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Search Results: 1 - 10 of 184678 matches for " Richard E. Staub "
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Bezielle Selectively Targets Mitochondria of Cancer Cells to Inhibit Glycolysis and OXPHOS
Vivian Chen, Richard E. Staub, Sylvia Fong, Mary Tagliaferri, Isaac Cohen, Emma Shtivelman
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0030300
Abstract: Bezielle (BZL101) is a candidate oral drug that has shown promising efficacy and excellent safety in the early phase clinical trials for advanced breast cancer. Bezielle is an aqueous extract from the herb Scutellaria barbata. We have reported previously that Bezielle was selectively cytotoxic to cancer cells while sparing non-transformed cells. In tumor, but not in non-transformed cells, Bezielle induced generation of ROS and severe DNA damage followed by hyperactivation of PARP, depletion of the cellular ATP and NAD, and inhibition of glycolysis. We show here that tumor cells' mitochondria are the primary source of reactive oxygen species induced by Bezielle. Treatment with Bezielle induces progressively higher levels of mitochondrial superoxide as well as peroxide-type ROS. Inhibition of mitochondrial respiration prevents generation of both types of ROS and protects cells from Bezielle-induced death. In addition to glycolysis, Bezielle inhibits oxidative phosphorylation in tumor cells and depletes mitochondrial reserve capacity depriving cells of the ability to produce ATP. Tumor cells lacking functional mitochondria maintain glycolytic activity in presence of Bezielle thus supporting the hypothesis that mitochondria are the primary target of Bezielle. The metabolic effects of Bezielle towards normal cells are not significant, in agreement with the low levels of oxidative damage that Bezielle inflicts on them. Bezielle is therefore a drug that selectively targets cancer cell mitochondria, and is distinguished from other such drugs by its ability to induce not only inhibition of OXPHOS but also of glycolysis. This study provides a better understanding of the mechanism of Bezielle's cytotoxicity, and the basis of its selectivity towards cancer cells.
Identification and Analysis of the Active Phytochemicals from the Anti-Cancer Botanical Extract Bezielle
Vivian Chen, Richard E. Staub, Scott Baggett, Ramesh Chimmani, Mary Tagliaferri, Isaac Cohen, Emma Shtivelman
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0030107
Abstract: Bezielle is a botanical extract that has selective anti-tumor activity, and has shown a promising efficacy in the early phases of clinical testing. Bezielle inhibits mitochondrial respiration and induces reactive oxygen species (ROS) in mitochondria of tumor cells but not in non-transformed cells. The generation of high ROS in tumor cells leads to heavy DNA damage and hyper-activation of PARP, followed by the inhibition of glycolysis. Bezielle therefore belongs to a group of drugs that target tumor cell mitochondria, but its cytotoxicity involves inhibition of both cellular energy producing pathways. We found that the cytotoxic activity of the Bezielle extract in vitro co-purified with a defined fraction containing multiple flavonoids. We have isolated several of these Bezielle flavonoids, and examined their possible roles in the selective anti-tumor cytotoxicity of Bezielle. Our results support the hypothesis that a major Scutellaria flavonoid, scutellarein, possesses many if not all of the biologically relevant properties of the total extract. Like Bezielle, scutellarein induced increasing levels of ROS of mitochondrial origin, progressive DNA damage, protein oxidation, depletion of reduced glutathione and ATP, and suppression of both OXPHOS and glycolysis. Like Bezielle, scutellarein was selectively cytotoxic towards cancer cells. Carthamidin, a flavonone found in Bezielle, also induced DNA damage and oxidative cell death. Two well known plant flavonoids, apigenin and luteolin, had limited and not selective cytotoxicity that did not depend on their pro-oxidant activities. We also provide evidence that the cytotoxicity of scutellarein was increased when other Bezielle flavonoids, not necessarily highly cytotoxic or selective on their own, were present. This indicates that the activity of total Bezielle extract might depend on a combination of several different compounds present within it.
Estrogenic Plant Extracts Reverse Weight Gain and Fat Accumulation without Causing Mammary Gland or Uterine Proliferation
Elise F. Saunier, Omar I. Vivar, Andrea Rubenstein, Xiaoyue Zhao, Moshe Olshansky, Scott Baggett, Richard E. Staub, Mary Tagliaferri, Isaac Cohen, Terence P. Speed, John D. Baxter, Dale C. Leitman
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0028333
Abstract: Long-term estrogen deficiency increases the risk of obesity, diabetes and metabolic syndrome in postmenopausal women. Menopausal hormone therapy containing estrogens might prevent these conditions, but its prolonged use increases the risk of breast cancer, as wells as endometrial cancer if used without progestins. Animal studies indicate that beneficial effects of estrogens in adipose tissue and adverse effects on mammary gland and uterus are mediated by estrogen receptor alpha (ERα). One strategy to improve the safety of estrogens to prevent/treat obesity, diabetes and metabolic syndrome is to develop estrogens that act as agonists in adipose tissue, but not in mammary gland and uterus. We considered plant extracts, which have been the source of many pharmaceuticals, as a source of tissue selective estrogens. Extracts from two plants, Glycyrrhiza uralensis (RG) and Pueraria montana var. lobata (RP) bound to ERα, activated ERα responsive reporters, and reversed weight gain and fat accumulation comparable to estradiol in ovariectomized obese mice maintained on a high fat diet. Unlike estradiol, RG and RP did not induce proliferative effects on mammary gland and uterus. Gene expression profiling demonstrated that RG and RP induced estradiol-like regulation of genes in abdominal fat, but not in mammary gland and uterus. The compounds in extracts from RG and RP might constitute a new class of tissue selective estrogens to reverse weight gain, fat accumulation and metabolic syndrome in postmenopausal women.
Drug and Cell Type-Specific Regulation of Genes with Different Classes of Estrogen Receptor β-Selective Agonists
Sreenivasan Paruthiyil, Aleksandra Cvoro, Xiaoyue Zhao, Zhijin Wu, Yunxia Sui, Richard E. Staub, Scott Baggett, Candice B. Herber, Chandi Griffin, Mary Tagliaferri, Heather A. Harris, Isaac Cohen, Leonard F. Bjeldanes, Terence P. Speed, Fred Schaufele, Dale C. Leitman
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0006271
Abstract: Estrogens produce biological effects by interacting with two estrogen receptors, ERα and ERβ. Drugs that selectively target ERα or ERβ might be safer for conditions that have been traditionally treated with non-selective estrogens. Several synthetic and natural ERβ-selective compounds have been identified. One class of ERβ-selective agonists is represented by ERB-041 (WAY-202041) which binds to ERβ much greater than ERα. A second class of ERβ-selective agonists derived from plants include MF101, nyasol and liquiritigenin that bind similarly to both ERs, but only activate transcription with ERβ. Diarylpropionitrile represents a third class of ERβ-selective compounds because its selectivity is due to a combination of greater binding to ERβ and transcriptional activity. However, it is unclear if these three classes of ERβ-selective compounds produce similar biological activities. The goals of these studies were to determine the relative ERβ selectivity and pattern of gene expression of these three classes of ERβ-selective compounds compared to estradiol (E2), which is a non-selective ER agonist. U2OS cells stably transfected with ERα or ERβ were treated with E2 or the ERβ-selective compounds for 6 h. Microarray data demonstrated that ERB-041, MF101 and liquiritigenin were the most ERβ-selective agonists compared to estradiol, followed by nyasol and then diarylpropionitrile. FRET analysis showed that all compounds induced a similar conformation of ERβ, which is consistent with the finding that most genes regulated by the ERβ-selective compounds were similar to each other and E2. However, there were some classes of genes differentially regulated by the ERβ agonists and E2. Two ERβ-selective compounds, MF101 and liquiritigenin had cell type-specific effects as they regulated different genes in HeLa, Caco-2 and Ishikawa cell lines expressing ERβ. Our gene profiling studies demonstrate that while most of the genes were commonly regulated by ERβ-selective agonists and E2, there were some genes regulated that were distinct from each other and E2, suggesting that different ERβ-selective agonists might produce distinct biological and clinical effects.
SO(10) inspired GMSB
Krauss, Manuel E.;Porod, Werner;Staub, Florian
High Energy Physics - Phenomenology , 2013,
Abstract: We consider a supersymmetric model motivated by a SO(10) GUT theory: the gauge sector near the SUSY scale consists of SU(3)_c x SU(2)_L x U(1)_R x U(1)_{B-L}. We embed this model in minimal gauge mediation and incorporate neutrino data via an inverse seesaw mechanism. Also in this restricted model the additional D-terms can rise the light Higgs mass in a sizable way. Therefore, it is much easier to obtain m_h \simeq 125 GeV without the need to push the SUSY spectrum to extremely large values as it happens in models with MSSM particle content only. We show that this model predicts a diphoton rate of the Higgs equal or smaller than the standard model expectation. We discuss briefly the collider phenomenology with a particular focus on the next to lightest supersymmetric particle where this model offers the sneutrino as an additional possiblity. Moreover we point out that also in this model variant supersymmetry can be discovered in Z' decays even in scenarios where the strongly interacting particles are too heavy to be produced at a sizable rate at LHC with 14 TeV. In addition, we show that lepton flavor violating observables constrain the size of the neutrino Yukawa couplings where in particular muon decays and \mu-e conversion in heavy atoms are of particular importance. Once these constraints are fullfilled the rates for \tau decays are predicted to be below the reach of near future experiments.
Principal Component Analysis of EBT2 Radiochromic Film for Multichannel Film Dosimetry  [PDF]
Richard E. Wendt III
International Journal of Medical Physics,Clinical Engineering and Radiation Oncology (IJMPCERO) , 2014, DOI: 10.4236/ijmpcero.2014.33021
Abstract:

Radiochromic film with a dye incorporated into the radiation sensitive layer [Gafchromic EBT2, Ashland, Inc.] may be digitized by a color transparency scanner, digitally processed, and calibrated so that a digital image in units of radiation absorbed dose is obtained. A transformation from raw scanner values to dose values was developed based upon a principal component analysis of the optical densities of the red, green and blue channels of the color image of a dose of 0.942 Gy delivered by a Sr-90/Y-90 disk-shaped source. In the order of increasing eigenvalue, the three eigenimages of the principal component analysis contained, by visual inspection, 1) mainly noise; 2) mainly a pattern of irregular streaks; and 3) most of the expected dose information along with some of the same background streaking that predominated in the second eigenimage. The combination of the second and third eigenimages that minimized the background streaking was converted into a transformation of the red, green and blue channels optical densities and applied to films with a range of doses from 0 to 63.7 Gy. The curve of dose vs. processed optical density was fit by a two-phase association curve. This processing was applied to a film exposed from its edge by a different Y-90 source in a configuration that was modeled by Monte Carlo simulation. The depth-dose curves of the measurement and simulation agree closely, suggesting that this approach is a valid method of processing EBT2 radiochromic film into maps of radiation absorbed dose.

Segmental arterial mediolysis: A clinical-pathologic review, its role in fibromuscular dysplasia and description and differential diagnosis of the masquerader-muscular artery cystic necrosis  [PDF]
Richard E. Slavin
World Journal of Cardiovascular Diseases (WJCD) , 2013, DOI: 10.4236/wjcd.2013.31013
Abstract:

Segmental arterial mediolysis (SAM) is an uncommon non-inflammatory iatrogenic arteriopathy caused by alpha-1 adrenergic agonists or Beta-2 agonists able to release norepinephrine from the peripheral nervous system. Causative agents include adrenergic agonists used to control blood pressure, B-2 tocolytic agonists, and ractopamine used as a repartitioning agent in animal husbandry. The liberated norepinephrine both injures and stimulates a robust reparative response in the muscular arteries in the abdomen, brain base, and coronary arteries. This response may be augmented by endothelin-1 formed in the arterial adventitia. Three types of arterial lesions develop in the injurious stage: 1) apoptotic induced mediolysis, 2) separation of the outer media from the adventitia and 3) the formation of arterial gaps. The latter enlarge, particularly in elderly patients, to form gap-aneurysms complicated by dissections and dissecting an- eurysms that when ruptured cause the calamitous hemorrhages that clinically announce SAM. The other types of injury remain clinically silent but with repair develop sequelae and can metamorphose into fibromuscular dysplasia. The sequelae are mainly asymptomatic but may cause arterial stenosis and ischemic lesions. The definitive diagnosis of SAM re- quires histological conformation but misinterpreta- tion of smooth muscle vacuolar change has caused di- agnostic errors. Muscular artery cystic necrosis a newly named non-inflammatory muscular artery ar- teriopathy may be confused with SAM both clinically and pathologically. This arteriopathy represents the muscular artery equivalent of cystic media necrosis of the elastic arteries since it exhibits similar morphol- ogic features and can occur concomitantly with this entity. Adrenergic agents to counter hemorrhagic shock in SAM are contraindicated since they may intensify injury and create new lesions. The use of norepinehrine antagonists introduces a new, but as yet untested, treatment option for SAM.

Exploring new models in all detail with SARAH
Florian Staub
Physics , 2015, DOI: 10.1155/2015/840780
Abstract: I give an overview about the features the Mathematica package SARAH provides to study new models. In general, SARAH can handle a wide range of models beyond the MSSM coming with additional chiral superfields, extra gauge groups, or distinctive features like Dirac gaugino masses. All of these models can be implemented in a compact form in SARAH and are easy to use: SARAH extracts all analytical properties of the given model like two-loop renormalization group equations, tadpole equations, mass matrices and vertices. Also one- and two-loop corrections to tadpoles and self-energies can be obtained. For numerical calculations SARAH can be interfaced to other tools to get the mass spectrum, to check flavour or dark matter constraints, and to test the vacuum stability, or to perform collider studies. In particular, the interface to SPheno allows a precise prediction of the Higgs mass in a given model comparable to MSSM precision by incorporating the important two-loop corrections. I show in great detail at the example of the B-L-SSM how SARAH together with SPheno, HiggsBounds/HiggsSignals, FlavorKit, Vevacious, CalcHep, MicrOmegas, WHIZARD, and MadGraph can be used to study all phenomenological aspects of a model. Even if I concentrate in this manuscript on the analysis of supersymmetric models most features are also available in the non-supersymmetric case.
Beyond-MSSM Higgs sectors
Florian Staub
Physics , 2014,
Abstract: This is a compact overview of Higgs sectors in extensions of the MSSM. The focus is on the summary of the main features of models with additional singlets and triplets as well as of models with Dirac gauginos. In addition, also important aspects of models with an extended gauge sector are shown. Finally, I comment on available tools which can be used for an adequate study of non-minimal SUSY models.
Influência de variáveis contextuais em medidas n?o-paramétricas de eficiência: uma aplica??o com métodos de reamostragem
Souza, Mirian Oliveira de;Souza, Geraldo da Silva e;Staub, Roberta Blass;
Pesquisa Operacional , 2009, DOI: 10.1590/S0101-74382009000200003
Abstract: we evaluate three bootstrap techniques for the statistical analysis of a non parametric production model for which a dea measure of efficiency is potentially affected by a set of exogenous factors. the application of interest relates to the assessment of the significance of the contextual variables income generation, processes improvement, intensity of partnerships, type and size on the technical efficiencies of embrapa's research centers. it is concluded that the bootstrap of the maximum likelihood estimator provides the best fit from the point of view of pearson correlation between observed and predicted values and is the most informative in regard to the significance of the variables considered. with the exception of size all contextual variables are statistically significant. income generation, processes improvement and intensity of partnerships are all positively associated with technical efficiency.
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