Showing papers by "Cancer Research UK published in 2019"
TL;DR: The need for strengthening cancer prevention is highlighted and the objectives of Cancer Prevention Europe are introduced, with a foreseen future role in reducing the European cancer burden.
57 citations
TL;DR: It is reported that single-dose radiotherapy (SDRT), a disruptive technique that ablates more than 90% of human cancers, operates a distinct dual-target mechanism, linking acid sphingomyelinase–mediated (ASMase-mediated) microvascular perfusion defects to DNA unrepair in tumor cells to confer tumor cell lethality.
Abstract: Tumor cure with conventional fractionated radiotherapy is 65%, dependent on tumor cell-autonomous gradual buildup of DNA double-strand break (DSB) misrepair. Here we report that single-dose radiotherapy (SDRT), a disruptive technique that ablates more than 90% of human cancers, operates a distinct dual-target mechanism, linking acid sphingomyelinase-mediated (ASMase-mediated) microvascular perfusion defects to DNA unrepair in tumor cells to confer tumor cell lethality. ASMase-mediated microcirculatory vasoconstriction after SDRT conferred an ischemic stress response within parenchymal tumor cells, with ROS triggering the evolutionarily conserved SUMO stress response, specifically depleting chromatin-associated free SUMO3. Whereas SUMO3, but not SUMO2, was indispensable for homology-directed repair (HDR) of DSBs, HDR loss of function after SDRT yielded DSB unrepair, chromosomal aberrations, and tumor clonogen demise. Vasoconstriction blockade with the endothelin-1 inhibitor BQ-123, or ROS scavenging after SDRT using peroxiredoxin-6 overexpression or the SOD mimetic tempol, prevented chromatin SUMO3 depletion, HDR loss of function, and SDRT tumor ablation. We also provide evidence of mouse-to-human translation of this biology in a randomized clinical trial, showing that 24 Gy SDRT, but not 3×9 Gy fractionation, coupled early tumor ischemia/reperfusion to human cancer ablation. The SDRT biology provides opportunities for mechanism-based selective tumor radiosensitization via accessing of SDRT/ASMase signaling, as current studies indicate that this pathway is tractable to pharmacologic intervention.
47 citations
Imperial College London1, Cancer Research UK2, Hammersmith Hospital3, University College London4, University of Lausanne5, Royal North Shore Hospital6, Flinders University7, Monash University8, Ain Shams University9, University of Helsinki10, French Institute of Health and Medical Research11, Charité12, Catholic University of the Sacred Heart13, Tokyo Medical University14, Aichi Medical University15, King Abdulaziz Medical City16, Seoul National University Hospital17, Keimyung University18, University of Ulsan19, Inje University20, Cardiovascular Institute of the South21, Universidad Francisco de Vitoria22, VU University Medical Center23, Istanbul University24, University of Florence25, Conquest Hospital26, Royal Devon and Exeter Hospital27, Anglia Ruskin University28, Emory University29, Veterans Health Administration30, Washington University in St. Louis31, Stony Brook University32, John Radcliffe Hospital33, Duke University34, Complutense University of Madrid35
TL;DR: iFR-guided deferral appears to be safe for patients with LAD lesions, and patients in whom iFR- guided deferral was performed had statistically significantly lower event rates than those with FFR-informed deferral.
33 citations
TL;DR: It is reported that dual-strand cluster transcript export requires CG13741/Bootlegger and the Drosophila Nuclear export factor family protein, Nxf3, which specifically binds to piRNA precursors and is essential for their export to pi RNA biogenesis sites, a process that is critical for germline transposon silencing.
Abstract: The piRNA pathway is a conserved, small RNA-based immune system that protects animal germ cell genomes from the harmful effects of transposon mobilisation. In Drosophila ovaries, most piRNAs originate from dual-strand clusters, which generate piRNAs from both genomic strands. Dual-strand clusters use non-canonical transcription mechanisms. Although transcribed by RNA polymerase II, cluster transcripts lack splicing signatures and poly(A) tails. mRNA processing is important for general mRNA export mediated by Nuclear export factor 1. Although UAP56, a component of the transcription and export complex, has been implicated in piRNA precursor export, it remains unknown how dual-strand cluster transcripts are specifically targeted for piRNA biogenesis by export from the nucleus to cytoplasmic processing centers. Here we report that dual-strand cluster transcript export requires CG13741/Bootlegger and the Drosophila Nuclear export factor family protein, Nxf3. Bootlegger is specifically recruited to piRNA clusters and in turn brings Nxf3. We find that Nxf3 specifically binds to piRNA precursors and is essential for their export to piRNA biogenesis sites, a process that is critical for germline transposon silencing. Our data shed light on how dual-strand clusters compensate for a lack of canonical features of mature mRNAs to be specifically exported via Nxf3, ensuring proper piRNA production.
16 citations
University of Edinburgh1, University of Leeds2, Cancer Research UK3, University of Alabama at Birmingham4, University of Oxford5, University of Cambridge6, Harvard University7, International Agency for Research on Cancer8, University of North Carolina at Chapel Hill9, University of Glasgow10, University of Bristol11, University of Freiburg12, University of California, Berkeley13, University of London14, University of Sheffield15, Ludwig Institute for Cancer Research16, Imperial College London17, Baylor College of Medicine18, University of Southern California19
TL;DR: An inaugural international Cancer Prevention and Nutrition Conference in London focused on the need for systematic, interdisciplinary approaches to better understand the relationships of nutrition, exercise, obesity and metabolic dysfunction with cancer development.
Abstract: Cancer Research UK and Ludwig Cancer Research convened an inaugural international Cancer Prevention and Nutrition Conference in London on December 3–4, 2018. Much of the discussion focused on the need for systematic, interdisciplinary approaches to better understand the relationships of nutrition, exercise, obesity and metabolic dysfunction with cancer development. Scientists at the meeting underscored the importance of studying the temporal natural history of exposures that may cumulatively impact cancer risk later in life. A robust dialogue identified obesity as a major risk for cancer, and the food environment, especially high energy and low nutrient processed foods, as strong and prevalent risk factors for obesity. Further engagement highlighted challenges in the post-diagnostic setting, where similar opportunities to understand the complex interplay of nutrition, physical activity, and weight will inform better health outcomes. Going forward, holistic research approaches, encompassing insights from multiple disciplines and perspectives, will catalyze progress urgently needed to prevent cancer and improve public health.
9 citations
TL;DR: Brexit negotiations have made it difficult to think about the next vital step: working out the future relationship between the UK and EU, and ensuring that global research continues to thrive after Brexit.
Abstract: EMBO Reports (2019) 20: e48026[OpenUrl][1][FREE Full Text][2]
Sometimes it can be hard to look ahead to what is coming next. Finalising a journal paper or thesis can understandably take over from working out the next line of inquiry that will progress a scientific idea. The same can be said about Brexit negotiations. We have been agreeing the terms of the UK's withdrawal from the EU for over two years, which has made it difficult to think about the next vital step: working out the future relationship between the UK and EU, and ensuring that global research continues to thrive after Brexit.
Cancer researchers across the world collaborate because we are motivated to understand the causes of cancer and to find new therapies for patients. International partnership is so embedded in what we do that we usually do not give it a second thought. Evidence shows that working with colleagues from overseas makes research more impactful. Publication citation scores reach almost double the world average when the UK and EU work together—benefiting research and patients globally [1]. Nearly 50% of all UK cancer research involves international collaboration, highlighting the importance of working across borders [2]. Cancer Research UK's (CRUK) scientific workforce is a prime example: half of all CRUK funded PhD students and 76% of post‐docs at CRUK institutes are from outside the UK.
Scientists have been offered some guarantees and clarity during the turbulent Brexit period, but uncertainty is still high. However, there has been some progress, driven by those in power and the collective action of the European research sector. When Prime Minister Theresa May set out her first twelve negotiating objectives for exiting the EU, one was maintaining a high‐quality UK science base …
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