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Vega K.J.,The University of Oklahoma Health Sciences Center | May R.,The University of Oklahoma Health Sciences Center | Sureban S.M.,The University of Oklahoma Health Sciences Center | Lightfoot S.A.,The University of Oklahoma Health Sciences Center | And 10 more authors.
Journal of Gastroenterology and Hepatology (Australia) | Year: 2012

Background and Aim: In Barrett's esophagus (BE), the normal esophageal squamous epithelium is replaced with a specialized metaplastic columnar epithelium. BE is a premalignant lesion that can progress to esophageal adenocarcinoma (EAC). Currently, there are no early molecular indicators that would predict progression from BE to EAC. As the only permanent residents of the epithelium, stem cells have been implicated in this metaplastic progression. The aim of the present study was to determine the expression of doublecortin and CaM kinase-like-1 (DCAMKL-1) and other putative gastrointestinal stem cell markers in normal esophageal mucosa (NEM), BE, and EAC. Methods: Human NEM, BE, EAC, and multitissue microarrays were analyzed for DCAMKL-1, and immunohistochemically scored based on staining intensity and tissue involvement, with epithelia and stroma scored separately. Total RNA isolated from BE and paired NEM was subjected to real-time reverse-transcription-polymerase chain reaction analysis for DCAMKL-1, leucine-rich repeat-containing G-protein-coupled receptor (LGR5), and Musashi-1 (Msi-1) mRNA expression. Results: DCAMKL-1 was minimally expressed in squamous NEM, but increased in BE (with and without dysplasia) and EAC tissues. In EAC, we found increased stromal DCAMKL-1 staining compared to adjacent epithelia. Within the submucosa of dysplastic BE tissues, an increase in the endothelial cell expression of DCAMKL-1 was observed. Finally, an upregulation of DCAMKL-1, LGR5, and Msi-1 mRNA was seen in BE compared to squamous NEM. Conclusions: In the present study, we report the progressive increase of DCAMKL-1 expression in BE from dysplasia to EAC. Furthermore, there was an increase in putative stem cell markers DCAMKL-1, LGR5, and Msi-1 mRNA. Taken together, these data suggest that the regulation of resident stem cells might play an important role in the progression of BE to EAC. © 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

May R.,The University of Oklahoma Health Sciences Center | Sureban S.M.,The University of Oklahoma Health Sciences Center | Lightfoot S.A.,The University of Oklahoma Health Sciences Center | Hoskins A.B.,The University of Oklahoma Health Sciences Center | And 10 more authors.
American Journal of Physiology - Gastrointestinal and Liver Physiology | Year: 2010

Stem cells are critical in maintaining adult homeostasis and have been proposed to be the origin of many solid tumors, including pancreatic cancer. Here we demonstrate the expression patterns of the putative intestinal stem cell marker DCAMKL-1 in the pancreas of uninjured C57BL/6 mice compared with other pancreatic stem/progenitor cell markers. We then determined the viability of isolated pancreatic stem/progenitor cells in isotransplantation assays following DCAMKL-1 antibody-based cell sorting. Sorted cells were grown in suspension culture and injected into the flanks of athymic nude mice. Here we report that DCAMKL-1 is expressed in the main pancreatic duct epithelia and islets, but not within acinar cells. Coexpression was observed with somatostatin, NGN3, and nestin, but not glucagon or insulin. Isolated DCAMKL-1+ cells formed spheroids in suspension culture and induced nodule formation in isotransplantation assays. Analysis of nodules demonstrated markers of early pancreatic development (PDX-1), glandular epithelium (cytokeratin-14 and Ep-CAM), and isletlike structures (somatostatin and secretin). These data taken together suggest that DCAMKL-1 is a novel putative stem/progenitor marker, can be used to isolate normal pancreatic stem/progenitors, and potentially regenerates pancreatic tissues. This may represent a novel tool for regenerative medicine and a target for anti-stem cell-based therapeutics in pancreatic cancer. Copyright © 2010 the American Physiological Society.

Sureban S.M.,The University of Oklahoma Health Sciences Center | May R.,The University of Oklahoma Health Sciences Center | Lightfoot S.A.,The University of Oklahoma Health Sciences Center | Hoskins A.B.,The University of Oklahoma Health Sciences Center | And 12 more authors.
Cancer Research | Year: 2011

Pancreatic cancer is an exceptionally aggressive disease in great need of more effective therapeutic options. Epithelial-mesenchymal transition (EMT) plays a key role in cancer invasion and metastasis, and there is a gain of stem cell properties during EMT. Here we report increased expression of the putative pancreatic stem cell marker DCAMKL-1 in an established KRAS transgenic mouse model of pancreatic cancer and in human pancreatic adenocarcinoma. Colocalization of DCAMKL-1 with vimentin, a marker of mesenchymal lineage, along with 14-3-3 s was observed within premalignant PanIN lesions that arise in the mouse model. siRNA-mediated knockdown of DCAMKL-1 in human pancreatic cancer cells induced microRNA miR-200a, an EMT inhibitor, along with downregulation of EMT-associated transcription factors ZEB1, ZEB2, Snail, Slug, and Twist. Furthermore, DCAMKL-1 knockdown resulted in downregulation of c-Myc and KRAS through a let-7a microRNA-dependent mechanism, and downregulation of Notch-1 through a miR-144 microRNA-dependent mechanism. These findings illustrate direct regulatory links between DCAMKL-1, microRNAs, and EMT in pancreatic cancer. Moreover, they demonstrate a functional role for DCAMKL-1 in pancreatic cancer. Together, our results rationalize DCAMKL-1 as a therapeutic target for eradicating pancreatic cancers. ©2011 AACR.

Vallianou I.,Aristotle University of Thessaloniki | Peroulis N.,Aristotle University of Thessaloniki | Pantazis P.,ADNA Inc. | Hadzopoulou-Cladaras M.,Aristotle University of Thessaloniki
PLoS ONE | Year: 2011

Background: Central to the pathology of coronary heart disease is the accumulation of lipids, cholesterol and triglycerides, within the intima of arterial blood vessels. The search for drugs to treat dislipidemia, remains a major pharmaceutical focus. In this study, we evaluated the hypolipidemic properties of the essential oil from Chios mastic gum (MGO). Methodology/Principal Findings: The hypolipidemic effect of MGO was investigated in naïve as well as in rats susceptible to detergent-induced hyperlipidemia. Serum cholesterol and triglycerides were determined using commercial kits. HMGCoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase activity was measured in HepG2 cell extracts using a radioactive assay; cellular cholesterol and cholesterol esters were assessed using gas chromatography. MGO administration into naïve rats resulted in a dose-dependent reduction in the constitutive synthesis of serum cholesterol and triglycerides. In hyperlipidemic rats, MGO treatment had also a strong hypolipidemic effect. By testing various components of MGO, we show for the first time that the hypolipidemic action is associated with camphene. Administration of camphene at a dose of 30 mg/gr of body weight in hyperlipidemic rats resulted in a 54.5% reduction of total cholesterol (<0.001), 54% of Low Density Lipoprotein (LDL)-cholesterol (<0.001) and 34.5% of triglycerides (<0.001). Treatment of HepG2 cells with camphene led to a decrease in cellular cholesterol content to the same extend as mevinolin, a known HMG-CoA reductase inhibitor. The hypolipidemic action of camphene is independent of HMG-CoA reductase activity, suggesting that its hypocholesterolemic and hypotriglyceridemic effects are associated with a mechanism of action different than that of statins. Conclusions: Given the critical role that the control of hyperlipidemia plays in cardiovascular disease, the results of our study provide insights into the use of camphene as an alternative lipid lowering agent and merits further evaluation. © 2011 Vallianou et al.

Sureban S.M.,The University of Oklahoma Health Sciences Center | May R.,The University of Oklahoma Health Sciences Center | Mondalek F.G.,Swaasth Inc. | Qu D.,The University of Oklahoma Health Sciences Center | And 7 more authors.
Journal of Nanobiotechnology | Year: 2011

Background: The development of effective drug delivery systems capable of transporting small interfering RNA (siRNA) has been elusive. We have previously reported that colorectal cancer tumor xenograft growth was arrested following treatment with liposomal preparation of siDCAMKL-1. In this report, we have utilized Nanoparticle (NP) technology to deliver DCAMKL-1 specific siRNA to knockdown potential key cancer regulators. In this study, mRNA/miRNA were analyzed using real-time RT-PCR and protein by western blot/immunohistochemistry. siDCAMKL-1 was encapsulated in Poly(lactide-co-glycolide)-based NPs (NP-siDCAMKL-1); Tumor xenografts were generated in nude mice, treated with NP-siDCAMKL-1 and DAPT (γ-secretase inhibitor) alone and in combination. To measure let-7a and miR-144 expression in vitro, HCT116 cells were transfected with plasmids encoding the firefly luciferase gene with let-7a and miR-144 miRNA binding sites in the 3'UTR.Results: Administration of NP-siDCAMKL-1 into HCT116 xenografts resulted in tumor growth arrest, downregulation of proto-oncogene c-Myc and Notch-1 via let-7a and miR-144 miRNA-dependent mechanisms, respectively. A corresponding reduction in let-7a and miR-144 specific luciferase activity was observed in vitro. Moreover, an upregulation of EMT inhibitor miR-200a and downregulation of the EMT-associated transcription factors ZEB1, ZEB2, Snail and Slug were observed in vivo. Lastly, DAPT-mediated inhibition of Notch-1 resulted in HCT116 tumor growth arrest and down regulation of Notch-1 via a miR-144 dependent mechanism.Conclusions: These findings demonstrate that nanoparticle-based delivery of siRNAs directed at critical targets such as DCAMKL-1 may provide a novel approach to treat cancer through the regulation of endogenous miRNAs. © 2011 Sureban et al; licensee BioMed Central Ltd.

Johnson R.P.,Muons, Inc. | Marhauser F.,Muons, Inc. | Bowman C.D.,ADNA Corporation | Vogelaar R.B.,ADNA Corporation
IPAC 2013: Proceedings of the 4th International Particle Accelerator Conference | Year: 2013

The 70,000 tons of US stored spent nuclear fuel (SNF) from conventional nuclear reactors is a resource that could provide all US electrical power for a century. Or, the SNF could provide a great amount of process heat for many applications like producing green diesel fuel from natural gas and renewable carbon. An accelerator system like the SNS at ORNL can generate neutrons to convert SNF into fissile isotopes to provide high temperature heat using technology developed at the ORNL Molten Salt Reactor Experiment. In the Green Energy Multiplier * Subcritical Technology Alternative Reactor (GEM*STAR) [1], the accelerator allows subcritical operation (no Chernobyls), the molten salt fuel allows volatiles to be continuously removed (no Fukushimas), and the SNF does not need to be enriched or reprocessed (to minimize weapons proliferation concerns). The molten salt fuel and the relaxed availability requirements of process heat applications imply that the required accelerator technology is available now. A new opportunity has arisen to use GEM*STAR to reduce the world's inventory of weapons-grade plutonium leaving only remnants that are permanently unusable for nuclear weapons. This could expedite the exploitation of this new technology.

Dimas K.S.,University of Thessaly | Pantazis P.,University of Thessaly | Ramanujam R.,ADNA Inc.
In Vivo | Year: 2012

Chios mastic gum (CMG) is a resin produced by the plant Pistacia lentiscus var. chia. CMG is used to extract the mastic gum essential oil (MGO). CMG and MGO consist of nearly 70 constituents and have demonstrated numerous and diverse biomedical and pharmacological properties including (a) eradication of bacteria and fungi that may cause peptic ulcers, tooth plaque formation and malodor of the mouth and saliva; (b) amelioration or dramatic reduction of symptoms of autoimmune diseases by inhibiting production of pro-inflammatory substances by activated macrophages, production of cytokines by peripheral blood mononuclear cells in patients with active Crohn's disease, and suppression of production of inflammatory cytokines and chemokines in an asthma model in mice; (c) protection of the cardiovascular system by effectively lowering the levels of total serum cholesterol, low-density lipoprotein and triglycerides in rats, and protection of low-density lipoprotein from oxidation in humans; (d) induction of apoptosis in human cancer cells in vitro and extensive inhibition of growth of human tumors xenografted in immunodeficient mice; and (e) improvement of symptoms in patients with functional dyspepsia. Collectively taken, these numerous and diverse medical and pharmaceutical properties of CMG and MGO warrant further research in an effort to enhance specific properties and identify specific constituent(s) that might be associated with each property.

Pantazis P.,ADNA Inc. | Dimas K.,University of Thessaly | Wyche J.H.,Howard University | Anant S.,University of Kansas Medical Center | And 3 more authors.
Methods in Molecular Biology | Year: 2012

Nanoparticles (NPs) formulated using poly (d,l-lactide-co-glycolide) (PLGA), a biodegradable, biocompatible, and clinically approved polymer, have been widely used for targeted drug delivery. Here we provide methods for preparing PLGA NPs that encapsulate small interfering RNA (siRNA). The siRNA NPs are formulated using a double-emulsion solvent evaporation technique with the addition of a small amount of the cationic polymer, polyethyleneimine, which significantly increases siRNA encapsulation. © 2012 Springer Science+Business Media, LLC.

Bowman C.D.,ADNA Corporation | Johnson R.P.,Muons, Inc.
IPAC 2011 - 2nd International Particle Accelerator Conference | Year: 2011

Reactors built using solid fissile materials sealed in fuel rods have an inherent safety problem in that volatile radioactive materials in the rods are accumulated and can be released in dangerous amounts. Accelerator parameters for subcritical reactors that have been considered in recent studies have primarily been based on using solid nuclear fuel much like that used in all operating critical reactors. An attractive alternative reactor design that used molten salts was experimentally studied at ORNL in the 1960s, where a critical molten salt reactor was successfully operated using enriched U235 or U233 tetrafluoride fuels. These experiments give confidence that accelerator-driven subcritical molten salt reactors will work as well or better than conventional reactors since they will have better efficiency due to their higher operating temperature, the inherent safety of subcritical operation, and constant purging of volatile radioactive elements to eliminate their accumulation and potential accidental release in dangerous amounts. Copyright © 2011 by IPAC'11/EPS-AG.

Mondalek F.G.,Swaasth Inc. | Mondalek F.G.,ADNA Inc. | Ponnurangam S.,Swaasth Inc. | Govind J.,Swaasth Inc. | And 6 more authors.
Journal of Nanobiotechnology | Year: 2010

Background: The redox dye, DCPIP, has recently shown to exhibit anti-melanoma activity in vitro and in vivo. On the other hand, there is increasing evidence that synthetic nanoparticles can serve as highly efficient carriers of drugs and vaccines for treatment of various diseases. These nanoparticles have shown to serve as potent tools that can increase the bioavailability of the drug/vaccine by facilitating absorption or conferring sustained and improved release. Here, we describe results on the effects of free- and nanoparticle-enclosed DCPIP as anti-angiogenesis and anti-inflammation agents in a human colon cancer HCT116 cell line in vitro, and in induced angiogenesis in ovo.Results: The studies described in this report indicate that (a) DCPIP inhibits proliferation of HCT116 cells in vitro; (b) DCPIP can selectively downregulate expression of the pro-angiogenesis growth factor, VEGF; (c) DCPIP inhibits activation of the transcriptional nuclear factor, NF-κB; (d) DCPIP can attenuate or completely inhibit VEGF-induced angiogenesis in the chick chorioallantoic membrane; (e) DCPIP at concentrations higher than 6 μg/ml induces apoptosis in HCT116 cells as confirmed by detection of caspase-3 and PARP degradation; and (f) DCPIP encapsulated in nanoparticles is equally or more effective than free DCPIP in exhibiting the aforementioned properties (a-e) in addition to reducing the expression of COX-2, and pro-inflammatory proteins IL-6 and IL-8.Conclusions: We propose that, DCPIP may serve as a potent tool to prevent or disrupt the processes of cell proliferation, tissue angiogenesis and inflammation by directly or indirectly targeting expression of specific cellular factors. We also propose that the activities of DCPIP may be long-lasting and/or enhanced if it is delivered enclosed in specific nanoparticles. © 2010 Mondalek et al; licensee BioMed Central Ltd.

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