bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical outcomes and cost-effectiveness analysis for the treatment of basilar tip aneurysms
Authors: Abecassis Isaac Josh , Sen Rajeev , Kelly Cory Michael , Levy Samuel , Barber Jason , Ghodke Basavaraj , Levitt Michael , Kim Louis J , Sekhar Laligam N 
Published: June 2019

BackgroundEndovascular treatment of basilar tip aneurysms is less invasive than microsurgical clipping, but requires closer follow-up.ObjectiveTo characterize the additional costs associated with endovascular treatment of basilar tip aneurysms rather than microsurgical clipping.Materials and methodsWe obtained clinical records and billing information for 141 basilar tip aneurysms treated with clip ligation (n=48) or endovascular embolization (n=93). Costs included direct and indirect costs associated with index hospitalization, as well as re-treatments, follow-up visits, imaging studies, rehabilitation, and disability. Effectiveness of treatment was quantified by converting functional outcomes (modified Rankin Scale (mRS) score) into quality-adjusted life-years (QALYs). Cost-effectiveness was performed using cost/QALY ratios.ResultsAverage index hospitalization costs were significantly higher for patients with unruptured aneurysms treated with clip ligation ($71 400 ± $47 100) compared with coil embolization ($33 500 ± $22 600), balloon-assisted coiling ($26 200 ± $11 600), and stent-assisted coiling ($38 500 ± $20 900). Multivariate predictors for higher index hospitalization cost included vasospasm requiring endovascular intervention, placement of a ventriculoperitoneal shunt, longer length of stay, larger aneurysm neck and width, higher Hunt-Hess grade, and treatment-associated complications. At 1 year, endovascular treatment was associated with lower cost/QALY than clip ligation in unruptured aneurysms ($52 000/QALY vs $137 000/QALY, respectively, p=0.006), but comparable rates in ruptured aneurysms ($193 000/QALY vs $233 000/QALY, p=0.277). Multivariate predictors for higher cost/QALY included worse mRS score at discharge, procedural complications, and larger aneurysm width.ConclusionsCoil embolization of basilar tip aneurysms is associated with a lower cost/QALY. This effect is sustained during follow-up. Clinical condition at discharge is the most significant predictor of overall cost/QALY at 1 year.
Production and metabolic consequences of high-energy and low-crude-protein diet fed to 49-wk-old Shaver white leghorn without or with top-dressed organic selenium
Authors: Robinson Sara , Kiarie Elijah G. 
Published: June 2019

Production and metabolic consequences of feeding 49-wk-old Shaver white hens a high-energy low-crude-protein (HELP) diet were investigated over 6 wk. The test diets included standard diet [2750 kcal kg−1apparent metabolizable energy (AME) and 17.5% crude protein (CP)], HELP (3000 kcal kg−1of AME and 13.0% CP) diet, and HELP top dressed with selenium (HELP + Se). All diets had 0.3 mg Se kg−1as part of premix. Hens (33) were procured, three birds necropsied for baseline liver samples, and the rest placed in individual cages and allocated diets (n = 10). Feed intake (FI), hen day egg production (HDEP), and egg weight (EW) were monitored weekly. Plasma and liver samples were collected from all birds. Birds fed standard and HELP diets had similar (P > 0.05) FI (with exception of weeks 4 and 5) and HDEP, whereas HELP + Se depressed (P < 0.05) feed and nutrient intake at weeks 5 and 6, HDEP, and EW. There were no (P > 0.05) diet effects on hepatic weight and crude fat content. Birds fed HELP diets had lower (P > 0.05) concentration of plasma total protein, macrominerals, and some enzymes. Overall, HELP diet had minimal impact on production and metabolism; however, addition of Se had negative effects on hen performance.
Taking a long look at QUIC
Authors: Kakhki Arash Molavi , Jero Samuel , Choffnes David , Nita-Rotaru Cristina , Mislove Alan 
Published: June 2019

Google's Quick UDP Internet Connections (QUIC) protocol, which implements TCP-like properties at the application layer atop a UDP transport, is now used by the vast majority of Chrome clients accessing Google properties but has no formal state machine specification, limited analysis, and ad-hoc evaluations based on snapshots of the protocol implementation in a small number of environ-merits. Further frustrating attempts to evaluate QUIC is the fact that the protocol is under rapid development, with extensive rewriting of the protocol occurring over the scale of months, making individual studies of the protocol obsolete before publication.
Given this unique scenario, there is a need for alternative techniques for understanding and evaluating QUIC when compared with previous transport-layer protocols. First, we develop an approach that allows us to conduct analysis across multiple versions of QUIC to understand how code changes impact protocol effectiveness. Next, we instrument the source code to infer QUIC's state machine from execution traces. With this model, we run QUIC in a large number of environments that include desktop and mobile, wired and wireless environments and use the state machine to understand differences in transport-and application-layer performance across multiple versions of QUIC and in different environments. QUIC generally outperforms TCP, but we also identified performance issues related to window sizes, re-ordered packets, and multiplexing large number of small objects; further, we identify that QUIC's performance diminishes on mobile devices and over cellular networks.
EN1 Is a Transcriptional Dependency in Triple-Negative Breast Cancer Associated with Brain Metastasis
Authors: Peluffo Guillermo , Subedee Ashim , Harper Nicholas W. , Kingston Natalie , Jovanović Bojana , Flores Felipe , Stevens Laura E. , Beca Francisco , Trinh Anne , Chilamakuri Chandra Sekhar Reddy , Papachristou Evangelia K. , Murphy Katherine , Su Ying , Marusyk Andriy , D'Santos Clive S. , Rueda Oscar M. , Beck Andrew H. , Caldas Carlos , Carroll Jason S. , Polyak Kornelia 
Published: June 2019

Abstract

To define transcriptional dependencies of triple-negative breast cancer (TNBC), we identified transcription factors highly and specifically expressed in primary TNBCs and tested their requirement for cell growth in a panel of breast cancer cell lines. We found that EN1 (engrailed 1) is overexpressed in TNBCs and its downregulation preferentially and significantly reduced viability and tumorigenicity in TNBC cell lines. By integrating gene expression changes after EN1 downregulation with EN1 chromatin binding patterns, we identified genes involved in WNT and Hedgehog signaling, neurogenesis, and axonal guidance as direct EN1 transcriptional targets. Quantitative proteomic analyses of EN1-bound chromatin complexes revealed association with transcriptional repressors and coactivators including TLE3, TRIM24, TRIM28, and TRIM33. High expression of EN1 correlated with short overall survival and increased risk of developing brain metastases in patients with TNBC. Thus, EN1 is a prognostic marker and a potential therapeutic target in TNBC.

Significance:
These findings show that the EN1 transcription factor regulates neurogenesis-related genes and is associated with brain metastasis in triple-negative breast cancer.
PPARδ Mediates the Effect of Dietary Fat in Promoting Colorectal Cancer Metastasis
Authors: Wang Dingzhi , Fu Lingchen , Wei Jie , Xiong Ying , DuBois Raymond N. 
Published: June 2019

Abstract

The nuclear hormone receptor peroxisome proliferator-activated receptor delta (PPARδ) is a ligand-dependent transcription factor involved in fatty acid metabolism, obesity, wound healing, inflammation, and cancer. Although PPARδ has been shown to promote intestinal adenoma formation and growth, the molecular mechanisms underlying the contribution of PPARδ to colorectal cancer remain unclear. Here, we demonstrate that activation of PPARδ induces expansion of colonic cancer stem cells (CSC) and promotes colorectal cancer liver metastasis by binding to the Nanog promoter and enhancing Nanog expression. Moreover, PPARδ mediated the effect of a high-fat diet in promoting liver metastasis and induction of colonic CSC expansion. Our findings uncover a novel role of dietary fats in colorectal cancer metastasis and reveal novel mechanisms underlying PPARδ-mediated induction of CSCs and those responsible for the contribution of dietary fats to colorectal cancer progression. These findings may provide a rationale for developing PPARδ antagonists to therapeutically target CSCs in colorectal cancer.

Significance:
These findings show that PPARδ contributes to colorectal cancer metastasis by expanding the CSC population, indicating that antagonists that target PPARδ may be beneficial in treating colorectal cancer.
VEGFR1+ Metastasis–Associated Macrophages Contribute to Metastatic Angiogenesis and Influence Colorectal Cancer Patient Outcome
Authors: Freire Valls Aida , Knipper Karl , Giannakouri Evangelia , Sarachaga Víctor , Hinterkopf Sascha , Wuehrl Michael , Shen Ying , Radhakrishnan Praveenkumar , Klose Johannes , Ulrich Alexis , Schneider Martin , Augustin Hellmut G. , Ruiz de Almodovar Carmen , Schmidt Thomas 
Published: June 2019

Abstract

Purpose:
To investigate the clinical relevance of macrophages in liver metastasis of colorectal cancer and their influence on angiogenesis and patient survival. Moreover to evaluate specific blood monocytes as markers of disease recurrence.
Experimental design: In a mouse model with spontaneous liver metastasis, the angiogenic characteristics of tumor- and metastasis (MAM)-associated macrophages were evaluated. Macrophages and the vasculature from 130 primary tumor (pTU) and 123 patients with liver metastasis were assessed. In vivo and in human samples, the clinical relevance of macrophage VEGFR1 expression was analyzed. Blood samples from patients (n = 157, 80 pTU and 77 liver metastasis) were analyzed for assessing VEGFR1-positive (VEGFR1+) cells as suitable biomarkers of disease recurrence.

Results:
The number of macrophages positively correlated with vascularization in metastasis. Both in the murine model as well as in primary isolated human cells, a subpopulation of MAMs expressing VEGFR1 were found highly angiogenic. While VEGFR1 expression in pTU patients did not predict prognosis; high percentage of VEGFR1+ cells in liver metastasis was associated with worse patient outcome. Interestingly, VEGFR1+-circulating monocytes in blood samples from patients with liver metastasis not only predicted progression but also site of recurrence.

Conclusions:
Our findings identify a new subset of proangiogenic VEGFR1+ MAMs in colorectal cancer that support metastatic growth and may become a liquid biomarker to predict disease recurrence in the liver.
Cigarette Smoke Induces Metabolic Reprogramming of the Tumor Stroma in Head and Neck Squamous Cell Carcinoma
Authors: Domingo-Vidal Marina , Whitaker-Menezes Diana , Martos-Rus Cristina , Tassone Patrick , Snyder Christopher M. , Tuluc Madalina , Philp Nancy , Curry Joseph , Martinez-Outschoorn Ubaldo 
Published: June 2019

Abstract

Head and neck squamous cell carcinoma (HNSCC) is comprised of metabolically linked distinct compartments. Cancer-associated fibroblasts (CAF) and nonproliferative carcinoma cells display a glycolytic metabolism, while proliferative carcinoma cells rely on mitochondrial oxidative metabolism fueled by the catabolites provided by the adjacent CAFs. Metabolic coupling between these reprogrammed compartments contributes to HNSCC aggressiveness. In this study, we examined the effects of cigarette smoke–exposed CAFs on metabolic coupling and tumor aggressiveness of HNSCC. Cigarette smoke (CS) extract was generated by dissolving cigarette smoke in growth media. Fibroblasts were cultured in CS or control media. HNSCC cells were cocultured in vitro and coinjected in vivo with CS or control fibroblasts. We found that CS induced oxidative stress, glycolytic flux and MCT4 expression, and senescence in fibroblasts. MCT4 upregulation was critical for fibroblast viability under CS conditions. The effects of CS on fibroblasts were abrogated by antioxidant treatment. Coculture of carcinoma cells with CS fibroblasts induced metabolic coupling with upregulation of the marker of glycolysis MCT4 in fibroblasts and markers of mitochondrial metabolism MCT1 and TOMM20 in carcinoma cells. CS fibroblasts increased CCL2 expression and macrophage migration. Coculture with CS fibroblasts also increased two features of carcinoma cell aggressiveness: resistance to cell death and enhanced cell migration. Coinjection of carcinoma cells with CS fibroblasts generated larger tumors with reduced apoptosis than control coinjections, and upregulation of MCT4 by CS exposure was a driver of these effects. We demonstrate that a tumor microenvironment exposed to CS is sufficient to modulate metabolism and cancer aggressiveness in HNSCC.

Implications:
CS shifts cancer stroma toward glycolysis and induces head and neck cancer aggressiveness with a mitochondrial profile linked by catabolite transporters and oxidative stress.

Visual Overview:
http://mcr.aacrjournals.org/content/molcanres/17/9/1893/F1.large.jpg.
Breast Hyperplasias, Risk Signature, and Breast Cancer
Authors: Poola Indira , Yue Qingqi , Gillespie John W. , Sullivan Peggy S. , Aguilar-Jakthong Josephine , Rao JianYu , Shaaban Abeer M. , Sauter Edward R. , Ricci Andrew J. 
Published: June 2019

Abstract
We address the dilemma faced by oncologists in administering preventative measures to “at risk” patients diagnosed with atypical and nonatypical hyperplasias due to lack of any molecular means of risk stratification and identifying high-risk subjects. Our study purpose is to investigate a four marker risk signature, MMP-1, CEACAM6, HYAL1, and HEC1, using 440 hyperplastic tissues for identifying high-risk subjects who will benefit from preventative therapies. We assayed the markers by IHC and combined their expression levels to obtain a composite value from 0–10, which we called a “Cancer Risk Score.” We demonstrate that the four marker-based risk scores predict subsequent cancer development with an accuracy of 91% and 86% for atypical and nonatypical subjects, respectively. We have established a correlation between risk scores and cancer rates by stratifying the samples into low risk (score ≤ 0.5); intermediate risk (score ≤ 5.4), and high risk (score &gt;5.4) groups using Kaplan–Meier survival analysis. We have evaluated cancer rates at 5, 10, and 15 years. Our results show that the average cancer rates in the first 5 years among low- and intermediate-risk groups were 2% and 15%, respectively. Among high-risk group, the average cancer rates at 5 years were 73% and 34% for atypical and nonatypical subjects, respectively. The molecular risk stratification described here assesses a patient's tumor biology–based risk level as low, intermediate, or high and for making informed treatment decisions. The outcomes of our study in conjunction with the available prophylactic measures could prevent approximately 20%–25% of sporadic breast cancers.
Anti–CTLA-4 Activates Intratumoral NK Cells and Combined with IL15/IL15Rα Complexes Enhances Tumor Control
Authors: Sanseviero Emilio , O’Brien Erin M. , Karras Jenna R. , Shabaneh Tamer B. , Aksoy Bulent Arman , Xu Wei , Zheng Cathy , Yin Xiangfan , Xu Xiaowei , Karakousis Giorgos C. , Amaravadi Ravi K. , Nam Brian , Turk Mary Jo , Hammerbacher Jeff , Rubinstein Mark P. , Schuchter Lynn M. , Mitchell Tara C. , Liu Qin , Stone Erica L. 
Published: June 2019

Abstract
Antibodies targeting CTLA-4 induce durable responses in some patients with melanoma and are being tested in a variety of human cancers. However, these therapies are ineffective for a majority of patients across tumor types. Further understanding the immune alterations induced by these therapies may enable the development of novel strategies to enhance tumor control and biomarkers to identify patients most likely to respond. In several murine models, including colon26, MC38, CT26, and B16 tumors cotreated with GVAX, anti–CTLA-4 efficacy depends on interactions between the Fc region of CTLA-4 antibodies and Fc receptors (FcR). Anti–CTLA-4 binding to FcRs has been linked to depletion of intratumoral T regulatory cells (Treg). In agreement with previous studies, we found that Tregs infiltrating CT26, B16-F1, and autochthonous BrafV600EPten−/− melanoma tumors had higher expression of surface CTLA-4 (sCTLA-4) than other T-cell subsets, and anti–CTLA-4 treatment led to FcR-dependent depletion of Tregs infiltrating CT26 tumors. This Treg depletion coincided with activation and degranulation of intratumoral natural killer cells. Similarly, in non–small cell lung cancer (NSCLC) and melanoma patient-derived tumor tissue, Tregs had higher sCTLA-4 expression than other intratumoral T-cell subsets, and Tregs infiltrating NSCLC expressed more sCTLA-4 than circulating Tregs. Patients with cutaneous melanoma who benefited from ipilimumab, a mAb targeting CTLA-4, had higher intratumoral CD56 expression, compared with patients who received little to no benefit from this therapy. Furthermore, using the murine CT26 model we found that combination therapy with anti–CTLA-4 plus IL15/IL15Rα complexes enhanced tumor control compared with either monotherapy.
IRF1 Inhibits Antitumor Immunity through the Upregulation of PD-L1 in the Tumor Cell
Authors: Shao Lulu , Hou Weizhou , Scharping Nicole E. , Vendetti Frank P. , Srivastava Rashmi , Roy Chandra Nath , Menk Ashley V. , Wang Yiyang , Chauvin Joe-Marc , Karukonda Pooja , Thorne Stephen H. , Hornung Veit , Zarour Hassane M. , Bakkenist Christopher J. , Delgoffe Greg M. , Sarkar Saumendra N. 
Published: June 2019

Abstract
Multiple studies have associated the transcription factor IRF1 with tumor-suppressive activities. Here, we report an opposite tumor cell–intrinsic function of IRF1 in promoting tumor growth. IRF1-deficient tumor cells showed reduced tumor growth in MC38 and CT26 colon carcinoma and B16 melanoma mouse models. This reduction in tumor growth was dependent on host CD8+ T cells. Detailed profiling of tumor-infiltrating leukocytes did not show changes in the various T-cell and myeloid cell populations. However, CD8+ T cells that had infiltrated IRF1-deficieint tumors in vivo exhibited enhanced cytotoxicity. IRF1-deficient tumor cells lost the ability to upregulate PD-L1 expression in vitro and in vivo and were more susceptible to T-cell–mediated killing. Induced expression of PD-L1 in IRF1-deficient tumor cells restored tumor growth. These results indicate differential activity of IRF1 in tumor escape.
Use of Genetic Variants Related to Antihypertensive Drugs to Inform on Efficacy and Side Effects
Authors: Gill Dipender , Georgakis Marios K. , Koskeridis Fotios , Jiang Lan , Feng Qiping , Wei Wei-Qi , Theodoratou Evropi , Elliott Paul , Denny Joshua C. , Malik Rainer , Evangelou Evangelos , Dehghan Abbas , Dichgans Martin , Tzoulaki Ioanna 
Published: June 2019

Background:
Drug effects can be investigated through natural variation in the genes for their protein targets. The present study aimed to use this approach to explore the potential side effects and repurposing potential of antihypertensive drugs, which are among the most commonly used medications worldwide.

Methods:
Genetic proxies for the effect of antihypertensive drug classes were identified as variants in the genes for the corresponding targets that associated with systolic blood pressure at genome-wide significance. Mendelian randomization estimates for drug effects on coronary heart disease and stroke risk were compared with randomized, controlled trial results. A phenome-wide association study in the UK Biobank was performed to identify potential side effects and repurposing opportunities, with findings investigated in the Vanderbilt University biobank (BioVU) and in observational analysis of the UK Biobank.

Results:
Suitable genetic proxies for angiotensin-converting enzyme inhibitors, β-blockers, and calcium channel blockers (CCBs) were identified. Mendelian randomization estimates for their effect on coronary heart disease and stroke risk, respectively, were comparable to results from randomized, controlled trials against placebo. A phenome-wide association study in the UK Biobank identified an association of the CCB standardized genetic risk score with increased risk of diverticulosis (odds ratio, 1.02 per standard deviation increase; 95% CI, 1.01–1.04), with a consistent estimate found in BioVU (odds ratio, 1.01; 95% CI, 1.00–1.02). Cox regression analysis of drug use in the UK Biobank suggested that this association was specific to nondihydropyridine CCBs (hazard ratio 1.49 considering thiazide diuretic agents as a comparator; 95% CI, 1.04–2.14) but not dihydropyridine CCBs (hazard ratio, 1.04; 95% CI, 0.83–1.32).

Conclusions:
Genetic variants can be used to explore the efficacy and side effects of antihypertensive medications. The identified potential effect of nondihydropyridine CCBs on diverticulosis risk could have clinical implications and warrants further investigation.
C
2
HEST Score and Prediction of Incident Atrial Fibrillation in Poststroke Patients: A French Nationwide Study
Authors: Li Yan‐Guang , Bisson Arnaud , Bodin Alexandre , Herbert Julien , Grammatico‐Guillon Leslie , Joung Boyoung , Wang Yu‐Tang , Lip Gregory Y. H. , Fauchier Laurent 
Published: June 2019

Background

The C
2
HEST score (coronary artery disease or chronic obstructive pulmonary disease [1 point each]; hypertension [1 point]; elderly [age ≥75 years, 2 points]; systolic heart failure [2 points]; thyroid disease [hyperthyroidism, 1 point]) was initially proposed for predicting incident atrial fibrillation (AF) in the general population. Its performance in poststroke patients remains to be established, especially because patients at high risk for incident AF should be targeted for more comprehensive screening. This study aimed to evaluate this newly established incident AF prediction risk score in a post–ischemic stroke population.

Methods and Results

Validation was based on a hospital‐based nationwide cohort with 240 459 French post–ischemic stroke patients. Kaplan–Meier curves for incident rate of AF depict differences between varying risk categories. Discrimination of the C
2
HEST score was evaluated using the C index, the net reclassification index, integrated discriminatory improvement, and decision curve analysis. During 7.9±11.5 months of follow‐up, 14 095 patients developed incident AF. The incidence of AF increased from 23.5 per 1000 patient‐years in patients with a C
2
HEST score of 0 to 196.8 per 1000 patient‐years in patients with a C
2
HEST score ≥6. Kaplan–Meier curves showed a clear difference among different risk strata (log‐rank
P
<0.0001). The C
2
HEST score had good discrimination with a C index of 0.734 (95% CI, 0.732–0.736), which was better than the Framingham risk score and the CHA
2
DS
2
‐VASc score (congestive heart failure, hypertension, age ≥75 [doubled], diabetes mellitus, stroke [doubled], vascular disease, age 65 to 74 years, and female sex) (
P
<0.0001, respectively). The C
2
HEST score was also superior to the Framingham risk score and the CHA
2
DS
2
‐VASc score as shown by the net reclassification index, integrated discriminatory improvement (
P
<0.0001, respectively) and decision curve analysis.

Conclusions

The C
2
HEST score performed well in discriminating the individual risk of developing incident AF in a white European population hospitalized with previous ischemic stroke. This simple score may potentially be used as a risk stratification tool for decision making in relation to a screening strategy for AF in post–ischemic stroke patients.