bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endoplasmic Reticulum Stress Signal Mediators Are Targets of Selenium Action
Authors: Wu Yue , Zhang Haitao , Dong Yan , Park Young-Mee , Ip Clement 
Published: October 2005

AbstractA monomethylated selenium metabolite, called methylseleninic acid (MSA), has recently been shown to cause global thiol redox modification of proteins. These changes represent a form of cellular stress due to protein misfolding or unfolding. An accumulation of aberrantly folded proteins in the endoplasmic reticulum (ER) triggers a defined set of transducers to correct the defects or commit the cells to apoptosis if the rescue effort is exhausted. Treatment of PC-3 human prostate cancer cells with MSA was found to induce a number of signature ER stress markers: (a) the survival/rescue molecules such as phosphorylated protein kinase–like ER-resident kinase (phospho-PERK), phosphorylated eukaryotic initiation factor-2α (phospho-eIF2α), glucose-regulated protein (GRP)-78, and GRP94; and (b) the apoptotic molecules such as caspase-12, caspase-7, and CAAT/enhancer binding protein homologous protein or growth arrest DNA damage-inducible gene 153 (CHOP/GADD153). Additional evidence suggested that CHOP/GADD153 might be an important transcription factor in apoptosis induction by MSA. In general, a higher concentration of MSA was required to elicit the apoptotic markers compared with the rescue markers. The apoptotic markers increased proportionally with the dose of MSA, whereas the rescue markers failed to keep pace with the increasing challenge from MSA. GRP78 is the rheostat of the ER stress transducers. In GRP78-overexpressing cells, the ability of MSA to up-regulate phospho-PERK, phospho-eIF2α, GRP94, caspase-12, caspase-7, and CHOP/GADD153 was significantly muted. A generous supply of GRP78 would allow cells to cope better with ER stress, thereby improving the odds for survival and negating the commitment to apoptotic death. The present study thus provides strong evidence to support an important role of ER stress response in mediating the anticancer effect of selenium.
A Community-Based Program to Encourage Patients’ Attention to Their Own Diabetes Care
Authors: Polonsky William H. , Zee Julia , Yee Martha Ah , Crosson Mary Ann , Jackson Richard A. 
Published: October 2005

Purpose The authors evaluated the ability of a brief educational program to enhance patients’ self-care behavior and their familiarity with the meaning and utility of 5 of the major clinical tests in diabetes (A1C, blood pressure, low-density lipoprotein [LDL] cholesterol, microalbumin, and the dilated eye examination). Methods Adults with type 1 or type 2 diabetes were invited to attend a free, 90-minute, small-group workshop about diabetes care, which included on-site metabolic testing that provided patients with immediate results and personalized feedback to understand those results. In total, 221 individuals with diabetes participated and completed baseline and 3-month follow-up questionnaires. Results From baseline to 3 months, participants reported significant improvement in following recommendations for meal planning (P < .001), regular exercise (P < .002), and blood glucose monitoring (P < .05) and a significant rise in test awareness for A1C, blood pressure, LDL cholesterol, and microalbumin (in all cases, P < .001). Conclusions A brief educational intervention appeared effective in encouraging patients toward better self-management and more regular metabolic testing and to become more aware of their own test results. Future research should aim to replicate and extend these findings in a randomized controlled trial.
Functional analysis of HGF/MET signaling and aberrant HGF-activator expression in diffuse large B-cell lymphoma
Authors: Tjin Esther P. M. , Groen Richard W. J. , Vogelzang Irma , Derksen Patrick W. B. , Klok Melanie D. , Meijer Helen P. , van Eeden Susanne , Pals Steven T. , Spaargaren Marcel 
Published: September 2005

AbstractInappropriate activation of MET, the receptor tyrosine kinase for hepatocyte growth factor (HGF), has been implicated in tumorigenesis. Although we have previously shown that HGF/MET signaling controls survival and proliferation of multiple myeloma (MM), its role in the pathogenesis of other B-cell malignancies has remained largely unexplored. Here, we have examined a panel of 110 B-cell malignancies for MET expression, which, apart from MM (48%), was found to be largely confined to diffuse large B-cell lymphomas (DLBCLs) (30%). No amplification of the MET gene was found; however, mutational analysis revealed 2 germ-line missense mutations: R1166Q in the tyrosine kinase domain in 1 patient, and R988C in the juxtamembrane domain in 4 patients. The R988C mutation has recently been shown to enhance tumorigenesis. In MET-positive DLBCL cells, HGF induces MEK-dependent activation of ERK and PI3K-dependent phosphorylation of PKB, GSK3, and FOXO3a. Furthermore, HGF induces PI3K-dependent α4β1 integrin-mediated adhesion to VCAM-1 and fibronectin. Within the tumor microenvironment of DLBCL, HGF is provided by macrophages, whereas DLBCL cells themselves produce the serine protease HGF activator (HGFA), which autocatalyzes HGF activation. Taken together, these data indicate that HGF/MET signaling, and secretion of HGFA by DLBCL cells, contributes to lymphomagenesis in DLBCL. (Blood. 2006;107:760-768)
Redundant roles of VEGF-B and PlGF during selective VEGF-A blockade in mice
Authors: Malik Ajay K. , Baldwin Megan E. , Peale Franklin , Fuh Germaine , Liang Wei-Ching , Lowman Henry , Meng Gloria , Ferrara Napoleone , Gerber Hans-Peter 
Published: September 2005

AbstractVascular endothelial growth factor-A (VEGF-A) and its 2 transmembrane tyrosine-kinase receptors, VEGFR-1 and VEGFR-2, constitute a ligand-receptor signaling system that is crucial for developmental angiogenesis. VEGF-B and placental growth factor (PlGF) activate VEGFR-1 selectively, however, mice lacking either ligand display only minor developmental defects. We hypothesized that the relative contributions of VEGF-B and PlGF to VEGFR-1 signaling may be masked in the presence of VEGF-A, which is abundantly expressed during postnatal development. To test this hypothesis, neonatal or adult mice were treated with a monoclonal antibody (G6-23-IgG) blocking murine VEGF-A or a soluble VEGFR-1 receptor IgG chimeric construct [mFlt(1-3)-IgG], which neutralizes VEGF-A, VEGF-B, and PlGF. Both compounds attenuated growth and survival of neonatal mice to similar extents and the pathophysiologic alterations, including a reduction in organ size and vascularization, changes in gene expression, and hematologic end points, were essentially indistinguishable. In adult mice, we observed only minor changes in response to treatment, which were similar between both anti-VEGF compounds. In conclusion, our findings suggest that PlGF and VEGF-B do not compensate during conditions of VEGF-A blockade, suggesting a minor role for compensatory VEGFR-1 signaling during postnatal development and vascular homeostasis in adults. The absence of compensatory VEGFR-1 signaling by VEGF-B and PlGF may have important implications for the development of anticancer strategies targeting the VEGF ligand/receptor system.
Deletion of the core region of 5′ HS2 of the mouse β-globin locus control region reveals a distinct effect in comparison with human β-globin transgenes
Authors: Hu Xiao , Bulger Michael , Bender M. A. , Fields Jennifer , Groudine Mark , Fiering Steven 
Published: September 2005

AbstractThe β-globin locus control region (LCR) is a large DNA element that is required for high-level expression of β-like globin genes from the endogenous mouse locus or in transgenic mice carrying the human β-globin locus. The LCR encompasses 6 DNaseI hypersensitive sites (HSs) that bind transcription factors. These HSs each contain a core of a few hundred base pairs (bp) that has most of the functional activity and exhibits high interspecies sequence homology. Adjoining the cores are 500- to 1000-bp “flanks” with weaker functional activity and lower interspecies homology. Studies of human β-globin transgenes and of the endogenous murine locus show that deletion of an entire HS (core plus flanks) moderately suppresses expression. However, human transgenes in which only individual HS core regions were deleted showed drastic loss of expression accompanied by changes in chromatin structure. To address these disparate results, we have deleted the core region of 5′HS2 from the endogenous murine β-LCR. The phenotype was similar to that of the larger 5′HS2 deletion, with no apparent disruption of chromatin structure. These results demonstrate that the greater severity of HS core deletions in comparison to full HS deletions is not a general property of the β-LCR. (Blood. 2006;107:821-826)
Inducible platelet-derived growth factor D-chain expression by angiotensin II and hydrogen peroxide involves transcriptional regulation by Ets-1 and Sp1
Authors: Liu Mary Yanxia , Eyries Melanie , Zhang Chunyan , Santiago Fernando S. , Khachigian Levon M. 
Published: September 2005

AbstractPlatelet-derived growth factor D-chain (PDGF-D) is the newest member of the PDGF family of mitogens and chemoattractants expressed in a wide variety of cell types, including vascular smooth muscle cells (SMCs). The molecular mechanisms regulating PDGF-D transcription are not known. Primer extension analysis mapped a single transcriptional start site to the ccAGCGC motif with several potential Ets motifs located upstream. Ets-1, but not Ets-1 bearing only the DNA-binding domain, activates the PDGF-D promoter and mRNA expression in SMCs. Ets site D3 (–470GGAT–467) is singly required for basal and Ets-1–inducible PDGF-D promoter-dependent expression. D3 supports the interaction of endogenous and recombinant Ets-1 and Sp1. Sp1, like Ets-1, induces PDGF-D transcription and mRNA expression, which is blocked by mutant Ets-1. H2O2 stimulates Ets-1, but not Sp1, and activates D3-dependent PDGF-D transcription. Ets-1 and Sp1 siRNA block peroxide-inducible PDGF-D expression. Angiotensin II (ATII) induction of PDGF-D and Ets-1 was blocked by prior incubation of the cells with PEG-catalase, but not BSA, indicating that ATII-inducible Ets-1 and PDGF-D expression is mediated via H2O2. Thus, 2 separate trans-acting factors regulate PDGF-D transcription, alone and in response to oxidative stress.
Elevated levels of homocysteine compromise blood-brain barrier integrity in mice
Authors: Kamath Atul F. , Chauhan Anil K. , Kisucka Janka , Dole Vandana S. , Loscalzo Joseph , Handy Diane E. , Wagner Denisa D. 
Published: September 2005

Abstract
Elevated levels of plasma homocysteine (Hcy) correlate with increased risk of cardiovascular and Alzheimer diseases. We studied the effect of elevated Hcy on the blood-brain barrier (BBB) to explore the possibility of a vascular link between the 2 diseases. On a hyperhomocysteinemic diet, cystathionine beta-synthase (Cbs)–heterozygous mice develop hyperhomocysteinemia. Intravital microscopy analysis of the mesenteric venules showed that leukocyte rolling velocity was markedly decreased and numbers of adherent cells were increased in the mutant mice. This was due at least in part to increased expression of P-selectin. BBB permeability was measured by Evans blue dye permeation and was found to be 25% greater in the Cbs+/– cortex compared with wild-type controls. Our study suggests an important toxic effect of elevated Hcy on brain microvessels and implicates Hcy in the disruption of the BBB.
Amphotericin B blunts erythropoietin response to hypoxia by reinforcing FIH-mediated repression of HIF-1
Authors: Yeo Eun-Jin , Ryu Ji-Hye , Cho Young-Suk , Chun Yang-Sook , Huang L. Eric , Kim Myung-Suk , Park Jong-Wan 
Published: September 2005

AbstractAmphotericin B (AmB) is widely used for treating severe systemic fungal infections. However, long-term AmB treatment is invariably associated with adverse effects such as anemia. The erythropoietin (EPO) suppression by AmB has been proposed to contribute to the development of anemia. However, the mechanism whereby EPO is suppressed remains obscure. In this study, we investigated the possibility that AmB inhibits the transcription of the EPO gene by inactivating HIF-1, which is a known key transcription factor and regulator of EPO expression. EPO mRNA levels were markedly attenuated by AmB treatment both in rat kidneys and in Hep3B cells. AmB inactivated the transcriptional activity of HIF-1α, but did not affect the expression or localization of HIF-1 subunits. Moreover, AmB was found to specifically repress the C-terminal transactivation domain (CAD) of HIF-1α, and this repression by AmB required Asn803, a target site of the factor-inhibiting HIF-1 (FIH); moreover, this repressive effect was reversed by FIH inhibitors. Furthermore, AmB stimulated CAD-FIH interaction and inhibited the p300 recruitment by CAD. We propose that this mechanism underlies the unexplained anemia associated with AmB therapy.
PKC412 inhibits in vitro growth of neoplastic human mast cells expressing the D816V-mutated variant of KIT: comparison with AMN107, imatinib, and cladribine (2CdA) and evaluation of cooperative drug effects
Authors: Gleixner Karoline V. , Mayerhofer Matthias , Aichberger Karl J. , Derdak Sophia , Sonneck Karoline , Böhm Alexandra , Gruze Alexander , Samorapoompichit Puchit , Manley Paul W. , Fabbro Doriano , Pickl Winfried F. , Sillaber Christian , Valent Peter 
Published: September 2005

AbstractIn most patients with systemic mastocytosis (SM), including aggressive SM and mast cell leukemia (MCL), neoplastic cells express the oncogenic KIT mutation D816V. KIT D816V is associated with constitutive tyrosine kinase (TK) activity and thus represents an attractive drug target. However, imatinib and most other TK inhibitors fail to block the TK activity of KIT D816V. We show that the novel TK-targeting drugs PKC412 and AMN107 counteract TK activity of D816V KIT and inhibit the growth of Ba/F3 cells with doxycycline-inducible expression of KIT D816V as well as the growth of primary neoplastic mast cells and HMC-1 cells harboring this KIT mutation. PKC412 was a superior agent with median inhibitory concentration (IC50) values of 50 to 250 nM without differences seen between HMC-1 cells exhibiting or lacking KIT D816V. By contrast, AMN107 exhibited more potent effects in KIT D816V- HMC-1 cells. Corresponding results were obtained with Ba/F3 cells exhibiting wild-type or D816V-mutated KIT. The growth-inhibitory effects of PKC412 and AMN107 on HMC-1 cells were associated with induction of apoptosis and down-regulation of CD2 and CD63. PKC412 was found to cooperate with AMN107, imatinib, and cladribine (2CdA) in producing growth inhibition in HMC-1, but synergistic drug interactions were observed only in cells lacking KIT D816V. Together, PKC412 and AMN107 represent promising novel agents for targeted therapy of SM. (Blood. 2006;107: 752-759)
Methodological modifications on quantification of phosphatidylethanol in blood from humans abusing alcohol, using high-performance liquid chromatography and evaporative light scattering detection
Authors: Aradottir Steina , Olsson Bo L 
Published: September 2005

Abstract

Background
Phosphatidylethanol (PEth) is an abnormal phospholipid formed slowly in cell membranes by a transphosphatidylation reaction from phosphatidylcholine in the presence of ethanol and catalyzed by the enzyme phospholipase D. PEth in blood is a promising new marker of ethanol abuse depending on the high specificity and sensitivity of this marker. None of the biological markers used in clinical routine at the present time are sensitive and specific enough for the diagnosis of alcohol abuse.
The method for PEth analysis includes lipid extraction of whole blood, a one-hour HPLC separation of lipids and ELSD (evaporative light scattering) detection of PEth.

Results
Methodological improvements are presented which comprise a simpler extraction procedure, the use of phosphatidylbutanol as internal standard and a new algorithm for evaluation of unknown samples. It is further demonstrated that equal test results are obtained with blood collected in standard test tubes with EDTA as with the previously used heparinized test tubes. The PEth content in blood samples is stable for three weeks in the refrigerator.

Conclusion
Methodological changes make the method more suitable for routine laboratory use, lower the limit of quantification (LOQ) and improve precision.
An analysis of extensible modelling for functional genomics data
Authors: Jones Andrew R , Paton Norman W 
Published: September 2005

Abstract
Background
Several data formats have been developed for large scale biological experiments, using a variety of methodologies. Most data formats contain a for allowing extensions to encode unanticipated data types. Extensions to data formats are important because the experimental methodologies tend to be fairly diverse and rapidly evolving, which hinders the creation of formats that will be stable over time.

Results
In this paper we review the data formats that exist in functional genomics, some of which have become de facto or de jure standards, with a particular focus on how each domain has been modelled, and how each format allows extensions. We describe the tasks that are frequently performed over data formats and analyse how well each task is supported by a particular modelling structure.

Conclusion
From our analysis, we make recommendations as to the types of modelling structure that are most suitable for particular types of experimental annotation. There are several standards currently under development that we believe could benefit from systematically following a set of guidelines.
SIMPROT: Using an empirically determined indel distribution in simulations of protein evolution
Authors: Pang Andy , Smith Andrew D , Nuin Paulo AS , Tillier Elisabeth RM 
Published: September 2005

Abstract
Background
General protein evolution models help determine the baseline expectations for the evolution of sequences, and they have been extensively useful in sequence analysis and for the computer simulation of artificial sequence data sets.

Results
We have developed a new method of simulating protein sequence evolution, including insertion and deletion (indel) events in addition to amino-acid substitutions. The simulation generates both the simulated sequence family and a true sequence alignment that captures the evolutionary relationships between amino acids from different sequences. Our statistical model for indel evolution is based on the empirical indel distribution determined by Qian and Goldstein. We have parameterized this distribution so that it applies to sequences diverged by varying evolutionary times and generalized it to provide flexibility in simulation conditions. Our method uses a Monte-Carlo simulation strategy, and has been implemented in a C++ program named Simprot.

Conclusion
Simprot will be useful for testing methods of analysis of protein sequence families particularly alignment methods, phylogenetic tree building, detection of recombination and horizontal gene transfer, and homology detection, where knowing the true course of sequence evolution is essential.
RLIP76, a non-ABC transporter, and drug resistance in epilepsy
Authors: Awasthi Sanjay , Hallene Kerri L , Fazio Vince , Singhal Sharad S , Cucullo Luca , Awasthi Yogesh C , Dini Gabriele , Janigro Damir 
Published: September 2005

AbstractBackgroundPermeability of the blood-brain barrier is one of the factors determining the bioavailability of therapeutic drugs and resistance to chemically different antiepileptic drugs is a consequence of decreased intracerebral accumulation. The ABC transporters, particularly P-glycoprotein, are known to play a role in antiepileptic drug extrusion, but are not by themselves sufficient to fully explain the phenomenon of drug-resistant epilepsy. Proteomic analyses of membrane protein differentially expressed in epileptic foci brain tissue revealed the frequently increased expression of RLIP76/RALBP1, a recently described non-ABC multi-specific transporter. Because of a significant overlap in substrates between P-glycoprotein and RLIP76, present studies were carried out to determine the potential role of RLIP76 in AED transport in the brain.ResultsRLIP76 was expressed in brain tissue, preferentially in the lumenal surface of endothelial cell membranes. The expression was most prominent in blood brain barrier tissue from excised epileptic foci. Saturable, energy-dependent, anti-gradient transport of both phenytoin and carbamazepine were demonstrated using recombinant RLIP76 reconstituted into artificial membrane liposomes. Immunotitration studies of transport activity in crude membrane vesicles prepared from whole-brain tissue endothelium showed that RLIP76 represented the dominant transport mechanism for both drugs. RLIP76-/-knockout mice exhibited dramatic toxicity upon phenytoin administration due to decreased drug extrusion mechanisms at the blood-brain barrier.ConclusionWe conclude that RLIP76 is the predominant transporter of AED in the blood brain barrier, and that it may be a transporter involved in mechanisms of drug-resistant epilepsy.
JTT-130, a microsomal triglyceride transfer protein (MTP) inhibitor lowers plasma triglycerides and LDL cholesterol concentrations without increasing hepatic triglycerides in guinea pigs
Authors: Aggarwal Dimple , West Kristy L , Zern Tosca L , Shrestha Sudeep , Vergara-Jimenez Marcela , Fernandez Maria Luz 
Published: September 2005

Abstract

Background
Microsomal transfer protein inhibitors (MTPi) have the potential to be used as a drug to lower plasma lipids, mainly plasma triglycerides (TG). However, studies with animal models have indicated that MTPi treatment results in the accumulation of hepatic TG. The purpose of this study was to evaluate whether JTT-130, a unique MTPi, targeted to the intestine, would effectively reduce plasma lipids without inducing a fatty liver.

Methods
Male guinea pigs (n = 10 per group) were used for this experiment. Initially all guinea pigs were fed a hypercholesterolemic diet containing 0.08 g/100 g dietary cholesterol for 3 wk. After this period, animals were randomly assigned to diets containing 0 (control), 0.0005 or 0.0015 g/100 g of MTPi for 4 wk. A diet containing 0.05 g/100 g of atorvastatin, an HMG-CoA reductase inhibitor was used as the positive control. At the end of the 7th week, guinea pigs were sacrificed to assess drug effects on plasma and hepatic lipids, composition of LDL and VLDL, hepatic cholesterol and lipoprotein metabolism.

Results
Plasma LDL cholesterol and TG were 25 and 30% lower in guinea pigs treated with MTPi compared to controls (P < 0.05). Atorvastatin had the most pronounced hypolipidemic effects with a 35% reduction in LDL cholesterol and 40% reduction in TG. JTT-130 did not induce hepatic lipid accumulation compared to controls. Cholesteryl ester transfer protein (CETP) activity was reduced in a dose dependent manner by increasing doses of MTPi and guinea pigs treated with atorvastatin had the lowest CETP activity (P < 0.01). In addition the number of molecules of cholesteryl ester in LDL and LDL diameter were lower in guinea pigs treated with atorvastatin. In contrast, hepatic enzymes involved in maintaining cholesterol homeostasis were not affected by drug treatment.

Conclusion
These results suggest that JTT-130 could have potential clinical applications due to its plasma lipid lowering effects with no alterations in hepatic lipid concentrations.