bluuebunny/crossref_metadata_2025 huggingface dataset:
ALMOST PERIODIC SOLUTION FOR A DISCRETE HEMATOPOIESIS MODEL WITH TIME DELAY
Authors: LI YONGKUN , ZHANG TIANWEI
Published: May 2011

In this paper, we consider the discrete Hematopoiesis model with a time delay: [Formula: see text] Sufficient conditions for the existence of a unique uniformly asymptotically stable positive almost periodic solution are obtained by the work of [S. N. Zhang, G. Zheng, Almost periodic solutions of delay difference systems, Appl. Math. Comput.131 (2002) 497–516]. Some examples are considered to illustrate the main results.
MODELING BINGE DRINKING
Authors: MULONE GIUSEPPE , STRAUGHAN BRIAN
Published: May 2011

We develop a two-stage (four component) model for youths with serious drinking problems and their treatment. The youths with alcohol problems are split into two classes, namely those who admit to having a problem and those who do not. It is shown that the model possesses two steady states, one where people have no alcohol problems and one where there is an endemic state involving those with an alcohol problem. The stability of these states is analyzed and a threshold established such that each state will be stable depending on whether the incidence rate is above or below the threshold. The model is analyzed in the context of actual data.
STABILITY ANALYSIS OF A PREDATOR-PREY MODEL
Authors: JIANG ZHICHAO , GUO ZHAOZHUANG , SUN YUEFANG
Published: May 2011

In this paper, a time-delayed predator-prey system is considered. The existence of Hopf bifurcations at the positive equilibrium is established by analyzing the distribution of the characteristic values. An explicit algorithm for determining the direction of the Hopf bifurcation and the stability of the bifurcating periodic solutions are derived by using the normal form and the center manifold theory. Numerical simulations to support the analytical conclusions are carried out.
CROSS-DIFFUSION INDUCED TURING PATTERNS IN A SEX-STRUCTURED PREDATOR–PREY MODEL
Authors: LIU JIA , ZHOU HUA , ZHANG LAI
Published: May 2011

In this paper, we consider a sex-structured predator–prey model with strongly coupled nonlinear reaction diffusion. Using the Lyapunov functional and Leray–Schauder degree theory, the existence and stability of both homogenous and heterogenous steady-states are investigated. Our results demonstrate that the unique homogenous steady-state is locally asymptotically stable for the associated ODE system and PDE system with self-diffusion. With the presence of the cross-diffusion, the homogeneous equilibrium is destabilized, and a heterogenous steady-state emerges as a consequence. In addition, the conditions guaranteeing the emergence of Turing patterns are derived.
MODELING STRATEGIES FOR CONTROLLING H1N1 OUTBREAKS IN CHINA
Authors: ZHANG JIN , XIAO YANNI
Published: May 2011

There has been a global attack of A/H1N1 virus in 2009, which widely affected the world's normal stability and economic development. Since the emergence of the first diagnosed A/H1N1 influenza infected person in 11 May 2009 in China, very strict policy including quarantine and isolation measures were widely implemented to control the spread of this disease before the vaccine appeared. We propose a compartmental model that mimics the infection process of A/H1N1 under control strategies taken in mainland China. Apart from theoretical analysis, using the statistic data of Shaanxi Province, we estimated the unknown epidemiological parameters of this disease in Shaanxi via least-squares fitting method. The estimated control reproductive number of H1N1 for its first peak was [Formula: see text] (95% CI: 2.362–2.748) and that for the second peak was [Formula: see text] (95% CI: 1.765–2.001). Our findings in this paper suggest that neither quarantine nor isolation measures could be relaxed, and the implementation of these interventions can reduce the pandemic outbreak of A/H1N1 pandemic significantly.
ANALYTICAL SOLUTIONS OF NON-FOURIER PENNES AND CHEN–HOLMES EQUATIONS
Authors: ZHU WEIPING , TIAN FANGBAO , RAN PENG
Published: May 2011

The analytical solutions of non-Fourier Pennes and Chen–Holmes equations are obtained using the Laplace transformation and particular solution method in the present paper. As an application, the effects of the thermal relaxation time τ, the blood perfusion wb, and the blood flow velocity v on the biological skin and inner tissue temperature T are studied in detail. The results obtained in this study provide a good alternative method to study the bio-heat and a biophysical insight into the understanding of the heat transfer in the biotissue.
THE DELAYED BARBOUR'S MODEL FOR SCHISTOSOMIASIS
Authors: QI LONGXING , CUI JING-AN
Published: May 2011

The transmission of schistosomiasis involves latent periods of infected hosts. In this paper, considering the latent periods of infected human, infected bovines and infected snails, we propose a delayed Barbour's model with two definitive hosts and define basic reproductive number. The stability of equilibria for the systems with and without time delays are both investigated. To study the impact of the latent periods on the transmission of schistosomiasis, some sensitivity analysis of the basic reproductive number on the three time delays are carried out. It is shown that the basic reproductive number decreases as the three time delays increase. Furthermore, the impact of the latent periods of infected snails on the system is stronger than that of the latent periods of infected human and infected bovines. Thus, to reduce the prevalence of schistosomiasis infection, prolonging the latent periods of infected snails by some measures could achieve better results than prolonging the latent periods of infected definitive hosts.
A NOTE ON COMPLEXITY OF GENETIC MUTATIONS
Authors: CHITTURI BHADRACHALAM
Published: May 2011

Genes, the functional segments of DNA, can be modeled akin to DNA by quaternary strings. Pevzner and Waterman posed various problems pertaining to DNA, e.g. DNA physical mapping, DNA sequencing, and DNA sequence comparison. DNA sequence comparison methods aim to compute the genetic mutation distance. Genetic mutation, a change that happens within a gene, can be modeled by an operation like a transposition or a reversal over a string where a string models a gene. The complexity of transforming quaternary strings under a given operation is equivalent to the complexity of computing the corresponding genetic mutation distance. We show that the string transformation distance under signed prefix reversals, translocations and transreversals is NP-complete.
The extent of interlimb transfer following adaptation to a novel visuomotor condition does not depend on awareness of the condition
Authors: Wang Jinsung , Joshi Mukta , Lei Yuming
Published: May 2011

There is a controversy in the literature as to whether transfer of motor learning across the arms occurs because of an individual's cognitive awareness of the learned condition. The purpose of this study was to test whether the extent of interlimb transfer following adaptation to a novel visuomotor rotation with one arm, as well as the rate of learning acquired by the other arm, would vary depending on the subjects' awareness of the rotation condition. Awareness of the condition was varied by employing three experimental conditions. In one condition, visual rotation of the display up to 32° was gradually introduced to minimize the subjects' awareness of the rotation during targeted reaching movement. In another condition, the 32° rotation was abruptly introduced from the beginning of the adaptation session. Finally, the subjects were informed regarding the rotation prior to the adaptation session. After adaptation with the left arm under the three conditions, subjects performed reaching movement with the right arm under the same 32° rotation condition. Our results showed that the amount of initial transfer, and also the changes in performance with the right arm, did not vary significantly across the three conditions. This finding suggests that interlimb transfer of visuomotor adaptation does not occur based on an individual's awareness of the manipulation, but rather as a result of implicit generalization of the obtained visuomotor transformation across the arms.
Statistics of visual responses in primate inferotemporal cortex to object stimuli
Authors: Lehky Sidney R. , Kiani Roozbeh , Esteky Hossein , Tanaka Keiji
Published: May 2011

We have characterized selectivity and sparseness in anterior inferotemporal cortex, using a large data set. Responses were collected from 674 monkey inferotemporal cells, each stimulated by 806 object photographs. This 806 × 674 matrix was examined in two ways: columnwise, looking at responses of a single neuron to all images (single-neuron selectivity), and rowwise, looking at the responses of all neurons caused by a single image (population sparseness). Selectivity and sparseness were measured as kurtosis of probability distributions. Population sparseness exceeded single-neuron selectivity, with specific values dependent on the size of the data sample. This difference was principally caused by inclusion, within the population, of neurons with a variety of dynamic ranges (standard deviations of responses over all images). Statistics of large responses were examined by quantifying how quickly the upper tail of the probability distribution decreased (tail heaviness). This analysis demonstrated that population responses had heavier tails than single-neuron responses, consistent with the difference between sparseness and selectivity measurements. Population responses with spontaneous activity subtracted had the heaviest tails, following a power law. The very light tails of single-neuron responses indicate that the critical feature for each neuron is simple enough to have a high probability of occurring within a limited stimulus set. Heavy tails of population responses indicate that there are a large number of different critical features to which different neurons are tuned. These results are inconsistent with some structural models of object recognition that posit that objects are decomposed into a small number of standard features.
Evolution of the epithelial sodium channel and the sodium pump as limiting factors of aldosterone action on sodium transport
Authors: Studer Romain A. , Person Emilie , Robinson-Rechavi Marc , Rossier Bernard C.
Published: May 2011

Despite large changes in salt intake, the mammalian kidney is able to maintain the extracellular sodium concentration and osmolarity within very narrow margins, thereby controlling blood volume and blood pressure. In the aldosterone-sensitive distal nephron (ASDN), aldosterone tightly controls the activities of epithelial sodium channel (ENaC) and Na,K-ATPase, the two limiting factors in establishing transepithelial sodium transport. It has been proposed that the ENaC/degenerin gene family is restricted to Metazoans, whereas the α- and β-subunits of Na,K-ATPase have homologous genes in prokaryotes. This raises the question of the emergence of osmolarity control. By exploring recent genomic data of diverse organisms, we found that: 1) ENaC/degenerin exists in all of the Metazoans screened, including nonbilaterians and, by extension, was already present in ancestors of Metazoa; 2) ENaC/degenerin is also present in Naegleria gruberi , an eukaryotic microbe, consistent with either a vertical inheritance from the last common ancestor of Eukaryotes or a lateral transfer between Naegleria and Metazoan ancestors; and 3) The Na,K-ATPase β-subunit is restricted to Holozoa, the taxon that includes animals and their closest single-cell relatives. Since the β-subunit of Na,K-ATPase plays a key role in targeting the α-subunit to the plasma membrane and has an additional function in the formation of cell junctions, we propose that the emergence of Na,K-ATPase, together with ENaC/degenerin, is linked to the development of multicellularity in the Metazoan kingdom. The establishment of multicellularity and the associated extracellular compartment (“internal milieu”) precedes the emergence of other key elements of the aldosterone signaling pathway.
Influenza and Bacterial Pathogen Coinfections in the 20th Century
Authors: Wang Xuan-Yi , Kilgore Paul E. , Lim Kyung Ah , Wang Song-Mei , Lee Jeongseok , Deng Wei , Mo Mei-Qi , Nyambat Batmunkh , Ma Jing-Chen , Favorov Michael O. , Clemens John D.
Published: May 2011

To help understand the potential impact of bacterial coinfection during pandemic influenza periods, we undertook a far-reaching review of the existing literature to gain insights into the interaction of influenza and bacterial pathogens. Reports published between 1950 and 2006 were identified from scientific citation databases using standardized search terms. Study outcomes related to coinfection were subjected to a pooled analysis. Coinfection with influenza and bacterial pathogens occurred more frequently in pandemic compared with seasonal influenza periods. The most common bacterial coinfections with influenza virus were due toS. pneumoniae,H. influenzae,Staphylococcus spp., andStreptococcus spp. Of these,S. pneumoniaewas the most common cause of bacterial coinfection with influenza and accounted for 40.8% and 16.6% of bacterial coinfections during pandemic and seasonal periods, respectively. These results suggest that bacterial pathogens will play a key role in many countries, as the H1N1(A) influenza pandemic moves forward. Given the role of bacterial coinfections during influenza epidemics and pandemics, the conduct of well-designed field evaluations of public health measures to reduce the burden of these common bacterial pathogens and influenza in at-risk populations is warranted.
Pemphigus Vulgaris Confined to the Gingiva: A Case Report
Authors: Ohta Mitsuhiro , Osawa Seiko , Endo Hiroyasu , Kuyama Kayo , Yamamoto Hirotsugu , Ito Takanori
Published: May 2011

Pemphigus Vulgaris (PV) is an autoimmune intraepithelial blistering disease involving the skin and mucous membranes. Oral mucosa is frequently affected in patients with PV, and oral lesions may be the first sign of the disease in majority of patients. In some patients, oral lesions may also be followed by skin involvement. Therefore, timely recognition and therapy of oral lesions is critical as it may prevent skin involvement. Early oral lesions of PV are, however, often regarded as difficult to diagnose, since the initial oral lesions may be relatively nonspecific, manifesting as superficial erosions or ulcerations, and rarely presenting with the formation of intact bullae. Lesions may occur anywhere on the oral mucosa including gingiva; however; desquamtive gingivitis is less common with PV than other mucocutaneous conditions such as pemphigoid or lichen planus. This paper describes the case of a patient presenting with a one-year history of painful gingival, who is finally diagnosed as having PV.
The Dynamics of Oxidized LDL during Atherogenesis
Authors: Itabe Hiroyuki , Obama Takashi , Kato Rina
Published: May 2011

Accumulating evidence indicates that oxidized low-density lipoprotein (OxLDL) is a useful marker for cardiovascular disease. The uptake of OxLDL by scavenger receptors leads to the accumulation of cholesterol within the foam cells of atherosclerotic lesions. OxLDL has many stimulatory effects on vascular cells, and the presence of OxLDL in circulating blood has been established. According to the classical hypothesis, OxLDL accumulates in the atherosclerotic lesions over a long duration, leading to advanced lesions. However, recent studies on time-course changes of OxLDLin vivoraised a possibility that OxLDL can be transferred between the lesions and the circulation. In this paper, thein vivodynamics of OxLDL are discussed.
Bayes Estimation of a Two‐Parameter Geometric Distribution under Multiply Type II Censoring
Authors: Shah J. B. , Patel M. N.
Published: May 2011

We derive Bayes estimators of reliability and the parameters of a two‐ parameter geometric distribution under the general entropy loss, minimum expected loss and linex loss, functions for a noninformative as well as beta prior from multiply Type II censored data. We have studied the robustness of the estimators using simulation and we observed that the Bayes estimators of reliability and the parameters of a two‐parameter geometric distribution under all the above loss functions appear to be robust with respect to the correct choice of the hyperparameters a(b) and a wrong choice of the prior parameters b(a) of the beta prior.
Antihypertriglyceridemia and Anti-Inflammatory Activities ofMonascus-Fermented Dioscorea in Streptozotocin-Induced Diabetic Rats
Authors: Shi Yeu-Ching , Liao Jiunn-Wang , Pan Tzu-Ming
Published: May 2011

The rice fermented byMonascus, called red mold rice (RMR), and has a long tradition in East Asia as a dietary staple.Monascus-fermented dioscorea called red mold dioscorea (RMD) contains various metabolites to perform the ability of reducing oxidative stress and anti-inflammatory response. We used Wistar rats and induced diabetes by injecting streptozotocin (STZ, 65 mg/kg i.p.). RMD was administered daily starting six weeks after disease onset. Throughout the experimental period, significantly () lowered plasma glucose, triglyceride, cholesterol, free fatty acid and low density lipoprotein levels were observed in the RMD-treated groups. The RMD-treated diabetic rats showed higher activities of glutathione disulfide reductase, glutathione reductase, catalase and superoxide dismutase () in the pancreas compared with the diabetic control rats. RMD also inhibited diabetes-induced elevation in the levels of interleukin (IL)-1β, IL-6, interferon-γand tumor necrosis factor-α. Pancreaticβ-cells damaged by STZ in the RMD supplemented groups were ameliorated. The results of this study clearly demonstrated that RMD possesses several treatment-oriented properties, including the control of hyperglycemia, antioxidant effects, pancreaticβ-cell protection and anti-inflammatory effects. Considering these observations, it appears that RMD may be a useful supplement to delay the development of diabetes and its complications.
Time to and Predictors of CD4+ T-Lymphocytes Recovery in HIV-Infected Children Initiating Highly Active Antiretroviral Therapy in Ghana
Authors: Renner Lorna , Prin Meghan , Li Fang-Yong , Goka Bamenla , Northrup Veronika , Paintsil Elijah
Published: May 2011

Background. CD4+ T-lymphocyte monitoring is not routinely available in most resource-limited settings. We investigated predictors of time to CD4+ T-lymphocyte recovery in HIV-infected children on highly active antiretroviral (HAART) at Korle-Bu Teaching Hospital, Ghana.Methods. Time to CD4+ T-lymphocyte recovery was defined as achieving percent CD4+ T-lymphocytes of 25%. We used Cox proportional hazard models for identifying significant predictor variables.Results. Of the 233 children with complete CD4+ T-lymphocyte data, the mean age at HAART initiation was 5.5 (SD=3.1) years. The median recovery time was 60 weeks (95% CL: 55–65). Evidence at baseline of severe suppression in CD4+ T-lymphocyte count adjusted for age, age at HAART initiation, gender, and having parents alive were statistically significant in predicting time to CD4+ T-lymphocyte recovery.Conclusions. A targeted approach based on predictors of CD4+ T-lymphocyte recovery can be a viable and cost-effective way of monitoring HAART in HIV-infected children in resource-limited settings.
Pancreatic Stellate Cells Radioprotect Pancreatic Cancer Cells through β1-Integrin Signaling
Authors: Mantoni Tine S. , Lunardi Serena , Al-Assar Osama , Masamune Atsushi , Brunner Thomas B.
Published: May 2011

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a strong desmoplastic reaction where the stromal compartment often accounts for more than half of the tumor volume. Pancreatic stellate cells (PSC) are a central mediator of desmoplasia. There is increasing evidence that desmoplasia is contributing to the poor therapeutic response of PDAC. We show that PSCs promote radioprotection and stimulate proliferation in pancreatic cancer cells (PCC) in direct coculture. Our in vivo studies show PSC-dependent radioprotection in response to a single dose and to fractionated radiation. Abrogating β1-integrin signaling abolishes the PSC-mediated radioprotection in PCCs. Furthermore, this effect is independent of PI3K (phosphoinositide 3-kinase) but dependent on FAK. Taken together, we show for the first time that PSCs promote radioprotection of PCCs in a β1-integrin–dependent manner. Cancer Res; 71(10); 3453–8. ©2011 AACR.
Pancreatic Ductal Adenocarcinoma Mice Lacking Mucin 1 Have a Profound Defect in Tumor Growth and Metastasis
Authors: Besmer Dahlia M. , Curry Jennifer M. , Roy Lopamudra D. , Tinder Teresa L. , Sahraei Mahnaz , Schettini Jorge , Hwang Sun-Il , Lee Yong Y. , Gendler Sandra J. , Mukherjee Pinku
Published: May 2011

MUC1 is overexpressed and aberrantly glycosylated in more than 60% of pancreatic ductal adenocarcinomas. The functional role of MUC1 in pancreatic cancer has yet to be fully elucidated due to a dearth of appropriate models. In this study, we have generated mouse models that spontaneously develop pancreatic ductal adenocarcinoma (KC), which are either Muc1-null (KCKO) or express human MUC1 (KCM). We show that KCKO mice have significantly slower tumor progression and rates of secondary metastasis, compared with both KC and KCM. Cell lines derived from KCKO tumors have significantly less tumorigenic capacity compared with cells from KCM tumors. Therefore, mice with KCKO tumors had a significant survival benefit compared with mice with KCM tumors. In vitro, KCKO cells have reduced proliferation and invasion and failed to respond to epidermal growth factor, platelet-derived growth factor, or matrix metalloproteinase 9. Further, significantly less KCKO cells entered the G2–M phase of the cell cycle compared with the KCM cells. Proteomics and Western blotting analysis revealed a complete loss of cdc-25c expression, phosphorylation of mitogen-activated protein kinase (MAPK), as well as a significant decrease in nestin and tubulin-α2 chain expression in KCKO cells. Treatment with a MEK1/2 inhibitor, U0126, abrogated the enhanced proliferation of the KCM cells but had minimal effect on KCKO cells, suggesting that MUC1 is necessary for MAPK activity and oncogenic signaling. This is the first study to utilize a Muc1-null PDA mouse to fully elucidate the oncogenic role of MUC1, both in vivo and in vitro. Cancer Res; 71(13); 4432–42. ©2011 AACR.
Connective Tissue Growth Factor Acts as a Therapeutic Agent and Predictor for Peritoneal Carcinomatosis of Colorectal Cancer
Authors: Lin Been-Ren , Chang Cheng-Chi , Chen Robert Jeen-Chen , Jeng Yung-Ming , Liang Jin-Tung , Lee Po-Huang , Chang King-Jen , Kuo Min-Liang
Published: May 2011

Purpose: Here, we aimed to investigate the role of connective tissue growth factor (CTGF) in peritoneal carcinomatosis (PC) associated with colorectal cancer (CRC) and to characterize the underlying mechanism of CTGF mediating adhesion.

Experimental Design: A cohort of 136 CRC patient specimens was analyzed in this study. CRC cell lines were used for in vitro adhesion assay and in vivo peritoneal dissemination experiment. Recombinant CTGF protein treatment, transfection of CTGF expression plasmids, and knockdown of CTGF expression in CRC cells were utilized to evaluate the integrin α5, which served as a target of CTGF in inhibiting peritoneal seeding.

Results: The analysis of CRC tissues revealed an inverse correlation between CTGF expression and prevalence of PC. Lower CTGF level in CRC patients was associated with higher peritoneal recurrence rate after surgery. Inducing CTGF expression in cancer cells resulted in decreased incidence of PC and increased rate of mice survival. The mice received intraperitoneal injection of recombinant CTGF protein simultaneously with cancer cells or following tumor formation; in both cases, peritoneal tumor dissemination was found to be effectively inhibited in the mouse model. Functional assay revealed that CTGF significantly decreased the CRC cell adhesion ability, and integrin α5 was confirmed by reverse transcriptase PCR and functional blocking assay as a downstream effector in the CTGF-mediated inhibition of CRC cell adhesion.

Conclusions: CTGF acts as a molecular predictor of PC and could be a potential therapeutic target for the chemoprevention and treatment of PC in CRC patients. Clin Cancer Res; 17(10); 3077–88. ©2011 AACR.
Recommendations from the iSBTc-SITC/FDA/NCI Workshop on Immunotherapy Biomarkers
Authors: Butterfield Lisa H. , Palucka A. Karolina , Britten Cedrik M. , Dhodapkar Madhav V. , Håkansson Leif , Janetzki Sylvia , Kawakami Yutaka , Kleen Thomas-Oliver , Lee Peter P. , Maccalli Cristina , Maecker Holden T. , Maino Vernon C. , Maio Michele , Malyguine Anatoli , Masucci Giuseppe , Pawelec Graham , Potter Douglas M. , Rivoltini Licia , Salazar Lupe G. , Schendel Dolores J. , Slingluff Craig L. , Song Wenru , Stroncek David F. , Tahara Hideaki , Thurin Magdalena , Trinchieri Giorgio , van Der Burg Sjoerd H. , Whiteside Theresa L. , Wigginton Jon M. , Marincola Francesco , Khleif Samir , Fox Bernard A. , Disis Mary L.
Published: May 2011

Purpose: To facilitate development of innovative immunotherapy approaches, especially for treatment concepts exploiting the potential benefits of personalized therapy, there is a need to develop and validate tools to identify patients who can benefit from immunotherapy. Despite substantial effort, we do not yet know which parameters of antitumor immunity to measure and which assays are optimal for those measurements.

Experimental Design: The iSBTc-SITC (International Society for Biological Therapy of Cancer-Society for Immunotherapy of Cancer), FDA (Food and Drug Administration), and NCI (National Cancer Institute) partnered to address these issues for immunotherapy of cancer. Here, we review the major challenges, give examples of approaches and solutions, and present our recommendations.

Results and Conclusions: Although specific immune parameters and assays are not yet validated, we recommend following standardized (accurate, precise, and reproducible) protocols and use of functional assays for the primary immunologic readouts of a trial; consideration of central laboratories for immune monitoring of large, multi-institutional trials; and standardized testing of several phenotypic and functional potential potency assays specific to any cellular product. When reporting results, the full QA (quality assessment)/QC (quality control) should be conducted and selected examples of truly representative raw data and assay performance characteristics should be included. Finally, to promote broader analysis of multiple aspects of immunity, and gather data on variability, we recommend that in addition to cells and serum, RNA and DNA samples be banked (under standardized conditions) for later testing. We also recommend that sufficient blood be drawn to allow for planned testing of the primary hypothesis being addressed in the trial, and that additional baseline and posttreatment blood is banked for testing novel hypotheses (or generating new hypotheses) that arise in the field. Clin Cancer Res; 17(10); 3064–76. ©2011 AACR.
Molecular Markers in Low-Grade Gliomas: Predictive or Prognostic?
Authors: Hartmann Christian , Hentschel Bettina , Tatagiba Marcos , Schramm Johannes , Schnell Oliver , Seidel Clemens , Stein Robert , Reifenberger Guido , Pietsch Torsten , von Deimling Andreas , Loeffler Markus , Weller Michael
Published: May 2011

Purpose: To investigate whether TP53 mutation, 1p/19q codeletions, O6-methylguanylmethyltransferase (MGMT) promoter methylation, and isocitrate dehydrogenase 1 (IDH1) mutation predict natural course of disease or response to radiotherapy or chemotherapy or both in low-grade glioma patients.

Experimental Design: Cohort A consisted of 89 patients with diffuse astrocytoma World Health Organization (WHO) grade II (n = 40), oligoastrocytoma (n = 23), or oligodendroglioma (n = 26) who did not receive radiotherapy or chemotherapy after first operation and were monitored until progression [progressive disease (PD); n = 59] and beyond or until the end of follow-up (n = 30). Cohort B consisted of 50 patients with WHO grade II gliomas who received radiotherapy or chemotherapy at diagnosis. Tumors were analyzed for TP53 mutations, 1p/19q codeletions, MGMT promoter methylation, and IDH1 mutations.

Results: Median progression-free survival (PFS) in cohort A was 4.1 years (95% CI: 3.1–5.1). No molecular marker was prognostic for PFS after surgery alone, using multivariate adjustment for histology, age, and extent of resection. IDH1 mutations were associated with prolonged survival from the diagnosis of PD in oligoastrocytomas (OA II)/oligodendrogliomas (O II) and with overall survival (OS) in all tumors. 1p/19q codeletion and IDH1 mutation were prognostic for PFS and OS in cohort B.

Conclusions: None of the parameters are sensitive prognostic biomarkers in WHO grade II glioma patients who do not receive radiotherapy or chemotherapy after surgery. Limitations of this study include the selection of patients with favorable outcome, the nonrandomized allocation of treatment, and the insufficient sample size to distinguish between effects of radiotherapy versus chemotherapy. Regardless of histology, IDH1 mutation status is the strongest prognostic marker for OS. Clin Cancer Res; 17(13); 4588–99. ©2011 AACR.
Instability of Foxp3 Expression Limits the Ability of Induced Regulatory T Cells to Mitigate Graft versus Host Disease
Authors: Beres Amy , Komorowski Richard , Mihara Masahiko , Drobyski William R.
Published: May 2011

Purpose: Graft versus host disease (GVHD) is the major complication of allogeneic bone marrow transplantation (BMT) and limits the therapeutic efficacy of this modality. Although the role of natural T-regulatory cells (nTreg) in attenuating GVHD has been extensively examined, the ability of induced T-regulatory cells (iTreg) to mitigate GVHD is unknown. The purpose of this study was to examine the ability of in vitro and in vivo iTregs to abrogate GVHD.

Experimental Design: We examined the ability of in vitro differentiated and in vivo iTregs to reduce the severity of GVHD in a clinically relevant mouse model of BMT. The effect of blockade of interleukin (IL) 6 signaling on the efficacy of these Treg populations was also studied.

Results: In vitro differentiated iTregs fail to protect mice from lethal GVHD even when administered at high Treg:effector T-cell ratios. Lack of GVHD protection was associated with loss of Foxp3 expression and in vivo reversion of these cells to a proinflammatory phenotype characterized by secretion of IFN-γ. Phenotypic reversion could not be abrogated by blockade of IL-6 signaling or by in vitro exposure of iTregs to all-trans retinoic acid. In contrast, the in vivo induction of iTregs was significantly augmented by IL-6 blockade and this resulted in reduced GVHD.

Conclusion: Instability of Foxp3 expression limits the utility of adoptively transferred iTregs as a source of cellular therapy for the abrogation of GVHD. Blockade of IL-6 signaling augments the ability of in vivo iTregs to prevent GVHD but has no effect on in vitro differentiated iTregs. Clin Cancer Res; 17(12); 3969–83. ©2011 AACR.
Targeting Superficial or Nodular Basal Cell Carcinoma with Topically Formulated Small Molecule Inhibitor of Smoothened
Authors: Tang Tracy , Tang Jean Y. , Li Dongwei , Reich Mike , Callahan Christopher A. , Fu Ling , Yauch Robert L. , Wang Frank , Kotkow Karen , Chang Kris S. , Shpall Elana , Wu Angela , Rubin Lee L. , Marsters James C. , Epstein Ervin H. , Caro Ivor , de Sauvage Frederic J.
Published: May 2011

Purpose: Inappropriate activation of the Hedgehog (Hh) signaling pathway in skin is critical for the development of basal cell carcinomas (BCC). We have investigated the anti-BCC efficacy of topically-applied CUR61414, an inhibitor of the Hh signal transduction molecule Smoothened.

Experimental Design: In preclinical studies, we used a depilatory model to evaluate the ability of topical formulations of CUR61414 to repress Hh responsive cells found at the base of hair follicles in normal skin. We also tested the in vivo effects of topical CUR61414 on murine BCCs developed in Ptch1 +/− K14-CreER2 p53 fl/fl mice. In a phase I clinical study, we evaluated the safety, tolerability, and efficacy of a multidose regimen of CUR61414 (0.09%, 0.35%, 1.1%, and 3.1%) applied topically to human superficial or nodular BCCs for up to 28 days.

Results: In mice, topical CUR61414 significantly inhibited skin Hh signaling, blocked the induction of hair follicle anagen, and shrank existing BCCs. However, we observed no clinical activity of this formulation in human superficial or nodular BCCs in a phase I clinical study.

Conclusions: Our data highlight some of the challenges of translating preclinical experience into successful human results for a topical anticancer agent. Clin Cancer Res; 17(10); 3378–87. ©2011 AACR.
Validity of Composite Outcomes in Meta-Analyses of Stroke Prevention Trials: The Case of Aspirin
Authors: McGrath Emer , O’Conghaile Aengus , Eikelboom John W. , Dinneen Sean F. , Oczkowski Colin , O’Donnell Martin J.
Published: May 2011

Background: Aspirin has been reported to be less effective for secondary vascular prevention in patients with ischaemic stroke, compared with other high-risk populations. This contention is largely based on results of meta-analyses that used a composite outcome of vascular death, myocardial infarction and stroke, reporting a 13% relative risk reduction. In this study, we explore whether the summary relative risk reduction for this composite outcome is representative of estimates for each of the individual components of the composite. Study Selection: All randomised controlled trials comparing aspirin with placebo/control in patients following ischaemic stroke or transient ischaemic attack, beyond the acute period (2 weeks). Data Analysis: A fixed-effects model was used and summary risk ratios were calculated for each of the outcomes: vascular mortality, recurrent non-fatal stroke, non-fatal myocardial infarction, composite of the latter three outcomes, all-cause mortality and non-vascular mortality. Results: Ten trials (n = 9,168) were included. For the composite of non-fatal stroke, non-fatal myocardial infarction and vascular death, aspirin was associated with a 13% reduction in risk (risk ratio, RR: 0.87; 95% CI: 0.81–0.94). For individual components of the composite, aspirin reduced the risk of non-fatal ischaemic stroke (RR: 0.81; 95% CI: 0.72–0.90) and non-fatal myocardial infarction (RR: 0.68; 95% CI: 0.52–0.87), but not vascular death (RR: 0.97; 95% CI: 0.86–1.1). Aspirin did reduce the risk of non-vascular death (RR: 0.79; 95% CI: 0.66–0.95), though, and had a trend towards a reduced risk of all-cause mortality (RR: 0.91; 95% CI: 0.81–1.01). Conclusions: Following ischaemic stroke, aspirin does not reduce the risk of vascular death, but provides a significant reduction in non-fatal stroke, myocardial infarction and non-vascular death. Our findings would support presenting the effect of aspirin therapy on individual outcomes rather than a composite including vascular death.
Experimental Study of the Spider™ Patent Foramen Ovale Occluder
Authors: Zhang Caojin , Huang Yigao , Bertog Stefan , Huang Tao , Huang Wenhui , Huang Xinsheng , Luo Donglan
Published: May 2011

Aim: To evaluate the feasibility, safety and efficacy of the Spider™ patent foramen ovale (PFO) occluder for the treatment of PFOs in an animal model. Method: The foramen ovale was punctured to establish an animal model of a PFO. Under fluoroscopic guidance, the PFO was occluded with the Spider PFO occluder. The piglets were electively sacrificed at months 1, 2, 3, 6 and 12 after occlusion for macroscopic and microscopic examination. Results: PFOs were successfully created and occluded percutaneously in 20 piglets. All piglets recovered from the procedure in good condition and completed follow-up. Macroscopic examination of all hearts showed complete closure of the PFO. The position of each device was correct. All devices were completely covered and embedded in pale and smooth tissue. There was no evidence of interference with adjacent structures of the heart or valves. The occluder was partially covered by endocardium after 1 month, almost completely covered by fresh endocardium after 3 months, and embedded within thick fibrous tissues and fresh vessels after 6 months. The tissue covering both occluder discs demonstrated some infiltration of inflammatory cells, including patches of lymphocyte aggregation. This inflammatory cell reaction diminished with increasing distance from the device. Furthermore, the number of inflammatory cells decreased gradually during follow-up and eventually, at 6-month follow-up, the inflammatory response was no longer visible. The 12-month histological findings did not differ from the 6-month findings. Conclusion: Transcatheter closure of PFO with the Spider PFO occluder is effective and safe in an animal model. These results support further investigation of this device in animals and, if the results are confirmed, in human clinical trials.
Toll-Like Receptor-Mediated Inflammatory Signaling Reprograms Cardiac Energy Metabolism by Repressing Peroxisome Proliferator-Activated Receptor γ Coactivator-1 Signaling
Authors: Schilling Joel , Lai Ling , Sambandam Nandakumar , Dey Courtney E. , Leone Teresa C. , Kelly Daniel P.
Published: May 2011

Background—

Currently, there are no specific therapies available to treat cardiac dysfunction caused by sepsis and other chronic inflammatory conditions. Activation of toll-like receptor 4 (TLR4) by lipopolysaccharide (LPS) is an early event in Gram-negative bacterial sepsis, triggering a robust inflammatory response and changes in metabolism. Peroxisome proliferator–activated receptor-γ coactivator-1 (PGC-1) α and β serve as critical physiological regulators of energy metabolic gene expression in heart.

Methods and Results—

Injection of mice with LPS triggered a myocardial fuel switch similar to that of the failing heart: reduced mitochondrial substrate flux and myocyte lipid accumulation. The LPS-induced metabolic changes were associated with diminished ventricular function and suppression of the genes encoding PGC-1α and β, known transcriptional regulators of mitochondrial function. This cascade of events required TLR4 and nuclear factor-κB activation. Restoration of PGC-1β expression in cardiac myocytes in culture and in vivo in mice reversed the gene regulatory, metabolic, and functional derangements triggered by LPS. Interestingly, the effects of PGC-1β overexpression were independent of the upstream inflammatory response, highlighting the potential utility of modulating downstream metabolic derangements in cardiac myocytes as a novel strategy to prevent or treat sepsis-induced heart failure.

Conclusions—

LPS triggers cardiac energy metabolic reprogramming through suppression of PGC-1 coactivators in the cardiac myocyte. Reactivation of PGC-1β expression can reverse the metabolic and functional derangements caused by LPS-TLR4 activation, identifying the PGC-1 axis as a candidate therapeutic target for sepsis-induced heart failure.
The Unrecognized Burden of Osteoporosis-Related Vertebral Fractures in Patients With Heart Failure
Authors: Lyons Kristin J. , Majumdar Sumit R. , Ezekowitz Justin A.
Published: May 2011

Background—

Heart failure (HF) is associated with several factors that contribute to both reduced bone mineral density and increased risk of osteoporosis-related fractures. Our objectives were to describe the prevalence and predictors of the most common osteoporotic fracture, vertebral compression fractures (VCF), in patients with HF.

Methods and Results—

We conducted a cross-sectional study in a random sample of patients attending a tertiary care HF Clinic in Edmonton, Alberta, Canada. We collected sociodemographic, clinical, medication, and chest radiograph information. Primary outcome was board-certified radiologist–documented VCF on chest radiographs. Multivariable logistic regression was used to determine independent correlates of VCF. Overall, 623 patients with HF were included; 32% were over 75 years of age, 31% were women, 65% had ischemic cardiomyopathy, and 38% had atrial fibrillation. Prevalence of VCF was 77 of 623 (12%; 95% confidence interval, 10% to 15%), and 42 of 77 (55%) patients had multiple fractures. Only 15% of those with VCF were treated for osteoporosis. In multivariable analyses adjusted for age, female sex, weight, and medications, the only remaining predictors independently associated with fracture were atrial fibrillation (present in 42 of 77 [55%] of those with VCF versus 197 of 540 [36%] of those without; adjusted odds ratio, 2.1; 95% confidence interval, 1.2 to 3.6;
P
=0.009) and lipid-lowering drugs (used by 36 of 77 [47%] of those with VCF versus 342 of 540 [63%] of those without; adjusted odds ratio, 0.2; 95% confidence interval, 0.1 to 0.9;
P
=0.03).

Conclusions—

About one-tenth of HF patients had a chest radiograph–documented VCF, and half of those with VCF had multiple fractures; most (85%) were not receiving an osteoporosis-specific therapy. A previously unrecognized risk factor—atrial fibrillation—was found to be independently associated with VCF. Chest radiograph reports may represent an important case-finding tool for osteoporosis-specific VCF, particularly in HF patients with atrial fibrillation.
High-performance PEN/GF crosslinkable thermoplastic composites: preparation, properties, and crosslinking reaction
Authors: Yang Jian , Zhong Jiachun , Zhao Rui , Liu Xiaobo
Published: May 2011

The continuous glass fiber-reinforced polyarylene ether nitriles (PEN) composites were successfully fabricated from PEN pre-impregnated glass fabric mates and PEN films using a film-stacking method. The work involved heat treatment for crosslinking reaction of PEN, and so it provided an interesting comparison of how heat treatment can influence the properties of composites. Detailed study on heat treatments for crosslinking reaction of PEN in the catalysis of the ZnCl2 at high temperature promoting the thermal and mechanical properties of composites were also investigated. The results showed that the thermal and mechanical properties of composites were enhanced by heat treatment, which is due to the fact that PEN resins could be crosslinked by the catalytic action of ZnCl2 at high temperature and formed triazine rings with a more thermally stable structure.
Alcohol Use Trajectories and Problem Drinking Over the Course of Adolescence
Authors: Cheadle Jacob E. , Whitbeck Les B.
Published: May 2011

This study investigated the links between alcohol use trajectories and problem drinking ( Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition abuse/dependence) using five waves of data from 727 North American Indigenous adolescents between 10 and 17 years from eight reservations sharing a common language and culture. Growth mixture models linking fundamental causes, social stressors, support, and psychosocial pathways to problem drinking via alcohol use trajectories over the early life course were estimated. Results indicated that 20 percent of the adolescents began drinking at 11 to 12 years of age and that another 20 percent began drinking shortly thereafter. These early drinkers were at greatly elevated risk for problem drinking, as were those who began drinking at age 13. The etiological analysis revealed that stressors (e.g., perceived discrimination) directly and indirectly influenced early and problem alcohol use by decreasing positive school attitudes while increasing feelings of anger and perceived delinquent friendships. Girls were found to be at risk independently of these other factors.
The split system approach to managing time in simulations of hybrid systems having continuous and discrete event components
Authors: Nutaro James , Kuruganti Phani Teja , Protopopescu Vladimir , Shankar Mallikarjun
Published: May 2011

The efficient and accurate management of time in simulations of hybrid models is an outstanding engineering problem. General a priori knowledge about the dynamic behavior of the hybrid system (i.e. essentially continuous, essentially discrete, or ‘truly hybrid’) facilitates this task. Indeed, for essentially discrete and essentially continuous systems, existing software packages can be conveniently used to perform quite sophisticated and satisfactory simulations. The situation is different for ‘truly hybrid’ systems, for which direct application of existing software packages results in a lengthy design process, cumbersome software assemblies, inaccurate results, or some combination of these independent of the designer’s a priori knowledge about the system’s structure and behavior. The main goal of this paper is to provide a methodology whereby simulation designers can use a priori knowledge about the hybrid model’s structure to build a straightforward, efficient, and accurate simulator with existing software packages. The proposed methodology is based on a formal decomposition and re-articulation of the hybrid system; this is the main theoretical result of the paper. To set the result in the right perspective, we briefly review the essentially continuous and essentially discrete approaches, which are illustrated with typical examples. Then we present our new, split system approach, first in a general formal context, then in three more specific guises that reflect the viewpoints of three main communities of hybrid system researchers and practitioners. For each of these variants we indicate an implementation path. Our approach is illustrated with an archetypal problem of power grid control.
Surface modification of textile materials with hydrophobins
Authors: Opwis Klaus , Gutmann Jochen S
Published: May 2011

Hydrophobins are native proteins with outstanding properties. Because of their special bifunctional molecular structure they can influence the wetting behavior of polymeric substrates. Here, the influence of thermally deposited hydrophobins on properties of various textile substrates is studied. The successful immobilization of hydrophobins can be demonstrated by a protein-selective color reaction with ninhydrin, which is positive even after a harsh washing and extraction procedure indicating the high permanence of the finishing process. Regarding the wetting properties, the modification of hydrophobic fabrics (demonstrated on polyethylene terephthalate) results in a significant hydrophilization, while hydrophilic textile substrates made of cotton and polyamide attain strong hydrophobic character. Moreover, the developed thermal deposition technique seems to be practical for use with coating technologies established in the textile industry and could be easily transferred to industrial praxis. Thus, non-toxic and biodegradable hydrophobins copied from nature could have great potential in textile surface modification.