bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heart rate-induced modifications of concentric left ventricular hypertrophy: exploration of a novel therapeutic concept
Authors: Klein Franziska J. , Bell Stephen , Runte K. Elisabeth , Lobel Robert , Ashikaga Takamuru , Lerman Lilach O. , LeWinter Martin M. , Meyer Markus 
Published: September 2016

Lowering the heart rate is considered to be beneficial in heart failure (HF) with reduced ejection fraction (HFrEF). In a dilated left ventricle (LV), pharmacological heart rate lowering is associated with a reduction in LV chamber size. In patients with HFrEF, this structural change is associated with better survival. HF with preserved ejection fraction (HFpEF) is increasingly prevalent but, so far, without any evidence-based treatment. HFpEF is typically associated with LV concentric remodeling and hypertrophy. The effects of heart rate on this structural phenotype are not known. Analogous with the benefits of a low heart rate on a dilated heart, we hypothesized that increased heart rates could lead to potentially beneficial remodeling of a concentrically hypertrophied LV. This was explored in an established porcine model of concentric LV hypertrophy and fibrosis. Our results suggest that a moderate increase in heart rate can be used to reduce wall thickness, normalize LV chamber volumes, decrease myocardial fibrosis, and improve LV compliance. Our results also indicate that the effects of heart rate can be titrated, are reversible, and do not induce HF. These findings may provide the rationale for a novel therapeutic approach for HFpEF and its antecedent disease substrate.Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/heart-rate-modeling/ .
Comparative Analysis of Bispecific Antibody and Streptavidin-Targeted Radioimmunotherapy for B-cell Cancers
Authors: Green Damian J. , Frayo Shani L. , Lin Yukang , Hamlin Donald K. , Fisher Darrell R. , Frost Sofia H.L. , Kenoyer Aimee L. , Hylarides Mark D. , Gopal Ajay K. , Gooley Theodore A. , Orozco Johnnie J. , Till Brian G. , O'Steen Shyril , Orcutt Kelly D. , Wilbur D. Scott , Wittrup K. Dane , Press Oliver W. 
Published: September 2016

Abstract
Streptavidin (SA)-biotin pretargeted radioimmunotherapy (PRIT) that targets CD20 in non-Hodgkin lymphoma (NHL) exhibits remarkable efficacy in model systems, but SA immunogenicity and interference by endogenous biotin may complicate clinical translation of this approach. In this study, we engineered a bispecific fusion protein (FP) that evades the limitations imposed by this system. Briefly, one arm of the FP was an anti-human CD20 antibody (2H7), with the other arm of the FP an anti-chelated radiometal trap for a radiolabeled ligand (yttrium[Y]-DOTA) captured by a very high-affinity anti-Y-DOTA scFv antibody (C825). Head-to-head biodistribution experiments comparing SA-biotin and bispecific FP (2H7-Fc-C825) PRIT in murine subjects bearing human lymphoma xenografts demonstrated nearly identical tumor targeting by each modality at 24 hours. However, residual radioactivity in the blood and normal organs was consistently higher following administration of 1F5-SA compared with 2H7-Fc-C825. Consequently, tumor-to-normal tissue ratios of distribution were superior for 2H7-Fc-C825 (P &lt; 0.0001). Therapy studies in subjects bearing either Ramos or Granta subcutaneous lymphomas demonstrated that 2H7-Fc-C825 PRIT is highly effective and significantly less myelosuppressive than 1F5-SA (P &lt; 0.0001). All animals receiving optimal doses of 2H7-Fc-C825 followed by 90Y-DOTA were cured by 150 days, whereas the growth of tumors in control animals progressed rapidly with complete morbidity by 25 days. In addition to demonstrating reduced risk of immunogenicity and an absence of endogenous biotin interference, our findings offer a preclinical proof of concept for the preferred use of bispecific PRIT in future clinical trials, due to a slightly superior biodistribution profile, less myelosuppression, and superior efficacy. Cancer Res; 76(22); 6669–79. ©2016 AACR.
Synthetic Lethality in PTEN-Mutant Prostate Cancer Is Induced by Combinatorial PI3K/Akt and BCL-XL Inhibition
Authors: Ren Wenying , Joshi Raghav , Mathew Paul 
Published: September 2016

Abstract
The bone-conserved metastatic phenotype of prostate cancer is a prototype of nonrandom metastatic behavior. Adhesion of prostate cancer cells to fibronectin via the integrin α5 (ITGA5) has been proposed as a candidate bone marrow niche localization mechanism. We hypothesized that the mechanisms whereby ITGA5 regulates the adhesion-mediated survival of prostate cancer cells will define novel therapeutic approaches. ITGA5 shRNA reduced expression of BCL-2 family members and induced apoptosis in PC-3 cells. In these PTEN-mutant cells, pharmacologic inhibition of the PI3K signaling pathway in combination with ITGA5 knockdown enhanced apoptosis. Chemical parsing studies with BH3 mimetics indicated that PI3K/Akt inhibition in combination with BCL-XL–specific inhibition induces synergistic apoptosis specifically in PTEN-mutant prostate cancer cells, whereas single-agent PI3K/Akt inhibitors did not. Given the importance of PTEN loss in the progression of prostate and other cancers, synthetic lethality induced by combinatorial PI3K/Akt and BCL-XL inhibition represents a valuable therapeutic strategy.
Implications: Activation of the PI3K pathway through PTEN loss represents a major molecular pathway in the progression of prostate and other cancers. This study defines a synthetic lethal therapeutic combination with significant translational potential.
Overview: Synthetic lethality in PTEN-mutant prostate cancer cells with combined PI3K/Akt and BCL-XL inhibition. PTEN-mutant prostate cancer cells expressing ITGA5 bind to fibronectin in the putative bone marrow niche and transduce survival signals to BCL-XL. Additional PTEN-regulated signals independent of the PI3K/Akt pathway likely feed into the BCL-XL–regulated survival program to explain synthetic lethality observed with the combination.
Visual Overview: http://mcr.aacrjournals.org/content/early/2016/12/02/1541-7786.MCR-16-0202/F1.large.jpg. Mol Cancer Res; 14(12); 1176–81. ©2016 AACR.
Response to Programmed Cell Death-1 Blockade in a Murine Melanoma Syngeneic Model Requires Costimulation, CD4, and CD8 T Cells
Authors: Homet Moreno Blanca , Zaretsky Jesse M. , Garcia-Diaz Angel , Tsoi Jennifer , Parisi Giulia , Robert Lidia , Meeth Katrina , Ndoye Abibatou , Bosenberg Marcus , Weeraratna Ashani T. , Graeber Thomas G. , Comin-Anduix Begoña , Hu-Lieskovan Siwen , Ribas Antoni 
Published: September 2016

AbstractThe programmed cell death protein 1 (PD-1) limits effector T-cell functions in peripheral tissues, and its inhibition leads to clinical benefit in different cancers. To better understand how PD-1 blockade therapy modulates the tumor–host interactions, we evaluated three syngeneic murine tumor models, the BRAFV600E-driven YUMM1.1 and YUMM2.1 melanomas, and the carcinogen-induced murine colon adenocarcinoma MC38. The YUMM cell lines were established from mice with melanocyte-specific BRAFV600E mutation and PTEN loss (BRAFV600E/PTEN−/−). Anti–PD-1 or anti–PD-L1 therapy engendered strong antitumor activity against MC38 and YUMM2.1, but not YUMM1.1. PD-L1 expression did not differ between the three models at baseline or upon interferon stimulation. Whereas mutational load was high in MC38, it was lower in both YUMM models. In YUMM2.1, the antitumor activity of PD-1 blockade had a critical requirement for both CD4 and CD8 T cells, as well as CD28 and CD80/86 costimulation, with an increase in CD11c+CD11b+MHC-IIhigh dendritic cells and tumor-associated macrophages in the tumors after PD-1 blockade. Compared with YUMM1.1, YUMM2.1 exhibited a more inflammatory profile by RNA sequencing analysis, with an increase in expression of chemokine-trafficking genes that are related to immune cell recruitment and T-cell priming. In conclusion, response to PD-1 blockade therapy in tumor models requires CD4 and CD8 T cells and costimulation that is mediated by dendritic cells and macrophages. Cancer Immunol Res; 4(10); 845–57. ©2016 AACR.
Decoding the Long Noncoding RNA During Cardiac Maturation
Authors: Touma Marlin , Kang Xuedong , Zhao Yan , Cass Ashley A. , Gao Fuying , Biniwale Reshma , Coppola Giovanni , Xiao Xinshu , Reemtsen Brian , Wang Yibin 
Published: September 2016

Background—
Cardiac maturation during perinatal transition of heart is critical for functional adaptation to hemodynamic load and nutrient environment. Perturbation in this process has major implications in congenital heart defects. Transcriptome programming during perinatal stages is an important information but incomplete in current literature, particularly, the expression profiles of the long noncoding RNAs (lncRNAs) are not fully elucidated.

Methods and Results—
From comprehensive analysis of transcriptomes derived from neonatal mouse heart left and right ventricles, a total of 45 167 unique transcripts were identified, including 21 916 known and 2033 novel lncRNAs. Among these lncRNAs, 196 exhibited significant dynamic regulation along maturation process. By implementing parallel weighted gene co-expression network analysis of mRNA and lncRNA data sets, several lncRNA modules coordinately expressed in a developmental manner similar to protein coding genes, while few lncRNAs revealed chamber-specific patterns. Out of 2262 lncRNAs located within 50 kb of protein coding genes, 5% significantly correlate with the expression of their neighboring genes. The impact of Ppp1r1b-lncRNA on the corresponding partner gene Tcap was validated in cultured myoblasts. This concordant regulation was also conserved in human infantile hearts. Furthermore, the Ppp1r1b-lncRNA/Tcap expression ratio was identified as a molecular signature that differentiated congenital heart defect phenotypes.

Conclusions—
The study provides the first high-resolution landscape on neonatal cardiac lncRNAs and reveals their potential interaction with mRNA transcriptome during cardiac maturation. Ppp1r1b-lncRNA was identified as a regulator of Tcap expression, with dynamic interaction in postnatal cardiac development and congenital heart defects.
Package Design Affects Accuracy Recognition for Medications
Authors: Endestad Tor , Wortinger Laura A. , Madsen Steinar , Hortemo Sigurd 
Published: September 2016

Objective: Our aim was to test if highlighting and placement of substance name on medication package have the potential to reduce patient errors. Background: An unintentional overdose of medication is a large health issue that might be linked to medication package design. In two experiments, placement, background color, and the active ingredient of generic medication packages were manipulated according to best human factors guidelines to reduce causes of labeling-related patient errors. Method: In two experiments, we compared the original packaging with packages where we varied placement of the name, dose, and background of the active ingredient. Age-relevant differences and the effect of color on medication recognition error were tested. In Experiment 1, 59 volunteers (30 elderly and 29 young students), participated. In Experiment 2, 25 volunteers participated. Results: The most common error was the inability to identify that two different packages contained the same active ingredient (young, 41%, and elderly, 68%). This kind of error decreased with the redesigned packages (young, 8%, and elderly, 16%). Confusion errors related to color design were reduced by two thirds in the redesigned packages compared with original generic medications. Conclusion: Prominent placement of substance name and dose with a band of high-contrast color support recognition of the active substance in medications. Application: A simple modification including highlighting and placing the name of the active ingredient in the upper right-hand corner of the package helps users realize that two different packages can contain the same active substance, thus reducing the risk of inadvertent medication overdose.
Implementing Lumberjacks and Black Swans Into Model-Based Tools to Support Human–Automation Interaction
Authors: Sebok Angelia , Wickens Christopher D. 
Published: September 2016

Objective: The objectives were to (a) implement theoretical perspectives regarding human–automation interaction (HAI) into model-based tools to assist designers in developing systems that support effective performance and (b) conduct validations to assess the ability of the models to predict operator performance. Background: Two key concepts in HAI, the lumberjack analogy and black swan events, have been studied extensively. The lumberjack analogy describes the effects of imperfect automation on operator performance. In routine operations, an increased degree of automation supports performance, but in failure conditions, increased automation results in more significantly impaired performance. Black swans are the rare and unexpected failures of imperfect automation. Method: The lumberjack analogy and black swan concepts have been implemented into three model-based tools that predict operator performance in different systems. These tools include a flight management system, a remotely controlled robotic arm, and an environmental process control system. Results: Each modeling effort included a corresponding validation. In one validation, the software tool was used to compare three flight management system designs, which were ranked in the same order as predicted by subject matter experts. The second validation compared model-predicted operator complacency with empirical performance in the same conditions. The third validation compared model-predicted and empirically determined time to detect and repair faults in four automation conditions. Conclusion: The three model-based tools offer useful ways to predict operator performance in complex systems. Application: The three tools offer ways to predict the effects of different automation designs on operator performance.
A Closed-Loop Model of Operator Visual Attention, Situation Awareness, and Performance Across Automation Mode Transitions
Authors: Johnson Aaron W. , Duda Kevin R. , Sheridan Thomas B. , Oman Charles M. 
Published: September 2016

Objective: This article describes a closed-loop, integrated human–vehicle model designed to help understand the underlying cognitive processes that influenced changes in subject visual attention, mental workload, and situation awareness across control mode transitions in a simulated human-in-the-loop lunar landing experiment. Background: Control mode transitions from autopilot to manual flight may cause total attentional demands to exceed operator capacity. Attentional resources must be reallocated and reprioritized, which can increase the average uncertainty in the operator’s estimates of low-priority system states. We define this increase in uncertainty as a reduction in situation awareness. Method: We present a model built upon the optimal control model for state estimation, the crossover model for manual control, and the SEEV (salience, effort, expectancy, value) model for visual attention. We modify the SEEV attention executive to direct visual attention based, in part, on the uncertainty in the operator’s estimates of system states. Results: The model was validated using the simulated lunar landing experimental data, demonstrating an average difference in the percentage of attention ≤3.6% for all simulator instruments. The model’s predictions of mental workload and situation awareness, measured by task performance and system state uncertainty, also mimicked the experimental data. Conclusion: Our model supports the hypothesis that visual attention is influenced by the uncertainty in system state estimates. Application: Conceptualizing situation awareness around the metric of system state uncertainty is a valuable way for system designers to understand and predict how reallocations in the operator’s visual attention during control mode transitions can produce reallocations in situation awareness of certain states.
Comparison of methods for measurement of the pressure exerted by knitted fabrics
Authors: Cieślak Małgorzata , Karaszewska Agnieszka , Gromadzińska Ewa , Jasińska Izabela , Kamińska Irena 
Published: September 2016

The article presents the results of measurements of pressure exerted by two model knitted products – bands with different structure (WI jersey weft-knitted fabric and WII openwork warp-knitted fabric). The tests were carried out with using the I-Scan system (in vivo and in vitro tests) and the STM 579 device (in vitro test). A comparative analysis of the in vivo and in vitro results for the I-Scan method and in vitro results for the I-Scan and STM 579 method was performed. It was found that the pressure values are lower for openwork warp-knitted fabric than for jersey weft-knitted fabric both in the case of the in vitro and in vivo tests, and the values of pressure for the same band are higher in the case of the in vitro tests.
A Trusted Source of Information
Authors: Paulsell Diane , Thomas Jaime , Monahan Shannon , Seftor Neil S. 
Published: September 2016

Background: Systematic reviews sponsored by federal departments or agencies play an increasingly important role in disseminating information about evidence-based programs and have become a trusted source of information for administrators and practitioners seeking evidence-based programs to implement. These users vary in their knowledge of evaluation methods and their ability to interpret systematic review findings. They must consider factors beyond program effectiveness when selecting an intervention, such as the relevance of the intervention to their target population, community context, and service delivery system; readiness for replication and scale-up; and the ability of their service delivery system or agency to implement the intervention. Objective: To support user decisions about adopting evidence-based practices, this article discusses current systematic review practices and alternative approaches to synthesizing and presenting findings and providing information. Method: We reviewed the publicly available information on review methodology and findings for eight federally funded systematic reviews in the labor, education, early childhood, mental health/substance abuse, family support, and criminal justice topic areas. Conclusion: The eight federally sponsored evidence reviews we examined all provide information that can help users to interpret findings on evidence of effectiveness and to make adoption decisions. However, they are uneven in the amount, accessibility, and consistency of information they report. For all eight reviews, there is room for improvement in supporting users’ adoption decisions through more detailed, accessible, and consistent information in these areas.
Hamstring Strength Asymmetry at 3 Years After Anterior Cruciate Ligament Reconstruction Alters Knee Mechanics During Gait and Jogging
Authors: Abourezk Matthew N. , Ithurburn Matthew P. , McNally Michael P. , Thoma Louise M. , Briggs Matthew S. , Hewett Timothy E. , Spindler Kurt P. , Kaeding Christopher C. , Schmitt Laura C. 
Published: September 2016

Background: Anterior cruciate ligament reconstruction (ACLR) using a hamstring tendon autograft often results in hamstring muscle strength asymmetry. However, the effect of hamstring muscle strength asymmetry on knee mechanics has not been reported. Hypothesis: Participants with hamstring strength asymmetry would demonstrate altered involved limb knee mechanics during walking and jogging compared with those with more symmetric hamstring strength at least 2 years after ACLR with a hamstring tendon autograft. Study Design: Controlled laboratory study. Methods: There were a total of 45 participants at least 2 years after ACLR (22 male, 23 female; mean time after ACLR, 34.6 months). A limb symmetry index (LSI) was calculated for isometric hamstring strength to subdivide the sample into symmetric hamstring (SH) (LSI ≥90%; n = 18) and asymmetric hamstring (AH) (LSI <85%; n = 18) groups. Involved knee kinematic and kinetic data were collected using 3-dimensional motion analysis during gait and jogging. Peak sagittal-, frontal-, and transverse-plane knee angles and sagittal-plane knee moments and knee powers were calculated. Independent-samples t tests and analyses of covariance were used to compare involved knee kinematic and kinetic variables between the groups. Results: There were no differences in sagittal- and frontal-plane knee angles between the groups ( P > .05 for all). The AH group demonstrated decreased tibial internal rotation during weight acceptance during gait ( P = .01) and increased tibial external rotation during jogging at initial contact ( P = .03) and during weight acceptance ( P = .02) compared with the SH group. In addition, the AH group demonstrated decreased peak negative knee power during midstance ( P = .01) during gait compared with the SH group, after controlling for gait speed, which differed between groups. Conclusion: Participants with hamstring strength asymmetry showed altered involved knee mechanics in the sagittal plane during gait and in the transverse plane during gait and jogging compared with those with more symmetric hamstring strength. Clinical Relevance: Hamstring strength asymmetry is common at 3 years after ACLR with a hamstring tendon autograft and affects involved knee mechanics during gait and jogging. Additional research is warranted to further investigate the longitudinal effect of these alterations on knee function and joint health after ACLR.