Summary
Background
Deregulation of mammalian target of rapamycin (mTOR) signalling is common in human hepatocellular carcinoma (HCC).
Aim
To determine the maximum tolerated dose (MTD) of the oral ...mTOR inhibitor everolimus in advanced HCC patients.
Methods
Patients with locally advanced or metastatic HCC (Child‐Pugh class A or B) were enrolled in an open‐label phase 1 study and randomly assigned to daily (2.5–10 mg) or weekly (20–70 mg) everolimus in a standard 3 + 3 dose‐escalation design. MTD was based on the rate of dose‐limiting toxicities (DLTs). Secondary endpoints included safety, pharmacokinetics and tumour response. In a post hoc analysis, serum hepatitis B virus (HBV) DNA levels were quantified.
Results
Thirty‐nine patients were enrolled. DLTs occurred in five of 21 patients in the daily and two of 19 patients in the weekly cohort. Daily and weekly MTDs were 7.5 mg and 70 mg respectively. Grade 3/4 adverse events with a ≥10% incidence were thrombocytopenia, hypophosphataemia and alanine transaminase (ALT) elevation. In four hepatitis B surface antigen (HBsAg)‐seropositive patients, grade 3/4 ALT elevations were accompanied by significant (>1 log) increases in serum HBV levels. The incidence of hepatitis flare (defined as ALT increase >100 IU/mL from baseline) in HBsAg‐seropositive patients with and without detectable serum HBV DNA before treatment was 46.2% and 7.1% respectively (P < 0.01, Fisher exact test). Disease control rates in the daily and weekly cohorts were 71.4% and 44.4% respectively.
Conclusions
The recommended everolimus dosing schedule for future hepatocellular carcinoma studies is 7.5 mg daily. Prophylactic anti‐viral therapy should be mandatory for HBsAg‐seropositive patients (ClinicalTrials.gov NCT00390195).
The India-Asia collision has formed the highest mountains on Earth and is thought to account for extensive intraplate deformation in Asia. The prevailing explanation considers the role of the Pacific ...and Sunda subduction zones as passive during deformation. Here we test the hypothesis that subduction played an active role and present geodynamic experiments of continental deformation that model Indian indentation and active subduction rollback. We show that the synchronous activity and interaction of the collision zone and subduction zones explain Asian deformation, and demonstrate that east-west extension in Tibet, eastward continental extrusion and Asian backarc basin formation are controlled by large-scale Pacific and Sunda slab rollback. The models require 1740 ± 300 km of Indian indentation such that backarc basins form and central East Asian extension conforms estimates. Indentation and rollback produce ~260-360 km of eastward extrusion and large-scale clockwise upper mantle circulation from Tibet towards East Asia and back to India.
We report the discovery of tidal structures around the intermediate-aged (∼700-800 Myr), nearby (∼85 pc) star cluster Coma Berenices. The spatial and kinematic grouping of stars is determined with ...the Gaia DR2 parallax and proper motion data, by a clustering analysis tool, StarGO, to map 5D parameters (X, Y, Z, ) onto a 2D neural network. Leading and trailing tails, each with an extension of ∼50 pc are revealed for the first time around this disrupting star cluster. The cluster members, totaling , are clearly mass-segregated, and exhibit a flat mass function with ∼ 0.79 0.16, in the sense of dN/dm ∝ m− , where N is the number of member stars and m is stellar mass, in the mass range of m = 0.25-2.51 M☉. Within the tidal radius of ∼6.9 pc, there are 77 member candidates with an average position, i.e., the cluster center, of R.A. = 186 8110, and decl. = 25 8112, and an average distance of 85.8 pc. Additional 120 member candidates reside in the tidal structures, i.e., outnumbering those in the cluster core. The expansion of escaping members lead to an anisotropy in the velocity field of the tidal tails. Our analysis also serendipitously uncovers an adjacent stellar group, part of which has been cataloged in the literature. We identify 218 member candidates, 10 times more than previously known. This star group is some 65 pc away from, and ∼400 Myr younger than, Coma Ber, but is already at the final stage of disruption.
The shapes and sizes of 116 Galactic globular clusters (GCs) are presented, based on the analysis of the spatial distribution of 2MASS point sources. In general, Galactic GCs are slightly flattened ...in shape, with a median axial ratio of 0.87. The GCs close to the Galactic bulge have various degrees of flattening, and those exhibiting obvious flattening tend to have their elongation pointing toward the Galactic center, manifesting the tidal effect from the bulge. In comparison, GCs away from the Galactic center tend to be spherical. A few GCs in the halo are also found to have elongated shape. Three notable cases of highly flattened clusters were previously known to be associated with stellar streams or particular dynamical history: NGC 5897 is known to have a stellar tidal tail extending to its equatorial north and south; NGC 6838 had a recent encounter with the Galactic plane; and IC 4499 is spatially close to, and collimated with, the 'Magellanic Stream'. We also found 31 GCs associated with possible clumpy structures in stellar distributions, as diagnosed by possible cluster members selected by colors and magnitudes. Four such cases of stellar debris are presented: NGC 6366 is experiencing heavy tidal stripping and NGC 2808 has been known to have multiple main-sequence branches. NGC 3201 and NGC 6397, like the flattened cluster, NGC 6838, also have their recent passage through the Galactic plane. Our sample is derived from the most inclusive analysis of the morphology of Galactic GCs, and should provide a valuable database to probe the mass distribution, or merging history of the Milky Way galaxy.
Recently, the ANITA collaboration reported on two upward-going extensive air shower events consistent with a primary particle that emerges from the surface of the Antarctic ice sheet. These events ...may be of ν τ origin, in which the neutrino interacts within the Earth to produce a τ lepton that emerges from the Earth, decays in the atmosphere, and initiates an extensive air shower. In this paper we estimate an upper bound on the ANITA acceptance to a diffuse ν τ flux detected via τ -lepton-induced air showers within the bounds of standard model uncertainties. By comparing this estimate with the acceptance of Pierre Auger Observatory and IceCube and assuming standard model interactions, we conclude that a ν τ origin of these events would imply a neutrino flux at least two orders of magnitude above current bounds.
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A multiscale model is developed to investigate the evolution mechanisms of site-specific grain structures during additive manufacturing (AM) of metallic alloys, using the selective ...electron beam melting (SEBM) fabrication of Ti-6Al-4V as an example. Specifically, finite-element method is utilized to predict the thermal response at macroscale during SEBM, and the extracted thermal information is then input into a temperature-dependent phase-field model to simulate the grain growth at mesoscale. The grain epitaxial growth, grain selection, grain nucleation and layer-by-layer manufacturing fashion are incorporated, in order to accurately predict grain structure development and relevant physical processes during AM. It is found that, the development of the predominant grain structures in the thick and thin walls, i.e., the large vertical columnar β//Nz grains and slanted columnar grains with various grain orientations, respectively, can be attributed to the competition and collaboration between the thermal gradient and the crystallographically preferred grain growth, as shown from the different growth stages in the simulations. Good agreements in the final grain structures and textures are achieved between the experimental observations and numerical simulations. The present study potentially offers valuable insights and guidance toward designing AM conditions to tailor the grain structures and textures.
Genera of phytopathogenic fungi: GOPHY 3 Marin-Felix, Y.; Hernández-Restrepo, M.; Iturrieta-González, I. ...
Studies in mycology,
09/2019, Letnik:
94, Številka:
1
Journal Article
Recenzirano
Odprti dostop
This paper represents the third contribution in the Genera of Phytopathogenic Fungi (GOPHY) series. The series provides morphological descriptions, information about the pathology, distribution, ...hosts and disease symptoms for the treated genera, as well as primary and secondary DNA barcodes for the currently accepted species included in these. This third paper in the GOPHY series treats 21 genera of phytopathogenic fungi and their relatives including: Allophoma, Alternaria, Brunneosphaerella, Elsinoe, Exserohilum, Neosetophoma, Neostagonospora, Nothophoma, Parastagonospora, Phaeosphaeriopsis, Pleiocarpon, Pyrenophora, Ramichloridium, Seifertia, Seiridium, Septoriella, Setophoma, Stagonosporopsis, Stemphylium, Tubakia and Zasmidium. This study includes three new genera, 42 new species, 23 new combinations, four new names, and three typifications of older names.
Background
Group 2 innate lymphoid cells (ILC2s) were closely associated with asthma. However, there were no perspective studies about the effects of glucocorticoid on ILC2s in asthma patients. Our ...objective was to perform a perspective study and evaluate the ILC2 activity after glucocorticoid therapy in asthma patients.
Methods
The asthma and asthma with allergic rhinitis patients were treated with glucocorticoid for 3 months. The circulating ILC2 levels were evaluated. The effects of glucocorticoid on ILC2s and possible signalling pathways were investigated in vitro.
Results
The patients were well‐controlled, and the high ILC2 levels were significantly decreased at 1 and 3 months after treatment. Peripheral blood monocytes from allergic patients produced dramatic IL‐5, IL‐13 and IL‐9 in response to IL‐25, IL‐33 plus IL‐2, and glucocorticoid significantly decreased their levels. Moreover, ILC2s were identified to be the predominant source of IL‐5, IL‐13 and IL‐9, and glucocorticoid treatment was able to reverse their high levels. STAT3, STAT5, STAT6, JAK3 and MEK signalling pathways were proved to be involved in regulating ILC2 activity under the glucocorticoid treatment.
Conclusion
The data suggested that glucocorticoid administration could be effective in treating asthma by regulating ILC2s via MEK/JAK‐STAT signalling pathways. This provides a new understanding of glucocorticoid application in regard to allergic diseases.
High circulating ILC2s were found in asthma and asthma with allergic rhinitis patients, and significantly decreased after treatment of glucocorticoid. High levels of IL‐5, IL‐13 and IL‐9 in response to epithelium‐derived cytokines were mostly produced by the increased ILC2s from asthma patients. Glucocorticoid treatment is able to reverse the high levels of IL‐5 and IL‐13 produced by ILC2s via STAT3, STAT5 and STAT6 signalling pathways.
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