ASC amino acid transporter 2, defined by enzyme-mediated activation of radical sources, enhances malignancy of GD2-positive small-cell lung cancer

Ganglioside GD2 is specifically expressed in small-cell lung cancer (SCLC) cells, leading to enhancement of malignant phenotypes, such as cell proliferation and migration. However, how GD2 promotes malignant phenotypes in SCLC cells is not well known. In this study, to reveal the mechanisms by which GD2 increases malignant phenotypes in SCLC cells, we used enzyme-mediated activation of radical sources combined with mass spectrometry in GD2+ SCLC cells. Consequently, we identified ASC amino acid transporter 2 (ASCT2), a major glutamine transporter, which coordinately works with GD2. We showed that ASCT2 was highly expressed in glycolipid-enriched microdomain/rafts in GD2+ SCLC cells, and colocalized with GD2 in both proximity ligation assay and immunocytostaining, and bound with GD2 in immunoprecipitation/TLC immunostaining. Malignant phenotypes of GD2+ SCLC cells were enhanced by glutamine uptake, and were suppressed by L-γ-glutamyl-p-nitroanilide, a specific inhibitor of ASCT2, through reduced phosphorylation of p70 S6K1 and S6. These results suggested that ASCT2 enhances glutamine uptake in glycolipid-enriched microdomain/rafts in GD2+ SCLC cells, leading to the enhancement of cell proliferation and migration through increased phosphorylation of the mTOR complex 1 signaling axis

Prolongation of total permissible circulatory arrest duration by deep hypothermic intermittent circulatory arrest

AbstractObjective: We determined whether the duration of permissible circulatory arrest could be prolonged by deep hypothermic intermittent circulatory arrest. Methods: Twenty-five beagles were cooled on bypass to 18° C to initiate deep hypothermia that was maintained for 3 hours. Five protocols were then studied: group 1, uninterrupted bypass during hypothermia; group 2, arrest for 40 minutes during hypothermia; group 3, arrest for 60 minutes during hypothermia; group 4, arrest for 80 minutes during hypothermia; and group 5, intermittent circulatory arrest, consisting of six cycles of 20 minutes of arrest followed by 10 minutes of systemic recirculation during hypothermia (total, 120 minutes of arrest). The oxyhemoglobin concentration in the brain was measured with near infrared spectrophotometry. Results: In groups 2, 3, and 4, the oxyhemoglobin concentration in the brain decreased continuously after arrest, finally reaching a plateau after 24.9 ± 1.2 minutes. This finding suggested that the available cerebral oxyhemoglobin was depleted. In contrast, the available cerebral oxyhemoglobin was not depleted during hypothermic intermittent arrest in group 5. The mitochondrial respiratory control index was significantly lower in group 4 than in the other groups (p < 0.05). However, there were no significant differences in the respiratory control index for groups 1, 2, 3, and 5. Moreover, the formation of brain edema was significantly lower in group 5 than in the other groups (p < 0.05). Conclusions: These results indicate that deep hypothermic intermittent arrest can increase the duration of total permissible circulatory arrest and will be a useful modality when prolonged arrest is anticipated. (J Thorac Cardiovasc Surg 1998;116:163-70

Phospho-Smad3 signaling is predictive biomarker for hepatocellular carcinoma risk assessment in primary biliary cholangitis patients

Introduction: Patients with primary biliary cholangitis (PBC) are at increased risk for development of hepatocellular carcinoma (HCC), particularly in the presence of comorbidities such as excessive alcohol consumption. Although liver fibrosis is an important risk factor for HCC development, earlier predictors of future HCC development in livers with little fibrosis are needed but not well defined. The transforming growth factor (TGF)-β/Smad signaling pathway participates importantly in hepatic carcinogenesis. Phosphorylated forms (phospho-isoforms) in Smad-related pathways can transmit opposing signals: cytostatic C-terminally-phosphorylated Smad3 (pSmad3C) and carcinogenic linker-phosphorylated Smad3 (pSmad3L) signals. Methods and results: To assess the balance between Smad signals as a biomarker of risk, we immunohistochemically compared Smad domain-specific Smad3 phosphorylation patterns among 52 PBC patients with various stages of fibrosis and 25 non-PBC patients with chronic hepatitis C virus infection. HCC developed in 7 of 11 PBC patients showing high pSmad3L immunoreactivity, but in only 2 of 41 PBC patients with low pSmad3L. In contrast, 9 of 20 PBC patients with minimal Smad3C phosphorylation developed HCC, while HCC did not occur during follow-up in 32 patients who retained hepatic tumor-suppressive pSmad3C. Further, PBC patients whose liver specimens showed high pSmad3L positivity were relatively likely to develop HCC even when little fibrosis was evident. Conclusion: In this study, Smad phospho-isoform status showed promise as a biomarker predicting likelihood of HCC occurrence in PBC. Eventually, therapies to shift favorably Smad phospho-isoforms might decrease likelihood of PBC-related HCC

Coincidence analysis to search for inspiraling compact binaries using TAMA300 and LISM data

Japanese laser interferometric gravitational wave detectors, TAMA300 and LISM, performed a coincident observation during 2001. We perform a coincidence analysis to search for inspiraling compact binaries. The length of data used for the coincidence analysis is 275 hours when both TAMA300 and LISM detectors are operated simultaneously. TAMA300 and LISM data are analyzed by matched filtering, and candidates for gravitational wave events are obtained. If there is a true gravitational wave signal, it should appear in both data of detectors with consistent waveforms characterized by masses of stars, amplitude of the signal, the coalescence time and so on. We introduce a set of coincidence conditions of the parameters, and search for coincident events. This procedure reduces the number of fake events considerably, by a factor $\sim 10^{-4}$ compared with the number of fake events in single detector analysis. We find that the number of events after imposing the coincidence conditions is consistent with the number of accidental coincidences produced purely by noise. We thus find no evidence of gravitational wave signals. We obtain an upper limit of 0.046 /hours (CL $= 90$) to the Galactic event rate within 1kpc from the Earth. The method used in this paper can be applied straightforwardly to the case of coincidence observations with more than two detectors with arbitrary arm directions.Comment: 28 pages, 17 figures, Replaced with the version to be published in Physical Review

Results of the search for inspiraling compact star binaries from TAMA300's observation in 2000-2004

We analyze the data of TAMA300 detector to search for gravitational waves from inspiraling compact star binaries with masses of the component stars in the range 1-3Msolar. In this analysis, 2705 hours of data, taken during the years 2000-2004, are used for the event search. We combine the results of different observation runs, and obtained a single upper limit on the rate of the coalescence of compact binaries in our Galaxy of 20 per year at a 90% confidence level. In this upper limit, the effect of various systematic errors such like the uncertainty of the background estimation and the calibration of the detector's sensitivity are included.Comment: 8 pages, 4 Postscript figures, uses revtex4.sty The author list was correcte

Observation results by the TAMA300 detector on gravitational wave bursts from stellar-core collapses

We present data-analysis schemes and results of observations with the TAMA300 gravitational-wave detector, targeting burst signals from stellar-core collapse events. In analyses for burst gravitational waves, the detection and fake-reduction schemes are different from well-investigated ones for a chirp-wave analysis, because precise waveform templates are not available. We used an excess-power filter for the extraction of gravitational-wave candidates, and developed two methods for the reduction of fake events caused by non-stationary noises of the detector. These analysis schemes were applied to real data from the TAMA300 interferometric gravitational wave detector. As a result, fake events were reduced by a factor of about 1000 in the best cases. The resultant event candidates were interpreted from an astronomical viewpoint. We set an upper limit of 2.2x10^3 events/sec on the burst gravitational-wave event rate in our Galaxy with a confidence level of 90%. This work sets a milestone and prospects on the search for burst gravitational waves, by establishing an analysis scheme for the observation data from an interferometric gravitational wave detector

Pretreatment glasgow prognostic score predicts survival among patients administered first-line atezolizumab plus carboplatin and etoposide for small cell lung cancer

BackgroundThere are no established predictive biomarkers for the effectiveness of first-line atezolizumab plus carboplatin and etoposide therapy in patients with small-cell lung cancer (SCLC). Therefore, the current study aimed to investigate whether the Glasgow prognostic score (GPS), neutrophil-to-lymphocyte ratio (NLR), and body mass index (BMI) can predict the effectiveness of first-line atezolizumab plus carboplatin and etoposide therapy in patients with extensive-disease SCLC.MethodsWe reviewed data from 84 patients who received first-line atezolizumab plus carboplatin and etoposide therapy for SCLC at nine Japanese institutions between August 2019 and May 2021. Further, we evaluated the prognostic value of the GPS, NLR, and BMI. The Kaplan–Meier and Cox proportional hazard models were used to examine differences in progression-free survival (PFS) and overall survival (OS). Moreover, the GPS, NLR, and BMI consisted of C-reactive protein and albumin concentrations, neutrophil and lymphocyte counts, and body weight and height, respectively.ResultsThe response rate was 72.6% (95% confidence interval: 63.0–82.1%). The median PFS and OS from the initiation of treatment were 5.4 (95% CI: 4.9–5.9) months and 15.4 (95% CI: 11.4–16.8) months, respectively. The GPS independently predicted the effectiveness of first-line atezolizumab plus carboplatin and etoposide treatment, as a favorable GPS (GPS 0–1) was correlated with significantly better PFS and OS rates compared to a poor GPS (GPS 2) (PFS: 5.8 vs. 3.8 months, p = 0.0005; OS: 16.5 vs. 8.4 months, p&lt;0.0001).ConclusionsThis is the first analysis to evaluate the association between the GPS, NLR, and BMI and the treatment effectiveness of survival among patients receiving first-line atezolizumab plus carboplatin and etoposide therapy for SCLC. Among patients receiving this treatment for SCLC, GPS was significantly associated with the PFS and OS rates, suggesting that GPS might be useful for evaluating therapeutic outcomes in these patients

Efficacy and safety of garenoxacin tablets on clinically diagnosed atypical pneumonia: Postmarketing surveillance in Japan

We performed a postmarketing surveillance study to determine the efficacy and safety of the oral quinolone antibacterial agent garenoxacin (Geninax R Tablets 200 mg) against atypical pneumonia. Between October 2009 and July 2011, patients with community-acquired pneumonia visited 26 facilities in Japan; we collected survey forms from 105 of these patients who were suspected of having atypical pneumonia based on the Japanese Respiratory Society Guidelines for the Management of Community-Acquired Pneumonia in Adults. We examined the safety in 105 patients and the efficacy in 71 patients. 1. The efficacy rates among patients suspected of having atypical pneumonia and those with a confirmed diagnosis of atypical pneumonia were 94.8% (55/58 patients) and 92.3% (12/13 patients), respectively. The efficacy rate was 4/4 for patients in whom Chlamydophila pneumoniae was detected (including 1 patient with a polymicrobial infection with another bacterial strain) and 90% (9/10 patients) for patients in whom Mycoplasma pneumoniae was detected (garenoxacin was ineffective in 1 of 2 patients with a polymicrobial infection with another bacterial strain). 2. The incidence of adverse drug reactions (including abnormal laboratory tests) was 4.8% (5/105 patients). Among the adverse drug reactions, gastrointestinal disorders, infection and infestation, nervous system disorder, and skin and subcutaneous tissue disorder were observed in 2.9% of patients (3/105), 1.0% (1/105), 1.0% (1/105), and 1.0% (1/105), respectively. In conclusion, garenoxacin showed an efficacy rate of greater than 90% for suspected atypical pneumonia and confirmed atypical pneumonia. Garenoxacin is considered to be useful in daily practice

Randomized controlled trial of daily teriparatide, weekly high-dose teriparatide, or bisphosphonate in patients with postmenopausal osteoporosis: The TERABIT study

Purpose: The effects of daily teriparatide (20 μg) (D-PTH), weekly high-dose teriparatide (56.5 μg) (W-PTH), or bisphosphonates (BPs) on areal bone mineral density (aBMD), bone turnover markers (BTMs), volumetric BMD (vBMD), microarchitecture, and estimated strength were investigated in postmenopausal osteoporosis patients.Methods: The study participants were 131 women with a history of fragility fractures. They were randomized to receive D-PTH, W-PTH, or BPs (alendronate or risedronate) for 18 months. Dual-energy X-ray absorptiometry (DXA), BTMs, and high-resolution peripheral quantitative CT (HR-pQCT) parameters were evaluated at baseline and after 6 and 18 months of treatment. The primary endpoint was the change (%) in cortical thickness (Ct.Th) after 18 months\u27 treatment compared with baseline.Results: DXA showed that D-PTH, W-PTH, and BPs increased lumbar spine aBMD (+12.0%, +8.5%, and +6.8%) and total hip aBMD (+3.0%, +2.1%, and +3.0%), but D-PTH and W-PTH decreased 1/3 radius aBMD (− 4.1%, − 3.0%, − 1.4%) after 18 months. On HR-pQCT, D-PTH increased trabecular vBMD (Tb.vBMD) at the distal radius and tibia after 18 months (+6.4%, +3.7%) compared with the BPs group, decreased cortical volumetric tissue mineral density (Ct.vTMD) (− 1.8%, − 0.9%) compared with the other groups, increased Ct.Th (+1.3%, +3.9%), and increased failure load (FL) (+4.7%, +4.4%). W-PTH increased Tb.vBMD (+5.3%, +1.9%), maintained Ct.vTMD (− 0.7%, +0.2%) compared with D-PTH, increased Ct.Th (+0.6%, +3.6%), and increased FL (+4.9%, +4.5%). The BPs increased Tb.vBMD only in the radius (+2.0%, +0.2%), maintained Ct.vTMD (− 0.6%, +0.3%), increased Ct.Th (+0.5%, +3.4%), and increased FL (+3.9%, +2.8%).Conclusions: D-PTH and W-PTH comparably increased Ct.Th, the primary endpoint. D-PTH had a strong effect on trabecular bone. Although D-PTH decreased Ct.vTMD, it increased Ct.Th and total bone strength. W-PTH had a moderate effect on trabecular bone, maintained Ct.vTMD, and increased Ct.Th and total bone strength to the same extent as D-PTH