bluuebunny/crossref_metadata_2025_split huggingface dataset:
Toward Value-Based Pricing to Boost Cancer Research and Innovation
Authors: Ocana Alberto , Amir Eitan , Tannock Ian F. 
Published: May 2016

Abstract
The high market price of new anticancer agents has stimulated debate about the long-term sustainability of healthcare systems and whether these new agents can continue to be supported by public healthcare or by private insurers. In addition, some drugs have been approved with limited clinical benefit, raising concerns about setting a minimum requirement for medical benefit. Options to resolve these problems include raising the bar for approval of new drugs and/or pricing of new agents based on the medical benefit that they offer to patients. In this commentary, we suggest that new agents should be marketed in a two-step process that would include first the approval of the new drug by the regulatory agencies and second the introduction of a market price based on the medical benefit that the new intervention offers to patients. Introduction of value-based pricing would maintain the sustainability of health care systems and would improve drug development, as it would pressure pharmaceutical companies to become more innovative and avoid the development of compounds with limited benefit. Value-based pricing could also stimulate the funding of research directed to development of new anticancer drugs with novel mechanisms of action. Cancer Res; 76(11); 3127–9. ©2016 AACR.
Impact of Pattern Recognition Receptors on the Prognosis of Breast Cancer Patients Undergoing Adjuvant Chemotherapy
Authors: Vacchelli Erika , Enot David P. , Pietrocola Federico , Zitvogel Laurence , Kroemer Guido 
Published: May 2016

Abstract
Pattern recognition receptors allow the innate immune system to perceive the presence of microbial products and to launch the first steps of the defense response. Some pattern recognition receptors also sense endogenous ligands that are released from uninfected dying cells, thereby activating immune responses against dead-cell antigens. This applies to toll-like receptors 3 and 4 (TLR3, TLR4), which sense double-stranded RNA and high-mobility group protein B1 (HMGB1), respectively, as well as to formyl peptide receptor-1 (FPR1), which interacts with Annexin A1 (ANXA1) from dead cells. Breast cancer patients who bear loss-of-function alleles in TLR3, TLR4, and FPR1 exhibit a reduced metastasis-free and overall survival after treatment with anthracycline-based adjuvant chemotherapy. These genetic defects are epistatic with respect to each other, suggesting that they act on the same pathway, linking chemotherapy to a therapeutically relevant anticancer immune response. Loss-of-function alleles in TLR4 and FPR1 also affect the prognosis of colorectal cancer patients treated with oxaliplatin-based chemotherapy. Altogether, these results support the idea that conventional anticancer treatments rely on stimulation of anticancer immune responses to become fully efficient. Cancer Res; 76(11); 3122–6. ©2016 AACR.
Depletion of FOXM1 via MET Targeting Underlies Establishment of a DNA Damage–Induced Senescence Program in Gastric Cancer
Authors: Francica Paola , Nisa Lluís , Aebersold Daniel M. , Langer Rupert , Bladt Friedhelm , Blaukat Andree , Stroka Deborah , Martínez María Rodríguez , Zimmer Yitzhak , Medová Michaela 
Published: May 2016

Abstract
Purpose: Deregulated signaling via the MET receptor tyrosine kinase is abundant in gastric tumors, with up to 80% of cases displaying aberrant MET expression. A growing body of evidence suggests MET as a potential target for tumor radiosensitization.
Experimental Design: Cellular proliferation and DNA damage-induced senescence were studied in a panel of MET-overexpressing human gastric cancer cell lines as well as in xenograft models after MET inhibition and/or ionizing radiation. Pathways activation and protein expression were assessed by immunoblotting and immunohistochemistry. Tumor tissue microarrays (91 gastric cancer patients) were generated and copy number alteration (178 patients) and gene expression (373 patients) data available at The Cancer Genome Atlas were analyzed to assess the coalterations of MET and FOXM1.
Results: MET targeting administered before ionizing radiation instigates DNA damage–induced senescence (∼80%, P &lt; 0.001) rather than cell death. MET inhibition–associated senescence is linked to the blockade of MAPK pathway, correlates with downregulation of FOXM1, and can be abrogated (11.8% vs. 95.3%, P &lt; 0.001) by ectopic expression of FOXM1 in the corresponding gastric tumor cells. Cells with ectopic FOXM1 expression demonstrate considerable (∼20%, P &lt; 0.001) growth advantage despite MET targeting, suggesting a novel clinically relevant resistance mechanism to MET inhibition as the copresence of both MET and FOXM1 protein (33%) and mRNA (30%) overexpression as well as gene amplification (24,7%) are common in patients with gastric cancer.
Conclusions: FOXM1, a negative regulator of senescence, has been identified as a key downstream effector and potential clinical biomarker that mediates MET signaling following infliction of DNA damage in gastric tumors. Clin Cancer Res; 22(21); 5322–36. ©2016 AACR.
Rectal Cancer: Assessment of Neoadjuvant Chemoradiation Outcome based on Radiomics of Multiparametric MRI
Authors: Nie Ke , Shi Liming , Chen Qin , Hu Xi , Jabbour Salma K. , Yue Ning , Niu Tianye , Sun Xiaonan 
Published: May 2016

Abstract
Purpose: To evaluate multiparametric MRI features in predicting pathologic response after preoperative chemoradiation therapy (CRT) for locally advanced rectal cancer (LARC).
Experimental Design: Forty-eight consecutive patients (January 2012–November 2014) receiving neoadjuvant CRT were enrolled. All underwent anatomical T1/T2, diffusion-weighted MRI (DWI) and dynamic contrast-enhanced (DCE) MRI before CRT. A total of 103 imaging features, analyzed using both volume-averaged and voxelized methods, were extracted for each patient. Univariate analyses were performed to evaluate the capability of each individual parameter in predicting pathologic complete response (pCR) or good response (GR) evaluated based on tumor regression grade. Artificial neural network with 4-fold validation technique was further utilized to select the best predictor sets to classify different response groups and the predictive performance was calculated using receiver operating characteristic (ROC) curves.
Results: The conventional volume-averaged analysis could provide an area under ROC curve (AUC) ranging from 0.54 to 0.73 in predicting pCR. While if the models were replaced by voxelized heterogeneity analysis, the prediction accuracy measured by AUC could be improved to 0.71–0.79. Similar results were found for GR prediction. In addition, each subcategory images could generate moderate power in predicting the response, which if combining all information together, the AUC could be further improved to 0.84 for pCR and 0.89 for GR prediction, respectively.
Conclusions: Through a systematic analysis of multiparametric MR imaging features, we are able to build models with improved predictive value over conventional imaging metrics. The results are encouraging, suggesting the wealth of imaging radiomics should be further explored to help tailoring the treatment into the era of personalized medicine. Clin Cancer Res; 22(21); 5256–64. ©2016 AACR.
Antitumor Efficacy of Anti-GD2 IgG1 Is Enhanced by Fc Glyco-Engineering
Authors: Xu Hong , Guo Hongfen , Cheung Irene Y. , Cheung Nai-Kong V. 
Published: May 2016

Abstract
The affinity of therapeutic antibodies for Fcγ receptors (FcγRs) strongly influences their antitumor potency. To generate antibodies with optimal binding and immunologic efficacy, we compared the affinities of different versions of an IgG1 Fc region that had an altered peptide backbone, altered glycans, or both. To produce IgG1 with glycans that lacked α1,6-fucose, we used CHO cells that were deficient in the enzyme UDP-N-acetylglucosamine: α-3-d-mannoside-β-1,2-N-acetylglucosaminyltransferase I (GnT1), encoded by the MGAT1 gene. Mature N-linked glycans require this enzyme, and without it, CHO cells synthesize antibodies carrying only Man5-GlcNAc2, which were more effective in antibody-dependent cell-mediated cytotoxicity (ADCC). Our engineered IgG1, hu3F8-IgG1, is specific for GD2, a neuroendocrine tumor ganglioside. Its peptide mutant is IgG1-DEL (S239D/I332E/A330L), both produced in wild-type CHO cells. When produced in GnT1-deficient CHO cells, we refer to them as IgG1n and IgG1n-DEL, respectively. Affinities for human FcγRs were measured using Biacore T-100 (on CD16 and CD32 polymorphic alleles), their immunologic properties compared for ADCC and complement-mediated cytotoxicity (CMC) in vitro, and pharmacokinetics and antitumor effects were compared in vivo in humanized mice. IgG1n and IgG1n-DEL contained only mannose and acetylglucosamine and had preferential affinity for activating CD16s, over inhibitory CD32B, receptors. In vivo, the antitumor effects of IgG1, IgG1-DEL, and IgG1n-DEL were similar but modest, whereas IgG1n was significantly more effective (P &lt; 0.05). Thus, IgG1n antibodies produced in GnT1-deficient CHO cells may have potential as improved anticancer therapeutics. Cancer Immunol Res; 4(7); 631–8. ©2016 AACR.
Comparative Effectiveness of Carotid Artery Stenting Versus Carotid Endarterectomy Among Medicare Beneficiaries
Authors: Jalbert Jessica J. , Nguyen Louis L. , Gerhard-Herman Marie D. , Kumamaru Hiraku , Chen Chih-Ying , Williams Lauren A. , Liu Jun , Rothman Andrew T. , Jaff Michael R. , Seeger John D. , Benenati James F. , Schneider Peter A. , Aronow Herbert D. , Johnston Joseph A. , Brott Thomas G. , Tsai Thomas T. , White Christopher J. , Setoguchi Soko 
Published: May 2016

Background—
Effectiveness of carotid artery stenting (CAS) relative to carotid endarterectomy (CEA) among Medicare patients has not been established. We compared effectiveness of CAS versus CEA among Medicare beneficiaries.

Methods and Results—
We linked Medicare data (2000–2009) to the Society for Vascular Surgery’s Vascular Registry (2005–2008) and the National Cardiovascular Data Registry's (NCDR) Carotid Artery Revascularization and Endarterectomy Registry (2006–2008/2009). Medicare patients were followed up from procedure date until death, stroke/transient ischemic attack, periprocedural myocardial infarction, or a composite end point for these outcomes. We derived high-dimensional propensity scores using registry and Medicare data to control for patient factors and adjusted for provider factors in a Cox regression model comparing CAS with CEA. Among 5254 Society for Vascular Surgery’s Vascular Registry (1999 CAS; 3255 CEA) and 4055 Carotid Artery Revascularization and Endarterectomy Registry (2824 CAS; 1231 CEA) Medicare patients, CAS patients had a higher comorbidity burden and were more likely to be at high surgical risk (Society for Vascular Surgery’s Vascular Registry: 96.7% versus 44.5%; Carotid Artery Revascularization and Endarterectomy Registry: 71.3% versus 44.7%). Unadjusted outcome risks were higher for CAS. Mortality risks remained elevated for CAS after adjusting for patient-level factors (hazard ratio, 1.24; 95% confidence interval, 1.06–1.46). After further adjustment for provider factors, differences between CAS and CEA were attenuated or no longer present (hazard ratio for mortality, 1.13; 95% confidence interval, 0.94–1.37). Performance was comparable across subgroups defined by sex and degree of carotid stenosis, but there was a nonsignificant trend suggesting a higher risk of adverse outcomes in older (>80) and symptomatic patients undergoing CAS.

Conclusions—
Outcomes after CAS and CEA among Medicare beneficiaries were comparable after adjusting for both patient- and provider-level factors.
A 12-week open-label, randomized, controlled trial and 24-week extension to assess the efficacy and safety of fluticasone propionate/formoterol in children with asthma
Authors: Emeryk Andrzej , Klink Rabih , McIver Tammy , Dalvi Prashant 
Published: May 2016

Objectives: The present study was conducted to assess the efficacy, safety and tolerability of fluticasone propionate/formoterol fumarate combination therapy (FP/FORM; Flutiform®) compared with fluticasone propionate/salmeterol xinafoate (FP/SAL; Seretide® Evohaler®) in children with asthma. Methods: This was an open-label, randomized, controlled, phase III trial and extension. Patients aged 4–12 years with reversible asthma [% predicted forced expiratory volume in 1 second (FEV1) 60–100%; documented reversibility of ⩾15% in FEV1] were randomized to receive FP/FORM (100/10 µg b.i.d.) or FP/SAL (100/50 µg b.i.d.) for 12 weeks. Eligible patients completing the 12-week core phase entered a 24-week extension phase with FP/FORM (100/10 µg b.i.d.). The primary efficacy endpoint was the change in predose FEV1 from day 0 to day 84. Secondary efficacy endpoints included change in predose to 2-hours postdose FEV1 from day 0 to day 84, peak expiratory flow rate (PEFR), patient-reported outcomes, rescue-medication use and asthma exacerbations. Results: In total, 211 patients were randomized and 210 completed the core phase; of these patients, 208 entered and 205 completed the extension phase of the study. Predose FEV1 increased from day 0 to day 84 [FP/FORM, 182 ml; 95% confidence interval (CI), 127, 236; FP/SAL, 212 ml, 95% CI, 160, 265] and FP/FORM was noninferior to FP/SAL: least squares (LS) mean treatment difference: –0.031 (95% CI, –0.093, 0.031; p = 0.026). Secondary efficacy analyses indicated similar efficacy with both therapies. There were no notable differences observed in the safety and tolerability profile between treatments. No safety concerns were identified with long-term FP/FORM therapy, and there was no evidence of an effect of FP/FORM on plasma cortisol. Conclusions: FP/FORM improved lung function and measures of asthma control with comparable efficacy to FP/SAL, and demonstrated a favourable safety and tolerability profile in children aged 4–12 years.
Adjuvant Liraglutide and Insulin Versus Insulin Monotherapy in the Closed-Loop System in Type 1 Diabetes
Authors: Ilkowitz Jeniece Trast , Katikaneni Ranjitha , Cantwell Martin , Ramchandani Neesha , Heptulla Rubina A. 
Published: May 2016

Background: The closed-loop (CL) system delivers insulin in a glucose-responsive manner and optimal postprandial glycemic control is difficult to achieve with the algorithm and insulin available. We hypothesized that adjunctive therapy with liraglutide, a once-daily glucagon-like peptide-1 agonist, would be more effective in normalizing postprandial hyperglycemia versus insulin monotherapy in the CL system, in patients with type 1 diabetes. Methods: This was a randomized, controlled, open-label, crossover design trial comparing insulin monotherapy versus adjuvant subcutaneous liraglutide 1.2 mg and insulin, using the CL system in 15 patients. Blood glucose (BG), insulin, and glucagon concentrations were analyzed. Results: The liraglutide arm was associated with overall decreased mean BG levels ( P = .0002). The average BG levels from 8:00 pm (day 1) to 9:00 pm (day 2) were lower in the liraglutide arm (144.6 ± 36.31 vs 159.7 ± 50.88 mg/dl respectively; P = .0002). Two-hour postbreakfast and lunch BG profiles were better in the liraglutide arm ( P < .05) and the insulin and glucagon assay values were lower ( P < .0001). Postprandially, the area under the curve (AUC) for 2-hour postbreakfast and lunch BG levels were significant ( P = .01, P = .03) and the AUC for glucagon, postbreakfast ( P < .0001) and lunch ( P < .05), was also significant. The incidence of hypoglycemia did not differ between arms ( P = .83, Fisher’s exact test). Overall, adjunct liraglutide therapy plus CL was well tolerated even with expected side effects. Conclusion: This is a proof-of-concept study showing liraglutide can be a potential adjunctive therapy in addition to CL with insulin to reduce postprandial hyperglycemia in type 1 diabetes.
Treatment with insulin analogs, especially Glargine and Lispro, associates with better renal function and higher hemoglobin levels in Type 1 diabetic patients with impaired kidney function
Authors: Hasslacher Christoph , Kulozik Felix , Lorenzo Bermejo Justo 
Published: May 2016

Objectives: The influence of type of insulin treatment - insulin analogs versus human insulin - on the development of diabetes related vascular complications has been sparsely investigated. We examine here possible differences regarding kidney function and hemoglobin levels. Methods: Multiple linear regression was used to investigate the relationship between the following characteristics measured in 509 type 1 diabetic patients who were recruited in an outpatient practice: current clinical status and treatment modalities, type of injected insulin and the routine laboratory parameters hemoglobin, HbA1c, serum creatinine, eGFR, hs CRP and urinary albumin/creatinine ratio. Results: Compared with human insulin, multiple regression analysis taking into account possible confounders revealed that treatment with insulin analogs was associated with increased eGFR (+7.1 ml/min; P=0.0002), lower urinary albumin/creatinine ratio (ratio logarithm -0.4; P=0.003) and higher hemoglobin concentration (+0.31 g/dl; P=0.04). Stratification by type of insulin showed the best renal status for treatment with insulins Glargine and Lispro. Differences were consistent both for patients with normal (eGFR → 90 ml/min) and with an impaired (eGFR ← 90 ml/min) kidney function. Conclusions: Present results suggest that treatment of type 1 diabetic patients with normal and impaired renal function with insulin analogs, especially Glargine and Lispro, is associated with better kidney function, lower urinary albumin/creatinine ratio and lower hemoglobin concentration compared to therapy with human insulin. If confirmed by other studies, treatment with insulin analogs may be a further possibility in delaying progression of nephropathy and in preventing early hemoglobin decline.
Music before Dental Surgery Suppresses Sympathetic Activity Derived from Preoperative Anxiety
Authors: Miyata K. , Odanaka H. , Nitta Y. , Shimoji S. , Kanehira T. , Kawanami M. , Fujisawa T. 
Published: May 2016

The aim of this study was to estimate the relieving effect of music intervention on preoperative anxiety by using heart rate variability (HRV) analysis. In this randomized controlled trial, 86 adult patients were scheduled to undergo impacted tooth extraction under intravenous sedation and local anesthesia and were classified as either fearful or nonfearful based on a questionnaire. Thereafter, the patients were subdivided into 2 groups: those who listened to music from the time that they arrived at the outpatient clinic until immediately before entering the operating room and those who did not listen to music. The effect of music intervention was evaluated by assessing 1) the low-frequency/high-frequency ratio of HRV, in which positive changes indicate increased sympathetic nervous activity, and 2) the coefficient of component variance for high frequency, in which positive changes indicate increased parasympathetic nervous activity, assessed by means of HRV analysis. Subjective preoperative anxiety was evaluated on a visual analog scale. For fearful patients, the mean magnitude of low-frequency/high frequency changes from baseline among those who listened to music was significantly lower as compared with those who did not listen to music (in the private room: −1.45 ± 1.88 vs. 1.05 ± 1.88, P = 0.0096, 95% confidence interval of effect size = −4.52 to −0.48, Cohen’s d = −0.75; in the operating waiting room: −2.18 ± 2.39 vs. −0.10 ± 3.37, P = 0.011, 95% confidence interval of effect size = −3.94 to −0.22, Cohen’s d = −0.71, respectively). Visual analog scale scores were also significantly different. Coefficient of component variance for high frequency and heart rate did not differ significantly between the 2 groups. From the perspective of autonomic nervous activity, music intervention is useful for relieving anxiety in patients with dental fear before they enter a dental outpatient operating room. Music intervention may relieve anxiety by reducing sympathetic nervous activity, while parasympathetic nervous activity is not involved (UMIN000016882). Knowledge Transfer Statement: The results of this study revealed that music intervention is useful for clinicians when planning preoperative anxiety management of patients with dental fear who undergo impacted tooth extraction under intravenous sedation and local anesthesia. As a bridging intervention, music intervention enables stress management to continue uninterrupted from the patient’s arrival at the dental outpatient clinic to intravenous sedation until completion of the dental surgery. With consideration of cost-effectiveness, absence of adverse physical effects, immediate effect, safety in terms of not using drugs, and lack of concerns about recovery, this information could lead to more appropriate decisions regarding anxiety management in dentistry.
CINOEDV: a co-information based method for detecting and visualizing n-order epistatic interactions
Authors: Shang Junliang , Sun Yingxia , Liu Jin-Xing , Xia Junfeng , Zhang Junying , Zheng Chun-Hou 
Published: May 2016

Abstract
Background
Detecting and visualizing nonlinear interaction effects of single nucleotide polymorphisms (SNPs) or epistatic interactions are important topics in bioinformatics since they play an important role in unraveling the mystery of “missing heritability”. However, related studies are almost limited to pairwise epistatic interactions due to their methodological and computational challenges.

Results
We develop CINOEDV (Co-Information based N-Order Epistasis Detector and Visualizer) for the detection and visualization of epistatic interactions of their orders from 1 to n (n ≥ 2). CINOEDV is composed of two stages, namely, detecting stage and visualizing stage. In detecting stage, co-information based measures are employed to quantify association effects of n-order SNP combinations to the phenotype, and two types of search strategies are introduced to identify n-order epistatic interactions: an exhaustive search and a particle swarm optimization based search. In visualizing stage, all detected n-order epistatic interactions are used to construct a hypergraph, where a real vertex represents the main effect of a SNP and a virtual vertex denotes the interaction effect of an n-order epistatic interaction. By deeply analyzing the constructed hypergraph, some hidden clues for better understanding the underlying genetic architecture of complex diseases could be revealed.

Conclusions
Experiments of CINOEDV and its comparison with existing state-of-the-art methods are performed on both simulation data sets and a real data set of age-related macular degeneration. Results demonstrate that CINOEDV is promising in detecting and visualizing n-order epistatic interactions. CINOEDV is implemented in R and is freely available from R CRAN: http://cran.r-project.org and https://sourceforge.net/projects/cinoedv/files/.