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At least 865 records · Page 48Linked to original sources
PubMed2006

Pigment epithelium-derived factor: a multimodal tumor inhibitor.

Pigment epithelium-derived factor (PEDF), a noninhibitory member of the serine protease inhibitor (serpin) family, is a well-known potent endogenous inhibitor of angiogenesis. It has been known for years to be aberrantly expressed in ocular disorders, but in recent years, down-regulation has been shown to be prevalent in a range of cancers as well. This review describes the trimodal anticancer activities of this interesting protein: antiangiogenesis, apoptosis-mediated tumor suppression, and tumor cell differentiation. The key to successful antitumor therapy with this protein is the ability to synthesize the recombinant form of the protein (or its active shortened forms) and deliver at therapeutic doses or alternatively to use gene transfer technology to prolong the effect in vivo. Although there is a substantial amount of work carried out at the preclinical stage with this protein, more groundwork has to be done before PEDF is tested against cancer in clinical trials.

Angiogenesis Inhibitors↗
PubMed1999

Establishment of pluripotent cell lines from vertebrate species--present status and future prospects.

Pluripotent embryonic stem (ES) cells are undifferentiated cell lines derived from early embryos and are capable of unlimited undifferentiated proliferation in vitro. They retain the ability to differentiate into all cell types including germ cells in chimeric animals in vivo, and can be induced to form derivatives of all three germ layers in vitro. Mouse ES cells represent one of the most important tools in genetic research. Major applications include the targeted mutation of specific genes by homologous recombination and the discovery of new genes by gene trap strategies. These applications would be of high interest for other model organisms and also for livestock species. However, in spite of tremendous research activities, no proven ES cells colonizing the germ line have been established for vertebrate species other than mouse and chicken thus far. This review summarizes the current status of deriving pluripotent embryonic stem cell lines from vertebrates and recent developments in nuclear transfer technology, which may provide an alternative tool for genetic modification of livestock animals.

Animals↗
PubMedDate not supplied

From gene identification to gene therapy.

Inner ear disease due to hair cell loss is common, and no restorative treatments for the balance and hearing impairment are currently available. To develop clinical means for enhancing protection and regeneration in the inner ear, it is necessary to understand the molecular basis for hereditary and acquired deafness and vestibular disorders. One approach is to identify and characterize genes that regulate protection or repair in other systems. For that purpose, we have used the differential display assay and compared gene expression between normal and acoustically traumatized inner ears of chicks. Several chick cDNAs that were identified are considered as candidates for roles in the reparative process that follows trauma in the basilar papilla. The mammalian vestibular epithelium has a limited regenerative capability. To identify genes that may participate in the regenerative response, we have used gene arrays profiling, comparing normal to drug-traumatized vestibular epithelia. We identified several genes that are differentially expressed in traumatized vestibular epithelium, including several insulin-like growth factor-I binding proteins. To use this molecular knowledge for enhancing protection and repair in the organ of Corti, it is necessary to overexpress the genes of choice in the inner ear. Using viral-mediated gene transfer, we overexpressed transgenic glial cell line-derived neurotrophic factor and demonstrated a robust protective effect against acoustic and ototoxic inner ear trauma. Future identification of the genes that are important for protection and regeneration, along with improved gene transfer technology, will allow the use of gene therapy for treating hereditary and environmental inner ear disease.

Animals↗
PubMed1995

Cardiac allograft survival in mice deficient in intercellular adhesion molecule-1.

BACKGROUND: Intercellular adhesion molecule-1 (ICAM-1, CD54) is a cell adhesion molecule that interacts with the leukocyte beta 2 integrins, lymphocyte function-associated antigen-1, and macrophage antigen-1. ICAM-1 is postulated to play a key role in several cell-cell interactions that are important in allograft rejection, including antigen presentation, transendothelial migration of leukocytes, and leukocyte-medicated myocyte injury. METHODS AND RESULTS: Mice homozygous for a gene-targeted mutation of ICAM-1 were used in two different cardiac transplant models to further define the role of ICAM-1 in the process of allograft rejection. In the first model, hearts from newborn mice were implanted in the ear pinnae of H-2-incompatible recipients. In the second model, intra-abdominal transplantation by direct vascular anastomosis was performed. Time to rejection was defined by the loss of pulsatile activity assessed by visual inspection in the ear model or by cessation of palpable cardiac impulse in the abdominal model. Allograft survival did not differ significantly between control groups that express normal levels of ICAM-1 and those groups using ICAM-1-deficient mutants as either donors or recipients. Histological examination of rejection of both normal and mutant (ICAM-1-deficient) cardiac allografts revealed similar patterns of infiltration of mononuclear and granulocytic leukocytes and myocyte necrosis. Immunostaining with anti-ICAM-1 antibodies showed ICAM-1-positive infiltrating cells in both mutant (ICAM-1-deficient) and normal allografts, with the graft endothelium negative for ICAM-1 staining in the mutant allografts. CONCLUSIONS: The absence of surface expression of ICAM-1 in the donor allograft or recipient is insufficient to produce a significant impact on cardiac allograft survival. This study highlights the need to understand more precisely the mechanism of action whereby monoclonal antibodies to ICAM-1 prolong cardiac allograft survival before new therapeutic strategies based on gene transfer technology or small molecule inhibitors are developed. Mutant mice with targeted mutations in cell adhesion molecules provide powerful tools to study the complex role that cell adhesion molecules play in the cellular interactions between donor graft tissue and the recipient that culminate in graft rejection.

Animals↗
PubMed2002

Transduction of a functional domain of the AT1 receptor in neurons by HIV-Tat PTD.

Despite advances in transgenic and gene transfer technologies, in vivo structure-function studies of the angiotensin II type I receptor (AT1R) have revealed limited information on the diverse actions of angiotensin II. Our objective in the present study was to determine if protein transduction technology with the use of the HIV-Tat protein transduction domain could fill this gap. Recombinant HIV-Tat protein transduction domain fused to EGFP and to the third intracellular loop of the AT1R was expressed. Incubation of hypothalamus and brainstem neurons with this peptide indicated an efficient transport of the protein to most of the cells. This transduction was accompanied by an increase in neuronal firing rate, an effect similar to that observed with angiotensin II stimulation of the neuronal AT1R. The characteristics of the chronotropic effects of recombinant third intracellular loop and its synthetic counterpart were similar and comparable to the effects of angiotensin II on these neurons. In addition, in the presence of the protein kinase C inhibitor calphostin C, the peptide failed to increase firing rate. These observations demonstrated that transduction of neurons with the third intracellular loop of the AT1R produces chronotropic effects similar to those induced by angiotensin II. The data suggests that protein transduction technology could be useful for in vivo AT1R domain transduction.

Action Potentials↗
PubMed1991

Structure, expression, and regulation of the murine renin genes.

It has long been known that the renin-angiotensin system plays an integral role in the regulation of blood pressure and electrolyte and fluid balance in mammals. The advent of molecular biologic techniques has afforded new insights into the genes regulating blood pressure. Laboratory mice and rats have been used as experimental models to examine the structural organization and expression of the renin gene. It is now well established that some mice, unlike rats and humans, contain a duplicated copy of the renin locus, which accounts for the high level of renin activity long known to be found in the submandibular gland of some mice. Indeed it is this fortuitous observation that facilitated the isolation of the first complementary DNA clones for renin and ultimately the many species-specific probes now available to analyze mammalian tissues for evidence of primary renin expression. The use of complementary DNAs as probes for primary renin expression helped confirm and further clarify earlier studies demonstrating the presence of renin activity in a number of extrarenal tissues. Although expression in some of these tissues is evolutionarily conserved, their significance has still been elusive. In this report we review the impact of molecular biology on our current understanding of renin gene structure and organization, tissue- and cell-specific expression and regulation, and the changes in renin expression throughout ontogeny. In addition, we describe how new developments in gene transfer technology have added important tools to our arsenal for examining renin gene regulation and how these technologies can be used to develop new tools for renin and hypertension research.

Animals↗
PubMed1999

Sustained inhibition of angiotensin I-converting enzyme (ACE) expression and long-term antihypertensive action by virally mediated delivery of ACE antisense cDNA.

Angiotensin I-converting enzyme (ACE) inhibitors have been proven to be highly effective and are for the most part the drugs of choice in the treatment and control of hypertension, congestive heart failure, and left ventricular dysfunction. Despite this, questions regarding side effects and compliance with this traditional pharmacological strategy remain. In view of these observations, coupled with recent advances in gene-transfer technology, our objective in this study was to determine whether the expression of ACE could be controlled on a permanent basis at a genetic level. We argued that the introduction of ACE antisense to inhibit the enzyme would be a prerequisite in considering the antisense gene therapy for the control of hypertension and other related pathological states. Retroviral vectors (LNSV) containing ACE sense (LNSV-ACE-S) and ACE antisense (LNSV-ACE-AS) sequences were constructed and were used in rat pulmonary artery endothelial cells (RPAECs) to determine the feasibility of this approach. Infection of rat RPAECs with LNSV-ACE-S and LNSV-ACE-AS resulted in a robust expression of transcripts corresponding to ACE-S and ACE-AS, respectively, for the duration of these experiments, ie, 8 consecutive passages. The expression of ACE-AS but not of ACE-S was associated with a permanent decrease of approximately 70% to 75% in ACE expression and a 50% increase in the B(max) for the AT(1)s. Although angiotensin II caused a concentration-dependent stimulation of intracellular Ca(2+) levels in both ACE-S- and ACE-AS-expressing cells, the stimulation was significantly higher in ACE-AS-expressing RPAECs. In vivo experiments demonstrated a prolonged expression of ACE-AS transcripts in cardiovascularly relevant tissues of rats. This was associated with a long-term reduction in blood pressure by approximately 15 mm Hg, exclusively in the spontaneously hypertensive rat. These observations demonstrate that delivery of ACE-AS by retroviral vector results in a permanent inhibition of ACE and a long-term reduction in high blood pressure in the spontaneously hypertensive rat.

Angiotensin II↗
PubMed2006

An update on affirmative businesses or social firms for people with mental illness.

Social firms, or "affirmative businesses" as they are known in North America, are businesses created to employ people with disabilities and to provide a needed product or service. This Open Forum offers an overview of the development and status of social firms. The model was developed in Italy in the 1970s for people with psychiatric disabilities and has gained prominence in Europe. Principles include that over a third of employees are people with a disability or labor market disadvantage, every worker is paid a fair-market wage, and the business operates without subsidy. Independent of European influence, affirmative businesses also have developed in Canada, the United States, Japan, and elsewhere. The success of individual social firms is enhanced by locating the right market niche, selecting labor-intensive products, having a public orientation for the business, and having links with treatment services. The growth of the social firm movement is aided by legislation that supports the businesses, policies that favor employment of people with disabilities, and support entities that facilitate technology transfer. Social firms can empower individual employees, foster a sense of community in the workplace, and enhance worker commitment through the organization's social mission.

Australia↗
PubMed1997

Poverty and mental illness.

OBJECTIVE: To assess the relationship between poverty and mental illness in order to stimulate debate on future international cooperation programs in mental health. METHOD: Epidemiological data in the international literature addressing the issue of material poverty as a risk factor for the development of mental illness and as a prognostic factor for the outcome of mental illness were reviewed. RESULTS: The international literature reviewed supports the notion that material poverty is a risk factor for a negative outcome among mentally ill people. In addition, preliminary epidemiological data suggest that service-related variables may be determinants of outcome of mental illnesses. In our view, cooperation with developing countries is a great opportunity to evaluate mental health services in a natural setting. CONCLUSIONS: A new generation of programs for international cooperation in mental health is needed, in which knowledge and technology transfer is based on a service-research attitude. Attention should be focused on variables related to the poverty of services that might be linked to the course and outcome of mental illnesses.

Cross-Cultural Comparison↗
PubMed2000

Re-engineering the soft machine: the impact of developing technology and changing practice on diagnostic radiographer skill requirements.

This paper describes research to investigate the extent to which new technology and changing work practices in diagnostic imaging have changed the skill requirements of working radiographers. Interviews were conducted with radiography managers, radiologists and industry representatives. While changes in technology were viewed as having a significant impact on skill requirements, levels of resourcing and both national and local policy were seen as key factors driving changes in work practice. Respondents believed that significant changes would be required to pre- and post-registration training requirements for radiographers in the light of changing practice.

Clinical Competence↗
PubMed1999

Signal transduction pathways controlling the switch between keratinocyte growth and differentiation.

Self-renewing epithelia are characterized by a high turnover rate and a fine balance between growth and differentiation. Such a balance is influenced by many exogenous factors, including gradients of diffusible molecules, cell/substrate adhesion contacts, and direct cell-cell communication. The inter-connection between these various extracellular signals and underlying intracellular pathways is clearly of great interest. Primary keratinocytes of either human or murine origin provide an ideal experimental system to elucidate early signaling events involved in the control of epithelial differentiation. Relative to established cell lines, use of a primary system eliminates the possibility of alterations in critical regulatory events which may occur during prolonged propagation in culture. Primary keratinocytes are easily grown in large numbers, and their differentiation can be induced under well-defined culture conditions. The ensuing rapid and homogeneous response is amenable to careful biochemical analysis. Gene transfer technology (transient transfections, adenoviral and retroviral vectors), together with the use of keratinocytes derived from gene knockout and transgenic mice, makes it possible to assess the specific contribution of individual genes to the control of the differentiation process. This review focuses on the significant progress that has been made over the last few years in our understanding of the specific signals that trigger keratinocyte differentiation, the underlying signaling pathways, and how they impinge on specific transcription and cell-cycle control mechanisms associated with the onset of keratinocyte differentiation. Recent developments and future directions in this important area of research will be highlighted.

Animals↗
PubMed2004

Continuous in vivo infusion of interferon-gamma (IFN-gamma) preferentially reduces myeloid progenitor numbers and enhances engraftment of syngeneic wild-type cells in Fancc-/- mice.

Fanconi anemia (FA) is characterized by bone marrow (BM) failure and cancer susceptibility. Identification of the cDNAs of many FA complementation types allows the potential of using gene transfer technology to introduce functional cDNAs as transgenes into autologous stem cells and provide a cure for the BM failure in FA patients. Previous studies in FA murine models and in a phase 1 clinical trial suggest that myelopreparation is required for significant engraftment of exogenous, genetically corrected stem cells. Since myeloid progenitors from Fancc-/- mice and human Fanconi anemia group C protein (FANCC) patients have increased apoptosis in response to interferon gamma (IFN-gamma) in vitro, we hypothesized that IFN-gamma may be useful as a nongenotoxic, myelopreparative conditioning agent. To test this hypothesis, IFN-gamma was administered as a continuous infusion to Fancc-/- and wild-type (WT) mice for 1 week. Primitive and mature myeloid lineages were preferentially reduced in IFN-gamma-treated Fancc-/- mice. Further, IFN-gamma conditioning of Fancc-/- recipients was sufficient as a myelopreparative regimen to allow consistent engraftment of isogenic WT repopulating stem cells. Collectively, these data demonstrate that Fancc-/- hematopoietic cell populations have increased hypersensitivity to IFN-gamma in vivo and that IFN-gamma conditioning may be useful as a nongenotoxic strategy for myelopreparation in this disorder.

Animals↗
PubMed2006

Continuous in vivo infusion of interferon-gamma (IFN-gamma) enhances engraftment of syngeneic wild-type cells in Fanca-/- and Fancg-/- mice.

Fanconi anemia (FA) is a heterogeneous genetic disorder characterized by bone marrow (BM) failure and cancer susceptibility. Identification of the cDNAs of FA complementation types allows the potential of using gene transfer technology to introduce functional cDNAs as transgenes into autologous stem cells and provide a cure for the BM failure in FA patients. However, strategies to enhance the mobilization, transduction, and engraftment of exogenous stem cells are required to optimize efficacy prior to widespread clinical use. Hypersensitivity of Fancc-/- cells to interferon-gamma (IFN-gamma), a nongenotoxic immune-regulatory cytokine, enhances engraftment of syngeneic wild-type (WT) cells in Fancc-/- mice. However, whether this phenotype is of broad relevance in other FA complementation groups is unresolved. Here we show that primitive and mature myeloid progenitors in Fanca-/- and Fancg-/- mice are hypersensitive to IFN-gamma and that in vivo infusion of IFN-gamma at clinically relevant concentrations was sufficient to allow consistent long-term engraftment of isogenic WT repopulating stem cells. Given that FANCA, FANCC, and FANCG complementation groups account for more than 90% of all FA patients, these data provide evidence that IFN-gamma conditioning may be a useful nongenotoxic strategy for myelopreparation in FA patients.

Animals↗
PubMed2000

Emerging strategies of bone and joint repair.

The advances in biomedicine over the past decade have provided revolutionary insights into molecules that mediate cell proliferation and differentiation. Findings on the complex interplay of cells, growth factors, matrix molecules and cell adhesion molecules in the process of tissue patterning have vitalized the revolutionary approach of bioregenerative medicine and tissue engineering. Here we review the impact of recent work in this interdisciplinary field on the treatment of musculoskeletal disorders. This novel concept combines the transplantation of pluripotent stem cells, and the use of specifically tailored biomaterials, arrays of bioactive molecules and gene transfer technologies to direct the regeneration of pathologically altered musculoskeletal tissues.

Bone Diseases↗
PubMed2005

Single gene effects in mouse models of host: pathogen interactions.

Inbred mouse strains have been known for many years to vary in their degree of susceptibility to different types of infectious diseases. The genetic basis of these interstrain differences is sometimes simple but often complex. In a few cases, positional cloning has been used successfully to identify single gene effects. The natural resistance-associated macrophage protein 1 (Nramp1) gene (Slc11a1) codes for a metal transporter active at the phagosomal membrane of macrophages, and Nramp1 mutations cause susceptibility to Mycobacterium, Salmonella, and Leishmania. Furthermore, recent advances in gene transfer technologies in transgenic mice have enabled the functional dissection of gene effects mapping to complex, repeated parts of the genome, such as the Lgn1 locus, causing susceptibility to Legionella pneumophila in macrophages. Finally, complex traits such as the genetically determined susceptibility to malaria can sometimes be broken down into multiple single gene effects. One such example is the case of pyruvate kinase, where a loss-of-function mutation was recently shown by our group to be protective against blood-stage infection with Plasmodium chabaudi. In all three cases reviewed, the characterization of the noted gene effect(s) has shed considerable light on the pathophysiology of the infection, including host response mechanisms.

Animals↗
PubMed1995

The British health care reforms, the American health care revolution, and purchaser/provider contracts.

The health care systems of the United States and the United Kingdom are changing rapidly. After the Thatcher government's 1989 white paper, the formerly unified British National Health Service (NHS) was split into purchaser and provider sides, with the NHS District Health Authorities becoming purchasers, and the NHS hospitals, now reconstructed as independent NHS trusts, becoming providers. The U.S. health care system, driven by market forces rather than government fiat, has been moving rapidly toward integration, with increasingly formalized purchaser and provider relationships. Contracts are found at the purchaser/provider interface in both systems. We reviewed American and British purchaser/provider contracts. The contracts address similar issues but often take disparate approaches. These dissimilarities illuminate the profound, continuing differences between the two systems. They also, however, offer possibilities to transfer contracting "technology" between the two contracting cultures.

Competitive Bidding↗
PubMed2005

Identification of sex-specific transcripts of the Anopheles gambiae doublesex gene.

The understanding of the molecular mechanisms of sex differentiation in the mosquito Anopheles gambiae could identify important candidate genes for inducing selective male sterility in transgenic lines or for sex-controlled expression of lethal genes. In many insects, doublesex (dsx) is the double-switch gene at the bottom of the somatic sex-determination cascade that determines the differentiation of sexually dimorphic traits. We report here on the identification of the dsx homologue in A. gambiae and on the characterization of its sex-specific transcripts. Agdsx consists of seven exons, distributed over an 85 kb region on chromosome 2R, which are sex-specifically spliced to produce the female and male AgdsxF and AgdsxM transcripts. AgdsxF contains a 795 bp ORF, coding for a protein of 265 amino acids, while AgdsxM comprises a much longer (1866 bp) ORF, coding for a 622 aa protein. Differences in the exon/intron organization suggest that Agdsx sex-specific splicing results from a different mechanism from Drosophila melanogaster dsx. These findings represent an important step towards the understanding of sex differentiation in Anopheles and will facilitate the use of gene transfer technologies to manipulate sex ratios for vector control programs based on the sterile insect technique.

Amino Acid Sequence↗