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151.
Avadhut D. Joshi Watcharin Loilome I-Mei Siu Betty Tyler Gary L. Gallia Gregory J. Riggins 《PloS one》2012,7(10)
Glioblastoma multiforme (GBM) is the most common intracranial cancer but despite recent advances in therapy the overall survival remains about 20 months. Whole genome exon sequencing studies implicate mutations in the receptor tyrosine kinase pathways (RTK) for driving tumor growth in over 80% of GBMs. In spite of various RTKs being mutated or altered in the majority of GBMs, clinical studies have not been able to demonstrate efficacy of molecular targeted therapies using tyrosine kinase inhibitors in GBMs. Activation of multiple downstream signaling pathways has been implicated as a possible means by which inhibition of a single RTK has been ineffective in GBM. In this study, we sought a combination of approved drugs that would inhibit in vitro and in vivo growth of GBM oncospheres. A combination consisting of gefitinib and sunitinib acted synergistically in inhibiting growth of GBM oncospheres in vitro. Sunitinib was the only RTK inhibitor that could induce apoptosis in GBM cells. However, the in vivo efficacy testing of the gefitinib and sunitinib combination in an EGFR amplified/ PTEN wild type GBM xenograft model revealed that gefitinib alone could significantly improve survival in animals whereas sunitinib did not show any survival benefit. Subsequent testing of the same drug combination in a different syngeneic glioma model that lacked EGFR amplification but was more susceptible to sunitinib in vitro demonstrated no survival benefit when treated with gefitinib or sunitinib or the gefitinib and sunitinib combination. Although a modest survival benefit was obtained in one of two animal models with EGFR amplification due to gefitinib alone, the addition of sunitinib, to test our best in vitro combination therapy, did not translate to any additional in vivo benefit. Improved targeted therapies, with drug properties favorable to intracranial tumors, are likely required to form effective drug combinations for GBM. 相似文献
152.
153.
Liu YZ Wilson SG Wang L Liu XG Guo YF Li J Yan H Deloukas P Soranzo N Chinappen-Horsley U Chinnapen-Horsley U Cervino A Cervino A Williams FM Xiong DH Zhang YP Jin TB Levy S Papasian CJ Drees BM Hamilton JJ Recker RR Spector TD Deng HW 《PloS one》2008,3(9):e3160
Osteoporosis, the most prevalent metabolic bone disease among older people, increases risk for low trauma hip fractures (HF) that are associated with high morbidity and mortality. Hip bone size (BS) has been identified as one of the key measurable risk factors for HF. Although hip BS is highly genetically determined, genetic factors underlying the trait are still poorly defined. Here, we performed the first genome-wide association study (GWAS) of hip BS interrogating approximately 380,000 SNPs on the Affymetrix platform in 1,000 homogeneous unrelated Caucasian subjects, including 501 females and 499 males. We identified a gene, PLCL1 (phospholipase c-like 1), that had four SNPs associated with hip BS at, or approaching, a genome-wide significance level in our female subjects; the most significant SNP, rs7595412, achieved a p value of 3.72x10(-7). The gene's importance to hip BS was replicated using the Illumina genotyping platform in an independent UK cohort containing 1,216 Caucasian females. Two SNPs of the PLCL1 gene, rs892515 and rs9789480, surrounded by the four SNPs identified in our GWAS, achieved p values of 8.62x10(-3) and 2.44x10(-3), respectively, for association with hip BS. Imputation analyses on our GWAS and the UK samples further confirmed the replication signals; eight SNPs of the gene achieved combined imputed p values<10(-5) in the two samples. The PLCL1 gene's relevance to HF was also observed in a Chinese sample containing 403 females, including 266 with HF and 177 control subjects. A SNP of the PLCL1 gene, rs3771362 that is only approximately 0.6 kb apart from the most significant SNP detected in our GWAS (rs7595412), achieved a p value of 7.66x10(-3) (odds ratio = 0.26) for association with HF. Additional biological support for the role of PLCL1 in BS comes from previous demonstrations that the PLCL1 protein inhibits IP3 (inositol 1,4,5-trisphosphate)-mediated calcium signaling, an important pathway regulating mechanical sensing of bone cells. Our findings suggest that PLCL1 is a novel gene associated with variation in hip BS, and provide new insights into the pathogenesis of HF. 相似文献
154.
Doukas J Mahesh S Umeda N Kachi S Akiyama H Yokoi K Cao J Chen Z Dellamary L Tam B Racanelli-Layton A Hood J Martin M Noronha G Soll R Campochiaro PA 《Journal of cellular physiology》2008,216(1):29-37
Age-related macular degeneration, diabetic retinopathy, and retinal vein occlusions are complicated by neovascularization and macular edema. Multi-targeted kinase inhibitors that inhibit select growth factor receptor tyrosine kinases and/or components of their down-stream signaling cascades (such as Src kinases) are rationale treatment strategies for these disease processes. We describe the discovery and characterization of two such agents. TG100572, which inhibits Src kinases and selected receptor tyrosine kinases, induced apoptosis of proliferating endothelial cells in vitro. Systemic delivery of TG100572 in a murine model of laser-induced choroidal neovascularization (CNV) caused significant suppression of CNV, but with an associated weight loss suggestive of systemic toxicity. To minimize systemic exposure, topical delivery of TG100572 to the cornea was explored, and while substantial levels of TG100572 were achieved in the retina and choroid, superior exposure levels were achieved using TG100801, an inactive prodrug that generates TG100572 by de-esterification. Neither TG100801 nor TG100572 were detectable in plasma following topical delivery of TG100801, and adverse safety signals (such as weight loss) were not observed even with prolonged dosing schedules. Topical TG100801 significantly suppressed laser-induced CNV in mice, and reduced fluorescein leakage from the vasculature and retinal thickening measured by optical coherence tomography in a rat model of retinal vein occlusion. These data suggest that TG100801 may provide a new topically applied treatment approach for ocular neovascularization and retinal edema. 相似文献
155.
156.
Pat B Killingsworth C Denney T Zheng J Powell P Tillson M Dillon AR Dell'Italia LJ 《American journal of physiology. Heart and circulatory physiology》2008,295(6):H2321-H2327
The low-pressure volume overload of isolated mitral regurgitation (MR) is associated with increased adrenergic drive, left ventricular (LV) dilatation, and loss of interstitial collagen. We tested the hypothesis that beta1-adrenergic receptor blockade (beta1-RB) would attenuate LV remodeling after 4 mo of MR in the dog. beta1-RB did not attenuate collagen loss or the increase in LV mass in MR dogs. Using MRI and three-dimensional (3-D) analysis, there was a 70% increase in the LV end-diastolic (LVED) volume-to-LV mass ratio, a 23% decrease in LVED midwall circumferential curvature, and a >50% increase in LVED 3-D radius/wall thickness in MR dogs that was not attenuated by beta1-RB. However, beta1-RB caused a significant increase in LVED length from the base to apex compared with untreated MR dogs. This was associated with an increase in isolated cardiomyocyte length (171+/-5 microm, P<0.05) compared with normal (156+/-3 microm) and MR (165+/-4 microm) dogs. Isolated cardiomyocyte fractional shortening was significantly depressed in MR dogs compared with normal dogs (3.73+/-0.31 vs. 5.02+/-0.26%, P<0.05) and normalized with beta1-RB (4.73+/-0.48%). In addition, stimulation with the beta-adrenergic receptor agonist isoproterenol (25 nM) increased cardiomyocyte fractional shortening by 215% (P<0.05) in beta1-RB dogs compared with normal (56%) and MR (50%) dogs. In summary, beta1-RB improved LV cardiomyocyte function and beta-adrenergic receptor responsiveness despite further cell elongation. The failure to attenuate LV remodeling associated with MR could be due to a failure to improve ultrastructural changes in extracellular matrix organization. 相似文献
157.
Mouse heart valve structure and function: echocardiographic and morphometric analyses from the fetus through the aged adult 总被引:1,自引:0,他引:1
Hinton RB Alfieri CM Witt SA Glascock BJ Khoury PR Benson DW Yutzey KE 《American journal of physiology. Heart and circulatory physiology》2008,294(6):H2480-H2488
The purpose of this study is to provide standard echocardiographic and morphometric data for normal mouse valve structure and function from late fetal to aged adult stages. Cross-sectional, two-dimensional and Doppler transthoracic echocardiography was performed in C57BL6 mice anesthetized with 1% to 2% isoflurane at embryonic day 18.5 (late fetal), 10 days (neonate), 1 mo (juvenile), 2 mo (young adult), 9 mo (old adult), and 16 mo (aged adult). Normal annulus dimensions indexed to age or weight, and selected flow velocities, were established by echocardiography. After echocardiographic imaging, hearts were harvested and histological and morphometric analyses were performed. Morphometric analysis demonstrated a progressive valve thinning and elongation during the fetal and juvenile stages that plateaued during adult stages (ANOVA, P < 0.01); however, there was increased thickening of the hinge of the aortic valve with advanced age, reminiscent of human aortic valve sclerosis. There was no age-related calcification. The results of this study provide comprehensive echocardiographic and morphometric data for normal mouse valve structure and function from late fetal to aged adult stages and should prove useful as a reference standard for future studies using mouse models of progressive valve disease. 相似文献
158.
橙腹田鼠中延缓性密度依赖效应和种群波动 总被引:1,自引:0,他引:1
LowellL.GETZ LauraE.SIMMS JoyceE.HOFMANN BettyMcGUIRE 《动物学报》2004,50(1):1-8
检验了延迟的密度依赖对橙腹田鼠 (Microtusochrogaster)一个波动种群的生存和生殖的影响 ,研究持续了 63个月 ,取样间隔为 3 5天。在研究期间 ,该种群的密度经历了 4次波动 ,每次波动的高峰都在 11月至次年 1月 ,种群数量在冬季下降。生存和生殖都有负面的密度依赖效应 ,最大效应具有 2个月的时滞。种群存活率增长对种群密度最大的正面效应具有 2个月的时滞 ,而对与增加生殖则有 3个月的时滞。内部因素和冬季都可能推延对生殖的密度依赖效应 ,但是本文未能检验这些内部因素的影响。季节性影响看来与对生存的延缓性密度依赖效应无关。负面的延缓性密度依赖效应对生存和生殖的净作用可能在于减少、而不是阻止橙腹田鼠种群波动的幅度 相似文献
159.
Effect of nonylphenol on serum testosterone levels and testicular steroidogenic enzyme activity in neonatal, pubertal, and adult rats. 总被引:3,自引:0,他引:3
Elizabeth M Laurenzana Ganesh Balasubramanian Constance Weis Betty Blaydes Retha R Newbold K Barry Delclos 《Chemico-biological interactions》2002,139(1):23-41
Previous dose range-finding studies with nonylphenol (NP) administered to rats in a soy- and alfalfa-free diet showed apparent feminization of several endpoints in male rats at doses of 25 ppm and above. One possible mechanism contributing to these effects is a reduction of testosterone at critical developmental periods. The present study was conducted as an adjunct to a multigeneration study and was designed to examine the effect of NP on testosterone production. Male rats in the F1 and F2 generations were exposed through their dams or directly to various dietary doses of NP (0, 25, 200 and 750 ppm) throughout gestation and until sacrifice at either postnatal day 2 (PND2), PND50, or PND140. Male pups in the F3 generation were examined only on PND2. At PND2, serum testosterone levels were significantly decreased in all groups exposed to NP in the F1 generation, but not in the F2 or F3 generations. The activity of 17alpha-hydroxylase/C17, 20 lyase (P450c17) in PND2 testicular homogenates was not affected by NP treatment. In F1 and F2 PND50 and PND140 rats, NP treatment did not affect serum testosterone levels. The absolute dorsolateral prostate weight was increased in the 200 and 750 ppm dose groups only in the F1 PND50 rats, however, no significant effects were observed in other male reproductive organs. NP treatment did not affect P450c17 activity in microsomes prepared from testes of F1 PND50 or PND140 rats. However, P450c17 activity was significantly decreased in testicular microsomes of F(2) PND50 (200 and 750 ppm dose groups) and PND140 (25, 200, and 750 ppm dose groups) rats. A decrease in testicular beta-nicotinamide adenine dinucleotide phosphate (NADPH) P450 reductase was also observed in all PND50 and PND140 NP-exposed rats of the F1 and F2 generations. The ability of NP to directly inhibit P450c17 activity in vitro at concentrations of 1-100 microM was also demonstrated. These results indicate that NP can inhibit the activity of enzymes involved in testosterone synthesis, but suggest minimal effects on testosterone or testosterone-dependent endpoints via this mechanism. 相似文献
160.
Sukehisa Nagano Margaret Takeda Lan Ma Betty Soliven 《Journal of neurochemistry》2001,77(6):1486-1495
Tumor necrosis factor-alpha and interferon-gamma are pleiotropic cytokines that regulate Schwann cell responses during injury and inflammatory demyelination. We have previously shown that cyclic AMP (cAMP)-elevating agents decrease the demyelination and Wallerian degeneration in experimental allergic neuritis. In this study, we examined the role of cAMP in cytokine-mediated signaling in a spontaneously immortal Schwann cell clone (iSC). We found that tumor necrosis factor-alpha and interferon-gamma exert synergistic inhibitory action on Schwann cell viability via the production of nitric oxide (NO) and ceramide (cer). Furthermore, we found that: (i) NO synthase inhibitors attenuate the cytokine-induced cer accumulation and cell death indicating that NO acts upstream of cer; and (ii) cytokine-induced cell death is decreased in iSCs pretreated continuously for 48-72 h with forskolin, an activator of adenylate cyclase. Although forskolin modulates the phosphorylation of ERKs and Akt, it decreases the susceptibility of iSC to cytokines via a separate mechanism operating after NO induction and before cer accumulation. We propose that the protective effect of cAMP-elevating agents in experimental allergic neuritis may be mediated in part via modulation of Schwann cell responses to cytokines. 相似文献