Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth.

Acetylation of histones by lysine acetyltransferases (KATs) is essential for chromatin organization and function1. Among the genes coding for the MYST family of KATs (KAT5-KAT8) are the oncogenes KAT6A (also known as MOZ) and KAT6B (also known as MORF and QKF)2,3. KAT6A has essential roles in normal haematopoietic stem cells4-6 and is the target of recurrent chromosomal translocations, causing acute myeloid leukaemia7,8. Similarly, chromosomal translocations in KAT6B have been identified in diverse cancers8. KAT6A suppresses cellular senescence through the regulation of suppressors of the CDKN2A locus9,10, a function that requires its KAT activity10. Loss of one allele of KAT6A extends the median survival of mice with MYC-induced lymphoma from 105 to 413 days11. These findings suggest that inhibition of KAT6A and KAT6B may provide a therapeutic benefit in cancer. Here we present highly potent, selective inhibitors of KAT6A and KAT6B, denoted WM-8014 and WM-1119. Biochemical and structural studies demonstrate that these compounds are reversible competitors of acetyl coenzyme A and inhibit MYST-catalysed histone acetylation. WM-8014 and WM-1119 induce cell cycle exit and cellular senescence without causing DNA damage. Senescence is INK4A/ARF-dependent and is accompanied by changes in gene expression that are typical of loss of KAT6A function. WM-8014 potentiates oncogene-induced senescence in vitro and in a zebrafish model of hepatocellular carcinoma. WM-1119, which has increased bioavailability, arrests the progression of lymphoma in mice. We anticipate that this class of inhibitors will help to accelerate the development of therapeutics that target gene transcription regulated by histone acetylation.

Factors Influencing the Intention of Actors in Hospitals to Use Indoor Positioning Systems: Reasoned Action Approach.

BACKGROUND: Indoor positioning systems (IPS) have become increasingly important for several branches of the economy (eg, in shopping malls) but are relatively new to hospitals and underinvestigated in that context. This research analyzes the intention of actors within a hospital to use an IPS to address this gap. OBJECTIVE: To investigate the intentions of hospital visitors and employees (as the main actors in a hospital) to use an IPS in a hospital. METHODS: The reasoned action approach was used, according to which the behavior of an individual is caused by behavioral intentions that are affected by (1) a persuasion that represents the individual's attitude toward the behavior, (2) perceived norms that describe the influence of other individuals, and (3) perceived norms that reflect the possibility of the individual influencing the behavior. RESULTS: The survey responses of 323 hospital visitors and 304 hospital employees were examined separately using SmartPLS 3.3.3. Bootstrapping procedures with 5000 subsamples were used to test the models (one-tailed test with a significance level of .05). The results show that attitude (ß=.536; P<.001; f²=.381) and perceived norms (ß=.236; P<.001; f²=.087) are predictors of hospital visitors' intention to use an IPS. In addition, attitude (ß=.283; P<.001; f²=.114), perceived norms (ß=.301; P<.001; f²=.126), and perceived behavioral control (ß=.178; P=.005; f²=.062) are predictors of hospital employees' intention to use an IPS. CONCLUSIONS: This study has two major implications: (1) our extended reasoned action approach model, which takes into account spatial abilities and personal innovativeness, is appropriate for determining hospital visitors' and employees' intention to use an IPS; and (2) hospitals should invest in implementing IPS with a focus on (a) navigational services for hospital visitors and (b) asset tracking for hospital employees.

Do taxpayers consider quality labels as a form of recommendation for good tax-preparation services? Evidence from Germany.

Quality labels are important measures for reducing the information asymmetry between principals and agents to enhance trust. However, little research is available on the effects of quality labels used in tax-preparation services from critical perspectives in accounting. The present research contributes to the field by addressing the underlying reasons for German taxpayers to consider quality labels for identifying good tax-preparation services. These contributions are based on a survey of 199 taxpayers in Germany. The results show that the intention to consider quality labels is mainly driven by taxpayers' attitude and trust in quality labels, perceived norms having some influence, and perceived behavioral control having no influence. Hence, we highlight that the reasoned action approach is appropriate for this study, and aim to identify the relevant factors that influence taxpayers' intention to consider quality labels. The results contribute to a general understanding of the importance of quality labels for tax-preparation services in the context of accounting, organizations, and society. Both academia and practitioners can utilize these insights for further research and consultation on quality labels and tax-preparation services.

Acceptance of AI in Health Care for Short- and Long-Term Treatments: Pilot Development Study of an Integrated Theoretical Model.

BACKGROUND: As digital technologies and especially artificial intelligence (AI) become increasingly important in health care, it is essential to determine whether and why potential users intend to use related health information systems (HIS). Several theories exist, but they focus mainly on aspects of health care or information systems, in addition to general psychological theories, and hence provide a small number of variables to explain future behavior. Thus, research that provides a larger number of variables by combining several theories from health care, information systems, and psychology is necessary. OBJECTIVE: This study aims to investigate the intention to use new HIS for decisions concerning short- and long-term medical treatments using an integrated approach with several variables to explain future behavior. METHODS: We developed an integrated theoretical model based on theories from health care, information systems, and psychology that allowed us to analyze the duality approach of adaptive and nonadaptive appraisals and their influence on the intention to use HIS. We applied the integrated theoretical model to the short-term treatment using AI-based HIS for surgery and the long-term treatment of diabetes tracking using survey data with structured equation modeling. To differentiate between certain levels of AI involvement, we used several scenarios that include treatments by physicians only, physicians with AI support, and AI only to understand how individuals perceive the influence of AI. RESULTS: Our results showed that for short- and long-term treatments, the variables perceived threats, fear (disease), perceived efficacy, attitude (HIS), and perceived norms are important to consider when determining the intention to use AI-based HIS. Furthermore, the results revealed that perceived efficacy and attitude (HIS) are the most important variables to determine intention to use for all treatments and scenarios. In contrast, abilities (HIS) were important for short-term treatments only. For our 9 scenarios, adaptive and nonadaptive appraisals were both important to determine intention to use, depending on whether the treatment is known. Furthermore, we determined R² values that varied between 57.9% and 81.7% for our scenarios, which showed that the explanation power of our model is medium to good. CONCLUSIONS: We contribute to HIS literature by highlighting the importance of integrating disease- and technology-related factors and by providing an integrated theoretical model. As such, we show how adaptive and nonadaptive appraisals should be arranged to report on medical decisions in the future, especially in the short and long terms. Physicians and HIS developers can use our insights to identify promising rationale for HIS adoption concerning short- and long-term treatments and adapt and develop HIS accordingly. Specifically, HIS developers should ensure that future HIS act in terms of HIS functions, as our study shows that efficient HIS lead to a positive attitude toward the HIS and ultimately to a higher intention to use.

Tumor immune evasion: insights from CRISPR screens and future directions.

Despite the clinical success of cancer immunotherapies including immune checkpoint blockade and adoptive cellular therapies across a variety of cancer types, many patients do not respond or ultimately relapse; however, the molecular underpinnings of this are not fully understood. Thus, a system-level understating of the routes to tumor immune evasion is required to inform the design of the next generation of immunotherapy approaches. CRISPR screening approaches have proved extremely powerful in identifying genes that promote tumor immune evasion or sensitize tumor cells to destruction by the immune system. These large-scale efforts have brought to light decades worth of fundamental immunology and have uncovered the key immune-evasion pathways subverted in cancers in an acquired manner in patients receiving immune-modulatory therapies. The comprehensive discovery of the main pathways involved in immune evasion has spurred the development and application of novel immune therapies to target this process. Although successful, conventional CRISPR screening approaches are hampered by a number of limitations, which obfuscate a complete understanding of the precise molecular regulation of immune evasion in cancer. Here, we provide a perspective on screening approaches to interrogate tumor-lymphocyte interactions and their limitations, and discuss further development of technologies to improve such approaches and discovery capability.

Determining design criteria for indoor positioning system projects in hospitals: A design science approach.

Objectives: Indoor navigation systems (indoor positioning systems) can improve orientation for patients in hospitals and help employees to track assets. Many hospitals would like to implement indoor positioning systems but do not know how. To support them in doing this, and to gain knowledge about the requirements for indoor positioning system implementation, our research identifies the design criteria relevant to indoor positioning system implementation projects. Methods: A design science research process is built to design and evaluate an artifact. For this, five indoor positioning system developers and five hospital IT management representatives from various hospitals and companies in Germany are interviewed. Further, controlled experiments are conducted in Germany, using an ultrasound-based indoor positioning system. Results: We determined and tested indoor positioning system functions, evaluated indoor positioning system performance criteria, and identified the operating conditions in hospitals. Our results show that indoor positioning system functions should provide a benefit to a hospital's daily operations, that some performance criteria are more important than others, and that operating conditions are important, e.g., radiation. Conclusion: As a theoretical contribution, we show how design science research can be applied to the context of indoor positioning systems in hospitals. In addition, we make a practical contribution in that our propositions can be used for future indoor positioning system developments.

The disease or the vaccination: Which is more important when deciding whether to vaccinate?

RATIONALE: Vaccinations provide adequate protection against many virus-related diseases. Nonetheless, many individuals refuse voluntary vaccinations, and their refusal could contribute to the spread of diseases. Previous research on the intention to vaccinate has been limited by focusing on a single target group. OBJECTIVE: In this study, we develop an integrated theoretical framework incorporating the dual approach with relevant theories related to both disease and vaccination. Our objective is to examine the behavioral reasons for the decision to vaccinate or not. The vaccination-related appraisals concern aspects of vaccination and the disease-related appraisals concern aspects of COVID-19. The framework is applied to the much-discussed context of COVID-19 vaccination. METHOD: We investigate the intention to vaccinate of two target groups, unvaccinated individuals and twice-vaccinated individuals, with a partial squares structured equation model. RESULTS: Our results show that unvaccinated individuals are driven in their intention to vaccinate by their attitude (toward vaccination); factors relating to the disease have no impact. In contrast, when deciding whether to be revaccinated, twice-vaccinated individuals balance factors relating to vaccination and factors relating to disease. CONCLUSIONS: We conclude that the proposed integrated theoretical model is appropriate for investigating diverse target groups and deriving implications.

Loss of TIP60 (KAT5) abolishes H2AZ lysine 7 acetylation and causes p53, INK4A, and ARF-independent cell cycle arrest.

Histone acetylation is essential for initiating and maintaining a permissive chromatin conformation and gene transcription. Dysregulation of histone acetylation can contribute to tumorigenesis and metastasis. Using inducible cre-recombinase and CRISPR/Cas9-mediated deletion, we investigated the roles of the histone lysine acetyltransferase TIP60 (KAT5/HTATIP) in human cells, mouse cells, and mouse embryos. We found that loss of TIP60 caused complete cell growth arrest. In the absence of TIP60, chromosomes failed to align in a metaphase plate during mitosis. In some TIP60 deleted cells, endoreplication occurred instead. In contrast, cell survival was not affected. Remarkably, the cell growth arrest caused by loss of TIP60 was independent of the tumor suppressors p53, INK4A and ARF. TIP60 was found to be essential for the acetylation of H2AZ, specifically at lysine 7. The mRNA levels of 6236 human and 8238 mouse genes, including many metabolism genes, were dependent on TIP60. Among the top 50 differentially expressed genes, over 90% were downregulated in cells lacking TIP60, supporting a role for TIP60 as a key co-activator of transcription. We propose a primary role of TIP60 in H2AZ lysine 7 acetylation and transcriptional activation, and that this fundamental role is essential for cell proliferation. Growth arrest independent of major tumor suppressors suggests TIP60 as a potential anti-cancer drug target.

The acetyltransferase KAT7 is required for thymic epithelial cell expansion, expression of AIRE target genes, and thymic tolerance.

The autoimmune regulator (AIRE) induces the transcription of thousands of peripheral tissue genes (PTGs) in thymic epithelial cells (TECs) to mediate immunological tolerance. The chromatin state required for optimal AIRE function in TECs and how this state is induced remains unclear. We tested the role of the histone acetyltransferase, KAT7 (also known as HBO1 or MYST2), which is essential for acetylation of histone 3 lysine 14, in TEC differentiation, AIRE-mediated PTG expression, and thymic tolerance. We find that KAT7 is required for optimal expansion of medullary TEC and has a major role in the expression of AIRE-dependent PTGs, associated with enhanced chromatin accessibility at these gene loci in TECs. Mice with TEC-specific Kat7 deletion develop organ-specific autoimmunity with features resembling those observed in Aire-deficient mice. These findings highlight critical roles for KAT7-mediated acetylation in promoting a chromatin state at PTG loci that enables AIRE function and the establishment of immunological tolerance.