Cancer develops as a result of somatic mutation and clonal selection, but quantitative measures of selection in cancer evolution are lacking. We adapted methods from molecular evolution and applied ...them to 7,664 tumors across 29 cancer types. Unlike species evolution, positive selection outweighs negative selection during cancer development. On average, <1 coding base substitution/tumor is lost through negative selection, with purifying selection almost absent outside homozygous loss of essential genes. This allows exome-wide enumeration of all driver coding mutations, including outside known cancer genes. On average, tumors carry ∼4 coding substitutions under positive selection, ranging from <1/tumor in thyroid and testicular cancers to >10/tumor in endometrial and colorectal cancers. Half of driver substitutions occur in yet-to-be-discovered cancer genes. With increasing mutation burden, numbers of driver mutations increase, but not linearly. We systematically catalog cancer genes and show that genes vary extensively in what proportion of mutations are drivers versus passengers.
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•Unlike the germline, somatic cells evolve predominantly by positive selection•Nearly all (∼99%) coding mutations are tolerated and escape negative selection•Exome-wide estimates of the total number of driver coding mutations per tumor•Half of the coding driver mutations occur outside of known cancer genes
Adapting an evolutionary genomics approach to cancer highlights a limited impact of negative selection on cancer genomes and significant variations in the proportion of coding driver mutations per tumor among different tumor types.
Bombardier beetles of the genus
Weber are notorious for their explosive defensive chemistry. Despite ongoing research on their defense mechanism, life history, and ecology, the group lacks a robust ...molecular-based phylogeny. In this study, three loci from mitochondrial and nuclear genomes (COI, CAD, 28S) are used to reconstruct the phylogeny of the large subgenus Neobrachinus, and test species group boundaries hypothesized by Erwin (1970) based on morphological characters. Erwin's
species group is found to be polyphyletic, and is herein re-defined with eight new species groups erected to reflect clades based on molecular evidence: the
,
,
,
,
,
,
, and
species groups. Erwin's
group is also expanded to include Brachinus (Neobrachinus) medius and the
group.
The design and operation of a miniature strain-board for measuring the resistivity of high temperature superconducting tapes as a function of uniaxial strain (<inline-formula><tex-math ...notation="LaTeX">\epsilon</tex-math></inline-formula>) are described. It was used inside a Physical Property Measurement System (PPMS) that provides access to high fields, variable temperature, and a rotator that can vary the angle of the sample with respect to the field. Resistivity measurements made using the strain-board over the strain range 0% to <inline-formula><tex-math notation="LaTeX">-1.1</tex-math></inline-formula>% in-field are presented for a REBCO (REBa<inline-formula><tex-math notation="LaTeX">_{2}</tex-math></inline-formula>Cu<inline-formula><tex-math notation="LaTeX">_{3}</tex-math></inline-formula>O<inline-formula><tex-math notation="LaTeX">_{7}</tex-math></inline-formula>, RE: Rare-earth element) tape from SuperPower with artificial pinning centres (APC). Values of the upper critical field (<inline-formula><tex-math notation="LaTeX">B_{c2}</tex-math></inline-formula>) were extracted from the resistivity data. We found that although the temperature and angular dependence of B <inline-formula><tex-math notation="LaTeX">_{c2}</tex-math></inline-formula> were similar to that found in previous studies using ac susceptibility measurements (i.e. the temperature index, <inline-formula><tex-math notation="LaTeX">n = 1.2</tex-math></inline-formula>, the anisotropy constant, <inline-formula><tex-math notation="LaTeX">\gamma = 1.4</tex-math></inline-formula> and the interlayer spacing <inline-formula><tex-math notation="LaTeX">s = 12</tex-math></inline-formula> Å), the upper critical field we found was almost strain independent and therefore quite different. We explain these results by considering the bimodal behaviour of REBCO under strain that is found in single crystal data, and the large parallel shunt the strain-board provided in the measurements. In our resistivity measurements, <inline-formula><tex-math notation="LaTeX">B_{c2}</tex-math></inline-formula> is determined by a small percolative supercurrent that preferentially flows through material with the highest critical parameters. Conversely, resistivity measurements at high currents, or ac susceptibility measurements, characterise the material with average or low critical parameters from the broad distribution of critical parameters produced in REBCO tapes under strain.
The single-event upset (SEU) sensitivity of ultra-thin silicon on insulator (SOI), SOI FinFET, and NanoWireFET static random access memories (SRAMs) is investigated using a straightforward ...multiple-scale approach based on open source and commercial codes. Both Monte-Carlo and technology computer aided design (TCAD) tools are used to estimate the SEU cross section of innovative technologies. Heavy-ion experiments performed on transistors are used to validate TCAD models and 3-D device structures. TCAD simulations are then performed on 3-D SRAM cells to calculate the upset threshold for each technology. It is used as upset criterion in Monte-Carlo simulations of deposited energy in silicon microvolumes to estimate the SEU cross section of innovative SOI technologies. Finally, multiple-bit upsets are addressed to draw trends on the sensitivity of such highly scaled technologies to multiple events.
At the time of approval of a new medicine, there are few long-term data on the medicine's benefit-risk balance. Clinical trials are designed to demonstrate efficacy, but have major limitations with ...regard to safety in terms of patient exposure and length of follow-up. This study of the number of patients who had been administered medicines at the time of medicine approval by the European Medicines Agency aimed to determine the total number of patients studied, as well as the number of patients studied long term for chronic medication use, compared with the International Conference on Harmonisation's E1 guideline recommendations.
All medicines containing new molecular entities approved between 2000 and 2010 were included in the study, including orphan medicines as a separate category. The total number of patients studied before approval was extracted (main outcome). In addition, the number of patients with long-term use (6 or 12 mo) was determined for chronic medication. 200 unique new medicines were identified: 161 standard and 39 orphan medicines. The median total number of patients studied before approval was 1,708 (interquartile range IQR 968-3,195) for standard medicines and 438 (IQR 132-915) for orphan medicines. On average, chronic medication was studied in a larger number of patients (median 2,338, IQR 1,462-4,135) than medication for intermediate (878, IQR 513-1,559) or short-term use (1,315, IQR 609-2,420). Safety and efficacy of chronic use was studied in fewer than 1,000 patients for at least 6 and 12 mo in 46.4% and 58.3% of new medicines, respectively. Among the 84 medicines intended for chronic use, 68 (82.1%) met the guideline recommendations for 6-mo use (at least 300 participants studied for 6 mo and at least 1,000 participants studied for any length of time), whereas 67 (79.8%) of the medicines met the criteria for 12-mo patient exposure (at least 100 participants studied for 12 mo).
For medicines intended for chronic use, the number of patients studied before marketing is insufficient to evaluate safety and long-term efficacy. Both safety and efficacy require continued study after approval. New epidemiologic tools and legislative actions necessitate a review of the requirements for the number of patients studied prior to approval, particularly for chronic use, and adequate use of post-marketing studies. Please see later in the article for the Editors' Summary.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Most cancers are characterized by the somatic acquisition of genomic rearrangements during tumour evolution that eventually drive the oncogenesis. Here, using multiplatform sequencing technologies, ...we identify and characterize a remarkable mutational mechanism in human hepatocellular carcinoma caused by Hepatitis B virus, by which DNA molecules from the virus are inserted into the tumour genome causing dramatic changes in its configuration, including non-homologous chromosomal fusions, dicentric chromosomes and megabase-size telomeric deletions. This aberrant mutational mechanism, present in at least 8% of all HCC tumours, can provide the driver rearrangements that a cancer clone requires to survive and grow, including loss of relevant tumour suppressor genes. Most of these events are clonal and occur early during liver cancer evolution. Real-time timing estimation reveals some HBV-mediated rearrangements occur as early as two decades before cancer diagnosis. Overall, these data underscore the importance of characterising liver cancer genomes for patterns of HBV integration.
The critical current of the core and shield of a 2.1 m long, 40 mm diameter Bi-2223 HTS coaxial cable was measured as part of an International Round Robin organised by Japan involving several ...international laboratories. In Durham, we found using a 100 <inline-formula><tex-math notation="LaTeX">\upmu</tex-math></inline-formula>Vm <inline-formula><tex-math notation="LaTeX">^{-1}</tex-math></inline-formula> criterion and an 8 minute trace time that I <inline-formula><tex-math notation="LaTeX">_{c}</tex-math></inline-formula> of the core and shield were 4386 A and 4143 A and the n -values were 19.6 and 14.4 respectively. 8 minute trace times were found to be a practical approximation of steady state conditions, with critical current values 0.5 % and 1.2 % larger than values obtained using 2 minute trace times, and n -values not significantly different to 2 minute trace values. Two minute trace time data were compared with equivalent data from other participating labs and excellent agreement was found: I <inline-formula><tex-math notation="LaTeX">_{c}</tex-math></inline-formula> was 0.6 % and 1.5 % larger for the core and shield respectively. The E -field range has a significant effect on the n -value measurements, which varied between groups. Good agreement between the participants for the shield was found for electric fields below 100 <inline-formula><tex-math notation="LaTeX">\upmu</tex-math></inline-formula> Vm<inline-formula><tex-math notation="LaTeX">^{-1}</tex-math></inline-formula>, although larger n -values were found at higher electric fields at Durham and some other laboratories. The polarity of the current and the proximity of the return power cable were demonstrated to have negligible effect (<inline-formula><tex-math notation="LaTeX">< </tex-math></inline-formula> 0.1 % ) on the I <inline-formula><tex-math notation="LaTeX">_{c}</tex-math></inline-formula> measurements. Removing conductive and ferromagnetic materials that were part of Durham's experimental set-up increased I <inline-formula><tex-math notation="LaTeX">_{c}</tex-math></inline-formula> by <inline-formula><tex-math notation="LaTeX">< </tex-math></inline-formula> 1 % . An intrinsic trace time dependency was found for I <inline-formula><tex-math notation="LaTeX">_{c}</tex-math></inline-formula> for trace times of less than 8 minutes that we attribute to the time required for fluxons to equilibrate with the underlying pinning landscape in a changing net magnetic field.
We provide evidence that a single mechanism-flux flow along channels-can explain the functional form of the critical current density (Jc) in the low-temperature superconductor Nb3Sn and in the ...high-temperature superconductors (HTS) YBa2Cu3O7−δ (YBCO) and (Bi,Pb)2Sr2Can−1CunOx (BiSCCO) in low and high magnetic fields. In this paper, we show that standard flux pinning theories, used for the past four decades to describe Jc in low-temperature superconductors (LTS), cannot explain the strain dependence of Jc in YBCO because Jc is a function of strain but the average superconducting properties are not. We conclude that in the polycrystalline samples presented here, the channels are grain boundaries that are narrow and metallic in Nb3Sn and YBCO but wide and semiconducting in BiSCCO. In Nb3Sn, strain alters Jc by changing the superconducting properties of the grains, whereas in YBCO, strain alters Jc by changing the properties of the grain boundaries.
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