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Saluja, K.

Publications and source records attributed to Saluja, K..

2 recordsLinked to original sources

Age associated alterations in the cortical representation of cardiac signals: A heartfelt tale

The brain continuously tracks signals from the body, including the heartbeat, which influence internal states such as the perception of time, well-known to accelerate with age and disrupted in disorders such as Parkinsons disease and dementia. The present study examined whether the representation of cardiac events onto spontaneous neural oscillations maps to regions responsible for processing time-perception, show age-related differences, and uncovered the mechanisms that may underlie any such reorganization. From a large cohort (N = 620), cortical heartbeat-evoked responses (HERs) were characterized and their sources were pinned to frontotemporal regions. Phase-based analyses demonstrated that cardiac signals affect phase of ongoing neural oscillations in the theta frequency band, rather than altering overall power, with this effect consolidating in older adults. Advanced statistical analysis further indicated that these changes are primarily driven by enhanced bottom-up heart-to-brain influences, revealing that altered interoceptive signaling can shape the age-related changes in time perception.

neuroscience↗

EZH2 synergizes with BRD4-NUT to drive NUT carcinoma growth through silencing of key tumor suppressor genes

NUT carcinoma (NC) is an aggressive carcinoma driven by the BRD4-NUT fusion oncoprotein, which activates chromatin to promote expression of pro-growth genes. BET bromodomain inhibitors (BETi) impede BRD4-NUTs ability to activate genes and are thus a promising treatment but limited as monotherapy. The role of gene repression in NC is unknown. Here, we demonstrate that EZH2, which silences genes through establishment of repressive chromatin, is a dependency in NC. Inhibition of EZH2 with the clinical compound tazemetostat (taz) potently blocked growth of NC cells. Epigenetic and transcriptomic analysis revealed that taz reversed the EZH2-specific H3K27me3 silencing mark, and restored expression of multiple tumor suppressor genes while having no effect on key oncogenic BRD4- NUT-regulated genes. CDKN2A was identified as the only gene amongst all taz-derepressed genes to confer resistance to taz in a CRISPR-Cas9 screen. Combined EZH2 inhibition and BET inhibition synergized to downregulate cell proliferation genes resulting in more pronounced growth arrest and differentiation than either inhibitor alone. In pre-clinical models, combined taz and BETi synergistically blocked growth and prolonged survival of NC-xenografted mice, with all mice cured in one cohort. STATEMENT OF SIGNIFICANCEIdentification of EZH2 as a dependency in NC substantiates the reliance of NC tumor cells on epigenetic dysregulation of functionally opposite, yet highly complementary chromatin regulatory pathways to maintain NC growth. In particular, repression of CDKN2A expression by EZH2 provides a mechanistic rationale for combining EZH2i with BETi for the clinical treatment of NC.

cancer biology↗