bluuebunny/crossref_metadata_2025 huggingface dataset:
Exercise reduces oxidative stress but does not alleviate hyperinsulinemia or renal dopamine D1receptor dysfunction in obese rats
Authors: Muhammad Abdul Bari , Lokhandwala Mustafa F. , Banday Anees A.
Published: October 2010

Impairment of renal dopamine D1receptor (D1R)-mediated natriuresis is associated with hypertension in humans and animal models, including obese Zucker rats. We have previously reported that treatment of these rats with antioxidants or insulin sensitizers reduced insulin levels and oxidative stress, restored D1R-mediated natriuresis, and reduced blood pressure. Furthermore, the redox-sensitive transcription factor, nuclear factor-κB (NF-κB), has been implicated in impairment of D1R-mediated natriuresis during oxidative stress. In this study, we investigated the effect of exercise on insulin levels, oxidative stress, nuclear translocation of NF-κB, blood pressure, albuminuria, and D1R-mediated natriuresis. The exercise protocol involved treadmill exercise from 3 wk of age for 8 wk. Exercise reduced oxidative stress, nuclear translocation of NF-κB, and albuminuria. However, exercise did not reduce plasma insulin levels or blood pressure. Also, selective D1R agonist (SKF-38393)-mediated increases in sodium excretion and guanosine 5′- O-(3-thiotriphosphate) binding were impaired in obese rats compared with lean rats, and exercise did not restore this defect. We conclude that, while exercise is beneficial in reducing oxidative stress and renal injury, reducing insulin levels may be required to restore D1R-mediated natriuresis in this model of obesity and metabolic syndrome. Furthermore, this study supports previous observations that restoring D1R function contributes to blood pressure reduction in this model.
Holographic Renormalization of Two‐Point Functions in Non‐AdS/Non‐CFT
Authors: Haack Michael , Mück Wolfgang
Published: October 2010

We review recent progress on holographic renormalization in the context of the gauge‐gravity correspondence when the bulk geometry is not asymptotically AdS. The prime example is the Klebanov‐Strassler background, whose dual gauge theory has logarithmically running couplings at all energy scales. The presented formalism provides the counterterms necessary for obtaining finite two‐point functions of the scalar operators in the corresponding dual gauge theories. The presentation is self‐contained and reviews all the relevant background material concerning a gauge‐invariant description of the fluctuations around holographic renormalization group backgrounds.
Identification of Aluminum Responsive Genes in Al-Tolerant Soybean Line PI 416937
Authors: Duressa Dechassa , Soliman Khairy , Chen Dongquan
Published: October 2010

Soybean is one of the most aluminum (Al) sensitive plants. The complex inheritance of Al tolerance trait has so far undermined breeding efforts to develop Al-tolerant soybeans. Discovering the genetic factors underlying the Al tolerance mechanisms would undoubtedly accelerate the pace of such endeavor. As a first step toward this goal, we analyzed the transcriptome profile in roots of Al-tolerant soybean line PI 416937 comparing Al-treated and untreated control plants using DNA microarrays. Many genes involved in transcription activation, stress response, cell metabolism and signaling were differentially expressed. Patterns of gene expression and mechanisms of Al toxicity and tolerance suggest that Cys2His2 and ADR6 transcription activators, cell wall modifying enzymes, and phytosulfokines growth factor play role in soybean Al tolerance. Our data provide insights into the molecular mechanisms of soybean Al tolerance and will have practical value in genetic improvement of Al tolerance trait.
Extraction and Purification of a Lectin from Red Kidney Bean and Preliminary Immune Function Studies of the Lectin and Four Chinese Herbal Polysaccharides
Authors: Hou Yufang , Hou Yubao , Yanyan Liu , Qin Guang , Li Jichang
Published: October 2010

Reversed micelles were used to extract lectin from red kidney beans and factors affecting reverse micellar systems (pH value, ionic strength and extraction time) were studied. The optimal conditions were extraction at pH 4–6, back extraction at pH 9–11, ion strength at 0.15 M NaCl, extraction for 4–6 minutes and back extraction for 8 minutes. The reverse micellar system was compared with traditional extraction methods and demonstrated to be a time-saving method for the extraction of red kidney bean lectin. Mitogenic activity of the lectin was reasonably good compared with commercial phytohemagglutinin (extracted fromPhaseolus vulgaris) Mitogenic properties of the lectin were enhanced when four Chinese herbal polysaccharides were applied concurrently, among which 50 μg/mLAstragalus mongholicuspolysaccharides (APS) with 12.5 μg/mL red kidney bean lectin yielded the highest mitogenic activity and 100 mg/kg/bw APS with 12.5 mg/kg/bw red kidney bean lectin elevated mouse nonspecific immunity.
A Battery-Aware High-Throughput MAC Layer Protocol in Sensor Networks
Authors: Watfa Mohamed K. , Selman Samir , Denkilkian Hovig
Published: October 2010

Energy savings have always been the primary concern in wireless sensor network protocols, however there are applications where latency and throughput are prioritized over energy efficiency and are so significant that the application would not be able to satisfy its requirements without them. The communication unit and the antenna operation consume most of the battery-powered energy of the node. Thus, the access to the medium must be controlled in a very strict manner in order to avoid collisions which result in lost transmissions and have a dramatic impact on the lifetime of the network. Although existing duty cycle MAC protocols are power efficient, they introduce significant end-to-end delivery latency and provide poor throughput. In this paper, we propose SN-MAC, a CDMA-based power controlled medium access protocol that uses both transmitter-based and receiver-based CDMA inside a formed cluster, and uses a TDMA schedule to make the cluster heads communicate with the base station. Our algorithm targets latency and throughput needs in addition to its ability to increase the overall network lifetime. We provide a head-to-head comparison with other protocols through extensive simulations focusing on the performance in terms of latency, throughput, and energy consumption.
Distributed Graph Coloring for Self‐Organization in LTE Networks
Authors: Ahmed Furqan , Tirkkonen Olav , Peltomäki Matti , Koljonen Juha-Matti , Yu Chia-Hao , Alava Mikko
Published: October 2010

Primary Component Carrier Selection and Physical Cell ID Assignment are two important self‐configuration problems pertinent to LTE‐Advanced. In this work, we investigate the possibility to solve these problems in a distributive manner using a graph coloring approach. Algorithms based on real‐valued interference pricing of conflicts converge rapidly to a local optimum, whereas algorithms with binary interference pricing have a chance to find a global optimum. We apply both local search algorithms and complete algorithms such as Asynchronous Weak‐Commitment Search. For system level performance evaluation, a picocellular scenario is considered, with indoor base stations in office houses placed in a Manhattan grid. We investigate a growing network, where neighbor cell lists are generated using practical measurement and reporting models. Distributed selection of conflict‐free primary component carriers is shown to converge with 5 or more component carriers, while distributed assignment of confusion‐free physical cell IDs is shown to converge with less than 15 IDs. The results reveal that the use of binary pricing of interference with an attempt to find a global optimum outperforms real‐valued pricing.
Discontinuous Time Relaxation Method for the Time-Dependent Navier-Stokes Equations
Authors: Neda Monika
Published: October 2010

A high-order family of time relaxation models based on approximate deconvolution
is considered. A fully discrete scheme using discontinuous finite elements is proposed and analyzed. Optimal velocity error estimates are derived. The dependence of these estimates with respect to the Reynolds number Re is , which is an improvement with respect to the continuous finite element method where the dependence is .
A New Scale for Evaluating the Risks for In-Hospital Falls of Newborn Infants: A Failure Modes and Effects Analysis Study
Authors: Abike Faruk , Tiras Sinan , Dünder İlkkan , Bahtiyar Ayfer , Akturk Uzun Ozlem , Demircan Ozlusen
Published: October 2010

We aimed to develop a new scale for evaluating risks and preventive measures for in-hospital falls of newborn infants, from admission to discharge of the expectant mother. Our study was prepared in accordance with Failure Modes and Effects Analysis criteria. The risks and preventive measures for in-hospital falls of newborns were determined. Risk Priority Numbers (RPNs) were determined by multiplication of the scores of severity, probability of occurrence, and probability of detection. Analyses showed that risks having the highest RPNs were the mother with epidural anesthesia (RPN: 350 point), holding of the baby at the moment of delivery (RPN: 240), and transportation of baby right after delivery (RPN: 240). A reduction was detected in all RPNs after the application of preventive measures. Our risk model can function as a guide for obstetric clinics that need to form strategies to prevent newborn falls.
Features and Outcomes In Utero and after Birth of Fetuses with Myocardial Disease
Authors: Fesslova Vlasta , Mongiovì Maurizio , Pipitone Salvatore , Brankovic Jelena , Villa Laura
Published: October 2010

Objectives. Ninety-one fetuses with dilated or hypertrophic cardiomyopathy (DCM, HCM) and myocarditis were studied.Results.Group 1 “DCM”included 19 fetuses: 13 with hydrops (FH) and 5 with associated extracardiac anomalies (ECAs) (15.8%).Group 2 “Myocarditis”included twelve fetuses, having 11 with FH.Group 3 “HCM”included sixty fetuses: 26 had associated ECAs, 17 had maternal diabetes, and 17 were “idiopathic”; however, in one case, a metabolic disorder was found postnatally, and 4 had familiarity for HCM.Outcomes. Ten cases opted for termination of pregnancy. Two cases with DCM and 1 with HCM were lost at follow-up. Out of the cases that continued pregnancy, with known follow-up, mortality was 68.75% in Group 1, 63.6% in Group 2, and 31.3% in Group 3 (the majority with severe ECAs). Surviving cases with DCM and myocarditis improved, 2 with HCM worsened, 6 remained stable, and 26 improved or normalized.Conclusions. Our data show more severe prognosis in DCM and myocarditis and forms with severe associated ECAs.
The p110αand p110βIsoforms of Class I Phosphatidylinositol 3-Kinase Are Involved in Toll-Like Receptor 5 Signaling in Epithelial Cells
Authors: Ivison Sabine M. , Khan Mohammed A. S. , Graham Nicholas R. , Shobab Leila A. , Yao Yu , Kifayet Arnawaz , Sly Laura M. , Steiner Theodore S.
Published: October 2010

Background. Bacterial flagellin triggers inflammation in mammalian cells via Toll-like receptor (TLR) 5. Release of the chemokine IL-8 in response to flagellin involves NF-κB, p38 MAP kinase, and phosphatidylinositol 3-kinase (PI3K). However, PI3K has been reported to be either pro- or anti-inflammatory in different model systems. We hypothesized that this could be due to different activities of the p110αandβisoforms of PI3K.Results. PI3K and Akt were rapidly activated in Caco-2 colon carcinoma cells by flagellin. Using a plasmid-based shRNA delivery system and novel p110 isoform-specific inhibitors, we found that flagellin-induced IL-8 production was dependent on both p110αand p110β. However in the mouse, inhibition of p110βbut not p110αreduced the increase of serum IL-6 levels induced by intraperitoneal injection of flagellin.Conclusions. These data demonstrate that the p110αandβisoforms of class IA PI3K are both required for the proinflammatory response to flagellin.
The Association between the Availability of Sugar-Sweetened Beverage in School Vending Machines and Its Consumption among Adolescents in California: A Propensity Score Matching Approach
Authors: Shi Lu
Published: October 2010

There is controversy over to what degree banning sugar-sweetened beverage (SSB) sales at schools could decrease the SSB intake. This paper uses the adolescent sample of 2005 California Health Interview Survey to estimate the association between the availability of SSB from school vending machines and the amount of SSB consumption. Propensity score stratification and kernel-based propensity score matching are used to address the selection bias issue in cross-sectional data. Propensity score stratification shows that adolescents who had access to SSB through their school vending machines consumed 0.170 more drinks of SSB than those who did not (). Kernel-based propensity score matching shows the SSB consumption difference to be 0.158 on the prior day (). This paper strengthens the evidence for the association between SSB availability via school vending machines and the actual SSB consumption, while future studies are needed to explore changes in other beverages after SSB becomes less available.
Conserved Molecular Mechanisms Underlying Homeostasis of the Golgi Complex
Authors: Wilson Cathal , Ragnini-Wilson Antonella
Published: October 2010

The Golgi complex performs a central function in the secretory pathway in the sorting and sequential processing of a large number of proteins destined for other endomembrane organelles, the plasma membrane, or secretion from the cell, in addition to lipid metabolism and signaling. The Golgi apparatus can be regarded as a self-organizing system that maintains a relatively stable morphofunctional organization in the face of an enormous flux of lipids and proteins. A large number of the molecular players that operate in these processes have been identified, their functions and interactions defined, but there is still debate about many aspects that regulate protein trafficking and, in particular, the maintenance of these highly dynamic structures and processes. Here, we consider how an evolutionarily conserved underlying mechanism based on retrograde trafficking that uses lipids, COPI, SNAREs, and tethers could maintain such a homeodynamic system.
Synthesis of Nanoporous TiO2and Its Potential Applicability for Dye-Sensitized Solar Cell Using Antocyanine Black Rice
Authors: Yuliarto Brian , Septina Wilman , Fuadi Kasyful , Fanani Fahiem , Muliani Lia , Nugraha
Published: October 2010

Nanoporous mesostructure TiO2powders were synthesized by sol-gel method, withTiCl4as a precursor in methanol solution. The Pluronic PE 6200 of block copolymer was used as the pores template. It was found from XRD measurements, both at400∘C and450∘C calcination temperatures, that the sol-gel technique yielded the nanoporous TiO2with anatase phase. Based onN2adsorption characterization using BET method, the TiO2samples have surface area of 108 m2/g and 88 m2/g for calcination temperatures of400∘C and of450∘C, respectively. From small-angle neutron scattering (SANS) patterns, TiO2samples were observed to have nanoporous structures with pore sizes between 22–24 nm. The TiO2also have order degree which depends on the calcination temperature. The potential applicability of the resulting TiO2is confirmed for dye-sensitized solar cell (DSSC), composed of nanoporous anatase TiO2and natural dye from antocyanine black rice. UV-Vis measurement of dye extracted from the black rice indicated that the antocyanine chelate can propagate into the TiO2nanoporous network. The short circuit photocurrent density (Jsc) under 100 mWcm−2reached 1.287 mAcm−2with open circuit photovoltage (Voc) of 550 mV and the fill factor of 33.4%. The results show that the hybrid organic-inorganic structures are very attractive for future low-cost devices.
Conjugacy Separability of Some One‐Relator Groups
Authors: Tieudjo D. , Moldavanskii D. I.
Published: October 2010

Conjugacy separability of any group of the class of one‐relator groups given by the presentation 〈a, b; [am, bn] = 1〉 (m, n > 1) is proven. The proof made used of theoretical combinatorial group methods, namely the structure of amalgamated free
products and some properties of the subgroups and quotients of any group of the class of
one‐relator groups given above.
Capnography and the Bispectral Index—Their Role in Pediatric Sedation: A Brief Review
Authors: Sammartino Maria , Volpe Barbara , Sbaraglia Fabio , Garra Rossella , D'Addessi Alessandro
Published: October 2010

Sedation in children is increasingly emerging as a minimally invasive technique that may be associated with local anaesthesia or diagnostic and therapeutic procedures which do not necessarily require general anaesthesia. Standard monitoring requirements are not sufficient to ensure an effective control of pulmonary ventilation and deep sedation. Capnography in pediatric sedation assesses the effect of different drugs on the occurrence of respiratory failure and records early indicators of respiratory impairment. The Bispectral index (BIS) allows the reduction of dose requirements of anaesthetic drugs, the reduction in the time to extubation and eye opening, and the reduction in the time to discharge. In the field of pediatric sedation, capnography should be recommended to prevent respiratory complications, particularly in spontaneous ventilation. The use of the BIS index, however, needs further investigation due to a lack of evidence, especially in infants. In this paper, we will investigate the role of capnography and the BIS index in improving monitoring standards in pediatric sedation.
Audit about Medical Decision: Data Transmission Concerning Patients with Dementia Entering French Nursing Homes Does Not Confirm the Diagnosis
Authors: Sébastien Cadier , Eva Hummers-Pradier , Marie Barais , Pierre Barraine , Benoit Chiron , Bernard Le Floch , Patrice Nabbe , Jean-Yves Le Reste
Published: October 2010

Background. Dementia was affecting 855.000 patients in France in 2007. Lanmeur's rural hospital population was representative of the French nursing home's population. The followup was assumed by local GPs, which is also usual care in France for nursing homes. The study looked at clinical and paraclinical data transmitted at the institutionalization time of patients suffering from dementia.
Aim. showing that admission letters did allow establishing a diagnosis of dementia for the GPs.
Method. we included all patients with dementia at the time of institutionalization between July 2000 and July 2007. We searched in the admission letters for 25 criteria extracted from the French guidelines for dementia and Alzheimer disease diagnosis (multiple cross-sectional analysis per year).
Results. 293 patients were included. The median number of diagnostic criteria present in the letters of admission is 1 (first quartile: zero, third quartile: 4, and maximum: 12).
Conclusions. the data in admission letters did not allow the diagnosis of dementia according to the French guidelines. We know that dementia is underchecked and undertreated in France according to the same guidelines. What consequences did this lack of basic data give on motivation for treatment and recurrent diagnosis process for GPs? This has to be evaluated.
Randomized Controlled Trials of Acupuncture (1997–2007): An Assessment of Reporting Quality with a CONSORT‐ and STRICTA‐Based Instrument
Authors: Hammerschlag Richard , Milley Ryan , Colbert Agatha , Weih Jeffrey , Yohalem-Ilsley Beth , Mist Scott , Aickin Mikel
Published: October 2010

The present study describes the development of a comprehensive quality of reporting assessment tool and its application to acupuncture RCTs from 1997–2007. This Oregon CONSORT STRICTA Instrument (OCSI) is based on the revised CONSORT guidelines as modified by the STRICTA recommendations for acupuncture trials. Each of the resulting 27 OCSI items were applied to English language prospective RCTs that compared acupuncture, using manual and/or electro‐stimulation, to no treatment, a sham procedure, or usual biomedical care. The 333 RCTs that met inclusion criteria were dispersed among 27 countries and 141 journals. Mean quality of reporting score for all articles was 63.0% (SD 16.5). Mean OCSI scores revealed a 30.9% improvement over the ten‐year period (P < .001). Our findings suggest that to enhance quality of reporting, authors should better attend to seven specific OCSI items in three categories: practitioner training, adverse events, and aspects of randomization and blinding (n = 5). The broad diversity in geographical origin, publication site and quality of reporting, viewed in light of the considerable room for improvement in mean OCSI scores, emphasizes the importance of making STRICTA as well as CONSORT more widely known to journals and to the acupuncture research community.
The Acute Effects of Swimming on Appetite, Food Intake, and Plasma Acylated Ghrelin
Authors: King James A. , Wasse Lucy K. , Stensel David J.
Published: October 2010

Swimming may stimulate appetite and food intake but empirical data are lacking. This study examined appetite, food intake, and plasma acylated ghrelin responses to swimming. Fourteen healthy males completed a swimming trial and a control trial in a random order. Sixty min after breakfast participants swam for 60 min and then rested for six hours. Participants rested throughout the control trial. During trials appetite was measured at 30 min intervals and acylated ghrelin was assessed periodically (0, 1, 2, 3, 4, 6, and 7.5 h. ). Appetite was suppressed during exercise before increasing in the hours after. Acylated ghrelin was suppressed during exercise. Swimming did not alter energy or macronutrient intake assessed at buffet meals (total trial energy intake: control 9161 kJ, swimming 9749 kJ). These findings suggest that swimming stimulates appetite but indicate that acylated ghrelin and food intake are resistant to change in the hours afterwards.
Utility of Accelerometers to Measure Physical Activity in Children Attending an Obesity Treatment Intervention
Authors: Robertson Wendy , Stewart-Brown Sarah , Wilcock Elizabeth , Oldfield Michelle , Thorogood Margaret
Published: October 2010

Objectives. To investigate the use of accelerometers to monitor change in physical activity in a childhood obesity treatment intervention.Methods. 28 children aged 7–13 taking part in “Families for Health” were asked to wear an accelerometer (Actigraph) for 7-days, and complete an accompanying activity diary, at baseline, 3-months and 9-months. Interviews with 12 parents asked about research measurements.Results. Over 90% of children provided 4 days of accelerometer data, and around half of children provided 7 days. Adequately completed diaries were collected from 60% of children. Children partake in a wide range of physical activity which uniaxial monitors may undermonitor (cycling, nonmotorised scootering) or overmonitor (trampolining). Two different cutoffs (4 METS or 3200 counts⋅min-1) for minutes spent in moderate and vigorous physical activity (MVPA) yielded very different results, although reached the same conclusion regarding a lack of change in MVPA after the intervention. Some children were unwilling to wear accelerometers at school and during sport because they felt they put them at risk of stigma and bullying.Conclusion. Accelerometers are acceptable to a majority of children, although their use at school is problematic for some, but they may underestimate children's physical activity.
Muscle Atrophy and Motor Neuron Degeneration in Human NEDL1 Transgenic Mice
Authors: Zhang Lin , Haraguchi Seiki , Koda Tadayuki , Hashimoto Kenji , Nakagawara Akira
Published: October 2010

Amyotrophic lateral sclerosis (ALS) is the most frequent adult‐onset motor neuron disease. Approximately 20% cases of familial ALS show the mutation in the superoxide dismutase‐1 (SOD1) gene. We previously demonstrated that homologue to E6AP carboxyl terminus‐ (HECT‐) type ubiquitin protein E3 ligase (NEDL1) physically bind to mutated SOD1 protein but not wild‐type SOD1 and promote the degradation of mutated SOD1 protein through ubiquitin‐mediated proteasome pathway. To further understand the role of NEDL1 involved in the pathogenesis of familial ALS, we generated transgenic mice with human NEDL1 cDNA. The transgenic mice with human NEDL1 expression showed motor dysfunctions in rotarod, hanging wire, and footprint pattern examination. Histological studies indicated degeneration of neurons in the lumbar spinal cord and muscle atrophy. The number of activated microglia in the spinal cord of transgenic mice was significantly higher than that of wild‐type mice, suggesting that inflammation might be observed in the spinal cord of transgenic mice. In conclusion, these findings suggest that the human NEDL1 transgenic mice might develop ALS‐like symptoms, showing signs of motor abnormalities, accompanied with significant reduction in muscle strength.
Biocompatible Metal-Oxide Nanoparticles: Nanotechnology Improvement of Conventional Prosthetic Acrylic Resins
Authors: Acosta-Torres Laura S. , López-Marín Luz M. , Núñez-Anita R. Elvira , Hernández-Padrón Genoveva , Castaño Victor M.
Published: October 2010

Nowadays, most products for dental restoration are produced from acrylic resins based on heat-cured Poly(Methyl MethAcrylate) (PMMA). The addition of metal nanoparticles to organic materials is known to increase the surface hydrophobicity and to reduce adherence to biomolecules. This paper describes the use of nanostructured materials, TiO2and Fe2O3, for simultaneously coloring and/or improving the antimicrobial properties of PMMA resins. Nanoparticles of metal oxides were included during suspension polymerization to produce hybrid metal oxides-alginate-containing PMMA. Metal oxide nanoparticles were characterized by dynamic light scattering, and X-ray diffraction. Physicochemical characterization of synthesized resins was assessed by a combination of spectroscopy, scanning electron microscopy, viscometry, porosity, and mechanical tests. Adherence ofCandida albicanscells and cellular compatibility assays were performed to explore biocompatibility and microbial adhesion of standard and novel materials. Our results show that introduction of biocompatible metal nanoparticles is a suitable means for the improvement of conventional acrylic dental resins.
Vascular Endothelial Growth Factor Receptor-1 Signaling Promotes Mobilization of Macrophage Lineage Cells from Bone Marrow and Stimulates Solid Tumor Growth
Authors: Muramatsu Masashi , Yamamoto Seiji , Osawa Tsuyoshi , Shibuya Masabumi
Published: October 2010

Vascular endothelial growth factor and its receptors, including Flt-1 and Flk-1, are involved in angiogenesis under physiologic and pathologic conditions. Recently, Flt-1–expressing cells were reported to contribute to the intracranial growth of glioma cells. However, the role of Flt-1 signaling in solid tumor growth in s.c. tissue has not been elucidated. To investigate how Flt-1 signaling is involved in the proliferation of solid tumors, we implanted tumor cells into wild-type (Wt) and Flt-1 tyrosine kinase (TK)–deficient (Flt-1 TK−/−) mice. Growth of HSML and B16 but not Lewis lung carcinoma cell in s.c. tissue was significantly decreased in Flt-1 TK−/− mice. Angiogenesis in HSML and B16 tumors was remarkably reduced in Flt-1 TK−/− mice. Moreover, the infiltration of macrophage lineage cells into HSML and B16 tumors was clearly suppressed in Flt-1 TK−/− mice. Pericyte marker+ cells were also reduced in Flt-1 TK−/− mice. However, in the border area of tumor, angiogenesis and the infiltration of macrophage lineage cell were basically similar between Wt and Flt-1 TK−/− mice. In bone marrow (BM) transplantation experiments, tumor angiogenesis, infiltration of macrophage lineage cells, and tumor growth were significantly suppressed in Wt/Flt-1 TK−/− mice implanted with Flt-1 TK−/− BM cells compared with those implanted with Wt BM cells. We conclude that Flt-1 signaling is involved in the function of BM-derived cell, such as the migration of macrophages into cancerous tissues, and significantly contributes to angiogenesis and tumor progression. Cancer Res; 70(20); 8211–21. ©2010 AACR.
In silicoModeling andIn vivoEfficacy of Cancer-Preventive Vaccinations
Authors: Palladini Arianna , Nicoletti Giordano , Pappalardo Francesco , Murgo Annalisa , Grosso Valentina , Stivani Valeria , Ianzano Marianna L. , Antognoli Agnese , Croci Stefania , Landuzzi Lorena , De Giovanni Carla , Nanni Patrizia , Motta Santo , Lollini Pier-Luigi
Published: October 2010

Cancer vaccine feasibility would benefit from reducing the number and duration of vaccinations without diminishing efficacy. However, the duration of in vivo studies and the huge number of possible variations in vaccination protocols have discouraged their optimization. In this study, we employed an established mouse model of preventive vaccination using HER-2/neu transgenic mice (BALB-neuT) to validate in silico–designed protocols that reduce the number of vaccinations and optimize efficacy. With biological training, the in silico model captured the overall in vivo behavior and highlighted certain critical issues. First, although vaccinations could be reduced in number without sacrificing efficacy, the intensity of early vaccinations was a key determinant of long-term tumor prevention needed for predictive utility in the model. Second, after vaccinations ended, older mice exhibited more rapid tumor onset and sharper decline in antibody levels than young mice, emphasizing immune aging as a key variable in models of vaccine protocols for elderly individuals. Long-term studies confirmed predictions of in silico modeling in which an immune plateau phase, once reached, could be maintained with a reduced number of vaccinations. Furthermore, that rapid priming in young mice is required for long-term antitumor protection, and that the accuracy of mathematical modeling of early immune responses is critical. Finally, that the design and modeling of cancer vaccines and vaccination protocols must take into account the progressive aging of the immune system, by striving to boost immune responses in elderly hosts. Our results show that an integrated in vivo–in silico approach could improve both mathematical and biological models of cancer immunoprevention. Cancer Res; 70(20); 7755–63. ©2010 AACR.
Carcinoembryonic Antigen Interacts with TGF-β Receptor and Inhibits TGF-β Signaling in Colorectal Cancers
Authors: Li Ying , Cao Hong , Jiao Zhongxian , Pakala Suresh B. , Sirigiri Divijendra Natha Reddy , Li Wenpin , Kumar Rakesh , Mishra Lopa
Published: October 2010

As a tumor marker for colorectal cancers, carcinoembryonic antigen (CEA) enhances the metastatic potential of cancer cells. CEA functions as an intercellular adhesion molecule and is upregulated in a wide variety of human cancers. However, the molecular mechanisms by which CEA mediates metastasis remain to be understood. Transforming growth factor-β (TGF-β) signaling regulates both tumor suppression and metastasis, and also contributes to the stimulation of CEA transcription and secretion in colorectal cancer cells. However, it remains unknown whether CEA, in turn, influences TGF-β functions and if a regulatory cross-talk exists between CEA and the TGF-β signaling pathway. Here, we report that CEA directly interacts with TGF-β receptor and inhibits TGF-β signaling. Targeting CEA with either CEA-specific antibody or siRNA rescues TGF-β response in colorectal cancer cell lines with elevated CEA, thereby restoring the inhibitory effects of TGF-β signaling on proliferation. CEA also enhances the survival of colorectal cancer cells in both local colonization and liver metastasis in animal study. Our study provides novel insights into the interaction between CEA and TGF-β signaling pathway and establishes a negative feedback loop in amplifying the progression of colon cancer cells to more invasive phenotypes. These findings offer new therapeutic opportunities to inhibit colorectal cancer cell proliferation by cotargeting CEA in promoting tumor-inhibitory action of the TGF-β pathway. Cancer Res; 70(20); 8159–68. ©2010 AACR.
hsa-miR-191 Is a Candidate Oncogene Target for Hepatocellular Carcinoma Therapy
Authors: Elyakim Eran , Sitbon Einat , Faerman Alexander , Tabak Sarit , Montia Eve , Belanis Liron , Dov Avital , Marcusson Eric G. , Bennett C. Frank , Chajut Ayelet , Cohen Dalia , Yerushalmi Noga
Published: October 2010

Hepatocellular carcinoma (HCC) is generally a fatal disease due to a paucity of effective treatment options. The identification of oncogenic microRNAs that exert pleiotropic effects in HCC cells may offer new therapeutic targets. In this study, we have identified the human microRNA miR-191 as a potential target for HCC therapy. Inhibition of miR-191 decreased cell proliferation and induced apoptosis in vitro and significantly reduced tumor masses in vivo in an orthotopic xenograft mouse model of HCC. Additionally, miR-191 was found to be upregulated by a dioxin, a known liver carcinogen, and was found to be a regulator of a variety of cancer-related pathways. Our findings offer a preclinical proof of concept for miR-191 targeting as a rational strategy to pursue for improving HCC treatment. Cancer Res; 70(20); 8077–87. ©2010 AACR.
Contextual Synthetic Lethality of Cancer Cell Kill Based on the Tumor Microenvironment
Authors: Chan Norman , Pires Isabel M. , Bencokova Zuzana , Coackley Carla , Luoto Kaisa R. , Bhogal Nirmal , Lakshman Minalini , Gottipati Ponnari , Oliver F. Javier , Helleday Thomas , Hammond Ester M. , Bristow Robert G.
Published: October 2010

Acute and chronic hypoxia exists within the three-dimensional microenvironment of solid tumors and drives therapy resistance, genetic instability, and metastasis. Replicating cells exposed to either severe acute hypoxia (16 hours with 0.02% O2) followed by reoxygenation or moderate chronic hypoxia (72 hours with 0.2% O2) treatments have decreased homologous recombination (HR) protein expression and function. As HR defects are synthetically lethal with poly(ADP-ribose) polymerase 1 (PARP1) inhibition, we evaluated the sensitivity of repair-defective hypoxic cells to PARP inhibition. Although PARP inhibition itself did not affect HR expression or function, we observed increased clonogenic killing in HR-deficient hypoxic cells following chemical inhibition of PARP1. This effect was partially reversible by RAD51 overexpression. PARP1−/− murine embryonic fibroblasts (MEF) showed a proliferative disadvantage under hypoxic gassing when compared with PARP1+/+ MEFs. PARP-inhibited hypoxic cells accumulated γH2AX and 53BP1 foci as a consequence of altered DNA replication firing during S phase–specific cell killing. In support of this proposed mode of action, PARP inhibitor–treated xenografts displayed increased γH2AX and cleaved caspase-3 expression in RAD51-deficient hypoxic subregions in vivo, which was associated with decreased ex vivo clonogenic survival following experimental radiotherapy. This is the first report of selective cell killing of HR-defective hypoxic cells in vivo as a consequence of microenvironment-mediated “contextual synthetic lethality.” As all solid tumors contain aggressive hypoxic cells, this may broaden the clinical utility of PARP and DNA repair inhibition, either alone or in combination with radiotherapy and chemotherapy, even in tumor cells lacking synthetically lethal, genetic mutations. Cancer Res; 70(20); 8045–54. ©2010 AACR.
Baseline Plasma Total Homocysteine and Adenoma Recurrence: Results from a Double Blind Randomized Clinical Trial of Aspirin and Folate Supplementation
Authors: Levine A. Joan , Grau Maria V. , Mott Leila A. , Ueland Per Magne , Baron John A.
Published: October 2010

Background: Elevated plasma total homocysteine (tHcy) is an accepted marker of functional folate deficiency but may have independent effects on colorectal neoplasia risk. It is uncertain whether plasma tHcy is associated with risk at the low levels common in a folate-fortified population.

Methods: Study subjects, about half of whom were recruited after fortification of grain products with folic acid in the United States and Canada, consisted of 871 individuals with a recent history of one or more colorectal adenomas who were randomized to receive either a 1 mg/day folic acid supplement or a placebo within one of three randomly assigned aspirin treatment groups (placebo, 81, or 325 mg/day). Nonfasting plasma tHcy was determined by a gas chromatograph mass chromatography method. We estimated adjusted risk ratios and 95% confidence intervals (95% CI) for one or more adenoma recurrences for each quartile of baseline plasma tHcy using generalized linear regression with an overdispersed Poisson approximation to the binomial.

Results: The Q4/Q1 adjusted risk ratio for any adenoma was 0.98 (95% CI, 0.70-1.38; P trend = 0.17) in the placebo group, and 0.81 (95% CI, 0.58-1.12; P-trend = 0.17) in the folic acid group. Results were similar for adenomas with advanced features. There was no modification by sex, aspirin treatment group or MTHFR 677C>T genotype.

Conclusions: Plasma tHcy is not an independent marker for an increase in colorectal adenoma recurrence risk in postfortification populations in which plasma tHcy levels are in the lower range of values.

Impact: Controlling plasma tHcy levels is unlikely to favorably modify adenoma recurrence risk in folate-fortified populations. Cancer Epidemiol Biomarkers Prev; 19(10); 2541–8. ©2010 AACR.
Transduction of Tumor-Specific T Cells with CXCR2 Chemokine Receptor Improves Migration to Tumor and Antitumor Immune Responses
Authors: Peng Weiyi , Ye Yang , Rabinovich Brian A. , Liu Chengwen , Lou Yanyan , Zhang Minying , Whittington Mayra , Yang Yan , Overwijk Willem W. , Lizée Gregory , Hwu Patrick
Published: October 2010

Purpose: One of the most important rate-limiting steps in adoptive cell transfer (ACT) is the inefficient migration of T cells to tumors. Because melanomas specifically express the chemokines CXCL1 and CXCL8 that are known to facilitate the CXCR2-dependent migration by monocytes, our aim is to evaluate whether introduction of the CXCR2 gene into tumor-specific T cells could further improve the effectiveness of ACT by enhancing T-cell migration to tumor.

Experimental Design: In this study, we used transgenic pmel-1 T cells, which recognize gp100 in the context of H-2Db, that were transduced with luciferase gene to monitor the migration of transferred T cells in vivo. To visualize luciferase-expressing T cells within a tumor, a nonpigmented tumor is required. Therefore, we used the MC38 tumor model, which naturally expresses CXCL1.

Results: Mice bearing MC38/gp100 tumor cells treated with CXCR2/luciferase-transduced pmel-1 T cells showed enhanced tumor regression and survival compared with mice receiving control luciferase-transduced pmel-1 T cells. We also observed preferential accumulation of CXCR2-expressing pmel-1 T cells in the tumor sites of these mice using bioluminescence imaging. A similar enhancement in tumor regression and survival was observed when CXCR2-transduced pmel-1 T cells were transferred into mice bearing CXCL1-transduced B16 tumors compared with mice treated with control pmel-1 T cells.

Conclusions: These results implicate that the introduction of the CXCR2 gene into tumor-specific T cells can enhance their localization to tumors and improve antitumor immune responses. This strategy may ultimately enable personalization of cancer therapies based on chemokine expression by tumors. Clin Cancer Res; 16(22); 5458–68. ©2010 AACR.
A Synergistic Interaction between Lapatinib and Chemotherapy Agents in a Panel of Cell Lines Is Due to the Inhibition of the Efflux Pump BCRP
Authors: Perry Jackie , Ghazaly Essam , Kitromilidou Christiana , McGrowder Eva H. , Joel Simon , Powles Thomas
Published: October 2010

Lapatinib is a specific HER1 and 2 targeted tyrosine kinase inhibitor now widely used in combination with chemotherapy in the clinical setting. In this work, we investigated the interactions between lapatinib and specific chemotherapy agents (cisplatin, SN-38, topotecan) in a panel of cell lines [breast (n = 2), lung (n = 2), testis (n = 4)]. A high-sensitivity cell proliferation/cytotoxicity ATP assay and flow cytometry were used to determine cell viability, apoptosis, and the effect of the drugs on cell-cycle distribution. CalcuSyn analysis was employed to formally identify synergistic interactions between drugs. Intracellular concentrations of SN-38 were measured using a novel high-performance liquid chromatography (HPLC) technique. Flow cytometry and HPLC techniques were used to identify the effect of lapatinib on drug influx and efflux pumps, using specific substrates and inhibitors of these pumps. Results showed significant synergy between SN-38, and lapatinib in the majority of cell lines (combination index < 0.75), associated with increased apoptosis. This synergy was not universal but, when observed (Susa S/R, H1975, H358, and MDA-MB-231 cell lines), was related to SN-38 intracellular accumulation (2.2- to 4.8-fold increase, P < 0.05 for each), attributable to the inhibition of the breast cancer–related protein (BCRP) efflux pump by lapatinib. Flow cytometry analysis showed that lapatinib (10 μmol/L) inhibited the efflux of mitoxantrone, a specific substrate of the BCRP pump, in a manner similar to fumitremorgin C, a known BCRP inhibitor, confirming lapatinib as a BCRP inhibitor. This work shows that lapatinib has a direct inhibitory effect on BCRP accounting for the synergistic findings. The synergy is cell line dependent and related to the activity of specific efflux pumps. Mol Cancer Ther; 9(12); 3322–9. ©2010 AACR.
The Quassinoid Derivative NBT-272 Targets Both the AKT and ERK Signaling Pathways in Embryonal Tumors
Authors: Castelletti Deborah , Fiaschetti Giulio , Di Dato Valeria , Ziegler Urs , Kumps Candy , De Preter Katleen , Zollo Massimo , Speleman Frank , Shalaby Tarek , De Martino Daniela , Berg Thorsten , Eggert Angelika , Arcaro Alexandre , Grotzer Michael A.
Published: October 2010

The quassinoid analogue NBT-272 has been reported to inhibit MYC, thus warranting a further effort 7to better understand its preclinical properties in models of embryonal tumors (ET), a family of childhood malignancies sharing relevant biological and genetic features such as deregulated expression of MYC oncogenes. In our study, NBT-272 displayed a strong antiproliferative activity in vitro that resulted from the combination of diverse biological effects, ranging from G1/S arrest of the cell cycle to apoptosis and autophagy. The compound prevented the full activation of both eukaryotic translation initiation factor 4E (eIF4E) and its binding protein 4EBP-1, regulating cap-dependent protein translation. Interestingly, all responses induced by NBT-272 in ET could be attributed to interference with 2 main proproliferative signaling pathways, that is, the AKT and the MEK/extracellular signal-regulated kinase pathways. These findings also suggested that the depleting effect of NBT-272 on MYC protein expression occurred via indirect mechanisms, rather than selective inhibition. Finally, the ability of NBT-272 to arrest tumor growth in a xenograft model of neuroblastoma plays a role in the strong antitumor activity of this compound, both in vitro and in vivo, with its potential to target cell-survival pathways that are relevant for the development and progression of ET. Mol Cancer Ther; 9(12); 3145–57. ©2010 AACR.
Targeting Aldehyde Dehydrogenase Cancer Stem Cells in Ovarian Cancer
Authors: Landen Charles N. , Goodman Blake , Katre Ashwini A. , Steg Adam D. , Nick Alpa M. , Stone Rebecca L. , Miller Lance D. , Mejia Pablo Vivas , Jennings Nicolas B. , Gershenson David M. , Bast Robert C. , Coleman Robert L. , Lopez-Berestein Gabriel , Sood Anil K.
Published: October 2010

Aldehyde dehydrogenase-1A1 (ALDH1A1) expression characterizes a subpopulation of cells with tumor-initiating or cancer stem cell properties in several malignancies. Our goal was to characterize the phenotype of ALDH1A1-positive ovarian cancer cells and examine the biological effects of ALDH1A1 gene silencing. In our analysis of multiple ovarian cancer cell lines, we found that ALDH1A1 expression and activity was significantly higher in taxane- and platinum-resistant cell lines. In patient samples, 72.9% of ovarian cancers had ALDH1A1 expression in which the percentage of ALDH1A1-positive cells correlated negatively with progression-free survival (6.05 vs. 13.81 months; P < 0.035). Subpopulations of A2780cp20 cells with ALDH1A1 activity were isolated for orthotopic tumor–initiating studies, where tumorigenicity was approximately 50-fold higher with ALDH1A1-positive cells. Interestingly, tumors derived from ALDH1A1-positive cells gave rise to both ALDH1A1-positive and ALDH1A1-negative populations, but ALDH1A1-negative cells could not generate ALDH1A1-positive cells. In an in vivo orthotopic mouse model of ovarian cancer, ALDH1A1 silencing using nanoliposomal siRNA sensitized both taxane- and platinum-resistant cell lines to chemotherapy, significantly reducing tumor growth in mice compared with chemotherapy alone (a 74%–90% reduction; P < 0.015). These data show that the ALDH1A1 subpopulation is associated with chemoresistance and outcome in ovarian cancer patients, and targeting ALDH1A1 sensitizes resistant cells to chemotherapy. ALDH1A1-positive cells have enhanced, but not absolute, tumorigenicity but do have differentiation capacity lacking in ALDH1A1-negative cells. This enzyme may be important for identification and targeting of chemoresistant cell populations in ovarian cancer. Mol Cancer Ther; 9(12); 3186–99. ©2010 AACR.
GD3 Synthase Expression Enhances Proliferation and Tumor Growth of MDA-MB-231 Breast Cancer Cells through c-Met Activation
Authors: Cazet Aurélie , Lefebvre Jonathan , Adriaenssens Eric , Julien Sylvain , Bobowski Marie , Grigoriadis Anita , Tutt Andrew , Tulasne David , Le Bourhis Xuefen , Delannoy Philippe
Published: October 2010

The disialoganglioside GD3 is overexpressed in ∼50% of invasive ductal breast carcinoma, and the GD3 synthase gene (ST8SIA1) displays higher expression among estrogen receptor–negative breast cancer tumors, associated with a decreased overall survival of breast cancer patients. However, no relationship between ganglioside expression and breast cancer development and aggressiveness has been reported. We have previously shown that overexpression of GD3 synthase induces the accumulation of b- and c-series gangliosides (GD3, GD2, and GT3) at the cell surface of MDA-MB-231 breast cancer cells together with the acquisition of a proliferative phenotype in the absence of serum. Here, we show that phosphoinositide 3-kinase/Akt and mitogen-activated protein kinase/extracellular signal-regulated kinase pathways are constitutively activated in GD3 synthase–expressing cells. Analysis of phosphorylation of tyrosine kinase receptors shows a specific c-Met constitutive activation in GD3 synthase–expressing cells, in the absence of its ligand, hepatocyte growth factor/scatter factor. In addition, inhibition of c-Met or downstream signaling pathways reverses the proliferative phenotype. We also show that GD3 synthase expression enhances tumor growth in severe combined immunodeficient mice. Finally, a higher expression of ST8SIA1 and MET in the basal subtype of human breast tumors are observed. Altogether, our results show that GD3 synthase expression is sufficient to enhance the tumorigenicity of MDA-MB-231 breast cancer cells through a ganglioside-dependent activation of the c-Met receptor. Mol Cancer Res; 8(11); 1526–35. ©2010 AACR.
After This Strange Starting: Method, Theory and the Philosophy of Religion(s)
Authors: Rennie Bryan
Published: October 2010

This paper argues for the ineluctably philosophical nature of “method and theory” in the academic study of religion. More to the point, it encourages a significant re-consideration of what passes for the “Philosophy of Religion,” a subfield whose concentration on mediaeval and contemporary Christian philosophical theology has impeded the development of an effective philosophical treatment of global human religious behavior. The paper seeks a History of Religions that is more informed by and about philosophy as a tradition and as a method and which therefore includes a disciplinary Philosophy of Religion(s) that is more relevant, practical, far-ranging, and productive.