bluuebunny/crossref_metadata_2025 huggingface dataset:
Cross-Linking Mast Cell Specific Gangliosides Stimulates the Release of Newly Formed Lipid Mediators and Newly Synthesized Cytokines
Authors: Filho Edismauro Garcia Freitas , da Silva Elaine Zayas Marcelino , Zanotto Camila Ziliotto , Oliver Constance , Jamur Maria Célia
Published: August 2016

Mast cells are immunoregulatory cells that participate in inflammatory processes. Cross-linking mast cell specific GD1b derived gangliosides by mAbAA4 results in partial activation of mast cells without the release of preformed mediators. The present study examines the release of newly formed and newly synthesized mediators following ganglioside cross-linking. Cross-linking the gangliosides with mAbAA4 released the newly formed lipid mediators, prostaglandins D2and E2, without release of leukotrienes B4and C4. The effect of cross-linking these gangliosides on the activation of enzymes in the arachidonate cascade was then investigated. Ganglioside cross-linking resulted in phosphorylation of cytosolic phospholipase A2and increased expression of cyclooxygenase-2. Translocation of 5-lipoxygenase from the cytosol to the nucleus was not induced by ganglioside cross-linking. Cross-linking of GD1b derived gangliosides also resulted in the release of the newly synthesized mediators, interleukin-4, interleukin-6, and TNF-α. The effect of cross-linking the gangliosides on the MAP kinase pathway was then investigated. Cross-linking the gangliosides induced the phosphorylation of ERK1/2, JNK1/2, and p38 as well as activating both NFκB and NFAT in a Syk-dependent manner. Therefore, cross-linking the mast cell specific GD1b derived gangliosides results in the activation of signaling pathways that culminate with the release of newly formed and newly synthesized mediators.
Theory of Nonlocal Point Transformations in General Relativity
Authors: Tessarotto Massimo , Cremaschini Claudio
Published: August 2016

A discussion of the functional setting customarily adopted in General Relativity (GR) is proposed. This is based on the introduction of the notion of nonlocal point transformations (NLPTs). While allowing the extension of the traditional concept of GR-reference frame, NLPTs are important because they permit the explicit determination of the map between intrinsically different and generally curved space-times expressed in arbitrary coordinate systems. For this purpose in the paper the mathematical foundations of NLPT-theory are laid down and basic physical implications are considered. In particular, explicit applications of the theory are proposed, which concern(1)a solution to the so-called Einstein teleparallel problem in the framework of NLPT-theory;(2)the determination of the tensor transformation laws holding for the acceleration 4-tensor with respect to the group of NLPTs and the identification of NLPT-acceleration effects, namely, the relationship established via general NLPT between particle 4-acceleration tensors existing in different curved space-times;(3)the construction of the nonlocal transformation law connecting different diagonal metric tensors solution to the Einstein field equations; and(4)the diagonalization of nondiagonal metric tensors.
Accumulation of MDSC and Th17 Cells in Patients with Metastatic Colorectal Cancer Predicts the Efficacy of a FOLFOX–Bevacizumab Drug Treatment Regimen
Authors: Limagne Emeric , Euvrard Romain , Thibaudin Marion , Rébé Cédric , Derangère Valentin , Chevriaux Angélique , Boidot Romain , Végran Frédérique , Bonnefoy Nathalie , Vincent Julie , Bengrine-Lefevre Leila , Ladoire Sylvain , Delmas Dominique , Apetoh Lionel , Ghiringhelli François
Published: August 2016

Host immunity controls the development of colorectal cancer, and chemotherapy used to treat colorectal cancer is likely to recruit the host immune system at some level. Athough preclinical studies have argued that colorectal cancer drugs, such as 5-fluorouracil (5-FU) and oxaliplatin, exert such effects, their combination as employed in the oncology clinic has not been evaluated. Here, we report the results of prospective immunomonitoring of 25 metastatic colorectal cancer (mCRC) patients treated with a first-line combination regimen of 5-FU, oxaliplatin, and bevacizumab (FOLFOX–bevacizumab), as compared with 20 healthy volunteers. Before this therapy was initiated, T regulatory cells (Treg), Th17, and granulocytic myeloid-derived suppressor cells (gMDSC) were increased significantly in mCRC, but only a high level of gMDSC was associated with a poor prognosis. Chemotherapy modulated the Treg/Th17 balance by decreasing Treg and increasing Th17 cell frequency by 15 days after the start of treatment. Increased Th17 frequency was associated with a poor prognosis. FOLFOX–bevacizumab treatment elicited a decrease in gMDSC in 15 of 25 patients and was associated with a better survival outcome. Notably, the gMDSCs that expressed high levels of PD-L1, CD39, and CD73 exerted a robust immunosuppressive activity, relative to other myeloid cells present in blood, which could be reversed by blocking the CD39/CD73 and PD-1/PD-L1 axes. Our work underscores the critical prognostic impact of early modifications in Th17 and gMDSC frequency in mCRC. Furthermore, it provides a clinical rationale to combine FOLFOX–bevacizumab chemotherapy with inhibitors of ATP ectonucleotidases and/or anti-PD-1/PD-L1 antibodies to more effectively treat this disease. Cancer Res; 76(18); 5241–52. ©2016 AACR.
Cancer-Associated Fibroblasts in Pancreatic Cancer Are Reprogrammed by Tumor-Induced Alterations in Genomic DNA Methylation
Authors: Xiao Qian , Zhou Donger , Rucki Agnieszka A. , Williams Jamila , Zhou Jiaojiao , Mo Guanglan , Murphy Adrian , Fujiwara Kenji , Kleponis Jennifer , Salman Bulent , Wolfgang Christopher L. , Anders Robert A. , Zheng Shu , Jaffee Elizabeth M. , Zheng Lei
Published: August 2016

Stromal fibrosis is a prominent histologic characteristic of pancreatic ductal adenocarcinoma (PDAC), but how stromal fibroblasts are regulated in the tumor microenvironment (TME) to support tumor growth is largely unknown. Here we show that PDAC cells can induce DNA methylation in cancer-associated fibroblasts (CAF). Upon direct contact with PDAC cells, DNA methylation of SOCS1 and other genes is induced in mesenchymal stem cells or in CAF that lack SOCS1 methylation at baseline. Silencing or decitabine treatment to block the DNA methylation enzyme DNMT1 inhibited methylation of SOCS1. In contrast, SOCS1 gene methylation and downregulation in CAF activated STAT3 and induced insulin-like growth factor-1 expression to support PDAC cell growth. Moreover, CAF facilitated methylation-dependent growth of PDAC tumor xenografts in mice. The ability of patient-derived CAF with SOCS1 methylation to promote PDAC growth was more robust than CAF without SOCS1 methylation. Overall, our results reveal how PDAC cells can reprogram CAF to modify tumor–stromal interactions in the TME, which promote malignant growth and progression. Cancer Res; 76(18); 5395–404. ©2016 AACR.
Evaluation of Alternative In Vivo Drug Screening Methodology: A Single Mouse Analysis
Authors: Murphy Brendan , Yin Han , Maris John M. , Kolb E. Anders , Gorlick Richard , Reynolds C. Patrick , Kang Min H. , Keir Stephen T. , Kurmasheva Raushan T. , Dvorchik Igor , Wu Jianrong , Billups Catherine A. , Boateng Nana , Smith Malcolm A. , Lock Richard B. , Houghton Peter J.
Published: August 2016

Traditional approaches to evaluating antitumor agents using human tumor xenograft models have generally used cohorts of 8 to 10 mice against a limited panel of tumor models. An alternative approach is to use fewer animals per tumor line, allowing a greater number of models that capture greater molecular/genetic heterogeneity of the cancer type. We retrospectively analyzed 67 agents evaluated by the Pediatric Preclinical Testing Program to determine whether a single mouse, chosen randomly from each group of a study, predicted the median response for groups of mice using 83 xenograft models. The individual tumor response from a randomly chosen mouse was compared with the group median response using established response criteria. A total of 2,134 comparisons were made. The single tumor response accurately predicted the group median response in 1,604 comparisons (75.16%). The mean tumor response correct prediction rate for 1,000 single mouse random samples was 78.09%. Models had a range for correct prediction (60%–87.5%). Allowing for misprediction of ± one response category, the overall mean correct single mouse prediction rate was 95.28%, and predicted overall objective response rates for group data in 66 of 67 drug studies. For molecularly targeted agents, occasional exceptional responder models were identified and the activity of that agent confirmed in additional models with the same genotype. Assuming that large treatment effects are targeted, this alternate experimental design has similar predictive value as traditional approaches, allowing for far greater numbers of models to be used that more fully encompass the heterogeneity of disease types. Cancer Res; 76(19); 5798–809. ©2016 AACR.
Metformin, Diabetes, and Survival among U.S. Veterans with Colorectal Cancer
Authors: Paulus Jessica K. , Williams Christina D. , Cossor Furha I. , Kelley Michael J. , Martell Robert E.
Published: August 2016

Background: Metformin has been associated with improved colorectal cancer survival, but investigations are limited by small numbers of patients and confounding by diabetic severity. We examined the association between metformin use and overall survival (OS) in patients with diabetes and colorectal cancer in a large population of U.S. veterans, while adjusting for measures of diabetic severity.

Methods: Patients diagnosed with colorectal cancer from January 2001 to December 2008 were identified from the Veterans Affairs Central Cancer Registry. Multivariable models were used to examine the adjusted association of OS with diabetes and use of antidiabetic medications.

Results: There were 21,352 patients diagnosed with colorectal cancer identified (n = 16,355 nondiabetic patients, n = 2,038 diabetic patients on metformin, n = 2,136 diabetic patients on medications other than metformin, n = 823 diabetic patients not on antidiabetic medication). Diabetic patients had a significantly worse OS than nondiabetic patients, but metformin users had only a 10% increase in death (HRadj 1.10; 95% CI, 1.03–1.17, P = 0.004), as compared with 22% for users of other antidiabetic medications (HRadj 1.22; 95% CI, 1.15–1.29, P < 0.0001). Among colorectal cancer patients with diabetes, metformin users had a 13% improved OS versus patients taking other antidiabetic medications (HRadj 0.87; 95% CI, 0.79–0.95, P = 0.003), while diabetic patients not on any antidiabetic medications did not differ with respect to OS (HRadj 1.02; 95% CI, 0.90–1.15, P = 0.76).

Conclusions: Among diabetics with colorectal cancer, metformin use is associated with improved survival, despite adjustments for diabetes severity and other risk factors.

Impact: These data lend further support to the conduct of randomized studies of possible anticancer effects of metformin among patients with colorectal cancer. Cancer Epidemiol Biomarkers Prev; 25(10); 1418–25. ©2016 AACR.
CD137 Stimulation Enhances Cetuximab-Induced Natural Killer: Dendritic Cell Priming of Antitumor T-Cell Immunity in Patients with Head and Neck Cancer
Authors: Srivastava Raghvendra M. , Trivedi Sumita , Concha-Benavente Fernando , Gibson Sandra P. , Reeder Carly , Ferrone Soldano , Ferris Robert L.
Published: August 2016

Purpose: Cetuximab, an EGFR-specific antibody (mAb), modestly improves clinical outcome in patients with head and neck cancer (HNC). Cetuximab mediates natural killer (NK) cell:dendritic cell (DC) cross-talk by cross-linking FcγRIIIa, which is important for inducing antitumor cellular immunity. Cetuximab-activated NK cells upregulate the costimulatory receptor CD137 (4-1BB), which, when triggered by agonistic mAb urelumab, might enhance NK-cell functions, to promote T-cell–based immunity.

Experimental design: CD137 expression on tumor-infiltrating lymphocytes was evaluated in a prospective cetuximab neoadjuvant trial, and CD137 stimulation was evaluated in a phase Ib trial, in combining agonistic urelumab with cetuximab. Flow cytometry and cytokine release assays using NK cells and DC were used in vitro, testing the addition of urelumab to cetuximab-activated NK, DC, and cross presentation to T cells.

Results: CD137 agonist mAb urelumab enhanced cetuximab-activated NK-cell survival, DC maturation, and tumor antigen cross-presentation. Urelumab boosted DC maturation markers, CD86 and HLA DR, and antigen-processing machinery (APM) components TAP1/2, leading to increased tumor antigen cross-presentation. In neoadjuvant cetuximab-treated patients with HNC, upregulation of CD137 by intratumoral, cetuximab-activated NK cells correlated with FcγRIIIa V/F polymorphism and predicted clinical response. Moreover, immune biomarker modulation was observed in an open label, phase Ib clinical trial, of patients with HNC treated with cetuximab plus urelumab.

Conclusions: These results suggest a beneficial effect of combination immunotherapy using cetuximab and CD137 agonist in HNC. Clin Cancer Res; 23(3); 707–16. ©2016 AACR.
Single Agent and Synergistic Activity of the “First-in-Class” Dual PI3K/BRD4 Inhibitor SF1126 with Sorafenib in Hepatocellular Carcinoma
Authors: Singh Alok R. , Joshi Shweta , Burgoyne Adam M. , Sicklick Jason K. , Ikeda Sadakatsu , Kono Yuko , Garlich Joseph R. , Morales Guillermo A. , Durden Donald L.
Published: August 2016

Deregulated PI3K/AKT/mTOR, Ras/Raf/MAPK, and c-Myc signaling pathways are of prognostic significance in hepatocellular carcinoma (HCC). Sorafenib, the only drug clinically approved for patients with advanced HCC, blocks the Ras/Raf/MAPK pathway but it does not inhibit the PI3K/AKT/mTOR pathway or c-Myc activation. Hence, there is an unmet medical need to identify potent PI3K/BRD4 inhibitors, which can be used either alone or in combination with sorafenib to treat patients with advanced HCC. Herein, we show that SF1126 (pan PI3K/BRD4 inhibitor) as single agent or in combination with sorafenib inhibited proliferation, cell cycle, apoptosis, and multiple key enzymes in PI3K/AKT/mTOR and Ras/Raf/MAPK pathway in Hep3B, HepG2, SK-Hep1, and Huh7 HCC cell lines. We demonstrate that the active moiety of the SF1126 prodrug LY294002 binds to and blocks BRD4 interaction with the acetylated histone-H4 chromatin mark protein and displaced BRD4 coactivator protein from the transcriptional start site of MYC in Huh7 and SK-Hep1 HCC cell lines. Moreover, SF1126 blocked expression levels of c-Myc in HCC cells. Treatment of SF1126 either alone or in combination with sorafenib showed significant antitumor activity in vivo. Our results establish that SF1126 is a dual PI3K/BRD4 inhibitor. This agent has completed a phase I clinical trial in humans with good safety profile. Our data support the potential future consideration of a phase II clinical trial of SF1126, a clinically relevant dual “first-in-class” PI3K/BRD4 inhibitor in advanced HCC, and a potential combination with sorafenib. Mol Cancer Ther; 15(11); 2553–62. ©2016 AACR.
Pharmacological Profile of BI 847325, an Orally Bioavailable, ATP-Competitive Inhibitor of MEK and Aurora Kinases
Authors: Sini Patrizia , Gürtler Ulrich , Zahn Stephan K. , Baumann Christoph , Rudolph Dorothea , Baumgartinger Rosa , Strauss Eva , Haslinger Christian , Tontsch-Grunt Ulrike , Waizenegger Irene C. , Solca Flavio , Bader Gerd , Zoephel Andreas , Treu Matthias , Reiser Ulrich , Garin-Chesa Pilar , Boehmelt Guido , Kraut Norbert , Quant Jens , Adolf Günther R.
Published: August 2016

Although the MAPK pathway is frequently deregulated in cancer, inhibitors targeting RAF or MEK have so far shown clinical activity only in BRAF- and NRAS-mutant melanoma. Improvements in efficacy may be possible by combining inhibition of mitogenic signal transduction with inhibition of cell-cycle progression. We have studied the preclinical pharmacology of BI 847325, an ATP-competitive dual inhibitor of MEK and Aurora kinases. Potent inhibition of MEK1/2 and Aurora A/B kinases by BI 847325 was demonstrated in enzymatic and cellular assays. Equipotent effects were observed in BRAF-mutant cells, whereas in KRAS-mutant cells, MEK inhibition required higher concentrations than Aurora kinase inhibition. Daily oral administration of BI 847325 at 10 mg/kg showed efficacy in both BRAF- and KRAS-mutant xenograft models. Biomarker analysis suggested that this effect was primarily due to inhibition of MEK in BRAF-mutant models but of Aurora kinase in KRAS-mutant models. Inhibition of both MEK and Aurora kinase in KRAS-mutant tumors was observed when BI 847325 was administered once weekly at 70 mg/kg. Our studies indicate that BI 847325 is effective in in vitro and in vivo models of cancers with BRAF and KRAS mutation. These preclinical data are discussed in the light of the results of a recently completed clinical phase I trial assessing safety, tolerability, pharmacokinetics, and efficacy of BI 847325 in patients with cancer. Mol Cancer Ther; 15(10); 2388–98. ©2016 AACR.
Alterative Expression and Localization of Profilin 1/VASPpS157 and Cofilin 1/VASPpS239 Regulates Metastatic Growth and Is Modified by DHA Supplementation
Authors: Ali Mehboob , Heyob Kathryn , Jacob Naduparambil K. , Rogers Lynette K.
Published: August 2016

Profilin 1, cofilin 1, and vasodialator-stimulated phosphoprotein (VASP) are actin-binding proteins (ABP) that regulate actin remodeling and facilitate cancer cell metastases. miR-17-92 is highly expressed in metastatic tumors and profilin1 and cofilin1 are predicted targets. Docosahexaenoic acid (DHA) inhibits cancer cell proliferation and adhesion. These studies tested the hypothesis that the metastatic phenotype is driven by changes in ABPs including alternative phosphorylation and/or changes in subcellular localization. In addition, we tested the efficacy of DHA supplementation to attenuate or inhibit these changes. Human lung cancer tissue sections were analyzed for F-actin content and expression and cellular localization of profilin1, cofilin1, and VASP (S157 or S239 phosphorylation). The metastatic phenotype was investigated in A549 and MLE12 cells lines using 8 Br-cAMP as a metastasis inducer and DHA as a therapeutic agent. Migration was assessed by wound assay and expression measured by Western blot and confocal analysis. miR-17-92 expression was measured by qRT-PCR. Results indicated increased expression and altered cellular distribution of profilin1/VASPpS157, but no changes in cofilin1/VASPpS239 in the human malignant tissues compared with normal tissues. In A549 and MLE12 cells, the expression patterns of profilin1/VASPpS157 or cofilin1/VASPpS239 suggested an interaction in regulation of actin dynamics. Furthermore, DHA inhibited cancer cell migration and viability, ABP expression and cellular localization, and modulated expression of miR-17-92 in A549 cells with minimal effects in MLE12 cells. Further investigations are warranted to understand ABP interactions, changes in cellular localization, regulation by miR-17-92, and DHA as a novel therapeutic. Mol Cancer Ther; 15(9); 2220–31. ©2016 AACR.
Preclinical Modeling of KIF5B–RET Fusion Lung Adenocarcinoma
Authors: Huang Qingling , Schneeberger Valentina E. , Luetteke Noreen , Jin Chengliu , Afzal Roha , Budzevich Mikalai M. , Makanji Rikesh J. , Martinez Gary V. , Shen Tao , Zhao Lichao , Fung Kar-Ming , Haura Eric B. , Coppola Domenico , Wu Jie
Published: August 2016

RET fusions have been found in lung adenocarcinoma, of which KIF5B–RET is the most prevalent. We established inducible KIF5B-RET transgenic mice and KIF5B–RET-dependent cell lines for preclinical modeling of KIF5B–RET-associated lung adenocarcinoma. Doxycycline-induced CCSP-rtTA/tetO-KIF5B-RET transgenic mice developed invasive lung adenocarcinoma with desmoplastic reaction. Tumors regressed upon suppression of KIF5B–RET expression. By culturing KIF5B–RET-dependent BaF3 (B/KR) cells with increasing concentrations of cabozantinib or vandetanib, we identified cabozantinib-resistant RETV804L mutation and vandetanib-resistant-RETG810A mutation. Among cabozantinib, lenvatinib, ponatinib, and vandetanib, ponatinib was identified as the most potent inhibitor against KIF5B–RET and its drug-resistant mutants. Interestingly, the vandetanib-resistant KIF5B-RETG810A mutant displayed gain-of-sensitivity (GOS) to ponatinib and lenvatinib. Treatment of doxycycline-induced CCSP-rtTA/tetO-KIF5B-RET bitransgenic mice with ponatinib effectively induced tumor regression. These results indicate that KIF5B-RET–associated lung tumors are addicted to the fusion oncogene and ponatinib is the most effective inhibitor for targeting KIF5B–RET in lung adenocarcinoma. Moreover, this study finds a novel vandetanib-resistant RETG810A mutation and identifies lenvatinib and ponatinib as the secondary drugs to overcome this vandetanib resistance mechanism. Mol Cancer Ther; 15(10); 2521–9. ©2016 AACR.
Barasertib (AZD1152), a Small Molecule Aurora B Inhibitor, Inhibits the Growth of SCLC Cell Lines In Vitro and In Vivo
Authors: Helfrich Barbara A. , Kim Jihye , Gao Dexiang , Chan Daniel C. , Zhang Zhiyong , Tan Aik-Choon , Bunn Paul A.
Published: August 2016

Small-cell lung cancer (SCLC) cells have rapid proliferation, universal Rb inactivation, and high rates of MYC family amplification, making aurora kinase inhibition a natural target. Preclinical studies have demonstrated activity for Aurora A and pan-Aurora inhibitors with some relationship to MYC family expression. A clinical trial showed activity for an Aurora kinase A inhibitor, but no biomarkers were evaluated. We screened a panel of 23 SCLC lines with and without MYC family gene amplification or high MYC family gene expression for growth inhibition by the highly potent, selective aurora kinase B inhibitor barasertib. Nine of the SCLC lines were very sensitive to growth inhibition by barasertib, with IC50 values of <50 nmol/L and >75% growth inhibition at 100 nmol/L. Growth inhibition correlated with cMYC amplification (P = 0.018) and cMYC gene expression (P = 0.026). Sensitive cell lines were also enriched in a published MYC gene signature (P = 0.042). In vivo, barasertib inhibited the growth of xenografts established from an SCLC line that had high cMYC gene expression, no cMYC amplification, and was positive for the core MYC gene signature. Our studies suggest that SCLC tumors with cMYC amplification/high gene expression will frequently respond to Aurora B inhibitors and that clinical studies coupled with predictive biomarkers are indicated. Mol Cancer Ther; 15(10); 2314–22. ©2016 AACR.
Direct Transcatheter Heart Valve Implantation Versus Implantation With Balloon Predilatation
Authors: Bernardi Fernando L.M. , Ribeiro Henrique B. , Carvalho Luiz A. , Sarmento-Leite Rogerio , Mangione José A. , Lemos Pedro A. , Abizaid Alexandre , Grube Eberhard , Rodés-Cabau Josep , de Brito Fábio S.
Published: August 2016

Background—

Direct transcatheter aortic valve replacement (TAVR) is regarded as having potential advantages over TAVR with balloon aortic valve predilatation (BAVP) in reducing procedural complications, but there are few data to support this approach.

Methods and Results—

Patients included in the Brazilian TAVR registry with CoreValve and Sapien-XT prosthesis were compared according to the implantation technique, with or without BAVP. Clinical and echocardiographic data were analyzed in overall population and after propensity score matching. A total of 761 consecutive patients (BAVP=372; direct-TAVR=389) were included. Direct-TAVR was possible in 99% of patients, whereas device success was similar between groups (BAVP=81.2% versus direct-TAVR=78.1%;
P
=0.3). No differences in clinical outcomes at 30 days and 1 year were observed, including all-cause mortality (7.6% versus 10%;
P
=0.25 and 18.1% versus 24.5%;
P
=0.07, respectively) and stroke (2.8% versus 3.8%;
P
=0.85 and 5.5% versus 6.8%;
P
=0.56, respectively). Nonetheless, TAVR with BAVP was associated with a higher rate of new onset persistent left bundle branch block with the CoreValve (47.7% versus 35.1%;
P
=0.01 at 1 year). Mean gradient and incidence of moderate/severe aortic regurgitation were similar in both groups at 1 year (11% versus 13.3%;
P
=0.57 and 9.8±5.5 versus 8.7±4.3;
P
=0.09, respectively). After propensity score matching analysis, all-cause mortality and stroke remained similar. By multivariable analysis, BAVP and the use of CoreValve were independent predictors of new onset persistent left bundle branch block.

Conclusions—

The 2 TAVR strategies, with or without BAVP, provided similar clinical and echocardiographic outcomes over a midterm follow-up although BAVP was associated with a higher rate of new onset persistent left bundle branch block, particularly in patients receiving a CoreValve.
Global Disparities of Hypertension Prevalence and Control
Authors: Mills Katherine T. , Bundy Joshua D. , Kelly Tanika N. , Reed Jennifer E. , Kearney Patricia M. , Reynolds Kristi , Chen Jing , He Jiang
Published: August 2016

Background:

Hypertension is the leading preventable cause of premature death worldwide. We examined global disparities of hypertension prevalence, awareness, treatment, and control in 2010 and compared secular changes from 2000 to 2010.

Methods:

We searched MEDLINE from 1995 through 2014 and supplemented with manual searches of retrieved article references. We included 135 population-based studies of 968 419 adults from 90 countries. Sex- and age-specific hypertension prevalences from each country were applied to population data to calculate regional and global numbers of hypertensive adults. Proportions of awareness, treatment, and control from each country were applied to hypertensive populations to obtain regional and global estimates.

Results:

In 2010, 31.1% (95% confidence interval, 30.0%–32.2%) of the world’s adults had hypertension; 28.5% (27.3%–29.7%) in high-income countries and 31.5% (30.2%–32.9%) in low- and middle-income countries. An estimated 1.39 (1.34–1.44) billion people had hypertension in 2010: 349 (337–361) million in high-income countries and 1.04 (0.99–1.09) billion in low- and middle-income countries. From 2000 to 2010, the age-standardized prevalence of hypertension decreased by 2.6% in high-income countries, but increased by 7.7% in low- and middle-income countries. During the same period, the proportions of awareness (58.2% versus 67.0%), treatment (44.5% versus 55.6%), and control (17.9% versus 28.4%) increased substantially in high-income countries, whereas awareness (32.3% versus 37.9%) and treatment (24.9% versus 29.0%) increased less, and control (8.4% versus 7.7%) even slightly decreased in low- and middle-income countries.

Conclusions:

Global hypertension disparities are large and increasing. Collaborative efforts are urgently needed to combat the emerging hypertension burden in low- and middle-income countries.
Comparison of Dabigatran and Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease
Authors: Ezekowitz Michael D. , Nagarakanti Rangadham , Noack Herbert , Brueckmann Martina , Litherland Claire , Jacobs Mark , Clemens Andreas , Reilly Paul A. , Connolly Stuart J. , Yusuf Salim , Wallentin Lars
Published: August 2016

Background:

The RE-LY trial (Randomized Evaluation of Long-Term Anticoagulant Therapy) compared dabigatran 150 and 110 mg twice daily with warfarin in 18 113 patients with atrial fibrillation. Those with prosthetic heart valves, significant mitral stenosis, and valvular heart disease (VHD) requiring intervention were excluded. Others with VHD were included.

Methods:

This is a post hoc analysis of the RE-LY trial.

Results:

There were 3950 patients with any VHD: 3101 had mitral regurgitation, 1179 with tricuspid regurgitation, 817 had aortic regurgitation, 471 with aortic stenosis, and 193 with mild mitral stenosis. At baseline, patients with any VHD had more heart failure, coronary disease, renal impairment, and persistent atrial fibrillation. Patients with any VHD had higher rates of major bleeds (hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.16–1.5) but similar stroke or systemic embolism event rates (HR, 1.09; 95% CI, 0.88–1.33). For patients receiving dabigatran 110 mg, major bleed rates were lower than for patients taking warfarin (HR, 0.73; 95% CI, 0.56–0.95 with VHD; HR, 0.84; 95% CI, 0.71–0.99 without VHD), and major bleed rates for dabigatran 150 mg were similar to those for warfarin in patients with VHD (HR, 0.82; 95% CI, 0.64–1.06) or without VHD (HR, 0.98; 95% CI, 0.83–1.15). For dabigatran 150 mg, stroke/systemic embolic event rates were lower compared with warfarin in those with VHD (HR, 0.59; 95% CI, 0.37–0.93) and those without VHD (HR, 0.67; 95% CI, 0.52–0.86), and stroke/systemic embolic event rates were similar for warfarin and dabigatran 110 mg regardless of the presence of VHD (HR, 0.97; 95% CI, 0.65–1.45; and HR, 0.88; 95% CI, 0.70–1.10). Intracranial bleeds and death rates for dabigatran 150 and 110 mg were lower compared with warfarin independently of the presence of VHD.

Conclusions:

The presence of any VHD did not influence the comparison of dabigatran with warfarin.

Clinical Trial Registration:

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00262600.
Oxidized Phospholipids on Lipoprotein(a) Elicit Arterial Wall Inflammation and an Inflammatory Monocyte Response in Humans
Authors: van der Valk Fleur M. , Bekkering Siroon , Kroon Jeffrey , Yeang Calvin , Van den Bossche Jan , van Buul Jaap D. , Ravandi Amir , Nederveen Aart J. , Verberne Hein J. , Scipione Corey , Nieuwdorp Max , Joosten Leo A.B. , Netea Mihai G. , Koschinsky Marlys L. , Witztum Joseph L. , Tsimikas Sotirios , Riksen Niels P. , Stroes Erik S.G.
Published: August 2016

Background:

Elevated lipoprotein(a) [Lp(a)] is a prevalent, independent cardiovascular risk factor, but the underlying mechanisms responsible for its pathogenicity are poorly defined. Because Lp(a) is the prominent carrier of proinflammatory oxidized phospholipids (OxPLs), part of its atherothrombosis might be mediated through this pathway.

Methods:

In vivo imaging techniques including magnetic resonance imaging,
18
F-fluorodeoxyglucose uptake positron emission tomography/computed tomography and single-photon emission computed tomography/computed tomography were used to measure subsequently atherosclerotic burden, arterial wall inflammation, and monocyte trafficking to the arterial wall. Ex vivo analysis of monocytes was performed with fluorescence-activated cell sorter analysis, inflammatory stimulation assays, and transendothelial migration assays. In vitro studies of the pathophysiology of Lp(a) on monocytes were performed with an in vitro model for trained immunity.

Results:

We show that subjects with elevated Lp(a) (108 mg/dL [50–195 mg/dL]; n=30) have increased arterial inflammation and enhanced peripheral blood mononuclear cells trafficking to the arterial wall compared with subjects with normal Lp(a) (7 mg/dL [2–28 mg/dL]; n=30). In addition, monocytes isolated from subjects with elevated Lp(a) remain in a long-lasting primed state, as evidenced by an increased capacity to transmigrate and produce proinflammatory cytokines on stimulation (n=15). In vitro studies show that Lp(a) contains OxPL and augments the proinflammatory response in monocytes derived from healthy control subjects (n=6). This effect was markedly attenuated by inactivating OxPL on Lp(a) or removing OxPL on apolipoprotein(a).

Conclusions:

These findings demonstrate that Lp(a) induces monocyte trafficking to the arterial wall and mediates proinflammatory responses through its OxPL content. These findings provide a novel mechanism by which Lp(a) mediates cardiovascular disease.

Clinical Trial Registration:

URL:
http://www.trialregister.nl
. Unique identifier: NTR5006 (VIPER Study).
Faulkner in France
Authors: Sapiro Gisèle
Published: August 2016

In the early 1930s, when he started being translated into French, Faulkner was an unknown author in the transnational literary field. Questioning the role of intermediaries—publishers, translators, critics, authors—in the circulation of literary works and in the making of world literature, this article focuses on the role of the French publisher Gallimard in the symbolic recognition of Faulkner. Based on the publisher’s archives, the study examines the editorial strategies implemented in order to introduce a foreign author in a country that occupied a central position in the transnational literary field, at a time American literature just began arising interest: selection and order of publication of the works, prefaces by famous French authors (Malraux), publication in literary journals. These prefaces as well as the first reviews of Faulkner’s novels also reveal different strategies of importation, from transfer of symbolic capital to subverting the local literary field (Sartre).
Translation, Adaptation, Circulation
Authors: Hitzke Diana
Published: August 2016

The article analyses the process of translation and adaptation as a movement between Gehen, Izlaženje and Ausgehen and as a means for their circulation in the field of World Literature. Barbi Marković published Izlaženje, her “remix” of Thomas Bernhard’s Gehen, in 2006 in the Serbian language and it was translated back to the German language as Ausgehen in 2009. In Izlaženje Bernhard’s marked style is translated into Serbian, Vienna is transformed into Belgrade, older men become younger women, and walking changes to clubbing. Contemporary theory on the relationship between translation and writing (Paul de Man and Jacques Derrida) and issues of translation and circulation in the field of World Literature (David Damrosch, João Ferreira Duarte and Lawrence Venuti) are discussed on the basis of this example.
The 2015 Plains Elevated Convection at Night Field Project
Authors: Geerts Bart , Parsons David , Ziegler Conrad L. , Weckwerth Tammy M. , Biggerstaff Michael I. , Clark Richard D. , Coniglio Michael C. , Demoz Belay B. , Ferrare Richard A. , Gallus William A. , Haghi Kevin , Hanesiak John M. , Klein Petra M. , Knupp Kevin R. , Kosiba Karen , McFarquhar Greg M. , Moore James A. , Nehrir Amin R. , Parker Matthew D. , Pinto James O. , Rauber Robert M. , Schumacher Russ S. , Turner David D. , Wang Qing , Wang Xuguang , Wang Zhien , Wurman Joshua
Published: August 2016

The central Great Plains region in North America has a nocturnal maximum in warm-season precipitation. Much of this precipitation comes from organized mesoscale convective systems (MCSs). This nocturnal maximum is counterintuitive in the sense that convective activity over the Great Plains is out of phase with the local generation of CAPE by solar heating of the surface. The lower troposphere in this nocturnal environment is typically characterized by a low-level jet (LLJ) just above a stable boundary layer (SBL), and convective available potential energy (CAPE) values that peak above the SBL, resulting in convection that may be elevated, with source air decoupled from the surface. Nocturnal MCS-induced cold pools often trigger undular bores and solitary waves within the SBL. A full understanding of the nocturnal precipitation maximum remains elusive, although it appears that bore-induced lifting and the LLJ may be instrumental to convection initiation and the maintenance of MCSs at night.

To gain insight into nocturnal MCSs, their essential ingredients, and paths toward improving the relatively poor predictive skill of nocturnal convection in weather and climate models, a large, multiagency field campaign called Plains Elevated Convection At Night (PECAN) was conducted in 2015. PECAN employed three research aircraft, an unprecedented coordinated array of nine mobile scanning radars, a fixed S-band radar, a unique mesoscale network of lower-tropospheric profiling systems called the PECAN Integrated Sounding Array (PISA), and numerous mobile-mesonet surface weather stations. The rich PECAN dataset is expected to improve our understanding and prediction of continental nocturnal warm-season precipitation. This article provides a summary of the PECAN field experiment and preliminary findings.
The Relationship between Age of Air and the Diabatic Circulation of the Stratosphere
Authors: Linz Marianna , Plumb R. Alan , Gerber Edwin P. , Sheshadri Aditi
Published: August 2016

The strength of the Brewer–Dobson circulation is difficult to estimate using observations. Trends in the age of stratospheric air, deduced from observations of transient tracers, have been used to identify trends in the circulation, but there are ambiguities in the relationship between age and the strength of the circulation. This paper presents a steady-state theory and a time-dependent extension to relate age of air directly to the diabatic circulation of the stratosphere. In steady state, it is the difference between the age of upwelling and downwelling air through an isentrope and not the absolute value of age that is a measure of the strength of the diabatic circulation through that isentrope. For the time-varying case, expressions for other terms that contribute to the age budget are derived. An idealized atmospheric general circulation model with and without a seasonal cycle is used to test the time-dependent theory and to find that these additional terms are small upon annual averaging. The steady-state theory holds as well for annual averages of a seasonally varying model as for a perpetual-solstice model. These results are a step toward using data to quantify the strength of the diabatic circulation.
Evaluating Land–Atmosphere Coupling Using a Resistance Pathway Framework
Authors: Hirsch A. L. , Pitman A. J. , Haverd V.
Published: August 2016

This paper presents a methodology for examining land–atmosphere coupling in a regional climate model by examining how the resistances to moisture transfer from the land to the atmosphere control the surface turbulent energy fluxes. Perturbations were applied individually to the aerodynamic resistance from the soil surface to the displacement height, the aerodynamic resistance from the displacement height to the reference level, the stomatal resistance, and the leaf boundary layer resistance. Only perturbations to the aerodynamic resistance from the soil surface to the displacement height systematically affected 2-m air temperature for the shrub and evergreen boreal forest plant functional types (PFTs). This was associated with this resistance systematically increasing the terrestrial and atmospheric components of the land–atmosphere coupling strength through changes in the partitioning of the surface energy balance. Perturbing the other resistances did contribute to changing the partitioning of the surface energy balance but did not lead to systematic changes in the 2-m air temperature. The results suggest that land–atmosphere coupling in the modeling system presented here acts mostly through the aerodynamic resistance from the soil surface to the displacement height, which is a function of both the friction velocity and vegetation height and cover. The results show that a resistance pathway framework can be used to examine how changes in the resistances affect the partitioning of the surface energy balance and how this subsequently influences surface climate through land–atmosphere coupling. Limitations in the present analysis include grid-scale rather than PFT-scale analysis, the exclusion of resistance dependencies, and the linearity assumption of how temperature responds to a resistance perturbation.
Role of Screening Tests in the Detection and Management of Blood Pressure Abnormalities Among Young Population
Authors: Karaduman Mehmet , Aparci Mustafa , Unlu Murat , Ozturk Cengiz , Balta Sevket , Celik Turgay
Published: August 2016

The prevalence of hypertension is increasing among young population worldwide. So there is an interest in detecting prehypertension and hypertension in childhood. We determined blood pressure (BP) recorded at a screening test in a young population. We retrospectively evaluated the medical records including systolic blood pressure (SBP), diastolic blood pressure (DBP), weight, height, and body mass index (BMI) of 685 male and 130 female apparently healthy adolescents. We evaluated the prevalence of BP categories: normotension, prehypertension, and hypertension. The prevalence of normotension (n = 369), prehypertension (n = 333), and hypertension (n = 113) was 45.3%, 40.9% and 13.9%, respectively; prehypertension and hypertension were significantly higher among males. The prevalence of prehypertension and hypertension was significantly higher among overweight males and females. The BMI significantly correlated with SBP, DBP, and heart rate among both genders. The prevalence of prehypertension and hypertension is high among Turkish adolescents. Screening tests focused on BP and BMI measurement may help detect the young population at risk of hypertension and cardiovascular disease in the future.
Haemoglobin variants may cause significant differences in haemoglobin A1c as measured by high-performance liquid chromatography and enzymatic methods in diabetic patients: a cross-sectional study
Authors: Otabe Shuichi , Nakayama Hitomi , Ohki Tsuyoshi , Soejima Eri , Tajiri Yuji , Yamada Kentaro
Published: August 2016

Background

We aimed to determine whether the discrepancy between haemoglobin A1c values determined by high-performance liquid chromatography and enzymatic haemoglobin A1c measurements in diabetic patients was clinically relevant.

Methods

We randomly recruited 1421 outpatients undergoing diabetic treatment and follow-up who underwent at least three haemoglobin A1c measurements between April 2014 and March 2015 at our clinic. In 6369 samples, haemoglobin A1c was simultaneously measured by HA-8160 and MetaboLead (enzymatic assay), and the values were compared.

Results

haemoglobin A1c measurements by high-performance liquid chromatography and enzymatic assay were strongly correlated (correlation coefficient: 0.9828, linear approximation curve y = 0.9986x − 0.2507). Mean haemoglobin A1c (6.8 ± 1.0%) measured by high-performance liquid chromatography was significantly higher than that measured by enzymatic assay (6.5 ± 1.0%, P < 0.0001). During the sample processing, four (0.3%) subjects presented consistently lower haemoglobin A1c values (<0.7%) by high-performance liquid chromatography than those from enzymatic assay. Of these, three had Hb Toranomon [β112 (G14) Cys→Trp]. The fourth had Hb Ube-2 [α68 (E17) Asn→Asp]. One other subject presented consistently higher haemoglobin A1c values (>1%) by high-performance liquid chromatography than those from enzymatic assay and was diagnosed with a −77 (T > C) mutation in the δ-globin gene. These unrelated asymptomatic subjects had normal erythrocyte profiles, without anaemia.

Conclusions

We showed that haemoglobin A1c values measured by high-performance liquid chromatography were significantly higher than those measured by enzymatic assay in diabetic subjects. However, when an oversized deviation (>0.7%) between glycaemic control status and haemoglobin A1c is apparent, clinicians should check the methods used to measure haemoglobin A1c and consider the possible presence of a haemoglobin variant.
Post-standardization of routine creatinine assays: are they suitable for clinical applications
Authors: Jassam Nuthar , Weykamp Cas , Thomas Annette , Secchiero Sandra , Sciacovelli Laura , Plebani Mario , Thelen Marc , Cobbaert Christa , Perich Carmen , Ricós Carmen , Paula Faria A , Barth Julian H
Published: August 2016

Introduction

Reliable serum creatinine measurements are of vital importance for the correct classification of chronic kidney disease and early identification of kidney injury. The National Kidney Disease Education Programme working group and other groups have defined clinically acceptable analytical limits for creatinine methods. The aim of this study was to re-evaluate the performance of routine creatinine methods in the light of these defined limits so as to assess their suitability for clinical practice.

Method

In collaboration with the Dutch External Quality Assurance scheme, six frozen commutable samples, with a creatinine concentration ranging from 80 to 239  μmol/L and traceable to isotope dilution mass spectrometry, were circulated to 91 laboratories in four European countries for creatinine measurement and estimated glomerular filtration rate calculation. Two out of the six samples were spiked with glucose to give high and low final concentrations of glucose.

Results

Results from 89 laboratories were analysed for bias, imprecision (%CV) for each creatinine assay and total error for estimated glomerular filtration rate. The participating laboratories used analytical instruments from four manufacturers; Abbott, Beckman, Roche and Siemens. All enzymatic methods in this study complied with the National Kidney Disease Education Programme working group recommended limits of bias of 5% above a creatinine concentration of 100  μmol/L. They also did not show any evidence of interference from glucose. In addition, they also showed compliance with the clinically recommended %CV of ≤4% across the analytical range. In contrast, the Jaffe methods showed variable performance with regard to the interference of glucose and unsatisfactory bias and precision.

Conclusion

Jaffe-based creatinine methods still exhibit considerable analytical variability in terms of bias, imprecision and lack of specificity, and this variability brings into question their clinical utility. We believe that clinical laboratories and manufacturers should work together to phase out the use of relatively non-specific Jaffe methods and replace them with more specific methods that are enzyme based.
Bone turnover marker reference intervals in young females
Authors: Callegari Emma T , Gorelik Alexandra , Garland Suzanne M , Chiang Cherie Y , Wark John D
Published: August 2016

Background

The use of bone turnover markers in clinical practice and research in younger people is limited by the lack of normative data and understanding of common causes of variation in bone turnover marker values in this demographic. To appropriately interpret bone turnover markers, robust reference intervals specific to age, development and sex are necessary. This study aimed to determine reference intervals of bone turnover markers in females aged 16–25 years participating in the Safe-D study.

Methods

Participants were recruited through social networking site Facebook and were asked to complete an extensive, online questionnaire and attend a site visit. Participants were tested for serum carboxy-terminal cross-linking telopeptide of type 1 collagen and total procollagen type 1 N-propeptide using the Roche Elecsys automated analyser. Reference intervals were determined using the 2.5th to 97.5th percentiles of normalized bone turnover marker values.

Results

Of 406 participants, 149 were excluded due to medical conditions or medication use (except hormonal contraception) which may affect bone metabolism. In the remaining 257 participants, the reference interval was 230–1000 ng/L for serum carboxy-terminal cross-linking telopeptide of type 1 collagen and 27–131  µg/L for procollagen type 1 N-propeptide. Both marker concentrations were inversely correlated with age and oral contraceptive pill use. Therefore, intervals specific to these variables were calculated.

Conclusions

We defined robust reference intervals for cross-linking telopeptide of type 1 collagen and procollagen type 1 N-propeptide in young females grouped by age and contraceptive pill use. We examined bone turnover markers’ relationship with several lifestyle, clinical and demographic factors. Our normative intervals should aid interpretation of bone turnover markers in young females particularly in those aged 16 to 19 years where reference intervals are currently provisional.