Biomedical subjects
Publications and source records attributed to G Giraldo.
Etiopathogenetic mechanisms involved in the development of Kaposi's sarcoma and the possible role of viruses, such as CMV, BKV, HBV, HHV-6 and retroviruses are reviewed. An etiopathogenetic model is also presented.
We studied neopterin excretion levels and immunological features of 20 patients affected by Kaposi's sarcoma (KS), compared to 30 normal controls. Eighteen patients had the classic form of Kaposi's sarcoma (CKS), while two patients were anti-human immunodeficiency virus (HIV) seropositive and affected by the epidemic form associated with the acquired immunodeficiency syndrome (AIDS). In CKS patients, a trend of an increase of neopterin levels with more advanced stages appeared from our data whereas a significant reduction in CD3+ and CD4+ lymphocytes subsets was observed already at early stages (P less than 0.01). CD8+ cells did not show significant variations. A significant increase in serum IgA immunoglobulins (P less than 0.05) was also observed. Comparative analysis of the two patients affected by AIDS/KS showed the profound deficit in T-cell immunity but also the prognostic value of neopterin monitoring. Furthermore these findings seem to confirm Kaposi's sarcoma as an 'opportunistic neoplasia' and indicate neopterin as a useful prognostic marker.
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A cell line of penile cancer from a 60-year-old Ugandan black patient has been studied by the authors. Transmission and scanning electron microscopy showed a large number of blebs and microvilli at cell surface; desmosomes were evident at TEM. Cytogenetic investigation (R-, C-, Nor-banding) showed the frequent presence of some markers: del(1p),del(1q),iso(3q),der(4),del(8p),11q+, t rob(13;14), 14p+, t rob(21;21). The epidemiology, geographical distribution, and aetiological role of human papilloma virus type 16 and herpes simplex type 2 are discussed.
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Three different assays for detection of antibodies to the human immunodeficiency virus (HIV) were conducted on 677 sera obtained from 1964 to 1975 from male and female children and adults in Uganda and other countries in Africa. Several sera were collected from individuals with Kaposi sarcoma. No evidence of antibodies to the virus was noted up to 1975. These results strongly suggest that the emergence of HIV in Africa occurred relatively recently. Further studies are required to determine the geographic origin of the acquired immunodeficiency syndrome virus.
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Out of 72 Kaposi's sarcoma patients diagnosed between 1951 and March 1976 at Kuluva Hospital, West Nile District, Uganda, 64 with known co-ordinates were plotted on a map. Sixty-two of these were noted to live at an altitude of 853 metres or more (greater than or equal to 2,800 feet). Twenty-four patients were thought to be still alive and visits were made to their homes. Space-time grouping of four cases was noted on two occasions, although analysis did not reveal statistically significant clustering. A case-control study employing an interview questionnaire with 32 variables was performed on 19 patients and their age- and sex-matched neighbourhood controls, and sera were collected from both groups and from their families for estimation of viral antibody titres. The results demonstrated that cases tended to be post-pubertal males, a high proportion of whom had been bitten by a blood-sucking insect identified as being similar to Haematopota. Both cases and controls had raised antibody levels to cytomegalovirus, but cases obtained their drinking water more commonly from rivers whereas controls tended to use water from springs, boreholes or pipes.
Previous studies have established an association between cytomegalovirus (CMV) and classic and endemic Kaposi's sarcoma (KS) which can be extended to include the epidemic form of KS. The identification of nucleic acid sequences homologous to CMV but not to Epstein-Barr virus (EBV) and Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) as well as the detection of CMV gene products, particularly early antigens, in tumour biopsies and/or early cultures derived from them is an important criterion in the establishment of the type of association. Detection of CMV early antigens but not late antigens as well as the failure to demonstrate virus particles in primary tumour biopsies rule out a simple passenger role of this virus or a preferential site for virus replication in neoplastic tissue. In the setting of a profound immune dysfunction, as in the case of acquired immune deficiency syndrome (AIDS), renal transplant recipients under immunosuppressive therapy, and other iatrogenically immunosuppressed patients (the three groups in which KS has been most frequently observed), the specific involvement of CMV oncogenes, of which at least two have been so far identified in experimental systems, is strongly indicated. Moreover, in vitro transformation experiments indicate that the virus is clearly involved in the initiation of transformation, while other factors (co-carcinogens, activation of cellular oncogenes?) might be required for the maintenance of the transformed phenotype. Endothelial cells, permissive for CMV infection, might be the prime target for these events, since there is evidence that they are a main constituent of KS tissue. Data obtained during 14 years of research on KS are reviewed and possible etiopathogenetic mechanisms giving rise to this type of tumour are discussed.
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The solid-phase immune electron microscopy-double-antibody technique, which takes less than 1 h to perform, was applied as a rapid, sensitive, and specific diagnostic tool in the demonstration of papovavirus particles. BK virus propagated in 82C human skin fibroblasts and a monospecific high-titer immune serum to BK virus were used to establish the test procedure. When Formvar-carbon-coated grids were treated with appropriately diluted antibody, a 28-fold increase of virus particles per square micrometer was observed. Viewing of the virus particles was facilitated by the addition of a second "decorator" antibody. BK virus preparations at concentrations of 10(2) to 10(3) PFU/ml could be detected by this technique. There was no cross-reaction with mouse polyomavirus.
We have recently reported that viral DNA sequences in inbred LSH hamster brain cells transformed by the GS variant of BK virus (LSH-BR-BK) are present predominantly in a free form (Beth et al., J. Virol. 40:276-284, 1981). In this report, we confirm that the presence of viral DNA sequences in these cells is not due to virus production, since viral capsid proteins were not detected by immunoprecipitation. Furthermore, we examined the status of viral DNA in 15 subclones of this cell line and detected free and integrated viral DNA sequences in only 5 of the subclones. The other 10 subclones contained exclusively integrated viral DNA sequences, as shown by the blot hybridization of high-molecular-weight cell DNA which was uncleaved or digested with HincII, for which there are no sites in viral DNA. The arrangement of viral DNA in these clones was further analyzed by cleavage of cellular DNA with HpaII and HindIII. Mitomycin (0.03 microgram/ml) treatment of subclones containing only integrated sequences resulted in the appearance of free viral DNA sequences in some of these cells. This result supports the postulation that free viral DNA in LSH-BR-BK cells is made up of excision products of observed tandemly repeated integrated sequences. In addition to the large T- and small t-antigens, LSH-BR-BK and all of its 15 subclones contained two antigen species which were larger than large T and one species which was smaller than small t. The number of tumor antigens in the LSH- BR-BK cell line and its subclones with a large copy number in a free form was not more than in the subclones with low copy number and integrated DNA. This suggests that free viral DNA is not a template for tumor antigen production in transformed cells.
In order to determine whether human cytomegalovirus- (CMV) DNA homologous sequences as well as CMV-specific RNA(s) and antigen(s) exist in tumor biopsies of Kaposi's sarcoma (KS) DNA-DNA reassociation, RNA-DNA in situ cytohybridization and anticomplement immunofluorescence test (ACIF) tests were applied. Three of 10 DNAs extracted from Kaposi sarcoma biopsies contained DNA sequences homologous to radioactively labelled human CMV DNA probe. The amount of CMV DNA in these sarcoma tissues was calculated to range from 0.7 to 1 genome equivalent per diploid cell. The presence of virus-specific RNA was also demonstrated in section from five of 10 tumor biopsies. CMV-determined nuclear antigen(s) CMNA) present in variable degrees were also demonstrated. In contrast, we could not detect any herpes simple virus type II (HSV-2) or Epstein-Barr virus (EBV) DNA sequences in DNA of these tumor biopsies. Furthermore, there were no detectable HSV-2 or EBV-specific RNA or virus-specific antigens in sections of these biopsies. These results provide new lines of evidence for the relationship between CMV and Kaposi's sarcoma.
Inbred LSH hamster brain cells were transformed in vitro by the GS strain of BK virus (BKV), and transplantable tumors classified as undifferentiated glioblastomas were induced in the syngeneic host. The viral status in the transformed cells, designated LSH-BR-BK, was established. About 46 genome equivalents per cell of viral DNA was detected, with the majority of sequences in a free form. The transformed cells expressed large quantities of tumor (T) antigen as well as surface (S) antigen as demonstrated by indirect immunofluorescence. Sixty-three percent of tumor-bearing hamsters produced high-titer antibodies against T, whereas 3 of 14 (21%) hamsters also produced antibodies against the BKV-specific S antigen. Furthermore, the relatedness of BKV early gene products, including T, S, and tumor-specific transplantation antigen, was established by the production of a rabbit antiserum against highly purified plasma membranes of LSH-BR-BK cells and by the induction of a BKV-specific tumor-specific transplantation antigen response by these plasma membranes in the syngeneic host.
In attempts to encompass multiple events responsible for the development of cancer in man, with a particular interest to the possible involvement of viruses, multidisciplinary studies have been conducted on KS during 1971-1979. There is accumulating evidence associating this malignancy with CMV. African KS patients have high antibody titers to CMV, but they are not significantly different from controls of the same regions (Ag-Ab complexes?). A specific serologic association of European and American KS with CMV was established. CMV-related antigens can be demonstrated in 22% of tumor biopsies and comparably in early passages of cell culture derived from them. Recently, CMV-DNA sequences have been detected in tumor biopsies. Furthermore, a CMV, strain K9V, has been isolated in tissue culture from a KS culture. Cells infected in vitro with K9V have shown some of the characteristics of cells transformed previously by other oncogenic CMV strains. In vivo K9V has induced a fatal disease in old world monkeys, mainly involving the lymphoid system. Moreover, a cluster type of occurrence of KS was detected in the West Nile District of Uganda, an area with as high incidence of KS as BL; and finally, there is a significantly higher incidence of a second primary tumor in KS patients, particularly of the lymphoreticular system. Whether CMV plays a role in the development of KS, a complex neoplasia which involves different cell types cannot be claimed by these results only. However, similarities between CMV and EBV, the latter being closely associated with BL and nasopharyngeal carcinoma are worthy of consideration.
DNA-DNA reassociation kinetics, anti-complement immunofluorescence (ACIF) and ACIF-blocking tests were used to search for cytomegalovirus (CMV) gene products in Kaposi's sarcoma (DS) biopsies and early cell cultures deriving from them. Three of eight tumor biopsies were positive for CMV DNA; two of them at 0.35 genome/cell and one at one copy 25% genome/cell. CMV-related antigens, mainly localized in the nucleus, were found in cryostat sections of seven of 31 tumor biopsies and four of 12 KS cell lines at early passage level. It appears that the antigen is present in a high number of tumor cells, like the Epstein-Barr virus nuclear antigen (EBNA) in EBV-transformed cells. Inevitably, the increasing data concerning the oncogenic potential of CMV lead on to consideration of the increasing evidence of its association with Kaposi's sarcoma, a multiple hemorrhagic sarcoma with an epidemiologic distribution in Africa similar to that of Burkitt's lymphoma.