bluuebunny/crossref_metadata_2025 huggingface dataset:
The evolution of the laws of software evolution
Authors: Herraiz Israel , Rodriguez Daniel , Robles Gregorio , Gonzalez-Barahona Jesus M.
Published: January 2014

After more than 40 years of life, software evolution should be considered as a mature field. However, despite such a long history, many research questions still remain open, and controversial studies about the validity of the laws of software evolution are common. During the first part of these 40 years, the laws themselves evolved to adapt to changes in both the research and the software industry environments. This process of adaption to new paradigms, standards, and practices stopped about 15 years ago, when the laws were revised for the last time. However, most controversial studies have been raised during this latter period. Based on a systematic and comprehensive literature review, in this article, we describe how and when the laws, and the software evolution field, evolved. We also address the current state of affairs about the validity of the laws, how they are perceived by the research community, and the developments and challenges that are likely to occur in the coming years.
Future of Cholesteryl Ester Transfer Protein Inhibitors
Authors: Rader Daniel J. , deGoma Emil M.
Published: January 2014

The cholesteryl ester transfer protein (CETP) plays an integral role in the metabolism of plasma lipoproteins. Despite two failures, CETP inhibitors are still in clinical development. We review the genetics of CETP and coronary disease, preclinical data on CETP inhibition and atherosclerosis, and the effects of CETP inhibition on cholesterol efflux and reverse cholesterol transport. We discuss the two failed CETP inhibitors, torcetrapib and dalcetrapib, and attempt to extract lessons learned. Two CETP inhibitors, anacetrapib and evacetrapib, are in phase III development, and we attempt to differentiate them from the failed drugs. Whether pharmacologic CETP inhibition will reduce the risk of cardiovascular disease is one of the most fascinating and important questions in the field of cardiovascular medicine.
Adaptive Clinical Trial Design
Authors: Chow Shein-Chung
Published: January 2014

In recent years, the use of adaptive design methods in clinical trials based on accumulated data at interim has received much attention because of its flexibility and efficiency in pharmaceutical/clinical development. In practice, adaptive design may provide the investigators a second chance to modify or redesign the trial while the study is still ongoing. However, it is a concern that a shift in target patient population may occur after significant adaptations are made. In addition, the overall type I error rate may not be preserved. Moreover, the results may not be reliable and hence are difficult to interpret. As indicated by the US Food and Drug Administration draft guidance on adaptive design clinical trials, the adaptive design has to be a prospectively planned opportunity and should be based on information collected within the study, with or without formal statistical hypothesis testing. This article reviews the relative advantages, limitations, and feasibility of commonly considered adaptive designs in clinical trials. Statistical concerns when implementing adaptive designs are also discussed.
The Fascinating Psychological Microfoundations of Strategy and Competitive Advantage
Authors: Ployhart Robert E. , Hale Donald
Published: January 2014

This article puts forth an agenda for the psychological study of strategy and competitive advantage. It centers this agenda within the microfoundations program, a program originating within strategy that seeks to understand firm heterogeneity and competitive advantage by examining individuals and their interrelationships. The article first reviews key theories and frameworks in strategy by taking a functionalist view, that is, by starting with a focus on organizational criteria (operational performance, organizational performance, competitive advantage). It then discusses the importance of resources and how psychology may contribute to an understanding of these resources. Organizational psychology and organizational behavior research that links to higher-level outcomes or resources is reviewed next. The article concludes with questions that we believe will fascinate scholars of organizational psychology and organizational behavior as well as with implications for practice. We hope this article helps stimulate a paradigmatic shift in organizational psychology and organizational behavior, as their theories and findings are much more strategic than is currently appreciated.
The Contemporary Career: A Work–Home Perspective
Authors: Greenhaus Jeffrey H. , Kossek Ellen Ernst
Published: January 2014

This article proposes a perspective on careers that recognizes the interdependencies between work and home over the life course and is particularly suitable to contemporary careers. We first discuss the meaning of a work–home (WH) perspective and elaborate on the economic, organizational, and workforce changes that have affected contemporary careers. We then illustrate the implications of adopting a WH perspective for four streams of scholarship relevant to contemporary careers (career self-management, career success, global careers, and sustainable careers), suggest directions for future research in each area, and discuss the practical implications of adopting a WH perspective. We conclude that contemporary careers can be better understood by considering how employees’ home lives influence and are influenced by career processes and that the adoption of a WH perspective requires understanding the role of gender norms in prescribing and sanctioning women’s and men’s participation in the work and home domains in a given culture.
Mapping Atomic Motions with Ultrabright Electrons: The Chemists' Gedanken Experiment Enters the Lab Frame
Authors: Miller R.J. Dwayne
Published: January 2014

This review documents the development of high–bunch charge electron pulses with sufficient combined spatiotemporal resolution and intensity to literally light up atomic motions. This development holds promise in coming to a first-principles understanding of diverse problems, ranging from molecular reaction dynamics and structure-function correlations in biology to cooperativity in strongly correlated electron-lattice systems. It is now possible to directly observe the key modes involved in propagating structural changes and the enormous reduction in dimensionality that occurs in barrier crossing regions, which is central to chemistry and makes reaction mechanisms transferrable concepts. This information will help direct theoretical advances that will undoubtedly lead to generalized principles with respect to scaling relations in structural dynamics that will bridge chemistry to biology. In this quest, the limitations and future directions for further development are discussed to give an overview of the present status of the field.
Approaches to Single-Nanoparticle Catalysis
Authors: Sambur Justin B. , Chen Peng
Published: January 2014

Nanoparticles are among the most important industrial catalysts, with applications ranging from chemical manufacturing to energy conversion and storage. Heterogeneity is a general feature among these nanoparticles, with their individual differences in size, shape, and surface sites leading to variable, particle-specific catalytic activity. Assessing the activity of individual nanoparticles, preferably with subparticle resolution, is thus desired and vital to the development of efficient catalysts. It is challenging to measure the activity of single-nanoparticle catalysts, however. Several experimental approaches have been developed to monitor catalysis on single nanoparticles, including electrochemical methods, single-molecule fluorescence microscopy, surface plasmon resonance spectroscopy, X-ray microscopy, and surface-enhanced Raman spectroscopy. This review focuses on these experimental approaches, the associated methods and strategies, and selected applications in studying single-nanoparticle catalysis with chemical selectivity, sensitivity, or subparticle spatial resolution.
Macroinvertebrate Richness Importance in Coastal Tropical Streams of Esmeraldas (Ecuador) and Its Use and Implications in Environmental Management Procedures
Authors: Martínez-Sanz Carlos , Puente-García Sara María , Rebolledo Eduardo Rodolfo , Jiménez-Prado Pedro
Published: January 2014

This study was aimed at determining the performance of some indices and community attributes frequently used to assess river quality and test the role of macroinvertebrate taxa richness as element of bioindication in several coastal tropical streams of western Esmeraldas (Ecuador). In addition, a macroinvertebrate taxon list of this region was provided for the first time. Thirteen sampled points distributed across nine streams were selected for this study and nineteen parameters and attributes of bioindication were tested. The differences between nonimpact and impact places were evaluated mainly using one-way analysis of variance. Jackknife 2 and Clench were used to estimate the regional richness and the quality of the inventory, respectively. Seventy taxa (principally genus and family) of the main groups of macroinvertebrates were collected. Measured richness and family richness were the best metric followed by Biological Monitoring Working Party/Colombia (BMWP/Col), Odonata richness, Shannon-Weiner, and EPT richness (Ephemeroptera + Plecoptera + Trichoptera) indices. Only a slight right trend (Ephemeroptera, Trichoptera, and Chironomidae attributes) or incorrect performances (Average Score Per Taxon (ASPT) and % EPT) were showed by frequently used metrics. Finally, several recommendations were made about taxonomic level used, the ranks of quality of taxa richness, and the effort-results relationship in the field of bioindication.
The Effect of Maternal Stress Activation on the Offspring during Lactation in Light of Vasopressin
Authors: Fodor Anna , Zelena Dóra
Published: January 2014

Although it is obvious that preconceptional effects as well as stressors during pregnancy profoundly influence the progeny, the lactation period seems to be at least as important. Here we summarize how maternal stressors during the lactation period affect the offspring. As vasopressin is one of the crucial components both for stress adaptation and social behavior, special emphasis was given to this neuropeptide. We can conclude that stressing the mother does not have the same acute effect on the hypothalamo-pituitary-adrenocortical axis (as the main target of stress adaptation) of the pups as stressing the pups, but later endocrine and behavioral consequences can be similar. Vasopressin plays a role in acute and later consequences of perinatal stressor applied either to the mother or to the offspring, thereby contributing to transmitting the mothers’ stress to the progeny. This mother-infant interaction does not necessarily mean a direct transmission of molecules, but rather is the result of programming the brain development through changes in maternal behavior. Thus, there is a time lag between maternal stress and stress-related changes in the offspring. The interactions are bidirectional as not only stress in the dam but also stress in the progeny has an effect on nursing.
Synergistic Effects of Orbital Shear Stress onIn VitroGrowth and Osteogenic Differentiation of Human Alveolar Bone-Derived Mesenchymal Stem Cells
Authors: Lim Ki Taek , Hexiu Jin , Kim Jangho , Seonwoo Hoon , Choung Pill-Hoon , Chung Jong Hoon
Published: January 2014

Cellular behavior is dependent on a variety of physical cues required for normal tissue function. In order to mimic native tissue environments, human alveolar bone-derived mesenchymal stem cells (hABMSCs) were exposed to orbital shear stress (OSS) in a low-speed orbital shaker. The synergistic effects of OSS on proliferation and differentiation of hABMSCs were investigated. In particular, we induced the osteoblastic differentiation of hABMSCs cultured in the absence of OM by exposing hABMSCs to OSS (0.86–1.51 dyne/cm2). Activation of Cx43 was associated with exposure of hABMSCs to OSS. The viability of cells stimulated for 10, 30, 60, 120, and 180 min/day increased by approximately 10% compared with that of control. The OSS groups with stimulation of 10, 30, and 60 min/day had more intense mineralized nodules compared with the control group. In quantification of vascular endothelial growth factor (VEGF) and bone morphogenetic protein-2 (BMP-2) protein, VEGF protein levels under stimulation for 10, 60, and 180 min/day and BMP-2 levels under stimulation for 60, 120, and 180 min/day were significantly different compared with those of the control. In conclusion, the results indicated that exposing hABMSCs to OSS enhanced their differentiation and maturation.
Efficient Depth Map Estimation Method Based on Gradient Weight Cost Aggregation Strategy for Distributed Video Sensor Networks
Authors: Hong Gwang-Soo , Kim Byung-Gyu , Kwon Kee-Koo
Published: January 2014

Video sensor networking technologies have developed very rapidly in the last ten years. In this paper, a cross-based framework strategy for cost aggregation is presented for the depth map estimation based on video sensor networks. We formulate the process as a local regression problem consisting of two main steps with a pair of video sensors. The first step is to calculate estimates for a set of points within a shape-adaptive local support region. The second step is to aggregate the matching cost for the gradient-based weight of the support region at the outmost pixel. The proposed algorithm achieves strong results in an efficient manner using the two main steps. We have achieved improvement of up to 6.9%, 8.4%, and 8.3%, when compared with adaptive support weight (ASW) algorithm. Comparing to cross-based algorithm, the proposed algorithm gives 2.0%, 1.3%, and 1.0% in terms of nonocclusion, all, and discontinuities, respectively.
Hybrid Integration of Taguchi Parametric Design, Grey Relational Analysis, and Principal Component Analysis Optimization for Plastic Gear Production
Authors: Mehat Nik Mizamzul , Kamaruddin Shahrul , Othman Abdul Rahim
Published: January 2014

The identification of optimal processing parameters is an important practice in the plastic injection moulding industry because of the significant effect of such parameters on plastic part quality and cost. However, the optimization design of injection moulding process parameters can be difficult because more than one quality characteristic is used in the evaluation. This study systematically develops a hybrid optimization method for multiple quality characteristics by integrating the Taguchi parameter design, grey relational analysis, and principal component analysis. A plastic gear is used to demonstrate the efficiency and validity of the proposed hybrid optimization method in controlling all influential injection moulding processing parameters during plastic gear manufacturing. To minimize the shrinkage behaviour in tooth thickness, addendum circle, and dedendum circle of moulded gear, the optimal combination of different process parameters is determined. The case study demonstrates that the proposed optimization method can produce plastic-moulded gear with minimum shrinkage behaviour of 1.8%, 1.53%, and 2.42% in tooth thickness, addendum circle, and dedendum circle, respectively; these values are less than the values in the main experiment. Therefore, shrinkage-related defects that lead to severe failure in plastic gears can be effectively minimized while satisfying the demand of the global plastic gear industry.
Early Onset Alzheimer’s Disease and Oxidative Stress
Authors: Meraz-Ríos Marco Antonio , Franco-Bocanegra Diana , Toral Rios Danira , Campos-Peña Victoria
Published: January 2014

Alzheimer’s disease (AD) is the most common cause of dementia in elderly adults. It is estimated that 10% of the world’s population aged more than 60–65 years could currently be affected by AD, and that in the next 20 years, there could be more than 30 million people affected by this pathology. One of the great challenges in this regard is that AD is not just a scientific problem; it is associated with major psychosocial and ethical dilemmas and has a negative impact on national economies. The neurodegenerative process that occurs in AD involves a specific nervous cell dysfunction, which leads to neuronal death. Mutations in APP, PS1, and PS2 genes are causes for early onset AD. Several animal models have demonstrated that alterations in these proteins are able to induce oxidative damage, which in turn favors the development of AD. This paper provides a review of many, although not all, of the mutations present in patients with familial Alzheimer’s disease and the association between some of these mutations with both oxidative damage and the development of the pathology.
Prognostic and Predictive Value of CpG Island Methylator Phenotype in Patients with Locally Advanced Nonmetastatic Sporadic Colorectal Cancer
Authors: Wang Yuwei , Long Yadong , Xu Ye , Guan Zuqing , Lian Peng , Peng Junjie , Cai Sanjun , Cai Guoxiang
Published: January 2014

Purpose. In the present study, the prognostic significance of CpG island methylator phenotype (CIMP) in stage II/III sporadic colorectal cancer was evaluated using a five-gene panel.Methods. Fifty stage II/III colorectal cancer patients who received radical resection were included in this study. Promoter methylation of p14ARF, hMLH1, p16INK4a, MGMT, and MINT1 was determined by methylation specific polymerase chain reaction (MSP). CIMP positive was defined as hypermethylation of three or more of the five genes. Impact factors on disease-free survival (DFS) and overall survival (OS) were analyzed using Kaplan-Meier method (log-rank test) and adjusted Cox proportional hazards model.Results. Twenty-four percent (12/50) of patients were characterized as CIMP positive. Univariate analysis showed stage III (P=0.049) and CIMP positive (P=0.014) patients who had significantly inferior DFS. In Cox regression analysis, CIMP positive epigenotype was independently related with poor DFS with HR = 2.935 and 95% CI: 1.193–7.220 (P=0.019). In patients with CIMP positive tumor, those receiving adjuvant chemotherapy had a poor DFS than those without adjuvant chemotherapy (P=0.023).Conclusions. CIMP positive was significantly correlated with decreased DFS in stage II/III colorectal cancer. Patients with CIMP positive locally advanced sporadic colorectal cancers may not benefit from 5-fluorouracil based adjuvant chemotherapy.
The CCN Family Proteins: Modulators of Bone Development and Novel Targets in Bone-Associated Tumors
Authors: Chen Po-Chun , Cheng Hsu-Chen , Yang Shun-Fa , Lin Chiao-Wen , Tang Chih-Hsin
Published: January 2014

The CCN family of proteins is composed of six extracellular matrix-associated proteins that play crucial roles in skeletal development, wound healing, fibrosis, and cancer. Members of the CCN family share four conserved cysteine-rich modular domains that trigger signal transduction in cell adhesion, migration, proliferation, differentiation, and survival through direct binding to specific integrin receptors and heparan sulfate proteoglycans. In the present review, we discuss the roles of the CCN family proteins in regulating resident cells of the bone microenvironment. In vertebrate development, the CCN family plays a critical role in osteo/chondrogenesis and vasculo/angiogenesis. These effects are regulated through signaling via integrins, bone morphogenetic protein, vascular endothelial growth factor, Wnt, and Notch via direct binding to CCN family proteins. Due to the important roles of CCN family proteins in skeletal development, abnormal expression of CCN proteins is related to the tumorigenesis of primary bone tumors such as osteosarcoma, Ewing sarcoma, and chondrosarcoma. Additionally, emerging studies have suggested that CCN proteins may affect progression of secondary metastatic bone tumors by moderating the bone microenvironment. CCN proteins could therefore serve as potential therapeutic targets for drug development against primary and metastatic bone tumors.
Hormetic Concentrations of Hydrogen Peroxide but Not Ethanol Induce Cross-Adaptation to Different Stresses in Budding Yeast
Authors: Semchyshyn Halyna M.
Published: January 2014

The biphasic-dose response of microorganisms to hydrogen peroxide is a phenomenon of particular interest in hormesis research. In different animal models, the dose-response curve for ethanol is also nonlinear showing an inhibitory effect at high doses but a stimulatory effect at low doses. In this study, we observed the hormetic-dose response to ethanol in budding yeastS. cerevisiae. Cross-protection is a phenomenon in which exposure to mild stress results in the acquisition of cellular resistance to lethal stress induced by different factors. Since both hydrogen peroxide and ethanol at low concentrations were found to stimulate yeast colony growth, we evaluated the role of one substance in cell cross-adaptation to the other substance as well as some weak organic acid preservatives. This study demonstrates that, unlike ethanol, hydrogen peroxide at hormetic concentrations causes cross-resistance ofS. cerevisiaeto different stresses. The regulatory protein Yap1 plays an important role in the hormetic effects by low concentrations of either hydrogen peroxide or ethanol, and it is involved in the yeast cross-adaptation by low sublethal doses of hydrogen peroxide.
Allyl Isothiocyanate Increases MRP1 Function and Expression in a Human Bronchial Epithelial Cell Line
Authors: Wang Dian-lei , Wang Chen-yin , Cao Yin , Zhang Xian , Tao Xiu-hua , Yang Li-li , Chen Jin-pei , Wang Shan-shan , Li Ze-geng
Published: January 2014

Multidrug resistance-associated protein 1 (MRP1), a member of the ATP-binding cassette (ABC) superfamily of transporters, plays an important role in normal lung physiology by protecting cells against oxidative stress and toxic xenobiotics. The present study investigates the effects of allyl isothiocyanate (AITC) onMRP1mRNA and MRP1 protein expression and transporter activity in the immortalised human bronchial epithelial cell line 16HBE14o-.MRP1mRNA and MRP1 protein expression in 16HBE14o- cells that were treated with allyl isothiocyanate were analysed by real-time PCR assay and Western blotting. The transport of carboxyfluorescein, a known MRP1 substrate, was measured by functional flow cytometry to evaluate MRP1 activity. Treatment with AITC at concentrations of 5–40 μM increased MRP1 protein levels in a concentration-dependent manner. AITC treatments at concentrations of 1–40 μM caused concentration-dependent increases inMRP1mRNA levels that were up to seven times greater than the levels found in control cells. Finally, AITC treatment at concentrations of 5–40 μM significantly increased MRP1-dependent efflux in 16HBE14o- cells. These results suggest that AITC can increase the expression and activity of MRP1 in 16HBE14o- cells in a concentration-dependent manner. The upregulation of MRP1 activity and expression by AITC could produce therapeutic effects in the treatment of lung disease.
Temperature Changes of Pulp Chamber duringIn VitroLaser Welding of Orthodontic Attachments
Authors: İşman Eren , Okşayan Rıdvan , Sökücü Oral , Üşümez Serdar
Published: January 2014

The use of lasers has been suggested for orthodontists to fabricate or repair orthodontic appliances by welding metals directly in the mouth. This work aimed to evaluate the temperature changes in the pulp chamber during welding of an orthodontic wire to an orthodontic molar band using Nd : YAG laserin vitro. A freshly extracted human third molar with eliminated pulpal tissues was used. J-type thermocouple wire was positioned in the pulp chamber. A conductor gel was used in the transferring of outside temperature changes to the thermocouple wire. An orthodontic band was applied to the molar tooth and bonded using light cured orthodontic cement. Twenty five mm length of 0.6 mm diameter orthodontic stainless steel wires was welded to the orthodontic band using Nd : YAG laser operated at 9.4 watt. Temperature variation was determined as the change from baseline temperature to the highest temperature was recorded during welding. The recorded temperature changes were between 1.8 and 6.8°C (mean: 3.3 ± 1.1°C). The reported critical 5.5°C level was exceeded in only one sample. The results of this study suggest that intraoral use of lasers holds great potential for the future of orthodontics and does not present a thermal risk. Further studies with larger samples and structural analysis are required.
Evaluation ofIn VitroAntimalarial Activity of Different Extracts ofArtemisia aucheriBoiss. andA. armeniacaLam. and Fractions of the Most Potent Extracts
Authors: Mojarrab Mahdi , Shiravand Ali , Delazar Abbas , Heshmati Afshar Fariba
Published: January 2014

Ten extracts with different polarity from two IranianArtemisiaspecies,A. armeniacaLam. andA. aucheriBoiss, were screened for their antimalarial properties byin vitro  β-hematin formation assay. Dichloromethane (DCM) extracts of both plants showed significant antimalarial activities with IC50values of 1.36 ± 0.01 and 1.83 ± 0.03 mg/mL and IC90values of 2.12 ± 0.04 and 2.62 ± 0.09 mg/mL forA. armeniacaandA. aucheri, respectively. Bioactivity-guided fractionation of DCM extracts of both plants by vacuum liquid chromatography (VLC) over silica gel with solvent mixtures of increasing polarities afforded seven fractions. Two fractions from DCM extract ofA. armeniacaand four fractions from DCM extract ofA. aucherishowed potent antimalarial activity with reducing IC50and IC90values compared to extracts. The most potent fraction belonged to DCM extract ofA. armeniacawith IC50and IC90values of 0.47 ± 0.006 and 0.71 ± 0.006 mg/mL, respectively.
On Conformal Conic Mappings of Spherical Domains
Authors: Bourchtein Andrei , Bourchtein Ludmila
Published: January 2014

The problem of the generation of homogeneous grids for spherical domains is considered in the class of conformal conic mappings. The equivalence between secant and tangent projections is shown and splitting the set of conformal conic mappings into equivalence classes is presented. The problem of minimization of the mapping factor variation is solved in the class of conformal conic mappings. Obtained results can be used in applied sciences, such as geophysical fluid dynamics and cartography, where the flattening of the Earth surface is required.
Novel Glycolipids Synthesized Using Plant Essential Oils and Their Application in Quorum Sensing Inhibition and as Antibiofilm Agents
Authors: Mukherji Ruchira , Prabhune Asmita
Published: January 2014

Essential oils (EOs) form an important part of traditional medicine so their anti-microbial and, in the recent past, antiquorum sensing activity has been well studied. However it is likely that due to their hydrophobic nature and reduced solubility in aqueous environments full potential of their activity cannot be realized. hence it is only rational to formulate a process to make these molecules more polar in nature. The present paper reports synthesis of sophorolipids using 12 different essential oils as substrates, thus providing surfactant-like properties to these EOs. The synthesis protocol makes the use ofCandida bombicolaATCC 22214 as producer organism. The production process required 7 days of incubation at 28°C and 180 rpm. Preliminary characterization of the synthesized essential oil sophorolipids (EOSLs) was performed using thin layer chromatography (TLC) and Fourier transform infrared spectroscopy (FTIR). Additionally, essential oils that were incapable of mediating quorum sensing inhibition (QSI) on their own became potent quorum sensing inhibitors upon conversion into their corresponding EOSLs. Antibiofilm potential of these EOSLs was also demonstrated usingV. choleraeas test organism. Use of essential oils as substrates for glycolipid synthesis has not been attempted previously, and hence this is the first report.
Sequential Gene Targeting to Make Chimeric Tumor Models with De Novo Chromosomal Abnormalities
Authors: Chambers Jennifer S. , Tanaka Tomoyuki , Brend Tim , Ali Hanif , Geisler Nicola J. , Khazin Leah , Cigudosa Juan C. , Neil Dear T. , MacLennan Kenneth , Rabbitts Terence H.
Published: January 2014

The discovery of chromosomal translocations in leukemia/lymphoma and sarcomas presaged a widespread discovery in epithelial tumors. With the advent of new-generation whole-genome sequencing, many consistent chromosomal abnormalities have been described together with putative driver and passenger mutations. The multiple genetic changes required in mouse models to assess the interrelationship of abnormalities and other mutations are severe limitations. Here, we show that sequential gene targeting of embryonic stem cells can be used to yield progenitor cells to generate chimeric offspring carrying all the genetic changes needed for cell-specific cancer. Illustrating the technology, we show that MLL–ENL fusion is sufficient for lethal leukocytosis and proof of genome integrity comes from germline transmission of the sequentially targeted alleles. This accelerated technology leads to a reduction in mouse numbers (contributing significantly to the 3Rs), allows fluorescence tagging of cancer-initiating cells, and provides a flexible platform for interrogating the interaction of chromosomal abnormalities with mutations. Cancer Res; 74(5); 1588–97. ©2014 AACR.
GRHL1Acts as Tumor Suppressor in Neuroblastoma and Is Negatively Regulated by MYCN and HDAC3
Authors: Fabian Johannes , Lodrini Marco , Oehme Ina , Schier Marie C. , Thole Theresa M. , Hielscher Thomas , Kopp-Schneider Annette , Opitz Lennart , Capper David , von Deimling Andreas , Wiegand Inga , Milde Till , Mahlknecht Ulrich , Westermann Frank , Popanda Odilia , Roels Frederik , Hero Barbara , Berthold Frank , Fischer Matthias , Kulozik Andreas E. , Witt Olaf , Deubzer Hedwig E.
Published: January 2014

Neuroblastoma is an embryonic solid tumor of neural crest origin and accounts for 11% of all cancer-related deaths in children. Novel therapeutic strategies are therefore urgently required. MYCN oncogene amplification, which occurs in 20% of neuroblastomas, is a hallmark of high risk. Here, we aimed to exploit molecular mechanisms that can be pharmacologically addressed with epigenetically modifying drugs, such as histone deacetylase (HDAC) inhibitors. Grainyhead-like 1 (GRHL1), a gene critical for Drosophila neural development, belonged to the genes most strongly responding to HDAC inhibitor treatment of neuroblastoma cells in a genome-wide screen. An increase in the histone H4 pan-acetylation associated with its promoter preceded transcriptional activation. Physically adjacent, HDAC3 and MYCN colocalized to the GRHL1 promoter and repressed its transcription. High-level GRHL1 expression in primary neuroblastomas correlated on transcriptional and translational levels with favorable patient survival and established clinical and molecular markers for favorable tumor biology, including lack of MYCN amplification. Enforced GRHL1 expression in MYCN-amplified neuroblastoma cells with low endogenous GRHL1 levels abrogated anchorage-independent colony formation, inhibited proliferation, and retarded xenograft growth in mice. GRHL1 knockdown in MYCN single-copy cells with high endogenous GRHL1 levels promoted colony formation. GRHL1 regulated 170 genes genome-wide, and most were involved in pathways regulated during neuroblastomagenesis, including nervous system development, proliferation, cell–cell adhesion, cell spreading, and cellular differentiation. In summary, the data presented here indicate a significant role of HDAC3 in the MYCN-mediated repression of GRHL1 and suggest drugs that block HDAC3 activity and suppress MYCN expression as promising candidates for novel treatment strategies of high-risk neuroblastoma. Cancer Res; 74(9); 2604–16. ©2014 AACR.
LEF1 and B9L Shield β-Catenin from Inactivation by Axin, Desensitizing Colorectal Cancer Cells to Tankyrase Inhibitors
Authors: de la Roche Marc , Ibrahim Ashraf E.K. , Mieszczanek Juliusz , Bienz Mariann
Published: January 2014

Hyperactive β-catenin drives colorectal cancer, yet inhibiting its activity remains a formidable challenge. Interest is mounting in tankyrase inhibitors (TNKSi), which destabilize β-catenin through stabilizing Axin. Here, we confirm that TNKSi inhibit Wnt-induced transcription, similarly to carnosate, which reduces the transcriptional activity of β-catenin by blocking its binding to BCL9, and attenuates intestinal tumors in ApcMin mice. By contrast, β-catenin's activity is unresponsive to TNKSi in colorectal cancer cells and in cells after prolonged Wnt stimulation. This TNKSi insensitivity is conferred by β-catenin's association with LEF1 and BCL9-2/B9L, which accumulate during Wnt stimulation, thereby providing a feed-forward loop that converts transient into chronic β-catenin signaling. This limits the therapeutic value of TNKSi in colorectal carcinomas, most of which express high LEF1 levels. Our study provides proof-of-concept that the successful inhibition of oncogenic β-catenin in colorectal cancer requires the targeting of its interaction with LEF1 and/or BCL9/B9L, as exemplified by carnosate. Cancer Res; 74(5); 1495–505. ©2014 AACR.
CBP-Mediated FOXO-1 Acetylation Inhibits Pancreatic Tumor Growth by Targeting SirT
Authors: Pramanik Kartick C. , Fofaria Neel M. , Gupta Parul , Srivastava Sanjay K.
Published: January 2014

Here, we investigated the potential mechanism of capsaicin-mediated apoptosis in pancreatic cancer cells. Capsaicin treatment phosphorylated c-jun-NH2-kinase (JNK); forkhead box transcription factor, class O (FOXO1); and BIM in BxPC-3, AsPC-1, and L3.6PL cells. The expression of BIM increased in response to capsaicin treatment. Capsaicin treatment caused cleavage of caspase-3 and PARP, indicating apoptosis. Antioxidants tiron and PEG-catalase blocked capsaicin-mediated JNK/FOXO/BIM activation and protected the cells from apoptosis. Furthermore, capsaicin treatment caused a steady increase in the nuclear expression of FOXO-1, leading to increased DNA binding. Capsaicin-mediated expression of BIM was found to be directly dependent on the acetylation of FOXO-1. The expression of CREB-binding protein (CBP) was increased, whereas SirT-1 was reduced by capsaicin treatment. Using acetylation mimic or defective mutants, our result demonstrated that phosphorylation of FOXO-1 was mediated through acetylation by capsaicin treatment. JNK inhibitor attenuated the phosphorylation of FOXO-1, activation of BIM, and abrogated capsaicin-induced apoptosis. Moreover, silencing FOXO1 by siRNA blocked capsaicin-mediated activation of BIM and apoptosis, whereas overexpression of FOXO-1 augmented its effects. Silencing Bim drastically reduced capsaicin-mediated cleavage of caspase-3 and PARP, indicating the role of BIM in apoptosis. Oral administration of 5 mg/kg capsaicin substantially suppressed the growth of BxPC-3 tumor xenografts in athymic nude mice. Tumors from capsaicin-treated mice showed an increase in the phosphorylation of JNK, FOXO-1, BIM, and levels of CBP, cleavage of caspase-3, PARP, and decreased SirT-1 expression. Taken together, our results suggest that capsaicin activated JNK and FOXO-1, leading to the acetylation of FOXO-1 through CBP and SirT-1. Acetylated FOXO1 induced apoptosis in pancreatic cancer cells through BIM activation. Mol Cancer Ther; 13(3); 687–98. ©2014 AACR.
Monosymptomatic Persistent Hematospermia due to Rarely Encountered Prostatic Utricle Stones
Authors: Şalvarcı Ahmet , İstanbulluoğlu Okan
Published: January 2014

We present a young patient who had hematospermia which was unresponsive to repeated medical therapies. In this patient prostatic utricle stones were detected via pelvic and transrectal ultrasonography, the presence of the stones was confirmed by transurethral fenestration, and persistent hematospermia disappeared following surgical excision. Thus, we conclude that prostatic utricle stones might have caused hematospermia in this young patient, who had no additional pathology likely to be responsible for this condition.
Percutaneous Transhepatic Biliary Drainage in Patients with Postsurgical Bile Leakage and Nondilated Intrahepatic Bile Ducts
Authors: de Jong E.A. , Moelker A. , Leertouwer T. , Spronk S. , Van Dijk M. , van Eijck C.H.J.
Published: January 2014

Objective and Background: Bile leakage is a serious postoperative complication and percutaneous transhepatic biliary drainage (PTBD) may be an option when endoscopic treatment is not feasible. In this retrospective study, we established technical and clinical success rates as well as the complication rates of PTBD in a large group of patients with postoperative bile leakage. Methods: Data on all patients with nondilated intrahepatic bile ducts who underwent a PTBD procedure for the treatment of bile leakage between January 2000 and August 2012 were retrospectively assessed. Data included type of surgery, site of bile leak, previous attempts of bile leak repair, interval between surgery and PTBD placement. Outcome measures were the technical and clinical success rates, the procedure-related complications, and mortality rate. Results: A total of 63 patients were identified; PTBD placement was technically successful in 90.5% (57/63) after one to three attempts. The clinical success rate was 69.8% (44/63). Four major complications were documented (4/63; 6.3%): liver laceration, pneumothorax, pleural empyema, and prolonged hemobilia. One minor complication involved pain. Conclusions: PTBD is an effective treatment with low complication rates for the management of postsurgical bile leaks in patients with nondilated bile ducts.
Prognosis of White-Coat and Masked Hypertension
Authors: Stergiou George S. , Asayama Kei , Thijs Lutgarde , Kollias Anastasios , Niiranen Teemu J. , Hozawa Atsushi , Boggia José , Johansson Jouni K. , Ohkubo Takayoshi , Tsuji Ichiro , Jula Antti M. , Imai Yutaka , Staessen Jan A.
Published: January 2014

Home blood pressure monitoring is useful in detecting white-coat and masked hypertension and is recommended for patients with suspected or treated hypertension. The prognostic significance of white-coat and masked hypertension detected by home measurement was investigated in 6458 participants from 5 populations enrolled in the International Database of HOme blood pressure in relation to Cardiovascular Outcomes. During a median follow-up of 8.3 years, 714 fatal plus nonfatal cardiovascular events occurred. Among untreated subjects (n=5007), cardiovascular risk was higher in those with white-coat hypertension (adjusted hazard ratio 1.42; 95% CI [1.06–1.91];
P
=0.02), masked hypertension (1.55; 95% CI [1.12–2.14];
P
<0.01) and sustained hypertension (2.13; 95% CI [1.66–2.73];
P
<0.0001) compared with normotensive subjects. Among treated patients (n=1451), the cardiovascular risk did not differ between those with high office and low home blood pressure (white-coat) and treated controlled subjects (low office and home blood pressure; 1.16; 95% CI [0.79–1.72];
P
=0.45). However, treated subjects with masked hypertension (low office and high home blood pressure; 1.76; 95% CI [1.23–2.53];
P
=0.002) and uncontrolled hypertension (high office and home blood pressure; 1.40; 95% CI [1.02–1.94];
P
=0.04) had higher cardiovascular risk than treated controlled patients. In conclusion, white-coat hypertension assessed by home measurements is a cardiovascular risk factor in untreated but not in treated subjects probably because the latter receive effective treatment on the basis of their elevated office blood pressure. In contrast, masked uncontrolled hypertension is associated with increased cardiovascular risk in both untreated and treated patients, who are probably undertreated because of their low office blood pressure.
Reoxygenation‐Derived Toxic Reactive Oxygen/Nitrogen Species Modulate the Contribution of Bone Marrow Progenitor Cells to Remodeling After Myocardial Infarction
Authors: Moldovan Nicanor I. , Anghelina Mirela , Varadharaj Saradhadevi , Butt Omer I. , Wang Tiangshen , Yang Fuchun , Moldovan Leni , Zweier Jay L.
Published: January 2014

Background

The core region of a myocardial infarction is notoriously unsupportive of cardiomyocyte survival. However, there has been less investigation of the potentially beneficial spontaneous recruitment of endogenous bone marrow progenitor cells (
BMPC
s) within infarcted areas. In the current study we examined the role of tissue oxygenation and derived toxic species in the control of
BMPC
engraftment during postinfarction heart remodeling.

Methods and Results

For assessment of cellular origin, local oxygenation, redox status, and fate of cells in the infarcted region, myocardial infarction in mice with or without LacZ
+
bone marrow transplantation was induced by coronary ligation. Sham‐operated mice served as controls. After 1 week, LacZ
+
BMPC
‐derived cells were found inhomogeneously distributed into the infarct zone, with a lower density at its core. Electron paramagnetic resonance (EPR) oximetry showed that
pO
2
in the infarct recovered starting on day 2 post–myocardial infarction, concomitant with wall thinning and erythrocytes percolating through muscle microruptures. Paralleling this reoxygenation, increased generation of reactive oxygen/nitrogen species was detected at the infarct core. This process delineated a zone of diminished
BMPC
engraftment, and at 1 week infiltrating cells displayed immunoreactive 3‐nitrotyrosine and apoptosis. In vivo treatment with a superoxide dismutase mimetic significantly reduced reactive oxygen species formation and amplified
BMPC
accumulation. This treatment also salvaged wall thickness by 43% and left ventricular ejection fraction by 27%, with significantly increased animal survival.

Conclusions

BMPC
engraftment in the infarct inversely mirrored the distribution of reactive oxygen/nitrogen species. Antioxidant treatment resulted in increased numbers of engrafted
BMPC
s, provided functional protection to the heart, and decreased the incidence of myocardial rupture and death.
Сказание о трясении Цареградском как памятник русской книжности
Authors: Алексеев Алексей И.
Published: January 2014

This article argues that the text of “Tales of the Constantinopolitan earthquake,” contained in the book of the famous Joseph-Volokolamsk Monastery church leader and scribe Niphont Kormilitsyn, goes back to the story of the Polish grandee Andrzhey Zakrzewski. The story was reconsidered by Volokolamsk scribes in the genre of edifying novella in order to emphasize the truth of Orthodox Christianity against Islam.
Truth and Fiction in A. I. Sulakadzev’s Chronograph of the Marriages of Tsar Ivan Vasil’evich
Authors: Martin Russell E.
Published: January 2014

Few sources have exerted more influence on the biography of Ivan IV (Ivan the Terrible) than the so-called Chronograph of the Marriages of Tsar Ivan Vasil’evich, but the source has not to date been properly studied, except to note that it is a likely forgery of the notorious bibliophile and manuscript forger Alexander Ivanovich Sulakadzev. This article offers the first dedicated treatment of the Chronograph’s contents, comparing the information in it about the number, identity, and biographies of Ivan’s wives with what we know about them from other, unquestionably authentic sources of the sixteenth and seventeenth centuries. The article provides ample proof that the Chronograph is a forgery, but also isolates and discusses some of the unique pieces of information in it, including the names of some of Ivan’s brides and the dates of his marriages – parsing out fact from likely fiction. It also discusses the possible sources for the information in the Chronograph, including links to the Istoriia gosudarstva Rossiiskogo [The History of the Russian State] by Nikolai M. Karazmin. The article’s conclusions will be of interest to biographers of Ivan IV, women’s historians, textual scholars, and specialists on the history of Russian literary culture in the sixteenth through nineteenth centuries.
Explaining Violent Intra-Ethnic Conflict
Authors: Warren T. Camber , Troy Kevin K.
Published: January 2014

Despite significant advances in the disaggregation of the study of civil conflict and intra-ethnic violence, intra-ethnic violence remains understudied. In this article, we present the first systematic, cross-national analysis of the conditions that promote violent, fragmentary conflict within politically active ethnic minorities. We propose a model of intra-ethnic conflict in which collective violence is produced by the interaction between subgroup entrepreneurs and the suppressive actions of the state. This two-level model predicts a curvilinear relationship between the relative size of an ethnic minority and its probability of experiencing large-scale intra-ethnic conflict. Additional hypotheses based on the proposed causal mechanism are also posited. These hypotheses are tested with data drawn from a global sample of politically active ethnic minorities, for the period 1990 through 2006, using a combination of parametric and semi-parametric regression techniques. The results strongly confirm the predicted curvilinear relationship while also demonstrating that the specific shape of this relationship shifts in predictable ways under varying social and political contexts.
The Doubly Disadvantaged: How Return Migrant Students Fail to Access and Deploy Capitals for Academic Success in Rural Schools
Authors: Koo Anita , Ming Holly , Tsang Bill
Published: January 2014

A growing number of ‘return migrant children’, who have lived in cities where they had access to the compulsory education system, are sent back to their rural hometowns to prepare for higher education in China. This study explores the resources that are available to return migrant students for further educational development and examines their difficulties with activating their educational capitals and translating them into human capital, in the form of academic knowledge and educational success after their remigration (a change in their field of practice). Using a framework based on the work of Bourdieu, this article conceptualizes the educational resources available to migrant families in terms of economic, social and cultural capitals. This article contributes to a better understanding of the transformation and deployment of educational capitals by revitalizing the importance of the concepts of ‘habitus’ and ‘field’ inherent in Bourdieu’s work.