bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic Polymorphisms in the EGFR (R521K) and Estrogen Receptor (T594T) Genes, EGFR and ErbB‐2 Protein Expression, and Breast Cancer Risk in Tunisia
Authors: Kallel Imen , Rebai Maha , Khabir Abdelmajid , Farid Nadir R. , Rebaï Ahmed
Published: July 2009

We evaluated the association of epidermal growth factor receptor (EGFR) 142285G>A (R521K) and estrogen receptor alpha (ESR1) 2014G>A (T594T) single nucleotide polymorphisms with breast cancer risk and prognosis in Tunisian patients. EGFR 142285G>A and ESR1 2014G>A were genotyped in a sample of 148 Tunisian breast cancer patients and 303 controls using PCR‐RFLP method. Immunohistochemitsry was used to evaluate the expression levels of EGFR, HER2, ESR1, progesterone receptor and BCL2 in tumors. We found no evidence for an association between EGFR R521K polymorphism and breast cancer risk. However, we found that the homozygous GG (Arg) genotype was more prevalent in patients with lymph node metastasis (P = .03) and high grade tumors (P = .011). The ESR1 2014G allele showed significant association with breast cancer risk (P = .025). The GG genotype was associated with HER2 overexpression and this association withstood univariate and multivariate analyses (P = .009; P = .021, resp.). These data suggest that the R521K might be a prognostic factor, because it correlates with both tumor grade and nodule status. The higher expression of HER2 in ESR1 T594T GG patients suggests the possibility that ESR1 gene polymorphisms accompanied by HER2 expression might influence the pathogenesis of breast cancers.
Anti-EGFR-Targeted Therapy for Esophageal and Gastric Cancers: An Evolving Concept
Authors: Dragovich Tomislav , Campen Christopher
Published: July 2009

Cancers of the esophagus and stomach present a major health burden worldwide. In the past 30 years we have witnessed some interesting shifts in terms of epidemiology of esophago gastric cancers. Regardless of a world region, the majority of patients diagnosed with esophageal or gastric cancers die from progression or recurrence of their disease. While there are many active cytotoxic agents for esophageal and stomach cancers, their impact on the disease course has been modest at best. Median survival for patients with advanced gastroesophageal cancer is still less than a year. Therefore, novel strategies, based on our understanding of biology and genetics, are desperately needed. Epidermal growth factor receptor (EGFR) pathway has been implicated in pathophysiology of many epithelial malignancies, including esophageal and stomach cancers. EGFR inhibitors, small molecule tyrosine kinase inhibitors and monoclonal antibodies, have been explored in patients with esophageal and gastric cancers. It appears that tumors of the distal esophagus and gastroesophageal junction (GEJ) may be more sensitive to EGFR blockade than distal gastric adenocarcinomas. Investigations looking into potential molecular predictors of sensitivity to EGFR inhibitors for patients with esophageal and GEJ cancers are ongoing. While we are still searching for those predictors, it is clear that they will be different from ones identified in lung and colorectal cancers. Further development of EGFR inhibitors for esophageal and GEJ cancers should be driven by better understanding of EGFR pathway disregulation that drives cancer progression in a sensitive patient population.
Mitigation of Railway Traffic Induced Vibrations: The Influence of Barriers in Elastic Half‐Space
Authors: Buonsanti Michele , Cirianni Francis , Leonardi Giovanni , Santini Adolfo , Scopelliti Francesco
Published: July 2009

In this paper, the problem of vibrations induced by trains and their propagation through the soil is studied. Particular attention is focused on the vibration induced by trains in motion and on the effects of such vibrations on the foundations of buildings in proximity of the tracks. The interaction between propagating waves induced by trains in motion and buildings foundations is a problem which does not admit a straightforward analytical solution; thus a solution is given by the use of a model based on the finite elements method. Firstly, we analyze the theoretical aspects of the problem by considering constant or harmonic loads moving along a straight railway track; then, we define a transfer function soil‐railway and the response function of the entire system. The study aims to address the wave propagation in an elastic semi‐space and the presence in the ground of a discontinuity element, such as a barrier of a given depth is considered. The efficiency variation of barriers is analyzed in function of the different materials used, and different numerical simulations are analyzed in order to study how the wave propagation and the track‐soil interaction are influenced by the membrane, seen as damping barrier.
Gα12-Mediated Pathway Promotes Invasiveness of Nasopharyngeal Carcinoma by Modulating Actin Cytoskeleton Reorganization
Authors: Liu Shu-Chen , Jen Yee-Min , Jiang Shih Sheng , Chang Junn-Liang , Hsiung Chao A. , Wang Chih-Hung , Juang Jyh-Lyh
Published: July 2009

The molecular mechanisms behind the aggressiveness of nasopharyngeal carcinoma (NPC), a highly invasive and metastatic head and neck malignancy, have not been made clear. In this study investigating these mechanisms, guanine nucleotide-binding protein α12 subunit (Gα12) signaling was found by microarray analysis to be increased in primary NPC cells and NPC-derived cell lines. Using small interfering RNA to knock down Gα12 in NPC cells resulted in a reduction in cell migration and invasion as well as a reversal in fibroblastoid morphology. Using microarray analysis, we also found a reduction in expression of key actin dynamics regulators and several epithelial-to-mesenchymal transition–related genes in Gα12-depleted NPC cells. Knocking down one of those genes, IQ motif containing GTPase activating protein 1, reduced the migration and formation of adherens junctions and reversed the fibroblastoid morphology of NPC cells, as knocking down Gα12 was found to do. Immunohistochemical analysis found NPC tumors to have significantly greater levels of Gα12 protein than the normal basal epithelial cells. Quantitative real-time PCR analysis revealed a significant correlation between Gα12 mRNA levels and NPC lymph node metastasis. Together, our findings support a model in which activation of Gα12 signaling promotes tumorigenesis and progression of NPC by modulating actin cytoskeleton reorganization and expression of epithelial-to-mesenchymal transition–related genes. [Cancer Res 2009;69(15):6122–30]
Loss of RhoB Expression Promotes Migration and Invasion of Human Bronchial Cells Via Activation of AKT1
Authors: Bousquet Emilie , Mazières Julien , Privat Maud , Rizzati Virginie , Casanova Anne , Ledoux Adeline , Mery Eliane , Couderc Bettina , Favre Gilles , Pradines Anne
Published: July 2009

Lung cancer is the leading cause of cancer-related death worldwide, mainly due to its highly metastatic properties. Previously, we reported an inverse correlation between RhoB expression and the progression of the lung cancer, occurring between preinvasive and invasive tumors. Herein, we mimicked the loss of RhoB observed throughout lung oncogenesis with RNA interference in nontumoral bronchial cell lines and analyzed the consequences on both cell transformation and invasion. Down-regulation of RhoB did not modify the cell growth properties but did promote migration and invasiveness. Furthermore, RhoB depletion was accompanied by modifications of actin and cell adhesion. The specific activation of the Akt1 isoform and Rac1 was found to be critical for this RhoB-mediated regulation of migration. Lastly, we showed that RhoB down-regulation consecutive to K-RasV12 cell transformation is critical for cell motility but not for cell proliferation. We propose that RhoB loss during lung cancer progression relates to the acquisition of invasiveness mediated by the phosphatidylinositol 3-kinase (PI3K)/AKT and Rac1 pathways rather than to tumor initiation. [Cancer Res 2009;69(15):6092–99]
Protein Kinase Cδ Activates RelA/p65 and Nuclear Factor-κB Signaling in Response to Tumor Necrosis Factor-α
Authors: Lu Zheng-Guang , Liu Hanshao , Yamaguchi Tomoko , Miki Yoshio , Yoshida Kiyotsugu
Published: July 2009

Nuclear factor-κB (NF-κB) is tightly modulated by IκB kinases and IκBα in the cytoplasm. On stimulation, NF-κB translocates into the nucleus to initiate transcription; however, regulation of its transcriptional activity remains obscure. Here, we show that protein kinase C (PKC) δ controls the main subunit of NF-κB, RelA/p65. On exposure to tumor necrosis factor-α (TNF-α), the expression of RelA/p65 target genes such as IκBα, RelB, and p100/p52 is up-regulated in a PKCδ-dependent manner. The results also show that PKCδ is targeted to the nucleus and forms a complex with RelA/p65 following TNF-α exposure. Importantly, kinase activity of PKCδ is required for RelA/p65 transactivation. In concert with these results, PKCδ activates RelA/p65 for its occupancy to target-gene promoters, including IκBα and p100/p52. Moreover, functional analyses show that inhibition of PKCδ is associated with substantial attenuation of NF-κB activity in response to TNF-α. These findings provide evidence that PKCδ orchestrates RelA/p65 transactivation, a requisite for NF-κB signaling pathway in the nucleus. [Cancer Res 2009;69(14):5927–35]
Kinome Profiling of Chondrosarcoma Reveals Src-Pathway Activity and Dasatinib as Option for Treatment
Authors: Schrage Yvonne M. , Briaire-de Bruijn Inge H. , de Miranda Noel F.C.C. , van Oosterwijk Jolieke , Taminiau Antonie H.M. , van Wezel Tom , Hogendoorn Pancras C.W. , Bovée Judith V.M.G.
Published: July 2009

Chondrosarcomas are notorious for their resistance to conventional chemotherapy and radiotherapy, indicating there are no curative treatment possibilities for patients with inoperable or metastatic disease. We therefore explored the existence of molecular targets for systemic treatment of chondrosarcoma using kinome profiling. Peptide array was performed for four chondrosarcoma cell lines and nine primary chondrosarcoma cultures with GIST882, MSCs, and colorectal cancer cell lines as controls. Activity of kinases was verified using immunoblot, and active Src- and platelet-derived growth factor receptor (PDGFR) signaling were further explored using imatinib and dasatinib on chondrosarcoma in vitro. The AKT1/GSK3B pathway was clearly active in chondrosarcoma. In addition, the PDGFR pathway and the Src kinase family were active. PDGFR and Src kinases can be inhibited by imatinib and dasatinib, respectively. Although imatinib did not show any effect on chondrosarcoma cell cultures, dasatinib showed a decrease in cell viability at nanomolar concentrations in seven of nine chondrosarcoma cultures. However, inhibition of phosphorylated Src (Y419) was found both in responsive and nonresponsive cells. In conclusion, using kinome profiling, we found the Src pathway to be active in chondrosarcoma. Moreover, we showed in vitro that the inhibitor of the Src pathway, dasatinib, may provide a potential therapeutic benefit for chondrosarcoma patients who are not eligible for surgery. [Cancer Res 2009;69(15):6216–22]
The G Protein–Coupled Receptor 87 Is Necessary for p53-Dependent Cell Survival in Response to Genotoxic Stress
Authors: Zhang Yanhong , Qian Yingjuan , Lu Wenfu , Chen Xinbin
Published: July 2009

p53 regulates an array of target genes, which mediates p53 tumor suppression by inducing cell cycle arrest, apoptosis, and cell survival. G protein–coupled receptors belong to a superfamily of cell surface molecules and are known to regulate cell proliferation, migration, and survival. Here, we found that G protein–coupled receptor 87 (GPR87) was up-regulated by p53 and by DNA damage in a p53-dependent manner. We also found that p53 directly regulated GPR87 potentially via a p53-responsive element in the GPR87 gene. To investigate the role of GPR87 in the p53 pathway, we generated multiple RKO and MCF7 cell lines in that GPR87 can be inducibly overexpressed or knocked down by a tetracycline-inducible system. We found that overexpression of GPR87 had little effect on cell growth. However, GPR87 knockdown sensitized cancer cells to DNA damage–induced growth suppression via enhanced p53 stabilization and activation. Importantly, the prosurvival activity of GPR87 can be reversed by knockdown of p53. Together, our results suggested that GPR87 is essential for p53-dependent cell survival in response to DNA damage. Thus, due to its expression on the cell surface and its role in cell survival, GPR87 may be explored as a novel therapeutic target for cancer treatment and prevention. [Cancer Res 2009;69(15):6049–56]
Autologous Melanoma Vaccine Induces Antitumor and Self-Reactive Immune Responses That Affect Patient Survival and Depend on MHC Class II Expression on Vaccine Cells
Authors: Lotem Michal , Machlenkin Arthur , Hamburger Tamar , Nissan Aviram , Kadouri Luna , Frankenburg Shoshana , Gimmon Zvi , Elias Orit , David Inna Ben , Kuznetz Anna , Shiloni Eitan , Peretz Tamar
Published: July 2009

Purpose: Autologous melanoma cells display a broad variety of tumor antigens and were used for treatment of American Joint Committee on Cancer stages III and IV melanoma as an adjuvant or active therapy. Survival data and immune response were evaluated in vaccinated patients.

Experimental Design: Forty-seven patients received 2,4-dinitrophenyl–conjugated autologous melanoma vaccine as an adjuvant (23 patients) or therapy (24 patients). CD4 and CD8 T-cell response in blood sampled before vaccination and after five or eight vaccine doses was evaluated against melanoma cells and autologous peripheral blood mononuclear cells using IFNγ enzyme–linked immunospot. Serum levels of antilivin, an inhibitor of apoptosis, and anti-gp100 IgG were determined.

Results: The immunologic effect of the vaccine differed between the two groups of patients. In the adjuvant group, there was a significant increase in CD8 melanoma-reactive T cells (P = 0.035) after vaccination and an increase in antimelanoma CD4 T cells correlating with improved overall survival (P = 0.04). In the therapeutic group, there was no objective tumor regression; antimelanoma T-cell reactivity increased by a small amount, stayed the same, or in some cases decreased. In all patients, a significant increase was noted in CD4 T-cell reactivity against autologous peripheral blood mononuclear cells (P = 0.02), which did not affect survival. Increased antilivin IgG was associated with improved survival. Expression of MHC class II on melanoma cells was vital for the immunogenicity of the vaccine.

Conclusion: Autologous melanoma cell vaccine is capable of inducing effective antimelanoma CD4 T-cell activity associated with improved survival. Patients with active metastatic disease generally displayed reduced immune response and gained little from active immunization.
The Y Chromosome of the Atelidae Family (Platyrrhini): Study by Chromosome Microdissection
Authors: Gifalli-Iughetti C. , Koiffmann C.P.
Published: July 2009

In order to study the intergeneric variability of the Y chromosome, we describe the hybridization of the Y chromosome of Brachytelesarachnoides, obtained by microdissection, to metaphases of Atelesbelzebuthmarginatus, Lagothrixlagothricha, and Alouatta male specimens. Brachytelesarachnoides (Atelinae) has 62 chromosomes and a very small Y chromosome. Our results showed that the Brachytelesarachnoides Y chromosome probe hybridized to Lagothrixlagothricha metaphases yielding one hybridization signal on only the tiny Y chromosome, and when hybridized with Atelesbelzebuthmarginatus metaphases it yielded one hybridization signal on two thirds of the small acrocentric Y chromosome. However, no hybridization signal was observed in Alouatta metaphases (subfamily Alouattinae), a closely related genus in the Atelidae family. Furthermore, our data support a close phylogenetic relationship among Brachyteles, Ateles, and Lagothrix and their placement in the Atelinae subfamily, but exclude Alouatta from this group indicating its placement as basal to this group.
A High-Resolution Radiation Hybrid Map of Sheep Chromosome X and Comparison with Human and Cattle
Authors: Goldammer T. , Brunner R.M. , Rebl A. , Wu C.H. , Nomura K. , Hadfield T. , Gill C. , Dalrymple B.P. , Womack J.E. , Cockett N.E.
Published: July 2009

A radiation hybrid (RH) map of sheep X chromosome (Ovisaries; OARX) containing 146 physically anchored loci was generated in this study, providing information for comparative X chromosome analysis between the maps of sheep, human, and cattle. Primers typed on the USUoRH5000 ovine whole-genome radiation hybrid panel were designed from sequences predicted to be on the ovine X chromosome, based on comparative mapping within the virtual sheep genome browser (v1.2). The resulting RH map for the ovine X chromosome consists of 4 linkage groups composed of 76 BAC end sequences (BES), 28 gene loci that were confirmed within ovine BAC clones in the CHORI-243 ovine BAC library, 28 additional gene loci from the ovine comparative map and 14 polymorphic sequence tagged sites (STS) from the OARX linkage map. This first-generation RH map of OARX contributes to the expansion of a comprehensive ovine genome map for sheep and provides evidence of rearrangements in loci order compared to the human and cattle orders.
Evolutionary Break Point Analysis between the Proximal Half of Bovine Chromosome 27 and Conserved Segments of the Human Genome
Authors: Goldammer T. , Kuehn C. , Brunner R.M. , Weikard R.
Published: July 2009

The proximal half of Bos taurus chromosome 27 (BTA27prox) delimited by microsatellite markers BM3507 and CSSM043 reveals complex rearrangements compared to its corresponding Homo sapiens chromosome (HSA) fragments. A comparative mapping approach combining somatic and radiation hybrid cell mapping techniques and related cytogenetic data resulted in an improved physical map for BTA27prox, which provides candidate genes for several important economic traits. The generated comprehensive map includes anchor loci for 103 genes and microsatellite markers. Mapping of genes proximal to BM3507 matching a region from 0.60 to 2.78 megabase pairs (Mb) of HSA8 confirmed recent sequence annotations on BTA27. Assignments of loci predicted to be on BTA27 to BTA1, BTA8, and BTA17 narrowed down evolutionary chromosome break points compared with corresponding chromosome segments in human. New physical anchors obtained in this study confirm in more detail the described evolutionary conservation between the proximal half of BTA27 and homologous segments of HSA4 and HSA8 and will contribute to the completion of the cattle DNA genome sequence.
Early Outcome of Combined Thrombolysis Based on the Mismatch on Perfusion CT
Authors: Kim Joon-Tae , Yoon Woong , Park Man-Seok , Nam Tai-Seung , Choi Seong-Min , Lee Seung-Han , Kim Byeong-Chae , Kim Myeong-Kyu , Cho Ki-Hyun
Published: July 2009

Background: Possible factors associated with early outcome after thrombolysis are the recanalization time and the status of tissue. We assessed whether combined intravenous (IV) and intra-arterial (IA) thrombolysis performed according to the status of tissue based on perfusion computed tomography (PCT) is beneficial for the early outcome in patients with acute ischemic stroke. Methods: To improve the recanalization time, we assumed that combined IA thrombolysis after IV thrombolysis would be beneficial. Eligible patients for combined thrombolysis were selected according to the status of tissue based on PCT. Recanalization was defined as Thrombolysis in Myocardial Infarction (TIMI) grade 2 or 3. ‘Good functional outcome’ was defined as a Modified Rankin Scale (mRS) score of 2 or less at discharge. Results: Eighteen patients (11 men) underwent combined IV/IA thrombolysis. The recanalization rate after combined IV/IA thrombolysis was 88.9% (TIMI 2, 4; TIMI 3, 12). A good functional outcome at discharge was noted in 12 patients (66.7%). The incidence of symptomatic intracranial hemorrhage was 5.6% (1/18). Conclusions: The results of this study suggest that combined IV/IA thrombolysis based on the presence of mismatches on PCT might have a relatively high rate of recanalization and a favorable early outcome. In addition, the incidence of symptomatic intracranial hemorrhage was acceptable.
Infective Endocarditis by Bartonellaquintana Masquerading as Antineutrophil Cytoplasmic Antibody-Associated Small Vessel Vasculitis
Authors: Sugiyama Hiroaki , Sahara Makoto , Imai Yasushi , Ono Minoru , Okamoto Koh , Kikuchi Ken , Nagai Ryozo
Published: July 2009

The Bartonella species have been recently recognized as important causative agents of culture-negative bacterial endocarditis. Antineutrophil cytoplasmic antibodies (ANCAs) have been associated with the spectrum of idiopathic small vessel vasculitis. However, a variety of infections can result in a false-positive ANCA test, and especially subacute bacterial endocarditis (SBE) with the presence of ANCAs occasionally mimics the clinical manifestations of an ANCA-associated vasculitis such as skin purpura and glomerulonephritis. In contrast, noninfectious endocardial involvement is known to be part of the spectrum of the manifestations of the ANCA-associated vasculitis. Therefore, it is crucial to distinguish an ANCA-positive SBE from an ANCA-associated vasculitis with endocardial compromise, because the misdiagnosis of an SBE as an ANCA-associated vasculitis can lead to an inappropriate immunosuppressive therapy with catastrophic consequences. The differential diagnosis is sometimes difficult, especially in the case of culture-negative infective endocarditis with a positive ANCA test. We describe here a case of a culture-negative SBE caused by Bartonellaquintana, accompanied with a positive cytoplasmic ANCA test and clinical findings masquerading as ANCA-associated vasculitis. Both a serological test for Bartonella and polymerase chain reaction restriction fragment length polymorphism analysis were helpful for a correct diagnosis and appropriate treatment.
Fiberoptic Endoscopic Dysphagia Severity Scale Predicts Outcome after Acute Stroke
Authors: Warnecke Tobias , Ritter Martin A. , Kröger Bjelka , Oelenberg Stephan , Teismann Inga , Heuschmann Peter U. , Ringelstein E. Bernd , Nabavi Darius G. , Dziewas Rainer
Published: July 2009

Background and Purpose: Fiberoptic endoscopic evaluation of swallowing (FEES) is a suitable method for dysphagia assessment after acute stroke. Recently, we developed the fiberoptic endoscopic dysphagia severity scale (FEDSS) for acute stroke patients, grading dysphagia into 6 severity codes (1 to 6; 1 being best). The purpose of this study was to investigate the impact of the FEDSS as a predictor of outcomes at 3 months and intermediate complications during acute treatment. Methods: A total of 153 consecutive first-ever acute stroke patients were enrolled. Dysphagia was classified according to the FEDSS, assessed within 24 h after admission. Intermediate outcomes were pneumonia and endotracheal intubation. Functional outcome was measured by the modified Rankin Scale (mRS) at 3 months. Multivariate regression analysis was used to identify whether the FEDSS was an independent predictor of outcome and intercurrent complications. Analyses were adjusted for sex, age and National Institutes of Health Stroke Scale (NIH-SS) on admission. Results: The FEDSS was found to predict the mRS at 3 months as well as but independent from the NIH-SS. For each additional point on the FEDSS, the likelihood of dependency at 3 months (mRS ≥ 3) raised by ∼50%. Each increase of 1 point on the FEDSS conferred a more than 2-fold increased chance of developing pneumonia. The odds for the necessity of endotracheal intubation raised by a factor of nearly 2.5 with each additional point on the FEDSS. Conclusions: The FEDSS strongly and independently predicts outcome and intercurrent complications after acute stroke. Thus, a baseline FEES examination provides valuable prognostic information for the treatment of acute stroke patients.
Functional Abilities in Older Adults with Mild Cognitive Impairment
Authors: Burton Catherine L. , Strauss Esther , Bunce David , Hunter Michael A. , Hultsch David F.
Published: July 2009

Background: A classification scheme and general set of criteria for diagnosing mild cognitive impairment (MCI) were recently proposed by a multidisciplinary group of experts who met at an international symposium on MCI. One of the proposed criteria included preserved basic activities of daily living and minimal impairment in complex instrumental activities of daily living (IADLs). Objective: To investigate whether older adults with MCI classified according to the subtypes identified by the Working Group (i.e. amnestic, single non-memory domain, and multiple domain with or without a memory component) differed from cognitively intact older adults on a variety of measures indexing IADLs and to examine how well measures of IADL predict concurrent MCI status. Methods: Two hundred and fifty community-dwelling older adults, ranging in age from 66 to 92, completed self-report measures of IADLs (Lawton and Brody IADL Scale, Scales of Independent Behaviour-Revised – SIB-R) and a measure of everyday problem solving indexing IADLs (Everyday Problems Test – EPT). Ratings of participants’ IADL functioning were also obtained from informants (e.g. spouse, adult child and friend). Results: Older adults with multiple-domain MCI demonstrated poorer IADL functioning than older adults with no cognitive impairment on the EPT and the SIB-R (both self- and informant-report versions). The multiple-domain MCI participants also demonstrated poorer IADLs than MCI participants with impairments in a single cognitive domain on the self-reported SIB-R and EPT. The single-domain MCI groups demonstrated poorer IADLs than older adults without cognitive impairment on the informant-reported SIB-R and EPT. No significant group differences were found on the Lawton and Brody IADL Scale. Using the EPT and SIB-R as predictors in a multinomial regression analysis, MCI group status was reliably predicted, but the classification rate was poor. Conclusion: Individuals with MCI demonstrated poorer IADL functioning compared to cognitively intact older adults. However, the changes in IADL functioning observed in MCI may be too subtle to be detected by certain measures, such as the Lawton and Brody IADL Scale.
Exercise and the Low-Security Inmate
Authors: Buckaloo Bobby J. , Krug Kevin S. , Nelson Koury B.
Published: July 2009

Exercise has a history of alleviating depression, stress, and anxiety in various populations, but research into its effects on low-security prison inmates is limited. Inmates who were exercising or not exercising prior to the beginning of the study completed the Beck Depression Inventory II, Life Experiences Survey, and Daily Hassles Survey. Those who performed aerobic or anaerobic exercise scored significantly lower on the Beck Depression Inventory II and Life Experiences Survey than the inmates who did not exercise. Current charges were the only significant predictor of group membership. The authors conclude that the lower levels of depression, stress, and anxiety seen among the inmates suggest that exercise is a coping strategy to deal with incarceration.
Pharmacokinetic and Pharmacodynamic Modeling of a Copper‐Selective Chelator (TETA) in Healthy Adults
Authors: Cho Hea‐Young , Blum Robert A. , Sunderland Tracey , Cooper Garth J. S. , Jusko William J.
Published: July 2009

The population pharmacokinetics (PK) and pharmacodynamics (PD) of triethylenetetramine (TETA) dihydrochloride (trientine, GC811007) administered orally as 100‐, 300‐, 600‐, or 1800‐mg twice‐daily doses were assessed in healthy adult male and female volunteers. This study was a randomized, double‐blind, placebo‐controlled, group‐sequential, dose‐escalating design. Forty participants, 10 per dose level (8 receiving TETA, 2 receiving placebo), received twice‐daily doses for 14 consecutive days. A 2‐compartment model for the PK and a linear direct effect model for drug‐induced copper excretion (PD) were employed. The population PK/PD model was applied using the NONMEM software. Covariates tested were glomerular filtration rate (GFR), body weight, and gender. Multiple daily doses of TETA were safe and generally well tolerated. The linear 2‐compartment model with first‐order absorption well characterized the serum concentration data. Although its role was small, GFR had a statistically significant (P < .05) influence on systemic clearance (CL/F). The augmentation of copper excretion was well described by a direct linear model in which the slope was related to GFR and gender (P < .001). The intersubject coefficient of variation was 22.2% for slope (SL) and 82.5% for intercept (ER0). TETA has consistent single/multiple‐dose pharmacokinetics and dose‐proportional and serum concentration‐proportional effects on enhancing copper excretion.
Prediction of Prasugrel Active Metabolite Concentrations From 2 Downstream Inactive Metabolite Concentrations Using Multilinear Regression Analysis
Authors: Ernest C. Steven , Heathman Michael A. , Wrishko Rebecca E.
Published: July 2009

Prasugrel is a thienopyridine prodrug that is metabolized to an active metabolite (Pras‐AM), which inhibits adenosine diphosphate (ADP)–induced platelet aggregation. The study objective was to describe a multilinear regression correlation model that was used to quantitatively predict concentrations of Pras‐AM from downstream inactive metabolites, R‐119251 and R‐106583, for the purpose of estimating Pras‐AM exposure in patients in the TRITON‐TIMI 38 sub‐studies. The model development included 1462 Pras‐AM, 1345 R‐119251, and 1456 R‐106583 concentration data points from 103 healthy participants with a prasugrel dose range of 15 to 80 mg. The model was shown to provide good correlation between predicted and observed concentrations with only a minor deviation of ∼6% from the unity line and described the variability within ∼4.5%. Examination of the data indicated that regardless of ethnicity, age, weight, moderate hepatic impairment, or renal impairment, predictions were reliable. Predicted Pras‐AM concentrations in TRITON‐TIMI 38 were comparable with historical data.
Exploring the Diagnosis of “Gifted/LD”: Characterizing Postsecondary Students With Learning Disability Diagnoses at Different IQ Levels
Authors: Lovett Benjamin J. , Sparks Richard L.
Published: July 2009

Increasing numbers of students are being diagnosed as simultaneously gifted and having a learning disability, although the identification procedures and characteristics of these students are matters of continuing debate. In the present study, postsecondary students with learning disability diagnoses ( N = 357) were grouped according to their IQ scores, and the groups’ cognitive and achievement characteristics were explored, with special attention to the proportions of each group that would meet various objective criteria for learning disability diagnosis. Many students in each group failed to meet any of the criteria, although higher IQ students were more likely to meet most of the criteria. In addition, the higher IQ group exhibited higher achievement scores than did the lower IQ group, although the achievement gaps were much smaller than the IQ differences. Implications for the validity of the gifted/LD category as well as future research directions are discussed.
Commercial Premixed Parenteral Nutrition: Is It Right for Your Institution?
Authors: Miller Sarah J.
Published: July 2009

Two‐compartment premixed parenteral nutrition (PN) products are heavily promoted in the United States. These products may present safety advantages over PN solutions mixed by a local pharmacy, although clinical data to support this assertion are scarce. Multicompartment products can be labor‐saving for pharmacy and therefore may be cost‐effective for some institutions. Before adopting such products for use, an institution must determine that standardized PN solutions are acceptable for many or most of their patients compared with customized PN compounded specifically for individual patients. A larger selection of premixed products is available in Europe and some other parts of the world compared with the United States. Availability of a broader selection of products in the United States, including 3‐compartment bags and a wider range of macronutrient concentrations and volumes, may make the use of such products more desirable in the future.
Fish Oil Lipid Emulsions and Immune Response: What Clinicians Need to Know
Authors: Waitzberg Dan Linetzky , Torrinhas Raquel Susana
Published: July 2009

Current evidence indicates that ω‐3 polyunsaturated fatty acids (PUFAs), particularly eicosapentaenoic acid and docosahexaenoic acid found in fish oil, can prevent the development of inflammatory diseases by affecting different steps of the immune response. The capacity of ω‐3 PUFAs to modulate synthesis of eicosanoids, activity of nuclear receptor and nuclear transcription factors, and production of resolvins may also mitigate inflammatory processes already present. Parenteral infusion of ω‐3 PUFAs is advantageous, particularly in severely ill patients, because the fatty acids are rapidly incorporated by cells. In addition, when fatty acids are given parenterally, there are no losses from digestion and absorption as there are with enteral infusion. Recently, lipid emulsions enriched with ω‐3 fish oil have been introduced as a component of parenteral nutrition. Currently, there is one lipid emulsion that contains only fish oil; it is infused together with conventionally used lipid emulsions. Other commercially available lipid emulsions contain fish oil in a fat mixture; one contains 10% fish oil and another 15% fish oil. Relevant experimental and clinical data from studies evaluating fish oil lipid emulsions are discussed in the present review. Administration of fish oil lipid emulsion, when compared with soybean oil lipid emulsion (rich in ω‐6 PUFA), decreases the length of hospital and intensive care unit stay in surgical patients.
Pediatric Parenteral Nutrition: Putting the Microscope on Macronutrients and Micronutrients
Authors: Slicker Julie , Vermilyea Sarah
Published: July 2009

Parenteral nutrition can be a life‐saving therapy, but its benefits need to be balanced with a unique set of risks and complications. Methods of practice vary because there is a dearth of research in the area of pediatric parenteral nutrition. This article reviews the available literature on parenteral nutrition in children and provides suggestions on prevention and management of parenteral nutrition–associated liver disease. Some of the issues discussed in this article include glucose infusion rates, cycling of parenteral nutrition, copper and manganese toxicity, and the provision of glutamine, selenium, and carnitine.
Video Game-Based Methodology for Business Research
Authors: Lawson Larry L. , Lawson Catherine L.
Published: July 2009

Experimental research in business and economics has exploded in recent years in both laboratory and field settings. The generality of findings from field experiments is limited by the specificity of the experimental environment. Laboratory studies, on the other hand, are criticized for being devoid of the contextual cues that may indicate to decision makers the nature of the problem and, thus, the appropriate approaches to problem solving. Virtual experiments provide a hybrid of strengths from each of these two experimental protocols that may overcome some of the limitations of each. Using a modified, commercial, adventure game with an appended Sequel database, this research reprises a well-known study of risk aversion within a virtual context. The results indicate that very similar overall measures of risk aversion can be obtained within an adventure game context. Furthermore, it shows that experimentation within this virtual environment permits outcomes to be recorded and analyzed regarding decision consistency, decision revisions, and psychological/behavioral variables that have not been available using either traditional lab or field research methods. As such, this study contributes both to the literature on behavioral business research methodology in general and to the literature on risk aversion in particular.
Lack of Association of Tegaserod With Adverse Cardiovascular Outcomes in a Matched Case-Control Study
Authors: Anderson Jeffrey L. , May Heidi T. , Bair Tami L. , Muhlestein Joseph B. , Horne Benjamin D. , Carlquist John F.
Published: July 2009

Tegaserod is a first-in class selective serotonin 4 receptor agonist approved for the treatment of irritable bowel syndrome. In March 2007, the US Food and Drug Administration (FDA) suspended its use citing increased cardiovascular (CV) events in clinical trials. However, there is no known mechanistic basis for an adverse CV effect. To reassess the CV safety of tegaserod, teagaserod-treated patients (pts) in the Intermountain Healthcare database were identified (n = 2603), matched 1:6 with untreated (n = 15,618) patients by age, sex, and date of tegaserod initiation, and followed for an average of 2.5 years. Age averaged 38.6 ± 13.5 years, and 94% were female. Cardiovascular event rates were low and similar in patients treated with tegaserod and matched untreated patients. For the primary composite CV endpoint, 54 (0.35%) untreated and 12 (0.46%) treated pts had an event (treated OR = 1.27, 95% CI: 0.68-2.38, P =.46), with 7 and 0 events, respectively, occurring within 3 months. A total of 12 (0.1%) untreated and 1 (<0.1%) treated pts were hospitalized for a myocardial infarction (MI). 36 (0.2%) untreated and 10 (0.4%) treated pts for a cardiovascular accident, and 1 pt in each group for unstable angina. A total of 6 (<0.1%) untreated and no treated pts died from cardiac causes. Event rates were comparable to expected rates in this population of mostly premenopausal women. This large epidemiologic study failed to confirm a reported large event differential for tegaserod that was noted incidentally in a clinical trials database, suggesting that the prior observation may have been due to chance.
Reciprocal differentiation and tissue-specific pathogenesis of Th1, Th2, and Th17 cells in graft-versus-host disease
Authors: Yi Tangsheng , Chen Ying , Wang Lin , Du Gong , Huang Daniel , Zhao Dongchang , Johnston Heather , Young James , Todorov Ivan , Umetsu Dale T. , Chen Lieping , Iwakura Yoichiro , Kandeel Fouad , Forman Stephen , Zeng Defu
Published: July 2009

In acute graft-versus-host disease (GVHD), naive donor CD4+ T cells recognize alloantigens on host antigen-presenting cells and differentiate into T helper (Th) subsets (Th1, Th2, and Th17 cells), but the role of Th subsets in GVHD pathogenesis is incompletely characterized. Here we report that, in an MHC-mismatched model of C57BL/6 donor to BALB/c recipient, WT donor CD4+ T cells predominantly differentiated into Th1 cells and preferentially mediated GVHD tissue damage in gut and liver. However, absence of interferon-γ (IFN-γ) in CD4+ T cells resulted in augmented Th2 and Th17 differentiation and exacerbated tissue damage in lung and skin; absence of both IL-4 and IFN-γ resulted in augmented Th17 differentiation and preferential, although not exclusive, tissue damage in skin; and absence of both IFN-γ and IL-17 led to further augmentation of Th2 differentiation and idiopathic pneumonia. The tissue-specific GVHD mediated by Th1, Th2, and Th17 cells was in part associated with their tissue-specific migration mediated by differential expression of chemokine receptors. Furthermore, lack of tissue expression of the IFN-γ–inducible B7-H1 played a critical role in augmenting the Th2-mediated idiopathic pneumonia. These results indicate donor CD4+ T cells can reciprocally differentiate into Th1, Th2, and Th17 cells that mediate organ-specific GVHD.
The development of a comparison approach for Illumina bead chips unravels unexpected challenges applying newest generation microarrays
Authors: Eggle Daniela , Debey-Pascher Svenja , Beyer Marc , Schultze Joachim L
Published: July 2009

Background

The MAQC project demonstrated that microarrays with comparable content show inter- and intra-platform reproducibility. However, since the content of gene databases still increases, the development of new generations of microarrays covering new content is mandatory. To better understand the potential challenges updated microarray content might pose on clinical and biological projects we developed a methodology consisting of in silico analyses combined with performance analysis using real biological samples.

Results

Here we clearly demonstrate that not only oligonucleotide design but also database content and annotation strongly influence comparability and performance of subsequent generations of microarrays. Additionally, using human blood samples and purified T lymphocyte subsets as two independent examples, we show that a performance analysis using biological samples is crucial for the assessment of consistency and differences.

Conclusion

This study provides an important resource assisting investigators in comparing microarrays of updated content especially when working in a clinical or regulatory setting.
Rooting human parechovirus evolution in time
Authors: Faria Nuno R , de Vries Michel , van Hemert Formijn J , Benschop Kimberley , van der Hoek Lia
Published: July 2009

Background

The Picornaviridae family contains a number of important pathogenic viruses, among which the recently reclassified human parechoviruses (HPeVs). These viruses are widespread and can be grouped in several types. Understanding the evolutionary history of HPeV could answer questions such as how long the circulating lineages last shared a common ancestor and how the evolution of this viral species is shaped by its population dynamics. Using both strict and relaxed clock Bayesian phylogenetics we investigated 1) the substitutions rates of the structural P1 and capsid VP1 regions and 2) evolutionary timescale of currently circulating HPeV lineages.

Results

Our estimates reveal that human parechoviruses exhibit high substitution rates for both structural P1 and capsid VP1 regions, respectively 2.21 × 10-3 (0.48 – 4.21 × 10-3) and 2.79 × 10-3 (2.05 – 3.66 × 10-3) substitutions per site per year. These are within the range estimated for other picornaviruses. By employing a constant population size coalescent prior, the date of the most recent common ancestor was estimated to be at around 1600 (1427–1733). In addition, by looking at the frequency of synonymous and non-synonymous substitutions within the VP1 gene we show that purifying selection constitutes the dominating evolutionary force leading to strong amino acid conservation.

Conclusion

In conclusion, our estimates provide a timescale for the evolution of HPeVs and suggest that genetic diversity of current circulating HPeV types has arisen about 400 years ago.
Gene expression profiling of intestinal regeneration in the sea cucumber
Authors: Ortiz-Pineda Pablo A , Ramírez-Gómez Francisco , Pérez-Ortiz Judit , González-Díaz Sebastián , Santiago-De Jesús Francisco , Hernández-Pasos Josue , Del Valle-Avila Cristina , Rojas-Cartagena Carmencita , Suárez-Castillo Edna C , Tossas Karen , Méndez-Merced Ana T , Roig-López José L , Ortiz-Zuazaga Humberto , García-Arrarás José E
Published: July 2009

Background

Among deuterostomes, the regenerative potential is maximally expressed in echinoderms, animals that can quickly replace most injured organs. In particular, sea cucumbers are excellent models for studying organ regeneration since they regenerate their digestive tract after evisceration. However, echinoderms have been sidelined in modern regeneration studies partially because of the lack of genome-wide profiling approaches afforded by modern genomic tools.

For the last decade, our laboratory has been using the sea cucumberHolothuria glaberrimato dissect the cellular and molecular events that allow for such amazing regenerative processes. We have already established an EST database obtained from cDNA libraries of normal and regenerating intestine at two different regeneration stages. This database now has over 7000 sequences.

Results

In the present work we used a custom-made microchip from Agilent with 60-mer probes for these ESTs, to determine the gene expression profile during intestinal regeneration. Here we compared the expression profile of animals at three different intestinal regeneration stages (3-, 7- and 14-days post evisceration) against the profile from normal (uneviscerated) intestines. The number of differentially expressed probes ranged from 70% at p < 0.05 to 39% at p < 0.001. Clustering analyses show specific profiles of expression for early (first week) and late (second week) regeneration stages. We used semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) to validate the expression profile of fifteen microarray detected differentially expressed genes which resulted in over 86% concordance between both techniques. Most of the differentially expressed ESTs showed no clear similarity to sequences in the databases and might represent novel genes associated with regeneration. However, other ESTs were similar to genes known to be involved in regeneration-related processes, wound healing, cell proliferation, differentiation, morphological plasticity, cell survival, stress response, immune challenge, and neoplastic transformation. Among those that have been validated, cytoskeletal genes, such asactins, and developmental genes, such asWntandHoxgenes, show interesting expression profiles during regeneration.

Conclusion

Our findings set the base for future studies into the molecular basis of intestinal regeneration. Moreover, it advances the use of echinoderms in regenerative biology, animals that because of their amazing properties and their key evolutionary position, might provide important clues to the genetic basis of regenerative processes.
The orphan adapter protein SLY1 as a novel anti-apoptotic protein required for thymocyte development
Authors: Reis Bernhard , Pfeffer Klaus , Beer-Hammer Sandra
Published: July 2009

Background

SH3 containing Lymphocyte Protein (SLY1) is a putative adapter protein exclusively expressed in lymphocytes which is involved in antigen receptor induced activation. We previously have generated SLY1Δ/Δmice harbouring a partial deletion in the N-terminal region of SLY1 which revealed profound immunological defects in T and B cell functions.

Results

In this study, T cell development in SLY1-/-and SLY1Δ/Δmice was analysedex vivoand upon cultivation with the bone marrow stromal cell line OP9. SLY1-deficient thymocytes were compromised in inducing nutrient receptor expression and ribosomal protein S6 phosphorylation, indicating a defect in mTOR complex activation. Furthermore, SLY1 was identified as a novel anti-apoptotic protein required for developmental progression of T cell precursors to the CD4+CD8+double-positive stage by protecting from premature programmed cell death initiation in developing CD4-CD8-double-negative thymocytes. In addition, SLY1 phosphorylation was differentially regulated upon Notch ligand-mediated stimulation and expression of the preTCR.

Conclusion

Thus, our results suggest a non-redundant role for SLY1 in integrating signals from both receptors in early T cell progenitors in the thymus.