bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Novel Recombinant Soluble Splice Variant of Met Is a Potent Antagonist of the Hepatocyte Growth Factor/Scatter Factor-Met Pathway
Authors: Tiran Zohar , Oren Anat , Hermesh Chen , Rotman Galit , Levine Zurit , Amitai Hagit , Handelsman Tal , Beiman Merav , Chen Aviva , Landesman-Milo Dalit , Dassa Liat , Peres Yair , Koifman Cynthia , Glezer Sarit , Vidal-Finkelstein Rinat , Bahat Kobi , Pergam Tania , Israel Cylia , Horev Judith , Tsarfaty Ilan , Ayalon-Soffer Michal 
Published: July 2008

Abstract
Purpose: The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor/scatter factor (HGF/SF), are involved in a wide range of biological activities, including cell proliferation, motility, invasion, and angiogenesis. The HGF/SF-Met signaling pathway is frequently activated in a variety of cancers, and uncontrolled Met activation correlates with highly invasive tumors and poor prognosis. In this study, we investigated the inhibitory effect of a novel soluble splice variant of Met on the HGF/SF-Met pathway.
Experimental Design: Using our alternative splicing modeling platform LEADS, we have identified a novel splice variant of the Met receptor, which encodes a truncated soluble form of the receptor. This variant was produced as a recombinant Fc-fused protein named Cgen-241A and was tested in various cell-based assays representing different outcomes of the HGF/SF-Met pathway.
Results: Cgen-241A significantly inhibited HGF/SF-induced Met phosphorylation as well as cell proliferation and survival. In addition, Cgen-241A showed a profound inhibitory effect on cell scattering, invasion, and urokinase up-regulation. The inhibitory effects of Cgen-241A were shown in multiple human and nonhuman cell types, representing different modes of Met activation. Furthermore, Cgen-241A showed direct binding to HGF/SF.
Conclusions: Taken together, our results indicate that Cgen-241A is a potent antagonist of the HGF/SF-Met pathway, underlining its potential as a therapeutic agent for the treatment of a wide variety of human malignancies that are dependent on this pathway.
Penetrance Analysis of the PALB2 c.1592delT Founder Mutation
Authors: Erkko Hannele , Dowty James G. , Nikkilä Jenni , Syrjäkoski Kirsi , Mannermaa Arto , Pylkäs Katri , Southey Melissa C. , Holli Kaija , Kallioniemi Anne , Jukkola-Vuorinen Arja , Kataja Vesa , Kosma Veli-Matti , Xia Bing , Livingston David M. , Winqvist Robert , Hopper John L. 
Published: July 2008

Abstract
Purpose: PALB2 is a recently identified breast cancer susceptibility gene. We have previously identified in the Finnish population a PALB2 c.1592delT founder truncation mutation that is associated with an increased risk of breast cancer. In the present study, we wanted to assess in more detail the increased risk (hazard ratio, HR) and the age-specific cumulative risk (penetrance) of c.1592delT with regard to susceptibility to breast and other forms of cancer.
Experimental Design: Modified segregation analyses fitted under maximum likelihood theory were used to estimate age-specific cumulative risks and HRs using the families of mutation carriers identified from a consecutive series of breast cancer cases unselected for age at onset or family history.
Results: We found a substantially increased risk of breast cancer [HR, 6.1; 95% confidence interval (95% CI), 2.2-17.2; P = 0.01] equivalent to a 40% (95% CI, 17-77) breast cancer risk by age 70 years, comparable to that for carriers of mutations in BRCA2. We found marginal evidence (P = 0.06) that the HR for breast cancer decreased with age by 4.2% per year (95% CI, 0.2-8.1), from 7.5-fold at age 30 years to 2.0-fold at age 60 years.
Conclusions: Our results suggest that it may be appropriate to offer PALB2 c.1592delT mutation testing to Finnish women with breast cancer, especially those with an early age at onset or a family history of breast or related cancers, and to offer carriers the option of participation in extended disease surveillance programs.
Randomized Phase III Clinical Trial Designs for Targeted Agents
Authors: Hoering Antje , LeBlanc Mike , Crowley John J. 
Published: July 2008

Abstract
Purpose: Cancer therapies with mechanisms of action which are very different from the more conventional chemotherapies are now being developed. In this article, we investigate the performance of several phase III clinical trial designs, both for testing the overall efficacy of a targeted agent and for testing its efficacy in a subgroup of patients with a tumor marker present. We study different designs and different underlying scenarios assuming continuous markers, and assess the trade-off between the number of patients on the study and the effectiveness of treatment in the subgroup of marker-positive patients.
Experimental Design: We investigate binary outcomes and use simulation studies to determine sample size and power for the different designs and the various scenarios. We also simulate marker prevalence and marker misclassification and evaluate their effect on power and sample size.
Results: In general, a targeted design which randomizes patients with the appropriate marker status performs the best in all scenarios with an underlying true predictive marker. Randomizing all patients regardless of their marker values performs as well as or better in most cases than a clinical trial that randomizes the patient to a treatment strategy based on marker value versus standard of care.
Conclusion: If there is the possibility that the new treatment helps marker-negative patients, or that the cutpoint determining marker status has not been well established and the marker prevalence is large enough, we recommend randomizing all patients regardless of marker values, but using a design such that both the overall and the targeted subgroup hypothesis can be tested.
Multi-Arm Clinical Trials of New Agents: Some Design Considerations
Authors: Freidlin Boris , Korn Edward L. , Gray Robert , Martin Alison 
Published: July 2008

Abstract
A major challenge in the development of anticancer therapies is the considerable time and resources needed for conducting randomized clinical trials (RCT). There is a need for more efficient RCT designs that accelerate development, minimize costs, and make trials more appealing to patients. We review the statistical and logistical characteristics of multi-arm designs that compare several experimental treatments to a common control arm. In particular, we present a rationale for not requiring multiplicity adjustment in multi-arm trials that are designed for logistical efficiency. Relative to conducting separate RCTs for each experimental agent, this multi-arm design is shown to require a lower total sample size than multiple two-arm trials.
Anti-invasive and Antimetastatic Activities of Ribosomal Protein S6 Kinase 4 in Breast Cancer Cells
Authors: Thakur Archana , Sun Yuan , Bollig Aliccia , Wu Jack , Biliran Hector , Banerjee Sanjeev , Sarkar Fazlul H. , Liao D. Joshua 
Published: July 2008

Abstract
Purpose: We have previously shown that p90 ribosomal protein S6 kinase 4 (RSK4), an X-linked gene, is highly up-regulated in mammary tumors of MMTV-c-Myc transgenic mice. In this study, we further investigated whether RSK4 inhibits or promotes breast tumor growth and progression.
Experimental Design: Stable overexpression or small interfering RNA–mediated knockdown of RSK4 was done in the MDA-MB-231 cell line. Stable clones were tested for cell proliferation, anchorage-independent growth in soft agar, invasive and metastatic ability of these clones in vitro and tumorigenesis, invasive and metastatic ability in vivo in severe combined immunodeficient mice.
Results: Here, we show that exogenous expression of RSK4 resulted in decreased cell proliferation and increased accumulation of cells in G0-G1 phase, which paralleled with enhanced expression of tumor suppressor genes: retinoblastoma protein, retinobl astoma-associated 46 kDa protein, and p21 protein. Overexpression of RSK4 resulted in reduced colony formation in soft agar and suppressed invasive and migratory activities of MDA-MB-231 cells both in vitro and in vivo. Importantly, RSK4-overexpressing cells showed up-regulation of claudin-2 and down-regulation of CXCR4, both of these play roles in invasion and chemotaxis.
Conclusions: These results indicate that RSK4 expression may limit the oncogenic, invasive, and metastatic potential of breast cancer cells. Anti-invasive and antimetastatic activities of RSK4 may be, in part, due to its regulation of claudin-2. Increased expression of RSK4 in c-Myc-overexpressing cells and a dose-dependent induction of luciferase reporter gene activity suggest that c-Myc may regulate RSK4 expression.
Children's Participation and Good Governance: Limitations of the Theoretical Literature
Authors: Hinton Rachel 
Published: July 2008

AbstractChildren are an important stakeholder group; they constitute 34% of the world's citizens and their actions will determine our collective future. The UNCRC created consensus that children's views must be taken seriously. Yet their opinions have failed to inform the allocation of resources used in their name. Their views are rarely sought during scrutiny of government despite their valuable insights on the functioning of public institutions. This paper summarises the debates around children's participation and argues that there has been little dialogue across the academic fields. The long history of children's participation in the South is only starting to inform the new wave of attention to children as active citizens in the North. The paper poses questions as a catalyst for further debate: Why do theoretical frameworks fail children? What is the impact of the process of 'participation'? Are children who lack the networks and social capital being excluded?
Children's Participation in Brazil – A Brief Genealogy and Recent Innovations
Authors: Mandel Butler Udi 
Published: July 2008

AbstractThis paper provides an overview of significant developments in Brazil in regard to children and young people's rights and participation in the public sphere. The paper addresses the importance of historically contextualizing particular practices and policies towards children and young people, in order to understand present manifestations of their "participation". Outlining the Brazilian context of deep inequality, the paper reflects how different childhoods, that of the rich and of the poor, have been differently categorised and acted upon. The paper goes on to give an account of the important movements of mass participation that emerged through the 1970s, in particular those concerning Popular Education, that sought to dismantle repressive institutions and relationships within the country, including those towards the children of the poorest sectors of the population. Important here is the influence of Brazilian pedagogue and activist Paulo Freire, whose ideas around 'conscientization' and their subsequent impact on participatory practices with children and young people are also addressed. The paper concludes with a brief overview of recent research on the multiple spaces of participation young people are engaged in, offering some possible avenues for future research.
Reflecting on Children and Young People's Participation in the UK
Authors: Gallagher Michael , M. Tisdall Kay , Davis John 
Published: July 2008

AbstractThe article interrogates how children and young people's participation in public decision-making has been promoted in the UK. It considers critically the reasons typically (and persuasively) put forward for such participation, which can be categorized as: the promotion of children's rights; alignment with consumerism and service user involvement; enhancing democracy; and developing children's well-being and development. Each of these reasons can appeal to particular agendas of policy-makers, professionals and other influential adults, to provide room and support for participation. But inevitably each reason has certain advantages and disadvantages, acted out in current trends and accompanying dilemmas in children and young people's participation activities.
Learning from Political Sociology: Structure, Agency and Inclusive Governance
Authors: Gale Richard , O'Toole Therese 
Published: July 2008

AbstractIn this article, we consider the inclusion of children and young people in participatory governance processes. Whilst limitations are often evident in such processes, we argue that even participatory opportunities that are provided by the state and regarded as spaces into which citizens are invited can be "conquered by civil society demands for inclusion" (Cornwall and Coelho, 2006: 1). To this end, we suggest a practice-based and diachronic approach to studying the interactions between participatory structures and children and young people's agency. Being attentive to the agency of children and young people, and adopting a more diachronic approach to evaluating participatory initiatives, point to the possibility, we suggest, of seeing these relationships unfold in sometimes unexpected ways.
Children's Participation: Learning from and for Community Development
Authors: Percy-Smith Barry , Taylor Marilyn 
Published: July 2008

AbstractInterest in children's participation has in the main come about as a result of the UNCRC. However, children's participation is also relevant to a wider global interest in citizen and community participation more generally. But there is surprisingly little sharing of experience and learning between the research communities concerned with children's participation on the one hand and community engagement and empowerment on the other. This article seeks to address that gap by reflecting on the learning from both of these traditions, drawing mainly on UK experience. It begins by outlining some of the key dilemmas and challenges facing children's participation. It then explores the parallels between that experience and the experience of community participation in New Labour's neighbourhood and democratic renewal programmes. It goes on to consider some theoretical tools for responding to the common dilemmas in both settings, before discussing the implications for children's participation. It ends by arguing that more attention to children's participation could benefit community engagement policy and practice more widely.
Foucault, Power and Participation
Authors: Gallagher Michael 
Published: July 2008

AbstractIn this paper, I argue that Foucault's work on power offers a distinctive and original perspective with the potential to afford insights into the nature of participation. I begin by providing a brief exegesis of Foucault's conceptualisation of power in his middle to late work. The notion of governmentality is drawn out as a potentially useful tool in understanding participation as a profoundly ambiguous phenomenon. I conclude by outlining some of the possible implications of Foucault's thinking about power for studying children's participation.
Is the Honeymoon Over? Children and Young People's Participation in Public Decision-Making
Authors: M. Tisdall Kay 
Published: July 2008

AbstractChildren and young people's participation in public decision-making is now firmly on international and national agendas. This article concludes the special issue on such participation, by discussing three central issues for children and young people's participation: what is counted – or discounted – as legitimate forms of participation; the potential usefulness of theorisations of governance, citizenship and social capital; and how the roles of adults (participation workers) can be understood. The article celebrates the success of the rhetorical push for children and young people's participation, while suggesting that the tensions and dilemmas of current practice and policy need to be addressed by new and revitalised ideas and challenging theorisations.
Sources of Knowledge Transfer Among Primary Care Pediatric Health Care Providers
Authors: Pappano Dante , Conners Gregory , McIntosh Scott , Humiston Sharon , Roma Domenick 
Published: July 2008

Objectives The authors sought to understand which informational sources pediatric health care providers perceive as most influential in how they stay current with health care innovations. Methods Rochester, New York, area pediatric health care providers were surveyed using a self-administered questionnaire. Two items pertained to the health care provider's ability to interpret primary research, and 9 items pertained to the influence and relative importance of various sources of information. Results A 61% response rate was obtained. Most (83%) respondents felt adequately trained to interpret primary research, fewer (31%) felt they have the time to do so. Almost all respondents (92%) felt that American Academy of Pediatrics (AAP) guidelines were a major influence, and 44% felt that AAP guidelines were the single most influential source of information in how they altered their practice over time. Conclusions In the setting of time constraints, and the volume and complexity of published therapeutic research, AAP guidelines are playing an increasing role in knowledge transfer.
Puranic Texts from Kashmir
Authors: Sharma Mahesh 
Published: July 2008

Focusing on the western Himalayan provinces of Kashmir and Himachal Pradesh, this article argues that the Indian hagiographic texts of the Puranas should be understood as a nuanced literature that sought to effect a paradigm shift in liturgy and praxis, fusing polity and religion, largely in contravention to the earlier Vedic–Upanishadic texts and their commentaries, but also building on them. Emphasis on local Sanskrit literature, specifically the Nilamata Purana, which uses popular iconographies of river goddesses, served many centuries ago to reconstruct the geography of the area within the wider context of the subcontinental sacred geography. Keeping within the Puranic tradition, the article focuses on the rituals and ceremonials associated with rivers, while also charting the process by which regional pilgrim centres were formed on their banks, devising a sacred space parallel to the subcontinental cosmos. This reinforces the logic of the sacred river, the worshipped deity, as a process by which brahmanic dominance was asserted in the peripheral areas of early India, or ideologically and politically contested regions such as Kashmir. In the sacrality of the river Vitasta, Brahmanism as an ideology reasserts itself by restating the tradition in relation to its sacral past, creating a new sacred space and devising a sacred icon to reclaim this particular geography for the devout Brahmanas.
The Contralateral Knee Joint in Cruciate Ligament Deficiency
Authors: Kozanek Michal , Van de Velde Samuel K. , Gill Thomas J. , Li Guoan 
Published: July 2008

BackgroundPatients with unilateral ligament deficiency are believed to have altered kinematics of the contralateral knee, increasing the risk of contralateral joint injury. Therefore, the contralateral knees might not be a reliable normal kinematic control.PurposeTo compare the in vivo kinematics of the uninjured contralateral knees of patients with anterior or posterior cruciate ligament deficiency with knee kinematics of age-matched patients without joint injury.Study DesignControlled laboratory study.MethodsTen subjects with bilateral healthy knees, 10 patients with acute unilateral anterior cruciate ligament injury, and 10 with acute unilateral posterior cruciate ligament injury participated in this study. Kinematics were measured from 0° to 90° of flexion using imaging and 3-dimensional modeling.ResultsNo significant differences were found across the groups in all rotations and translations during weightbearing flexion (P > .9).ConclusionPatients with unilateral cruciate ligament deficiency did not alter kinematics of the contralateral uninjured knee during weightbearing flexion. In addition, these findings suggest that the included patients with anterior cruciate ligament or posterior cruciate ligament deficiency did not have preexisting abnormal kinematics of the knee.Clinical RelevanceAs the contralateral joint kinematics of the injured patients were not affected by the ipsilateral ligament injury in the short term, physicians and researchers might use the contralateral knee as a reliable normal kinematic control.
Monitoring Adherence and Defaulting for Antiretroviral Therapy in 5 East African Countries: An Urgent Need for Standards
Authors: Chalker John , Andualem Tenaw , Minzi Omary , Ntaganira Joseph , Ojoo Atieno , Waako Paul , Ross-Degnan Dennis 
Published: July 2008

Objectives: A cross-sectional survey was performed in 24 systems of care providing antiretroviral medications in Ethiopia, Kenya, Rwanda, Tanzania, and Uganda to examine current practices in monitoring rates of treatment adherence and defaulting. Results: Only 20 of 48 facilities reported routinely measuring individual patient adherence levels; only 12 measured rates of adherence for the clinic population. The rules for determining which patients were included in the calculation of rates were unclear. Fourteen different definitions of treatment defaulting were in use. Facilities routinely gather potentially useful data, but the frequency of doing so varied widely. Conclusions: Individual and program treatment adherence and defaulting are not routinely monitored; when done, the operational definitions and methods varied widely, making comparisons across programs unreliable. There is a pressing need to determine which measures are the most feasible and reliable to collect, the most useful for clinical counseling, and most informative for program management.
Igbp1 is part of a positive feedback loop in stem cell factor–dependent, selective mRNA translation initiation inhibiting erythroid differentiation
Authors: Grech Godfrey , Blázquez-Domingo Montserrat , Kolbus Andrea , Bakker Walbert J. , Müllner Ernst W. , Beug Hartmut , von Lindern Marieke 
Published: July 2008

AbstractStem cell factor (SCF)–induced activation of phosphoinositide-3-kinase (PI3K) is required for transient amplification of the erythroblast compartment. PI3K stimulates the activation of mTOR (target of rapamycin) and subsequent release of the cap-binding translation initiation factor 4E (eIF4E) from the 4E-binding protein 4EBP, which controls the recruitment of structured mRNAs to polysomes. Enhanced expression of eIF4E renders proliferation of erythroblasts independent of PI3K. To investigate which mRNAs are selectively recruited to polysomes, we compared SCF-dependent gene expression between total and polysome-bound mRNA. This identified 111 genes primarily subject to translational regulation. For 8 of 9 genes studied in more detail, the SCF-induced polysome recruitment of transcripts exceeded 5-fold regulation and was PI3K-dependent and eIF4E-sensitive, whereas total mRNA was not affected by signal transduction. One of the targets, Immunoglobulin binding protein 1 (Igbp1), is a regulatory subunit of protein phosphatase 2A (Pp2a) sustaining mTOR signaling. Constitutive expression of Igbp1 impaired erythroid differentiation, maintained 4EBP and p70S6k phosphorylation, and enhanced polysome recruitment of multiple eIF4E-sensitive mRNAs. Thus, PI3K-dependent polysome recruitment of Igbp1 acts as a positive feedback mechanism on translation initiation underscoring the important regulatory role of selective mRNA recruitment to polysomes in the balance between proliferation and maturation of erythroblasts.