bluuebunny/crossref_metadata_2025 huggingface dataset:
Point-of-Care Testing as an Influenza Surveillance Tool: Methodology and Lessons Learned from Implementation
Authors: Gren Lisa H. , Porucznik Christina A. , Joy Elizabeth A. , Lyon Joseph L. , Staes Catherine J. , Alder Stephen C.
Published: April 2013

Objectives. Disease surveillance combines data collection and analysis with dissemination of findings to decision makers. The timeliness of these activities affects the ability to implement preventive measures. Influenza surveillance has traditionally been hampered by delays in both data collection and dissemination. Methods. We used statistical process control (SPC) to evaluate the daily percentage of outpatient visits with a positive point-of-care (POC) influenza test in the University of Utah Primary Care Research Network. Results. Retrospectively, POC testing generated an alert in each of 4 seasons (2004–2008, median 16 days before epidemic onset), suggesting that email notification of clinicians would be 9 days earlier than surveillance alerts posted to the Utah Department of Health website. In the 2008-09 season, the algorithm generated a real-time alert 19 days before epidemic onset. Clinicians in 4 intervention clinics received email notification of the alert within 4 days. Compared with clinicians in 6 control clinics, intervention clinicians were 40% more likely to perform rapid testing () and twice as likely to vaccinate for seasonal influenza () after notification. Conclusions. Email notification of SPC-generated alerts provided significantly earlier notification of the epidemic onset than traditional surveillance. Clinician preventive behavior was not significantly different in intervention clinics.
Interval Oscillation Criteria for a Class of Fractional Differential Equations with Damping Term
Authors: Qi Chunxia , Cheng Junmo
Published: April 2013

Some new interval oscillation criteria are established based onthe certain Riccati transformation and inequality techniquefor a class of fractional differential equations with damping term. For illustrating the validity of the established results, we also present some applications for them.
A Special Ingredient (VtR) Containing Oligostilbenes Isolated fromVitis thunbergiiPrevents Bone Loss in Ovariectomized Mice:In VitroandIn VivoStudy
Authors: Huang Yu-Ling , Liu Yen-Wenn , Huang Yu-Jou , Chiou Wen-Fei
Published: April 2013

Vitis thunbergiiis used in Taiwan as a botanical supplement for inflammatory bone diseases. This study aims to examine its direct effect on bone metabolism. Three-month-old female mice were randomly divided into ovariectomized control (OVX), sham operated (SHAM), and ovariectomy treated with either 17β-estradiol or a special ingredient (VtR) fractionated from an ethanol extract ofV. thunbergiistarted two weeks after ovariectomy. VtR treatment for 8 weeks significantly ameliorated the deterioration of bone mineral density and reversed all the ovariectomy-induced changes in  μ-CT parameters. The antiosteoporotic effect of VtR accompanied decrease in serum levels of C-terminal telopeptides of type I collagen (CTx), interleukin-7, and ration of RANKL/osteoprotegerin (OPG) but rise in osteocalcin concentration. Sparse calcified microarchitecture and less alkaline-phosphatase- (ALP-) positive cells were observed at the femur and vertebral sites in OVX mice while VtR remarkably restored such variation. HPLC analysis showed (+)-vitisin-A, (−)-vitisin-B, and ampelopsin C predominated in VtR. Both (−)-vitisin B and ampelopsin C increased ALP activity and bone nodule formation in cultured osteoblasts. Instead of stimulating osteoblastogenesis, (+)-vitisin A dramatically repressed osteoclasts differentiation and bone resorption. The results suggested VtR composed of diverse components to reciprocally drive osteoblastogenesis and interdict osteoclastogenesis may serve as a potential botanic drug for osteoporosis therapy.
Antioptimisation of Trusses Using Two-Level Population-Based Incremental Learning
Authors: Tontragunrat Phinit , Bureerat Sujin
Published: April 2013

Practical optimum design of structures often involves parameters with uncertainties. There have been several ways to deal with such optimisation problems, and one of the approaches is an antioptimisation process. The task is to find the optimum solution of common design variables while simultaneously searching for the worst case scenario of those parameters with uncertainties. This paper proposed a metaheuristic based on population-based incremental learning (PBIL) for solving antioptimisation of trusses. The new algorithm is called two-level PBIL which consists of outer and inner loops. Five antioptimisation problems are posed to test the optimiser performance. The numerical results show that the concept of using PBIL probability vectors for handling the antioptimisation of truss is powerful and effective. The two-level PBIL can be considered a powerful optimiser for antioptimisation of trusses.
A Preconditioner for FETI-DP Method of Stokes Problem with Mortar-TypeCR(h)-P0(h)Discretization
Authors: Wang Chunmei
Published: April 2013

FETI-DP method is developed for incompressible Stokes problem discretized by mortar-typeCR(h)−P0(h)mixed elements. A preconditioner is proposed, and it is proved that the condition number of the preconditioned FETI-DP operator is bounded by(1+log(H/h))2, whereHandhare mesh sizes. Finally, the numerical tests are presented to verify the theoretical results.
The Fractional Complex Step Method
Authors: Ibrahim Rabha W. , Jalab Hamid A.
Published: April 2013

It is well known that the complex step method is a tool that calculates derivatives by imposing a complex step in a strict sense. We extended the method by employing the fractional calculus differential operator in this paper. The fractional calculus can be taken in the sense of the Caputo operator, Riemann-Liouville operator, and so forth. Furthermore, we derived several approximations for computing the fractional order derivatives. Stability of the generalized fractional complex step approximations is demonstrated for an analytic test function.
Approximate Controllability of Fractional Neutral Evolution Equations in Banach Spaces
Authors: Mahmudov N. I.
Published: April 2013

We discuss the approximate controllability of semilinear fractional neutral differential systems with infinite delay under the assumptions that the corresponding linear system is approximately controllable. Using Krasnoselkii's fixed-point theorem, fractional calculus, and methods of controllability theory, a new set of sufficient conditions for approximate controllability of fractional neutral differential equations with infinite delay are formulated and proved. The results of the paper are generalization and continuation of the recent results on this issue.
Methodology of an International Study of People with Multiple Sclerosis Recruited through Web 2.0 Platforms: Demographics, Lifestyle, and Disease Characteristics
Authors: Hadgkiss Emily J. , Jelinek George A. , Weiland Tracey J. , Pereira Naresh G. , Marck Claudia H. , van der Meer Dania M.
Published: April 2013

Background. Despite evidence of the potential importance of the role of health and lifestyle behaviours in multiple sclerosis (MS) outcomes, there has not been a significant focus on this area of research.Aim. We aimed to recruit an international sample of people with MS at baseline and over a five-year timeframe, examine their health and lifestyle behaviours, and determine the relationship of these behaviours to self-reported disability, disease activity, and quality of life.Methods. People with MS were recruited through web 2.0 platforms including interactive websites, social media, blogs, and forums and completed a comprehensive, multifaceted online questionnaire incorporating validated and researcher-derived tools.Results. 2519 participants met inclusion criteria for this study. This paper describes the study methodology in detail and provides an overview of baseline participant demographics, clinical characteristics, summary outcome variables, and health and lifestyle behaviours. The sample described is unique due to the nature of recruitment through online media and due to the engagement of the group, which appears to be well informed and proactive in lifestyle modification.Conclusion. This sample provides a sound platform to undertake novel exploratory analyses of the association between a variety of lifestyle factors and MS outcomes.
Occurrence of White Sharks (Carcharodon carcharias) in Hawaiian Waters
Authors: Weng Kevin , Honebrink Randy
Published: April 2013

White sharks (Carcharodon carcharias) have been known in Hawaii (~158°W, 22°N) since the time of ancient Hawaiians. We compiled sightings and records from 1926 to the present (4 females, 2 males, and 8 unknown sex; 3.3–4.5 m total length) and compared them with satellite tracking records (7 females, 9 males, and 6 unknown; 3.7–5.3 m total length). White sharks have been sighted in Hawaii throughout the year, whereas satellite tracking studies show individuals near the North American coast during fall and offshore during spring for the eastern North Pacific population (northern fall/spring). The mismatch of these datasets could hypothetically be consistent with fall-sighted individuals being sourced from a different population or part of a resident population. However, recently documented multiyear movements of North American sharks revealed that the annual nearshore-offshore pattern does not hold for mature females, which ranged over larger areas and were offshore during the fall. We found that fall white shark sightings in Hawaii are predominantly of females, most likely visitors from the eastern North Pacific population. Misidentification of other species as white sharks frequently occurs by fishers and in the news media, and we suggest methods for discrimination of related species.
Comparison Study of Airway Reactivity Outcomes due to a Pharmacologic Challenge Test: Impulse Oscillometry versus Least Mean Squared Analysis Techniques
Authors: Rodriguez Elena , Bullard Charrell M. , Armani Milena H. , Miller Thomas L. , Shaffer Thomas H.
Published: April 2013

The technique of measuring transpulmonary pressure and respiratory airflow with manometry and pneumotachography using the least mean squared analysis (LMS) has been used broadly in both preclinical and clinical settings for the evaluation of neonatal respiratory function during tidal volume breathing for lung tissue and airway frictional mechanical properties measurements. Whereas the technique of measuring respiratory function using the impulse oscillation technique (IOS) involves the assessment of the relationship between pressure and flow using an impulse signal with a range of frequencies, requires less cooperation and provides more information on total respiratory system resistance (chest wall, lung tissue, and airways). The present study represents a preclinical animal study to determine whether these respiratory function techniques (LMS and IOS) are comparable in detecting changes in respiratory resistance derived from a direct pharmacological challenge.
The Amyand’s Hernia: A Rare Clinical Entity Diagnosed by Computed Tomography
Authors: Keskin Suat , Şimşek Cihan , Keskin Zeynep
Published: April 2013

Amyand’s hernia, named for the first person to describe an inguinal hernia containing the vermiform appendix, is an uncommon variant of an inguinal hernia. Amyand’s hernia is an extremely rare condition and is often misdiagnosed. Traditionally, these hernias have been diagnosed at surgery but are increasingly diagnosed by abdominal computed tomography (CT) scans. CT of the abdomen may help in guiding the diagnosis.
A 6LoWPAN Routing Optimization Mechanism for WMSN
Authors: Li Jing , Shen Chong , Kwong Kae Hsiang
Published: April 2013

In Wireless sensor networks (WSNs), group mobility is important in many practical application scenarios, and it is inconvenient for traditional static WSNs to collect information. In this paper, we propose a WSN model based on IPv6 over Low power Wireless Personal Area Networks (6LoWPANs) in mobile sensing application scenarios. Wireless mesh sensor network (WMSN) infrastructure and Network Mobility (NEMO) protocol are deployed to ensure the continuity of the communications. The routing optimization mechanism in the nested network is then discussed. By taking mobile network partition and IP address configuration in the nested network, the corresponding signaling flow is discussed. Simulation results indicate that our mechanism is able to minimize the transmission costing, handoff delay, throughput and energy consumption of sensor nodes. Energy of each mobile router (MR) saves around 0.2 J per 3 seconds.
A Review of the Clinical Outcomes for Patients Diagnosed with Brainstem Metastasis and Treated with Stereotactic Radiosurgery
Authors: Lamm Andrew F. , Elaimy Ameer L. , Lamoreaux Wayne T. , Mackay Alexander R. , Fairbanks Robert K. , Demakas John J. , Cooke Barton S. , Lee Christopher M.
Published: April 2013

Only 3%–5% of all brain metastases are located in the brainstem. We present a comprehensive review of the clinical outcomes from modern studies that treated patients with brainstem metastasis using either a Gamma Knife or a linear accelerator-based stereotactic radiosurgery. The median survival time of patients was compared to better understand what clinical or treatment factors are predictive of improved survival. This information can then be utilized to optimize patient care. The data suggests that higher prescribed marginal dose and the associated greater local control of brainstem lesions are associated with longer patient survival. Further research is necessary to better describe the most effective dose for individual brainstem lesions and to tailor optimum therapy to specific patient subgroups.
Adsorption Behaviors of Oxytetracycline onto Sediment in the Weihe River, Shaanxi, China
Authors: Cheng Dong-Hui , Yang Sheng-Ke , Zhao Yue , Chen Jing
Published: April 2013

Adsorption behaviors of oxytetracycline onto sediment in the Weihe River were described. The impact factors in the processes of adsorption, such as contact time, solution pH, temperature, and ionic strength, were determined by experiments. The experimental results were analyzed by kinetic and isotherm models. The adsorption kinetics was found to follow a pseudo‐first‐order model. The equilibrium adsorption data fitted well with the Langmuir and Freundlich isotherm models. However, the Langmuir isotherm was more suitable to describe the adsorption. Thermodynamics parameters such as Gibbs‐free energy change (ΔG°), enthalpy change (ΔH°), and entropy change (ΔS°) were calculated. Results showed that the adsorption was feasible, spontaneous, entropy increasing, and endothermic in nature, which reached equilibrium in about 24 hours. The adsorption capacity did not cause obvious change at solution pH 4.0–7.0, and both decreased in solution pH 7.0–10.0 and 4.0–2.0. The presence of electrolytes such as NaCl in aqueous solution had a significant negative effect on the adsorption. The mechanisms controlling the adsorption were supposed to be chemisorption.
Bacteriophages InfectingPropionibacterium acnes
Authors: Brüggemann Holger , Lood Rolf
Published: April 2013

Viruses specifically infecting bacteria, or bacteriophages, are the most common biological entity in the biosphere. As such, they greatly influence bacteria, both in terms of enhancing their virulence and in terms of killing them. Since the first identification of bacteriophages in the beginning of the 20th century, researchers have been fascinated by these microorganisms and their ability to eradicate bacteria. In this review, we will cover the history of thePropionibacterium acnesbacteriophage research and point out how bacteriophage research has been an important part of the research onP. acnesitself. We will further discuss recent findings from phage genome sequencing and the identification of phage sequence signatures in clustered regularly interspaced short palindromic repeats (CRISPRs). Finally, the potential to useP. acnesbacteriophages as a therapeutic strategy to combatP. acnes-associated diseases will be discussed.
Cystoid Macular Edema Induced by Low Doses of Nicotinic Acid
Authors: Domanico Daniela , Carnevale Carmela , Fragiotta Serena , Verboschi Francesca , Altimari Simona , Vingolo Enzo Maria
Published: April 2013

Cystoid macular edema (CME) is a condition that involves the macula, causing painless vision loss. In this paper, we report a case of niacin-induced bilateral cystoid macular edema (CME) in a middle-age woman taking low dose of niacin (18 mg of nicotinic acid). Optical coherence tomography (OCT) showed retinal thickening and cystoid spaces in both eyes, whereas fluorescein angiography (FA; HRA 2, Heidelberg Engineering) revealed the absence of fluorescein leakage also in later phases. Four weeks after discontinuation of therapy there were a complete disappearance of macular edema at funduscopic examination and an improvement of visual acuity in both eyes. Furthermore OCT showed a normal retinal profile in both eyes. In our opinion considering the wide availability of niacin, medical monitoring and periodical examination should be considered during niacin administration. To our knowledge, this is the first report in the literature that described the very low-dose niacin-induced bilateral niacin maculopathy.
Elevated Cardiac Troponins in Setting of Systemic Inflammatory Response Syndrome, Sepsis, and Septic Shock
Authors: Hussain Nasir
Published: April 2013

Elevation of cardiac troponins and creatinine kinase is frequently observed in setting of systemic inflammatory response syndrome (SIRS), sepsis, or septic shock. Underlying pathophysiologic mechanism for such troponin leak, its clinical significance, and what different could be done in such settings remain elusive. In this paper we have briefly overviewed the proposed pathogenic mechanisms for SIRS, sepsis, or septic shock-related troponin elevation (SRTE) and have provided brief overview on its clinical significance. Upon review of the relevant literature we found that majority of patients with the SRTE with no prior history of coronary artery disease (CAD) upon testing are found not to have any CADs. We have also briefly discussed the possible pharmacologic agents and potential targets which are important from pathophysiologic and pharmacologic point of view that may alter the outcomes of SRTE-related myocardial depression in near future.
A New Smoothing Nonlinear Conjugate Gradient Method for Nonsmooth Equations with Finitely Many Maximum Functions
Authors: Chen Yuan-yuan , Du Shou-qiang
Published: April 2013

The nonlinear conjugate gradient method is of particular importance for solving unconstrained optimization. Finitely many maximum functions is a kind of very useful nonsmooth equations, which is very useful in the study of complementarity problems, constrained nonlinear programming problems, and many problems in engineering and mechanics. Smoothing methods for solving nonsmooth equations, complementarity problems, and stochastic complementarity problems have been studied for decades. In this paper, we present a new smoothing nonlinear conjugate gradient method for nonsmooth equations with finitely many maximum functions. The new method also guarantees that any accumulation point of the iterative points sequence, which is generated by the new method, is a Clarke stationary point of the merit function for nonsmooth equations with finitely many maximum functions.
Seismic Analysis of Deep Water Pile Foundation Based on Three-Dimensional Potential-Based Fluid Elements
Authors: Wei Kai , Yuan Wancheng
Published: April 2013

This paper investigates the use of three-dimensional (3D) ϕ-u potential-based fluid elements for seismic analyses of deep water pile foundation. The mathematical derivations of the potential-based formulations are presented for reference. The potential-based modeling technique is studied and validated through experimental data and analytical solutions. Earthquake time history analyses for a 9-pile foundation in dry and different water environments are conducted, respectively. The seismic responses are discussed to investigate the complex effect of earthquake-induced fluid-structure interaction. Through the analyses, the potential-based fluid and interface elements are shown to perform adequately for the seismic analyses of pile foundation-water systems, and some interesting conclusions and recommendations are drawn.
On the Spectral Asymptotics of Operators on Manifolds with Ends
Authors: Coriasco Sandro , Maniccia Lidia
Published: April 2013

We deal with the asymptotic behaviour, forλ→+∞, of the counting functionNP(λ)of certain positive self-adjoint operatorsPwith double order(m,μ),m,μ>0,  m≠μ, defined on a manifold with endsM. The structure of this class of noncompact manifolds allows to make use of calculi of pseudodifferential operators and Fourier integral operators associated with weighted symbols globally defined onℝn. By means of these tools, we improve known results concerning the remainder terms of the Weyl Formulae forNP(λ)and show how their behaviour depends on the ratiom/μand the dimension ofM.
The Use of Gramian Matrices for Aeroelastic Stability Analysis
Authors: Bueno Douglas Domingues , Marqui Clayton Rodrigo , Sandoval Góes Luiz Carlos , Gonçalves Paulo José Paupitz
Published: April 2013

Most of the established procedures for analysis of aeroelastic flutter in the development of aircraft are based on frequency domain methods. Proposing new methodologies in this field is always a challenge, because the new methods need to be validated by many experimental procedures. With the interest for new flight control systems and nonlinear behavior of aeroelastic structures, other strategies may be necessary to complete the analysis of such systems. If the aeroelastic model can be written in time domain, using state-space formulation, for instance, then many of the tools used in stability analysis of dynamic systems may be used to help providing an insight into the aeroelastic phenomenon. In this respect, this paper presents a discussion on the use of Gramian matrices to determine conditions of aeroelastic flutter. The main goal of this work is to introduce how observability gramian matrix can be used to identify the system instability. To explain the approach, the theory is outlined and simulations are carried out on two benchmark problems. Results are compared with classical methods to validate the approach and a reduction of computational time is obtained for the second example.
Global Convergence of a New Nonmonotone Filter Method for Equality Constrained Optimization
Authors: Su Ke , Liu Wei , Lu Xiaoli
Published: April 2013

A new nonmonotone filter trust region method is introduced for solving optimization problems with equality constraints. This method directly uses the dominated area of the filter as an acceptability criterion for trial points and allows the dominated area decreasing nonmonotonically. Compared with the filter-type method, our method has more flexible criteria and can avoid Maratos effect in a certain degree. Under reasonable assumptions, we prove that the given algorithm is globally convergent to a first order stationary point for all possible choices of the starting point. Numerical tests are presented to show the effectiveness of the proposed algorithm.
Enhanced Effector Responses in Activated CD8+ T Cells Deficient in Diacylglycerol Kinases
Authors: Riese Matthew J. , Wang Liang-Chuan S. , Moon Edmund K. , Joshi Rohan P. , Ranganathan Anjana , June Carl H. , Koretzky Gary A. , Albelda Steven M.
Published: April 2013

Recent clinical trials have shown promise in the use of chimeric antigen receptor (CAR)-transduced T cells; however, augmentation of their activity may broaden their clinical use and improve their efficacy. We hypothesized that because CAR action requires proteins essential for T-cell receptor (TCR) signal transduction, deletion of negative regulators of these signaling pathways would enhance CAR signaling and effector T-cell function. We tested CAR activity and function in T cells that lacked one or both isoforms of diacylglycerol kinase (dgk) expressed highly in T cells, dgkα and dgkζ, enzymes that metabolize the second messenger diacylglycerol (DAG) and limit Ras/ERK activation. We found that primary murine T cells transduced with CARs specific for the human tumor antigen mesothelin showed greatly enhanced cytokine production and cytotoxicity when cocultured with a murine mesothelioma line that stably expresses mesothelin. In addition, we found that dgk-deficient CAR-transduced T cells were more effective in limiting the growth of implanted tumors, both concurrent with and after establishment of tumor. Consistent with our studies in mice, pharmacologic inhibition of dgks also augments function of primary human T cells transduced with CARs. These results suggest that deletion of negative regulators of TCR signaling enhances the activity and function of CAR-expressing T cells and identify dgks as potential targets for improving the clinical potential of CARs. Cancer Res; 73(12); 3566–77. ©2013 AACR.
Pak1 Kinase Links ErbB2 to β-Catenin in Transformation of Breast Epithelial Cells
Authors: Arias-Romero Luis E. , Villamar-Cruz Olga , Huang Min , Hoeflich Klaus P. , Chernoff Jonathan
Published: April 2013

p21-Activated kinase-1 (Pak1) is frequently upregulated in human breast cancer and is required for transformation of mammary epithelial cells by ErbB2. Here, we show that loss of Pak1, but not the closely related Pak2, leads to diminished expression of β-catenin and its target genes. In MMTV-ErbB2 transgenic mice, loss of Pak1 prolonged survival, and mammary tissues of such mice showed loss of β-catenin. Expression of a β-catenin mutant bearing a phospho-mimetic mutation at Ser 675, a specific Pak1 phosphorylation site, restored transformation to ErbB2-positive, Pak1-deficient mammary epithelial cells. Mice bearing xenografts of ErbB2-positive breast cancer cells showed tumor regression when treated with small-molecule inhibitors of Pak or β-catenin, and combined inhibition by both agents was synergistic. These data delineate a signaling pathway from ErbB2 to Pak to β-catenin that is required for efficient transformation of mammary epithelial cells, and suggest new therapeutic strategies in ErbB2-positive breast cancer. Cancer Res; 73(12); 3671–82. ©2013 AACR.
Phase I Study of the Hedgehog Pathway Inhibitor IPI-926 in Adult Patients with Solid Tumors
Authors: Jimeno Antonio , Weiss Glen J. , Miller Wilson H. , Gettinger Scott , Eigl Bernard J.C. , Chang Anne Lynne S. , Dunbar Joi , Devens Shannon , Faia Kerrie , Skliris Georgios , Kutok Jeff , Lewis Karl D. , Tibes Raoul , Sharfman William H. , Ross Robert W. , Rudin Charles M.
Published: April 2013

Purpose: To conduct a first-in-human phase I study to determine the dose-limiting toxicities (DLT), characterize the pharmacokinetic profile, and document the antitumor activity of IPI-926, a new chemical entity that inhibits the Hedgehog pathway (HhP).

Experimental Design: Patients with solid tumors refractory to standard therapy were given IPI-926 once daily (QD) by mouth in 28-day cycles. The starting dose was 20 mg, and an accelerated titration schedule was used until standard 3 + 3 dose-escalation cohorts were implemented. Pharmacokinetics were evaluated on day −7 and day 22 of cycle 1.

Results: Ninety-four patients (32F, 62M; ages, 39–87) received doses ranging from 20 to 210 mg QD. Dose levels up to and including 160 mg administered QD were well tolerated. Toxicities consisted of reversible elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT) and bilirubin, fatigue, nausea, alopecia, and muscle spasms. IPI-926 was not associated with hematologic toxicity. IPI-926 pharmacokinetics were characterized by a slow absorption (Tmax = 2–8 hours) and a terminal half-life (t1/2) between 20 and 40 hours, supporting QD dosing. Of those HhP inhibitor-naïve patients with basal cell carcinoma (BCC) who received more than one dose of IPI-926 and had a follow-up clinical or Response Evaluation Criteria in Solid Tumors (RECIST) assessment, nearly a third (8 of 28 patients) showed a response to IPI-926 at doses ≥130 mg.

Conclusions: IPI-926 was well tolerated up to 160 mg QD within 28-day cycles, which was established as the recommended phase II dose and schedule for this agent. Single-agent activity of IPI-926 was observed in HhP inhibitor–naïve patients with BCC. Clin Cancer Res; 19(10); 2766–74. ©2013 AACR.
SMARCB1/INI1 Genetic Inactivation Is Responsible for Tumorigenic Properties of Epithelioid Sarcoma Cell Line VAESBJ
Authors: Brenca Monica , Rossi Sabrina , Lorenzetto Erica , Piccinin Elena , Piccinin Sara , Rossi Francesca Maria , Giuliano Alberto , Dei Tos Angelo Paolo , Maestro Roberta , Modena Piergiorgio
Published: April 2013

Epithelioid sarcoma is a rare soft tissue neoplasm that usually arises in the distal extremities of young adults. Epithelioid sarcoma presents a high rate of recurrences and metastases and frequently poses diagnostic dilemmas. We previously reported loss of tumor suppressor SMARCB1 protein expression and SMARCB1 gene deletion in the majority of epithelioid sarcoma cases. Unfortunately, no appropriate preclinical models of such genetic alteration in epithelioid sarcoma are available. In the present report, we identified lack of SMARCB1 protein due to a homozygous deletion of exon 1 and upstream regulatory region in epithelioid sarcoma cell line VAESBJ. Restoration of SMARCB1 expression significantly affected VAESBJ cell proliferation, anchorage-independent growth, and cell migration properties, thus supporting the causative role of SMARCB1 loss in epithelioid sarcoma pathogenesis. We investigated the translational relevance of this genetic background in epithelioid sarcoma and showed that SMARCB1 ectopic expression significantly augmented VAESBJ sensitivity to gamma irradiation and acted synergistically with flavopiridol treatment. In VAESBJ, both activated ERBB1/EGFR and HGFR/MET impinged on AKT and ERK phosphorylation. We showed a synergistic effect of combined inhibition of these 2 receptor tyrosine kinases using selective small-molecule inhibitors on cell proliferation. These observations provide definitive support to the role of SMARCB1 inactivation in the pathogenesis of epithelioid sarcoma and disclose novel clues to therapeutic approaches tailored to SMARCB1-negative epithelioid sarcoma. Mol Cancer Ther; 12(6); 1060–72. ©2013 AACR.
BRCA1: A Missing Link in the Fanconi Anemia/BRCA Pathway
Authors: D'Andrea Alan D.
Published: April 2013

Summary: Domchek and colleagues provide a case report of a 28-year-old woman with congenital abnormalities, inherited ovarian cancer, and carboplatin hypersensitivity. Interestingly, the woman had validated germline mutations in both BRCA1 alleles. These findings further implicate BRCA1 in the Fanconi anemia/BRCA pathway and have important implications for BRCA1 genetic testing. Cancer Discov; 3(4); 376–8. ©2013 AACR.

See related article by Domchek et al., p. 399
Hit Parade for Adoptive Cell Transfer Therapy: The Best T Cells for Superior Clinical Responses
Authors: Speiser Daniel E.
Published: April 2013

Summary: Adoptive cell transfer (ACT) of T cells has great clinical potential, but the numerous variables of this therapy make choices difficult. A new study takes advantage of a novel technology for characterizing the T-cell responses of patients. If applied systematically, this approach may identify biomedical correlates of protection, thereby supporting treatment optimization. Cancer Discov; 3(4); 379–81. ©2013 AACR.

See related article by Ma et al., p. 418
Rare Variant Association Testing for Next-Generation Sequencing Data via Hierarchical Clustering
Authors: Tachmazidou Ioanna , Morris Andrew , Zeggini Eleftheria
Published: April 2013

Objectives: It is thought that a proportion of the genetic susceptibility to complex diseases is due to low-frequency and rare variants. Next-generation sequencing in large populations facilitates the detection of rare variant associations to disease risk. In order to achieve adequate power to detect association at low-frequency and rare variants, locus-specific statistical methods are being developed that combine information across variants within a functional unit and test for association with this enriched signal through so-called burden tests. Methods: We propose a hierarchical clustering approach and a similarity kernel-based association test for continuous phenotypes. This method clusters individuals into groups, within which samples are assumed to be genetically similar, and subsequently tests the group effects among the different clusters. Results: The power of this approach is comparable to that of collapsing methods when causal variants have the same direction of effect, but its power is significantly higher compared to burden tests when both protective and risk variants are present in the region of interest. Overall, we observe that the Sequence Kernel Association Test (SKAT) is the most powerful approach under the allelic architectures considered. Conclusions: In our overall comparison, we find the analytical framework within which SKAT operates to yield higher power and to control type I error appropriately.
Identification of Rare Variants from Exome Sequence in a Large Pedigree with Autism
Authors: Marchani E.E. , Chapman N.H. , Cheung C.Y.K. , Ankenman K. , Stanaway I.B. , Coon H.H. , Nickerson D. , Bernier R. , Brkanac Z. , Wijsman E.M.
Published: April 2013

We carried out analyses with the goal of identifying rare variants in exome sequence data that contribute to disease risk for a complex trait. We analyzed a large, 47-member, multigenerational pedigree with 11 cases of autism spectrum disorder, using genotypes from 3 technologies representing increasing resolution: a multiallelic linkage marker panel, a dense diallelic marker panel, and variants from exome sequencing. Genome-scan marker genotypes were available on most subjects, and exome sequence data was available on 5 subjects. We used genome-scan linkage analysis to identify and prioritize the chromosome 22 region of interest, and to select subjects for exome sequencing. Inheritance vectors (IVs) generated by Markov chain Monte Carlo analysis of multilocus marker data were the foundation of most analyses. Genotype imputation used IVs to determine which sequence variants reside on the haplotype that co-segregates with the autism diagnosis. Together with a rare-allele frequency filter, we identified only one rare variant on the risk haplotype, illustrating the potential of this approach to prioritize variants. The associated gene, MYH9, is biologically unlikely, and we speculate that for this complex trait, the key variants may lie outside the exome.
Using Affected Sib-Pairs to Uncover Rare Disease Variants
Authors: Perdry Hervé , Müller-Myhsok Bertram , Clerget-Darpoux Françoise
Published: April 2013

Objective: We propose a new test for rare variant mapping, based on an affected sib-pair sample and a control sample. In each sib-pair, only the index case needs to be sequenced, and the number of alleles shared identical-by-descent between the sibs is used as complementary information. The test makes use of both association and linkage information. We compare this test to the Armitage test on case-control data, with cases either from the general population of cases or from a sample of cases having an affected sib. Methods: A score test based on the likelihood in a multiplicative risk model is proposed. Its power is estimated by simulations and compared to Armitage test's power. Results: The affected sib-pairs design allows a tremendous gain of power over the case-control design (from 1 to 99% for a moderate sample size and relative risk values around 3, at an α level of 10-11). When cases are ascertained in a sample of cases having an affected sib, the use of linkage information in our test allows a gain of power of more than 20% in certain situations. Conclusion: We demonstrate the interest in using familial data and both association and linkage information for rare variant mapping.
Integrin αIIbβ3
Authors: Bledzka Kamila , Smyth Susan S. , Plow Edward F.
Published: April 2013

From the initial description of platelets in 1882, their propensity to aggregate and to contribute to thrombosis was apparent. Indeed, excessive platelet aggregation is associated with myocardial infarction and other thrombotic diseases whereas Glanzmann thrombasthenia, in which platelet aggregation is reduced, is a bleeding syndrome. Over the last half of the 20th century, many investigators have provided insights into the cellular and molecular basis for platelet aggregation. The major membrane protein on platelets, integrin αIIbβ3, mediates this response by rapidly transiting from its resting to an activated state in which it serves as a receptor for ligands that can bridge platelets together. Monoclonal antibodies, natural products, and small peptides were all shown to inhibit αIIbβ3 dependent platelet aggregation, and these inhibitors became the forerunners of antagonists that proceeded through preclinical testing and into large patient trials to treat acute coronary syndromes, particularly in the context of percutaneous coronary interventions. Three such αIIbβ3 antagonists, abciximab, eptifibatide, and tirofiban, received Food and Drug Administration approval. Over the past 15 years, millions of patients have been treated with these αIIbβ3 antagonists and many lives have been saved by their administration. With the side effect of increased bleeding and the development of new antithrombotic drugs, the use of αIIbβ3 antagonists is waning. Nevertheless, they are still widely used for the prevention of periprocedural thrombosis during percutaneous coronary interventions. This review focuses on the biology of αIIbβ3, the development of its antagonists, and some of the triumphs and shortcomings of αIIbβ3 antagonism.
The Supreme Court in the 21st Century
Authors: Stone Geoffrey R.
Published: April 2013

How does the Supreme Court serve the “common good”? What is the Court's responsibility, as the ultimate interpreter of the Constitution, in our constitutional system of government? This essay explores that question with an eye on the recent performance of the Court in highly controversial and divisive cases. What explains the Court's decisions in cases involving such issues as campaign finance regulation, gun control, abortion, affirmative action, health care reform, voting rights, and even the 2000 presidential election? This essay argues that there is a right and a wrong way for the Supreme Court to interpret and apply the Constitution; and whereas the Warren Court properly understood its responsibilities, the Court in more recent decades has adopted a less legitimate and more troubling mode of constitutional interpretation.
What is the Common Good? The Case for Transcending Partisanship
Authors: Edwards Mickey
Published: April 2013

Even if most of us can agree on a definition of the “common good” (not a simple matter), there are substantial barriers to establishing public policies in accord with that agreement. The “democratic” element in our political system – the right of voters to choose the men and women who will create our laws – depends on the views of those voters being given considerable weight in determining eventual policy outcomes. Unfortunately, we have developed a political system – both in our elections and in the governing process – that gives disproportionate influence to relatively small numbers of voters (who are also the most partisan) and allows political parties through their closed procedures to limit the choices available to general election voters. Coupled with legislative rules that allow partisans to determine the makeup of legislative committees, the resulting process leaves the common good, however defined, a secondary consideration at best.
Citizens United: Robbing America of Its Democratic Idealism
Authors: Leach Jim
Published: April 2013

The 2010 Citizens United ruling has been widely reviewed from the lens of legal precedent. In this critique, the author suggests the need to examine the logic and effects of the ruling from a historical, philosophical, and linguistic perspective. He challenges the Court's basis for providing inanimate entities First Amendment protection to “invest” in politics by equating corporations with individuals and money with speech. He holds that Citizens United employs parallel logic to the syllogism embedded in the most repugnant ruling the Court ever made, the 1857 Dred Scott decision. To justify slavery, the Court in Dred Scott defined a class of human beings as private property. To magnify corporate power a century-and-ahalf later, it defines a class of private property (corporations) as people. The effect is to undercut the democratic basis of American governance.
Reluctant Stewards: Journalism in a Democratic Society
Authors: Schudson Michael
Published: April 2013

Journalists are reluctant stewards for democracy because they believe that democracy makes citizens their own stewards. They resist donning the mantle of moral guides on behalf of those who are authorized to guide themselves. Yet sometimes journalists do exercise responsibility for the public good in ways that are not subsumed under their professional duty to be nonpartisan, accurate, and fair-minded. Examining some of these exceptions, this essay argues that journalistic stewardship should be loosely defined, decentralized, multiform, and open to invention. In fact, today's economic crisis in journalism (and the identity crisis it stimulated) has launched a new set of initiatives – from fact-checking to organized crowd-sourcing – that have each sought to address a specific problem of democracy, truthseeking, or the public good. Pluralism, pragmatism, and decentralized invention may do better at stewarding democracy than a coherent philosophy of moral guardianship ever could.
The Invisible Hand Illusion: Multisensory Integration Leads to the Embodiment of a Discrete Volume of Empty Space
Authors: Guterstam Arvid , Gentile Giovanni , Ehrsson H. Henrik
Published: April 2013

The dynamic integration of signals from different sensory modalities plays a key role in bodily self-perception. When visual information is used in the multisensory process of localizing and identifying one's own limbs, the sight of a body part often plays a dominant role. For example, it has repeatedly been shown that a viewed object must resemble a humanoid body part to permit illusory self-attribution of that object. Here, we report a perceptual illusion that challenges these assumptions by demonstrating that healthy (nonamputated) individuals can refer somatic sensations to a discrete volume of empty space and experience having an invisible hand. In 10 behavioral and one fMRI experiment, we characterized the perceptual rules and multisensory brain mechanisms that produced this “invisible hand illusion.” Our behavioral results showed that the illusion depends on visuotactile-proprioceptive integration that obeys key spatial and temporal multisensory rules confined to near-personal space. The fMRI results associate the illusion experience with increased activity in regions related to the integration of multisensory body-related signals, most notably the bilateral ventral premotor, intraparietal, and cerebellar cortices. We further showed that a stronger feeling of having an invisible hand is associated with a higher degree of effective connectivity between the intraparietal and ventral premotor cortices. These findings demonstrate that the integration of temporally and spatially congruent multisensory signals in a premotor-intraparietal circuit is sufficient to redefine the spatial boundaries of the bodily self, even when visual information directly contradicts the presence of a physical limb at the location of the perceived illusory hand.
Hemispheric Differences in the Voluntary Control of Spatial Attention: Direct Evidence for a Right-Hemispheric Dominance within Frontal Cortex
Authors: Duecker Felix , Formisano Elia , Sack Alexander T.
Published: April 2013

Lesion studies in neglect patients have inspired two competing models of spatial attention control, namely, Heilman's “hemispatial” theory and Kinsbourne's “opponent processor” model. Both assume a functional asymmetry between the two hemispheres but propose very different mechanisms. Neuroimaging studies have identified a bilateral dorsal frontoparietal network underlying voluntary shifts of spatial attention. However, lateralization of attentional processes within this network has not been consistently reported. In the current study, we aimed to provide direct evidence concerning the functional asymmetry of the right and left FEF during voluntary shifts of spatial attention. To this end, we applied fMRI-guided neuronavigation to disrupt individual FEF activation foci with a longer-lasting inhibitory patterned TMS protocol followed by a spatial cueing task. Our results indicate that right FEF stimulation impaired the ability of shifting spatial attention toward both hemifields, whereas the effects of left FEF stimulation were limited to the contralateral hemifield. These results provide strong direct evidence for right-hemispheric dominance in spatial attention within frontal cortex supporting Heilman's “hemispatial” theory. This complements previous TMS studies that generally conform to Kinsbourne's “opponent processor” model after disruption of parietal cortex, and we therefore propose that both theories are not mutually exclusive.
The Fluidity between the Oppressed of Israel and Israel the Oppressed Some Additional Notes to B. Gregory’s Analysis of Ben Sira 35:14-26
Authors: Beentjes Pancratius C.
Published: April 2013

Abstract

In his analysis of Sir 35:14-26, B.C. Gregory argues that this passage opens with a plight of the individual poor person, but rather soon turns into a prayer by the nation of Israel. This short note adduces further evidence to that view by drawing attention to a particular function the Book of Lamentations has for the Ben Sira passage under investigation.
An Akkadian Demon in the Talmud: Between Šulak and Bar-Širiqa
Authors: Bamberger Avigail Manekin
Published: April 2013

Abstract

This article examines the resemblance between the Talmudic privy demon (“Shed Bet ha-Kise”) and Šulak, a well-known Akkadian demon. There are four considerations that point to identifying the privy demon of the Talmud with the Babylonian demon Šulak: (1) They both dwell in the privy; (2) they both are demons that cause epilepsy, strokes, or sudden falls; (3) they both seem to have the form of a lion; and (4) their names (“Šulak” and “Bar Širiqa”) are very similar. This suggestion is yet another example of the presence of beliefs and opinions from the Ancient Near East that found an echo in the Babylonian Talmud, one that may be added to a number of examples given by M. Geller.
WITHIN–TREE VARIATION IN PHLOEM CELL DIMENSIONS AND PROPORTIONS IN EUCALYPTUS GLOBULUS
Authors: Quilhó Teresa , Pereira Helena , Richter Hans Georg
Published: April 2013

The axial variation of bark thickness and quantitative anatomical features of Eucalyptus globulus bark were analysed for one site based on individual measurements of ten 15-year-old trees at six height levels (DBH, 5%, 15%, 35%, 55% and 75% of total tree height). The parameters studied were: length, tangential diameter and percentage of sieve tubes; length, width, cell wall thickness and percentage of fibres; height and percentage of rays; percentage of sclereids in the secondary phloem. Bark thickness decreases from base to top of the tree. Fibre width and wall thickness decrease from base upwards. No distinct axial patterns of variation were observed for the other biometric variables studied. Parenchyma is the main cell type of the bark (50%) followed by fibres (27.9%), rays (12.1%), sieve tubes (2.7%), and sclereids (7.3%). The cell type proportions vary significantly within the tree, i.e., parenchyma, ray and sclereid proportions decrease, fibre and sieve tube proportions increase towards the top of the tree.