Complementation of bloom cellular phenotype by human chromosome 15.
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Biomedical subjects
Publications and source records attributed to A Bonfatti.
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BK virus (BKV) is a human papovavirus that readily transforms rodent cells, but not human cells, to a neoplastic phenotype, suggesting that tumor-suppressor functions expressed in human cells control BKV oncogenicity. Transfer of a normal human chromosome 11 to BKV-transformed mouse cells suppresses the malignant phenotype. In this report we map the regions of chromosome 11 involved in tumor suppression. Transfer of chromosome 11 to the BKV-transformed hamster cell line HKBK produces monochromosomic hybrids retaining only portions of the transferred human chromosome. We have compared the tumorigenicity of the hybrids with the molecular mapping of chromosome 11 retained regions. This analysis indicated that 3 regions of human chromosome 11, 11p15.5, 11p13 and 11q13, cooperate in tumor suppression. However, 11q13 seems the most important, since all the HKBK/H11-induced tumors analysed had lost this region, whereas 11p15.5 and 11p13 were sometimes retained. The chromosomal regions identified in this study are deleted in several types of human tumors, suggesting that the BKV transformation system specifically detects tumor-suppressor genes on chromosome 11 that are involved in human oncogenesis. This model may be of use in isolating and cloning such genes. The results of this report raise the possibility that BKV may have a synergistic tumorigenic effect in human cells where tumor-suppressor genes controlling its oncogenic potential are inactivated.
Viral transformation models may be useful to detect and map human tumor suppressor genes. BK virus (BKV), a human papovavirus, readily transforms rodent cells but is unable to transform human cells, suggesting that oncosuppressive functions expressed in human cells control BKV oncogenic activity. We have transferred human chromosome 6 to BKV-transformed mouse pRPcT1ss1 cells. The great majority of the colonies growing in selective medium degenerated by senescence. Only five hybrid pRPcT1ss1/H6 clones maintained the immortalized phenotype of the recipient cell line. All the immortalized clones had two common regions of deletion involving bands 6q21-22 and the SOD2 gene in 6q25. Senescent colonies carried an intact chromosome 6. A specific human sequence in 6q21-22 was amplified by PCR in senescent cells, suggesting that this region harbors a gene inducing senescence. The SOD2 deletion confirms recent data on the role of the Mn-dependent superoxide dismutase in inhibition of proliferation. The monochromosomic hybrids bearing a deleted chromosome 6 showed a reverted phenotype in vitro and a significantly longer latency period before they were tumorigenic in nude mice, indicating the presence of a tumor suppressor gene in the residual regions of chromosome 6. Molecular mapping suggests that this gene is located in 6q27. The BKV transformation model detects genes inducing senescence and tumor suppressor genes on human chromosome 6 and may represent a useful system to isolate and clone such genes.
The individual variations of pericentromeric heterochromatin in human chromosome 18 were analysed using the C-banding techniques and nonradioactive fluorescence in situ hybridization (FISH) with chromosome 18 alpha-satellite DNA probe. FISH analysis shows heteromorphisms almost undetectable by C-banding and which regularly segregate in a family.
Viral transformation models may be useful for detecting and mapping human tumor suppressor genes. BK virus (BKV), a human papovavirus, readily transforms rodent cells but is unable to transform human cells, suggesting that oncosuppressive functions expressed in human cells control BKV oncogenic activity. We have transferred human chromosome 11 to BKV-transformed mouse cells. All of the cell clones were suppressed in the tumorigenic phenotype and anchorage-independent growth, except one clone which was nontumorigenic but maintained the ability to grow in soft agar. Cytogenetic analysis and DNA hybridization with chromosome 11-specific probes showed that all the reverted hybrids had an intact human chromosome 11, except the clone growing in semisolid medium which had lost the short arm. The results suggest that a gene located on 11p controls anchorage independence, whereas a gene on 11q controls the tumorigenicity of BKV-transformed cells. BKV T-antigen was expressed in all the hybrid clones at the same level as in the parental cell line, indicating that the putative human tumor suppressor gene(s) do not inhibit expression of the viral oncogene and must operate by another mechanism in inducing reversion of the oncogenic phenotype. Since BKV-transformed mouse cells are highly susceptible to retrovirus infection, this model can be used for searching and cloning tumor suppressor gene(s) by retrovirus-mediated "insertional mutagenesis".
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Ten patients, 3 males and 7 females, aging less then 50 years (M: 37), suffering from at least one year for a Raynaud's phenomenon surely not due to a costo-clavicular syndrome, were studied. A Doppler ultrasound evaluation was first done recording the pressure and the speed at the omeral, radial, ulnar, and digital arteries. The patients were then submitted to an angiography in general anaesthesia through puncture of the omeral artery and to screening tests to detect possible associated immunopathological diseases. In the patients affected by Raynaud's phenomenon the vascular lesions are generally distal to the omeral artery; the only surgical indication is a thoracic gangliectomy. Our experience shows that the Doppler velocimetry gives all the data necessary to check the efficacy of a pharmacological treatment and to state a correct surgical indication.
The authors review the past five year's case history covering the humeral arteriographies carried out for the purpose of studying the vascularization of the hand in patients presenting Raynaud-like symptomatology. It is pointed out that in the majority of cases digital arteries show significant lesions and that a certain percentage of these are accompanied by haemodynamically significant alterations of the peripheral part of arteries of the forearm and of the metacarpus. Deep general narcosis is fundamental for a correct interpretation of the angiographies. Within the cases recorded the clinical data are a concomitant of arterious lesions typical of Raynaud's disease.
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An 18ph+ variant formerly detected by QFQ/CBG was subsequently analyzed by CBG and fluorescence in situ hybridization. It was found to be the consequence of amplification of alphoid DNA specific for centromeric heterochromatin of chromosome 18.
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The authors here refer about the clinical case of a patient suffering from cirrhosis and hyperdynamic circulatory state due to a giantism of the hepatic artery. The surgical ligature of the main hepatic artery determined the complete regression of the abdominal pain and melena: the high output cardiac failure also disappeared with surgical correction.