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1. Factors for the Variability of Three Acceptable Maximal Expiratory Flow–Volume Curves in Chronic Obstructive Pulmonary Disease

Author

Yamamoto M, Konno S, Makita H, Nitta K, Shimizu K, Suzuki M, Nishida M, Sugita J, Teshima T, and Nishimura M

Subjects
chronic obstructive pulmonary disease coefficient of variation flow-volume curve forced expiratory volume in 1 second variability, Diseases of the respiratory system, RC705-779
Abstract

Masafumi Yamamoto,1 Satoshi Konno,2 Hironi Makita,2,3 Katsuaki Nitta,4 Kaoruko Shimizu,2 Masaru Suzuki,2 Mutsumi Nishida,1 Junichi Sugita,1 Takanori Teshima,1 Masaharu Nishimura2,3 1Division of Laboratory and Transfusion Medicine, Hokkaido University Hospital, Sapporo, Hokkaido, Japan; 2Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan; 3Hokkaido Institute of Respiratory Diseases, Sapporo, Hokkaido, Japan; 4Makita Hospital, Sapporo, Hokkaido, JapanCorrespondence: Masaharu NishimuraDepartment of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, N-15 W-7, Kita-Ku, Sapporo, 060-8638, JapanTel +81-11-706-5911Fax +81-11-706-7899Email ma-nishi@med.hokudai.ac.jpBackground: Generally, the maximal expiratory flow–volume (MEFV) curve must be measured for the diagnosis and staging of chronic obstructive pulmonary disease (COPD). As this test is effort dependent, international guidelines recommend that three acceptable trials are required for each test. However, no study has examined the magnitude and factors for the variability in parameters among three acceptable trials.Methods: We evaluated the intra-individual variations in several parameters among three acceptable MEFV curves obtained at one-time point in patients with COPD (n = 28, stage 1; n = 36, stage 2; n = 21, stages 3– 4). Next, the factors for such variations were examined using forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC).Results: The averages of coefficient of variation (CV) for FEV1 and FVC were 2.0% (range: 1.0– 3.0%) and 1.6% (0.9– 2.2%), respectively. Both parameters were significantly better than peak expiratory flow rate, forced expiratory flow at 50% of expired FVC, and forced expiratory flow at 75% of expired FVC (CVs: 5.0– 6.9%). A higher spirometric stage was significantly associated with higher CVs for FVC and FEV1, and older age was significantly correlated with a higher variation in FEV1 alone. Furthermore, a significantly inverse association was observed between emphysema severity, and the CVs for FEV1, but not that for FVC, regardless of spirometric stage.Conclusion: Both FVC and FEV1 are highly reproducible; nevertheless, older age, lower FEV1 at baseline, and non-emphysema phenotype are factors for a higher variability in FEV1 in patients with COPD.Keywords: chronic obstructive pulmonary disease, coefficient of variation, flow–volume curve, forced expiratory volume in 1 second, variability

Published
2021

2. Improvement in Clinical Symptoms and Fecal Microbiome After Fecal Microbiota Transplantation in a Dog with Inflammatory Bowel Disease

Author

Niina A, Kibe R, Suzuki R, Yuchi Y, Teshima T, Matsumoto H, Kataoka Y, and Koyama H

Subjects
fecal microbiota transplantation, inflammatory bowel disease, canine, dysbiosis, microbiome, diversity, Veterinary medicine, SF600-1100
Abstract

Ayaka Niina,1 Ryoko Kibe,2 Ryohei Suzuki,1 Yunosuke Yuchi,1 Takahiro Teshima,1 Hirotaka Matsumoto,1 Yasushi Kataoka,2 Hidekazu Koyama1 1Laboratory of Veterinary Internal Medicine, School of Veterinary Medicine, Faculty of Veterinary Medicine, Nippon Veterinary and Life Science University, Musashino, Tokyo, Japan; 2Laboratory of Veterinary Microbiology, School of Veterinary Medicine, Faculty of Veterinary Medicine, Nippon Veterinary and Life Science University, Musashino, Tokyo, JapanCorrespondence: Ayaka NiinaLaboratory of Veterinary Internal Medicine, School of Veterinary Medicine, Faculty of Veterinary Medicine, Nippon Veterinary and Life Science University, 1-7-1 Kyonan-Cho, Musashino-Shi, Tokyo 180-8602, JapanTel +81 422 31 4151Fax +81 422 31 4560Email a.niina2173@gmail.comPurpose: Recently, fecal microbiota transplantation (FMT) has been tested in veterinary medicine as a treatment option for multiple gastrointestinal (GI) diseases, such as inflammatory bowel disease (IBD). However, there are no reports of changes in the microbial diversity of fecal microbiome after treatment with FMT in canine IBD cases. Moreover, little is known about the long-term efficacy and safety of FMT treatment for dogs. Herein, we present a case of canine intractable IBD treated with repeated, long-term FMT.Patients and methods: The patient was a 10-year-old, neutered, male, 4-kg Toy Poodle with a prolonged history of vomiting and diarrhea. Fecal examination for pathogens was negative. Despite treatment with multiple antibacterial and antidiarrheal agents, the patient showed no improvement. Endoscopic mucus sampling diagnosed a case of lymphocytic-plasmacytic duodenitis, ie, idiopathic IBD. Eventually, we performed periodic, long-term fecal microbiota transplantation of fresh donor feces collected from a 4-year-old, 32.8-kg, neutered male Golden Retriever by rectal enema. Additionally, we performed 16S rRNA sequence analysis, before and after FMT, to evaluate the microbiome diversity.Results: Fecal microbiome diversity after FMT resembled that of the healthy donor dog’s fecal microbiome, before FMT, which led us to conclude that the fecal microbiome in our patient normalized with FMT. Moreover, the clinical symptoms improved remarkably with regard to the changes in the fecal microbiome. Additionally, we noted no observable side effects during FMT treatment.Conclusion: This report indicates the efficacy and safety of long-term, periodic FMT for a case of canine IBD based on attenuation of clinical symptoms and changes in fecal microbiome diversity. Therefore, FMT could be chosen as a treatment option for IBD in canines in the future.Keywords: fecal microbiota transplantation, inflammatory bowel disease, canine, dysbiosis, microbiome, diversity

Published
2019

3. \phi\to\pi^0\eta\gamma and \phi\to\pi^0\pi^0\gamma decays and Mixing Between Low and High Mass Scalar Mesons

Author

Teshima, T., Kitamura, I., and Morisita, N.

Subjects
High Energy Physics - Phenomenology
Abstract

Radiative decays \phi\to\eta\pi^0\gamma and \phi\to\pi^0\pi^0\gamma are studied assuming that these decays are caused through the intermediate a_0(980)\gamma and f_0(980)\gamma states, respectively. Fitting the experimental data of the \eta\pi^0 and \pi^0\pi^0 invariant mass spectrum in the decays \phi\to\eta\pi^0\gamma and \pi^0\pi^0\gamma, it is shown that the processes \phi\to a_0\gamma and \phi\to f_0\gamma are dominated by the K^+K^- loop interaction rather than the contact \phi a_0(f_0)\gamma one both for the non-derivative and derivative SPP coupling. The experimental data of \Gamma[\phi\to f_0\gamma]/\Gamma[\phi\to a_0\gamma] predicts that g_{f_0K\bar{K}}/g_{a_0K\bar{K}} \sim 2. Considering the effects of the mixing between low mass scalar qq\bar{q}\bar{q} states and high mass scalar q\bar{q} states to these coupling constants g_{f_0K\bar{K}} and g_{a_0K\bar{K}}, one suggests that the mixing is rather large., Comment: 15 pages, 10 figures

Published
2007
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4. Flavor Mass and Mixing and S_3 Symmetry -- An S_3 Invariant Model Reasonable to All --

Author

Teshima, T.

Subjects
High Energy Physics - Phenomenology
Abstract

We assume that weak bases of flavors (u, c)_{L,R}, (d,s)_{L,R}, (e, \mu) _{L,R}, (\nu_e, \nu_\mu)_{L,R} are the S_3 doublet and t_{L,R}, b_{L,R}, \tau_{L,R}, {\nu_\tau}_{L,R} are the S_3 singlet and further there are S_3 doublet Higgs (H_D^1, H_D^2) and S_3 singlet Higgs H_S. We suggest an S_3 invariant Yukawa interaction, in which masses caused from the interaction of S_3 singlet flavors and Higgs is very large and masses caused from interactions of S_3 doublet flavors and Higgs are very small, and the vacuum expectation value <|H_D^1|>_0 is rather small compared to the <|H_D^2|>_0. In this model, we can explain the quark sector mass hierarchy, flavor mixing V_{CKM} and measure of CP violation naturally. The leptonic sector mass hierarchy and flavor mixing described by V_{MNS} having one-maximal and one-large mixing character can also be explained naturally with no other symmetry restriction. In our model, an origin of Cabibbo angle is the ratio \lambda=<|H_D^1|>_0 /<|H_D^2|>_0 and an origin of CP violation is the phase of H_D^1., Comment: 16 pages

Published
2005
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5. Radiative Decays Involving $f_0(980)$ and $a_0(980)$ and Mixing Between Low and High Mass Scalar Mesons

Author

Teshima, T., Kitamura, I., and Morisita, N.

Subjects
High Energy Physics - Phenomenology
Abstract

We analyze the experimental data for $\phi\to f_0(980)\gamma$, $\phi\to a_0(980)\gamma$, $f_0(980)\to\gamma\gamma$ and $a_0(980)\to\gamma\gamma$ decay widths in a framework where $f_0(980)$ and $a_0(980)$ are assumed to be mainly $qq\bar{q}\bar{q}$ low mass scalar mesons and mixed with $q\bar{q}$ high mass scalar mesons. Applied the vector meson dominance model (VDM), these decays amplitudes are expressed by coupling parameters $B$ describing the S ($qq\bar{q}\bar{q}$ scalar meson)-V(vector meson)- V(vector meson) coupling and $B'$ describing the S' ($q\bar{q}$ scalar meson)-V-V coupling. Adopting the magnitudes for $B$ and $B'$ as $2.8{GeV^{-1}}$ and $12{GeV^{-1}}$, respectively, the mixing angle between $a_0(980)$ and $a_0(1450)$ as 9 degrees, and the mixing parameter $\lambda_{01}$ causing the mixing between I=0 $qq\bar{q}\bar{q}$ state and $q\bar{q}$ state as $0.24{GeV}^2$, we can interpret these experimental data, consistently., Comment: 15 pages, 6 figures

Published
2005
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6. Results of a multi-institutional, randomized, non-inferiority, phase III trial of accelerated fractionation versus standard fractionation in radiation therapy for T1-2N0M0 glottic cancer: Japan Clinical Oncology Group Study (JCOG0701)

Author

Kodaira, T., Kagami, Y., Shibata, T., Shikama, N., Nishimura, Y., Ishikura, S., Nakamura, K., Saito, Y., Matsumoto, Y., Teshima, T., Ito, Y., Akimoto, T., Nakata, K., Toshiyasu, T., Nakagawa, K., Nagata, Y., Nishimura, T., Uno, T., Kataoka, M., Yorozu, A., and Hiraoka, M.

Published
2018
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7. Wide-Area Mapping of 155 Micron Continuum Emission from the Orion Molecular Cloud Complex

Author

Arimura, S., Shibai, H., Teshima, T., Nakagawa, T., Narita, M., Makiuti, S., Doi, Y., Verma, R. P., Ghosh, S. K., Rengarajan, T. N., Tanaka, M., and Okuda, H.

Subjects
Astrophysics
Abstract

We present the results of a wide-area mapping of the far-infrared continuum emission toward the Orion complex by using a Japanese balloon-borne telescope. The 155-um continuum emission was detected over a region of 1.5 deg^2 around the KL nebula with 3' resolution similar to that of the IRAS 100-um map. Assuming a single-temperature model of the thermal equilibrium dust, maps of the temperature and the optical depth were derived from the 155 um intensity and the IRAS 100 um intensity. The derived dust temperature is 5 - 15 K lower and the derived dust optical thickness were derived from the 155-um intensity and the IRAS 100-um intensity. The derived dust temperature is 5 - 15 K lower and the derived dust optical depth is 5 - 300 times larger than those derived from the IRAS 60 and 100-um intensities due to the significant contribution of the statistically heated very small grains to the IRAS 60-um intensity. The optical-thickness distribution shows a filamentary dust ridge that has a 1.5 degrees extent in the north - south direction and well resembles the Integral-Shaped Filament (ISF) molecular gas distribution. The gas-to-dust ratio derived from the CO molecular gas distribution along the ISF is in the range 30 - 200, which may be interpreted as being an effect of CO depletion due to the photodissociation and/or the freezing on dust grains., Comment: 23 pages, 7 figures, 1 table, to appear in PASJ, Vol. 56, No. 1

Published
2004
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8. Effects to Scalar Meson Decays of Strong Mixing between Low and High Mass Scalar Mesons

Author

Teshima, T., Kitamura, I., and Morisita, N.

Subjects
High Energy Physics - Phenomenology
Abstract

We analyze the mass spectroscopy of low and high mass scalar mesons and get the result that the coupling strengths of the mixing between low and high mass scalar mesons are very strong and the strengths of mixing for $I=1, 1/2$ scalar mesons and those of I=0 scalar mesons are almost same. Next, we analyze the decay widths and decay ratios of these mesons and get the results that the coupling constants $A'$ for $I=1, 1/2$ which represents the coupling of high mass scalar meson $N'$ -> two pseudoscalar mesons $PP$ are almost same as the coupling $A'$ for the I=0. On the other hand, the coupling constant $A$ for $I=1, I=1/2$ which represents the low mass scalar meson $N$ -> $PP$ are far from the coupling constant $A$ for I=0. We consider a resolution for this discrepancy. Coupling constant $A''$ for glueball $G$ -> $PP$ is smaller than the coupling $A'$. $\theta_P$ is $40^\circ \sim 50^\circ$., Comment: 15 pages, 6 figures

Published
2003
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9. Neutrino Large Mixing in Universal Yukawa Coupling Model with Small Violation

Author

Teshima, T., Asai, T., and Abe, Y.

Subjects
High Energy Physics - Phenomenology
Abstract

We have analyzed the possibility that the universal Yukawa coupling (democratic mass matrix) with small violations of Dirac and Majorana neutrinos can induce the large mixing of neutrinos through the seesaw mechanism. The possibility can be achieved by the condition that the violation parameters of Majorana neutrinos are sufficiently smaller than the violation parameters of Dirac neutrinos. Allowed regions of the violation parameters producing the observed neutrino mass hierarchy and large neutrino mixing are not so restricted at present in contrast to the violation parameters for quark sector., Comment: 14 pages, 4figures

Published
2002
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10. Mixing among light scalar mesons and L=1 q\bar{q} scalar mesons

Author

Teshima, T., Kitamura, I., and Morisita, N.

Subjects
High Energy Physics - Phenomenology
Abstract

Following the re-establishment of the \sigma(600) and the \kappa(900), the light scalar mesons a_0(980) and f_0(980) together with the \sigma(600) and the \kappa(900) are considered as the chiral scalar partner of pseudoscalar nonet in SU(3) chiral symmetry, and the high mass scalar mesons a_0(1450), K^*_0(1430), f_0(1370) and f_0(1710) turned out to be considered as the L=1 q\bar{q} scalar mesons. We assume that the high mass of the L=1 q\bar{q} scalar mesons is caused by the mixing with the light scalar mesons. For the structure of the light scalar mesons, we adopted the qq\bar{q}\bar{q} model in order to explain the "scalar meson puzzle". The inter-mixing between the light scalar nonet and the high mass L=1 q\bar{q} nonet and the intra-mixing among each nonet are analyzed by including the glueball into the high mass scalar nonet., Comment: 16 pages, 5 figures

Published
2001
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11. Small Violation of Universal Yukawa Coupling and Neutrino Large Mixing

Author

Teshima, T. and Asai, T.

Subjects
High Energy Physics - Phenomenology
Abstract

We assume the universal Yukawa coupling (democratic mass matrix) with small violations for quarks, charged leptons and neutrinos masses. We could reproduce the mass hierarchy for quark masses and V_{CKM} matrix elements precisely. We adopt the see-saw mechanism for the explanation of smallness of neutrino masses and introduce the right-handed Majorana neutrinos and Dirac neutrinos. We assume the universal Yukawa coupling with small violations for Majorana and Dirac neutrinos. We can get the hierarchy of charged lepton masses and effective neutrino masses and the large mixing of neutrinos expressed in V_{NMS}., Comment: 12 pages, 4 figures, LaTeX

Published
2000
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12. Analysis of atmospheric neutrino oscillations in three-flavor neutrinos

Author

Teshima, T. and Sakai, T.

Subjects
High Energy Physics - Phenomenology
Abstract

We analyze the atmospheric neutrino experiments of Super-Kamiokande (830-920 live days) using the three-flavor neutrino framework with the mass hierarchy m_1 nearly equal m_2 << m_3. We study the sub-GeV, multi- GeV neutrinos and upward through-going and stopping muons zenith angle distributions taking account of the Earth matter effects thoroughly. We obtain the allowed regions of mass and mixing parameters Delm^2_{23}, theta_{13} and theta_{23}. Delm^2_{23} is restricted to 0.002-0.01eV^2 and theta_{13}<13degrees, 35degrees

Published
2000
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13. Atmospheric neutrino oscillations in three-flavor neutrinos

Author

Teshima, T. and Sakai, T.

Subjects
High Energy Physics - Phenomenology
Abstract

We analyzed the atmospheric neutrino experiments of SuperKamiokande including zenith angle dependence's using the three-flavor neutrino framework with the hierarchy m^2_1 \approx m^2_2<

Published
1998
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14. Analysis of neutrino oscillation in three-flavor neutrinos

Author

Teshima, T., Sakai, T., and Inagaki, O.

Subjects
High Energy Physics - Phenomenology
Abstract

We analyzed the solar, terrestrial and atmospheric neutrinos experiments using the three-flavor neutrino framework and got the allowed regions for parameters (\Delta m_{12}^2, \sin^22\theta_{12}, \Delta m_{23}^2, \theta_{13}, \theta_{23}). In solar neutrino experiments, we got the large angle solution (\Delta m_{12}^2, \sin^22\theta_{12})=(4x10^{-6} - 7x10^{-5}eV^2, 0.6 - 0.9) and small angle solution (3x10^{-6} - 1.2x10^{-5}eV^2, 0.003 - 0.01) for \theta_{13}=0^\circ - 20^\circ. From the terrestrial and atmospheric neutrino experiments, we got the allowed regions (\theta_{13}<4^\circ, 24^\circ<\theta_{23}<26^\circ) for \Delta m_{23}^2=2eV^2, (\theta_{13}<4^\circ, 24^\circ<\theta_{23} <45^\circ) for \Delta m_{23}^2=0.2eV^2 and (\theta_{13}<14^\circ, \theta_{23}=40^\circ) for \Delta m_{23}^2=0.02eV^2. It seems that the large angle solution for (\Delta m_{12}^2, \sin^22\theta_{12}) is favored than the small angle slution from the analysis of zenith angle dependence in atmospheric neutrino sub-GeV experiment., Comment: 25 pages, LaTeX, 8 postscript figures included

Published
1998
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15. Defibrotide plus best standard of care compared with best standard of care alone for the prevention of sinusoidal obstruction syndrome (HARMONY): a randomised, multicentre, phase 3 trial

Author

Grupp, S. A., Corbacioglu, S., Kang, H. J., Teshima, T., Khaw, S. L., Locatelli, Franco, Maertens, J., Stelljes, M., Stepensky, P., Lopez, P., Amber, V., Pagliuca, A., Richardson, P. G., Mohty, M., Locatelli F. (ORCID:0000-0002-7976-3654), Grupp, S. A., Corbacioglu, S., Kang, H. J., Teshima, T., Khaw, S. L., Locatelli, Franco, Maertens, J., Stelljes, M., Stepensky, P., Lopez, P., Amber, V., Pagliuca, A., Richardson, P. G., Mohty, M., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

Background: Sinusoidal obstruction syndrome, also known as veno-occlusive disease, is a potentially life-threatening complication of haematopoietic stem-cell transplantation (HSCT). We aimed to compare defibrotide prophylaxis plus best supportive care versus best supportive care alone for sinusoidal obstruction syndrome prevention after HSCT. Methods: This open-label, randomised, multicentre, phase 3 trial was done in 104 centres in 14 countries. Patients who were at least 1 month old, were scheduled to receive allogeneic HSCT (adult [aged >16 years] or paediatric [aged >1 month to ≤16 years] patients) or autologous HSCT (paediatric patients only), and were at high risk or very high risk of developing sinusoidal obstruction syndrome were eligible for inclusion. Patients were randomly assigned (1:1) by an interactive web response system to receive intravenous defibrotide 25 mg/kg per day (four equal doses [6·25 mg/kg per dose]) and best supportive care (determined by individual institutional guidelines; defibrotide prophylaxis group) or best supportive care only (best supportive care group). Randomisation was stratified by sinusoidal obstruction syndrome risk, age, and country. The primary endpoint, sinusoidal obstruction syndrome-free survival at day 30 after HSCT, was assessed by an independent Endpoint Adjudication Committee in the intention-to-treat (ITT) population. Safety was assessed in all patients who received protocol treatment. The trial is registered with ClinicalTrials.gov, NCT02851407. Findings: Between Jan 11, 2017, and Oct 20, 2020, 372 patients (172 [46%] women and 200 [54%] men; median age 14·0 years [IQR 4·0–41·0] were randomly assigned to the defibrotide prophylaxis group (n=190) or best supportive care group (n=182; ITT population). On the basis of recommendations from the Independent Data Monitoring Committee following completion of the planned interim analysis in the first 280 recruited patients on April 29, 2020, enrolment was prematurel

Published
2023

16. Neutrino Mass and Mixing in the Universal Yukawa Coupling Framework

Author

Teshima, T., Sakai, T., and Inagaki, O.

Subjects
High Energy Physics - Phenomenology
Abstract

We present an analysis of neutrino oscillations which are consistent with current solar, atmospheric and terrestrial experiments in a framework with three neutrino mixing. The solutions satisfying these experiments have the large mixing (not maximal mixing) between electron neutrino- muon neutrino or muon neutrino-tau neutrino in m3 to be about several eV, where m3 is the heaviest neutrino mass. From these results, we conjecture a form for the mass matrices of charged lepton and neutrino which are described by the universal Yukawa coupling with small violations., Comment: 14 pages, TeX

Published
1997

17. Multimessenger Characterization of Markarian 501 during Historically Low X-Ray and $γ$-Ray Activity

Author

Abe, Abe, H., Acciari, S., Agudo, V. A., Aniello, I., Ansoldi, T., Antonelli, S., Arbet-Engels, L. A., Arcaro, A., Artero, C., Asano, M., Baack, K., Babić, D., Baquero, A., de Almeida, A., Barres, Barrio, U., Batković, J. A., Baxter, I., Becerra González, J., Bednarek, J., Bernardini, W., Bernardos, E., Berti, M., Besenrieder, A., Bhattacharyya, J., Bigongiari, W., Biland, C., Blanch, A., Bonnoli, O., Bošnjak, G., Burelli, Ž., Busetto, I., Carosi, G., Carretero-Castrillo, R., Castro-Tirado, M., Ceribella, A. J., Chai, G., Chilingarian, Y., Cikota, A., Colombo, S., Contreras, E., Cortina, J. L., Covino, J., D’Amico, S., D’Elia, G., Da Vela, V., Dazzi, P., De Angelis, F., De Lotto, A., Del Popolo, B., Delfino, A., Delgado, M., Delgado Mendez, J., Depaoli, C., Di Pierro, D., Di Venere, F., Souto Espiñeira, L., Dominis Prester, E., Donini, D., Dorner, A., Doro, D., Elsaesser, M., Emery, D., Escudero, G., Fallah Ramazani, J., Fariña, V., Fattorini, L., Foffano, A., Font, L., Fruck, L., Fukami, C., Fukazawa, S., García López, Y., Garczarczyk, R. J., Gasparyan, M., Gaug, S., Giesbrecht Paiva, M., Giglietto, J. G., Giordano, N., Gliwny, F., Godinović, P., Grau, N., Green, R., Green, D., Hadasch, J. G., Hahn, D., Hassan, A., Heckmann, T., Herrera, L., Hrupec, J., Hütten, D., Imazawa, M., Inada, R., Iotov, T., Ishio, R., Jiménez Martínez, K., Jormanainen, I., Kerszberg, J., Kobayashi, D., Kubo, Y., Kushida, H., Lamastra, J., Lelas, A., Leone, D., Lindfors, F., Linhoff, E., Lombardi, L., Longo, S., López-Coto, F., López-Moya, R., López-Oramas, M., Loporchio, A., Lorini, S., Lyard, A., Machado de Oliveira Fraga, E., Majumdar, B., Makariev, P., Maneva, M., Mang, G., Manganaro, N., Mangano, M., Mannheim, S., Mariotti, K., Martínez, M., Mas-Aguilar, M., Mazin, A., Menchiari, D., Mender, S., Mićanović, S., Miceli, S., Miener, D., Miranda, T., Mirzoyan, J. M., Molina, R., Mondal, E., Moralejo, H. A., Morcuende, A., Moreno, D., Nakamori, V., Nanci, T., Nava, C., Neustroev, L., Nievas Rosillo, V., Nigro, M., Nilsson, C., Nishijima, K., Njoh Ekoume, K., Noda, T., Nozaki, K., Ohtani, S., Oka, Y., Okumura, T., Otero-Santos, A., Paiano, J., Palatiello, S., Paneque, M., Paoletti, D., Paredes, R., Pavletić, J. M., Persic, L., Pihet, M., Pirola, M., Podobnik, G., Moroni, F., Prada, Prandini, P. G., Principe, E., Priyadarshi, G., Rhode, C., Ribó, W., Rico, M., Righi, J., Rugliancich, C., Sahakyan, A., Saito, N., Sakurai, T., Satalecka, S., Saturni, K., Schleicher, F. G., Schmidt, B., Schmuckermaier, K., Schubert, F., Schweizer, J. L., Sitarek, T., Sliusar, J., Sobczynska, V., Spolon, D., Stamerra, A., Strišković, A., Strom, J., Strzys, D., Suda, M., Surić, Y., Tajima, T., Takahashi, H., Takeishi, M., Tavecchio, R., Temnikov, F., Terauchi, P., Terzić, K., Teshima, T., Tosti, M., Truzzi, L., Tutone, S., Ubach, A., van Scherpenberg, S., Acosta, J., Vazquez, Ventura, M., Verguilov, S., Viale, V., Vigorito, I., Vitale, C. F., Vovk, V., Walter, I., Will, R., Wunderlich, M., Yamamoto, C., Zarić, T., Cerruti, D., Acosta-Pulido, M., Apolonio, J. A., Bachev, G., Baloković, R., Benítez, M., Björklund, E., Bozhilov, I., Brown, V., Bugg, L. F., Carbonell, A., Carnerero, W., Carosati, M. I., Casadio, D., Chamani, C., Chen, W., Chigladze, W. P., Damljanovic, R. A., Epps, G., Erkenov, K., Feige, A., Finke, M., Fuentes, J., Gazeas, A., Giroletti, K., Grishina, M., Gupta, T. S., Heidemann, A. C., Gurwell, M. A., Hiriart, E., Hou, D., Hovatta, W. J., Ibryamov, T., Joner, S., Jorstad, M. D., Kania, S. G., Kiehlmann, J., Kimeridze, S., Kopatskaya, G. N., Kopp, E. N., Korte, M., Kotas, M., Koyama, B., Kramer, S., Kunkel, J. A., Kurtanidze, L., Kurtanidze, S. O., Lähteenmäki, O. M., López, A., Larionov, J. M., Larionova, V. M., Larionova, E. G., Leto, L. V., Lorey, C., Mújica, C., Madejski, R., Marchili, G. M., Marscher, N., Minev, A. P., Modaressi, M., Morozova, A., Mufakharov, D. A., Myserlis, T., Nikiforova, I., Nikolashvili, A. A., Ovcharov, M. G., Perri, E., Raiteri, M., Readhead, C. M., Reimer, A. C. S., Reinhart, A., Righini, D., Rosenlehner, S., Sadun, K., Savchenko, A. C., Scherbantin, S. S., Schneider, A., Schoch, L., Seifert, K., Semkov, D., Sigua, E., Singh, L. A., Sola, C., Sotnikova, P., Spencer, Y., Steineke, M., Stojanovic, R., Strigachev, M., Tornikoski, A., Traianou, M., Tramacere, E., Troitskaya, A., Troitskiy, Yu. V., Trump, I. S., Tsai, J. B., Valcheva, A., Vasilyev, A., Verrecchia, A. A., Villata, F., Vince, M., Vrontaki, O., Weaver, K., Zaharieva, Z. R., and Zottmann, E.

Subjects
ddc:520
Abstract

The astrophysical journal / Supplement series 266(2), 37 (2023). doi:10.3847/1538-4365/acc181, We study the broadband emission of Mrk 501 using multiwavelength observations from 2017 to 2020 performed with a multitude of instruments, involving, among others, MAGIC, Fermi's Large Area Telescope (LAT), NuSTAR, Swift, GASP-WEBT, and the Owens Valley Radio Observatory. Mrk 501 showed an extremely low broadband activity, which may help to unravel its baseline emission. Nonetheless, significant flux variations are detected at all wave bands, with the highest occurring at X-rays and very-high-energy (VHE) $γ$-rays. A significant correlation (>3σ) between X-rays and VHE $γ$-rays is measured, supporting leptonic scenarios to explain the variable parts of the emission, also during low activity. This is further supported when we extend our data from 2008 to 2020, and identify, for the first time, significant correlations between the Swift X-Ray Telescope and Fermi-LAT. We additionally find correlations between high-energy γ-rays and radio, with the radio lagging by more than 100 days, placing the γ-ray emission zone upstream of the radio-bright regions in the jet. Furthermore, Mrk 501 showed a historically low activity in X-rays and VHE $γ$-rays from mid-2017 to mid-2019 with a stable VHE flux (>0.2 TeV) of 5% the emission of the Crab Nebula. The broadband spectral energy distribution (SED) of this 2 $γ$r long low state, the potential baseline emission of Mrk 501, can be characterized with one-zone leptonic models, and with (lepto)-hadronic models fulfilling neutrino flux constraints from IceCube. We explore the time evolution of the SED toward the low state, revealing that the stable baseline emission may be ascribed to a standing shock, and the variable emission to an additional expanding or traveling shock., Published by Institute of Physics Publ., London

Published
2023
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19. Long-term safety for patients with tisagenlecleucel-treated relapsed/refractory diffuse large B-cell lymphoma

Author

Jaeger, U, Tam, CS, Borchmann, P, McGuirk, JP, Johansen, M, Waller, EK, Jaglowski, S, Andreadis, C, Foley, SR, Westin, JR, Fleury, I, Ho, PJ, Mielke, S, Teshima, T, Salles, G, Schuster, SJ, He, F, Maziarz, RT, Mayer, S, Makita, S, Kersten, MJ, Ghosh, M, Wagner-Johnston, N, Kato, K, Corradini, P, Goto, H, Colicino, S, Agarwal, A, Lobetti-Bodoni, C, Bishop, MR, Jaeger, U, Tam, CS, Borchmann, P, McGuirk, JP, Johansen, M, Waller, EK, Jaglowski, S, Andreadis, C, Foley, SR, Westin, JR, Fleury, I, Ho, PJ, Mielke, S, Teshima, T, Salles, G, Schuster, SJ, He, F, Maziarz, RT, Mayer, S, Makita, S, Kersten, MJ, Ghosh, M, Wagner-Johnston, N, Kato, K, Corradini, P, Goto, H, Colicino, S, Agarwal, A, Lobetti-Bodoni, C, and Bishop, MR

Published
2022

20. S212: PHASE I STUDY OF YTB323, A CHIMERIC ANTIGEN RECEPTOR (CAR)-T CELL THERAPY MANUFACTURED USING T-CHARGE™, IN PATIENTS WITH RELAPSED/REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA

Author

Dickinson, M., primary, Kwon, M., additional, Briones, J., additional, Jäger, U., additional, Kato, K., additional, Bachy, E., additional, Blaise, D., additional, Boissel, N., additional, Shah, N., additional, Frigault, M, additional, Riedell, P., additional, Shune, L., additional, Teshima, T., additional, Zhu, X., additional, Orlando, E., additional, Yi, L., additional, Davis, J., additional, Bleickardt, E., additional, Flinn, I., additional, and Barba, P., additional

Published
2022
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21. S235: A TWO-PART, SINGLE- AND TWO-ARM RANDOMIZED, OPEN-LABEL STUDY TO EVALUATE THE SAFETY, TOLERABILITY AND PHARMACOKINETICS OF THE S1P RECEPTOR MODULATOR KRP203 IN SUBJECTS WITH HEMATOLOGICAL MALIGNANCIES

Author

dertschnig, S., primary, finke, J., additional, heim, D., additional, schanz, U., additional, holler, E., additional, holtick, U., additional, socié, G., additional, teshima, T., additional, bucher, C., additional, and passweg, J., additional

Published
2022
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22. P1389: RUXOLITINIB DEMONSTRATES A GREATER CORTICOSTEROID-SPARING EFFECT THAN BEST AVAILABLE THERAPY IN PATIENTS WITH CORTICOSTEROID-REFRACTORY/DEPENDENT CHRONIC GRAFT-VS-HOST DISEASE

Author

Zeiser, R., primary, Russo, D., additional, Ram, R., additional, Hashmi, S., additional, Chakraverty, R., additional, Moritz Middeke, J., additional, Giebel, S., additional, Sarkar, R., additional, Gowda, M., additional, Gunes, S., additional, Stefanelli, T., additional, Lee, S. J., additional, Teshima, T., additional, and Locatelli, F., additional

Published
2022
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24. Bone marrow central memory and memory stem T-cell exhaustion in AML patients relapsing after HSCT

Author

Noviello, M, Manfredi, F, Ruggiero, E, Perini, T, Oliveira, G, Cortesi, F, De Simone, P, Toffalori, C, Gambacorta, V, Greco, R, Peccatori, J, Casucci, M, Casorati, G, Dellabona, P, Onozawa, M, Teshima, T, Griffioen, M, Halkes, C, Falkenburg, J, Stolzel, F, Altmann, H, Bornhauser, M, Waterhouse, M, Zeiser, R, Finke, J, Cieri, N, Bondanza, A, Vago, L, Ciceri, F, Bonini, C, Noviello M., Manfredi F., Ruggiero E., Perini T., Oliveira G., Cortesi F., De Simone P., Toffalori C., Gambacorta V., Greco R., Peccatori J., Casucci M., Casorati G., Dellabona P., Onozawa M., Teshima T., Griffioen M., Halkes C. J. M., Falkenburg J. H. F., Stolzel F., Altmann H., Bornhauser M., Waterhouse M., Zeiser R., Finke J., Cieri N., Bondanza A., Vago L., Ciceri F., Bonini C., Noviello, M, Manfredi, F, Ruggiero, E, Perini, T, Oliveira, G, Cortesi, F, De Simone, P, Toffalori, C, Gambacorta, V, Greco, R, Peccatori, J, Casucci, M, Casorati, G, Dellabona, P, Onozawa, M, Teshima, T, Griffioen, M, Halkes, C, Falkenburg, J, Stolzel, F, Altmann, H, Bornhauser, M, Waterhouse, M, Zeiser, R, Finke, J, Cieri, N, Bondanza, A, Vago, L, Ciceri, F, Bonini, C, Noviello M., Manfredi F., Ruggiero E., Perini T., Oliveira G., Cortesi F., De Simone P., Toffalori C., Gambacorta V., Greco R., Peccatori J., Casucci M., Casorati G., Dellabona P., Onozawa M., Teshima T., Griffioen M., Halkes C. J. M., Falkenburg J. H. F., Stolzel F., Altmann H., Bornhauser M., Waterhouse M., Zeiser R., Finke J., Cieri N., Bondanza A., Vago L., Ciceri F., and Bonini C.

Abstract

The major cause of death after allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for acute myeloid leukemia (AML) is disease relapse. We investigated the expression of Inhibitory Receptors (IR; PD-1/CTLA-4/TIM-3/LAG-3/2B4/KLRG1/GITR) on T cells infiltrating the bone marrow (BM) of 32 AML patients relapsing (median 251 days) or maintaining complete remission (CR; median 1 year) after HSCT. A higher proportion of early-differentiated Memory Stem (T SCM ) and Central Memory BM-T cells express multiple IR in relapsing patients than in CR patients. Exhausted BM-T cells at relapse display a restricted TCR repertoire, impaired effector functions and leukemia-reactive specificities. In 57 patients, early detection of severely exhausted (PD-1 + Eomes + T-bet − ) BM-T SCM predicts relapse. Accordingly, leukemia-specific T cells in patients prone to relapse display exhaustion markers, absent in patients maintaining long-term CR. These results highlight a wide, though reversible, immunological dysfunction in the BM of AML patients relapsing after HSCT and suggest new therapeutic opportunities for the disease.

Published
2019

25. Ruxolitinib for Chronic Graft-versus-Host Disease. Reply

Author

Zeiser, R., Teshima, T., Locatelli, Franco, Locatelli F. (ORCID:0000-0002-7976-3654), Zeiser, R., Teshima, T., Locatelli, Franco, and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

no abstract available

Published
2021

26. Ruxolitinib for glucocorticoid-refractory chronic graft-versus-host disease

Author

Zeiser, R., Polverelli, N., Ram, R., Hashmi, S. K., Chakraverty, R., Middeke, J. M., Musso, M., Giebel, S., Uzay, A., Langmuir, P., Hollaender, N., Gowda, M., Stefanelli, T., Lee, S. J., Teshima, T., Locatelli, Franco, Locatelli F. (ORCID:0000-0002-7976-3654), Zeiser, R., Polverelli, N., Ram, R., Hashmi, S. K., Chakraverty, R., Middeke, J. M., Musso, M., Giebel, S., Uzay, A., Langmuir, P., Hollaender, N., Gowda, M., Stefanelli, T., Lee, S. J., Teshima, T., Locatelli, Franco, and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

BACKGROUND Chronic graft-versus-host disease (GVHD), a major complication of allogeneic stem-cell transplantation, becomes glucocorticoid-refractory or glucocorticoid-dependent in approximately 50% of patients. Robust data from phase 3 randomized studies evaluating second-line therapy for chronic GVHD are lacking. In retrospective surveys, ruxolitinib, a Janus kinase (JAK1-JAK2) inhibitor, showed potential efficacy in patients with glucocorticoid-refractory or -dependent chronic GVHD. METHODS This phase 3 open-label, randomized trial evaluated the efficacy and safety of ruxolitinib at a dose of 10 mg twice daily, as compared with the investigator's choice of therapy from a list of 10 commonly used options considered best available care (control), in patients 12 years of age or older with moderate or severe glucocorticoid-refractory or -dependent chronic GVHD. The primary end point was overall response (complete or partial response) at week 24; key secondary end points were failure-free survival and improved score on the modified Lee Symptom Scale at week 24. RESULTS A total of 329 patients underwent randomization; 165 patients were assigned to receive ruxolitinib and 164 patients to receive control therapy. Overall response at week 24 was greater in the ruxolitinib group than in the control group (49.7% vs. 25.6%; odds ratio, 2.99; P<0.001). Ruxolitinib led to longer median failure-free survival than control (>18.6 months vs. 5.7 months; hazard ratio, 0.37; P<0.001) and higher symptom response (24.2% vs. 11.0%; odds ratio, 2.62; P=0.001). The most common (occurring in ≥10% patients) adverse events of grade 3 or higher up to week 24 were thrombocytopenia (15.2% in the ruxolitinib group and 10.1% in the control group) and anemia (12.7% and 7.6%, respectively). The incidence of cytomegalovirus infections and reactivations was similar in the two groups. CONCLUSIONS Among patients with glucocorticoid-refractory or -dependent chronic GVHD, ruxolitinib led to sign

Published
2021

28. Monitoring of the radio galaxy M 87 during a low-emission state from 2012 to 2015 with MAGIC

Author

Acciari, V A, Ansoldi, Antonelli, S, L A, Arbet&nbsp, Engels, Arcaro, A, Baack, C, Babić, D, Banerjee, A, Bangale, B, Barres&nbsp, de&nbsp, Almeida, P, Barrio, U, J A, Becerra&nbsp, González, Bednarek, J, Bellizzi, W, Bernardini, L, Berti, E, Besenrieder, A, Bhattacharyya, J, Bigongiari, W, Biland, C, Blanch, A, Bonnoli, O, Bošnjak, G, Busetto, Ž, Carosi, G, Ceribella, R, Chai, G, Chilingaryan, Y, Cikota, A, Colak, S, S M, Colin, Colombo, U, Contreras, E, J L, Cortina, Covino, J, D’Elia, S, Da&nbsp, Vela, V, Dazzi, P, De&nbsp, Angelis, F, Lotto, A, Delfino, B, Delgado, M, Depaoli, J, Di&nbsp, Pierro, D, Venere, F, Do&nbsp, Souto&nbsp, Espiñeira, L, Dominis&nbsp, Prester, E, Donini, D, Dorner, A, Doro, D, Elsaesser, M, Fallah&nbsp, Ramazani, D, Fattorini, V, Fernández-Barral, A, Ferrara, A, Fidalgo, G, Foffano, D, Fonseca, L, M V, Font, Fruck, L, Fukami, C, García&nbsp, López, S, R J, Garczarczyk, Gasparyan, M, Gaug, S, Giglietto, M, Giordano, N, Godinović, F, Green, N, Guberman, D, Hadasch, D, Hahn, D, Herrera, A, Hoang, J, Hrupec, J, Hütten, D, Inada, M, Inoue, T, Ishio, S, Iwamura, K, Jouvin, Y, Kerszberg, L, Kubo, D, Kushida, H, Lamastra, J, Lelas, A, D, Leone, F., Lindfors, E., Lombardi, Longo, S, López, F, López-Coto, M, López-Oramas, R, Loporchio, A, Machado&nbsp, Oliveira&nbsp, Fraga, S, Maggio, B, Majumdar, C, Makariev, P, Mallamaci, M, Maneva, M, Manganaro, G, Mannheim, M, Maraschi, K, Mariotti, L, Martínez, M, Masuda, M, Mazin, S, Mićanović, D, Miceli, S, Minev, D, Miranda, M, J M, Mirzoyan, Molina, R, Moralejo, E, Morcuende, A, Moreno, D, Moretti, V, Munar-Adrover, E, Neustroev, P, Nigro, V, Nilsson, C, Ninci, K, Nishijima, D, Noda, K, Nogués, K, Nöthe, L, Nozaki, M, Paiano, S, Palacio, S, Palatiello, J, Paneque, M, Paoletti, D, Paredes, R, Peñil, Peresano, P, Persic, M, Prada&nbsp, Moroni, M, P G, Prandini, Puljak, E, Rhode, I, Ribó, W, Rico, M, Righi, J, Rugliancich, C, Saha, A, Sahakyan, L, Saito, N, Sakurai, T, Satalecka, S, Schmidt, K, Schweizer, K, Sitarek, T, Šnidarić, J, Sobczynska, I, Somero, D, Stamerra, A, Strom, A, Strzys, D, Suda, M, Surić, Y, Takahashi, T, Tavecchio, M, Temnikov, F, Terzić, P, Teshima, T, Torres-Albà, M, Tosti, N, Tsujimoto, L, Vagelli, S, van&nbsp, Scherpenberg, V, Vanzo, J, Acosta, G, M Vazquez, Vigorito, C F, Vitale, Vovk, V, Will, I, Zarić, M, Asano, D, Collaborators: K, Hada, Harris, K, D E, Giroletti, Jermak, M, H E, Madrid, J P, Massaro, Richter, F, Spanier, S, Steele, F, I A, Walker, R, C, European Space Agency, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), National Aeronautics and Space Administration (US), Agencia Estatal de Investigación (España), European Commission, Acciari, V. A., Ansoldi, S., Antonelli, L. A., Arbet Engels, A., Arcaro, C., Baack, D., Babic, A., Banerjee, B., Bangale, P., Barres de Almeida, U., Barrio, J. A., Becerra Gonzalez, J., Bednarek, W., Bellizzi, L., Bernardini, E., Berti, A., Besenrieder, J., Bhattacharyya, W., Bigongiari, C., Biland, A., Blanch, O., Bonnoli, G., Bosnjak, Z., Busetto, G., Carosi, R., Ceribella, G., Chai, Y., Chilingaryan, A., Cikota, S., Colak, S. M., Colin, U., Colombo, E., Contreras, J. L., Cortina, J., Covino, S., D'Elia, V., da Vela, P., Dazzi, F., de Angelis, A., de Lotto, B., Delfino, M., Delgado, J., Depaoli, D., Di Pierro, F., Di Venere, L., Do Souto Espineira, E., Dominis Prester, D., Donini, A., Dorner, D., Doro, M., Elsaesser, D., Fallah Ramazani, V., Fattorini, A., Fernandez-Barral, A., Ferrara, G., Fidalgo, D., Foffano, L., Fonseca, M. V., Font, L., Fruck, C., Fukami, S., Garcia Lopez, R. J., Garczarczyk, M., Gasparyan, S., Gaug, M., Giglietto, N., Giordano, F., Godinovic, N., Green, D., Guberman, D., Hadasch, D., Hahn, A., Herrera, J., Hoang, J., Hrupec, D., Hutten, M., Inada, T., Inoue, S., Ishio, K., Iwamura, Y., Jouvin, L., Kerszberg, D., Kubo, H., Kushida, J., Lamastra, A., Lelas, D., Leone, F., Lindfors, E., Lombardi, S., Longo, F., Lopez, M., Lopez-Coto, R., Lopez-Oramas, A., Loporchio, S., Machado de Oliveira Fraga, B., Maggio, C., Majumdar, P., Makariev, M., Mallamaci, M., Maneva, G., Manganaro, M., Mannheim, K., Maraschi, L., Mariotti, M., Martinez, M., Masuda, S., Mazin, D., Micanovic, S., Miceli, D., Minev, M., Miranda, J. M., Mirzoyan, R., Molina, E., Moralejo, A., Morcuende, D., Moreno, V., Moretti, E., Munar-Adrover, P., Neustroev, V., Nigro, C., Nilsson, K., Ninci, D., Nishijima, K., Noda, K., Nogues, L., Nothe, M., Nozaki, S., Paiano, S., Palacio, J., Palatiello, M., Paneque, D., Paoletti, R., Paredes, J. M., Penil, P., Peresano, M., Persic, M., Prada Moroni, P. G., Prandini, E., Puljak, I., Rhode, W., Ribo, M., Rico, J., Righi, C., Rugliancich, A., Saha, L., Sahakyan, N., Saito, T., Sakurai, S., Satalecka, K., Schmidt, K., Schweizer, T., Sitarek, J., Snidaric, I., Sobczynska, D., Somero, A., Stamerra, A., Strom, D., Strzys, M., Suda, Y., Suric, T., Takahashi, M., Tavecchio, F., Temnikov, P., Terzic, T., Teshima, M., Torres-Alba, N., Tosti, L., Tsujimoto, S., Vagelli, V., van Scherpenberg, J., Vanzo, G., Vazquez Acosta, M., Vigorito, C. F., Vitale, V., Vovk, I., Will, M., Zaric, D., Asano, K., Hada, K., Harris, D. E., Giroletti, M., Jermak, H. E., Madrid, J. P., Massaro, F., Richter, S., Spanier, F., Steele, I. A., Walker, R. C., 30588766 - Arcaro, Cornelia, 25433822 - Richter, Stephan, and 25161814 - Spanier, Felix Alexander

Subjects
galaxies [Gamma rays], Photon, Radio galaxy, VHE [gamma ray], radiation mechanisms non-thermal, galaxies active, galaxies individual M 87, galaxies jets, gamma rays galaxies, magnetic field, Astrophysics, jet [Galaxies], 01 natural sciences, Power law, law.invention, galaxies: individual: M 87, law, flux [gamma ray], radiation mechanisms: non-thermal, galaxies: active, galaxies: jets, gamma rays: galaxies, Astrophysics - High Energy Astrophysical Phenomena, 010303 astronomy & astrophysics, QC, QB, High Energy Astrophysical Phenomena (astro-ph.HE), astro-ph.HE, Physics, galaxie [Gamma rays], photon, Synchrotron, Magnetic field, Wavelength, Galaxies: active, Galaxies: individual: M 87, Galaxies: jets, Gamma rays: galaxies, Radiation mechanisms: non-thermal, Spectral energy distribution, Astrophysics and Astronomy, active [Galaxies], Astrophysics::High Energy Astrophysical Phenomena, radio wave [galaxy], FOS: Physical sciences, Astrophysics::Cosmology and Extragalactic Astrophysics, GLAST, GeneralLiterature_MISCELLANEOUS, Telescope, emission [gamma ray], synchrotron, 0103 physical sciences, Astrophysics::Galaxy Astrophysics, non-thermal [Radiation mechanisms], hybrid, 010308 nuclear & particles physics, ComputingMilieux_PERSONALCOMPUTING, individual: M 87 [galaxies], Astronomy and Astrophysics, MAGIC, monitoring, Space and Planetary Science, ddc:520, spectral, jets [Galaxies], individual: M 87 [Galaxies], non-thermal [adiation mechanisms]
Abstract

MAGIC Collaboration: et al., M 87 is one of the closest (z = 0.004 36) extragalactic sources emitting at very high energies (VHE, E > 100 GeV). The aim of this work is to locate the region of the VHE gamma-ray emission and to describe the observed broad-band spectral energy distribution (SED) during the low VHE gamma-ray state. The data from M 87 collected between 2012 and 2015 as part of a MAGIC monitoring programme are analysed and combined with multiwavelength data from Fermi-LAT, Chandra, HST, EVN, VLBA, and the Liverpool Telescope. The averaged VHE gamma-ray spectrum can be fitted from ∼100 GeV to ∼10 TeV with a simple power law with a photon index of (−2.41 ± 0.07), while the integral flux above 300 GeV is (1.44±0.13)×10−12cm−2s−1⁠. During the campaign between 2012 and 2015, M 87 is generally found in a low-emission state at all observed wavelengths. The VHE gamma-ray flux from the present 2012–2015M 87 campaign is consistent with a constant flux with some hint of variability (⁠∼3σ⁠) on a daily time-scale in 2013. The low-state gamma-ray emission likely originates from the same region as the flare-state emission. Given the broad-band SED, both a leptonic synchrotron self-Compton and a hybrid photohadronic model reproduce the available data well, even if the latter is preferred. We note, however, that the energy stored in the magnetic field in the leptonic scenario is very low, suggesting a matter-dominated emission region., The financial support of the German BMBF and MPG, the Italian Istituto Nazionale di Fisica Nucleare (INFN) and Istituto Nazionale di Astrofisica (INAF), the Swiss National Fund (SNF), the ERDF under the Spanish Ministry of Economy and Competitiveness (MINECO) (FPA2015-69818-P, FPA2012-36668, FPA2015-68378-P, FPA2015-69210-C6-2-R, FPA2015-69210-C6-4-R, FPA2015-69210-C6-6-R, AYA2015-71042-P, AYA2016-76012-C3-1-P, ESP2015-71662-C2-2-P, FPA2017-90566-REDC), the Indian Department of Atomic Energy, the Japanese JSPS and MEXT, and the Bulgarian Ministry of Education and Science, National RI Roadmap Project DO1-153/28.08.2018, is gratefully acknowledged. This work was also supported by the Spanish Centro de Excelencia ‘Severo Ochoa’ SEV-2016-0588 and SEV2015-0548, and Unidad de Excelencia ‘Maria de Maeztu’ MDM2014-0369, by the Croatian Science Foundation (HrZZ) Project IP-2016-06-9782 and the University of Rijeka Project 13.12.1.3.02, by the DFG Collaborative Research Centers grants SFB823/C4 and SFB876/C3, by the Polish National Research Centre grant UMO2016/22/M/ST9/00382, and by the Brazilian MCTIC, CNPq, and FAPERJ. The Very Long Baseline Array is operated by the National Radio Astronomy Observatory, which is a facility of the National Science Foundation operated under cooperative agreement by Associated Universities, Inc. The work of FM is supported by the ‘Departments of Excellence 2018–2022’ Grant awarded by the Italian Ministry of Education, University and Research (MIUR) (L. 232/2016). His research has made also use of resources provided by the Compagnia di San Paolo for the grant awarded on the BLENV project (S1618 L1 MASF 01) and by the Ministry of Education, Universities and Research for the grant MASF FFABR 17 01. This investigation is supported by the National Aeronautics and Space Administration (NASA) grants GO4-15096X, AR6-17012X, and GO6-17081X. This work made use of the Swinburne University of Technology software correlator, developed as part of the Australian Major National Research Facilities Programme and operated under licence. Based in part on observations made with the NASA/European Space Agency (ESA) Hubble Space Telescope, obtained at the Space Telescope Science Institute, which is operated by the Association of Universities for Research in Astronomy, Inc., under NASA contract NAS5-26555. These observations are associated with programmes GO 12293, 12671, 13061, and 13759.

Published
2020

29. Correlative analyses of patient and clinical characteristics associated with efficacy in tisagenlecleucel-treated relapsed/refractory diffuse large B-cell lymphoma patients in the JULIET trial

Author

Westin, J., Tam, C. S., Borchmann, P., Jaeger, U., McGuirk, J. P., Holte, H., Waller, E. K., Jaglowski, S., Bishop, M. R., Andreadis, C., Foley, S. R., Fleury, I, Ho, P. J., Mielke, S., Teshima, T., Schuster, S. J., Bachanova, V, Maziarz, R. T., Besien, K., V, Izutsu, K., Kersten, M. J., Wagner-Johnston, N. D., Kato, K., Corradini, P., Han, X., Tiwari, R., Eldjerou, L. K., Pacaud, L. B., Salles, G. A., Westin, J., Tam, C. S., Borchmann, P., Jaeger, U., McGuirk, J. P., Holte, H., Waller, E. K., Jaglowski, S., Bishop, M. R., Andreadis, C., Foley, S. R., Fleury, I, Ho, P. J., Mielke, S., Teshima, T., Schuster, S. J., Bachanova, V, Maziarz, R. T., Besien, K., V, Izutsu, K., Kersten, M. J., Wagner-Johnston, N. D., Kato, K., Corradini, P., Han, X., Tiwari, R., Eldjerou, L. K., Pacaud, L. B., and Salles, G. A.

Published
2020

30. Correlation of Bridging Therapy (BT) and Lymphodepleting Chemotherapy (LDC) with clinical outcomes in patients (pts) with relapsed/refractory Diffuse Large B-cell Lymphoma (r/r DLBCL) treated with tisagenlecleucel

Author

Andreadis, C., Tam, C. S., Borchmann, P., Jaeger, U., McGuirk, J. P., Holte, H., Waller, E. K., Jaglowski, S., Bishop, M. R., Foley, S. R., Westin, J. R., Fleury, I, Ho, P. J., Mielke, S., Teshima, T., Salles, G. A., Schuster, S. J., Bachanova, V, Maziarz, R. T., Besien, K., V, Izutsu, K., Wagner-Johnston, N. D., Kato, K., Corradini, P., Tiwari, R., Awasthi, R., Lawniczek, T., Eldjerou, L. K., Kersten, M. J., Andreadis, C., Tam, C. S., Borchmann, P., Jaeger, U., McGuirk, J. P., Holte, H., Waller, E. K., Jaglowski, S., Bishop, M. R., Foley, S. R., Westin, J. R., Fleury, I, Ho, P. J., Mielke, S., Teshima, T., Salles, G. A., Schuster, S. J., Bachanova, V, Maziarz, R. T., Besien, K., V, Izutsu, K., Wagner-Johnston, N. D., Kato, K., Corradini, P., Tiwari, R., Awasthi, R., Lawniczek, T., Eldjerou, L. K., and Kersten, M. J.

Published
2020

31. Patient-reported long-term quality of life after tisagenlecleucel in relapsed/refractory diffuse large B-cell lymphoma

Author

Maziarz, RT, Waller, EK, Jaeger, U, Fleury, I, McGuirk, J, Holte, H, Jaglowski, S, Schuster, SJ, Bishop, MR, Westin, JR, Mielke, S, Teshima, T, Bachanova, V, Foley, SR, Borchmann, P, Salles, GA, Zhang, J, Tiwari, R, Pacaud, LB, Ma, Q, Tam, CS, Maziarz, RT, Waller, EK, Jaeger, U, Fleury, I, McGuirk, J, Holte, H, Jaglowski, S, Schuster, SJ, Bishop, MR, Westin, JR, Mielke, S, Teshima, T, Bachanova, V, Foley, SR, Borchmann, P, Salles, GA, Zhang, J, Tiwari, R, Pacaud, LB, Ma, Q, and Tam, CS

Abstract

The JULIET phase 2 trial evaluated a single infusion of tisagenlecleucel in adult patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL). The objective of the current analysis was to evaluate patient-reported health-related quality of life (HRQoL) with a median follow-up of 19.3 months among patients infused with a single dose of tisagenlecleucel. Patients enrolled were ≥18 years of age with r/r DLBCL after ≥2 lines of therapy and had either undergone a failed autologous stem cell transplant or were ineligible for the procedure. Two validated HRQoL instruments, Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) and Short Form-36 (SF-36) Health Survey, were used to measure HRQoL at baseline and months 3, 6, 12, and 18. At data cutoff (21 May 2018), 115 patients had received tisagenlecleucel infusion. Among the 99 patients evaluated, overall response rate was 54%, and 40% of patients achieved complete response (CR). Initially, 108 patients completed the HRQoL assessments at baseline, including 57 patients who eventually achieved CR or partial response (PR). Further, 30 and 21 patients in clinical response who completed assessments at baseline also completed assessments at months 12 and 18, respectively. Patients who achieved CR or PR sustained HRQoL improvement in all FACT scores at all time points. SF-36 instruments showed improvement above the minimal clinically important differences on 5 of 8 subscales. Long-term follow-up in the phase 2 JULIET study demonstrated that patients with r/r DLBCL who respond to tisagenlecleucel therapy had sustained, clinically meaningful improvements in HRQoL. This trial was registered at www.clinicaltrials.gov as #NCT02445248.

Published
2020

32. Activation of RHOA–VAV1 signaling in angioimmunoblastic T-cell lymphoma

Author

Fujisawa, M, Sakata-Yanagimoto, M, Nishizawa, S, Komori, D, Gershon, P, Kiryu, M, Tanzima, S, Fukumoto, K, Enami, T, Muratani, M, Yoshida, K, Ogawa, S, Matsue, K, Nakamura, N, Takeuchi, K, Izutsu, K, Fujimoto, K, Teshima, T, Miyoshi, H, Gaulard, P, and Ohshima, K

Abstract

Somatic G17V RHOA mutations were found in 50–70% of angioimmunoblastic T-cell lymphoma (AITL). The mutant RHOA lacks GTP binding capacity, suggesting defects in the classical RHOA signaling. Here, we discovered the novel function of the G17V RHOA: VAV1 was identified as a G17V RHOA-specific binding partner via high-throughput screening. We found that binding of G17V RHOA to VAV1 augmented its adaptor function through phosphorylation of 174Tyr, resulting in acceleration of T-cell receptor (TCR) signaling. Enrichment of cytokine and chemokine-related pathways was also evident by the expression of G17V RHOA. We further identified VAV1 mutations and a new translocation, VAV1–STAP2, in seven of the 85 RHOA mutation-negative samples (8.2%), whereas none of the 41 RHOA mutation-positive samples exhibited VAV1 mutations. Augmentation of 174Tyr phosphorylation was also demonstrated in VAV1–STAP2. Dasatinib, a multikinase inhibitor, efficiently blocked the accelerated VAV1 phosphorylation and the associating TCR signaling by both G17V RHOA and VAV1–STAP2 expression. Phospho-VAV1 staining was demonstrated in the clinical specimens harboring G17V RHOA and VAV1 mutations at a higher frequency than those without. Our findings indicate that the G17V RHOA–VAV1 axis may provide a new therapeutic target in AITL.

Published
2017

33. Pembrolizumab plus lenalidomide and dexamethasone for patients with treatment-naive multiple myeloma (KEYNOTE-185): a randomised, open-label, phase 3 trial.

Author

Usmani S.Z., Oriol A., Karlin L., Cavo M., Rifkin R.M., Hayek F., Kirschner E., Bharany N., Overton L., Mannem S., Harroff A., Jain S., Roque T., McIntyre K., Yasencha C.K., Houck W., Schjesvold F., Yimer H.A., LeBlanc R., Takezako N., McCroskey R.D., Lim A.B.M., Suzuki K., Kosugi H., Grigoriadis G., Avivi I., Facon T., Jagannath S., Lonial S., Ghori R.U., Farooqui M.Z.H., Marinello P., San-Miguel J., Lim A., Walker T., Nicol A., Reece D., Elemary M., Boudreault Pedneault J.S., Attal M., Weisel K., Engelhardt M., Mackensen A., Quinn J., Cohen A., Magen-Nativ H., Benyamini N., Larocca A., Matsumoto M., Iida S., Ishikawa T., Kondo Y., Sunami K., Ando K., Teshima T., Chou T., Iwasaki H., Miki H., Matsumura I., Onishi Y., Izutsu K., Kizaki M., George A., Blacklock H., Simpson D., Waage A., Samoilova O., Nikitin E., Chagorova T., McDonald A., Patel M., Oriol Rocafiguera A., San Miguel Izquierdo J., Mateos M., Streetly M., Forsyth P., Jackson G., Jenkins S., Rifkin R., Yimer H., McCroskey R., Martincic D., Tarantolo S., Larson S., Faroun Y., Vaughn J., Baz R., Saylors G., Neppalli A., Raptis A., Fung H., Janosky M., Stevens D., Coleman M., Costa D., Cross S., Fanning S., Berges D.F., Harris T., Zackon I., Atanackovic D., Lee K., Oliff I., Lee W., Bensinger W., Lutzky J., Baron A., Usmani S.Z., Oriol A., Karlin L., Cavo M., Rifkin R.M., Hayek F., Kirschner E., Bharany N., Overton L., Mannem S., Harroff A., Jain S., Roque T., McIntyre K., Yasencha C.K., Houck W., Schjesvold F., Yimer H.A., LeBlanc R., Takezako N., McCroskey R.D., Lim A.B.M., Suzuki K., Kosugi H., Grigoriadis G., Avivi I., Facon T., Jagannath S., Lonial S., Ghori R.U., Farooqui M.Z.H., Marinello P., San-Miguel J., Lim A., Walker T., Nicol A., Reece D., Elemary M., Boudreault Pedneault J.S., Attal M., Weisel K., Engelhardt M., Mackensen A., Quinn J., Cohen A., Magen-Nativ H., Benyamini N., Larocca A., Matsumoto M., Iida S., Ishikawa T., Kondo Y., Sunami K., Ando K., Teshima T., Chou T., Iwasaki H., Miki H., Matsumura I., Onishi Y., Izutsu K., Kizaki M., George A., Blacklock H., Simpson D., Waage A., Samoilova O., Nikitin E., Chagorova T., McDonald A., Patel M., Oriol Rocafiguera A., San Miguel Izquierdo J., Mateos M., Streetly M., Forsyth P., Jackson G., Jenkins S., Rifkin R., Yimer H., McCroskey R., Martincic D., Tarantolo S., Larson S., Faroun Y., Vaughn J., Baz R., Saylors G., Neppalli A., Raptis A., Fung H., Janosky M., Stevens D., Coleman M., Costa D., Cross S., Fanning S., Berges D.F., Harris T., Zackon I., Atanackovic D., Lee K., Oliff I., Lee W., Bensinger W., Lutzky J., and Baron A.

Abstract

Background: Lenalidomide and dexamethasone has been a standard of care in transplant-ineligible patients with newly diagnosed multiple myeloma. The addition of a third drug to the combination is likely to improve treatment efficacy. KEYNOTE-185 assessed the efficacy and safety of lenalidomide and dexamethasone with and without pembrolizumab in patients with previously untreated multiple myeloma. Here, we present the results of an unplanned interim analysis done to assess the benefit-risk of the combination at the request of the US Food and Drug Administration (FDA). Method(s): KEYNOTE-185 was a randomised, open-label, phase 3 trial done at 95 medical centres across 15 countries (Australia, Canada, France, Germany, Ireland, Israel, Italy, Japan, New Zealand, Norway, Russia, South Africa, Spain, UK, and USA). Transplantation-ineligible patients aged 18 years and older with newly diagnosed multiple myeloma, Eastern Cooperative Oncology Group performance status of 0 or 1, and who were treatment naive were enrolled, and randomly assigned 1:1 to receive either pembrolizumab plus lenalidomide and dexamethasone or lenalidomide and dexamethasone alone using an interactive voice or integrated web response system. Patients received oral lenalidomide 25 mg on days 1-21 and oral dexamethasone 40 mg on days 1, 8, 15, and 22 of repeated 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The primary endpoint was progression-free survival, which was investigator-assessed because of early trial termination. Efficacy was analysed in all randomly assigned patients and safety was analysed in all patients who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT02579863, and it is closed for accrual. Finding(s): Between Jan 7, 2016, and June 9, 2017, 301 patients were randomly assigned to the pembrolizumab plus lenalidomide and dexamethasone group (n=151) or the lenalidomide and dexamethasone group (n=150). On Jul

Published
2019

34. Lactose drives Enterococcus expansion to promote graft-versus-host disease

Author

Stein-Thoeringer, C. K., Nichols, K. B., Lazrak, A., Docampo, M. D., Slingerland, A. E., Slingerland, J. B., Clurman, A. G., Armijo, G., Gomes, A. L. C., Shono, Y., Staffas, A., da Silva, M. Burgos, Devlin, S. M., Markey, K. A., Bajic, D., Pinedo, R., Tsakmaklis, A., Littmann, E. R., Pastore, A., Taur, Y., Monette, S., Arcila, M. E., Pickard, A. J., Maloy, M., Wright, R. J., Amoretti, L. A., Fontana, E., Pham, D., Jamal, M. A., Weber, D., Sung, A. D., Hashimoto, D., Scheid, C., Xavier, J. B., Messina, J. A., Romero, K., Lew, M., Bush, A., Bohannon, L., Hayasaka, K., Hasegawa, Y., Vehreschild, M. J. G. T., Cross, J. R., Ponce, D. M., Perales, M. A., Giralt, S. A., Jenq, R. R., Teshima, T., Holler, E., Chao, N. J., Pamer, E. G., Peled, J. U., van den Brink, M. R. M., Stein-Thoeringer, C. K., Nichols, K. B., Lazrak, A., Docampo, M. D., Slingerland, A. E., Slingerland, J. B., Clurman, A. G., Armijo, G., Gomes, A. L. C., Shono, Y., Staffas, A., da Silva, M. Burgos, Devlin, S. M., Markey, K. A., Bajic, D., Pinedo, R., Tsakmaklis, A., Littmann, E. R., Pastore, A., Taur, Y., Monette, S., Arcila, M. E., Pickard, A. J., Maloy, M., Wright, R. J., Amoretti, L. A., Fontana, E., Pham, D., Jamal, M. A., Weber, D., Sung, A. D., Hashimoto, D., Scheid, C., Xavier, J. B., Messina, J. A., Romero, K., Lew, M., Bush, A., Bohannon, L., Hayasaka, K., Hasegawa, Y., Vehreschild, M. J. G. T., Cross, J. R., Ponce, D. M., Perales, M. A., Giralt, S. A., Jenq, R. R., Teshima, T., Holler, E., Chao, N. J., Pamer, E. G., Peled, J. U., and van den Brink, M. R. M.

Abstract

Disruption of intestinal microbial communities appears to underlie many human illnesses, but the mechanisms that promote this dysbiosis and its adverse consequences are poorly understood. In patients who received allogeneic hematopoietic cell transplantation (allo-HCT), we describe a high incidence of enterococcal expansion, which was associated with graft-versus-host disease (GVHD) and mortality. We found that Enterococcus also expands in the mouse gastrointestinal tract after allo-HCT and exacerbates disease severity in gnotobiotic models. Enterococcus growth is dependent on the disaccharide lactose, and dietary lactose depletion attenuates Enterococcus outgrowth and reduces the severity of GVHD in mice. Allo-HCT patients carrying lactose-nonabsorber genotypes showed compromised clearance of postantibiotic Enterococcus domination. We report lactose as a common nutrient that drives expansion of a commensal bacterium that exacerbates an intestinal and systemic inflammatory disease.

Published
2019

38. Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells

Author

Mathew, N.R., Baumgartner, F., Braun, L., O'Sullivan, D., Thomas, S., Waterhouse, M., Muller, T.A., Hanke, K., Taromi, S., Apostolova, P., Illert, A.L., Melchinger, W., Duquesne, S., Schmitt-Graeff, A., Osswald, L., Yan, K.L., Weber, A, Tugues, S., Spath, S., Pfeifer, D., Follo, M., Claus, R., Lubbert, M., Rummelt, C., Bertz, H., Wasch, R., Haag, J., Schmidts, A., Schultheiss, M., Bettinger, D., Thimme, R., Ullrich, E., Tanriver, Y., Vuong, G.L., Arnold, R., Hemmati, P., Wolf, D., Ditschkowski, M., Jilg, C., Wilhelm, K., Leiber, C., Gerull, S., Halter, J., Lengerke, C., Pabst, T., Schroeder, T., Kobbe, G., Rosler, W., Doostkam, S., Meckel, S., Stabla, K., Metzelder, S.K., Halbach, S., Brummer, T., Hu, Z, Dengjel, J., Hackanson, B., Schmid, C., Holtick, U., Scheid, C., Spyridonidis, A., Stolzel, F., Ordemann, R., Muller, L.P., Sicre-de-Fontbrune, F., Ihorst, G., Kuball, J., Ehlert, J.E., Feger, D., Wagner, E.M., Cahn, J.Y., Schnell, J., Kuchenbauer, F., Bunjes, D., Chakraverty, R., Richardson, S., Gill, S., Kroger, N., Ayuk, F., Vago, L., Ciceri, F., Muller, A.M., Kondo, T., Teshima, T., Klaeger, S., Kuster, B., Kim, D.D.H., Weisdorf, D., Velden, W.J. van der, Dorfel, D., Bethge, W., Hilgendorf, I., Hochhaus, A., Andrieux, G., Borries, M., Busch, H., Magenau, J., Reddy, P., Labopin, M., Antin, J.H., et al., Mathew, N.R., Baumgartner, F., Braun, L., O'Sullivan, D., Thomas, S., Waterhouse, M., Muller, T.A., Hanke, K., Taromi, S., Apostolova, P., Illert, A.L., Melchinger, W., Duquesne, S., Schmitt-Graeff, A., Osswald, L., Yan, K.L., Weber, A, Tugues, S., Spath, S., Pfeifer, D., Follo, M., Claus, R., Lubbert, M., Rummelt, C., Bertz, H., Wasch, R., Haag, J., Schmidts, A., Schultheiss, M., Bettinger, D., Thimme, R., Ullrich, E., Tanriver, Y., Vuong, G.L., Arnold, R., Hemmati, P., Wolf, D., Ditschkowski, M., Jilg, C., Wilhelm, K., Leiber, C., Gerull, S., Halter, J., Lengerke, C., Pabst, T., Schroeder, T., Kobbe, G., Rosler, W., Doostkam, S., Meckel, S., Stabla, K., Metzelder, S.K., Halbach, S., Brummer, T., Hu, Z, Dengjel, J., Hackanson, B., Schmid, C., Holtick, U., Scheid, C., Spyridonidis, A., Stolzel, F., Ordemann, R., Muller, L.P., Sicre-de-Fontbrune, F., Ihorst, G., Kuball, J., Ehlert, J.E., Feger, D., Wagner, E.M., Cahn, J.Y., Schnell, J., Kuchenbauer, F., Bunjes, D., Chakraverty, R., Richardson, S., Gill, S., Kroger, N., Ayuk, F., Vago, L., Ciceri, F., Muller, A.M., Kondo, T., Teshima, T., Klaeger, S., Kuster, B., Kim, D.D.H., Weisdorf, D., Velden, W.J. van der, Dorfel, D., Bethge, W., Hilgendorf, I., Hochhaus, A., Andrieux, G., Borries, M., Busch, H., Magenau, J., Reddy, P., Labopin, M., and Antin, J.H., et al.

Abstract

Contains fulltext : 190745.pdf (publisher's version ) (Closed access), Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD(+) leukemia cells. This synergized with the allogeneic CD8(+) T cell response, leading to long-term survival in six mouse models of FLT3-ITD(+) AML. Sorafenib-related IL-15 production caused an increase in CD8(+)CD107a(+)IFN-gamma(+) T cells with features of longevity (high levels of Bcl-2 and reduced PD-1 levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced expression of the transcription factor ATF4, thereby blocking negative regulation of interferon regulatory factor 7 (IRF7) activation, which enhanced IL-15 transcription. Both IRF7 knockdown and ATF4 overexpression in leukemia cells antagonized sorafenib-induced IL-15 production in vitro. Human FLT3-ITD(+) AML cells obtained from sorafenib responders following sorafenib therapy showed increased levels of IL-15, phosphorylated IRF7, and a transcriptionally active IRF7 chromatin state. The mitochondrial spare respiratory capacity and glycolytic capacity of CD8(+) T cells increased upon sorafenib treatment in sorafenib responders but not in nonresponders. Our findings indicate that the synergism of T cells and sorafenib is mediated via reduced ATF4 expression, causing activation of the IRF7-IL-15 axis in leukemia cells and thereby leading to metabolic reprogramming of leukemia-reactive T cells in humans. Therefore, sorafenib treatment has the potential to contribute to an immune-mediated cure of FLT3-ITD-mutant AML relapse, an otherwise fatal complication after allo-HCT.

Published
2018

39. The Microbiome and Hematopoietic Cell Transplantation: Past, Present, and Future

Author

Andermann, T. M., Peled, J. U., Ho, C., Reddy, P., Riches, M., Storb, R., Teshima, T., van den Brink, M. R. M., Alousi, A., Balderman, S., Chiusolo, Patrizia, Clark, W. B., Holler, E., Howard, A., Kean, L. S., Koh, A. Y., Mccarthy, P. L., Mccarty, J. M., Mohty, M., Nakamura, R., Rezvani, K., Segal, B. H., Shaw, B. E., Shpall, E. J., Sung, A. D., Weber, D., Whangbo, J., Wingard, J. R., Wood, W. A., Perales, M. -A., Jenq, R. R., Bhatt, A. S., Chiusolo P. (ORCID:0000-0002-1355-1587), Andermann, T. M., Peled, J. U., Ho, C., Reddy, P., Riches, M., Storb, R., Teshima, T., van den Brink, M. R. M., Alousi, A., Balderman, S., Chiusolo, Patrizia, Clark, W. B., Holler, E., Howard, A., Kean, L. S., Koh, A. Y., Mccarthy, P. L., Mccarty, J. M., Mohty, M., Nakamura, R., Rezvani, K., Segal, B. H., Shaw, B. E., Shpall, E. J., Sung, A. D., Weber, D., Whangbo, J., Wingard, J. R., Wood, W. A., Perales, M. -A., Jenq, R. R., Bhatt, A. S., and Chiusolo P. (ORCID:0000-0002-1355-1587)

Abstract

N/A

Published
2018

40. HCV in Lymphoid Neoplasms

Author

Teshima T, Ryo Kikuchi, Yamamoto Y, Matsuoka S, Tsutsumi Y, Naruse H, and Shinichi Ito

Subjects
business.industry, Open access publishing, Hepatitis C virus, medicine, Library science, Rituximab, Lymphoid neoplasms, business, medicine.disease_cause, medicine.disease, Virology, medicine.drug, Non-Hodgkin's lymphoma
Published
2016

41. GvHD after umbilical cord blood transplantation for acute leukemia : an analysis of risk factors and effect on outcomes

Author

Chen, Y-B, Wang, T., Hemmer, M. T., Brady, C., Couriel, D. R., Alousi, A., Pidala, J., Urbano-Ispizua, A., Choi, S. W., Nishihori, T., Teshima, T., Inamoto, Y., Wirk, B., Marks, D. I., Abdel-Azim, H., Lehmann, L., Yu, L., Bitan, M., Cairo, M. S., Qayed, M., Salit, R., Gale, R. P., Martino, R., Jaglowski, S., Bajel, A., Savani, B., Frangoul, H., Lewis, I. D., Storek, J., Askar, M., Kharfan-Dabaja, M. A., Aljurf, M., Ringden, O., Reshef, R., Olsson, R. F., Hashmi, S., Seo, S., Spitzer, T. R., MacMillan, M. L., Lazaryan, A., Spellman, S. R., Arora, M., Cutler, C. S., Chen, Y-B, Wang, T., Hemmer, M. T., Brady, C., Couriel, D. R., Alousi, A., Pidala, J., Urbano-Ispizua, A., Choi, S. W., Nishihori, T., Teshima, T., Inamoto, Y., Wirk, B., Marks, D. I., Abdel-Azim, H., Lehmann, L., Yu, L., Bitan, M., Cairo, M. S., Qayed, M., Salit, R., Gale, R. P., Martino, R., Jaglowski, S., Bajel, A., Savani, B., Frangoul, H., Lewis, I. D., Storek, J., Askar, M., Kharfan-Dabaja, M. A., Aljurf, M., Ringden, O., Reshef, R., Olsson, R. F., Hashmi, S., Seo, S., Spitzer, T. R., MacMillan, M. L., Lazaryan, A., Spellman, S. R., Arora, M., and Cutler, C. S.

Abstract

Using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, we analyzed 1404 umbilical cord blood transplantation (UCBT) patients (single (>= 18 years) = 810, double (< 18 years) = 594) with acute leukemia to define the incidence of acute GvHD (aGvHD) and chronic GvHD (cGvHD), analyze clinical risk factors and investigate outcomes. After single UCBT, 100-day incidence of grade II-IV aGvHD was 39% (95% confidence interval (CI), 36-43%), grade III-IV aGvHD was 18% (95% CI, 15-20%) and 1-year cGvHD was 27% (95% CI, 24-30%). After double UCBT, 100-day incidence of grade II-IV aGvHD was 45% (95% CI, 41-49%), grade III-IV aGvHD was 22% (95% CI, 19-26%) and 1-year cGvHD was 26% (95% CI, 22-29%). For single UCBT, multivariate analysis showed that absence of antithymocyte globulin (ATG) was associated with aGvHD, whereas prior aGvHD was associated with cGvHD. For double UCBT, absence of ATG and myeloablative conditioning were associated with aGvHD, whereas prior aGvHD predicted for cGvHD. Grade III-IV aGvHD led to worse survival, whereas cGvHD had no significant effect on disease-free or overall survival. GvHD is prevalent after UCBT with severe aGvHD leading to higher mortality. Future research in UCBT should prioritize prevention of GvHD.

Published
2017
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43. Granulocyte Colony-Stimulating Factor–Mobilized Allogeneic Stem Cell Transplantation Maintains Graft-Versus-Leukemia Effects Through a Perforin-Dependent Pathway While Preventing Graft-Versus-Host Disease

Author

Pan, Lp, Teshima, T., Geoffrey Hill, Bungard, D., Brinson, Ys, Reddy, Vs, Cooke, Kr, and Ferrara, Lm

Subjects
surgical procedures, operative, Immunology, Cell Biology, Hematology, Biochemistry
Abstract

Minimization of graft-versus-host disease (GVHD) with preservation of the graft-versus-leukemia (GVL) effect is a crucial step to improve the overall survival of allogeneic bone marrow transplantation (BMT) for patients with hematological malignancies. We and other investigators have shown that granulocyte colony-stimulating factor (G-CSF)–mobilized allogeneic peripheral stem cell transplantation (PBSCT) reduces the severity of acute GVHD in murine models. In this study, we investigated whether G-CSF–mobilized PBSC maintain their GVL effect in a murine allogeneic transplant model (B6 → B6D2F1). B6 mice (H-2b) were injected subcutaneously with human G-CSF (100 μg/kg/d) for 6 days and their splenocytes were harvested on day 7 as a source of PBSC. G-CSF mobilization dramatically improved transplant survival compared with nonmobilized controls (95% v0%, P < .001). Systemic levels of lipopolysaccharide and tumor necrosis factor- were markedly reduced in recipients of allogeneic G-CSF–mobilized donors, but cytolytic T lymphocyte (CTL) activity against host tumor target cells p815 was retained in those recipients. When leukemia was induced in recipients by coinjection of p815 tumor cells (H-2d) at the time of transplantation, all surviving recipients of G-CSF–mobilized B6 donors were leukemia-free at day 70 after transplant, whereas all mice who received T-cell–depleted (TCD) splenocytes from G-CSF–mobilized B6 donors died of leukemia. When splenocytes from G-CSF–mobilized perforin-deficient (pfp−/−) mice were used for transplantation, 90% of recipients died of leukemia, demonstrating that perforin is a crucial pathway mediating GVL effects after G-CSF–mobilized PBSCT. These data illustrate that G-CSF–mobilized allogeneic PBSCT separate GVL from GVHD by preserving perforin-dependent donor CTL activity while reducing systemic inflammation.

Published
1999

45. CD4/CD8 Double-negative T-cell Lymphoma: A Variant of Primary Cutaneous CD8+ Aggressive Epidermotropic Cytotoxic T-cell Lymphoma?

Author

Miyauchi, T, primary, Abe, R, additional, Morita, Y, additional, Adachi, M, additional, Shiba, K, additional, Hamade, Y, additional, Saito, N, additional, Nishimura, M, additional, Ibata, M, additional, Okada, K, additional, Shigematsu, A, additional, Endo, T, additional, Kawai, K, additional, Teshima, T, additional, and Shimizu, H, additional

Published
2015
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46. Excellent Quality of Lives for Previously Treated Adult T-Cell Leukemia/Lymphoma Patients After Autologous Dendritic Cell Vaccine Therapy Targeting Htlv-1 Tax Antigens

Author

Suehiro, Y., primary, Iino, T., additional, Hasegawa, A., additional, Watanabe, N., additional, Matsuoka, M., additional, Tanosaki, R., additional, Utsunomiya, A., additional, Choi, I., additional, Shiratsuchi, M., additional, Teshima, T., additional, Akashi, K.A., additional, Kannagi, M., additional, Uike, N., additional, and Okamura, J., additional

Published
2014
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49. Activation of RHOA–VAV1 signaling in angioimmunoblastic T-cell lymphoma

Author

Fujisawa, M, Sakata-Yanagimoto, M, Nishizawa, S, Komori, D, Gershon, P, Kiryu, M, Tanzima, S, Fukumoto, K, Enami, T, Muratani, M, Yoshida, K, Ogawa, S, Matsue, K, Nakamura, N, Takeuchi, K, Izutsu, K, Fujimoto, K, Teshima, T, Miyoshi, H, Gaulard, P, Ohshima, K, and Chiba, S

Abstract

Somatic G17V RHOA mutations were found in 50–70% of angioimmunoblastic T-cell lymphoma (AITL). The mutant RHOA lacks GTP binding capacity, suggesting defects in the classical RHOA signaling. Here, we discovered the novel function of the G17V RHOA: VAV1 was identified as a G17V RHOA-specific binding partner via high-throughput screening. We found that binding of G17V RHOA to VAV1 augmented its adaptor function through phosphorylation of 174Tyr, resulting in acceleration of T-cell receptor (TCR) signaling. Enrichment of cytokine and chemokine-related pathways was also evident by the expression of G17V RHOA. We further identified VAV1 mutations and a new translocation, VAV1–STAP2, in seven of the 85 RHOA mutation-negative samples (8.2%), whereas none of the 41 RHOA mutation-positive samples exhibited VAV1 mutations. Augmentation of 174Tyr phosphorylation was also demonstrated in VAV1–STAP2. Dasatinib, a multikinase inhibitor, efficiently blocked the accelerated VAV1 phosphorylation and the associating TCR signaling by both G17V RHOA and VAV1–STAP2 expression. Phospho-VAV1 staining was demonstrated in the clinical specimens harboring G17V RHOA and VAV1 mutations at a higher frequency than those without. Our findings indicate that the G17V RHOA–VAV1 axis may provide a new therapeutic target in AITL.

Published
2018
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50. Initial experience with the quality assurance program of radiation therapy on behalf of Japan Radiation Oncology Group (JAROG)

Author

Isobe, K, Kagami, Y, Higuchi, K, Kodaira, T, Hasegawa, M, Shikama, N, Nakazawa, M, Fukuda, I, Nihei, K, Ito, K, Teshima, T, Oguchi, M, Isobe, K, Kagami, Y, Higuchi, K, Kodaira, T, Hasegawa, M, Shikama, N, Nakazawa, M, Fukuda, I, Nihei, K, Ito, K, Teshima, T, and Oguchi, M

Abstract

This is a pre-copy-editing, author-produced PDF of an article accepted for publication in [JAPANESE JOURNAL OF CLINICAL ONCOLOGY] following peer review. The definitive publisher-authenticated version [JAPANESE JOURNAL OF CLINICAL ONCOLOGY. 37(2): 135-139 (2007)] is available online at: http://jjco.oxfordjournals.org/cgi/content/abstract/37/2/135

Published
2007

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