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Biomedical subjects

J L Cleveland

Publications and source records attributed to J L Cleveland.

At least 55 records · Page 3Linked to original sources
PubMed1997

Induction of ornithine decarboxylase by IL-3 is mediated by sequential c-Myc-independent and c-Myc-dependent pathways.

Enforced c-Myc expression promotes continuous, growth factor-independent, cell cycle progression and activates expression of the ornithine decarboxylase (ODC) gene and its promoter. c-Myc-responsiveness of murine ODC is mediated by two conserved c-Myc:Max E-boxes in ODC intron 1. c-Myc and ODC are both required for cell growth and their expression is sequentially induced in G0/G1 cells stimulated with mitogens, yet their expression is not modulated by the cell cycle in proliferating cells. Here we demonstrate that regulation of ODC and its promoter by Interleukin-3 (IL-3) in murine myeloid cells is mediated in part by c-Myc, c-Myc induced ODC through the same transcription start site as IL-3 and, in asynchronously growing cells, maximal activity of the ODC promoter required the intronic c-Myc binding sites. However, induction of ODC following IL-3 stimulation of quiescent cells is mediated by at least two pathways. The first phase of this response was independent of the intronic c-Myc:Max E-boxes and de novo protein synthesis. Sustained induction of the ODC promoter however required the c-Myc:Max binding sites and protein synthesis. Accumulation of c-Myc following stimulation of quiescent cells with IL-3 correlated with the delayed phase of the response. Consistent with a two pathway model of ODC regulation, inducible overexpression of dominant negative form of c-Myc (In373-Myc), which specifically inhibits the c-Myc-Max network, inhibited the delayed, but not immediate, induction of ODC promoter activity in response to IL-3. Dominant negative c-Myc protein also effectively suppressed induction of the endogenous ODC gene by IL-3. Therefore, c-Myc functions as a direct and required-regulator of ODC. These results also suggest a model whereby c-Myc's role in regulating its targets may be to convert a transient, immediate-early, activation event into the persistent induction of gene expression.

Animals↗
PubMed1997

Pivotal role for the NFIL3/E4BP4 transcription factor in interleukin 3-mediated survival of pro-B lymphocytes.

The E2A-HLF (hepatic leukemia factor) oncoprotein, generated in pro-B lymphocytes by fusion of the trans-activation domain of E2A to the basic region/leucine zipper (bZIP) domain of HLF, functions as an anti-apoptotic transcription factor in leukemic cell transformation. When introduced into interleukin 3 (IL-3)-dependent mouse pro-B lymphocytes, E2A-HLF prevents apoptosis induced by growth factor deprivation, suggesting that IL-3 mediates cell survival through activation of a transcription factor whose activity can be constitutively replaced by the chimeric oncoprotein. We considered four bZIP transcription factors as candidates for this putative IL-3-regulated factor, each of which binds avidly to the DNA consensus sequence recognized by E2A-HLF and is related to the Caenorhabditis elegans CES-2 (cell death specification protein) neuron-specific mediator of cell death. The expression and binding activity of the Nfil3 protein (also called E4bp4), but not of Hlf, Dbp, or Tef, was found to be regulated by IL-3 in mouse pro-B cell lines (Baf-3 and FL5.12). Northern blot analysis showed that Nfil3/E4bp4 is regulated as a "delayed-early" IL-3-responsive gene, requiring de novo protein synthesis. In the absence of IL-3, enforced expression of the human NFIL3/E4BP4 cDNA promoted the survival but not the growth of IL-3-dependent pro-B cells. Our results implicate NFIL3/E4BP4 (nuclear factor regulated by IL-3/adenovirus E4 promoter binding protein) in a distinct growth factor-regulated signaling pathway that is responsible for the survival of early B-cell progenitors, and whose alteration by E2A-HLF leads to childhood B lineage leukemia.

Adenovirus E4 Proteins↗
PubMed1997

Percutaneous injuries during oral and maxillofacial surgery procedures.

PURPOSE: This study estimated the frequency of percutaneous injuries (Pls) to dental health-care workers during oral and maxillofacial surgery and examined the circumstances surrounding the incidents. MATERIAL AND METHODS: A self-reported, prospective study was conducted to document Pls incurred during oral and maxillofacial surgery performed on outpatients and inpatients over 1-month and 6-month periods, respectively. Among the study variables examined were the numbers of patients treated, number and types of procedures performed, duration of treatment, numbers and types of health care workers at risk, treatment setting, and number of injuries. RESULTS: Four injuries were recorded during 362 operating room procedures on 236 inpatients, for a rate of 1.1 Pls per 100 procedures (95% confidence interval: 0.3 to 2.8) and 1.7 Pls per 100 patients (95% confidence interval: 0.5 to 4.6). These four injuries occurred during 1,665 person-procedures (mean number of workers present at each procedure times the total number of procedures) for a rate of 0.24 Pls per 100 person-procedures (95% confidence interval: 0.1 to 1.0). Three injuries took place during fracture reductions; two were caused by surgical wire and the third by a needlepoint Bovie tip. One injury occurred during orthognathic surgery and involved a Woodson elevator. Residents recorded no injuries while treating 521 outpatients (0 Pls per 100 patients; 95% confidence interval: 0 to 0.6). CONCLUSION: The results support previous findings that Pls rarely occur during outpatients oral and maxillofacial surgery procedures. However, the findings suggest that operating room procedures for oral and maxillofacial surgery that use wire or involve fracture reduction may be associated with an increased risk of injury. Strategies such as using a cork or sponge to cap sharp wires or instruments, and protecting hands and fingers by double gloving, may be used to decrease the risk of Pl.

Accidents, Occupational↗
PubMed1997

Fas activates NF-kappaB and induces apoptosis in T-cell lines by signaling pathways distinct from those induced by TNF-alpha.

The p55 tumor necrosis factor (TNF) receptor and the Fas (CD95/APO-1) receptor share an intracellular domain necessary to induce apoptosis, suggesting they utilize common signaling pathways. To define pathways triggered by Fas and TNF-alpha we utilized human CEM-C7 T-cells. As expected, stimulation of either receptor induced apoptosis and TNF-alpha-induced signaling included the activation of NF-kappaB. Surprisingly, Fas-induced signaling also triggered the activation of NF-kappaB in T cells, yet the kinetics of NF-kappaB induction by Fas was markedly delayed. NF-kappaB activation by both pathways was persistent and due to the sequential degradation of IkappaB-alpha and IkappaB-beta. However, the kinetics of IkappaB degradation were different and there were differential effects of protease inhibitors and antioxidants on NF-kappaB activation. Signaling pathways leading to activation of apoptosis were similarly separable and were also independent of NF-kappaB activation. Thus, the Fas and TNF receptors utilize distinct signal transduction pathways in T-cells to induce NF-kappaB and apoptosis.

Journal Article↗
PubMed1997

Occupational blood exposures in dentistry: a decade in review.

This review summarizes data from self-reported and observational studies describing the nature, frequency, and circumstances of occupational blood exposures among US dental workers between 1986 and 1995. These studies suggest that, among US dentists, percutaneous injuries have declined steadily over the 10-year period. Data also suggest that, in 1995, most dental workers (dentists, hygienists assistants, and oral surgeons) experienced approximately three injuries per year. Work practices (eg, using an instrument instead of fingers to retract tissue), safer instrumentation or design (eg, self-sheathing needles, changes in dental-unit design), and continued worker education may reduce occupational blood exposures in dentistry further.

Blood-Borne Pathogens↗
PubMed1997

A role for c-myc in chemically induced renal-cell death.

A variety of genes, including c-myc, are activated by chemical toxicants in vivo and in vitro. Although enforced c-myc expression induces apoptosis after withdrawing survival factors, it is not clear if activation of the endogenous c-myc gene is an apoptotic signal after toxicant exposure. The renal tubular epithelium is a target for many toxicants. c-myc expression is activated by tubular damage. In quiescent LLC-PK1 renal epithelial cells, c-myc but not max or mad mRNA is induced by the nephrotoxicant S-(1,2-dichlorovinyl)-L-cysteine (DCVC). The kinetics of DCVC-induced c-myc expression and apoptosis suggested an association between cell death and prolonged activation of c-myc expression after toxicant exposure. Accordingly, prolonged activation of an estrogen receptor-Myc fusion construct, but not a construct in which a c-Myc transactivation domain had been deleted, was sufficient to induce apoptosis in LLC-PK1 cells. Moreover, under conditions in which necrosis was the predominant cell death pathway caused by DCVC in parental cells, overexpressing c-myc biased the cell death pathway toward apoptosis. DCVC also induced ornithine decarboxylase (odc) mRNA and activated the odc promoter. Activation of the odc promoter by DCVC required consensus c-Myc-Max binding sites in odc intron 1. Inhibiting ODC activity with alpha-difluoromethylornithine delayed DCVC-induced cell death. Therefore, odc is a target gene in the DCVC apoptotic pathway involving c-myc activation and contributes to apoptosis. Finally, a structurally related cytotoxic but nongenotoxic analog of DCVC did not induce c-myc and did not activate the odc promoter or induce apoptosis. The data support the hypothesis that activation of apoptotic cell death in quiescent renal epithelial cells involves induction of c-myc. This is the first study to demonstrate that c-myc induction by a specific nephrotoxicant leads to gene activation and cell death.

Apoptosis↗
PubMed1997

E2F-1 cooperates with topoisomerase II inhibition and DNA damage to selectively augment p53-independent apoptosis.

Mutations in the retinoblastoma (pRb) tumor suppressor pathway including its cyclin-cdk regulatory kinases, or cdk inhibitors, are a hallmark of most cancers and allow unrestrained E2F-1 transcription factor activity, which leads to unregulated G1-to-S-phase cell cycle progression. Moderate levels of E2F-1 overexpression are tolerated in interleukin 3 (IL-3)-dependent 32D.3 myeloid progenitor cells, yet this induces apoptosis when these cells are deprived of IL-3. However, when E2F activity is augmented by coexpression of its heterodimeric partner, DP-1, the effects of survival factors are abrogated. To determine whether enforced E2F-1 expression selectively sensitizes cells to cytotoxic agents, we examined the effects of chemotherapeutic agents and radiation used in cancer therapy. E2F-1 overexpression in the myeloid cells preferentially sensitized cells to apoptosis when they were treated with the topoisomerase II inhibitor etoposide. Although E2F-1 alone induces moderate levels of p53 and treatment with drugs markedly increased p53, the deleterious effects of etoposide in E2F-1-overexpressing cells were independent of p53 accumulation. Coexpression of Bcl-2 and E2F-1 in 32D.3 cells protected them from etoposide-mediated apoptosis. However, Bcl-2 also prevented apoptosis of these cells upon exposure to 5-fluorouracil and doxorubicin, which were also cytotoxic for control cells. Pretreating E2F-1-expressing cells with ICRF-193, a second topoisomerase II inhibitor that does not damage DNA, protected the cells from etoposide-induced apoptosis. However, ICRF-193 cooperated with DNA-damaging agents to induce apoptosis. Therefore, topoisomerase II inhibition and DNA damage can cooperate to selectively induce p53-independent apoptosis in cells that have unregulated E2F-1 activity resulting from mutations in the pRb pathway.

Antineoplastic Agents↗
PubMed1996

c-Myc induces apoptosis and cell cycle progression by separable, yet overlapping, pathways.

Enforced c-Myc expression promotes inappropriate cell cycle progression of growth factor deprived cells and triggers concomitant apoptosis. However, it is not clear what role dysregulation of the cell cycle plays in c-Myc-induced apoptosis. Ornithine decarboxylase (ODC) is a transcriptional target of c-Myc and contributes to c-Myc induced apoptosis. Here we have established that high levels of ODC overexpression in interleukin-3 (IL-3)-dependent 32D.3 myeloid cells induces apoptosis at rates comparable to those induced by enforced c-Myc expression. However, ODC-induced apoptosis was not accompanied by dysregulation of cell cycle controls, indicating that cell death was not triggered by inappropriate cell cycle progression. Nonetheless, ODC was required downstream of c-Myc for myeloid cell growth. These results suggested that c-Myc-induced pathways leading to cell cycle progression and apoptosis are separable, yet that they share common mediators. In agreement with this concept, treatment of cells over-expressing c-Myc with the growth inhibitory agent dibutyryl cyclic AMP (Bt2cAMP) arrested these cells G1, without inducing apoptosis. However, c-Myc retained the ability to induce apoptosis of Bt2cAMP-arrested cells following removal of IL-3, demonstrating that Bt2cAMP selectively inhibits c-Myc-induced pathways promoting cell cycle progression but not apoptosis. These results suggest a "multiple effectors' model in which c-Myc regulates the expression of mediators which alone are sufficient to induce apoptosis in the absence of survival factors, yet are required in concert to promote cell cycle progression.

Animals↗
PubMed1996

Cytokines suppress apoptosis independent of increases in reactive oxygen levels.

Antioxidants suppress apoptosis induced by diverse stimuli in many cells, including immune cells, suggesting that reactive oxygen species (ROS) are common mediators of apoptosis. We evaluated the potential role for ROS in the apoptosis of myeloid progenitors following withdrawal of survival factors and in the apoptosis triggered by enforced c-myc expression, two model systems of programmed cell death. ROS are potential mediators of these cell deaths, as low concentrations of H2O2 (0.1-0.2 mM) or menadione (less than = 10 microM) induced myeloid cell apoptosis, and cytokines effectively suppressed this cell death. Apoptosis following IL-3 withdrawal and c-Myc-induced cell death was also effectively suppressed by the antioxidants pyrrolidine dithiocarbamate and glutathione peroxidase. Moreover, measurements of intracellular ROS in cells treated with oxidants or antioxidants showed a correlation between levels of reactive oxygen and the induction or suppression of apoptosis. However, apoptosis following IL-3 withdrawal and c-Myc-induced cell death was not associated with increased reactive oxygen. Therefore, myeloid programmed cell death is not associated with increases in ROS.

Animals↗
PubMed1996

Hepatitis B vaccination and infection among U.S. dentists, 1983-1992 .

The hepatitis B vaccine became commercially available in 1982. Since then, health care workers, including dentists, have been encouraged to be vaccinated. This study examines the prevalence of hepatitis B vaccination and infection among U.S. dentists from 1983 to 1992.

Chi-Square Distribution↗
PubMed1995

Vav and Ras induce fibroblast transformation by overlapping signaling pathways which require c-Myc function.

Recent evidence has suggested that the Vav oncoprotein may function as a hematopoietic-specific GTP exchange factor for the Ras superfamily of proteins. However, transformation of NIH3T3 fibroblast cells by Vav is morphologically distinct from that induced by activated Ras oncogenes, suggesting that the two oncoproteins induce separate signal transduction pathways which promote transformation. To address this issue, the effects of dominant negative mutants of H-ras and proto-Vav (proto-VavR695L, a mutation in the VavSH2 domain) were tested on Vav- and Ras-induced transformation. These mutants partially inhibited both Vav- and Ras-induced transformation, suggesting that they may induce a common downstream signaling pathway which potentiates transformation. As an independent measure of Vav function we also tested the ability of the purified protein encoded by VavSH2 to influence Germinal Vesicle Breakdown (GVBD) during Xenopus oocyte maturation. Microinjection of the VavSH2 protein alone, but not mutant VavR695L SH2 protein, was sufficient to induce GVBD and accelerated maturation induced by normal Ras, suggesting that in this system as well Vav and Ras signals overlap through a common effector. A key target of multiple signalling pathways is c-Myc. Dominant negative versions of c-Myc totally abolished morphologic transformation of NIH3T3 cells by both Vav and Ras oncogenes. These results suggest that distinct, but overlapping, signalling pathways are induced by Vav and Ras and that fibroblast cell transformation by either oncogene requires c-Myc functions.

3T3 Cells↗
PubMed1995

The Evi-1 zinc finger myeloid transforming protein binds to genomic fragments containing (GATA)n sequences.

The EVI1 gene is activated by chromosomal translocations and inversions in approximately 5% of human acute myeloid leukemia (AML) and by retroviral insertion in approximately 20% of murine myeloid leukemias. EVI1 encodes a nuclear DNA-binding protein having 10 zinc finger motifs in two noncontiguous domains consisting of an amino-terminal domain of seven fingers and a carboxyl domain containing three fingers. To evaluate the sequence specificity of Evi-1 binding and potentially identify genomic targets, whole-genome PCR was utilized to isolate multiple Sau3A fragments which specifically bind to the amino-terminal zinc finger domain. The majority of these clones represented single copy sequences and virtually all contained variable numbers of repeats of the GATA motif, the target sequence for the erythroid-specific transcription factor GATA-1. GST/Evi-1 fusion proteins containing the amino-terminal domain of zinc fingers bound the GATA motif in these clones as well as to those present in the human gamma-globin promoter, similar to the binding of purified GATA-1 protein. By obtaining corresponding large genomic clones for eight of these fragments, transcription units were found associated with two. One corresponded to the glyceraldehyde-3-phosphate dehydrogenase gene and its expression was not affected by Evi-1. The second is a novel gene whose expression is repressed in murine myeloid cell lines that express Evi-1.

Animals↗
PubMed1995

Investigations of patients of health care workers infected with HIV. The Centers for Disease Control and Prevention database.

OBJECTIVE: To assess the risk for transmission of the human immunodeficiency virus (HIV) from an infected health care worker to patients. DESIGN: Survey of investigators from health departments, hospitals, and other agencies who had elected to notify patients who had received care from health care workers infected with HIV. MEASUREMENTS: Information was collected about infected health care workers, their work practices, their patients' HIV test results, procedures that they did on those of their patients who were tested for HIV, and patient notification procedures. RESULTS: As of 1 January 1995, information about investigations of 64 health care workers infected with HIV was reported to the Centers for Disease Control and Prevention; HIV test results were available for approximately 22,171 patients of 51 of the 64 health care workers. For 37 of the 51 workers, no seropositive patients were reported among 13,063 patients tested for HIV. For the remaining 14 health care workers, 113 seropositive patients were reported among 9108 patients. Epidemiologic and laboratory follow-up did not show any health care worker to have been a source of HIV for any of the patients tested. CONCLUSION: Despite limitations, these data are consistent with previous assessments that state that the risk for transmission of HIV from a health care worker to a patient is very small. These data also support current recommendations that state that retrospective patient notification need not be done routinely.

Centers for Disease Control and Prevention, U.S.↗
PubMed1995

Structural and functional analysis of the promoter of the murine V gamma 1.1 T cell receptor gene.

The expression of the germ-line gene V gamma 1.1-C gamma 4 of the T cell receptor (TcR) gamma chain depends on interleukin (IL)-3 induction in hematopoietic cells, while in T cells, the rearranged gene is expressed constitutively. To understand the mechanism that controls TcR gamma gene expression, we cloned and characterized the structure and function of the V gamma 1.1-C gamma 4 TcR promoter. IL-3-dependent cell lines and T cell lines utilized the same transcriptional start sites. In chloramphenicol acetyltransferase (CAT) assays, the minimal 70-bp promoter confers strong transcriptional activity which is 50-60% of the Moloney long terminal repeat promoter activity. The 500-bp promoter region linked to the CAT gene exhibits IL-3 dependency similar to the endogenous TcR gamma gene. The immediate 3' and 5' flanking sequences inhibit the promoter activity two- to fourfold. The promoter lacks an obvious TATA box or CAAT box sequences, but contains a GC box in the untranslated region 3' to the promoter. The GC box is the core sequence of the element which binds Sp1-like proteins. Cloning of this Sp1 binding element in front of the thymidine kinase (TK) promoter and mutations generated in this site demonstrate its function as a silencer. Ultraviolet cross-linking analysis with the Sp1 binding site from the TcR gamma promoter revealed binding of a 90-100-kDa protein in a T cell line (EL-4) and 40-50 and 90-100-kDa proteins in FDC-P1 cells. The possible function of the Sp1-like protein in silencing the minimal promoter activity is discussed.

3T3 Cells↗
PubMed1995

The role of ornithine decarboxylase in c-Myc-induced apoptosis.

Translocations or amplifications which activate members of the myc gene family are common in human cancer. c-Myc is a central regulator of normal cell proliferation and differentiation (Luscher and Eisenman, 1991; Marcu et al. 1992) and can induce apoptosis (Askew et al. 1991, 1993; Evan et al. 1992; Bissonette et al. 1992; Shi et al. 1992). c-Myc is a transcription factor (Amati et al. 1992; Kretzner et al. 1992), however, the targets regulated by c-Myc which mediate its activities are not known. Here, we discuss the role of the ornithine decarboxylase (ODC) gene as a direct transcriptional target of c-Myc and demonstrate a role for ODC enzyme activity in c-Myc-induced apoptosis.

Animals↗
PubMed1995

Multidrug-resistant Mycobacterium tuberculosis in an HIV dental clinic.

OBJECTIVE: To investigate possible transmission of multidrug-resistant tuberculosis (MDR-TB) in a dental setting. DESIGN: A retrospective, descriptive study of dental workers (DWs), patients, and practice characteristics. PATIENTS: Two dental workers (DW1 and DW2) with acquired immunodeficiency syndrome and MDR-TB. SETTING: A hospital-based (Hospital X) human immunodeficiency virus (HIV) dental clinic in New York City. METHODS: To identify dental patients with tuberculosis (TB), patients treated in the dental clinic at Hospital X during 1990 were cross-matched with those listed in the New York City Department of Health Tuberculosis Registry. Mycobacterium tuberculosis isolates from both DWs and from dental patients with TB were tested for antimicrobial susceptibility and typed by restriction fragment length polymorphism (RFLP) analysis. Infection control practices were reviewed. RESULTS: M tuberculosis isolates infecting DW1 and DW2 were resistant to isoniazid and rifampin and had identical RFLP patterns. DW1 and DW2 worked in close proximity to each other in a small HIV dental clinic in Hospital X during 1990. Of 472 patients treated in the dental clinic in 1990, 41 (8.7%) had culture-proven M tuberculosis infection. Of these 41, 5 had isolates with resistance patterns similar to both DWs; however, for four available isolates, the RFLP patterns were different from the patterns of the DWs. Sixteen of the 41 patients received dental treatment while potentially infectious. Dental patients were not routinely questioned about TB by dental staff, nor were all dental staff screened routinely for TB. No supplemental environmental measures for TB were employed in the dental clinic in 1990. CONCLUSIONS: Our investigation suggests that MDR-TB transmission may have occurred between two DWs in an HIV dental clinic. Opportunities for transmission of TB among dental staff and patients were identified. TB surveillance programs for DWs and appropriate infection control strategies, including worker education, are needed to monitor and minimize exposure to TB in dental settings providing care to patients at risk for TB.

Acquired Immunodeficiency Syndrome↗