bluuebunny/crossref_metadata_2025 huggingface dataset:
Ionotropic glutamate receptor activation increases intracellular calcium in prolactin-releasing cells of the adenohypophysis
Authors: Bellinger Frederick P. , Fox Bradley K. , Chan Wing Yan , Davis Lori K. , Andres Marilou A. , Hirano Tetsuya , Grau E. Gordon , Cooke Ian M.
Published: July 2006

Endocrine cells of the anterior pituitary are controlled by the central nervous system through hormonal interactions and are not believed to receive direct synaptic connections from the brain. Studies suggest that some pituitary cells may be modulated by the neurotransmitter glutamate ( 5 , 16 ). We investigated prolactin (PRL)-releasing cells of the anterior pituitary of a euryhaline fish, the tilapia ( Oreochromis mossambicus), for the presence of possible glutamate receptors (GluRs). Fura-2 imaging addressed the ability of glutamate to increase intracellular calcium. We observed a dose-dependent increase in intracellular calcium with transient perfusion (1–2 min) of glutamate (10 nM to 1 mM) in two-thirds of imaged cells. This increase was attenuated by the ionotropic GluR antagonist kynurenic acid (0.5–1.0 mM). The increase was also blocked or attenuated by antagonists of L-type voltage-gated calcium channels. The GluR agonist α-amino-3-hydroxy-5-methylisoxazole propionic acid (AMPA; 100 μM) produced intracellular calcium increases that were reversibly blocked by the selective AMPA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). In contrast, the selective agonist N-methyl-d-aspartate (NMDA; 100 μM to 1 mM in magnesium-free solution with 10 μM glycine) had no effect on intracellular calcium. Radioimmunoassays demonstrated that glutamate stimulated PRL release. CNQX but not the NMDA receptor antagonist 2-amino-5-phosphonovaleric acid blocked this release. Antibodies for mammalian AMPA- and NMDA-type GluR produced a similar punctate immunoreactivity in the periphery of PRL cells. However, the NMDA antibody recognized a protein of a different molecular mass in PRL cells compared with brain cells. These results clearly indicate the presence of GluRs on tilapia PRL cells that can stimulate PRL release.
AMP-activated protein kinase and the regulation of glucose transport
Authors: Fujii Nobuharu , Jessen Niels , Goodyear Laurie J.
Published: July 2006

The AMP-activated protein kinase (AMPK) is an energy-sensing enzyme that is activated by acute increases in the cellular [AMP]/[ATP] ratio. In skeletal and/or cardiac muscle, AMPK activity is increased by stimuli such as exercise, hypoxia, ischemia, and osmotic stress. There are many lines of evidence that increasing AMPK activity in skeletal muscle results in increased rates of glucose transport. Although similar to the effects of insulin to increase glucose transport in muscle, it is clear that the underlying mechanisms for AMPK-mediated glucose transport involve proximal signals that are distinct from that of insulin. Here, we discuss the evidence for AMPK regulation of glucose transport in skeletal and cardiac muscle and describe research investigating putative signaling mechanisms mediating this effect. We also discuss evidence that AMPK may play a role in enhancing muscle and whole body insulin sensitivity for glucose transport under conditions such as exercise, as well as the use of the AMPK activator AICAR to reverse insulin-resistant conditions. The identification of AMPK as a novel glucose transport mediator in skeletal muscle is providing important insights for the treatment and prevention of type 2 diabetes.
Differential regulation of intestinal lipid metabolism-related genes in obesity-resistant A/J vs. obesity-prone C57BL/6J mice
Authors: Kondo Hidehiko , Minegishi Yoshihiko , Komine Yumiko , Mori Takuya , Matsumoto Ichiro , Abe Keiko , Tokimitsu Ichiro , Hase Tadashi , Murase Takatoshi
Published: July 2006

The effects of high-fat (HF) feeding on gene expression in the small intestine were examined using obesity-resistant A/J mice and obesity-prone C57BL/6J (B6) mice. Both strains of mice were maintained on low-fat (LF; 5% fat) or HF (30% fat) diets for 2 wk. Quantitative reverse transcription-PCR analysis revealed that lipid metabolism-related genes, including carnitine palmitoyltransferase (CPT) I, liver fatty acid binding protein, pyruvate dehydrogenase kinase-4, and NADP+-dependent cytosolic malic enzyme, were upregulated by HF feeding in both strains of mice. The upregulated gene expression levels were higher in A/J mice than in B6 mice, suggesting more active lipid metabolism in the small intestine of A/J mice. The prominent upregulation of the lipid metabolism-related genes were specific to the small intestine; the expression levels were little or unchanged in the liver, muscle, and white adipose tissue. The increase by HF feeding and predominant expression of the intestinal lipid metabolism-related genes in A/J mice were reflected in the enzyme activities; malic enzyme, CPT, and β-oxidation activities were increased by HF feeding, and the upregulated malic enzyme and CPT activities were significantly higher in obesity-resistant A/J mice compared with those in obesity-prone B6 mice. These findings suggest that intestinal lipid metabolism is associated with susceptibility to obesity.
Forebrain neural patterns associated with sex differences in autonomic and cardiovascular function during baroreceptor unloading
Authors: Kimmerly D. S. , Wong S. , Menon R. , Shoemaker J. K.
Published: July 2006

Generally, women demonstrate smaller autonomic and cardiovascular reactions to stress, compared with men. The mechanism of this sex-dependent difference is unknown, although reduced baroreflex sensitivity may be involved. Recently, we identified a cortical network associated with autonomic cardiovascular responses to baroreceptor unloading in men. The current investigation examined whether differences in the neural activity patterns within this network were related to sex-related physiological responses to lower body negative pressure (LBNP, 5, 15, and 35 mmHg). Forebrain activity in healthy men and women ( n = 8 each) was measured using functional magnetic resonance imaging with blood oxygen level-dependent (BOLD) contrast. Stroke volume (SV), heart rate (HR), and muscle sympathetic nerve activity (MSNA) were collected on a separate day. Men had larger decreases in SV than women ( P < 0.01) during 35 mmHg LBNP only. At 35 mmHg LBNP, HR increased more in males then females (9 ± 1 beats/min vs. 4 ± 1 beats/min, P < 0.05). Compared with women, increases in total MSNA were similar at 15 mmHg LBNP but greater during 35 mmHg LBNP in men [1,067 ± 123 vs. 658 ± 103 arbitrary units (au), P < 0.05]. BOLD signal changes ( P < 0.005, uncorrected) were identified within discrete forebrain regions associated with these sex-specific HR and MSNA responses. Men had larger increases in BOLD signal within the right insula and dorsal anterior cingulate cortex than women. Furthermore, men demonstrated greater BOLD signal reductions in the right amygdala, left insula, ventral anterior cingulate, and ventral medial prefrontal cortex vs. women. The greater changes in forebrain activity in men vs. women may have contributed to the elevated HR and sympathetic responses observed in men during 35 mmHg LBNP.
Regulation of renin in mice with Cre recombinase-mediated deletion of G protein Gsα in juxtaglomerular cells
Authors: Chen Limeng , Kim Soo Mi , Oppermann Mona , Faulhaber-Walter Robert , Huang Yuning , Mizel Diane , Chen Min , Lopez Maria Luisa Sequeira , Weinstein Lee S. , Gomez R. Ariel , Briggs Josie P. , Schnermann Jurgen
Published: July 2006

By crossing mice with expression of Cre recombinase under control of the endogenous renin promoter (Sequeira Lopez ML, Pentz ES, Nomasa T, Smithies O, Gomez RA. Dev Cell 6: 719–728, 2004) with mice in which exon 1 of the Gnas gene was flanked by loxP sites (Chen M, Gavrilova O, Liu J, Xie T, Deng C, Nguyen AT, Nackers LM, Lorenzo J, Shen L, Weinstein LS. Proc Natl Acad Sci USA), we generated animals with preferential and nearly complete excision of Gsα in juxtaglomerular granular (JG) cells. Compared with wild-type animals, mice with conditional Gsα deficiency had markedly reduced basal levels of renin expression and very low plasma renin concentrations. Furthermore, the acute release responses to furosemide, hydralazine, and isoproterenol were virtually abolished. Consistent with a state of primary renin depletion, Gsα-deficient mice had reduced arterial blood pressure, reduced levels of aldosterone, and a low glomerular filtration rate. Renin content and renin secretion of JG cells in primary culture were drastically reduced, and the stimulatory response to the addition of PGE2or isoproterenol was eliminated. Unexpectedly, Gsα recombination was also observed in the renal medulla, and this was associated with a vasopressin-resistant concentrating defect. Our study shows that Cre recombinase under control of the renin promoter can be used for the excision of floxed targets from JG cells. We conclude that Gsα-mediated signal transduction is essential and nonredundant in the control of renin synthesis and release.
Fast Amplification of Dynamic Synaptic Inputs in Spinal Motoneurons In Vivo
Authors: Jones Sarah M. , Lee Robert H.
Published: July 2006

The ability of voltage-dependent inward currents (likely Na+) of the adult cat lumbar motoneurons to amplify rapidly changing (i.e., dynamic) synaptic inputs was investigated using in vivo intracellular recording techniques. Fast amplification was assessed by measuring the magnitude of the high-frequency (180 Hz) component of the Ia synaptic input due to tendon vibration as a function of somatic voltage and was compared with the previously observed amplification of steady inputs (steady state response of PICs to slow inputs). Data from 17 experiments show that amplification of the dynamic input indeed occurred and was directly linked to neuromodulatory drive (standard state: decerebrate with intact descending neuromodulatory systems vs. minimal state: pentobarbital with said systems significantly inhibited). Fast amplification factors averaged 2.0 ± 0.7 (mean ± SD) in the standard neuromodulatory state. That is, the effective synaptic current was nearly twice as large at its peak as it was at hyperpolarized levels, ranging as high as 2.6. Although fast amplification was often smaller than the amplification of steady inputs, the difference was not statistically significant. However, the voltage at which fast amplification began was ∼10 mV more depolarized ( P < 0.01). It is concluded that both dynamic and steady inputs can be amplified, but there may be differences in mechanism.
Inhibition of Pulmonary and Skeletal Metastasis by a Transforming Growth Factor-β Type I Receptor Kinase Inhibitor
Authors: Bandyopadhyay Abhik , Agyin Joseph K. , Wang Long , Tang Yuping , Lei Xiufen , Story Beryl M. , Cornell John E. , Pollock Bradley H. , Mundy Gregory R. , Sun Lu-Zhe
Published: July 2006

Transforming growth factor-β (TGF-β) signaling has been shown to promote invasion and metastasis in various models of human cancers. In this study, we investigated the efficacy of a TGF-β type I receptor kinase inhibitor (TβRI-I) to limit early systemic metastases in an orthotopic xenograft model of lung metastasis and in an intracardiac injection model of experimental bone and lung metastasis using human breast carcinoma MDA-MB-435-F-L cells, a highly metastatic variant of human breast cancer MDA-MB-435 cells, expressing the enhanced green fluorescent protein (EGFP). Treatment of the cells with the TβRI-I had no effect on their growth but blocked TGF-β-stimulated expression of integrin αvβ3 and cell migration in vitro. Systemic administration of the TβRI-I via i.p. injection effectively reduced the number and size of the lung metastasis in both orthotopic xenograft and experimental metastasis models with no effects on primary tumor growth rate compared with controls. TβRI-I treatment also reduced the incidence of widespread early skeletal metastases in the femur, tibia, mandible, and spine detected by whole-body EGFP fluorescence imaging. Tumor burden in femora and tibiae was also reduced after TβRI-I treatment as detected by histomorphometry analysis compared with the placebo controls. Our results indicate for the first time that abrogation of TGF-β signaling by systemic administration of the TβRI-I can inhibit both early lung and bone metastasis in animal model systems and suggest antimetastatic therapeutic potential of the TβRI-I.(Cancer Res 2006; 66(13): 6714-21)
Overexpression of Cox-2 in Human Osteosarcoma Cells Decreases Proliferation and Increases Apoptosis
Authors: Xu Zheng , Choudhary Shilpa , Voznesensky Olga , Mehrotra Meenal , Woodard Monica , Hansen Marc , Herschman Harvey , Pilbeam Carol
Published: July 2006

Overexpression of cyclooxygenase-2 (COX-2) is generally considered to promote tumorigenesis. To investigate a potential role of COX-2 in osteosarcoma, we overexpressed COX-2 in human osteosarcoma cells. Saos-2 cells deficient in COX-2 expression were retrovirally transduced or stably transfected with murine COX-2 cDNA. Functional expression of COX-2 was confirmed by Northern and Western analyses and prostaglandin production. Overexpression of COX-2 reduced cell numbers by 50% to 70% compared with controls. Decreased proliferation in COX-2-overexpressing cells was associated with cell cycle prolongation in G2-M. Apoptosis, measured by both Annexin V binding assay and terminal deoxyribonucleotidyl transferase–mediated dUTP nick end labeling staining, was increased in cells overexpressing COX-2, and the increase was not reversed by treatment with NS-398, indicating that the effects were not mediated by prostaglandins. Retroviral COX-2 overexpression in two other human osteosarcoma cell lines, U2OS and TE85, also decreased cell viability. However, in the human colon carcinoma HCT-116 cell line, which is deficient in COX-2, retroviral overexpression of COX-2, at similar efficiency as in Saos-2 cells, increased resistance to apoptosis. Reactive oxygen species (ROS), measured by flow cytometry, were increased by COX-2 overexpression in Saos-2 cells but not in HCT-116 cells. Inhibition of peroxidase activity, but not of COX activity, blocked the ROS increase. Antioxidants blocked the increase in ROS and the increase in apoptosis due to COX-2 overexpression in Saos-2 cells. Our results suggest that (a) COX-2 overexpression in osteosarcoma cells may increase resistance to tumorigenesis by increasing ROS to levels that decrease cell viability and (b) the effects of COX-2 overexpression are cell type/tissue dependent.(Cancer Res 2006; 66(13): 6657-64)
Phenethyl Isothiocyanate Triggers Apoptosis in Jurkat Cells Made Resistant by the Overexpression of Bcl-2
Authors: Thomson Susan J. , Brown Kristin K. , Pullar Juliet M. , Hampton Mark B.
Published: July 2006

Isothiocyanates are a class of naturally occuring chemopreventive agents known to be effective at triggering apoptosis. In this study, we show that whereas overexpression of the oncoprotein Bcl-2 renders Jurkat T-lymphoma cells resistant to a range of cytotoxic agents, phenethyl isothiocyanate is able to overcome the inhibitory action of Bcl-2 and trigger apoptosis. A 50-fold increase in Bcl-2 expression shifted the dose-response curve, with an increase in the phenethyl isothiocyanate LD50 from 7 to 15 μmol/L, but there was still a complete loss in cell viability at doses in excess of 20 μmol/L. At these concentrations, cytotoxicity was strongly associated with caspase activation, phosphatidylserine exposure, and morphologic changes characteristic of apoptosis. Cytotoxicity was inhibited by treatment of the cells with a broad-spectrum caspase inhibitor. A structure-activity analysis showed that the phenethyl and benzyl isothiocyanates were most effective at triggering apoptosis in cells overexpressing Bcl-2 whereas phenyl isothiocyanate and benzyl thiocyanate had no proapoptotic activity. Allyl isothiocyanate also had limited efficacy despite its ability to trigger apoptosis in the parental Jurkat cell line. From this information, we propose that isothiocyanates modify a key cysteine residue in an apoptosis regulatory protein and that the aromatic side chain facilitates access to the target site. An in-depth investigation of the cellular targets of the aromatic isothiocyanates is warranted.(Cancer Res 2006; 66(13): 6772-7)
Genome-Wide Analysis of Epigenetic Silencing Identifies BEX1 and BEX2 as Candidate Tumor Suppressor Genes in Malignant Glioma
Authors: Foltz Greg , Ryu Gi-Yung , Yoon Jae-Geun , Nelson Timothy , Fahey Jessica , Frakes Amanda , Lee Hwahyung , Field Lorie , Zander Kaitlin , Sibenaller Zita , Ryken Timothy C. , Vibhakar Rajeev , Hood Leroy , Madan Anup
Published: July 2006

Promoter hypermethylation and histone deacetylation are common epigenetic mechanisms implicated in the transcriptional silencing of tumor suppressor genes in human cancer. We treated two immortalized glioma cell lines, T98 and U87, and 10 patient-derived primary glioma cell lines with trichostatin A (TSA), a histone deacetylase inhibitor, or 5-aza-2′-deoxycytidine (5-AzaC), a DNA methyltransferase inhibitor, to comprehensively identify the cohort of genes reactivated through the pharmacologic reversal of these distinct but related epigenetic processes. Whole-genome microarray analysis identified genes induced by TSA (653) or 5-AzaC treatment (170). We selected a subset of reactivated genes that were markedly induced (greater than two-fold) after treatment with either TSA or 5-AzaC in a majority of glioma cell lines but not in cultured normal astrocytes. We then characterized the degree of promoter methylation and transcriptional silencing of selected genes in histologically confirmed human tumor and nontumor brain specimens. We identified two novel brain expressed genes, BEX1 and BEX2, which were silenced in all tumor specimens and exhibited extensive promoter hypermethylation. Viral-mediated reexpression of either BEX1 or BEX2 led to increased sensitivity to chemotherapy-induced apoptosis and potent tumor suppressor effects in vitro and in a xenograft mouse model. Using an integrated approach, we have established a novel platform for the genome-wide screening of epigenetically silenced genes in malignant glioma. This experimental paradigm provides a powerful new method for the identification of epigenetically silenced genes with potential function as tumor suppressors, biomarkers for disease diagnosis and detection, and therapeutically reversible modulators of critical regulatory pathways important in glioma pathogenesis. (Cancer Res 2006; 66(13): 6665-74)
Cannabinoids Induce Apoptosis of Pancreatic Tumor Cells via Endoplasmic Reticulum Stress–Related Genes
Authors: Carracedo Arkaitz , Gironella Meritxell , Lorente Mar , Garcia Stephane , Guzmán Manuel , Velasco Guillermo , Iovanna Juan L.
Published: July 2006

Pancreatic adenocarcinomas are among the most malignant forms of cancer and, therefore, it is of especial interest to set new strategies aimed at improving the prognostic of this deadly disease. The present study was undertaken to investigate the action of cannabinoids, a new family of potential antitumoral agents, in pancreatic cancer. We show that cannabinoid receptors are expressed in human pancreatic tumor cell lines and tumor biopsies at much higher levels than in normal pancreatic tissue. Studies conducted with MiaPaCa2 and Panc1 cell lines showed that cannabinoid administration (a) induced apoptosis, (b) increased ceramide levels, and (c) up-regulated mRNA levels of the stress protein p8. These effects were prevented by blockade of the CB2 cannabinoid receptor or by pharmacologic inhibition of ceramide synthesis de novo. Knockdown experiments using selective small interfering RNAs showed the involvement of p8 via its downstream endoplasmic reticulum stress–related targets activating transcription factor 4 (ATF-4) and TRB3 in Δ9-tetrahydrocannabinol–induced apoptosis. Cannabinoids also reduced the growth of tumor cells in two animal models of pancreatic cancer. In addition, cannabinoid treatment inhibited the spreading of pancreatic tumor cells. Moreover, cannabinoid administration selectively increased apoptosis and TRB3 expression in pancreatic tumor cells but not in normal tissue. In conclusion, results presented here show that cannabinoids lead to apoptosis of pancreatic tumor cells via a CB2 receptor and de novo synthesized ceramide-dependent up-regulation of p8 and the endoplasmic reticulum stress–related genes ATF-4 and TRB3. These findings may contribute to set the basis for a new therapeutic approach for the treatment of pancreatic cancer. (Cancer Res 2006; 66(13): 6748-55)
RUNX3 Is Frequently Inactivated by Dual Mechanisms of Protein Mislocalization and Promoter Hypermethylation in Breast Cancer
Authors: Lau Quek Choon , Raja Erna , Salto-Tellez Manuel , Liu Qiang , Ito Kosei , Inoue Masafumi , Putti Thomas Choudary , Loh Marie , Ko Tun Kiat , Huang Canhua , Bhalla Kapil N. , Zhu Tao , Ito Yoshiaki , Sukumar Saraswati
Published: July 2006

A tumor suppressor function has been attributed to RUNX3, a member of the RUNX family of transcription factors. Here, we examined alterations in the expression of three members, RUNX1, RUNX2, and RUNX3, and their interacting partner, CBF-β, in breast cancer. Among them, RUNX3 was consistently underexpressed in breast cancer cell lines and primary tumors. Fifty percent of the breast cancer cell lines (n = 19) showed hypermethylation at the promoter region and displayed significantly lower levels of RUNX3 mRNA expression (P < 0.0001) and protein (P < 0.001). In primary Singaporean breast cancers, 9 of 44 specimens showed undetectable levels of RUNX3 by immunohistochemistry. In 35 of 44 tumors, however, low levels of RUNX3 protein were present. Remarkably, in each case, protein was mislocalized to the cytoplasm. In primary tumors, hypermethylation of RUNX3 was observed in 23 of 44 cases (52%) and was undetectable in matched adjacent normal breast epithelium. Mislocalization of the protein, with or without methylation, seems to account for RUNX3 inactivation in the vast majority of the tumors. In in vitro and in vivo assays, RUNX3 behaved as a growth suppressor in breast cancer cells. Stable expression of RUNX3 in MDA-MB-231 breast cancer cells led to a more cuboidal phenotype, significantly reduced invasiveness in Matrigel invasion assays, and suppressed tumor formation in immunodeficient mice. This study provides biological and mechanistic insights into RUNX3 as the key member of the family that plays a role in breast cancer. Frequent protein mislocalization and methylation could render RUNX3 a valuable marker for early detection and risk assessment. (Cancer Res 2006; 66(13): 6512-20)
Estrogen Receptor-α Methylation Predicts Melanoma Progression
Authors: Mori Takuji , Martinez Steve R. , O'Day Steven J. , Morton Donald L. , Umetani Naoyuki , Kitago Minoru , Tanemura Atsushi , Nguyen Sandy L. , Tran Andy N. , Wang He-Jing , Hoon Dave S.B.
Published: July 2006

The role of estrogen receptor α (ER-α) in melanoma is unknown. ER-α expression may be regulated in melanoma via hypermethylation of promoter CpG islands. We assessed ER-α hypermethylation in primary and metastatic melanomas and sera as a potential tumor progression marker. ER-α methylation status in tumor (n = 107) and sera (n = 109) from American Joint Committee on Cancer (AJCC) stage I to IV melanoma patients was examined by methylation-specific PCR. The clinical significance of serum methylated ER-α was assessed among AJCC stage IV melanoma patients receiving biochemotherapy with tamoxifen. Rates of ER-α methylation in AJCC stage I, II, and III primary melanomas were 36% (4 of 11), 26% (5 of 19), and 35% (8 of 23), respectively. Methylated ER-α was detected in 42% (8 of 19) of stage III and 86% (30 of 35) of stage IV metastatic melanomas. ER-α was methylated more frequently in metastatic than primary melanomas (P = 0.0003). Of 109 melanoma patients' sera in AJCC stage I, II, III, and IV, methylated ER-α was detected in 10% (2 of 20), 15% (3 of 20), 26% (5 of 19), and 32% (16 of 50), respectively. Serum methylated ER-α was detected more frequently in advanced than localized melanomas (P = 0.03) and was the only factor predicting progression-free [risk ratio (RR), 2.64; 95% confidence interval (95% CI), 1.36-5.13; P = 0.004] and overall survival (RR, 2.31; 95% CI, 1.41-5.58; P = 0.003) in biochemotherapy patients. Hypermethylated ER-α is a significant factor in melanoma progression. Serum methylated ER-α is an unfavorable prognostic factor. (Cancer Res 2006; 66(13): 6692-8)
Acidic Extracellular pH Promotes Experimental Metastasis of Human Melanoma Cells in Athymic Nude Mice
Authors: Rofstad Einar K. , Mathiesen Berit , Kindem Kristil , Galappathi Kanthi
Published: July 2006

Extracellular pH (pHe) is lower in many tumors than in the corresponding normal tissue. The significance of acidic pHe in the development of metastatic disease was investigated in the present work. Human melanoma cells (A-07, D-12, and T-22) were cultured in vitro at pHe 6.8 or 7.4 (control) before being inoculated into the tail vein of BALB/c nu/nu mice for formation of experimental pulmonary metastases. Cell invasiveness was studied in vitro by using Matrigel invasion chambers and angiogenesis was studied in vivo by using an intradermal assay. Protein secretion was measured by ELISA and immunocapture assays. Cells cultured at acidic pHe showed increased secretion of proteinases and proangiogenic factors, enhanced invasive and angiogenic potential, and enhanced potential to develop experimental metastases. Acidity-induced metastasis was inhibited by treatment with the general matrix metalloproteinase (MMP) inhibitor GM6001, the general cysteine proteinase inhibitor E-64, or blocking antibody against vascular endothelial growth factor-A (VEGF-A) or interleukin-8 (IL-8). Our study indicates that acidic pHe promotes experimental pulmonary metastasis in A-07, D-12, and T-22 human melanoma cells by a common mechanism involving acidity-induced up-regulation of the proteolytic enzymes MMP-2, MMP-9, cathepsin B, and cathepsin L and acidity-induced up-regulation of the proangiogenic factors VEGF-A and IL-8. One consequence of this observation is that treatment strategies involving deliberate tumor acidification to improve the efficacy of chemotherapy, photodynamic therapy, and hyperthermia should be avoided. Moreover, the possibility that the pHe of the primary tumor may be an important prognostic parameter for melanoma patients merits clinical investigation. (Cancer Res 2006; 66(13): 6699-707)
The Ghostly Prelude to Deutero-Isaiah
Authors: Landy Francis
Published: July 2006

The article is a close reading of Isa. 40:1-11, which focuses on its function as a prologue to Deutero-Isaiah, and hence distinguished by its promise of a new beginning, and on its dependence on, and reversal of, the past, the spectral voices it seeks to repatriate. It is concerned with the secondariness of Deutero-Isaiah, and the consequent ambiguity of its messages. The voice of the poet/prophet is refracted through disembodied voices, which themselves cite other voices, before finally adopting that of the female herald, through whom the advent of God becomes manifest, only to be indefinitely deferred through metaphor and simile. In the background there is the frequently asserted relationship with Isaiah 6 as a metapoetic key to the book. Does its purview extend to Isaiah 40, and is the message of comfort conveyed by Deutero-Isaiah subverted by the incomprehensibility mandated by it? The complexities of the passage, and hence of the book as a whole, require attention to the detail of each its parts, but also to its fragmentariness, as it seeks to reconstruct a fractured reality. This is achieved in part through the emphasis on the materiality of the voice, as flesh (basar) and sonority, and as the matrix (mebasseret) of the future. The analysis proceeds from the voice of maternal comfort in vv. 1-2, to the announcement of the way and the universal theophany in vv. 3-5, to the pathos of transience in vv. 6-8, and finally to the deferred resolution in vv. 9-11. In the conclusion I discuss the relation of the text to the Freudian uncanny, the correspondence and non-correspondence with chapter 6, and the question of the relationship between historical and literary approaches.
The Chaldean Oracles of Zoroaster, Hekate's Couch,and Platonic Orientalism in Psellos and Plethon Die Chaldäischen Orakel des Zoroaster, die Couch der Hekate und platonischer Orientalismus in Psellos und Plēthon
Authors: Burns Dylan
Published: July 2006

Die vorliegende Untersuchung geht der Frage nach, auf welche Weise Michael Psellos und Georgios Gemistos Plēthon die Chaldäischen Orakel als eine Quelle uralter orientalischer Weisheit interpretierten. Psellos geht als ein Häresiologe an die Orakel heran, wenn auch mit ambivalenten Aussagen hinsichtlich der Rolle von Magie sowohl in der Lehre der Orakel als in seiner eigenen Philosophie. Der Artikel untersucht, inwieweit in der mittelalterlichen byzantinischen Vorstellung Magie mit Konstruktionen orientalischer “Dekadenz” verbunden war, die ihrerseits Einfluss hatten auf Psellos' eigene Auffassung, bei den Orakeln handele es sich um illegitime östliche Zauberkunst, ungeachtet des Wertes ihrer metaphysischen Lehre. Plēthon hingegen greift die Orakel im Kontext eines Diskurses neopaganer Alterität auf, in welchem er sie mit einer antiken östlichen Weisheit identifiziert, die gegen das orthodoxe Christentum in Stellung gebracht wurde. Obwohl er keinerlei Kenntnisse über persische Religion besaß, schrieb er dem Zoroaster die Autorschaft der Orakel zu, und zwar nicht aus schlichter Naivität, sondern im Zuge eines gängigen Deutungsmusters, das James Walbridge “Platonischen Orientalismus” nennt: die Neigung neoplatonischer Denker, uraltes Wissen nicht nur Platon zuzuschreiben, sondern auch anderen Weisen aus dem Osten. Plēthon, selbsternannter Neuheide in einem christlich orthodoxen Reich, fühlte sich angesprochen von der orientalischen Otherness der Orakel und identifizierte sich mit ihnen. Sein Manuskript der Orakel, welches ursprünglich Psellos gehörte, half ihm bei diesem Unternehmen. Seit Psellos waren wichtige Fragmente, die Askese, Dualismus und pagane Gottheiten betrafen, verloren oder doch unvollständig. Ohne diese fehlenden Fragmente war es ein Leichtes für Plēthon, die Orakel als eine holistische persische Theologie zu lesen, und nicht als eine hellenistische, mittelplatonisch-dualistische. Die Unterschiede zwischen Plēthons Exemplar der Orakel und jenen der frühen Neuplatonisten mögen ein Grund dafür sein, dass Plēthon der erste Platonist war, der Zoraster als den Autor der Orakel identifizierte, eine Zuschreibung, die entscheidend werden sollte für die Rezeption und Interpretation der Orakel in Renaissance und moderner Esoterik.
Developmentally Sensitive Forensic Interviewing of Preschool Children: Some Guidelines Drawn From Basic Psychological Research
Authors: Tang Connie M.
Published: July 2006

Interviewing preschool children who are victims or witnesses of crime to ensure accuracy and completeness of their recall is no easy task. Rising up to the challenge, a large number of empirical psychological studies related to interviewing young children have been conducted in the past decades. Most of these studies were applied research, simulating circumstances of real forensic interviews. It is believed, however, that more basic research could also be informative. The present article thus selectively reviews more basic psychological research in the areas of memory development, language development, and conceptual development as they relate to the forensic interviewing of preschool children. Based on characteristics of preschool children’s development in these areas, some useful guidelines are generated for forensic interviewers. Recommendations for future research are also made.
E Pluribus Unum (Out of Many, One)
Authors: Boylorn Robin M.
Published: July 2006

Written to initiate a dialogue about race in the academy, this narrative focuses on the experience of Black Ph.D. students in predominantly White academic institutions. Experimental in method and representation, this article poses important questions about race in academia. The author utilizes several qualitative opportunities, writing as autoethnography, poetry, and narrative. As a participant and researcher of the experience, the author is given the unique position of telling and listening, observing and explaining, strategizing and editing. The author takes your story (a construction developed to create a bridge between your world and mine) and combines it with her story, (the author’s motivations for writing about this experience), and folds it into their story (compiling the findings of the research based on an interview), to create our story (a collective narrative of the Black Ph.D. experience). Hence, the title, “E Pluribus Unum,” which translates “out of many, one.”
Confucian View of Learning and Implications for Developing Human Resources
Authors: Yang Baiyin , Zheng Wei , Li Mingfei
Published: July 2006

The problem and the solution. Confucian philosophy has dominated Chinese society for more than 2,000 years, and it has had a strong influence in many Asian countries. This philosophy has a unique view of teaching and learning. This article identifies Confucian values and beliefs in relation to teaching and learning. Implications for developing human resources in China are discussed.
Worldviews of Adult Learning in the Workplace Through a Mormonism Lens
Authors: Nielson Troy R. , Madsen Susan R. , Hammond Scott C.
Published: July 2006

The problem and the solution. With membership exceeding 12 million individuals in 170 countries, it is increasingly likely that Mormons will be found in the workplaces of organizations around the world. This article provides a brief overview of key concepts of Mormonism as they relate to adult learning in the workplace. It also explores several implications of these concepts for human resource development (HRD) practice and theory.
Clay minerals of the Permian Rotliegend Group in the North Sea and adjacent areas
Authors: Ziegler K.
Published: July 2006

The nature, distribution and origin of clay minerals in the hydrocarbon-bearing Permian Rotliegend sandstones of the North Sea and the adjacent areas of the Netherlands and Germany are reviewed. The clay minerals occur as detrital coatings of smectite and smectite-illite on the surfaces of sandgrains, and as later diagenetic cements of kaolinite, chlorite (two varieties), and illite in the pore spaces of those sandstones. Two diagenetic clay mineral assemblages are predominant in the Rotliegend of the North Sea. The kaolinite-illite assemblage is restricted to the Rotliegend of shelf areas which underwent shallow burial followed by strong Jurassic/Cretaceous (Late Cimmerian) structural inversions, whereas the illite-chlorite assemblage is associated with basinal areas that underwent deep and rapid burial throughout the Mesozoic.

The factors controlling mineralogy, crystal chemistry and morphology of those diagenetic clay minerals, as well as their regional distribution and origin, are numerous, complicated, and inter- related. Evidence suggests that the following aspects were important parameters: (1) variations in the original depositional arid desert environment; (2) the chemistry and flow patterns of the porewaters; (3) temperature and timing of clay mineral formation; (4) local burial history; (5) the presence or absence of meteoric water; and (6) the structural setting of the Rotliegend sandstones.

Oxygen isotope data indicate that the illite cements formed over a wide range of temperatures (24–140°C) that is consistent with the deep burial conditions prevailing in the palaeo-basins. In contrast, oxygen isotopes indicate that kaolinite cements formed over a more restricted temperature range (40–80°C) and under the influence of meteoric water penetrating the sandstones of the shelf areas as a result of their Late Cimmerian uplift and associated erosion. Hypotheses suggesting that the absence of kaolinite cement from the deeply buried Rotliegend sandstones is caused by its illitization during burial, and that the chlorite cements have formed by the alteration of earlier smectite, smectite-chlorite and corrensite cements, are not supported by evidence.
AMDA: an R package for the automated microarray data analysis
Authors: Pelizzola Mattia , Pavelka Norman , Foti Maria , Ricciardi-Castagnoli Paola
Published: July 2006

Background

Microarrays are routinely used to assess mRNA transcript levels on a genome-wide scale. Large amount of microarray datasets are now available in several databases, and new experiments are constantly being performed. In spite of this fact, few and limited tools exist for quickly and easily analyzing the results. Microarray analysis can be challenging for researchers without the necessary training and it can be time-consuming for service providers with many users.

Results

To address these problems we have developed an automated microarray data analysis (AMDA) software, which provides scientists with an easy and integrated system for the analysis of Affymetrix microarray experiments. AMDA is free and it is available as an R package. It is based on the Bioconductor project that provides a number of powerful bioinformatics and microarray analysis tools. This automated pipeline integrates different functions available in the R and Bioconductor projects with newly developed functions. AMDA covers all of the steps, performing a full data analysis, including image analysis, quality controls, normalization, selection of differentially expressed genes, clustering, correspondence analysis and functional evaluation. Finally a LaTEX document is dynamically generated depending on the performed analysis steps. The generated report contains comments and analysis results as well as the references to several files for a deeper investigation.

Conclusion

AMDA is freely available as an R package under the GPL license. The package as well as an example analysis report can be downloaded in the Services/Bioinformatics section of the Genopolis http://www.genopolis.it/
Association of SARS susceptibility with single nucleic acid polymorphisms of OAS1 and MxA genes: a case-control study
Authors: He Jing , Feng Dan , de Vlas Sake J , Wang Hongwei , Fontanet Arnaud , Zhang Panhe , Plancoulaine Sabine , Tang Fang , Zhan Lin , Yang Hong , Wang Tianbao , Richardus Jan H , Habbema J Dik F , Cao Wuchun
Published: July 2006

Background

Host genetic factors may play a role in susceptibility and resistance to SARS associated coronavirus (SARS-CoV) infection. The study was carried out to investigate the association between the genetic polymorphisms of 2',5'-oligoadenylate synthetase 1 (OAS1) gene as well as myxovirus resistance 1 (MxA) gene and susceptibility to SARS in Chinese Han population.

Methods

A hospital-based case-control study was conducted. A collective of 66 SARS cases and 64 close contact uninfected controls were enrolled in this study. End point real time polymerase chain reaction (PCR) and PCR-based Restriction Fragment Length Polymorphism (RFLP) analysis were used to detect the single nucleic polymorphisms (SNPs) in OAS1 and MxA genes. Information on other factors associated with SARS infection was collected using a pre-tested questionnaire. Univariate and multivariate logistic analyses were conducted.

Results

One polymorphism in the 3'-untranslated region (3'-UTR) of the OAS1 gene was associated with SARS infection. Compared to AA genotype, AG and GG genotypes were found associated with a protective effect on SARS infection with ORs (95%CI) of 0.42 (0.20~0.89) and 0.30 (0.09~0.97), respectively. Also, a GT genotype at position 88 in the MxA gene promoter was associated with increased susceptibility to SARS infection compared to a GG genotype (OR= 3.06, 95%CI: 1.25~7.50). The associations of AG genotype in OAS1 and GT genotype in MxA remained significant in multivariate analyses after adjusting for SARS protective measures (OR= 0.38, 95%CI: 0.14~0.98 andOR= 3.22, 95%CI: 1.13~9.18, respectively).

Conclusion

SNPs in the OAS1 3'-UTR and MxA promoter region appear associated with host susceptibility to SARS in Chinese Han population.
A simple statistical model for prediction of acute coronary syndrome in chest pain patients in the emergency department
Authors: Björk Jonas , Forberg Jakob L , Ohlsson Mattias , Edenbrandt Lars , Öhlin Hans , Ekelund Ulf
Published: July 2006

Background

Several models for prediction of acute coronary syndrome (ACS) among chest pain patients in the emergency department (ED) have been presented, but many models predict only the likelihood of acute myocardial infarction, or include a large number of variables, which make them less than optimal for implementation at a busy ED. We report here a simple statistical model for ACS prediction that could be used in routine care at a busy ED.

Methods

Multivariable analysis and logistic regression were used on data from 634 ED visits for chest pain. Only data immediately available at patient presentation were used. To make ACS prediction stable and the model useful for personnel inexperienced in electrocardiogram (ECG) reading, simple ECG data suitable for computerized reading were included.

Results

Besides ECG, eight variables were found to be important for ACS prediction, and included in the model: age, chest discomfort at presentation, symptom duration and previous hypertension, angina pectoris, AMI, congestive heart failure or PCI/CABG. At an ACS prevalence of 21% and a set sensitivity of 95%, the negative predictive value of the model was 96%.

Conclusion

The present prediction model, combined with the clinical judgment of ED personnel, could be useful for the early discharge of chest pain patients in populations with a low prevalence of ACS.
FGFR4 Arg388 Allele Is Associated With Resistance to Adjuvant Therapy in Primary Breast Cancer
Authors: Thussbas Christoph , Nahrig Jorg , Streit Sylvia , Bange Johannes , Kriner Monika , Kates Ronald , Ulm Kurt , Kiechle Marion , Hoefler Heinz , Ullrich Axel , Harbeck Nadia
Published: July 2006

Purpose

A recent study presented first evidence that a single nucleotide polymorphism (SNP) at codon 388 of fibroblast growth factor receptor 4 (FGFR4) gene, causing a transmembrane domain missense mutation (Gly388Arg), is associated with disease outcome in node-positive breast cancer. This article addresses the clinical relevance of this SNP, FGFR4 genotype, phenotype, and HER2 regarding patient outcome and influence of adjuvant systemic therapy in a substantial primary breast cancer collective (n = 372; median follow-up, 94.5 months).

Methods

Polymerase chain reaction restriction fragment length polymorphism analysis of germ-line polymorphism was performed in uninvolved lymph nodes; FGFR4 and HER2 expression were assessed immunohistochemically in tissue microarrays.

Results

In 51% of patients, homo- or heterozygous Arg388 allele was present. No correlation existed between FGFR4 genotype and expression or HER2 status. In node-negative patients, FGFR4 genotype was not correlated with disease outcome. In node-positive patients, however, FGFR4 Arg388 was significantly associated with poor disease-free survival (DFS; P = .02) and overall survival (OS; P = .04). Notably, this association seems to be attributable to relatively poor therapy response in Arg388 carriers, reflected in their significantly shorter DFS (P = .02) and OS (P = .045) among patients receiving adjuvant systemic therapy. It is also seen as a significant interaction term in a multivariate proportional hazards model with Arg388 carriers having only about half as much benefit from adjuvant systemic therapy as wild-type carriers.

Conclusion

According to this study, FGFR4 Arg388 genotype is a marker for breast cancer progression in patients with adjuvant systemic therapy, particularly chemotherapy, and thus may indicate therapy resistance.
Untreated Vestibular Schwannoma: Vertigo Is a Powerful Predictor Forhealth-Related Quality of Life
Authors: Myrseth Erling , Møller Per , Wentzel-Larsen Tore , Goplen Frederik , Lund-Johansen Morten
Published: July 2006

OBJECTIVE

The aim of the present study was to characterise the relation between quality of life (QOL) and the four major complaints (hearing loss, tinnitus, vertigo and unsteadiness) caused by unilateral vestibular schwannoma (versus) in a cohort of well-characterised untreated patients.

METHODS

One hundred and ninety-nine consecutive patients (91 men, 108 women) with a mean age of 56.9 years were studied prospectively during the 4-year period 2001–2004. The average time span from symptom onset to the radiological diagnosis was 4.2 years. The patients were subject to a standardised examination including MRI, evaluation of hearing acuity, balance function by stabilometry, and a visual analogue scale (VAS) self-evaluation of tinnitus and vertigo. Furthermore, the patients responded to two questionnaires, Short-Form 36 (SF-36) and Glasgow Benefit Inventory (GBI)). A reference population was recruited from 80 adult persons who visited Haukeland University Hospital as non-patients or non-staff members. All data were recorded prospectively in a customised case report form. Statistical analysis was done with SPSS software.

RESULTS

The response rates of the Short-Form 36 and Glasgow Benefit Inventoryquestionnaires were 91.5 and 89.9%, respectively. According to the SF-36 questionnaire the patients scored significantly below that of expected norms with exception of physical function and mental health. Patients report negative benefit on the general and physical sections of the GBI questionnaire. Regression analysis showed that vertigo had a strong negative impact on QOL, whilst unilateral hearing loss and tinnitus had less impact on QOL.

CONCLUSION

Vertigo is the symptom causing the most pronounced negative effect on QOL in patients with versus The more frequent versus-symptoms unilateral hearing loss and tinnitus seem to be less important in the patients' perception of QOL evaluated by the questionnaires used in this study. If vertigo could be relieved by treatment, this symptom should be more in focus when discussing treatment options in small to medium sized versus
Electrochemical Behaviors of Ferrocene Derivatives at an Electrode Modified with Terminally Substituted Alkanethiol Monolayer Assemblies
Authors: Takehara Kô , Takemura Hiroyuki
Published: July 2006

Self-assembled monolayers of 11-mercapto-1-undecanol (MUO), 11-mercaptoundecanoic acid (MUA), and 11-amino-1-undecanethiol (AUT) were formed on a gold disk electrode. The effects of the terminal charges of these monolayers on the redox responses of 1,1′ -ferrocenedimethanol (FcDM), (ferrocenylmethyl)trimethylammoniun bromide (FcMA) and ammonium ferrocenesulfonate (FcSA) were evaluated by using voltammetric (CV) techniques. The CV responses of FcDM and FcMA decreased in the order of MUA/Au (MUA modified gold electrode), MUO/Au, and AUT/Au. In contrast, the CV response of FcSA increased in the order of MUA/Au, MUO/Au, and AUT/Au. From these results, the effects of the terminal charges on the CV responses were measured in relation to the diffuse layer potential and the electrostatic interaction between the terminal unit and redox species.