bluuebunny/crossref_metadata_2025_split huggingface dataset:
Focal Adhesion Kinase, a Downstream Mediator of Raf-1 Signaling, Suppresses Cellular Adhesion, Migration, and Neuroendocrine Markers in BON Carcinoid Cells
Authors: Ning Li , Chen Herbert , Kunnimalaiyaan Muthusamy 
Published: April 2010

Abstract
We have recently reported that activation of the Raf-1/mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase 1/2 (MEK1/2)/ERK1/2 signaling cascade in gastrointestinal carcinoid cell line (BON) alters cellular morphology and neuroendocrine phenotype. The mechanisms by which Raf-1 mediates these changes in carcinoid cells are unclear. Here, we report that activation of the Raf-1 signaling cascade in BON cells induced the expression of focal adhesion kinase (FAK) protein, suppressed the production of neuroendocrine markers, and resulted in significant decreases in cellular adhesion and migration. Importantly, inactivation of MEK1/2 by 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene or abolition of FAK induction in Raf-1–activated BON cells by targeted siRNA led to reversal of the Raf-1–mediated reduction in neuroendocrine markers and cellular adhesion and migration. Phosphorylation site-specific antibodies detected the phosphorylated FAKTyr407, but not FAKTyr397, in these Raf-1–activated cells, indicating that FAKTyr407 may be associated with changes in the neuroendocrine phenotype. Overexpression of constitutively active FAK plasmids (wild-type FAK or FAKTyr397 mutant) into BON cells reduced neuroendocrine markers, whereas the FAKTyr407 mutant plasmid did not show any decrease in the levels of neuroendocrine markers, indicating that phosphorylation of FAK at the Tyr407 residue may be important for these effects. Our results showed for the first time that FAK is an essential downstream effector of the Raf-1/MEK1/2/ERK1/2 signaling cascade and negatively regulated the neuroendocrine and metastatic phenotype in BON cells. Mol Cancer Res; 8(5); 775–82. ©2010 AACR.
STAT1 Represses Skp2 Gene Transcription to Promote p27Kip1 Stabilization in Ras-Transformed Cells
Authors: Wang Shuo , Raven Jennifer F. , Koromilas Antonis E. 
Published: April 2010

Abstract
The S-phase kinase-associated protein 2 (Skp2) is an F-box protein that serves as a subunit of the Skp1-Cullin-F-box ubiquitin protein ligase complex. Skp2 is overexpressed in many tumors and promotes tumor formation through its ability to induce the degradation of proteins with antiproliferative and tumor-suppressor functions, such as p27Kip1. The signal transducer and activator of transcription 1 (STAT1) is a key regulator of the immune system through its capacity to act downstream of interferons. STAT1 exhibits tumor-suppressor properties by inhibiting oncogenic pathways and promoting tumor immunosurveillance. Previous work established the antitumor function of STAT1 in Ras-transformed cells through the induction of p27Kip1 at the transcriptional level. Herein, we unveil a novel pathway used by STAT1 to upregulate p27Kip1. Specifically, we show that STAT1 impedes Skp2 gene transcription by binding to Skp2 promoter DNA in vitro and in vivo. Decreased Skp2 expression by STAT1 is accompanied by the increased stability of p27Kip1 in Ras-transformed cells. We further show that impaired expression of STAT1 in human colon cancer cells containing an activated form of K-Ras is associated with the upregulation of Skp2 and downregulation of p27Kip1. Our study identifies Skp2 as a new target gene of STAT1 in Ras-transformed cells with profound implications in cell transformation and tumorigenesis. Mol Cancer Res; 8(5); 798–805. ©2010 AACR.
CREB1 Is a Strong Genetic Predictor of the Variation in Exercise Heart Rate Response to Regular Exercise
Authors: Rankinen Tuomo , Argyropoulos George , Rice Treva , Rao D.C. , Bouchard Claude 
Published: April 2010

Background—
A genome-wide linkage scan identified a quantitative trait locus for exercise training–induced changes in submaximal exercise (50 W) heart rate (ΔHR50) on chromosome 2q33.3-q34 in the HERITAGE Family Study (n=472).

Methods and Results—

To fine-map the region, 1450 tag SNPs were genotyped between 205 and 215 Mb on chromosome 2. The strongest evidence of association with ΔHR50 was observed with 2 single-nucleotide polymorphisms (SNPs) located in the 5′ region of the cAMP-responsive element-binding protein 1 (
CREB1
) gene (rs2253206:
P
=1.6×10
−5
and rs2360969:
P
=4.3×10
−5
). The associations remained significant (
P
=0.01 and
P
=0.023, respectively) after accounting for multiple testing. Regression modeling of the 39 most significant SNPs in the single-SNP analysis identified 9 SNPs that collectively explained 20% of the ΔHR50 variance.
CREB1
SNP rs2253206 had the strongest effect (5.45% of variance), followed by SNPs in the
FASTKD2
(3.1%),
MAP2
(2.6%),
SPAG16
(2.1%),
ERBB4
(3 SNPs≈1.4% each),
IKZF2
(1.4%), and
PARD3B
(1.0%) loci. In conditional linkage analysis, 6 SNPs from the final regression model (
CREB1, FASTKD2, MAP2, ERBB4, IKZF2
, and
PARD3B
) accounted for the original linkage signal: The log of the odds score dropped from 2.10 to 0.41 after adjusting for all 6 SNPs. Functional studies revealed that the common allele of rs2253206 exhibits significantly (
P
<0.05) lower promoter activity than the minor allele.

Conclusions—

Our data suggest that functional DNA sequence variation in the
CREB1
locus is strongly associated with ΔHR50 and explains a considerable proportion of the quantitative trait locus variance. However, at least 5 additional SNPs seem to be required to fully account for the original linkage signal.
Joint Diagnostic of the Surface Air Temperature in Southern South America and the Madden–Julian Oscillation
Authors: Naumann Gustavo , Vargas Walter M. 
Published: April 2010

Abstract
The objective of this research is to explore the relationship between maximum and minimum temperatures, daily precipitation, and the Madden–Julian oscillation (MJO). It was found that the different phases of the MJO show a consistent signal on winter temperature variability and precipitation in southeastern South America. Additionally, this paper explores the spatial–temporal variations of mutual information and joint entropy between temperature and the MJO. A defined spatial pattern was observed with an increased signal in northeastern Argentina and southern Brazil. In the local mutual information analysis, periods in which the mutual information doubled the average values were observed over the entire region. These results indicate that these connections can be used to forecast winter temperatures with a better skill score in situations where both variables covary.
Perception of the Impact of Type 1 Diabetes on Low-Income Families
Authors: Edmonds-Myles Sadiqa , Tamborlane William V. , Grey Margaret 
Published: April 2010

Purpose The purpose of this study was to explore the psychosocial impact of type 1 diabetes (T1DM) on low-income families of various racial/ethnic backgrounds. Methods A qualitative study using qualitative descriptive methods was conducted with a total of 21 patient-parent dyads from African American, Hispanic, and white heritage, respectively. An interview guide was developed to explore each family’s attitudes and beliefs related to diabetes. Results Although all subjects were in excellent metabolic control (mean A1C levels were between 7.3% and 7.6%), there were a number of identifiable differences in the perception of the impact of T1DM among the 3 groups. Themes in the data demonstrated differences in the following areas: (1) view of diabetes and its effects on the family; (2) ability to successfully treat diabetes; (3) ability to cope with diabetes; and (4) experiences with the health care system. Most notable themes include a disparity across racial/ethnic groups in the preoccupation with the disease after diagnosis, cultural and financial factors identified, and differences in treatment modalities and reasons for their use. Conclusions Diabetes education and care need to carefully address such differences. Although these differences are likely multifactorial, with components of socioeconomic status, family structure, and family experiences involved, it is evident that ethnicity itself is an important factor that can affect the ability of families to manage and cope with diabetes.
Trends in the application of dynamic allocation methods in multi-arm cancer clinical trials
Authors: Pond Gregory R , Tang Patricia A , Welch Stephen A , Chen Eric X 
Published: April 2010

Background Dynamic allocation (DA) methods which attempt to balance baseline prognostic factors between treatment arms, can be used in multi-arm clinical trials to sequentially allocate patients to treatment. Although some experts express concern regarding the validity of inference from trials using DA, others believe DA methods produce more credible results. Purpose A review of published multi-arm cancer clinical trials was conducted to explore the frequency of DA use in oncology. Methods Multi-arm phase III clinical trials of at least 100 patients per arm, published in 13 major oncology journals from 1995—2005 were manually reviewed. Information about reported use of DA methods, or randomization via random permuted blocks (PB), was extracted along with trial characteristics. Results Of 476 published clinical trials, 112 (23.5%) reported using some form of DA method, while 103 (21.6%) reported using PB methods. Most trials (403 or 84.7%) reported stratifying on at least one baseline factor. The mean number of stratification factors was 2.70 per trial, and 78.6% of DA trials reported 3 or more stratification factors compared with 30.2% of non-DA trials (p < 0.001). The frequency of DA use increased over time, with 20.2%, 21.3%, 25.8%, 28.8% and 38.9% of trials reported use in 1995—2001, 2002, 2003, 2004, and 2005, respectively. Use of DA methods was more frequently reported in trials involving an academic co-operative group (28.4% vs. 13.8%), however, no difference was observed between industry-funded and other-funded trials (24.0% vs. 23.2%) or geographical region (19.7% of North American trials, 26.2% of European trials and 21.7% of multinational/other trials). Limitations As a retrospective analysis, the true frequency of DA use is likely underreported. Few trials gave complete details of the allocation method used, thus it is possible some manuscripts reported incorrect allocation methods. Journals were selected which were assumed to publish most large, multi-arm clinical trials in cancer from 1995—2005, however, some trials were likely reported in journals other than what was reviewed. Conclusions DA methods are frequently used in multi-arm cancer clinical trials. The use of DA appears to becoming more common over time and are used more frequently when an academic cooperative group is involved. No relationship between industry funded trials or geographic region and allocation method was observed. Clinical Trials 2010; 7: 227—234. http://ctj.sagepub.com
Rac2 GTPase deficiency depletes BCR-ABL+ leukemic stem cells and progenitors in vivo
Authors: Sengupta Amitava , Arnett Jorden , Dunn Susan , Williams David A. , Cancelas Jose A. 
Published: April 2010

Abstract
Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disease (MPD) initiated by p210-BCR-ABL–mediated transformation of hematopoietic stem cells (HSCs). Inhibition of the ABL kinase alone is not sufficient to eradicate leukemic stem cells (LSCs). We have previously shown that the deficiency of Rac2 GTPase signaling, but not Rac1, in p210-BCR-ABL–transduced hematopoietic cells prolonged survival of mice with MPD. Here we demonstrate that absence of Rac2 GTPase prolongs survival of HSC-initiated, inducible Scl/p210-BCR-ABL (Scl/p210) binary transgenic mice, it induces apoptosis, and, unlike in normal HSC and progenitor (HSC/P), impairs LSC and progenitor (LSC/P) proliferation in vivo. As a result, Rac2 deficiency causes functional exhaustion of the LSC pool in vivo. This defect is not due to impaired interaction with the hematopoietic microenvironment as reflected by its unaltered adhesion, migration, and homing to recipient organs. In summary, Rac2 deficiency exhausts the LSC pool in vivo through impairment of oncogene-induced proliferation and survival signals.
Iron control of erythroid development by a novel aconitase-associated regulatory pathway
Authors: Bullock Grant C. , Delehanty Lorrie L. , Talbot Anne-Laure , Gonias Sara L. , Tong Wing-Hang , Rouault Tracey A. , Dewar Brian , Macdonald Jeffrey M. , Chruma Jason J. , Goldfarb Adam N. 
Published: April 2010

AbstractHuman red cell differentiation requires the action of erythropoietin on committed progenitor cells. In iron deficiency, committed erythroid progenitors lose responsiveness to erythropoietin, resulting in hypoplastic anemia. To address the basis for iron regulation of erythropoiesis, we established primary hematopoietic cultures with transferrin saturation levels that restricted erythropoiesis but permitted granulopoiesis and megakaryopoiesis. Experiments in this system identified as a critical regulatory element the aconitases, multifunctional iron-sulfur cluster proteins that metabolize citrate to isocitrate. Iron restriction suppressed mitochondrial and cytosolic aconitase activity in erythroid but not granulocytic or megakaryocytic progenitors. An active site aconitase inhibitor, fluorocitrate, blocked erythroid differentiation in a manner similar to iron deprivation. Exogenous isocitrate abrogated the erythroid iron restriction response in vitro and reversed anemia progression in iron-deprived mice. The mechanism for aconitase regulation of erythropoiesis most probably involves both production of metabolic intermediates and modulation of erythropoietin signaling. One relevant signaling pathway appeared to involve protein kinase Cα/β, or possibly protein kinase Cδ, whose activities were regulated by iron, isocitrate, and erythropoietin.
Netrin-4 induces lymphangiogenesis in vivo
Authors: Larrieu-Lahargue Frederic , Welm Alana L. , Thomas Kirk R. , Li Dean Y. 
Published: April 2010

Abstract
Netrin-4, a laminin-related secreted protein is an axon guidance cue recently shown essential outside of the nervous system, regulating mammary and lung morphogenesis as well as blood vascular development. Here, we show that Netrin-4, at physiologic doses, induces proliferation, migration, adhesion, tube formation and survival of human lymphatic endothelial cells in vitro comparable to well-characterized lymphangiogenic factors fibroblast growth factor-2 (FGF-2), hepatocyte growth factor (HGF), vascular endothelial growth factor-A (VEGF-A), and vascular endothelial growth factor-C (VEGF-C). Netrin-4 stimulates phosphorylation of intracellular signaling components Akt, Erk and S6, and their specific inhibition antagonizes Netrin-4–induced proliferation. Although Netrin receptors Unc5B and neogenin, are expressed by human lymphatic endothelial cells, suppression of either or both does not suppress Netrin-4–promoted in vitro effects. In vivo, Netrin-4 induces growth of lymphatic and blood vessels in the skin of transgenic mice and in breast tumors. Its overexpression in human and mouse mammary carcinoma cancer cells leads to enhanced metastasis. Finally, Netrin-4 stimulates in vitro and in vivo lymphatic permeability by activating small GTPases and Src family kinases/FAK, and down-regulating tight junction proteins. Together, these data provide evidence that Netrin-4 is a lymphangiogenic factor contributing to tumor dissemination and represents a potential target to inhibit metastasis formation.
Pegylated arginase I: a potential therapeutic approach in T-ALL
Authors: Hernandez Claudia P. , Morrow Kevin , Lopez-Barcons Lluis A. , Zabaleta Jovanny , Sierra Rosa , Velasco Cruz , Cole John , Rodriguez Paulo C. 
Published: April 2010

Abstract
Adult patients with acute lymphoblastic T cell leukemia (T-ALL) have a very poor prognosis and few effective therapeutic options. Therefore, novel therapies that increase the efficacy of the treatments and that prolong T-ALL patient survival are needed. Malignant T cells require high concentrations of nutrients to sustain their increased rate of proliferation. In this study, we determined whether L-Arginine depletion by the pegylated form of the L-Arginine-metabolizing enzyme arginase I (peg-Arg I) impairs the proliferation of malignant T cells. Our results show that peg-Arg I depleted L-Arginine levels in vitro and in vivo. In addition, treatment of malignant T-cell lines with peg-Arg I significantly impaired their proliferation, which correlated with a decreased progression into the cell cycle, followed by the induction of apoptosis. Furthermore, peg-Arg I impaired the expression of cyclin D3, a fundamental protein in T-ALL proliferation, through a global arrest in protein synthesis. Injection of peg-Arg I plus chemotherapy agent Cytarabine prolonged survival in mice bearing T-ALL tumors. This antitumoral effect correlated with an inhibition of T-ALL proliferation in vivo, a decreased expression of cyclin D3, and T-ALL apoptosis. The results suggest the potential benefit of L-Arginine depletion by peg-Arg I in the treatment of T-cell malignancies.
Anxiety- and depressive-like responses and c-fos activity in preproenkephalin knockout mice: Oversensitivity hypothesis of enkephalin deficit-induced posttraumatic stress disorder
Authors: Kung Jen-Chuang , Chen Tsung-Chieh , Shyu Bai-Chuang , Hsiao Sigmund , Huang Andrew Chih Wei 
Published: April 2010

AbstractThe present study used the preproenkephalin knockout (ppENK) mice to test whether the endogenous enkephalins deficit could facilitate the anxiety- and depressive-like symptoms of posttraumatic stress disorder (PTSD). On Day 1, sixteen wildtype (WT) and sixteen ppENK male mice were given a 3 mA or no footshock treatment for 10 seconds in the footshock apparatus, respectively. On Days 2, 7, and 13, all mice were given situational reminders for 1 min per trial, and the freezing response was assessed. On Day 14, all mice were tested in the open field test, elevated plus maze, light/dark avoidance test, and forced swim test. Two hours after the last test, brain tissues were stained to examine c-fosexpression in specific brain areas. The present results showed that the conditioned freezing response was significant for different genotypes (ppENK vs WT). The conditioned freezing effect of the ppENK mice was stronger than those of the WT mice. On Day 14, the ppENK mice showed more anxiety- and depressive-like responses than WT mice. The magnitude of Fos immunolabeling was also significantly greater in the primary motor cortex, bed nucleus of the stria terminalis-lateral division, bed nucleus of the stria terminalis-supracapsular division, paraventricular hypothalamic nucleus-lateral magnocellular part, central nucleus of the amygdala, and basolateral nucleus of the amygdala in ppENK mice compared with WT mice. In summary, animals with an endogenous deficit in enkephalins might be more sensitive to PTSD-like aversive stimuli and elicit stronger anxiety and depressive PTSD symptoms, suggesting an oversensitivity hypothesis of enkephalin deficit-induced PTSD.
SNP-RFLPing 2: an updated and integrated PCR-RFLP tool for SNP genotyping
Authors: Chang Hsueh-Wei , Cheng Yu-Huei , Chuang Li-Yeh , Yang Cheng-Hong 
Published: April 2010

Abstract

Background
PCR-restriction fragment length polymorphism (RFLP) assay is a cost-effective method for SNP genotyping and mutation detection, but the manual mining for restriction enzyme sites is challenging and cumbersome. Three years after we constructed SNP-RFLPing, a freely accessible database and analysis tool for restriction enzyme mining of SNPs, significant improvements over the 2006 version have been made and incorporated into the latest version, SNP-RFLPing 2.

Results
The primary aim of SNP-RFLPing 2 is to provide comprehensive PCR-RFLP information with multiple functionality about SNPs, such as SNP retrieval to multiple species, different polymorphism types (bi-allelic, tri-allelic, tetra-allelic or indels), gene-centric searching, HapMap tagSNPs, gene ontology-based searching, miRNAs, and SNP500Cancer. The RFLP restriction enzymes and the corresponding PCR primers for the natural and mutagenic types of each SNP are simultaneously analyzed. All the RFLP restriction enzyme prices are also provided to aid selection. Furthermore, the previously encountered updating problems for most SNP related databases are resolved by an on-line retrieval system.

Conclusions
The user interfaces for functional SNP analyses have been substantially improved and integrated. SNP-RFLPing 2 offers a new and user-friendly interface for RFLP genotyping that can be used in association studies and is freely available at http://bio.kuas.edu.tw/snp-rflping2.
Genome-wide comparison between IL-17 and combined TNF-alpha/IL-17 induced genes in primary murine hepatocytes
Authors: Sparna Titus , Rétey Julia , Schmich Kathrin , Albrecht Ute , Naumann Katrin , Gretz Norbert , Fischer Hans-Peter , Bode Johannes G , Merfort Irmgard 
Published: April 2010

Abstract

Background
Cytokines such as TNF-alpha and IL-1beta are known for their contribution to inflammatory processes in liver. In contrast, the cytokine IL-17 has not yet been assigned a role in liver diseases. IL-17 can cooperate with TNF-alpha to induce a synergistic response on several target genes in different cell lines, but no data exist for primary hepatocytes. To enhance our knowledge on the impact of IL-17 alone and combined with TNF-alpha in primary murine hepatocytes a comprehensive microarray study was designed. IL-1beta was included as this cytokine is suggested to act in a similar manner as the combination of TNF-alpha and IL-17, especially with respect to its role in mRNA stabilization.

Results
The present microarray analysis demonstrates that primary murine hepatocytes responded to IL-17 stimulation by upregulation of chemokines and genes, which are functionally responsible to increase and sustain inflammation. Cxcl2, Nfkbiz and Zc3h12a were strongly induced, whereas the majority of the genes were only very moderately up-regulated. Promoter analysis revealed involvement of NF-kappaB in the activation of many genes. Combined stimulation of TNF-alpha/IL-17 resulted in enhanced induction of gene expression, but significantly synergistic effects could be applied only to a few genes, such as Nfkbiz, Cxcl2, Zc3h12 and Steap4. Comparison of the gene expression profile obtained after stimulation of TNF-alpha/IL-17 versus IL-1beta proposed an "IL-1beta-like effect" of the latter cytokine combination. Moreover, evidence was provided that modulation of mRNA stability may be a major mechanism by which IL-17 regulates gene expression in primary hepatocytes. This assumption was exemplarily proven for Nfkbiz mRNA for the first time in hepatocytes. Our studies also suggest that RNA stability can partially be correlated to the existence of AU rich elements, but further mechanisms like the RNase activity of the up-regulated Zc3h12a have to be considered.

Conclusions
Our microarray analysis gives new insights in IL-17 induced gene expression in primary hepatocytes highlighting the crosstalk with the NF-kappaB signaling pathway. Gene expression profile suggests IL-17 alone and in concert with TNF-alpha a role in sustaining liver inflammatory processes. IL-17 might exceed this function by RNA stabilization.