bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endosialin-Expressing Pericytes Promote Metastatic Dissemination
Authors: Viski Carmen , König Courtney , Kijewska Magdalena , Mogler Carolin , Isacke Clare M. , Augustin Hellmut G. 
Published: September 2016

Abstract
Metastasis is a multistep process that is critically dependent on the interaction of metastasizing tumor cells with cells in the local microenvironment. Within this tumor stroma, vessel-associated pericytes and myofibroblasts share a number of traits, including the upregulated expression of the transmembrane receptor endosialin (CD248). Comparative experiments in wild-type and endosialin-deficient mice revealed that stromal endosialin does not affect primary tumor growth but strongly promotes spontaneous metastasis. Mechanistically, endosialin-expressing pericytes in the primary tumor facilitate distant site metastasis by promoting tumor cell intravasation in a cell contact–dependent manner, resulting in elevated numbers of circulating tumor cells. Corresponding to these preclinical experiments, in independent cohorts of primary human breast cancers, upregulated endosialin expression significantly correlates with increased metastasis and poorer patient survival. Together, the data demonstrate a critical role for endosialin-expressing primary tumor pericytes in mediating metastatic dissemination and identify endosialin as a promising therapeutic target in breast cancer. Cancer Res; 76(18); 5313–25. ©2016 AACR.
p21(WAF1) Mediates Cell-Cycle Inhibition, Relevant to Cancer Suppression and Therapy
Authors: El-Deiry Wafik S. 
Published: September 2016

Abstract
p21 (WAF1/CIP1; CDKN1a) is a universal cell-cycle inhibitor directly controlled by p53 and p53-independent pathways. Knowledge of the regulation and function of p21 in normal and cancer cells has opened up several areas of investigation and has led to novel therapeutic strategies. The discovery in 1993 and subsequent work on p21 has illuminated basic cellular growth control, stem cell phenotypes, the physiology of differentiation, as well as how cells respond to stress. There remain open questions in the signaling networks, the ultimate role of p21 in the p53-deficiency phenotype in the context of other p53 target defects, and therapeutic strategies continue to be a work in progress. Cancer Res; 76(18); 5189–91. ©2016 AACR.
See related article by El-Deiry et al., Cancer Res 1994;54:1169–74.
Visit the Cancer Research 75th Anniversary timeline.
Chronic Myelogenous Leukemia– Initiating Cells Require Polycomb Group Protein EZH2
Authors: Xie Huafeng , Peng Cong , Huang Jialiang , Li Bin E. , Kim Woojin , Smith Elenoe C. , Fujiwara Yuko , Qi Jun , Cheloni Giulia , Das Partha P. , Nguyen Minh , Li Shaoguang , Bradner James E. , Orkin Stuart H. 
Published: September 2016

Abstract
Tyrosine kinase inhibitors (TKI) have revolutionized chronic myelogenous leukemia (CML) management. Disease eradication, however, is hampered by innate resistance of leukemia-initiating cells (LIC) to TKI-induced killing, which also provides the basis for subsequent emergence of TKI-resistant mutants. We report that EZH2, the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), is overexpressed in CML LICs and required for colony formation and survival and cell-cycle progression of CML cell lines. A critical role for EZH2 is supported by genetic studies in a mouse CML model. Inactivation of Ezh2 in conventional conditional mice and through CRISPR/Cas9-mediated gene editing prevents initiation and maintenance of disease and survival of LICs, irrespective of BCR–ABL1 mutational status, and extends survival. Expression of the EZH2 homolog EZH1 is reduced in EZH2-deficient CML LICs, creating a scenario resembling complete loss of PRC2. EZH2 dependence of CML LICs raises prospects for improved therapy of TKI-resistant CML and/or eradication of disease by addition of EZH2 inhibitors.
Significance: This work defines EZH2 as a selective vulnerability for CML cells and their LICs, regardless of BCR–ABL1 mutational status. Our findings provide an experimental rationale for improving disease eradication through judicious use of EZH2 inhibitors within the context of standard-of-care TKI therapy. Cancer Discov; 6(11); 1237–47. ©2016 AACR.
See related article by Scott et al., p. 1248.
This article is highlighted in the In This Issue feature, p. 1197
Epigenetic Reprogramming Sensitizes CML Stem Cells to Combined EZH2 and Tyrosine Kinase Inhibition
Authors: Scott Mary T. , Korfi Koorosh , Saffrey Peter , Hopcroft Lisa E.M. , Kinstrie Ross , Pellicano Francesca , Guenther Carla , Gallipoli Paolo , Cruz Michelle , Dunn Karen , Jorgensen Heather G. , Cassels Jennifer E. , Hamilton Ashley , Crossan Andrew , Sinclair Amy , Holyoake Tessa L. , Vetrie David 
Published: September 2016

Abstract
A major obstacle to curing chronic myeloid leukemia (CML) is residual disease maintained by tyrosine kinase inhibitor (TKI)–persistent leukemic stem cells (LSC). These are BCR–ABL1 kinase independent, refractory to apoptosis, and serve as a reservoir to drive relapse or TKI resistance. We demonstrate that Polycomb Repressive Complex 2 is misregulated in chronic phase CML LSCs. This is associated with extensive reprogramming of H3K27me3 targets in LSCs, thus sensitizing them to apoptosis upon treatment with an EZH2-specific inhibitor (EZH2i). EZH2i does not impair normal hematopoietic stem cell survival. Strikingly, treatment of primary CML cells with either EZH2i or TKI alone caused significant upregulation of H3K27me3 targets, and combined treatment further potentiated these effects and resulted in significant loss of LSCs compared to TKI alone, in vitro, and in long-term bone marrow murine xenografts. Our findings point to a promising epigenetic-based therapeutic strategy to more effectively target LSCs in patients with CML receiving TKIs.
Significance: In CML, TKI-persistent LSCs remain an obstacle to cure, and approaches to eradicate them remain a significant unmet clinical need. We demonstrate that EZH2 and H3K27me3 reprogramming is important for LSC survival, but renders LSCs sensitive to the combined effects of EZH2i and TKI. This represents a novel approach to more effectively target LSCs in patients receiving TKI treatment. Cancer Discov; 6(11); 1248–57. ©2016 AACR.
See related article by Xie et al., p. 1237.
This article is highlighted in the In This Issue feature, p. 1197
Outcomes of Transvenous Lead Extraction for Cardiovascular Implantable Electronic Device Infections in Patients With Prosthetic Heart Valves
Authors: Huang Xin-miao , Fu Hai-xia , Zhong Li , Cao Jiang , Asirvatham Samuel J. , Baddour Larry M. , Sohail M. Rizwan , Nkomo Vuyisile T. , Nishimura Rick A. , Greason Kevin L. , Suri Rakesh M. , Friedman Paul A. , Cha Yong-Mei 
Published: September 2016

Background—
Lead-related or valve-related endocarditis can complicate cardiovascular implantable electronic device (CIED) infection in patients with both CIED and prosthetic valves. The objective of this study was to determine the outcomes of transvenous lead extraction for CIED infection in patients with prosthetic valves.

Methods and Results—

We retrospectively screened 794 transvenous lead extraction procedures, between September 1, 2001 and August 31, 2012, at Mayo Clinic to identify patients with prosthetic valves who underwent lead extraction for infection. Demographic, clinical, and follow-up characteristics were analyzed. In total, 51 patients (6%) met the study inclusion criteria, of whom 20 had pocket infection and 31 had lead-related or valve-related, or both, endocarditis or bloodstream infection (mean age, 67 [18] years). Staphylococcal species were the most common pathogens, including
Staphylococcus aureus
in 20 cases (39%) and coagulase-negative staphylococci in 19 cases (37%). Overall, 127 transvenous leads (median lead age, 52 months) were extracted. Of these leads, 123 (97%) were removed completely. The in-hospital mortality rate was 9.8%; no deaths were attributable to the extraction procedure. Ninety-five percent of patients who survived had no evidence of recurrent device-related or valve-related infection.

Conclusions—
Transvenous lead extraction seems safe and curative in patients with CIED infection and prosthetic valves. Cure of infection can be achieved in the majority of patients with complete CIED removal and antimicrobial therapy and without valve surgery.
Conversion to Purkinje-Related Monomorphic Ventricular Tachycardia After Ablation of Ventricular Fibrillation in Ischemic Heart Disease
Authors: Masuda Keita , Nogami Akihiko , Kuroki Kenji , Igarashi Miyako , Sekiguchi Yukio , Komatsu Yuki , Kowase Shinya , Kurosaki Kenji , Nishihara Shuzo , Niwa Koichiro , Tsuchiya Taketsugu , Igawa Masayuki , Aonuma Kazutaka 
Published: September 2016

Background—
Catheter ablation is an effective therapy for ventricular fibrillation (VF) arising from the Purkinje system in ischemic heart disease. However, some patients experience newly emergent monomorphic ventricular tachycardia (VT) after the ablation of VF. We evaluated the prevalence and mechanism of monomorphic VT after VF ablation.

Methods and Results—
Twenty-one consecutive patients with primary VF because of ischemic heart disease who underwent catheter ablation were retrospectively analyzed. Twenty of 21 patients were in electrical storm. Ventricular premature contractions triggering VF arose from the left Purkinje system and were targeted for ablation. Before the ablation, 14 of 21 patients had only VF, and the other 7 had VF and concomitant monomorphic VT. Four of the 14 patients with only VF (29%) exhibited newly emergent monomorphic VT after VF ablation. Three of these patients had Purkinje-related VTs, which were successfully eliminated by the ablation of a Purkinje network located in the same low-voltage area as the site of prior successful VF ablation. During a median follow-up of 28 months (interquartile range, 16–68 months), VF recurred in 6 of 21 patients (29%); however, there were neither electrical storms nor monomorphic VT, and all recurring arrhythmias were controlled by medical therapy alone.

Conclusions—
Over one fifth of patients with primary ischemic VF experienced newly emergent Purkinje-related monomorphic VT after VF ablation. The circuit of the monomorphic VT associated with the Purkinje network was located in the same low-voltage area as the Purkinje tissue that triggered VF and could be suppressed by additional ablation.
Clinical Experience With the Subcutaneous Implantable Cardioverter–Defibrillator in Adults With Congenital Heart Disease
Authors: Moore Jeremy P. , Mondésert Blandine , Lloyd Michael S. , Cook Stephen C. , Zaidi Ali N. , Pass Robert H. , John Anitha S. , Fish Frank A. , Shannon Kevin M. , Aboulhosn Jamil A. , Khairy Paul 
Published: September 2016

Background—
Sudden cardiac death is a major contributor to mortality for adults with congenital heart disease. The subcutaneous implantable cardioverter–defibrillator (ICD) has emerged as a novel tool for prevention of sudden cardiac death, but clinical performance data for adults with congenital heart disease are limited.

Methods and Results—

A retrospective study involving 7 centers over a 5-year period beginning in 2011 was performed. Twenty-one patients (median 33.9 years) were identified. The most common diagnosis was single ventricle physiology (52%), 9 palliated by Fontan operation and 2 by aortopulmonary shunts:
d
-transposition of the great arteries after Mustard/Senning (n=2), tetralogy of Fallot (n=2), aortic valve disease (n=2), and other biventricular surgery (n=4). A prior cardiac device had been implanted in 7 (33%). The ICD indication was primary prevention in 67% and secondary in 33% patients. The most common reason for subcutaneous ICD placement was limited transvenous access for ventricular lead placement (n=10) followed by intracardiac right-to-left shunt (n=5). Ventricular arrhythmia was induced in 17 (81%) and was converted with ≤80 Joules in all. There was one implant complication related to infection, not requiring device removal. Over a median follow-up of 14 months, 4 patients (21%) received inappropriate and 1 (5%) patient received appropriate shocks. There was one arrhythmic death related to asystole in a single ventricle patient.

Conclusions—
Subcutaneous ICD implantation is feasible for adults with congenital heart disease patients. Most candidates have single ventricle heart disease and limited transvenous options for ICD placement. Despite variable anatomy, this study demonstrates successful conversion of induced ventricular arrhythmia and reasonable rhythm discrimination during follow-up.
Experimentally Increasing the Compliance of Titin Through RNA Binding Motif-20 (RBM20) Inhibition Improves Diastolic Function In a Mouse Model of Heart Failure With Preserved Ejection Fraction
Authors: Methawasin Mei , Strom Joshua G. , Slater Rebecca E. , Fernandez Vanessa , Saripalli Chandra , Granzier Henk 
Published: September 2016

Background:
Left ventricular (LV) stiffening contributes to heart failure with preserved ejection fraction (HFpEF), a syndrome with no effective treatment options. Increasing the compliance of titin in the heart has become possible recently through inhibition of the splicing factor RNA binding motif-20. Here, we investigated the effects of increasing the compliance of titin in mice with diastolic dysfunction.

Methods:

Mice in which the RNA recognition motif (RRM) of one of the RNA binding motif-20 alleles was floxed and that expressed the MerCreMer transgene under control of the αMHC promoter (referred to as
cRbm20

ΔRRM

mice) were used. Mice underwent transverse aortic constriction (TAC) surgery and deoxycorticosterone acetate (DOCA) pellet implantation. RRM deletion in adult mice was triggered by injecting raloxifene (
cRbm20

ΔRRM

-raloxifene), with dimethyl sulfoxide (DMSO)–injected mice (
cRbm20

ΔRRM

-DMSO) as the control. Diastolic function was investigated with echocardiography and pressure-volume analysis; passive stiffness was studied in LV muscle strips and isolated cardiac myocytes before and after elimination of titin-based stiffness. Treadmill exercise performance was also studied. Titin isoform expression was evaluated with agarose gels.

Results:

cRbm20

ΔRRM

-raloxifene mice expressed large titins in the hearts, called supercompliant titin (N2BAsc), which, within 3 weeks after raloxifene injection, made up ≈45% of total titin. TAC/DOCA
cRbm20

ΔRRM

-DMSO mice developed LV hypertrophy and a marked increase in LV chamber stiffness as shown by both pressure-volume analysis and echocardiography. LV chamber stiffness was normalized in TAC/DOCA
cRbm20
ΔRRM
-raloxifene mice that expressed N2BAsc. Passive stiffness measurements on muscle strips isolated from the LV free wall revealed that extracellular matrix stiffness was equally increased in both groups of TAC/DOCA mice (
cRbm20

ΔRRM

-DMSO and
cRbm20

ΔRRM

-raloxifene). However, titin-based muscle stiffness was reduced in the mice that expressed N2BAsc (TAC/DOCA
cRbm20

ΔRRM

-raloxifene). Exercise testing demonstrated significant improvement in exercise tolerance in TAC/DOCA mice that expressed N2BAsc.

Conclusions:
Inhibition of the RNA binding motif-20–based titin splicing system upregulates compliant titins, which improves diastolic function and exercise tolerance in the TAC/DOCA model. Titin holds promise as a therapeutic target for heart failure with preserved ejection fraction.
Impacts of a Groundwater Scheme on Hydroclimatological Conditions over Southern South America
Authors: Martinez J. Alejandro , Dominguez Francina , Miguez-Macho Gonzalo 
Published: September 2016

Abstract
A sensitivity study of the impact of a groundwater scheme on hydrometeorological variables in coupled land–atmosphere simulations over southern South America is presented. It is found that shallow water tables in the groundwater scheme lead to reduced drainage and even upward capillary fluxes over parts of the central and southern La Plata basin. This leads to an increase in the simulated moisture in the root zone, which in turn produces an increase in evapotranspiration (ET) over the southern part of the domain, where ET is water limited. There is also a decrease in the near-surface temperature, in the range 0.5°–1.0°C. During the dry season, the increases in ET and relative humidity over the central La Plata coincide with an increase in precipitation downstream. Including groundwater leads to an increase in precipitation over parts of the central and southern La Plata basin during the early rainy season (October–December). The overall increase in ET and precipitation over the southern La Plata basin during the early rainy season is 13% and 10%, respectively. The additional precipitation comes from both an increase in the availability of atmospheric moisture when the groundwater scheme is used and its effect on the atmospheric instability. In the La Plata basin, including a representation of groundwater increases simulated precipitation and partially alleviates a warm and dry bias present in simulations without realistic subsurface hydrology.
Making Aircraft Vortices Visible to Radar by Spraying Water into the Wake
Authors: Shariff Karim 
Published: September 2016

AbstractAircraft trailing vortices pose a danger to following aircraft during takeoff and landing. This necessitates spacing rules, based on aircraft type, to be enforced during approach in instrument flight regulation (IFR) conditions; this can limit airport capacity. To help choose aircraft spacing based on the actual location and strength of the wake, it is proposed that wake vortices can be detected using conventional ground-based precipitation and cloud radars. This is enabled by spraying a small quantity of water into the wake from near the wing. The vortex strength is revealed by the Doppler velocity of the droplets. In the present work, droplet size distributions produced by nozzles used for aerial spraying are considered. Droplet trajectory and evaporation in the flow field is numerically calculated for a heavy aircraft, followed by an evaluation of radar reflectivity at 6 nautical miles (n mi) behind the aircraft. Small droplets evaporate, while larger droplets fall out of the wake. In the humid conditions that typically prevail during IFR, a sufficient number of droplets remain in the wake and give good signal-to-noise ratios (SNR). For conditions of average humidity, higher-frequency radars combined with spectral processing give good SNR.
Stabilization of circulating thyroglobulin mRNA transcripts in patients treated for differentiated thyroid carcinoma
Authors: Feddersen Søren , Bastholt Lars , Pedersen Susanne M 
Published: September 2016

Background The clinical utility of serum thyroglobulin in the follow-up of patients with differentiated thyroid carcinoma may be compromised by the presence of endogenous antithyroglobulin antibodies. To prevent interference by antithyroglobulin antibodies several groups have developed real-time PCR-based assays for quantification of blood thyroglobulin mRNA levels. For accurate quantification of thyroglobulin mRNA in blood preanalytical factors must be recognized and controlled. In this study, we evaluate the effect of different blood RNA stabilizing systems – the Tempus Blood RNA system and the PAXgene Blood RNA system – and storage time on RNA yield and quality, and thyroglobulin mRNA stability. Methods Blood samples from 11 patients previously treated for differentiated thyroid carcinoma were collected in K2-EDTA, Tempus and PAXgene tubes and maintained at room temperature. RNA was isolated following storage for 0 and 72 h, and RNA yield, integrity and purity was determined. Thyroglobulin, GAPDH and ACTB mRNA levels were quantified by semi-quantitative real-time PCR. Results The RNA yield was significantly higher for blood collected in Tempus tubes compared with PAXgene tubes following storage for 72 h at room temperature ( P = 0.0011). High-quality RNA could be extracted from blood collected in PAXgene and Tempus tubes. Blood collected in K2-EDTA tubes, but not in PAXgene and Tempus tubes, showed significant changes in thyroglobulin mRNA levels following storage for 72 h at room temperature ( P = 0.0263). Conclusions Stabilization of blood in PAXgene and Tempus tubes enables storage at room temperature for up to 72 h, without compromising thyroglobulin mRNA levels.
Deeply Embedded Core Normative Values and Legitimacy of Law Enforcement Authorities
Authors: Mehozay Yoav , Factor Roni 
Published: September 2016

Objectives: The current research proposes that beliefs about the legitimacy of law enforcement authorities also derive from core normative values (i.e., notions of the good and virtuous life) that stem from deeply embedded cultural orientations through which individuals operate in and interpret the world. Methods: We developed a typology of four sets of core normative value systems using multiple correspondence analysis. Data are from the European Social Survey, including 52,253 respondents from 27 countries. Results: Three of the four sets of core normative values show an association with levels of legitimacy. Conclusions: The findings provide preliminary support for our model and indicate that legitimacy perceptions are associated with core normative values, which may extend beyond individuals’ perceptions of enforcement institutions. This means that even optimal procedural conduct or efficiency may not affect the attitudes of some populations, particularly in diverse, multicultural societies. Taking into consideration, the effects of internalized core values can help inform community interventions by the police and other institutions.
Nucleoside diphosphate kinase B regulates angiogenic responses in the endothelium via caveolae formation and c-Src-mediated caveolin-1 phosphorylation
Authors: Gross Shalini , Devraj Kavi , Feng Yuxi , Macas Jadranka , Liebner Stefan , Wieland Thomas 
Published: September 2016

Nucleoside diphosphate kinase B (NDPK-B) is an enzyme required for nucleoside triphosphate homeostasis, which has been shown to interact with caveolin-1 (Cav-1). In endothelial cells (ECs), NDPK-B contributes to the regulation of angiogenesis and adherens junction (AJ) integrity. We therefore investigated whether an interaction of NDPK-B with Cav-1 in ECs is required for this regulation and the involvement of VEGF signaling herein. We report that simultaneous depletion of NDPK-B/Cav-1 in HUVECs synergistically impaired sprouting angiogenesis. NDPK-B depletion alone impaired caveolae formation, VEGF-induced phosphorylation of c-Src/Cav-1 but not of ERK1/2/AKT/eNOS. In vivo, Cav-1−/− mice showed impaired retinal vascularization at postnatal-day five, whereas NDPK-B−/− mice did not. Primary mouse brain ECs (MBMECs) from NDPK-B−/− mice showed no change in caveolae content and transendothelial-electrical resistance upon VEGF stimulation. Interestingly, NDPK-B−/− MBMECs displayed an accumulation of intracellular vesicles and increased Cav-1 levels. Dextran tracer analysis showed increased vascular permeability in the brain of NDPK-B−/− mice compared to wild type. In conclusion, our data indicate that NDPK-B is required for the correct localization of Cav-1 at the plasma membrane and the formation of caveolae. The genetic ablation of NDPK-B could partially be compensated by an increased Cav-1 content, which restored caveolae formation and some endothelial functions.