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Biology subjects

Abbas, S.

Publications and source records attributed to Abbas, S..

3 recordsLinked to original sources

Causal network structure predicts memory organization and neural reinstatement across events

Endel Tulving proposed that episodic memory is organized by spatiotemporal relationships, and current theories center the role of time and space in organizing memory. However, these theories are supported by paradigms that eliminate other forms of relationships, like causality. Here, we used fMRI to reveal the organization of neural representations that support episodic memory with a paradigm that decoupled time and causal relationships. Participants were scanned while watching and recalling a TV show featuring five temporally interleaved storylines. Behaviorally, the order of recalled events was best predicted by the strongest cause-effect relationship relative to temporal, spatial, or semantic associations. Neural similarity across different events in regions of the default mode network (DMN) reflected causal structure, and DMN patterns at event boundaries specifically reactivated prior, causally related events, suggesting causality allows us to stitch together related events across temporal gaps. Additionally, causal network distance between successive events predicted the strength of DMN pattern changes across event boundaries, suggesting causality also predicts stronger representational switching between unrelated events. Together, these findings suggest that the DMN supports the construction of the complex causal networks that play a central role in organizing how we understand and remember events.

neuroscience↗

Genomic copy number predicts oesophageal cancer years before transformation

Cancer arises through a process of somatic evolution and recent studies have shown that aneuploidies and driver gene mutations precede cancer diagnosis by several years to decades1-4 Here, we address the question whether such genomic signals can be used for early detection and pre-emptive cancer treatment. To this end we study Barretts oesophagus, a genomic copy number driven neoplastic precursor lesion to oesophageal adenocarcinoma5. We use shallow whole genome sequencing of 777 biopsies sampled from 88 patients in surveillance for Barretts oesophagus over a period of up to 15 years. These data show that genomic signals exist that distinguish progressive from stable disease with an AUC of 0.87 and a sensitivity of 50% even ten years prior to histopathological disease transformation. These finding are validated on two independent cohorts of 75 and 248 patients. Compared against current patient management guidelines genomic risk classification enables earlier treatment for high risk patients as well as reduction of unnecessary treatment and monitoring for patients who are unlikely to develop cancer.

genomics↗

The landscape of selection in 551 Esophageal Adenocarcinomas defines genomic biomarkers for the clinic

Esophageal Adenocarcinoma (EAC) is a poor prognosis cancer type with rapidly rising incidence. Our understanding of genetic events which drive EAC development is limited and there are few molecular biomarkers for prognostication or therapeutics. We have accumulated a cohort of 551 genomically characterised EACs (73% WGS and 27% WES) with clinical annotation and matched RNA-seq. Using a variety of driver gene detection methods, we discover 77 EAC driver genes (73% novel) and 21 non-coding driver elements (95% novel), and describe mutation and CNV types with specific functional impact. We identify a mean of 4.4 driver events per case derived from both copy number events and mutations. We compare driver mutation rates to the exome-wide mutational excess calculated using Non-synonymous vs Synonymous mutation rates (dNdS). We observe mutual exclusivity or co-occurrence of events within and between a number of EAC pathways (GATA factors, Core Cell cycle genes, TP53 regulators and the SWI/SNF complex) suggestive of important functional relationships. These driver variants correlate with tumour differentiation, sex and prognosis. Poor prognostic indicators (SMAD4, GATA4) are verified in independent cohorts with significant predictive value. Over 50% of EACs contain sensitising events for CDK4/6 inhibitors which are highly correlated with clinically relevant sensitivity in a panel EAC cell lines and organoids.

cancer biology↗