bluuebunny/crossref_metadata_2025 huggingface dataset:
Combined Adenovirus Vector and Hepatitis C Virus Envelope Protein Prime-Boost Regimen Elicits T Cell and Neutralizing Antibody Immune Responses
Authors: Chmielewska Alicja M. , Naddeo Mariarosaria , Capone Stefania , Ammendola Virginia , Hu Ke , Meredith Luke , Verhoye Lieven , Rychlowska Malgorzata , Rappuoli Rino , Ulmer Jeffrey B. , Colloca Stefano , Nicosia Alfredo , Cortese Riccardo , Leroux-Roels Geert , Balfe Peter , Bienkowska-Szewczyk Krystyna , Meuleman Philip , McKeating Jane A. , Folgori Antonella
Published: March 2014

Despite the recent progress in the development of new antiviral agents, hepatitis C virus (HCV) infection remains a major global health problem, and there is a need for a preventive vaccine. We previously reported that adenoviral vectors expressing HCV nonstructural proteins elicit protective T cell responses in chimpanzees and were immunogenic in healthy volunteers. Furthermore, recombinant HCV E1E2 protein formulated with adjuvant MF59 induced protective antibody responses in chimpanzees and was immunogenic in humans. To develop an HCV vaccine capable of inducing both T cell and antibody responses, we constructed adenoviral vectors expressing full-length and truncated E1E2 envelope glycoproteins from HCV genotype 1b. Heterologous prime-boost immunization regimens with adenovirus and recombinant E1E2 glycoprotein (genotype 1a) plus MF59 were evaluated in mice and guinea pigs. Adenovirus prime and protein boost induced broad HCV-specific CD8
+
and CD4
+
T cell responses and functional Th1-type IgG responses. Immune sera neutralized luciferase reporter pseudoparticles expressing HCV envelope glycoproteins (HCVpp) and a diverse panel of recombinant cell culture-derived HCV (HCVcc) strains and limited cell-to-cell HCV transmission. This study demonstrated that combining adenovirus vector with protein antigen can induce strong antibody and T cell responses that surpass immune responses achieved by either vaccine alone.

IMPORTANCE
HCV infection is a major health problem. Despite the availability of new directly acting antiviral agents for treating chronic infection, an affordable preventive vaccine provides the best long-term goal for controlling the global epidemic. This report describes a new anti-HCV vaccine targeting the envelope viral proteins based on adenovirus vector and protein in adjuvant. Rodents primed with the adenovirus vaccine and boosted with the adjuvanted protein developed cross-neutralizing antibodies and potent T cell responses that surpassed immune responses achieved with either vaccine component alone. If combined with the adenovirus vaccine targeting the HCV NS antigens now under clinical testing, this new vaccine might lead to a stronger and broader immune response and to a more effective vaccine to prevent HCV infection. Importantly, the described approach represents a valuable strategy for other infectious diseases in which both T and B cell responses are essential for protection.
Improving the preoperative care of patients with femoral neck fractures through the development and implementation of a checklist
Authors: Agha Riaz , Edison Eric , Fowler Alexander
Published: March 2014

The incidence of femoral neck fractures (FNFs) is expected to rise with life expectancy. It is important to improve the safety of these patients whilst under the care of orthopaedic teams.

This study aimed to increase the performance of vital preoperative tasks in patients admitted for femoral neck fracture operations by producing and implementing a checklist as an aide memoir. The checklist was designed primarily for use by senior house officers (SHOs) admitting patients from the emergency department.

A list of 12 preoperative tasks was identified. A baseline audit of 10 random patients showed that the mean proportion of the 12 tasks completed was 53% (range 25% - 83%). A survey of 14 nurses and surgeons found that the majority of respondents agreed that there was a problem with the performance of most of the tasks. The tasks were incorporated into a checklist which was refined in three plan-do-study-act cycles and introduced into the femoral neck fracture pathway.

In the week following the introduction of the checklist, 77% of the checklist tasks were completed, 24% more than at the baseline audit (53%). In week 3, the completion of checklist tasks rose to 88% and to 95% in week 4.

In conclusion, a simple checklist can markedly improve the performance and recording of preoperative tasks by SHOs. We recommend the wider adoption of the new checklist to be produced as a sticker for patients’ medical records. Further study is required to ascertain the effect of the checklist on clinical outcomes.
Looking a store horse in the mouth
Authors: Collins Joe
Published: March 2014

THIS series gives readers the opportunity to consider and contribute to discussion of some of the ethical dilemmas that can arise in veterinary practice. Each month, a case scenario is presented, followed by discussion of some of the issues involved.

In addition, a possible way forward is suggested; however, there is rarely a cut‐and‐dried answer in such cases, and readers may wish to suggest an alternative approach. This month's dilemma, ‘Looking a store horse in the mouth’, was submitted and is discussed by Joe Collins. Readers with comments to contribute are invited to send them as soon as possible, so that they can be considered for publication in the next issue. Discussion of the dilemma ‘The case of the whelping bitch’, which was published in the February issue of In Practice, appears on page 159.

The series is being coordinated by Siobhan Mullan, of the University of Bristol. It is hoped it will provide a framework that will help practices find solutions when facing similar dilemmas.
How do we learn?
Authors: Bell Catriona , Paterson Jessie , Murison Pamela , Warman Sheena
Published: March 2014

Almost all veterinary surgeons teach, yet very little training is provided to vets on how to teach effectively. This article forms the first in a series aimed at providing veterinary staff and students with tips and tools to enhance the teaching opportunities that arise in practice.
Reactivity of low-oxidation state tin compounds: an overview of the benefits of combining DFT Theory and experimental NMR spectroscopy
Authors: De Proft Frank , Broeckaert Lies , Turek Jan , Růžička Aleš , Willem Rudolph
Published: March 2014

The reactivity and complexation properties of dicoordinated Sn(II) and Sn(0) compounds are reviewed. The (dominant) electrophilicity of the stannylenes was confirmed and quantified through density functional theory (DFT) based reactivity indices. For these compounds, combining theoretical DFT calculations and experimental nuclear magnetic resonance (NMR) spectroscopic results has evidenced their potential to undergo π-complexation from aromatic π clouds in addition to significantly stronger σ-complexation. Moreover, their potential as Lewis bases was scrutinized in their interactions and reactions with iron and tungsten carbonyl Lewis acids. Finally, a prospective comparison of the reactivity of divalent stannylenes and stannylones, with a 0 oxidation state at the Sn atom, is presented.
Transient Behaviors of Multiple Memristor Circuits Based on Flux Charge Relationship
Authors: Budhathoki Ram Kaji , Sah Maheshwar P. D. , Yang Changju , Kim Hyongsuk , Chua Leon
Published: March 2014

Memristor, a new electrical element, can have various configurations of multiple memristors, including serial and parallel connections like previous elements R, L and C. When input voltage/current is supplied to a circuit with multiple memristors, the composite behavior of the memristor circuit exhibits transient states before it enters a steady state. During the transient state period, the behavior is very complex and not predictable due to each memristor's different action depending upon its connection polarity and initial state. In this paper, the transient characteristics of a composite memristor are analyzed via the relationships of charge, flux and memristance of each memristor. Also, the behavior of an individual memristor is formulated mathematically and a general computation method of composite memristance for multiple-memristor circuits of diverse configurations is proposed. Various simulations have also been performed to verify the effectiveness of the proposed method for differently configured memristor circuits, in terms of polarities and initial states.
Potential Function in a Continuous Dissipative Chaotic System: Decomposition Scheme and Role of Strange Attractor
Authors: Ma Yian , Tan Qijun , Yuan Ruoshi , Yuan Bo , Ao Ping
Published: March 2014

We demonstrate, first in literature, that potential functions can be constructed in a continuous dissipative chaotic system and can be used to reveal its dynamical properties. To attain this aim, a Lorenz-like system is proposed and rigorously proved chaotic for exemplified analysis. We explicitly construct a potential function monotonically decreasing along the system's dynamics, revealing the structure of the chaotic strange attractor. The potential function is not unique for a deterministic system. We also decompose the dynamical system corresponding to a curl-free structure and a divergence-free structure, explaining for the different origins of chaotic attractor and strange attractor. Consequently, reasons for the existence of both chaotic nonstrange attractors and nonchaotic strange attractors are discussed within current decomposition framework.
A DISCRETE TIME VARIABLE INDEX FOR SUPPORTING DYNAMIC MULTI-CRITERIA DECISION MAKING
Authors: ZULUETA YELENY , MARTÍNEZ-MORENO JUAN , PÉREZ RAFAEL BELLO , MARTÍNEZ LUIS
Published: March 2014

While Multi-Criteria Decision Making (MCDM) models are focused on selecting the best alternative from a finite number of feasible solutions according to a set of criteria, in Dynamic Multi-Criteria Decision Making (DMCDM) the selection process also takes into account the temporal performance of such alternatives during different time periods. In this paper a new discrete time variable index is proposed, to handling differences in temporal behavior of alternatives, which are not discriminated in preceding dynamic approaches, also considering rating-based perspectives for discrimination of the decision maker by modeling different attitudes to deal with the rating changes along different time periods. Moreover a DMCDM for supplier selection example is provided to illustrate the feasibility and effectiveness of the proposed index.
MULTISCALE DETRENDED FLUCTUATION ANALYSIS OF TRAFFIC INDEX SERIES
Authors: DU GUAN , SHANG PENGJIAN , ZHAO XIAOJUN
Published: March 2014

In this paper, we present a multiscale detrended fluctuation analysis (DFA) for describing the traffic fractal dynamics with a spectrum of scale exponents, a(s), rather than by a model of lumped parameters a1 and a2. The method combines DFA with moving fitting window to analyze the traffic index (TI) series in different scales, shows more details of scale properties and provides a reliable analysis. We also quantify the effects of weather, traffic peaks and traffic control on exponent spectra a(s). The results indicate clearly that at large scales, the exponents show large volatility and they all have their own exponent patterns. In addition, for the effect of traffic control, the scale exponents of traffic control are continuously obviously larger than those without traffic control at small scales. The multiscale DFA method provides new ways to measure the TI series and distinguishes groups in different conditions.
Identification of Active Valuable Nodes in Temporal Online Social Network with Attributes
Authors: Qiu Dehong , Li Hao , Li Yuan
Published: March 2014

The rapidly growing online social networks have generated great expectations connected with their potential business values. The aim of this paper is to identify the active valuable nodes that can spread business information to a large fraction of the individuals in large-scale temporal online social networks as quickly as possible. Most studies focus on static social networks, the study on the identification of active valuable nodes in temporal online social networks with quantitative attributes is still young. In this paper, we propose a method to identify active valuable nodes based on their static structural properties and temporal behavioral attributes. The method first chooses the candidates of the active valuable nodes by the static analysis of their structural properties. Then, the candidate's behavioral trend is extracted from its activity records. Through analyzing the spatio-temporal characteristics of the behavioral trend, the method distinguishes active valuable nodes from inactive ones and reveals typical evolutionary processes. We perform experiments on two practical online social networks with thousands of nodes. The experimental results demonstrate that the method can identify the active valuable nodes for information diffusion in large-scale temporal online social networks accurately and efficiently. It would be useful for business applications.
An ONIOM study of the distribution of skeletal aluminum and Brønsted acidity in ZSM-48 zeolite
Authors: Liu Rui , Zhang Jie , Sun Xiuliang , Huang Chongpin , Chen Biaohua
Published: March 2014

A density functional theory (DFT) study was performed on distribution of skeletal aluminum and Brønsted acid (B-acid) sites as well as the acid strength in ZSM-48 zeolite. The correlation between Si / Al molar ratio and the general acid strength was also investigated. The calculations were performed based on 51T and 90T cluster models by using two-layered ONIOM schemes (B3LYP/6-31G (d,p): AM1) method. The former 51T cluster is used for the calculation of single- Al substitution and the latter is for the multi- Al substitution study. The properties of Si / Al substitution energy, deprotonation energy, bridging hydroxyl stretching vibration frequency and adsorption energy for the probe molecule were calculated and used to measure Brønsted acid location and strength. As the result shows, T2 is the most readily to be replaced by Al and the Brønsted acids prefer to be formed at Al 2– O 7– Si 3 site. Al 2– O 6– Si 2 is the highest in Brønsted acid strength. Besides, the acid strength weakens with the decrease of Si / Al .
EXAMINING THE RELATIONSHIP BETWEEN ORGANISATIONAL JUSTICE, JOB SATISFACTION AND THE INNOVATIVE BEHAVIOUR OF NURSING EMPLOYEES
Authors: XERRI MATTHEW J.
Published: March 2014

This research examines the impact of three organisational factors on the innovative behaviour of nurses. Social exchange theory is used as a framework to develop an understanding about a path from organisational justice, to the job satisfaction and innovative behaviour of nursing employees. This study uses a quantitative approach, surveying 210 nurses. The findings confirm that the procedural justice and job satisfaction of nursing employees are positively and significantly related to their innovative behaviour. In addition, the findings also outline that interactional justice directly effects job satisfaction and indirectly effects innovative behaviour through job satisfaction. This research adds to the current body of literature by providing insight into the impact of organisational justice and job satisfaction on the individual innovativeness of nurses. This research, therefore, provides implications for management who are aiming to develop positive perceptions amongst nursing employees, improve job satisfaction and in-turn foster innovative behaviour in the workplace.
Microgeometry, piezoelectric sensitivity and anisotropy of properties in porous materials based on Pb(Zr, Ti)O3
Authors: Filippov Sergei E. , Vorontsov Alexander A. , Brill Olga E. , Topolov Vitaly Yu.
Published: March 2014

Relations between the microgeometry, piezoelectric sensitivity and piezoelectric anisotropy are studied in porous composite materials based on Pb ( Zr , Ti ) O 3 ceramics. Systems of micrographs of cuts being parallel and perpendicular to the polarization direction are first shown for the porosity range v p = 0.05 - 0.57, and examples of microcracking at v p = 0.57 are considered. Experimental data on longitudinal and hydrostatic piezoelectric coefficients and squared figures of merit are represented as functions of v p , and nonmonotonic behavior of the piezoelectric anisotropy factor with increasing v p is analyzed in the context of changes in the microgeometry. Experimental results are compared to those derived from approximation formulae for the related porous ceramic.
Systematic Design and Implementation of a Micro Unmanned Quadrotor System
Authors: Phang Swee King , Li Kun , Yu Kok Hwa , Chen Ben M. , Lee Tong Heng
Published: March 2014

This paper presents a guideline to systematically design and construct a micro quadrotor unmanned aerial vehicle (UAV), capable of autonomous flight. The designed micro UAV has a gross weight of less than 40 g including power supply sufficient for an 8-min flight. The design is divided into three parts. First, investigation is made on the structural design of a conventional quadrotor. The quadrotor frame is then carefully designed to avoid any potential structural natural frequencies within the range of rotors operating speeds, based on simulation results obtained from MSC Nastran. Second, avionic system of the aircraft will be discussed in detail, mainly focusing on the design of printed circuit boards which include sensors, microprocessors and four electronic speed controllers, specially catered for micro quadrotor design. Last, a mathematical model for the micro quadrotor is derived based on Newton–Euler formalism, followed by methods of identifying the parameters. The flight test results are later described, analyzed and illustrated in this paper.
Studies of construction methods for Bentonite engineered barrier systems for sub-surface disposal: vibratory compaction
Authors: Yamada Atsuo , Akiyama Yoshihiro , Nakajima Masaki , Yada Tsutomu , Chijimatsu Masakazu , Nakajima Takahiro
Published: March 2014

Bentonite buffer is a part of the engineered barrier systems (EBS) for sub-surface disposal. The EBS is required to meet two quality standards at completion of construction. One is very low permeability of less than 5×10
−13
m s
−1
and the other is very low diffusibility of less than 1×10
−12
m
2
s
−1
. The bentonite buffer is required for the first quality standard of low permeability and must be constructed with high density in order to make the buffer a low-permeability layer. To confirm that the bentonite buffer is actually constructed with high density, we have carried out a full-scale mock-up test for part of the Demonstration Test of Underground Cavern-Type Disposal Facilities commissioned by the Japanese government in fiscal year 2005. This paper covers the test results from the construction of the bentonite buffer.
Human erythrocytes transport dehydroascorbic acid and sugars using the same transporter complex
Authors: Sage Jay M. , Carruthers Anthony
Published: March 2014

GLUT1, the primary glucose transport protein in human erythrocytes [red blood cells (RBCs)], also transports oxidized vitamin C [dehydroascorbic acid (DHA)]. A recent study suggests that RBC GLUT1 transports DHA as its primary substrate and that only a subpopulation of GLUT1 transports sugars. This conclusion is based on measurements of cellular glucose and DHA equilibrium spaces, rather than steady-state transport rates. We have characterized RBC transport of DHA and 3- O-methylglucose (3-OMG), a transported, nonmetabolizable sugar. Steady-state 3-OMG and DHA uptake in the absence of intracellular substrate are characterized by similar Vmax (0.16 ± 0.01 and 0.13 ± 0.02 mmol·l−1·min−1, respectively) and apparent Km (1.4 ± 0.2 and 1.6 ± 0.7 mM, respectively). 3-OMG and DHA compete for uptake, with Ki(app) of 0.7 ± 0.4 and 1.1 ± 0.1 mM, respectively. Uptake measurements using RBC inside-out-membrane vesicles demonstrate that 3-OMG and DHA compete at the cytoplasmic surface of the membrane, with Ki(app) of 0.7 ± 0.1 and 0.6 ± 0.1 mM, respectively. Intracellular 3-OMG stimulates unidirectional uptake of 3-OMG and DHA. These findings indicate that DHA and 3-OMG bind at mutually exclusive sites at exo- and endofacial surfaces of GLUT1 and are transported via the same GLUT1 complex.
Delayed skin wound repair in proline-rich protein tyrosine kinase 2 knockout mice
Authors: Koppel Aaron C. , Kiss Alexi , Hindes Anna , Burns Carole J. , Marmer Barry L. , Goldberg Gregory , Blumenberg Miroslav , Efimova Tatiana
Published: March 2014

Proline-rich protein tyrosine kinase 2 (Pyk2) is a member of the focal adhesion kinase family. We used Pyk2 knockout (Pyk2-KO) mice to study the role of Pyk2 in cutaneous wound repair. We report that the rate of wound closure was delayed in Pyk2-KO compared with control mice. To examine whether impaired wound healing of Pyk2-KO mice was caused by a keratinocyte cell-autonomous defect, the capacities of primary keratinocytes from Pyk2-KO and wild-type (WT) littermates to heal scratch wounds in vitro were compared. The rate of scratch wound repair was decreased in Pyk2-KO keratinocytes compared with WT cells. Moreover, cultured human epidermal keratinocytes overexpressing the dominant-negative mutant of Pyk2 failed to heal scratch wounds. Conversely, stimulation of Pyk2-dependent signaling via WT Pyk2 overexpression induced accelerated scratch wound closure and was associated with increased expression of matrix metalloproteinase (MMP)-1, MMP-9, and MMP-10. The Pyk2-stimulated increase in the rate of scratch wound repair was abolished by coexpression of the dominant-negative mutant of PKCδ and by GM-6001, a broad-spectrum inhibitor of MMP activity. These results suggest that Pyk2 is essential for skin wound reepithelialization in vivo and in vitro and that it regulates epidermal keratinocyte migration via a pathway that requires PKCδ and MMP functions.
Signal transduction of aortic and carotid sinus baroreceptors is not modified by central command during spontaneous motor activity in decerebrate cats
Authors: Matsukawa Kanji , Ishii Kei , Kadowaki Akito , Ishida Tomoko , Idesako Mitsuhiro , Liang Nan
Published: March 2014

Our laboratory has suggested that central command provides selective inhibition of the cardiomotor component of aortic baroreflex at the start of exercise, preserving carotid sinus baroreflex. It is postulated that central command may modify the signal transduction of aortic baroreceptors, so as to decrease aortic baroreceptor input to the cardiovascular centers, and, thereby, can cause the selective inhibition of aortic baroreflex. To test the hypothesis, we directly analyzed the responses in multifiber aortic nerve activity (AoNA) and carotid sinus nerve activity (CsNA) during spontaneous motor activity in decerebrate, paralyzed cats. The increases of 62–104% in mean AoNA and CsNA were found during spontaneous motor activity, in proportion to a rise of 35 ± 3 mmHg (means ± SE) in mean arterial blood pressure (MAP), and had an attenuating tendency by restraining heart rate (HR) at the lower intrinsic frequency of 154 ± 6 beats/min. Brief occlusion of the abdominal aorta was conducted before and during spontaneous motor activity to produce a mechanically evoked increase in MAP and, thereby, to examine the stimulus-response relationship of arterial baroreceptors. Although the sensitivity of the MAP-HR baroreflex curve was markedly blunted during spontaneous motor activity, the stimulus-response relationships of AoNA and CsNA were not influenced by spontaneous motor activity, irrespective of the absence or presence of the HR restraint. Thus, it is concluded that aortic and carotid sinus baroreceptors can code beat-by-beat blood pressure during spontaneous motor activity in decerebrate cats and that central command is unlikely to modulate the signal transduction of arterial baroreceptors.
Genetic disruption of the On visual pathway affects cortical orientation selectivity and contrast sensitivity in mice
Authors: Sarnaik Rashmi , Chen Hui , Liu Xiaorong , Cang Jianhua
Published: March 2014

The retina signals stimulus contrast via parallel On and Off pathways and sends the information to higher visual centers. Here we study the role of the On pathway using mice that have null mutations in the On-specific GRM6 receptor in the retina (Pinto LH, Vitaterna MH, Shimomura K, Siepka SM, Balannik V, McDearmon EL, Omura C, Lumayag S, Invergo BM, Brandon M, Glawe B, Cantrell DR, Donald R, Inayat S, Olvera MA, Vessey KA, Kirstan A, McCall MA, Maddox D, Morgans CW, Young B, Pletcher MT, Mullins RF, Troy JB, Takahashi JS. Vis Neurosci 24: 111–123, 2007; Maddox DM, Vessey KA, Yarbrough GL, Invergo BM, Cantrell DR, Inayat S, Balannik V, Hicks WL, Hawes NL, Byers S, Smith RS, Hurd R, Howell D, Gregg RG, Chang B, Naggert JK, Troy JB, Pinto LH, Nishina PM, McCall MA. J Physiol 586: 4409–4424, 2008). In these “nob” mice, single unit recordings in the primary visual cortex (V1) reveal degraded selectivity for orientations due to an increased response at nonpreferred orientations. Contrast sensitivity in the nob mice is reduced with severe deficits at low contrast, consistent with the phenotype of night blindness in human patients with mutations in Grm6. These cortical deficits can be largely explained by reduced input drive and increased response variability seen in nob V1. Interestingly, increased variability is also observed in the superior colliculus of these mice but does not affect its tuning properties. Further, the increased response variability in the nob mice is traced to the retina, a result phenocopied by acute pharmacological blockade of the On pathway in wild-type retina. Together, our results suggest that the On and Off pathways normally interact to increase response reliability in the retina, which in turn propagates to various central visual targets and affects their functional properties.
Emerging feed-forward inhibition allows the robust formation of direction selectivity in the developing ferret visual cortex
Authors: Van Hooser Stephen D. , Escobar Gina M. , Maffei Arianna , Miller Paul
Published: March 2014

The computation of direction selectivity requires that a cell respond to joint spatial and temporal characteristics of the stimulus that cannot be separated into independent components. Direction selectivity in ferret visual cortex is not present at the time of eye opening but instead develops in the days and weeks following eye opening in a process that requires visual experience with moving stimuli. Classic Hebbian or spike timing-dependent modification of excitatory feed-forward synaptic inputs is unable to produce direction-selective cells from unselective or weakly directionally biased initial conditions because inputs eventually grow so strong that they can independently drive cortical neurons, violating the joint spatial-temporal activation requirement. Furthermore, without some form of synaptic competition, cells cannot develop direction selectivity in response to training with bidirectional stimulation, as cells in ferret visual cortex do. We show that imposing a maximum lateral geniculate nucleus (LGN)-to-cortex synaptic weight allows neurons to develop direction-selective responses that maintain the requirement for joint spatial and temporal activation. We demonstrate that a novel form of inhibitory plasticity, postsynaptic activity-dependent long-term potentiation of inhibition (POSD-LTPi), which operates in the developing cortex at the time of eye opening, can provide synaptic competition and enables robust development of direction-selective receptive fields with unidirectional or bidirectional stimulation. We propose a general model of the development of spatiotemporal receptive fields that consists of two phases: an experience-independent establishment of initial biases, followed by an experience-dependent amplification or modification of these biases via correlation-based plasticity of excitatory inputs that compete against gradually increasing feed-forward inhibition.
Optimization of Natural Killer T Cell–Mediated Immunotherapy in Cancer Using Cell-Based and Nanovector Vaccines
Authors: Faveeuw C. , Trottein F.
Published: March 2014

α-Galactosylceramide (α-GalCer) represents a new class of immune stimulators and vaccine adjuvants that activate type I natural killer T (NKT) cells to swiftly release cytokines and to exert helper functions for acquired immune responses. This unique property prompted clinicians to exploit the antitumor potential of NKT cells. Here, we review the effects of α-GalCer in (pre)clinics and discuss current and future strategies that aim to optimize NKT cell–mediated antitumor therapy, with a particular focus on cell-based and nanovector vaccines. Cancer Res; 74(6); 1632–8. ©2014 AACR.
Noncanonical Functions of Telomerase: Implications in Telomerase-Targeted Cancer Therapies
Authors: Li Yinghui , Tergaonkar Vinay
Published: March 2014

Telomerase plays a pivotal role in bypassing cellular senescence and maintaining telomere homeostasis, essential properties required for the sustenance and progression of cancer. However, recent investigations have uncovered extratelomeric properties of telomerase that are independent of its role in telomere extension. This review summarizes recent insights to the noncanonical functions of telomerase reverse transcriptase (TERT) catalytic subunit, in particular in cancer progression, and highlights two major signaling mechanisms involved in the cross-talk with TERT—the NF-κB and Wnt/β-catenin pathways. We propose a feed-forward regulatory loop mechanism underlying TERT activation in cancers in which TERT acts as a transcriptional modulator of oncogenic signaling pathways that sustain its own levels and control the induction of target genes critical for tumor cell survival and proliferation. Finally, we provide a new perspective on telomerase-targeted cancer therapies and suggest possible interventions targeting the nontelomeric roles of TERT. This therapeutic strategy can be used in the future targeting of other telomerase components that exhibit novel nontelomeric functions in cancer and other ailments. Cancer Res; 74(6); 1639–44. ©2014 AACR.
Beyond Histology: Translating Tumor Genotypes into Clinically Effective Targeted Therapies
Authors: Meador Catherine B. , Micheel Christine M. , Levy Mia A. , Lovly Christine M. , Horn Leora , Warner Jeremy L. , Johnson Douglas B. , Zhao Zhongming , Anderson Ingrid A. , Sosman Jeffrey A. , Vnencak-Jones Cindy L. , Dahlman Kimberly B. , Pao William
Published: March 2014

Increased understanding of intertumoral heterogeneity at the genomic level has led to significant advancements in the treatment of solid tumors. Functional genomic alterations conferring sensitivity to targeted therapies can take many forms, and appropriate methods and tools are needed to detect these alterations. This review provides an update on genetic variability among solid tumors of similar histologic classification, using non–small cell lung cancer and melanoma as examples. We also discuss relevant technological platforms for discovery and diagnosis of clinically actionable variants and highlight the implications of specific genomic alterations for response to targeted therapy. Clin Cancer Res; 20(9); 2264–75. ©2014 AACR.
SERMs Attenuate Estrogen-Induced Malignant Transformation of Human Mammary Epithelial Cells by Upregulating Detoxification of Oxidative Metabolites
Authors: Hemachandra L.P. Madhubhani P. , Patel Hitisha , Chandrasena R. Esala P. , Choi Jaewoo , Piyankarage Sujeewa C. , Wang Shuai , Wang Yijin , Thayer Emily N. , Scism Robert A. , Michalsen Bradley T. , Xiong Rui , Siklos Marton I. , Bolton Judy L. , Thatcher Gregory R.J.
Published: March 2014

The risk of developing hormone-dependent cancers with long-term exposure to estrogens is attributed both to proliferative, hormonal actions at the estrogen receptor (ER) and to chemical carcinogenesis elicited by genotoxic, oxidative estrogen metabolites. Nontumorigenic MCF-10A human breast epithelial cells are classified as ER− and undergo estrogen-induced malignant transformation. Selective estrogen receptor modulators (SERM), in use for breast cancer chemoprevention and for postmenopausal osteoporosis, were observed to inhibit malignant transformation, as measured by anchorage-independent colony growth. This chemopreventive activity was observed to correlate with reduced levels of oxidative estrogen metabolites, cellular reactive oxygen species (ROS), and DNA oxidation. The ability of raloxifene, desmethylarzoxifene (DMA), and bazedoxifene to inhibit this chemical carcinogenesis pathway was not shared by 4-hydroxytamoxifen. Regulation of phase II rather than phase I metabolic enzymes was implicated mechanistically: raloxifene and DMA were observed to upregulate sulfotransferase (SULT 1E1) and glucuronidase (UGT 1A1). The results support upregulation of phase II metabolism in detoxification of catechol estrogen metabolites leading to attenuated ROS formation as a mechanism for inhibition of malignant transformation by a subset of clinically important SERMs. Cancer Prev Res; 7(5); 505–15. ©2014 AACR.
Homoharringtonine Combined with Cytarabine to Treat Chronic Myelogenous Leukemia in Myeloid Blast Crisis and Its Impact on Bone Marrow CD34+CD7+ Cells
Authors: Li Yuanyuan , Deng Zhikui , Zhu Jiabin , Ding Banhe , Shi Yuye , Li Yufeng
Published: March 2014

Background: The therapeutic response of chronic myelogenous leukemia in myeloid blast crisis (CML-MBC) is very poor. Aim: To explore the therapeutic effect of homoharringtonine (HHT) combined with cytarabine (HA regimen) on CML-MBC and its influence on bone marrow CD34+CD7+ cells. Results: Thirty-four patients with CML-MBC were treated with the HA regimen and bone marrow CD34+CD7+ cells were assayed prior to and after treatment. Among 33 evaluable patients, the overall hematological response (complete/partial hematological response and hematological improvement) was 60.1%. Seven patients (21.2%) had a cytogenetic response 12 months after treatment. In the untreated CML-MBC patients, the proportion of bone marrow CD34+CD7+ cells was much higher than in the control group (19.4 ± 7.9 vs. 4.4 ± 1.5%, p < 0.05) and decreased to 14.1 ± 7.1% (p < 0.05) after treatment. Before treatment, the proportion of CD34+CD7+ cells was lower in the patients who had a hematological response to the HA regimen than in the patients who did not respond. Conclusion: The HA regimen is an effective treatment for CML-MBC and CD34+CD7+ cells may be one of the valuable clinical parameters to assess treatment effectiveness.
Composition of Enamel Pellicle from Dental Erosion Patients
Authors: Carpenter G. , Cotroneo E. , Moazzez R. , Rojas-Serrano M. , Donaldson N. , Austin R. , Zaidel L. , Bartlett D. , Proctor G.
Published: March 2014

Oral health is dependent upon a thin mobile film of saliva on soft and hard tissues. Salivary proteins adhere to teeth to form the acquired enamel pellicle which is believed to protect teeth from acid erosion. This study investigated whether patients suffering diet-induced dental erosion had altered enamel pellicles. Thirty patients suffering erosion were compared to healthy age-matched controls. Subjects wore a maxillary splint holding hydroxyapatite and human enamel blocks for 1 h. The acquired enamel pellicle was removed from the blocks and compared to the natural incisor pellicle. Basic Erosive Wear Examination scores confirmed that dental erosion was present in erosion patients and absent from healthy age-matched controls. Erosion patients had half the amount of proteins (BCA assay) within the acquired pellicle forming on splint blocks compared to normal controls (p < 0.05). In particular, statherin, a calcium-binding protein, was 35% less abundant (p < 0.05). Calcium concentration within the acquired pellicle was also reduced by 50% in erosion patients (p < 0.001). In contrast, the natural pellicle on the incisor had similar amounts of total protein in erosion patients and healthy controls. In summary, the formation of new acquired pellicles on surfaces was reduced in erosion patients, which may explain their greater susceptibility to acid erosion of teeth.
Acute Kidney Injury following Unselected Emergency Admission: Role of the Inflammatory Response, Medication and Co-Morbidity
Authors: Pankhurst T. , Mani D. , Ray D. , Jham S. , Borrows R. , Coleman J.J. , Rosser D. , Ball S.
Published: March 2014

Background/Aims: Acute kidney injury (AKI) following admission to hospital is associated with increased mortality, morbidity and length of stay. Factors that predispose patients to AKI frequently co-exist. The precise description of their representation in unselected admissions could help define mechanistic inter-relationships and optimise risk stratification strategies. Our aim was therefore to define precisely, using electronically available data, the variables that are associated with AKI. Methods: A cohort study of 112,987 emergency admissions to an urban academic medical centre between 2006 and 2010 was performed. Post-admission AKI was defined using KDIGO aligned, proportionate changes in serum creatinine, denominated by the first measured. AKI correlated with co-morbidities, medications received and the C-reactive protein concentration (CRP). Results: The relationship between post-admission AKI and putative risk factors was defined in univariate and multivariate analyses. Inclusion of CRP in multivariate analyses significantly reduced the strength of association between some co-variables such as radiological contrast and gentamicin administration but not others. Conclusion: The effect of CRP in these analyses supports the role of systemic inflammation in susceptibility to post-admission AKI. It accounts for the greater part of univariate associations between AKI and some nephrotoxic agents, placing the risk attributable to their use in context. Quantification of the systemic inflammatory response may have utility in AKI risk stratification, integrating various determinants of susceptibility.
Postnatal and Adult Immunoglobulin Repertoires of Innate-Like CD19+CD45Rlo B Cells
Authors: Prado Carmen , Rodríguez Mercedes , Cortegano Isabel , Ruiz Carolina , Alía Mario , de Andrés Belén , Gaspar María Luisa
Published: March 2014

The diversity in antibody repertoire relies on different B cell populations working efficiently to fulfil distinct specific functions. We recently described an innate-like CD19+CD45R-/lo (19+45Rlo) cell population in postnatal unstimulated adult mice, a heterogeneous population containing cells expressing immunoglobulin M (IgM) and others behaving as differentiated mature B lymphocytes (intracytoplasmic IgG1, AID+, Blimp-1+RAG2-). In the present study, we characterized the Ig repertoire expressed by splenic 19+45Rlo cells, assuming that they would bear a restricted repertoire biased for germline rearrangements and low mutation rates similar to other innate-like cells. Sequences from 19+45Rlo cells displayed a variety of V, D and J regions, and the analysis of the CDR-H3 region revealed an intermediate overall CDR-H3 length and moderate hydrophobicity. Both IgM and switched sequences of PD15 19+45Rlo cells had shorter CDR-H3 region and fewer non-template N nucleotides than adult sequences, as expected for profiles that correspond to an immature phenotype. Regarding the mutation rate in the VH regions, IgG1 sequences already carried a high rate of replacement mutations at PD15, which increased further in the sequences obtained from adult mice. Moreover, statistical models suggest that a proportion of the switched sequences in adult 19+45Rlo cells had experienced antigen selection, unlike other innate-like B cell compartments.
Clinical Application of a Revised Screw Technique via the C1 Posterior Arch and Lateral Mass in the Pediatric Population
Authors: Yi Ping , Dong Liang , Tan Mingsheng , Wang Wenjun , Tang Xiangsheng , Yang Feng , Zhang Guangbo
Published: March 2014

Objective: Pediatric patients with insufficient height (≤4 mm) of the C1 posterior arch may restrict atlas screw placement via the posterior arch and lateral mass (PALM). For these patients, we modified this technique, called the ‘pedicle exposure technique' (PET). We aimed to analyze the clinical feasibility and safety of the PET in the pediatric population. Methods: Twenty pediatric patients with atlantoaxial instability (AAI) were enrolled in this study. The average C1 posterior arch was 3.1 (2.5-3.9) mm on CT scan. All patients underwent the C1 PET and C2 pedicle screw fixation. The imaging was performed to evaluate the accuracy of screw placement and bony fusion. Results: Forty screws were inserted via C1 PALM using the PET. Venous plexus bleeding occurred in 1 patient and the internal wall of the C1 lateral mass was perforated in 1 patient. There were no perioperative neurological deficits or vertebral artery injury. Follow-up was performed in all 20 cases over a period ranging from 6 to 80 months. Bony union was seen within 3-6 months. At the final follow-up visit, 14 patients had experienced an improvement, while 6 had complete resolution of their neck pain. Myelopathy symptoms were improved in 9 patients with spinal compression. Conclusion: The PET is an effective alternative for pediatric AAI when the height of the C1 posterior arch is <4 mm. Because of the higher screw entry point through the C1 posterior arch, there is effective biomechanical stability and less irritation of the venous plexus and C2 nerve root.
IgA Nephropathy with Pathologic Features of Membranoproliferative Glomerulonephritis following Burn Injury
Authors: Zhu Jili , Wang Huiming , Yang Dingping
Published: March 2014

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, accounting for approximately 30-40% of patients undergoing renal biopsy in Asia. The characteristic and diagnostic lesion of IgAN is the deposition of glomerular IgA. The morphological lesions observed by light microscopy are extremely variable. A causal relationship between IgAN and burn injury has not been established, and the correlation between them is not clear if they appear at the same time. We have explored the cause of severe proteinuria of a Chinese patient with burns of 2nd or 3rd degree after a gas leakage accident 2 weeks ago. The diffuse proliferative glomerulonephritis of this patient revealed type I membranoproliferative glomerulonephritis-like symptoms. Moreover, this patient showed a sensitive response to prednisone. This case report demonstrates the intrinsic relationship between kidney disease and burn injury, which will facilitate a feasible treatment strategy for proteinuria after burn injury.
Deep-water species of Crangonidae and Glyphocrangonidae (Decapoda, Caridea) collected during the TALUD XV cruise off the west coast of southern Baja California, Mexico
Authors: Hendrickx Michel E.
Published: March 2014

Four species of Crangonidae and Glyphocrangonidae were collected during a survey of the deep-water fauna off the west coast of the southern part of the Baja California Peninsula, Mexico. A total of 168 specimens were collected, with a clear dominance of Glyphocrangon spinulosa Faxon, 1893 (85% of collected specimens). A new northernmost distribution limit is set for Paracrangon areolata Faxon, 1893, Sclerocrangon atrox Faxon, 1893 and Glyphocrangon alata Faxon, 1893, while first records are made available for G. spinulosa off the west coast of the Baja California Peninsula.
Diversity and bathymetric distribution of decapod crustaceans attracted to baited traps from the middle slope of the northern Aegean Sea
Authors: Gönülal O. , Sezgin M. , Öztürk B.
Published: March 2014

We sampled the decapod crustaceans inhabiting the depth zone between 500 and 1500 m off Gökçeada Island (northern Aegean Sea) from May 2010 to November 2011. The deep-slope decapod fauna of the northern Aegean Sea was sampled with baited traps. A total of 23 species of decapods have been identified at 32 stations. The results were analysed in terms of composition and distribution of benthic and benthopelagic bait-attracted species between regions. In addition, they were compared between stations in relation to the depth gradient. The results are discussed in relation to previous studies carried out in the eastern and western Mediterranean. Also, the use of traps is commented for different regions and the effects of the sampler on benthic species are discussed. The most common species was the penaeid shrimp, Parapenaeus longirostris in samples taken between 500 and 600 m. It is followed by Polycheles typhlops and the pandalid shrimp Plesionika martia martia. These species constitute more than 50% of all decapods. Differences among the strata at 500-1500 m depth were tentatively explained using the Shannon-Weaver diversity index (H′). The highest H′ value was found for the 800-1000 m depth strata. The lowest number of species was observed between 1000 and 1500 m, which lowered the diversity index values (H′). The results of similarity percentage analysis (SIMPER) showed a change in the decapod fauna below 1000 m depth. The present results are preliminary; further data collection and analysis will be required to evaluate the role of palaeoecolgical conditions and trophic factors, and how these could be supposed to interact.
Variation of Von Vaupel Klein’s organ among genera of the Calanidae and Megacalanidae (Copepoda, Calanoida)
Authors: Fornshell John A. , Ferrari Frank D.
Published: March 2014

Von Vaupel Klein’s organ (VVKO), an association of the basal seta and proximal segment on the endopod of swimming leg 1 on many gymnoplean copepods, is surveyed on one species each of eight genera of calanids, viz., Calanoides acutus Giesbrecht, 1902, Calanus finmarchicus (Gunnerus, 1770), Canthocalanus pauper (Giesbrecht, 1888), Cosmocalanus caroli (Giesbrecht, 1888), Mesocalanus lighti (Bowman, 1955), Nannocalanus minor (Claus, 1863), Neocalanus robustior (Giesbrecht, 1888) and Undinula vulgaris (Dana, 1849), and three of megacalanids, viz., Bathycalanus richardi Sars, 1905, Bradycalanus typicus Sewell, 1947 and Megacalanus longicornis Sars, 1905. In this exploratory survey, VVKO shows significant variability among the eleven species in the shape of the distodorsal corner of the proximal endopodal segment, presence and location of denticles on the anterior face of the segment, presence and size of denticles along the distal margin of the segment, number of pores on the segment, shape of the seta that originates on the basis, and the nature of the basis at the origin of the seta.
On the Normalization of Sub-State Diplomacy
Authors: Cornago Noé
Published: March 2014

Against conventional approaches that tend to minimize the importance of sub-state diplomacy, this article argues that this reality is presently undergoing a process of legal and political normalization throughout the world and deserves greater attention from both diplomatic practitioners and experts. This process, which is embedded in wider structural transformations, is driven simultaneously by two competing forces that are present in virtually all states: first, international mobilization of sub-state governments themselves, since they increasingly pursue relevant political objectives in the international field through their own methods and instruments; and second, the various attempts to limit and control that activism deployed by central governments through various legal and political instruments. After a brief discussion on the notion of normalization in critical social theory and its validity for diplomatic studies, this article examines the normalization of sub-state diplomacy through four, closely interconnected conceptual lenses: normalization as generalization; normalization as regionalization; normalization as reflective adaptation; and, finally, normalization as contentious regulation. Normalization enables the diplomatic system to operate in an increasingly complex environment while simultaneously affirming its own hierarchical structure. The limits of that normalization process, as well as its wider implications for diplomatic theory and practice, are also discussed.