Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS

An overview of KSTAR results

Since the first H-mode discharges in 2010, the duration of the H-mode state has been extended and a significantly wider operational window of plasma parameters has been attained. Using a second neutral beam (NB) source and improved tuning of equilibrium configuration with real-time plasma control, a stored energy of Wtot ??? 450 kJ has been achieved with a corresponding energy confinement time of ??E ??? 163 ms. Recent discharges, produced in the fall of 2012, have reached plasma ??N up to 2.9 and surpassed the n = 1 ideal no-wall stability limit computed for H-mode pressure profiles, which is one of the key threshold parameters defining advanced tokamak operation. Typical H-mode discharges were operated with a plasma current of 600 kA at a toroidal magnetic field BT = 2 T. L-H transitions were obtained with 0.8-3.0 MW of NB injection power in both single- and double-null configurations, with H-mode durations up to ???15 s at 600 kA of plasma current. The measured power threshold as a function of line-averaged density showed a roll-over with a minimum value of ???0.8 MW at . Several edge-localized mode (ELM) control techniques during H-mode were examined with successful results including resonant magnetic perturbation, supersonic molecular beam injection (SMBI), vertical jogging and electron cyclotron current drive injection into the pedestal region. We observed various ELM responses, i.e. suppression or mitigation, depending on the relative phase of in-vessel control coil currents. In particular, with the 90?? phase of the n = 1 RMP as the most resonant configuration, a complete suppression of type-I ELMs was demonstrated. In addition, fast vertical jogging of the plasma column was also observed to be effective in ELM pace-making. SMBI-mitigated ELMs, a state of mitigated ELMs, were sustained for a few tens of ELM periods. A simple cellular automata ('sand-pile') model predicted that shallow deposition near the pedestal foot induced small-sized high-frequency ELMs, leading to the mitigation of large ELMs. In addition to the ELM control experiments, various physics topics were explored focusing on ITER-relevant physics issues such as the alteration of toroidal rotation caused by both electron cyclotron resonance heating (ECRH) and externally applied 3D fields, and the observed rotation drop by ECRH in NB-heated plasmas was investigated in terms of either a reversal of the turbulence-driven residual stress due to the transition of ion temperature gradient to trapped electron mode turbulence or neoclassical toroidal viscosity (NTV) torque by the internal kink mode. The suppression of runaway electrons using massive gas injection of deuterium showed that runaway electrons were avoided only below 3 T in KSTAR. Operation in 2013 is expected to routinely exceed the n = 1 ideal MHD no-wall stability boundary in the long-pulse H-mode (10 s) by applying real-time shaping control, enabling n = 1 resistive wall mode active control studies. In addition, intensive works for ELM mitigation, ELM dynamics, toroidal rotation changes by both ECRH and NTV variations, have begun in the present campaign, and will be investigated in more detail with profile measurements of different physical quantities by techniques such as electron cyclotron emission imaging, charge exchange spectroscopy, Thomson scattering and beam emission spectroscopy diagnostics.close9

Overview of KSTAR initial operation

Since the successful first plasma generation in the middle of 2008, three experimental campaigns were successfully made for the KSTAR device, accompanied with a necessary upgrade in the power supply, heating, wall-conditioning and diagnostic systems. KSTAR was operated with the toroidal magnetic field up to 3.6 T and the circular and shaped plasmas with current up to 700 kA and pulse length of 7 s, have been achieved with limited capacity of PF magnet power supplies. The mission of the KSTAR experimental program is to achieve steady-state operations with high performance plasmas relevant to ITER and future reactors. The first phase (2008-2012) of operation of KSTAR is dedicated to the development of operational capabilities for a super-conducting device with relatively short pulse. Development of start-up scenario for a super-conducting tokamak and the understanding of magnetic field errors on start-up are one of the important issues to be resolved. Some specific operation techniques for a super-conducting device are also developed and tested. The second harmonic pre-ionization with 84 and 110 GHz gyrotrons is an example. Various parameters have been scanned to optimize the pre-ionization. Another example is the ICRF wall conditioning (ICWC), which was routinely applied during the shot to shot interval. The plasma operation window has been extended in terms of plasma beta and stability boundary. The achievement of high confinement mode was made in the last campaign with the first neutral beam injector and good wall conditioning. Plasma control has been applied in shape and position control and now a preliminary kinetic control scheme is being applied including plasma current and density. Advanced control schemes will be developed and tested in future operations including active profiles, heating and current drives and control coil-driven magnetic perturbation.X111932sciescopu