bluuebunny/crossref_metadata_2025_split huggingface dataset:
Copper deprivation in rats induces islet hyperplasia and hepatic metaplasia in the pancreas
Authors: Tosh David , Shen Chia‐Ning , Alison Malcolm R. , Sarraf Catherine E. , Slack Jonathan M.W. 
Published: December 2006

Background information. Prolonged copper deprivation in rats followed by refeeding with a normal diet has previously been used to induce the appearance of hepatocyte‐like cells in the pancreas, but the effects on islet size and morphology have not been determined.Results. In the present study we investigated the distribution of pancreatic α‐ and β‐cells and of hepatocytes in adult rats fed a copper‐deficient diet followed by refeeding with a normal diet. Immunohistochemical staining for insulin and glucagon showed that the islets of the copper‐deficient group were up to 2.4 times larger in mass compared with controls. The islets were disorganized, with α‐cells found in multiple layers at the periphery of the islet and sometimes deep in the core. Isolated α‐ and β‐cells were also found in increased numbers in the ductular system. Copper deprivation caused almost complete ablation of the acinar cells, and refeeding induced adipogenesis, acinar regeneration and hepatocyte‐like cells. Ductular proliferation and nerve hyperplasia were also present. The hepatocytes tended to be associated with islets or with ducts, rather than with residual pancreatic exocrine tissue.Conclusions. These data show that copper deficiency in rats, as well as inducing the appearance of hepatocytes, is capable of causing islet hyperplasia.
Skin conductance or entropy for detection of non‐noxious stimulation during different clinical levels of sedation
Authors: Gjerstad A. C. , Storm H. , Hagen R. , Huiku M. , Qvigstad E. , Ræder J. 
Published: December 2006

Background:  State entropy (SE) measures electroencephalographic signals, whereas response entropy (RE) also includes frontal electromyographic activity. In the presence of electromyographic activity, the RE index is larger than the SE index, the difference being denoted as RE‐Δ (RE‐Δ= RE – SE). Skin conductance (SC) may be expressed by a slow reacting variable, the mean SC level, the derivate of the mean SC level (D‐SC), the number of SC fluctuations (NSCF) or the amplitude of the SC fluctuations (ASCF), which directly shows skin sympathetic nerve activity. The goal of this study was to evaluate whether these SC and entropy variables could differentiate between the responses obtained to load sound stimuli at different sedation levels before the induction of general anaesthesia.Methods:  Twenty women scheduled for gynaecological laparotomy were studied. The modified observer’s assessment of alertness sedation (OAAS) was used to classify the patients’ hypnotic levels. White sounds (98 dB) were given at OAAS level 5 without propofol, at OAAS levels 4–3 and 3–2 with propofol and at OAAS levels 3–2 and < 2 with propofol and remifentanil.Results:  RE and SE showed a steady decline from OAAS level 5 to level < 2 (P < 0.01). RE‐Δ did not discriminate between any of the OAAS levels (P= NS). The mean SC level discriminated between OAAS levels 4–3 to < 2 (P < 0.01). D‐SC discriminated between all the different OAAS levels (P < 0.01). NSCF discriminated between OAAS levels 5 to 3–2 (P < 0.05), but did not discriminate at OAAS level 3–2 between propofol alone or combined with remifentanil, or between OAAS level 3–2 and < 2. ASCF differentiated between OAAS levels 5 and 4 (P < 0.001) and OAAS levels 3–2 and < 2 (P < 0.05) only.Conclusion:  RE, SE and D‐SC showed a similar discrimination between sound responses at the different sedation levels.
HIV‐1 neuropathogenesis: glial mechanisms revealed through substance abuse
Authors: Hauser Kurt F. , El‐Hage Nazira , Stiene‐Martin Anne , Maragos William F. , Nath Avindra , Persidsky Yuri , Volsky David J. , Knapp Pamela E. 
Published: December 2006

AbstractNeuronal dysfunction and degeneration are ultimately responsible for the neurocognitive impairment and dementia manifest in neuroAIDS. Despite overt neuronal pathology, HIV‐1 does not directly infect neurons; rather, neuronal dysfunction or death is largely an indirect consequence of disrupted glial function and the cellular and viral toxins released by infected glia. A role for glia in HIV‐1 neuropathogenesis is revealed in experimental and clinical studies examining substance abuse–HIV‐1 interactions. Current evidence suggests that glia are direct targets of substance abuse and that glia contribute markedly to the accelerated neurodegeneration seen with substance abuse in HIV‐1 infected individuals. Moreover, maladaptive neuroplastic responses to chronic drug abuse might create a latent susceptibility to CNS disorders such as HIV‐1. In this review, we consider astroglial and microglial interactions and dysfunction in the pathogenesis of HIV‐1 infection and examine how drug actions in glia contribute to neuroAIDS.
Molecular cloning of prostaglandin EP3 receptors from canine sensory ganglia and their facilitatory action on bradykinin‐induced mobilization of intracellular calcium
Authors: Kozaki Yasuko , Kambe Fukushi , Hayashi Yoshitaka , Ohmori Sachiko , Seo Hisao , Kumazawa Takao , Mizumura Kazue 
Published: December 2006

AbstractWe previously demonstrated that the activation of prostaglandin E‐prostanoid‐3 (EP3) receptor sensitized the canine nociceptor response to bradykinin (BK). To elucidate the molecular mechanism for this sensitization, we cloned two cDNAs encoding EP3s with different C‐terminals, from canine dorsal root ganglia, and established the transformed cell lines stably expressing them. In both transformants, EP3 agonist did not increase intracellular cAMP levels, but it attenuated forskolin‐dependent cAMP accumulation in a pertussis toxin (PTX)‐sensitive manner and increased intracellular calcium levels in a PTX‐resistant manner, indicating that both EP3s can couple with Gi and Gq, but not with Gs proteins. As the nociceptor response to BK is mediated by BK B2 receptor, it was transfected into the transformants and the effects of EP3 agonist on BK‐dependent calcium mobilization were investigated. When BK was applied twice with a 6‐min interval, the second response was markedly attenuated. Pre‐treatment with EP3 agonist had no effect on the initial response, but restored the second response in a PTX‐sensitive manner. A protein kinase A inhibitor mimicked the effect of EP3 agonist. These results demonstrate that the activation of EP3 restores the response to BK by attenuating the desensitization of BK B2 receptor activity via Gi protein.
HIV‐1 gp120 as Well as Alcohol Affect Blood–Brain Barrier Permeability and Stress Fiber Formation: Involvement of Reactive Oxygen Species
Authors: Shiu Carlum , Barbier Elisabeth , Cello Francescopaolo Di , Choi Hee Jung , Stins Monique 
Published: December 2006

Background: HIV‐1 infection commonly leads to serious HIV‐1–associated neurological disorders, such as HIV‐1–associated encephalopathy and dementia. In addition, alcohol is commonly used and/or abused among AIDS patients, but it is unclear whether alcohol affects the disease progression and if it affects it, how this occurs. We hypothesized that alcohol could affect the blood–brain barrier (BBB) integrity and thus could affect the onset and/or progression of HIV‐associated neurological disorders.Methods: Human brain microvascular endothelial cells (HBMEC) in a BBB model system were pretreated with alcohol (17 and 68 mM) and subsequently coexposed with HIV‐1 gp120. Expression of chemokine receptors CCR3, CCR5, and CXCR4 was assessed by enzyme‐linked immunosorbent assay and real‐time polymerase chain reaction. Changes in the permeability of the HBMEC monolayer were assessed using paracellular markers [3H]inulin or propidium iodide. Actin rearrangements in HBMEC were visualized by fluorescence microscopy and viability assessed using Live/Dead™ stain.Results: Both gp120 and alcohol increased the permeability of the BBB model by up to 141%, without affecting HBMEC viability. Cotreatment with alcohol and gp120 did not result in a significant synergistic effect. Gp120 permeability involved chemokine receptor CCR5. Alcohol did not affect chemokine receptor expression on brain endothelial cells. Both gp120 and alcohol reorganized the cytoskeleton and induced stress fiber formation. Inhibition of reactive oxygen species (ROS) formation through NADPH blocked the effects of both gp120 and alcohol on permeability and stress fiber formation.Conclusion: These results indicate that both HIV‐1 gp120 and alcohol induce stress fibers, causing increased permeability of the human BBB endothelium. Alcohol (68 mM)‐mediated permeability increase was linked to ROS formation. The alcohol‐mediated physiological changes in the HBMEC monolayers may increase diffusion of plasma components and viral penetration across the BBB. This suggests that alcohol, especially at levels attained in heavy drinkers, can potentially contribute in a negative fashion to HIV‐1 neuropathogenesis.
Beneficial Effect of Prolyl Oligopeptidase Inhibition on Spatial Memory in Young but Not in Old Scopolamine‐Treated Rats
Authors: Jalkanen Aaro J. , Puttonen Katja A. , Venäläinen Jarkko I. , Sinervä Veijo , Mannila Anne , Ruotsalainen Sirja , Jarho Elina M. , Wallén Erik A. A. , Männistö Pekka T. 
Published: December 2006

Abstract:  The effects of a novel prolyl oligopeptidase (POP) inhibitor KYP‐2047 on spatial memory of young (3‐month‐old) and old (8‐ to 9‐month‐old) scopolamine‐treated rats (0.4 mg/kg intraperitoneally) was investigated in the Morris water maze. In addition, the concentrations of promnesic neuropeptide substrates of POP, substance P and neurotensin in various brain areas after acute and chronic POP inhibition were measured in young rats. In addition, inositol‐1,4,5‐trisphosphate (IP3) levels were assayed in rat cortex and hippocampus after effective 2.5‐day POP inhibition. KYP‐2047 (1 or 5 mg/kg 30 min. before daily testing) dose‐dependently improved the escape performance (i.e. latency to find the hidden platform and swimming path length) of the young but not the old rats in the water maze. POP inhibition had no consistent effect on substance P levels in cortex, hippocampus or hypothalamus, and only a modest increase in neurotensin concentration was observed in the hypothalamus after a single dose of KYP‐2047. Moreover, IP3 concentrations remained unaffected in cortex and hippocampus after POP inhibition. In conclusion, the behavioural data support the earlier findings of the promnesic action of POP inhibitors, but the mechanism of the memory‐enhancing action remains unclear.
Our Common European Model of Agriculture
Authors: Korkeaoja Juha 
Published: December 2006

Our Common European Model of AgricultureFuture internal and external forces on European agriculture mean that the CAP may look very different after 2013. However large these changes, the CAP will need to retain its common principles based on the European Model of Agriculture (EMA). This became clear in an informal September meeting of EU agriculture ministers in Oulu, arranged by the Finnish Presidency. A strong CAP will be needed in the future but it will have to evolve to meet upcoming challenges. Work on the future CAP will need to start soon and the Oulu meeting may become known as the starting point for those discussions. The CAP will have to provide a reasonable environment for practicing agriculture for very different farmers in very diverse conditions, and facilitate the supply of a wide variety of goods and services to consumers and taxpayers as only truly multifunctional agriculture can. If the CAP can maintain these characteristics it has an important role to play in a future Europe. The meeting in Oulu was also an important milestone for a very special reason: for the first time, all ten New Member States took an active part in the EMA‐debate with full rights and responsibilities as part of the Union. Once again this underlines the central role of our common European Model of Agriculture.
The EU Budget and the CAP: An Agenda for the Review?
Authors: Ackrill Rob , Kay Adrian , Harvey David 
Published: December 2006

Counterpoint ‐ Ackrill and KayProfessor David Harvey's proposed agenda for CAP reform in EuroChoices 5(1) is, we believe, unrealistic. It pays insufficient attention to the politics of EU policy‐making and ignores the importance countries place on protecting their shares of EU spending. We recognise the incremental nature of CAP reform, but believe this can lead to significant cumulative effects. Our proposal builds on modulation to transfer more CAP spending from Pillar I to Pillar II. Farmers receiving the largest payments should have their payments cut through higher compulsory modulation rates. We also seek a reduction of EU spending on the CAP, with greater national contributions achieved through the established channel of co‐financing.Reply to Ackrill and Kay ‐ David HarveyAckrill and Kay (A&K) say my suggestions for national subscription, co‐financing and discretion for CAP Pillar 1 spending and associated elimination of the troublesome UK rebate risk a stalemate, and that the further reform will necessarily be incremental, rather than radical. In reply, I argue that some radical reform will eventually be necessary, so that it makes sense to think about the required directions now. I also argue that my own suggestions are not so far from A&K's analysis as they seem to suppose. My suggestions seem little more likely to generate a stalemate than A&K's incremental change forecasts.
Discovery and development of anticancer aptamers
Authors: Ireson Christopher R. , Kelland Lloyd R. 
Published: December 2006

Abstract
Aptamers, also termed as decoys or “chemical antibodies,” represent an emerging class of therapeutics. They are short DNA or RNA oligonucleotides or peptides that assume a specific and stable three-dimensional shape in vivo, thereby providing specific tight binding to protein targets. In some cases and as opposed to antisense oligonucleotides, effects can be mediated against extracellular targets, thereby preventing a need for intracellular transportation. The first aptamer approved for use in man is a RNA-based molecule (Macugen, pegaptanib) that is administered locally (intravitreally) to treat age-related macular degeneration by targeting vascular endothelial growth factor. The most advanced aptamer in the cancer setting is AS1411, formerly known as AGRO100, which is being administered systemically in clinical trials. AS1411 is a 26-mer unmodified guanosine-rich oligonucleotide, which induces growth inhibition in vitro, and has shown activity against human tumor xenografts in vivo. The mechanism underlying its antiproliferative effects in cancer cells seems to involve initial binding to cell surface nucleolin and internalization, leading to an inhibition of DNA replication. In contrast to other unmodified oligonucleotides, AS1411 is relatively stable in serum-containing medium, probably as a result of the formation of dimers and a quartet structure. In a dose escalation phase I study in patients with advanced solid tumors, doses up to 10 mg/kg/d (using a four or seven continuous infusion regime) have been studied. Promising signs of activity have been reported (multiple cases of stable disease and one near complete response in a patient with renal cancer) in the absence of any significant adverse effects. Further trials are ongoing in renal and non–small cell lung cancers. In preclinical studies, additional aptamers have been described against several cancer targets, such as tenascin-C, the transcription factor signal transducer and activator of transcription 3, and antiapoptotic and Ku proteins. [Mol Cancer Ther 2006;5(12):2957–62]
Growth inhibition and induction of apoptosis in acute myeloid leukemia cells by new indolinone derivatives targeting fibroblast growth factor, platelet-derived growth factor, and vascular endothelial growth factor receptors
Authors: Kulimova Emma , Oelmann Elisabeth , Bisping Guido , Kienast Joachim , Mesters Rolf M. , Schwäble Joachim , Hilberg Frank , Roth Gerald J. , Munzert Gerd , Stefanic Martin , Steffen Björn , Brandts Christian , Müller-Tidow Carsten , Kolkmeyer Astrid , Büchner Thomas , Serve Hubert , Berdel Wolfgang E. 
Published: December 2006

Abstract
In acute myeloid leukemia (AML), receptor tyrosine kinase ligands promote growth and survival and contribute to AML-associated marrow neoangiogenesis. We have tested simultaneous inhibition of vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor receptor signaling by novel indolinone derivatives using 14 myeloid, including 11 human leukemic, cell lines. Compounds inhibited colony formation of all cell lines in a dose-dependent fashion. Inhibitory concentrations for 50% of the colony formation/survival (IC50) for BIBF1000 were &lt;100 nmol/L for 3 of 11, ≤500 nmol/L for 6 of 11, and &lt;1,000 nmol/L for 10 of 11 leukemic cell lines, with one cell line being resistant in the dose range &lt;1,000 nmol/L. BIBF1120 was less effective with 4 of 11 leukemic cell lines being resistant within the dose range &lt;1,000 nmol/L. Testing of myeloid 32D cells transfected with empty vector, wild-type Flt3, or Flt3 carrying an internal tandem duplication mutation revealed higher resistance for the internal tandem duplication mutant. These effects of the compounds were associated with inhibition of tyrosine phosphorylation and the mitogen-activated protein kinase pathway. Furthermore, both compounds induced apoptosis in the sensitive cell lines. In Mono-Mac1 cells, the compounds had a direct proapoptotic effect that was increasing the proapoptotic effect of 1-β-d-arabinofuranosylcytosine. The data provide a rationale for clinical evaluation of these tyrosine kinase inhibitors in AML. [Mol Cancer Ther 2006;5(12):3105–12]
Glucocorticoid receptor transcriptional isoforms and resistance in multiple myeloma cells
Authors: Sánchez-Vega Beatriz , Krett Nancy , Rosen Steven T. , Gandhi Varsha 
Published: December 2006

AbstractAlthough glucocorticoids play an important role in the treatment of multiple myeloma, some patients do not respond or develop resistance. The glucocorticoid receptor (GR), a single gene, mediates the effects of glucocorticoids. Using a model system of a multiple myeloma cell line sensitive to glucocorticoids and its early and late resistant variants, we have analyzed mutations in the GR gene, detected the presence of different transcriptional isoforms, quantified their levels of expression, and identified the promoters that regulate their expression. Levels of GR transcripts were comparable with the expression of total GR protein. Development of resistance correlates with an overall reduction in GR mRNA levels. This decrease in GR levels is neither due to mutation of the gene nor due to methylation. GRα is the predominant isoform in the sensitive cell line decreasing in expression in the early resistant cells and virtually undetectable in late resistant cells. GR-P is expressed at equivalent levels in both sensitive and early resistant cells, whereas in the late resistant cells, GR-P is the predominant isoform. GR-A is only expressed in the early resistant cell line. GRβ is the least expressed isoform in all cell lines. Interestingly, the level of expression of exon 1-exon 2 RNA fragments remains similar in sensitive and resistant cell lines. Resistant cells became sensitive to glucocorticoids after GRα transfection. In conclusion, we show different patterns of expression of the GR isoforms and provide evidence that a decline in the expression of GRα may be associated with development of resistance. [Mol Cancer Ther 2006;5(12):3062–70]
Photodynamic therapy mediates the oxygen-independent activation of hypoxia-inducible factor 1α
Authors: Mitra Soumya , Cassar Scott E. , Niles David J. , Puskas John A. , Frelinger John G. , Foster Thomas H. 
Published: December 2006

Abstract
Photodynamic therapy (PDT) induces the expression of the hypoxia-inducible factor 1α (HIF-1α) subunit of the HIF-1 transcription factor and its target genes in vitro and in vivo. PDT also induces the expression of the enzyme cyclooxygenase-2 and its metabolite, prostaglandin E2 (PGE2). PGE2 and hypoxia act independently and synergistically to increase HIF-1α accumulation and nuclear translocation. To examine the expression of HIF-1 target genes in response to PDT-mediated oxidative stress and PGE2 under normoxic conditions, we established EMT6 cells transfected with a plasmid consisting of a hypoxia response element promoter and a downstream gene encoding for green fluorescent protein (GFP). To examine the temporal kinetics of HIF-1α nuclear translocation in response to PDT, we transfected a second line of EMT6 cells with a GFP-tagged HIF-1α fusion vector. Cell monolayers were incubated with 1 μg mL−1 Photofrin for 24 h and irradiated with fluences of 1, 2.5, and 5 J cm−2. Direct measurement of oxygen concentration during irradiation confirmed that cells remained well oxygenated. Cells were also exposed to 1 and 10 μmol/L PGE2 for 3 h. In normoxic conditions, Photofrin, PDT, and PGE2 treatment activated HIF-1α and induced its nuclear translocation. Maximal Photofrin-PDT–mediated HIF-1α activation was intermediate in magnitude between that induced by PGE2 and that by the hypoxia mimic cobalt chloride. This work establishes that PDT induces significant activation of the HIF-1α pathway in the absence of hypoxia and supports the interpretation that the induction of HIF-1 target genes by PDT may be mediated, at least in part, by the prostaglandin pathway. [Mol Cancer Ther 2006;5(12):3268–74]
Gallic acid causes inactivating phosphorylation of cdc25A/cdc25C-cdc2 via ATM-Chk2 activation, leading to cell cycle arrest, and induces apoptosis in human prostate carcinoma DU145 cells
Authors: Agarwal Chapla , Tyagi Alpna , Agarwal Rajesh 
Published: December 2006

Abstract
We recently reported that gallic acid is a major active agent responsible for grape seed extract activity in DU145 human prostate carcinoma cells. The present study was conducted to examine its efficacy and associated mechanism. Gallic acid treatment of DU145 cells resulted in a strong cell growth inhibition, cell cycle arrest, and apoptotic death in a dose- and time-dependent manner, together with a decrease in cyclin-dependent kinases and cyclins but strong induction in Cip1/p21. Additional mechanistic studies showed that gallic acid induces an early Tyr15 phosphorylation of cell division cycle 2 (cdc2). Further upstream, gallic acid also induced phosphorylation of both cdc25A and cdc25C via ataxia telangiectasia mutated (ATM)-checkpoint kinase 2 (Chk2) activation as a DNA damage response evidenced by increased phospho-histone 2AX (H2A.X) that is phosphorylated by ATM in response to DNA damage. Time kinetics of ATM phosphorylation, together with those of H2A.X and Chk2, was in accordance with an inactivating phosphorylation of cdc25A and cdc25C phosphatases and cdc2 kinase, suggesting that gallic acid increases cdc25A/C-cdc2 phosphorylation and thereby inactivation via ATM-Chk2 pathway following DNA damage that induces cell cycle arrest. Caffeine, an ATM/ataxia telangiectasia-rad3-related inhibitor, reversed gallic acid–caused ATM and H2A.X phosphorylation and cell cycle arrest, supporting the role of ATM pathway in gallic acid–induced cell cycle arrest. Additionally, gallic acid caused caspase-9, caspase-3, and poly(ADP)ribose polymerase cleavage, but pan-caspase inhibitor did not reverse apoptosis, suggesting an additional caspase-independent apoptotic mechanism. Together, this is the first report identifying gallic acid efficacy and associated mechanisms in an advanced and androgen-independent human prostate carcinoma DU145 cells, suggesting future in vivo efficacy studies with this agent in preclinical prostate cancer models. [Mol Cancer Ther 2006;5(12):3294–302]