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141.
Powell NA Kohrt JT Filipski KJ Kaufman M Sheehan D Edmunds JE Delaney A Wang Y Bourbonais F Lee DY Schwende F Sun F McConnell P Catana C Chen H Ohren J Perrin LA 《Bioorganic & medicinal chemistry letters》2012,22(1):190-193
We report the discovery of a novel series of spiroindoline-based inhibitors of Sky kinase that bind in the ATP-binding site and exhibit high levels of kinome selectivity through filling the Ala571-subpocket. These inhibitors exhibit moderate oral bioavailability in the rat due to low absorption across the gut wall. 相似文献
142.
Zanzonico P 《Radiation research》2012,177(4):349-364
The underlying principles of nuclear medicine imaging involve the use of unsealed sources of radioactivity in the form of radiopharmaceuticals. The ionizing radiations that accompany the decay of the administered radioactivity can be quantitatively detected, measured, and imaged in vivo with instruments such as gamma cameras. This paper reviews the design and operating principles, as well as the capabilities and limitations, of instruments used clinically and preclinically for in vivo radionuclide imaging. These include gamma cameras, single-photon emission computed tomography (SPECT) scanners, and positron emission tomography (PET) scanners. The technical basis of autoradiography is reviewed as well. 相似文献
143.
Peter M Szabó Miklós Pintér Diana Rita Szabó Adrienn Zsippai Attila Patócs András Falus Károly Rácz Peter Igaz 《BMC medical genomics》2012,5(1):1-19
Background
Pheochromocytoma and neuroblastoma are the most common neural crest-derived tumors in adults and children, respectively. We have performed a large-scale in silico analysis of altogether 1784 neuroblastoma and 531 pheochromocytoma samples to establish similarities and differences using analysis of mRNA and microRNA expression, chromosome aberrations and a novel bioinformatics analysis based on cooperative game theory.Methods
Datasets obtained from Gene Expression Omnibus and ArrayExpress have been subjected to a complex bioinformatics analysis using GeneSpring, Gene Set Enrichment Analysis, Ingenuity Pathway Analysis and own software.Results
Comparison of neuroblastoma and pheochromocytoma with other tumors revealed the overexpression of genes involved in development of noradrenergic cells. Among these, the significance of paired-like homeobox 2b in pheochromocytoma has not been reported previously. The analysis of similar expression patterns in neuroblastoma and pheochromocytoma revealed the same anti-apoptotic strategies in these tumors. Cancer regulation by stathmin turned out to be the major difference between pheochromocytoma and neuroblastoma. Underexpression of genes involved in neuronal cell-cell interactions was observed in unfavorable neuroblastoma. By the comparison of hypoxia- and Ras-associated pheochromocytoma, we have found that enhanced insulin like growth factor 1 signaling may be responsible for the activation of Src homology 2 domain containing transforming protein 1, the main co-factor of RET. Hypoxia induced factor 1?? and vascular endothelial growth factor signaling included the most prominent gene expression changes between von Hippel-Lindau- and multiple endocrine neoplasia type 2A-associated pheochromocytoma.Conclusions
These pathways include previously undescribed pathomechanisms of neuroblastoma and pheochromocytoma and associated gene products may serve as diagnostic markers and therapeutic targets. 相似文献144.
Devenny JJ Godonis HE Harvey SJ Rooney S Cullen MJ Pelleymounter MA 《Obesity (Silver Spring, Md.)》2012,20(8):1645-1652
Dapagliflozin is a potent and selective sodium glucose cotransporter-2 (SGLT2) inhibitor which promotes urinary glucose excretion and induces weight loss. Since metabolic compensation can offset a negative energy balance, we explored the potential for a compensatory physiological response to the weight loss induced by dapagliflozin. Dapagliflozin was administered (0.5-5 mpk; p.o.) to diet-induced obese (DIO) rats with or without ad libitum access to food for 38 days. Along with inducing urinary glucose excretion, chronic administration of dapagliflozin dose-dependently increased food and water intake relative to vehicle-treated controls. Despite this, it reduced body weight by 4% (relative to controls) at the highest dose. The degree of weight loss was increased by an additional 9% if hyperphagia was prevented by restricting food intake to that of vehicle controls. Neither oxygen consumption (vO2) or the respiratory exchange ratio (RER) were altered by dapagliflozin treatment alone. Animals treated with dapagliflozin and pair-fed to vehicle controls (5 mpk PF-V) showed a reduction in RER and an elevation in nonfasting β-hydroxybutyrate (BHBA) relative to ad libitum-fed 5 mpk counterparts. Fasting BHBA was elevated in the 1 mpk, 5 mpk, and 5 mpk PF-V groups. Serum glucose was reduced in the fasted, but not the unfasted state. Insulin was reduced in the non-fasted state. These data suggest that in rodents, the persistent urinary glucose excretion induced by dapagliflozin was accompanied by compensatory hyperphagia, which attenuated the weight loss induced by SGLT2 inhibition. Therefore, it is possible that dapagliflozin-induced weight loss could be enhanced with dietary intervention. 相似文献
145.
David S Gibson Ji Qiu Eliseo A Mendoza Kristi Barker Madeleine E Rooney Joshua LaBaer 《Arthritis research & therapy》2012,14(2):R77-13
Introduction
Juvenile idiopathic arthritis (JIA) is a heterogeneous disease characterized by chronic joint inflammation of unknown cause in children. JIA is an autoimmune disease and small numbers of autoantibodies have been reported in JIA patients. The identification of antibody markers could improve the existing clinical management of patients.Methods
A pilot study was performed on the application of a high-throughput platform, the nucleic acid programmable protein array (NAPPA), to assess the levels of antibodies present in the systemic circulation and synovial joint of a small cohort of juvenile arthritis patients. Plasma and synovial fluid from 10 JIA patients was screened for antibodies against 768 proteins on NAPPAs.Results
Quantitative reproducibility of NAPPAs was demonstrated with > 0.95 intra-array and inter-array correlations. A strong correlation was also observed for the levels of antibodies between plasma and synovial fluid across the study cohort (r = 0.96). Differences in the levels of 18 antibodies were revealed between sample types across all patients. Patients were segregated into two clinical subtypes with distinct antibody signatures by unsupervised hierarchical cluster analysis.Conclusion
The NAPPAs provide a high-throughput quantitatively reproducible platform to screen for disease-specific autoantibodies at the proteome level on a microscope slide. The strong correlation between the circulating antibody levels and those of the inflamed joint represents a novel finding and provides confidence to use plasma for discovery of autoantibodies in JIA, thus circumventing the challenges associated with joint aspiration. We expect that autoantibody profiling of JIA patients on NAPPAs could yield antibody markers that can act as criteria to stratify patients, predict outcomes and understand disease etiology at the molecular level. 相似文献146.
D Haddad CH Chen S Carlin G Silberhumer NG Chen Q Zhang V Longo SG Carpenter A Mittra J Carson J Au M Gonen PB Zanzonico AA Szalay Y Fong 《PloS one》2012,7(8):e41647
Introduction
Oncolytic viruses show promise for treating cancer. However, to assess therapy and potential toxicity, a noninvasive imaging modality is needed. This study aims to determine the in vivo biodistribution, and imaging and timing characteristics of a vaccinia virus, GLV-1h153, encoding the human sodium iodide symporter (hNIS.Methods
GLV-1h153 was modified from GLV-1h68 to encode the hNIS gene. Timing of cellular uptake of radioiodide 131I in human pancreatic carcinoma cells PANC-1 was assessed using radiouptake assays. Viral biodistribution was determined in nude mice bearing PANC-1 xenografts, and infection in tumors confirmed histologically and optically via Green Fluorescent Protein (GFP) and bioluminescence. Timing characteristics of enhanced radiouptake in xenografts were assessed via 124I-positron emission tomography (PET). Detection of systemic administration of virus was investigated with both 124I-PET and 99m-technecium gamma-scintigraphy.Results
GLV-1h153 successfully facilitated time-dependent intracellular uptake of 131I in PANC-1 cells with a maximum uptake at 24 hours postinfection (P<0.05). In vivo, biodistribution profiles revealed persistence of virus in tumors 5 weeks postinjection at 109 plaque-forming unit (PFU)/gm tissue, with the virus mainly cleared from all other major organs. Tumor infection by GLV-1h153 was confirmed via optical imaging and histology. GLV-1h153 facilitated imaging virus replication in tumors via PET even at 8 hours post radiotracer injection, with a mean %ID/gm of 3.82±0.46 (P<0.05) 2 days after intratumoral administration of virus, confirmed via tissue radiouptake assays. One week post systemic administration, GLV-1h153-infected tumors were detected via 124I-PET and 99m-technecium-scintigraphy.Conclusion
GLV-1h153 is a promising oncolytic agent against pancreatic cancer with a promising biosafety profile. GLV-1h153 facilitated time-dependent hNIS-specific radiouptake in pancreatic cancer cells, facilitating detection by PET with both intratumoral and systemic administration. Therefore, GLV-1h153 is a promising candidate for the noninvasive imaging of virotherapy and warrants further study into longterm monitoring of virotherapy and potential radiocombination therapies with this treatment and imaging modality. 相似文献147.
Eleanor M. Donnelly Nicolas N. Madigan Gemma E. Rooney Andrew Knight Bingkun Chen Bret Ball Lisa Kinnavane Yolanda Garcia Peter Dockery John Fraher Padraig M. Strappe Anthony J. Windebank Timothy O'Brien Siobhan S. McMahon 《Cytotherapy》2012,14(10):1235-1244
Background aimsIn this study we investigated the effect of neurotrophin-3 (NT-3) and knockdown of NG2, one of the main inhibitory chondroitin sulfate proteoglycans (CSPG), in the glial scar following spinal cord injury (SCI).MethodsShort hairpin (sh) RNA were designed to target NG2 and were cloned into a lentiviral vector (LV). A LV was also constructed containing NT-3. LV expressing NT-3, shRNA to NG2 or combinations of both vectors were injected directly into contused rat spinal cords 1 week post-injury. Six weeks post-injection of LV, spinal cords were examined by histology for changes in scar size and by immunohistochemistry for changes in expression of CSPG, NT-3, astrocytes, neurons and microglia/macrophages. Motor function was assessed using the Basso, Beattie and Bresnahan (BBB) locomotor scale.ResultsAnimals that received the combination treatment of LV shNG2 and LV NT-3 showed reduced scar size. These animals also showed an increase in levels of neurons and NG2, a decrease in levels of astrocytes and a significant functional recovery as assessed using the BBB locomotor scale at 2 weeks post-treatment.ConclusionsThe improvement in locomotor recovery and decrease in scar size shows the potential of this gene therapy approach as a therapeutic treatment for SCI. 相似文献
148.
Isabella Maiellaro Konstantinos Lefkimmiatis Mary Pat Moyer Silvana Curci Aldebaran M. Hofer 《Journal of cellular and molecular medicine》2012,16(11):2715-2725
Diverse pathophysiological processes (e.g. obesity, lifespan determination, addiction and male fertility) have been linked to the expression of specific isoforms of the adenylyl cyclases (AC1‐AC10), the enzymes that generate cyclic AMP (cAMP). Our laboratory recently discovered a new mode of cAMP production, prominent in certain cell types, that is stimulated by any manoeuvre causing reduction of free [Ca2+] within the lumen of the endoplasmic reticulum (ER) calcium store. Activation of this ‘store‐operated’ pathway requires the ER Ca2+ sensor, STIM1, but the identity of the enzymes responsible for cAMP production and how this process is regulated is unknown. Here, we used sensitive FRET‐based sensors for cAMP in single cells combined with silencing and overexpression approaches to show that store‐operated cAMP production occurred preferentially via the isoform AC3 in NCM460 colonic epithelial cells. Ca2+ entry via the plasma membrane Ca2+ channel, Orai1, suppressed cAMP production, independent of store refilling. These findings are an important first step towards defining the functional significance and to identify the protein composition of this novel Ca2+/cAMP crosstalk system. 相似文献
149.
150.