bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential effects of saturated and unsaturated fatty acid diets on cardiomyocyte apoptosis, adipose distribution, and serum leptin
Authors: Okere Isidore C. , Chandler Margaret P. , McElfresh Tracy A. , Rennison Julie H. , Sharov Victor , Sabbah Hani N. , Tserng Kou-Yi , Hoit Brian D. , Ernsberger Paul , Young Martin E. , Stanley William C.
Published: January 2006

Fatty acids are the primary fuel for the heart and are ligands for peroxisome proliferator-activated receptors (PPARs), which regulate the expression of genes encoding proteins involved in fatty acid metabolism. Saturated fatty acids, particularly palmitate, can be converted to the proapoptotic lipid intermediate ceramide. This study assessed cardiac function, expression of PPAR-regulated genes, and cardiomyocyte apoptosis in rats after 8 wk on either a low-fat diet [normal chow control (NC); 10% fat calories] or high-fat diets composed mainly of either saturated (Sat) or unsaturated fatty acids (Unsat) (60% fat calories) ( n = 10/group). The Sat group had lower plasma insulin and leptin concentrations compared with the NC or Unsat groups. Cardiac function and mass and body mass were not different. Cardiac triglyceride content was increased in the Sat and Unsat groups compared with NC ( P < 0.05); however, ceramide content was higher in the Sat group compared with the Unsat group (2.9 ± 0.2 vs. 1.4 ± 0.2 nmol/g; P < 0.05), whereas the NC group was intermediate (2.3 ± 0.3 nmol/g). The number of apoptotic myocytes, assessed by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling staining, was higher in the Sat group compared with the Unsat group (0.28 ± 0.05 vs. 0.17 ± 0.04 apoptotic cells/1,000 nuclei; P < 0.04) and was positively correlated to ceramide content ( P < 0.02). Both high-fat diets increased the myocardial mRNA expression of the PPAR-regulated genes encoding uncoupling protein-3 and pyruvate dehydrogenase kinase-4, but only the Sat diet upregulated medium-chain acyl-CoA dehydrogenase. In conclusion, dietary fatty acid composition affects cardiac ceramide accumulation, cardiomyocyte apoptosis, and expression of PPAR-regulated genes independent of cardiac mass or function.
Laser microdissection and pressure-catapulting technique to study gene expression in the reoxygenated myocardium
Authors: Kuhn Donald E. , Roy Sashwati , Radtke Jared , Gupta Sudip , Sen Chandan K.
Published: January 2006

For focal events such as myocardial infarction, it is important to dissect infarction-induced biological responses as a function of space with respect to the infarct core. Laser microdissection pressure catapulting (LMPC) represents a recent variant of laser capture microdissection that enables robot-assisted rapid capture of catapulted tissue without direct user contact. This work represents the maiden effort to apply laser capture microdissection to study spatially resolved biological responses in myocardial infarction. Infarcted areas of the surviving ischemic-reperfused murine heart were identified using a standardized hematoxylin QS staining procedure. Standard staining techniques fail to preserve tissue RNA. Exposure of the tissue to an aqueous medium (typically used during standard immunohistochemical staining), with or without RNase inhibitors, resulted in a rapid degradation of genes, with ∼80% loss in the 1st h. Tissue elements (1 × 104–4 × 106μm2) captured from infarcted and noninfarcted sites with micrometer-level surgical precision were collected in a chaotropic RNA lysis solution. Isolated RNA was analyzed for quality by microfluidics technology and reverse transcribed to generate high-quality cDNA. Real-time PCR analysis of the cDNA showed marked (200- and 400-fold, respectively) induction of collagen Ia and IIIa at the infarcted site compared with the noninfarcted site. This work reports a sophisticated yet rapid approach to measurement of relative gene expressions from tissue elements captured from spatially resolved microscopic regions in the heart with micrometer-level precision.
Rescue of ΔF508-CFTR trafficking and gating in human cystic fibrosis airway primary cultures by small molecules
Authors: Van Goor Fredrick , Straley Kimberly S. , Cao Dong , González Jesús , Hadida Sabine , Hazlewood Anna , Joubran John , Knapp Tom , Makings Lewis R. , Miller Mark , Neuberger Timothy , Olson Eric , Panchenko Victor , Rader James , Singh Ashvani , Stack Jeffrey H. , Tung Roger , Grootenhuis Peter D. J. , Negulescu Paul
Published: January 2006

Cystic fibrosis (CF) is a fatal genetic disease caused by mutations in cftr, a gene encoding a PKA-regulated Cl−channel. The most common mutation results in a deletion of phenylalanine at position 508 (ΔF508-CFTR) that impairs protein folding, trafficking, and channel gating in epithelial cells. In the airway, these defects alter salt and fluid transport, leading to chronic infection, inflammation, and loss of lung function. There are no drugs that specifically target mutant CFTR, and optimal treatment of CF may require repair of both the folding and gating defects. Here, we describe two classes of novel, potent small molecules identified from screening compound libraries that restore the function of ΔF508-CFTR in both recombinant cells and cultures of human bronchial epithelia isolated from CF patients. The first class partially corrects the trafficking defect by facilitating exit from the endoplasmic reticulum and restores ΔF508-CFTR-mediated Cl−transport to more than 10% of that observed in non-CF human bronchial epithelial cultures, a level expected to result in a clinical benefit in CF patients. The second class of compounds potentiates cAMP-mediated gating of ΔF508-CFTR and achieves single-channel activity similar to wild-type CFTR. The CFTR-activating effects of the two mechanisms are additive and support the rationale of a drug discovery strategy based on rescue of the basic genetic defect responsible for CF.
Attenuation of the pulmonary inflammatory response following butylated hydroxytoluene treatment of cytosolic phospholipase A2null mice
Authors: Meyer Amy M. , Dwyer-Nield Lori D. , Hurteau Gregory , Keith Robert L. , Ouyang Yanli , Freed Brian M. , Kisley Lori R. , Geraci Mark W. , Bonventre Joseph V. , Nemenoff Raphael A. , Malkinson Alvin M.
Published: January 2006

Administration of butylated hydroxytoluene (BHT) to mice causes lung damage characterized by the death of alveolar type I pneumocytes and the proliferation and subsequent differentiation of type II cells to replace them. Herein, we demonstrate this injury elicits an inflammatory response marked by chemokine secretion, alveolar macrophage recruitment, and elevated expression of enzymes in the eicosanoid pathway. Cytosolic phospholipase A2(cPLA2) catalyzes release of arachidonic acid from membrane phospholipids to initiate the synthesis of prostaglandins and other inflammatory mediators. A role for cPLA2in this response was examined by determining cPLA2expression and enzymatic activity in distal respiratory epithelia and macrophages and by assessing the consequences of cPLA2genetic ablation. BHT-induced lung inflammation, particularly monocyte infiltration, was depressed in cPLA2null mice. Monocyte chemotactic protein-1 (MCP-1) content in bronchoalveolar lavage fluid increases after BHT treatment but before monocyte influx, suggesting a causative role. Bronchiolar Clara cells isolated from cPLA2null mice secrete less MCP-1 than Clara cells from wild-type mice, consistent with the hypothesis that cPLA2is required to secrete sufficient MCP-1 to induce an inflammatory monocytic response.
Differential induction of apoptosis by cigarette smoke extract in primary human lung fibroblast strains: implications for emphysema
Authors: Baglole Carolyn J. , Bushinsky Seth M. , Garcia Tatiana M. , Kode Aruna , Rahman Irfan , Sime Patricia J. , Phipps Richard P.
Published: January 2006

Cigarette smoke is the principal cause of emphysema. Recent attention has focused on the loss of alveolar fibroblasts in the development of emphysema. Fibroblasts may become damaged by oxidative stress and undergo apoptosis as a result of cigarette smoke exposure. Not all smokers develop lung diseases associated with tobacco smoke, a fact that may reflect individual variation among human fibroblast strains. We hypothesize that fibroblasts from different human beings vary in their ability to undergo apoptosis after cigarette smoke exposure. This could account for emphysematous changes that occur in the lungs of some but not all smokers. Primary human lung fibroblast strains were exposed to cigarette smoke extract (CSE) and assessed for viability, morphological changes, and mitochondrial transmembrane potential as indicators of apoptosis. We also examined the generation of intracellular reactive oxygen species (ROS), 4-hydroxy-2-nonenal, and changes in glutathione (GSH) and glutathione disulfide (GSSG) levels. Each human lung fibroblast strain exhibited a differential sensitivity to CSE as judged by changes in mitochondrial membrane potential, viability, ROS generation, and glutathione production. Interestingly, the thiol antioxidants N-acetyl-l-cysteine and GSH eliminated CSE-induced changes in fibroblast morphology such as membrane blebbing, nuclear condensation, and cell size and prevented alterations in mitochondrial membrane potential and the generation of ROS. These findings support the concept that oxidative stress and apoptosis are responsible for fibroblast death associated with exposure to tobacco smoke. Variations in the sensitivity of fibroblasts to cigarette smoke may account for the fact that only some smokers develop emphysema.
Peroxisome proliferator-activated receptor-γ inhibits cigarette smoke solution-induced mucin production in human airway epithelial (NCI-H292) cells
Authors: Lee Sung Yong , Kang Eun Joo , Hur Gyu Young , Jung Ki Hwan , Jung Hye Cheol , Lee Sang Yeub , Kim Je Hyeong , Shin Chol , In Kwang Ho , Kang Kyung Ho , Yoo Se Hwa , Shim Jae Jeong
Published: January 2006

The main etiologic factor for chronic bronchitis is cigarette smoke. Exposure to cigarette smoke is reported to induce goblet cell hyperplasia and mucus production. Mucin synthesis in airways has been reported to be regulated by the EGFR system. Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a member of the ligand-activated nuclear receptor superfamily. PPAR-γ is implicated in anti-inflammatory responses, but mechanisms underlying these varied roles remain ill-defined. Recently, reports have shown that upregulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) might be one of the mechanisms through which PPAR-γ agonists exert their anti-inflammatory actions. However, no data are available on the role of PPAR-γ in smoke-induced mucin production. In this study, we investigated the effect of PPAR-γ agonist (rosiglitazone) on smoke-induced mucin production in NCI-H292 cells. Exposure to cigarette smoke causes a significant decrease in PTEN expression and increases dose-dependent EGFR-specific tyrosine phosphorylation, resulting in MUC5AC mucin production in NCI-H292 cells. PPAR-γ agonists or specific inhibitors of phosphoinositide 3-kinase exert inhibition of cigarette smoke-induced mucin production, with the upregulation of PTEN signaling and downregulation of Akt expression. This study demonstrates that PPAR-γ agonist functions as a regulator of epithelial cell inflammation that may result in reduction of mucin-producing cells in airway epithelium.
Inhaled NO restores lung structure in eNOS-deficient mice recovering from neonatal hypoxia
Authors: Balasubramaniam Vivek , Maxey Anne M. , Morgan Danielle B. , Markham Neil E. , Abman Steven H.
Published: January 2006

We have previously shown that neonatal mice deficient in endothelial nitric oxide synthase (eNOS−/−) are more susceptible to hypoxic inhibition of alveolar and vascular growth. Although eNOS is downregulated, the role of nitric oxide (NO) during recovery after neonatal lung injury is poorly understood. We hypothesized that lung vascular and alveolar growth would remain impaired in eNOS−/− mice during recovery in room air and that NO therapy would augment compensatory lung growth in the eNOS−/− mice during recovery. Mice (1 day old) from heterozygous (eNOS+/−) parents were placed in hypobaric hypoxia (FiO2= 0.16). After 10 days, pups were to recovered in room air (HR group) or inhaled NO (10 parts/million; HiNO group) until 3 wk of age, when lung tissue was collected. Morphometric analysis revealed that the eNOS−/− mice in the HR group had persistently abnormal lung structure compared with eNOS-sufficient (eNOS+/+) mice (increased mean linear intercept and reduced radial alveolar counts, nodal point density, and vessel density). Lung morphology of the eNOS+/− was not different from eNOS+/+. Inhaled NO after neonatal hypoxia stimulated compensatory lung growth in eNOS−/− mice that completely restored normal lung structure. eNOS+/− mice (HR group) had a 2.5-fold increase in lung vascular endothelial growth factor (VEGFR)-2 protein compared with eNOS+/+ ( P < 0.05). eNOS−/− mice (HiNO group) had a 66% increase in lung VEGFR-2 protein compared with eNOS−/− (HR group; P < 0.01). We conclude that deficiency of eNOS leads to a persistent failure of lung growth during recovery from neonatal hypoxia and that, after hypoxia, inhaled NO stimulates alveolar and vascular growth in eNOS−/− mice.
Characterization of acid signaling in rat vagal pulmonary sensory neurons
Authors: Gu Qihai , Lee Lu-Yuan
Published: January 2006

Local tissue acidosis frequently occurs in airway inflammatory and ischemic conditions. The effect of physiological/pathophysiological-relevant low pH (7.0–5.5) on isolated rat vagal pulmonary sensory neurons was investigated using whole cell perforated patch-clamp recordings. In voltage-clamp recordings, vagal pulmonary sensory neurons exhibited distinct pH sensitivities and different phenotypes of inward current in responding to acidic challenge. The current evoked by lowering the pH of extracellular solution to 7.0 consisted of only a transient, rapidly inactivating component with small amplitude. The amplitude of this transient current increased when the proton concentration was elevated. In addition, a slow, sustained inward current began to emerge when pH was reduced to <6.5. The current-voltage curve indicated that the transient component of acid-evoked current was carried predominantly by Na+. This transient component was dose-dependently inhibited by amiloride, a common blocker of acid-sensing ion channels (ASICs), whereas the sustained component was significantly attenuated by capsazepine, a selective antagonist of transient receptor potential vanilloid receptor subtype-1 (TRPV1). The two components of acid-evoked current also displayed distinct recovery kinetics from desensitization. Furthermore, in current-clamp recordings, transient extracellular acidification depolarized the membrane potential and generated action potentials in these isolated neurons. In summary, our results have demonstrated that low pH can stimulate rat vagal pulmonary sensory neurons through the activation of both ASICs and TRPV1. The relative roles of these two current species depend on the range of pH and vary between neurons.
Genetic restoration of aldose reductase to the collecting tubules restores maturation of the urine concentrating mechanism
Authors: Yang James Y. , Tam W. Y. , Tam Sidney , Guo Hong , Wu Xiaochun , Li Guohua , Chau Jenny F. L. , Klein Janet D. , Chung Sookja K. , Sands Jeff M. , Chung Stephen S. M.
Published: February 2006

To investigate the underlying causes for aldose reductase deficiency-induced diabetes insipidus, we carried out studies with three genotypic groups of mice. These included wild-type mice, knockout mice, and a newly created bitransgenic line that was homozygous for both the aldose reductase null mutation and an aldose reductase knockin transgene driven by the kidney-specific cadherin promoter to direct transgene expression in the collecting tubule epithelial cells. We found that from early renal developmental stages onward, urine osmolality did not exceed 1,000 mosmol/kgH2O in aldose reductase-deficient mice. The functional defects were correlated with significant renal cellular and structural abnormalities that included cell shrinkage, apoptosis, disorganized tubular and vascular structures, and segmental atrophy. In contrast, the transgenic aldose reductase expression in the bitransgenic mice largely but incompletely rescued urine concentrating capacity and significantly improved renal cell survival, cellular morphology, and renal structures. Together, these results suggest that aldose reductase not only plays important roles in osmoregulation and medullary cell survival but may also be essential for the full maturation of the urine concentrating mechanism.
Somato-Dendritic Morphology Predicts Physiology for Neurons That Contribute to Several Kinds of Limb Movements
Authors: Berkowitz Ari , Yosten Gina L. C. , Ballard R. Mark
Published: February 2006

It has been difficult to predict the behavioral roles of vertebrate CNS neurons based solely on their morphologies, especially for the neurons that control limb movements in adults. We examined the morphologies of spinal interneurons involved in limb movement control, using intracellular recording followed by Neurobiotin injection in the in vivo adult turtle spinal cord preparation. We report here the first description of a class of spinal interneurons whose somato-dendritic morphologies predict their robust activity during multiple forms of ipsilateral and contralateral fictive hindlimb scratching and fictive hindlimb withdrawal. These “transverse interneurons” or T cells have a mediolaterally elongated soma and a simple dendritic tree that is extensive in the transverse plane but restricted rostrocaudally. During fictive scratching, these cells display strong rhythmic modulation with higher peak firing rates than other scratch-activated interneurons. These higher peak firing rates are at least partly caused by T cells having larger phase-locked membrane potential oscillations and narrower action potentials with briefer afterhyperpolarizations than other scratch-activated interneurons. Many T cells have axon terminal arborizations in the ventral horn of the spinal cord hindlimb enlargement. Identification of this morphological and physiological class of spinal interneurons should facilitate further exploration of the mechanisms of hindlimb motor pattern selection and generation.
The Raf Inhibitor BAY 43-9006 (Sorafenib) Induces Caspase-Independent Apoptosis in Melanoma Cells
Authors: Panka David J. , Wang Wei , Atkins Michael B. , Mier James W.
Published: February 2006

Mitogen-activated protein kinase (MAPK) is activated in the majority of melanomas, and its activity is essential for cell survival. In this report, we examined the effects of a novel raf inhibitor BAY 43-9006 on melanoma cell viability and intracellular signaling and found that it induces apoptosis through a caspase-independent mechanism. At concentrations that suppress extracellular signal-regulated kinase (ERK) phosphorylation, BAY 43-9006 dephosphorylates Bad on Ser75 and Ser99, activates Bak and Bax, and reduces the mitochondrial transmembrane potential. BAY 43-9006 (sorafenib) down-modulates the levels of Bcl-2 and Bcl-XL in a MAPK-independent manner in A2058 and SKMEL5 melanoma cells but not in the more resistant A375 cells. Of the three lines tested, only A375 cells were rescued from BAY 43-9006–induced apoptosis by knocking down Bad. BAY 43-9006 induced poly(ADP-ribose) polymerase cleavage and the mitochondrial release of cytochrome c and SMAC. However, the pan-caspase inhibitor Z-VAD-fmk had only a modest protective effect against the drug, suggesting that BAY 43-9006–induced apoptosis is largely caspase independent. BAY 43-9006 but not the MAP/ERK kinase inhibitors PD98059 or U0126 induced the nuclear translocation of apoptosis-inducing factor (AIF) in A2058 and SKMEL5 cells, and the introduction of a small interfering RNA (siRNA) for AIF partially protected these cells from BAY 43-9006–induced apoptosis. The AIF siRNA had little effect in A375 cells, in which drug-induced AIF release was negligible. These data indicate that in sensitive cell lines, BAY 43-9006–induced apoptosis is independent of Bad dephosphorylation and caspase activation and largely mediated through the nuclear translocation of AIF. (Cancer Res 2006; 66(3): 1611-9)
Increased Efficacy and Safety in the Treatment of Experimental Liver Cancer with a Novel Adenovirus-Alphavirus Hybrid Vector
Authors: Guan Min , Rodriguez-Madoz Juan R. , Alzuguren Pilar , Gomar Celia , Kramer M. Gabriela , Kochanek Stefan , Prieto Jesus , Smerdou Cristian , Qian Cheng
Published: February 2006

An improved viral vector for cancer gene therapy should be capable of infecting tumors with high efficiency, inducing specific and high-level expression of transgene in the tumor and selectively destroying tumor cells. In the design of such a vector to treat hepatocellular carcinoma, we took advantage of (a) the high infectivity of adenoviruses for hepatic cells, (b) the high level of protein expression and proapoptotic properties that characterize Semliki Forest virus (SFV) replicon, and (c) tumor selectivity provided by α-fetoprotein (AFP) promoter. We constructed a hybrid viral vector composed of a helper-dependent adenovirus containing an SFV replicon under the transcriptional control of AFP promoter and a transgene driven by SFV subgenomic promoter. Hybrid vectors containing murine interleukin-12 (mIL-12) genes or reporter gene LacZ showed very specific and high-level expression of transgenes in AFP-expressing hepatocellular carcinoma cells, both in vitro and in an in vivo hepatocellular carcinoma animal model. Infected hepatocellular carcinoma cells were selectively eliminated due to the induction of apoptosis by SFV replication. In a rat orthotopic liver tumor model, treatment of established tumors with a hybrid vector carrying mIL-12 gene resulted in strong antitumoral activity without accompanying toxicity. This new type of hybrid vectors may provide a potent and safe tool for cancer gene therapy. (Cancer Res 2006; 66(3): 1620-9)
Low-Dose Metronomic Daily Cyclophosphamide and Weekly Tirapazamine: A Well-Tolerated Combination Regimen with Enhanced Efficacy That Exploits Tumor Hypoxia
Authors: Emmenegger Urban , Morton Gerard C. , Francia Giulio , Shaked Yuval , Franco Marcela , Weinerman Adina , Man Shan , Kerbel Robert S.
Published: February 2006

The recent clinical successes of antiangiogenic drug-based therapies have also served to highlight the problem of acquired resistance because, similar to other types of cancer therapy, tumors that initially respond eventually stop doing so. Consequently, strategies designed to delay resistance or treat resistant subpopulations when they arise have assumed considerable importance. This requires a better understanding of the various possible mechanisms for resistance. In this regard, reduced oxygenation is thought to be a key mediator of the antitumor effects of antiangiogenic therapies; accordingly, increased hypoxia tolerance of the tumor cells presents a potential mechanism of resistance. However, hypoxia can also be exploited therapeutically through the use of hypoxic cell cytotoxins, such as tirapazamine. With this in mind, we measured the oxygenation of PC-3 human prostate cancer xenografts subjected to chronic low-dose metronomic (LDM) antiangiogenic chemotherapy using cyclophosphamide given through the drinking water. We found that LDM cyclophosphamide impairs the oxygenation of PC-3 xenografts even during relapse, coinciding with reduced microvessel density. Combination of LDM cyclophosphamide with tirapazamine results in significantly improved tumor control in the PC-3, HT-29 colon adenocarcinoma, and MDA-MB-231 breast cancer human xenograft models without having a negative effect on the favorable toxicity profile of LDM cyclophosphamide. These results provide further evidence that reduced vascular dependence/increased hypoxia tolerance may be a basis for eventual resistance of tumors exposed to long-term LDM chemotherapy. (Cancer Res 2006; 66(3): 1664-74)
L-Selectin Facilitation of Metastasis Involves Temporal Induction ofFut7-Dependent Ligands at Sites of Tumor Cell Arrest
Authors: Läubli Heinz , Stevenson Jennifer L. , Varki Ajit , Varki Nissi M. , Borsig Lubor
Published: February 2006

Hematogenous carcinoma metastasis is supported by aggregated platelets and leukocytes, forming tumor cell emboli. Early tumor cell-platelet interactions can be mediated by P-selectin binding to tumor cell surface ligands and this process is blocked by heparin. We previously showed that L-selectin deficiency also attenuates experimental metastasis. However, the mechanisms and timing of L-selectin action remained unknown. Here, we study how L-selectin facilitates establishment of pulmonary metastatic foci in syngeneic mice by using experimental metastasis to time events following entry of tumor cells into the bloodstream. Although L-selectin deficiency did not affect platelet aggregation or initial tumor cell embolization, the association of leukocytes with tumor cells was reduced and tumor cell survival was diminished 24 hours later. Temporal inhibition of L-selectin by a function-blocking antibody reduced metastasis. Moreover, although selectin blockade by heparin 6 to 18 hours after tumor cell injection was synergistic with P-selectin deficiency in reducing metastasis, there was no further effect in L-selectin-deficient animals. Thus, heparin apparently works at these time points primarily by blocking L-selectin. Endogenous L-selectin ligands were concomitantly induced adjacent to established intravascular tumor cell emboli in a similar time window when leukocytes were also present. Metastasis was attenuated in mice missing these induced endogenous L-selectin ligands due to fucosyltransferase-7 deficiency. Thus, L-selectin facilitation of metastasis progression involves leukocyte-endothelial interactions at sites of intravascular arrest supported by local induction of L-selectin ligands via fucosyltransferase-7. These data provide the first explanation for how leukocyte L-selectin facilitates tumor metastasis. (Cancer Res 2006; 66(3): 1536-42)
Messenger RNAs under Differential Translational Control in Ki-ras–Transformed Cells
Authors: Spence Jean , Duggan Brendan M. , Eckhardt Colleen , McClelland Michael , Mercola Dan
Published: January 2006

Microarrays have been used extensively to identify differential gene expression at the level of transcriptional control in oncogenesis. However, increasing evidence indicates that changes in translational control are critical to oncogenic transformation. This study identifies mRNA transcripts that are differentially regulated, primarily at the level of translation, in the immortalized human embryonic prostate epithelial cell line 267B1 and the v-Ki-ras–transformed counterpart by comparing total mRNA to polysome-bound mRNA by using Affymetrix oligonucleotide microarrays. Among the transcripts that were identified were those encoding proteins involved in DNA replication, cell cycle control, cell-to-cell interactions, electron transport, G protein signaling, and translation. Many of these proteins are known to contribute to oncogenesis or have the potential to contribute to oncogenesis. Differential expression of RNA-binding proteins and the presence of highly conserved motifs in the 5′ and 3′ untranslated regions of the mRNAs are consistent with multiple pathways and mechanisms governing the changes in translational control. Although Alu sequences were found to be associated with increased translation in transformed cells, an evolutionarily conserved motif was identified in the 3′ untranslated regions of ephrinB1, calreticulin, integrinα3, and mucin3B that was associated with decreased polysome association in 267B1/Ki-ras. (Mol Cancer Res 2006;4(1):47–60)
Heregulins Implicated in Cellular Functions Other Than Receptor Activation
Authors: Breuleux Madlaina , Schoumacher Fabrice , Rehn Daniel , Küng Willy , Mueller Heinz , Eppenberger Urs
Published: January 2006

Heregulins (HRG) are known as soluble secreted growth factors that, on binding and activating ErbB3 and ErbB4 cell surface receptors, are involved in cell proliferation, metastasis, survival, and differentiation in normal and malignant tissues. Previous studies have shown that some HRG1 splice variants are translocated to the nucleus. By investigating the subcellular localization of HRGα1-241, nuclear translocation and accumulation in nuclear dot-like structures was shown in breast cancer cells. This subcellular distribution pattern depends on the presence of at least one of two nuclear localization sequences and on two domains on the HRG construct that were found to be necessary for nuclear dot formation. Focusing on the nuclear function of HRG, a mammary gland cDNA library was screened with the mature form of HRGα in a yeast two-hybrid system, and coimmunoprecipitation of endogenous HRG was done. The data reveal positive interactions of HRGα1-241 with nuclear factors implicated in different biological functions, including transcriptional control as exemplified by interaction with the transcriptional repressor histone deacetylase 2. In addition, HRGα1-241 showed transcriptional repression activity in a reporter gene assay. Furthermore, a potential of HRG proteins to form homodimers was reported and the HRG sequence responsible for dimerization was identified. These observations strongly support the notion that HRG1 splice variants have multifunctional properties, including previously unknown regulatory functions within the nucleus that are different from the activation of ErbB receptor signaling. (Mol Cancer Res 2006;4(1):27–37)
A Constitutively Active Lck Kinase Promotes Cell Proliferation and Resistance to Apoptosis through Signal Transducer and Activator of Transcription 5b Activation
Authors: Shi Mingjian , Cooper John C. , Yu Chao-Lan
Published: January 2006

Lck is a Src family protein tyrosine kinase and is expressed predominantly in T cells. Aberrant expression or activation of Lck kinase has been reported in both lymphoid and nonlymphoid malignancies. However, the mechanisms underlying Lck-mediated oncogenesis remain largely unclear. In this report, we establish a tetracycline-inducible system to study the biochemical and biological effects of a constitutively active Lck mutant with a point mutation at the negative regulatory tyrosine. Expression of the active Lck kinase induces both tyrosine phosphorylation and DNA-binding activity of signal transducer and activator of transcription 5b (STAT5b), a STAT family member activated in a variety of tumor cells. The active Lck kinase interacts with STAT5b in cells, suggesting that Lck may directly phosphorylate STAT5b. Expression of the constitutively active Lck mutant in interleukin-3 (IL-3)–dependent BaF3 cells promotes cell proliferation. In addition, the active Lck kinase protects BaF3 cells from IL-3 withdrawal-induced apoptotic death and leads to IL-3-independent growth. These transforming properties of the oncogenic Lck kinase can be further augmented by expression of exogenous wild-type STAT5b but attenuated by a dominant-negative form of STAT5b. All together, our results suggest the potential involvement of STAT5b in Lck-mediated cellular transformation. (Mol Cancer Res 2006;4(1):39–45)
Chymase Gene (CMA1) Polymorphisms in Dutch and Japanese Sarcoidosis Patients
Authors: Kruit Adrian , Grutters Jan C. , Ruven Henk J.T. , Sato Hiroe , Izumi Takateru , Nagai Sonoko , Welsh Kenneth I. , du Bois Roland M. , van den Bosch Jules M.M.
Published: January 2006

Background: Chymase is released from mast cells following activation. Evidence suggests that chymase plays an important role in tissue injury and remodeling of the lungs, heart and skin. Objective: We postulated that chymase gene (CMA1) polymorphisms are associated with pulmonary fibrosis in Dutch and with cardiac and skin involvement in Japanese sarcoidosis patients. Patients and Methods: Dutch (n = 153) and Japanese (n = 122) sarcoidosis patients with controls (Dutch, n = 309; Japanese, n = 111) were studied. Pulmonary involvement in Dutch patients as well as clinical manifestations in Japanese patients was evaluated for association with five CMA1 polymorphisms. Results: The CMA1 polymorphisms were not associated with disease susceptibility in either population, or with radiographic evolution in the Dutch or with cardiac or skin involvement in the Japanese patients. The –526 T allele was associated with a lower iVC in Dutch patients. Conclusions: The CMA1 polymorphisms studied do not contribute to disease susceptibility in Japanese or Dutch sarcoidosis patients. CMA1 polymorphisms do not influence radiographic evolution in Dutch sarcoidosis patients, nor do they predispose to cardiac or skin involvement in Japanese patients. However, the association between CMA1 –526 C/T and iVC in the Dutch patients suggests that chymase may modify the functional outcome of pulmonary sarcoidosis.
Distribution of Costameric Proteins in the Diaphragm of Patients with Chronic Obstructive Pulmonary Disease
Authors: Wijnhoven J.H. , Hafmans T. , Dekhuijzen P.N.R.
Published: January 2006

Background: Chronic obstructive pulmonary disease (COPD) is associated with an increased load on the diaphragm. Increased (eccentric) loading has been shown to result in disturbances in the cytoskeleton. Objectives: We hypothesized that due to a continuous overload of the diaphragm in COPD patients, distinct alterations in the membrane-associated cytoskeleton occur, especially in the costameres. Methods: Diaphragm biopsies from 7 COPD patients (forced expiratory volume in 1 s 62 ± 3% predicted) and 5 non-COPD patients (forced expiratory volume in 1 s 105 ± 6% predicted) were obtained. Cryosections of these biopsies were stained with antibodies against the costameric proteins of the focal adhesion complex (vinculin, talin and integrin-β1), the dystroglycan complex (dystrophin and β-dystroglycan) and the spectrin-based membrane cytoskeleton (β-spectrin). Furthermore, in these cryosections, the basal membrane protein laminin was stained. Results: We found no differences in the distribution and staining intensity of the costameric proteins of the focal adhesion complex, the dystroglycan complex and the spectrin-based membrane cytoskeleton in the diaphragm between the COPD and the non-COPD patients. Furthermore, no differences were observed in the expression of laminin in the diaphragm between COPD and non-COPD patients. Conclusions: These results indicate that the increased loading to which the diaphragm is exposed in COPD does not result in disturbances in expression of the costameric system and histological damage of the sarcolemma.
Drug-Induced Pneumonitis Associated with Imatinib Mesylate in a Patient with Idiopathic Pulmonary Fibrosis
Authors: Yamasawa Hideaki , Sugiyama Yukihiko , Bando Masashi , Ohno Shoji
Published: January 2006

A 74-year-old man with idiopathic pulmonary fibrosis (IPF) developed severe dyspnea on exertion after the readministration of imatinib mesylate for chronic myeloid leukemia. Chest X-ray and CT showed ground-glass opacities in both lungs in addition to preexisting honeycombing. Discontinuation of imatinib and methylprednisolone pulse therapy followed by administration of oral prednisolone resulted in improvement in both symptoms and radiographic findings. Imatinib-induced pneumonitis was diagnosed based on the clinical course and findings. Only five previous reports of imatinib-induced pneumonitis have been published in the literature, and this is the first case reported in a patient with IPF.
CymetraTM Injections to Treat Leakage around a Tracheoesophageal Puncture
Authors: Seshamani Meena , Ruiz Cesar , Kasper Schwartz Sandra , Mirza Natasha
Published: February 2006

Tracheoesophageal puncture (TEP) is a commonly used method of voice restoration following total laryngectomy, but leakage around the prosthesis is prevalent. Several treatments for leakage have been proposed in the literature, but with varying success. This paper examines the efficacy of CymetraTM to help shrink the TEP site and stop leakage. Six patients with leaking TEP sites refractory to downsizing and/or cautery were selected for the study. Injection sites were determined based on the primary sites of leakage. Cymetra was rehydrated with 1.0 % lidocaine saline solution and injected via a 23-gauge needle a few millimeters deep to the mucosa, approximately 2 mm from the edge. The patients were followed for up to 13 months. Following 1 trial of Cymetra injection, 4 patients achieved successful results. Only 1 patient has not yet achieved full resolution of leakage. Cymetra may provide a safer and more effective option for resolution of leakage than other methods currently employed.
From Méliès to Galaxy Quest: The Dark Matter of the Popular Imagination
Authors: Punt Michael , Blassnigg Martha , Surman David
Published: January 2006

The authors argue that an interrogation of cinema can reveal the fragility of our knowledge and the underlying imperatives that the social construction of space responds to. A revisionist overview of the issue of professional interfaces in the popular arts is followed by a discussion of the influence of space technology and natural space phenomena on human personal and collective belief systems in order to open the way for an outline of the concept of participatory cultures and the relationship between fiction and science.
The Philippine Triad and Western Dichotomous Philosophies: A Contest of Traditions in Three Audio-Performance Projects
Authors: Lasay Fatima
Published: January 2006

The author's three projects draw upon her analysis of a triumvirate of social roles in ancient Philippine society, especially in connection with the maintenance of ritual in that society. Each project addresses the historical function of ritual as well as how it is carried over into art.
Infinity and Accident: Strategies of Enfoldment in Islamic Art and Computer Art
Authors: Marks Laura U.
Published: January 2006

Computer art and Islamic art, the two largest bodies of aniconic art, share a surprising number of formal properties, two of which are explored here. The common properties of computer art and classical Islamic art can be understood in light of moments in the history of Islamic philosophy. In these two cases, Islamic Neoplatonism and Mu'tazili atomism are shown to parallel, respectively, the logic of relations between one and infinity, and the basic pixel structure, that inform some historical monuments of Islamic art as well as some contemporary works of computer art. It is suggested that these parallels are in part a result of Islamic influences on Western modernism and thus that the genealogy of computer art includes classical Islamic art and the philosophies that informed it.
Internet Artworks, Artists and Computer Programmers: Sharing the Creative Process
Authors: Fourmentraux Jean-Paul
Published: January 2006

Internet artwork no longer refers to the concept of a finalized object, but rather to a dynamic process, a collective, open and interactive device. Due to the increasing sophistication of tools, the design of an Internet artwork now requires hybrid skills. The necessary cooperation with computer specialists in order to create suitable programs thus changes the status of the artwork and its author. This paper presents an ethnographic case study of cooperation between a computer programmer and an artist. It examines the processes of shared design, negotiated authorship and artwork appropriation. From an analysis of the means of communication, various technical media and “intermediary tools,” the author focuses on role allocation, task sharing and artwork appropriation as the artwork is modified throughout the creative process.
An Artist's Works through the Eyes of a Physicist: Graphic Illustration of Particle Symmetries
Authors: Darvas György , Farkas Tamás F.
Published: January 2006

The paper presents remarks by a physicist and a graphic artist on an artwork series produced by the artist. They associate the colors and twists represented in these graphics with the properties of subatomic particles—their structures and connections. The authors use graphical representation to visualize the inner structure of atoms, the classification of quarks and the metaphorical names of abstract physical properties. No textbooks that make visible these basic properties by means of art are currently available. Artistic visualization brings these “mysterious” physical objects closer to the understanding of students and the general public and leaves physicists better able to discover new secrets of the internal structure of quarks and their properties.
Contemplations on Our Physical Links to the Universe: Searching for and Finding the Hidden Harmony
Authors: Unnikrishnan C.S.
Published: January 2006

The author discusses the evidence and consequences of our indissoluble physical links to the entire universe. He finds that the apparent conflicts in fundamental physical theories regarding issues of causality and locality are not real conflicts based in the physical world. He presents an emergent worldview interpreted in the context of a cultural, philosophical and linguistic background in which a strong tension between inseparability of the whole and the local causal flow of events seems not to exist. The existence of the whole can be felt in the parts, as something real, measurable and undeniable. Its simplicity and harmony are spiritually enriching and emotionally moving.
Technoetic Pathways toward the Spiritual in Art: A Transdisciplinary Perspective on Connectedness, Coherence and Consciousness
Authors: Ascott Roy
Published: January 2006

The coherence of living systems may be due in part to an information network of biophotons emitted by DNA molecules. This network can be seen as parallel to the telematic networks that connect the planet. Nanotechnology can play a significant role in the emergence of a moistmedia substrate for technoetic art. Immaterial connectedness confers a spiritual dimension on both telematic art and quantum mechanics. Field theory supports the contention that the material body may be a consequence rather than a cause of consciousness. A technoetic art may locate its ground in the triangulation of connectivity, syncretism and field theory.
Astro Black Morphologies: Music and Science Lovers
Authors: Motion Flow
Published: January 2006

Acompressed series of possible histories of science in modern music, the text outlines the themes of poetic and historic correspondences between music, cosmology and the body that informed the making of Astro Black Morphologies/Astro Dub Morphologies, a multimedia installation and live sound-art performance by Flow Motion in which data from possible black hole Cygnus X1 is transformed into an immersive electronic sound-and-image environment.
What is the Mars Patent and What Does it do?
Authors: Reiche Claudia , Oldenburg Helene von
Published: January 2006

The authors invite readers and others, including aliens (provided they claim to have female first names), to submit “things” to the MARS PATENT project for interplanetary exhibition on Mars and on the Internet. The MARS PATENT High Reality Machine will teleport sculptures, theories, web art and other things, imaginable or not fully imaginable, to the exhibition site on the red planet. The authors have also established the Oldenburg-Reiche Prize, an open competition challenging artists, scientists and others to come up with a satisfying explanation for how the High Reality Machine works.
Athena and the Paphlagonian in Aristophanes' Knights. Re-considering Equites 1090-5, 1172-81
Authors: Lauriola Rosanna
Published: January 2006

This paper re-examines the treatment of Athena in some passages of Aristophanes' Knights along the lines of a previous study by C.A. Anderson (1991 and 1995). Two topics will be considered: the dream-oracles of Athena (Eq. 1090-5), and some epithets characterizing the goddess during the food-serving contest (Eq. 1172-81). The Paphlagonian's and Sausage-Seller's portraits of Athena are self-referential images in that they are able both to play a significant 'dramatic' role in the contest for the steward-ship of Dêmos, by preparing for the final fate of each character within the comic plot (Eq. 1090-5), and to mirror, respectively, the war-mongering, grasping and violent nature of Cleon (Eq. 1172-81), and the poet's and Athenians' political ideal. By focusing on the self-referential nature of the Paphlagonian's portrait of Athena, I shall argue that Athena's image also resonates with a particular trait of Cleon, which is a constant object of Aristophanes' denunciation concerning the manipulative politics of the demagogue, i.e. his tendency to make people believe that the polis' welfare is his main concern; in other words, his pretense to be a good leader, sincerely interested in the citizens' well-being. This meaning of the Paphlagonian's portrait of Athena is corroborated by the characterization of the goddess through specific epithets in the food-serving contest.
Sicilicissitat (Plautus, Menaechmi 12) and Early Geminate Writing in Latin (with an Appendix on Men. 13)
Authors: Fontaine Michael
Published: January 2006

1. The morphologically anomalous word sicilicissitat in v. 12 of Plautus' Menaechmi is, I argue, a Joycean 'portmanteau', or punning composite word coined for the nonce, meaning, simultaneously, the plot (i) 'affects a Sicilian atmosphere', from the Greek verb σικελιζειν, and (ii) 'is double' or 'counts twice', from the Latin noun sicilicus, a diacritical mark which served as a nota for gemination of consonants. 2. Although the evidence is inconclusive, I suggest that, on the strength of the pun, we can retrodate the period in which sicilici were used to the era before Ennius' arrival in Rome in 204 BC. 3. (Appendix) In Men. 13 read antēloquium, not antelogium.
Rusticitas Versus Urbanitas in the Literary Programmes of Tibullus and Persius
Authors: Tzounakas Spyridon
Published: January 2006

Tibullus and Persius are characteristic examples of poets who in their programmatic poems take a stance as to the literary juxtaposition of rusticitas and urbanitas and side with the first. Thus, they express their opposition to the mores of urban society and support the rustic way of life, which points to moral probity, simplicity, frugality, an unaffected style, Roman thematology, an indifference towards praise and heroic action. Persius' views could be associated with Propertius' latent attack against Tibullus' rusticitas and can be interpreted as disagreement with Propertius' urbanitas. It is possible that in this way Persius expresses his disappointment in the replacement of some elegiac motifs of the past with elegidia and of the frugal, 'poor' Tibullus with the crudi proceres, who are praised in the aula Neroniana. Therefore, the fact that Persius is siding with Tibullus in his dispute with Propertius could suggest a poetic model more similar to his own.
Amphiaraos As Alkman: Compositional Strategy and Mythological Innovation in Pindar's Pythian 8.39-60
Authors:   van 't Wout
Published: January 2006

It is argued that Amphiaraos' prophecy in Pindar's eighth Pythian takes place not at the time of the second expedition against Thebes, but at the moment of his heroisation, during the first battle. In the passage leading up to this prophecy, Pindar creates for his audience a listening experience analogous to Amphiaraos' visionary experience, effectuating a fusion of time-layers. In the coda to the speech, it is revealed that this version of the heroisation of Amphiaraos, which centers on the seer's vision of his son Alkman, originates in a vision of Alkman that Pindar himself experienced. Pindar's vision serves as an authoritative source for what appears to be an innovative aspect of the episode.