Glioblastomas, the most frequent and malignant of primary brain tumors, have a very poor prognosis. Gene therapy of glioblastomas is limited by the short survival of viral vectors and by their difficulty in reaching glioblastoma cells infiltrating the brain parenchyma. Neural stem/progenitor cells can be engineered to produce therapeutic molecules and have the potential to overcome these limitations because they may travel along the white matter, like neoplastic cells, and engraft stably into the brain. Retrovirus-mediated transfer of the gene for interleukin-4 is an effective treatment for rat brain glioblastomas. Here, we transferred the gene for interleukin-4 into C57BL6J mouse primary neural progenitor cells and injected those cells into established syngeneic brain glioblastomas. This led to the survival of most tumor-bearing mice. We obtained similar results by implanting immortalized neural progenitor cells derived from Sprague-Dawley rats into C6 glioblastomas. We also documented by magnetic resonance imaging the progressive disappearance of large tumors, and detected 5-bromodeoxyuridine-labeled progenitor cells several weeks after the injection. These findings support a new approach for gene therapy of brain tumors, based on the grafting of neural stem cells producing therapeutic molecules.
The best-known situation indissolubly linked to mosaicism is the uniparental disomy where a trisomic or monosomic zygote develops at least one cell line with 46 chromosomes. The mosaicism normal/abnormal cell lines may remain confined to placenta or persist in the embryo. Here, we describe a second situation that might also be indissolubly linked to a mosaic condition or at least to a confined placental mosaicism. We analysed the case of a mosaicism del(8p)/inv dup(8p) found in prenatal diagnosis. We had already demonstrated that the first product of the abnormal meiotic recombination at the basis of the inv dup rearrangements is a dicentric chromosome. Its breakage leads to the formation of a deleted and an inv dup chromosome. Although we had previously assumed that the dicentric underwent a breakage at meiosis II so that the zygote inherited the inv dup chromosome, our findings and those of others indeed indicate that the dicentric may be inherited in the zygote and that it might persist as such in early postzygotic stages, then undergoing different breakages in different cells leading to different abnormal chromosomes, either deleted or duplicated. Selection versus the most viable cell line(s) results either in a confined placental mosaicism with the inv dup cell line as the only one present in the embryo or in children with both the deleted and the inv dup cell lines. Phenotype/karyotype relationships in inv dup rearrangements must also take into account the influence of the other abnormal cell line during embryogenesis.
Gene therapy approaches to the treatment of experimental mice. The size of IL-4 inoculated tumors on the right side cancer are usually based on established neoplastic cell was significantly smaller than that of controlateral lines which are manipulated in vitro and subsequently untreated tumors, suggesting a local effect of IL-4. In transplanted in host animals. However, the relevance of addition, the non-injected tumors on the left side of treated these artificial models to the biology and therapy of human animals were significantly smaller than those arising in tumors is uncertain. We have previously validated an control transgenic mice, suggesting that IL-4 can also experimental model based on MMTV-neu transgenic mice inhibit tumor growth systemically. These findings suggest in which breast tumors arise spontaneously in 100% of anithat IL-4 gene transfer can significantly reduce the growth mals and have many features in common with their human rate of spontaneously arising breast tumors and that counterpart, including the involvement of the neu oncoimmune-based gene therapy could efficiently complement gene and the ability to metastatize. In this article we report other approaches based on different mechanisms, such as the effect of intratumoral, retrovirus-mediated, IL-4 suicide gene transfer or antisense technology. expression on the growth of breast tumors arising in these
Retroviral-mediated gene transfer of the IL-4 gene into experimental gliomas can cause tumor rejection, supporting the clinical use of this form of gene therapy for glioblastomas (GBM). In a clinical setting, the administration of dexamethasone (dex) is a standard procedure for GBM patients. This led us to examine the effects of dex on IL-4 gene therapy. We injected intracranially Fischer 344 rats with phosphatebuffered saline, 9L gliosarcoma cells mixed with E86.L4SN 200 cells (retroviral producer cells, RPC, transducing IL-4 cDNA) and 9L cells mixed with PA317.STK.SBA cells (control RPC expressing the HSV-tk gene). The rats from each group were treated with 0, 50, 100 or 250 mg dex/ kg/day released by osmotic pumps implanted subcutaneously. While 80-100% of rats receiving 9L cells mixed with IL-4 RPC and not treated by dex survived for at least 2 months following tumor injection, only 50% and 17% of rats receiving 50 or 100 mg/kg/day of dex, respectively, reached this time point. These results indicate that dex significantly diminished the anti-tumor effect of IL-4. Thus, in a clinical setting, IL-4 gene transfer should be performed when low levels of dex are administered or in the absence of dex. Gene Therapy (2003) 10, 188-192. doi:10.1038/sj.gt.3301863 Keywords: IL-4; glioma; dexamethasone Glucocorticosteroids (GC) play an important role in the management of malignant brain tumors, either primary or secondary and perioperatively in brain surgery. 1 Dexamethasone (dex) is the GC given in the majority of neuro-oncologic patients, at an empirically chosen dosage of 4 mg qid. Dex has a dramatic effect on symptoms in patients with brain tumors by decreasing the blood-tumor barrier permeability and the regional cerebral blood volume. 2 Furthermore, dex may decrease brain-tumor-associated edema by counteracting the action of VEGF. 3 Steroid medications, including dex, also have immunosuppressive functions. Studies based on flow cytometry to quantify the extent of inflammatory cell infiltration in the immunogenic rat C6 glioma model showed that a 7-day course of dex (100 mg/kg/day) resulted in a greater than 50% inhibition of microglia and lymphocyte (but not macrophage) infiltration into tumors. 4 Dex may specifically inhibit the action of IL-4 by decreasing the expression of the IL-4 receptor alpha. 5 These findings should be considered when experimental immunotherapeutic strategies are evaluated for clinical application. We and others previously found that viral-mediated transfer of the interleukin-4 (IL-4) gene may significantly inhibit the growth of C6, 9L and GL261 experimental gliomas. [6][7][8][9][10][11] In these experiments IL-4 gene transfer was associated with tumor infiltration by inflammatory cells and particularly T-lymphocytes and macrophages. Thus, in view of future clinical trials based on IL-4 gene transfer in gliomas we have evaluated the effects of dex administration on IL-4 gene therapy of 9L malignant gliomas.In experiment A, we tested the effects of 250 mg/kg/ day of dex administered for ...
A.A.A.); Mario.carminati@grupposandonato.it (M.C.);Abstract: Alagille syndrome (AGS) is an autosomal-dominant disorder characterized by various degrees of abnormalities in the liver, heart, eyes, vertebrae, kidneys, face, vasculature, skeleton, and pancreas. This case report describes a newborn child exhibiting a congenital neural tube defect and peculiar craniofacial appearance characterized by a prominent forehead, deep-set eyes, bulbous nasal tip, and subtle upper lip. Just a few hours after birth, congenital heart disease was suspected for cyanosis and confirmed by heart evaluation. In particular, echocardiography indicated pulmonary atresia with ventricular septal defect with severe hypoplasia of the pulmonary branches (1.5 mm), large patent ductus arteriosus and several major aortopulmonary collateral arteries. Due to the association of peculiar craniofacial appearance and congenital heart disease, a form of Alagille syndrome was suspected. In addition, on the fifth day after birth, the patient developed jaundice, had acholic stools, and high levels of conjugated bilirubin and gamma-glutamyltransferase (GGT) were detected in the blood. Genetic testing revealed the novel variant c.802del in a single copy of the JAG1 gene. No variants in the NOTCH2 gene were detected. To the best of our knowledge, this is the first clinical description of a congenital neural tube defect in a molecularly confirmed Alagille patient. This work demonstrates a novel pathogenic heterozygous JAG1 mutation is associated with an atypical form of Alagille syndrome, suggesting an increased risk for neural tube defects compared to other Alagille patients.
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