bluuebunny/crossref_metadata_2025 huggingface dataset:
Pulmonary veins in the normal lung and pulmonary hypertension due to left heart disease
Authors: Hunt James M. , Bethea Brian , Liu Xiang , Gandjeva Aneta , Mammen Pradeep P. A. , Stacher Elvira , Gandjeva Marina R. , Parish Elisabeth , Perez Mario , Smith Lynelle , Graham Brian B. , Kuebler Wolfgang M. , Tuder Rubin M.
Published: September 2013

Despite the importance of pulmonary veins in normal lung physiology and the pathobiology of pulmonary hypertension with left heart disease (PH-LHD), pulmonary veins remain largely understudied. Difficult to identify histologically, lung venous endothelium or smooth muscle cells display no unique characteristic functional and structural markers that distinguish them from pulmonary arteries. To address these challenges, we undertook a search for unique molecular markers in pulmonary veins. In addition, we addressed the expression pattern of a candidate molecular marker and analyzed the structural pattern of vascular remodeling of pulmonary veins in a rodent model of PH-LHD and in lung tissue of patients with PH-LHD obtained at time of placement on a left ventricular assist device. We detected urokinase plasminogen activator receptor (uPAR) expression preferentially in normal pulmonary veins of mice, rats, and human lungs. Expression of uPAR remained elevated in pulmonary veins of rats with PH-LHD; however, we also detected induction of uPAR expression in remodeled pulmonary arteries. These findings were validated in lungs of patients with PH-LHD. In selected patients with sequential lung biopsy at the time of removal of the left ventricular assist device, we present early data suggesting improvement in pulmonary hemodynamics and venous remodeling, indicating potential regression of venous remodeling in response to assist device treatment. Our data indicate that remodeling of pulmonary veins is an integral part of PH-LHD and that pulmonary veins share some key features present in remodeled yet not normotensive pulmonary arteries.
Mixed Species Allometric Models for Estimating above-Ground Liana Biomass in Tropical Primary and Secondary Forests, Ghana
Authors: Addo-Fordjour Patrick , Rahmad Zakaria B.
Published: September 2013

The study developed allometric models for estimating liana stem and total above-ground (TAGB) biomass in primary and secondary forests in the Asenanyo Forest Reserve, Ghana. Liana biomass was determined for 50 individuals for each forest using destructive sampling. Various predictors involving liana diameter and length were run against liana biomass in regression analysis, andR2, RMSE, and Furnival's index of fit (FI) were used for model comparison. The equations comprised models fitted to untransformed and log-transformed data. Forest type had a significant influence (P<0.05) on liana allometric models in the current study, resulting in the development of forest-type-specific equations. There were significant and strong linear relationships between liana biomass and the predictors in both forests (R2>0.970). Liana diameter was a better predictor of biomass than liana length. Generally, the models which were based on log-transformed data showed better fit (higher FI values) than those fitted to untransformed data. Comparison of the site specific models in the current study with previously published models indicated that the models of the current study differed from the previous ones. This indicates the need for forest specific equations to be used for accurate determination of above-ground liana biomass.
Synthesis of Polyethers Containing Triazole Units in the Backbone by Click Chemistry in a Tricomponent Reaction
Authors: Mansour Lakouraj Moslem , Hasantabar Vahid , Bagheri Nazanin
Published: September 2013

A series of linear aromatic polyethers containing triazole units were synthesized via the direct click reaction of dibromide and bisethynyl compounds in the presence of sodium azide as one pot reaction. The structures of polymers were approved by using IR and 1H NMR techniques. The solubility experiments showed that polymers have good solubility in polar aprotic solvents such as DMSO, DMF, and NMP at higher temperatures. Thermal stability of the polymers was measured using thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) which indicated that they possessed good thermal stability ( up to 558°C) and high (191.7–260°C) under N2 atmosphere. All the polymers were amorphous according to the DSC and X-ray diffraction. These polymers exhibited strong UV-vis absorption maxima near to 400 nm and up to 500 nm in DMSO solution.
Nephrolithiasis: Molecular Mechanism of Renal Stone Formation and the Critical Role Played by Modulators
Authors: Aggarwal Kanu Priya , Narula Shifa , Kakkar Monica , Tandon Chanderdeep
Published: September 2013

Urinary stone disease is an ailment that has afflicted human kind for many centuries. Nephrolithiasis is a significant clinical problem in everyday practice with a subsequent burden for the health system. Nephrolithiasis remains a chronic disease and our fundamental understanding of the pathogenesis of stones as well as their prevention and cure still remains rudimentary. Regardless of the fact that supersaturation of stone-forming salts in urine is essential, abundance of these salts by itself will not always result in stone formation. The pathogenesis of calcium oxalate stone formation is a multistep process and essentially includes nucleation, crystal growth, crystal aggregation, and crystal retention. Various substances in the body have an effect on one or more of the above stone-forming processes, thereby influencing a person’s ability to promote or prevent stone formation. Promoters facilitate the stone formation while inhibitors prevent it. Besides low urine volume and low urine pH, high calcium, sodium, oxalate and urate are also known to promote calcium oxalate stone formation. Many inorganic (citrate, magnesium) and organic substances (nephrocalcin, urinary prothrombin fragment-1, osteopontin) are known to inhibit stone formation. This review presents a comprehensive account of the mechanism of renal stone formation and the role of inhibitors/promoters in calcium oxalate crystallisation.
On the Existence of Polynomials with Chaotic Behaviour
Authors: Bernardes Nilson C. , Peris Alfredo
Published: September 2013

We establish a general result on the existence of hypercyclic (resp., transitive, weakly mixing, mixing, frequently hypercyclic) polynomials on locally convex spaces. As a consequence we prove that every (real or complex) infinite-dimensional separable Frèchet space admits mixing (hence hypercyclic) polynomials of arbitrary positive degree. Moreover, every complex infinite-dimensional separable Banach space with an unconditional Schauder decomposition and every complex Frèchet space with an unconditional basis support chaotic and frequently hypercyclic polynomials of arbitrary positive degree. We also study distributional chaos for polynomials and show that every infinite-dimensional separable Banach space supports polynomials of arbitrary positive degree that have a dense distributionally scrambled linear manifold.
A Multidimensional and Multimembership Clustering Method for Social Networks and Its Application in Customer Relationship Management
Authors: Zhao Peixin , Zhang Cun-Quan , Wan Di , Zhang Xin
Published: September 2013

Community detection in social networks plays an important role in cluster analysis. Many traditional techniques for one-dimensional problems have been proven inadequate for high-dimensional or mixed type datasets due to the data sparseness and attribute redundancy. In this paper we propose a graph-based clustering method for multidimensional datasets. This novel method has two distinguished features: nonbinary hierarchical tree and the multi-membership clusters. The nonbinary hierarchical tree clearly highlights meaningful clusters, while the multimembership feature may provide more useful service strategies. Experimental results on the customer relationship management confirm the effectiveness of the new method.
Future Prospects in the Diagnosis and Management of Localized Prostate Cancer
Authors: Tefekli Ahmet , Tunc Murat
Published: September 2013

Prostate cancer (PCa) is the commonest visceral cancer in men worldwide. Introduction of serum PSA as a highly specific biomarker for prostatic diseases has led to a dramatic increase in the diagnosis of early stage PCa in last decades. Guidelines underline that benefits as well as risks and squeals of early diagnosis and treatment should be discussed with patients. There are several new biomarkers (Pro‐PSA, PCA‐3 test, and TMPRSS2‐ERG) available on the market but new ones are awaited in order to improve specificity and sensitivity. Investigators have also focused on identifying and isolating the gene, or genes, responsible for PCa. Current definitive treatment options for clinically localized PCa with functional and oncological success rates up to 95% include surgery (radical prostatectomy), external‐beam radiation therapy, and interstitial radiation therapy (brachytherapy). Potential complications of overdiagnosis and overtreatment have resulted in arguments about screening and introduced a new management approach called “active surveillance.” Improvements in diagnostic techniques, especially multiparametric magnetic resonance imaging, significantly ameliorated the accuracy of tumor localization and local staging. These advances will further support focal therapies as emerging treatment alternatives for localized PCa. As a conclusion, revolutionary changes in the diagnosis and management of PCa are awaited in the near future.
A Sensitive Chemotaxis Assay Using a Novel Microfluidic Device
Authors: Zhang Chen , Jang Sunyoung , Amadi Ovid C. , Shimizu Koichi , Lee Richard T. , Mitchell Richard N.
Published: September 2013

Existing chemotaxis assays do not generate stable chemotactic gradients and thus—over time—functionally measure only nonspecific random motion (chemokinesis). In comparison, microfluidic technology has the capacity to generate a tightly controlled microenvironment that can be stably maintained for extended periods of time and is, therefore, amenable to adaptation for assaying chemotaxis. We describe here a novel microfluidic device for sensitive assay of cellular migration and show its application for evaluating the chemotaxis of smooth muscle cells in a chemokine gradient.
Locally Applied Valproate Enhances Survival in Rats after Neocortical Treatment with Tetanus Toxin and Cobalt Chloride
Authors: Altenmüller Dirk-Matthias , Hebel Jonas M. , Rassner Michael P. , Volz Silvanie , Freiman Thomas M. , Feuerstein Thomas J. , Zentner Josef
Published: September 2013

Purpose. In neocortical epilepsies not satisfactorily responsive to systemic antiepileptic drug therapy, local application of antiepileptic agents onto the epileptic focus may enhance treatment efficacy and tolerability. We describe the effects of focally applied valproate (VPA) in a newly emerging rat model of neocortical epilepsy induced by tetanus toxin (TeT) plus cobalt chloride (CoCl2).Methods. In rats, VPA (n=5) or sodium chloride (NaCl) (n=5) containing polycaprolactone (PCL) implants were applied onto the right motor cortex treated before with a triple injection of 75 ng TeT plus 15 mg CoCl2. Video-EEG monitoring was performed with intracortical depth electrodes.Results. All rats randomized to the NaCl group died within one week after surgery. In contrast, the rats treated with local VPA survived significantly longer (P<0.01). In both groups, witnessed deaths occurred in the context of seizures. At least3/4of the rats surviving the first postoperative day developed neocortical epilepsy with recurrent spontaneous seizures.Conclusions. The novel TeT/CoCl2approach targets at a new model of neocortical epilepsy in rats and allows the investigation of local epilepsy therapy strategies. In this vehicle-controlled study, local application of VPA significantly enhanced survival in rats, possibly by focal antiepileptic or antiepileptogenic mechanisms.
High Pressure Elastic Behavior of Synthetic Mg3Y2(SiO4)3Garnet up to 9 GPa
Authors: Fan Dawei , Ma Maining , Wei Shuyi , Chen Zhiqiang , Xie Hongsen
Published: September 2013

The compression behavior of synthetic magnesium- (Mg-) yttrium (Y) garnet Mg3Y2(SiO4)3has been investigated upto about 8.79 GPa at 300 K usingin situangle-dispersive X-ray diffraction and a diamond anvil cell at the beamline X17C, National Synchrotron Light Source, Brookhaven National Laboratory. No phase transition has been observed within the pressure range investigated. The unit-cell parameters and volume decreased systematically with increasing pressure, and a reliable isothermal bulk modulus (KT0) and its pressure derivative (KT0′) were obtained in this study. The values of zero-pressure volumeV0,K0, andK0′refined with a third-order Birch-Murnaghan equation of state areV0=1727.9±0.2 Å3,KT0=145±3 GPa, andK0′=8.5±0.9. IfKT0′is fixed at 4,KT0is obtained as158±2 GPa.
Development and Validation of RP-HPLC Method for Azilsartan Medoxomil Potassium Quantitation in Human Plasma by Solid Phase Extraction Procedure
Authors: Vekariya Paras P. , Joshi Hitendra S.
Published: September 2013

Simple and rapid reverse phase high-performance liquid chromatography (RP-HPLC) method was developed and validated using solid phase extraction (SPE) technique for the determination of Azilsartan Medoxomil Potassium (AMP) in human plasma; detection was carried out by photo diode array detector. Chromatographic separation of the analyte AMP was achieved within 7.5 min by Waters symmetry C18 (4.6 × 250 mm, 5 µm) column, mobile phase was 25 mM ammonium acetate buffer (pH 5.5): acetonitrile 55 : 45 v/v, flow rate was 1.0 mL/min, and the detection was carried out at 254 nm. Calibration curve was linear (r2 > 0.9985) in the range of 1.0–9.0 µg/mL, limit of detection (LOD) and limit of quantitation (LOQ) were 0.150 µg/mL and 0.400 µg/mL, respectively, and intra- and interday deviations were between 1.53–8.41% and 1.78–4.59%, respectively. The overall mean recovery of AMP was 92.35%. No any endogenous constituents were found to interfere at retention time of the analyte. This new RP-HPLC method was successfully validated and may be applied to conduct bioavailability and bioequivalence studies of AMP.
Approximate Multi-Jensen, Multi-Euler-Lagrange Additive and Quadratic Mappings in -Banach Spaces
Authors: Xu Tian Zhou
Published: September 2013

We prove the generalized Hyers-Ulam stability of multi-Jensen, multi-Euler-Lagrange additive, and quadratic mappings in -Banach spaces, using the socalled direct method. The corollaries from our main results correct some outcomes from Park (2011).
Observational Studies on Evaluating the Safety and Adverse Effects of Traditional Chinese Medicine
Authors: Lai Jung-Nein , Tang Jin-Ling , Wang Jung-Der
Published: September 2013

Background. This study aims to share our experiences when carrying out observational studies of traditional Chinese medicine (TCM).Methods. We have proactively monitored the safety profiles ofDuhuo Jisheng Tang (DJT),Suan Zao Ren Tang (SZRT), and TMN-1. A list of adverse events (AEs), complete blood counts, and liver and kidney function tests were obtained from the participants during their scheduled hospital visits. Retrospective observational studies were conducted based on the reimbursement database of the National Health Insurance system, Taiwan, to explore the relationship between the use of TCM that have been adulterated by aristolochic acid and the risk from both nephrotoxins and carcinogens.Results. A total of 221, 287, and 203 AEs were detected afterSZRT,DJT, and TMN-1 had been taken, respectively. Dizziness, headache, stomach ache, and diarrhea were judged to be probably related toSZRTtreatment. Retrospective observational studies found an association between the consumption of aristolochic acid-containing Chinese formulae such asMu Tongand an increased risk of CKD, ESRD, and urinary tract cancer.Conclusion.Prospective and retrospectiveobservational studies seem to have specific advantages when investigating the safety and adverse effects of TCM therapies, as well as possibly other alternative/complementary therapies.
In Vitro Evaluation of Cytotoxicity of Colloidal Amorphous Silica Nanoparticles Designed for Drug Delivery on Human Cell Lines
Authors: Balakrishnan Venugopal , Ab Wab Hajarul Azwana , Abdul Razak Khairunisak , Shamsuddin Shaharum
Published: September 2013

Silica nanoparticles are being developed and tested vigorously in drug delivery systems to treat various diseases. There are many advantages of using silica nanoparticles as a nanodelivery system because they are relatively inexpensive to produce, chemically inert, thermally stable and can be tailored to contain porous structures for drug encapsulation and to be hydrophilic for higher solubility in the human body. Despite these tremendous benefits, one of the pivotal requirements of these drug delivery systems is to be biocompatible with the human body. In this study, the cytotoxicity of colloidal amorphous silica nanoparticles synthesized using the micelle formation method has been tested against normal human foreskin fibroblast cell line (Hs27) as well as selected human bone carcinoma (U‐2 OS), human breast cancer (MCF‐7), and human cervical carcinoma (HeLa) and (Ca Ski) cell lines to determine the IC50 values. Two different sizes of silica nanoparticles, 20 nm and 40 nm, were used to study the relationship between their size and the level of toxicity exerted on the different cells being tested. The cytotoxicity results indicated that 20 nm and 40 nm silica nanoparticles significantly reduce cell viability in a dose‐ and cell‐type‐dependent manner in the normal and cancerous cells tested.
Large Scale Near‐Duplicate Celebrity Web Images Retrieval Using Visual and Textual Features
Authors: Qiao Fengcai , Wang Cheng , Zhang Xin , Wang Hui
Published: September 2013

Near‐duplicate image retrieval is a classical research problem in computer vision toward many applications such as image annotation and content‐based image retrieval. On the web, near‐duplication is more prevalent in queries for celebrities and historical figures which are of particular interest to the end users. Existing methods such as bag‐of‐visual‐words (BoVW) solve this problem mainly by exploiting purely visual features. To overcome this limitation, this paper proposes a novel text‐based data‐driven reranking framework, which utilizes textual features and is combined with state‐of‐art BoVW schemes. Under this framework, the input of the retrieval procedure is still only a query image. To verify the proposed approach, a dataset of 2 million images of 1089 different celebrities together with their accompanying texts is constructed. In addition, we comprehensively analyze the different categories of near duplication observed in our constructed dataset. Experimental results on this dataset show that the proposed framework can achieve higher mean average precision (mAP) with an improvement of 21% on average in comparison with the approaches based only on visual features, while does not notably prolong the retrieval time.
Borel Cayley Graph-Based Topology Control for Consensus Protocol in Wireless Sensor Networks
Authors: Ryu Junghun , Yu Jaewook , Noel Eric , Tang K. Wendy
Published: September 2013

Borel Cayley graphs have been shown to be an efficient candidate topology in interconnection networks due to their small diameter, short path length, and low degree. In this paper, we propose topology control algorithms based on Borel Cayley graphs. In particular, we propose two methods to assign node IDs of Borel Cayley graphs as logical topologies in wireless sensor networks. The first one aims at minimizing communication distance between nodes, while the entire graph is imposed as a logical topology; while the second one aims at maximizing the number of edges of the graph to be used, while the network nodes are constrained with a finite radio transmission range. In the latter case, due to the finite transmission range, the resultant topology is an “incomplete” version of the original BCG. In both cases, we apply our algorithms in consensus protocol and compare its performance with that of the random node ID assignment and other existing topology control algorithms. Our simulation indicates that the proposed ID assignments have better performance when consensus protocols are used as a benchmark application.
RNA Interference TargetingSnailInhibits the Transforming Growth Factorβ2-Induced Epithelial-Mesenchymal Transition in Human Lens Epithelial Cells
Authors: Li Ping , Jing Jiaona , Hu Jianyan , Li Tiejun , Sun Yuncheng , Guan Huaijin
Published: September 2013

Epithelial-msenchymal transition (EMT) contributes to posterior capsule opacification (PCO) type of cataract. Transcription factorsSnailis a key trigger of EMT activated by transforming growth factorβ(TGFβ). This study was done to investigate the effect ofSnailtargeting siRNA on TGFβ2-induced EMT in human lens epithelial cells. TGFβ2 treatment of cultured human epithelial cell line (HLEB3) upregulated the expression ofSnailand the EMT relevant molecules such as vimentin andα-SMA but downregulated the expression of keratin and E-cadherin. After the stimulation of TGFβ2, the HLEB3 cells became fibroblast-like in morphology, and the junctions of cell-cell disappeared. TGFβ2 treatment also enhanced migration ability of HLEB3 cells. TGFβ2-inducedSnailexpression and EMT were significantly inhibited bySnailsiRNA. By analyzing the response characteristics of HLEB3 in TGFβ2-induced EMT model with/withoutSnail-specific siRNA, we concluded thatSnailis an element in the EMT of HLEB3 cells induced by TGFβ2.SnailsiRNA targeting can block the induced EMT and therefore has the potential to suppress the development of PCO.
Modelling and Simulation of a Packed Bed of Pulp Fibers Using Mixed Collocation Method
Authors: Ganaie Ishfaq Ahmad , Arora Shelly , Kukreja V. K.
Published: September 2013

A convenient computational approach for solving mathematical model related to diffusion dispersion during flow through packed bed is presented. The algorithm is based on the mixed collocation method. The method is particularly useful for solving stiff system arising in chemical and process engineering. The convergence of the method is found to be of order 2 using the roots of shifted Chebyshev polynomial. Model is verified using the literature data. This method has provided a convenient check on the accuracy of the results for wide range of parameters, namely, Peclet numbers. Breakthrough curves are plotted to check the effect of Peclet number on average and exit solute concentrations.
Factors Influencing Aggression Levels in Root Vole Populations under the Effect of Food Supply and Predation
Authors: Nie Haiyan , Yao Mingcan , Liu Jike
Published: September 2013

Which factor determines animal aggressivity? Wynn-Edwards proposed the hypothesis that aggressive level increases with population density; Adams and Mesterton-Gibbons proposed the hypothesis that body weight is an indicator of animal aggressivity; however, Smith and Price hypothesized that aggression level varied with external conditions; that is, the population lived in the most unfavorable environment demonstrated the highest average aggression level, and the population that lived under the most favorable external conditions demonstrated the lowest average aggression level. In this paper, we tested these three hypotheses by manipulating enclosed root vole (Microtus oeconomus) populations under different food and predation treatments and observed their aggressive behavior. Aggressive behavior was measured by matching mice in a neutral arena. The experimental results supported Smith and Price’s hypothesis and Adams and Mesterton-Gibbons’s hypothesis; however, they did not support Wynn-Edwards’ hypothesis. Moreover, we found that reproductively active individuals were more aggressive. We concluded that the growth of population density did not cause or otherwise bring about increased aggressive behavior of root voles, but the external factors (predation and food supply) and physical factors (body weight and reproductive condition) were significantly correlated with aggression levels in a root vole population.
Antitumor Efficacy of a Monoclonal Antibody That Inhibits the Activity of Cancer-Associated Carbonic Anhydrase XII
Authors: Gondi Gabor , Mysliwietz Josef , Hulikova Alzbeta , Jen Jian Ping , Swietach Pawel , Kremmer Elisabeth , Zeidler Reinhard
Published: September 2013

Carbonic anhydrase XII (CA XII) is a membrane-tethered cell surface enzyme that is highly expressed on many human tumor cells. Carbonic anhydrase members in this class of exofacial molecules facilitate tumor metabolism by facilitating CO2 venting and intracellular pH regulation. Accordingly, inhibition of exofacial CAs has been proposed as a general therapeutic strategy to target cancer. The recent characterization of 6A10, the first CA XII-specific inhibitory monoclonal antibody, offered an opportunity to evaluate this strategy with regard to CA XII-mediated catalysis. Using functional assays, we showed that 6A10 inhibited exofacial CA activity in CA XII-expressing cancer cells. 6A10 reduced spheroid growth in vitro under culture conditions where CA XII was active (i.e., alkaline pH) and where its catalytic activity was likely rate-limiting (i.e., restricted extracellular HCO3− supply). These in vitro results argued that the antibody exerted its growth-retarding effect by acting on the catalytic process, rather than on antigen binding per se. Notably, when administered in a mouse xenograft model of human cancer, 6A10 exerted a significant delay on tumor outgrowth. These results corroborate the notion that exofacial CA is critical for cancer cell physiology and they establish the immunotherapeutic efficacy of targeting CA XII using an inhibitory antibody. Cancer Res; 73(21); 6494–503. ©2013 AACR.
Targeting Protein Kinase CK2 Suppresses Prosurvival Signaling Pathways and Growth of Glioblastoma
Authors: Zheng Ying , McFarland Braden C. , Drygin Denis , Yu Hao , Bellis Susan L. , Kim Hyunsoo , Bredel Markus , Benveniste Etty N.
Published: September 2013

Purpose: Gliomas are the most frequently occurring primary malignancies in the brain, and glioblastoma is the most aggressive of these tumors. Protein kinase CK2 is composed of two catalytic subunits (α and/or α′) and two β regulatory subunits. CK2 suppresses apoptosis, promotes neoangiogenesis, and enhances activation of the JAK/STAT, NF-κB, PI3K/AKT, Hsp90, Wnt, and Hedgehog pathways. Aberrant activation of the NF-κB, PI3K/AKT, and JAK/STAT-3 pathways is implicated in glioblastoma progression. As CK2 is involved in their activation, the expression and function of CK2 in glioblastoma was evaluated.

Experimental Design and Results: Analysis of 537 glioblastomas from The Cancer Genome Atlas Project demonstrates the CSNK2A1 gene, encoding CK2α, has gene dosage gains in glioblastoma (33.7%), and is significantly associated with the classical glioblastoma subtype. Inhibition of CK2 activity by CX-4945, a selective CK2 inhibitor, or CK2 knockdown by siRNA suppresses activation of the JAK/STAT, NF-κB, and AKT pathways and downstream gene expression in human glioblastoma xenografts. On a functional level, CX-4945 treatment decreases the adhesion and migration of glioblastoma cells, in part through inhibition of integrin β1 and α4 expression. In vivo, CX-4945 inhibits activation of STAT-3, NF-κB p65, and AKT, and promotes survival of mice with intracranial human glioblastoma xenografts.

Conclusions: CK2 inhibitors may be considered for treatment of patients with glioblastoma. Clin Cancer Res; 19(23); 6484–94. ©2013 AACR.
Variation within 3′-UTRs of Base Excision Repair Genes and Response to Therapy in Colorectal Cancer Patients: A Potential Modulation of microRNAs Binding
Authors: Pardini Barbara , Rosa Fabio , Barone Elisa , Di Gaetano Cornelia , Slyskova Jana , Novotny Jan , Levy Miroslav , Garritano Sonia , Vodickova Ludmila , Buchler Tomas , Gemignani Federica , Landi Stefano , Vodicka Pavel , Naccarati Alessio
Published: September 2013

Purpose: Colorectal cancer is routinely treated with a 5-fluorouracil (5-FU)–based chemotherapy. 5-FU incorporates into DNA, and the base excision repair (BER) pathway specifically recognizes such damage. We investigated the association of single-nucleotide polymorphisms (SNP) in the 3′-untranslated regions (UTR) of BER genes, and potentially affecting the microRNA (miRNA) binding, on the risk of colorectal cancer, its progression, and prognosis. SNPs in miRNA-binding sites may modulate the posttranscriptional regulation of gene expression operated by miRNAs and explain interindividual variability in BER capacity and response to 5-FU.

Experimental Design: We tested 12 SNPs in the 3′-UTRs of five BER genes for colorectal cancer susceptibility in a case–control study (1,098 cases and 1,459 healthy controls). Subsequently, we analyzed the role of these SNPs on clinical outcomes of patients (866 in the Training set and 232 in the Replication set).

Results: SNPs in the SMUG1 and NEIL2 genes were associated with overall survival. In particular, SMUG1 rs2233921 TT carriers showed increased survival compared with those with GT/GG genotypes [HR, 0.54; 95% confidence interval (CI), 0.36–0.81; P = 0.003] in the Training set and after pooling results from the Replication set. The association was more significant following stratification for 5-FU–based chemotherapy (P = 5.6 × 10−5). A reduced expression of the reporter gene for the T allele of rs2233921 was observed when compared with the common G allele by in vitro assay. None of the genotyped BER polymorphisms were associated with colorectal cancer risk.

Conclusions: We provide the first evidence that variations in miRNA-binding sites in BER genes 3′-UTR may modulate colorectal cancer prognosis and therapy response. Clin Cancer Res; 19(21); 6044–56. ©2013 AACR.
The mTOR Kinase Inhibitors, CC214-1 and CC214-2, Preferentially Block the Growth of EGFRvIII-Activated Glioblastomas
Authors: Gini Beatrice , Zanca Ciro , Guo Deliang , Matsutani Tomoo , Masui Kenta , Ikegami Shiro , Yang Huijun , Nathanson David , Villa Genaro R. , Shackelford David , Zhu Shaojun , Tanaka Kazuhiro , Babic Ivan , Akhavan David , Lin Kelly , Assuncao Alvaro , Gu Yuchao , Bonetti Bruno , Mortensen Deborah S. , Xu Shuichan , Raymon Heather K. , Cavenee Webster K. , Furnari Frank B. , James C. David , Kroemer Guido , Heath James R. , Hege Kristen , Chopra Rajesh , Cloughesy Timothy F. , Mischel Paul S.
Published: September 2013

Purpose: mTOR pathway hyperactivation occurs in approximately 90% of glioblastomas, but the allosteric mTOR inhibitor rapamycin has failed in the clinic. Here, we examine the efficacy of the newly discovered ATP-competitive mTOR kinase inhibitors CC214-1 and CC214-2 in glioblastoma, identifying molecular determinants of response and mechanisms of resistance, and develop a pharmacologic strategy to overcome it.

Experimental Design: We conducted in vitro and in vivo studies in glioblastoma cell lines and an intracranial model to: determine the potential efficacy of the recently reported mTOR kinase inhibitors CC214-1 (in vitro use) and CC214-2 (in vivo use) at inhibiting rapamycin-resistant signaling and blocking glioblastoma growth and a novel single-cell technology—DNA Encoded Antibody Libraries—was used to identify mechanisms of resistance.

Results: Here, we show that CC214-1 and CC214-2 suppress rapamycin-resistant mTORC1 signaling, block mTORC2 signaling, and significantly inhibit the growth of glioblastomas in vitro and in vivo. EGFRvIII expression and PTEN loss enhance sensitivity to CC214 compounds, consistent with enhanced efficacy in strongly mTOR-activated tumors. Importantly, CC214 compounds potently induce autophagy, preventing tumor cell death. Genetic or pharmacologic inhibition of autophagy greatly sensitizes glioblastoma cells and orthotopic xenografts to CC214-1- and CC214-2–induced cell death.

Conclusions: These results identify CC214-1 and CC214-2 as potentially efficacious mTOR kinase inhibitors in glioblastoma, and suggest a strategy for identifying patients most likely to benefit from mTOR inhibition. In addition, this study also shows a central role for autophagy in preventing mTOR-kinase inhibitor-mediated tumor cell death, and suggests a pharmacologic strategy for overcoming it. Clin Cancer Res; 19(20); 5722–32. ©2013 AACR.
Identification of Preferred Chemotherapeutics for Combining with a CHK1 Inhibitor
Authors: Xiao Yang , Ramiscal Judi , Kowanetz Kaska , Del Nagro Christopher , Malek Shiva , Evangelista Marie , Blackwood Elizabeth , Jackson Peter K. , O'Brien Thomas
Published: September 2013

Here we report that GNE-783, a novel checkpoint kinase-1 (CHK1) inhibitor, enhances the activity of gemcitabine by disabling the S- and G2 cell-cycle checkpoints following DNA damage. Using a focused library of 51 DNA-damaging agents, we undertook a systematic screen using three different cell lines to determine which chemotherapeutics have their activity enhanced when combined with GNE-783. We found that GNE-783 was most effective at enhancing activity of antimetabolite-based DNA-damaging agents; however, there was a surprisingly wide range of activity within each class of agents. We, next, selected six different therapeutic agents and screened these in combination with GNE-783 across a panel of cell lines. This revealed a preference for enhanced chemopotentiation of select agents within tumor types, as, for instance, GNE-783 preferentially enhanced the activity of temozolomide only in melanoma cell lines. Additionally, although p53 mutant status was important for the overall response to combinations with some agents; our data indicate that this alone was insufficient to predict synergy. We finally compared the ability of a structurally related CHK1 inhibitor, GNE-900, to enhance the in vivo activity of gemcitabine, CPT-11, and temozolomide in xenograft models. GNE-900 significantly enhanced activity of only gemcitabine in vivo, suggesting that strong chemopotentiation in vitro can translate into chemopotentiation in vivo. In conclusion, our results show that selection of an appropriate agent to combine with a CHK1 inhibitor needs to be carefully evaluated in the context of the genetic background and tumor type in which it will be used. Mol Cancer Ther; 12(11); 2285–95. ©2013 AACR.
Advances in Understanding the Expression and Function of Dipeptidyl Peptidase 8 and 9
Authors: Zhang Hui , Chen Yiqian , Keane Fiona M. , Gorrell Mark D.
Published: September 2013

DPP8 and DPP9 are recently identified members of the dipeptidyl peptidase IV (DPPIV) enzyme family, which is characterized by the rare ability to cleave a post-proline bond two residues from the N-terminus of a substrate. DPP8 and DPP9 have unique cellular localization patterns, are ubiquitously expressed in tissues and cell lines, and evidence suggests important contributions to various biological processes including: cell behavior, cancer biology, disease pathogenesis, and immune responses. Importantly, functional differences between these two proteins have emerged, such as DPP8 may be more associated with gut inflammation whereas DPP9 is involved in antigen presentation and intracellular signaling. Similarly, the DPP9 connections with H-Ras and SUMO1, and its role in AKT1 pathway downregulation provide essential insights into the molecular mechanisms of DPP9 action. The recent discovery of novel natural substrates of DPP8 and DPP9 highlights the potential role of these proteases in energy metabolism and homeostasis. This review focuses on the recent progress made with these post-proline dipeptidyl peptidases and underscores their emerging importance. Mol Cancer Res; 11(12); 1487–96. ©2013 AACR.
Carotid Atherosclerosis and Incident Atrial Fibrillation
Authors: Willeit Karin , Pechlaner Raimund , Egger Georg , Weger Siegfried , Oberhollenzer Martin , Willeit Johann , Kiechl Stefan
Published: September 2013

Objective—

Atrial fibrillation (AF) and atherosclerotic vascular disease are closely entangled disorders and often coexist. Whether atherosclerosis predisposes to the development of AF has not been fully elucidated.

Approach and Results—

This study was performed within the framework of the Bruneck Study, a population-based survey with near-complete participation (932 of 1000), long-term follow-up (1990–2010), and thorough assessment of AF. The carotid arteries served as a window to systemic atherosclerosis and were scanned every 5 years. Pooled logistic regression and multistate proportional hazards models were used to identify risk predictors of incident AF and effects of AF on mortality. During follow-up, 118 new cases of AF were detected (incidence per 1000 person-years of 8.1; 95% confidence interval, 6.8–9.6). Individuals with atherosclerosis were more likely to develop AF than individuals without (odds ratio, 1.8; 95% confidence interval, 1.1–3.1;
P
=0.021). This finding applied to women and men and to both baseline and incident atherosclerosis during follow-up. Subjects with atherosclerosis and AF were significantly more likely to die than those with either condition alone (
P
=0.0034), and mortality in this group was ≈4-fold compared with individuals free of atherosclerosis and AF (hazard ratio, 4.2; 95% confidence interval, 2.6–6.8;
P
<0.0001).

Conclusions—

We found that subjects with carotid atherosclerosis are at high risk of developing AF.
Evolution of Ventricular Tachycardia and Its Electrophysiological Substrate Early After Myocardial Infarction
Authors: Hsieh Calvin H.C. , Chia Ee-May , Huang Kaimin , Lu Juntang , Barry Michael , Pouliopoulos Jim , Ross David L. , Thomas Stuart P. , Kovoor Pramesh
Published: September 2013

Background—

Sudden arrhythmic death after myocardial infarction (MI) is most frequent in the first month. Early programmed ventricular stimulation (within 1 week) post-MI has been able to identify long-term ventricular tachycardia (VT) occurrence. We aimed to determine the timing of development and stabilization of VT circuits after MI and how the evolution of the underlying substrate differs with VT inducibility.

Methods and Results—

MIs were induced in 36 sheep. The 21 survivors underwent serial electroanatomic mapping and programmed ventricular stimulation. Animals were classified as VT
pos
(inducible VT) or VT
neg
(noninducible VT) at day 8. Forty-three percent of MI survivors were VT
pos
on day 8 (9/21), and all remained inducible on day 100 with 1.5 (1.0–2.0) and 1.0 (1.0–2.0) morphologies per animal on days 8 and 100, respectively. Twelve-lead electrocardiogram matched in 15 of 19 VTs between days 8 and 100. The earliest presystolic ventricular activations during VT circuits were in similar locations at the 2 time points. The 12 VT
neg
animals remained noninducible on day 100. There was no difference in voltage or velocity substrate with time or inducibility. The area with fractionated signals increased with time and VT inducibility. VT
pos
animals had more linear regions of slowed conduction forming conducting channels.

Conclusions—

The inducibility and earliest presystolic endocardial activation sites of VT as well as voltage and velocity substrate on day 8 predicted those on day 100 postinfarct, indicating early formation and stabilization of the arrhythmogenic substrate. VT inducibility was influenced by the distribution of conducting channels and increased complex fractionated signals.
Contrast-Enhanced MRI–Derived Scar Patterns and Associated Ventricular Tachycardias in Nonischemic Cardiomyopathy
Authors: Piers Sebastiaan R.D. , Tao Qian , van Huls van Taxis Carine F.B. , Schalij Martin J. , van der Geest Rob J. , Zeppenfeld Katja
Published: September 2013

Background—

There are limited data on typical arrhythmogenic substrates and associated ventricular tachycardias (VT) in patients with nonischemic cardiomyopathy. The substrate location may have implications for the ablation strategy.

Methods and Results—

Nineteen consecutive patients with nonischemic cardiomyopathy (age 58±14 years, 79% men, left ventricular ejection fraction 41±11%) who underwent contrast-enhanced MRI and VT ablation were included. On the basis of 3-dimensional contrast-enhanced MRI–derived scar reconstructions, 8 patients (42%) had predominant basal anteroseptal scar, 9 patients (47%) had predominant inferolateral scar, and 2 patients (11%) had other scar types. Three distinct VT morphologies (≥1 of 3 inducible in 16/19 patients) were associated with underlying scar type. In 9 patients with anteroseptal scar–related VT (8/9 predominant scar, 1/9 nonpredominant), ablation target sites (defined as sites with ≥11/12 pacemap, concealed entrainment or VT termination during ablation) were located in the aortic root and/or anteroseptal left ventricular endocardium in 8 patients (89%) and in the anterior cardiac vein in 1 patient (11%), with additional target sites at the right ventricular septum in 2 patients (22%) and at the epicardium in 1 patient (11%). In contrast, in 8 patients with predominant inferolateral scar–related VT, target sites were located at the epicardium in 5 patients (63%) and in the endocardial inferolateral left ventricle in 3 patients (37%).

Conclusions—

Two typical scar patterns (anteroseptal and inferolateral) account for 89% of arrhythmogenic substrates in patients with nonischemic cardiomyopathy. Three distinct VT morphologies are highly suggestive of the presence of these scars. Anteroseptal scars were, in general, most effectively approached from the aortic root or anteroseptal left ventricular endocardium, whereas inferolateral scars frequently required an epicardial approach.
Electrocardiographic Screening of 1-Month-Old Infants for Identifying Prolonged QT Intervals
Authors: Yoshinaga Masao , Ushinohama Hiroya , Sato Seiichi , Tauchi Nobuo , Horigome Hitoshi , Takahashi Hideto , Sumitomo Naokata , Kucho Yuu , Shiraishi Hirohiko , Nomura Yuichi , Shimizu Wataru , Nagashima Masami
Published: September 2013

Background—

Neonatal electrocardiographic screening is used to screen infants with prolonged QT intervals, as previously shown in whites. However, this procedure needs to be confirmed in other ethnic groups.

Methods and Results—

In 8 areas in Japan, an ECG was recorded in 4285 infants at 1-month medical checkup. A prospective study showed that a provisional criterion of QTc ≥470 ms was appropriate for infants. To assess the validity of the criterion, all infants with a QTc between 460 and 470 ms were followed up. Five infants had a QTc ≥470 ms. Four infants were diagnosed with prolonged QT intervals from follow-up ECGs. Four infants showed no symptoms and did not have a family history of long-QT syndrome. Two infants showed progressive prolongation of QT intervals, and medication was started. Genetic testing was performed in 3 of 4 infants with prolonged QT intervals, and it revealed a
KCNH2
mutation (3065 delT, L1021fs+34X) in 1 infant. One infant with a QTc ≥470 ms and 2 infants with a QTc between 460 and 470 ms showed a decline in their QTc values during follow-up. The study screened another infant with Wolff–Parkinson–White syndrome who was diagnosed with noncompaction before symptoms appeared.

Conclusions—

Neonatal electrocardiographic screening can identify infants likely to be affected by long-QT syndrome in the Japanese population, as already shown in whites. This screening may also be useful in identifying other important cardiac diseases.
Value of an Exercise Workload ≥10 Metabolic Equivalents for Predicting Inducible Myocardial Ischemia
Authors: Peteiro Jesús , Bouzas-Mosquera Alberto , Broullón Francisco , Martinez Dolores , Yañez Juan , Castro-Beiras Alfonso
Published: September 2013

Background—

We sought to identify extensive ischemia on exercise echocardiography (ExE) relative to workload in patients without known coronary artery disease and to investigate whether ExE is useful in predicting outcomes in those with high exercise capacity (≥10 metabolic equivalents [METs]) plus a maximal test (≥85% of their maximal age-predicted heart rate [MAPHR]).

Methods and Results—

The analysis was performed on 4269 patients who underwent ExE, of whom 3995 achieved ≥85% of their MAPHR. These patients were divided according to the reached workload (<7, 7–9, or ≥10 METs) and compared for ExE results. Outcomes in the group achieving ≥10 METs plus ≥85% of their MAPHR (n=2221) were specifically assessed. Ischemia was defined as new/worsening wall motion abnormalities with exercise. ExE results were different between groups because the METs were lower. Still, among patients achieving ≥10 METs plus ≥85% of their MAPHR, 9.3% had extensive ischemia and 6% multiterritory disease. During follow-up in this subgroup, 108 patients died and 42 had a major cardiac event. Annualized mortality and major cardiac event rates were 0.84% and 0.32% in patients without ischemia versus 2.26% and 0.84% in those with ischemia, respectively (
P
<0.001 and
P
=0.002, respectively). Ischemia was an independent predictor of mortality (hazard ratio, 1.88; 95% confidence interval, 1.23–2.89;
P
=0.004) and major cardiac event (hazard ratio, 2.39; 95% confidence interval, 1.22–4.71;
P
=0.01).

Conclusions—

Patients without known coronary artery disease achieving ≥10 METs plus ≥85% of their MAPHR may still have ischemia. However, the low event rates even in those with ischemia limit the usefulness of imaging for assessing outcomes in this group.
Valvuloarterial Impedance, But Not Aortic Stenosis Severity, Predicts Syncope in Patients With Aortic Stenosis
Authors: Harada Kenji , Saitoh Takeji , Tanaka Jun , Shibayama Kentaro , Berdejo Javier , Shiota Takahiro
Published: September 2013

Background—

The presence of syncope in patients with aortic valve stenosis (AS) predicts a grave prognosis. However, the evaluation of AS severity has been limited to valve-specific factors such as aortic valve area and mean transaortic pressure gradient. Recently, valvuloarterial impedance (Zva) was proposed for the estimation of global left ventricular afterload. Therefore, because predictors of syncope in patients with AS have not been investigated in recent years, we assessed the effect of clinical characteristics and echocardiographic parameters, including Zva, on syncope in patients with AS.

Methods and Results—

We retrospectively studied 451 patients with moderate and severe AS without low left ventricular ejection fraction (<40%). Patients with syncope (n=79; 18%) had higher Zva (5.1±0.9 versus 4.4±0.9 mm Hg/mL per m
2
;
P
<0.001) than those without (n=372; 82%). However, no significant differences existed in the mean transaortic pressure gradient (
P
=0.076) or the aortic valve area (
P
=0.160) between the 2 groups. In the multivariable analysis, only Zva was an independent predictor of syncope in patients with AS (odds ratio, 2.02; 95% confidence interval, 1.54–2.64;
P
<0.001). However, systolic blood pressure, relative wall thickness, the early transmitral flow velocity to peak early diastolic mitral annular velocity ratio, and mean transaortic pressure gradient were not identified as independent predictors. Receiver operating characteristic curve analysis identified Zva ≥4.7 mm Hg/mL per m
2
as the cutoff value associated with syncope in patients with AS.

Conclusions—

Our study suggests that high Zva, but not conventional parameters of AS, identifies AS patients with an increased risk of syncope.