bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics of Zanamivir following Intravenous Administration to Subjects with and without Renal Impairment
Authors: Weller Stephen , Jones Lori S. , Lou Yu , Peppercorn Amanda , Ng-Cashin Judith 
Published: April 2013

ABSTRACT

Intravenous zanamivir is in clinical development for the treatment of influenza in hospitalized patients, many of whom have renal impairment. This open-label study evaluated zanamivir pharmacokinetics and clinical safety following a single 100-mg intravenous infusion dose in subjects with impaired renal function compared with normal renal function. Male and female subjects between 18 and 79 years of age were recruited, four subjects to each renal function group (normal function and mild, moderate, and severe impairment). Serial blood samples were collected up to 24 h after dose administration (48 h for the severe renal impairment group) to estimate zanamivir serum pharmacokinetic parameters. Urine was collected over the same 24-h (or 48-h) period for estimation of renal clearance (CL
R
). Zanamivir pharmacokinetics were assessed by regression analysis of systemic clearance (CL) and CL
R
as a function of creatinine clearance (CL
CR
). Safety evaluations included adverse-event monitoring, vital signs, electrocardiogram, and clinical laboratory assessments. Zanamivir clearance (total and renal) significantly decreased with decreasing renal function, with corresponding increases in area under the concentration-time curve and elimination half-life. Renal impairment had no apparent effects on peak concentration or volume of distribution. Regression analysis indicated that zanamivir clearance was highly correlated (
r
2
= 0.89) with creatinine clearance: CL ≅ 7.08 + 0.826 · CL
CR
. There were no patterns or trends in adverse events, and no new safety concerns were identified following administration of intravenous zanamivir. Results from this study support the inclusion of subjects with renal impairment, with appropriate dose adjustment, in studies to evaluate intravenous zanamivir in the treatment of influenza.
Redundant Catalases Detoxify Phagocyte Reactive Oxygen and Facilitate Histoplasma capsulatum Pathogenesis
Authors: Holbrook Eric D. , Smolnycki Katherine A. , Youseff Brian H. , Rappleye Chad A. 
Published: April 2013

ABSTRACTHistoplasma capsulatumis a respiratory pathogen that infects phagocytic cells. The mechanisms allowingHistoplasmato overcome toxic reactive oxygen molecules produced by the innate immune system are an integral part ofHistoplasma's ability to survive during infection. To probe the contribution ofHistoplasmacatalases in oxidative stress defense, we created and analyzed the virulence defects of mutants lacking CatB and CatP, which are responsible for extracellular and intracellular catalase activities, respectively. Both CatB and CatP protectedHistoplasmafrom peroxide challengein vitroand from antimicrobial reactive oxygen produced by human neutrophils and activated macrophages. Optimal protection required both catalases, as the survival of a double mutant lacking both CatB and CatP was lower than that of single-catalase-deficient cells. Although CatB contributed to reactive oxygen species defensesin vitro, CatB was dispensable for lung infection and extrapulmonary disseminationin vivo. Loss of CatB from a strain also lacking superoxide dismutase (Sod3) did not further reduce the survival ofHistoplasmayeasts. Nevertheless, some catalase function was required for pathogenesis since simultaneous loss of both CatB and CatP attenuatedHistoplasmavirulencein vivo. These results demonstrate thatHistoplasma's dual catalases comprise a system that enablesHistoplasmato efficiently overcome the reactive oxygen produced by the innate immune system.
USING CELLULAR AUTOMATA EXPERIMENTS TO MODEL PERIODONTITIS: A FIRST STEP TOWARDS UNDERSTANDING THE NONLINEAR DYNAMICS OF THE DISEASE
Authors: PAPANTONOPOULOS G. , TAKAHASHI K. , BOUNTIS T. , LOOS B. G. 
Published: April 2013

Cellular automata (CA) are time and space discrete dynamical systems that can model biological systems. The aim of this study is to simulate by CA experiments how the disease of periodontitis propagates along the dental root surface. Using a Moore neighborhood on a grid copy of the pattern of periodontal ligament fibers (PDLF) supporting and anchoring the teeth to bone, we investigate the fractal structure of the associated pattern using all possible outer-totalistic CA rules. On the basis of the propagation patterns, CA rules are classified in three groups, according to whether the disease was spreading, remaining constant or receding. These are subsequently introduced in a finite state Markov model as probabilistic "state-rules" and the model is validated using datasets retrieved from previous studies. Based on the maximum entropy production principle, we identified the "state-rule" that most appropriately describes the PDLF pattern, showing a power law distribution of periodontitis propagation rates with exponent 1.3. Entropy rates and mutual information of Markov chains were estimated by extensive data simulation. The scale factor of the PDLF used to estimate the conditional entropy of Markov chains was seen to be nearly equal 1.85. This possibly reflects the fact that a dataset representing tooth percentage with bone loss equal to 50% or more of their root length, is found to have a fractal dimension (FD) of about 1.84. Similarly, datasets of serum neutrophil, basophil, eosinophil, monocyte counts and IgG, IgA, IgM levels taken from periodontitis patients, showed a FD ranging from 1.82 to 1.87. Our study presents the first mathematical model to our knowledge that suggests periodontitis is a nonlinear dynamical process. Moreover, the model we propose implies that the entropy rate of the immune-inflammatory host response dictates the rate of periodontitis progression. This is validated by clinical data and suggests that our model can serve as a basis for detecting periodontitis susceptible individuals and shaping prognosis for treated periodontitis patients.
Serum Factors and Clinical Characteristics Associated with Serum E-Screen Activity
Authors: Wang Jue , Trentham-Dietz Amy , Hemming Jocelyn D.C. , Hedman Curtis J. , Sprague Brian L. 
Published: April 2013

AbstractBackground: The E-Screen bioassay can measure the mitogenicity of human serum and thus may be useful as a biomarker in epidemiologic studies of breast cancer. While the assay's MCF-7 cells are known to proliferate in response to estrogen, the specific determinants of variation in E-Screen activity in human serum samples are poorly understood. We sought to identify serum molecules and patient characteristics associated with serum E-Screen activity among postmenopausal women.Methods: Postmenopausal women (N = 219) aged 55 to 70 years with no history of postmenopausal hormone use or breast cancer completed a questionnaire and provided a blood sample. Serum was analyzed for E-Screen activity and a variety of molecules including sex hormones, growth factors, and environmental chemicals. Stepwise selection procedures were used to identify correlates of E-Screen activity.Results: Serum samples from all women had detectable E-Screen activity, with a median estradiol equivalents value of 0.027 ng/mL and interquartile range of 0.018–0.036 ng/mL. In the final multivariable-adjusted model, serum E-Screen activity was positively associated with serum estradiol, estrone, insulin-like growth factor–binding protein (IGFBP)-3, and testosterone levels (all P &lt; 0.05), as well as body mass index (P = 0.03). Serum E-Screen activity was lower among women with higher SHBG (P &lt; 0.0001) and progesterone levels (P = 0.03).Conclusion: Serum E-Screen activity varies according to levels of endogenous estrogens and other serum molecules. Obesity appears to confer additional serum mitogenicity beyond its impact on the measured hormones and growth factors.Impact: By capturing mitogenicity due to a variety of patient and serum factors, the E-Screen may provide advantages for use as a biomarker in breast cancer studies. Cancer Epidemiol Biomarkers Prev; 22(5); 962–71. ©2013 AACR.
Preclinical Antitumor Activity of Cabazitaxel, a Semisynthetic Taxane Active in Taxane-Resistant Tumors
Authors: Vrignaud Patricia , Sémiond Dorothée , Lejeune Pascale , Bouchard Hervé , Calvet Loreley , Combeau Cecile , Riou Jean-François , Commerçon Alain , Lavelle François , Bissery Marie-Christine 
Published: April 2013

Abstract
Purpose: Taxanes are important chemotherapeutic agents with proven efficacy in human cancers, but their use is limited by resistance development. We report here the preclinical characteristics of cabazitaxel (XRP6258), a semisynthetic taxane developed to overcome taxane resistance.
Experimental Design: Cabazitaxel effects on purified tubulin and on taxane-sensitive or chemotherapy-resistant tumor cells were evaluated in vitro. Antitumor activity and pharmacokinetics of intravenously administered cabazitaxel were assessed in tumor-bearing mice.
Results: In vitro, cabazitaxel stabilized microtubules as effectively as docetaxel but was 10-fold more potent than docetaxel in chemotherapy-resistant tumor cells (IC50 ranges: cabazitaxel, 0.013–0.414 μmol/L; docetaxel, 0.17–4.01 μmol/L). The active concentrations of cabazitaxel in these cell lines were achieved easily and maintained for up to 96 hours in the tumors of mice bearing MA16/C tumors treated with cabazitaxel at 40 mg/kg. Cabazitaxel exhibited antitumor efficacy in a broad spectrum of murine and human tumors (melanoma B16, colon C51, C38, HCT 116, and HT-29, mammary MA17/A and MA16/C, pancreas P03 and MIA PaCa-2, prostate DU 145, lung A549 and NCI-H460, gastric N87, head and neck SR475, and kidney Caki-1). Of particular note, cabazitaxel was active in tumors poorly sensitive or innately resistant to docetaxel (Lewis lung, pancreas P02, colon HCT-8, gastric GXF-209, mammary UISO BCA-1) or with acquired docetaxel resistance (melanoma B16/TXT).
Conclusions: Cabazitaxel is as active as docetaxel in docetaxel-sensitive tumor models but is more potent than docetaxel in tumor models with innate or acquired resistance to taxanes and other chemotherapies. These studies were the basis for subsequent clinical evaluation. Clin Cancer Res; 19(11); 2973–83. ©2013 AACR.
Early Telomere Shortening and Genomic Instability in Tubo-Ovarian Preneoplastic Lesions
Authors: Chene Gautier , Tchirkov Andrei , Pierre-Eymard Eleonore , Dauplat Jacques , Raoelfils Ines , Cayre Anne , Watkin Emmanuel , Vago Philippe , Penault-Llorca Frederique 
Published: April 2013

AbstractPurpose: Genetic instability plays an important role in ovarian carcinogenesis. We investigated the level of telomere shortening and genomic instability in early and preinvasive stages of ovarian cancer, serous tubal intraepithelial carcinoma (STIC), and tubo-ovarian dysplasia (TOD).Experimental Design: Fifty-one TOD from prophylactic salpingo-oophorectomies with BRCA1 or 2 mutation, 12 STICs, 53 tubo-ovarian high-grade serous carcinoma, and 36 noncancerous controls were laser capture microdissected from formalin-fixed, paraffin-embedded sections, analyzed by comparative genomic hybridization (array CGH) and for telomere length (using quantitative real-time PCR based on the Cawthon's method). TOD and STICs were defined by morphologic scores and immunohistochemical expressions of p53, Ki67, and γH2AX.Results: TOD showed marked telomere shortening compared with noncancerous controls (P &lt; 10−7). STICs had even shorter telomeres than TOD (P = 0.0008). Ovarian carcinoma had shorter telomeres than controls but longer than STICs and dysplasia. In TOD, telomeres were significantly shorter in those with BRCA1 mutation than in those with BRCA2 mutation (P = 0.005). In addition, γH2AX expression in TOD and STIC groups with short telomeres was significantly increased (P &lt; 10−7). In dysplastic epithelium, we found subtle genomic alterations, in contrast to more important genomic imbalances in STICs. The total number of genetic alterations was the highest in ovarian cancers.Conclusions: These findings suggest that genetic instability occurs in early stages of ovarian tumorigenesis. STICs and noninvasive dysplasia are likely an important step in early serous ovarian neoplasia. Clin Cancer Res; 19(11); 2873–82. ©2013 AACR.
Colon Cancer–Specific Cytochrome P450 2W1 Converts Duocarmycin Analogues into Potent Tumor Cytotoxins
Authors: Travica Sandra , Pors Klaus , Loadman Paul M. , Shnyder Steven D. , Johansson Inger , Alandas Mohammed N. , Sheldrake Helen M. , Mkrtchian Souren , Patterson Laurence H. , Ingelman-Sundberg Magnus 
Published: April 2013

Abstract
Purpose: Cytochrome P450 2W1 (CYP2W1) is a monooxygenase detected in 30% of colon cancers, whereas its expression in nontransformed adult tissues is absent, rendering it a tumor-specific drug target for development of novel colon cancer chemotherapy. Previously, we have identified duocarmycin synthetic derivatives as CYP2W1 substrates. In this study, we investigated whether two of these compounds, ICT2705 and ICT2706, could be activated by CYP2W1 into potent antitumor agents.
Experimental Design: The cytotoxic activity of ICT2705 and ICT2706 in vitro was tested in colon cancer cell lines expressing CYP2W1, and in vivo studies with ICT2706 were conducted on severe combined immunodeficient mice bearing CYP2W1-positive colon cancer xenografts.
Results: Cells expressing CYP2W1 suffer rapid loss of viability following treatment with ICT2705 and ICT2706, whereas the CYP2W1-positive human colon cancer xenografts display arrested growth in the mice treated with ICT2706. The specific cytotoxic metabolite generated by CYP2W1 metabolism of ICT2706 was identified in vitro. The cytotoxic events were accompanied by an accumulation of phosphorylated H2A.X histone, indicating DNA damage as a mechanism for cancer cell toxicity. This cytotoxic effect is most likely propagated by a bystander killing mechanism shown in colon cancer cells. Pharmacokinetic analysis of ICT2706 in mice identified higher concentration of the compound in tumor than in plasma, indicating preferential accumulation of drug in the target tissue.
Conclusion: Our findings suggest a novel approach for treatment of colon cancer that uses a locoregional activation of systemically inactive prodrug by the tumor-specific activator enzyme CYP2W1. Clin Cancer Res; 19(11); 2952–61. ©2013 AACR.
Divergent Mitochondrial Biogenesis Responses in Human Cardiomyopathy
Authors: Ahuja Preeti , Wanagat Jonathan , Wang Zhihua , Wang Yibin , Liem David A. , Ping Peipei , Antoshechkin Igor A. , Margulies Kenneth B. , MacLellan W. Robb 
Published: April 2013

Background—
Mitochondria are key players in the development and progression of heart failure (HF). Mitochondrial (mt) dysfunction leads to diminished energy production and increased cell death contributing to the progression of left ventricular failure. The fundamental mechanisms that underlie mt dysfunction in HF have not been fully elucidated.

Methods and Results—

To characterize mt morphology, biogenesis, and genomic integrity in human HF, we investigated left ventricular tissue from nonfailing hearts and end-stage ischemic (ICM) or dilated (DCM) cardiomyopathic hearts. Although mt dysfunction was present in both types of cardiomyopathy, mt were smaller and increased in number in DCM compared with ICM or nonfailing hearts. mt volume density and mtDNA copy number was increased by ≈2-fold (
P
<0.001) in DCM hearts in comparison with ICM hearts. These changes were accompanied by an increase in the expression of mtDNA-encoded genes in DCM versus no change in ICM. mtDNA repair and antioxidant genes were reduced in failing hearts, suggestive of a defective repair and protection system, which may account for the 4.1-fold increase in mtDNA deletion mutations in DCM (
P
<0.05 versus nonfailing hearts,
P
<0.05 versus ICM).

Conclusions—
In DCM, mt dysfunction is associated with mtDNA damage and deletions, which could be a consequence of mutating stress coupled with a peroxisome proliferator-activated receptor γ coactivator 1α–dependent stimulus for mt biogenesis. However, this maladaptive compensatory response contributes to additional oxidative damage. Thus, our findings support further investigations into novel mechanisms and therapeutic strategies for mt dysfunction in DCM.
The US Struggles in APEC’s Trade Politics: Coalition-Building and Regional Integration in the Asia-Pacific
Authors: Terada Takashi 
Published: April 2013

Abstract
From a perspective of change in the institution’s function, the history of the Asia-Pacific Economic Cooperation (APEC) can be divided into four periods: 1989–1995, 1996–2001, 2001–2006, and 2007–present. APEC’s activities in each of these periods have been organized around major themes: respectively, the establishment of guidelines for liberalization; the implementation of liberalization measures; security issues such as counter-terrorism; and the establishment of a free trade area. American political will can be seen as a major driving force behind these changes in APEC’s agenda-setting. However, norm setting during the first and second periods encountered objections from China and Japan, respectively. During the third period, the Bush administration’s interest in combating terrorism through APEC was not supported by Asian members, who emphasized APEC’s primary role as a framework for economic cooperation, instead placed higher priorities on East Asian regionalism that excluded the US. In light of this shift, in the fourth period, the US once again urged that APEC should be used as a framework for liberalization and pushed for the Trans-Pacific Partnership (TPP). This period saw the discriminatory, legally-binding and reciprocity-based norms for trade liberalization take root in APEC, resulting largely from the American coalition-building approach through the promotion of the TPP as an existing integration framework. This has helped to create a critical mass while competition with China over regional trade policies becomes more intense, demonstrating the case where the US successfully set its own preferred agenda and norm together for the first time.
The Clash of Negotiations: The Impact of Outside Options on Multilateral Trade Negotiations
Authors: da Conceição-Heldt Eugénia 
Published: April 2013

Abstract
While the number of preferential trade agreements (PTA) has increased rapidly in recent years, the Doha round of multilateral trade negotiations has been deadlocked since 2006. Most PTAs were even concluded after the start of the Doha round. Does the shift to PTAs “marginalize” the multilateral system? And is there a clash between preferential and multilateral trade liberalization? To answer these questions, we build upon negotiation analysis literature, arguing that the proliferation of PTAs draws negotiating capacity away from the multilateral level and thus reduces the incentives to agree on multilateral trade agreements. The willingness of actors to move from their initial bargaining positions and make concessions at the multilateral level depends on their outside options, that is, their best or worst alternatives to a negotiated agreement. The more credible an actor’s argument that he has a good alternative to multilateralism, the greater his bargaining power will be. In order to support the argument we will analyze the negotiation process at the multilateral level and link it to PTAs under negotiation by the EU, US, Brazil, Australia, and India.
Conference, Arbitration and the Triple Intervention of 1895: Relevance of the Western Ways of Dispute Settlement in East Asia
Authors: Fujisawa Iwao 
Published: April 2013

Abstract
This article attempts to understand how East Asian nations dealt with the norms and concepts of Western international law and for that purpose takes up the peace process of the Sino-Japanese War. It argues that in that incident neither China nor Japan passively accepted the methods of dispute settlement developed in Western international law and that rather those countries tried to pick and choose among the legal institutions of that law according to their respective interests. This article concludes that the incident suggests Western international law was not immune to changes through the interaction between Europeans and East Asians in the process of its expansion.
Learning Needs of Youth With Type 2 Diabetes
Authors: Richards Denise , Larkin Mary , Milaszewski Kerry , Javier Elaine , Casey Terri , Grey Margaret 
Published: April 2013

Purpose The purpose of this study was to examine reports of diabetes learning needs by youth with type 2 diabetes and their family support person (FSP) and to examine correlations of these perceptions with demographic variables. Methods Data were analyzed from the Participant Needs Assessment (PNA), a routinely self-administered questionnaire designed to assess learning needs, in 191 youth (mean age = 14.0 ± 1.9 years, duration 8.78 ± 6.30 months; 36% black, non-Hispanic; 40% Hispanic; 20% white) enrolled in the TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study. Youth and their FSPs completed the PNA at scheduled study visits, rating their learning needs on a 5-point scale, with higher scores indicating higher needs. Paired t tests and ANOVA were used. Results There were no differences in reported learning needs by gender, although scores on the Teen Issues scale approached significance, with girls reporting higher needs than boys. Youth and FSPs were similar on their reports of needs on 3 scales (Ordinary Day, Nutrition, and Living With Diabetes), but youth reported higher needs than FSPs on Focus and Teen Issues. Controlling for duration of diabetes, these differences between youth and FSPs persisted. In general, learning needs for both youth and FSPs decreased over time. Conclusions Youth with type 2 diabetes and their FSPs have high levels of ongoing learning needs despite completion of a standard diabetes education program. Continued assessment of learning needs, follow-up education, and behavioral approaches are warranted for these high-risk youth.
Should palliative care patients’ hope be truthful, helpful or valuable? An interpretative synthesis of literature describing healthcare professionals’ perspectives on hope of palliative care patients
Authors: Olsman Erik , Leget Carlo , Onwuteaka-Philipsen Bregje , Willems Dick 
Published: April 2013

Background: Healthcare professionals’ perspectives on palliative care patients’ hope influence communication. However, these perspectives have hardly been examined. Aim: To describe healthcare professionals’ perspectives on palliative care patients’ hope found in the literature. Design: The interpretative synthesis consisted of a quality assessment and thematic analysis of included articles. Data sources: Literature search of articles between January 1980 and July 2011 in PubMed, CINAHL, PsycINFO and EMBASE and references of included studies. Search strategy: (palliat* or hospice or terminal* in title/abstract or as subject heading) AND (hope* or hoping or desir* or optimis* in title or as subject heading). Results: Of the 37 articles, 31 articles were of sufficient quality. The majority of these 31 articles described perspectives of nurses or physicians. Three perspectives on hope of palliative care patients were found: (1) realistic perspective – hope as an expectation should be truthful, and healthcare professionals focused on adjusting hope to truth, (2) functional perspective – hope as coping mechanism should help patients, and professionals focused on fostering hope, and (3) narrative perspective – hope as meaning should be valuable for patients, and healthcare professionals focused on interpreting it. Conclusions: Healthcare professionals who are able to work with three perspectives on hope may improve their communication with their palliative care patients, which leads to a better quality of care.