P-glycoprotein silencing with siRNA delivered by DOPEmodified PEI overcomes doxorubicin resistance in breast cancer cells

AIMS: Multidrug resistance (MDR) mediated by overexpression of drug efflux transporters such as P-glycoprotein (P-gp), is a major problem, limiting successful chemotherapy of breast cancer. The use of siRNA to inhibit P-gp expression in MDR tumors is an attractive strategy to improve the effectiveness of anticancer drugs. METHOD: We have synthesized a novel conjugate between a phospholipid (dioleoylphosphatidylethanolamine) and polyethylenimine (PEI) for siRNA delivery, for the purpose of silencing P-gp to overcome doxorubicin resistance in MCF-7 human breast cancer cells. RESULTS: The dioleoylphosphatidylethanolamine-PEI conjugate enhanced the transfection efficacy of low-molecular-weight PEI, which was otherwise totally ineffective. In addition, the polyethylene glycol/lipid coating of the new complexes gave rise to small micelle-like nanoparticles with improved biocompatibility properties. Both coated and noncoated formulations delivered P-gp-specific siRNA to MDR cells. DISCUSSION: The combination of doxorubicin and P-gp silencing formulations led to a twofold increase of doxorubicin uptake and a significant improvement of the therapeutic effect of doxorubicin in resistant cells

Mapping disparities in education across low- and middle-income countries

Analyses of the proportions of individuals who have completed key levels of schooling across all low- and middle-income countries from 2000 to 2017 reveal inequalities across countries as well as within populations. Educational attainment is an important social determinant of maternal, newborn, and child health(1-3). As a tool for promoting gender equity, it has gained increasing traction in popular media, international aid strategies, and global agenda-setting(4-6). The global health agenda is increasingly focused on evidence of precision public health, which illustrates the subnational distribution of disease and illness(7,8); however, an agenda focused on future equity must integrate comparable evidence on the distribution of social determinants of health(9-11). Here we expand on the available precision SDG evidence by estimating the subnational distribution of educational attainment, including the proportions of individuals who have completed key levels of schooling, across all low- and middle-income countries from 2000 to 2017. Previous analyses have focused on geographical disparities in average attainment across Africa or for specific countries, but-to our knowledge-no analysis has examined the subnational proportions of individuals who completed specific levels of education across all low- and middle-income countries(12-14). By geolocating subnational data for more than 184 million person-years across 528 data sources, we precisely identify inequalities across geography as well as within populations.Peer reviewe

Pileup mitigation at CMS in 13 TeV data

With increasing instantaneous luminosity at the LHC come additional reconstruction challenges. At high luminosity, many collisions occur simultaneously within one proton-proton bunch crossing. The isolation of an interesting collision from the additional "pileup" collisions is needed for effective physics performance. In the CMS Collaboration, several techniques capable of mitigating the impact of these pileup collisions have been developed. Such methods include charged-hadron subtraction, pileup jet identification, isospin-based neutral particle "δβ" correction, and, most recently, pileup per particle identification. This paper surveys the performance of these techniques for jet and missing transverse momentum reconstruction, as well as muon isolation. The analysis makes use of data corresponding to 35.9 fb$^{-1}$ collected with the CMS experiment in 2016 at a center-of-mass energy of 13 TeV. The performance of each algorithm is discussed for up to 70 simultaneous collisions per bunch crossing. Significant improvements are found in the identification of pileup jets, the jet energy, mass, and angular resolution, missing transverse momentum resolution, and muon isolation when using pileup per particle identification

Identification of heavy, energetic, hadronically decaying particles using machine-learning techniques

Machine-learning (ML) techniques are explored to identify and classify hadronic decays of highly Lorentz-boosted W/Z/Higgs bosons and top quarks. Techniques without ML have also been evaluated and are included for comparison. The identification performances of a variety of algorithms are characterized in simulated events and directly compared with data. The algorithms are validated using proton-proton collision data at √s = 13TeV, corresponding to an integrated luminosity of 35.9 fb−1. Systematic uncertainties are assessed by comparing the results obtained using simulation and collision data. The new techniques studied in this paper provide significant performance improvements over non-ML techniques, reducing the background rate by up to an order of magnitude at the same signal efficiency

A measurement of the Higgs boson mass in the diphoton decay channel

A measurement of the mass of the Higgs boson in the diphoton decay channel is presented. This analysis is based on 35.9fb$^{-1}$ of proton-proton collision data collected during the 2016 LHC running period, with the CMS detector at a centre-of-mass energy of 13TeV. A refined detector calibration and new analysis techniques have been used to improve the precision of this measurement. The Higgs boson mass is measured to be m$_{H}$=125.78 ±0.26 GeV. This is combined with a measurement of mHalready performed in the H→ZZ→4${l}$ decay channel using the same data set, giving m$_{H}$=125.46 ±0.16 GeV. This result, when further combined with an earlier measurement of mHusing data collected in 2011 and 2012 with the CMS detector, gives a value for the Higgs boson mass of m$_{H}$=125.38 ±0.14 GeV. This is currently the most precise measurement of the mass of the Higgs boson

Measurement of the Y(1S) pair production cross section and search for resonances decaying to Y(1S)μ⁺μ⁻ in proton-proton collisions at √s = 13 TeV

The fiducial cross section for Y(1S)pair production in proton-proton collisions at a center-of-mass energy of 13TeVin the region where both Y(1S)mesons have an absolute rapidity below 2.0 is measured to be 79 ± 11 (stat) ±6 (syst) ±3 (B)pbassuming the mesons are produced unpolarized. The last uncertainty corresponds to the uncertainty in the Y(1S)meson dimuon branching fraction. The measurement is performed in the final state with four muons using proton-proton collision data collected in 2016 by the CMS experiment at the LHC, corresponding to an integrated luminosity of 35.9fb$^{-1}$. This process serves as a standard model reference in a search for narrow resonances decaying to Y(1S)μ$^{+}$μ$^{-}$ in the same final state. Such a resonance could indicate the existence of a tetraquark that is a bound state of two bquarks and two b̅ antiquarks. The tetraquark search is performed for masses in the vicinity of four times the bottom quark mass, between 17.5 and 19.5GeV, while a generic search for other resonances is performed for masses between 16.5 and 27GeV. No significant excess of events compatible with a narrow resonance is observed in the data. Limits on the production cross section times branching fraction to four muons via an intermediate Y(1S)resonance are set as a function of the resonance mass

Global, regional, and national age-sex-specific mortality and life expectancy, 1950–2017: a systematic analysis for the Global Burden of Disease Study 2017

BACKGROUND: Assessments of age-specific mortality and life expectancy have been done by the UN Population Division, Department of Economics and Social Affairs (UNPOP), the United States Census Bureau, WHO, and as part of previous iterations of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD). Previous iterations of the GBD used population estimates from UNPOP, which were not derived in a way that was internally consistent with the estimates of the numbers of deaths in the GBD. The present iteration of the GBD, GBD 2017, improves on previous assessments and provides timely estimates of the mortality experience of populations globally. METHODS: The GBD uses all available data to produce estimates of mortality rates between 1950 and 2017 for 23 age groups, both sexes, and 918 locations, including 195 countries and territories and subnational locations for 16 countries. Data used include vital registration systems, sample registration systems, household surveys (complete birth histories, summary birth histories, sibling histories), censuses (summary birth histories, household deaths), and Demographic Surveillance Sites. In total, this analysis used 8259 data sources. Estimates of the probability of death between birth and the age of 5 years and between ages 15 and 60 years are generated and then input into a model life table system to produce complete life tables for all locations and years. Fatal discontinuities and mortality due to HIV/AIDS are analysed separately and then incorporated into the estimation. We analyse the relationship between age-specific mortality and development status using the Socio-demographic Index, a composite measure based on fertility under the age of 25 years, education, and income. There are four main methodological improvements in GBD 2017 compared with GBD 2016: 622 additional data sources have been incorporated; new estimates of population, generated by the GBD study, are used; statistical methods used in different components of the analysis have been further standardised and improved; and the analysis has been extended backwards in time by two decades to start in 1950. FINDINGS: Globally, 18·7% (95% uncertainty interval 18·4–19·0) of deaths were registered in 1950 and that proportion has been steadily increasing since, with 58·8% (58·2–59·3) of all deaths being registered in 2015. At the global level, between 1950 and 2017, life expectancy increased from 48·1 years (46·5–49·6) to 70·5 years (70·1–70·8) for men and from 52·9 years (51·7–54·0) to 75·6 years (75·3–75·9) for women. Despite this overall progress, there remains substantial variation in life expectancy at birth in 2017, which ranges from 49·1 years (46·5–51·7) for men in the Central African Republic to 87·6 years (86·9–88·1) among women in Singapore. The greatest progress across age groups was for children younger than 5 years; under-5 mortality dropped from 216·0 deaths (196·3–238·1) per 1000 livebirths in 1950 to 38·9 deaths (35·6–42·83) per 1000 livebirths in 2017, with huge reductions across countries. Nevertheless, there were still 5·4 million (5·2–5·6) deaths among children younger than 5 years in the world in 2017. Progress has been less pronounced and more variable for adults, especially for adult males, who had stagnant or increasing mortality rates in several countries. The gap between male and female life expectancy between 1950 and 2017, while relatively stable at the global level, shows distinctive patterns across super-regions and has consistently been the largest in central Europe, eastern Europe, and central Asia, and smallest in south Asia. Performance was also variable across countries and time in observed mortality rates compared with those expected on the basis of development. INTERPRETATION: This analysis of age-sex-specific mortality shows that there are remarkably complex patterns in population mortality across countries. The findings of this study highlight global successes, such as the large decline in under-5 mortality, which reflects significant local, national, and global commitment and investment over several decades. However, they also bring attention to mortality patterns that are a cause for concern, particularly among adult men and, to a lesser extent, women, whose mortality rates have stagnated in many countries over the time period of this study, and in some cases are increasing