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PubMed2006

Methylenetetrahydrofolate reductase polymorphisms modify BRCA1-associated breast and ovarian cancer risks.

Methylenetetrahydrofolate reductase (MTHFR), a key regulatory enzyme in the metabolism of folate, is suspected to play a role in the etiology of cancer, via its effects on DNA methylation and nucleotide synthesis. In this study we have investigated the effect of two functional polymorphisms of the MTHFR gene, MTHFR_677_C > T and MTHFR_1298_A > C, on breast and ovarian cancer risk in Polish BRCA1 mutation carriers. The study included 319 breast cancer cases, 146 ovarian cancer cases and 290 controls unaffected by breast and ovarian cancer, in situ breast cancer or any other kind of cancer. Genotyping analysis was performed using polymerase chain reaction followed by restriction fragment length polymorphism analysis. Odds ratios (OR) were calculated using univariate and multivariate logistic regression taking into account a series of confounding variables that potentially could have biased any association. The results revealed that the MTHFR_677_C > T change was associated with an increased risk of breast and ovarian cancer. The MTHFR_1298_A > C polymorphism was only associated with a decrease in breast cancer risk. Together, it appears that functional polymorphisms in the MTHFR gene modify the risk of breast and may potentially alter the risk of ovarian cancer in women with an inherited predisposition.

Body Mass Index↗
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↗
PubMed1991

Cotransformation and gene targeting in mouse embryonic stem cells.

We have investigated cotransformation in mammalian cells and its potential for identifying cells that have been modified by gene targeting. Selectable genes on separate DNA fragments were simultaneously introduced into cells by coelectroporation. When the introduced fragments were scored for random integration, 75% of the transformed cells integrated both fragments within the genome of the same cell. When one of the cointroduced fragments was scored for integration at a specific locus by gene targeting, only 4% of the targeted cells cointegrated the second fragment. Apparently, cells that have been modified by gene targeting with one DNA fragment rarely incorporate a second DNA fragment. Despite this limitation, we were able to use the cotransformation protocol to identify targeted cells by screening populations of colonies that had been transformed with a cointroduced selectable gene. When hypoxanthine phosphoribosyltransferase (hprt) targeting DNA was coelectroporated with a selectable neomycin phosphotransferase (neo) gene into embryonic stem (ES) cells, hprt-targeted colonies were isolated from the population of neo transformants at a frequency of 1 per 70 G418-resistant colonies. In parallel experiments with the same targeting construct, hprt-targeted cells were found at a frequency of 1 per 5,500 nonselected colonies. Thus, an 80-fold enrichment for targeted cells was observed within the population of colonies transformed with the cointroduced DNA compared with the population of nonselected colonies. This enrichment for targeted cells after cotransformation should be useful in the isolation of colonies that contain targeted but nonselectable gene alterations.

Animals↗
PubMed2005

Orthopaedic applications of gene therapy.

Gene therapy presents a novel approach to biological treatment. Several orthopaedic diseases can cause changes in biological signalling at the tissue level that potentially can be repaired or modified by inserting genes into the cells or tissues to modulate gene expression. Impaired bone healing, need for extensive bone formation, cartilage repair and metabolic bone diseases are all conditions where alterations of the signalling peptides involved may provide cure or improvement. In orthopaedic oncology, gene therapy may achieve induction of tumour necrosis and increased tumour sensitivity to chemotherapy. In the last decade, extensive improvements have been made to optimise gene therapy and have been tested on several orthopaedic conditions. How far this development has come in orthopaedics is highlighted in this paper.

Bone Diseases↗
PubMed1998

Modulation of transgene expression in mesothelial cells by activation of an inducible promoter.

BACKGROUND: The efficacy of peritoneal dialysis and its success as a long-term treatment depends on the preservation of the integrity of the peritoneal membrane. With increasing time on dialysis, the membrane may become compromised resulting in decreased dialysing capacity. We have pursued an innovative strategy, i.e. genetic modification of the mesothelial cell to change the properties of the membrane to potentially improve its dialysing capacity and longevity, and have demonstrated the feasibility of this approach in a rat model of ex vivo gene transfer. The potential to regulate transgene expression in this model is examined here. METHODS: Rat peritoneal mesothelial cells (MCs) were stably modified to express human growth hormone (hGH) under control of the heavy metal ion and glucocorticoid-regulatable murine metallothionein-1 promoter. The effect of zinc and the synthetic glucocorticoid dexamethasone on hGH expression was analysed in MC clones maintained in continuous passage or stationary phase, and in our rat model of ex vivo gene transfer. RESULTS: Exposure of these clones to zinc and dexamethasone, either singly or in combination, resulted in significant (i.e. 2-200-fold) increases in hGH production. Zinc-induced modulation of hGH production was demonstrated in cells in continuous passage and stationary culture. Regulation was also demonstrated after ex vivo gene transfer by both the intraperitoneal administration of zinc ions or the systemic administration of dexamethasone. CONCLUSIONS: Our results demonstrate the modulation of transgene expression in MCs in vitro and in vivo, and suggest the potential for the regulation of gene expression in a genetically modified mesothelium that may ultimately be used for the delivery of therapeutic proteins to maintain peritoneal membrane viability in the peritoneal dialysis patient.

Animals↗
PubMed2006

Transposon-mediated expansion and diversification of a family of ULP-like genes.

Transposons comprise a major component of eukaryotic genomes, yet it remains controversial whether they are merely genetic parasites or instead significant contributors to organismal function and evolution. In plants, thousands of DNA transposons were recently shown to contain duplicated cellular gene fragments, a process termed transduplication. Although transduplication is a potentially rich source of novel coding sequences, virtually all appear to be pseudogenes in rice. Here we report the results of a genome-wide survey of transduplication in Mutator-like elements (MULEs) in Arabidopsis thaliana, which shows that the phenomenon is generally similar to rice transduplication, with one important exception: KAONASHI (KI). A family of more than 97 potentially functional genes and apparent pseudogenes, evidently derived at least 15 MYA from a cellular small ubiquitin-like modifier-specific protease gene, KI is predominantly located in potentially autonomous non-terminal inverted repeat MULEs and has evolved under purifying selection to maintain a conserved peptidase domain. Similar to the associated transposase gene but unlike cellular genes, KI is targeted by small RNAs and silenced in most tissues but has elevated expression in pollen. In an Arabidopsis double mutant deficient in histone and DNA methylation with elevated KI expression compared to wild type, at least one KI-MULE is mobile. The existence of KI demonstrates that transduplicated genes can retain protein-coding capacity and evolve novel functions. However, in this case, our evidence suggests that the function of KI may be selfish rather than cellular.

Amino Acid Sequence↗
PubMed2004

Gene transfer to epidermal stem cells: implications for tissue engineering.

The skin is an attractive target for gene therapy because it is easily accessible and shows great potential as an ectopic site for protein delivery in vivo. Genetically modified epidermal cells can be used to engineer three-dimensional skin substitutes, which when transplanted can act as in vivo 'bioreactors' for delivery of therapeutic proteins locally or systemically. Although some gene transfer technologies have the potential to afford permanent genetic modification, differentiation and eventual loss of genetically modified cells from the epidermis results in temporary transgene expression. Therefore, to achieve stable long-term gene expression, it is critical to deliver genes to epidermal stem cells, which possess unlimited growth potential and self-renewal capacity. This review discusses the recent advances in epidermal stem cell isolation, gene transfer and engineering of skin substitutes. Recent efforts that employ gene therapy and tissue engineering for the treatment of genetic diseases, chronic wounds and systemic disorders, such as leptin deficiency or diabetes, are reviewed. Finally, the use of gene-modified tissue-engineered skin as a biological model for understanding tissue development, wound healing and epithelial carcinogenesis is also discussed.

Animals↗
PubMed2006

Hox control of organ size by regulation of morphogen production and mobility.

Selector genes modify developmental pathways to sculpt animal body parts. Although body parts differ in size, the ways in which selector genes create size differences are unknown. We have studied how the Drosophila Hox gene Ultrabithorax (Ubx) limits the size of the haltere, which, by the end of larval development, has approximately fivefold fewer cells than the wing. We find that Ubx controls haltere size by restricting both the transcription and the mobility of the morphogen Decapentaplegic (Dpp). Ubx restricts Dpp's distribution in the haltere by increasing the amounts of the Dpp receptor, thickveins. Because morphogens control tissue growth in many contexts, these findings provide a potentially general mechanism for how selector genes modify organ sizes.

Animals↗
PubMed2005

Deoxycholic acid-conjugated chitosan oligosaccharide nanoparticles for efficient gene carrier.

To develop chitosan based efficient gene carriers, highly purified chitosan oligosaccharides (COSs) were chemically modified with deoxycholic acid (DOCA). Owing to the amphiphilic characters, the DOCA-conjugated COSs (COSDs) formed self-aggregated nanoparticles in aqueous milieu. The physicochemical characterization revealed that the particle size of the nanoparticles was in the range of 200 approximately 240 nm and the critical aggregation concentration (cacs) was 0.012 approximately 0.046 g/L, depending on the degree of substitution (DS). As efficient gene carriers, the COSD nanoparticles showed superior gene condensation and protection of condensed gene from endonuclease attack than unmodified COSs. Furthermore, COSDs showed great potential for gene carrier with the high level of gene transfection efficiencies, even in the presence of serum. Considered with the negligible cytotoxic effects, DOCA-modified chitosan oligosaccharides can be considered as potential candidates for efficient non-viral gene carriers.

Chemical Phenomena↗
PubMedDate not supplied

Immune monitoring of human gene therapy trials: potential application to leukemia and lymphoma.

Therapeutic genetically modified vaccines administered to patients with cancer are expected to induce and sustain tumor-specific immune responses. To measure these responses, monitoring strategies including a range of antibody-based and cellular assays have been developed. Single-cell cellular assays capable of detecting fewer than 1/10,000 of antigen-specific T lymphocytes in the tested population are currently in demand. ELISPOT assay, cytokine flow cytometry, and tetramer binding were recently compared by us in the context of monitoring of a dendritic cell-based multi-peptide vaccination trial in patients with metastatic melanoma. These single-cell assays were not found to be concordant in measurements of the frequency of peptide-specific T cells or in detecting pre- to post-vaccine changes in the frequency of these T cells. Implications of the results for monitoring of genetically modified vaccines are discussed, and the plan for a rational approach to monitoring and for selection of monitoring assays is proposed. Monitoring of human gene therapy or vaccination trials in patients with advanced cancers, who are often immunocompromised and thus poorly responsive, is a challenge. This challenge is best met by utilizing experienced reference laboratories for immune monitoring of clinical trials.

Cancer Vaccines↗
PubMed2005

Association between the neuron-specific RNA-binding protein ELAVL4 and Parkinson disease.

Inflammatory processes have been implicated in the cascade of events that lead to nerve cell death. In the nervous system, a number of genes involved in inflammation pathways are regulated post-transcriptionally via the interaction of their mRNAs with specific RNA-binding Hu proteins, the vertebrate homologues of the Drosophila ELAV (for embryonic lethal abnormal vision). The gene encoding ELAVL4, a member of the Hu family of proteins, is located 2 Mb from the chromosome 1p linkage region peak for age-at-onset (AAO) of Parkinson disease (PD) (LOD = 3.41). Nine single-nucleotide polymorphisms (SNPs) in ELAVL4 were genotyped for 266 multiplex families (1,223 samples). Additional genotyping in 377 singleton families was performed for a subset of five SNPs (SNPs 1-5) that were not in linkage disequilibrium. SNP 2 (located in the first intron of ELAVL4) showed a strong significant association with AAO of PD (P = 0.006), and SNP 5 (a coding SNP in ELAVL4) showed a moderately significant association (P = 0.035). Haplotype analysis revealed that the A-C haplotype at SNPs 2 and 3 has the strongest significant association with AAO (P = 0.0001) among all combinations of two or three loci. The A-C haplotype remained significant for AAO after the inclusion of the C allele at SNP 5 to this haplotype (A-C-C haplotype, P = 0.00018). Although SNP 5 was found to associate with PD risk in the early-onset subset of PD families (at least one affected with AAO <40 years, 60 families), we believe that it is a by-product of its association with AAO. Taken together, these results suggest a potential role for ELAVL4 as a modifier gene for AAO of PD.

Adult↗
PubMed1991

Isolation and transcriptional characterization of a morphological modifier: the Aspergillus nidulans stunted (stuA) gene.

The functions of at least four potential regulatory genes are known to overlap temporally during elaboration of the multicellular asexual reproductive apparatus (conidiophore) of Aspergillus nidulans. One of these, the stuA (stunted) gene, has been previously classified as a morphological modifier essential for correct spatial organization of the conidiophore. The gene was cloned by complementation of a strain carrying the stuA1 mutation and has been localized to a 5.0 kb KpnI fragment that encodes a 3.3 kb mRNA. The stuA mRNA was detected at very low levels in mature conidia and in somatic hyphae that had not established developmental competence. A dramatic increase in the abundance of this mRNA occurred coincidentally with the establishment of competence, but prior to the induction of conidiation. RNA abundance remained at this elevated level during conidiophore morphogenesis. These results are consistent with genetic data suggesting that stuA gene function is required from the very earliest events of asexual reproduction until completion of conidiophore development, but is not specifically required for differentiation of conidia. The expression of the stuA transcript was not affected by any of the other characterized developmental mutations. These latter results suggest that transcriptional activation at the onset of competence is mediated by an as yet unidentified genetic locus or loci.

Aspergillus nidulans↗
PubMed2002

Gene therapy in transplantation.

Gene transfer and gene therapy represent a relatively new field that has grown and expanded enormously in the last 5-10 years. The application of gene transfer and gene medicines to transplantation is currently in its infancy. Consideration for gene medicines in transplantation requires delivery of vectors, either to the graft or to the immune system. Delivery of vectors to the graft provides a choice of potential immunologic targets including: costimulatory signals; inhibitory cytokines; adhesion molecules; and molecules relating to apoptosis. In addition, non-immunologic targets, that increase graft protective mechanisms by reducing ischemic and immunologic damage, represent significant targets for gene transfer. Delivery of vectors to the immune system includes potential targets to modify the immune system, and results in tolerance. Other considerations for gene therapy include the development of additional technologies, such as gene conversion or transgenesis coupled with xenotransplantation, which may provide genetically modified organs. Another important aspect of gene transfer relates to regulation of the transgene expression. A variety of issues concerning innate immunity, adaptive immunity, response to vector components, response to transgene products, and entry of vectors into the antigen presentation and processing pathway require further investigation and refinement of approaches. Lastly, regulatable promoters and the understanding of their interaction with individual cells, tissues and organs, and their interaction with innate and adaptive immunity, are of paramount importance to improving the efficacy and utility of gene transfer. There is no doubt that there is much exciting basic and translational science to be accomplished in the next decade in order to solve these potential barriers and advance gene medicines into the clinical realm in transplantation.

Abatacept↗
PubMed1994

D4 dopamine receptor-mediated signaling events determined in transfected Chinese hamster ovary cells.

A Chinese hamster ovary (CHO) cell line stably expressing a recombinant human D4 dopamine receptor made from a synthetic gene has been used to determine potential D4-mediated signaling events. We designed and synthesized a modified gene coding for a human D4 receptor with reduced G + C content but unaltered encoded amino acids. Stable expression of this gene was obtained in two cell lines, inducible expression in CHO lacI cells and constitutive expression in HEK293 cells. In CHO lacI cells induced to express D4 receptors but not in uninduced cells, dopamine and quinpirole inhibit forskolin-stimulated cAMP accumulation and potentiate ATP-stimulated [3H]arachidonic acid release through a mechanism that requires protein kinase C but is unaffected by membrane-soluble cAMP analogs. In addition, D4 receptor activation causes an increase in the rate of extracellular acidification measured by microphysiometry. This response is unaffected by protein kinase C down-regulation but is inhibited by removal of extracellular sodium and inhibitors of NaH-1 exchange, suggesting the involvement of a Na+/H+ exchanger. All responses are blocked by clozapine and are sensitive to pertussis toxin. D4 receptors, like other G(i)/G(o)-linked receptors, mediate multiple signaling events, and the pathways activated are similar to those used by D2 and D3 receptors expressed in similar cells.

Amiloride↗
PubMed2006

Polymorphisms in the thymidylate synthase promoter and the DNA repair genes XRCC1 and XPD in a Brazilian population.

Polymorphisms in genes responsible for maintaining genomic integrity are potential modifiers of disease risk. Since considerable interindividual and interethnic variation in DNA repair capacity has been associated with polymorphic alleles, we evaluated the frequency of the 2R/3R variants in the TS promoter, Arg194Trp and Arg399Gln in the XRCC1 gene, and Asp312Asn and Lys751Gln in the XPD gene in 364 healthy individuals from a Brazilian population separated by ethnicity (European ancestry and African ancestry). The genotypes were determined by PCR (TS) or by PCR-RFLP (XRCC1 and XPD). The frequency of the TS 3R allele was 0.56 for whites and 0.51 for nonwhites. In the case of the XRCC1 MspI polymorphism, the allele frequencies were 0.09 for 194Trp in both nonwhites and whites and 0.27 and 0.28 for 399Gln in nonwhites and whites, respectively. For the XPD 312Asn allele, we found a frequency of 0.25 in white individuals, which was significantly different (P = 0.025) from that seen in nonwhites (0.15). Similarly, the 751Gln polymorphic allele of the XPD gene was significantly more frequent (P < 0.002) in whites (0.30) than in nonwhites (0.20). The genotype frequencies were within Hardy-Weinberg equilibrium. We concluded that the genotype and allele frequencies of XPD gene polymorphism differed between white and nonwhite Brazilians, and that the frequencies of the XPD 312Asn and XRCC1 399Gln alleles in this Brazilian population showed ethnic variability when compared with those observed in other populations.

Brazil↗
PubMed2005

Genetic polymorphisms of TGF-beta1 & TNF-beta and breast cancer risk.

OBJECTIVE: The proliferation of malignant breast epithelial cells is regulated by various stimuli including cytokines and growth factors, thus the variants of those genes may modify the breast cancer risk. To evaluate the potential influences of TGF-beta1 T29C and TNF-beta A252G gene polymorphisms on breast cancer risk, a case-control study was conducted in Korea. METHODS: Histologically confirmed breast cancer cases (n=560) and controls (n=509) with no previous history of cancer were recruited from three teaching hospitals in Seoul, Korea. Genotypes were determined by PCR-CTPP (polymerase chain reaction with confronting two-pair primers) method. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression model adjusting for age, body mass index, education, parity, age at first full-term pregnancy, and family history of breast cancer. RESULTS: The TGF-beta1 29C-allele containing genotypes posed an increased risk of breast cancer (OR=1.3, 95% CI=1.02-1.79), especially in postmenopausal women (OR=1.6, 95% CI=1.01-2.44). Similarly, the TNF-beta 252G-allele containing genotypes posed an increased risk of postmenopausal breast cancer (OR=1.7, 95% CI=1.09-2.55). The risk of postmenopausal breast cancer increased in parallel with the number of the risk genotypes (p for trend <0.01). When data were stratified by the presumed non-genetic risk factors, TGF-beta1 C-allele containing genotypes were found to increase breast cancer risk almost two-fold in postmenopausal women with greater than median body mass index (>22.8 kg/m2) (OR=1.9, 95% CI=1.04-3.37). CONCLUSION: The results of this study therefore suggest that polymorphisms of TGF-beta1 and TNF-beta genes may modify individual susceptibility to breast cancer in Korean women.

Breast Neoplasms↗
PubMed2006

Human mesenchymal stem cells (hMSCs) expressing truncated soluble vascular endothelial growth factor receptor (tsFlk-1) following lentiviral-mediated gene transfer inhibit growth of Burkitt's lymphoma in a murine model.

BACKGROUND: Efficient gene transfer to bone marrow derived mesenchymal stem cells (MSC) would provide an important opportunity to express potent anticancer agents in the tumour microenvironment because of their contribution to the tumour stroma. METHODS: HIV-based lentiviral vectors were pseudotyped with four different envelope proteins; amphotropic murine leukaemia virus (ampho), murine leukaemia virus (10A1), feline endogenous virus (RD114), and the vesicular stomatitis virus glycoprotein (VSVG). These pseudotypes were examined for transduction efficiency in human bone marrow derived MSC. The effect of lentiviral expression of truncated soluble vascular endothelial growth factor decoy receptor (tsFlk-1) in MSC on growth of Raji cells was determined, both in vitro and in vivo. RESULTS: All lentiviral vectors produced significant levels of transduction at an multiplicity of infection (MOI) of 1, those bearing the RD114 envelope glycoprotein consistently produced higher transduction levels (mean 70 +/- 6%) compared with the other pseudotyped lentiviral vectors, although there was significant inter-donor variation. Stable transgene expression was achieved after multiple rounds of transduction with VSVG-pseudotyped particles, without alteration in the differentiative capacity of transduced cells. Co-injection of MSC stably expressing tsFlk-1 with Raji Burkitt's lymphoma cells significantly impaired subcutaneous tumour growth in immunodeficient mice when compared to controls where either unmanipulated MSC or GFP-expressing MSC were used. CONCLUSIONS: Human MSC are easily transduced by pseudotyped lentiviral particles but there is inter-donor variation in transduction efficiency. Gene-modified MSC expressing a gene of therapeutic potential can moderate growth of haematological malignancies.

Animals↗
PubMed2001

In situ gene therapy for prostate cancer: immunomodulatory approaches.

The development of effective treatments for prostate cancer is thwarted by the natural history of the disease. The biological and clinical potential of most individual cancers is uncertain. In many cases the disease will not progress to clinical significance but experimental and clinical studies indicate that prostate cancer can and may metastasis early in the course of the disease from relatively small foci (i.e., not necessarily the largest or index cancer). Localised prostate cancer is potentially curable with localised therapies (radical prostatectomy or irradiation therapy). However, there are no curative therapies for metastatic prostate cancer. Gene therapy, especially those approaches with an immunomodulatory component, may provide additional therapeutic options with the potential to affect both localised and systemic disease. We have pioneered the development and application of in situ gene therapy protocols using adenoviral vectors to transduce specific genes that generate cytotoxic activity and/or a systemic antitumour immune response. In addition we have completed initial studies that demonstrate the therapeutic potential of adenoviral vector-mediated gene modified cell-based vaccines. Our review discusses preclinical studies focused on the development of immunostimulatory in situ gene therapy approaches that hopefully will provide novel and effective treatments for localised and metastatic prostate cancer.

Animals↗