bluuebunny/crossref_metadata_2025_split huggingface dataset:
P2X7 signaling promotes microsphere embolism-triggered microglia activation by maintaining elevation of Fas ligand
Authors: Lu Ying-mei , Tao Rong-rong , Huang Ji-yun , Li Li-tao , Liao Mei-hua , Li Xiao-ming , Fukunaga Kohji , Hong Ze-Hui , Han Feng 
Published: July 2012

Abstract

Background
The cerebral microvascular occlusion elicits microvascular injury which mimics the different degrees of stroke severity observed in patients, but the mechanisms underlying these embolic injuries are far from understood. The Fas ligand (FasL)-Fas system has been implicated in a number of pathogenic states. Here, we examined the contribution of microglia-derived FasL to brain inflammatory injury, with a focus on the potential to suppress the FasL increase by inhibition of the P2X7-FasL signaling with pharmacological or genetic approaches during ischemia.

Methods
The cerebral microvascular occlusion was induced by microsphere injection in experimental animals. Morphological changes in microglial cells were studied immunohistochemically. The biochemical analyses were used to examine the intracellular changes of P2X7/FasL signaling. The BV-2 cells and primary microglia from mice genetically deficient in P2X7 were used to further establish a linkage between microglia activation and FasL overproduction.

Results
The FasL expression was continuously elevated and was spatiotemporally related to microglia activation following microsphere embolism. Notably, P2X7 expression concomitantly increased in microglia and presented a distribution pattern that was similar to that of FasL in ED1-positive cells at pathological process of microsphere embolism. Interestingly, FasL generation in cultured microglia cells subjected to oxygen-glucose deprivation-treated neuron-conditioned medium was prevented by the silencing of P2X7. Furthermore, FasL induced the migration of BV-2 microglia, whereas the neutralization of FasL with a blocking antibody was highly effective in inhibiting ischemia-induced microglial mobility. Similar results were observed in primary microglia from wild-type mice or mice genetically deficient in P2X7. Finally, the degrees of FasL overproduction and neuronal death were consistently reduced in P2X7
−/− mice compared with wild-type littermates following microsphere embolism insult.

Conclusion
FasL functions as a key component of an immunoreactive response loop by recruiting microglia to the lesion sites through a P2X7-dependent mechanism. The specific modulation of P2X7/FasL signaling and aberrant microglial activation could provide therapeutic benefits in acute and subacute phase of cerebral microembolic injury.
Peer relations scale for adolescents treated for substance use disorder: a factor analytic presentation
Authors: Yao Ping , Ciesla James R , Mazurek Kathryn D , Spear Sherilynn F 
Published: July 2012

Abstract

Background
The literature indicates that peer relations are an important aspect of the treatment and recovery of adolescents with substance use disorder (SUD). Unfortunately, no standard measure of peer relations exists. The objective of this research is to use exploratory factor analysis to examine the underlying factor structure of a 14-item peer relations scale for use in this treatment population.

Methods
Participants are 509 adolescents discharged from primary substance abuse treatment from 2003–2010. The data are from research conducted between six and twelve months post discharge via a 230-item questionnaire that included the 14-item peer relations scale. The scale has questions that assess the degree to which the adolescent's social contacts conform to norms of positive behavior and therefore foster non-use and recovery. The response rate was 62%.

Results
The scale was decomposed by principal component factor analysis. When the matrix was rotated by varimax a three factor solution explaining 99.99% of the common variance emerged. The first factor yielded ten items that measure association with peers who engage in positive versus delinquent social behavior (positive versus negative social behavior). The three items in the second factor specify association with peers who use versus those who don’t use drugs, and thereby encourage recovery and discourage drug use (drug use). The third and factor contained two items measuring the degree to which the recovering adolescent associates with new or previous friends (post treatment peer association).

Conclusions
This scale is useful as a standard measure in that it begins to identify the measurable dimensions of peer relations that influence sustaining post treatment recovery.
Sphingosine kinase/sphingosine 1-phosphate axis: a new player for insulin-like growth factor-1-induced myoblast differentiation
Authors: Bernacchioni Caterina , Cencetti Francesca , Blescia Sabrina , Donati Chiara , Bruni Paola 
Published: July 2012

Abstract

Background
Insulin-like growth factor-1 (IGF-1) is the most important physiological regulator of skeletal muscle progenitor cells, which are responsible for adult skeletal muscle regeneration. The ability of IGF-1 to affect multiple aspects of skeletal muscle cell biology such as proliferation, differentiation, survival and motility is well recognized, although the molecular mechanisms implicated in its complex biological action are not fully defined. Since sphingosine 1-phosphate (S1P) has recently emerged as a key player in skeletal muscle regeneration, we investigated the possible involvement of the sphingosine kinase (SK)/S1P receptor axis on the biological effects of IGF-1 in murine myoblasts.

Methods
RNA interference, chemical inhibition and immunofluorescence approaches were used to assess the role of the SK/S1P axis on the myogenic and mitogenic effects of IGF-1 in C2C12 myoblasts.

Results
We show that IGF-1 increases SK activity in mouse myoblasts. The effect of the growth factor does not involve transcriptional regulation of SK1 or SK2, since the protein content of both isoforms is not affected; rather, IGF-1 enhances the fraction of the active form of SK. Moreover, transactivation of the S1P2 receptor induced by IGF-1 via SK activation appears to be involved in the myogenic effect of the growth factor. Indeed, the pro-differentiating effect of IGF-1 in myoblasts is impaired when SK activity is pharmacologically inhibited, or SK1 or SK2 are specifically silenced, or the S1P2 receptor is downregulated. Furthermore, in this study we show that IGF-1 transactivates S1P1/S1P3 receptors via SK activation and that this molecular event negatively regulates the mitogenic effect elicited by the growth factor, since the specific silencing of S1P1 or S1P3 receptors increases cell proliferation induced by IGF-1.

Conclusions
We demonstrate a dual role of the SK/S1P axis in response to myoblast challenge with IGF-1, that likely is important to regulate the biological effect of this growth factor. These findings add new information to the understanding of the mechanism by which IGF-1 regulates skeletal muscle regeneration.
Polymorphisms in cytochrome P450 2C19 enzyme and cessation of leflunomide in patients with rheumatoid arthritis
Authors: Wiese Michael D , Schnabl Matthew , O'Doherty Catherine , Spargo Llewellyn D , Sorich Michael J , Cleland Leslie G , Proudman Susanna M 
Published: July 2012

Abstract
Introduction
Rational selection of disease modifying anti-rheumatic drugs in the treatment of rheumatoid arthritis (RA) has many potential advantages, including rapid disease control, reduced long-term disability and reduced overall cost to the healthcare system. Inter-individual genetic differences are particularly attractive as markers to predict efficacy and toxicity, as they can be determined rapidly prior to drug selection. The aims of this study, therefore, were to investigate the association between differences in genes associated with the metabolism, clearance and efficacy of leflunomide with its cessation in a group of rheumatoid arthritis patients who were treated with an intensive contemporary, treat-to-target approach.

Methods
This retrospective cohort study identified all individuals who received leflunomide and were enrolled in the Early Arthritis inception cohort at the Royal Adelaide Hospital between 2001 and July 2011. Inclusion criteria were age (>18) and a diagnosis of rheumatoid arthritis. Patients were excluded if a DNA sample was not available, if they withdrew from the cohort or if clinical data were insufficient. Subjects were followed for 12 months or until either another disease modifying antirheumatic drug was added or leflunomide was ceased. The following single nucleotide polymorphisms (SNPs) were determined: CYP2C19*2 (rs4244285), CYP2C19*17 (rs12248560), ABCG2 421C>A (rs2231142), CYP1A2*1F (rs762551) and DHODH 19C>A (rs3213422). The effects of variables on cessation were assessed with Cox Proportional Hazard models.

Results
Thirty-three of 78 (42.3%) patients ceased leflunomide due to side effects. A linear trend between cytochrome P450 2C19 (CYP2C19) phenotype and leflunomide cessation was observed, with poor and intermediate metabolizers ceasing more frequently (adjusted Hazard Ratio = 0.432 for each incremental change in phenotype, 95% CI 0.237 to 0.790, P = 0.006). Previously observed associations between cytochrome P450 1A2 (CYP1A2) and dihydro-orotate dehydrogenase (DHODH) genotype and toxicity were not apparent, but there was a trend for ATP-binding cassette sub-family G member 2 (ABCG2) genotype to be associated with cessation due to diarrhea.

Conclusions
CYP2C19 phenotype was associated with cessation due to toxicity, and since CYP2C19 intermediate and poor metabolizers have lower teriflunomide concentrations, it is likely that they have a particularly poor risk:benefit ratio when using this drug.
Fibroblast-secreted hepatocyte growth factor mediates epidermal growth factor receptor tyrosine kinase inhibitor resistance in triple-negative breast cancers through paracrine activation of Met
Authors: Mueller Kelly L , Madden Julie M , Zoratti Gina L , Kuperwasser Charlotte , List Karin , Boerner Julie L 
Published: July 2012

Abstract
Introduction
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have shown clinical efficacy in lung, colon, and pancreatic cancers. In lung cancer, resistance to EGFR TKIs correlates with amplification of the hepatocyte growth factor (HGF) receptor tyrosine kinase Met. Breast cancers do not respond to EGFR TKIs, even though EGFR is overexpressed. This intrinsic resistance to EGFR TKIs in breast cancer does not correlate with Met amplification. In several tissue monoculture models of human breast cancer, Met, although expressed, is not phosphorylated, suggesting a requirement for a paracrine-produced ligand. In fact, HGF, the ligand for Met, is not expressed in epithelial cells but is secreted by fibroblasts in the tumor stroma. We have identified a number of breast cancer cell lines that are sensitive to EGFR TKIs. This sensitivity is in conflict with the observed clinical resistance to EGFR TKIs in breast cancers. Here we demonstrate that fibroblast secretion of HGF activates Met and leads to EGFR/Met crosstalk and resistance to EGFR TKIs in triple-negative breast cancer (TNBC).

Methods
The SUM102 and SUM149 TNBC cell lines were used in this study. Recombinant HGF as well as conditioned media from fibroblasts expressing HGF were used as sources for Met activation. Furthermore, we co-cultured HGF-secreting fibroblasts with Met-expressing cancer cells to mimic the paracrine HGF/Met pathway, which is active in the tumor microenvironment. Cell growth, survival, and transformation were measured by cell counting, clonogenic and MTS assays, and soft agar colony formation, respectively. Student's t test was used for all statistical analysis.

Results
Here we demonstrate that treatment of breast cancer cells sensitive to EGFR TKIs with recombinant HGF confers a resistance to EGFR TKIs. Interestingly, knocking down EGFR abrogated HGF-mediated cell survival, suggesting a crosstalk between EGFR and Met. HGF is secreted as a single-chain pro-form, which has to be proteolytically cleaved in order to activate Met. To determine whether the proteases required to activate pro-HGF were present in the breast cancer cells, we utilized a fibroblast cell line expressing pro-HGF (RMF-HGF). Addition of pro-HGF-secreting conditioned fibroblast media to TNBC cells as well as co-culturing of TNBC cells with RMF-HGF fibroblasts resulted in robust phosphorylation of Met and stimulated proliferation in the presence of an EGFR TKI.

Conclusions
Taken together, these data suggest a role for Met in clinical resistance to EGFR TKIs in breast cancer through EGFR/Met crosstalk mediated by tumor-stromal interactions.
The impact of statin use on pneumonia risk and outcome: a combined population-based case-control and cohort study
Authors: Nielsen Anders Gunnar , Nielsen Rikke Beck , Riis Anders Hammerich , Johnsen Søren Paaske , Sørensen Henrik Toft , Thomsen Reimar Wernich 
Published: July 2012

Abstract
Introduction
The impact of statin use on pneumonia risk and outcome remains unclear. We therefore examined this risk in a population-based case-control study and did a 5-year update of our previous 30-day mortality analyses.

Methods
We identified 70,953 adults with a first-time hospitalization for pneumonia between 1997 and 2009 in Northern Denmark. Ten age- and sex-matched population controls were selected for each pneumonia patient. To control for potential confounders, we retrieved individual-level data on other medications, comorbidities, recent surgery, socioeconomic indicators, influenza vaccination, and other markers of frailty or health awareness from medical databases. We followed all pneumonia patients for 30 days after hospital admission.

Results
A total of 7,223 pneumonia cases (10.2%) and 64 523 controls (9.1%) were statin users before admission, corresponding to an age- and sex-matched odds ratio (OR) of 1.17 (95% confidence interval [CI]: 1.14-1.21). After controlling for higher comorbidity and a wide range of other potential confounders, the adjusted OR for pneumonia associated with current statin use dropped to 0.80 (95% CI: 0.77-0.83). Previous statin use was not associated with decreased pneumonia risk (adjusted OR = 0.97, 95% CI: 0.91-1.02). Decreased risk remained significant after further adjustment for frailty and health awareness markers.
The prevalence of statin use among Danish pneumonia patients increased from 1% in 1997 to 24% in 2009. Thirty-day mortality following pneumonia hospitalization was 11.3% among statin users versus 15.1% among nonusers. This corresponded to a 27% reduced mortality rate (adjusted hazard ratio = 0.73, 95% CI: 0.67-0.79), corroborating our earlier findings.

Conclusions
Current statin use was associated with both a decreased risk of hospitalization for pneumonia and lower 30-day mortality following pneumonia.
The HIV-1 protease inhibitor nelfinavir activates PP2 and inhibits MAPK signaling in macrophages: a pathway to reduce inflammation
Authors: Wallet Mark A , Reist Caroline M , Williams Julie C , Appelberg Sofia , Guiulfo Giorgio L , Gardner Brent , Sleasman John W , Goodenow Maureen M 
Published: July 2012

Abstract
Nelfinavir has anti-inflammatory effects directly upon human macrophages independent of antiviral activity.
The HIV-1 PI NFV has off-target effects upon host enzymes, including inhibition of the 20S proteasome, resulting in activation of PP1. HIV-1-associated monocyte/macrophage activation, in part a result of systemically elevated levels of microbial products including LPS, is associated with risk of mortality, independent of viremia or CD4 T cell loss. This study tested the hypothesis that activation of protein phosphatases by NFV would reduce activation of monocytes/macrophages through dephosphorylation of signal transduction proteins. NFV uniquely blocked LPS-induced production by human monocyte-derived macrophages of the inflammatory cytokines TNF and IL-6, as well as sCD14. Although NFV failed to modulate NF-κB, NFV treatment reduced phosphorylation of AKT and MAPKs. Inhibition of PP2 with okadaic acid blocked the anti-inflammatory effect of NFV, whereas the PP1 inhibitor calyculin A failed to counter the anti-inflammatory effects of NFV. For in vivo studies, plasma sCD14 and LPS were monitored in a cohort of 31 pediatric HIV-1 patients for over 2 years of therapy. Therapy, including NFV, reduced sCD14 levels significantly compared with IDV or RTV, independent of ΔLPS levels, VL, CD4 T cell frequency, or age. The hypothesis was supported as NFV induced activation of PP2 in macrophages, resulting in disruption of inflammatory cell signaling pathways. In vivo evidence supports that NFV may offer beneficial effects independent of antiviral activity by reducing severity of chronic innate immune activation in HIV-1 infection.
Adsorption and Enrichment of Alkalids from Areca Nut by Means of Macroporous Resins
Authors: Ding Yan , Yang Xiao-Ming , Pan Guo-Bo , Ma Hai-Le , Liu Wei-Min 
Published: July 2012

Resin adsorption as a means of separating and enriching areca alkalids from areca nut extracts was investigated. The adsorption/desorption properties of areca alkalids on six macroporous adsorption resins and a macroporous cation-exchange resin D151 were evaluated. The results showed that D151, AB-8 and XAD-7 resins presented a higher adsorption capacity, adsorption ratio and desorption ratio than the other resins studied. Equilibrium and kinetic adsorption data for areca alkalids onto these three resins were obtained. Such data were best fitted by the Langmuir isotherm model and the pseudo-first-order kinetic model. The thermodynamic and kinetic parameters showed that D151 resin possessed the greatest adsorption capacity and the highest adsorption rate of the three resins, with the adsorption of areca alkalids being spontaneous and endothermic. To optimize the operating parameters for enriching areca alkalids, dynamic adsorption and desorption tests were undertaken employing a column packed with D151 resin. The optimum parameters for adsorption were an inlet areca alkalid concentration of 2.24 mg/mℓ, a feed volume of 7 BV and a flow rate of 6 BV/h; for desorption, the corresponding conditions were the use of ethanol as the elution solvent at a feed volume of 8 BV and a flow rate of 1.5 BV/h. After treatment for only one cycle with D151 resin, the content of areca alkalids in the product was increased from 8.28% to 81.78% with an overall recovery of 87.40%. Moreover, D151 resin exhibited excellent re-usability for at least three adsorption/desorption cycles. The results obtained showed that macroporous resin could provide a feasible means for the large-scale preparation of areca alkalids from areca nut extract.
Scattering, Diffraction, and Geometric Light Trapping in Thin Film Amorphous Silicon Solar Cells on Plastic Substrates
Authors: de Jong M.M. , Baggerman J. , van Rijn C.J.M. , Sonneveld P.J. , Swinkels G.L.A.M. , Holterman H.J. , Rath J.K. , Schropp R.E.I. 
Published: July 2012

ABSTRACTIn this study we compare light trapping in hydrogenated amorphous silicon (a-Si:H) solar cells deposited directly onto polycarbonate (PC) at low temperature (< 130°C). To that end, we embossed PC substrates with 400 nm and 10 μm square based pyramids to induce light trapping based on diffraction and on geometric effects. As a comparison, we deposited a-Si:H cells on flat glass substrates and on Asahi U-type TCO glass. The cells on PC generate current densities comparable (slightly higher) than cells on Asahi TCO glass, but suffer from a slightly lower Voc, resulting in cells with an initial efficiency of 6.8% and 7.4% on sub-micron pyramid and micro-pyramid structured PC substrates respectively, compared to 7.6% for cells on Asahi. This shows great potential for a-Si:H cells deposited directly onto cheap plastics.
Detection of Lectins using Glyco-Functionalized Nanosensors
Authors: Chen Yanan , Vedala Harindra , Kotchey Gregg P. , Audfray Aymeric , Cecioni Samy , Imberty Anne , Vidal Sébastien , Star Alexander 
Published: July 2012

ABSTRACTWe have used single-walled carbon nanotube field-effect transistor (SWNT-FET) and chemically converted graphene field-effect transistor (CCG-FET) devices to probe the interactions between carbohydrates and their recognition lectins. Porphyrin- and pyrene-based glycoconjugates were used as receptor molecules and the target lectins were two bacterial lectins that present different carbohydrate preference, namely PA-IL, PA-IIL from Pseudomonas aeruginosa and a plant lectin Concanavalin A. The specific binding between lectin and carbohydrate can be transduced to the change in FET device conductance. An initial study with SWNT-FET noncovalently functionalized with porphyrin-based glycoconjugates showed both good selectivity and sensitivity. To compare SWNT and CCG performance, pyrene- and porphyrin-based glycoconjugates were functionalized noncovalently on the surface of CCG-FET and SWNT-FET devices, which were then treated with non-specific and specific lectins. The responses were compared and rationalized using computer-aided models of carbon nanostructure/glycoconjugate interactions. Fluorescence microscopy, atomic force microscopy, UV-vis-NIR spectroscopy and Isothermal titration microcalorimetry (ITC) measurements were used to confirm the electrical results.
Altered Phenotype of Peripheral Blood Dendritic Cells in Pediatric Type 1 Diabetes
Authors: Nieminen Janne K. , Vakkila Jukka , Salo Harri M. , Ekström Nina , Härkönen Taina , Ilonen Jorma , Knip Mikael , Vaarala Outi 
Published: July 2012

OBJECTIVEDendritic cells (DCs) are largely responsible for the activation and fine-tuning of T-cell responses. Altered numbers of blood DCs have been reported in type 1 diabetes (T1D). We aimed at characterizing the less well-known phenotypic properties of DCs in T1D.RESEARCH DESIGN AND METHODSIn a case-control setting, samples from a total of 90 children were studied by flow cytometry or by quantitative real-time PCR (qPCR).RESULTSWe found decreased numbers of myeloid DCs (mDCs) (8.97 vs. 13.4 cells/μL, P = 0.009, n = 31) and plasmacytoid DCs (pDCs) (9.47 vs. 14.6 cells/μL, P = 0.018, n = 30) in recent-onset T1D. Using a panel of antibodies against functionally important DC markers, we detected a decreased expression of CC chemokine receptor 2 (CCR2) on mDCs (percentage above negative control, P = 0.002, n = 29) and pDCs (median intensity, P = 0.003, n = 30) from T1D patients. In an independent series of children, the reduced expression of CCR2 was confirmed by qPCR in isolated mDCs (P = 0.043, n = 20). Serum concentrations of CCR2 ligands monocyte chemotactic protein-1 and -3 did not differ between the groups. A trend for an enhanced responsiveness of the nuclear factor-κB pathway (P = 0.063, n = 39) was seen in mDCs from children with β-cell autoantibodies, which is possibly related to the reduced CCR2 expression, since CCR2 on mDCs was downregulated by nuclear factor-κB–activating agents.CONCLUSIONSGiven the role of CCR2 in DC chemotaxis and in DC-elicited Th1 differentiation, our results may indicate a functionally important DC abnormality in T1D affecting the initiation and quality of immune responses.