bluuebunny/crossref_metadata_2025 huggingface dataset:
Dual PPARα/γAgonism Normalizes Lipoprotein Profile of Renal Dyslipidemia
Authors: Samuelsson O. , Attman P. O. , Gause-Nilsson I. , Svensson M. K. , Alaupovic P.
Published: March 2013

Chronic kidney disease (CKD) is characterised by specific lipoprotein abnormalities and insulin resistance. Dual activation of the peroxisome proliferators-activated receptors (PPAR)αandγcan significantly improve insulin sensitivity. The aim of the study was to investigate the effects of a dual PPARα/γagonist on lipoprotein abnormalities in patients with CKD. One mg of the dual PPARα/γagonist tesaglitazar was given once daily during six weeks to CKD patients, and to healthy subjects. Plasma lipids, apolipoproteins (apo) and discrete lipoprotein subclasses were measured at baseline and end of treatment. In the CKD patients apoA-I increased significantly by 9%, and apoB decreased by 18%. There was an increase of apoC-III in HDL by 30%, and a parallel decrease of apoC-III in VLDL + LDL by 13%. Both the apoB-containing cholesterol-rich and the triglyceride-rich subclasses decreased significantly. With the exception of ApoC-III,all plasma lipids apolipoproteins and lipoprotein subclasses were reduced by treatment down to similar levels as the baseline levels of a healthy group of reference subjects. This study suggests that by improving insulin sensitivity a dual PPARα/γagonist has the potential to normalise most of the lipoprotein abnormalities in patients with CKD.
Pirogow’s Amputation: A Modification of the Operation Method
Authors: Bueschges M. , Muehlberger T. , Mauss K. L. , Bruck J. C. , Ottomann C.
Published: March 2013

Introduction. Pirogow’s amputation at the ankle presents a valuable alternative to lower leg amputation for patients with the corresponding indications. Although this method offers the ability to stay mobile without the use of a prosthesis, it is rarely performed. This paper proposes a modification regarding the operation method of the Pirogow amputation. The results of the modified operation method on ten patients were objectified 12 months after the operation using a patient questionnaire (Ankle Score).Material and Methods. We modified the original method by rotating the calcaneus. To fix the calcaneus to the tibia, Kirschner wire and a 3/0 spongiosa tension screw as well as a Fixateur externe were used.Results. 70% of those questioned who were amputated following the modified Pirogow method indicated an excellent or very good result in total points whereas in the control group (original Pirogow’s amputation) only 40% reported excellent or very good result. In addition, the level of pain experienced one year after the completed operation showed different results in favour of the group being operated with the modified way. Furthermore, patients in both groups showed differences in radiological results, postoperative leg length difference, and postoperative mobility.Conclusion. The modified Pirogow amputation presents a valuable alternative to the original amputation method for patients with the corresponding indications. The benefits are found in the significantly reduced pain, difference in reduced radiological complications, the increase in mobility without a prosthesis, and the reduction of postoperative leg length difference.
Normality of Ethernet Traffic at Large Time Scales
Authors: Lu Zhiping , Li Ming , Zhao Wei
Published: March 2013

We contribute the quantitative descriptions of the large time scales for the Ethernet traffic to be Gaussian. We focus on the normality property of the accumulated traffic data under different time scales. The investigation is carried out graphically by the quantile-quantile (QQ) plots and numerically by statistical tests. The present results indicate that the larger the time scale, the more normal the Ethernet traffic.
Studies on Structural, Spectral, and Optical Properties of Organic Nonlinear Optical Single Crystal: 2-Amino-4,6-dimethylpyrimidinium p-Hydroxybenzoate
Authors: Sudhahar S. , Krishna Kumar M. , Silambarasan A. , Muralidharan R. , Mohan Kumar R.
Published: March 2013

2-Amino-4,6-dimethylpyrimidinium p-hydroxybenzoate (ADPHB), a novel organic material, was synthesized, and crystals were grown by slow evaporation solution growth method. The cell parameters and crystalline perfection of the grown crystal were studied by single crystal and powder X-ray diffraction analyses. The presence of various functional groups of the grown crystal was confirmed using Fourier Transform infrared spectral analysis. UV-Visible spectrum shows that ADPHB crystals have high transmittance in the range 305–900 nm. The refractive index and transient photoluminescence properties of the grown crystal were analyzed. The laser induced surface damage threshold, optical birefringence, and second harmonic generation efficiency of the grown crystal were studied.
In VitroEvaluations of Cytotoxicity of Eight Antidiabetic Medicinal Plants and Their Effect on GLUT4 Translocation
Authors: Kadan Sleman , Saad Bashar , Sasson Yoel , Zaid Hilal
Published: March 2013

Despite the enormous achievements in conventional medicine, herbal-based medicines are still a common practice for the treatment of diabetes.Trigonella foenum-graecum,Atriplex halimus,Olea europaea,Urtica dioica,Allium sativum,Allium cepa,Nigella sativa, andCinnamomum cassiaare strongly recommended in the Greco-Arab and Islamic medicine for the treatment and prevention of diabetes. Cytotoxicity (MTT and LDH assays) of the plant extracts was assessed using cells from the liver hepatocellular carcinoma cell line (HepG2) and cells from the rat L6 muscle cell line. The effects of the plant extracts (50% ethanol in water) on glucose transporter-4 (GLUT4) translocation to the plasma membrane was tested in an ELISA test on L6-GLUT4myc cells. Results obtained indicate thatCinnamomon cassiais cytotoxic at concentrations higher than 100 μg/mL, whereas all other tested extracts exhibited cytotoxic effects at concentrations higher than 500 μg/mL. Exposing L6-GLUT4myc muscle cell to extracts fromTrigonella foenum-graecum,Urtica dioica,Atriplex halimus, andCinnamomum verumled to a significant gain in GLUT4 on their plasma membranes at noncytotoxic concentrations as measured with MTT assay and the LDH leakage assay. These findings indicate that the observed anti-diabetic properties of these plants are mediated, at least partially, through regulating GLUT4 translocation.
Texture Enhancement for Medical Images Based on Fractional Differential Masks
Authors: Jalab Hamid A. , Ibrahim Rabha W.
Published: March 2013

Texture enhancement for medical images is the most important technique in medical image diagnosis. This paper introduces a texture enhancement technique for medical images by using fractional differential (FD) masks based on Srivastava-Owa fractional operators. We also construct a 2D isotropic gradient mask based on generalized fractional operators. Texture enhancement performance is measured by applying experiments according to visual perception and by using Sobel/Canny edge filters and gray-level co-occurrence matrix. We discuss the capability of the FD mask for texture enhancement. The experiments and analysis show that the operator can extract subtle information and make the edges prominent.
Differentiation of Human Dermal Mesenchymal Stem Cells into Cardiomyocytes by Treatment with 5-Azacytidine: Concept for Regenerative Therapy in Myocardial Infarction
Authors: Potdar Pravin D. , Prasannan Preeti
Published: March 2013

Myocardial infarction (MI) is the leading cause of death worldwide. Stem cells regenerative medicine offers a promising approach to cure such degenerative disorders. Mesenchymal stem cells are thought to be one of the important types of stem cells which can differentiate into various lineages such as neuron, hepatocytes, and cardiomyocytes. In the present study, human dermal mesenchymal stem cells (hDMSCs) have been developed from human scalp punch biopsy and characterized for their mesenchymal phenotype so that these cells can be useful for differentiating into cardiomyocytes. 5-Azacytidine induces cardiomyocyte differentiation in vitro and therefore it has been used to differentiate hDMSCs cells into cardiomyocytes. It was observed that hDMSCs differentiated into cardiomyocyte within a period of 4 days to 15 days after treatment with 10 μM and 20 μM of 5-azacytidine. The cardiomyocyte phenotype was confirmed by studying expression of α-cardiac actin, β-myosin heavy chain, and cardiac troponin T. Thus, this paper describes the differentiation of hDMSCs into cardiomyocytes which can be further be used for treatment of MI. This type of cell-based cardiac therapy will offer a new hope for millions of patients worldwide who are suffering from heart disease.
Expiratory Flow Limitation Definition, Mechanisms, Methods, and Significance
Authors: Tantucci Claudio
Published: March 2013

When expiratory flow is maximal during tidal breathing and cannot be increased unless operative lung volumes move towards total lung capacity, tidal expiratory flow limitation (EFL) is said to occur. EFL represents a severe mechanical constraint caused by different mechanisms and observed in different conditions, but it is more relevant in terms of prevalence and negative consequences in obstructive lung diseases and particularly in chronic obstructive pulmonary disease (COPD). Although in COPD patients EFL more commonly develops during exercise, in more advanced disorder it can be present at rest, before in supine position, and then in seated-sitting position. In any circumstances EFL predisposes to pulmonary dynamic hyperinflation and its unfavorable effects such as increased elastic work of breathing, inspiratory muscles dysfunction, and progressive neuroventilatory dissociation, leading to reduced exercise tolerance, marked breathlessness during effort, and severe chronic dyspnea.
Positive Solutions of Fractional Differential Equation with -Laplacian Operator
Authors: Ren Teng , Chen Xiaochun
Published: March 2013

The basic assumption of ecological economics is that resource allocation exists social optimal solution, and the social optimal solution and the optimal solution of enterprises can be complementary. The mathematical methods and the ecological model are one of the important means in the study of ecological economics. In this paper, we study an ecological model arising from ecological economics by mathematical method, that is, study the existence of positive solutions for the fractional differential equation with -Laplacian operator , , , , , and , where are the standard Riemann-Liouville derivatives, -Laplacian operator is defined as , and the nonlinearity may be singular at both and By finding more suitable upper and lower solutions, we omit some key conditions of some existing works, and the existence of positive solution is established.
Conditional Nonlinear Optimal Perturbation of a Coupled Lorenz Model
Authors: Yang Lili
Published: March 2013

The conditional nonlinear optimal perturbation (CNOP) technique is a useful tool for studying the limits of predictability in numerical weather forecasting and climate predictions. The CNOP is the optimal combined mode of the initial and model parameter perturbations that induce the largest departure from a given reference state. The CNOP has two special cases: the CNOP-I is linked to initial perturbations and has the largest nonlinear evolution at the time of prediction, while the other case, CNOP-P, is related to the parameter perturbations that cause the largest departure from a given reference state at a given future time. Solving the CNOPs of a numerical model is a mathematical problem. In this paper, we calculate the CNOP, CNOP-I, and CNOP-P of a coupled Lorenz model and study the properties of these CNOPs. We find that the CNOP, CNOP-I, and CNOP-P always locate the boundary of their respective constraints. This property is also demonstrated analytically for the model whose solutions depend continuously on the initial and parameter perturbations, which provides a theoretical basis for testing the accountability of the numerically computed CNOPs. In addition, we analyze the features of the CNOPs for the coupled Lorenz model and explain their structures.
High-Resolution Direction-of-Arrival Estimation via Concentric Circular Arrays
Authors: Ata Serdar Ozgur , Isik Cevdet
Published: March 2013

Estimating the direction of arrival (DOA) of source signals is an important research interest in application areas including radar, sonar, and wireless communications. In this paper, the problem of DOA estimation is addressed on concentric circular antenna arrays (CCA) in detail as an alternative to the well-known geometries of the uniform linear array (ULA) and uniform circular array (UCA). We define the steering matrix of the CCA geometry and investigate the performance analysis of the array in the DOA-estimation problem by simulations that are realized through varying the parameters of signal-to-noise ratio, number of sensors, and resolution angle of sensor arrays by using the MUSIC (Multiple Signal Classification) algorithm. The results present that CCA geometries provide higher angle resolutions compared to UCA geometries and require less physical area for the same number of sensor elements. However, as a cost-increasing effect, higher computational power is needed to estimate the DOA of source signals in CCAs compared to ULAs.
Temporal Trends in Chorioamnionitis by Maternal Race/Ethnicity and Gestational Age (1995–2010)
Authors: Fassett Michael J. , Wing Deborah A. , Getahun Darios
Published: March 2013

Objective. To characterize trends in chorioamnionitis (CAM) by maternal race/ethnicity and gestational age.Study Design. We examined trends in CAM from 1995–2010 among singleton births in all Kaiser Permanente Southern California hospitals (). Data were extracted from Perinatal Service System and clinical utilization records. Gestational age- and race/ethnicity-specific biannual diagnosis rates were estimated using the Poisson regression after adjusting for potential confounding factors.Results. Overall diagnosis rates of CAM increased from 2.7% in 1995-1996 to 6.0% in 2009-2010 with a relative increase of 126% (95% confidence intervals [CI] 113%–149%). From 1995-1996 to 2009-2010, CAM increased among the Whites (1.8% to 4.3%, -value for trend <.001), Blacks (2.2% to 3.7%, -value for trend <.001), Hispanics (2.4% to 5.8%, -value for trend <.001), and Asian/Pacific Islanders (3.6% to 9.0%, -value for trend <.001). The adjusted relative percentage change in CAM from 1995-1996 to 2009-2010 was for Whites [preterm 21% (9%–78%), term 138% (108%–173%)], for Blacks [preterm 24% (−9%–81%), term 62% (30%–101%)], for Hispanics [preterm 31% (3%–66%), term 135% (114%–159%)], and for Asian/Pacific Islanders [preterm 44% (9%–127%), term 145% (109%–188%)].Conclusion. The findings suggest that CAM diagnosis rate has increased for all race/ethnic groups. This increase is primarily due to increased diagnosis at term gestation.
Adult-Onset Type 1 Diabetes and Pregnancy: Three Case Reports
Authors: Bonsembiante Barbara , Dalfrà Maria Grazia , Masin Michela , Gallo Alessandra , Lapolla Annunziata
Published: March 2013

From 5% to 10% of diabetic patients have type 1 diabetes. Here we describe three cases of adult-onset type 1 diabetes in pregnancy treated at our clinic between 2009 and 2012. Two patients came for specialist examination during pregnancy, the third after pregnancy. These women had no prior overt diabetes and shared certain characteristics, that is, no family diabetes history, age over 35, normal prepregnancy BMI, need for insulin therapy as of the early weeks of pregnancy, and high-titer anti-GAD antibody positivity. The patients had persistent diabetes after delivery, suggesting that they developed adult-onset type 1 diabetes during pregnancy. About 10% of GDM patients become pancreatic autoantibody positive and the risk of developing overt diabetes is higher when two or more autoantibodies are present (particularly GAD and ICA). GAD-Ab shows the highest sensitivity for type 1 diabetes prediction. We need to bear in mind that older patients might conceivably develop an adult-onset type 1 diabetes during or after pregnancy. So we suggest that women with GDM showing the described clinical features shall be preferably tested for autoimmunity. Pregnant patients at risk of type 1 diabetes should be identified to avoid the maternal and fetal complications and the acute onset of diabetes afterwards.
Optimal Coordinated Design of Multiple Damping Controllers Based on PSS and UPFC Device to Improve Dynamic Stability in the Power System
Authors: Hussain A. N. , Malek F. , Rashid M. A. , Mohamed L. , Mohd Affendi N. A.
Published: March 2013

Unified Power Flow Controller (UPFC) device is applied to control power flow in transmission lines. Supplementary damping controller can be installed on any control channel of the UPFC inputs to implement the task of Power Oscillation Damping (POD) controller. In this paper, we have presented the simultaneous coordinated design of the multiple damping controllers between Power System Stabilizer (PSS) and UPFC-based POD or between different multiple UPFC-based POD controllers without PSS in a single-machine infinite-bus power system in order to identify the design that provided the most effective damping performance. The parameters of the damping controllers are optimized utilizing a Chaotic Particle Swarm Optimization (CPSO) algorithm based on eigenvalue objective function. The simulation results show that the coordinated design of the multiple damping controllers has high ability in damping oscillations compared to the individual damping controllers. Furthermore, the coordinated design of UPFC-based POD controllers demonstrates the superiority over the coordinated design of PSS and UPFC-based POD controllers for enhancing greatly the stability of the power system.
High-Throughput Tyrosine Kinase Activity Profiling Identifies FAK as a Candidate Therapeutic Target in Ewing Sarcoma
Authors: Crompton Brian D. , Carlton Anne L. , Thorner Aaron R. , Christie Amanda L. , Du Jinyan , Calicchio Monica L. , Rivera Miguel N. , Fleming Mark D. , Kohl Nancy E. , Kung Andrew L. , Stegmaier Kimberly
Published: March 2013

Limited progress has been made in the treatment of advanced-stage pediatric solid tumors despite the accelerated pace of cancer discovery over the last decade. Tyrosine kinase inhibition is one tractable therapeutic modality for treating human malignancy. However, little is known about the kinases critical to the development or maintenance of many pediatric solid tumors such as Ewing sarcoma. Using a fluorescent, bead-based technology to profile activated tyrosine kinases, we identified focal adhesion kinase (FAK, PTK2) as a candidate target in Ewing sarcoma. FAK is a tyrosine kinase critical for cellular adhesion, growth, and survival. As such, it is a compelling target for cancer-based therapy. In this study, we have shown that FAK is highly phosphorylated in primary Ewing sarcoma tumor samples and that downregulation of FAK by short hairpin RNA and treatment with a FAK-selective kinase inhibitor, PF-562271, impaired growth and colony formation in Ewing sarcoma cell lines. Moreover, treatment of Ewing sarcoma cell lines with PF-562271 induced apoptosis and led to downregulation of AKT/mTOR and CAS activity. Finally, we showed that small-molecule inhibition of FAK attenuated Ewing sarcoma tumor growth in vivo. With FAK inhibitors currently in early-phase clinical trials for adult malignancies, these findings may bear immediate relevance to patients with Ewing sarcoma. Cancer Res; 73(9); 2873–83. ©2013 AACR.
Th-MYCN Mice with Caspase-8 Deficiency Develop Advanced Neuroblastoma with Bone Marrow Metastasis
Authors: Teitz Tal , Inoue Madoka , Valentine Marcus B. , Zhu Kejin , Rehg Jerold E. , Zhao Wei , Finkelstein David , Wang Yong-Dong , Johnson Melissa D. , Calabrese Christopher , Rubinstein Marcelo , Hakem Razqallah , Weiss William A. , Lahti Jill M.
Published: March 2013

Neuroblastoma, the most common extracranial pediatric solid tumor, is responsible for 15% of all childhood cancer deaths. Patients frequently present at diagnosis with metastatic disease, particularly to the bone marrow. Advances in therapy and understanding of the metastatic process have been limited due, in part, to the lack of animal models harboring bone marrow disease. The widely used transgenic model, the Th-MYCN mouse, exhibits limited metastasis to this site. Here, we establish the first genetic immunocompetent mouse model for metastatic neuroblastoma with enhanced secondary tumors in the bone marrow. This model recapitulates 2 frequent alterations in metastatic neuroblasoma, overexpression of MYCN and loss of caspase-8 expression. Mouse caspase-8 gene was deleted in neural crest lineage cells by crossing a Th-Cre transgenic mouse with a caspase-8 conditional knockout mouse. This mouse was then crossed with the neuroblastoma prone Th-MYCN mouse. Although overexpression of MYCN by itself rarely caused bone marrow metastasis, combining MYCN overexpression and caspase-8 deletion significantly enhanced bone marrow metastasis (37% incidence). Microarray expression studies of the primary tumors mRNAs and microRNAs revealed extracellular matrix structural changes, increased expression of genes involved in epithelial to mesenchymal transition, inflammation, and downregulation of miR-7a and miR-29b. These molecular changes have been shown to be associated with tumor progression and activation of the cytokine TGF-β pathway in various tumor models. Cytokine TGF-β can preferentially promote single cell motility and blood-borne metastasis and therefore activation of this pathway may explain the enhanced bone marrow metastasis observed in this animal model. Cancer Res; 73(13); 4086–97. ©2013 AACR.
Tumor–Immune Dynamics Regulated in the Microenvironment Inform the Transient Nature of Immune-Induced Tumor Dormancy
Authors: Wilkie Kathleen P. , Hahnfeldt Philip
Published: March 2013

Cancer in a host induces responses that increase the ability of the microenvironment to sustain the growing mass, for example, angiogenesis, but cancer cells can have varying sensitivities to these sustainability signals. Here, we show that these sensitivities are significant determinants of ultimate tumor fate, especially in response to treatments and immune interactions. We present a mathematical model of cancer–immune interactions that modifies generalized logistic growth with both immune-predation and immune-recruitment. The role of a growing environmental carrying capacity is discussed as a possible regulatory mechanism for tumor growth, and this regulation is shown to modify cancer–immune interactions and the possibility of achieving immune-induced tumor dormancy. This mathematical model qualitatively matches experimental observations of immune-induced tumor dormancy as it predicts dormancy as a transient period of growth that necessarily ends in either tumor elimination or tumor escape. As dormant tumors may exist asymptomatically and may be easier to treat with conventional therapy, an understanding of the mechanisms behind tumor dormancy may lead to new treatments aimed at prolonging the dormant state or converting an aggressive cancer to the dormant state. Cancer Res; 73(12); 3534–44. ©2013 AACR.
NIK Controls Classical and Alternative NF-κB Activation and Is Necessary for the Survival of Human T-cell Lymphoma Cells
Authors: Odqvist Lina , Sánchez-Beato Margarita , Montes-Moreno Santiago , Martín-Sánchez Esperanza , Pajares Raquel , Sánchez-Verde Lydia , Ortiz-Romero Pablo L. , Rodriguez Jose , Rodríguez-Pinilla Socorro M. , Iniesta-Martínez Francisca , Solera-Arroyo Juan Carlos , Ramos-Asensio Rafael , Flores Teresa , Palanca Javier Menarguez , Bragado Federico García , Franjo Purificación Domínguez , Piris Miguel A.
Published: March 2013

Purpose: Peripheral T-cell lymphomas (PTCL) are a heterogeneous entity of neoplasms with poor prognosis, a lack of effective therapies, and a largely unknown molecular pathology. Deregulated NF-κB activity has been associated with several lymphoproliferative diseases, but its importance in T-cell lymphomagenesis is poorly understood. We investigated the function of the NF-κB–inducing kinase (NIK), in this pathway and its role as a potential molecular target in T-cell lymphomas.

Experimental Design: We used immunohistochemistry to analyze the expression of different NF-κB members in primary human PTCL samples and to study its clinical impact. With the aim of inhibiting the pathway, we used genetic silencing of NIK in several T-cell lymphoma cell lines and observed its effect on downstream targets and cell viability.

Results: We showed that the NF-κB pathway was activated in a subset of PTCLs associated with poor overall survival. NIK was overexpressed in a number of PTCL cell lines and primary samples, and a pivotal role for NIK in the survival of these tumor cells was unveiled. NIK depletion led to a dramatic induction of apoptosis in NIK-overexpressing cell lines and also showed a more pronounced effect on cell survival than inhibitor of kappa B kinase (IKK) knockdown. NIK silencing induced a blockage of both classical and alternative NF-κB activation and reduced expression of several prosurvival and antiapoptotic factors.

Conclusions: The results of the present study indicate that NIK could be a promising therapeutic target in these aggressive malignancies. Clin Cancer Res; 19(9); 2319–30. ©2013 AACR.
Identification and Validation of a Blood-Based 18-Gene Expression Signature in Colorectal Cancer
Authors: Xu Ye , Xu Qinghua , Yang Li , Ye Xun , Liu Fang , Wu Fei , Ni Shujuan , Tan Cong , Cai Guoxiang , Meng Xia , Cai Sanjun , Du Xiang
Published: March 2013

Purpose: The early detection of colorectal cancer (CRC) is crucial for successful treatment and patient survival. However, compliance with current screening methods remains poor. This study aimed to identify an accurate blood-based gene expression signature for CRC detection.

Experimental Design: Gene expression in peripheral blood samples from 216 patients with CRC tumors and 187 controls was investigated in the study. We first conducted a microarray analysis to select candidate genes that were significantly differentially expressed between patients with cancer and controls. A quantitative reverse transcription PCR assay was then used to evaluate the expression of selected genes. A gene expression signature was identified using a training set (n = 200) and then validated using an independent test set (n = 160).

Results: We identified an 18-gene signature that discriminated the patients with CRC from controls with 92% accuracy, 91% sensitivity, and 92% specificity. The signature performance was further validated in the independent test set with 86% accuracy, 84% sensitivity, and 88% specificity. The area under the receiver operating characteristics curve was 0.94. The signature was shown to be enriched in genes related to immune functions.

Conclusions: This study identified an 18-gene signature that accurately discriminated patients with CRC from controls in peripheral blood samples. Our results prompt the further development of blood-based gene expression biomarkers for the diagnosis and early detection of CRC. Clin Cancer Res; 19(11); 3039–49. ©2013 AACR.
Suppression of Survivin Induced by a BCR-ABL/JAK2/STAT3 Pathway Sensitizes Imatinib-Resistant CML Cells to Different Cytotoxic Drugs
Authors: Stella Stefania , Tirrò Elena , Conte Enrico , Stagno Fabio , Di Raimondo Francesco , Manzella Livia , Vigneri Paolo
Published: March 2013

The BCR-ABL oncoprotein of chronic myelogenous leukemia (CML) displays exclusive cytoplasmic localization and constitutive tyrosine kinase activity leading to the activation of different pathways that favor cell proliferation and survival. BCR-ABL induces survivin expression at both the mRNA and protein level, thus inhibiting the apoptotic machinery of CML cells and contributing to the expansion of the leukemic clone. We report that, in human CML cell lines, BCR-ABL–mediated upregulation of survivin involves the JAK2/STAT3 pathway since silencing of either protein caused a consistent reduction in survivin expression. Cell lines unresponsive to imatinib mesylate (IM) because of BCR-ABL gene amplification were not resensitized to the drug after survivin downregulation. However, cells insensitive to IM because of point mutations in the BCR-ABL kinase domain were highly responsive to hydroxyurea (HU) after survivin silencing. To address the possible clinical applications of our results, we used shepherdin, a cell-permeable peptidomimetic compound that downregulates survivin expression by preventing its interaction with Hsp90. Incubation with shepherdin of immortalized cell lines both sensitive and resistant to IM enhanced cell death induced by HU and doxorubicin. Similarly, the combination of shepherdin with first- and second-generation tyrosine kinase inhibitors reduced the colony-forming potential of human progenitors derived from both patients with IM-sensitive and IM-resistant CML. These results suggest that strategies aimed at reducing survivin levels may represent a potential therapeutic option for patients with CML unresponsive to IM. Mol Cancer Ther; 12(6); 1085–98. ©2013 AACR.
Expression of Leukemia-Associated Fusion Proteins Increases Sensitivity to Histone Deacetylase Inhibitor–Induced DNA Damage and Apoptosis
Authors: Petruccelli Luca A. , Pettersson Filippa , del Rincón Sonia V. , Guilbert Cynthia , Licht Jonathan D. , Miller Wilson H.
Published: March 2013

Histone deacetylase inhibitors (HDI) show activity in a broad range of hematologic and solid malignancies, yet the percentage of patients in any given malignancy who experience a meaningful clinical response remains small. In this study, we sought to investigate HDI efficacy in acute myeloid leukemia (AML) cells expressing leukemia-associated fusion proteins (LAFP). HDIs have been shown to induce apoptosis, in part, through accumulation of DNA damage and inhibition of DNA repair. LAFPs have been correlated with a DNA repair–deficient phenotype, which may make them more sensitive to HDI-induced DNA damage. We found that expression of the LAFPs PLZF-RARα, PML-RARα, and RUNX1-ETO (AML1-ETO) increased sensitivity to DNA damage and apoptosis induced by the HDI vorinostat. The increase in apoptosis correlated with an enhanced downregulation of the prosurvival protein BCL2. Vorinostat also induced expression of the cell-cycle regulators p19INK4D and p21WAF1 and triggered a G2–M cell cycle arrest to a greater extent in LAFP-expressing cells. The combination of LAFP and vorinostat further led to a greater downregulation of several base excision repair (BER) enzymes. These BER genes represent biomarker candidates for response to HDI-induced DNA damage. Notably, repair of vorinostat-induced DNA double-strand breaks was found to be impaired in PLZF-RARα–expressing cells, suggesting a mechanism by which LAFP expression and HDI treatment cooperate to cause an accumulation of damaged DNA. These data support the continued study of HDI-based treatment regimens in LAFP-positive AMLs. Mol Cancer Ther; 12(8); 1591–604. ©2013 AACR.
HGF as a Circulating Biomarker of Onartuzumab Treatment in Patients with Advanced Solid Tumors
Authors: Penuel Elicia , Li Congfen , Parab Vaishali , Burton Luciana , Cowan Kyra J. , Merchant Mark , Yauch Robert L. , Patel Premal , Peterson Amy , Hampton Garret M. , Lackner Mark R. , Hegde Priti S.
Published: March 2013

The objective of this study was to evaluate circulating hepatocyte growth factor (cHGF) as a pharmacodynamic biomarker of Met inhibition for onartuzumab (MetMAb, OA5D5v2) in a phase I trial in patients with advanced cancers and a phase II trial in non–small cell lung cancer (NSCLC). The phase I study was a dose escalation trial with onartuzumab administered i.v. once every three weeks. The phase II study was a randomized two-arm trial in which onartuzumab or placebo was administered in combination with erlotinib in 137 patients with second and third line (2/3L) NSCLC. cHGF levels were evaluated by ELISA at multiple time points over the treatment period. Onartuzumab administration resulted in an acute and sustained rise in cHGF in both the phase I and phase II studies. Elevation in cHGF was independent of dose or drug exposure and was restricted to onartuzumab treatment. Neither higher baseline nor elevated change in cHGF levels upon treatment could simply be attributed to tumor burden or number of liver metastasis. We have shown that elevated cHGF can consistently and reproducibly be measured as a pharmacodynamic biomarker of onartuzumab activity. The elevation in cHGF is independent of tumor type, dose administered, or dose duration. Although these studies were not powered to directly address the contribution of cHGF as a predictive, on-treatment, circulating biomarker, these data suggest that measurement of cHGF in future expanded studies is warranted. Mol Cancer Ther; 12(6); 1122–30. ©2013 AACR.
Canonical Wnt/β-catenin Signaling Drives Human Schwann Cell Transformation, Progression, and Tumor Maintenance
Authors: Watson Adrienne L. , Rahrmann Eric P. , Moriarity Branden S. , Choi Kwangmin , Conboy Caitlin B. , Greeley Andrew D. , Halfond Amanda L. , Anderson Leah K. , Wahl Brian R. , Keng Vincent W. , Rizzardi Anthony E. , Forster Colleen L. , Collins Margaret H. , Sarver Aaron L. , Wallace Margaret R. , Schmechel Stephen C. , Ratner Nancy , Largaespada David A.
Published: March 2013

Genetic changes required for the formation and progression of human Schwann cell tumors remain elusive. Using a Sleeping Beauty forward genetic screen, we identified several genes involved in canonical Wnt signaling as potential drivers of benign neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs). In human neurofibromas and MPNSTs, activation of Wnt signaling increased with tumor grade and was associated with downregulation of β-catenin destruction complex members or overexpression of a ligand that potentiates Wnt signaling, R-spondin 2 (RSPO2). Induction of Wnt signaling was sufficient to induce transformed properties in immortalized human Schwann cells, and downregulation of this pathway was sufficient to reduce the tumorigenic phenotype of human MPNST cell lines. Small-molecule inhibition of Wnt signaling effectively reduced the viability of MPNST cell lines and synergistically induced apoptosis when combined with an mTOR inhibitor, RAD-001, suggesting that Wnt inhibition represents a novel target for therapeutic intervention in Schwann cell tumors.

Significance: We show canonical Wnt/β-catenin signaling is a novel genetic driver of Schwann cell tumor development and progression, due to downregulation of β-catenin destruction complex members and overexpression of RSPO2. Inhibitors of Wnt signaling alone, or in combination with RAD-001, may have therapeutic value for patients with MPNSTs or neurofibromas. Cancer Discov; 3(6); 674–89. ©2013 AACR.

See related commentary by Reilly, p. 610

This article is highlighted in the In This Issue feature, p. 591
Nobiletin, a polymethoxyflavone in citrus fruits, reduces TAFI expression in HepG2 cells through transcriptional inhibition
Authors: Takada Kimihiko , Seike Toru , Sasaki Tomoyuki , Masuda Yutaka , Ito Akira , Ishii Hidemi
Published: March 2013

Thrombin-activatable fibrinolysis inhibitor (TAFI, carboxypeptidase B2) is a 58-kDa plasma glycoprotein secreted by hepatocytes as an inactive form. TAFI is activated by the thrombin-thrombomodulin complex, and activated TAFI (TAFIa) plays an important role in regulating the balance between coagulation and fibrinolysis through inhibition of fibrinolysis. It has been suggested that high levels of TAFI in circulating plasma increase the risks of cardiovascular death and acute phase in ischaemic stroke. However, the mechanisms of regulating TAFI expression have been unclear. The present study investigated the effects of nobiletin (a polymethoxy flavonoid contained in the rind of citrus fruits) on TAFI gene (CPB2) and TAFI antigen expression in cultured human hepatoma HepG2 cells. Nobiletin decreased the release of TAFI antigen from HepG2 cells into conditioned medium in parallel with decreased levels of CPB2 mRNA and antigen. The half-life time of CPB2 mRNA in nobiletin-treated cells was unchanged compared to that of untreated control cells. Using nobiletin-treated cells that were transfected with a luciferase CPB2 promoter reporter plasmid, activity decreased to half of that in untreated control cells. A series of luciferase reporter constructs containing 5´-flanking region deletions of the human CPB2 gene showed that the sequences from –150 bp to –50 bp were essential for transcription of CPB2 and contained an AP-1 binding sequence at ∼ –119 bp to – 99 bp in the CPB2 promoter. The amount of complexed nuclear protein and sequences from ∼ –119 bp to –99 bp was decreased in nobiletin-treated cells. ChIP assays showed that c-Jun bound to the ∼ –119 bp to –99 bp region of the CPB2 promoter and that the amount of the immunocomplex decreased after nobiletin treatment. Therefore, nobiletin-induced repression of CPB2 transcription might involve AP-1 inhibition and/or prevention of AP-1 binding in a specific region on the CPB2 gene in HepG2 cells.
Role of the Ubiquitin Proteasome System in the Heart
Authors: Pagan Julia , Seto Tiffany , Pagano Michele , Cittadini Antonio
Published: March 2013

Proper protein turnover is required for cardiac homeostasis and, accordingly, impaired proteasomal function appears to contribute to heart disease. Specific proteasomal degradation mechanisms underlying cardiovascular biology and disease have been identified, and such cellular pathways have been proposed to be targets of clinical relevance. This review summarizes the latest literature regarding the specific E3 ligases involved in heart biology, and the general ways that the proteasome regulates protein quality control in heart disease. The potential for therapeutic intervention in Ubiquitin Proteasome System function in heart disease is discussed.
Shear Stress Regulates Endothelial Microparticle Release
Authors: Vion Anne-Clémence , Ramkhelawon Bhama , Loyer Xavier , Chironi Gilles , Devue Cecile , Loirand Gervaise , Tedgui Alain , Lehoux Stéphanie , Boulanger Chantal M.
Published: March 2013

Rationale:

Endothelial activation and apoptosis release membrane-shed microparticles (EMP) that emerge as important biological effectors.

Objective:

Because laminar shear stress (SS) is a major physiological regulator of endothelial survival, we tested the hypothesis that SS regulates EMP release.

Methods and Results:

EMP levels were quantified by flow cytometry in medium of endothelial cells subjected to low or high SS (2 and 20 dyne/cm
2
). EMP levels augmented with time in low SS conditions compared with high SS conditions. This effect was sensitive to extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and Rho kinases inhibitors but unaffected by caspase inhibitors. Low SS-stimulated EMP release was associated with increased endothelial Rho kinases and ERK1/2 activities and cytoskeletal reorganization. Overexpression of constitutively active RhoA stimulated EMP release under high SS. We also examined the effect of nitric oxide (NO) in mediating SS effects. L-NG-nitroarginine methyl ester (L-NAME), but not D-NG-nitroarginine methyl ester, increased high SS-induced EMP levels by 3-fold, whereas the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP) decreased it. L-NAME and SNAP did not affect Rho kinases and ERK1/2 activities. Then, we investigated NO effect on membrane remodeling because microparticle release is abolished in ABCA1-deficient cells. ABCA1 expression, which was greater under low SS than under high SS, was augmented by L-NAME under high SS and decreased by SNAP under low SS conditions.

Conclusions:

Altogether, these results demonstrate that sustained atheroprone low SS stimulates EMP release through activation of Rho kinases and ERK1/2 pathways, whereas atheroprotective high SS limits EMP release in a NO-dependent regulation of ABCA1 expression and of cytoskeletal reorganization. These findings, therefore, identify endothelial SS as a physiological regulator of microparticle release.
Risk-Taking and Self-Regulation
Authors: Evans-Chase Michelle , Kim Minseop , Zhou Huiquan
Published: March 2013

The purpose of this study was to investigate the juvenile justice intervention literature for the statistical consideration given the impact that age, as a marker of neuropsychosocial development, may have on delinquency outcomes. A systematic review of 117 studies published between 1996 and 2009 was conducted to assess the methods by which curvilinear and moderating effects of age were included in the analysis of delinquency outcomes. Ninety-one percent of studies may have underestimated intervention effects through the misspecification of the effect of age on delinquency outcomes. Of the 10 studies that did test for curvilinear and interaction effects, 80% had findings consistent with neuropsychosocial theories of age on delinquency. To account for age effects on delinquency, the regular use of multiple age groups in analysis may increase both the precision with which intervention effects are measured and the identification of specific age groups with whom individual interventions are most effective.
Variation of inlet boundary conditions on the combustion characteristics of a typical cavity-based scramjet combustor
Authors: Huang Wei , Wang Zhen-Guo , Yan Li , Li Shi-Bin , Ingham Derek B
Published: March 2013

The influences of wall functions, reaction model, and wall Prandtl number on the reacting flow field characteristics of a typical cavity-based scramjet combustor have been investigated numerically, and the computed results have been compared with the available experimental data in the open literature. The computed results are in reasonable agreement with the experimental data, but the pressure downstream of the leading edge of the cavity is overpredicted. Meanwhile, the grid discrepancy has been analyzed by employing three different grid scales, namely the coarse, the moderate, and the refined grids. The obtained results show that the moderate grid may be employed with confidence to compute the reacting flow field of the scramjet combustor. The wall functions, reaction model, and wall Prandtl number have a large impact on the pressure distribution along the floor face of the cavity, and this may be due to the influence of the variance of the flow separation point on the top wall for the different cases investigated with different inlet boundary conditions. The static pressure along the floor face of the cavity decreases with an increase in the wall Prandtl number, and then increases when the wall Prandtl number is large enough, namely 1.2 in the current study. This points out that there exists an optimal wall Prandtl number for the prediction of the reacting flow field of the cavity-based scramjet combustor.
UCN-01 induces S and G2/M cell cycle arrest through the p53/p21waf1or CHK2/CDC25C pathways and can suppress invasion in human hepatoma cell lines
Authors: Wu Guoyi , Xu Linan , Lin Nan , Liu Bo
Published: March 2013

Background

UCN-01 (7-hydroxystaurosporine), a protein kinase inhibitor, has attracted a great deal of attention as a potent antitumour agent. Several clinical trials of UCN-01 alone or in combination with other agents for different tumour types are currently underway, and some of these trials have had positive results. Hepatocellular carcinoma has high incidence rates and is associated with poor prognosis and high mortality rates.

Methods

Three different hepatoma cell lines (Huh7, HepG2, and Hep3B) were treated with different concentrations of UCN-01, and the anti-tumour effects of UCN-01 were evaluated. Following UCN-01 treatment, cell growth was measured using an MTT assay, cell cycle arrest was assayed using flow cytometry, and the mechanisms of cell cycle arrest and invasion inhibition were investigated through western blotting and a Matrigel invasion assay.

Results

After a 72-h UCN-01 treatment, the growth of different hepatoma cell lines was significantly inhibited in a dose-dependent manner, with IC50 values ranging from 69.76 to 222.74 nM. Flow cytometry results suggested that UCN-01 inhibits proliferation in the hepatoma cells by inducing S and G2/M phase arrest, but not G1/S arrest, which differs from previous reports that used other tumour cell lines. Western blot results illustrated that UCN-01 induces a G2/M phase arrest, regardless of the status of the p53/P21waf1pathway, whereas the CHK2/CDC25C pathway and the p53/p21waf1pathway were involved in the UCN-01-induced S phase arrest. UCN-01 remarkably inhibited Huh7 cell invasion in a time-dependent manner. Suppression of Huh7 cell invasion may be due to the down-regulation of phosphorylated β-catenin by UCN-01.

Conclusions

These findings suggest that UCN-01 induces hepatoma cell growth inhibition by regulating the p53/p21waf1and CHK2/CDC25 pathways. Suppression of Huh7 cell invasion by UCN-01 may be due to the down-regulation of phosphorylated β-catenin. These data lend support for further studies on UCN-01 as a promising anti-HCC candidate.
An outbreak of norovirus gastroenteritis associated with a secondary water supply system in a factory in south China
Authors: Li Yuan , Guo Hongxiong , Xu Zhenghui , Zhou Xiaotao , Zhang Hailong , Zhang Lijie , Miao Jing , Pan Yi
Published: March 2013

Background

Between September 17 and October 3, 2009, hundreds of workers employed in a manufacturing factory in Shenzhen, a city in south China developed a sudden onset of acute gastroenteritis. A retrospective cohort study is designed to identify the risk factors and control this outbreak.

Methods

Information on demographic characteristics, working place, the history of contact with a person having diarrhea and/or vomiting, drink water preference and frequency, eating in the company cafeteria or outside the company, hand-washing habits and eating habits is included. Furthermore, in order to find the contamination source, we investigated the environment around the underground reservoir and collected water samples from the junction between municipal supply water system and underground reservoir to test potential bacteria and virus, examine the seepage tracks on the wall of the underground reservoir from the side of septic tank, and check the integrity and attitude of this lid. Relative risk was presented and Chi-square test was performed. All the analyses were performed with OpenEpi software version 2.3.1 online.

Results

The cohort study demonstrated that the workers who had direct drink water were 3.0 fold more likely to suffer from acute gastroenteritis than those who consumed commercial bottled water. The direct drinking water, water of the tank of buildings, and the underground reservoir were positive only for norovirus. Norovirus was also detected from stool and rectal swab samples from patients with acute gastroenteritis. The underground reservoir was found to be the primary contamination source. Further environmental investigation showed that the norovirus contaminated substance entered into the underground reservoir via access holes in lid covering this underground reservoir.

Conclusion

This acute gastroenteritis outbreak was caused by the secondary supply system contaminated by norovirus in this factory. The outbreak of gastroenteritis cases caused by norovirus frequently occurred in China due to a lack of surveillance and supervision, and due to faults in the construction of such water systems. Therefore, more attentions should pay to the secondary supply water system in China.