Lobo, T. | bioRxiv Science

bioRxiv2022

β-catenin activity induces an RNA biosynthesis program promoting therapy resistance in T Acute Lymphoblastic Leukemia

Understanding the molecular mechanisms that contribute to the appearance of chemotherapy resistant cell populations is necessary to improve cancer treatment. We have now investigated the role of {beta}-catenin/CTNNB1 in the evolution of T-Acute Lymphoblastic Leukemia (T-ALL) patients and its involvement in therapy resistance. We have identified a specific gene signature that is directly regulated by {beta}-catenin, TCF/LEF factors and ZBTB33/Kaiso in T-ALL cell lines, which is highly and significantly represented in 5 out of 6 refractory patients from a cohort of 40 children with T-ALL. By subsequent refinement of this gene signature, we found that a subset of {beta}-catenin target genes involved with RNA-processing function are sufficient to segregate T-ALL refractory patients in three independent cohorts. We demonstrate the implication of {beta}-catenin in RNA and protein synthesis in T-ALL and provide experimental evidence that {beta}-catenin is crucial for the cellular response to chemotherapy, mainly in the cellular recovery phase after treatment. We propose that combination treatments involving chemotherapy plus {beta}-catenin inhibitors will enhance chemotherapy response and prevent disease relapse in T-ALL patients.

cancer biology↗

bioRxiv2021

Can the causal role of brain oscillations be studied through rhythmic brain stimulation?

Many studies have investigated the causal relevance of brain-oscillations using rhythmic stimulation, either through direct-brain or sensory stimulation. Yet, how intrinsic rhythms interact with the externally generated rhythm is largely unknown. We either presented a flickered (60 Hz) visual grating or its correspondent unflickered stimulus in a psychophysical change-detection-task during simultaneous MEG-recordings to humans, to test the effect of visual entrainment on induced gamma-oscillations. Notably, we generally observed the co-existence of the broadband induced gamma-rhythm with the entrained flicker-rhythm (reliably measured in each participant), with the peak frequency of the induced response remaining unaltered in approximately half of participants -relatively independently of their native frequency. However, flicker increased broadband induced-gamma-power, and this was stronger in participants with a native frequency closer to the flicker-frequency ( resonance), and led to strong phase-entrainment. Presence of flicker did not change behaviour itself, but profoundly altered brain-behaviour correlates across the sample: whilst broadband induced gamma-oscillations correlated with reaction-times for unflickered stimuli (as known previously), for the flicker, the amplitude of the entrained flicker-rhythm (but no more the induced oscillation) correlated with reaction-times. This, however, strongly depended on whether a participants peak frequency shifted to the entrained rhythm. Our results suggests that rhythmic brain-stimulation leads to a coexistence of two partially independent oscillations with heterogeneous effects across participants on the downstream relevance of these rhythms for behaviour. This may explain the inconsistency of findings related to external entrainment of brain-oscillations and poses further questions towards causal manipulations of brain-oscillations in general.

neuroscience↗