bluuebunny/crossref_metadata_2025 huggingface dataset:
An Imaging and Histological Study on Intrahepatic Microvascular Passage of Contrast Materials in Rat Liver
Authors: Xia Qian , Feng Yuanbo , Yin Ting , Liu Yewei , Zhang Guozhi , Liu Jianjun , Tong Linjun , Willemyns Robin , Yu Jie , Oyen Raymond , Huang Gang , Ni Yicheng
Published: February 2017

Background. Lipiodol has been applied for decades in transarterial chemoembolization to treat liver malignancies, but its intrahepatic pathway through arterioportal shunt (APS) in the liver has not been histologically revealed. This rodent experiment was conducted to provide evidence for the pathway of Lipiodol delivered through the hepatic artery (HA) but found in the portal vein (PV) and to elucidate the observed unidirectional APS. Methods. Thirty rats were divided into 5 groups receiving systemic or local arterial infusion of red-stained iodized oil (RIO) or its hydrosoluble substitute barium sulfate suspension (BSS), or infusion of BSS via the PV, monitored by real-time digital radiography. Histomorphology of serial frozen and paraffin sections was performed and quantified. Results. After HA infusion, RIO and BSS appeared extensively in PV lumens with peribiliary vascular plexus (PVP) identified as the responsible anastomotic channel. After PV infusion, BSS appeared predominantly in the PV and surrounding sinusoids and to a much lesser extent in the PVP and HA (P<0.001). Fluid mechanics well explains the one-way-valve phenomenon of APS. Conclusions. Intravascularly injected rat livers provide histomorphologic evidences: (1) the PVP exists in between the HA and PV, which is responsible to the APS of Lipiodol; and (2) the intrahepatic vascular inflow appears HA-PVP-PV unidirectional without a physical one-way valve, which can be postulated by the fluid mechanics.
Nitrogen Removal Characteristics of Pseudomonas putida Y-9 Capable of Heterotrophic Nitrification and Aerobic Denitrification at Low Temperature
Authors: Xu Yi , He Tengxia , Li Zhenlun , Ye Qing , Chen Yanli , Xie Enyu , Zhang Xue
Published: February 2017

The cold-adapted bacterium Pseudomonas putida Y-9 was investigated and exhibited excellent capability for nitrogen removal at 15°C. The strain capable of heterotrophic nitrification and aerobic denitrification could efficiently remove ammonium, nitrate, and nitrite at an average removal rate of 2.85 mg, 1.60 mg, and 1.83 mg NL−1 h−1, respectively. Strain Y-9 performed nitrification in preference to denitrification when ammonium and nitrate or ammonium and nitrite coexisted in the solution. Meantime, the presence of nitrate had no effect on the ammonium removal rate of strain Y-9, and yet the presence of high concentration of nitrite would inhibit the cell growth and decrease the nitrification rate. The experimental results indicate that P. putida Y-9 has potential application for the treatment of wastewater containing high concentrations of ammonium along with its oxidation products at low temperature.
Dental Implant Placement with Simultaneous Anterior Maxillary Reconstruction with Block and Particulate Fresh Frozen Allograft Bone: A Case Report with 24-Month Follow-Up Data
Authors: Vieira J. S. , Brandão-Filho E. M. , Deliberador F. R. , Zielak J. C. , Giovanini A. F. , Deliberador T. M.
Published: February 2017

Fresh frozen allograft bone is routinely used in orthopedic surgery for the reconstruction of large bone defects, and its use in oral and maxillofacial surgery is increasing. The purpose of this case was to demonstrate the installation of dental implants and the use of fresh frozen bone for reconstruction of anterior maxilla in the same surgery. This case report presents the insertion of dental implants followed immediately by a placement of fresh frozen allograft in block and particle for a reconstruction of atrophic anterior maxillary in the same surgery. Ten months subsequent to this procedure, provisional fixed prosthesis was installed on the implants. Four months later (postoperative month 14), the final fixed prosthesis was installed and the clinical success was observed. The insertion of dental implants followed immediately by a placement of fresh frozen allograft is a safe and efficient process that results in the successful return of dental function and aesthetic rehabilitation for the patient.
Shear Creep Simulation of Structural Plane of Rock Mass Based on Discontinuous Deformation Analysis
Authors: Zhang Guoxin , Lei Zhengqi , Cheng Heng
Published: February 2017

Numerical simulations of the creep characteristics of the structural plane of rock mass are very useful. However, most existing simulation methods are based on continuum mechanics and hence are unsuitable in the case of large displacements and deformations. The discontinuous deformation analysis method proposed by Genhua is a discrete one and has a significant advantage when simulating the contacting problem of blocks. In this study, we combined the viscoelastic rheological model of Burgers with the discontinuous deformation analysis (DDA) method. We also derived the recurrence formula for the creep deformation increment with the time step during numerical simulations. Based on the minimum potential energy principle, the general equilibrium equation was derived, and the shear creep deformation in the structural plane was considered. A numerical program was also developed and its effectiveness was confirmed based on the curves obtained by the creep test of the structural plane of a rock mass under different stress levels. Finally, the program was used to analyze the mechanism responsible for the creep features of the structural plane in the case of the toppling deformation of the rock slope. The results showed that the extended DDA method is an effective one.
Integrating miRNA and mRNA Expression Profiling Uncovers miRNAs Underlying Fat Deposition in Sheep
Authors: Zhou Guangxian , Wang Xiaolong , Yuan Chao , Kang Danju , Xu Xiaochun , Zhou Jiping , Geng Rongqing , Yang Yuxin , Yang Zhaoxia , Chen Yulin
Published: February 2017

MicroRNAs (miRNAs) are endogenous, noncoding RNAs that regulate various biological processes including adipogenesis and fat metabolism. Here, we adopted a deep sequencing approach to determine the identity and abundance of miRNAs involved in fat deposition in adipose tissues from fat-tailed (Kazakhstan sheep, KS) and thin-tailed (Tibetan sheep, TS) sheep breeds. By comparing HiSeq data of these two breeds, 539 miRNAs were shared in both breeds, whereas 179 and 97 miRNAs were uniquely expressed in KS and TS, respectively. We also identified 35 miRNAs that are considered to be putative novel miRNAs. The integration of miRNA-mRNA analysis revealed that miRNA-associated targets were mainly involved in the gene ontology (GO) biological processes concerning cellular process and metabolic process, and miRNAs play critical roles in fat deposition through their ability to regulate fundamental pathways. These pathways included the MAPK signaling pathway, FoxO and Wnt signaling pathway, and focal adhesion. Taken together, our results define miRNA expression signatures that may contribute to fat deposition and lipid metabolism in sheep.
Implications of a Spatial Multicriteria Decision Analysis for Urban Development in Ulaanbaatar, Mongolia
Authors: Myagmartseren Purevtseren , Buyandelger Myagmarsuren , Brandt S. Anders
Published: February 2017

New technology has provided new tools for effective spatial planning. Through the example of locating suitable sites for urban development in Ulaanbaatar, this paper illustrates how multicriteria decision analysis and geographical information systems can be used for more effective urban planning. Several constraint and factor criteria were identified, transformed into map layers, and weighted together using the analytic hierarchy process. Besides localization results, this study shows the effect of using poor elevation data and how a sensitivity analysis can be applied to yield further information, spot weighting weaknesses, and assess the quality of the criteria.
Evaluation of Prognostic and Predictive Significance of Circulating MicroRNAs in Ovarian Cancer Patients
Authors: Halvorsen Ann Rita , Kristensen Gunnar , Embleton Andy , Adusei Cybil , Barretina-Ginesta Maria Pilar , Beale Philip , Helland Åslaug
Published: February 2017

Ovarian cancer patients are recognized with poor prognosis. This study aimed to identify microRNAs in plasma for predicting response to treatment and outcome. We have investigated microRNAs in plasma from ovarian cancer patients enrolled in a large multicenter study (ICON7), investigating the effect of adding bevacizumab to standard chemotherapy in patients diagnosed with epithelial ovarian cancer. Patients with different histology, grade, and FIGO stages were included (n=207) in this study. Screening of 754 unique microRNAs was performed in the discovery phase (n=91) using TaqMan Low Density Arrays. The results were validated using single assays and RT-qPCR. Low levels of miR-200b, miR-1274A (tRNALys5), and miR-141 were significantly associated with better survival, confirmed with log-rank test in the validation set. The level of miR-1274A (tRNALys5) correlated with outcome was especially pronounced in the high-grade serous tumors. Interestingly, low level of miR-200c was associated with 5-month prolongation of PFS when treated with bevacizumab compared to standard chemotherapy. We found prognostic significance of miR-200b, miR-141, and miR-1274A (tRNALys5) in all histological types, where miR-1274A (tRNALys5) may be a specific marker in high-grade serous tumors. The level of miR-200c may be predictive of effect of treatment with bevacizumab. However, this needs further validation.
Electromagnetic Characterization of a Composite (RE-CB-MT) by Time Domain Spectroscopy
Authors: Bounar Amina , Bouzit Nacerdine , Bourouba Nacerdine
Published: February 2017

The aim of this article is to study the dielectric behavior (ε, σ) in microwaves domain of composites made with Epoxy Resin (RE), Carbon Black (CB), and Magnesium Titanate (MT) on a large band of frequency. This kind of composites is very solicited for applications and miniaturization of the components circuits (cavities, antennas, substrates, etc.) in hyperfrequency electronics. In this study we have also highlighted the effect of the fillers nature and their concentrations on the behavior of these composites. The results obtained by time domain spectroscopy (TDS) have revealed the strong dependence of complex permittivity of the composite materials on both the nature and the concentration of conductive environment. Low frequency analysis (500 MHz) has been investigated to determine the conductivity of composites which is related to the percolation phenomenon. Moreover, the comparison between experimental results and theoretical models shows that the modeling Lichtenecker law is applicable to the ternary mixture in this frequency range and is in accordance with the approach postulated by Bottreau.
Combined Ligand/Structure-Based Virtual Screening and Molecular Dynamics Simulations of Steroidal Androgen Receptor Antagonists
Authors: Wang Yuwei , Han Rui , Zhang Huimin , Liu Hongli , Li Jiazhong , Liu Huanxiang , Gramatica Paola
Published: February 2017

The antiandrogens, such as bicalutamide, targeting the androgen receptor (AR), are the main endocrine therapies for prostate cancer (PCa). But as drug resistance to antiandrogens emerges in advanced PCa, there presents a high medical need for exploitation of novel AR antagonists. In this work, the relationships between the molecular structures and antiandrogenic activities of a series of 7α-substituted dihydrotestosterone derivatives were investigated. The proposed MLR model obtained high predictive ability. The thoroughly validated QSAR model was used to virtually screen new dihydrotestosterones derivatives taken from PubChem, resulting in the finding of novel compounds CID_70128824, CID_70127147, and CID_70126881, whose in silico bioactivities are much higher than the published best one, even higher than bicalutamide. In addition, molecular docking, molecular dynamics (MD) simulations, and MM/GBSA have been employed to analyze and compare the binding modes between the novel compounds and AR. Through the analysis of the binding free energy and residue energy decomposition, we concluded that the newly discovered chemicals can in silico bind to AR with similar position and mechanism to the reported active compound and the van der Waals interaction is the main driving force during the binding process.
Gabapentin Inhibits Protein Kinase C Epsilon Translocation in Cultured Sensory Neurons with Additive Effects When Coapplied with Paracetamol (Acetaminophen)
Authors: Vellani Vittorio , Giacomoni Chiara
Published: February 2017

Gabapentin is a well-established anticonvulsant drug which is also effective for the treatment of neuropathic pain. Although the exact mechanism leading to relief of allodynia and hyperalgesia caused by neuropathy is not known, the blocking effect of gabapentin on voltage-dependent calcium channels has been proposed to be involved. In order to further evaluate its analgesic mechanisms, we tested the efficacy of gabapentin on protein kinase C epsilon (PKCε) translocation in cultured peripheral neurons isolated from rat dorsal root ganglia (DRGs). We found that gabapentin significantly reduced PKCεtranslocation induced by the pronociceptive peptides bradykinin and prokineticin 2, involved in both inflammatory and chronic pain. We recently showed that paracetamol (acetaminophen), a very commonly used analgesic drug, also produces inhibition of PKCε. We tested the effect of the combined use of paracetamol and gabapentin, and we found that the inhibition of translocation adds up. Our study provides a novel mechanism of action for gabapentin in sensory neurons and suggests a mechanism of action for the combined use of paracetamol and gabapentin, which has recently been shown to be effective, with a cumulative behavior, in the control of postoperative pain in human patients.
Limiting Energy Consumption by Decreasing Packets Retransmissions in 5G Network
Authors: Apiecionek Łukasz
Published: February 2017

This article presents the potential of using Multipath Transmission Control Protocol for limiting the energy consumption in 5G network. The number of errors occurring during packet transmissions and in effect the number of retransmissions affect the consumption of energy by the devices in the network. The paper analyzes the potential energy savings from implementing an algorithm for detecting problems and predicting the future retransmissions. Although this is the main object of the paper, it must be emphasized that the proposed method also allows increasing the speed of transmission and improving the security of the data and it is easy to implement in 5G networks.
Production of Human Cu,Zn SOD with Higher Activity and Lower Toxicity inE. colivia Mutation of Free Cysteine Residues
Authors: Zhang Kun , Zhang Yuejuan , Zi Jing , Xue Xiaochang , Wan Yi
Published: February 2017

Although, as an antioxidant enzyme, human Cu,Zn superoxide dismutase 1 (hSOD1) can mitigate damage to cell components caused by free radicals generated by aerobic metabolism, large-scale manufacturing and clinical use of hSOD1 are still limited by the challenge of rapid and inexpensive production of high-quality eukaryotic hSOD1 in recombinant forms. We have demonstrated previously that it is a promising strategy to increase the expression levels of soluble hSOD1 so as to increase hSOD1 yields inE. coli. In this study, a wild-type hSOD1 (wtSOD1) and three mutant SOD1s (mhSOD1s), in which free cysteines were substituted with serine, were constructed and their expression in soluble form was measured. Results show that the substitution of Cys111 (mhSOD1/C111S) increased the expression of soluble hSOD1 inE. coliwhereas substitution of the internal Cys6 (mhSOD1/C6S) decreased it.Besides, raised levels of soluble expression led to an increase in hSOD1 yields. In addition, mhSOD1/C111S expressed at a higher soluble level showed lower toxicity and stronger whitening and antiradiation activities than those of wtSOD1. Taken together, our data demonstrate that C111S mutation in hSOD1 is an effective strategy to develop new SOD1-associated reagents and that mhSOD1/C111S is a satisfactory candidate for large-scale production.
Association of Gait Characteristics and Depression in Patients with Parkinson’s Disease Assessed in Goal-Directed Locomotion Task
Authors: Kincses Péter , Kovács Norbert , Karádi Kázmér , Feldmann Ádám , Dorn Krisztina , Aschermann Zsuzsanna , Komoly Sámuel , Szolcsányi Tibor , Csathó Árpád , Kállai János
Published: February 2017

Introduction.In the genesis of Parkinson’s disease (PD) clinical phenomenology the exact nature of the association between bradykinesia and affective variables is unclear. In the present study, we analyzed the gait characteristics and level of depression in PD and healthy volunteers.Methods.Patients with PD (n=48) and healthy controls (n=52) were recruited for the present study. Walking speed, stride length, and cadence were compared between groups while participants completed a goal-directed locomotion task under visually controlled (VC) and visually noncontrolled conditions (VnC).Results.Significantly higher depression scores were found in PD comparing to healthy control groups. In PD, depression was associated with gait components in the VC wherein the place of the target was visible. In contrast, in healthy subjects the depression was associated with gait components in VnC wherein the location and image of the target were memorized and recalled. In patients with PD and depression, the visually deprived multitask augments the rate of cadence and diminishes stride length, while velocity remains relatively unchanged. The depression associated with gait characteristics as a comorbid affective factor in PD, and that impairs the coherence of gait pattern.Conclusion.The relationship between depression and gait parameters appears to indicate that PD not only is a neurological disease but also incorporates affective disturbances that associate with the regulation of gait characteristics.
Patients’ Experience of Winter Depression and Light Room Treatment
Authors: Rastad Cecilia , Wetterberg Lennart , Martin Cathrin
Published: February 2017

Background. There is a need for more knowledge on the effects of light room treatment in patients with seasonal affective disorder and to explore patients’ subjective experience of the disease and the treatment.Methods. This was a descriptive and explorative study applying qualitative content analysis. A purposeful sample of 18 psychiatric outpatients with a major depressive disorder with a seasonal pattern and a pretreatment score ≥12 on the 9-item Montgomery-Åsberg Depression self-rating scale was included (10 women and 8 men, aged 24–65 years). All patients had completed light room treatment (≥7/10 consecutive weekdays). Data was collected two weeks after treatment using a semistructured interview guide.Results. Patients described a clear seasonal pattern and a profound struggle to adapt to seasonal changes during the winter, including deterioration in sleep, daily rhythms, energy level, mood, activity, and cognitive functioning. Everyday life was affected with reduced work capacity, social withdrawal, and disturbed relations with family and friends. The light room treatment resulted in a radical and rapid improvement in all the major symptoms with only mild and transient side effects.Discussion. The results indicate that light room treatment is essential for some patients’ ability to cope with seasonal affective disorder.
The Effect of Concentration of Lawsonia inermis as a Corrosion Inhibitor for Aluminum Alloy in Seawater
Authors: Zulkifli F. , Ali Nora’aini , Yusof M. Sukeri M. , Khairul Wan M. , Rahamathullah Rafizah , Isa M. I. N. , Wan Nik W. B.
Published: February 2017

Lawsonia inermis also known as henna was studied as a corrosion inhibitor for aluminum alloy in seawater. The inhibitor has been characterized by optical study via Fourier transform infrared spectroscopy (FTIR). The FTIR proves the existence of hydroxyl and carbonyl functional groups in Lawsonia inermis. Aluminum alloy 5083 immersed in seawater in the absence and presence of Lawsonia inermis was tested using electrochemistry method, namely, electrochemical impedance spectroscopy (EIS) and potentiodynamic polarization (PP). EIS and PP measurements suggest that the addition of Lawsonia inermis has caused the adsorption of inhibitor on the aluminum surface. The adsorption behavior of the inhibitor follow Langmuir adsorption model where the value of free energy of adsorption, -ΔG, is less than 40 kJ/mol indicates that it is a physical adsorption. Finally, it was inferred that Lawsonia inermis has a real potential to act as a corrosion inhibitor for aluminum alloy in seawater.
Optimizing Terminal Delivery of Perishable Products considering Customer Satisfaction
Authors: Wang Xuping , Sun Xiaoyu , Dong Jie , Wang Meng , Ruan Junhu
Published: February 2017

Freshness of products and timeliness of delivery are two critical factors which have impact on customer satisfaction in terminal delivery of perishable products. This paper investigates how to make a cost‐saving vehicle scheduling for perishable products by maximizing customer satisfaction. Customer satisfaction is defined from the two aspects of freshness and time window. Then we develop a priority function based on customer satisfaction and use the hierarchical clustering method to identify customer service priority. Based on the priority, a multiobjective vehicle scheduling optimization model for perishable products is formulated to maximize customer satisfaction and minimize total delivery costs. To solve the proposed model, a priority‐based genetic algorithm (PB‐GA) is designed. Numerical experiments and sensitivity analysis are performed to show the validity and advantage of our approach. Results indicate that PB‐GA can achieve better solutions than traditional genetic algorithm. The improvement of customer satisfaction is higher than the decrease rate of total costs within a certain shelf life range, which reveals that the proposed method is applicable to the terminal delivery of perishable products.
The Roles of Insulin-Like Growth Factors in Mesenchymal Stem Cell Niche
Authors: Youssef Amer , Aboalola Doaa , Han Victor K. M.
Published: February 2017

Many tissues contain adult mesenchymal stem cells (MSCs), which may be used in tissue regeneration therapies. However, the MSC availability in most tissues is limited which demands expansion in vitro following isolation. Like many developing cells, the state of MSCs is affected by the surrounding microenvironment, and mimicking this natural microenvironment that supports multipotent or differentiated state in vivo is essential to understand for the successful use of MSC in regenerative therapies. Many researchers are, therefore, optimizing cell culture conditions in vitro by altering growth factors, extracellular matrices, chemicals, oxygen tension, and surrounding pH to enhance stem cells self-renewal or differentiation. Insulin-like growth factors (IGFs) system has been demonstrated to play an important role in stem cell biology to either promote proliferation and self-renewal or enhance differentiation onset and outcome, depending on the cell culture conditions. In this review, we will describe the importance of IGFs, IGF-1 and IGF-2, in development and in the MSC niche and how they affect the pluripotency or differentiation towards multiple lineages of the three germ layers.
Screw Remaining Life Prediction Based on Quantum Genetic Algorithm and Support Vector Machine
Authors: Zhang Xiaochen , Jiang Dongxiang
Published: February 2017

To predict the remaining life of ball screw, a screw remaining life prediction method based on quantum genetic algorithm (QGA) and support vector machine (SVM) is proposed. A screw accelerated test bench is introduced. Accelerometers are installed to monitor the performance degradation of ball screw. Combined with wavelet packet decomposition and isometric mapping (Isomap), the sensitive feature vectors are obtained and stored in database. Meanwhile, the sensitive feature vectors are randomly chosen from the database and constitute training samples and testing samples. Then the optimal kernel function parameter and penalty factor of SVM are searched with the method of QGA. Finally, the training samples are used to train optimized SVM while testing samples are adopted to test the prediction accuracy of the trained SVM so the screw remaining life prediction model can be got. The experiment results show that the screw remaining life prediction model could effectively predict screw remaining life.
Antihypertensive and Antihypertrophic Effects of Acupuncture at PC6 Acupoints in Spontaneously Hypertensive Rats and the Underlying Mechanisms
Authors: Xin Juan-Juan , Gao Jun-Hong , Wang Yuan-Yuan , Lu Feng-Yan , Zhao Yu-Xue , Jing Xiang-Hong , Yu Xiao-Chun
Published: February 2017

The aim of this work is to investigate the effect of electroacupuncture (EA) at PC6 on the hypertension and myocardial hypertrophy in spontaneously hypertensive rats (SHRs). Thirty SHRs were randomized into model, SHR + EA, and SHR + Sham EA group with WKY rats as normal control. EA was applied once a day in 8 consecutive weeks. The blood pressure (BP), cardiac function, and hypertrophy as well as the underlying mechanisms were investigated. After EA treatment, the enhanced BP in SHR + EA group was significantly lower compared to both the period before EA and model group. Echocardiographic, morphological studies showed that the enhanced left ventricular anterior and posterior wall end‐diastolic (LVAWd and LVPWd) thickness, diameters and cross‐sectional area (CSA) of cardiac myocyte, as well as the ratio of heart weight to body weight (HW/BW), were markedly diminished in SHR + EA group, while the reduced left ventricular ejection fraction, left ventricular short axis fraction shortening, and E/A ratio were significantly ameliorated. The levels of Angiotensin‐converting enzyme (ACE) and Angiotensin II Type 1 and 2 receptors (AT1R, AT2R) in SHRs were also significantly attenuated by EA. The results suggest that EA at bilateral PC6 could arrest the hypertension development and ameliorate the cardiac hypertrophy and malfunction in SHRs, which might be mediated by the regulation of ACE, AT1R, and AT2R.
Cancer Stem Cells Regulate Cancer-Associated Fibroblasts via Activation of Hedgehog Signaling in Mammary Gland Tumors
Authors: Valenti Giovanni , Quinn Hazel M. , Heynen Guus J.J.E. , Lan Linxiang , Holland Jane D. , Vogel Regina , Wulf-Goldenberg Annika , Birchmeier Walter
Published: February 2017

Many tumors display intracellular heterogeneity with subsets of cancer stem cells (CSC) that sustain tumor growth, recurrence, and therapy resistance. Cancer-associated fibroblasts (CAF) have been shown to support and regulate CSC function. Here, we investigate the interactions between CSCs and CAFs in mammary gland tumors driven by combined activation of Wnt/β-catenin and Hgf/Met signaling in mouse mammary epithelial cells. In this setting, CSCs secrete the Hedgehog ligand SHH, which regulate CAFs via paracrine activation of Hedgehog signaling. CAFs subsequently secrete factors that promote expansion and self-renewal of CSCs. In vivo treatment of tumors with the Hedgehog inhibitor vismodegib reduce CAF and CSC expansion, resulting in an overall delay of tumor formation. Our results identify a novel intracellular signaling module that synergistically regulates CAFs and CSCs. Targeting CAFs with Hedgehog inhibitors may offer a novel therapeutic strategy against breast cancer. Cancer Res; 77(8); 2134–47. ©2017 AACR.
Scavenger Receptor A1 Prevents Metastasis of Non–Small Cell Lung Cancer via Suppression of Macrophage Serum Amyloid A1
Authors: Zhang Yan , Wei Yongyue , Jiang Bin , Chen Lili , Bai Hui , Zhu Xudong , Li Xiaoyu , Zhang Hanwen , Yang Qing , Ma Junqing , Xu Yong , Ben Jingjing , Christiani David C. , Chen Qi
Published: February 2017

Mechanisms of cross-talk between tumor cells and tumor-associated macrophages (TAM), which drive metastasis, are not fully understood. Scavenger receptor A1 (SR-A1) expressed primarily in macrophages has been associated with lung tumorigenesis. In this study, we used population genetics, transcriptomics, and functional analyses to uncover how SR-A1 is involved in lung cancer and its prognosis. SR-A1 genetic variants were investigated for possible association with survival of advanced stage NSCLC patients in the Harvard Lung Cancer Study cohort. Two SNPs (rs17484273, rs1484751) in SR-A1 were associated significantly with poor overall survival in this cohort. Data from The Cancer Genome Atlas showed considerable downregulation of SR-A1 in lung tumor tissues. The association of SR-A1 with prognosis was validated in animal models in the context of lung cancer metastasis. Macrophages derived from mice genetically deficient for SR-A1 exhibited accelerated metastasis in a model of lung cancer. On the other hand, tumor cell seeding, migration, and invasion, as well as macrophage accumulation in lung cancer tissue, were enhanced in SR-A1–deficient mice. SR-A1 deletion upregulated serum amyloid A1 (SAA1) in macrophages via MAPK/IκB/NFκB signaling. SAA1 promoted tumor cell invasion and macrophage migration in vitro and in vivo, but these effects were blocked by administration of an anti-SAA1 antibody. Overall, our findings show how SR-A1 suppresses lung cancer metastasis by downregulating SAA1 production in TAMs. Cancer Res; 77(7); 1586–98. ©2017 AACR.
Modeling the Genetic Regulation of Cancer Metabolism: Interplay between Glycolysis and Oxidative Phosphorylation
Authors: Yu Linglin , Lu Mingyang , Jia Dongya , Ma Jianpeng , Ben-Jacob Eshel , Levine Herbert , Kaipparettu Benny Abraham , Onuchic José N.
Published: February 2017

Abnormal metabolism is a hallmark of cancer, yet its regulation remains poorly understood. Cancer cells were considered to utilize primarily glycolysis for ATP production, referred to as the Warburg effect. However, recent evidence suggests that oxidative phosphorylation (OXPHOS) plays a crucial role during cancer progression. Here we utilized a systems biology approach to decipher the regulatory principle of glycolysis and OXPHOS. Integrating information from literature, we constructed a regulatory network of genes and metabolites, from which we extracted a core circuit containing HIF-1, AMPK, and ROS. Our circuit analysis showed that while normal cells have an oxidative state and a glycolytic state, cancer cells can access a hybrid state with both metabolic modes coexisting. This was due to higher ROS production and/or oncogene activation, such as RAS, MYC, and c-SRC. Guided by the model, we developed two signatures consisting of AMPK and HIF-1 downstream genes, respectively, to quantify the activity of glycolysis and OXPHOS. By applying the AMPK and HIF-1 signatures to The Cancer Genome Atlas patient transcriptomics data of multiple cancer types and single-cell RNA-seq data of lung adenocarcinoma, we confirmed an anticorrelation between AMPK and HIF-1 activities and the association of metabolic states with oncogenes. We propose that the hybrid phenotype contributes to metabolic plasticity, allowing cancer cells to adapt to various microenvironments. Using model simulations, our theoretical framework of metabolism can serve as a platform to decode cancer metabolic plasticity and design cancer therapies targeting metabolism. Cancer Res; 77(7); 1564–74. ©2017 AACR.
Gut Microbiota Promotes Obesity-Associated Liver Cancer through PGE2-Mediated Suppression of Antitumor Immunity
Authors: Loo Tze Mun , Kamachi Fumitaka , Watanabe Yoshihiro , Yoshimoto Shin , Kanda Hiroaki , Arai Yuriko , Nakajima-Takagi Yaeko , Iwama Atsushi , Koga Tomoaki , Sugimoto Yukihiko , Ozawa Takayuki , Nakamura Masaru , Kumagai Miho , Watashi Koichi , Taketo Makoto M. , Aoki Tomohiro , Narumiya Shuh , Oshima Masanobu , Arita Makoto , Hara Eiji , Ohtani Naoko
Published: February 2017

Obesity increases the risk of cancers, including hepatocellular carcinomas (HCC). However, the precise molecular mechanisms through which obesity promotes HCC development are still unclear. Recent studies have shown that gut microbiota may influence liver diseases by transferring its metabolites and components. Here, we show that the hepatic translocation of obesity-induced lipoteichoic acid (LTA), a Gram-positive gut microbial component, promotes HCC development by creating a tumor-promoting microenvironment. LTA enhances the senescence-associated secretory phenotype (SASP) of hepatic stellate cells (HSC) collaboratively with an obesity-induced gut microbial metabolite, deoxycholic acid, to upregulate the expression of SASP factors and COX2 through Toll-like receptor 2. Interestingly, COX2-mediated prostaglandin E2 (PGE2) production suppresses the antitumor immunity through a PTGER4 receptor, thereby contributing to HCC progression. Moreover, COX2 overexpression and excess PGE2 production were detected in HSCs in human HCCs with noncirrhotic, nonalcoholic steatohepatitis (NASH), indicating that a similar mechanism could function in humans.

Significance: We showed the importance of the gut–liver axis in obesity-associated HCC. The gut microbiota–driven COX2 pathway produced the lipid mediator PGE2 in senescent HSCs in the tumor microenvironment, which plays a pivotal role in suppressing antitumor immunity, suggesting that PGE2 and its receptor may be novel therapeutic targets for noncirrhotic NASH-associated HCC. Cancer Discov; 7(5); 522–38. ©2017 AACR.

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The Prosody of the Czech Discourse Marker ‘Jasně': An Analysis of Forms and Functions
Authors: Volin Jan , Weingartová Lenka , Niebuhr Oliver
Published: February 2017

Words like yeah, okay and (al)right are fairly unspecific in their lexical semantics, and not least for this reason there is a general tendency for them to occur with highly varied and expressive prosodic patterns across languages. Here we examine in depth the prosodic forms that express eight pragmatic functions of the Czech discourse marker jasně, including resignation, reassurance, surprise, indifference or impatience. Using a collection of 172 tokens from a corpus of scripted dialogues by 30 native speakers, we performed acoustic analyses, applied classification algorithms and solicited judgments from native listeners in a perceptual experiment. There appeared to be multi-parametric differences between jasně realizations in terms of their F0, timing and intensity patterns, which gave rise to generally consistent form-function mappings. For example, resignation seems to be realized with a falling intonation contour, relatively slow tempo, long wordinitial consonant and a short word-final vowel. Although the most significant prosodic parameters used for clustering analysis involved segment durations, all pragmatic functions were expressed by patterns of multiple features.
Structural and Referent-Based Effects on Prosodic Expression in Russian
Authors: Luchkina Tatiana , Cole Jennifer S.
Published: February 2017

This study examines prosody in read productions of two published narratives by 15 Russian speakers. Two distinct sources of variation in acoustic-prosodic expression are considered: structural and referent-based. Structural effects refer to the particular linearization of words in a sentence or phrase. Referent-based effects relate to the semantic and pragmatic characteristics of the discourse referent of a word, and to grammatical roles that are partially dependent on referent characteristics. Here, we examine referent animacy and the related grammatical function of subjecthood, and the relative accessibility or information status of a word. We document patterns of prosodic augmentation and prosodic reduction due to structural and referent-based factors, as evident from change in values of acoustic-prosodic measures mean intensity, duration and f0 range. Prosodic augmentation due to structural effects is observed for words positioned ex-situ, independent of their semantic, grammatical or pragmatic features. Prosodic augmentation due to referent-based effects is observed for words that are grammatical subjects with animate referents. Prosodic expression is further affected by referent information status. Discourse-given and discourse-new information show greater prosodic augmentation than inferable information. A closer look at individual speakers' production styles reveals that structural and referent-based variations occur in combination and interact.
Perspectives on Speech Timing: Coupled Oscillator Modeling of Polish and Finnish
Authors: Malisz Zofia , O’Dell Michael , Nieminen Tommi , Wagner Petra
Published: February 2017

This stud y was ai med at analyzing empirical duration data for Polish spoken at different tempos using an updated version of the Coupled Oscillator Model of speech timing and rhythm variability (O'Dell and Nieminen, 1999, 2009). We use Bayesian inference on parameters relating to speech rate to investigate how tempo affects timing in Polish. The model parameters found are then compared with parameters obtained for equivalent material in Finnish to shed light on which of the effects represent general speech rate mechanisms and which are specific to Polish. We discuss the model and its predictions in the context of current perspectives on speech timing.
An Outbreak of Acute Hepatitis Caused by Genotype IB Hepatitis A Viruses Contaminating the Water Supply in Thailand
Authors: Ruchusatsawat Kriangsak , Wongpiyabovorn Jongkonnee , Kawidam Chonthicha , Thiemsing Laddawan , Sangkitporn Somchai , Yoshizaki Sayaka , Tatsumi Masashi , Takeda Naokazu , Ishii Koji
Published: February 2017

Background: In 2000, an outbreak of acute hepatitis A was reported in a province adjacent to Bangkok, Thailand. Aims: To investigate the cause of the 2000 hepatitis A outbreaks in Thailand using molecular epidemiological analysis. Methods: Serum and stool specimens were collected from patients who were clinically diagnosed with acute viral hepatitis. Water samples from drinking water and deep-drilled wells were also collected. These specimens were subjected to polymerase chain reaction (PCR) amplification and sequencing of the VP1/2A region of the hepatitis A virus (HAV) genome. The entire genome sequence of one of the fecal specimens was determined and phylogenetically analyzed with those of known HAV sequences. Results and Conclusions: Eleven of 24 fecal specimens collected from acute viral hepatitis patients were positive as determined by semi- nested reverse transcription PCR targeting the VP1/2A region of HAV. The nucleotide sequence of these samples had an identical genotype IB sequence, suggesting that the same causative agent was present. The complete nucleotide sequence derived from one of the samples indicated that the Thai genotype IB strain should be classified in a unique phylogenetic cluster. The analysis using an adjusted odds ratio showed that the consumption of groundwater was the most likely risk factor associated with the disease.
Carfilzomib Inhibits Constitutive NF-κB Activation in Mantle Cell Lymphoma B Cells and Leads to the Induction of Apoptosis
Authors: Zhang Yong-Li , Guang Matthew Ho Zhi , Zhuo Hui-Qin , Min Xiang-Hui , Yao Qin , Gu Ai-Qi , Wu Sheng-Hua , Zhang Dai-Bo , Lu Jing-Yuan , Chen Yan , Chen Yu-Han , Zhang Ke-Jie
Published: February 2017

Mantle cell lymphoma (MCL) remains incurable and new treatments are needed, especially in the relapsed/refractory setting. We therefore investigated the effects of carfilzomib, a novel, long-acting, second-generation proteasome inhibitor, in MCL cells. Eight established MCL cell lines and freshly isolated primary MCL cells were treated with carfilzomib. Cell proliferation was assessed by a 3H-thymidine incorporation assay. Cell apoptosis was evaluated by flow cytometry with annexin V and propidium iodide. Electrophoresis mobility shift (EMSA), Western blot, and luciferase assays were used to analyze NF-κB activation and related signaling proteins. Carfilzomib inhibited growth and induced apoptosis in both established MCL cell lines and freshly isolated primary MCL cells in a dose-dependent manner. In contrast, carfilzomib was less toxic to normal peripheral blood mononuclear cells from healthy individuals. The carfilzomib-induced apoptosis of MCL cells occurred in a caspase-dependent manner through both intrinsic and extrinsic caspase pathways. In addition, carfilzomib inhibited constitutive activation of the NF-κB signaling cascade, both in MCL cell lines and primary MCL cells, by completely blocking the phosphorylation of IκBα. Our results demonstrate that carfilzomib can induce growth arrest and apoptosis in MCL cells and that the mechanism may involve the NF-κB signaling pathway.
Maternal Uniparental Disomy 14 (Temple Syndrome) as a Result of a Robertsonian Translocation
Authors: Bertini Veronica , Fogli Antonella , Bruno Rossella , Azzarà Alessia , Michelucci Angela , Mattina Teresa , Bertelloni Silvano , Valetto Angelo
Published: February 2017

Maternal uniparental disomy of chromosome 14 (upd(14)mat) or Temple syndrome is an imprinting disorder associated with a relatively mild phenotype. The absence of specific congenital malformations makes this condition underdiagnosed in clinical practice. A boy with a de novo robertsonian translocation 45,XY,rob(13;14)(q10;q10) is reported; a CGH/SNP array showed a loss of heterozygosity in 14q11.2q13.1. The final diagnosis of upd(14)mat was made by microsatellite analysis, which showed a combination of heterodisomy and isodisomy for different regions of chromosome 14. Obesity after initial failure to thrive developed, while compulsive eating habits were not present, which was helpful for the clinical differential diagnosis of Prader-Willi syndrome. In addition, the boy presented with many phenotypic features associated with upd(14)mat along with hypoesthesia to pain, previously unreported in this disorder, and bilateral cryptorchidism, also rarely described. These features, as well as other clinical manifestations (i.e., truncal obesity, altered pubertal timing), may suggest a hypothalamic-pituitary involvement. A detailed cytogenetic and molecular characterization of the genomic rearrangement is presented. Early genetic diagnosis permits a specific follow-up of children with upd(14)mat in order to optimize the long-term outcome.
Serum Lipid Fractions and Cerebral Microbleeds in a Healthy Japanese Population
Authors: Mitaki Shingo , Nagai Atsushi , Oguro Hiroaki , Yamaguchi Shuhei
Published: February 2017

Background: Cerebral microbleeds (CMBs) are associated with focal hemosiderin deposits and represent a form of cerebral small vessel disease. To date, indefinite and inconsistent reports are available regarding the association between serum lipid fractions and CMBs. In addition, these previous studies did not include Asian populations, who may have a higher risk of cerebral hemorrhage. The purpose of this study was to examine the associations between serum lipid fractions and CMBs in healthy Japanese subjects. Methods: We performed a cross-sectional study involving 4,024 neurologically normal Japanese subjects (mean age 61.6 years). All the participants underwent 1.5-Tesla magnetic resonance imaging scan, and CMBs were classified into 3 groups based on their locations. The concentrations of lipid fractions were categorized into quartiles and the association between the lipid fractions and CMBs were investigated using logistic regression analysis. Results: CMBs were observed in 164 (4.1%) of participants. Of these participants with CMBs, 33 (20.1%) had lobar CMBs and 91 (55.5%) had deep CMBs. Subjects with deep CMBs had lower total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) levels. After adjusting for confounding factors, lower TC and HDL-C levels were still associated with the presence of deep CMBs (OR for the highest vs. the lowest quartiles of TC and HDL-C was 2.28 [95% CI 1.05-4.94], and 1.93 [95% CI 1.02-3.65], respectively). The presence of subcortical infarcts and periventricular hyperintensities was more frequently observed in deep CMBs, whereas white matter hyperintensities were more frequently observed in lobar CMBs. Conclusions: Our results suggest that low serum TC and HDL-C levels are closely associated with deep CMBs.
ABCB1 and SLCO1B3 Gene Polymorphisms and Their Impact on Digoxin Pharmacokinetics in Atrial Fibrillation Patients among the Tunisian Population
Authors: Tounsi Nejia , Trabelsi Imen , Kerkeni Emna , Grissa Mohamed Habib , Fredj Nizar , Sekma Adel , Mzali Malek , Hellara Ilhem , Monastiri Kamel , Douki Wahiba , Nouira Semir
Published: February 2017

Background: Digoxin is a substrate of P-glycoprotein (P-gp) and organic anion transporting polypeptide transporters that are encoded by ABCB1 and SLCO1B3 genes. Genetic polymorphisms in both genes may explain inter-individual variability of serum digoxin concentration (SDC). This study evaluates the possible effect of the most common ABCB1 and SLCO1B3 polymorphisms on SDC after a single oral dose of digoxin in Tunisian atrial fibrillation (AF) patients. Methods:ABCB1 and SLCO1B3 genotypes were analyzed in 102 patients with AF who received digoxin (0.5 mg) without (group I, n = 58) or with the co-administration of P-gp inhibitors (group II, n = 44). SDCs were determined at 6 h following the oral dose. Results: SDCs levels were significantly higher in patients who were co-administered P-gp inhibitors. No influence was noted in ABCB1 and SLCO1B3 polymorphisms on SDC in group I patients. However, SDCs values were significantly different among ABCB1 single nucleotide polymorphisms (SNPs) genotypes of 2677G>T/A (TT, GG>GT, p < 0.05) and 3435C>T (TT, CC>CT, p < 0.05) only in group II with no effect of 1236C>T and SLCO1B3 SNPs. Conclusion: Results suggest that P-gp inhibitors and ABCB1 gene polymorphisms may affect digoxin pharmacokinetics.
Pulmonary Carcinoids and Low-Grade Gastrointestinal Neuroendocrine Tumors Show Common MicroRNA Expression Profiles, Different from Adenocarcinomas and Small Cell Carcinomas
Authors: Yoshimoto Toyoki , Motoi Noriko , Yamamoto Noriko , Nagano Hiroko , Ushijima Masaru , Matsuura Masaaki , Okumura Sakae , Yamaguchi Toshiharu , Fukayama Masashi , Ishikawa Yuichi
Published: February 2017

Background: It is still uncertain whether small cell lung carcinomas (SCLCs), pulmonary carcinoids, and the gastrointestinal neuroendocrine tumors (GI-NETs) have a common origin. MicroRNA (miRNA) expression may clarify their genetic relationships and origin. Methods: First, we compared the miRNA expression signature of formalin-fixed paraffin-embedded (FFPE) samples with frozen samples to verify the applicability of microarray analysis. Second, we compared the comprehensive miRNA expression patterns of pulmonary carcinoids and GI-NETs as well as other types of tumors and normal tissues from each organ using FFPE samples. These data were analyzed by hierarchical clustering and consensus clustering with nonnegative matrix factorization. Results: We confirmed that FFPE samples retained the miRNA signatures. In the first hierarchical clustering comparing carcinoids/NETs with adenocarcinomas and normal tissues, most of the carcinoids (48/50) formed 1 major cluster with loose subpartitioning into each organ type, while all the adenocarcinomas (9/9) and normal tissues (15/15) formed another major cluster. The nonnegative matrix factorization approach largely matched the classification of the hierarchical clustering. In the additional cluster analysis comparing carcinoids/NETs with SCLCs, most carcinoids/NETs (17/22) formed a major cluster, while SCLCs (9/9) grouped together with pulmonary adenocarcinomas (3/3) and normal tissues (6/6) in another major cluster. Furthermore, a subset of miRNAs was successfully identified that exhibited significant expression in carcinoids/NETs. Conclusion: Carcinoids/NETs had a characteristic pattern of miRNA expression, suggesting a common origin for pulmonary carcinoids and GI-NETs. The expression profiles of pulmonary carcinoids and SCLCs were quite different, indicating the distinct histogenesis of these neuroendocrine neoplasms.