bluuebunny/crossref_metadata_2025 huggingface dataset:
A Computer-Aided Process Simulation Model to Navigate Value Chain Reconfiguration Using a Three-Layered Methodology
Authors: Tsai Chung-Chou , Siengthai Sununta , Krairit Donyaprueth , Johri Lalit M.
Published: January 2012

This paper develops a computer-aided process simulation model (CPSM) to navigate value chain reconfiguration. The model uses a three-layered methodology incorporating the principle of knowledge-integrated traceability (KIT) to create more efficient performance measures and provides a rigorous and stepwise clustered module structure that will act as a guideline for all entities decision makers are involved. The model is based on three kinds of mature toolsets variable. First, an in-depth interview of a group of experts makes the BSC (Balanced Scorecard) KIT model along with AHP (Analytic Hierarchy Process) technique into an integrated AHP-BSC structure. Second, internal validation of core propositions during CPSM development is then used to construct an account both qualitative and quantitative decision factors in the best delivery causality diagram of theory-building mode. Defining the KIT of toolset variables into two specific themes allows a practical hierarchy for AHP-BSC structure to be evaluated without excessive computation barriers, and the systems thinking archetype of strategic activities in the ARIS-EPCs (Architecture of Integrated Information System/extending Event-driven Process Chains) architecture delivers the validity and reliability of research methodology as validation model of CPSM development. Third, the hybrid ST-ARIS (System Thinking) simulation model is constructed based on the feasibility test of relevant decision factors whether or not KPI (Key Performance Indicator) could be measured. The reconfiguration provides new insights for contributing to the foundations to link the process capability of the value chain with the three-layered methodology, and emphasises the CPSM development by highlighting a specific approach associated with KIT.
QUARTETS AND UNROOTED PHYLOGENETIC NETWORKS
Authors: GAMBETTE PHILIPPE , BERRY VINCENT , PAUL CHRISTOPHE
Published: January 2012

Phylogenetic networks were introduced to describe evolution in the presence of exchanges of genetic material between coexisting species or individuals. Split networks in particular were introduced as a special kind of abstract network to visualize conflicts between phylogenetic trees which may correspond to such exchanges. More recently, methods were designed to reconstruct explicit phylogenetic networks (whose vertices can be interpreted as biological events) from triplet data. In this article, we link abstract and explicit networks through their combinatorial properties, by introducing the unrooted analog of level-k networks. In particular, we give an equivalence theorem between circular split systems and unrooted level-1 networks. We also show how to adapt to quartets some existing results on triplets, in order to reconstruct unrooted level-k phylogenetic networks. These results give an interesting perspective on the combinatorics of phylogenetic networks and also raise algorithmic and combinatorial questions.
STRATEGIC ENVIRONMENTAL ASSESSMENT EFFECTIVENESS AND THE INITIATIVE FOR THE INTEGRATION OF REGIONAL INFRASTRUCTURE IN SOUTH AMERICA (IIRSA): A MULTIPLE CASE REVIEW
Authors: KIS MADRID CLAUDIA , HICKEY GORDON M. , BOUCHARD MICHEL A.
Published: January 2012

Over the last decade, South American countries have been promoting physical integration of the territory in response to regional export-driven industrialisation policies and the global demand for agriculture products, livestock, and energy sources. A prominent example of this is the Initiative for the Integration of Regional Infrastructure in South America (IIRSA), which was launched at the Meeting of South American Presidents in 2000. At the time of writing, 514 infrastructure projects (including roads, pipelines, waterways, dams and telecommunications systems), with an estimated investment of US$69 billion, had been initiated. Importantly, previous similar development processes in the region have caused serious negative environmental and social impacts. Therefore, Strategic Environmental Assessment (SEA) has been mandated to ensure that the social and environmental issues are adequately addressed in the project planning process. This paper identifies the conditions under which: (a) the SEAs of the IIRSA projects have been undertaken, and (b) the Action Plans have been (or will be) implemented. Using case studies, it analyses whether the SEAs that have been carried out for the IIRSA's projects can be considered effective under these conditions. Finally, drawing on the case study findings, potential ways for improving SEA performance and maximising effectiveness in South America are discussed.
CO-VALUATION: EXPLORING METHODS FOR EXPERT AND STAKEHOLDER VALUATION
Authors: VAN SCHIE NIENKE , DUIJN MIKE , EDELENBOS JURIAN
Published: January 2012

Many scholars describe a trend towards stakeholder involvement. Also in Dutch water management, this is expected to generate more support and better-informed information for decision-making. An approach or methodology for the combined involvement of stakeholder and expert inputs in decision-making, however, is lacking (Rinaudo and Garin, 2005; Petts and Brooks, 2006; Leach, 2006; Sabatier et al., 2005; Scholz and Stiftel, 2005). In this article we focus on methodological aspects of an integral stakeholder approach in relation to its expected contribution to decision-making. We describe and analyse an approach of co-valuation for spatial issues, including multiple actors involved. Experiences with this approach in a case study on Dutch spatial water management reconfirm that existing assessment methodology does not provide for the involvement of stakeholder inputs and focuses on expert-based information. An interactive approach of (existing) (e)valuation (methods) may involve these various knowledge bases in assessment.
ADAPTIVE NEURO-FUZZY INFERENCE SYSTEM APPROACH FOR FAULT DETECTION AND DIAGNOSIS OF PNEUMATIC VALVE IN CEMENT INDUSTRY
Authors: SUBBARAJ P. , KANNAPIRAN B.
Published: January 2012

The detection and diagnosis of faults in technical systems are of great practical significance and paramount importance for the safe operation of the plant. The early detection of fault can help avoid system shutdown, breakdown and even catastrophe involving human fatalities and material damage. Since the operator cannot monitor all the variables simultaneously, an automated approach is needed for the real time monitoring and diagnosis of the system. This paper presents the design and development of adaptive neuro-fuzzy inference system (ANFIS) model based for the fault detection of pneumatic valve in cooler water spray system in cement industry. The fault detection model is developed by using two different approaches, namely, ANFIS and feed forward network with back propagation algorithm (BPN). The training and testing data required are developed for the ANFIS model and BPN model that were generated at different operating conditions by operating the pneumatic valve and by creating various faults in real time in a laboratory experimental model. The performance of the developed ANFIS model and back propagation were tested and also compared for a total of 19 faults in pneumatic valve used in cooler water spray system. Obtained results of the ANFIS performed better than BPN.
Overexpression of a short human seipin/BSCL2 isoform in mouse adipose tissue results in mild lipodystrophy
Authors: Cui Xin , Wang Yuhui , Meng Lingjun , Fei Weihua , Deng Jingna , Xu Guoheng , Peng Xingui , Ju Shenghong , Zhang Ling , Liu George , Zhao Liping , Yang Hongyuan
Published: January 2012

Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) is a recessive disorder characterized by an almost complete loss of adipose tissue, insulin resistance, and fatty liver. BSCL2 is caused by loss-of-function mutations in the BSCL2/seipin gene, which encodes seipin. The essential role for seipin in adipogenesis has recently been established both in vitro and in vivo. However, seipin is highly upregulated at later stages of adipocyte development, and its role in mature adipocytes remains to be elucidated. We therefore generated transgenic mice overexpressing a short isoform of human BSCL2 gene (encoding 398 amino acids) using the adipocyte-specific aP2 promoter. The transgenic mice produced ∼150% more seipin than littermate controls in white adipose tissue. Surprisingly, the increased expression of seipin markedly reduced the mass of white adipose tissue and the size of adipocytes and lipid droplets. This may be due in part to elevated lipolysis rates in the transgenic mice. Moreover, there was a nearly 50% increase in the triacylglycerol content of transgenic liver. These results suggest that seipin promotes the differentiation of preadipocytes but may inhibit lipid storage in mature adipocytes.
Cannabinoid receptor CB2 protects against balloon-induced neointima formation
Authors: Molica Filippo , Matter Christian M. , Burger Fabienne , Pelli Graziano , Lenglet Sébastien , Zimmer Andreas , Pacher Pal , Steffens Sabine
Published: January 2012

Cannabinoid receptor CB2 activation inhibits inflammatory proliferation and migration of vascular smooth muscle cells in vitro. The potential in vivo relevance of these findings is unclear. We performed carotid balloon distension injury in hypercholesterolemic apolipoprotein E knockout (ApoE−/−) mice receiving daily intraperitoneal injection of the CB2 agonist JWH133 (5 mg/kg) or vehicle, with the first injection given 30 min before injury. Alternatively, we subjected CB2−/− and wild-type (WT) mice to balloon injury. We determined CB2 mRNA and protein expression in dilated arteries of ApoE−/− mice. Neointima formation was assessed histologically. We used bone marrow-derived murine CB2−/− and WT macrophages to study adhesion to plastic, fibronectin, or collagen, and migration was assayed by modified Boyden chamber. Aortic smooth muscle cells were isolated to determine in vitro proliferation rates. We found increased vascular CB2 expression in ApoE−/− mice in response to balloon injury. Seven to twenty-one days after dilatation, injured vessels of JWH133-treated mice had less intimal nuclei numbers as well as intimal and medial areas, associated with less staining for proliferating cells, smooth muscle cells, and macrophages. Complete endothelial repair was observed after 14 days in both JWH133- and vehicle-treated mice. CB2 deficiency resulted in increased intima formation compared with WT, whereas JWH133 did not affect intimal formation in CB2−/− mice. Apoptosis rates assessed by in situ terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling staining 1 h postballooning were significantly higher in the CB2 knockouts. In vitro, bone marrow-derived CB2−/− macrophages showed enhanced adherence and migration compared with WT cells and elevated mRNA levels of adhesion molecules, chemokine receptors CCR1 and 5, and chemokine CCL2. Proliferation rates were significantly increased in CB2−/− smooth muscle cells compared with WT. In conclusion, pharmacological activation or genetic deletion of CB2 receptors modulate neointima formation via protective effects in macrophages and smooth muscle cells.
G protein-mediated stretch reception
Authors: Storch Ursula , Schnitzler Michael Mederos y , Gudermann Thomas
Published: January 2012

Mechanosensation and -transduction are important for physiological processes like the senses of touch, hearing, and balance. The mechanisms underlying the translation of mechanical stimuli into biochemical information by activating various signaling pathways play a fundamental role in physiology and pathophysiology but are only poorly understood. Recently, G protein-coupled receptors (GPCRs), which are essential for the conversion of light, olfactory and gustatory stimuli, as well as of primary messengers like hormones and neurotransmitters into cellular signals and which play distinct roles in inflammation, cell growth, and differentiation, have emerged as potential mechanosensors. The first candidate for a mechanosensitive GPCR was the angiotensin-II type-1 (AT1) receptor. Agonist-independent mechanical receptor activation of AT1receptors induces an active receptor conformation that appears to differ from agonist-induced receptor conformations and entails the activation of G proteins. Mechanically induced AT1receptor activation plays an important role for myogenic vasoconstriction and for the initiation of cardiac hypertrophy. A growing body of evidence suggests that other GPCRs are involved in mechanosensation as well. These findings highlight physiologically relevant, ligand-independent functions of GPCRs and add yet another facet to the polymodal activation spectrum of this ubiquitous protein family.
Direct and indirect roles for β-catenin in facultative basal progenitor cell differentiation
Authors: Smith Mary Kathryn , Koch Peter J. , Reynolds Susan D.
Published: January 2012

The conducting airway epithelium is maintained and repaired by endogenous progenitor cells. Dysregulated progenitor cell proliferation and differentiation is thought to contribute to epithelial dysplasia in chronic lung disease. Thus modification of progenitor cell function is an attractive therapeutic goal and one that would be facilitated by knowledge of the molecular pathways that regulate their behavior. We modeled the human tracheobronchial epithelium using primary mouse tracheal epithelial cell cultures that were differentiated by exposure to the air-liquid-interface (ALI). A basal cell subset, termed facultative basal cell progenitors (FBP), initiate these cultures and are the progenitor for tracheal-specific secretory cells, the Clara-like cell, and ciliated cells. To test the hypothesis that β-catenin is necessary for FBP function, ALI cultures were generated from mice homozygous for the Ctnbflox(E2–6)allele. In this model, exons 2–6 of the β-catenin gene are flanked by LoxP sites, allowing conditional knockout of β-catenin. The β-catenin locus was modified through transduction with Adenovirus-5-encoding Cre recombinase. This approach generated a mosaic epithelium, comprised of β-catenin wild-type and β-catenin knockout cells. Dual immunostaining and quantitative histomorphometric analyses demonstrated that β-catenin played a direct role in FBP-to-ciliated cell differentiation and that it regulated cell-cell interactions that were necessary for FBP-to-Clara-like cell differentiation. β-catenin was also necessary for FBP proliferation and long-term FBP viability. We conclude that β-catenin is a critical determinant of FBP function and suggest that dysregulation of the β-catenin signaling pathway may contribute to disease pathology.
Pulmonary intravascular macrophages and lung health: What are we missing?
Authors: Schneberger David , Aharonson-Raz Karin , Singh Baljit
Published: January 2012

Pulmonary intravascular macrophages (PIMs) are constitutively found in species such as cattle, horse, pig, sheep, goat, cats, and whales and can be induced in species such as rats, which normally lack them. It is believed that human lung lacks PIMs, but there are previous suggestions of their induction in patients suffering from liver dysfunction. Recent data show induction of PIMs in bile-duct ligated rats and humans suffering from hepato-pulmonary syndrome. Because constitutive and induced PIMs are pro-inflammatory in response to endotoxins and bacteria, there is a need to study their biology in inflammatory lung diseases such as sepsis, asthma, chronic obstructive pulmonary diseases, or hepato-pulmonary syndrome. We provide a review of PIM biology to make an argument for increased emphasis and better focus on the study of human PIMs to better understand their potential role in the pathophysiology and mechanisms of pulmonary diseases.
Somatosensory control of balance during locomotion in decerebrated cat
Authors: Musienko Pavel , Courtine Gregoire , Tibbs Jameson E. , Kilimnik Vyacheslav , Savochin Alexandr , Garfinkel Alan , Roy Roland R. , Edgerton V. Reggie , Gerasimenko Yury
Published: January 2012

Postmammillary decerebrated cats can generate stepping on a moving treadmill belt when the brain stem or spinal cord is stimulated tonically and the hindquarters are supported both vertically and laterally. While adequate propulsion seems to be generated by the hindlimbs under these conditions, the ability to sustain equilibrium during locomotion has not been examined extensively. We found that tonic epidural spinal cord stimulation (5 Hz at L5) of decerebrated cats initiated and sustained unrestrained weight-bearing hindlimb stepping for extended periods. Detailed analyses of the relationships among hindlimb muscle EMG activity and trunk and limb kinematics and kinetics indicated that the motor circuitries in decerebrated cats actively maintain equilibrium during walking, similar to that observed in intact animals. Because of the suppression of vestibular, visual, and head-neck-trunk sensory input, balance-related adjustments relied entirely on the integration of somatosensory information arising from the moving hindquarters. In addition to dynamic balance control during unperturbed locomotion, sustained stepping could be reestablished rapidly after a collapse or stumble when the hindquarters switched from a restrained to an unrestrained condition. Deflecting the body by pulling the tail laterally induced adaptive modulations in the EMG activity, step cycle features, and left-right ground reaction forces that were sufficient to maintain lateral stability. Thus the brain stem-spinal cord circuitry of decerebrated cats in response to tonic spinal cord stimulation can control dynamic balance during locomotion using only somatosensory input.
Identification of prognostic and diagnostic biomarkers of glucose intolerance in ApoE3Leiden mice
Authors: Wopereis Suzan , Radonjic Marijana , Rubingh Carina , van Erk Marjan , Smilde Age , van Duyvenvoorde Wim , Cnubben Nicole , Kooistra Teake , van Ommen Ben , Kleemann Robert
Published: January 2012

The prevalence of diabetes mellitus Type 2 could be significantly reduced by early identification of subjects at risk, allowing for better prevention and earlier treatment. Glucose intolerance (GI) is a hallmark of the prediabetic stage. This study aims at identifying 1) prognostic biomarkers predicting the risk of developing GI later in life and 2) diagnostic biomarkers reflecting the degree of already manifest GI. To this end, disease development was followed over time in mice, and biomarkers were identified using lipidomics and transcriptomics. Young adult ApoE3Leiden mice were treated a high-fat diet for 12 wk to induce GI. Blood was collected before and during disease development. The individual extent of GI was determined with a glucose tolerance test and the area under the curve (AUC) was calculated for each animal. Subject-specific AUC values were correlated to the plasma lipidome ( t = 0) and the white blood cell (WBC) transcriptome ( t = 0, 6, and 12 wk) to identify prognostic and diagnostic biomarkers, respectively. The plasma ratio of specific free fatty acids prior to high-fat feeding (C16:1/C16:0, C18:1/C18:0 and C18:2/C22:6) was significantly correlated with the AUC and predictive for future GI. Subsequently, the expression level of specific WBC genes ( Acss2, Arfgap1, Tfrc, Cox6b2, Barhl2, Abcb4, Cyp4b1, Sars2, Fgf16, and Tceal8) reflected the individual degree of GI during disease progression. Specific plasma free fatty acids as well as their ratio can be used to predict future GI. The expression levels of specific WBC genes can serve as easy accessible markers to diagnose and monitor already existing GI.
Study of Antibacterial Efficacy of Hybrid Chitosan-Silver Nanoparticles for Prevention of Specific Biofilm and Water Purification
Authors: Ghosh Somnath , Ranebennur Tasneem Kausar , Vasan H. N.
Published: January 2012

Antibacterial efficacy of silver nanoparticles (Ag NPs) deposited alternatively layer by layer (LBL) on chitosan polymer in the form of a thin film over a quartz plate and stainless steel strip has been studied. An eight-bilayer chitosan/silver (Cs/Ag)8 hybrid was prepared having a known concentration of silver. Techniques such as UV-visible spectroscopy, inductively coupled plasma optical emission spectroscopy (ICP-OES), and atomic force microscopy (AFM) were carried out to understand and elucidate the physical nature of the film. Gram-negative bacteria, Escherichia coli (E. coli), were used as a test sample in saline solution for antibacterial studies. The growth inhibition at different intervals of contact time and, more importantly, the antibacterial properties of the hybrid film on repeated cycling in saline solution have been demonstrated. AFM studies are carried out for the first time on the microbe to know the morphological changes affected by the hybrid film. The hybrid films on aging (3 months) are found to be as bioactive as before. Cytotoxicity experiments indicated good biocompatibility. The hybrid can be a promising bioactive material for the prevention of biofilms specific to E. coli and in purification of water for safe drinking.
Mutations in Lettuce Improvement
Authors: Mou Beiquan
Published: January 2012

Lettuce is a major vegetable in western countries. Mutations generated genetic variations and played an important role in the domestication of the crop. Many traits derived from natural and induced mutations, such as dwarfing, early flowering, male sterility, and chlorophyll deficiency, are useful in physiological and genetic studies. Mutants were also used to develop new lettuce products including miniature and herbicide-tolerant cultivars. Mutant analysis was critical in lettuce genomic studies including identification and cloning of disease-resistance genes. Mutagenesis combined with genomic technology may provide powerful tools for the discovery of novel gene alleles. In addition to radiation and chemical mutagens, unconventional approaches such as tissue or protoplast culture, transposable elements, and space flights have been utilized to generate mutants in lettuce. Since mutation breeding is considered nontransgenic, it is more acceptable to consumers and will be explored more in the future for lettuce improvement.
Life History ofAricoris propitia(Lepidoptera: Riodinidae)—A Myrmecophilous Butterfly Obligately Associated with Fire Ants
Authors: Kaminski Lucas A. , Carvalho-Filho Fernando S.
Published: January 2012

The immature stages ofAricoris propitia(Stichel) are described and illustrated for the first time, using both light and scanning electron microscopy. Females oviposit in at least seven host-plant families, always in the presence of fire ants (Solenopsis saevissima(Smith) complex), without being attacked by them. Larvae are tended by ants during all larval and pupal stages. From the fourth instar on, larvae feed at night and rest during the day inside underground shelters constructed by ants on the host plant roots, and where pupation occurs. Several observed features, including ant-mediated oviposition, persistent ant attendance throughout all instars, and high spatiotemporal fidelity indicate thatA. propitiais a myrmecophile obligately associated with fire ants. We proposeA. propitiaas an extraordinary model for studies on ant-butterfly evolutionary history in the Neotropics.
Towards Curative Therapy in Burkitt Lymphoma: The Role of Early African Studies in Demonstrating the Value of Combination Therapy and CNS Prophylaxis
Authors: Magrath Ian
Published: January 2012

This paper describes the treatment of Burkitt lymphoma (BL) from the time of its discovery in Africa up to the present. Pioneer investigators explored the value of chemotherapy since surgery and radiation were not effective modalities. Complete response was observed with many drugs used as single agents, but Ziegler and colleagues showed that patients resistant to one drug could achieve cure and potentially long-term survival with other drugs. Subsequently, a combination of cyclophosphamide (CTX), vincristine (VCR), and methotrexate (MTX) was shown to be active, but a survival advantage compared to CTX alone could not be demonstrated because effective CNS prophylactic therapy, in the form of intrathecal therapy, was not given. A recent re-evaluation of this regimen in Africa with multiple doses of intrathecal therapy compares favourably with recent studies of single agent CTX, and other drugs have been shown to be non-cross resistant. Optimal results for patients with extensive disease probably require 5 or 6 effective drugs along with intrathecal therapy, using MTX and Ara-C. In Africa, doses must be lower, because of limitations in supportive care, but in technically advanced countries cure rates in excess of 90% can be obtained. Rituximab may improve the results in some patient groups and allow less intensive therapy without a reduction in survival in others.
Dilation Properties for Weighted Modulation Spaces
Authors: Cordero Elena , Okoudjou Kasso A.
Published: January 2012

We give a sharp estimate on the norm of the scaling operatorUλf(x)=f(λx)acting on the weighted modulation spacesMs,tp,q(ℝd). In particular, we recover and extend recent results by Sugimoto and Tomita in the unweighted case. As an application of our results, we estimate the growth in time of solutions of the wave and vibrating plate equations, which is of interest when considering the well-posedness of the Cauchy problem for these equations. Finally, we provide new embedding results between modulation and Besov spaces.
Adult Congenital Permanent Bilateral Dislocation of the Patella with Full Knee Function: Case Report and Literature Review
Authors: Bistolfi Alessandro , Massazza Giuseppe , Backstein David , Ventura Stefano , Cerlon Raul , Crova Maurizio
Published: January 2012

Congenital permanent dislocation of the patella is a rare disorder of the knee joint in which the patella is permanently displaced, even in extension and is fixed on the lateral aspect of the femoral condyle. The dislocation is irreducible without surgical techniques. This rare condition is usually detected within the first decade of life, because of inability of active extension in the knee and impaired ability during walking. This report presents an unusual case of a 51-year-old man with bilateral congenital permanent dislocation of the patella. The pathology had never been treated because there were few symptoms. The patient presented with right knee pain caused by a fall on the knee during his work. The right knee was painful on the lateral side and the clinical signs were positive for pathology of the lateral meniscus, confirmed by MRI. The clinical and the imaging findings suggested a lesion of the lateral meniscus as the probable cause of the pain. Therefore we performed a knee arthroscopy, whose intra-operative findings confirmed the MRI findings. During the surgery we performed just a selective arthroscopic meniscectomy, without correcting patella dislocation, because the condition was unusually asymptomatic before the trauma.
A Nonimmunosuppressant Approach on Asia Psoriasis Subjects: 5-Year Followup and 11-Year Data Analysis
Authors: Tang Tony Yuqi
Published: January 2012

Mono- or combine immunosuppressants are commonly used for psoriasis; however the side effect caused by potent systemic immunosuppressants frequently incurred; moreover the inflammation flares up shortly after immunosuppressants are discontinued. An alternative nonimmunosuppressive therapy was introduced to psoriasis subjects. A retrospective observational study consisted of 1583 psoriasis patients who were treated with Herose Psoria capsule 1440 mg three times daily at two clinical centres, one in China, the other in Singapore, from 1 January 2000 to 1 January 2011. Psoriasis lesion evolution was photographed at monthly visit, and efficacy and safety were assessed using psoriasis area severity index PASI score grading, renal and liver function testing, and adverse event reporting and supplemented by information obtained during targeted telephone interviews. The effectiveness of Herose on psoriasis was inversely associated to prior immunosuppressants exposure (r=0.9154), significant improvements occurred in non-immunosuppressants subjects, and complete clearance was achieved in 8 months (87.5%, 14 of 16); the wavelike evolution of psoriatic lesion appeared in prior immunosuppressants subjects.
Tracheostomy Wound Myiasis in a Child: Case Report and Review of the Literature
Authors: Blejter J.
Published: January 2012

An 8-year-old tracheostomized, gastrostomized, and with cerebral palsy boy was admitted for tracheostomy wound myiasis and cellulitis. Ether was applied in the wound, and then all the accessible larvae were removed. Antibiotic therapy was initiated. The procedure had to be repeated three more times to extract all the larvae. An airway endoscopy was performed and ruled out the presence of larvae in the airway, as well as any damage to the wall of the trachea. The patient recovered uneventfully and was discharged.
Of “Host Forms” and Host Races: Terminological Issues in Ecological Speciation
Authors: Funk Daniel J.
Published: January 2012

Successful communication and accurate inferences in science depend on the common understanding and consistent usage of the terms we apply to concepts of interest. Likewise, new terminology is required when important concepts have gone unnamed. Here, I focus on terminological issues about biological variation and ecological speciation, especially in herbivorous insects but also more generally. I call for the more restricted use of concepts that have sometimes been misapplied, and thus caution against synonymizing ecological speciation with sympatric speciation and the unwarranted invocation of “host races” to describe herbivorous insect differentiation. I also call for the qualified application of terms for different kinds of biological variation and for host range when confronting uncertainty. Among other “missing terms” introduced here is “host form,” a generic term describing any case of host-associated differences for which current evidence does not allow diagnosis of the specific kind of variation. Embracing the use of host form should free host race from its current overapplication. Finally, I present a case study in whichNeochlamisusleaf beetle populations previously described as host forms are hereby declared to be host races, based on accumulated evidence supporting each of the associated criteria.
Flagellar Motility ofTrypanosoma cruziEpimastigotes
Authors: Ballesteros-Rodea G. , Santillán M. , Martínez-Calvillo S. , Manning-Cela R.
Published: January 2012

The hemoflagellateTrypanosoma cruziis the causative agent of American trypanosomiasis. Despite the importance of motility in the parasite life cycle, little is known aboutT. cruzimotility, and there is no quantitative description of its flagellar beating. Using video microscopy and quantitative vectorial analysis of epimastigote trajectories, we find a forward parasite motility defined by tip-to-base symmetrical flagellar beats. This motion is occasionally interrupted by base-to-tip highly asymmetric beats, which represent the ciliary beat of trypanosomatid flagella. The switch between flagellar and ciliary beating facilitates the parasite's reorientation, which produces a large variability of movement and trajectories that results in different distance ranges traveled by the cells. An analysis of the distance, speed, and rotational angle indicates that epimastigote movement is not completely random, and the phenomenon is highly dependent on the parasite behavior and is characterized by directed and tumbling parasite motion as well as their combination, resulting in the alternation of rectilinear and intricate motility paths.
Quantitative Cell-Free DNA, KRAS, and BRAF Mutations in Plasma from Patients with Metastatic Colorectal Cancer during Treatment with Cetuximab and Irinotecan
Authors: Spindler Karen-Lise Garm , Pallisgaard Niels , Vogelius Ivan , Jakobsen Anders
Published: January 2012

Purpose: The present study investigated the levels of circulating cell-free DNA (cfDNA) in plasma from patients with metastatic colorectal cancer (mCRC) in relation to third-line treatment with cetuximab and irinotecan and the quantitative relationship of cfDNA with tumor-specific mutations in plasma.

Experimental Design: Inclusion criteria were histopathologically verified chemotherapy-resistant mCRC, adequate Eastern Cooperative Oncology Group performance status, and organ function. Treatment consisted of irinotecan being administered at 350 mg/m2 for 3 weeks and weekly administration of 250 mg/m2 cetuximab until progression or unacceptable toxicity. A quantitative PCR method was developed to assess the number of cfDNA alleles and KRAS and BRAF mutation alleles in plasma at baseline.

Results: The study included 108 patients. Only three patients were positive for BRAF mutations. The majority of KRAS mutations detected in tumors were also found in the plasma [32 of 41 (78%)]. Plasma cfDNA and plasma mutant KRAS levels (pmKRAS) were strongly correlated (r = 0.85, P < 10−4). The disease control rate was 77% in patients with low cfDNA (<25% quartile) and 30% in patients with high cfDNA [>75% quartile (P = 0.009)]. Patients with pmKRAS levels higher than 75% had a disease control rate of 0% compared with 42% in patients with lower pmKRAS (P = 0.048). Cox analysis confirmed the prognostic importance of both cfDNA and pmKRAS. High levels were clear indicators of a poor outcome.

Conclusions: KRAS analysis in plasma is a viable alternative to tissue analysis. Quantitative levels of cfDNA and pmKRAS are strongly correlated and hold promise of clinical application. Clin Cancer Res; 18(4); 1177–85. ©2012 AACR.
Clarifying the Spectrum of Driver Oncogene Mutations in Biomarker-Verified Squamous Carcinoma of Lung: Lack of EGFR/KRAS and Presence of PIK3CA/AKT1 Mutations
Authors: Rekhtman Natasha , Paik Paul K. , Arcila Maria E. , Tafe Laura J. , Oxnard Geoffrey R. , Moreira Andre L. , Travis William D. , Zakowski Maureen F. , Kris Mark G. , Ladanyi Marc
Published: January 2012

Purpose: There is persistent controversy as to whether EGFR and KRAS mutations occur in pulmonary squamous cell carcinoma (SQCC). We hypothesized that the reported variability may reflect difficulties in the pathologic distinction of true SQCC from adenosquamous carcinoma (AD-SQC) and poorly differentiated adenocarcinoma due to incomplete sampling or morphologic overlap. The recent development of a robust immunohistochemical approach for distinguishing squamous versus glandular differentiation provides an opportunity to reassess EGFR/KRAS and other targetable kinase mutation frequencies in a pathologically homogeneous series of SQCC.

Experimental Design: Ninety-five resected SQCCs, verified by immunohistochemistry as ΔNp63+/TTF-1−, were tested for activating mutations in EGFR, KRAS, BRAF, PIK3CA, NRAS, AKT1, ERBB2/HER2, and MAP2K1/MEK1. In addition, all tissue samples from rare patients with the diagnosis of EGFR/KRAS-mutant “SQCC” encountered during 5 years of routine clinical genotyping were reassessed pathologically.

Results: The screen of 95 biomarker-verified SQCCs revealed no EGFR/KRAS [0%; 95% confidence interval (CI), 0%–3.8%], four PIK3CA (4%; 95% CI, 1%–10%), and one AKT1 (1%; 95% CI, 0%–5.7%) mutations. Detailed morphologic and immunohistochemical reevaluation of EGFR/KRAS-mutant “SQCC” identified during clinical genotyping (n = 16) resulted in reclassification of 10 (63%) cases as AD-SQC and five (31%) cases as poorly differentiated adenocarcinoma morphologically mimicking SQCC (i.e., adenocarcinoma with “squamoid” morphology). One (6%) case had no follow-up.

Conclusions: Our findings suggest that EGFR/KRAS mutations do not occur in pure pulmonary SQCC, and occasional detection of these mutations in samples diagnosed as “SQCC” is due to challenges with the diagnosis of AD-SQC and adenocarcinoma, which can be largely resolved by comprehensive pathologic assessment incorporating immunohistochemical biomarkers. Clin Cancer Res; 18(4); 1167–76. ©2012 AACR.
Epidermal Growth Factor Receptor Protein Detection in Head and Neck Cancer Patients: A Many-Faceted Picture
Authors: Thariat Juliette , Etienne-Grimaldi Marie-Christine , Grall Dominique , Bensadoun René-Jean , Cayre Anne , Penault-Llorca Frédérique , Veracini Laurence , Francoual Mireille , Formento Jean-Louis , Dassonville Olivier , De Raucourt Dominique , Geoffrois Lionel , Giraud Philippe , Racadot Séverine , Morinière Sylvain , Milano Gérard , Van Obberghen-Schilling Ellen
Published: January 2012

Purpose: Epidermal growth factor receptor (EGFR) overexpression is associated with poor prognosis in head and neck squamous cell carcinoma (HNSCC). Despite intensive biomarker studies, a consensual method for assessing EGFR protein expression is still lacking. Here we set out to compare three EGFR detection methods in tumor specimens from HNSCC patients.

Experimental Design: Tumors were prospectively excised from a series of 79 high-risk HNSCC patients enrolled in a GORTEC-sponsored clinical trial. EGFR expression was determined using a ligand-binding assay on membranes, Western blotting (WB) on membranes and total homogenates, and immunohistochemistry (IHC) on tissue microarrays. In addition, phosphorylated EGFR (pEGFR) was measured by WB on membranes.

Results: Distributions and ranges of tumor EGFR expression were method dependent. Moderate positive correlations (Spearman coefficient r ≈ 0.50) were observed between EGFR expression measured by the binding assay and WB or IHC. pEGFR levels positively and significantly correlated with total EGFR expression measured by WB or ligand binding, but not by IHC. The highest correlation (r = 0.85) was observed between EGFR and pEGFR levels, both measured by WB on membranes. Interestingly, the fraction of phosphorylated receptor (pEGFR/EGFR both measured by WB on membranes) significantly declined with increasing tumor EGFR expression, by all assessment methods used.

Conclusion: This study shows significant correlations between EGFR detection methods. The observed relationships between EGFR and pEGFR indicate that high-throughput pEGFR/EGFR analyses merit further investigations and consideration for routine use in patient samples. Clin Cancer Res; 18(5); 1313–22. ©2012 AACR.
Evaluation of Deuterated 18F- and 11C-Labeled Choline Analogs for Cancer Detection by Positron Emission Tomography
Authors: Witney Timothy H. , Alam Israt S. , Turton David R. , Smith Graham , Carroll Laurence , Brickute Diana , Twyman Frazer J. , Nguyen Quang-Dé , Tomasi Giampaolo , Awais Ramla O. , Aboagye Eric O.
Published: January 2012

Purpose: 11C-Choline–positron emission tomography (PET) has been exploited to detect the aberrant choline metabolism in tumors. Radiolabeled choline uptake within the imaging time is primarily a function of transport, phosphorylation, and oxidation. Rapid choline oxidation, however, complicates interpretation of PET data. In this study, we investigated the biologic basis of the oxidation of deuterated choline analogs and assessed their specificity in human tumor xenografts.

Experimental Design: 11C-Choline, 11C-methyl-[1,2-2H4]-choline (11C-D4-choline), and 18F-D4-choline were synthesized to permit comparison. Biodistribution, metabolism, small-animal PET studies, and kinetic analysis of tracer uptake were carried out in human colon HCT116 xenograft–bearing mice.

Results: Oxidation of choline analogs to betaine was highest with 11C-choline, with reduced oxidation observed with 11C-D4-choline and substantially reduced with 18F-D4-choline, suggesting that both fluorination and deuteration were important for tracer metabolism. Although all tracers were converted intracellularly to labeled phosphocholine (specific signal), the higher rate constants for intracellular retention (Ki and k3) of 11C-choline and 11C-D4-choline, compared with 18F-D4-choline, were explained by the rapid conversion of the nonfluorinated tracers to betaine within HCT116 tumors. Imaging studies showed that the uptake of 18F-D4-choline in three tumors with similar radiotracer delivery (K1) and choline kinase α expression—HCT116, A375, and PC3-M—were the same, suggesting that 18F-D4-choline has utility for cancer detection irrespective of histologic type.

Conclusion: We have shown here that both deuteration and fluorination combine to provide protection against choline oxidation in vivo. 18F-D4-choline showed the highest selectivity for phosphorylation and warrants clinical evaluation. Clin Cancer Res; 18(4); 1063–72. ©2012 AACR.
Pathway-Specific Analysis of Gene Expression Data Identifies the PI3K/Akt Pathway as a Novel Therapeutic Target in Cervical Cancer
Authors: Schwarz Julie K. , Payton Jacqueline E. , Rashmi Ramachandran , Xiang Tao , Jia Yunhe , Huettner Phyllis , Rogers Buck E. , Yang Qin , Watson Mark , Rader Janet S. , Grigsby Perry W.
Published: January 2012

Purpose: Cervical tumor response on posttherapy 2[18F]fluoro-2-deoxy-d-glucose-positron emission tomography (FDG-PET) is predictive of survival outcome. The purpose of this study was to use gene expression profiling to identify pathways associated with tumor metabolic response.

Experimental Design: This was a prospective tissue collection study for gene expression profiling of 62 pretreatment biopsies from patients with advanced cervical cancer. Patients were treated with definitive radiation. Fifty-three patients received concurrent chemotherapy. All patients underwent a pretreatment and a 3-month posttherapy FDG-PET/computed tomography (CT). Tumor RNA was harvested from fresh frozen tissue and hybridized to Affymetrix U133Plus2 GeneChips. Gene set enrichment analysis (GSEA) was used to identify signaling pathways associated with tumor metabolic response. Immunohistochemistry and in vitro FDG uptake assays were used to confirm our results.

Results: There were 40 biopsies from patients with a complete metabolic response (PET-negative group) and 22 biopsies from patients with incomplete metabolic response (PET-positive group). The 3-year cause-specific survival estimates were 98% for the PET-negative group and 39% for the PET-positive group (P < 0.0001). GSEA identified alterations in expression of genes associated with the PI3K/Akt signaling pathway in patients with a positive follow-up PET. Immunohistochemistry using a tissue microarray of 174 pretreatment biopsies confirmed p-Akt as a biomarker for poor prognosis in cervical cancer. The phosphoinositide 3-kinase (PI3K) inhibitor LY294002 inhibited FDG uptake in vitro in cervical cancer cell lines.

Conclusions: Activation of the PI3K/Akt pathway is associated with incomplete metabolic response in cervical cancer. Targeted inhibition of PI3K/Akt may improve response to chemoradiation. Clin Cancer Res; 18(5); 1464–71. ©2012 AACR.
TheEGFRT790M Mutation in Acquired Resistance to an Irreversible Second-Generation EGFR Inhibitor
Authors: Kim Youngwook , Ko Jeonghun , Cui ZhengYun , Abolhoda Amir , Ahn Jin Seok , Ou Sai-Hong , Ahn Myung-Ju , Park Keunchil
Published: January 2012

Molecular target therapies using first-generation, reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as gefitinib or erlotinib, have been shown to be effective for patients with non-small cell lung cancer (NSCLC) who harbor activating mutations in EGFR. However, these patients eventually develop resistance to the reversible TKIs, and this has led to the development of second-generation, irreversible EGFR inhibitors. Currently, the mechanism of acquired resistance to irreversible EGFR inhibitors is not clear. Using an in vitro cell culture system, we modeled the acquired resistance to first-line treatment with second-generation EGFR-TKIs using an EGFR-mutant NSCLC cell line. Here, we report a mechanism of resistance involving T790M secondary mutation as well as a corresponding clinical case. The results of these findings suggest that inhibition of EGFR by currently available second-generation EGFR-TKIs may not be sufficient to physiologically prevent the emergence of cells that are still dependent on EGFR signaling. This finding bears important implications on the limitations of currently available second-generation EGFR-TKIs. Mol Cancer Ther; 11(3); 784–91. ©2012 AACR.
Expression of Caveolin-1, Caveolin-2 and Caveolin-3 in Thyroid Cancer and Stroma
Authors: Kim Dokyung , Kim Haeryoung , Koo Ja Seung
Published: January 2012

Objective: To study the expression status of caveolin-1, caveolin-2 and caveolin-3 in the epithelial and stromal compartments of conventional papillary thyroid carcinoma (PTC), diffuse sclerosing variant of papillary carcinoma (DSVPC) and anaplastic carcinoma (AC). Methods: Tissue microarrays were constructed from 70 PTC, 41 DSVPC and 12 AC, and immunohistochemical stains were performed with caveolin-1, caveolin-2, caveolin-3, cytokeratin, vimentin and E-cadherin. The expression status of these markers in the epithelial and stromal cells was evaluated, and the results were correlated with the clinicopathologic variables. Results: Epithelial caveolin-3 expression was absent in the majority of PTC and DSPVC, and was significantly increased in AC (p < 0.001). The stromal expression of caveolin-1, caveolin-2 and caveolin-3 increased in frequency from PTC to DSVPC to AC, and was significantly increased in the stroma of AC (p < 0.001). Cytokeratin and E-cadherin were more frequently negative in AC compared to PTC (p = 0.003) and DSVPC (p < 0.001), while vimentin was more frequently expressed in AC compared to PTC and DSVPC (both p < 0.001). Conclusion: Epithelial caveolin-3 expression is increased in AC compared to PTC and DSVPC, and this may be linked to the epithelial-mesenchymal transition process of AC. In addition, stromal caveolin-1, caveolin-2 and caveolin-3 expression was more frequent in AC compared to PTC and DSVPC, and the specific expression of caveolin-3 in the stroma of AC could suggest a possible role of myofibroblasts.
Urinary Survivin mRNA Expression and Urinary Nuclear Matrix Protein 22 BladderChek® and Urine Cytology in the Detection of Transitional Cell Carcinoma of the Bladder
Authors: Al-Maghrebi May , Kehinde Elijah O. , Kapila Kusum , Anim Jehoram T.
Published: January 2012

Objective: To compare the diagnostic performance of urine cytology (UC), survivin mRNA expression, and the NMP22 BladderChek® (NMP22BC) test for the detection, grading and staging of transitional cell carcinoma (TCC) of the bladder. Materials and Methods: Voided urine samples collected from 25 healthy controls and 80 patients diagnosed with TCC of the bladder were subjected to UC, the NMP22BC test and reverse-transcription real-time PCR for survivin mRNA expression. Results: Survivin mRNA expression showed the highest sensitivity (87.5%) followed by the NMP22BC test (61.3%) while UC exhibited the lowest sensitivity (40%). All three urine markers had a similar specificity of 96% (95% CI 80.5–99.3%). Survivin mRNA expression was the only urine marker that showed a significant difference in relation to tumour histological grade (χ2 8.5, p = 0.015). None of the three urine markers was significantly related to tumour pathological stages. Conclusion: The diagnostic sensitivity of urinary survivin mRNA expression was superior to that of UC and the NMP22BC test and correlates with tumour pathological grade but not stage.