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DNA methyltransferase inhibitor exposure–response: Challenges and opportunities
Although DNA methyltransferase inhibitors (DNMTis), such as azacitidine and decitabine, are used extensively in the treatment of myelodysplastic syndromes and acute myeloid leukemia, there remain unanswered questions about DNMTi's mechanism of action and predictors of clinical response. Because patients often remain on single‐agent DNMTis or DNMTi‐containing regimens for several months before knowing whether clinical benefit can be achieved, the development and clinical validation of response‐predictive biomarkers represents an important unmet need in oncology. In this review, we will summarize the clinical studies that led to the approval of azacitidine and decitabine, as well as the real‐world experience with these drugs. We will then focus on biomarker development for DNMTis—specifically, efforts at determining exposure–response relationships and challenges that remain impacting the broader clinical translation of these methods. We will highlight recent progress in liquid‐chromatography tandem mass spectrometry technology that has allowed for the simultaneous measurement of decitabine genomic incorporation and global DNA methylation, which has significant potential as a mechanism‐of‐action based biomarker in patients on DNMTis. Last, we will cover important research questions that need to be addressed in order to optimize this potential biomarker for clinical use.
Journal Article
Applying Systemic Functional Linguistics
Applying Systemic Functional Linguistics: The State of the Art in China Today showcases new work from leading scholars in China, as well as offering perspectives on this work from M.A.K. Halliday and Jim Martin. The range of topics covers graphology/phonology, lexis, group and clause, clause complex, text, typology, semiotics, multimodality, stylistics, translation, and teaching. Not only will this book introduce the latest research into language and multimodal discourse being undertaken by scholars in China today, but also suggest the way forward in terms of where linguistics should be going if the aim is (still) to create ‘the innovative producers of social semiotic theory, description and practice the world rightfully expects from the intellectual superpower China is economically positioned to become’ (Jim Martin). This book is essential reading for scholars involved with systemic functional linguistics and interested in its shifting dynamics.
eBook
Retraction Note: A thematic analysis of system wide learning from first wave Covid-19 in the east of England
This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1186/s12913-022-07797-7.
Journal Article
A thematic analysis of system wide learning from first wave Covid-19 in the East of England
The Covid-19 pandemic has created an unprecedented challenge for health and social care systems globally. There is an urgent need for research on experiences of COVID-19 at different levels of health systems, including lessons from professional, organisational and local system responses, that can be used to inform managerial and policy responses.
This paper presents the findings from a thematic analysis of front-line staff experiences working across the Norfolk and Waveney integrated care system (ICS) in the East of England during April and October 2020 to address the question \"What are the experiences and perceptions of partner organisations and practitioners at multiple levels of the health system in responding to COVID-19 during the first wave of the pandemic?\" This question was posed to learn from how practitioners, interdependent partner organisations and the system experienced the pandemic and responded. 176 interview transcripts derived from one to one and focus group interviews, meeting notes and feedback from a \"We Care Together\" Instagram campaign were submitted for qualitative thematic analysis to an external research team at a regional University commissioned to undertake an independent evaluation. Three phases of qualitative analysis were systematically undertaken to derive the findings.
Thirty-one themes were distilled highlighting lessons learned from things that went well compared with those that did not; challenges compared with the celebrations and outcomes; learning and insights gained; impact on role; and system headlines. The analysis supported the ICS to inform and capitalise on system wide learning for integration, improvement and innovations in patient and care home resident safety, and staff wellbeing to deal with successive waves of the pandemic as well as prioritising workforce development priorities as part of its People Plan.
The findings contribute to a growing body of knowledge about what impact the pandemic has had on health and social care systems and front-line practitioners globally. It is important to understand the impact at all three levels of the system (micro, meso and macro) as it is the meso and macro system levels that ultimately impact front line staff experiences and the ability to deliver person centered safe and effective care in any context. The paper presents implications for future workforce and health services policy, practice innovation and research.
Journal Article
Mobile app validation: a digital health scorecard approach
While digital health solutions continue to grow in number and in complexity, the ability for stakeholders in healthcare to easily discern quality lags far behind. This challenge is in part due to the lack of a transparent and standardized approach to validation. Evaluation of mobile health applications (apps) is further burdened by low barriers to development and direct-to-user marketing, leading to a crowded and confusing landscape. In this context, we investigated the pragmatic application of a previously described framework for digital health validation, the Digital Health Scorecard, in a cohort of 22 popular mobile health oncology apps. The apps evaluated using this framework performed poorly, scoring 49.4% across all evaluation criteria as a group. Performance across component domains varied considerably with cost scoring highest at 100%, usability at 56.7%, technical at 37.3%, and clinical at 15.9%. satisfaction of prospectively determined end-user requirements derived from patient, family, and clinician consensus scored 37.2%. While cost outperformed consistently and usability was adequate, the results also suggested that apps suffered from significant technical limitations, were of limited clinical value, and generally did not do what end users wanted. These large gaps further support the need for transparent and standardized evaluation to help all stakeholders in healthcare improve the quality of mobile health.
Journal Article
AMPK inhibition sensitizes acute leukemia cells to BH3 mimetic-induced cell death
BH3 mimetics, including the BCL2/BCLX
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/BCLw inhibitor navitoclax and MCL1 inhibitors S64315 and tapotoclax, have undergone clinical testing for a variety of neoplasms. Because of toxicities, including thrombocytopenia after BCLX
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inhibition as well as hematopoietic, hepatic and possible cardiac toxicities after MCL1 inhibition, there is substantial interest in finding agents that can safely sensitize neoplastic cells to these BH3 mimetics. Building on the observation that BH3 mimetic monotherapy induces AMP kinase (AMPK) activation in multiple acute leukemia cell lines, we report that the AMPK inhibitors (AMPKis) dorsomorphin and BAY-3827 sensitize these cells to navitoclax or MCL1 inhibitors. Cell fractionation and phosphoproteomic analyses suggest that sensitization by dorsomorphin involves dephosphorylation of the proapoptotic BCL2 family member BAD at Ser75 and Ser99, leading BAD to translocate to mitochondria and inhibit BCLX
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. Consistent with these results, BAD knockout or mutation to BAD S75E/S99E abolishes the sensitizing effects of dorsomorphin. Conversely, dorsomorphin synergizes with navitoclax or the MCL1 inhibitor S63845 to induce cell death in primary acute leukemia samples ex vivo and increases the antitumor effects of navitoclax or S63845 in several xenograft models in vivo with little or no increase in toxicity in normal tissues. These results suggest that AMPK inhibition can sensitize acute leukemia to multiple BH3 mimetics, potentially allowing administration of lower doses while inducing similar antineoplastic effects.
Journal Article