We present the results from modeling the coronal mass ejection (CME) properties that have an effect on the Faraday rotation (FR) signatures that may be measured with an imaging radio antenna array such as the Murchison Widefield Array (MWA). These include the magnetic flux rope orientation, handedness, magnetic-field magnitude, velocity, radius, expansion rate, electron density, and the presence of a shock/sheath region. We find that simultaneous multiple radio source observations (FR imaging) can be used to uniquely determine the orientation of the magnetic field in a CME, increase the advance warning time on the geoeffectiveness of a CME by an order of magnitude from the warning time possible from in-situ observations at L 1, and investigate the extent and structure of the shock/sheath region at the leading edge of fast CMEs. The magnetic field of the heliosphere is largely “invisible” with only a fraction of the interplanetary magnetic-field lines convecting past the Earth; remote sensing the heliospheric magnetic field through FR imaging from the MWA will advance solar physics investigations into CME evolution and dynamics.

Background

Pembrolizumab demonstrated robust antitumor activity and safety in the phase Ib KEYNOTE-001 study (NCT01295827) of advanced melanoma. Five-year outcomes in all patients and treatment-naive patients are reported herein. Patients whose disease progressed following initial response and who received a second course of pembrolizumab were also analyzed.

Patients and methods

Patients aged ≥18 years with previously treated or treatment-naive advanced/metastatic melanoma received pembrolizumab 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks until disease progression, intolerable toxicity, or patient/investigator decision to withdraw. Kaplan-Meier estimates of overall survival (OS) and progression-free survival (PFS) were calculated. Objective response rate and PFS were based on immune-related response criteria by investigator assessment (data cut-off, September 1, 2017).

Results

KEYNOTE-001 enrolled 655 patients with melanoma; median follow-up was 55 months. Estimated 5-year OS was 34% in all patients and 41% in treatment-naive patients; median OS was 23.8 months (95% CI, 20.2-30.4) and 38.6 months (95% CI, 27.2-not reached), respectively. Estimated 5-year PFS rates were 21% in all patients and 29% in treatment-naive patients; median PFS was 8.3 months (95% CI, 5.8-11.1) and 16.9 months (95% CI, 9.3-35.5), respectively. Median response duration was not reached; 73% of all responses and 82% of treatment-naive responses were ongoing at data cut-off; the longest response was ongoing at 66 months. Four patients [all with prior response of complete response (CR)] whose disease progressed during observation subsequently received second-course pembrolizumab. One patient each achieved CR and partial response (after data cut-off). Treatment-related AEs (TRAEs) occurred in 86% of patients and resulted in study discontinuation in 7.8%; 17% experienced grade 3/4 TRAE.

Conclusions

This 5-year analysis of KEYNOTE-001 represents the longest follow-up for pembrolizumab to date and confirms the durable antitumor activity and tolerability of pembrolizumab in advanced melanoma.

Clinical trial registry

ClinicalTrials.gov, NCT01295827.

The DNA base excision repair (BER) glycosylase MUTYH prevents DNA mutations by catalyzing adenine (A) excision from inappropriately formed 8-oxoguanine (8-oxoG):A mismatches. The importance of this mutation suppression activity in tumor suppressor genes is underscored by the association of inherited variants of MUTYH with colorectal polyposis in a hereditary colorectal cancer syndrome known as MUTYH-associated polyposis, or MAP. Many of the MAP variants encompass amino acid changes that occur at positions surrounding the two-metal cofactor-binding sites of MUTYH. One of these cofactors, found in nearly all MUTYH orthologs, is a [4Fe-4S]²⁺ cluster coordinated by four Cys residues located in the N-terminal catalytic domain. We recently uncovered a second functionally relevant metal cofactor site present only in higher eukaryotic MUTYH orthologs: a Zn²⁺ ion coordinated by three Cys residues located within the extended interdomain connector (IDC) region of MUTYH that connects the N-terminal adenine excision and C-terminal 8-oxoG recognition domains. In this work, we identified a candidate for the fourth Zn²⁺ coordinating ligand using a combination of bioinformatics and computational modeling. In addition, using in vitro enzyme activity assays, fluorescence polarization DNA binding assays, circular dichroism spectroscopy, and cell-based rifampicin resistance assays, the functional impact of reduced Zn²⁺ chelation was evaluated. Taken together, these results illustrate the critical role that the "Zn²⁺ linchpin motif" plays in MUTYH repair activity by providing for proper engagement of the functional domains on the 8-oxoG:A mismatch required for base excision catalysis. The functional importance of the Zn²⁺ linchpin also suggests that adjacent MAP variants or exposure to environmental chemicals may compromise Zn²⁺ coordination, and ability of MUTYH to prevent disease.

We report the results of a multi-instrument, multi-technique, coordinated study of the solar eruptive event of 13 May 2005. We discuss the resultant Earth-directed (halo) coronal mass ejection (CME), and the effects on the terrestrial space environment and upper Earth atmosphere. The interplanetary CME (ICME) impacted the Earth’s magnetosphere and caused the most-intense geomagnetic storm of 2005 with a Disturbed Storm Time (Dst) index reaching −263 nT at its peak. The terrestrial environment responded to the storm on a global scale. We have combined observations and measurements from coronal and interplanetary remote-sensing instruments, interplanetary and near-Earth in-situ measurements, remote-sensing observations and in-situ measurements of the terrestrial magnetosphere and ionosphere, along with coronal and heliospheric modelling. These analyses are used to trace the origin, development, propagation, terrestrial impact, and subsequent consequences of this event to obtain the most comprehensive view of a geo-effective solar eruption to date. This particular event is also part of a NASA-sponsored Living With a Star (LWS) study and an on-going US NSF-sponsored Solar, Heliospheric, and INterplanetary Environment (SHINE) community investigation.

The GEp-III and GEp-2γ experiments, carried out in Jefferson Lab's Hall C from 2007–2008, consisted of measurements of polarization transfer in elastic electron–proton scattering at momentum transfers of Q2=2.5,5.2,6.8, and 8.54 GeV 2. These measurements were carried out to improve knowledge of the proton electromagnetic form factor ratio R=μpGEp∕GMp at large values of Q2 and to search for effects beyond the Born approximation in polarization transfer observables at Q2=2.5GeV2. The final results of both experiments were reported in a recent archival publication. A full reanalysis of the data from both experiments was carried out in order to reduce the systematic and, for the GEp-2γ experiment, statistical uncertainties. This technical note provides additional details of the final analysis omitted from the main publication, including the final evaluation of the systematic uncertainties.

Subsequent to the release of our original paper, we discovered in the context of preparing our technical supplement [1] for journal publication that a typographical error had existed in the text file that the analysis program used to construct the beam polarization "database" for both the original analysis, published in Ref. [2], and our final analysis. The electron-beam polarization P e and the analyzing power A y cancel exactly in the ratio R , which is proportional to the ratio P t / P l of the transferred polarization components. On the other hand, the extraction of the relative e dependence of P l / P Born l relies on knowledge of the beam polarization. As such, data taking was interrupted roughly every two days during the GEp - 2 ? experiment to perform invasive measurements of the beam polarization using the Hall C Moller polarimeter [3]. The run range affected by the typographical error was entirely contained within the data collected at Q 2 = 2.5 GeV 2 with a beam energy of E e = 3.680 GeV during January 2008. The data from this configuration were combined with the data collected at E e = 3.548 GeV due to the nearly complete overlap of these two settings in terms of Q 2 and e acceptance. It is worth remarking that this typographical error went unnoticed for so long because it only affected a small fraction of the data (less than half of the combined data for ? e ? = 0.790 ) and the difference between the actually assigned beam polarization and the polarization that should have been assigned was comparable in magnitude to the point-to-point systematic uncertainty of the measurement itself. As such, its effect did not show up in various diagnostic plots and statistical tests, such as the time stability of the extracted P l / P Born l ratio. The data for both E e = 3.548 and E e = 3.680 GeV were reprocessed using the corrected beam polarizations to determine the effect of the typographical error on the combined physics results at ? e ? = 0.790 . Because the value of P e cancels in the ratio R , changes in the assumed beam polarization can only affect the results for R via statistical fluctuations due to changes in the relative weighting of different run ranges in the unbinned maximum-likelihood estimators for R . These effects are negligible on the scale of both the statistical and the systematic uncertainties of the data. More noticeable changes are expected in the ratio P l / P Born l since the extracted value of P l is inversely proportional to the assumed value of P e . Table I shows the effect of the corrected beam polarization database on the polarization transfer observables for the combined data for the ? e ? = 0.790 setting, the only measurement affected by the typographical error. The analyzing power did not need to be recalibrated since it was determined using the ? e ? = 0.153 data, which were not affected by the typographical error. As expected, the change in the ratio R is negligible. The value of P Born l , which is computed event by event from the global fit described in the Appendix of the original paper and does not depend on P e , is also unchanged. The magnitudes of P t , P l , and P l / P Born l are reduced by a common multiplicative factor, reflecting the fact that the beam polarization had been underestimated for the run range affected by the typographical error. The most important result of the corrected analysis is that the ratio P l / P Born l has decreased by 0.0024 from 1.0167 to 1.0143, a change comparable in magnitude to the statistical uncertainty but small compared to the total and point-to-point systematic uncertainties. The P l / P Born l result for the original publication [2] would be reduced by the same multiplicative factor as the final result. The physics conclusions of both publications are not materially changed by this correction. (Table Presented). (Figure Presented).

Background: Interest in the behavior of nucleon electromagnetic form factors at large momentum transfers has steadily increased since the discovery, using polarization observables, of the rapid decrease of the ratio GEp/GMp of the proton's electric and magnetic form factors for momentum transfers Q21 GeV2, in strong disagreement with previous extractions of this ratio using the traditional Rosenbluth separation technique. Purpose: The GEp-III and GEp-2γ experiments were carried out in Jefferson Laboratory's (JLab's) Hall C from 2007 to 2008, to extend the knowledge of GEp/GMp to the highest practically achievable Q2 given the maximum beam energy of 6 GeV and to search for effects beyond the Born approximation in polarization transfer observables of elastic ∫ - p scattering. This article provides an expanded description of the common experimental apparatus and data analysis procedures, and reports the results of a final reanalysis of the data from both experiments, including the previously unpublished results of the full-acceptance dataset of the GEp-2γ experiment. Methods: Polarization transfer observables in elastic ∫ - p→∫ - scattering were measured at central Q2 values of 2.5, 5.2, 6.8, and 8.54 GeV2. At Q2=2.5GeV2, data were obtained for central values of the virtual photon polarization parameter ϵ of 0.149, 0.632, and 0.783. The Hall C High Momentum Spectrometer detected and measured the polarization of protons recoiling elastically from collisions of JLab's polarized electron beam with a liquid hydrogen target. A large-acceptance electromagnetic calorimeter detected the elastically scattered electrons in coincidence to suppress inelastic backgrounds. Results: The final GEp-III data are largely unchanged relative to the originally published results. The statistical uncertainties of the final GEp-2γ data are significantly reduced at ϵ=0.632 and 0.783 relative to the original publication. Conclusions: The final GEp-III results show that the decrease with Q2 of GEp/GMp continues to Q2=8.5GeV2, but at a slowing rate relative to the approximately linear decrease observed in earlier Hall A measurements. At Q2=8.5GeV2, GEp/GMp remains positive but is consistent with zero. At Q2=2.5GeV2, GEp/GMp derived from the polarization component ratio R-Pt/P shows no statistically significant ϵ dependence, as expected in the Born approximation. On the other hand, the ratio P""/P""Born of the longitudinal polarization transfer component to its Born value shows an enhancement of roughly 1.7% at ϵ=0.783 relative to ϵ=0.149, with ≈2.2σ significance based on the total uncertainty, implying a similar effect in the transverse component Pt that cancels in the ratio R.

The strong interaction is not well understood at low energies or for interactions with low momentum transfer. Chiral perturbation theory gives testable predictions for the nucleonic generalized polarizabilities, which are fundamental quantities describing the nucleon’s response to an external field. We report a measurement of the proton’s generalized spin polarizabilities extracted with a polarized electron beam and a polarized solid ammonia target in the region where chiral perturbation theory is expected to be valid. The investigated structure function g2 characterizes the internal spin structure of the proton. From its moments, we extract the longitudinal–transverse spin polarizability δLT and twist-3 matrix element and polarizability d2¯. Our results provide discriminating power between existing chiral perturbation theory calculations and will help provide a better understanding of this strong quantum chromodynamics regime.

In response to the 2013 Update of the European Strategy for Particle Physics, the Future Circular Collider (FCC) study was launched, as an international collaboration hosted by CERN. This study covers a highest-luminosity high-energy lepton collider (FCC-ee) and an energy-frontier hadron collider (FCC-hh), which could, successively, be installed in the same 100 km tunnel. The scientific capabilities of the integrated FCC programme would serve the worldwide community throughout the 21st century. The FCC study also investigates an LHC energy upgrade, using FCC-hh technology. This document constitutes the second volume of the FCC Conceptual Design Report, devoted to the electron-positron collider FCC-ee. After summarizing the physics discovery opportunities, it presents the accelerator design, performance reach, a staged operation scenario, the underlying technologies, civil engineering, technical infrastructure, and an implementation plan. FCC-ee can be built with today’s technology. Most of the FCC-ee infrastructure could be reused for FCC-hh. Combining concepts from past and present lepton colliders and adding a few novel elements, the FCC-ee design promises outstandingly high luminosity. This will make the FCC-ee a unique precision instrument to study the heaviest known particles (Z, W and H bosons and the top quark), offering great direct and indirect sensitivity to new physics.

In response to the 2013 Update of the European Strategy for Particle Physics (EPPSU), the Future Circular Collider (FCC) study was launched as a world-wide international collaboration hosted by CERN. The FCC study covered an energy-frontier hadron collider (FCC-hh), a highest-luminosity high-energy lepton collider (FCC-ee), the corresponding 100 km tunnel infrastructure, as well as the physics opportunities of these two colliders, and a high-energy LHC, based on FCC-hh technology. This document constitutes the third volume of the FCC Conceptual Design Report, devoted to the hadron collider FCC-hh. It summarizes the FCC-hh physics discovery opportunities, presents the FCC-hh accelerator design, performance reach, and staged operation plan, discusses the underlying technologies, the civil engineering and technical infrastructure, and also sketches a possible implementation. Combining ingredients from the Large Hadron Collider (LHC), the high-luminosity LHC upgrade and adding novel technologies and approaches, the FCC-hh design aims at significantly extending the energy frontier to 100 TeV. Its unprecedented centre-of-mass collision energy will make the FCC-hh a unique instrument to explore physics beyond the Standard Model, offering great direct sensitivity to new physics and discoveries.