bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cyclin-Dependent Kinase Inhibitor AT7519 as a Potential Drug for MYCN-Dependent Neuroblastoma
Authors: Dolman M. Emmy M. , Poon Evon , Ebus Marli E. , den Hartog Ilona J.M. , van Noesel Carel J.M. , Jamin Yann , Hallsworth Albert , Robinson Simon P. , Petrie Kevin , Sparidans Rolf W. , Kok Robbert J. , Versteeg Rogier , Caron Huib N. , Chesler Louis , Molenaar Jan J. 
Published: July 2015

Abstract
Purpose: MYCN-dependent neuroblastomas have low cure rates with current multimodal treatment regimens and novel therapeutic drugs are therefore urgently needed. In previous preclinical studies, we have shown that targeted inhibition of cyclin-dependent kinase 2 (CDK2) resulted in specific killing of MYCN-amplified neuroblastoma cells. This study describes the in vivo preclinical evaluation of the CDK inhibitor AT7519.
Experimental Design: Preclinical drug testing was performed using a panel of MYCN-amplified and MYCN single copy neuroblastoma cell lines and different MYCN-dependent mouse models of neuroblastoma.
Results: AT7519 killed MYCN-amplified neuroblastoma cell lines more potently than MYCN single copy cell lines with a median LC50 value of 1.7 compared to 8.1 μmol/L (P = 0.0053) and a significantly stronger induction of apoptosis. Preclinical studies in female NMRI homozygous (nu/nu) mice with neuroblastoma patient-derived MYCN-amplified AMC711T xenografts revealed dose-dependent growth inhibition, which correlated with intratumoral AT7519 levels. CDK2 target inhibition by AT7519 was confirmed by significant reductions in levels of phosphorylated retinoblastoma (p-Rb) and nucleophosmin (p-NPM). AT7519 treatment of Th-MYCN transgenic mice resulted in improved survival and clinically significant tumor regression (average tumor size reduction of 86% at day 7 after treatment initiation). The improved efficacy of AT7519 observed in Th-MYCN mice correlated with higher tumor exposure to the drug.
Conclusions: This study strongly suggests that AT7519 is a promising drug for the treatment of high-risk neuroblastoma patients with MYCN amplification. Clin Cancer Res; 21(22); 5100–9. ©2015 AACR.
Multiple Gastrointestinal Polyps in Patients Treated with BRAF Inhibitors
Authors: Amaravadi Ravi K. , Hamilton Kathryn E. , Ma Xiaohong , Piao Shengfu , Portillo Armando Del , Nathanson Katherine L. , Carlino Matteo S. , Long Georgina V. , Puzanov Igor , Xu Xiaowei , Morrissette Jennifer J.D. , Tsai Kenneth Y. , Flaherty Keith T. , Sosman Jeffrey A. , Goodman Grant R. , McArthur Grant A. , Rustgi Anil K. , Metz David C. , Schuchter Lynn M. , Chapman Paul B. , Sepulveda Antonia R. 
Published: July 2015

Abstract
Purpose: BRAF inhibitors (BRAFi) extend survival in BRAF-mutant melanoma but can promote the growth of Ras-mutant neoplasms. This study determined if gastrointestinal polyps found in BRAFi-treated patients harbored Ras mutations.
Experimental Design: Colonic and gastric polyps were identified and resected from BRAFi-treated melanoma patients. Next-generation sequencing (NGS) was performed on polyps. The ability of BRAFi to promote polyp formation was functionally characterized in Apc Min+/− mice. MAPK and β-catenin pathway activity was assessed by immunohistochemistry in mouse and human polyps.
Results: Fourteen patients treated with BRAFi underwent endoscopy to assess for polyps. Seven out of 7 patients &gt;40 years of age and treated for &gt;2 years were found to have colonic tubular adenomas with 4 out of the 7 patients having 5 or more polyps. One patient presented with bleeding from hyperplastic gastric polyps that recurred 6 months after BRAFi rechallenge. NGS performed on polyps found no mutations in MAPK pathway genes, but found APC mutations in all tubular adenomas. A significant increase in the number of polyps was observed in BRAFi-treated compared with control-treated Apc Min+/− mice (20.8 ± 9.2 vs 12.8 ± 0.1; P = 0.016). No polyps were observed in BRAFi-treated wild-type mice.
Conclusions: BRAFi may increase the risk of developing hyperplastic gastric polyps and colonic adenomatous polyps. Due to the risk of gastrointestinal bleeding and the possibility of malignant transformation, further studies are needed to determine whether or not endoscopic surveillance should be recommended for patients treated with BRAFi. Clin Cancer Res; 21(23); 5215–21. ©2015 AACR.
EGFR Exon 18 Mutations in Lung Cancer: Molecular Predictors of Augmented Sensitivity to Afatinib or Neratinib as Compared with First- or Third-Generation TKIs
Authors: Kobayashi Yoshihisa , Togashi Yosuke , Yatabe Yasushi , Mizuuchi Hiroshi , Jangchul Park , Kondo Chiaki , Shimoji Masaki , Sato Katsuaki , Suda Kenichi , Tomizawa Kenji , Takemoto Toshiki , Hida Toyoaki , Nishio Kazuto , Mitsudomi Tetsuya 
Published: July 2015

Abstract
Purpose: Lung cancers harboring common EGFR mutations respond to EGFR tyrosine kinase inhibitors (TKI), whereas exon 20 insertions (Ins20) are resistant to them. However, little is known about mutations in exon 18.
Experimental Design: Mutational status of lung cancers between 2001 and 2015 was reviewed. Three representative mutations in exon 18, G719A, E709K, and exon 18 deletion (Del18: delE709_T710insD) were retrovirally introduced into Ba/F3 and NIH/3T3 cells. The 90% inhibitory concentrations (IC90s) of first-generation (1G; gefitinib and erlotinib), second-generation (2G; afatinib, dacomitinib, and neratinib), and third-generation TKIs (3G; AZD9291 and CO1686) were determined.
Results: Among 1,402 EGFR mutations, Del19, L858R, and Ins20 were detected in 40%, 47%, and 4%, respectively. Exon 18 mutations, including G719X, E709X, and Del18, were present in 3.2%. Transfected Ba/F3 cells grew in the absence of IL3, and NIH/3T3 cells formed foci with marked pile-up, indicating their oncogenic abilities. IC90s of 1G and 3G TKIs in G719A, E709K, and Del18 were much higher than those in Del19 (by &gt;11–50-fold), whereas IC90s of afatinib were only 3- to 7-fold greater than those for Del19. Notably, cells transfected with G719A and E709K exhibited higher sensitivity to neratinib (by 5–25-fold) than those expressing Del19. Patients with lung cancers harboring G719X exhibited higher response rate to afatinib or neratinib (∼80%) than to 1G TKIs (35%–56%) by compilation of data in the literature.
Conclusions: Lung cancers harboring exon 18 mutations should not be overlooked in clinical practice. These cases can be best treated with afatinib or neratinib, although the currently available in vitro diagnostic kits cannot detect all exon 18 mutations. Clin Cancer Res; 21(23); 5305–13. ©2015 AACR.
“Braking” the Cycle of Resistance in Endocrine Therapy for Breast Cancer
Authors: DeMichele Angela , Chodosh Lewis A. 
Published: July 2015

Abstract
Endocrine resistance leads to recurrence and death from breast cancer. Animal models of endocrine resistance enable preclinical identification of efficacious therapeutic combinations and further our understanding of resistance. This strategy provides new insights into optimally targeting interactions between estrogen receptor (ESR-1) activity and the cell cycle by CDK4/6 inhibitors. Clin Cancer Res; 21(22); 4999–5001. ©2015 AACR.
See related article by Wardell et al., p. 5121
NSCLC Driven by DDR2 Mutation Is Sensitive to Dasatinib and JQ1 Combination Therapy
Authors: Xu Chunxiao , Buczkowski Kevin A. , Zhang Yanxi , Asahina Hajime , Beauchamp Ellen M. , Terai Hideki , Li Yvonne Y. , Meyerson Matthew , Wong Kwok-kin , Hammerman Peter S. 
Published: July 2015

Abstract
Genetically engineered mouse models of lung cancer have demonstrated an important role in understanding the function of novel lung cancer oncogenes and tumor-suppressor genes identified in genomic studies of human lung cancer. Furthermore, these models are important platforms for preclinical therapeutic studies. Here, we generated a mouse model of lung adenocarcinoma driven by mutation of the discoidin domain receptor 2 (DDR2) gene combined with loss of TP53. DDR2L63V;TP53L/L mice developed poorly differentiated lung adenocarcinomas in all transgenic animals analyzed with a latency of 40 to 50 weeks and a median survival of 67.5 weeks. Mice expressing wild-type DDR2 with combined TP53 loss did not form lung cancers. DDR2L63V;TP53L/L tumors displayed robust expression of DDR2 and immunohistochemical markers of lung adenocarcinoma comparable with previously generated models, though also displayed concomitant expression of the squamous cell markers p63 and SOX2. Tumor-derived cell lines were not solely DDR2 dependent and displayed upregulation of and partial dependence on MYCN. Combined treatment with the multitargeted DDR2 inhibitor dasatinib and BET inhibitor JQ1 inhibited tumor growth in vitro and in vivo. Together, these results suggest that DDR2 mutation can drive lung cancer initiation in vivo and provide a novel mouse model for lung cancer therapeutics studies. Mol Cancer Ther; 14(10); 2382–9. ©2015 AACR.
Regulatory T-cell Response to EnterotoxigenicBacteroides fragilisColonization Triggers IL17-Dependent Colon Carcinogenesis
Authors: Geis Abby L. , Fan Hongni , Wu Xinqun , Wu Shaoguang , Huso David L. , Wolfe Jaime L. , Sears Cynthia L. , Pardoll Drew M. , Housseau Franck 
Published: July 2015

AbstractMany epithelial cancers are associated with chronic inflammation. However, the features of inflammation that are procarcinogenic are not fully understood. Regulatory T cells (Treg) typically restrain overt inflammatory responses and maintain intestinal immune homeostasis. Their immune-suppressive activity can inhibit inflammation-associated cancers. Paradoxically, we show that colonic Tregs initiate IL17-mediated carcinogenesis in multiple intestinal neoplasia mice colonized with the human symbiote enterotoxigenic Bacteroides fragilis (ETBF). Depletion of Tregs in ETBF-colonized C57BL/6 FOXP3DTR mice enhanced colitis but diminished tumorigenesis associated with shifting of mucosal cytokine profile from IL17 to IFNγ; inhibition of ETBF-induced colon tumorigenesis was dependent on reduced IL17 inflammation and was independent of IFNγ. Treg enhancement of IL17 production is cell-extrinsic. IL2 blockade restored Th17 responses and tumor formation in Treg-depleted animals. Our findings demonstrate that Tregs limit the availability of IL2 in the local microenvironment, allowing the Th17 development necessary to promote ETBF-triggered neoplasia, and thus unveil a new mechanism whereby Treg responses to intestinal bacterial infection can promote tumorigenesis.Significance: Tregs promote an oncogenic immune response to a common human symbiote associated with inflammatory bowel disease and colorectal cancer. Our data define mechanisms by which mucosal Tregs, despite suppressing excessive inflammation, promote the earliest stages of immune procarcinogenesis via enhancement of IL17 production at the expense of IFNγ production. Cancer Discov; 5(10); 1098–109. ©2015 AACR.See related commentary by Irrazabal and Martin, p. 1021.This article is highlighted in the In This Issue feature, p. 1005
HMGB1 binds to activated platelets via the receptor for advanced glycation end products and is present in platelet rich human coronary artery thrombi
Authors: Bode Michael , Haenel David , Hagemeyer Christoph E. , Seeba Hannah , Duerschmied Daniel , Bassler Nicole , Jandeleit-Dahm Karin A. , Sweet Matthew J. , Agrotis Alex , Bobik Alex , Peter Karlheinz , Ahrens Ingo , Chen Yung-Chih , Topcic Danijal 
Published: July 2015

SummaryHigh mobility group box 1 (HMGB1) acts as both a nuclear protein that regulates gene expression, as well as a pro-inflammatory alarmin that is released from necrotic or activated cells. Recently, HMGB1-expression in human atherosclerotic plaques was identified. Therapeutic blockade of HMGB1 reduced the development of diet-induced atherosclerosis in ApoE knockout mice. Thus, we hypothesised an interaction between HMGB1 and activated platelets. Binding of recombinant HMGB1 to platelets was assessed by flow cytometry. HMGB1 bound to thrombin-activated human platelets (MFI 2.49 vs 25.01, p=0.0079). Blood from wild-type, TLR4 and RAGE knockout mice was used to determine potential HMGB1 receptors on platelets. HMGB1 bound to platelets from wild type C57Bl6 (MFI 2.64 vs 20.3, p< 0.05), and TLR4-/- mice (MFI 2.11 vs 25.65, p< 0.05) but failed to show binding to platelets from RAGE-/- mice (p > 0.05). RAGE expression on human platelets was detected by RT-PCR with mRNA extracted from highly purified platelets and confirmed by Western blot and immunofluorescence microscopy. Platelet activation increased RAGE surface expression (MFI 4.85 vs 6.74, p< 0.05). Expression of HMGB1 in human coronary artery thrombi was demonstrated by immunohistochemistry and revealed high expression levels. Platelets bind HMGB1 upon thrombin-induced activation. Platelet specific expression of RAGE could be detected at the mRNA and protein level and is involved in the binding of HMGB1. Furthermore, platelet activation up-regulates platelet surface expression of RAGE. HMGB1 is highly expressed in platelet-rich human coronary artery thrombi pointing towards a central role for HMGB1 in atherothrombosis, thereby suggesting the possibility of platelet targeted anti-inflammatory therapies for atherothrombosis.
Extracorporeal Membrane Oxygenation as a Bridge to Pediatric Heart Transplantation
Authors: Dipchand Anne I. , Mahle William T. , Tresler Margaret , Naftel David C. , Almond Christopher , Kirklin James K. , Pruitt Elizabeth , Webber Steven A. 
Published: July 2015

Background—
Current organ allocation algorithms direct hearts to the sickest recipients to mitigate death while waiting. This may result in lower post-transplant (Tx) survival for high-risk candidates mandating close examination to determine the appropriateness of different technologies as a bridge to Tx.

Methods and Results—

We analyzed all patients (<18 years old) from the Pediatric Heart Transplant Study (PHTS) database listed for heart Tx (1993–2013) to determine the effect of extracorporeal membrane oxygenation (ECMO) support at the time of listing and the time of Tx on waitlist mortality and post-Tx outcomes. Eight percent of patients were listed on ECMO, and within 12 months, 49% had undergone Tx, 35% were deceased, and 16% were alive waiting. Survival at 12 months after listing (censored at Tx) was worse in patients on ECMO at listing (50%) compared with ventricular assist device at listing (76%) or not on ECMO or ventricular assist device at listing (76%;
P
<0.0001). Two hundred three (5%) patients underwent Tx from ECMO; 135 (67%) had been on ECMO since listing, and 67 (33%) had deteriorated to ECMO support while waiting. Survival after Tx was worse in patients who underwent Tx from ECMO (3 years: 64%) versus on ventricular assist device at Tx (3 years: 84%) or not on ECMO/ventricular assist device at Tx (3 years: 85%;
P
<0.0001). Patients transplanted from ECMO at age <1 year had the worst survival.

Conclusions—
Pediatric patients requiring ECMO support before heart Tx have poor outcomes. Prioritization of donor hearts to children waitlisted on ECMO warrants careful consideration because of ECMO’s high pre- and post-Tx mortality.
Residual Risk of Stroke and Death in Anticoagulated Patients According to the Type of Atrial Fibrillation
Authors: Senoo Keitaro , Lip Gregory Y.H. , Lane Deirdre A. , Büller Harry R. , Kotecha Dipak 
Published: July 2015

Background and Purpose—
Atrial fibrillation (AF) and heart failure frequently coexist and are associated with increased morbidity and mortality. We investigated the prognosis of anticoagulated patients with permanent AF and nonpermanent AF according to preexisting heart failure in the AMADEUS (Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients With Atrial Fibrillation) trial.

Methods—
The primary outcome was a composite of cardiovascular death and stroke or systemic embolism, analyzed using a Cox proportional hazards model, adjusted for baseline age, sex, diabetes mellitus, hypertension, creatinine, and previous cardiovascular diseases. The median follow-up was 11.6 months (interquartile range, 6.2–15.2).

Results—

Nonpermanent AF was present in 2072 patients (46% of cohort), of which 339 (16%) had preexisting heart failure. A total of 2484 patients had permanent AF (54% of cohort), with a higher burden of heart failure including 730 patients (29%;
P
<0.001). Overall, death because of cardiovascular causes occurred in 57 patients and 45 had stroke or systemic embolism (1.4/100 person-years for each). Overall, the adjusted incidence of the composite outcome was higher in patients with permanent AF than in patients with nonpermanent AF. In multivariate analysis, permanency of AF, creatinine, prior cerebrovascular events, and previous coronary disease were independently associated with the primary outcome. The hazard ratio for permanent versus nonpermanent AF was 1.68 (95% confidence interval, 1.08–2.55;
P
=0.02). The presence of heart failure increased the risk of adverse outcomes in a similar way in both permanent and nonpermanent AF (interaction
P
value=0.76).

Conclusions—
The risk of cardiovascular death, stroke, or systemic embolism is higher in anticoagulated patients with permanent AF than in those with nonpermanent AF, regardless of preexisting heart failure.
Prevalence of Individuals Experiencing the Effects of Stroke in Canada
Authors: Krueger Hans , Koot Jacqueline , Hall Ruth E. , O’Callaghan Christina , Bayley Mark , Corbett Dale 
Published: July 2015

Background and Purpose—
Previous estimates of the number and prevalence of individuals experiencing the effects of stroke in Canada are out of date and exclude critical population groups. It is essential to have complete data that report on stroke disability for monitoring and planning purposes. The objective was to provide an updated estimate of the number of individuals experiencing the effects of stroke in Canada (and its regions), trending since 2000 and forecasted prevalence to 2038.

Methods—
The prevalence, trends, and projected number of individuals experiencing the effects of stroke were estimated using region-specific survey data and adjusted to account for children aged <12 years and individuals living in homes for the aged.

Results—
In 2013, we estimate that there were 405 000 individuals experiencing the effects of stroke in Canada, yielding a prevalence of 1.15%. This value is expected to increase to between 654 000 and 726 000 by 2038. Trends in stroke data between 2000 and 2012 suggest a nonsignificant decrease in stroke prevalence, but a substantial and rising increase in the number of individuals experiencing the effects of stroke. Stroke prevalence varied considerably between regions.

Conclusions—
Previous estimates of stroke prevalence have underestimated the true number of individuals experiencing the effects of stroke in Canada. Furthermore, the projected increases that will result from population growth and demographic changes highlight the importance of maintaining up-to-date estimates.
Implications of the Methodological Choices for Hydrologic Portrayals of Climate Change over the Contiguous United States: Statistically Downscaled Forcing Data and Hydrologic Models
Authors: Mizukami Naoki , Clark Martyn P. , Gutmann Ethan D. , Mendoza Pablo A. , Newman Andrew J. , Nijssen Bart , Livneh Ben , Hay Lauren E. , Arnold Jeffrey R. , Brekke Levi D. 
Published: July 2015

Abstract
Continental-domain assessments of climate change impacts on water resources typically rely on statistically downscaled climate model outputs to force hydrologic models at a finer spatial resolution. This study examines the effects of four statistical downscaling methods [bias-corrected constructed analog (BCCA), bias-corrected spatial disaggregation applied at daily (BCSDd) and monthly scales (BCSDm), and asynchronous regression (AR)] on retrospective hydrologic simulations using three hydrologic models with their default parameters (the Community Land Model, version 4.0; the Variable Infiltration Capacity model, version 4.1.2; and the Precipitation–Runoff Modeling System, version 3.0.4) over the contiguous United States (CONUS). Biases of hydrologic simulations forced by statistically downscaled climate data relative to the simulation with observation-based gridded data are presented. Each statistical downscaling method produces different meteorological portrayals including precipitation amount, wet-day frequency, and the energy input (i.e., shortwave radiation), and their interplay affects estimations of precipitation partitioning between evapotranspiration and runoff, extreme runoff, and hydrologic states (i.e., snow and soil moisture). The analyses show that BCCA underestimates annual precipitation by as much as −250 mm, leading to unreasonable hydrologic portrayals over the CONUS for all models. Although the other three statistical downscaling methods produce a comparable precipitation bias ranging from −10 to 8 mm across the CONUS, BCSDd severely overestimates the wet-day fraction by up to 0.25, leading to different precipitation partitioning compared to the simulations with other downscaled data. Overall, the choice of downscaling method contributes to less spread in runoff estimates (by a factor of 1.5–3) than the choice of hydrologic model with use of the default parameters if BCCA is excluded.
A Nonvariational Consistent Hybrid Ensemble Filter
Authors: Bishop Craig H. , Huang Bo , Wang Xuguang 
Published: July 2015

Abstract
A consistent hybrid ensemble filter (CHEF) for using hybrid forecast error covariance matrices that linearly combine aspects of both climatological and flow-dependent matrices within a nonvariational ensemble data assimilation scheme is described. The CHEF accommodates the ensemble data assimilation enhancements of (i) model space ensemble covariance localization for satellite data assimilation and (ii) Hodyss’s method for improving accuracy using ensemble skewness. Like the local ensemble transform Kalman filter (LETKF), the CHEF is computationally scalable because it updates local patches of the atmosphere independently of others. Like the sequential ensemble Kalman filter (EnKF), it serially assimilates batches of observations and uses perturbed observations to create ensembles of analyses. It differs from the deterministic (no perturbed observations) ensemble square root filter (ESRF) and the EnKF in that (i) its analysis correction is unaffected by the order in which observations are assimilated even when localization is required, (ii) it uses accurate high-rank solutions for the posterior error covariance matrix to serially assimilate observations, and (iii) it accommodates high-rank hybrid error covariance models. Experiments were performed to assess the effect on CHEF and ESRF analysis accuracy of these differences. In the case where both the CHEF and the ESRF used tuned localized ensemble covariances for the forecast error covariance model, the CHEF’s advantage over the ESRF increased with observational density. In the case where the CHEF used a hybrid error covariance model but the ESRF did not, the CHEF had a substantial advantage for all observational densities.