Functional analysis of the ATM-p53-p21 pathway in the LRF CLL4 trial: blockade at the level of p21 is associated with short response duration.

PURPOSE: This study sought to establish whether functional analysis of the ATM-p53-p21 pathway adds to the information provided by currently available prognostic factors in patients with chronic lymphocytic leukemia (CLL) requiring frontline chemotherapy. EXPERIMENTAL DESIGN: Cryopreserved blood mononuclear cells from 278 patients entering the LRF CLL4 trial comparing chlorambucil, fludarabine, and fludarabine plus cyclophosphamide were analyzed for ATM-p53-p21 pathway defects using an ex vivo functional assay that uses ionizing radiation to activate ATM and flow cytometry to measure upregulation of p53 and p21 proteins. Clinical endpoints were compared between groups of patients defined by their pathway status. RESULTS: ATM-p53-p21 pathway defects of four different types (A, B, C, and D) were identified in 194 of 278 (70%) samples. The type A defect (high constitutive p53 expression combined with impaired p21 upregulation) and the type C defect (impaired p21 upregulation despite an intact p53 response) were each associated with short progression-free survival. The type A defect was associated with chemoresistance, whereas the type C defect was associated with early relapse. As expected, the type A defect was strongly associated with TP53 deletion/mutation. In contrast, the type C defect was not associated with any of the other prognostic factors examined, including TP53/ATM deletion, TP53 mutation, and IGHV mutational status. Detection of the type C defect added to the prognostic information provided by TP53/ATM deletion, TP53 mutation, and IGHV status. CONCLUSION: Our findings implicate blockade of the ATM-p53-p21 pathway at the level of p21 as a hitherto unrecognized determinant of early disease recurrence following successful cytoreduction.

The Reliability and Validity of a Child and Adolescent Participation in Decision Making Questionnaire

Background
There is a growing impetus across the research, policy and practice communities for children and young people to participate in decisions that affect their lives. Furthermore, there is a dearth of general instruments that measure children and young people’s views on their participation in decision making. This paper presents the reliability and validity of the Child and Adolescent Participation in Decision Making Questionnaire (CAP-DMQ) and specifically looks at a population of looked-after children where a lack of participation in decision making is an acute issue.
Methods
The participants were 151 looked after children and adolescents between 10-23 years of age who completed the 10 item CAP-DMQ. Of the participants 113 were in receipt of an advocacy service that had an aim of increasing participation in decision-making with the remaining participants not having received this service.
Results
The results showed that the CAP-DMQ had good reliability (Cronbach’s alpha = .94) and showed promising uni-dimensional construct validity through an exploratory factor analysis. The items in the CAP-DMQ also demonstrated good content validity by overlapping with prominent models of child and adolescent participation (Lundy 2007) and decision making (Halpern 2014). A regression analysis showed that age and gender were not significant predictors of CAP-DMQ scores but receipt of advocacy was a significant predictor of scores (effect size d=.88), thus showing appropriate discriminant criterion validity.
Conclusion
Overall, the CAP-DMQ showed good reliability and validity. Therefore, the measure has excellent promise for theoretical investigation in the area of child and adolescent participation in decision making and equally shows empirical promise for use as a measure in evaluating services which have increasing the participation of children and adolescents in decision making as an intended outcome.

The making of professionals: Embedded civil society development in a transition country

The paper addresses the development of non-governmental organisations (NGOs) in transition settings. Caught in the balance of knowledge exchange and translation of ideas from abroad, organisations in turbulent setting legitimise their existence by learning through professional networks. By association, organisational actors gain acknowledgement by their sector by traversing the corridors of influence provided by international partnerships. What they learn is how to conduct themselves as agents of change in society, and how to deliver on stated missions and goals, therefore, legitimising their presence in a budding civil society at home. The paper presents a knowledge production and learning practices framework which indicates a presence of dual identity of NGOs - their “embeddedness” locally and internationally. Selected framework dimensions and qualitative case study themes are discussed with respect to the level of independence of organisational actors in the East from their partners in the West in a post-socialist context. A professional global civil society as organisations are increasingly managed in similar, professional ways (Anheier & Themudo 2002). Here knowledge “handling” and knowledge “translation” take place through partnership exchanges fostering capable and/or competitive change-inducing institutions (Czarniawska & Sevon 2005; Hwang & Suarez 2005). How professional identity presents itself in the third sector, as well as the sector’s claim to expertise, need further attention, adding to ongoing discussions on professions in institutional theory (Hwang & Powell 2005; Scott 2008; Noordegraaf 2011). A conceptual framework on the dynamic involved for the construction professional fields follows: • Multiple case analysis provides a taxonomy for understanding what is happening in knowledge transition, adaptation, and organisational learning capacity for NGOs with respect to their role in a networked civil society. With the model we can observe the types of knowledge produced and learning employed by organisations. • There are elements of professionalisation in third sector work organisational activity with respect to its accreditation, sources and routines of learning, knowledge claims, interaction with the statutory sector, recognition in cross-sector partnerships etc. • It signals that there is a dual embeddedness in the development of the sector at the core to the shaping the sector’s professional status. This is instrumental in the NGOs’ goal to gain influence as institutions, as they are only one part of a cross-sector mission to address complex societal problems The case study material highlights nuances of knowledge production and learning practices in partnerships, with dual embeddedness a main feature of the findings. This provides some clues to how professionalisation as expert-making takes shape in organisations: • Depending on the type of organisations’ purpose, over its course of development there is an increase in participation in multiple networks, as opposed to reliance on a single strategic partner for knowledge artefacts and practices; • Some types of organisations are better connected within international and national networks than others and there seem to be preferences for each depending on the area of work; • The level of interpretation or adaptation of the knowledge artefacts is related to an organisation’s embeddedness locally, in turn giving it more influence within the network of key institutions; An overreaching theme across taxonomy categories (Table 1)is “professionalisation” or developing organisational “expertise”, embodied at the individual, organisational, and sector levels. Questions relevant to the exercise of power arise: Is competence in managing a dual embeddedness signals the development of a dual identity in professionalisation? Is professionalisation in this sense a sign of organisations maturing into more capable partners to the arguably more experienced (Western) institutions, shifting the power balance? Or is becoming more professional a sign of domestication to the agenda of certain powerful stakeholders, who define the boundaries of the profession? Which dominant dynamics can be observed in a broadly-defined transition country civil society, where individual participation in the form of activism may be overtaking the traditional forms of organised development work, especially with the spread of social media?