bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of CDK4/6 by Palbociclib Significantly Extends Survival in Medulloblastoma Patient-Derived Xenograft Mouse Models
Authors: Cook Sangar Michelle L. , Genovesi Laura A. , Nakamoto Madison W. , Davis Melissa J. , Knobluagh Sue E. , Ji Pengxiang , Millar Amanda , Wainwright Brandon J. , Olson James M. 
Published: June 2017

Abstract
Purpose: Bioinformatics analysis followed by in vivo studies in patient-derived xenograft (PDX) models were used to identify and validate CDK 4/6 inhibition as an effective therapeutic strategy for medulloblastoma, particularly group 3 MYC-amplified tumors that have the worst clinical prognosis.
Experimental Design: A protein interaction network derived from a Sleeping Beauty mutagenesis model of medulloblastoma was used to identify potential novel therapeutic targets. The top hit from this analysis was validated in vivo using PDX models of medulloblastoma implanted subcutaneously in the flank and orthotopically in the cerebellum of mice.
Results: Informatics analysis identified the CDK4/6/CYCLIN D/RB pathway as a novel “druggable” pathway for multiple subgroups of medulloblastoma. Palbociclib, a highly specific inhibitor of CDK4/6, was found to inhibit RB phosphorylation and cause G1 arrest in PDX models of medulloblastoma. The drug caused rapid regression of Sonic hedgehog (SHH) and MYC-amplified group 3 medulloblastoma subcutaneous tumors and provided a highly significant survival advantage to mice bearing MYC-amplified intracranial tumors.
Conclusions: Inhibition of CDK4/6 is potentially a highly effective strategy for the treatment of SHH and MYC-amplified group 3 medulloblastoma. Clin Cancer Res; 23(19); 5802–13. ©2017 AACR.
Modulation of Plasma Metabolite Biomarkers of the MAPK Pathway with MEK Inhibitor RO4987655: Pharmacodynamic and Predictive Potential in Metastatic Melanoma
Authors: Ang Joo Ern , Pal Akos , Asad Yasmin J. , Henley Alan T. , Valenti Melanie , Box Gary , de haven Brandon Alexis , Revell Victoria L. , Skene Debra J. , Venturi Miro , Rueger Ruediger , Meresse Valerie , Eccles Suzanne A. , de Bono Johann S. , Kaye Stanley B. , Workman Paul , Banerji Udai , Raynaud Florence I. 
Published: June 2017

Abstract
MAPK pathway activation is frequently observed in human malignancies, including melanoma, and is associated with sensitivity to MEK inhibition and changes in cellular metabolism. Using quantitative mass spectrometry–based metabolomics, we identified in preclinical models 21 plasma metabolites including amino acids, propionylcarnitine, phosphatidylcholines, and sphingomyelins that were significantly altered in two B-RAF–mutant melanoma xenografts and that were reversed following a single dose of the potent and selective MEK inhibitor RO4987655. Treatment of non–tumor-bearing animals and mice bearing the PTEN-null U87MG human glioblastoma xenograft elicited plasma changes only in amino acids and propionylcarnitine. In patients with advanced melanoma treated with RO4987655, on-treatment changes of amino acids were observed in patients with disease progression and not in responders. In contrast, changes in phosphatidylcholines and sphingomyelins were observed in responders. Furthermore, pretreatment levels of seven lipids identified in the preclinical screen were statistically significantly able to predict objective responses to RO4987655. The RO4987655 treatment–related changes were greater than baseline physiological variability in nontreated individuals. This study provides evidence of a translational exo-metabolomic plasma readout predictive of clinical efficacy together with pharmacodynamic utility following treatment with a signal transduction inhibitor. Mol Cancer Ther; 16(10); 2315–23. ©2017 AACR.
Tyrosine Kinase Inhibitors Protect the Salivary Gland from Radiation Damage by Inhibiting Activation of Protein Kinase C-δ
Authors: Wie Sten M. , Wellberg Elizabeth , Karam Sana D. , Reyland Mary E. 
Published: June 2017

Abstract
In patients undergoing irradiation (IR) therapy, injury to nontumor tissues can result in debilitating, and sometimes permanent, side effects. We have defined protein kinase C-δ (PKCδ) as a regulator of DNA damage–induced apoptosis and have shown that phosphorylation of PKCδ by c-Abl and c-Src activates its proapoptotic function. Here, we have explored the use of tyrosine kinase inhibitors (TKI) of c-Src and c-Abl to block activation of PKCδ for radioprotection of the salivary gland. Dasatinib, imatinib, and bosutinib all suppressed tyrosine phosphorylation of PKCδ and inhibited IR-induced apoptosis in vitro. To determine whether TKIs can provide radioprotection of salivary gland function in vivo, mice were treated with TKIs and a single or fractionated doses of irradiation. Delivery of dasatinib or imatinib within 3 hours of a single or fractionated dose of irradiation resulted in &gt;75% protection of salivary gland function at 60 days. Continuous dosing with dasatinib extended protection to at least 5 months and correlated with histologic evidence of salivary gland acinar cell regeneration. Pretreatment with TKIs had no impact on clonogenic survival of head and neck squamous cell carcinoma (HNSCC) cells, and in mice harboring HNSCC cell–derived xenografts, combining dasatinib or imatinib with fractionated irradiation did not enhance tumor growth. Our studies indicate that TKIs may be useful clinically to protect nontumor tissue in HNC patients undergoing radiotherapy, without negatively impacting cancer treatment. Mol Cancer Ther; 16(9); 1989–98. ©2017 AACR.
Sex‐Based Differences in the Performance of the HEART Score in Patients Presenting to the Emergency Department With Acute Chest Pain
Authors: Bank Ingrid E. M. , de Hoog Vince C. , de Kleijn Dominique P. V. , Pasterkamp Gerard , Doevendans Pieter A. , den Ruijter Hester M. , Dalmeijer Geertje , Wildbergh Thierry X. , Mosterd Arend , Timmers Leo 
Published: June 2017

Background
Sex‐based differences in clinical presentation, pathophysiology, and outcomes of patients with acute chest pain are increasingly being recognized, but are not implemented in guidelines and clinical prediction tools. We evaluated the performance of the HEART score in women versus men, because sex‐based differences may exist among the algorithm's components: history, electrocardiogram, age, risk factors, and admission troponin level.

Methods and Results

The HEART score was retrospectively assessed in 831 women and 1084 men presenting to the emergency department with acute chest pain, assigning patients to the low‐, intermediate‐, or high‐risk category for the occurrence of major adverse cardiac events (MACE) within 6 weeks. MACE, consisting of myocardial infarction, coronary revascularization, and all‐cause death, also included events during index visit. Six‐week MACE rates were 2 times lower in women than men (10.0% versus 20.8%;
P
<0.01). Despite similar discriminatory accuracy of the HEART score among women and men (c‐statistic, 0.80 [0.75–0.84] versus 0.77 [0.74–0.81];
P
=0.43), 6‐week MACE rates were significantly lower in women than men across all HEART risk categories: 2.1% versus 6.5% (
P
<0.01) in the low‐risk category, 12.7% versus 21.3% (
P
<0.01) in intermediate‐risk category, and 53.1% versus 77.0% (
P
=0.02) in the high‐risk category. The HEART score‐adjusted risk ratio for men was 1.6 (1.3–2.0;
P
<0.01).

Conclusions
The markedly higher 6‐week MACE risk in men across all HEART risk categories should be taken into account when using the HEART score to guide clinical decision making; early discharge with a low‐risk HEART score appears less safe for men than women with acute chest pain.
A Physically Based Horizontal Subgrid-Scale Turbulent Mixing Parameterization for the Convective Boundary Layer
Authors: Zhou Bowen , Zhu Kefeng , Xue Ming 
Published: June 2017

Abstract
Compared to the representation of vertical turbulent mixing through various planetary boundary layer (PBL) schemes, the treatment of horizontal turbulent mixing in the boundary layer has received much less attention. In mesoscale and convective-scale models, subgrid-scale horizontal turbulent mixing has traditionally been associated with mesoscale circulations or eddies. Its parameterization most often adopts the gradient-diffusion model, where the horizontal mixing coefficients are usually set constant, or through the 2D Smagorinsky formulation, or in some cases based on the 1.5-order turbulence kinetic energy (TKE) closure. For horizontal turbulent mixing associated with boundary layer eddies, the traditional schemes are shown to perform poorly. This work investigates the characteristic turbulence velocity and length scales based on analysis of a well-resolved, wide-domain large-eddy simulation of a convective boundary layer (CBL). To improve the representation of horizontal turbulent mixing by CBL eddies, a class of schemes is proposed with different levels of sophistication. The first two schemes can be used together with first-order PBL schemes, while the third uses TKE to define its characteristic velocity scale and can be used together with TKE-based higher-order PBL schemes. The proposed parameterizations are tested a posteriori in idealized simulations of turbulent dispersion of a passive scalar. Comparisons show improved horizontal dispersion by the proposed schemes and further demonstrate the weakness of the existing schemes.
Low-Pass Filtering, Heat Flux, and Atlantic Multidecadal Variability
Authors: Cane Mark A. , Clement Amy C. , Murphy Lisa N. , Bellomo Katinka 
Published: June 2017

Abstarct
In this model study the authors explore the possibility that the internal component of the Atlantic multidecadal oscillation (AMO) sea surface temperature (SST) signal is indistinguishable from the response to white noise forcing from the atmosphere and ocean. Here, complex models are compared without externally varying forcing with a one-dimensional noise-driven model for SST. General analytic expressions are obtained for both unfiltered and low-pass filtered lead–lag correlations. It is shown that this simple model reproduces many of the simulated lead–lag relationships among temperature, rate of change of temperature, and surface heat flux. It is concluded that the finding that at low frequencies the ocean loses heat to the atmosphere when the temperature is warm, which has been interpreted as showing that the ocean circulation drives the AMO, is a necessary consequence of the fact that at long periods the net heat flux (ocean plus atmosphere) is zero to a good approximation. It does not distinguish between the atmosphere and ocean as the source of the AMO and is consistent with the hypothesis that the AMO is driven by white noise heat fluxes. It is shown that some results in the literature are artifacts of low-pass filtering, which creates spurious low-frequency signals when the underlying data are white or red noise. It is concluded that in the absence of external forcing the AMO in most GCMs is consistent with being driven by white noise, primarily from the atmosphere.
A Direct Estimate of the Seasonal Cycle of Evapotranspiration over the Amazon Basin
Authors: Swann Abigail L. S. , Koven Charles D. 
Published: June 2017

Abstract
Evapotranspiration (ET) is a critical term in the surface energy budget as well as the water cycle. There are few direct measurements of ET, and thus the magnitude and variability are poorly constrained at large spatial scales. Estimates of the annual cycle of ET over the Amazon are critical because they influence predictions of the seasonal cycle of carbon fluxes, as well as atmospheric dynamics and circulation. The authors estimate ET for the Amazon basin using a water budget approach by differencing rainfall, discharge, and time-varying storage from the Gravity Recovery and Climate Experiment. It is found that the climatological annual cycle of ET over the Amazon basin upstream of Óbidos shows suppression of ET during the wet season and higher ET during the dry season, consistent with flux-tower-based observations in seasonally dry forests. They also find a statistically significant decrease in ET over the time period 2002–15 of −1.46 mm yr−1. The direct estimate of the seasonal cycle of ET is largely consistent with previous indirect estimates, including energy-budget-based approaches, an upscaled station-based estimate, and land surface model estimates, but suggests that suppression of ET during the wet season is underestimated by existing products.
Breaking New Ground in Severe Weather Prediction: The 2015 NOAA/Hazardous Weather Testbed Spring Forecasting Experiment
Authors: Gallo Burkely T. , Clark Adam J. , Jirak Israel , Kain John S. , Weiss Steven J. , Coniglio Michael , Knopfmeier Kent , Correia James , Melick Christopher J. , Karstens Christopher D. , Iyer Eswar , Dean Andrew R. , Xue Ming , Kong Fanyou , Jung Youngsun , Shen Feifei , Thomas Kevin W. , Brewster Keith , Stratman Derek , Carbin Gregory W. , Line William , Adams-Selin Rebecca , Willington Steve 
Published: June 2017

Abstract
Led by NOAA’s Storm Prediction Center and National Severe Storms Laboratory, annual spring forecasting experiments (SFEs) in the Hazardous Weather Testbed test and evaluate cutting-edge technologies and concepts for improving severe weather prediction through intensive real-time forecasting and evaluation activities. Experimental forecast guidance is provided through collaborations with several U.S. government and academic institutions, as well as the Met Office. The purpose of this article is to summarize activities, insights, and preliminary findings from recent SFEs, emphasizing SFE 2015. Several innovative aspects of recent experiments are discussed, including the 1) use of convection-allowing model (CAM) ensembles with advanced ensemble data assimilation, 2) generation of severe weather outlooks valid at time periods shorter than those issued operationally (e.g., 1–4 h), 3) use of CAMs to issue outlooks beyond the day 1 period, 4) increased interaction through software allowing participants to create individual severe weather outlooks, and 5) tests of newly developed storm-attribute-based diagnostics for predicting tornadoes and hail size. Additionally, plans for future experiments will be discussed, including the creation of a Community Leveraged Unified Ensemble (CLUE) system, which will test various strategies for CAM ensemble design using carefully designed sets of ensemble members contributed by different agencies to drive evidence-based decision-making for near-future operational systems.
An Innovative Approach to Addressing the HIV Care Continuum: Implementation of a Clinical Pharmacy Resident in a Veterans Affairs HIV Specialty Clinic
Authors: Bagwell Autumn , McFarland M. Shawn , Hulgan Todd 
Published: June 2017

Purpose: Engagement of patients in the HIV care continuum and adherence to antiretroviral therapy (ART) continue to limit successful viral suppression. Innovative practices to improve this continuum and ameliorate potential physician shortages are needed. The objective of this evaluation was to determine the clinical benefits of incorporating pharmacy resident involvement on a multidisciplinary team in caring for patients with HIV. Methods: A single-center pre–post cohort pilot evaluation was conducted at the Tennessee Valley Healthcare Systems VA Medical Center. Patients were enrolled in an HIV pharmacotherapy clinic implemented by an ambulatory care pharmacy resident. The primary end point of the evaluation was the percentage of patients achieving an undetectable plasma HIV viral load after enrollment. Secondary end points included change from baseline in CD4 T-cell count and self-reported adherence. Results: A total of 55 patients were seen in the HIV pharmacotherapy clinic over a 28-week evaluation period. Of those patients with detectable viral load at enrollment, 70% reached viral suppression during follow-up, with a significant 0.75 log10 decrease in the median viral load ( P < .0001 for both). The median CD4 T-cell count increased from 464 to 525 cells/mm3 ( P = .01). Reported adherence, assessed using the Visual Analogue adherence Scale (VAS) increased significantly ( P = .0001). Conclusion: After enrollment in an HIV pharmacotherapy clinic, a significant decrease in viral load was seen, as were improvements in secondary end points of CD4 T cells and adherence. These data demonstrate the clinical benefits of pharmacy resident involvement on a multidisciplinary team in caring for patients with HIV.
Use of computed tomography to define a sacral safe corridor for placement of 2.7 mm cortical screws in feline sacroiliac luxation
Authors: Philp Helen , Durand Alexane , De Vicente Felipe 
Published: June 2017

Objectives This study aimed to define a safe corridor for 2.7 mm cortical sacroiliac screw insertion in the dorsal plane (craniocaudal direction) using radiography and CT, and in the transverse plane (dorsoventral direction) using CT in feline cadavers. A further aim was to compare the values obtained by CT with those previously reported by radiography in the transverse plane. Methods Thirteen pelvises were retrieved from feline cadavers and dissected to expose one of the articular surfaces of the sacrum. A 2.7 mm screw was placed in the sacrum to a depth of approximately 1 cm in each exposed articular surface. Dorsoventral radiography and CT scanning of each specimen were performed. Multiplanar reconstructions were performed to allow CT evaluation in both the dorsal and transverse planes. Calculations were made to find the maximum, minimum and optimum angles for screw placement in craniocaudal (radiography and CT) and dorsoventral (CT) directions when using a 2.7 mm cortical screw. Results Radiographic measurement showed a mean optimum craniocaudal angle of 106° (range 97–112°). The mean minimum angle was 95° (range 87–107°), whereas the mean maximum angle was 117° (108–124°). Measurement of the dorsal CT scan images showed a mean optimum craniocaudal angle of 101° (range 94–110°). The mean minimum angle was 90° (range 83–99°), whereas the mean maximum angle was 113° (104–125°). The transverse CT scan images showed a mean dorsoventral minimum angle of 103° (range 95–113°), mean maximum angle of 115° (104–125°) and mean optimum dorsoventral angle of 111° (102–119°). Conclusions and relevance An optimum craniocaudal angle of 101° is recommended for 2.7 mm cortical screw placement in the feline sacral body, with a safety margin between 99° and 104°. No single angle can be recommended in the dorsoventral direction and therefore preoperative measuring on individual cats using CT images is recommended to establish the ideal individual angle in the transverse plane.
Effects of a mindfulness-based intervention on symptoms and signs in chronic heart failure: A feasibility study
Authors: Norman Jonna , Fu Michael , Ekman Inger , Björck Lena , Falk Kristin 
Published: June 2017

Aims:Despite treatment recommended by guidelines, many patients with chronic heart failure remain symptomatic. Evidence is accumulating that mindfulness-based interventions (MBIs) have beneficial psychological and physiological effects. The aim of this study was to explore the feasibility of MBI on symptoms and signs in patients with chronic heart failure in outpatient clinical settings.Methods:A prospective feasibility study. Fifty stable but symptomatic patients with chronic heart failure, despite optimized guideline-recommended treatment, were enrolled at baseline. In total, 40 participants (median age 76 years; New York Heart Association (NYHA) classification II−III) adhered to the study. Most patients ( n=17) were randomized into MBI, a structured eight-week mindfulness-based educational and training programme, or controls with usual care ( n=16). Primary outcome was self-reported fatigue on the Fatigue severity scale. Secondary outcomes were self-reported sleep quality, unsteadiness/dizziness, NYHA functional classification, walking distance in the six-minute walk test, and heart and respiratory rates. The Mann–Whitney U test was used to analyse median sum changes from baseline to follow-up (week 10±1).Results:Compared with usual care (zero change), MBI significantly reduced the self-reported impact of fatigue (effect size −8.0; p=0.0165), symptoms of unsteadiness/dizziness ( p=0.0390) and breathlessness/tiredness related to physical functioning (NYHA class) ( p=0.0087). No adverse effects were found.Conclusions:In stable but symptomatic outpatients with chronic heart failure, MBI alleviated self-reported symptoms in addition to conventional treatment. The sample size is small and further studies are needed, but findings support the role of MBI as a feasible complementary option, both clinically and as home-based treatment, which might contribute to reduction of the symptom burden in patients diagnosed with chronic heart failure.
Planting the Seeds of Change: Growing Lifestyle Medicine Interest Groups With the Donald A. Pegg Award
Authors: Stiegmann Regan A. , Abreu Alyssa , Gardner James E. , Hipple Jessie M. , Poling P. Elainee , Frates Elizabeth Pegg 
Published: June 2017

The practice of Lifestyle medicine (LM) focuses on helping patients make healthy choices to prevent and treat disease. While such interventions are considered first-line treatment for many diseases, many medical schools have not yet been able to include lifestyle medicine classes in the core curriculum but most are able to offer a parallel curriculum that does not interfere with the schedule of core classes. Lifestyle Medicine Interest Groups (LMIGs) are being created around the country and around the globe. Many students and faculty members are interested in starting and sustaining a LMIG at their schools, but some do not have enough funding or they lack the framework that provides structure to their efforts. To address this situation, the American College of Lifestyle Medicine (ACLM) has encouraged the development of LMIGs, which are student-run organizations that provide a parallel curriculum in LM. To support and strengthen this effort, the ACLM initiated the Donald A. Pegg award to fund four allied health students in founding and augmenting their institution’s LMIGs. The 2016 inaugural winners were James Gardner, P. Elainee Poling, Alyssa Abreu, and Jessie M. Hipple. Their LMIG activities have included events such as nutrition and cooking classes, exercise prescription seminars, group fitness sessions, and patient lifestyle counseling in various clinical settings. Pearls of wisdom for building successful LMIGs include cultivating strong faculty mentorship, marketing the personal benefits to students who attend activities, and collaborating with other student groups.
The role of special education teachers in facilitating peer relationships among students with mild intellectual disabilities in lower secondary school
Authors: Sigstad Hanne Marie Høybråten 
Published: June 2017

Background: Students with intellectual disabilities may lack sufficiently developed skills to initiate qualitatively good social interactions; thus, they might be in need of assistance. This study examined special education teachers’ role in facilitating peer relationships among students with mild intellectual disabilities in a mainstream school context. Materials and Methods: The study was based on qualitative semi-structured interviews with nine special education teachers who belong to special education groups in lower secondary schools. A thematic structural analysis was used to identify themes. Results: The teachers made substantial efforts to promote social competence and ensure optimal conditions to foster peer interactions. An “academic-oriented” education, divergent attitudes, challenges in teacher collaboration, and organizational constraints may be barriers. Conclusions: In a mainstream school, the role of special education teachers appears to be dependent on the basic values of the school management in terms of real opportunities to foster peer relationships among students with mild intellectual disabilities.