Notch signaling is often and aberrantly activated by hypoxia during tumor progression; however, the exact pathological role of hypoxia-induced Notch signaling in tumor metastasis is as yet poorly ...understood. In this study, we aimed to define the mechanism of Notch-ligand activation by hypoxia in both primary tumor and bone stromal cells in the metastatic niche and to clarify their roles in tumor progression. We have analyzed the expression profiles of various Notch ligands in 779 breast cancer patients in GEO database and found that the expression of Jagged2 among all five ligands is most significantly correlated with the overall- and metastasis-free survival of breast cancer patients. The results of our immunohistochemical (IHC) analysis for Jagged2 in 61 clinical samples also revealed that both Jagged2 and Notch signaling were strongly upregulated at the hypoxic invasive front. Activation of Jagged2 by hypoxia in tumor cells induced EMT and also promoted cell survival in vitro. Notably, a γ-secretase inhibitor significantly blocked Notch-mediated invasion and survival under hypoxia by promoting expression of E-cadherin and inhibiting Akt phosphorylation. Importantly, Jagged2 was also found to be upregulated in bone marrow stroma under hypoxia and promoted the growth of cancer stem-like cells by activating their Notch signaling. Therefore, hypoxia-induced Jagged2 activation in both tumor invasive front and normal bone stroma has a critical role in tumor progression and metastasis, and Jagged2 is considered to be a valuable prognostic marker and may serve as a novel therapeutic target for metastatic breast cancer.
A low oxygen induction thermal plasma (LO-ITP) system was developed and a cold-welding behavior of bare fine metallic aluminum powders prepared by the system developed here was observed. This ...behavior is suitable for a metal precursor for metal matrix composites (MMC) since fine and bare metal particles may contribute to obtaining a well-dispersed state and a high relative density respectively, which lead to the enhancement of the reinforcement of MMC properties. The electric conductivity of the aluminum green pellet compacted at 200 MPa reached 2.9 × 107 S/m, which is comparable to that of bulk aluminum, indicating that the cold welding was taken place since the surface contamination layer such as an oxide may be negligibly thin. Therefore, the powder obtained in this work is expected to be useful in enhancing the reinforcement of MMC properties.
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•A new low oxygen induction thermal plasma system was developed.•Bare fine metallic Al powders were successfully prepared.•The electric conductivity of the Al green pellet reached that of bulk Al.•This system can be used as a production process for fine bare metal powders.
High-quality epitaxial Bi1-xSbx (BiSb) films were formed by two-step growth using molecular beam epitaxy. The use of two-step growth, which involves lower-temperature growth at ~150 °C followed by ...higher-temperature (~250 °C) growth, and lattice-matched substrates such as BaF2 (111) are key to obtain high-quality BiSb films. The composition of the BiSb films can also be systematically tuned using this growth procedure. The epitaxial BiSb films showed higher crystallinity (full width at half maximum: ~0.69°) and higher mobility (~2100 cm2/Vs), which indicate that sufficient quality films were obtained. Such films are expected to pave the way for the fabrication of electronic devices using topological BiSb.
•High-quality epitaxial BiSb films were formed by using molecular beam epitaxy.•Two-step growth and the use of lattice-matched substrates are necessary.•The BaF2 (111) substrate is one of the best substrates for the growth of BiSb films.
FOLFIRI and FOLFOX have shown equivalent efficacy for metastatic colorectal cancer (mCRC), but their comparative effectiveness is unknown when combined with bevacizumab.
WJOG4407G was a randomized, ...open-label, phase III trial conducted in Japan. Patients with previously untreated mCRC were randomized 1:1 to receive either FOLFIRI plus bevacizumab (FOLFIRI + Bev) or mFOLFOX6 plus bevacizumab (mFOLFOX6 + Bev), stratified by institution, adjuvant chemotherapy, and liver-limited disease. The primary end point was non-inferiority of FOLFIRI + Bev to mFOLFOX6 + Bev in progression-free survival (PFS), with an expected hazard ratio (HR) of 0.9 and non-inferiority margin of 1.25 (power 0.85, one-sided α-error 0.025). The secondary end points were response rate (RR), overall survival (OS), safety, and quality of life (QoL) during 18 months. This trial is registered to the University Hospital Medical Information Network, number UMIN000001396.
Among 402 patients enrolled from September 2008 to January 2012, 395 patients were eligible for efficacy analysis. The median PFS for FOLFIRI + Bev (n = 197) and mFOLFOX6 + Bev (n = 198) were 12.1 and 10.7 months, respectively HR, 0.905; 95% confidence interval (CI) 0.723–1.133; P = 0.003 for non-inferiority. The median OS for FOLFIRI + Bev and mFOLFOX6 + Bev were 31.4 and 30.1 months, respectively (HR, 0.990; 95% CI 0.785–1.249). The best overall RRs were 64% for FOLFIRI + Bev and 62% for mFOLFOX6 + Bev. The common grade 3 or higher adverse events were leukopenia (11% in FOLFIRI + Bev/5% in mFOLFOX6 + Bev), neutropenia (46%/35%), diarrhea (9%/5%), febrile neutropenia (5%/2%), peripheral neuropathy (0%/22%), and venous thromboembolism (6%/2%). The QoL assessed by FACT-C (TOI-PFC) and FACT/GOG-Ntx was favorable for FOLFIRI + Bev during 18 months.
FOLFIRI plus bevacizumab was non-inferior for PFS, compared with mFOLFOX6 plus bevacizumab, as the first-line systemic treatment for mCRC.
UMIN000001396.
Abstract
We revisit the role of longitudinal waves in driving the solar wind. We study how the
p
-mode-like vertical oscillation on the photosphere affects the properties of solar winds in the ...framework of Alfvén-wave-driven winds. We perform a series of one-dimensional magnetohydrodynamical numerical simulations from the photosphere to beyond several tens of solar radii. We find that the mass-loss rate drastically increases with the longitudinal-wave amplitude at the photosphere by up to a factor of ∼4, in contrast to the classical understanding that acoustic waves hardly affect the energetics of the solar wind. The addition of the longitudinal fluctuation induces longitudinal-to-transverse wave mode conversion in the chromosphere, which results in enhanced Alfvénic Poynting flux in the corona. Consequently, coronal heating is promoted to give higher coronal density by chromospheric evaporation, leading to the increased mass-loss rate. This study clearly shows the importance of longitudinal oscillation in the photosphere and mode conversion in the chromosphere in determining the basic properties of the wind from solar-like stars.
The six-layered neocortex permits complex information processing in all mammalian species. Because its homologous region (the pallium) in nonmammalian amniotes has a different architecture, the ...ability of neocortical progenitors to generate an orderly sequence of distinct cell types was thought to have arisen in the mammalian lineage. This study, however, shows that layer-specific neuron subtypes do exist in the chick pallium. Deep- and upper-layer neurons are not layered but are segregated in distinct mediolateral domains in vivo. Surprisingly, cultured chick neural progenitors produce multiple layer-specific neuronal subtypes in the same chronological sequence as seen in mammals. These results suggest that the temporal sequence of the neocortical neurogenetic program was already inherent in the last common ancestor of mammals and birds and that mammals use this conserved program to generate a uniformly layered neocortex, whereas birds impose spatial constraints on the sequence to pattern the pallium.
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► Layer-specific neuron subtypes of the mammalian neocortex exist in the chick pallium ► Deep- and upper-layer neurons are generated by distinct progenitors in chick in vivo ► The layer-specific neurons are sequentially generated by common progenitors in vitro ► Neocortical neurogenetic program existed before the emergence of layer structure
Suzuki et al. find that “layer-specific” neuron subtypes typical of mammalian neocortex are arranged mediolaterally in the chick pallium. Their results indicate that mammalian neocortical and chick pallial progenitors use the same temporally ordered neurogenetic program to generate subtype-specific progeny, but chick pallial output is spatially constrained by developmental patterning.
Despite many studies on seafloor hydrothermal systems conducted to date, the generation mechanism of seafloor massive sulfide (SMS) deposits is not yet fully understood. To elucidate this mechanism, ...this study clarifies the three‐dimensional regional temperature distribution and fluid flow of a seafloor hydrothermal system of the Iheya North Knoll, middle Okinawa Trough. Lateral flow and boiling of hydrothermal fluids below a caprock were the main features found by the simulation. A caprock formation generated by anhydrite precipitation and hydrothermal alteration is the most plausible cause of these features, because caprocks can increase the temperature and induce boiling of fluids by preventing seawater inflow. Such a formation also gradually makes the top of the conduit less permeable; thus, lateral flow occurs. Consequently, vapor‐rich hydrothermal fluids poor in metals are discharged from vents as white smokers, whereas liquid‐dominated hydrothermal fluids rich in metals flow laterally below the caprocks, forming subseafloor SMS deposits.
Plain Language Summary
In seafloor hydrothermal systems, the seawater heated by magma circulates under the seafloor and forms seafloor massive sulfide (SMS) deposits. Recently, SMS deposits have attracted interest as a new metal resource, the generation mechanism and model of which must be established for accurate resource exploration. However, the mechanism is not yet fully understood. To address this problem, we applied a hydrothermal flow simulation and clarified the temperature distribution and fluid flow in the Iheya North Knoll, southwestern Japan. The result revealed that lateral flow and boiling of hydrothermal fluids occur below the seafloor. A low permeability caprock formation generated by anhydrite and clay mineral development is the most plausible cause of these occurrences, because a caprock can increase the temperature and induce boiling of fluids by suppressing the seawater inflow. This formation also makes fluid outlets less permeable, thus induces lateral flow. Consequently, vapor‐rich hydrothermal fluids poor in metals are discharged from vents, while liquid‐dominated hydrothermal fluids rich in metals flow laterally below the caprocks, forming subseafloor SMS deposits.
Key Points
Numerical simulation of multiphase fluid flow revealed regional temperature, fluid‐flow patterns, and physical property distributions
Integration of results with geologic interpretations provided a plausible generation mechanism of seafloor massive sulfide deposits
Formation of caprocks below the seafloor induces boiling and lateral flow of hydrothermal fluid and, consequently, the deposit generation
Based on high-resolution spectra obtained during gravitational microlensing events we present a detailed elemental abundance analysis of 32 dwarf and subgiant stars in the Galactic bulge. Combined ...with the sample of 26 stars from the previous papers in this series, we now have 58 microlensed bulge dwarfs and subgiants that have been homogeneously analysed. The results from the microlensed bulge dwarf stars in combination with other findings in the literature, in particular the evidence that the bulge has cylindrical rotation, indicate that the Milky Way could be an almost pure disk galaxy. The bulge would then just be a conglomerate of the other Galactic stellar populations, residing together in the central parts of the Galaxy, influenced by the Galactic bar.
There has been no phase III study of comparing the efficacy of first- and second-generation 5-HT3 receptor antagonists in the triplet regimen with dexamethasone and aprepitant for preventing ...chemotherapy-induced nausea and vomiting after highly emetogenic chemotherapy (HEC).
Patients with a malignant solid tumor who would receive HEC containing 50 mg/m2 or more cisplatin were randomly assigned to either palonosetron (0.75 mg) arm (Arm P) or granisetron (1 mg) arm (Arm G), on day 1, both arms with dexamethasone (12 mg on day 1 and 8 mg on days 2–4) and aprepitant (125 mg on day 1 and 80 mg on days 2–3). The primary end point was complete response (CR; no vomiting/retching and no rescue medication) at the 0–120 h period and secondary end points included complete control (CC; no vomiting/retching, no rescue medication, and no more than mild nausea) and total control (TC; no vomiting/retching, no rescue medication, and no nausea).
Between July 2011 and June 2012, 842 patients were enrolled. Of 827 evaluable, 272 of 414 patients (65.7%) in Arm P had a CR at the 0–120 h period when compared with 244 of 413 (59.1%) in Arm G (P = 0.0539). Both arms had the same CR rate of 91.8% at the acute (0–24 h) period, while at the delayed (24–120 h) period, Arm P had a significantly higher CR rate than Arm G (67.2% versus 59.1%; P = 0.0142). In secondary end points, Arm P had significantly higher rates than Arm G at the 0–120 h period (CC rate: 63.8% versus 55.9%, P = 0.0234; TC rate: 47.6% versus 40.7%, P = 0.0369) and delayed periods (CC rate: 65.2% versus 55.9%, P = 0.0053; TC rate: 48.6% versus 41.4%, P = 0.0369).
The present study did not show the superiority of palonosetron when compared with granisetron in the triplet regimen regarding the primary end point.
UMIN000004863.
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