bluuebunny/crossref_metadata_2025_split huggingface dataset:
MYC-targeted WDR4 promotes proliferation, metastasis, and sorafenib resistance by inducing CCNB1 translation in hepatocellular carcinoma
Authors: Xia Peng , Zhang Hao , Xu Kequan , Jiang Xiang , Gao Meng , Wang Ganggang , Liu Yingyi , Yao Ye , Chen Xi , Ma Weijie , Zhang Zhonglin , Yuan Yufeng 
Published: July 2021

AbstractHepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. However, there still remains a lack of effective diagnostic and therapeutic targets for this disease. Increasing evidence demonstrates that RNA modifications play an important role in the progression of HCC, but the role of the N7-methylguanosine (m7G) methylation modification in HCC has not been properly evaluated. Thus, the goal of the present study was to investigate the function and mechanism of the m7G methyltransferase WD repeat domain 4 (WDR4) in HCC as well as its clinical relevance and potential value. We first verified the high expression of WDR4 in HCC and observed that upregulated WDR4 expression increased the m7G methylation level in HCC. WDR4 promoted HCC cell proliferation by inducing the G2/M cell cycle transition and inhibiting apoptosis in addition to enhancing metastasis and sorafenib resistance through epithelial-mesenchymal transition (EMT). Furthermore, we observed that c-MYC (MYC) can activate WDR4 transcription and that WDR4 promotes CCNB1 mRNA stability and translation to enhance HCC progression. Mechanistically, we determined that WDR4 enhances CCNB1 translation by promoting the binding of EIF2A to CCNB1 mRNA. Furthermore, CCNB1 was observed to promote PI3K and AKT phosphorylation in HCC and reduce P53 protein expression by promoting P53 ubiquitination. In summary, we elucidated the MYC/WDR4/CCNB1 signalling pathway and its impact on PI3K/AKT and P53. Furthermore, the result showed that the m7G methyltransferase WDR4 is a tumour promoter in the development and progression of HCC and may act as a candidate therapeutic target in HCC treatment.
Teprotumumab for the treatment of chronic thyroid eye disease
Authors: Ugradar Shoaib , Kang Julia , Kossler Andrea L. , Zimmerman Erin , Braun Jenna , Harrison Andrew R. , Bose Swaraj , Cockerham Kimberly , Douglas Raymond S. 
Published: July 2021

Abstract
Background
Teprotumumab, a novel IGF-1R antibody was recently shown to significantly reduce the signs of active Thyroid eye disease (TED). The current study reviews its efficacy in chronic TED.

Methods
In this retrospective review, consecutive patients with chronic stable TED (>2 years), who had received ≥3 infusions of teprotumumab were included. All patients had measurements of proptosis, and calculation of the CAS and diplopia scores before and after therapy. Five-point strabismus scores were also calculated. Patients who had imaging within 4 months prior to therapy and 6 weeks post therapy underwent orbital 3D volumetric analysis.

Results
Thirty-one patients met the inclusion criteria. The mean (SD) duration of TED was 81 months (56) and the mean (SD) number of infusions received by each patient was 7 (2). Mean (SD) reduction in proptosis for each study orbit was 3.5 mm (0.4) and 3 mm (0.3) for the fellow orbit. The CAS response was 90% for the study orbit and 87% for the fellow orbit. Of the 15 patients who had diplopia at baseline, 67% had a clinically significant response, while 47% had complete resolution following treatment. Following teprotumumab, mean (SD) reduction of muscle tissue was 2011 mm3 (1847) in the study orbit and 1620 mm3 (1759) in the fellow orbit. The mean (SD) reduction of fat volume was 2101 mm3 (1681) in the study orbit and 1370 mm3 (1181) in the fellow orbit.

Conclusion
Teprotumumab significantly reduces proptosis, inflammation, diplopia, strabismus and orbital soft tissue volume in patients with chronic TED.
Evaluation of standard of care intravitreal aflibercept treatment of diabetic macular oedema treatment-naive patients in the UK: DRAKO study 12-month outcomes
Authors: Sivaprasad Sobha , Ghanchi Faruque , Kelly Simon P. , Kotagiri Ajay , Talks James , Scanlon Peter , McGoey Hellen , Nolan Andrew , Saddiq Moneeb , Napier Jackie ,   on behalf of the DRAKO study group
Published: July 2021

Abstract
Objectives
DRAKO (NCT02850263) is a 24-month, prospective, non-interventional, multi-centre cohort study which enroled patients diagnosed with centre-involving diabetic macular oedema (DMO). The study aims to evaluate standard of care with intravitreal aflibercept (IVT-AFL) treatment in the UK. This analysis describes the anti-vascular endothelial growth factor (anti-VEGF) treatment-naive patient cohort after 12-month follow-up.

Methods
Study eyes were treated with IVT-AFL as per local standard of care. The mean change in best-corrected visual acuity (BCVA) and central subfield thickness (CST) from baseline at 12 months were measured and stratified by baseline factors. The number of injections and safety data were also evaluated.

Results
A total of 507 patients were enroled from 35 centres. Mean (SD) baseline BCVA was 71.4 (12.0) letters and CST was 448.7 (88.7) µm, with 63.1% of patients presenting with baseline BCVA ≥ 70 letters (mean 78.1). Mean (SD) change in BCVA of 2.5 (12.2) letters and CST of −119.1 (116.4) µm was observed at month 12. A 7.3 letter gain was observed in patients with baseline BCVA < 70 letters. Mean number (SD) of injections in year one was 6.4 (2.1). No significant adverse events were recorded.

Conclusion
Year one results indicated that IVT-AFL was an effective treatment for DMO in standard of care UK clinical practice, maintaining or improving visual acuity in treatment-naive patients with good baseline visual acuity, despite some patients being undertreated versus the summary of product characteristics. These results also demonstrated the clinical importance and meaningful impact of diabetic retinopathy screening in the UK.
Common irrigation drivers of freshwater salinisation in river basins worldwide
Authors: Thorslund Josefin , Bierkens Marc F. P. , Oude Essink Gualbert H. P. , Sutanudjaja Edwin H. , van Vliet Michelle T. H. 
Published: July 2021

AbstractFreshwater salinisation is a growing problem, yet cross-regional assessments of freshwater salinity status and the impact of agricultural and other sectoral uses are lacking. Here, we assess inland freshwater salinity patterns and evaluate its interactions with irrigation water use, across seven regional river basins (401 river sub-basins) around the world, using long-term (1980–2010) salinity observations. While a limited number of sub-basins show persistent salinity problems, many sub-basins temporarily exceeded safe irrigation water-use thresholds and 57% experience increasing salinisation trends. We further investigate the role of agricultural activities as drivers of salinisation and find common contributions of irrigation-specific activities (irrigation water withdrawals, return flows and irrigated area) in sub-basins of high salinity levels and increasing salinisation trends, compared to regions without salinity issues. Our results stress the need for considering these irrigation-specific drivers when developing management strategies and as a key human component in water quality modelling and assessment.
In situ observation of thermal-driven degradation and safety concerns of lithiated graphite anode
Authors: Liu Xiang , Yin Liang , Ren Dongsheng , Wang Li , Ren Yang , Xu Wenqian , Lapidus Saul , Wang Hewu , He Xiangming , Chen Zonghai , Xu Gui-Liang , Ouyang Minggao , Amine Khalil 
Published: July 2021

AbstractGraphite, a robust host for reversible lithium storage, enabled the first commercially viable lithium-ion batteries. However, the thermal degradation pathway and the safety hazards of lithiated graphite remain elusive. Here, solid-electrolyte interphase (SEI) decomposition, lithium leaching, and gas release of the lithiated graphite anode during heating were examined by in situ synchrotron X-ray techniques and in situ mass spectroscopy. The source of flammable gas such as H2 was identified and quantitively analyzed. Also, the existence of highly reactive residual lithium on the graphite surface was identified at high temperatures. Our results emphasized the critical role of the SEI in anode thermal stability and uncovered the potential safety hazards of the flammable gases and leached lithium. The anode thermal degradation mechanism revealed in the present work will stimulate more efforts in the rational design of anodes to enable safe energy storage.
Subduction history of the Caribbean from upper-mantle seismic imaging and plate reconstruction
Authors: Braszus Benedikt , Goes Saskia , Allen Rob , Rietbrock Andreas , Collier Jenny , Harmon Nick , Henstock Tim , Hicks Stephen , Rychert Catherine A. , Maunder Ben , van Hunen Jeroen , Bie Lidong , Blundy Jon , Cooper George , Davy Richard , Kendall J. Michael , Macpherson Colin , Wilkinson Jamie , Wilson Marjorie 
Published: July 2021

AbstractThe margins of the Caribbean and associated hazards and resources have been shaped by a poorly understood history of subduction. Using new data, we improve teleseismicP-wave imaging of the eastern Caribbean upper mantle and compare identified subducted-plate fragments with trench locations predicted from plate reconstruction. This shows that material at 700–1200 km depth below South America derives from 90–115 Myr old westward subduction, initiated prior to Caribbean Large-Igneous-Province volcanism. At shallower depths, an accumulation of subducted material is attributed to Great Arc of the Caribbean subduction as it evolved over the past 70 Ma. We interpret gaps in these subducted-plate anomalies as: a plate window and tear along the subducted Proto-Caribbean ridge; tearing along subducted fracture zones, and subduction of a volatile-rich boundary between Proto-Caribbean and Atlantic domains. Phases of back-arc spreading and arc jumps correlate with changes in age, and hence buoyancy, of the subducting plate.
Effective silencing of miR-126 after ischemic stroke by means of intravenous α-tocopherol–conjugated heteroduplex oligonucleotide in mice
Authors: Suzuki Motohiro , Ishibashi Satoru , Iwasawa Eri , Oguma Takahiro , Saito Yasuhiro , Li Fuying , Otsu Shinichi , Ichinose Keiko , Yoshioka Kotaro , Nagata Tetsuya , Yokota Takanori 
Published: July 2021

AbstractBrain endothelial cells (BECs) are involved in the pathogenesis of ischemic stroke. Recently, several microRNAs (miRNAs) in BECs were reported to regulate the endothelial function in ischemic brain. Therefore, modulation of miRNAs in BECs by a therapeutic oligonucleotide to inhibit miRNA (antimiR) could be a useful strategy for treating ischemic stroke. However, few attempts have been made to achieve this strategy via systemic route due to lack of efficient delivery-method toward BECs. Here, we have developed a new technology for delivering an antimiR into BECs and silencing miRNAs in BECs, using a mouse ischemic stroke model. We designed a heteroduplex oligonucleotide, comprising an antimiR against miRNA-126 (miR-126) known as the endothelial-specific miRNA and its complementary RNA, conjugated to α-tocopherol as a delivery ligand (Toc-HDO targeting miR-126). Intravenous administration of Toc-HDO targeting miR-126 remarkably suppressed miR-126 expression in ischemic brain of the model mice. In addition, we showed that Toc-HDO targeting miR-126 was delivered into BECs more efficiently than the parent antimiR in ischemic brain, and that it was delivered more effectively in ischemic brain than non-ischemic brain of this model mice. Our study highlights the potential of this technology as a new clinical therapeutic option for ischemic stroke.
The effect of total factor productivity of forestry industry on CO2 emissions: a spatial econometric analysis of China
Authors: Zhong Shen , Wang Hongli 
Published: July 2021

AbstractForestry plays an essential role in reducing CO2 emissions and promoting green and sustainable development. This paper estimates the CO2 emissions of 30 provinces in China from 2008 to 2017, and uses Global DEA-Malmquist to measure the total factor productivity of the forestry industry and its decomposition index. On this basis, by constructing a spatial econometric model, this paper aims to empirically study the impact of forestry industry's total factor productivity and its decomposition index on CO2 emissions, and further analyze its direct, indirect and total effects. The study finds that the impact of forestry industry's total factor productivity on CO2 emissions shows an "inverted U-shaped" curve and the inflection point is 0.9395. The spatial spillover effect of CO2 emissions is significantly negative. The increase of CO2 emissions in adjacent areas will provide a "negative case" for the region, so that the region can better address its own energy conservation and emission reduction goals. TFP of forestry industry also has positive spatial spillover effect. However, considering the particularity of forestry industry, this effect is not very significant. For other factors, such as foreign direct investment, urbanization level, industrial structure and technology market turnover will also significantly affect regional CO2 emissions.
Ball-milling synthesis of sulfonyl quinolines via coupling of haloquinolines with sulfonic acids
Authors: Liu Xiao-Wen , Wang Jia-Qian , Ma Hui , Zhu Qi , Xie Long-Yong 
Published: July 2021

A practical and environment-friendly methodology for the construction of sulfonyl quinolines through ball milling promoted coupling of haloquinolines with sulfonic acid under metal-, base-, solvent- and additive-free conditions was developed.
Prostasin regulates PD-L1 expression in human lung cancer cells
Authors: Chen Li-Mei , Chai Julius C. , Liu Bin , Strutt Tara M. , McKinstry K. Kai , Chai Karl X. 
Published: July 2021

Abstract
The serine protease prostasin is a negative regulator of lipopolysaccharide-induced inflammation and has a role in the regulation of cellular immunity. Prostasin expression in cancer cells inhibits migration and metastasis, and reduces epithelial–mesenchymal transition. Programmed death-ligand 1 (PD-L1) is a negative regulator of the immune response and its expression in cancer cells interferes with immune surveillance. The aim of the present study was to investigate if prostasin regulates PD-L1 expression. We established sublines overexpressing various forms of prostasin as well as a subline deficient for the prostasin gene from the Calu-3 human lung cancer cells. We report here that PD-L1 expression induced by interferon-γ (IFNγ) is further enhanced in cells overexpressing the wildtype membrane-anchored prostasin. The PD-L1 protein was localized on the cell surface and released into the culture medium in extracellular vesicles (EVs) with the protease-active prostasin. The epidermal growth factor-epidermal growth factor receptor (EGF-EGFR), protein kinase C (PKC), and mitogen-activated protein kinase (MAPK) participated in the prostasin-mediated up-regulation of PD-L1 expression. A Gene Set Enrichment Analysis (GSEA) of patient lung tumors in The Cancer Genome Atlas (TCGA) database revealed that prostasin and PD-L1 regulate common signaling pathways during tumorigenesis and tumor progression.
Unravelling the tangled web of hypertension and cancer
Authors: Sionakidis Aristeidis , McCallum Linsay , Padmanabhan Sandosh 
Published: July 2021

Abstract
Cardiovascular disease remains the primary cause of mortality globally, being responsible for an estimated 17 million deaths every year. Cancer is the second leading cause of death on a global level with roughly 9 million deaths per year being attributed to neoplasms. The two share multiple common risk factors such as obesity, poor physical exercise, older age, smoking and there exists rare monogenic hypertension syndromes. Hypertension is the most important risk factor for cardiovascular disease and affects more than a billion people worldwide and may also be a risk factor for the development of certain types of cancer (e.g. renal cell carcinoma (RCC)). The interaction space of the two conditions becomes more complicated when the well-described hypertensive effect of certain antineoplastic drugs is considered along with the extensive amount of literature on the association of different classes of antihypertensive drugs with cancer risk/prevention. The cardiovascular risks associated with antineoplastic treatment calls for efficient management of relative adverse events and the development of practical strategies for efficient decision-making in the clinic. Pharmacogenetic interactions between cancer treatment and hypertension-related genes is not to be ruled out, but the evidence is not still ample to be incorporated in clinical practice. Precision Medicine has the potential to bridge the gap of knowledge regarding the full spectrum of interactions between cancer and hypertension (and cardiovascular disease) and provide novel solutions through the emerging field of cardio-oncology. In this review, we aimed to examine the bidirectional associations between cancer and hypertension including pharmacotherapy.
Modelling and solving of IGBT's transient analysis model based on the finite state machine
Authors: Hao Bin , Wu Yingzhe , Peng Cheng , Tang Xinling , Zhao Zhibin 
Published: July 2021

AbstractTo accurately obtain the switching characteristics of insulated gate bipolar transistors (IGBT), this paper proposes an IGBT's transient analysis model (TAM) based on the finite state machine (FSM). Firstly, the IGBT switching process in the basic converter unit is segmented in the time domain, and the circuit equations among the variables are obtained based on Kirchhoff's law. Then, the switching mechanism and parameters of the IGBT are decoupled based on time segmentation, and clarifying state equations and the transition events for each stage. Subsequently, all the stages and events are modeled in an FSM, thus establishing the IGBT's TAM, and it was realized the Stateflow toolbox of Matlab/Simulink. Finally, some experiments were performed on IGBTs with different current and voltage. The results show that the TAM can accurately describe the switching characteristics of IGBT and is suitable for different voltage and current levels.
Joint primary frequency regulation strategy for asynchronous power grids connected by a VSC‐MTDC system
Authors: Wang Guoteng , Zhang Zheren , Xu Zheng 
Published: July 2021

AbstractAsynchronous interconnection will reduce the inertia of each grid, and it is difficult for a small inertia grid to maintain frequency stability under the fluctuation of new energy or load. In order to improve the frequency stability of asynchronous power grids connected by a voltage source converters based multi‐terminal direct current (VSC‐MTDC) system, a joint primary frequency regulation (JPFR) strategy is proposed in this paper. The main principle of the proposed JPFR strategy is firstly to formulate frequency regulation protocols (FRPs) between asynchronous power grids. Next, an improved analytical steady‐state model of the VSC‐MTDC system is adopted. The improved model can calculate the power reference of each VSC according to the FRP, avoiding the impact on the grid not participating in the protocol. Then, based on the sequential search method, the results of the improved model are modified to prevent overload. Finally, simulations of a four‐terminal VSC‐MTDC system are carried out for validating the proposed JPFR strategy.
Seismic performance of frame‐bent structures subjected to near‐fault ground motions
Authors: Zhang Shuyun , Huang Lei , Wang Gang , Ma Yousufu 
Published: July 2021

AbstractReinforced concrete frame‐bent structures are one of the structural forms commonly used in industrial factory buildings. In order to study the seismic behaviour of frame‐bent structures located near fault areas, eight pulse‐like, eight non‐pulse near‐fault motions and eight far‐fault ground motions have been selected in this paper. The finite element model of a reinforced concrete frame‐bent structure was established to study seismic responses to near‐fault and far‐field ground motions. Numerical analysis results indicate that the maximum base shear of the structure under the action of near‐fault ground motion was 5.10 times that of far‐fault and 1.47 times that of non‐pulsed near‐fault ground motion; the maximum story drift angle under pulse‐like near‐fault ground motion was 3.8 times that of non‐pulse and 19.7 times that of far‐fault ground motion. Therefore, engineering designers should pay more attention to the seismic performance of frame‐bent structures under the action of near‐fault ground vibration.
Überprüfung der Kompetenzen von Notfallsanitätern – Umfragestudie zu
Umsetzung und Rahmenbedingungen durch Ärztliche Leiter
Rettungsdienst
Authors: Ostmeier Stefan , Eismann Hendrik , Hofmann Thomas , Flentje Markus 
Published: July 2021

Zusammenfassung
Hintergrund Eine Kompetenzüberprüfung von Notfallsanitätern (NFS) ist
durch die Ärztlichen Leiter Rettungsdienst (ÄLRD) empfohlen. Die Umsetzung
erfolgt individuell im Rettungsdienstbereich. Ziel der Studie ist die
Beschreibung der aktuellen Situation als Diskussionsbeitrag für
Weiterentwicklungen.
Methode In der Zeit von Sept. 2019 bis Mai 2020 wurden die ÄLRD zu ihren
verfügbaren Ressourcen, der Art der Kompetenzüberprüfung, der Konsequenzen und
Bewertung der eigenen Arbeit befragt.
Ergebnisse Siebzig ÄLRD sind im Mittel für 311 NFS zuständig. Die
Überprüfung wird in 87,1% von Praxisanleitern (PA) unterstützt. Am häufigsten
werden Fallszenarien eingesetzt. 10% überprüfen nicht. Die ÄLRD bewerten ihre
eigene Arbeit mit der Schulnote befriedigend und nennen mangelnde Ressourcen als
Haupthinderungsgrund. Bei Nichtbestehen werden Wiederholungsprüfungen angeboten
und der Einsatz als Transportführer ausgesetzt.
Schlussfolgerung In vielen Bereichen findet eine Überprüfung nach Vorgaben
des Pyramidenprozesses II statt. Einzelne Bereiche überprüfen die Kompetenz
nicht oder wenden nichtgeeignete Prüfungsformate an. Die Praxisanleiter leisten
einen wichtigen Beitrag. Übergreifende Konzepte mit Transparenz und Qualität
sind weiterzuentwickeln, um Konsequenzen aus Überprüfungen zu rechtfertigen.
Bundesweite Konzepte können ÄLRD entlasten und die Einsatzflexibilität der
Mitarbeiter erhöhen.