bluuebunny/crossref_metadata_2025 huggingface dataset:
Remote usability evaluation
Authors: Millen David R.
Published: May 2014

A case study is presented in which remote usability evaluation methods were used in the development of a new Internet service. The new service provided access to email using a standard web browser. User session logs, which included keystroke level event records, were examined for approximately 600 of the service trial users. This allowed temporal and activity analysis of user behavior, as well as the detection of general session usage patterns. In addition to keystroke level data, feedback about the service was collected using a public discussion forum. The user feedback messages were coded and analyzed to confirm important service benefits, and to identify and understand potential service enhancements. The trial feedback, taken collectively, suggests important attributes that both prevent and invite user adoption of a new email client application.
Collaborative and co-operative information seeking
Authors: Churchill Elizabeth F. , Sullivan Joseph W. , Golovchinsky Gene , Snowdon Dave
Published: May 2014

Collaborative and cooperative aspects of information storage, seeking and retrieval have become a hot topic in recent years e.g. [1,2,4]. The acknowledgement that information seeking is a collaborative activity is part of a trend toward foregrounding the social in system design [5].The goal of this workshop was to discuss current conceptions of collaborative and cooperative information seeking activities, and to identify future research issues in the design and use of digital information spaces and information seeking tools. Our starting point was that information seeking is much more than the transmission of information from a system to a solitary user on the basis of queries issued by that user. Therefore, models of information seeking that underpin system design must move away from thinking of information seeking as single-user problem solving. Rather, such models need to explicitly address social aspects of information seeking activities.
Cross-organisational workflow management and co-ordination
Authors: Ludwig Heiko , Shan Ming-Chien , Bussler Christoph , Grefen Paul
Published: May 2014

The increasing deployment of Workflow Management Systems (WfMSs) and other co-ordination and process support systems on the one hand and the proliferation of cheap networking, namely the Internet, on the other hand raises the issue of how to connect these systems across organisational boundaries. Current WfMSs do not provide suitable means for cross-organisational connections. The workshop "Cross-Organizational Workflow Management and Co-ordination" at the International Joint Conference on Work Activities Coordination and Collaboration, San Francisco, February 22 - 25, 1999 provided a forum to discuss workflow management and co-ordination in situations in which processes span multiple independent organisations. The workshop helped the ca. 30 participants understand the key problems and clarified ways in which existing products and prototypes as well as current projects contribute to enable cross-organisational workflow execution.
Community development in the information society
Authors: Day Peter
Published: May 2014

Harnessing information communication technologies (ICT) for economic development and sustainability in the information society is currently the focus of much academic and policy debate within the European Union. The doctoral research project, University of Brighton, from which this paper is drawn contributes to this paradigmatic discourse by critically analysing current information society policies at both macro and micro levels, investigating a range of European community ICT initiatives and promoting an alternative, more inclusive approach to policy development and implementation in the information society.The research suggests that the techno-economic model of information society development exacerbates rather than addresses social exclusion. This paper outlines how a more democratic and inclusive approach to the information society is emerging through community networks. In this context the needs and aspirations of local communities form the focus of debate. This contrasts dramatically with the Tele- or Digital City approach of EC policy makers, where people appear to be viewed as little more than passive consumers of the vast array of services and products currently bombarding the global market-place.
Community enterprise networks
Authors: Gurstein Michael
Published: May 2014

A Community Enterprise Network (CEN) is an alliance of many stakeholders, including Community Access sites, libraries, schools, municipalities, local businesses and other interested groups. Public access Internet sites are not likely to stimulate significant economic activity as isolated units. However, when these nodes come together to form a CEN, they form both a distribution network for the delivery of government, educational and corporate services (e.g., Job Banks, Health information, Internet banking, Distance Education, Telework), and a flexible network for matching and coordinating available resources to specific production contracts. Such a coordinated network would enable types of work and jobs now limited to urban areas to be decentralized to rural areas, and would enable a higher quality of delivery of services at lower cost than present distribution systems. Activities of these CENs need not be limited to Information and Communications Technology (ICT) products and services. ICT could also be used as an "enabling technology" to facilitate decentralized, distributed production, management, and the marketing and distribution of a wide variety of goods and services. In addition, on-line library services could be made accessible from any node in the network.
Lots of data, lots of evaluation—lots of findings?
Authors: Ovaska Saila
Published: May 2014

I describe experiences from three separate groupware evaluation projects in which I have participated. The three cases cover the areas of face-to-face planning with a simple shared editor, developing and using an organizational memory based on Lotus Notes, and student group learning with Web-based discussion forums. The case studies all share richness and wealth of data collection, but the generalizable findings from each study are still few.
Nested effects testing
Authors: Andriessen J. H. Erik
Published: May 2014

Testing the extent to which the human interface of software is 'usable' for the individual user knows a well-developed methodology (see e.g. [6]). However there are many more issues that determine the value of CSCW systems. Among these issues are whether the system improves access to information and Supports interpersonal communicative behaviour and co-operation, whether it contributes to group member's purposes and to the organisation's objectives. Assessment of side effects, related to e.g. quality of work, privacy or power(re)distribution is also relevant. An adequate evaluation approach should include these issues in a comprehensive approach. We developed such an approach, the 'Nested Effects Testing-approach', developed in a European Union sponsored project (MEGATAQ 1), called Methods and Guidelines for the Assessment of Telematics Applications Quality (MEGATAQ) contains a framework aimed at covering most of these aspects. The approach It is based on a combination of various theoretical approaches, stemming from four research traditions [1 ]:• human-computer-interaction,• communication theory,• group dynamics• organisational effectivenessThe techniques focus on the user-centred aspects of evaluation, including interface usability, human communicative behaviour, collaborative work, and teamwork within the social context.Many of these theories adhere to one of two basic perspectives on the effectiveness of CSCW systems, i.e. the 'media match' perspective (technical systems have to fit the task and the context) or the 'adaptation' perspective (users adapt the system, the context and themselves to each other [see e.g. 3, 4, 5].The objective of MEGATAQ is to provide so called Telematics Applications Projects with guidelines and techniques for effective evaluation. These techniques can be used when TA Project consortia are developing and validating Telematics Applications. The techniques focus on the user-centred aspects of evaluation, including interface usability, human communicative behaviour, collaborative work, and teamwork within the social context.
Collaborative environments as border agents
Authors: Young Eunice R.
Published: May 2014

What information do entities within an enterprise need to share in order to be considered collaborating? How do those entities make decisions? Is this process one that can be captured and implemented in software or stored for future learning? These questions are typical of those asked at the onset of process modeling or for gathering user requirements, but recent work at the US/Mexico border to understand import/export procedures cast them in a new framework. A more critical question may be how does an organization, as typified by their culture, perceive and therefore manage technology?Cultural differences in software development are not always as easily perceived as those at an international border, yet they are just as strong. On one hand, there are "code jocks" that feel that developing software is intensely personal and should not be constrained by a pre-defined process. On the other, "process weenies" that test and accept software for corporate use and wish for order and consistency in how we develop our products. Who is right? They both are. A challenge to collaborative environments is managing the expectations of both.
Conventions and articulation work in a mobile workplace
Authors: Christensen Ulrik
Published: May 2014

My research interest is in the role of information technology in cooperative systems. My work is grounded in ethnomethodologically informed observation-based workplace studies focussing on procedures, conventions and coordinative artefacts. Recently I have started investigating work settings characterized by a high degree of mobility. This work is part of the project "Developing a Research Methodology for Studying Mobile IT Usage and Person Mobility", that I work on with Gloria Mark.
Designing for mobility, collaboration and information use by blue-collar workers
Authors: Brodie Jacqueline , Perry Mark
Published: May 2014

The uptake of mobile phones in the UK has increased exponentially in the past two years, indicating that a wider range of users are now utilising mobile technologies in different contexts than ever before. Still little is known about how mobile technologies are used amongst different populations in specific contexts and this research addresses the context of work use by blue-collar workers with an aim to augmenting this with new mobile technologies better suited to their informational and communicative needs.Most of the current public domain research into mobile device use practice concentrates primarily on professional workers (the ubiquitous 'mobile professional') and 'knowledge workers' (e.g. Bellotti and Bly, 1996; O'Hara
et al.
2001). It seeks to discover how mobile technology, particularly Personal Digital Assistants (PDA's) and 'communicators', can be designed to help mobile professionals retain a sense of awareness of their workplace and work colleagues while they are away from their traditional workplaces. To a lesser extent, 'teens' (Ling, 2000) using SMS/text messaging and novice users (e.g. Palen, 2000) are also examined, but there is very little understanding of the nature of other, and equally as important (in terms of the numbers of users and their importance to the economy), less well represented user groups.
Place, media and activity
Authors: Chalmers Matthew
Published: May 2014

The workshop's call for participation points out the changes in work and society related to the development of new technologies, forms of work and patterns of activity. The traditional notion of workplace is challenged by the convergence and intercommunication of technological devices, as are our approaches to design and theory. I'd like to argue that this is only problematic because the traditional view is rather reductionist and simplistic. I'd like to explore a different notion of what place is, and hence workplace. This builds on and extends the discussion of space and place in CSCW by Harrison and Dourish, taking an approach based on post-structuralist semiology that takes fuller account of the interdependence of media in human activity than older HCI and CSCW People's activity continually combines and cuts across different media, interweaving those media and building up the patterns of association and use that make meaning. How people act and work is determined by the full combination of media that they can use, and hence a narrow focus on space as the paramount determinant of activity underrates the influence of other media. 'Place' is not solely determined by the physical medium of space. A person's work or activity may be influenced by the configuration of space around them and the interactions that space affords, but also by books, telephones, hypermedia, 3D computer graphics and so forth. Recent technological developments heighten or highlight a phenomenon already familiar through analysis of the effect of older media such as written text, maps and cinema. This stance is now being explored in the
city
project, which focuses on a treatment of the city that deliberately blurs the boundaries between physical and digital spaces. By combining mobile computers, hypermedia and virtual environments in one system, and allowing each person using each medium or combination of media to interact with people using every other medium, our system is both driven by our theoretical approach and driving the development of theory.
Exception handling with workflow evolution in ADOME-WFMS
Authors: Chiu Dickson K. W. , Li Qing , Karlapalem Kamalakar
Published: May 2014

Handling in workflow management systems (WFMSs) is very important since it is not possible to specify all possible outcomes and alternatives beforehand. In this regard, we have been developing ADOME-WFMS to address the problem of workflow exception handling. ADOME is an active OODBMS extended with role facilities for supporting the dynamic features required for online exception handling. Our WFMS features advanced modeling, integrated environment, and effective coordination of human resources [1].
Groupware related task design
Authors: Wolf Martin
Published: May 2014

This report summarizes the results of a workshop on
Groupware related task design
which took place at the International Conference on Supporting Group Work Group'99, Arizona, from 14
th
to 17
th
November 1999.The workshop was addressed to people from different viewpoints, backgrounds, and domains:• Researchers dealing with questions of task analysis and task modeling for Groupware application from an academic point of view. They may contribute model-based design approaches or theoretically oriented work• Practitioners with experience in the design and everyday use of groupware systems. They might refer to the practical side of the topic: "real" tasks, "real" problems, "real" users, etc.
Interactive environment by narrative playmates toys
Authors: Kanjo Eiman , Astheimer Peter
Published: May 2014

Narration is an important part of play. Toys inspire children to imagine stories. Adding the power of the computer to toys environment can make playing time more cognitive as well as more entertaining. This paper describes our work in developing physical human-computer interface, which merges ordinary children's playsets with computer that can see via a webcam in order to enhance children's playing technique. The proposed interface with the tracking technology and narrative control can turn a normal child's playset into a fantasyland where children can sense of their world in ways that were not feasible up to date.
Web of communities and individuals
Authors: Tomek Ivan
Published: May 2014

We postulate that computing environments supporting formal and informal user communities should be based on a universal foundation - a combination of a common metaphor, common architecture, and common protocols. We outline our view of the nature of these three parameters and hypothesize that universal community support based on these principles will make possible effective deployment of interoperable applications supporting dynamic user communities on a much larger scale than is currently the case.
The active lurker
Authors: Takahashi Masamichi , Fujimoto Masakazu , Yamasaki Nobuhiro
Published: May 2014

In this study, we focus on participants called lurkers, who do not post any messages in an online community such as interactive mailing lists and bulletin board systems. We propose a method of classifying participants including lurkers based on two criteria: what types of actions they take outside the online community, and whether or not the online community affects their thoughts. We conduct a questionnaire survey of all participants in two in-house online communities to verify our method. There are a considerable number of lurkers who have a strong and wide influence outside the online community. We conclude that such lurkers cannot be neglected in an evaluation of online communities within a company. These results could also lead us to discuss a possibility of an online community management by focusing on not only posters but also lurkers who are indirect contributors to increasing the influence of an online community on its outside environment.
Chemoprevention in Gastrointestinal Physiology and Disease. Natural products and microbiome
Authors: Greiner Allen K. , Papineni Rao V. L. , Umar Shahid
Published: May 2014

The human intestinal tract harbors a complex ecosystem of commensal bacteria that play a fundamental role in the well-being of their host. There is a general consensus that diet rich in plant-based foods has many advantages in relation to the health and well-being of an individual. In adults, diets that have a high proportion of fruit and vegetables and a low consumption of meat are associated with a highly diverse microbiota and are defined by a greater abundance of Prevotella compared with Bacteroides, whereas the reverse is associated with a diet that contains a low proportion of plant-based foods. In a philosophical term, our consumption of processed foods, widespread use of antibiotics and disinfectants, and our modern lifestyle may have forever altered our ancient gut microbiome. We may never be able to identify or restore our microbiomes to their ancestral state, but dietary modulation to manipulate specific gut microbial species or groups of species may offer new therapeutic approaches to conditions that are prevalent in modern society, such as functional gastrointestinal disorders, obesity, and age-related nutritional deficiency. We believe that this will become an increasingly important area of health research.
Role of transient receptor potential vanilloid 4 activation in indomethacin-induced intestinal damage
Authors: Yamawaki Hidemoto , Mihara Hiroshi , Suzuki Nobuhiro , Nishizono Hirofumi , Uchida Kunitoshi , Watanabe Shiro , Tominaga Makoto , Sugiyama Toshiro
Published: May 2014

Gastrointestinal ulcers and bleeding are serious complications of nonsteroidal anti-inflammatory drug (NSAID) use. Although administration of antibiotics and Toll-like receptor 4 knockdown mitigate NSAID-induced enteropathy, the molecular mechanism of these effects is poorly understood. Intestinal hyperpermeability is speculated to trigger the initial damage due to NSAID use. Transient receptor potential vanilloid 4 (TRPV4) is a nonselective cation channel expressed throughout the gastrointestinal tract epithelium that is activated by temperature, extension, and chemicals such as 5,6-epoxyeicosatrienoic acid (5,6-EET). The aim of this study was to investigate the possible role of TRPV4 in NSAID-induced intestinal damage. TRPV4 mRNA and protein expression was confirmed by RT-PCR and immunochemistry, respectively, in mouse and human tissues while TRPV4 channel activity of the intestinal cell line IEC-6 was assessed by Ca2+-imaging analysis. TRPV4 activators or the NSAID indomethacin significantly decreased transepithelial resistance (TER) in IEC-6 cells, and indomethacin-induced TER decreases were inhibited by specific TRPV4 inhibitors or small-interfering RNA TRPV4 knockdown, as well as by the epoxygenase inhibitor N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide, which decreased 5,6-EET levels. In TRPV4 knockout mice, indomethacin-induced intestinal damage was significantly reduced compared with WT mice. Taken together, these results show that TRPV4 activation in the intestinal epithelium caused epithelial hyperpermeability in response to NSAID-induced arachidonic acid metabolites and contributed to NSAID-induced intestinal damage. Thus, TRPV4 could be a promising new therapeutic target for the prevention of NSAID-induced intestinal damage.
Mitochondrial calcium handling within the interstitial cells of Cajal
Authors: Means Shawn A. , Cheng Leo K.
Published: May 2014

The interstitial cells of Cajal (ICC) drive rhythmic pacemaking contractions in the gastrointestinal system. The ICC generate pacemaking signals by membrane depolarizations associated with the release of intracellular calcium (Ca2+) in the endoplasmic reticulum (ER) through inositol-trisphosphate (IP3) receptors (IP3R) and uptake by mitochondria (MT). This Ca2+ dynamic is hypothesized to generate pacemaking signals by calibrating ER Ca2+ store depletions and membrane depolarization with ER store-operated Ca2+ entry mechanisms. Using a biophysically based spatio-temporal model of integrated Ca2+ transport in the ICC, we determined the feasibility of ER depletion timescale correspondence with experimentally observed pacemaking frequencies while considering the impact of IP3R Ca2+ release and MT uptake on bulk cytosolic Ca2+ levels because persistent elevations of free intracellular Ca2+ are toxic to the cell. MT densities and distributions are varied in the model geometry to observe MT influence on free cytosolic Ca2+ and the resulting frequencies of ER Ca2+ store depletions, as well as the sarco-endoplasmic reticulum Ca2+ ATP-ase (SERCA) and IP3 agonist concentrations. Our simulations show that high MT densities observed in the ICC are more relevant to ER establishing Ca2+ depletion frequencies than protection of the cytosol from elevated free Ca2+, whereas the SERCA pump is more relevant to containing cytosolic Ca2+ elevations. Our results further suggest that the level of IP3 agonist stimulating ER Ca2+ release, subsequent MT uptake, and eventual activation of ER store-operated Ca2+ entry may determine frequencies of rhythmic pacemaking exhibited by the ICC across species and tissue types.
Changes in H reflex and neuromechanical properties of the trapezius muscle after 5 weeks of eccentric training: a randomized controlled trial
Authors: Vangsgaard Steffen , Taylor Janet L. , Hansen Ernst A. , Madeleine Pascal
Published: May 2014

Trapezius muscle Hoffman (H) reflexes were obtained to investigate the neural adaptations induced by a 5-wk strength training regimen, based solely on eccentric contractions of the shoulder muscles. Twenty-nine healthy subjects were randomized into an eccentric training group ( n = 15) and a reference group ( n = 14). The eccentric training program consisted of nine training sessions of eccentric exercise performed over a 5-wk period. H-reflex recruitment curves, the maximal M wave (Mmax), maximal voluntary contraction (MVC) force, rate of force development (RFD), and electromyographic (EMG) voluntary activity were recorded before and after training. H reflexes were recorded from the middle part of the trapezius muscle by electrical stimulation of the C3/4 cervical nerves; Mmax was measured by electrical stimulation of the accessory nerve. Eccentric strength training resulted in significant increases in the maximal trapezius muscle H reflex (Hmax) (21.4% [5.5–37.3]; P = 0.01), MVC force (26.4% [15.0–37.7]; P < 0.01), and RFD (24.6% [3.2–46.0]; P = 0.025), while no significant changes were observed in the reference group. Mmax remained unchanged in both groups. A significant positive correlation was found between the change in MVC force and the change in EMG voluntary activity in the training group ( r = 0.57; P = 0.03). These results indicate that the net excitability of the trapezius muscle H-reflex pathway increased after 5 wk of eccentric training. This is the first study to investigate and document changes in the trapezius muscle H reflex following eccentric strength training.
MRI-based measurements of aerosol deposition in the lung of healthy and elastase-treated rats
Authors: Oakes Jessica M. , Breen Ellen C. , Scadeng Miriam , Tchantchou Ghislain S. , Darquenne Chantal
Published: May 2014

Aerosolized drugs are increasingly being used to treat chronic lung diseases or to deliver therapeutics systemically through the lung. The influence of disease, such as emphysema, on particle deposition is not fully understood. With the use of magnetic resonance imaging (MRI), the deposition pattern of iron oxide particles with a mass median aerodynamic diameter of 1.2 μm was assessed in the lungs of healthy and elastase-treated rats. Tracheostomized rats were ventilated with particles, at a tidal volume of 2.2 ml, and a breathing frequency of 80 breaths/min. Maximum airway pressure was significantly lower in the elastase-treated (Paw = 7.71 ± 1.68 cmH2O) than in the healthy rats (Paw = 10.43 ± 1.02 cmH2O; P < 0.01). This is consistent with an increase in compliance characteristic of an emphysema-like lung structure. Following exposure, lungs were perfusion fixed and imaged in a 3T MR scanner. Particle concentration in the different lobes was determined based on a relationship with the MR signal decay rate, R2*. Whole lung particle deposition was significantly higher in the elastase-treated rats (CE,part = 3.03 ± 0.61 μm/ml) compared with the healthy rats (CH,part = 1.84 ± 0.35 μm/ml; P < 0.01). However, when particle deposition in each lobe was normalized by total deposition in the lung, there was no difference between the experimental groups. However, the relative dispersion [RD = standard deviation/mean] of R2* was significantly higher in the elastase-treated rats (RDE = 0.32 ± 0.02) compared with the healthy rats (RDH = 0.25 ± 0.02; P < 0.01). These data show that particle deposition is higher and more heterogeneously distributed in emphysematous lungs compared with healthy lungs.
Protease inhibitor 15, a candidate gene for abdominal aortic internal elastic lamina ruptures in the rat
Authors: Falak Samreen , Schafer Sebastian , Baud Amelie , Hummel Oliver , Schulz Herbert , Gauguier Dominique , Hubner Norbert , Osborne-Pellegrin Mary
Published: May 2014

The inbred Brown Norway (BN) rat develops spontaneous ruptures of the internal elastic lamina (RIEL) of the abdominal aorta (AA) and iliac arteries. Prior studies with crosses of the BN/Orl RJ (susceptible) and LOU/M (resistant) showed the presence of a significant QTL on chromosome 5 and the production of congenic rats proved the involvement of this locus. In this study, we further dissected the above-mentioned QTL by creating a new panel of LOU.BN(chr5) congenic and subcongenic lines and reduced the locus to 5.2 Mb. Then we studied 1,002 heterogeneous stock (HS) rats, whose phenotyping revealed a low prevalence and high variability for RIEL. High-resolution mapping in the HS panel detected the major locus on chromosome 5 (log P > 35) and refined it to 1.4 Mb. Subsequently, RNA-seq analysis on AA of BN, congenics, and LOU revealed expression differences for only protease inhibitor 15 (Pi15) gene and a putative long intergenic noncoding RNA (lincRNA) within the linkage region. The high abundance of lincRNA with respect to reduced Pi15 expression, in conjunction with exertion of longitudinal strain, may be related to RIEL, indicating the potential importance of proteases in biological processes related to defective aortic internal elastic lamina structure. Similar mechanisms may be involved in aneurysm initiation in the human AA.
Identification of the crucial molecular events during the large-scale myoblast fusion in sheep
Authors: Wei Caihong , Li Li , Su Hongwei , Xu Lingyang , Lu Jian , Zhang Li , Liu Wenzhong , Ren Hangxing , Du Lixin
Published: May 2014

It is well known that in sheep most myofibers are formed before birth; however, the crucial myogenic stage and the cellular and molecular mechanisms underpinning phenotypic variation of fetal muscle development remain to be ascertained. We used histological, microarray, and quantitative real-time PCR (qPCR) methods to examine the developmental characteristics of fetal muscle at 70, 85, 100, 120, and 135 days of gestation in sheep. We show that day 100 is an important checkpoint for change in muscle transcriptome and histomorphology in fetal sheep and that the period of 85–100 days is the vital developmental stage for large-scale myoblast fusion. Furthermore, we identified the cis-regulatory motifs for E2F1 or MEF2A in a list of decreasingly or increasingly expressed genes between 85 and 100 days, respectively. Further analysis demonstrated that the mRNA and phosphorylated protein levels of E2F1 and MEF2A significantly declined with myogenic progression in vivo and in vitro. qRT-PCR analysis indicated that PI3K and FST, as targets of E2F1, may be involved in myoblast differentiation and fusion and that downregulation of MEF2A contributes to transition of myofiber types by differential regulation of the target genes involved at the stage of 85–100 days. We clarify for the first time the timing of myofiber proliferation and development during gestation in sheep, which would be beneficial to meat sheep production. Our findings present a repertoire of gene expression in muscle during large-scale myoblast fusion at transcriptome-wide level, which contributes to elucidate the regulatory network of myogenic differentiation.
Oncogenic Protein MTBP Interacts with MYC to Promote Tumorigenesis
Authors: Grieb Brian C. , Gramling Mark W. , Arrate Maria Pia , Chen Xi , Beauparlant Stephen L. , Haines Dale S. , Xiao Hua , Eischen Christine M.
Published: May 2014

Despite its involvement in most human cancers, MYC continues to pose a challenge as a readily tractable therapeutic target. Here we identify the MYC transcriptional cofactors TIP48 and TIP49 and MYC as novel binding partners of Mdm2-binding protein (MTBP), a functionally undefined protein that we show is oncogenic and overexpressed in many human cancers. MTBP associated with MYC at promoters and increased MYC-mediated transcription, proliferation, neoplastic transformation, and tumor development. In breast cancer specimens, we determined overexpression of both MYC and MTBP was associated with a reduction in 10-year patient survival compared with MYC overexpression alone. MTBP was also frequently co-amplified with MYC in many human cancers. Mechanistic investigations implicated associations with TIP48/TIP49 as well as MYC in MTBP function in cellular transformation and the growth of human breast cancer cells. Taken together, our findings show MTBP functions with MYC to promote malignancy, identifying this protein as a novel general therapeutic target in human cancer. Cancer Res; 74(13); 3591–602. ©2014 AACR.
Prolyl Isomerase Pin1 Acts Downstream of miR200c to Promote Cancer Stem–like Cell Traits in Breast Cancer
Authors: Luo Man-Li , Gong Chang , Chen Chun-Hau , Lee Daniel Y. , Hu Hai , Huang Pengyu , Yao Yandan , Guo Wenjun , Reinhardt Ferenc , Wulf Gerburg , Lieberman Judy , Zhou Xiao Zhen , Song Erwei , Lu Kun Ping
Published: May 2014

Breast cancer stem–like cells (BCSC) have been implicated in tumor growth, metastasis, drug resistance, and relapse but druggable targets in appropriate subsets of this cell population have yet to be identified. Here we identify a fundamental role for the prolyl isomerase Pin1 in driving BCSC expansion, invasiveness, and tumorigenicity, defining it as a key target of miR200c, which is known to be a critical regulator in BCSC. Pin1 overexpression expanded the growth and tumorigenicity of BCSC and triggered epithelial–mesenchymal transition. Conversely, genetic or pharmacological inhibition of Pin1 reduced the abundance and self-renewal activity of BCSC. Moreover, moderate overexpression of miR200c-resistant Pin1 rescued the BCSC defect in miR200c-expressing cells. Genetic deletion of Pin1 also decreased the abundance and repopulating capability of normal mouse mammary stem cells. In human cells, freshly isolated from reduction mammoplasty tissues, Pin1 overexpression endowed BCSC traits to normal breast epithelial cells, expanding both luminal and basal/myoepithelial lineages in these cells. In contrast, Pin1 silencing in primary breast cancer cells freshly isolated from clinical samples inhibited the expansion, self-renewal activity, and tumorigenesis of BCSC in vitro and in vivo. Overall, our work demonstrated that Pin1 is a pivotal regulator acting downstream of miR200c to drive BCSC and breast tumorigenicity, highlighting a new therapeutic target to eradicate BCSC. Cancer Res; 74(13); 3603–16. ©2014 AACR.
Use of CA125 and HE4 Serum Markers to Predict Ovarian Cancer in Elevated-Risk Women
Authors: Karlan Beth Y. , Thorpe Jason , Watabayashi Kate , Drescher Charles W. , Palomares Melanie , Daly Mary B. , Paley Pam , Hillard Paula , Andersen M. Robyn , Anderson Garnet , Drapkin Ronny , Urban Nicole
Published: May 2014

Background: Serum markers are used before pelvic imaging to improve specificity and positive predictive value (PPV) of ovarian cancer multimodal screening strategies.

Methods: We conducted a randomized controlled pilot trial to estimate surgical PPV of a “2 of 3 tests positive” screening rule, and to compare use of HE4 as a first-line (Arm 1) versus a second-line (Arm 2) screen, in women at high and elevated risk for epithelial ovarian cancer (EOC) at five study sites. Semiannual screening was offered to 208 women ages 25 to 80 years with deleterious BRCA germline mutations and to 834 women ages 35 to 80 years with pedigrees suggesting inherited susceptibility. Annual screening was offered to 130 women ages 45 to 80 years (Risk Group 3) with epidemiologic and serum marker risk factors. Rising marker levels were identified using the parametric empirical Bayes algorithm.

Results: Both strategies yielded surgical PPV above 25%. Protocol-indicated surgery was performed in 6 women, identifying two ovarian malignancies and yielding a surgical PPV in both arms combined of 33% (95% confidence interval: 4%–78%), 25% in Arm 1 and 50% in Arm 2. Surgical consultation was recommended for 37 women (26 in Arm 1 and 11 in Arm 2). On the basis of 12 women with at least 2 of 3 tests positive (CA125, HE4, or imaging), an intent-to-treat analysis yielded PPV of 14% in Arm 1 and 20% in Arm 2.

Conclusions: Positive screens were more frequent when HE4 was included in the primary screen.

Impact: HE4 may be useful as a confirmatory screen when rising CA125 is used alone as a primary screen. Cancer Epidemiol Biomarkers Prev; 23(7); 1383–93. ©2014 AACR.
A Randomized, Multicenter, Placebo-Controlled Clinical Trial of Racotumomab-Alum Vaccine as Switch Maintenance Therapy in Advanced Non–Small Cell Lung Cancer Patients
Authors: Alfonso Sailyn , Valdés-Zayas Anet , Santiesteban Eduardo R. , Flores Yoanna I. , Areces Fernando , Hernández Maurenis , Viada Carmen E. , Mendoza Ivis C. , Guerra Pedro P. , García Elena , Ortiz Ramón A. , de la Torre Ana V. , Cepeda Meylán , Pérez Kirenia , Chong Eric , Hernández Ana María , Toledo Darien , González Zuyén , Mazorra Zaima , Crombet Tania , Pérez Rolando , Vázquez Ana María , Macías Amparo E.
Published: May 2014

Purpose: Racotumomab-alum is an anti-idiotype vaccine targeting the NeuGcGM3 tumor-associated ganglioside. This clinical trial was conducted to provide a preliminary estimate of efficacy and safety of racotumomab as switch maintenance for patients with advanced non–small cell lung cancer (NSCLC).

Experimental design: Patients with stage IIIb/IV NSCLC who have at least stable disease after first-line chemotherapy were randomized 1:1 to racotumomab-alum (5 immunizations every 2 weeks and re-immunizations every 4 weeks) or placebo. Treatment was administered beyond progressive disease, until severe performance status worsening or toxicity. At progression, only five patients per group received further anticancer therapy. The primary endpoint was overall survival (OS).

Results: One-hundred and seventy-six patients were randomized to racotumomab-alum (n = 87) and placebo (n = 89). Median OS was 8.23 and 6.80 months, respectively [HR, 0.63; 95% confidence interval (CI), 0.46–0.87; P = 0.004]. Median progression-free survival (PFS) in vaccinated patients was 5.33 versus 3.90 months for placebo (HR, 0.73; 95% CI 0.53–0.99; P = 0.039). The most common adverse events in the racotumomab-alum arm were burning and pain at the injection site, bone pain, and asthenia. A high antibody response of IgM and IgG isotype against the NeuGcGM3 ganglioside was obtained. Hyperimmune sera were able to specifically recognize and kill the NeuGcGM3-expressing L1210 cell line. Patients who developed anti-NeuGcGM3 antibodies capable to bind and kill ≥30% L1210 cells showed longer median survival times.

Conclusions: Switch maintenance with racotumomab-alum is an effective and a well-tolerated treatment option for patients with advanced NSCLC. Clin Cancer Res; 20(14); 3660–71. ©2014 AACR.
Molecular Pathways: Harnessing E2F1 Regulation for Prosenescence Therapy in p53-Defective Cancer Cells
Authors: Laine Anni , Westermarck Jukka
Published: May 2014

Induction of terminal proliferation arrest, senescence, is important for in vivo tumor-suppressive function of p53. Moreover, p53-mutant cells are highly resistant to senescence induction by either oncogenic signaling during cellular transformation or in response to different therapies. Senescence resistance in p53-mutant cells has been attributed mostly to inhibition of the checkpoint function of p53 in response to senescence-inducing stress signals. Here, we review very recent evidence that offers an alternative explanation for senescence resistance in p53-defective cancer cells: p21-mediated E2F1 expression. We discuss the potential relevance of these findings for senescence-inducing therapies and highlight cyclin-dependent kinases (CDK) and mechanisms downstream of retinoblastoma protein (RB) as prospective prosenescence therapeutic targets. In particular, we discuss recent findings indicating an important role for the E2F1–CIP2A feedback loop in causing senescence resistance in p53-compromised cancer cells. We further propose that targeting of the E2F1–CIP2A feedback loop could provide a prosenescence therapeutic approach that is effective in both p53-deficient and RB-deficient cancer cells, which together constitute the great majority of all cancer cells. Diagnostic evaluation of the described senescence resistance mechanisms in human tumors might also be informative for patient stratification for already existing therapies. Clin Cancer Res; 20(14); 3644–50. ©2014 AACR.
Computational Repositioning and Preclinical Validation of Pentamidine for Renal Cell Cancer
Authors: Zerbini Luiz Fernando , Bhasin Manoj K. , de Vasconcellos Jaira F. , Paccez Juliano D. , Gu Xuesong , Kung Andrew L. , Libermann Towia A.
Published: May 2014

Although early stages of clear cell renal cell carcinoma (ccRCC) are curable, survival outcome for metastatic ccRCC remains poor. We previously established a highly accurate signature of differentially expressed genes that distinguish ccRCC from normal kidney. The purpose of this study was to apply a new individualized bioinformatics analysis (IBA) strategy to these transcriptome data in conjunction with Gene Set Enrichment Analysis of the Connectivity Map (C-MAP) database to identify and reposition FDA-approved drugs for anticancer therapy. Here, we demonstrate that one of the drugs predicted to revert the RCC gene signature toward normal kidney, pentamidine, is effective against RCC cells in culture and in a RCC xenograft model. ccRCC-specific gene expression signatures of individual patients were used to query the C-MAP software. Eight drugs with negative correlation and P-value <0.05 were analyzed for efficacy against RCC in vitro and in vivo. Our data demonstrate consistency across most patients with ccRCC for the set of high-scoring drugs. Most of the selected high-scoring drugs potently induce apoptosis in RCC cells. Several drugs also demonstrate selectivity for Von Hippel-Lindau negative RCC cells. Most importantly, at least one of these drugs, pentamidine, slows tumor growth in the 786-O human ccRCC xenograft mouse model. Our findings suggest that pentamidine might be a new therapeutic agent to be combined with current standard-of-care regimens for patients with metastatic ccRCC and support our notion that IBA combined with C-MAP analysis enables repurposing of FDA-approved drugs for potential anti-RCC therapy. Mol Cancer Ther; 13(7); 1929–41. ©2014 AACR.
Tim-3: An Emerging Target in the Cancer Immunotherapy Landscape
Authors: Anderson Ana C.
Published: May 2014

The cancer immunotherapy field has grown exponentially in the past few years, largely driven by the success of immune checkpoint blockade. Therapies targeting the immune checkpoint molecules CTLA-4 and PD-1 have achieved objective responses in melanoma, renal cancer, and lung cancer; however, a large number of patients are still suffering with these cancers that are not benefiting from these therapies. Moreover, several cancers have proved to be largely refractory to therapies that target CTLA-4 and PD-1. This has catalyzed interest in targeting novel immune checkpoint receptors with the goal of realizing the full potential of checkpoint blockade for treating cancer. In this regard, the immune checkpoint receptor Tim-3 exhibits several unique features that make it an intriguing candidate for the next wave of therapies that target immune checkpoints in cancer. Cancer Immunol Res; 2(5); 393–8. ©2014 AACR.
Mixed-Lineage Kinase 3 Deficiency Promotes Neointima Formation Through Increased Activation of the RhoA Pathway in Vascular Smooth Muscle Cells
Authors: Gadang Vidya , Konaniah Eddy , Hui David Y. , Jaeschke Anja
Published: May 2014

Objective—

Mitogen-activated protein kinase pathways play an important role in neointima formation secondary to vascular injury, in part by promoting proliferation of vascular smooth muscle cells (VSMC). Mixed-lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase that activates multiple mitogen-activated protein kinase pathways and has been implicated in regulating proliferation in several cell types. However, the role of MLK3 in VSMC proliferation and neointima formation is unknown. The aim of this study was to determine the function of MLK3 in the development of neointimal hyperplasia and to elucidate the underlying mechanisms.

Approach and Results—

Neointima formation was analyzed after endothelial denudation of carotid arteries from wild-type and MLK3-deficient mice. MLK3 deficiency promoted injury-induced neointima formation and increased proliferation of primary VSMC derived from aortas isolated from MLK3-deficient mice compared with wild-type mice. Furthermore, MLK3 deficiency increased the activation of p63Rho guanine nucleotide exchange factor, RhoA, and Rho kinase in VSMC, a pathway known to promote neointimal hyperplasia, and reconstitution of MLK3 expression attenuated Rho kinase activation. Furthermore, cJun NH
2
-terminal kinase activation was decreased in MLK3-deficient VSMC, and proliferation of wild-type but not MLK3 knockout cells treated with a cJun NH
2
-terminal kinase inhibitor was attenuated.

Conclusions—

We demonstrate that MLK3 limits RhoA activation and injury-induced neointima formation by binding to and inhibiting the activation of p63Rho guanine nucleotide exchange factor, a RhoA activator. In MLK3-deficient cells, activation of p63Rho guanine nucleotide exchange factor proceeds in an unchecked manner, leading to a net increase in RhoA pathway activation. Reconstitution of MLK3 expression restores MLK3/p63Rho guanine nucleotide exchange factor interaction, which is attenuated by feedback from activated cJun NH
2
-terminal kinase.
Stem Cell Factor Is a Potent Endothelial Permeability Factor
Authors: Kim Ji Yeon , Choi Jun-Sub , Song Sun-Hwa , Im Ji-Eun , Kim Jung-Mo , Kim Kyungjong , Kwon Soonboem , Shin Hwa Kyoung , Joo Choun-Ki , Lee Byung Ho , Suh Wonhee
Published: May 2014

Objective—

Although stem cell factor (SCF) has been shown to play a critical role in hematopoiesis, gametogenesis, and melanogenesis, the function of SCF in the regulation of vascular integrity has not been studied.

Approach and Results—

We demonstrated that SCF binds to and activates the cKit receptor in endothelial cells, thereby increasing the internalization of vascular endothelial-cadherin and enhancing extravasation of dyes to a similar extent as vascular endothelial growth factor. SCF-mediated cKit activation in endothelial cells enhanced the phosphorylation of endothelial nitric oxide (NO) synthase via the phosphoinositide 3-kinase/Akt signaling pathway and subsequently increased the production of NO. Inhibition of endothelial NO synthase expression and NO synthesis using small interfering RNA knockdown and chemical inhibitors substantially diminished the ability of SCF to increase the internalization of vascular endothelial-cadherin and in vitro endothelial permeability. SCF-induced increase in extravasation of the dyes was abrogated in endothelial NO synthase knockout mice, which indicates that endothelial NO synthase–mediated NO production was responsible for the SCF-induced vascular leakage. Furthermore, we demonstrated that the expression of SCF and cKit was significantly higher in the retina of streptozotocin-injected diabetic mice than in the nondiabetic control animals. Depletion of SCF by intravitreous injection of anti-SCF–neutralizing immunoglobulin G significantly prevented vascular hyperpermeability in the retinas of streptozotocin-injected diabetic mice.

Conclusions—

Our data reveal that SCF disrupts the endothelial adherens junction and enhances vascular leakage, as well as suggest that anti-SCF/cKit therapy may hold promise as a potential therapy for the treatment of hyperpermeable vascular diseases.