bluuebunny/crossref_metadata_2025 huggingface dataset:
Parametric Conversion in Micrometer and Submicrometer Structured Ferroelectric Crystals by Surface Poling
Authors: Busacca Alessandro C. , Stivala Salvatore , Curcio Luciano , Assanto Gaetano
Published: February 2012

We report on recent technological improvements concerning nonlinear patterning of lithium niobate and lithium tantalate in the micrometer and submicrometer scales using surface periodic poling for ferroelectric domain inversion. The fabricated samples were employed for frequency doubling via quasiphase-matching both in bulk and guided wave geometries, including forward and backward configurations and wavelength conversion in bands C and L. We also investigated short-period quasiperiodic samples with randomly distributed mark-to-space ratios.
Evaluation of Fluid Responsiveness: Is Photoplethysmography a Noninvasive Alternative?
Authors: Antonsen Lars Prag , Kirkebøen Knut Arvid
Published: February 2012

Background. Goal-directed fluid therapy reduces morbidity and mortality in various clinical settings. Respiratory variations in photoplethysmography are proposed as a noninvasive alternative to predict fluid responsiveness during mechanical ventilation. This paper aims to critically evaluate current data on the ability of photoplethysmography to predict fluid responsiveness.Method. Primary searches were performed in PubMed, Medline, and Embase on November 10, 2011.Results. 14 papers evaluating photoplethysmography and fluid responsiveness were found. Nine studies calculated areas under the receiver operating characteristic curves forΔPOP (>0.85 in four, 0.75–0.85 in one, and <0.75 in four studies) and seven for PVI (values ranging from 0.54 to 0.98). Correlations betweenΔPOP/PVI andΔPP/other dynamic variables vary substantially.Conclusion. Although photoplethysmography is a promising technique, predictive values and correlations with other hemodynamic variables indicating fluid responsiveness vary substantially. Presently, it is not documented that photoplethysmography is adequately valid and reliable to be included in clinical practice for evaluation of fluid responsiveness.
New Genetic Insights from Autoimmune Thyroid Disease
Authors: Davies Terry F. , Latif Rauf , Yin Xiaoming
Published: February 2012

The autoimmune thyroid diseases (AITDs) (Graves’ disease and Hashimoto’s thyroiditis) are complex genetic diseases which most likely have more than 20 genes contributing to the clinical phenotypes. To date, the genes known to be contributing fall into two categories: immune regulatory genes (includingHLA, CTLA4, PTPN22, CD40, CD25, and FCRL3) and thyroid-specific genes (TG and TSHR). However, none of these genes contribute more than a 4-fold increase in risk of developing one of these diseases, and none of the polymorphisms discovered is essential for disease development. Hence, it appears that a variety of different gene interactions can combine to cause the same clinical disease pattern, but the contributing genes may differ from patient to patient and from population to population. Furthermore, this possible mechanism leaves open the powerful influence of the environment and epigenetic modifications of gene expression. For the clinician, this means that genetic profiling of such patients is unlikely to be fruitful in the near future.
Spectral Analysis of Surface Wave for Empirical Elastic Design of Anchored Foundations
Authors: Chen S. E. , Ong C. K.
Published: February 2012

Helical anchors are vital support components for power transmission lines. Failure of a single anchor can lead to the loss of an entire transmission line structure which results in the loss of power for downstream community. Despite being important, it is not practical to use conventional borehole method of subsurface exploration, which is labor intensive and costly, for estimating soil properties and anchor holding capacity. This paper describes the use of an empirical and elasticity-based design technique coupled with the spectral analysis of surface wave (SASW) technique to provide subsurface information for anchor foundation designs. Based on small-strain wave propagation, SASW determines shear wave velocity profile which is then correlated to anchor holding capacity. A pilot project involving over 400 anchor installations has been performed and demonstrated that such technique is reliable and can be implemented into transmission line structure designs.
An Algorithm for Global Optimization Inspired by Collective Animal Behavior
Authors: Cuevas Erik , González Mauricio , Zaldivar Daniel , Pérez-Cisneros Marco , García Guillermo
Published: February 2012

A metaheuristic algorithm for global optimization called the collective animal behavior (CAB) is introduced. Animal groups, such as schools of fish, flocks of birds, swarms of locusts, and herds of wildebeest, exhibit a variety of behaviors including swarming about a food source, milling around a central locations, or migrating over large distances in aligned groups. These collective behaviors are often advantageous to groups, allowing them to increase their harvesting efficiency, to follow better migration routes, to improve their aerodynamic, and to avoid predation. In the proposed algorithm, the searcher agents emulate a group of animals which interact with each other based on the biological laws of collective motion. The proposed method has been compared to other well‐known optimization algorithms. The results show good performance of the proposed method when searching for a global optimum of several benchmark functions.
Long-Term Biostability of Pet Vascular Prostheses
Authors: Dieval Florence , Khoffi Foued , Mir Riaz , Chaouch Walid , Le Nouen Didier , Chakfe Nabil , Durand Bernard
Published: February 2012

PET Vascular prostheses are susceptible to physical modification and chemical degradation leading sometimes to global deterioration and rupture of the product. To understand the mechanisms of degradation, we studied 6 vascular prostheses that were explanted due to medical complications. We characterized their level of degradation by comparing them with a virgin prosthesis and carried out physicochemical and mechanical analyses. Results showed an important reduction of the fabric’s mechanical properties in specific areas. Moreover, PET taken from these areas exhibited structural anomalies and was highly degraded even in virgin prostheses. These results suggest that vascular prostheses have weak areas prior to implantation and that these areas are much more prone to in vivo degradation by human metabolism. Manufacturing process could be responsible for these weaknesses as well as designing of the compound. Therefore, we suggest that a more controlled manufacturing process could lead to a vascular prosthesis with enhanced lifespan.
Effect of PVP Intermediate Layer on the Properties of SAPO 34 Membrane
Authors: Das Jugal K. , Das Nandini , Bandyopadhyay Sibdas
Published: February 2012

SAPO 34 zeolite membranes were prepared on a tubular mullite support. Before membrane preparation, the support surfaces were coated with seed crystals. Seeds particles were prepared by hydrothermal synthesis. Before seeding, the substrates were treated with polyvinylpyrrolidone (PVP) to orient the seeds. Both the treated and untreated supports were seeded, and membranes were synthesized on those support tubes by ex situ hydrothermal method. The PVP molecule exists in the two resonance structures. Hence the acylamino bond –N+= C–O-– acts as intermediate linker between support surface and seed surface. Due to charge interaction, the seed crystals were anchored strongly to support surface. The synthesized membranes along with seed crystals were characterized by XRD, FESEM, and EDAX analysis. The single-gas permeation with CO2and H2was investigated. Up to 5 bar of feed pressure, the permselectivity of CO2and H2was as high as 4.2.
Quality Evaluation for Microcrystalline Silicon Thin-Film Solar Cells by Single-Layer Absorption
Authors: Chen Sheng-Hui , Chang Ting-Wei , Wang Hsuan-Wen
Published: February 2012

The absorption coefficient at 1.4 eV is divided by the value at 0.9 eV to obtain the factor used to judge the quality of μc-Si:H. PV device performance can be predicted by multiplyingVocwithIscwhen using this layer as an intrinsic layer. The results show a good relationship between the quality factor and the product of open-circuit voltage and short-circuit current. However, the final efficiency is influenced by the identities of the interface in the multilayer structure.
Development of an Inflammation-Associated Colorectal Cancer Model and Its Application for Research on Carcinogenesis and Chemoprevention
Authors: Tanaka Takuji
Published: February 2012

Chronic inflammation is a well-recognized risk factor for development of human cancer in several tissues, including large bowel. Inflammatory bowel disease, including ulcerative colitis and Crohn’s disease, is a longstanding inflammatory disease of intestine with increased risk for colorectal cancer development. Several molecular events involved in chronic inflammatory process may contribute to multistep carcinogenesis of human colorectal cancer in the inflamed colon. They include overproduction of reactive oxygen and nitrogen species, overproduction and upregulation of productions and enzymes of arachidonic acid biosynthesis pathway and cytokines, and intestinal immune system dysfunction. In this paper, I will describe several methods to induce colorectal neoplasm in the inflamed colon. First, I will introduce a protocol of a novel inflammation-associated colon carcinogenesis in mice. In addition, powerful tumor-promotion/progression activity of dextran sodium sulfate in the large bowel ofApcMin/+mice will be described. Finally, chemoprevention of inflammation-associated colon carcinogenesis will be mentioned.
A Novel Technique for Identifying Patients with ICU Needs Using Hemodynamic Features
Authors: Jalali A. , Ghorbanian P. , Ghaffari A. , Nataraj C.
Published: February 2012

Identification of patients requiring intensive care is a critical issue in clinical treatment. The objective of this study is to develop a novel methodology using hemodynamic features for distinguishing such patients requiring intensive care from a group of healthy subjects. In this study, based on the hemodynamic features, subjects are divided into three groups: healthy, risky and patient. For each of the healthy and patient subjects, the evaluated features are based on the analysis of existing differences between hemodynamic variables: Blood Pressure and Heart Rate. Further, four criteria from the hemodynamic variables are introduced: circle criterion, estimation error criterion, Poincare plot deviation, and autonomic response delay criterion. For each of these criteria, three fuzzy membership functions are defined to distinguish patients from healthy subjects. Furthermore, based on the evaluated criteria, a scoring method is developed. In this scoring method membership degree of each subject is evaluated for the three classifying groups. Then, for each subject, the cumulative sum of membership degree of all four criteria is calculated. Finally, a given subject is classified with the group which has the largest cumulative sum. In summary, the scoring method results in 86% sensitivity, 94.8% positive predictive accuracy and 82.2% total accuracy.
Glutathione Homeostasis and Functions: Potential Targets for Medical Interventions
Authors: Lushchak Volodymyr I.
Published: February 2012

Glutathione (GSH) is a tripeptide, which has many biological roles including protection against reactive oxygen and nitrogen species. The primary goal of this paper is to characterize the principal mechanisms of the protective role of GSH against reactive species and electrophiles. The ancillary goals are to provide up-to-date knowledge of GSH biosynthesis, hydrolysis, and utilization; intracellular compartmentalization and interorgan transfer; elimination of endogenously produced toxicants; involvement in metal homeostasis; glutathione-related enzymes and their regulation; glutathionylation of sulfhydryls. Individual sections are devoted to the relationships between GSH homeostasis and pathologies as well as to developed research tools and pharmacological approaches to manipulating GSH levels. Special attention is paid to compounds mainly of a natural origin (phytochemicals) which affect GSH-related processes. The paper provides starting points for development of novel tools and provides a hypothesis for investigation of the physiology and biochemistry of glutathione with a focus on human and animal health.
Design and Implementation of an Educational Program in Advanced Airway Management for Anesthesiology Residents
Authors: Borovcanin Zana , Shapiro Janine R.
Published: February 2012

Education and training in advanced airway management as part of an anesthesiology residency program is necessary to help residents attain the status of expert in difficult airway management. The Accreditation Council for Graduate Medical Education (ACGME) emphasizes that residents in anesthesiology must obtain significant experience with a broad spectrum of airway management techniques. However, there is no specific number required as a minimum clinical experience that should be obtained in order to ensure competency. We have developed a curriculum for a new Advanced Airway Techniques rotation. This rotation is supplemented with a hands-on Difficult Airway Workshop. We describe here this comprehensive advanced airway management educational program at our institution. Future studies will focus on determining if education in advanced airway management results in a decrease in airway related morbidity and mortality and overall better patients’ outcome during difficult airway management.
PLGA Nanoparticles for Ultrasound-Mediated Gene Delivery to Solid Tumors
Authors: Figueiredo Marxa , Esenaliev Rinat
Published: February 2012

This paper focuses on novel approaches in the field of nanotechnology-based carriers utilizing ultrasound stimuli as a means to spatially target gene delivery in vivo, using nanoparticles made with either poly(lactic-co-glycolic acid) (PLGA) or other polymers. We specifically discuss the potential for gene delivery by particles that are echogenic (amenable to destruction by ultrasound) composed either of polymers (PLGA, polystyrene) or other contrast agent materials (Optison, SonoVue microbubbles). The use of ultrasound is an efficient tool to further enhance gene delivery by PLGA or other echogenic particles in vivo. Echogenic PLGA nanoparticles are an attractive strategy for ultrasound-mediated gene delivery since this polymer is currently approved by the US Food and Drug Administration for drug delivery and diagnostics in cancer, cardiovascular disease, and also other applications such as vaccines and tissue engineering. This paper will review recent successes and the potential of applying PLGA nanoparticles for gene delivery, which include (a) echogenic PLGA used with ultrasound to enhance local gene delivery in tumors or muscle and (b) PLGA nanoparticles currently under development, which could benefit in the future from ultrasound-enhanced tumor targeted gene delivery.
Analytical Method and Semianalytical Method for Analysis of Scattering by Anisotropic Sphere: A Review
Authors: Wan Chao , Li Hongning
Published: February 2012

The history of methods for the electromagnetic scattering by an anisotropic sphere has been reviewed. Two main methods, angular expansion method and T-matrix method, which are widely used for the anisotropic sphere, are expressed in Cartesian coordinate firstly. The comparison of those and the further exploration on the scattering field are illustrated afterwards. Based on the most general form concluded by variable separation method, the coupled electric field and magnetic field of radial anisotropic sphere can be derived. By simplifying the condition, simpler case of uniaxial anisotropic media is expressed with confirmed coefficients for the internal and external field. Details of significant phenomenon are presented.
Anti-VEGF Treatment Strategies for Wet AMD
Authors: Kovach Jaclyn L. , Schwartz Stephen G. , Flynn Harry W. , Scott Ingrid U.
Published: February 2012

Over the past few years, antivascular endothelial growth factor (VEGF) therapy has become a standard treatment for neovascular age-related macular degeneration (AMD). During this time, treatment strategies have evolved from a monthly dosing schedule to individualized regimens. This paper will review the currently available anti-VEGF agents and evidence-based treatment strategies.
Pixel-Based Machine Learning in Medical Imaging
Authors: Suzuki Kenji
Published: February 2012

Machine learning (ML) plays an important role in the medical imaging field, including medical image analysis and computer-aided diagnosis, because objects such as lesions and organs may not be represented accurately by a simple equation; thus, medical pattern recognition essentially require “learning from examples.” One of the most popular uses of ML is classification of objects such as lesions into certain classes (e.g., abnormal or normal, or lesions or nonlesions) based on input features (e.g., contrast and circularity) obtained from segmented object candidates. Recently, pixel/voxel-based ML (PML) emerged in medical image processing/analysis, which use pixel/voxel values in images directly instead of features calculated from segmented objects as input information; thus, feature calculation or segmentation is not required. Because the PML can avoid errors caused by inaccurate feature calculation and segmentation which often occur for subtle or complex objects, the performance of the PML can potentially be higher for such objects than that of common classifiers (i.e., feature-based MLs). In this paper, PMLs are surveyed to make clear (a) classes of PMLs, (b) similarities and differences within (among) different PMLs and those between PMLs and feature-based MLs, (c) advantages and limitations of PMLs, and (d) their applications in medical imaging.
Real-Time Analysis of Specific Protein-DNA Interactions with Surface Plasmon Resonance
Authors: Ritzefeld Markus , Sewald Norbert
Published: February 2012

Several proteins, like transcription factors, bind to certain DNA sequences, thereby regulating biochemical pathways that determine the fate of the corresponding cell. Due to these key positions, it is indispensable to analyze protein-DNA interactions and to identify their mode of action. Surface plasmon resonance is a label-free method that facilitates the elucidation of real-time kinetics of biomolecular interactions. In this article, we focus on this biosensor-based method and provide a detailed guide how SPR can be utilized to study binding of proteins to oligonucleotides. After a description of the physical phenomenon and the instrumental realization including fiber-optic-based SPR and SPR imaging, we will continue with a survey of immobilization methods. Subsequently, we will focus on the optimization of the experiment, expose pitfalls, and introduce how data should be analyzed and published. Finally, we summarize several interesting publications of the last decades dealing with protein-DNA and RNA interaction analysis by SPR.
Detection of Herplex Simplex Virus-1 and -2 in Cardiac Myxomas
Authors: Pateras Ioannis S. , Evangelou Konstantinos , Tsimaratou Katerina , Liontos Michalis , Sakellariou Stratigoula , Barlogiannis Theodoros , Karakitsos Petros , Papalois Apostolos , Kotsinas Athanassios , Gorgoulis Vassilis G.
Published: February 2012

The etiology of sporadic cardiac myxomas remains elusive. The tendency for these lesions to recur following resection, their immunopathological characteristics, along with their histological and molecular profile, may implicate the presence of an infective agent in this type of tumor. In this study, we investigated the presence of herpes simplex virus (HSV) DNA in a cohort of cardiac myxomas in a tertiary referral centre. Twenty-nine formalin-fixed paraffin-embedded (FFPE) sporadic cardiac myxomas were obtained, 17 of which were shown to be informative. These were compared to 19 macroscopically and microscopically normal heart tissue specimens. The detection of HSV-1 and -2 genomic sequences was achieved with the use of a combined nested PCR-Restriction Fragment Length Polymorphism methodology. The presence of HSV-1 and/or -2 DNA was demonstrated in 6 of 17 (35%) informative sporadic cardiac myxomas, whereas no HSV DNA was detected in normal heart tissues (P<0.01). The existence of HSV-1/2 DNA in sporadic cardiac myxomas, along with its absence from normal heart tissues, reinforces the possibility that HSV infection might be involved in the development of these lesions. Our findings raise the point of anti-HSV medication postsurgically with a potential benefit in reducing the rate of recurrences.
Is There Anything to Smile about? A Review of Oral Care for Individuals with Intellectual and Developmental Disabilities
Authors: Fisher Kathleen
Published: February 2012

Individuals with intellectual and developmental disabilities (I/DD) are at risk for dental disease and face substantial challenges in accessing both routine and preventive dental services. In terms of unmet needs it ranks third, following residential services and employment opportunities for this particular group of people. Poorer oral health status negatively impacts overall health and one’s quality of life. Factors contributing to this problem include significantly higher rates of dental caries, periodontal disease, poor oral hygiene, low expectations, fear of treatment, and lack of awareness among individuals and carers. Additional factors include problems accessing dental care or denial of services because of inadequate education and clinical training, inappropriate bias, or inadequate levels of compensation to providers. Strategies to improve service delivery include individualized and coordinated care services, education of individuals, carers, and providers, including both classroom and clinical experiences with special needs patients in dental programs.
Effect of HSV-2 Suppressive Therapy on Genital Tract HIV-1 RNA Shedding among Women on HAART: A Pilot Randomized Controlled Trial
Authors: Nijhawan A. E. , DeLong A. K. , Chapman S. , Rana A. , Kurpewski J. , Ingersoll J. , Caliendo A. M. , Cu-Uvin S.
Published: February 2012

Background. The role of suppressive HSV therapy in women coinfected with HSV-2 and HIV-1 taking highly active antiretroviral therapy (HAART) is unclear.Methods. 60 women with HIV-1/HSV-2 coinfection on HAART with plasma HIV-1 viral load (PVL) ≤75 copies/mL were randomized to receive acyclovir (N=30) or no acyclovir (N=30). PVL, genital tract (GT) HIV-1, and GT HSV were measured every 4 weeks for one year.Results. Detection of GT HIV-1 was not significantly different in the two arms (OR 1.23,P=0.67), although this pilot study was underpowered to detect this difference. When PVL was undetectable, the odds of detecting GT HIV were 0.4 times smaller in the acyclovir arm than in the control arm, though this was not statistically significant (P=0.07). The odds of detecting GT HSV DNA in women receiving acyclovir were significantly lower than in women in the control group, OR 0.38,P<0.05.Conclusions. Chronic suppressive therapy with acyclovir in HIV-1/HSV-2-positive women on HAART significantly reduces asymptomatic GT HSV shedding, though not GT HIV shedding or PVL. PVL was strongly associated with GT HIV shedding, reinforcing the importance of HAART in decreasing HIV sexual transmission.
Do Clopidogrel Nonresponders Have an Increased Risk of Adverse Events during Supra-Aortal Angioplasty and Stenting?
Authors: Koerner Heiko , Derveaux Christian , Alexandrou Maria , Graeber Stefan , Roth Christian , Papanagiotou Panagiotis , Eichler Hermann , Reith Wolfgang
Published: February 2012

Objective. The aim of the present study was to correlate new periprocedural diffusion-weighted imaging (DWI) lesions during stenting of supra-aortal arteries with the level of platelet inhibition using point-of-care analysis.Background. Cardiological studies have shown that patients undergoing coronary PTA have a significantly elevated risk of severe thrombotic complications if patients show insufficient inhibition of platelet function.Methods. From August 2008 to June 2009, 44 patients with an indication of supra-aortal angioplasty and/or stenting were prospectively enrolled. Platelet reactivity was tested using a Multiplate device (Dynabyte). These patients underwent MRI before and after the intervention to determine the prevalence of new DWI lesions. The primary endpoint was the prevalence of DWI lesions; the secondary endpoint was clinical status until discharge from hospital.Results. There was no significant relationship between the primary endpoint and the degree of platelet function. Patients with high platelet reactivity showed the same amount of periprocedural complications as patients with sufficient inhibition of platelets.Conclusions. Clopidogrel did not have a protective effect on periprocedural complications, nor did it decrease the number of silent DWI lesions after the procedure. The predescribed strong relationship between high platelet reactivity and early post-procedural adverse events was not observed in our cohort.
Improvement of Sepsis by Hepatocyte Growth Factor, an Anti-Inflammatory Regulator: Emerging Insights and Therapeutic Potential
Authors: Mizuno Shinya , Nakamura Toshikazu
Published: February 2012

Sepsis-induced multiple organ failure (MOF) is the most frequent lethal disease in intensive care units. Thus, it is important to elucidate the self-defensive mechanisms of sepsis-induced MOF. Hepatocyte growth factor (HGF) is now recognized as an organotrophic factor, which is essential for organogenesis during embryonic growth and regeneration in adulthood. HGF production is enhanced in response to infectious challenges, but the increase in endogenous HGF levels is transient and insufficient, with a time lag between tissue injuries and HGF upregulation, during progression of septic MOF. Thus, administration of active-formed HGF might be a new candidate for therapeutic development of MOF. HGF has an ability to target endotoxin-challenged macrophages and inhibits the upregulation of inflammatory cytokines through nuclear factor-κB-inactivated mechanisms. HGF also targets the endothelium and epithelium of various organs to suppress local inflammation, coagulation, and apoptotic death. This paper summarizes the novel mechanisms of HGF for attenuating sepsis-related pathological conditions with a focus on sepsis-induced MOF.
Floating Knee Injury Associated with Patellar Tendon Rupture: A Case Report and Review of Literature
Authors: Vaidyanathan Singaravadivelu , Panchanathan Ganesan Jagannath , Moongilpatti Sengodan Mugundhan
Published: February 2012

Floating knee injuries are frequently associated with other concomitant injuries to the ipsilateral limb or other parts of body of which injury to the ipsilateral knee ligaments carries significance for various reasons. A middle-aged man sustained a floating knee injury following RTA. DCS fixation by bridge plating technique for the distal femur and lateral buttress plating by MIPO technique for proximal tibia were planned and executed under spinal anesthesia with image intensifier. In addition, there were patellar tendon rupture along with avulsion of VMO from the medial border of patella and torn MPFL, which we have missed initially. To the best of our knowledge no similar case has been reported in English literature so far. We have reviewed the literature and proposed a different interpretation of Blake and McBride classification.
PD-L1-Expressing Dendritic Cells Contribute to Viral Resistance during Acute HSV-1 Infection
Authors: Bryant-Hudson Katie M. , Carr Daniel J. J.
Published: February 2012

The inhibitory receptor, Programmed Death 1 (PD-1), and its ligands (PD-L1/PD-L2) are thought to play a role in immune surveillance during chronic viral infection. The contribution of the receptor/ligand pair during an acute infection is less understood. To determine the role of PD-L1 and PD-L2 during acute ocular herpes simplex virus type 1 (HSV-1) infection, HSV-1-infected mice administered neutralizing antibody to PD-L1 or PD-L2 were assessed for viral burden and host cellular immune responses. Virus titers were elevated in cornea and trigeminal ganglia (TG) of anti-PD-L1-treated mice which corresponded with a reduced number of CD80-expressing dendritic cells, PD-L1+dendritic cells, and HSV-1-specific CD8+T cells within the draining (mandibular) lymph node (MLN). In contrast, anti-PD-L2 treatment had no effect on viral replication or changes in the MLN population. Notably, analysis of CD11c-enriched MLN cells from anti-PD-L1-treated mice revealed impaired functional capabilities. These studies indicate PD-L1-expressing dendritic cells are important for antiviral defense during acute HSV-1 infection.
AZD4547: An Orally Bioavailable, Potent, and Selective Inhibitor of the Fibroblast Growth Factor Receptor Tyrosine Kinase Family
Authors: Gavine Paul R. , Mooney Lorraine , Kilgour Elaine , Thomas Andrew P. , Al-Kadhimi Katherine , Beck Sarah , Rooney Claire , Coleman Tanya , Baker Dawn , Mellor Martine J. , Brooks A. Nigel , Klinowska Teresa
Published: February 2012

The fibroblast growth factor (FGF) signaling axis is increasingly implicated in tumorigenesis and chemoresistance. Several small-molecule FGF receptor (FGFR) kinase inhibitors are currently in clinical development; however, the predominant activity of the most advanced of these agents is against the kinase insert domain receptor (KDR), which compromises the FGFR selectivity. Here, we report the pharmacologic profile of AZD4547, a novel and selective inhibitor of the FGFR1, 2, and 3 tyrosine kinases. AZD4547 inhibited recombinant FGFR kinase activity in vitro and suppressed FGFR signaling and growth in tumor cell lines with deregulated FGFR expression. In a representative FGFR-driven human tumor xenograft model, oral administration of AZD4547 was well tolerated and resulted in potent dose-dependent antitumor activity, consistent with plasma exposure and pharmacodynamic modulation of tumor FGFR. Importantly, at efficacious doses, no evidence of anti-KDR–related effects were observed, confirming the in vivo FGFR selectivity of AZD4547. Taken together, our findings show that AZD4547 is a novel selective small-molecule inhibitor of FGFR with potent antitumor activity against FGFR-deregulated tumors in preclinical models. AZD4547 is under clinical investigation for the treatment of FGFR-dependent tumors. Cancer Res; 72(8); 2045–56. ©2012 AACR.
Effect of Depo-Medroxyprogesterone Acetate on Breast Cancer Risk among Women 20 to 44 Years of Age
Authors: Li Christopher I. , Beaber Elisabeth F. , Chen Tang Mei Tzu , Porter Peggy L. , Daling Janet R. , Malone Kathleen E.
Published: February 2012

Depo-medroxyprogesterone acetate (DMPA) is an injectable contraceptive that contains the same progestin as the menopausal hormone therapy regimen found to increase breast cancer risk among postmenopausal women in the Women's Health Initiative clinical trial. However, few studies have evaluated the relationship between DMPA use and breast cancer risk. Here, we conducted a population-based case–control study among 1,028 women ages 20 to 44 years to assess the association between DMPA use and breast cancer risk. Detailed information on DMPA use and other relevant covariates was obtained through structured interviewer-administered in-person questionnaires, and unconditional logistic regression was used to evaluate associations between various aspects of DMPA use and breast cancer risk. We found that recent DMPA use for 12 months or longer was associated with a 2.2-fold [95% confidence interval (CI), 1.2–4.2] increased risk of invasive breast cancer. This risk did not vary appreciably by tumor stage, size, hormone receptor expression, or histologic subtype. Although breast cancer is rare among young women and the elevated risk of breast cancer associated with DMPA appears to dissipate after discontinuation of use, our findings emphasize the importance of identifying the potential risks associated with specific forms of contraceptives given the number of available alternatives. Cancer Res; 72(8); 2028–35. ©2012 AACR.
Expression of Epstein-Barr Virus–Encoded Proteins in Extranodal NK/T-cell Lymphoma, Nasal Type (ENKL): Differences in Biologic and Clinical Behaviors of LMP1-Positive and -Negative ENKL
Authors: Kanemitsu Naoko , Isobe Yasushi , Masuda Azuchi , Momose Shuji , Higashi Morihiro , Tamaru Jun-ichi , Sugimoto Koichi , Komatsu Norio
Published: February 2012

Purpose: Extranodal NK/T-cell lymphoma, nasal type (ENKL) is closely associated with Epstein-Barr virus (EBV). To elucidate its pathogenetic role, we examined the expression profiles of EBV-encoded proteins, especially focusing on latent membrane protein 1 (LMP1).

Experimental Design: Immunohistochemistry was carried out using clinical samples from ENKL cases, which were diagnosed between 1996 and 2010 at our institution. We statistically assessed the correlation between LMP1 positivity and the clinicopathologic data and further examined phosphorylation status of NF-κB RelA and Akt in ENKL cell lines.

Results: Most of the 30 examined cases showed pleomorphic morphology, natural killer cell immunophenotype, and a localized disease. Immunohistochemistry detected EBERs, but not EBNA2, in all cases. LMP1 and LMP2A were positive in 22 (73.3%) and 12 cases (40.0%), respectively. LMP1-positive cases tended to show a localized disease (P = 0.060, the Fisher exact test). Nuclear localization of phosphorylated RelA and detection of phosphorylated Akt were predominantly observed in LMP1-positive cases (P = 0.002 and P < 0.001, respectively, the Fisher exact test). RNA silencing experiments of LMP1 in Hank1 cells suggested a positive correlation between LMP1 expression and phosphorylation of RelA and Akt. With a median follow-up period of 26.7 months (range, 0.2–142.3 months), the 2.5-year overall survival rates for LMP1-positive and -negative cases were estimated at 78.3% and 12.5%, respectively (P = 0.001, log-rank test).

Conclusions: LMP1 expression shows correlations with phosphorylation of RelA and Akt and possibly has a favorable impact on clinical outcome in ENKL. Clin Cancer Res; 18(8); 2164–72. ©2012 AACR.
Mesothelin Overexpression Promotes Mesothelioma Cell Invasion and MMP-9 Secretion in an Orthotopic Mouse Model and in Epithelioid Pleural Mesothelioma Patients
Authors: Servais Elliot L. , Colovos Christos , Rodriguez Luis , Bograd Adam J. , Nitadori Jun-ichi , Sima Camelia , Rusch Valerie W. , Sadelain Michel , Adusumilli Prasad S.
Published: February 2012

Purpose: Mesothelin (MSLN) is a tumor-associated antigen, being investigated as a biomarker and therapeutic target in malignant pleural mesothelioma (MPM). The biologic function of MSLN overexpression in MPM is unknown. We hypothesized that MSLN may promote tumor invasion in MPM, a tumor characterized primarily by regional aggressiveness and rare distant metastases.

Experimental Design: Human and murine MPM cells with MSLN forced expression and short hairpin RNA knockdown were examined for proliferation, invasion, and matrix metalloproteinase (MMP) secretion. The influence of MSLN overexpression on MPM cell invasion was assessed in an orthotopic mouse model and in patient samples.

Results: MSLN expression promotes MPM cell invasion and MMP secretion in both human and murine MPM cells. In an orthotopic MPM mouse model characterized by our laboratory, MPM cells with MSLN overexpression preferentially localized to the tumor invading edge, colocalized with MMP-9 expression, and promoted decreased survival without an increase in tumor burden progression. In a tissue microarray from epithelioid MPM patients (n = 139, 729 cores), MSLN overexpression correlated with higher MMP-9 expression at individual core level. Among stage III MPM patients (n = 72), high MSLN expression was observed in 26% of T2 tumors and 51% of T3 tumors.

Conclusions: Our data provide evidence elucidating a biologic role for MSLN as a factor promoting tumor invasion and MMP-9 expression in MSLN expressing MPM. As regional invasion is the characteristic feature in MSLN expressing solid cancers (MPM, pancreas, and ovarian), our observations add rationale to studies investigating MSLN as a therapeutic target. Clin Cancer Res; 18(9); 2478–89. ©2012 AACR.
Multimodal CT Imaging and Recanalizing Therapy in Acute Ischemic Stroke: Retrospective Analysis of a One-Year Single-Center Experience
Authors: Eyding Jens , Wiebringhaus Reinhard , Klein Frauke G. , Skodda Sabine , Schlegel Uwe , Alekseyev Andriy , Heuser Lothar
Published: February 2012

Background: Recanalizing therapy in ischemic stroke is restricted to thrombolysis within 3 h. Multimodal imaging of vessel and parenchymal perfusion status may allow the extension of this time window. Aim: To retrospectively analyze treatment results of any recanalizing therapy in clinical practice. Methods: Patients comprised three groups: ‘standard’ intravenous thrombolysis within 3 h; ‘off-label’ intravenous thrombolysis, and off-label interventional therapy. Recanalizing therapy was applied dependent on multimodal CT according to standardized pathways. Short-term clinical courses were analyzed. Results: Of 543 patients (ischemic stroke, TIA), 68 (12.5%) received some type of recanalizing therapy. Of these, 47 (mean age 73.4, 24 female, mean symptom onset and hospital admission 62 min) received standard and 10 off-label thrombolysis (70.8, 6 female, 332 min), and 11 interventional therapy, mostly mechanical thrombectomy (mean age 62.5, 7 female, 186 min). Mean Δ short-term National Institutes of Health Stroke Scale (2–5 days) in these three groups were 3.7 ± 4.7, 3.9 ± 4.4, and 4.1 ± 5.8, respectively. The short-term clinical benefit was similar in the three groups. Conclusion: Off-label therapy is considered to have a higher risk of complications. However, if multimodal CT imaging of acute ischemic stroke is incorporated in everyday clinical decision-making, the rate of effective recanalizing procedures may be increased without an apparent negative effect on short-term outcome.
Long-Term Course of Brain-Derived Neurotrophic Factor Serum Levels in a Patient Treated with Deep Brain Stimulation of the Lateral Habenula
Authors: Hoyer Carolin , Kranaster Laura , Sartorius Alexander , Hellweg Rainer , Gass Peter
Published: February 2012

Introduction: According to the neurotrophin hypothesis, a brain-derived neurotrophic factor (BDNF) decrease has been postulated as a pivotal pathomechanism in affective disorder, and the treatment-associated increase in peripheral BDNF has been linked to therapeutic efficacy of antidepressant drugs and electroconvulsive therapy. However, in deep brain stimulation (DBS), a still experimental antidepressant treatment approach, this issue has not yet been investigated. Methods: We examine the long-term course of serum BDNF levels in a 64-year-old woman who is being treated with DBS of the lateral habenula for severe major depressive disorder. Results: Our main findings are a significant increase in BDNF serum levels following DBS of the lateral habenula and an inverse U-shaped correlation of depression scores and BDNF levels. Discussion: The data indicate that DBS, like other effective antidepressant treatments, may contribute to an increase in peripheral BDNF levels, which are thought to reflect central nervous DBS-induced neuroplastic changes. Moreover, our observations underscore the complex nature of disease-associated BDNF alterations. Their identification as either state or trait marker remains controversial and requires larger-scale longitudinal studies.
Macrophage Inflammatory Protein-1β and Fibrinogen Are Synergistic Predictive Markers of Prognosis of Intermediate Coronary Artery Lesions
Authors: Xu Feng , Lv Shuzheng , Chen Yundai , Song Xiantao , Jin Zening , Yuan Fei , Zhou Yuan , Li Hong
Published: February 2012

Objective: We tested the hypothesis that the plasma levels of fibrinogen and macrophage inflammatory protein (MIP)-1β are synergistic predictive markers of the prognosis of intermediate coronary artery lesions. Methods: A prospective study was performed on 670 patients with intermediate coronary artery lesions. Fibrinogen and MIP-1β were measured. Major adverse cardiac event (MACE) was defined as a composite of cardiovascular death, nonfatal myocardial infarction, revascularization and readmission due to angina pectoris. Results: During follow-up, 72 events occurred; 5 patients died, 7 patients suffered a nonfatal myocardial infarction, 11 patients underwent revascularization and 49 patients were readmitted for angina pectoris. In patients with above-median levels of MIP-1β, a 2.62-fold risk of a MACE [95% confidence interval (CI) 1.53–4.48] was predicted compared with patients with below-median levels of MIP-1β. However, the strongest risk prediction was achieved by assessing MIP-1β and fibrinogen together. After adjusting for traditional risk factors, a multivariate Cox proportional hazards analysis showed that patients with both MIP-1β and fibrinogen above the median had a 4.37-fold risk of a MACE (95% CI 1.89–10.11). Conclusion: MIP-1β accurately predicted MACEs. Considering MIP-1β and fibrinogen together may improve long-term risk assessment. These two biomarkers have a synergistic effect for assessing long-term risk in patients with intermediate coronary artery lesions.
Progressive External Ophthalmoplegia in Southwestern Finland: A Clinical and Genetic Study
Authors: Martikainen Mika H. , Hinttala Reetta , Röyttä Matias , Jääskeläinen Satu , Wendelin-Saarenhovi Maria , Parkkola Riitta , Majamaa Kari
Published: February 2012

Background: Progressive external ophthalmoplegia (PEO) is a common phenotype of mitochondrial disease. Molecu- lar etiologies include sporadic, large-scale deletions in mitochondrial DNA (mtDNA), multiple mtDNA deletions secondary to autosomal dominant or recessive mutations and mtDNA point mutations. Methods: We studied the prevalence and clinical and genetic characteristics of PEO in a defined population in southwestern Finland. A total of 620 patients were first identified from the patient registry at the Turku University Hospital over an 18-year period. The medical records of these patients were scrutinized, and those with clinical features compatible with PEO were ascertained. Results: We identified 10 patients with possible PEO. The patients were examined clinically, and DNA was analyzed for mtDNA deletions and for the m.3243A>G and m.8344A>G mtDNA point mutations. The ANT1, PEO1, POLG1 and POLG2 genes were sequenced. We confirmed the clinical diagnosis of PEO in 6 patients. Large-scale mtDNA deletions were detected in 3 out of 6 PEO patients and mutations in the POLG1 gene in 1 out of 6. We did not find any mutations in the ANT1, PEO1 or POLG2 genes. Conclusions: Our results suggest that molecular investigation of patients with PEO, either sporadic or familial, should start with an analysis for mtDNA deletions, followed by an analysis of the POLG1 gene.
Prognostic Nomogram for Disease-Free Survival in Patients with Renal Adenocarcinoma
Authors: Di Capua Sacoto C. , Budia A. , Garcia-Fadrique G. , Lujan S. , Ruiz-Cerdá J.L. , Jimenez-Cruz J.F.
Published: February 2012

Objective: The aim of this study was to develop a postoperative prognostic nomogram for disease-free survival in patients with renal adenocarcinoma. Materials and Methods: A total of 224 patients with organ-confined or locally advanced renal adenocarcinoma were treated with radical or partial nephrectomy. The variables included in the model were age, histological type, pathological stage, Fuhrman grade and DNA ploidy. Tumor recurrence was defined as any clinical evidence of recurrence. The probability of progression-free survival was calculated using the Kaplan-Meier estimate, and multivariate analysis was performed using a Cox regression. The nomogram was created using the data obtained from the Cox regression. Results: Tumor recurrence was detected in 89 patients (39.74%). The median progression-free time in these patients was 9.55 months (range 0–133). Of these patients, 70.9% relapsed during the first 2 years, and only 15 patients (6.9%) were alive but ill at the end of the study. The probability of progression-free survival at 5 and 10 years was 66.64 and 61.97%, respectively. We performed a statistical validation of the model with accurate predictions that were discriminated with a confidence interval of 0.75 (comparing the predicted and actual probability). According to the nomogram obtained, patients with low-grade, diploid, organ-confined tumors would be candidates for follow-up not exceeding 5 years due to the low probability of recurrence (<40 points). Conclusion: The nomogram we developed is clinically relevant and can provide prognostic information for both patients and researchers. In addition, it can be used by researchers during the monitoring protocols that categorize patients based on their relative risk of disease progression.
Synergistic Effects of Erlotinib and Everolimus on Bronchial Carcinoids and Large-Cell Neuroendocrine Carcinomas with Activated EGFR/AKT/mTOR Pathway
Authors: Bago-Horvath Zsuzsanna , Sieghart Wolfgang , Grusch Michael , Lackner Andreas , Hayden Hubert , Pirker Christine , Komina Oxana , Węsierska-Gądek Józefa , Haitel Andrea , Filipits Martin , Berger Walter , Schmid Katharina
Published: February 2012

Background: Epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (mTOR) are crucial targets in cancer therapy. Combined inhibition of both targets yielded synergistic effects in vitro and in vivo in several cancer entities. However, the impact of EGFR and mTOR expression and combined inhibition in neuroendocrine lung tumors other than small-cell lung cancer remains unclear. Material and Methods: Expression and activation of EGFR/AKT/mTOR pathway constituents were investigated in typical and atypical bronchial carcinoid (AC) tumors and large-cell neuroendocrine lung carcinomas (LCNEC) by immunohistochemistry in 110 tumor samples, and correlated with clinicopathological parameters and patient survival. Cytotoxicity of mTOR inhibitor everolimus and EGFR inhibitor erlotinib alone and in combination was assessed using growth inhibition assay in NCI-H720 AC and SHP-77 LCNEC cells. Cell cycle phase distribution was determined by FACS. Apoptosis-associated activation of caspase-3/7 was measured by Caspase-Glo® assay. Activity status of EGFR and mTOR pathway components was analyzed by immunoblotting. Results: Activation of the EGFR/AKT/mTOR axis could be demonstrated in all entities and was significantly increased in higher grade tumors. Neoadjuvant chemotherapy correlated significantly with p-AKT expression and p-ERK loss. Erlotinib combined with everolimus exerted synergistic combination effects in AC and LCNEC cells by induction of apoptosis, while cell cycle phase distribution remained unaffected. These effects could be explained by synergistic downregulation of phospho-mTOR, phospho-p70S6 kinase and phospho-AKT expression by everolimus and erlotinib. Conclusions: Our study indicates that EGFR and mTOR are clinically important targets in bronchial neuroendocrine tumors, and further in vivo and clinical exploration of combined inhibition is warranted.