Personalized recurrence risk assessment following the birth of a child with a pathogenic de novo mutation

Following the diagnosis of a paediatric disorder caused by an apparently de novo mutation, a recurrence risk of 1-2% is frequently quoted due to the possibility of parental germline mosaicism; but for any specific couple, this figure is usually incorrect. We present a systematic approach to providing individualized recurrence risk. By combining locus-specific sequencing of multiple tissues to detect occult mosaicism with long-read sequencing to determine the parent-of-origin of the mutation, we show that we can stratify the majority of couples into one of seven discrete categories associated with substantially different risks to future offspring. Among 58 families with a single affected offspring (representing 59 de novo mutations in 49 genes), the recurrence risk for 35 (59%) was decreased below 0.1%, but increased owing to parental mixed mosaicism for 5 (9%)-that could be quantified in semen for paternal cases (recurrence risks of 5.6-12.1%). Implementation of this strategy offers the prospect of driving a major transformation in the practice of genetic counselling.Published version, accepted versionThis article is freely available online. Click on the 'Additional Link' above to access the full-text via the publisher's site

A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer

The lysyl oxidase family represents a promising target in stromal targeting of solid tumors due to the importance of this family in crosslinking and stabilizing fibrillar collagens and its known role in tumor desmoplasia. Using small-molecule drug-design approaches, we generated and validated PXS-5505, a first-in-class highly selective and potent pan-lysyl oxidase inhibitor. We demonstrate in vitro and in vivo that pan-lysyl oxidase inhibition decreases chemotherapy-induced pancreatic tumor desmoplasia and stiffness, reduces cancer cell invasion and metastasis, improves tumor perfusion and enhances the efficacy of chemotherapy in the autochthonous genetically engineered KPC model, while also demonstrating antifibrotic effects in human patient-derived xenograft models of pancreatic cancer. PXS-5505 is orally bioavailable, safe and effective at inhibiting lysyl oxidase activity in tissues. Our findings present the rationale for progression of a pan-lysyl oxidase inhibitor aimed at eliciting a reduction in stromal matrix to potentiate chemotherapy in pancreatic ductal adenocarcinoma

Thinking disability orientation : practicing affirmation

Introduction: Occupational therapy’s theoretical base is informed by beliefs in empowerment, partnership, choice and hope — all key components in client-centred practice (Sumsion and Law 2006). In order to be client-centred, it is important to appreciate an individual’s perception of their own disability, known as their disability orientation. Disability orientation, as described by Darling and Heckert (2010), includes three aspects: disability identity; adherence to a particular model of disability, and involvement in disability rights activism. Each type of disability orientation will affect the disabled person’s beliefs and feelings about themselves, their impaired bodies and their disabled lives. This, in turn, is likely to influence their expectations of and satisfaction with occupational therapy services. Therefore, occupational therapists aiming to work within a client-centred approach should be cognisant of this concept and consider its possible impact on their therapeutic approach. This seminar will: – Explore the concept of disability orientation and discuss examples of different orientations; – Examine the affirmative disability orientation as it relates to occupational therapy; – Enable participants to analyse and understand their clients’ disability orientation; – Discuss strategies to provide intervention informed by a client’s disability orientation. Case studies will be used to promote discussion and explore practical ways to ascertain an individual’s disability orientation. The affirmative disability orientation will be discussed in particular. Impact on service users: Understanding disability orientation could lead to enhanced client-centred and culturally sensitive practice. Implications for occupational therapy: Contribution to the improvement of practice through the development of culturally sensitive therapeutic strategies