Development of new experimental platform ‘MARS’—Multiple Artificial-gravity Research System—to elucidate the impacts of micro/partial gravity on mice

This Japan Aerospace Exploration Agency project focused on elucidating the impacts of partial gravity (partial g) and microgravity (μg) on mice using newly developed mouse habitat cage units (HCU) that can be installed in the Centrifuge-equipped Biological Experiment Facility in the International Space Station. In the first mission, 12 C57BL/6 J male mice were housed under μg or artificial earth-gravity (1 g). Mouse activity was monitored daily via downlinked videos; μg mice floated inside the HCU, whereas artificial 1 g mice were on their feet on the floor. After 35 days of habitation, all mice were returned to the Earth and processed. Significant decreases were evident in femur bone density and the soleus/gastrocnemius muscle weights of μg mice, whereas artificial 1 g mice maintained the same bone density and muscle weight as mice in the ground control experiment, in which housing conditions in the flight experiment were replicated. These data indicate that these changes were particularly because of gravity. They also present the first evidence that the addition of gravity can prevent decreases in bone density and muscle mass, and that the new platform ‘MARS’ may provide novel insights on the molecular-mechanisms regulating biological processes controlled by partial g/μg

Down-regulation of GATA1-dependent erythrocyte-related genes in the spleens of mice exposed to a space travel

Secondary lymphoid organs are critical for regulating acquired immune responses. The aim of this study was to characterize the impact of spaceflight on secondary lymphoid organs at the molecular level. We analysed the spleens and lymph nodes from mice flown aboard the International Space Station (ISS) in orbit for 35 days, as part of a Japan Aerospace Exploration Agency mission. During flight, half of the mice were exposed to 1 g by centrifuging in the ISS, to provide information regarding the effect of microgravity and 1 g exposure during spaceflight. Whole-transcript cDNA sequencing (RNA-Seq) analysis of the spleen suggested that erythrocyte-related genes regulated by the transcription factor GATA1 were significantly down-regulated in ISS-flown vs. ground control mice. GATA1 and Tal1 (regulators of erythropoiesis) mRNA expression was consistently reduced by approximately half. These reductions were not completely alleviated by 1 g exposure in the ISS, suggesting that the combined effect of space environments aside from microgravity could down-regulate gene expression in the spleen. Additionally, plasma immunoglobulin concentrations were slightly altered in ISS-flown mice. Overall, our data suggest that spaceflight might disturb the homeostatic gene expression of the spleen through a combination of microgravity and other environmental changes

Mitochonic Acid 5 (MA-5) Facilitates ATP Synthase Oligomerization and Cell Survival in Various Mitochondrial Diseases

Mitochondrial dysfunction increases oxidative stress and depletes ATP in a variety of disorders. Several antioxidant therapies and drugs affecting mitochondrial biogenesis are undergoing investigation, although not all of them have demonstrated favorable effects in the clinic. We recently reported a therapeutic mitochondrial drug mitochonic acid MA-5 (Tohoku J. Exp. Med., 2015). MA-5 increased ATP, rescued mitochondrial disease fibroblasts and prolonged the life span of the disease model “Mitomouse” (JASN, 2016). To investigate the potential of MA-5 on various mitochondrial diseases, we collected 25 cases of fibroblasts from various genetic mutations and cell protective effect of MA-5 and the ATP producing mechanism was examined. 24 out of the 25 patient fibroblasts (96%) were responded to MA-5. Under oxidative stress condition, the GDF-15 was increased and this increase was significantly abrogated by MA-5. The serum GDF-15 elevated in Mitomouse was likewise reduced by MA-5. MA-5 facilitates mitochondrial ATP production and reduces ROS independent of ETC by facilitating ATP synthase oligomerization and supercomplex formation with mitofilin/Mic60. MA-5 reduced mitochondria fragmentation, restores crista shape and dynamics. MA-5 has potential as a drug for the treatment of various mitochondrial diseases. The diagnostic use of GDF-15 will be also useful in a forthcoming MA-5 clinical trial

Comparison of peginterferon alfa-2a and alfa-2b for treatment of patients with chronic hepatitis C:a retrospective study using the Japanese Interferon Database

Izumi Sato,1 Takuro Shimbo,2 Yohei Kawasaki,3 Naohiko Masaki41Department of Clinical Study and Informatics, Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan; 2Ohta Nishinouchi Hospital, Fukushima, Japan; 3Department of Mathematics, Tokyo University of Science, Tokyo, Japan; 4The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, JapanPurpose: We aimed to compare the rates of sustained virologic response (SVR) achieved with peginterferon (PEG-IFN) alfa-2a and alfa-2b in combination with ribavinin (RBV) for chronic hepatitis C, using a large database of hepatitis cases to improve the generalizability of these results.Methods: We identified patients with chronic hepatitis C who were treated with PEG-IFN alfa-2a or alfa-2b and RBV, from the Japanese Interferon Database, between December 2009 and April 2013. This database contains the medical records of IFN treatment collected from 36 prefectures in Japan. Multivariable logistic regression analysis was used to compare SVR rates obtained with PEG-IFN alfa-2a and alfa-2b, in combination with RBV. Results: A total of 16,349 patients were recorded in the Japanese Interferon Database. After application of the exclusion criteria, 12,706 patients (3,578 [1,710 males, 1,868 females] on PEG-IFN alfa-2a; and 9,128 [4,652 males, 4,476 females] on PEG-IFN alfa-2b) were included in this analysis. The SVR rate in the PEG-IFN alfa-2b group was 62.0%, as compared with a rate of 55.1% in the PEG-IFN alfa-2a group (crude odds ratio =1.31; 95% confidence interval [CI]: 1.23 to 1.44). There was no significant difference in the adjusted SVR rates between the two groups (adjusted odds ratio =0.96; 95% CI: 0.88 to 1.05). Similar proportions of adverse events were observed in the two groups, with the exception of thrombocytopenia, retinopathy, and anemia.Conclusion: There was no significant difference in the SVR rates and safety profile between chronic hepatitis C patients treated with the PEG-IFN alfa-2a and alfa-2b.Keywords: sustained virologic response, HCV genotype, sustained virologic response, adverse event

Association between prostate cancer characteristics and BRCA1/2-associated family cancer history in a Japanese cohort.

In addition to breast, ovarian, and pancreatic cancers, BRCA1/2 genes have been associated with prostate cancer (PC). However, the role of BRCA1/2-associated family cancer history (FCH) has remained unexplored in treating these four cancer types as a homogenous pathophysiological group. We aimed to clarify the relationship between BRCA1/2-associated FCH and PC, and to assess its relationship with cancer aggressiveness. Patient characteristics, positive family history of BRCA1/2-associated cancer, and cancer characteristics (Gleason score, prostate specific antigen level at diagnosis, and clinical tumor stage) were analyzed. Among the 1,985 eligible candidates, 473 (23.83%) patients had adequately detailed FCH, obtained via questionnaire, and were thus included in the study. BRCA1/2-associated FCH was observed in 135 (28.54%) patients with PC (68, 14.38%), breast (44, 9.30%), pancreatic (31, 6.55%), or ovarian (8, 1.69%) cancers. BRCA1/2-associated FCH was not significantly associated with high Gleason score (≥ 8). Patients with BRCA-associated FCH were less likely to present with high clinical tumor stage, and no difference was observed in prostate-specific antigen level, presence of metastatic lesions at diagnosis, or likelihood of high-risk classification between patients with and without BRCA-associated FCH. This is the first report of BRCA1/2-associated FCH in Japanese men, indicating that family history did not affect the severity or aggressiveness of PC