bluuebunny/crossref_metadata_2025_split huggingface dataset:
FSTL1 promotes arthritis in mice by enhancing inflammatory cytokine/chemokine expression
Authors: Chaly Yury , Marinov Anthony D. , Oxburgh Leif , Bushnell Daniel S. , Hirsch Raphael 
Published: October 2011

AbstractObjectiveFSTL1 is a secreted glycoprotein that exacerbates murine arthritis and is overexpressed in human arthritis. The aim of this study was to determine the mechanism by which FSTL1 promotes arthritis.MethodsCollagen‐induced arthritis was induced in mice hypomorphic for FSTL1, generated with a gene trap–targeted mutant embryonic stem cell line. Arthritis was assessed by measuring paw swelling and using a qualitative arthritis index. Bone marrow–derived mesenchymal stromal cells from hypomorphic mice, as well as mouse stromal ST2 cells transduced with short hairpin RNA to suppress FSTL1 expression, were stimulated with interleukin‐1β (IL‐1β), tumor necrosis factor α, and IL‐17. The monocyte cell line U937, which does not express FSTL1, was transfected with a plasmid encoding FSTL1 and stimulated with phorbol myristate acetate and lipopolysaccharide. Cell supernatants were assayed for IL‐6, IL‐8, monocyte chemotactic protein 1 (MCP‐1), and FSTL1 by enzyme‐linked immunosorbent assay.ResultsFSTL1 hypomorphic mice had reduced levels of FSTL1 compared to littermate controls. Following induction of arthritis, a significant correlation was observed between serum FSTL1 levels and both paw swelling and the arthritis index. Similar correlations were observed between the amount of FSTL1 produced by mesenchymal stromal cells, stromal ST2 cells, and monocytes and the secretion of IL‐6, IL‐8, and MCP‐1.ConclusionThese findings demonstrate that FSTL1 up‐regulates proinflammatory mediators important in the pathology of arthritis, and that serum levels of FSTL1 correlate with severity of arthritis. The latter supports the possibility that FSTL1 might be a target for treatment of certain forms of arthritis.
CXCR3 promotes the production of IgG1 autoantibodies but is not essential for the development of lupus nephritis in NZB/NZW mice
Authors: Moser Katrin , Kalies Kathrin , Szyska Martin , Humrich Jens Y. , Amann Kerstin , Manz Rudolf A. 
Published: October 2011

AbstractObjectiveAutoantibody immune complexes and cellular infiltrates drive nephritis in patients with systemic lupus erythematosus (SLE) and in murine lupus. The chemokine receptor CXCR3 is assumed to promote cellular infiltration of inflamed tissues. Moreover, CXCR3 deficiency ameliorates lupus nephritis in the MRL/MpJ‐Faslpr (MRL/lpr) mouse model of SLE. Hence, CXCR3 blockade has been suggested as a novel therapeutic strategy for the treatment of lupus nephritis. We undertook this study to test the effect of CXCR3 in the (NZB × NZW)F1 (NZB/NZW) mouse model of SLE.MethodsCXCR3−/− NZB/NZW mice were generated and monitored for survival, proteinuria, and kidney infiltration. Anti–double‐stranded DNA (anti‐dsDNA) and total IgG1, IgG2a, and IgG2b antibody levels were determined by enzyme‐linked immunosorbent assay. T cell and plasma cell infiltrates in the kidneys and interferon‐γ production were determined by flow cytometry. Plasma cell infiltrates were measured using enzyme‐linked immunospot assay. Kidney tissue was evaluated for pathologic changes.ResultsCXCR3−/− NZB/NZW mice exhibited reduced production of total and anti‐dsDNA antibodies of the IgG1 subclass, but had normal titers of IgG2a and IgG2b antibodies compared to CXCR3+/+ NZB/NZW mice. Cellular infiltrates and glomerulonephritis were not reduced in CXCR3−/− mice.ConclusionCXCR3 has an effect on (auto)antibody production but is not essential for lupus pathogenesis in NZB/NZW mice, indicating that the effect of CXCR3 on the development of kidney disease varies between MRL/lpr and NZB/NZW mice. These results suggest that CXCR3‐dependent and ‐independent mechanisms can mediate lupus nephritis. Hence, therapeutic CXCR3 blockade could be beneficial for only a subgroup of patients with SLE.
Adrenomedullin22–52 combats inflammation and prevents systemic bone loss in murine collagen‐induced arthritis
Authors: Kioon Marie‐Dominique Ah , Asensio Carine , Ea Hang‐Korng , Velard Frédéric , Uzan Benjamin , Rullé Sandrine , Bazille Céline , Marty Caroline , Falgarone Géraldine , Nguyen Christelle , Collet Corinne , Launay Jean‐Marie , Cohen‐Solal Martine , Lioté Frédéric 
Published: October 2011

AbstractObjectiveAdrenomedullin22–52 is a truncated peptide derived from adrenomedullin, a growth factor with antiapoptotic and immunoregulatory properties. It can act as an agonist or an antagonist depending on cell type. Its in vivo effects are unknown, but adrenomedullin22–52 could possess immunomodulatory properties. This study was undertaken to evaluate the effect of adrenomedullin22–52 in a mouse model of arthritis.MethodsDBA/1 mice with collagen‐induced arthritis (CIA) were treated with 1.2 μg/gm adrenomedullin22–52, adrenomedullin, or saline at arthritis onset. Bone mineral density was measured at the beginning of the experiment and when mice were killed. Mouse joints were processed for histologic analysis and protein studies, and spleens were examined for Treg cell expression. Cytokine expression was studied in mouse joint tissue and serum.ResultsIn mice with CIA, adrenomedullin and adrenomedullin22–52 reduced clinical and histologic arthritis scores and shifted the pattern of articular and systemic cytokine expression from Th1 to Th2, as compared to untreated mice with CIA (controls). Tumor necrosis factor α, interleukin‐6 (IL‐6), and IL‐17A levels were significantly decreased in the joints of mice with CIA treated with adrenomedullin or adrenomedullin22–52 as compared to controls, whereas IL‐4 and IL‐10 levels were increased. Adrenomedullin22–52 was more effective than adrenomedullin in modulating cytokine content and enhanced Treg cell function without changing Treg cell expression compared to controls. Adrenomedullin receptor binding and transcriptional adrenomedullin receptor expression were markedly increased in joints from controls, whereas adrenomedullin receptor binding was considerably decreased in treated animals. Mice with CIA treated with adrenomedullin or adrenomedullin22–52 had considerably fewer apoptotic chondrocytes and diminished cartilage degradation. Adrenomedullin22–52 completely prevented systemic bone loss by preserving osteoblastic activity, but without changes in osteoclastic activity.ConclusionOur findings indicate that adrenomedullin22–52, which has no vasoactive or tumor‐inducing effects, is a potent antiinflammatory and bone‐protective agent in this arthritis model.
Light it up: Highly efficient multigene delivery in mammalian cells
Authors: Trowitzsch Simon , Klumpp Martin , Thoma Ralf , Carralot Jean‐Philippe , Berger Imre 
Published: October 2011

AbstractMultigene delivery and expression systems are emerging as key technologies for many applications in contemporary biology. We have developed new methods for multigene delivery and expression in eukaryotic hosts for a variety of applications, including production of protein complexes for structural biology and drug development, provision of multicomponent protein biologics, and cell‐based assays. We implemented tandem recombineering to facilitate rapid generation of multicomponent gene expression constructs for efficient transformation of mammalian cells, resulting in homogenous cell populations. Analysis of multiple parameters in living cells may require co‐expression of fluorescently tagged sensors simultaneously in a single cell, at defined and ideally controlled ratios. Our method enables such applications by overcoming currently limiting challenges.Here, we review recent multigene delivery and expression strategies and their exploitation in mammalian cells. We discuss applications in drug discovery assays, interaction studies, and biologics production, which may benefit in the future from our novel approach.
On tree intensity estimation for forest inventories: Some statistical issues
Authors: Comas Carlos , Mateu Jorge , Delicado Pedro 
Published: October 2011

AbstractThe effect of the plot shape, number of subplots and their spatial arrangement on the sample variance for spatially explicit point populations is analysed for a simple intensity estimator. We derive the sample variance and covariance for sampling designs involving more than one subplot. Some numerical approximations are also presented. If a clustered point pattern has to be sampled, the best strategy to reduce the sample variance is to consider as many rectangular subplots as possible, for a prescribed total sample area, distributed over a grid. In contrast, if a regular point pattern is to be sampled, then a single circular subplot should be considered. If we assume that the point configuration is Poisson, then we can consider any subplot shape and spatial distribution ensuring no overlapping between the subplots. A case study in forestry is considered to assess the validity of our results.
Note on simultaneous inferences about non‐inferiority and superiority for a primary and a secondary endpoint
Authors: Guilbaud Olivier 
Published: October 2011

AbstractIn their review of challenges to multiple testing in clinical trials, Hung and Wang (2010) considered the situation where a treatment is to be compared with an active comparator and the aim is to show non‐inferiority and (if possible) superiority with respect to a primary and a secondary endpoint. This note extends their discussion of this particular situation, taking the sequentially rejective procedure they used for illustration as a starting point. Some alternative multiple testing procedures (MTPs) are considered, and corresponding simultaneous confidence regions are discussed that provide additional information “for free”. The choice may then be based on the properties of these MTPs and corresponding confidence regions.
Synthesis, X‐ray crystal structure and optical properties of novel 2‐aryl‐3‐ethoxycarbonyl‐4‐phenylpyrido[1,2‐a]benzimidazoles
Authors: Chen Xia , Yang He , Ge Yanqing , Feng Lei , Jia Jiong , Wang Jianwu 
Published: October 2011

ABSTRACTA series of novel 2‐aryl‐3‐ethoxycarbonyl‐4‐phenylpyrido[1,2‐a]benzimidazole derivatives were synthesized by the tandem reaction of 2‐benzoyl benzimidazole and (Z)‐ethyl 4‐bromo‐3‐arylbut‐2‐enoate in the presence of potassium carbonate. The compounds were characterized using IR, 1H‐NMR, 13C‐NMR, HRMS and the structure of 6f was further determined by X‐ray crystallography. Both absorption and fluorescence spectra characteristics of the compounds were investigated in acetonitrile and dichloromethane. The results showed that the absorption maxima of the compounds varied from 220 to 284 nm, depending on the structure of 2‐aryl group. The fluorescence results revealed that these compounds exhibited blue‐green fluorescence (463–475 nm) in dilute solutions and showed acceptable fluorescence quantum yields (ФPL = 0.13–0.73) in dichloromethane. Copyright © 2011 John Wiley & Sons, Ltd.
Fiber alignment and coculture with fibroblasts improves the differentiated phenotype of murine embryonic stem cell‐derived cardiomyocytes for cardiac tissue engineering
Authors: Parrag Ian C. , Zandstra Peter W. , Woodhouse Kimberly A. 
Published: October 2011

AbstractEmbryonic stem cells (ESCs) are an important source of cardiomyocytes for regenerating injured myocardium. The successful use of ESC‐derived cardiomyocytes in cardiac tissue engineering requires an understanding of the important scaffold properties and culture conditions to promote cell attachment, differentiation, organization, and contractile function. The goal of this work was to investigate how scaffold architecture and coculture with fibroblasts influences the differentiated phenotype of murine ESC‐derived cardiomyocytes (mESCDCs). Electrospinning was used to process an elastomeric biodegradable polyurethane (PU) into aligned or unaligned fibrous scaffolds. Bioreactor produced mESCDCs were seeded onto the PU scaffolds either on their own or after pre‐seeding the scaffolds with mouse embryonic fibroblasts (MEFs). Viable mESCDCs attached to the PU scaffolds and were functionally contractile in all conditions tested. Importantly, the aligned scaffolds led to the anisotropic organization of rod‐shaped cells, improved sarcomere organization, and increased mESCDC aspect ratio (length‐to‐diameter ratio) when compared to cells on the unaligned scaffolds. In addition, pre‐seeding the scaffolds with MEFs improved mESCDC sarcomere formation compared to mESCDCs cultured alone. These results suggest that both fiber alignment and pre‐treatment of scaffolds with fibroblasts improve the differentiation of mESCDCs and are important parameters for developing engineered myocardial tissue constructs using ESC‐derived cardiac cells. Biotechnol. Bioeng. 2012; 109:813–822. © 2011 Wiley Periodicals, Inc.
Polymorphisms of GSTT1, GSTM1, and EPHX genotypes in patients with cryptogenic polyneuropathy: a case–control study
Authors: Lindh Jonas , Söderkvist Peter , Fredrikson Mats , Hosseininia Shahrzad , Tondel Martin , Persson Bodil , Vrethem Magnus 
Published: October 2011

AbstractThe aim of this study was to analyze whether polymorphisms for the null alleles of Glutathione S‐Transferase Mu‐1 (GSTM1), Glutathione S‐Transferase Theta‐1 (GSTT1), and a low‐activity genetic variation of epoxide hydrolase exon three (EPHX*3) affect the risk of developing polyneuropathy. The enzymes of these genes are important in the metabolism of toxic compounds. Seventy‐nine patients with cryptogenic polyneuropathy (equivalent to chronic idiopathic axonal neuropathy) and 398 controls were tested for the genetic polymorphism. Medical records were reviewed to collect data regarding clinical findings at diagnosis, and exposure data was collected via questionnaires. The odds ratios (ORs) for the null forms of GSTM1 and GSTT1 and the normal activity YY form of EPHX*3 were close to one except GSTT1, which reached 1.86. The highest risk of polyneuropathy was found in smokers with GSTT1 null, who had a 3.7 times increased risk. Interactions between genes were analyzed and confirmed the increased OR for GSTT1, which was strongest if the patients had the low‐activity HH form of EPHX*3 (OR 2.37). Our hypothesis is that the GSTT1 null polymorphism may be related to an impaired metabolism of toxic substances that could lead to nerve damage in the peripheral nervous system.
Mathematical modelling of chemical processes—obtaining the best model predictions and parameter estimates using identifiability and estimability procedures
Authors: McLean Kevin A. P. , McAuley Kim B. 
Published: October 2011

AbstractChemical engineers who develop fundamental models often have difficulties estimating all model parameters due to problems with parameter identifiability and estimability. These two concepts are reviewed, as are techniques for assessing identifiability and estimability. When some parameters are not estimable from the data, modellers must decide whether to conduct new experiments, change the model structure, or to estimate only a subset of the parameters and leave the others at fixed values. Estimating a reduced number of parameters can lead to better model predictions with lower mean squared error (MSE). MSE‐based techniques for parameter subset selection are discussed and compared. © 2011 Canadian Society for Chemical Engineering
Current and emerging targeted therapies for metastatic breast cancer
Authors: Perez Edith A. , Spano Jean‐Philippe 
Published: October 2011

AbstractThe success of endocrine therapies for hormone receptor‐positive breast cancer and trastuzumab and lapatinib for targeting human epidermal growth factor receptor 2 (HER2)‐positive tumors has paved the way for the clinical development of several other metastatic breast cancer (MBC)‐targeted therapies. Although the benefit of the anti‐VEGF (vascular endothelial growth factor) monoclonal antibody bevacizumab in the MBC setting has become a topic of debate, clinical trial results are accumulating, and phase 3 evaluations are ongoing for newer HER2‐targeted agents (pertuzumab and trastuzumab‐maytansine immunoconjugate) and VEGF‐targeted agents (aflibercept), as well as dual, epidermal growth factor receptor/HER2‐targeted agents (afatinib [BIBW 2992] and neratinib), multitargeted tyrosine kinase inhibitors (sunitinib and pazopanib), and mammalian target of rapamycin (everolimus) and poly (ADP‐ribose) polymerase 1 inhibitors (iniparib, olaparib). These agents as well as other novel classes of anticancer agents are being tested in clinical trials with the potential of addressing unmet therapeutic needs in the MBC patient population. Cancer 2012;118: 3014–25. © 2011 American Cancer Society.
A phase II study of the survivin suppressant YM155 in patients with refractory diffuse large B‐cell lymphoma
Authors: Cheson Bruce D. , Bartlett Nancy L. , Vose Julie M. , Lopez‐Hernandez Andres , Seiz Amanda L. , Keating Anne T. , Shamsili Setareh 
Published: October 2011

AbstractBACKGROUND:Few effective therapeutic options exist for patients with refractory diffuse large B‐cell lymphoma (DLBCL). YM155 is a survivin suppressant with activity against DLBCL in a phase I trial. This phase II study was conducted to better characterize the toxicity and efficacy of this small molecule in patients with refractory DLBCL.METHODS:Forty‐one patients with a median age of 66 years and 3 prior regimens were enrolled and treated with a YM155 dose of 5 mg/m2/d by continuous infusion for 168 hours every 21 days for up to 15 cycles of treatment. The median number of completed cycles was 3.RESULTS:One patient had a complete remission (CR) (2.4%) with an additional 2 patients (5.9%) responding, with a median progression‐free survival of 58 days.CONCLUSIONS:YM155 was well tolerated with major toxicities including anemia and fatigue. Whereas YM155 had limited single‐agent activity, preclinical data suggest its role in combination with other agents, including rituximab, and a study of that combination in ongoing. Cancer 2012;118: 3128–34. © 2011 American Cancer Society.
A phase 1 study of weekly everolimus (RAD001) in combination with docetaxel in patients with metastatic breast cancer
Authors: Moulder Stacy , Gladish Gregory , Ensor Joe , Gonzalez‐Angulo Ana Maria , Cristofanilli Massimo , Murray James L. , Booser Daniel , Giordano Sharon H. , Brewster Abeena , Moore Julia , Rivera Edgardo , Hortobagyi Gabriel N. , Tran Hai T. 
Published: October 2011

AbstractBACKGROUND:Inhibition of mammalian target of rapamycin with everolimus may improve the efficacy of taxanes. Everolimus and docetaxel are both metabolized by CYP3A4, which could result in a pharmacokinetic (PK) interaction.METHODS:Fifteen patients with metastatic breast cancer were treated with docetaxel (doses of 40‐75 mg/m2 intravenously on day 1 of a 21‐day cycle) in combination with everolimus (doses ranging from 20 to 50 mg orally on days 1 and 8 of a 21‐day cycle) in a phase 1 trial using the continuous reassessment method to determine maximum tolerated dose. The first 2 patients developed a dose‐limiting toxicity (neutropenic infection), prompting a mandatory dose reduction and PK evaluation of both everolimus and docetaxel for patients enrolled in subsequent dosing cohorts.RESULTS:Fifteen patients were treated. Dose‐limiting toxicity included grade 3 mucositis (n = 1), prolonged grade 4 neutropenia (n = 1), and grade 3 infection/febrile neutropenia (n = 3). Day 8 of everolimus was commonly held for neutropenia despite a dose reduction in docetaxel to 40 mg/m2. Eleven patients underwent complete PK evaluation for everolimus, and 9 patients underwent complete PK evaluation for both everolimus and docetaxel. Widely variable changes in clearance were seen for both drugs, and the study was terminated because of lack of efficacy and concerns regarding toxicity seen with the combination.CONCLUSIONS:Weekly everolimus in combination with docetaxel every 3 weeks was associated with excessive neutropenia and variable clearance of both drugs, making combination therapy unpredictable, even at low doses of both drugs. Cancer 2012. © 2011 American Cancer Society.
MicroRNA expression profiling is a potential diagnostic tool for thyroid cancer
Authors: Vriens Menno R. , Weng Julie , Suh Insoo , Huynh Nhung , Guerrero Marlon A. , Shen Wen T. , Duh Quan‐Yang , Clark Orlo H. , Kebebew Electron 
Published: October 2011

AbstractBACKGROUND:Approximately 30% of fine‐needle aspiration (FNA) biopsies of thyroid nodules are indeterminate or nondiagnostic. Recent studies suggest microRNA (miRNA, miR) is differentially expressed in malignant tumors and may have a role in carcinogenesis, including thyroid cancer. The authors therefore tested the hypothesis that miRNA expression analysis would identify putative markers that could distinguish benign from malignant thyroid neoplasms that are often indeterminate on FNA biopsy.METHODS:A miRNA array was used to identify differentially expressed genes (5‐fold higher or lower) in pooled normal, malignant, and benign thyroid tissue samples. Real‐time quantitative polymerase chain reaction was used to confirm miRNA array expression data in 104 tissue samples (7 normal thyroid, 14 hyperplastic nodule, 12 follicular variant of papillary thyroid cancer, 8 papillary thyroid cancer, 15 follicular adenoma, 12 follicular carcinoma, 12 Hurthle cell adenoma, 20 Hurthle cell carcinoma, and 4 anaplastic carcinoma cases), and 125 indeterminate clinical FNA samples. The diagnostic accuracy of differentially expressed genes was determined by analyzing receiver operating characteristics.RESULTS:Ten miRNAs showed >5‐fold expression difference between benign and malignant thyroid neoplasms on miRNA array analysis. Four of the 10 miRNAs were validated to be significantly differentially expressed between benign and malignant thyroid neoplasms by quantitative polymerase chain reaction (P < .002): miR‐100, miR‐125b, miR‐138, and miR‐768‐3p were overexpressed in malignant samples of follicular origin (P < .001), and in Hurthle cell carcinoma samples alone (P < .01). Only miR‐125b was significantly overexpressed in follicular carcinoma samples (P < .05). The accuracy for distinguishing benign from malignant thyroid neoplasms was 79% overall, 98% for Hurthle cell neoplasms, and 71% for follicular neoplasms. The miR‐138 was overexpressed in the FNA samples (P = .04) that were malignant on final pathology with an accuracy of 75%.CONCLUSIONS:MicroRNA expression differs for normal, benign, and malignant thyroid tissue. Expression analysis of differentially expressed miRNA could help distinguish benign from malignant thyroid neoplasms that are indeterminate on thyroid FNA biopsy. Cancer 2011. © 2011 American Cancer Society.