Pharmacological inhibition of RAS overcomes FLT3 inhibitor resistance in FLT3-ITD+ AML through AP-1 and RUNX1

\ua9 2024 The Author(s). AML is characterized by mutations in genes associated with growth regulation such as internal tandem duplications (ITD) in the receptor kinase FLT3. Inhibitors targeting FLT3 (FLT3i) are being used to treat patients with FLT3-ITD+ but most relapse and become resistant. To elucidate the resistance mechanism, we compared the gene regulatory networks (GRNs) of leukemic cells from patients before and after relapse, which revealed that the GRNs of drug-responsive patients were altered by rewiring their AP-1-RUNX1 axis. Moreover, FLT3i induces the upregulation of signaling genes, and we show that multiple cytokines, including interleukin-3 (IL-3), can overcome FLT3 inhibition and send cells back into cycle. FLT3i leads to loss of AP-1 and RUNX1 chromatin binding, which is counteracted by IL-3. However, cytokine-mediated drug resistance can be overcome by a pan-RAS inhibitor. We show that cytokines instruct AML growth via the transcriptional regulators AP-1 and RUNX1 and that pan-RAS drugs bypass this barrier

Using low-cost sensor technologies and advanced computational methods to improve dose estimations in health panel studies: results of the AIRLESS project.

BACKGROUND: Air pollution epidemiology has primarily relied on fixed outdoor air quality monitoring networks and static populations. METHODS: Taking advantage of recent advancements in sensor technologies and computational techniques, this paper presents a novel methodological approach that improves dose estimations of multiple air pollutants in large-scale health studies. We show the results of an intensive field campaign that measured personal exposures to gaseous pollutants and particulate matter of a health panel of 251 participants residing in urban and peri-urban Beijing with 60 personal air quality monitors (PAMs). Outdoor air pollution measurements were collected in monitoring stations close to the participants' residential addresses. Based on parameters collected with the PAMs, we developed an advanced computational model that automatically classified time-activity-location patterns of each individual during daily life at high spatial and temporal resolution. RESULTS: Applying this methodological approach in two established cohorts, we found substantial differences between doses estimated from outdoor and personal air quality measurements. The PAM measurements also significantly reduced the correlation between pollutant species often observed in static outdoor measurements, reducing confounding effects. CONCLUSIONS: Future work will utilise these improved dose estimations to investigate the underlying mechanisms of air pollution on cardio-pulmonary health outcomes using detailed medical biomarkers in a way that has not been possible before.This project is funded under the Newton Fund Programme awarded by Natural Environmental Research Council (NERC Grant NE/N007018/1) with support from Medical Research Council (MRC) and by the National Natural Science Foundation of China (NSFC Grant 81571130100). The NSFC funding is mainly used to support the field work in China, and NERC funding is mainly used for coordination and the further analysis

Gene regulatory network analysis predicts cooperating transcription factor regulons required for FLT3-ITD+ AML growth

Acute myeloid leukemia (AML) is a heterogeneous disease caused by different mutations. Previously, we showed that each mutational subtype develops its specific gene regulatory network (GRN) with transcription factors interacting within multiple gene modules, many of which are transcription factor genes themselves. Here, we hypothesize that highly connected nodes within such networks comprise crucial regulators of AML maintenance. We test this hypothesis using FLT3-ITD-mutated AML as a model and conduct an shRNA drop-out screen informed by this analysis. We show that AML-specific GRNs predict crucial regulatory modules required for AML growth. Furthermore, our work shows that all modules are highly connected and regulate each other. The careful multi-omic analysis of the role of one (RUNX1) module by shRNA and chemical inhibition shows that this transcription factor and its target genes stabilize the GRN of FLT3-ITD+ AML and that its removal leads to GRN collapse and cell death.</p

From sleep spindles of natural sleep to spike and wave discharges of typical absence seizures: is the hypothesis still valid?

The temporal coincidence of sleep spindles and spike-and-wave discharges (SWDs) in patients with idiopathic generalized epilepsies, together with the transformation of spindles into SWDs following intramuscular injection of the weak GABAA receptor (GABAAR) antagonist, penicillin, in an experimental model, brought about the view that SWDs may represent ‘perverted’ sleep spindles. Over the last 20 years, this hypothesis has received considerable support, in particular by in vitro studies of thalamic oscillations following pharmacological/genetic manipulations of GABAARs. However, from a critical appraisal of the evidence in absence epilepsy patients and well-established models of absence epilepsy it emerges that SWDs can occur as frequently during wakefulness as during sleep, with their preferential occurrence in either one of these behavioural states often being patient dependent. Moreover, whereas the EEG expression of both SWDs and sleep spindles requires the integrity of the entire cortico-thalamo-cortical network, SWDs initiates in cortex while sleep spindles in thalamus. Furthermore, the hypothesis of a reduction in GABAAR function across the entire cortico-thalamo-cortical network as the basis for the transformation of sleep spindles into SWDs is no longer tenable. In fact, while a decreased GABAAR function may be present in some cortical layers and in the reticular thalamic nucleus, both phasic and tonic GABAAR inhibitions of thalamo-cortical neurons are either unchanged or increased in this epileptic phenotype. In summary, these differences between SWDs and sleep spindles question the view that the EEG hallmark of absence seizures results from a transformation of this EEG oscillation of natural sleep

Powers of Romance: The Liminal Challenges of Managing Organizational Intimacy

© The Author(s) 2014 Problematic organizational relationships have recently been at the core of highly visible media coverage. Most analyses of sexual relations in organizations have been, however, simplistic and unidimensional, and have placed insufficient systematic emphasis on the role of governmentality in the social construction of organizational romance. In this article, we proceed in two theoretical steps. First, we elaborate a typology of organizational romance that covers different manifestations of this nuanced process. We think of these as organizational strategies of governmentality. Second, we elaborate and identify liminal cases that fall into the interstices of the four predominant ways of managing sexual relationships in organizations. We think of these as vases of liquid love and life that evade the border controls of regulation by governmentality. Finally, we relate these issues to debates about the nature of the civilizational process and suggest hypotheses for future research

Denudation of the continental shelf between Britain and France at the glacial-interglacial timescale

The erosional morphology preserved at the sea bed in the eastern English Channel dominantly records denudation of the continental shelf by fluvial processes over multiple glacial-interglacial sea-level cycles rather than by catastrophic flooding through the Straits of Dover during the mid-Quaternary. Here, through the integration of multibeam bathymetry and shallow sub-bottom 2D seismic reflection profiles calibrated with vibrocore records, the first stratigraphic model of erosion and deposition on the eastern English Channel continental shelf is presented. Published Optical Stimulated Luminescence (OSL) and C ages were used to chronometrically constrain the stratigraphy and allow correlation of the continental shelf record with major climatic/sea-level periods. Five major erosion surfaces overlain by discrete sediment packages have been identified. The continental shelf in the eastern English Channel preserves a record of processes operating from Marine Isotope Stage (MIS) 6 to MIS 1. Planar and channelised erosion surfaces were formed by fluvial incision during lowstands or relative sea-level fall. The depth and lateral extent of incision was partly conditioned by underlying geology (rock type and tectonic structure), climatic conditions and changes in water and sediment discharge coupled to ice sheet dynamics and the drainage configuration of major rivers in Northwest Europe. Evidence for major erosion during or prior to MIS 6 is preserved. Fluvial sediments of MIS 2 age were identified within the Northern Palaeovalley, providing insights into the scale of erosion by normal fluvial regimes. Seismic and sedimentary facies indicate that deposition predominantly occurred during transgression when accommodation was created in palaeovalleys to allow discrete sediment bodies to form. Sediment reworking over multiple sea-level cycles (Saalian-Eemian-early Weichselian) by fluvial, coastal and marine processes created a multi-lateral, multi-storey succession of palaeovalley-fills that are preserved as a strath terrace. The data presented here reveal a composite erosional and depositional record that has undergone a high degree of reworking over multiple sea-level cycles leading to the preferential preservation of sediments associated with the most recent glacial-interglacial period

TNF-dependent regulation and activation of innate immune cells are essential for host protection against cerebral tuberculosis

BACKGROUND: Tuberculosis (TB) affects one third of the global population, and TB of the central nervous system (CNS-TB) is the most severe form of tuberculosis which often associates with high mortality. The pro-inflammatory cytokine tumour necrosis factor (TNF) plays a critical role in the initial and long-term host immune protection against Mycobacterium tuberculosis (M. tuberculosis) which involves the activation of innate immune cells and structure maintenance of granulomas. However, the contribution of TNF, in particular neuron-derived TNF, in the control of cerebral M. tuberculosis infection and its protective immune responses in the CNS were not clear. METHODS: We generated neuron-specific TNF-deficient (NsTNF / ) mice and compared outcomes of disease against TNF f/f control and global TNF / mice. Mycobacterial burden in brains, lungs and spleens were compared, and cerebral pathology and cellular contributions analysed by microscopy and flow cytometry after M. tuberculosis infection. Activation of innate immune cells was measured by flow cytometry and cell function assessed by cytokine and chemokine quantification using enzyme-linked immunosorbent assay (ELISA). RESULTS: Intracerebral M. tuberculosis infection of TNF / mice rendered animals highly susceptible, accompanied by uncontrolled bacilli replication and eventual mortality. In contrast, NsTNF / mice were resistant to infection and presented with a phenotype similar to that in TNF f/f control mice. Impaired immunity in TNF / mice was associated with altered cytokine and chemokine synthesis in the brain and characterised by a reduced number of activated innate immune cells. Brain pathology reflected enhanced inflammation dominated by neutrophil influx. CONCLUSION: Our data show that neuron-derived TNF has a limited role in immune responses, but overall TNF production is necessary for protective immunity against CNS-TB