SOX transcription factors are essential for embryonic development and play critical roles in cell fate determination, differentiation and proliferation. We previously reported that the SOX2 protein ...is expressed in normal gastric mucosae but downregulated in some human gastric carcinomas. To clarify the roles of SOX2 in gastric carcinogenesis, we carried out functional characterisation of SOX2 in gastric epithelial cell lines. Exogenous expression of SOX2 suppressed cell proliferation in gastric epithelial cell lines. Flow cytometry analysis revealed that SOX2-overexpressing cells exhibited cell-cycle arrest and apoptosis. We found that SOX2-mediated cell-cycle arrest was associated with decreased levels of cyclin D1 and phosphorylated Rb, and an increased p27(Kip1) level. These cells exhibited further characteristics of apoptosis, such as DNA laddering and caspase-3 activation. SOX2 hypermethylation signals were observed in some cultured and primary gastric cancers with no or weak SOX2 expression. Among the 52 patients with advanced gastric cancers, those with cancers showing SOX2 methylation had a significantly shorter survival time than those without this methylation (P=0.0062). Hence, SOX2 plays important roles in growth inhibition through cell-cycle arrest and apoptosis in gastric epithelial cells, and the loss of SOX2 expression may be related to gastric carcinogenesis and poor prognosis.
Leptin acts on its receptor (ObR) in the hypothalamus to inhibit food intake and energy expenditure. Leptin and ObR are also expressed in the gastrointestinal tract; however, the physiological ...significance of leptin signaling in the gut remains uncertain. Suppressor of cytokine signaling 3 (SOCS3) is a key negative feedback regulator of ObR-mediated signaling in the hypothalamus. We now show that gastrointestinal epithelial cell-specific SOCS3 conditional knockout (T3b-SOCS3 cKO) mice developed gastric tumors by enhancing leptin production and the ObRb/signal transducer and activator of transcription 3 (STAT3) signaling pathway. All T3b-SOCS3 cKO mice developed tumors in the stomach but not in the bowels by 2 months of age, even though the SOCS3 deletion occurred in both the epithelium of stomach and bowels. The tumors developed in the absence of the inflammatory response and all cKO mice died within 6 months. These tumors displayed pathology and molecular alterations, such as an increase in MUC2 (Mucin 2, oligomeric mucus/gel-forming) and TFF3 (trefoil factor 3), resembling human intestinal-type gastric tumors. Administration of antileptin antibody to T3b-SOCS3 cKO mice reduced hyperplasia of gastric mucosa, which is the step of the initiation of gastric tumor. These data suggest that SOCS3 is an antigastric tumor gene that suppresses leptin overexpression and ObRb/STAT3 hyperactivation, supporting the hypothesis that the leptin/ObRb/STAT3 axis accelerates tumorigenesis and that it may represent a new therapeutic target for the treatment of gastric cancer.
Satellite Laser Ranging (SLR) is a powerful technique able to measure spin rate and spin axis orientation of the fully passive, geodetic satellites. This work presents results of the spin ...determination of LARES – a new satellite for testing General Relativity. 529 SLR passes measured between February 17 and June 9, 2012, were spectrally analyzed. Our results indicate that the initial spin frequency of LARES is f0=86.906mHz (RMS=0.539mHz). A new method for spin axis determination, developed for this analysis, gives orientation of the axis at RA=12h22m48s (RMS=49m), Dec=−70.4° (RMS=5.2°) (J2000.0 celestial reference frame), and the clockwise (CW) spin direction. The half-life period of the satellite’s spin is 214.924days and indicates fast slowing down of the spacecraft.
The Graz kHz Satellite Laser Ranging (SLR) system is the first system operating with a 2-kHz-repetition-rate laser. Using Graz 2-kHz SLR data only, we applied a new analytical approach to determine ...the spin period of the passive satellite AJISAI. This method analyzes the range measurements to the single corner-cube-reflector panels of AJISAI, allowing accurate determination of an actual attitude of this satellite during day and night. Using Graz kHz SLR data of more than five years, we processed 877 passes of AJISAI (October 9, 2003-December 22, 2008) and calculated its spin period ( ~ 2 s) with an accuracy of 0.0042% (84 ¿s). This spin period ( T ) is increasing, following an exponential trend: T =1.9028 ·Exp (0.014859 . (Year - 2003.0)) s. This slow down is mainly caused by the gravitational and magnetic fields of the Earth. The high accuracy allows, for the first time, the detection of small perturbations of the spin period caused by nongravitational effects related to the solar energy flux to which the satellite is exposed.
The Graz 2
kHz Satellite Laser Ranging (SLR) measurements allow determination of the spin axis orientation of the geodetic satellite Ajisai. The high repetition rate of the laser makes it possible to ...determine the epoch time when the laser is pointing directly between two corner cube reflector (CCR) rings of the satellite. Identification of many such events during a few (up to 3) consecutive passes allows to state the satellite orientation in the celestial coordinate system. Six years of 2
kHz SLR data (October 2003–October 2009) delivered 331 orientation values which clearly show precession of the axis along a cone centered at 14
h56
m2.8
s in right ascension and 88.512° in declination (J2000.0 celestial reference frame) and with an half-aperture angle
θ of 1.405°. The spin axis precesses with a period of 117
days, which is equal to the period of the right ascension of the ascending node of Ajisai’s orbit. We present a model of the axis precession which allows prediction of the satellite orientation – necessary for the envisaged laser time transfer via Ajisai mirrors.
Background
Secondary hyperparathyroidism (SHPT) is a serious major complication in hemodialysis patients with chronic kidney disease. Long-term maintenance of serum phosphate, calcium, and ...parathyroid hormone (PTH) levels in appropriate ranges in these patients is a major challenge. We investigated the efficacy and safety of long-term treatment with etelcalcetide, a novel intravenous calcimimetic, in Japanese SHPT patients on long-term hemodialysis.
Methods
This study was a multicenter open-label study. A total of 191 hemodialysis patients with serum intact PTH (iPTH) > 240 pg/mL were enrolled. Etelcalcetide was administered thrice weekly for 52 weeks, with an initial dose of 5 mg and flexibility to adjust the dose between 2.5 and 15 mg and to adjust the dosing of concomitant medications for SHPT. The efficacy endpoint was the proportion of patients with serum iPTH decreased to the target range (60–240 pg/mL).
Results
Serum iPTH levels decreased immediately after etelcalcetide was started. At the end of the study, 87.5% (95% confidence interval 81.4–92.2; 140/160 patients) of patients achieved target serum iPTH levels, with control of serum calcium and phosphate levels. Adverse events, mostly mild to moderate, were reported by 96.8% of patients and led to study discontinuation in 7.4% of patients. Nausea, vomiting, and symptomatic hypocalcemia were found in 4.7, 9.5, and 1.1%, with 0.5, 1.1, and 1.1% considered treatment-related.
Conclusions
Etelcalcetide effectively maintained serum iPTH, calcium, and phosphate levels in appropriate ranges with concomitant medications for SHPT for 52 weeks in Japanese hemodialysis patients, and was safe and well tolerated.
Registration Number
JapicCTI-142665.
Satellite Laser Ranging (SLR) is a powerful and efficient technique to measure spin parameters of satellites equipped with corner cube reflectors. We obtained spin period determination of the ...satellite AJISAI from SLR data only: 17246 pass-by-pass estimates from standard 1–15
Hz SLR data (14/Aug/1986–30/Dec/2008) and 1444 pass-by-pass estimates (9/Oct/2003–30/Dec/2008) from data of the first 2
kHz SLR system from Graz, Austria. A continuous history of the slowing down of AJISAI spin is derived from frequency analysis, and corrected for the apparent effects. The apparent corrections, elaborated here, allowed very accurate determination of AJISAI initial spin period: 1.4855
±
0.0007 s. The paper identifies also non-gravitational effects as a source of the periodical changes in the rate of slowing down of the satellite.
► Spectral response of Ajisai is obtained with SLR simulations. ► Spectral analysis is used for spin axis determination of geodetic satellite. ► Special retroreflector array makes possible satellite ...attitude analysis with SLR.
The design of the retroreflector array (RRA) of the fast spinning Experimental Geodetic Satellite (Ajisai) allows to determine orientation of its spin axis by means of frequency analysis. Moving spectral analysis (MSA) of the simulated Satellite Laser Ranging (SLR) data gives information about frequencies which can be obtained for the whole range of the incident angle between the laser beam vector and the spin axis of the spacecraft. This frequency signal changes as the incident laser beam crosses consecutive rings of the RRA.
Knowledge about spectral response of Ajisai allows successful application of MSA to the Graz 2kHz SLR data (2003–2011) and determination of 78 spin axis orientation values. The obtained results show that the spin axis of Ajisai is stable around RA 15h22m24.0s, Dec 88.05° (J2000.0 celestial reference frame), and is almost parallel to the spin axis of Earth.
The Graz 2kHz Satellite Laser Ranging (SLR) measurements allow determination of the spin axis orientation of the geodetic satellite Ajisai. The high repetition rate of the laser makes it possible to ...determine the epoch time when the laser is pointing directly between two corner cube reflector (CCR) rings of the satellite. Identification of many such events during a few (up to 3) consecutive passes allows to state the satellite orientation in the celestial coordinate system. Six years of 2kHz SLR data (October 2003-October 2009) delivered 331 orientation values which clearly show precession of the axis along a cone centered at 14h56m2.8s in right ascension and 88.512A in declination (J2000.0 celestial reference frame) and with an half-aperture angle I of 1.405A. The spin axis precesses with a period of 117days, which is equal to the period of the right ascension of the ascending node of Ajisai's orbit. We present a model of the axis precession which allows prediction of the satellite orientation - necessary for the envisaged laser time transfer via Ajisai mirrors.
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