bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of screentime on the health and well-being of children and adolescents: a systematic review of reviews
Authors: Stiglic Neza , Viner Russell M 
Published: January 2019

ObjectivesTo systematically examine the evidence of harms and benefits relating to time spent on screens for children and young people’s (CYP) health and well-being, to inform policy.MethodsSystematic review of reviews undertaken to answer the question ‘What is the evidence for health and well-being effects of screentime in children and adolescents (CYP)?’ Electronic databases were searched for systematic reviews in February 2018. Eligible reviews reported associations between time on screens (screentime; any type) and any health/well-being outcome in CYP. Quality of reviews was assessed and strength of evidence across reviews evaluated.Results13 reviews were identified (1 high quality, 9 medium and 3 low quality). 6 addressed body composition; 3 diet/energy intake; 7 mental health; 4 cardiovascular risk; 4 for fitness; 3 for sleep; 1 pain; 1 asthma. We found moderately strong evidence for associations between screentime and greater obesity/adiposity and higher depressive symptoms; moderate evidence for an association between screentime and higher energy intake, less healthy diet quality and poorer quality of life. There was weak evidence for associations of screentime with behaviour problems, anxiety, hyperactivity and inattention, poorer self-esteem, poorer well-being and poorer psychosocial health, metabolic syndrome, poorer cardiorespiratory fitness, poorer cognitive development and lower educational attainments and poor sleep outcomes. There was no or insufficient evidence for an association of screentime with eating disorders or suicidal ideation, individual cardiovascular risk factors, asthma prevalence or pain. Evidence for threshold effects was weak. We found weak evidence that small amounts of daily screen use is not harmful and may have some benefits.ConclusionsThere is evidence that higher levels of screentime is associated with a variety of health harms for CYP, with evidence strongest for adiposity, unhealthy diet, depressive symptoms and quality of life. Evidence to guide policy on safe CYP screentime exposure is limited.PROSPERO registration numberCRD42018089483.
Stromal morphological changes and immunophenotypic features of precancerous lesions and hepatocellular carcinoma
Authors: Chen Dingbao , Li Zhao , Zhu Weihua , Cheng Qian , Song Qiujing , Qian Lihua , Zhu Ji-Ye 
Published: January 2019

AimsTo evaluate stromal histopathological features and immunostaining expression for differential diagnosis of low- and high-grade dysplastic nodules (HGDN) to early and progressed hepatocellular carcinomas (eHCC, pHCC).MaterialsWe evaluated sinusoid capillarisation (SC), solitary artery (SA), ductular reaction (DR), stromal invasion and expression of six biomarkers (GPC3, HSP70, GS, CD34, CK19, EpCAM) in a series of 97 cases.ResultsStromal morphological changes, including SC, DR and SA, exhibited significant differences in differential diagnosis. In one indicator, SC had the best sensitivity (90.00%) and accuracy (85.42%), and SA had the best specificity at 88.89 %. In combinations, SC +and SA +were favourable and optimal. The immunoreactivity of GPC3, HSP70 and GS increased significantly in line with the stepwise progression of hepatocarcinogenesis.ConclusionsStromal histopathology features are useful for diagnosing HGDN, eHCC and small HCC. The immunostaining panel of GPC3, HSP70 and GS can also be supplementary.
Measuring the research impact of the book
Folding and Fracturing of Rocks
by John G. Ramsay
Authors: Lisle Richard J. , Bastida Fernando , Aller Jesús 
Published: January 2019

Abstract

On the 50th anniversary of the publication of the book
Folding and Fracturing of Rocks
by John G. Ramsay we use an analysis of citations to assess the book's impact on research in the field of structural geology. Five topics dealt with in the book have had special success in terms of the number of citations: (1) superimposed folding; (2) fold classification based on layer thickness variation; (3) simple shear deformation; (4) the

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f

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φ
method; and (5) the flexural-slip mechanism of folding. The great impact of this book can be seen in several examples where the book has inspired new lines of research, such as: progressive deformation, strain analysis, shear zones and folding analysis. Ramsay's great merit in writing his book was to have wisely known to apply the quantitative methodology of continuum mechanics to the analysis of the geological structures. We conclude that
Folding and Fracturing of Rocks
is the most influential textbook in the field of structural geology research.
Game semantics for quantum programming
Authors: Clairambault Pierre , De Visme Marc , Winskel Glynn 
Published: January 2019

Quantum programming languages permit a hardware independent, high-level description of quantum algo rithms. In particular, the quantum lambda-calculus is a higher-order programming language with quantum primitives, mixing quantum data and classical control. Giving satisfactory denotational semantics to the quantum lambda-calculus is a challenging problem that has attracted significant interest in the past few years. Several models have been proposed but for those that address the whole quantum λ-calculus, they either do not represent the dynamics of computation, or they lack the compositionality one often expects from denotational models.
In this paper, we give the first compositional and interactive model of the full quantum lambda-calculus, based on game semantics. To achieve this we introduce a model of quantum games and strategies, combining quantum data with a representation of the dynamics of computation inspired from causal models of concurrent systems. In this model we first give a computationally adequate interpretation of the affine fragment. Then, we extend the model with a notion of symmetry, allowing us to deal with replication. In this refined setting, we interpret and prove adequacy for the full quantum lambda-calculus. We do this both from a sequential and a parallel interpretation, the latter representing faithfully the causal independence between sub-computations.
Probabilistic programming with densities in SlicStan: efficient, flexible, and deterministic
Authors: Gorinova Maria I. , Gordon Andrew D. , Sutton Charles 
Published: January 2019

Stan is a probabilistic programming language that has been increasingly used for real-world scalable projects. However, to make practical inference possible, the language sacrifices some of its usability by adopting a block syntax, which lacks compositionality and flexible user-defined functions. Moreover, the semantics of the language has been mainly given in terms of intuition about implementation, and has not been formalised.
This paper provides a formal treatment of the Stan language, and introduces the probabilistic programming language SlicStan --- a compositional, self-optimising version of Stan. Our main contributions are (1) the formalisation of a core subset of Stan through an operational density-based semantics; (2) the design and semantics of the Stan-like language SlicStan, which facilities better code reuse and abstraction through its compositional syntax, more flexible functions, and information-flow type system; and (3) a formal, semantic-preserving procedure for translating SlicStan to Stan.
Weak-consistency specification via visibility relaxation
Authors: Emmi Michael , Enea Constantin 
Published: January 2019

Effective software specifications enable modular reasoning, allowing clients to establish program properties without knowing the details of module implementations. While some modules’ operations behave atomically, others admit weaker consistencies to increase performance. Consequently, since current methodologies do not capture the guarantees provided by operations of varying non-atomic consistencies, specifications are ineffective, forfeiting the ability to establish properties of programs that invoke non-atomic operations.
In this work we develop a methodology for specifying software modules whose operations satisfy multiple distinct consistency levels. In particular, we develop a simple annotation language for specifying weakly-consistent operations via visibility relaxation, wherein annotations impose varying constraints on the visibility among operations. To integrate with modern software platforms, we identify a novel characterization of consistency called sequential happens-before consistency, which admits effective validation. Empirically, we demonstrate the efficacy of our approach by deriving and validating relaxed-visibility specifications for Java concurrent objects. Furthermore, we demonstrate an optimality of our annotation language, empirically, by establishing that even finer-grained languages do not capture stronger specifications for Java objects.
Estimation of the baroreflex total loop gain by the power spectral analysis of continuous arterial pressure recordings
Authors: Mannoji Hiroshi , Saku Keita , Nishikawa Takuya , Tohyama Takeshi , Kamada Kazuhiro , Abe Kiyokazu , Sunagawa Genya , Kishi Takuya , Sunagawa Kenji , Tsutsui Hiroyuki 
Published: January 2019

Baroreflex dysfunction contributes to the pathogenesis of cardiovascular diseases. The baroreflex comprises a negative feedback loop to stabilize arterial pressure (AP); its pressure-stabilizing capacity is defined as the gain ( G) of the transfer function ( H) of the baroreflex total loop. However, no method exists to evaluate G in a clinical setting. A feedback system with H attenuates pressure disturbance (PD) to PD/(1 + H). We hypothesized that the baroreflex attenuates the power spectrum density (PSD) of AP in the baroreflex functioning frequency range. We created graded baroreflex dysfunction in rats using a modified sinoaortic denervation (SAD) method [SAD; control (no SAD): n = 9; partial SAD (SAD in the right carotid sinus): n = 6, and total SAD (SAD in the bilateral carotid sinuses): n = 6] and evaluated the PSD of 12-h telemetric AP recordings in the light phase. Using the ratio of PSD at 0.01–0.1 Hz (PSD slope), we normalized them with the PSD in rats with complete baroreflex failure and derived the baroreflex index (BRI), which directly reflects G. We compared BRI and G obtained from a baroreflex open-loop experiment (reference G). The PSD slope became steeper with progression of baroreflex dysfunction. BRI (control: 2.00 ± 0.31, partial SAD: 1.28 ± 0.30, and total SAD: 0.06 ± 0.10, P < 0.05) was linearly correlated with reference G ( R2 = 0.91, P < 0.01). BRI accurately estimated G of the baroreflex and may serve as a novel tool for estimating the pressure-stabilizing capacity of the baroreflex in clinical settings. NEW & NOTEWORTHY This study proposed a novel method to estimate the gain of the baroreflex total loop, the so-called “baroreflex index” (BRI). BRI focuses on action potential variability in the frequency domain, considering baroreflex low-pass filter characteristics within 0.01–0.1 Hz. We demonstrated that BRI was linearly correlated with the reference gain of baroreflex in rats. Thus, BRI may contribute greatly to the development of a clinical tool for estimating baroreflex pressure-stabilizing capacity.
Tumor-Associated Macrophages Enhance Tumor Hypoxia and Aerobic Glycolysis
Authors: Jeong Hoibin , Kim Sehui , Hong Beom-Ju , Lee Chan-Ju , Kim Young-Eun , Bok Seoyeon , Oh Jung-Min , Gwak Seung-Hee , Yoo Min Young , Lee Min Sun , Chung Seock-Jin , Defrêne Joan , Tessier Philippe , Pelletier Martin , Jeon Hyeongrin , Roh Tae-Young , Kim Bumju , Kim Ki Hean , Ju Ji Hyeon , Kim Sungjee , Lee Yoon-Jin , Kim Dong-Wan , Kim Il Han , Kim Hak Jae , Park Jong-Wan , Lee Yun-Sang , Lee Jae Sung , Cheon Gi Jeong , Weissman Irving L. , Chung Doo Hyun , Jeon Yoon Kyung , Ahn G-One 
Published: January 2019

Abstract

Tumor hypoxia and aerobic glycolysis are well-known resistance factors for anticancer therapies. Here, we demonstrate that tumor-associated macrophages (TAM) enhance tumor hypoxia and aerobic glycolysis in mice subcutaneous tumors and in patients with non–small cell lung cancer (NSCLC). We found a strong correlation between CD68 TAM immunostaining and PET 18fluoro-deoxyglucose (FDG) uptake in 98 matched tumors of patients with NSCLC. We also observed a significant correlation between CD68 and glycolytic gene signatures in 513 patients with NSCLC from The Cancer Genome Atlas database. TAM secreted TNFα to promote tumor cell glycolysis, whereas increased AMP-activated protein kinase and peroxisome proliferator-activated receptor gamma coactivator 1-alpha in TAM facilitated tumor hypoxia. Depletion of TAM by clodronate was sufficient to abrogate aerobic glycolysis and tumor hypoxia, thereby improving tumor response to anticancer therapies. TAM depletion led to a significant increase in programmed death-ligand 1 (PD-L1) expression in aerobic cancer cells as well as T-cell infiltration in tumors, resulting in antitumor efficacy by PD-L1 antibodies, which were otherwise completely ineffective. These data suggest that TAM can significantly alter tumor metabolism, further complicating tumor response to anticancer therapies, including immunotherapy.

Significance:
These findings show that tumor-associated macrophages can significantly modulate tumor metabolism, hindering the efficacy of anticancer therapies, including anti-PD-L1 immunotherapy.
Exosome-Transmitted PSMA3 and PSMA3-AS1 Promote Proteasome Inhibitor Resistance in Multiple Myeloma
Authors: Xu Hongxia , Han Huiying , Song Sha , Yi Nengjun , Qian Chen'ao , Qiu Yingchun , Zhou Wenqi , Hong Yating , Zhuang Wenyue , Li Zhengyi , Li Bingzong , Zhuang Wenzhuo 
Published: January 2019

Abstract

Purpose:
How exosomal RNAs released within the bone marrow microenvironment affect proteasome inhibitors' (PI) sensitivity of multiple myeloma is currently unknown. This study aims to evaluate which exosomal RNAs are involved and by which molecular mechanisms they exert this function.
Experimental Design: Exosomes were characterized by dynamic light scattering, transmission electron microscopy, and Western blot analysis. Coculture experiments were performed to assess exosomal RNAs transferring from mesenchymal stem cells (MSC) to multiple myeloma cells. The role of PSMA3-AS1 in PI sensitivity was further evaluated in vivo. To determine the prognostic significance of circulating exosomal PSMA3 and PSMA3-AS1, a cohort of patients with newly diagnosed multiple myeloma was enrolled to study. Cox regression models and Kaplan–Meier curves were used to analyze progression-free survival (PFS) and overall survival (OS).

Results:
We identified that PSMA3 and PSMA3-AS1 in MSCs could be packaged into exosomes and transferred to myeloma cells, thus promoting PI resistance. PSMA3-AS1 could form an RNA duplex with pre-PSMA3, which transcriptionally promoted PSMA3 expression by increasing its stability. In xenograft models, intravenously administered siPSMA3-AS1 was found to be effective in increasing carfilzomib sensitivity. Moreover, plasma circulating exosomal PSMA3 and PSMA3-AS1 derived from patients with multiple myeloma were significantly associated with PFS and OS.

Conclusions:
This study suggested a unique role of exosomal PSMA3 and PSMA3-AS1 in transmitting PI resistance from MSCs to multiple myeloma cells, through a novel exosomal PSMA3-AS1/PSMA3 signaling pathway. Exosomal PSMA3 and PSMA3-AS1 might act as promising therapeutic targets for PI resistance and prognostic predictors for clinical response.
Cortactin Phosphorylation by Casein Kinase 2 Regulates Actin-Related Protein 2/3 Complex Activity, Invadopodia Function, and Tumor Cell Invasion
Authors: Markwell Steven M. , Ammer Amanda G. , Interval Erik T. , Allen Jessica L. , Papenberg Brenen W. , Hames River A. , Castaño Johnathan E. , Schafer Dorothy A. , Weed Scott A. 
Published: January 2019

Abstract

Malregulation of the actin cytoskeleton enhances tumor cell motility and invasion. The actin-binding protein cortactin facilitates branched actin network formation through activation of the actin-related protein (Arp) 2/3 complex. Increased cortactin expression due to gene amplification is observed in head and neck squamous cell carcinoma (HNSCC) and other cancers, corresponding with elevated tumor progression and poor patient outcome. Arp2/3 complex activation is responsible for driving increased migration and extracellular matrix (ECM) degradation by governing invadopodia formation and activity. Although cortactin-mediated activation of Arp2/3 complex and invadopodia regulation has been well established, signaling pathways responsible for governing cortactin binding to Arp2/3 are unknown and potentially present a new avenue for anti-invasive therapeutic targeting. Here we identify casein kinase (CK) 2α phosphorylation of cortactin as a negative regulator of Arp2/3 binding. CK2α directly phosphorylates cortactin at a conserved threonine (T24) adjacent to the canonical Arp2/3 binding motif. Phosphorylation of cortactin T24 by CK2α impairs the ability of cortactin to bind Arp2/3 and activate actin nucleation. Decreased invadopodia activity is observed in HNSCC cells with expression of CK2α phosphorylation-null cortactin mutants, shRNA-mediated CK2α knockdown, and with the CK2α inhibitor Silmitasertib. Silmitasertib inhibits HNSCC collective invasion in tumor spheroids and orthotopic tongue tumors in mice. Collectively these data suggest that CK2α-mediated cortactin phosphorylation at T24 is critical in regulating cortactin binding to Arp2/3 complex and pro-invasive activity, identifying a potential targetable mechanism for impairing HNSCC invasion.

Implications:
This study identifies a new signaling pathway that contributes to enhancing cancer cell invasion.
Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/4/987/F1.large.jpg.
Epigenetic Suppression of SERPINB1 Promotes Inflammation-Mediated Prostate Cancer Progression
Authors: Lerman Irina , Ma Xiaoting , Seger Christina , Maolake Aerken , Garcia-Hernandez Maria de la Luz , Rangel-Moreno Javier , Ackerman Jessica , Nastiuk Kent L. , Susiarjo Martha , Hammes Stephen R. 
Published: January 2019

Abstract

Granulocytic myeloid infiltration and resultant enhanced neutrophil elastase (NE) activity is associated with poor outcomes in numerous malignancies. We recently showed that NE expression and activity from infiltrating myeloid cells was high in human prostate cancer xenografts and mouse Pten-null prostate tumors. We further demonstrated that NE directly stimulated human prostate cancer cells to proliferate, migrate, and invade, and inhibition of NE in vivo attenuated xenograft growth. Interestingly, reduced expression of SERPINB1, an endogenous NE inhibitor, also correlates with diminished survival in some cancers. Therefore, we sought to characterize the role of SERPINB1 in prostate cancer. We find that SERPINB1 expression is reduced in human metastatic and locally advanced disease and predicts poor outcome. SERPINB1 is also reduced in Pten-null mouse prostate tumors compared with wild-type prostates, and treatment with sivelestat (SERPINB1 pharmacomimetic) attenuates tumor growth. Knockdown of highly expressed SERPINB1 in nonmalignant prostatic epithelial cells (RWPE-1) increases proliferation, decreases apoptosis, and stimulates expression of epithelial-to-mesenchymal transition markers. In contrast, stable SERPINB1 expression in normally low-expressing prostate cancer cells (C4-2) reduces xenograft growth in vivo. Finally, EZH2-mediated histone (H3K27me3) methylation and DNA methyltransferase–mediated DNA methylation suppress SERPINB1 expression in prostate cancer cells. Analysis of The Cancer Genome Atlas and pyrosequencing demonstrate hypermethylation of the SERPINB1 promoter in prostate cancer compared with normal tissue, and the extent of promoter methylation negatively correlates with SERPINB1 mRNA expression.

Implications:
Our findings suggest that the balance between SERPINB1 and NE is physiologically important within the prostate and may serve as a biomarker and therapeutic target in prostate cancer.
Reactive Oxygen Species (ROS)-Inducing Triterpenoid Inhibits Rhabdomyosarcoma Cell and Tumor Growth through Targeting Sp Transcription Factors
Authors: Kasiappan Ravi , Jutooru Indira , Mohankumar Kumaravel , Karki Keshav , Lacey Alexandra , Safe Stephen 
Published: January 2019

Abstract

Methyl 2-trifluoromethyl-3,11-dioxo-18β-olean-1,12-dien-3-oate (CF3DODA-Me) is derived synthetically from glycyrrhetinic acid, a major component of licorice, and this compound induced reactive oxygen species (ROS) in RD and Rh30 rhabdomyosarcoma (RMS) cells. CF3DODA-Me also inhibited growth and invasion and induced apoptosis in RMS cells, and these responses were attenuated after cotreatment with the antioxidant glutathione, demonstrating the effective anticancer activity of ROS in RMS. CF3DODA-Me also downregulated expression of specificity protein (Sp) transcription factors Sp1, Sp3, and Sp4 and prooncogenic Sp-regulated genes including PAX3-FOXO1 (in Rh30 cells). The mechanism of CF3DODA-Me–induced Sp-downregulation involved ROS-dependent repression of c-Myc and cMyc-regulated miR-27a and miR-17/20a, and this resulted in induction of the miRNA-regulated Sp repressors ZBTB4, ZBTB10, and ZBTB34. The cell and tumor growth effects of CF3DODA-Me further emphasize the sensitivity of RMS cells to ROS inducers and their potential clinical applications for treating this deadly disease.

Implications:
CF3DODA-Me and HDAC inhibitors that induce ROS-dependent Sp downregulation could be developed for clinical applications in treating rhabdomyosarcoma.
Multiclonality and Marked Branched Evolution of Low-Grade Endometrioid Endometrial Carcinoma
Authors: Lazo de la Vega Lorena , Samaha Mia C. , Hu Kevin , Bick Nolan R. , Siddiqui Javed , Hovelson Daniel H. , Liu Chia-Jen , Carter Cody S. , Cho Kathleen R. , Sciallis Andrew P. , Tomlins Scott A. 
Published: January 2019

Abstract

The molecular events driving low-grade endometrioid endometrial carcinoma (LGEC) development—like in many cancers—are incompletely understood. Hence, here we performed multiregion, comprehensive somatic molecular profiling of routinely processed formalin-fixed, paraffin-embedded (FFPE) material from 13 cases of LGEC totaling 64 minute, spatially defined cell populations ranging from presumed precursor lesions through invasive LGEC. Shared driving PTEN, PIK3R1, or PIK3CA mutations support clonal origin of the samples in each case, except for two cases with two clonally distinct neoplastic populations, consistent with unexpected multiclonality in LGEC development. Although substantial heterogeneity in driving somatic alterations was present across populations in nearly all cases, these alterations were usually clonal in a given population, supporting continued selection and clonal sweeping of driving alterations in populations with both precursor and LGEC histology. Importantly, CTNNB1 mutational status, which has been proposed as both prognostic and predictive in LGEC, was frequently heterogeneous and subclonal, occurring both exclusively in precursor or cancer populations in different cases. Whole-transcriptome profiling of coisolated RNA from 12 lesions (from 5 cases) was robust and confirmed histologic and molecular heterogeneity, including activated Wnt signaling in CTNNB1-mutant versus wild-type populations. Taken together, we demonstrate clinically relevant multiclonality and intratumoral heterogeneity during LGEC development with important implications for diagnosis, prognosis, and therapeutic prediction. More broadly, our methodology is broadly scalable to enable high-throughput genomic and transcriptomic characterization of precursor and invasive cancer populations from routine FFPE specimens.

Implications:
Multiregion profiling of LGEC populations using a highly scalable approach demonstrates clinically relevant multiclonality and intratumoral heterogeneity.