bluuebunny/crossref_metadata_2025 huggingface dataset:
CapZ and actin capping dynamics increase in myocytes after a bout of exercise and abates in hours after stimulation ends
Authors: Lin Ying-Hsi , Li Jieli , Swanson Erik R. , Russell Brenda
Published: March 2013

The time course of the response and recovery after acute activity seen in exercise is not well understood. The goal of this work is to address how proteins of the thin filament (actin and its capping protein CapZ) are changed by 1 h of mechanical stimulation and return to baseline over time. Neonatal rat ventricular myocytes in culture were subjected to cyclic 10% strain at 1 Hz for 1 h to mimic increased mechanical loading during exercise. CapZ and actin dynamics were analyzed by fluorescence recovery after photobleaching (FRAP) using CapZβ1-GFP, actin-GFP, or actin-RFP. After cyclic strain, CapZ dynamics increased above resting controls and abated 2–3 h after cessation of the cyclic strain. Similarly, actin dynamics initially increased and abated 1.5–2 h after the end of stimulation. Neurohormonal hypertrophic stimulation by phenylephrine or norepinephrine treatments also elevated actin dynamics but required a much longer time of treatment (24–48 h) to be detectable. The actin capping mechanism was explored by use of expression of CapZβ1 with a COOH-terminal deletion (CapZβ1ΔC). Increased dynamics of actin seen with CapZβ1ΔC was similar to the response to cyclic strain. Thus it is possible that mechanical stimulation alters the dynamics for CapZ capping of the actin filament through the CapZβ1 COOH terminus, known as the β tentacle, thereby remodeling sarcomeres in cardiac myocytes. This adaptive mechanism, which is probably regulating thin-filament addition, declines a few hours after the end of a bout of exercise.
Growth and Neutron Diffraction Investigation of Ca3NbGa3Si2O14 and La3Ga5.5Nb0.5O14 Crystals
Authors: Kaurova I. A. , Kuz’micheva G. M. , Rybakov V. B. , Cousson A. , Zaharko O. , Domoroshchina E. N.
Published: March 2013

Langanite (La3Ga5.5Nb0.5O14, growth atmosphere: 99% Ar + 1% O2) and kanigasite (Ca3NbGa3Si2O14, growth atmosphere: 100% Ar) crystals grown by the Czochralski technique in Ir crucibles along <0001> direction have been firstly investigated by neutron diffraction. The difference between the compositions of upper (La2.935(2)□0.065)(Ga0.450Nb0.550(3))Ga3(Ga1.965(4)□0.035)(O13.90(1)□0.10) and lower (La2.940(1)□0.060)(Ga0.590Nb0.410(2))Ga5(O13.82(1)□0.18) parts of orange langanite crystal was found. It was established that the colorless Ca3NbGa3Si2O14 crystal grown by using the single-crystal charge has the composition (Ca2.95□0.05(1))NbGa3Si2O14 and is less defective in comparison to the yellow one grown by using the charge prepared by conventional solid-state reaction. For Ca3NbGa3Si2O14 and La3Ga5.5Nb0.5O14 crystals the possibility of microtwin formation (two unit cells connected by the translation: 1/2 z) was revealed for the first time. It was found that the difference between the color of crystals is attributed to the qualitative differentiation of oxygen vacancies.
Development and Environmental Applications of Activated Carbon Cloths
Authors: Cukierman Ana Lea
Published: March 2013

Activated carbon cloths have received growing attention because they offer comparative advantages over the traditional powdered or granular forms of this well-known adsorbent, providing further potential uses for technological innovations in several fields. The present article provides an overview of research studies and advances concerned with the development of activated carbon cloths and their use as adsorbent in environmental applications, mostly reported in the last years. The influence of some fabrics and textile wastes used as precursors, and of main activation process variables on the development and physicochemical, mechanical and/or electrical properties of the resulting activated carbon cloths are first reviewed. Then, investigations dealing with the removal of water and air pollutants by adsorption onto activated carbon cloths, including advances toward optimizing their regeneration after organic vapors saturation, are presented.
Ultrastructural Comparison of the Nasal Epithelia of Healthy and Naturally Affected Rabbits withPasteurella multocidaA
Authors: Esquinas Paula , Botero Lucía , Patiño María del Pilar , Gallego Carolina , Iregui Carlos
Published: March 2013

An ultrastructural comparison between the nasal cavities of healthy rabbits and those suffering from two forms of spontaneous infection withPasteurella multocidawas undertaken. Twelve commercially produced rabbits of different ages and respiratory health status were divided into four groups: healthy from 0 to 21 days (G1,n=2); healthy from 23 to 49 days (G2,n=2); healthy from 51 to 69 days (G3,n=2); diseased rabbits with septicemia and the rhinitic form ofP. multocidainfection (G4,n=3). The main ultrastructural changes observed were a widening of the interepithelial spaces, increased activity and number of goblet cells, the formation of two types of vacuoles in epithelial cells, the degranulation and migration of heterophils between the epithelial cells, and the association of this migration with some of the other changes. No bacteria were observed adhering to the epithelium, and very few were observed free in the mucus. Scant inter-epithelial spaces were found in healthy rabbits, but they were not as large and numerous as those found in diseased animals. We discuss the origin and meaning of these changes but, we focus on the significance of the inter-epithelial spaces and goblet cells for the defense of the upper respiratory airways against the bacterium and its lipopolysaccharide.
Super-Liouville Theory from Superstring Theory in the Presence of Gauge Worldsheet Fields
Authors: EL Boukili A. , Nach M. , Bilal K. , Sedra M. B.
Published: March 2013

We obtain in this work the super-Liouville theory induced from the action of the superstring theory in the presence of gauge worldsheet fields; such construction is based on a special ansatz that gives a special value of -fields . We discuss the integrability of super-Liouville theory through the Lax formulation, and we establish also the superfields formulation of super-Liouville equations.
The Analysis of Several Models of Investment Value of Logistics Project Evaluation
Authors: Zhou Ke Qiu Cheng
Published: March 2013

The study of the logistics project evaluation model features reviews the traditional value evaluation model. On the basis of this, using the fuzzy theory, we establish several logistics project evaluation models under fuzzy environment. The analysis of the respective characteristics and the comparison of the calculated results of the three models show that these models are important methods of investment value of logistics evaluation.
Designing of Adaptive Model-Free Controller Based on Output Error and Feedback Linearization
Authors: Pezeshki S. , Badamchizadeh M. A. , Ghaemi S. , Poor M. A.
Published: March 2013

This paper introduces a new approach to design Model-Free Adaptive Controller (MFAC) using adaptive fuzzy procedure as a feedback linearization based on output error. The basic idea is to transfer the control signal to an appropriate surface and then, depending on the output error of system, the control signal changes around this surface. Some examples are provided as well to illustrate the efficiency of the proposed approach. The obtained simulation results have shown good performances of the proposed controller.
Synthesis and Characterization of Trivalent Cerium Complexes of p‐tert‐Butylcalix[4,6,8]Arenes: Effect of Organic Solvents
Authors: Zahir Md. Hasan
Published: March 2013

Reaction of Ce3+ with p‐tert‐butylcalix[n]arene (n = 4, 6, 8) yields purple crystalline complexes structurally as [Ce(p‐tert‐butylcalix[4]arene‐3H)2(NO3)(DMF) x](2 − x)DMF (1), [Ce(p‐tert‐butylcalix[6]arene‐4H)2(NO3)(DMF) x](3 − x)DMF (2), and [Ce(p‐tert‐butylcalix[8]arene‐7H)2(NO3)(DMF)6] (3), where DMF = N,N‐dimethylformamide. The properties and coordination characteristics of the three calixarene complexes were determined by elemental analyses, electronic absorption, X‐ray absorption spectroscopy (EXAFS), TG‐DTA, FT‐IR, SEM, and 1H‐NMR spectroscopy. The effect of various organic solvents on complexes 1, 2, and 3 has been discussed based on results from electronic absorption spectra. The polar protic solvents showed the most significant molar extinction coefficients in comparison with those of nonpolar and polar aprotic solvents. The Ce3+ ions in the complexes are proved to combine with the ligand phenolic groups, oxygen atoms of DMF molecules, and/or OH− ions.
Evanescent Field Enhancement in Liquid Crystal Optical Fibers: A Field Characteristics Based Analysis
Authors: Choudhury P. K.
Published: March 2013

The paper presents the analysis of the electromagnetic wave propagation through liquid crystal optical fibers (LCOFs) of two different types—conventional guides loaded with liquid crystals (addressed as LCOFs) and those with additional twists due to conducting helical windings (addressed as HCLCOFs). More precisely, the three-layer optical waveguide structures are considered along with its outermost region being loaded with radially anisotropic liquid crystal material and the inner regions being made of usual silica, as used in conventional optical fibers. In addition to that, LCOF with twists introduced in the form of conducting helical windings at the interface of the silica core and the liquid crystal clad is also taken into account. Emphasis has been put on the power confinements by the lower-order TE modes sustained in the different sections of the LCOF structure. The results demonstrate useful applications of these guides in integrated optics as the power sustained in the liquid crystal section by the excited TE modes remains very high. In the case of twisted clad liquid crystal guides, descriptions are limited to the nature of dispersion relation only under the TE mode excitation, and corresponding to the cases of helix orientations being parallel and perpendicular to the optical axis.
Nucleosides 8 [18]: Ribosylation of Fused Quinazolines—Synthesis of New [1,2,4]Triazolo[5,1‐b]‐ and [1,2,4]Triazino[3,2‐b]quinazoline Nucleosides of Fluorescence Interest
Authors: Break Laila Mohamed , Abdelnabi Mosselhi Mosselhi , Elshafai Nagi Mohamed
Published: March 2013

[1,2,4]Triazolo[5,1‐b]‐ and [1,2,4]triazino[3,2‐b] quinazolines have been ribosylated by coupling with 1‐O‐acetyl‐2,3,5‐tri‐O‐benzoyl‐β‐D‐ribofuranose and by using the silylation method, followed by debenzoylation by methanolic sodium methoxide to afford the corresponding free N‐nucleosides. Nucleosides obtained have been identified by their spectral analysis. From the UV‐visible and fluorescence studies of some nucleosides synthesized, it is found that they have fluorescence properties.
Pricing Currency Option Based on the Extension Principle and Defuzzification via Weighting Parameter Identification
Authors: Xu Jixiang , Tan Yanhua , Gao Jinggui , Feng Enmin
Published: March 2013

We present a fuzzy version of the Garman-Kohlhagen (FG-K) formula for pricing European currency option based on the extension principle. In order to keep consistent with the real market, we assume that the interest rate, the spot exchange rate, and the volatility are fuzzy numbers in the FG-K formula. The conditions of a basic proposition about the fuzzy-valued functions of fuzzy subsets are modified. Based on the modified conditions and the extension principle, we prove that the fuzzy price obtained from the FG-K formula for European currency option is a fuzzy number. To simplify the trade, the weighted possibilistic mean (WPM) value with a weighting function is adopted to defuzzify the fuzzy price to a crisp price. The numerical example shows our method makes theα-level set of fuzzy price smaller, which decreases the fuzziness. The example also indicates that the WPM value has different approximation effects to real market price by taking different values of weighting parameter in the weighting function. Inspired by this example, we provide a method, which can identify the optimal parameter.
The Evidence Regarding Maintenance Tocolysis
Authors: Elliott John P. , Morrison John C.
Published: March 2013

Preterm delivery is a public health issue of major proportion. More than 12% of deliveries in the United States that occur at less than 37 weeks gestation preterm labor (PTL) represents the largest single reason for preterm birth (PTB). Attempts to prevent PTB have been unsuccessful. This paper of maintenance tocolytic therapy will examine the efficacy and safety of the drugs, both oral and subcutaneous, which have been utilized for prolongation of pregnancy following successful arrest of a documented episode of acute preterm labor. The evidence for oral tocolytics as maintenance therapy as well as parenteral medications for such patients is offered. Finally, the effects in the United States of the Food and Drug Administration (FDA) action on such medications are reported.
An Upper Bound for the Symmetric Tensor Rank of a Low Degree Polynomial in a Large Number of Variables
Authors: Ballico E.
Published: March 2013

Fix integers m≥5 and d≥3. Let f be a degree d homogeneous polynomial in m+1 variables. Here, we prove that f is the sum of at most d·⌈(m+dm)/(m+1)⌉d-powers of linear forms (of course, this inequality is nontrivial only if m≫d.)
A Review on the Synthesis of Manganese Oxide Nanomaterials and Their Applications on Lithium‐Ion Batteries
Authors: Liu Xiaodi , Chen Changzhong , Zhao Yiyang , Jia Bin
Published: March 2013

Most recently, manganese oxides nanomaterials, including MnO and MnO2, have attracted great interest as anode materials in lithium‐ion batteries (LIBs) for their high theoretical capacity, environmental benignity, low cost, and special properties. Up to now, manganese oxides nanostructures with excellent properties and various morphologies have been successfully synthesized. Herein, we provide an in‐depth discussion of recent development of the synthesis of manganese oxides nanomaterials and their application in the field of LIBs.
Inventory Management and Maintenance in Offshore Vessel Industry
Authors: Ben Hmida Jalel , Regan Grant , Lee Jim
Published: March 2013

An evaluation of the inventory policy at an offshore vessel company was conducted. Currently the items in inventory are used at random intervals as they are used only when parts fail. To solve the problem of reducing a very large inventory but keep enough to allow an uninterrupted service to the customer, we propose a real and economically efficient multicriteria inventory policy using inventory classification method integrated with a preventive maintenance program. The proposed method can be summarized in the following three steps: first, rank the parts according to both the lead time from supplier and the cost of downtime failure and use a matrix display to show the most critical items. In the second step develop a preventive maintenance program for the most critical parts to minimize downtime due to failure. Finally in the third step standardize most critical parts to reduce the inventory which saves the company money while maintaining the same level of service to its customers. Our study showed that the company with a very large inventory could effectively reduce its size by focusing on key parts.
New Species of Exomalopsis and Its Associated Cleptoparasite Nomada from Colombia with Description of the Nest (Hymenoptera: Apoidea: Anthophila: Apidae)
Authors: Velez-Ruiz Rita I. , Smith-Pardo Allan H.
Published: March 2013

We describe two new species of bees from Colombia; one is a species of Exomalopsis found nesting in the city of Medellin, Colombia, (the host) and its cleptoparasitic bee, a species of the genus Nomada. In addition, we provide information on the nest architecture of the new species and provide data on occupancy by both the host bee and its cleptoparasite. We present an updated list of the species of Exomalopsis and Nomada of Colombia and taxonomic keys to the species of Exomalopsis.
Faired MISO B-Spline Fuzzy Systems and Its Applications
Authors: Yanhua Tan , Hongxing Li
Published: March 2013

We construct two classes of faired MISO B-spline fuzzy systems using the fairing method in computer-aided geometric design (CAGD) for reducing adverse effects of the inexact data. Towards this goal, we generalize the faring method to high-dimension cases so that the faring method only for SISO and DISO B-spline fuzzy systems is extended to fair the MISO ones. Then the problem to construct a faired MISO B-spline fuzzy systems is transformed into solving an optimization problem with a strictly convex quadratic objective function and the unique optimal solution vector is taken as linear combination coefficients of the basis functions for a certain B-spline fuzzy system to obtain a faired MISO B-spline fuzzy system. Furthermore, we design variable universe adaptive fuzzy controllers by B-spline fuzzy systems and faired B-spline fuzzy systems to stabilize the double inverted pendulum. The simulation results show that the controllers by faired B-spline fuzzy systems perform better than those by B-spline fuzzy systems, especially when the data for fuzzy systems are inexact.
Disrupted Central Inhibition after Transcranial Magnetic Stimulation of Motor Cortex in Schizophrenia with Long-Term Antipsychotic Treatment
Authors: Ahlgrén-Rimpiläinen Aulikki , Lauerma Hannu , Kähkönen Seppo , Rimpiläinen Ilpo
Published: March 2013

Aims. Schizophrenia is a neuropsychiatric disorder associated with mental and motor disturbances. We aimed to investigate motor control, especially central silent period (CSP) in subjects with schizophrenia (n=11) on long-term antipsychotic treatment compared to healthy controls (n=9). Methods. Latency and duration of motor evoked potentials (MEPs) and CSPs were measured with the help of single pulse transcranial magnetic stimulation (TMS) and intramuscular electrodes. After stimulation of the dominant and nondominant motor cortex of abductor digiti minimi (ADM) and tibialis anterior (TA) muscle areas, respective responses were measured on the contralateral side. Results. MEPs did not differ significantly between the groups. Multiple CSPs were found predominantly in subjects with schizophrenia, which showed a higher number of CSPs in the dominant ADM and the longest summarized duration of CSPs in the nondominant ADM (P<0.05) compared to controls. Conclusions. There were multiple CSPs predominantly in the upper extremities and in the dominant body side in subjects with schizophrenia. Behind multiple CSPs may lie an impaired regulation of excitatory or inhibitory neurotransmitter systems in central motor pathways. Further research is needed to clarify the role of the intramuscular recording methods and the effect of antipsychotics on the results.
The Human Frontal Lobes and Frontal Network Systems: An Evolutionary, Clinical, and Treatment Perspective
Authors: Hoffmann Michael
Published: March 2013

Frontal lobe syndromes, better termed as frontal network systems, are relatively unique in that they may manifest from almost any brain region, due to their widespread connectivity. The understandings of the manifold expressions seen clinically are helped by considering evolutionary origins, the contribution of the state-dependent ascending monoaminergic neurotransmitter systems, and cerebral connectivity. Hence, the so-called networktopathies may be a better term for the syndromes encountered clinically. An increasing array of metric tests are becoming available that complement that long standing history of qualitative bedside assessments pioneered by Alexander Luria, for example. An understanding of the vast panoply of frontal systems' syndromes has been pivotal in understanding and diagnosing the most common dementia syndrome under the age of 60, for example, frontotemporal lobe degeneration. New treatment options are also progressively becoming available, with recent evidence of dopaminergic augmentation, for example, being helpful in traumatic brain injury. The latter include not only psychopharmacological options but also device-based therapies including mirror visual feedback therapy.
Clinical Trials with Pegylated Liposomal Doxorubicin in the Treatment of Ovarian Cancer
Authors: Pisano Carmela , Cecere Sabrina Chiara , Di Napoli Marilena , Cavaliere Carla , Tambaro Rosa , Facchini Gaetano , Scaffa Cono , Losito Simona , Pizzolorusso Antonio , Pignata Sandro
Published: March 2013

Among the pharmaceutical options available for treatment of ovarian cancer, increasing attention has been progressively focused on pegylated liposomal doxorubicin (PLD), whose unique formulation prolongs the persistence of the drug in the circulation and potentiates intratumor accumulation. Pegylated liposomal doxorubicin (PLD) has become a major component in the routine management of epithelial ovarian cancer. In 1999 it was first approved for platinum-refractory ovarian cancer and then received full approval for platinum-sensitive recurrent disease in 2005. PLD remains an important therapeutic tool in the management of recurrent ovarian cancer in 2012. Recent interest in PLD/carboplatin combination therapy has been the object of phase III trials in platinum-sensitive and chemonaïve ovarian cancer patients reporting response rates, progressive-free survival, and overall survival similar to other platinum-based combinations, but with a more favorable toxicity profile and convenient dosing schedule. This paper summarizes data clarifying the role of pegylated liposomal doxorubicin (PLD) in ovarian cancer, as well as researches focusing on adding novel targeted drugs to this cytotoxic agent.
Factors Perceived by Caretakers as Barriers to Health Care for Under-Five Children in Mazabuka District, Zambia
Authors: Halwindi H. , Siziya S. , Magnussen P. , Olsen A.
Published: March 2013

In rural areas of Zambia primary health care is provided by rural health centres (RHCs). However, accessibility to these services is limited. In the catchment areas of two RHCs in Mazabuka district (Chivuna and Magoye RHCs) we investigated factors that caretakers perceived as barriers to health care for under five children and how they cope with the barriers. Ten Focus Group Discussions (FGDs) with caretakers of children under-five years of age and key informant interviews with six health workers from the two RHCs, and eight community health workers were conducted in May 2006. The major factors perceived as barriers were poor quality of health services, unavailability of medicines, financial constraints, weak outreach programmes, bad scheduling of health programmes, poor communication, long distance to RHCs and low awareness levels of the importance of taking children for child health week among caretakers. Caretakers’ main coping strategy was the use of the folk sector of health care. The findings of this study highlight the challenges that exist in accessing of health care in resource-poor settings and underscore that the provision of health care services of good quality remains a major challenge.
Novel HSP90 Inhibitor NVP-HSP990 Targets Cell-Cycle Regulators to Ablate Olig2-Positive Glioma Tumor–Initiating Cells
Authors: Fu Jun , Koul Dimpy , Yao Jun , Wang Shuzhen , Yuan Ying , Colman Howard , Sulman Erik. P. , Lang Frederick. F. , Alfred Yung W.K.
Published: March 2013

Genetic heterogeneity and signaling alterations diminish the effectiveness of single-agent therapies in glioblastoma multiforme (GBM). HSP90 is a molecular chaperone for several signaling proteins that are deregulated in glioma cells. Thus, HSP90 inhibition may offer an approach to coordinately correct multiple signaling pathways as a strategy for GBM therapy. In this study, we evaluated the effects of a novel HSP90 inhibitor, NVP-HSP990, in glioma tumor–initiating cell (GIC) populations, which are strongly implicated in the root pathobiology of GBM. In GIC cultures, NVP-HSP990 elicited a dose-dependent growth inhibition with IC50 values in the low nanomolar range. Two GIC subgroups with different responses were observed with an Olig2-expressing subset relatively more sensitive to treatment. We also showed that Olig2 is a functional marker associated with cell proliferation and response to NVP-HSP990, as NVP-HSP990 attenuated cell proliferation in Olig2-high GIC lines. In addition, NVP-HSP990 disrupted cell-cycle control mechanism by decreasing CDK2 and CDK4 and elevating apoptosis-related molecules. Mechanistic investigations revealed molecular interactions between CDK2/CDK4 and Olig2. Inhibition of CDK2/CDK4 activity disrupted Olig2–CDK2/CDK4 interactions and attenuated Olig2 protein stability. In vivo evaluation showed a relative prolongation of median survival in an intracranial model of GIC growth. Our results suggest that GBM characterized by high-expressing Olig2 GIC may exhibit greater sensitivity to NVP-HSP990 treatment, establishing a foundation for further investigation of the role of HSP90 signaling in GBM. Cancer Res; 73(10); 3062–74. ©2013 AACR.
Hsp27 Regulates Epithelial Mesenchymal Transition, Metastasis, and Circulating Tumor Cells in Prostate Cancer
Authors: Shiota Masaki , Bishop Jennifer L. , Nip Ka Mun , Zardan Anousheh , Takeuchi Ario , Cordonnier Thomas , Beraldi Eliana , Bazov Jenny , Fazli Ladan , Chi Kim , Gleave Martin , Zoubeidi Amina
Published: March 2013

Defining the mechanisms underlying metastatic progression of prostate cancer may lead to insights into how to decrease morbidity and mortality in this disease. An important determinant of metastasis is epithelial-to-mesenchymal transition (EMT), and the mechanisms that control the process of EMT in cancer cells are still emerging. Here, we report that the molecular chaperone Hsp27 (HSPB1) drives EMT in prostate cancer, whereas its attenuation reverses EMT and decreases cell migration, invasion, and matrix metalloproteinase activity. Mechanistically, silencing Hsp27 decreased IL-6–dependent STAT3 phosphorylation, nuclear translocation, and STAT3 binding to the Twist promoter, suggesting that Hsp27 is required for IL-6–mediated EMT via modulation of STAT3/Twist signaling. We observed a correlation between Hsp27 and Twist in patients with prostate cancer, with Hsp27 and Twist expression each elevated in high-grade prostate cancer tumors. Hsp27 inhibition by OGX-427, an antisense therapy currently in phase II trials, reduced tumor metastasis in a murine model of prostate cancer. More importantly, OGX-427 treatment decreased the number of circulating tumor cells in patients with metastatic castration-resistant prostate cancer in a phase I clinical trial. Overall, this study defines Hsp27 as a critical regulator of IL-6–dependent and IL-6–independent EMT, validating this chaperone as a therapeutic target to treat metastatic prostate cancer. Cancer Res; 73(10); 3109–19. ©2013 AACR.
The Prognostic Significance and Therapeutic Potential of Hedgehog Signaling in Intrahepatic Cholangiocellular Carcinoma
Authors: Tang Liang , Tan Ye-Xiong , Jiang Bei-Ge , Pan Yu-Fei , Li Shuang-Xi , Yang Guang-Zhen , Wang Min , Wang Qing , Zhang Jian , Zhou Wei-Ping , Dong Li-Wei , Wang Hong-Yang
Published: March 2013

Purpose: The correlation of the hedgehog signaling pathway with the progression, prognosis, and therapeutics of intrahepatic cholangiocellular carcinoma (ICC) has not been well documented. The study aimed to investigate the expression, prognostic significance, and therapeutic value of hedgehog components in ICC.

Experimental Design: Two independent cohorts of 200 patients with ICC were enrolled. By real-time PCR and immunohistochemistry assay, hedgehog components expression was evaluated. The prognostic values of hedgehog proteins were identified and verified. Cyclopamine or siRNA-targeting Gli was used to block the hedgehog signaling. Cell proliferation and apoptosis were observed by CCK8, cell cycle, and annexin V staining assays. In vivo murine tumor model was used to evaluate the role of hedgehog in ICC.

Results: In ICC tissues, the Gli1 nuclear immune-intensity was associated with intrahepatic metastasis and the expression of Gli2 was associated with intrahepatic metastasis, venous invasion, and Unio Internationale Contra Cancrum (UICC) pT characteristics. In survival analysis, high Gli1 or Gli2 expressers had an unfavorable overall survival (OS) prognosis and a shorter disease-free survival (DFS) than those with low expression. In multivariate analysis, Gli1 expression was found to be an independent prognostic factor of OS, which was validated by another independent cohort. Furthermore, blocking the hedgehog signaling by cyclopamine or siRNA-targeting Gli1 resulted in apoptosis and growth inhibition in ICC cells.

Conclusions: This study shows, for the first time, activation of hedgehog pathway associated with the progression and metastasis in ICC, which may provide prognostic and therapeutic values for this tumor. Clin Cancer Res; 19(8); 2014–24. ©2013 AACR.
Antiviral and Antitumor T-cell Immunity in Patients Treated with GM-CSF–Coding Oncolytic Adenovirus
Authors: Kanerva Anna , Nokisalmi Petri , Diaconu Iulia , Koski Anniina , Cerullo Vincenzo , Liikanen Ilkka , Tähtinen Siri , Oksanen Minna , Heiskanen Raita , Pesonen Saila , Joensuu Timo , Alanko Tuomo , Partanen Kaarina , Laasonen Leena , Kairemo Kalevi , Pesonen Sari , Kangasniemi Lotta , Hemminki Akseli
Published: March 2013

Purpose: Multiple injections of oncolytic adenovirus could enhance immunologic response. In the first part of this article, the focus was on immunologic aspects. Sixty patients previously naïve to oncolytic virus and who had white blood cells available were treated. Thirty-nine of 60 were assessed after a single virus administration, whereas 21 of 60 received a “serial treatment” consisting of three injections within 10 weeks. In the second part, we focused on 115 patients treated with a granulocyte macrophage colony-stimulating factor (GM–CSF)–coding capsid chimeric adenovirus, CGTG-102.

Results: Following serial treatment, both increase and decrease in antitumor T cells in blood were seen more frequently, findings which are compatible with induction of T-cell immunity and trafficking of T cells to tumors, respectively. Safety was good in both groups. In 115 patients treated with CGTG-102 (Ad5/3-D24-GMCSF), median overall survival was 111 days following single and 277 days after serial treatment in nonrandomized comparison. Switching the virus capsid for avoiding neutralizing antibodies in a serial treatment featuring three different viruses did not impact safety or efficacy. A correlation between antiviral and antitumor T cells was seen (P = 0.001), suggesting that viral oncolysis can result in epitope spreading and breaking of tumor-associated immunologic tolerance. Alternatively, some patients may be more susceptible to induction of T-cell immunity and/or trafficking.

Conclusions: These results provide the first human data linking antiviral immunity with antitumor immunity, implying that oncolytic viruses could have an important role in cancer immunotherapy. Clin Cancer Res; 19(10); 2734–44. ©2013 AACR.
Epstein-Barr Virus DNA Load in Nasopharyngeal Brushings and Whole Blood in Nasopharyngeal Carcinoma Patients before and after Treatment
Authors: Adham Marlinda , Greijer Astrid E. , Verkuijlen Sandra A.W.M. , Juwana Hedy , Fleig Sabine , Rachmadi Lisnawati , Malik Octavia , Kurniawan A.N. , Roezin Averdi , Gondhowiardjo Soehartati , Atmakusumah Djumhana , Stevens Servi J.C. , Hermani Bambang , Tan I. Bing , Middeldorp Jaap M.
Published: March 2013

Purpose: Nasopharyngeal carcinoma (NPC) is consistently associated with Epstein-Barr virus (EBV) and highly prevalent in Indonesia. EBV-DNA load can be used for early diagnosis and may have prognostic value. In this study, EBV-DNA load was evaluated in minimal invasive nasopharyngeal (NP) brushings and whole blood for initial diagnosis and therapy assessment against the standard-of-care diagnosis by biopsy with EBV-RISH and standard EBV-IgA serology.

Experimental Design: NP brushings and blood samples were collected from 289 consecutive ENT patients suspected of NPCs and 53 local healthy controls. EBV-DNA load was quantified by real-time PCR and serology by peptide-based EBV-IgA ELISA. Tissue biopsies were examined by routine histochemistry and by EBER RNA in situ hybridization.

Results: Repeated NP brushing was well tolerated by patients and revealed high viral load in the 228 NPC cases at diagnosis than 61 non-NPC cancer cases and healthy controls (P < 0.001). The diagnostic value of EBV-DNA load in blood and EBV-IgA serology was inferior to the NP brush results. The level of EBV-DNA load in brushes of patients with NPC was not related to T, N, or M stage, whereas elevated EBV-DNA load in blood correlated with N and M stage. EBV-DNA levels in brushings and whole blood showed a significant reduction at 2 months after treatment (P = 0.001 and P = 0.005, respectively), which was not reflected in EBV-IgA serology.

Conclusions: NP brush sampling combined with EBV-DNA load analysis is a minimal invasive and well-tolerated diagnostic procedure, suited for initial diagnosis and follow-up monitoring of NPCs. Clin Cancer Res; 19(8); 2175–86. ©2013 AACR.
Aberrant BAF57 Signaling Facilitates Prometastatic Phenotypes
Authors: Balasubramaniam Sucharitha , Comstock Clay E.S. , Ertel Adam , Jeong Kwang Won , Stallcup Michael R. , Addya Sankar , McCue Peter A. , Ostrander William F. , Augello Michael A. , Knudsen Karen E.
Published: March 2013

Purpose: BAF57, a component of the switching-defective and sucrose nonfermenting (SWI/SNF) chromatin-remodeling complex conglomerate, modulates androgen receptor activity to promote prostate cancer. However, the molecular consequences of tumor-associated BAF57 expression have remained undefined in advanced disease such as castration-resistant prostate cancer and/or metastasis.

Experimental Design: Clinical human specimens of primary and metastatic prostate cancer were immunohistochemically examined for tumor-grade association of BAF57 expression. Global gene expression analyses were conducted in models mimicking tumor-associated BAF57 expression. Aberrant BAF57-dependent gene expression changes, bypass of androgen-mediated signaling, and chromatin-specific SWI/SNF complex alterations with respect to cytoskeletal remodelers such as integrins were validated. Cell migration assays were used to profile the biologic phenotypes conferred under conditions simulating tumor-derived BAF57 expression.

Results: Immunohistochemical quantitation of primary human specimens revealed that BAF57 was significantly and aberrantly elevated as a function of tumor grade. Critically, gene expression analyses showed that BAF57 deregulation circumvented androgen-mediated signaling, elicited α2 integrin upregulation, and altered other SWI/SNF complex components at the α2 integrin locus. BAF57-dependent α2 integrin induction conferred a prometastatic migratory advantage, which was attenuated by anti-α2 integrin antibody blockade. Furthermore, BAF57 was found to be markedly upregulated in human prostate cancer metastases of the lung, lymph node, and dura.

Conclusion: The findings herein, identifying tumor-associated BAF57 perturbation as a means to bypass androgen-signaling events that facilitate novel prometastatic phenotypes, link BAF57 upregulation to tumor dissemination. These data thereby establish BAF57 as a putative marker of metastatic potential that could be leveraged for therapeutic intervention. Clin Cancer Res; 19(10); 2657–67. ©2013 AACR.
Elevated TNFR1 and Serotonin in Bone Metastasis Are Correlated with Poor Survival following Bone Metastasis Diagnosis for Both Carcinoma and Sarcoma Primary Tumors
Authors: Chiechi Antonella , Novello Chiara , Magagnoli Giovanna , Petricoin Emanuel F. , Deng Jianghong , Benassi Maria S. , Picci Piero , Vaisman Iosif , Espina Virginia , Liotta Lance A.
Published: March 2013

Purpose: There is an urgent need for therapies that will reduce the mortality of patients with bone metastasis. In this study, we profiled the protein signal pathway networks of the human bone metastasis microenvironment. The goal was to identify sets of interacting proteins that correlate with survival time following the first diagnosis of bone metastasis.

Experimental Design: Using Reverse Phase Protein Microarray technology, we measured the expression of 88 end points in the bone microenvironment of 159 bone metastasis tissue samples derived from patients with primary carcinomas and sarcomas.

Results: Metastases originating from different primary tumors showed similar levels of cell signaling across tissue types for the majority of proteins analyzed, suggesting that the bone microenvironment strongly influences the metastatic tumor signaling profiles. In a training set (72 samples), TNF receptor 1, alone (P = 0.0013) or combined with serotonin (P = 0.0004), TNFα (P = 0.0214), and RANK (P = 0.0226), was associated with poor survival, regardless of the primary tumor of origin. Results were confirmed by (i) analysis of an independent validation set (71 samples) and (ii) independent bioinformatic analysis using a support vector machine learning model. Spearman rho analysis revealed a highly significant number of interactions intersecting with ERα S118, serotonin, TNFα, RANKL, and matrix metalloproteinase in the bone metastasis signaling network, regardless of the primary tumor. The interaction network pattern was significantly different in the short versus long survivors.

Conclusions: TNF receptor 1 and neuroendocrine-regulated protein signal pathways seem to play an important role in bone metastasis and may constitute a novel drug-targetable mechanism of seed-soil cross talk in bone metastasis. Clin Cancer Res; 19(9); 2473–85. ©2013 AACR.
Construction and Characterization of Novel, Completely Human Serine Protease Therapeutics Targeting Her2/neu
Authors: Cao Yu , Mohamedali Khalid A. , Marks John W. , Cheung Lawrence H. , Hittelman Walter N. , Rosenblum Michael G.
Published: March 2013

Immunotoxins containing bacterial or plant toxins have shown promise in cancer-targeted therapy, but their long-term clinical use may be hampered by vascular leak syndrome and immunogenicity of the toxin. We incorporated human granzyme B (GrB) as an effector and generated completely human chimeric fusion proteins containing the humanized anti-Her2/neu single-chain antibody 4D5 (designated GrB/4D5). Introduction of a pH-sensitive fusogenic peptide (designated GrB/4D5/26) resulted in comparatively greater specific cytotoxicity although both constructs showed similar affinity to Her2/neu–positive tumor cells. Compared with GrB/4D5, GrB/4D5/26 showed enhanced and long-lasting cellular uptake and improved delivery of GrB to the cytosol of target cells. Treatment with nanomolar concentrations of GrB/4D5/26 resulted in specific cytotoxicity, induction of apoptosis, and efficient downregulation of PI3K/Akt and Ras/ERK pathways. The endogenous presence of the GrB proteinase inhibitor 9 did not impact the response of cells to the fusion construct. Surprisingly, tumor cells resistant to lapatinib or Herceptin, and cells expressing MDR-1 resistant to chemotherapeutic agents showed no cross-resistance to the GrB-based fusion proteins. Administration (intravenous, tail vein) of GrB/4D5/26 to mice bearing BT474 M1 breast tumors resulted in significant tumor suppression. In addition, tumor tissue excised from GrB/4D5/26–treated mice showed excellent delivery of GrB to tumors and a dramatic induction of apoptosis compared with saline treatment. This study clearly showed that the completely human, functionalized GrB construct can effectively target Her2/neu–expressing cells and displays impressive in vitro and in vivo activity. This construct should be evaluated further for clinical use. Mol Cancer Ther; 12(6); 979–91. ©2013 AACR.
PPP2R2C Loss Promotes Castration-Resistance and Is Associated with Increased Prostate Cancer-Specific Mortality
Authors: Bluemn Eric G. , Spencer Elysia Sophie , Mecham Brigham , Gordon Ryan R. , Coleman Ilsa , Lewinshtein Daniel , Mostaghel Elahe , Zhang Xiaotun , Annis James , Grandori Carla , Porter Christopher , Nelson Peter S.
Published: March 2013

Metastatic prostate cancers generally rely on androgen receptor (AR) signaling for growth and survival, even following systemic androgen-deprivation therapy (ADT). However, recent evidence suggests that some advanced prostate cancers escape ADT by using signaling programs and growth factors that bypass canonical AR ligand-mediated mechanisms. We used an in vitro high-throughput RNA interference (RNAi) screen to identify pathways in androgen-dependent prostate cancer cell lines whose loss-of-function promotes androgen ligand-independent growth. We identified 40 genes where knockdown promoted proliferation of both LNCaP and VCaP prostate cancer cells in the absence of androgen. Of these, 14 were downregulated in primary and metastatic prostate cancer, including two subunits of the protein phosphatase 2 (PP2A) holoenzyme complex: PPP2R1A, a structural subunit with known tumor-suppressor properties in several tumor types; and PPP2R2C, a PP2A substrate-binding regulatory subunit that has not been previously identified as a tumor suppressor. We show that loss of PPP2R2C promotes androgen ligand depletion-resistant prostate cancer growth without altering AR expression or canonical AR-regulated gene expression. Furthermore, cell proliferation induced by PPP2R2C loss was not inhibited by the AR antagonist MDV3100, indicating that PPP2R2C loss may promote growth independently of known AR-mediated transcriptional programs. Immunohistochemical analysis of PPP2R2C protein levels in primary prostate tumors determined that low PPP2R2C expression significantly associated with an increased likelihood of cancer recurrence and cancer-specific mortality. These findings provide insights into mechanisms by which prostate cancers resist AR-pathway suppression and support inhibiting PPP2R2C complexes or the growth pathway(s) activated by PPP2R2C as a therapeutic strategy. Mol Cancer Res; 11(6); 568–78. ©2013 AACR.
Geographical Distribution of Dental Caries Prevalence and Associated Factors in Young Adults in Finland
Authors: Kämppi A. , Tanner T. , Päkkilä J. , Patinen P. , Järvelin M.-R. , Tjäderhane L. , Anttonen V.
Published: March 2013

Oral health of the young has been reported to be associated with the place of residence, due to differences in socio-economic status. The results of studies on the effect of fluoride in drinking water on caries prevalence have been contradictory. The main aim of our study was to investigate the geographical distribution of dental caries prevalence in Finland and analyse possible regional, associated factors. Oral health of 13,564 men born between 1990 and 1992 was screened using a method based on criteria of the World Health Organization for epidemiological studies by 15 calibrated dentists in 20/24 garrisons of the Finnish Defence Forces in 2011. Mean DMFT and DT values in provinces were calculated. Multilevel analysis was applied to the data using generalized linear mixed models and a logit link function. The binary outcome variable was the cariological treatment need (yes/no) and the garrison was treated as random effect. Mean DMFT and DT values varied significantly between provinces in Finland. Increased levels of fluoride in drinking water, Swedish as the main language in the municipality, and living in urban areas were protective factors against cariological treatment need. Dentist density did not affect caries prevalence. The geographical distribution of dental caries further supported estimates of the protective effects of high fluoride levels in drinking water, Swedish as the main language in the municipality, as well as living in urban areas. Effect of fluoride on caries prevalence still exists, and association with the socio-economic status was confirmed.
The Usefulness of Job Relocation and Serum Eosinophil Cationic Protein in Baker's Asthma
Authors: Kim Min-Hye , Jung Jae-Woo , Kang Hye-Ryun
Published: March 2013

Background: Although the most widely recommended treatment for occupational asthma is to completely avoid the causative agents, job relocation within the same company is often substituted for a complete career change. However, there is not much data on the efficacy of job relocation within the workplace and appropriate follow-up parameters. We investigated baker's asthma patients to validate the efficacy of job relocation and follow-up markers. Methods: Twelve bakery plant workers diagnosed with baker's asthma were enrolled in the study. Asthma-related symptoms and methacholine provocation test were followed up 6 months after a job relocation. Skin prick test and ELISA to detect wheat flour-specific IgE and eosinophil cationic protein (ECP) in sputum and serum were also followed up to evaluate the status of allergic inflammation. Results: After a 6-month job relocation, all 12 workers showed an improvement in symptoms, and airway hyperresponsiveness to methacholine was negatively converted in 9 of them. There were no significant differences in skin reactivity and serum flour-specific IgE levels before and after the relocation. While sputum ECP levels did not show a significant difference (338.3 ± 93.0 μg/l vs. 175.0 ± 78.9 μg/l, p = 0.118), there was a remarkable difference in serum ECP levels before and after the relocation (12.2 ± 3.0 μg/l vs. 2.8 ± 3.1 μg/l, p = 0.004). Conclusions: Job relocation was effective in managing baker's asthma. Serum ECP level was a useful follow-up marker of baker's asthma.
Physiological Difference in Autophagic Flux in Macrophages From 2 Mouse Strains Regulates Cholesterol Ester Metabolism
Authors: Robinet Peggy , Ritchey Brian , Smith Jonathan D.
Published: March 2013

Objective—

DBA/2 apoE
−/−
mice have ≈10-fold larger lesions than AKR apoE
−/−
mice. The objective of this study was to determine whether macrophages from these 2 strains had altered cholesterol metabolism that might play a role in their divergent atherosclerosis susceptibility.

Approach and Results—

AKR and DBA/2 macrophages incubated with acetylated low-density lipoprotein resulted in higher cholesterol ester (CE) and lower free cholesterol accumulation in the DBA/2 cells. However, these strains had equivalent acetylated low-density lipoprotein uptake and cholesterol esterification activity. Cholesterol efflux from unloaded cells to apolipoprotein A-I or high-density lipoprotein was similar in the 2 strains. However, on acetylated low-density lipoprotein loading, cholesterol efflux was impaired in the DBA/2 cells, but this impairment was corrected by loading in the presence of an inhibitor of cholesterol esterification. Thus, the cholesterol efflux capabilities are similar in these strains, but there seemed to be a defect in lipid droplet–stored CE mobilization in DBA/2 cells. Lalistat 1, a specific inhibitor of lysosomal acid lipase, completely blocked the hydrolysis of lipid droplet–stored CE, implying that lipid droplet autophagy is responsible for CE turnover in these cells. CE turnover was 2-fold slower in DBA/2 versus AKR cells. Autophagic flux, estimated by a fluorescent light chain 3-II reporter and the increase in p62 levels after chloroquine treatment, was higher in AKR versus DBA/2 macrophages, which had an apparent decrease in autophagosome fusion with lysosomes. When autophagy was activated by amino acid starvation, CE levels decreased in DBA/2 cells.

Conclusions—

Physiological regulation of autophagy in macrophages controls CE accumulation and may modify atherosclerosis susceptibility.