bluuebunny/crossref_metadata_2025 huggingface dataset:
CD55 limits sensitivity to complement-dependent cytolysis triggered by heterologous expression of α-gal xenoantigen in colon tumor cells
Authors: Wu Yanxia , Wang Yaogeng , Qin Feng , Wang Zhu , Wang Yu , Yang Yajun , Zheng Hong , Wang Yanping
Published: April 2014

Engineering cancer cells to express heterologous antigen α-gal and induce the destruction of tumor cells depending on the complement cascade may be a promising strategy of tumor therapy. However, the feasibility and effect of using α-gal to induce colorectal adenocarcinoma cell line cytolysis is not yet known. In this study, we evaluated α-gal expression's ability to sensitize human colorectal adenocarcinoma cell lines to complement attack in cell lines LoVo, SW620, and Ls-174T. Nearly all α-gal-expressing LoVo and SW620 cells were killed by normal human serum (NHS), but α-gal-expressing Ls-174T cells showed no significant lysis. We analyzed the expression levels of membrane-bound complement regulatory proteins (mCRPs) on the three cell lines, and their protective role in α-gal-mediated activation of the complement. LoVo showed no expression of any of the three proteins. CD59 was strongly expressed by SW620 and Ls-174T. CD46 and CD55 varied between the two cell lines. CD46 on SW620 was only half the intensity of CD46 on Ls-174T. Ls-174T showed a notable expression of CD55, while expression of CD55 on SW620 was not detected. The sensitivity of Ls-174T expressing α-gal to NHS greatly increased following the downregulation of CD46 and CD55 with short hairpin RNA (shRNA). However, there is no increase in cell killing when CD59 expression was diminished. Our findings suggest that the use of α-gal as antigen to induce tumor cell killing may be a potential therapeutic strategy in colon cancer and that CD55 plays a primary role in conferring resistance to lysis.
Rat lungs show a biphasic formation of new alveoli during postnatal development
Authors: Tschanz Stefan A. , Salm Lilian A. , Roth-Kleiner Matthias , Barré Sebastien F. , Burri Peter H. , Schittny Johannes C.
Published: April 2014

Roughly 90% of the gas-exchange surface is formed by alveolarization of the lungs. To the best of our knowledge, the formation of new alveoli has been followed in rats only by means of morphological description or interpretation of semiquantitative data until now. Therefore, we estimated the number of alveoli in rat lungs between postnatal days 4 and 60 by unambiguously counting the alveolar openings. We observed a bulk formation of new alveoli between days 4 and 21 (17.4 times increase from 0.8 to 14.3 millions) and a second phase of continued alveolarization between days 21 and 60 (1.3 times increase to 19.3 million). The (number weighted) mean volume of the alveoli decreases during the phase of bulk alveolarization from ∼593,000 μm3at day 4 to ∼141,000 μm3at day 21, but increases again to ∼298,000 μm3at day 60. We conclude that the “bulk alveolarization” correlates with the mechanism of classical alveolarization (alveolarization before the microvascular maturation is completed) and that the “continued alveolarization” follows three proposed mechanisms of late alveolarization (alveolarization after microvascular maturation). The biphasic pattern is more evident for the increase in alveolar number than for the formation of new alveolar septa (estimated as the length of the free septal edge). Furthermore, a striking negative correlation between the estimated alveolar size and published data on retention of nanoparticles was detected.
Analysis of Product Sampling for New Product Diffusion Incorporating Multiple-Unit Ownership
Authors: Hu Zhineng , Pei Yurong , Xie Ruikun
Published: April 2014

Multiple-unit ownership of nondurable products is an important component of sales in many product categories. Based on the Bass model, this paper develops a new model considering the multiple-unit adoptions as a diffusion process under the influence of product sampling. Though the analysis aims to determine the optimal dynamic sampling effort for a firm and the results demonstrate that experience sampling can accelerate the diffusion process, the best time to send free samples is just before the product being launched. Multiple-unit purchasing behavior can increase sales to make more profit for a firm, and it needs more samples to make the product known much better. The local sensitivity analysis shows that the increase of both external coefficients and internal coefficients has a negative influence on the sampling level, but the internal influence on the subsequent multiple-unit adoptions has little significant influence on the sampling. Using the logistic regression along with linear regression, the global sensitivity analysis gives a whole analysis of the interaction of all factors, which manifests the external influence and multiunit purchase rate are two most important factors to influence the sampling level and net present value of the new product, and presents a two-stage method to determine the sampling level.
Provider Education about Glaucoma and Glaucoma Medications during Videotaped Medical Visits
Authors: Sleath Betsy , Blalock Susan J. , Carpenter Delesha M. , Muir Kelly W. , Sayner Robyn , Lawrence Scott , Giangiacomo Annette L. , Hartnett Mary Elizabeth , Tudor Gail , Goldsmith Jason , Robin Alan L.
Published: April 2014

Objective. The purpose of this study was to examine how patient, physician, and situational factors are associated with the extent to which providers educate patients about glaucoma and glaucoma medications, and which patient and provider characteristics are associated with whether providers educate patients about glaucoma and glaucoma medications.Methods. Patients with glaucoma who were newly prescribed or on glaucoma medications were recruited and a cross-sectional study was conducted at six ophthalmology clinics. Patients’ visits were videotape recorded and patients were interviewed after visits. Generalized estimating equations were used to analyze the data.Results. Two hundred and seventy-nine patients participated. Providers were significantly more likely to educate patients about glaucoma and glaucoma medications if they were newly prescribed glaucoma medications. Providers were significantly less likely to educate African American patients about glaucoma. Providers were significantly less likely to educate patients of lower health literacy about glaucoma medications.Conclusion. Eye care providers did not always educate patients about glaucoma or glaucoma medications.Practice Implications. Providers should consider educating more patients about what glaucoma is and how it is treated so that glaucoma patients can better understand their disease. Even if a patient has already been educated once, it is important to reinforce what has been taught before.
Dynamic Hip Screw for the Treatment of Femoral Neck Fractures: A Prospective Study with 96 Patients
Authors: Schwartsmann Carlos Roberto , Jacobus Lucas Senger , Spinelli Leandro de Freitas , Boschin Leonardo Carbonera , Gonçalves Ramiro Zilles , Yépez Anthony Kerbes , Barreto Rodrigo Py Gonçalves , Silva Marcelo Faria
Published: April 2014

Objectives. To study the correlation between avascular necrosis and the demographics, time elapsed from fracture to surgery, quality of reduction, Garden classification, and the position of the screw following use of the dynamic hip screw (DHS) in the treatment of subcapital neck fractures.Methods. A prospective study of 96 patients with subcapital neck fractures was carried out in a faculty hospital. Patients underwent surgery with closed reduction and internal fixation with DHS.Results. There were 58% male and 42% female patients, with a mean age of 53 years (+/−14). In terms of Garden classification, 60% were Garden IV, 26% were Garden III, and 14% were Garden II. Nonunion was observed in three cases (3%) and was treated with valgus intertrochanteric osteotomy, in all cases leading to successful healing. Avascular necrosis was observed in 16% of patients. The positioning of the screw into the femoral head showed a significant correlation with necrosis.Conclusions. The incidence of necrosis in patients under the age of 50 years is twice as high as that in older patients. Displacement is a predictive factor regarding osteonecrosis and is associated with a high and anterior position of the screw in the femoral head. Level II of evidence. Study Type: therapeutic study.
An Efficient Spectral Element Model with Electric DOFs for the Static and Dynamic Analysis of a Piezoelectric Bimorph
Authors: Dong Xingjian , Peng Zhike , Zhang Wenming , Hua HongXing , Meng Guang
Published: April 2014

An efficient spectral element (SE) model for static and dynamic analysis of a piezoelectric bimorph is proposed. It combines an equivalent single layer (ESL) model for the mechanical displacement field with a sublayer approximation for the electric potential. The 2D Gauss‐Lobatto‐Legendre (GLL) shape functions are used to discretize the displacements and then the governing equation of motion is derived following the standard SE method procedure. It is shown numerically that the present SE model can well predict both the global and local responses such as mechanical displacements, natural frequencies, and the electric potentials across the bimorph thickness. In the case of bimorph sensor application, it is revealed that the distribution of the induced electric potential across the thickness does not affect the global natural frequencies much. Furthermore, the effects of the order of Legendre polynomial and the mesh size on the convergence rate are investigated. Comparison of the present results for a bimorph sensor with those from 3D finite element (FE) simulations establishes that the present SE model is accurate, robust, and computationally efficient.
Comparison of Satellite and Ground-Based Phenology in China’s Temperate Monsoon Area
Authors: Wang Huanjiong , Dai Junhu , Ge Quansheng
Published: April 2014

Continuous satellite datasets are widely used in tracking vegetation responses to climate variability. Start of season (SOS), for example, can be derived using a number of methods from the time series of satellite reflectance data; however, various methods often produce different SOS measures which limit the application of satellite data in phenological studies. Therefore, we employed five methods to estimate SOS from the Advanced Very High Resolution Radiometer (AVHRR)/normalized difference vegetation index (NDVI) dataset. Subsequently, we compared the SOS with the ground-based first leaf date (FLD) of 12 deciduous broadleaved plant species at 12 sites of the Chinese Phenological Observation Network (CPON). The results show that the latitudinal patterns of five satellite-derived SOS measures are similar to each other but different from the pattern of ground phenology. For individual methods, the variability of SOS time series is significantly different from ground phenology except for HANTS, Polyfit, and Midpoint methods. The SOS calculated using the Midpoint method showed significant correlations with ground phenophases most frequently (in 47.1% of cases). Using the SOS derived from the Midpoint method, significantly earlier trends in SOS were detected in 50.7% of the natural vegetation area from 1982 to 2006.
Existence for Nonlinear Evolution Equations and Application to Degenerate Parabolic Equation
Authors: Su Ning , Zhang Li
Published: April 2014

We consider an abstract Cauchy problem for a doubly nonlinear evolution equation of the formd/dt𝒜u+ℬu∋ftinV′,t∈0, T, whereVis a real reflexive Banach space,𝒜andℬare maximal monotone operators (possibly multivalued) fromVto its dualV′. In view of some practical applications, we assume that𝒜andℬare subdifferentials. By using the back difference approximation, existence is established, and our proof relies on the continuity of𝒜and the coerciveness ofℬ. As an application, we give the existence for a nonlinear degenerate parabolic equation.
A New Noninterior Continuation Method for Solving a System of Equalities and Inequalities
Authors: Zhu Jianguang , Hao Binbin
Published: April 2014

By using slack variables and minimum function, we first reformulate the system of equalities and inequalities as a system of nonsmooth equations, and, using smoothing technique, we construct the smooth operator. A new noninterior continuation method is proposed to solve the system of smooth equations. It shows that any accumulation point of the iteration sequence generated by our algorithm is a solution of the system of equalities and inequalities. Some numerical experiments show the feasibility and efficiency of the algorithm.
Isolated Enteric Cyst in the Neck
Authors: Mahore Amit , Ramdasi Raghvendra , Popat Palak , Sankhe Shilpa , Tikeykar Vishakha
Published: April 2014

We report an extremely rare case of isolated enteric cyst in the neck region which was diagnosed on the histopathological examination. It was suspected to be duplication cyst on radiology. We have also evaluated the differential diagnosis and management issues.
Natural Filtrations of Infinite-Dimensional Modular Contact Superalgebras
Authors: Mu Qiang
Published: April 2014

The natural filtration of the infinite-dimensional contact superalgebra over an algebraic closed field of positive characteristic is proved to be invariant under automorphisms by characterizing ad-nilpotent elements and the subalgebras generated by certain ad-nilpotent elements. Moreover, we obtain an intrinsic characterization of contact superalgebras and a property of automorphisms of these Lie superalgebras.
Simple Hybrid Scaling-Free CORDIC Solution for FPGAs
Authors: Moroz Leonid , Nagayama Shinobu , Mykytiv Taras , Kirenko Ihor , Boretskyy Taras
Published: April 2014

COordinate Rotation DIgital Computer (CORDIC) is an effective method that is used in digital signal processing applications for computing various trigonometric, hyperbolic, linear, and transcendental functions. This paper presents the theoretical basis and practical implementation of circular (sine-cosine) CORDIC-based generator. Synthesis results of this generator based on Altera Stratix III FPGA (EP3SL340F1517C2) using Quartus II version 9.0 show that the proposed hybrid FPGA architecture significantly reduces latency (42% reduction) with a small area overhead, compared to the conventional version. The proposed algorithm has been simulated for sine and cosine function evaluation, and it has been verified that the accuracy is comparable with conventional algorithm.
Carbon Nanotubes: An Emerging Drug Carrier for Targeting Cancer Cells
Authors: Rastogi Vaibhav , Yadav Pragya , Bhattacharya Shiv Sankar , Mishra Arun Kumar , Verma Navneet , Verma Anurag , Pandit Jayanta Kumar
Published: April 2014

During recent years carbon nanotubes (CNTs) have been attracted by many researchers as a drug delivery carrier. CNTs are the third allotropic form of carbon-fullerenes which were rolled into cylindrical tubes. To be integrated into the biological systems, CNTs can be chemically modified or functionalised with therapeutically active molecules by forming stable covalent bonds or supramolecular assemblies based on noncovalent interactions. Owing to their high carrying capacity, biocompatibility, and specificity to cells, various cancer cells have been explored with CNTs for evaluation of pharmacokinetic parameters, cell viability, cytotoxicty, and drug delivery in tumor cells. This review attempts to highlight all aspects of CNTs which render them as an effective anticancer drug carrier and imaging agent. Also the potential application of CNT in targeting metastatic cancer cells by entrapping biomolecules and anticancer drugs has been covered in this review.
Wolfe Type Second Order Nondifferentiable Symmetric Duality in Multiobjective Programming over Cone with Generalized (K, F)-Convexity
Authors: Tripathy A. K.
Published: April 2014

A new class of second order (K, F) pseudoconvex function is introduced with example. A pair of Wolfe type second order nondifferentiable symmetric dual programs over arbitrary cones with square root term is formulated. The duality results are established under second order (K, F) pseudoconvexity assumption. Also a Wolfe type second order minimax mixed integer programming problem is formulated and the symmetric duality results are established under second order (K, F) pseudoconvexity assumption.
An Interval Type‐2 Fuzzy System with a Species‐Based Hybrid Algorithm for Nonlinear System Control Design
Authors: Li Chung-Ta , Lee Ching-Hung , Chang Feng-Yu , Lin Chih-Min
Published: April 2014

We propose a species‐based hybrid of the electromagnetism‐like mechanism (EM) and back‐propagation algorithms (SEMBP) for an interval type‐2 fuzzy neural system with asymmetric membership functions (AIT2FNS) design. The interval type‐2 asymmetric fuzzy membership functions (IT2 AFMFs) and the TSK‐type consequent part are adopted to implement the network structure in AIT2FNS. In addition, the type reduction procedure is integrated into an adaptive network structure to reduce computational complexity. Hence, the AIT2FNS can enhance the approximation accuracy effectively by using less fuzzy rules. The AIT2FNS is trained by the SEMBP algorithm, which contains the steps of uniform initialization, species determination, local search, total force calculation, movement, and evaluation. It combines the advantages of EM and back‐propagation (BP) algorithms to attain a faster convergence and a lower computational complexity. The proposed SEMBP algorithm adopts the uniform method (which evenly scatters solution agents over the feasible solution region) and the species technique to improve the algorithm’s ability to find the global optimum. Finally, two illustrative examples of nonlinear systems control are presented to demonstrate the performance and the effectiveness of the proposed AIT2FNS with the SEMBP algorithm.
Evaluating Cytotoxicity of Hyaluronate Targeted Solid Lipid Nanoparticles of Etoposide on SK-OV-3 Cells
Authors: Mohammadi Ghalaei Parviz , Varshosaz Jaleh , Sadeghi Aliabadi Hojatollah
Published: April 2014

The epithelial ovarian carcinoma is one of the most fatal gynecological cancers. Etoposide is used in treating platinum-resistant ovarian cancer. Sodium hyaluronate is a substance that binds to the CD44 receptors overexpressed in SK-OV-3 cells of epithelial ovarian carcinoma. The aim of the present work was to study the cytotoxicity effect of hyaluronate targeted solid lipid nanoparticles (SLNs) of etoposide on SK-OV-3 cells. The cytotoxicity of the targeted and nontargeted SLNs of etoposide was compared to free drug on the SK-OV-3 cells by MTT assay method. The cellular uptake of the targeted and nontargeted nanoparticles containing sodium fluorescein was also studied. The difference of cell vitality between nontargeted nanoparticles and also targeted nanoparticles with free drug was significant. Targeted nanoparticles also caused more toxicity than nontargeted nanoparticles (P<0.05). After 4 hours of incubating, the fluorescence was remarkably higher in the cells treated by targeted SLNs rather than nontargeted ones, and there was no observable fluorescence in cells incubated with pure sodium fluorescein. Hyaluronate targeted SLNs containing etoposide increased the cytotoxicity of etoposide on SK-OV-3 cells which may be a worthwhile potential method for reducing the prescribed dose and systemic side effects of this drug in epithelial ovarian carcinoma.
Effect of Pregabalin and Dexamethasone on Postoperative Analgesia after Septoplasty
Authors: Demirhan Abdullah , Akkaya Akcan , Tekelioglu Umit Yasar , Apuhan Tayfun , Bilgi Murat , Yurttas Veysel , Bayir Hakan , Yildiz Isa , Gok Uzeyir , Kocoglu Hasan
Published: April 2014

Objectives. The aim of this study was to explore effect of a combination of pregabalin and dexamethasone on pain control after septoplasty operations. Methods. In this study, 90 patients who were scheduled for septoplasty under general anesthesia were randomly assigned into groups that received either placebo (Group C), pregabalin (Group P), or pregabalin and dexamethasone (Group PD). Preoperatively, patients received either pregabalin 300 mg one hour before surgery, dexamethasone 8 mg intravenously during induction, or placebo according to their allocation. Postoperative pain treatment included tramadol and diclofenac sodium 30 minutes before the end of the operation. Numeric rating scale (NRS) for pain assessment, side effects, and consumption of tramadol, pethidine, and ondansetron were recorded. Results. The median NRS score at the postoperative 0 and the 2nd h was significantly higher in Group C than in Group P and Group PD ( for both). The 24 h tramadol and pethidine, consumptions were significantly reduced in Groups P and PD compared to Group C (). The incidence of blurred vision was significantly higher in Group PD compared to Group C within both 0–2 h and 0–24 h periods (, resp.). Conclusions. We conclude that administration of 300 mg pregabalin preoperatively may be an adequate choice for pain control after septoplasty. Addition of dexamethasone does not significantly reduce pain in these patients.
A Prospective Study of Plasma Selenoprotein P and Lung Cancer Risk among Low-Income Adults
Authors: Epplein Meira , Burk Raymond F. , Cai Qiuyin , Hargreaves Margaret K. , Blot William J.
Published: April 2014

Background: Epidemiologic studies have shown increased risks of lung cancer among adults with low blood levels of selenium, although evidence is inconsistent. In the United States, the incidence of lung cancer is higher and mean serum selenium levels lower among Blacks than Whites, but prior studies have not assessed the selenium–lung cancer association among Blacks.

Methods: From the prospective Southern Community Cohort Study, we identified 372 participants who provided blood samples and subsequently developed lung cancer. Selenoprotein P (SEPP1), the most abundant selenoprotein in plasma and a biomarker of selenium nutriture, was measured in the plasma from these individuals and from 716 matched controls.

Results: Mean SEPP1 levels were significantly (P < 0.0001) lower among Blacks than Whites. Conditional logistic regression models accounting for smoking revealed a significant trend of increasing OR of lung cancer with decreasing SEPP1 tertiles among Blacks (P = 0.0006) but not Whites (P = 0.69; Pinteraction = 0.10). The ORs and corresponding 95% confidence intervals of lung cancer risk among those with lowest versus highest tertile levels of SEPP1 were 2.4 (1.5–3.0) among Blacks and 1.1 (0.6–2.1) among Whites.

Conclusions: Among a mostly low-income population in the southeastern United States, lower levels of SEPP1 were associated with an increasing risk of lung cancer among Blacks but not Whites.

Impact: The combined findings of higher prevalence of low selenium status and higher lung cancer risk associated with low status raise the possibility that selenium deficiency may contribute to observed racial disparities in lung cancer incidence. Cancer Epidemiol Biomarkers Prev; 23(7); 1238–44. ©2014 AACR.
Cell Phone Use and Parotid Salivary Gland Alterations: No Molecular Evidence
Authors: de Souza Fabrício T.A. , Correia-Silva Jeane F. , Ferreira Efigênia F. , Siqueira Elisa C. , Duarte Alessandra P. , Gomez Marcus Vinícius , Gomez Ricardo S. , Gomes Carolina C.
Published: April 2014

Background: The association between cell phone use and the development of parotid tumors is controversial. Because there is unequivocal evidence that the microenvironment is important for tumor formation, we investigated in the parotid glands whether cell phone use alters the expression of gene products related to cellular stress.

Methods: We used the saliva produced by the parotid glands of 62 individuals to assess molecular alterations compatible with cellular stress, comparing the saliva from the gland exposed to cell phone radiation (ipsilateral) to the saliva from the opposite, unexposed parotid gland (contralateral) of each individual. We compared salivary flow, total protein concentration, p53, p21, reactive oxygen species (ROS), and salivary levels of glutathione (GSH), heat shock proteins 27 and 70, and IgA between the ipsilateral and contralateral parotids.

Results: No difference was found for any of these parameters, even when grouping individuals by period of cell phone use in years or by monthly average calls in minutes.

Conclusion and Impact: We provide molecular evidence that the exposure of parotid glands to cell phone use does not alter parotid salivary flow, protein concentration, or levels of proteins of genes that are directly or indirectly affected by heat-induced cellular stress. Cancer Epidemiol Biomarkers Prev; 23(7); 1428–31. ©2014 AACR.
Combined PET/MRI Improves Diagnostic Accuracy in Patients with Prostate Cancer: A Prospective Diagnostic Trial
Authors: Hartenbach Markus , Hartenbach Sabrina , Bechtloff Winfried , Danz Burkhardt , Kraft Klaus , Klemenz Burkhard , Sparwasser Christoph , Hacker Marcus
Published: April 2014

Purpose: The pretherapeutic assessment of prostate cancer is challenging and still holds the risk of over- or undertreatment. This prospective trial investigates positron emission tomography (PET) with [18F]fluoroethylcholine (FEC) combined with endorectal magnetic resonance imaging (MRI) for the assessment of primary prostate cancer.

Experimental design: Patients with prostate cancer based on needle biopsy findings, scheduled for radical prostatectomy, were assessed by FEC-PET and MRI in identical positioning. After prostatectomy, imaging results were compared with histologic whole-mount sections, and the PET/MRI lesion-based semiquantitative FEC uptake was compared with biopsy Gleason scores and postoperative histology.

Results: PET/MRI showed a patient-based sensitivity of 95% (36/38; 95% confidence interval (CI), 82%–99%). The analysis of 128 prostate lesions demonstrated a sensitivity/specificity/positive predictive value/negative predictive value/accuracy of 67%/35%/59%/44%/54% (P = 0.8295) for MRI and 85%/45%/68%/69%/68% (P = 0.0021) for PET, which increased to 84%/80%/85%/78%/82% (P < 0.0001) by combined FEC-PET/MRI in lesions >5 mm (n = 98). For lesions in patients with Gleason >6 tumors (n = 43), MRI and PET achieved 73%/31%/71%/33%/60% (P = 1.0000) and 90%/62%/84%/73%/81% (P = 0.0010), which were improved to 87%/92%/96%/75%/88% (P < 0.0001) by combined PET/MRI. Applying semiquantitative PET analysis, carcinomas with Gleason scores >6 were distinguished from those with Gleason ≤6 with a specificity of 90% and a positive predictive value of 83% (P = 0.0011; needle biopsy 71%/60%, P = 0.1071).

Conclusions: In a prospective diagnostic trial setting, combined FEC-PET/MRI achieved very high sensitivity in the detection of the dominant malignant lesion of the prostate, and markedly improved upon PET or MRI alone. Noninvasive Gleason score assessment was more precise than needle biopsy in this patient cohort. Hence, FEC-PET/MRI merits further investigation in trials of randomized, multiarm design. Clin Cancer Res; 20(12); 3244–53. ©2014 AACR.
Regorafenib Inhibits Colorectal Tumor Growth through PUMA-Mediated Apoptosis
Authors: Chen Dongshi , Wei Liang , Yu Jian , Zhang Lin
Published: April 2014

Purpose: Regorafenib, a multikinase inhibitor targeting the Ras/Raf/MEK/ERK pathway, has recently been approved for the treatment of metastatic colorectal cancer. However, the mechanisms of action of regorafenib in colorectal cancer cells have been unclear. We investigated how regorafenib suppresses colorectal cancer cell growth and potentiates effects of other chemotherapeutic drugs.

Experimental Design: We determined whether and how regorafenib induces the expression of PUMA, a p53 target and a critical mediator of apoptosis in colorectal cancer cells. We also investigated whether PUMA is necessary for the killing and chemosensitization effects of regorafenib in colorectal cancer cells. Furthermore, xenograft tumors were used to test if PUMA mediates the in vivo antitumor, antiangiogenic, and chemosensitization effects of regorafenib.

Results: We found that regorafenib treatment induces PUMA in colorectal cancer cells irrespective of p53 status through the NF-κB pathway following ERK inhibition and glycogen synthase kinase 3β activation. Upregulation of PUMA is correlated with apoptosis induction in different colorectal cancer cell lines. PUMA is necessary for regorafenib-induced apoptosis in colorectal cancer cells. Chemosensitization by regorafenib is mediated by enhanced PUMA induction through different pathways. Furthermore, deficiency in PUMA abrogates the in vivo antitumor, antiangiogenic, and chemosensitization effects of regorafenib.

Conclusions: Our results demonstrate a key role of PUMA in mediating the anticancer effects of regorafenib in colorectal cancer cells. They suggest that PUMA induction can be used as an indicator of regorafenib sensitivity, and also provide a rationale for manipulating the apoptotic machinery to improve the therapeutic efficacy of regorafenib and other targeted drugs. Clin Cancer Res; 20(13); 3472–84. ©2014 AACR.
Tissue Plasminogen Activator Promotes Postischemic Neutrophil Recruitment via Its Proteolytic and Nonproteolytic Properties
Authors: Uhl Bernd , Zuchtriegel Gabriele , Puhr-Westerheide Daniel , Praetner Marc , Rehberg Markus , Fabritius Matthias , Hessenauer Maximilian , Holzer Martin , Khandoga Andrej , Fürst Robert , Zahler Stefan , Krombach Fritz , Reichel Christoph A.
Published: April 2014

Objective—

Neutrophil infiltration of the postischemic tissue considerably contributes to organ dysfunction on ischemia/reperfusion injury. Beyond its established role in fibrinolysis, tissue-type plasminogen activator (tPA) has recently been implicated in nonfibrinolytic processes. The role of this serine protease in the recruitment process of neutrophils remains largely obscure.

Approach and Results—

Using in vivo microscopy on the postischemic cremaster muscle, neutrophil recruitment and microvascular leakage, but not fibrinogen deposition at the vessel wall, were significantly diminished in tPA
−/−
mice. Using cell transfer techniques, leukocyte and nonleukocyte tPA were found to mediate ischemia/reperfusion-elicited neutrophil responses. Intrascrotal but not intra-arterial application of recombinant tPA induced a dose-dependent increase in the recruitment of neutrophils, which was significantly higher compared with stimulation with a tPA mutant lacking catalytic activity. Whereas tPA-dependent transmigration of neutrophils was selectively reduced on the inhibition of plasmin or gelatinases, neutrophil intravascular adherence was significantly diminished on the blockade of mast cell activation or lipid mediator synthesis. Moreover, stimulation with tPA caused a significant elevation in the leakage of fluorescein isothiocyanate dextran to the perivascular tissue, which was completely abolished on neutrophil depletion. In vitro, tPA-elicited macromolecular leakage of endothelial cell layers was abrogated on the inhibition of its proteolytic activity.

Conclusions—

Endogenously released tPA promotes neutrophil transmigration to reperfused tissue via proteolytic activation of plasmin and gelatinases. As a consequence, tPA on transmigrating neutrophils disrupts endothelial junctions allowing circulating tPA to extravasate to the perivascular tissue, which, in turn, amplifies neutrophil recruitment through the activation of mast cells and release of lipid mediators.
Assessment of the Vasodepressor Reflex in Carotid Sinus Syndrome
Authors: Solari Diana , Maggi Roberto , Oddone Daniele , Solano Alberto , Croci Francesco , Donateo Paolo , Wieling Wouter , Brignole Michele
Published: April 2014

Background—

Assessment of the vasodepressor reflex in carotid sinus syndrome is influenced by the method of execution of the carotid sinus massage and the coexistence of the cardioinhibitory reflex.

Methods and Results—

Carotid sinus massage reproduced spontaneous symptoms in 164 patients in the presence of hypotension or bradycardia (method of symptoms). When an asystolic pause was induced, the vasodepressor reflex was reassessed after suppression of the asystolic reflex by means of 0.02 mg/kg IV atropine. An isolated vasodepressor form was found in 32 (20%) patients, who had lowest systolic blood pressure (SBP) of 65±15 mm Hg. Of these, only 21 (66%) patients had an SBP fall ≥50 mm Hg, which is the universally accepted cut-off value for the diagnosis of the vasodepressor form. Conversely, a lowest SBP value of ≤85 mm Hg (corresponding to the fifth percentile) detected 97% of vasodepressor patients, but was also present in 84% of the 132 patients with an asystolic reflex. These latter patients had both asystole ≥3 s (mean 7.6±2.2 s) and SBP fall to 63±22 mm Hg: in 46 (28%) patients, symptoms persisted after atropine (mixed form), in the remaining 86 (52%) patients, symptoms did not (cardioinhibitory form) persist.

Conclusions—

The current definition of ≥50 mm Hg SBP fall failed to identify one third of patients with isolated vasodepressor form. A cut-off value of symptomatic SBP of ≤85 mm Hg seems more appropriate, but it is unable to identify cardioinhibitory forms. In asystolic forms, atropine testing is able to distinguish a cardioinhibitory form from a mixed form.
Sodium Channelopathy Underlying Familial Sick Sinus Syndrome With Early Onset and Predominantly Male Characteristics
Authors: Abe Keisuke , Machida Taku , Sumitomo Naokata , Yamamoto Hirokazu , Ohkubo Kimie , Watanabe Ichiro , Makiyama Takeru , Fukae Satoki , Kohno Masaki , Harrell Daniel T. , Ishikawa Taisuke , Tsuji Yukiomi , Nogami Akihiko , Watabe Taichi , Oginosawa Yasushi , Abe Haruhiko , Maemura Koji , Motomura Hideki , Makita Naomasa
Published: April 2014

Background—

Sick sinus syndrome (SSS) is a common arrhythmia often associated with aging or organic heart diseases but may also occur in a familial form with a variable mode of inheritance. Despite the identification of causative genes, including cardiac Na channel (
SCN5A
), the pathogenesis and molecular epidemiology of familial SSS remain undetermined primarily because of its rarity.

Methods and Results—

We genetically screened 48 members of 15 SSS families for mutations in several candidate genes and determined the functional properties of mutant Na channels using whole-cell patch clamping. We identified 6
SCN5A
mutations including a compound heterozygous mutation. Heterologously expressed mutant Na channels showed loss-of-function properties of reduced or no Na current density in conjunction with gating modulations. Among 19 family members with
SCN5A
mutations, QT prolongation and Brugada syndrome were associated in 4 and 2 individuals, respectively. Age of onset in probands carrying
SCN5A
mutations was significantly less (mean±SE, 12.4±4.6 years; n=5) than in
SCN5A
-negative probands (47.0±4.6 years; n=10;
P
<0.001) or nonfamilial SSS (74.3±0.4 years; n=538;
P
<0.001). Meta-analysis of SSS probands carrying
SCN5A
mutations (n=29) indicated profound male predominance (79.3%) resembling Brugada syndrome but with a considerably earlier age of onset (20.9±3.4 years).

Conclusions—

The notable pathophysiological overlap between familial SSS and Na channelopathy indicates that familial SSS with
SCN5A
mutations may represent a subset of cardiac Na channelopathy with strong male predominance and early clinical manifestations.
Cytochrome P450 Gene Variants, Race, and Mortality Among Clopidogrel-Treated Patients After Acute Myocardial Infarction
Authors: Cresci Sharon , Depta Jeremiah P. , Lenzini Petra A. , Li Allie Y. , Lanfear David E. , Province Michael A. , Spertus John A. , Bach Richard G.
Published: April 2014

Background—

Clopidogrel is recommended after acute myocardial infarction but has variable efficacy and safety, in part related to the effect of cytochrome P450 (
CYP
) polymorphisms on its metabolism. The effect of
CYP
polymorphisms on cardiovascular events among clopidogrel-treated patients after acute myocardial infarction remains controversial, and no studies to date have investigated the association of
CYP
variants with outcomes in black patients.

Methods and Results—

Subjects (2732: 2062 whites; 670 blacks) hospitalized with acute myocardial infarction enrolled in the prospective, multicenter TRIUMPH study were genotyped for
CYP
polymorphisms. The majority of whites (79%) and blacks (64.4%) were discharged on clopidogrel. Among whites, carriers of the loss-of-function
CYP2C19
*2 allele had significantly increased 1-year mortality (adjusted hazards ratio [HR]: 1.70; confidence interval [CI]: 1.01–2.86;
P
=0.046) and a trend toward increased rate of recurrent MI (adjusted HR: 2.10; CI: 0.95–4.63;
P
=0.066). Among blacks, increased 1-year mortality was associated with the gain-of-function
CYP2C19
*17 allele (adjusted HR for *1/*17 versus *1/*1: 2.02; CI: 0.92–4.44; *17/*17 versus *1/*1: 8.97; CI: 3.34–24.10;
P
<0.0001) and the
CYP1A2
*1C allele (adjusted HR for *1/*1C versus *1/*1: 1.89; CI: 0.85–4.22; *1C/*1C versus *1/*1: 4.96; CI: 1.69–14.56;
P
=0.014). Bleeding events were significantly more common among black carriers of
CYP2C19
*17 or
CYP1A2
*1C.

Conclusions—

Both loss-of-function and gain-of-function
CYP
polymorphisms affecting clopidogrel metabolism are associated with increased mortality among clopidogrel-treated patients after acute myocardial infarction; the specific polymorphism and the putative mechanism vary according to race.
Metabolomic Analysis of Pressure-Overloaded and Infarcted Mouse Hearts
Authors: Sansbury Brian E. , DeMartino Angelica M. , Xie Zhengzhi , Brooks Alan C. , Brainard Robert E. , Watson Lewis J. , DeFilippis Andrew P. , Cummins Timothy D. , Harbeson Matthew A. , Brittian Kenneth R. , Prabhu Sumanth D. , Bhatnagar Aruni , Jones Steven P. , Hill Bradford G.
Published: April 2014

Background—

Cardiac hypertrophy and heart failure are associated with metabolic dysregulation and a state of chronic energy deficiency. Although several disparate changes in individual metabolic pathways have been described, there has been no global assessment of metabolomic changes in hypertrophic and failing hearts in vivo. Hence, we investigated the impact of pressure overload and infarction on myocardial metabolism.

Methods and Results—

Male C57BL/6J mice were subjected to transverse aortic constriction or permanent coronary occlusion (myocardial infarction [MI]). A combination of LC/MS/MS and GC/MS techniques was used to measure 288 metabolites in these hearts. Both transverse aortic constriction and MI were associated with profound changes in myocardial metabolism affecting up to 40% of all metabolites measured. Prominent changes in branched-chain amino acids were observed after 1 week of transverse aortic constriction and 5 days after MI. Changes in branched-chain amino acids after MI were associated with myocardial insulin resistance. Longer duration of transverse aortic constriction and MI led to a decrease in purines, acylcarnitines, fatty acids, and several lysolipid and sphingolipid species but a marked increase in pyrimidines as well as ascorbate, heme, and other indices of oxidative stress. Cardiac remodeling and contractile dysfunction in hypertrophied hearts were associated with large increases in myocardial, but not plasma, levels of the polyamines putrescine and spermidine as well as the collagen breakdown product prolylhydroxyproline.

Conclusions—

These findings reveal extensive metabolic remodeling common to both hypertrophic and failing hearts that are indicative of extracellular matrix remodeling, insulin resistance and perturbations in amino acid, and lipid and nucleotide metabolism.
Role of the Autonomic Nervous System in Atrial Fibrillation
Authors: Chen Peng-Sheng , Chen Lan S. , Fishbein Michael C. , Lin Shien-Fong , Nattel Stanley
Published: April 2014

Autonomic nervous system activation can induce significant and heterogeneous changes of atrial electrophysiology and induce atrial tachyarrhythmias, including atrial tachycardia and atrial fibrillation (AF). The importance of the autonomic nervous system in atrial arrhythmogenesis is also supported by circadian variation in the incidence of symptomatic AF in humans. Methods that reduce autonomic innervation or outflow have been shown to reduce the incidence of spontaneous or induced atrial arrhythmias, suggesting that neuromodulation may be helpful in controlling AF. In this review, we focus on the relationship between the autonomic nervous system and the pathophysiology of AF and the potential benefit and limitations of neuromodulation in the management of this arrhythmia. We conclude that autonomic nerve activity plays an important role in the initiation and maintenance of AF, and modulating autonomic nerve function may contribute to AF control. Potential therapeutic applications include ganglionated plexus ablation, renal sympathetic denervation, cervical vagal nerve stimulation, baroreflex stimulation, cutaneous stimulation, novel drug approaches, and biological therapies. Although the role of the autonomic nervous system has long been recognized, new science and new technologies promise exciting prospects for the future.
Rivaroxaban for Stroke Prevention in East Asian Patients From the ROCKET AF Trial
Authors: Wong Ka Sing Lawrence , Hu Dai Yi , Oomman Abraham , Tan Ru-San , Patel Manesh R. , Singer Daniel E. , Breithardt Günter , Mahaffey Kenneth W. , Becker Richard C. , Califf Robert , Fox Keith A.A. , Berkowitz Scott D. , Hacke Werner , Hankey Graeme J.
Published: April 2014

Background and Purpose—

In Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial, rivaroxaban was noninferior to dose-adjusted warfarin in preventing stroke or systemic embolism among patients with nonvalvular atrial fibrillation at moderate to high stroke risk. Because of differences in patient demographics, epidemiology, and stroke risk management in East Asia, outcomes and relative effects of rivaroxaban versus warfarin were assessed to determine consistency among East Asians versus other ROCKET AF participants.

Methods—

Baseline demographics and interaction of treatment effects of rivaroxaban and warfarin among patients within East Asia and outside were assessed.

Results—

A total of 932 (6.5%) ROCKET AF participants resided in East Asia. At baseline, East Asians had lower weight, creatinine clearance, and prior vitamin K antagonist use; higher prevalence of prior stroke; and less congestive heart failure and prior myocardial infarction than other participants. Despite higher absolute event rates for efficacy and safety outcomes in East Asians, the relative efficacy of rivaroxaban (20 mg once daily; 15 mg once daily for creatinine clearance of 30–49 mL/min) versus warfarin with respect to the primary efficacy end point (stroke/systemic embolism) was consistent among East Asians and non–East Asians (interaction
P
=0.666). Relative event rates for the major or nonmajor clinically relevant bleeding in patients treated with rivaroxaban and warfarin were consistent among East Asians and non–East Asians (interaction
P
=0.867).

Conclusions—

Observed relative efficacy and safety of rivaroxaban versus warfarin were similar among patients within and outside East Asia. Rivaroxaban, 20 mg once daily, is an alternative to warfarin for stroke prevention in East Asians with nonvalvular atrial fibrillation.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00123456.
Dog at My Feet: A Moment of Identity Construction within Dissertation Acknowledgements
Authors: Billany Ruth
Published: April 2014

Abstract

Human-animal studies (has) is a legitimate and multidisciplinary academic endeavor. In the last three decades, there has been a proliferation of articles revealing multiple ways of knowing about the human-animal relationship. This paper, informed by social psychological theories, turns the mirror upon new researchers as they emerge as professional selves into academia. Post-graduate students engage multiple and sometimes contradicting identities throughout their candidatures. The unit of analysis is the dissertation acknowledgement (da) at both a structural and functional level. The das have recently become objects of serious empirical investigation as linguistic choice promotes a situated academic, cultural, and social identity in a moment of time. This paper examines the generic structure and purpose of 104 das, with a particular focus on the student-writer’s identity with relationship to nonhuman animals in their lives. Fourteen sub-themes are subsumed into thanking, reflecting, and announcing moves. A case is made that the study of das is a potentially fecund research area for a unique moment of identity construction.
Not Coming to Terms: Nonhuman Animals and the Edge of Theory
Authors: Prade Juliane
Published: April 2014

Abstract

In the emerging field of animal studies, criticism turns to questions of ethics and animal rights by reading representations of nonhuman animals in philosophy and literature. A rhetoric of coming to terms often shapes such readings and points to a lack of satisfactory answers to two questions: why read nonhuman animals, and why now? These questions are crucial to animal studies but can only be answered by understanding this critical approach as an element of the anthropological discourse, fundamental to philosophy. Examining Aristotle’s and Heidegger’s approaches to thinking about the human-animal relation, it seems that the interest in reading how animals are presented in philosophy is not in coming to definitive terms with this relation or in correcting earlier theories. Rather, it appears to lie in reading the concept of the Animal as marking a limit of terminological language, and thus of theory. The Animal marks the point at which philosophy touches on poetry and withdraws. Criticism is concerned with animals now because the concept of “the animals” keeps casting doubt on theoretical conceptions of the Human and of human language.
What Happened to the Internet? Scientific Communities in Three Low-income Areas, 2000-2010
Authors: Shrum Wesley , Palackal Antony , Dzorgbo Dan-Bright , Mbatia Paul , Schafer Mark , Miller Paige
Published: April 2014

Abstract

This ten year study suggests that the digital divide in connectivity may have largely closed for the scientific community in parts of the world that were previously unconnected. Almost a decade ago Ynalvezet al. (2005) examined the diffusion of information and communication technologies (icts) in the knowledge production sectors of three developing areas, using data collected at the turn of the millennium. We supplement this data set with a similar survey ten years later. Our analysis addresses the extent to which research communities in three low-income areas (Kenya, Ghana, and Kerala) now have access toicts, providing the first longitudinal data on changes in access to computers, email, and the Internet. In contrast to 2000, where the majority of scientists viewed themselves as users of email but with shared and irregular access to computers and the Internet—access to technology has become almost universal, though significant regional differences remain.
The Korean Wave Hallyu in Looking at Escapism in Peruvian Society
Authors: Ko Nusta Carranza , Kim Jeong-Nam , No Song I. , Simoes Ronald Gobbi
Published: April 2014

Abstract

Overcoming geographic, cultural, and linguistic differences, the second phase of the Korean wave Hallyu made its mark in Latin America. From the results of the field research conducted in two Latin American countries Brazil and Peru during the summer of 2012, this study examines the effects of the second wave of Hallyu on Peruvian society. In doing so, it regards the demographics, education level, and socio-economic status of the Hallyu consumer groups that reflects the situation of inequality and escapism embedded in Peruvian society. The continuous access to a different culture, distinct from that of one’s own reality through a virtual environment of cyberspace may be a reflection of the individual’s own awareness of despair in the reality in which they find themselves, characterized by inequality and a cyclical nature of class differences.