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BACKGROUND. Phase 1 study of ATR inhibition alone or with radiation therapy (PATRIOT) was a first-in-human phase I study of the oral ATR (ataxia telangiectasia and Rad3-related) inhibitor ceralasertib (AZD6738) in advanced solid tumors. METHODS. The primary objective was safety. Secondary objectives included assessment of antitumor responses and pharmacokinetic (PK) and pharmacodynamic (PD) studies. Sixty-seven patients received 20-240 mg ceralasertib BD continuously or intermittently (14 of a 28-day cycle). RESULTS. Intermittent dosing was better tolerated than continuous, which was associated with dose-limiting hematological toxicity. The recommended phase 2 dose of ceralasertib was 160 mg twice daily for 2 weeks in a 4-weekly cycle. Modulation of target and increased DNA damage were identified in tumor and surrogate PD. There were 5 (8%) confirmed partial responses (PRs) (40-240 mg BD), 34 (52%) stable disease (SD), including 1 unconfirmed PR, and 27 (41%) progressive disease. Durable responses were seen in tumors with loss of AT-rich interactive domain-containing protein 1A (ARID1A) and DNA damageresponse defects. Treatment-modulated tumor and systemic immune markers and responding tumors were more immune inflamed than nonresponding. CONCLUSION. Ceralasertib monotherapy was tolerated at 160 mg BD intermittently and associated with antitumor activity. TRIAL REGISTRATION. Clinicaltrials.gov: NCT02223923, EudraCT: 2013-003994-84. FUNDING. Cancer Research UK, AstraZeneca, UK Department of Health (National Institute for Health Research), Rosetrees Trust, Experimental Cancer Medicine Centre., Introduction ATR (ataxia telangiectasia and Rad3-related) is a critical kinase in the DNA damage response (DDR) (1, 2). Preclinical data have identified multiple cancer-related phenotypes sensitizing tumor cells to monotherapy [...]

An interdisciplinary team of academics and representatives of fishing fleets and government collaborated to study the emerging requirements for sustainability in Canada's fisheries. Fisheries assessment and management has focused on biological productivity with insufficient consideration of social (including cultural), economic, and institutional (governance) aspects. Further, there has been little discussion or formal evaluation of the effectiveness of fisheries management. The team of over 50 people (i) identified a comprehensive set of management objectives for a sustainable fishery system based on Canadian policy statements, (ii) combined objectives into an operational framework with relevant performance indicators for use in management planning, and (iii) undertook case studies that investigated some social, economic, and governance aspects in greater detail. The resulting framework extends the suite of widely accepted ecological aspects (productivity and trophic structure, biodiversity, and habitat-ecosystem integrity) to include comparable economic (viability and prosperity, sustainable livelihoods, distribution of access and benefits, regional-community benefits), social (health and well-being, sustainable communities, ethical fisheries), and institutional (legal obligations, good governance structure, effective decision-making) aspects of sustainability. This work provides a practical framework for implementation of a comprehensive approach to sustainability in Canadian fisheries. The project also demonstrates the value of co-construction of collaborative research and co-production of knowledge that combines and builds on the strengths of academics, industry, and government. Une equipe interdisciplinaire d'universitaires et de representants gouvernementaux et de flottes de peche a collabore a l'etude des nouvelles exigences en matiere de perennite des ressources halieutiques canadiennes. L'evaluation et la gestion de ces ressources ont mis l'accent sur la productivite biologique en ne tenant pas suffisamment compte d'aspects sociaux (y compris des aspects culturels), economiques et institutionnels (de gouvernance). L'efficacite de la gestion des peches a en outre fait l'objet de tres peu de discussions ou d'evaluations formelles. L'equipe composee de plus de 50 membres a (i) cerne un ensemble exhaustif d'objectifs de gestion pour un systeme de peches perenne reposant sur des enonces de principes canadiens, (ii) regroupe ces objectifs en un cadre operationnel comptant des indicateurs de rendement pertinents a utiliser dans la planification de la gestion et (iii) realise des etudes de cas pour examiner plus en detail certains aspects sociaux, economiques et de gouvernance. Le cadre en decoulant elargit l'ensemble des aspects ecologiques (productivite et structure trophique, biodiversite et integrite des habitats et ecosystemes) largement acceptes pour y inclure des aspects economiques (viabilite et prosperite, moyens de subsistance durables, repartition de l'acces et des benefices, avantages pour les regions-collectivites), sociaux (sante et bien-etre, collectivites durables, peches ethiques) et institutionnels (obligations legales, structure de bonne gouvernance, processus decisionnel efficace) comparables de la perennite. Ces travaux fournissent un cadre pratique pour la mise en oeuvre d'une approche integree visant la perennite des ressources halieutiques canadiennes. Le projet demontre egalement la valeur de la construction collective de recherches collaboratives et de la production collective de connaissances qui mettent en commun les forces des universitaires, de l'industrie et des gouvernements. [Traduit par la Redaction], Introduction Canada's legislation and international commitments require attention to ecological, social (including cultural), economic, and institutional (governance) aspects of fisheries. The Federal Sustainable Development Strategy (ECCC 2016), which, along with [...]

Atlantic hurricane activity has increased significantly since 1995 (refs 1-4), but the underlying causes of this increase remain uncertain (2,5-15). It is widely thought that rising Atlantic sea surface temperatures [...]

Author(s): Mark A. Saunders (corresponding author) [1]; Adam S. Lea [1] Atlantic hurricane activity has increased significantly since 1995 (refs 1-4), but the underlying causes of this increase remain uncertain [...]

Author(s): Mark A. Saunders (corresponding author); Adam S. Lea Much of the property damage from natural hazards in the United States is caused by landfalling hurricanes [1, 2, 3]--strong tropical [...]

Conventional structures used for age determinations of teleost fishes (e.g. fin rays, otoliths, scales) cannot be used for elasmobranchs in which these structures are cartilaginous. However, vertebral centra with systematic [...]

European Union policy that allows professionals from member countries to migrate and practice their profession in another member country without having to requalify has been slow to evolve. However, such an impediment has not deterred the migration of professionals who demonstrate a willingness to undergo requalification. Identification of such barriers for various immigrant types is imperative to reducing the impact of forces working against freedom of movement., Introduction The right of a professionally qualified European Union (EU) citizen to practise on the same basis as any national in a host state has been deemed essential since the [...]

The fall of the Saddam Hussein regime in Iraq created a drastic gap in governmental services--so drastic that many of the Iraqi prisons were evacuated. The only prisons that remained [...]

It is said that many things in the business of corrections are cyclical--that is, everything has been tried before and is periodically resurrected and tried again, usually with a different [...]

A research undertaken in the English Language Teaching division of an educational publishing house is reported. The research found that writers expected publishers to provide enthusiasm, excitement, support, encouragement and a gate-keeping role and they indicated a gap between expectations and perceptions with regards to feedback on sales and promotional trips.

The effects of the functional view and the ontological view of initiation on the whole life of the church are outlined. The church exists as an ongoing process of formation and reformation as it struggles to live faithfully to the story of God.

Correctional programming today is at a level of effectiveness that exceeds previous expectations. Jurisdictions throughout North America are utilizing research-based programs to educate, train and motivate offenders. Gone are the [...]