Metabolically activated heterocyclic N-oxide compounds for killing and visualizing hypoxic cancer cells

The entire thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file; a non-technica public abstract appears in the public.pdf file.Title from PDF of title page (University of Missouri--Columbia, viewed on January 28, 2011).Thesis advisor: Dr. Kent S. Gates.Vita.Ph. D. University of Missouri--Columbia, 2009.Tirapazamine (TPZ) is currently undergoing a variety of phase I, II, and III clinical trials for the treatment of various human cancers. TPZ derives its medicinal activity by inducing DNA damage in poorly oxygenated tumor cells. Selective bioreductive enzymatic metabolism of TPZ in tumor cells leads to radical intermediates, which primarily contribute oxidative DNA damage. The nature of radical intermediates responsible for DNA damage is still a matter of debate. At the same time, there is an ongoing effort to prepare TPZ analogues as potential new antitumor agents. Thus, there is immediate need for the development of synthetic methods for the preparation of TPZ analogues. The very first part of this dissertation provides the utility of Suzuki coupling in the synthesis of 3-alkyl and 3-aryl derivatives of the antitumor agent TPZ. In these studies, the bromo substrate provided improved yields that chloro. To the best of our knowledge, we have provided general scope of Suzuki coupling reaction on the benzotriazine-1-oxide substrates involving various 3-aryl, and 3-cyclopropyl boronic acid to build a series of TPZ analogues. In addition to this work, we prepared novel 3-cyclopropyl-1,2,4-benzotriazine 1,4- dioxide which damages DNA under bioreductive hypoxic conditions. We also, utilized another 3-alkyl derivative of TPZ, 3-methyl-1,2,4-benzotriazine-di-N-oxide, to reinvestigate the mechanism of TPZ action. Our data imply the release of hydroxyl radical from activated TPZ is a reasonable mechanism to explain the DNA damage. This information is critical to our understanding of the effect of anticancer agent TPZ on various solid tumors We also show for the first time that other class of heterocyclic N-oxides such as natural product myxin and methylmyxin behave like redox activated hypoxia selective DNA damaging agent tirapazamine. In the last part of this thesis, we have explored for the first time the chemistry of the benzotriazine scaffold as a hypoxia-selective fluorescent probe. We have studied with a series of known benzotriazine compounds, and have found a few with a moderate fluorescence quantum yield and molar extinction coefficient. Our novel effort toward hypoxia directed fluorescent small molecule probes may be useful for imaging in cancer therapy, and other hypoxia related diseases.Includes bibliographical reference

Dark Energy from pNGB Mediated Dirac Neutrino Condensate

We consider an extension of the Standard Model that provide an unified description of eV scale neutrino mass and dark energy. An explicit model is presented by augmenting the Standard Model with an $SU(2)_L$ doublet scalar, a singlet scalar and right handed neutrinos where all of them are assumed to be charged under a global $U(1)_X$ symmetry. A light pseudo-Nambu-Goldstone Boson, associated with the spontaneously broken $U(1)_{X}$ symmetry, acts as a mediator of an attractive force leading to a Dirac neutrino condensate, with large correlation length, and a non-zero gap in the right range providing a cosmologically feasible dark energy scenario. The neutrino mass is generated through the usual Dirac seesaw mechanism. Parameter space, reproducing viable dark energy scenario while having neutrino mass in the right ballpark, is presented.Comment: 12 pages, 2 figures, 2 tables; new clarifications and discussions are added; updated reference list; matches published versio

A Goal Driven Framework for Service Discovery in Service-Oriented Architecture: A Multiagent Based Approach

Automated service discovery is one of the very important features in any Semantic Web Service (SWS) based framework. Achieving this functionality in e-resource sharing system is not an easy task due to its hugeness and heterogeneity among the available resources. Any efficient automated service discovery will remain worthless until discovered services fulfill the required goal(s) demanded by the user or the client program. In this paper we have proposed a goal driven approach towards an automated service discovery using Agent Swarm in an innovative way .A novel multi agent based architecture has been introduced here for service discovery. Communications among the agent in service-oriented framework for the said purpose has also been illustrated here. Finally, the pictorial view of the running agent in the system is shown

A COMACT MICROSTRIP PATCH ANTENNA FOR WIRELESS COMMUNICATION

Abstract—A single feed compact rectangular microstrip antenna is presented in this paper. A triangular slot is introduced at the upper edge of the patch to reduce the resonant frequency. A small piece of triangular patch is added within the area of the triangular slot to improve the gain bandwidth performance of the antenna. The antenna size has been reduced by 46.2 % when compared to a conventional square microstrip patch antenna with a maximum of 160MHz bandwidth and −27.36 dB return loss. The characteristics of the designed structure are investigated by using MoM based electromagnetic solver, IE3D. An extensive analysis of the return loss, radiation pattern, gain and efficiency of the proposed antenna is shown in this paper. The simple configuration and low profile nature of the proposed antenna leads to easy fabrication and make it suitable for th

Metabolite profiling and pharmacokinetic evaluation of hydrocortisone in a perfused 3D human liver bioreactor

Endotoxin lipopolysaccharide (LPS) is known to cause liver injury primarily involving inflammatory cells such as Kupffer cells, but few in vitro culture models are applicable for investigation of inflammatory effects on drug metabolism. We have developed a 3D human microphysiological hepatocyte-Kupffer-cell coculture system and evaluated the anti-inflammatory effect of glucocorticoids on liver cultures. LPS was introduced to the cultures to elicit an inflammatory response and assessed by the release of pro-inflammatory cytokines, IL6 and TNFα. A sensitive and specific RP-UHPLC-QTOF-MS method was used to evaluate hydrocortisone disappearance and metabolism at near physiological levels. For this, the systems were dosed with 100 nM hydrocortisone and circulated for two days; hydrocortisone was depleted to approximately 30 nM, with first-order kinetics. Phase I metabolites, including tetrahydrocortisone and dihydrocortisol, accounted for 8-10 % of the loss, and 45-52 % was phase II metabolites, including glucuronides of tetrahydrocortisol and tetrahydrocortisone. Pharmacokinetic parameters, i.e., half-life (t1/2), rate of elimination (kel), clearance (CL), and area under the curve (AUC), were 23.03 h, 0.03 h-1, 6.6x10-5 L. h-1 and 1.03 mg/L*h respectively. The ability of the bioreactor to predict the in vivo clearance of hydrocortisone was characterized and the obtained intrinsic clearance values correlated with human data. This system offers a physiologically-relevant tool for investigating hepatic function in an inflamed liver. Endotoxin lipopolysaccharide (LPS) is known to cause liver injury primarily involving inflammatory cells such as Kupffer cells, but few in vitro culture models are applicable for investigation of inflammatory effects on drug metabolism. We have developed a 3D human microphysiological hepatocyte-Kupffer-cell coculture system and evaluated the anti-inflammatory effect of glucocorticoids on liver cultures. LPS was introduced to the cultures to elicit an inflammatory response and assessed by the release of pro-inflammatory cytokines, IL6 and TNFα. A sensitive and specific RP-UHPLC-QTOF-MS method was used to evaluate hydrocortisone disappearance and metabolism at near physiological levels. For this, the systems were dosed with 100 nM hydrocortisone and circulated for two days; hydrocortisone was depleted to approximately 30 nM, with first-order kinetics. Phase I metabolites, including tetrahydrocortisone and dihydrocortisol, accounted for 8-10 % of the loss, and 45-52 % was phase II metabolites, including glucuronides of tetrahydrocortisol and tetrahydrocortisone. Pharmacokinetic parameters, i.e., half-life (t[subscript 1/2]), rate of elimination (k[subscript el]), clearance (CL), and area under the curve (AUC), were 23.03 h, 0.03 h[superscript -1], 6.6x10[superscript -5] L. h-1 and 1.03 mg/L*h respectively. The ability of the bioreactor to predict the in vivo clearance of hydrocortisone was characterized and the obtained intrinsic clearance values correlated with human data. This system offers a physiologically-relevant tool for investigating hepatic function in an inflamed liver.United States. Defense Advanced Research Projects Agency (DARPA-BAA-11-73 Microphysiological Systems W911NF-12-2-0039)National Institutes of Health (U.S.) (5-UH2-TR000496)Massachusetts Institute of Technology. Center for Environmental Health Sciences (P30-ES002109

Quantitative Systems Pharmacology Approaches Applied to Microphysiological Systems (MPS): Data Interpretation and Multi-MPS Integration

Our goal in developing Microphysiological Systems (MPS) technology is to provide an improved approach for more predictive preclinical drug discovery via a highly integrated experimental/computational paradigm. Success will require quantitative characterization of MPSs and mechanistic analysis of experimental findings sufficient to translate resulting insights from in vitro to in vivo. We describe herein a systems pharmacology approach to MPS development and utilization that incorporates more mechanistic detail than traditional pharmacokinetic/pharmacodynamic (PK/PD) models. A series of studies illustrates diverse facets of our approach. First, we demonstrate two case studies: a PK data analysis and an inflammation response––focused on a single MPS, the liver/immune MPS. Building on the single MPS modeling, a theoretical investigation of a four-MPS interactome then provides a quantitative way to consider several pharmacological concepts such as absorption, distribution, metabolism, and excretion in the design of multi-MPS interactome operation and experiments.United States. Defense Advanced Research Projects Agency. Microphysiological Systems Program (W911NF-12-2-0039)National Institutes of Health (U.S.) Microphysiological Systems Program (4-UH3-TR000496-03)Massachusetts Institute of Technology. Center for Environmental Health Sciences (NIEHS Grant P30-ES002109

"The fruits of independence": Satyajit Ray, Indian nationhood and the spectre of empire

Challenging the longstanding consensus that Satyajit Ray's work is largely free of ideological concerns and notable only for its humanistic richness, this article shows with reference to representations of British colonialism and Indian nationhood that Ray's films and stories are marked deeply and consistently by a distinctively Bengali variety of liberalism. Drawn from an ongoing biographical project, it commences with an overview of the nationalist milieu in which Ray grew up and emphasizes the preoccupation with colonialism and nationalism that marked his earliest unfilmed scripts. It then shows with case studies of Kanchanjangha (1962), Charulata (1964), First Class Kamra (First-Class Compartment, 1981), Pratidwandi (The Adversary, 1970), Shatranj ke Khilari (The Chess Players, 1977), Agantuk (The Stranger, 1991) and Robertsoner Ruby (Robertson's Ruby, 1992) how Ray's mature work continued to combine a strongly anti-colonial viewpoint with a shifting perspective on Indian nationhood and an unequivocal commitment to cultural cosmopolitanism. Analysing how Ray articulated his ideological positions through the quintessentially liberal device of complexly staged debates that were apparently free, but in fact closed by the scenarist/director on ideologically specific notes, this article concludes that Ray's reputation as an all-forgiving, ‘everybody-has-his-reasons’ humanist is based on simplistic or even tendentious readings of his work