bluuebunny/crossref_metadata_2025 huggingface dataset:
Future bronchodilator therapy: a bitter pill to swallow?
Authors: Clifford Rachel L. , Knox Alan J.
Published: September 2012

Maintenance of airway tone, prevention of airway obstruction, and acute relief from bronchospasm are key targets of asthma therapy. This role is currently performed by β-agonists. However, chronic use of β-agonists to treat asthma is associated with desensitization of β-agonist signaling and a resultant loss of bronchodilator effect, worsening of airway hyperreactivity, and increased incidence of asthma-related morbidity and mortality. There have been several attempts to identify novel non-β-agonist bronchodilators including ATP-sensitive potassium channel (KATP) agonists such as cromakalim and its active enantiomer BRL-38227 and the cGMP activators atrial natriuretic peptide (ANP) and BAY 41-22722. However, these either have not made it to clinical trial, required high doses, had little effect in patients, or had a high incidence of side effects. Recent data suggests that a novel bronchodilator target exists, the bitter taste receptor TAS2R. Two recent studies [An SS, Wang WC, Koziol-White CJ, Ahn K, Lee DY, Kurten RC, Panettieri RA Jr, Liggett SB. Am J Physiol Lung Cell Mol Physiol 303: L304–L311, 2012; Pulkkinen V, Manson ML, Säfholm J, Adner M, Dahlén SE. Am J Physiol Lung Cell Mol Physiol. doi:10.1152/ajplung.00205.2012.] provide new understanding of the signaling pathways utilized by TAS2Rs to mediate their bronchodilatory effects and how TAS2R-mediated bronchodilation is affected by β-agonist signaling desensitization. As our understanding of TAS2Rs and their agonists increases, they move closer to a viable therapeutic option; however, further definition is still required and questions remain to be answered. This editorial focus discusses these studies within the context of existing literature and raises questions and challenges for the future development of bitter (better?) therapies for asthma.
Influence of Selected Alkoxysilanes on Dispersive Properties and Surface Chemistry of Titanium Dioxide and TiO2–SiO2 Composite Material
Authors: Siwińska-Stefańska Katarzyna , Ciesielczyk Filip , Nowacka Magdalena , Jesionowski Teofil
Published: September 2012

The paper reports on characterisation of titanium dioxide and coprecipitated TiO2–SiO2 composite material functionalised with selected alkoxysilanes. Synthetic composite material was obtained by an emulsion method with cyclohexane as the organic phase, titanium sulfate as titanium precursor, and sodium silicate solution as precipitating agent were applied. Structures of titania and composite material samples were studied by the wide angle X‐ray scattering method. The chemical composition of TiO2–SiO2 composite material precipitated was evaluated based on the energy dispersive X‐ray spectroscopy technique. The functionalised TiO2 and TiO2–SiO2 composite material were thoroughly characterised to determine the yield of functionalisation with silanes. The characterisation included determination of dispersion and morphology of the systems (particle size distribution, scanning electron microscope images), adsorption properties (nitrogen adsorption isotherms), and electrokinetic properties (zeta potential).
Exenatide Pretreatment Improved Graft Function in Nonhuman Primate Islet Recipients Compared to Treatment after Transplant Only
Authors: Buss Jill L. , Rajab Amer , Essig Elizabeth D. , Bergdall Valerie K. , Wang Jie , Osei Kwame
Published: September 2012

The GLP-1 receptor agonist, exenatide, has previously been shown to improve insulin secretion, protect beta cells from apoptosis, and promote beta cell regeneration. We propose that pretreatment with exenatide will promote islet graft survival and improve graft function. Pancreatectomized cynomolgus monkeys underwent islet allotransplantation and were treated with exenatide beginning on day 0 or day −2. A third group of animals was treated with an immunosuppressive regimen while a fourth group remained untreated. Fasting blood glucose (FBG) was used to evaluate graft function along with intravenous glucose tolerance tests (IVGTTs) performed at study endpoint (day 10 for untreated and posttransplant exenatide or day 90 for pretreatment exenatide and immunosuppression). The average FBG for pre-treated animals day 5 following transplant was52.7±14.8 mg/dl, compared to154.3±105.5 mg/dl for animals treated only following transplant, 59.4 mg/dl±12.1for animals treated with immunosuppression, and265.5±172.3 mg/dl for untreated animals. IVGTTs performed at study endpoint showed normal glucose and insulin curves in the pre-treated exenatide and immunosuppression groups only, with beta cell function actually improving after transplant in the pre-treated group. We conclude, therefore, that exenatide pre-treatment can successfully maintain islet graft survival in nonhuman primates.
An Aproximation to Solution of Space and Time Fractional Telegraph Equations by the Variational Iteration Method
Authors: He Ji-Huan
Published: September 2012

Sevimlican suggested an effective algorithm for space and time fractional telegraph equations by the variational iteration method. This paper shows that algorithm can be updated by either variational iteration algorithm‐II or the fractional variational iteration method.
Combination Phototherapy with a Histone Deacetylase Inhibitor and a Potent DNA-Binding Bibenzimidazole: Effects in Haematological Cell Lines
Authors: Rodd Annabelle L. , Ververis Katherine , Karagiannis Tom C.
Published: September 2012

Current treatment for cutaneous T-cell lymphoma includes phototherapy, which involves either the use of narrowband ultraviolet B light or UVA in combination with a psoralen photosensitiser. Therapy typically involves administration of the photosensitiser followed by topical exposure to UVA. A different approach is extracorporeal photopheresis, an ex vivo strategy which is used for more advanced stages of disease. Further, histone deacetylase inhibitors are emerging as potent anticancer agents with suberoylanilide hydroxamic acid and depsipeptide, having received FDA approval for the treatment of cutaneous T-cell lymphoma. We have developed UVASens, an extremely potent, DNA minor groove-binding UVA sensitizer for potential use in phototherapy. We have previously demonstrated the extreme photopotency of UVASens in human erythroleukemic K562 cells. Here we have extended those studies by investigating the photopotency of UVASens in four haematological cell lines, namely, K562, T-cell leukaemic CEM-CCRF, P-glycoprotein overexpressing R100, and transformed B-lymphoblastoid cell lines (LCL) cells. In addition, we investigated the effects of suberoylanilide hydroxamic acid in combination with UVASens. Using γH2AX as the endpoint, our findings indicate that UVASens-induced phototoxicity in all four of the haematological cell lines. The addition of suberoylanilide hydroxamic acid augmented the photopotency of UVASens highlighting the potential clinical applicability of combination therapies.
Nuclear Power Plant Instrumentation Fault Detection Using Fuzzy Logic
Authors: Holbert Keith E. , Lin Kang
Published: September 2012

Economic constraints are driving the electric power industry to seek improved methods for monitoring, control, and diagnostics. To increase plant availability, various techniques have been implemented in industry to assess equipment condition to prevent system inoperability. The availability of a large number of measured signals and additional component information and the increasing number of signal processing options to analyze sampled data motivate the assimilation of such diverse information into a plantwide condition monitor. The use of fuzzy logic is described herein for the purpose of performing the decision making regarding the system status and the possible need for component maintenance. Fuzzy-logic-based diagnostic monitoring is applied to data acquired from instrumentation within operating facilities.
N-Acetyl Cysteine Protects against Methamphetamine-Induced Dopaminergic Neurodegeneration via Modulation of Redox Status and Autophagy in Dopaminergic Cells
Authors: Chandramani Shivalingappa Prashanth , Jin Huajun , Anantharam Vellareddy , Kanthasamy Anumantha , Kanthasamy Arthi
Published: September 2012

Methamphetamine- (MA-) induced neurotoxicity is associated with mitochondrial dysfunction and enhanced oxidative stress. Our previous study demonstrated that MA induces autophagy in a dopaminergic neuronal cell model (N27 cells). The cellular mechanisms underlying MA-induced autophagy and apoptosis remain poorly characterized. In the present study we sought to investigate the importance of GSH redox status in MA-induced neurotoxicity using a thiol antioxidant, N-acetylcysteine (NAC). Morphological and biochemical analysis revealed that MA-induced autophagy in N27 dopaminergic cells was associated with pronounced depletion of GSH levels. Moreover, pretreatment with NAC reduced MA-induced GSH depletion and autophagy, while depletion of GSH using L-buthionine sulfoximine (L-BSO) enhanced autophagy. Furthermore, treatment with NAC significantly attenuated MA-induced apoptotic cell death as well as oxidative stress markers, namely, 3-nitrotyrosine (3-NT) and 4-hydroxynonenal (4-HNE). Together, these results suggest that NAC exhibits significant protective effects against MA-induced dopaminergic cell death, presumably via modulation of the GSH level and autophagy. Collectively, our data provide mechanistic insights into the role of cellular GSH redox status in MA-induced autophagy and apoptotic cell death, and additional studies are needed to determine the therapeutic effectiveness of cellular redox modifiers in attenuating dopaminergic neurodegenerationin vivo.
Operational Readiness Simulator: Optimizing Operational Availability Using a Virtual Environment
Authors: Horning Shaun , Leung Philip , Fitzgerald Andy , Mrad Nezih
Published: September 2012

The maintenance and logistics systems that support aircraft fleets are complex and often very integrated. The complexity of these systems makes it difficult to assess the impact of events that affect operational capability, to identify the need for resources that can affect aircraft availability, or to assess the impact and potential benefits of the system and procedural changes. This problem is further complicated by the adoption of condition-based maintenance approaches resulting in dynamic maintenance planning as maintenance tasks are condition directed instead of scheduled or usage based. A proof of concept prototype for an aircraft operational readiness simulator (OR-SIM) has been developed for the Canadian Forces CH-146 Griffon helicopter. The simulator provides a synthetic environment to forecast and assess the ability of a fleet, squadron, or aircraft to achieve desired flying rates and the capability of the sustainment systems to respond to the resultant demands. The prototype was used to assess several typical scenarios including adjustment of preventative maintenance schedules including impact of condition-based maintenance, variation of the annual flying rate, and investigation of deployment options. This paper provides an overview of the OR-SIM concept, prototype model, and sample investigations and a discussion of the benefits of such an operational readiness simulator.
Sensitization of Cervical Cancer Cells to Cisplatin by Genistein: The Role of NFB and Akt/mTOR Signaling Pathways
Authors: Sahin K. , Tuzcu M. , Basak N. , Caglayan B. , Kilic U. , Sahin F. , Kucuk O.
Published: September 2012

Cervical cancer is among the top causes of death from cancer in women. Cisplatin-based chemotherapy has been shown to improve survival; however, cisplatin treatment is associated with toxicity to healthy cells. Genistein has been used as an adjunct to chemotherapy to enhance the activity of chemotherapeutic agents without causing increased toxicity. The present study was designed to investigate the effect of genistein (25 μM) on antitumor activity of cisplatin (250 nM) on HeLa cervical cancer cells. We have examined the alterations in expression of NF-B, p-mTOR, p-p70S6K1, p-4E-BP1, and p-Akt protein levels in response to treatment. The combination of 25 μM genistein with 250 nM cisplatin resulted in significantly greater growth inhibition (). Genistein enhanced the antitumor activity of cisplatin and reduced the expression of NF-B, p-mTOR, p-p70S6K1, p-4E-BP1, and p-Akt. The results in the present study suggest that genistein could enhance the activity of cisplatin via inhibition of NF-κB and Akt/mTOR pathways. Genistein is a promising nontoxic nutritional agent that may enhance treatment outcome in cervical cancer patients when given concomitantly with cisplatin. Clinical trials of genistein and cisplatin combination are warranted to test this hypothesis.
Synthesis and Properties of Polysilsesquioxanes Having Ethoxysulfonyl Group as a Side Chain
Authors: Gunji Takahiro , Yamamoto Kazuki , Tomobe Akira , Abe Noritaka , Abe Yoshimoto
Published: September 2012

Polysilsesquioxane having an ethoxysulfonyl group as a side chain was synthesized to prepare a proton-conductive film composed of a main chain of siloxane. At first, sodium 4-(2-methylallyloxy)benzenesulfonate was chlorinated with thionyl chloride. Next, hydrosilylation with trichlorosilane was carried out in the presence of platinum catalyst followed by treatment with ethanol. Finally, the hydrolytic polycondensation was carried out to provide poly(3-(4-ethoxysulfonylphenoxy)-2-methylpropyl)silsesquioxane. This polysilsesquioxane was heated to form a free-standing film that was brittle and brown in color.
Formation of Composite Surface during Friction Surfacing of Steel with Aluminium
Authors: Janakiraman S. , Bhat K. Udaya
Published: September 2012

Commercial pure aluminium was deposited on medium carbon steel using friction surfacing route. An aluminium rod was used as the consumable tool. Normal load and tool rotation speed were the variables. Under certain combinations of load and speed the deposition was continuous and uniform. The deposit consisted of Al embedded with fine particles of iron. The interface between substrate material and deposited material was smooth and relatively small. A mechanism is discussed for formation of a composite surface on the steel substrate.
A “Non-Invasive” Technique for Qualifying the Reinforced Concrete Structure
Authors: Guida Antonella , Pagliuca Antonello , Tranquillino Minerva Alessandro
Published: September 2012

In recent years, a lot of studies on built heritage emphasize the need to use appropriate techniques to evaluate the current condition of the structure before designing an intervention. The research focuses on the restoration of reinforced concrete buildings that begin to show signs of decay and deterioration. To verify the state of a building, it’s possible to use the “destructive” methods (that require a local removal of material) and “nondestructive” tests. The combined results from different “nondestructive” tests are very interesting instruments to assess the concrete strength. This methodological approach can help to reduce the possible errors when using the sclerometer and ultrasonic tests separately; in this way, the combined method called “SonReb” (SONic + REBound) was developed. This paper would highlight the importance with respect to cultural heritage buildings and on the studied structure and contribute to developed engineering strategies to maintenance and restoration. The above-defined methodology has been tested on a postwar building which is located in Gravina in Puglia (Italy): the “Centrone” theatre; it was built using a mixed structure, that is, reinforced concrete and bearing masonry built of local stone. The building was used until the 1990s and now is abandoned. The analysis and qualification of the masonry structures of built heritage show how this approach is useful for classifying the pathological events on each building and to implement the innovative solutions to improve the durability of a restoration intervention.
Layered Capacity-Based Relay-and-Antenna Joint Selection for MIMO-AF-Multiple-Relay Systems in Correlated Channels
Authors: Hu Chia-Chang , Li Jheng-Siang , Wu Bo-Liang
Published: September 2012

A computationally efficient two-stage greedy capacity maximization (GCM) relay-and-antenna joint selection is proposed for a dual-hop nonregenerative amplify-and-forward (AF) multiple-input multiple-output (MIMO) multiple-relay system with multiple antennas equipped at each node in correlated fading channels. This modified GCM (MGCM) antenna selection strategy selects a subset of antenna pairs from available relays based on the concept of channel capacity maximization subject to an optimal power allocation constraint across the activated antenna pairs. In order to reduce system hardware complexity, antenna selection schemes are performed at the destination node as well. Finally, simulations are conducted to compare the channel capacity of the proposed two-layered antenna selection technique with other existing antenna selection algorithms for half-duplex AF-MIMO multiple-relay systems.
What Teachers Think about Self-Regulated Learning: Investigating Teacher Beliefs and Teacher Behavior of Enhancing Students’ Self-Regulation
Authors: Dignath-van Ewijk Charlotte , van der Werf Greetje
Published: September 2012

In order to foster self-regulated learning (SRL), teachers should provide students with learning strategies, as well as with constructivist learning environments that allow them to self-regulate their learning. These two components complement each other. When investigating teachers’ promotion of SRL, not only teacher behavior, but also teachers’ beliefs as well as their knowledge about SRL are relevant aspects to consider. Therefore, this study seeks to examine teachers’ knowledge and beliefs on promoting SRL, as well as their predictive value on teachers’ promotion of SRL in the classroom. Forty-seven primary school teachers completed questionnaires on knowledge and beliefs towards both components of the promotion of SRL: strategy instruction and a constructivist learning environment. In addition, teachers had to answer open-ended questions on their understanding of SRL, as well as their implementation of SRL in their classroom. The results show that teachers are more positive towards constructivist than towards SRL (teacher beliefs), and most teachers mentioned characteristics of constructivist learning environments, while only few teachers addressed strategy instruction when being asked about their understanding of SRL (teacher knowledge). Moreover, teacher beliefs are the only predictor for teacher behavior. The results indicate how teacher education could support teachers to learn how to promote SRL effectively.
Effects ofRhizophora mangleon Experimental Colitis Induced by TNBS in Rats
Authors: de Faria Felipe Meira , Luiz-Ferreira Anderson , Socca Eduardo Augusto Rabelo , de Almeida Ana Cristina Alves , Dunder Ricardo José , Manzo Luis Paulo , da Silva Marcelo Aparecido , Vilegas Wagner , Rozza Ariane Leite , Pellizzon Cláudia Helena , dos Santos Lourdes Campaner , Souza Brito Alba Regina Monteiro
Published: September 2012

Male Unib-WH rats were pretreated for two weeks with butanolic (BuOH) and ethyl acetate (EtOAc) fractions. Colitis was induced by rectal administration of TNBS, the treatment continued, and animals were sacrificed on day 7 after the TNBS administration. Phytochemical studies were performed in order to provide the characterization of the tannins present in the bark ofR. mangle. Results showed that EtOAc fraction increased the levels of IL-10 (**P<0.01) and diminished the levels of TNF-α(***P<0.001) and IL-6 (**P<0.01). BuOH fraction reduced the MPO activity (**P<0.01) and levels of TBARS (***P<0.001); it also increased COX-1 expression, diminished the levels of TNF-α(***P<0.001), and increased the levels of IL-12 (***P<0.001). Besides, both treatments augmented the levels of GSH (*P<0.05), the activity of GSH-Px (**P<0.01for BuOH fraction and ***P<0.001for EtOAc fraction), and CAT (**P<0.01). In conclusion, both treatments ameliorated the injury induced by TNBS through different mechanisms, probably by their chemical composition which directed its activity into an antioxidant or anti-inflammatory response, leading to an immune modulation.
Normalized Born Approximation‐Based Two‐Stage Reconstruction Algorithm for Quantitative Fluorescence Molecular Tomography
Authors: Yi Huangjian , Chen Duofang , Li Wei , Zhou Shuang , Ning Miao , Zhu Shouping , Tian Jie , Liang Jimin
Published: September 2012

Fluorescence molecular tomography (FMT) is a promising technique for in vivo small animal imaging. In this paper, a two‐stage reconstruction method based on normalized Born approximation is developed for FMT, which includes two steps for quantitative reconstruction. First, the localization of fluorescent fluorophore is determined by l1‐norm regularization method. Then, in the location region of fluorophore, which is provided by the first stage, algebraic reconstruction technique (ART) is utilized for the fluorophore concentration reconstruction. The validity of the two‐stage quantitative reconstruction algorithm is testified by simulation experiments on a 3D digital mouse atlas and physical experiments on a phantom. The results suggest that we are able to recover the fluorophore location and concentration.
Metabolic Profiling Study of Yang Deficiency Syndrome in Hepatocellular Carcinoma byH1NMR and Pattern Recognition
Authors: Huang Xueqiang , Chen Qunwei , Yang Genjin , Dai Weixing , Lang Qingbo , Du Juan , Yan Shikai , Zhang Weidong , Ling Changquan
Published: September 2012

This study proposes a1H NMR-based metabonomic approach to explore the biochemical characteristics of Yang deficiency syndrome in hepatocellular carcinoma (HCC) based on serum metabolic profiling. Serum samples from 21 cases of Yang deficiency syndrome HCC patients (YDS-HCC) and 21 cases of non-Yang deficiency syndrome HCC patients (NYDS-HCC) were analyzed using1H NMR spectroscopy and partial least squares discriminant analysis (PLS-DA) was applied to visualize the variation patterns in metabolic profiling of sera from different groups. The differential metabolites were identified and the biochemical characteristics were analyzed. We found that the intensities of six metabolites (LDL/VLDL, isoleucine, lactate, lipids, choline, and glucose/sugars) in serum of Yang deficiency syndrome patients were lower than those of non-Yang deficiency syndrome patients. It implies that multiple metabolisms, mainly including lipid, amino acid, and energy metabolisms, are unbalanced or weakened in Yang deficiency syndrome patients with HCC. The decreased intensities of metabolites including LDL/VLDL, isoleucine, lactate, lipids, choline, and glucose/sugars in serum may be the distinctive metabolic variations of Yang deficiency syndrome patients with HCC. And these metabolites may be potential biomarkers for diagnosis of Yang deficiency syndrome in HCC.
EGFR Monoclonal Antibodies in the Treatment of Squamous Cell Carcinoma of the Head and Neck: A View beyond Cetuximab
Authors: Kono Scott A. , Haigentz Missak , Yom Sue S. , Saba Nabil
Published: September 2012

Squamous cell carcinoma of the head and neck (SCCHN) is a prevalent disease both in the United States and worldwide with an overall poor prognosis, in part due to limited activity of existing therapy. Primary therapy is largely dictated by the anatomical origin of the cancer and whether distant disease is present. Many patients with localized disease are treated with chemoradiotherapy, either in the definitive or adjuvant setting, and those with metastatic disease are treated with palliative chemotherapy. The chemotherapy used in SCCHN can be toxic, whether given with radiation or alone. The epidermal growth factor receptor (EGFR) is highly expressed in SCCHN and serves as a logical therapeutic target. EGFR-directed monoclonal antibodies (MoAbs) have higher activity in SCCHN than small molecule tyrosine kinase inhibitors. Cetuximab, a widely studied EGFR MoAb, is FDA approved in the metastatic setting, as well as with radiation for locally advanced disease. Despite improvements in survival when cetuximab is incorporated with chemotherapy for metastatic disease, the prognosis of patients remains poor. Novel EGFR MoAbs are being developed with the goal of improving efficacy and tolerability. This paper will summarize the use of EGFR-directed MoAbs in treating SCCHN with a focus on novel agents being tested.
Regulatory T Cells in HIV Infection: Can Immunotherapy Regulate the Regulator?
Authors: Jenabian Mohammad-Ali , Ancuta Petronela , Gilmore Norbert , Routy Jean-Pierre
Published: September 2012

Regulatory T cells (Tregs) have a dominant role in self-tolerance and control of autoimmune diseases. These cells also play a pivotal role in chronic viral infections and cancer by limiting immune activation and specific immune response. The role of Tregs in HIV pathogenesis remains poorly understood as their function, changes according to the phases of infection. Tregs can suppress anti-HIV specific responses and conversely can have a beneficial role by reducing the deleterious impact of immune activation. We review the frequency, function and homing potential of Tregs in the blood and lymphoid tissues as well as their interaction with dendritic cells in the context of HIV infection. We also examine the new insights generated by recombinant IL-2 and IL-7 clinical trials in HIV-infected adults, including the immunomodulatory effects of Tregs. Based on their detrimental role in limiting anti-HIV responses, we propose Tregs as potential targets for immunotherapeutic strategies aimed at decreasing Tregs frequency and/or immunosuppressive function. However, such approaches require a better understanding of the time upon infection when interfering with Treg function may not cause a deleterious state of hyperimmune activation.
Arginine 16 Glycine Polymorphism inβ2-Adrenergic Receptor Gene Is Associated with Obesity, Hyperlipidemia, Hyperleptinemia, and Insulin Resistance in Saudis
Authors: Daghestani Maha H. , Warsy Arjumand , Daghestani Mazin H. , Al-odaib Ali N. , Eldali Abdelmoneim , Al-Eisa Nadia A. , Omer Sawsan A. , Hassan Zeinab K.
Published: September 2012

Background. Several studies have shown an association between codon 16 polymorphism of theβ2AR gene and obesity.Methods. We studied the association between Arg16Gly polymorphism and obesity and its influence on anthropometric parameters, lipids, insulin resistance and leptin in Saudi individuals. The study group included 329 individuals (males: 109 and females: 220). Metabolic parameters, including glucose, lipids, insulin, and leptin were analyzed and anthropometric parameters including waist and hip circumference, waist/hip (W/H) ratio, and body mass index (BMI) were measured and HOMA-IR was calculated. Genotyping was conducted by DNA sequencing of 353 bp fragments, carrying the Arg16Gly polymorphic site.Results and Conclusion. Overweight and obese subjects had a significantly higher frequency of Gly16 (0.375 and 0.38, resp.) compared with normal-weight subjects (0.200). In addition, subjects carrying Gly16 allele regardless of their BMI had greater waist and hip circumference, W/H ratio, plasma lipids, leptin, glucose level, and insulin resistance as judged from the HOMA-IR, compared to those with the wild-type allele. The findings of this study show a significant association between the Arg16Gly polymorphism inβ2AR gene and the development of insulin resistance, overweight, and obesity in Saudi populations with an influence on the levels of lipid and leptin.
A Novel Dual‐Loop Disturbance Observer‐Based Attitude Control for a Space‐Based Observation Microsatellite
Authors: Sun Jian , Yu Jian , Rong Haijun
Published: September 2012

Aiming at strong coupling and nonlinear dynamic equations for a space‐based observation satellite, a sliding mode controller with feed‐forward compensation is proposed in this paper. The theorem of moment of momentum is applied to formulate the exact nonlinear dynamic equations of a multibody satellite. On this basis, sliding‐mode control‐based, dual‐loop forward‐feed compensation control is used to control the attitude of the space‐based observation microsatellite. By comparing with the conventional control method, simulation results demonstrate that the proposed control method has superior performance in terms of suppression from external disturbances and vibration. Better dynamic and static performance indices than the conventional control method are achieved.
Kinetics, Equilibrium, and Thermodynamic Studies on Adsorption of Methylene Blue by Carbonized Plant Leaf Powder
Authors: Gunasekar V. , Ponnusami V.
Published: September 2012

Carbon synthesized from plant leaf powder was employed for the adsorption of methylene blue from aqueous effluent. Effects of pH (2, 4, 6, 8, and 9), dye concentration (50, 100, 150, and 200 mg/dm3), adsorbent dosage (0.5, 1.0, 1.5, and 2.0 g/dm3), and temperature (303, 313, and 323 K) were studied. The process followed pseudo‐second‐order kinetics. Equilibrium data was examined with Langmuir and Freundlich isotherm models and Langmuir model was found to be the best fitting model with high R2 and low chi2 values. Langmuir monolayer adsorption capacity of the adsorbent was found to be 61.22 mg/g. From the thermodynamic analysis, ΔH, ΔG, and ΔS values for the adsorption of MB onto the plant leaf carbon were found out. From the values of free energy change, the process was found out to be feasible process. From the magnitude of ΔH, the process was found to be endothermic physisorption.
Synthesis of Stable Tetraethylenepentamine‐Functionalized Mesocellular Silica Foams for CO2 Adsorption
Authors: Liu Shou-Heng , Hsiao Wei-Che , Chiang Chia-Chin
Published: September 2012

Various amounts of tetraethylenepentamine (TEPA) loading on mesocellular silica foams (TEPA‐MSF‐x) were fabricated via a chemical grafting method in this study. The performance of dry 15%  CO2 adsorption on the TEPA‐MSF‐x was tested by a microbalance at 348 K under ambient pressure. Experimentally, CO2 adsorption capacities of the TEPA‐MSF‐x sorbents were found to be 28.5–66.7 mg CO2/g‐sorbent. In addition, TEPA‐MSF‐x sorbents exhibited enhanced durability during repeated adsorption‐desorption cycles compared to the conventional sorbents prepared by a physical impregnation method. This significant enhancement in the stability of CO2 adsorption‐desorption process was most likely due to the decreased leaching of TEPA which is covalently tethered to the surface of MSF.
FGFR3 Stimulates Stearoyl CoA Desaturase 1 Activity to Promote Bladder Tumor Growth
Authors: Du Xiangnan , Wang Qian-Rena , Chan Emily , Merchant Mark , Liu Jinfeng , French Dorothy , Ashkenazi Avi , Qing Jing
Published: September 2012

Fibroblast growth factor receptor 3 (FGFR3) belongs to a family of receptor tyrosine kinases that control cell proliferation, differentiation, and survival. Aberrant activation of FGFR3 via overexpression or mutation is a frequent feature of bladder cancer; however, its molecular and cellular consequences and functional relevance to carcinogenesis are not well understood. Through transcriptional profiling of bladder carcinoma cells subjected to short hairpin RNA knockdown of FGFR3, we identified a gene-signature linking FGFR3 signaling with de novo sterol and lipid biosynthesis and metabolism. We found that FGFR3 signaling promotes the cleavage and activation of the master transcriptional regulator of lipogenesis, sterol regulatory element-binding protein 1(SREBP1/SREBF1), in a PI3K-mTORC1-dependent fashion. In turn, SREBP1 regulates the expression of key lipogenic enzymes, including stearoyl CoA desaturase 1 (SCD1/SCD). SCD1 is the rate-limiting enzyme in the biosynthesis of monounsaturated fatty acids and is crucial for lipid homeostasis. In human bladder cancer cell lines expressing constitutively active FGFR3, knockdown of SCD1 by siRNA markedly attenuated cell-cycle progression, reduced proliferation, and induced apoptosis. Furthermore, inducible knockdown of SCD1 in a bladder cancer xenograft model substantially inhibited tumor progression. Pharmacologic inhibition of SCD1 blocked fatty acid desaturation and also exerted antitumor activity in vitro and in vivo. Together, these findings reveal a previously unrecognized role of FGFR3 in regulating lipid metabolism to maintain tumor growth and survival, and also identify SCD1 as a potential therapeutic target for FGFR3-driven bladder cancer. Cancer Res; 72(22); 5843–55. ©2012 AACR.
Loss of SNAIL Regulated miR-128-2 on Chromosome 3p22.3 Targets Multiple Stem Cell Factors to Promote Transformation of Mammary Epithelial Cells
Authors: Qian PengXu , Banerjee Arindam , Wu Zheng-Sheng , Zhang Xiao , Wang Hong , Pandey Vijay , Zhang Wei-Jie , Lv Xue-Fei , Tan Sheng , Lobie Peter E. , Zhu Tao
Published: September 2012

A discontinuous pattern of LOH at chromosome 3p has been reported in 87% of primary breast cancers. Despite the identification of several tumor suppressor genes in this region, there has yet to be a detailed analysis of noncoding RNAs including miRNAs in this region. In this study, we identified 16 aberrant miRNAs in this region and determined several that are frequently lost or amplified in breast cancer. miR-128-2 was the most commonly deleted miRNA. Embedded in the intron of the ARPP21 gene at chromosome 3p22.3, miR-128-2 was frequently downregulated along with ARPP21 in breast cancer, where it was negatively associated with clinicopathologic characteristics and survival outcome. Forced expression of miR-128 impeded several oncogenic traits of mammary carcinoma cells, whereas depleting miR-128-2 expression was sufficient for oncogenic transformation and stem cell-like behaviors in immortalized nontumorigenic mammary epithelial cells, both in vitro and in vivo. miR-128-2 silencing enabled transforming capacity partly by derepressing a cohort of direct targets (BMI1, CSF1, KLF4, LIN28A, NANOG, and SNAIL), which together acted to stimulate the PI3K/AKT and STAT3 signaling pathways. We also found that miR-128-2 was directly downregulated by SNAIL and repressed by TGF-β signaling, adding 2 additional negative feedback loops to this network. In summary, we have identified a novel TGF-β/SNAIL/miR-128 axis that provides a new avenue to understand the basis for oncogenic transformation of mammary epithelial cells. Cancer Res; 72(22); 6036–50. ©2012 AACR.
DDX31 Regulates the p53-HDM2 Pathway and rRNA Gene Transcription through Its Interaction with NPM1 in Renal Cell Carcinomas
Authors: Fukawa Tomoya , Ono Masaya , Matsuo Taisuke , Uehara Hisanori , Miki Tsuneharu , Nakamura Yusuke , Kanayama Hiro-omi , Katagiri Toyomasa
Published: September 2012

Studies of renal cell carcinoma (RCC) have led to the development of new molecular-targeted drugs but its oncogenic origins remain poorly understood. Here, we report the identification and critical roles in renal carcinogenesis for DDX31, a novel nucleolar protein upregulated in the vast majority of human RCC. Immunohistochemical overexpression of DDX31 was an independent prognostic factor for patients with RCC. RNA interference (RNAi)-mediated attenuation of DDX31 in RCC cells significantly suppressed outgrowth, whereas ectopic DDX31 overexpression in human 293 kidney cells drove their proliferation. Endogenous DDX31 interacted and colocalized with nucleophosmin (NPM1) in the nucleoli of RCC cells, and attenuation of DDX31 or NPM1 expression decreased pre-ribosomal RNA biogenesis. Notably, in DDX31-attenuated cells, NPM1 was translocated from nucleoli to the nucleoplasm or cytoplasm where it bound to HDM2. As a result, HDM2 binding to p53 was reduced, causing p53 stablization with concomitant G1 phase cell-cycle arrest and apoptosis. Taken together, our findings define a mechanism through which control of the DDX31–NPM1 complex is likely to play critical roles in renal carcinogenesis. Cancer Res; 72(22); 5867–77. ©2012 AACR.
Antibody-Dependent Cell-Mediated Cytotoxicity Overcomes NK Cell Resistance in MLL-Rearranged Leukemia Expressing Inhibitory KIR Ligands but Not Activating Ligands
Authors: Chan Wing Keung , Kung Sutherland May , Li Ying , Zalevsky Jonathan , Schell Sarah , Leung Wing
Published: September 2012

Purpose: Leukemias with MLL gene rearrangement are associated with a poor prognosis. Natural killer (NK) cell therapy is a potential treatment, but leukemia cells may be resistant. Here, we sought to determine the susceptibility of MLL-rearranged leukemia cells to NK cell lysis and to develop a novel immunotherapeutic approach to optimize NK cell therapy, including the use of an antibody against leukemia-associated antigen and the elimination of killer-cell immunoglobulin-like receptor (KIR)–mediated inhibition.

Experimental Design: Three MLL-rearranged leukemia cell lines (RS4;11, SEM, and MV4-11) and primary leukemia blasts were assessed for surface phenotype and susceptibility to NK cell lysis with or without antibodies against CD19 (XmAb5574), CD33 (lintuzumab), or KIR ligands.

Results: All three cell lines were resistant to NK cell lysis, had some inhibitory KIR ligands and protease inhibitor-9, and expressed low levels of NKG2D activating ligands and adhesion molecules. After treatment with XmAb5574 or lintuzumab, MLL-rearranged leukemia cells were efficiently killed by NK cells. The addition of pan–major histocompatibility complex class I antibody, which blocked inhibitory KIR-HLA interaction, further augmented degranulation in all three KIR2DL1, KIR2DL2/3, and KIR3DL1 subsets of NK cells based on the rule of missing-self recognition. A mouse model showed a decreased rate of leukemia progression in vivo as monitored by bioluminescence imaging and longer survival after antibody treatment.

Conclusion: Our data support the use of a triple immunotherapy approach, including an antibody directed against tumor-associated antigen, KIR-mismatched NK cell transplantation, and inhibitory KIR blockade, for the treatment of NK cell–resistant MLL-rearranged leukemias. Clin Cancer Res; 18(22); 6296–305. ©2012 AACR.
Using Pharmacokinetic and Pharmacodynamic Data in Early Decision Making Regarding Drug Development: A Phase I Clinical Trial Evaluating Tyrosine Kinase Inhibitor, AEE788
Authors: Baselga José , Mita Alain C. , Schöffski Patrick , Dumez Herlinde , Rojo Frederico , Tabernero Josep , DiLea Clifford , Mietlowski William , Low Christie , Huang Jerry , Dugan Margaret , Parker Kathryn , Walk Eric , van Oosterom Allan , Martinelli Erika , Takimoto Chris H.
Published: September 2012

Purpose: In this first-in-human study of AEE788, a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), HER-2, and VEGFR-2, a comprehensive pharmacodynamic program was implemented in addition to the evaluation of safety, pharmacokinetics, and preliminary efficacy of AEE788 in cancer patients.

Experimental design: Patients with advanced, solid tumors received escalating doses of oral AEE788 once daily. Primary endpoints were to determine dose-limiting toxicities (DLTs) and maximum-tolerated dose (MTD). A nonlinear model (Emax model) was used to describe the relationship between AEE788 exposure and target-pathway modulation in skin and tumor tissues.

Results: Overall, 111 patients were treated (25 to 550 mg/day). DLTs included rash and diarrhea; MTD was 450 mg/day. Effects on biomarkers correlated to serum AEE788 concentrations. The concentration at 50% inhibition (IC50) for EGFR in skin (0.033 μmol/L) and tumor (0.0125 μmol/L) were similar to IC50in vitro suggesting skin may be surrogate tissue for estimating tumor EGFR inhibition. No inhibition of p-MAPK and Ki67 was observed in skin vessels at ≤MTD. Hence, AEE788 inhibited EGFR, but not VEGFR, at doses ≤MTD. A total of 16 of 96 evaluable patients showed a >10% shrinkage of tumor size; one partial response was observed.

Conclusion: Our pharmacodynamic-based study showed effective inhibition of EGFR, but not of VEGFR at tolerable AEE788 doses. Emax modeling integrated with biomarker data effectively guided real-time decision making in the early development of AEE788. Despite clinical activity, target inhibition of only EGFR led to discontinuation of further AEE788 development. Clin Cancer Res; 18(22); 6364–72. ©2012 AACR.
Model T Muscle CARs Can Treat Brain Tumors
Authors: Johnson Laura A.
Published: September 2012

Despite standard treatment with resection, radiation, and chemotherapy, glioblastoma remains a deadly disease with a dismal prognosis. Redirecting patient T cells to target the glioblastoma-associated antigen, IL13Rα2, offers a promising translational immunotherapy with the potential to make a meaningful impact for patients with this disease. Clin Cancer Res; 18(21); 5834–6. ©2012 AACR.
A Multiscale Model for the Modulation and Rectification of the ITCZ
Authors: Biello Joseph A. , Majda Andrew J.
Published: September 2012

The authors introduce the modulation of the ITCZ equations (M-ITCZ), which describes the multiscale dynamics of the ITCZ on diurnal to monthly time scales in which mesoscale convectively coupled Rossby waves in the ITCZ are modulated by a large-scale gravity wave that is also generated by convection. Westward-propagating disturbances are observed to cause ITCZ breakup over the course of a few days, and the M-ITCZ meso-/planetary-scale coupled waves provide a mechanism for this interaction, thereby providing a framework to study the modulation and rectification of the Hadley circulation over long zonal length scales in the ITCZ.

The authors consider examples of zonally symmetric heating profiles in the M-ITCZ system and generate a Hadley circulation consistent with the observed winds. Zonally localized heating creates a wind response throughout the tropics that is carried by a pair of zonally propagating gravity bores driving mean easterlies at the base and mean westerlies at the top of the troposphere. The bores carry low-temperature and upward velocity perturbations to the west of the heating and high-temperature and downward velocity perturbations to the east, making the westward-propagating branch favorable to convective triggering and the eastward-propagating branch favorable to convective suppression.

The mesoscale dynamics of the M-ITCZ describe convectively forced, nonlinear Rossby waves propagating in the zonal winds created by the planetary-scale gravity wave. The authors suggest that convective coupling slows the westward-propagating gravity wave, thereby creating a coupled gravity–Rossby wave that is similar to the westward-propagating disturbances seen in the ITCZ.
A Comparison of the Water Budgets between Clouds from AMMA and TWP-ICE
Authors: Zeng Xiping , Tao Wei-Kuo , Powell Scott W. , Houze Robert A. , Ciesielski Paul , Guy Nick , Pierce Harold , Matsui Toshihisa
Published: September 2012

Two field campaigns, the African Monsoon Multidisciplinary Analysis (AMMA) and the Tropical Warm Pool–International Cloud Experiment (TWP-ICE), took place in 2006 near Niamey, Niger, and Darwin, Northern Territory, Australia, providing extensive observations of mesoscale convective systems (MCSs) near a desert and a tropical coast, respectively. Under the constraint of their observations, three-dimensional cloud-resolving model simulations are carried out and presented in this paper to replicate the basic characteristics of the observed MCSs. All of the modeled MCSs exhibit a distinct structure having deep convective clouds accompanied by stratiform and anvil clouds. In contrast to the approximately 100-km-scale MCSs observed in TWP-ICE, the MCSs in AMMA have been successfully simulated with a scale of about 400 km.

These modeled AMMA and TWP-ICE MCSs offer an opportunity to understand the structure and mechanism of MCSs. Comparing the water budgets between AMMA and TWP-ICE MCSs suggests that TWP-ICE convective clouds have stronger ascent while the mesoscale ascent outside convective clouds in AMMA is stronger. A case comparison, with the aid of sensitivity experiments, also suggests that vertical wind shear and ice crystal (or dust aerosol) concentration can significantly impact stratiform and anvil clouds (e.g., their areas) in MCSs. In addition, the obtained water budgets quantitatively describe the transport of water between convective, stratiform, and anvil regions as well as water sources/sinks from microphysical processes, providing information that can be used to help determine parameters in the convective and cloud parameterizations in general circulation models (GCMs).
Climate Impacts of Land-Cover and Land-Use Changes in Tropical Islands under Conditions of Global Climate Change
Authors: Comarazamy Daniel E. , González Jorge E. , Luvall Jeffrey C. , Rickman Douglas L. , Bornstein Robert D.
Published: September 2012

Land-cover and land-use (LCLU) changes have significant climate impacts in tropical coastal regions with the added complexity of occurring within the context of a warming climate. The individual and combined effects of these two factors in tropical islands are investigated by use of an integrated mesoscale atmospheric modeling approach, taking the northeastern region of Puerto Rico as the test case. To achieve this goal, an ensemble of climate simulations is performed, combining two LCLU and global warming scenarios. Reconstructed agricultural maps and sea surface temperatures form the past (1955–59) scenario, while the present (2000–04) scenario is supported with high-resolution remote sensing LCLU data. Here, the authors show that LCLU changes produced the largest near-surface (2-m AGL) air temperature differences over heavily urbanized regions and that these changes do not penetrate the boundary layer. The influence of the global warming signal induces a positive inland gradient of maximum temperature, possibly because of increased trade winds in the present climatology. These increased winds also generate convergence zones and convection that transport heat and moisture into the boundary layer. In terms of minimum temperatures, the global warming signal induces temperature increases along the coastal plains and inland lowlands.
Seasonality of Airmass Pathways to Coastal Antarctica: Ramifications for Interpreting High-Resolution Ice Core Records
Authors: Sinclair Kate E. , Bertler Nancy A. N. , Trompetter W. J. , Baisden W. T.
Published: September 2012

Understanding airmass pathways is critical for ice core interpretation, and the ability to determine the broadscale characteristics and seasonality of synoptic-scale flow using paleoclimate records offers great potential to improve the understanding of past atmospheric circulation. The dominant airmass pathways to a coastal Antarctic ice core site at the Whitehall Glacier in the Ross Sea are modeled using snowfall and high-resolution stable isotope data between 1979 and 2006, combined with back trajectories produced from both NCEP–NCAR and ECMWF Interim Re-Analysis (ERA-Interim) data. Back trajectories generated from both datasets produce comparable results. They show that high snowfall is associated with cyclonic airflow in the Ross Sea with a strong meridional component along the western Ross Sea coast. Over a 28-yr time frame, trajectories also reveal a clear distinction between flow paths associated with above- and below-average annual temperatures (high and low δD) in the ice core record. In cold months (low δD), when there is a strengthened trough of low pressure around the continent, synoptically driven incursions of marine air across West Antarctica and trajectories originating from coastal East Antarctica are dominant. Conversely, in warmer months (high δD), airmass pathways are centered over the Ross Sea and the adjacent Southern Ocean. These trajectories are slower moving and are expected to draw marine moisture from high-latitude seasonally open oceans.