bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dose‐finding approach for dose escalation with overdose control considering incomplete observations
Authors: Mauguen A. , Le Deley M. C. , Zohar S. 
Published: February 2011

AbstractWe propose a hybrid design, the time‐to‐event dose‐escalation method with overdose control (TITE‐EWOC), introducing the time‐to‐event approach, developed by Cheungit et al., in the EWOC method, developed by Babb et al. The aim of this new design is to decrease the dose‐finding trial duration, without impairing the characteristics of the EWOC design, especially the overdose control ability. We conducted a simulation study, exploring four dose–toxicity relationships and three mean inter‐patient arrival times. Performances of TITE‐EWOC were compared with those of the EWOC method. This study shows that the trial duration can be greatly decreased with the TITE‐EWOC, without impacting the proportion of overdosed patients or the number of dose‐limiting toxicities by trial, for all explored dose–toxicity relationships, except for very short inter‐patient arrival times. The ability of the method to find the true maximum tolerated dose remains unchanged. Copyright © 2011 John Wiley & Sons, Ltd.
Multiple imputation analysis of case–cohort studies
Authors: Marti Helena , Chavance Michel 
Published: February 2011

AbstractThe usual methods for analyzing case–cohort studies rely on sometimes not fully efficient weighted estimators. Multiple imputation might be a good alternative because it uses all the data available and approximates the maximum partial likelihood estimator. This method is based on the generation of several plausible complete data sets, taking into account uncertainty about missing values. When the imputation model is correctly defined, the multiple imputation estimator is asymptotically unbiased and its variance is correctly estimated. We show that a correct imputation model must be estimated from the fully observed data (cases and controls), using the case status among the explanatory variable. To validate the approach, we analyzed case–cohort studies first with completely simulated data and then with case–cohort data sampled from two real cohorts. The analyses of simulated data showed that, when the imputation model was correct, the multiple imputation estimator was unbiased and efficient. The observed gain in precision ranged from 8 to 37 per cent for phase‐1 variables and from 5 to 19 per cent for the phase‐2 variable. When the imputation model was misspecified, the multiple imputation estimator was still more efficient than the weighted estimators but it was also slightly biased. The analyses of case–cohort data sampled from complete cohorts showed that even when no strong predictor of the phase‐2 variable was available, the multiple imputation was unbiased, as precised as the weighted estimator for the phase‐2 variable and slightly more precise than the weighted estimators for the phase‐1 variables. However, the multiple imputation estimator was found to be biased when, because of interaction terms, some coefficients of the imputation model had to be estimated from small samples. Multiple imputation is an efficient technique for analyzing case–cohort data. Practically, we suggest building the analysis model using only the case–cohort data and weighted estimators. Multiple imputation can eventually be used to reanalyze the data using the selected model in order to improve the precision of the results. Copyright © 2011 John Wiley & Sons, Ltd.
Generalized propensity score for estimating the average treatment effect of multiple treatments
Authors: Feng Ping , Zhou Xiao‐Hua , Zou Qing‐Ming , Fan Ming‐Yu , Li Xiao‐Song 
Published: February 2011

AbstractThe propensity score method is widely used in clinical studies to estimate the effect of a treatment with two levels on patient's outcomes. However, due to the complexity of many diseases, an effective treatment often involves multiple components. For example, in the practice of Traditional Chinese Medicine (TCM), an effective treatment may include multiple components, e.g. Chinese herbs, acupuncture, and massage therapy. In clinical trials involving TCM, patients could be randomly assigned to either the treatment or control group, but they or their doctors may make different choices about which treatment component to use. As a result, treatment components are not randomly assigned. Rosenbaum and Rubin proposed the propensity score method for binary treatments, and Imbens extended their work to multiple treatments. These authors defined the generalized propensity score as the conditional probability of receiving a particular level of the treatment given the pre‐treatment variables. In the present work, we adopted this approach and developed a statistical methodology based on the generalized propensity score in order to estimate treatment effects in the case of multiple treatments. Two methods were discussed and compared: propensity score regression adjustment and propensity score weighting. We used these methods to assess the relative effectiveness of individual treatments in the multiple‐treatment IMPACT clinical trial. The results reveal that both methods perform well when the sample size is moderate or large. Copyright © 2011 John Wiley & Sons, Ltd.
Engineering Nanocarriers for siRNA Delivery
Authors: Tan Shawn J. , Kiatwuthinon Pichamon , Roh Young Hoon , Kahn Jason S. , Luo Dan 
Published: February 2011

AbstractThe discovery of RNA interference has revitalized the long ongoing pursuit of gene therapy for the treatment of diseases. Nevertheless, despite promising results from experimental studies, there remains a pressing need for the development of nanocarriers that are clinically‐relevant, biocompatible, efficient, and that can be tailored to specific disease targets. This review surveys the broad spectrum of nanomaterials and their functional add‐ons, and aims to provide a guide towards engineering nanocarriers for effective siRNA delivery.
Controlled Release of Fe3O4 Nanoparticles in Encapsulated Microbubbles to Tumor Cells via Sonoporation and Associated Cellular Bioeffects
Authors: Yang Fang , Zhang Miao , He Wen , Chen Ping , Cai Xiaowei , Yang Li , Gu Ning , Wu Junru 
Published: February 2011

AbstractFe3O4 nanoparticles embedded in the shells of encapsulated microbubbles could be used therapeutically as in situ drug‐delivery vehicles. Bioeffects on liver tumor cells SMMC‐7721 due to the excitation of Fe3O4 nanoparticles attached to microbubbles generated by ultrasound (US) are studied in an in vitro setting. The corresponding release phenomenon of Fe3O4 nanoparticles from the shells of the microbubbles into the cells via sonoporation and related phenomena, including nanoparticle delivery efficiency, cell trafficking, cell apoptosis, cell cycle, and disturbed flow of intracellular calcium ions during this process, are also studied. Experimental observations show that Fe3O4 nanoparticles embedded in the shells of microbubbles can be delivered into the tumor cells; the delivery rate can be controlled by adjusting the acoustic intensity. The living status or behavior of Fe3O4‐tagged tumor cells can then be noninvasively tracked by magnetic resonance imaging (MRI). It is further demonstrated that the concentration of intracellular Ca2+ in situ increases as a result of sonoporation. The elevated Ca2+ is found to respond to the disrupted site in the cell membrane generated by sonoporation for the purpose of cell self‐resealing. However, the excessive Ca2+ accumulation on the membrane results in disruption of cellular Ca2+ cycling that may be one of the reasons for the death of the cells at the G1 phase. The results also show that the Fe3O4‐nanoparticle‐embedded microbubbles have a lower effect on cell bioeffects compared with the non‐Fe3O4‐nanoparticle‐embedded microbubbles under the same US intensity, which is beneficial for the delivery of nanoparticles and simultaneously maintains the cellular viability.
Discovering programming rules and violations by mining interprocedural dependences
Authors: Chang Ray‐yaung , Podgurski Andy 
Published: February 2011

SUMMARYThis paper presents a novel approach to discovering implicit programming rules and rule violations in a code base, which integrates static interprocedural analysis and graph mining techniques to identify both function‐call ordering rules and conditional rules that check input parameters or return values of functions. The approach discovers rules even when rule instances cross function boundaries. Rules are modeled as graph minors of dependence graphs augmented with edges indicating shared data dependences. The approach employs two innovative algorithms: a greedy one for mining maximal frequent minors from a set of interprocedural dependence spheres and a heuristic minor‐matching algorithm for discovering rule violations. We evaluated our approach on the latest versions of three applications: net‐snmp, openssl, and the Apache HTTP server. It detected 62 new bugs (24 involving rules with interprocedural instances), 35 of which have been confirmed and fixed recently by developers based on our reports. Copyright © 2011 John Wiley & Sons, Ltd.
Scenarios‐based testing of systems with distributed ports
Authors: Hierons Robert M. , Merayo Mercedes G. , Núñez Manuel 
Published: February 2011

SUMMARYDistributed systems are usually composed of several distributed components that communicate with their environment through specific ports. When testing such a system we separately observe sequences of inputs and outputs at each port rather than a global sequence and potentially cannot reconstruct the global sequence that occurred. Typically, the users of such a system cannot synchronize their actions during use or testing. However, the use of the system might correspond to a sequence of scenarios, where each scenario involves a sequence of interactions with the system that, for example, achieves a particular objective. When this is the case there is the potential for a significant delay between two scenarios and this effectively allows the users of the system to synchronize between scenarios. If we represent the specification of the global system by using a state‐based notation, we say that ait scenario is any sequence of events that happens between two of these operations. We can encode scenarios in two different ways. The first approach consists of marking some of the states of the specification to denote these synchronization points. It transpires that there are two ways to interpret such models and these lead to two implementation relations. The second approach consists of adding a set of traces to the specification to represent the traces that correspond to scenarios. We show that these two approaches have similar expressive power by providing an encoding from marked states to sets of traces. In order to assess the appropriateness of our new framework, we show that it represents a conservative extension of previous implementation relations defined in the context of the distributed test architecture: if we consider that all the states are marked then we simply obtain ioco (the classical relation for single‐port systems) while if no state is marked then we obtain dioco (our previous relation for multi‐port systems). Finally, we concentrate on the study of controllable test cases, that is, test cases such that each local tester knows exactly when to apply inputs. We give two notions of controllable test cases, define an implementation relation for each of these notions and relate them. We also show how we can decide whether a test case satisfies these conditions. Copyright © 2011 John Wiley & Sons, Ltd.
D‐cycloserine facilitates extinction of cocaine self‐administration in rats
Authors: Thanos Panayotis K. , Bermeo Carlos , Wang Gene‐Jack , Volkow Nora D. 
Published: February 2011

AbstractPrevious research has indicated that D‐cycloserine [DCS; a N‐methyl‐D‐aspartate (NMDA) partial agonist] facilitates the extinction of conditioned fear as well as the extinction of cocaine conditioned place preference. Sprague Dawley rats were first trained to self‐administer cocaine and then we compared their extinction behavior (lever pressing) following treatment with vehicle; 15 mg/kg DCS; or 30 mg/kg DCS. We showed that 30 mg/kg DCS, but not 15 mg/kg significantly accelerated extinction of cocaine self‐administration behavior when compared with saline by almost half (4 days vs. 9 days). At 2 weeks when all animals had extinguished, there were no longer differences between the groups. The present findings support of the potential of NMDA partial agonists as prospectively valuable in facilitating the extinction of cocaine‐seeking behavior. More specifically, we demonstrate that 30 mg/kg DCS was effective at significantly accelerating the extinction of cocaine self‐administration behavior in rats. These results provide further support for the potential of DCS as a treatment strategy for addiction. Synapse, 2011. © 2011 Wiley‐Liss, Inc.
Altered expression of Dscam in temporal lobe tissue from human and experimental animals
Authors: Shen Lan , Xiao Zheng , Pan Yumin , Fang Min , Li Chengshan , Chen Dan , Wang Liang , Xi Zhiqin , Xiao Fei , Wang Xuefeng 
Published: February 2011

AbstractDown syndrome cell adhesion molecule (Dscam) is a neural adhesion molecule that plays an essential role in the establishment of neural circuits. Considerable evidence suggests that Dscam is required for axon guidance and dendritic arborization. Our aim was to investigate the expression of Dscam in the temporal lobes of patients with intractable epilepsy (IE) and of experimental animals. In this study, we used immunohistochemistry, immunofluorescence, and western blotting to examine Dscam expression in thirty‐five surgical samples from brains of IE patients and 15 control brain samples. We also measured the levels of Dscam during the entire epileptic process in a rat model of temporal lobe epilepsy. Dscam expression in IE patients was significantly higher compared with that in the controls. In addition, Dscam was also highly expressed in the rat brain during the different phases of the epileptic process. It is the first time to find abnormal expression of Dscam in the brain tissues in patients with IE. And this finding provides an experimental evidence for the study of neuronal circuit remodeling and synaptic plasticity in IE, furthermore, our results also suggest that Dscam may be involved in the generation and the development of IE. Synapse, 2011. © 2011 Wiley‐Liss, Inc.
Inhibition of 3,4‐methylenedioxymethamphetamine metabolism leads to marked decrease in 3,4‐dihydroxymethamphetamine formation but no change in serotonin neurotoxicity: Implications for mechanisms of neurotoxicity
Authors: Mueller Melanie , Yuan Jie , Maldonado Adrian Concepcion , Mccann Una D. , Ricaurte George A. 
Published: February 2011

Abstract3,4‐Methylenedioxymethamphetamine (MDMA)'s O‐demethylenated metabolite, 3,4‐dihydroxymethamphetamine (HHMA), has been hypothesized to serve as a precursor for the formation of toxic catechol‐thioether metabolites (e.g., 5‐N‐acetylcystein‐S‐yl‐HHMA) that mediate MDMA neurotoxicity. To further test this hypothesis, HHMA formation was blocked with dextromethorphan (DXM), which competitively inhibits cytochrome P450 enzyme‐mediated O‐demethylenation of MDMA to HHMA. In particular, rats were randomly assigned to one of four treatment groups (n = 9–12 per group): (1) Saline/MDMA; (2) DXM/MDMA; (3) DXM/Saline; (4) Saline/Saline. During drug exposure, time‐concentration profiles of MDMA and its metabolites were determined, along with body temperature. One week later, brain serotonin (5‐HT) neuronal markers were measured in the same animals. DXM did not significantly alter core temperature in MDMA‐treated animals. A large (greater than 70%) decrease in HHMA formation had no effect on the magnitude of MDMA neurotoxicity. These results cast doubt on the role of HHMA‐derived catechol‐thioether metabolites in the mechanism of MDMA neurotoxicity. Synapse, 2011. © 2011 Wiley‐Liss, Inc.
Evaluation of dopamine D2/3specific binding in the cerebellum for the positron emission tomography radiotracer [11C]FLB 457: Implications for measuring cortical dopamine release
Authors: Narendran Rajesh , Mason N. Scott , Chen Chi‐Min , Himes Michael , Keating Patrick , May Maureen A. , Rabiner Eugenii A. , Laruelle Marc , Mathis Chester A. , Frankle W. Gordon 
Published: February 2011

AbstractIn a recent positron emission tomography (PET) study, we demonstrated the ability to measure amphetamine‐induced dopamine (DA) release in the human cortex with the DA D2/3 radioligand [11C]FLB 457. As previous studies in animals have shown that a relatively high fraction of the [11C]FLB 457 signal in the cerebellum represents specific binding to D2/3 receptors, there was concern that the use of the cerebellum as a measure of nonspecific binding (i.e., reference region) to derive [11C]FLB 457 binding potential (BP) (BPND) would bias cortical DA release measurements. Thus, we evaluated the fractional contribution of specific binding to D2/3 receptors in the human cerebellum for [11C]FLB 457. Six healthy human subjects (5M/1F) were studied twice with [11C]FLB 457, once at baseline and again following a single oral dose of 15 mg of aripiprazole, a D2/3 partial agonist. [11C]FLB 457 distribution volume (VT) was estimated using kinetic analysis in the cortical regions of interest and potential reference regions. The change in [11C]FLB 457 VT following aripiprazole ranged from −33 to −42% in the cortical regions of interest (ROIs). The aripiprazole‐induced change in [11C]FLB 457 VT in three potential reference regions suggests significant specific binding the cerebellum (CER, –17 ± 12%), but not pons (PON, –10 ± 10%) and centrum semiovale (CESVL, –3 ± 12%). Nevertheless, a reanalysis of the published [11C]FLB 457 test–retest and amphetamine studies suggests that the use of the PON VT and CESVL VT as an estimate of nonspecific binding to derive [11C]FLB 457 BPND in DA release studies is unlikely to be successful because it leads to less reproducible outcome measures, which in turn diminishes the ability to measure DA release in the cortex. D2/3 blocking studies with aripiprazole and [11C]FLB 457 suggest specific binding to D2/3 receptors in the cerebellum. These data also suggest that the contribution of specific binding to D2/3 receptors in the cerebellum is lower than that in the cortical ROIs and that CER VT is mostly representative of nonspecific binding. Nevertheless, caution is advised when using reference tissue methods that rely solely on the cerebellum signal as an input function to quantify [11C]FLB 457 BPND. Synapse, 2011. © 2011 Wiley‐Liss, Inc.
Assessing equity beyond knowledge‐ and skills‐based outcomes: A comparative ethnography of two fourth‐grade reform‐based science classrooms
Authors: Carlone Heidi B. , Haun‐Frank Julie , Webb Angela 
Published: February 2011

AbstractWhen evaluating equity, researchers often look at the “achievement gap.” Privileging knowledge and skills as primary outcomes of science education misses other, more subtle, but critical, outcomes indexing inequitable science education. In this comparative ethnography, we examined what it meant to “be scientific” in two fourth‐grade classes taught by teachers similarly committed to reform‐based science (RBS) practices in the service of equity. In both classrooms, students developed similar levels of scientific understanding and expressed positive attitudes about learning science. However, in one classroom, a group of African American and Latina girls expressed outright disaffiliation with promoted meanings of “smart science person” (“They are the science people. We aren't like them”), despite the fact that most of them knew the science equally well or, in one case, better than, their classmates. To make sense of these findings, we examine the normative practice of “sharing scientific ideas” in each classroom, a comparison that provided a robust account of the differently accessible meanings of scientific knowledge, scientific investigation, and scientific person in each setting. The findings illustrate that research with equity aims demands attention to culture (everyday classroom practices that promote particular meanings of “science”) and normative identities (culturally produced meanings of “science person” and the accessibility of those meanings). The study: (1) encourages researchers to question taken‐for‐granted assumptions and complexities of RBS and (2) demonstrates to practitioners that enacting what might look like RBS and producing students who know and can do science are but pieces of what it takes to achieve equitable science education. © 2011 Wiley Periodicals, Inc., Inc. J Res Sci Teach 48: 459–485, 2011
Nanotechnology for surgeons
Authors: Weldon Christopher , Tian Bozhi , Kohane Daniel S. 
Published: February 2011

AbstractAt first glance it might appear that nanomedicine is irrelevant to surgery as it is practiced today, as surgery is generally concerned with the manipulation of decidedly macroscopic devices. However, surgery as a discipline is obviously not limited to clinical procedures, but dovetails with parallel medical therapeutics. Consequently, methodologies that can enhance overall perioperative care are important. An alternative view is that nanomedicine is perhaps destined to put surgeons out of certain kinds of business—much as minimally invasive techniques including invasive radiology have progressively infringed on clinical areas that were once the purview of more conventional surgical approaches. As is often the case, the truth is somewhere in the middle. In any event nanotechnology certainly has the potential to affect the field. It is important to understand that potential and how it can be harnessed. WIREs Nanomed Nanobiotechnol 2011 3 223–228 DOI: 10.1002/wnan.128This article is categorized under:

Diagnostic Tools > Diagnostic Nanodevices
Implantable Materials and Surgical Technologies > Nanoscale Tools and Techniques in Surgery
Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials
Systems biology and the future of medicine
Authors: Loscalzo Joseph , Barabasi Albert‐Laszlo 
Published: February 2011

AbstractContemporary views of human disease are based on simple correlation between clinical syndromes and pathological analysis dating from the late 19th century. Although this approach to disease diagnosis, prognosis, and treatment has served the medical establishment and society well for many years, it has serious shortcomings for the modern era of the genomic medicine that stem from its reliance on reductionist principles of experimentation and analysis. Quantitative, holistic systems biology applied to human disease offers a unique approach for diagnosing established disease, defining disease predilection, and developing individualized (personalized) treatment strategies that can take full advantage of modern molecular pathobiology and the comprehensive data sets that are rapidly becoming available for populations and individuals. In this way, systems pathobiology offers the promise of redefining our approach to disease and the field of medicine. WIREs Syst Biol Med 2011 3 619–627 DOI: 10.1002/wsbm.144This article is categorized under:

Translational, Genomic, and Systems Medicine > Translational Medicine