bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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

Abstract
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

Abstract
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.
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.
Syntactic Complexity and Frequency in the Neurocognitive Language System
Authors: Yang Yun-Hsuan , Marslen-Wilson William D. , Bozic Mirjana 
Published: April 2017

AbstractProminent 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

Abstract
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.
Tupistra ashihoi (Asparagaceae), a new species from north-eastern India
Authors: ROY DILIP KR. , ODYUO N. , AVERYANOV LEONID V. 
Published: April 2017

Tupistra Ker Gawler (1814: 1655) belonging to Asparagaceae subfamily Nolinoideae (APG 2009, Chase et al. 2009), includes about 26 species (Govaerts 2016). These taxa spread mainly in south and south-east of continental Asia, including Nepal, Bhutan, India, Myanmar, China, Laos, Vietnam, Thailand and Malaysia (Tanaka 2003a, 2003b, 2010a, 2010b, Averyanov et al. 2016). This genus is characterised by leaves with slender petiolar base, relatively large stigma broader than the style, stout columnar style almost as thick as the ovary and usually tuberculate, dirty green, globular berry-like fruit (Tanaka 2003a, 2010a). In India, Tupistra is represented so far by four species, namely Tupistra clarkei Hooker (1894: 325), T. nutans Wall. ex Lindley (1839: 1223), T. stoliczana Kurz (1875: 199) and T. tupistroides (Kunth 1848: 12) Dandy (1932: 329).