Biomedical subjects

Ho-Young Lee

Publications and source records attributed to Ho-Young Lee.

At least 19 recordsLinked to original sources

PubMed2006

Heterodimerization of insulin-like growth factor receptor/epidermal growth factor receptor and induction of survivin expression counteract the antitumor action of erlotinib.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been used to treat non-small cell lung cancer (NSCLC). However, the overall response rate to EGFR TKIs is limited, and the mechanisms mediating resistance to the drugs are poorly understood. Here, we report that insulin-like growth factor-I receptor (IGF-IR) activation interferes with the antitumor activity of erlotinib, an EGFR TKI. Treatment with erlotinib increased the levels of EGFR/IGF-IR heterodimer localized on cell membrane, activated IGF-IR and its downstream signaling mediators, and stimulated mammalian target of rapamycin (mTOR)-mediated de novo protein synthesis of EGFR and survivin in NSCLC cells. Inhibition of IGF-IR activation, suppression of mTOR-mediated protein synthesis, or knockdown of survivin expression abolished resistance to erlotinib and induced apoptosis in NSCLC cells in vitro and in vivo. Our data suggest that enhanced synthesis of survivin protein mediated by the IGFR/EGFR heterodimer counteracts the antitumor action of erlotinib, indicating the needs of integration of IGF-IR-targeted agents to the treatment regimens with EGFR TKI for patients with lung cancer.

Animals↗

PubMed2006

Down-regulation of inhibitor of apoptosis proteins by deguelin selectively induces apoptosis in breast cancer cells.

The identification of differentially regulated apoptotic signals in normal and tumor cells allows the development of cancer cell-selective therapies. Increasing evidence shows that the inhibitor of apoptosis (IAP) proteins survivin and XIAP are highly expressed in tumor cells but are absent or have very low levels of expression in normal adult tissues. We found that inhibiting AKT activity with 10 to 100 nM deguelin, a small molecule derived from natural products, markedly reduced the levels of both survivin and XIAP, inducing apoptosis in human breast cancer cells but not in normal cells. It is noteworthy that we detected an elevated level of cleaved poly(ADP-ribose) polymerase, a signature of caspase activation, without a significant increase in caspase activity in deguelin-treated cancer cells. Our results suggest that severe down-regulation of the IAPs by deguelin releases their inhibitory activity over pre-existing active caspases present in cancer cells, inducing apoptosis without the need for further caspase activation. Because normal cells have very low levels of p-AKT, XIAP, survivin, and pre-existing caspase activity, deguelin had little effect on those cells. In addition, we found that combining deguelin with chemotherapy drugs enhanced drug-induced apoptosis selectively in human tumor cells, which suggests that deguelin has great potential for chemosensitization and could represent a new therapeutic agent for treatment of breast cancer.

Apoptosis↗

PubMed2006

Involvement of mitochondrial and Akt signaling pathways in augmented apoptosis induced by a combination of low doses of celecoxib and N-(4-hydroxyphenyl) retinamide in premalignant human bronchial epithelial cells.

Celecoxib is being evaluated as a chemopreventive agent. However, its mechanism of action is not clear because high doses were used for in vitro studies to obtain antitumor effects. We found that celecoxib inhibited the growth of premalignant and malignant human bronchial epithelial cells with IC(50) values between 8.9 and 32.7 micromol/L, irrespective of cyclooxygenase-2 (COX-2) expression. Normal human bronchial epithelial cells were less sensitive to celecoxib. Because these concentrations were higher than those attainable in vivo (<or=5.6 micromol/L), we surmised that combining celecoxib with the synthetic retinoid N-(4-hydroxyphenyl) retinamide (4HPR) might improve its efficacy. Treatment of premalignant lung cell lines with combinations of clinically relevant concentrations of celecoxib (<or=5 micromol/L) and 4HPR (<or=0.25 micromol/L) resulted in greater growth inhibition, apoptosis induction, and suppression of colony formation than did either agent alone. This combination also decreased the levels of Bcl-2, induced the release of mitochondrial cytochrome c, activated caspase-9 and caspase-3, and induced cleavage of poly(ADP-ribose)polymerase at concentrations at which each agent alone showed no or minimal effects. Furthermore, combinations of celecoxib and 4HPR suppressed the phosphorylation levels of serine/threonine kinase Akt and its substrate glycogen synthase kinase-3beta more effectively than the single agents did. Accordingly, overexpression of constitutively active Akt protected bronchial epithelial cells from undergoing apoptosis after incubation with both celecoxib and 4HPR. These findings indicate that activation of the mitochondrial apoptosis pathway and suppression of the Akt survival pathway mediate the augmented apoptosis and suggest that this combination may be useful for lung cancer chemoprevention.

Anticarcinogenic Agents↗

PubMed2006

Ictal SPECT in neocortical epilepsies: clinical usefulness and factors affecting the pattern of hyperperfusion.

INTRODUCTION: The aims of this analysis were to: (1) determine the value of ictal SPECT in the localization of neocortical epileptogenic foci, (2) evaluate the relationships between the results of ictal SPECT and other potential affecting factors, and (3) compare traditional visual analysis and the subtraction method. METHODS: We retrospectively analyzed 81 consecutive patients with neocortical epilepsy who underwent epilepsy surgery and achieved a favourable surgical outcome, including 36 patients with normal MRI. Side-by-side visual analysis and subtraction images were classified as correctly localizing,correctly lateralizing, or non-localizing/non-lateralizing images according to the resected lobe. RESULTS: Side-by-side visual analysis and subtraction SPECT correctly localized the epileptogenic lobe in 58.9% and 63.0% of patients, respectively. The two methods were complementary and the diagnostic sensitivity of ictal SPECT using the two methods was 79.0%. Ictal SPECT using the visual method correctly localized the epileptogenic lobe more frequently in patients with a localizing pattern of ictal scalp EEG at the time of radioligand injection. When using subtraction images, an injection delay of less than 20 s after seizure onset was significantly correlated with correct localization. The subtraction method was superior to the visual method for localizing frontal lobe epilepsy (FLE) and parietal lobe epilepsy (PLE), and in patients with non-localizing/non-lateralizing EEG at onset. CONCLUSIONS: Ictal SPECT analyses using visual and subtraction methods are useful and complementary for the localization of the epileptogenic foci of neocortical epilepsy. Early radioligand injection and ictal EEG patterns are related to ictal SPECT localization. The subtraction method may be more useful in some epileptic syndromes.

Adolescent↗

PubMed2006

The relationship between regional cerebral blood flow and response to methylphenidate in children with attention-deficit hyperactivity disorder: comparison between non-responders to methylphenidate and responders.

In a sample of children with attention-deficit hyperactivity disorder (ADHD), a voxel based investigation of regional cerebral blood flow (rCBF) during resting state was conducted to identify functional differences between non-responders to methylphenidate (MPH) and responders. Thirty-four children with ADHD were examined by technetium-99m-hexamethylporphylenamine oxime (HMPAO) SPECT. According to clinical response after 8 weeks of treatment with MPH, they were classified as non-responders to MPH and responders. Using SPM analysis, we compared the SPECT images of non-responders to MPH with those of responders. Non-responders to MPH had higher rCBF in the left anterior cingulate cortex, the left claustrum, the right anterior cingulate cortex, and the right putamen relative to responders. In addition, lower rCBF was found in the right superior parietal lobule in non-responders to MPH relative to responders. Further stepwise discriminant analysis revealed that 88.2% could be correctly classified as either non-responders to MPH or responders when considering the extracted rCBF values in the left anterior cingulate cortex, the left claustrum, and the right superior parietal lobule. The current findings suggest that non-responders to MPH may have different patterns of rCBF in brain regions, which have been known as a part of frontal-striatal circuitry and posterior attentional system, respectively.

Attention Deficit Disorder with Hyperactivity↗

PubMed2006

Regional cerebral perfusion abnormalities in developmental language disorder. Statistical parametric mapping analysis.

OBJECTIVE: A voxel based investigation of cerebral blood flow was conducted to identify brain functional differences during resting state between children with developmental language disorder (DLD) and normal controls. METHOD: Using DSM-IV criteria, we selected 21 children with DLD. All children were examined by technetium-99m-HMPAO Brain SPECT. Using SPM analyses, we compared the SPECT images of children with DLD and those of 17 control subjects on a voxel by voxel basis using ANCOVA covarying for age. RESULTS: Reduced cerebral blood flow in the right putamen,the right inferior parietal cortex, and the left globus pallidus were found in children with DLD versus the controls. However, no area of increased cerebral blood flow was observed in children with DLD compared to the controls. CONCLUSION: Though results should be interpreted cautiously, this study confirms the presence of functional defects in the basal ganglia and the inferior parietal lobe during the resting state of the brains of children with DLD. It also gives further evidence for functional deficits in basal ganglia as an important factor in the etiology of DLD.

Age Factors↗

PubMed2006

Properties and cyclic fatigue of glass infiltrated tape cast alumina cores produced using a water-based solvent.

OBJECTIVE: The purpose of this study was to investigate the properties of tape cast alumina composite produced using a water-based solvent and its possible clinical use as an all ceramic crown system in a fixed partial denture. Durability of the system will be measured by fatigue test to simulate the masticating conditions of the oral cavity. METHODS: The optimal weight ratio of water-based alumina tape was determined by tensile strength, shrinkage ratio and durability. The coefficient of thermal expansion, fracture toughness, biaxial flexural strength and flexural strength after fatigue test of a composite produced from alumina tape at optimal weight ratios were determined and compared to In-Ceram alumina core (control). RESULTS: The weight ratio of alumina/(alumina+binder+plasticizer) of 0.84 and binder/(binder+plasticizer) of 0.5 was observed to be the optimal composition for achieving excellent composite properties. Coefficient of thermal expansion of the sintered alumina tape was observed to be 7.3x10(-6)/degrees C, and this value was increased to 7.5x10(-6)/degrees C after infiltrating the sintered tape with glass. The fracture toughness and biaxial flexural strength of glass infiltrated alumina tape was observed to be 4.6 MPa m(1/2) and 498 MPa, respectively. After cyclic loading for 10(2)-10(6) cycles, no significant change in the biaxial flexural strength was observed between the glass infiltrated alumina core and the In-Ceram alumina core (p>0.05). SIGNIFICANCE: The observed properties provide evidence that the water-based tape cast alumina-glass composite is suitable for clinical use as an all ceramic crown system in a fixed partial denture.

Aluminum Oxide↗

PubMed2006

Identification of insulin-like growth factor binding protein-3 as a farnesyl transferase inhibitor SCH66336-induced negative regulator of angiogenesis in head and neck squamous cell carcinoma.

The farnesyl transferase inhibitor (FTI) SCH66336 has been shown to have antitumor activities in head and neck squamous cell carcinoma (HNSCC) in vitro and in vivo. However, its mechanism of action has not been well defined. Here, we report that the insulin-like growth factor (IGF) binding protein (IGFBP)-3 mediates antitumor activities of SCH66336 in HNSCC by inhibiting angiogenesis. SCH66336 significantly suppressed HNSCC tumor growth and angiogenesis via mechanisms that are independent of H-Ras and RhoB. By inducing IGFBP-3 secretion from HNSCC cells, this compound suppresses angiogenic activities of endothelial cells, including vessel formation in chorioallantoic membranes of chick, endothelial cell sprouting from chick aorta, and capillary tube formation of human umbilical vascular endothelial cells (HUVEC). Knockdown of IGFBP-3 expression in HNSCC cells by RNA interference or depletion of IGFBP-3 in HUVECs by neutralizing antibody effectively blocked the effects of IGFBP-3 secreted from SCH66336-treated HNSCC cells on HUVECs. These findings suggest that IGFBP-3 could be a primary target for antitumor activities of FTIs and that IGFBP-3 is an effective therapeutic approach against angiogenesis in HNSCC.

Animals↗

PubMed2006

Antimetastatic activity of insulin-like growth factor binding protein-3 in lung cancer is mediated by insulin-like growth factor-independent urokinase-type plasminogen activator inhibition.

Insulin-like growth factor binding protein-3 (IGFBP-3), a major IGF-binding protein in human serum, regulates the growth of non-small cell lung cancer (NSCLC) cells through IGF-dependent and IGF-independent mechanisms. However, the role of IGFBP-3 in lung cancer metastasis is not well known. In the present study, we showed that noncytotoxic doses of adenoviral or recombinant IGFBP-3 significantly decreased the migration and invasion of H1299 and A549 NSCLC cells. Furthermore, treatment of human lung fibroblasts with recombinant IGFBP-3 suppressed their ability to stimulate the invasion of H1299 cells. Overexpression of IGFBP-3 markedly reduced lung metastasis of A549 cells in an experimental animal model system and prolonged the survival time of the animals. Urokinase-type plasminogen activator (uPA) inhibitor treatment or uPA small interfering RNA transfection of A549 and H1299 cells resulted in a significant decrease in invasion. Corresponding ELISA, Western blot, gelatin zymogram, and semiquantitative reverse transcription-PCR analyses revealed that IGFBP-3 reduced the expression of uPA mRNA through IGF-independent mechanisms. The specific role of uPA in anti-invasive activity of IGFBP-3 was further confirmed in NSCLC cells, in which uPA expression/activity was suppressed by the transfection with synthetic small interfering RNA or by the treatment with uPA inhibitor or induced by the infection with an adenoviral vector. IGFBP-3 also decreased the expression/activity of matrix metalloproteinase-2 through IGF-dependent but uPA-independent pathways. Taken together, our data suggest that IGFPB-3 effectively block uPA- and matrix metalloproteinase-2-stimulated invasion pathways, ultimately reducing lung cancer cell metastasis. Our findings indicate that IGFBP-3 may be a promising anti-invasive and antimetastatic therapeutic agent in lung cancer.

Animals↗

PubMed2006

Lonafarnib in cancer therapy.

Farnesyl transferase inhibitors (FTIs) are anticancer agents that were designed to block the post-translational attachment of the prenyl moiety to C-terminal cysteine residue of Ras and thus inactivate it. Because Ras plays an important role in tumour progression and the ras mutation is one of the most frequent aberrations in cancer, FTIs have been expected to exert excellent therapeutic activities. Phase I and II clinical trials confirmed relevant antitumour activity and low toxicity; however, no improvement in overall survival has been reported in Phase III trials. The exact mechanism of action of this class of agents is currently unknown. Increasing lines of evidence indicate that the cytotoxic actions of FTIs are not due to the inhibition of Ras proteins exclusively, but to the modulation of other targets, including RhoB, the centromere-binding proteins and other proteins that have not yet been identified. This review describes the pharmacological and clinical data as well as mechanisms of action of FTIs, especially lonafarnib (SCH-66336), a non-peptidomimetic inhibitor that has shown anticancer activity.

Animals↗

PubMed2005

Chemopreventive effects of deguelin, a novel Akt inhibitor, on tobacco-induced lung tumorigenesis.

Tobacco carcinogens induce Akt activation and lung carcinogenesis. We previously demonstrated that deguelin, a natural plant product, specifically inhibits the proliferation of premalignant and malignant human bronchial epithelial cells by blocking Akt activation. To evaluate the ability of deguelin to block tobacco carcinogen-induced lung tumorigenesis, we evaluated the in vivo effects of deguelin on Akt activation and lung tumorigenesis in transgenic mice in which Akt expression was induced by tamoxifen and in 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK)/benzo(a)pyrene (BaP)-treated A/J mice. Deguelin suppressed Akt activation in vivo, as measured by immunohistochemistry and immunoblotting, and statistically significantly reduced NNK/BaP-induced lung tumor multiplicity, volume, and load in A/J mice, as monitored by microcomputed tomography image analysis, with no detectable toxicity. These results indicate that deguelin warrants consideration as a chemopreventive agent for early-stage lung carcinogenesis in a clinical lung cancer chemoprevention trial.

Animals↗

PubMed2005

Arsenic trioxide inhibits nuclear receptor function via SEK1/JNK-mediated RXRalpha phosphorylation.

We have previously published that 2 proven treatments for acute promyelocytic leukemia, As2O3 and retinoic acid, can be antagonistic in vitro. We now report that As2O3 inhibits ligand-induced transcription of the retinoic acid receptor, as well as other nuclear receptors that heterodimerize with the retinoid X receptor alpha (RXRalpha). As2O3 did not inhibit transactivation of the estrogen receptor or the glucocorticoid receptor, which do not heterodimerize with RXRalpha. We further show that As2O3 inhibits expression of several target genes of RXRalpha partners. Phosphorylation of RXRalpha has been reported to inhibit nuclear receptor signaling, and we show by in vivo labeling and phosphoamino acid detection that As2O3 phosphorylated RXRalpha in the N-terminal ABC region exclusively on serine residues. Consistent with our previous data implying a role for JNK in As2O3-induced apoptosis, we show that pharmacologic or genetic inhibition of JNK activation decreased As2O3-induced RXRalpha phosphorylation and blocked the effects of As2O3 on RXRalpha-mediated transcription. A mutational analysis indicated that phosphorylation of a specific serine residue, S32, was primarily responsible for inhibition of RXRalpha-mediated transcription. These data may provide some insight into the rational development of chemotherapeutic combinations involving As2O3 as well as into molecular mechanisms of arsenic-induced carcinogenesis resulting from environmental exposure.

Animals↗

PubMed2005

The prognostic role of loss of insulin-like growth factor-binding protein-3 expression in head and neck carcinogenesis.

The activities of insulin-like growth factors (IGFs) in regulating cell proliferation, differentiation, and apoptosis are modulated by a family of high-affinity specific IGF-binding proteins (IGFBPs), IGFBP-3 being the most abundant in circulation. Down-regulation of IGFBP-3 has been shown to be associated with a shorter disease-specific survival probability in early non-small-cell lung cancer (NSCLC). We examined the prognostic role of IGFBP-3 protein expression loss in 34 squamous cell carcinomas (SCC) of the tongue (stages II-IV) and 30 premalignant lesions of the oral cavity and the larynx. Reduced IGFBP-3 expression was found in 11 (32%) of 34 tongue SCC cases, and was associated with significantly shorter disease-specific and disease-free survival (P=0.0002 and <0.0001 by Log-rank test). In premalignant lesions, IGFBP3 loss was found in 8 (27%) of 30 cases without significant association with cancer-free survival. Therefore, down-regulation of IGFBP-3 is an early event during head and neck carcinogenesis, that bears an adverse prognostic significance in tongue cancer and could serve as both a marker of aggressive disease and target for intervention.

Aged↗

PubMed2005

Resistance to epidermal growth factor receptor-targeted therapy.

The epidermal growth factor receptor (EGFR) has been a major target of molecular anticancer therapy. Two approaches have been developed, involving monoclonal antibodies and receptor tyrosine kinase inhibitors, and both have demonstrated benefit in clinical trials. However, evidence of resistance to these drugs has been described. Cellular levels of EGFR do not always correlate with response to the EGFR tyrosine kinase inhibitors, indicating acquired resistance to these drugs. Since EGFR antagonists interfere with the activation of several intracellular pathways that control cell proliferation, survival, apoptosis, angiogenesis, invasion and metastasis, acquired resistance can occur as a result of several different molecular mechanisms: autocrine/paracrine production of ligand, receptor mutation, constitutive activation of the downstream pathway and activation of alternative pathways. We will describe here potential mechanisms that can cause resistance to EGFR-targeted drugs. Combinations of EGFR antagonists with inhibitors targeting different signaling mechanism(s) - such as insulin-like growth factor receptor and vascular endothelial growth factor receptor - that share the same downstream mediator (e.g., phosphatidylinositol 3-kinase/Akt, mitogen-activated protein kinase), may circumvent or delay the development of resistance to EGFR antagonists resulting in enhanced antitumor activities.

Animals↗

PubMed2005

Hypoxia-inducible factor 1alpha and antiangiogenic activity of farnesyltransferase inhibitor SCH66336 in human aerodigestive tract cancer.

BACKGROUND: The farnesyltransferase inhibitor SCH66336, in combination with other receptor tyrosine kinase inhibitors, inhibits the growth of non-small-cell lung cancer (NSCLC) cells. We examined whether SCH66336 inhibits angiogenesis of aerodigestive tract cancer cells. METHODS: Antiangiogenic activities of SCH66336 against NSCLC, head and neck squamous cell carcinoma (HNSCC), and endothelial cells were examined with cell proliferation, capillary tube formation, and chick aorta (under hypoxic, normoxic, insulin-like growth factor I (IGF)-stimulated, and unstimulated conditions); reverse transcription-polymerase chain reaction; and western blot analyses. The specific roles of the ubiquitin-mediated proteasome machinery, mitogen-activated protein kinase (MAPK) and Akt pathways, and heat shock protein 90 (Hsp90) in the SCH66336-mediated degradation of hypoxia-inducible factor 1alpha (HIF-1alpha) were assessed with ubiquitin inhibitors and adenoviral vectors that express constitutively active MAP kinase kinase (MEK)1, constitutively active Akt, or Hsp90. RESULTS: SCH66336 showed antiangiogenic activities and decreased the expression of vascular endothelial cell growth factor (VEGF) and HIF-1alpha in hypoxic, IGF-stimulated, and unstimulated aerodigestive tract cancer and endothelial cells. SCH66336 reduced the half-life of the HIF-1alpha protein, and ubiquitin inhibitors protected the hypoxia- or IGF-stimulated HIF-1alpha protein from SCH66336-mediated degradation. SCH66336 inhibited the interaction between HIF-1alpha and Hsp90. The overexpression of Hsp90, but not constitutive Akt or constitutive MEK, restored HIF-1alpha expression in IGF-stimulated or hypoxic cells but not in unstimulated cells. CONCLUSIONS: SCH66336 appears to inhibit angiogenic activities of NSCLC and HNSCC cells by decreasing hypoxia- or IGF-stimulated HIF-1alpha expression and to inhibit VEGF production by inhibiting the interaction between HIF-1alpha and Hsp90, resulting in the proteasomal degradation of HIF-1alpha.

Alkyl and Aryl Transferases↗

PubMed2005

Response of non-small cell lung cancer cells to the inhibitors of phosphatidylinositol 3-kinase/Akt- and MAPK kinase 4/c-Jun NH2-terminal kinase pathways: an effective therapeutic strategy for lung cancer.

PURPOSE: We previously showed that phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) pathways cooperate to promote non-small cell lung cancer (NSCLC) cell proliferation in vitro. This study was designed to explore whether inhibition of these pathways effectively inhibits NSCLC tumor growth in vivo. EXPERIMENTAL DESIGN: The effects of PI3K/Akt inhibitors {LY294002, adenoviruses expressing dominant-negative mutant of the p85alpha adaptor subunit of PI3K (Ad-dnp85alpha), dominant-negative Akt [Ad-HA-Akt(KM)], or PTEN (Ad-PTEN)}, MKK4/c-jun NH2-terminal kinase (JNK) inhibitor [SP600215, adenovirus expressing dominant-negative MKK4, Ad-MKK4(KR)], and their combinations on proliferation and apoptosis in NSCLC cells were tested in vitro and in vivo using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, a flow cytometry-based terminal deoxynucleotidyl transferase-mediated nick-end labeling assay, Western blot and immunohistochemical analyses, and an NSCLC xenograft tumor model. RESULTS: Ad-dnp85alpha significantly inhibited proliferation of a subset of NSCLC cell lines used in our study. Intratumoral injection of Ad-dnp85alpha induced a significant decrease in the growth of H1299 NSCLC xenograft tumors. Concurrent inhibition of the PI3K/Akt and MKK4/JNK pathways showed enhanced antiproliferative effects on H1299 cells in vitro and in vivo by increasing apoptosis. CONCLUSIONS: PI3K/Akt and MKK4/JNK pathways cooperate to stimulate NSCLC cell proliferation by maintaining cell survival, suggesting that simultaneously targeting these two pathways might be an effective therapeutic strategy against NSCLC.

Adenoviridae↗

PubMed2005

Effects of 9-cis-retinoic acid on the insulin-like growth factor axis in former smokers.

PURPOSE: Insulin-like growth factor (IGF) axis has been associated with the risk of lung cancer. 9-cis-retinoic acid (9-cis-RA) has shown potential chemopreventive activities in former smokers. This study was designed to evaluate the effects of 9-cis-RA on IGF axis in former smokers to identify any benefit the retinoid may have in preventing lung cancer. PATIENTS AND METHODS: Serum concentrations of IGF-I, IGF binding protein (IGFBP)-3, and their molar ratio (IGF-I/IGFBP-3) were measured with radioimmunoassay kits in stored blood samples from the participants of an original chemoprevention trial. The participants had ceased smoking for at least 12 months and were randomly assigned to receive 3 months of daily oral 9-cis-RA (100 mg) or placebo. All statistical tests were two-sided. RESULTS: A total of 111 samples from the study's baseline and 84 samples from the 3 months treatment were analyzed. The serum concentrations of IGF-I and IGF-I/IGFBP-3 at baseline were significantly lower in female than in male participants. After 3 months of treatment, the serum level of IGF-I and IGF-I/IGFBP-3 were significantly lower in the 9-cis-RA group than in the placebo group (P = .03 and P < .01, respectively), but the IGFBP-3 level was significantly higher (P = .03). CONCLUSION: 9-cis-RA treatment modulated the IGF axis in former smokers, suggesting that the IGF axis is a potential target for the chemopreventive activities of 9-cis-RA and that the serum concentrations of IGF, IGFBP-3, and IGF-I/IGFBP-3 could serve as surrogate end point biomarkers of 9-cis-RA treatment.

Adult↗

PubMed2005

Prediction of the clinical outcome of pediatric moyamoya disease with postoperative basal/acetazolamide stress brain perfusion SPECT after revascularization surgery.

BACKGROUND AND PURPOSE: We evaluated whether basal/acetazolamide stress brain perfusion SPECT performed after revascularization surgery can predict the further clinical outcome of patients with pediatric moyamoya disease. METHODS: A total of 77 (31 males, 46 females, age 6.6+/-3.2 years) patients with postoperative pediatric moyamoya disease who underwent basal/acetazolamide stress brain perfusion SPECT 6 to 12 months after revascularization surgery and who were followed-up >12 months after SPECT were included. Mean follow-up period after SPECT was 36+/-19 months. Sixty-two patients underwent bilateral ribbon encephaloduroarteriosynangiosis (EDAS), 14 bilateral EDAS, and 1 unilateral EDAS. Ordinal logistic regression analysis using 5 independent variables (infarction on preoperative MRI, age at the first operation, highest Suzuki stage on cerebral angiography, and regional cerebrovascular reserve on postoperative SPECT) against postoperative clinical outcomes was performed. RESULTS: Fifty-one patients had preserved reserve on postoperative SPECT and their clinical outcomes were excellent (30), good (15), fair (4), and poor (2); 26 patients had decreased reserve (excellent, 1; good, 7; fair, 14; poor, 4). On ordinal logistic regression analysis, age at the first operation (P=0.033) and reserve on postoperative SPECT (P<0.001) were statistically significant. CONCLUSIONS: Basal/acetazolamide stress brain perfusion SPECT performed at 6 to 12 months after the indirect bypass operation could predict the further clinical outcome of pediatric patients with moyamoya disease. Patients with decreased cerebrovascular reserve will have remaining neurological deficit and ischemic attacks on follow-up.

Acetazolamide↗