SEARCH · Search PubMed

Results for “Potential modifier genes”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 145 records · Page 8Linked to original sources

PubMed2005

Versatile peptide dendrimers for nucleic acid delivery.

Dendrimers are nonviral vectors that have attracted interest on account of a number of features. They are structurally versatile because their size, shape, and surface charge can be selectively altered. Here we examine the functions of a new family of composite dendrimers that were synthesized with lipidic amino acid cores. These dendrimers are bifunctional because they are characterized by positively charged (lysine) modules for interaction with nucleic acids and neutral lipidic moieties for membrane lipid-bilayer transit. We assessed their structure-function correlations by a combination of molecular and biophysical techniques. Our assessment revealed an unexpected pleitropy of functions subserved by these vectors that included plasmid and oligonucleotide delivery. We also generated a firefly luciferase cell line in which we could modulate luciferase activity by RNA interference. We found that these vectors could also mediate RNA suppression of luciferase expression by delivering double-stranded luciferase transcripts generated in vitro. The structural uniqueness of these lipidic peptide dendrimers coupled with their ease and specificity of assembly and the versatility in their choice of cargo, puts them in a new category of macromolecule carriers. These vectors, therefore, have potential applications as epigenetic modifiers of gene function.

Animals↗

PubMed1995

Drug treatment in children with juvenile rheumatoid arthritis. Past, present, and future.

Rheumatology made its debut as a legitimate subspecialty of pediatrics sometime in the 1940s in Europe, and in the 1970s in North America. Therapy of juvenile rheumatoid arthritis has evolved from salicylates and gold injections to newer, less toxic nonsteroidal anti-inflammatory drugs and methotrexate. Corticosteroids remain as important drugs when life-threatening complications or blinding iridocyclitis develop. Immune response modifiers and gene therapies offer considerable potential for eventually halting or curing the disease but have yet to make a substantial impact on therapy. Methods for the correct conduct and interpretation of data from clinical trials are discussed.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1999

Immunization with a plasmid encoding a modified hepatitis B surface antigen carrying the receptor binding site for hepatocytes.

Intramuscular injection of a plasmid encoding a modified hepatitis B surface antigen (HBsAg) induced humoral and cytotoxic responses in C57BL/6 mice. This modified HBsAg contains a preS1-derived peptide (amino acids 21 to 47), that carries the HBV receptor binding site for hepatocytes fused to the C-terminus of the small protein (at the position of amino acid 223). After a single DNA injection, the immunized mice elicited high titers of anti-HBs and anti-preS1 antibodies, and produced strong HBV specific cytotoxic T-lymphocyte (CTL) responses. The immune response induced after a single injection of this modified HBsAg gene in HBsAg-transgenic mice resulted in the clearance of circulating HBsAg and the appearance of anti-HBs and anti-preS1 antibodies. The high titers of preS1 antibody in transgenic mice were comparable to those found in non-transgenic controls and may be efficient to clear Dane particles existing in sera from chronic carriers. These data indicated that a genetic vaccine consisting of this modified HBsAg gene may have a potential use for both prophylactic and therapeutic purposes.

Animals↗

PubMed2002

Epigenetic risks related to assisted reproductive technologies: short- and long-term consequences for the health of children conceived through assisted reproduction technology: more reason for caution?

Does the manipulation of gametes and embryos as practised in human IVF invoke perturbations in fetal and neonatal phenotype? There is increasing evidence that the answer is 'yes', although the degree of perturbation may be less acute than observed in other species. However, the long-term consequences are not known, and may prove to be considerable. There is now a substantial body of evidence from animal models suggesting that assisted reproductive technologies (ART) are associated with altered outcomes in fetal and neonatal development. Epigenetic modification of gene expression is an attractive hypothesis that accounts for these differences and is one of a number of causal pathways that may be activated by cellular stress invoked during manipulation. Here we widen the debate to propose that environment-induced cellular stress also acts to modify fetal and placental gene expression, potentially also contributing to phenotype skewing after ART.

Animals↗

PubMed2006

Microsatellite instability in the development of DNA mismatch repair deficient tumors.

Microsatellites are highly abundant short repetitive sequences found in the genomes across different species. They have gained increasing interest in recent years because length alterations in several coding as well as non-coding microsatellites are associated with a variety of different disorders. Particularly, microsatellite mutations play an important role in tumorigenesis of DNA mismatch repair deficient tumors that account for up to a 15% of colorectal, endometrial, and various other cancers. The systematic analysis of the distribution and function of affected microsatellite sequences has facilitated to unravel important steps in the selection processes that drive tumorigenesis. Here, we review the role of microsatellite mutations in the development of cancers with DNA mismatch repair deficiency, outlining biostatistical approaches for the identification of MSI target genes with relevance to MSI associated carcinogenesis. Knowledge about the biological impact of microsatellite mutations in these genes will potentially help to develop modified clinical concepts for diagnosis, prevention, and treatment of microsatellite unstable human cancers.

Colorectal Neoplasms, Hereditary Nonpolyposis↗

PubMed2005

Farnesyltransferase inhibitor therapy in acute myelogenous leukemia.

Acute myelogenous leukemia (AML) remains a clinical challenge with poor long-term survival. Low remission rates and high treatment-related mortality persist as major obstacles, particularly in older patients. The design of novel agents based on the identification of genetic lesions and aberrant signaling pathways provides opportunity to improve the standard treatment paradigm of intensive cytotoxic chemotherapy. Farnesyltransferase inhibitors (FTIs) show potential to fill this niche. The preclinical concept of farnesyltransferase blockade as a targeted therapy against oncogenic Ras has clearly evolved with the recognition that many proteins involved signaling pathways in tumor cells undergo farnesylation. Phase I/II trials of FTI monotherapy in AML demonstrate encouraging responses and good tolerability. The FTI tipifarnib (R115777, Zarnestra; Johnson & Johnson, Titusville, NJ) has advanced the furthest in clinical trials, with the most promising activity in previously untreated, high-risk AML patients. A major emphasis of current clinical studies has been to analyze potential candidate genes and signaling pathways modified by FTIs in order to identify mechanisms of response and resistance. Preclinical concepts related to the development of FTIs, the rationale for their use in AML, and efficacy and safety results from recent clinical trials are evaluated in this paper.

Acute Disease↗

PubMed2002

Suppression of heterochromatic gene variegation can be used to distinguish and characterize E(var) genes potentially important for chromosome structure in Drosophila melanogaster.

Hundreds of genic modifiers of position effect variegation (PEV) have been isolated in Drosophila melanogaster with a view to identifying genes important for chromosome structure. Here we propose a supplementary genetic screen to pinpoint candidate genes that are most likely to function in chromosome organization, within the enhancer of variegation [E(var)] class of modifiers. Our strategy takes advantage of the fact that variegating euchromatic and heterochromatic genes respond oppositely to changes in the dosage of heterochromatin proteins. Consequently, only when enhancement of euchromatic gene variegation results from increased formation of heterochromatin should suppression of heterochromatic gene variegation be observed. Mutations in four E(var) genes were tested for the ability to suppress variegation of multiple alleles of the heterochromatic light ( lt) gene in a variety of tissues and at several developmental stages. Mutations in E(var)3-4, E(var)3-5 and modifier of mdg4 [ mod(mdg4)] suppressed lt variegation. In contrast, a mutation in the Trithorax-like ( Trl) gene, which encodes GAGA factor, enhanced or had no effect on lt variegation, consistent with its known role in promoting transcription. These data show that suppression of lt variegation can be used as an assay to distinguish between members of the E(var) class of modifiers.

Animals↗

PubMed2005

Influence of mechanical and biological signals on gene expression in human MG-63 cells: evidence for a complex interplay between hydrostatic compression and vitamin D3 or TGF-beta1 on MMP-1 and MMP-3 mRNA levels.

Biological mediators can influence the activity and differentiation of bone cells. 1,25-dihydroxy-vitamin D3 (1,25-(OH)2D3) is known to induce differentiation of precursors into mature osteoblasts, and transforming growth factor-beta1 (TGF-beta1) can modulate the activity of bone cells leading to alterations in proliferation and gene expression patterns. Bone-derived cells were loaded via intermittent cyclic hydrostatic pressure (icHP) on cells under basal conditions and in the presence of 1,25-(OH)2D3 or TGF-beta1. Evaluating the effects of loading on the cells allowed for a comparison to be made between responsiveness to biomechanical and biochemical stimuli and their potential interplay. The effects of icHP on mRNA levels for the specific genes involved in bone remodelling and differentiation were measured in MG-63 cells using reverse transcription-polymerase chain reaction (RT-PCR). The mRNA levels for matrix metalloproteinase-1 and -3 (MMP-1 and MMP-3) were significantly, and uniquely, increased (p < 0.001) in cells exposed to icHP under serum-free conditions for 4-12 h. However, mRNA levels for MMP-3, but not MMP-1, were significantly enhanced in cells subjected to static hydrostatic pressure (HP). Treatment of cells with 1,25-(OH)2D3 resulted in increased (p < 0.001) mRNA levels for osteocalcin and decreased (p < 0.001) mRNA levels for both MMP-1 and MMP-3. In cells exposed to icHP and 1,25-(OH)2D3, the mRNA levels for both MMP-1 and MMP-3 were elevated (p < 0.001) compared with hormone alone, but not to the same degree (p < 0.01) as cells subjected to icHP alone. Addition of TGF-beta1 to cells led to increases in cell proliferation and expression of collagen I, as well as decreases in expression of osteocalcin and MMP-1 and MMP-3. Exposure of cells to icHP and TGF-beta1 again led to unique and significant increases in expression of MMP-1 and MMP-3. No changes in mRNA levels for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) or any of the other 9 genes assessed, including those for MMP-2 and MMP-13, were detected under any of the conditions described. Therefore, icHP can induce alterations in mRNA levels for a specific subset of genes in both premature and mature osteoblasts. Such stimuli can modulate the impact of potent biological mediators in defining patterns of gene expression by bone cells and potentially modify function in vivo.

Adolescent↗

PubMed2001

Modifications to the hand-held Gene Gun: improvements for in vitro biolistic transfection of organotypic neuronal tissue.

Transfection and subsequent expression of DNA in living neuronal tissue is problematic and no technique has emerged that is completely non-damaging, efficient and reproducible. The Bio-Rad hand-held Gene Gun has overcome some of these problems by exploiting a biolistic method in which small gold particles carrying plasmid DNA are propelled into neurons whilst causing minimal detectable cell damage. In its current configuration, however, the Bio-Rad Gene Gun is optimised for transfecting cells in dispersed cultures, and therefore delivers particles superficially over a relatively wide area. Here we report modifications to the Bio-Rad Gene Gun that both enhance its accuracy by restricting its target area, and increase the depth penetration achieved by gold particles, thereby allowing smaller and deeper tissues to be transfected. These alterations make the modified Gene Gun more applicable for in vitro transfection of organotypic cultures and enhance its potential utility for in vivo gene delivery. Moreover, the modified configuration operates successfully at lower gas pressures, thereby reducing even further the degree of cell damage incurred during transfection.

Air Pressure↗

PubMed1999

Angiogenesis and gene therapy in man: dream or reality?

Preclinical studies indicate that angiogenic growth factors can stimulate the development of collateral arteries in animal models of peripheral or myocardial ischaemia, a concept termed 'therapeutic angiogenesis'. The goal of this review is to provide a brief overview of the advantages and disadvantages of gene versus recombinant protein therapy for therapeutic angiogenesis. We also discuss different options for delivering genes to patients, including plasmids and modified viral vectors. Recently, the safety and potential utility of gene therapy for ischaemic disease were demonstrated in 3 clinical trials involving the delivery of plasmid DNA encoding the 165 amino acid isoform of human vascular endothelial growth factor (phVEGF165), a factor that specifically promotes the proliferation and migration of vascular endothelial cells. Two trials involved the administration of phVEGF165 for peripheral arterial disease. In one trial, the plasmid was administered to the arterial wall from a hydrogel-coated angioplasty balloon, while a second trial examined the direct injection of phVEGF165 into the skeletal muscle of the affected limb. More recently, phVEGF165 was directly injected into ischaemic myocardium. In all these trials, it appears that administration of phVEGF165 led to improvements in tissue perfusion.

Angiogenesis Inducing Agents↗

PubMed1999

Angiogenesis and gene therapy in man: dream or reality?

Angiogenesis Inducing Agents↗

PubMed1994

H-2Kb and H-2Db gene transfections in B16 melanoma differently affect non-immunological properties relevant to the metastatic process. Involvement of integrin molecules.

Modification of non-immunological cell adhesion properties plays a major role in the decrease in metastatic ability observed after transfection of the H-2Kb gene in H-2-negative B16-derived melanoma clone cells. To investigate the role played by different class-I major histocompatibility complex (MHC) genes on non-immunological properties relevant for metastasis, transfection with the H-2Db gene alone or in conjunction with the H-2Kb gene was performed. H-2Db gene transfection did not modify either metastatic potential or non-immunological cell adhesion properties. Double KbDb transfectants showed a decreased metastatic ability when compared to control clones and to Db transfectants; a decrease in homotypic adhesive ability was also observed, even though not in all clones studied: therefore expression of the Db gene is also relevant. The mechanisms of homotypic cell adhesion were studied and found to be dependent upon temperature and divalent cations. Adhesion was partially inhibited by an antiserum directed against the beta 1 integrin subunit, whereas anti-alpha IIb beta 3 was ineffective. Cell pre-treatment with anti-beta 1 serum reduced metastatic ability. A decreased expression of alpha 4 and alpha 6 integrin subunits was observed in Kb clones, whereas no difference in the levels of some homophilic cell adhesion molecules, such as N-CAM and alpha IIb beta 3, was found. Adhesion required the activity of tyrosine kinases, as suggested by the decreased adhesive properties and impaired metastatic ability of cells pre-treated with the tyrosine-kinase-inhibitor genistein. These results are compatible with involvement of integrin molecules of the beta 1 family in the adhesive ability of these cells. Our data show that: (a) immunological and non-immunological effects of MHC transfection are correlated and depend on the class-I gene used, suggesting that MHC gene therapy can be highly successful only if appropriate MHC genes are transfected; (b) non-immunological cell-adhesion properties modified after MHC transfection could be related to an impairment of integrin-mediated adhesive interactions.

Animals↗

PubMed2004

Characterization of stem cell factor gene-modified human natural killer cell line, NK-92 cells: implication in NK cell-based adoptive cellular immunotherapy.

NK-92 cells are effective against a broad range of malignant targets both in vitro and in vivo. Stem cell factor (SCF) is an important early acting cytokine for NK cell development. The characterization and implication in clinic of SCF gene-modified NK-92 cells need to be investigated. SCF cDNA was inserted into pcDNA3 eukaryotic expression vector and the recombinant vector (pcDNA3-SCF) was transfected into NK-92 cells. The SCF gene-modified NK-92 cells (NK92-SCF) were cloned and characterized by cytokine gene expression, proliferation potential, cytotoxic function and surface phenotype. NK92-SCF cells continuously produced a high level of SCF in culture supernatant, which made the cells proliferate significantly more rapidly in response to IL-2 or IL-15 stimulation, the cumulative amount of cells in long-term culture was significantly higher. NK92-SCF cells exerted stronger cytotoxicity against a broad range of target tumor cells than their parent NK-92 cells, which was correlated to the increased expression of cytotoxic effector molecules such as perforin and Fas ligand. NK92-SCF cells became more heterogeneous; the CD56(High) and CD56(Low) subsets appeared, which may, at least partly, explain the increased proliferating and cytotoxic potential of NK92-SCF cells. SCF gene-modified NK-92 cells (NK92-SCF cells) are more promising than their parent cells for adoptive cellular immunotherapy.

Cell Division↗

PubMed2004

Anti-human immunodeficiency virus hematopoietic progenitor cell-delivered ribozyme in a phase I study: myeloid and lymphoid reconstitution in human immunodeficiency virus type-1-infected patients.

A phase I gene transfer clinical study was undertaken to examine the ability to introduce a potential anti-human immunodeficiency virus (HIV) gene therapeutic into hematopoietic progenitor cells (HPC), thereby contributing to multilineage engraftment. The potential therapeutic effect of genetically modifying HPC with protective genes in HIV-infected adults depends in part on the presence of adult thymic activity and myeloid capacity in the setting of HIV replication. Herein we report the presence and expression of a retroviral vector encoding an anti-HIV-1 ribozyme in mature hematopoietic cells of different lineages, and de novo T-lymphocyte development ensuing from genetically engineered CD34(+) HPC. Sustained output of vector-containing mature myeloid and T-lymphoid cells was detected even in patients with multidrug-resistant infection. In addition, the study showed that the degree of persistence of gene-containing cells was dependent on transduced HPC dose. These novel findings support the concept of gene therapy as a modality to effect immune reconstitution with cells engineered to inhibit HIV replication and this report represents the first demonstration of long-term maintenance of a potential therapeutic transgene in HIV disease.

Adult↗

PubMed1990

Autologous fibroblast implantation. Feasibility and potential problems in gene replacement therapy.

Autologous implants of genetically modified fibroblasts may be an ideal approach to gene replacement therapy. However, primary fibroblasts have limited life span and their use for gene therapy is questionable. We have developed a rat model to evaluate the feasibility of this approach. Primary fibroblasts initiated from rat skin biopsies were transfected with plasmid DNA. The transkaryotic fibroblasts were implanted into the original rat donors. A plasmid-encoded gene product, human growth hormone, was detected in the donor rats' circulation but less than 1% of the expected amount was recovered. Implantation at intraperitoneal, intramuscular or subcutaneous sites were effective in delivering the novel gene product. Fluctuating levels of human growth hormone were detected for over 6 months but their determination was rendered unreliable due to interference by extremely high titers of antibodies developed against the human growth hormone. In some cases, the antibody titer continued rising for more than 6 months, indicative of the continued presence of the antigen. One of the recipients developed two intra-abdominal fibrosarcomas that were shown to be derived from the implanted cells. In conclusion, this model demonstrates that autologous fibroblast implantation is a feasible approach to delivering novel gene products lasting for several months. Strong and prolonged immuno-reaction against the gene product will occur if the recipient's immune system is naive to the replacement product, as would occur in patients with CRM- mutations. The potential for neoplastic development from the implanted fibroblasts should prompt further evaluation of the long-term safety in gene replacement therapy.

Animals↗

PubMed2002

Experimental genomic evolution: extensive compensation for loss of DNA ligase activity in a virus.

Deletion of the viral ligase gene drastically reduced the fitness of bacteriophage T7 on a ligase-deficient host. Viral evolution recovered much of this fitness during long-term passage, but the final fitness remained below that of the intact virus. Compensatory changes occurred chiefly in genes involved in DNA metabolism: the viral endonuclease, helicase, and DNA polymerase. Two other compensatory changes of unknown function also occurred. Using a method to distinguish compensatory mutations from other beneficial mutations, five additional substitutions from the recovery were shown to enhance adaptation to culture conditions and were not compensatory for the deletion. In contrast to the few previous studies of viral recovery from deletions, the compensatory changes in T7 did not restore the deletion or duplicate major regions of the genome. The ability of this deleted genome to recover much of the lost fitness via mutations in its remaining genes reveals a considerable evolutionary potential to modify the interactions of its elements in maintaining an essential set of functions.

Adaptation, Physiological↗

PubMed2002

The Opitz syndrome gene Mid1 is transcribed from a human endogenous retroviral promoter.

Human endogenous retroviruses (HERVs) and other long terminal repeat (LTR)-containing elements comprise a significant portion (8%) of the human genome and are likely vestiges of retroviral infections during primate evolution. Many of the HERVs present in human DNA have retained functional promoter, enhancer, and polyadenylation signals, and these regulatory sequences have the potential to modify the expression of nearby genes. To identify retroviral elements that contribute to the transcription of human genes, we screened sequence databases for chimeric (viral-cellular) transcripts. These searches revealed a fusion transcript containing the LTR of an HERV-E element linked to the Opitz syndrome gene Mid1. We confirmed the authenticity of the chimeric transcript by 5' rapid amplification of cDNA ends (RACE) and established that the Mid1 mRNA isoform was transcribed from a retroviral LTR. The identification of a retroviral first exon suggested the existence of alternative promoters for Mid1 because nonretroviral (native) 5' untranslated regions (UTRs) had been reported previously for this gene. Although Mid1 transcripts could be detected in all tissues tested, quantitative real-time reverse transcription-polymerase chain reaction indicated that the retroviral promoter contributes significantly to the level of Mid1 transcripts in placenta and embryonic kidney, where chimeric mRNAs were found to represent 25% and 22% of overall Mid1 mRNAs, respectively. Transient transfection studies supported a role for the LTR as a strong tissue-specific promoter in placental and embryonic kidney cell lines and suggested a function for the LTR as an enhancer. These findings provide further evidence that some endogenous retroviruses have evolved a biological function by contributing transcriptional regulatory elements to cellular genes.

Base Sequence↗

PubMed2006

Adenoviral vector-mediated RTVP-1 gene-modified tumor cell-based vaccine suppresses the development of experimental prostate cancer.

We previously identified a novel p53 target gene, RTVP-1, that possesses unique cytotoxic and immunostimulatory activities which make it potentially useful for cancer gene therapy. To test the therapeutic potential of RTVP-1 in a gene-modified tumor cell-based vaccine model, we used an adenoviral vector capable of efficient transduction and expression of RTVP-1 (AdRTVP-1), together with a highly metastatic mouse prostate cancer cell line (178-2 BMA). A vaccine was prepared with 178-2 BMA cells transduced with AdRTVP-1 or a control adenoviral vector expressing beta-galactosidase (Adbetagal). After irradiation of the cells, syngeneic 129/Sv mice were vaccinated three times at weekly intervals. After 3 weeks, they were challenged with orthotopic 178-2 BMA cells. After 21 days, fewer than 60% of the RTVP-1-cell-vaccinated mice developed tumors compared to 100% of the control mice. The RTVP-1-cell vaccine significantly reduced primary tumor wet weight compared with control Adbetagal-cell vaccine (P<0.0001 at 7 and 14 days). Experimental metastasis to lung was also significantly reduced (P=0.0377), and survival significantly increased (P=0.0002). In addition, significantly increased NK and CTL activities were demonstrated in the AdRTVP-1-cell-vaccinated mice. These findings indicate that RTVP-1 gene-modified cell-based vaccines may be useful in the prevention of recurrent prostate cancer.

Adenoviridae↗