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Background: Lenvatinib is appropriate for reducing the production of nitric oxide (NO) and facilitating as block angiogenesis. However, to our knowledge, there are no data that support the correlation between NO and clinical response in patients who received lenvatinib therapy for HCC. Therefore, we investigated whether or not NO influence a therapeutic response and adverse events (AEs) after lenvatinib therapy for unresectable hepatocellular carcinoma (HCC).Methods: This study was conducted using previously collected data from another study. We enrolled 70 patients who received lenvatinib for advanced or unresectable HCC. NO was measured by converting nitrate (NO3–) to nitrite (NO2–) with nitrate reductase, followed by quantitation of NO2– based on Griess reagent. To determine whether lenvatinib influences NO in unresectable HCC, we evaluated the influence of maximal therapeutic response and SAE on the change rate of NO from baseline after administration of lenvatinib.Results: After lenvatinib administration, a change rate in the NO from 0.27 to 4.16 was observed. There was no difference between the clinical response to lenvatinib and the change rate of NO (P = 0.193). However, the change rate of NO was significantly higher in patients with AEs than in those without AEs (P = 0.013). When a reduction in NO rate of < 0.8 was defined as a clinically significant reduction of NO (CSRN), the CSRN group had significantly worse progression-free survival (PFS) and overall survival (OS) than the non-CSRN group (P = 0.040 and P = 0.005, respectively)ConclusionDecreased NO levels were associated with the occurrence of AEs and worse prognosis after lenvatinib administration. Change rate in serum NO can be used as predictive markers in patients receiving lenvatinib therapy for HCC.

Microorganisms can evolve and become resistant to antimicrobials, and this is known as antimicrobial resistance (AMR). Inappropriate use of antibiotics contributes to AMR, and antimicrobial stewardship programs have been developed to mitigate AMR. The Appropriate Use of Carbapenems Program was implemented in March 2019 in a university hospital and its effect was evaluated.We conducted a prospective audit and feedback on carbapenems at the time of prescription daily. Additionally, we compared a monthly survey of the total days of therapy (DOTs) per 1000 patient-days for carbapenems, piperacillin/tazobactam, and fluoroquinolones. The susceptibility of Pseudomonas aeruginosa to meropenem, piperacillin/tazobactam, and levofloxacin was tested before (January 2018 to February 2019) and after (March 2019 to December 2020) the intervention.The monthly median DOTs of carbapenem usage decreased after the intervention; carbapenem use immediately declined during the intervention period. The monthly median DOTs of piperacillin/tazobactam and fluoroquinolones also decreased and continued to decline significantly after the intervention. Susceptibility of P. aeruginosa to meropenem, piperacillin/tazobactam, and levofloxacin did not change significantly during the study.The implementation of the Appropriate Use of Carbapenems Program was effective in reducing the use of broad-spectrum antibiotics and maintaining the antibiotic susceptibility of P. aeruginosa.

We investigated whether or not nitric oxide synthase 3 (NOS3) rs2070744 genotypes can affect the response for lenvatinib treatment in patients with hepatocellular carcinoma (HCC). We evaluated the relation of the NOS3 rs2070744 genotypes to the tumor response, progression-free survival (PFS), and overall survival (OS) as the response for lenvatinib. We also examined the association between fibroblast growth factor receptor (FGFR) gene polymorphisms, a potential feature of lenvatinib, and the response. There were no significant differences between the studies for either PFS or OS, even though patients with the TT genotype had a longer mean PFS (hazard ratio [HR] 0.60; p = 0.069) and mean OS (HR 0.46; p = 0.075) than those with the TC/CC genotypes. However, patients with a single-nucleotide polymorphism (SNP) combination pattern of the NOS3 rs2070744 TC/CC and FGFR4 rs351855 CT/TT genotypes had a significantly shorter mean PFS (HR 2.56; p = 0.006) and mean OS (HR 3.36; p = 0.013) than those with the other genotypes. The NOS3 rs2070744 genotypes did not influence the clinical response. However, the SNP combination pattern of the NOS3 rs2070744 and FGFR4 rs351855 genotypes may be helpful as treatment effect predictors and prognostic factors for HCC patients treated with lenvatinib.

When plate tectonics began on the Earth has been long debated and here we argue this topic based on the records of Earth-Moon geology and asteroid belt to conclude that the onset of plate tectonics was during the middle Hadean (4.37–4.20 Ga). The trigger of the initiation of plate tectonics is the ABEL Bombardment, which delivered oceanic and atmospheric components on a completely dry reductive Earth, originally comprised of enstatite chondrite-like materials. Through the accretion of volatiles, shock metamorphism processed with vaporization of both CI chondrite and supracrustal rocks at the bombarded location, and significant recrystallization went through under wet conditions, caused considerable eclogitization in the primordial continents composed of felsic upper crust of 21 km thick anorthosite, and 50 km or even thicker KREEP lower crust. Eclogitization must have yielded a powerful slab-pull force to initiate plate tectonics in the middle Hadean. Another important factor is the size of the bombardment. By creating Pacific Ocean class crater by 1000 km across impactor, rigid plate operating stagnant lid tectonics since the early Hadean was severely destroyed, and oceanic lithosphere was generated to have bi-modal lithosphere on the Earth to enable the operation of plate tectonics. Considering the importance of the ABEL Bombardment event which initiated plate tectonics including the appearance of ocean and atmosphere, we propose that the Hadean Eon can be subdivided into three periods: (1) early Hadean (4.57–4.37 Ga), (2) middle Hadean (4.37–4.20 Ga), and (3) late Hadean (4.20–4.00 Ga). Keywords: Initiation of plate tectonics, ABEL Bombardment, Eclogitization, Stagnant lid tectonics, Primordial continents

A rotational diamond anvil cell is the most suitable deformation apparatus with which to investigate the rheological properties of deep-Earth materials at pressures similar to those found in the lo...

Geological observations indicate that there are only a few rocks of Archean Earth and no Hadean rocks on the surface of the present-day Earth. From these facts, many scientists believe that the primordial continents never existed during Hadean Earth, and the continental volume has kept increasing. On the other hand, recent studies reported the importance of the primordial continents on the origin of life, implying their existence. In this paper, we discussed the possible process that could explain the loss of the primordial continents with the assumption that they existed in the Hadean. Although depending on the timing of the initiation of plate tectonics and its convection style, subduction erosion, which is observed on the present-day Earth, might have carried the primordial continents into the deep mantle.

Ancient Mars likely hosted oceans similar to those on Earth; however, such water is not presently observed on Mars. One possible explanation for the lack of present-day oceans is that surface water was transported into and stored within the interior of Mars throughout the geological history. As water can influence the rheological structure of the Martian lithosphere, we investigated the sensitivity of the elastic thickness of the lithosphere to water using recent laboratory data. Calculations indicate that the presence of water results in a significant decrease in elastic thickness relative to dry conditions at a given thermal structure. Gravity and topographic data acquired by the Mars Global Surveyor and other orbiters indicate a temporal change in elastic thickness during the geological history of Mars. The extremely thin elastic layer during the planet’s early history can be explained by a water-rich rheological model, whereas a dry rheology can account for the relatively thick elastic layer inferred during the later evolution of Mars. Although thermal evolution of Mars has a large uncertainty, the strong sensitivity of elastic lithospheric thickness to water suggests possible sequestered water into deeper levels during the early history of Mars.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A series of simple-shear experiments on blueschist was performed at 400–500°C and 1–2.5 GPa to understand the deformation of seismically active, subducting oceanic crust. The experiments show that brittle microstructures are mainly found at pressures of 1–2 GPa, whereas ductile microstructures form at 2.5 GPa. J-indices (a measure of fabric intensity) of glaucophane crystal preferred orientations change systematically with changing shear strain and confining pressure, and the angle between the slip plane and the shear direction of samples deformed at >2 GPa is similar to that of a strain ellipsoid. These results, together with the variable orientations of fine grains in a selected area electron diffraction image at 2 GPa, indicate that the brittle–ductile transition for glaucophane occurs at ~2 GPa. In contrast to this, lawsonite in the experiments show abundant fracturing in most specimens and a poor correlation between the J-index, shear strain, and confining pressure. This demonstrates that lawsonite deformed by brittle failure under all experimental conditions. In the case of a starting material that has a strong fabric and deformed under dry experimental conditions, the brittle–ductile transition zone of glaucophane will be much shallower than 2 GPa. Therefore, our initial experimental results on the deformation behavior of blueschist indirectly support the dehydration embrittlement of subducting oceanic crust (glaucophane) as an important factor in the origin of intraplate earthquakes.

Strength contrast between plagioclase and olivine was tested utilizing two-layer deformation experiments under hydrous conditions at the pressure and temperature corresponding to the Moho (P = 1.0 GPa and T = 400-800 °C). Deformation microstructures characterized by lattice-preferred orientation and dislocation density indicate that both minerals were plastically deformed via dislocation-controlled creep. Our experimental results show that olivine is weaker than plagioclase at T = 400 °C, whereas plagioclase is weaker than olivine at T = 800 °C. Consequently, strength contrast between plagioclase and olivine is sensitive to temperature, and olivine may be weaker than plagioclase, or display almost no difference in strength between these materials under the wet continental Moho. This suggests that the “creme brulee” model, in which the upper mantle is weak and the strength is limited to the crust, is expected as a rheological layer model of the water-rich Moho conditions.

A large-strain, torsional deformation apparatus has been developed based on diamond anvil cells at high pressures, up to 135 GPa with a help of hard nano-polycrystalline diamond anvils. These pressure conditions correspond to the base of the Earth's mantle. An X-ray laminography technique is introduced for high-pressure in situ 3D observations of the strain markers. The technique developed in this study introduces the possibility of the in situ rheological measurements of the deep Earth materials under ultrahigh-pressure conditions.

Plate tectonics is largely responsible for material and heat circulation in Earth, but for unknown reasons it does not exist on Venus. The strength of planetary materials is a key control on plate tectonics because physical properties, such as temperature, pressure, stress and chemical composition, result in strong rheological layering and convection in planetary interiors. Our deformation experiments show that crustal plagioclase is much weaker than mantle olivine at conditions corresponding to the Moho in Venus. Consequently, this strength contrast may produce a mechanical decoupling between the Venusian crust and interior mantle convection. One-dimensional numerical modeling using our experimental data confirms that this large strength contrast at the Moho impedes the surface motion of the Venusian crust and, as such, is an important factor in explaining the absence of plate tectonics on Venus.

Porphyrin-based supramolecular nanostructures have been produced by the self-assembly of porphyrin macrorings with three benzoic acid groups (Acid-R) on each side of the rings through cooperative carboxyl-carboxyl hydrogen bonds. Structures of the organized Acid-R were analyzed by AFM, and two clear distribution peaks were observed at 3 and 27 nm in the height-distribution histogram. From the overall assessment, the higher objects are considered to be one-dimensional structures standing vertically on the mica substrate. The height corresponds to an 11-mer of a unit Acid-R. Light-harvesting functions were examined by using fluorescence titration, whereby an energy-acceptor molecule (Tripod 2) was employed that strongly interacted with Acid-R units (association constant: 2.0×10(8) M(-1) ), specifically from the inner pore. The titration results showed that the apparent stoichiometry [Tripod 2]/[Acid-R] was

The evolution of Mars has been greatly influenced by temporal changes in its rheological structure, which may explain the difference in tectonics between Mars and Earth. Some previous studies have shown the rheological structures of Mars calculated from the flow law of rocks and the predicted thermal structure. However, the Peierls mechanism, which is the dominant deformation mechanism at relatively low temperature, and the evolution of water reservoirs on Mars were not considered in such studies. In this paper, we apply the Peierls mechanism to refine the rheological structure of Mars to show a new history of the planet that considers the most recent reports on its evolution of water reservoirs. Considering the Peierls creep and the evolution of water reservoirs, we attempt to explain why the tectonics of Mars is inactive compared with that of Earth. On early Mars, the lithospheric thickness inferred from the brittle–ductile transition was small, and the lithospheric strength was low (~200–300 MPa) under wet conditions at 4 Gya. This suggests that plate boundaries could have developed on the early “wet” Mars, which is a prerequisite for the operation of plate tectonics. Our results also imply that the lithospheric strength had significantly increased in the Noachian owing to water loss. Therefore, plate tectonics may have ceased or could no longer be initiated on Mars. At the least, the tectonic style of Mars would have dramatically changed during the Noachian.

The primordial crust on the Earth formed from the crystallization of the surface magma ocean during the Hadean. However, geological surveys have found no evidence of rocks dating back to more than 4 Ga on the Earth's surface, suggesting the Hadean crust was lost due to some processes. We investigated the subduction of one of the possible candidates for the primordial crust, anorthosite and KREEP crust similar to the Moon, which is also considered to have formed from the crystallization of the magma ocean. Similar to the present Earth, the subduction of primordial crust by subduction erosion is expected to be an effective way of eliminating primordial crust from the surface. In this study, the subduction rate of the primordial crust via subduction channels is evaluated by numerical simulations. The subduction channels are located between the subducting slab and the mantle wedge and are comprised of primordial crust materials supplied mainly by subduction erosion. We have found that primordial anorthosite and KREEP crust of up to ∼50 km thick at the Earth's surface was able to be conveyed to the deep mantle within 0.1-2 Gy by that mechanism.