bluuebunny/crossref_metadata_2025_split huggingface dataset:
Problems with the Path of Phillips Brooks
Authors: Wells Christopher 
Published: November 2008

ABSTRACTThis article takes the opportunity of Gillis Harp's recent biography of nineteenth-century American Episcopalian Phillips Brooks to engage Harp's theological situation of the Episcopal Church. Harp's revisionist historiographical argument, rejecting the Broad Church ‘myth of synthesis’ for a more agonized tale of trenchant party battles, is welcome for its perceptiveness and depth of analysis, not least as these historical difficulties remain at the centre of contemporary intra-Anglican and ecumenical conversations. Harp's commitment to a ‘Reformed’ and ‘evangelical’ Anglicanism, however, raises a series of questions – concerning the nature of orthodoxy and Christian doctrine, as well as ‘Protestant’ identity – that deserve greater investigation, and that historians and theologians would do well to pursue together.
Endoplasmic reticulum stress is a target for therapy in Waldenstrom macroglobulinemia
Authors: Leleu Xavier , Xu Lian , Jia Xiaoying , Sacco Antonio , Farag Mena , Hunter Zachary R. , Moreau Anne-Sophie , Ngo Hai T. , Hatjiharissi Evdoxia , Ho Allen W. , Santos Daniel D. , Adamia Sofia , O'Connor Kelly , Ciccarelli Bryan , Soumerai Jacob , Manning Robert J. , Patterson Christopher J. , Roccaro Aldo M. , Ghobrial Irene M. , Treon Steven P. 
Published: November 2008

AbstractWaldenstrom macroglobulinemia (WM) is an incurable low-grade lymphoma characterized by bone marrow (BM) involvement of IgM secreting lymphoplasmacytic cells. The induction of unfolded protein response (UPR) genes (“physiologic” UPR) enables cells to differentiate into professional secretory cells capable of production of high amounts of endoplasmic reticulum (ER)–processed proteins, such as immunoglobulins. Ultimately, the initially cytoprotective UPR triggers an apoptotic cascade if ER stress is not corrected, called proapoptotic/terminal UPR. We show that WM cells inherently express the physiologic UPR machinery compared with normal BM cells, and that increased ER stress leads to proapoptotic/terminal UPR in WM cells. We therefore examined tunicamycin, ER stress inducer, for potential antitumor effects in WM. Tunicamycin induced significant cytotoxicity, apoptosis and cell-cycle arrest, and inhibited DNA synthesis in WM cell lines and primary BM CD19+ cells from patients with WM with an inhibitory concentration (IC50) of 0.5 μg/mL to 1 μg/mL, but not in healthy donor cells. Importantly, coculture of WM cells in the context of the BM microenvironment did not inhibit tunicamycin-induced cytotoxicity. Finally, we demonstrate that ER stress inducer synergizes with other agents used in the treatment of WM. These preclinical studies provide a framework for further evaluation of ER stress inducing agents as therapeutic agents in WM.
Safety and efficacy of long-term treatment with romiplostim in thrombocytopenic patients with chronic ITP
Authors: Bussel James B. , Kuter David J. , Pullarkat Vinod , Lyons Roger M. , Guo Matthew , Nichol Janet L. 
Published: November 2008

AbstractChronic immune thrombocytopenic purpura (ITP) is characterized by low platelet counts and mucocutaneous bleeding. In previous studies romiplostim (AMG531), a thrombopoiesis-stimulating protein, increased platelet counts in most patients with chronic ITP. This ongoing, long-term open-label, single-arm study investigated safety and efficacy in patients who completed a previous romiplostim study and had platelet counts less than 5 × 109/L. One hundred forty-two patients were treated for up to 156 weeks (mean, 69 weeks). Platelet responses (platelet count ≥ 50 × 109/L and double baseline) were observed in 87% of all patients and occurred on average 67% of the time in responding patients. In 77% of patients, the romiplostim dose remained within 2 μg/kg of their most frequent dose at least 90% of the time. Ninety patients (63%) received treatment by self-administration. Treatment-related serious adverse events were reported in 13 patients (9%). Bone marrow reticulin was observed in 8 patients; marrows were not routinely performed in this study, so the true incidence of this event cannot be determined. Severe bleeding events were reported in 12 patients (9%). Thrombotic events occurred in 7 patients (5%). In conclusion, romiplostim increased platelet counts in most patients for up to 156 weeks without tachyphylaxis and had an acceptable safety profile. (ClinicalTrials.gov Identifier NCT00116688).
The Raf-1 inhibitor GW5074 and dexamethasone suppress sidestream smoke-induced airway hyperresponsiveness in mice
Authors: Lei Ying , Cao Yong-Xiao , Xu Cang-Bao , Zhang Yaping 
Published: November 2008

AbstractBackgroundSidestream smoke is closely associated with airway inflammation and hyperreactivity. The present study was designed to investigate if the Raf-1 inhibitor GW5074 and the anti-inflammatory drug dexamethasone suppress airway hyperreactivity in a mouse model of sidestream smoke exposure.MethodsMice were repeatedly exposed to smoke from four cigarettes each day for four weeks. After the first week of the smoke exposure, the mice received either dexamethasone intraperitoneally every other day or GW5074 intraperitoneally every day for three weeks. The tone of the tracheal ring segments was recorded with a myograph system and concentration-response curves were obtained by cumulative administration of agonists. Histopathology was examined by light microscopy.ResultsFour weeks of exposure to cigarette smoke significantly increased the mouse airway contractile response to carbachol, endothelin-1 and potassium. Intraperitoneal administration of GW5074 or dexamethasone significantly suppressed the enhanced airway contractile responses, while airway epithelium-dependent relaxation was not affected. In addition, the smoke-induced infiltration of inflammatory cells and mucous gland hypertrophy were attenuated by the administration of GW5074 or dexamethasone.ConclusionSidestream smoke induces airway contractile hyperresponsiveness. Inhibition of Raf-1 activity and airway inflammation suppresses smoking-associated airway hyperresponsiveness.
Learning transcriptional regulatory networks from high throughput gene expression data using continuous three-way mutual information
Authors: Luo Weijun , Hankenson Kurt D , Woolf Peter J 
Published: November 2008

AbstractBackgroundProbability based statistical learning methods such as mutual information and Bayesian networks have emerged as a major category of tools for reverse engineering mechanistic relationships from quantitative biological data. In this work we introduce a new statistical learning strategy, MI3 that addresses three common issues in previous methods simultaneously: (1) handling of continuous variables, (2) detection of more complex three-way relationships and (3) better differentiation of causal versus confounding relationships. With these improvements, we provide a more realistic representation of the underlying biological system.ResultsWe test the MI3 algorithm using both synthetic and experimental data. In the synthetic data experiment, MI3 achieved an absolute sensitivity/precision of 0.77/0.83 and a relative sensitivity/precision both of 0.99. In addition, MI3 significantly outperformed the control methods, including Bayesian networks, classical two-way mutual information and a discrete version of MI3. We then used MI3 and control methods to infer a regulatory network centered at the MYC transcription factor from a published microarray dataset. Models selected by MI3 were numerically and biologically distinct from those selected by control methods. Unlike control methods, MI3 effectively differentiated true causal models from confounding models. MI3 recovered major MYC cofactors, and revealed major mechanisms involved in MYC dependent transcriptional regulation, which are strongly supported by literature. The MI3 network showed that limited sets of regulatory mechanisms are employed repeatedly to control the expression of large number of genes.ConclusionOverall, our work demonstrates that MI3 outperforms the frequently used control methods, and provides a powerful method for inferring mechanistic relationships underlying biological and other complex systems. The MI3 method is implemented in R in the "mi3" package, available under the GNU GPL fromhttp://sysbio.engin.umich.edu/~luow/downloads.phpand from the R package archive CRAN.
Silencing of directional migration in roundabout4 knockdown endothelial cells
Authors: Kaur Sukhbir , Samant Ganesh V , Pramanik Kallal , Loscombe Philip W , Pendrak Michael L , Roberts David D , Ramchandran Ramani 
Published: November 2008

Abstract

Background
Roundabouts are axon guidance molecules that have recently been identified to play a role in vascular guidance as well. In this study, we have investigated gene knockdown analysis of endothelial Robos, in particular roundabout 4 (robo4), the predominant Robo in endothelial cells using small interfering RNA technology in vitro.

Results

Robo1 and Robo4 knockdown cells display distinct activity in endothelial cell migration assay. The knockdown of robo4 abrogated the chemotactic response of endothelial cells to serum but enhanced a chemokinetic response to Slit2, while robo1 knockdown cells do not display chemotactic response to serum or VEGF. Robo4 knockdown endothelial cells unexpectedly show up regulation of Rho GTPases. Zebrafish Robo4 rescues both Rho GTPase homeostasis and serum reduced chemotaxis in robo4 knockdown cells. Robo1 and Robo4 interact and share molecules such as Slit2, Mena and Vilse, a Cdc42-GAP. In addition, this study mechanistically implicates IRSp53 in the signaling nexus between activated Cdc42 and Mena, both of which have previously been shown to be involved with Robo4 signaling in endothelial cells.

Conclusion
This study identifies specific components of the Robo signaling apparatus that work together to guide directional migration of endothelial cells.
Evolution of conserved secondary structures and their function in transcriptional regulation networks
Authors: Xie Hai-Bing , Irwin David M , Zhang Ya-Ping 
Published: November 2008

Abstract

Background
Many conserved secondary structures have been identified within conserved elements in the human genome, but only a small fraction of them are known to be functional RNAs. The evolutionary variations of these conserved secondary structures in human populations and their biological functions have not been fully studied.

Results
We searched for polymorphisms within conserved secondary structures and identified a number of SNPs within these elements even though they are highly conserved among species. The density of SNPs in conserved secondary structures is about 65% of that of their flanking, non-conserved, sequences. Classification of sites as stems or as loops/bulges revealed that the density of SNPs in stems is about 62% of that found in loops/bulges. Analysis of derived allele frequency data indicates that sites in stems are under stronger evolutionary constraint than sites in loops/bulges. Intergenic conserved secondary structures tend to associate with transcription factor-encoding genes with genetic distance being the measure of regulator-gene associations. A substantial fraction of intergenic conserved secondary structures overlap characterized binding sites for multiple transcription factors.

Conclusion
Strong purifying selection implies that secondary structures are probably important carriers of biological functions for conserved sequences. The overlap between intergenic conserved secondary structures and transcription factor binding sites further suggests that intergenic conserved secondary structures have essential roles in directing gene expression in transcriptional regulation networks.
mtDNA depletion confers specific gene expression profiles in human cells grown in culture and in xenograft
Authors: Magda Darren , Lecane Philip , Prescott Julia , Thiemann Patricia , Ma Xuan , Dranchak Patricia K , Toleno Donna M , Ramaswamy Krishna , Siegmund Kimberly D , Hacia Joseph G 
Published: November 2008

Abstract

Background
Interactions between the gene products encoded by the mitochondrial and nuclear genomes play critical roles in eukaryotic cellular function. However, the effects mitochondrial DNA (mtDNA) levels have on the nuclear transcriptome have not been defined under physiological conditions. In order to address this issue, we characterized the gene expression profiles of A549 lung cancer cells and their mtDNA-depleted ρ0 counterparts grown in culture and as tumor xenografts in immune-deficient mice.

Results
Cultured A549 ρ0 cells were respiration-deficient and showed enhanced levels of transcripts relevant to metal homeostasis, initiation of the epithelial-mesenchymal transition, and glucuronidation pathways. Several well-established HIF-regulated transcripts showed increased or decreased abundance relative to the parental cell line. Furthermore, growth in culture versus xenograft has a significantly greater influence on expression profiles, including transcripts involved in mitochondrial structure and both aerobic and anaerobic energy metabolism. However, both in vitro and in vivo, mtDNA levels explained the majority of the variance observed in the expression of transcripts in glucuronidation, tRNA synthetase, and immune surveillance related pathways. mtDNA levels in A549 xenografts also affected the expression of genes, such as AMACR and PHYH, involved in peroxisomal lipid metabolic pathways.

Conclusion
We have identified mtDNA-dependent gene expression profiles that are shared in cultured cells and in xenografts. These profiles indicate that mtDNA-depleted cells could provide informative model systems for the testing the efficacy of select classes of therapeutics, such as anti-angiogenesis agents. Furthermore, mtDNA-depleted cells grown culture and in xenografts provide a powerful means to investigate possible relationships between mitochondrial activity and gene expression profiles in normal and pathological cells.
Isolation, characterization and comparison of Atlantic and Chinook salmon growth hormone 1 and 2
Authors: von Schalburg Kristian R , Yazawa Ryosuke , de Boer Johan , Lubieniecki Krzysztof P , Goh Benjamin , Straub Christopher A , Beetz-Sargent Marianne R , Robb Adrienne , Davidson William S , Devlin Robert H , Koop Ben F 
Published: November 2008

Abstract

Background
Growth hormone (GH) is an important regulator of skeletal growth, as well as other adapted processes in salmonids. The GH gene (gh) in salmonids is represented by duplicated, non-allelic isoforms designated as gh1 and gh2. We have isolated and characterized gh-containing bacterial artificial chromosomes (BACs) of both Atlantic and Chinook salmon (Salmo salar and Oncorhynchus tshawytscha) in order to further elucidate our understanding of the conservation and regulation of these loci.

Results
BACs containing gh1 and gh2 from both Atlantic and Chinook salmon were assembled, annotated, and compared to each other in their coding, intronic, regulatory, and flanking regions. These BACs also contain the genes for skeletal muscle sodium channel oriented in the same direction. The sequences of the genes for interferon alpha-1, myosin alkali light chain and microtubule associated protein Tau were also identified, and found in opposite orientations relative to gh1 and gh2. Viability of each of these genes was examined by PCR. We show that transposon insertions have occurred differently in the promoters of gh, within and between each species. Other differences within the promoters and intronic and 3'-flanking regions of the four gh genes provide evidence that they have distinct regulatory modes and possibly act to function differently and/or during different times of salmonid development.

Conclusion
A core proximal promoter for transcription of both gh1 and gh2 is conserved between the two species of salmon. Nevertheless, transposon integration and regulatory element differences do exist between the promoters of gh1 and gh2. Additionally, organization of transposon families into the BACs containing gh1 and for the BACs containing gh2, are very similar within orthologous regions, but much less clear conservation is apparent in comparisons between the gh1- and gh2-containing paralogous BACs for the two fish species. This is consistent with the hypothesis that a burst of transposition activity occurred during the speciation events which led to Atlantic and Pacific salmon. The Chinook and other Oncorhynchus GH1s are strikingly different in comparison to the other GHs and this change is not apparent in the surrounding non-coding sequences.
Erratum to: PAIS: paracetamol (acetaminophen) in stroke; protocol for a randomized, double blind clinical trial. [ISCRTN74418480]
Authors: den Hertog Heleen M , Worp H Bart van der , van Gemert H Maarten A , Algra Ale , Kappelle L Jaap , van Gijn Jan , Koudstaal Peter J , Dippel Diederik WJ ,   the PAIS investigators
Published: November 2008

Abstract

Background
The Paracetamol (Acetaminophen) In Stroke (PAIS) study is a phase III multicenter, double blind, randomized, placebo-controlled clinical trial of high-dose acetaminophen in patients with acute stroke. The trial compares treatment with a daily dose of 6 g acetaminophen, started within 12 hours after the onset of symptoms, with matched placebo. The purpose of this study is to assess whether treatment with acetaminophen for 3 days will result in improved functional outcome through a modest reduction in body temperature and prevention of fever.
The previously planned statistical analysis based on a dichotomization of the scores on the modified Rankin Scale (mRS) may not make the most efficient use of the available baseline information. Therefore, the planned primary analysis of the PAIS study has been changed from fixed dichotomization of the mRS to a sliding dichotomy analysis.

Methods
Instead of taking a single definition of good outcome for all patients, the definition is tailored to each individual patient's baseline prognosis on entry into the trial.

Conclusion
The protocol change was initiated because of both advances in statistical approaches and to increase the efficiency of the trial by improving statistical power.

Trial Registration
Current Controlled Trials [ISCRTN74418480]
The clinicopathologic characteristics and prognostic significance of triple-negativity in node-negative breast cancer
Authors: Rhee Jiyoung , Han Sae-Won , Oh Do-Youn , Kim Jee Hyun , Im Seock-Ah , Han Wonshik , Ae Park In , Noh Dong-Young , Bang Yung-Jue , Kim Tae-You 
Published: November 2008

Abstract

Background
Triple-negative (TN) breast cancer, which is defined as being negative for the estrogen receptor (ER), the progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER-2), represents a subset of breast cancer with different biologic behaviour. We investigated the clinicopathologic characteristics and prognostic indicators of lymph node-negative TN breast cancer.

Methods
Medical records were reviewed from patients with node-negative breast cancer who underwent curative surgery at Seoul National University Hospital between Jan. 2000 and Jun. 2003. Clinicopathologic variables and clinical outcomes were evaluated.

Results
Among 683 patients included, 136 had TN breast cancer and 529 had non-TN breast cancer. TN breast cancer correlated with younger age (< 35 y, p = 0.003), and higher histologic and nuclear grade (p < 0.001). It also correlated with a molecular profile associated with biological aggressiveness: negative for bcl-2 expression (p < 0.001), positive for the epidermal growth factor receptor (p = 0.003), and a high level of p53 (p < 0.001) and Ki67 expression (p < 0.00). The relapse rates during the follow-up period (median, 56.8 months) were 14.7% for TN breast cancer and 6.6% for non-TN breast cancer (p = 0.004). Relapse free survival (RFS) was significantly shorter among patients with TN breast cancer compared with those with non-TN breast cancer (4-year RFS rate 85.5% vs. 94.2%, respectively; p = 0.001). On multivariate analysis, young age, close resection margin, and triple-negativity were independent predictors of shorter RFS.

Conclusion
TN breast cancer had higher relapse rate and more aggressive clinicopathologic characteristics than non-TN in node-negative breast cancer. Thus, TN breast cancer should be integrated into the risk factor analysis for node-negative breast cancer.
Voluntary exercise inhibits intestinal tumorigenesis in Apc
Min/+mice and azoxymethane/dextran sulfate sodium-treated mice
Authors: Ju Jihyeung , Nolan Bonnie , Cheh Michelle , Bose Mousumi , Lin Yong , Wagner George C , Yang Chung S 
Published: November 2008

Abstract

Background
Epidemiological studies suggest that physical activity reduces the risk of colon cancer in humans. Results from animal studies, however, are inconclusive. The present study investigated the effects of voluntary exercise on intestinal tumor formation in two different animal models, Apc
Min/+ mice and azoxymethane (AOM)/dextran sulfate sodium (DSS)-treated mice.

Methods
In Experiments 1 and 2, five-week old female Apc
Min/+ mice were either housed in regular cages or cages equipped with a running wheel for 6 weeks (for mice maintained on the AIN93G diet; Experiment 1) or 9 weeks (for mice on a high-fat diet; Experiment 2). In Experiment 3, male CF-1 mice at 6 weeks of age were given a dose of AOM (10 mg/kg body weight, i.p.) and, 12 days later, 1.5% DSS in drinking fluid for 1 week. The mice were then maintained on a high-fat diet and housed in regular cages or cages equipped with a running wheel for 16 weeks.

Results
In the Apc
Min/+ mice maintained on either the AIN93G or the high-fat diet, voluntary exercise decreased the number of small intestinal tumors. In the AOM/DSS-treated mice maintained on a high-fat diet, voluntary exercise also decreased the number of colon tumors. In Apc
Min/+ mice, voluntary exercise decreased the ratio of serum insulin like growth factor (IGF)-1 to IGF binding protein (BP)-3 levels. It also decreased prostaglandin E2 and nuclear β-catenin levels, but increased E-cadherin levels in the tumors.

Conclusion
These results indicate hat voluntary exercise inhibited intestinal tumorigenesis in Apc
Min/+ mice and AOM/DSS-treated mice, and the inhibitory effect is associated with decreased IGF-1/IGFBP-3 ratio, aberrant β-catenin signaling, and arachidonic acid metabolism.