bluuebunny/crossref_metadata_2025 huggingface dataset:
Finding answers, improving outcomes: a case study of the Canada fetal alcohol spectrum disorder research network
Authors: Badry Dorothy , Coons-Harding Kelly D. , Cook Jocelynn , Bocking Alan
Published: December 2018

Purpose

The purpose of this paper is to present a profile of the Canada fetal alcohol spectrum disorder (CanFASD) research network which is descriptive in nature and profiles the work of the network and its national activities. CanFASD is a unique Canadian, non-governmental organization whose aim is to engage cross-disciplinary research and knowledge translation for stakeholders and partners including communities, policy makers and governments.

Design/methodology/approach

A case study approach was undertaken to describe the network whose main focus and purpose is specifically research related to FASD.

Findings

The creation of CanFASD has contributed to a strong network of researchers on key topic areas including diagnosis, prevention, intervention, justice and child welfare, with a focus on evidence-based decision making, research and knowledge exchange. A key role of the network is to provide access to research and education on FASD nationally.

Research limitations/implications

A case study approach, while descriptive, does not provide the details of specific research projects.

Originality/value

CanFASD has had a key role in stimulating meaningful dialogue and research in the field of FASD. The need exists to collaboratively work on a national and international basis in response to the distinct challenges posed by FASD for individuals, families and society.
Numerical analysis of mixed convection of different nanofluids in concentric annulus
Authors: Abedini Ahad , Emadoddin Saeed , Armaghani Taher
Published: December 2018

Purpose

This study aims to investigate the numerical analysis of mixed convection within the horizontal annulus in the presence of water-based fluid with nanoparticles of aluminum oxide, copper, silver and titanium oxide. Numerical solution is performed using a finite-volume method based on the SIMPLE algorithm, and the discretization of the equations is generally of the second order. Inner and outer cylinders have a constant temperature, and the inner cylinder temperature is higher than the outer one. The two cylinders can be rotated in both directions at a constant angular velocity. The effect of parameters such as Rayleigh, Richardson, Reynolds and the volume fraction of nanoparticles on heat transfer and flow pattern are investigated. The results show that the heat transfer rate increases with the increase of the Rayleigh number, as well as by increasing the volume fraction of the nanoparticles, the heat transfer rate increases, and this increase is about 8.25 per cent for 5 per cent volumetric fraction. Rotation of the cylinders reduces the overall heat transfer. Different directions of rotation have a great influence on the flow pattern and isotherms, and ultimately on heat transfer. The addition of nanoparticles does not have much effect on the flow pattern and isotherms, but it is quantitatively effective. The extracted results are in good agreement with previous works.

Design/methodology/approach

Studying mixed convection heat transfer in the horizontal annulus in the presence of a water-based fluid with aluminum oxide, copper, silver and titanium oxide nanoparticles is carried out quantitatively using a finite-volume method based on the SIMPLE algorithm.

Findings

Increasing the Rayleigh number increases the Nusselt number. Increasing the Richardson number increases heat transfer. Adding nanoparticles does not have much effect on the flow pattern but is effective quantitatively on heat transfer parameters. The addition of nanoparticles sometimes increases the heat transfer rate by about 8.25 per cent. In constant Rayleigh numbers, increasing the Reynolds number reduces heat transfer. The Rayleigh and Reynolds numbers greatly affect the isotherms and streamlines. In addition to the thermal conductivity of nanoparticles, the thermo-physical properties of nanoparticles has great effect in the formation of isotherms and streamlines and ultimately heat transfer.

Originality/value

Studying the effect of different direction of rotation on the isotherms and streamlines, as well as the comparison of different nanoparticles on mixed convection heat transfer in annulus.
Behavioural economics and social economics: opportunities for an expanded curriculum
Authors: Manning Paul
Published: December 2018

Purpose

The global financial crisis (GFC) undermined the legitimacy of orthodox economic assumptions, which nevertheless continue to frame business school pedagogy. In consequence, there is an opportunity for socio-economic insights to be more fully incorporated into the business school curriculum. This paper reports and reflects on a socio-economic case study that was delivered to MBA students. The purpose of this paper is to demonstrate that the developing literature on behavioural economics (BE) has the potential to enhance students’ social economic understanding of key areas of the curriculum.

Design/methodology/approach

The paper presents an inter-disciplinary socio-economic teaching case that was informed by insights from BE. The teaching case concerned a socio-economic understanding of corruption and white-collar crime. It was also inter-disciplinary to include inputs from business history and criminology. The aim of the teaching case was to develop an appreciation among students that corruption and white-collar crime can be analysed within a social economics lens.

Findings

The teaching case example discussed in this paper offered an alternative socio-economic understanding to core areas of the MBA curriculum, enabling students to apply a behavioural economic approach to corruption and more generally to white-collar crime. The findings derived from this case study are that behavioural economics has the potential to enhance the teaching of socio-economics.

Practical implications

The GFC presents an opportunity to re-shape the business school curriculum to acknowledge the centrality of socio-economics and consequently to offer an alternative to the dominant ontological assumptions – taken from the economic understanding of rationality – that have previously under-pinned business school pedagogy.

Originality/value

The originality of this paper is to apply BE to a socio-economic teaching case studies in core subject areas of the MBA curriculum.
“Robots do not replace a nurse with a beating heart”
Authors: Tuisku Outi , Pekkarinen Satu , Hennala Lea , Melkas Helinä
Published: December 2018

Purpose

The purpose of this paper is to investigate the publicity around the implementation of the Zora robot in elderly-care services in Lahti, Finland. The aim is to discover opinions concerning the use of robots in elderly care as well as the arguments and justifications behind those opinions. Zora is a humanoid robot intended to promote mobility and rehabilitation. The Lahti pilot was the first Zora pilot in Finland in public elderly-care services. It received much publicity, both regionally and nationally.

Design/methodology/approach

This study is based on an empirical case study on the implementation of the Zora robot in elderly-care services. The data consist of interviews with personnel who operated Zora and comments from the general public about the “Zora” robot. Two data sources were used: 107 comments were collected from online and print media, and the personnel (n=39) who worked with Zora were interviewed. The data were analysed by means of interpretative content analysis.

Findings

The results show that public opinion is mainly negative, but that the commentators apparently have little information about the robot and its tasks. The personnel had more positive views; they saw it as a recreational tool, not as a replacement for their own roles.

Originality/value

There is clearly a need for more information, for a better informed discussion on how robots can be used in elderly care and how to involve the general public in this discussion in a constructive way.
Knowledge transfer between building operation and building projects
Authors: Jensen Per Anker , Rasmussen Helle Lohmann , Chatzilazarou Stamatia
Published: December 2018

Purpose

This paper aims to investigate how knowledge concerning operation and maintenance of buildings can be stored and transferred between the parties responsible for building operation and new building projects.

Design/methodology/approach

The paper is theoretically based on knowledge management with a particular focus on interdepartmental knowledge transfer between departments responsible for operation and maintenance and departments responsible for building projects in organisations with large and fast changing building portfolios. The paper includes a case study of the facilities management organisation of the Technical University of Denmark with data collection mainly by interviews with managers and staff in the relevant departments in this organisation.

Findings

The case organisation seems to be aware of the importance of sharing and transferring their organisational knowledge. Over the past five years, the organisation has developed different tools and adopted several processes, aiming at integration of the knowledge they possess from many years of operation and maintenance of the existing buildings. However, there are many situations, where the tools and processes do not work efficiently, and therefore the knowledge transfer is not sufficiently effective. It is apparent that the best results can be achieved only if the different actors involved in a construction project collaborate aiming towards the same objectives.

Originality/value

The paper presents and evaluates a case of interdepartmental knowledge transfer in an organisation, which has a strong focus on improving the interconnections between building operations and planning new building projects.
The factors behind working in virtual community
Authors: Acharya Anitha
Published: December 2018

Purpose

In this paper, the prior research on virtual teams was reviewed to assess the state of the literature. The purpose of this paper is to determine why individuals prefer working in virtual teams (also termed liquid workers and part-time workers). Previous researchers have focussed on the benefits that organizations receive if they hire liquid workers, but to date, no research has been conducted to determine the perspective of these liquid workers. The various definitions of virtual teams are discussed and an integrative definition is proposed that suggests all teams may be defined in terms of their extent of virtualness.

Design/methodology approach

A systematic review of the literature on virtual teams was conducted. The data were collected from 12 informants. A thematic analysis was used to analyse the data.

Findings

Six main themes were identified, namely, pliability, opportunities, increased earnings, vigour, family and transportation.

Research limitations/implications

This study was conducted in a three-metropolitan city in India and warrants being extended to rural and international settings to gain additional insights and confirmation of the research findings.

Practical implications

It is suggested that organizations who recruit liquid workers will be in a position for substantial cost savings; this is because organizations usually make payment of liquid workers’ wages on an hourly basis. This will help the organizations to schedule the number of working hours depending on their needs.

Originality/value

The current study is novel as there is a paucity of research in identifying the factors behind working in the virtual community in India. This study presents the first research of its kind to the best knowledge of the author, and the findings will be valuable for companies who are looking for cost savings.
Are there preferred coping and communication strategies while undergoing IVF, and do cognitive behavioral interventions help?
Authors: Czamanski-Cohen Johanna , Sarid Orly , Cwikel Julie , Levitas Eliahu , Har-Vardi Iris
Published: December 2018

Purpose

Coping and communication strategies affect how one perceives potentially stressful life events, such as infertility. Cognitive behavioral interventions (CBI) can reduce the distress related to undergoing in vitro fertilization (IVF). The purpose of this paper is to examine the effect of CBI on the coping and communication skills as well as perceived stress and depressive symptoms of women undergoing IVF treatment. The authors also explored the relationship between coping strategies and pregnancy rates.

Design/methodology/approach

The authors conducted a randomized controlled trial of CBI in 50 women undergoing IVF (NCT00685282).

Findings

The authors found that CBI was associated with reductions in active-confrontive coping among over 50 percent of participants, which was also found to be positively related to depressive symptoms. Furthermore, high meaning-based coping at baseline and high-avoidant coping at the end of IVF treatment were associated with increased pregnancy rates.

Research limitations/implications

CBI can be helpful in reducing the perceived stress of women undergoing IVF; however, the adaptiveness of individual coping skills and communication skills vary. Since different coping strategies seem to be of benefit at different time points, further studies might benefit from the examination of engaging in context-dependent coping strategies.

Practical implications

Integrating mental health care on infertility units may assist in reducing the stress and thus quality of care in women undergoing IVF. Mental health care can be tailored to meet the individual needs of infertility patients based on their preferred coping strategies and communication style. Further research is needed to examine the cost benefit of reducing perceived stress in fertility patients.

Social implications

Infertility is a social and medical problem that has vast implications on the mental health of individuals. Providing support along with practical tools for stress reduction and improved coping and communication can result in reduced stress and improved coping.

Originality/value

This paper examined the effect of a cognitive behavioral intervention on the coping strategies and communication skills of women undergoing IVF and can contribute to our understanding of the value of integrating mental health and medical care.
Assessment of mechanical properties and flammability of magnesium oxide/PA12 composite material for SLS process
Authors: Tiwari Sunil Kumar , Pande Sarang , Bobade Santosh M. , Kumar Santosh
Published: December 2018

Purpose

The purpose of this paper is to propose and develop PA2200-based composite powder containing 0-15 Wt.% magnesium oxide before directly using it in selective laser sintering (SLS) machine to produce end-use products for low-volume production in the engineering applications with keen focus to meet the functional requirements which rely on material properties.

Design/methodology/approach

The methodology reported emphasises PA2200-based composite powder containing 0-15 Wt.% magnesium oxide development for SLS process which starts with preparation and characterisation of composite material, thermal and rheological study of composite material to decide optimum process parameters for SLS process machine to get optimal part properties. Further, to verify composite material properties, a conventional casting methodology is used. The composition of composite materials those possessing good properties are further selected for processing in SLS process under optimal processing parameters.

Findings

The process parameters of SLS machine are material-dependent. The effect of temperature in X-ray diffraction profile is negligible in the case of magnesium oxide reinforced PA2200 composite material. The cyclic heating of material increases melting point temperature, this grounds to modify part bed temperature of material every time before processing on SLS machine to uphold build part properties, as well as material. With the rise in temperature, the Melt flow index and rheological property of materials change. The magnesium oxide reinforced PA2200 composite material has high thermal stability than pure PA2200 material. By the addition of small quantity of magnesium oxide, most of the mechanical property and flammability property improves while elongation at break (percentage) decreases significantly.

Practical implications

The proposed PA2200-based composite powder containing 0-15 Wt.% magnesium oxide material development system and casting metrology to verify developed material properties will be very useful to develop new composite material for SLS process with use of less material. The developed methodology has proven, especially in the case where non-experts or student need to develop composite material for SLS process according to the property requirement of applications.

Originality/value

Unlike earlier composite material development methodology, the projected methodology of polymer-based composite material and confirmation of material properties instead of commencing SLS process provides straight forward means for SLS process composite materials development with less use of the material and period of time.
Innovative reward as a strategical culture designer
Authors: Hepner Lionel
Published: December 2018

Purpose

The paper intends to share with the reader some ideas that position the management of compensations as a strategic factor for the organizational culture shaping.

Design/methodology/approach

The author shares some ideas and examples that demonstrate how we could understand reward management as a key aspect of HR strategy. Through practical examples, will show why it has a deep impact on the so-called soft areas of HR. A strategic compensation model is introduced for the promotion of culture of innovation and the creation of new businesses through the employees of the organization.

Findings

Reward systems are part of a fundamental strategy to modelize organizational culture through the installation of symbols that has direct impact on the employee value proposition. Thinking Outside the Box can be promoted within employees through reward systems, so they can create new businesses according to the nowadays VUCA context. We are living in a volatile, uncertain, complex and ambiguous world that forces us to open our minds and be prepared to change with agility the products and services that our companies offer. An HR professional can modelize the employee value proposition through intelligent rewarding systems

Originality/value

This paper presents innovative ideas to manage the human resources strategy through reward systems. This scheme represents a new paradigm of human resources management to lead the current business challenges through people.
Evaluating potential transformational leaders: weighing charisma vs. credibility
Authors: Raffo Deana , Williams Ralph
Published: December 2018

Purpose

The purpose of this paper is to explore credibility, as an alternative to charisma, as an important attribute of transformational and authentic leadership. 10;

Design/methodology/approach

This is a conceptual paper. From leadership literature, we discuss transformational leadership, authentic leadership, charisma, and credibility. The literature on leadership and credibility is limited, yet we provide relevant examples.

Findings

The authors conclude that credibility, rather than charisma, provides a more accessible and ethical framework to capture the essence of transformational and authentic leadership. Yet, charisma may enhance leadership. Practical recommendations are provided related to charisma and credibility.

Practical implications

Practical recommendations are given to help leaders think about charisma differently and consider credibility as a core attribute to embrace in leading others. 10; 10;

Originality/value

The literature on credibility and leadership is limited, but this topic is frequently discussed in business, politics, religion, media, etc.
S‐wave splitting intensity analysis and inversion
Authors: Boiero Daniele , Bagaini Claudio
Published: December 2018

Analysing S‐wave splitting has become a routine step in processing multicomponent data. Typically, this analysis leads to determining the principal directions of a transversely isotropic medium with a horizontal symmetry axis, which is assumed to be responsible for azimuthal anisotropy, and to the time delays between the fast and slow S‐waves. These parameters are commonly estimated layer‐by‐layer from the top. Errors in layer stripping occurring in shallow layers might propagate to deeper layers.

We propose a method for S‐wave splitting analysis and compensation that consists of inverting interval values of splitting intensity to obtain a model of anisotropic parameters that vary with time and/or depth. Splitting intensity is a robust attribute with respect to structural variations and is commutative, which means that it can be summed along a ray (or throughout a sensitivity kernel volume) and can be linearly related to anisotropic perturbations at depth. Therefore, it is possible to estimate anisotropic properties within a geological formation (e.g. the reservoir) by analysing the differences of splitting intensity measured at the top and at the bottom of the layer. This allows us to avoid layer stripping, in particular, for shallow layers where anisotropic parameters are difficult to estimate due to poor coverage, and it makes S‐wave splitting analysis simpler to apply. We demonstrate this method on synthetic and real data.

Because the splitting intensity attribute shows usefulness in S‐wave splitting analysis in transversely isotropic media, we extend the splitting intensity theory to lower symmetry classes. It enables the characterization of tilted transversely isotropic and tilted orthorhombic media, opening new opportunities for anisotropic model building.
‘What's cooking?’ A comparison of an activity‐oriented and a table‐top programme of therapy on the language performance of people with aphasia
Authors: Bruce Carolyn , Newton Caroline
Published: December 2018

Background

Many people with aphasia have word‐finding difficulties, with some showing particular difficulties with verbs. Picture‐naming therapy is often used to improve naming, but gains are usually limited to therapy items and do not transfer to conversation. Therapy where words are produced in sentences and in real‐life activities may be more effective.

Aims

The current pilot study investigated whether an activity‐oriented therapy approach would be accepted and viable if implemented in a community setting, and whether communicating whilst cooking was more beneficial than using paper‐based activities. If successful, it would be expected that verb production would improve in structured and unstructured tasks in both naming and narrative tasks.

Methods & Procedures

The study employed a case‐series repeated‐measures design, with testing of treated and control items. Seven adults with anomia participated, although only five completed the full programme. Participants were divided into two groups and each group completed both treatments, but in different orders. Each treatment was employed for six 2‐h sessions over a 3‐week period.

Outcomes & Results

Naming of both treated and untreated verbs showed a statistically significant improvement following both treatments and this continued into the maintenance phase. There was a numerical but not statistically significant gain in the variety of verbs used in spoken narratives. Participants predominantly chose positive terms to describe their experience of the programme, but did not prefer one therapy over the other.

Conclusions & Implications

Preliminary findings suggest that an activity‐oriented therapy approach, whether it involves carrying out tasks or paper‐based activities, can result in clinically meaningful improvements for people with chronic aphasia. Further research using a randomized control trial is required to determine whether cooking therapy alone is effective.
Viral transmission in honey bees and native bees, supported by a global black queen cell virus phylogeny
Authors: Murray Elizabeth A. , Burand John , Trikoz Natalia , Schnabel Julia , Grab Heather , Danforth Bryan N.
Published: December 2018

In recent decades, we have realized that honey bee viruses are not, in fact, exclusive to honey bees. The potential impact of Apis‐affiliated viruses on native pollinators is prompting concern. Our research addresses the issue of virus crossover between honey bees and native bees foraging in the same localities. We measured the presence of black queen cell virus (BQCV), deformed wing virus (DWV) and sacbrood virus (SBV) in managed Apis mellifera (honey bees) and native Andrena spp. (subgenus Melandrena) bee populations in five commercial orchards. We identified viral presence across sites and bees and related these data to measures of bee community diversity. All viruses were found in both managed and native bees, and BQCV was the most common virus in each. To establish evidence for viral crossover between taxa, we undertook an additional examination of BQCV where 74 samples were sequenced and placed in a global phylogenic framework of hundreds of BQCV strains. We demonstrate pathogen sharing across managed honey bees and distantly related wild bees. This phylogenetic analysis contributes to growing evidence for host switching and places local incidence patterns in a worldwide context, revealing multispecies viral transmission.
Reading engagement and reading literacy performance: effective policy and practices at home and in school
Authors: Ho Esther Sui Chu , Lau Kit‐ling
Published: December 2018

Based on the data of Program for International Student Assessment 2009, this paper examines how various aspects of home literacy environment, school climate and students' reading engagement related to their reading performance. A profile of Hong Kong students' three indices of reading engagement – namely, reading enjoyment, reading diversity and online reading – relative to other East Asian societies is first presented. The relative contributions of different family‐level and classroom‐level factors on Hong Kong students' reading engagement are then examined by using hierarchical linear modelling. Assessment of the relative impact of the three engagement indices on reading performance shows that reading enjoyment is the strongest predictor. That home‐school cooperation in cultivating a positive reading climate, nurturing a good reading habit for all students and enhancing the classroom and teaching climate appear to be promising avenues for improving students' reading engagement and performance may be of importance for shaping future policy and practice.
What really matters: The role of behavioural engagement in multiple document literacy tasks
Authors: Bråten Ivar , Brante Eva W. , Strømsø Helge I.
Published: December 2018

One‐hundred and twenty‐seven Norwegian upper‐secondary school students completing college preparatory courses (41% female) were asked to select the texts they wanted to use in order to write a letter to the editor about a socio‐scientific topic, with 60 students assigned the topic of climate change and 67 students assigned the topic of nuclear power. Afterwards, they were asked to justify their text selections, read the selected texts and write their letters to the editor. Across both topics, hierarchical multiple regression analyses showed that students' behavioural engagement in the selection, justification, reading and writing tasks contributed to their performance over and above their reading comprehension, topic knowledge and topic interest. Specifically, behavioural engagement in the selection and justification tasks improved the prediction of their content‐based and source‐feature based justifications for text selection, and behavioural engagement in the reading and writing tasks improved the prediction of the content coverage and content integration observed in their written products, with large effect sizes obtained for behavioural engagement across the two topics. The theoretical and educational significance of the study is discussed and directions for future research are suggested.
Manure and adoption of modern seeds in cereal‐based systems in West African drylands: linkages and (non)complementarities
Authors: Kpadonou Rivaldo A. B. , Barbier Bruno , Owiyo Tom , Denton Fatima , Rutabingwa Franck
Published: December 2018

Using a stepwise approach that combines several econometric methods, we assessed whether or not the adoption of modern seeds and the use of manure in cereal‐based systems are linked and, if so, what are the driving forces of the linkages between these two agricultural technologies under dry‐climate conditions in West Africa. We found complementary and substitutability linkages arising from jointness and endogeneity between the two technologies. Specifically, our findings reveal positive joint determination along with negative endogeneity between the two technologies indicating that, controlling for observable variables, both technologies are positively linked, but unobserved factors that affect one adoption decision are negatively correlated with the other. After controlling for jointness and endogeneity, we found significant complementarity linkages showing a significant positive effect of manure use on the adoption of modern seeds, which is also significantly and positively affected by the number of cash crops grown and remittances. The two technologies are reversely affected by schooling and the incidence of soil fertility problems within the farm, whereas the amount of healthy land has a positive effect on both. The study suggests that organic fertilizer can serve as an enabling factor for greater adoption of modern seeds, especially in less favourable climate areas, and strongly supports the argument behind the need to breed seeds suitable for the use of organic fertilizers. These findings provide avenues for re‐orientation of policies that promote the use of modern seeds in dryland areas in sub‐Saharan Africa, with a possibility of breeding and promoting them in packages with organic fertilizers to upscale their adoption.
Bouveret's Syndrome: A rare cause of gastric outlet obstruction
Authors: Sheung Robin Lok‐Man , Lam Dennis Chin‐Tou , Leung David Kai‐Wing
Published: December 2018

Bouveret's Syndrome is a rare cause of gastric outlet obstruction secondary to the impaction of a gallstone within a cholecystogastric or cholecystoduodenal fistula. It is a rare variant of gallstone ileus. Prompt diagnosis, appropriate investigations and proper treatment are essential. The aim of the present case report was to review the currently‐available literature regarding Bouveret's syndrome management approach and to share our experience. A 69‐year‐old man presented to our surgical unit with a 1‐week history of upper gastrointestinal bleeding and gastric outlet obstruction symptoms. The diagnosis of Bouveret's Syndrome was confirmed with computed tomography. He subsequently underwent a one‐stage open partial gastrectomy and cholecystectomy with Roux‐en‐Y anastomosis and controlled duodenostomy. Postoperative recovery was uneventful and the patient was discharged on postoperative day 11. With the current paucity of high‐level evidence regarding the management approach for Bouveret's syndrome, the gold standard management algorithm is yet to be developed. The management approach should be tailored, with an appropriate choice of treatment based on the patient's clinical presentation and comorbidities and the expertise available. Surgical approach should be considered if endoscopic treatment is not feasible or has failed.
MYD88 L265P mutations identify a prognostic gene expression signature and a pathway for targeted inhibition in CLL
Authors: Improgo Ma. Reina , Tesar Bethany , Klitgaard Josephine L. , Magori‐Cohen Reuma , Yu Lijian , Kasar Siddha , Chaudhary Divya , Miao Wenyan , Fernandes Stacey M. , Hoang Kevin , Westlin William F. , Kim Haesook T. , Brown Jennifer R.
Published: December 2018

The L265P somatic mutation in the Myeloid Differentiation Primary Response 88 (MYD88) gene is a recurrent mutation in chronic lymphocytic leukaemia (CLL). This mutation has functional effects in various haematological malignancies but its role in CLL remains to be fully elucidated. Here, we report that MYD88 L265P mutations are associated with mutated immunoglobulin heavy‐chain gene (IGHV‐M) status and that among IGHV‐M patients, the presence of MYD88 L265P is associated with younger age at diagnosis. Using microarray and RNA‐Seq gene expression analysis, we further observe that the MYD88 L265P mutation is associated with a distinctive gene expression signature that predicts both failure‐free survival and overall survival. This association was validated in an independent cohort of patients. To determine whether MYD88 L265P mutations can be therapeutically exploited in CLL, we treated primary cells with an inhibitor of interleukin 1 receptor‐associated kinase 4 (IRAK4), a critical effector of the MYD88 pathway. IRAK4 inhibition decreased downstream nuclear factor‐κB signalling and cell viability in CLL cells, indicating the potential of the MYD88 pathway as a therapeutic target in CLL.
PML/RARA inhibits expression of HSP90 and its target AKT
Authors: Piredda Maria Liliana , Gaur Girish , Catalano Gianfranco , Divona Mariadomenica , Banella Cristina , Travaglini Serena , Puzzangara Maria Carmen , Voso Maria Teresa , Lo‐Coco Francesco , Noguera Nelida Ines
Published: December 2018

Essential for cell survival, the 90 kD Heat Shock Proteins (HSP90) are molecular chaperons required for conformational stabilization and trafficking of numerous client proteins. Functional HSP90 is required for the stability of AKT, a serine‐threonine kinase phosphorylated in response to growth factor stimulation. AKT plays a crucial regulatory role in differentiation, cell cycle, transcription, translation, metabolism and apoptosis. Acute promyelocytic leukaemia (APL) is characterized by the presence of the promyelocytic leukaemia/retinoic acid receptor alpha (PML/RARA) fusion protein, which deregulates expression of several genes involved in differentiation and apoptosis. Here, we report inhibition of HSP90AA1 and HSP90AB1 isomer transcription in blasts isolated from patients with APL, associated with reduction of HSP90 protein expression and loss of control on AKT protein phosphorylation. We show that in vitro treatment of PML/RARA expressing cells with all‐trans retinoic acid (ATRA) up‐regulates HSP90 expression and stabilizes AKT. Addition of the HSP90‐inhibitor 17‐(allylamino)‐17‐demethoxygeldanamycin in combination with ATRA, blocks upregulation of AKT protein, indicating that HSP90 is necessary for ATRA action on AKT. This is the first report proving that expression of HSP90 isomers are directly and differentially repressed by PML/RARA, with critical results on cellular homeostasis of target proteins, such as AKT, in APL blasts.
Simvastatin and the Rho‐kinase inhibitor Y‐27632 prevent myofibroblast transformation in Peyronie's disease‐derived fibroblasts via inhibition of YAP/TAZ nuclear translocation
Authors: Milenkovic Uros , Ilg Marcus M. , Zuccato Carola , Ramazani Yasaman , De Ridder Dirk , Albersen Maarten
Published: December 2018

Objectives

To uncover the anti‐myofibroblast (MFB) properties of Rho‐kinase inhibitor (compound Y‐27632) and simvastatin in an in vitro model of Peyronie's disease (PD), a sexually debilitating disease caused by an irreversible fibrotic plaque in the penile tunica albuginea (TA).

Materials and Methods

Primary human fibroblasts (FBs) were isolated from surgically obtained TA tissue from patients with PD. To induce MFB status, cells were stimulated with 3 ng/mL transforming growth factor‐β1 (TGF‐β1). Increasing doses of Y‐27632 and simvastatin were added. Real‐time quantitative PCR was used to assess mRNA expression of α‐smooth muscle actin (α‐SMA), collagen III, elastin and connective tissue growth factor (CTGF) after 72 h. Western blot analysis was used to quantify α‐SMA protein contents, and immunofluorescence (IF) was used to visualize MFB differentiation by staining for α‐SMA after 72 h. A resazurin‐based assay was used to assess cell viability to ensure the anti‐MFB effect of the drugs. A mechanistic study was performed using IF staining for YAP/TAZ nuclear translocation.

Results

After 72 h of stimulation with TGF‐β1, a six‐ to 10‐fold upregulation of α‐SMA could be observed. When treated with Y‐27632 or simvastatin, the α‐SMA, collagen III, elastin and CTGF mRNA expression was impeded. Additionally, TGF‐β1 stimulation showed a twofold increase in α‐SMA protein expression, which was reversed to non‐stimulated levels after treatment with Y‐27632 and simvastatin. Using IF, stimulated cells were identified as MFB (α‐SMA+, Vim+) as opposed to the non‐stimulated, Y‐27632‐ and simvastatin‐treated cells (α‐SMA−, Vim+). The resazurin‐based assay confirmed that the cell viability was not compromised by the administered drugs. On stimulation with TGF‐β1, nuclear translocation of YAP/TAZ could be observed, which was prevented by adding the aforementioned compounds.

Conclusion

Transformation of FBs into the contractile and extracellular matrix‐producing MFBs occurs after TGF‐β1 stimulation. In our experiments, Rho‐kinase inhibition and simvastatin treatment were shown to prevent this in TGF‐β1‐stimulated cells on an RNA and protein level through the inhibition of YAP/TAZ nuclear translocation. Y‐27632 and simvastatin could become a novel treatment option in the early treatment of PD.
Sine oculis homeobox 1 promotes proliferation and migration of human colorectal cancer cells through activation of Wnt/β‐catenin signaling
Authors: Song Wenxin , Ma Jian , Lei Bingbing , Yuan Xin , Cheng Binfeng , Yang Haijie , Wang Mian , Feng Zhiwei , Wang Lei
Published: December 2018

Sine oculis homeobox 1 (Six1) is a homeodomain transcription factor that is aberrantly expressed in a variety of human cancers, including colorectal cancer (CRC). Six1 has been reported to play a key role in the proliferation and migration of CRC cells but the underlying molecular mechanisms are still poorly characterized. In the present study, we found that Six1 overexpression promoted the proliferation and migration of CRC cells. Consistently, Six1 knockdown (KD) significantly inhibited proliferation and migration of CRC cells. In addition, we showed that Six1 promoted proliferation and migration of CRC cells through activation of Wnt/β‐catenin signaling, as evidenced by promotion of nuclear localization of β‐catenin. Silencing of β‐catenin expression with siRNA or inhibiting Wnt signaling with a specific inhibitor, xav939, significantly blocked Six1‐induced nuclear localization of β‐catenin and mitigated Six1‐promoted proliferation and migration of CRC cells. We further confirmed the involvement of β‐catenin in Six1‐promoted proliferation and migration of CRC cells by activation of Wnt signaling with lithium chloride (LiCl) in Six1 KD CRC cells and results showed that LiCl restores defective β‐catenin nuclear localization and proliferation and migration of CRC cells. Taken together, these results suggest that Six1 homeoprotein promotes the proliferation and migration of CRC cells by activating the Wnt/β‐catenin signaling pathway, and strategies targeting Six1 may be promising for the treatment of CRC.
Anti‐tumor effects of mAb against l‐type amino acid transporter 1 (LAT1) bound to human and monkey LAT1 with dual avidity modes
Authors: Ueda Shiho , Hayashi Hidemi , Miyamoto Takako , Abe Shinya , Hirai Kana , Matsukura Kanji , Yagi Hideki , Hara Yuta , Yoshida Kinji , Okazaki Shogo , Tamura Masakazu , Abe Yuki , Agatsuma Toshinori , Niwa Shin‐ichiro , Masuko Kazue , Masuko Takashi
Published: December 2018

l‐Type amino acid transporter 1 (LAT1) disulfide linked to CD98 heavy chain (hc) is highly expressed in most cancer cells, but weakly expressed in normal cells. In the present study, we developed novel anti‐LAT1 mAbs and showed internalization activity, inhibitory effects of amino acid uptake and cell growth and antibody‐dependent cellular cytotoxicity, as well as in vivo antitumor effects in athymic mice. Furthermore, we examined the reactivity of mAbs with LAT1 of Macaca fascicularis to evaluate possible side‐effects of antihuman LAT1 mAbs in clinical trials. Antihuman LAT1 mAbs reacted with ACHN human and MK.P3 macaca kidney‐derived cells, and this reactivity was significantly decreased by siRNAs against LAT1. Macaca LAT1 cDNA was cloned from MK.P3, and only two amino acid differences between human and macaca LAT1 were seen. RH7777 rat hepatoma and HEK293 human embryonic kidney cells expressing macaca LAT1 were established as stable transfectants, and antihuman LAT1 mAbs were equivalently reactive against transfectants expressing human or macaca LAT1. Dual (high and low) avidity modes were detected in transfectants expressing macaca LAT1, MK.P3, ACHN and HCT116 human colon cancer cells, and KA values were increased by anti‐CD98hc mAb, suggesting anti‐LAT1 mAbs detect an epitope on LAT1‐CD98hc complexes on the cell surface. Based on these results, LAT1 may be a promising anticancer target and Macaca fascicularis can be used in preclinical studies with antihuman LAT1 mAbs.
Serum cotinine, vitamin D exposure levels and dental caries experience in U.S. adolescents
Authors: Akinkugbe Aderonke A. , Moreno Oswaldo , Brickhouse Tegwyn H.
Published: December 2018

Introduction

Epidemiologic studies of risk and protective factors for poor oral health have mostly been among children and adults, seldom focusing on adolescents. The aims of this study were to examine whether serum cotinine, a marker of tobacco exposure, and serum vitamin D are independently associated with dental caries experience among adolescents.

Methods

Cross‐sectional data from 2579 adolescent participants in the 2005‐2008 National Health and Nutritional Examination Survey were analysed. The exposures, cotinine and vitamin D, were measured in serum while dental caries experience was determined by screening examination, and a case defined as having ≥1 decayed or filled teeth. Survey‐adjusted logistic regression estimated prevalence odds ratios (POR) and 95% confidence intervals (CI) between the respective exposures and outcome.

Results

The overall median (IQR) serum cotinine level was 0.15 ng/mL (0.04, 1.80) while the mean (SE) serum vitamin D concentration was 68.2 nmol/L (1.36). In contrast to participants with serum cotinine ≤3 ng/L, those with levels >3 ng/L had covariate‐adjusted estimate of 1.69 (1.16, 2.47) for caries experience. Each additional mean (ng/L) serum cotinine level was associated with an 8% (95% CI = 1.01, 1.16) greater adjusted prevalence odds of having caries experience. In contrast to participants with vitamin D ≥ 50 nmol/L, those with levels of30‐ < 50 nmol/L and <30 nmol/L had non‐statistically significant adjusted estimates of 1.02 (0.72, 1.44) and 1.23 (0.70, 2.16) respectively for caries experience.

Conclusions

Serum cotinine is associated with dental caries experience among adolescents and while deficient (<30 nmol/L) levels of vitamin D appear to be associated with greater prevalence odds of caries experience, this association is inconclusive.
Encouraging trends in the prevalence of cerebral palsy: available to all?
Authors: Durkin Maureen S
Published: December 2018

This commentary is on the original article by Galea et al. on pages 186–193 of this issue.
How representative of a general type 2 diabetes population are patients included in cardiovascular outcome trials with SGLT2 inhibitors? A large European observational study
Authors: Birkeland Kåre I. , Bodegard Johan , Norhammar Anna , Kuiper Josephina G. , Georgiado Elena , Beekman‐Hendriks Wendy L. , Thuresson Marcus , Pignot Marc , Herings Ron M. C. , Kooy Adriaan
Published: December 2018

Aims

Enrollment criteria vary substantially among cardiovascular outcome trials (CVOTs) of sodium‐glucose cotransporter‐2 inhibitors (SGLT‐2is), which impacts the relationship between a trial population and the general type 2 diabetes (T2D) population. The aim of this study was to evaluate the representativeness of four SGLT‐2i CVOTs of a general T2D population.

Methods

T2D patients from Germany, The Netherlands, Norway and Sweden were included in the study. Given the available data per country, key inclusion and exclusion criteria were defined by diagnoses, procedures and drug treatments to facilitate comparability among countries. Representativeness was determined by dividing the number of patients fulfilling the key enrolment criteria of each CVOT (CANVAS, DECLARE‐TIMI 58, EMPA‐REG OUTCOME, VERTIS‐CV) by the total T2D population.

Results

In 2015, a total T2D population of 803 836 patients was identified in Germany (n = 239 485), in The Netherlands (n = 36 213), in Norway (n = 149 782) and in Sweden (n = 378 356). These populations showed a 25% to 44% cardiovascular (CV) disease baseline prevalence and high CV‐preventive drug use (>80%). The general T2D population had less prevalent CV disease and patients were slightly older than those included in the CVOTs. The DECLARE‐TIMI 58 trial had the highest representativeness, 59% compared to the general T2D population, and this representativeness was almost 2‐, 3‐ and 4‐fold higher compared to the CANVAS (34%), EMPA‐REG OUTCOME (21%) and VERTIS‐CV (17%) trials, respectively.

Conclusions

In large T2D populations within Europe, consistent patterns of representativeness of CVOTs were found when applying the main enrolment criteria. The DECLARE‐TMI 58 trial had the highest representativeness, indicating that it included and examined patients who are most representative of the general T2D patients in the studied countries.
The effects of incretin‐based therapies on β‐cell function and insulin resistance in type 2 diabetes: A systematic review and network meta‐analysis combining 360 trials
Authors: Wu Shanshan , Gao Le , Cipriani Andrea , Huang Yi , Yang Zhirong , Yang Jun , Yu Shuqing , Zhang Yuan , Chai Sanbao , Zhang Zilu , Sun Feng , Zhan Siyan
Published: December 2018

Aim

To evaluate the comparative effects of incretin‐based therapies, including glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) and dipeptidyl peptidase‐4 inhibitors (DPP‐4Is), on β‐cell function and insulin resistance in patients with type 2 diabetes mellitus (T2DM).

Materials and Methods

Medline, Embase, the Cochrane Library and www.clinicaltrials.gov were searched for randomized controlled trials (RCTs) with a duration of at least 4 weeks. Network meta‐analysis was performed, followed by subgroup analysis and meta‐regression. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to assess the quality of evidence. Outcomes of interest include homeostasis model assessment for β cell function (HOMA‐β) and insulin resistance (HOMA‐IR), fasting C‐peptide and fasting plasma glucose (FPG). Weighted mean difference (WMD) with 95% confidence interval (CI) was calculated as the measure of effect size.

Results

A total of 360 RCTs (74% at least double‐blinded) with 157 696 patients were included. Incretin‐based therapies were compared with six other classes of glucose‐lowering drugs or with placebo. Compared with placebo, a significant increase in HOMA‐β and fasting C‐peptide was detected for GLP‐1RAs (WMD = 20.31 [95% CI, 16.34‐24.39] with low quality; WMD = 0.16 ng/mL [95% CI, 0.03‐0.29] with low quality) and for DPP‐4Is (WMD = 9.90 [95% CI, 8.27‐11.61] with moderate quality; WMD = 0.09 ng/mL [95% CI, 0.04‐0.14] with moderate quality) separately, while a significant reduction in HOMA‐IR and FPG were found in favour of GLP‐1RAs (WMD = −0.67 [95% CI, −1.08 to −0.27] with low quality; WMD = −1.04 mmol/L [95% CI, −1.26 to −0.83] with moderate quality) and DPP‐4Is (WMD = −0.23 [95% CI, −0.38 to −0.08] with low quality; WMD = −0.77 mmol/L [95% CI, −0.98 to −0.57] with moderate quality), respectively.

Conclusions

Incretin‐based therapies not only show an increase in HOMA‐β and fasting C‐peptide level, but also achieve a reduction in HOMA‐IR and FPG in comparison with placebo. Although GRADE scores indicate low to moderate for most comparisons, incretin‐based therapies seem to be an advisable option for long‐term treatment to preserve β‐cell function.