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Protocol for a systematic review of thank you interventions to aid retention in randomised clinical trials

Additional File 1. DISC Trial Participating Sites.

Summary The SRC-family kinase LYN is highly expressed in triple-negative/basal-like breast cancer (TNBC) and in the cell of origin of these tumors, c-KIT-positive luminal progenitors. Here, we demonstrate LYN is a downstream effector of c-KIT in normal mammary cells and protective of apoptosis upon genotoxic stress. LYN activity is modulated by PIN1, a prolyl isomerase, and in BRCA1 mutant TNBC PIN1 upregulation activates LYN independently of c-KIT. Furthermore, the full-length LYN splice isoform (as opposed to the Δaa25–45 variant) drives migration and invasion of aggressive TNBC cells, while the ratio of splice variants is informative for breast cancer-specific survival across all breast cancers. Thus, dual mechanisms—uncoupling from upstream signals and splice isoform ratios—drive the activity of LYN in aggressive breast cancers., Graphical Abstract, Highlights • LYN kinase is a downstream effector of the c-KIT receptor in normal breast cells • Loss of BRCA1 function hyperactivates LYN via prolyl isomerase 1 upregulation • The full-length LYN isoform promotes tumor cell invasion • Time to breast cancer death is shorter in tumors with a high LYNA::B isoform ratio, Tornillo et al. show that in aggressive breast cancers, LYN activity is deregulated by a change in patterns of splice isoform expression. In BRCA1-dysfunctional breast cancers, LYN activity is upregulated by a prolyl isomerase (PIN1) that is normally repressed by BRCA1.

Supplemental material, Supplementary_Figures_and_Tablesv2 for Pin1 plays a key role in the response to treatment and clinical outcome in triple negative breast cancer by Catherine Knowlson, Paula Haddock, Victoria Bingham, Stephen McQuaid, Paul B. Mullan and Niamh E. Buckley in Therapeutic Advances in Medical Oncology

The SRC-family kinase LYN is highly expressed in triple-negative/basal-like breast cancer (TNBC) and in the cell-of-origin of these tumors, c-KIT-positive luminal progenitors. Here we demonstrate LYN is a downstream effector of c-KIT in normal mammary cells and protective of apoptosis upon genotoxic stress. LYN activity is modulated by PIN1, a prolyl isomerase, and in BRCA1-mutant TNBC PIN1 upregulation activates LYN independently of c-KIT. Furthermore, the full-length LYN splice isoform (as opposed to the Δaa25-45 variant) drives migration and invasion of aggressive TNBC cells, while the ratio of splice variants is informative for breast cancer-specific survival across all breast cancers. Thus, dual mechanisms – uncoupling from upstream signals and splice isoform ratios – drive the activity of LYN in aggressive breast cancers.

The RECOVERY trial is a large multi-armed, adaptive randomised controlled trial of treatments for Covid-19. It has rapidly recruited and demonstrated that hydroxychloroquine is ineffective in reducing mortality for hospitalised patients, whilst dexamethasone significantly reduces mortality among those patients using supplemental oxygen or on a ventilator. We estimate that the speed of recruitment and dissemination has probably decreased mortality in the UK by at least 200 hospitalised patients in the first month since the British Prime Minister announced the results. Despite its impressive speed, the trial only recruited about 15% of eligible patients, with recruitment rates ranging between 3% to 80% at participating hospitals. Had the trial recruited 50% of the eligible patients then our analysis suggests that more than 2,000 additional lives could have been saved. In a pandemic, rapid recruitment with high centre recruitment is absolutely essential to reduce deaths. Methods of improving site specific recruitment rates need investigating urgently. Key Words: Covid-19; RECOVERY trial; recruitment.