bluuebunny/crossref_metadata_2025_split huggingface dataset:
Die Bedeutung der organischen Synthese bei der Entstehung und Entwicklung von Antikörper‐Wirkstoff‐Konjugaten als gezielte Krebstherapien
Authors: Nicolaou K. C. , Rigol Stephan 
Published: April 2019

AbstractMit einigen Antikörper‐Wirkstoff‐Konjugaten (ADCs), die für den klinischen Einsatz als zielgerichtete Krebstherapien zugelassenen sind, und zahlreichen Kandidaten in klinischen Studien, entwickelt sich das Gebiet der ADCs zu einem hochaktuellen biomedizinischen Forschungsfeld, insbesondere im Bereich der Krebsbehandlung. Chemiker, Biologen und Mediziner kombinieren ihre Expertisen, um Design, Synthese, Wirksamkeit und Präzision zu verbessern, während sie danach streben, dieses Grundprinzip der personalisierten und zielgerichteten Medizin voranzutreiben, um Krebspatienten effektiver zu behandeln und ihren Anwendungsbereich auf andere Indikationen auszudehnen. So wie Alexander Flemings Penicillin und die unzähligen anderen bioaktiven Naturstoffe, die auf dessen Entdeckung und seinen Erfolg in der Klinik folgten, nach dem Zweiten Weltkrieg eine Revolution in der Medizin auslösten, so haben Calicheamicin γ1I und andere hochwirksame, natürlich vorkommende Antitumorverbindungen ebenso eine zentrale Rolle gespielt, wenn es darum geht, die Einführung dieses neuen Konzepts der medizinischen Intervention “biologisch‐niedermolekularer Hybride” zu ermöglichen. Heute gibt es vier klinisch zugelassene Medikamente des ADC‐Konzepts: Mylotarg, Adcetris, Kadcyla und Besponsa, von denen das erst‐ sowie das letztgenannte den gleichen von Calicheamicin γ1I abgeleiteten Wirkstoff tragen. Dieser Aufsatz deckt onkologische Anwendungen ab und konzentriert sich nach einer kurzen Geschichte der Entstehung des Bereichs der ADCs, welcher vor mehr als einem Jahrhundert durch Paul Ehrlichs Konzept der Zauberkugel begründet wurde, in erster Linie auf die Aspekte der chemischen Synthese des multidisziplinären Forschungsunternehmens der ADCs.
Transition‐Metal‐Free Deconstructive Lactamization of Piperidines
Authors: Romero‐Ibañez Julio , Cruz‐Gregorio Silvano , Sandoval‐Lira Jacinto , Hernández‐Pérez Julio M. , Quintero Leticia , Sartillo‐Piscil Fernando 
Published: April 2019

AbstractOne of the major challenges in organic synthesis is the activation or deconstructive functionalization of unreactive C(sp3)–C(sp3) bonds, which requires using transition or precious metal catalysts. We present here an alternative: the deconstructive lactamization of piperidines without using transition metal catalysts. To this end, we use 3‐alkoxyamino‐2‐piperidones, which were prepared from piperidines through a dual C(sp3)–H oxidation, as transitory intermediates. Experimental and theoretical studies confirm that this unprecedented lactamization occurs in a tandem manner involving an oxidative deamination of 3‐alkoxyamino‐2‐piperidones to 3‐keto‐2‐piperidones, followed by a regioselective Baeyer–Villiger oxidation to give N‐carboxyanhydride intermediates, which finally undergo a spontaneous and concerted decarboxylative intramolecular translactamization.
Investigation of the molecular reactivity of bioactive oxiranylmethyloxy anthraquinones
Authors: Ribaudo Giovanni , Ongaro Alberto , Zorzan Maira , Pezzani Raffaele , Redaelli Marco , Zagotto Giuseppe , Memo Maurizio , Gianoncelli Alessandra 
Published: April 2019

AbstractThe design of a multitarget and multifunctional small molecule containing two functional groups reacting through different mechanisms represents an attractive goal for the medicinal chemist. The preparation of two bifunctional oxiranylmethyloxy anthraquinones, previously investigated as anticancer agents, is described here. These compounds combine a planar, DNA‐intercalating and pro‐oxidant anthraquinone scaffold and the alkylating epoxide functions which can covalently react with the nucleic acid. Their multilevel molecular reactivity was studied through a combination of analytical techniques: The DNA‐binding properties were investigated using a mass spectrometry‐based binding assay and by nuclear magnetic resonance, highlighting the formation of a covalent adduct with a nucleobase. Moreover, the contribution of the pro‐oxidant redox cycling was evaluated.
Bau einer Bahnbrücke aus bewehrtem UHFB
Authors: Brühwiler Eugen , Friedl Herbert , Rupp Christoph , Escher Hanspeter 
Published: April 2019

AbstractAm 11. November 2017 wurde die weltweit erste Bahnbrücke aus bewehrtem UHFB auf einer Hauptlinie in Betrieb genommen. Das Bauvorhaben der Schweizerischen Bundesbahnen (SBB) wurde im Rahmen des Ersatzneubaus einer doppelspurigen Bahnbrücke kurzer Spannweite bei Sempach im Kanton Luzern, Schweiz, realisiert. UHFB ist ein neuartiger faserverstärkter, zementgebundener Verbundbaustoff, der durch seine hohe Festigkeit und Dichtigkeit ideale Voraussetzungen für den Einsatz bei Infrastrukturbauwerken mit sich bringt. Neben geringeren Lebenszykluskosten können durch eine modulare Bauweise mit hohem Vorfabrikationsgrad kürzere Bauzeiten realisiert werden, womit geringere Betriebseinschränkungen verursacht werden. An der UHFB‐Brückenplatte einer Spannweite von 6,0 m wurde ein Monitoringsystem installiert, um das Tragverhalten bei Zugüberfahrten zu erfassen. Erste Ergebnisse der Messungen bestätigen die erwarteten Werte, die deutlich unter den berechneten Kenngrößen liegen. Dieser Aufsatz beschreibt den Entwurf, die Bemessung, die Ausführung und das Monitoring dieser neuartigen Brückenkonstruktion.
RNA Dynamics by NMR Spectroscopy
Authors: Marušič Maja , Schlagnitweit Judith , Petzold Katja 
Published: April 2019

AbstractAn ever‐increasing number of functional RNAs require a mechanistic understanding. RNA function relies on changes in its structure, so‐called dynamics. To reveal dynamic processes and higher energy structures, new NMR methods have been developed to elucidate these dynamics in RNA with atomic resolution. In this Review, we provide an introduction to dynamics novices and an overview of methods that access most dynamic timescales, from picoseconds to hours. Examples are provided as well as insight into theory, data acquisition and analysis for these different methods. Using this broad spectrum of methodology, unprecedented detail and invisible structures have been obtained and are reviewed here. RNA, though often more complicated and therefore neglected, also provides a great system to study structural changes, as these RNA structural changes are more easily defined—Lego like—than in proteins, hence the numerous revelations of RNA excited states.
Probing the Substrate Promiscuity of Isopentenyl Phosphate Kinase as a Platform for Hemiterpene Analogue Production
Authors: Lund Sean , Courtney Taylor , Williams Gavin J. 
Published: April 2019

AbstractIsoprenoids are a large class of natural products with wide‐ranging applications. Synthetic biology approaches to the manufacture of isoprenoids and their new‐to‐nature derivatives are limited due to the provision in nature of just two hemiterpene building blocks for isoprenoid biosynthesis. To address this limitation, artificial chemo‐enzymatic pathways such as the alcohol‐dependent hemiterpene (ADH) pathway serve to leverage consecutive kinases to convert exogenous alcohols into pyrophosphates that could be coupled to downstream isoprenoid biosynthesis. To be successful, each kinase in this pathway should be permissive of a broad range of substrates. For the first time, we have probed the promiscuity of the second enzyme in the ADH pathway—isopentenyl phosphate kinase from Thermoplasma acidophilum—towards a broad range of acceptor monophosphates. Subsequently, we evaluate the suitability of this enzyme to provide unnatural pyrophosphates and provide a critical first step in characterizing the rate‐limiting steps in the artificial ADH pathway.
Advanced Electro‐Oxidation with Boron‐Doped Diamond for Acetaminophen Removal from Real Wastewater in a Microfluidic Reactor: Kinetics and Mass‐Transfer Studies
Authors: Mousset Emmanuel , Puce Marta , Pons Marie‐Noëlle 
Published: April 2019

AbstractThe removal of hazardous organic micropollutants in municipal wastewater treatment plants (WWTP) has become a common concern for public decision‐makers and stakeholders. An advanced electro‐oxidation with boron‐doped diamond (BDD) anode material is proposed to remove acetaminophen as a representative micropollutant in synthetic solution. A customized microfluidic reactor was run in batch mode, and the main operating parameters (i. e. current density, interelectrode distance and solution conductivity) were optimized by minimizing the energy requirement. An optimal current density of 4 mA cm−2 and an optimal interelectrode distance of 500 μm were newly obtained and explained. Mass transport limitation was observed at lower gaps, with a 3.4‐fold decrease in the mass transfer coefficient from 500 μm to 50 μm intervals. In addition, the kinetics of degradation decreased dramatically after a certain electrolysis time. This was attributed to the increase in gas bubble production with treatment time. An increase in the solution conductivity from 0.23 to 2.0 mS cm−1 increased the degradation rate efficiency twofold and decreased the specific energy from 0.88 to 0.17 kWh g−1 at 85 % acetaminophen decay yield. The influence of a real matrix from low‐conductivity reclaimed WWTP (0.86 mS cm−1) highlighted slightly lower kinetics of degradation, but similar energy efficiency until 60 % of pollutant degradation and higher energy efficiency than in conventional macro‐reactors.
SGLT2 inhibition to address the unmet needs in diabetic nephropathy
Authors: Barutta Federica , Bernardi Sara , Gargiulo Giuseppe , Durazzo Marilena , Gruden Gabriella 
Published: April 2019

SummaryCurrent treatment of diabetic nephropathy is effective; however, substantial gaps in care still remain and new therapies are urgently needed to reduce the global burden of the complication. Desirable properties of an “ideal” new drug should include primary prevention of microalbuminuria, additive/synergistic anti‐proteinuric effect in combination therapy with renin angiotensin system blockers, reduction of chronic kidney disease progression to lower the risk of end‐stage renal disease, and cardiovascular protection. Growing evidence suggests that sodium‐glucose cotransporter 2 inhibitors (SGLT2i) may fulfil many of these criteria and represent novel tools to cover the unmet needs in diabetic nephropathy care. However, the underlying mechanisms of SGLT2i renal benefits are still poorly understood and promising results from cardiovascular outcome trials with SGLT2i need confirmation in dedicated renal outcome trials.
A four‐component classification of uncertainties in biological invasions: implications for management
Authors: Latombe G. , Canavan S. , Hirsch H. , Hui C. , Kumschick S. , Nsikani M. M. , Potgieter L. J. , Robinson T. B. , Saul W.‐C. , Turner S. C. , Wilson J. R. U. , Yannelli F. A. , Richardson D. M. 
Published: April 2019

AbstractAlthough uncertainty is an integral part of any science, it raises doubts in public perception about scientific evidence, is exploited by denialists, and therefore potentially hinders the implementation of management actions. As a relatively young field of study, invasion science contains many uncertainties. This may explain why, despite international policies aimed at mitigating biological invasions, the implementation of national‐ and regional‐scale measures to prevent or control alien species has done little to slow the increase in extent of invasions and the magnitude of impacts. Uncertainty is therefore a critical aspect of invasion science that should be addressed to enable the field to progress further. To improve how uncertainties in invasion science are captured and characterized, we propose a framework, which is also applicable to other applied research fields such as climate and conservation science, divided into four components: the need (1) to clearlycircumscribethe phenomenon, (2) to measure and provide evidence for the phenomenon (i.e.,confirmation), (3) to understand the mechanisms thatcausethe phenomenon, and (4) to understand the mechanisms through which the phenomenon results inconsequences. We link these issues to three major types of uncertainty: linguistic, psychological, and epistemic. The application of this framework shows that the four components tend to be characterized by different types of uncertainty in invasion science. We explain how these uncertainties can be detrimental to the implementation of management measures and propose ways to reduce them. Since biological invasions are increasingly tightly embedded in complex socio‐ecological systems, many problems associated with these uncertainties have convoluted solutions. They demand the consensus of many stakeholders to define and frame the dimensions of the phenomenon, and to decide on appropriate actions. While many of the uncertainties cannot be eliminated completely, we believe that using this framework to explicitly identify and communicate them will help to improve collaboration between researchers and managers, increase scientific, political, and public support for invasion research, and provide a stronger foundation for sustainable management strategies.
Migration triggers in a large herbivore: Galápagos giant tortoises navigating resource gradients on volcanoes
Authors: Bastille‐Rousseau Guillaume , Yackulic Charles B. , Gibbs James P. , Frair Jacqueline L. , Cabrera Freddy , Blake Stephen 
Published: April 2019

AbstractTo understand how migratory behavior evolved and to predict how migratory species will respond to global environmental change it is important to quantify the fitness consequences of intra‐ and inter‐individual variation in migratory behavior. Intra‐individual variation includes behavioral responses to changing environmental conditions and hence behavioral plasticity in the context of novel or variable conditions. Inter‐individual variation determines the degree of variation on which selection can act and the rate of evolutionary responses to changes in average and extreme environmental conditions. Here we focus on variation in the partial migratory behavior of giant Galápagos tortoises (Chelonoidis spp.) and its energetic consequences. We evaluate the extent and mechanisms by which tortoises adjust migration timing in response to varying annual environmental conditions, and integrate movement data within a bioenergetic model of tortoise migration to quantify the fitness consequences of migration timing. We find strong inter‐individual variation in the timing of migration, which was not affected by environmental conditions prevailing at the time of migration but rather by average expectations estimated from multi‐annual averaged conditions. This variation is associated with an average annual loss in efficiency of ~15% relative to optimal timing based on year‐specific conditions. These results point towards a limited ability of tortoises to adjust the timing of their migrations based on prevailing (and, by extension, future) conditions, suggesting that the adaptability of tortoise migratory behavior to changing conditions is predicated more by past “normal” conditions than responses to prevailing, changing conditions. Our work offers insights into the level of environmental‐tuning in migratory behavior and a general framework for future research across taxa.
Federal Right to Try: Where Is It Going?
Authors: Folkers Kelly , Chapman Carolyn , Redman Barbara 
Published: April 2019

AbstractPolicy‐makers, bioethicists, and patient advocates have been engaged in a fierce battle about the merits and potential harms of a federal right‐to‐try law. This debate about access to investigational medical products has raised profound questions about the limits of patient autonomy, appropriate government regulation, medical paternalism, and political rhetoric. For example, do patients have a right to access investigational therapies, as the right‐to‐try movement asserts? What is government’s proper role in regulating and facilitating access to drugs that are still in development? In this review, we analyze the history of the right‐to‐try movement, review the arguments put forth by supporters and opponents of the legislation, and consider the movement’s consequences. Two possible scenarios may emerge. One is that the right‐to‐try pathway may fail to meaningfully increase patient access to investigational products. Alternatively, certain companies may attempt to rely on the federal right‐to‐try legislation to sell investigational products, taking advantage of the provision that allows for direct costs, as there is currently no clear mechanism for enforcement or monitoring of cost calculations.
Activated cytotoxic T cells within zoonotic cutaneous leishmaniasis lesions
Authors: Boussoffara Thouraya , Boubaker Mohamed Samir , Ben Ahmed Melika , Mokni Mourad , Feriani Salma , Ben Salah Afif , Louzir Hechmi 
Published: April 2019

AbstractIntroductionZoonotic cutaneous leishmaniasis (ZCL), due to infection by Leishmania (L). major, is characterized by polymorphic clinical manifestations which could be attributed to the host's immune response. In this study we investigated the involvement of cytotoxic cells on the outcome of the disease.MethodsExpression of granzyme B (GrB), granulysine (Grly), and interferon (IFN)‐γ was evaluated within ZCL lesion specimens using the technique of real‐time quantitative polymerase chain reaction (RT‐qPCR). Immunohistochemical staining was performed using anti‐CD3, CD4, CD8, CD56, GrB, and IFN‐γ antibodies to identify the phenotype of GrB and IFN‐γ‐producing cells.ResultsGrB and Grly mRNA was detected within 75% and 80% of ZCL lesions, respectively. Statistical analysis demonstrated a significant correlation between levels of GrB and Grly. Interestingly, expression of these molecules correlates negatively with the lesion's age. The highest levels were measured in early lesions (E‐ZCL) (lesion age ≤1 month) comparing to late lesions (L‐ZCL) (lesion age >1 month). Otherwise, IFN‐γ mRNA was detected only within 56% and a positive correlation was found between levels of this cytokine and those of GrB. Immunohistochemical analysis showed that GrB is produced essentially by CD8+T cells whereas IFN‐γ is produced by both CD4+ and CD8+T cells.ConclusionTogether our results demonstrate the presence of cytotoxic cells producing GrB and Grly within leishmaniasis cutaneous lesions.
Resilience in the midst of chaos: Socioecological model applied to women with depressive symptoms and socioeconomic disadvantage
Authors: Poleshuck Ellen , Perez‐Diaz Wanda , Wittink Marsha , ReQua Michelle , Harrington Amy , Katz Jennifer , Juskiewicz Iwona , Stone Jennifer Thompson , Bell Elaine , Cerulli Catherine 
Published: April 2019

AbstractSocioeconomic disadvantage is extremely common among women with depressive symptoms presenting for women's health care. While social stressors related to socioeconomic disadvantage can contribute to depression, health care tends to focus on patients’ symptoms in isolation of context. Health care providers may be more effective by addressing issues related to socioeconomic disadvantage. It is imperative to identify common challenges related to socioeconomic disadvantage, as well as sources of resilience. In this qualitative study, we interviewed 20 women's health patients experiencing depressive symptoms and socioeconomic disadvantage about their views of their mental health, the impact of social stressors, and their resources and skills. A Consensual Qualitative Research approach was used to identify domains consisting of challenges and resiliencies. We applied the socioecological model when coding the data and identified cross‐cutting themes of chaos and distress, as well as resilience. These findings suggest the importance of incorporating context in the health care of women with depression and socioeconomic disadvantage.
The role of academic mentors for Latino/a adolescents exposed to community violence
Authors: Fike Kayla J. , Ceballo Rosario , Kennedy Traci M. 
Published: April 2019

AbstractAimsWe examined the protective role of academic mentors for Latino/a youth exposed to community violence. We tested whether the mentor facilitation of positive growth and mentor school involvement moderated the relations between exposure to violence and Latino/a youth's educational values, school effort, and academic efficacy.MethodsWe used hierarchical linear regressions to examine these relations among 210 Latino/a high school students.ResultsWitnessing violence and personal victimization was negatively related to all three educational outcomes. Mentor school involvement was positively related to all three educational outcomes, whereas mentor facilitation of growth was positively related to educational values only. A significant interaction between witnessing violence and mentor school involvement indicated that the negative relation between witnessing violence and educational values weakened at high levels of mentor school involvement.ConclusionWe discuss the benefits of academic mentoring and exploring effective mentoring characteristics with Latino/a youth exposed to violence.
Prognostic utility and clinical significance of lysyl oxidase‐like 2 protein expression in digestive system cancers
Authors: Zhang Yi , Liu Wanwei , Xu Jiwei 
Published: April 2019

AbstractLysyl oxidase‐like 2 (LOXL2) participates in the occurrence and development of digestive system cancers (DSCs). The aim of this study was to determine whether LOXL2 protein could serve as a prognostic biomarker in patients with DSCs. Relevant studies published before October 1, 2018 were identified from a comprehensive literature review in PubMed, Web of Science, and Embase. This meta‐analysis was conducted via STATA/SE 14.1 software. Finally, a total of 12 publications and 6 different kinds of DSCs were identified. Meta‐analysis indicated that increased expression of LOXL2 protein was significantly correlated with reduced overall survival (hazard ratios [HR]: 1.52; 95% confidence interval [CI]: 1.32–1.72) and worse progression‐free survival/disease‐free survival (HR: 2.15; 95% CI: 1.48–2.83) in cases with DSCs. In addition, clinicopathological parameters, including tumor invasion, lymph node metastasis, distant metastasis, and clinical stage were significantly related to LOXL2 protein expression in DSCs. High LOXL2 protein expression is significantly associated with worse clinical outcomes in DSCs and its expression level may represent a candidate prognostic biomarker in these cancers.
A novel microRNA signature predicts vascular invasion in hepatocellular carcinoma
Authors: Han Bing , Zheng Yujia , Wang Le , Wang Haixu , Du Jiaxin , Ye Fanglei , Sun Tongwen , Zhang Lianfeng 
Published: April 2019

AbstractVascular invasion (VI) in hepatocellular carcinoma (HCC) is an important clinical parameter to predict survival. In this study, we collected microRNA (miRNA) expression data from HCC patients using The Cancer Genome Atlas database and identified a novel miRNA signature associated with VI. First, we categorized HCC patients into groups with or without VI (VI+ and VI−). We identified three miRNAs (miRNA‐210, miRNA‐10b, and miRNA‐9‐1) that were associated with VI according to a Kaplan–Meier analysis. This three‐miRNA signature exhibited good predictive ability for VI in patients with HCC according to a receiver operating characteristic curve analysis at 1, 3, and 5 years. Patients with HCC with a high risk score exhibited a trend toward worse outcomes as determined by multivariable Cox regression and stratified analyses. This three‐miRNA signature provides an accurate prediction of VI and can be used as an independent prognostic indicator for predicting VI in HCC patients.