bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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

Abstract
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 &lt; 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

Abstract
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

Abstract
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

AbstractAlthough 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

Abstract
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

Abstract
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

Abstract
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 &lt;50 nmol/L and &gt;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.