bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of contraction-inducible CXC chemokines and their roles in C2C12myocytes
Authors: Nedachi Taku , Hatakeyama Hiroyasu , Kono Tatsuyoshi , Sato Masaaki , Kanzaki Makoto
Published: July 2009

Physical exercise triggers the release of several cytokines/chemokines from working skeletal muscles, but the underlying mechanism(s) by which skeletal muscles decipher and respond to highly complex contractile stimuli remains largely unknown. In an effort to investigate the regulatory mechanisms of the expressions of two contraction-inducible CXC chemokines, CXCL1/KC and CXCL5/LIX, in contracting skeletal muscle cells, we took advantage of our in vitro exercise model using highly developed contractile C2C12myotubes, which acquire properties similar to those of in vivo skeletal muscle via manipulation of Ca2+transients with electric pulse stimulation (EPS). Production of these CXC chemokines was immediately augmented by EPS-evoked contractile activity in a manner dependent on the activities of JNK and NF-κB, but not p38, ERK1/2, or calcineurin. Intriguingly, exposure of myotubes to cyclic mechanical stretch also induced expression of these CXC chemokines; however, a much longer period of stimulation (∼12 h) was required, despite rapid JNK phosphorylation. We also demonstrate herein that CXCL1/KC and CXCL5/LIX have the ability to raise intracellular Ca2+concentrations via CXCR2-mediated activation of pertussis toxin-sensitive Gαiproteins in C2C12myoblasts, an action at least partially responsible for their migration and differentiation. Although we revealed a possible negative feedback regulation of their own production in response to the contractile activity in differentiated myotubes, exogenous administration of these CXC chemokines did not acutely influence either insulin-induced Akt phosphorylation or GLUT4 translocation in C2C12myotubes. Taken together, these data shed light on the fundamental characteristics of contraction-inducible CXC chemokine production and their potential roles in skeletal muscle cells.
Tertiary active transport of amino acids reconstituted by coexpression of System A and L transporters inXenopusoocytes
Authors: Baird Fiona E. , Bett Kevin J. , MacLean Catherine , Tee Andrew R. , Hundal Harinder S. , Taylor Peter M.
Published: July 2009

The System L transporter facilitates cellular import of large neutral amino acids (AAs) such as Leu, a potent activator of the intracellular target of rapamycin (TOR) pathway, which signals for cell growth. System L is an AA exchanger, proposed to accumulate certain AAs by coupling to dissipation of concentration gradient(s) of exchange substrates generated by secondary active AA transporters such as System A (SNAT2). We addressed the hypothesis that this type of coupling (termed tertiary active transport) acts as an indirect mechanism to extend the range of AA stimulating TOR to those transported by both Systems A and L (e.g., Gln) through downstream enhancement of Leu accumulation. System A overexpression enabled Xenopus oocytes to accumulate substrate AAs (notably Ser, Gln, Ala, Pro, Met; totaling 2.6 nmol/oocyte) from medium containing a physiological AA mixture at plasma concentrations. Net accumulation of System L (4F2hc-xLAT1) substrates from this medium by System L-overexpressing oocytes was increased by 90% (from 0.7 to 1.35 nmol/oocyte; mainly Leu, Ile) when Systems A and L were coexpressed, coincident with a decline in accumulation of specific System A substrates (Gln, Ser, Met), as expected if the latter were also System L substrates and functional coupling of the transport Systems occurred. AA flux coupling was confirmed as trans-stimulation of Leu influx in System L-expressing oocytes by Gln injection (0.5 nmol/oocyte). The observed changes in Leu accumulation are sufficient to activate the TOR pathway in oocytes, although intracellular AA metabolism limits the potential for AA accumulation by tertiary active transport in this system.
Magnitude and control of mitochondrial sensitivity to ADP
Authors: Jeneson Jeroen A. L. , Schmitz Joep P. J. , van den Broek Nicole M. A. , van Riel Natal A. W. , Hilbers Peter A. J. , Nicolay Klaas , Prompers Jeanine J.
Published: July 2009

The transduction function for ADP stimulation of mitochondrial ATP synthesis in skeletal muscle was reconstructed in vivo and in silico to investigate the magnitude and origin of mitochondrial sensitivity to cytoplasmic ADP concentration changes. Dynamic in vivo measurements of human leg muscle phosphocreatine (PCr) content during metabolic recovery from contractions were performed by31P-NMR spectroscopy. The cytoplasmic ADP concentration ([ADP]) and rate of oxidative ATP synthesis (Jp) at each time point were calculated from creatine kinase equilibrium and the derivative of a monoexponential fit to the PCr recovery data, respectively. Reconstructed [ADP]-Jp relations for individual muscles containing more than 100 data points were kinetically characterized by nonlinear curve fitting yielding an apparent kinetic order and ADP affinity of 1.9 ± 0.2 and 0.022 ± 0.003 mM, respectively (means ± SD; n = 6). Next, in silico [ADP]-Jp relations for skeletal muscle were generated using a computational model of muscle oxidative ATP metabolism whereby model parameters corresponding to mitochondrial enzymes were randomly changed by 50–150% to determine control of mitochondrial ADP sensitivity. The multiparametric sensitivity analysis showed that mitochondrial ADP ultrasensitivity is an emergent property of the integrated mitochondrial enzyme network controlled primarily by kinetic properties of the adenine nucleotide translocator.
Selective regulation of cellular and secreted multimeric adiponectin by antidiabetic therapies in humans
Authors: Phillips Susan A. , Kung Jacqueline , Ciaraldi Theodore P. , Choe Charles , Christiansen Louis , Mudaliar Sunder , Henry Robert R.
Published: July 2009

Adiponectin, an insulin-sensitizing factor secreted from adipose tissue, is decreased in individuals with type 2 diabetes (T2D) and increased in response to thiazolidinedione (TZD) therapy. Changes in its secretion and assembly into higher-order forms affect insulin sensitivity. To determine the relative potency of TZDs on intra-adipocyte multimerization and secretion of adiponectin, we assessed the impact of in vivo low- or high-dose rosiglitazone treatment alone or combined with metformin in subjects with T2D. T2D subjects received high-dose rosiglitazone (8 mg/day), high-dose metformin (2,000 mg/day), or low-dose combination rosiglitazone-metformin therapy (4 mg + 1,000 mg/day) for 4 mo. All subjects were then switched to high-dose rosiglitazone-metformin combination therapy (8 mg + 2,000 mg/day) for another 4 mo. Low-dose rosiglitazone increased serum adiponectin, whereas the high dose increased both adipocyte content and serum adiponectin levels. TZDs selectively increased the percentage of circulating adiponectin in the potent, high-molecular-weight (HMW) form. No TZD effects were evident on multimer distribution in the cell. Expression of the chaperone protein ERp44, which retains adiponectin within the cell, was decreased by TZD treatment. No changes occurred in Ero1-Lα expression. Metformin had no effect on any of these measures. Increases in adiponectin correlated with improvements in insulin sensitivity. In vivo, TZDs have apparent dose-dependent effects on cellular and secreted adiponectin. TZD-mediated improvements in whole body insulin sensitivity are associated with increases in circulating but not cellular levels of the HMW adiponectin multimer. Finally, TZDs promote the selective secretion of HMW adiponectin, potentially, in part, through decreasing the expression of the adiponectin-retaining protein ERp44.
Leptin modulates ACAT1 expression and cholesterol efflux from human macrophages
Authors: Hongo Shigeki , Watanabe Takuya , Arita Shigeko , Kanome Tomoko , Kageyama Haruaki , Shioda Seiji , Miyazaki Akira
Published: July 2009

Leptin is an adipose tissue-derived hormone implicated in atherosclerosis and macrophage foam cell formation. The current study was conducted to examine the effect of leptin on cholesteryl ester accumulation in human monocytes/macrophages. Exogenously added leptin at 5 nM during differentiation of monocytes into macrophages for 7 days accelerated acetylated LDL (acetyl-LDL)-induced cholesteryl ester accumulation by 30–50%. Leptin did not affect endocytic uptake of acetyl-LDL; however, it increased ACAT activity 1.8-fold and ACAT-1 protein expression 1.9-fold. Among the four ACAT-1 mRNA transcripts, two shorter transcripts (2.8 and 3.6 kb) were upregulated ∼1.7-fold upon leptin treatment. The enhanced expression of ACAT-1 protein by leptin was suppressed by inhibitors of Janus-activated kinase2 (JAK2) and phosphatidylinositol 3-kinase (PI3K). HDL-mediated cholesterol efflux was suppressed by leptin, which was canceled by K-604, an ACAT-1 inhibitor. Expression of long form of leptin receptor was upregulated during monocytic differentiation into macrophages and sustained after differentiation. Thus, the results suggest that leptin accelerates cholesteryl ester accumulation in human monocyte-derived macrophages by increasing ACAT-1 expression via JAK2 and PI3K, thereby suppressing cholesterol efflux.
The Electrocorticogram Signal Can Be Modulated With Deep Brain Stimulation of the Subthalamic Nucleus in the Hemiparkinsonian Rat
Authors: Lehmkuhle M. J. , Bhangoo S. S. , Kipke D. R.
Published: July 2009

Electrocorticogram (ECoG) recordings of the 6-hydroxydopamine (6-OHDA)–lesioned parkinsonian rat have shown an increase in the power of cortical β-band (15–30 Hz) oscillations ipsilateral to the lesion. The power of these oscillations is decreased with dopamine agonist administration. Here, we demonstrate that stimulation of an electrode implanted in the subthalamic nucleus alters the power of cortical β and γ oscillations in 6-OHDA–lesioned animals. These alterations are dependent on stimulation frequency, charge, and amplitude/pulse width. Oscillations were significantly reduced during 200- and 350-Hz stimulation. A minimum charge of 4 nC was required to elicit a reduction in oscillation power. A number of amplitude and pulse width combinations that reached 4 nC were tested; it was found that only the combinations of 33 μA/120 μs and 65 μA/60 μs significantly reduced cortical oscillations. The reduction in β/γ oscillation power due to deep brain stimulation (DBS) was consistent with a significant reduction in the animals' rotational behavior, a typical symptom of parkinsonism in the rat. A significant shift from high β to low γ was observed in the peak frequencies of ECoG recordings while animals were at rest versus walking on a treadmill. However, DBS exhibited no differential effect on oscillations between these two states. EEG recordings from rodent models of DBS may provide surrogate information about the neural signatures of Parkinson's disease relative to the efficacy of DBS.
Transcriptional profiling of human cavernosal endothelial cells reveals distinctive cell adhesion phenotype and role for claudin 11 in vascular barrier function
Authors: Wessells Hunter , Sullivan Chris J. , Tsubota Yoshiaki , Engel Karen L. , Kim Bryan , Olson N. Eric , Thorner Daniel , Chitaley Kanchan
Published: July 2009

To determine specific molecular features of endothelial cells (ECs) relevant to the physiological process of penile erection we compared gene expression of human EC derived from corpus cavernosum of men with and without erectile dysfunction (HCCEC) to coronary artery (HCAEC) and umbilical vein (HUVEC) using Affymetrix GeneChip microarrays and GeneSifter software. Genes differentially expressed across samples were partitioned around medoids to identify genes with highest expression in HCCEC. A total of 190 genes/transcripts were highly expressed only in HCCEC. Gene Ontology classification indicated cavernosal enrichment in genes related to cell adhesion, extracellular matrix, pattern specification and organogenesis. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed high expression of genes relating to ECM-receptor interaction, focal adhesions, and cytokine-cytokine receptor interaction. Real-time PCR confirmed expression differences in cadherins 2 and 11, claudin 11 (CLDN11), desmoplakin, and versican. CLDN11, a component of tight junctions not previously described in ECs, was highly expressed only in HCCEC and its knockdown by siRNA significantly reduced transendothelial electrical resistance in HCCEC. Overall, cavernosal ECs exhibited a transcriptional profile encoding matrix and adhesion proteins that regulate structural and functional characteristics of blood vessels. Contribution of the tight junction protein CLDN11 to barrier function in endothelial cells is novel and may reflect hemodynamic requirements of the corpus cavernosum.
Gene expression profiles of bovine caruncular and intercaruncular endometrium at implantation
Authors: Mansouri-Attia Nadéra , Aubert Julie , Reinaud Pierrette , Giraud-Delville Corinne , Taghouti Géraldine , Galio Laurent , Everts Robin E. , Degrelle Séverine , Richard Christophe , Hue Isabelle , Yang Xiangzhong , Tian X. Cindy , Lewin Harris A. , Renard Jean-Paul , Sandra Olivier
Published: July 2009

At implantation the endometrium undergoes modifications necessary for its physical interactions with the trophoblast as well as the development of the conceptus. We aim to identify endometrial factors and pathways essential for a successful implantation in the caruncular (C) and the intercaruncular (IC) areas in cattle. Using a 13,257-element bovine oligonucleotide array, we established expression profiles at day 20 of the estrous cycle or pregnancy (implantation), revealing 446 and 1,295 differentially expressed genes (DEG) in C and IC areas, respectively (false discovery rate = 0.08). The impact of the conceptus was higher on the immune response function in C but more prominent on the regulation of metabolism function in IC. The C vs. IC direct comparison revealed 1,177 and 453 DEG in cyclic and pregnant animals respectively (false discovery rate = 0.05), with a major impact of the conceptus on metabolism and cell adhesion. We selected 15 genes including C11ORF34, CXCL12, CXCR4, PLAC8, SCARA5, and NPY and confirmed their differential expression by quantitative RT-PCR. The cellular localization was analyzed by in situ hybridization and, upon pregnancy, showed gene-specific patterns of cell distribution, including a high level of expression in the luminal epithelium for C11ORF34 and MX1. Using primary cultures of bovine endometrial cells, we identified PTN, PLAC8, and CXCL12 as interferon-τ (IFNT) target genes and MSX1 and CXCR7 as IFNT-regulated genes, whereas C11ORF34 was not an IFNT-regulated gene. Our transcriptomic data provide novel molecular insights accounting for the biological functions related to the C or IC endometrial areas and may contribute to the identification of potential biomarkers for normal and perturbed early pregnancy.
The Imbalance in Serum Concentration of Th-1- and Th-2-Derived Chemokines as One of the Factors Involved in Pathogenesis of Atopic Dermatitis
Authors: Narbutt Joanna , Lesiak Aleksandra , Sysa-Jedrzeiowska Anna , Zakrzewski Marcin , Bogaczewicz Jarosław , Stelmach Iwona , Kuna Piotr
Published: July 2009

Atopic dermatitis (AD) is an inflammatory skin disease in which pathogenesis chemokines are partially involved. The aim of the paper was to assess the serum level of CXCL-9, CXCL-10, CXCL-11, CXCL-12, CCL-17, CCL-20, CCL-21, CCL-22, CCL-27, and IL-18 chosen in AD patients by ELISA assay. Forty patients (mean age 11.4 years old) with AD and 50 healthy controls were enrolled into the study. The patients and controls were divided into two age categories: under 10 years old (Group 1 and Control 1) and over 10 years old (Group 2 and Control 2). Significantly lower serum concentration of CXCL-9, CXCL-10, CCL-17, and IL-18 and higher concentration of CXCL-12 and CCL-27 were found in Group 1 when compared to Control 1. In Group 2 serum concentration of CXCL-12, CCL-17, CCL-22 was higher than in Control 2. The obtained results indicate the imbalance in chemokine serum levels in AD what suggests their role in the disease pathogenesis.
A Taxonomy of Reconfigurable Single‐/Multiprocessor Systems‐on‐Chip
Authors: Göhringer Diana , Perschke Thomas , Hübner Michael , Becker Jürgen
Published: July 2009

Runtime adaptivity of hardware in processor architectures is a novel trend, which is under investigation in a variety of research labs all over the world. The runtime exchange of modules, implemented on a reconfigurable hardware, affects the instruction flow (e.g., in reconfigurable instruction set processors) or the data flow, which has a strong impact on the performance of an application. Furthermore, the choice of a certain processor architecture related to the class of target applications is a crucial point in application development. A simple example is the domain of high‐performance computing applications found in meteorology or high‐energy physics, where vector processors are the optimal choice. A classification scheme for computer systems was provided in 1966 by Flynn where single/multiple data and instruction streams were combined to four types of architectures. This classification is now used as a foundation for an extended classification scheme including runtime adaptivity as further degree of freedom for processor architecture design. The developed scheme is validated by a multiprocessor system implemented on reconfigurable hardware as well as by a classification of existing static and reconfigurable processor systems.
Chromatin from Peripheral Blood Mononuclear Cells as Biomarkers for Epigenetic Abnormalities in Schizophrenia
Authors: Gavin David P. , Sharma Rajiv P.
Published: July 2009

Background. Studies have implicated abnormalities in epigenetic gene regulation in schizophrenia. Presentation. We hypothesize that identifying abnormalities in chromatin structure and the epigenetic machinery in peripheral blood mononuclear cells (PBMC) from schizophrenia patients could (a) help characterize a subset of schizophrenia patients and (b) lead to targeted pharmacological interventions. Testing. Investigate the relationship between clinical symptoms, demographics, hormonal fluctuations, substance abuse, disease characteristics across the major mental illnesses, and epigenetic parameters in PBMC. In addition, examine the effects of individual antipsychotics, mood stabilizers, as well as experimental agents both as clinically prescribed as well as in cultured PBMC to understand the effects of these agents on chromatin. Implications. If PBMC could serve as a reliable model of overall epigenetic mechanisms then this could lead to a “biomarker” approach to revealing pathological chromatin state in schizophrenia. This approach may provide an informed method for selecting chromatin modifying agents for psychiatric disorders.
A Plastic Temporal Brain Code for Conscious State Generation
Authors: Dresp-Langley Birgitta , Durup Jean
Published: July 2009

Consciousness is known to be limited in processing capacity and often described in terms of a unique processing stream across a single dimension: time. In this paper, we discuss a purely temporal pattern code, functionally decoupled from spatial signals, for conscious state generation in the brain. Arguments in favour of such a code include Dehaene et al.'s long-distance reverberation postulate, Ramachandran's remapping hypothesis, evidence for a temporal coherence index and coincidence detectors, and Grossberg's Adaptive Resonance Theory. A time-bin resonance model is developed, where temporal signatures of conscious states are generated on the basis of signal reverberation across large distances in highly plastic neural circuits. The temporal signatures are delivered by neural activity patterns which, beyond a certain statistical threshold, activate, maintain, and terminate a conscious brain state like a bar code would activate, maintain, or inactivate the electronic locks of a safe. Such temporal resonance would reflect a higher level of neural processing, independent from sensorial or perceptual brain mechanisms.
Singular Positone and Semipositone Boundary Value Problems of Nonlinear Fractional Differential Equations
Authors: Yuan Chengjun , Jiang Daqing , Xu Xiaojie
Published: July 2009

We present some new existence results for singular positone and semipositone nonlinear fractional boundary value problem ,  0 < t < 1, u(0) = u(1) = u′(0) = u′(1) = 0, where μ > 0, a, and f are continuous, α ∈ (3, 4] is a real number, and is Riemann‐Liouville fractional derivative. Throughout our nonlinearity may be singular
in its dependent variable. Two examples are also given to illustrate the main results.
New Improved Exponential Stability Criteria for Discrete‐Time Neural Networks with Time‐Varying Delay
Authors: Liu Zixin , Lv Shu , Zhong Shouming , Ye Mao
Published: July 2009

The robust stability of uncertain discrete‐time recurrent neural networks with time‐varying delay is investigated. By decomposing some connection weight matrices, new Lyapunov‐Krasovskii functionals are constructed, and serial new improved stability criteria are derived. These criteria are formulated in the forms of linear matrix inequalities (LMIs). Compared with some previous results, the new results are less conservative. Three numerical examples are provided to demonstrate the less conservatism and effectiveness of the proposed method.
Loss of Histone Deacetylase 4 Causes Segregation Defects during Mitosis of p53-Deficient Human Tumor Cells
Authors: Cadot Bruno , Brunetti Mirko , Coppari Sabina , Fedeli Silvia , de Rinaldis Emanuele , Russo Claudio Dello , Gallinari Paola , De Francesco Raffaele , Steinkühler Christian , Filocamo Gessica
Published: July 2009

We investigated the role of histone deacetylase 4 (HDAC4) using RNA interference (RNAi) and knockout cells to specifically address its role in cell cycle progression in tumor and normal cells. Ablation of HDAC4 led to growth inhibition in human tumor cells but not to detectable effects in normal human dermal fibroblasts (NHDF) or myelopoietic progenitors. HDAC4−/+ or HDAC4−/− murine embryonic fibroblasts showed no detectable growth defects. On the other hand, HDAC4 RNAi in HeLa cells produced mitotic arrest followed by caspase-dependent apoptosis. Mitotically arrested cells showed chromosome segregation defects. Even though the growth of both p53–wild-type and p53-null tumor cells were affected by HDAC4 ablation, segregation defects were observed only in p53-null cells. HDAC4 associates with the PP2A-B56 regulatory subunit, which is known to be involved in chromosome segregation, and RNAi of either the structural subunit A or the regulatory subunit B56 of PP2A also caused chromosome segregation defects. We conclude that HDAC4 is required for cell cycle progression of tumor cells by multiple mechanisms, one of which seems to be specific to p53-deficient cells through chromosome segregation defects. On the contrary, HDAC4 is not required for the progression of NHDF. We therefore suggest that systemic selective interference with the expression or function of HDAC4 is expected to have a significant therapeutic window, in particular, for p53-deficient tumors. [Cancer Res 2009;69(15):6074–82]
Differentiation-Related Gene-1 Decreases Bim Stability by Proteasome-Mediated Degradation
Authors: Ambrosini Grazia , Seelman Sharon L. , Schwartz Gary K.
Published: July 2009

Drg1 was identified as a differentiation-related, putative metastatic suppressor gene in human colon and prostate cancer. Its expression is associated with resistance to irinotecan (CPT-11) therapy in preclinical colorectal cancer models both in vitro and in vivo. However, the functional significance of Drg1 in these processes is unknown. We have shown for the first time that Drg1 directly binds to the BH3-only proapoptotic protein Bim. Depletion of Drg1 by small interfering RNA induced up-regulation of Bim and its accumulation in the mitochondria, which correlated with loss of mitochondrial membrane potential and induction of apoptosis in cells exposed to SN-38. Further analyses revealed that Drg1 promotes degradation of Bim through the Cullin2/ElonginB-CIS ubiquitin-protein ligase complex. Conversely, in the absence of Drg1, Bim was stabilized and bound more abundantly to Hsp70. These results show that Drg1 renders cancer cells more resistant to chemotherapy through enhanced proteasome-mediated Bim degradation. [Cancer Res 2009;69(15):6115–21]
Immunity to Murine Prostatic Tumors: Continuous Provision of T-Cell Help Prevents CD8 T-Cell Tolerance and Activates Tumor-Infiltrating Dendritic Cells
Authors: Shafer-Weaver Kimberly A. , Watkins Stephanie K. , Anderson Michael J. , Draper Lauren J. , Malyguine Anatoli , Alvord W. Gregory , Greenberg Norman M. , Hurwitz Arthur A.
Published: July 2009

We reported previously that tumor-specific CD8+ T cells (TcR-I) become tolerant in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. In this study, we show that CD4+ TcR transgenic (TcR-II) T cells transferred into TRAMP mice became activated in lymph nodes, trafficked to the prostate, and initially functioned as TH1 cells. Although a single cotransfer of TcR-II cells delayed TcR-I cell tolerization, repeated transfer of TcR-II cells was required to prevent TcR-I cell tolerization and significantly slowed progression of TRAMP prostate tumors. After transfer of TcR-II cells, dendritic cells within the tumor expressed higher levels of costimulatory molecules and displayed an enhanced ability to stimulate proliferation of naive T cells. Blockade of CD40-CD40L interactions during TcR-II transfer resulted in a profound reduction in dendritic cell stimulatory capacity and a partial loss of TcR-I effector functions and tumor immunity. These data show that sustained provision of activated tumor-specific CD4+ T cells alters the immunosuppressive tumor microenvironment, ultimately leading to the control of tumor growth. These findings will assist in the design of more effective immunotherapeutic approaches for cancer. [Cancer Res 2009;69(15):6256–64]
Blockade of PAR1 Signaling with Cell-Penetrating Pepducins Inhibits Akt Survival Pathways in Breast Cancer Cells and Suppresses Tumor Survival and Metastasis
Authors: Yang Eric , Boire Adrienne , Agarwal Anika , Nguyen Nga , O'Callaghan Katie , Tu Powen , Kuliopulos Athan , Covic Lidija
Published: July 2009

Protease-activated receptor 1 (PAR1) is a G protein–coupled receptor that is not expressed in normal breast epithelia but is up-regulated in invasive breast carcinomas. In the present study, we found that matrix metalloprotease-1 (MMP-1) robustly activates the PAR1-Akt survival pathway in breast carcinoma cells. This process is blocked by a cell-penetrating lipopeptide “pepducin,” P1pal-7, which is a potent inhibitor of cell viability in breast carcinoma cells expressing PAR1. Both a MMP-1 inhibitor and P1pal-7 significantly promote apoptosis in breast tumor xenografts and inhibit metastasis to the lungs by up to 88%. Dual therapy with P1pal-7 and Taxotere inhibits the growth of MDA-MB-231 xenografts by 95%. Consistently, biochemical analysis of xenograft tumors treated with P1pal-7 or MMP-1 inhibitor showed attenuated Akt activity. Ectopic expression of constitutively active Akt rescues breast cancer cells from the synergistic cytotoxicity of P1pal-7 and Taxotere, suggesting that Akt is a critical component of PAR1-dependent cancer cell viability. Together, these findings indicate that blockade of MMP1-PAR1 signaling may provide a benefit beyond treatment with Taxotere alone in advanced, metastatic breast cancer. [Cancer Res 2009;69(15):6223–31]
Tumor Vascular Changes Mediated by Inhibition of Oncogenic Signaling
Authors: Qayum Naseer , Muschel Ruth J. , Im Jae Hong , Balathasan Lukxmi , Koch Cameron J. , Patel Sonal , McKenna W. Gillies , Bernhard Eric J.
Published: July 2009

Many inhibitors of the epidermal growth factor receptor (EGFR)-RAS-phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway are in clinical use or under development for cancer therapy. Here, we show that treatment of mice bearing human tumor xenografts with inhibitors that block EGFR, RAS, PI3K, or AKT resulted in prolonged and durable enhancement of tumor vascular flow, perfusion, and decreased tumor hypoxia. The vessels in the treated tumors had decreased tortuosity and increased internodal length accounting for the functional alterations. Inhibition of tumor growth cannot account for these results, as the drugs were given at doses that did not alter tumor growth. The tumor cell itself was an essential target, as HT1080 tumors that lack EGFR did not respond to an EGFR inhibitor but did respond with vascular alterations to RAS or PI3K inhibition. We extended these observations to spontaneously arising tumors in MMTV-neu mice. These tumors also responded to PI3K inhibition with decreased tumor hypoxia, increased vascular flow, and morphologic alterations of their vessels, including increased vascular maturity and acquisition of pericyte markers. These changes are similar to the vascular normalization that has been described after the antiangiogenic treatment of xenografts. One difficulty in the use of vascular normalization as a therapeutic strategy has been its limited duration. In contrast, blocking tumor cell RAS-PI3K-AKT signaling led to persistent vascular changes that might be incorporated into clinical strategies based on improvement of vascular flow or decreased hypoxia. These results indicate that vascular alterations must be considered as a consequence of signaling inhibition in cancer therapy. [Cancer Res 2009;69(15):6347–54]
Host-Derived Tumor Endothelial Marker 8 Promotes the Growth of Melanoma
Authors: Cullen Mike , Seaman Steven , Chaudhary Amit , Yang Mi Young , Hilton Mary Beth , Logsdon Daniel , Haines Diana C. , Tessarollo Lino , St. Croix Brad
Published: July 2009

Tumor endothelial marker 8 (TEM8) was initially identified as a gene overexpressed in the vasculature of human tumors and was subsequently identified as an anthrax toxin receptor. To assess the functional role of TEM8, we disrupted the TEM8 gene in mice by targeted homologous recombination. TEM8−/− mice were viable and reached adulthood without defects in physiologic angiogenesis. However, histopathologic analysis revealed an excess of extracellular matrix in several tissues, including the ovaries, uterus, skin, and periodontal ligament of the incisors, the latter resulting in dental dysplasia. When challenged with B16 melanoma, tumor growth was delayed in TEM8−/− mice, whereas the growth of other tumors, such as Lewis lung carcinoma, was unaltered. These studies show that host-derived TEM8 promotes the growth of certain tumors and suggest that TEM8 antagonists may have utility in the development of new anticancer therapies. [Cancer Res 2009;69(15):6021–6]
Genome-Wide Identification of Direct Target Genes Implicates Estrogen-Related Receptor α as a Determinant of Breast Cancer Heterogeneity
Authors: Deblois Geneviève , Hall Jacqueline A. , Perry Marie-Claude , Laganière Josée , Ghahremani Majid , Park Morag , Hallett Michael , Giguère Vincent
Published: July 2009

Estrogen-related receptor α (ERRα) is an orphan nuclear receptor, the expression of which correlates with negative prognosis in breast cancer. ERRα shares functional features with the estrogen receptor α (ERα) and its activity is modulated by the ERBB2 signaling pathway. Using genome-wide binding sites location analyses in ERα-positive and ERα-negative breast cancer cell lines, we show that ERRα and ERα display strict binding site specificity and maintain independent mechanisms of transcriptional activation. Nonetheless, ERRα and ERα coregulate a small subset of common target genes via binding either to a dual-specificity binding site or to distinct cognate binding sites located within the extended promoter region of the gene. Although ERRα signaling in breast cancer cells is mostly independent of ERα, the small fraction of common ERRα/ERα targets comprises genes with high relevance to breast tumor biology, including genes located within the ERBB2 amplicon and GATA3. Finally, unsupervised hierarchical clustering based on the expression profiling of ERRα direct target genes in human breast tumors revealed four main clusters that recapitulate established tumor subtypes. Taken together, the identification and functional characterization of the ERRα transcriptional network implicate ERRα signaling as a determinant of breast cancer heterogeneity. [Cancer Res 2009;69(15):6149–57]
Effective Treatment of Advanced Human Melanoma Metastasis in Immunodeficient Mice Using Combination Metronomic Chemotherapy Regimens
Authors: Cruz-Munoz William , Man Shan , Kerbel Robert S.
Published: July 2009

Purpose: The development of effective therapeutic approaches for treatment of metastatic melanoma remains an immense challenge. Present therapies offer minimal benefit. Although dacarbazine chemotherapy remains the standard therapy, it mediates only low response rates, usually of short duration, even when combined with other chemotherapeutic agents. Thus, new therapeutic strategies are urgently needed.

Experimental Design: Using a newly developed preclinical model, we evaluated the efficacy of various doublet metronomic combination chemotherapy against established advanced melanoma metastasis and compared these with the standard maximum tolerated dose dacarbazine (alone or in combination with chemotherapeutic agents or vascular endothelial growth factor receptor–blocking antibody).

Results: Whereas maximum tolerated dose dacarbazine therapy did not cause significant improvement in median survival, a doublet combination of low-dose metronomic vinblastine and low-dose metronomic cyclophosphamide induced a significant increase in survival with only minimal toxicity. Furthermore, we show that the incorporation of the low-dose metronomic vinblastine/low-dose metronomic cyclophosphamide combination with a low-dose metronomic dacarbazine regimen also results in a significant increase in survival, but not when combined with maximum tolerated dose dacarbazine therapy. We also show that a combination of metronomic vinblastine therapy and a vascular endothelial growth factor receptor 2–blocking antibody (DC101) results in significant control of metastatic disease and that the combination of low-dose metronomic vinblastine/DC101 and low-dose metronomic dacarbazine induced a significant improvement in median survival.

Conclusions: The effective control of advanced metastatic melanoma achieved by these metronomic-based chemotherapeutic approaches warrants clinical consideration of this treatment concept, given the recent results of a number of metronomic-based chemotherapy clinical trials.
Clinical and Pharmacodynamic Evaluation of Metronomic Cyclophosphamide, Celecoxib, and Dexamethasone in Advanced Hormone-refractory Prostate Cancer
Authors: Fontana Andrea , Galli Luca , Fioravanti Anna , Orlandi Paola , Galli Costanza , Landi Lorenza , Bursi Simona , Allegrini Giacomo , Fontana Eloise , Di Marsico Roberta , Antonuzzo Andrea , D'Arcangelo Manolo , Danesi Romano , Del Tacca Mario , Falcone Alfredo , Bocci Guido
Published: July 2009

Purpose: The aims of the present study were to evaluate the clinical activity and the pharmacodynamic profile of the novel schedule of a single i.v. standard dose of cyclophosphamide (CTX) immediately followed by an oral metronomic CTX regimen with celecoxib (CXB) and dexamethasone (DEX) in advanced hormone-refractory prostate cancer patients.

Experimental Design: Twenty-eight patients (68% docetaxel-resistant) received 500 mg/m2 CTX i.v. bolus on day 1 and, from day 2, 50 mg/day CTX p.o. plus 200 mg/twice a day CXB p.o. and 1 mg/day DEX p.o. until disease progression. Plasma vascular endothelial growth factor (VEGF) and thrombospondin-1 were detected by ELISA, and real-time reverse transcription-PCR of VEGF and thrombospondin-1 gene expression on peripheral blood mononuclear cell and of VE-cadherin (VE-C) in blood samples was done.

Results: A confirmed prostate-specific antigen decrease of ≥50% from baseline was observed in 9 of 28 patients (32%). Median progression-free survival and overall survival were 3 months (95% confidence interval, 2.2-4.2 months) and 21 months (95% confidence interval, 12.4-29.4 months), respectively. Toxicity was mild and no grade 3 to 4 toxicities occurred. A significant relationship was found between plasma VEGF and prostate-specific antigen values (r = 0.4223; P < 0.001). VEGF levels significantly increased in nonresponders, whereas the responder patients maintained significantly lower levels of VE-C gene expression after the beginning of the treatment if compared with nonresponder ones.

Conclusion: Metronomic CTX plus CXB and DEX showed favorable toxicity and activity profile in patients. VE-C gene expression and VEGF levels represent potentially useful pharmacodynamic markers for the clinical response.
Cardiac Mechanics in Mild Hypertensive Heart Disease
Authors: Narayanan Arumugam , Aurigemma Gerard P. , Chinali Marcello , Hill Jeffrey C. , Meyer Theo E. , Tighe Dennis A.
Published: July 2009

Background—

We hypothesized that abnormalities in regional systolic strain (ε) might be present among hypertensive subjects with normal ejection fraction, and, if present, could be used to identify patients at high risk for heart failure. The aim of the current case-control study was to use speckle tracking imaging to identify subclinical global and regional systolic function abnormalities in hypertensive subjects with normal ejection fraction.

Methods and Results—

Standard 2D Doppler echocardiography, tissue Doppler imaging, and 2D speckle strain imaging were performed in 52 hypertensive subjects with normal ejection fraction and 52 control subjects of similar age. Peak systolic (S′), and diastolic (E′) annular velocities were obtained by tissue Doppler imaging, whereas longitudinal myocardial systolic velocity (V
l
) and circumferential, longitudinal, and radial strains (ε
c
, ε
l
, ε
r
) were obtained by speckle tracking. Midwall shortening and peak basal longitudinal strain (ε
l
) were used as indices of regional function. Hypertensive subjects had lower velocities—tissue Doppler imaging E′ and S′, and V
l
—and evidence of reduced regional function. Surprisingly, however, global ε values did not differentiate hypertensive subjects from control subjects. Among hypertensive patients, significant inverse associations were found between left ventricular mass and global longitudinal and circumferential ε (both
P
<0.05).

Conclusions—

Hypertensive heart disease with normal ejection fraction is associated with reduced myocardial velocities and reduced regional function but normal global ε. Our data suggest that velocity abnormalities occur early in hypertension and may be an appropriate target for preventive strategies because they occur before abnormalities in global ε.
In Vivo Metabolic Phenotyping of Myocardial Substrate Metabolism in Rodents
Authors: Shoghi Kooresh I. , Finck Brian N. , Schechtman Kenneth B. , Sharp Terry , Herrero Pilar , Gropler Robert J. , Welch Michael J.
Published: July 2009

Background—

Cardiovascular disease is the leading cause of death among diabetic patients, with alteration in myocardial substrate metabolism being a likely contributor. We aimed to assess noninvasively the efficacy of metformin and rosiglitazone monotherapy in normalizing myocardial substrate metabolism in an animal model of type 2 diabetes mellitus.

Methods and Results—

The study used 18 male ZDF rats
(fa/fa)
with 6 rats in each group: an untreated group; a group treated with metformin (16.6 mg/kg/d), and a group treated with rosiglitazone (4 mg/kg). Each rat was scanned at age 14 weeks (baseline) and subsequently at 19 weeks with small-animal positron emission tomography to estimate myocardial glucose utilization (MGU) and myocardial utilization (MFAU), oxidation (MFAO), and esterification (MFAE). Treatment lasted for 5 weeks after baseline imaging. At week 19, rats were euthanized and hearts were extracted for expression analysis of select genes encoding for GLUT transporters and fatty acid transport and oxidation genes. In addition, echocardiography measurements were obtained at weeks 13 and 18 to characterize cardiac function. Metformin had no significant effect on either MGU or MFAU and MFAO. In contrast, rosiglitazone tended to enhance MGU and significantly reduced MFAU and MFAO. Rosiglitazone-induced increase in glucose uptake correlated significantly with increased expression of GLUT4, whereas diminished MFAO correlated significantly with decreased expression of FATP-1 and MCAD. Finally, changes in fractional shortening as a measure of cardiac function were unchanged throughout the study.

Conclusions—

Treatment with rosiglitazone enhanced glucose utilization and diminished MFAO, thus reversing the metabolic phenotype of the diabetic heart.
Behavioural response of Meloidogyne incognita to benzyl isothiocyanate
Authors: Zasada Inga A. , Masler Edward P. , Halbrendt John M. , Rogers Stephen T.
Published: July 2009

The breakdown of brassicaceous plant material produces nematotoxic
isothiocyanates (ITCs). However, after the incorporation of brassicaceous
plant material into soil, many nematodes are likely to be exposed only to
sublethal concentrations of these compounds. Although unknown, the effect of
these low ITC concentrations on the behaviour of plant-parasitic nematodes
could play a role in nematode suppression. To address this question, the
behaviour of infective second-stage juveniles (J2) of Meloidogyne incognita
was evaluated following in vitro exposure to sublethal concentrations of
benzyl isothiocyanate (BITC). Behaviour was qualitatively and quantitatively
affected. Overall nematode activity in treatment groups scored visually, and
individual nematode movement frequencies, quantified by video assay, were
each significantly reduced within 2 h of exposure to 0.01 mM BITC. All
responses were dose dependent. Infectivity of BITC-treated J2 of M.
incognita on soybean (Glycine max) was measured directly by root staining
and gall rating, and indirectly by egg production. All experiments showed
significantly reduced infectivity after treatment of J2 with 0.01 mM BITC.
In addition, egg production was almost completely eliminated (<5% of
control) by 0.03 mM BITC. The correlation between the effect of BITC
concentrations on J2 activity and infectivity was positive, with decreased
J2 activity and infectivity resulting in decreased egg production. BITC
concentrations that do not cause mortality significantly affect the
behaviour of M. incognita J2, indicating that sublethal concentrations
contribute to the overall nematode suppression by brassicaceous green
manures.
Knowing Social Reality: A Critique of Bhaskar and Archer’s Attempt to Derive a Social Ontology from Lay Knowledge
Authors: Cruickshank Justin
Published: July 2009

Critical realists argue that the condition of possibility of the sciences is that they are based on a correct set of ontological assumptions or definitions. The task of philosophy is to underlabor for the sciences, by ensuring that the explanations developed are congruent with the ontological condition of possibility of the sciences. This requires critical realists to justify their claims about ontology and, to do this, they turn to ontological assumptions that are held to obtain in natural scientific knowledge and social agents’ lay knowledge. A number of problems with this approach are discussed and a problem-solving alternative is advocated.
Psychological Predictors of Media Involvement
Authors: Greenwood Dara N. , Long Christopher R.
Published: July 2009

Does intense engagement with entertainment media programs and characters reflect a psychological need for companionship? The research findings to date have been equivocal. The present study investigates how parasocial interaction (PSI) with media characters and transportation into media programs are related to specific kinds of solitude experiences, as well as to the need to belong (NTB). Results of a questionnaire study (N = 301) show that solitude experienced as self-expansion (e.g., self-discovery), diversion (e.g., engaging in distracting activities), and Other orientation (e.g., loneliness) each contribute to increased PSI with favorite TV characters. Self-expansion and Other-oriented solitude each also predicts increased tendency to transport into media programs and identify with characters. Furthermore, Other-oriented solitude appears to account for the significant association between NTB and PSI. Results provide new evidence for both compensatory and complementary uses and gratifications of entertainment media.
Beyond Supermax Administrative Segregation
Authors: Kupers Terry A. , Dronet Theresa , Winter Margaret , Austin James , Kelly Lawrence , Cartier William , Morris Timothy J. , Hanlon Stephen F. , Sparkman Emmitt L. , Kumar Parveen , Vincent Leonard C. , Norris Jim , Nagel Kim , Mcbride Jennifer
Published: July 2009

Litigation in Mississippi required the Department of Corrections to ameliorate substandard conditions at the supermaximum Unit 32 of Mississippi State Penitentiary at Parchman, remove prisoners with serious mental illness from administrative segregation and provide them with adequate treatment, and reexamine the entire classification system. Pursuant to two federal consent decrees, the Department of Corrections greatly reduced the population in administrative segregation and established a step-down mental health treatment unit for the prisoners excluded from administrative segregation. This article describes and discusses not only the process of enacting the changes but also the outcomes, including the large reductions in rates of misconduct, violence, and use of force.
Cost-effectiveness of Diabetes Self-management Programs in Community Primary Care Settings
Authors: Brownson Carol A. , Hoerger Thomas J. , Fisher Edwin B. , Kilpatrick Kerry E.
Published: July 2009

Purpose

The purpose of this study is to estimate the cost-effectiveness of diabetes self-management programs in real-world community primary care settings. Estimates incorporated lifetime reductions in disease progression, costs of adverse events, and increases in quality of life.

Methods

Clinical results and costs were based on programs of the Diabetes Initiative of the Robert Wood Johnson Foundation, implemented in primary care and community settings in disadvantaged areas with notable health disparities. Program results were used as inputs to a Markov simulation model to estimate the long-term effects of self-management interventions. A health systems perspective was adopted.

Results

The simulation model estimates that the intervention does reduce discounted lifetime treatment and complication costs by $3385, but this is more than offset by the $15 031 cost of implementing the intervention and maintaining its effects in subsequent years. The intervention is estimated to reduce long-term complications, leading to an increase in remaining life-years and quality-adjusted life-years (QALYs). The incremental cost-effectiveness ratio is $39 563/QALY, well below a common benchmark of $50 000/QALY. Sensitivity analyses tested the robustness of the model’s estimates under various alternative assumptions. The model generally predicts acceptable cost-effectiveness ratios.

Conclusions

Self-management programs for type 2 diabetes are cost-effective from a health systems perspective when the cost savings due to reductions in long-term complications are recognized. These findings may justify increased reimbursement for effective self-management programs in diverse settings.