A Novel Therapeutic and Prophylactic Vaccine (HVJ-Envelope / Hsp65 DNA + IL-12 DNA) against Tuberculosis Using the Cynomolgus Monkey Model

AbstractWe have developed a novel tuberculosis (TB) vaccine; a combination of the DNA vaccines expressing mycobacterial heat shock protein 65 (HSP65) and interleukin 12 (IL-12) delivered by the hemagglutinating virus of Japan (HVJ)-envelope and –liposome (HSP65 + IL-12/HVJ). An IL-12 expression vector (IL-12DNA) encoding single-chain IL-12 proteins comprised of p40 and p35 subunits were constructed. This vaccine provided remarkable protective efficacy in mouse and guinea pig models compared to the BCG vaccine on the basis of C.F.U of number of TB, survival, an induction of the CD8 positive CTL activity and improvement of the histopathological tuberculosis lesions. This vaccine also provided therapeutic efficacy against multi-drug resistant TB (MDR-TB) and extremely drug resistant TB (XDR-TB) (prolongation of survival time and the decrease in the number of TB in the lung) in murine models. Furthermore, we extended our studies to a cynomolgus monkey model, which is currently the best animal model of human tuberculosis. This novel vaccine provided a higher level of the protective efficacy than BCG based upon the assessment of mortality, the ESR, body weight, chest X-ray findings and immune responses. All monkeys in the control group (saline) died within 8 months, while 50% of monkeys in the HSP65+hIL-12/HVJ group survived more than 14 months post-infection (the termination period of the experiment). Furthermore, the BCG priming and HSP65 + IL-12/HVJ vaccine (booster) by the priming-booster method showed a synergistic effect in the TB-infected cynomolgus monkey (100% survival). In contrast, 33% of monkeys from BCG Tokyo alone group were alive (33% survival). Furthermore, this vaccine exerted therapeutic efficacy (100% survival) and augmentation of immune responses in the TB-infected monkeys. These data indicate that our novel DNA vaccine might be useful against Mycobacterium tuberculosis including XDR-TB and MDR-TB for human therapeutic clinical trials

Novel Prophylactic Vaccine Using a Prime-Boost Method and Hemagglutinating Virus of Japan-Envelope against Tuberculosis

Objective. Mycobacterium tuberculosis infection is a major global threat to human health. The only tuberculosis (TB) vaccine currently available is bacillus Calmette-Guérin (BCG), although it has no efficacy in adults. Therefore, the development of a novel vaccine against TB for adults is desired. Method. A novel TB vaccine expressing mycobacterial heat shock protein 65 (HSP65) and interleukin-12 (IL-12) delivered by the hemagglutinating virus of Japan- (HVJ)- envelope was evaluated against TB infection in mice. Bacterial load reductions and histopathological assessments were used to determine efficacy. Results. Vaccination by BCG prime with IgHSP65+murine IL-12/HVJ-envelope boost resulted in significant protective efficacy (>10, 000-fold versus BCG alone) against TB infection in the lungs of mice. In addition to bacterial loads, significant protective efficacy was demonstrated by histopathological analysis of the lungs. Furthermore, the vaccine increased the number of T cells secreting IFN-γ. Conclusion. This vaccine showed extremely significant protection against TB in a mouse model, consistent with results from a similar paper on cynomolgus monkeys. The results suggest that further development of the vaccine for eventual testing in clinical trials may be warranted

Phobos Regolith Simulant for MMX Mission: Spectral Measurement for Remote Target Identification and Deconvolution System Training

The two natural satellites of Mars, Phobos and Deimos are both important targets for scientific investigation. The JAXA mission Martian Moons eXplorer (MMX) is designed to explore Phobos and Deimos, with a launch date scheduled for 2024. The MMX spacecraft will observe both Martian moons and will land on one of them (Phobos, most likely), to collect a sample and bring it back to Earth. The designs of both the landing and sampling devices depend largely on the surface properties of the target body and on how its surface is reacting to an external action in the low gravity conditions of the target. The Landing Operation Working Team (LOWT) of MMX started analyzing previous observations and theoretical/experimental considerations to better understand the nature of Phobos surface material, developing a Phobos regolith simulant material for the MMX mission [1]. At the Institute for Planetary Research of the German aerospace Center (DLR) in Berlin we performed a spectral characterization of the Phobos regolith simulant. Those data will be used to train an Artificial Neural Network (NN) to produce a system that could rapidly classify data during the mission and for endmember decomposition

Macro-Porosity and Grain Density of C-Type Asteroid (162173) Ryugu

The Macroporosity of (162173) Ryugu is estimated based on the observed boulder size-frequency distribution

Cross calibration between Hayabusa2/ONC-T and OSIRIS-REx/MapCam for comparative analyses between asteroids Ryugu and Bennu

Proximity observations of (162173) Ryugu by the telescopic Optical Navigation Camera onboard Hayabusa2 and (101955) Bennu by MapCam onboard Origins, Spectral Interpretation, Resource Identification, and Security-Regolith Explorer found opposite spectral trends of space weathering on these carbonaceous asteroids. Whether the space weathering trends on these asteroids evolved from the same starting spectra would place an important constraint for understanding their relation. However, systematic error between data obtained by the two imagers needed to be reduced for accurate comparison. To resolve this problem, we cross calibrated albedo and color data using the Moon as the common standard. We show that the cross-calibrated reflectance can be obtained by upscaling the pre-cross-calibrated reflectance of Bennu by 12 +/- 2% at v-band, reducing the systematic errors down to 2%. The cross-calibrated data show that Bennu is brighter by 16 +/- 2% at v-band and bluer in spectral slope by 0.19 +/- 0.05 (/um) than Ryugu. The spectra of fresh craters on Ryugu and Bennu before cross calibration appeared to follow two parallel trend lines with offset, but they converged to a single trend after cross calibration. Such a post-cross-calibration perspective raise the possibility that Ryugu and Bennu evolved from materials with similar visible spectra but evolved in diverging directions by space weathering. The divergent evolution can be caused by the difference in space weathering dose/process and/or composition of the starting material. Thus, comparing the composition of samples returned from Ryugu and Bennu may change the way we interpret the spectral variation of C-complex asteroids

Aerosolized amikacin for treatment of pulmonary Mycobacterium avium infections: an observational case series

BACKGROUND: Current systemic therapy for nontuberculous mycobacterial pulmonary infection is limited by poor clinical response rates, drug toxicities and side effects. The addition of aerosolized amikacin to standard oral therapy for nontuberculous mycobacterial pulmonary infection may improve treatment efficacy without producing systemic toxicity. This study was undertaken to assess the safety, tolerability and preliminary clinical benefits of the addition of aerosolized amikacin to a standard macrolide-based oral treatment regimen. CASE PRESENTATIONS: Six HIV-negative patients with Mycobacterium avium intracellulare pulmonary infections who had failed standard therapy were administered aerosolized amikacin at 15 mg/kg daily in addition to standard multi-drug macrolide-based oral therapy. Patients were monitored clinically and serial sputum cultures were obtained to assess response to therapy. Symptomatic improvement with radiographic stabilization and eradication of mycobacterium from sputum were considered markers of success. Of the six patients treated with daily aerosolized amikacin, five responded to therapy. All of the responders achieved symptomatic improvement and four were sputum culture negative after 6 months of therapy. Two patients became re-infected with Mycobacterium avium intracellulare after 7 and 21 months of treatment. One of the responders who was initially diagnosed with Mycobacterium avium intracellulare became sputum culture positive for Mycobacterium chelonae resistant to amikacin after being on intermittent therapy for 4 years. One patient had progressive respiratory failure and died despite additional therapy. There was no evidence of nephrotoxicity or ototoxicity associated with therapy. CONCLUSION: Aerosolized delivery of amikacin is a promising adjunct to standard therapy for pulmonary nontuberculous mycobacterial infections. Larger prospective trials are needed to define its optimal role in therapy of this disease

Histone modifications as markers of cancer prognosis: a cellular view

Alterations in modifications of histones have been linked to deregulated expression of many genes with important roles in cancer development and progression. The effects of these alterations have so far been interpreted from a promoter-specific viewpoint, focussing on gene–gene differences in patterns of histone modifications. However, recent findings suggest that cancer tissues also display cell–cell differences in total amount of specific histone modifications. This novel cellular epigenetic heterogeneity is related to clinical outcome of cancer patients and may serve as a valuable marker of prognosis

An artificial impact on the asteroid (162173) Ryugu formed a crater in the gravity-dominated regime

The Hayabusa2 spacecraft investigated the small asteroid Ryugu, which has a rubble-pile structure. We describe an impact experiment on Ryugu using Hayabusa2’s Small Carry-on Impactor. The impact produced an artificial crater with a diameter >10 meters, which has a semicircular shape, an elevated rim, and a central pit. Images of the impact and resulting ejecta were recorded by the Deployable CAMera 3 for >8 minutes, showing the growth of an ejecta curtain (the outer edge of the ejecta) and deposition of ejecta onto the surface. The ejecta curtain was asymmetric and heterogeneous and it never fully detached from the surface. The crater formed in the gravity-dominated regime; in other words, crater growth was limited by gravity not surface strength. We discuss implications for Ryugu’s surface age