bluuebunny/crossref_metadata_2025_split huggingface dataset:
MELK Inhibition in Diffuse Intrinsic Pontine Glioma
Authors: Meel Michaël H. , de Gooijer Mark C. , Guillén Navarro Miriam , Waranecki Piotr , Breur Marjolein , Buil Levi C.M. , Wedekind Laurine E. , Twisk Jos W.R. , Koster Jan , Hashizume Rintaro , Raabe Eric H. , Montero Carcaboso Angel , Bugiani Marianna , van Tellingen Olaf , van Vuurden Dannis G. , Kaspers Gertjan J.L. , Hulleman Esther 
Published: July 2018

Abstract
Purpose: Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brain tumor, for which no effective therapeutic options currently exist. We here determined the potential of inhibition of the maternal embryonic leucine zipper kinase (MELK) for the treatment of DIPG.
Experimental Design: We evaluated the antitumor efficacy of the small-molecule MELK inhibitor OTSSP167 in vitro in patient-derived DIPG cultures, and identified the mechanism of action of MELK inhibition in DIPG by RNA sequencing of treated cells. In addition, we determined the blood–brain barrier (BBB) penetration of OTSSP167 and evaluated its translational potential by treating mice bearing patient-derived DIPG xenografts.
Results: This study shows that MELK is highly expressed in DIPG cells, both in patient samples and in relevant in vitro and in vivo models, and that treatment with OTSSP167 strongly decreases proliferation of patient-derived DIPG cultures. Inhibition of MELK in DIPG cells functions through reducing inhibitory phosphorylation of PPARγ, resulting in an increase in nuclear translocation and consequent transcriptional activity. Brain pharmacokinetic analyses show that OTSSP167 is a strong substrate for both MDR1 and BCRP, limiting its BBB penetration. Nonetheless, treatment of Mdr1a/b;Bcrp1 knockout mice carrying patient-derived DIPG xenografts with OTSSP167 decreased tumor growth, induced remissions, and resulted in improved survival.
Conclusions: We show a strong preclinical effect of the kinase inhibitor OTSSP167 in the treatment of DIPG and identify the MELK–PPARγ signaling axis as a putative therapeutic target in this disease. Clin Cancer Res; 24(22); 5645–57. ©2018 AACR.
Circulating Cell-Free miR-375 as Surrogate Marker of Tumor Burden in Merkel Cell Carcinoma
Authors: Fan Kaiji , Ritter Cathrin , Nghiem Paul , Blom Astrid , Verhaegen Monique E. , Dlugosz Andrzej , Ødum Niels , Woetmann Anders , Tothill Richard W. , Hicks Rodney J. , Sand Michael , Schrama David , Schadendorf Dirk , Ugurel Selma , Becker Jürgen C. 
Published: July 2018

AbstractPurpose:Merkel cell carcinoma (MCC) is an aggressive skin cancer with neuroendocrine differentiation. There is an unmet need for MCC-specific blood-based surrogate biomarkers of tumor burden; circulating cell-free miRNA may serve this purpose.Experimental Design:Expression of miR-375 was quantified in 24 MCC and 23 non-MCC cell lines, 67 MCC and 58 non-MCC tumor tissues, sera of 2 preclinical MCC models, and sera of 109 patients with MCC and 30 healthy controls by nCounter human-v2-miRNA expression or miR-375–specific real-time PCR assays. The patients’ sera consisted of two retrospective (discovery and training) and two prospective (validation) cohorts.Results:miR-375 expression was high in MCC cell lines and tissues compared with non-MCCs. It was readily detected in MCC-conditioned medium and sera of preclinical models bearing MCC xenografts. miR-375 levels were higher in sera from tumor-bearing patients with MCC than in tumor-free patients or healthy controls (P &lt; 0.0005). Moreover, miR-375 serum levels correlated with tumor stage in tumor-bearing (P = 0.037) but not in tumor-free (P = 0.372) patients with MCC. miR-375 serum level showed high diagnostic accuracy to discriminate tumor-bearing and tumor-free patients with MCC as demonstrated by ROC curve analysis in the retrospective cohorts (AUC = 0.954 and 0.800) as well as in the prospective cohorts (AUC = 0.929 and 0.959). miR-375 serum level reflected dynamic changes in tumor burden of patients with MCC during therapeutic interventions.Conclusions:Circulating cell-free miR-375 proved as a surrogate marker for tumor burden in MCC without restriction to polyomavirus positivity; it thus appears to be useful for therapy monitoring and the follow-up of patients with MCC.
Genomic cfDNA Analysis of Aqueous Humor in Retinoblastoma Predicts Eye Salvage: The Surrogate Tumor Biopsy for Retinoblastoma
Authors: Berry Jesse L. , Xu Liya , Kooi Irsan , Murphree A. Linn , Prabakar Rishvanth K. , Reid Mark , Stachelek Kevin , Le Bao Han A. , Welter Lisa , Reiser Bibiana J. , Chévez-Barrios Patricia , Jubran Rima , Lee Thomas C. , Kim Jonathan W. , Kuhn Peter , Cobrinik David , Hicks James 
Published: July 2018

Abstract
Tumor-derived cell-free DNA (cfDNA) has biomarker potential; therefore, this study aimed to identify cfDNA in the aqueous humor (AH) of retinoblastoma eyes and correlate somatic chromosomal copy-number alterations (SCNA) with clinical outcomes, specifically eye salvage. AH was extracted via paracentesis during intravitreal injection of chemotherapy or enucleation. Shallow whole-genome sequencing was performed using isolated cfDNA to assess for highly recurrent SCNAs in retinoblastoma including gain of 1q, 2p, 6p, loss of 13q, 16q, and focal MYCN amplification. Sixty-three clinical specimens of AH from 29 eyes of 26 patients were evaluated; 13 eyes were enucleated and 16 were salvaged (e.g., saved). The presence of detectable SCNAs was 92% in enucleated eyes versus 38% in salvaged eyes (P = 0.006). Gain of chromosome 6p was the most common SCNA found in 77% of enucleated eyes, compared with 25% of salvaged eyes (P = 0.0092), and associated with a 10-fold increased odds of enucleation (OR, 10; 95% CI, 1.8–55.6). The median amplitude of 6p gain was 1.47 in enucleated versus 1.07 in salvaged eyes (P = 0.001). The presence of AH SCNAs was correlated retrospectively with eye salvage. The probability of ocular salvage was higher in eyes without detectable SCNAs in the AH (P = 0.0028), specifically 6p gain. This is the first study to correlate clinical outcomes with SCNAs in the AH from retinoblastoma eyes, as such these findings indicate that 6p gain in the aqueous humor is a potential prognostic biomarker for poor clinical response to therapy.
Implications: The correlation of clinical outcomes and SCNAs in the AH identified in the current study requires prospective studies to validate these finding before SCNAs, like 6p gain, can be used to predict clinical outcomes at diagnosis. Mol Cancer Res; 16(11); 1701–12. ©2018 AACR.
Having a Drink with Tchaikovsky: The Crossmodal Influence of Background Music on the Taste of Beverages
Authors: Hauck Pia , Hecht Heiko 
Published: July 2018

Abstract
Previous research has shown that auditory cues can influence the flavor of food and drink. For instance, wine tastes better when preferred music is played. We have investigated whether a music background can modify judgments of the specific flavor pattern of a beverage, as opposed to mere preference. This was indeed the case. We explored the nature of this crosstalk between auditory and gustatory perception, and hypothesized that the ‘flavor’ of the background music carries over to the perceived flavor (i.e., descriptive and evaluative aspects) of beverages. First, we collected ratings of the subjective flavor of different music pieces. Then we used a between-subjects design to cross the music backgrounds with taste evaluations of several beverages. Participants tasted four different samples of beverages under two contrasting audio conditions and rated their taste experiences. The emotional flavor of the music had the hypothesized effects on the flavor of the beverages. We also hypothesized that such an effect would be stronger for music novices than for music experts, and weaker for aqueous solutions than for wines. However, neither music expertise nor liquid type produced additional effects. We discuss implications of this audio-gustatory interaction.
Estimation of the prevalence of cholesteryl ester storage disorder in a cohort of patients with clinical features of familial hypercholesterolaemia
Authors: Ashfield-Watt Pauline , Haralambos Kate , Edwards Rhiannon , Townsend Delyth , Gingell Rob , Wa Li Kah , Humphries Steve E , McDowell Ian 
Published: July 2018

Background and aim Familial hypercholesterolaemia is caused by variants in the low-density lipoprotein cholesterol metabolic pathway involving LDLR, APOB and PCSK9 genes. A national genetic testing service in Wales, UK has observed that no familial hypercholesterolaemia variant is found in almost 80% patients with the familial hypercholesterolaemia phenotype. It has recently been suggested that some adult patients with a familial hypercholesterolaemia phenotype may have cholesteryl ester storage disease which can also present as a mixed hyperlipidaemia. The commonest genetic cause of cholesteryl ester storage disease is an exon 8 splice junction variant in the LIPA gene (rs116928232, c.894G>A; E8SJM) previously found to have an allele frequency of 0.0011 (1 in 450 individuals) in a large European population. This study investigated the prevalence of the E8SJM in patients with a familial hypercholesterolaemia phenotype in Wales, UK. Method A total of 1203 patients with a clinical suspicion of familial hypercholesterolaemia but no familial hypercholesterolaemia variant were invited to participate. Of these, 668 patients provided informed written consent. Stored DNA samples from 663 patients were genotyped for the E8SJM variant. Results Three heterozygotes were identified (allele frequency 0.0023). Whole gene sequencing of the LIPA gene was undertaken in these three individuals, but no other variants were found. Therefore, there were no cholesteryl ester storage disease patients (homozygote or compound heterozygote) identified in this cohort. Conclusion The allele frequency 0.0023 (1 in 221 individuals) for the E8SJM variant was more prevalent in this cohort than in a European population study; however, no cholesteryl ester storage disease homozygotes were identified. We found no evidence to support routine testing for cholesteryl ester storage disease in adult patients with a familial hypercholesterolaemia phenotype.
Strain and Satisfaction in Caregivers of Veterans With Type 2 Diabetes
Authors: Wakefield Bonnie J. , Vaughan-Sarrazin Mary 
Published: July 2018

Purpose The purpose of this study was to identify predictors of informal caregiver strain and satisfaction associated with caring for veterans with type 2 diabetes (T2DM). Methods This study is a secondary analysis of data from 2 prior studies of caregiving in the Veterans Health Administration. The original studies used a telephone survey to examine veteran and caregiver (CG) characteristics associated with caregivers’ responses to caregiving. The data reported here include 202 veterans with T2DM and 202 caregivers. Linear regression models were generated alternatively using forward and backward selection of veteran and caregiver characteristics. Results Higher caregiver strain was associated with the CG providing activities of daily living assistance, CG receiving less help from friends and relatives and use of unpaid help, CG use of coping strategies, and CG depression scores. Predictors of CG satisfaction included better relationship quality with the veteran and receipt of social support. Conclusions The important role of family and friends in supporting patients with T2DM is widely accepted. Clinicians may engage the caregiver when there is inadequate self-care by the patient. However, less attention has been focused on the effect of caregiving on the caregiver. Greater attention needs to be focused on in-depth exploration of family needs to design and test effective interventions to meet these needs.
Left ventricular dysfunction after two hours of polarizing or depolarizing cardioplegic arrest in a porcine model
Authors: Aass Terje , Stangeland Lodve , Moen Christian Arvei , Solholm Atle , Dahle Geir Olav , Chambers David J. , Urban Malte , Nesheim Knut , Haaverstad Rune , Matre Knut , Grong Ketil 
Published: July 2018

Introduction: This experimental study compares myocardial function after prolonged arrest by St. Thomas’ Hospital polarizing cardioplegic solution (esmolol, adenosine, Mg2+) with depolarizing (hyperkalaemic) St. Thomas’ Hospital No 2, both administered as cold oxygenated blood cardioplegia. Methods: Twenty anaesthetized pigs on tepid (34°C) cardiopulmonary bypass (CPB) were randomised to cardioplegic arrest for 120 min with antegrade, repeated, cold, oxygenated, polarizing (STH-POL) or depolarizing (STH-2) blood cardioplegia every 20 min. Cardiac function was evaluated at Baseline and 60, 150 and 240 min after weaning from CPB, using a pressure-conductance catheter and epicardial echocardiography. Regional tissue blood flow, cleaved caspase-3 activity and levels of malondialdehyde were evaluated in myocardial tissue samples. Results: Preload recruitable stroke work (PRSW) was increased after polarizing compared to depolarizing cardioplegia 150 min after declamping (73.0±3.2 vs. 64.3±2.4 mmHg, p=0.047). Myocardial tissue blood flow rate was high in both groups compared to the Baseline levels and decreased significantly in the STH-POL group only, from 60 min to 150 min after declamping (p<0.005). Blood flow was significantly reduced in the STH-POL compared to the STH-2 group 240 min after declamping (p<0.05). Left ventricular mechanical efficiency, the ratio between total pressure-volume area and blood flow rate, gradually decreased after STH-2 cardioplegia and was significantly reduced compared to STH-POL cardioplegia after 150 and 240 min (p<0.05 for both). Conclusion: Myocardial protection for two hours of polarizing cardioplegic arrest with STH-POL in oxygenated blood is non-inferior compared to STH-2 blood cardioplegia. STH-POL cardioplegia alleviates the mismatch between myocardial function and perfusion after weaning from CPB
Melodic intonation therapy in post-stroke nonfluent aphasia: a randomized pilot trial
Authors: Haro-Martínez Ana M , Lubrini Genny , Madero-Jarabo Rosario , Díez-Tejedor Exuperio , Fuentes Blanca 
Published: July 2018

Objective: To collect data to estimate the sample size of a definitive randomized controlled trial to evaluate the effects of Melodic Intonation Therapy in post-stroke nonfluent aphasia. Design: A randomized, crossover, interventional pilot trial. Setting: Departments of Neurology and Rehabilitation from a university general hospital. Participants: Stroke survivors with post-stroke nonfluent aphasia. Interventions: Patients randomized to group 1 had treatment with Melodic Intonation Therapy first (12 sessions over six weeks) followed by no treatment; the patients in group 2 started active treatment between three and six months after their inclusion in the study, serving as waiting list controls for the first phase. Main measures: The Communicative Activity Log (CAL) questionnaire and the Boston Diagnostic Aphasia Examination (BDAE) were evaluated at baseline, and at six and 12 weeks. Results: Twenty patients were included. Four of the patients allocated to group 2 crossed over to group 1, receiving the treatment at first. Intention-to-treat analysis: after adjustment for baseline scores, the mean difference in the CAL evaluation from baseline in the treated group was 8.5 points (95% confidence interval (CI), 0.11–17.0; P = .043), with no significant change in any of the BDAE sections. Per-protocol analysis showed similar results with a clear treatment effect ( P = .043) on the CAL. Conclusion: Melodic Intonation Therapy might have a positive effect on the communication skills of stroke survivors with nonfluent aphasia as measured by the CAL questionnaire. A full-scale trial with at least 27 patients per group is necessary to confirm these results.
In-vitro blood–brain barrier modeling: A review of modern and fast-advancing technologies
Authors: Sivandzade Farzane , Cucullo Luca 
Published: July 2018

The development of realistic in vitro blood–brain barrier (BBB) models that recapitulate the physiological parameters and molecular aspect of the neurovascular unit (NVU) is of fundamental importance not only in CNS drug discovery but also in translational research. Successful modeling of the NVU would provide an invaluable tool to aid in dissecting out the pathological factors, mechanism of action (and corresponding targets) prodromal to the onset of CNS disorders. The field of BBB in vitro modeling has seen many radical changes in the last few years with the introduction on novel technologies and methods to improve over existing models and develop new ones. Therefore, the goal of this review is to provide the readers with updated technical and operational details concerning current BBB platforms with special focus on stem cell technology used to establish a functional BBB model in vitro. Furthermore, we provide a detailed update on rapidly advancing 3D printing technologies used for engineering BBB models which use is now fast expanding among researchers.
Pravastatin polarizes the phenotype of macrophages toward M2 and elevates serum cholesterol levels in apolipoprotein E knockout mice
Authors: Zhang Xiaoling , Xiao Shengjun , Li Quanzhong 
Published: July 2018

Objective Statins are clinically used for protection against cardiovascular disease with lipid-lowering and anti-inflammatory properties. These properties tip the balance of macrophage polarization, which is an essential process in the development and progression of atherosclerosis. This study aimed to investigate the effect of pravastatin on atherosclerosis of the aorta in apolipoprotein E knockout (apoE-KO) mice without high lipid feeding. Methods Six 8-week-old apoE-KO male mice were randomly divided into two groups: a control group and a pravastatin (40 mg·kg−1·day−1)-treated group. At 35 weeks, the mice were sacrificed and the size of plaques on the aorta was assessed by Oil Red O staining. M1 and M2 macrophages were identified by inducible nitric oxide synthase and arginase-I, respectively, using immunohistochemistry. Results Pravastatin increased the size of atherosclerotic plaques in apoE-KO mice without high lipid feeding. The ratio of M1/M2 macrophages increased in atherosclerotic plaques, which might slow the process of atherosclerosis, while blood cholesterol levels were elevated. Conclusion Our study suggests that pravastatin polarizes the phenotype of macrophages toward M2 in atherosclerotic lesions, despite an increase in serum cholesterol levels in ApoE-KO mice.
Do managers forecast asymmetric cost behaviour?
Authors: Bradbury Michael E , Scott Tom 
Published: July 2018

This article examines cost behaviour in a municipal (local government) setting and finds evidence of cost stickiness. We also find that costs are super-sticky as they increase even when revenues decrease. Municipals in New Zealand are required to produce forecasts, which allow us to investigate whether asymmetric cost behaviour is incorporated into forecasts. Forecast cost behaviour is found to be statistically indistinguishable from actual behaviour. In our tests, we control for asset intensity, employee intensity, expected demand, operating slack and past cost structure. The finding that the asymmetric relation between costs and revenues is incorporated into managerial forecasts suggests that cost stickiness is understood by managers rather than being merely a mechanistic outcome of cost structure. JEL Classification: M41, D24, H72
Expression of mitofusin 2 in human sperm and its relationship to sperm motility and cryoprotective potentials
Authors: Fang Fang , Ni Ke , Shang Jin , Zhang Xiaoke , Xiong Chengliang , Meng Tianqing 
Published: July 2018

Mitofusin 2 is a kind of mitochondria membrane protein that has been implicated in maintenance of mitochondrial morphology and function. However, the expression and function of mitofusin 2 in human sperm are not well described at present. The aim of this study was to explore the location of mitofusin 2 in human sperm and to discover its relationship to human sperm functions like motility and cryoprotective potentials. Our result showed that mitofusin 2 is specifically localized in the 5–7 μm midpiece between the neck and main part of human sperm tail. The expression level of mitofusin 2 in human sperm was significantly different between the normozoospermia and asthenozoospermia groups ( P < 0.05); meanwhile, the sperm of the asthenozoospermia group had a lower mitochondrial membrane potential ( P < 0.05), but the results of TUNEL assay did not show significant difference between the two groups. Furthermore, we found that the expression level of mitofusin 2 in the freeze-resistant group (cryo-survival rate >40%) was significantly higher than that of the freeze-intolerant group (cryo-survival rate ≤40%) ( P < 0.05). These results demonstrate that the expression level of mitofusin 2 is related to motility and cryoprotective potentials of human sperm. Mitofusin 2 may play a crucial role in the function of human sperm, which needs further research to discover the mechanism.Impact statementThe exact function of mitochondria in human sperm before and during fertilization process remains controversial. MFN2 is a kind of mitochondria membrane protein and participates in the regulation of mitochondrial morphology and function. In this study, we discover the relationship of MFN2 expression to human sperm motility and cryoprotective potentials. Our results suggest that MFN2 could be a new target for the mechanism research of asthenozoospermia. MFN2 may also serve as a protein marker predicting the ability of human sperm to sustain cryopreservation.
Effects on Aortoiliac Fluid Dynamics After Endovascular Sealing of Abdominal Aneurysms
Authors: Casciaro Mariano E. , Dottori Javier , El-Batti Salma , Alsac Jean-Marc , Mousseaux Elie , Larrabide Ignacio , Craiem Damian 
Published: July 2018

Objectives: To evaluate the effects on aortoiliac fluid dynamics after the implantation of an endograft based on endovascular aneurysm sealing (EVAS) versus endovascular aneurysm repair (EVAR) strategy. Methods: An adaptive geometrical deformable model was used for aortic lumen segmentation in 8 patients before and after the surgery. Abdominal aneurysms were treated with an endograft based on the EVAS system (Nellix, n = 4) and with a device based on an anatomical fixation technology (n = 4). Pressure, blood velocity, and wall shear stress (WSS) were estimated at different aortic regions using computational fluid dynamics methods. Physiologic inlet/outlet flow values at the abdominal aorta, the celiac trunk, and the mesenteric and the renal arteries were set. Pressure references were set at iliac arteries outlet. Results: Maximum aneurysm sizes were similar for both groups in the preoperative scans. The lumen area was lower after EVAR ( P < .05) and EVAS ( P < .01) compared to preoperative aortic lumen sizes. Pressure increase was higher in the proximal abdominal aorta after EVAS compared to EVAR (2.3 ± 0.3 mm Hg vs 0.9 ± 0.3 mm Hg, P < .001). Peak blood velocities inside the endografts were 3-fold higher for EVAS compared to EVAR (54 ± 5 cm/s vs 17 ± 4 cm/s, P < .01). Velocities at the iliac arteries also remained higher for EVAS (38 ± 4 cm/s vs 24 ± 4 cm/s, P < .05). Peak WSS at the iliac arteries remained higher for EVAS compared to EVAR group ( P < .05). Conclusion: The significant modification of the aortic bifurcation anatomy after EVAS alters aortoiliac fluid dynamics, showing a pressure impact at the renal arteries level and an acceleration of the blood velocity at the iliac region with a concomitant increase in peak WSS.
Mechanisms of establishment and functional significance of DNA demethylation during erythroid differentiation
Authors: Bartholdy Boris , Lajugie Julien , Yan Zi , Zhang Shouping , Mukhopadhyay Rituparna , Greally John M. , Suzuki Masako , Bouhassira Eric E. 
Published: July 2018

Key Points
We have generated allele-specific base resolution methylomes of primary basophilic erythroblasts. DNA demethylation during differentiation of HSPC into BasoE occurs mostly in inactive regions causing formation of PMD in 74% of methylome.