Biomedical subjects

L S Levy

Publications and source records attributed to L S Levy.

At least 55 records · Page 3Linked to original sources

PubMed1993

Coincident involvement of flvi-2, c-myc, and novel env genes in natural and experimental lymphosarcomas induced by feline leukemia virus.

The flvi-2 locus is a target of insertional mutagenesis in thymic lymphosarcomas induced by feline leukemia virus (FeLV). flvi-2 encodes the gene bmi-1, whose product is implicated as a myc-collaborator in the induction of B- and T-cell lymphoma. We have examined the involvement of flvi-2 and myc in natural and experimentally induced FeLV-positive feline lymphosarcomas which are heterogeneous in anatomical origin, geographic origin, and strain of FeLV involved. We further compared these findings with previous reports of novel FeLV env genes in the same tumors. The results show that proviral insertion at flvi-2 occurs commonly in natural and experimental feline thymic lymphosarcomas of diverse origins [52% overall], and that alterations in c-myc commonly accompany insertional mutagenesis of flvi-2 [54% overall]. However, 46% of tumors with flvi-2 insertions apparently lack involvement of c-myc. These observations support the hypothesis that interruption of flvi-2 may be an early event in a multistep cascade, one possibility for completion of which is activation of c-myc. Interruption of flvi-2 was not observed in nonthymic lymphosarcomas of alimentary or multicentric origin, although c-myc may be involved. A proportion of both thymic and nonthymic tumors have been shown previously to contain FeLV proviruses with recombinant or mutant env genes. Our findings strongly implicate the insertional mutagenesis of flvi-2, the activation of c-myc, and the emergence of novel env genes in FeLV-mediated lymphomagenesis, particularly in the induction of thymic lymphosarcoma. The data show that these events may overlap, but do not necessarily occur concurrently.

Animals↗

PubMed1993

The setting of an occupational exposure limit for phosphamidon in the workplace--a Chinese approach.

This paper describes the approach of setting an occupational exposure limit for phosphamidon, an organophosphorus pesticide, in the workplace in China. Apart from a general review of the literature relating to various toxicological studies, special emphasis has been placed on the results of a systematic occupational health survey on the workers exposed to phosphamidon. As a result of the survey, together with the literature review, a 'maximum allowable concentration' (MAC) for phosphamidon in the air of workplace is suggested as 0.02 mg m-3 but on the condition that the route of skin entry be blocked effectively. In addition, based on the description of the standard-setting process in China, a comparison has been made to the current U.K. approach.

China↗

PubMed1993

Monitoring of total chromium in rat fluids and lymphocytes following intratracheal administration of soluble trivalent or hexavalent chromium compounds.

1. Intratracheal instillation of sodium dichromate (CrVI) and chromium acetate hydroxide (CrIII) to male Wistar rats gave rise to increased chromium concentrations in whole blood, plasma and urine up to 72 h post exposure; peak concentrations were reached at 6 h after exposure. 2. The ratio of whole blood chromium to plasma chromium concentrations was significantly different for Cr(VI) and Cr(III) treatments. Both blood chromium and plasma chromium assays should therefore be used for the assessment of chromium exposure. 3. Chromium was also detected in peripheral lymphocytes. Cr(VI), but not Cr(III) accumulated significantly in the lymphocytes after treatment. These cells have potential to be used for biomarkers of the assessment of exposure to chromium compounds.

Acetates↗

PubMed1993

Expression of c-myc, c-myb, and c-sis in fibroblasts from affected and unaffected skin of patients with systemic sclerosis.

We examined c-sis, c-myc, and c-myb proto-oncogene expression in fibroblasts cultured from affected and unaffected skin of patients with systemic sclerosis (SSc), and from healthy donor skin. Total cellular RNA from cultured dermal fibroblasts was used in slot blot analysis and scanning densitometry or phosphorimaging to quantify steady-state levels of proto-oncogene mRNAs. PDGF B-chain levels in culture supernatants of fibroblasts were determined by ELISA. Our results demonstrate that steady-state levels of c-myc and c-myb mRNA were elevated 1.5- to 5.6-fold in intralesional fibroblasts from SSc patients as compared to other cells examined. Levels of c-sis mRNA and PDGF-B protein were comparable regardless of source. Elevated c-myc and c-myb expression may be indicative of, and may contribute to, fibroblast activation in SSc.

Adult↗

PubMed1993

flvi-2, a target of retroviral insertional mutagenesis in feline thymic lymphosarcomas, encodes bmi-1.

LC-FeLV is a myc-containing strain of feline leukemia virus which induces thymic lymphosarcoma in the domestic cat with short latency. A locus in feline DNA, termed flvi-2, is commonly interrupted in naturally occurring and experimentally induced thymic lymphosarcomas containing LC-FeLV; thus, interruption of a gene encoded by flvi-2 may cooperate with the myc oncogene in the induction of T-cell tumors by LC-FeLV. Clones homologous to flvi-2 have been isolated from a normal human thymus cDNA library. Nucleotide sequence analysis of the cDNA clones demonstrates that flvi-2 encodes bmi-1, a gene previously identified as a target for MoMuLV integration and as a myc-collaborator in retrovirally-induced B-cell lymphomas in E mu-myc transgenic mice. In feline thymic lymphomas, retroviral integrations occur downstream of the gene, and result in enhanced expression of a bmi-1 transcript of normal size. These findings demonstrate the interruption of bmi-1 in natural as well as experimentally induced tumors, implicate the activation of bmi-1 in the induction of T-cell as well as B-cell lymphoma, and support the premise that bmi-1 functions as a myc collaborator.

Amino Acid Sequence↗

PubMed1992

Neurobehavioral effects of long-term occupational exposure to organic solvents: two comparable studies.

Two comparable cross-sectional studies were carried out employing the same methodology but involving two separate solvent-exposed populations (N = 90, N = 144). In each study, solvent-exposed workers were compared with age-matched controls on tests selected from the Neurobehavioral Evaluation System and on standardized questionnaire measures of symptomatology and psychiatric state. A similar pattern of results was obtained in the two studies indicating a significant effect on cognitive functioning, after controlling for confounding variables, occurring in those with more than 30 years of exposure. A more specific effect on learning processes was observed in those with more than 10 years of exposure. There were no indications in either study of a solvent-related increase in psychiatric symptoms.

Adult↗

PubMed1992

Human recombinant interleukin-4 induces proliferation and interleukin-6 production by cultured human skin fibroblasts.

The effect of human recombinant interleukin-4 (hrIL-4) on normal human adult dermal fibroblasts in terms of proliferation and IL-6 production was studied. Fibroblasts were exposed to different concentrations of IL-4 for various periods of time. Proliferation was measured using a [3H]thymidine incorporation assay. IL-6 production was measured at the transcriptional, protein, and functional levels by Northern blot analysis, radioimmunoassay, and B9 bioassay, respectively. Our results show that hrIL-4 significantly stimulated (two- to fivefold) fibroblasts to increase the incorporation of [3H]thymidine in a dose- and time-dependent manner. However, hrIL-1, hrIL-2, hrIL-5, or hrTNF alpha, at the same concentration (100 U/ml) and for the same time period (4 days), did not. In addition, IL-4 significantly induced (four- to eightfold) the production of immunoreactive and biologically functional IL-6. However, IL-4 was not as potent an inducer of IL-6 as IL-1. The IL-4-induced IL-6 production was dose and time dependent and was due, at least in part, to a dramatic increase in the steady-state levels of IL-6 mRNA. This is the first report describing the ability of IL-4 to activate human dermal fibroblasts in terms of proliferation and IL-6 production.

Adult↗

PubMed1992

Production of 8-hydroxydeoxyguanosine in isolated DNA by chromium(VI) and chromium(V).

Chromium(VI) and Cr(V) compounds increased the concentration of 8-hydroxydeoxyguanosine (oh8dG) in isolated DNA, whereas no such increase was seen with Cr(III). Furthermore, incubating DNA with H2O2 and Cr(VI) or Cr(V) potentiated the formation of oh8dG above levels observed with either chromium compound alone. In the presence of catalase, the increase in DNA oxidation observed with Cr(VI) was inhibited, the base oxidation observed being equivalent to background levels, and this indicated involvement of H2O2 in the mechanism. Glutathione did not enhance chromium-induced formation of this oxidized base. These results help to explain a mechanism of chromium-induced DNA oxidation involving H2O2 via a Fenton-type reaction.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed1992

Insertional mutagenesis of flvi-2 in tumors induced by infection with LC-FeLV, a myc-containing strain of feline leukemia virus.

LC-FeLV is a myc-containing strain of feline leukemia virus (FeLV) which exhibits only partial transforming activity in vitro and in vivo. LC-FeLV infection in kittens may induce, but does not necessarily induce, thymic lymphosarcoma in viremic animals after a short latency. These observations suggest that infection with LC-FeLV is not sufficient to induce complete transformation and that another genetic event(s) is required. One possibility for such an event is that the integrating provirus acts as an insertional mutagen and thereby disrupts the structure or function of another proto-oncogene. Using a strategy of transposon tagging, this possibility was examined in eight feline T-cell lymphosarcomas, including four induced by experimental infection with LC-FeLV, three induced by natural infection with FeLV, and one FeLV-negative tumor. The analysis demonstrated one locus, termed flvi-2, to be structurally altered in six of the tumors examined, including three induced by LC-FeLV and three in which no activated myc oncogene is apparent. Inverse polymerase chain reaction was used to demonstrate the presence and transcriptional orientation of proviruses integrated at flvi-2 in five of these tumors. The flvi-2 locus does not hybridize to cloned probes representing 21 previously identified proto-oncogenes or common domains of retroviral integration. Thus, the data suggest that interruption of the flvi-2 locus cooperates with the myc oncogene in the induction of T-cell lymphomas by LC-FeLV; indeed, the observations indicate that the insertional mutagenesis of flvi-2 plays a role in T-cell lymphomagenesis even in the absence of feline v-myc.

Animals↗

PubMed1992

Induction of DNA strand breaks in peripheral lymphocytes by soluble chromium compounds.

1. Incubation of human lymphocytes with sodium dichromate (CrVI) at 37 degrees C for 3 h resulted in a dose-dependent increase in DNA strand breaks without concurrent cytotoxicity. In contrast, chromium acetate hydroxide (CrIII) failed to induce DNA strand breaks at sub-cytotoxic concentrations. 2. DNA strand breaks were also detected in the peripheral lymphocytes of Wistar rats, 24 h after intratracheal instillation of sodium dichromate (1.3 and 2.5 mg kg-1). Instillation of chromium acetate hydroxide (up to 21.8 mg kg-1) failed to induce DNA strand breaks in peripheral lymphocytes. In accord with previous studies, hexavalent chromium was found to be more readily absorbed from the lungs into the peripheral blood than chromium in its trivalent form. 3. The results of this study indicate that fluorometric analysis of DNA unwinding (FADU) in peripheral lymphocytes might be a convenient method of measuring an important biological effect of chromium in occupationally-exposed workers.

Animals↗

PubMed1992

Mechanisms of pathogenesis in scleroderma. I. Overproduction of interleukin 6 by fibroblasts cultured from affected skin sites of patients with scleroderma.

Fibroblasts were cultured from affected skin sites of patients with progressive systemic sclerosis (PSS), from unaffected skin sites of the same patients, and from a healthy donor. The concentration of interleukin 6 (IL-6) in culture medium conditioned by the growth of early passage cells was determined by radioimmunoassay and by quantitative bioassay. Results demonstrated that fibroblasts from affected PSS skin produce from 6 to 30-fold higher levels of biologically active IL-6 compared to unaffected and control cells. In contrast, serum IL-6 concentrations in 6 of 8 patients examined were not significantly different from healthy donors. Serum IL-6 levels were elevated 2 to 3-fold in 2 of 8 patients examined. Thus, the overproduction of IL-6 by affected scleroderma fibroblasts does not necessarily correlate with a systemic increase in IL-6, but may increase its concentration locally. In view of its biological activities, including stimulation of antibody production and T cell activation, the overproduction of IL-6 by PSS fibroblasts in the lesions may play a significant role in the pathogenesis of PSS and may profoundly influence the course of the disease.

Adult↗

PubMed1992

Mechanisms of pathogenesis in scleroderma. II. Effects of serum and conditioned culture medium on fibroblast function in scleroderma.

Scleroderma (progressive systemic sclerosis; PSS) is a connective tissue disorder in which excessive collagen is deposited in the skin and internal organs. Mediators of abnormal fibroblast function in PSS have not yet been identified. Our objective was to examine the possibility that factors present in serum from patients with PSS, or in culture medium conditioned by PSS fibroblast growth, serve to regulate fibroblast function. Fibroblasts from affected and unaffected skin sites of patients with PSS and from normal adult skin were cultured in the presence of various human sera or conditioned media. Results indicate that (1) the proliferative influence of serum of patients with PSS is not different from that of normal donors, (2) increased proliferation and procollagen gene expression are not linked in affected or unaffected dermal fibroblasts, and (3) affected PSS fibroblasts produce a stimulatory factor(s) for procollagen gene expression to which they are differentially sensitive.

Adult↗

PubMed1991

Evolutionary conservation and chromosomal localization of flvi-1.

A locus in feline DNA, termed flvi-1, has been identified as harboring retroviral integrations commonly found in natural feline lymphomas induced by infection with feline leukemia virus (FeLV). Southern blot analysis of human and murine DNA using restriction fragments representing flvi-1 demonstrates its phylogenetic conservation among mammals, flvi-1 is localized to murine chromosome 2, proximal portion of band E, by in situ hybridization to metaphase chromosomes. This position is adjacent to that of another putative proto-oncogene, sfpi-1, although probes representing flvi-1 and sfpi-1 do not cross-hybridize. The repeated implication of flvi-1 in natural feline leukemogenesis, its evolutionary conservation and its chromosomal position support the hypothesis that flvi-1 may represent a previously unidentified protooncogene.

Animals↗

PubMed1990

An unusual retrovirus-like sequence identified in human DNA.

The human genome contains many different types of endogenous proviruses and retrovirus-like elements. An unusual element of this kind has been isolated from human DNA on the basis of its relatedness to the integrase-coding domain of the pol gene of feline leukaemia virus (FeLV). The element, termed Hs5, is related to FeLV only over a short region of 81 nucleotides predicted to encode the carboxyl terminus of the FeLV integrase protein, p46pol. The region of relatedness between Hs5 and FeLV identifies a short conserved amino acid stretch which is shared among distantly related retroviruses. The conservation of this sequence, its position, and predicted secondary structure suggest that it may represent a conserved substrate binding site or active site of the integrase enzyme. Nucleotide sequence analysis of Hs5 reveals that it is not an intact retrovirus, but contains only the 3' terminus of pol and a defective env gene without apparent long terminal repeat; Hs5 is unusual among human endogenous retrovirus-like elements in this respect.

Amino Acid Sequence↗

PubMed1990

flvi-1, a common integration domain of feline leukemia virus in naturally occurring lymphomas of a particular type.

A locus in feline DNA, termed flvi-1, which may play an important role in the natural induction of lymphomas by feline leukemia virus (FeLV) was identified. Examination of a bank of 21 naturally occurring FeLV-positive feline lymphomas revealed that FeLV proviral integration occurs at flvi-1 in four independent tumors (19%). Independent integrations occurred within a 2.4-kilobase region of flvi-1, the probability of which by random chance can be estimated as 10(-16). Several lines of evidence, including sequence analysis of the long terminal repeat, demonstrated that proviruses integrated at flvi-1 are exogenously acquired and are oriented in the same transcriptional direction with respect to the locus. Molecularly cloned flvi-1 did not hybridize with probes representing several previously described proviral integration domains or with probes representing 10 oncogenes. The natural feline lymphomas examined in this study were heterogeneous with respect to tissue of origin, cell type, and number of monoclonal proviral integrations. The four tumors in which flvi-1 is interrupted were classified as members of a phenotypic subgroup containing seven lymphomas, i.e., at least four (57%) of seven lymphomas of this type contained FeLV proviral integration at flvi-1. Members of this phenotypic subgroup are non-T-cell lymphomas isolated from the spleen and contain an average of three proviruses, compared with an average of eight among all of the tumors examined. The small number of proviral integrations in tumors of this subgroup suggests that an early proviral integration event into flvi-1 can induce malignant change.

Animals↗

PubMed1988

Tumorigenic potential of a myc-containing strain of feline leukemia virus in vivo in domestic cats.

The oncogenic capacity of a myc-containing strain of feline leukemia virus (FeLV), termed LC-FeLV, has been examined after inoculation of the virus into neonatal kittens. Like other myc-containing strains of FeLV, LC-FeLV may induce with relatively short latency, but does not necessarily induce, thymic lymphosarcoma in viremic animals. Naturally occurring and experimentally induced tumors are T-cell lymphomas which contain clonally integrated LC-FeLV proviral DNA and which cannot readily be cultivated in vitro in the presence or absence of exogenously supplied interleukin-2. Acquisition of myc by FeLV decreases the period of latency before the appearance of tumors but does not expand the spectrum of tumors induced by FeLV alone.

Animals↗

PubMed1987

Transforming potential of a myc-containing variant of feline leukemia virus in vitro in early-passage feline cells.

We studied a naturally occurring variant of feline leukemia virus (FeLV) in which the oncogene myc has substituted for a portion of the viral structural genes (myc-FeLV). myc-FeLV was rescued by replication in the presence of FeLV as helper, and its biological activity was examined in early-passage feline cells in vitro. Infection of leukocytes from peripheral blood, spleen, or thymus, or of kitten fibroblasts did not immortalize these cells or alter them morphologically. Northern blot (RNA blot) analysis of virion RNA prepared from the supernatant of infected cells demonstrated the 8.2-kilobase genome of FeLV, but did not demonstrate the 5.0-kilobase genome of myc-FeLV. Apparently, the myc-FeLV genome was lost in the absence of the selective pressure of transformation. In contrast, infection of embryonic fibroblasts with myc-FeLV(FeLV) rendered these cells capable of greatly increased, if not infinite, proliferative potential. The cells were morphologically altered compared with controls and were only loosely adherent to the substrate. The cells failed to proliferate in semisolid medium and did not form tumors when inoculated subcutaneously into athymic mice. Blot analyses demonstrated the presence and expression of integrated proviral DNAs of both FeLV and myc-FeLV in these cells. They appear, then, to represent cells partially transformed by infection with myc-FeLV(FeLV). The action of feline v-myc in early-passage cells in vitro was compared to that of avian v-myc.

Animals↗

PubMed1986

Carcinogenicity and mutagenicity of chromium compounds: the association between bronchial metaplasia and neoplasia.

Over the last 40 years, experiments with animals and epidemiology of exposed human populations have established that certain hexavalent chromium-containing compounds are capable of causing cancer whilst trivalent materials are not. More recently, a variety of short-term genotoxicity tests (predictive of carcinogenicity) have clearly demonstrated that Cr[VI] is genotoxic per se, and that all Cr[VI]-containing materials which have been tested are genotoxic. What experiments have failed to demonstrate clearly, however, is which of the myriad of industrially available hexavalent materials are carcinogenic and which are not. In this long-term study we have looked at the incidence of squamous metaplasia in the bronchial epithelium of rats exposed to a range of chromium-containing materials by intrabronchial implantation. Squamous metaplasia is generally considered to be a transformed state from which squamous carcinoma may arise. We have shown that its incidence is increased in all groups exposed to Cr[VI]-materials, and in rats exposed to the reference carcinogen 20-methylcholanthrene. Squamous metaplasia was not increased in rats exposed to Cr[III] materials. Of rats exposed to Cr[VI], only those receiving materials of sparing aqueous solubility developed bronchial squamous carcinoma at statistically significant levels. These results strongly support the hypothesis that although Cr[VI] per se is biologically active, producing genotoxic effects and pathological changes which may predispose to the development of cancer, only Cr[VI] materials of sparing aqueous solubility seem to be capable of evoking a carcinogenic response.

Animals↗