bluuebunny/crossref_metadata_2025 huggingface dataset:
Symbolic WCET Computation
Authors: Ballabriga Clément , Forget Julien , Lipari Giuseppe
Published: December 2017

Parametric Worst-case execution time (WCET) analysis of a sequential program produces a formula that represents the worst-case execution time of the program, where parameters of the formula are user-defined parameters of the program (as loop bounds, values of inputs, or internal variables, etc).

In this article we propose a novel methodology to compute the parametric WCET of a program. Unlike other algorithms in the literature, our method is not based on Integer Linear Programming (ILP). Instead, we follow an approach based on the notion of symbolic computation of WCET formulae. After explaining our methodology and proving its correctness, we present a set of experiments to compare our method against the state of the art. We show that our approach dominates other parametric analyses and produces results that are very close to those produced by non-parametric ILP-based approaches, while keeping very good computing time.
Information Flow under Budget Constraints
Authors: Naumov Pavel , Tao Jia
Published: December 2017

Although first proposed in the database theory as properties of functional dependencies between attributes, Armstrong’s axioms capture general principles of information flow by describing properties of dependencies between sets of pieces of information. This article generalizes Armstrong’s axioms to a setting in which there is a cost associated with information. The proposed logical system captures general principles of dependencies between pieces of information constrained by a given budget.
Practical guide to using the YFCC100M and MMCOMMONS on a budget
Authors: Choi Jaeyoung , Thomee Bart , Larson Martha
Published: December 2017

The Yahoo-Flickr Creative Commons 100 Million (YFCC100M), the largest freely usable multimedia dataset to have been released so far, is widely used by students, researchers and engineers on topics in multimedia that range from computer vision to machine learning. However, its sheer volume, one of the traits that make the dataset unique and valuable, can pose a barrier to those who do not have access to powerful computing resources. In this article, we introduce useful information and tools to boost the usability and accessibility of the YFCC100M, including the supplemental material provided by the Multimedia Commons (MMCOMMONS) community. In particular, we provide a practical guide on how to set up a feasible and cost effective research and development environment locally or in the cloud that can access the data without having to download it first.
An interview with Prof. Ramesh Jain
Authors: Jain Ramesh , Riegler Michael
Published: December 2017

Ramesh Jain is an entrepreneur, researcher, and educator. He is a Donald Bren Professor in Information & Computer Sciences at University of California, Irvine. Earlier he has been at Georgia Tech, University of California, San Diego, University of Michigan, and some other universities in many countries. He was educated at Nagpur University (B.E.) and Indian Institute of Technology, Kharagpur (Ph.D.) in India. His current research is in Social Life Networks including EventShop and Objective Self, and Health Intelligence. He has been an active member of professional community serving in various positions and contributing more than 400 research papers and coauthoring several books including text books in Machine Vision and Multimedia Computing. He is a Fellow of AAAI, AAAS, ACM, IEEE, IAPR, and SPIE.

Ramesh co-founded several companies, managed them in initial stages, and then turned them over to professional management. He also advised major companies in multimedia and search technology. He still enjoys the thrill of start-up environment.

His research and entrepreneurial interests have been in computer vision, AI, multimedia, and social computing. He is the founding director of Institute for Future Health at UCI.
Comparative Researches of Semen Arecae and Charred Semen Arecae on Gastrointestinal Motility, Motilin, Substance P, and CCK in Chronically Stressed Rats
Authors: Zhang Sanyin , Yang Peng , Li Xixiong , Wang Xin , Song Jiage , Peng Wei , Wu Chunjie
Published: December 2017

Aims. To compare the effects of Semen Arecae (SA) and Charred Semen Arecae (CSA) on gastrointestinal motility, motilin, substance P (SP), and cholecystokinin (CCK) in chronically stressed rats. Methods. Rats were randomly divided into control group and stress group. Rats in stress group were randomly exposed to a variety of unpredictable stimulations for 21 days. Then, the rats were treated orally with distilled water, SA, CSA, and mosapride for 7 days. Gastric residue rate and intestinal propulsion rate were evaluated. Serum levels of motilin and SP were measured by enzyme‐linked immunosorbent assay (ELISA). CCK mRNA was quantified by using quantitative real‐time PCR (qRT‐PCR). Results. Both SA and CSA improved the intestinal propulsion and reduced the gastric residue in chronically stressed rats. Furthermore, the serum levels of motilin and SP were significantly higher and the CCK mRNA expressions in intestine and hypothalamus were downregulated in SA and CSA groups. Furthermore, it was found that CSA is more effective. Conclusion. Both SA and CSA enhanced gastrointestinal motility and increased serum levels of motilin and SP in chronically stressed rats via downregulating CCK mRNA expressions in intestine and hypothalamus. Importantly, CSA possessed more effective promoting effects.
Numerical Simulation of One-Dimensional Fractional Nonsteady Heat Transfer Model Based on the Second Kind Chebyshev Wavelet
Authors: Zhao Fuqiang , Xie Jiaquan , Huang Qingxue
Published: December 2017

In the current study, a numerical technique for solving one-dimensional fractional nonsteady heat transfer model is presented. We construct the second kind Chebyshev wavelet and then derive the operational matrix of fractional-order integration. The operational matrix of fractional-order integration is utilized to reduce the original problem to a system of linear algebraic equations, and then the numerical solutions obtained by our method are compared with those obtained by CAS wavelet method. Lastly, illustrated examples are included to demonstrate the validity and applicability of the technique.
First-Line Helicobacter pylori Eradication in Patients with Chronic Kidney Diseases in Taiwan
Authors: Liang Chih-Ming , Chiu Chien-Hua , Wang Hsing-Ming , Tai Wei-Chen , Yao Chih-Chien , Tsai Cheng-En , Kuo Chung-Mou , Chiu Yi-Chun , Wu Keng-Liang , Lee Chen-Hsiang , Tsai Kai-Lung , Huang Chih-Fang , Chuah Seng-Kee
Published: December 2017

Aims. Patients with chronic kidney disease (CKD) and Helicobacter pylori (H. pylori) infection have a higher incidence of gastroduodenal diseases and therefore are recommended to receive eradication therapies. This study aimed to assess the efficacy of a 7-day standard triple therapy in patients with CKD (eGFR < 60 ml/min/1.73 m2) and to investigate the clinical factors influencing the success of eradication. Methods. A total of 758 patients with H. pylori infection receiving a 7-day standard first-line triple therapy between January 1, 2013, and December 31, 2014, were recruited. Patients were divided into two groups: CKD group (N=130) and non-CKD group (N=628). Results. The eradication rates attained by the CKD and non-CKD groups were 85.4% and 85.7%, respectively, in the per-protocol analysis (p=0.933). The eradication rate in CKD stage 3 was 84.5% (82/97), in stage 4 was 88.2% (15/17), and in those who received hemodialysis was 87.5% (14/16). There were no significant differences in the various stages of CKD (p=0.982). The adverse events were similar between the two groups (3.1% versus 4.6%, p=0.433). Compliance between the two groups was good (100.0% versus 99.8%, p=0.649). There was no significant clinical factor influencing the H. pylori eradication rate in the non-CKD and CKD groups. Conclusions. This study suggests that the H. pylori eradication rate and adverse rate in patients with CKD are comparable to those of non-CKD patients.
PBAT/TPS Composite Films Reinforced with Starch Nanoparticles Produced by Ultrasound
Authors: da Silva Normane Mirele Chaves , Correia Paulo Romano Cruz , Druzian Janice Izabel , Fakhouri Farayde Matta , Fialho Rosana Lopes Lima , de Albuquerque Elaine Christine Magalhães Cabral
Published: December 2017

The objective of the present work was to study the incorporation of starch nanoparticles (SNP) produced by ultrasound in blends of poly(butylene adipate-co-terephthalate) (PBAT) and thermoplastic starch (TPS). The films were produced by extrusion using varying percentages of SNP (1, 2, 3, 4, and 5% w/w). The SNP were prepared in water without the addition of any chemical reagent. The results revealed that ultrasound treatment results in the formation of SNP less than 100 nm in size and of an amorphous character and lower thermal stability and low gelatinization temperature when compared with cassava starch. Scanning electron microscopy (SEM) showed that films presented some starch granules. The relative crystallinity (RC) of films decreases with increasing concentration of SNP. The addition of SNP slightly affected the thermal degradation of the films. The DSC results showed that the addition did not modify the interaction between the different components of the films. Mechanical tests revealed an increase in Young’s modulus (36%) and elongation-at-break (35%) with the incorporation of 1% SNP and this concentration reduced the water vapor permeability (53%) and significantly decreased the water absorption of the films, demonstrating that low concentrations of SNP can be used as reinforcement in a polymeric matrix.
Random Finite Set Based Data Assimilation for Dynamic Data Driven Simulation of Maritime Pirate Activity
Authors: Wang Peng , Li Ge , Ju Rusheng , Peng Yong
Published: December 2017

Maritime piracy is posing a genuine threat to maritime transport. The main purpose of simulation is to predict the behaviors of many actual systems, and it has been successfully applied in many fields. But the application of simulation in the maritime domain is still scarce. The rapid development of network and measurement technologies brings about higher accuracy and better availability of online measurements. This makes the simulation paradigm named as dynamic data driven simulation increasingly popular. It can assimilate the online measurements into the running simulation models and ensure much more accurate prediction of the complex systems under study. In this paper, we study how to utilize the online measurements in the agent based simulation of the maritime pirate activity. A new random finite set based data assimilation algorithm is proposed to overcome the limitations of the conventional vectors based data assimilation algorithms. The random finite set based general data model, measurement model, and simulation model are introduced to support the proposed algorithm. The details of the proposed algorithm are presented in the context of agent based simulation of maritime pirate activity. Two groups of experiments are used to practically prove the effectiveness and superiority of the proposed algorithm.
Structure Optimization of a Vibration Suppression Device for Underwater Moored Platforms Using CFD and Neural Network
Authors: Mao Zhaoyong , Zhao Fuliang
Published: December 2017

We only consider the underwater mooring platform (UMP) and the plate moving in the transverse direction, and the plate can be relative to the UMP free rotation. In the case of constant flow rate (U=1 m/s), the effect of different dimensionless plate length (Lp/D) and damping value (c) on the UMP was studied. We get the sample data point set by computational fluid dynamics (CFD) simulation with changing the dimensionless plate length (Lp/D=0.3, 0.5, 0.75, 1.0, 1.25, 1.5) and damping value (c=50, 75, 100, 125, 175, 250, 300 (N × s/m)). The optimal value of the vibration suppression rate is obtained by backpropagation (BP) neural network and genetic algorithm. The optimal vibration suppression rate is Py=0.9878 and the corresponding variable value is Lp/D=1.0342, c=57.9631 (N × s/m). In order to verify the accuracy of the optimization, we perform the CFD numerical simulation with the optimized parameters and compare the theoretical optimization results with the CFD simulation result. The absolute error between CFD simulation and optimal Py is only 0.0037. Finally, we compare the results of CFD simulation based on optimal parameter with the bare UMP and analyze their dimensionless amplitude, wake structure, and lift coefficient. It is shown that BP neural network and generic algorithm are effective.
Longitudinal Brain Functional Connectivity Changes of the Cortical Motor-Related Network in Subcortical Stroke Patients with Acupuncture Treatment
Authors: Li Yongxin , Wang Ya , Liao Chenxi , Huang Wenhua , Wu Ping
Published: December 2017

In clinical practice, the effectiveness of the rehabilitation therapy such as acupuncture combining conventional Western medicine (AG) on stroke people’s motor-related brain network and their behaviors has not been systematically studied. In the present study, seventeen adult ischemic patients were collected and divided into two groups: the conventional Western medicine treatment group (CG) and the AG. The neurological deficit scores (NDS) and resting-state functional MRI data were collected before and after treatment. Compared with the CG patients, AG patients exhibited a significant enhancement of the percent changes of NDS from pre- to posttreatment intervention. All patients showed significant changes of functional connectivity (FC) between the pair of cortical motor-related regions. After treatment, both patient groups showed a recovery of brain connectivity to the nearly normal level compared with the controls in these pairs. Moreover, a significant correlation between the percent changes of NDS and the pretreatment FC values of bilateral primary motor cortex (M1) in all patients was found. In conclusion, our results showed that AG therapy can be an effective means for ischemic stroke patients to recover their motor function ability. The FC strengths between bilateral M1 of stroke patients can predict stroke patients’ treatment outcome after rehabilitation therapy.
Effect of Uniaxial Tensile Cyclic Loading Regimes on Matrix Organization and Tenogenic Differentiation of Adipose-Derived Stem Cells Encapsulated within 3D Collagen Scaffolds
Authors: Subramanian Gayathri , Stasuk Alexander , Elsaadany Mostafa , Yildirim-Ayan Eda
Published: December 2017

Adipose-derived mesenchymal stem cells have become a popular cell choice for tendon repair strategies due to their relative abundance, ease of isolation, and ability to differentiate into tenocytes. In this study, we investigated the solo effect of different uniaxial tensile strains and loading frequencies on the matrix directionality and tenogenic differentiation of adipose-derived stem cells encapsulated within three-dimensional collagen scaffolds. Samples loaded at 0%, 2%, 4%, and 6% strains and 0.1 Hz and 1 Hz frequencies for 2 hours/day over a 7-day period using a custom-built uniaxial tensile strain bioreactor were characterized in terms of matrix organization, cell viability, and musculoskeletal gene expression profiles. The results displayed that the collagen fibers of the loaded samples exhibited increased matrix directionality with an increase in strain values. Gene expression analyses demonstrated that ASC-encapsulated collagen scaffolds loaded at 2% strain and 0.1 Hz frequency showed significant increases in extracellular matrix genes and tenogenic differentiation markers. Importantly, no cross-differentiation potential to osteogenic, chondrogenic, and myogenic lineages was observed at 2% strain and 0.1 Hz frequency loading condition. Thus, 2% strain and 0.1 Hz frequency were identified as the appropriate mechanical loading regime to induce tenogenic differentiation of adipose-derived stem cells cultured in a three-dimensional environment.
The Method of Solving Structural Reliability with Multiparameter Correlation Problem
Authors: Du Juan , Li Haibin , He Yun
Published: December 2017

Correlation among variables must be considered to accurately reflect the level of structure reliability. This problem has referential value to engineering practice and has attracted attention from relevant scholars and industries. In this paper, Copula function was used to build the joint probability density function among all variables. The key is to describe the correlation among variables, solve the correlation parameter θ of Copula function, and select the type of correlation structure among variables. The correlation parameter θ of Copula function was solved using Pearson linear correlation coefficient and maximum likelihood estimation. Based on the Akaike information criteria (AIC) and Bayesian information criteria (BIC), the optimal Copula function was selected, and the correlation structure among variables was determined. Monte Carlo method, which is based on Nataf inverse transformation, was introduced and used to evaluate the reliability of the correlated variable. Finally, this paper proposed the reliability calculation method based on dual neural network and direct integration by establishing the dual neural network of original and integrand functions. Compared with the Monte Carlo method, the proposed method can be utilized to efficiently and precisely calculate the structure reliability of multiple correlated random variables.
Preoperative Anaemia and Associated Postoperative Outcomes in Noncardiac Surgery Patients in Central Region of Ghana
Authors: Amponsah Gladys , Charwudzi Alice
Published: December 2017

Introduction. Several studies suggest that preoperative anaemia (PA) is associated with adverse postoperative outcomes, but little is known about these outcomes in the Central Region of Ghana. This study aims to determine the prevalence of PA among noncardiac surgical patients and its implications for their postoperative outcomes.Methods. This study was designed as an observational study; data including demographics and clinical and laboratory results were collected from the patients’ records and through interviews.Results. A total of 893 inpatient surgical cases undergoing elective and emergency operations, aged 15 years and above with mean age of 44.2 ± 17.0 yrs, were enrolled. The prevalence of PA was 54.3%, mostly microcytic with or without hypochromia (57.2%). The prevalence was higher in females than males (p≤0.001). Preoperative anaemia was significantly associated with prolonged length of hospital stay (OR: 2.12 (95% CI: 1.49–3.10)). Allogeneic blood transfusion significantly prolonged the length of hospital stay (OR 4.48 (95% CI: 2.67–7.51)). 15.5% of the anaemic patients received oral iron supplements compared to 2.2% of nonanaemic patients (p≤0.001).Conclusion. Preoperative anaemia is common among noncardiac surgical patients. It is independently and significantly associated with prolonged hospital stay leading to the use of increased healthcare resources. It is also the main predictor for perioperative allogeneic blood transfusions and the use of haematinics.
Generation and Control of Basic Geometric Trajectories for a Robot Manipulator Using CompactRIO®
Authors: Aroca Trujillo Jorge Luis , Pérez-Ruiz Alexander , Rodriguez Serrezuela Ruthber
Published: December 2017

The utility of a robot manipulator focuses on the ability to locate its end effector in a position with a determined orientation following a specified trajectory. For this, algorithms were used in order to generate and control the movements joints of robot in a synchronized way. The high-level languages to program robots are based on three types of movement: joint interpolation (MOVEJ), linear interpolation (MOVES), and circular arcs (MOVEC), which are used to develop any type of task. In this work, these three movements are implemented in the industrial controller CompactRIO, as part of the reconditioning process of a robot manipulator of five degrees of freedom (5 DOF) whose controller was obsolete. As a result, it will have an interface in LabVIEW where you can view and modify the basic parameters implemented in the industrial controller. In addition, the results of the validation tests of the joint positions and the end effector of the manipulator will be found.
Linking Cancer Cachexia‐Induced Anabolic Resistance to Skeletal Muscle Oxidative Metabolism
Authors: Hardee Justin P. , Montalvo Ryan N. , Carson James A.
Published: December 2017

Cancer cachexia, a wasting syndrome characterized by skeletal muscle depletion, contributes to increased patient morbidity and mortality. While the intricate balance between protein synthesis and breakdown regulates skeletal muscle mass, the suppression of basal protein synthesis may not account for the severe wasting induced by cancer. Therefore, recent research has shifted to the regulation of “anabolic resistance,” which is the impaired ability of nutrition and exercise to stimulate protein synthesis. Emerging evidence suggests that oxidative metabolism can regulate both basal and induced muscle protein synthesis. While disrupted protein turnover and oxidative metabolism in cachectic muscle have been examined independently, evidence suggests a linkage between these processes for the regulation of cancer‐induced wasting. The primary objective of this review is to highlight the connection between dysfunctional oxidative metabolism and cancer‐induced anabolic resistance in skeletal muscle. First, we review oxidative metabolism regulation of muscle protein synthesis. Second, we describe cancer‐induced alterations in the response to an anabolic stimulus. Finally, we review a role for exercise to inhibit cancer‐induced anabolic suppression and mitochondrial dysfunction.
Synthesis and Study of Chemical, Thermal, Mesomorphic, and Optical Properties of Terphenyls Modified with Nitrile Groups
Authors: Mota González M. L. , Carrillo Castillo A. , Ambrosio Lázaro R. C. , Flores Méndez J. , Moreno Mario , Luque Priscy A. , Navarro Dámaso
Published: December 2017

We report the synthesis, characterization, and the thermotropic and photoluminescence properties of dialkoxyterphenyls with (T12-CN and T12-2CN) and without (T12) nitrile groups. These terphenyls were prepared through the Suzuki-Miyaura cross-coupling reaction using a palladium-based catalyst. The products obtained were analyzed as powders or after being drop-casted or spin-coated on glass. Nuclear Magnetic Resonance (1H NMR) and Fourier Transform Infrared (FTIR) spectroscopy techniques confirmed the structure and purity of the synthesized terphenyls. The mesomorphic behavior was studied by differential scanning calorimetry (DSC), polarizing optical microscopy (POM), and X-ray diffraction (XRD). T12 developed various mesophases, whereas T12-CN and T12-2CN displayed one single mesophase of low order over a wide temperature range. The films topology was studied by AFM and the optical properties were determined by ultraviolet-visible (UV-Vis) spectroscopy and spectrofluorometry. Higher roughness was found for the films prepared with the asymmetric terphenyl (T12-CN). The photoluminescence (PL) spectrum obtained for the asymmetric terphenyl (T12-CN) exhibited the expected characteristics with an emission band centered at 381 nm and an overtone around 760 nm.
Urinary and Serum Metabolomics Analyses Uncover That Total Glucosides of Paeony Protect Liver against Acute Injury Potentially via Reprogramming of Multiple Metabolic Pathways
Authors: Li Haojie , Cao Wenli , Lu Mengxi , Wu Chunxiao , Wang Xinguo , Niu Liying
Published: December 2017

Total glucosides of paeony (TGP) have been confirmed to be hepatoprotective. However, the underlying mechanism is largely unclear. In this study, we investigated the metabolic profiles of urine and serum in rats with carbon tetrachloride‐ (CCl4‐) induced experimental liver injury and TGP administration by using ultra‐performance liquid chromatography‐mass spectrometry (UPLC‐MS). The vehicle or a single dose of TGP was intragastrically administered to Wistar rats once a day for 14 consecutive days. To induce ALI, 50% CCl4 was injected intraperitoneally into these rats 2 hours after the last time administration of saline of TGP at the 14th day. The results indicated that TGP administration could protect rats from CCl4‐induced ALI and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation, as well as hepatocyte apoptosis and inflammation. Furthermore, metabolomics analysis showed that TGP treatment significantly attenuated CCl4‐triggered deregulation of multiple metabolites in both urine and serum, including glycine, alanine, proline, and glutamine. Metabolite set enrichment and pathway analyses demonstrated that amino acid cycling and glutathione metabolism were two main pathways involved in CCl4‐induced experimental liver injury and TGP administration. Taken together, these findings revealed that regulation of metabolites potentially plays a pivotal role in the protective effect of TGP on ALI.
Fabrication and Characterization of In Situ Synthesized SiC/Al Composites by Combustion Synthesis and Hot Press Consolidation Method
Authors: Yang Hongyu , Dong Erting , Zhang Bingqi , Yuan Yanyan , Shu Shili
Published: December 2017

The in situ SiC/Al composites were fabricated in Al-Si-C systems with different Si/C mass ratios and holding time by the method of combustion synthesis and hot press consolidation. The influences of Si/C mass ratio and holding time on the phase constitution, microstructure, and hardness of the composites were investigated. The results indicate that the increase of Si/C mass ratio leads to more uniform size distribution of the SiC particles in the Al matrix. Moreover, by improving the Si/C mass ratio from 4 : 1 to 5 : 1, the maximum size of SiC particle was reduced from 4.1 μm to 2.0 μm. Meanwhile, the percentage of submicroparticles was increased from 22% to 63%, and the average hardness value of the composites was increased by 13%. In addition, when the holding time is set to be fifteen minutes, the Al4C3 phase did not exist in the composites because of its total reactions with Si atoms to form SiC particles, and the average hardness value was 73.8 HB.
Local Anesthetics, Procaine, Lidocaine, and Mepivacaine Show Vasodilatation but No Type 1 Allergy: A Double-Blind, Placebo-Controlled Study
Authors: Weinschenk Stefan , Mergenthaler Caroline , Armstrong Christina , Göllner Richard , Hollmann Markus W. , Strowitzki Thomas
Published: December 2017

Background. Therapy with local anesthetics (LAs), also known as neural therapy, is used in integrative medicine because of its anti-inflammatory properties. Ester-linked LAs are often avoided because of their alleged high allergenicity. Little data supports this assumption and hence the importance of our investigation on type-1 allergies against ester- and amide-linked LAs. We performed a prospective, double-blinded, placebo-controlled observational study. Methods. 177 patients received 340 intracutaneous injections with 1% procaine, 0.5% lidocaine, 1% mepivacaine, or saline solution. Every patient received two different tests on each forearm. Reactions were monitored for 15 minutes. Results. No type-1 allergy was observed. The mean erythema diameter of the wheals after 10 minutes was procaine 8.0±6.4 mm, mepivacaine 7.6±6.3 mm, lidocaine 4.4±4.8 mm, and NaCl 3.7±3.2 mm. The wheal diameter of all substances showed a crescendo-decrescendo phenomenon. The procaine and mepivacaine wheals were significantly larger than those of lidocaine and NaCl. No general signs of hypersensitivity were observed. Diameter and intensity were independent of the injection site, order of injection, age, gender, and body mass index. Conclusion. This study shows no higher type-1 allergenicity of the ester-linked LA procaine, compared to the amide-linked LAs lidocaine and mepivacaine, and supports its use in therapy and short-track surgery.
Empresas y Derechos Humanos
Authors: Ljubetic Yerko
Published: December 2017

La actividad económica, tanto pública como privada suele tener un impacto directo sobre las personas y comunidades  que se desenvuelven tanto en su entorno como en su interior. Las consecuencias sobre el medio ambiente, la salud, la afectación de los derechos de las comunidades, especialmente indígenas, la vulneración de los derechos fundamentales de sus trabajadores, particularmente a través de la adopción de medidas discriminatorias de distinta naturaleza, son los ejemplos más reiterativos de una realidad cada vez más acuciante. Este articulo plantea desafío de las empresas de revisar sus formas de organización a los efectos de dar debida cuenta de estas responsabilidades.
miR-204-5p and miR-211-5p Contribute to BRAF Inhibitor Resistance in Melanoma
Authors: Díaz-Martínez Marta , Benito-Jardón Lucía , Alonso Lola , Koetz-Ploch Lisa , Hernando Eva , Teixidó Joaquin
Published: December 2017

Melanoma treatment with the BRAF V600E inhibitor vemurafenib provides therapeutic benefits but the common emergence of drug resistance remains a challenge. We generated A375 melanoma cells resistant to vemurafenib with the goal of investigating changes in miRNA expression patterns that might contribute to resistance. Increased expression of miR-204-5p and miR-211-5p occurring in vemurafenib-resistant cells was determined to impact vemurafenib response. Their expression was rapidly affected by vemurafenib treatment through RNA stabilization. Similar effects were elicited by MEK and ERK inhibitors but not AKT or Rac inhibitors. Ectopic expression of both miRNA in drug-naïve human melanoma cells was sufficient to confer vemurafenib resistance and more robust tumor growth in vivo. Conversely, silencing their expression in resistant cells inhibited cell growth. Joint overexpression of miR-204-5p and miR-211-5p durably stimulated Ras and MAPK upregulation after vemurafenib exposure. Overall, our findings show how upregulation of miR-204-5p and miR-211-5p following vemurafenib treatment enables the emergence of resistance, with potential implications for mechanism-based strategies to improve vemurafenib responses.

Significance: Identification of miRNAs that enable resistance to BRAF inhibitors in melanoma suggests a mechanism-based strategy to limit resistance and improve clinical outcomes. Cancer Res; 78(4); 1017–30. ©2017 AACR.
Genomic and Epigenomic Signatures in Ovarian Cancer Associated with Resensitization to Platinum Drugs
Authors: Fang Fang , Cardenas Horacio , Huang Hao , Jiang Guanglong , Perkins Susan M. , Zhang Chi , Keer Harold N. , Liu Yunlong , Nephew Kenneth P. , Matei Daniela
Published: December 2017

DNA methylation aberrations have been implicated in acquired resistance to platinum drugs in ovarian cancer. In this study, we elucidated an epigenetic signature associated with platinum drug resensitization that may offer utility in predicting the outcomes of patients who are coadministered a DNA methyltransferase inhibitor. The ovarian cancer specimens we analyzed were derived from a recent clinical trial that compared the responses of patients with recurrent platinum-resistant ovarian cancer who received carboplatin plus the DNA methyltransferase inhibitor guadecitabine or a standard-of-care chemotherapy regimen selected by the treating physician. Tumor biopsies or malignant ascites were collected from patients before treatment (day 1, cycle 1) or after treatment (after 2 cycles) for epigenomic and transcriptomic profiling using the Infinium HumanMethylation450 BeadChip (HM450). We defined 94 gene promoters that were hypomethylated significantly by guadecitabine, with 1,659 genes differentially expressed in pretreatment versus posttreatment tumors. Pathway analysis revealed that the experimental regimen significantly altered immune reactivation and DNA repair pathways. Progression-free survival correlated with baseline expression levels of 1,155 genes involved in 25 networks. In functional investigations in ovarian cancer cells, engineered upregulation of certain signature genes silenced by promoter methylation (DOK2, miR-193a, and others) restored platinum drug sensitivity. Overall, our findings illuminate how inhibiting DNA methylation can sensitize ovarian cancer cells to platinum drugs, in large part by altering gene expression patterns related to DNA repair and immune activation, with implications for improving the personalized care and survival outcomes of ovarian cancer patients.

Significance: Epigenomic targeting may improve therapeutic outcomes in platinum-resistant and recurrent ovarian cancer in part by effects on DNA repair and antitumor immune responses. Cancer Res; 78(3); 631–44. ©2017 AACR.
Race Disparities in the Contribution of miRNA Isoforms and tRNA-Derived Fragments to Triple-Negative Breast Cancer
Authors: Telonis Aristeidis G. , Rigoutsos Isidore
Published: December 2017

Triple-negative breast cancer (TNBC) is a breast cancer subtype characterized by marked differences between White and Black/African-American women. We performed a systems-level analysis on datasets from The Cancer Genome Atlas to elucidate how the expression patterns of mRNAs are shaped by regulatory noncoding RNAs (ncRNA). Specifically, we studied isomiRs, that is, isoforms of miRNAs, and tRNA-derived fragments (tRF). In normal breast tissue, we observed a marked cohesiveness in both the ncRNA and mRNA layers and the associations between them. This cohesiveness was widely disrupted in TNBC. Many mRNAs become either differentially expressed or differentially wired between normal breast and TNBC in tandem with isomiR or tRF dysregulation. The affected pathways included energy metabolism, cell signaling, and immune responses. Within TNBC, the wiring of the affected pathways with isomiRs and tRFs differed in each race. Multiple isomiRs and tRFs arising from specific miRNA loci (e.g., miR-200c, miR-21, the miR-17/92 cluster, the miR-183/96/182 cluster) and from specific tRNA loci (e.g., the nuclear tRNAGly and tRNALeu, the mitochondrial tRNAVal and tRNAPro) were strongly associated with the observed race disparities in TNBC. We highlight the race-specific aspects of transcriptome wiring by discussing in detail the metastasis-related MAPK and the Wnt/β-catenin signaling pathways, two of the many key pathways that were found differentially wired. In conclusion, by employing a data- and knowledge-driven approach, we comprehensively analyzed the normal and cancer transcriptomes to uncover novel key contributors to the race-based disparities of TNBC.

Significance: This big data-driven study comparing normal and cancer transcriptomes uncovers RNA expression differences between Caucasian and African-American patients with triple-negative breast cancer that might help explain disparities in incidence and aggressive character. Cancer Res; 78(5); 1140–54. ©2017 AACR.
Progesterone Receptor Isoforms, Nuclear Corepressor-1 and Steroid Receptor Coactivator-1 and B-Cell Lymphoma 2 and Akt and Akt Phosphorylation Status in Uterine Myomas after Ulipristal Acetate Treatment: A Systematic Immunohistochemical Evaluation
Authors: Courtoy Guillaume E. , Donnez Jacques , Marbaix Etienne , Barreira Matilde , Luyckx Mathieu , Dolmans Marie-Madeleine
Published: December 2017

Objective: To investigate whether ulipristal acetate (UPA) treatment modifies the expression of progesterone receptor (PR), its nuclear cofactors steroid receptor coactivator-1 (SRC1) and nuclear corepressor-1 (NCoR1), prosurvival factor B-cell lymphoma 2 (Bcl-2), and Akt in uterine myomas. Patients: Prospective study of 59 women with symptomatic myomas undergoing myomectomy. Forty-two patients were treated preoperatively with UPA; the remaining 17 were not and they served as controls. Method: Tissue microarrays were obtained from surgical specimens and immunohistochemistry was performed. Blinded quantification of expression of PR (PR-A vs. PR-B), coactivator SRC1 and corepressor NCoR1, and prosurvival factor Bcl-2, and Akt and evaluation of Akt phosphorylation levels. Results: Compared with the control group, UPA does not alter PR protein levels or expression patterns in myomas, and the PR-A/PR-B ratio was similar, as well as cytoplasmic or nuclear expression of cofactors SRC1 and NCoR1. Bcl-2 was heterogeneously expressed throughout the samples and no significant modification in expression was evidenced. No significant difference was found in Akt expression and phosphorylation between treated and untreated myomas. Conclusion: This study did not find any significant change in the expression of the studied factors in myomas after UPA exposure. In conclusion, various theories on myomas cells proposed on the basis of in vitro studies are not supported in vivo.
Stroke Chameleons Manifesting as Distinct Radial Neuropathies: Expertise Can Hasten the Diagnosis
Authors: de Lima Fabrício Diniz , Luvizutto Gustavo José , Schelp Arthur Oscar , Braga Gabriel Pereira , Bazan Rodrigo
Published: December 2017

Objective: Stroke chameleons encompass an atypical group of syndromes that do not initially appear to be cerebrovascular accidents. The objective of this study was to report patients with different lesions of central origin clinically presenting as wrist drop and with a semiology similar to that produced by peripheral lesions of the radial nerve at different topographical levels. Methods: This is a case series study of patients presenting with wrist drop during the acute phase of stroke who were assessed by clinical examination and CT and MRI brain scans. Results: Three cases presenting as monoparesis were evaluated. In all patients, the MRI revealed restricted diffusion in the pre- and post-central gyrus. Electromyography showed that the functionality of the radial, median, and ulnar nerves were intact in all three cases. The monoparesis resolved completely within 1 month of rehabilitation therapy, and no evidence of recurrent or new events was reported during the 6-month follow-up after stenting. Conclusion: The central message of this study is that when acute onset symptoms are present in a relatively old patient with vascular risk factors, stroke should be considered as the possible aetiology until proven otherwise, and the appropriate steps should be taken to avoid a delay in the treatment and to improve outcomes.
Spectral-Domain Optical Coherence Tomography Angiography for the Diagnosis and Evaluation of Polypoidal Choroidal Vasculopathy
Authors: de Carlo Talisa E. , Kokame Gregg T. , Shantha Jessica G. , Lai James C. , Wee Raymond
Published: December 2017

Purpose: To compare the diagnostic ability of optical coherence tomography angiography (OCTA) with indocyanine green angiography (ICGA) in polypoidal choroidal vasculopathy (PCV). Methods: Retrospective review of 47 eyes with PCV imaged with ICGA and OCTA. For each eye, it was determined which imaging modality better delineated the PCV complex. The presence of a branching vascular network (BVN) and polyp(s) were noted. Results: PCV was better visualized with ICGA in 21 eyes (44.7%) and with OCTA in 9 eyes (19.2%). The results were comparable in 17 eyes (36.2%). Of the 44 eyes with BVN on ICGA, 41 eyes (93.2%) also showed BVN on OCTA. Of the 28 eyes with polyp(s) on ICGA, 22 eyes (78.6%) also showed polyp(s) on OCTA. Polyps were high-flow lesions or faint low-flow dilations on OCTA. Conclusion: OCTA readily detects BVNs and can detect most polyps, but in many cases ICGA is better able to detect the PCV complex.
A Native Haitian Woman with Unverricht-Lundborg Disease
Authors: Mohamadpour Maliheh , Gabriel Genevieve , Grant Arthur C.
Published: December 2017

Unverricht-Lundborg disease (ULD) is an autosomal recessive progressive myoclonic epilepsy. The prevalence is highest in specific European countries and North Africa. Affected individuals have myoclonic and tonic-clonic seizures and a variable degree of ataxia and cognitive impairment. We report a native Haitian woman with ULD who was wheelchair bound due to nearly continuous myoclonic seizures exacerbated by activity and emotional distress. The seizures and their dramatic increase with volitional activity were recorded during video electroencephalography monitoring. Rational antiepileptic drug therapy controlled the seizures well enough for the patient to achieve a level of independence she had not experienced in over 25 years.
Gamma-Secretase Inhibitors Attenuate Neurotrauma and Neurogenic Acute Lung Injury in Rats by Rescuing the Accumulation of Hypertrophic Microglia
Authors: Lin Hung-Jung , Hsu Chien-Chin , Chio Chung-Ching , Tian Yu-Feng , Lin Mao-Tsun , Lin Ting-Wei , Chang Chih-Hsien , Chang Ching-Ping
Published: December 2017

Background/Aims: In response to traumatic brain injury (TBI), activated microglia exhibit changes in their morphology from the resting ramified phenotype toward the activated hypertrophic or amoeboid phenotype. Here, we provide the first description of the mechanism underlying the neuroprotective effects of γ-secretase inhibitors on TBI outcomes in rats. Methods: The neuroprotective effects of γ-secretase inhibitors such as LY411575 or CHF5074 on TBI-induced neurotoxicity were analysed using a neurological motor function evaluation, cerebral contusion assay, immunohistochemical staining for microglia phenotypes, lung injury score and Evans Blue dye extravasation assay of brain and lung oedema. Results: Hypertrophic or amoeboid microglia accumulated in the injured cortex, the blood-brain-barrier was disrupted and neurological deficits and acute lung injury were observed 4 days after TBI in adult rats. However, a subcutaneous injection of LY411575 (5 mg/kg) or CHF5074 (30 mg/kg) immediately after TBI and once daily for 3 consecutive days post-TBI significantly attenutaed the accumulation of hypertrophic microglia in the injured brain, neurological injury, and neurogenic acute lung injury. Conclusion: Gamma-secretase inhibitors attenuated neurotrauma and neurogenic acute lung injury in rats by reducing the accumulation of hypertrophic microglia in the vicinity of the lesion.
Serum Hepcidin and Iron Indices Affect Anemia Status Differently According to the Kidney Function of Non-Dialysis Chronic Kidney Disease Patients: Korean Cohort Study For Outcome in Patients with Chronic Kidney Disease (KNOW-CKD)
Authors: Lee Sung Woo , Kim Yeong Hoon , Chung Wookyung , Park Sue K. , Chae Dong Wan , Ahn Curie , Kim Yong-Soo , Sung Su Ah
Published: December 2017

Background/Aims: No studies have examined the association among serum hepcidin, iron indices, or anemia status based on the kidney function of non-dialysis chronic kidney disease (CKD) patients. Methods: We reviewed data of 2238 patients from a large-scale multicenter prospective Korean study (2011–2016) and excluded 198 patients with missing data regarding serum hepcidin, hemoglobin, transferrin saturation (TSAT), ferritin, and usage of erythropoiesis-stimulating agents (ESA) or supplemental iron and 363 patients using ESA or supplemental iron. Finally, 1677 patients were included. Results: The mean patient age was 53.5 years, and 65.4% were men. TSAT and serum hepcidin were significantly associated with anemia status, whereas serum ferritin was not, regardless of anemia severity. For patients with an estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m2, a 10% increase of TSAT was associated with hemoglobin <13 g/dL (odds ratio [OR], 0.628; 95% confidence interval [CI], 0.515-0.765; P<0.001) and hemoglobin <11.5 g/dL (OR, 0.672; 95% CI, 0.476-0.950; P=0.024), whereas a 10-ng/mL increase of serum hepcidin was associated with hemoglobin <11.5 g/dL (OR, 1.379; 95% CI, 1.173-1.620; P<0.001) and hemoglobin <10.0 g/dL (OR, 1.360; 95% CI, 1.115-1.659; P=0.002) for patients with eGFR <45 mL/min/1.73 m2 according to multivariate logistic analysis. Conclusions: TSAT was associated with less severe anemia in early CKD patients. Serum hepcidin was associated with more severe anemia in advanced CKD patients.
Opposing Actions of Fibroblast and Cardiomyocyte Smad3 Signaling in the Infarcted Myocardium
Authors: Kong Ping , Shinde Arti V. , Su Ya , Russo Ilaria , Chen Bijun , Saxena Amit , Conway Simon J. , Graff Jonathan M. , Frangogiannis Nikolaos G.
Published: December 2017

Background:

Transforming growth factor–βs regulate a wide range of cellular responses by activating Smad-dependent and Smad-independent cascades. In the infarcted heart, Smad3 signaling is activated in both cardiomyocytes and interstitial cells. We hypothesized that cell-specific actions of Smad3 regulate repair and remodeling in the infarcted myocardium.

Methods:

To dissect cell-specific Smad3 actions in myocardial infarction, we generated mice with Smad3 loss in activated fibroblasts or cardiomyocytes. Cardiac function was assessed after reperfused or nonreperfused infarction using echocardiography. The effects of cell-specific Smad3 loss on the infarcted heart were studied using histological studies, assessment of protein, and gene expression levels. In vitro, we studied Smad-dependent and Smad-independent actions in isolated cardiac fibroblasts.

Results:

Mice with fibroblast-specific Smad3 loss had accentuated adverse remodeling after reperfused infarction and exhibited an increased incidence of late rupture after nonreperfused infarction. The consequences of fibroblast-specific Smad3 loss were not a result of effects on acute infarct size but were associated with unrestrained fibroblast proliferation, impaired scar remodeling, reduced fibroblast-derived collagen synthesis, and perturbed alignment of myofibroblast arrays in the infarct. Polarized light microscopy in Sirius red–stained sections demonstrated that the changes in fibroblast morphology were associated with perturbed organization of the collagenous matrix in the infarcted area. In contrast, α-smooth muscle actin expression by infarct myofibroblasts was not affected by Smad3 loss. Smad3 critically regulated fibroblast function, activating integrin-mediated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase–2 (NOX-2) expression. Smad3 loss in cardiomyocytes attenuated remodeling and dysfunction after infarction. Cardiomyocyte-specific Smad3 loss did not affect acute infarct size but was associated with attenuated cardiomyocyte apoptosis in the remodeling myocardium, accompanied by decreased myocardial NOX-2 levels, reduced nitrosative stress, and lower matrix metalloproteinase–2 expression.

Conclusions:

In healing myocardial infarction, myofibroblast- and cardiomyocyte-specific activation of Smad3 has contrasting functional outcomes that may involve activation of an integrin/reactive oxygen axis.