bluuebunny/crossref_metadata_2025 huggingface dataset:
HLA associations reveal genetic heterogeneity in psoriatic arthritis and in the psoriasis phenotype
Authors: Winchester Robert , Minevich Gregory , Steshenko Valeria , Kirby Brian , Kane David , Greenberg David A. , FitzGerald Oliver
Published: October 2011

Objective

Rigorously ascertained cases of psoriatic arthritis in subjects presenting to a rheumatology unit were compared with cases of psoriasis in subjects presenting to a dermatology unit, where subjects with musculoskeletal features were excluded, to address 1) the extent to which the contribution of the major histocompatibility complex (MHC) to psoriatic arthritis susceptibility resembles that in psoriasis, and 2) whether MHC genes determine quantitative traits within the psoriatic arthritis phenotype.

Methods

Separate discovery and validation subcohorts of patients recruited from a relatively homogeneous population were studied by sequence‐based HLA typing, in which frequencies of the HLA–B and HLA–C alleles and haplotypes were compared.

Results

In patients with psoriatic arthritis, the frequency of C*06:02 was lower than that in patients with psoriasis (28.7% versus 57.5%; P = 9.9 × 10−12). Three haplotypes containing B*27:05 or B*39:01 were significantly increased in frequency in patients with psoriatic arthritis, but not in those with psoriasis. The structurally related B*39:06 allele was not increased in frequency. B*27 was associated with an interval of 0.98 years between skin and musculoskeletal disease (P = 2.05 × 10−6), compared with an interval of 10.14 years for C*06. Preliminary evidence suggested that B*38:01 and B*08 may be associated with psoriatic arthritis susceptibility, and that allotypes encoding P2 pockets that bind side chains opposite in charge from those encoded by the B*27 and B*39 molecules may exert a protective role.

Conclusion

These findings suggest that the psoriasis phenotype results from two patterns of MHC effect. The first involves the classic psoriasis susceptibility gene C*06, which confers more penetrant skin disease with less prevalent and more time‐dependent musculoskeletal phenotype development. The second pattern appears to be mediated by HLA–B alleles, notably B*27, and includes temporally more coincident musculoskeletal involvement that is nearly equivalent in penetrance to that of the skin disease.
The CD14brightCD16+ monocyte subset is expanded in rheumatoid arthritis and promotes expansion of the Th17 cell population
Authors: Rossol Manuela , Kraus Stephan , Pierer Matthias , Baerwald Christoph , Wagner Ulf
Published: October 2011

Objective

Circulating monocytes contain a subpopulation of CD14+CD16+ cells; this subpopulation of cells has been described to be proinflammatory and to have an increased frequency in rheumatoid arthritis (RA). New evidence suggests that this subpopulation can be further subdivided into CD14dimCD16+ and CD14brightCD16+ cells. The aim of this study was to determine which of the two CD16+ monocyte subpopulations is expanded in patients with RA and to investigate their possible role in disease pathogenesis.

Methods

The frequencies of monocyte subpopulations in the peripheral blood of healthy donors and patients with RA were determined by flow cytometry. Monocyte subpopulations were sorted and cocultured with CD4+ T cells. Cytokines were determined in the supernatant, and Th17 cell frequencies were measured by flow cytometry.

Results

In comparison with the other monocyte subpopulations, CD14brightCD16+ cells showed higher HLA–DR and CCR5 expression and responded with higher tumor necrosis factor production to direct cell contact with preactivated T cells. They were observed at increased frequencies in the peripheral blood of patients with RA, while CD14dimCD16+ monocyte frequencies were not increased. CD14brightCD16+ cells were extremely potent inducers of Th17 cell expansion in vitro. Their frequency in the peripheral blood of patients with RA correlated closely with Th17 cell frequencies determined ex vivo.

Conclusion

This study is the first to provide a link between the increased frequency of the CD14brightCD16+ monocyte subpopulation in RA and the expansion of Th17 cells, which are likely to have a role in the pathogenesis of autoimmunity.
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

Objective

FSTL1 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.

Methods

Collagen‐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.

Results

FSTL1 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.

Conclusion

These 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

Objective

Autoantibody 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.

Methods

CXCR3−/− 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.

Results

CXCR3−/− 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.

Conclusion

CXCR3 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

Objective

Adrenomedullin22–52 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.

Methods

DBA/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.

Results

In 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.

Conclusion

Our 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

Multigene 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

The 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

In 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

A 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

Embryonic 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

The 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

Chemical 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

The 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 tale of 2 perspectives
Authors: Albertsen Peter
Published: October 2011

Prostate cancer in the elderly is seen from a different perspective.
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

BACKGROUND:

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

BACKGROUND:

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

BACKGROUND:

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.
Effect of histologic subtype on treatment and outcomes for esophageal cancer in the United States
Authors: Merkow Ryan P. , Bilimoria Karl Y. , McCarter Martin D. , Chow Warren B. , Gordon Howard S. , Stewart Andrew K. , Ko Clifford Y. , Bentrem David J.
Published: October 2011

BACKGROUND:

Esophageal adenocarcinoma (AC) and squamous cell carcinoma (SCC) have distinct clinico‐pathologic characteristics; however, it is unclear whether treatment patterns differ by histologic subtype. The objective of this study was to examine differences in treatment use and outcomes by histologic subtype for esophageal cancer in the United States.

METHODS:

From the National Cancer Data Base, patients with esophageal cancer were identified. Regression models were formulated to assess the influence of histologic subtype on treatment use and overall survival.

RESULTS:

From 1998 to 2007, 80,961 patients were identified with esophageal cancer in the United States. A higher percentage of patients with nonmetastatic AC underwent surgical resection compared with patients with nonmetastatic SCC (AC, 65.7%; SCC, 36.0%; P<.001), who were more often treated with chemoradiotherapy alone (AC, 25.7%; SCC, 54.1%; P<.001). High‐volume academic centers used surgery more frequently for both AC and SCC than did other centers, yet even at high‐volume academic centers, surgery was used much less often to treat SCC than AC (AC, 79.3%; SCC, 53.7%; P<.001). The likelihood of operative treatment for nonmetastatic disease was significantly lower in patients with SCC compared with patients with AC (P<.001). Overall survival was lower for patients with stage II/III disease of either histologic subtype treated with chemoradiotherapy alone compared with surgery plus chemoradiotherapy (P<.001).

CONCLUSION:

A large proportion of patients with esophageal cancer are being treated nonoperatively, and treatment use varies according to tumor histology, particularly by center type. Cancer 2011. © 2011 American Cancer Society.
Toward a target and coupling function of three different Information Security Management Systems
Authors: Boehmer Wolfgang
Published: October 2011

The limits of traditional (static) policies are well known in many areas of computer science and information security and are extensively discussed in the literature. Although some flexibility has been achieved with the introduction of dynamic policies, these efforts have only addressed a fraction of the requirements necessary to secure today's enterprises. Currently, no feedback mechanisms are in place to evaluate the effectiveness or economic impacts of static or dynamic policy implementation. Here, we address the requirement for feedback and present a policy for the next generation. This is a policy that includes a dynamic feedback response to the effectiveness of changes. The structure of this new type of policy, called a ‘management system’, is borrowed from discrete event system theory and functions as a control loop. A management system consists of four elements (control system, sensor, controller, and actuator) that are involved in a control law. In this article, we present also an analytical description of the optimal structure through which the three management systems (Information Security Management System (ISMS), Business Continuity Management System, and IT Service Management) should be linked in a company. We define a coupling parameter and, using an equation for the discrete control loop, show that ISMS and IT Service Management should ideally be strongly coupled, and ISMS and Business Continuity Management System should be weakly coupled. Furthermore, two types of management system can be defined. A simple management system (1 st order management system) responds to and regulates only perturbations. An advanced management system (2 nd order management system) has an overarching target function that influences the controller. This target function is usually economically oriented. Copyright © 2011 John Wiley & Sons, Ltd.
Frontal EEG asymmetry and fear reactivity in different contexts at 10 months
Authors: Diaz Anjolii , Bell Martha Ann
Published: October 2011

Individual differences in observed and maternal‐rated fear behaviors and frontal electroencephalogram (EEG) asymmetry were examined in normally developing 10‐month‐old infants. EEG was recorded during resting baseline, as well as during stranger approach, mask presentation, and toy spider presentation. Mothers completed the Infant Behavior Questionnaire. For mask presentation, baseline and task right frontal EEG asymmetry as well as maternal ratings predicted fear behavior during the mask task. For stranger approach, task‐related right frontal EEG asymmetry predicted fear behavior during stranger approach after controlling for baseline asymmetry. There was a trend for task‐related right frontal EEG asymmetry to predict fear during presentation of a toy spider after controlling for baseline asymmetry. Maternal report of temperament only added unique variance to the prediction of one fear task after controlling for baseline and task EEG. Assessing fear in multiple situations revealed context‐specific individual differences in infant fear. © 2011 Wiley Periodicals,Inc. Dev Psychobiol 54: 536–545, 2012.
Members of the BMP, Shh, and FGF morphogen families promote chicken statoacoustic ganglion neurite outgrowth and neuron survival in vitro
Authors: Fantetti Kristen N. , Fekete Donna M.
Published: October 2011

Mechanosensory hair cells of the chicken inner ear are innervated by the peripheral processes of statoacoustic ganglion (SAG) neurons. Members of several morphogen families are expressed within and surrounding the chick inner ear during stages of SAG axon outgrowth and pathfinding. On the basis of their localized expression patterns, we hypothesized that bone morphogenetic proteins (BMPs), fibroblast growth factors (FGFs), and sonic hedgehog (Shh) may function as guidance cues for growing axons and/or may function as trophic factors once axons have reached their targets. To test this hypothesis, three‐dimensional collagen cultures were used to grow Embryonic Day 4 (E4) chick SAG explants for 24 h in the presence of purified proteins or beads soaked in proteins. The density of neurite outgrowth was quantified to determine effects on neurite outgrowth. Explants displayed enhanced neurite outgrowth when cultured in the presence of purified BMP4, BMP7, a low concentration of Shh, FGF8, FGF10, or FGF19. In contrast, SAG neurons appeared unresponsive to FGF2. Collagen gel cultures were labeled with terminal dUTP nick‐end labeling and immunostained with anti‐phosphohistone H3 to determine effects on neuron survival and proliferation, respectively. Treatments that increased neurite outgrowth also yielded significantly fewer apoptotic cells, with no effect on cell proliferation. When presented as focal sources, BMP4, Shh, and FGFs ‐8, ‐10, and ‐19 promoted asymmetric outgrowth from the ganglion in the direction of the beads. BMP7‐soaked beads did not induce this response. These results suggest that a subset of morphogens enhance both survival and axon outgrowth of otic neurons. © 2011 Wiley Periodicals, Inc. Develop Neurobiol, 2012
Tbx5 overexpression favors a first heart field lineage in murine embryonic stem cells and in Xenopus laevis embryos
Authors: Herrmann Franziska , Bundschu Karin , Kühl Susanne J. , Kühl Michael
Published: October 2011

The T‐box transcription factor Tbx5 is involved in several developmental processes including cardiogenesis. Early steps of cardiac development are characterised by the formation of two cardiogenic lineages, the first (FHF) and the second heart field (SHF) lineage, which arise from a common cardiac progenitor cell population. To further investigate the function of Tbx5 during cardiogenesis, we generated a murine embryonic stem cell line constitutively overexpressing Tbx5. Differentiation of these cells is characterised by an earlier and increased appearance of contracting cardiomyocytes that beat with a higher frequency than control cells. In semi‐quantitative and quantitative RT‐PCR analyses, we observed an up‐regulation of cardiac marker genes such as Troponin T, endogenous Tbx5, and Nkx2.5 and a down‐regulation of others like BMP4 and Hand2. Similar data were gained in Xenopus laevis arguing for a conserved function of Tbx5. Furthermore, markers of the conduction system and atrial cardiomyocytes were increased. Developmental Dynamics 240:2634–2645, 2011. © 2011 Wiley Periodicals, Inc.
Transcriptional control of macrophage diversity and specialization
Authors: Ostuni Renato , Natoli Gioacchino
Published: October 2011

The key driving force underlying cell identity is represented by the complex and dynamic interplay between cell‐intrinsic, lineage‐restricted developmental pathways on the one hand, and cell‐extrinsic, tissue‐specific microenvironmental signals on the other. In this context, macrophages are a paradigmatic cell population whose functional specialization in vivo reflects the impact of the local microenvironment on the intrinsic differentiation program, leading to a variety of specialized macrophage types in different tissues and conditions; however, how this is translated into a biological outcome is not appreciably understood. The kind of investigations described in this Viewpoint aim to explore the inner determinants of cell identity and functional diversification at a genomic level; mechanisms that permit plastic cell types, like macrophages, to adapt to different environments.
The role of macrophages and dendritic cells in the clearance of apoptotic cells in advanced atherosclerosis
Authors: Thorp Edward , Subramanian Manikandan , Tabas Ira
Published: October 2011

Accumulating evidence supports the notion that defective phagocytic clearance of dying cells, or defective “efferocytosis,” is causally linked to the progression of advanced atherosclerosis. In advanced atherosclerotic lesions, defective efferocytosis leads to post‐apoptotic necrosis, expansion of plaque necrotic cores, and susceptibility to atherothrombosis. Both macrophages and DC‐like efferocytes are juxtaposed near expanding necrotic cores, where they engage apoptotic cells. In this Viewpoint, we discuss how reduced efferocytosis by macrophages and CD11cHI DC‐like cells may combine to reduce overall plaque stability and therefore promote susceptibility to acute atherothrombosis.
Macrophage heterogeneity and acute inflammation
Authors: Liddiard Kate , Rosas Marcela , Davies Luke C. , Jones Simon A. , Taylor Philip R.
Published: October 2011

In this Viewpoint, we concentrate on the aspects of macrophage biology that we believe are fundamental for an appropriate contextual understanding of macrophage function during acute inflammation. These are the different origins of macrophage populations (and the implications of this for the renewal of these populations in the adult); and the impact of specific homeostatic or disease‐associated microenvironments upon cellular heterogeneity, activation and effector functions.
T helper cell populations: As flexible as the skin?
Authors: Waisman Ari
Published: October 2011

T helper cells can be defined by the cytokines they produce and are divided into Th1, Th2, Th17, TFH or regulatory T cells. Th17 cells have been shown to produce, in addition to IL‐17, IL‐22. In the current issue of the European Journal of Immunology, an article by Larsen et al. (Eur. J. Immunol. 2011. 41: 2596–2605) provides evidence that human T helper cells, like murine cells, can also express IL‐22 in the absence of the other T helper cell signature cytokines. Moreover, they show that these IL‐22‐producing cells, namely Th22 cells, can be found in the skin of psoriasis patients, where they might contribute to the pathogenesis of this inflammatory skin disease. Finally, they show that, molecularly, Th22 cells are related to Th17 cells, and might therefore be derived from the latter. In this Commentary, the development of the pro‐inflammatory T helper populations in the skin are discussed and a model that explains the development of Th22 cells found in the skin of psoriasis patients is proposed.
CD8+ T‐cell cross‐competition is governed by peptide–MHC class I stability
Authors: Galea Ian , Stasakova Jana , Dunscombe Melanie S. , Ottensmeier Christian H. , Elliott Tim , Thirdborough Stephen M.
Published: October 2011

A major contributing factor to the final magnitude and breadth of CD8+ T‐cell responses to complex antigens is immunodomination, where CD8+ T cells recognizing their cognate ligand inhibit the proliferation of other CD8+ T cells engaged with the same APC. In this study, we examined how the half‐life of cell surface peptide–MHC class I complexes influences this phenomenon. We found that primary CD8+ T‐cell responses to DNA vaccines in mice are shaped by competition among responding CD8+ T cells for nonspecific stimuli early after activation and prior to cell division. The susceptibility of CD8+ T cells to ‘domination’ was a direct correlate of higher kinetic stability of the competing CD8+ T‐cell cognate ligand. When high affinity competitive CD8+ T cells were deleted by self‐antigen expression, competition was abrogated. These findings show, for the first time to our knowledge, the existence of regulatory mechanisms that direct the responding CD8+ T‐cell repertoire toward epitopes with high‐stability interactions with MHC class I molecules. They also provide an insight into factors that facilitate CD8+ T‐cell coexistence, with important implications for vaccine design and delivery.
Diversity‐Oriented Synthesis of Useful Chiral Building Blocks from D‐Mannitol
Authors: Aravind Appu , Kumar Ponminor Senthil , Sankar Muthukumar Gomathi , Baskaran Sundarababu
Published: October 2011

A diversity‐oriented synthesis is described for functionalized chiral building blocks (i.e., 7, 9, 10, 16, and 17) and the biologically active iminosugar, fucosidase inhibitor (2S,3R,4R,5R)‐2‐(hydroxymethyl)‐5‐methylpyrrolidine‐3,4‐diol (22), starting from common chiral intermediate 1a which is obtained through a regioselective reductive cleavage of a bis(benzylidene) acetal.
Linear polyalkylamines as fingerprinting agents in capillary electrophoresis of low‐molecular‐weight heparins and glycosaminoglycans
Authors: King J. Timothy , Desai Umesh R.
Published: October 2011

Glycosaminoglycan (GAG) analysis represents a challenging frontier despite the advent of many high‐resolution technologies because of their unparalleled structural complexity. We previously developed a resolving agent‐aided capillary electrophoretic approach for fingerprinting low‐molecular‐weight heparins (LMWHs) to profile their microscopic differences and assess batch‐to‐batch variability. In this report, we study the application of this approach for fingerprinting other GAGs and analyze the basis for the fingerprints observed in CE. Although the resolving agents, linear polyalkylamines, could resolve the broad featureless electropherogram of LMWH into a large number of distinct, highly reproducible peaks, longer GAGs such as chondroitin sulfate, dermatan sulfate, and heparin responded in a highly individualistic manner. Full‐length heparin interacted with linear polyalkylamines very strongly followed by dermatan sulfate, whereas chondroitin sulfate remained essentially unaffected. Oversulfated chondroitin sulfate could be easily identified from full‐length heparin. Scatchard analysis of the binding profile of enoxaparin with three linear polyalkylamines displayed a biphasic binding profile suggesting two distinctly different types of interactions. Some LMWH chains were found to interact with linear polyalkylamines with affinities as high as 10 nM, whereas others displayed nearly 5000‐fold weaker affinities. These observations provide fundamental insight into the basis for fingerprinting of LMWHs by linear polyalkylamine‐based resolving agents, which could be utilized in the design of advanced resolving agents for compositional profiling, direct sequencing, and chemoinformatics studies.
Sensitivity enhancement in capillary electrophoresis‐mass spectrometry of anionic metabolites using a triethylamine‐containing background electrolyte and sheath liquid
Authors: Kok Miranda G. M. , de Jong Gerhardus J. , Somsen Govert W.
Published: October 2011

Analyte responses in CE‐ESI‐MS using negative ionization are frequently relatively low, thereby limiting sensitivity in metabolomics applications. In order to enhance the ionization efficiency of anionic metabolites, BGEs and sheath liquids (SLs) of various compositions were evaluated. Pressure‐induced infusion and CE‐MS experiments showed that addition of triethylamine (TEA) to the BGE and SL enhanced analyte intensities. A BGE consisting of 25 mM TEA (pH 11.7) and an SL of water–methanol (1:1, v/v) containing 5 mM TEA was selected, providing separation and detection of ten representative test metabolites with good reproducibility (migration time RSDs<1%) and linearity (R2>0.99). This BGE yielded lower limits of detection (0.7–9.1 μM) for most test compounds when compared with common CE‐MS methods using a BGE and SL containing ammonium acetate (NH4Ac) (25 and 5 mM, respectively). CE‐MS of human urine revealed an average amount of 231 molecular features in negative ionization mode when TEA was used in the BGE and SL, whereas 115 and 102 molecular features were found with an NH4Ac‐containing BGE and SL, employing a bare fused‐silica (BFS) and Polybrene‐dextran sulfate‐Polybrene (PB‐DS‐PB)‐coated capillary, respectively. With the CE‐MS method using TEA, about 170 molecular features were observed that were not detected with the NH4Ac‐based CE‐MS methods. For more than 82% of the molecular features that were detected with the TEA as well as the NH4Ac‐containg BGEs (i.e. common features), the peak intensities were higher using TEA with gain factors up to 7. Overall, the results demonstrate that BGEs and SLs containing TEA are quite favorable for the analysis of anionic metabolites in CE‐MS.
A compact and rapid aptasensor platform based on surface plasmon resonance
Authors: Henseleit Anja , Schmieder Stefan , Bley Thomas , Sonntag Frank , Schilling Niels , Quenzel Philipp , Danz Norbert , Klotzbach Udo , Boschke Elke
Published: October 2011

Aptamers are synthetic single‐stranded oligonucleotides which bind specifically to their target. They offer several advantages over antibodies. For example, aptamers can be produced under unphysiological conditions against almost any target, including toxic or pathological substances. They are also quicker and cheaper produced than antibodies, and are easy to modify without loss of activity. Furthermore, they exhibit high stability under a width range of conditions. Consequently, they make excellent receptors for the use in biosensors. This article describes the evaluation of a novel aptasensor based on the Surface Plasmon Resonance (SPR)‐system developed by the Fraunhofer Institute for Applied Optics and Precision Engineering IOF (Jena, Germany) using a thrombin–aptamer interaction as a model system. The biotin‐tagged aptamer was attached to the sensor's gold surface by means of its interaction with streptavidin. Thrombin solutions of different concentrations were pumped over this surface, and the interaction was measured under buffer flow. The binding signals for the thrombin–aptamer interaction were compared to those arising from a control random‐oligonucleotide of the same size and bearing the same modifications. Using this approach, we were able to obtain reproducible, significant and stable signals with a limit of detection of about 26 nmol/L.
Grey‐box modelling of flow in sewer systems with state‐dependent diffusion
Authors: Breinholt Anders , Thordarson Fannar Örn , Møller Jan Kloppenborg , Grum Morten , Mikkelsen Peter Steen , Madsen Henrik
Published: October 2011

Generating flow forecasts with uncertainty limits from rain gauge inputs in sewer systems require simple models with identifiable parameters that can adequately describe the stochastic phenomena of the system. In this paper, a simple grey‐box model is proposed that is attractive for both forecasting and control purposes. The grey‐box model is based on stochastic differential equations and a key feature is the separation of the total noise into process and measurement noise. The grey‐box approach is properly introduced and hypothesis regarding the noise terms are formulated. Three different hypotheses for the diffusion term are investigated and compared: one that assumes additive diffusion; one that assumes state proportional diffusion; and one that assumes state exponentiated diffusion. To implement the state dependent diffusion terms Itô's formula and the Lamperti transform are applied. It is shown that an additive diffusion noise term description leads to a violation of the physical constraints of the system, whereas a state dependent diffusion noise avoids this problem and should be favoured. It is also shown that a logarithmic transformation of the flow measurements secures positive lower flow prediction limits, because the observation noise is proportionally scaled with the modelled output. Finally it is concluded that a state proportional diffusion term best and adequately describes the one‐step flow prediction uncertainty, and a proper description of the system noise is important for ascertaining the physical parameters in question. Copyright © 2011 John Wiley & Sons, Ltd.