Types of treatment collaboration between conventional and alternative practitioners—results from a research project at a Danish MS hospital

<strong>Introduction:</strong> More than 50% of the People with Multiple Sclerosis (PwMS) in Denmark use alternative treatment. Most of them combine alternative and conventional treatment, but PwMS often find that there is no dialogue, coordination or synergy between the parallel courses of treatment offered. For this reason the Danish Multiple Sclerosis Society conducted a research project to develop and examine different models for collaboration between conventional and alternative treatment providers. <br /><strong>Materials and methods: </strong>Empirical material consist of individual interviews with practitioners, a group interview with practitioners, a group interview with professional staff at the Danish MS hospital that provided the organisational framework for the project, interviews with patients as well as written responses from participating treatment providers in connection with practitioner-researcher seminars held. <br /><strong>Results:</strong> Collaboration between researchers and the treatment team resulted in the development examination of several models which describe the strengths and weaknesses of various types of collaboration. The models also show that the various types of collaboration place different requirements on the degree of 1) mutual acknowledgement and understanding among practitioners, 2) flexibility and resources in the organizational framework, and 3) patients' activities and own efforts, respectively.    <br /><strong>Perspectives:</strong> The relationship between integration and pluralism can contribute to a fruitful discussion in regards to the value of treatment collaboration. In addition to the many positive perspectives the characterise integration of different treatment modalities the project points to the importance of not overlooking the opportunities, values and potential inherent in a pluralistic ideal in the form of patients' own active efforts and the dynamism that can arise when the patient becomes a co-informant, co-coordinator and/or co-integrator.  <br /><br /

Brobygning mellem etablerede og alternative behandlere

Det er ofte et problem for mennesker med MS (MmMS), at de modtager mange forskellige symptomrettede behandlinger, som ikke er  koordineret i en behandlingsplan. I stigende grad søger MmMS behandlere, der forholder sig til hele personen, og ikke splitter personen op i symptomer. Mange MmMS opsøger alternative behandlere for at afprøve deres behandlinger og behandlingsresultater. Der initieres imidlertid sjældent et samarbejde mellem de etablerede og alternative behandlere, som patienterne vælger selv at kombinere. I erkendelse af at mange MmMS søger alternative behandlere, besluttede Scleroseforeningen i 2004 at søsætte et behandlings- og forskningsprojekt, der har til formål at udvikle og afprøve en model for brobygning mellem etablerede og alternative behandlere baseret på en forskningsbaseret evaluering og udforske, om et samarbejde baseret på denne model kan forbedre behandlingsresultater for MmMS. I denne artikel sætter vi fokus på udviklingen af en model for brobygning

Activation of the ATR kinase by the RPA-binding protein ETAA1

Activation of the ATR kinase following perturbations to DNA replication relies on a complex mechanism involving ATR recruitment to RPA-coated single-stranded DNA via its binding partner ATRIP and stimulation of ATR kinase activity by TopBP1. Here, we discovered an independent ATR activation pathway in vertebrates, mediated by the uncharacterized protein ETAA1 (Ewing's tumour-associated antigen 1). Human ETAA1 accumulates at DNA damage sites via dual RPA-binding motifs and promotes replication fork progression and integrity, ATR signalling and cell survival after genotoxic insults. Mechanistically, this requires a conserved domain in ETAA1 that potently and directly stimulates ATR kinase activity independently of TopBP1. Simultaneous loss of ETAA1 and TopBP1 gives rise to synthetic lethality characterized by massive genome instability and abrogation of ATR-dependent signalling. Our findings demonstrate that parallel TopBP1-and ETAA1-mediated pathways underlie ATR activation and that their combined action is essential for coping with replication stress

Concerted SUMO-targeted ubiquitin ligase activities of TOPORS and RNF4 are essential for stress management and cell proliferation

Protein SUMOylation provides a principal driving force for cellular stress responses, including DNA–protein crosslink (DPC) repair and arsenic-induced PML body degradation. In this study, using genome-scale screens, we identified the human E3 ligase TOPORS as a key effector of SUMO-dependent DPC resolution. We demonstrate that TOPORS promotes DPC repair by functioning as a SUMO-targeted ubiquitin ligase (STUbL), combining ubiquitin ligase activity through its RING domain with poly-SUMO binding via SUMO-interacting motifs, analogous to the STUbL RNF4. Mechanistically, TOPORS is a SUMO1-selective STUbL that complements RNF4 in generating complex ubiquitin landscapes on SUMOylated targets, including DPCs and PML, stimulating efficient p97/VCP unfoldase recruitment and proteasomal degradation. Combined loss of TOPORS and RNF4 is synthetic lethal even in unstressed cells, involving defective clearance of SUMOylated proteins from chromatin accompanied by cell cycle arrest and apoptosis. Our findings establish TOPORS as a STUbL whose parallel action with RNF4 defines a general mechanistic principle in crucial cellular processes governed by direct SUMO–ubiquitin crosstalk.</p