bluuebunny/crossref_metadata_2025 huggingface dataset:
Gastro-Oesophageal Reflux in Noncystic Fibrosis Bronchiectasis
Authors: Lee Annemarie L. , Button Brenda M. , Denehy Linda , Wilson John W.
Published: November 2011

The clinical presentation of noncystic fibrosis bronchiectasis may be complicated by concomitant conditions, including gastro-oesophageal reflux (GOR). Increased acidic GOR is principally caused by gastro-oesophageal junction incompetence and may arise from lower oesophageal sphincter hypotension, including transient relaxations, hiatus hernia, and oesophageal dysmotility. Specific pathophysiological features which are characteristic of respiratory diseases including coughing may further increase the risk of GOR in bronchiectasis. Reflux may impact on lung disease severity by two mechanisms, reflex bronchoconstriction and pulmonary microaspiration. Symptomatic and clinically silent reflux has been detected in bronchiectasis, with the prevalence of 26 to 75%. The cause and effect relationship has not been established, but preliminary reports suggest that GOR may influence the severity of bronchiectasis. Further studies examining the implications of GOR in this condition, including its effect across the disease spectrum using a combination of diagnostic tools, will clarify the clinical significance of this comorbidity.
An Envelope Correlation Formula for(N,N)MIMO Antenna Arrays Using Input Scattering Parameters, and Including Power Losses
Authors: Dama Y. A. S. , Abd-Alhameed R. A. , Jones S. M. R. , Zhou D. , McEwan N. J. , Child M. B. , Excell P. S.
Published: November 2011

The scattering parameter formulation for the envelope correlation in an(N,N)MIMO antenna array has been modified to take the intrinsic antenna power losses into account. This method of calculation provides a major simplification over the use of antenna radiation field patterns. Its accuracy is illustrated in three examples, which also show that the locations of the correlation minima are sensitive to the intrinsic losses.
Comparative Study between Dye-Sensitized and CdS Quantum-Dots-Sensitized TiO2 Solar Cells Using Photoinduced Absorption Spectroscopy
Authors: Bedja Idriss , Hagfeldt Anders
Published: November 2011

Two 8 μm thick TiO2 photoelectrodes have been sensitized separately by N719 dye molecules and CdS quantum dots for a comparison study. Photoinduced absorption (PIA) spectroscopy was employed to investigate the mechanistic properties of electrons under illumination conditions comparable to sunlight. The PIA spectrum of both electrodes (in the presence of electrolyte) is due to electrons in TiO2 and iodine radicals in the electrolyte. In the absence of redox electrolyte, both electrodes show long-lived photoinduced charge-separation with lifetime in a millisecond range (8.5 ms for Q-dot-sensitized TiO2 and 11.5 ms for dye-sensitized TiO2).
Efficiency Considerations and Application Limits of Single-Phase Active Power Filter with Converters for Photoenergy Applications
Authors: Sladić Saša , Skok Srđan , Nedeljković David
Published: November 2011

A new way of connecting PV sources to adaptive voltage active power filter (AV APF) has been compared with classic approach including active power filter (APF). In standard active power filter applications a relatively high DC link voltage (500 V or even more) with a buck converter or lower voltage (approx. 100 V) with boost converter can be used. These two converters appear also in adaptive voltage circuit of AV APF, but in this case it is possible to achieve many different connections of DC source. Benefit of this approach is that the same circuit is used for improving switching conditions in APF and for connection of solar cells. It appears that these two functions support each other and a large variety of DC voltages and currents can be connected to AC mains. Experimental results confirm expectations of increased energy transfer from additional DC source to network, especially for DC voltages being lower than DC link voltage.
A Novel Innate Immune-Enhancement Strategy Combined with IVIG Rescues Mice from FatalStaphylococcus aureusSepticemia
Authors: Rajam Gowrisankar , Hammons Gabrielle M. , Carlone George M. , Sampson Jacquelyn S. , Ades Edwin W.
Published: November 2011

Staphylococcus aureus(SA) is a major community-acquired pathogen. The emergence of drug-resistant strains like, methicillin-resistant SA (MRSA), poses stiff challenges to therapeutic intervention. Passive immune-therapy with specific antibodies is being actively examined to treat fulminant infections with limited success. In this study, we demonstrate that P4, a 28-amino acid peptide, derived from pneumococcal surface adhesin A along with pathogen-specific antibody (IVIG; P4 therapy) is successful in enhancing the opsonophagocytic killing (OPK) ofS. aureus in vitro. We questioned if it is possible to expand P4 therapy to treat staphylococcal infectionsin vivo. P4 therapy in combination with IVIG rescued 7/10 morbidly illS. aureus-infected mice while only 2/10 survived in the control group.
On the Use of Molecular Weight Cutoff Cassettes to Measure Dynamic Relaxivity of Novel Gadolinium Contrast Agents: Example Using Hyaluronic Acid Polymer Complexes in Phosphate-Buffered Saline
Authors: Kasraie Nima , Oviatt Henry Wayne , Clarke Geoffrey David
Published: November 2011

The aims of this study were to determine whether standard extracellular contrast agents of Gd(III) ions in combination with a polymeric entity susceptible to hydrolytic degradation over a finite period of time, such as Hyaluronic Acid (HA), have sufficient vascular residence time to obtain comparable vascular imaging to current conventional compounds and to obtain sufficient data to show proof of concept that HA with Gd-DTPA ligands could be useful as vascular imaging agents. We assessed the dynamic relaxivity of the HA bound DTPA compounds using a custom-made phantom, as well as relaxation rates at 10.72 MHz with concentrations ranging between 0.09 and 7.96 mM in phosphate-buffered saline. Linear dependences of static longitudinal relaxation rate (R1) on concentration were found for most measured samples, and the HA samples continued to produce high signal strength after 24 hours after injection into a dialysis cassette at 3T, showing superior dynamic relaxivity values compared to conventional contrast media such as Gd-DTPA-BMA.
Current Controversies in Newer Therapies to Treat Birth Asphyxia
Authors: Wintermark Pia
Published: November 2011

Despite major advances in monitoring technology and knowledge of fetal and neonatal pathophysiology, neonatal hypoxic-ischemic encephalopathy (HIE) remains one of the main causes of severe adverse neurological outcome in children. Until recently, there were no therapies other than supportive measures. Over the past several years, mild hypothermia has been proven to be safe to treat HIE. Unfortunately, this neuroprotective strategy seems efficient in preventing brain injury in some asphyxiated newborns, but not in all of them. Thus, there is increasing interest to rapidly understand how to refine hypothermia therapy and add neuroprotective or neurorestorative strategies. Several promising newer treatments to treat birth asphyxia and prevent its devastating neurological consequences are currently being tested. In this paper, the physiopathology behind HIE, the currently available treatment, the potential alternatives, and the next steps before implementation of these other treatments are reviewed.
Thermal and Mechanical Properties of Polyethylene/Doped-TiO2Nanocomposites Synthesized Using In Situ Polymerization
Authors: Abdul Kaleel S. H. , Bahuleyan Bijal Kottukkal , Masihullah J. , Al-Harthi Mamdouh
Published: November 2011

Ethylene polymerization was carried out using highly active metallocene catalysts (Cp2ZrCl2and Cp2TiCl2) in combination with methylaluminoxane. Titanium (IV) oxide containing 1% Mn as dopant was used as nanofillers. The effects of filler concentration, reaction temperature, and pressure on the thermal and mechanical properties of polymer were analyzed. The improvement of nanoparticles dispersion in the polyethylene matrix was checked by WAXD. The thermal properties were analyzed using differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). The filler impact on the melting temperature of polyethylene synthesized using Cp2ZrCl2was very minimal which is due to the degree of short-chain branching. The ash content was also analyzed for each nanocomposite and found to be in line with the activity of the catalyst. There was a significant increase in the mechanical properties of the polyethylene by addition of filler.
Biosynthetic Pathways and the Role of the Mas Receptor in the Effects of Angiotensin-(1–7) in Smooth Muscles
Authors: Fressatto de Godoy Marcio Augusto , Pernomian Larissa , de Oliveira Ana Maria , Rattan Satish
Published: November 2011

Ang-(1–7) is produced via degradation of Ang II by the human angiotensin converting enzyme, also known as ACE2. In the cardiovascular system, Ang-(1–7) has been shown to produce effects that are opposite to those of Ang II. These include smooth muscle relaxation and cardioprotection. While the roles of Ang-(1–7) in other systems are currently topic of intense research, functional data suggest a relaxation action in gastrointestinal smooth muscles in a way that corroborates the results obtained from vascular tissues. However, more studies are necessary to determine a relevant role for Ang-(1–7) in the gastrointestinal system. The Ang-(1–7) actions are mediated by a distinct, functional, Ang-(1–7) receptor: theMas receptoras shown by diverse studies involving site-specific binding techniques, selective antagonists, and targeted gene deletion. This paper provides an overview of the functional role and the molecular pathways involved in the biosynthesis and activity of Ang-(1–7) in diverse systems.
Protective Role ofFicus caricaStem Extract against Hepatic Oxidative Damage Induced by Methanol in Male Wistar Rats
Authors: Saoudi Mongi , El Feki Abdelfattah
Published: November 2011

The present study was aimed to investigate the antioxidant activity ofFicus caricastem extract (FE) in methanol-induced hepatotoxicity in male Wistar rats. The rats were divided into two batches: 16 control rats (C) drinking tap water and 16 treated rats drinkingFicus caricastem extract for six weeks. Then, each group was divided into two subgroups, and one of them was intraperitoneally injected (i.p.) daily methanol at a dose of 2.37 g/kg body weight i.p. for 30 days, for four weeks. The results showed that FE was found to contain large amounts of polyphenols and carotenoids. The treatment with methanol exhibited a significant increase of serum hepatic biochemical parameters (ALT, AST, ALP, and LDH) and hepatic lipid peroxidation. Hepatic antioxidant enzymes, namely, SOD, CAT, and GSH-Px, were significantly decreased in methanol-treated animals. FE treatment prior to methanol intoxication has significant role in protecting animals from methanol-induced hepatic oxidative damage.
Local Regeneration of Dentin-Pulp Complex Using Controlled Release of FGF-2 and Naturally Derived Sponge-Like Scaffolds
Authors: Kitamura Chiaki , Nishihara Tatsuji , Terashita Masamichi , Tabata Yasuhiko , Washio Ayako
Published: November 2011

Restorative and endodontic procedures have been recently developed in an attempt to preserve the vitality of dental pulp after exposure to external stimuli, such as caries infection or traumatic injury. When damage to dental pulp is reversible, pulp wound healing can proceed, whereas irreversible damage induces pathological changes in dental pulp, eventually requiring its removal. Nonvital teeth lose their defensive abilities and become severely damaged, resulting in extraction. Development of regeneration therapy for the dentin-pulp complex is important to overcome limitations with presently available therapies. Three strategies to regenerate the dentin-pulp complex have been proposed; regeneration of the entire tooth, local regeneration of the dentin-pulp complex from amputated dental pulp, and regeneration of dental pulp from apical dental pulp or periapical tissues. In this paper, we focus on the local regeneration of the dentin-pulp complex by application of exogenous growth factors and scaffolds to amputated dental pulp.
Preparation of Porous F-WO3/TiO2Films with Visible-Light Photocatalytic Activity by Microarc Oxidation
Authors: Yeh Chung-Wei , Wu Kee-Rong , Hung Chung-Hsuang , Chang Hao-Cheng , Hsu Chuan-Jen
Published: November 2011

Porous F-WO3/TiO2(mTiO2) films are prepared on titanium sheet substrates using microarc oxidation (MAO) technique. The X-ray diffraction patterns show that visible-light (Vis) enabling mTiO2films with a very high content of anatase TiO2and high loading of WO3are successfully synthesized at a low applied voltage of 300 V using electrolyte contenting NaF and Na2WO4without subsequent heat treatment. The cross-sectional transmission electron microscopy micrograph reveals that the mTiO2films feature porous networks connected by many micron pores. The diffused reflection spectrum displays broad absorbance across the UV-Vis regions and a significant red shift in the band gap energy (∼2.23 eV) for the mTiO2film. Owing to the high specific surface area from the porous microstructure, the mTiO2film shows a 61% and 50% rate increase in the photocatalytic dye degradation, as compared with the N,C-codoped TiO2films under UV and Vis irradiation, respectively.
Clinical Experience of Auditory Brainstem Response Testing on Pediatric Patients in the Operating Room
Authors: Zhou Guangwei , Dornan Briana , Hinchion Wheaton
Published: November 2011

Objectives. To review our experience of conducting auditory brainstem response (ABR) test on children in the operating room and discuss the benefits versus limitations of this practice.Methods. Retrospective review study conducted in a pediatric tertiary care facility. A total of 267 patients identified with usable data, including ABR results, medical and surgical notes, and follow-up evaluation.Results. Hearing status successfully determined in all patients based on the ABR results form the operating room. The degrees and the types of hearing loss also documented in most of the cases. In addition, multiple factors that may affect the outcomes of ABR in the operating room identified.Conclusions. Hearing loss in children with complicated medical issues can be accurately evaluated via ABR testing in the operating room. Efforts should be made to eliminate adverse factors to ABR recording, and caution should be taken when interpreting ABR results from the operating room.
The Use of Geographically Weighted Regression for the Relationship among Extreme Climate Indices in China
Authors: Wang Chunhong , Zhang Jiangshe , Yan Xiaodong
Published: November 2011

The changing frequency of extreme climate events generally has profound impacts on our living environment and decision‐makers. Based on the daily temperature and precipitation data collected from 753 stations in China during 1961–2005, the geographically weighted regression (GWR) model is used to investigate the relationship between the index of frequency of extreme precipitation (FEP) and other climate extreme indices including frequency of warm days (FWD), frequency of warm nights (FWN), frequency of cold days (FCD), and frequency of cold nights (FCN). Assisted by some statistical tests, it is found that the regression relationship has significant spatial nonstationarity and the influence of each explanatory variable (namely, FWD, FWN, FCD, and FCN) on FEP also exhibits significant spatial inconsistency. Furthermore, some meaningful regional characteristics for the relationship between the studied extreme climate indices are obtained.
HIC-5: A Mobile Molecular Scaffold Regulating the Anchorage Dependence of Cell Growth
Authors: Shibanuma Motoko , Mori Kazunori , Nose Kiyoshi
Published: November 2011

HIC-5 is a multidomain LIM protein homologous to paxillin that serves as a molecular scaffold at focal adhesions and in the nucleus. It forms mobile molecular units with LIM-only proteins, PINCH, and CRP2 and translocates in and out of the nucleus via a nuclear export signal (NES). Of note, NES of HIC-5 is distinctive in its sensitivity to the cellular redox state. Recently, the mobile units of HIC-5 have been suggested to be involved in the regulation of the anchorage dependence of cell growth. On loss of adhesion, an increase in reactive oxygen species in the cells modifies NES and stops shuttling, which leads to cell-cycle control. More specifically, the system circumvents nuclear localization of cyclin D1 and transactivatesp21Cip1in detached cells, thereby avoiding anchorage-independent cell growth. Thus, the HIC-5-LIM only protein complex has emerged as a fail-safe system for regulating the anchorage dependence of cell growth.
Photodegradation of Malachite Green by Nanostructured BiWO Visible Light-Induced Photocatalyst
Authors: Chen Yijie , Zhang Yaqin , Liu Chen , Lu Aimin , Zhang Weihua
Published: November 2011

Bi2WO6photocatalyst was first utilized to degrade malachite green. The effects of the concentration of malachite green, the pH value, and the concentration of Bi2WO6on the photocatalytic efficiency were investigated. This study presents a strategy to eliminate highly toxic and persistent dyes such as malachite green.
BartonellaInfection in Immunocompromised Hosts: Immunology of Vascular Infection and Vasoproliferation
Authors: Mosepele Mosepele , Mazo Dana , Cohn Jennifer
Published: November 2011

Most infections by genusBartonellain immunocompromised patients are caused byB. henselaeandB. quintana. Unlike immunocompetent hosts who usually develop milder diseases such as cat scratch disease and trench fever, immunocompromised patients, including those living with HIV/AIDS and posttransplant patients, are more likely to develop different and severe life-threatening disease. This paper will discussBartonella'smanifestations in immunosuppressed patients and will examineBartonella'sinteraction with the immune system including its mechanisms of establishing infection and immune escape. Gaps in current understanding of the immunology ofBartonellainfection in immunocompromised hosts will be highlighted.
A Validated RP-HPLC Method for the Estimation of Pizotifen in Pharmaceutical Dosage Form
Authors: Basaveswara Rao M. V. , Nagendrakumar A. V. D , Maiti Sushanta , Chandrasekhar N.
Published: November 2011

A simple, selective, linear, precise, and accurate RP-HPLC method was developed and validated for rapid assay of Pizotifen in pharmaceutical dosage form. Isocratic elution at a flow rate of 1.0 mL/min was employed on Chromosil C18 (250 mm × 4.6 mm, 5 μm) column at ambient temperature. The mobile phase consists of methanol : acetonitrile in the ratio of 10 : 90 v/v. The UV detection wavelength was 230 nm, and 20 μL sample was injected. The retention time for Pizotifen was 2.019 min. The percent RSD for accuracy of the method was found to be 0.2603%. The method was validated as per the ICH guidelines. The method can be successfully applied for routine analysis of Pizotifen in the rapid and reliable determination of Pizotifen in pharmaceutical dosage form.
Tanshinone IIA Inhibits Growth of Keratinocytes through Cell Cycle Arrest and Apoptosis: Underlying Treatment Mechanism of Psoriasis
Authors: Li Fu-Lun , Xu Rong , Zeng Qing-chun , Li Xin , Chen Jie , Wang Yi-Fei , Fan Bin , Geng Lin , Li Bin
Published: November 2011

The aim of the present investigation was to elucidate the cellular mechanisms whereby Tanshinone IIA (Tan IIA) leads to cell cycle arrest and apoptosisin vitroin keratinocytes, the target cells in psoriasis. Tan IIA inhibited proliferation of mouse keratinocytes in a dose- and time-dependent manner and induced apoptosis, resulting in S phase arrest accompanied by down-regulation of pCdk2 and cyclin A protein expression. Furthermore, Tan IIA-induced apoptosis and mitochondrial membrane potential changes were also further demonstrated by DNA fragmentation, single-cell gel electrophoresis assay (SCGE), and flow cytometry methods. Apoptosis was partially blocked by the caspase-3 inhibitor Ac-DEVD-CHO. Mitochondrial regulation of apoptosis further downstream was investigated, showing changes in the mitochondrial membrane potential, cytochrome c release into the cytoplasm, and enhanced activation of cleaved caspase-3 and Poly ADP-ribose polymerase (PARP). There was also no translocation of apoptosis-inducing factor (AIF) from mitochondria to the nucleus in apoptotic keratinocytes, indicating Tan IIA-induced apoptosis occurs mainly through the caspase pathway. Our findings provide the molecular mechanisms by which Tan IIA can be used to treat psoriasis and support the traditional use ofSalvia miltiorrhiza Bungee (Labiatae)for psoriasis and related skin diseases.
Phase I, Dose-Escalation Trial of the Oral Cyclin-Dependent Kinase 4/6 Inhibitor PD 0332991, Administered Using a 21-Day Schedule in Patients with Advanced Cancer
Authors: Flaherty Keith T. , LoRusso Patricia M. , DeMichele Angela , Abramson Vandana G. , Courtney Rachel , Randolph Sophia S. , Shaik M. Naveed , Wilner Keith D. , O'Dwyer Peter J. , Schwartz Gary K.
Published: November 2011

Purpose: To identify the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of the first-in-class, oral CDK4/6 inhibitor PD 0332991 administered once daily for 21 of 28 days (3/1 schedule) in patients with retinoblastoma protein (Rb)-positive advanced solid tumors and to describe pharmacokinetic–pharmacodynamic relationships relative to drug effects.

Experimental Design: This open-label phase I study (NCT00141297) enrolled patients who received PD 0332991 orally in six dose-escalation cohorts in a standard 3 + 3 design.

Results: Forty-one patients were enrolled. DLTs were observed in five patients (12%) overall; at the 75, 125, and 150 mg once daily dose levels. The MTD and recommended phase II dose of PD 0332991 was 125 mg once daily. Neutropenia was the only dose-limiting effect. After cycle 1, grade 3 neutropenia, anemia, and leukopenia occurred in five (12%), three (7%), and one (2%) patient(s), respectively. The most common non-hematologic adverse events included fatigue, nausea, and diarrhea. Thirty-seven patients were evaluable for tumor response; 10 (27%) had stable disease for ≥4 cycles of whom six derived prolonged benefit (≥10 cycles). PD 0332991 was slowly absorbed (median Tmax, 5.5 hours), and slowly eliminated (mean half-life was 25.9 hours) with a large volume of distribution (mean, 2,793 L). The area under the concentration–time curve increased linearly with dose. Using an Emax model, neutropenia was shown to be proportional to exposure.

Conclusions: PD 0332991 warrants phase II testing at 125 mg once daily, at which dose neutropenia was the sole significant toxicity. Clin Cancer Res; 18(2); 568–76. ©2011 AACR.
Ran Is a Potential Therapeutic Target for Cancer Cells with Molecular Changes Associated with Activation of the PI3K/Akt/mTORC1 and Ras/MEK/ERK Pathways
Authors: Yuen Hiu-Fung , Chan Ka-Kui , Grills Claire , Murray James T. , Platt-Higgins Angela , Eldin Osama Sharaf , O'Byrne Ken , Janne Pasi , Fennell Dean A. , Johnston Patrick G. , Rudland Philip S. , El-Tanani Mohamed
Published: November 2011

Purpose: Cancer cells have been shown to be more susceptible to Ran knockdown than normal cells. We now investigate whether Ran is a potential therapeutic target of cancers with frequently found mutations that lead to higher Ras/MEK/ERK [mitogen-activated protein/extracellular signal-regulated kinase (ERK; MEK)] and phosphoinositide 3-kinase (PI3K)/Akt/mTORC1 activities.

Experimental Design: Apoptosis was measured by flow cytometry [propidium iodide (PI) and Annexin V staining] and MTT assay in cancer cells grown under different conditions after knockdown of Ran. The correlations between Ran expression and patient survival were examined in breast and lung cancers.

Results: Cancer cells with their PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways inhibited are less susceptible to Ran silencing–induced apoptosis. K-Ras–mutated, c-Met–amplified, and Pten-deleted cancer cells are also more susceptible to Ran silencing–induced apoptosis than their wild-type counterparts and this effect is reduced by inhibitors of the PI3K/Akt/mTORC1 and MEK/ERK pathways. Overexpression of Ran in clinical specimens is significantly associated with poor patient outcome in both breast and lung cancers. This association is dramatically enhanced in cancers with increased c-Met or osteopontin expression, or with oncogenic mutations of K-Ras or PIK3CA, all of which are mutations that potentially correlate with activation of the PI3K/Akt/mTORC1 and/or Ras/MEK/ERK pathways. Silencing Ran also results in dysregulation of nucleocytoplasmic transport of transcription factors and downregulation of Mcl-1 expression, at the transcriptional level, which are reversed by inhibitors of the PI3K/Akt/mTORC1 and MEK/ERK pathways.

Conclusion: Ran is a potential therapeutic target for treatment of cancers with mutations/changes of expression in protooncogenes that lead to activation of the PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways. Clin Cancer Res; 18(2); 380–91. ©2011 AACR.
TP53 Disruptive Mutations Lead to Head and Neck Cancer Treatment Failure through Inhibition of Radiation-Induced Senescence
Authors: Skinner Heath D. , Sandulache Vlad C. , Ow Thomas J. , Meyn Raymond E. , Yordy John S. , Beadle Beth M. , Fitzgerald Alison L. , Giri Uma , Ang K. Kian , Myers Jeffrey N.
Published: November 2011

Purpose: Mortality of patients with head and neck squamous cell carcinoma (HNSCC) is primarily driven by tumor cell radioresistance leading to locoregional recurrence (LRR). In this study, we use a classification of TP53 mutation (disruptive vs. nondisruptive) and examine impact on clinical outcomes and radiation sensitivity.

Experimental Design: Seventy-four patients with HNSCC treated with surgery and postoperative radiation and 38 HNSCC cell lines were assembled; for each, TP53 was sequenced and the in vitro radioresistance measured using clonogenic assays. p53 protein expression was inhibited using short hairpin RNA (shRNA) and overexpressed using a retrovirus. Radiation-induced apoptosis, mitotic cell death, senescence, and reactive oxygen species (ROS) assays were carried out. The effect of the drug metformin on overcoming mutant p53-associated radiation resistance was examined in vitro as well as in vivo, using an orthotopic xenograft model.

Results: Mutant TP53 alone was not predictive of LRR; however, disruptive TP53 mutation strongly predicted LRR (P = 0.03). Cell lines with disruptive mutations were significantly more radioresistant (P < 0.05). Expression of disruptive TP53 mutations significantly decreased radiation-induced senescence, as measured by SA-β-gal staining, p21 expression, and release of ROS. The mitochondrial agent metformin potentiated the effects of radiation in the presence of a disruptive TP53 mutation partially via senescence. Examination of our patient cohort showed that LRR was decreased in patients taking metformin.

Conclusions: Disruptive TP53 mutations in HNSCC tumors predicts for LRR, because of increased radioresistance via the inhibition of senescence. Metformin can serve as a radiosensitizer for HNSCC with disruptive TP53, presaging the possibility of personalizing HNSCC treatment. Clin Cancer Res; 18(1); 290–300. ©2011 AACR.
Single-Chain Antibody-Based Immunotoxins Targeting Her2/neu: Design Optimization and Impact of Affinity on Antitumor Efficacy and Off-Target Toxicity
Authors: Cao Yu , Marks James D. , Huang Qian , Rudnick Stephen I. , Xiong Chiyi , Hittelman Walter N. , Wen Xiaoxia , Marks John W. , Cheung Lawrence H. , Boland Kim , Li Chun , Adams Gregory P. , Rosenblum Michael G.
Published: November 2011

Recombinant immunotoxins, consisting of single-chain variable fragments (scFv) genetically fused to polypeptide toxins, represent potentially effective candidates for cancer therapeutics. We evaluated the affinity of various anti-Her2/neu scFv fused to recombinant gelonin (rGel) and its effect on antitumor efficacy and off-target toxicity. A series of rGel-based immunotoxins were created from the human anti-Her2/neu scFv C6.5 and various affinity mutants (designated ML3-9, MH3-B1, and B1D3) with affinities ranging from 10−8 to 10−11 mol/L. Against Her2/neu-overexpressing tumor cells, immunotoxins with increasing affinity displayed improved internalization and enhanced autophagic cytotoxicity. Targeting indices were highest for the highest affinity B1D3/rGel construct. However, the addition of free Her2/neu extracellular domain (ECD) significantly reduced the cytotoxicity of B1D3/rGel because of immune complex formation. In contrast, ECD addition had little impact on the lower affinity constructs in vitro. In vivo studies against established BT474 M1 xenografts showed growth suppression by all immunotoxins. Surprisingly, therapy with the B1D3-rGel induced significant liver toxicity because of immune complex formation with shed Her2/neu antigen in circulation. The MH3-B1/rGel construct with intermediate affinity showed effective tumor growth inhibition without inducing hepatotoxicity or complex formation. These findings show that while high-affinity constructs can be potent antitumor agents, they may also be associated with mistargeting through the facile formation of complexes with soluble antigen leading to significant off-target toxicity. Constructs composed of intermediate-affinity antibodies are also potent agents that are more resistant to immune complex formation. Therefore, affinity is an exceptionally important consideration when evaluating the design and efficacy of targeted therapeutics. Mol Cancer Ther; 11(1); 143–53. ©2011 AACR.
Curing “Incurable” Cancer
Authors: Watson James D.
Published: November 2011

Cancer cells are preferentially killed by anticancer agents because key signals for growth and cell division are “always on” as opposed to the alternative “on” and “off” signaling of normal cells. Too much of today's anticancer drug discovery effort may go toward reversing genetically promoted “always on” signals. More effective anticancer drug targets may be found through use of RNAi technologies that pinpoint the key gene regulatory and metabolic weakness of the “always on” cancer cells. Cancer Discovery; 1(6); 477–80. ©2011 AACR.
mTORC 2:1 for Chemotherapy Sensitization in Glioblastoma
Authors: Wick Wolfgang , Blaes Jonas , Weiler Markus
Published: November 2011

mTOR signaling is frequently deregulated in cancer, including brain tumors. Although the signaling of mTOR complex 1 (mTORC1) has been subject to intensive investigations and mTORC1 itself has been a well-established cancer drug target for years, the role of the second complex, mTORC2, remains elusive. Tanaka et al. reveal an EGFRvIII-mTORC2-NFκB signaling cascade and demonstrate that mTORC2 mediates cisplatin resistance through NF-κB in an Akt-independent manner in glioblastoma. Uncovering the role of mTORC2 in chemotherapy resistance in glioblastoma highlights the need for further investigations of mTORC2 inhibition. Cancer Discovery; 1(6); 475–76. ©2011 AACR.

Commentary on Tanaka et al., p. 524.
Cell Death, Damage-Associated Molecular Patterns, and Sterile Inflammation in Cardiovascular Disease
Authors: Zheng Yue , Gardner Sarah E. , Clarke Murray C.H.
Published: November 2011

Cell death and inflammation are ancient processes of fundamental biological importance in both normal physiology and pathology. This is evidenced by the profound conservation of mediators, with ancestral homologues identified from plants to humans, and the number of diseases driven by aberrant control of either process. Apoptosis is the most well-studied cell death, but many forms exist, including autophagy, necrosis, pyroptosis, paraptosis, and the obscure dark cell death. Cell death occurs throughout the cardiovascular system, from initial shaping of the heart and vasculature during development to involvement in pathologies, including atherosclerosis, aneurysm, cardiomyopathy, restenosis, and vascular graft rejection. However, determining whether cell death primarily drives pathology or is a secondary bystander effect is difficult. Inflammation, the primary response of innate immunity, is considered essential in initiating and driving vascular diseases. Cell death and inflammation are inextricably linked with their effectors modulating the other process. Indeed, an evolutionary link between cell death and inflammation occurs at caspase-1 (which activates interleukin-1β), which can induce death by pyroptosis, and is a member of the caspase family vital for apoptosis. This review examines cell death in vascular disease, how it can induce inflammation, and finally the emergence of inflammasomes in vascular pathology.
Community-Based Design: The Democratization of Musical Interface Construction
Authors: Vallis Owen , Kapur Ajay
Published: November 2011

The advent of on-line communities has democratized the process of musical interface design and allowed users to directly participate in the future development of the devices they use. On-line communities, acting as centralized repositories for information pertaining to the development of an interface, allow users to discuss their experiences and ideas as well as providing a framework for managing information pertaining to an interface. This centralized access to information regarding the design, use and development of an interface both focuses and accelerates the developmental process.
Trading Faures: Virtual Musicians and Machine Ethics
Authors: Collins Nick
Published: November 2011

Increased maturity in modeling human musicianship leads to many interesting artistic achievements and challenges. This article takes the opportunity to reflect on future situations in which virtual musicians are traded like baseball cards, associated content-creator and autonomous musical agent rights, and the musical and moral conundrums that may result. Although many scenarios presented here may seem far-fetched with respect to the current level of artificial intelligence, it remains prudent and artistically stimulating to consider them. Accepting basic human curiosity and research teleology, it is salutary to consider the more distant consequences of our actions with respect to aesthetics and ethics.
Spiking Neural P Systems with Astrocytes
Authors: Pan Linqiang , Wang Jun , Hoogeboom Hendrik Jan
Published: November 2011

In a biological nervous system, astrocytes play an important role in the functioning and interaction of neurons, and astrocytes have excitatory and inhibitory influence on synapses. In this work, with this biological inspiration, a class of computation devices that consist of neurons and astrocytes is introduced, called spiking neural P systems with astrocytes (SNPA systems). The computation power of SNPA systems is investigated. It is proved that SNPA systems with simple neurons (all neurons have the same rule, one per neuron, of a very simple form) are Turing universal in both generative and accepting modes. If a bound is given on the number of spikes present in any neuron along a computation, then the computation power of SNPA systems is diminished. In this case, a characterization of semilinear sets of numbers is obtained.
Construction of Stratospheric Temperature Data Records from Stratospheric Sounding Units
Authors: Wang Likun , Zou Cheng-Zhi , Qian Haifeng
Published: November 2011

In recognizing the importance of Stratospheric Sounding Unit (SSU) onboard historical NOAA polar-orbiting satellites in assessment of long-term stratospheric temperature changes and limitations in previous available SSU datasets, this study constructs a fully documented, publicly accessible, and well-merged SSU time series for climate change investigations. Focusing on methodologies, this study describes the details of data processing and bias corrections in the SSU observations for generating consistent stratospheric temperature data records, including 1) removal of the instrument gas leak effect in its CO2 cell; 2) correction of the atmospheric CO2 increase effect; 3) adjustment for different observation viewing angles; 4) removal of diurnal sampling biases due to satellite orbital drift; and 5) statistical merging of SSU observations from different satellites. After reprocessing, the stratospheric temperature records are composed of nadirlike, gridded brightness temperatures that correspond to identical weighting functions and a fixed local observation time. The 27-yr reprocessed SSU data record comprises global monthly and pentad layer temperatures, with grid resolution of 2.5° latitude by 2.5° longitude, of the midstratosphere (TMS), upper stratosphere (TUS), and top stratosphere (TTS), which correspond to the three SSU channel observations. For 1979–2006, the global mean trends for TMS, TUS, and TTS, are respectively −1.236 ± 0.131, −0.926 ± 0.139, and −1.006 ± 0.194 K decade−1. Spatial trend pattern analyses indicated that this cooling occurred globally with larger cooling over the tropical stratosphere.
New Roles for the Trade Unions
Authors: Kristensen Peer Hull , Rocha Robson Sø
Published: November 2011

This article builds on lessons from Denmark and the Nordic area to offer a novel and comprehensive logic of action within the emerging political economy that may be used to assess the possible new roles that unions can take on. The authors argue that unions are capable of “civilizing” globalization and current forms of governance by becoming responsible for pushing for a governance regime in a new and more egalitarian direction.
Ethnic Inequality in Choice-driven Education Systems
Authors: Jackson Michelle , Jonsson Jan O. , Rudolphi Frida
Published: November 2011

The authors ask whether choice-driven education systems, with comprehensive schools and mass education at the secondary and tertiary level, represented in this article by England and Sweden, provide educational opportunities for ethnic minorities. In studying educational attainment, the authors make a theoretical distinction between mechanisms connected with school performance on the one hand (primary effects) and educational choice, given performance, on the other (secondary effects). Using large national data sets and recently developed methods, they show that performance effects tend to depress the educational attainment of most, although not all, ethnic minorities, whereas choice effects increase the transition rates of these students. This pattern is repeated at the transition to university education. These results are true for many immigrant categories in both England and Sweden, although immigrant students are a heterogeneous group. Black Caribbean students in England and children of Turkish and South American descent in Sweden fare worst, while several Asian groups do extremely well. The authors conclude that it may be a generic feature of choice-driven school systems in Western societies to benefit non-European immigrants, and they discuss some possible explanations for this.
The Influence of Depression on the Progression of HIV
Authors: Schuster Randi , Bornovalova Marina , Hunt Elizabeth
Published: November 2011

The authors suggest a theoretical model of pathways of HIV progression, with a focus on the contributions of depression—as well as secondary, behavioral and emotional variables. Literature was reviewed regarding (a) comorbid depression and the direct physiological effects on HIV progression and (b) intermediary factors between HIV and disease progression. Intermediary factors included (a) substance use, (b) social support, (c) hopelessness, (d) medication nonadherence, and (e) risky sexual behavior and the contraction of secondary infections. The authors suggest direct physiological pathways from depression to HIV progression and indirect pathways (e.g., behavioral, social, and psychological). In addition to depression, substance use, poor social support, hopelessness, medication nonadherence, and risky sexual behavior seem to be integral in HIV progression. Based on the individual relationships of these variables to depression and HIV progression, a comprehensive multipath model, incorporating all factors, serves to explain how severe emotional distress may lead to accelerated progression to AIDS.
How wikis can be used to manage knowledge in SMEs
Authors: Razmerita Liana , Kirchner Kathrin
Published: November 2011

Companies are exploring new ways of knowledge sharing, collaboration and communication with employees, partners and customers, using social media tools like wikis, blogs or social networks. This article briefly reviews the literature concerning the introduction of social media into organizations and reports a small case study in an IT consulting company following the introduction of a wiki-based solution into its daily practices. The usage of the wiki and its impact on knowledge work are explored. The authors then compare the findings from the literature review with those from the case study. The comparison shows that introducing knowledge processes can start ‘bottom-up’ through an initiative to better manage personal knowledge. Furthermore, the articulation of personal and collective knowledge is possible synergistically and in a more transparent manner.
Out of the box – A life with rubbish information
Authors: James Roger
Published: November 2011

Technology has been largely responsible for the revolution in information science and knowledge management over the last decade. The initial implementations, limited by technology, were concerned with content management which extended and reinforced the focus on structured, encoded and abstract material. Recently technology has extended its impact to massive, extensive messaging – or social media. Whilst social media has simply expanded available content, a more profound shift is to the new capability to manage context: recognizing the patterns of activity as a new source of information. Context management has great potential to address complex, often social, questions providing new insights which we present in a new science of context management. Context management opens up new possibilities in productively using ‘information waste’ – perhaps collected for different purposes or as a by-product of a transactional system – and we predict new companies will emerge from the use of information waste.
Cohesion policy and regional disparities: The recent experience of Greece
Authors: Christofakis Manolis , Papadaskalopoulos Athanasios
Published: November 2011

Twenty years after the beginning of the implementation of EU Cohesion Policy in Greece in the current programming period, 2007–13, for the first time Greek regions have been excluded from Objective 1 ‘Convergence’, a situation that it seems will continue in the next period. As it appears, Cohesion Policy has helped the country and its regions to converge to the European average. However, at an intra-national level, it seems that this is not the case, since internal inter-regional disparities appear to have increased in recent years. To these developments should be added the impact of the economic crisis, which according to early indications has negative repercussions for almost all Greek regions, with varying levels of intensity. These findings, combined with the constantly deteriorating economic situation at national and regional level, sustain the argument that Cohesion Policy will continue to be one of the most important policies of the EU and should constitute a powerful tool against the crisis and its regional dimensions.
Regional economic development policy in Europe: Where next?
Authors: Walburn David , Saublens Christian
Published: November 2011

The recent financial crisis has raised important questions about the future of regional economic development policy in Europe. Budget cuts at a time when economic growth is a priority indicates some lack of confidence by governments in the effectiveness of economic development. Deflationary policies to defend the euro in poorer Member States of the European Union are sharply increasing divergence between economies, with the long-standing economic development imperative of convergence taking a back seat. Migration from poorer to richer countries is likely to increase as a result. Yet EU governments individually and collectively show every sign of wishing to continue to be seen to be doing economic development, even with reduced resources. Thechallenge for economic developers and policy makers is to devise programmes which are not blown off course by sudden changes at the macro level, can demonstrate their value at the regional and national level, and can attract sufficient political support to be sustained for the long term. This article suggests some ways forward.
Mobility and the smart, green and inclusive Europe
Authors: Smith Ian , Atkinson Rob
Published: November 2011

The article sets out a two-dimensional regional typology combining measures of migration and visiting rates. It argues that forms of mobility are interrelated but that the relationship varies by broad type of region and it argues for a place-based approach in managing the interaction of mobility across Europe. Such an approach would require a territorial assessment of both the different dimensions of mobility in specific localities and the conceptualisation of a mobility carrying capacity for localities.
A pilot study of a crossover trial with randomized use of ankle-foot orthoses for people with Charcot–Marie–Tooth disease
Authors: Phillips Margaret F , Robertson Zoe , Killen Brian , White Barney
Published: November 2011

Objectives: This was a pilot and feasibility study of a crossover trial with randomized use of ankle-foot orthoses by people with Charcot–Marie–Tooth (CMT) disease, investigating the effects of these on gait parameters, practical aspects of use and achievement of goals.

Design: A randomized crossover trial.

Setting: The community and ambulatory care.

Participants: Eight adults with CMT disease type 1 or 2.

Interventions: Ligaflex™, custom-made polypropylene and silicone ankle-foot orthoses worn in randomized order for three weeks each, with a washout week in-between; the orthoses of each participant’s choice were then worn until 28 weeks.

Main outcome measures: The primary outcome measure was gait velocity; other outcome measures included Goal Attainment Scaling; Likert scores, concerning aspects of orthosis use and gait analysis parameters.

Results: Gait velocity was greatest wearing polypropylene orthoses, median 0.96 (interquartile range (IQR) 0.75–1.18) ms−1, compared with silicone orthoses, median 0.88 (0.71–1.12) ms−1, and no orthosis, median 0.79 (0.56–0.84) ms−1, P=0.006. The silicone orthoses met goals more successfully and scored more favourably for comfort, 5.0 (5.0–6.0), P=0.003 and pain, 5.5 (4.0–7.0), P=0.015. Future modifications to study methodology were identified, such as a longer period of wear and measurement of walking in different situations.

Conclusions: This study confirmed the feasibility of a larger trial. It indicated differences in walking velocity and parameters concerning wear of the orthoses that could be explored further. A further crossover trial would require 27 participants in order to show a clinically meaningful difference in velocity of 0.13 ms−1 with 90% power and alpha of 5%.