bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety of CollagenaseClostridium histolyticumInjection Therapy for Peyronie Disease in Patients Continuing Antiplatelet or Anticoagulant Therapy
Authors: Amighi Arash , Regets Keith Vincent , Nork Justin James , Mendhiratta Neil , Mills Jesse Nelson , Eleswarapu Sriram Venkata
Published: December 2019

Introduction

The initial clinical trials for intralesional collagenase Clostridium histolyticum (CCh) injection therapy for Peyronie disease (PD) excluded men on antiplatelet or anticoagulant medications except those on low-dose aspirin. Men with PD who take such medications present a challenging clinical scenario because of a lack of evidence regarding the safety of CCh while on these drugs.

Aim

To evaluate safety outcomes among patients continuing anticoagulant and antiplatelet therapy during ongoing intralesional CCh injection treatment for PD.

Methods

An institutional review board approved a database of 187 patients treated with CCh at an academic men's health practice from January 2016 through April 2019 was reviewed. Men on antiplatelet/anticoagulant medications were not instructed to stop these agents. Data on patient demographics, comorbidities, CCh injection details, use or nonuse of antiplatelet/anticoagulant medications, and adverse events were extracted from the electronic medical record. Rates of hematoma formation, bruising, swelling, and corporal rupture were determined. Univariate statistical analysis compared clinical data and adverse events between men on or off antiplatelet/anticoagulant medications.

Main Outcome Measure

Statistical comparison of adverse events in those taking or not taking antiplatelet or anticoagulant medications while undergoing intralesional CCh injection therapy for PD.

Results

Of 187 men undergoing CCh treatment, 33 (17.6%) were on concomitant antiplatelet or anticoagulant therapy. Aspirin 81 mg alone was the most common pharmacologic agent (58% of men on antiplatelet/anticoagulants); medications also included other antiplatelet drugs, warfarin, and novel oral anticoagulants (NOACs). Men taking blood thinners during intralesional CCh injection therapy experienced no statistical difference in rates of bruising, swelling, or hematoma formation compared with men not on antiplatelet/anticoagulants. No corporal ruptures were observed in either group. Men on antiplatelet or anticoagulant therapy were more likely to be older (64 vs 58 years old, P = 0.005), have hypertension (P = 0.025), and have hyperlipidemia (0.009).

Clinical Implications

Intralesional CCh injection therapy may be offered to men on antiplatelet/anticoagulant medications without increased risk of adverse events.

Strength & Limitations

This study evaluated the experience of a single surgeon, with a systematic evaluation of adverse events captured in a robust electronic medical record. The retrospective nature of this study limits conclusions but builds upon work performed in the initial clinical trials for CCh.

Conclusion

Our findings suggest that antiplatelet and anticoagulant medications do not increase the risk of adverse events during intralesional CCh injection therapy for PD.
Satire and the Public Emotions
Authors: Phiddian Robert
Published: December 2019

The dream of political satire - to fearlessly speak truth to power - is not matched by its actual effects. This study explores the role of satirical communication in licensing public expression of harsh emotions defined in neuroscience as the CAD (contempt, anger, disgust) triad. The mobilisation of these emotions is a fundamental distinction between satirical and comic laughter. Phiddian pursues this argument particularly through an account of Jonathan Swift and his contemporaries. They played a crucial role in the early eighteenth century to make space in the public sphere for intemperate dissent, an essential condition of free political expression.
Some remarks on the volume of log varieties
Authors: Filipazzi Stefano
Published: December 2019

In this note, using methods introduced by Haconet al. [‘Boundedness of varieties of log general type’, Proceedings of Symposia in Pure Mathematics, Volume 97 (American Mathematical Society, Providence, RI, 2018) 309–348], we study the accumulation points of volumes of varieties of log general type. First, we show that if the set of boundary coefficientsΛsatisfies the descending chain condition (DCC), is closed under limits and contains 1, then the corresponding set of volumes satisfies the DCC and is closed under limits. Then, we consider the case ofε-log canonical varieties, for 0 < ε < 1. In this situation, we prove that ifΛis finite, then the corresponding set of volumes is discrete.
Aristotle and Natural Law
Authors: Duke George
Published: December 2019

This paper seeks to clarify the long-standing controversy over Aristotle's relationship to the natural law tradition. The paper argues that a precondition for any adequate assessment of Aristotle's natural law credentials is a close analysis of theNicomachean EthicsV.7 discussion of the just by nature. Such an investigation, the primary concern of section 1, reveals that Aristotle's characterization of the politically just as partly natural and partly conventional does entail that nature serves as a normative ground for just law. With this conclusion in place, section 2 then turns more directly to Aristotle's relation to the natural law tradition. Despite important differences between Aristotle's account of the normative foundations of law and those found in the paradigmatic natural law teachings of the Stoics and Aquinas, I argue, there are nonetheless features of later natural law thought on the purpose and evaluation of law which are genuinely Aristotelian in orientation.
Alasdair MacIntyre and Leo Strauss on the Activity of Philosophy
Authors: Pinkoski Nathan J.
Published: December 2019

Followers of Leo Strauss have criticized Alasdair MacIntyre's account of the activity of philosophy as historicist. MacIntyre himself has been dismissive of Strauss. I argue that these apparent disagreements obscure their deeper agreements about the activity of philosophy. Rather than holding to historicism, MacIntyre's account of philosophy has a strong symmetry with Strauss's. To counter modern dogmatism, both Strauss and MacIntyre argue for a balanced mixture of history and philosophy to contend that philosophy's task is to gain knowledge of natural reality. Yet both place similar epistemic limits on philosophy, arguing that philosophy's gains are modest and always open to revision. Moreover, both hold that no authority other than human reason can direct the activity of philosophy. Putting MacIntyre and Strauss in a more careful conversation enriches the account of the fundamental philosophical problems that each addresses.
AGE OF ONSET, TYPE OF EXPOSURE, AND ULTIMATE ATTAINMENT OF L2 MORPHO-SYNTACTIC SENSITIVITY
Authors: Lee Eun-Kyoung Rosa
Published: December 2019

The present study examined whether early immersive L2 exposure in a foreign language learning context can yield long-term advantages in L2 morpho-syntactic sensitivity. Participants were 40 Korean university students with high English proficiency, who had either attended an English kindergarten or begun learning English in a classroom, and a control group of native English speakers. All participants performed a speeded aural grammaticality judgment task that included the following features: articles, subcategorization, plural -s, third-person -s. Results showed that the English-kindergarten group outperformed the late-classroom group in terms of accuracy for ungrammatical sentences, while the two groups did not differ significantly on grammatical sentences and in reaction time measures. The learners altogether scored higher in plural -s and third-person -s compared to articles. While the native speakers showed near-perfect accuracy and fast reaction times, the highly proficient learners were at near-chance level in detecting morpho-syntactic errors during online L2 aural processing.
Jousting Over Jurisdiction: Sovereignty and International Law in Late Nineteenth-Century South Asia
Authors: Saksena Priyasha
Published: December 2019

The article examines the relationship between colonialism and international law by focusing on late nineteenth century debates surrounding the sovereignty of the “princely states” of colonial South Asia. The princely states were ruled by indigenous rulers and were not considered to be British territory, but remained subject to British “influence;” as a result, there were numerous controversies over their legal status. During the course of jurisdictional disputes, a variety of interested players - British politicians, colonial officials, international lawyers, rulers and advisors of princely states - engaged in debates over the idea of sovereignty to resolve questions of legal status, the extent of rights and powers, and to construct a political order that supported their interests and aspirations. I focus on legal texts written by British international lawyers and colonial officials as well as material relating to two jurisdictional disputes (one between the state of Travancore and the British Government and another between the state of Baroda and the British Government) to trace two versions of sovereignty that were articulated in late nineteenth century South Asia - unitary and divisible. In doing so, I argue that international law, and the doctrine of sovereignty in particular, became the shared language for participants to debate political problems and a key forum for the negotiation of political power.
Advance Healthcare Directives: Binding or Informational Value?
Authors: MONTANARI VERGALLO GIANLUCA
Published: December 2019

Advance directives entail a refusal expressed by a still-healthy patient. Three consequences stem from that fact: (a) advance refusal is unspecific, since it is impossible to predict what the patient’s conditions and the risk-benefit ratio may be in the foreseeable future; (b) those decisions cannot be as well informed as those formulated while the disease is in progress; (c) while both current consent and refusal can be revoked as the disease unfolds, until the treatment starts out, advance directives become effective when the patient becomes incapable or unconscious; such decisions can therefore not be revoked at any stage of the disease. Therefore, advance directives are binding for doctors only at the stage of advance treatment planning, i.e., only if they refer to an illness already in progress.
Heimliche Rückfälle während einer Entwöhnungstherapie
Authors: Wetterling1 T. , Dibbelt L. , Wetterling G. , Junghanns K.
Published: December 2019

Zusammenfassung. Hintergrund: Viele Patienten, die im Rahmen einer Entwöhnungstherapie von Wochenend-Heimfahrten zurückkehren, verschweigen ihre Rückfälle. Hier sollte überprüft werden, ob die Therapeuten der Patienten heimliche Rückfälle gut entdecken können. Methodik: In dieser explorativen Studie wurden die Rückfälle von Patienten einer Entwöhnungstherapie anhand von Patientenangaben und Atemalkoholwerten bei Rückkehr in die Therapie und anhand von post hoc ausgewerteten Ethylglukuronid-Bestimmungen im Urin mit den Therapeuteneinschätzungen verglichen. Ergebnisse: Nach der Therapeuteneinschätzung hatte in 1190 von 1501 (79,3 %) erfassten Heimfahrten wahrscheinlich kein Rückfall stattgefunden. In 231 Fällen (15,4 %) hatten die Therapeuten die Rückfallwahrscheinlichkeit mit 40–60 % angegeben. In 80 Fällen (5,3 %) nahmen sie einen Rückfall auf der Heimfahrt als sehr wahrscheinlich (70–100 %) an. Der Vergleich der Therapeuteneinschätzungen mit den EtG-Bestimmungen zeigte keine Übereinstimmung (Kappa .077), d. h. viele Rückfälle waren von den Therapeuten nicht erkannt worden. Schlussfolgerungen: Die Ergebnisse zeigen, dass die Therapeuten die Rückfallhäufigkeit von Patienten während der Heimfahrten am Wochenende während einer Langzeittherapie deutlich unterschätzten. Um Rückfälle konstruktiv in der Therapie aufarbeiten zu können, sollten diese deshalb mit laborchemischen Methoden wie der EtG-Bestimmung gesichert werden.
Neue Psychoaktive Substanzen: ein kurzgefasster Überblick
Authors: Wodarz Norbert , Mühlig Stephan , Thomasius Rainer
Published: December 2019

Zusammenfassung. Hintergrund und Zielsetzung: Seit 2008 hat sich die Anzahl der in Europa erfassten Neuen Psychoaktiven Stoffe (NPS) um ca. 700 erhöht. Ziel ist ein komprimierter Überblick über die wichtigsten Substanz(grupp)en unter Einbeziehung der verfügbaren wissenschaftlichen Literatur, sowie Berichten von Behörden. Substanzcharakteristika: Die (Neben-)Wirkungen der „Neuen Psychoaktiven Stoffe“ sind höchst unterschiedlich und meist nicht systematisch untersucht. Neben den bislang größten Gruppen (synthetische Cannabinoide (SC), Amphetamin-Type-Stimulants, inkl. Cathinone) finden sich auch immer häufiger neuartige Substanzen, die keiner bisher bekannten Stoffgruppe zugeordnet werden können. Das Marktangebot ändert sich ständig und schnell, die Wirkpotenzen stiegen zuletzt erheblich an, z. B. bei den SC und Fentanylen. Verbreitung: NPS sind in Deutschland nach Cannabis die am zweithäufigsten konsumierten illegalen Substanzen. Hauptbezugsweg scheint das Internet („Darknez“) darzustellen. Konsumrisiken: Das Risiko einer akuten Überdosierung ist sehr hoch (z. B. hohe Wirkpotenz), die Langzeitrisiken weitgehend unbekannt. Schlussfolgerungen: Die Behandlung der häufig vorkommenden Intoxikationen ist schwierig, da meist weder die verursachende Substanz, noch evidenzbasiert wirksame Maßnahmen bekannt sind. Systematische Untersuchungen, wie viele Intoxikationen mit NPS gar nicht als solche erkannt werden, fehlen. In Anlehnung an britische Erfahrungen könnte sich die Etablierung spezifischer Präventions- und Schadensminimierungsstrategien für NPS lohnen.
Wertfacetten im Grundschulalter in drei Fächern: Differenzierung, Entwicklung, Geschlechtseffekte und Zusammenhänge zu Noten
Authors: Arens A. Katrin
Published: December 2019

Zusammenfassung. Im Rahmen der Erwartungs-Wert-Theorie zur schulischen Motivation betrachtete die Studie die beiden Wertfacetten intrinsischer Wert und Wichtigkeit in den Fächern Mathematik, Deutsch und Sachunterricht. Untersucht wurden die Ausdifferenzierung der beiden Wertfacetten, ihr Entwicklungsverlauf am Ende der Grundschule, Geschlechtseffekte und Zusammenhänge zu Noten. Die Stichprobe bestand aus N = 2.317 Schülern; die Variablen wurden zu drei Messzeitpunkten im Verlauf der dritten und vierten Klassenstufe erfasst. Die Schüler unterschieden in allen drei Fächern zwischen den beiden Wertfacetten; jedoch zeigten die beiden Wertfacetten im Sachunterricht einen besonders hohen positiven Zusammenhang. Die Ausdifferenzierung zwischen beiden Wertfacetten veränderte sich nicht über die drei Messzeitpunkte. In latenten Wachstumskurvenmodellen zeigte sich ein Einbruch in der mittleren Ausprägung des intrinsischen Werts in Mathematik. Zunahmen konnten in den mittleren Ausprägungen der Wichtigkeit in Deutsch und der Wichtigkeit in Sachunterricht verzeichnet werden. Allerdings waren die Veränderungen sehr klein und kaum praktisch bedeutsam, so dass man eher von Stabilität als von Veränderung in der mittleren Ausprägung fachspezifischer Wertfacetten am Ende der Grundschulzeit sprechen kann. Jungen und Mädchen zeigten eine ähnliche Struktur der fachspezifischen Wertfacetten, unterschieden sich aber in den mittleren Ausprägungen. Jungen berichteten höhere Ausprägungen auf beiden Wertfacetten in Mathematik; Mädchen berichteten höhere Ausprägungen auf beiden Wertfacetten in Deutsch. Jungen und Mädchen unterschieden sich nicht in der Wichtigkeit in Sachunterricht; Jungen hatten zu zwei Messzeitpunkten höhere Ausprägungen auf dem intrinsischen Wert in Sachunterricht. In allen drei Fächern zeigten beide Wertfacetten einen ähnlich hohen positiven Zusammenhang zu den fachspezifischen Noten. In allen drei Fächern wirkten sich gute Noten positiv auf den nachfolgenden intrinsischen Wert und auf die nachfolgende Wichtigkeit aus. In Mathematik hatte die Wichtigkeit zudem positive Auswirkungen auf nachfolgende Noten. Die Ergebnisse werden in Zusammenhang gebracht mit den Ergebnissen aus Studien mit Sekundarschülern und vor dem Hintergrund des Grundschulübergangs diskutiert.
Evaluation of a Peer-Led Implementation of a Suicide Prevention Gatekeeper Training Program for College Students
Authors: Samuolis Jessica , Harrison Angela J. , Flanagan Karen
Published: December 2019

Abstract. Background: Research on models of implementation that enable widespread dissemination of suicide prevention to young adults is needed to address the critical public health issue of suicide among young adults. A peer-to-peer implementation approach may increase widespread dissemination of suicide prevention on college campuses.  Aims: The current study involved the evaluation of a peer-led implementation of the evidence-based program Question, Persuade, and Refer Gatekeeper Training for Suicide Prevention (QPR). Method: A total of 161 college students attended one of eight QPR implementations conducted by student peer educators certified as QPR trainers. Questionnaires were administered at pretest and posttest to assess knowledge of suicide, likelihood of intervening with someone suicidal, and self-efficacy to intervene with someone suicidal. Results: Results from a series of paired-samples t tests showed significant increases from pretest to posttest on the three outcomes of interest – knowledge of suicide, self-efficacy to intervene with someone suicidal, and likelihood to intervene with someone suicidal. Limitations: The short time frame of the current study is a limitation. Conclusion: Support for a peer-led model of implementation for college students has critical implications in terms of increasing the capacity for widespread dissemination of suicide prevention efforts on college campuses.
A Causal Replication Framework for Designing and Assessing Replication Efforts
Authors: Steiner Peter M. , Wong Vivian C. , Anglin Kylie
Published: December 2019

Abstract. Replication has long been a cornerstone for establishing trustworthy scientific results, but there remains considerable disagreement about what constitutes a replication, how results from these studies should be interpreted, and whether direct replication of results is even possible. This article addresses these concerns by presenting the methodological foundations for a replication science. It provides an introduction to the causal replication framework, which defines “replication” as a research design that tests whether two (or more) studies produce the same causal effect within the limits of sampling error. The framework formalizes the conditions under which replication success can be expected, and allows for the causal interpretation of replication failures. Through two applied examples, the article demonstrates how the causal replication framework may be utilized to plan prospective replication designs, as well as to interpret results from existing replication efforts.
Seasonal and Interannual Variability of the Subsurface Velocity Profile of the Indonesian Throughflow at Makassar Strait
Authors: Jiang Guo‐Qing , Wei Jun , Malanotte‐Rizzoli Paola , Li Mingting , Gordon Arnold L.
Published: December 2019

Although there have been many previous studies that have interpreted the variability of Indonesian Throughflow transport, the processes that determine its vertical structure have rarely been investigated due to limited observations and model inefficiencies. In this study, a regionally coupled model is developed to address this issue. The model adopts an unstructured model grid, with an ~3‐km resolution within the Indonesian seas and straits, and reveals somewhat inconsistent results compared to previous models with coarser resolutions. The results suggest that the seasonal variability of the depth of the Indonesian Throughflow velocity maximum is partially controlled by the seasonally reversed Karimata throughflow, while the remainder primarily originated from the Mindanao–Sulawesi inflow rather than the Sibutu Strait throughflow. The Mindanao–Sulawesi inflow possesses a subsurface velocity core similar to that of the Makassar Strait, with a deep (shallow) maximum during El Niño (La Niña) years that plays a crucial role in determining the downstream Makassar throughflow profile in the interannual time scale. A sensitivity experiment by fixing Indian Ocean boundary condition shows that the impacts from the Indian Ocean might be significant only within the intraseasonal to seasonal time scales.
Imaging and Monitoring Temporal Changes of Shallow Seismic Velocities at the Garner Valley Near Anza, California, Following the M7.2 2010 El Mayor‐Cucapah Earthquake
Authors: Qin Lei , Ben‐Zion Yehuda , Bonilla Luis Fabian , Steidl Jamison H.
Published: December 2019

Seismograms from ~700 local earthquakes recorded at various depths (0, 6, 15, 22, 50, and 150 m) by sensors of the Garner Valley Downhole Array in Southern California are used to analyze the shallow velocity structure and temporal changes of seismic velocities after the 2010 M7.2 El Mayor‐Cucapah (EMC) earthquake. The direct P and S wave travel times between surface and borehole stations reveal very low shear wave velocities (178–259 m/s) and very high Vp/Vs ratios (6.2) in the top 22 m. Temporal changes of seismic velocities after the EMC earthquake are estimated using autocorrelations of data in moving time windows at two borehole stations (22 and 50 m) and seismic interferometry between multiple station pairs of the Garner Valley Downhole Array. The S wave velocity in the top 6 m drops abruptly by 14.3 ± 3.3%, during the passage of surface waves from the EMC event with a peak ground acceleration of 39 Gal, and recovers in ~236 s. The average velocity reductions decrease with depth and are 10.9 ± 3.1%, 8.5 ± 2.1%, 6.3 ± 2.1%, and 4.5 ± 2.0% in the top 15, 22, 50, and 150 m, respectively. Comparisons of seismic interferometry results between sensor pairs at 0–22 and 22–150 m indicate that statistically significant velocity changes are limited at the site to the top 22 m. Pore pressure data are in phase with the surface displacement and reach maxima when the highest velocity drop occurs, suggesting fluid effects contribute to the observed velocity reductions.
Shallow Megathrust Slip During Large Earthquakes That Have High P Coda Levels
Authors: Wu Zhenbo , Lay Thorne , Ye Lingling
Published: December 2019

Determining the up‐dip extent of slip during large megathrust earthquakes is important for understanding tsunami generation, potential for subsequent failure of the shallow megathrust, and plate contact depth‐varying frictional properties. Recent measurements of early Pcoda amplitudes relative to direct P signals for the period range 7 to 15 s find high Pcoda/P ratios for many events with finite‐fault rupture models that have slip extending to near deep trenches, resulting in enhanced pwP (water‐reverberation) generation. However, some events with high Pcoda/P measures have finite‐fault model solutions that vary in, or lack, shallow slip. We reexamine six large megathrust earthquakes with unexplained high Pcoda/P ratios (30 July 1995 Chile, MW 8.0; 17 November 2003 Aleutian, MW 7.7; 12 November 1996 Peru, MW 7.7; 7 October 2009 Vanuatu, MW 7.6; 5 May 2015 Papua New Guinea, MW 7.5; and 5 March 2002 Mindanao, MW 7.5), inverting for slip models with depth‐varying dip and varying bathymetry, adjusting kinematic parameters to better allow for the possibility of late shallow slip with associated strong pwP excitation. We confirm that modest patchy late shallow slip (~1 to 3 m) occurred near the trench for the 1995 and 2003 events, accounting for observed high Pcoda levels and minor tsunamis. The 2009 event appears to have minor shallow slip, whereas the 1996, 2002, and 2015 events do not; their coda amplitudes are likely enhanced by early aftershocks. Refined modeling of the later stages of large megathrust ruptures, guided by Pcoda levels, improves resolution of the up‐dip limit of co‐seismic slip.
Full noncontact laser ultrasound: first human data
Authors: Zhang Xiang , Fincke Jonathan R. , Wynn Charles M. , Johnson Matt R. , Haupt Robert W. , Anthony Brian W.
Published: December 2019

Full noncontact laser ultrasound (LUS) imaging has several distinct advantages over current medical ultrasound (US) technologies: elimination of the coupling mediums (gel/water), operator-independent image quality, improved repeatability, and volumetric imaging. Current light-based ultrasound utilizing tissue-penetrating photoacoustics (PA) generally uses traditional piezoelectric transducers in contact with the imaged tissue or carries an optical fiber detector close to the imaging site. Unlike PA, the LUS design presented here minimizes the optical penetration and specifically restricts optical-to-acoustic energy transduction at the tissue surface, maximizing the generated acoustic source amplitude. With an appropriate optical design and interferometry, any exposed tissue surfaces can become viable acoustic sources and detectors. LUS operates analogously to conventional ultrasound but uses light instead of piezoelectric elements. Here, we present full noncontact LUS results, imaging targets at ~5 cm depths and at a meter-scale standoff from the target surface. Experimental results demonstrating volumetric imaging and the first LUS images on humans are presented, all at eye- and skin-safe optical exposure levels. The progression of LUS imaging from tissue-mimicking phantoms, to excised animal tissue, to humans in vivo is shown, with validation from conventional ultrasound images. The LUS system design insights and results presented here inspire further LUS development and are a significant step toward the clinical implementation of LUS.
Type 1 IGF receptor associates with adverse outcome and cellular radioresistance in paediatric high-grade glioma
Authors: Simpson Aaron D. , Soo Ying Wei Jenetta , Rieunier Guillaume , Aleksic Tamara , Ansorge Olaf , Jones Chris , Macaulay Valentine M.
Published: December 2019

High-grade glioma (HGG) is highly resistant to therapy, prompting us to investigate the contribution of insulin-like growth factor receptor (IGF-1R), linked with radioresistance in other cancers. IGF-1R immunohistochemistry in 305 adult HGG (aHGG) and 103 paediatric/young adult HGG (pHGG) cases revealed significant association with adverse survival in pHGG, with median survival of 13.5 vs 29 months for pHGGs with moderate/strong vs negative/weak IGF-1R (p = 0.011). Secondly, we tested IGF-1R inhibitor BMS-754807 in HGG cells, finding minimal radiosensitisation of 2/3 aHGG cell lines (dose enhancement ratios DERs < 1.60 at 2–8 Gy), and greater radiosensitisation of 2/2 pHGG cell lines (DERs ≤ 4.16). BMS-754807 did not influence radiation-induced apoptosis but perturbed the DNA damage response with altered induction/resolution of γH2AX, 53BP1 and RAD51 foci. These data indicate that IGF-1R promotes radioresistance in pHGG, potentially contributing to the association of IGF-1R with adverse outcome and suggesting IGF-1R as a candidate treatment target in pHGG.
A model combining clinical and genomic factors to predict response to PD-1/PD-L1 blockade in advanced urothelial carcinoma
Authors: Nassar Amin H. , Mouw Kent W. , Jegede Opeyemi , Shinagare Atul B. , Kim Jaegil , Liu Chia-Jen , Pomerantz Mark , Harshman Lauren C. , Van Allen Eliezer M. , Wei Xiao X. , McGregor Bradley , Choudhury Atish D. , Preston Mark A. , Dong Fei , Signoretti Sabina , Lindeman Neal I. , Bellmunt Joaquim , Choueiri Toni K. , Sonpavde Guru , Kwiatkowski David J.
Published: December 2019

Background

In metastatic urothelial carcinoma (mUC), predictive biomarkers that correlate with response to immune checkpoint inhibitors (ICIs) are lacking. Here, we interrogated genomic and clinical features associated with response to ICIs in mUC.

Methods

Sixty two mUC patients treated with ICI who had targeted tumour sequencing were studied. We examined associations between candidate biomarkers and clinical benefit (CB, any objective reduction in tumour size) versus no clinical benefit (NCB, no change or objective increase in tumour size). Both univariable and multivariable analyses for associations were conducted. A comparator cohort of 39 mUC patients treated with taxanes was analysed by using the same methodology.

Results

Nine clinical and seven genomic factors correlated with clinical outcomes in univariable analysis in the ICI cohort. Among the 16 factors, neutrophil-to-lymphocyte ratio (NLR) ≥5 (OR = 0.12, 95% CI, 0.01–1.15), visceral metastasis (OR = 0.05, 95% CI, 0.01–0.43) and single-nucleotide variant (SNV) count < 10 (OR = 0.04, 95% CI, 0.006–0.27) were identified as independent predictors of NCB to ICI in multivariable analysis (c-statistic = 0.90). None of the 16 variables were associated with clinical benefit in the taxane cohort.

Conclusions

This three-factor model includes genomic (SNV count >9) and clinical (NLR <5, lack of visceral metastasis) variables predictive for benefit to ICI but not taxane therapy for mUC. External validation of these hypothesis-generating results is warranted to enable use in routine clinical care.
TAS-116 inhibits oncogenic KIT signalling on the Golgi in both imatinib-naïve and imatinib-resistant gastrointestinal stromal tumours
Authors: Saito Yurina , Takahashi Tsuyoshi , Obata Yuuki , Nishida Toshirou , Ohkubo Shuichi , Nakagawa Fumio , Serada Satoshi , Fujimoto Minoru , Ohkawara Tomoharu , Nishigaki Takahiko , Sugase Takahito , Koh Masahiro , Ishida Tomo , Tanaka Koji , Miyazaki Yasuhiro , Makino Tomoki , Kurokawa Yukinori , Nakajima Kiyokazu , Yamasaki Makoto , Hirota Seiichi , Naka Tetsuji , Mori Masaki , Doki Yuichiro
Published: December 2019

Background

Despite the effectiveness of imatinib mesylate (IM), most gastrointestinal stromal tumours (GISTs) develop IM resistance, mainly due to the additional kinase-domain mutations accompanied by concomitant reactivation of KIT tyrosine kinase. Heat-shock protein 90 (HSP90) is one of the chaperone molecules required for appropriate folding of proteins such as KIT.

Methods

We used a novel HSP90 inhibitor, TAS-116, which showed specific binding to HSP90α/β with low toxicity in animal models. The efficacy and mechanism of TAS-116 against IM-resistant GIST were evaluated by using IM-naïve and IM-resistant GIST cell lines. We also evaluated the effects of TAS-116 on the other HSP90 client protein, EGFR, by using lung cell lines.

Results

TAS-116 inhibited growth and induced apoptosis in both IM-naïve and IM-resistant GIST cell lines with KIT activation. We found KIT was activated mainly in intracellular compartments, such as trans-Golgi cisternae, and TAS-116 reduced autophosphorylated KIT in the Golgi apparatus. In IM-resistant GISTs in xenograft mouse models, TAS-116 caused tumour growth inhibition. We found that TAS-116 decreased phosphorylated EGFR levels and inhibited the growth of EGFR-mutated lung cancer cell lines.

Conclusion

TAS-116 may be a novel promising drug to overcome tyrosine kinase inhibitor-resistance in both GIST and EGFR-mutated lung cancer.
Higher cholesterol levels, not statin use, are associated with a lower risk of hepatocellular carcinoma
Authors: Yi Sang-Wook , Kim Se Hwa , Han Ki Jun , Yi Jee-Jeon , Ohrr Heechoul
Published: December 2019

We aimed to examine whether statin users have a lower risk of hepatocellular carcinoma (HCC) after careful consideration of prevalent statin use and cholesterol levels. During a mean prospective follow-up of 8.4 years in 400,318 Koreans, 1686 individuals were diagnosed with HCC. When prevalent users were included, HCC risk was reduced by >50% in statin users, regardless of adjustment for total cholesterol (TC). When prevalent users were excluded, new users who initiated statins within 6 months after baseline had a 40% lower risk of HCC (hazard ratio [HR] = 0.59) in a TC-unadjusted analysis. However, this relationship disappeared (HR = 1.16, 95% CI = 0.80–1.69) after adjusting for TC levels measured within 6 months before statin initiation. TC levels had strong inverse associations with HCC in each model. High cholesterol levels at statin initiation, not statin use, were associated with reduced risk of HCC. Our study suggests no protective effect of statins against HCC.
HnRNP F/H associate with hTERC and telomerase holoenzyme to modulate telomerase function and promote cell proliferation
Authors: Xu Chenzhong , Xie Nan , Su Yuanyuan , Sun Zhaomeng , Liang Yao , Zhang Na , Liu Doudou , Jia Shuqin , Xing Xiaofang , Han Limin , Li Guodong , Tong Tanjun , Chen Jun
Published: December 2019

Human telomerase RNA component hTERC comprises multiple motifs that contribute to hTERC biogenesis, holoenzyme activity, and enzyme recruitment to telomeres. hTERC contains several guanine tracts (G-tracts) at its 5′-end, but its associated proteins and potential roles in telomerase function are still poorly understood. The heterogeneous nuclear ribonucleoproteins F, H1, and H2 (hnRNP F/H) are splicing factors that preferentially bind to poly(G)-rich sequences RNA. Here, we demonstrate that hnRNP F/H associate with both hTERC and telomerase holoenzyme to regulate telomerase activity. We reveal hnRNP F/H bind to the 5′-end region of hTERC in vitro and in vivo, and identify the first three G-tracts of hTERC and qRRM1 domain of hnRNP F/H are required for their interaction. Furthermore, hnRNP F/H also directly interact with telomerase holoenzyme. Functionally, we show that hnRNP F/H plays important roles in modulating telomerase activity and telomere length. Moreover, hnRNP F/H deletion greatly impair cancer and stem cell proliferation, and induce stem cell senescence, while hnRNP F/H overexpression delay stem cell senescence. Collectively, our findings unveil a novel role of hnRNP F/H as the binding partners of hTERC and telomerase holoenzyme to regulate telomerase function.
The impact of oncogenic RAS on redox balance and implications for cancer development
Authors: Lim Jonathan K. M. , Leprivier Gabriel
Published: December 2019

The RAS family of proto-oncogenes comprises HRAS, KRAS, and NRAS, which are among the most mutated genes in human cancers. The RAS family genes encode small GTPases that coordinate key signaling pathways in response to growth factors. Mutations in RAS result in a constitutively active form of the protein that supports cellular transformation and tumorigenesis. The mechanisms of oncogenic RAS-mediated transformation encompass uncontrolled proliferation and inhibition of cell death through overactivation of the RAF-MEK-ERK and the PI3K-AKT pathways, respectively. In addition, the control of redox balance by RAS has also been proposed to play a role in its oncogenic properties. However, the exact role of redox balance in mediating mutant RAS transformation is still under debate. Here, we present, on one hand, the involvement of pro-oxidant components in oncogenic RAS transformation, such as NADPH oxidases and mitochondrial reactive oxygen species, and how these promote transformation. On the other hand, we describe the contribution of antioxidant components to mutant RAS transformation, including Nrf2, glutathione biosynthesis and xCT, as well as the mechanisms by which antioxidant programs drive transformation. Finally, we aim to reconcile the seemingly opposite effects of oncogenic RAS on redox balance and discuss a model for the complementary role of both pro-oxidant and antioxidant pathways in mutant RAS-driven tumor progression.
Breathing chromium spinels: a showcase for a variety of pyrochlore Heisenberg Hamiltonians
Authors: Ghosh Pratyay , Iqbal Yasir , Müller Tobias , Ponnaganti Ravi T. , Thomale Ronny , Narayanan Rajesh , Reuther Johannes , Gingras Michel J. P. , Jeschke Harald O.
Published: December 2019

We address the long-standing problem of the microscopic origin of the richly diverse phenomena in the chromium breathing pyrochlore material family. Combining electronic structure and renormalization group techniques we resolve the magnetic interactions and analyze their reciprocal-space susceptibility. We show that the physics of these materials is principally governed by long-range Heisenberg Hamiltonian interactions, a hitherto unappreciated fact. Our calculations uncover that in these isostructural compounds, the choice of chalcogen triggers a proximity of the materials to classical spin liquids featuring degenerate manifolds of wave-vectors of different dimensions: A Coulomb phase with three-dimensional degeneracy for LiInCr4O8 and LiGaCr4O8, a spiral spin liquid with two-dimensional degeneracy for CuInCr4Se8 and one-dimensional line degeneracies characteristic of the face-centered cubic antiferromagnet for LiInCr4S8, LiGaCr4S8, and CuInCr4S8. The surprisingly complex array of prototypical pyrochlore behaviors we discovered in chromium spinels may inspire studies of transition paths between different semi-classical spin liquids by doping or pressure.
Shift rotation, circadian misalignment and excessive body weight influence psychomotor performance: a prospective and observational study under real life conditions
Authors: Rosa Dayane Eusenia , Marot Luisa Pereira , de Mello Marco Túlio , Narciso Fernanda Veruska , Gonçalves Bruno da Silva Brandão , Marqueze Elaine Cristina , Crispim Cibele Aparecida
Published: December 2019

We aimed to evaluate the influence of shift work rotation, circadian misalignment and being overweight/obese on psychomotor performance throughout a complete shift rotation schedule. The study was conducted with 30 males working rotating shifts from a mining company under real life conditions. Individuals were evaluated over seven days in a shift schedule carried out as follow: two shifts in the morning (D1 and D2), two shifts in the afternoon (D3 and D4), 24 hour free day (D5) and two shifts at night (D6 and D7). Work performance was evaluated by psychomotor vigilance task tests (PVT), and actigraphy was used to characterise the rest-activity rhythm based on intradaily variability (IV) and interdaily stability (IS) of nonparametric functions. We found a significant effect of the shift, body mass index (BMI), IS and IV on lapses in attention. More lapses occurred on D7 than D1, D2, D3 and D4 of the schedule shift. The obese group presented a higher number of lapses in attention than eutrophic. The interaction between day and IS showed that less synchronised individuals presented a higher number of lapses in attention on D7 than D1 and, for the interaction between day and IV, more fragmented individuals presented a higher number of lapses in attention on D7 than D6. We conclude that higher BMI, lower synchronisation and higher fragmentation of the rest-activity pattern influenced lapses in attention throughout the shift rotation.
Mesenchymal Stromal Cells Induce Podocyte Protection in the Puromycin Injury Model
Authors: Ornellas Felipe Mateus , Ramalho Rodrigo J. , Fanelli Camilla , Garnica Margoth Ramos , Malheiros Denise M. A. C. , Martini Sabrina Vargas , Morales Marcelo Marcos , Noronha Irene L.
Published: December 2019

Podocytes are specialized cells with a limited capacity for cell division that do not regenerate in response to injury and loss. Insults that compromise the integrity of podocytes promote proteinuria and progressive renal disease. The aim of this study was to evaluate the potential renoprotective and regenerative effects of mesenchymal stromal cells (mSC) in a severe form of the podocyte injury model induced by intraperitoneal administration of puromycin, aggravated by unilateral nephrectomy. Bone derived mSC were isolated and characterized according to flow cytometry analyses and to their capacity to differentiate into mesenchymal lineages. Wistar rats were divided into three groups: Control, PAN, and PAN+ mSC, consisting of PAN rats treated with 2 × 105 mSC. PAN rats developed heavy proteinuria, hypertension, glomerulosclerosis and significant effacement of the foot process. After 60 days, PAN rats treated with mSC presented a significant amelioration of all these abnormalities. In addition, mSC treatment recovered WT1 expression, improved nephrin, podocin, synaptopodin, podocalyxin, and VEGF expression, and downregulated proinflammatory Th1 cytokines in the kidney with a shift towards regulatory Th2 cytokines. In conclusion, mSC administration induced protection of podocytes in this experimental PAN model, providing new perspectives for the treatment of renal diseases associated with podocyte damage.
Exploring genetic architecture of grain yield and quality traits in a 16-way indica by japonica rice MAGIC global population
Authors: Zaw Hein , Raghavan Chitra , Pocsedio Arnel , Swamy B. P. Mallikarjuna , Jubay Mona Liza , Singh Rakesh Kumar , Bonifacio Justine , Mauleon Ramil , Hernandez Jose E. , Mendioro Merlyn S. , Gregorio Glenn B. , Leung Hei
Published: December 2019

Identification of Quantitative Trait Loci (QTL) has been a challenge for complex traits due to the use of populations with narrow genetic base. Most of QTL mapping studies were carried out from crosses made within the subspecies, either indica × indica or japonica × japonica. In this study we report advantages of using Multi-parent Advanced Generation Inter-Crosses global population, derived from a combination of eight indica and eight japonica elite parents, in QTL discovery for yield and grain quality traits. Genome-wide association study and interval mapping identified 38 and 34 QTLs whereas Bayesian networking detected 60 QTLs with 22 marker-marker associations, 32 trait-trait associations and 65 marker-trait associations. Notably, nine known QTLs/genes qPH1/OsGA20ox2, qDF3/OsMADS50, PL, QDg1, qGW-5b, grb7-2, qGL3/GS3, Amy6/Wx gene and OsNAS3 were consistently identified by all approaches for nine traits whereas qDF3/OsMADS50 was co-located for both yield and days-to-flowering traits on chromosome 3. Moreover, we identified a number of candidate QTLs in either one or two analyses but further validations will be needed. The results indicate that this new population has enabled identifications of significant QTLs and interactions for 16 traits through multiple approaches. Pyramided recombinant inbred lines provide a valuable source for integration into future breeding programs.
Ultrastructural modeling of small angle scattering from photosynthetic membranes
Authors: Jakubauskas Dainius , Kowalewska Łucja , Sokolova Anna V. , Garvey Christopher J. , Mortensen Kell , Jensen Poul Erik , Kirkensgaard Jacob J. K.
Published: December 2019

The last decade has seen a range of studies using non-invasive neutron and X-ray techniques to probe the ultrastructure of a variety of photosynthetic membrane systems. A common denominator in this work is the lack of an explicitly formulated underlying structural model, ultimately leading to ambiguity in the data interpretation. Here we formulate and implement a full mathematical model of the scattering from a stacked double bilayer membrane system taking instrumental resolution and polydispersity into account. We validate our model by direct simulation of scattering patterns from 3D structural models. Most importantly, we demonstrate that the full scattering curves from three structurally typical cyanobacterial thylakoid membrane systems measured in vivo can all be described within this framework. The model provides realistic estimates of key structural parameters in the thylakoid membrane, in particular the overall stacking distance and how this is divided between membranes, lumen and cytoplasmic liquid. Finally, from fitted scattering length densities it becomes clear that the protein content in the inner lumen has to be lower than in the outer cytoplasmic liquid and we extract the first quantitative measure of the luminal protein content in a living cyanobacteria.
Computational discovery of hidden breaks in 28S ribosomal RNAs across eukaryotes and consequences for RNA Integrity Numbers
Authors: Natsidis Paschalis , Schiffer Philipp H. , Salvador-Martínez Irepan , Telford Maximilian J.
Published: December 2019

In some eukaryotes, a ‘hidden break’ has been described in which the 28S ribosomal RNA molecule is cleaved into two subparts. The break is common in protostome animals (arthropods, molluscs, annelids etc.), but a break has also been reported in some vertebrates and non-metazoan eukaryotes. We present a new computational approach to determine the presence of the hidden break in 28S rRNAs using mapping of RNA-Seq data. We find a homologous break is present across protostomes although it has been lost in a small number of taxa. We show that rare breaks in vertebrate 28S rRNAs are not homologous to the protostome break. A break is found in just 4 out of 331 species of non-animal eukaryotes studied and, in three of these, the break is located in the same position as the protostome break suggesting a striking instance of convergent evolution. RNA Integrity Numbers (RIN) rely on intact 28S rRNA and will be consistently underestimated in the great majority of animal species with a break.
Tailings microbial community profile and prediction of its functionality in basins of tungsten mine
Authors: Chung Ana Paula , Coimbra Carina , Farias Pedro , Francisco Romeu , Branco Rita , Simão Francisco V. , Gomes Elsa , Pereira Alcides , Vila Maria C. , Fiúza António , Mortensen Martin S. , Sørensen Søren J. , Morais Paula V.
Published: December 2019

In a circular economy concept, where more than 300 million tons of mining and quarrying wastes are produced annually, those are valuable resources, supplying metals that are extracted today by other processes, if innovative methods and processes for efficient extraction of these elements are applied. This work aims to assess microbiological and chemical spatial distribution within two tailing basins from a tungsten mine, using a MiSeq approach targeting the 16S rRNA gene, to relate microbial composition and function with chemical variability, thus, providing information to enhance the efficiency of the exploitation of these secondary sources. The tailings sediments core microbiome comprised members of family Anaerolineacea and genera Acinetobacter, Bacillus, Cellulomonas, Pseudomonas, Streptococcus and Rothia, despite marked differences in tailings physicochemical properties. The higher contents of Al and K shaped the community of Basin 1, while As-S-Fe contents were correlated with the microbiome composition of Basin 2. The predicted metabolic functions of the microbiome were rich in genes related to metabolism pathways and environmental information processing pathways. An in-depth understanding of the tailings microbiome and its metabolic capabilities can provide a direction for the management of tailings disposal sites and maximize their potential as secondary resources.
Locking Two Rigid-body Bundles in an Outward-Facing Conformation: The Ion-coupling Mechanism in a LeuT-fold Transporter
Authors: Li Jing , Zhao Zhiyu , Tajkhorshid Emad
Published: December 2019

Secondary active transporters use electrochemical gradient of ions to fuel the “uphill” translocation of the substrate following the alternating-access model. The coupling of ions to conformational dynamics of the protein remains one of the least characterized aspects of the transporter function. We employ extended molecular dynamics (MD) simulations to examine the Na+-binding effects on the structure and dynamics of a LeuT-fold, Na+-coupled secondary transporter (Mhp1) in its major conformational states, i.e., the outward-facing (OF) and inward-facing (IF) states, as well as on the OF ↔ IF state transition. Microsecond-long, unbiased MD simulations illustrate that Na+stabilizes an OF conformation favorable for substrate association, by binding to a highly conserved site at the interface between the two helical bundles and restraining their relative position and motion. Furthermore, a special-protocol biased simulation for state transition suggests that Na+binding hinders the OF ↔ IF transition. These synergistic Na+-binding effects allosterically couple the ion and substrate binding sites and modify the kinetics of state transition, collectively increasing the lifetime of an OF conformation with high substrate affinity, thereby facilitating substrate recruitment from a low-concentration environment. Based on the similarity between our findings for Mhp1 and experimental reports on LeuT, we propose that this model may represent a general Na+-coupling mechanism among LeuT-fold transporters.