Repression of factor VIII inhibitor development with apoptotic factor VIII-expressing embryonic stem cells

Development of factor VIII (fVIII)-neutralizing antibodies, called inhibitors, is a challenging problem in the management of hemophilia A patients. We explored the possibility of pretreatment with apoptotic fVIII-expressing embryonic stem (ES) cells to prevent the development of fVIII inhibitors. Murine ES cells integrated with the human F8 gene were differentiated into embryoid bodies, dissociated to a single cell suspension, subjected to hypo-osmotic shock to induce apoptosis, and intraperitoneally injected into hemophilia A mice. Inhibitors were induced by periodic intraperitoneal injections of recombinant human fVIII (rhfVIII). In the groups in which intraperitoneal injections of rhfVIII began at 1-3 weeks after pretreatment, the titers of inhibitors were significantly lower after the third administration of rhfVIII compared with that in the control group in which apoptotic Ainv18 ES cells (without the human F8 gene) were used for pretreatment, and continued to show lower levels until the sixth administration of rhfVIII. These results suggest that pretreatment with apoptotic hfVIII-expressing ES cells might be promising for the prevention of fVIII inhibitor development in hemophilia A patients

Differential lactate and cholesterol synthetic activities in XY and XX Sertoli cells

SRY, a sex-determining gene, induces testis development in chromosomally female (XX) individuals. However, mouse XX Sertoli cells carrying Sry (XX/Sry Sertoli cells) are incapable of fully supporting germ cell development, even when the karyotype of the germ cells is XY. While it has therefore been assumed that XX/Sry Sertoli cells are not functionally equivalent to XY Sertoli cells, it has remained unclear which specific functions are affected. To elucidate the functional difference, we compared the gene expression of XY and XX/Sry Sertoli cells. Lactate and cholesterol metabolisms, essential for nursing the developing germ cells, were down-regulated in XX/Sry cells, which appears to be caused at least in part by the differential expression of histone modification enzymes SMCX/SMCY (H3K4me3 demethylase) and UTX/UTY (H3K27me3 demethylase) encoded by the sex chromosomes. We suggest that down-regulation of lactate and cholesterol metabolism that may be due to altered epigenetic modification affects the nursing functions of XX/Sry Sertoli cells.This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Number 21249018 and 16H05142 (K. Mo.), Ministry of Education, Culture, Sports, Science, and Technology, Japan (MEXT) KAKENHI Grant Number 22132002 (K. Mo.), the Uehara Memorial Foundation, and Takeda Science Foundation (T.B.)

Enzalutamide versus abiraterone as a first-line endocrine therapy for castration-resistant prostate cancer (ENABLE study for PCa): A study protocol for a multicenter randomized phase III trial

金沢大学附属病院泌尿器科Background: Both enzalutamide and abiraterone have demonstrated improved radiographic progression-free and overall survival for castration-resistant prostate cancer (CRPC) compared with placebo controls before docetaxel treatment in phase III studies. These oral agents target androgen and androgen receptor signaling and are thought to be less toxic than chemotherapy. Cross-resistance to these agents was recently reported because of their similar mechanism of action, and it is important to assess which agent is more effective to use initially for CRPC. Methods/design: The present study is a phase III, investigator-initiated, multicenter, head-to-head, randomized controlled trial investigating enzalutamide vs. abiraterone as a first-line treatment for CRPC patients. Patients will be randomly assigned to an enzalutamide or an abiraterone treatment group. The primary endpoint is the time to prostate-specific antigen progression. The target sample size is set at 100 patients per group (total, 200 patients). The study duration is 5 years, and the duration for recruitment is 2 years and 6 months. Discussion: Thus far, there have been no prospective head-to-head studies comparing enzalutamide and abiraterone. This ENABLE study will clarify which agent should be prioritized for CRPC patients and enable clinicians to decide the appropriate treatment before chemotherapy. Trial registration: University hospital Medical Information Network (UMIN) Center identifier UMIN000015529. Registrated 11/1/2014. © 2017 The Author(s)

Fundamental physics activities with pulsed neutron at J-PARC(BL05)

"Neutron Optics and Physics (NOP/ BL05)" at MLF in J-PARC is a beamline for studies of fundamental physics. The beamline is divided into three branches so that different experiments can be performed in parallel. These beam branches are being used to develop a variety of new projects. We are developing an experimental project to measure the neutron lifetime with total uncertainty of 1 s (0.1%). The neutron lifetime is an important parameter in elementary particle and astrophysics. Thus far, the neutron lifetime has been measured by several groups; however, different values are obtained from different measurement methods. This experiment is using a method with different sources of systematic uncertainty than measurements conducted to date. We are also developing a source of pulsed ultra-cold neutrons (UCNs) produced from a Doppler shifter are available at the unpolarized beam branch. We are developing a time focusing device for UCNs, a so called "rebuncher", which can increase UCN density from a pulsed UCN source. At the low divergence beam branch, an experiment to search an unknown intermediate force with nanometer range is performed by measuring the angular dependence of neutron scattering by noble gases. Finally the beamline is also used for the research and development of optical elements and detectors. For example, a position sensitive neutron detector that uses emulsion to achieve sub-micrometer resolution is currently under development. We have succeeded in detecting cold and ultra-cold neutrons using the emulsion detector.Comment: 9 pages, 5 figures, Proceedings of International Conference on Neutron Optics (NOP2017

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements