bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reproductive and Hormonal Factors and Lung Cancer Risk in the NIH-AARP Diet and Health Study Cohort
Authors: Brinton Louise A. , Gierach Gretchen L. , Andaya Abegail , Park Yikyung , Schatzkin Arthur , Hollenbeck Albert R. , Spitz Margaret R. 
Published: May 2011

Abstract
Background: Lung cancer exhibits unique patterns among women including high adenocarcinoma rates among nonsmokers. Inconsistent findings about hormonal factors on risk may reflect incomplete control for confounding, misclassification of exposures, or insufficient attention to variation by histology.
Methods: Among 185,017 women, ages 50 to 71 years, recruited during 1995 and 1996 for the NIH-AARP (American Association of Retired Persons) Diet and Health Study, we identified 3,512 incident lung cancers (including 276 in never smokers) in follow-up through December 2006. Multivariable Cox proportional hazards models estimated relative risks (RR) and 95% CIs for self-reported hormonally related risk factors.
Results: After adjustment for smoking and other confounders, subjects with late menarche were at reduced risk, with the association specific for adenocarcinomas (RR = 0.72 for menarche 15+ vs. &lt;11, Ptrend &lt; 0.01). Subjects with early ages at ovarian cessation (either from natural menopause or bilateral oophorectomy) were at an increased risk for adenocarcinomas and squamous cell tumors, but the associations were strongest for smokers, suggesting either residual confounding or an enhanced effect of menopausally related factors among subjects with decreased endogenous estrogens. In contrast, we saw no relationships of risk with either parity, age at first birth, or exogenous hormone use.
Conclusions: Elevated levels of hormones may adversely affect lung function early in life while assisting with cellular and immunologic responses later in life. Additional attention toward the role of hormonal factors may further our understanding of lung carcinogenesis.
Impact: Our findings provide some support for a role of hormonal factors in the etiology of lung cancer, although the mechanisms appear complicated. Cancer Epidemiol Biomarkers Prev; 20(5); 900–11. ©2011 AACR.
No Association of Risk Variants for Diabetes and Obesity with Breast Cancer: The Multiethnic Cohort and PAGE Studies
Authors: Chen Fang , Wilkens Lynne R. , Monroe Kristine R. , Stram Daniel O. , Kolonel Laurence N. , Henderson Brian E. , Marchand Loïc Le , Haiman Christopher A. 
Published: May 2011

AbstractBackground: Body mass index is an established risk factor for postmenopausal breast cancer. Epidemiologic studies have also reported a positive association between type 2 diabetes (T2D) and breast cancer risk.Methods: To investigate a genetic basis linking these common phenotypes with breast cancer, we tested 31 common variants for T2D and obesity in a case–control study of 1,915 breast cancer cases and 2,884 controls nested within the Multiethnic Cohort (MEC) study.Results: Following adjustment for multiple tests, we found no significant association between any variant and breast cancer risk. Summary scores comprising the numbers of risk alleles for T2D and/or obesity were also not found to be significantly associated with breast cancer risk.Conclusions: Our findings provide no evidence for association between established T2D and/or obesity risk variants and breast cancer risk among women of various ethnicities.Impact: These results suggest that the potential for a shared biology between T2D/obesity and breast cancer is not due to pleiotropic effects of these risk variants. Cancer Epidemiol Biomarkers Prev; 20(5); 1039–42. ©2011 AACR.
Metformin Amplifies Chemotherapy-Induced AMPK Activation and Antitumoral Growth
Authors: Rocha Guilherme Z. , Dias Marília M. , Ropelle Eduardo R. , Osório-Costa Felipe , Rossato Franco A. , Vercesi Anibal E. , Saad Mario J.A. , Carvalheira José B.C. 
Published: May 2011

Abstract
Purpose: Metformin is a widely used antidiabetic drug whose anticancer effects, mediated by the activation of AMP-activated protein kinase (AMPK) and reduction of mTOR signaling, have become noteworthy. Chemotherapy produces genotoxic stress and induces p53 activity, which can cross-talk with AMPK/mTOR pathway. Herein, we investigate whether the combination of metformin and paclitaxel has an effect in cancer cell lines.
Experimental Design: Human tumors were xenografted into severe combined immunodeficient (SCID) mice and the cancer cell lines were treated with only paclitaxel or only metformin, or a combination of both drugs. Western blotting, flow cytometry, and immunohistochemistry were then used to characterize the effects of the different treatments.
Results: The results presented herein show that the addition of metformin to paclitaxel leads to quantitative potentialization of molecular signaling through AMPK and a subsequent potent inhibition of the mTOR signaling pathway. Treatment with metformin and paclitaxel resulted in an increase in the number of cells arrested in the G2–M phase of the cell cycle, and decreased the tumor growth and increased apoptosis in tumor-bearing mice, when compared with individual drug treatments.
Conclusion: We have provided evidence for a convergence of metformin and paclitaxel induced signaling at the level of AMPK. This mechanism shows how different drugs may cooperate to augment antigrowth signals, and suggests that target activation of AMPK by metformin may be a compelling ally in cancer treatment. Clin Cancer Res; 17(12); 3993–4005. ©2011 AACR.
Identification and characterisation of monoclonal antibodies that impair the activation of human thrombin activatable fibrinolysis inhibitor through different mechanisms
Authors: Mishra Niraj , Vercauteren Ellen , Develter Jan , Bammens Riet , Declerck Paul J. , Gils Ann 
Published: May 2011

SummaryThrombin activatable fibrinolysis inhibitor (TAFI) forms a molecular link between coagulation and fibrinolysis and is a putative target to develop profibrinolytic drugs. Out of a panel of monoclonal antibodies (MA) raised against TAFI-ACIIYQ, we selected MA-TCK11A9, MA-TCK22G2 and MA-TCK27A4, which revealed high affinity towards human TAFITI- wt. MA-TCK11A9 was able to inhibit mainly plasmin-mediated TAFI activation, MA-TCK22G2 inhibited plasmin- and thrombin-mediated TAFI activation and MA-TCK27A4 inhibited TAFI activation by plasmin, thrombin and thrombin/thrombomodulin (T/TM) in a dose-dependent manner. These MA did not interfere with TAFIa activity. Using an eightfold molar excess of MA over TAFI, all three MA were able to reduce clot lysis time significantly, i.e. in the presence of exogenous TM, MATCK11A9, MA-TCK22G2 and MA-TCK27A4 reduced clot lysis time by 47 ± 9.1%, 80 ± 8.6% and 92 ± 14%, respectively, compared to PTCI. This effect was even more pronounced in the absence of TM i.e. MATCK11A9, MA-TCK22G2 and MA-TCK27A4 reduced clot lysis time by 90 ± 14%, 140 ± 12% and 147 ± 29%, respectively, compared to PTCI. Mutagenesis analysis revealed that residues at position 268, 272 and 276 are involved in the binding of MA-TCK11A9, residues 147 and 148 in the binding of MA-TCK22G2 and residue 113 in the binding of MATCK27A4. The present study identified three MA, with distinct epitopes, that impair the activation of human TAFI and demonstrated that MATCK11A9 which mainly impairs plasmin-mediated TAFI activation can also reduce significantly clot lysis time in vitro.
Effect of edoxaban on markers of coagulation in venous and shed blood compared with fondaparinux
Authors: Samama Meyer , Kapiotis Stylianos , Ogata Koichiro , Mendell Jeanne , Kunitada Satoshi , Wolzt Michael 
Published: May 2011

SummaryEdoxaban, an oral direct factor Xa (FXa) inhibitor, is in phase III clinical development for stroke prevention in atrial fibrillation and treatment of venous thromboembolism. The shed blood model allows for study of activated coagulation at a site of standardised tissue injury due to local release of tissue factor. The objective of this study was to evaluate the effect of three doses of edoxaban on markers of coagulation in shed and venous blood versus placebo and a standard prophylactic dose of fondaparinux. A total of 100 healthy male subjects were randomised to receive single doses of one of five treatments: subcutaneously administered fondaparinux 2.5 mg; orally administered edoxaban 30, 60, or 120 mg; or placebo. The primary objective was measurement of blood coagulation markers prothrombin fragment 1+2 (F1+2) and thrombinantithrombin (TAT) complex, and platelet activation marker β-thromboglobulin (β-TG), in venous and shed blood. Secondary objectives included pharmacokinetics, shed blood volume, and safety of edoxaban. Single doses of edoxaban caused rapid and significant decreases of F1+2, TAT, and β-TG in the shed blood model, indicating inhibition of thrombin generation and platelet activation. Inhibition was significantly less for fondaparinux versus edoxaban. Baseline-corrected F1+2, TAT, and β-TG values demonstrated sustained inhibition up to 24 hours for shed blood in the edoxaban groups but no significant inhibition in venous blood. Overall, edoxaban treatments were well tolerated. In conclusion, single oral doses of edoxaban 30, 60, or 120 mg caused rapid and sustained inhibition of coagulation up to 24 hours in the shed blood model.
Proton pump inhibitors, genetic polymorphisms and response to clopidogrel therapy
Authors: Fernando Himawan , Dart Anthony , Peter Karlheinz , Shaw James 
Published: May 2011

SummaryClopidogrel has become part of the mainstay of therapy for acute coronary syndromes and in patients post stenting. Clopidogrel is a pro drug and is metabolised by liver enzymes, particularly CYP2C19, into its active form. A considerable proportion of patients have a poor response to clopidogrel and this may be due to several factors. Genetic polymorphisms involved in clopidogrel’s absorption, metabolism and activity at the platelet may interfere with its antiplatelet actions. Further, proton pump inhibitors (PPI) may interfere with clopidogrel’s actions by functionally reducing the ability of CYP2C19 to convert clopidogrel to its active metabolite. By attenuating clopidogrel’s actions, both polymorphisms and drug interactions may increase the risk of thrombotic events during clopidogrel therapy. This review will explore the current evidence relating to the association between PPIs, genetic polymorphisms and poor response to clopidogrel. Routine genetic testing cannot be recommended for patients receiving dual antiplatelet therapy (DAPT). However, it may have a role for patients with an episode of stent thrombosis, prior to planned high-risk stenting or major bleeding. Regarding concomitant clopidogrel and PPI therapy, it is recommended that only patients with previous gastrointestinal (GI) bleeding or multiple risk factors for GI bleeding should be prescribed gastroprotection. This is due to the uncertainty surrounding the clinical significance of this interaction given the discordant biochemical and clinical data, conflicting results from observational studies and the limitations of the COGENT study. Pantoprazole seems least likely to interact with clopidogrel and most suitable for use in patients receiving DAPT.
Interdecadal Relationships between the Asian–Pacific Oscillation and Summer Climate Anomalies over Asia, North Pacific, and North America during a Recent 100 Years
Authors: Zhao Ping , Yang Song , Wang Huijun , Zhang Qiang 
Published: May 2011

Abstract
Summertime relationships between the Asian–Pacific Oscillation (APO) and climate anomalies over Asia, the North Pacific, and North America are examined on an interdecadal time scale. The values of APO were low from the 1880s to the mid-1910s and high from the 1920s to the 1940s. When the APO was higher, tropospheric temperatures were higher over Asia and lower over the Pacific and North America. From the low-APO decades to the high-APO decades, both upper-tropospheric highs and lower-tropospheric low pressure systems strengthened over South Asia and weakened over North America. As a result, anomalous southerly–southwesterly flow prevailed over the Asian monsoon region, meaning stronger moisture transport over Asia. On the contrary, the weakened upper-tropospheric high and lower-tropospheric low over North America caused anomalous sinking motion over the region. As a result, rainfall generally enhanced over the Asian monsoon regions and decreased over North America.
Frequency and syndrome specificity of antibodies to aquaporin-4 in neurological patients with rheumatic disorders
Authors: Jarius Sven , Jacobi Christian , de Seze Jerome , Zephir Helene , Paul Friedemann , Franciotta Diego , Rommer Paulus , Mader Simone , Kleiter Ingo , Reindl Markus , Akman-Demir Gulsen , Seifert-Held Thomas , Kristoferitsch Wolfgang , Melms Arthur , Wandinger Klaus-Peter , Wildemann Brigitte 
Published: May 2011

Background: A new autoantibody (termed NMO-IgG, or AQP4-Ab) has recently been described in patients with neuromyelitis optica (NMO) and its formes frustes, longitudinally extensive transverse myelitis (LETM) and recurrent optic neuritis (rON). However, AQP4-Ab has been found also in patients with co-existing rheumatic diseases such as systemic lupus erythematosus (SLE) or Sjögren’s syndrome (SS), conditions which are characterized by broad, polyspecific B cell activation. Objectives: In this study, we aimed at evaluating the syndrome specificity and frequency of AQP4-Ab in patients with rheumatic diseases and neurological symptoms. Methods: For this purpose, serum samples from 109 neurological patients with established connective tissue disorders (CTD) ( n = 54), possible CTD ( n = 42), or vasculitis ( n = 13) were analysed for the presence of AQP4-Ab by a cell-based assay employing recombinant human AQP4. Results: AQP4-Ab was detectable in 31/40 (78%) patients with CTD and NMO spectrum disorders (median titre, 1:1000) but in none of the samples obtained from patients with CTD or vasculitis and neurological disorders other than NMO, LETM, or rON ( n = 69). Conclusion: The high syndrome specificity of the antibody for neuromyelitis optica spectrum disorders (NMOSDs) in patients with CTD supports the concept of AQP4-Ab being involved in the pathogenesis of these neurological conditions, and argues against AQP4-Ab simply being part of the polyclonal B cell activation generally associated with rheumatic diseases. Moreover, the finding that AQP4-Ab is present in patients with CTD and co-existing NMOSD with approximately the same frequency as in patients without CTD strengthens the case of CTD and AQP4-Ab positive NMOSD representing two co-existing yet distinct entities in the majority of patients.
Brain abnormalities as an initial manifestation of neuromyelitis optica spectrum disorder
Authors: Kim Woojun , Kim Su-Hyun , Hyun Lee Sang , Feng Li Xue , Jin Kim Ho 
Published: May 2011

Background: Although brain abnormalities are being recognized more frequently in patients with neuromyelitis optica spectrum disorder (NMOSD), most brain lesions in previous reports have accompanied pre-existing NMOSD. Here, we describe clinical and imaging characteristics of patients with NMOSD who presented with brain symptoms as their first manifestation of the condition. Methods: Anti-aquaporin-4 antibody was measured using cell-based assays and/or enzyme-linked immunosorbent assay in the sera of 257 patients with inflammatory diseases of the central nervous system who attended the multiple sclerosis clinic of the National Cancer Center, Korea, between May 2005 and December 2009. Eighty-three were seropositive, and 15 of these who presented with brain symptoms were included in this study. We retrospectively reviewed these individuals’ clinical and radiological findings. Results: Patients with NMOSD were followed for a mean of 90 months. Median age at onset was 24 years (6–54 years) and there was a female preponderance (94%). The initial manifestation was classified into two groups according to clinical characteristics: encephalopathy mimicking acute disseminated encephalomyelitis or posterior reversible encephalopathy syndrome and characteristic brainstem symptoms such as intractable hiccup and vomiting. The majority of brain symptoms and lesions resolved. Intriguingly, eight patients (53%) experienced brain relapses that followed a similar pattern during the course of their disease. Conclusion: It is important to recognize that NMO or NMOSD can initially present with brain symptoms.
The Circus That Wasn't: The Republican Party's Quest for Order in California's 2003 Gubernatorial Recall Election
Authors: Masket Seth E. 
Published: May 2011

AbstractContrary to media reports, California's 2003 recall election was anything but a circus. Despite the presence of 135 candidates, just 3 managed to split 94% of the vote, and the winner came close to achieving a majority. In this article, the author uses elite interviews and a social network analysis of campaign donations to study how the Republican Party sought to impose order on the potentially chaotic political environment. The author finds that a network of Republican donors, activists, and officeholders coordinated their efforts to advantage Arnold Schwarzenegger and pressure other Republicans out of the race.
Where Politicians Gave Power to the People: Adoption of the Citizen Initiative in the U.S. States
Authors: Bridges Amy , Kousser Thad 
Published: May 2011

AbstractWhat led elites in some U.S. states to surrender policy-making power to voters between 1898 and 1918, while leaders elsewhere retained only representative democracy? The authors argue that progressives behaved as strategic politicians by supporting direct democracy when they were stymied at achieving their goals in the legislature and were confident that the voters who would be empowered by initiatives that agreed with progressive policies. They made their delegation of power conditional on who would receive it. The presence of these underlying conditions made adoption of the citizen initiative likely, the authors posit, while the timing of reforms came when insurgent reformers had a strong presence in state government, when the results of a galvanizing election sent a clear signal, or when the adoption of the initiative in one state diffused to its neighbors. Exploring these hypotheses by analyzing a new data set, the authors find strong support for their expectations about the conditions that created fertile ground for direct democracy.
A Bootstrap Method for Conducting Statistical Inference with Clustered Data
Authors: Harden Jeffrey J. 
Published: May 2011

AbstractU.S. state politics researchers often analyze data with observations grouped into clusters. This structure commonly produces unmodeled correlation within clusters, leading to downward bias in the standard errors of regression coefficients. Estimating robust cluster standard errors (RCSE) is a common approach to correcting this bias. However, despite their frequent use, recent work indicates that RCSE can also be biased downward. Here the author provides evidence of that bias and offers a potential solution. Through Monte Carlo simulation of an ordinary least squares (OLS) regression model, the author compares conventional standard error (OLS-SE) and RCSE performance to that of a bootstrap method that resamples clusters of observations (BCSE). The author shows that both OLS-SEandRCSE are biased downward, with OLS-SE being the most biased. In contrast, BCSE are not biased and consistently outperform the other two methods. The author concludes with three replications from recent work and offers recommendations to researchers.
Human X-linked variable immunodeficiency caused by a hypomorphic mutation in XIAP in association with a rare polymorphism in CD40LG
Authors: Rigaud Stéphanie , Lopez-Granados Eduardo , Sibéril Sophie , Gloire Geoffrey , Lambert Nathalie , Lenoir Christelle , Synaeve Cindy , Stacey Maria , Fugger Lars , Stephan Jean-Louis , Fischer Alain , Picard Capucine , Durandy Anne , Chapel Helen , Latour Sylvain 
Published: May 2011

AbstractThe present study focuses on a large family with an X-linked immunodeficiency in which there are variable clinical and laboratory phenotypes, including recurrent viral and bacterial infections, hypogammaglobulinemia, Epstein-Barr virus–driven lymphoproliferation, splenomegaly, colitis, and liver disease. Molecular and genetic analyses revealed that affected males were carriers of a hypomorphic hemizygous mutation in XIAP (XIAPG466X) that cosegregated with a rare polymorphism in CD40LG (CD40 ligandG219R). These genes are involved in the X-linked lymphoproliferative syndrome 2 and the X-linked hyper-IgM syndrome, respectively. Single expression of XIAPG466X or CD40LG219R had no or minimal effect in vivo, although in vitro, they lead to altered functional activities of their gene products, which suggests that the combination of XIAP and CD40LG mutations contributed to the expression of clinical manifestations observed in affected individuals. Our report of a primary X-linked immunodeficiency of oligogenic origin emphasizes that primary immunodeficiencies are not caused by a single defective gene, which leads to restricted manifestations, but are likely to be the result of an interplay between several genetic determinants, which leads to more variable clinical phenotypes.
Recombinant expression and functional analysis of proteases from Streptococcus pneumoniae, Bacillus anthracis, and Yersinia pestis
Authors: Kwon Keehwan , Hasseman Jeremy , Latham Saeeda , Grose Carissa , Do Yu , Fleischmann Robert D , Pieper Rembert , Peterson Scott N 
Published: May 2011

Abstract

Background
Uncharacterized proteases naturally expressed by bacterial pathogens represents important topic in infectious disease research, because these enzymes may have critical roles in pathogenicity and cell physiology. It has been observed that cloning, expression and purification of proteases often fail due to their catalytic functions which, in turn, cause toxicity in the E. coli heterologous host.

Results
In order to address this problem systematically, a modified pipeline of our high-throughput protein expression and purification platform was developed. This included the use of a specific E. coli strain, BL21(DE3) pLysS to tightly control the expression of recombinant proteins and various expression vectors encoding fusion proteins to enhance recombinant protein solubility. Proteases fused to large fusion protein domains, maltosebinding protein (MBP), SP-MBP which contains signal peptide at the N-terminus of MBP, disulfide oxidoreductase (DsbA) and Glutathione S-transferase (GST) improved expression and solubility of proteases. Overall, 86.1% of selected protease genes including hypothetical proteins were expressed and purified using a combination of five different expression vectors. To detect novel proteolytic activities, zymography and fluorescence-based assays were performed and the protease activities of more than 46% of purified proteases and 40% of hypothetical proteins that were predicted to be proteases were confirmed.

Conclusions
Multiple expression vectors, employing distinct fusion tags in a high throughput pipeline increased overall success rates in expression, solubility and purification of proteases. The combinatorial functional analysis of the purified proteases using fluorescence assays and zymography confirmed their function.