bluuebunny/crossref_metadata_2025_split huggingface dataset:
QLT0267, a small molecule inhibitor targeting integrin-linked kinase (ILK), and docetaxel can combine to produce synergistic interactions linked to enhanced cytotoxicity, reductions in P-AKT levels, altered F-actin architecture and improved treatment outcomes in an orthotopic breast cancer model
Authors: Kalra Jessica , Warburton Corinna , Fang Karen , Edwards Lincoln , Daynard Tim , Waterhouse Dawn , Dragowska Wieslawa , Sutherland Brent W , Dedhar Shoukat , Gelmon Karen , Bally Marcel 
Published: May 2009

Abstract
Introduction
Substantial preclinical evidence has indicated that inhibition of integrin linked-kinase (ILK) correlates with cytotoxic/cytostatic cellular effects, delayed tumor growth in animal models of cancer, and inhibition of angiogenesis. Widely anticipated to represent a very promising therapeutic target in several cancer indications, it is increasingly evident that optimal therapeutic benefits obtained using ILK targeting strategies will only be achieved in combination settings. The purpose of this study was to investigate the therapeutic potential of the ILK small molecule inhibitor, QLT0267 (267), alone or in combination with chemotherapies commonly used to treat breast cancer patients.

Methods
A single end-point metabolic assay was used as an initial screen for 267 interactions with selected chemotherapeutic agents. These in vitro assays were completed with seven breast cancer cell lines including several which over-expressed human epidermal growth factor receptor 2 (Her2). One agent, docetaxel (Dt), consistently produced synergistic interactions when combined with 267. Dt/267 interactions were further characterized by measuring therapeutic endpoints linked to phosphorylated protein kinase B (P-AKT) suppression, inhibition of vascular endothelial growth factor (VEGF) secretion and changes in cytoarchitecture. In vivo efficacy studies were completed in mice bearing orthotopic xenografts where tumor growth was assessed by bioluminescence and calliper methods.

Results
The combination of 267 and Dt resulted in increased cytotoxic activity, as determined using an assay of metabolic activity. Combinations of cisplatin, doxorubicin, vinorelbine, paclitaxel, and trastuzumab produced antagonistic interactions. Further endpoint analysis in cell lines with low Her2 levels revealed that the 267/Dt combinations resulted in: a three-fold decrease in concentration (dose) of 267 required to achieve 50% inhibition of P-AKT; and a dramatic disruption of normal filamentous-actin cellular architecture. In contrast to Her2-positive cell lines, three-fold higher concentrations of 267 were required to achieve 50% inhibition of P-AKT when the drug was used in combination with Dt. In vivo studies focusing on low Her2-expressing breast cancer cells (LCC6) implanted orthotopically demonstrated that treatment with 267/Dt engendered improved therapeutic effects when compared with mice treated with either agent alone.

Conclusions
The findings indicate that the 267/Dt drug combination confers increased (synergistic) therapeutic efficacy towards human breast cancer cells that express low levels of Her2.
Systemic analysis of the response of Aspergillus nigerto ambient pH
Authors: Andersen Mikael R , Lehmann Linda , Nielsen Jens 
Published: May 2009

Abstract
Background
The filamentous fungus Aspergillus niger is an exceptionally efficient producer of organic acids, which is one of the reasons for its relevance to industrial processes and commercial importance. While it is known that the mechanisms regulating this production are tied to the levels of ambient pH, the reasons and mechanisms for this are poorly understood.

Methods
To cast light on the connection between extracellular pH and acid production, we integrate results from two genome-based strategies: A novel method of genome-scale modeling of the response, and transcriptome analysis across three levels of pH.

Results
With genome scale modeling with an optimization for extracellular proton-production, it was possible to reproduce the preferred pH levels for citrate and oxalate. Transcriptome analysis and clustering expanded upon these results and allowed the identification of 162 clusters with distinct transcription patterns across the different pH-levels examined. New and previously described pH-dependent cis-acting promoter elements were identified. Combining transcriptome data with genomic coordinates identified four pH-regulated secondary metabolite gene clusters. Integration of regulatory profiles with functional genomics led to the identification of candidate genes for all steps of the pal/pacC pH signalling pathway.

Conclusions
The combination of genome-scale modeling with comparative genomics and transcriptome analysis has provided systems-wide insights into the evolution of highly efficient acidification as well as production process applicable knowledge on the transcriptional regulation of pH response in the industrially important A. niger. It has also made clear that filamentous fungi have evolved to employ several offensive strategies for out-competing rival organisms.
Differential regulation of HIF-1α isoforms in murine macrophages by TLR4 and adenosine A2A receptor agonists
Authors: Ramanathan Madhuri , Luo Wenting , Csóka Balázs , Haskó György , Lukashev Dmitry , Sitkovsky Michail V , Leibovich Samuel Joseph 
Published: May 2009

Abstract
Up-regulation of adenosine A2A receptors (A2ARs) and the HIF-1αl. 1 isoform plays an important role in the switch of macrophages from an inflammatory (M1) to an angiogenic (M2-like) phenotype.
Adenosine A2AR and TLR agonists synergize to induce an “angiogenic switch” in macrophages, down-regulating TNF-α and up-regulating VEGF expression. This switch involves transcriptional regulation of VEGF by HIF-1, transcriptional induction of HIF-1α by LPS (TLR4 agonist), and A2AR-dependent post-transcriptional regulation of HIF-1α stability. Murine HIF-1α is expressed as two mRNA isoforms: HIF-1αI.1 and -I.2, which contain alternative first exons and promoters. HIF-1αI.2 is expressed ubiquitously, and HIF-1αI.1 is tissue-specific. We investigated the regulation of these isoforms in macrophages by TLR4 and A2AR agonists. HIF-1αI.1 is induced strongly compared with HIF-1αI.2 upon costimulation with LPS and A2AR agonists (NECA or CGS21680). In unstimulated cells, the I.1 isoform constituted ∼4% of HIF-1α transcripts; in LPS and NECA- or CGS21680-treated macrophages, this level was ∼15%, indicating a substantial contribution of HIF-1αI.1 to total HIF-1α expression. The promoters of both isoforms were induced by LPS but not enhanced further by NECA, suggesting A2AR-mediated post-transcriptional regulation. LPS/NECA-induced expression of HIF-1αI.1 was down-regulated by Bay 11-7085 (NF-κB inhibitor) and ZM241385 (A2AR antagonist). Although VEGF and IL-10 expression by HIF-1αI.1−/− macrophages was equivalent to that of wild-type macrophages, TNF-α, MIP-1α, IL-6, IL-12p40, and IL-1β expression was significantly greater, suggesting a role for HIF-1αI.1 in modulating expression of these cytokines. A2AR expression in unstimulated macrophages was low but was induced rapidly by LPS in a NF-κB-dependent manner. LPS-induced expression of A2ARs and HIF-1α and A2AR-dependent HIF-1α mRNA and protein stabilization provide mechanisms for the synergistic effects of LPS and A2AR agonists on macrophage VEGF expression.
Human defensins activate monocyte-derived dendritic cells, promote the production of proinflammatory cytokines, and up-regulate the surface expression of CD91
Authors: Presicce Pietro , Giannelli Stefania , Taddeo Adriano , Villa Maria Luisa , Della Bella Silvia 
Published: May 2009

Abstract
Immunostimulatory properties of defensins on DC promote maturation and proinflammatory response.
Defensins are endogenous defense peptides with well-defined antimicrobial activity against a broad spectrum of pathogens including bacteria, fungi, viruses, and parasites. Several lines of evidence suggest that defensins might also contribute to the regulation of host innate and adaptive immunity, but their immunomodulatory functions are still poorly understood. Herein, we studied the impact of human defensins on multiple functions of DCs, which are a central player in all immune responses, bridging innate and adaptive immunity. We challenged DCs differentiated in vitro from human moDCs with HNP-1 α-defensin or HBD-1. HNP-1 and HBD-1 were chemotactic for moDCs. Both defensins promoted the activation and maturation of moDCs, as assessed by up-regulation of surface expression of the costimulatory molecules CD80, CD86, and CD40, the maturation marker CD83, and HLA-DR. HNP-1 and HBD-1 also enhanced the production of the proinflammatory cytokines TNF-α, IL-6, and IL-12p70 but did not affect the production of the regulatory cytokine IL-10. According to these stimulatory effects, HNP-1 and HBD-1 increased the allostimulatory activity of moDCs significantly. Finally, HNP-1 and HBD-1 promoted the up-regulation of CD91 on the DC surface. CD91 is a scavenger receptor involved in the recognition of multiple ligands including defensins, thus suggesting that defensins may amplify their own effects through the activation of an autocrine loop. Taken together, our observations may provide new insight into the immunomodulatory properties of human defensins and may aid the exploration of new therapeutic strategies to potentiate antimicrobial and antitumor immunity.
Delayed-onset post-traumatic stress disorder among war veterans in primary care clinics
Authors: Frueh B. Christopher , Grubaugh Anouk L. , Yeager Derik E. , Magruder Kathryn M. 
Published: May 2009

BackgroundOnly limited empirical data support the existence of delayed-onset post-traumatic stress disorder (PTSD).AimsTo expand our understanding of delayed-onset PTSD prevalence and phenomenology.MethodA cross-sectional, epidemiological design (n = 747) incorporating structured interviews to obtain relevant information for analyses in a multisite study of military veterans.ResultsA small percentage of veterans with identified current PTSD (8.3%, 7/84), current subthreshold PTSD (6.9%, 2/29), and lifetime PTSD only (5.4%, 2/37) met criteria for delayed onset with PTSD symptoms initiating more than 6 months after the index trauma. Altogether only 0.4% (3/747) of the entire sample had current PTSD with delayed-onset symptoms developing more than 1 year after trauma exposure, and no PTSD symptom onset was reported more than 6 years posttrauma.ConclusionsRetrospective reports of veterans reveal that delayed-onset PTSD (current, subthreshold or lifetime) is extremely rare 1 year post-trauma, and there was no evidence of PTSD symptom onset 6 or more years after trauma exposure.
Naltrexone implants after in-patient treatment for opioid dependence: randomised controlled trial
Authors: Kun⊘e Nikolaj , Lobmaier Philipp , Vederhus John Kåre , Hjerkinn Bj⊘rg , Hegstad Solfrid , Gossop Michael , Kristensen Øistein , Waal Helge 
Published: May 2009

BackgroundNaltrexone has considerable potential in helping to prevent relapse in heroin dependency. A longer-lasting formulation for naltrexone treatment is desirable to further reduce non-adherence and relapse during treatment of opiate dependence.AimsTo evaluate the safety and effectiveness of a 6-month naltrexone implant in reducing opioid use after in-patient treatment.MethodA group of 56 abstinence-oriented patients who completed in-patient treatment for opioid dependence were randomly and openly assigned to receive either a 6-month naltrexone implant or their usual aftercare. Drug use and other outcomes were assessed at 6-month follow-up.ResultsPatients receiving naltrexone had on average 45 days less heroin use and 60 days less opioid use than controls in the 180-day period (bothP<0.05). Blood tests showed naltrexone levels above 1 ng/ml for the duration of 6 months. Two patients died, neither of whom had received an implant.ConclusionsNaltrexone implant treatment safely and significantly reduces opioid use in a motivated population of patients.
Is hypochondriasis an anxiety disorder?
Authors: Olatunji Bunmi O. , Deacon Brett J. , Abramowitz Jonathan S. 
Published: May 2009

SummaryAlthough hypochondriasis is currently classified as a somatoform
disorder, the underlying cognitive processes may be more consistent with
an anxiety disorder. This observation has important implications for
treatment and subsequent revisions of the diagnostic classification of
hypochondriasis.
The dangers of inflation: memories of trauma and post-traumatic stress disorder
Authors: Greenberg Neil , Wessely Simon 
Published: May 2009

SummaryPeople who suffer from post-traumatic stress disorder (PTSD) are likely to find that their quality of life is substantially impaired. However, unlike other diagnoses, in order for clinicians to make a diagnosis of PTSD people have to be able to accurately recall the details of a traumatic incident. Yet recent evidence suggests that recall of such incidents is often unreliable. Clinicians should therefore exercise caution to avoid making inaccurate diagnoses.
Chondrocyte-Specific Modulation of Cyp27b1 Expression Supports a Role for Local Synthesis of 1,25-Dihydroxyvitamin D3 in Growth Plate Development
Authors: Naja Roy Pascal , Dardenne Olivier , Arabian Alice , St. Arnaud René 
Published: May 2009

AbstractThe Cyp27b1 enzyme (25-hydroxyvitamin D-1α-hydroxylase) that converts 25-hydroxyvitamin D into the active metabolite, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], is expressed in kidney but also in other cell types such as chondrocytes. This suggests that local production of 1,25(OH)2D3 could play an important role in the differentiation of these cells. To test this hypothesis, we engineered mutant mice that do not express the Cyp27b1 gene in chondrocytes. Inactivation of both alleles of the Cyp27b1 gene led to decreased RANKL expression and reduced osteoclastogenesis, increased width of the hypertrophic zone of the growth plate at embryonic d 15.5, increased bone volume in neonatal long bones, and increased expression of the chondrocytic differentiation markers Indian Hedgehog and PTH/PTHrP receptor. The expression of the angiogenic marker VEGF was decreased, accompanied by decreased platelet/endothelial cell adhesion molecule-1 staining in the neonatal growth plate, suggesting a delay in vascularization. In parallel, we engineered strains of mice overexpressing a Cyp27b1 transgene in chondrocytes by coupling the Cyp27b1 cDNA to the collagen α1(II) promoter. The transgenic mice showed a mirror image phenotype when compared with the tissue-specific inactivation, i.e. a reduction in the width of the hypertrophic zone of the embryonic growth plate, decreased bone volume in neonatal long bones, and inverse expression patterns of chondrocytic differentiation markers. These results support an intracrine role of 1,25(OH)2D3 in endochondral ossification and chondrocyte development in vivo.
Estradiol-17β Inhibits Gonadotropin-Releasing Hormone-Induced Ca2+ in Gonadotropes to Regulate Negative Feedback on Luteinizing Hormone Release
Authors: Iqbal Javed , Latchoumanin Olivier , Sari Ika P. , Lang Richard J. , Coleman Harold A. , Parkington Helena C. , Clarke Iain J. 
Published: May 2009

Abstract
In pituitary gonadotropes, estrogens have biphasic actions to cause an initial negative feedback followed by a positive feedback on LH secretion, but the mechanisms involved are not clearly understood. To investigate the feedback effects of estrogen, we used mixed ovine pituitary cell cultures (48–72 h), which were treated with 10−9m estradiol-17β (E2) or vehicle followed by a pulse of 10−9m GnRH. Medium was collected for LH assay and cells extracted to determine activation of MAPK (phosphorylated ERK-1/2). E2 treatment for 5 min reduced GnRH-induced LH release and caused phosphorylation of ERK-1/2. E2 alone also caused phosphorylation of ERK-1/2, similar to the response evoked by GnRH alone. GnRH increased cytoplasmic intracellular free calcium concentration ([Ca2+]i) and this was abolished by 2 min pretreatment with E2 or E-bovine serum albumen conjugate. Blockade of Ca2+ channels with nifedipine had no effect on the initial peak of GnRH-induced increase in [Ca2+]i but reduced its duration by 27 ± 6%. Depletion of intracellular Ca2+ stores with thapsigargin prevented GnRH-induced increase in [Ca2+]i. Thapsigargin (10−7m) or nifedipine (10−5m) pretreatment (15 min) of cells lowered GnRH-induced LH secretion by 30 ± 6 and 50% ± 4%, respectively. We conclude that inhibition of the GnRH-induced increase in [Ca2+]i in gonadotropes by E2 is a likely mechanism for the negative feedback effect of E2 on LH secretion involving a rapid nongenomic effect of E2. Activation of the MAPK pathway by E2 may be the mechanism for the time-delayed positive feedback effect on LH secretion at the level of the gonadotrope.
Rapid acceleration in dogs: ground forces and body posture dynamics
Authors: Walter Rebecca M. , Carrier David R. 
Published: May 2009

SUMMARY
Because the ability to accelerate rapidly is crucial to the survival and reproductive fitness of most terrestrial animals, it is important to understand how the biomechanics of rapid acceleration differs from that of steady-state locomotion. Here we compare rapid acceleration with high-speed galloping in dogs to investigate the ways in which body and limb posture and ground forces are altered to produce effective acceleration. Seven dogs were videotaped at 250 Hz as they performed `maximum effort' accelerations,starting in a standing position on a force plate and one and two strides before it. These dogs began accelerations by rapidly flexing their ankles and knees as they dropped into a crouch. The crouched posture was maintained in the first accelerating stride such that the ankle and knee were significantly more flexed than during steady high-speed galloping. The hindlimb was also significantly more retracted over the first stance period than during high-speed galloping. Ground forces differed from steady-state locomotion in that rapidly accelerating dogs supported only 43% of their body weight with the forelimbs, compared with 56–64% in steady-state locomotion. The hindlimbs applied greater peak accelerating forces than the forelimbs, but the forelimbs contributed significantly to the dogs' acceleration by producing 43%of the total propulsive impulse. Kinematically, rapid acceleration differs from steady-state galloping in that the limbs are more flexed and more retracted, while the back undergoes greater pitching movement. Ground reaction forces also differ significantly from steady-state galloping in that almost no decelerating forces are applied while propulsive force impulses are three to six times greater.
Plasmatocyte-spreading peptide (PSP) plays a central role in insect cellular immune defenses against bacterial infection
Authors: Eleftherianos I. , Xu M. , Yadi H. , ffrench-Constant R. H. , Reynolds S. E. 
Published: May 2009

SUMMARY
Insect hemocytes (blood cells) are a central part of the insect's cellular response to bacterial pathogens, and these specialist cells can both recognize and engulf bacteria. During this process, hemocytes undergo poorly characterized changes in adhesiveness. Previously, a peptide termed plasmatocyte-spreading peptide (PSP), which induces the adhesion and spreading of plasmatocytes on foreign surfaces, has been identified in lepidopteran insects. Here, we investigate the function of this peptide in the moth Manduca sexta using RNA interference (RNAi) to prevent expression of the precursor protein proPSP. We show that infection with the insect-specific bacterial pathogen Photorhabdus luminescens and non-pathogenic Escherichia coli induces proPSP mRNA transcription in the insect fat body but not in hemocytes; subsequently, proPSP protein can be detected in cell-free hemolymph. We used RNAi to silence this upregulation of proPSP and found that the knock-down insects succumbed faster to infection with P. luminescens, but not E. coli. RNAi-treated insects infected with E. coli showed a reduction in the number of circulating hemocytes and higher bacterial growth in hemolymph as well as a reduction in overall cellular immune function compared with infected controls. Interestingly,RNAi-mediated depletion of proPSP adversely affected the formation of melanotic nodules but had no additional effect on other cellular responses when insects were infected with P. luminescens, indicating that this pathogen employs mechanisms that suppress key cellular immune functions in M. sexta. Our results provide evidence for the central role of PSP in M. sexta cellular defenses against bacterial infections.
The involvement of H+-ATPase and carbonic anhydrase in intestinal HCO3– secretion in seawater-acclimated rainbow trout
Authors: Grosell M. , Genz J. , Taylor J. R. , Perry S. F. , Gilmour K. M. 
Published: May 2009

SUMMARYPyloric caeca and anterior intestine epithelia from seawater-acclimated rainbow trout exhibit different electrophysiological parameters with lower transepithelial potential and higher epithelial conductance in the pyloric caeca than the anterior intestine. Both pyloric caeca and the anterior intestine secrete HCO3– at high rates in the absence of serosal HCO3–/CO2,demonstrating that endogenous CO2 is the principal source of HCO3– under resting control conditions. Apical,bafilomycin-sensitive, H+ extrusion occurs in the anterior intestine and probably acts to control luminal osmotic pressure while enhancing apical anion exchange; both processes with implications for water absorption. Cytosolic carbonic anhydrase (CAc) activity facilitates CO2 hydration to fuel apical anion exchange while membrane-associated, luminal CA activity probably facilitates the conversion of HCO3– to CO2. The significance of membrane-bound, luminal CA may be in part to reduce HCO3– gradients across the apical membrane to further enhance anion exchange and thus Cl– absorption and to facilitate the substantial CaCO3 precipitation occurring in the lumen of marine teleosts. In this way, membrane-bound, luminal CA thus promotes the absorption of osmolytes and reduction on luminal osmotic pressure, both of which will serve to enhance osmotic gradients to promote intestinal water absorption.
Seasonal changes in thermoregulatory responses to hypoxia in the Eastern chipmunk (Tamias striatus)
Authors: Levesque Danielle L. , Tattersall Glenn J. 
Published: May 2009

SUMMARY
Mammalian heterotherms are known to be more tolerant of low oxygen levels than homeotherms. However, heterotherms demonstrate extreme seasonality in daily heterothermy and torpor expression. Because hypoxia depresses body temperature (Tb) and metabolism in mammals, it was of interest to see if seasonal comparisons of normothermic animals of a species capable of hibernation produce changes in their responses to hypoxia that would reflect a seasonal change in hypoxia tolerance. The species studied, the Eastern chipmunk (Tamias striatus, Linnaeus 1758), is known to enter into torpor exclusively in the winter. To test for seasonal differences in the metabolic and thermoregulatory responses to hypoxia (9.9 kPa), flow-through respirometry was used to compare oxygen consumption, minimum thermal conductance and Tb under fixed ambient temperature(Ta) conditions whereas a thermal gradient was used to assess selected Ta and Tb in response to hypoxia, in both summer- and winter-acclimated animals. No differences were observed between seasons in resting metabolism or thermal conductance in normoxic, normothermic animals. Providing the animals with a choice of Ta in hypoxia attenuated the hypoxic drop in Tb in both seasons, suggesting that the reported fall in Tb in hypoxia is not fully manifested in the behavioural pathways responsible for thermoregulation in chipmunks. Instead, Tb in hypoxia tends to be more variable and dependent on both Ta and season. Although Tbdropped in hypoxia in both seasons, the decrease was less in the winter with no corresponding decrease in metabolism, indicating that winter chipmunks are more tolerant to hypoxia than summer animals.