bluuebunny/crossref_metadata_2025 huggingface dataset:
Subcritical Multiplication Parameters of the Accelerator-Driven System with 100 MeV Protons at the Kyoto University Critical Assembly
Authors: Lim Jae-Yong , Pyeon Cheol Ho , Yagi Takahiro , Misawa Tsuyoshi
Published: May 2012

Basic experiments on the accelerator-driven system (ADS) at the Kyoto University Critical Assembly are carried out by combining a solid-moderated and -reflected core with the fixed-field alternating gradient accelerator. The reaction rates are measured by the foil activation method to obtain the subcritical multiplication parameters. The numerical calculations are conducted with the use of MCNPX and JENDL/HE-2007 to evaluate the reaction rates of activation foils set in the core region and at the location of the target. Here, a comparison between the measured and calculated eigenvalues reveals a relative difference of around 10% in C/E values. A special mention is made of the fact that the reaction rate analyses in the subcritical systems demonstrate apparently the actual effect of moving the tungsten target into the core on neutron multiplication. A series of further ADS experiments with 100 MeV protons needs to be carried out to evaluate the accuracy of subcritical multiplication parameters.
Implementation of Surface Radiation and Fluid-Structure Thermal Coupling in Atmospheric Reentry
Authors: Joshi Ojas , Leyland Pénélope
Published: May 2012

During atmospheric reentry, radiative heating is one of the most important component of the total heat flux. In this paper, we investigate how the thermal radiation coming from the postshock region interacts with the spacecraft structure. A model that takes into account the radiation reflected by the surface is developed and implemented in a solid solver. A partitioned algorithm performs the coupling between the fluid and the solid thermal fields. Numerical simulation of a hollow cone head and a deployed flap region shows the effects of the radiative cooling and the significance of the surface radiation.
Effect of Marine Omega 3 Fatty Acids on Methylmercury-Induced Toxicity in Fish and Mammalian CellsIn Vitro
Authors: Nøstbakken O. J. , Bredal I. L. , Olsvik P. A. , Huang T. S. , Torstensen B. E.
Published: May 2012

Methylmercury (MeHg) is a ubiquitous environmental contaminant which bioaccumulates in marine biota. Fish constitute an important part of a balanced human diet contributing with health beneficial nutrients but may also contain contaminants such as MeHg. Interactions between the marine n-3 fatty acids eicosapentaenoic acid (20:5n-3, EPA) and docosahexaenoic acid (22:6n-3, DHA) with MeHg-induced toxicity were investigated. Different toxic and metabolic responses were studied in Atlantic salmon kidney (ASK) cell line and the mammalian kidney-derived HEK293 cell line. Both cell lines were preincubated with DHA or EPA prior to MeHg-exposure, and cell toxicity was assessed differently in the cell lines by MeHg-uptake in cells (ASK and HEK293), proliferation (HEK293 and ASK), apoptosis (ASK), oxidation of the red-ox probe roGFP (HEK293), and regulation of selected toxicological and metabolic transcriptional markers (ASK). DHA was observed to decrease the uptake of MeHg in HEK293, but not in ASK cells. DHA also increased, while EPA decreased, MeHg-induced apoptosis in ASK. MeHg exposure induced changes in selected metabolic and known MeHg biomarkers in ASK cells. Both DHA and MeHg, but not EPA, oxidized roGFP in HEK293 cells. In conclusion, marine n-3 fatty acids may ameliorate MeHg toxicity, either by decreasing apoptosis (EPA) or by reducing MeHg uptake (DHA). However, DHA can also augment MeHg toxicity by increasing oxidative stress and apoptosis when combined with MeHg.
Evaluation of Congestion Relief Proposals in a Capital City
Authors: Fowdur Sudhir C. , Rughooputh Soonil D. D. V.
Published: May 2012

This paper aims at analyzing three different solutions suggested for traffic congestion relief in Port Louis, the busiest city of Mauritius. It evaluates the impact of the three alternatives which are the use of Light Rail Transit (LRT) as an alternative mode of transport, the construction of a Ring road around Port Louis, and the upgrading of the current bus network into a Bus Rapid Transit (BRT) system. The impact of these three solutions has been evaluated by performing Traffic Cellular Automata (TCA) simulations. Our studies reveal that the Ring road will lead to more congestion while introducing the LRT or upgrading the current bus network will reduce congestion significantly.
Intraductal Proliferative Lesions of the Breast—Terminology and Biology Matter: Premalignant Lesions or Preinvasive Cancer?
Authors: Costarelli Leopoldo , Campagna Domenico , Mauri Maria , Fortunato Lucio
Published: May 2012

Morphological criteria for the diagnosis of intraductal proliferative lesions of the breast have been an object of research and much controversy, and its terminology is rather confusing. Knowledge of the molecular aspects of this disease probably necessitates further research to clarify if these entities can be identified as breast cancer precursors or as a malignant preinvasive disease. These issues are of great interest not only for their biological implications, but also to the clinician who must understand the disease and direct therapies. Molecular studies have shown that epitheliosis (usual ductal hyperplasia) is not monoclonal, while malignant lesions (atypical ductal hyperplasia, flat epithelial atypia, low-grade and high-grade intraductal carcinoma) constantly show these characteristics. These malignant lesions, classified with a DIN grading system (ductal intraepithelial neoplasia), are not obligate precursors of invasive ductal carcinoma and do not represent different evolving grades in a linear model of cancerogenesis. Breast cancerogenesis probably has different pathways with different morphologic precursors.
Comparative Study of the West African Continental, Coastal, and Marine Atmospheric Profiles during the Summer of 2006
Authors: Kante Ibrahima Kalil , Badiane Daouda , Sall Saïdou Moustapha , Deme Abdoulaye , Diedhiou Arona
Published: May 2012

We used sounding data of the Multidisciplinary Analysis of the African Monsoon experience in summer 2006 at continental and coastal sites of West Africa, respectively, to analyze the vertical profiles of relative humidity, temperature, dew point, and speed and wind direction for the JJAS rainy period. The vertical gradient method is applied to the profiles of some thermodynamic parameters estimated from sounding data to do a comparative study of the structure and thermal properties, moisture, and static stability of the atmospheric boundary layer of inland, coastal, and marine sites to show consistent differences related to geographic factors. In vertical profiles of relative humidity, the intensity is higher in Dakar than in Niamey particularly in the core of the season. There are dry intrusions in the low levels at the beginning and end of the season in Dakar, which do not exist in Niamey. The mixing layer on the continent during the day can reach a height greater than 1100 m, and the inversion layer height can exceed 1700 m. Therefore, the maximum thickness of the boundary layer is observed on the continent during the day, while at night the marine boundary layer is the thickest. The diurnal evolution shows that the mixing layer thickness decreases during the night over the continent but increases at the coast and at sea. In the night at the continental site there is a division of the mixing layer with a consistent residual mixing layer. Continental boundary layer is more unstable during the day, while at night it is the marine boundary layer that is more unstable than the coastal and inland ones.
Hyperthermic Intraoperative Thoracoabdominal Chemotherapy
Authors: Sugarbaker Paul H. , Chang David , Stuart O. Anthony
Published: May 2012

Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment option for selected patients with pseudomyxoma peritonei (PMP) and diffuse malignant peritoneal mesothelioma (DMPM). Tumor infiltration of the hemidiaphragm requiring partial resection occurs as a result of large volume and/or invasive disease at this anatomic site. Transmission of disease from abdomen to chest is a great danger in this group of patients. From a prospective database, patients who had diaphragm resection and then hyperthermic thoracoabdominal chemotherapy (HITAC) as a component of a cytoreductive surgical procedure were identified. Data from control patients receiving HIPEC or hyperthermic intrathoracic chemotherapy (HITOC) were analyzed for comparison. The morbidity, mortality, survival, and recurrence rate within the thoracic space were presented. Thirty patients had partial resection of a hemidiaphragm as part of a cytoreductive surgical procedure that utilized HITAC. The pharmacologic benefit of intracavitary chemotherapy administration was documented with an area under the curve ratio of intracavitary concentration times time to plasma concentration times time of 27 ± 10 for mitomycin C and 75 ± 26 for doxorubicin. Comparing percent chemotherapy absorbed for a ninety-minute treatment showed the largest for HIPEC, then for HITAC, and lowest for HITOC. The incidence of grade 3 and 4 adverse events was 43%. There was no mortality. Adjustments in the chemotherapy dose are not necessary with HITAC. The morbidity was high, the survival was acceptable, and intrathoracic recurrence was low.
Environmental Sound Recognition Using Time-Frequency Intersection Patterns
Authors: Guo Xuan , Toyoda Yoshiyuki , Li Huankang , Huang Jie , Ding Shuxue , Liu Yong
Published: May 2012

Environmental sound recognition is an important function of robots and intelligent computer systems. In this research, we use a multistage perceptron neural network system for environmental sound recognition. The input data is a combination of time-variance pattern of instantaneous powers and frequency-variance pattern with instantaneous spectrum at the power peak, referred to as a time-frequency intersection pattern. Spectra of many environmental sounds change more slowly than those of speech or voice, so the intersectional time-frequency pattern will preserve the major features of environmental sounds but with drastically reduced data requirements. Two experiments were conducted using an original database and an open database created by the RWCP project. The recognition rate for 20 kinds of environmental sounds was 92%. The recognition rate of the new method was about 12% higher than methods using only an instantaneous spectrum. The results are also comparable with HMM-based methods, although those methods need to treat the time variance of an input vector series with more complicated computations.
Two General Algorithms for Computing Fixed Points of Nonexpansive Mappings in Banach Spaces
Authors: Wang Shuang
Published: May 2012

Recently, Yao et al. (2011) introduced two algorithms for solving a system of nonlinear variational inequalities. In this paper, we consider two general algorithms and obtain the extension results for computing fixed points of nonexpansive mappings in Banach spaces. Moreover, the fixed points solve the same system of nonlinear variational inequalities.
Numerical Self-Consistent Analysis of VCSELs
Authors: Sarzała Robert , Czyszanowski Tomasz , Wasiak Michał , Dems Maciej , Piskorski Łukasz , Nakwaski Włodzimierz , Panajotov Krassimir
Published: May 2012

Vertical-cavity surface-emitting lasers (VCSELs) yield single-longitudinal-mode operation, low-divergence circular output beam, and low threshold current. This paper gives an overview on theoretical, self-consistent modelling of physical phenomena occurring in a VCSEL. The model has been experimentally confirmed. We present versatile numerical methods for nitride, arsenide, and phosphide VCSELs emitting light at wavelengths varying from violet to near infrared. We also discuss different designs with respect to optical confinement: gain guidance using tunnel junctions and index guidance using oxide confinement or photonic crystal and we focus on the problem of single-transverse-mode operation.
Statistical Analysis of Single-Trial Granger Causality Spectra
Authors: Brovelli Andrea
Published: May 2012

Granger causality analysis is becoming central for the analysis of interactions between neural populations and oscillatory networks. However, it is currently unclear whether single-trial estimates of Granger causality spectra can be used reliably to assess directional influence. We addressed this issue by combining single-trial Granger causality spectra with statistical inference based on general linear models. The approach was assessed on synthetic and neurophysiological data. Synthetic bivariate data was generated using two autoregressive processes with unidirectional coupling. We simulated two hypothetical experimental conditions: the first mimicked a constant and unidirectional coupling, whereas the second modelled a linear increase in coupling across trials. The statistical analysis of single-trial Granger causality spectra, based ont-tests and linear regression, successfully recovered the underlying pattern of directional influence. In addition, we characterised the minimum number of trials and coupling strengths required for significant detection of directionality. Finally, we demonstrated the relevance for neurophysiology by analysing two local field potentials (LFPs) simultaneously recorded from the prefrontal and premotor cortices of a macaque monkey performing a conditional visuomotor task. Our results suggest that the combination of single-trial Granger causality spectra and statistical inference provides a valuable tool for the analysis of large-scale cortical networks and brain connectivity.
Percutaneous Holmium Laser Fulguration of Calyceal Diverticula
Authors: Alwaal Amjad , Azhar Raed A. , Andonian Sero
Published: May 2012

Introduction. Calyceal diverticular stones are uncommon findings that represent a challenge in their treatment, due to the technical difficulty in accessing the diverticulum, and the high risk of their recurrence. Current percutaneous technique for calyceal diverticular stones involves establishing a renal access, clearing the stone, and fulguration of the diverticular lining with a roller-ball cautery electrode using hypotonic irrigation solution such as sterile water or glycine solution which may be associated with the absorption of hypotonic fluids with its inherent electrolyte disturbances.Case Report. In this paper, we present for the first time percutaneous holmium laser fulguration of calyceal diverticula in 2 patients using normal saline. Their immediate postoperative sodium was unchanged and their follow-up imaging showed absence of stones. Both patients remain asymptomatic at 30 months post-operatively.Conclusion. This demonstrates that holmium laser is a safe alternative method to fulgurate the calyceal diverticulum after clearing the stone percutaneously.
Inflammation-Mediated Regulation of MicroRNA Expression in Transplanted Pancreatic Islets
Authors: Bravo-Egana Valia , Rosero Samuel , Klein Dagmar , Jiang Zhijie , Vargas Nancy , Tsinoremas Nicholas , Doni Marco , Podetta Michele , Ricordi Camillo , Molano R. Damaris , Pileggi Antonello , Pastori Ricardo L.
Published: May 2012

Nonspecific inflammation in the transplant microenvironment results inβ-cell dysfunction and death influencing negatively graft outcome. MicroRNA (miRNA) expression and gene target regulation in transplanted islets are not yet well characterized. We evaluated the impact of inflammation on miRNA expression in transplanted rat islets. Islets exposedin vitroto proinflammatory cytokines and explanted syngeneic islet grafts were evaluated by miRNA arrays. A subset of 26 islet miRNAs was affected by inflammation bothin vivoandin vitro. Induction of miRNAs was dependent on NF-κB, a pathway linked with cytokine-mediated islet cell death. RT-PCR confirmed expression of 8 miRNAs. The association between these miRNAs and mRNA target-predicting algorithms in genome-wide RNA studies ofβ-cell inflammation identified 238 potential miRNA gene targets. Several genes were ontologically associated with regulation of insulin signaling and secretion, diabetes, and islet physiology. One of the most activated miRNAs was miR-21. Overexpression of miR-21 in insulin-secreting MIN6 cells downregulated endogenous expression of the tumor suppressor Pdcd4 and of Pclo, a Ca2+sensor protein involved in insulin secretion. Bioinformatics identified both as potential targets. The integrated analysis of miRNA and mRNA expression profiles revealed potential targets that may identify molecular targets for therapeutic interventions.
The Biphasic Role of Microglia in Alzheimer's Disease
Authors: Mizuno Tetsuya
Published: May 2012

Neuroinflammation is involved in the pathogenesis of Alzheimer's disease (AD). Microglia, macrophage-like resident immune cells in the brain, play critical roles in the inflammatory aspects of AD. Microglia may be activated by oligomeric and fibrillar species of amyloidβ(Aβ) that are constituents of senile plaques and by molecules derived from degenerated neurons, such as purines and chemokines, which enhance their migration and phagocytosis. The main neurotoxic molecules produced by activated microglia may be reactive oxygen species, glutamate, and inflammatory cytokines such as tumor-necrosis-factor-αand interleukin- (IL-) 1βThese molecules differentially induce neurotoxicity. Aβitself directly damages neurons. In terms of neuroprotective properties, microglia treated with fractalkine or IL-34 attenuate Aβneurotoxicity by Aβclearance and the production of antioxidants. Therefore, regulation of the microglial role in neuroprotection may be a useful therapeutic strategy for AD.
Common Fixed Points of Weak Contractions in Cone Metric Spaces
Authors: Ding Hui-Sheng , Kadelburg Zoran , Karapınar Erdal , Radenović Stojan
Published: May 2012

Results on common fixed points of mappings in cone metric spaces under weak contractive conditions (B. S. Choudhury and N. Metiya (2010)) are unified and generalized. Also, cone metric versions of some other related results on weak contractions are proved. Examples show that our results are different than the existing ones.
Role of Cytokines in Systemic Lupus Erythematosus: Recent Progress from GWAS and Sequencing
Authors: Connolly John J. , Hakonarson Hakon
Published: May 2012

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder, known to have a strong genetic component. Concordance between monozygotic twins is approximately 30–40%, which is 8–20 times higher than that of dizygotic twins. In the last decade, genome-wide approaches to understanding SLE have yielded many candidate genes, which are important to understanding the pathophysiology of the disease and potential targets for pharmaceutical intervention. In this paper, we focus on the role of cytokines and examine how genome-wide association studies, copy number variation studies, and next-generation sequencing are being employed to understand the etiology of SLE. Prominent genes identified by these approaches includeBLK, FCγR3B,andTREX1. Our goal is to present a brief overview of genomic approaches to SLE and to introduce some of the key discussion points pertinent to the field.
The Molecular Biology of Soft-Tissue Sarcomas and Current Trends in Therapy
Authors: Quesada Jorge , Amato Robert
Published: May 2012

Basic research in sarcoma models has been fundamental in the discovery of scientific milestones leading to a better understanding of the molecular biology of cancer. Yet, clinical research in sarcoma has lagged behind other cancers because of the multiple clinical and pathological entities that characterize sarcomas and their rarity. Sarcomas encompass a very heterogeneous group of tumors with diverse pathological and clinical overlapping characteristics. Molecular testing has been fundamental in the identification and better definition of more specific entities among this vast array of malignancies. A group of sarcomas are distinguished by specific molecular aberrations such as somatic mutations, intergene deletions, gene amplifications, reciprocal translocations, and complex karyotypes. These and other discoveries have led to a better understanding of the growth signals and the molecular pathways involved in the development of these tumors. These findings are leading to treatment strategies currently under intense investigation. Disruption of the growth signals is being targeted with antagonistic antibodies, tyrosine kinase inhibitors, and inhibitors of several downstream molecules in diverse molecular pathways. Preliminary clinical trials, supported by solid basic research and strong preclinical evidence, promises a new era in the clinical management of these broad spectrum of malignant tumors.
Biomarkers for Hepatocellular Carcinoma
Authors: Behne Tara , Copur M. Sitki
Published: May 2012

The hepatocellular carcinoma (HCC) is one of the most common malignant tumors and carries a poor survival rate. The management of patients at risk for developing HCC remains challenging. Increased understanding of cancer biology and technological advances have enabled identification of a multitude of pathological, genetic, and molecular events that drive hepatocarcinogenesis leading to discovery of numerous potential biomarkers in this disease. They are currently being aggressively evaluated to establish their value in early diagnosis, optimization of therapy, reducing the emergence of new tumors, and preventing the recurrence after surgical resection or liver transplantation. These markers not only help in prediction of prognosis or recurrence but may also assist in deciding appropriate modality of therapy and may represent novel potential targets for therapeutic interventions. In this paper, a summary of most relevant available data from published papers reporting various tissue and serum biomarkers involved in hepatocellular carcinoma was presented.
Care-Seeking Pattern among Persons with Depression and Anxiety: A Population-Based Study in Sweden
Authors: Wallerblad Anna , Möller Jette , Forsell Yvonne
Published: May 2012

Background. In primary care, a vast majority of patients affected with depression and anxiety present with somatic symptoms. Detection rate of psychiatric symptoms is low, and knowledge of factors influencing care seeking in persons affected by depressive and anxiety disorders on a population level is limited. Objective. This study aims to describe if persons, affected by depression and anxiety disorders, seek care and which type of care they seek as well as factors associated with care seeking. Method. Data derives from a longitudinal population-based study of mental health conducted in the Stockholm County in 1998–2010 and the present study includes 8387 subjects. Definitions of anxiety and depressive disorders were made according to DSM-IV criteria, including research criteria, using validated diagnostic scales. 2026 persons (24%) fulfilled the criteria for any depressive or anxiety disorder. Results. Forty-seven percent of those affected by depression and/or anxiety had been seeking care for psychological symptoms within the last year. A major finding was that seeking care for psychological symptoms was associated with having treatment for somatic problems. Conclusions. As a general practitioner, it is of great importance to increase awareness of mild mental illness, especially among groups that might be less expected to be affected.
Crystallinity Improvement of ZnO Thin Film on Different Buffer Layers Grown by MBE
Authors: Ting Shao-Ying , Chen Po-Ju , Wang Hsiang-Chen , Liao Che-Hao , Chang Wen-Ming , Hsieh Ya-Ping , Yang C. C.
Published: May 2012

The material and optical properties of ZnO thin film samples grown on different buffer layers on sapphire substrates through a two‐step temperature variation growth by molecular beam epitaxy were investigated. The thin buffer layer between the ZnO layer and the sapphire substrate decreased the lattice mismatch to achieve higher quality ZnO thin film growth. A GaN buffer layer slightly increased the quality of the ZnO thin film, but the threading dislocations still stretched along the c‐axis of the GaN layer. The use of MgO as the buffer layer decreased the surface roughness of the ZnO thin film by 58.8% due to the suppression of surface cracks through strain transfer of the sample. From deep level emission and rocking curve measurements it was found that the threading dislocations play a more important role than oxygen vacancies for high‐quality ZnO thin film growth.
Low-Cost Monitoring and Intruders Detection Using Wireless Video Sensor Networks
Authors: Bahi Jacques M. , Guyeux Christophe , Makhoul Abdallah , Pham Congduc
Published: May 2012

There is a growing interest in the use of video sensor networks in surveillance applications in order to detect intruders with low cost. The essential concern of such networks is whether or not a specified target can pass or intrude the monitored region without being detected. This concern forms a serious challenge to wireless video sensor networks of weak computation and battery power. In this paper, our aim is to prolong the whole network lifetime while fulfilling the surveillance application needs. We present a novel scheduling algorithm where only a subset of video nodes contributes significantly to detect intruders and prevent malicious attacker to predict the behavior of the network prior to intrusion. Our approach is chaos based, where every node based on its last detection, a hash value and some pseudorandom numbers easily compute a decision function to go to sleep or active mode. We validate the efficiency of our approach through theoretical analysis and demonstrate the benefits of our scheduling algorithm by simulations. Results show that in addition to being able to increase the whole network lifetime and to present comparable results against random attacks (low stealth time), our scheme is also able to withstand malicious attacks due to its fully unpredictable behavior.
A Problem Concerning Yamabe‐Type Operators of Negative Admissible Metrics
Authors: Liang Jin , Zhu Huan
Published: May 2012

This paper is about a problem concerning nonlinear Yamabe‐type operators of negative admissible metrics. We first give a result on σk Yamabe problem of negative admissible metrics by virtue of the degree theory in nonlinear functional analysis and the maximum principle and then establish an existence and uniqueness theorem for the solutions to the problem.
Acquired Resistance to Tamoxifen Is Associated with Loss of the Type I Insulin-like Growth Factor Receptor: Implications for Breast Cancer Treatment
Authors: Fagan Dedra H. , Uselman Ryan R. , Sachdev Deepali , Yee Douglas
Published: May 2012

The role of the insulin-like growth factor (IGF) system in breast cancer is well defined, and inhibitors of this pathway are currently in clinical trials. The majority of anti-IGF1R clinical trials are in estrogen receptor–positive patients who have progressed on prior endocrine therapy; early reports show no benefit for addition of IGF1R inhibitors to endocrine therapy in this setting. In this study, we examined the effectiveness of IGF1R inhibitors in vitro by generating tamoxifen-resistant (TamR) cells. We found that TamR cells had diminished levels of IGF1R with unchanged levels of insulin receptor (IR), and failed to respond to IGF-I–induced Akt activation, proliferation, and anchorage-independent growth while retaining responsiveness to both insulin and IGF-II. The IGF1R antibody dalotuzumab inhibited IGF-I–mediated Akt phosphorylation, proliferation, and anchorage-independent growth in parental cells, but had no effect on TamR cells. An IGF1R tyrosine kinase inhibitor, AEW541, with equal potency for the IGF1R and IR, inhibited IGF-I-, IGF-II-, and insulin-stimulated Akt phosphorylation, proliferation, and anchorage-independent growth in parental cells. Interestingly, AEW541 also inhibited insulin- and IGF-II–stimulated effects in TamR cells. Tamoxifen-treated xenografts also had reduced levels of IGF1R, and dalotuzumab did not enhance the effect of tamoxifen. We conclude that cells selected for tamoxifen resistance in vitro have downregulated IGF1R making antibodies directed against this receptor ineffective. Inhibition of IR may be necessary to manage tamoxifen-resistant breast cancer. Cancer Res; 72(13); 3372–80. ©2012 AACR.
Integrative Array-Based Approach Identifies MZB1 as a Frequently Methylated Putative Tumor Suppressor in Hepatocellular Carcinoma
Authors: Matsumura Satoshi , Imoto Issei , Kozaki Ken-ichi , Matsui Takeshi , Muramatsu Tomoki , Furuta Mayuko , Tanaka Shinji , Sakamoto Michiie , Arii Shigeki , Inazawa Johji
Published: May 2012

Purpose: The aim of this study was the identification of novel tumor suppressor genes (TSG) silenced by DNA hypermethylation in hepatocellular carcinoma (HCC).

Experimental Design: We conducted integrative array-based approach for genome-wide screening of methylation targets using a methylated DNA immunoprecipitation-CpG island microarray and expression array in three universal hepatoma cell lines and normal liver tissue. Through detailed expression and functional analyses using hepatoma cell lines and primary HCC samples, we isolated novel TSGs for HCC.

Results: A total of 642 genes were identified as methylated in three hepatoma cell lines but unmethylated in normal liver tissue, whereas 204 genes on autosomes were identified as genes unexpressed but restored after treatment with 5-aza-2′-deoxycytidine in these cell lines and expressed in normal tissue. Through the integration of results of the two-array analyses and further validation analyses of expression and methylation status in 17 cell lines and 30 primary tumors of hepatoma, we identified MZB1, marginal zone B and B1 cell-specific protein, encoding an endoplasmic reticulum protein, as a putative TSG frequently methylated within its CpG island in hepatoma. Among 162 patients with primary HCC, silencing of MZB1 protein was significantly and independently associated with a worse outcome. Restoration of MZB1 expression in hepatoma cells reduced cell proliferation in vitro and in vivo through G1-arrest.

Conclusions: These results suggest that methylation-mediated silencing of MZB1 expression leads to loss of its tumor-suppressive activity, which may be a factor in the hepatocarcinogenesis, and is a useful prognosticator in HCC. Clin Cancer Res; 18(13); 3541–51. ©2012 AACR.
Increased miR-708 Expression in NSCLC and Its Association with Poor Survival in Lung Adenocarcinoma from Never Smokers
Authors: Jang Jin Sung , Jeon Hyo-Sung , Sun Zhifu , Aubry Marie Christine , Tang Hui , Park Cheol-Hong , Rakhshan Fariborz , Schultz Debra A. , Kolbert Christopher P. , Lupu Ruth , Park Jae Yong , Harris Curtis C. , Yang Ping , Jen Jin
Published: May 2012

Purpose: miRNA plays an important role in human disease and cancer. We seek to investigate the expression status, clinical relevance, and functional role of miRNA in non–small cell lung cancer.

Experimental Design: We conducted miRNA expression profiling in matched lung adenocarcinoma and uninvolved lung using 56 pairs of fresh-frozen (FF) and 47 pairs of formalin-fixed, paraffin-embedded (FFPE) samples from never smokers. The most differentially expressed miRNA genes were evaluated by Cox analysis and log-rank test. Among the best candidate, miR-708 was further examined for differential expression in two independent cohorts. Functional significance of miR-708 expression in lung cancer was examined by identifying its candidate mRNA target and through manipulating its expression levels in cultured cells.

Results: Among the 20 miRNAs most differentially expressed between tested tumor and normal samples, high expression level of miR-708 in the tumors was most strongly associated with an increased risk of death after adjustments for all clinically significant factors including age, sex, and tumor stage (FF cohort: HR, 1.90; 95% CI, 1.08–3.35; P = 0.025 and FFPE cohort: HR, 1.93; 95% CI, 1.02–3.63; P = 0.042). The transcript for TMEM88 gene has a miR-708 binding site in its 3′ UTR and was significantly reduced in tumors high of miR-708. Forced miR-708 expression reduced TMEM88 transcript levels and increased the rate of cell proliferation, invasion, and migration in culture.

Conclusions: miRNA-708 acts as an oncogene contributing to tumor growth and disease progression by directly downregulating TMEM88, a negative regulator of the Wnt signaling pathway in lung cancer. Clin Cancer Res; 18(13); 3658–67. ©2012 AACR.
Targeting Fibroblast Growth Factor Receptor Signaling Inhibits Prostate Cancer Progression
Authors: Feng Shu , Shao Longjiang , Yu Wendong , Gavine Paul , Ittmann Michael
Published: May 2012

Purpose: Extensive correlative studies in human prostate cancer as well as studies in vitro and in mouse models indicate that fibroblast growth factor receptor (FGFR) signaling plays an important role in prostate cancer progression. In this study, we used a probe compound for an FGFR inhibitor, which potently inhibits FGFR-1–3 and significantly inhibits FGFR-4. The purpose of this study is to determine whether targeting FGFR signaling from all four FGFRs will have in vitro activities consistent with inhibition of tumor progression and will inhibit tumor progression in vivo.

Experimental Design: Effects of AZ8010 on FGFR signaling and invasion were analyzed using immortalized normal prostate epithelial (PNT1a) cells and PNT1a overexpressing FGFR-1 or FGFR-4. The effect of AZ8010 on invasion and proliferation in vitro was also evaluated in prostate cancer cell lines. Finally, the impact of AZ8010 on tumor progression in vivo was evaluated using a VCaP xenograft model.

Results: AZ8010 completely inhibits FGFR-1 and significantly inhibits FGFR-4 signaling at 100 nmol/L, which is an achievable in vivo concentration. This results in marked inhibition of extracellular signal–regulated kinase (ERK) phosphorylation and invasion in PNT1a cells expressing FGFR-1 and FGFR-4 and all prostate cancer cell lines tested. Treatment in vivo completely inhibited VCaP tumor growth and significantly inhibited angiogenesis and proliferation and increased cell death in treated tumors. This was associated with marked inhibition of ERK phosphorylation in treated tumors.

Conclusions: Targeting FGFR signaling is a promising new approach to treating aggressive prostate cancer. Clin Cancer Res; 18(14); 3880–8. ©2012 AACR.
Rapid Angiogenesis Onset after Discontinuation of Sunitinib Treatment of Renal Cell Carcinoma Patients
Authors: Griffioen Arjan W. , Mans Laurie A. , de Graaf Annemarie M.A. , Nowak-Sliwinska Patrycja , de Hoog Céline L.M.M. , de Jong Trees A.M. , Vyth-Dreese Florry A. , van Beijnum Judy R. , Bex Axel , Jonasch Eric
Published: May 2012

Purpose: To investigate the angiogenic changes in primary tumor tissue of renal cell carcinoma (RCC) patients treated with VEGF-targeted therapy.

Experimental Design: Phase II trials of VEGF pathway–targeted therapy given before cytoreductive surgery were carried out with metastatic RCC patients with the primary tumor in situ to investigate the necessity of nephrectomy. Primary tumor tissues were obtained and assessed for angiogenesis parameters. Results were compared with similar analyses on untreated tumors.

Results: Sunitinib or bevacizumab pretreatment resulted in a significant reduction of microvessel density in the primary tumor. Also, an increase in vascular pericyte coverage was found in sunitinib-pretreated tumors, consistent with efficient angiogenesis inhibition. Expression of several key regulators of angiogenesis was found to be suppressed in pretreated tissues, among which VEGFR-1 and VEGFR-2, angiopoietin-1 and angiopoietin-2 and platelet-derived growth factor-B. In addition, apoptosis in tumor and endothelial cells was induced. Interestingly, in sunitinib-pretreated tissues a dramatic increase of the number of proliferating endothelial cells was observed, which was not the case in bevacizumab-pretreated tumors. A positive correlation with the interval between halting the therapy and surgery was found, suggesting a compensatory angiogenic response caused by the discontinuation of sunitinib treatment.

Conclusion: This study describes, for the first time, the angiostatic response in human primary renal cancers at the tissue level upon treatment with VEGF-targeted therapy. Discontinuation of treatment with tyrosine kinase inhibitors leads to accelerated endothelial cell proliferation. The results of this study contribute important data to the ongoing discussion on the discontinuation of treatment with kinase inhibitors. Clin Cancer Res; 18(14); 3961–71. ©2012 AACR.
Making Sense of MEK1 Mutations in Intrinsic and Acquired BRAF Inhibitor Resistance
Authors: Paraiso Kim H. T. , Smalley Keiran S. M.
Published: May 2012

In this issue of Cancer Discovery, Shi and colleagues add further insight into the role of exon 3 MEK1 mutations in BRAF inhibitor resistance by demonstrating the presence of P124SMEK1 and I111SMEK1 mutations concurrently with V600E/KBRAF mutations at baseline in 16% of melanoma specimens. Although the presence of P124SMEK1 or I111SMEK1 mutations did not predict for resistance, and these alleles were not selected for upon BRAF inhibition, other exon 3 MEK1 mutations, such as C121S, did convey resistance, suggesting a role for defined exon 3 MEK1 mutations in acquired BRAF inhibitor resistance. Cancer Discov; 2(5); 390–2. ©2012 AACR.

Commentary on Shi et al., p. 414.
Circulating Endothelial Progenitors and Tumor Resistance to Vascular-Targeting Therapies
Authors: De Palma Michele , Nucera Silvia
Published: May 2012

Acute mobilization of circulating endothelial progenitors has been implicated in tumor resistance to vascular-disrupting agents. In the current issue of Cancer Discovery, Taylor and colleagues provide novel insight into the kinetics of endothelial progenitor mobilization by vascular-disrupting agents in both mouse tumor models and cancer patients. Cancer Discov; 2(5); 395–7. ©2012 AACR.

Commentary on Taylor et al., p. 434.
Occupy EGFR
Authors: Park Jin H. , Lemmon Mark A.
Published: May 2012

Erlotinib and gefitinib inhibit the growth of non–small cell lung cancer tumors that harbor activating epidermal growth factor receptor (EGFR) mutations but are ineffective against EGFR variants found in glioblastoma. New studies by Barkovich and colleagues and Vivanco and colleagues show that these drugs only occupy the active sites of glioblastoma-derived EGFR mutants to a limited extent and fail to inhibit the activated receptor. Other EGFR inhibitors that target distinct receptor conformations are more effective in the treatment of glioblastoma. These studies reveal distinct drug selectivities for different EGFR mutations and show that an analysis of binding-site occupancy should be considered as a biomarker for inhibitor efficacy in targeting EGFR. Cancer Discov; 2(5); 398–400. ©2012 AACR.

Commentary on Barkovich et al., p. 450 and Vivanco et al., p. 458.
Predialysis Systolic Blood Pressure Evolution in Incident Hemodialysis Patients: Effects of the Dry Weight Method and Prognostic Value
Authors: Chazot Charles , Vo-Van Cyril , Deleaval Patrik , Lorriaux Christie , Hurot Jean Marc , Mayor Brice , Jean Guillaume
Published: May 2012

Background: The relationship between predialysis blood pressure (BP) and hemodialysis (HD) patient outcomes is controversial. We report the evolution of predialysis BP in incident patients treated with the dry weight method and its relationship with patients’ outcomes. Methods: Between January 2000 and 2009, 308 patients started HD treatment. Fluid was progressively removed. The patients were encouraged to accept long-hour dialysis session and to follow a salt-restricted diet. BP and body weight (BW) were recorded and analyzed at start (week 1, W1) and weeks 8, 12, 26 and 52. Results: The predialysis systolic BP decreased from 142.1 at W1 to 130.7 mm Hg at W52. Postdialysis BW decreased from W1 to W8 (–5.0 ± 4.5%). It was correlated with the decrease of the predialysis systolic BP at W26 and W52. Whereas the patient survival was significantly lower in the lower predialysis systolic BP tertile at W1 like in previous reports calling this phenomenon ‘reverse epidemiology’, no relationship between predialysis BP levels and outcomes was found at W12, W26 and W52. The patients in the tertile of the greater predialysis systolic BP decrease at W12 had significantly better survival in the whole group and in hypertensive patients. This relationship remained significant in the Cox proportional-hazards analysis. Conclusions: Hence the dry weight method is efficient in decreasing the predialysis BP in incident HD patients. The initial BW decrease was correlated with BP decrease at W26 and W52. Early correction of BP by fluid removal erases the reverse epidemiology for BP and influences positively the patient survival.
Temporal Trends in Peritonitis Rates, Microbiology and Outcomes: The Major Clinical Complication of Peritoneal Dialysis
Authors: Rocha Ana , Rodrigues Anabela , Teixeira Laetitia , Carvalho Maria João , Mendonça Denisa , Cabrita António
Published: May 2012

Peritonitis remains a common complication of peritoneal dialysis (PD). The aim of this study was to analyze, in a PD center, long-term temporal trends in peritonitis rates, microbiology and outcomes. We treated 588 cases of peritonitis that occurred during 11,833.6 months at risk. Y-set and twin-bag disconnecting systems were introduced in 1990, mupirocin at the exit site in 2000 and fluconazole prophylaxis in 2005. Vancomycin and ceftazidime were the empiric protocol. Global and 5-year cohort rates were expressed as episodes/patient-year (ep/p-y). A global peritonitis rate reduction was found from 1.02 to 0.47 ep/p-y (p = 0.008). Poisson analyses performed in each of the subgroups of Gram-positive and Gram-negative peritonitis revealed no significant changes over time. No case of vancomycin resistance was identified. There was a downward trend in peritonitis-related hospitalization over time to 0.11 ep/p-y (p ≤ 0.001). Trend analysis showed a favorable, but changing evolution, highlighting the importance of accurate longitudinal PD center registry data and quality control.
Executive Function and Activities of Daily Living in Alzheimer’s Disease: A Correlational Meta-Analysis
Authors: Martyr Anthony , Clare Linda
Published: May 2012

Background: The assessment of executive function (EF) and activities of daily living (ADL) are important elements in the diagnosis of Alzheimer’s disease. Methods: Following a comprehensive search in three databases, a random-effects meta-analysis was used to investigate the association between ADL ability and seventeen tests of EF, three tests of attention and working memory and the Mini-Mental State Examination. The association between EF and ADL ability was further investigated in relation to four different methods of assessing ADL, and one specific ADL, driving. Results: Forty-nine studies met the inclusion criteria, and a total of 3,663 participants were included, the majority of whom were diagnosed with Alzheimer’s disease. Most of the individual tests, including commonly used tests of EF such as the Clock Drawing Test, Letter Fluency and the Trail Making Test Part B, showed a significant moderate association with ADL. Associations between EF and ADL ability were similar for all four methods of assessing ADL ability. Driving ability was also moderately associated with EF. Conclusion: The meta-analysis suggests a consistent moderate association between ADL and EF, supporting the growing evidence for a link between ADL and executive dysfunction in early dementia.
Efficacy and Safety of Donepezil 23 mg versus Donepezil 10 mg for Moderate-to-Severe Alzheimer’s Disease: A Subgroup Analysis in Patients Already Taking or Not Taking Concomitant Memantine
Authors: Doody Rachelle S. , Geldmacher David S. , Farlow Martin R. , Sun Yijun , Moline Margaret , Mackell Joan
Published: May 2012

Background/Aims: A large multicenter trial of donepezil 23 mg/day versus donepezil 10 mg/day for moderate-to-severe Alzheimer’s disease allowed patients taking concomitant memantine. We evaluated the efficacy/safety of donepezil 23 and 10 mg/day in this trial, with respect to concomitant memantine use. Methods: Prespecified analysis of data from a 24-week, randomized, double-blind trial. Patients were randomized to donepezil doses (23 vs. 10 mg/day) and stratified by concomitant memantine use (yes or no). Efficacy and safety were assessed for each donepezil dose in subgroups taking or not taking concomitant memantine. Results: At week 24, donepezil 23 mg/day provided significant cognitive benefits over 10 mg/day (p < 0.01) on the Severe Impairment Battery, with or without concomitant memantine (ANCOVA adjusted for baseline score, country and treatment). The higher dose showed no benefit on the global function, Mini-Mental State Examination or activities of daily living measures in either memantine subgroup. Rates of treatment-emergent adverse events (AEs) were higher for donepezil 23 mg/day with memantine (80.7%) than 23 mg/day without memantine (69.7%) or 10 mg/day with/without memantine (66.7/62.0%); across all treatment groups, most events were mild/moderate in severity. Individual rates of serious AEs were low (<1.0%), regardless of concomitant memantine use. Conclusion: In this population, concomitant memantine use did not alter the response profile of donepezil 23 vs. 10 mg/day. Donepezil 23 mg was generally safe and well tolerated among patients receiving donepezil alone and among patients receiving a combination of donepezil and memantine therapy.
Mesenteric Ischemia in Patients with End-Stage Renal Disease: A Nationwide Longitudinal Study
Authors: Li Szu-Yuan , Chen Yung-Tai , Chen Tzeng-Ji , Tsai Lung-Wen , Yang Wu-Chang , Chen Tzen-Wen
Published: May 2012

Background and Aims: Mesenteric ischemia is an uncommon disorder associated with an extremely high mortality rate. Only limited studies have evaluated this lethal disease among patients with end-stage renal disease (ESRD). The objective of this study was to evaluate the risks of mesenteric ischemia among ESRD patients and compare the incidence between two dialysis modalities. Methods: Records of all ESRD patients older than 20 years of age from 1998 to 2007 and a control group consisting of 1 million records were retrieved from the Taiwan National Health Insurance Research Database. Hospitalizations for mesenteric ischemic events were retrieved using ICD-9-CM diagnosis codes and ICD-9-CM operation codes from inpatient claims. Results: Among 55,807 incident ESRD patients who received hemodialysis or peritoneal dialysis, there were 458 mesenteric ischemic events, corresponding to an incidence rate of 2.7 per 1,000 patient-years. Multivariate Cox regression analysis indicated that the independent risk factors were old age (HR 1.42 per 10 years), diabetes (HR 2.85), peripheral vascular disease (HR 2.66), atrial fibrillation (HR 2.15), heart failure (HR 1.65), chronic pulmonary disease (HR 1.41), neoplasm (HR 1.54), peptic ulcer disease (HR 1.86), and peritoneal dialysis (HR 1.51, all p < 0.05). There was no effect of dialysis modality on the mesenteric ischemia mortality rate. Conclusion: The risk of mesenteric ischemia for ESRD patients was 44.1 (95% confidence interval 13.4–106.2, p < 0.001) times higher than that of the general population. Compared to hemodialysis, peritoneal dialysis was associated with a higher risk of mesenteric ischemia.