Faculty Profiles - ARIMA, Hiroshi

Papers - ARIMA, Hiroshi

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Basigin deficiency prevents anaplerosis and ameliorates insulin resistance and hepatosteatosis Reviewed

Ryuge, A; Kosugi, T; Maeda, K; Banno, R; Gou, Y; Zaitsu, K; Ito, T; Sato, Y; Hirayama, A; Tsubota, S; Honda, T; Nakajima, K; Ozaki, T; Kondoh, K; Takahashi, K; Kato, N; Ishimoto, T; Soga, T; Nakagawa, T; Koike, T; Arima, H; Yuzawa, Y; Minokoshi, Y; Maruyama, S; Kadomatsu, K

JCI INSIGHT Vol. 6 ( 20 ) 2021.10

Adult-onset autoimmune diabetes identified by glutamic acid decarboxylase autoantibodies: a retrospective cohort study. Reviewed International journal

Eri Wada, Takeshi Onoue, Tamaki Kinoshita, Ayaka Hayase, Tomoko Handa, Masaaki Ito, Mariko Furukawa, Takayuki Okuji, Tomoko Kobayashi, Shintaro Iwama, Mariko Sugiyama, Hiroshi Takagi, Daisuke Hagiwara, Hidetaka Suga, Ryoichi Banno, Motomitsu Goto, Hiroshi Arima

Diabetologia Vol. 64 ( 10 ) page： 2183 - 2192 2021.10

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

AIMS/HYPOTHESIS: Patients with GAD antibodies (GADAb) showing clinical features of type 2 diabetes typically exhibit progression to an insulin-dependent state in several months or years. This condition is diagnosed as slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM) or latent autoimmune diabetes in adults, a subtype of adult-onset autoimmune diabetes. However, some patients diagnosed with adult-onset autoimmune diabetes do not progress to an insulin-dependent state. We conducted a retrospective cohort study to identify patients with non-insulin-dependent diabetes among those diagnosed with adult-onset autoimmune diabetes using measurable indicators in routine clinical practice. METHODS: We surveyed data from the electronic medical records of all patients with GADAb from eight medical centres in Japan for selecting and analysing patients who matched the diagnostic criteria of SPIDDM. RESULTS: Overall, 345 patients were analysed; of these, 162 initiated insulin therapy (insulin therapy group), whereas 183 did not (non-insulin therapy group) during the follow-up period (median 3.0 years). Patients in the non-insulin therapy group were more likely to be male and presented a later diabetes onset, shorter duration of diabetes, higher BMI, higher blood pressure levels, lower HbA1c levels, lower GADAb levels and lesser antidiabetic agent use than those in the insulin therapy group when GADAb was first identified as positive. A Cox proportional hazards model showed that BMI, HbA1c levels and GADAb levels were independent factors for progression to insulin therapy. Kaplan-Meier analyses revealed that 86.0% of the patients with diabetes having GADAb who presented all three factors (BMI ≥ 22 kg/m2, HbA1c < 75 mmol/mol [9.0%] and GADAb <10.0 U/ml) did not require insulin therapy for 4 years. CONCLUSIONS/INTERPRETATION: Higher BMI (≥22 kg/m2), lower HbA1c (<75 mmol/mol [9.0%]) and lower GADAb levels (<10.0 U/ml) can predict a non-insulin-dependent state for at least several years in Japanese patients with diabetes having GADAb.

DOI： 10.1007/s00125-021-05516-1

Web of Science

PubMed

GABAB receptor signaling in the caudate putamen is involved in binge-like consumption during a high fat diet in mice. Reviewed International coauthorship International journal

Runan Sun, Taku Tsunekawa, Tomonori Hirose, Hiroshi Yaginuma, Keigo Taki, Akira Mizoguchi, Takashi Miyata, Tomoko Kobayashi, Mariko Sugiyama, Takeshi Onoue, Hiroshi Takagi, Daisuke Hagiwara, Yoshihiro Ito, Shintaro Iwama, Hidetaka Suga, Ryoichi Banno, Bernhard Bettler, Hiroshi Arima

Scientific reports Vol. 11 ( 1 ) page： 19296 - 19296 2021.9

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

Previous studies suggest that signaling by the gamma-aminobutyric acid (GABA) type B receptor (GABABR) is involved in the regulation of binge eating, a disorder which might contribute to the development of obesity. Here, we show that intermittent access to a high fat diet (HFD) induced binge-like eating behavior with activation of dopamine receptor d1 (drd1)-expressing neurons in the caudate putamen (CPu) and nucleus accumbens (NAc) in wild-type (WT) mice. The activation of drd1-expressing neurons during binge-like eating was substantially increased in the CPu, but not in the NAc, in corticostriatal neuron-specific GABABR-deficient knockout (KO) mice compared to WT mice. Treatment with the GABABR agonist, baclofen, suppressed binge-like eating behavior in WT mice, but not in KO mice, as reported previously. Baclofen also suppressed the activation of drd1-expressing neurons in the CPu, but not in the NAc, during binge-like eating in WT mice. Thus, our data suggest that GABABR signaling in CPu neurons expressing drd1 suppresses binge-like consumption during a HFD in mice.

DOI： 10.1038/s41598-021-98590-9

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PubMed

Prevention of Worsening Diabetes through Behavioral Changes by an IoT-based Self-Monitoring System in Japan (PRISM-J): Study design and rationale for a multicenter, open-label, randomized parallel-group trial.

Bouchi R, Izumi K, Ohtsu H, Miyo K, Tanaka S, Satoh-Asahara N, Hara K, Odawara M, Kusunoki Y, Koyama H, Onoue T, Arima H, Tsushita K, Watada H, Kadowaki T, Ueki K

GHM open Vol. 1 ( 1 ) page： 3 - 11 2021.8

Deficiency of WFS1 leads to the impairment of AVP secretion under dehydration in male mice. Reviewed International journal

Junki Kurimoto, Hiroshi Takagi, Takashi Miyata, Yuichi Hodai, Yohei Kawaguchi, Daisuke Hagiwara, Hidetaka Suga, Tomoko Kobayashi, Mariko Sugiyama, Takeshi Onoue, Yoshihiro Ito, Shintaro Iwama, Ryoichi Banno, Katsuya Tanabe, Yukio Tanizawa, Hiroshi Arima

Pituitary Vol. 24 ( 4 ) page： 582 - 588 2021.8

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

Wolfram syndrome (WS) is mainly caused by mutations in the WFS1 gene and characterized by diabetes mellitus, optic atrophy, hearing loss, and central diabetes insipidus (CDI). WFS1 is an endoplasmic reticulum (ER)-resident transmembrane protein, and Wfs1 knockout (Wfs1-/-) mice, which have been used as a mouse model for WS, reportedly manifested impairment of glucose tolerance due to pancreatic β-cell loss. In the present study, we examined water balance, arginine vasopressin (AVP) secretion, and ER stress in AVP neurons of the hypothalamus in Wfs1-/- mice. There were no differences in urine volumes between Wfs1-/- and wild-type mice with free access to water. Conversely, when mice were subjected to intermittent water deprivation (WD) for 20 weeks, during which water was unavailable for 2 days a week, urine volumes were larger in Wfs1-/- mice, accompanied by lower urine AVP concentrations and urine osmolality, compared to wild-type mice. The mRNA expression of immunoglobulin heavy chain binding protein, a marker of ER stress, was significantly increased in the supraoptic nucleus and paraventricular nuclei in Wfs1-/- mice compared to wild-type mice after WD. Our results thus showed that Wfs1 knockout leads to a decrease in AVP secretion during dehydration, which could explain in part the mechanisms by which Wfs1 mutations cause CDI in humans.

DOI： 10.1007/s11102-021-01135-6

Web of Science

PubMed

Prediabetes is associated with proteinuria development but not with glomerular filtration rate decline: A longitudinal observational study Reviewed

Furukawa, M; Onoue, T; Kato, K; Wada, T; Shinohara, Y; Kinoshita, F; Goto, M; Arima, H; Tsushita, K

DIABETIC MEDICINE Vol. 38 ( 8 ) page： e14607 2021.8

Preoperative and long-term efficacy and safety of lanreotide autogel in patients with thyrotropin-secreting pituitary adenoma: a multicenter, single-arm, phase 3 study in Japan. Invited International coauthorship

Shimatsu A, Nakamura A, Takahashi Y, Fujio S, Satoh F, Tahara S, Nishioka H, Takano K, Yamashita M, Arima H, Tominaga A, Tateishi S, Matsushita Y

Endocrine journal Vol. 68 ( 7 ) page： 791 - 805 2021.7

Glucocorticoid receptor signaling in ventral tegmental area neurons increases the rewarding value of a high-fat diet in mice. Reviewed International journal

Akira Mizoguchi, Ryoichi Banno, Runan Sun, Hiroshi Yaginuma, Keigo Taki, Tomoko Kobayashi, Mariko Sugiyama, Taku Tsunekawa, Takeshi Onoue, Hiroshi Takagi, Daisuke Hagiwara, Yoshihiro Ito, Shintaro Iwama, Hidetaka Suga, Taku Nagai, Kiyofumi Yamada, Hiroshi Arima

Scientific reports Vol. 11 ( 1 ) page： 12873 - 12873 2021.6

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

The reward system, which consists of dopaminergic neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens and caudate-putamen in the striatum, has an important role in the pathogenesis of not only drug addiction but also diet-induced obesity. In the present study, we examined whether signaling through glucocorticoid receptors (GRs) in the reward system affects the rewarding value of a high-fat diet (HFD). To do so, we generated mice that lack functional GRs specifically in dopaminergic neurons (D-KO mice) or corticostriatal neurons (CS-KO mice), subjected the mice to caloric restriction stress conditions, and evaluated the rewarding value of a HFD by conditioned place preference (CPP) test. Caloric restriction induced increases in serum corticosterone to similar levels in all genotypes. While CS-KO as well as WT mice exhibited a significant preference for HFD in the CPP test, D-KO mice exhibited no such preference. There were no differences between WT and D-KO mice in consumption of HFD after fasting or cognitive function evaluated by a novel object recognition test. These data suggest that glucocorticoid signaling in the VTA increases the rewarding value of a HFD under restricted caloric stress.

DOI： 10.1038/s41598-021-92386-7

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PubMed

Comparison of High-Resolution Manometry in Patients Complaining of Dysphagia among Patients with or without Diabetes Mellitus. Reviewed International journal

Muroi K, Miyahara R, Funasaka K, Furukawa K, Sawada T, Maeda K, Yamamura T, Ishikawa T, Ohno E, Nakamura M, Kawashima H, Onoue T, Arima H, Hirooka Y, Fujishiro M

Digestion Vol. 102 ( 4 ) page： 554 - 562 2021.6

Language：English Publishing type：Research paper (scientific journal)

INTRODUCTION: Dysphagia is a common symptom that occurs in patients with diabetes mellitus (DM). There have been few prospective observational studies on esophageal motility disorders in DM using high-resolution manometry (HRM). This study aimed to clarify the characteristics of esophageal motility disorders using HRM in patients with dysphagia and compare them between DM and non-DM patients. METHODS: Patients with dysphagia were prospectively recruited between October 2018 and July 2019. Patients (n = 89) underwent esophagogastroduodenoscopy and HRM and completed the Gastrointestinal Symptom Rating Scale (GSRS) questionnaire. Manometry parameters and motility disorder classifications were compared between DM and non-DM patients. We also investigated the differences in clinical backgrounds and questionnaire scores among DM patients with normal and abnormal manometry results. RESULTS: A higher prevalence of esophageal motility disorder was observed in DM patients (60%, 21/35) compared to non-DM patients (29.6%, 16/54) (p = 0.001). The prevalence of minor disorders such as ineffective esophageal motor disorder and fragmented peristalsis was significantly higher (45 vs. 11%), and the distal contractile integral, integrated relaxation pressure, and contractile front velocity values were lower in the DM group. Among DM patients, those with abnormal esophageal motility had a significantly higher prevalence of neuropathy, retinopathy, and nephropathy, as well as higher reflux or constipation scores on the GSRS, than those with normal results. CONCLUSIONS: Among patients with dysphagia, the frequency of minor esophageal motility disorders was higher in DM patients than in non-DM patients. Abnormal esophageal motility related to poor esophageal clearance was associated with higher prevalence of diabetic complications.

DOI： 10.1159/000510081

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PubMed

【内分泌疾患2】(Part 2)どこまでを専門家がみて,どこから総合内科医がみるのか? 下垂体中枢性尿崩症,SIADH

須賀英隆, 高木博史, 有馬寛

Hospitalist Vol. 9 ( 2 ) page： 417 - 423 2021.6

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：(株)メディカル・サイエンス・インターナショナル

＜文献概要＞key point 中枢性尿崩症 ▼尿崩症を疑うきっかけの多くは多尿であるが,頻尿との判別に注意する。▼多尿の症例では尿浸透圧を評価し,低浸透圧尿であれば,内分泌専門医へ紹介する。▼デスモプレシン(経鼻製剤または経口製剤)による治療が開始され,その管理を内分泌専門医から引き継いだ場合,薬効が切れて尿量が増加する時間帯を適宜設けさせ,過量投与による水中毒の発生を回避する。特に渇感障害を合併する症例は管理が難しく,毎日の体重測定が投与量調整に有効である。抗利尿ホルモン分泌過剰症(SIADH) ▼SIADHを疑うきっかけは,主に低ナトリウム血症であり,無症状のことが多いが,重症例や急速進行例では倦怠感などの症状を呈することがある。▼水分制限を実施しても低ナトリウム血症が改善しない症例は,内分泌専門医に紹介する。▼内分泌専門医からトルバプタンによる治療を引き継いだ場合,状況に合わせた飲水方針を決定したうえで,血清ナトリウム値の定期フォローを行う。

Efficacies of programmed cell death 1 ligand 1 blockade in non-small cell lung cancer patients with acquired resistance to prior programmed cell death 1 inhibitor and development of diabetic ketoacidosis caused by two different etiologies: a retrospective case series. Reviewed

Azusa Ishi, Ichidai Tanaka, Shintaro Iwama, Toshihiro Sakakibara, Toshinori Mastui, Tomoko Kobayashi, Tetsunari Hase, Masahiro Morise, Mitsuo Sato, Hiroshi Arima, Naozumi Hashimoto

Endocrine journal Vol. 68 ( 5 ) page： 613 - 620 2021.5

Language：English Publishing type：Research paper (scientific journal)

The programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) axis is vital for immune resistance during tumor development, while PD-L1 inhibitors can also inhibit the PD-L1/B7-1 (CD80) interaction, indicating one of the molecular differences between PD-1 and PD-L1 inhibitors. However, the clinical benefits of PD-L1 inhibitors in patients previously treated with PD-1 inhibitors remain unknown. In this study, we retrospectively analyzed the clinical data of eight patients with non-small cell lung cancer who received the PD-L1 inhibitor atezolizumab and previously treated with the PD-1 inhibitor nivolumab. The median progression-free survival was 2.1 months (1.8-18.7 months), and 4 of 8 patients achieved at least stable disease. In two of these patients, atezolizumab treatment resulted in longer progression-free survival (PFS) compared with that of nivolumab. Conversely, one patient exhibited grade 4 diabetic ketoacidosis (DKA) within 2 weeks after the initial administration of atezolizumab. Another patient had developed type 1 diabetes mellitus (T1DM) during the prior nivolumab treatment and then developed DKA due to an infection after the initiation of atezolizumab. Both of them had high-risk human leukocyte antigen-DR/DQ types relevant to T1DM. These results demonstrate the potential efficacy of PD-L1 inhibitors to some tumors that have acquired resistance to PD-1 inhibitors and suggest that appropriate managements are required for not only a newly onset of T1DM but also blood glucose control after the development of T1DM during a reiteration of the PD-1/PD-L1 blockade.

DOI： 10.1507/endocrj.EJ20-0769

PubMed

Macrophages rely on extracellular serine to suppress aberrant cytokine production Reviewed

Kurita, K; Ohta, H; Shirakawa, I; Tanaka, M; Kitaura, Y; Iwasaki, Y; Matsuzaka, T; Shimano, H; Aoe, S; Arima, H; Ogawa, Y; Ito, A; Suganami, T

SCIENTIFIC REPORTS Vol. 11 ( 1 ) page： 11137 2021.5

A new primate model of hypophyseal dysfunction

Teppei Kawabata, Hidetaka Suga, Kazuhito Takeuchi, Yuichi Nagata, Mayu Sakakibara, Kaori Ushida, Chikafumi Ozone, Atsushi Enomoto, Ikuo Kawamoto, Iori Itagaki, Hideaki Tsuchiya, Hiroshi Arima, Toshihiko Wakabayashi

Scientific Reports Vol. 11 ( 1 ) page： 10729 2021.5

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

<title>Abstract</title>For pituitary regenerative medicine, the creation of a hypophyseal model in monkeys is necessary to conduct future preclinical studies; however, previous studies reported that hypophysectomy in monkeys is not always safe or satisfactory. This study aimed to create a hypophyseal dysfunction model in a cynomolgus monkey using a safer surgical technique and establish the protocol of pituitary hormone replacement therapy for this model. Surgical resection of the pituitary gland of a 7.8-year-old healthy adult cynomolgus male monkey weighing 5.45 kg was performed to create a hypophyseal dysfunction model for future regenerative studies. Endoscopic transoral transsphenoidal surgery was used to perform hypophysectomy under navigation support. These procedures were useful for confirming total removal of the pituitary gland without additional bone removal and preventing complications such as cerebrospinal fluid leakage. Total removal was confirmed by pathological examination and computed tomography. Hypopituitarism was verified with endocrinological examinations including stimulation tests. Postoperatively, the monkey’s general condition of hypopituitarism was treated with hormone replacement therapy, resulting in long-term survival. The success of a minimally invasive and safe surgical method and long-term survival indicate the creation of a hypophyseal dysfunction model in a cynomolgus monkey; hence, this protocol can be employed in the future.

DOI： 10.1038/s41598-021-90209-3

Web of Science

PubMed

Other Link： http://www.nature.com/articles/s41598-021-90209-3

CD4+ T cells are essential for the development of destructive thyroiditis induced by anti-PD-1 antibody in thyroglobulin-immunized mice. Reviewed International journal

Yoshinori Yasuda, Shintaro Iwama, Daisuke Sugiyama, Takayuki Okuji, Tomoko Kobayashi, Masaaki Ito, Norio Okada, Atsushi Enomoto, Sachiko Ito, Yue Yan, Mariko Sugiyama, Takeshi Onoue, Taku Tsunekawa, Yoshihiro Ito, Hiroshi Takagi, Daisuke Hagiwara, Motomitsu Goto, Hidetaka Suga, Ryoichi Banno, Masahide Takahashi, Hiroyoshi Nishikawa, Hiroshi Arima

Science translational medicine Vol. 13 ( 593 ) 2021.5

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

Immune-related adverse events induced by anti-programmed cell death-1 antibodies (PD-1-Ab), including destructive thyroiditis (thyroid-irAE), are thought to be caused by activated T cells. However, the T cell subsets that are directly responsible for damaging self-organs remain unclear. To clarify which T cell subsets are involved in the development of thyroid-irAE, a mouse model of thyroid-irAE was analyzed. PD-1-Ab administration 2.5 months after immunization with thyroglobulin caused destructive thyroiditis. Thyroiditis was completely prevented by previous depletion of CD4+ T cells and partially prevented by depleting CD8+ T cells. The frequencies of central and effector memory CD4+ T cell subsets and the secretion of interferon-γ after stimulation with thyroglobulin were increased in the cervical lymph nodes of mice with thyroid-irAE compared with controls. Histopathological analysis revealed infiltration of CD4+ T cells expressing granzyme B in thyroid glands and major histocompatibility complex class II expression on thyrocytes in mice with thyroid-irAE. Adoptive transfer of CD4+ T cells from cervical lymph nodes in mice with thyroid-irAE caused destruction of thyroid follicular architecture in the irradiated recipient mice. Flow cytometric analyses showed that the frequencies of central and effector memory CD4+ T cells expressing the cytotoxic marker CD27 were higher in peripheral blood mononuclear cells collected from patients with thyroid-irAE induced by PD-1-Ab versus those without. These data suggest a critical role for cytotoxic memory CD4+ T cells activated by PD-1-Ab in the pathogenesis of thyroid-irAE.

DOI： 10.1126/scitranslmed.abb7495

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PubMed

High-fat Feeding Causes Inflammation and Insulin Resistance in the Ventral Tegmental Area in Mice. International journal

Neuroscience Vol. 461 page： 72 - 79 2021.5

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

The reward system plays an important role in the pathogenesis of not only drug addiction, but also diet-induced obesity. Recent studies have shown that insulin and leptin receptor signaling in the ventral tegmental area (VTA) regulate energy homeostasis and that their dysregulation is responsible for obesity and altered food preferences. Although a high-fat diet (HFD) induces inflammation that leads to insulin and leptin resistance in the brain, it remains unclear whether HFD induces inflammation in the VTA. In the present study, we placed male mice on a chow diet or HFD for 3, 7, and 28 days and evaluated the mRNA expression of inflammatory cytokines and microglial activation markers in the VTA. The HFD group showed significantly elevated mRNA expressions of IL1β at 3 days; tumor necrosis factor-alpha (TNFα), IL1β, IL6, Iba1, and CD11b at 7 days; and TNFα, IL1β, Iba1, and CD11b at 28 days. The changes in TNFα were also confirmed in immunohistochemical analysis. Next, after administration of chow or HFD for 7 days, we selected mice with equal weights in both groups. In experiments using these mice, Akt phosphorylation in the VTA was significantly decreased after intracerebroventricular injection of insulin, whereas no change in STAT3 phosphorylation was found with leptin. Taken together, these results suggest that HFD induces inflammation at least partly associated with microglial activation in the VTA leading to insulin resistance, independently of the energy balance. Our data provide new insight into the pathophysiology of obesity caused by a dysfunctional reward system under HFD conditions.

DOI： 10.1016/j.neuroscience.2021.02.009

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PubMed

Anti-pituitary antibodies and susceptible human leukocyte antigen alleles as predictive biomarkers for pituitary dysfunction induced by immune checkpoint inhibitors Reviewed

Tomoko Kobayashi, Shintaro Iwama, Daisuke Sugiyama, Yoshinori Yasuda, Takayuki Okuji, Masaaki Ito, Sachiko Ito, Mariko Sugiyama, Takeshi Onoue, Hiroshi Takagi, Daisuke Hagiwara, Yoshihiro Ito, Hidetaka Suga, Ryoichi Banno, Hiroyoshi Nishikawa, Hiroshi Arima

Journal for ImmunoTherapy of Cancer Vol. 9 ( 5 ) page： e002493 - e002493 2021.5

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：BMJ

Background

Pituitary dysfunction is a life-threatening immune-related adverse event (irAE) induced by immune checkpoint inhibitors (ICIs). To date, it is not possible to identify patients who may develop pituitary irAEs prior to ICI treatment. The aim of this study was to characterize the predisposition for ICI-induced pituitary irAEs by analyzing anti-pituitary antibodies (APAs) and human leukocyte antigens (HLAs).

Methods

In this case–control study, APAs and HLA alleles were analyzed in 62 patients (17 who developed ICI-induced isolated adrenocorticotropic hormone deficiency (ICI-IAD), 5 who developed ICI-induced hypophysitis (ICI-H) and 40 who did not develop pituitary irAEs) treated with ICIs between November 2, 2015, and March 31, 2020, at Nagoya University Hospital. The main outcome measures in this study were the association between the development of pituitary irAEs with APAs at baseline and after treatment and HLA alleles.

Results

Eleven of 17 (64.7%) patients who developed ICI-IAD had APAs at baseline, whereas APAs were positive only in 1 of 40 (2.5%) control patients. Although APAs were negative at baseline in all patients who developed ICI-H, they had become positive before the onset of ICI-H in 3 of 4 patients several weeks after ipilimumab administration. At the onset of ICI-IAD and ICI-H, APAs were positive in 15 of 17 (88.2%) and 4 of 5 (80%) patients, respectively. The prevalence of HLA-Cw12, HLA-DR15, HLA-DQ7, and HLA-DPw9 was significantly higher in patients with ICI-IAD, whereas that of HLA-Cw12 and HLA-DR15 was significantly higher in patients with ICI-H than in controls.

Conclusions

This study showed distinct and overlapped patterns of APAs and HLA alleles between ICI-IAD and ICI-H. Our findings also showed that positive APAs at baseline and after treatment, together with susceptible HLA alleles, could become predictive biomarkers for ICI-IAD and ICI-H, respectively.

Trial registration number

UMIN000019024.

DOI： 10.1136/jitc-2021-002493

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PubMed

Arginine vasopressin-Venus reporter mice as a tool for studying magnocellular arginine vasopressin neurons. International journal

Daisuke Hagiwara, Masayoshi Tochiya, Yoshinori Azuma, Tetsuro Tsumura, Yuichi Hodai, Yohei Kawaguchi, Takashi Miyata, Tomoko Kobayashi, Mariko Sugiyama, Takeshi Onoue, Hiroshi Takagi, Yoshihiro Ito, Shintaro Iwama, Hidetaka Suga, Ryoichi Banno, Hiroshi Arima

Peptides Vol. 139 page： 170517 - 170517 2021.5

Language：English Publishing type：Research paper (scientific journal)

Arginine vasopressin (AVP) synthesized in the magnocellular neurons of the hypothalamus is transported through their axons and released from the posterior pituitary into the systemic circulation to act as an antidiuretic hormone. AVP synthesis and release are precisely regulated by changes in plasma osmolality. Magnocellular AVP neurons receive innervation from osmosensory and sodium-sensing neurons, but previous studies showed that AVP neurons per se are osmosensitive as well. In the current study, we made AVP-Venus reporter mice and showed that Venus was expressed exclusively in AVP neurons and was upregulated under water deprivation. In hypothalamic organotypic cultures from the AVP-Venus mice, Venus-labeled AVP neurons in the supraoptic and paraventricular nuclei survived for 1 month, and Venus expression was upregulated by forskolin. Furthermore, in dissociated Venus-labeled magnocellular neurons, treatment with NaCl, but not with mannitol, decreased Venus fluorescence in the soma of the AVP neurons. Thus, Venus expression in AVP-Venus transgenic mice, as well as in primary cultures, faithfully showed the properties of intrinsic AVP expression. These findings indicate that AVP-Venus mice as well as the primary hypothalamic cultures could be useful for studying magnocellular AVP neurons.

DOI： 10.1016/j.peptides.2021.170517

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Clinical Characteristics, Management, and Potential Biomarkers of Endocrine Dysfunction Induced by Immune Checkpoint Inhibitors Invited Reviewed

Iwama, S; Kobayashi, T; Arima, H

ENDOCRINOLOGY AND METABOLISM Vol. 36 ( 2 ) page： 312 - 321 2021.4

イピリムマブ誘発下垂体炎発症者で高抗体価を示す自己抗体の同定 Reviewed

奥地剛之, 岩間信太郎, 周キン, 伊藤雅晃, 小林朋子, 安田康紀, 有馬寛

日本内分泌学会雑誌 Vol. 97 ( 1 ) page： 262 - 262 2021.4

抗PD-1抗体誘発甲状腺炎マウスモデルにおける抗サイログロブリン抗体の役割 Reviewed

安田康紀, 岩間信太郎, 伊藤雅晃, 奥地剛之, 小林朋子, 有馬寛

日本内分泌学会雑誌 Vol. 97 ( 1 ) page： 267 - 267 2021.4

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Papers - ARIMA, Hiroshi