Biology subjects

Ye, R.

Publications and source records attributed to Ye, R..

3 recordsLinked to original sources

bioRxiv2020

ATM-deficient lung, prostate and pancreatic cancer cells are acutely sensitive to the combination of olaparib and the ATR inhibitor AZD6738

BackgroundThe ataxia telangiectasia mutated (ATM) protein kinase is mutated in several human cancers, presenting potential opportunities for targeted cancer therapy. We previously reported that the poly-ADP ribose polymerase (PARP) inhibitor olaparib induced transient G2 arrest but not cell death in ATM-deficient A549 lung cancer cells, while the combination of olaparib with the ATM-, Rad3-related (ATR) inhibitor VE-821 induced cell death. Here, we show that the clinically relevant ATR inhibitor, AZD6738, sensitizes ATM-deficient A549 lung, prostate and pancreatic cancer cells to olaparib. MethodsATM was depleted from A549 lung cancer cells, PC-3 prostate cancer cells and Panc 10.05 pancreatic cancer cells, and the effects of olaparib alone and in combination with AZD6738 were determined. ResultsThe combination of olaparib plus AZD6738 induced cell death in ATM-deficient lung, prostate and pancreatic cancer cells with little effect on their ATM-proficient counterparts. ConclusionsLung, prostate and pancreatic patients whose tumours exhibit loss or inactivation of ATM may benefit from combination of a PARP inhibitor plus an ATR inhibitor.

cancer biology↗

bioRxiv2020

An in vivo Probabilistic Atlas of the Human Locus Coeruleus at Ultra-high Field

Early and profound pathological changes are evident in the locus coeruleus (LC) in dementia and Parkinsons disease, with effects on arousal, attention, cognitive and motor control. The LC can be identified in vivo using non-invasive magnetic resonance imaging techniques which have potential as biomarkers for detecting and monitoring disease progression. Technical limitations of existing imaging protocols have impaired the sensitivity to regional contrast variance or the spatial variability on the rostrocaudal extent of the LC, with spatial mapping consistent with post mortem findings. The current study employs a sensitive magnetisation transfer sequence using ultrahigh field 7T MRI to investigate the LC structure in vivo at high-resolution (resolution 0.4x0.4x0.5 mm, duration seven minutes). Magnetisation transfer images from 53 healthy older volunteers (52-84 years) revealed the spatial features of the LC and were used to create a probabilistic LC atlas for older adults, appropriate for clinical research. Consistent rostrocaudal gradients of slice-wise volume, contrast and variance differences of the LC were observed, mirroring distinctive ex vivo spatial distributions of LC cells in its subregions. The contrast-to-noise ratios were calculated for the peak voxels, and for the averaged signals within the atlas, to accommodate the volumetric differences in estimated contrast. The probabilistic atlas is freely available, and the MRI dataset is available for researchers, for replication or to facilitate accurate LC localisation and unbiased contrast extraction in future studies.

neuroscience↗

bioRxiv2019

LFMD: a new likelihood-based method to detect low-frequency mutations without molecular tags

As next-generation sequencing (NGS) and liquid biopsy become more prevalent in research and in the clinic, there is an increasing need for better methods to reduce cost and improve sensitivity and specificity of low-frequency mutation detection (where the Alternative Allele Frequency, or AAF, is less than 1%). Here we propose a likelihood-based approach, called Low-Frequency Mutation Detector (LFMD), which combines the advantages of duplex sequencing (DS) and the bottleneck sequencing system (BotSeqS) to maximize the utilization of duplicate reads. Compared with the existing state-of-the-art methods, DS, Du Novo, UMI-tools, and Unified Consensus Maker, our method achieves higher sensitivity, higher specificity (< 4 x 10-10 errors per base sequenced) and lower cost (reduced by ~70% at best) without involving additional experimental steps, customized adapters or molecular tags. LFMD is useful in areas where high precision is required, such as drug resistance prediction and cancer screening. As an example of LFMDs applications, mitochondrial heterogeneity analysis of 28 human brain samples across different stages of Alzheimers Disease (AD) showed that the canonical oxidative damage related mutations, C:G>A:T, are significantly increased in the mid-stage group. This is consistent with the Mitochondrial Free Radical Theory of Aging, suggesting that AD may be linked to the aging of brain cells induced by oxidative damage.

bioinformatics↗