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Supplemental material, sj-pdf-1-jcb-10.1177_0271678X211040056 for Malignant astrocyte swelling and impaired glutamate clearance drive the expansion of injurious spreading depolarization foci by ��kos Menyh��rt, Rita Frank, Attila E Farkas, Zolt��n S��le, Vikt��ria �� Varga, ��d��m Ny��l-T��th, Anne Meiller, Orsolya Iv��nkovits-Kiss, Coline L Lemale, ��risz Szab��, R��ka T��th, D��niel Z��lei-Sz��n��si, Johannes Woitzik, Stephane Marinesco, Istv��n A Krizbai, Ferenc Bari, Jens P Dreier and Eszter Farkas in Journal of Cerebral Blood Flow & Metabolism

PURPOSE The CheckMate 066 trial investigated nivolumab monotherapy as first-line treatment for patients with previously untreated BRAF wild-type advanced melanoma. Five-year results are presented herein. PATIENTS AND METHODS In this multicenter, double-blind, phase III study, 418 patients with previously untreated, unresectable, stage III/IV, wild-type BRAF melanoma were randomly assigned 1:1 to receive nivolumab 3 mg/kg every 2 weeks or dacarbazine 1,000 mg/m2 every 3 weeks. The primary end point was overall survival (OS), and secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety. RESULTS Patients were followed for a minimum of 60 months from the last patient randomly assigned (median follow-up, 32.0 months for nivolumab and 10.9 months for dacarbazine). Five-year OS rates were 39% with nivolumab and 17% with dacarbazine; PFS rates were 28% and 3%, respectively. Five-year OS was 38% in patients randomly assigned to dacarbazine who had subsequent therapy, including nivolumab (n 5 37). ORR was 42% with nivolumab and 14% with dacarbazine; among patients alive at 5 years, ORR was 81% and 39%, respectively. Of 42 patients treated with nivolumab who had a complete response (20%), 88% (37 of 42) were alive as of the 5-year analysis. Among 75 nivolumab-treated patients alive and evaluable at the 5-year analysis, 83% had not received subsequent therapy; 23% were still on study treatment, and 60% were treatment free. Safety analyses were similar to the 3-year report. CONCLUSION Results from this 5-year analysis confirm the significant benefit of nivolumab over dacarbazine for all end points and add to the growing body of evidence supporting long-term survival with nivolumab monotherapy. Survival is strongly associated with achieving a durable response, which can be maintained after treatment discontinuation, even without subsequent systemic therapies. © 2020 by American Society of Clinical Oncology

Background: The analysis of the BRAF mutational status has been established as a standard procedure during diagnosis of advanced malignant melanoma due to the fact that BRAF inhibitors constitute a cornerstone in the treatment of metastatic disease. However, the general impact of BRAF mutational status on survival remains unclear. Our study aimed to assess the underlying prognostic significance of BRAF mutant versus wild type (WT) malignant melanoma on overall survival (OS), disease-free survival (DFS) and progression-free survival (PFS). Material and methods: A systematic literature search in EMBASE, Medline and Cochrane CENTRAL was performed. Studies were included if they reported survival outcomes for BRAF mutant versus WT patients as hazard ratios (HR) or in Kaplan-Meier (KM) curves. Random-effects meta-analysis models were used to pool HRs across the studies. Results: Data from 52 studies, representing 7519 patients, were pooled for analysis of OS. The presence of a BRAF mutation was statistically significantly associated with a reduced OS (HR [95% confidence interval (CI)]: 1.23 [1.09–1.38]), however, with substantial heterogeneity between the studies (I2: 58.0%). Meta-regression and sensitivity analyses showed that age, sex and BRAF mutation testing method did not have a significant effect on the OS HR. BRAF mutant melanoma showed comparable effect on DFS to non-BRAF mutant melanoma in stage I–III melanoma (combined HR: 1.16, 95% CI: 0.92–1.46), and on PFS in stage III–IV (HR: 0.98 (95% CI: 0.68−1.40)). Conclusion: Although there was substantial heterogeneity between the studies, the overall results demonstrated a poorer prognosis and OS in patients harbouring BRAF mutations. Future studies should take this into account when evaluating epidemiological data and treatment effects of new interventions in patients with malignant melanoma.

Importance: This analysis provides long-term follow-up in patients with BRAF wild-type advanced melanoma receiving first-line therapy based on anti-programmed cell death 1 receptor inhibitors. Objective: To compare the 3-year survival with nivolumab vs that with dacarbazine in patients with previously untreated BRAF wild-type advanced melanoma. Design, Setting, and Participants: This follow-up of a randomized phase 3 trial analyzed 3-year overall survival data from the randomized, controlled, double-blind CheckMate 066 phase 3 clinical trial. For this ongoing, multicenter academic institution trial, patients were enrolled from January 2013 through February 2014. Eligible patients were 18 years or older with confirmed unresectable previously untreated stage III or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 but without a BRAF mutation. Interventions: Patients were treated until progression or unacceptable toxic events with nivolumab (3 mg/kg every 2 weeks plus dacarbazine-matched placebo every 3 weeks) or dacarbazine (1000 mg/m2 every 3 weeks plus nivolumab-matched placebo every 2 weeks). Main Outcome and Measure: Overall survival. Results: At minimum follow-ups of 38.4 months among 210 participants in the nivolumab group (median age, 64 years [range, 18-86 years]; 57.6% male) and 38.5 months among 208 participants in the dacarbazine group (median age, 66 years [range, 25-87 years]; 60.1% male), 3-year overall survival rates were 51.2% (95% CI, 44.1%-57.9%) and 21.6% (95% CI, 16.1%-27.6%), respectively. The median overall survival was 37.5 months (95% CI, 25.5 months-not reached) in the nivolumab group and 11.2 months (95% CI, 9.6-13.0 months) in the dacarbazine group (hazard ratio, 0.46; 95% CI, 0.36-0.59; P

We explore the effect of mechanical strain on the electronic spectrum of patterned graphene based heterostructures. We focus on the competition of Kekul��-O type distortion favoring a trivial phase and commensurate Kane-Mele type spin-orbit coupling generating a topological phase. We derive a simple low-energy Dirac Hamiltonian incorporating the two gap promoting mechanisms and include terms corresponding to uniaxial strain. The derived effective model explains previous ab initio results through a simple physical picture. We show that while the trivial gap is sensitive to mechanical distortions, the topological gap stays resilient., 9 pages, 6 figures. Comments are welcomed

Topological properties of quantum systems could provide protection of information against environmental noise, and thereby drastically advance their potential in quantum information processing. Most proposals for topologically protected quantum gates are based on many-body systems, e.g., fractional quantum Hall states, exotic superconductors, or ensembles of interacting spins, bearing an inherent conceptual complexity. Here, we propose and study a topologically protected quantum gate, based on a one-dimensional single-particle tight-binding model, known as the Su-Schrieffer-Heeger chain. The proposed $Y$ gate acts in the two-dimensional zero-energy subspace of a Y junction assembled from three chains, and is based on the spatial exchange of the defects supporting the zero-energy modes. With numerical simulations, we demonstrate that the gate is robust against hopping disorder but is corrupted by disorder in the on-site energy. Then we show that this robustness is topological protection, and that it arises as a joint consequence of chiral symmetry, time-reversal symmetry and the spatial separation of the zero-energy modes bound to the defects. This setup will most likely not lead to a practical quantum computer, nevertheless it does provide valuable insight to aspects of topological quantum computing as an elementary minimal model. Since this model is non-interacting and non-superconducting, its dynamics can be studied experimentally, e.g., using coupled optical waveguides., 11 pages, 9 figures

Research collaborations are continuously emerging catalyzed by online platforms, where people can share their codes, calculations, data and results. These virtual research platforms are innovative, community oriented, flexible and secure as required by modern scientific approaches. A wide range of open source and commercial solutions are available in this field emphasizing the relevant aspects of such a platform differently. In this paper we present our open source and modular platform, KOOPLEX, which combines the key concepts of dynamic collaboration, customizable research environment, data sharing, access to datahubs, reproducible research and reporting. It is easily deployable and scalable to serve more users or access large computational resources., 22 pages, 4 figures, 6 tables

We explore the electronic structure and topological phase diagram of heterostructures formed of graphene and ternary bismuth tellurohalide layers. We show that mechanical strain inherently present in fabricated samples could induce a topological phase transition in single-sided heterostructures, turning the sample into a novel experimental realisation of a time reversal invariant topological insulator. We construct an effective tight binding description for low energy excitations and fit the model's parameters to ab initio band structures. We propose a simple approach for predicting phase boundaries as a function of mechanical distortions and hence gain a deeper understanding on how the topological phase in the considered system may be engineered., 20 pages, 7 figures, Accepted Manuscript

We present a computational method to determine the exchange constants in isotropic spin models. The method uses the Hamiltonian and overlap matrices computed from density functional schemes that are based on nonorthogonal basis sets. We demonstrate that the new method as implemented in the SIESTA code reproduces the Heisenberg interactions of simple metallic bulk ferromagnets as obtained from former well--established computational approaches. Then we address $sp$ magnetism in graphene nanostructures. For fluorinated graphene we obtain exchange interactions in fairly good agreement with previous calculations using maximally localized Wannier functions and we confirm the theoretical prediction of a 120$^\circ$ N��el state. Associated with the magnetic edge-states of a zigzag graphene nanoribbon we find rapidly decaying exchange interactions, however, with an unconventional distance dependence of $\exp(-\sqrt{r/��})$. We show that the stiffness constant derived from the exchange interactions is consistent with previous estimate based on total energy differences of twisted spin configurations. We highlight that our method is an efficient tool for the analysis of novel hybrid nano-structures where metallic and organic components are integrated to form exotic magnetic patterns.

Experimental correlation analysis and first-principles theory are used to probe the structure and evolution of Ag-CO-Ag single-molecule junctions, both before the formation, and after the rupture of the junctions. Two dimensional correlation histograms and conditional histograms demonstrate that prior to the single-molecule bridge configuration the CO molecule is already bound parallel to the Ag single-atom contact. This molecular precursor configuration is accompanied by the opening of additional conductance channels compared to the single-channel transport in pure Ag monoatomic junctions. To investigate the post-rupture evolution of the junction we introduce a cross-correlation analysis between the opening and the subsequent closing conductance traces. This analysis implies that the molecule is bound rigidly to the apex of one electrode, and so the same single-molecule configuration is re-established as the junction is closed. The experimental results are confirmed by ab initio simulations of the evolution of contact geometries, transmission eigenvalues and scattering wavefunctions.

By calculating the spectral density of states in the ferromagnetic (FM) ground state and in the high temperature paramagnetic (PM) phase we provide the first concise study of finite temperature effects on the electronic structure of the bulk and the surface of gadolinium metal. The variation of calculated spectral properties of the Fermi surface and the density of states in the bulk and at the surface are in good agreement with recent photoemission experiments performed in both ferromagnetic and paramagnetic phases. In the paramagnetic state we find vanishing spin splitting of the conduction band, but finite local spin moments both in bulk and at the surface. We clearly demonstrate that the formation of these local spin moments in the conduction band is due to the asymmetry of the density of states in the two spin channels, suggesting a complex, non-Stoner behavior. We, therefore, suggest that the vanishing or nearly vanishing spin splitting of spectral features cannot be used as an indicator for Stoner-like magnetism.

This course-based primer provides newcomers to the field with a concise introduction to some of the core topics in the emerging field of topological insulators. The aim is to provide a basic understanding of edge states, bulk topological invariants, and of the bulk--boundary correspondence with as simple mathematical tools as possible. The present approach uses noninteracting lattice models of topological insulators, building gradually on these to arrive from the simplest one-dimensional case (the Su-Schrieffer-Heeger model for polyacetylene) to two-dimensional time-reversal invariant topological insulators (the Bernevig-Hughes-Zhang model for HgTe). In each case the discussion of simple toy models is followed by the formulation of the general arguments regarding topological insulators. The only prerequisite for the reader is a working knowledge in quantum mechanics, the relevant solid state physics background is provided as part of this self-contained text, which is complemented by end-of-chapter problems.

Several lattices, such as the dice or the Lieb lattice, possess Dirac cones and a flat band crossing the Dirac point, whose effective model is the pseudospin-1 Dirac-Weyl equation. We investigate the fate of the flat band in the presence of disorder by focusing on the density of states (DOS) and dc conductivity. While the central hub-site does not reveal the presence of the flat band, the sublattice resolved DOS on the non-central sites exhibits a narrow peak with height ~ 1/\sqrt{g} with g the dimensionless disorder variance. Although the group velocity is zero on the flat band, the dc conductivity diverges as ln(1/g) with decreasing disorder due to interband transitions around the band touching point between the propagating and the flat band. Generalizations to higher pseudospin are given., 5 pages, 5 figures

It is shown that, contrary to the naive expectation, single particle spectral gaps can be opened on the surface states of three dimensional topological insulators by using commensurate out- and in-plane antiferromagnetic or ferrimagnetic insulating thin films., 5 pages, 3 figures

Aliment Pharmacol Ther 2011; 33: 1113-1122 SUMMARY: Background Many patients with gastro-oesophageal reflux disease (GERD) are hypersensitive to heat and acid and may respond insufficiently to standard treatment. Antagonists of the heat and acid receptor 'transient receptor potential vanilloid 1'(TRPV1) are a potential drug class for GERD treatment. Aim To investigate the effect of a TRPV1 antagonist (AZD1386) on experimentally induced oesophageal pain. Methods Twenty-two healthy men (20-31 years) participated in this randomised, placebo-controlled, double-blinded, crossover study examining the effects of a single-dose oral AZD1386 (30 and 95 mg). Subjects were block-randomised. On treatment days, participants were stimulated with painful heat, distension, electrical current and acid in the oesophagus. Heat and pressure pain on the forearm were somatic control stimuli. Data analysis: intention-to-treat. Results A total of 21 participants completed the protocol and 1 voluntarily discontinued. In the oesophagus, both 30 and 95 mg of AZD1386 increased pain thresholds to heat stimuli 23% [95% confidence interval (CI): 10-38%] and 28%, respectively (CI: 14-43%). The skin heat tolerance was increased 2.1 °C (CI: 1.1-3.2 °C) after 30 mg AZD1386 and 4.0 °C (CI: 3.0-5.0 °C) after 95 mg. Heat analgesia persisted for 2.5 h. Pain thresholds to the other stimuli were unaffected by AZD1386. 50% reported 'feeling cold' and body temperature increased in all subjects exposed to 30 and 95 mg AZD1386 (mean increase 0.4 ± 0.3 °C and 0.7 ± 0.3 °C, respectively, P

Using the Kubo formula we develop a general and simple expression for the minimal conductivity in systems described by a two by two Hamiltonian. As an application we derive an analytical expression for the minimal conductivity tensor of bilayer graphene as a function of a complex parameter $w$ related to recently proposed symmetry breaking mechanisms resulting from electron-electron interaction or strain applied to the sample. The number of Dirac points changes with varying parameter w, this directly affect the minimal conductivity. Our analytic expression is confirmed using an independent calculation based on Landauer approach and we find remarkably good agreement between the two methods. We demonstrate that the minimal conductivity is very sensitive to the change of the parameter $w$ and the orientation of the electrodes with respect to the sample. Our results show that the minimal conductivity is closely related to the topology of the low energy band structure., Extended version of v1, 8 pages, 4 figures

International audience; *