bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of Rutin on Nitric Oxide Synthesis in Human Umbilical Vein Endothelial Cells
Authors: Ugusman Azizah , Zakaria Zaiton , Chua Kien Hui , Megat Mohd Nordin Nor Anita , Abdullah Mahdy Zaleha
Published: June 2014

Nitric oxide (NO), produced by endothelial nitric oxide synthase (eNOS), is a major antiatherogenic factor in the blood vessel. Oxidative stress plays an important role in the pathogenesis of various cardiovascular diseases, including atherosclerosis. Decreased availability of endothelial NO promotes the progression of endothelial dysfunction and atherosclerosis. Rutin is a flavonoid with multiple cardiovascular protective effects. This study aimed to investigate the effects of rutin on eNOS and NO production in cultured human umbilical vein endothelial cells (HUVEC). HUVEC were divided into four groups: control; oxidative stress induction with 180 μM H2O2; treatment with 300 μM rutin; and concomitant induction with rutin and H2O2for 24 hours. HUVEC treated with rutin produced higher amount of NO compared to control (P<0.01). In the oxidative stress-induced HUVEC, rutin successfully induced cells’ NO production (P<0.01). Rutin promoted NO production in HUVEC by inducing eNOS gene expression (P<0.05), eNOS protein synthesis (P<0.01), and eNOS activity (P<0.05). Treatment with rutin also led to increased gene and protein expression of basic fibroblast growth factor (bFGF) in HUVEC. Therefore, upregulation of eNOS expression by rutin may be mediated by bFGF. The results showed that rutin may improve endothelial function by augmenting NO production in human endothelial cells.
Antihyperglycemic and Anti‐Inflammatory Effects of Standardized Curcuma xanthorrhiza Roxb. Extract and Its Active Compound Xanthorrhizol in High‐Fat Diet‐Induced Obese Mice
Authors: Kim Mi-Bo , Kim Changhee , Song Youngwoo , Hwang Jae-Kwan
Published: June 2014

Xanthorrhizol, a natural compound isolated from Curcuma xanthorrhiza Roxb. (Java turmeric), has been reported to possess antioxidant and anticancer properties; however, its effects on metabolic disorders remain unknown. The aim of the present study was to evaluate the effects of xanthorrhizol (XAN) and C. xanthorrhiza extract (CXE) with standardized XAN on hyperglycemia and inflammatory markers in high‐fat diet‐ (HFD‐) induced obese mice. Treatment with XAN (10 or 25 mg/kg/day) or CXE (50 or 100 mg/kg/day) significantly decreased fasting and postprandial blood glucose levels in HFD‐induced obese mice. XAN and CXE treatments also lowered insulin, glucose, free fatty acid (FFA), and triglyceride (TG) levels in serum. Epididymal fat pad and adipocyte size were decreased by high doses of XAN (26.6% and 20.1%) and CXE (25.8% and 22.5%), respectively. XAN and CXE treatment also suppressed the development of fatty liver by decreasing liver fat accumulation. Moreover, XAN and CXE significantly inhibited production of inflammatory cytokines, such as tumor necrosis factor‐alpha (TNF‐α), interleukin‐6 (IL‐6), interleukin‐1β (IL‐1β), and C‐reactive protein (CRP) in adipose tissue (27.8–82.7%), liver (43.9–84.7%), and muscle (65.2–92.5%). Overall, these results suggest that XAN and CXE, with their antihyperglycemic and anti‐inflammatory activities, might be used as potent antidiabetic agents for the treatment of type 2 diabetes.
Cell Senescence in Myxoid/Round Cell Liposarcoma
Authors: Kåbjörn Gustafsson Christina , Ståhlberg Anders , Engtröm Katarina , Danielsson Anna , Turesson Ingela , Åman Pierre
Published: June 2014

Myxoid/round cell liposarcoma (MLS/RCLS) is the second most common liposarcoma type and characterized by the fusion oncogenesFUS-DDIT3orEWSR1-DDIT3. Previous analysis of cell cycle regulatory proteins revealed a prominent expression of G1-cyclins, cyclin dependent kinases, and their inhibitors but very few cells progressing through the G1/S boundary. Here, we extend the investigation to proteins involved in cell senescence in an immunohistochemistry based study of 17 MLS/RCLS cases. Large subpopulations of tumor cells expressed the RBL2 pocket protein and senescence associated heterochromatin 1γand IL8 receptorβ. We conclude that MLS/RCLS tissues contain major populations of senescent tumor cells and this may explain the slow growth rate of this tumor type.
Prediction of Protein-Protein Interaction Strength Using Domain Features with Supervised Regression
Authors: Kamada Mayumi , Sakuma Yusuke , Hayashida Morihiro , Akutsu Tatsuya
Published: June 2014

Proteins in living organisms express various important functions by interacting with other proteins and molecules. Therefore, many efforts have been made to investigate and predict protein-protein interactions (PPIs). Analysis of strengths of PPIs is also important because such strengths are involved in functionality of proteins. In this paper, we propose several feature space mappings from protein pairs using protein domain information to predict strengths of PPIs. Moreover, we perform computational experiments employing two machine learning methods, support vector regression (SVR) and relevance vector machine (RVM), for dataset obtained from biological experiments. The prediction results showed that both SVR and RVM with our proposed features outperformed the best existing method.
Evidence of Inflammatory System Involvement in Parkinson’s Disease
Authors: Chao Yinxia , Wong Siew Cheng , Tan Eng King
Published: June 2014

Parkinson’s disease (PD) is a chronic neurodegenerative disease underpinned by both genetic and environmental etiologic factors. Recent findings suggest that inflammation may be a pathogenic factor in the onset and progression of both familial and sporadic PD. Understanding the precise role of inflammatory factors in PD will likely lead to understanding of how the disease arises.In vivoevidence for inflammation in PD includes dysregulated molecular mediators such as cytokines, complement system and its receptors, resident microglial activation, peripheral immune cells invasion, and altered composition and phenotype of peripheral immune cells. The growing awareness of these factors has prompted novel approaches to modulate the immune system, although it remains whether these approaches can be used in humans. Influences of ageing and differential exposure to environmental agents suggest potential host-pathogen specific pathophysiologic factors. There is a clear need for research to further unravel the pathophysiologic role of immunity in PD, with the potential of developing new therapeutic targets for this debilitating condition.
Urinary N-Acetyl-beta-D-glucosaminidase as an Early Marker for Acute Kidney Injury in Full-Term Newborns with Neonatal Hyperbilirubinemia
Authors: Cheng Bangning , Jin Yulian , Liu Guanghui , Chen Zhiheng , Dai Hongmei , Liu Min
Published: June 2014

Purpose. To investigate renal function estimated by markers in full-term newborns with hyperbilirubinemia.Methods. A total of 332 full-term newborns with hyperbilirubinemia and 60 healthy full-term newborns were enrolled. Total serum bilirubin, serum creatinine (Cr), serum blood urea nitrogen (BUN), serum cystatin C (Cys-C), urinary beta-2-microglobulin (β2MG) index, and urinary N-acetyl-beta-D-glucosaminidase (NAG) index were measured before and after treatment. All newborns were divided into three groups according to total serum bilirubin levels: group 1 (221-256), group 2 (256-342), and group 3 (>342).Results. The control group and group 1 did not differ significantly in regard to serum Cr, serum BUN, serum Cys-C, urinaryβ2MG index, and urinary NAG index. Urinary NAG index in group 2 was significantly higher than that in control group (P<0.001). Between control group and group 3, serum Cys-C, urinaryβ2MG index, and urinary NAG index differed significantly. The significant positive correlation between total serum bilirubin and urinary NAG index was found in newborns when total serum bilirubin level was more than 272 μmol/L.Conclusions. High unconjugated bilirubin could result in acute kidney injury in full-term newborns. Urinary NAG might be the suitable marker for predicting acute kidney injury in full-term newborns with hyperbilirubinemia.
Waste Material Adsorbents for Zinc Removal from Wastewater: A Comprehensive Review
Authors: Zwain Haider M. , Vakili Mohammadtaghi , Dahlan Irvan
Published: June 2014

This review examines a variety of adsorbents and discusses mechanisms, modification methods, recovery and regeneration, and commercial applications. A summary of available researches has been composed by a wide range of potentially low-cost modified adsorbents including activated carbon, natural source adsorbents (clay, bentonite, zeolite, etc.), biosorbents (black gram husk, sugar-beet pectin gels, citrus peels, banana and orange peels, carrot residues, cassava waste, algae, algal, marine green macroalgae, etc.), and byproduct adsorbents (sawdust, lignin, rice husk, rice husk ash, coal fly ash, etc.). From the literature survey, different adsorbents were compared in terms of Zn2+adsorption capacity; also Zn2+adsorption capacity was compared with other metals adsorption. Thus, some of the highest adsorption capacities reported for Zn2+are 168 mg/g powdered waste sludge, 128.8 mg/g dried marine green macroalgae, 73.2 mg/g lignin, 55.82 mg/g cassava waste, and 52.91 mg/g bentonite. Furthermore, modification of adsorbents can improve adsorption capacity. Regeneration cost is important, but if consumption of virgin adsorbent is reduced, then multiple economic, industrial, and environmental benefits can be gained. Finally, the main drawback of the already published Zn2+adsorption researches is that their use is still in the laboratory stage mostly without scale-up, pilot studies, or commercialization.
Instantaneous Power Theory with Fourier and Optimal Predictive Controller Design for Shunt Active Power Filter
Authors: Tiyarachakun Suksan , Areerak Kongpol , Areerak Kongpan
Published: June 2014

This paper presents a novel harmonic identification algorithm of shunt active power filter for balanced and unbalanced three-phase systems based on the instantaneous power theory called instantaneous power theory with Fourier. Moreover, the optimal design of predictive current controller using an artificial intelligence technique called adaptive Tabu search is also proposed in the paper. These enhancements of the identification and current control parts are the aim of the good performance for shunt active power filter. The good results for harmonic mitigation using the proposed ideas in the paper are confirmed by the intensive simulation using SPS in SIMULINK. The simulation results show that the enhanced shunt active power filter can provide the minimum %THD (Total Harmonic Distortion) of source currents and unity power factor after compensation. In addition, the %THD also follows the IEEE Std.519-1992.
Towards Accurate Node-Based Detection of P2P Botnets
Authors: Yin Chunyong
Published: June 2014

Botnets are a serious security threat to the current Internet infrastructure. In this paper, we propose a novel direction for P2P botnet detection called node-based detection. This approach focuses on the network characteristics of individual nodes. Based on our model, we examine node’s flows and extract the useful features over a given time period. We have tested our approach on real-life data sets and achieved detection rates of 99-100% and low false positives rates of 0–2%. Comparison with other similar approaches on the same data sets shows that our approach outperforms the existing approaches.
Many Local Pattern Texture Features: Which Is Better for Image-Based Multilabel Human Protein Subcellular Localization Classification?
Authors: Yang Fan , Xu Ying-Ying , Shen Hong-Bin
Published: June 2014

Human protein subcellular location prediction can provide critical knowledge for understanding a protein’s function. Since significant progress has been made on digital microscopy, automated image-based protein subcellular location classification is urgently needed. In this paper, we aim to investigate more representative image features that can be effectively used for dealing with the multilabel subcellular image samples. We prepared a large multilabel immunohistochemistry (IHC) image benchmark from the Human Protein Atlas database and tested the performance of different local texture features, including completed local binary pattern, local tetra pattern, and the standard local binary pattern feature. According to our experimental results from binary relevance multilabel machine learning models, the completed local binary pattern, and local tetra pattern are more discriminative for describing IHC images when compared to the traditional local binary pattern descriptor. The combination of these two novel local pattern features and the conventional global texture features is also studied. The enhanced performance of final binary relevance classification model trained on the combined feature space demonstrates that different features are complementary to each other and thus capable of improving the accuracy of classification.
Is Bisphosphonate-Related Osteonecrosis of the Jaw an Infection? A Histological and Microbiological Ten-Year Summary
Authors: Hinson A. M. , Smith C. W. , Siegel E. R. , Stack B. C.
Published: June 2014

The role of infection in the etiology of bisphosphonate-related osteonecrosis of the jaw (BRONJ) is poorly understood. Large-scale epidemiological descriptions of the histology and microbiology of BRONJ are not found in the literature. Herein, we present a systematic review of BRONJ histology and microbiology (including demographics, immunocompromised associations, clinical signs and symptoms, disease severity, antibiotic and surgical treatments, and recovery status) validating that infection should still be considered a prime component in the multifactorial disease.
Coexpression within Integrated Mitochondrial Pathways Reveals Different Networks in Normal and Chemically Treated Transcriptomes
Authors: Chen Cong , Hyun Tae Kyung , Han Xiao , Feng Zhihui , Li Yuan , Liu Xiaolong , Liu Jiankang
Published: June 2014

As energy producers, mitochondria play a pivotal role in multiple cellular processes. Although several lines of evidence suggest that differential expression of mitochondrial respiratory complexes (MRCs) has a significant impact on mitochondrial function, the role of integrated MRCs in the whole coexpression network has yet to be revealed. In this study, we construct coexpression networks based on microarray datasets from different tissues and chemical treatments to explore the role of integrated MRCs in the coexpression network and the effects of different chemicals on the mitochondrial network. By grouping MRCs as one seed target, the hypergeometric distribution allowed us to identify genes that are significantly coexpress with whole MRCs. Coexpression among 46 MRC genes (approximately 78% of MRC genes tested) was significant in the normal tissue transcriptome dataset. These MRC genes are coexpressed with genes involved in the categories “muscle system process,” “metabolic process,” and “neurodegenerative disease pathways,” whereas, in the chemically treated tissues, coexpression of these genes mostly disappeared. These results indicate that chemical stimuli alter the normal coexpression network of MRC genes. Taken together, the datasets obtained from the different coexpression networks are informative about mitochondrial biogenesis and should contribute to understanding the side effects of drugs on mitochondrial function.
Complex Fuzzy Set-Valued Complex Fuzzy Measures and Their Properties
Authors: Ma Shengquan , Li Shenggang
Published: June 2014

LetF*(K)be the set of all fuzzy complex numbers. In this paper some classical and measure-theoretical notions are extended to the case of complex fuzzy sets. They are fuzzy complex number-valued distance onF*(K), fuzzy complex number-valued measure onF*(K), and some related notions, such as null-additivity, pseudo-null-additivity, null-subtraction, pseudo-null-subtraction, autocontionuous from above, autocontionuous from below, and autocontinuity of the defined fuzzy complex number-valued measures. Properties of fuzzy complex number-valued measures are studied in detail.
MR Imaging Findings in Alcoholic and Nonalcoholic Acute Wernicke’s Encephalopathy: A Review
Authors: Manzo Gaetana , De Gennaro Angela , Cozzolino Attilio , Serino Antonietta , Fenza Giacomo , Manto Andrea
Published: June 2014

Wernicke’s encephalopathy (WE) is a severe neurological syndrome caused by thiamine (vitamin B1) deficiency and clinically characterized by the sudden onset of mental status changes, ocular abnormalities, and ataxia. Apart from chronic alcoholism, the most common cause of WE, a lot of other conditions causing malnutrition and decreasing thiamine absorption such as gastrointestinal surgical procedures and hyperemesis gravidarum must be considered as predisposing factors. Due to its low prevalence and clinical heterogeneity, WE is often misdiagnosed, leading to persistent dysfunctions and, in some cases, to death. Nowadays, MR imaging of the brain, showing T2 and FLAIR hyperintensities in typical (thalami, mammillary bodies, tectal plate, and periaqueductal area) and atypical areas (cerebellum, cranial nerve nuclei, and cerebral cortex), is surely the most important and effective tool in the diagnostic assessment of WE. The aim of this paper is to propose a state of the art of the role of MR imaging in the early diagnosis of this complex disease.
Seropositivity and Coinfection of Hepatitis B and C among Patients Seeking Hospital Care in Islamabad, Pakistan
Authors: Khan Jafar , Shafiq Mehwish , Mushtaq Sameera , Ayaz Sultan , Ullah Riaz , AbdEI-Salam Naser M. , Fouad H. , Wasim Mohammad Abdul
Published: June 2014

The undertaken study was conducted to find out the seroprevalence and coinfection of HBV and HCV infection among patients seeking hospital care. A total of 845 samples were received at tertiary care hospital of Islamabad and were screened for hepatitis B and C. The ELISA was used to detect antigen for HBV and antibodies for HCV in patient serum. Among 845 collected samples, 255 (30.1%) were seropositive for HBV and HCV. Out of 255 seropositive samples, 45 (5.3%) were positive for HBsAg while 199 (23.5%) were positive for anti-HCV. Among 255, 11 (1.3%) were seropositive for both HBsAg and anti-HCV (coinfection). Among the seropositive male, HBV was more prevalent (23.8%) while female patients had a high incidence of HCV (52.2%). Among the age group variable, HBV, HCV, and coinfection were found to be more common in the age groups of 21–30 (29%) and 30–40 (24%) years. The seropositivity for HBsAg was higher in unmarried individuals (31.2%) while anti-HCV was more prevalent in married individuals (84%). The present study provides the preliminary information about high HCV and HBV prevalence. Findings from the current study will be helpful for the better management and control of viral hepatitis among patients seeking hospital care.
Sloped Terrain Segmentation for Autonomous Drive Using Sparse 3D Point Cloud
Authors: Cho Seoungjae , Kim Jonghyun , Ikram Warda , Cho Kyungeun , Jeong Young-Sik , Um Kyhyun , Sim Sungdae
Published: June 2014

A ubiquitous environment for road travel that uses wireless networks requires the minimization of data exchange between vehicles. An algorithm that can segment the ground in real time is necessary to obtain location data between vehicles simultaneously executing autonomous drive. This paper proposes a framework for segmenting the ground in real time using a sparse three-dimensional (3D) point cloud acquired from undulating terrain. A sparse 3D point cloud can be acquired by scanning the geography using light detection and ranging (LiDAR) sensors. For efficient ground segmentation, 3D point clouds are quantized in units of volume pixels (voxels) and overlapping data is eliminated. We reduce nonoverlapping voxels to two dimensions by implementing a lowermost heightmap. The ground area is determined on the basis of the number of voxels in each voxel group. We execute ground segmentation in real time by proposing an approach to minimize the comparison between neighboring voxels. Furthermore, we experimentally verify that ground segmentation can be executed at about 19.31 ms per frame.
The Annual Modulation Signature for Dark Matter: DAMA/LIBRA-Phase1 Results and Perspectives
Authors: Bernabei Rita , Belli Pierluigi , Cappella Fabio , Caracciolo Vincenzo , Castellano Simone , Cerulli Riccardo , Dai Chang Jang , d’Angelo Annelisa , d’Angelo Silio , Di Marco Alessandro , He H. L. , Incicchitti Antonella , Kuang H. H. , Ma X. H. , Montecchia Francesco , Sheng X. D. , Wang Rui Guang , Ye Zi-Piao
Published: June 2014

The results obtained with the total exposure of 1.04 ton × yr collected by DAMA/LIBRA-phase1 deep underground at the Gran Sasso National Laboratory (LNGS) of the I.N.F.N. during 7 annual cycles are summarized. The DAMA/LIBRA-phase1 and the former DAMA/NaI data (cumulative exposure 1.33 ton × yr, corresponding to 14 annual cycles) give evidence at 9.3 σ C.L. for the presence of Dark Matter (DM) particles in the galactic halo, on the basis of the exploited model independent DM annual modulation signature by using highly radiopure NaI(Tl) target. The modulation amplitude of thesingle-hitevents in the (2–6) keV energy interval is0.0112±0.0012 cpd/kg/keV; the measured phase is144±7days and the measured period is0.998±0.002 yr; values are in a good well in agreement with those expected for DM particles. No systematic or side reactions able to mimic the exploited DM signature have been found or suggested by anyone over more than a decade. Some of the perspectives of the presently running DAMA/LIBRA-phase2 are outlined.
Anticancer and Antioxidant Activity of Bread Enriched with Broccoli Sprouts
Authors: Gawlik-Dziki Urszula , Świeca Michał , Dziki Dariusz , Sęczyk Łukasz , Złotek Urszula , Różyło Renata , Kaszuba Kinga , Ryszawy Damian , Czyż Jarosław
Published: June 2014

This study is focused on antioxidant and anticancer capacity of bread enriched with broccoli sprouts (BS) in the light of their potential bioaccessibility and bioavailability. Generally, bread supplementation elevated antioxidant potential of product (both nonenzymatic and enzymatic antioxidant capacities); however, the increase was not correlated with the percent of BS. A replacement up to 2% of BS gives satisfactory overall consumers acceptability and desirable elevation of antioxidant potential. High activity was especially found for extracts obtained after simulated digestion, which allows assuming their protective effect for upper gastrointestinal tract; thus, the anticancer activity against human stomach cancer cells (AGS) was evaluated. A prominent cytostatic response paralleled by the inhibition of AGS motility in the presence of potentially mastication-extractable phytochemicals indicates that phenolic compounds of BS retain their biological activity in bread. Importantly, the efficient phenolics concentration was about 12 μM for buffer extract, 13 μM for extracts after digestionin vitro, and 7 μM for extract after absorptionin vitro. Our data confirm chemopreventive potential of bread enriched with BS and indicate that BS comprise valuable food supplement for stomach cancer chemoprevention.
A Numerical Approach to Solving an Inverse Heat Conduction Problem Using the Levenberg‐Marquardt Algorithm
Authors: Min Tao , Chen Xing , Sun Yao , Huang Qiang
Published: June 2014

This paper is intended to provide a numerical algorithm involving the combined use of the Levenberg‐Marquardt algorithm and the Galerkin finite element method for estimating the diffusion coefficient in an inverse heat conduction problem (IHCP). In the present study, the functional form of the diffusion coefficient is unknown a priori. The unknown diffusion coefficient is approximated by the polynomial form and the present numerical algorithm is employed to find the solution. Numerical experiments are presented to show the efficiency of the proposed method.
Credit Risk Prediction Using Fuzzy Immune Learning
Authors: Kamalloo Ehsan , Saniee Abadeh Mohammad
Published: June 2014

The use of credit has grown considerably in recent years. Banks and financial institutions confront credit risks to conduct their business. Good management of these risks is a key factor to increase profitability. Therefore, every bank needs to predict the credit risks of its customers. Credit risk prediction has been widely studied in the field of data mining as a classification problem. This paper proposes a new classifier using immune principles and fuzzy rules to predict quality factors of individuals in banks. The proposed model is combined with fuzzy pattern classification to extract accurate fuzzy if-then rules. In our proposed model, we have used immune memory to remember good B cells during the cloning process. We have designed two forms of memory: simple memory andk-layer memory. Two real world credit data sets in UCI machine learning repository are selected as experimental data to show the accuracy of the proposed classifier. We compare the performance of our immune-based learning system with results obtained by several well-known classifiers. Results indicate that the proposed immune-based classification system is accurate in detecting credit risks.
Optimal Manufacturing-Remanufacturing Production Policy for a Closed-Loop Supply Chain under Fill Rate and Budget Constraint in Bifuzzy Environments
Authors: Kundu Soumita , Chakrabarti Tripti , Jana Dipak Kumar
Published: June 2014

We study a closed-loop supply chain involving a manufacturing facility and a remanufacturing facility. The manufacturer satisfies stochastic market demand by remanufacturing the used product into “as-new” one and producing new products from raw material in the remanufacturing facility and the manufacturing facility, respectively. The remanufacturing cost depends on the quality of used product. The problem is maximizing the manufacturer’s expected profit by jointly determining the collected quantity of used product and the ordered quantity of raw material. Following that we analyze the model with a fill rate constraint and a budget constraint separately and then with both the constraints. Next, to handle the imprecise nature of some parameters of the model, we develop the model with both constraints in bifuzzy environment. Finally numerical examples are presented to illustrate the models. The sensitivity analysis is also conducted to generate managerial insight.
Real Time Traceability and Monitoring System for Agricultural Products Based on Wireless Sensor Network
Authors: Ko Daesik , Kwak Yunsik , Song Seokil
Published: June 2014

A system to monitor and trace the yields and distribution of agricultural products is an important precision agricultural application. The system can be used to predict the next year's yields or provide the distribution channel of agricultural products from farmers to customers. Existing traceability and monitoring systems, usually, are implemented by using both wireless sensor network (WSN) and radio frequency identification (RFID) techniques. In this paper, we propose a system architecture that only requires WSN techniques and implement it. The implementing system consists of sensor nodes, communication hubs, a communication protocol, and an event detection engine. We define events to trace and monitor agricultural products, and our event detection engine detects those events by using the current location and the status of each sensor node. We describe the overall architecture of the proposed system and implementation details.
On Less Conservative Stability Criteria for Neural Networks with Time‐Varying Delays Utilizing Wirtinger‐Based Integral Inequality
Authors: Kwon O. M. , Park M. J. , Park Ju H. , Lee S. M. , Cha E. J.
Published: June 2014

This paper investigates the problem of stability analysis for neural networks with time‐varying delays. By utilizing the Wirtinger‐based integral inequality and constructing a suitable augmented Lyapunov‐Krasovskii functional, two less conservative delay‐dependent criteria to guarantee the asymptotic stability of the concerned networks are derived in terms of linear matrix inequalities (LMIs). Three numerical examples are included to explain the superiority of the proposed methods by comparing maximum delay bounds with the recent results published in other literature.
A Novel Case of Symptomatic BK Viraemia in a Patient Undergoing Treatment for Hodgkin Lymphoma
Authors: Perram Jacinta , Estell Jane
Published: June 2014

Symptomatic BK viral infection in the immunocompromised host is well described, most commonly seen in renal transplant recipients, bone marrow transplant recipients, and HIV positive patients. The present case describes a novel clinical scenario of symptomatic urological BK virus infection in a patient receiving treatment for Hodgkin lymphoma. This case highlights the importance of casting a wide diagnostic net for adverse events encountered with novel therapeutic agents or regimens.
A Cornea Substitute Derived from Fish Scale: 6-Month Followup on Rabbit Model
Authors: Yuan Fei , Wang Liyan , Lin Chien-Chen , Chou Cheng-Hung , Li Lei
Published: June 2014

A fish scale-derived cornea substitute (Biocornea) is proposed as an alternative for human donor corneal tissue. We adopt a regenerative medicine approach to design a primary alternative to the use of fish scale for restoring sight by corneal replacement. Biocornea with corneal multilayer arrangement collagen was implanted to rabbits by pocket implantation. Our study demonstrated the safety and detailed morphologic and physiologic results from the 6 months of followup of rabbit model. In the peripheral Biocornea, the collagen fibrils were arranged in reticular fashion. Slit lamp examination showed that haze and an ulcer were not observed in all groups at 3 months postoperatively while all corneas with Biocornea were clear at both 3 months and 6 months postoperatively. The interface of Biocornea and stromal tissue were filled successfully and without observable immune cells at postoperative day 180. Moreover, the Biocornea was not dissolved and degenerated but remained transparent and showed no apparent fragmentation. Our study demonstrated that the Biocornea derived from fish scale as a good substitute had high biocompatibility and support function after a long-term evaluation. This revealed that the new approach of using Biocornea may yield an ideal artificial cornea substitute for long-term inlay placement.
Trevor’s Disease: A Literature Review regarding Classification, Treatment, and Prognosis apropos of a Case
Authors: Arealis Georgios , Nikolaou Vassilios S. , Lacon Andrew , Ashwood Neil , Hayward Keith , Karagkevrekis Charalampos
Published: June 2014

Background. Dysplasia epiphysealis hemimelica (DEH) is rare and its main characteristic is osteochondromas of the epiphysis of long bones.Methods. We report a case of DEH of the ankle in an 8-year-old boy that was resected in 2005. Additionally we collect all the reported cases of DEH. The literature is reviewed regarding the treatment, prognosis, long term function, and patterns and areas affected by DEH.Results. In our case no complications were noted and our patient remains asymptomatic. Reviewing the literature we found that 73 authors have reported 144 cases from 1926 to 2013. We propose and describe a new classification that correlates with prognosis. According to our classification DEH is classified as types 1 with single lower limb involvement, 2 with multiple lower limb, 3 with single upper limb, 4 with multiple upper limb, 5 with upper and lower limb, and 6 with spine.Conclusions. All single lesions should be followed up and if indicated a whole body nuclear bone scan can be useful in identifying the existence of multiple affected joints. Type 1 lesions have better prognosis than 2 and have less chances of developing OA even if not resected. Resection, even if partial, can be a successful treatment for DEH.
Immune Recovery Uveitis: Pathogenesis, Clinical Symptoms, and Treatment
Authors: Urban Beata , Bakunowicz-Łazarczyk Alina , Michalczuk Marta
Published: June 2014

IRU is the most common form of immune reconstitution inflammatory syndrome in HIV-infected patients with cytomegalovirus retinitis who are receiving highly active antiretroviral therapy (HAART). Among patients with CMV in the HAART era, immune recovery may be associated with a greater number of inflammatory complications, including macular edema and epiretinal membrane formation. Given the range of ocular manifestations of HIV, routine ocular examinations and screening for visual loss are recommended in patients with CD4 counts <50 cells/μL. With the increasing longevity of these patients due to the use of HAART, treatment of IRU may become an issue in the future. The aim of this paper is to review the current literature concerning immune recovery uveitis. The definition, epidemiology, pathophysiology, clinical findings, complications, diagnosis, and treatment are presented.
Molecular Pathways: Targeting ETS Gene Fusions in Cancer
Authors: Feng Felix Y. , Brenner J. Chad , Hussain Maha , Chinnaiyan Arul M.
Published: June 2014

Rearrangements, or gene fusions, involving the ETS family of transcription factors are common driving events in both prostate cancer and Ewing sarcoma. These rearrangements result in pathogenic expression of the ETS genes and trigger activation of transcriptional programs enriched for invasion and other oncogenic features. Although ETS gene fusions represent intriguing therapeutic targets, transcription factors, such as those comprising the ETS family, have been notoriously difficult to target. Recently, preclinical studies have demonstrated an association between ETS gene fusions and components of the DNA damage response pathway, such as PARP1, the catalytic subunit of DNA protein kinase (DNAPK), and histone deactylase 1 (HDAC1), and have suggested that ETS fusions may confer sensitivity to inhibitors of these DNA repair proteins. In this review, we discuss the role of ETS fusions in cancer, the preclinical rationale for targeting ETS fusions with inhibitors of PARP1, DNAPK, and HDAC1, as well as ongoing clinical trials targeting ETS gene fusions. Clin Cancer Res; 20(17); 4442–8. ©2014 AACR.
Biomarkers of Bone Remodeling in Multiple Myeloma Patients to Tailor Bisphosphonate Therapy
Authors: Patel Chirayu G. , Yee Andrew J. , Scullen Tyler A. , Nemani Neeharika , Santo Loredana , Richardson Paul G. , Laubach Jacob P. , Ghobrial Irene M. , Schlossman Robert L. , Munshi Nikhil C. , Anderson Kenneth C. , Raje Noopur S.
Published: June 2014

Background: Patients with multiple myeloma may be susceptible to osteonecrosis of the jaw (ONJ) and stress fractures due to long-term aminobisphosphonate (aBP) therapy. However, it is unknown whether urinary N-telopeptide (NTX) or other bone biomarkers are predictive of skeletal-related events (SRE) or the impact of cessation of aBP therapy on bone remodeling.

Methods: We studied markers of bone turnover over a 6-month period after a single dose of zoledronic acid in 29 patients with multiple myeloma in remission who previously received 8 to 12 doses of pamidronate or zoledronate (NCT00577642). Our primary objective was to determine the duration of time urinary NTX levels remain suppressed after a single dose of zoledronate. A secondary objective was to identify and correlate other markers of bone remodeling with NTX changes. Thirty cytokines, based on their possible role in bone remodeling, were tested using cytokine arrays. Candidates were confirmed by ELISA.

Results: All patients had continued suppression of NTX levels, except 1 patient who had an increase in NTX levels associated with an SRE. GDF-15 and decorin were found to decrease, whereas bone-specific alkaline phosphatase (BSALP) increased. Although not significant in aggregate, osteopontin and osteoprotegerin levels increased in at least half of the patients.

Conclusion: Our data show that NTX levels continue to be suppressed after aBP therapy, and suggest that suppressed NTX levels may be predictive of freedom from SRE in this patient population. Furthermore, osteoblast suppression by aBP may be reversible in myeloma. These data provide the basis for less frequent dosing of aBPs. Clin Cancer Res; 20(15); 3955–61. ©2014 AACR.
Dose Selection, Pharmacokinetics, and Pharmacodynamics of BRAF Inhibitor Dabrafenib (GSK2118436)
Authors: Falchook Gerald S. , Long Georgina V. , Kurzrock Razelle , Kim Kevin B. , Arkenau H.-Tobias , Brown Michael P. , Hamid Omid , Infante Jeffrey R. , Millward Michael , Pavlick Anna , Chin Melvin T. , O'Day Steven J. , Blackman Samuel C. , Curtis C. Martin , Lebowitz Peter , Ma Bo , Ouellet Daniele , Kefford Richard F.
Published: June 2014

Purpose: Dabrafenib is a selective, potent ATP-competitive inhibitor of the BRAFV600-mutant kinase that has demonstrated efficacy in clinical trials. We report the rationale for dose selection in the first-in-human study of dabrafenib, including pharmacokinetics, tissue pharmacodynamics, 2[18F]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) pharmacodynamics, and dose–response relationship.

Experimental Design: Dabrafenib was administered orally once, twice (BID), or three times daily (TID). Selected dose cohorts were expanded to collect adequate data on safety, pharmacokinetics, or pharmacodynamics. A recommended phase II dose (RP2D) was chosen based on safety, pharmacokinetic, pharmacodynamic, and response data.

Results: One hundred and eighty-four patients were enrolled and treated with doses ranging from 12 mg once daily to 300 mg BID in 10 cohorts. Pharmacokinetic assessment of dabrafenib demonstrated a less-than-dose-proportional increase in exposure after repeat dosing above 150 mg BID. Similar to parent drug concentrations, exposure for all metabolites demonstrated less-than-dose-proportional increases. Predicted target inhibition of pERK (>80%) was achieved at 150 mg BID, with a similar magnitude of inhibition at higher doses in BRAFV600 mutation melanoma biopsy samples. Although there was large variability between patients, FDG uptake decreased with higher daily doses in patients with BRAFV600 mutation–positive melanoma. A favorable activity and tolerability profile was demonstrated at 150 mg BID. There was no improvement with TID dosing compared with BID dosing, based on FDG-PET and tumor response analyses in patients with melanoma.

Conclusion: The RP2D of dabrafenib was determined to be 150 mg BID after considering multiple factors, including pharmacokinetics, tissue pharmacodynamics, FDG-PET pharmacodynamics, and the dose–response relationship. A maximum tolerated dose for dabrafenib was not determined. Clin Cancer Res; 20(17); 4449–58. ©2014 AACR.
CALGB 150905 (Alliance): Rituximab Broadens the Antilymphoma Response by Activating Unlicensed NK Cells
Authors: Du Juan , Lopez-Verges Sandra , Pitcher Brandelyn N. , Johnson Jeffrey , Jung Sin-Ho , Zhou Lili , Hsu Katharine , Czuczman Myron S. , Cheson Bruce , Kaplan Lawrence , Lanier Lewis L. , Venstrom Jeffrey M.
Published: June 2014

Natural killer (NK) cells contribute to clinical responses in patients treated with rituximab, but the rules determining NK-cell responsiveness to mAb therapies are poorly defined. A deeper understanding of the mechanisms responsible for antibody-dependent cellular cytotoxicity (ADCC) could yield useful biomarkers for predicting clinical responses in patients. Unlicensed NK cells, defined as NK cells lacking expression of an inhibitory KIR for self-HLA class I ligands, are hyporesponsive in steady state, but are potent effectors in inflammatory conditions. We hypothesized that antitumor antibodies such as rituximab can overcome NK-cell dependence on licensing, making unlicensed NK cells important for clinical responses. Here, we examined the influences of variations in KIR and HLA class I alleles on in vitro responses to rituximab. We tested the clinical significance in a cohort of patients with follicular lymphoma treated with rituximab-containing mAb combinations, and show that rituximab triggers responses from all NK-cell populations regardless of licensing. Neither IL2 nor accessory cells are required for activating unlicensed NK cells, but both can augment rituximab-mediated ADCC. Moreover, in 101 patients with follicular lymphoma treated with rituximab-containing mAb combinations, a “missing ligand” genotype (predictive of unlicensed NK cells) is associated with a higher rate of progression-free survival. Our data suggest that the clinical efficacy of rituximab may be driven, in part, by its ability to broaden the NK-cell repertoire to include previously hyporesponsive, unlicensed NK cells. A “missing ligand” KIR and HLA class I genotype may be predictive of this benefit and useful for personalizing treatment decisions in lymphomas and other tumors. Cancer Immunol Res; 2(9); 878–89. ©2014 AACR.
Lifestyle Factors Related to Mortality and Survival: A Mini-Review
Authors: Rizzuto D. , Fratiglioni L.
Published: June 2014

As the world's population ages, elderly people are becoming an increasingly important group that merits special attention with regard to health and social issues. Lifestyles affect health and survival at all ages, but the consequences of poor lifestyle behaviors may be different for elderly people than for younger adults. They can also be heavily dependent on exposure earlier in life. Our current state of knowledge is based predominantly on studies conducted among middle-aged adults or young elderly people. Moreover, studies are sparse throughout the entire older age spectrum, from 65 to 90 years. This article summarizes the evidence regarding the impact of lifestyle behaviors on mortality among elderly people. It focuses on behaviors modifiable by individual actions and public health interventions, such as smoking, obesity and sedentary behavior, which predispose numerous people to diseases that rank among the leading causes of death, including heart disease, cancer, stroke, diabetes and dementia. These factors not only shorten life but, when they occur together, also have a major impact on survival beyond that associated with each single lifestyle factor. We propose an integrated life course model to guide research on longevity to answer questions that remain open and to find new strategies to ensure a longer and healthier life for future generations.
An Overview of the Natural History of Inflammatory Bowel Diseases
Authors: Domènech Eugeni , Mañosa Míriam , Cabré Eduard
Published: June 2014

Inflammatory bowel disease includes two main conditions: Crohn's disease (CD) and ulcerative colitis (UC). Natural history studies of these two entities have shown relevant differences in several clinical outcomes, mainly a more chronic and persistent (although often subclinical) inflammatory activity and the development of complications related to long-term tissue damage in CD. This led in recent years to different long-term therapeutic strategies in each disease. In this article, we review the main phenotypic features of UC and CD at the time of disease diagnosis and their changes along the course of the disease, as well as their consequences regarding drug therapy and surgical requirements.
Standardized Recording of Parameters Related to the Natural History of Inflammatory Bowel Disease: From Montreal to Paris
Authors: Hyams Jeffrey S.
Published: June 2014

Similar to adults, there is heterogeneous phenotypic expression of inflammatory bowel disease (IBD) in children. Thus, a classification system for disease characteristics is obligatory if one seeks to understand and eventually change the natural history of IBD. Extrapolation of adult clinical trial results to children also depends upon comparable classifications of disease. Features that can differentiate IBD in children from adults include more extensive and severe disease at presentation, frequent corticosteroid dependency, change in location and behavior over time, and the implications of disease for growth and sexual maturation. In contrast to the Montreal classification where all patients <17 years were grouped together, the Paris classification recognizes the different expression of pediatric IBD between those patients aged <10 years and those 10-17 years of age. The recent identification of monogenic disorders in very young children (<2 years) with severe IBD-like disease has further clouded the issue of where appropriate pediatric age guidelines should be drawn, though it is clear these infantile-onset cases should not be grouped with older children. The Paris classification recognizes the importance of upper tract disease on natural history by dividing it into L4a and L4b (proximal and distal to the ligament of Treitz, respectively), while the Montreal system groups all upper-tract patients together. Complicated disease behavior in the Montreal system mandated a single category preventing the concomitant designation as stricturing and penetrating, whereas the Paris classification recognizes that both stricturing and penetrating behavior may occur at the same or different times. Growth delay is recognized only in the Paris classification as a serious manifestation of IBD in children affecting therapeutic decisions. As our understanding of the basic molecular mechanisms of disease pathogenesis in IBD changes over time, it is likely that the IBD classification will change as well. A single classification system that reflects both pediatric and adult disease is needed.
Can We Change the Natural History of Crohn's Disease with Early Immunomodulation?
Authors: Markowitz James
Published: June 2014

In both children and adults, the natural history of Crohn's disease (CD) is characterized by relapsing and remitting bouts of intestinal inflammation, often associated with a progressive shift from inflammatory to complicated stricturing or penetrating disease behavior. The past 2 decades have seen a dramatic shift in therapeutic approach with the increasingly common use of early thiopurine immunomodulation. These maintenance medications were initially introduced primarily as corticosteroid-sparing agents capable of minimizing recurrent flares of inflammatory disease and have proven to be quite efficacious. Increasing evidence suggests, however, that thiopurines may only delay rather than prevent the development of complicated disease behavior. Data from both adult and pediatric CD populations from around the world are reviewed in terms of the effect of early immunomodulation on progression to complicated disease behavior, need for surgery, and prevention of recurrent disease after resection. The effect of thiopurines on the growth of children is also reviewed.