bluuebunny/crossref_metadata_2025_split huggingface dataset:
An RNA-Based Digital Circulating Tumor Cell Signature Is Predictive of Drug Response and Early Dissemination in Prostate Cancer
Authors: Miyamoto David T. , Lee Richard J. , Kalinich Mark , LiCausi Joseph A. , Zheng Yu , Chen Tianqi , Milner John D. , Emmons Erin , Ho Uyen , Broderick Katherine , Silva Erin , Javaid Sarah , Kwan Tanya Todorova , Hong Xin , Dahl Douglas M. , McGovern Francis J. , Efstathiou Jason A. , Smith Matthew R. , Sequist Lecia V. , Kapur Ravi , Wu Chin-Lee , Stott Shannon L. , Ting David T. , Giobbie-Hurder Anita , Toner Mehmet , Maheswaran Shyamala , Haber Daniel A. 
Published: January 2018

Abstract
Blood-based biomarkers are critical in metastatic prostate cancer, where characteristic bone metastases are not readily sampled, and they may enable risk stratification in localized disease. We established a sensitive and high-throughput strategy for analyzing prostate circulating tumor cells (CTC) using microfluidic cell enrichment followed by digital quantitation of prostate-derived transcripts. In a prospective study of 27 patients with metastatic castration-resistant prostate cancer treated with first-line abiraterone, pretreatment elevation of the digital CTCM score identifies a high-risk population with poor overall survival (HR = 6.0; P = 0.01) and short radiographic progression-free survival (HR = 3.2; P = 0.046). Expression of HOXB13 in CTCs identifies 6 of 6 patients with ≤12-month survival, with a subset also expressing the ARV7 splice variant. In a second cohort of 34 men with localized prostate cancer, an elevated preoperative CTCL score predicts microscopic dissemination to seminal vesicles and/or lymph nodes (P &lt; 0.001). Thus, digital quantitation of CTC-specific transcripts enables noninvasive monitoring that may guide treatment selection in both metastatic and localized prostate cancer.
Significance: There is an unmet need for biomarkers to guide prostate cancer therapies, for curative treatment of localized cancer and for application of molecularly targeted agents in metastatic disease. Digital quantitation of prostate CTC-derived transcripts in blood specimens is predictive of abiraterone response in metastatic cancer and of early dissemination in localized cancer. Cancer Discov; 8(3); 288–303. ©2018 AACR.
See related commentary by Heitzer and Speicher, p. 269.
This article is highlighted in the In This Issue feature, p. 253
Alteration of von Willebrand Factor after Transcatheter Aortic Valve Replacement in the Absence of Paravalvular Regurgitation
Authors: Pawlitschek Felix , Keyl Cornelius , Zieger Barbara , Budde Ulrich , Beyersdorf Friedhelm , Neumann Franz-Josef , Stratz Christian , Nührenberg Thomas , Trenk Dietmar 
Published: January 2018

AbstractModerate or severe paravalvular regurgitation after transcatheter aortic valve implantation (TAVI) is frequently associated with a loss of high-molecular-weight multimers of von Willebrand factor (VWF) and a reduced VWF collagen-binding capacity. It is unclear whether this phenomenon can also be observed in patients with mild paravalvular regurgitation, and whether there are differences between patients undergoing conventional aortic valve replacement (AVR) or TAVI. We analysed the multimeric structure of VWF and the ratio of VWF collagen-binding capacity to VWF antigen pre- and postoperatively in 12 patients scheduled for AVR and in 31 patients scheduled for TAVI. Echocardiographic examinations were performed pre-, intra- and postoperatively. Nine patients (75%) undergoing AVR and 18 patients (58%) undergoing TAVI showed pathological VWF functionality preoperatively (p = 0.48). Five to 7 days postoperatively, VWF functionality normalised in all patients with AVR, four of them with mild paravalvular regurgitation. VWF functionality was still altered in nine patients after TAVI (p = 0.044 between groups), five of them with and four without mild paravalvular regurgitation (p = 0.1).Altered VWF functionality was observed in nearly one-third of patients after TAVI, but not after AVR. This phenomenon was not related to paravalvular regurgitation, but may indicate differences in the response of the haemostatic system to the prosthetic heart valve design or the valve replacement procedure.
Amino-Fucoidan as a Vector for rtPA-Induced Fibrinolysis in Experimental Thrombotic Events
Authors: Ghebouli Radouane , Loyau Stephane , Maire Murielle , Saboural Pierre , Collet Jean-Philippe , Jandrot-Perrus Martine , Letourneur Didier , Chaubet Frédéric , Michel Jean-Baptiste 
Published: January 2018

AbstractAcute ischaemic stroke, myocardial infarction and pulmonary embolism are the main causes of mortality and morbidity worldwide. Thrombolysis by intravenous injection of recombinant tissue plasminogen activator (rtPA) remains the most common non-interventional treatment to recanalize occluded vessels. However, this procedure is limited by significant drawbacks, including high doses and bleeding complications. Recent studies showed that fucoidan targets the intraluminal thrombus in vivo. We have developed a chimaera covalently linking fucoidan, able to target platelets within the thrombus, to dilysine, able to non-covalently bind rtPA. We hypothesize that this construct should vectorize rtPA to the thrombus, thus increasing its fibrinolytic efficacy and avoiding its deleterious effects. In vitro, rtPA mixed to dilysine fucoidan (DLF) shows a greater fibrinolytic effect than rtPA alone, both on platelet-rich thrombus and in whole blood. In vivo, occluded mesenteric vessels, carotid artery and vena cava were more efficiently recanalized by DLF complexed to rtPA than by rtPA alone. This study thus provides evidence that DLF may be a promising therapeutic tool to fight against acute thrombosis by enhancing rtPA fibrinolytic efficiency.
Clinical Impact and Course of Anticoagulant-Related Major Bleeding in Cancer Patients
Authors: Kraaijpoel Noémie , van Es Nick , Bleker Suzanne , Brekelmans Marjolein , Eerenberg Elise , Middeldorp Saskia , Cohen Alexander , Raskob Gary , Büller Harry 
Published: January 2018

AbstractCancer patients with venous thromboembolism (VTE) have a two- to six-fold increased risk of anticoagulant-related major bleeding events compared with VTE patients without cancer. It is unknown whether major bleeding events are more severe in cancer patients than in those without cancer. Individual patient data from four randomized phase III trials that compared factor Xa inhibitors and vitamin K antagonists for the treatment of VTE were used to compare the severity of major bleeding events in patients with and without cancer. Using predefined criteria, the severity of the clinical presentation and course of major bleeding events were classified into four categories of increasing severity. A one-stage meta-analysis was used to evaluate the effect of cancer on the severity of the clinical presentation and course by estimating crude odds ratios (ORs) and ORs adjusted for age, sex and anticoagulant type with 95% confidence intervals (CIs). The study group comprised 290 patients with major bleeding, of whom 50 (17%) had cancer. The clinical presentation was judged to be severe (category 3 or 4) in 38% of patients with cancer and 44% of patients without cancer (adjusted OR, 0.90; 95% CI, 0.47–1.72). The clinical course was found to be severe in 20 and 25% of patients with and without cancer, respectively (adjusted OR, 0.75; 95% CI, 0.35–1.61). The present study suggests that the clinical presentation and course of anticoagulant-related major bleeding events are not more severe in cancer patients than in patients without cancer. This may be reassuring for physicians who treat cancer patients with anticoagulant-related bleeding.
Defibrotide Stimulates Angiogenesis and Protects Endothelial Cells from Calcineurin Inhibitor-Induced Apoptosis via Upregulation of AKT/Bcl-xL
Authors: Wang Xiangmin , Pan Bin , Hashimoto Yuko , Ohkawara Hiroshi , Xu Kailin , Zeng Lingyu , Ikezoe Takayuki 
Published: January 2018

AbstractSinusoidal obstruction syndrome is a life-threatening complication that can occur after haematopoietic stem cell transplantation. Defibrotide (DF) has been approved for the treatment of individuals with severe sinusoidal obstruction syndrome following haematopoietic stem cell transplantation in the European Union and the United States. However, the precise mechanisms by which DF protects endothelial cells remain to be elucidated. In this study, we found that DF stimulated angiogenesis in vitro and in vivo as assessed by vascular tube formation, scratch-wound repair and Matrigel plug assays. These effects were associated with an activation of pro-survival signalling pathways, including AKT (protein kinase B), ERK (extracellular signal–regulated kinases) and p38. More importantly, DF alleviated calcineurin inhibitor–induced growth inhibition and apoptosis of human umbilical vein endothelial cells and human hepatic sinusoidal endothelial cells in parallel with upregulation of anti-apoptotic protein B-cell lymphoma–extra-large (Bcl-xL), which was mediated by AKT (protein kinase B). Notably, these effects were abrogated when Bcl-xL was depleted by small interfering RNA (ribonucleic acid). In addition, DF counteracted calcineurin inhibitor–induced activation of nuclear factor-κB and Janus kinase 2 (JAK2)/Signal Transducer and Activator of Transcription 3 (STAT3) signalling and production of cytokines in vascular endothelial cell–derived EA.hy926 cells. Taken together, DF has pro-angiogenic, anti-apoptotic and anti-inflammatory effects on endothelial cells. DF is a potentially useful agent to prevent the development of, and treat individuals with, endothelial cell injury–related complications after haematopoietic stem cell transplantation.
Insights into 3D Structure of ADAMTS13: A Stepping Stone towards Novel Therapeutic Treatment of Thrombotic Thrombocytopenic Purpura
Authors: Ercig Bogac , Wichapong Kanin , Reutelingsperger Chris , Vanhoorelbeke Karen , Voorberg Jan , Nicolaes Gerry 
Published: January 2018

AbstractADAMTS13 (a disintegrin and metalloprotease with a thrombospondin type-1 motif, member 13) and von Willebrand factor (VWF) can be considered as scale weights which control platelet adhesion during primary haemostasis. In a very uncommon condition designated thrombotic thrombocytopenic purpura (TTP), functional absence of ADAMTS13 tips the balance toward VWF-mediated platelet adhesion in the microcirculation. TTP is associated with a high mortality and arises from either a congenital or acquired autoimmune deficiency of the plasma enzyme ADAMTS13. In case of acquired ADAMTS13 deficiency, autoantibodies bind to and inhibit the function of ADAMTS13. Currently available treatments of TTP aim to supply ADAMTS13 through plasma exchange or are aimed at B-cell depletion with rituximab. None of the available therapeutics, however, aims at protection of ADAMTS13 from circulating autoantibodies. In this review, our aim is to describe the structure–function relationship of ADAMTS13 employing homology models and previously published crystal structures. Structural bioinformatics investigation of ADAMTS13 reveals many insights and explains how mutations and autoantibodies may lead to the pathophysiology of TTP. The results of these studies provide a roadmap for the further development of rationally designed therapeutics for the treatment of patients with acquired TTP. In addition, we share our opinion on the state of the art of the open–closed conformations of ADAMTS13 which regulate the activity of this highly specific VWF cleaving protease.
Rationale, Design and Methodology of the Computerized Registry of Patients with Venous Thromboembolism (RIETE)
Authors: Bikdeli Behnood , Jimenez David , Hawkins Mayra , Ortíz Salvador , Prandoni Paolo , Brenner Benjamin , Decousus Hervé , Masoudi Frederick , Trujillo-Santos Javier , Krumholz Harlan , Monreal Manuel ,   for the RIETE Investigators
Published: January 2018

AbstractVenous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a preventable cause of in-hospital death, and one of the most prevalent vascular diseases. There is a lack of knowledge with regards to contemporary presentation, management and outcomes of patients with VTE. Many clinically important subgroups (including the elderly, those with recent bleeding and pregnant patients) have been under-represented in clinical trials. Furthermore, design of clinical trials is challenging in some scenarios, such as in those with hemodynamically unstable PE. RIETE (Registro Informatizado Enfermedad TromboEmbolica) is a large prospective multinational ongoing registry, designed to address these unmet needs using representative data from multiple centres. Initiated in Spain in 2001, RIETE currently includes 179 centres in 24 countries and has enrolled more than 72,000 patients. RIETE has helped characterize the pattern of presentation and outcomes of VTE, including the aforementioned understudied subgroups. RIETE has recently expanded to collect long-term outcome data, and has broadened its inclusion criteria to enrol other forms of venous thrombosis (such as cerebral vein thrombosis and splanchnic vein thrombosis). The RIETE platform is also being used to conduct pragmatic comparative effectiveness studies, including randomized trials. Future steps would focus on collaboration with additional centres across the world, and efforts to ensure the quality and expansion of the registry. In conclusion, RIETE is a large ongoing registry of patients with VTE and other thrombotic conditions. Its results could be helpful for improving our understanding of the epidemiology, patterns of care and outcomes of patients with thrombotic disease.
The Pathophysiological Role of Neutrophil Extracellular Traps in Inflammatory Diseases
Authors: Bonaventura Aldo , Liberale Luca , Carbone Federico , Vecchié Alessandra , Diaz-Cañestro Candela , Camici Giovanni , Montecucco Fabrizio , Dallegri Franco 
Published: January 2018

AbstractNeutrophil pathogen-killing mechanism termed neutrophil extracellular traps (NETs) has been recently identified. NETs consist of chromatin and histones along with serine proteases and myeloperoxidase and are induced by a great variety of infectious and non-infectious stimuli. NETosis is a kind of programmed neutrophil death characterized by chromatin decondensation and release of nuclear granular contents, mainly driven by peptidylarginine deiminase 4 citrullination of histones. Although classically related to the protection against infectious pathogens, nowadays NETs have been described as a player of several pathophysiological processes. Neutrophil dysregulation has been demonstrated in the pathogenesis of most representative vascular diseases, such as acute coronary syndrome, stroke and venous thrombosis. Indeed, NETs have been identified within atherosclerotic lesions and arterial thrombi in both human beings and animal models. Moreover, an imbalance in this mechanism has been proposed as a critical source of modified and/or externalized autoantigens in autoimmune and inflammatory diseases. Finally, an update on the role of NETs in the pathogenesis of cancer has been included. In the present review, based on papers released on PubMed and MEDLINE up to July 2017, we point to update the knowledge on NETs, from their structure to their roles in infectious diseases as well as in cardiovascular diseases, autoimmunity, metabolic disorders and cancer, with a look to future perspectives and therapeutic opportunities.
Trends in use of hydroxychloroquine during pregnancy in systemic lupus erythematosus patients from 2001 to 2015
Authors: Bermas B L , Kim S C , Huybrechts K , Mogun H , Hernandez-Diaz S , Bateman B T , Desai R J 
Published: January 2018

Background Evidence suggests that continuing hydroxychloroquine (HCQ) during pregnancy in women with systemic lupus erythematosus (SLE) improves outcomes. We sought to describe time trends in the continuation, initiation, and duration of HCQ in a large population-based cohort of pregnant SLE women. Methods A cohort of pregnant women with SLE enrolled continuously in public (Medicaid, 2001–2010) or private (Optum Clinformatics, 2003–2015) health insurance between three months prior to conception and one month after delivery was identified. We assessed the proportion of women initiating or continuing HCQ and the duration of therapy during each calendar year in the study. Results A total of 5300 women with SLE were included. Of these, 852 (16.1%) were on HCQ treatment in the three-month period prior to their pregnancy. During pregnancy, the overall proportion of women with SLE taking HCQ increased from 12.4% in 2001 to 37.7% in 2015. Initiation of HCQ therapy during pregnancy increased from 2.7% in 2001 to 7.5% in 2010 (  p = 0.0002) (Medicaid) and from 4.9% in 2003 to 13.6% in 2015 (  p = 0.0001) (Clinformatics). Continuation of HCQ during pregnancy did not change significantly over time in either data set. The average cumulative day-supply of HCQ prescriptions during pregnancy increased from 37 days in 2001 to 77 days in 2010 (  p = 0.05) among HCQ initiators and from 79 days in 2001 to 125 days in 2010 (  p = 0.0009) among HCQ continuers in Medicaid. Among privately insured women, the average cumulative day-supply of HCQ prescriptions among HCQ continuers increased from 84 in 2004 to 163 in 2015 (  p = 0.0006) but did not change significantly among HCQ initiators. Conclusion The proportion of women initiating HCQ during pregnancy and the average cumulative day-supply of HCQ increased from 2001 to 2015. While these findings are encouraging, overall HCQ use during pregnancy remains low.
The association between metabolic syndrome and its components with systemic lupus erythematosus: a comprehensive systematic review and meta-analysis of observational studies
Authors: Hallajzadeh J , Khoramdad M , Izadi N , Karamzad N , Almasi-Hashiani A , Ayubi E , Qorbani M , Pakzad R , Sullman M J M , Safiri S 
Published: January 2018

Objectives Based upon inflammatory-related factors in chronic systemic lupus erythematosus (SLE), as well as the long-term prescription of corticosteroids, metabolic syndrome (MetS) prevalence is expected to be higher in SLE patients than among those without SLE. The aim of this study was to systematically analyze: (1) the worldwide prevalence of MetS in patients with SLE using different criteria, (2) the risk of MetS in patients with SLE compared with those without SLE, and (3) the risk of MetS component in patients with SLE compared with healthy controls. Methods We searched international databases, such as: Web of Science, Medline, PubMed, Scopus, Embase, CABI, CINAHL, DOAJ and Google Scholar. The articles which reported the prevalence of MetS in SLE patients, between 2006 and 2017, were included in the study if they had a: clear study design, study time and location, sound sampling approach and appropriate statistical analyses. Studies without sufficient data to determine the prevalence of MetS were excluded. Also, studies in patients suffering from other clinical diseases were not included. Results The meta-analyses of the prevalence (40 studies ( n = 6085)) and risk (20 studies ( n = 2348)) of MetS in SLE patients were conducted separately. The pooled prevalence of MetS among SLE patients was found to be 26% (95% confidence interval (CI): 22–30%), but varied from 18% (95% CI: 11–25%) to 34% (95% CI: 25–42%), depending upon the diagnostic criteria used. The overall pooled odds ratio (OR) of MetS in SLE patients, compared with healthy controls, was (OR = 2.50; 95% CI: 1.86–3.35), but this ranged from (OR = 1.23; 95% CI: 0.61–2.49) to (OR = 10.71; 95% CI: 1.33–86.48), depending upon the criteria used. Also, the risk of high fasting blood sugar (FBS; OR = 1.59; 95% CI: 1.05–2.40), low high-density lipoprotein cholesterol (HDL-C; OR = 1.43; 95% CI: 1.02–2.01), high blood pressure (BP; OR = 2.76; 95% CI: 2.19–3.47), high triglycerides (TG; OR = 2.85; 95% CI: 2.05–3.95) and high waist circumference (WC; OR = 1.37; 95% CI: 0.97–1.94) were all found to be higher in SLE patients compared with healthy controls. Conclusions The risk of MetS was significantly higher in SLE patients, compared with healthy controls, even after adjusting for publication bias. Among MetS components, high TG and high BP were most strongly associated with SLE. Considering that high TG and high BP are preventable, there is an international need to implement effective interventions to reduce MetS components in SLE patients in order to prevent serious outcomes such as cardiovascular diseases and mortality.
Analysis of Arch Widths in Patients With Isolated Pierre Robin Sequence
Authors: Ohashi A. S. C. , Varela T. , Marques I. L. , Brosco T. V. S. , Oliveira R. P. , Garib D. G. , Ozawa T. O. 
Published: January 2018

Objective: To compare arch widths of patients with isolated Robin sequence (IRS) operated using modified von Langenbeck technique and modified Furlow double-opposing z-plasty. Design: Retrospective, transversal study. Setting: Hospital of Rehabilitation of Craniofacial Anomalies, University of São Paulo, Bauru, Brazil. Patients: Three groups of patients were analyzed. Group VL comprised 30 patients with IRS operated by von Langenbeck technique (mean age of 8.1 years); group FL included 30 patients with IRS operated by Furlow technique (7.6 years); and the control group included 30 noncleft patients with class I occlusion (7.4 years). The palate repair was performed between 1.0 and 1.7 years of age in both study groups. Transversal measurements of maxillary and mandibular arches were performed digitally on 3D digital models. Statistic: The intergroup comparison was performed using analysis of variance and Tukey test. An independent t test was used to compare the complete and incomplete types of cleft in both study groups. The level of significance was 5%. Results: No statistically significant difference was found between the VL and FL groups for maxillary and mandibular arches. However, both groups showed decreased transversal dimensions compared with the control group ( P < .01) for both dental arches. No differences for arch widths were observed for complete or incomplete palatal clefts. Conclusions: No influence of palate repair techniques was observed in the transversal arch widths in patients with IRS. Children with IRS operated for palate repair showed constriction of the maxillary and mandibular dental arches compared with noncleft children regardless the palatal cleft extension.