bluuebunny/crossref_metadata_2025_split huggingface dataset:
Temporal dynamics of cardiac hypertrophic growth in response to pressure overload
Authors: Wang Yuan , Zhang Yuannyu , Ding Guanqiao , May Herman I. , Xu Jian , Gillette Thomas G. , Wang Hang , Wang Zhao V. 
Published: August 2017

Hypertension is one of the most important risk factors of heart failure. In response to high blood pressure, the left ventricle manifests hypertrophic growth to ameliorate wall stress, which may progress into decompensation and trigger pathological cardiac remodeling. Despite the clinical importance, the temporal dynamics of pathological cardiac growth remain elusive. Here, we took advantage of the puromycin labeling approach to measure the relative rates of protein synthesis as a way to delineate the temporal regulation of cardiac hypertrophic growth. We first identified the optimal treatment conditions for puromycin in neonatal rat ventricular myocyte culture. We went on to demonstrate that myocyte growth reached its peak rate after 8–10 h of growth stimulation. At the in vivo level, with the use of an acute surgical model of pressure-overload stress, we observed the maximal growth rate to occur at day 7 after surgery. Moreover, RNA sequencing analysis supports that the most profound transcriptomic changes occur during the early phase of hypertrophic growth. Our results therefore suggest that cardiac myocytes mount an immediate growth response in reply to pressure overload followed by a gradual return to basal levels of protein synthesis, highlighting the temporal dynamics of pathological cardiac hypertrophic growth. NEW & NOTEWORTHY We determined the optimal conditions of puromycin incorporation in cardiac myocyte culture. We took advantage of this approach to identify the growth dynamics of cardiac myocytes in vitro. We went further to discover the protein synthesis rate in vivo, which provides novel insights about cardiac temporal growth dynamics in response to pressure overload.
Optoacoustic Detection of Early Therapy-Induced Tumor Cell Death Using a Targeted Imaging Agent
Authors: Xie Bangwen , Tomaszewski Michal R. , Neves André A. , Ros Susana , Hu De-En , McGuire Sarah , Mullins Stefanie R. , Tice David , Sainson Richard C.A. , Bohndiek Sarah E. , Wilkinson Robert W. , Brindle Kevin M. 
Published: August 2017

Abstract
Purpose: The development of new treatments and their deployment in the clinic may be assisted by imaging methods that allow an early assessment of treatment response in individual patients. The C2A domain of Synaptotagmin-I (C2Am), which binds to the phosphatidylserine (PS) exposed by apoptotic and necrotic cells, has been developed as an imaging probe for detecting cell death. Multispectral optoacoustic tomography (MSOT) is a real-time and clinically applicable imaging modality that was used here with a near infrared (NIR) fluorophore-labeled C2Am to image tumor cell death in mice treated with a TNF-related apoptosis-inducing ligand receptor 2 (TRAILR2) agonist and with 5-fluorouracil (5-FU).
Experimental Design: C2Am was labeled with a NIR fluorophore and injected intravenously into mice bearing human colorectal TRAIL-sensitive Colo205 and TRAIL-resistant HT-29 xenografts that had been treated with a potent agonist of TRAILR2 and in Colo205 tumors treated with 5-FU.
Results: Three-dimensional (3D) MSOT images of probe distribution showed development of tumor contrast within 3 hours of probe administration and a signal-to-background ratio in regions containing dead cells of &gt;10 after 24 hours. A site-directed mutant of C2Am that is inactive in PS binding showed negligible binding. Tumor retention of the active probe was strongly correlated (R2 = 0.97, P value &lt; 0.01) with a marker of apoptotic cell death measured in histologic sections obtained post mortem.
Conclusions: The rapid development of relatively high levels of contrast suggests that NIR fluorophore-labeled C2Am could be a useful optoacoustic imaging probe for detecting early therapy-induced tumor cell death in the clinic. Clin Cancer Res; 23(22); 6893–903. ©2017 AACR.
Synergy of WEE1 and mTOR Inhibition in Mutant KRAS-Driven Lung Cancers
Authors: Hai Josephine , Liu Shengwu , Bufe Lauren , Do Khanh , Chen Ting , Wang Xiaoen , Ng Christine , Li Shuai , Tsao Ming-Sound , Shapiro Geoffrey I. , Wong Kwok-Kin 
Published: August 2017

Abstract
Purpose: KRAS-activating mutations are the most common oncogenic driver in non–small cell lung cancer (NSCLC), but efforts to directly target mutant KRAS have proved a formidable challenge. Therefore, multitargeted therapy may offer a plausible strategy to effectively treat KRAS-driven NSCLCs. Here, we evaluate the efficacy and mechanistic rationale for combining mTOR and WEE1 inhibition as a potential therapy for lung cancers harboring KRAS mutations.
Experimental Design: We investigated the synergistic effect of combining mTOR and WEE1 inhibitors on cell viability, apoptosis, and DNA damage repair response using a panel of human KRAS-mutant and wild type NSCLC cell lines and patient-derived xenograft cell lines. Murine autochthonous and human transplant models were used to test the therapeutic efficacy and pharmacodynamic effects of dual treatment.
Results: We demonstrate that combined inhibition of mTOR and WEE1 induced potent synergistic cytotoxic effects selectively in KRAS-mutant NSCLC cell lines, delayed human tumor xenograft growth and caused tumor regression in a murine lung adenocarcinoma model. Mechanistically, we show that inhibition of mTOR potentiates WEE1 inhibition by abrogating compensatory activation of DNA repair, exacerbating DNA damage in KRAS-mutant NSCLC, and that this effect is due in part to reduction in cyclin D1.
Conclusions: These findings demonstrate that compromised DNA repair underlies the observed potent synergy of WEE1 and mTOR inhibition and support clinical evaluation of this dual therapy for patients with KRAS-mutant lung cancers. Clin Cancer Res; 23(22); 6993–7005. ©2017 AACR.
Airway Basal Cell Heterogeneity and Lung Squamous Cell Carcinoma
Authors: Hynds Robert E. , Janes Sam M. 
Published: August 2017

Abstract
Basal cells are stem/progenitor cells that maintain airway homeostasis, enact repair following epithelial injury, and are a candidate cell-of-origin for lung squamous cell carcinoma. Heterogeneity of basal cells is recognized in terms of gene expression and differentiation capacity. In this Issue, Pagano and colleagues isolate a subset of immortalized basal cells that are characterized by high motility, suggesting that they might also be heterogeneous in their biophysical properties. Motility-selected cells displayed an increased ability to colonize the lung in vivo. The possible implications of these findings are discussed in terms of basal cell heterogeneity, epithelial cell migration, and modeling of metastasis that occurs early in cancer evolution. Cancer Prev Res; 10(9); 491–3. ©2017 AACR.
See related article by Pagano et al., p. 514
CD28 and 41BB Costimulation Enhances the Effector Function of CD19-Specific Engager T Cells
Authors: Velasquez Mireya Paulina , Szoor Arpad , Vaidya Abishek , Thakkar Aarohi , Nguyen Phuong , Wu Meng-Fen , Liu Hao , Gottschalk Stephen 
Published: August 2017

Abstract
T cells expressing CD19-specific chimeric antigen receptors (CARs) with endodomains that encode a signaling domain derived from CD3ζ and CD28 or 41BB have potent antitumor activity in early-phase clinical studies for B-cell malignancies. Besides CD19-specific CARs, other approaches are actively being pursued to redirect T cells to CD19, including recombinant bispecific T-cell engager (BiTE) proteins or T cells genetically modified to express BiTEs [engager (ENG) T cells]. As BiTEs provide no costimulation, we investigated here if provision of costimulation through CD28 and 41BB enhances the effector function of CD19-ENG T cells. CD19-ENG T cells expressing CD80 and 41BBL on their cell surface (CD19-ENG.41BBL/CD80 T cells) were generated by retroviral transduction. CD19-ENG.41BBL/CD80 T cells retained their antigen specificity and had superior effector function compared with both unmodified T cells and CD19-ENG T cells expressing either CD80, 41BBL, or no costimulatory molecule, as judged by cytokine (IFNγ and IL2) production, T-cell proliferation, and their ability to sequentially kill target cells. In vivo, CD19-ENG.41BBL/CD80 T cells had superior antileukemia activity in the BV173 xenograft model, resulting in a survival advantage in comparison to CD19-ENG T cells. Thus, provision of costimulation is critical for the effector function of ENG T cells. Cancer Immunol Res; 5(10); 860–70. ©2017 AACR.
Storybridging: Four steps for constructing effective health narratives
Authors: Boeijinga Anniek , Hoeken Hans , Sanders José 
Published: August 2017

Objective: To develop a practical step-by-step approach to constructing narrative health interventions in response to the mixed results and wide diversity of narratives used in health-related narrative persuasion research. Method: Development work was guided by essential narrative characteristics as well as principles enshrined in the Health Action Process Approach. Results: The ‘storybridging’ method for constructing health narratives is described as consisting of four concrete steps: (a) identifying the stage of change, (b) identifying the key elements, (c) building the story, and (d) pre-testing the story. These steps are illustrated by means of a case study in which an effective narrative health intervention was developed for Dutch truck drivers: a high-risk, underprivileged occupational group. Conclusion: Although time and labour intensive, the Storybridging approach suggests integrating the target audience as an important stakeholder throughout the development process. Implications and recommendations are provided for health promotion targeting truck drivers specifically and for constructing narrative health interventions in general.
Early Congenital Syphilis: Recognising Symptoms of an Increasingly Prevalent Disease
Authors: Patel Nupur U. , Oussedik Elias , Landis Erin T. , Strowd Lindsay C. 
Published: August 2017

Background: Congenital syphilis (CS) is an infectious disease resulting from transplacental transmission of Treponema pallidum spirochetes from an infected mother to fetus during pregnancy. While uncommon, CS has shown an increased incidence in Canada and the United States since 2001 and 2012, respectively. Case Report: We present the case of a 5-week-old female infant with blistering rash on the palms and soles. The infant displayed decreased movement of the left upper extremity, clinically consistent with Parrot pseudoparalysis. Cutaneous involvement was limited to few tan crusted papules on the palms and soles. Mother reported a “false-positive” result of rapid plasma reagin (RPR) testing at 31 weeks. Cerebrospinal fluid studies of the infant resulted with positive Venereal Disease Research Laboratory (VRDL) test and positive m﻿icrohemagglutination assay (MHA-TP). Histopathology of a crusted papule revealed a lichenoid infiltrate composed of lymphocytes, histiocytes, and plasma cells. Immunohistochemical staining for T pallidum was negative. The patient completed treatment with a 10-day course of intravenous penicillin. Discussion: While CS is largely considered a historic entity, it has been increasing in incidence in the United States since 2012 and in Canada since the early 2000s. Diagnosis of CS can be difficult as infants may be asymptomatic or present with nonspecific signs. This case highlights the presentation of minimal cutaneous involvement as well as skeletal involvement after birth. RPR testing may result in false negatives or indeterminate results, further complicating diagnosis. Given these difficulties in screening and the increasing incidence of CS, clinicians may need to refamiliarise themselves with its clinical findings.
Patient-derived antibody recognizes a unique CD43 epitope expressed on all AML and has antileukemia activity in mice
Authors: Gillissen Marijn A. , de Jong Greta , Kedde Martijn , Yasuda Etsuko , Levie Sophie E. , Moiset Gemma , Hensbergen Paul J. , Bakker Arjen Q. , Wagner Koen , Villaudy Jullien , van Helden Pauline M. , Spits Hergen , Hazenberg Mette D. 
Published: August 2017

Key Points
AT1413 is a monoclonal antibody isolated from a cured patient with AML that recognizes CD43s, a novel epitope expressed by AML and MDS blasts. AT1413 eliminates CD43s-expressing leukemic blasts in vitro and in vivo and may have potential as a therapeutic antibody.
The impact of von Willebrand factor on factor VIII memory immune responses
Authors: Chen Juan , Schroeder Jocelyn A. , Luo Xiaofeng , Shi Qizhen 
Published: August 2017

Key PointsVWF attenuates primed T-cell proliferation and memory B-cell differentiation. VWF mitigates FVIII memory responses in FVIIInull mice.
Rolling neutrophils form tethers and slings under physiologic conditions in vivo
Authors: Marki Alex , Buscher Konrad , Mikulski Zbigniew , Pries Axel , Ley Klaus 
Published: August 2017

Abstract
Human and mouse neutrophils are known to form tethers when rolling on selectins in vitro. Tethers are ∼0.2 μm thin, ∼5–10 μm-long structures behind rolling cells that can swing around to form slings that serve as self-adhesive substrates. Here, we developed a mouse intravital imaging method, where the neutrophil surface is labeled by injecting fluorescently labeled mAb to Ly-6G. Venules in the cremaster muscle of live mice were imaged at a high frame rate using a confocal microscope equipped with a fast resonant scanner. We observed 270 tethers (median length 3.5 μm) and 31 slings (median length 6.9 µm) on 186 neutrophils of 15 mice. Out of 199 tether break events, 123 were followed by immediate acceleration of the rolling cell, which shows that tethers are load-bearing structures in vivo. In venules with a high wall shear stress (WSS; &gt; 12 dyn/cm2), median rolling velocity was higher (19 μm/s), and 43% of rolling neutrophils had visible tethers. In venules with WSS &lt; 12 dyn/cm2, only 26% of rolling neutrophils had visible tethers. We conclude that neutrophil tethers are commonly present and stabilize rolling in vivo.
LDL switches the LRP6 internalization route from flotillin dependent to clathrin dependent in hepatic cells
Authors: Yamamoto Hideki , Umeda Daisuke , Matsumoto Shinji , Kikuchi Akira 
Published: August 2017

ABSTRACT
Low-density lipoprotein (LDL) receptor-related protein 6 (LRP6) was originally identified as a co-receptor of the Wnt signalling pathway and has been shown to be involved in LDL transport. In polarized hepatocytes, many apical proteins are sorted to the basolateral membrane and then internalized and transported to the apical bile canalicular membrane – a process known as transcytosis. We show that LRP6 is transcytosed to the apical membrane of polarized hepatic HepG2 cells via a flotillin-dependent manner in the absence of LDL. LRP6 formed a complex with Niemann–Pick type C1-like 1 (NPC1L1), which is localized to the bile canalicular membrane of the liver and is involved in cholesterol absorption from the bile. LRP6 was required for apical membrane localization of NPC1L1 in the absence of LDL. Clathrin-dependent LRP6 internalization occurred in the presence of LDL, which resulted in trafficking of LRP6 to the lysosome, thereby reducing apical sorting of LRP6 and NPC1L1. These results suggest that LRP6 endocytosis proceeds by two routes, depending on the presence of LDL, and that LRP6 controls the intracellular destination of NPC1L1 in hepatocytes.
Mosaic loss of non-muscle myosin IIA and IIB is sufficient to induce mammary epithelial proliferation
Authors: Nguyen-Ngoc Kim-Vy , Silvestri Vanesa L. , Georgess Dan , Fairchild Amanda N. , Ewald Andrew J. 
Published: August 2017

ABSTRACT
The mammary epithelium elaborates through hormonally regulated changes in proliferation, migration and differentiation. Non-muscle myosin II (NMII) functions at the interface between contractility, adhesion and signal transduction. It is therefore a plausible regulator of mammary morphogenesis. We tested the genetic requirement for NMIIA and NMIIB in mammary morphogenesis through deletion of the three NMII heavy chain-encoding genes (NMHCIIA, NMHCIIB and NMHCIIC; also known as MYH9, MYH10 and MYH14, respectively) that confer specificity to the complex. Surprisingly, mosaic loss, but not ubiquitous loss, of NMHCIIA and NMHCIIB induced high levels of proliferation in 3D culture. This phenotype was observed even when cells were cultured in basal medium, which does not support tissue level growth of wild-type epithelium. Mosaic loss of NMIIA and NMIIB combined with FGF signaling to induce hyperplasia. Mosaic analysis revealed that the cells that were null for both NMIIA and NMIIB, as well as wild-type cells, proliferated, indicating that the regulation of proliferation is both cell autonomous and non-autonomous within epithelial tissues. This phenotype appears to be mediated by cell–cell contact, as co-culture did not induce proliferation. Mosaic loss of NMIIA and NMIIB also induced excess proliferation in vivo. Our data therefore reveal a role for NMIIA and NMIIB as negative regulators of proliferation in the mammary epithelium.
Financial Constraints: Do They Matter to Allocate R&D Subsidies?
Authors: Silva Filipe , Carreira Carlos 
Published: August 2017

Abstract
We examine whether subsidies are allocated to financially constrained firms and if they effectively alleviate these constraints. We claim that in addition to the usual “public good” arguments behind the allocation of subsidies, the extent to which firms are able to obtain external funding should not be overlooked. Overall, our results question both the allocation and the effectiveness of subsidies in alleviating financial constraints of firms willing to innovate. Additionally, the decision criteria for allocating public funds seem to be similar from those used by the private investors. These results have important implications on the design of future innovation policy.
Fertility and labor supply of the old with pay-as-you-go pension and child allowances
Authors: Chen Hung-Ju , Miyazaki Koichi 
Published: August 2017

Abstract
We investigate the effects of pay-as-you-go pension and child allowances on fertility, labor supply of the old, and welfare. For this purpose, we analyze a small open overlapping-generations model in which fertility and an old agent’s labor supply (retirement time) are endogenized with pay-as-you-go pension and child allowances. We find that how the pay-as-you-go pension tax rate affects the fertility rate depends on whether an old agent retires. When an old agent fully retires, then the size of the interest rate and fertility rate determine the effect of the pay-as-you-go pension tax rate on the fertility rate. When an old agent works, the pay-as-you-go pension tax rate certainly reduces the fertility rate. In addition, how child allowances affect the fertility rate depends on whether an old agent works. If an old agent retires fully, then an increase in the child allowance tax rate increases the fertility rate. When an old agent works, this is not necessarily true, which suggests that an old agent’s labor status should be taken into account when we evaluate the effects of the social security system on economic variables. In addition, we examine the effect of the social security tax rates on welfare and provide numerical examples.
The role of IPRs on prices, wages and growth in a two country directed technical change model
Authors: Afonso Óscar 
Published: August 2017

Abstract
We develop a two country, Innovator and Follower, directed technical change model between tradable and nontradable sectors. The Innovator performs innovative R&D. The Follower imitates, in a pre-trade context, and adopts, in a trade scenario, the available technological knowledge. We start by considering the pre-trade context and then we analyze the trade scenario. In both regimes – imitation and adoption – and in BGP, international IPRs protection, R&D productivity, scale-effects intensity and substitutability between sectors determine the stable and unique worldwide economic growth rate and the technological-knowledge bias, which, in turn, affects relative prices and wages. Depending on IPRs protection, imitation and adoption can either amplify or slow down the technological-knowledge bias and thus the real exchange rate, the wage inequality and the worldwide growth rate. For example, under technological-knowledge adoption with positive international IPRs protection and substitutability, wages tend to be higher in the Innovator, technological knowledge and intra-country wage inequality are biased towards the tradable sector, and the real exchange rate accommodates the Balassa-Samuelson proposal.
Biomechanical comparison of a novel monocortical and two common bicortical external fixation systems regarding rigidity and dynamic stability
Authors: Varady Patrick A. , Greinwald Markus , Augat Peter 
Published: August 2017

Abstract

Aim:
To biomechanically compare a monocortical single frame external fixator (Orthofix UNYCO) with two bicortical fixator systems (dual frame: Stryker Hoffmann and single frame: Synthes LEF) with respect to system rigidity and stability under cyclic loading.

Methods:
The fixator systems were assessed for axial rigidity under loads which would occur clinically during fixator application and dynamic stability (cyclic fatigue) under loads which would occur in the first week postoperatively. Tests were performed on porcine tibiae (n>5 per group) with characteristic frame configurations. Loads were applied with an electrodynamic material testing machine and pin and frame deformations were continuously monitored with a marker based motion capturing system.

Results:
The bicortical single frame fixator revealed the largest rigidity (276±55) N/mm and was 20% (p=0.116) stiffer compared to the bicortical dual frame configuration and 39% (p=0.003) stiffer compared to the monocortical system. All systems survived 4000 cycles of loading, with the smallest vertical displacement (2.44±0.54 mm) observed for the bicortical dual frame system, followed by the monocortical single frame (3±0.55 mm, p=0.85) and bicortical single frame (3.25±0.96 mm, p=0.215).

Conclusion:
The monocortical fixation system performed comparably to the bicortical systems for its intended use as a temporary treatment before a definitive fracture osteosynthesis by plating or nailing.