Comprehensive molecular characterization of adenoid cystic carcinoma reveals tumor suppressors as novel drivers and prognostic biomarkers

© 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Adenoid cystic carcinoma (ACC) is a MYB-driven head and neck malignancy with high rates of local recurrence and distant metastasis and poor long-term survival. New effective targeted therapies and clinically useful biomarkers for patient stratification are needed to improve ACC patient survival. Here, we present an integrated copy number and transcriptomic analysis of ACC to identify novel driver genes and prognostic biomarkers. A total of 598 ACCs were studied. Clinical follow-up was available from 366 patients, the largest cohort analyzed to date. Copy number losses of 1p36 (70/492; 14%) and of the tumor suppressor gene PARK2 (6q26) (85/343; 25%) were prognostic biomarkers; patients with concurrent losses (n = 20) had significantly shorter overall survival (OS) than those with one or no deletions (p < 0.0001). Deletion of 1p36 independently predicted short OS in multivariate analysis (p = 0.02). Two pro-apoptotic genes, TP73 and KIF1B, were identified as putative 1p36 tumor suppressor genes whose reduced expression was associated with poor survival and increased resistance to apoptosis. PARK2 expression was markedly reduced in tumors with 6q deletions, and PARK2 knockdown increased spherogenesis and decreased apoptosis, indicating that PARK2 is a tumor suppressor in ACC. Moreover, analysis of the global gene expression pattern in 30 ACCs revealed a transcriptomic signature associated with short OS, multiple copy number alterations including 1p36 deletions, and reduced expression of TP73. Taken together, the results indicate that TP73 and PARK2 are novel putative tumor suppressor genes and potential prognostic biomarkers in ACC. Our studies provide new important insights into the pathogenesis of ACC. The results have important implications for biomarker-driven stratification of patients in clinical trials. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.info:eu-repo/semantics/publishedVersio

Standardization as Institutional Work: The Regulatory Power of a Responsible Investment Standard

This paper conceptualizes standardization as institutional work to study the emergence of a standard and the deployment of its regulatory power. We rely on unique access to longitudinal archival data for exploring how the FTSE4Good index, a responsible investment index, emerged as a standard for socially responsible corporate behavior. Our results show how three types of standardization work - calculative framing, engaging and valorizing - support the design, legitimation and monitoring processes whereby a standard acquires its regulatory power. Our findings reveal new facets in the dynamics of standardization by approaching standardization as a product of institutional work and in showing how unintended consequences of that work can be recaptured to strengthen the regulatory power of the standard

Making Projects Real in a Higher Education Context

Challenging educators to rethink projects and see them as a practice rather than as a model of management the authors explore the possibilities for using live projects to enhance real world learning in higher education. Drawing on the work of the ‘critical projects movement’ the chapter outlines a theoretical underpinning for reconceptualising projects as a practice and proposes a new pedagogic model that of ‘agile learning’. Framing the use of live projects is a mode of real world learning that generates encounters with industry professionals and provides real-value outputs for clients. The chapter explores the challenges that face educators who wish to foreground ‘social learning’ and engagement with communities of practice as a means of easing the transition for students from education to the world of work

Metaphorical and interlingual translation in moving organizational practices across languages

Organizational scholars refer to translation as a metaphor in order to describe the transformation and movement of organizational practices across institutional contexts. However, they have paid relatively little attention to the challenges of moving organizational practices across language boundaries. In this conceptual paper, we theorize that when organizational practices move across contexts that differ not only in terms of institutions and cultures but also in terms of languages, translation becomes more than a metaphor; it turns into reverbalization of meaning in another language. We argue that the meeting of languages opens up a whole new arena for translator agency to unfold. Interlingual and metaphorical translation are two distinct but interrelated forms of translation that are mutually constitutive. We identify possible constellations between interlingual and metaphorical translation and illustrate agentic translation with published case examples. We also propose that interlingual translation is a key resource in the discursive constitution of multilingual organizations. This paper contributes to the stream of research in organization studies that has made translation a core aspect of its inquiry

Inducing institutional change through projects? : Three models of projectified governance

The study of short-term projects to implement policy has lately gained ground among scholars of environmental governance and public administration. The increasing reliance on and prevalence of projects, or ‘projectification’, has spurred critical debates on the ability of projects to contribute to long-term goals, including sustainability, as well as institutional change. Yet, the literature on projectification lacks specificity in terms of how projects are understood, how the relationship between projects and permanent organizations looks like, and how projects can influence institutional orders. The aim of this paper is to systematize the literature in order to uncover the process of transforming project outputs into institutional change. Three models of projectified governance – mechanistic, organic, and adaptive – is presented, providing a conceptual apparatus that advances the study of projects in environmental policy and governance. The paper argues that the adaptive model, with its reliance on multi-scalar networks for the coordination of project activities and knowledge, shows most promise in achieving institutional change to address complex environmental problems.Peer reviewe

Ambiguous workarounds in policy piloting in the NHS: Tensions, trade‐offs and legacies of organisational change projects

Pilot projects are increasingly used as a mechanism to enact organisational change, particularly government policy. Information technology's centrality to organisations often makes it key to the introduction of new processes. However, it can give rise to workarounds as employees circumvent impediments it presents by rejecting its prescribed use. Workarounds tend to be conceptualised dichotomously, as either ‘good’ problem solving, or ‘bad’ subversion of the technology. In pilot projects, workarounds are more ambiguous because those that support projects' successful completion in the short‐term may undermine day to day operations longer term. We draw on interview data from a policy pilot in general practice in the National Health Service in England aimed at extending access to care. We problematise the dichotomous conceptualisation of workarounds, finding they can be simultaneously supportive and undermining of policy pilots. Workarounds thereby become political, as employees are required to trade‐off consequences for themselves and the wider organisation

HF-EPR, Raman, UV/VIS Light Spectroscopic, and DFT Studies of the Ribonucleotide Reductase R2 Tyrosyl Radical from Epstein-Barr Virus

Epstein-Barr virus (EBV) belongs to the gamma subfamily of herpes viruses, among the most common pathogenic viruses in humans worldwide. The viral ribonucleotide reductase small subunit (RNR R2) is involved in the biosynthesis of nucleotides, the DNA precursors necessary for viral replication, and is an important drug target for EBV. RNR R2 generates a stable tyrosyl radical required for enzymatic turnover. Here, the electronic and magnetic properties of the tyrosyl radical in EBV R2 have been determined by X-band and high-field/high-frequency electron paramagnetic resonance (EPR) spectroscopy recorded at cryogenic temperatures. The radical exhibits an unusually low g1-tensor component at 2.0080, indicative of a positive charge in the vicinity of the radical. Consistent with these EPR results a relatively high C-O stretching frequency associated with the phenoxyl radical (at 1508 cm−1) is observed with resonance Raman spectroscopy. In contrast to mouse R2, EBV R2 does not show a deuterium shift in the resonance Raman spectra. Thus, the presence of a water molecule as a hydrogen bond donor moiety could not be identified unequivocally. Theoretical simulations showed that a water molecule placed at a distance of 2.6 Å from the tyrosyl-oxygen does not result in a detectable deuterium shift in the calculated Raman spectra. UV/VIS light spectroscopic studies with metal chelators and tyrosyl radical scavengers are consistent with a more accessible dimetal binding/radical site and a lower affinity for Fe2+ in EBV R2 than in Escherichia coli R2. Comparison with previous studies of RNR R2s from mouse, bacteria, and herpes viruses, demonstrates that finely tuned electronic properties of the radical exist within the same RNR R2 Ia class

Being careful what we wish for? Challenges and opportunities afforded through engagement with business and management research

Despite the proliferation of work within construction management that draws upon management and organizational theory, two omissions stand out from the body of published work: the absence of any real debate about the values of rigour and relevance in research; and the under-use of dominant perspectives in business and management research (such as institutional theory) to frame construction management and organizational issues. Drawing specifically upon the ideas of institutional logics and institutional work, this paper explores the tensions, ironies and contradictions of the rigour-relevance debate; and the challenges and opportunities facing construction management research (CMR) and its institutions in furthering management and organizational research agendas. In doing so, attention is directed to the complex, contested and changing nature of the knowledge base within the business and management field; as well as key differences between that community of practice and CMR

Spectroscopic Studies of the Iron and Manganese Reconstituted Tyrosyl Radical in Bacillus Cereus Ribonucleotide Reductase R2 Protein

Ribonucleotide reductase (RNR) catalyzes the rate limiting step in DNA synthesis where ribonucleotides are reduced to the corresponding deoxyribonucleotides. Class Ib RNRs consist of two homodimeric subunits: R1E, which houses the active site; and R2F, which contains a metallo cofactor and a tyrosyl radical that initiates the ribonucleotide reduction reaction. We studied the R2F subunit of B. cereus reconstituted with iron or alternatively with manganese ions, then subsequently reacted with molecular oxygen to generate two tyrosyl-radicals. The two similar X-band EPR spectra did not change significantly over 4 to 50 K. From the 285 GHz EPR spectrum of the iron form, a g1-value of 2.0090 for the tyrosyl radical was extracted. This g1-value is similar to that observed in class Ia E. coli R2 and class Ib R2Fs with iron-oxygen cluster, suggesting the absence of hydrogen bond to the phenoxyl group. This was confirmed by resonance Raman spectroscopy, where the stretching vibration associated to the radical (C-O, ν7a = 1500 cm−1) was found to be insensitive to deuterium-oxide exchange. Additionally, the 18O-sensitive Fe-O-Fe symmetric stretching (483 cm−1) of the metallo-cofactor was also insensitive to deuterium-oxide exchange indicating no hydrogen bonding to the di-iron-oxygen cluster, and thus, different from mouse R2 with a hydrogen bonded cluster. The HF-EPR spectrum of the manganese reconstituted RNR R2F gave a g1-value of ∼2.0094. The tyrosyl radical microwave power saturation behavior of the iron-oxygen cluster form was as observed in class Ia R2, with diamagnetic di-ferric cluster ground state, while the properties of the manganese reconstituted form indicated a magnetic ground state of the manganese-cluster. The recent activity measurements (Crona et al., (2011) J Biol Chem 286: 33053–33060) indicates that both the manganese and iron reconstituted RNR R2F could be functional. The manganese form might be very important, as it has 8 times higher activity

From practice to field:a multi-level model of practice-driven institutional change

This article develops a model of practice-driven institutional change - or change that originates in the everyday work of individuals but results in a shift in field-level logic. In demonstrating how improvisations at work can generate institutional change, we attend to the earliest moments of change, which extant research has neglected; and we contrast existing accounts that focus on active entrepreneurship and the contested nature of change. We outline the specific mechanisms by which change emerges from everyday work, becomes justified, and diffuses within an organization and field, as well as precipitating and enabling dynamics that trigger and condition these mechanisms. © Academy of Management Journal