Search

Ritsuko Kubota-Koketsu,1,2,* Mikihiro Yunoki,3,* Yoshinobu Okuno,4 Kazuyoshi Ikuta1 1Department of Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan; 2Surveillance Section, Research and Production Technology Department, The Research Foundation for Microbial Diseases of Osaka University, Kagawa, Japan; 3Research and Development Division, Japan Blood Products Organization, Tokyo, Japan; 4Kanonji Institute, The Research Foundation for Microbial Diseases of Osaka University, Kagawa, Japan*These authors contributed equally to this workCorrespondence: Ritsuko Kubota-KoketsuDepartment of Viral Infections, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, JapanTel +1-6-6879-8348Fax +1-6-6879-8347Email koketsu@biken.osaka-u.ac.jpMikihiro YunokiResearch and Development Division, Japan Blood Products Organization, 15F Tamachi Station Tower N, 3-1-1 Shibaura, Minato-ku, Tokyo, 108-0023, JapanTel +81-3-6435-6500Fax +81-3-6435-6274Email yunoki-mikihiro@jbpo.or.jpPurpose: Highly pathogenic avian influenza viruses are a threat to human health. Although donor populations have not experienced pandemic, they have been immunized by natural infections and/or vaccinations of influenza viruses such as A/H1N1, A/H3N2, and B. Therefore, it is considered that human intravenous immunoglobulin (IVIG) derived from healthy donors does not include IgG against avian influenza viruses. However, cross-reactivity has not been evaluated yet. In this study, cross-reactivity against the avian influenza virus A/H5N1, A/H7N1, A/H7N2, A/H7N7, A/H7N9, and A/H10N9 was evaluated.Materials and Methods: Several lots of IVIG derived from healthy donors in Japan were tested for virus neutralization using single- or multi-cycle virus neutralizing (S-VN or M-VN) assays that evaluate the infection-step associated with HA or the infection and propagation steps associated with HA and NA, respectively. In addition, anti-NA activities were evaluated by inhibiting the enzymatic activity in NAI assays.Results: IVIG lots showed high neutralizing activities against three A/H5N1 strains in M-VN assays, whereas activities in S-VN assays were unstable. In addition, A/H7N2 was also neutralized in S-VN and M-VN assays, with higher activity in M-VN than in S-VN assays. A/H7N1 was neutralized in S-VN and M-VN assays. In contrast, weak or no activity against A/H7N7, A/H7N9, and A/H10N9 was observed in S-VN and M-VN assays. NAI assay results show that IVIG lots had inhibitory activities against N1 and N2; however, N2 activities differed depending on the strain. In contrast, no activities were observed against N7 and N9.Conclusion: These results suggest that IVIG lots have neutralizing activity against avian influenza viruses during the virus propagation step, except for one strain, although no or weak activity was observed during the infection step.Keywords: avian influenza virus, A/H5, A/H7, neutralizing, intravenous immunoglobulin

Takumi Takeuchi,1 Kazuki Maki,1 Yumiko Okuno,1 Mami Hattori-Kato,2 Koji Mikami1 1Department of Urology, Japan Organization of Occupational Health and Safety, Kanto Rosai Hospital, Nakahara-ku, Kawasaki, Japan; 2Department of Urology, Tokyo Teishin Hospital, Chiyoda-ku, Tokyo 102-8798, JapanCorrespondence: Takumi TakeuchiDepartment of Urology, Japan Organization of Occupational Health and Safety, Kanto Rosai Hospital, 1-1 Kizukisumiyoshi-Cho, Nakahara-ku, Kawasaki 211-8510, JapanEmail takeuchit@abelia.ocn.ne.jpObjective: We herein attempted to select male patients with an elevated nocturnal urinary frequency possibly due to a shortage of AVP. These patients may be good candidates for low-dose oral desmopressin administration.Patients and Methods: Serum and spot urine osmolality, electrolytes, serum creatinine, casual blood glucose, plasma brain natriuretic polypeptide (BNP), and plasma AVP were measured at the same time in 97 elderly male patients with urinary symptoms under free water drinking.Results: A binary plot of plasma AVP and serum osmolality indicated a region at which patients had relatively lower AVP considering higher serum osmolality. It was tentatively named the desmopressin region. Twenty out of 97 (20.6%) patients were in the desmopressin region. Daily urine output did not exceed 3 L in any patient. Urine osmolality was slightly lower in patients in the desmopressin region. No significant differences were observed in urine volume, urinary frequency, or urination questionnaire scores between both groups.Conclusion: AVP-shortage patients may be selected for treatment with oral desmopressin based on measurements of serum osmolality and plasma AVP.Keywords: AVP, osmolality, desmopressin, urination

High-throughput DNA sequencing significantly contributed to diagnosis and prognostication in patients with myelodysplastic syndromes (MDS). We determined the biological and prognostic significance of genetic aberrations in MDS. In total, 944 patients with various MDS subtypes were screened for known/putative mutations/deletions in 104 genes using targeted deep sequencing and array-based genomic hybridization. In total, 845/944 patients (89.5%) harbored at least one mutation (median, 3 per patient; range, 0-12). Forty-seven genes were significantly mutated with TET2, SF3B1, ASXL1, SRSF2, DNMT3A, and RUNX1 mutated in >10% of cases. Many mutations were associated with higher risk groups and/or blast elevation. Survival was investigated in 875 patients. By univariate analysis, 25/48 genes (resulting from 47 genes tested significantly plus PRPF8) affected survival (P

Toshihiko Inoue,1 Yoshishige Okuno,1 Iku Nishiguchi,1 Koji Ikenaga,1 Osamu Mimura2 1Department of Radiation Oncology, Ashiya Radiotherapy Clinic Nozomi, Ashiya, Japan; 2Department of Neuro-Ophthalmological Therapeutics, Hyogo College of Medicine, Nishinomiya, Japan Purpose: To report the outcomes of early intervention with fractionated stereotactic radiotherapy (FSRT) in a patient with primary optic nerve sheath meningioma (ONSM).Patient and methods: A male patient in his early 40s underwent 5-beam FSRT at a prescribed dose of 50 Gy in 25 fractions over 35 days. The patient had an 11-month history of progressive visual impairment at the time of FSRT.Results: On day 14 of treatment, the patient reported early improvement in his vision. Two weeks after the completion of FSRT, his left eye visual acuity and field recovered completely. However, the tumor regressed only slightly in the 2 years of follow-up.Conclusion: Early intervention with FSRT for optic nerve sheath meningioma resulted in a rapid response and complete improvement of visual impairment. Keywords: fractionated stereotactic radiotherapy, optic nerve sheath meningioma, early intervention, rapid recovery of visual impairment

We present stable polarization of a long-wavelength vertical-cavity surface-emitting laser (LW VCSEL). The polarization control was achieved through growing its active region on a (113)B InP substrate, which was integrated to (001) GaAs-based distributed Bragg reflectors by a wafer-bonding technique. Theoretical investigation showed that to achieve high polarization stability, a large dichroism such as an anisotropic gain is needed. It was also shown that the (113)B and other planes of the (11n) family have asymmetry, which results in asymmetric stress and anisotropic optical gain in a strained multiquantum well. An index-guiding mesa structure was fabricated in an asymmetric shape. The index guiding either enhanced or distracted the polarization stability originating from gain anisotropy, depending on its orientation of the asymmetry, as was confirmed by a statistical summary. Using a VCSEL with an appropriate index-guiding structure, we performed 1-Gb/s modulation and confirmed single polarization under large-signal modulation.

A new long-wavelength vertical-cavity surface-emitting laser structure is described that utilizes AlGaAs-GaAs mirrors bonded to AlInGaAs-InP quantum wells with an intracavity buried tunnel junction. This structure offers complete wavelength flexibility in the 1250-1650 nm fiber communication bands and reduces the high free-carrier losses and bonded junction voltage drops in previous devices. The intracavity contacts electrically bypass the bonded junctions to reduce threshold voltage. N-type current spreading layers and undoped AlGaAs mirrors minimize optical losses. This has enabled 134 degreesC maximum continuous-wave lasing temperature, 2-mW room-temperature continuous-wave single-mode power, and 1-mW single-mode power at 80 degreesC, in various devices in the 1310-1340 nm wavelength range.

We propose and demonstrate a long-wavelength vertical cavity surface emitting laser (VCSEL) which consists of a (311)B InP-based active region and (100) GaAs-based distributed Bragg reflectors (DBRs), with an aim to control the in-plane polarization of output power. Crystal growth on (311)B InP substrates was performed under low-migration conditions to achieve good crystalline quality. The VCSEL was fabricated by wafer bonding, which enables us to combine different materials regardless of their lattice and orientation mismatch without degrading their quality. The VCSEL was polarized with a power extinction ratio of 31 dB. (C) 2003 American Institute of Physics.

We demonstrate the first, long-wavelength two-dimensional wavelength-division-multiplexed vertical cavity surface-emitting laser array. The eight-channel single-mode array covers the C-band from 1532 to 1565 nm. The devices are fabricated using two separate active regions laterally integrated using nonplanar wafer bonding. We achieved single-mode powers up to 0.8 mW, 2-dB output power uniformity across the array, and sidemode suppression ratios in excess of 43 dB. This fabrication technique can be used to maintain the gain-peak and cavity-mode alignment across wide-band arrays and, with the use of nontraditional mirrors, can be extended to the fabrication of arrays covering the entire C-, S-, and L-bands as well as the 1310-nin transmission band.

Hiroyuki Onodera,1 Takeru Urayama,2 Kazue Hirota,3 Kazuhiro Maeda,3 Ritsuko Kubota-Koketsu,3,4 Kazuo Takahashi,5 Katsuro Hagiwara,6 Yoshinobu Okuno,3 Kazuyoshi Ikuta,3,4 Mikihiro Yunoki,2,4,6 1Medical Information Department, 2Research and Development Division, Japan Blood Products Organization, Tokyo, 3Research and Development Division, The Research Foundation for Microbial Diseases of Osaka University, Kagawa, 4Former Department of Virology, Research Institute for Microbial Diseases, Osaka University, 5Virology Division, Department of Infectious Diseases, Osaka Prefectural Institute of Public Health, Osaka, 6Pathogenic Risk Evaluation, Graduate School of Veterinary Medicine, Rakuno Gakuen University, Hokkaido, Japan Abstract: Influenza viruses A/H1N1, A/H3N2, and B are known seasonal viruses that undergo annual mutation. Intravenous immunoglobulin (IVIG) contains anti-seasonal influenza virus globulins. Although the virus-neutralizing (VN) titer is an indicator of protective antibodies, changes in this titer over extended time periods have yet to be examined. In this study, variations in hemagglutination inhibition (HI) and VN titers against seasonal influenza viruses in IVIG lots over extended time periods were examined. In addition, the importance of monitoring the reactivity of IVIG against seasonal influenza viruses with varying antigenicity was evaluated. A/H1N1, A/H3N2, and B influenza virus strains and IVIG lots manufactured from 1999 to 2014 were examined. The HI titer was measured by standard methods. The VN titer was measured using a micro-focus method. IVIG exhibited significant HI and VN titers against all investigated strains. Our results suggest that the donor population maintains both specific and cross-reactive antibodies against seasonal influenza viruses, except in cases of pandemic viruses, despite major antigen changes. The titers against seasonal influenza vaccine strains, including past strains, were stable over short time periods but increased slowly over time. Keywords: IVIG, influenza, seasonal, neutralization, vaccine

Mikihiro Yunoki,1-3 Takeshi Kurosu,2 Ritsuko Kubota Koketsu,2,4 Kazuo Takahashi,5 Yoshinobu Okuno,4 Kazuyoshi Ikuta2,4 1Research and Development Division, Japan Blood Products Organization, Tokyo, 2Department of Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, 3Pathogenic Risk Evaluation, Graduate School of Veterinary Medicine, Rakuno Gakuen University, Hokkaido, 4Research and Development Division, The Research Foundation for Microbial Diseases of Osaka University, Kagawa, 5Osaka Prefectural Institute of Public Health, Osaka, Japan Abstract: Japanese encephalitis virus (JEV), West Nile virus (WNV), and dengue virus (DenV) are causal agents of Japanese encephalitis, West Nile fever, and dengue fever, respectively. JEV is considered to be indigenized and widespread in Japan, whereas WNV and DenV are not indigenized in Japan. Globulin products seem to reflect the status of the donor population according to antivirus neutralization activity. However, the anti-JEV, -WNV, and -DenV neutralization activities of globulin products derived from donors in Japan have not been clarified. Furthermore, potential candidates for the development of an effective immunotherapeutic drug for encephalitis caused by JEV, WNV, or DenV have also not been identified. Therefore, the aim of this study was to determine the overall status of the donor population in Japan based on globulin products by evaluating anti-JEV, -WNV, and -DenV neutralizing activities of intravenous immunoglobulin. Overall, intravenous immunoglobulin products showed stable neutralizing activity against JEV but showed no or only weak activity against WNV or DenV. These results suggest that the epidemiological level against WNV and DenV in the donor population of Japan is still low, suggesting that these viruses are not yet indigenized. In addition, JEV vaccinations and/or infections in the donor population do not induce a cross-reactive antibody against WNV. Keywords: Japanese encephalitis virus, West Nile virus, dengue virus, intravenous immunoglobulin, neutralization

Aim: We tested the hypothesis that stimulation by electro-resection of bladder tissue induces stem cells in the tissue repair process. Materials & Methods: After primary transurethral resection of a bladder tumor and surrounding tissue (TUR-Bt), second TUR-Bt was performed. Tissues excised by second TUR-Bt were immunohistochemically stained for Oct4, a marker of pluripotency, and for CD90 and CD73, markers of mesenchymal stromal cells, when no bladder tumor cells remained. Results and Conclusions: Oct4B protein was sporadically stained in the cytoplasm of interstitial cells in four out of eight cases. CD90 and CD73 are upregulated in interstitial and vascular endothelial cells without CD45 expression. Mesenchymal stromal cells, but not pluripotent stem cells, may be mainly involved in bladder tissue repair.

Takumi Takeuchi, Yumiko Okuno, Mami Hattori-Kato, Masayoshi Zaitsu, Koji MikamiDepartment of Urology, Kanto Rosai Hospital, Kawasaki, JapanAbstract: A splice variant of androgen receptor (AR), AR-V7, lacks in androgen-binding portion and leads to aggressive cancer characteristics. Reverse transcription-polymerase chain reactions (PCRs) and subsequent nested PCRs for the amplification of AR-V7 and prostate-specific antigen (PSA) transcripts were done for whole blood of patients with prostate cancer and male controls. With primary reverse transcription PCRs, AR-V7 and PSA were detected in 4.5% and 4.7% of prostate cancer, respectively. With nested PCRs, AR-V7 messenger RNA (mRNA) was positive in 43.8% of castration-sensitive prostate cancer and 48.1% of castration-resistant prostate cancer (CRPC), while PSA mRNA was positive in 6.3% of castration-sensitive prostate cancer and 18.5% of CRPC. Whole-blood samples of controls showed AR-V7 mRNA expression by nested PCR. Based on multivariate analysis, expression of AR-V7 mRNA in whole blood was not significantly correlated with clinical parameters and PSA mRNA in blood, while univariate analysis showed a correlation between AR-V7 mRNA and metastasis at initial diagnosis. Detection of AR-V7 mRNA did not predict the reduction of serum PSA in patients with CRPC following abiraterone and enzalutamide administration. In conclusion, AR-V7 mRNA expression in normal hematopoietic cells may have annihilated the manifestation of aggressiveness of prostate cancer and the prediction of the effectiveness of abiraterone and enzalutamide by the assessment of AR-V7 mRNA in blood.Keywords: AR-V7, prostate cancer, castration-resistant

Shoji Ideno,1,3 Kaoru Sakai,1 Mikihiro Yunoki,2–4 Ritsuko Kubota-Koketsu,3,5 Yuji Inoue,3 Shota Nakamura,6 Teruo Yasunaga,6 Yoshinobu Okuno,5 Kazuyoshi Ikuta3 1Infectious Pathogen Research Section, Central Research Laboratory, Research and Development Division, Japan Blood Products Organization, Kobe, Japan; 2Research and Development Promotion Section, Research and Development Division, Japan Blood Products Organization, Tokyo, Japan; 3Department of Virology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan; 4Department of Veterinary Microbiology, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido, Japan; 5Kanonji Institute, The Research Foundation for Microbial Diseases of Osaka University, Kanonji, Kagawa, Japan; 6Department of Genome Informatics, Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan Background: There is increasing concern about the speed with which health care providers can administer prophylaxis and treatment in an influenza pandemic. Generally, it takes several months to manufacture an influenza vaccine by propagation of the virus in chicken eggs or cultured cells. Newer, faster protocols for the production of vaccines that induce broad-spectrum immunity are therefore highly desirable. We previously developed human monoclonal antibody B-1 that shows broadly neutralizing activity against influenza A virus H3N2. B-1 recognizes an epitope region that includes an antiparallel β-sheet structure underneath the receptor binding site of influenza hemagglutinin (HA). In this study, the efficacy of a synthetic peptide vaccine derived from this epitope region against influenza A was evaluated. Materials and methods: Two peptides were synthesized, the upper and lower peptides. These peptides comprise amino acid residues 167–187 and 225–241, respectively, of the B-1 epitope region of HA, which is involved in forming the β-sheet structure. Both peptides were then coupled to keyhole limpet hemocyanin, and the peptides, alone or in combination, were used to immunize rabbits. The resulting antibody responses were examined by enzyme-linked immunosorbent assay. The upper peptide, but not the lower peptide, elicited antibodies that were reactive to HA. Interestingly, the use of both peptides together could elicit antibodies with a higher reactivity to HA than either peptide alone. The antibodies were found to react to HA at the N-terminus of the upper peptide, which is exposed at the surface of trimeric HA on influenza virions. Discussion: The higher production of HA-reactive antibodies following immunization with both peptides suggests that the upper peptide forms the effective epitope structure in the binding state, and the lower peptide enhances the production of HA antibodies. This study could be the first step towards the development of pandemic viral vaccines that can be produced within short time periods. Keywords: influenza A, hemagglutinin, epitope, synthetic peptide, rabbit

Ritsuko Kubota-Koketsu,1,2 Mikihiro Yunoki,2,3 Yoshinobu Okuno,1 Kazuyoshi Ikuta21Kanonji Institute, The Research Foundation for Microbial Diseases of Osaka University, Kagawa; 2Department of Virology, Research Institute for Microbial Diseases, Osaka University, 3Pathogenic Risk Management, Benesis Corporation, Osaka, JapanAbstract: Influenza A H2N2 virus, also known as the Asian flu, spread worldwide from 1957 to 1967, although there have been no cases reported in humans in the past 40 years. A vaccination program was introduced in Japan in the 1960s. Older Japanese donors could have been naturally infected with the H2N2 virus or vaccinated in the early 1960s. Human intravenous immunoglobulin (IVIG) reflects the epidemiological status of the donating population in a given time period. Here, the possible viral neutralizing (VN) activities of IVIG against the H2N2 virus were examined. Hemagglutination inhibition (HI) and VN activities of IVIG lots manufactured from 1993 to 2010 in Japan and the United States were evaluated against H2N2 viruses. High HI and VN activities against H2N2 viruses were found in all the IVIG lots investigated. HI titers were 32–64 against the isolate in 1957 and 64–128 against the isolates in 1965. VN titers were 80–320 against the isolate in 1957 and 1280–5120 against the isolates in 1965. Both the HI and VN titers were higher against the isolate in 1965 than in 1957. Thus, antibody titers of IVIG against influenza viruses are well correlated with the history of infection and the vaccine program in Japan. Therefore, evaluation of antibody titers provides valuable information about IVIGs, which could be used for immune stimulation when a new influenza virus emerges in the human population.Keywords: IVIG, influenza, H2N2, neutralization

The LHCf experiment, optimized for the study of forward physics at LHC, completes its main physics program in this year 2015, with the proton-proton collisions at the energy of 13 TeV. LHCf gives important results on the study of neutral particles at extreme pseudo-rapidity, both for proton-proton and for proton-ion interactions. These results are an important reference for tuning the models of the hadronic interaction currently used for the simulation of the atmospheric showers induced by very high energy cosmic rays. The results of this analysis and the future perspective are presented in this paper.

InGaP solar cells are not predicted to be susceptible to displacement damage by irradiation with electrons at energies lower than 100 keV from non-ionizing energy loss (NIEL) calculations. However, it is recently observed that InGaP solar cells are shown to degrade by irradiation with 60 keV electrons. This degradation is considered to be caused by radiation defects but is not clear. In this study, the kind of the defects generated by electrons at energies lower than 100 keV is found by deep-level transient spectroscopy (DLTS). The result of DLTS indicates that the prediction of primary knock-on atoms by using the radiation damage model is different from the experiment. In order to suggest the generation mechanism of radiation defects, we propose a new displacement threshold energy (Ed) by using a new technique in which NIEL and the introduction rate of radiation defects are combined. The degradation prediction by using estimated Ed is found to agree well with the degradation of electric power of InGaP solar cells irradiated by low-energy electrons. From the theory of radiation defects, we propose a new obtaining process of suitable degradation prediction by the displacement damage dose method. [ABSTRACT FROM AUTHOR]

The LHCf experiment is a CERN experiment dedicated to forward physics which is optimized to measure the neutral particle flow at extreme pseudo-rapidity values, ranging from 8.4 up to infinity. LHCf results are extremely important for the calibration of the hadronic interaction models used for the study of the development of atmospheric showers in the Earth atmosphere. Starting from the recent run of proton-Lead nucleus interactions at LHC, the LHCf and ATLAS collaborations have performed a common data taking which allows a combined study of the central and forward regions of the interaction. The latest results of LHCf, the upgrade of the detectors for the next 6.5 TeV + 6.5 TeV proton–proton run and the status of the LHCf-ATLAS common activities are summarized in this paper.