bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Cytochrome P450 Slow Metabolizers CYP2C9*2 and CYP2C9*3 Directly Regulate Tumorigenesis via Reduced Epoxyeicosatrienoic Acid Production
Authors: Sausville Lindsay N. , Gangadhariah Mahesha H. , Chiusa Manuel , Mei Shaojun , Wei Shouzuo , Zent Roy , Luther James M. , Shuey Megan M. , Capdevila Jorge H. , Falck John R. , Guengerich F. Peter , Williams Scott M. , Pozzi Ambra 
Published: July 2018

Abstract
Increased expression of cytochrome P450 CYP2C9, together with elevated levels of its products epoxyeicosatrienoic acids (EET), is associated with aggressiveness in cancer. Cytochrome P450 variants CYP2C9*2 and CYP2C9*3 encode proteins with reduced enzymatic activity, and individuals carrying these variants metabolize drugs more slowly than individuals with wild-type CYP2C9*1, potentially affecting their response to drugs and altering their risk of disease. Although genetic differences in CYP2C9-dependent oxidation of arachidonic acid (AA) have been reported, the roles of CYP2C9*2 and CYP2C9*3 in EET biosynthesis and their relevance to disease are unknown. Here, we report that CYP2C9*2 and CYP2C9*3 metabolize AA less efficiently than CYP2C9*1 and that they play a role in the progression of non–small cell lung cancer (NSCLC) via impaired EET biosynthesis. When injected into mice, NSCLC cells expressing CYP2C9*2 and CYP2C9*3 produced lower levels of EETs and developed fewer, smaller, and less vascularized tumors than cells expressing CYP2C9*1. Moreover, endothelial cells expressing these two variants proliferated and migrated less than cells expressing CYP2C*1. Purified CYP2C9*2 and CYP2C9*3 exhibited attenuated catalytic efficiency in producing EETs, primarily due to impaired reduction of these two variants by NADPH-P450 reductase. Loss-of-function SNPs within CYP2C9*2 and CYP2C9*3 were associated with improved survival in female cases of NSCLC. Thus, decreased EET biosynthesis represents a novel mechanism whereby CYPC29*2 and CYP2C9*3 exert a direct protective role in NSCLC development.
Significance: These findings report single nucleotide polymorphisms in the human CYP2C9 genes, CYP2C9*2 and CYP2C9*3, exert a direct protective role in tumorigenesis by impairing EET biosynthesis. Cancer Res; 78(17); 4865–77. ©2018 AACR.
Activation of NKT Cells in an Anti-PD-1–Resistant Tumor Model Enhances Antitumor Immunity by Reinvigorating Exhausted CD8 T Cells
Authors: Bae Eun-Ah , Seo Hyungseok , Kim Byung-Seok , Choi Jeongwon , Jeon Insu , Shin Kwang-Soo , Koh Choong-Hyun , Song Boyeong , Kim Il-Kyu , Min Byung Soh , Han Yoon Dae , Shin Sang Joon , Kang Chang-Yuil 
Published: July 2018

Abstract
PD-1–based cancer immunotherapy is a successful example of immune checkpoint blockade that provides long-term durable therapeutic effects in patients with cancer across a wide spectrum of cancer types. Accumulating evidence suggests that anti-PD-1 therapy enhances antitumor immunity by reversing the function of exhausted T cells in the tumor environment. However, the responsiveness rate of patients with cancer to anti-PD-1 therapy remains low, providing an urgent need for optimization and improvement. In this study, we designed an anti-PD-1–resistant mouse tumor model and showed that unresponsiveness to anti-PD-1 is associated with a gradual increase in CD8 T-cell exhaustion. We also found that invariant natural killer T cell stimulation by the synthetic ligand α-galactosylceramide (αGC) can enhance the antitumor effect in anti-PD-1–resistant tumors by restoring the effector function of tumor antigen–specific exhausted CD8 T cells. IL2 and IL12 were among the cytokines produced by αGC stimulation critical for reinvigorating exhausted CD8 T cells in tumor-bearing mice and patients with cancer. Furthermore, we observed a synergistic increase in the antitumor effect between αGC-loaded antigen-presenting cells and PD-1 blockade in a therapeutic murine tumor model. Our study suggests NKT cell stimulation as a promising therapeutic strategy for the treatment of patients with anti-PD-1–resistant cancer.
Significance: These findings provide mechanistic insights into the application of NKT cell stimulation as a potent adjuvant for immunotherapy against advanced cancer. Cancer Res; 78(18); 5315–26. ©2018 AACR.
Activating Transcription Factor 4 Modulates TGFβ-Induced Aggressiveness in Triple-Negative Breast Cancer via SMAD2/3/4 and mTORC2 Signaling
Authors: González-González Adrián , Muñoz-Muela Esperanza , Marchal Juan A. , Cara Francisca E. , Molina Maria P. , Cruz-Lozano Marina , Jiménez Gema , Verma Akanksha , Ramírez Alberto , Qian Wei , Chen Wen , Kozielski Anthony J. , Elemento Olivier , Martín-Salvago María D. , Luque Rafael J. , Rosa-Garrido Carmen , Landeira David , Quintana-Romero María , Rosato Roberto R. , García Maria A. , Ramirez-Tortosa Cesar L. , Kim Hanna , Rodriguez-Aguayo Cristian , Lopez-Berestein Gabriel , Sood Anil K. , Lorente Jose A. , Sánchez-Rovira Pedro , Chang Jenny C. , Granados-Principal Sergio 
Published: July 2018

Abstract
Purpose: On the basis of the identified stress-independent cellular functions of activating transcription factor 4 (ATF4), we reported enhanced ATF4 levels in MCF10A cells treated with TGFβ1. ATF4 is overexpressed in patients with triple-negative breast cancer (TNBC), but its impact on patient survival and the underlying mechanisms remain unknown. We aimed to determine ATF4 effects on patients with breast cancer survival and TNBC aggressiveness, and the relationships between TGFβ and ATF4. Defining the signaling pathways may help us identify a cell signaling–tailored gene signature.
Experimental Design: Patient survival data were determined by Kaplan–Meier analysis. Relationship between TGFβ and ATF4, their effects on aggressiveness (tumor proliferation, metastasis, and stemness), and the underlying pathways were analyzed in three TNBC cell lines and in vivo using patient-derived xenografts (PDX).
Results: ATF4 overexpression correlated with TNBC patient survival decrease and a SMAD-dependent crosstalk between ATF4 and TGFβ was identified. ATF4 expression inhibition reduced migration, invasiveness, mammosphere-forming efficiency, proliferation, epithelial–mesenchymal transition, and antiapoptotic and stemness marker levels. In PDX models, ATF4 silencing decreased metastases, tumor growth, and relapse after chemotherapy. ATF4 was shown to be active downstream of SMAD2/3/4 and mTORC2, regulating TGFβ/SMAD and mTOR/RAC1–RHOA pathways independently of stress. We defined an eight-gene signature with prognostic potential, altered in 45% of 2,509 patients with breast cancer.
Conclusions: ATF4 may represent a valuable prognostic biomarker and therapeutic target in patients with TNBC, and we identified a cell signaling pathway–based gene signature that may contribute to the development of combinatorial targeted therapies for breast cancer. Clin Cancer Res; 24(22); 5697–709. ©2018 AACR.
IFNL4-ΔG Allele Is Associated with an Interferon Signature in Tumors and Survival of African-American Men with Prostate Cancer
Authors: Tang Wei , Wallace Tiffany A. , Yi Ming , Magi-Galluzzi Cristina , Dorsey Tiffany H. , Onabajo Olusegun O. , Obajemu Adeola , Jordan Symone V. , Loffredo Christopher A. , Stephens Robert M. , Silverman Robert H. , Stark George R. , Klein Eric A. , Prokunina-Olsson Ludmila , Ambs Stefan 
Published: July 2018

Abstract
Purpose: Men of African ancestry experience an excessive prostate cancer mortality that could be related to an aggressive tumor biology. We previously described an immune-inflammation signature in prostate tumors of African-American (AA) patients. Here, we further deconstructed this signature and investigated its relationships with tumor biology, survival, and a common germline variant in the IFNλ4 (IFNL4) gene.
Experimental Design: We analyzed gene expression in prostate tissue datasets and performed genotype and survival analyses. We also overexpressed IFNL4 in human prostate cancer cells.
Results: We found that a distinct interferon (IFN) signature that is analogous to the previously described “IFN-related DNA damage resistance signature” (IRDS) occurs in prostate tumors. Evaluation of two independent patient cohorts revealed that IRDS is detected about twice as often in prostate tumors of AA than European-American men. Furthermore, analysis in TCGA showed an association of increased IRDS in prostate tumors with decreased disease-free survival. To explain these observations, we assessed whether IRDS is associated with an IFNL4 germline variant (rs368234815-ΔG) that controls production of IFNλ4, a type III IFN, and is most common in individuals of African ancestry. We show that the IFNL4 rs368234815-ΔG allele was significantly associated with IRDS in prostate tumors and overall survival of AA patients. Moreover, IFNL4 overexpression induced IRDS in three human prostate cancer cell lines.
Conclusions: Our study links a germline variant that controls production of IFNλ4 to the occurrence of a clinically relevant IFN signature in prostate tumors that may predominantly affect men of African ancestry. Clin Cancer Res; 24(21); 5471–81. ©2018 AACR.
Evolutionary Expression of HER2 Conferred by Chromosome Aneuploidy on Circulating Gastric Cancer Cells Contributes to Developing Targeted and Chemotherapeutic Resistance
Authors: Li Yilin , Zhang Xiaotian , Liu Dan , Gong Jifang , Wang Daisy Dandan , Li Shan , Peng Zhi , Li Yanyan , Wang Xiaojuan , Lin Peter Ping , Li Min , Shen Lin 
Published: July 2018

Abstract
Purpose: Previous human epidermal growth factor receptor-2 (HER2)-derived resistance studies were based on ex vivo models, which could not mirror evolutionary expression of HER2 during therapy. To investigate dynamic expression of HER2 and its contribution to developing therapeutic resistance conferred by chromosome aneuploidy, both the HER2 phenotype and chromosome 8 (Chr 8) aneuploidy on circulating tumor cells (CTC) were coexamined in advanced gastric cancer (AGC) patients.
Experimental Design: A total of 115 AGC patients, including 56 of histopathologic HER2+ (hHER2+) subjects who received first-line HER2-targeted therapy plus chemotherapy, and 59 of hHER2− patients who received chemotherapy alone, were prospectively enrolled. Both HER2 phenotype and Chr8 aneuploidy of CTCs in patients were coexamined by HER2-iFISH during therapy.
Results: A fluctuated positive HER2 phenotype on CTCs (cHER2+) was revealed, showing cHER2+ at different time intervals during treatment. Acquisition of the cHER2+ phenotype in 91.0% of hHER2+ and 76.2% hHER2− patients was demonstrated to correlate with development of resistance to trastuzumab-targeted therapy for hHER2+ patients and chemotherapy alone for hHER2− patients. Aneuploid Chr8 was demonstrated to participate in the acquisition of the cHER2+ phenotype, which provides a growth advantage to HER2+ CTCs against therapeutic pressure, leading to the development of therapeutic resistance.
Conclusions: Compared with low positivity of conventional histopathologic hHER2 examination routinely performed once, significant higher positivity of cHER2+ on CTCs was observed. Continuously examining cHER2 shows unique advantages with respect to monitoring therapeutic resistance in real time in carcinoma patients. Moreover, contribution of chromosome aneuploidy to the phenotypic evolution of HER2 expression on CTCs may help elucidate underlying mechanisms of developing therapeutic resistance. Clin Cancer Res; 24(21); 5261–71. ©2018 AACR.
Cost-Effectiveness of Quantitative Magnetic Resonance Angiography Screening and Submaximal Angioplasty for Symptomatic Vertebrobasilar Disease
Authors: Esfahani Darian R. , Pandey Dilip , Du Xinjian , Rose-Finnell Linda , Charbel Fady T. , Derdeyn Colin P. , Amin-Hanjani Sepideh ,   on behalf of the VERiTAS Study Group
Published: July 2018

Background and Purpose—
The VERiTAS (Vertebrobasilar Flow Evaluation and Risk of Transient Ischemic Attack and Stroke) study demonstrated posterior circulation distal flow status, determined by quantitative magnetic resonance angiography, is a robust predictor of vertebrobasilar stroke risk in patients with symptomatic atherosclerotic vertebrobasilar disease. Flow-compromised high-risk patients may benefit from flow-restoring endovascular procedures, such as submaximal angioplasty. In this study, we examine the cost-effectiveness of quantitative magnetic resonance angiography screening to identify patients who may benefit from submaximal angioplasty to restore vertebrobasilar flow.

Methods—
A Markov model was created comparing a no screening strategy with standard medical management alone and a screening strategy involving quantitative magnetic resonance angiography imaging and submaximal angioplasty for treatable patients with low vertebrobasilar flow for a 30-year time horizon. Outcomes included quality-adjusted life years (QALY) and lifetime costs. Rates of stroke and death were obtained from VERiTAS data, and disability rates and costs were derived from VERiTAS and the literature. A sensitivity analysis was performed with periprocedural stroke rate from angioplasty the primary variable of interest.

Results—
At a 6% periprocedural stroke risk, the screening strategy saved an average of 0.364 QALYs per patient and a lifetime cost savings of $7312 versus the no screening strategy. Among patients with low flow suitable for intervention, the benefit was substantially higher, averaging 1.485 QALYs saved and lifetime cost savings of $21 294. Across the entire cohort, QALY savings were observed at the end of the first year and economic savings at year 6. The benefit of screening declined at higher periprocedural risk.

Conclusions—
Quantitative magnetic resonance angiography screening and submaximal angioplasty with 6% periprocedural risk in suitable patients are cost effective both in terms of QALY and lifetime costs for patients with symptomatic vertebrobasilar occlusive disease. With potential health and economic savings, a clinical trial examining the periprocedural risk of submaximal angioplasty is warranted.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00590980.
Affordable Rotating Fluid Demonstrations for Geoscience Education: The DIYnamics Project
Authors: Hill Spencer A. , Lora Juan M. , Khoo Norris , Faulk Sean P. , Aurnou Jonathan M. 
Published: July 2018

AbstractDemonstrations using rotating tanks of fluid can help demystify otherwise counterintuitive behaviors of atmospheric, oceanic, and planetary interior fluid motions. But the expense and complicated assembly of existing rotating table platforms limit their appeal for many schools, especially those below the university level. Here, we introduce Do-It-Yourself Dynamics (DIYnamics), a project developing extremely low-cost rotating tank platforms and accompanying teaching materials. The devices can be assembled in a few minutes from household items, all available for purchase online. Ordering, assembly, and operation instructions are available on the DIYnamics website. Videos using these and other rotating tables to teach specific concepts such as baroclinic instability are available on the DIYnamics YouTube channel—including some in Spanish. The devices, lesson plans, and demonstrations have been successfully piloted at multiple middle schools, in a university course, and at public science outreach events. These uses to date convince us of the DIYnamics materials’ pedagogical value for instructors from well-versed university professors to K–12 science teachers with little background in fluid dynamics.
Investigating the Relative Contributions of Charge Deposition and Turbulence in Organizing Charge within a Thunderstorm
Authors: Brothers Matthew D. , Bruning Eric C. , Mansell Edward R. 
Published: July 2018

Abstract
Large-eddy-resolving simulations using the Collaborative Model for Multiscale Atmospheric Simulation (COMMAS), which contains microphysical charging and branched-lightning parameterizations, produce much more complex net charge structures than conventionally visualized from previous observations, simulations, and conceptual diagrams. Many processes contribute to the hydrometeor charge budget within a thunderstorm, including advection, hydrometeor differential sedimentation, subgrid turbulent mixing and diffusion, ion drift, microphysical separation, and the attachment of ion charge deposited by the lightning channel. The lightning deposition, sedimentation, and noninductive charging tendencies contribute the most overall charge at relatively large scales, while the advection tendency, from resolved turbulence, provides the most “texture” at small scales to the net charge density near the updraft region of the storm. The scale separation increases for stronger storm simulations. In aggregate, lightning deposition and sedimentation resemble the smoother distribution of the electric potential, while evidence suggests individual flashes could be responding to the fine texture in the net charge. The clear scale separation between the advection and other net charge tendencies suggest the charge advection is most capable of providing net charge texture; however, a clear-cut causality is not obtained from this study.
Development and Implementation of an End-of-Life Curriculum for Pediatric Residents
Authors: Wilson Paria M. , Herbst Lori A. , Gonzalez-del-Rey Javier 
Published: July 2018

Background: Caring for a child near the end of life (EOL) can be a stressful experience. Resident physicians are often the frontline providers responsible for managing symptoms, communicating difficult information, and pronouncing death, yet they often receive minimal education on EOL care. Objective: To develop and implement an EOL curriculum and to study its impact on resident comfort and attitudes surrounding EOL care. Design: Kern’s 6-step approach to curriculum development was used as a framework for curriculum design and implementation. Setting/Participants: Categorical and combined pediatric residents at a large quaternary care children’s hospital were exposed to the curriculum. Measurements: A cross-sectional survey was distributed pre- and postimplementation of the curriculum to evaluate its impact on resident comfort and attitudes surrounding EOL care. Results: One-hundred twenty-six (49%) of 258 residents completed the preimplementation survey, and 65 (32%) of 201 residents completed the postimplementation survey. Over 80% of residents reported caring for a dying patient, yet less than half the residents reported receiving prior education on EOL care. Following curriculum implementation, the percentage of residents dissatisfied with their EOL education fell from 36% to 14%, while the percentage of residents satisfied with their education increased from 14% to 29%. The postimplementation survey identified that resident comfort with communication-based topics improved, and they sought additional training in symptom management. Conclusions: The implementation of a longitudinal targeted multimodal EOL curriculum improved resident satisfaction with EOL education and highlighted the need for additional EOL education.
Catecholamine and Indolamine Pathway: A Case–Control Study in Fibromyalgia
Authors: Rus Alma , Molina Francisco , Del Moral María Luisa , Ramírez-Expósito María Jesús , Martínez-Martos José Manuel 
Published: July 2018

Objectives:Fibromyalgia (FM) is a complex syndrome characterized by widespread pain. Its etiology is unclear, and diagnosis is difficult. The aim of this study was to assess plasma levels of monoamine neurotransmitters (catecholamines, indolamines, and intermediate metabolites) in patients with FM and healthy controls to investigate possible alterations in the metabolism of these molecules in FM. We also examined potential relationships between monoamine neurotransmitters and clinical features of FM. The predictive value of these molecules in FM was determined by receiver operating characteristic analysis.Method:We measured plasma catecholamines (epinephrine, norepinephrine, and dopamine), as well as indolamines and intermediary metabolites (serotonin or 5-hydroxytryptamine [5-HT], 5-hydroxyindolacetic acid [5-HIAA], 5-hydroxytryptophan [5-HTP], and N-acetyl-5-hydroxytryptamine [Nac-5-HT]) in 35 women with FM and 12 age-matched healthy women.Results:Higher levels of norepinephrine and lower levels of dopamine, 5-HT, 5-HIAA, and 5-HTP were found in women with FM in comparison with controls. Epinephrine and Nac-5-HT levels did not differ significantly between groups. Higher norepinephrine levels were associated with worse physical health status in FM patients. Also, plasma norepinephrine levels > 694.69 pg/ml might be an accurate predictor of FM.Conclusions:These findings show evidence of the dysregulation of the catecholamine and indolamine pathway in patients with FM, which may contribute to the physiopathology of this syndrome. In addition, the determination of plasma norepinephrine levels could help in the FM diagnosis.
A Langendorff-like system to quantify cardiac pump function in adult zebrafish
Authors: Zhang Hong , Dvornikov Alexey V. , Huttner Inken G. , Ma Xiao , Santiago Celine F. , Fatkin Diane , Xu Xiaolei 
Published: July 2018

ABSTRACT
Zebrafish are increasingly used as a vertebrate model to study human cardiovascular disorders. Although heart structure and function are readily visualized in zebrafish embryos because of their optical transparency, the lack of effective tools for evaluating the hearts of older, nontransparent fish has been a major limiting factor. The recent development of high-frequency echocardiography has been an important advance for in vivo cardiac assessment, but it necessitates anesthesia and has limited ability to study acute interventions. We report the development of an alternative experimental ex vivo technique for quantifying heart size and function that resembles the Langendorff heart preparations that have been widely used in mammalian models. Dissected adult zebrafish hearts were perfused with a calcium-containing buffer, and a beat frequency was maintained with electrical stimulation. The impact of pacing frequency, flow rate and perfusate calcium concentration on ventricular performance (including end-diastolic and end-systolic volumes, ejection fraction, radial strain, and maximal velocities of shortening and relaxation) were evaluated and optimal conditions defined. We determined the effects of age on heart function in wild-type male and female zebrafish, and successfully detected hypercontractile and hypocontractile responses after adrenergic stimulation or doxorubicin treatment, respectively. Good correlations were found between indices of cardiac contractility obtained with high-frequency echocardiography and with the ex vivo technique in a subset of fish studied with both methods. The ex vivo beating heart preparation is a valuable addition to the cardiac function tool kit that will expand the use of adult zebrafish for cardiovascular research.