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Enteric coatings that deliver drugs to specific regions of the small intestine were examined. Hypromellose acetate succinate (HPMCAS) with different values of succinoyl group contents was used. Decreasing the succinoyl group content resulted in an increase in the pH at which HPMCAS started to dissolve. Drug-containing granules with or without enteric coating were prepared and their in vitro dissolution in a simulated intestinal fluid of pH 6.8 was examined. Granules coated with HPMCAS having the succinoyl group content of 6.2% showed a lag time of about 30 min, although drug release from granules without coating was completed within 20 min. The time lag and dissolution rate were extended and reduced, respectively, as the succinoyl group content was decreased. Rat experiments indicated that enteric-coated granules disintegrated and the bulk of the drugs was immediately released when the granules reached a specific site of the small intestine where the pH corresponded to the pH at which the enteric coating agent started to dissolve. Similar results were observed in monkey experiments. It was suggested that HPMCAS with the succinoyl group content of about 5% was suitable as an enteric coating agent for delivering drugs to the middle-to-lower region of the small intestine.

Gene therapy, a potential solution to hereditary and nonhereditary diseases, faces the challenges of safe and specific gene delivery. Cationic carrier molecules (e.g., liposome and polymers) that form noncovalent complexes with negatively charged DNA have been in use as nonviral gene delivery vectors. Although they tend to be relatively less efficient than viral systems, they have inherent advantages of flexibility and safety. Their derivatives, in conjugation with functional molecules such as peptides, proteins, growth factors, and antibodies, have been focused on to generate nanocarriers with low toxicity, high stability, high efficiency, and cell-specific targeting features. Here we describe internalizing polyclonal and monoclonal antibodies against a stress chaperone, mortalin/mtHsp70. We demonstrate that these internalizing anti-mortalin antibodies (i-mot Ab) could be employed for (1) internalization of nanoparticles (quantum dots, Qdots) and the generation of illuminating cells and (2) gene delivery. By using cancer and normal human cells in parallel, we further demonstrate that gene delivery can be specifically enhanced in human cancer cells if cationic polymer polyethylenimine (PEI) and i-mot Ab complex are used and may provide a novel cancer-targeting nanocarrier.

Background Chemotherapy for unresectable pancreatic cancer should not only prolong survival but maintain quality of life, considering its limited life expectancy. To achieve these goals, biweekly gemcitabine plus S-1 was assessed in the clinical practice setting. Methods Fifty-two patients with either locally advanced or metastatic pancreatic cancer who received biweekly gemcitabine plus S-1 as a first-line anti-cancer treatment were included in this study. Treatment delivery, toxicity, response, and survival were reviewed to assess the feasibility and efficacy. Results The completion rate of treatment delivery was 95.1%, with relative dose intensity of 97.1% for gemcitabine and 97.3% for S-1. Overall, grade 3 or worse adverse events were rare, with hematologic toxicities occurring in 5.8%. The objective response rate was 30.8%, and more than a 50% reduction of CA19-9 was observed in 77.1%. Surgical conversion was completed with a margin-negative resection in four patients whose tumor had shrunk for at least 6 months. The median progression-free and overall survivals were 10.4 and 18.2 months, respectively. Reduction of CA19-9 was associated with longer survival. Conclusions Biweekly gemcitabine plus S-1 may be a good alternative to current standard chemotherapies for unresectable pancreatic cancer with less toxicity and less treatment burden without losing efficacy.

We studied the seawater carbon dioxide (CO2) system in the Palau coral reef by measuring total alkalinity (TA) and total dissolved inorganic carbon (DIC). Variation in the CO2 system on the reef flat and in the lagoon was analyzed by TA–DIC diagrams, taking into accounts the differing residence times of seawater. CO2 in the offshore water was relatively stable in space and time, but on the reef flat it was subject to rapid (about 3 h) and substantial changes due to photosynthesis and calcification during the day and due to respiration and calcification at night. Water flowed into the lagoon where decomposition of organic matter and continuing calcification occurred over relatively long residence times (,30 d). Despite the spatial and temporal variations, the center of the lagoon had relatively constant TA and DIC values similar to the mean values for the entire lagoon. A long-term 30–40% decrease in reef productivity and calcification has occurred over the last decade, primarily a result of degradation of the reef environment following a major coral reef bleaching event in 1998. This is reflected in decreases in the differences in TA and DIC between offshore lagoon waters and those in center of the lagoon.

We report a straightforward method for the site-specific modification of long double-stranded DNA by using a maleimide adduct of deoxycytidine. This novel nucleoside analogue was efficiently incorporated at the 3'-termini of DNA by terminal deoxynucleotidyl transferase (TdT). Thiol-containing compounds can be covalently linked to the maleimide moieties. We added a nuclear localization signal peptide to the 3'-terminal of a 350 bp-long DNA that encoded short-hairpin RNA, and these modifications resulted in the enhancement of silencing activity by RNA interference. This enhancement is mainly attributed to increased stability of the template DNA.

Proteins containing unnatural amino acids have immense potential in biotechnology and medicine. We prepared several histidine analogues including a novel histidine analogue, beta-(1,2,3-triazol-4-yl)-DL-alanine. These histidine analogues were assayed for translational activity in histidine-auxotrophic Escherichia coli strain UTH780. We observed that several histidine analogues, including our novel histidine analogue, were efficiently incorporated into the protein in vivo; however, other analogues were rejected. These results suggest that the hydrogen atom at a specific position seriously affects incorporation.

Coral reef seawater samples from Bora Bay off Miyako Island in Okinawa, Japan were incubated with an initial volume of 20 liters. The degradation of organic carbon in this seawater was monitored for more than three months in dark, unstirred polycarbonate vessels by measuring the concentration of organic carbon in the seawater. The concentration of organic carbon gradually decreased to the background level of the refractory organic matter. The ratio of labile organic carbon to total organic carbon was about 30% in the water within the reef, and 10% in the water outside. The concentration of inorganic nutrients gradually increased with the degradation of the organic matter. In terms of the cell density and cell biomass of bacteria, the doubling rate was initially about twice a day and then declined during the incubation. Rate of degradation of labile organic carbon was about 20mmol C/m2/day in the reef. It was much smaller than the respiration rate reported for the whole coral reef community. This indicates that benthos like corals plays a major role in carbon dynamics in the coral reef. The result that the refractory organic concentration in the reef is lower than that in the outer sea indicates that the coral reef has the role of carbon sink in that organic carbon might be absorbed to the sedimentation particle.

The last few years have seen a considerable increase in our understanding of catalysis by naturally occurring RNA molecules called ribozymes. The biological functions of RNA molecules depend upon their adoption of appropriate three-dimensional structures. The structure of RNA has a very important electrostatic component, which results from the presence of charged phosphodiester bonds. Metal ions are usually required to stabilize the folded structures and/or catalysis. Some ribozymes utilize metal ions as catalysts, whereas others use the ions to maintain appropriate three-dimensional structures. In the latter case, the correct folding of the RNA structures can perturb the pKa values of the nucleotide(s) within a catalytic pocket such that they act as general acid/bases catalysts.

During cell cultivation on conventional culture dishes, various events results in strong stresses that lead to the production of bioactive species such as reactive oxygen species (ROS) and nitric oxide. These reactive species cause variable damage to cells and stimulate cellular responses. Here, we report the design of a novel biocompatible surface that decreases stress by not only morphologically modifying the dish surface by using poly(ethylene glycol) tethered chains, but also actively scavenging oxidative stress by using our novel nitroxide radical-containing polymer. A block copolymer, poly(ethylene glycol)-b-poly[(2,2,6,6-tetramethylpiperidine-N-oxyl)aminomethylstyrene] (PEG-b-PMNT) was used to coat the surface of a dish. Differentiation of undifferentiated human leukemia (HL-60) cells was found to be suppressed on the polymer-coated dish. Notably, HL-60 cell cultivation caused apoptosis under high-density conditions, while spontaneous apoptosis was suppressed in cells plated on the PEG-b-PMNT-modified surface, because a healthy mitochondrial membrane potential was maintained. In contrast, low molecular weight antioxidants did not have apparent effects on the maintenance of mitochondria. We attribute this to the lack of cellular internalization of our immobilized polymer and selective scavenging of excessive ROS generated outside of cells. These results demonstrate the utility of our novel biocompatible material for actively scavenging ROS and thus maintaining cellular morphology.

Reactive oxygen species (ROS) play important roles in regulating cellular morphology. The balance between generation and elimination of ROS is essential for the maintenance of signaling pathways. Disturbances in the redox balance results in changes in cellular morphology and disturbs cellular homeostasis. Therefore, it is essential to suppress the excess ROS in order to maintain cellular homeostasis. In this work, we constructed new biocompatible surfaces based on ROS scavenging character and demonstrate the utility of a ROS-scavenging polymer as a novel biocompatible material.

Calixarene-based porphyrins in which the calixarene scaffold is connected with porphyrin units by an alkyl chain as a spacer have been prepared. Porphyrin with ethano bridge exhibits extremely high...

The mechanism of direct strand cleavage induced by anaerobic irradiation of 5-bromouracil ( Br U)-containing DNA was investigated. The formation of an oligonucleotide fragment containing 3′-furanyladenine end like 5 was observed as a major photoproduct for the direct strand breaks.

Poly(ethylene glycol) (PEG) is the most widely used polymer and also the gold standard in the field of drug delivery. Therapeutic oligonucleotides, for example, are modified with PEG at the terminus to increases nuclease resistance and the circulating half-lives. The surface of nanoparticle such as micelle and liposome has been also modified with PEG. At present, one PEGylated therapeutic oligonucleotide has been approved for the market and several more PEGylated products including oligonucleotide and liposome are being tested in clinical settings. This review summarizes the methods and effects of PEGylation on gene delivery. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014, 131, 40293.

Reactive oxygen species (ROS) play important roles in regulating cellular morphology. In particular, mitochondrial ROS are involved in the regulation of cellular physiology. The balance between generation and elimination of ROS is essential for signaling pathway maintenance. However, excessive ROS are generated during cell culture in response to high oxygen concentration, cell contact with cell culture instruments and pro-oxidants in culture medium also generate ROS. Redox balance disruptions lead to changes in cellular morphology and disturb cellular homeostasis. Therefore, suppression of excessively generated ROS during cell subculture and treatments is very important issue, especially in the field of cellular therapeutics where cellular morphology should be strictly controlled. Though addition of low molecular weight (LMW) antioxidants to culture media suppresses such effect to some extent, they cause unwanted morphological changes of cultivating cells after internalization into the cells. In this work, we constructed a new biocompatible instrument based on ROS scavenging character and demonstrated the utility of a ROS-scavenging polymer as a novel biocompatible material. A polymer (PEG-b-PMNT) composed of poly(ethylene glycol) (PEG) and polystyrene segment with a nitroxide radicals (TEMPO) as a side chain, which catalytically scavenges ROS, was coated onto the surface of a dish via covalent linkage. Differentiation and spontaneous apoptosis of several kinds of cells including hematopoietic stem cells were suppressed on the polymer-coated dish. In contrast, LMW antioxidants showed disruption of mitochondrial membrane potential and induction of cellular differentiations. These adverse effects were likely due to the internalization of LMW antioxidants into mitochondria, resulting in a disrupted redox balance. In contrast, ROS-scavenging polymer could not internalize in cells and, therefore, could not have any adverse effects within the cell or mitochondria. These results demonstrate the utility of our novel biocompatible material for actively scavenging ROS and thus maintaining cellular properties.

Hypoxia is a feature of solid tumors and tumor hypoxia is known to promote mutagenesis, invasiveness. A strategy for targeting the hypoxic region of tumors is highly required; however, several issues such as adverse effects and poor penetration property of drugs have hampered developments. In this study, we developed a novel system in which antitumor prodrug is inactivated by the modification with the functional group and reduces the adverse effect to normal tissues which are generally present under normoxia condition but releases active anticancer drug under hypoxic condition. We have applied this technology to several anticancer drugs. In vivo experiments, doxorubicin prodrug (pro-Dox) was evaluated using tumor bearing mice and significant anti-tumor effect of pro-Dox was observed. Importantly, administration of pro-Dox did not show any apparent adverse effect and drastically improved survival rate of mice. Immunofluorescence analyses confirmed that the designed prodrug localized at the hypoxic region, in contrast to conventional anticancer drugs, which localized only at the normoxic region. These results indicate that the developed prodrug drastically improved the therapeutic effect by reducing adverse effects, improving drug penetration, and specifically activating the drug at hypoxic regions

Thirty-one patients with chronic sinusitis were treated with 150 mg of roxithromycin (RXM) per day for 12 weeks.The percentages of patients with an excellent or a good subjective response after 12 weeks of therapy were: 37.9% with reduced frequency of nose blowing, 37.9% with increased ease of nose blowing, 36.0% with reduced frequency of postnasal drip, 36.0% with easier removal of postnasal drip, 45.9% with less nasal obstruction, 40.0% with less headache, 45.5% with improved sense of smell.Objective findings were reduced as follows: redness of the nasal mucosa in 31.8%, edema of the nasal mucosa in 34.4%, quantity of the nasal discharge in 48.3%. The quality of the nasal discharge was improved in 48.3%, and the X-ray findings in the maxillary sinus (36 sides) were improved in 11.1%, and in the ethmoid sinus (38 sides) in 10.5%.The percentages of patients improved after 4, 8, and 12 weeks of therapy were not significantly different.No side effects of RXM were noted during this investigation.

This volume consists of collected essays, which was first read at the International Workshop on the Study of the Pentateuch with Special Emphasis on Textual Transmission History in the Hellenistic and Roman Periods held August 28-31, 2007 in Tokyo.

Mechanistic studies on the formation of deoxyribonolactone by UV irradiation of hexamer d(GC 1 BrUGC)2 (ODN 2a ) containing 1′-deuterio-2′-deoxyadenosine 1 was examined. The kinetic isotope effect (kH/kD) for the formation of C1′ oxidation product 3 was 1.7±0.1. ESI-MS of d(pUGC) ( 7 ) obtained from the photoreaction of ODN 2a indicated that 1′ deuterium was abstracted by uracilyl-5-yl radical and incorporated into 7 in 96% yield.

Gene therapy has generated worldwide attention as a new medical technology. While non-viral gene vectors are promising candidates as gene carriers, they have several issues such as toxicity and low transfection efficiency. We have hypothesized that the generation of reactive oxygen species (ROS) affects gene expression in polyplex supported gene delivery systems. The effect of ROS on the gene expression of polyplex was evaluated using a nitroxide radical-containing nanoparticle (RNP) as an ROS scavenger. When polyethyleneimine (PEI)/pGL3 or PEI alone was added to the HeLa cells, ROS levels increased significantly. In contrast, when (PEI)/pGL3 or PEI was added with RNP, the ROS levels were suppressed. The luciferase expression was increased by the treatment with RNP in a dose-dependent manner and the cellular uptake of pDNA was also increased. Inflammatory cytokines play an important role in ROS generation in vivo. In particular, tumor necrosis factor (TNF)-α caused intracellular ROS generation in HeLa cells and decreased gene expression. RNP treatment suppressed ROS production even in the presence of TNF-α and increased gene expression. This anti-inflammatory property of RNP suggests that it may be used as an effective adjuvant for non-viral gene delivery systems.

PEGylation refers to the covalent attachment of polyethylene glycol to proteins to reduce immunogenicity and extend their time in blood circulation. PEGylation is recognized as a promising method for increasing the therapeutic efficacy of medicines in clinical settings. The main advantages of PEGylation are (1) an increase in the size of drug molecule, resulting in reduced filtration by kidneys, (2) an increase in solubility, and (3) protection from enzymatic digestion and recognition by antibodies. A variety of molecules, such as small molecules, peptides, proteins, enzymes, antibodies and their fragments, and nanoparticles have been modified with PEG. Several PEGylated drugs have been approved by the US Food and Drug Administration (FDA) and several more are being tested in clinical settings. This review summarizes the methodologies and effects of PEGylation on drug delivery and highlights recent developments in PEGylated drugs.

Lipid composition of the eggs of three reef building corals, Acropora millepora, A. tenuis and Montipora digitata, were determined. Sixty to 70% of the egg dry weight was lipid, which consisted of wax esters (69.5–81.8%), triacylglycerols (1.1–8.4%) and polar lipids c/mainly phospholipids (11.9–13.2%). Montipora digitata also contained some polar lipids typical of the thylakoid membrane in chloroplasts, probably due to the presence of symbiotic zooxanthellae in the eggs. The wax esters appeared to be the major contributor to positive buoyancy of the eggs, and specific gravity of wax esters in A. millepora was estimated to be 0.92. Among the fatty acids of the wax esters, 34.9–51.3% was hexadecanoic acid (16:0) while the major fatty acids in polar lipids were octadecenoic acid (18:1), hexadecanoic acid (16:0), eicosapentaenoic acid (20:5) and eicosatetraenoic acid (20:4). The wax ester appears to be the main component of the 4.5 6.0 μm diameter lipid droplets which fill most of the central mass of the coral eggs.

This paper describes a case of dietetic ileus due to “mochi” capable of being confirmed by preoperative CT examination of the abdomen. A 53-year-old man was seen at the hospital because of abdominal pain and vomiting. Simple abdominal X-ray examination revealed a remarkable dilatation of the small intestine. Abdominal CT showed shadows of foreign body in the terminal ileum and stomach. The patient was diagnosed as intestinal obstruction due to some foreign body and underwent emergency operation. On laparotomy a great number of pieces of “mochi” was found in the terminal ileum and stomach. It was dietetic ileus caused by “mochi”. These mochi pieces were removed by incision of the intestine and stomach. This paper also presents a review of the literature.

A novel oligonucleotide carrier which can scavenge ROS is described. The synthesized graft polymer is composed of a PEG segment and a TEMPO-containing hydrophobic segment for scavenging ROS. This graft polymer can form a PIC through electrostatic interaction with oligonucleotides such as siRNA. The amount of ROS was monitored by fluorescence measurements using H₂ DCFDA as a probe, and it was confirmed that the ROS level was effectively suppressed. The cellular uptake of PIC containing the fluorescence-labeled oligonucleotide was evaluated by fluorescence microscopy. Delivered siRNA suppressed the expression of the mRNA. The prepared graft copolymer is thus a promising candidate as a novel oligonucleotide carrier which also reduces ROS damage generated by cationic polymer carriers.

A facile method for the construction of an immunoconjugate which displays targeting ligands, such as antibody fragments, with a high density is reported. For this purpose, we synthesized a novel trifunctional crosslinking reagent. By the use of this reagent, ligands targeting the specific cell can be displayed on the surface of the drug carrier with a high density. In this study, we display HER2 (human epidermal growth-factor receptor-2) binding ligands on branched polyethylenimine (PEI), which can form polyplexes with plasmid DNA. Kinetic analysis of the binding to the extracellular domain of HER2 show the PEI displaying a high density of ligands binds to the target more strongly compared to the PEI displaying ligands at a low density. The increased density of HER2 ligands displayed on the gene carrier contributes to the improved transfection efficiency. This approach can be applied to other drug delivery systems, including liposome, micelle, and so on.

Food–drug interactions may reduce the bioavailability of drugs taken after meals (negative food effects). We designed enteric-coated tablets that start to disintegrate when they reach the middle-to-lower region of the small intestine, and examined whether they could reduce negative food effects in dogs. Tablets containing trientine as a model drug were coated with hypromellose acetate succinate (HPMCAS) with various values of succinoyl group content. The time lag of drug dissolution from these enteric-coated tablets in simulated intestinal fluid of pH 6.8 increased as the succinoyl group content was decreased. The AUC of trientine after oral administration of its aqueous solution to fed dogs was one-eighth of that in fasted dogs. The low drug absorption in fed dogs was improved when trientine was administered as enteric-coated tablets. The average ratio of AUC in the fed state to that in the fasted state increased with decreasing succinoyl group content of HPMCAS. Negative food effects completely disappeared after oral administration of tablets coated with HPMCAS having a succinoyl group content of 6.2% or less, which probably disintegrated in the middle-to-lower small intestine. Our results indicated that food–drug interactions were avoided by separating the main absorption site of drugs from that of food components. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:5341–5353, 2008

Our interest in suppression of harmonic disturbances arose in the development of feedback control strategies for next generation aircraft. The control objective is to track a prescribed trajectory while suppressing the disturbance produced by a harmonic exogenous system. This is a slight modification of the standard problem of output regulation, in which the reference trajectory itself is also assumed to be generated by an exosystem. As part of an on going research effort, we are developing a solution to the problem for a nonlinear system which incorporates both the rigid body dynamics and certain aerodynamic states. In this paper, we illustrate our use of the internal model principle to solve this problem for continuous-time linear systems. Interestingly, the internal model based controller design leads to a Linear Matrix Inequlaity (LMI) constraint on the design parameters, yielding a convex problem which is easily solved.

RNA interference (RNAi) has become a powerful tool of knocking down a specific gene in vivo. In applications of RNAi, chemically synthesized short interfering RNAs (siRNAs) are commonly used because of their easiness and simplicity. However, siRNAs are cost inhibitive and their effect is transient. DNA which encodes siRNA can overcome these problems. In this study, we compared the stability and expression efficiency of plasmid DNA vector, short and long dumbbell-shaped DNA vectors. We found that the short dumbbell-shaped DNA vector is more stable and results in long-term expression of siRNA.

RNA interference (RNAi) is a post-transcriptional gene-silencing phenomenon that is triggered by double-stranded RNA (dsRNA). Since many diseases are associated with the inappropriate production of specific proteins, attempts are being made to exploit RNAi in a clinical settings. However, before RNAi can be exploited as therapeutically, several obstacles must be overcome. For example, small interfering RNA (siRNA) is unstable in the blood stream so any effects of injected siRNA are only transient. Accordingly, methods must be developed to prolong its activity. Furthermore, the efficient and safe delivery of siRNA into target tissues and cells is critical for successful therapy. Any useful delivery method should be designed to target siRNA to specific cells and to promote gene-silencing activity once the siRNA is inside the cells. Recent chemical modifications of siRNA have overcome problems associated with the instability of siRNA, and various ligands, including glycosylated molecules, peptides, proteins, antibodies and engineered antibody fragments, appear to be very useful or have considerable potential for the targeted delivery of siRNA. The use of such ligands improves the efficiency, specificity and, as a consequence, the safety of the corresponding delivery systems.

[1] Monitoring seawater CO2 for a full year with seasonal observations of community metabolism in Ishigaki Island, Japan, revealed seasonal variation and anomalous values owing to the bleaching event in 1998. The daily average pCO2 showed a seasonal pattern on an annual scale, 280 to 320 μatm in winter and 360 to 400 μatm in summer, which was determined primarily by the seasonal change in seawater temperature. By contrast, the range in the diel variation in pCO2, 400 to 500 μatm in summer 200 to 300 μatm in winter, was attributed to the seasonal variation in community metabolism: Gross primary production (Pg) and respiration (R) were high in summer and low in winter. During the 1998 bleaching event, although Pg and R increased, community excess organic production (E) decreased by three quarters compared with the same month in 1999, when the coral community showed high recovery. This change in metabolism led to large diel range and increased average value of pCO2 levels in the seawater on the reef flat. The decrease in the range and increase in the average value of pCO2 were observed by monitoring the Palau barrier reef flat, where overall mortality of corals occurred after the bleaching. All the metabolic parameters, Pg, R, E and calcification (G) were reduced by half after the bleaching, which increased the average pCO2 value by 10 μatm and decreased its diel range from 200–400 μatm to 100–200 μatm. Bleaching and resultant mortality of coral reefs led to degradation of their metabolic performance, and thus resulted in the loss of their active interaction with the carbon cycle.

This report describes work performed to investigate adaptive nonlinear control for UCAVs. Specifc control techniques investigated were Internal Model Principle Nonliear Output Regulation for UCAV flight control desing and aero-servo-elastic filter deisgn; and Adaptive Inverse Control for electromagnetic actuator control design for UAVs and advaced missiles. Simulation results show good command following (or reference tracking) characteristic of the Internal Model Priciple Output Regulation technique for designs of flight control and actuator control. The simulation results also show good disturbance allenuation charnctenstic of the Intemal Model Principle Output Regulation technique for aero-serve-elastic filter design. Neural Networks Adaptive Control was also evaluated in the UCAV flight control application, and similar results to those with the Internal Model Priciple Output Regulation control were observed. The Adaptive Inverrse Control technique showed some potential for comtrolling the electromagnetic actuators which contain nonilear elemets such as dead-zone, backlash, friction, and quantization errors. However, it introduced chaflering and sensitivity to the initial estimation error of the unknow parameters. The Internal Model Priciple Output Regualtion technique was also applied to the eletromagnetic actuator model and resolved the chattering and sensitivity to the parameter estimation errors.

Under the Air Force sponsored "Reconfigurable Systems for Tailless Fighter Aircraft - RESTORE" program, Boeing Phantom Works developed multiple control allocation algorithms based on linear programming and quadratic programming. According to the comparison analyses performed by the Boeing RESTORE program, the linear programming approach produced the best results in terms of maximum attainable moment space and chatter, but at the expense of increased computational time. The quadratic programming approach, on the other hand, reduced computational time but achieved less in maximum attainable moment space. Based on these observations, a study on control allocation problem was conducted using the Boeing-in-house LI optimization code, which is similar to simplex method of linear programming. The objective of this study is to evaluate the performance of the LI optimization code when applied to control allocation problem, and make assessment toward implementation. The Tailless Advanced Fighter Aircraft (TAFA) model along with its baseline control laws is used as a test bed. The assessment is made by comparisons between the LI optimization and quadratic programming in performance and execution.

The problem of designing flight control systems for high performance tailless fighter aircraft is discussed in the report. The research uses linear matrix inequalities and semidefinite programming to addresses three areas of tailless fighter flight control. The first area investigates H2 and Hinf controller design using linear matrix inequalities. The second area uses linear matrix inequalities and linear parameter varying models to develop stability analysis tools for gain scheduled and reconfigurable control laws. The third area focused on using linear matrix inequalities to design aeroservoelastic fitters.

A method for controlling fluid flow in real-time is discussed. The approach taken here for designing a controller is based on modern control theory. Modern control theory can provide a powerful tool for designing a controller. It provides a way not only to design a controller but also to design an optimal one if the system model is known. Hence, the system modeling plays a key role. In this paper, the system consists of a fluid flow to be controlled, and is modeled based on input-output relationship of the system rather than equations based on flow physics, since the latter requires computationally too intense and timeconsuming algorithms for real-time control. The specific modern controller design technique used in this paper is Linear Quadratic Gaussian (LQG). To demonstrate the schemes of the system modeling and control, an application to downstream temperature control of a jet is also discussed.

The anti-inflammatory effect of flurbiprofen tape (FP-T) by topical application was investigated, and the findings were compared with the results of oral administration of flurbiprofen to adjuvant arthritic rats. The topical application of FP-T significantly suppressed both applied and non-applied hind paw edema, with a potency similar to that seen with the oral administration of flurbiprofen. Body weight also increased with these treatments. Plasma levels of flurbiprofen differed little between topical application of FP-T and oral administration of flurbiprofen. Gastric damage induced by topical application of FP-T was significantly less than that seen in case of oral administration of flurbiprofen. These results suggest that the anti-inflammatory effects of FP-T cannot be entirely explained by flurbiprofen permeating inflamed tissue below the application site; rather, flurbiprofen penetrating into the systemic circulation may explain these actions.

Quantitative Feedback Theory (QFT) is applied to design flight control laws for the AlAA Controls Design Challenge nonlinear aircraft model. The control laws are designed in two steps. First, the aircraft model is linearized and baseline control laws are designed with the LQGATR technique. Then the QFT control design concept is applied to enhance robustness of baseline control laws in order to account for nonlinearities of the aircraft dynamics. The QFT technique loop shapes baseline control laws so that the resulting closed loop responses satisfy the inner loop design specifications. The outer loop control laws are designed using the LQG technique to provide hands-off autopilot for specified maneuvers.

Our own and other previous studies demonstrate marked anti-proliferative activity of the tyrophostin adaphostin (NSC680410) in a variety of hematologic malignancies including chronic myelocytic leukemia (CML), chronic lymphcytic leukemia (CLL), acute myelocytic leukemia (AML), and Multiple Myeloma. Here we show that adaphostin (NSC680410), similar to bortezomib, additionally inhibits tumor angiogenesis within the MM bone marrow (BM) microenvironment. This effect is elicited both indirectly by inhibition of VEGF production and secretion in MM cells, as well as directly by abrogation of endothelial cell growth. Specifically, adaphostin triggers marked downregulation of nuclear c-Myc expression in MM cells. Both adaphostin, as well as specific downregulation of c-Myc using siRNA, lead to a decrease in cobalt chloride- induced Hif-1alpha- expression and Hif-1alpha activity, as evidenced by western blot analysis and expression of Hif-1alpha- driven luciferase, respectively. Indeed secretion of the Hif-1alpha target gene VEGF is markedly inhibited in a dose- and time- dependent manner. Importantly, neither knockdown of c-Abl expression nor exogenous overexpression of caspase- cleavage- induced c-Abl fragment abrogates drug- induced Hif-1alpha downregulation or inhibition of its activity. Taken together, these results indicate the existence of a c-Myc/ Hif-1alpha- dependent, but c-Abl- independent, pathway modulating MM cell production and secretion of VEGF. In contrast, we demonstrate a direct antiangiogenic effect of adaphostin on endothelial cells, similar to H2O2, is mediated via c-Jun upregulation, inhibition of cell proliferation, and the induction of cell apoptosis. Moreover, our data further demonstrate activity of adaphostin within the BM microenvironment. Adaphostin, similar to bortezomib, significantly inhibits VEGF secretion triggered by adhesion of MM cells to BMSCs and endothelial cells. Consequently, conditioned medium derived from adaphostin- treated co-cultures markedly inhibits endothelial cell growth and tubule formation in a dose- dependent manner. Finally, we confirmed these in vitro results using an in vivo xenograft mouse model of human MM. Specifically, western blot analysis, as well as immunohistochemistry, demonstrate marked downregulation of both Hif-1alpha and CD31 in tumors isolated from adaphostin- treated animals versus control animals, confirming the in vivo antiangiogenic effect of adaphostin. Similar effects were obtained using a SCIDhu mouse model as well as a significant decrease of MM- related bone disease, due to anti- VEGF activity of adaphostin. Taken together, these data provide the rationale for the clinical evaluation of adaphostin to target both MM cells and the BM milieu to improve patient outcome in Multiple Myeloma.