Search

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

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

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

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.

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.

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.

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

Radiative decays ��\to����^0��and ��\to��^0��^0��are studied assuming that these decays are caused through the intermediate a_0(980)��and f_0(980)��states, respectively. Fitting the experimental data of the ����^0 and ��^0��^0 invariant mass spectrum in the decays ��\to����^0��and ��^0��^0��, it is shown that the processes ��\to a_0��and ��\to f_0��are dominated by the K^+K^- loop interaction rather than the contact ��a_0(f_0)��one both for the non-derivative and derivative SPP coupling. The experimental data of ��[��\to f_0��]/��[��\to a_0��] 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., 15 pages, 10 figures

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

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 _0 is rather small compared to the _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=_0 /_0 and an origin of CP violation is the phase of H_D^1., Comment: 16 pages

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

The purpose of this prospective study was to follow the changes in functional parameters of radionuclide lung perfusion scans and their role in prognostication of lung cancer cases after noninvasive therapy. We studied 91 patients of lung cancer treated with chemotherapy and/or radiotherapy during 1993 to 1997 in our hospital. Lung perfusion scans were acquired pre and post-therapy. An index of lung perfusion, called Improvement Ratio (IR) was defined as a change in the perfusion of diseased lung as a result of treatment. IR was calculated by the following equation under the assumption that perfusion of contralateral lung remained unaffected. [formula: see text] where Q and Q' are pulmonary arterial blood flow pre and post therapy respectively, p is perfusion ratio of diseased lung before therapy and q is that after therapy. We further studied the relationship between IR and change in tumor size. The influence of tumor location, histopathological diagnosis and prognosis of lung cancer were correlated with this newly defined index. IR in the group of patients with complete response or partial response was significantly higher than in those with poor response (2.72 +/- 0.78 versus 0.99 +/- 0.09, p0.05). There was no statistical difference between the group with and without radiotherapy. The score was significantly higher for patients with hilar disease compared to those with peripheral lesions (2.80 +/- 0.83 versus 1.02 +/- 0.03, p0.05). Similarly, patients with small cell lung cancer depicted higher values of IR than non-small cell lung cancer (3.36 +/- 1.10 versus 1.06 +/- 0.07, p0.05). All those subjects who showed IR1 had longer survival time than those with IR1 (p0.05). It is suggested that improvement in the perfusion of diseased lung predicted better prognosis. We conclude that the evaluation of physiological parameters during therapy using lung perfusion scanning, in addition to lesion size assessment will contribute to the comprehensive follow-up of lung cancer.

The conceptual design and fabrication test of a full-scale ceramic overpack were performed from the viewpoint of structural barriers as a part of program to evaluate their potential use as overpack under conditions of deep geological disposal. Materials investigated were porcelain (used for insulators) and Al$_{2}$O$_{3}$ with high purity of 99.7\%. The selected design consisted of a cylindrical body with hemispherical heads at each end. The design thickness of overpack is the sum of the structural thickness and corrosion allowance. The thickness required to resist the lithostatic pressure was estimated by the basic cylinder buckling formulas and finite element stress analyses in both case of uniform and non-unifom external pressure conditions. These analyses showed that structural thickness of 119 mm was necessary for overpack of porcelain and 40 mm for Al$_{2}$0$_{3}$ under the predicted maximum uniform pressure. In addition, fracture probability of delayed failure, one of significant degradation mode, was estimated for overpack of porcelain. A full-scale overpack of porcelain, of dimensions 800 mm outer diameter $\times$ 2200 mm length $\times$ 150mm wall thickness, was fabricated under the ordinary level of fabrication technology., 本研究は,炭素鋼等のオーバーパック材料の代替候補としてより長期の閉じ込め性が期待できるセラミック製オーバーパックの開発を目的とするものであり,その成果は次の通りである。(1) 処分条件として地下1,000mの花崗岩体中を想定し,材料は構造材料への適用実績を考慮して磁器およびAl2O3の2種類を対象として設計した。(2) 形状は,円筒状の胴部と半球状の底/蓋部の構成とした。設計肉厚は,強度上の肉厚と腐食代の合計であり,解析の結果,強度上の必要肉厚は磁器: 119mm, Al2O3:40mmとなった。腐食代に関する予備試験等の結果を考慮し,設計肉厚は磁器: 150mm, Al2O3:50mmに設定した。(3) 製作技術の比較的確立した磁器材料により実寸大オーバーパック(800mmO.D.$\times$2200mmH$\times$150mmt)を試作し今後の開発課題を摘出した。(4) 外圧が不均一荷重の場合は,磁器材料では製作限界を超えるため,材料としてAl2O3等のファインセラミックスが必要となることがわかった。(5) 長期寿命評価上重要な劣化モードである遅れ破壊に関して評価を実施した。本論文はMaterial Ressarch Society第13回国際シンポジウム(1989年11月,ボストン)での発表をまとめたものである。

4, KJ00004202063

4, KJ00004202051, 論説, Treatise

9, KJ00004202029

8, KJ00004202013

腐食モデルによる長期にわたる腐食量予測は、オーバーパックの寿命評価上重要課題の1つである。このため、我国の処分環境に対応した腐食モデルを開発する上で参考とすべく、海外の腐食モデルの開発状況を調査した。調査はオーバーパック関連文献(約160件)から腐食モデルを扱っているものを抽出し、対象とする処分環境、基本的な考え方等を整理した。その結果、腐食モデルには経験式によるモデルと数学的モデルがあり、経験式によるモデルでは、温度、地下水組成等の処分環境と時間をパラメータとして腐食量を予測する形式が主体であることがわかった。数学的モデルは、経験式の長時間の外挿により生ずる不確実性を排除するため、腐食メカニズムに基づき開発されているものであるが、現状ではその基本的な考え方が提案され一部試験結果との比較が実施されている段階である。また、調査結果を基にケーススタディとして経験式によるモデルを用いた1,000年間の腐食量予測及び内部の試験結果との比較を行った。今後も、既存モデルの調査を継続するとともに、その長所・問題点を明確にし腐食モデルの開発に反映していく予定である。, None

Allogeneic bone marrow transplantation (BMT) is currently restricted to hematological malignancies because of a lack of antitumor activity against solid cancers. We have tested a novel treatment strategy to stimulate specific antitumor activity against a solid tumor after BMT by vaccination with irradiated tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF). Using the B16 melanoma model, we found that vaccination elicited potent antitumor activity in recipients of syngeneic BMT in a time-dependent fashion, and that immune reconstitution was critical for the development of antitumor activity. Vaccination did not stimulate antitumor immunity after allogeneic BMT because of the post-BMT immunodeficiency associated with graft-versus-host disease (GVHD). Remarkably, vaccination was effective in stimulating potent and long-lasting antitumor activity in recipients of T-cell-depleted (TCD) allogeneic bone marrow. Recipients of TCD bone marrow who showed significant immune reconstitution by 6 weeks after BMT developed B16-specific T-cell-cytotoxic, proliferative, and cytokine responses as a function of vaccination. T cells derived from donor stem cells were, therefore, able to recognize tumor antigens, although they remained tolerant to host histocompatibility antigens. These results demonstrate that GM-CSF-based tumor cell vaccines after allogeneic TCD BMT can stimulate potent antitumor effects without the induction of GVHD, and this strategy has important implications for the treatment of patients with solid malignancies.

The major obstacles to successful outcome after allogeneic bone marrow transplantation (BMT) for leukemia remain graft-versus-host disease (GVHD) and leukemic relapse. Improved survival after BMT therefore requires more effective GVHD prophylaxis that does not impair graft-versus-leukemia (GVL) effects. We studied the administration of human recombinant keratinocyte growth factor (KGF) in a well- characterized murine BMT model for its effects on GVHD. KGF administration from day -3 to +7 significantly reduced GVHD mortality and the severity of GVHD in the gastrointestinal (GI) tract, reducing serum lipopolysaccharide (LPS) and tumor necrosis factor (TNF) levels, but preserving donor T-cell responses (cytotoxic T lymphocyte [CTL] activity, proliferation, and interleukin [IL]-2 production) to host antigens. When mice received lethal doses of P815 leukemia cells at the time of BMT, KGF treatment significantly decreased acute GVHD compared with control-treated allogeneic mice and resulted in a significantly improved leukemia-free survival (42%v 4%, P < .001). KGF administration thus offers a novel approach to the separation of GVL effects from GVHD.

Transplantation of hematopoietic cells from a healthy individual (allogeneic hematopoietic cell transplantation (allo-HCT)) demonstrates that adoptive immunotherapy can cure blood cancers: still, post-transplantation relapses remain frequent. To explain their drivers, we analyzed the genomic and gene expression profiles of acute myeloid leukemia (AML) blasts purified from patients at serial time-points during their disease history. We identified a transcriptional signature specific for post-transplantation relapses and highly enriched in immune-related processes, including T cell costimulation and antigen presentation. In two independent patient cohorts we confirmed the deregulation of multiple costimulatory ligands on AML blasts at post-transplantation relapse (PD-L1, B7-H3, CD80, PVRL2), mirrored by concomitant changes in circulating donor T cells. Likewise, we documented the frequent loss of surface expression of HLA-DR, -DQ and -DP on leukemia cells, due to downregulation of the HLA class II regulator CIITA. We show that loss of HLA class II expression and upregulation of inhibitory checkpoint molecules represent alternative modalities to abolish AML recognition from donor-derived T cells, and can be counteracted by interferon-gamma or checkpoint blockade, respectively. Our results demonstrate that the deregulation of pathways involved in T cell-mediated allorecognition is a distinctive feature and driver of AML relapses after allo-HCT, which can be rapidly translated into personalized therapies.

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 (TSCM) 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-TSCM 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., Allogeneic hematopoietic cell transplantation is the standard treatment of acute myeloid leukemia, but many patients relapse. Here the authors show increased markers of exhaustion and cancer antigen specificity within bone marrow-residing memory T cells precede and potentially predict the relapse.

Tisagenlecleucel is an autologous anti-CD19 chimeric antigen receptor-T cell therapy with clinically meaningful outcomes demonstrated in patients with relapsed/refractory (r/r) B-cell lymphoma. In a previous pilot study of tisagenlecleucel in r/r follicular lymphoma (FL), 71% of patients achieved a complete response (CR). Here we report the primary, prespecified interim analysis of the ELARA phase 2 multinational trial of tisagenlecleucel in adults with r/r FL after two or more treatment lines or who relapsed after autologous stem cell transplant (no. NCT03568461). The primary endpoint was CR rate (CRR). Secondary endpoints included overall response rate (ORR), duration of response, progression-free survival, overall survival, pharmacokinetics and safety. As of 29 March 2021, 97/98 enrolled patients received tisagenlecleucel (median follow-up, 16.59 months; interquartile range, 13.8–20.21). The primary endpoint was met. In the efficacy set (n = 94), CRR was 69.1% (95% confidence interval, 58.8–78.3) and ORR 86.2% (95% confidence interval, 77.5–92.4). Within 8 weeks of infusion, rates of cytokine release syndrome were 48.5% (grade ≥3, 0%), neurological events 37.1% (grade ≥3, 3%) and immune effector cell-associated neurotoxicity syndrome (ICANS) 4.1% (grade ≥3, 1%) in the safety set (n = 97), with no treatment-related deaths. Tisagenlecleucel is safe and effective in extensively pretreated r/r FL, including in high-risk patients., The study was sponsored and designed by Novartis Pharmaceuticals Corporation and was approved by the IRB at each participating institution.

Summary 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). Methods 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. Findings 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 July 3, 2017, the FDA decided to halt the study because of the imbalance in the proportion of death between groups. At database cutoff (June 2, 2017), with a median follow-up of 6·6 months (IQR 3·4–9·6), 149 patients in the pembrolizumab plus lenalidomide and dexamethasone group and 145 in the lenalidomide and dexamethasone group had received their assigned study drug. Median progression-free survival was not reached in either group; progression-free survival estimates at 6-months were 82·0% (95% CI 73·2–88·1) versus 85·0% (76·8–90·5; hazard ratio [HR] 1·22; 95% CI 0·67–2·22; p=0·75). Serious adverse events were reported in 81 (54%) patients in the pembrolizumab plus lenalidomide and dexamethasone group versus 57 (39%) patients in the lenalidomide and dexamethasone group; the most common serious adverse events were pneumonia (nine [6%]) and pyrexia (seven [5%]) in the pembrolizumab plus lenalidomide and dexamethasone group and pneumonia (eight [6%]) and sepsis (two [1%]) in the lenalidomide and dexamethasone group. Six (4%) treatment-related deaths occurred in the pembrolizumab plus lenalidomide and dexamethasone group (cardiac arrest, cardiac failure, myocarditis, large intestine perforation, pneumonia, and pulmonary embolism) and two (1%) in the lenalidomide and dexamethasone group (upper gastrointestinal haemorrhage and respiratory failure). Interpretation The results from this unplanned, FDA-requested, interim analysis showed that the benefit–risk profile of pembrolizumab plus lenalidomide and dexamethasone is unfavourable for patients with newly diagnosed, previously untreated multiple myeloma. Long-term safety and survival follow-up is ongoing. Funding Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc (Kenilworth, NJ, USA).