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SUMMARYGene transfer has potential as a once-only treatment that reduces viral load, preserves the immune system, and avoids lifetime highly active antiretroviral therapy. This study, the first randomized, double-blind, placebo-controlled, phase II cell-delivered gene transfer clinical trial, was conducted in 74 HIV-1 infected adults who received a tat/vpr specific anti-HIV ribozyme (OZ1) or placebo delivered in autologous CD34+ hematopoietic progenitor cells. There were no OZ1-related adverse events. There was no statistical difference in viral load between the OZ1 and placebo group at the primary end-point (average at weeks 47 and 48) but time weighted areas under the curve from weeks 40-48 and 40-100 were significantly lower in the OZ1 group. Throughout the 100 weeks, CD4+ lymphocyte counts were higher in the OZ1 group. This study provides the first indication that cell-delivered gene transfer is safe and biologically active in HIV patients and can be developed as a conventional therapeutic product.

Many studies suggest that a multi-tissue tumour suppressor gene is located at human chromosome 7q31.1. We have cloned and characterized a novel gene at this locus. The TES gene lies within the minimal region of overlap of several LOH studies and appears to possess the properties of a tumour suppressor. TES is widely expressed and is predicted to encode a protein of 421 amino acids, with three C-terminal LIM domains. Mutation analysis of the coding TES exons in 21 human tumour-derived cell lines revealed the presence of a frameshift mutation in one allele in the breast cancer cell line ZR-75. Methylation of the CpG island at the 5' end of TES appears to be a remarkably frequent ®nding, occurring in seven out of 10 ovarian carcinomas and in each of the 30 tumour-derived cell lines tested. Moreover, forced expression of TES in HeLa or OVCAR5 cells, resulted in a profound reduction in growth potential, as determined by the colony formation assay. We believe that TES is a tumour suppressor gene that is inactivated primarily by transcriptional silencing resulting from CpG island methylation. Oncogene (2001) 20, 2844 ± 2853.

Evidence of myc gene transduction by feline leukaemia virus in several spontaneous lymphoid tumours of cats suggests that recombinant viruses carrying oncogenes may be much more involved in oncogenesis in natural conditions than previously recognized.

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Dupuytren's disease (DD) is a superficial fibromatosis of the hand. Although the molecular mechanisms responsible for this disease are unknown, recent studies suggest that beta-catenin may be a key factor involved in fibromatosis. In this study, we analysed the in vivo and in vitro expression levels of beta-catenin in DD, using surgical specimens and primary cell lines. Although no somatic mutations (exon 3) of beta-catenin were detected, Western blot analysis revealed high levels of beta-catenin in diseased palmar fascia, and low to undetectable levels of beta-catenin in patient-matched normal palmar fascia. Immunohistochemistry analysis showed high levels of beta-catenin expression within the disease fascia, as well as cytoplasmic and nuclear accumulations of the protein.Immunoprecipitation of beta-catenin from seven patient lesions showed the protein to be tyrosine phosphorylated. Lastly, Western analysis of three patient-matched (disease and normal fascia) primary cell cultures showed significantly elevated levels of beta-catenin in disease cells cultured in three-dimensional collagen lattices. This is the first extensive in vivo and in vitro characterization of betacatenin in DD, and the first to suggest that the extracellular matrix may play an important role in modulating beta-catenin stability in DD.

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