bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA30: Combined targeted therapies, where to next
Authors: Long Georgina V. 
Published: July 2015

Abstract
Combined BRAF and MEK inhibition has improved patient outcomes beyond single agent BRAF inhibition in BRAF-mutant metastatic melanoma, however 25% of patients do not have a RECIST-response and 30% progress within six months. Analysis of melanoma progressing metastases from combination-treated patients reveals that early resistance via the MAP kinase pathway is more common than that observed with single agent BRAF inhibition, which raises the questions of whether even stronger MAP kinase pathway inhibition would be of benefit to patients, and whether this is achievable therapeutically. However, the combination of MAP kinase inhibitors with immunotherapy may be a more effective strategy. Preliminary results in human tissues suggest that the presence of tumor-infiltrating lymphocytes and tumor-cell PDL1 expression may assist in patient selection for such a strategy. Early-during treatment responding metastases from combined BRAF and MEK inhibition-treated patients demonstrate similar levels of tumor-infiltrating lymphocytes as observed with single agent BRAF inhibition, suggesting that MEK inhibitors may not negatively impact the immunogenicity of targeted therapy early-on, and supports the concept that concurrent targeted- and immuno-therapy strategies may provide a greater opportunity for disease control than in sequence.
Citation Format: Georgina V. Long. Combined targeted therapies, where to next. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr IA30.
Rapid stabilisation of atherosclerotic plaque with 5-aminolevulinic acid-mediated sonodynamic therapy
Authors: Wang Liping , Wang Tengyu , Peng Chenghai , Wang Wei , Tian Zhen , Zhao Ruibo , Cao Wenwu , Li Zhitao , Sun Xin , Guo Shuyuan , Tian Ye 
Published: July 2015

Summary5-Aminolevulinic acid-mediated sonodynamic therapy (ALA-SDT) effectively induces the apoptosis of atherogenic macrophages, but whether it can stabilise atherosclerotic plaque in vivo is unclear. Here, we used an animal model to evaluate the effects of ALA-SDT on plaque stabilisation. Sixty rabbits were induced atherosclerotic plaques in the femoral artery with a combination of silastic tube placement with atherogenic diet, and randomly assigned into control (n = 12) and SDT (n = 48) groups. In the SDT group, after intravenous injected with ALA (60 mg/kg) animals underwent the treatment of ultrasound with intensities of 0.75, 1.00, 1.50 and 2.00 W/cm2 (n = 12 for each intensity). Seven days after the treatment, the plaque disruption assay was performed to test plaque stability. We found that ALA-SDT with ultrasound intensity of 1.5 W/cm2 showed the strongest efficacy to stabilise plaques. Under this condition, the frequency of plaque disruption decreased by 88 % (p < 0.01), positive area of macrophages reduced by 94 % (p < 0.001) and percentage content of lipids dropped by 60 % (p < 0.001), while percentage content of collagens increased by 127 % (p < 0.001). We also found that the plaque stabilisation by ALA-SDT was associated with increased macrophage apoptosis and apoptotic cell clearance. Moreover, ALA-SDT decreased the contents and activities of matrix metalloproteinase-2,9 and increased the levels of tissue inhibitors of matrix metalloproteinase-1,2 in plaques. Our studies demonstrate that ALA-SDT promotes plaque stabilisation by inducing macrophage elimination and inhibiting matrix degradation. This method might be a promising regimen for atherosclerosis therapy.
High levels of TSP1+/CD142+ platelet-derived microparticles characterise young patients with high cardiovascular risk and subclinical atherosclerosis
Authors: Suades Rosa , Padró Teresa , Alonso Rodrigo , Mata Pedro , Badimon Lina 
Published: July 2015

SummaryCirculating microparticles (cMPs) play important roles in cellular crosstalk and are messengers of cell activation. We have previously reported that platelet-released microparticles (pMPs) stimulate thrombosis and that lipid-lowering treatment as per guidelines in patients with familial hypercholesterolaemia (FH) is not sufficiently effective in reducing pro-inflammatory cell activation and, consequently, CD45+/CD3+-lymphocyte-derived cMP shedding. FH patients, due to life-long vascular exposure to high LDL-cholesterol levels, are at high cardiovascular risk (HCVR) and develop premature coronary artery disease. Our objectives were to investigate a) whether patients with HCVR have cMPs with a prothrombotic phenotype, and b) whether patients with magnetic resonance imaging (MRI) evidence of lipid-rich atherosclerotic lesions have a specific cMP profile regarding prothrombotic protein cargos. cMPs were isolated from HCVR-patients and from age/gender/treatment-matched control patients. cMP phenotype was characterised by triple-labelling flow cytometry. HCVR--patients have higher numbers of pMPs derived from activated platelets as well as of tissue factor-rich microparticles (TF+-cMPs) than controls (P< 0.0001). TF+-cMPs showed procoagulant activity, which associate with atherosclerotic plaque burden, indicating that TF in the cMPs is functional. In HCVR-patients, overall TF+-cMPs (monocyte-derived [CD142+/CD14+] and platelet-derived [CD142+/TSP1+]) and activated pMPs directly correlate with MRI-detected lipid-rich atherosclerotic plaques while inversely correlate with MRI-detected calcified plaques. C-statistics analysis showed that prothrombotic cMPs add significant prognostic value to a risk factor model for the prediction of lipid-rich plaques. In conclusion, the activation status of blood cells in HCVR-patients differed markedly from controls as shown by higher circulating levels of prothrombotic and TF+-cMPs. Prothrombotic cMP numbers identify subclinical atherosclerotic plaque burden.
Clinical Characteristics and Outcomes of Intravenous Inotropic Therapy in Advanced Heart Failure
Authors: Hashim Taimoor , Sanam Kumar , Revilla-Martinez Marina , Morgan Charity J. , Tallaj Jose A. , Pamboukian Salpy V. , Loyaga-Rendon Renzo Y. , George James F. , Acharya Deepak 
Published: July 2015

Background—
Inotrope use in heart failure treatment was associated with improved symptoms, but worse survival in clinical trials. However, these studies predated use of modern heart failure therapies. This study evaluates contemporary outcomes on long-term inotropes.

Methods and Results—

We collected baseline and postinotrope data on 197 patients discharged on inotropes between January 2007 and March 2013. Baseline characteristics, hemodynamic and clinical changes on inotropes, and survival were evaluated. Patients initiated on inotropes had refractory heart failure, with median baseline New York Heart Association class IV, cardiac index of 1.7 L/min per m
2
, pulmonary capillary wedge pressure of 25.6 mm Hg, and left ventricular ejection fraction of 18.7%. Inotropes were used in patients listed for transplant or scheduled for left ventricular assist device (LVAD; 60 patients), in patients being evaluated for LVAD/transplant (20 patients), for stabilization pending cardiac resynchronization therapy/percutaneous coronary intervention (4 patients), in patients who were offered LVAD but chose inotropes (15 patients), and for palliation (98 patients). Milrinone was used in 84.8% and dobutamine in 15.2%. At the end of the study, 68 patients had died, 24 were weaned off inotropes, 23 were transplanted, 32 received LVADs, and 50 remained on inotropes. Patients who received inotropes for palliation or those who preferred inotropes over LVAD had median survival of 9.0 months (interquartile range, 3.1–37.1 months), actuarial 1-year survival of 47.6%, and 2-year survival of 38.4%. Of 60 patients who were placed on inotropes as a bridge to transplant/LVAD, 55 were successfully maintained on inotropes until transplant/LVAD.

Conclusions—
Survival on inotropes for patients who are not candidates for transplant/LVAD is modestly better than previously reported, but remains poor. Inotropes are effective as a bridge to transplant/LVAD.
Ensemble Projections of Regional Climatic Changes over Ontario, Canada
Authors: Wang Xiuquan , Huang Guohe , Liu Jinliang , Li Zhong , Zhao Shan 
Published: July 2015

AbstractIn this study, high-resolution climate projections over Ontario, Canada, are developed through an ensemble modeling approach to provide reliable and ready-to-use climate scenarios for assessing plausible effects of future climatic changes at local scales. The Providing Regional Climates for Impacts Studies (PRECIS) regional modeling system is adopted to conduct ensemble simulations in a continuous run from 1950 to 2099, driven by the boundary conditions from a HadCM3-based perturbed physics ensemble. Simulations of temperature and precipitation for the baseline period are first compared to the observed values to validate the performance of the ensemble in capturing the current climatology over Ontario. Future projections for the 2030s, 2050s, and 2080s are then analyzed to help understand plausible changes in its local climate in response to global warming. The analysis indicates that there is likely to be an obvious warming trend with time over the entire province. The increase in average temperature is likely to be varying within [2.6, 2.7]°C in the 2030s, [4.0, 4.7]°C in the 2050s, and [5.9, 7.4]°C in the 2080s. Likewise, the annual total precipitation is projected to increase by [4.5, 7.1]% in the 2030s, [4.6, 10.2]% in the 2050s, and [3.2, 17.5]% in the 2080s. Furthermore, projections of rainfall intensity–duration–frequency (IDF) curves are developed to help understand the effects of global warming on extreme precipitation events. The results suggest that there is likely to be an overall increase in the intensity of rainfall storms. Finally, a data portal named Ontario Climate Change Data Portal (CCDP) is developed to ensure decision-makers and impact researchers have easy and intuitive access to the refined regional climate change scenarios.
Feasibility of a Randomized Clinical Trial for Treatment of Femoroacetabular Impingement of the Hip
Authors: Boye Gloria N. , Murray Kerri , Clohisy John C. , Kim Young-Jo 
Published: July 2015

Background: Symptomatic femoroacetabular impingement (FAI) is currently corrected by surgery. However, it is possible that nonsurgical treatment could resolve symptomatic FAI in some patients; thus, uncertainty about the necessity of surgical treatment exists. The current equipoise concerning FAI treatment presents an opportunity to conduct a randomized controlled trial (RCT) of surgical and nonsurgical treatment options. Given the unique challenge of adequate patient enrollment in RCTs, it is important that a preliminary study is done to appraise the feasibility of conducting an RCT. Purpose: To estimate enrollment rates of a planned future RCT to compare surgical and nonsurgical treatments for symptomatic FAI and to identify factors associated with patients’ willingness to participate in the randomized trial. Study Design: Cross-sectional study; Level of evidence, 4. Methods: Patients diagnosed with FAI at 2 orthopaedic centers were presented with a hypothetical randomized trial comparing 2 treatment options for FAI. All patients completed forms providing information regarding their willingness to participate and treatment preferences. Results: A total of 75 patients participated in the study: 53 and 22 from 2 centers, respectively. Twenty-eight percent indicated absolute willingness to participate in the trial, 40% were probably willing or unsure, and 32% were definitely not willing; 18.7% had a strong preference for surgery while 2.7% strongly preferred nonsurgical treatment. The majority (78.6%) had no strong preference for either treatment arm. There were correlations between treatment preferences and willingness to participate. Patients with a strong treatment preference and/or a preference for surgery were less likely to be willing to participate. Conclusion: The study findings suggest that sufficient patient accrual for a randomized trial of FAI treatment is currently feasible while equipoise still exists among patients and surgeons.
Identification of IncRNA Expression Profile in the Spinal Cord of Mice following Spinal Nerve Ligation-Induced Neuropathic Pain
Authors: Jiang Bao-Chun , Sun Wen-Xing , He Li-Na , Cao De-Li , Zhang Zhi-Jun , Gao Yong-Jing 
Published: July 2015

Background Neuropathic pain that caused by lesion or dysfunction of the nervous system is associated with gene expression changes in the sensory pathway. Long noncoding RNAs (lncRNAs) have been reported to be able to regulate gene expression. Identifying lncRNA expression patterns in the spinal cord under normal and neuropathic pain conditions is essential for understanding the genetic mechanisms behind the pathogenesis of neuropathic pain. Results Spinal nerve ligation (SNL) induced rapid and persistent pain hypersensitivity, characterized by mechanical allodynia and heat hyperalgesia. Meanwhile, astrocytes and microglia were dramatically activated in the ipsilateral spinal cord dorsal horn at 10 days after SNL. Further lncRNA microarray and mRNA microarray analysis showed that the expression profiles of lncRNA and mRNA between SNL and sham-operated mice were greatly changed at 10 days. The 511 differentially expressed (>2 fold) lncRNAs (366 up-regulated, 145 down-regulated) and 493 mRNAs (363 upregulated, 122 down-regulated) were finally identified. The expression patterns of several lncRNAs and mRNAs were further confirmed by qPCR. Functional analysis of differentially expressed (DE) mRNAs showed that the most significant enriched biological processes of up-regulated genes in SNL include immune response, defense response, and inflammation response, which are important pathogenic mechanisms underlying neuropathic pain. 35 DE lncRNAs have neighboring or overlapping DE mRNAs in genome, which is related to Toll-like receptor signaling, cytokine–cytokine receptor interaction, and peroxisome proliferator-activated receptor signaling pathway. Conclusion Our findings uncovered the expression pattern of lncRNAs and mRNAs in the mice spinal cord under neuropathic pain condition. These lncRNAs and mRNAs may represent new therapeutic targets for the treatment of neuropathic pain.
Epigenome data release: a participant-centered approach to privacy protection
Authors: Dyke Stephanie O. M. , Cheung Warren A. , Joly Yann , Ammerpohl Ole , Lutsik Pavlo , Rothstein Mark A. , Caron Maxime , Busche Stephan , Bourque Guillaume , Rönnblom Lars , Flicek Paul , Beck Stephan , Hirst Martin , Stunnenberg Henk , Siebert Reiner , Walter Jörn , Pastinen Tomi 
Published: July 2015

AbstractLarge-scale epigenome mapping by the NIH Roadmap Epigenomics Project, the ENCODE Consortium and the International Human Epigenome Consortium (IHEC) produces genome-wide DNA methylation data at one base-pair resolution. We examine how such data can be made open-access while balancing appropriate interpretation and genomic privacy. We propose guidelines for data release that both reduce ambiguity in the interpretation of open-access data and limit immediate access to genetic variation data that are made available through controlled access.
Epratuzumab inhibits the production of the proinflammatory cytokines IL-6 and TNF-α, but not the regulatory cytokine IL-10, by B cells from healthy donors and SLE patients
Authors: Fleischer Vanessa , Sieber Julia , Fleischer Sarah J. , Shock Anthony , Heine Guido , Daridon Capucine , Dörner Thomas 
Published: July 2015

Abstract
Introduction
Cytokines produced by B cells are believed to play important roles in autoimmune diseases. CD22 targeting by epratuzumab has been demonstrated to inhibit phosphorylation of B cell receptor (BCR) downstream signaling in B cells. It has been shown that other sialoadhesin molecules related to CD22 have immunoregulatory functions; therefore, in the present study, we addressed the role of epratuzumab on the production of key cytokines by B cells of patients with systemic lupus erythematosus (SLE) and of healthy donors (HD).

Methods
Peripheral blood B cells were purified and activated by BCR with or without Toll-like receptor 9 (TLR9) stimulation in the presence or absence of epratuzumab. Cytokine production by B cells (interleukin [IL]-6, tumor necrosis factor [TNF]-α and IL-10) in the supernatant and the induction of IL-10+ B cells from patients with SLE and HD were analyzed.

Results
The secretion of the proinflammatory cytokines TNF-α and IL-6 by anti-BCR and BCR- and/or TLR9-activated B cells from HD and patients with SLE was inhibited by epratuzumab. In contrast, the production of IL-10 by B cells was not affected by epratuzumab under either stimulation condition. Consistently, the induction of IL-10–producing B cells in culture was not affected by epratuzumab.

Conclusions
Epratuzumab, by targeting CD22, was able to inhibit the production of the proinflammatory cytokines IL-6 and TNF-α by B cells, in contrast to IL-10, in vitro. These data suggest that targeting CD22 alters the balance between proinflammatory cytokines (TNF-α, IL-6) and the regulatory cytokine IL-10 as another B cell effector mechanism.
A survey of attitudes toward clinical trials and genetic disclosure in autosomal dominant Alzheimer’s disease
Authors: Grill Joshua D. , Bateman Randall J. , Buckles Virginia , Oliver Angela , Morris John C. , Masters Colin L. , Klunk William E. , Ringman John M. ,   for the Dominantly Inherited Alzheimer’s Network
Published: July 2015

Abstract
Introduction
Because of its genetic underpinnings and consistent age of onset within families, autosomal dominant Alzheimer’s disease (ADAD) provides a unique opportunity to conduct clinical trials of investigational agents as preventative or symptom-delaying treatments. The design of such trials may be complicated by low rates of genetic testing and disclosure among persons at risk of inheriting disease-causing mutations.

Methods
To better understand the attitudes toward genetic testing and clinical trials of persons at risk for ADAD, we surveyed participants in the Dominantly Inherited Alzheimer’s Network (DIAN), a multisite longitudinal study of clinical and biomarker outcomes in ADAD that does not require learning genetic status to participate.

Results
Eighty participants completed a brief anonymous survey by mail or on-line; 40 % reported knowing if they carried a gene mutation, 15 % did not know but expressed a desire to learn their genetic status, and 45 % did not know and did not desire to know their genetic status. Among participants who knew or wished to know their genetic status, 86 % were interested in participating in a clinical trial. Seventy-two percent of participants who did not wish to learn their genetic status reported that they would change their mind, if learning that they carried a mutation gave them the opportunity to participate in a clinical trial. Nearly all participants responded that they would be interested if an open-label extension were offered.

Conclusions
These results suggest that the availability of clinical trials to prevent ADAD can affect persons’ desire to undergo genetic testing and that consideration can be given to performing studies in which such testing is required.
Nonlinear multichannel impedance inversion by total-variation regularization
Authors: Gholami Ali 
Published: July 2015

The analysis of acoustic impedance (AI) allows for the mapping of seismic reflection data to lithology, and hence it plays an important role in the interpretation of poststack seismic data. The AI is obtainable from the inversion of the earth reflectivity series. Efficient deconvolution methods have been developed for recovering the reflectivity series from band-limited poststack data, which are multiple free, zero offset, and migrated. However, calculation of the AI from the reflectivity, when considering the spatial correlation of the impedance parameters, demands the solution of a constrained nonlinear inverse problem. Two efficient algorithms are proposed for solving the nonlinear impedance problem in multichannel form with the total-variation (TV) constraint to recover impedance maps with blocky structures. The first uses the continuous earth model for reflectivity, which allows linearizing the problem in the logarithm domain. The second uses the discrete (layered) earth model for reflectivity. In this case, a nonlinear problem is solved in the original domain. The main properties of the algorithms, which are built based on the split-Bregman technique and the discrete cosine transform are as follows: (1) They are multichannel inversion procedures, so they respect the spatial and temporal correlation of the data, (2) they impose the TV constraint on the parameters to generate blocky structures, (3) they are fast such that a large 3D impedance model with a blocky structure can be recovered easily on a personal computer, and (4) the computational complexities of both algorithms are the same. Numerical tests using simulated 2D data obtained from a benchmark Marmousi model and also 2D and 3D field data confirmed that the proposed algorithm generates more accurate with higher resolution impedance models compared with the conventional methods.
A review of caesarean delivery in Southwest Ethiopia: incidence, indications and outcomes
Authors: Akki Jebessa Shekuro , Gemeda Desta Hiko , Akessa Geremew Muleta 
Published: July 2015

Background/Aims: Although the rate of caesarean delivery has increased dramatically worldwide, data reported from 1991 to 2003 show that most low-income countries have a caesarean delivery rate of less than 10%, while more than 30% of middle- and high-income countries exceeded 20%. The most recently available data from the World Health Organization (WHO) indicate that more than half of high-income countries have a caesarean delivery rate in excess of 25%, with caesarean sections accounting for approximately 32.3% of births in the US. The four most common indications for caesarean deliveries are: i) failure to progress during labour; ii) previous hysterectomy; iii) non-reassuring fetal status; and iv) fetal malpresentation. In this article, the authors aimed to investigate the incidence, indications and outcomes of caesarean sections in Southwest Ethiopia. Methods: A hospital-based cross-sectional survey was conducted and data were collected and analysed for statistical significance. Results: Based on the data collected, the region's caesarean delivery rate was found to be 27.6%. The average age of patients in the study was 26.9±5.04 years (15–40 years). The leading indications for caesarean section are: cephalopelvic disproportion (32.3%); previous caesarean section (24.2%); fetal distress (18.1%); malpresentation and malposition (8.8%); and antepartum haemorrhage (4.2%). There were no maternal deaths recorded, but the overall maternal morbidity rate was 15.4%. Conclusions: The caesarean delivery rate in Southwest Ethiopia is markedly higher than the recommended rate set by WHO for developing countries (15%). However, the maternal morbidity rate is still high and further research needs to be carried out on the causes and prevention of such cases.