Biology subjects

Lad, M.

Publications and source records attributed to Lad, M..

2 recordsLinked to original sources

bioRxiv2019

Interaction between DNA damage response, translation and apoptosome determines cancer susceptibility to TOP2 poisons

Topoisomerase II poisons are one of the most common class of chemotherapeutics used in cancer. We show that glioblastoma (GBM), the most malignant of all primary brain tumors in adults is responsive to TOP2 poisons. To identify genes that confer susceptibility to this drug in gliomas, we performed a genome-scale CRISPR knockout screen with etoposide. Genes involved in protein synthesis and DNA damage were implicated in etoposide susceptibility. To define potential biomarkers for TOP2 poisons, CRISPR hits were overlapped with genes whose expression correlates with susceptibility to this drug across glioma cell lines, revealing ribosomal protein subunit RPS11, 16, 18 as putative biomarkers for response to TOP2 poisons. Loss of RPS11 impaired the induction of pro-apoptotic gene APAF1 following etoposide treatment, and led to resistance to this drug and doxorubicin. The expression of these ribosomal subunits was also associated with susceptibility to TOP2 poisons across cell lines from multiple cancers.\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=93 SRC=\"FIGDIR/small/614024v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (14K):\norg.highwire.dtl.DTLVardef@310f7org.highwire.dtl.DTLVardef@14ed578org.highwire.dtl.DTLVardef@a0d9c0org.highwire.dtl.DTLVardef@37f59a_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2019

Characterising memory loss in patients with autoimmune limbic encephalitis hippocampal lesions

Since the publication of Scoville and Milners (1957) seminal paper, the precise functional role played by the hippocampus in support of human memory has been fiercely debated. For instance, the single question of whether the hippocampus plays a time-limited or an indelible role in the recollection of personal memories led to a deep and tenacious schism within the field. Similar polarisations arose between those who debated the precise nature of the role played by the hippocampus in support of semantic relative to episodic memories and in recall/recollection relative to familiarity-based recognition. At the epicentre of these divisions lies conflicting neuropsychological findings. These differences likely arise due to the consistent use of heterogeneous patient populations to adjudicate between these positions. Here we utilised traditional neuropsychological measures in a homogenous patient population with a highly discrete hippocampal lesion (i.e. patients with voltage-gated potassium channel complex antibody associated limbic encephalitis (VGKC-LE)). We observed impairment of recent but not remote episodic memory, a preservation of semantic memory, and recall but not recognition memory deficits. We conclude that this increasingly well-characterised group of patients may represent an important homogeneous population in which the functional role played by the hippocampus may be more precisely delineated.

neuroscience↗