Biomedical subjects

Z Zhang

Publications and source records attributed to Z Zhang.

At least 19 recordsLinked to original sources

PubMed2026

DNA methylome responses to biotic and abiotic stress in Arabidopsis thaliana: A multi-study analysis.

RATIONALE: Plants experience diverse biotic and abiotic stresses that can induce changes in DNA methylation. However, comparisons among existing studies are complicated by differences in analytical methods and experimental designs. We aimed to identify shared and stress-specific DNA methylation responses across studies. METHODS: We reanalysed 16 whole-genome bisulphite sequencing datasets from 13 Arabidopsis thaliana studies using a unified bioinformatics pipeline. Differentially methylated regions (DMRs) were assessed in the CG, CHG and CHH contexts and examined in relation to genes, transposable elements (TEs), Gene Ontology terms, gene-proximal TE superfamilies and epimutation-prone loci. RESULTS: Global methylation levels were generally stable, whereas the number and genomic distribution of DMRs varied according to stress type and methylation context. CG-DMRs occurred primarily in gene bodies, while CHG- and CHH-DMRs were enriched in TEs. Functional analysis identified shared stress-related processes across conditions. Gene-proximal LINE/L1, RathE1_cons and DNA/HAT elements were enriched for stress-responsive methylation changes. A subset of stress-associated CG-DMRs overlapped loci known to accumulate stable epimutations over generations. CONCLUSIONS: Standardized cross-study analysis revealed both shared and stress-specific methylation patterns. The association of stress-responsive DMRs with gene-proximal TEs and epimutation-prone loci suggests potential links among environmental responses, genome regulation and long-term epigenetic variation.

Arabidopsis thaliana↗

PubMed2007

Hepatitis B virus (HBV) antigen-pulsed monocyte-derived dendritic cells from HBV-associated hepatocellular carcinoma patients significantly enhance specific T cell responses in vitro.

To investigate whether hepatitis B virus (HBV) antigen-pulsed monocyte-derived dendritic cells (MoDC) could mount a T cell response in hepatocellular carcinoma (HCC) patients associated with chronic HBV infection, peripheral blood mononuclear cells (PBMCs) from 36 HBV-associated HCC patients were induced into MoDC and pulsed with hepatitis B core antigen (HBcAg) and hepatitis B surface antigen (HBsAg), alone and in combination. Co-stimulatory molecules CD80, CD86 and CD40, as well as human leucocyte antigens D-related (HLA-DR) were found to express at the highest level on MoDC pulsed with HBcAg or HBsAg + HBcAg, at a median level on MoDC pulsed with HBcAg or HBsAg alone, and at the lowest level on non-antigen-pulsed MoDC. Interleukin (IL)-10 and IL-12 cytokines were released by antigen-pulsed MoDC at increased levels in the order: no-antigen < HBsAg < HBcAg < HBcAg + HBsAg. MoDC pulsed with HBcAg or HBsAg + HBcAg also had the strongest ability to stimulate autologous T cell proliferation and intracellular interferon (IFN)-gamma production. HBcAg- or HBsAg + HBcAg-pulsed MoDC could also induce HBV core peptide-specific CD8(+) T cell proliferation determined by tetramer staining. In addition, the antigen-pulsed MoDC were found to have a stronger capacity to produce IL-12 and induce T cell response in vitro for patients with higher alanine transaminase (ALT) levels than those with lower ALT levels, indicating that antigen pulse could substantially reverse the impaired function of MoDC in primary HCC patients with active chronic hepatitis B. In conclusion, HBV antigen-pulsed MoDC from HCC patients with chronic hepatitis B could induce HBV-specific T cell response in vitro.

Adult↗

PubMed2006

Establishment of stable human fibroblast cell lines constitutively expressing active Rho-GTPases.

Small GTP-binding proteins of the Rho family (RhoA, Cdc42, Rac1) regulate the organisation and the turnover of the cell's cytoskeleton and adhesion structures. A significant function of these cellular structures is to translate and counterbalance forces applied to, or generated by, cells in order to maintain homeostasis and control cell movement. We therefore hypothesised that Rho-GTPases are directly involved in cellular gravity perception and may participate in the alterations induced in microgravity. To define an adequate cellular model allowing to investigate this issue, we have established stable cell lines constitutively expressing active forms of either RhoA, Cdc42, or Rac1. The three cell lines differ by morphology and by their ability to form filopodia, lamellipodia, and bundles of actin stress fibers. Overexpression of the active form of either RhoA, Cdc42, or Rac1 is compatible with cell viability and does not affect cell population doubling time. Thus, our series of mutant cells appear well suited to gain further knowledge on the molecular mechanisms of cellular gravity perception.

Actin Cytoskeleton↗

PubMed2006

The effects of a novel nicotinic receptor antagonist N,N-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB) on acute and repeated nicotine-induced increases in extracellular dopamine in rat nucleus accumbens.

The present study examined the effects of the novel nicotinic acetylcholine receptor (nAChR) antagonist, N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB), after acute and repeated nicotine treatment on extracellular dopamine (DA) levels in rat nucleus accumbens (NAcc), using in vivo microdialysis. Acute nicotine (0.4mg/kg, sc) injection produced an increase (232% of basal) in extracellular DA, which was attenuated by pretreatment with the nAChR antagonist mecamylamine (4mg/kg, sc). Pretreatment with bPiDDB (1 or 3mg/kg, sc) dose-dependently reduced the increase in extracellular DA produced by nicotine (0.4mg/kg, sc), but not by amphetamine (0.5mg/kg, sc). Basal levels of NAcc DA increased in animals that had been pretreated with nicotine (0.4mg/kg, sc) for 5 days compared to saline. In addition, nicotine challenge further increased extracellular DA (237% of basal). The increase in DA in NAcc following repeated nicotine was blocked by pretreatment with mecamylamine (4mg/kg, sc) and bPiDDB (1 or 3mg/kg, sc). These results indicate that bPiDDB likely acts as an antagonist at neuronal nAChRs to inhibit DA release in NAcc after acute or repeated nicotine administration. The ability of bPiDDB to inhibit the effect of nicotine in NAcc, combined with previous studies showing decreased nicotine self-administration in rats provides support for bPiDDB as a potential lead compound for the development of a novel pharmacotherapy for nicotine dependence.

Amphetamine↗

PubMed2006

Technical note: Use of marker-based relationships with multiple-trait derivative-free restricted maximal likelihood.

The widespread use of the set of multiple-trait derivative-free REML programs for prediction of breeding values and estimation of variance components has led to significant improvement in traits of economic importance. The initial version of this software package, however, was generally limited to pedigree-based relationships. With continued advances in genomic research and the increased availability of genotyping, relationships based on molecular markers are obtainable and desirable. The addition of a new program to the set of multiple-trait derivative-free REML programs is described that allows users the flexibility to calculate relationships using standard pedigree files or an arbitrary relationship matrix based on genetic marker information. The strategy behind this modification and its design is described. An application is illustrated in a QTL association study for canine hip dysplasia.

Animals↗

PubMed2006

Imaging water dissociation on TiO2(110): Evidence for inequivalent geminate OH groups.

Identical regions of partially reduced TiO2(110) surfaces with bridge-bonded oxygen vacancy (BBO(V)) concentrations of approximately 10% ML (1 ML = 5.2 x 10(14) cm(-2)) were imaged using scanning tunneling microscopy (STM) before and after dosing H2O at ambient temperature (approximately 300 K). Atomically resolved images confirm that H2O adsorbs dissociatively on the BBO(V) sites, producing two hydroxyl species, one positioned at BBO(V) and denoted OH(V) and the other, denoted OH(B), formed by protonation at either of the two nearest-neighbor bridge-bonded oxygen atoms. Hydrogen hopping along the [001] direction is observed at ambient temperature, with a strong preference for OH(B) (approximately 10x) hydrogen motion. This powerful imbalance demonstrates the inequality of OH(V) and OH(B) and suggests differences in their charge and/or binding configuration.

Journal Article↗

PubMed2006

Source-zone characterization of a chlorinated-solvent contaminated Superfund site in Tucson, AZ.

An extensive site-characterization project was conducted at a large chlorinated-solvent contaminated Superfund site in Tucson, AZ. The project consisted of several components, including traditional site-characterization activities, tracer tests, laboratory experiments conducted with core material collected from the site, and mathematical modeling. The primary focus of the work presented herein is the analysis of induced-gradient contaminant elution tests conducted in a source zone at the site, investigation of the potential occurrence of immiscible liquid in the saturated zone, characterization of the relationship between mass flux reduction and mass removal, and evaluation of the impact of source-zone management on site remediation. The results of the present study, along with those of prior work, indicate that immiscible liquid is likely present in the saturated zone at the site source zones. Extensive tailing and rebound was observed for the contaminant-elution tests, indicating nonideal transport and mass-transfer behavior. The elution data were analyzed with a source-zone-scale mathematical model, and the results indicated that nonideal immiscible-liquid dissolution was the primary cause of the observed behavior. The time-continuous relationship between mass flux reduction and mass removal associated with the plume-scale pump-and-treat operation exhibited an initial large drop in mass flux with minimal mass removed, followed by a period of minimal mass flux reduction and a second period of large reduction. This behavior reflects the impact of both source-zone and aqueous-plume mass removal dynamics. Ultimately, a greater than 90% reduction in mass flux was achieved for a mass removal of approximately 50%. The influence of source-zone management on site remediation was evaluated by conducting two predictive simulations, one for which the source zones were controlled and one for which they were not. A plume-scale model was used to simulate the composite contaminant concentrations associated with groundwater extracted with the pump-and-treat system, which were compared to measured data. The information generated from this study was used to enhance the site conceptual model, help optimize operation of the pump-and-treat system, and evaluate the utility of source-zone remediation.

Arizona↗

PubMed2006

The use of tissue-engineered bone with human bone morphogenetic protein-4-modified bone-marrow stromal cells in repairing mandibular defects in rabbits.

In this study, the capacity of hBMP-4 gene therapy combined with tissue-engineering techniques to improve the repair of mandibular osseous defects in rabbits was explored. A mammalian plasmid vector expressing enhanced green fluorescent protein-human bone morphogenetic protein-4 (pEGFP-hBMP-4) was initially constructed through subcloning techniques. Bone-marrow stromal cells (bMSCs) from New Zealand White rabbits were cultured and either transfected with pEGFP-hBMP-4 or pEGFP, or left untransfected in vitro. Once the transfer efficiency was determined through the expression of EGFP, cells from the three groups were combined with natural non-organic bone (NNB) at a concentration of 50 x 10(6)cells/ml and placed in 15 mm x 6 mm bilateral, full-thickness, mandibular defects surgically made in 12 rabbits. Together with NNB control, there were six samples per group. Four weeks after surgery, the implants were harvested and evaluated histomorphologically. Under optimal experimental conditions, gene transfer efficiency reached a maximum of 38.2+/-9.4%. While the percentage of new bone area in the NNB control group was 8.8+/-3.1%, in the untransfected bMSC group 22.5+/-8.2%, and in the pEGFP group 18.1+/-9.0%, a significantly higher amount of 32.5+/-6.1% was observed in the pEGFP-hBMP-4 group. These results suggest that transfection of bMSCs with hBMP-4 enhances their inherent osteogenic capacity for maxillofacial bone tissue-engineering applications.

Animals↗

PubMed2006

Potent antitumor efficacy of XAF1 delivered by conditionally replicative adenovirus vector via caspase-independent apoptosis.

XAF1 is a newly identified tumor-suppressor gene that can antagonize XIAP and sensitize cells to other cell death triggers. In this study, we utilized ZD55, a conditionally replicative adenovirus (CRAd) similar to ONYX-015 as the vector to transfer XAF1 into the tumor cells to evaluate its antitumor efficacy in vitro and in vivo. Potent and specific cytopathic effect (CPE) was observed upon infection with ZD55-XAF1 in tumor cell lines. Importantly, ZD55-XAF1 exhibited a superior suppression of tumor growth in an animal model of colorectal carcinoma in nude mice compared with Ad-XAF1 (E1-deleted replication-defective viral) and ONYX-015. Complete eradication of the established tumors was observed in four of eight mice. Our data also showed that infection with ZD55-XAF1 resulted in caspase-independent apoptosis. Although caspase-3, poly(ADP-ribose) polymerase were mildly activated in response to ZD55-XAF1 infection, pretreatment with pan-caspase inhibitor hardly influence its apoptosis-inducing activity. In summary, our study strongly suggested that ZD55-XAF1 could serve as an effective gene-virotherapy strategy and has highly potential against human cancers.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Probing spin-flip scattering in ballistic nanosystems.

Because spin-flip length is longer than the electron mean-free path in a metal, past studies of spin-flip scattering are limited to the diffusive regime. We propose to use a magnetic double barrier tunnel junction to study spin-flip scattering in the nanometer sized spacer layer near the ballistic limit. We extract the voltage and temperature dependence of the spin-flip conductance Gs in the spacer layer from magnetoresistance measurements. In addition to spin scattering information including the mean-free path (70 nm) and the spin-flip length (1.0-2.6 microm) at 4.2 K, this technique also yields information on the density of states and quantum well resonance in the spacer layer.

Journal Article↗

PubMed2006

The role of conjugated linoleic acid in reducing body fat and preventing holiday weight gain.

OBJECTIVE: The incidence of obesity and overweight in the US has increased considerably during the past two decades and currently affects 65% of the adult population. Research has indicated that small, yet irreversible, gains during the holiday season contribute to increases in weight during adulthood. Conjugated linoleic acid (CLA), a naturally occurring dietary fatty acid, has been found to reduce weight gain and dramatically decrease fat mass in animals. Although research in humans has shown inconsistent results, most studies have been of insufficient duration or have utilized body composition methods that are less accurate than the currently accepted criterion. DESIGN: Randomized, double-blind, placebo-controlled study of 3.2 g/day CLA for 6 months. SUBJECTS: Forty healthy, overweight subjects (age: 18-44 years; body mass index: 25-30 kg/m(2)). MEASUREMENTS: Body composition by the four-compartment model, resting metabolic rate (RMR) by indirect calorimetry, self-reported physical activity and dietary intake, and blood chemistries were determined at baseline and after 6 months. Body weight was measured monthly during the pre-holiday season (August-October), holiday season (November-December) and post-holiday season (January-March). Adverse events were assessed monthly. RESULTS: Compared to CLA, the placebo group showed a greater rate of weight gain during the holiday season (P=0.01). Within the placebo group, holiday weight change was significantly greater compared to the pre-holiday period (August-October) (P=0.03). Six-month change in body composition was improved with CLA compared to placebo (P=0.02), and body fat was significantly reduced within the CLA group (-1.0+/-2.2 kg, P=0.05). CLA had no effect on RMR, physical activity or dietary intake. The rate of reported negative emotions decreased significantly with CLA, although there was no difference in any other category of adverse event. In comparison to the placebo, CLA did not affect insulin resistance, blood lipids and markers of liver function or markers of inflammation, with the exception of a significant decrease in a biomarker of endothelial dysfunction. CONCLUSION: CLA supplementation among overweight adults significantly reduced body fat over 6 months and prevented weight gain during the holiday season. Although no adverse effects were seen, additional studies should evaluate the effect of prolonged use of CLA.

Adipose Tissue↗

PubMed2006

Quorum sensing and phenazines are involved in biofilm formation by Pseudomonas chlororaphis (aureofaciens) strain 30-84.

The biological control bacterium Pseudomonas chlororaphis (aureofaciens) strain 30-84 employs two quorum sensing (QS) systems: PhzR/PhzI regulates the production of the antibiotics phenazine-1-carboxylic acid, 2-hydroxy-phenazine-1-carboxylic acid, and 2-hydroxy-phenazine, whereas CsaR/CsaI regulates currently unknown aspects of the cell surface. Previously characterized derivatives of strain 30-84 with mutations in each QS system and in the phenazine biosynthetic genes were screened for their ability to form surface-attached biofilm populations in vitro, using microtiter plate and flow cell biofilm assays, and on seeds and roots. Results from in vitro, seed, and root studies demonstrated that the PhzR/PhzI and the CsaR/CsaI QS regulatory systems contribute to the establishment of biofilms, with mutations in PhzR/PhzI having a significantly greater effect than mutations in CsaR/CsaI. Interestingly, phenazine antibiotic production was necessary for biofilm formation to the same extent as the PhzR/PhzI QS system, suggesting the loss of phenazines was responsible for the majority of the biofilm defect in these mutants. In vitro analysis indicated that genetic complementation or AHL addition to the growth medium restored the ability of the AHL synthase phzI mutant to form biofilms. However, only phenazine addition or genetic complementation of the phenazine biosynthetic mutation in trans restored biofilm formation by mutants defective in the transcriptional activator phzR or the phzB structural mutant. QS and phenazine production were also involved in the establishment of surface-attached populations on wheat seeds and plant roots, and, as observed in vitro, the addition of AHL extracts restored the ability of phzI mutants, but not phzR mutants, to form surface attached populations on seeds. Similarly, the presence of the wild type in mixtures with the mutants restored the ability of the mutants to colonize wheat roots, demonstrating that AHL and/or phenazine production by the wild-type population could complement the AHL- and phenazine-deficient mutants in situ. Together, these data demonstrate that both QS systems are involved in the formation of surface-attached populations required for biofilm formation by P. chlororaphis strain 30-84, and indicate a new role for phenazine antibiotics in rhizosphere community development beyond inhibition of other plant-associated microorganisms.

Bacterial Proteins↗

PubMed2006

Single-walled carbon nanotubes-mediated in vivo and in vitro delivery of siRNA into antigen-presenting cells.

Antigen-presenting cells such as dendritic cells (DCs) play a critical role in inducing and regulating immune responses. One effective strategy for DC-based immunotherapy is to regulate maturation and function of DC. In this study, we apply single-walled carbon nanotubes (SWNTs) to carry small interfering RNA (siRNA) to reach, enter and genetically modify DCs in vivo. We prepared positively charged SWNTs (SWNTs+) using 1,6-diaminohexane which was demonstrated by transmission electron microscopy equipped with energy-dispersive X-ray spectroscopy and atomic force microscope. The functionalized SWNTs+ could absorb siRNA to form complexes of siRNA with SWNTs. These siRNA:SWNT+ complexes were preferentially taken up by splenic CD11c+ DCs, CD11b+ cells and also Gr-1+CD11b+ cells comprising DCs, macrophages and other myeloid cells to silence the targeting gene. Suppressor of cytokine signaling 1 (SOCS1) restricts the ability of DCs to break self-tolerance and induce antitumor immunity. Infusion of SWNTs+ carrying SOCS1siRNA reduced SOCS1 expression and retarded the growth of established B16 tumor in mice, indicating the possibility of in vivo immunotherapeutics using SWNTs-based siRNA transfer system.

Animals↗

PubMed2006

Asthma, eczema, and reports on pollen and cat allergy among pupils in Shanxi province, China.

OBJECTIVES: To study self-reported asthma, eczema, and pollen and furry pet allergy among pupils (9-20 years) in Shanxi province, China, in relation to dietary and environmental factors. METHODS: A standardised questionnaire was distributed to pupils in two primary and two secondary schools, one in Taiyuan city (3.0 milj. inhabitants), the others in Qingxu county, a rural area 30 km outside Taiyuan. Totally, 2,116 pupils (90%) participated. RESULTS: Fifty percent were girls, 61% had been growing up on the countryside, 18% lived in Taiyuan now, 1.7% had ever had asthma, 0.8% had doctor's diagnosed asthma, 1.4% pollen allergy, 1.7% cat allergy, and 0% had dog allergy. Multiple logistic regression was applied, controlling for age, gender, diet, indoor exposures, rural childhood, and current urban residency. Girls had less eczema (OR = 0.51; 95%CI 0.28-0.92). Pupils in the city had more eczema (OR = 5.05; 95% CI 1.11-23.3). Those with a rural childhood had less asthma (OR = 0.17; 95% CI 0.05-0.60), eczema (OR = 0.15; 95% CI 0.13-0.66) and pollen/cat allergy (OR = 0.50; 95%CI 0.25-0.99). None of the indoor variables was related to asthma or allergy. Children with frequent fruit consumption had less asthma (OR = 0.40; 95% CI 0.19-0.82) and pollen/cat allergy (OR = 0.49; 95% CI 0.29-0.84). Those with frequent fish consumption had less asthma (OR = 0.32; 95% CI 0.11-0.97). Those with frequent hamburgers consumption had more asthma (OR = 2.05; 95% CI 1.09-3.87) and eczema (OR = 1.85; 95% CI 1.12-3.04). CONCLUSION: Asthma, eczema, and pollen or pet allergy was uncommon, compared with western countries and other areas in China. Pupils with a rural childhood had less asthma and allergy, which is consistent with the "hygiene hypothesis". Fruit and fish consumption may reduce, and fast food consumption may increase the risk for asthma. Finally, the higher prevalence of asthma and eczema among younger children, born in the 1990s, indicates a cohort effect similar to that observed in western countries.

Adolescent↗

PubMed2006

On the use of CCD area detectors for high-resolution specular X-ray reflectivity.

The use and application of charge coupled device (CCD) area detectors for high-resolution specular X-ray reflectivity is discussed. Direct comparison of high-resolution specular X-ray reflectivity data measured with CCD area detectors and traditional X-ray scintillator ('point') detectors demonstrates that the use of CCD detectors leads to a substantial (approximately 30-fold) reduction in data acquisition rates because of the elimination of the need to scan the sample to distinguish signal from background. The angular resolution with a CCD detector is also improved by a factor of approximately 3. The ability to probe the large dynamic range inherent to high-resolution X-ray reflectivity data in the specular reflection geometry was demonstrated with measurements of the orthoclase (001)- and alpha-Al2O3 (012)-water interfaces, with measured reflectivity signals varying by a factor of approximately 10(6) without the use of any beam attenuators. Statistical errors in the reflectivity signal are also derived and directly compared with the repeatability of the measurements.

Equipment Design↗

PubMed2006

Early infiltration of CD8+ macrophages/microglia to lesions of rat traumatic brain injury.

Local inflammatory responses play an important role in mediating secondary tissue damage in traumatic brain injury. Characterization of leukocytic subpopulations contributing to the early infiltration of the damaged tissue might aid in further understanding of lesion development and contribute to definition of cellular targets for selective immunotherapy. In a rat traumatic brain injury model, significant CD8+ cell accumulation was observed 3 days post-injury. The CD8+ cells were strictly distributed to the pannecrotic areas and around the pannecrotic perimeter. The morphology, time course of accumulation and distribution of CD8+ cells were similar to that of reactive ED1+ and endothelial monocyte-activating polypeptide II+ microglia/macrophages, but different from W3/13+ T cells. Further double-labeling experiments confirmed that the major cellular sources of CD8 were reactive macrophages/microglia. Both the location of these CD8+ macrophages/microglia to the border of the pannecrosis and their co-expression of endothelial monocyte-activating polypeptide II and P2X4 receptor suggest they might have a central role in lesion development and might thus be candidates for development of immunotherapeutic, anti-inflammatory strategies.

Animals↗

PubMed2006

Aberrant promoter methylation and silencing of the POU2F3 gene in cervical cancer.

POU2F3 (OCT11, Skn-1a) is a keratinocyte-specific POU transcription factor whose expression is tied to squamous epithelial stratification. It is also a candidate tumor suppressor gene in cervical cancer (CC) because it lies in a critical loss of heterozygosity region on 11q23.3 in that cancer, and its expression is lost in more than 50% of CC tumors and cell lines. We now report that the loss of POU2F3 expression is tied to the hypermethylation of CpG islands in the POU2F3 promoter. Bisulfite sequencing analysis revealed that methylation of specific CpG sites (-287 to -70 bp) correlated with POU2F3 expression, which could be reactivated with a demethylating agent. Combined bisulfite restriction analysis revealed aberrant methylation of the POU2F3 promoter in 18 of 46 (39%) cervical tumors but never in normal epithelium. POU2F3 expression was downregulated and inversely correlated with promoter hypermethylation in 10 out of 11 CC cell lines. Immunohistochemical analysis on a cervical tissue microarray detected POU2F3 protein in the epithelium above the basal layer. As the disease progressed, expression also decreased, especially in invasive squamous cell cancer (70% loss). Thus, aberrant DNA methylation of the CpG island in POU2F3 promoter appears to play a key role in silencing this gene expression in human CC. The results suggested that POU2F3 might be one of the CC-related tumor suppressor genes, which are disrupted by both epigenetic and genetic mechanisms.

Adenocarcinoma↗

PubMed2006

Prevention of lung cancer progression by bexarotene in mouse models.

Bexarotene (Targretin), is a synthetic high-affinity RXR receptor agonist with limited affinity for RAR receptors. Bexarotene has shown efficacy in a phase I/II trial of non-small-cell lung cancers. However, the chemopreventive efficacy of bexarotene has not been determined in mouse lung cancer models. In this study, we have investigated the ability of bexarotene to inhibit lung tumor progression in the mutant A/J mouse models with genetic alterations in p53 or K-ras, two of the most commonly altered genes in human lung tumorigenesis. Mice were administered vinyl carbamate (VC), a carcinogen, by a single intraperitoneal injection (i.p.) at 6 weeks of age. Bexarotene was given by gavage starting at 16 weeks after VC and was continued for 12 weeks. Although all mice developed lung tumors, only 7% of lung tumors were adenocarcinomas in wild-type mice, whereas 22 and 26% of lung tumors were adenocarcinomas in p53 transgenic or K-ras heterozygous deficient mice. Bexarotene inhibited both tumor multiplicity and tumor volume in mice of all three genotypes. Furthermore, bexarotene reduced the progression of adenoma to adenocarcinoma by approximately 50% in both p53(wt/wt)K-ras(ko/wt) and p53(wt/wt)K-ras(wt/wt) mice. Thus, bexarotene appears to be an effective preventive agent against lung tumor growth and progression.

Adenocarcinoma↗