Biology subjects

Knight, L.

Publications and source records attributed to Knight, L..

5 recordsLinked to original sources

bioRxiv2026

Whole genome sequencing of endometrial cancer identifies novel subgroups, drivers, and actionable alterations

Endometrial cancer (EC) is the most common gynaecological malignancy in high income countries, and is increasing in incidence. While molecular stratification has improved its management, precision care is hampered by incomplete characterization of the EC genome. We address this by analysis of whole genome sequencing (WGS) of 665 ECs generated by the UK Genomics England 100,000 Genome Project (100kGP). 5% of cases were associated with germline pathogenic variants in cancer genes, including BRCA1 which we confirmed predisposes to EC. We identified 107 putative coding driver genes, 35% of which had no prior established role in EC. Novel structural variants included gains of MYCN and loss of its negative regulator NEDD4.1 which were significantly mutually exclusive in copy number (CN) high tumours. Immunogenomic analysis confirmed selection for driver alterations of low immunogenicity based on patient HLA haplotype, and pervasive immune escape through multiple mechanisms. Unsupervised clustering of mutational signatures and genomic alterations identified known and novel molecular subgroups, including a CN-high subset with mutational signatures of homologous recombination deficiency (HRD) and favourable outcome. Independent prognostic value of single nucleotide variant (SNV) burden, CN burden and multiple coding drivers, along with the identification of targetable molecular alterations in over one-third of cases, underscores the promise of WGS for precision medicine in EC.

genomics↗

bioRxiv2026

Long-Term Expression and Safety of AAV1-Mediated PI3Kδ Overexpression in the Adult Rat Cortex

Mature CNS neurons are incapable of sufficiently regenerating their axons following spinal cord injury (SCI). This is largely due to developmental changes in epigenetic control leading to suppression of axon growth transcriptomic profile, leading to a shift towards synapse function support. Recently, manipulating the PI3K/Akt/mTOR pathway through PI3K{delta} overexpression in cortical neurons enhanced axonal regeneration of corticospinal tract axons, which was accompanied by functional recovery monitored for up to 16 weeks. However, PI3K is more widely known for its role as an oncogene, and since overexpression is achieved by the use of AAVs, valid safety concerns are raised as it is unknown what the long-term consequences of sustained PI3K{delta} expression in the brain are, which may be necessary to achieve complete re-establishment of the motor pathway. In this study, AAV1-hSYN-PIK3CD was injected into the motor cortex of rats, which survived for 1 year. Comparison with uninjected control animals reveal stable PI3K{delta} expression and sustained pathway activation through increased pS6. PI3K{delta}-treated animals show absence of tumour formation, neural soma hypertrophy, glial cell activation, or haematological or biochemical abnormalities. Thus, long-term neuronal PI3K{delta} expression appears to be well tolerated and may provide a safe and durable strategy to promote functional repair following SCI.

neuroscience↗

bioRxiv2023

Hyperactive PI3Kinase delta enables long distance regeneration of the rat corticospinal tract

Maturation of central nervous system neurons leads to loss of their intrinsic regeneration potential. In particular after injury of the adult spinal cord there is minimal regeneration of corticospinal axons, which control gait and fine movement. Previous work has shown that knockdown of PTEN to increase PIP3 levels can promote regeneration in young animals, but the effect is much less in adults probably due to low PIP3 production. Here, we have transduced sensorimotor cortex neurons with a hyperactive form of PI3K, PI3K{delta}, which increases PIP3 in mature neurons. This enables cortical neurons to regenerate corticospinal axons and improve behavioural outcomes. We used a C4 dorsal column lesion model in adult rats and injected the right motor cortex at 4 sites concurrently with a mixture AAV1-PIK3CD and AAV1-eGFP or titre matched AAV1-eGFP only. We allowed rats to survive for 6, 9, 12 or 16 weeks. Immunostaining showed 70 - 80% co-expression in cortical neurons which remained stable at both 12 and 16 weeks. We counted GFP labelled axons in 20 m spinal cord sections. In PI3KCD-treated animals many axons were seen to have regenerated around the margins of lesions, collecting into a knot of axons with the typical appearance of regeneration at the caudal end. Tracing down the cord, and excluding axons and neurites that could have come from unlesioned ventral CST, we found axons extending up to 1 cm below lesions, numbers decreasing with distance from the lesion. After 16 weeks there were circa 200 axons at the caudal end of lesions with a regeneration index of 0.2, with half this number at 12 weeks. Behavioural testing for 16 weeks revealed functional improvements in skilled paw reaching, grip strength and ladder rung walking in rats treated with PIK3CD compared to GFP only controls. In addition to behavioural testing, functional recovery of PIK3CD treated rats was confirmed with electrophysiological recordings during which we stimulated the right pyramid. Cord dorsum potentials (CDPs) above and below lesion and EMG forepaw distal flexor muscles showed greatly increased connectivity compared with GFP only controls, lesion only controls and uninjured shams. We conclude that forcing upregulation of PI3K{delta} in cortical neurons leads to robust regeneration after spinal cord injury that results in functional restoration.

neuroscience↗

bioRxiv2023

The RNA binding proteins LARP4A and LARP4B promote sarcoma and carcinoma growth and metastasis

RNA-binding proteins (RBPs) are emerging as important regulators of pathogenesis, including cancer. Here we reveal that the recently characterised RBPs LARP4A and LARP4B are differentially overexpressed in primary osteosarcoma and osteosarcoma lung metastases, as well as in prostate cancer. Depletion of LARP4A and LARP4B inhibited primary tumour growth and metastatic spread in xenograft studies, as well as inhibiting cell proliferation, motility and migration. Transcriptomic profiling combined with high content multiparametric cell cycle analysis unveiled a central role for LARP4B, but not LARP4A, in regulating cell cycle progression in osteosarcoma and prostate cancer cell lines, potentially through modulating the post-transcriptional regulation of RNA targets that include key cell cycle proteins such as Cyclins B1 and E2, Aurora B and E2F1. Our work assigns new functions to LARP4A and LARP4B as pro-tumorigenic proteins in bone and prostate cancer, highlights their similarities while indicating distinct functional aspects, and adds significantly to the rapidly increasing roles of RBPs in different cancer models. Uncovering clear biological roles for these paralogous proteins provides new avenues for identifying novel tissue-specific targets and potential druggable intervention.

cancer biology↗

bioRxiv2021

Altered brain criticality in Schizophrenia: New insights from MEG

Schizophrenia has a complex etiology and symptomatology that is difficult to untangle. After decades of research, important advancements towards a central biomarker are still lacking. One of the missing pieces is a better understanding of how non-linear neural dynamics are altered in this patient population. In this study, the resting-state neuromagnetic signals of schizophrenia patients and healthy controls were analyzed in the framework of criticality. When biological systems like the brain are in a state of criticality, they are thought to be functioning at maximum efficiency (e.g., optimal communication and storage of information) and with maximum adaptability to incoming information. Here, we assessed the self-similarity and multifractality of resting-state brain signals recorded with magnetoencephalography in patients with schizophrenia patients and in matched controls. Our analysis showed a clear ascending, rostral to caudal gradient of self-similarity values in healthy controls, and an opposite gradient for multifractality (descending values, rostral to caudal). Schizophrenia patients had similar, although attenuated, gradients of self-similarity and multifractality values. Statistical tests showed that patients had higher values of self-similarity than controls in fronto-temporal regions, indicative of more regularity and memory in the signal. In contrast, patients had less multifractality than controls in the parietal and occipital regions, indicative of less diverse singularities and reduced variability in the signal. In addition, supervised machine-learning, based on logistic regression, successfully discriminated the two groups using measures of self-similarity and multifractality as features. Our results provide new insights into the baseline cognitive functioning of schizophrenia patients by identifying key alterations of criticality properties in their resting-state brain data.

neuroscience↗