bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nodal Signaling as a Developmental Therapeutics Target in Oncology
Authors: Kalyan Aparna , Carneiro Benedito A. , Chandra Sunandana , Kaplan Jason , Chae Young Kwang , Matsangou Maria , Hendrix Mary J.C. , Giles Francis 
Published: May 2017

Abstract
The tumor microenvironment is a vital feature of oncogenesis and tumor progression. There are several parallels between cancer cells and early developmental stem cells, including their plasticity and signaling mechanisms. In early fetal development, Nodal is expressed for endodermal and mesodermal differentiation. This expression has been shown reemerge in the setting of epithelial cancers, such as breast and melanoma. High Nodal expression correlates to an aggressive tumor grade in these malignancies. Nodal signal begins with its interaction with its coreceptor, Cripto-1, leading to activation of Smad2/Smad3 and ultimately downstream transcription and translation. Lefty is the natural inhibitor of Nodal and controls Nodal signaling during fetal development. However, cancer cells lack the presence of Lefty, thus leading to uncontrolled tumor growth. Given this understanding, inhibition of the Nodal pathway offers a new novel therapeutic target in oncology. Mol Cancer Ther; 16(5); 787–92. ©2017 AACR.
Combined Inhibition of NEDD8-Activating Enzyme and mTOR Suppresses NF2 Loss–Driven Tumorigenesis
Authors: Cooper Jonathan , Xu Qingwen , Zhou Lu , Pavlovic Milica , Ojeda Virginia , Moulick Kamalika , de Stanchina Elisa , Poirier John T. , Zauderer Marjorie , Rudin Charles M. , Karajannis Matthias A. , Hanemann C. Oliver , Giancotti Filippo G. 
Published: May 2017

Abstract
Inactivation of NF2/Merlin causes the autosomal-dominant cancer predisposition syndrome familial neurofibromatosis type 2 (NF2) and contributes to the development of malignant pleural mesothelioma (MPM). To develop a targeted therapy for NF2-mutant tumors, we have exploited the recent realization that Merlin loss drives tumorigenesis by activating the E3 ubiquitin ligase CRL4DCAF1, thereby inhibiting the Hippo pathway component Lats. Here, we show that MLN4924, a NEDD8-activating enzyme (NAE) inhibitor, suppresses CRL4DCAF1 and attenuates activation of YAP in NF2-mutant tumor cells. In addition, MLN4924 sensitizes MPM to traditional chemotherapy, presumably as a result of collateral inhibition of cullin-RING ubiquitin ligases (CRL) involved in DNA repair. However, even in combination with chemotherapy, MLN4924 does not exhibit significant preclinical activity. Further analysis revealed that depletion of DCAF1 or treatment with MLN4924 does not affect mTOR hyperactivation in NF2-mutant tumor cells, suggesting that loss of Merlin activates mTOR independently of CRL4DCAF1. Intriguingly, combining MLN4924 with the mTOR/PI3K inhibitor GDC-0980 suppresses the growth of NF2-mutant tumor cells in vitro as well as in mouse and patient-derived xenografts. These results provide preclinical rationale for the use of NAE inhibitors in combination with mTOR/PI3K inhibitors in NF2-mutant tumors.
Risk for Incident Heart Failure: A Subject‐Level Meta‐Analysis From the Heart “OMics” in AGEing (HOMAGE) Study
Authors: Jacobs Lotte , Efremov Ljupcho , Ferreira João Pedro , Thijs Lutgarde , Yang Wen‐Yi , Zhang Zhen‐Yu , Latini Roberto , Masson Serge , Agabiti Nera , Sever Peter , Delles Christian , Sattar Naveed , Butler Javed , Cleland John G. F. , Kuznetsova Tatiana , Staessen Jan A. , Zannad Faiez , Pinet Florence , Pizard Anne , Rouet Philippe , Leenders Joost , Diez Javier , Odili Augustine , Wei Fang‐Fei , Newman Anne , Papadimitrious Lampros , Davoli Marina , Mureddu Gian Francesco , Ford Ian , Jukema Wouter , Stott David J. , Poulter Neil 
Published: May 2017

Background
To address the need for personalized prevention, we conducted a subject‐level meta‐analysis within the framework of the Heart “OMics” in AGEing (HOMAGE) study to develop a risk prediction model for heart failure (HF) based on routinely available clinical measurements.

Methods and Results

Three studies with elderly persons (Health Aging and Body Composition [Health ABC],
Valutazione della PREvalenza di DIsfunzione Cardiaca asinTOmatica e di scompenso cardiaco
[PREDICTOR], and Prospective Study of Pravastatin in the Elderly at Risk [PROSPER]) were included to develop the
HF
risk function, while a fourth study (Anglo‐Scandinavian Cardiac Outcomes Trial [ASCOT]) was used as a validation cohort. Time‐to‐event analysis was conducted using the Cox proportional hazard model. Incident
HF
was defined as
HF
hospitalization. The Cox regression model was evaluated for its discriminatory performance (area under the receiver operating characteristic curve) and calibration (Grønnesby‐Borgan χ
2
statistic). During a follow‐up of 3.5 years, 470 of 10 236 elderly persons (mean age, 74.5 years; 51.3% women) developed
HF
. Higher age, BMI, systolic blood pressure, heart rate, serum creatinine, smoking, diabetes mellitus, history of coronary artery disease, and use of antihypertensive medication were associated with increased
HF
risk. The area under the receiver operating characteristic curve of the model was 0.71, with a good calibration (χ
2
7.9,
P
=0.54). A web‐based calculator was developed to allow easy calculations of the
HF
risk.

Conclusions

Simple measurements allow reliable estimation of the short‐term
HF
risk in populations and patients. The risk model may aid in risk stratification and future
HF
prevention strategies.
Projected Future Changes of Tropical Cyclone Activity over the Western North and South Pacific in a 20-km-Mesh Regional Climate Model
Authors: Zhang Chunxi , Wang Yuqing 
Published: May 2017

AbstractA high-resolution regional atmospheric model is employed to project the late twenty-first-century changes of tropical cyclone (TC) activity over the western North Pacific (WP) and southwest Pacific (SP). The model realistically reproduces the basic features of the TC climatology in the present-day simulation. Future projections under the representative concentration pathway 4.5 (RCP45) and 8.5 (RCP85) scenarios are investigated. The results show no significant change of TC genesis frequency (TCGF) in the WP by RCP45 due to the cancellation of the reduction over the western part and the increase over the eastern part together with a considerable decrease of TCGF by RCP85 due to the excessive TCGF reduction in the western part. The TCGF over the SP consistently decreases from RCP45 to RCP85. Despite the fact that the simulated maximum surface wind speeds are below 52 m s−1, the change with more strong TCs and fewer weak TCs is robust. The future changes in the TC genesis locations and translational speeds modulate the TC lifetime and frequency of occurrence. The TC genesis potential index (GPI) is used to evaluate the projected TCGF changes. The results show that low-level vorticity and midtropospheric vertical velocity largely contribute to the reduction of GPI in the western part of the WP, while vertical wind shear and midtropospheric vertical velocity mainly contribute to the decrease of GPI over the SP. The weakening of the monsoon trough is found to be responsible for the decreases of GPI and TCGF over the western part of the WP.
Estimation of the Tropical Pacific Ocean State 2010–13
Authors: Verdy Ariane , Cornuelle Bruce , Mazloff Matthew R. , Rudnick Daniel L. 
Published: May 2017

AbstractA data-assimilating ⅓° regional dynamical ocean model is evaluated on its ability to synthesize components of the Tropical Pacific Ocean Observing System. The four-dimensional variational data assimilation (4DVAR) method adjusts initial conditions and atmospheric forcing for overlapping 4-month model runs, or hindcasts, that are then combined to give an ocean state estimate for the period 2010–13. Consistency within uncertainty with satellite SSH and Argo profiles is achieved. Comparison to independent observations from Tropical Atmosphere Ocean (TAO) moorings shows that for time scales shorter than 100 days, the state estimate improves estimates of TAO temperature relative to an optimally interpolated Argo product. The improvement is greater at time scales shorter than 20 days, although unpredicted variability in the TAO temperatures implies that TAO observations provide significant information in that band. Larger discrepancies between the state estimate and independent observations from Spray gliders deployed near the Galápagos, Palau, and Solomon Islands are attributed to insufficient model resolution to capture the dynamics in strong current regions and near coasts. The sea surface height forecast skill of the model is assessed. Model forecasts using climatological forcing and boundary conditions are more skillful than climatology out to 50 days compared to persistence, which is a more skillful forecast than climatology out to approximately 20 days. Hindcasts using reanalysis products for atmospheric forcing and open boundary conditions are more skillful than climatology for approximately 120 days or longer, with the exact time scale depending on the accuracy of the state estimate used for initializing and on the reanalysis forcing. Estimating the model representational error is a goal of these experiments.
Clinical associations of proinflammatory cytokines, oxidative biomarkers and vitamin D levels in systemic lupus erythematosus
Authors: Willis R , Smikle M , DeCeulaer K , Romay-Penabad Z , Papalardo E , Jajoria P , Harper B , Murthy V , Petri M , Gonzalez E B 
Published: May 2017

Background The abnormal biological activity of cytokines plays an important role in the pathophysiology of both systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). Several studies have highlighted the association of vitamin D and certain pro-inflammatory cytokines with disease activity in SLE. However, there are limited data on the association of vitamin D and antiphospholipid antibodies (aPL) with various proinflammatory biomarkers in these patients and their relative impact on clinical outcomes. Methods The serum levels of several aPL, 25-hydroxy-vitamin D, pro-inflammatory cytokines including IFNα, IL-1β, IL-6, IL-8, IP10, sCD40L, TNFα and VEGF were measured in 312 SLE patients from the Jamaican ( n = 45) and Hopkins ( n = 267) lupus cohorts using commercial Milliplex and ELISA assays. Oxidized LDL/β2glycoprotein antigenic complexes (oxLβ2Ag) and their associated antibodies were also measured in the Jamaican cohort. Healthy controls for oxidative marker and cytokine testing were used. Results Abnormally low vitamin D levels were present in 61.4% and 73.3% of Hopkins and Jamaican SLE patients, respectively. Median concentrations of IP10, TNFα, sCD40L and VEGF were elevated in both cohorts, oxLβ2Ag and IL-6 were elevated in the Jamaican cohort, and IFNα, IL-1β and IL-8 were the same or lower in both cohorts compared to controls. IP10 and VEGF were independent predictors of disease activity, aPL, IP10 and IL-6 were independent predictors of thrombosis and IL-8, and low vitamin D were independent predictors of pregnancy morbidity despite there being no association of vitamin D with pro-inflammatory cytokines. Conclusions Our results indicate that aPL-mediated pro-inflammatory cytokine production is likely a major mechanism of thrombus development in SLE patients. We provide presumptive evidence of the role IL-8 and hypovitaminosis D play in obstetric pathology in SLE but further studies are required to characterize the subtle complexities of vitamin D’s relationship with cytokine production and disease activity in these patients.
Roles of silent information regulator 1–serine/arginine-rich splicing factor 10–lipin 1 axis in the pathogenesis of alcohol fatty liver disease
Authors: Li Yuanyuan , Zhou Junying 
Published: May 2017

Alcohol exposure is a major reason of morbidity and mortality all over the world, with much of detrimental consequences attributing to alcoholic liver disease (ALD). With the continued ethanol consumption, alcoholic fatty liver disease (AFLD, the earliest and reversible form of ALD) can further develop to more serious forms of alcoholic liver damage, including alcoholic steatohepatitis, fibrosis/cirrhosis, and even eventually progress to hepatocellular carcinoma and liver failure. Furthermore, cell trauma, inflammation, oxidative stress, regeneration, and bacterial translocation are crucial promoters of ethanol-mediated liver lesions. AFLD is characterized by excessive fat deposition in liver induced by excessive drinking, which is related closely to the raised synthesis of fatty acids and triglyceride, reduction of mitochondrial fatty acid β-oxidation, and the aggregation of very-low-density lipoprotein (VLDL). Although little is known about the cellular and molecular mechanisms of AFLD, it seems to be correlated to diverse signal channels. Massive studies have suggested that liver steatosis is closely associated with the inhibition of silent information regulator 1 (SIRT1) and the augment of lipin1 β/α ratio mediated by ethanol. Recently, serine/arginine-rich splicing factor 10 (SFRS10), a specific molecule functioning in alternative splicing of lipin 1 (LPIN1) pre-mRNAs, has emerged as the central connection between SIRT1 and lipin1 signaling. It seems a new signaling axis, SIRT1–SFRS10–LPIN1 axis, acting in the pathogenesis of AFLD exists. This article aims to further explore the interactions among the above three molecules and their influences on the development of AFLD. Impact statement ALD is a major health burden in industrialized countries as well as China. AFLD, the earliest and reversible form of ALD, can progress to hepatitis, fibrosis/cirrhosis, even hepatoma. While the mechanisms, by which ethanol consumption leads to AFLD, are complicated and multiple, and remain incompletely understood. SIRT1, SFRS10, and LIPIN1 had been separately reported to participate in lipid metabolism and the pathogenesis of AFLD. Noteworthy, we found the connection among them via searching articles in PubMed and we had elaborated the connection in detail in this minireview. It seems a new signaling axis, SIRT1–SFRS10–LIPIN1 axis, acting in the pathogenesis of AFLD exists. Further study aimed at SIRT1–SFRS10–LIPIN1 signaling system will possibly offer a more effective therapeutic target for AFLD.
ITIM receptors: more than just inhibitors of platelet activation
Authors: Coxon Carmen H. , Geer Mitchell J. , Senis Yotis A. 
Published: May 2017

AbstractSince their discovery, immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptors have been shown to inhibit signaling from immunoreceptor tyrosine-based activation motif (ITAM)-containing receptors in almost all hematopoietic cells, including platelets. However, a growing body of evidence has emerged demonstrating that this is an oversimplification, and that ITIM-containing receptors are versatile regulators of platelet signal transduction, with functions beyond inhibiting ITAM-mediated platelet activation. PECAM-1 was the first ITIM-containing receptor identified in platelets and appeared to conform to the established model of ITIM-mediated attenuation of ITAM-driven activation. PECAM-1 was therefore widely accepted as a major negative regulator of platelet activation and thrombosis for many years, but more recent findings suggest a more complex role for this receptor, including the facilitation of αIIbβ3-mediated platelet functions. Since the identification of PECAM-1, several other ITIM-containing platelet receptors have been discovered. These include G6b-B, a critical regulator of platelet reactivity and production, and the noncanonical ITIM-containing receptor TREM-like transcript-1, which is localized to α-granules in resting platelets, binds fibrinogen, and acts as a positive regulator of platelet activation. Despite structural similarities and shared binding partners, including the Src homology 2 domain-containing protein-tyrosine phosphatases Shp1 and Shp2, knockout and transgenic mouse models have revealed distinct phenotypes and nonredundant functions for each ITIM-containing receptor in the context of platelet homeostasis. These roles are likely influenced by receptor density, compartmentalization, and as-yet unknown binding partners. In this review, we discuss the diverse repertoire of ITIM-containing receptors in platelets, highlighting intriguing new functions, controversies, and future areas of investigation.
PD-1 blockade for relapsed lymphoma post–allogeneic hematopoietic cell transplant: high response rate but frequent GVHD
Authors: Haverkos Bradley M. , Abbott Diana , Hamadani Mehdi , Armand Philippe , Flowers Mary E. , Merryman Reid , Kamdar Manali , Kanate Abraham Sebastian , Saad Ayman , Mehta Amitkumar , Ganguly Siddhartha , Fenske Timothy S. , Hari Parameswaran , Lowsky Robert , Andritsos Leslie , Jagasia Madan , Bashey Asad , Brown Stacey , Bachanova Veronika , Stephens Deborah , Mineishi Shin , Nakamura Ryotaro , Chen Yi-Bin , Blazar Bruce R. , Gutman Jonathan , Devine Steven M. 
Published: May 2017

Key Points
Checkpoint blockade via anti–PD-1 mAbs was associated with a high overall response rate in relapsed Hodgkin lymphoma allo-HCT patients. Checkpoint blockade via anti–PD-1 mAbs after allo-HCT can be complicated by rapid onset of severe and treatment-refractory GVHD.
Predicting the higher rate of intracranial hemorrhage in glioma patients receiving therapeutic enoxaparin
Authors: Mantia Charlene , Uhlmann Erik J. , Puligandla Maneka , Weber Griffin M. , Neuberg Donna , Zwicker Jeffrey I. 
Published: May 2017

Key Points
Therapeutic enoxaparin was associated with a greater than threefold increased risk of major ICH in patients with glioma. The PANWARDS risk score was a sensitive predictor of major ICH in glioma.
Participação direta em coprodução é democrática? Controle vetorial da dengue em Campo Grande – MS
Authors: Chaebo Gemael , Medeiros Janann Joslin 
Published: May 2017

A abordagem de coprodução considera a participação ativa dos usuários essencial para a implementação de políticas, estando essa maior influência direta nos rumos de política pública alinhada a princípios democráticos. Com a intenção de compreender melhor essa relação entre participação dos usuários e democracia em coprodução, o objetivo deste artigo foi caracterizar a participação dos usuários na coprodução do controle vetorial da dengue em Campo Grande – MS, Brasil. Os dados coletados em cinco bairros do município foram analisados por meio de análise de conteúdo. Constatou-se que, nos casos pesquisados, os usuários: (i) são incluídos no relacionamento com os profissionais, (ii) são capazes de produzir resultados de política pública e (iii) se beneficiam desses resultados alcançados. No entanto, para o alcance de uma plena participação democrática em coprodução, ainda falta aos usuários influenciar outros processos de políticas públicas – não limitando sua participação (apenas) à execução de ações propostas pelo poder público.
Incidence, Predictors, and Outcomes of Hospital‐Acquired Anemia
Authors: Makam Anil N. , Nguyen Oanh K. , Clark Christopher , Halm Ethan A. 
Published: May 2017

BACKGROUNDAlthough hypothesized to be a hazard of hospitalization, it is unclear whether hospital‐acquired anemia (HAA) is associated with increased adverse outcomes following discharge.OBJECTIVETo examine the incidence, predictors, and postdischarge outcomes associated with HAA.DESIGNObservational cohort study using electronic health record data.SUBJECTSConsecutive medicine discharges between November 1, 2009 and October 30, 2010 from 6 Texas hospitals, including safety‐net, teaching, and nonteaching sites. Patients with anemia on admission or missing hematocrit values at admission or discharge were excluded.MEASURESHAA was defined using the last hematocrit value prior to discharge and categorized by severity. The primary outcome was a composite of 30‐day mortality and nonelective readmission.RESULTSAmong 11,309 patients, one‐third developed HAA (21.6% with mild HAA; 10.1% with moderate HAA; and 1.4% with severe HAA). The 2 strongest potentially modifiable predictors of developing moderate or severe HAA were length of stay (adjusted odds ratio [OR], 1.26 per day; 95% confidence interval [CI], 1.23‐1.29) and receipt of a major procedure (adjusted OR, 5.09; 95% CI, 3.79‐6.82). Patients without HAA had a 9.7% incidence for the composite outcome versus 16.4% for those with severe HAA. Severe HAA was independently associated with a 39% increase in the odds for 30‐day readmission or death (95% CI, 1.09‐1.78). Most patients with severe HAA (85%) underwent a major procedure, had a discharge diagnosis of hemorrhage, and/or a discharge diagnosis of hemorrhagic disorder.CONCLUSIONSSevere HAA is associated with increased odds for 30‐day mortality and readmission after discharge; however, it is uncertain whether severe HAA is preventable.
Association of Inpatient Antimicrobial Utilization Measures with Antimicrobial Stewardship Activities and Facility Characteristics of Veterans Affairs Medical Centers
Authors: Graber Christopher J. , Jones Makoto M. , Chou Ann F. , Zhang Yue , Goetz Matthew Bidwell , Madaras‐Kelly Karl , Samore Matthew H. , Glassman Peter A. 
Published: May 2017

BACKGROUNDAntimicrobial stewardship programs (ASPs) have been advocated to improve antimicrobial utilization, but program implementation is variable.OBJECTIVETo determine associations between ASPs and facility characteristics, and inpatient antimicrobial utilization measures in the Veterans Affairs (VA) system in 2012.DESIGN: In 2012, VA administered a survey on antimicrobial stewardship practices to designated ASP contacts at VA acute care hospitals. From the survey, we identified 34 variables across 3 domains (evidence, organizational context, and facilitation) that were assessed using multivariable least absolute shrinkage and selection operator regression against 4 antimicrobial utilization measures from 2012: aggregate acute care antimicrobial use, antimicrobial use in patients with non‐infectious primary discharge diagnoses, missed opportunities to convert from parenteral to oral antimicrobial therapy, and double anaerobic coverage.SETTINGAll 130 VA facilities with acute care services.RESULTSVariables associated with at least 3 favorable changes in antimicrobial utilization included presence of postgraduate physician/pharmacy training programs, number of antimicrobial‐specific order sets, frequency of systematic de‐escalation review, presence of pharmacists and/or infectious diseases (ID) attendings on acute care ward teams, and formal ID training of the lead ASP pharmacist. Variables associated with 2 unfavorable measures included bed size, the level of engagement with VA Antimicrobial Stewardship Task Force online resources, and utilization of antimicrobial stop orders.CONCLUSIONSFormalization of ASP processes and presence of pharmacy and ID expertise are associated with favorable utilization. Systematic de‐escalation review and order set establishment may be high‐yield interventions.
Measuring carer burden in informal carers of patients with long-term conditions
Authors: Kudra Aleksandra , Lees Carolyn , Morrell-Scott Nicola 
Published: May 2017

Introduction: The aim of this literature review is to identify the most common tools used to measure burden in carers of people with Parkinson's disease (PD), heart failure (HF), multiple sclerosis (MS) and chronic obstructive pulmonary disease (COPD). Method: Databases such as Medline, PsycINFO, CINAHL and Academic Search Complete were searched. Studies in which carer burden was measured were included. Results: Zarit Burden Inventory and Caregiver Reaction Assessment were most commonly used to measure carer burden, regardless of the chronic condition. A wide range of other instruments were also used. Conclusions: Even though a range of tools are available, further improvements are necessary in order to enable healthcare professionals to identify carers experiencing high burden.