Intravital imaging of mouse urothelium reveals activation of extracellular signal-regulated kinase by stretch-induced intravesical release of ATP

To better understand the roles played by signaling molecules in the bladder, we established a protocol of intravital imaging of the bladder of mice expressing a Förster/fluorescence resonance energy transfer (FRET) biosensor for extracellular signal-regulated kinase (ERK), which plays critical roles not only in cell growth but also stress responses. With an upright two-photon excitation microscope and a vacuum-stabilized imaging window, cellular ERK activity was visualized in the whole bladder wall, from adventitia to urothelium. We found that bladder distention caused by elevated intravesical pressure (IVP) activated ERK in the urothelium, but not in the detrusor smooth muscle. When bladder distension was prevented, high IVP failed to activate ERK, suggesting that mechanical stretch, but not the high IVP, caused ERK activation. To delineate its molecular mechanism, the stretch-induced ERK activation was reproduced in an hTERT-immortalized human urothelial cell line (TRT-HU1) in vitro. We found that uniaxial stretch raised the ATP concentration in the culture medium and that inhibition of ATP signaling by apyrase or suramin suppressed the stretch-induced ERK activation in TRT-HU1 cells. In agreement with this in vitro observation, pretreatment with apyrase or suramin suppressed the high IVP-induced urothelial ERK activation in vivo. Thus, we propose that mechanical stretch induces intravesical secretion of ATP and thereby activates ERK in the urothelium. Our method of intravital imaging of the bladder of FRET biosensor-expressing mice should open a pathway for the future association of physiological stimuli with the activities of intracellular signaling networks

Three-dimensional Structure of Nylon Hydrolase and Mechanism of Nylon-6 Hydrolysis

This research was originally published in the Journal of Biological Chemistry. Seiji Negoro, Naoki Shibata, Yusuke Tanaka, Kengo Yasuhira, Hiroshi Shibata, Haruka Hashimoto, Young-Ho Lee, Shohei Oshima, Ryuji Santa, Shohei Oshima, Kozo Mochiji, Yuji Goto, Takahisa Ikegami, Keisuke Nagai, Dai-ichiro Kato, Masahiro Takeo and Yoshiki Higuchi. Three-dimensional Structure of Nylon Hydrolase and Mechanism of Nylon-6 Hydrolysis. J. Biol. Chem. 2012; 287, 5079-5090. © the American Society for Biochemistry and Molecular Biolog

Pattern of disease progression during third-line or later chemotherapy with nivolumab associated with poor prognosis in advanced gastric cancer: a multicenter retrospective study in Japan

[Background] Accelerated tumor growth during immunotherapy in pre-existing measurable lesions, hyperprogressive disease (HPD), has been reported. However, progression of non-measurable lesions and new lesions are frequently observed in patients with advanced gastric cancer (AGC). [Methods] This retrospective study involved AGC patients at 24 Japanese institutions who had measurable lesions and received nivolumab after ≥ 2 lines of chemotherapy. HPD was defined as a ≥ two-fold increase in the tumor growth rate of measurable lesions. The pattern of disease progression was classified according to new lesions in different organs and ascites appeared/increase of ascites. [Results] Of 245 patients, 147 (60.0%) showed progressive disease (PD) as the best response and 41 (16.7%) showed HPD during nivolumab monotherapy. There was no significant difference in overall survival (OS) between patients with HPD and those with PD other than HPD (median OS 5.0 vs 4.8 months; hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.6–1.5; p = 1.0). Fifty-three patients developed new lesions in different organs and 58 had appearance/increase of ascites; these patients showed shorter OS than those without each of these features (median OS 3.3 vs 7.1 months, HR 1.8, 95% CI 1.2–2.7, p = 0.0031 for new lesions, and 3.0 vs 7.8 months, HR 2.6, 95% CI 1.8–3.8, p < 0.0001 for ascites). Thirty-one patients who had both features showed the worst prognosis (median OS 2.6 months). [Conclusions] New lesions in different organs and appearance/increase of ascites, rather than the original definition of HPD, are the patterns of disease progression associated with poor prognosis in AGC patients receiving nivolumab whose best response was PD

Prevalence and Outcomes of Acute Hepatitis B in Okayama, Japan, 2006-2010

Hepatitis B virus (HBV) is one of the major viruses causing acute hepatitis. Recently, the incidence of acute hepatitis with genotype A has been increasing in Japan. The aim of this study was to investigate acute hepatitis B (AHB) in Okayama prefecture, with special attention to HBV genotype A. AHB patients who visited one of 12 general hospitals in Okayama prefecture between 2006 and 2010 were retrospectively analyzed. Over the course of the study period, 128 patients were diagnosed with AHB. Sexual transmission was supposed in the majority of patients (78 patients, 61%), including 59 (76%) having sex with heterosexual partners. The genotypes of HBV were assessed in 90 patients (70%), of whom 27 patients were infected with genotype A, 5 with genotype B, and 58 with genotype C. The prevalence of genotype A was significantly higher among male patients (28.7%), aged 20-29 (35.6%, p＜0.01), among men who had sex with men (100%, p＜0.005), and among patients having sex with unspecified partners (44.8%, p＜0.005). Genotype A was not a significant factor associated with delayed HBsAg disappearance. Caution should be exercised with regard to sexually transmissible diseases in order to slow the pandemic spread of AHB due to genotype A

Monitor of All-sky X-ray Image (MAXI)

Abstract. Monitor of All-sky X-ray Image (MAXI) is the first astrophysical payload which will be mounted on the Japanese Experiment Module (JEM) Exposed Facility in 2004. It is an X-ray all-sky monitor with unprecedented sensitivity to watch the activities of the X-ray sources in the whole sky in every 90 minutes. MAXI is boxshaped in 0.8 x 1.0 x 1.85 m with the weight of 500 kg. The mission life will be at least 2 years. MAXI has two fan-like field of views (FOV), 160 x 1.5 degree each. The X-ray instruments are Gas Slit Camera (GSC) and Solid-state Slit Camera (SSC). The GSC uses gas one-dimensional position sensitive proportional counters with 5340 cm 2 effective area in total and the SSC uses CCDs with 200 cm 2 . Both are capable to detect one-dimensional image, which is used to obtain the locations of the X-ray sources in the FOV along the long direction. Together with the scan which determine the other direction, MAXI can scan almost all sky with a precision of better than 1 degree in the energy range of 0.5-30 keV. The CCD is electrically cooled to -60°C and the camera body is radiatively cooled to -20°C. The CCD chip itself and the radiators may suffer contamination problem. The continuous Ethernet down link will enable us to alert the astronomers in all over the world to the appearance of X-ray transients, novae, bursts, flares etc. We made a test counter and test chips in 1998. Those are being tested in RIKEN, NASDA and Osaka-university. In this paper the test results will be presented, as well as the general description of the MAXI mission

IRIS plus panitumumab for metastatic CRC

Background Irinotecan plus S-1 (IRIS) is the only oral fluoropyrimidine-based regimen reported to be non-inferior to FOLFIRI and widely used in clinical practice for metastatic colorectal cancer (mCRC) patients. However, the combination of IRIS plus an anti-EGFR agent has not been evaluated previously. This study aimed to investigate the feasibility and efficacy of IRIS with panitumumab as second-line therapy for wild-type KRAS mCRC. Methods Main inclusion criteria were patients with wild-type KRAS mCRC refractory to one prior chemotherapy regimen for mCRC, ECOG PS 0-2, and age ≥ 20 years. Patients received panitumumab (6mg/kg) and irinotecan (100mg/m2) on days 1 and 15 and S-1 (40-60 mg according to body surface area) twice daily for 2 weeks, repeated every 4 weeks. The primary endpoint was the feasibility of the therapy. The secondary endpoints were response rate (RR), progression-free survival (PFS), and overall survival (OS). Results A total of 36 patients received protocol treatment in eight centers. Of these, 23 patients (63.9%) completed protocol treatment, demonstrating achievement of the primary endpoint. The most frequent grade 3/4 toxicities were diarrhea (16.7%), acne-like rash (13.9%), and neutropenia (11.1%). The overall RR was 33.3% (12/36). Of these 4 five underwent conversion surgery. Median PFS and OS were 9.5 months (95% CI 3.5-15.4 months) and 20.1 months (95% CI 16.7-23.2 months), respectively. Conclusion IRIS plus panitumumab has an acceptable toxicity profile and a promising efficacy in patients with previously treated wild-type KRAS mCRC. Accordingly, this regimen can be an additional treatment option for second-line chemotherapy in wild-type KRAS mCRC