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The role of T-cell immunoglobulin mucin-3 and its ligand galectin-9 in antitumor immunity and cancer immunotherapy

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Science China(Life Sciences) 2017年第10期60卷 1058-1064页

作者： Riyao Yang Mien-chie Hung Department of Molecular and Cellular Oncology The University of Texas MD Anderson Cancer Center Center for Molecular Medicine and Graduate Institute of Biomedical Sciences China Medical University Department of Biotechnology Asia University

Cancer treatment in the past few years has been transformed by a new kind of therapy that targets the immune system instead of the cancer itself to reinvigorate antitumor immunity with astonishing results. However, primary and acquired resistance to this type of treatment, namely immune checkpoint blockade(ICB), continue to counter treatment efficacy. In many cases, resistance has been attributed to defective or chronically enhanced interferon signaling and/or upregulation of alternative immune checkpoints,including T-cell immunoglobulin mucin-3(Tim-3) and its ligand galactin-9(Gal-9). In this article, we briefly describe the current knowledge of common checkpoint resistance mechanisms, focusing on the Tim-3/Gal-9 pathway as an alternative checkpoint that holds great promise as another target for ICB.

关键词： cancer Tim-3 galectin-9 immune checkpoints immunotherapy

Induction of CD69 expression by cag PAI-positive Helicobacter pylori infection

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World Journal of Gastroenterology 2011年第32期17卷 3691-3699页

作者： Naoki Mori chie Ishikawa Masachika Senba Department of Microbiology and Oncology Graduate School of Medicine University of the Ryukyus Nishihara Okinawa 903-0215 Japan Department of Internal Medicine Omoromachi Medical Center 1-3-1 Uenoya Naha Okinawa 900-0011 Japan Transdisciplinary Research Organization for Subtropics and Island Studies University of the Ryukyus Nishihara Okinawa 903-0213 Japan Department of Pathology Institute of Tropical Medicine Nagasaki University Nagasaki 852-8523 Japan

AIM: To investigate and elucidate the molecular mechanism that regulates inducible expression of CD69 by Helicobacter pylori (H. pylori ) infection. METHODS: The expression levels of CD69 in a T-cell line, Jurkat, primary human peripheral blood mononuclear cells (PBMCs), and CD4 + T cells, were assessed by immunohistochemistry, reverse transcription polymerase chain reaction, and flow cytometry. Activation of CD69 promoter was detected by reporter gene. Nuclear factor (NF)-κB activation in Jurkat cells infected with H. pylori was evaluated by electrophoretic mobility shift assay. The role of NF-κB signaling in H. pylori-induced CD69 expression was analyzed using inhibitors of NF-κB and dominant-negative mutants. The isogenic mutants with disrupted cag pathogenicity island (cag PAI) and virD4 were used to elucidate the role of cag PAI-encoding type Ⅳ secretion system and CagA in CD69 ***: CD69 staining was detected in mucosal lymphocytes and macrophages in specimens of pa- tients with H. pylori-positive gastritis. Although cag PAI- positive H. pylori and an isogenic mutant of virD4 induced CD69 expression, an isogenic mutant of cag-PAI failed to induce this in Jurkat cells. H. pylori also induced CD69 expression in PBMCs and CD4 + T cells. The activation of the CD69 promoter by H. pylori was mediated through NF-κB. Transfection of dominant-negative mutants of IκBs, IκB kinases, and NF-κB-inducing kinase inhibited H. pylori-induced CD69 activation. Inhibitors of NF-κB suppressed H. pylori-induced CD69 mRNA expression. CONCLUSION: The results suggest that H. pylori induces CD69 expression through the activation of NF-κB. cagPAI might be relevant in the induction of CD69 expression in T cells. CD69 in T cells may play a role in H. pylori-induced gastritis.

关键词： CD69 T cells Helicobacter pylori cag pathogenicity island Nuclear factor-κB

Mucosal-associated invariant T cells from induced pluripotent stem cells:A novel approach for modeling human diseases

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World Journal of Stem Cells 2016年第4期8卷 158-169页

作者： chie Sugimoto Hiroyoshi Fujita Hiroshi Wakao Department of Hygiene and Cellular Preventive Medicine Graduate School of MedicineHokkaido University

Mice have frequently been used to model human diseases involving immune dysregulation such as autoimmune and inflammatory *** models help elucidatethe mechanisms underlying the disease and in the development of novel ***,if mice are deficient in certain cells and/or effectors associated with human diseases,how can their functions be investigated in this species?Mucosal-associated invariant T(MAIT)cells,a novel innate-like T cell family member,are a good *** cells are abundant in humans but scarce in laboratory *** cells harbor an invariant T cell receptor and recognize nonpeptidic antigens vitamin B2metabolites from bacteria and *** studies have shown that MAIT cells play a pivotal role in human diseases such as bacterial infections and autoimmune and inflammatory *** cells possess granulysin,a human-specific effector molecule,but granulysin and its homologue are absent in ***,MAIT cells show poor proliferation in *** overcome these problems and further our knowledge of MAIT cells,we have established a method to expand MAIT cells via induced pluripotent stem cells(iP SCs).In this review,we describe recent advances in the field of MAIT cell research and our approach for human disease modeling with iP SCderived MAIT cells.

关键词： Mucosal-associated invariant T cells Induced pluripotent stem cells Differentiation Adoptive transfer Inflammatory diseases Autoimmune diseases Disease modeling Infectious diseases Immunocompromised mouse

Beneficial effects of fucoidan in patients with chronic hepatitis C virus infection

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World Journal of Gastroenterology 2012年第18期18卷 2225-2230页

作者： Naoki Mori Kazunori Nakasone Koh Tomimori chie Ishikawa Department of Microbiology and Oncology Graduate School of MedicineUniversity of the RyukyusNishiharaOkinawa 903-0215Japan Nakasonekazu Medical Clinic NahaOkinawa 902-0062Japan Department of Psychiatry Naha City HospitalNahaOkinawa 902-8511Japan Transdisciplinary Research Organization for Subtropics and Island Studies University of the RyukyusNishiharaOkinawa 903-0213Japan

AIM:To evaluate the effects of fucoidan,a complex sulfated polysaccharide extract from marine seaweed,on hepatitis C virus(HCV) RNA load both in vitro and in ***:HCV-1b replicon-expressing cells were cultured in the presence of fucoidan obtained from Cladosiphon okamuranus Tokida cultivated in Okinawa,Japan,and quantified the level of HCV *** an open-label uncontrolled study,15 patients with chronic hepatitis C,and HCV-related cirrhosis and hepatocellular carcinoma were treated with fucoidan(0.83 g/d) for 12 *** clinical symptoms,biochemical tests,and HCV RNA levels were assessed before,during,and after ***:Fucoidan dose-dependently inhibited the expression of HCV *** 8-10 mo of treatment with fucoidan,HCV RNA levels were significantly lower relative to the *** same treatment also tended to lower serum alanine aminotransferase levels,and the latter correlated with HCV RNA ***,the improved laboratory tests did not translate into significant clinical *** had no serious adverse ***:Our findings suggest that fucoidan is safe and useful in the treatment of patients with HCVrelated chronic liver *** controlled clinical trials are needed to confirm the present findings.

关键词： Fucoidan Hepatitis C virus Replicon

Development of sequential type iron salt-catalyzed Nazarov/Michael reaction in an ionic liquid solvent system

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Science China Chemistry 2012年第8期55卷 1627-1632页

作者： IBARA chie FUJIWARA Masamune HAYASE Shuichi KAWATSURA Motoi ITOH Toshiyuki Department of Chemistry and Biotechnology Graduate School of Engineering Tottori University 4-101 Koyama-minami Tottori 680-8552 Japan

Sequential type one pot Nazarov/Michael reaction of pyrrole derivatives has been demonstrated using 5 tool% Fe（C104）3· A120 as catalyst in an ionic liquid as solvent. We succeeded in obtaining 4,5-dihydrocyclopenta[b]pyrrol-6（1H）-one derivative in good yield for five repetitions of the reactions without any addition of the catalyst using an ionic liquid, [bmim][NTf2], as sol- vent system.

关键词： Nazarov cyclization Michael reaction green synthesis iron catalyst ionic liquids

PARP inhibitors as precision medicine for cancer treatment

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National Science Review 2017年第4期4卷 576-592页

作者： Yi Du Hirohito Yamaguchi Jennifer L.Hsu Mien-chie Hung Department of Molecular and Cellular Oncology The University of Texas MD Anderson Cancer Center Graduate Institute of Biomedical Sciences and Center for Molecular Medicine China Medical University Department of Biotechnology Asia University Graduate Institute of Biomedical Sciences and Center for Molecular Medicine China Medical UniversityTaichung

Personalized or precision medicine is an emerging treatment approach tailored to individuals or certain groups of patients based on their unique characteristics. These types of therapies guided by biomarkers tend to be more effective than traditional approaches, especially in cancer. The inhibitor against poly(ADP-ribose) polymerase(PARP), olaparib(Lynparza, Astra Zeneca), which was approved by the US Food and Drug Administration(FDA) in 2014, demonstrated efficacy specifically for ovarian cancer patients harboring mutations in BRCA genes, which encode proteins in DNA double-strand break ***, the response to PARP inhibitors has been less encouraging in other cancer types that also carry defects in the BRCA genes. Thus, furthering our understanding of the underlying mechanism of PARP inhibitors and resistance is critical to improve their efficacy. In this review, we summarize the results of preclinical studies and the clinical application of PARP inhibitors, and discuss the future direction of PARP inhibitors as a potential marker-guided personalized medicine for cancer treatment.

关键词： PARP inhibitor kinase DNA damage precision medicine combination therapy

Auditory symptoms and psychological characteristics in adults with auditory processing disorders

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Journal of Otology 2017年第3期12卷 132-137页

作者： chie Obuchi Sayaka Ogane Yuki Sato Kimitaka Kaga Department of Speech and Hearing Sciences International University of Health and WelfareTochigi3248501Japan

Most adults with auditory processing disorder(APD) often have trouble at work. It is possible that these listening problems in adults with APD influence their mental health. Thus, we have to take the subject's personality and mental status into consideration when supporting subjects with APD. However, studies on APD in adults are comparatively rare. In this study, we aimed to evaluate the relationships between the results of auditory tests, APD symptoms, and psychological status in subjects with APD. This study included 22 adults who complained of listening problems in everyday life, and they underwent auditory processing tests and were questioned regarding their psychological *** the results of the auditory processing tests, all subjects showed low scores on at least one test; therefore, they were suspected of having APD. Especially, the scores were low on the auditory memory test. Furthermore, subjects with APD show relatively similar psychological characteristics to each other. However, there was no significant relationship between the results of the auditory processing tests and psychological *** have to take notice of a subject's psychological state when they perceive their listening difficulties as a large-scale problem and feel anxious as a result. For this purpose, we should take psychological characteristics into consideration at the time of the medical examination interview before audio-psychological testing.

关键词： Auditory processing disorder Psychological characteristics Egogram Developmental disorder

Activation of phagocytosis by immune checkpoint blockade

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Frontiers of Medicine 2018年第4期12卷 473-480页

作者： Chia-Wei Li Yun-Ju Lai Jennifer L. Hsu Mien-chie Hung Department of Molecular and Cellular Oncology The University of Texas MD Anderson Cancer Center Houston TX 77030 USA Department of Neurology McGovern Medical School The University of Texas Health Science Center at Houston Houston TX 77030 USA

Inhibition of macrophage-mediated phagocytosis has emerged as an essential mechanism for tumor immune evasion. One mechanism inhibiting the innate response is the presence of the macrophage inhibitory molecule, signal regulatory protein-a （SIRPa）, on tumor-associated macrophages （TAMs） and its cognate ligand cluster of differentiation 47 （CD47） on tumor cells in the tumor microenvironment. On the basis of a recently discovered programmed death protein 1 （PD-1） in TAMs, we discuss the potential inhibitory receptors that possess new functions beyond T cell exhaustion in this review. As more and more immune receptors are found to be expressed on TAMs, the corresponding therapies may also stimulate macrophages for phagocytosis and thereby provide extra anti-tumor benefits in cancer therapy. Therefore, identification of biomarkers and combinatorial therapeutic strategies, have the potential to improve the efficacy and safety profiles of current immunotherapies.

关键词： CD47 PD-1 PD-L1 immunotherapy TAM phagocytosis macrophage

Binaural integration abilities in bilateral cochlear implant user

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Journal of Otology 2015年第4期10卷 150-153页

作者： chie Obuchi Masae Shiroma Sayaka Ogane Kimitaka Kaga Department of Speech and Hearing Sciences International University of Health and Welfare

Bilateral Cochlear implants (CIs) improved speech intelligibility, speech perception in background noise, and sound localization in quiet and noisy situations. However, it is unclear whether these advantages essentially result in binaural integration of acoustic stimuli from each ear. In this study, we investigated the effectiveness of binaural integration by bilateral CIs placement using binaural hearing tests and subjective auditory perceptual assessment. A 61-year-old bilateral CIs subject underwent the following four tests:the Japanese Hearing in Noise Test (HINT-J), the dichotic listening test (DLT), the Rapidly Alternating Speech Perception (RASP) test, and subjective auditory perceptual assessment. The HINT-J score was significantly higher for bilateral CIs than for a unilateral CI. However, DLT and the RASP test revealed contradictory results. Subjective auditory perceptual assessment revealed active and bright impressions for bilateral hearing, which were also noisy and strong compared with those for unilateral hearing. The results of this study revealed that bilateral CIs improved speech perception in background noise and an improved auditory impression, although the bilateral integration abilities were not improved. This was probably because the patient was required to combine information from the two ears into a single perception in DLT and the RASP test. More longitudinal data should be collected and analyzed in future studies to evaluate the long-term effects of bilateral CIs. Copyright ? 2016, PLA General Hospital Department of Otolaryngology Head and Neck Surgery. Production and hosting by Elsevier (Singapore) Pte Ltd. This is an open access article under the CC BY-NC-ND license (http://***/licenses/by-nc-nd/4.0/).

关键词： Bilateral cochlear implants Binaural integration ability Subjective auditory perceptual assessment