bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ligand-Independent EPHA2 Signaling Drives the Adoption of a Targeted Therapy–Mediated Metastatic Melanoma Phenotype
Authors: Paraiso Kim H.T. , Thakur Meghna Das , Fang Bin , Koomen John M. , Fedorenko Inna V. , John Jobin K. , Tsao Hensin , Flaherty Keith T. , Sondak Vernon K. , Messina Jane L. , Pasquale Elena B. , Villagra Alejandro , Rao Uma N. , Kirkwood John M. , Meier Friedegund , Sloot Sarah , Gibney Geoffrey T. , Stuart Darrin , Tawbi Hussein , Smalley Keiran S.M. 
Published: December 2014

Abstract
Many patients with BRAF inhibitor resistance can develop disease at new sites, suggesting that drug-induced selection pressure drives metastasis. Here, we used mass spectrometry–based phosphoproteomic screening to uncover ligand-independent EPHA2 signaling as an adaptation to BRAF inhibitor therapy that led to the adoption of a metastatic phenotype. The EPHA2-mediated invasion was AKT-dependent and readily reversible upon removal of the drug as well as through PI3K and AKT inhibition. In xenograft models, BRAF inhibition led to the development of EPHA2-positive metastases. A retrospective analysis of patients with melanoma on BRAF inhibitor therapy showed that 68% of those failing therapy develop metastases at new disease sites, compared with 35% of patients on dacarbazine. Further IHC staining of melanoma specimens taken from patients on BRAF inhibitor therapy as well as metastatic samples taken from patients failing therapy showed increased EPHA2 staining. We suggest that inhibition of ligand-independent EPHA2 signaling may limit metastases associated with BRAF inhibitor therapy.
Significance: This study provides evidence that BRAF inhibition promotes the adoption of a reversible, therapy-driven metastatic phenotype in melanoma. The cotargeting of ligand-independent EPHA2 signaling and BRAF may be one strategy to prevent the development of therapy-mediated disease at new sites. Cancer Discov; 5(3); 264–73. ©2014 AACR.
See related article by Miao et al., p. 274
This article is highlighted in the In This Issue feature, p. 213
EPHA2 Is a Mediator of Vemurafenib Resistance and a Novel Therapeutic Target in Melanoma
Authors: Miao Benchun , Ji Zhenyu , Tan Li , Taylor Michael , Zhang Jianming , Choi Hwan Geun , Frederick Dennie T. , Kumar Raj , Wargo Jennifer A. , Flaherty Keith T. , Gray Nathanael S. , Tsao Hensin 
Published: December 2014

Abstract
BRAFV600E is the most common oncogenic lesion in melanoma and results in constitutive activation of the MAPK pathway and uncontrolled cell growth. Selective BRAF inhibitors such as vemurafenib have been shown to neutralize oncogenic signaling, restrain cellular growth, and improve patient outcome. Although several mechanisms of vemurafenib resistance have been described, directed solutions to overcome these resistance lesions are still lacking. Herein, we found that vemurafenib resistance can be (i) mediated by EPHA2, a member of the largest receptor tyrosine kinases (RTK) subfamily erythropoietin-producing hepatocellular (EPH) receptors, and (ii) associated with a greater phenotypic dependence on EPHA2. Furthermore, we developed a series of first-in-class EPHA2 inhibitors and show that these new compounds potently induce apoptosis, suppress viability, and abrogate tumorigenic growth of melanoma cells, including those that are resistant to vemurafenib. These results provide proof of concept that RTK-guided growth, and therapeutic resistance, can be prospectively defined and selectively targeted.
Significance: In this study, we show that resistance to selective BRAF inhibitors can be mediated by the RTK EPHA2. Furthermore, direct targeting of EPHA2 can successfully suppress melanoma growth and mitigate therapeutic resistance. Cancer Discov; 5(3); 274–87. ©2014 AACR.
See related article by Paraiso et al., p. 264
This article is highlighted in the In This Issue feature, p. 213
Retargeting T Cells to GD2 Pentasaccharide on Human Tumors Using Bispecific Humanized Antibody
Authors: Xu Hong , Cheng Ming , Guo Hongfen , Chen Yuedan , Huse Morgan , Cheung Nai-Kong V. 
Published: December 2014

AbstractAnti-disialoganglioside GD2 IgG antibodies have shown clinical efficacy in solid tumors that lack human leukocyte antigens (e.g., neuroblastoma) by relying on Fc-dependent cytotoxicity. However, there are pain side effects secondary to complement activation. T-cell retargeting bispecific antibodies (BsAb) also have clinical potential, but it is thus far only effective against liquid tumors. In this study, a fully humanized hu3F8-BsAb was developed, in which the anti-CD3 huOKT3 single-chain Fv fragment (ScFv) was linked to the carboxyl end of the anti-GD2 hu3F8 IgG1 light chain, and was aglycosylated at N297 of Fc to prevent complement activation and cytokine storm. In vitro, hu3F8-BsAb activated T cells through classic immunologic synapses, inducing GD2-specific tumor cytotoxicity at femtomolar EC50 with &gt;105-fold selectivity over normal tissues, releasing Th1 cytokines (TNFα, IFNγ, and IL2) when GD2(+) tumors were present. In separate murine neuroblastoma and melanoma xenograft models, intravenous hu3F8-BsAb activated T cells in situ and recruited intravenous T cells for tumor ablation, significantly prolonging survival from local recurrence or from metastatic disease. Hu3F8-BsAb, but not control BsAb, drove T cells and monocytes to infiltrate tumor stroma. These monocytes were necessary for sustained T-cell proliferation and/or survival and contributed significantly to the antitumor effect. The in vitro and in vivo antitumor properties of hu3F8-BsAb and its safety profile support its further clinical development as a cancer therapeutic, and provide the rationale for exploring aglycosylated IgG-scFv as a structural platform for retargeting human T cells. Cancer Immunol Res; 3(3); 266–77. ©2014 AACR.
Syndecan-1 Modulates the Motility and Resolution Responses of Macrophages
Authors: Angsana Julianty , Chen Jiaxuan , Smith Sumona , Xiao Jiantao , Wen Jing , Liu Liying , Haller Carolyn A. , Chaikof Elliot L. 
Published: December 2014

Objective—
Syndecan-1 (Sdc-1) is a member of a family of cell surface proteoglycans, which has been reported to participate in the regulation of events relevant to tissue repair and chronic injury responses, including cell–substrate interactions, matrix remodeling, and cell migration. In this study, we report the functional significance of Sdc-1 in polarized macrophage populations and its role in adhesion and motility events relevant to resolution of the inflammatory program.

Approach and Results—

Macrophage Sdc-1 expression is associated with differentiated M2 macrophages with high intrinsic motility, and Sdc-1 deficiency is characterized by impaired migration and enhanced adhesion. Leukocyte infiltration and emigration were examined in a thioglycollate-induced model of peritonitis in Sdc-1
+/+
and Sdc-1
−/−
mice. Although the infiltration of inflammatory cells was similar in both cohorts, a significant delay in the lymphatic clearance of Sdc-1
−/−
macrophages was observed. Moreover, we observed enhanced inflammation and greater burden of atherosclerotic plaques in ApoE
−/−
Sdc-1
−/−
mice maintained on a Western diet.

Conclusions—

These results demonstrate that defective motility in Sdc-1
−/−
macrophages promotes a persistent inflammatory state with relevance to the pathogenesis of atherosclerosis.
Limited Reliability of Computed Tomographic Perfusion Acute Infarct Volume Measurements Compared With Diffusion-Weighted Imaging in Anterior Circulation Stroke
Authors: Schaefer Pamela W. , Souza Leticia , Kamalian Shervin , Hirsch Joshua A. , Yoo Albert J. , Kamalian Shahmir , Gonzalez R. Gilberto , Lev Michael H. 
Published: December 2014

Background and Purpose—
Diffusion-weighted imaging (DWI) can reliably identify critically ischemic tissue shortly after stroke onset. We tested whether thresholded computed tomographic cerebral blood flow (CT-CBF) and CT-cerebral blood volume (CT-CBV) maps are sufficiently accurate to substitute for DWI for estimating the critically ischemic tissue volume.

Methods—
Ischemic volumes of 55 patients with acute anterior circulation stroke were assessed on DWI by visual segmentation and on CT-CBF and CT-CBV with segmentation using 15% and 30% thresholds, respectively. The contrast:noise ratios of ischemic regions on the DWI and CT perfusion (CTP) images were measured. Correlation and Bland–Altman analyses were used to assess the reliability of CTP.

Results—

Mean contrast:noise ratios for DWI, CT-CBF, and CT-CBV were 4.3, 0.9, and 0.4, respectively. CTP and DWI lesion volumes were highly correlated (
R
2
=0.87 for CT-CBF;
R
2
=0.83 for CT-CBV;
P
<0.001). Bland–Altman analyses revealed little systemic bias (−2.6 mL) but high measurement variability (95% confidence interval, ±56.7 mL) between mean CT-CBF and DWI lesion volumes, and systemic bias (−26 mL) and high measurement variability (95% confidence interval, ±64.0 mL) between mean CT-CBV and DWI lesion volumes. A simulated treatment study demonstrated that using CTP-CBF instead of DWI for detecting a statistically significant effect would require at least twice as many patients.

Conclusions—
The poor contrast:noise ratios of CT-CBV and CT-CBF compared with those of DWI result in large measurement error, making it problematic to substitute CTP for DWI in selecting individual acute stroke patients for treatment. CTP could be used for treatment studies of patient groups, but the number of patients needed to identify a significant effect is much higher than the number needed if DWI is used.
An Anatomically Based Analysis of Objectively Measured Pediatric Snoring
Authors: Brietzke Scott E. , Pusz Max D. 
Published: December 2014

ObjectiveTo assess pediatric habitual snoring (PS) using home sleep test (HST) technology and attempt to correlate the objective components of PS to specific upper airway anatomy. In addition, the effects of adenotonsillectomy (± turbinoplasty) on objective measures of PS were evaluated.Study DesignProspective cohort study.SettingTertiary medical center.Subjects and MethodsPediatric patients with a chief complaint of snoring and probable obstructive sleep apnea underwent an HST (SNAP Diagnostics, Wheeling, Illinois) with a detailed acoustical snoring analysis prior to adenotonsillectomy (± turbinoplasty). During surgery, detailed anatomical measurements were performed and correlated to snoring analysis results. After surgery, patients were offered another HST with snoring analysis. Data analysis was performed using descriptive statistics and statistical correlation with attention to the multiple‐comparisons paradox.ResultsTwenty‐two patients (45% male; mean age, 5.4 years [range, 2.4‐8.4 years]) completed the preoperative HST and operative measurements. Unlike typical adult snoring, only a minority of PS was from palatal flutter (mean palatal component, 24%; median, 10%). The resistance occurrence percentage (ROP, percentage of breathing events with snoring noise) was associated with body mass index (BMI; Spearman ρ = 0.55; P =. 017), subjective turbinate size (0.54; P =. 032), palatal obstruction (0.63; P =. 008), and mean oxygen saturation (−0.729; P =. 0003) but not adenotonsillar hypertrophy. Twelve patients (54%) completed a postoperative HST. The ROP was significantly reduced (median, 20.5% vs 6.5%; P =. 006, sign rank test) postoperatively. The magnitude of the ROP reduction was proportional to the volume of the removed tonsils (0.74; P =. 022).ConclusionPediatric snoring has different acoustical characteristics than adult snoring. Objective PS is associated with BMI, turbinate size, and palatal obstruction. Adenotonsillectomy (± turbinoplasty) may significantly reduce objective PS.
When to Stop CPR and When to Perform Rhythm Analysis
Authors: Giberson Brandon , Uber Amy , F. Gaieski David , Miller Joseph B. , Wira Charles , Berg Katherine , Giberson Tyler , Cocchi Michael N. , S. Abella Benjamin , Donnino Michael W. 
Published: December 2014

Background: Health care providers nationwide are routinely trained in Advanced Cardiac Life Support (ACLS), an American Heart Association program that teaches cardiac arrest management. Recent changes in the ACLS approach have de-emphasized routine pulse checks in an effort to promote uninterrupted chest compressions. We hypothesized that this new ACLS algorithm may lead to uncertainty regarding the appropriate action following detection of a pulse during a cardiac arrest. Methods: We conducted an observational study in which a Web-based survey was sent to ACLS-trained medical providers at 4 major urban tertiary care centers in the United States. The survey consisted of 5 multiple-choice, scenario-based ACLS questions, including our question of interest. Adult staff members with a valid ACLS certification were included. Results: A total of 347 surveys were analyzed. The response rate was 28.1%. The majority (53.6%) of responders were between 18 and 32 years old, and 59.9% were female. The majority (54.2%) of responders incorrectly stated that they would continue CPR and possibly administer additional therapies when a team member detects a pulse immediately following defibrillation. Secondarily, only 51.9% of respondents correctly chose to perform a rhythm check following 2 minutes of CPR. The other 3 survey questions were correctly answered an average of 89.1% of the time. Conclusion: Confusion exists regarding whether or not CPR and cardiac medications should be continued in the presence of a pulse. Education may be warranted to emphasize avoiding compressions and medications when a palpable pulse is detected.
New horizon in dialysis depuration: Characterization of a polysulfone membrane able to break the ‘albumin wall’
Authors: Cuoghi A , Caiazzo M , Monari E , Bellei E , Bergamini S , Sereni L , Aucella F , Loschiavo C , Atti M , Tomasi A 
Published: December 2014

The uremic syndrome is attributed to the progressive retention of a large number of toxins, which under normal conditions are excreted by the healthy kidneys. Standard dialytic membranes do not purify middle-high molecular weight toxins. Haemodiafiltration with endogenous reinfusion coupled with a highly permeable membrane could break the limit of the ‘albumin wall’ improving the dialytic depuration without loss of important nutrients. The aim of this study was to evaluate the performance of a new polysulfone membrane, Synclear 0.2, to remove uremic molecules. Surface Enhanced Laser Desorption Ionization-Time of Flight was employed to evaluate the proteomic profile of ultrafiltrate and Electrospray Ionization-Quadruple-ToF coupled with on-chip elution was used for proteins identification. A high and specific permeability for middle-high molecular weight molecules was revealed by mass spectrometry for the investigated membrane. The identified proteins are mostly uremic toxins: their relative abundance, estimated in the ultrafiltrate by exponentially modified protein abundance index, showed a high purification efficiency of the new membrane when compared with conventional ones. In conclusion, Synclear 0.2, used as convective membrane in hemodiafiltration with endogenous reinfusion treatment, permits to break the ‘albumin wall’, clearing middle-high molecular weight uremic toxins, improving the dialytic treatment purification efficiency.
Validity and reliability of the Lupus QoL index in Turkish systemic lupus erythematosus patients
Authors: Pamuk O N , Onat A M , Donmez S , Mengüs C , Kisacik B 
Published: December 2014

Background Systemic lupus erythematosus (SLE) patients have seriously impaired quality of life (QoL). In addition to activity and damage indices used in the past, tools to evaluate QoL in SLE have been developed in recent years. In this study, we test the validity of the Turkish version of the Lupus-QoL (LupusQoL-TR) score, and investigate its association with clinical findings and activity indices. Methods A total of 132 patients diagnosed with SLE according to ACR 1997 criteria were included. The clinical and demographic features, and biochemical data were retrieved from hospital records. SLE Disease Activity Index (SLEDAI) and damage score (SLICC-ACR) were determined at the time of administration of Lupus-QoL questionnaire. The Lupus-QoL includes 34 questions divided into eight domains. We reevaluated the LupusQoL-TR and pretested its understandability. SLE patients were concomitantly administered the LupusQoL-TR and generic SF-36. Internal consistency, test-retest reliability, convergent and discriminant validity were calculated. Results The mean age of our SLE patients was 37.9 ± 12.8 years. Internal consistency reliability ranged from 0.88 to 0.93, and test-retest reliability from 0.84 to 0.94. LupusQoL-related domains in SF-36 were correlated (from 0.66 to 0.74). Most LupusQoL-TR domains, except planning, were able to discriminate between active and inactive SLE groups. Scores in all domains of the LupusQoL-TR were found to be discriminative for patients with and without damage according to SLICC-ACR score. Conclusion The LupusQoL-TR was found to be a valid patient-reported outcome measure method when evaluating QoL in Turkish SLE patients.
Increased DNA double-strand breaks and enhanced apoptosis in patients with lupus nephritis
Authors: Souliotis V L , Sfikakis P P 
Published: December 2014

Objective DNA double-strand breaks (DSBs) lead to mutations, genomic instability and apoptotic death, whereas accumulation of apoptotic cells results in excessive autoantigen presentation and autoantibody formation. We aimed to measure DSB levels in lupus nephritis, a severe complication of the prototypic systemic autoimmune disease. Methods The intrinsic DNA damage and the apoptosis induction/DSB levels were evaluated in peripheral blood mononuclear cells of six patients and 10 healthy controls following exposure to genotoxic agents (melphalan, cisplatin) ex vivo. DSBs were assessed using immunofluorescence quantification of γH2AX foci and comet assay. Results Intrinsic DNA damage was increased in lupus versus control cells in both assays (Olive Tail Moment units of 15.8 ± 2.3 versus 3.0 ± 1.4 in comet, p < 0.01; % γH2AX-positive cells: 13.6 ± 1.8 versus 4.6 ± 0.9, p < 0.01, respectively). Melphalan or cisplatin doses as low as 9.9 ± 4.8 or 29.8 ± 8.3 µg/ml, respectively, were sufficient to induce apoptosis in lupus cells; control cells required doses of 32.3 ± 7.7 and 67.7 ± 5.5 µg/ml, respectively. Drug-induced DSB levels were increased in lupus versus control cells, with the area under the curve (AUC) for melphalan-induced DSBs being 3050 ± 610 (% γH2AX-positive staining cells) × (drug dose) in patients and 1580 ± 350 in controls ( p < 0.05); the corresponding values for cisplatin-induced AUC were 13900 ± 1800 for lupus and 4500 ± 750 for controls ( p < 0.01). Interestingly, within either lupus patients or controls examined, the accumulation of DSBs correlated with apoptosis degrees (all p < 0.01). Results in lupus cells were not associated with individual disease activity level or treatment modalities at the time of the study. Conclusion These findings suggest a novel mechanism by which increased accumulation of DSBs may render cells more sensitive to apoptosis, thus contributing to the induction of systemic autoimmunity.
Evaluation and perceived results of moral case deliberation
Authors: Janssens Rien MJPA , van Zadelhoff Ezra , van Loo Ger , Widdershoven Guy AM , Molewijk Bert AC 
Published: December 2014

Background: Moral case deliberation is increasingly becoming part of various Dutch healthcare organizations. Although some evaluation studies of moral case deliberation have been carried out, research into the results of moral case deliberation within aged care is scarce. Research questions: How did participants evaluate moral case deliberation? What has moral case deliberation brought to them? What has moral case deliberation contributed to care practice? Should moral case deliberation be further implemented and, if so, how? Research design: Quantitative analysis of a questionnaire study among participants of moral case deliberation, both caregivers and team leaders. Qualitative analysis of written answers to open questions, interview study and focus group meetings among caregivers and team leaders. Participants and research context: Caregivers and team leaders in a large organization for aged care in the Netherlands. A total of 61 moral case deliberation sessions, carried out on 16 care locations belonging to the organization, were evaluated and perceived results were assessed. Ethical considerations: Participants gave informed consent and anonymity was guaranteed. In the Netherlands, the law does not prescribe independent ethical review by an Institutional Review Board for this kind of research among healthcare professionals. Findings: Moral case deliberation was evaluated positively by the participants. Content and atmosphere of moral case deliberation received high scores, while organizational issues regarding the moral case deliberation sessions scored lower and merit further attention. Respondents indicated that moral case deliberation has the potential to contribute to care practice as relationships among team members improve, more openness is experienced and more understanding for different perspectives is fostered. If moral case deliberation is to be successfully implemented, top-down approaches should go hand in hand with bottom-up approaches. Conclusion: The relevance of moral case deliberation for care practice received wide acknowledgement from the respondents. It can contribute to the team’s cohesion as mutual understanding for one another’s views is fostered. If implemented well, moral case deliberation has the potential to improve care, according to the respondents.
Expectile and quantile regression—David and Goliath?
Authors: Waltrup Linda Schulze , Sobotka Fabian , Kneib Thomas , Kauermann Göran 
Published: December 2014

Recent interest in modern regression modelling has focused on extending available (mean) regression models by describing more general properties of the response distribution. An alternative approach is quantile regression where regression effects on the conditional quantile function of the response are assumed. While quantile regression can be seen as a generalization of median regression, expectiles as alternative are a generalized form of mean regression. Generally, quantiles provide a natural interpretation even beyond the 0.5 quantile, the median. A comparable simple interpretation is not available for expectiles beyond the 0.5 expectile, the mean. Nonetheless, expectiles have some interesting properties, some of which are discussed in this article. We contrast the two approaches and show how to get quantiles from a fine grid of expectiles. We compare such quantiles from expectiles with direct quantile estimates regarding efficiency. We also look at regression problems where both quantile and expectile curves have the undesirable property that neighbouring curves may cross each other. We propose a modified method to estimate non-crossing expectile curves based on splines. In an application, we look at the expected shortfall, a risk measure used in finance, which requires both expectiles and quantiles for estimation and which can be calculated easily with the proposed methods in the article.