The association among pathological response, recurrence-free survival (RFS) and overall survival (OS) with neoadjuvant therapy in melanoma remains unclear. In this study, we pooled data from six ...clinical trials of anti-PD-1-based immunotherapy or BRAF/MEK targeted therapy. In total, 192 patients were included; 141 received immunotherapy (104, combination of ipilimumab and nivolumab; 37, anti-PD-1 monotherapy), and 51 received targeted therapy. A pathological complete response (pCR) occurred in 40% of patients: 47% with targeted therapy and 33% with immunotherapy (43% combination and 20% monotherapy). pCR correlated with improved RFS (pCR 2-year 89% versus no pCR 50%, P < 0.001) and OS (pCR 2-year OS 95% versus no pCR 83%, P = 0.027). In patients with pCR, near pCR or partial pathological response with immunotherapy, very few relapses were seen (2-year RFS 96%), and, at this writing, no patient has died from melanoma, whereas, even with pCR from targeted therapy, the 2-year RFS was only 79%, and OS was only 91%. Pathological response should be an early surrogate endpoint for clinical trials and a new benchmark for development and approval in melanoma.
A central question in the underdoped cuprates pertains to the nature of the pseudogap ground state. A conventional metallic ground state of the pseudogap region has been argued to host quantum ...oscillations upon destruction of the superconducting order parameter by modest magnetic fields. Here, we use low applied measurement currents and millikelvin temperatures on ultrapure single crystals of underdoped Formula: see text to unearth an unconventional quantum vortex matter ground state characterized by vanishing electrical resistivity, magnetic hysteresis, and nonohmic electrical transport characteristics beyond the highest laboratory-accessible static fields. A model of the pseudogap ground state is now required to explain quantum oscillations that are hosted by the bulk quantum vortex matter state without experiencing sizable additional damping in the presence of a large maximum superconducting gap; possibilities include a pair density wave.
Neuropathic pain and allodynia may arise from sensitization of central circuits. We report a mechanism of disinhibition-based central sensitization resulting from long-term depression (LTD) of ...GABAergic interneurons as a consequence of TRPV1 activation in the spinal cord. Intrathecal administration of TRPV1 agonists led to mechanical allodynia that was not dependent on peripheral TRPV1 neurons. TRPV1 was functionally expressed in GABAergic spinal interneurons and activation of spinal TRPV1 resulted in LTD of excitatory inputs and a reduction of inhibitory signaling to spinothalamic tract (STT) projection neurons. Mechanical hypersensitivity after peripheral nerve injury was attenuated in TRPV1−/− mice but not in mice lacking TRPV1-expressing peripheral neurons. Mechanical pain was reversed by a spinally applied TRPV1 antagonist while avoiding the hyperthermic side effect of systemic treatment. Our results demonstrate that spinal TRPV1 plays a critical role as a synaptic regulator and suggest the utility of central nervous system-specific TRPV1 antagonists for treating neuropathic pain.
► Mechanical allodynia mediated by spinal TRPV1 is independent of peripheral TRPV1 ► GABAergic substantia gelatinosa neurons express TRPV1 and show TRPV1-dependent LTD ► TRPV1-dependent LTD in GABAergic neurons disinhibits spinal projection neurons ► Postsynaptic spinal TRPV1 contributes to chronic neuropathic mechanical allodynia
Kim et al. show that TRPV1 expressed in GABAergic spinal interneurons mediates long-term synaptic depression that is distinct from its role in primary nociceptors and results in mechanical allodynia via disinhibition of spinal cord projection neurons.
ABSTRACT Hot Jupiters are giant planets on orbits of a few hundredths of an AU. They do not share their system with low-mass close-in planets, despite the latter being exceedingly common. Two ...migration channels for hot Jupiters have been proposed: through a protoplanetary gas disk or by tidal circularization of highly eccentric planets. We show that highly eccentric giant planets that will become hot Jupiters clear out any low-mass inner planets in the system, explaining the observed lack of such companions to hot Jupiters. A less common outcome of the interaction is that the giant planet is ejected by the inner planets. Furthermore, the interaction can implant giant planets on moderately high eccentricities at semimajor axes AU, a region otherwise hard to populate. Our work supports the hypothesis that most hot Jupiters reached their current orbits following a phase of high eccentricity, possibly excited by other planetary or stellar companions.
We study how close-in systems such as those detected by Kepler are affected by the dynamics of bodies in the outer system. We consider two scenarios: outer systems of giant planets potentially ...unstable to planet-planet scattering and wide binaries that may be capable of driving Kozai or other secular variations of outer planets' eccentricities. Dynamical excitation of planets in the outer system reduces the multiplicity of Kepler-detectable planets in the inner system in ~20-25 per cent of our systems. Accounting for the occurrence rates of wide-orbit planets and binary stars, ≈18 per cent of close-in systems could be destabilized by their outer companions in this way. This provides some contribution to the apparent excess of systems with a single transiting planet compared to multiple; however, it only contributes at most 25 per cent of the excess. The effects of the outer dynamics can generate systems similar to Kepler-56 (two coplanar planets significantly misaligned with the host star) and Kepler-108 (two significantly non-coplanar planets in a binary). We also identify three pathways to the formation of eccentric warm Jupiters resulting from the interaction between outer and inner systems: direct inelastic collision between an eccentric outer and an inner planet; secular eccentricity oscillations that may 'freeze out' when scattering resolves in the outer system; and scattering in the inner system followed by 'uplift', where inner planets are removed by interaction with the outer planets. In these scenarios, the formation of eccentric warm Jupiters is a signature of a past history of violent dynamics among massive planets beyond ~1 au.
The uses of tetrafluoroborates and boron trifluoride as fluoride sources in the Balz-Scheimann reaction are examined. Topics discussed include nucleophilic fluorinating agents and fluorinations of ...strained rings.
Abstract
White dwarfs (WDs) often show metal lines in their spectra, indicating accretion of asteroidal material. Our Sun is to become a WD in several gigayears. Here, we examine how the solar WD ...accretes from the three major small body populations: the main belt asteroids (MBAs), Jovian Trojan asteroids (JTAs), and trans-Neptunian objects (TNOs). Owing to the solar mass loss during the giant branch, 40% of the JTAs are lost but the vast majority of MBAs and TNOs survive. During the WD phase, objects from all three populations are sporadically scattered onto the WD, implying ongoing accretion. For young cooling ages ≲100 Myr, accretion of MBAs predominates; our predicted accretion rate ∼10
6
g s
−1
falls short of observations by two orders of magnitude. On gigayear timescales, thanks to the consumption of the TNOs that kicks in ≳100 Myr, the rate oscillates around 10
6
–10
7
g s
−1
until several gigayears and drops to ∼10
5
g s
−1
at 10 Gyr. Our solar WD accretion rate from 1 Gyr and beyond agrees well with those of the extrasolar WDs. We show that for the solar WD, the accretion source region evolves in an inside-out pattern. Moreover, in a realistic small body population with individual sizes covering a wide range as WD pollutants, the accretion is dictated by the largest objects. As a consequence, the accretion rate is lower by an order of magnitude than that from a population of bodies of a uniform size and the same total mass and shows greater scatter.
ABSTRACT
Stars formed in clusters can encounter other stars at close distances. In typical open clusters in the Solar neighbourhood containing hundreds or thousands of member stars, 10–20 per cent of ...Solar-mass member stars are expected to encounter another star at distances closer than 100 au. These close encounters strongly perturb the planetary systems, directly causing ejection of planets or their capture by the intruding star, as well as exciting the orbits. Using extensive N-body simulations, we study such fly-by encounters between two Solar system analogues, each with four giant planets from Jupiter to Neptune. We quantify the rates of loss and capture immediately after the encounter, e.g. the Neptune analogue is lost in one in four encounters within 100 au, and captured by the flying-by star in 1 in 12 encounters. We then perform long-term (up to 1 Gyr) simulations investigating the ensuing post-encounter evolution. We show that large numbers of planets are removed from systems due to planet–planet interactions and that captured planets further enhance the system instability. While encounters can initially leave a planetary system containing more planets by inserting additional ones, the long-term instability causes a net reduction in planet number. A captured planet ends up on a retrograde orbit in half of the runs in which it survives for 1Gyr; also, a planet bound to its original host star but flipped during the encounter may survive. Thus, encounters between planetary systems are a channel to create counter-rotating planets, This would happen in around 1 per cent of systems, and such planets are potentially detectable through astrometry or direct imaging.
ABSTRACT
Atmospheric heavy elements have been observed in more than a quarter of white dwarfs (WDs) at different cooling ages, indicating ongoing accretion of asteroidal material, whilst only a ...few per cent of the WDs possess a dust disc, and all these WDs are accreting metals. Here, assuming that a rubble-pile asteroid is scattered inside a WD’s Roche lobe by a planet, we study its tidal disruption and the long-term evolution of the resulting fragments. We find that after a few pericentric passages, the asteroid is shredded into its constituent particles, forming a flat, thin ring. On a time-scale of Myr, tens of per cent of the particles are scattered on to the WD, and are therefore directly accreted without first passing through a circularized close-in disc. Fragment mutual collisions are most effective for coplanar fragments, and are thus only important in 103−104 yr before the orbital coplanarity is broken by the planet. We show that for a rubble pile asteroid with a size frequency distribution of the component particles following that of the near earth objects, it has to be roughly at least 10 km in radius such that enough fragments are generated and $\ge 10{{\ \rm per\ cent}}$ of its mass is lost to mutual collisions. At relative velocities of tens of km s−1, such collisions grind down the tidal fragments into smaller and smaller dust grains. The WD radiation forces may shrink those grains’ orbits, forming a dust disc. Tidal disruption of a monolithic asteroid creates large km-size fragments, and only parent bodies ≥100 km are able to generate enough fragments for mutual collisions to be significant. Hence, those large asteroids experience a disc phase before being accreted.
ABSTRACT
Planetary systems formed in clusters may be subject to stellar encounter flybys. Here, we create a diverse range of representative planetary systems with different orbital scales and ...planets’ masses and examine encounters between them in a typical open cluster. We first explore the close-in multisuper Earth systems ≲0.1 au. They are resistant to flybys in that only ones inside a few au can destabilize a planet or break the resonance between such planets. But these systems may capture giant planets on to wide orbits from the intruding star during distant flybys. If so, the original close-in small planets’ orbits may be tilted together through Kozai–Lidov mechanism, forming a ‘cold’ system that is significantly inclined against the equator of the central host. Moving to the intermediately placed planets around solar-like stars, we find that the planets’ mass gradient governs the systems’ long-term evolution post-encounter: more massive planets have better chances to survive. Also, a system’s angular momentum deficit, a quantity describing how eccentric/inclined the orbits are, measured immediately after the encounter, closely relates to the longevity of the systems – whether or not and when the systems turn unstable in the ensuing evolution millions of years post-encounter. We compare the orbits of the surviving planets in the unstable systems through (1) the immediate consequence of the stellar fly or (2) internal interplanetary scattering long post-encounter and find that those for the former are systematically colder. Finally, we show that massive wide-orbit multiplanet systems like that of HR 8799 can be easily disrupted and encounters at a few hundreds of au suffice.
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