bluuebunny/crossref_metadata_2025 huggingface dataset:
Multi-Contact Locomotion Using a Contact Graph with Feasibility Predictors
Authors: Kang Changgu , Lee Sung-Hee
Published: April 2017

Multi-contact locomotion that uses both the hands and feet in a complex environment remains a challenging problem in computer animation. To address this problem, we present a contact graph, which is a motion graph augmented by learned feasibility predictors, namely contact spaces and an occupancy estimator, for a motion clip in each graph node. By estimating the feasibilities of candidate contact points that can be reached by modifying a motion clip, the predictors allow us to find contact points that are likely to be valid and natural before attempting to generate the actual motion for the contact points. The contact graph thus enables the efficient generation of multi-contact motion in two steps: planning contact points to the goal and then generating the whole-body motion. We demonstrate the effectiveness of our method by creating several climbing motions in complex and cluttered environments by using only a small number of motion samples.
Fundamental Challenges Toward Making the IoT a Reachable Reality
Authors: Xue Yuankun , Li Ji , Nazarian Shahin , Bogdan Paul
Published: April 2017

Constantly advancing integration capability is paving the way for the construction of the extremely large scale continuum of the Internet where entities or things from vastly varied domains are uniquely addressable and interacting seamlessly to form a giant networked system of systems known as the Internet-of-Things (IoT). In contrast to this visionary networked system paradigm, prior research efforts on the IoT are still very fragmented and confined to disjoint explorations of different applications, architecture, security, services, protocol, and economical domains, thus preventing design exploration and optimization from a unified and global perspective. In this context, this survey article first proposes a mathematical modeling framework that is rich in expressivity to capture IoT characteristics from a global perspective. It also sets forward a set of fundamental challenges in sensing, decentralized computation, robustness, energy efficiency, and hardware security based on the proposed modeling framework. Possible solutions are discussed to shed light on future development of the IoT system paradigm.
Gene expression effects of glucocorticoid and mineralocorticoid receptor agonists and antagonists on normal human skeletal muscle
Authors: Chadwick Jessica A. , Hauck J. Spencer , Gomez-Sanchez Celso E. , Gomez-Sanchez Elise P. , Rafael-Fortney Jill A.
Published: April 2017

Mineralocorticoid and glucocorticoid receptors are closely related steroid hormone receptors that regulate gene expression through many of the same hormone response elements. However, their transcriptional activities and effects in skeletal muscles are largely unknown. We recently identified mineralocorticoid receptors (MR) in skeletal muscles after finding that combined treatment with the angiotensin-converting enzyme inhibitor lisinopril and MR antagonist spironolactone was therapeutic in Duchenne muscular dystrophy mouse models. The glucocorticoid receptor (GR) agonist prednisolone is the current standard-of-care treatment for Duchenne muscular dystrophy because it prolongs ambulation, likely due to its anti-inflammatory effects. However, data on whether glucocorticoids have a beneficial or detrimental direct effect on skeletal muscle are controversial. Here, we begin to define the gene expression profiles in normal differentiated human skeletal muscle myotubes treated with MR and GR agonists and antagonists. The MR agonist aldosterone and GR agonist prednisolone had highly overlapping gene expression profiles, supporting the notion that prednisolone acts as both a GR and MR agonist that may have detrimental effects on skeletal muscles. Co-incubations with aldosterone plus either nonspecific or selective MR antagonists, spironolactone or eplerenone, resulted in similar numbers of gene expression changes, suggesting that both drugs can block MR activation to a similar extent. Eplerenone treatment alone decreased a number of important muscle-specific genes. This information may be used to develop biomarkers to monitor clinical efficacy of MR antagonists or GR agonists in muscular dystrophy, develop a temporally coordinated treatment with both drugs, or identify novel therapeutics with more specific downstream targets.
Micellar Delivery of miR-34a Modulator Rubone and Paclitaxel in Resistant Prostate Cancer
Authors: Wen Di , Peng Yang , Lin Feng , Singh Rakesh K. , Mahato Ram I.
Published: April 2017

Treatment of prostate cancer with paclitaxel often fails due to the development of chemoresistance caused by downregulation of the tumor suppressor gene miR-34a. In this study, we demonstrate that codelivery of paclitaxel and 2'-hydroxy-2,4,4',5,6'-pentamethoxychalcone (termed rubone) drives upregulation of miR-34a and chemosensitizes paclitaxel-resistant prostate cancer cells, killing both cancer stem–like cells (CSC) and bulk tumor cells. Rubone upregulated miR-34a and reversed its downstream target genes in DU145-TXR and PC3-TXR cells. Paclitaxel and rubone combination therapy inhibited tumor cell growth, migration, and CSC population growth. We synthesized poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol; PEG-PCD) to prepare micelles. The drug-loading capacities were 9.70% ± 0.10% and 5.34% ± 0.02% for paclitaxel and rubone, respectively, controlling a drug release of 60.20% ± 2.67% and 60.62% ± 4.35% release of paclitaxel and rubone at 24 hours. Delivery of miR-34a and rubone decreased PC3-TXR cell viability with increasing paclitaxel concentration. Coincubation with a miR-34a inhibitor diminished the effect of rubone. Paclitaxel IC50 in PC3 and PC3-TXR cells was 55.6 and 2,580 nmol/L, respectively, but decreased to 49.8 and 93.2 nmol/L when treated in combination with rubone, demonstrating a reversal of paclitaxel resistance by rubone. Systemic administration of micelles carrying paclitaxel and rubone inhibited orthotopic prostate tumor growth in nude mice, compared with monotherapy, by reversing the expression of miR-34a, SIRT1, cyclin D1, and E-cadherin. In summary, our results showed how rubone acts as an efficient small-molecule modulator of miR-34a to reverse chemoresistance and further enhance the therapeutic efficacy of paclitaxel in paclitaxel-resistant prostate cancer. Cancer Res; 77(12); 3244–54. ©2017 AACR.
Whither Radioimmunotherapy: To Be or Not To Be?
Authors: Green Damian J. , Press Oliver W.
Published: April 2017

Therapy of cancer with radiolabeled monoclonal antibodies has produced impressive results in preclinical experiments and in clinical trials conducted in radiosensitive malignancies, particularly B-cell lymphomas. Two “first-generation,” directly radiolabeled anti-CD20 antibodies, 131iodine-tositumomab and 90yttrium-ibritumomab tiuxetan, were FDA-approved more than a decade ago but have been little utilized because of a variety of medical, financial, and logistic obstacles. Newer technologies employing multistep “pretargeting” methods, particularly those utilizing bispecific antibodies, have greatly enhanced the therapeutic efficacy of radioimmunotherapy and diminished its toxicities. The dramatically improved therapeutic index of bispecific antibody pretargeting appears to be sufficiently compelling to justify human clinical trials and reinvigorate enthusiasm for radioimmunotherapy in the treatment of malignancies, particularly lymphomas. Cancer Res; 77(9); 2191–6. ©2017 AACR.
Immune Gene Expression Is Associated with Genomic Aberrations in Breast Cancer
Authors: Safonov Anton , Jiang Tingting , Bianchini Giampaolo , Győrffy Balázs , Karn Thomas , Hatzis Christos , Pusztai Lajos
Published: April 2017

The presence of tumor-infiltrating lymphocytes (TIL) is a favorable prognostic factor in breast cancer, but what drives immune infiltration remains unknown. Here we examine if clonal heterogeneity, total mutation load, neoantigen load, copy number variations (CNV), gene- or pathway-level somatic mutations, or germline polymorphisms (SNP) are associated with immune metagene expression in breast cancer subtypes. Thirteen published immune metagenes correlated separately with genomic metrics in the three major breast cancer subtypes. We analyzed RNA-Seq, DNA copy number, mutation and germline SNP data of 627 ER+, 207 HER2+, and 191 triple-negative (TNBC) cancers from The Cancer Genome Atlas. P-values were adjusted for multiple comparisons, and permutation testing was used to assess false discovery rates. Increased immune metagene expression associated significantly with lower clonal heterogeneity estimated by MATH score in all subtypes and with a trend for lower overall mutation, neoantigen, and CNV loads in TNBC and HER2+ cancers. In ER+ cancers, mutation load, neoantigen load, and CNV load weakly but positively associated with immune infiltration, which reached significance for overall mutation load only. No highly recurrent single gene or pathway level mutations associated with immune infiltration. High immune gene expression and lower clonal heterogeneity in TNBC and HER2+ cancers suggest an immune pruning effect and equilibrium between immune surveillance and clonal expansion. Thus, immune checkpoint inhibitors may tip the balance in favor of immune surveillance in these cancers. Cancer Res; 77(12); 3317–24. ©2017 AACR.
In Vivo Detection of EGFRvIII in Glioblastoma via Perfusion Magnetic Resonance Imaging Signature Consistent with Deep Peritumoral Infiltration: The ϕ-Index
Authors: Bakas Spyridon , Akbari Hamed , Pisapia Jared , Martinez-Lage Maria , Rozycki Martin , Rathore Saima , Dahmane Nadia , O'Rourke Donald M. , Davatzikos Christos
Published: April 2017

Purpose: The epidermal growth factor receptor variant III (EGFRvIII) mutation has been considered a driver mutation and therapeutic target in glioblastoma, the most common and aggressive brain cancer. Currently, detecting EGFRvIII requires postoperative tissue analyses, which are ex vivo and unable to capture the tumor's spatial heterogeneity. Considering the increasing evidence of in vivo imaging signatures capturing molecular characteristics of cancer, this study aims to detect EGFRvIII in primary glioblastoma noninvasively, using routine clinically acquired imaging.

Experimental Design: We found peritumoral infiltration and vascularization patterns being related to EGFRvIII status. We therefore constructed a quantitative within-patient peritumoral heterogeneity index (PHI/ϕ-index), by contrasting perfusion patterns of immediate and distant peritumoral edema. Application of ϕ-index in preoperative perfusion scans of independent discovery (n = 64) and validation (n = 78) cohorts, revealed the generalizability of this EGFRvIII imaging signature.

Results: Analysis in both cohorts demonstrated that the obtained signature is highly accurate (89.92%), specific (92.35%), and sensitive (83.77%), with significantly distinctive ability (P = 4.0033 × 10−10, AUC = 0.8869). Findings indicated a highly infiltrative-migratory phenotype for EGFRvIII+ tumors, which displayed similar perfusion patterns throughout peritumoral edema. Contrarily, EGFRvIII− tumors displayed perfusion dynamics consistent with peritumorally confined vascularization, suggesting potential benefit from extensive peritumoral resection/radiation.

Conclusions: This EGFRvIII signature is potentially suitable for clinical translation, since obtained from analysis of clinically acquired images. Use of within-patient heterogeneity measures, rather than population-based associations, renders ϕ-index potentially resistant to inter-scanner variations. Overall, our findings enable noninvasive evaluation of EGFRvIII for patient selection for targeted therapy, stratification into clinical trials, personalized treatment planning, and potentially treatment-response evaluation. Clin Cancer Res; 23(16); 4724–34. ©2017 AACR.
Long-Term Efficacy, Survival, and Safety of [177Lu-DOTA0,Tyr3]octreotate in Patients with Gastroenteropancreatic and Bronchial Neuroendocrine Tumors
Authors: Brabander Tessa , van der Zwan Wouter A. , Teunissen Jaap J.M. , Kam Boen L.R. , Feelders Richard A. , de Herder Wouter W. , van Eijck Casper H.J. , Franssen Gaston J.H. , Krenning Eric P. , Kwekkeboom Dik J.
Published: April 2017

Purpose: Bronchial and gastroenteropancreatic neuroendocrine tumors (NET) are slow-growing tumors, which frequently express somatostatin receptors on their cell membranes. These receptors are targets for therapy with Lutetium-177–labeled somatostatin analogues. We have treated over 1,200 patients with peptide receptor radionuclide therapy (PRRT) with [177Lu-DOTA0,Tyr3]octreotate (177Lu-DOTATATE) since the year 2000 and present the results on efficacy, survival, and toxicity of this therapy.

Experimental Design: For safety analysis, 610 patients treated with a cumulative dose of at least 100 mCi (3.7 GBq) 177Lu-DOTATATE were included. A subgroup of 443 Dutch patients who were treated with a cumulative dose of at least 600 mCi (22.2 GBq) 177Lu-DOTATATE before 2013 was further analyzed for efficacy and survival.

Results: The objective response rate of the total group of patients was 39%. Stable disease was reached in 43% of patients. Progression-free survival (PFS) and overall survival (OS) for all NET patients were 29 months [95% confidence interval (CI), 26–33 months] and 63 months (95% CI, 55–72 months). Long-term toxicity included acute leukemia in four patients (0.7%) and myelodysplastic syndrome in nine patients (1.5%). No therapy-related long-term renal or hepatic failure occurred.

Conclusions: PRRT with 177Lu-DOTATATE is a favorable therapeutic option in patients with metastatic bronchial and gastroenteropancreatic NETs that express somatostatin receptors. PRRT with 177Lu-DOTATATE is safe with few side-effects and shows good response rates with PFS of 29 months and OS of 63 months. Clin Cancer Res; 23(16); 4617–24. ©2017 AACR.
The Role of Minimal Residual Disease Testing in Myeloma Treatment Selection and Drug Development: Current Value and Future Applications
Authors: Anderson Kenneth C. , Auclair Daniel , Kelloff Gary J. , Sigman Caroline C. , Avet-Loiseau Hervé , Farrell Ann T. , Gormley Nicole J. , Kumar Shaji K. , Landgren Ola , Munshi Nikhil C. , Cavo Michele , Davies Faith E. , Di Bacco Alessandra , Dickey Jennifer S. , Gutman Steven I. , Higley Howard R. , Hussein Mohamad A. , Jessup J. Milburn , Kirsch Ilan R. , Little Richard F. , Loberg Robert D. , Lohr Jens G. , Mukundan Lata , Omel James L. , Pugh Trevor J. , Reaman Gregory H. , Robbins Michael D. , Sasser A. Kate , Valente Nancy , Zamagni Elena
Published: April 2017

Treatment of myeloma has benefited from the introduction of more effective and better tolerated agents, improvements in supportive care, better understanding of disease biology, revision of diagnostic criteria, and new sensitive and specific tools for disease prognostication and management. Assessment of minimal residual disease (MRD) in response to therapy is one of these tools, as longer progression-free survival (PFS) is seen consistently among patients who have achieved MRD negativity. Current therapies lead to unprecedented frequency and depth of response, and next-generation flow and sequencing methods to measure MRD in bone marrow are in use and being developed with sensitivities in the range of 10−5 to 10−6 cells. These technologies may be combined with functional imaging to detect MRD outside of bone marrow. Moreover, immune profiling methods are being developed to better understand the immune environment in myeloma and response to immunomodulatory agents while methods for molecular profiling of myeloma cells and circulating DNA in blood are also emerging. With the continued development and standardization of these methodologies, MRD has high potential for use in gaining new drug approvals in myeloma. The FDA has outlined two pathways by which MRD could be qualified as a surrogate endpoint for clinical studies directed at obtaining accelerated approval for new myeloma drugs. Most importantly, better understanding of MRD should also contribute to better treatment monitoring. Potentially, MRD status could be used as a prognostic factor for making treatment decisions and for informing timing of therapeutic interventions. Clin Cancer Res; 23(15); 3980–93. ©2017 AACR.
Mechanisms of Pinometostat (EPZ-5676) Treatment–Emergent Resistance in MLL-Rearranged Leukemia
Authors: Campbell Carly T. , Haladyna Jessica N. , Drubin David A. , Thomson Ty M. , Maria Michael J. , Yamauchi Taylor , Waters Nigel J. , Olhava Edward J. , Pollock Roy M. , Smith Jesse J. , Copeland Robert A. , Blakemore Stephen J. , Bernt Kathrin M. , Daigle Scott R.
Published: April 2017

DOT1L is a protein methyltransferase involved in the development and maintenance of MLL-rearranged (MLL-r) leukemia through its ectopic methylation of histones associated with well-characterized leukemic genes. Pinometostat (EPZ-5676), a selective inhibitor of DOT1L, is in clinical development in relapsed/refractory acute leukemia patients harboring rearrangements of the MLL gene. The observation of responses and subsequent relapses in the adult trial treating MLL-r patients motivated preclinical investigations into potential mechanisms of pinometostat treatment-emergent resistance (TER) in cell lines confirmed to have MLL-r. TER was achieved in five MLL-r cell lines, KOPN-8, MOLM-13, MV4-11, NOMO-1, and SEM. Two of the cell lines, KOPN-8 and NOMO-1, were thoroughly characterized to understand the mechanisms involved in pinometostat resistance. Unlike many other targeted therapies, resistance does not appear to be achieved through drug-induced selection of mutations of the target itself. Instead, we identified both drug efflux transporter dependent and independent mechanisms of resistance to pinometostat. In KOPN-8 TER cells, increased expression of the drug efflux transporter ABCB1 (P-glycoprotein, MDR1) was the primary mechanism of drug resistance. In contrast, resistance in NOMO-1 cells occurs through a mechanism other than upregulation of a specific efflux pump. RNA-seq analysis performed on both parental and resistant KOPN-8 and NOMO-1 cell lines supported two unique candidate pathway mechanisms that may explain the pinometostat resistance observed in these cell lines. These results are the first demonstration of TER models of the DOT1L inhibitor pinometostat and may provide useful tools for investigating clinical resistance. Mol Cancer Ther; 16(8); 1669–79. ©2017 AACR.
Determinants of Perceived Stress in Individuals with Obesity: Exploring the Relationship of Potentially Obesity-Related Factors and Perceived Stress
Authors: Junne Florian , Ziser Katrin , Giel Katrin Elisabeth , Schag Kathrin , Skoda Eva , Mack Isabelle , Niess Andreas , Zipfel Stephan , Teufel Martin
Published: April 2017

Objective: Associations of specific types of stress with increased food intake and subsequent weight gain have been demonstrated in animal models as well as in experimental and epidemiological studies on humans. This study explores the research question of to what extent potentially obesity-related factors determine perceived stress in individuals with obesity. Methods: N = 547 individuals with obesity participated in a cross-sectional study assessing perceived stress as the outcome variable and potential determinants of stress related to obesity. Based on the available evidence, a five factorial model of ‘obesity-related obesogenic stressors' was hypothesized, including the dimensions, ‘drive for thinness', ‘impulse regulation', ‘ineffectiveness', ‘social insecurity', and ‘body dissatisfaction'. The model was tested using multiple linear regression analyses. Results: The five factorial model of ‘potentially obesity-related stressors' resulted in a total variance explanation of adjusted R² = 0.616 for males and adjusted R² = 0.595 for females for perceived stress. The relative variance contribution of the five included factors differed substantially for the two sexes. Conclusion: The findings of this cross-sectional study support the hypothesized, potentially obesity-related factors: ‘drive for thinness', ‘impulse regulation', ‘ineffectiveness', ‘social insecurity', and ‘body dissatisfaction' as relevant determinants of perceived stress in individuals with obesity.
Radiofrequency Lesions through Deep Brain Stimulation Electrodes in Movement Disorders: Case Report and Review of the Literature
Authors: Pérez-Suárez Javier , Torres Díaz Cristina V. , López Manzanares Lydia , Navas García Marta , Pastor Jesús , Barrio Fernández Patricia , G. de Sola Rafael
Published: April 2017

Background: Although there are few reports of radiofrequency lesions performed through deep brain stimulation (DBS) electrodes in patients with movement disorders, experience with this method is scarce. Methods: We present 2 patients who had been previously treated with DBS of subthalamic nuclei (STN) and the ventral intermediate (VIM) nucleus of the thalamus for Parkinson's disease and essential tremor, respectively, and underwent a radiofrequency lesion through their DBS electrodes after developing a hardware infection. The authors conduct a review of the literature regarding this method. Results: Both patients had a good clinical outcome after 20 and 8 months, respectively, as assessed by a reduction in Fahn-Tolosa-Marin Scale and Unified Parkinson's Disease Rating Scale scores. The second patient underwent a second DBS system implantation surgery after his radiofrequency treatment to optimize his management, achieving optimal clinical control with lower current and drug requirements than before the radiofrequency intervention. No adverse effects were observed. Conclusions: Radiofrequency lesions through DBS electrodes allow the creation of small and localized lesions. Its effectiveness and low-risk profile, in addition to its low cost, make this procedure suitable and a possible alternative in the therapeutic repertoire for the surgical treatment of movement disorders.
Interferon-β 1a Modulates Expression of RAGE but Not S100A12 and Nuclear Factor-κB in Multiple Sclerosis Patients
Authors: Asadikaram Gholamreza , Noroozi Saam , Ebrahimi Meimand Hossein Ali , Sanjari Mojgan , Zainodini Nahid , Khoramdelazad Hossein , Shahrokhi Nader , Kazemi Arababadi Mohammad
Published: April 2017

Objectives: Interferon-β 1a (IFN-β 1a) is a common strategy therapy for multiple sclerosis (MS) with unknown mechanisms. S100A12 (S100 calcium-binding protein A12) is a damage-associated molecular pattern molecule which binds to its receptor, RAGE (receptor for advanced glycation end products), and activates nuclear factor-κB (NF-κB). NF-κB is transcribed from proinflammatory molecules, which may participate in the pathogenesis of MS. Therefore, the aims of this study were to compare mRNA levels of S100A12, RAGE, and NF-κB in newly diagnosed MS patients with healthy controls and determine whether IFN-β 1a therapy affects the expression of the molecules. Methods: S100A12, RAGE, and NF-κB mRNA levels in 30 new cases of untreated MS patients and 35 healthy controls were evaluated using the real-time PCR technique. The mRNA levels were also evaluated in the MS patients after 6 months of IFN-β 1a therapy. Results: S100A12, RAGE, and NF-κB mRNA levels were significantly decreased in the new cases of untreated MS patients in comparison to healthy controls. IFN-β 1a therapy results in upregulation of RAGE in MS patients, but not S100A12 and NF-κB. Conclusions: It appears that S100A12 participates in the pathogenesis of MS, and it seems that IFN-β 1a modulates immune responses in an S100A12-independent manner. Based on the reported anti-inflammatory effects of RAGE, it seems that RAGE may be considered as a mechanism by IFN-β 1a to modulate immune responses. NF-κB is produced permanently in the human cells and is inactive in the cytoplasm; therefore, the effects of IFN-β 1a may be related to its functions rather than expressions.
The cHS4 Chromatin Insulator Reduces the Rate of Retroviral Vector-Mediated Gene Dysregulation Associated with Aberrant Vector Transcription
Authors: Zhou Xianyao , Liu Qiujun , Wang Da , Zhang Xuemei , Emery David W. , Li Chang L.
Published: April 2017

Integrating gammaretroviral vectors can dysregulate the expression of cellular genes through a variety of mechanisms, leading to genotoxicity and malignant transformation. Although most attention has focused on the activation of cellular genes by vector enhancers, aberrant fusion transcripts involving cellular gene sequences and vector promoters, vector splice elements, and vector transcription termination sequences have also been mechanistically associated with dysregulated expression of cellular genes. Chromatin insulators have emerged as an effective tool for reducing the frequency of vector-mediated genotoxicity and malignant transformation and have been shown to block the activation of cellular genes by vector enhancers. We report here evidence that flanking a gammaretroviral reporter vector with the cHS4 chromatin insulator also reduces the frequency of vector-mediated cellular gene dysregulation associated with aberrant vector transcripts, including vector transcription run-through and aberrant splicing. We demonstrate that the cHS4 element does not function to terminate transcription directly, implicating other mechanisms for this activity.
Apolipoprotein A1 Inhibits the TGF-β1-Induced Endothelial-to-Mesenchymal Transition of Human Coronary Artery Endothelial Cells
Authors: Feng Juling , Zhang Jingjing , Jackson Ampadu O. , Zhu Xiao , Chen Hainan , Chen Wen , Gui Qingjun , Yin Kai
Published: April 2017

Objective: Transforming growth factor β1 (TGF-β1) is the major cytokine for stimulating endothelial cells (ECs) to transdifferentiate to mesenchymal cells (MCs) in the process known as endothelial-to-mesenchymal transition (EndMT). Recently, TGF-β1-induced EndMT has been implicated in the pathogenesis of atherosclerosis (AS). It has been identified that apolipoprotein A1 (ApoA-I) obstructs TGF-β1-induced endothelial dysfunction, providing a protective effect for ECs and also anti-AS activity. However, the exact role of ApoA-I in TGF-β1-induced EndMT is not clear. In this study, we aimed to investigate whether ApoA-I can modulate TGF-β1-induced EndMT in human coronary artery ECs (HCAECs). Methods and Results: The HCAECs were treated with TGF-β1 with or without ApoA-I. Morphological changes in HCAECs and the expression of EndMT-related markers were evaluated. HCAECs treated with TGF-β1 were found to transform to MC morphology, with inconspicuous expression of EC markers such as vascular endothelial cadherin and CD31, and conspicuous expression of fibroblast-specific protein 1 (FSP-1) and α-smooth muscle actin. The treatment of HCAECs with ApoA-I inhibited the TGF-β1-induced EndMT, and elevated expression of EC markers was observed but reduced expression of MC markers. Moreover, ApoA-I impeded the expression level of Slug and Snail, crucial transcriptional factors of EndMT, and it inhibited the TGF-β1-induced phosphorylation of Smad2 and Smad3 which affected the EC morphology. In addition, the knockdown of ABCA1 by RNA interference eliminated the inhibition effect of ApoA-I on TGF-β1-induced EndMT. Conclusions: Our findings revealed a novel mechanism for the ApoA-I protective effect on endothelium function via the inhibition of TGF-β1-induced EndMT. This might provide new insights for developing strategies for modulating AS and vascular remodeling.
Impact of Weight-Related Discrimination, Body Dissatisfaction and Self-Stigma on the Desire to Weigh Less
Authors: Jung Franziska , Spahlholz Jenny , Hilbert Anja , Riedel-Heller Steffi G. , Luck-Sikorski Claudia
Published: April 2017

Aim: Currently, health care professionals plead for stabilization of weight and improving health conditions rather than focusing on weight loss only. Individuals with obesity have been shown to report weight loss goals that are much higher than what has been suggested by guidelines. The aim was to determine whether weight discrimination and body dissatisfaction have an impact on how much weight an individual with obesity wants to lose. Methods: In this representative telephone survey, 878 participants with obesity were asked about their experiences with weight stigma, their body image concerns, and about the amount of weight they would like to weigh using random digital dialing and Kish selection grid to ensure random selection of participants. Results: Regression analysis reveals that being female, having a higher BMI, being younger, and trying to lose weight was related to a greater discrepancy between current weight and desired weight. The discrepancy between current weight and desired weight was greater when participants reported discrimination due to their weight as well as internalized stigma and body image concerns. Conclusion: Independent on the weight loss method, treating obesity should include realistic weight loss goals without being affected by social pressure or weight stigma, especially since stigma can result in further weight gain and decline health issues related to obesity and overweight.
Unsuccessful Treatment of Alopecia Areata with Simvastatin/Ezetimibe: Experience in 12 Patients
Authors: Freitas Gouveia Mabe , Trüeb Ralph M.
Published: April 2017

Background/Aims: Alopecia areata is a common immune-mediated hair condition with limited treatment options and success rates. There is evidence that statins, which are used for reducing atherogenesis and cardiovascular disease, have immunomodulatory activities and therefore may also be used for treatment of selected dermatologic conditions, including alopecia areata. Among treatments evaluated for alopecia areata, oral simvastatin/ezetimibe therapy is currently under the scrutiny of expert opinion. Methods: Prospective observational study of the efficacy and tolerability of simvastatin/ezetimibe 40/10 mg (Inegy; MSD Merck Sharp & Dohme AG, Lucerne, Switzerland) over a treatment period of 6 months in alopecia totalis, universalis, multipatch involvement of the scalp >30%, ophiasis, or diffuse alopecia areata. Results: Of the 12 patients included in the study, 67% had no hair regrowth, 24% transient diffuse or patchy hair regrowth, and 24% patchy regrowth of pigmented hair which was not considered cosmetically satisfactory. Adverse effects were observed in 24% of patients, who reported myalgia. One patient showed elevation of creatine phosphokinase. Conclusion: Simvastatin/ezetimibe is not effective for treatment of alopecia areata, at least in severe and/or cases refractory to other treatments, either as monotherapy or as adjuvant. Ultimately, in choosing such a treatment with questionable benefit, one must take the risk of serious adverse effects into careful consideration.
Maturation of Platelet Function During Murine Fetal Development In Vivo
Authors: Margraf Andreas , Nussbaum Claudia , Rohwedder Ina , Klapproth Sarah , Kurz Angela R.M. , Florian Annamaria , Wiebking Volker , Pircher Joachim , Pruenster Monika , Immler Roland , Dietzel Steffen , Kremer Ludmila , Kiefer Friedemann , Moser Markus , Flemmer Andreas W. , Quackenbush Elizabeth , von Andrian Ulrich H. , Sperandio Markus
Published: April 2017

Objective—

Platelet function has been intensively studied in the adult organism. However, little is known about the function and hemostatic capacity of platelets in the developing fetus as suitable in vivo models are lacking.

Approach and Results—

To examine fetal platelet function in vivo, we generated a fetal thrombosis model and investigated light/dye-induced thrombus formation by intravital microscopy throughout gestation. We observed that significantly less and unstable thrombi were formed at embryonic day (E) 13.5 compared with E17.5. Flow cytometry revealed significantly lower platelet counts in E13.5 versus E17.5 fetuses versus adult controls. In addition, fetal platelets demonstrated changed activation responses of surface adhesion molecules and reduced P-selectin content and mobilization. Interestingly, we also measured reduced levels of the integrin-activating proteins Kindlin-3, Talin-1, and Rap1 during fetal development. Consistently, fetal platelets demonstrated diminished spreading capacity compared with adults. Transfusion of adult platelets into the fetal circulation led to rapid platelet aggregate formation even in young fetuses. Yet, retrospective data analysis of a neonatal cohort demonstrated no correlation of platelet transfusion with closure of a persistent ductus arteriosus, a process reported to be platelet dependent.

Conclusions—

Taken together, we demonstrate an ontogenetic regulation of platelet function in vivo with physiologically low platelet numbers and hyporeactivity early during fetal development shedding new light on hemostatic function during fetal life.
microRNA-33 Regulates Macrophage Autophagy in Atherosclerosis
Authors: Ouimet Mireille , Ediriweera Hasini , Afonso Milessa Silva , Ramkhelawon Bhama , Singaravelu Ragunath , Liao Xianghai , Bandler Rachel C. , Rahman Karishma , Fisher Edward A. , Rayner Katey J. , Pezacki John P. , Tabas Ira , Moore Kathryn J.
Published: April 2017

Objective—

Defective autophagy in macrophages leads to pathological processes that contribute to atherosclerosis, including impaired cholesterol metabolism and defective efferocytosis. Autophagy promotes the degradation of cytoplasmic components in lysosomes and plays a key role in the catabolism of stored lipids to maintain cellular homeostasis. microRNA-33 (miR-33) is a post-transcriptional regulator of genes involved in cholesterol homeostasis, yet the complete mechanisms by which miR-33 controls lipid metabolism are unknown. We investigated whether miR-33 targeting of autophagy contributes to its regulation of cholesterol homeostasis and atherogenesis.

Approach and Results—

Using coherent anti-Stokes Raman scattering microscopy, we show that miR-33 drives lipid droplet accumulation in macrophages, suggesting decreased lipolysis. Inhibition of neutral and lysosomal hydrolysis pathways revealed that miR-33 reduced cholesterol mobilization by a lysosomal-dependent mechanism, implicating repression of autophagy. Indeed, we show that miR-33 targets key autophagy regulators and effectors in macrophages to reduce lipid droplet catabolism, an essential process to generate free cholesterol for efflux. Notably, miR-33 regulation of autophagy lies upstream of its known effects on ABCA1 (ATP-binding cassette transporter A1)-dependent cholesterol efflux, as miR-33 inhibitors fail to increase efflux upon genetic or chemical inhibition of autophagy. Furthermore, we find that miR-33 inhibits apoptotic cell clearance via an autophagy-dependent mechanism. Macrophages treated with anti-miR-33 show increased efferocytosis, lysosomal biogenesis, and degradation of apoptotic material. Finally, we show that treating atherosclerotic
Ldlr
−/−
mice with anti-miR-33 restores defective autophagy in macrophage foam cells and plaques and promotes apoptotic cell clearance to reduce plaque necrosis.

Conclusions—

Collectively, these data provide insight into the mechanisms by which miR-33 regulates cellular cholesterol homeostasis and atherosclerosis.
Deficiency of Cholesteryl Ester Transfer Protein Protects Against Atherosclerosis in Rabbits
Authors: Zhang Jifeng , Niimi Manabu , Yang Dongshan , Liang Jingyan , Xu Jie , Kimura Tokuhide , Mathew Anna V. , Guo Yanhong , Fan Yanbo , Zhu Tianqing , Song Jun , Ackermann Rose , Koike Yui , Schwendeman Anna , Lai Liangxue , Pennathur Subramaniam , Garcia-Barrio Minerva , Fan Jianglin , Chen Y. Eugene
Published: April 2017

Objective—

CETP (cholesteryl ester transfer protein) plays an important role in lipoprotein metabolism; however, whether inhibition of CETP activity can prevent cardiovascular disease remains controversial.

Approach and Results—

We generated CETP knockout (KO) rabbits by zinc finger nuclease gene editing and compared their susceptibility to cholesterol diet–induced atherosclerosis to that of wild-type (WT) rabbits. On a chow diet, KO rabbits showed higher plasma levels of high-density lipoprotein (HDL) cholesterol than WT controls, and HDL particles of KO rabbits were essentially rich in apolipoprotein AI and apolipoprotein E contents. When challenged with a cholesterol-rich diet for 18 weeks, KO rabbits not only had higher HDL cholesterol levels but also lower total cholesterol levels than WT rabbits. Analysis of plasma lipoproteins revealed that reduced plasma total cholesterol in KO rabbits was attributable to decreased apolipoprotein B–containing particles, while HDLs remained higher than that in WT rabbits. Both aortic and coronary atherosclerosis was significantly reduced in KO rabbits compared with WT rabbits. Apolipoprotein B–depleted plasma isolated from CETP KO rabbits showed significantly higher capacity for cholesterol efflux from macrophages than that from WT rabbits. Furthermore, HDLs isolated from CETP KO rabbits suppressed tumor necrosis factor-α–induced vascular cell adhesion molecule 1 and E-selectin expression in cultured endothelial cells.

Conclusions—

These results provide evidence that genetic ablation of CETP activity protects against cholesterol diet–induced atherosclerosis in rabbits.
Detrimental Effects of Centrally Administered Angiotensin II are Enhanced in a Mouse Model of Alzheimer Disease Independently of Blood Pressure
Authors: Takane Koki , Hasegawa Yu , Lin Bowen , Koibuchi Nobutaka , Cao Cheng , Yokoo Takashi , Kim‐Mitsuyama Shokei
Published: April 2017

Background

The significance of brain angiotensin
II
in Alzheimer disease (
AD
) is unclear.

Methods and Results

To examine the role of brain angiotensin
II
in
AD
, intracerebroventricular angiotensin
II
infusion was performed on 5
XFAD
mice, a mouse model of
AD
, and wild‐type mice, and the detrimental effects of brain angiotensin
II
was compared between the 2 strains of mice. Intracerebroventricular angiotensin
II
infusion significantly impaired cognitive function in 5
XFAD
mice but not in wild‐type mice. This vulnerability of 5
XFAD
mice to brain angiotensin
II
was associated with enhancement of hippocampal inflammation and oxidative stress and with increased cerebrovascular amyloid β deposition. We also compared the effect of brain angiotensin
II
on the heart and skeletal muscle between the 2 strains because
AD
is associated with heart failure and sarcopenia. We found that cardiac compensatory response of 5
XFAD
mice to brain angiotensin
II
–induced hypertension was less than that of wild‐type mice. Brain angiotensin
II
caused skeletal muscle atrophy and injury in 5
XFAD
mice more than in wild‐type mice.

Conclusions

Brain angiotensin
II
seems to be involved in cognitive impairment and brain injury in
AD
, which is associated with oxidative stress, inflammation, and cerebral amyloid angiopathy. Further, brain angiotensin
II
may participate in cardiac disease and sarcopenia observed in
AD
.
Syntactic Complexity and Frequency in the Neurocognitive Language System
Authors: Yang Yun-Hsuan , Marslen-Wilson William D. , Bozic Mirjana
Published: April 2017

Prominent neurobiological models of language follow the widely accepted assumption that language comprehension requires two principal mechanisms: a lexicon storing the sound-to-meaning mapping of words, primarily involving bilateral temporal regions, and a combinatorial processor for syntactically structured items, such as phrases and sentences, localized in a left-lateralized network linking left inferior frontal gyrus (LIFG) and posterior temporal areas. However, recent research showing that the processing of simple phrasal sequences may engage only bilateral temporal areas, together with the claims of distributional approaches to grammar, raise the question of whether frequent phrases are stored alongside individual words in temporal areas. In this fMRI study, we varied the frequency of words and of short and long phrases in English. If frequent phrases are indeed stored, then only less frequent items should generate selective left frontotemporal activation, because memory traces for such items would be weaker or not available in temporal cortex. Complementary univariate and multivariate analyses revealed that, overall, simple words (verbs) and long phrases engaged LIFG and temporal areas, whereas short phrases engaged bilateral temporal areas, suggesting that syntactic complexity is a key factor for LIFG activation. Although we found a robust frequency effect for words in temporal areas, no frequency effects were found for the two phrasal conditions. These findings support the conclusion that long and short phrases are analyzed, respectively, in the left frontal network and in a bilateral temporal network but are not retrieved from memory in the same way as simple words during spoken language comprehension.
Distractor-resistant Short-Term Memory Is Supported by Transient Changes in Neural Stimulus Representations
Authors: Derrfuss Jan , Ekman Matthias , Hanke Michael , Tittgemeyer Marc , Fiebach Christian J.
Published: April 2017

Goal-directed behavior in a complex world requires the maintenance of goal-relevant information despite multiple sources of distraction. However, the brain mechanisms underlying distractor-resistant working or short-term memory (STM) are not fully understood. Although early single-unit recordings in monkeys and fMRI studies in humans pointed to an involvement of lateral prefrontal cortices, more recent studies highlighted the importance of posterior cortices for the active maintenance of visual information also in the presence of distraction. Here, we used a delayed match-to-sample task and multivariate searchlight analyses of fMRI data to investigate STM maintenance across three extended delay phases. Participants maintained two samples (either faces or houses) across an unfilled pre-distractor delay, a distractor-filled delay, and an unfilled post-distractor delay. STM contents (faces vs. houses) could be decoded above-chance in all three delay phases from occipital, temporal, and posterior parietal areas. Classifiers trained to distinguish face versus house maintenance successfully generalized from pre- to post-distractor delays and vice versa, but not to the distractor delay period. Furthermore, classifier performance in all delay phases was correlated with behavioral performance in house, but not face, trials. Our results demonstrate the involvement of distributed posterior, but not lateral prefrontal, cortices in active maintenance during and after distraction. They also show that the neural code underlying STM maintenance is transiently changed in the presence of distractors and reinstated after distraction. The correlation with behavior suggests that active STM maintenance is particularly relevant in house trials, whereas face trials might rely more strongly on contributions from long-term memory.
The Eye of Truth (L’œil de la verité)
Authors: Hoffmann Katrin
Published: April 2017

Written in the last decades of the sixteenth century and anonymously published for the first time in 1616, Agrippa d’Aubigné’s epic poem Les Tragiques offers an unusual literary testimony of interconfessional violence during the Wars of Religion in early modern France. Focusing on Aubigné’s aim to give a documentation of violence for generations to come, this article discusses the complex relationship between testimony and epic narration.

Agrippa d’Aubignés Epos Les Tragiques, das der Autor 1616 nach jahrzehntelanger Bearbeitungszeit erstmals anonym veröffentlicht, stellt in Hinblick auf die gewaltsamen konfessionellen Auseinandersetzungen, die Frankreich in der zweiten Hälfte des 16. Jahrhunderts erschütterten, ein außergewöhnliches Beispiel literarischer Zeugenschaft dar. Mit Blick auf das unverkennbare Anliegen des Autors, die erlittene Gewalt zu bezeugen und der Nachwelt zugänglich zu machen, erörtert der vorliegende Artikel das testimoniale Potenzial epischen Erzählens.
Fictional Debates on Tolerance (Fiktive Debatten über Toleranz)
Authors: Hars Angela
Published: April 2017

This article examines two printed pamphlets written at the beginning of the English Restoration (1660–1688). One was published by the influential author Roger L’Estrange. The other appeared anonymously and was written by the Franciscan friar Vincent Canes. Both pamphlets reflect the ongoing controversy about toleration in form of an imaginary dialogue. Focusing on the question of how the two writers tried to influence their audience and the current political debate, the article explores their motives and ingenious rhetorical methods.

In England wurden zu Beginn der Restaurationszeit (1660–1688) zwei Pamphlete veröffentlicht, welche die hitzig geführten Diskussionen um Glaubensfreiheit in Form fiktiver Dialoge aufgriffen. Das eine stammt von dem einflussreichen politischen Autor Roger L’Estrange. Das andere erschien anonym und ist dem Franziskanermönch Vincent Canes zuzuschreiben. Im Beitrag wird der Frage nachgegangen, mit welchen Argumenten und rhetorischen Mitteln die beiden Autoren versuchten, die Leser und die aktuelle polische Debatte zu beeinflussen.
“We Don’t Have a Permanent Settlement Here” (“Wir haben hier keine bleibende Stadt”)
Authors: Lehmann Sarah , Stützinger Sarah
Published: April 2017

Early Modern funeral sermons explore the space between life and death. In order to console and exhort individuals and congregations left behind, they aim to overcome the silence of death through specific images and thoughts. The Epistle to the Hebrews offers particularly striking linguistic images which both Lutheran and Catholic funeral sermons employ. This article presents examples of how preachers of both denominations used these metaphors, both transcending and emphasizing confessional differences.

Die Leichenpredigten der Frühen Neuzeit stehen im Spannungsfeld zwischen Leben und Tod, mithin zwischen den Lebenden und den Toten. Sie sind Predigten, die im Moment des Todes tröstend und auch mahnend an die Hinterbliebenen und die Gemeinde gerichtet sind. Dabei muss die Leichenpredigt in die Sprachlosigkeit angesichts des Todes mit einer das Schweigen durchbrechenden Bild- und Gedankenwelt hinein sprechen. Dass der Hebräerbrief in diesem Zusammenhang besonders eindrückliche sprachliche Bilder bietet, welche lutherische und katholische Leichenprediger teils konfessionsübergreifend, teils jedoch konfessionell zugespitzt verwenden, soll im Folgenden exemplarisch dargestellt werden.
Comedy and Biography in the Reckless Student (Anonymous, 1681) (Schwankhaftes und Biographisches im Ruchlosen Studenten (anonym, 1681))
Authors: Lickhardt Maren
Published: April 2017

This essay discusses the transformation and breakdown of the picaresque in the late 17th century, with specific reference to narrative strategies used in Der ruchlose Student (1681), an anonymous and fragmentary German translation of a Dutch text – picaresque in the broader sense. These strategies, it is argued, reveal both an internalisation of the first-person narrator and early manifestations of a causally motivated (biographical) syntagma. By way of example, it is demonstrated how the typical affectively flat, villainous narrator of earlier picaresque novels, as well as the episodic structure of these texts, are transformed in Der ruchlose Student such as to enable the emergence of a more modern individual within the framework of a more consistent story line. As such, this essay contributes indirectly to scholarly discussions relating to the embourgeoisement of the picaro figure.

Der folgende Text stellt einen Beitrag zu Um- und Abbauten des Pikaresken gegen Ende des 17. Jahrhunderts dar. Er widmet sich den narrativen Strategien in dem anonym verfassten Romanfragment Der ruchlose Student (1681), der deutschen Übersetzung eines niederländischen Schelmenromans im weiteren Sinne, die eine Verinnerlichung des pikaresken Ich-Erzählers sowie erste Ausprägungen eines kausal motivierten (biographischen) Syntagmas erkennen lassen. Exemplarisch wird also herausgearbeitet, wie sich der typische pikareske statische Erzähler älterer Schelmenromane sowie deren episodische Handlungsführung in Ansätzen transformieren und ein moderneres Individuum in einem konsistenteren Handlungsgefüge aufscheint. Indirekt schließt der Beitrag damit an die Debatte um die Verbürgerlichung des Pikaros an.