Publications by authors named "Ryuji Suzuki"

127 Publications

Pharmacological MEK inhibition promotes polyclonal T-cell reconstitution and suppresses xenogeneic GVHD.

Cell Immunol 2021 Sep 13;367:104410. Epub 2021 Jul 13.

Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan.

Rapid immune reconstitution without developing graft-versus-host disease (GVHD) is required for the success of allogeneic hematopoietic stem cell transplantation. Here, we analyzed the effects of pharmacological MEK inhibition on human polyclonal T-cell reconstitution in a humanized mouse GVHD model utilizing deep sequencing-based T-cell receptor (TCR) repertoire analysis. GVHD mice exhibited a skewed TCR repertoire with a common clone within target organs. The MEK inhibitor trametinib ameliorated GVHD and enabled engraftment of diverse T-cell clones. Furthermore, trametinib also ameliorated GVHD sparing diverse T cell repertoire, even when it was given from day 15 through 28. Although tacrolimus also reduced development of GVHD, it disturbed diverse T cell reconstitution and resulted in skewed TCR repertoire. Thus, trametinib not only suppresses GVHD-inducing T cells but also promotes human T cell reconstitution in vivo, providing a novel rationale for translational studies targeting human GVHD.
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http://dx.doi.org/10.1016/j.cellimm.2021.104410DOI Listing
September 2021

Skewing of the B cell receptor repertoire in myalgic encephalomyelitis/chronic fatigue syndrome.

Brain Behav Immun 2021 07 29;95:245-255. Epub 2021 Mar 29.

Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan; Multiple Sclerosis Center, National Center Hospital, NCNP, Tokyo, Japan. Electronic address:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition characterized by fatigue and post-exertional malaise, accompanied by various signs of neurological and autonomic dysfunction. ME/CFS is often triggered by an infectious episode and associated with an aberrant immune system. Here we report that ME/CFS is a disorder characterized by skewed B cell receptor gene usage. By applying a next-generation sequencing to determine the clone-based IGHV/IGHD/IGHJ repertoires, we revealed a biased usage of several IGHV genes in peripheral blood B cells from ME/CFS patients. Results of receiver operating characteristic (ROC) analysis further indicated a possibility of distinguishing patients from healthy controls, based on the skewed B cell repertoire. Meanwhile, B cell clones using IGHV3-30 and IGHV3-30-3 genes were more frequent in patients with an obvious infection-related episode at onset, and correlated to expression levels of interferon response genes in plasmablasts. Collectively, these results imply that B cell responses in ME/CFS are directed against an infectious agents or priming antigens induced before disease onset.
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http://dx.doi.org/10.1016/j.bbi.2021.03.023DOI Listing
July 2021

Clonal Expansion of Tumor-Infiltrating T Cells and Analysis of the Tumor Microenvironment within Esophageal Squamous Cell Carcinoma Relapsed after Definitive Chemoradiation Therapy.

Int J Mol Sci 2021 01 22;22(3). Epub 2021 Jan 22.

Department of Rheumatology and Clinical Immunology, Clinical Research Center for Rheumatology and Allergy, National Hospital Organization Sagamihara National Hospital, 18-1 Sakuradai, Minami-ku, Sagamihara 252-0385, Japan.

(1) Background: Comparable prognoses after definitive chemoradiation therapy (CRT) to surgery alone for esophageal squamous cell carcinoma (ESCC) have been previously reported; however, no robust prognostic markers have been established. The clonality of tumor-infiltrating lymphocytes (TILs) and tumor microenvironments (TMEs) in ESCC relapsed after CRT were examined to explore prognostic markers. (2) Methods: Clonality of TIL and TME were examined in ESCC with and without preceding CRT, as well as oral squamous cell carcinoma (OSCC) and healthy volunteers as controls. The clonality of TIL was assessed by T-cell receptor (TCR) α and β repertoire analyses and evaluated by diversity indices. The TME was assessed by quantitative polymerase chain reaction evaluating and . (3) Results: The clonal expansion of TIL was significantly induced within ESCCs and OSCCs, when compared to healthy volunteers, and was mostly induced within ESCCs after definitive CRT. Diversity indices of TIL were not associated with the prognosis, but the ratio of mRNA to mRNA in TME was significantly associated with a poor prognosis after salvage surgery ( = 0.007). (4) Conclusions: The clonal expansion of TIL is induced after definitive CRT for ESCC, and the ratio of mRNA to mRNA within tumor tissues is a prognostic marker candidate for salvage esophagectomy after CRT.
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http://dx.doi.org/10.3390/ijms22031098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865796PMC
January 2021

T-cell receptor repertoire of cytomegalovirus-specific cytotoxic T-cells after allogeneic stem cell transplantation.

Sci Rep 2020 12 17;10(1):22218. Epub 2020 Dec 17.

Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo, 113-8677, Japan.

Cytomegalovirus (CMV) infection is a major complication during allogeneic stem cell transplantation (allo-SCT). However, mechanisms of adaptive immunity that drive this remain unclear. To define early immunological responses to CMV after transplantation, we using next-generation sequencing to examine the repertoire of T-cell receptors in CD8/CMV pp65 tetramer cells (CMV-CTLs) in peripheral blood samples obtained from 16 allo-SCT recipients with HLA-A*24:02 at the time of CMV reactivation. In most patients, TCR beta repertoire of CMV-CTLs was highly skewed (median Inverse Simpson's index: 1.595) and, 15 of 16 patients shared at least one TCR-beta clonotype with ≥ 2 patients. The shared TCRs were dominant in 12 patients and, two clonotypes were shared by about half of the patients. Similarity analysis showed that CDR3 sequences of shared TCRs were more similar than unshared TCRs. TCR beta repertoires of CMV-CTLs in 12 patients were also analyzed after 2-4 weeks to characterize the short-term dynamics of TCR repertoires. In ten patients, we observed persistence of prevailing clones. In the other two patients, TCR repertoires became more diverse, major clones declined, and new private clones subsequently emerged. These results provided the substantive clue to understand the immunological behavior against CMV reactivation after allo-SCT.
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http://dx.doi.org/10.1038/s41598-020-79363-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747720PMC
December 2020

Adoptive transfer of zoledronate-expanded autologous Vγ9Vδ2 T-cells in patients with treatment-refractory non-small-cell lung cancer: a multicenter, open-label, single-arm, phase 2 study.

J Immunother Cancer 2020 09;8(2)

Department of Thoracic Surgery, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan

Background: Not all non-small cell lung cancer (NSCLC) patients possess drug-targetable driver mutations, and response rates to immune checkpoint blockade therapies also remain unsatisfactory. Therefore, more effective treatments are still needed. Here, we report the results of a phase 2 clinical trial of adoptive cell therapy using zoledronate-expanded autologous Vγ9Vδ2 T-cells for treatment-refractory NSCLC.

Methods: NSCLC patients who had undergone at least two regimens of standard chemotherapy for unresectable disease or had had at least one treatment including chemotherapy or radiation for recurrent disease after surgery were enrolled in this open-label, single-arm, multicenter, phase 2 study. After preliminary testing of Vγ9Vδ2 T-cell proliferation, autologous peripheral blood mononuclear cells were cultured with zoledronate and IL-2 to expand the Vγ9Vδ2 T-cells. Cultured cells (>1×10) were intravenously administered every 2 weeks for six injections. The primary endpoint of this study was progression-free survival (PFS), and secondary endpoints included overall survival (OS), best objective response rate (ORR), disease control rate (DCR), safety and immunomonitoring. Clinical efficacy was defined as median PFS significantly >4 months.

Results: Twenty-five patients (20 adenocarcinoma, 4 squamous cell carcinoma and 1 large cell carcinoma) were enrolled. Autologous Vγ9Vδ2 T-cell therapy was administered to all 25 patients, of which 16 completed the foreseen course of 6 injections of cultured cells. Median PFS was 95.0 days (95% CI 73.0 to 132.0 days); median OS was 418.0 days (179.0-479.0 days), and best overall responses were 1 partial response, 16 stable disease (SD) and 8 progressive disease. ORR and DCR were 4.0% (0.1%-20.4%) and 68.0% (46.5%-85.1%), respectively. Severe adverse events developed in nine patients, mostly associated with disease progression. In one patient, pneumonitis and inflammatory responses resulted from Vγ9Vδ2 T-cell infusions, together with the disappearance of a massive tumor.

Conclusions: Although autologous Vγ9Vδ2 T-cell therapy was well tolerated and may have an acceptable DCR, this trial did not meet its primary efficacy endpoint.

Trial Registration Number: UMIN000006128.
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http://dx.doi.org/10.1136/jitc-2020-001185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511646PMC
September 2020

Circulation of gut-preactivated naïve CD8 T cells enhances antitumor immunity in B cell-defective mice.

Proc Natl Acad Sci U S A 2020 09 9;117(38):23674-23683. Epub 2020 Sep 9.

Department of Immunology and Genomic Medicine, Kyoto University Graduate School of Medicine, 606-8501 Kyoto, Japan;

The gut microbiome has garnered attention as an effective target to boost immunity and improve cancer immunotherapy. We found that B cell-defective (BCD) mice, such as µ-membrane targeted deletion (µMT) and activation-induced cytidine deaminase (AID) knockouts (KOs), have elevated antitumor immunity under specific pathogen-free but not germ-free conditions. Microbial dysbiosis in these BCD mice enriched the type I IFN (IFN) signature in mucosal CD8 T cells, resulting in up-regulation of the type I IFN-inducible protein stem cell antigen-1 (Sca-1). Among CD8 T cells, naïve cells predominantly circulate from the gut to the periphery, and those that had migrated from the mesenteric lymph nodes (mLNs) to the periphery had significantly higher expression of Sca-1. The gut-educated Sca-1 naïve subset is endowed with enhanced mitochondrial activity and antitumor effector potential. The heterogeneity and functional versatility of the systemic naïve CD8 T cell compartment was revealed by single-cell analysis and functional assays of CD8 T cell subpopulations. These results indicate one of the potential mechanisms through which microbial dysbiosis regulates antitumor immunity.
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http://dx.doi.org/10.1073/pnas.2010981117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519229PMC
September 2020

Experience as an Informal Caregiver and Discussions Regarding Advance Care Planning in Japan.

J Pain Symptom Manage 2021 01 17;61(1):63-70. Epub 2020 Jul 17.

Department of Healthcare Epidemiology, School of Public Health in the Graduate School of Medicine, Kyoto University, Kyoto, Japan; Institute for Health Outcomes and Process Evaluation Research (iHope International), Kyoto, Japan. Electronic address:

Context: Advance care planning (ACP) is vital for end-of-life care management. Experiences as informal family caregivers might act as a catalyst to promote ACP.

Objectives: We investigated the association between ACP discussions and caregiving experiences.

Methods: A nationwide survey in Japan was conducted in December 2016 using a quota sampling method to select a sample representative of the general Japanese population. The responses of 3167 individuals aged 20-84 years (mean age: 50.9 ± 16.8) were analyzed. The outcome was measured by asking if respondents had ever engaged in ACP discussions. The exposure was measured by asking whether and for how long respondents had experience as informal caregivers for family members. We analyzed informal caregiving experience related to the occurrence of ACP discussions using multivariable logistic regression models that adjusted for possible covariates.

Results: Respondents with informal caregiving experience had significantly higher odds of having ACP discussions than those without caregiving experience (adjusted odds ratio: 1.93, 95% CI = 1.63, 2.29). Stronger effects were identified in younger adults (aged 20-65 years) and those with a higher education level (education duration > 12 years) than in older adults (aged ≥65 years) and those with a lower education level, respectively.

Conclusion: Experiences as informal caregivers for family members may facilitate ACP discussions among Japanese adults, especially younger adults with higher educational attainment. Our findings may help health-care providers screen those at risk for inadequate ACP discussions, and informal caregiving experience should be considered when health-care providers initiate discussions of end-of-life care.
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http://dx.doi.org/10.1016/j.jpainsymman.2020.07.010DOI Listing
January 2021

Cross-Reactivity of Palladium in a Murine Model of Metal-Induced Allergic Contact Dermatitis.

Int J Mol Sci 2020 Jun 5;21(11). Epub 2020 Jun 5.

Department of Clinical Immunology, Clinical Research Center for Rheumatology and Allergy, Sagamihara National Hospital, National Hospital Organization, 18-1 Sakuradai, Minami-ku, Sagamihara, Kanagawa 252-0392, Japan.

Metal allergy is usually diagnosed by patch testing, however, the results do not necessarily reflect the clinical symptoms because of cross-reactivity between different metals. In this study, we established the novel mouse model of cross-reactive metal allergy, and aimed to elucidate the immune response in terms of T-cell receptor repertoire. This model was classified into two groups: the sensitization to nickel and challenge with palladium group, and the sensitization to chromium and challenge with palladium group. This model developed spongiotic edema with intra- and peri-epithelial infiltration of CD4 T cells in the inflamed skin that resembles human contact dermatitis. Using T cell receptor analysis, we detected a high proportion of T cells bearing and in the Ni- and Cr-sensitized Pd-challenged mice. Furthermore, mucosal-associated invariant T cells and invariant natural killer T cells were also detected. Our results indicated that T cells bearing and induced the development of palladium-cross reactive allergy, and that mucosal-associated invariant T and invariant natural killer T cells were also involved in the cross-reactivity between different metals.
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http://dx.doi.org/10.3390/ijms21114061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313072PMC
June 2020

Antiferromagnet-Semiconductor Van Der Waals Heterostructures: Interlayer Interplay of Exciton with Magnetic Ordering.

Nano Lett 2020 Jun 22;20(6):4625-4630. Epub 2020 May 22.

Quantum-Phase Electronics Center (QPEC), The University of Tokyo, Tokyo 113-8656, Japan.

Van der Waals (vdW) heterostructures have attracted great interest because of their rich material combinations. The discovery of two-dimensional magnets has provided a new platform for magnetic vdW heterointerfaces; however, research on magnetic vdW heterointerfaces has been limited to those with ferromagnetic surfaces. Here, we report a magnetic vdW heterointerface using layered intralayer-antiferromagnetic PSe ( = Mn, Fe) and monolayer transition-metal dichalcogenides (TMDs). We found an anomalous upshift of the excitonic peak in monolayer TMDs below the antiferromagnetic transition temperature in the PSe, capturing a signature of the interlayer exciton-magnon coupling. This is a concept extended from single materials to heterointerfaces. Moreover, this coupling strongly depends on the in-plane magnetic structure and stacking direction, showing its sensitivity to their magnetic interfaces. Our finding offers an opportunity to investigate interactions between elementary excitations in different materials across interfaces and to search for new functions of magnetic vdW heterointerfaces.
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http://dx.doi.org/10.1021/acs.nanolett.0c01493DOI Listing
June 2020

High-throughput sequencing of IgG B-cell receptors reveals frequent usage of the rearranged IGHV4-28/IGHJ4 gene in primary immune thrombocytopenia.

Sci Rep 2019 06 14;9(1):8645. Epub 2019 Jun 14.

Repertoire Genesis Incorporation, Ibaraki, Japan.

Primary immune thrombocytopenia (ITP) is an acquired form of thrombocytopenia caused by IgG anti-platelet autoantibodies and represents an organ-specific autoimmune disorder. Although the glycoprotein (GP)IIb/IIIa and GPIb/IX have been shown to be targets for autoantibodies, the antigen specificity of autoantibodies is not fully elucidated. To identify the characteristics of IgG B-cell receptor (BCR) repertoires in ITP, we took advantage of adaptor-ligation PCR and high-throughput DNA sequencing methods for analyzing the clone-based repertoires of IgG-expressing peripheral blood B cells. A total of 2,009,943 in-frame and 315,469 unique reads for IGH (immunoglobulin heavy) were obtained from twenty blood samples. Comparison of the IGHV repertoires between patients and controls revealed an increased usage of IGHV4-28 in ITP patients. One hundred eighty-six distinct IGHV4-28-carrying sequences were identified in ITP patients and the majority of these clones used an IGHJ4 segment. The IGHV4-28/IGHJ4-carrying B-cell clones were found in all ITP patients. Oligoclonal expansions of IGHV4-28/IGHJ4-carrying B cells were accompanied by multiple related clones with single amino substitution in the CDR3 region suggesting somatic hypermutation. Taken together, the expansion of IGHV4-28/IGHJ4-carrying IgG-expressing B cells in ITP may be the result of certain antigenic pressure and may provide a clue for the immune pathophysiology of ITP.
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http://dx.doi.org/10.1038/s41598-019-45264-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6570656PMC
June 2019

Characterization of T cell receptors in a novel murine model of nickel-induced intraoral metal contact allergy.

PLoS One 2018 17;13(12):e0209248. Epub 2018 Dec 17.

Department of Clinical Immunology, Clinical Research Center for Rheumatology and Allergy, Sagamihara National Hospital, National Hospital Organization, Sagamihara, Japan.

Nickel is a component of several alloy types that are widely used in our environment, including several dental alloy types that cause intraoral metal contact allergy. However, metal-specific immune responses in the oral mucosa have not been elucidated because a suitable animal model has not been established. In this study, we established a novel murine model of nickel-induced intraoral metal contact allergy and aimed to elucidate the immune response in terms of T-cell receptor repertoire and cytokine profiles in inflamed oral mucosa. The intraoral metal contact allergy model was induced by two sensitizations of nickel plus lipopolysaccharide solution into the postauricular skin followed by a single nickel challenge of the buccal mucosa. Cytokine expression profiles and T-cell phenotypes were determined by quantitative polymerase chain reaction. T cells accumulated in the cervical lymph nodes and inflamed oral mucosa were characterized by analyzing their T-cell receptor α- and β-chain repertoires, and the nucleotide sequences of complementary determining region 3. Significant swelling and pathological features were histologically evident at 1 day after challenge in mice with nickel allergy. At 1 day after the challenge, CD8-positive T cells producing high levels of T helper 1 type cytokines had accumulated in the allergic oral mucosa. At 7 days after the challenge, excessive nickel allergy in the oral mucosa was suppressed by regulatory T cells. Characterization of the T-cell receptor repertoire in nickel allergic mice revealed the presence of natural killer T cells and T cells bearing Trav6-6-Traj57 at 1 day after the challenge. Our murine model of nickel-induced intraoral metal contact allergy showed that natural killer T cells and T cells bearing Trav6-6-Traj57 might be involved in the immune responses of nickel-induced intraoral metal contact allergy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0209248PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296741PMC
May 2019

Epstein-Barr virus-related diffuse large B-cell lymphoma in mogamulizumab-treated adult T-cell leukemia with incomplete T-cell reconstitution.

Int J Hematol 2019 Feb 27;109(2):221-227. Epub 2018 Oct 27.

Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan.

Adult T-cell leukemia (ATL) is an aggressive mature T-cell malignancy with a poor prognosis. The anti-C-C motif chemokine receptor 4 (CCR4) antibody mogamulizumab (moga) reduces ATL cells and induces reconstitution of polyclonal T cells; however, ATL cases often remain resistant and moga sometimes causes fatal immunopathology. Epstein-Barr virus (EBV)-related B-cell lymphoma develops in severely immunocompromised subjects, and is particularly associated with impaired T-cell immunity. Here, we report an ATL patient who had received conventional chemotherapy plus moga, and subsequently developed EBV-related diffuse large B-cell lymphoma (DLBCL) of the central nervous system. Next-generation sequencing-based T-cell receptor repertoire analyses identified residual abnormal clones and revealed that reconstitution of polyclonal T cells was incomplete, even after moga treatment. Furthermore, a skin rash that developed after moga treatment was found to contain ATL clones. This case suggests that the limited therapeutic effects of moga and incomplete T-cell reconstitution are associated with severely impaired T-cell immunity and subsequent development of EBV-related DLBCL.
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http://dx.doi.org/10.1007/s12185-018-2552-xDOI Listing
February 2019

Electric-field Control of Electronic States in WS2 Nanodevices by Electrolyte Gating.

J Vis Exp 2018 04 12(134). Epub 2018 Apr 12.

Quantum-Phase Electronics Center (QPEC) and Department of Applied Physics, The University of Tokyo; RIKEN Center for Emergent Matter Science (CEMS).

A method of carrier number control by electrolyte gating is demonstrated. We have obtained WS2 thin flakes with atomically flat surface via scotch tape method or individual WS2 nanotubes by dispersing the suspension of WS2 nanotubes. The selected samples have been fabricated into devices by the use of the electron beam lithography and electrolyte is put on the devices. We have characterized the electronic properties of the devices under applying the gate voltage. In the small gate voltage region, ions in the electrolyte are accumulated on the surface of the samples which leads to the large electric potential drop and resultant electrostatic carrier doping at the interface. Ambipolar transfer curve has been observed in this electrostatic doping region. When the gate voltage is further increased, we met another drastic increase of source-drain current which implies that ions are intercalated into layers of WS2 and electrochemical carrier doping is realized. In such electrochemical doping region, superconductivity has been observed. The focused technique provides a powerful strategy for achieving the electric-filed-induced quantum phase transition.
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http://dx.doi.org/10.3791/56862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933487PMC
April 2018

Next-Generation Immune Repertoire Sequencing as a Clue to Elucidate the Landscape of Immune Modulation by Host-Gut Microbiome Interactions.

Front Immunol 2018 3;9:668. Epub 2018 Apr 3.

Repertoire Genesis Incorporation, Ibaraki, Japan.

The human immune system is a fine network consisted of the innumerable numbers of functional cells that balance the immunity and tolerance against various endogenous and environmental challenges. Although advances in modern immunology have revealed a role of many unique immune cell subsets, technologies that enable us to capture the whole landscape of immune responses against specific antigens have been not available to date. Acquired immunity against various microorganisms including host microbiome is principally founded on T cell and B cell populations, each of which expresses antigen-specific receptors that define a unique clonotype. Over the past several years, high-throughput next-generation sequencing has been developed as a powerful tool to profile T- and B-cell receptor repertoires in a given individual at the single-cell level. Sophisticated immuno-bioinformatic analyses by use of this innovative methodology have been already implemented in clinical development of antibody engineering, vaccine design, and cellular immunotherapy. In this article, we aim to discuss the possible application of high-throughput immune receptor sequencing in the field of nutritional and intestinal immunology. Although there are still unsolved caveats, this emerging technology combined with single-cell transcriptomics/proteomics provides a critical tool to unveil the previously unrecognized principle of host-microbiome immune homeostasis. Accumulation of such knowledge will lead to the development of effective ways for personalized immune modulation through deeper understanding of the mechanisms by which the intestinal environment affects our immune ecosystem.
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http://dx.doi.org/10.3389/fimmu.2018.00668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891584PMC
June 2019

Quantitative T-cell repertoire analysis of peripheral blood mononuclear cells from lung cancer patients following long-term cancer peptide vaccination.

Cancer Immunol Immunother 2018 06 22;67(6):949-964. Epub 2018 Mar 22.

Department of Chest Surgery, School of Medicine, Fukushima Medical University, Fukushima, 960-1295, Japan.

Therapeutic cancer peptide vaccination is an immunotherapy designed to elicit cytotoxic T-lymphocyte (CTL) responses in patients. A number of therapeutic vaccination trials have been performed, nevertheless there are only a few reports that have analyzed the T-cell receptors (TCRs) expressed on tumor antigen-specific CTLs. Here, we use next-generation sequencing (NGS) to analyze TCRs of vaccine-induced CTL clones and the TCR repertoire of bulk T cells in peripheral blood mononuclear cells (PBMCs) from two lung cancer patients over the course of long-term vaccine therapy. In both patients, vaccination with two epitope peptides derived from cancer/testis antigens (upregulated lung cancer 10 (URLC10) and cell division associated 1 (CDCA1)) induced specific CTLs expressing various TCRs. All URLC10-specific CTL clones tested showed Ca influx, IFN-γ production, and cytotoxicity when co-cultured with URLC10-pulsed tumor cells. Moreover, in CTL clones that were not stained with the URLC10/MHC-multimer, the CD3 ζ chain was not phosphorylated. NGS of the TCR repertoire of bulk PBMCs demonstrated that the frequency of vaccine peptide-specific CTL clones was near the minimum detectable threshold level. These results demonstrate that vaccination induces antigen-specific CTLs expressing various TCRs at different time points in cancer patients, and that some CTL clones are maintained in PBMCs during long-term treatment, including some with TCRs that do not bind peptide/MHC-multimer.
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http://dx.doi.org/10.1007/s00262-018-2152-xDOI Listing
June 2018

Comparative immunity of antigen recognition, differentiation, and other functional molecules: similarities and differences among common marmosets, humans, and mice.

Exp Anim 2018 Jul 8;67(3):301-312. Epub 2018 Mar 8.

Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.

The common marmoset (CM; Callithrix jacchus) is a small New World monkey with a high rate of pregnancy and is maintained in closed colonies as an experimental animal species. Although CMs are used for immunological research, such as studies of autoimmune disease and infectious disease, their immunological characteristics are less defined than those of other nonhuman primates. We and others have analyzed antigen recognition-related molecules, the development of hematopoietic stem cells (HSCs), and the molecules involved in the immune response. CMs systemically express Caja-G, a major histocompatibility complex class I molecule, and the ortholog of HLA-G, a suppressive nonclassical HLA class I molecule. HSCs express CD117, while CD34 is not essential for multipotency. CD117+ cells developed into all hematopoietic cell lineages, but compared with human HSCs, B cells did not extensively develop when HSCs were transplanted into an immunodeficient mouse. Although autoimmune models have been successfully established, sensitization of CMs with some bacteria induced a low protective immunity. In CMs, B cells were observed in the periphery, but IgG levels were very low compared with those in humans and mice. This evidence suggests that CM immunity is partially suppressed systemically. Such immune regulation might benefit pregnancy in CMs, which normally deliver dizygotic twins, the placentae of which are fused and the immune cells of which are mixed. In this review, we describe the CM immune system and discuss the possibility of using CMs as a model of human immunity.
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http://dx.doi.org/10.1538/expanim.17-0150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6083031PMC
July 2018

Deep sequencing of the T cell receptor visualizes reconstitution of T cell immunity in mogamulizumab-treated adult T cell leukemia.

Oncoimmunology 2018;7(3):e1405204. Epub 2017 Dec 11.

Department of Hematology, Respiratory Medicine and Oncology, Saga University School of Medicine, Saga, Japan.

Although the anti-CCR4 antibody mogamulizumab (moga) shows striking antitumor activity against adult T cell leukemia (ATL), it can also cause fatal immunological pathology such as severe skin rash and graft-versus-host disease, which might be attributed to depletion of CCR4 regulatory T cells. We previously showed that next generation sequencing enables precise analysis of the T cell receptor (TCR) repertoire, and we here used the technique to reveal the immunological dynamics in moga-treated ATL patients. Treatment with moga resulted in remarkable reduction or elimination of clonal cells, and enhanced reconstitution of non-tumor polyclonal CD4 T cells and oligoclonal CD8 T cells. Interestingly, cutaneous T cells infiltrating moga-related skin rashes did not share the same major clones in peripheral blood, which minimizes the possibility of cross-reaction. Thus, deep sequencing of the TCR can reveal the immune reconstitution of moga-treated ATL and provides powerful insights into its mode of action.
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http://dx.doi.org/10.1080/2162402X.2017.1405204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5790365PMC
December 2017

Increased diversity with reduced "diversity evenness" of tumor infiltrating T-cells for the successful cancer immunotherapy.

Sci Rep 2018 01 18;8(1):1058. Epub 2018 Jan 18.

Department of Immunotherapeutics, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan.

To facilitate the optimization of cancer immunotherapy lacking immune-related adverse events, we performed TCR repertoire analysis of tumor-infiltrating CD8 T-cells in B16 melanoma-bearing mice receiving anti-PD-1, anti-CTLA-4, anti-4-1BB, anti-CD4 or a combination of anti-PD-1 and 4-1BB antibodies. Although CD8 T-cells in the tumor were activated and expanded to a greater or lesser extent by these therapies, tumor growth suppression was achieved only by anti-PD-1, anti-PD-1/4-1BB combined, or by anti-CD4 treatment, but not by anti-CTLA-4 or anti-4-1BB monotherapy. Increased CD8 T cell effector function and TCR diversity with enrichment of certain TCR clonotypes in the tumor was associated with anti-tumor effects. In contrast, polyclonal activation of T-cells in the periphery was associated with tissue damage. Thus, optimal combination therapy increases TCR diversity with extended activation of selective CD8 T-cells specifically in the tumor but not in the periphery. Incorporation of the concept of evenness for the TCR diversity is proposed.
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http://dx.doi.org/10.1038/s41598-018-19548-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773695PMC
January 2018

Potential Profile of Stabilized Field-Induced Lateral p-n Junction in Transition-Metal Dichalcogenides.

ACS Nano 2017 12 29;11(12):12583-12590. Epub 2017 Nov 29.

Department of Applied Physics and Quantum-Phase Electronics Center (QPEC), The University of Tokyo , Tokyo 113-8656, Japan.

Electric field-induced p-n junctions are often used to realize peculiar functionalities in various materials. This method can be applied not only to conventional semiconductors but also to carbon nanotubes, graphene, and organic semiconductors to which the conventional chemical doping method is difficult to apply. Transition-metal dichalcogenides (TMDs) are one of such materials where the field-induced p-n junctions play crucial roles in realizing solar cell and light-emitting diode operations as well as circularly polarized electroluminescence. Although the field-induced p-n junction is a well-established technique, many of its physical properties are left to be understood because their doping mechanism is distinct from that of conventional p-n junctions. Here we report a direct electrical measurement of the potential variation along the field-induced p-n junction using multiple pairs of voltage probes. We detected the position of the junction, estimated the built-in potential, and monitored the effect of the bias voltage. We found that the built-in potential becomes negative under a forward bias voltage range where field-induced TMD p-n junctions have been operated as light-emitting diodes. This feature well reproduced the circularly polarized electroluminescence from the WSe p-n junction, indicating that the present observation provides a useful background for understanding and functionalizing field-induced p-n junctions.
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http://dx.doi.org/10.1021/acsnano.7b06752DOI Listing
December 2017

Marmosets (Callithrix jacchus) as a non-human primate model for evaluation of candidate dengue vaccines: induction and maintenance of specific protective immunity against challenges with clinical isolates.

J Gen Virol 2017 12 21;98(12):2955-2967. Epub 2017 Nov 21.

National Institute of Infectious Diseases, Tokyo, Japan.

Dengue virus (DENV) is one of the major infectious diseases in tropical regions and approximately half of the world population is at risk of infection. Vaccines would offer an effective control measure against this disease. We previously reported on the utility of marmosets as an animal model for studying primary and secondary dengue infections. Infected marmosets consistently develop viraemia and antibody kinetics that reflect those of patients with dengue. Thus, it is important to determine the utility of marmosets as an animal model for demonstrating vaccine efficacy. In this study, marmosets were inoculated with candidate vaccine and parent strains and challenged with a clinical DENV strain. The viraemia and antibody kinetics in these marmosets were determined. Marmosets consistently develop lower viraemia with an attenuated vaccine strain. During secondary challenge, the IgM response was delayed, whereas the IgG levels rose rapidly, indicating a secondary antibody response. The neutralizing activities against the homotypic serotype were high; all marmosets were protected against viraemia following secondary inoculation. The viraemia markers and antibody responses were consistent with those of human DENV infection and vaccinees. These results demonstrate the utility of marmosets as an animal model for the study of vaccine efficacy.
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http://dx.doi.org/10.1099/jgv.0.000913DOI Listing
December 2017

Combination immunotherapy with TLR agonists and checkpoint inhibitors suppresses head and neck cancer.

JCI Insight 2017 09 21;2(18). Epub 2017 Sep 21.

Moores Cancer Center, UCSD, La Jolla, California, USA.

Checkpoint inhibitors have demonstrated efficacy in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). However, the majority of patients do not benefit from these agents. To improve the efficacy of checkpoint inhibitors, intratumoral (i.t.) injection with innate immune activators, TLR7 and TLR9 agonists, were tested along with programmed death-1 receptor (PD-1) blockade. The combination therapy suppressed tumor growth at the primary injected and distant sites in human papillomavirus-negative (HPV-negative) SCC7 and MOC1, and HPV-positive MEER syngeneic mouse models. Abscopal effects and suppression of secondary challenged tumor suggest that local treatment with TLR agonists in combination with anti-PD-1 provided systemic adaptive immunity. I.t. treatment with a TLR7 agonist increased the ratio of M1 to M2 tumor-associated macrophages (TAMs) and promoted the infiltration of tumor-specific IFNγ-producing CD8+ T cells. Anti-PD-1 treatment increased T cell receptor (TCR) clonality of CD8+ T cells in tumors and spleens of treated mice. Collectively, these experiments demonstrate that combination therapy with i.t. delivery of TLR agonists and PD-1 blockade activates TAMs and induces tumor-specific adaptive immune responses, leading to suppression of primary tumor growth and prevention of metastasis in HNSCC models.
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http://dx.doi.org/10.1172/jci.insight.93397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5621908PMC
September 2017

Fexofenadine Suppresses Delayed-Type Hypersensitivity in the Murine Model of Palladium Allergy.

Int J Mol Sci 2017 Jun 25;18(7). Epub 2017 Jun 25.

Department of Rheumatology and Clinical Immunology, Clinical Research Center for Rheumatology and Allergy, Sagamihara National Hospital, National Hospital Organization, 18-1 Sakuradai, Minami-ku, Sagamihara 252-0392, Japan.

Palladium is frequently used in dental materials, and sometimes causes metal allergy. It has been suggested that the immune response by palladium-specific T cells may be responsible for the pathogenesis of delayed-type hypersensitivity in study of palladium allergic model mice. In the clinical setting, glucocorticoids and antihistamine drugs are commonly used for treatment of contact dermatitis. However, the precise mechanism of immune suppression in palladium allergy remains unknown. We investigated inhibition of the immune response in palladium allergic mice by administration of prednisolone as a glucocorticoid and fexofenadine hydrochloride as an antihistamine. Compared with glucocorticoids, fexofenadine hydrochloride significantly suppressed the number of T cells by interfering with the development of antigen-presenting cells from the sensitization phase. Our results suggest that antihistamine has a beneficial effect on the treatment of palladium allergy compared to glucocorticoids.
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http://dx.doi.org/10.3390/ijms18071357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5535850PMC
June 2017

Quantifying van der Waals Interactions in Layered Transition Metal Dichalcogenides from Pressure-Enhanced Valence Band Splitting.

Nano Lett 2017 08 3;17(8):4982-4988. Epub 2017 Jul 3.

Department of Materials Science and Engineering, University of California , Berkeley, California 94720, United States.

van der Waals (vdW) forces, despite being relatively weak, hold the layers together in transition metal dichalcogenides (TMDs) and play a key role in their band structure evolution, hence profoundly affecting their physical properties. In this work, we experimentally probe the vdW interactions in MoS and other TMDs by measuring the valence band maximum (VBM) splitting (Δ) at K point as a function of pressure in a diamond anvil cell. As high pressure increases interlayer wave function coupling, the VBM splitting is enhanced in 2H-stacked MoS multilayers but, due to its specific geometry, not in 3R-stacked multilayers, hence allowing the interlayer contribution to be separated out of the total VBM splitting, as well as predicting a negative pressure (2.4 GPa) where the interlayer contribution vanishes. This negative pressure represents the threshold vdW interaction beyond which neighboring layers are electronically decoupled. This approach is compared to first-principles calculations and found to be widely applicable to other group-VI TMDs.
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http://dx.doi.org/10.1021/acs.nanolett.7b02159DOI Listing
August 2017

Highly functional T-cell receptor repertoires are abundant in stem memory T cells and highly shared among individuals.

Sci Rep 2017 06 16;7(1):3663. Epub 2017 Jun 16.

Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine (RIRBM), Hiroshima University, Hiroshima, Japan.

To expand our knowledge of the ontogeny of the T-cell receptor (TCR) repertoire of antigen-specific T-cell subsets, we combined next-generation deep sequencing and single-cell multiplex clonotype analysis to evaluate the diversity and frequency of paired TCRs, their functions and whether clonotypic TCRs are shared among different individuals. Using an HLA-A*02-restricted cytomegalovirus (CMV) pp65-derived immunogenic peptide, we found that the more dominant pp65-specific TCR clonotypes in the blood of healthy donors have higher binding affinities for the CMV peptide and arise from clonotypes that are highly shared among individuals. Interestingly, these highly shared HLA-A*02-restricted CMV-specific TCRs were detected in a CMV-seronegative individual as well as in HLA-A*02-negative donors albeit at lower frequency. More intriguingly, these shared TCR clonotypes were abundant in the stem memory T-cell subset, and TCR diversity of the stem memory T-cell repertoire was significantly lower than in the central memory and effector memory T-cell repertoires. These results suggest that the stem memory T-cell subset may serve as a reservoir of highly shared and highly functional memory T-cells.
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http://dx.doi.org/10.1038/s41598-017-03855-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473819PMC
June 2017

Different Somatic Hypermutation Levels among Antibody Subclasses Disclosed by a New Next-Generation Sequencing-Based Antibody Repertoire Analysis.

Front Immunol 2017 3;8:389. Epub 2017 May 3.

Repertoire Genesis Incorporation, Ibaraki, Japan.

A diverse antibody repertoire is primarily generated by the rearrangement of V, D, and J genes and subsequent somatic hypermutation (SHM). Class-switch recombination (CSR) produces various isotypes and subclasses with different functional properties. Although antibody isotypes and subclasses are considered to be produced by both direct and sequential CSR, it is still not fully understood how SHMs accumulate during the process in which antibody subclasses are generated. Here, we developed a new next-generation sequencing (NGS)-based antibody repertoire analysis capable of identifying all antibody isotype and subclass genes and used it to examine the peripheral blood mononuclear cells of 12 healthy individuals. Using a total of 5,480,040 sequences, we compared percentage frequency of variable (V), junctional (J) sequence, and a combination of V and J, diversity, length, and amino acid compositions of CDR3, SHM, and shared clones in the IgM, IgD, IgG3, IgG1, IgG2, IgG4, IgA1, IgE, and IgA2 genes. The usage and diversity were similar among the immunoglobulin (Ig) subclasses. Clonally related sequences sharing identical V, D, J, and CDR3 amino acid sequences were frequently found within multiple Ig subclasses, especially between IgG1 and IgG2 or IgA1 and IgA2. SHM occurred most frequently in IgG4, while IgG3 genes were the least mutated among all IgG subclasses. The shared clones had almost the same SHM levels among Ig subclasses, while subclass-specific clones had different levels of SHM dependent on the genomic location. Given the sequential CSR, these results suggest that CSR occurs sequentially over multiple subclasses in the order corresponding to the genomic location of IGHCs, but CSR is likely to occur more quickly than SHMs accumulate within Ig genes under physiological conditions. NGS-based antibody repertoire analysis should provide critical information on how various antibodies are generated in the immune system.
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http://dx.doi.org/10.3389/fimmu.2017.00389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413556PMC
May 2017

Production of a Locus- and Allele-Specific Monoclonal Antibody for the Characterization of SLA-1*0401 mRNA and Protein Expression Levels in MHC-Defined Microminipigs.

PLoS One 2016 19;11(10):e0164995. Epub 2016 Oct 19.

Department of Molecular Life Science, Division of Basic Medical Science, Tokai University School of Medicine, Isehara, Kanagawa, Japan.

The class I major histocompatibility complex (MHC) presents self-developed peptides to specific T cells to induce cytotoxity against infection. The MHC proteins are encoded by multiple loci that express numerous alleles to preserve the variability of the antigen-presenting ability in each species. The mechanism regulating MHC mRNA and protein expression at each locus is difficult to analyze because of the structural and sequence similarities between alleles. In this study, we examined the correlation between the mRNA and surface protein expression of swine leukocyte antigen (SLA)-1*0401 after the stimulation of peripheral blood mononuclear cells (PBMCs) by Staphylococcus aureus superantigen toxic shock syndrome toxin-1 (TSST-1). We prepared a monoclonal antibody (mAb) against a domain composed of Y102, L103 and L109 in the α2 domain. The Hp-16.0 haplotype swine possess only SLA-1*0401, which has the mAb epitope, while other haplotypes possess 0 to 3 SLA classical class I loci with the mAb epitopes. When PBMCs from SLA-1*0401 homozygous pigs were stimulated, the SLA-1*0401 mRNA expression level increased until 24 hrs and decreased at 48 hrs. The kinetics of the interferon regulatory transcription factor-1 (IRF-1) mRNA level were similar to those of the SLA-1*0401 mRNA. However, the surface protein expression level continued to increase until 72 hrs. Similar results were observed in the Hp-10.0 pigs with three mAb epitopes. These results suggest that TSST-1 stimulation induced both mRNA and surface protein expression of class I SLA in the swine PBMCs differentially and that the surface protein level was sustained independently of mRNA regulation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0164995PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070868PMC
June 2017

A new high-throughput sequencing method for determining diversity and similarity of T cell receptor (TCR) α and β repertoires and identifying potential new invariant TCR α chains.

BMC Immunol 2016 10 11;17(1):38. Epub 2016 Oct 11.

Repertoire Genesis Incorporation, 104 Saito-Bioincubator, 7-7-15, Saito-asagi, Ibaraki, Osaka, 567-0085, Japan.

Background: High-throughput sequencing of T cell receptor (TCR) genes is a powerful tool for analyses of antigen specificity, clonality and diversity of T lymphocytes. Here, we developed a new TCR repertoire analysis method using 454 DNA sequencing technology in combination with an adaptor-ligation mediated polymerase chain reaction (PCR). This method allows the amplification of all TCR genes without PCR bias. To compare gene usage, diversity and similarity of expressed TCR repertoires among individuals, we conducted next-generation sequencing (NGS) of TRA and TRB genes in peripheral blood mononuclear cells from 20 healthy human individuals.

Results: From a total of 267,037 sequence reads from 20 individuals, 149,216 unique sequence reads were identified. Preferential usage of several V and J genes were observed while some recombinations of TRAV with TRAJ appeared to be restricted. The extent of TCR diversity was not significantly different between TRA and TRB, while TRA repertoires were more similar between individuals than TRB repertoires were. The interindividual similarity of TRA depended largely on the frequent presence of shared TCRs among two or more individuals. A publicly available TRA had a near-germline TCR with a shorter CDR3. Notably, shared TRA sequences, especially those shared among a large number of individuals', often contained TCRα related with invariant TCRα derived from invariant natural killer T cells and mucosal-associated invariant T cells.

Conclusion: These results suggest that retrieval of shared TCRs by NGS would be useful for the identification of potential new invariant TCRα chains. This NGS method will enable the comprehensive quantitative analysis of TCR repertoires at a clonal level.
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http://dx.doi.org/10.1186/s12865-016-0177-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5059964PMC
October 2016

Atomically phase-matched second-harmonic generation in a 2D crystal.

Light Sci Appl 2016 Aug 26;5(8):e16131. Epub 2016 Aug 26.

Department of Mechanical Engineering, NSF Nanoscale Science and Engineering Center, University of California, Berkeley, CA 94720, USA.

Second-harmonic generation (SHG) has found extensive applications from hand-held laser pointers to spectroscopic and microscopic techniques. Recently, some cleavable van der Waals (vdW) crystals have shown SHG arising from a single atomic layer, where the SH light elucidated important information such as the grain boundaries and electronic structure in these ultra-thin materials. However, despite the inversion asymmetry of the single layer, the typical crystal stacking restores inversion symmetry for even numbers of layers leading to an oscillatory SH response, drastically reducing the applicability of vdW crystals such as molybdenum disulfide (MoS). Here, we probe the SHG generated from the noncentrosymmetric 3R crystal phase of MoS. We experimentally observed quadratic dependence of second-harmonic intensity on layer number as a result of atomically phase-matched nonlinear dipoles in layers of the 3R crystal that constructively interfere. By studying the layer evolution of the A and B excitonic transitions in 3R-MoS using SHG spectroscopy, we also found distinct electronic structure differences arising from the crystal structure and the dramatic effect of symmetry and layer stacking on the nonlinear properties of these atomic crystals. The constructive nature of the SHG in this 2D crystal provides a platform to reliably develop atomically flat and controllably thin nonlinear media.
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http://dx.doi.org/10.1038/lsa.2016.131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6059936PMC
August 2016

Overexpression of ErbB4 is an independent marker for lymph node metastasis in Japanese patients with oral squamous cell carcinoma.

Oral Surg Oral Med Oral Pathol Oral Radiol 2016 Sep 11;122(3):313-21. Epub 2016 May 11.

Department of Clinical Immunology, Clinical Research Center for Allergy and Rheumatology, Sagamihara National Hospital, National Hospital Organization, Kanagawa, Japan. Electronic address:

Objective: Overexpression of the epidermal growth factor receptor (EGFR) family is common in oral squamous cell carcinoma (OSCC). Therefore, we analyzed the expression profiles of the four EGFR family members (ErbB1, ErbB2, ErbB3, and ErbB4) in OSCC of Japanese patients.

Study Design: Sixty-eight primary tumors and 18 normal oral mucosal tissue specimens were evaluated in this study. We analyzed EGFR family members using quantitative polymerase chain reaction and immunohistochemistry, as well as their relationships with clinical factors.

Results: The expression level of ErbB1 messenger RNA (mRNA) was markedly increased in OSCC. By comparing the gene expression levels of EGFR family members in OSCC tissues that had lymph node metastasis with those in the absence of lymph node metastasis, we found that ErbB4 mRNA expression was increased significantly. There was also a significant correlation between the mRNA expression level of ErbB4 and those of ErbB2 and ErbB3 in cases with lymph node metastasis. Moreover, we confirmed protein expression of ErbB4 in the cytoplasm and membrane of tumor cells, which was stronger in cases with lymph node metastasis.

Conclusions: ErbB4 is an independent marker for lymph node metastasis in OSCC.
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http://dx.doi.org/10.1016/j.oooo.2016.04.017DOI Listing
September 2016

High-Contrast Imaging of Intermediate-Mass Giants with Long-Term Radial Velocity Trends.

Astrophys J 2016 Jul 12;825(2). Epub 2016 Jul 12.

National Astronomical Observatory of Japan, 2-21-1 Osawa, Mitaka, Tokyo 181-8588, Japan.

A radial velocity (RV) survey for intermediate-mass giants has been operated for over a decade at Okayama Astrophysical Observatory (OAO). The OAO survey has revealed that some giants show long-term linear RV accelerations (RV trends), indicating the presence of outer companions. Direct imaging observations can help clarify what objects generate these RV trends. We present the results of high-contrast imaging observations of six intermediate-mass giants with long-term RV trends using the Subaru Telescope and HiCIAO camera. We detected co-moving companions to Hya , HD 5608 B (0.10 ± 0.01 ), and HD 109272 B (0.28 ± 0.06 ). For the remaining targets( Dra, 18 Del, and HD 14067) we exclude companions more massive than 30-60 at projected separations of 1-7. We examine whether these directly imaged companions or unidentified long-period companions can account for the RV trends observed around the six giants. We find that the Kozai mechanism can explain the high eccentricity of the inner planets Dra b, HD 5608 b, and HD 14067 b.
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http://dx.doi.org/10.3847/0004-637X/825/2/127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402361PMC
July 2016
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