Feasibility of a prehabilitation programme dedicated to older patients with cancer before complex medical-surgical procedures: the PROADAPT pilot study protocol.

BACKGROUND: Ageing is associated with an increased prevalence of comorbidities and sarcopenia as well as a decline of functional reserve of multiple organ systems, which may lead, in the context of the disease-related and/or treatment-related stress, to functional deconditioning. The multicomponent 'Prehabilitation & Rehabilitation in Oncogeriatrics: Adaptation to Deconditioning risk and Accompaniment of Patients' Trajectories (PROADAPT)' intervention was developed multiprofessionally to implement prehabilitation in older patients with cancer. METHODS: The PROADAPT pilot study is an interventional, non-comparative, prospective, multicentre study. It will include 122 patients oriented to complex medical-surgical curative procedures (major surgery or radiation therapy with or without chemotherapy). After informed consent, patients will undergo a comprehensive geriatric assessment and will be offered a prehabilitation kit that includes an advice booklet with personalised objectives and respiratory rehabilitation devices. Patients will then be called weekly and monitored for physical and respiratory rehabilitation, preoperative renutrition, motivational counselling and iatrogenic prevention. Six outpatient visits will be planned: at inclusion, a few days before the procedure and at 1, 3, 6 and 12 months after the end of the procedure. The main outcome of the study is the feasibility of the intervention, defined as the ability to perform at least one of the components of the programme. Clinical data collected will include patient-specific and cancer-specific characteristics. ETHICS AND DISSEMINATION: The study protocol was approved by the Ile de France 8 ethics committee on 5 June 2018. The results of the primary and secondary objectives will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03659123. Pre-results of the trial.

Regulation of the specialized DNA polymerase eta: revisiting the biological relevance of its PCNA- and ubiquitin-binding motifs.

During translesion synthesis (TLS), low-fidelity polymerases of the Y-family polymerases bypass DNA damages that block the progression of conventional processive DNA polymerases, thereby allowing the completion of DNA replication. Among the TLS polymerases, DNA polymerase eta (polη) performs nucleotide incorporation past ultraviolet (UV) photoproducts and is deficient in cancer-prone xeroderma pigmentosum variant (XPV) syndrome. Upon UV irradiation, the DNA sliding clamp PCNA is monoubiquitylated on its conserved Lys-164. This event is considered to facilitate the TLS process in vivo since polη preferentially interacts with monoubiquitylated PCNA through its ubiquitin-binding domain (UBZ) as well as its PCNA interacting peptide (PIP)-box. However, recent observations questioned this model. Therefore, in this study, we re-examined the relative contribution of the regulatory UBZ and PIP domains of polη in response to UVC. We show that simultaneous invalidation of both motifs confers sensitivity to UVC, sensitization by low concentrations of caffeine, prolonged inhibition of DNA synthesis and persistent S phase checkpoint activation, all characteristic features of XPV cells. While each domain is essential for efficient accumulation of polη in replication factories, mutational inactivation of UBZ or PIP motif only confers a slight sensitivity to UVC indicating that, although informative, polη focus analysis is not a reliable tool to assess the polη's ability to function in TLS in vivo. Taken together, these data indicate that PIP and UBZ motifs are not required for recruitment but for retention of polη at sites of stalled replication forks. We propose that this is a way to ensure that a sufficient amount of the protein is available for its bypass function.