bluuebunny/crossref_metadata_2025_split huggingface dataset:
23814, an Inhibitory Antibody of Ligand-Mediated Notch1 Activation, Modulates Angiogenesis and Inhibits Tumor Growth without Gastrointestinal Toxicity
Authors: Proia Theresa , Jiang Feng , Bell Alisa , Nicoletti Richard , Kong Lingxin , Kreuter Kelly , Poling Laura , Winston William M. , Flaherty Meghan , Weiler Solly , Perino Samantha , O'Hagan Ronan , Lin Jie , Gyuris Jeno , Okamura Heidi 
Published: May 2015

Abstract
Dysregulation of Notch signaling has been implicated in the development of many different types of cancer. Notch inhibitors are being tested in the clinic, but in most cases gastrointestinal and other toxicities have limited the dosage and, therefore, the effectiveness of these therapies. Herein, we describe the generation of a monoclonal antibody against the ligand-binding domain of the Notch1 receptor that specifically blocks ligand-induced activation. This antibody, 23814, recognizes both human and murine Notch1 with similar affinity, enabling examination of the effects on both tumor and host tissue in preclinical models. 23814 blocked Notch1 function in vivo, inhibited functional angiogenesis, and inhibited tumor growth without causing gastrointestinal toxicity. The lack of toxicity allowed for combination of 23814 and the VEGFR inhibitor tivozanib, resulting in significant growth inhibition of several VEGFR inhibitor-resistant tumor models. Analysis of the gene expression profiles of an extensive collection of murine breast tumors enabled the successful prediction of which tumors were most likely to respond to the combination of 23814 and tivozanib. Therefore, the use of a specific Notch1 antibody that does not induce significant toxicity may allow combination treatment with angiogenesis inhibitors or other targeted agents to achieve enhanced therapeutic benefit. Mol Cancer Ther; 14(8); 1858–67. ©2015 AACR.
ZBTB7A Suppresses Melanoma Metastasis by Transcriptionally Repressing MCAM
Authors: Liu Xue-Song , Genet Matthew D. , Haines Jenna E. , Mehanna Elie K. , Wu Shaowei , Chen Hung-I Harry , Chen Yidong , Qureshi Abrar A. , Han Jiali , Chen Xiang , Fisher David E. , Pandolfi Pier Paolo , Yuan Zhi-Min 
Published: May 2015

Abstract
The excessive metastatic propensity of melanoma makes it the most deadly form of skin cancer, yet the underlying mechanism of metastasis remains elusive. Here, mining of cancer genome datasets discovered a frequent loss of chromosome 19p13.3 and associated downregulation of the zinc finger transcription factor ZBTB7A in metastatic melanoma. Functional assessment of ZBTB7A-regulated genes identified MCAM, which encodes an adhesion protein key to melanoma metastasis. Using an integrated approach, it is demonstrated that ZBTB7A directly binds to the promoter and transcriptionally represses the expression of MCAM, establishing ZBTB7A as a bona fide transcriptional repressor of MCAM. Consistently, downregulation of ZBTB7A results in marked upregulation of MCAM and enhanced melanoma cell invasion and metastasis. An inverse correlation of ZBTB7A and MCAM expression in association with melanoma metastasis is further validated with data from analysis of human melanoma specimens.
Implications: Together, these results uncover a previously unrecognized role of ZBTB7A in negative regulation of melanoma metastasis and have important clinical implications. Mol Cancer Res; 13(8); 1206–17. ©2015 AACR.
Metformin reduces hyper-reactivity of platelets from patients with polycystic ovary syndrome by improving mitochondrial integrity
Authors: Elgheznawy Amro , Popp Rüdiger , Rogowski Paul , Dornauf Imke , Dröse Stefan , Fleming Ingrid , Randriamboavonjy Voahanginirina , Mann W. Alexander 
Published: May 2015

SummaryPolycystic ovary syndrome (PCOS) is associated with decreased fertility, insulin resistance and an increased risk of developing cardiovascular disease. Treating PCOS patients with metformin improves fertility and decreases cardiovascular complications. Given that platelet activation contributes to both infertility and cardiovascular disease development, we assessed platelet reactivity in PCOS patients and the consequences of metformin treatment. Compared to washed platelets from healthy donors, platelets from PCOS patients demonstrated enhanced reactivity and impaired activation of the AMP-activated kinase (AMPK). PCOS platelets also demonstrated enhanced expression of mitochondrial proteins such as the cytochrome c reductase, ATP synthase and the voltage-dependent anion channel-1. However, mitochondrial function was impaired as demonstrated by a decreased respiration rate. In parallel, the phosphorylation of dynamin-related protein-1 (Drp-1) on Ser616 was increased while that on Ser637 decreased. The latter changes were accompanied by decreased mitochondrial size. In insulin-resistant PCOS patients (HOMA-IR> 2) metformin treatment (1.7 g per day for 4 weeks to 6 months) improved insulin sensitivity, restored mitochondrial integrity and function and normalised platelet aggregation. Treatment was without effect in PCOS patients with HOMA-IR< 2. Moreover, treatment of megakaryocytes with metformin enhanced mitochondrial content and in the same cells metformin enhanced the phosphorylation of the Drp-1 on Ser637 via an AMPK[uni03B1]1-dependent mechanism. In conclusion, the improvement of mitochondrial integrity and platelet reactivity may contribute to the beneficial effects of metformin on cardiovascular disease.
An atypical IgM class platelet cold agglutinin induces GPVI-dependent aggregation of human platelets
Authors: Sánchez Guiu Isabel , Martínez-Martinez Irene , Martínez Constantino , Navarro-Fernandez José , Garcia-Candel Faustino , Ferrer-Marín Francisca , Vicente Vicente , Watson Steve , Andrews Robert , Gardiner Elizabeth , Rivera José , Lozano María 
Published: May 2015

SummaryPlatelet cold agglutinins (PCA) cause pseudothrombocytopenia, spurious thrombocytopenia due to ex vivo platelet clumping, complicating clinical diagnosis, but mechanisms and consequences of PCA are not well defined. Here, we characterised an atypical immunoglobulin (Ig)M PCA in a 37-year-old woman with lifelong bleeding and chronic moderate thrombocytopenia, that induces activation and aggregation of autologous or allogeneic platelets via interaction with platelet glycoprotein (GP)VI. Patient temperature-dependent pseudothrombocytopenia was EDTA-independent, but was prevented by integrin αIIbβ3 blockade. Unstimulated patient platelets revealed elevated levels of bound IgM, increased expression of activation markers (P-selectin and CD63), low GPVI levels and abnormally high thromboxane (TX)A2 production. Patient serum induced temperature- and αIIbβ3-dependent decrease of platelet count in allogeneic donorcitrated platelet-rich plasma (PRP), but not in PRP from Glanzmann’s thrombasthenia or afibrinogenaemia patients. In allogeneic platelets, patient plasma induced shape change, P-selectin and CD63 expression, 14C-serotonin release, and TXA2 production. Activation was not inhibited by aspirin, cangrelor or blocking anti-Fc receptor (FcγRIIA) antibody, but was abrogated by inhibitors of Src and Syk, and by a soluble GPVI-Fc fusion protein. GPVI-deficient platelets were not activated by patient plasma. These data provide the first evidence for an IgM PCA causing platelet activation/aggregation via GPVI. The PCA activity persisted over a five-year follow-up period, supporting a causative role in patient chronic thrombocytopenia and bleeding.
Prehospital administration of P2Y12 inhibitors and early coronary reperfusion in primary PCI: an observational comparative study
Authors: Ratcovich Hanna , Biasco Luigi , Pedersen Frants , Helqvist Steffen , Saunamaki Kari , Tilsted Hans-Henrik , Clemmensen Peter , Olivecrona Goran , Kelbaek Henning , Jørgensen Erik , Engstrøm Thomas , Holmvang Lene , Backer Ole De 
Published: May 2015

SummaryThe newer oral P2Y12 inhibitors prasugrel and ticagrelor have been reported to be more potent and faster-acting antiplatelet agents than clopidogrel. This study aimed to investigate whether prehospital loading with prasugrel or ticagrelor improves early coronary reperfusion as compared to prehospital loading with clopidogrel in a real-world ST-elevation myocardial infarction (STEMI) setting. Over a 70-month period, 3497 patients with on-going STEMI of less than 6 hours and without cardiac arrest or cardiogenic shock underwent primary percutaneous coronary intervention (PPCI) at our centre. The primary endpoint of this study was the proportion of patients who did not meet the criteria for TIMI (Thrombolysis In Myocardial Infarction) flow grade 3 in the infarct-related artery at initial angiography before PPCI. Pre-hospital loading with prasugrel (n = 883) or ticagrelor (n = 491) did not significantly improve coronary reperfusion as compared to prehospital loading with clopidogrel (n = 1,532) – a TIMI-flow 3 at initial angiography was absent in 71.7 %, 69.0 % and 71.5 % of patients, respectively. Major adverse cardiac event (MACE) rates were low at 30 days (3.4 % to 4.0 %) and did not significantly differ between the different P2Y12 inhibitor regimens. In conclusion, this large observational, non-randomised study is the first to show that prehospital loading with the newer P2Y12 inhibitors does not improve early coronary reperfusion as compared to prehospital loading with clopidogrel in a PPCI cohort excluding cardiac arrest and cardiogenic shock.
Active but inoperable thrombin is accumulated in a plasma protein layer surrounding Streptococcus pyogenes
Authors: Hurley Sinead , Malmström Erik , Plug Tom , Shannon Oonagh , Meijers Joost , Mörgelin Matthias , Björck Lars , Herwald Heiko , Naudin Clément 
Published: May 2015

SummaryActivation of thrombin is a critical determinant in many physiological and pathological processes including haemostasis and inflammation. Under physiological conditions many of these functions are involved in wound healing or eradication of an invading pathogen. However, when activated systemically, thrombin can contribute to severe and life-threatening conditions by causing complications such as multiple multi-organ failure and disseminated intravascular coagulation. In the present study we investigated how the activity of thrombin is modulated when it is bound to the surface of Streptococcus pyogenes. Our data show that S. pyogenes bacteria become covered with a proteinaceous layer when incubated with human plasma, and that thrombin is a constituent of this layer. Though the coagulation factor is found attached to the bacteria with a functional active site, thrombin has lost its capacity to interact with its natural substrates and inhibitors. Thus, the interaction of bacteria with human plasma renders thrombin completely inoperable at the streptococcal surface. This could represent a host defense mechanism to avoid systemic activation of coagulation which could be otherwise induced when bacteria enter the circulation and cause systemic infection.
Two doses of rivaroxaban versus aspirin for prevention of recurrent venous thromboembolism
Authors: Bauersachs Rupert , Beyer-Westendorf Jan , Bounameaux Henri , Brighton Timothy , Cohen Alexander , Davidson Bruce , Holberg Gerlind , Kakkar Ajay , Lensing Anthonie , Prins Martin , Haskell Lloyd , Bellen Bonno van , Verhamme Peter , Wells Philip , Prandoni Paolo , Weitz Jeffrey ,   the EINSTEIN CHOICE Investigators
Published: May 2015

SummaryPatients with unprovoked venous thromboembolism (VTE) are at high risk for recurrence. Although rivaroxaban is effective for extended VTE treatment at a dose of 20 mg once daily, use of the 10 mg dose may further improve its benefit-to-risk ratio. Low-dose aspirin also reduces rates of recurrent VTE, but has not been compared with anticoagulant therapy. The EINSTEIN CHOICE study is a multicentre, randomised, double-blind, active-controlled, event-driven study comparing the efficacy and safety of two once daily doses of rivaroxaban (20 and 10 mg) with aspirin (100 mg daily) for the prevention of recurrent VTE in patients who completed 6–12 months of anticoagulant therapy for their index acute VTE event. All treatments will be given for 12 months. The primary efficacy objective is to determine whether both doses of rivaroxaban are superior to aspirin for the prevention of symptomatic recurrent VTE, while the principal safety outcome is the incidence of major bleeding. The trial is anticipated to enrol 2,850 patients from 230 sites in 31 countries over a period of 27 months. In conclusion, the EINSTEIN CHOICE study will provide new insights into the optimal antithrombotic strategy for extended VTE treatment by comparing two doses of rivaroxaban with aspirin (clinicaltrials.gov NCT02064439).
Sleep apnea and venous thromboembolism
Authors: Mattiuzzi Camilla , Franchini Massimo , Lippi Giuseppe 
Published: May 2015

SummaryRecent evidence suggests that obstructive sleep apnea is a significant and independent risk factor for a number of cardiovascular disorders. Since the association between obstructive sleep apnea and cardiovascular disease is mediated by endothelial dysfunction, hypercoagulability and platelet abnormalities, we sought to investigate whether sleep apnea may also be considered a risk factor for venous thromboembolism (VTE). We carried out an electronic search in Medline and Scopus using the keywords “apnea” OR “apnoea” AND “venous thromboembolism” OR “deep vein thrombosis” OR “pulmonary embolism” in “Title/Abstract/Keywords”, with no language or date restriction. Fifteen studies (8 case-control, 4 retrospective observational, 2 prospective case-control and 1 prospective observational) were finally selected for this systematic review. In all studies except one (14/15; 93%), obstructive sleep apnea was found to be an independent risk factor for VTE, either deep-vein thrombosis (DVT) or pulmonary embolism (PE). In the two prospective case-control studies the risk of DVT or PE was found to be two-to three-fold higher in patients with obstructive sleep apnea than in those without. In conclusion, the current epidemiological evidence supports the hypothesis that obstructive sleep apnea may be an independent risk factor for VTE.
Feedback Mechanisms for Cardiac-Specific MicroRNAs and cAMP Signaling in Electrical Remodeling
Authors: Myers Richard , Timofeyev Valeriy , Li Ning , Kim Catherine , Ledford Hannah A. , Sirish Padmini , Lau Victor , Zhang Yinuo , Fayyaz Kiran , Singapuri Anil , Lopez Javier E. , Knowlton Anne A. , Zhang Xiao-Dong , Chiamvimonvat Nipavan 
Published: May 2015

Background—

Loss of transient outward K
+
current (I
to
) is well documented in cardiac hypertrophy and failure both in animal models and in humans. Electrical remodeling contributes to prolonged action potential duration and increased incidence of arrhythmias. Furthermore, there is a growing body of evidence linking microRNA (miR) dysregulation to the progression of both conditions. In this study, we examined the mechanistic basis underlying miR dysregulation in electrical remodeling and revealed a novel interaction with the adrenergic signaling pathway.

Methods and Results—

We first used a tissue-specific knockout model of
Dicer1
in cardiomyocytes to reveal the overall regulatory effect of miRs on the ionic currents and action potentials. We then validated the inducible cAMP early repressor as a target of
miR-1
and took advantage of a clinically relevant model of post myocardial infarction and miR delivery to probe the mechanistic basis of miR dysregulation in electrical remodeling. These experiments revealed the role of inducible cAMP early repressor as a repressor of
miR-1
and I
to
, leading to prolonged action potential duration post myocardial infarction. In addition, delivery of
miR-1
and
miR-133a
suppressed inducible cAMP early repressor expression and prevented both electrical remodeling and hypertrophy.

Conclusions—
Taken together, our results illuminate the mechanistic links between miRs, adrenergic signaling, and electrical remodeling. They also serve as a proof-of-concept for the therapeutic potential of miR delivery post myocardial infarction.
Reactivity to the p305 Epitope of the α
1G
T‐Type Calcium Channel and Autoimmune‐Associated Congenital Heart Block
Authors: Markham Androo J. , Rasmussen Sara E. , Salmon Jane E. , Martinez‐Ortiz Wilnelly , Cardozo Timothy J. , Clancy Robert M. , Buyon Jill P. 
Published: May 2015

Background

Only 2% of mothers positive for anti‐
SSA
/Ro (Ro) antibodies have children with congenital heart block (
CHB
). This study aimed to determine whether reactivity with p305, an epitope within the α
1G
T‐type calcium channel, confers added risk over anti‐Ro antibodies.

Methods and Results

Using sera from anti‐Ro‐exposed pregnancies resulting in offspring with
CHB
, no disease but
CHB
‐sibling, and no disease and no
CHB
‐sibling, as well as disease (lupus without anti‐Ro) and healthy controls, reactivities were determined for binding to Ro60, p305, and an epitope within Ro60, p133‐Ro60, which shares structural properties with p305, including key amino acids and an α‐helical structure. Candidate peptides were further evaluated in an in vitro model that assessed the binding of maternal antibodies to apoptotic cells. In anti‐Ro‐positive mothers, anti‐p305 autoantibodies (>3
SD
above healthy controls) were detected in 3/59 (5%)
CHB
pregnancies, 4/30 (13%) unaffected pregnancies with a
CHB
‐sibling, and 0/42 (0%) of unaffected pregnancies with no
CHB
‐sibling. For umbilical bloods (61
CHB
, 41 healthy with
CHB
sibling), no association of anti‐p305 with outcome was detected; however, overall levels of anti‐p305 were elevated compared to mothers during pregnancy in all groups studied. For anti‐p133‐Ro60, reactivity paralleled that of anti‐p305. In the screen employing apoptotic cells, p133‐Ro60, but not p305, significantly attenuated the binding of immunoglobulin G isolated from a mother whose child had
CHB
(42.1% reduced to 13.9%, absence/presence of p133‐Ro60, respectively,
P
<0.05).

Conclusions

These data suggest that anti‐p305 is not a robust maternal marker for assessing increased risk of
CHB
during an anti‐
SSA
/Ro pregnancy.
Centennial Changes of the Global Water Cycle in CMIP5 Models
Authors: Levang Samuel J. , Schmitt Raymond W. 
Published: May 2015

Abstract
The global water cycle is predicted to intensify under various greenhouse gas emissions scenarios. Here the nature and strength of the expected changes for the ocean in the coming century are assessed by examining the output of several CMIP5 model runs for the periods 1990–2000 and 2090–2100 and comparing them to a dataset built from modern observations. Key elements of the water cycle, such as the atmospheric vapor transport, the evaporation minus precipitation over the ocean, and the surface salinity, show significant changes over the coming century. The intensification of the water cycle leads to increased salinity contrasts in the ocean, both within and between basins. Regional projections for several areas important to large-scale ocean circulation are presented, including the export of atmospheric moisture across the tropical Americas from Atlantic to Pacific Ocean, the freshwater gain of high-latitude deep water formation sites, and the basin averaged evaporation minus precipitation with implications for interbasin mass transports.
Political Change, State Autonomy, and Post-Neoliberalism in Ecuador, 2007–2012
Authors: Gallegos Franklin Ramírez 
Published: May 2015

Along with other progressive experiments in the region, the government of the Citizens’ Revolution has restored the state to a central position with regard to social coordination and the promotion of economic development. The open conflict created by the return of the state between 2007 and 2012 transformed power relationships, allowing civil government to expand the state’s relative autonomy and orient it toward constructing a public policy agenda associated with transcending neoliberalism. The challenge of this transition has been to modify the pattern of commodity specialization away from the primacy of primary exports. While reappropriating the surplus that comes from the income from strategic resources increases national sovereignty, it may also contribute to preserving the nation’s position in the international division of labor. The National Plan for Living Well aims at overcoming the centrality of the primary sector and of oil exports in the national economy. En convergencia con otros gobiernos progresistas de la region, el gobierno del la Revolución Ciudadana relanza el Estado al primer plano de la coordinación social y la promoción del desarrollo. El conflictivo proceso político abierto en relación a dicho retorno estatal entre 2007 y 2012 trastrocó de los factores de poder y permitió al gobierno civil ampliar la autonomía relativa del Estado y orientarlo hacia la construcción de una agenda de políticas públicas asociada con la superación del neoliberalismo. El desafio de dicha transición reside en la posibilidad de modificar el patrón de especialización productiva más allá de la centralidad de las exportaciones primarias. Aunque la estrategia estatal de reapropriación del excedente que proviene de las rentas de recursos estratégicos eleva los márgenes de soberanía nacional respecto a la determinación global, también puede contribuir a la continuidad del lugar del país en la vigente división internacional del trabajo. El Plan Nacional del Buen Vivir apunta a superar en el mediano plazo la centralidad del sector primario y de las exportaciones petroleras en la economía nacional.
MRI and comparison mammography: a worthy diagnostic alliance for breast microcalcifications?
Authors: Brnic Dijana , Brnic Darko , Simundic Ivan , Vanjaka Rogosic Lucija , Tadic Tade 
Published: May 2015

Background There is a lack of data concerning diagnostic performance of magnetic resonance imaging (MRI) in patients with new or increasing microcalcifications. Purpose To evaluate suspicious microcalcifications by using comparison mammography, MRI, and a combination of both methods. Material and Methods Our study group consisted of 55 patients with mammographically detected BI-RADS (Breast Imaging Reporting and Data System) 3–5 microcalcifications for whom comparison mammograms were available. All patients underwent breast MRI before SVAB (stereotactic vacuum-assisted biopsy). Diagnostic performances of comparison mammography and MRI were evaluated, as well as the combination of the respective imaging findings. Results Of the 55 microcalcification cases, 35 showed progression and 20 were stable between interval screenings. The negative predictive value (NPV) of comparison mammography was 100%, whereas the NPV of MRI was 92%. However, the specificity of combination of findings was 97%, significantly higher than the 42% specificity of comparison mammography ( P < 0.001). Additionally, the positive predictive value of combination of findings was 93% versus 44% of comparison mammography ( P = 0.001). Conclusion A biopsy is recommended when MRI positive lesion corresponding the area of new or increasing mammographic microcalcifications is detected. Patients with stable microcalcifications can continue follow-up mammography, regardless of MRI result.