Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen

The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.Peer reviewe

Maden als potentieller Vektor für die Übertragung von Krankheitserregern und Konsequenzen für die Entsorgung

Background and aims: Debridement therapy with sterile bred larvae in non-healing wounds is a widely accepted safe and efficient treatment modality. However, during application in the contaminated wound bed microbial contamination with potential microbial pathogen spread after escape from the wound or after unreliable disposal procedure may happen, particularly in the case of not using bio-bags. The aims of this work were first to investigate the release of ingested bacteria into the environment by maggots and second to examine the common practice of freezing the maggots after use and/or disposal in trash-bags. Potential methods for hygienic safe disposal of used maggots should be deduced.Methods: First, Maggots were contaminated with S. aureus by allowing them to crawl over an agar surface completely covered with bacterial growth over 24 h at 37°C. After external disinfection maggots were transferred onto sterile Columbia agar plates and shedding of S. aureus was visualized. Second, maggots were frozen at -20°C for 1, 2, 5, 10, 30, and 60 min. After exposure, the larvae were transferred onto Columbia blood agar with consecutive incubation at 37°C over 48 h. The larvae were analyzed visually for mobility and eating activities. The frozen bodies of dead larvae were examined for viable bacteria.Results: We could demonstrate that maggots release formerly ingested pathogens (S. aureus ). Freezing at -20°C for at least 60 min was able to kill all maggots, however the contaminant bacteria inside could survive.Conclusion: Since freezing is apparently able to kill maggots but not to reliabely inactivate the ingested bacterial pathogens, we recommend the disposal of free-range larvae in screw cap vials after use to achieve full hygienic control.Zielsetzung: Der Einsatz steriler handelsüblicher Larven zum Debridement chronischer Wunden ist ein akzeptiertes Therapieverfahren. Allerdings kann es bei Anwendung in der mikrobiell kontaminierten Wunde zur Weiterverbreitung von in der Wunde vorkommenden Erregern durch die Maden insbesondere nach unzuverlässiger Entsorgung kommen und wenn keine Biobags verwendet werden. Daher sollten sowohl die Freisetzung der von Maden ingestierten Bakterien in die Umgebung als auch die zur Inaktivierung der Maden übliche Praxis des Tiefgefrierens auf die ingestierten Bakterien vor der Entsorgung untersucht werden, um Schlussfolgerungen für eine sichere Entsorgung abzuleiten.Methode: Maden wurden mit S. aureus kontaminiert, indem ihnen das Kriechen über eine komplett bewachsene Agarplatte nach Kultivierung für 24 h bei 37°C gewährt wurde. Nach äußerlicher Desinfektion wurden die Maden auf sterile Columbia Blutagarplatten überführt, um die Ausscheidung von S. aureus festzustellen. Zur Überprüfung des Einflusses von -20 °C für 1, 2, 5, 10, 30 bzw. 60 min wurden die Maden auf Columbia Blutagarplatten überführt und 48 h bei 37°C kultiviert. Danach wurden die Mobilität und Fressaktivität der Maden visuell bewertet und der gefrorene Körper toter Maden wurde auf lebensfähige Bakterien untersucht.Ergebnisse: Maden setzen zuvor ingestierte Bakterien (S. aureus ) frei. Durch Gefrieren bei -20°C für mindestens 60 min werden die Maden abgetötet, während die ingestierten Bakterien überleben.Schlussfolgerung: Da nur die Maden, nicht aber ingestierte Bakterien durch Einfrieren bei -20°C für 60 min abgetötet werden, ist die Entsorgung frei beweglicher Maden in Fläschchen mit Schraubverschluss zu empfehlen

Job insecurity during an economic crisis: the psychological consequences of widespread corporate cost-cutting announcements.

Economic crises, such as the one induced by the COVID-19 pandemic, and resulting widespread corporate cost-cutting, drastically alter the nature of work. Job insecurity represents a critical intermediate between the economic ramifications of an economic crisis and work and stress outcomes, however, the underlying cognitive consequences of job insecurity and how to buffer those effects are not well understood. We examine how corporate cost-cutting announcements indirectly relate to employees' attention through their relationship with employee job insecurity and investigate supervisor support as a potential buffer of these relationships. We used multi-source data to test our research model, combining data on cost-cutting announcements (budget cuts, layoffs, and furloughs) in news articles for 165 organizations with survey data from 421 full-time employees from these organizations between March 26, 2020 and April 8, 2020. Cost-cutting announcements are positively related to job insecurity, which is related to employee’s attention with supervisor support mitigating the effects of job insecurity on attention. Grounded in self-regulation theories, we contribute to and extend the theoretical understanding of the organizational context for job insecurity and cognitive outcomes. We discuss the implications for organizations to manage and prepare for future economic crises, specifically on organizational communication and supervisor interventions

Co-production of Public Services:Institutional Barriers to the Involvement of Citizens in Policy Implementation

Co-production refers to the involvement of citizens/service users in the direct implementation of policy. In practice, this means that public servants and citizens act jointly to deliver public services that would traditionally be the domain of the public servant alone. Co-production is increasingly posited as a desirable model of implementation for health and social policies, development and environment programs, and community safety, among other areas. However, while we have some understanding about the role of context in shaping approaches to policy implementation generally, comparatively less attention has been paid to the contextual contingency of co-production. This chapter employs an institutional logics framework to consider the different ways in which co-production plays a role - or not - in policy implementation. In particular, I discuss the way that a community logic, professional logic, market logic, and state logic in different sectors and different contexts shape public servants’ perceptions of their role visà- vis citizens in policy implementation and produce opportunities and barriers for co-production with citizens.</p