bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTGF Mediates Tumor–Stroma Interactions between Hepatoma Cells and Hepatic Stellate Cells to Accelerate HCC Progression
Authors: Makino Yuki , Hikita Hayato , Kodama Takahiro , Shigekawa Minoru , Yamada Ryoko , Sakamori Ryotaro , Eguchi Hidetoshi , Morii Eiichi , Yokoi Hideki , Mukoyama Masashi , Hiroshi Suemizu , Tatsumi Tomohide , Takehara Tetsuo 
Published: July 2018

Abstract
Connective tissue growth factor (CTGF) is a matricellular protein related to hepatic fibrosis. This study aims to clarify the roles of CTGF in hepatocellular carcinoma (HCC), which usually develops from fibrotic liver. CTGF was overexpressed in 93 human HCC compared with nontumorous tissues, primarily in tumor cells. Increased CTGF expression was associated with clinicopathologic malignancy of HCC. CTGF was upregulated in hepatoma cells in hepatocyte-specific Kras-mutated mice (Alb-Cre KrasLSL-G12D/+). Hepatocyte-specific knockout of CTGF in these mice (Alb-Cre KrasLSL-G12D/+ CTGFfl/fl) decreased liver tumor number and size. Hepatic stellate cells (HSC) were present in both human and murine liver tumors, and α-SMA expression, a marker of HSC activation, positively correlated with CTGF expression. Forced expression of CTGF did not affect growth of PLC/PRF/5 cells, a hepatoma cell line with little CTGF expression, but facilitated their growth in the presence of LX-2 cells, an HSC line. The growth of HepG2 cells, which express high levels of CTGF, was promoted by coculture with LX-2 cells compared with monoculture. Growth promotion by LX-2 cells was negated by an anti-CTGF antibody in both culture and xenografts. Coculturing LX-2 cells with HepG2 cells drove LX-2-derived production of IL6, which led to STAT-3 activation and proliferation of HepG2 cells. An anti-CTGF antibody reduced IL6 production in LX-2 cells and suppressed STAT-3 activation in HepG2 cells. In conclusion, our data identify tumor cell–derived CTGF as a keystone in the HCC microenvironment, activating nearby HSC that transmit progrowth signals to HCC cells, and this interaction is susceptible to inhibition by an anti-CTGF antibody.
Significance: Protumor cross-talk between cancer cells and hepatic stellate cells presents an opportunity for therapeutic intervention against HCC.
Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/17/4902/F1.large.jpg. Cancer Res; 78(17); 4902–14. ©2018 AACR.
CRISPR/Cas9-Mediated Knockout of DGK Improves Antitumor Activities of Human T Cells
Authors: Jung In-Young , Kim Yoon-Young , Yu Ho-Sung , Lee Myoungsoo , Kim Seokjoong , Lee Jungmin 
Published: July 2018

Abstract
The efficacy of T-cell therapy is inhibited by various tumor-associated immunosuppressive ligands and soluble factors. Such inhibitory signals turn specific T-cell signaling pathways on or off, impeding the anticancer functions of T cells. Many studies have focused on PD-1 or CTLA-4 blockade to invigorate T-cell functions through CD28/B7 signaling, but obtaining robust clinical outcomes remains challenging. In this study, we use CRISPR/Cas9 to potentiate T-cell function by increasing CD3 signaling via knockout of diacylglycerol kinase (DGK), an enzyme that metabolizes diacylglycerol to phosphatidic acid. Knockout of DGK augmented the effector functions of CAR-T cells in vitro via increased TCR signaling. DGK knockout from CAR-T cells rendered them resistant to soluble immunosuppressive factors such as TGFβ and prostaglandin E2 and sustained effector functions under conditions of repeated tumor stimulation. Moreover, DGK knockout caused significant regression of U87MGvIII glioblastoma tumors through enhanced effector functions in a xenograft mouse model. Collectively, our study shows that knockout of DGK effectively enhances the effector functions of CAR-T cells, suggesting that CRISPR/Cas9-mediated knockout of DGK could be applicable as part of a multifaceted clinical strategy to treat solid cancers.
Significance: This novel study demonstrates efficient ablation of diacylglycerol kinase in human CAR-T cells that leads to improved antitumor immunity and may have significant impact in human cancer immunotherapy. Cancer Res; 78(16); 4692–703. ©2018 AACR.
Resistance to Systemic Therapies in Clear Cell Renal Cell Carcinoma: Mechanisms and Management Strategies
Authors: Makhov Peter , Joshi Shreyas , Ghatalia Pooja , Kutikov Alexander , Uzzo Robert G. , Kolenko Vladimir M. 
Published: July 2018

Abstract
Renal cell carcinoma (RCC) is the most common form of kidney cancer. It is categorized into various subtypes, with clear cell RCC (ccRCC) representing about 85% of all RCC tumors. The lack of sensitivity to chemotherapy and radiation therapy prompted research efforts into novel treatment options. The development of targeted therapeutics, including multi-targeted tyrosine kinase inhibitors (TKI) and mTOR inhibitors, has been a major breakthrough in ccRCC therapy. More recently, other therapeutic strategies, including immune checkpoint inhibitors, have emerged as effective treatment options against advanced ccRCC. Furthermore, recent advances in disease biology, tumor microenvironment, and mechanisms of resistance formed the basis for attempts to combine targeted therapies with newer generation immunotherapies to take advantage of possible synergy. This review focuses on the current status of basic, translational, and clinical studies on mechanisms of resistance to systemic therapies in ccRCC. Mol Cancer Ther; 17(7); 1355–64. ©2018 AACR.
Cultural responses towards the aftermath of suicide among the Acholi in Northern Uganda
Authors: Mugisha James , Muyinda Herbert , Hjelmeland Heidi , Kinyanda Eugene , Vancampfort Davy , Knizek Birthe Loa 
Published: July 2018

Background: Suicide is a public health problem in Uganda among indigenous societies, and different societies manage its aftermath differently. Aim: To explore how the Acholi in Northern Uganda manage the aftermath of suicide. Methods: We conducted a qualitative study in Gulu district, a post-conflict area in Northern Uganda. We conducted a total of four focus group discussions (FGDs) and 12 key informant (KI) interviews. KI interviews were conducted with community leaders, while the FGDs were conducted with members of the general population. We analysed the data by means of Grounded Theory. Results: Our findings indicate that rituals form a large part in managing suicide among the Acholi. Study communities practised distancing (symbolically and physically) as a way of dealing with the threat of suicide. Conclusion: Distancing was organized into two broad themes: affect regulation and securing future generations. It is recommended that public health interventions should utilize cultural institutions in the prevention of suicide.
From Industrial Regulation to Controlled Economy
Authors: Flamme M.-A. 
Published: July 2018

(Précis of a course of lectures on Industrial Legislation) by M.-A. Flamme Lecturer at the University of Brussels The author begins by defining « Industrial Legislation » as an academic field. This subject is optional for undergraduates of the Faculties of Laws of the four Belgian Universities, in the last two semesters of their studies. But its scope has never yet been determined precisely. French, and Belgian, authors writing on Industrial Legislation, in point of fact treat only of labour legislation — classed in Belgian universities under « Social Legislation ». Yet, between Private and Public Law, there is an important sector, the limits of which are not closely defined, comprising inter alia Transport, Motive Power, and Mines, considered as « the big three » of Industrial Legislation. The author reviews: rail transport, both railways proper and the rural lines operated respectively (in Belgium) by the Société Nationale des Chemins de fer Belges and the Société Nationale des Chemins de fer Vicinaux; tramways (of which the Brussels Intercommunal régie or « directly operated public enterprise » is the most advanced example); road transport, both passengers and goods; inland waterways transport; air transport, for each of which the regime of concessions, of control, and, in some cases, of direct operation comes under consideration. The second chapter deals with power production and distribution; the third with mines. Further, the doctrinal aspects of the freedom of trade and of industry are studied, in Law. In conclusion, the author finds that the title Industrial Legislation, is somewhat of a misnomer. Economists often place industry in opposition to trade, whilst jurists group them both under « Commercial Law ». Speaking more generally, human industry is a global concept. And it is hard to say under what heading industrial ownership, distinct or not from freedom of trade and industry, is to be classed, in view of problems such as that of the civil or the public rights involved. Industrial Legislation would appear to come best under Economic Administrative Law, or Economic Public Law, concerned with State regulatory powers and protectionism, or even interventionism. Freedom or Control of industry? The choice between the two is the very crux of modern existence.
Computational Model for Predicting the Relationship Between Micro-RNAs and Their Target Messenger RNAs in Breast and Colon Cancers
Authors: Kim Shinuk 
Published: July 2018

Motivation: Uncovering the relationship between micro-RNAs (miRNAs) and their target messenger RNAs (mRNAs) can provide critical information regarding the mechanisms underlying certain types of cancers. In this context, we have proposed a computational method, referred to as prediction analysis by optimization method (PAOM), to predict miRNA-mRNA relations using data from normal and cancer tissues, and then applying the relevant algorithms to colon and breast cancers. Specifically, we used 26 miRNAs and 26 mRNAs with 676 (= 26 × 26) relationships to be recovered as unknown parameters. Results: Optimization methods were used to detect 61 relationships in breast cancer and 32 relationships in colon cancer. Using sequence filtering, we detected 18 relationships in breast cancer and 15 relationships in colon cancer. Among the 18 relationships, CD24 is the target gene of let-7a and miR-98, and E2F1 is the target gene of miR-20. In addition, the frequencies of the target genes of miR-223, miR-23a, and miR-20 were significant in breast cancer, and the frequencies of the target genes of miR-17, miR-124, and miR-30a were found to be significant in colon cancer. Availability: The numerical code is available from the authors on request.
Randomized Controlled Trials of Interventions Addressing Intimate Partner Violence in Sub-Saharan Africa: A Systematic Review
Authors: Cork Cliodhna , White Ross , Noel Pia , Bergin Niamh 
Published: July 2018

Background: Intimate partner violence (IPV) perpetrated by males is the most prevalent form of violence against women across the globe. A systematic review was carried out to identify published randomized controlled trials of interventions aiming to prevent or reduce IPV in Sub-Saharan Africa. Details were sought on the interventions, outcomes, and risk of bias in evaluations. Methods: Articles were identified by searching MEDLINE, Embase, Web of Science, and PsycInfo. The search included terms pertaining to IPV, the research design, and the target geographical region. To be included, studies needed to have assessed the impact of an intervention on reported incidence, prevalence of IPV, or measures of related attitudes and behaviors. Fifteen papers were included in the final review. Risk of bias was evaluated using the Cochrane Library “Risk of Bias” tool. Results: Findings suggest that interventions have the potential to reduce IPV-related behaviors and attitudes. Certain types of IPV were more amenable to change than others. Higher levels of efficacy were identified in interventions that had longer follow-up, addressed IPV as a main aim, and occurred at the community level or multiple levels of the social ecology. Conclusions: Findings should be interpreted in light of varying risks of bias. Suggestions are made for future research and practice.
谈唐兰先生 “三书说” 对传统六书说的批判和继承
Authors: 陈英杰  
Published: July 2018

摘要 唐兰先生的三书说不是另起炉灶, 而是在充分吸收历代文字学研究成果基础上, 对传统六书说作了不同层次的剥离, 这种剥离工作密切结合了历时的、动态的文字发展过程。其所作 “剥离” 工作表现在如下六个方面: 一、文与字的剥离（象形、指事和形声、会意的剥离）；二、图画文字和形声文字的剥离（把文字分为上古期和近古期）；三、文字构成和文字构成过程的剥离（三书和六技, 包含了造字法和用字法的剥离）；四、指事字内部构成的剥离（结果是取消了指事字）；五、会意字内部构成的剥离（结论是 “古文字只有象意没有会意” ）；六、形声字内部构成的剥离（主要是从形声字产生方法角度进行剥离, 剥离的一个重要成果就是声化象意字的析出）。这些工作是形成他的文字分期观和文字发生发展观的重要基础, 反过来, 他的文字分期观和文字发生发展观, 又进一步影响着他对历代研究成果的评鉴、吸收和对具体文字资料的分析、利用。限于篇幅, 本文主要分析了唐兰先生对汉代三套六书体系的批判, 以及对六书中指事、会意的意见, 并基于他的理论体系, 纠正了学界认为唐先生把 “三书” 跟文字形音义三方面相比附的误解。
Show it Simply
Authors: Abdomerovic M. , Blakemore G. , Stewart J. 
Published: July 2018

Project management reports must be simple, yet useful. However, the Communications Planning process in A Guide to the Project Management Body of Knowledge ( PMBOK® Guide) used in the creation of the reports can be more or less complex, depending on the project data structures. The purpose of this paper is to recommend how multiple data structures can be related to produce a report structure. The scope of this paper includes the methods that will identify the project management information needs and sources of the information for the report structure. The paper analyzes the results of the reports for approximately $500 million worth of construction projects and answers, who needs what information? As a side result of this analysis, an important fact was discovered: the Work Breakdown Structure (WBS) belongs as one of the inputs to the PMBOK® Guide Inputs to Communications Planning. Implicitly, this idea contributes to the reengineering of the PMBOK® Guide and suggests changes that need to be made and how they may be controlled.
Root Metaphors for the Management of Projects: Toward a Knowledge-Based View
Authors: Ahern Terence , Byrne P. J. , Leavy Brian 
Published: July 2018

In traditional project management, knowledge integration assumes upfront plans as explicit knowledge. For complex projects that cannot be fully specified in advance, however, knowledge integration requires emergent learning in situated contexts (Lindkvist), which involves explicit knowledge (know-that) and experiential knowledge (know-how). To expand the knowledge boundaries of traditional project management, the root-metaphor perspectives of American philosopher Stephen Pepper (1942) are interpreted as a project management framework, focusing on Mechanism for traditional project management and Contextualism for situated approaches. Using this root-metaphor framework, explicit knowledge and experiential knowledge are mutually complementary when projects are viewed as modes of organizing and learning for temporary undertakings, which encompasses process and task. The implications for research and practice include using the framework for situated research, where Contextualism has greater explanatory power, and for the management of project diversity—traditional, complex, portfolio, and program projects.
How I treat the young patient with multiple myeloma
Authors: Gandolfi Sara , Prada Claudia Paba , Richardson Paul G. 
Published: July 2018

AbstractThe treatment landscape for multiple myeloma has been transformed by the introduction of novel agents, including immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies. These have been shown to be more effective and generally better tolerated than conventional chemotherapy, with their introduction into clinical practice leading to improved survival. Furthermore, a better understanding of disease biology, improved diagnostic criteria, and the development of sensitive and specific tools for disease prognostication have contributed to better outcome. Treatment in the younger patient can now be individualized based on host and disease features with enhanced monitoring of response and use of high-sensitivity techniques for evaluating residual disease. The current standard of care has been significantly enhanced by novel agents with a paradigm shift toward optional or delayed autologous stem cell transplant as a reasonable choice in selected patients. Conversely, extended treatment with induction of remission followed by maintenance strategies is now a standard of care, conferring prolonged disease control with more manageable toxicities in both the short and long term, as well as improved quality of life.
Insights and Implications of Genome-Wide Association Studies of Height
Authors: Guo Michael H , Hirschhorn Joel N , Dauber Andrew 
Published: July 2018

Abstract

Context
In the last decade, genome-wide association studies (GWASs) have catalyzed our understanding of the genetics of height and have identified hundreds of regions of the genome associated with adult height and other height-related body measurements.

Evidence Acquisition
GWASs related to height were identified via PubMed search and a review of the GWAS catalog.

Evidence Synthesis
The GWAS results demonstrate that height is highly polygenic: that is, many thousands of genetic variants distributed across the genome each contribute to an individual’s height. These height-associated regions of the genome are enriched for genes in known biological pathways involved in growth, such as fibroblast growth factor signaling, as well as for genes expressed in relevant tissues, such as the growth plate. GWASs can also uncover previously unappreciated biological pathways, such as theSTC2/PAPPA/IGFBP4 pathway. The genes implicated by GWASs are often the same genes that are the genetic causes of Mendelian growth disorders or skeletal dysplasias, and GWAS results can provide complementary information about these disorders.

Conclusions
Here, we review the rationale behind GWASs and what we have learned from GWASs for height, including how it has enhanced our understanding of the underlying biology of human growth. We also highlight the implications of GWASs in terms of prediction of adult height and our understanding of Mendelian growth disorders.
The ESCRT protein CHMP2B acts as a diffusion barrier on reconstituted membrane necks
Authors: De Franceschi Nicola , Alqabandi Maryam , Miguet Nolwenn , Caillat Christophe , Mangenot Stephanie , Weissenhorn Winfried , Bassereau Patricia 
Published: July 2018

ABSTRACT
Endosomal sorting complexes required for transport (ESCRT)-III family proteins catalyze membrane remodeling processes that stabilize and constrict membrane structures. It has been proposed that stable ESCRT-III complexes containing CHMP2B could establish diffusion barriers at the post-synaptic spine neck. In order to better understand this process, we developed a novel method based on fusion of giant unilamellar vesicles to reconstitute ESCRT-III proteins inside GUVs, from which membrane nanotubes are pulled. The new assay ensures that ESCRT-III proteins polymerize only when they become exposed to physiologically relevant membrane topology mimicking the complex geometry of post-synaptic spines. We establish that CHMP2B, both full-length and with a C-terminal deletion (ΔC), preferentially binds to membranes containing phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. Moreover, we show that CHMP2B preferentially accumulates at the neck of membrane nanotubes, and provide evidence that CHMP2B-ΔC prevents the diffusion of PI(4,5)P2 lipids and membrane-bound proteins across the tube neck. This indicates that CHMP2B polymers formed at a membrane neck may function as a diffusion barrier, highlighting a potential important function of CHMP2B in maintaining synaptic spine structures.
This article has an associated First Person interview with the first author of the paper.
Metabolic costs imposed by hydrostatic pressure constrain bathymetric range in the lithodid crab Lithodes maja
Authors: Brown Alastair , Thatje Sven , Morris James P. , Oliphant Andrew , Morgan Elizabeth A. , Hauton Chris , Jones Daniel O. B. , Pond David W. 
Published: July 2018

ABSTRACT
The changing climate is shifting the distributions of marine species, yet the potential for shifts in depth distributions is virtually unexplored. Hydrostatic pressure is proposed to contribute to a physiological bottleneck constraining depth range extension in shallow-water taxa. However, bathymetric limitation by hydrostatic pressure remains undemonstrated, and the mechanism limiting hyperbaric tolerance remains hypothetical. Here, we assess the effects of hydrostatic pressure in the lithodid crab Lithodes maja (bathymetric range 4–790 m depth, approximately equivalent to 0.1 to 7.9 MPa hydrostatic pressure). Heart rate decreased with increasing hydrostatic pressure, and was significantly lower at ≥10.0 MPa than at 0.1 MPa. Oxygen consumption increased with increasing hydrostatic pressure to 12.5 MPa, before decreasing as hydrostatic pressure increased to 20.0 MPa; oxygen consumption was significantly higher at 7.5–17.5 MPa than at 0.1 MPa. Increases in expression of genes associated with neurotransmission, metabolism and stress were observed between 7.5 and 12.5 MPa. We suggest that hyperbaric tolerance in L. maja may be oxygen-limited by hyperbaric effects on heart rate and metabolic rate, but that L. maja's bathymetric range is limited by metabolic costs imposed by the effects of high hydrostatic pressure. These results advocate including hydrostatic pressure in a complex model of environmental tolerance, where energy limitation constrains biogeographic range, and facilitate the incorporation of hydrostatic pressure into the broader metabolic framework for ecology and evolution. Such an approach is crucial for accurately projecting biogeographic responses to changing climate, and for understanding the ecology and evolution of life at depth.
The metabolic costs of fighting and host exploitation in a seed-drilling parasitic wasp
Authors: Boisseau Romain P. , Woods H. Arthur , Goubault Marlène 
Published: July 2018

ABSTRACT
Oviposition sites may be challenging and energetically costly to access for females in the presence of competitors contesting that resource. Additionally, oviposition sites may be difficult to reach, and penetrating a hard substrate can raise energy costs. In the seed-drilling parasitic wasp Eupelmus vuilleti, females actively fight with conspecific competitors over access to hosts. They are often observed laying eggs on already parasitized hosts (superparasitism) living inside cowpea seeds despite the resulting larval competition. Using flow-through respirometry, we quantified the metabolic costs of fighting and of drilling through the seed to access the host, to understand the wasp’s fighting strategies and the occurrence of superparasitism. Agonistic interactions such as kicks or pushes generated very small instantaneous costs, but the females that won their contests had higher pre-contest metabolic rates, suggesting a potential long-term cost associated with dominance. We also found that drilling holes through the seed accounted for approximately 15% of a wasp's estimated daily energy budget, and that females can reduce these drilling costs by reusing existing holes. Because exploiting new seeds incurs both drilling costs and the risk of fights, it appears cost effective in some situations for females to avoid confrontations and lay eggs in existing holes, on already parasitized hosts. Our study helps explain the evolution of superparasitism in this system.