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Biomedical subjects

M Lee

Publications and source records attributed to M Lee.

At least 19 recordsLinked to original sources
PubMed2006

Changes in the levels of interferon-gamma and transforming growth factor-beta influence bronchial stenosis during the treatment of endobronchial tuberculosis.

BACKGROUND: Endobronchial tuberculosis (EBTB) has been shown to frequently complicate bronchial stenosis, a condition which can induce dyspnea as a result of airway obstruction, and is also frequently misdiagnosed as either bronchial asthma or lung cancer. OBJECTIVES: This study attempted to determine whether there was a correlation between interferon-gamma (IFN-gamma) and transforming growth factor-beta (TGF-beta) levels in the serum and bronchial washing fluid (BWF), and the results of the treatment of EBTB patients. METHODS: Thirty patients, all of whom were diagnosed as EBTB, were enrolled, as were 10 healthy control subjects. IFN-gamma and TGF-beta levels were measured by the ELISA method in the serum and BWF of these 30 EBTB patients before and after treatment. The EBTB patients were divided into two groups: those who exhibited bronchial stenosis after treatment and those who did not. Chest computed tomography (CT) and pulmonary function test (PFT) were performed in 16 and 25 patients, respectively, at initial bronchoscopy. RESULTS: IFN-gamma and TGF-beta levels in the BWF of the EBTB patients were elevated compared to the controls (p < 0.05). After 2 months of treatment, 13 of the 30 EBTB patients exhibited bronchial fibrostenosis and the other 17 cases had recovered without sequelae. In the bronchial stenosis group, the initial serum TGF-beta levels were lower than in the patients without bronchial stenosis (p < 0.05). Moreover, the levels of serum TGF-beta after treatment were shown to have decreased more than in the patients without bronchial stenosis (p < 0.05). On chest CT findings of 16 EBTB patients, bronchial narrowing was suspected except in 2 cases (1 edematous-hyperemic type, 1 actively caseating type of segmental bronchus). The common features of PFT in EBTB at the initial diagnosis were a restrictive pattern and normal ventilatory function. CONCLUSIONS: Elevated IFN-gamma and TGF-beta levels in the BWF of the EBTB patients may be related to EBTB pathogenesis. Lowered initial serum TGF-beta levels as well as the observed changes in the levels of TGF-beta in the serum after treatment have been implicated in bronchial fibrostenosis during the course of the disease.

Adult↗
PubMed2006

Pharmacological inhibitors of NF-kappaB accelerate apoptosis in chronic lymphocytic leukaemia cells.

Nuclear factor-kappaB (NF-kappaB) is a transcription factor that plays a critical role in the inappropriate survival of various types of malignant cells. Chronic lymphocytic leukaemia (CLL) is the most common B-cell malignancy in the Western world. Although overexpression and regulation of NF-kappaB has been described in CLL, its function remains unclear. Exposure of CLL cells to BAY117082 or Kamebakaurin, potent pharmacological inhibitors of the NF-kappaB pathway, accelerated apoptosis in approximately 70% of cases. Sensitivity to NF-kappaB pathway inhibitors was not related to the prognostic markers VH status, CD38 or Zap70 expression, or to the levels of nuclear NF-kappaB. Normal peripheral B cells were resistant to the apoptosis-inducing effects of these compounds. Cell death induced by the inhibitors was associated with activation of caspase-9 and -3, and loss of mitochondrial membrane polarization, but did not involve changes in the expression of Bcl-2 or Mcl-1. Inhibitors caused an increase in c-jun NH2-terminal kinase activity in CLL, but this did not appear to be important for apoptosis. Microarray analysis identified some potential novel NF-kappaB target genes, including interleukin-16- and the Bcl-2- related survival protein Bcl-w. These results demonstrate that a substantial proportion of CLL are dependent on NF-kappaB for enhanced survival and suggest that inhibition of NF-kappaB may have therapeutic potential.

ADP-ribosyl Cyclase 1↗
PubMed2006

Quantitative trait loci for callus initiation and totipotency in maize (Zea mays L.).

Induction of embryogenic callus in culture is an important step in plant transformation procedures, but response is genotype specific and the genetics of the trait are not well understood. Quantitative trait loci (QTL) were mapped in a set of 126 recombinant inbred lines (RILs) of inbred H99 (high Type I callus response) by inbred Mo17 (low Type I callus response) that were evaluated over two years for Type I callus response. QTL were observed in a total of eleven bins on eight chromosomes, including eight QTL with main effects and three epistatic interactions. Many of the QTL were mapped to the same or bordering chromosomal bins as candidate genes for abscisic acid metabolism, indicating a possible role for the hormone in the induction of embryogenic callus, as has previously been indicated in microspore embryo induction. Further examinations of allelic variability for known candidate genes located near the observed QTL could be useful for expanding the understanding of the genetic basis of induction embryogenic callus. The QTL observed herein could also be used in a marker assisted selection (MAS) program to improve the response of agronomically useful inbreds, but only if the resources required for MAS are lower than those required for phenotypic selection.

Chromosome Mapping↗
PubMed2006

Validity of a new automated software program for visceral adipose tissue estimation.

INTRODUCTION: Given the considerable time and research cost of analyzing biomedical images to quantify adipose tissue volumes, automated image analysis methods are highly desirable. Hippo Fat is a new software program designed to automatically quantify adipose tissue areas from magnetic resonance images without user inputs. Hippo Fat has yet to be independently validated against commonly used image analysis software programs. OBJECTIVE: Our aim was to compare estimates of VAT (visceral adipose tissue) and SAT (subcutaneous adipose tissue) using the new Hippo Fat software against those from a widely used, validated, computer-assisted manual method (slice-O-matic version 4.2, Tomovision, Montreal, CA, USA) to assess its potential utility for large-scale studies. METHODS: A Siemens Magnetom Vision 1.5-T whole-body scanner and a T1-weighted fast-spin echo pulse sequence were used to collect multiple, contiguous axial images of the abdomen from a sample of 40 healthy adults (20 men) aged 18-77 years of age, with mean body mass index of 29 kg/m(2) (range=19-43 kg/m(2)). RESULTS: Hippo Fat provided estimates of VAT and SAT that were highly correlated with estimates using slice-O-matic (R (2)>0.9). Average VAT was 9.4% lower and average SAT was 3.7% higher using Hippo Fat compared to slice-O-matic; the overestimation of SAT tended to be greater among individuals with greater adiposity. Individual-level differences for VAT were also substantial; Hippo Fattrade mark gave estimates of VAT ranging from 1184 cm(3) less to 566 cm(3) more than estimates for the same person using slice-O-matic. CONCLUSION: Hippo Fat provides a rapid method of quantifying total VAT, although the method does not provide estimates that are interchangeable with slice-O-matic at either the group (mean) or individual level.

Adolescent↗
PubMed2006

Unique and common genetic effects between bone mineral density and calcaneal quantitative ultrasound measures: the Fels Longitudinal Study.

INTRODUCTION: Areal bone mineral density (BMD) and calcaneal quantitative ultrasound (QUS) measures are correlated, and both traits predict osteoporotic fracture risk independently. However, few studies have examined whether common genetic effects (i.e., pleiotropy) exist between these traits in extended families. In this study, we estimated the additive genetic correlation and random environmental correlation between BMD measured at various skeletal sites and calcaneal QUS measures. METHODS: Our sample included 537 adults (251 men and 286 women) from 110 families participating in the Fels Longitudinal Study. Total hip, femoral neck, lumbar spine, and total body BMD were measured using dual energy X-ray absorptiometry. Three measures of calcaneal structure--broadband ultrasound attenuation (BUA), speed of sound (SOS), and quantitative ultrasound index (QUI)--were collected from the non-dominant heel using the Sahara sonometer. Applying a variance components-based maximum likelihood method, we estimated the heritability of each trait and estimated the genetic and environmental correlations between the different BMD and QUS measures. RESULTS: Heritability estimates were significant for all measures of BMD and QUS ranging from 0.55 to 0.78. Significant non-zero genetic correlations were found between the different BMD and QUS measures. All genetic correlations were also significantly different from 1. Genetic correlations between total hip BMD and each of the QUS measures were 0.63 with BUA, 0.50 with SOS, and 0.56 with QUI. For femoral neck BMD, genetic correlations were similar to those between total hip BMD and QUS measures. Genetic correlations between BMD of the lumbar spine and QUS measures ranged from 0.34 to 0.38, and those between total body BMD and QUS measures, from 0.51 to 0.54. In contrast, all random environmental correlations were not significantly different from zero. CONCLUSION: This study demonstrates that BMD and calcaneal QUS measures among healthy men and women are significantly heritable and are, in part, jointly influenced by a common set of underlying genes. Additionally, this study also provides evidence for a unique set of genes that independently influences each individual trait.

Absorptiometry, Photon↗
PubMed2006

Investigation into the impact of couch sag on delivered dose.

The effect of couch sag on treatment delivery accuracy has been investigated by modelling the variation of delivered dose from planned dose due to the difference between the treatment and simulation couches. The couch sag of the Siemens (Concord, USA) Primus linac was determined relative to the couch sag of the Siemens (Germany) Sensation 4 CT Scanner. A phantom planning study was then undertaken to evaluate the likely clinical impact of the couch sag through an evaluation of changes in dose distribution, dose volume histograms and monitor units. The couch sag was simulated by altering the angle of the CT gantry when obtaining image studysets. A second investigation into the effects of couch sag was undertaken using an existing patient CT studyset. For this investigation, the couch sag was simulated by appropriate rotation of the gantry and collimator angles. The effect of couch sag on calculated monitor units (MU) was found to be statistically insignificant. The small monitor unit changes observed were likely to result from differences in the average linear attenuation coefficient along the beam path to the isocentre. The major differences seen however were in the regions away from the central axis. The dose volume histograms showed that both the bladder and rectum were further spared with increasing tilt angle whilst the PTV dose was unchanged. The only issue at South West Sydney Cancer Services (SWSCS) in terms of patient position variation arises from the angle induced by the couch sag (or more precisely, the difference in couch sag angle between the CT and Linac couches). Due to the relatively uniform structures (of PTV, bladder and rectum), and the proximity of these critical structures to the isocentre, this angular rotation about the isocentre did not cause any major variations to the DVH, MU and isodoses for realistic levels of couch sag (i.e. less than 20mm).

Artifacts↗
PubMed2006

Quantitative genetic analysis of blood pressure reactivity to orthostatic tilt using principal components analysis.

Blood pressure (BP) reactivity to orthostatic tilt may be predictive of cardiovascular disease. However, the genetic and environmental influences on BP reactivity to tilt have not been well examined. Identifying different influences on BP at rest and BP during tilt is complicated by the intercorrelation among multiple measurements. In this study, we use principal components analysis (PCA) to reduce multivariate BP data into components that are orthogonal. The objective of this study is to characterize and examine the genetic architecture of BP at rest and during head-up tilt (HUT). Specifically, we estimate the heritability of individual BP measures and three principal components (PC) derived from multiple BP measurements during HUT. Additionally, we estimate covariate effects on these traits. The study sample consisted of 444 individuals, distributed across four large families. HUT consisted of 70 degrees head-up table tilting while strapped to a tilt table. BP reactivity (deltaBP) was defined as BP during HUT minus BP while supine. Three PC extracted from the PCA were interpreted as 'general BP' (PC1), 'pulse pressure' (PC2) and 'BP reactivity' (PC3). Variance components methods were used to estimate the heritabilities of resting BP, HUT BP, deltaBP, as well as the three BP PC. Significant (P<0.05) heritabilities were found for all BP measurements, except for systolic deltaBP at 1 and 3 min, and diastolic deltaBP at 2 min. Significant genetic effects were also found for the three PC. Each of these orthogonal components is significantly influenced by somewhat different sets of covariates.

Adolescent↗
PubMed2006

The pharmacokinetics of coagulation factors.

In this article, we provide a summary of the generally accepted approaches to the design and analysis of studies examining the pharmacokinetic (PK) profile of an infused coagulation factor in patients with a deficiency of one or more of these factors. Furthermore, we briefly review the known PK results for various commercially available coagulation factor preparations under single and continuous infusion.

Blood Coagulation Factors↗
PubMed2006

Enhanced biodegradation of diesel oil by a newly identified Rhodococcus baikonurensis EN3 in the presence of mycolic acid.

AIMS: The aim of the present study was to isolate and characterize a bacterium, strain EN3, capable of using diesel oil as a major carbon and energy source, and to analyse the enhancement of diesel oil degradation by this organism using synthetic mycolic acid (2-hexyl-3-hydroxyldecanoic acid). METHOD AND RESULTS: An actinomycete with the ability to degrade diesel oil was isolated from oil contaminated soil and characterized. The strain had phenotypic properties consistent with its classification in the genus Rhodococcus showing a 16S rRNA gene similarity of 99.7% with Rhodococcus baikonurensis DSM 44587(T). The ability of the characterized strain to degrade diesel oil at various concentrations (1000, 5000, 10 000 and 20 000 mg l(-1)) was determined. The effect of synthetic mycolic acid on the biodegradation of diesel oil was investigated at the 20 000 mg l(-1) concentration; the surfactant was added to the flask cultures at three different concentrations (10, 50 and 100 mg l(-1)) and degradation followed over 7 days. Enhanced degradation was found at all three concentrations of the surfactant. In addition, the enhancement of diesel oil degradation by other surfactants was observed. CONCLUSIONS: The synthetic mycolic acid has potential for the remediation of petroleum-contaminated sites from both an economic and applied perspective as it can stimulate biodegradation at low concentrations. SIGNIFICANCE AND IMPACT OF THE STUDY: This study showed that the synthesized mycolic acid can be used for potential applications in the bioremediation industries, for example, in oil spill clean-up, diesel fuel remediation and biostimulation.

Biodegradation, Environmental↗
PubMed2006

Influence of phenol on the biodegradation of pyridine by freely suspended and immobilized Pseudomonas putida MK1.

AIMS: To study the effect of co-contaminants (phenol) on the biodegradation of pyridine by freely suspended and calcium alginate immobilized bacteria. METHODS AND RESULTS: Varying concentrations of phenol were added to free and calcium alginate immobilized Pseudomonas putida MK1 (KCTC 12283) to examine the effect of this pollutant on pyridine degradation. When the concentration of phenol reached 0.38 g l(-1), pyridine degradation by freely suspended bacteria was inhibited. The increased inhibition with the higher phenol levels was apparent in increased lag times. Pyridine degradation was essentially completely inhibited at 0.5 g l(-1) phenol. However, immobilized cells showed tolerance against 0.5 g l(-1) phenol and pyridine degradation by immobilized cell could be achieved. CONCLUSIONS: This works shows that calcium alginate immobilization of microbial cells can effectively increase the tolerance of P. putida MK1 to phenol and results in increased degradation of pyridine. SIGNIFICANCE AND IMPACT OF THE STUDY: Treatment of wastewater stream can be negatively affected by the presence of co-pollutants. This work demonstrates the potential of calcium alginate immobilization of microbes to protect cells against compound toxicity resulting in an increase in pollutant degradation.

Anti-Bacterial Agents↗
PubMed2006

Screening for lung cancer using low dose CT scanning: results of 2 year follow up.

BACKGROUND: Screening with low dose chest computed tomographic scanning (LDCCT) may improve survival by identifying early asymptomatic lung cancer. METHODS: Four hundred and forty nine high risk subjects were screened with serial LDCCT scanning over 2 years. Fine needle aspiration biopsy was recommended for non-calcified nodules (NCNs) of >10 mm diameter or demonstrating interval growth. RESULTS: NCNs were identified in 111 subjects (24.7%), three of which were lung cancer. The overall prevalence (0.4%) and incidence (1.3%) rates of lung cancer detection were low. Three of the six lung cancers detected in the study were stage 1 non-small cell lung cancer; the remainder were unresectable central tumours. By contrast, eight subjects developed extrathoracic malignancy during the study period and other incidental pathology was noted in 221 subjects (49.2%). Smoking cessation rates at 19% were higher than in the general population, but 60.8% of subjects continued to smoke. CONCLUSION: LDCCT scanning is useful in detecting early peripheral non-small cell lung cancers but its usefulness as a screening tool is limited by low specificity and by poor sensitivity for central tumours.

Aged↗
PubMed2006

Psychological effects of ketamine in healthy volunteers. Phenomenological study.

BACKGROUND: The psychosis-inducing effect of ketamine is important evidence supporting the glutamate hypothesis of schizophrenia. However, the symptoms the drug produces have not been described systematically. AIM: To examine the effects of ketamine in healthy people using a structured psychiatric interview. METHOD: Ketamine (200 ng/ml) or placebo was administered by continuous infusion to 15 healthy volunteers. Symptoms were rated using the Present State Examination, the Thought, Language and Communication Scale and the Scale for Assessment of Negative Symptoms. RESULTS: Ketamine induced a range of perceptual distortions, but not hallucinations. Referential ideas were seen in nearly half the sample. There were only mild and infrequent ratings on the thought disorder scale. Affective flattening and alogia were seen in some volunteers. CONCLUSIONS: Ketamine does not reproduce the full picture of schizophrenia. The main point of similarity concerns referential thinking. Phenomena resembling negative symptoms are also seen, but the distinction of these from the drug's sedative effects requires further elucidation.

Adult↗
PubMed2006

Differential responses of the growth hormone axis in two rat models of streptozotocin-induced insulinopenic diabetes.

The impact of streptozotocin (STZ)-induced, insulinopenic diabetes on the GH axis of rats and mice differs from study to study, where this variation may be related to the induction scheme, severity of the diabetes and/or the genetic background of the animal model used. In order to begin differentiate between these possibilities, we compared the effects of two different STZ induction schemes on the GH axis of male Sprague-Dawley rats: (1) a single high-dose injection of STZ (HI STZ, 80 mg/kg, i.p.), which results in rapid chemical destruction of the pancreatic beta-cells, and (2) multiple low-dose injections of STZ (LO STZ, 20 mg/kg for 5 consecutive days, i.p.), which results in a gradual, autoimmune destruction of beta-cells. STZ-treated animals were killed after 3 weeks of hyperglycemia (>400 mg/dl), and in both paradigms circulating insulin levels were reduced to <40% of vehicle-treated controls. HI STZ-treated rats lost weight, while body weights of LO STZ-treated animals gradually increased over time, similar to vehicle-treated controls. As previously reported, HI STZ resulted in a decrease in circulating GH and IGF-I levels which was associated with a rise in hypothalamic neuropeptide Y (NPY) mRNA (355% of vehicle-treated controls) and a fall in GH-releasing hormone (GHRH) mRNA (45% of vehicle-treated controls) levels. Changes in hypothalamic neuropeptide expression were reflected by an increase in immunoreactive NPY within the arcuate and paraventricular nuclei and a decrease in GHRH immunoreactivity in the arcuate nucleus, as assessed by immunohistochemistry. Consistent with the decline in circulating GH and hypothalamic GHRH, pituitary GH mRNA levels of HI STZ-treated rats were 58% of controls. However, pituitary receptor mRNA levels for GHRH and ghrelin increased and those for somatostatin (sst2, sst3 and sst5) decreased following HI STZ treatment. The impact of LO STZ treatment on the GH axis differed from that observed following HI STZ treatment, despite comparable changes in circulating glucose and insulin. Specifically, LO STZ treatment did suppress circulating IGF-I levels to the same extent as HI STZ treatment; however, the impact on hypothalamic NPY mRNA levels was less dramatic (158% of vehicle-treated controls) where NPY immunoreactivity was increased only within the paraventricular nucleus. Also, there were no changes in circulating GH, hypothalamic GHRH or pituitary receptor expression following LO STZ treatment, with the exception that pituitary sst3 mRNA levels were suppressed compared with vehicle-treated controls. Taken together these results clearly demonstrate that insulinopenia, hyperglycemia and reduced circulating IGF-I levels are not the primary mediators of hypothalamic and pituitary changes in the GH axis of rats following HI STZ treatment. Changes in the GH axis of HI STZ-treated rats were accompanied by weight loss, and these changes are strikingly similar to those observed in the fasted rat, which suggests that factors associated with the catabolic state are critical in modifying the GH axis following STZ-induced diabetes.

Animals↗
PubMed2006

Characteristics of sludge reduction in an integrated pretreatment and aerobic digestion process.

In this study, integrated pretreatments and aerobic digestion processes were investigated in order to provide a feasible alternative that can achieve effective sludge reduction. An ozone treatment in the presence of ionic manganese, a catalyst, increased the sludge reduction ratio three times higher than that of a single ozonation, presumably due to an increase in OH radical production. The ozone treatment yielded the effective sludge reduction ratio with an increasing ozone dosage, and an effective dosage of the catalyst was found to be 4 mg-Mn/g-TS. When a mechanical pretreatment and an ozone/catalyst were applied in a series, the integrated process, even at a half mechanical intensity and a half level of ozone dosage, showed higher and faster sludge reduction than each single process did. In addition, the integrated pretreatment process showed the highest dewaterability of the treated sludges. A ratio of sludge cake generation, which was newly introduced to quantify overall performance of sludge treatment processes, showed that the integrated pretreatment followed by the aerobic digestion yielded approximately a half of the sludge cake volume compared to the single aerobic digestion. Therefore, the integrated pretreatment can be a feasible method for the effective reduction of total suspended solid and the final volume.

Aerobiosis↗
PubMed2005

Isolation of C15: a novel antibody generated by phage display against mesenchymal stem cell-enriched fractions of adult human marrow.

Adult bone marrow stroma contains a source of mesenchymal stem cells (MSC) that have the capacity to self-renew and differentiate into multiple stromal lineages. These rare cells can be visualised indirectly by the formation of heterogeneous colonies, containing stem cells and their differentiated progeny in long-term culture. If MSC and their associated progenitor and precursor populations are to reach their full therapeutic potential, markers will be required to identify and characterize specific bone marrow stromal subsets. We sought to use phage display to generate antibodies against bone marrow mononuclear cells (BMMNC) enriched for colony forming cells. Initially, we identified our target cell population by comparing the colony forming efficiency (CFE) of CD49a-positive, STRO-1-positive and CD45-negative BMMNC subpopulations with unseparated BMMNC. Selection with anti-CD49a gave the greatest enrichment (19-fold) of colony forming cells and in light of these findings, we generated phage antibodies against CD49a-positive BMMNC by simultaneous positive/negative selection. A dominant clone (C15), generated after 3 rounds of selection, has been isolated and sequenced, then characterized for cell and tissue specificity. Sequence analysis showed that the V(H) and V(L) gene segments of C15 aligned most closely to the VH26/DP-47 and IGLV3S1/DPL16 germline V segments found in the synthetic repertoire. C15 bound to 4% of freshly isolated BMMNC and localized to osteoblastic cells and proximal marrow cells in areas of active bone formation in sections of osteophyte. C15 binding was upregulated in cultured bone marrow stromal cells (BMSC) and was also detected on bone-derived cell lines. This report demonstrates that phage display is a powerful tool for the isolation of antibodies against rare cell populations, and provides a platform for the future application of this technology in the search for antigens on MSC and other rare cell populations.

Adult↗
PubMed2005

Quantitative trait loci for cell wall components in recombinant inbred lines of maize (Zea mays L.) II: leaf sheath tissue.

While maize silage is a significant feed component in animal production operations, little information is available on the genetic bases of fiber and lignin concentrations in maize, which are negatively correlated with digestibility. Fiber is composed largely of cellulose, hemicellulose and lignin, which are the primary components of plant cell walls. Variability for these traits in maize germplasm has been reported, but the sources of the variation and the relationships between these traits in different tissues are not well understood. In this study, 191 recombinant inbred lines of B73 (low-intermediate levels of cell wall components, CWCs) x De811 (high levels of CWCs) were analyzed for quantitative trait loci (QTL) associated with CWCs in the leaf sheath. Samples were harvested from plots at two locations in 1998 and one in 1999 and assayed for neutral detergent fiber (NDF), acid detergent fiber (ADF) and acid detergent lignin (ADL). QTL were detected on all ten chromosomes, most in tissue specific clusters in concordance with the high genotypic correlations for CWCs within the same tissue. Adjustment of NDF for its subfraction, ADF, revealed that most of the genetic variation in NDF was probably due to variation in ADF. The low to moderate genotypic correlations for the same CWC across leaf sheath and stalk tissues indicate that some genes for CWCs may only be expressed in certain tissues. Many of the QTL herein were detected in other populations, and some are linked to candidate genes for cell wall carbohydrate biosynthesis.

Breeding↗
PubMed2005

The retinoid anticancer signal: mechanisms of target gene regulation.

Retinoids induce growth arrest, differentiation, and cell death in many cancer cell types. One factor determining the sensitivity or resistance to the retinoid anticancer signal is the transcriptional response of retinoid-regulated target genes in cancer cells. We used cDNA microarray to identify 31 retinoid-regulated target genes shared by two retinoid-sensitive neuroblastoma cell lines, and then sought to determine the relevance of the target gene responses to the retinoid anticancer signal. The pattern of retinoid responsiveness for six of 13 target genes (RARbeta2, CYP26A1, CRBP1, RGS16, DUSP6, EGR1) correlated with phenotypic retinoid sensitivity, across a panel of retinoid-sensitive or -resistant lung and breast cancer cell lines. Retinoid treatment of MYCN transgenic mice bearing neuroblastoma altered the expression of five of nine target genes examined (RARbeta2, CYP26A1, CRBP1, DUSP6, PLAT) in neuroblastoma tumour tissue in vivo. In retinoid-sensitive neuroblastoma, lung and breast cancer cell lines, direct inhibition of retinoid-induced RARbeta2 expression blocked induction of only one of eight retinoid target genes (CYP26A1). DNA demethylation, histone acetylation, and exogenous overexpression of RARbeta2 partially restored retinoid-responsive CYP26A1 expression in RA-resistant MDA-MB-231 breast, but not SK-MES-1 lung, cancer cells. Combined, rather than individual, inhibition of DUSP6 and RGS16 was required to block retinoid-induced growth inhibition in neuroblastoma cells, through phosphorylation of extracellular-signal-regulated kinase. In conclusion, sensitivity to the retinoid anticancer signal is determined in part by the transcriptional response of key retinoid-regulated target genes, such as RARbeta2, DUSP6, and RGS16.

Animals↗