RESUMO
Inhalation anthrax has three clinical stages: early-prodromal, intermediate-progressive, and late-fulminant. We report the comprehensive characterization of anthrax toxins, including total protective antigen (PA), total lethal factor (LF), total edema factor (EF), and their toxin complexes, lethal toxin and edema toxin in plasma, during the course of inhalation anthrax in 23 cynomolgus macaques. The toxin kinetics were predominantly triphasic with an early rise (phase-1), a plateau/decline (phase-2), and a final rapid rise (phase-3). Eleven animals had shorter survival times, mean±standard deviation of 58.7±7.6 hours (fast progression), 11 animals had longer survival times, 113±34.4 hours (slow progression), and one animal survived. Median (lower-upper quartile) LF levels at the end-of-phase-1 were significantly higher in animals with fast progression [138 (54.9-326) ng/mL], than in those with slow progression [23.8 (15.6-26.3) ng/mL] (p = 0.0002), and the survivor (11.1 ng/mL). The differences were also observed for other toxins and bacteremia. Animals with slow progression had an extended phase-2 plateau, with low variability of LF levels across all time points and animals. Characterization of phase-2 toxin levels defined upper thresholds; critical levels for exiting phase-2 and entering the critical phase-3, 342 ng/mL (PA), 35.8 ng/mL (LF), and 1.10 ng/mL (EF). The thresholds were exceeded earlier in animals with fast progression (38.5±7.4 hours) and later in animals with slow progression (78.7±15.2 hours). Once the threshold was passed, toxin levels rose rapidly in both groups to the terminal stage. The time from threshold to terminal was rapid and similar; 20.8±7.4 hours for fast and 19.9±7.5 hours for slow progression. The three toxemic phases were aligned with the three clinical stages of anthrax for fast and slow progression which showed that anthrax progression is toxin- rather than time-dependent. This first comprehensive evaluation of anthrax toxins provides new insights into disease progression.
Assuntos
Antraz , Bacillus anthracis , Infecções Respiratórias , Animais , Antígenos de Bactérias , Macaca mulattaRESUMO
The primary objective of this study was to characterize the disease course in cynomolgus macaques exposed to Sudan virus (SUDV), to determine if infection in this species is an appropriate model for the evaluation of filovirus countermeasures under the FDA Animal Rule. Sudan virus causes Sudan virus disease (SVD), with an average case fatality rate of approximately 50%, and while research is ongoing, presently there are no approved SUDV vaccines or therapies. Well characterized animal models are crucial for further developing and evaluating countermeasures for SUDV. Twenty (20) cynomolgus macaques were exposed intramuscularly to either SUDV or sterile phosphate-buffered saline; 10 SUDV-exposed animals were euthanized on schedule to characterize pathology at defined durations post-exposure and 8 SUDV-exposed animals were not part of the scheduled euthanasia cohort. Survival was assessed, along with clinical observations, body weights, body temperatures, hematology, clinical chemistry, coagulation, viral load (serum and tissues), macroscopic observations, and histopathology. There were statistically significant differences between SUDV-exposed animals and mock-exposed animals for 26 parameters, including telemetry body temperature, clinical chemistry parameters, hematology parameters, activated partial thromboplastin time, serum viremia, and biomarkers that characterize the disease course of SUDV in cynomolgus macaques.
RESUMO
The Biomedical Advanced Research and Development Authority, part of the Administration for Strategic Preparedness and Response within the U.S. Department of Health and Human Services, recognizes that the evaluation of medical countermeasures under the Animal Rule requires well-characterized and reproducible animal models that are likely to be predictive of clinical benefit. Marburg virus (MARV), one of two members of the genus Marburgvirus, is characterized by a hemorrhagic fever and a high case fatality rate for which there are no licensed vaccines or therapeutics available. This natural history study consisted of twelve cynomolgus macaques challenged with 1000 PFU of MARV Angola and observed for body weight, temperature, viremia, hematology, clinical chemistry, and coagulation at multiple time points. All animals succumbed to disease within 8 days and exhibited signs consistent with those observed in human cases, including viremia, fever, systemic inflammation, coagulopathy, and lymphocytolysis, among others. Additionally, this study determined the time from exposure to onset of disease manifestations and the time course, frequency, and magnitude of the manifestations. This study will be instrumental in the design and development of medical countermeasures to Marburg virus disease.
Assuntos
Doença do Vírus de Marburg , Marburgvirus , Contramedidas Médicas , Humanos , Animais , Marburgvirus/fisiologia , Viremia , Macaca fascicularisRESUMO
Marburg virus (MARV) is a filovirus that can infect humans and nonhuman primates (NHPs), causing severe disease and death. Of the filoviruses, Ebola virus (EBOV) has been the primary target for vaccine and therapeutic development. However, MARV has an average case fatality rate of approximately 50%, the infectious dose is low, and there are currently no approved vaccines or therapies targeted at infection with MARV. The purpose of this study was to characterize disease course in cynomolgus macaques intramuscularly exposed to MARV Angola variant. There were several biomarkers that reliably correlated with MARV-induced disease, including: viral load; elevated total clinical scores; temperature changes; elevated ALT, ALP, BA, TBIL, CRP and decreased ALB values; decreased lymphocytes and platelets; and prolonged PTT. A scheduled euthanasia component also provided the opportunity to study the earliest stages of the disease. This study provides evidence for the application of this model to evaluate potential vaccines and therapies against MARV and will be valuable in improving existing models.
RESUMO
We have developed a dual-antigen COVID-19 vaccine incorporating genes for a modified SARS-CoV-2 spike protein (S-Fusion) and the viral nucleocapsid (N) protein with an Enhanced T-cell Stimulation Domain (N-ETSD) to increase the potential for MHC class II responses. The vaccine antigens are delivered by a human adenovirus serotype 5 platform, hAd5 [E1-, E2b-, E3-], previously demonstrated to be effective in the presence of Ad immunity. Vaccination of rhesus macaques with the hAd5 S-Fusion + N-ETSD vaccine by subcutaneous prime injection followed by two oral boosts elicited neutralizing anti-S IgG and T helper cell 1-biased T-cell responses to both S and N that protected the upper and lower respiratory tracts from high titer (1 x 106 TCID50) SARS-CoV-2 challenge. Notably, viral replication was inhibited within 24 hours of challenge in both lung and nasal passages, becoming undetectable within 7 days post-challenge.
Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Adenovírus Humanos/genética , Adenovírus Humanos/imunologia , Adenovírus Humanos/metabolismo , Administração Oral , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Vacinas contra COVID-19/administração & dosagem , Citocinas/sangue , Imunização Secundária/métodos , Imunoglobulina G/sangue , Pulmão/virologia , Macaca mulatta , Nariz/virologia , Fosfoproteínas/imunologia , Domínios Proteicos/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Vacinação , Replicação Viral/imunologiaRESUMO
The anthrax vaccine candidate AV7909 is being developed as a next-generation vaccine for post-exposure prophylaxis (PEP) against inhalational anthrax. In clinical studies, two vaccinations with AV7909 administered either two or four weeks apart induced an enhanced immune response compared to BioThrax® (Anthrax Vaccine Adsorbed) (AVA). Anthrax toxin-neutralizing antibody (TNA) levels on Day 70 following initial vaccination that were associated with protection of animals exposed to inhalational anthrax were previously reported for the 0, 4-week AV7909 vaccination regimen. The current study shows that a 0, 2-week AV7909 vaccination regimen protected guinea pigs (GPs) and nonhuman primates (NHPs) against a lethal inhalational anthrax challenge on Days 28 and 70 after the first immunization. An earlier induction of protective TNA levels using a 0, 2-week AV7909 vaccination regimen may provide benefit over the currently approved AVA PEP 0, 2, and 4-week vaccination regimen.
Assuntos
Vacinas contra Antraz , Antraz , Bacillus anthracis , Animais , Antraz/prevenção & controle , Anticorpos Antibacterianos , Anticorpos Neutralizantes , Antígenos de Bactérias , Cobaias , Profilaxia Pós-Exposição , PrimatasRESUMO
The anthrax vaccine candidate AV7909 is being developed as a next-generation vaccine for a post-exposure prophylaxis (PEP) indication against anthrax. AV7909 consists of the anthrax vaccine adsorbed (AVA) (Emergent BioSolutions Inc., Lansing, MI) bulk drug substance adjuvanted with the immunostimulatory oligodeoxynucleotide (ODN) compound, CPG 7909. The addition of CPG 7909 to AVA enhances both the magnitude and the kinetics of antibody responses in animals and human subjects, making AV7909 a suitable next-generation vaccine for use in a PEP setting. Emergent has produced a thermostable (lyophilized) formulation of AV7909 vaccine utilizing drying technology. The purpose of the study described here was to assess the immunogenicity and efficacy of the lyophilized formulation of the AV7909 vaccine candidate as compared with the liquid formulation in the guinea pig general-use prophylaxis (GUP) model. The study also provides initial information on the relationship between the immune response induced by the thermostable formulation of the vaccine, as measured by the toxin neutralization assay (TNA), and animal survival following lethal anthrax aerosol challenge. Results demonstrated that there were no significant differences in the immunogenicity or efficacy of lyophilized AV7909 against lethal anthrax spore aerosol challenge in the guinea pig model as compared to liquid AV7909. For both vaccine formulations, logistic regression modeling showed that the probability of survival increased as the pre-challenge antibody levels increased.
Assuntos
Vacinas contra Antraz/química , Vacinas contra Antraz/imunologia , Anticorpos Antibacterianos/sangue , Imunogenicidade da Vacina , Temperatura , Adjuvantes Imunológicos , Animais , Antraz/prevenção & controle , Anticorpos Neutralizantes/sangue , Antígenos de Bactérias/imunologia , Feminino , Liofilização , Cobaias , Masculino , Oligodesoxirribonucleotídeos/imunologia , Profilaxia Pós-Exposição , Vacinação , Potência de VacinaRESUMO
Burkholderia pseudomallei, the etiological agent of melioidosis, has been hypothesized to be endemic throughout the Caribbean, including the impoverished nation of Haiti. However, because of the protean clinical manifestations, presence of asymptomatic infections, and limited medical diagnostic capacity, the identification of active melioidosis cases remains challenging. A seroepidemiological study was conducted using a novel enzyme-linked immunosorbent assay (ELISA) to detect antibodies toward B. pseudomallei in the native population. The performance of an indirect ELISA with purified lipopolysaccharide (LPS) from B. pseudomallei was evaluated using serum collected from rhesus macaques exposed to aerosolized B. pseudomallei. After optimization, serum collected from asymptomatic population members (n = 756) was screened for polyvalent (immunoglobulin M [IgM]/ immunoglobulin G [IgG]/ immunoglobulin A) and monoclonal (IgG or IgM) immunoglobulins against B. pseudomallei LPS. The population seroprevalence was 11.5% (95% confidence interval [CI]: 9.2, 13.8) for polyvalent immunoglobulins, 9.8% (95% CI: 7.7, 11.9) for IgG, and 1.7% (95% CI: 0.8, 2.6%) for IgM. The seroprevalence was not significantly different by gender (P = 0.16), but increased significantly (P < 0.001) with age, yielding an estimated annual seroconversion rate of 1.05% (95% CI: 0.81, 1.3). The detection of both recent (IgM+) and previous (IgG+) exposure to B. pseudomallei provides serological evidence that melioidosis is endemic in Haiti.
Assuntos
Anticorpos Antibacterianos/sangue , Burkholderia pseudomallei/imunologia , Melioidose/epidemiologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Animais , Infecções Assintomáticas/epidemiologia , Criança , Pré-Escolar , Doenças Endêmicas , Ensaio de Imunoadsorção Enzimática , Feminino , Haiti/epidemiologia , Humanos , Lipopolissacarídeos , Macaca mulatta/imunologia , Masculino , Melioidose/imunologia , Pessoa de Meia-Idade , Estudos Soroepidemiológicos , Adulto JovemRESUMO
The anthrax vaccine candidate AV7909 is being developed as a next generation vaccine for a post-exposure prophylaxis (PEP) indication against anthrax. AV7909 consists of the Anthrax Vaccine Adsorbed (AVA, BioThrax®) bulk drug substance adjuvanted with the immunostimulatory oligodeoxynucleotide (ODN) compound, CPG 7909. The addition of CPG 7909 to AVA enhances both the magnitude and the kinetics of antibody responses in animals and human subjects, making AV7909 a suitable next-generation vaccine for use in a PEP setting. The studies described here provide initial information on AV7909-induced toxin-neutralizing antibody (TNA) levels associated with the protection of animals from lethal Bacillus anthracis challenge. Guinea pigs or nonhuman primates (NHPs) were immunized on Days 0 and 28 with various dilutions of AV7909, AVA or a saline or Alhydrogel+CPG 7909 control. Animals were challenged via the inhalational route with a lethal dose of aerosolized B. anthracis (Ames strain) spores and observed for clinical signs of disease and mortality. The relationship between pre-challenge serum TNA levels and survival following challenge was determined in order to calculate a threshold TNA level associated with protection. Immunisation with AV7909 induced a rapid, highly protective TNA response in guinea pigs and NHPs. Surprisingly, the TNA threshold associated with a 70% probability of survival for AV7909 immunized animals was substantially lower than the threshold which has been established for the licensed AVA vaccine. The results of this study suggest that the TNA threshold of protection against anthrax could be modified by the addition of an immune stimulant such as CPG 7909 and that the TNA levels associated with protection may be vaccine-specific.
Assuntos
Vacinas contra Antraz/imunologia , Anticorpos Neutralizantes/imunologia , Animais , Cobaias , Profilaxia Pós-Exposição , Primatas , VacinaçãoRESUMO
Bacillus anthracis toxins can be neutralized by antibodies against protective antigen (PA), a component of anthrax toxins. Anthrivig (human anthrax immunoglobulin), also known as AIGIV, derived from plasma of humans immunized with BioThrax (anthrax vaccine adsorbed), is under development for the treatment of toxemia following exposure to anthrax spores. The pharmacokinetics (PK) of AIGIV was assessed in naive animals and healthy human volunteers, and the efficacy of AIGIV was assessed in animals exposed via inhalation to aerosolized B. anthracis spores. In the clinical study, safety, tolerability, and PK were evaluated in three dose cohorts (3.5, 7.1, and 14.2 mg/kg of body weight of anti-PA IgG) with 30 volunteers per cohort. The elimination half-life of AIGIV in rabbits, nonhuman primates (NHPs), and humans following intravenous infusion was estimated to be approximately 4, 12, and 24 days, respectively, and dose proportionality was observed. In a time-based treatment study, AIGIV protected 89 to 100% of animals when administered 12 h postexposure; however, a lower survival rate of 39% was observed when animals were treated 24 h postexposure, underscoring the need for early intervention. In a separate set of studies, animals were treated on an individual basis upon detection of a clinical sign or biomarker of disease, namely, a significant increase in body temperature (SIBT) in rabbits and presence of PA in the serum of NHPs. In these trigger-based intervention studies, AIGIV induced up to 75% survival in rabbits depending on the dose and severity of toxemia at the time of treatment. In NHPs, up to 33% survival was observed in AIGIV-treated animals. (The clinical study has been registered at ClinicalTrials.gov under registration no. NCT00845650.).
Assuntos
Vacinas contra Antraz/administração & dosagem , Antraz/prevenção & controle , Anticorpos Antibacterianos/administração & dosagem , Bacillus anthracis/efeitos dos fármacos , Imunoglobulinas Intravenosas/farmacocinética , Infecções Respiratórias/prevenção & controle , Esporos Bacterianos/efeitos dos fármacos , Animais , Antraz/imunologia , Antraz/microbiologia , Antraz/mortalidade , Vacinas contra Antraz/imunologia , Anticorpos Antibacterianos/imunologia , Anticorpos Antibacterianos/isolamento & purificação , Antígenos de Bactérias/sangue , Antígenos de Bactérias/imunologia , Bacillus anthracis/imunologia , Bacillus anthracis/patogenicidade , Toxinas Bacterianas/sangue , Toxinas Bacterianas/imunologia , Biomarcadores/análise , Método Duplo-Cego , Feminino , Meia-Vida , Humanos , Imunoglobulinas Intravenosas/imunologia , Imunoglobulinas Intravenosas/isolamento & purificação , Infusões Intravenosas , Macaca fascicularis , Masculino , Coelhos , Infecções Respiratórias/imunologia , Infecções Respiratórias/microbiologia , Infecções Respiratórias/mortalidade , Esporos Bacterianos/imunologia , Esporos Bacterianos/patogenicidade , Análise de Sobrevida , Fatores de Tempo , VacinaçãoRESUMO
Burkholderia pseudomallei is the causative agent of melioidosis. Treatment of melioidosis is suboptimal and developing improved melioidosis therapies requires animal models. In this report, we exposed male BALB/c mice to various amounts of aerosolized B. pseudomallei 1026b to determine lethality. After establishing a median lethal dose (LD(50)) of 2,772 colony forming units (cfu)/animal, we tested the ability of doxycycline administered 6â hours after exposure to a uniformly lethal dose of ~20 LD(50) to prevent death and eliminate bacteria from the lung and spleens. Tissue bacterial burdens were examined by PCR analysis. We found that 100% of mice treated with doxycycline survived and B. pseudomallei DNA was not amplified from the lungs or spleens of most surviving mice. We conclude the BALB/c mouse is a useful model of melioidosis. Furthermore, the data generated in this mouse model indicate that doxycycline is likely to be effective in post-exposure prophylaxis of melioidosis.
Assuntos
Antibacterianos/administração & dosagem , Burkholderia pseudomallei/patogenicidade , Doxiciclina/administração & dosagem , Melioidose/tratamento farmacológico , Melioidose/microbiologia , Aerossóis , Animais , Carga Bacteriana , Modelos Animais de Doenças , Dose Letal Mediana , Masculino , Melioidose/mortalidade , CamundongosRESUMO
Nonhuman primates (NHPs) and rabbits are the animal models most commonly used to evaluate the efficacy of medical countermeasures against anthrax in support of licensure under the FDA's "Animal Rule." However, a need for an alternative animal model may arise in certain cases. The development of such an alternative model requires a thorough understanding of the course and manifestation of experimental anthrax disease induced under controlled conditions in the proposed animal species. The guinea pig, which has been used extensively for anthrax pathogenesis studies and anthrax vaccine potency testing, is a good candidate for such an alternative model. This study was aimed at determining the median lethal dose (LD50) of the Bacillus anthracis Ames strain in guinea pigs and investigating the natural history, pathophysiology, and pathology of inhalational anthrax in this animal model following nose-only aerosol exposure. The inhaled LD50 of aerosolized Ames strain spores in guinea pigs was determined to be 5.0 × 10(4) spores. Aerosol challenge of guinea pigs resulted in inhalational anthrax with death occurring between 46 and 71 h postchallenge. The first clinical signs appeared as early as 36 h postchallenge. Cardiovascular function declined starting at 20 h postexposure. Hematogenous dissemination of bacteria was observed microscopically in multiple organs and tissues as early as 24 h postchallenge. Other histopathologic findings typical of disseminated anthrax included suppurative (heterophilic) inflammation, edema, fibrin, necrosis, and/or hemorrhage in the spleen, lungs, and regional lymph nodes and lymphocyte depletion and/or lymphocytolysis in the spleen and lymph nodes. This study demonstrated that the course of inhalational anthrax disease and the resulting pathology in guinea pigs are similar to those seen in rabbits and NHPs, as well as in humans.
Assuntos
Antraz/patologia , Antraz/fisiopatologia , Bacillus anthracis/patogenicidade , Modelos Animais de Doenças , Animais , Antraz/mortalidade , Feminino , Cobaias , Dose Letal Mediana , Masculino , Análise de Sobrevida , Fatores de TempoRESUMO
Botulinum neurotoxins (BoNT) are the deadliest agents known. Previously, we reported an endopeptidase activity based method (Endopep-MS) that detects and differentiates BoNT serotypes A-G. This method uses serotype specific monoclonal antibodies and the specific enzymatic activity of BoNT against peptide substrates which mimic the toxin's natural target. Cleavage products from the reaction are detected by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. We have now developed a multiple reaction monitoring method to quantify the biological activity of BoNT serotypes A (BoNT/A) and B (BoNT/B) present in 0.5 mL of serum using electrospray mass spectrometry. The limit of quantification for each serotype is 1 mouse intraperitoneal lethal dose (MIPLD(50)) corresponding to 31 pg of BoNT/A and 15 pg of BoNT/B in this study. This method was applied to serum from rhesus macaques with inhalational botulism following exposure to BoNT/B, showing a maximum activity of 6.0 MIPLD(50)/mL in surviving animals and 653.6 MIPLD(50)/mL in animals that died in the study. The method detects BoNT/B in serum 2-5 h after exposure and up to 14 days. This is the first report of a quantitative method with sufficient sensitivity, selectivity, and low sample size requirements to measure circulating BoNT activity at multiple times during the course of botulism.
Assuntos
Toxinas Botulínicas Tipo A/sangue , Toxinas Botulínicas/sangue , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Animais , Anticorpos Monoclonais/imunologia , Macaca mulatta , Especificidade por SubstratoRESUMO
A recombinant botulinum vaccine (rBV A/B) is being developed for protection against inhalational intoxication with botulinum neurotoxin (BoNT) complex serotype A, subtype A1 (BoNT/A1), and BoNT serotype B, subtype B1 (BoNT/B1). A critical component for evaluating rBV A/B efficacy will be the use of animal models in which the pathophysiology and dose-response relationships following aerosol exposure to well-characterized BoNT are thoroughly understood and documented. This study was designed to estimate inhaled 50% lethal doses (LD(50)) and to estimate 50% lethal exposure concentrations relative to time (LCt(50)) in rhesus macaques exposed to well-characterized BoNT/A1 and BoNT/B1. During the course of this study, clinical observations, body weights, clinical hematology results, clinical chemistry results, circulating neurotoxin levels, and telemetric parameters were documented to aid in the understanding of disease progression. The inhaled LD(50) and LCt(50) for BoNT/A1 and BoNT/B1 in rhesus macaques were determined using well-characterized challenge material. Clinical observations were consistent with the recognized pattern of botulism disease progression. A dose response was demonstrated with regard to the onset of these clinical signs for both BoNT/A1 and BoNT/B1. Dose-related changes in physiologic parameters measured by telemetry were also observed. In contrast, notable changes in body weight, hematology, and clinical chemistry parameters were not observed. Circulating levels of BoNT/B1 were detected in animals exposed to the highest levels of BoNT/B1; however, BoNT/A1 was not detected in the circulation at any aerosol exposure level. The rhesus macaque aerosol challenge model will be used for future evaluations of rBV A/B efficacy against inhalational BoNT/A1 and BoNT/B1 intoxication.
Assuntos
Toxinas Botulínicas Tipo A/toxicidade , Toxinas Botulínicas/toxicidade , Botulismo/patologia , Botulismo/fisiopatologia , Aerossóis , Animais , Análise Química do Sangue , Peso Corporal , Modelos Animais de Doenças , Feminino , Dose Letal Mediana , Macaca mulatta , Masculino , Camundongos , Análise de SobrevidaRESUMO
BACKGROUND: Although a number of reports have investigated the effects of IL-6 family cytokines on prostate cell growth, there is limited information available identifying IL-6 inducible downstream effector genes and their function in growth control. Previous studies have demonstrated that IL-6 treatment results in the activation of signal transducer and activator of transcription3 (STAT3) in prostate cancer cells. The goal of this study was to investigate the influence of IL-6 treatment and activation of the Jak/STAT signal transduction pathway on C/EBPdelta gene expression and growth inhibition of human prostate cancer cells. METHODS: Expression of C/EBPdelta and STAT3 activation were assayed using Northern and Western blotting techniques. Proliferation was assessed by [(3)H] thymidine incorporation, flow cytometry, and colony formation analyses. The analysis of the transcriptional regulation of C/EBPdelta was performed using luciferase-reporter constructs. RESULTS: In this report, we demonstrate that IL-6 treatment induces STAT3 activation (pSTAT3), pSTAT3 binds to the human C/EBPdelta gene promoter and induces its expression. We also demonstrate that C/EBPdelta over-expression is capable of suppressing prostate cancer cell growth. CONCLUSIONS: These results demonstrate that C/EBPdelta gene expression is increased in IL-6 treated LNCaP cells. Increased C/EBPdelta gene expression plays an important role in IL-6/STAT3 mediated growth arrest of LNCaP prostate cancer cells. Ongoing studies are investigating the mechanism by which C/EBPdelta controls prostate cancer cell growth and the potential role of C/EBPdelta in the survival and chemo resistance of prostate cancer metastasis. (c) 2004 Wiley-Liss, Inc.