bluuebunny/crossref_metadata_2025 huggingface dataset:
Establishing past environmental conditions and tracking long-term environmental change in the Canadian Maritime provinces using lake sediments
Authors: Korosi Jennifer B. , Ginn Brian K. , Cumming Brian F. , Smol John P.
Published: January 2013

Freshwater lakes in the Canadian Maritime provinces have been detrimentally influenced by multiple, often synergistic, anthropogenically-sourced environmental stressors. These include surface-water acidification (and a subsequent decrease in calcium loading to lakes); increased nutrient inputs; watershed development; invasive species; and climate change. While detailed studies of these stressors are often hindered by a lack of predisturbance monitoring information; in many cases, these missing data can be determined using paleolimnological techniques, along with inferences on the full extent of environmental change (and natural variability), the timing of changes, and linkages to probable causes for change. As freshwater resources are important for fisheries, agriculture, municipal drinking water, and recreational activities, among others, understanding long-term ecological changes in response to anthropogenic stressors is critical. To assess the impacts of the major water-quality issues facing freshwater resources in this ecologically significant region, a large number of paleolimnological studies have recently been conducted in Nova Scotia and southern New Brunswick. These studies showed that several lakes in southwestern Nova Scotia, especially those in Kejimkujik National Park, have undergone surface-water acidification (mean decline of 0.5 pH units) in response to local-source SO2emissions and the long-range transport of airborne pollutants. There has been no measureable chemical or biological recovery since emission restrictions were enacted. Lakewater calcium (Ca) decline, a recently recognized environmental stressor that is inextricably linked to acidification, has negatively affected the keystone zooplankter Daphnia in at least two lakes in Nova Scotia (and likely more), with critical implications for aquatic food webs. A consistent pattern of increasing planktonic diatoms and scaled chrysophytes was observed in lakes across Nova Scotia and New Brunswick, suggesting that the strength and duration of lake thermal stratification has increased since pre-industrial times in response to warming temperatures (∼1.5 °C since 1870). These include three lakes near Bridgewater, Nova Scotia, that are among the last known habitat for critically endangered Atlantic whitefish (Coregonus huntsmani). Overall, these studies suggest that aquatic ecosystems in the Maritime Provinces are being affected by multiple anthropogenic stressors and paleolimnology can be effective for inferring the ecological implications of these stressors.
APPROXIMATING THE SPANNING k-TREE FOREST PROBLEM
Authors: LIAO CHUNG-SHOU , ZHANG LOUXIN
Published: January 2013

The spanning star forest problem is an interesting algorithmic problem in combinatorial optimization and finds different applications. We generalize it into the spanning k-tree forest problem, which is to find a maximum spanning forest in which each tree component has a central vertex and other vertices in the component have distance at most k away from the central vertex. We show that this new problem can be approximated with ratio [Formula: see text] in polynomial time for both undirected and directed graphs. In the weighted distance model, a ½-approximation algorithm is presented for it.
A NOVEL DRIVING STRATEGY FOR DYNAMIC SIMULATION OF HOISTING ROPE WITH TIME-VARYING LENGTH
Authors: WANG JINJIE , CAO GUOHUA , WANG YANDONG , WU RONGHUA
Published: January 2013

A simulation method for investigating the vibration behavior of hoisting rope with time-varying length is improved. By previously creating markers in the MSC.ADAMS software package, the parametric model of the rope wound along helix is established based on the concentrated-mass theory with multi-degree of freedom (multi-DOF). A novel driving strategy, cooperating fixed joints with angle sensors under the control of driving script, is proposed to substitute conventional contact force. Researching on the hoisting rope in the sinking winch mechanism, an equivalent discretization model is obtained with complicated boundary conditions considered. The differential equations of motion of the hoisting system are formulated employing Lagrange's equation and numerically solved using Runge–Kutta method. The simulation indicates that the horizontal swing is decreased in principle and the simulation with 800 discrete ropes is not performed more than 61 min. Therefore, this feasible strategy could not only guarantee the accuracy but also promote simulation efficiency and stability. The motion curves exported from ADAMS simulation coincide with one in numerical simulation, which validates both the numerical model and the driving strategy.
Lymphotoxin-α is a novel adiponectin expression suppressor following myocardial ischemia/reperfusion
Authors: Lau Wayne Bond , Zhang Yanqing , Zhao Jianli , Liu Baojiang , Wang Xiaoliang , Yuan Yuexing , Christopher Theodore A. , Lopez Bernard , Gao Erhe , Koch Walter J. , Ma Xin L. , Wang Yajing
Published: January 2013

Recent clinical observations demonstrate adiponectin (APN), an adipocytokine with potent cardioprotective actions, is significantly reduced following myocardial ischemia/reperfusion (MI/R). However, mechanisms responsible for MI/R-induced hypoadiponectinemia remain incompletely understood. Adult male mice were subjected to 30-min MI followed by varying reperfusion periods. Adipocyte APN mRNA and protein expression and plasma APN and TNFα concentrations were determined. APN expression/production began to decline 3 h after reperfusion (reaching nadir 12 h after reperfusion), returning to control levels 7 days after reperfusion. Plasma TNFα levels began to increase 1 h after reperfusion, peaking at 3 h and returning to control levels 24 h after reperfusion. TNFα knockout significantly increased plasma APN levels 12 h after reperfusion but failed to improve APN expression/production 72 h after reperfusion. In contrast, TNF receptor-1 (TNFR1) knockout significantly restored APN expression 12 and 72 h after reperfusion, suggesting that other TNFR1 binding cytokines contribute to MI/R-induced APN suppression. Among many cytokines increased after MI/R, lymphotoxin-α (LTα) was the only cytokine remaining elevated 24–72 h after reperfusion. LTα knockout did not augment APN levels 12 h post-reperfusion, but did so by 72 h. Finally, in vitro treatment of adipocytes with TNFα and LTα at concentrations seen in MI/R plasma additively inhibited APN expression/production in TNFR1-dependent fashion. Our study demonstrates for the first time that LTα is a novel suppressor of APN expression and contributes to the sustained hypoadiponectinemia following MI/R. Combining anti-TNFα with anti-LTα strategies may achieve the best effects restoring APN in MI/R patients.
MicroRNA 299-3p modulates replicative senescence in endothelial cells
Authors: Jong Hui-Lan , Mustafa Mohd Rais , Vanhoutte Paul M. , AbuBakar Sazaly , Wong Pooi-Fong
Published: January 2013

MicroRNAs (miRNAs) regulate various cellular processes. While several genes associated with replicative senescence have been described in endothelial cells, miRNAs that regulate these genes remain largely unknown. The present study was designed to identify miRNAs associated with replicative senescence and their target genes in human umbilical vein endothelial cells (HUVECs). An integrated miRNA and gene profiling approach revealed that hsa-miR-299-3p is upregulated in senescent HUVECs compared with the young cells, and one of its target genes could be IGF1. IGF1 was upregulated in senescent compared with young HUVECs, and knockdown of hsa-miR-299-3p dose-dependently increased the mRNA expression of IGF1, more significantly observed in the presenescent cells ( passage 19) compared with the senescent cells ( passage 25). Knockdown of hsa-miR-299-3p also resulted in significant reduction in the percentage of cells positively stained for senescence-associated β-galactosidase and increases in cell viability measured by MTT assay but marginal increases in cell proliferation and cell migration capacity measured by real-time growth kinetics analysis. Moreover, knockdown of hsa-miR-299-3p also increased proliferation of cells treated with H2O2to induce senescence. These findings suggest that hsa-miR-299-3p may delay or protect against replicative senescence by improving the metabolic activity of the senesced cells but does not stimulate growth of the remaining cells in senescent cultures. Hence, these findings provide an early insight into the role of hsa-miR-299-3p in the modulation of replicative senescence in HUVECs.
Nuclear receptor atlas of female mouse liver parenchymal, endothelial, and Kupffer cells
Authors: Li Zhaosha , Kruijt J. Kar , der Sluis Ronald J. van , Berkel Theo J. C. Van , Hoekstra Menno
Published: January 2013

The liver consists of different cell types that together synchronize crucial roles in liver homeostasis. Since nuclear receptors constitute an important class of drug targets that are involved in a wide variety of physiological processes, we have composed the hepatic cell type-specific expression profile of nuclear receptors to uncover the pharmacological potential of liver-enriched nuclear receptors. Parenchymal liver cells (hepatocytes) and liver endothelial and Kupffer cells were isolated from virgin female C57BL/6 wild-type mice using collagenase perfusion and counterflow centrifugal elutriation. The hepatic expression pattern of 49 nuclear receptors was generated by real-time quantitative PCR using the NUclear Receptor Signaling Atlas (NURSA) program resources. Thirty-six nuclear receptors were expressed in total liver. FXR-α, EAR2, LXR-α, HNF4-α, and CAR were the most abundantly expressed nuclear receptors in liver parenchymal cells. In contrast, NUR77, COUP-TFII, LXR-α/β, FXR-α, and EAR2 were the most highly expressed nuclear receptors in endothelial and Kupffer cells. Interestingly, members of orphan receptor COUP-TF family showed a distinct expression pattern. EAR2 was highly and exclusively expressed in parenchymal cells, while COUP-TFII was moderately and exclusively expressed in endothelial and Kupffer cells. Of interest, the orphan receptor TR4 showed a similar expression pattern as the established lipid sensor PPAR-γ. In conclusion, our study provides the most complete quantitative assessment of the nuclear receptor distribution in liver reported to date. Our gene expression catalog suggests that orphan nuclear receptors such as COUP-TFII, EAR2, and TR4 may be of significant importance as novel targets for pharmaceutical interventions in liver.
Microwave-Osmotic Dehydration of Cranberries under Continuous Flow Medium Spray Conditions
Authors: Wray Derek , Ramaswamy Hosahalli S.
Published: January 2013

Microwave-osmotic dehydration of cranberries was evaluated under continuous flow medium spray (MWODS) conditions after some pretreatments. A central composite rotatable design was used with three input variables at five levels (temperature, 33°C–67°C; sucrose concentration, 33°B–67°B; and contact time, 5–55 min). Responses were moisture loss (ML), solids gain (SG), and weight reduction (WR) as well as color and texture parameters. The responses were related to process variables using response surface methodology and statistical analysis: each model was tested for lack of fit to assure nonsignificance (P>0.05) and each process variable was tested for significance (P<0.05  or  P<0.0001). Temperature was found to have the most prominent effect as it was significant with all drying (ML, SG, and WR) and quality (hardness and chewiness) parameters, while contact time was found to be significant with ML and WR. Concentration wasn’t found to be significant for any response. Increasing skin pretreatment severity generally promoted SG but had little effect on ML. The exception was chemical peeling, which favored ML but had no effect on SG. Overall, MWODS enables food dehydration in a much faster period of time than conventional osmotic dehydration (COD), while specifically promoting moisture loss over solids gain.
Role of NHE1 in Nociception
Authors: Torres-López Jorge Elías , Guzmán-Priego Crystell Guadalupe , Rocha-González Héctor Isaac , Granados-Soto Vinicio
Published: January 2013

Intracellular pH is a fundamental parameter to cell function that requires tight homeostasis. In the absence of any regulation, excessive acidification of the cytosol would have the tendency to produce cellular damage. Mammalian Na+/H+exchangers (NHEs) are electroneutral Na+-dependent proteins that exchange extracellular Na+for intracellular H+. To date, there are 9 identified NHE isoforms where NHE1 is the most ubiquitous member, known as the housekeeping exchanger. NHE1 seems to have a protective role in the ischemia-reperfusion injury and other inflammatory diseases. In nociception, NHE1 is found in neurons along nociceptive pathways, and its pharmacological inhibition increases nociceptive behavior in acute pain models at peripheral and central levels. Electrophysiological studies also show that NHE modulates electrical activity of primary nociceptive terminals. However, its role in neuropathic pain still remains controversial. In humans, NHE1 may be responsible for inflammatory bowel diseases since its expression is reduced in Crohn’s disease and ulcerative colitis. The purpose of this work is to provide a review of the evidence about participation of NHE1 in the nociceptive processing.
Clonazepam as Agonist Substitution Treatment for Benzodiazepine Dependence: A Case Report
Authors: Maremmani Angelo Giovanni Icro , Rovai Luca , Rugani Fabio , Bacciardi Silvia , Pacini Matteo , Dell'Osso Liliana , Maremmani Icro
Published: January 2013

Nowadays, the misuse of benzodiazepines (BZDs) is a cause for a serious concern among pharmacologically inexperienced patients, whether treated or untreated, that could lead to significant complications, including tolerance, dependence, and addiction. We present a case report in which an Italian patient affected by anxiety disorder and treated with BZDs presented a severe case of dependence on BZDs. We treated him according to an agonist substitution approach, switching from the abused BZD to a slow-onset, long-acting, high potency agonist (clonazepam), and looking at the methadone treatment model as paradigm. We decided to use clonazepam for its pharmacokinetic properties. The advantage of choosing a slow-onset, long-lasting BZD for the treatment of our patient was that it led us to a remarkable improvement in the clinical situation, including the cessation of craving, absence of withdrawal symptoms, reduced anxiety, improvements in social functioning, and a better cognition level.
Effects of Aroma Massage on Home Blood Pressure, Ambulatory Blood Pressure, and Sleep Quality in Middle-Aged Women with Hypertension
Authors: Ju Myeong-Sook , Lee Sahng , Bae Ikyul , Hur Myung-Haeng , Seong Kayeon , Lee Myeong Soo
Published: January 2013

The purpose of this study was to evaluate the effects of aroma massage applied to middle-aged women with hypertension. The research study had a nonequivalent control group, nonsynchronized design to investigate the effect on home blood pressure (BP), ambulatory BP, and sleep. The hypertensive patients were allocated into the aroma massage group (n=28), the placebo group (n=28), and the no-treatment control group (n=27). To evaluate the effects of aroma massage, the experimental group received a massage with essential oils prescribed by an aromatherapist once a week and body cream once a day. The placebo group received a massage using artificial fragrance oil once a week and body cream once a day. BP, pulse rate, sleep conditions, and 24-hour ambulatory BP were monitored before and after the experiment. There was a significant difference in home systolic blood pressure (SBP) (F=6.71,P=0.002) between groups after intervention. There was also a significant difference in SBP (F=13.34,P=0.001) and diastolic blood pressure (DBP) (F=8.46,P=0.005) in the laboratory between aroma massage and placebo groups. In sleep quality, there was a significant difference between groups (F=6.75,P=0.002). In conclusion, aroma massage may help improve patient quality of life and maintain health as a nursing intervention in daily life.
A Game-Theoretic Analysis of Bandwidth Allocation under a User-Grouping Constraint
Authors: Hsu Shun-Pin , Hsu Shun-Liang , Tsai Alan Shenghan
Published: January 2013

A new bandwidth allocation model is studied in this paper. In this model, a system, such as a communication network, is composed of a finite number of users, and they compete for limited bandwidth resources. Each user adopts the decision that maximizes his or her own benefit characterized by the utility function. The decision space of each user is subject to constraints. In addition, some users form a group, and their joint decision space is also subject to constraints. Under the assumption that each user’s utility function satisfies some continuity and concavity conditions, the existence, uniqueness, and fairness, in some appropriate sense, of the Nash equilibrium point in the allocation game are proved. An algorithm yielding a sequence converging to the equilibrium point is proposed. Finally, a numerical example with detailed analysis is provided to illustrate the effectiveness of our work.
Nutrition and Pregnancy after Bariatric Surgery
Authors: Kaska Lukasz , Kobiela Jarek , Abacjew-Chmylko Anna , Chmylko Lukasz , Wojanowska-Pindel Magdalena , Kobiela Paulina , Walerzak Anna , Makarewicz Wojciech , Proczko-Markuszewska Monika , Stefaniak Tomasz
Published: January 2013

Obesity is an escalating problem in all age groups and it is observed to be more common in females than males. About 25% of women meet the criteria of obesity and one-third of them are in the reproductive age. Because morbid obesity requiring surgical treatment is observed with increasing frequency, surgeons and gynecologists are undergoing new challenges. It is not only a matter of women’s health and their quality of life but also proper development of the fetus, which should be a concern during bariatric treatment. Therefore complex perinatal care has to be provided for morbid obesity patients. The paper reviews pregnancy and fertility issues in bariatric surgery patients.
The Relationship between the UPPS-P Impulsivity Dimensions and Nonsuicidal Self-Injury Characteristics in Male and Female High-School Students
Authors: Claes Laurence , Muehlenkamp Jennifer
Published: January 2013

The present study investigated the association between nonsuicidal self-injury characteristics, functions, and the UPPS-P impulsivity-related traits in high-school students using self-report questionnaires. More than 17% of the 613 students engaged in at least one type of NSSI behavior. Compared to male students, female students engaged more often in cutting and less in head banging. All NSSI behaviors were significantly related to Negative and Positive Urgency, that is, the tendency to act impulsive in the presence of negative/positive affect. Interactions between different UPPS-P impulsivity dimensions did not increase the percentage of explained variance in the different NSSI behaviors. Furthermore, severe cutting was negatively related to Lack of Premeditation. Different NSSI functions showed differential relationships with the five UPPS-P impulsivity dimensions.
Amyloid Beta-Protein and Neural Network Dysfunction
Authors: Peña-Ortega Fernando
Published: January 2013

Understanding the neural mechanisms underlying brain dysfunction induced by amyloid beta-protein (Aβ) represents one of the major challenges for Alzheimer’s disease (AD) research. The most evident symptom of AD is a severe decline in cognition. Cognitive processes, as any other brain function, arise from the activity of specific cell assemblies of interconnected neurons that generate neural network dynamics based on their intrinsic and synaptic properties. Thus, the origin of Aβ-induced cognitive dysfunction, and possibly AD-related cognitive decline, must be found in specific alterations in properties of these cells and their consequences in neural network dynamics. The well-known relationship between AD and alterations in the activity of several neural networks is reflected in the slowing of the electroencephalographic (EEG) activity. Some features of the EEG slowing observed in AD, such as the diminished generation of different network oscillations, can be induced in vivo and in vitro upon Aβ application or by Aβ overproduction in transgenic models. This experimental approach offers the possibility to study the mechanisms involved in cognitive dysfunction produced by Aβ. This type of research may yield not only basic knowledge of neural network dysfunction associated with AD, but also novel options to treat this modern epidemic.
Prediction of Deleterious Nonsynonymous Single‐Nucleotide Polymorphism for Human Diseases
Authors: Wu Jiaxin , Jiang Rui
Published: January 2013

The identification of genetic variants that are responsible for human inherited diseases is a fundamental problem in human and medical genetics. As a typical type of genetic variation, nonsynonymous single‐nucleotide polymorphisms (nsSNPs) occurring in protein coding regions may alter the encoded amino acid, potentially affect protein structure and function, and further result in human inherited diseases. Therefore, it is of great importance to develop computational approaches to facilitate the discrimination of deleterious nsSNPs from neutral ones. In this paper, we review databases that collect nsSNPs and summarize computational methods for the identification of deleterious nsSNPs. We classify the existing methods for characterizing nsSNPs into three categories (sequence based, structure based, and annotation based), and we introduce machine learning models for the prediction of deleterious nsSNPs. We further discuss methods for identifying deleterious nsSNPs in noncoding variants and those for dealing with rare variants.
Enhancements of G3-PLC Technology for Smart-Home/Building Applications
Authors: Di Bert Luca , D'Alessandro Salvatore , Tonello Andrea M.
Published: January 2013

To enable the smart grid concept, it is fundamental to consider the in-home/building context where, beside the conventional home networking services, home automation and smart energy management services have to be offered. In this paper, we consider the in-home/building scenario, for which we propose a convergent network architecture to enhance the performance of the narrowband power line communication (PLC) G3-PLC technology through its integration with an Ethernet-based network. To this end, we define the protocols characterizing the network modules, namely, switches and routers, which allow for integrating the G3-PLC with Ethernet devices. Since Ethernet represents a convergent standard for many communication devices, by adding this functionality to G3-PLC, interconnectivity with other heterogeneous nodes can be offered. Furthermore, since the G3-PLC medium access control layer is based on a carrier sense multiple access scheme, its performance decreases when the number of network nodes contending for the channel increases. Therefore, we evaluate the network performance when an optimized time division multiple access scheme is adopted. The proposed convergent network architecture has been implemented in the OMNeT++ network simulator.
Variational Image Denoising Approach with Diffusion Porous Media Flow
Authors: Barbu Tudor
Published: January 2013

A novel PDE-based image denoising approach is proposed in this paper. One designs here a nonlinear filter for image noise reduction based on the diffusion flow generated by the porous media equation∂u/∂t=Δβ(u), whereβis a nonlinear continuous function of the formβ(u)=λum,0<m<1. With respect to standard 2D Gaussian smoothing and some nonlinear PDE-based filters, this one is more efficient to remove noise from degraded images and also to reduce “staircasing” effects and preserve the image edges.
A Tradeoff between Rich Multipath and High Receive Power in MIMO Capacity
Authors: Cheng Zimu , Chen Binghao , Zhong Zhangdui
Published: January 2013

A discussion about which of the two factors, rich multipath (in NLOS) or signal-to-noise ratio (SNR) (usually in LOS), affects the Multiple-Input Multiple-Output (MIMO) channel capacity more is presented in this paper. This interesting discussion is investigated by performing simulations using simple circle scatterer model and WINNER II channel model. And the simulation shows that these two factors behave differently as the channel condition varyies. When the scatterer number in channel is low, the high receive SNR is more important to capacity. The multipath richness will have greater influence when the scatterer number exceeds a certain threshold. However, the channel capacity will not change much as the scatterers continue to increase.
Ovarian Cancer Stem Cells: A New Target for Cancer Therapy
Authors: Zhan Qinglei , Wang Chunmei , Ngai Saiming
Published: January 2013

Ovarian cancer is a highly lethal disease among all gynecologic malignancies and is the fifth leading cause of cancer-related death in women. Although the standard combination of surgery and chemotherapy was initially effective in patients with ovarian cancer, disease relapse commonly occurred due to the generation of chemoresistance. It has been reported that cancer stem cells (CSCs) are involved in drug resistance and cancer recurrence. Over the past decades, increasing studies have been done to identify CSCs from human ovarian cancer cells. The present paper will summarize different investigations on ovarian CSCs, including isolation, mechanisms of chemoresistance, and therapeutic approaches. Although there are still numerous challenges to translate basic research to clinical applications, understanding the molecular details of CSCs is essential for developing effective strategies to prevent ovarian cancer and its recurrence.
Diagnosis of Short-Circuit Fault in Large-Scale Permanent-Magnet Wind Power Generator Based on CMAC
Authors: Hsieh Chin-Tsung , Yau Her-Terng , Shiu Jen
Published: January 2013

This study proposes a method based on the cerebellar model arithmetic controller (CMAC) for fault diagnosis of large-scale permanent-magnet wind power generators and compares the results with Error Back Propagation (EBP). The diagnosis is based on the short-circuit faults in permanent-magnet wind power generators, magnetic field change, and temperature change. Since CMAC is characterized by inductive ability, associative ability, quick response, and similar input signals exciting similar memories, it has an excellent effect as an intelligent fault diagnosis implement. The experimental results suggest that faults can be diagnosed effectively after only training CMAC 10 times. In comparison to training 151 times for EBP, CMAC is better than EBP in terms of training speed.
A Retrospectively Diagnosed Case of IgG4-Related Tubulointerstitial Nephritis Showing Good Renal Outcome and Pathological Progress
Authors: Wu Qiong , Nakazawa Raima , Tanaka Hisae , Endoh Masayuki , Fukagawa Masafumi
Published: January 2013

A 74-year-old man was hospitalized for diabetic nephropathy evaluation and assessment of the effect of treatment on his tubulointerstitial nephritis (TIN). When he was 62 years old, he developed polyarthralgia and had superficial lymph node swelling, mildly increased serum creatinine concentration, hypergammaglobulinemia, hypocomplementemia, high serum IL-2R level, and positive titer of antinuclear antibody. Several tissues were biopsied. Mild chronic sialadenitis and reactive lymphadenitis were identified. Renal specimen showed mild glomerular ischemia, extensive storiform fibrosis, and abundant infiltrating monocytes and plasma cells. He was treated with oral prednisolone and cyclophosphamide. After the treatment, most of his clinical parameters quickly returned to within the reference range. However, he developed diabetes mellitus soon after steroid therapy. At the time of rebiopsy, a high level of serum IgG4 was detected. The second renal biopsy showed diabetic nephropathy without any tubulointerstitial damage. The first biopsied tissues were retrospectively investigated. Large numbers of IgG4-positive plasma cells were detected in the kidneys and lymph nodes. A retrospective diagnosis of IgG4-related TIN with lymph node involvement was made. In conclusion, this paper describes a retrospectively diagnosed case of IgG4-related TIN with lymph node involvement, showing good clinical and pathological prognosis.
Deficiency of Phospholipase A2 Group 7 Decreases Intestinal Polyposis and Colon Tumorigenesis in ApcMin/+ Mice
Authors: Xu Changxin , Reichert Ethan C. , Nakano Tomoyuki , Lohse Mariah , Gardner Alison A. , Revelo Mónica P. , Topham Matthew K. , Stafforini Diana M.
Published: January 2013

Platelet-activating factor (PAF) is a naturally occurring phospholipid that mediates diverse effects such as physiological and pathological inflammation, immunosuppression, and cancer. Several lines of evidence support both positive and negative roles for PAF in carcinogenesis. PAF stimulates cell growth, oncogenic transformation, and metastasis, but can also limit proliferation and induce apoptosis. The biological context and microenvironment seem to define whether PAF has pro- or anticarcinogenic effects. To investigate the role of exacerbated PAF signaling in colon cancer, we conducted cell-based and in vivo studies using genetically engineered mice lacking expression of phospholipase A2 group 7 (PLA2G7), an enzyme that specifically metabolizes PAF and structurally related glycerophospholipids. Absence of Pla2g7 robustly decreased intestinal polyposis and colon tumor formation in ApcMin/+ mice, suggesting an antitumorigenic role for PAF in settings characterized by aberrant function of the tumor suppressor Adenomatous polyposis coli (Apc). In colonic epithelial cells, exposure to a PAF analog led to dephosphorylation of Akt at serine-473 and induction of apoptosis. The mechanism of this response involved formation of a complex between β-arrestin 1 and the Akt phosphatase PHLPP2, and activation of the intrinsic pathway of apoptosis. Our results suggest that strategies based on inhibiting PLA2G7 activity or increasing PAF-mediated signaling hold promise for the treatment of intestinal malignancies that harbor mutations in APC. Cancer Res; 73(9); 2806–16. ©2013 AACR.
Efficacy, Safety, Pharmacokinetics, and Biomarkers of Cediranib Monotherapy in Advanced Hepatocellular Carcinoma: A Phase II Study
Authors: Zhu Andrew X. , Ancukiewicz Marek , Supko Jeffrey G. , Sahani Dushyant V. , Blaszkowsky Lawrence S. , Meyerhardt Jeffrey A. , Abrams Thomas A. , McCleary Nadine Jackson , Bhargava Pankaj , Muzikansky Alona , Sheehan Susan , Regan Eileen , Vasudev Eamala , Knowles Michelle , Fuchs Charles S. , Ryan David P. , Jain Rakesh K. , Duda Dan G.
Published: January 2013

Purpose: We conducted a single-arm phase II study of cediranib, a pan-VEGFR tyrosine kinase inhibitor, in patients with advanced hepatocellular carcinoma (HCC).

Experimental Design: Patients with histologically confirmed measurable advanced HCC and adequate hematologic, hepatic, and renal functions received cediranib 30-mg orally once daily (4 weeks/cycle). The primary endpoint was progression-free survival (PFS) rate at 3 months. Other endpoints included response rates, overall survival (OS), pharmacokinetics (PK), and biomarkers for cediranib.

Results: Cediranib treatment resulted in an estimated 3-month PFS rate of 77% (60%, 99%). Median PFS was 5.3 (3.5,9.7) months, stable disease was seen in 5/17 patients (29%), and median OS was 11.7 (7.5–13.6) months. Grade 3 toxicities included hypertension (29%), hyponatremia (29%), and hyperbilirubinemia (18%). Cediranib PK were comparable to those seen in cancer patients with normal hepatic function. Plasma levels of VEGF and PlGF increased and sVEGFR1, sVEGFR2, and Ang-2 decreased after cediranib treatment. PFS was inversely correlated with baseline levels of VEGF, sVEGFR2, and bFGF and with on-treatment levels of bFGF and IGF-1, and directly associated with on-treatment levels of IFN-γ. OS was inversely correlated with baseline levels of sVEGFR1, Ang-2, TNF-α, CAIX, and CD34+CD133+CD45dim circulating progenitor cells and on-treatment levels of sVEGFR2.

Conclusions: Despite the limitations of primary endpoint selection, cediranib at 30-mg daily showed a high incidence of toxicity and preliminary evidence of antitumor activity in advanced HCC. Hepatic dysfunction did not seem to affect the steady-state PK of cediranib. Exploratory studies suggested proangiogenic and inflammatory factors as potential biomarkers of anti-VEGF therapy in HCC. Clin Cancer Res; 19(6); 1557–66. ©2013 AACR.
CPEB1 Regulates the Expression of MTDH/AEG-1 and Glioblastoma Cell Migration
Authors: Kochanek Dawn M. , Wells David G.
Published: January 2013

Cytoplasmic polyadenylation element-binding protein 1 (CPEB1) is an mRNA-binding protein present in both neurons and glia. CPEB1 is capable of both repressing mRNA translation and activating it depending upon its phosphorylation state. CPEB1-bound mRNAs are held in translational dormancy until CPEB1 is phosphorylated, leading to the cytoplasmic polyadenylation of the bound mRNA that triggers translation. Here, we show that CPEB1 can bind to and regulate translation of the mRNA-encoding metadherin (MTDH, also known as AEG-1 and Lyric) in the rat glioblastoma cell line CNS1. MTDH/AEG-1 is being revealed as a critical signaling molecule in tumor progression, playing roles in invasion, metastasis, and chemoresistance. By using a mutant of CPEB1 that cannot be phosphorylated (thereby holding target mRNAs in translational arrest), we show that inhibiting CPEB1-mediated translation blocks MTDH/AEG-1 expression in vitro and inhibits glioblastomas tumor growth in vivo. CPEB1-mediated translation is likely to impact several signaling pathways that may promote tumor progression, but we present evidence suggesting a role in directed cell migration in glioblastoma cells. In addition, reporter mRNA containing CPEB1-binding sites is transported to the leading edge of migrating cells and translated, whereas the same mRNA with point mutations in the binding sites is synthesized perinuclearly. Our findings show that CPEB1 is hyperactive in rat glioblastoma cells and is regulating an important cohort of mRNAs whose increased translation is fueling the progression of tumor proliferation and dispersal in the brain. Thus, targeting CPEB1-mediated mRNA translation might be a sound therapeutic approach. Mol Cancer Res; 11(2); 149–60. ©2012 AACR.
Genome-Wide Association Study Identifies Novel Loci Associated With Concentrations of Four Plasma Phospholipid Fatty Acids in the De Novo Lipogenesis Pathway
Authors: Wu Jason H.Y. , Lemaitre Rozenn N. , Manichaikul Ani , Guan Weihua , Tanaka Toshiko , Foy Millennia , Kabagambe Edmond K. , Djousse Luc , Siscovick David , Fretts Amanda M. , Johnson Catherine , King Irena B. , Psaty Bruce M. , McKnight Barbara , Rich Stephen S. , Chen Yii-Der I. , Nettleton Jennifer A. , Tang Weihong , Bandinelli Stefania , Jacobs David R. , Browning Brian L. , Laurie Cathy C. , Gu Xiangjun , Tsai Michael Y. , Steffen Lyn M. , Ferrucci Luigi , Fornage Myriam , Mozaffarian Dariush
Published: January 2013

Background—

Palmitic acid (16:0), stearic acid (18:0), palmitoleic acid (16:1n-7), and oleic acid (18:1n-9) are major saturated and monounsaturated fatty acids that affect cellular signaling and metabolic pathways. They are synthesized via de novo lipogenesis and are the main saturated and monounsaturated fatty acids in the diet. Levels of these fatty acids have been linked to diseases including type 2 diabetes mellitus and coronary heart disease.

Methods and Results—

Genome-wide association studies were conducted in 5 population-based cohorts comprising 8961 participants of European ancestry to investigate the association of common genetic variation with plasma levels of these 4 fatty acids. We identified polymorphisms in 7 novel loci associated with circulating levels of ≥1 of these fatty acids.
ALG14
(asparagine-linked glycosylation 14 homolog) polymorphisms were associated with higher 16:0 (
P
=2.7×10
−11
) and lower 18:0 (
P
=2.2×10
−18
).
FADS1
and
FADS2
(desaturases) polymorphisms were associated with higher 16:1n-7 (
P
=6.6×10
−13
) and 18:1n-9 (
P
=2.2×10
−32
) and lower 18:0 (
P
=1.3×10
−20
).
LPGAT1
(lysophosphatidylglycerol acyltransferase) polymorphisms were associated with lower 18:0 (
P
=2.8×10
−9
).
GCKR
(glucokinase regulator;
P
=9.8×10
−10
) and
HIF1AN
(factor inhibiting hypoxia-inducible factor-1;
P
=5.7×10
−9
) polymorphisms were associated with higher 16:1n-7, whereas
PKD2L1
(polycystic kidney disease 2-like 1;
P
=5.7×10
−15
) and a locus on chromosome 2 (not near known genes) were associated with lower 16:1n-7 (
P
=4.1×10
−8
).

Conclusions—

Our findings provide novel evidence that common variations in genes with diverse functions, including protein-glycosylation, polyunsaturated fatty acid metabolism, phospholipid modeling, and glucose- and oxygen-sensing pathways, are associated with circulating levels of 4 fatty acids in the de novo lipogenesis pathway. These results expand our knowledge of genetic factors relevant to de novo lipogenesis and fatty acid biology.
Procedural Safety and Predictors of Acute Outcome of Intracoronary Administration of Progenitor Cells in 775 Consecutive Procedures Performed for Acute Myocardial Infarction or Chronic Heart Failure
Authors: De Rosa Salvatore , Seeger Florian H. , Honold Jörg , Fischer-Rasokat Ulrich , Lehmann Ralf , Fichtlscherer Stephan , Schächinger Volker , Dimmeler Stefanie , Zeiher Andreas M. , Assmus Birgit
Published: January 2013

Background—

Cell-based therapies are a promising option in patients with acute myocardial infarction or chronic heart failure (CHF). However, administration of cells requires intracoronary or intracardiac instrumentation, which is potentially associated with periprocedural risks. Therefore, we analyzed periprocedural complications and 30-day outcome in 775 consecutive procedures of intracoronary administration of progenitor cells using the stop-flow technique.

Methods and Results—

Indications for cell administration were acute myocardial infarction (n=126) and CHF of ischemic (n=562) or nonischemic (n=87) etiology. Vessel injury was observed in a total of 9 procedures (1.2%) and could be promptly managed by additional progenitor cell injection (PCI) in all but 1 case. No procedural deaths were observed. A periprocedural increase in troponin T was observed in 3.2% of the CHF procedures, in which no concomitant PCI was performed and troponin levels were not elevated before the procedure. Independent significant predictors of troponin T increase were higher New York Heart Association (NYHA) class (NYHA I versus NYHA IV;
P
=0.01; NYHA I versus III;
P
=0.19; NYHA I versus II;
P
=0.55), concomitant revascularization (
P
<0.01), presence of elevated troponin T before the procedure (
P
<0.01), and peripheral occlusive disease (
P
=0.04). At 30 days, there were 4 deaths (0.5%), 1 stroke (0.13%), 8 acute myocardial infarctions (1%), and 5 hospitalizations for exacerbation of heart failure (0.64%).

Conclusions—

Intracoronary infusion of progenitor cells can be performed with adequate safety in patients with acute myocardial infarction or CHF, because the safety profile was similar to what is usually expected from a coronary angiogram in the present cohort.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00962364, NCT00284713, and NCT00289822.
Intra-arterial Cell Transplantation Provides Timing-Dependent Cell Distribution and Functional Recovery After Stroke
Authors: Ishizaka Shunsuke , Horie Nobutaka , Satoh Katsuya , Fukuda Yuhtaka , Nishida Noriyuki , Nagata Izumi
Published: January 2013

Background and Purpose—

Intra-arterial cell transplantation offers a novel therapeutic strategy for stroke; however, it remains unclear how the timing of cell administration affects cell distribution, brain repair processes, and functional recovery. Here, we investigate the hypothesis that the timing of cell transplantation changes the behavior of the cell graft and the host environment in a way that affects functional recovery.

Methods—

Rats received human mesenchymal stem cells via the internal carotid artery at 1, 4, or 7 days (D1, D4, or D7) after middle cerebral artery occlusion and reperfusion. Animals were euthanized at various time points to assess cell distribution, infiltration of activated microglia, expression of brain-derived neurotrophic factor, reactive astrocytes, angiogenesis, and functional recovery.

Results—

Human mesenchymal stem cells were widely distributed both in the peri-infarct and core in D1, and dominantly in the peri-infarct in D4. Very few cells were observed on D7. At day 7 poststroke, microglia activation was significantly suppressed in both the peri-infarct and core in D1, and predominantly in the peri-infarct in D4. At day 21 poststroke, brain-derived neurotrophic factor was widely distributed throughout the peri-infarct in D1 and D4, along with many reactive astrocytes and considerable angiogenesis. Motor function improved earlier in D1 and later in D4, but no recovery was obtained in D7.

Conclusions—

Our results indicate that intra-arterial cell transplantation provides timing-dependent cell distribution and poststroke functional recovery via a combination of neuroprotection, reactive astrocyte enhancement, and angiogenesis.
Short-Term Dose–Response Characteristics of 2-Iminobiotin Immediately Postinsult in the Neonatal Piglet After Hypoxia-Ischemia
Authors: Bjorkman S. Tracey , Ireland Zoe , Fan Xiyong , van der Wal Willem M. , Roes Kit C.B. , Colditz Paul B. , Peeters-Scholte Cacha M.P.C.D.
Published: January 2013

Background and Purpose—

To determine the optimal dose of 2-iminobiotin (2-IB) for the treatment of moderate to severe asphyxia in a neonatal piglet model of hypoxia-ischemia.

Methods—

Newborn piglets were subjected to a 30-minute hypoxia-ischemia insult and randomly treated with vehicle or 2-IB (0.1 mg/kg, 0.2 mg/kg, or 1.0 mg/kg). aEEG background and seizure activity were scored after hypoxia-ischemia every 4 h until 24 h and at 48 h and neurobehavioral scores were obtained. Brain tissue was collected and processed for analysis of caspase-3 activity, histology, and tyrosine nitration.

Results—

A dose range of 0.1 to 1.0 mg/kg/dose of 2-IB improved short-term outcome as demonstrated by an increased survival with a normal aEEG and decreased nitrotyrosine staining in the 2-IB–treated animals, indicating decreased cellular damage. Neurobehavior, caspase-3 activity in thalamus, and histology scores were not significantly different.

Conclusions—

Based on survival with a normal aEEG, 0.2 mg/kg 2-IB is likely to be the most appropriate dose for use in future clinical trials in neonates with perinatal hypoxia-ischemia.
Effects of Institutional Caseload of Subarachnoid Hemorrhage on Mortality
Authors: McNeill Lisa , English Shane W. , Borg Nicholas , Matta Basil F. , Menon David K.
Published: January 2013

Background and Purpose—

Procedures requiring specific skill sets often have been shown to depend on institutional volume, that is, centers receiving a higher volume observe better outcomes in those patients. This relationship recently has been shown to exist for subarachnoid hemorrhage(SAH) patients in a large study in the United States. We aim to examine this relationship for SAH patients in England, restricting analysis to specialist neurosurgical units.

Methods—

Aggregate counts of patients with SAH in 25 specialist neuroscience centers in England, from 2005 to 2011, were obtained from the Hospital Episode Statistics database maintained by the National Health Service Information Center. These data were linked with national mortality statistics to obtain counts of deaths. Poisson regression was used to investigate the relationship between institutional caseload of SAH and 6-month mortality from any cause. Six-month mortality rates and mortality ratios were computed.

Results—

Annual institutional caseload of admissions with SAH was inversely related to 6-month mortality (
P
=0.009;
r
2
=0.26). Each 100-patient increase in annual patient volume was associated with a 24% reduction in mortality (adjusted mortality ratio, 0.76; confidence interval, 0.67–0.87). This relationship was consistent across the entire range of annual institutional caseloads examined (29–367 cases for the lowest and highest volumes seen in a single center in 1 year).

Conclusions—

Our results provide support for management of SAH at high-volume centers and suggest that health care policy in this setting should pursue regionalization while ensuring an adequate geographic spread of access to care.
Spatial Remapping in the Audio-tactile Ventriloquism Effect: A TMS Investigation on the Role of the Ventral Intraparietal Area
Authors: Renzi Chiara , Bruns Patrick , Heise Kirstin-Friederike , Zimerman Maximo , Feldheim Jan-Frederik , Hummel Friedhelm C. , Röder Brigitte
Published: January 2013

Previous studies have suggested that the putative human homologue of the ventral intraparietal area (hVIP) is crucially involved in the remapping of tactile information into external spatial coordinates and in the realignment of tactile and visual maps. It is unclear, however, whether hVIP is critical for the remapping process during audio-tactile cross-modal spatial interactions. The audio-tactile ventriloquism effect, where the perceived location of a sound is shifted toward the location of a synchronous but spatially disparate tactile stimulus, was used to probe spatial interactions in audio-tactile processing. Eighteen healthy volunteers were asked to report the perceived location of brief auditory stimuli presented from three different locations (left, center, and right). Auditory stimuli were presented either alone (unimodal stimuli) or concurrently to a spatially discrepant tactile stimulus applied to the left or right index finger (bimodal stimuli), with the hands adopting either an uncrossed or a crossed posture. Single pulses of TMS were delivered over the hVIP or a control site (primary somatosensory cortex, SI) 80 msec after trial onset. TMS to the hVIP, compared with the control SI-TMS, interfered with the remapping of touch into external space, suggesting that hVIP is crucially involved in transforming spatial reference frames across audition and touch.
Panda Diplomacy: The Cutest Part of China’s Public Diplomacy
Authors: Hartig Falk
Published: January 2013

Summary

In late 2011 and early 2012, the People’s Republic of China drew on its most unique diplomatic tool: the giant panda. Although this phenomenon is widely covered by the global media, the practice of panda diplomacy is only barely discussed in diplomatic or international relations studies. This article uses the most recent revival of this diplomatic practice for a closer analysis and locates it as a special version of animal diplomacy within the frame of public diplomacy. It first argues that panda diplomacy is — besides all the efforts to promote and support animal conservation and biological research — a political undertaking, which is symbolically used by the Chinese government to win hearts and minds in selected foreign countries. Second, it highlights an important aspect of some Chinese public diplomacy initiatives, namely China’s ability to integrate international partners in its attempts to shape its global image.