bluuebunny/crossref_metadata_2025 huggingface dataset:
Restricted transfer of learning between unimanual and bimanual finger sequences
Authors: Yokoi Atsushi , Bai Wenjun , Diedrichsen Jörn
Published: December 2016

When training bimanual skills, such as playing piano, people sometimes practice each hand separately and at a later stage combine the movements of the two hands. This poses the critical question of whether motor skills can be acquired by separately practicing each subcomponent or should be trained as a whole. In the present study, we addressed this question by training human subjects for 4 days in a unimanual or bimanual version of the discrete sequence production task. Both groups were then tested on trained and untrained sequences on both unimanual and bimanual versions of the task. Surprisingly, we found no evidence of transfer from trained unimanual to bimanual or from trained bimanual to unimanual sequences. In half the participants, we also investigated whether cuing the sequences on the left and right hand with unique letters would change transfer. With these cues, untrained sequences that shared some components with the trained sequences were performed more quickly than sequences that did not. However, the amount of this transfer was limited to ∼10% of the overall sequence-specific learning gains. These results suggest that unimanual and bimanual sequences are learned in separate representations. Making participants aware of the interrelationship between sequences can induce some transferrable component, although the main component of the skill remains unique to unimanual or bimanual execution.

NEW & NOTEWORTHY Studies in reaching movement demonstrated that approximately half of motor learning can transfer across unimanual and bimanual contexts, suggesting that neural representations for unimanual and bimanual movements are fairly overlapping at the level of elementary movement. In this study, we show that little or no transfer occurred across unimanual and bimanual sequential finger movements. This result suggests that bimanual sequences are represented at a level of the motor hierarchy that integrates movements of both hands.
Bursting deep dorsal horn neurons: the pharmacological target for the antispastic effects of zolmitriptan?
Authors: Carlsen Eva Meier , Rasmussen Rune
Published: December 2016

In a recent publication, Thaweerattanasinp et al. ( J Neurophysiol 116: 1644–1653, 2016) investigated spinal cord injury and firing properties of deep dorsal horn neurons during NMDA or zolmitriptan application by employing electrophysiology in an in vitro spinal cord preparation. Deep dorsal horn neurons were classified into bursting, simple, or tonic firing groups,with bursting neurons showing NMDA and zolmitriptan sensitivity. We discuss the findings in a methodological framework and propose future experiments of importance for translating the results into physiological settings.
Localized Patch-Based Fuzzy Active Contours for Image Segmentation
Authors: Fang Jiangxiong , Liu Hesheng , Liu Huaxiang , Zhang Liting , Liu Jun
Published: December 2016

This paper presents a novel fuzzy region-based active contour model for image segmentation. By incorporating local patch-energy functional along each pixel of the evolving curve into the fuzziness of the energy, we construct a patch-based energy function without the regurgitation term. Its purpose is not only to make the active contour evolve very stably without the periodical initialization during the evolution but also to reduce the effect of noise. In particular, in order to reject local minimal of the energy functional, we utilize a direct method to calculate the energy alterations instead of solving the Euler-Lagrange equation of the underlying problem. Compared with other fuzzy active contour models, experimental results on synthetic and real images show the advantages of the proposed method in terms of computational efficiency and accuracy.
Muse Cells: Nontumorigenic Pluripotent Stem Cells Present in Adult Tissues—A Paradigm Shift in Tissue Regeneration and Evolution
Authors: Simerman Ariel A. , Phan Julia D. , Dumesic Daniel A. , Chazenbalk Gregorio D.
Published: December 2016

Muse cells are a novel population of nontumorigenic pluripotent stem cells, highly resistant to cellular stress. These cells are present in every connective tissue and intrinsically express pluripotent stem markers such as Nanog, Oct3/4, Sox2, and TRA1‐60. Muse cells are able to differentiate into cells from all three embryonic germ layers both spontaneously and under media‐specific induction. Unlike ESCs and iPSCs, Muse cells exhibit low telomerase activity and asymmetric division and do not undergo tumorigenesis or teratoma formation when transplanted into a host organism. Muse cells have a high capacity for homing into damaged tissue and spontaneous differentiation into cells of compatible tissue, leading to tissue repair and functional restoration. The ability of Muse cells to restore tissue function may demonstrate the role of Muse cells in a highly conserved cellular mechanism related to cell survival and regeneration, in response to cellular stress and acute injury. From an evolutionary standpoint, genes pertaining to the regenerative capacity of an organism have been lost in higher mammals from more primitive species. Therefore, Muse cells may offer insight into the molecular and evolutionary bases of autonomous tissue regeneration and elucidate the molecular and cellular mechanisms that prevent mammals from regenerating limbs and organs, as planarians, newts, zebrafish, and salamanders do.
A Generalized Hermite-Hadamard Inequality for Coordinated Convex Function and Some Associated Mappings
Authors: Rehman Atiq Ur , Farid Gulam , Malik Sidra
Published: December 2016

We have discussed the generalization of Hermite-Hadamard inequality introduced by Lupaş for convex functions on coordinates defined in a rectangle from the plane. Also we define that mappings are related to it and their properties are discussed.
Qualitative Assessment of the Feasibility, Usability, and Acceptability of a Mobile Client Data App for Community-Based Maternal, Neonatal, and Child Care in Rural Ghana
Authors: Rothstein Jessica D. , Jennings Larissa , Moorthy Anitha , Yang Fan , Gee Lisa , Romano Karen , Hutchful David , Labrique Alain B. , LeFevre Amnesty E.
Published: December 2016

Mobile phone applications may enhance the delivery of critical health services and the accuracy of health service data. Yet, the opinions and experiences of frontline health workers on using mobile apps to track pregnant and recently delivered women are underreported. This evaluation qualitatively assessed the feasibility, usability, and acceptability of a mobile Client Data App for maternal, neonatal, and child client data management by community health nurses (CHNs) in rural Ghana. The mobile app enabled CHNs to enter, summarize, and query client data. It also sent visit reminders for clients and provided a mechanism to report level of care to district officers. Fourteen interviews and two focus groups with CHNs, midwives, and district health officers were conducted, coded, and thematically analyzed. Results indicated that the app was easily integrated into care, improved CHN productivity, and was acceptable due to its capacity to facilitate client follow-up, data reporting, and decision-making. However, the feasibility and usability of the app were hindered by high client volumes, staff shortages, and software and device challenges. Successful integration of mobile client data apps for frontline health workers in rural and resource-poor settings requires real-time monitoring, program investments, and targeted changes in human resources.
Synergistic Effects of Vascular Endothelial Growth Factor on Bone Morphogenetic Proteins Induced Bone Formation In Vivo: Influencing Factors and Future Research Directions
Authors: Li Bo , Wang Hai , Qiu Guixing , Su Xinlin , Wu Zhihong
Published: December 2016

Vascular endothelial growth factor (VEGF) and bone morphogenetic proteins (BMPs), as key mediators in angiogenesis and osteogenesis, are used in a combined delivery manner as a novel strategy in bone tissue engineering. VEGF has the potential to enhance BMPs induced bone formation. Both gene delivery and material-based delivery systems were incorporated in previous studies to investigate the synergistic effects of VEGF and BMPs. However, their results were controversial due to variation of methods incorporated in different studies. Factors influencing the synergistic effects of VEGF on BMPs induced bone formation were identified and analyzed in this review to reduce confusion on this issue. The potential mechanisms and directions of future studies were also proposed here. Further investigating mechanisms of the synergistic effects and optimizing these influencing factors will help to generate more effective bone regeneration.
Detection of Doppler Microembolic Signals Using High Order Statistics
Authors: Geryes Maroun , Ménigot Sebastien , Hassan Walid , Mcheick Ali , Charara Jamal , Girault Jean-Marc
Published: December 2016

Robust detection of the smallest circulating cerebral microemboli is an efficient way of preventing strokes, which is second cause of mortality worldwide. Transcranial Doppler ultrasound is widely considered the most convenient system for the detection of microemboli. The most common standard detection is achieved through the Doppler energy signal and depends on an empirically set constant threshold. On the other hand, in the past few years, higher order statistics have been an extensive field of research as they represent descriptive statistics that can be used to detect signal outliers. In this study, we propose new types of microembolic detectors based on the windowed calculation of the third moment skewness and fourth moment kurtosis of the energy signal. During energy embolus-free periods the distribution of the energy is not altered and the skewness and kurtosis signals do not exhibit any peak values. In the presence of emboli, the energy distribution is distorted and the skewness and kurtosis signals exhibit peaks, corresponding to the latter emboli. Applied on real signals, the detection of microemboli through the skewness and kurtosis signals outperformed the detection through standard methods. The sensitivities and specificities reached 78% and 91% and 80% and 90% for the skewness and kurtosis detectors, respectively.
Modal Analysis of a Single-Structure Multiaxis MEMS Gyroscope
Authors: Shah Muhammad Ali , Iqbal Faisal , Shah Ibrar Ali , Lee Byeungleul
Published: December 2016

This paper reports on designing a single-structure triaxes MEMS capacitive gyroscope which is capable of measuring the three angular velocities on a single drive. A Z-shaped beam for the support of folded coupling spring has been applied to suppress the unwanted mode and decrease the stress effect at the spring ends. The unique coupling spring has changed the driving motion, due to which slide film damping in the driving mode has been reduced. This reduction can lead to higher performance of the sensor with less requirements on vacuum level which decreases the cost of fabrication. Simulation analysis has been performed in COMSOL Multiphysics and Matlab Simulink to finalize the design for fabrication. After finite element analysis, the driving, x-sensing, z-sensing, and y-sensing are, respectively, found to be 13.30 KHz, 13.40 KHz, 13.47 KHz, and 13.51 KHz.
Coordinated Plasticity between Barrel Cortical Glutamatergic and GABAergic Neurons during Associative Memory
Authors: Yan Fenxia , Gao Zilong , Chen Pin , Huang Li , Wang Dangui , Chen Na , Wu Ruixiang , Feng Jing , Cui Shan , Lu Wei , Wang Jin-Hui
Published: December 2016

Neural plasticity is associated with memory formation. The coordinated refinement and interaction between cortical glutamatergic and GABAergic neurons remain elusive in associative memory, which we examine in a mouse model of associative learning. In the mice that show odorant-induced whisker motion after pairing whisker and odor stimulations, the barrel cortical glutamatergic and GABAergic neurons are recruited to encode the newly learnt odor signal alongside the innate whisker signal. These glutamatergic neurons are functionally upregulated, and GABAergic neurons are refined in a homeostatic manner. The mutual innervations between these glutamatergic and GABAergic neurons are upregulated. The analyses by high throughput sequencing show that certain microRNAs related to regulating synapses and neurons are involved in this cross-modal reflex. Thus, the coactivation of the sensory cortices through epigenetic processes recruits their glutamatergic and GABAergic neurons to be the associative memory cells as well as drive their coordinated refinements toward the optimal state for the storage of the associated signals.
In Vivo Evaluation of the Anti‐Inflammatory Effect of Pistacia lentiscus Fruit Oil and Its Effects on Oxidative Stress
Authors: Ben Khedir Sameh , Mzid Masarra , Bardaa Sana , Moalla Dorsaf , Sahnoun Zouheir , Rebai Tarek
Published: December 2016

In order to find new topical anti‐inflammatory agents, we had recourse to a medicinal plant. This work was designed to determine the topical anti‐inflammatory effect of Pistacia lentiscus fruit oil (PLFO), using carrageenan‐induced paw edema rat model, and to evaluate its effects on oxidative stress. The topical anti‐inflammatory activity of PLFO was compared to Inflocine® and estimated by measuring the diameter of paw edema, for 5 hours at a 1‐hour interval. After that the rats were scarified and the inflamed paw tissue was removed for the exploration of some parameters of oxidative stress and histopathology. PLFO showed a significant anti‐inflammatory activity in comparison with the Inflocine. The percentages of edema inhibition were 70% and % 51.5% (p < 0.01), respectively, after five hours. The treatment with PLFO and Inflocine led to significant increases (p ≤ 0.05) in the activities of CAT, SOD, and GPX and significant decreases in the MDA level and AOPP activity in the paw tissue after Carr injection, in comparison with the Carr group. Therefore, our findings demonstrate that PLFO might accelerate the development of new drugs which could be used scientifically as a source for natural health products in the treatment of topical inflammation.
Investigating Mutations to Reduce Huntingtin Aggregation by Increasing Htt-N-Terminal Stability and Weakening Interactions with PolyQ Domain
Authors: Smaoui Mohamed R. , Mazza-Anthony Cody , Waldispühl Jérôme
Published: December 2016

Huntington’s disease is a fatal autosomal genetic disorder characterized by an expanded glutamine-coding CAG repeat sequence in the huntingtin (Htt) exon 1 gene. The Htt protein associated with the disease misfolds into toxic oligomers and aggregate fibril structures. Competing models for the misfolding and aggregation phenomena have suggested the role of the Htt-N-terminal region and the CAG trinucleotide repeats (polyQ domain) in affecting aggregation propensities and misfolding. In particular, one model suggests a correlation between structural stability and the emergence of toxic oligomers, whereas a second model proposes that molecular interactions with the extended polyQ domain increase aggregation propensity. In this paper, we computationally explore the potential to reduce Htt aggregation by addressing the aggregation causes outlined in both models. We investigate the mutation landscape of the Htt-N-terminal region and explore amino acid residue mutations that affect its structural stability and hydrophobic interactions with the polyQ domain. Out of the millions of 3-point mutation combinations that we explored, the (L4K E12K K15E) was the most promising mutation combination that addressed aggregation causes in both models. The mutant structure exhibited extreme alpha-helical stability, low amyloidogenicity potential, a hydrophobic residue replacement, and removal of a solvent-inaccessible intermolecular side chain that assists oligomerization.
Efficient Computation of Wideband RCS Using Singular Value Decomposition Enhanced Improved Ultrawideband Characteristic Basis Function Method
Authors: Nie Wen-yan , Wang Zhong-gen
Published: December 2016

The singular value decomposition (SVD) enhanced improved ultrawideband characteristic basis function method (IUCBFM) is proposed to efficiently analyze the wideband scattering problems. In the conventional IUCBFM, the SVD is only applied to reduce the linear dependency among the characteristic basis functions (CBFs) due to the overestimation of incident plane waves. However, the increase in the size of the targets under analysis will require a large number of incident plane waves and it will become very time-consuming to solve such numbers of the matrix equation. In this paper, the excitation matrix is compressed by using the SVD in order to reduce both the number of matrix equation solutions and the number of CBFs compared with the traditional IUCBFM. Furthermore, the dimensions of the reduced matrix and the reduced matrix filling time are significantly reduced. Numerical results demonstrate that the proposed method is accurate and efficient.
Control Performance and Robustness of Pounding Tuned Mass Damper for Vibration Reduction in SDOF Structure
Authors: Xue Qichao , Zhang Jingcai , He Jian , Zhang Chunwei
Published: December 2016

This paper investigates the control performance of pounding tuned mass damper (PTMD) in reducing the dynamic responses of SDOF (Single Degree of Freedom) structure. Taking an offshore jacket-type platform as an example, the optimal damping ratio and the gap between mass block and viscoelastic material are presented depending on a parametric study. Control efficiency influenced by material properties and contact geometries for PTMD is analyzed here, as well as robustness of the device. The results of numerical simulations indicated that satisfactory vibration mitigation and robustness can be achieved by an optimally designed PTMD. Comparisons between PTMD and traditional TMD demonstrate the advantages of PTMD, not only in vibration suppression and costs but also in effective frequency bandwidth.
Human Endogenous Retroviruses-K (HML-2) Expression Is Correlated with Prognosis and Progress of Hepatocellular Carcinoma
Authors: Ma Weijie , Hong Zhenfei , Liu Hailing , Chen Xi , Ding Lu , Liu Zhisu , Zhou Fuling , Yuan Yufeng
Published: December 2016

Background. The association between human endogenous retroviruses-K (HERV-K) (HML-2) and human disease, including a variety of cancers, has been indicated. However, the function of HERV-K (HML-2) in the progression of hepatocellular carcinoma (HCC) still remains largely unclear.Methods. We detected the expression of HERV-K (HML-2) in 84 HCC tissues and adjacent nontumor tissues by quantitative real-time PCR (qRT-PCR) and analyzed its correlation with the clinical parameters.Result. The HEVR-K level was significantly increased in HCC compared with adjacent normal tissues (P<0.01) which was proved to be significantly associated with cirrhosis (P<0.05), tumor differentiation (P<0.05), and TNM stage (P<0.05). Moreover, the high expression of HERV-K (HML-2) had a poorer overall survival than patients with lower expression by a Kaplan-Meier survival analysis (P<0.01). The multivariate Cox regression analysis indicated that the level of HERV-K (HML-2) was an independent prognostic factor for the overall survival rate of HCC patients. Receiver operating characteristic (ROC) curves demonstrated the diagnostic accuracy of HERV-K (HML-2) expression in HCC (AUC = 0.729, 74.7% sensitivity, and 67.8% specificity).Conclusions. Our results suggested that upregulation of HERV-K (HML-2) in HCC patients was significantly related to cancer progression and poor outcome, indicating that HERV-K (HML-2) might be a novel candidate prognostic biomarker for HCC.
Relation between Age-Related Macular Degeneration and Cardiovascular Events and Mortality: A Systematic Review and Meta-Analysis
Authors: Wang Jie , Xue Yangjing , Thapa Saroj , Wang Luping , Tang Jifei , Ji Kangting
Published: December 2016

Data on the association between age-related macular degeneration (AMD) and cardiovascular disease and mortality are conflicting. The purpose of this report is to conduct a systematic review to better understand the role of AMD as a risk factor for CVD events and mortality. We searched Medline (Ovid) and Embase (Ovid) for trials published from 1980 to 2015. We included 20 cohort studies that reported relative risks with 95% confidence intervals for the association of AMD and cardiovascular events and mortality, involving 29,964,334 participants. In a random-effects model, the adjusted RR (95% confidence interval [CI]) associated with AMD was 1.08 (1.00–1.117) for all-cause mortality (8 studies) and 1.18 (0.98–1.43) for cardiovascular disease mortality (5 studies). The pooled RR (95% CI) was 1.17 (0.94–1.45) for coronary heart disease (CHD; 3 studies) and 1.13 (0.93–1.36) for stroke (8 studies). Findings from this systematic review support that AMD is associated with increased risk of all-cause mortality. The evidence that AMD predicts incident CVD events or CVD mortality remains inclusive and warrants further study in the future.
The Relation between Degree and Strength in the Complex Network Derived from an Individual Stock
Authors: Zhang Zelin , Luo Maokang , Deng Ke , Lai Li
Published: December 2016

A method based on coarse-graining to construct a directed weighted complex network which models the transformation of the trading data of an individual stock is introduced. The degree (strength) distribution of derived network follows a power-law. A moderated regression equation with interaction effects of average return and out-degree (in-degree) on out-strength (in-strength) is established. Moreover, we found that the differences of nodes affect the network’s structure and average return level impacts nodes’ eigenvector centrality and pagerank, significantly.
Role of Uric Acid Metabolism-Related Inflammation in the Pathogenesis of Metabolic Syndrome Components Such as Atherosclerosis and Nonalcoholic Steatohepatitis
Authors: Kushiyama Akifumi , Nakatsu Yusuke , Matsunaga Yasuka , Yamamotoya Takeshi , Mori Keiichi , Ueda Koji , Inoue Yuki , Sakoda Hideyuki , Fujishiro Midori , Ono Hiraku , Asano Tomoichiro
Published: December 2016

Uric acid (UA) is the end product of purine metabolism and can reportedly act as an antioxidant. However, recently, numerous clinical and basic research approaches have revealed close associations of hyperuricemia with several disorders, particularly those comprising the metabolic syndrome. In this review, we first outline the two molecular mechanisms underlying inflammation occurrence in relation to UA metabolism; one is inflammasome activation by UA crystallization and the other involves superoxide free radicals generated by xanthine oxidase (XO). Importantly, recent studies have demonstrated the therapeutic or preventive effects of XO inhibitors against atherosclerosis and nonalcoholic steatohepatitis, which were not previously considered to be related, at least not directly, to hyperuricemia. Such beneficial effects of XO inhibitors have been reported for other organs including the kidneys and the heart. Thus, a major portion of this review focuses on the relationships between UA metabolism and the development of atherosclerosis, nonalcoholic steatohepatitis, and related disorders. Although further studies are necessary, XO inhibitors are a potentially novel strategy for reducing the risk of many forms of organ failure characteristic of the metabolic syndrome.
The Modified Femoral Neck-Shaft Angle: Age- and Sex-Dependent Reference Values and Reliability Analysis
Authors: Boese Christoph Kolja , Frink Michael , Jostmeier Janine , Haneder Stefan , Dargel Jens , Eysel Peer , Lechler Philipp
Published: December 2016

Background. The femoral neck-shaft angle (NSA) is of high importance for the diagnostics and treatment of various conditions of the hip. However, rotational effects limit its precision and applicability using plain radiographs. This study introduces a novel method to measure the femoral NSA: the modified NSA (mNSA), possibly being less susceptible against rotational effects compared to the conventional NSA.Patients and Methods. The method of measurement is described and its applicability was tested in 400 pelvis computed tomography scans (800 hips). Age- and gender-dependent reference values are given and intra- and interrater reliability are analyzed.Results. The mean age of all 400 patients (800 hips) was 54.32 years (18–100, SD 22.05 years). The mean mNSA was 147.0° and the 95% confidence interval was 146.7°–147.4°. Differences of the mNSA between sexes, age groups, and sides were nonsignificant. The absolute difference between NSA and mNSA was 16.3° (range 3–31°; SD 4.4°); the correlation was high (0.738;p<0.001). Overall, the intra- and interrater reliability were excellent for the mNSA.Interpretation. We introduced a novel concept for the analysis of the neck-shaft angle. The high reliability of the measurement has been proven and its robustness to hip rotation was demonstrated.
Mechanosynthesis of MFe2O4 (M = Co, Ni, and Zn) Magnetic Nanoparticles for Pb Removal from Aqueous Solution
Authors: Vazquez-Olmos America R. , Abatal Mohamed , Sato-Berru Roberto Y. , Pedraza-Basulto G. K. , Garcia-Vazquez Valentin , Sainz-Vidal Arianee , Perez-Bañuelos R. , Quiroz A.
Published: December 2016

Adsorption of Pb(II) from aqueous solution using MFe2O4 nanoferrites (M = Co, Ni, and Zn) was studied. Nanoferrite samples were prepared via the mechanochemical method and were characterized by X-ray powder diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), micro-Raman, and vibrating sample magnetometry (VSM). XRD analysis confirms the formation of pure single phases of cubic ferrites with average crystallite sizes of 23.8, 19.4, and 19.2 nm for CoFe2O4, NiFe2O4, and ZnFe2O4, respectively. Only NiFe2O4 and ZnFe2O4 samples show superparamagnetic behavior at room temperature, whereas CoFe2O4 is ferromagnetic. Kinetics and isotherm adsorption studies for adsorption of Pb(II) were carried out. A pseudo-second-order kinetic describes the sorption behavior. The experimental data of the isotherms were well fitted to the Langmuir isotherm model. The maximum adsorption capacity of Pb(II) on the nanoferrites was found to be 20.58, 17.76, and 9.34 mg·g−1 for M = Co, Ni, and Zn, respectively.
On the Usefulness of Cooperation in N Person Games
Authors: Nikolskii Mikhail Sergeevich , Moussa Aboubacar
Published: December 2016

The N person games in which each player maximizes his payoff function are considered. We have studied an interesting question for the cooperative game theory about the usefulness of uniting the N players in a union. The aim of such cooperation is for each player to get a positive increase to his guaranteed payoff. We have obtained some effective sufficient conditions under which the joining of the players in union is useful for each player. The linear case, specially, is being considered. In the second part of the paper, we have studied the question about the usefulness of cooperation of the N players in the presence of the (N+1)th player, an ill-intentioned destructive player, whose whole aim is not to win but to harm each player individually, and also the union of these players, for example, global terrorism. It should be noted that the considered situation in the second part is related to A. V. Kryazhimskiy’s talk delivered in the summer of 2014. We obtain constructive conditions under which the union of the players is beneficial in this situation as well.
Navigated Pattern Laser System versus Single-Spot Laser System for Postoperative 360-Degree Laser Retinopexy
Authors: Kulikov Alexei N. , Maltsev Dmitrii S. , Boiko Ernest V.
Published: December 2016

Purpose. To compare three 360°-laser retinopexy (LRP) approaches (using navigated pattern laser system, single-spot slit-lamp (SL) laser delivery, and single-spot indirect ophthalmoscope (IO) laser delivery) in regard to procedure duration, procedural pain score, technical difficulties, and the ability to achieve surgical goals.Material and Methods. Eighty-six rhegmatogenous retinal detachment patients (86 eyes) were included in this prospective randomized study. The mean procedural time, procedural pain score (using 4-point Verbal Rating Scale), number of laser burns, and achievement of the surgical goals were compared between three groups (pattern LRP (Navilas® laser system), 36 patients; SL-LRP, 28 patients; and IO-LRP, 22 patients).Results. In the pattern LRP group, the amount of time needed for LRP and pain level were statistically significantly lower, whereas the number of applied laser burns was higher compared to those in the SL-LRP group and in the IO-LRP group. In the pattern LRP, SL-LRP, and IO-LRP groups, surgical goals were fully achieved in 28 (77.8%), 17 (60.7%), and 13 patients (59.1%), respectively (p>0.05).Conclusion. The navigated pattern approach allows improving the treatment time and pain in postoperative 360° LRP. Moreover, 360° pattern LRP is at least as effective in achieving the surgical goal as the conventional (slit-lamp or indirect ophthalmoscope) approaches with a single-spot laser.
DNA Methylation-Derived Neutrophil-to-Lymphocyte Ratio: An Epigenetic Tool to Explore Cancer Inflammation and Outcomes
Authors: Koestler Devin C. , Usset Joseph , Christensen Brock C. , Marsit Carmen J. , Karagas Margaret R. , Kelsey Karl T. , Wiencke John K.
Published: December 2016

Background: The peripheral blood neutrophil-to-lymphocyte ratio (NLR) is a cytologic marker of both inflammation and poor outcomes in patients with cancer. DNA methylation is a key element of the epigenetic program defining different leukocyte subtypes and may provide an alternative to cytology in assessing leukocyte profiles. Our aim was to create a bioinformatic tool to estimate NLR using DNA methylation, and to assess its diagnostic and prognostic performance in human populations.

Methods: We developed a DNA methylation–derived NLR (mdNLR) index based on normal isolated leukocyte methylation libraries and established cell-mixture deconvolution algorithms. The method was applied to cancer case–control studies of the bladder, head and neck, ovary, and breast, as well as publicly available data on cancer-free subjects.

Results: Across cancer studies, mdNLR scores were either elevated in cases relative to controls, or associated with increased hazard of death. High mdNLR values (>5) were strong indicators of poor survival. In addition, mdNLR scores were elevated in males, in nonHispanic white versus Hispanic ethnicity, and increased with age. We also observed a significant interaction between cigarette smoking history and mdNLR on cancer survival.

Conclusions: These results mean that our current understanding of mature leukocyte methylomes is sufficient to allow researchers and clinicians to apply epigenetically based analyses of NLR in clinical and epidemiologic studies of cancer risk and survival.

Impact: As cytologic measurements of NLR are not always possible (i.e., archival blood), mdNLR, which is computed from DNA methylation signatures alone, has the potential to expand the scope of epigenome-wide association studies. Cancer Epidemiol Biomarkers Prev; 26(3); 328–38. ©2016 AACR.
Transcriptomic Microenvironment of Lung Adenocarcinoma
Authors: Bossé Yohan , Sazonova Olga , Gaudreault Nathalie , Bastien Nathalie , Conti Massimo , Pagé Sylvain , Trahan Sylvain , Couture Christian , Joubert Philippe
Published: December 2016

Background: Tissues surrounding tumors are increasingly studied to understand the biology of cancer development and identify biomarkers.

Methods: A unique geographic tissue sampling collection was obtained from patients that underwent curative lobectomy for stage I pulmonary adenocarcinoma. Tumor and nontumor lung samples located at 0, 2, 4, and 6 cm away from the tumor were collected. Whole-genome gene expression profiling was performed on all samples (n = 5 specimens × 12 patients = 60). Analyses were carried out to identify genes differentially expressed in the tumor compared with adjacent nontumor lung tissues at different distances from the tumor as well as to identify stable and transient genes in nontumor tissues with respect to tumor proximity.

Results: The magnitude of gene expression changes between tumor and nontumor sites was similar with increasing distance from the tumor. A total of 482 up- and 843 downregulated genes were found in tumors, including 312 and 566 that were consistently differentially expressed across nontumor sites. Twenty-nine genes induced and 34 knocked-down in tumors were also identified. Tumor proximity analyses revealed 15,700 stable genes in nontumor lung tissues. Gene expression changes across nontumor sites were subtle and not statistically significant.

Conclusions: This study describes the transcriptomic microenvironment of lung adenocarcinoma and adjacent nontumor lung tissues collected at standardized distances relative to the tumor.

Impact: This study provides further insights about the molecular transitions that occur from normal tissue to lung adenocarcinoma and is an important step to develop biomarkers in nonmalignant lung tissues. Cancer Epidemiol Biomarkers Prev; 26(3); 389–96. ©2016 AACR.
Bone Marrow Cell Trafficking Analyzed by 89Zr-oxine Positron Emission Tomography in a Murine Transplantation Model
Authors: Asiedu Kingsley O. , Koyasu Sho , Szajek Lawrence P. , Choyke Peter L. , Sato Noriko
Published: December 2016

Purpose: The success of hematopoietic stem cell transplantation (HSCT) depends on donor cell homing to the bone marrow. However, there is no reliable method of noninvasively monitoring the kinetics and distribution of transferred cells. Using zirconium-89 (89Zr)-oxine cell labeling combined with PET imaging, we sought to visualize and quantify donor cell homing in a mouse bone marrow transplantation model.

Experimental Design: The effect of 89Zr-oxine labeling on bone marrow cell viability and differentiation was evaluated in vitro. 89Zr-labeled bone marrow cells (2 × 107 cells, 16.6 kBq/106 cells) were transferred intravenously, and serial microPET images were obtained (n = 5). The effect of a CXCR4 inhibitor, plerixafor (5 mg/kg) and G-CSF (2.5 μg) on bone marrow homing and mobilization were examined (n = 4). Engraftment of the transferred 89Zr-labeled cells was evaluated (n = 3).

Results: 89Zr-oxine–labeled bone marrow cells showed delayed proliferation, but differentiated normally. Transferred bone marrow cells rapidly migrated to the bone marrow, spleen, and liver (n = 5). Approximately 36% of donor cells homed to the bone marrow within 4 hours, irrespective of prior bone marrow ablation. Inhibition of CXCR4 by plerixafor alone or with G-CSF significantly blocked the bone marrow homing (P < 0.0001, vs. nontreated, at 2 hours), confirming a crucial role of the CXCR4–CXCL12 system. Mobilization of approximately 0.64% of pretransplanted bone marrow cells induced a 3.8-fold increase of circulating bone marrow cells. 89Zr-labeled donor cells engrafted as well as nonlabeled cells.

Conclusions: 89Zr-oxine PET imaging reveals rapid bone marrow homing of transferred bone marrow cells without impairment of their stem cell functions, and thus, could provide useful information for optimizing HSCT. Clin Cancer Res; 23(11); 2759–68. ©2016 AACR.
Involvement of c-Fos in the Promotion of Cancer Stem-like Cell Properties in Head and Neck Squamous Cell Carcinoma
Authors: Muhammad Naoshad , Bhattacharya Sourav , Steele Robert , Phillips Nancy , Ray Ratna B.
Published: December 2016

Purpose: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Although improvements in surgical techniques, chemotherapy and radiation delivery, and supportive care have improved quality of life for patients with HNSCC, regional and distant recurrence remain common. Recent evidence suggests that cancer stem-like cells (CSC) play a significant role in recurrence and chemoresistance. We previously observed that c-Fos was highly upregulated in the HNSCC sphere–forming cells. Consequences of c-Fos upregulation for the biology of HNSCC-CSCs are poorly understood. In this study, we investigated the role of c-Fos in renewal of stemness of HNSCC and tumor growth.

Experimental Design and Results: We generated stable HNSCC cell lines ectopically expressing the c-Fos gene. Exogenous expression of c-Fos in nontumorigenic MDA1386Tu cells makes these cells tumorigenic in nude mice. Furthermore, subcutaneous transplantation of c-Fos–overexpressing Cal27 cells (tumorigenic) into immunocompromised mice enhanced tumor growth as compared with parental cells. Mechanistic investigations demonstrated that c-Fos overexpression enhanced the epithelial–mesenchymal transition (EMT) state and expression of CSC markers (Nanog, c-Myc, Sox2, and Notch1). Ectopic expression of c-Fos in HNSCC cells also displays increased sphere formation. We further observed that overexpression of c-Fos increased the expression of pERK and cyclin D1 in HNSCC cells.

Conclusions: Together, our results strongly suggest a novel role of c-Fos as a regulator of EMT and cancer stem cell reprogramming in HNSCC cells, which may hold potential as a CSC-directed therapeutic approach to improve HNSCC treatment. Clin Cancer Res; 23(12); 3120–8. ©2016 AACR.
Dual-Targeting Nanoparticles for In Vivo Delivery of Suicide Genes to Chemotherapy-Resistant Ovarian Cancer Cells
Authors: Cocco Emiliano , Deng Yang , Shapiro Erik M. , Bortolomai Ileana , Lopez Salvatore , Lin Ken , Bellone Stefania , Cui Jiajia , Menderes Gulden , Black Jonathan D. , Schwab Carlton L. , Bonazzoli Elena , Yang Fan , Predolini Federica , Zammataro Luca , Altwerger Gary , de Haydu Christopher , Clark Mitchell , Alvarenga Julio , Ratner Elena , Azodi Masoud , Silasi Dan-Arin , Schwartz Peter E. , Litkouhi Babak , Saltzman W. Mark , Santin Alessandro D.
Published: December 2016

Ovarian cancer is the most lethal gynecologic cancer. Claudin-3 and -4, the receptors for Clostridium perfringens enterotoxin (CPE), are overexpressed in more than 70% of these tumors. Here, we synthesized and characterized poly(lactic-co-glycolic-acid) (PLGA) nanoparticles (NPs) modified with the carboxy-terminal–binding domain of CPE (c-CPE-NP) for the delivery of suicide gene therapy to chemotherapy-resistant ovarian cancer cells. As a therapeutic payload, we generated a plasmid encoding for the diphtheria toxin subunit-A (DT-A) under the transcriptional control of the p16 promoter, a gene highly differentially expressed in ovarian cancer cells. Flow cytometry and immunofluorescence demonstrated that c-CPE-NPs encapsulating the cytomegalovirus (CMV) GFP plasmid (CMV GFP c-CPE-NP) were significantly more efficient than control NPs modified with a scrambled peptide (CMV GFP scr-NP) in transfecting primary chemotherapy-resistant ovarian tumor cell lines in vitro (P = 0.03). Importantly, c-CPE-NPs encapsulating the p16 DT-A vector (p16 DT-A c-CPE-NP) were significantly more effective than control p16 DT-A scr-NP in inducing ovarian cancer cell death in vitro (% cytotoxicity: mean ± SD = 32.9 ± 0.15 and 7.45 ± 7.93, respectively, P = 0.03). In vivo biodistribution studies demonstrated efficient transfection of tumor cells within 12 hours after intraperitoneal injection of CMV GFP c-CPE-NP in mice harboring chemotherapy-resistant ovarian cancer xenografts. Finally, multiple intraperitoneal injections of p16 DT-A c-CPE-NP resulted in a significant inhibition of tumor growth compared with control NP in chemotherapy-resistant tumor-bearing mice (P = 0.041). p16 DT-A c-CPE-NP may represent a novel dual-targeting therapeutic approach for the selective delivery of gene therapy to chemotherapy-resistant ovarian cancer cells. Mol Cancer Ther; 16(2); 323–33. ©2016 AACR.
A Rare Case of Intraductal Papillary Mucinous Neoplasm of the Biliary Duct in a Patient with Prostate Adenocarcinoma
Authors: Parekh Ravish , Krol Gregory , Piraka Cyrus , Batra Surinder
Published: December 2016

Intraductal papillary mucinous neoplasms (IPMNs) are mucin-producing papillary neoplasms of the pancreatic or biliary ductal system that exhibit variable cellular atypia and cause ductal dilation. There are few reported cases of IPMN arising from the biliary tree in the literature. It has a higher propensity to undergo malignant transformation compared to IPMN arising from the pancreatic duct. An 80-year-old male underwent cross-sectional tomography (CT) imaging of the abdomen for evaluation of prostate adenocarcinoma, which revealed an incidental 2.3 × 2.7 cm soft tissue mass centered at the porta hepatis with diffuse dilatation of the left intrahepatic biliary ductal system and mild prominence of the right intrahepatic ductal system. Endoscopic ultrasound showed 2 adjacent hilar masses involving the common hepatic duct and the left hepatic duct with protrusion of the tissue into the lumen of the duct and upstream ductal dilatation. Endoscopic retrograde cholangiopancreatography revealed a large filling defect in the common hepatic duct extending into the left hepatic duct. A large amount of clot and soft tissue with a fish-egg appearance was retrieved. The patient underwent left hepatic lobectomy, radical resection of the common hepatic duct with Roux-en-Y hepaticojejunostomy to the right hepatic duct. Histopathological examination of the resected specimen revealed intraductal papillary mucinous neoplasm with diffuse high-grade dysplasia. Follow-up CT scan of the abdomen 2 months after the surgery was negative for any masses.
A Case of Poorly Differentiated Large-Cell Neuroendocrine Carcinoma of the Cecum: A Rare Malignancy, with Review of the Literature
Authors: Mertz Andrew T. , Ojemuyiwa Michelle A.
Published: December 2016

Poorly differentiated neuroendocrine carcinomas (NECs) are rare tumors that can arise anywhere along the gastrointestinal tract. They often present in advanced stage and portend a poor prognosis when compared to adenocarcinomas of the same stage. Characterization of these tumors is best accomplished with tissue biopsy, as peripheral tumor markers commonly used in NECs are of little utility. Therapeutic strategies often involve chemotherapeutic regimens that have been used to treat small-cell lung cancer. Recent studies have shown that programmed death-ligand 1 (PD-L1) expression within poorly differentiated NECs is a poor prognostic indicator. However, PD-L1 expression may represent a possible target for immunotherapy drugs, often called checkpoint inhibitors, such as anti-PD-1 inhibitors.
Gene Network for Identifying the Entropy Changes of Different Modules in Pediatric Sepsis
Authors: Yang Jing , Zhang Pingli , Wang Lumin
Published: December 2016

Background/Aims: Pediatric sepsis is a disease that threatens life of children. The incidence of pediatric sepsis is higher in developing countries due to various reasons, such as insufficient immunization and nutrition, water and air pollution, etc. Exploring the potential genes via different methods is of significance for the prevention and treatment of pediatric sepsis. This study aimed to identify potential genes associated with pediatric sepsis utilizing analysis of gene network and entropy. Methods: The mRNA expression in the blood samples collected from 20 septic children and 30 healthy controls was quantified by using Affymetrix HG-U133A microarray. Two condition-specific protein-protein interaction networks (PINs), one for the healthy control and the other one for the children with sepsis, were deduced by combining the fundamental human PINs with gene expression profiles in the two phenotypes. Subsequently, distinct modules from the two conditional networks were extracted by adopting a maximal clique-merging approach. Delta entropy (ΔS) was calculated between sepsis and control modules. Results: Then, key genes displaying changes in gene composition were identified by matching the control and sepsis modules. Two objective modules were obtained, in which ribosomal protein RPL4 and RPL9 as well as TOP2A were probably considered as the key genes differentiating sepsis from healthy controls. Conclusion: According to previous reports and this work, TOP2A is the potential gene therapy target for pediatric sepsis. The relationship between pediatric sepsis and RPL4 and RPL9 needs further investigation.
Astragaloside IV Enhances Cisplatin Chemosensitivity in Non-Small Cell Lung Cancer Cells Through Inhibition of B7-H3
Authors: He Cheng-Shi , Liu Yi-Cheng , Xu Zhi-Peng , Dai Peng-Chen , Chen Xiao-Wei , Jin De-Hai
Published: December 2016

Background: Chemoresistance is a major obstacle to successful chemotherapy for human non-small cell lung cancer (NSCLC). Astragaloside IV, the component of Astragalus membranaceus, has been reported to exhibit anti-inflammation, anti-cancer and immunoregulatory properties. In the present study, we investigated the role of astragaloside IV in the chemoresistance to cisplatin in NSCLC cells. Methods: We established astragaloside IV-suppressed NSCLC cell lines including A549, HCC827, and NCI-H1299 and evaluated their sensitivity to cisplatin in vitro. In addition, we examined the mRNA and protein levels of B7-H3 in response to cisplatin-based chemotherapy. Results: We showed that high doses of astragaloside IV (10, 20, 40 ng/ml) inhibited NSCLC cell growth, whereas low concentrations of astragaloside IV (1, 2.5, 5 ng/ml) had no obvious cytotoxicity on cell viability. Moreover, combined treatment with astragaloside IV significantly increased chemosensitivity to cisplatin in NSCLC cells. On the molecular level, astragaloside IV co-treatment significantly inhibited the mRNA and protein levels of B7-H3 in the presence of cisplatin. In addition, ectopic expression of B7-H3 diminished the sensitization role of astragaloside IV in cellular responses to cisplatin in NSCLC cells. Conclusion: These results demonstrate that astragaloside IV enhances chemosensitivity to cisplatin via inhibition of B7-H3 and that treatment with astragaloside IV and inhibition of B7-H3 serve as potential therapeutic approach for lung cancer patients.