bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pan‐cancer population pharmacokinetics and exposure‐safety and ‐efficacy analyses of atezolizumab in patients with high tumor mutational burden
Authors: Shemesh Colby S. , Chan Phyllis , Legrand Fatema A. , Shames David S. , Das Thakur Meghna , Shi Jane , Bailey Lorna , Vadhavkar Shweta , He Xian , Zhang Wei , Bruno René 
Published: November 2020

AbstractWe retrospectively investigated the pharmacokinetics and exposure‐efficacy/safety relationships of single‐agent atezolizumab based on tissue tumor mutational burden (tTMB) status (high vs low [≥16 vs <16 mutations/megabase]) in a pan‐tumor population from seven clinical trials. Data sources included the OAK, POPLAR, BIRCH, FIR, IMvigor210, IMvigor211, and PCD4989g studies; 986 of 2894 treated patients (34%) had TMB data. Exposure metrics were obtained using a prior two‐compartment intravenous‐infusion population‐pharmacokinetics model, merged with prognostic, biomarker, efficacy, and safety variables. Baseline demographic/clinical characteristics and prognostic factors were well balanced between patients with high (n = 175) and low (n = 811) tTMB. Exposure was similar in the high‐ and low‐tTMB subgroups, with no difference seen in the evaluable vs total treated populations. The objective response rate (ORR) was 29.7% vs 13.4%, complete response rate was 6.9% vs 3.2%, and median duration of response (95% CI) was 29.0 (18.6‐NE) months vs 15.9 (12.5‐20.5) months for patients with high‐tTMB vs low‐tTMB tumors, respectively. A flat exposure‐efficacy relationship was seen for ORR in patients with high‐tTMB based on the cycle 1 minimum atezolizumab concentration and area under the serum concentration time curve (AUC). A nonsignificant exposure‐safety profile was seen for grade 3/4 adverse events and adverse events of special interest based on the AUC of atezolizumab in the high‐tTMB population. tTMB is an additional predictive biological factor affecting response to atezolizumab, and quantitative investigations of atezolizumab exposure and relationships of exposure with safety and efficacy support the use of a 1200‐mg, every 3‐week regimen in a tumor‐agnostic high‐tTMB population.
Next waves in veridical network embedding*
Authors: Ward Owen G. , Huang Zhen , Davison Andrew , Zheng Tian 
Published: November 2020

AbstractEmbedding nodes of a large network into a metric (e.g., Euclidean) space has become an area of active research in statistical machine learning, which has found applications in natural and social sciences. Generally, a representation of a network object is learned in a Euclidean geometry and is then used for subsequent tasks regarding the nodes and/or edges of the network, such as community detection, node classification and link prediction. Network embedding algorithms have been proposed in multiple disciplines, often with domain‐specific notations and details. In addition, different measures and tools have been adopted to evaluate and compare the methods proposed under different settings, often dependent of the downstream tasks. As a result, it is challenging to study these algorithms in the literature systematically. Motivated by the recently proposed PCS framework for Veridical Data Science, we propose a framework for network embedding algorithms and discuss how the principles of predictability, computability, and stability (PCS) apply in this context. The utilization of this framework in network embedding holds the potential to motivate and point to new directions for future research.
A Sustainable and Efficient Artificial Microgel System: Toward Creating a Configurable Synthetic Cell
Authors: Wang Chen , Geng Yuhao , Sun Qi , Xu Jianhong , Lu Yuan 
Published: November 2020

AbstractArtificial cells are a powerful platform in the study of synthetic biology and other valuable fields. They share a great potential in defining and utilizing the superiority of the living system. Here, a protein synthesis system based on thermal responsive hydrogels with porous structure is reported. The hydrogels can immobilize plasmids on the surface inside their porous structure through a volume phase transition upon 34 °C, forming an aggregation state of DNAs as in nature conditions. The artificial microgels can carry out bioreactions in cell‐free systems and exhibit a sustainable and efficient performance for protein translation. The protein synthesis level reaches a maximum of twice more than that in a conventional solution system when the plasmid concentration is 10–20 ng µL−1, along with a doubled effective interval. This is perhaps attributed to confined transcription and translation processes in the near‐surface area of hydrogels. Summarily, the research provides an easy‐handling approach in fabricating effective microgels for cell‐free synthesis and also inspirations for constructing a configurable artificial cell.
World Flora Online: Placing taxonomists at the heart of a definitive and comprehensive global resource on the world's plants
Authors: Borsch Thomas , Berendsohn Walter , Dalcin Eduardo , Delmas Maïté , Demissew Sebsebe , Elliott Alan , Fritsch Peter , Fuchs Anne , Geltman Dmitry , Güner Adil , Haevermans Thomas , Knapp Sandra , le Roux M. Marianne , Loizeau Pierre‐André , Miller Chuck , Miller James , Miller Joseph T. , Palese Raoul , Paton Alan , Parnell John , Pendry Colin , Qin Hai‐Ning , Sosa Victoria , Sosef Marc , von Raab‐Straube Eckhard , Ranwashe Fhatani , Raz Lauren , Salimov Rashad , Smets Erik , Thiers Barbara , Thomas Wayt , Tulig Melissa , Ulate William , Ung Visotheary , Watson Mark , Jackson Peter Wyse , Zamora Nelson 
Published: November 2020

AbstractIt is time to synthesize the knowledge that has been generated through more than 260 years of botanical exploration, taxonomic and, more recently, phylogenetic research throughout the world. The adoption of an updated Global Strategy for Plant Conservation (GSPC) in 2011 provided the essential impetus for the development of the World Flora Online (WFO) project. The project represents an international, coordinated effort by the botanical community to achieve GSPC Target 1, an electronic Flora of all plants. It will be a first‐ever unique and authoritative global source of information on the world's plant diversity, compiled, curated, moderated and updated by an expert and specialist‐based community (Taxonomic Expert Networks – “TENs” – covering a taxonomic group such as family or order) and actively managed by those who have compiled and contributed the data it includes. Full credit and acknowledgement will be given to the original sources, allowing users to refer back to the primary data. A strength of the project is that it is led and endorsed by a global consortium of more than 40 leading botanical institutions worldwide. A first milestone for producing the World Flora Online is to be accomplished by the end of 2020, but the WFO Consortium is committed to continuing the WFO programme beyond 2020 when it will develop its full impact as the authoritative source of information on the world's plant biodiversity.
FeynOnium: using FeynCalc for automatic calculations in Nonrelativistic Effective Field Theories
Authors: Brambilla Nora , Chung Hee Sok , Shtabovenko Vladyslav , Vairo Antonio 
Published: November 2020

AbstractWe present new results on FeynOnium, an ongoing project to develop a general purpose software toolkit for semi-automatic symbolic calculations in nonrelativistic Effective Field Theories (EFTs). Building upon FeynCalc, an existing Mathematicapackage for symbolic evaluation of Feynman diagrams, we have created a powerful framework for automatizing calculations in nonrelativistic EFTs (NREFTs) at tree- and 1-loop level. This is achieved by exploiting the novel features of FeynCalcthat support manipulations of Cartesian tensors, Pauli matrices and nonstandard loop integrals. Additional operations that are common in nonrelativistic EFT calculations are implemented in a dedicated add-on called FeynOnium. While our current focus is on EFTs for strong interactions of heavy quarks, extensions to other systems that admit a nonrelativistic EFT description are planned for the future. All our codes are open-source and publicly available. Furthermore, we provide several example calculations that demonstrate how FeynOniumcan be employed to reproduce known results from the literature.
Wechselwirkungen in der dermatologischen Systemtherapie
Authors: Krause Kristina , Jahn Katharina , Homey Bernhard 
Published: November 2020

ZusammenfassungSchwere Arzneimittelnebenwirkungen stellen mit 5–7 % einen häufigen Grund für eine Krankenhauseinweisung dar. Die Prävalenz von unerwünschten Arzneimittelwirkungen (UAW) während eines stationären Aufenthaltes liegt sogar bei etwa 11,5 %. Die Ursache sind oftmals Medikamentenwechselwirkungen, bedingt durch die Polypharmazie der multimorbiden älteren Patienten. So nimmt ein 65-jähriger Patient im Durchschnitt 5 Medikamente gleichzeitig ein. Aufgrund des zunehmenden Einsatzes von Systemtherapeutika in der Dermatologie und der gleichzeitig zunehmenden Polypharmazie ist das Wissen um Medikamenteninteraktionen für den Dermatologen zur Vermeidung schwerer Arzneimittelnebenwirkungen wesentlich. Dieser Beitrag soll eine Hilfestellung bieten, Patienten und Medikamente mit einem hohen Risiko für schwerwiegende Interaktionen zu identifizieren und dadurch das Auftreten unerwünschter Wirkungen oder auch die Verminderung des therapeutischen Effektes von Wirkstoffen zu vermeiden. Wir möchten darauf hinweisen, dass die folgende Arbeit einzelne Aspekte behandelt und nicht von der Überprüfung einzelner Arzneimittelinteraktionen mittels Interaktionsprogrammen entbindet. Nicht außer Acht gelassen werden sollte, dass neben verschreibungspflichtigen Medikamenten auch Nahrungsmittel, Nahrungsergänzungsmittel und Kräuter zu Interaktionen mit Medikamenten führen können.
Altered hormonal and autonomic nerve responses to hypo- and hyperglycaemia are found in overweight and insulin-resistant individuals and may contribute to the development of type 2 diabetes
Authors: Lundqvist Martin H. , Almby Kristina , Wiklund Urban , Abrahamsson Niclas , Kamble Prasad G. , Pereira Maria J. , Eriksson Jan W. 
Published: November 2020

Abstract
Aims/hypothesis
Results from animal models and some clinical work suggest a role for the central nervous system (CNS) in glucose regulation and type 2 diabetes pathogenesis by modulation of glucoregulatory hormones and the autonomic nervous system (ANS). The aim of this study was to characterise the neuroendocrine response to various glucose concentrations in overweight and insulin-resistant individuals compared with lean individuals.

Methods
Overweight/obese (HI, n = 15, BMI ≥27.0 kg/m2) and lean (LO, n = 15, BMI <27.0 kg/m2) individuals without diabetes underwent hyperinsulinaemic euglycaemic–hypoglycaemic clamps and hyperglycaemic clamps on two separate occasions with measurements of hormones, Edinburgh Hypoglycaemic Symptom Scale (ESS) score and heart rate variability (HRV). Statistical methods included groupwise comparisons with Mann–Whitney U tests, multilinear regressions and linear mixed models between neuroendocrine responses and continuous metabolic variables.

Results
During hypoglycaemic clamps, there was an elevated cortisol response in HI vs LO (median ΔAUC 12,383 vs 4793 nmol/l × min; p = 0.050) and a significantly elevated adrenocorticotropic hormone (ACTH) response in HI vs LO (median ΔAUC 437.3 vs 162.0 nmol/l × min; p = 0.021). When adjusting for clamp glucose levels, obesity (p = 0.033) and insulin resistance (p = 0.009) were associated with elevated glucagon levels. By contrast, parasympathetic activity was less suppressed in overweight individuals at the last stage of hypoglycaemia compared with euglycaemia (high-frequency power of HRV, p = 0.024). M value was the strongest predictor for the ACTH and PHF responses, independent of BMI and other variables. There was a BMI-independent association between the cortisol response and ESS score response (p = 0.024). During hyperglycaemic clamps, overweight individuals displayed less suppression of glucagon levels (median ΔAUC −63.4% vs −73.0%; p = 0.010) and more suppression of sympathetic relative to parasympathetic activity (low-frequency/high-frequency power, p = 0.011).

Conclusions/interpretation
This study supports the hypothesis that altered responses of insulin-antagonistic hormones and the ANS to glucose fluctuations occur in overweight and insulin-resistant individuals, and that these responses are probably partly mediated by the CNS. Their potential role in development of type 2 diabetes needs to be addressed in future research.
Do chief sustainability officers and CSR committees influence CSR-related outcomes? A structured literature review based on empirical-quantitative research findings
Authors: Velte Patrick , Stawinoga Martin 
Published: November 2020

AbstractAlthough an increasing amount of empirical research has been linked to the impact of management control and governance on corporate social responsibility (CSR) issues since the financial crisis of 2008/09, heterogeneous results have characterised this research field. Regarding the group level of corporate governance, the efficacy of board committees (e.g., audit, compensation or CSR committees) has been included in recent research designs. However, analyses of corporate governance at the individual level are related to the effects of top management members [e.g., chief executive officer (CEO), chief financial officer (CFO) or chief sustainability officer (CSO)] on CSR outcomes. This paper aims to convey a detailed understanding of sustainable management control’s impact as CSR-related board expertise. In more detail, we focus on the influence of both CSR committees and CSOs on three CSR measures mainly analysed in empirical-quantitative research: (1) CSR reporting; (2) CSR assurance (CSRA); and (3) CSR performance. We motivate our analysis with increased relevance from practical, regulatory and research perspectives, and we employ a systematic literature review of the symbolic vs. substantive effects of sustainability-related board composition. Based on our theoretical model (legitimacy theory, stakeholder theory and upper-echelons theory), we selected 48 quantitative peer-reviewed empirical studies on this research topic. Our analysis shows that CSR committees positively influence CSR reporting and performance. Thus, there are indications that the implementation of a CSR committee is not a symbolic act, but instead substantively contributes to CSR activities. However, in light of inconclusive empirical research results and a lack of studies that have analysed CSO-related effects, a notable research gap has been identified. Moreover, we note the main limitations of prior research in this review and develop an agenda with useful recommendations for future studies.
Implementation and management outcomes of pharmacogenetic CYP2C19 testing for clopidogrel therapy in clinical practice
Authors: Russmann Stefan , Rahmany Ali , Niedrig David , Hatz Karl-Dietrich , Ludin Katja , Burden Andrea M. , Englberger Lars , Backhaus Roland , Serra Andreas , Béchir Markus 
Published: November 2020

Abstract
Purpose
The antiplatelet prodrug clopidogrel is bioactivated by the polymorphic enzyme CYP2C19. Prospective clinical studies demonstrated an association between CYP2C19 loss of function (LoF) variants and an increased risk of thrombotic events under clopidogrel, but pharmacogenetic (PGx) testing is not frequently implemented in clinical practice. We report our experience with PGx-guided clopidogrel therapy with particular regard to clinically relevant patient management changes.

Methods
We conducted an observational study analyzing patients that underwent PGx testing for clopidogrel therapy at two Swiss hospitals. Primary outcome was the proportion of patients with clinically relevant PGx-based management recommendations and their implementation. The association of recurrent ischemic events under clopidogrel with CYP2C19 LoF variants and other factors was explored in a multivariate case-control analysis.

Results
Among 56 patients undergoing PGx testing, 18 (32.1%) were classified as CYP2C19 intermediate or poor metabolizers. This resulted in 17 recommendations for a change of antiplatelet therapy, which were implemented in 12 patients (70.1%). In the remaining five patients, specific reasons for non-implementation could be identified. Recurrent ischemic events under clopidogrel were associated with LoF variants (OR 2.2, 95% CI 0.3–14.4) and several cardiovascular risk factors. Associations were not statistically significant in our small study, but plausible and in line with estimates from large prospective studies.

Conclusion
PGx-guided clopidogrel therapy can identify patients with an elevated risk of ischemic events and offer evidence-based alternative treatments. Successful implementation in clinical practice requires a personalized interdisciplinary service that evaluates indications and additional risk factors, provides specific recommendations, and proactively follows their implementation.
Tumor suppression, dose-limiting toxicity and wellbeing with the fetal estrogen estetrol in patients with advanced breast cancer
Authors: Schmidt Marcus , Lenhard Hans , Hoenig Arnd , Zimmerman Yvette , Krijgh Jan , Jansen Monique , Coelingh Bennink Herjan J. T. 
Published: November 2020

Abstract
Purpose
The aim of this study (the ABCE4 study) was to assess dose-limiting toxicity (DLT), safety, tolerability and preliminary efficacy of high doses of the fetal estrogen estetrol (E4) in postmenopausal patients with heavily pretreated, locally advanced and/or metastatic ER+/HER2−breast cancer, resistant to anti-estrogens.

Methods
This was a multicenter, open-label, phase IB/IIA, dose-escalation study with a 3 + 3 cohort design, whereby successive cohorts of three patients received 20 mg, 40 mg or 60 mg E4 per day for 12 weeks by oral administration. DLTs, safety and wellbeing were evaluated after 4, 8 and 12 weeks of treatment. Anti-tumor effects were investigated by computer tomography scanning and evaluated according to RECIST criteria before and after 12 weeks of treatment. Wellbeing was judged weekly by the investigator and by quality-of-life questionnaires by the patients. In view of the small number of patients, no statistical testing was performed.

Results
All 12 patients enrolled had progressive, heavily pre-treated advanced breast cancer. No treatment-related serious adverse events or DLTs occurred during the first 4 weeks of E4 treatment allowing the investigation of all three doses. Five of nine patients completing 12 weeks of E4 treatment showed objective anti-tumor effects and six of nine patients reported improved wellbeing.

Conclusion
High doses of estetrol seem to be safe and are well tolerated during 12 weeks of treatment without dose-limiting toxicity and with anti-tumor effects in five of nine heavily treated patients with progressive, anti-estrogen resistant, advanced breast cancer.
Comparison of bone regenerative capacity of donor-matched human adipose–derived and bone marrow mesenchymal stem cells
Authors: Mohamed-Ahmed Samih , Yassin Mohammed A. , Rashad Ahmad , Espedal Heidi , Idris Shaza B. , Finne-Wistrand Anna , Mustafa Kamal , Vindenes Hallvard , Fristad Inge 
Published: November 2020

AbstractAdipose-derived stem cells (ASC) have been used as an alternative to bone marrow mesenchymal stem cells (BMSC) for bone tissue engineering. However, the efficacy of ASC in bone regeneration in comparison with BMSC remains debatable, since inconsistent results have been reported. Comparing ASC with BMSC obtained from different individuals might contribute to this inconsistency in results. Therefore, this study aimed to compare the bone regenerative capacity of donor-matched human ASC and BMSC seeded onto poly(l-lactide-co-ε-caprolactone) scaffolds using calvarial bone defects in nude rats. First, donor-matched ASC and BMSC were seeded onto the co-polymer scaffolds to evaluate their in vitro osteogenic differentiation. Seeded scaffolds and scaffolds without cells (control) were then implanted in calvarial defects in nude rats. The expression of osteogenesis-related genes was examined after 4 weeks. Cellular activity was investigated after 4 and 12 weeks. Bone formation was evaluated radiographically and histologically after 4, 12, and 24 weeks. In vitro, ASC and BMSC demonstrated mineralization. However, BMSC showed higher alkaline phosphatase activity than ASC. In vivo, human osteogenesis–related genes Runx2 and collagen type I were expressed in defects with scaffold/cells. Defects with scaffold/BMSC had higher cellular activity than defects with scaffold/ASC. Moreover, bone formation in defects with scaffold/BMSC was greater than in defects with scaffold/ASC, especially at the early time-point. These results suggest that although ASC have the potential to regenerate bone, the rate of bone regeneration with ASC may be slower than with BMSC. Accordingly, BMSC are more suitable for bone regenerative applications.
The evolution of biogeochemistry: revisited
Authors: Bianchi Thomas S. 
Published: November 2020

AbstractThe evolution of biogeochemistry, retraces the important historical steps in part, covered by Gorham (Biogeochemistry 13:199–239, 1991) in the 18–19th centuries—with new emergent linkages and trends in 20–21st centuries. In the post-phlogiston period, key synthetic connections are made between weathering, atmospheric chemistry, carbon cycling, and climate change. Early work in the 19th century, focused on weathering and the importance of organisms in the exchange of carbon dioxide between the rocks and the atmosphere, provided foundations for new analytical approaches. The role microbes in connecting abiotic and biotic processes begins to emerge, based largely on the existing knowledge of stoichiometry in agricultural soils and plants. This in part, leads to the founding of ecology and its linkages with evolution and biogeography. Verandsky boldly emerges in the 20th century, with his concepts of a biosphere and a noosphere, as concerns begin to arise about human impacts on nature. The development of organic geochemistry as a discipline, allowed for new roots to develop in the evolution of biogeochemistry through linkages between short and long-term carbon cycles. In the 20th century, a new interesting stoichiometry emerges in biogeochemistry—as related to the Green Revolution, human population growth, and eutrophication problems. The advent of long-term and large-scale experiments help to constrain the complexity of non-linearity and regional differences in fluxes and rates in biogeochemical work. A new age begins in the 21st century whereby molecular approaches (e.g. omics) combined with large-scale satellite, monitoring, survey, observatory approaches are combined in the development of Earth System models. These new connections with ecological/evolutionary genetics are one of the more dramatic and important aspects of biogeochemistry in modern times.