriptional machinery. We have established a transgenic mouse model system to define the spectrum of tissues in vivo that are capable of supporting Tax-mediated transcriptional transactivation. Transgenic mice carrying the HTLV-I LTR driving expression of the Escherichia coli beta-galactosidase (beta gal) gene were generated, and this LTR-beta gal gene was transcriptionally inactive in all tissues. When LTR-beta gal mice were mated to transgenic mice carrying the same LTR driving expression of the HTLV-I tax gene, mice that carried both transgenes showed restricted expression of the beta gal reporter gene in several tissues including muscle, bone, salivary glands, skin, and nerve. In addition, a dramatic increase in the number of beta gal-expressing cells was seen in response to wounding. These observations provide direct evidence for viral transactivation in vivo, delimit the tissues capable of supporting that transactivation, and provide a model system to study the mechanism of gene regulation by Tax.

Animals↗
PubMed1993

Mice transgenic for HTLV-I LTR-tax exhibit tax expression in bone, skeletal alterations, and high bone turnover.

HTLV-I infection can result in adult T cell leukemia with accompanying hypercalcemia and increased bone resorption. A viral etiology has also been invoked for Paget's disease, a disease of high bone turnover. Delineation of pathogenetic mechanisms of viral-associated bone diseases has been impeded by the complexity of viral and host factors. In order to consider the relationship of HTLV-I infection to skeletal changes we have evaluated the role of a single viral gene in mice transgenic for HTLV-I tax under the control of the viral promoter. Tax mice exhibited severe skeletal abnormalities characterized by high bone turnover, increases in osteoblast and osteoclast numbers and activity, and myelofibrosis. These changes were apparent as early as two months of age. Tax mRNA and protein were highly expressed in bone but not in bone marrow nor in any other tissues except, as previously reported, salivary gland and neurofibromas when they did develop. Within bone, tax protein was detected in only two cell types, mature osteoclasts and spindle-shaped cells within the endosteal myelofibrosis. These observations suggest that local expression of the tax gene, which encodes a viral regulatory protein known to influence host gene expression, can induce within the bone environment marked changes in bone cell activity, resulting in profound skeletal alterations.

Animals↗
PubMed1993

Stress and exercise among the Japanese elderly.

This study seeks to replicate and extend research on the stress process by examining the relationships among stress, social support, physical exercise, and depressive symptoms with data provided by a recent nationwide survey of older adults in Japan. The findings reveal that more frequent physical exercise is associated with less psychological distress. Moreover, the data suggest that some (but not all) types of stressors tend to diminish the frequency of physical activity. Finally, and perhaps most important, the results reveal that social support tends to promote more frequent exercise. This can occur in two ways. First, more emotional support was related to better exercise habits. In addition, negative interaction was also associated with more frequent exercise, suggesting that informal social sanctions can foster positive health behaviors.

Aged↗
PubMed1993

Upper-extremity deep-vein thrombosis: thrombolytic therapy with anistrepalase.

A patient with primary axillary vein thrombosis was treated successfully in the emergency department with a single IV bolus of anistrepalase followed by continuous IV heparin. The patient's symptoms resolved quickly, and a repeat venogram 16 hours later showed near-complete resolution of the venous obstruction. We discuss briefly the role of thrombolytic therapy in the treatment of upper-extremity deep-vein thrombosis and the potential advantages of using anistrepalase.

Adult↗
PubMed1993

Extravasation and transcytosis of liposomes in Kaposi's sarcoma-like dermal lesions of transgenic mice bearing the HIV tat gene.

Transgenic mice bearing the HIV tat gene develop dermal lesions resembling a common malignant tumor in AIDS, Kaposi's sarcoma (KS). To evaluate the permeability characteristics of these lesions and the therapeutic potential of drug-carrying liposomes, we have studied the localization of sterically stabilized liposomes, which show long circulation time in blood and increased accumulation in tumors. Liposomes encapsulating colloidal gold were injected intravenously into transgenic mice bearing KS lesions, and tissues were processed 24 hours later for both electron microscopy and for light microscopy with silver enhancement. Liposomes and silver marker were detected predominantly in the dermis surrounding the early and mature KS lesions, which were characterized by a proliferation of fibroblast-like spindle cells and abnormal blood vessels close to the epidermis. The silver-enhanced gold marker often surrounded vascular channels and scattered erythrocytes. As determined by electron microscopy, some spindle cells and macrophages had ingested intact liposomes. Transendothelial transport of liposomes was observed both through open channels between endothelial cells and also through endothelial cells lining intact vessels. Both extravasation and transcytosis of liposomes through irregular endothelium were much higher in KS lesions than in the adjacent normal skin. The high accumulation of sterically stabilized liposomes in KS lesions and their intracellular uptake by some spindle cells enhances their potential as carriers of chemotherapeutic agents against this neoplasm.

Animals↗
PubMed1993

Neoplastic transformation of a human keratinocyte cell line by the v-fos oncogene.

To analyze the role of the fos oncogene in the growth of human epithelial cells, we have transfected a non-tumorigenic human epidermal keratinocyte line (RHEK-1) immortalized by the Ad12-SV40 hybrid virus with a plasmid carrying the v-fos gene together with plasmid pSV2-neo which confers resistance to neomycin. Individual neomycin-resistant clones were isolated and characterized with respect to morphological alteration. Of 16 independent clones analyzed, two appeared morphologically transformed and formed foci in culture. Only the two clones with a transformed phenotype were found by Southern blot hybridization analysis to contain the transfected v-fos gene. These clones formed colonies in soft agar and induced tumors when transplanted into nude mice. Analysis of fos specific mRNA and protein demonstrated that the transfected v-fos gene was expressed in these two clonal lines. These findings suggest that expression of the v-fos gene might facilitate the process of neoplastic transformation of human epithelial cells in culture. This appears to represent the first demonstration of the transforming potential of the v-fos gene in human cells.

Animals↗
PubMed1992

Altering the boundaries of Hox3.1 expression: evidence for antipodal gene regulation.

To investigate the function of region-specific patterns of mouse homeobox gene expression during embryogenesis, we programmed a minimal change in the distribution of Hox3.1 transcripts along the anteroposterior body axis in transgenic mice. Regulatory sequences from Hox1.4, a gene normally expressed more anteriorly than Hox3.1, were chosen to direct expression of a Hox3.1 transgene. Offspring of independent transgenic lines expressed the transgene more anteriorly than the Hox3.1 gene. Rather than predicted posterior transformations, we observed anterior transformations of vertebrae in newborn mice. Transgenic mice also developed profound gastrointestinal tissue malformations, which may provide a molecular explanation for human developmental disorders often involving these same two regions. Paradoxically, vertebral transformations in the transgenic mice were strikingly similar to those reported in mice homozygous for a null mutation of the Hox3.1 gene. This observation suggests that Hox genes may be regulated antipodally, with over- or underexpression resulting in similar phenotypes.

Animals↗
PubMed1992

Regulating gene expression in transgenic animals.

Regardless of the field of application, the raison d'etre of transgenic animals is to study gene regulation and function. With increasing frequency, mammalian genes are being isolated with no concomitant knowledge of their function. The human genome mapping initiative will undoubtedly produce a cornucopia of such genes. While the merit of taking a transgenic route to study genes of unknown function is axiomatic, the choices of strategies for gene regulation in vivo may not be fully appreciated. This review will address two main points: first, the targeted and regulated expression of genes, and second, the structural and functional ablation of genes.

Animals↗
PubMed1992

The activity of single-agent carboplatin in advanced seminoma.

Between 1982 and 1990, 70 patients with advanced metastatic seminoma were treated with 4-6 courses of single-agent carboplatin (SAC) administered at 400 mg/m2 every 3-4 weeks. Treatment was of low toxicity and no patients suffered neurotoxicity, ototoxicity or significant renal damage. There was only one episode of neutropenic sepsis and no thrombocytopenic bleeding. The median follow-up of surviving patients was 3 years. 16 patients have relapsed and 4 of these 16 have died, thus the actuarial 3-year relapse-free survival was 77% (95% CI 65-86%), cause-specific survival was 94% (95% CI 82-99%) and overall survival was 91% (95% CI 80-96%). The risk of relapse was reduced by post-chemotherapy irradiation (PCRT) to involved nodes, occurring in 1/20 patients treated with PCRT compared with 11/31 who could have been treated but were not (P = 0.04). Of the 16 patients who relapsed, 12(75%) have been salvaged with combination chemotherapy and remain free from further relapse with a median follow-up of 18 months. Though this level of survival is equivalent to that obtained with initial cisplatin-based combination chemotherapy, the recurrence rate indicates that SAC remains an investigative treatment, except for unfit patients.

Adult↗