bluuebunny/crossref_metadata_2025 huggingface dataset:
Hybrid Algorithm of Fixed Point for Weak Relatively NonexpansiveMultivalued Mappings and Applications
Authors: Zhang Jingling , Su Yongfu , Cheng Qingqing
Published: November 2012

The purpose of this paper is to present the notion of weak relatively
nonexpansive multi‐valued mapping and to prove the strong convergence theorems of fixed point for weak relatively nonexpansive multivalued mappings in Banach spaces. The weak relatively nonexpansive multivalued mappings are more generalized than relatively nonexpansive multivalued mappings. In this paper, an example will be given which is a weak relatively nonexpansive multivalued mapping but not a relatively nonexpansive multivalued mapping. In order to get the strong convergence theorems for weak relatively nonexpansive multivalued mappings, a new monotone hybrid iteration algorithm with generalized (metric) projection is presented and is used to approximate the fixed point of weak relatively nonexpansive multivalued mappings. In this paper, the notion of multivalued resolvent of maximal monotone operator has been also presented which is a weak relatively nonexpansive multivalued mapping and can be used to find the zero point of maximal monotone operator.
Property Evaluation of Bletilla striata/Polyvinyl Alcohol Nano Fibers and Composite Dressings
Authors: Lin Jia-Horng , Lu Chao-Tsang , Hu Jin-Jia , Chen Yueh-Sheng , Huang Chen-Hung , Lou Ching-Wen
Published: November 2012

This study used nonwoven manufacture and electrospinning to create wound dressings with solid mechanical properties and hemostasis function. 10% Polyvinyl alcohol (PVA) and 5% Bletilla striata (BS) were blended into the PVA/BS solution, which can be made into nanomaterial with high specific surface area by electrospinning. The PVA/BS solution was electrospun onto the dressing matrix made of polyester (PET) and absorbent cotton (AC), forming the PVA/BS composite dressings. According to the experiment results, when the volume ratio of PVA to BS was 9 : 1, the resulting dressings had optimal fiber formation, the finest average diameter, and the lowest toxicity.
Integral Solution of the Interface Profile of Grain Boundary Grooving by Surface Diffusion
Authors: Wang Caifang , Xing Hui , Yao Fengping , Chen Changle , Wang Jianyuan , Fan Fei
Published: November 2012

In polycrystalline thin films, formation of grain boundary grooving is investigated widely due to its effects on their properties. Infinite series solution of the interface of grain-boundary grooving by surface diffusion has been obtained. In this paper, with Fourier transform, a novel integral solution of the profile of grain boundary grooving is derived. Numerical examples are taken to test the performance of the integral solution. According to the numerical examples, we find that the novel solution is in accordance with the infinite series solution.
Methodology and Application of Adaptive and Sequential Approaches in Contemporary Clinical Trials
Authors: Chen Zhengjia , Zhao Yichuan , Cui Ye , Kowalski Jeanne
Published: November 2012

The clinical trial, a prospective study to evaluate the effect of interventions in humans under prespecified conditions, is a standard and integral part of modern medicine. Many adaptive and sequential approaches have been proposed for use in clinical trials to allow adaptations or modifications to aspects of a trial after its initiation without undermining the validity and integrity of the trial. The application of adaptive and sequential methods in clinical trials has significantly improved the flexibility, efficiency, therapeutic effect, and validity of trials. To further advance the performance of clinical trials and convey the progress of research on adaptive and sequential methods in clinical trial design, we review significant research that has explored novel adaptive and sequential approaches and their applications in Phase I, II, and III clinical trials and discuss future directions in this field of research.
Subdural Hematoma: An Adverse Event of Electroconvulsive Therapy—Case Report and Literature Review
Authors: Kulkarni Ranganath R. , Melkundi Sateesh
Published: November 2012

Electroconvulsive therapy (ECT) is commonly used in the management of medication nonresponsive depressive disorder, with proven efficacy in psychiatric practice since many decades. A rare complication of intracranial bleed following this therapeutic procedure has been reported in sporadic case reports in the English literature. We report a case of such a complication in a 42-year-old male, a known case of nonorganic medication nonresponsive depressive disorder for the last two years who required ECT application. Presenting symptoms included altered mental state, urinary incontinence, and repeated episodes of vomiting; following ECT procedure with magnetic resonance imaging (MRI) of the brain suggestive of bilateral acute subdural hematoma. Despite the view that it may be used in neurological conditions without raised intracranial tension, it will be worthwhile to be vigilant during post-ECT recovery for any emergent complications.
Uncertainty Propagation Analysis for PWR Burnup Pin-Cell Benchmark by Monte Carlo Code McCARD
Authors: Park Ho Jin , Shim Hyung Jin , Kim Chang Hyo
Published: November 2012

In the Monte Carlo (MC) burnup analyses, the uncertainty of a tally estimate at a burnup step may be induced from four sources: the statistical uncertainty caused by a finite number of simulations, the nuclear covariance data, uncertainties of number densities, and cross-correlations between the nuclear data and the number densities. In this paper, the uncertainties ofkinf, reaction rates, and number densities for a PWR pin-cell benchmark problem are quantified by an uncertainty propagation formulation in the MC burnup calculations. The required sensitivities of tallied parameters to the microscopic cross-sections and the number densities are estimated by the MC differential operator sampling method accompanied by the fission source perturbation. The uncertainty propagation analyses are conducted with two nuclear covariance data—ENDF/B-VII.1 and SCALE6.1/COVA libraries—and the numerical results are compared with each other.
Common Fixed Point Theorems of Altman Integral Type Mappings in G‐Metric Spaces
Authors: Gu Feng , Ye Hongqing
Published: November 2012

We introduce the concept of φ‐weakly commuting self‐mapping pairs in G‐metric space. Using this concept, we establish a new common fixed point theorem of Altman integral type for six self‐mappings in the framework of complete G‐metric space. An example is provided to support our result. The results obtained in this paper differ from the recent relative results in the literature.
A New Optimized Runge‐Kutta Pair for the Numerical Solution of the Radial Schrödinger Equation
Authors: Fang Yonglei , Li Qinghong , Ming Qinghe , Wang Kaimin
Published: November 2012

A new embedded pair of explicit modified Runge‐Kutta (RK) methods for the
numerical integration of the radial Schrödinger equation is presented. The two RK
methods in the pair have algebraic orders five and four, respectively. The two methods
of the embedded pair are derived by nullifying the phase lag, the first derivative of
the phase lag of the fifth‐order method, and the phase lag of the fourth‐order method. Nu
merical experiments show the efficiency and robustness of our new methods compared
with some well‐known integrators in the literature.
Computing the Square Roots of a Class of Circulant Matrices
Authors: Mei Ying
Published: November 2012

We first investigate the structures of the square roots of a class of circulant matrices and give classifications of the square roots of these circulant matrices. Then, we develop several algorithms for computing their square roots. We show that our algorithms are faster than the standard algorithm which is based on the Schur decomposition.
Effect ofAtractylodes macrocephalaon Hypertonic Stress-Induced Water Channel Protein Expression in Renal Collecting Duct Cells
Authors: Lee Yong Pyo , Lee Yun Jung , Lee So Min , Yoon Jung Joo , Kim Hye Yoom , Kang Dae Gill , Lee Ho Sub
Published: November 2012

Edema is a symptom that results from the abnormal accumulation of fluid in the body. The cause of edema is related to the level of aquaporin (AQP)2 protein expression, which regulates the reabsorption of water in the kidney. Edema is caused by overexpression of the AQP2 protein when the concentration of Na+in the blood increases. The rhizome ofAtractylodes macrocephalahas been used in traditional oriental medicine as a diuretic drug; however, the mechanism responsible for the diuretic effect of the aqueous extract fromA. macrocephalarhizomes (AAMs) has not yet been identified. We examined the effect of the AAM on the regulation of water channels in the mouse inner medullary collecting duct (mIMCD)-3 cells under hypertonic stress. Pretreatment of AAM attenuates a hypertonicity-induced increase in AQP2 expression as well as the trafficking of AQP2 to the apical plasma membrane. Tonicity-responsive enhancer binding protein (TonEBP) is a transcription factor known to play a central role in cellular homeostasis by regulating the expression of some proteins, including AQP2. Western immunoblot analysis demonstrated that the protein and mRNA expression levels of TonEBP also decrease after AAM treatment. These results suggest that the AAM has a diuretic effect by suppressing water reabsorption via the downregulation of the TonEBP-AQP2 signaling pathway.
Modeling and Parameter Identification Involving 3‐Hydroxypropionaldehyde Inhibitory Effects in Glycerol Continuous Fermentation
Authors: Gong Zhaohua , Liu Chongyang , Yu Yongsheng
Published: November 2012

Mathematical modeling and parameter estimation are critical steps in the optimization of biotechnological processes. In the 1,3‐propanediol (1,3‐PD) production by glycerol fermentation process under anaerobic conditions, 3‐hydroxypropionaldehyde (3‐HPA) accumulation would arouse an irreversible cessation of the fermentation process. Considering 3‐HPA inhibitions to cells growth and to activities of enzymes, we propose a novel mathematical model to describe glycerol continuous cultures. Some properties of the above model are discussed. On the basis of the concentrations of extracellular substances, a parameter identification model is established to determine the kinetic parameters in the presented system. Through the penalty function technique combined with an extension of the state space method, an improved genetic algorithm is then constructed to solve the parameter identification model. An illustrative numerical example shows the appropriateness of the proposed model and the validity of optimization algorithm. Since it is difficult to measure the concentrations of intracellular substances, a quantitative robustness analysis method is given to infer whether the model is plausible for the intracellular substances. Numerical results show that the proposed model is of good robustness.
Quantitative Sensory Testing in Painful Hand Osteoarthritis Demonstrates Features of Peripheral Sensitisation
Authors: Wajed Julekha , Ejindu Vivian , Heron Christine , Hermansson Monika , Kiely Patrick , Sofat Nidhi
Published: November 2012

Hand osteoarthritis (HOA) is a prevalent condition for which treatments are based on analgesia and physical therapies. Our primary objective was to evaluate pain perception in participants with HOA by assessing the characteristics of nodal involvement, pain threshold in each hand joint, and radiological severity. We hypothesised that inflammation in hand osteoarthritis joints enhances sensitivity and firing of peripheral nociceptors, thereby causing chronic pain. Participants with proximal and distal interphalangeal (PIP and DIP) joint HOA and non-OA controls were recruited. Clinical parameters of joint involvement were measured including clinical nodes, VAS (visual analogue score) for pain (0–100 mm scale), HAQ (health assessment questionnaire), and Kellgren-Lawrence scores for radiological severity and pain threshold measurement were performed. The mean VAS in HOA participants was 59.3 mm ± 8.19 compared with 4.0 mm ± 1.89 in the control group (). Quantitative sensory testing (QST) demonstrated lower pain thresholds in DIP/PIP joints and other subgroups in the OA group including the thumb, metacarpophalangeal (MCPs), joints, and wrists () but not in controls (). Our data demonstrate that HOA subjects are sensitised to pain due to increased firing of peripheral nociceptors. Future work to evaluate mechanisms of peripheral sensitisation warrants further investigation.
Periodontal Status and Risk Factors among Adults of Sebha City (Libya)
Authors: Peeran Syed Wali , Singh A. J. A. Ranjith , Alagamuthu G. , Peeran Syed Ali , Naveen Kumar P. G.
Published: November 2012

The present study was aimed at assessing the periodontal status and risk factors like age, gender, tooth brushing habit, and smoking among the adult population of Sebha city, Libya. 452 adults, aged 35–54 years, comprised the study sample. 266 (58.84%) were females and 186 (41.15%) were males. Data was collected by interview and clinical examination using CPI of CPITN index. Chi-square test and ANOVA were used for statistical analysis at 5% level of significance. Results indicate that 76.32% used toothbrush and paste; 8.84% were current smokers and were all males. Majority, 52.65% were, detected with shallow pockets followed by 30.08% with calculus, 12.17% had deep pockets, 3.31% had bleeding, and only 1.33% were healthy. Age, gender, current smoking status and frequency of tooth brushing showed statistically significant difference with CPI codes. Health professionals can utilize this data to identify individuals at risk and to target population level interventions.
Proteomic Analysis Reveals the Deregulation of Inflammation-Related Proteins in Acupuncture-Treated Rats with Asthma Onset
Authors: Xu Yu-Dong , Cui Jian-Mei , Wang Yu , Yin Lei-Miao , Gao Chang-Ke , Liu Xiao-Yan , Wei Ying , Liu Yan-Yan , Jiang Yong-Liang , Shan Chun-Xiao , Yang Yong-Qing
Published: November 2012

Although the beneficial effects of acupuncture in asthma treatment have been well documented, little is known regarding the biological basis of this treatment. Changes in the lung proteome of acupuncture-treated rats with asthma onset were comparatively analyzed using a two-dimensional gel electrophoresis (2DE) and mass-spectrometry- (MS-) based proteomic approach. Acupuncture on specific acupuncture points appeared to improve respiratory function and reduce the total number of leukocytes and eosinophils in bronchoalveolar lavage fluid in OVA-induced asthma onset. Image analysis of 2DE gels revealed 32 differentially expressed acupuncture-specific protein spots in asthma onset; 30 of which were successfully identified as 28 unique proteins using LC-MS/MS. Bioinformatic analyses indicated that these altered proteins are most likely involved in inflammation-related biological functions, and the functional associations of these proteins result in an inflammation signaling pathway. Acupuncture regulates the pathway at different levels by regulating several key nodal proteins, including downregulating of proinflammatory proteins (e.g., S100A8, RAGE, and S100A11) and upregulating of anti-inflammatory proteins (e.g., CC10, ANXA5, and sRAGE). These deregulated inflammation-related proteins may mediate, at least in part, the antiasthmatic effect of acupuncture. Further functional investigation of these acupuncture-specific effector proteins could identify new drug candidates for the prophylaxis and treatment of asthma.
Combination Therapy with Losartan and Pioglitazone Additively Reduces Renal Oxidative and Nitrative Stress Induced by Chronic High Fat, Sucrose, and Sodium Intake
Authors: Kong Xiang , Zhang Yan , Wu Hai-bing , Li Fang-xia , Zhang Dao-you , Su Qing
Published: November 2012

We recently showed that combination therapy with losartan and pioglitazone provided synergistic effects compared with monotherapy in improving lesions of renal structure and function in Sprague-Dawley rats fed with a high-fat, high-sodium diet and 20% sucrose solution. This study was designed to explore the underlying mechanisms of additive renoprotection provided by combination therapy. Losartan, pioglitazone, and their combination were orally administered for 8 weeks. The increased level of renal malondialdehyde and expression of nicotinamide adenine dinucleotide phosphate oxidase subunitp47phoxand nitrotyrosine as well as the decreased total superoxide dismutase activity and copper, zinc-superoxide dismutase expression were tangible evidence for the presence of oxidative and nitrative stress in the kidney of model rats. Treatment with both drugs, individually and in combination, improved these abnormal changes. Combination therapy showed synergistic effects in reducing malondialdehyde level,p47phox, and nitrotyrosine expression to almost the normal level compared with monotherapy. All these results suggest that the additive renoprotection provided by combination therapy might be attributed to a further reduction of oxidative and nitrative stress.
Bcl3 Selectively Promotes Metastasis of ERBB2-Driven Mammary Tumors
Authors: Wakefield Alison , Soukupova Jitka , Montagne Amelie , Ranger Jill , French Rhiannon , Muller William J. , Clarkson Richard W. E.
Published: November 2012

Bcl3 is a putative proto-oncogene deregulated in hematopoietic and solid tumors. Studies in cell lines suggest that its oncogenic effects are mediated through the induction of proliferation and inhibition of cell death, yet its role in endogenous solid tumors has not been established. Here, we address the oncogenic effect of Bcl3 in vivo and describe how this Stat3-responsive oncogene promotes metastasis of ErbB2-positive mammary tumors without affecting primary tumor growth or normal mammary function. Deletion of the Bcl3 gene in ErbB2-positive (MMTV-Neu) mice resulted in a 75% reduction in metastatic tumor burden in the lungs with a 3.6-fold decrease in cell turnover index in these secondary lesions with no significant effect on primary mammary tumor growth, cyclin D1 levels, or caspase-3 activity. Direct inhibition of Bcl3 by siRNA in a transplantation model of an Erbb2-positive mammary tumor cell line confirmed the effect of Bcl3 in malignancy, suggesting that the effect of Bcl3 was intrinsic to the tumor cells. Bcl3 knockdown resulted in a 61% decrease in tumor cell motility and a concomitant increase in the cell migration inhibitors Nme1, Nme2, and Nme3, the GDP dissociation inhibitor Arhgdib, and the metalloprotease inhibitors Timp1 and Timp2. Independent knockdown of Nme1, Nme2, and Arhgdib partially rescued the Bcl3 motility phenotype. These results indicate for the first time a cell-autonomous disease-modifying role for Bcl3 in vivo, affecting metastatic disease progression rather than primary tumor growth. Cancer Res; 73(2); 745–55. ©2012 AACR.
DNA Damage–Specific Control of Cell Death by Cryptochrome in p53-Mutant Ras–Transformed Cells
Authors: Lee Jin Hyup , Gaddameedhi Shobhan , Ozturk Nuri , Ye Rui , Sancar Aziz
Published: November 2012

The main feedback loop driving circadian rhythm in mice is controlled, in part, by the genes encoding the cryptochromes Cry1 and Cry2. Targeted mutation of both Cry1 and Cry2 delay the early onset of tumor formation in p53-null mutant mice. Furthermore, Ras-transformed p53- and Cry-null mouse skin fibroblasts are more sensitive than p53 mutants to apoptotic cell death initiated by agents that activate either the intrinsic or the extrinsic apoptosis pathways. Here, we investigated the effect of Cry1 and Cry2 mutations on cell death by other genotoxic agents that generate alkylated bases, interstrand crosslinks, DNA–protein crosslinks, and double-strand breaks. Both ultraviolet (UV) and the UV mimetic compound oxaliplatin and the radiomimetic compound doxorubicin promoted apoptosis by upregulating the tumor suppressor p73. However, only the UV and oxaliplatin-induced upregulation of p73 mediated by the transcription factor Egr1, but not the doxorubicin-induced upregulation mediated by the transcription factor E2F1, was enhanced by Cry1/Cry2 double mutation. Accordingly, Egr1 downregulation reduced oxaliplatin-induced apoptosis, whereas E2F1 downregulation reduced doxorubicin-induced apoptosis. Our findings establish distinct roles for cryptochromes in intrinsic apoptosis induced by UV mimetic and radiomimetic agents. Cancer Res; 73(2); 785–91. ©2012 AACR.
RNA Trafficking by Acute Myelogenous Leukemia Exosomes
Authors: Huan Jianya , Hornick Noah I. , Shurtleff Matthew J. , Skinner Amy M. , Goloviznina Natalya A. , Roberts Charles T. , Kurre Peter
Published: November 2012

Extrinsic signaling cues in the microenvironment of acute myelogenous leukemia (AML) contribute to disease progression and therapy resistance. Yet, it remains unknown how the bone marrow niche in which AML arises is subverted to support leukemic persistence at the expense of homeostatic function. Exosomes are cell membrane–derived vesicles carrying protein and RNA cargoes that have emerged as mediators of cell–cell communication. In this study, we examined the role of exosomes in developing the AML niche of the bone marrow microenvironment, investigating their biogenesis with a focus on RNA trafficking. We found that both primary AML and AML cell lines released exosome-sized vesicles that entered bystander cells. These exosomes were enriched for several coding and noncoding RNAs relevant to AML pathogenesis. Furthermore, their uptake by bone marrow stromal cells altered their secretion of growth factors. Proof-of-concept studies provided additional evidence for the canonical functions of the transferred RNA. Taken together, our findings revealed that AML exosome trafficking alters the proliferative, angiogenic, and migratory responses of cocultured stromal and hematopoietic progenitor cell lines, helping explain how the microenvironmental niche becomes reprogrammed during invasion of the bone marrow by AML. Cancer Res; 73(2); 918–29. ©2012 AACR.
Antitumor Immunotherapeutic and Toxic Properties of an HDL-Conjugated Chimeric IL-15 Fusion Protein
Authors: Ochoa Maria C. , Fioravanti Jessica , Rodriguez Inmaculada , Hervas-Stubbs Sandra , Azpilikueta Arantza , Mazzolini Guillermo , Gúrpide Alfonso , Prieto Jesus , Pardo Julian , Berraondo Pedro , Melero Ignacio
Published: November 2012

Interleukin (IL)-15 effects on CD8 T and natural killer (NK) lymphocytes hold promise to treat cancer. Fusion proteins have been engineered to provide IL-15 receptor alpha (IL-15Rα) mediated trans-presentation to lymphocytes and extend the plasma half-life of the cytokine. In this study, we report on a triple fusion protein combining apolipoprotein A-I (Apo A-I), IL-15, and IL-15Rα's sushi domain. Apo A-I conveys IL-15 to high-density lipoproteins (HDL), from which the cytokine is trans-presented by the IL-15Rα's sushi domain. Such a construction was tested by hydrodynamic gene transfer to the liver of mice. Lethal toxicity was observed upon injection of 10 μg of the expression plasmid. Mice died from an acute lymphocytic pneumonitis in which T and NK cells dominate a severe inflammatory infiltrate. Importantly, mice devoid of NK cells were not susceptible to such toxicity and mice lacking granzymes A and B also survived the otherwise lethal gene transfer. Lower plasmid doses (<2.5 μg) were tolerated and dramatically increased the numbers of NK and memory CD8 T lymphocytes in the liver, spleen, and lungs, to the point of rescuing the deficiency of such lymphocyte subsets in IL-15Rα−/− mice. Doses of plasmid within the therapeutic window successfully treated metastatic tumor models, including B16OVA lung metastasis of melanoma and MC38 colon cancer liver metastasis. Sushi-IL-15-Apo as a recombinant protein was also bioactive in vivo, became conjugated to HDL, and displayed immunotherapeutic effects against metastatic disease. Cancer Res; 73(1); 139–49. ©2012 AACR.
Tasquinimod Is an Allosteric Modulator of HDAC4 Survival Signaling within the Compromised Cancer Microenvironment
Authors: Isaacs John T. , Antony Lizamma , Dalrymple Susan L. , Brennen W. Nathaniel , Gerber Stephanie , Hammers Hans , Wissing Michel , Kachhap Sushant , Luo Jun , Xing Li , Björk Per , Olsson Anders , Björk Anders , Leanderson Tomas
Published: November 2012

Tasquinimod is an orally active antiangiogenic drug that is currently in phase III clinical trials for the treatment of castration-resistant prostate cancer. However, the target of this drug has remained unclear. In this study, we applied diverse strategies to identify the histone deacetylase HDAC4 as a target for the antiangiogenic activity of tasquinimod. Our comprehensive analysis revealed allosteric binding (Kd 10–30 nmol/L) to the regulatory Zn2+ binding domain of HDAC4 that locks the protein in a conformation preventing HDAC4/N-CoR/HDAC3 complex formation. This binding inhibited colocalization of N-CoR/HDAC3, thereby inhibiting deacetylation of histones and HDAC4 client transcription factors, such as HIF-1α, which are bound at promoter/enhancers where epigenetic reprogramming is required for cancer cell survival and angiogenic response. Through this mechanism, tasquinimod is effective as a monotherapeutic agent against human prostate, breast, bladder, and colon tumor xenografts, where its efficacy could be further enhanced in combination with a targeted thapsigargin prodrug (G202) that selectively kills tumor endothelial cells. Together, our findings define a mechanism of action of tasquinimod and offer a perspective on how its clinical activity might be leveraged in combination with other drugs that target the tumor microenvironment. Cancer Res; 73(4); 1386–99. ©2012 AACR.
Definition of Molecular Determinants of Prostate Cancer Cell Bone Extravasation
Authors: Barthel Steven R. , Hays Danielle L. , Yazawa Erika M. , Opperman Matthew , Walley Kempland C. , Nimrichter Leonardo , Burdick Monica M. , Gillard Bryan M. , Moser Michael T. , Pantel Klaus , Foster Barbara A. , Pienta Kenneth J. , Dimitroff Charles J.
Published: November 2012

Advanced prostate cancer commonly metastasizes to bone, but transit of malignant cells across the bone marrow endothelium (BMEC) remains a poorly understood step in metastasis. Prostate cancer cells roll on E-selectin+ BMEC through E-selectin ligand-binding interactions under shear flow, and prostate cancer cells exhibit firm adhesion to BMEC via β1, β4, and αVβ3 integrins in static assays. However, whether these discrete prostate cancer cell–BMEC adhesive contacts culminate in cooperative, step-wise transendothelial migration into bone is not known. Here, we describe how metastatic prostate cancer cells breach BMEC monolayers in a step-wise fashion under physiologic hemodynamic flow. Prostate cancer cells tethered and rolled on BMEC and then firmly adhered to and traversed BMEC via sequential dependence on E-selectin ligands and β1 and αVβ3 integrins. Expression analysis in human metastatic prostate cancer tissue revealed that β1 was markedly upregulated compared with expression of other β subunits. Prostate cancer cell breaching was regulated by Rac1 and Rap1 GTPases and, notably, did not require exogenous chemokines as β1, αVβ3, Rac1, and Rap1 were constitutively active. In homing studies, prostate cancer cell trafficking to murine femurs was dependent on E-selectin ligand, β1 integrin, and Rac1. Moreover, eliminating E-selectin ligand-synthesizing α1,3 fucosyltransferases in transgenic adenoma of mouse prostate mice dramatically reduced prostate cancer incidence. These results unify the requirement for E-selectin ligands, α1,3 fucosyltransferases, β1 and αVβ3 integrins, and Rac/Rap1 GTPases in mediating prostate cancer cell homing and entry into bone and offer new insight into the role of α1,3 fucosylation in prostate cancer development. Cancer Res; 73(2); 942–52. ©2012 AACR.
Targeting CXCR1/2 Significantly Reduces Breast Cancer Stem Cell Activity and Increases the Efficacy of Inhibiting HER2 via HER2-Dependent and -Independent Mechanisms
Authors: Singh Jagdeep K. , Farnie Gillian , Bundred Nigel J. , Simões Bruno M , Shergill Amrita , Landberg Göran , Howell Sacha J. , Clarke Robert B.
Published: November 2012

Purpose: Breast cancer stem-like cells (CSC) are an important therapeutic target as they are predicted to be responsible for tumor initiation, maintenance, and metastases. Interleukin (IL)-8 is upregulated in breast cancer and is associated with poor prognosis. Breast cancer cell line studies indicate that IL-8 via its cognate receptors, CXCR1 and CXCR2, is important in regulating breast CSC activity. We investigated the role of IL-8 in the regulation of CSC activity using patient-derived breast cancers and determined the potential benefit of combining CXCR1/2 inhibition with HER2-targeted therapy.

Experimental Design: CSC activity of metastatic and invasive human breast cancers (n = 19) was assessed ex vivo using the mammosphere colony-forming assay.

Results: Metastatic fluid IL-8 level correlated directly with mammosphere formation (r = 0.652; P < 0.05; n = 10). Recombinant IL-8 directly increased mammosphere formation/self-renewal in metastatic and invasive breast cancers (n = 17). IL-8 induced activation of EGFR/HER2 and downstream signaling pathways and effects were abrogated by inhibition of SRC, EGFR/HER2, phosphoinositide 3-kinase (PI3K), or MEK. Furthermore, lapatinib, which targets EGFR/HER2, inhibited the mammosphere-promoting effect of IL-8 in both HER2-positive and negative patient-derived cancers. CXCR1/2 inhibition also blocked the effect of IL-8 on mammosphere formation and added to the efficacy of lapatinib in HER2-positive cancers.

Conclusions: These studies establish a role for IL-8 in the regulation of patient-derived breast CSC activity and show that IL-8/CXCR1/2 signaling is partly mediated via a novel SRC and EGFR/HER2-dependent pathway. Combining CXCR1/2 inhibitors with current HER2-targeted therapies has potential as an effective therapeutic strategy to reduce CSC activity in breast cancer and improve the survival of HER2-positive patients. Clin Cancer Res; 19(3); 643–56. ©2012 AACR.
Interleukin 15 Provides Relief to CTLs from Regulatory T Cell–Mediated Inhibition: Implications for Adoptive T Cell–Based Therapies for Lymphoma
Authors: Perna Serena K. , De Angelis Biagio , Pagliara Daria , Hasan Sayyeda T. , Zhang Lan , Mahendravada Aruna , Heslop Helen E. , Brenner Malcolm K. , Rooney Cliona M. , Dotti Gianpietro , Savoldo Barbara
Published: November 2012

Purpose: Systemic administration of recombinant interleukin (IL)-2 is used to support the expansion and persistence of adoptively transferred antigen-specific CTLs in patients with cancer. However, IL-2 also expands regulatory T cells (Treg) that in turn impair the antitumor activity of CTLs. As recombinant IL-15 is approaching clinical applications, we assessed the effects of this cytokine on the proliferation and antitumor activity of CTLs in the presence of Tregs. We used the model of adoptive transfer of Epstein–Barr virus (EBV)-CTLs, as these cells induce responses in patients with EBV-associated Hodgkin lymphoma, and Tregs are frequently abundant in these patients.

Experimental Design: Tregs were isolated from the peripheral blood of healthy donors and patients with Hodgkin lymphoma or from Hodgkin lymphoma tumors and assessed for their ability to inhibit the proliferation and antitumor activity of EBV-CTLs in the presence of IL-15 or IL-2. Specific molecular pathways activated by IL-15 were also explored.

Results: We found that in the presence of Tregs, IL-15, but not IL-2, promoted the proliferation, effector function, and resistance to apoptosis of effectors T cells and EBV-CTLs. IL-15 did not reverse or block Tregs but instead preferentially supported the proliferation of CTLs and effector T cells as compared with Tregs.

Conclusions: IL-15 selectively favors the survival, proliferation, and effector function of antigen-specific CTLs in the presence of Tregs, and thus IL-15, unlike IL-2, would have a significant impact in sustaining expansion and persistence of adoptively transferred CTLs in patients with cancer, including those infused with EBV-CTLs for treatment of EBV-associated malignancies. Clin Cancer Res; 19(1); 106–17. ©2012 AACR.
Myocardial Structural Associations With Local Electrograms
Authors: Sasaki Takeshi , Miller Christopher F. , Hansford Rozann , Yang Juemin , Caffo Brian S. , Zviman Menekhem M. , Henrikson Charles A. , Marine Joseph E. , Spragg David , Cheng Alan , Tandri Harikrishna , Sinha Sunil , Kolandaivelu Aravindan , Zimmerman Stefan L. , Bluemke David A. , Tomaselli Gordon F. , Berger Ronald D. , Calkins Hugh , Halperin Henry R. , Nazarian Saman
Published: November 2012

Background—

The association of scar on late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) with local electrograms on electroanatomic mapping has been investigated. We aimed to quantify these associations to gain insights regarding LGE-CMR image characteristics of tissues and critical sites that support postinfarct ventricular tachycardia (VT).

Methods and Results—

LGE-CMR was performed in 23 patients with ischemic cardiomyopathy before VT ablation. Left ventricular wall thickness and postinfarct scar thickness were measured in each of 20 sectors per LGE-CMR short-axis plane. Electroanatomic mapping points were retrospectively registered to the corresponding LGE-CMR images. Multivariable regression analysis, clustered by patient, revealed significant associations among left ventricular wall thickness, postinfarct scar thickness, and intramural scar location on LGE-CMR, and local endocardial electrogram bipolar/unipolar voltage, duration, and deflections on electroanatomic mapping. Anteroposterior and septal/lateral scar localization was also associated with bipolar and unipolar voltage. Antiarrhythmic drug use was associated with electrogram duration. Critical sites of postinfarct VT were associated with >25% scar transmurality, and slow conduction sites with >40 ms stimulus-QRS time were associated with >75% scar transmurality.

Conclusions—

Critical sites for maintenance of postinfarct VT are confined to areas with >25% scar transmurality. Our data provide insights into the structural substrates for delayed conduction and VT and may reduce procedural time devoted to substrate mapping, overcome limitations of invasive mapping because of sampling density, and enhance magnetic resonance–based ablation by feature extraction from complex images.
Diagnosis, Treatment, and Outcome of Giant-Cell Myocarditis in the Era of Combined Immunosuppression
Authors: Kandolin Riina , Lehtonen Jukka , Salmenkivi Kaisa , Räisänen-Sokolowski Anne , Lommi Jyri , Kupari Markku
Published: November 2012

Background—

Giant-cell myocarditis often escapes diagnosis until autopsy or transplantation and has defied proper treatment trials for its rarity and deadly behavior. Current therapy rests on multiple-drug immunosuppression but its prognostic influence remains poorly known. We set out to analyze (1) our experience in diagnosing giant-cell myocarditis and (2) the outcome of patients on combined immunosuppression.

Methods and Results—

We reviewed the histories, diagnostic procedures, details of treatment, and outcome of 32 consecutive patients with histologically verified giant-cell myocarditis treated in our hospital since 1991. Twenty-six patients (81%) were diagnosed by endomyocardial or surgical biopsies and 6 at autopsy or post-transplantation. Twenty-eight (88%) patients underwent endomyocardial biopsy. The sensitivity of transvenous endomyocardial biopsy increased from 68% (19/28 patients) to 93% (26/28) after up to 2 repeat procedures. The 26 biopsy-diagnosed patients were treated with combined immunosuppression (2–4 drugs) including cyclosporine in 20 patients. The Kaplan-Meier estimates of transplant-free survival from symptom onset were 69% at 1 year, 58% at 2 years, and 52% at 5 years. Of the transplant-free survivors, 10/17 (59%) experienced sustained ventricular tachyarrhythmias during follow-up and 3 received intracardiac defibrillator shocks for ventricular tachycardia or fibrillation.

Conclusions—

Repeat endomyocardial biopsies are frequently needed to diagnose giant-cell myocarditis. On contemporary immunosuppession, two thirds of patients reach a partial clinical remission characterized by freedom from severe heart failure and need of transplantation but continuing proneness to ventricular tachyarrhythmias.
Impact of Diabetes Mellitus on Vessel Response in the Drug-Eluting Stent Era
Authors: Sakata Kenji , Waseda Katsuhisa , Kume Teruyoshi , Otake Hiromasa , Nakatani Daisaku , Yock Paul G. , Fitzgerald Peter J. , Honda Yasuhiro
Published: November 2012

Background—

Exaggerated neointimal hyperplasia is considered as the primary mechanism for increased restenosis in patients with diabetes mellitus (DM) treated with bare-metal stent. However, the vessel response in DM and non-DM treated with different drug-eluting stents (DES) has not been systematically evaluated.

Methods and Results—

We investigated 3D intravascular ultrasound (postprocedure and 6 to 9 months) in 971 patients (267 with DM and 704 without DM) treated with sirolimus- (n=104), paclitaxel- (n=303), zotarolimus- (n=391), or everolimus- (n=173) eluting stents. Volumetric data were standardized by length as volume index (VI). At postprocedure, lumen VI at the stented segment was significantly smaller in DM than in non-DM, whereas vessel VI was similar between the 2 groups. At follow-up, neointimal obstruction and maximum cross-sectional narrowing (neointimal area/stent area) were not significantly different between the 2 groups with no interaction for the DES type. Consequently, lumen VI was smaller in DM than in non-DM at follow-up. In the reference segments, residual plaque burden at postprocedure was significantly greater in DM than in non-DM, although change in lumen VI was similar between the 2 groups. The arterial responses at the reference segments also showed no interaction for the DES type.

Conclusions—

DM and non-DM lesions showed similar vessel response in both in-stent and reference segments regardless of the DES type. In the DES era, the follow-up lumen in DM patients seems to be determined primarily by the smaller lumen at postprocedure rather than exaggerated neointima within the stent or plaque proliferation at the reference segments.
Circulating 25-Hydroxy-Vitamin D and Risk of Cardiovascular Disease
Authors: Wang Lu , Song Yiqing , Manson JoAnn E. , Pilz Stefan , März Winfried , Michaëlsson Karl , Lundqvist Annamari , Jassal Simerjot K. , Barrett-Connor Elizabeth , Zhang Cuilin , Eaton Charles B. , May Heidi T. , Anderson Jeffrey L. , Sesso Howard D.
Published: November 2012

Background—

Vitamin D status has been linked to the risk of cardiovascular disease (CVD). However, the optimal 25-hydroxy-vitamin D (25[OH]-vitamin D) levels for potential cardiovascular health benefits remain unclear.

Methods and Results—

We searched MEDLINE and EMBASE from 1966 through February 2012 for prospective studies that assessed the association of 25(OH)-vitamin D concentrations with CVD risk. A total of 24 articles met our inclusion criteria, from which 19 independent studies with 6123 CVD cases in 65 994 participants were included for a meta-analysis. In a comparison of the lowest with the highest 25(OH)-vitamin D categories, the pooled relative risk was 1.52 (95% confidence interval, 1.30–1.77) for total CVD, 1.42 (95% confidence interval, 1.19–1.71) for CVD mortality, 1.38 (95% confidence interval, 1.21–1.57) for coronary heart disease, and 1.64 (95% confidence interval, 1.27–2.10) for stroke. These associations remained strong and significant when analyses were limited to studies that excluded participants with baseline CVD and were better controlled for season and confounding. We used a fractional polynomial spline regression analysis to assess the linearity of dose–response association between continuous 25(OH)-vitamin D and CVD risk. The CVD risk increased monotonically across decreasing 25(OH)-vitamin D below ≈60 nmol/L, with a relative risk of 1.03 (95% confidence interval, 1.00–1.06) per 25-nmol/L decrement in 25(OH)-vitamin D.

Conclusions—

This meta-analysis demonstrated a generally linear, inverse association between circulating 25(OH)-vitamin D ranging from 20 to 60 nmol/L and risk of CVD. Further research is needed to clarify the association of 25(OH)-vitamin D higher than 60 nmol/L with CVD risk and assess causality of the observed associations.
Diastolic Spontaneous Calcium Release From the Sarcoplasmic Reticulum Increases Beat-to-Beat Variability of Repolarization in Canine Ventricular Myocytes After β-Adrenergic Stimulation
Authors: Johnson Daniel M. , Heijman Jordi , Bode Elizabeth F. , Greensmith David J. , van der Linde Henk , Abi-Gerges Najah , Eisner David A. , Trafford Andrew W. , Volders Paul G.A.
Published: November 2012

Rationale:

Spontaneous Ca
2+
release (SCR) from the sarcoplasmic reticulum can cause delayed afterdepolarizations and triggered activity, contributing to arrhythmogenesis during β-adrenergic stimulation. Excessive beat-to-beat variability of repolarization duration (BVR) is a proarrhythmic marker. Previous research has shown that BVR is increased during intense β-adrenergic stimulation, leading to SCR.

Objective:

We aimed to determine ionic mechanisms controlling BVR under these conditions.

Methods and Results:

Membrane potentials and cell shortening or Ca
2+
transients were recorded from isolated canine left ventricular myocytes in the presence of isoproterenol. Action-potential (AP) durations after delayed afterdepolarizations were significantly prolonged. Addition of slowly activating delayed rectifier K
+
current (I
Ks
) blockade led to further AP prolongation after SCR, and this strongly correlated with exaggerated BVR. Suppressing SCR via inhibition of ryanodine receptors, Ca2+/calmodulin-dependent protein kinase II inhibition, or by using Mg
2+
or flecainide eliminated delayed afterdepolarizations and decreased BVR independent of effects on AP duration. Computational analyses and voltage-clamp experiments measuring L-type Ca
2+
current (I
CaL
) with and without previous SCR indicated that I
CaL
was increased during Ca
2+
-induced Ca
2+
release after SCR, and this contributes to AP prolongation. Prolongation of QT, T
peak
-T
end
intervals, and left ventricular monophasic AP duration of beats after aftercontractions occurred before torsades de pointes in an in vivo dog model of drug-induced long-QT1 syndrome.

Conclusions:

SCR contributes to increased BVR by interspersed prolongation of AP duration, which is exacerbated during I
Ks
blockade. Attenuation of Ca
2+
-induced Ca
2+
release by SCR underlies AP prolongation via increased I
CaL.
These data provide novel insights into arrhythmogenic mechanisms during β-adrenergic stimulation besides triggered activity and illustrate the importance of I
Ks
function in preventing excessive BVR.
Attenuating Endoplasmic Reticulum Stress as a Novel Therapeutic Strategy in Pulmonary Hypertension
Authors: Dromparis Peter , Paulin Roxane , Stenson Trevor H. , Haromy Alois , Sutendra Gopinath , Michelakis Evangelos D.
Published: November 2012

Background—

Evidence suggestive of endoplasmic reticulum (ER) stress in the pulmonary arteries of patients with pulmonary arterial hypertension has been described for decades but has never been therapeutically targeted. ER stress is a feature of many conditions associated with pulmonary arterial hypertension like hypoxia, inflammation, or loss-of-function mutations. ER stress signaling in the pulmonary circulation involves the activation of activating transcription factor 6, which, via induction of the reticulin protein Nogo, can lead to the disruption of the functional ER-mitochondria unit and the increasingly recognized cancer-like metabolic shift in pulmonary arterial hypertension that promotes proliferation and apoptosis resistance in the pulmonary artery wall. We hypothesized that chemical chaperones known to suppress ER stress signaling, like 4-phenylbutyrate (PBA) or tauroursodeoxycholic acid, will inhibit the disruption of the ER-mitochondrial unit and prevent/reverse pulmonary arterial hypertension.

Methods and Results—

PBA in the drinking water both prevented and reversed chronic hypoxia–induced pulmonary hypertension in mice, decreasing pulmonary vascular resistance, pulmonary artery remodeling, and right ventricular hypertrophy and improving functional capacity without affecting systemic hemodynamics. These results were replicated in the monocrotaline rat model. PBA and tauroursodeoxycholic acid improved ER stress indexes in vivo and in vitro, decreased activating transcription factor 6 activation (cleavage, nuclear localization, luciferase, and downstream target expression), and inhibited the hypoxia-induced decrease in mitochondrial calcium and mitochondrial function. In addition, these chemical chaperones suppressed proliferation and induced apoptosis in pulmonary artery smooth muscle cells in vitro and in vivo.

Conclusions—

Attenuating ER stress with clinically used chemical chaperones may be a novel therapeutic strategy in pulmonary hypertension with high translational potential.
Pulsatile Hemodynamics and Microcirculation
Authors: Muiesan Maria Lorenza , Salvetti Massimo , Rizzoni Damiano , Paini Anna , Agabiti-Rosei Claudia , Aggiusti Carlo , Bertacchini Fabio , Stassaldi Deborah , Gavazzi Alice , Porteri Enzo , De Ciuceis Carolina , Agabiti-Rosei Enrico
Published: November 2012

The possible relationships between indicators of small resistance artery structure and of arterial stiffness and central hemodynamics have not yet been evaluated. Aim of this study was to assess the relationship between indicators of large arteries stiffness, including carotido-femoral pulse wave velocity and of vascular alterations in small resistance arteries (media/lumen ratio, M/L) in patients with primary and secondary hypertension. In 73 patients (mean age, 53±14 years, 34 females, 25 with type 2 diabetes mellitus, 18 never treated) with essential (n=37) and secondary (n=36) hypertension, carotido-femoral pulse wave velocity was measured. In all patients, small resistance arteries were dissected from subcutaneous fat biopsies and mounted on an isometric myograph, for the measurement of the M/L. Pulse wave analysis was performed in 67 patients. M/L ratio was significantly related to brachial systolic blood pressure and pulse pressure (
r
=0.36 and 0.31,
P
<0.001, respectively) and to central systolic and pulse pressure (
r
=0.44 and 0.42,
P
<0.001, respectively). A positive correlation was observed between M/L ratio and carotido-femoral pulse wave velocity (
r
=0.45;
P
<0.001); this correlation remained statistically significant after adjustment for age and mean blood pressure. M/L ratio was also associated to aortic augmentation index (
r
=0.33;
P
=0.008), and this correlations remained statistically significant after adjustment for potential confounders. In hypertensive patients, the presence of structural alterations of small resistance arteries may be associated with the increase in large arteries stiffness and possibly contribute to an increase in central pressure by increasing the magnitude of wave reflections.