Endocrine Journal
Online ISSN : 1348-4540
Print ISSN : 0918-8959
ISSN-L : 0918-8959
Advance online publication
Showing 1-50 articles out of 66 articles from Advance online publication
  • Shuai Liu, Xianchun Wang, Yue Kai, Chenrui Tian, Sheng Guo, Ling He, D ...
    Type: Original
    Article ID: EJ21-0381
    Published: 2021
    [Advance publication] Released: October 15, 2021
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    High mobility group box 1 (HMGB1) is an alarmin that may link to obesity and type 2 diabetes mellitus (T2DM). The present study analyzed the correlation between HMGB1/ Toll-like receptor 4 (TLR4) and certain biochemical parameters in obese (OB) diabetic patients. 40 normal glucose tolerant subjects (NGT) and 40 patients with newly diagnosed T2DM were enrolled. All patients were further divided into non-obese NGT (NGT-NOB), obese NGT (NGT-OB), non-obese T2DM (T2DM-NOB) and obese T2DM (T2DM-OB) groups according to body mass index (BMI).The levels of HMGB1 in serum were quantified using ELISA, whereas the mRNA expression levels of TLR4 in peripheral blood mononuclear cells were assessed using reverse transcription-quantitative PCR. The results suggested that the levels of HMGB1 and TLR4 were higher in NGT-OB and T2DM-NOB groups compared with those in NGT-NOB group. Similarly, the levels of these two markers were higher in T2DM-OB group compared with those in NGT-OB group. Correlation analysis indicated that the levels of HMGB1 and TLR4 were positively correlated with triglyceride (TG), fasting plasma glucose (FPG) levels and BMI, whereas a negative correlation between HMGB1 and high density lipoprotein (HDL) was noted. Linear regression analysis suggested that HMGB1 was associated with FPG and TG levels, whereas TLR4 was strongly associated with TG levels and BMI. The results demonstrated that the expression levels of HMGB1 and TLR4 in patients with T2DM or obesity were increased, which were associated with glycolipid metabolism disorders. Therefore, the HMGB1/TLR4 may serve a role in inflammatory process associated with obesity and T2DM.

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  • Mirai Yamazaki, Hiroya Yamada, Eiji Munetsuna, Keisuke Maeda, Yoshitak ...
    Type: Note
    Article ID: EJ21-0339
    Published: 2021
    [Advance publication] Released: October 14, 2021
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    Metabolic syndrome (MetS) is cluster of metabolic diseases, including abdominal obesity, hyperglycemia, high blood pressure, and dyslipidemia, that directly escalate the risk of type 2 diabetes, heart disease, and stroke. Thioredoxin-interacting protein (TXNIP) is a binding protein for thioredoxin, a molecule that is a key inhibitor of cellular oxidation, and thus regulates the cellular redox state. Epigenetic alteration of the TXNIP-encoding locus has been associated with components of MetS. In the present study, we sought to determine whether the level of TXNIP methylation in blood is associated with MetS in the general Japanese population. DNA was extracted from the peripheral blood cells of 37 subjects with and 392 subjects without MetS. The level of TXNIP methylation at cg19693031 was assessed by the bisulfite-pyrosequencing method. We observed that TXNIP methylation levels were lower in MetS subjects (median 74.9%, range 71.7–78.4%) than in non-MetS subjects (median 77.7%, range 74.4–80.5%; p = 0.0024). Calculation of the confounding factor-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for hypomethylation revealed that subjects with MetS exhibited significantly higher ORs for hypomethylation than did those without MetS (OR, 2.92; 95% CI, 1.33–6.62; p = 0.009). Our findings indicated that lower levels of TXNIP methylation are associated with MetS in the general Japanese population. Altered levels of DNA methylation in TXNIP at cg19693031 might play an important role in the pathogenesis of ‍MetS.

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  • Takatoshi Maeyama, Chihiro Ichikawa, Yosuke Okada, Akihisa Sawada, Mas ...
    Type: Note
    Article ID: EJ21-0366
    Published: 2021
    [Advance publication] Released: October 14, 2021
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    The pathogenesis of gonadotropin-independent precocious puberty (PP) includes both congenital and acquired forms, the latter of which may be associated with neoplasms, such as sex-steroid hormone-producing tumors. Beta-human chorionic gonadotropin (β-hCG)-producing tumors also cause gonadotropin-independent PP by stimulating the production of testosterone in Leydig cells. Germ cell tumors and hepatoblastoma both produce β-hCG; however, there is limited evidence to show that gonadotropin-independent PP is caused by other β-hCG-producing tumors. We herein report the first case of β-hCG-producing neuroblastoma associated with the development of gonadotropin-independent PP. A 2-year-old boy presented with an increased penile length, enlargement of the testes, pigmentation of the external genitalia, and growth acceleration. Imaging, blood, and urinary examinations revealed the presence of neuroblastoma in the right adrenal region. Decreased levels of luteinizing hormone and follicle-stimulating hormone with an increased testosterone level were indicative of gonadotropin-independent PP. Since serum β-hCG was elevated, β-hCG-producing neuroblastoma was suspected. Histological findings of the resected tumor were compatible with neuroblastoma. An immunohistochemical analysis using serial sections revealed staining for β-hCG in synaptophysin-positive cells. Furthermore, immunofluorescence showed the co-staining of β-hCG with neuron-specific enolase. These results suggested that β-hCG was produced by tumor cells. Surgical removal of the tumor promptly normalized serum β-hCG and testosterone levels. In conclusion, we propose the addition of neuroblastoma to the list of differential diagnoses of gonadotropin-independent PP with β-hCG positivity in serum that includes germ cell tumors and hepatoblastoma.

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  • Takuya Murata, Shuichi Chiba, Mitsumori Kawaminami
    Type: Original
    Article ID: EJ21-0397
    Published: 2021
    [Advance publication] Released: October 12, 2021
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    Gonadotropin-releasing hormone (GnRH) stimulation of annexin A1 (ANXA1) and A5 (ANXA5) mRNA expression was analyzed in LβT2 gonadotrope cells. Quantitative polymerase chain reaction results showed that a GnRH analog (GnRHa) stimulated the expression of both ANXA1 and A5 mRNA with a peak at 12 h of incubation; however, ANXA1 mRNA was extremely stimulated (60 folds). Immunocytochemical analysis confirmed these findings. A GnRH antagonist inhibited the effect of GnRHa. ANXA1 and A5 mRNA levels were significantly increased by protein kinase C (PKC) activator (12-O-Tetradecanoylphorbol-13-acetate; TPA), but not by dibutyryl cAMP. GnRHa-stimulated induction of ANXA1 and A5 mRNA was inhibited by PKC (GF109203) and MEK inhibitors (PD98059). TPA increased ANXA1 and A5 mRNA expression in a dose-dependent manner (1 nM to 10 μM), while the extent of the increase was much greater in ANXA1. After stimulation with 10 nM or 1 μM TPA, ANXA1 and A5 mRNA levels were increased at 6 h. ANXA1 mRNA levels were higher in the 1 μM TPA than in the 10 nM TPA treatment, whereas 1 μM TPA did not show further stimulation of ANXA5 mRNA compared to 10 nM TPA. These results clearly show that ANXA1 mRNA expression is stimulated by GnRH through PKC like ANXA5, and the response of ANXA1 is much larger than that of ANXA5. A close relationship between these annexins and a significant role for ANXA1 in GnRH action at gonadotropes is suggested.

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  • Mao Zheng, Li Chen, Xiaomin Nie, Dong Wang, Jie Zhu, Wei Wang, An Ren, ...
    Type: Original
    Article ID: EJ21-0297
    Published: 2021
    [Advance publication] Released: October 09, 2021
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    Supplementary material

    Pancreatic neuroendocrine tumors (P-NETs) secreting ectopic adrenocorticotropic hormones (ACTH) are rare and often delayed in diagnosis due to their atypical clinical characteristics. Here, we describe a case of P-NET in the pancreatic tail. The tumor had metastasized to the liver and secreted gastrin and ACTH. A 60-year-old female patient was diagnosed with gastrinoma in the pancreatic tail with liver metastases in 2015. After 3 months, the patient presented refractory hypokalemia and thyroid dysfunction. The final diagnosis was P-NET with ectopic ACTH syndrome (EAS). After cytoreductive surgery and the use of long-acting somatostatin analogs, plasma potassium levels and thyroid function were effectively corrected. Although Sandostatin LAR® Depot and proton pump inhibitors (PPIs) were used throughout the follow-up period, the tumor relapsed 4 years later. After aggressive treatment, including right hepatectomy, microwave coagulation of the left liver, and cholecystectomy, the tumor returned 4 months later. Finally, the patient underwent three hepatic artery embolizations and 12 courses of CAPTEM regimen chemotherapy. The markers of disease were almost maintained in the normal ranges until now. We have followed up on this case for more than 5 years. A timely and comprehensive examination of hormones and immunohistochemistry is essential. The prognosis of P-NET is poor. Regular long-term follow-up and the application of combined therapies are helpful to control the disease and improve the prognosis.

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  • Yasuno Yamaguchi, Kohei Uchimura, Kazuya Takahashi, Toshihisa Ishii, S ...
    Type: Original
    Article ID: EJ21-0395
    Published: 2021
    [Advance publication] Released: October 09, 2021
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    Thyroid hormones are critical regulators of vertebrate development and metabolism. Under hyperthyroid conditions, excess thyroid hormones induce expression of several enzymes and activities via activation of ligand-bound thyroid hormone receptors (TRs). Arginase (ARG) is downstream of a ligand-bound TR and overexpression of ARG2 induces the production of reactive oxygen species and subsequent exacerbation of kidney ischemia/reperfusion (I/R) injury. To clarify the association between I/R-induced kidney injury and hyperthyroidism, mice were pretreated with L-thyroxine (LT4) or vehicle alone, then subjected to I/R. Proximal tubular cell-specific conditional knockout of thyroid hormone receptor β (TRβcKO) mice was generated and the effects of I/R were analyzed. Hyperthyroidism enhanced tubular damage and fibrosis in the kidneys of mice after I/R. Hyperthyroidism induced tubular cell necroptosis following inflammatory cell accumulation in the kidney after I/R. ARG2 expressions and reactive oxygen species accumulated in the kidneys of hyperthyroid mice after I/R, but these changes were ameliorated in the kidneys of TRβcKO mice. Hyperthyroidism-enhanced kidney injury was ameliorated in the kidney of TRβcKO mice after I/R. These results suggest that excess thyroid hormones are disadvantageous for the kidney under ischemic stress. Overt hypothyroidism represents a severe thyroid hormone deficiency disease that requires LT4 treatment, while overreplacement or iatrogenic thyrotoxicosis might cause kidney injury.

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  • Lucia Sugawara, Takaaki Nakamura, Yoshitaka Ishizuka, Hiroshi Maegawa
    Type: Original
    Article ID: EJ21-0187
    Published: 2021
    [Advance publication] Released: September 17, 2021
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    The etiology of central diabetes insipidus (DI) is classified into (1) idiopathic, (2) familial, and (3) secondary. Of these, familial central diabetes insipidus shows an autosomal dominant inheritance. We herein report a case in which this disease was diagnosed based on a family history of nocturnal enuresis. A 40-year-old man had had symptoms of polydipsia, polyuria and nocturia since childhood and found that his daughter had the same symptoms. Despite reaching nine years old, his daughter’s nocturnal enuresis still had not improved, resulting in her consulting a pediatrician. She was suspected of having familial neurohypophyseal diabetes insipidus (FNDI) based on her family history and was referred along with her father for a detailed examination and treatment. A hypertonic saline load test (HSLT) to evaluate the arginine vasopressin (AVP) reaction was performed in both the proband and his daughter. The results showed no increase in AVP levels in response to high plasma osmolality. The water deprivation test (WDT) revealed he was suffering from partial DI. Based on the above findings and considering the possibility of familial central diabetes insipidus, we performed a gene mutation analysis of AVP-neurophysin II (NPII). Both the father and daughter had an exon 2 abnormality in this gene (c232_234delGAG; pGlu78del), and this gene mutation is known to cause NPII protein abnormality, abolishing the function of AVP as a carrier protein. This case was considered to have provided an opportunity to understand the role of an NPII gene abnormality in familial central diabetes insipidus.

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  • Shuji Fukata, Mitsuru Ito, Mitsushige Nishikawa, Toshihiko Kasahara, E ...
    Type: Note
    Article ID: EJ21-0387
    Published: 2021
    [Advance publication] Released: October 06, 2021
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    Nephrotic syndrome (NS) is characterized by massive urinary protein leakage and associated hypoproteinemia due to increased protein permeability caused by impaired renal glomerular connections. Although there have been several sporadic reports regarding the relationship between NS and thyroid dysfunction, a consensus has yet to be reached. The mechanism of hypothyroidism in NS is attributed to the loss of protein-bound thyroid hormones, such as thyroxine-binding globulin, transthyretin, and albumin, into the urine. Herein, we report four adults with hypothyroidism that developed or worsened due to the onset of NS. The patients’ underlying thyroid status was post-total thyroidectomy with supplemental levothyroxine (L-T4) in two patients, hypothyroidism with supplemental L-T4 due to Hashimoto’s disease in one patient, and Hashimoto’s disease with normal thyroid function in one patient. Our results suggest that the presence of a reduced thyroid reserve may predispose patients to hypothyroidism in NS. We conclude that NS may cause or exacerbate hypothyroidism. In such cases, an NS assessment, including a urine test, is required.

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  • Yozen Fuse, Yoshiya Ito, Nobu Tsukada, Yoshimasa Shishiba, Minoru Irie
    Type: Original
    Article ID: EJ21-0479
    Published: 2021
    [Advance publication] Released: October 02, 2021
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    Iodine is an essential component of thyroid hormones and a dietary micronutrient for humans, and adequate iodine intake is necessary to maintain thyroid function. A population’s iodine intake and nutritional status are assessed based on urinary iodine excretion. There are few studies on iodine nutritional status for all age groups residing in the same area in Japan. Between 2010 and 2017, a total of 769 healthy subjects aged 6.4–73 years in three sites in Yokohama City, were enrolled in the survey. The urinary iodine concentration (UIC), iodine to creatinine (Cr) ratio (UI/Cr) and estimated 24-h urinary iodine excretion (UIE) in single spot urine samples were measured, and habitual dietary iodine intake was assessed by food frequency questionnaires. The estimated 24-h UIE was calculated using individual predicted 24-h creatinine excretion by the validated equations developed for healthy Japanese children and adults which vary by age, gender and anthropometry. The median UIC for all participants was 219 μg/L, suggesting adequate iodine intake for this population. There was an increasing trend in median UI/Cr and estimated 24-h UIE by age. A significant correlation between UIC and UI/Cr (r = 0.6378), UIC and estimated 24-h UIE (r = 0.6804), and UI/Cr and estimated 24-h UIE (r = 0.5756) were observed. These estimates can be feasible, convenient and alternative methods to 24-h urine collection in order to assess iodine status in some populations such as ethnically or racially homogeneous and well-nourished people. Additional studies are required to validate these findings.

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  • Toshiaki Tanaka, Shun Soneda, Naoko Sato, Kentaro Kishi, Masahiro Noda ...
    Type: Original
    Article ID: EJ21-0209
    Published: 2021
    [Advance publication] Released: September 29, 2021
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    We investigated whether growth hormone (GH) treatment could accelerate the onset of puberty in patients with isolated GH deficiency (GHD). Of the 135 boys and 89 girls who started GH treatment before the onset of puberty and were followed up at Tanaka Growth Clinic, 83 boys and 51 girls who started GH treatment sufficiently earlier than the average age at onset of puberty of GHD patients (<10 years vs. 11.7 years for boys; <9.5 years vs. 11.4 years for girls) were analyzed. Age at onset of puberty significantly positively correlated to age at the start of GH treatment (boys: r = 0.427, p < 0.0001; girls: r = 0.302, p < 0.05). When the subjects were divided into two groups each: for boys, Groups A (n = 45) and B (n = 39), treatment was started at age <8 and 8 to <10 years, respectively; for girls, Groups A (n = 26) and B (n = 21), treatment was started at age <7 and 7 to <9.5 years, respectively, age at the onset of puberty was significantly lower in Groups A than in Groups B by the Mann-Whitney U test (boys: p < 0.01; girls: p < 0.05) and Kaplan-Meier log-rank test (boys: p < 0.01; girls: p < 0.05). These results indicate that GH treatment accelerates the delayed onset of puberty in patients with GHD. Heights at the onset of puberty in Groups A and B were not significantly different, suggesting that early treatment does not increase adult height.

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  • Chunhu Wang, Meng Wang, Jiguang Ma
    Type: Original
    Article ID: EJ20-0734
    Published: 2021
    [Advance publication] Released: September 28, 2021
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    Supplementary material

    Obesity is a chronic and complex psychosomatic disease that is becoming increasingly prevalent worldwide. This study aimed to analyze whole methylation profiles to uncover the epigenetic mechanisms associated with obesity. DNA methylation profiles in blood samples from patients with obesity and normal controls were studied using the Illumina 850 K methylation microarray. The diagnostic value of the differentially methylated genes was determined using receiver operating characteristic (ROC) analysis. The expression of selected candidate genes was verified using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and pyrosequencing. A total of 9,371 significantly differentially methylated sites (7,974 hypermethylated sites and 1,397 hypomethylated sites) were identified in 4,571 genes. A difference in the distribution of differentially methylated sites (hypermethylated and hypomethylated) in both gene structures and CpG islands was observed. A total of 114 key differentially methylated sites were identified in the CpG islands. ROC results indicated that Inhibin Subunit Beta B (INHBB), Homeobox A9 (HOXA9), Troponin T3 (TNNT3), Cyclic adenosine monophosphate (cAMP)-responsive element binding protein (CREB)-regulated transcription coactivator 1 (CRTC1) and Zinc finger and BTB domain-containing 7 B (ZBTB7B) could discriminate patients with obesity from normal controls. RT-qPCR results of CRTC1 and ZBTB7B were consistent with our methylation profile results. The pyrosequencing results showed that the methylation levels of CRTC1 CpG sites (CpG1 and CpG2-cg11660071) and INHBB CpG sites (CpG2) were significantly changed in patients with obesity compared with normal controls, which was consistent with our DNA methylation profile results. Our study provides new insights into the pathological mechanism of obesity.

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  • Xianjiao Cao, Jian Zhu, Xiaolei Li, Yunhan Ma, Qingqing He
    Type: Original
    Article ID: EJ21-0076
    Published: 2021
    [Advance publication] Released: September 28, 2021
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    The receptors of chemokines play a significance role in the aggressiveness of tumor. CXCR4/CXCR7 promote metastasis of papillary thyroid carcinoma (PTC). This study examined the expresssion of chemokine receptors CXCR4/CXCR7 in human tissue specimens of PTC and peritumoral nonmalignant tissues. The correlation between CXCR4/CXCR7 and the clinicopathological factors in PTC was also determined. CXCR4/CXCR7 were examined in 115 PTC tissues from 115 patients using immunohistochemistry. Staining intensity was compared with patients and tumor characteristics including gender, age, tumor size, capsule invasion, multifocality, lymph node metastasis, and nature of paracancerous tissue. [Statistics: rank sum test, Spearman rank order correlation test; p < 0.05]. Higher expression rates of CXCR4/CXCR7 exhibited in PTC compared with peritumoral nonmalignant tissues. The expression of them was correlated in cancer and paracancerous specimens. A trend toward higher CXCR4/CXCR7 expression was found among tumors showing positive lymph nodes and capsule invasion, while no association with sex, age, tumor size, and nature of paracancerous tissue. Number of lymph nodes was associated with higher intensity IHC staining for CXCR4/CXCR7. Intense staining for CXCR4 was also associated with multifocality. Expression of CXCR4/CXCR7 by PTCs was correlated with lymph node metastasis and capsule invasion. Although multiple bias, they were thought to play a significance role in the aggressiveness of PTC, which provides potential targets for therapeutic interventions.

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  • Tomomi Taguchi, Agena Suzuki, Koji Takano
    Type: Original
    Article ID: EJ21-0439
    Published: 2021
    [Advance publication] Released: September 28, 2021
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    Acromegaly is often complicated by impaired glucose tolerance. The accuracy of glycated hemoglobin (HbA1c) and glycated albumin (GA) levels in representing glycemic profiles in patients with endocrine disorders, such as acromegaly, is unclear. This retrospective study reviewed data from patients whose GA levels had been recorded. 14 patients with acromegaly without diabetes mellitus (DM) (the acromegaly group), 15 patients with severe adult GH deficiency without DM (the growth hormone deficiency (GHD) group), and 55 nondiabetic patients (the control group) were included in this study. GA levels were significantly increased in the acromegaly group compared with the control and GHD groups, but no significant differences were observed between the control and GHD groups. The three groups were matched using propensity score matching (13 patients with acromegaly, 13 with GHD, and 13 control patients). Nonetheless, the results after matching were the same as those before matching. GA levels in the acromegaly group were significantly associated with plasma glucose (PG) levels at 0, 30, and 120 min after a 75-g oral glucose tolerance test (OGTT). Further, GH levels at 120 min after a 75-g OGTT in the acromegaly group were significantly correlated with GA levels and the difference in PG levels at baseline and 30 min. Our findings suggest that increases in PG levels attributable to excess GH after glucose loading are related to increases in GA levels in patients with acromegaly without DM. Hence, both HbA1c and GA should be checked to accurately assess impaired glucose tolerance in patients with acromegaly.

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  • Haibo Zheng, Qingfeng Fu, Kaili Ma, Shuai Shi, Yantao Fu
    Type: Original
    Article ID: EJ20-0498
    Published: 2021
    [Advance publication] Released: September 25, 2021
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    Circular RNAs (circRNAs) are a group of non-coding RNAs featured by covalently closed circular structure. CircRNA_0079558 (circ_0079558) is derived from RAPGEF5 gene, and it has been found to be significantly up-regulated in papillary thyroid carcinoma (PTC). However, the role and working mechanism of circ_0079558 in PTC progression have never been illustrated. The levels of circ_0079558 and MET proto-oncogene, receptor tyrosine kinase (MET) were up-regulated in PTC tissues and cell lines, as evidenced by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot assay. The silencing of circ_0079558 or MET restrained cell proliferation, migration and invasion whereas triggered cell apoptosis in PTC cells, as verified by Cell Counting Kit-8 (CCK8) assay, plate colony formation assay, transwell invasion assay, wound healing assay and flow cytometry. Through using MET specific inhibitor PHA665752, we found that circ_0079558 overexpression enhanced the malignant behaviors of PTC cells through activating MET/AKT pathway. Through dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay, microRNA-26b-5p (miR-26b-5p) was identified to be the intermediary molecular between circ_0079558 and MET, and circ_0079558 knockdown reduced the expression of MET partly through elevating miR-26b-5p in PTC cells. The miR-198/FGFR1 pathway was identified as another signal axis downstream of circ_0079558, and the co-overexpression of FGFR1 and MET largely rescued the proliferation ability of circ_0079558-silenced PTC cells. Through xenograft tumor model, we found that circ_0079558 silencing restrained xenograft tumor growth in vivo. In conclusion, circ_0079558 facilitated the proliferation and motility whereas inhibited the apoptosis of PTC cells largely through mediating miR-26b-5p/MET/AKT signaling.

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  • Kenji Ohba, Shigekazu Sasaki, Hiroko Misawa Nakamura, Akio Matsushita, ...
    Type: Original
    Article ID: EJ21-0390
    Published: 2021
    [Advance publication] Released: September 22, 2021
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    Resistance to thyroid hormone beta (RTHβ) caused by germline mutations in genes encoding thyroid hormone receptor beta (TRβ) is a rare disorder. Little information is available regarding the clinical experience of this syndrome in Japan. We retrospectively reviewed the records of 34 patients with RTHβ (21 adult females and 13 adult males) with positive TRβ mutations identified at our division between 2000 and 2020. Of the 24 patients with available clinical history, 10 (41.7%) received inappropriate treatments such as antithyroid drugs, thyroidectomy, or radioactive iodine. Diagnostic delay and inappropriate management of RTHβ are still present in Japan. Every patient except one demonstrated thyroid hormone profiles indicative of syndrome of inappropriate secretion of thyrotropin (SITSH), characterized by a hormonal profile of hyperthyroxinemia with a non-suppressed TSH concentration. Since the most common forms of hyperthyroidism including Graves’ disease feature elevated thyroid hormone levels with suppressed TSH concentrations, early diagnosis of SITSH is critical for preventing inappropriate management. One patient positive for anti-thyroglobulin antibody (Tg-Ab) and anti-thyroperoxidase antibody (TPO-Ab) showed remarkably elevated TSH (>200 μIU/mL) despite thyroid hormone concentrations within the reference ranges. At least one thyroid autoantibody (Tg-Ab, TPO-Ab, or thyrotropin receptor antibodies) was identified in 37.9% (11/29) of the patients tested. One patient developed overt Graves’ disease nine years after ‍RTHβ diagnosis. These findings suggest that RTHβ is frequently comorbid with additional autoimmune thyroid disorders. ‍Further research is required to identify the most appropriate treatments for RTHβ patients who develop a second thyroid ‍disorder.

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  • Ken Okamura, Hiroko Ibayashi, Kaori Sato, Megumi Fujikawa, Sachiko Ban ...
    Type: Original
    Article ID: EJ21-0340
    Published: 2021
    [Advance publication] Released: September 18, 2021
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    A 28-year-old Japanese woman positive for TSH receptor antibody and anti-nuclear antibody complained of difficulty seeing nearby objects, severe throbbing retro-orbital pain, diplopia, blepharoptosis and upward gaze palsy when she became hypothyroid during treatment with 30 mg methylmercaptoimidazole for Graves’ hyperthyroidism. Brain magnetic resonance imaging revealed slightly swollen bilateral inferior rectus muscles, suggesting the external ophthalmoplegia due to the muscle pathology commonly encountered in Graves’ disease. The retro-orbital pain was associated with marked accommodation failure and the pupillary abnormalities. The left and/or right eye showed intermittent, asymmetric and fluctuating mydriasis, being unresponsive to ordinary light but slowly responsive to strong sunlight and slowly responsive in a dark room. During the 5-year period, mydriasis was observed 9 times on both sides, 11 times only on the right side and 4 times only on the left side. Internal ophthalmoplegia with tonic pupils and accommodation failure affecting both the pupillary sphincter muscle and ciliary muscle due to damage to the parasympathetic outflow to these muscles was suggested. Autoimmune mechanism and/or the mechanism underlying channelopathy affecting the ciliary ganglion or short ciliary nerves might be responsible for this fluctuating complication. This very rare panophthalmopathy affecting both external and internal muscles occurred when the patient was suffering from iatrogenic hypothyroidism during the 30 mg methylmercaptimidazole treatment for Graves’ disease.

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  • Hiroshi Kamma, Kaori Kameyama, Tetsuo Kondo, Yoshiaki Imamura, Masahir ...
    Type: Original
    Article ID: EJ21-0388
    Published: 2021
    [Advance publication] Released: September 15, 2021
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    The Japanese Society of Thyroid Pathology and the Japan Association of Endocrine Surgeons developed the eighth edition of the General Rules for the Description of Thyroid Cancer (GRDTC) in December 2019. This article describes the pathological diagnosis of the GRDTC, which has been improved through repeated revisions based on the experience of Japanese pathologists and translated into English to introduce the Japanese diagnostic standard to foreign countries. In this edition of the GRDTC, the histopathological classification and descriptions differ in some respects from those of the fourth edition of the World Health Organization (WHO) classification as revised in 2017. For example, the GRDTC does not adopt the concept of borderline lesions (FT-UMP, WDT-UMP, and NIFTP) of the WHO, taking into consideration the popular histological criteria accepted by Japanese pathologists. The cytological reporting system of the GRDTC was partly modified from the Bethesda system in 2015. It has an additional cyst fluid category separated from the unsatisfactory category that has been demonstrated to be useful in Japan. This translated edition makes it easy to submit Japanese clinicopathological studies of thyroid tumors in an international journal. We also wish to contribute to the improvement, standardization, and globalization of the pathological diagnosis of thyroid tumors.

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  • Mizuho Minakata, Mitsuru Ito, Taketoshi Kishi, Mikiko Hada, Yuzuki Mas ...
    Type: Original
    Article ID: EJ21-0109
    Published: 2021
    [Advance publication] Released: September 14, 2021
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    The dose of L-T4 replacement for hypothyroidism often needs to be increased after pregnancy. In our institution, patients are instructed to double the dose 2 days a week after pregnancy. However, there is scarce evidence supporting the need for a dose increase after pregnancy in patients with preconception thyroid-stimulating hormone (TSH) suppression (TSH <0.3 μIU/mL). This study aimed to determine the need for a dose increase in L-T4 among women with a TSH-suppressive dose of L-T4 before pregnancy. In this retrospective observational study, between January 2008 and December 2018, we analyzed 166 pregnancies in 134 patients on TSH suppression treatment after total thyroidectomy for papillary carcinoma. Thyroid function tests were performed before and in the first trimester of pregnancy. The dose was adjusted and maintained during the first trimester of pregnancy in 76 pregnancies (group A) and 90 pregnancies (group B), respectively. The median ‍serum TSH level was significantly lower in group A than that in group B (0.014 μIU/mL (IQR, 0.005–0.071) vs. 0.155 ‍μIU/mL (IQR, 0.021–0.657), p < 0.001). TSH suppression could not be maintained after pregnancy in 15.8% and 38.9% of the pregnancies in groups A and B, respectively. Increasing the post-pregnancy dose by an average of 27.4% resulted in maintenance of TSH suppression after pregnancy in 84.2% of pregnancies. In conclusion, this study suggests that increasing the L-T4 dose after pregnancy may be appropriate in postoperative thyroid cancer patients whose serum TSH levels should be ‍suppressed.

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  • Minna Zhang, Junlan Yan, Xueyan Liu, Peiru Zhou, Jiewei Huang, Kaiming ...
    Type: Original
    Article ID: EJ21-0114
    Published: 2021
    [Advance publication] Released: September 14, 2021
    JOURNAL FREE ACCESS ADVANCE PUBLICATION

    Peripheral arterialdisease (PAD) can result in diabetic foot ulcers, gangrene, and even amputation. Since most cases of PAD in diabetic patients are associated with peripheral neuropathy, the symptoms of vascular disease are easily concealed by the symptoms of neuropathy and are ignored by people, so it is critical for health care providers to screen PAD for the diabetes patients. This study was carried out to identify theprevalence and related factors of PAD in diabetes mellitus inpatients. This was a cross-sectional observational study. A total of 855 patients were enrolled in the study from December 2018 to December 2019. The patients were divided into a non-PAD group (ABI = 0.9–1.3) and a PAD group (ABI <0.9). Logistic multivariate regression analysis showed that age, LDL-C, dorsalis pedis artery pulsation (left foot), and sensory-current threshold (right foot) were related factors for peripheral arterial disease. Patients who are older and have a higher LDL-C level, abnormal dorsal foot pulse, and abnormal sensory-current threshold must be vigilant, and receive early screening for PAD diagnosis and treatment to avoid a malignant outcome. In clinical work, medical staff should actively apply PAD screening to diabetic patients, identify risk factors as early as possible, conduct early interventions, reduce the risk of PAD in patients, and avoid the occurrence of adverse outcomes.

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  • Masato Iwabu, Miki Okada-Iwabu, Takashi Kadowaki, Toshimasa Yamauchi
    Type: Review
    Article ID: EJ21-0294
    Published: 2021
    [Advance publication] Released: September 11, 2021
    JOURNAL FREE ACCESS ADVANCE PUBLICATION

    While it is well recognized that exercise represents a radical preventive and therapeutic measure for lifestyle-related diseases, it is clear that contemporary lifestyles abound with situations where exercise may be found difficult to implement on a continuous basis. Indeed, this has led to global expectations for elucidation of the exercise-activated skeletal muscle signaling pathways as well as for development of exercise mimics that effectively activate such pathways. It is shown that exercise activates the transcriptional coactivator PGC-1α via AMPK/SIRT1 in muscle, thereby not only enhancing mitochondrial function and muscle endurance but upregulating energy metabolism. Further, adipocyte-derived adiponectin is also shown to activate AMPK/SIRT1/PGC-1α via its receptor AdipoR1 in skeletal muscles. Thus, adiponectin/AdipoR1 signaling is thought to constitute exercise-mimicking signaling. Indeed, it has become clear that AMPK, SIRT1 and AdipoR activators act as exercise mimetics. With the crystal structures of AdipoR elucidated and humanized AdipoR mice generated toward optimization of candidate AdipoR-activators for human use, expectations are mounting for the clinical application in the near future of AdipoR activators as exercise mimetics in humans. This review provides an overview of molecules activated by exercise and compounds activating these molecules, with a focus on the therapeutic potential of AdipoR activators as exercise mimetics.

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  • Hui Liu, Xi-yu Yao, Zong-qing Zheng, Shun-jin Chen
    Type: Original
    Article ID: EJ21-0073
    Published: 2021
    [Advance publication] Released: September 07, 2021
    JOURNAL FREE ACCESS ADVANCE PUBLICATION

    Posterior recurrent laryngeal nerve (RLN) lymph node dissection remains controversial in the operation of thyroid cancer, especially in cases of papillary thyroid microcarcinoma (PTMC). The present study aimed to evaluate the risk factors for posterior RLN lymph node metastasis in patients with PTMC. Two hundred and thirty-nine patients pathologically diagnosed with PTMC after surgery between June 2016 and June 2017 were included. Risk factors including age, sex, tumor diameter, multiple tumor focus, membrane invasion and lateral cervical lymph node metastasis condition, were analyzed, and their corresponding OR values were calculated. The results indicated that posterior RLN lymph node metastasis was pathologically identified in 27/239 patients. Membrane invasion (p = 0.024), VIa lymph node metastasis (p < 0.01), and lateral cervical lymph node metastasis (p < 0.01) were considered to be risk factors for posterior RLN lymph node metastasis. It is concluded that membrane invasion, VIa lymph node metastasis, and lateral cervical lymph node metastasis significantly increased the incidence of posterior RLN lymph node metastasis. Complete dissection of the posterior RLN lymph node was essential for patients with these risk factors.

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  • Yuka Natsuki, Tomoaki Morioka, Shinya Fukumoto, Yoshinori Kakutani, Yu ...
    Type: Original
    Article ID: EJ21-0185
    Published: 2021
    [Advance publication] Released: September 08, 2021
    JOURNAL FREE ACCESS ADVANCE PUBLICATION

    Fibroblast growth factor 23 (FGF23) is a key regulator of phosphate metabolism. Circulating FGF23 levels are associated with obesity, metabolic syndrome, and cardiovascular disease in the general population, but the underlying mechanism remains unclear. Therefore, we aimed to determine the associations between serum FGF23 levels and visceral adiposity as well as serum adiponectin levels in 189 adults without diabetes and with normal kidney function who were selected from the MedCity21 health examination registry. The exclusion criteria included diabetes mellitus or impaired kidney function (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2). Levels of serum FGF23 and total adiponectin, and visceral fat area (VFA) on computed tomography images were measured. Serum FGF23 levels were higher and VFA was greater, whereas serum adiponectin levels were lower in men than in women. Serum FGF23 levels positively correlated with VFA in men; they remained marginally significant after adjusting for age, eGFR, and serum levels of calcium, phosphate, intact parathyroid hormone, and 1,25-dihydroxyvitamin D. Importantly, when serum adiponectin levels were included as a covariate, serum adiponectin levels comprised an independent determinant of serum FGF23 levels in men, whereas VFA did not. In conclusion, lower serum adiponectin, rather than a greater VFA, was associated with higher serum FGF23 levels in non-diabetic men with normal kidney function. These findings suggest that adiponectin plays a role in the relationship between visceral adiposity and FGF23 in men.

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  • Han-Chong Zhang, Tie Wen, Yu-Zhong Cai
    Type: Original
    Article ID: EJ21-0177
    Published: 2021
    [Advance publication] Released: September 04, 2021
    JOURNAL FREE ACCESS ADVANCE PUBLICATION

    In the current study, we aimed to study the effect of miR-146a on proliferation and migration in an in vitro diabetic foot ulcer (DFU) model by targeting A-kinase-anchoring protein 12 (AKAP12). An in vitro DFU model was initially established using HaCaT cells derived from human keratinocytes and induced by advanced glycation end products (AGEs). The effects of overexpression of miR-146a on proliferation and migration ability were analysed. The expression levels of miR-146a and AKAP12 were measured by quantitative real-time polymerase chain reaction (qRT-PCR), and AKAP12, hypoxia-inducible factor-1α (HIF-1α), Wnt3a and β-catenin protein levels were measured by western blotting. The cell proliferation ability was measured by MTT, and the migration ability was analysed by a cell scratch assay. The binding between miR-146a and AKAP12 was identified using a luciferase reporter assay. The results demonstrated that AGEs significantly suppressed cell proliferation and migration, while the expression of miR-146a decreased and the expression of AKAP12 increased. A luciferase reporter assay revealed that miR-146a could directly target AKAP12. Overexpression of miR-146a promoted cell proliferation and migration in an in vitro DFU model and also promoted the expression of HIF-1α, Wnt3a and β-catenin but suppressed the expression of AKAP12. Co-overexpression of miR-146a and AKAP12 reversed the effect of miR-146a on cell proliferation and migration. Our findings revealed that miR-146a directly targeted AKAP12 and promoted cell proliferation and migration in an in vitro DFU model. This study provides a new perspective for the study of miR-146a in the treatment of DFU.

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  • Satoshi Yamagata, Kazunori Kageyama, Takeshi Usui, Kohei Saito, Shinob ...
    Type: Original
    Article ID: EJ21-0266
    Published: 2021
    [Advance publication] Released: September 03, 2021
    JOURNAL FREE ACCESS ADVANCE PUBLICATION

    17α-Hydroxylase/17,20-lyase deficiency (17OHD) is caused by pathogenic mutations in CYP17A1. Impaired 17α-hydroxylase and 17,20-lyase activities typically induce hypertension, hypokalemia, sexual infantilism, and amenorrhea. Most patients with 17OHD are diagnosed in adolescence. Here, we report a female (46, XX) patient with 17OHD who was diagnosed at the age of 67 years. Genetic analysis was performed using direct DNA sequencing of polymerase chain reaction (PCR) products and multiplex ligation-dependent probe amplification (MLPA) analysis. Direct DNA sequencing revealed a homozygous c.1039C>T in CYP17A1, corresponding to a p.R347C amino acid change. MLPA probe signals showed that the ‍CYP17A1 mutation was present in the homozygous carrier state. The patient’s dehydroepiandrosterone sulfate and androstenedione levels were extremely low, despite elevated adrenocorticotropic hormone (ACTH) and normal cortisol levels. A corticotropin-releasing hormone (CRH) test showed no response of cortisol, despite a normal response of ACTH. Rapid ACTH injection resulted in elevations in the deoxycorticosterone, corticosterone, aldosterone, and 17-hydroxypregnenolone levels, but not in the cortisol level. These results suggested that 17α-hydroxylase/17,20-lyase activities were partially impaired. Computed tomography revealed bilateral adrenal hyperplasia and a hypoplastic uterus. A high basal plasma ACTH level and a discrepancy between ACTH and cortisol responses in a CRH test may provide a definitive diagnostic clue for this ‍disease.

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  • Aki Kondo, Takaaki Murakami, Toshihito Fujii, Makiko Tatsumi, Yoriko U ...
    Type: Note
    Article ID: EJ21-0359
    Published: 2021
    [Advance publication] Released: September 03, 2021
    JOURNAL FREE ACCESS ADVANCE PUBLICATION

    Opioids are widely used for treatment of acute and chronic pain. However, opioids have several well-known clinical adverse effects such as constipation, nausea, respiratory depression and drowsiness. Endocrine dysfunctions are also opioid-induced adverse effects but remain under-diagnosed in clinical settings, especially opioid-induced adrenal insufficiency (OIAI). A 46-year-old woman was treated with transdermal fentanyl at a dose of 90–120 mg daily morphine milligram equivalent for non-malignant chronic pain for four years. Fatigue, loss of appetite and decrease in vitality began about two years after starting fentanyl. Subsequently, constipation and abdominal pain appeared and became worse, which led to suspicion of adrenal insufficiency. Clinical diagnosis of OIAI was established based on laboratory findings of secondary adrenal insufficiency, including corticotropin-releasing hormone stimulation test, clinical history of long-term fentanyl use, and exclusion of other hypothalamic-pituitary diseases. Oral corticosteroid replacement therapy was unable to relieve her abdominal pain and constipation; opioid-rotation and dose-reduction of fentanyl were not feasible because of her persistent pain and severe anxiety. While her clinical course clearly suggested that long-term, relatively high-dose transdermal fentanyl treatment may have contributed to the development of secondary adrenal insufficiency, the symptoms associated with OIAI are generally non-specific and complex. Together with under-recognition of OIAI as a clinical entity, the non-specific, wide range of symptoms can impede prompt diagnosis. Thus, vigilance for early symptoms enabling treatments including corticosteroid replacement therapy is necessary for patients taking long-term and/or high dose opioid treatment.

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  • Fang Zhao, Quan-wei Wei, Bo-jiang Li, Qian-nan Weng, Yi Jiang, Cai-bo ...
    Type: Original
    Article ID: EJ21-0184
    Published: 2021
    [Advance publication] Released: August 28, 2021
    JOURNAL FREE ACCESS ADVANCE PUBLICATION

    Chronic stress affects the reproductive health of mammals; however, the impact of adrenocorticotropin hormone (ACTH) level elevation during chronic stress on the reproduction of weaned sows remains unclear. In this study, nine weaned sows with the same parturition date were randomly divided into control group (n = 4) and ACTH group (n = 5). Each group received intravenous administration of ACTH three times daily for 7 days. Blood samples were collected every 3 h after injection. A radioimmunoassay was used to measure the concentrations of cortisol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), progesterone (P4) and estradiol-17β (E2) in the blood. Estrus was determined according to changes in the vulva and the boar contact test. The mRNA expressions of glucocorticoid receptor, FSH receptor, LH receptor (LHR) in the corpus luteum (CL) were detected by qRT-PCR. The results showed that ACTH administration substantially delayed the initiation of estrus and the pre-ovulatory LH peak. The sows of control group ovulated within 10 days and the ovulation rate was 100%, while it was 60% in the ACTH group. Two sows of ACTH group showed pseudo-estrus. The E2 concentrations significantly decreased in the ACTH group at 36 h, 42 h and 66 h of the experimental period. The P4 concentrations in the ACTH group significantly decreased at 132, 138, and 147 h of the experimental period. ACTH significantly reduced the LHR mRNA expression in CLs. In conclusion, long-term repeated ACTH administration affects the endocrinology, estrus onset, and ovarian function of weaned sows.

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  • Hiroshi Yokomichi, Mie Mochizuki, Reiji Kojima, Sayaka Horiuchi, Tadao ...
    Type: Original
    Article ID: EJ21-0168
    Published: 2021
    [Advance publication] Released: August 26, 2021
    JOURNAL FREE ACCESS ADVANCE PUBLICATION

    In this study, we aimed to determine the association of neonatal/post-neonatal hypothyroidism with mother’s iodine exposure, especially povidone iodine disinfection, and hysterosalpingography. Participants were mother–child pairs in a Japanese birth cohort (n = 100,286). Risk factors of hypothyroidism were supplement intake, seaweed intake, other daily iodine intake, povidone iodine disinfection at delivery, and maternal history of hysterosalpingography, thyroid disease (Graves’ disease and Hashimoto’s thyroiditis), and medication (thiamazole and levothyroxine). Congenital hypothyroidism (CH) at age 1 year was assessed using a questionnaire. Transient hypothyroidism was defined as elevated thyroid stimulating hormone level at birth and absence of CH at age 1 year. The incidence of CH at age 1 year per 100 children was 1.1 for those born at 22–30 weeks’ gestation, 0.17 following povidone iodine disinfection, and 0.07, 0.95, 0.81, 1.17, and 1.15 with a maternal history of hysterosalpingography, Graves’ disease, Hashimoto’s thyroiditis, thiamazole use, and levothyroxine use, respectively. Odds ratios (95% confidence intervals) of CH at age 1 year for povidone iodine disinfection, hysterosalpingography history, maternal Graves’ disease, and maternal Hashimoto’s thyroiditis were 1.13 (0.71–1.79), 0.47 (0.07–3.36), 7.06 (3.70–13.5), and 5.93 (2.90–12.1), respectively. For transient hypothyroidism for povidone iodine disinfection and hysterosalpingography history, these values were 1.99 (1.51–2.62) and 0.63 (0.20–1.96), respectively. Maternal thyroid disease greatly increased neonatal/post-neonatal hypothyroidism risk. Povidone iodine disinfection may increase transient hypothyroidism risk but not the risk at 1 year of age. Hysterosalpingography does not increase hypothyroidism risk from birth to age 1 year.

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  • Norikazu Toi, Masafumi Kurajoh, Daichi Miyaoka, Yuki Nagata, Shinsuke ...
    Type: Original
    Article ID: EJ21-0313
    Published: 2021
    [Advance publication] Released: August 25, 2021
    JOURNAL FREE ACCESS ADVANCE PUBLICATION

    Bexarotene-induced central hypothyroidism (CH), for which levothyroxine (LT4) replacement is recommended, has been shown to be caused by pituitary but not hypothalamic disorder experimentally, though the underlying mechanism in humans remains unclear. Here, the pathophysiology of bexarotene-induced CH was examined using a TRH stimulation test in cutaneous T-cell lymphoma (CTCL) patients. In this retrospective longitudinal observational study, serum TSH and free T4 (F-T4) levels were measured in 10 euthyroid patients with CTCL during 24 weeks of bexarotene treatment. TRH stimulation testing was performed following CH diagnosis, with LT4 replacement dosage adjusted to maintain F-T4 at the pre-treatment level. After one week of bexarotene administration, all 10 patients developed CH, based on combined findings of low or low-normal F-T4 with low or normal TSH levels. TSH peak response after a stimulation test at one week was reached at 30 minutes. However, that was <4 μIU/mL in all patients, indicating a blunted though not exaggerated and delayed TSH response. In eight who continued bexarotene for 24 weeks, median LT4 replacement dosage was 125 (range, 75–150) μg/day. TSH level at 30 as well as 15, 60, 90, and 120 minutes after TRH stimulation was significantly correlated with LT4 replacement dosage (ρ = –0.913, p = 0.002), whereas TSH and F-T4 basal levels at one week were not. These results suggest that pituitary hypothyroidism is responsible for bexarotene-induced CH, while TSH levels after TRH stimulation precisely reflect residual pituitary-thyroid function in patients receiving bexarotene.

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  • Biyan Qin, Litao Qincao, Shuying He, Yan Liao, Jie Shi, Fang Xie, Na D ...
    Type: Original
    Article ID: EJ20-0728
    Published: 2021
    [Advance publication] Released: August 18, 2021
    JOURNAL FREE ACCESS ADVANCE PUBLICATION
    Supplementary material

    Obesity, closely related to systematic metabolic disorders, has become a major public health problem in recent decades. Here, we aimed to study the function of Parathyroid hormone-related protein (PTHrP) on high fat diet (HFD) induced murine obesity. Male C57BL/6J mice were transduced with adeno-associated virus vector encoding PTHrP (AAV-PTHrP) or adeno-associated virus control vector (AAV-Vehicle), following with HFD for 8 weeks. In addition, mice without transduction were fed on normal diet or HFD, respectively. Histological, metabolic and biochemical changes were detected. At the endpoint of experiment, body weight of mice treated with AAV-PTHrP did not increase as much as mice with AAV-Vehicle, but similar as mice with normal diet. Food efficiency ratio and weight of interscapular brown adipose tissue and epididymal white adipose tissue in mice overexpressed PTHrP were also lower than mice transducted with AAV-Vehicle. Besides, administration of AAV-PTHrP inhibited HFD-induced adipocyte hypertrophy. Protein level of PKA signaling pathway and thermogenic gene in adipose tissue exhibited a significant raise in HFD + AAV-PTHrP group, whereas transcription of inflammatory gene were decreased. Additionally, PTHrP overexpression ameliorated HFD-induced dyslipidemia, hepatic steatosis and insulin sensitivity. In HFD-induced murine obesity model, PTHrP is crucial to maintain metabolic homeostasis. PTHrP drives white adipose tissue browning and inhibits whitening of brown adipose tissue. Most importantly, PTHrP prevented HFD-induced obesity, hepatic steatosis and insulin resistance.

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  • Jieun Kim, Jung Hee Shin, Young Lyun Oh, Soo Yeon Hahn, Ko Woon Park
    Type: Original
    Article ID: EJ21-0300
    Published: 2021
    [Advance publication] Released: August 18, 2021
    JOURNAL FREE ACCESS ADVANCE PUBLICATION

    This study evaluated how to manage Bethesda category III (Bethesda III) (atypia of undetermined significance/follicular lesion of undetermined significance [AUS/FLUS]) thyroid nodules according to the Korean Thyroid Imaging Reporting and Data System (K-TIRADS) to reduce unnecessary surgeries. A total of 161 thyroid nodules diagnosed as Bethesda III underwent surgery from 2016 to 2019. Ultrasonography-guided fine-needle aspiration (US-FNA) or core needle biopsy (CNB) was used for repeat examination. K-TIRADS category was assigned to the thyroid nodules. The proportion of malignancy in Bethesda III nodules confirmed by surgery were significantly increased in proportion relative to K-TIRADS with 60.0% low suspicion, 88.2% intermediate suspicion, and 100% high suspicion nodules (p < 0.001). The proportion of malignancy in AUS and FLUS were significantly different (94.2% vs. 40.0% p = 0.003). The proportion of malignancy in AUS increased with K-TIRADS categories, but there was no difference in FLUS. All K-TIRADS high suspicion nodules were AUS as papillary carcinomas (99%), while 80% of FLUS nodules and 50% of follicular carcinomas showed K-TIRADS low suspicion. In 116 nodules with repeat FNA or CNB after initial Bethesda III results, the conclusive result rate was significantly increased in proportion to K-TIRADS with 58.3% low suspicion, 83.3% intermediate suspicion, and 88.8% high suspicion nodules (p = 0.015). K-TIRADS low suspicion nodules of Bethesda III nodules should be managed after risk-benefit consideration rather than immediate surgery or repeat examination. K-TIRADS for Bethesda III nodules can predict papillary carcinoma well, but not follicular carcinoma.

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  • Kei Takasawa, Akari Nakamura-Utsunomiya, Naoko Amano, Tomohiro Ishii, ...
    Type: Original
    Article ID: EJ21-0292
    Published: 2021
    [Advance publication] Released: August 07, 2021
    JOURNAL FREE ACCESS ADVANCE PUBLICATION

    To manage of 21-hydroxylase deficiency (21-OHD), transition medicine from pediatric to adult health care is an important process and requires individually optimized approaches. We sent cross-sectional questionnaire surveys on the current status of transition from pediatric to adult health care in 21-OHD patients to all councillors of the Japanese Society for Pediatric Endocrinology. Many pediatric departments (42.2%) experienced adult 21-OHD patients, and 115 patients (53 males, mean age of 26) in 46 institutions were identified. Whereas almost two-thirds of pediatric endocrinologists regarded the problems of counterparts and cooperation as hindrance of transition medicine, the major reason for continuing to be treated in pediatrics was the patient’s own request. The prevalence of long-term complications including obesity, osteoporosis, infertility, menstrual disorder, gender dysphoria, and testicular adrenal rest tumor were 27.5%, 8.8%, 11.1%, 26.3%, 7.1%, 12.5%, respectively, which is comparable to those of other cohorts previously reported. However, several items, especially infertility and osteoporosis were not checked well enough in adult 21-OHD patients treated in pediatrics. Though 44 of 62 female patients had genital reconstructive surgery, more than half of them were not followed up by gynecologists or pediatric urologists. Quite a few adult 21-OHD patients had been followed up in pediatrics even after coming of age; however, surveillance by pediatric endocrinologists of gynecological, reproductive, and mental problems may be insufficient. Therefore, multidisciplinary approaches should be required in transition medicine for 21-OHD and prerequisite for graduation of pediatrics. Pediatric endocrinologists will need to play a leading role in the development of transition systems.

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  • Masashi Shimoda, Akiko Mashiko, Yukino Katakura, Junpei Sanada, Yoshir ...
    Type: Note
    Article ID: EJ21-0161
    Published: 2021
    [Advance publication] Released: July 31, 2021
    JOURNAL FREE ACCESS ADVANCE PUBLICATION
    Supplementary material

    Advances in insulin preparations and administration methods have produced a gradual improvement in glycemic control in patients with type 1 diabetes mellitus (DM). Nevertheless, glycated hemoglobin (HbA1c) levels in patients with type 1 DM are still poor compared to those in patients with type 2 DM. Here, we sought to assess the efficacy and safety of the sodium-glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin (IPRA) in patients with type 1 DM. This study was retrospectively conducted with data from type 1 DM patients who had a history of IPRA therapy. The primary endpoint was HbA1c level at 24 weeks. The baseline characteristics of a total of 12 subjects were as follows: age, 50.1 ± 13.2 years; diabetes duration, 17.3 ± 10.5 years; body mass index (BMI), 22.9 ± 2.1 kg/m2; HbA1c, 8.8 ± 1.3%; and daily insulin dose, 0.60 ± 0.21 units/kg. IPRA decreased HbA1c levels to 8.2 ± 1.2% (p < 0.05) and reduced insulin dose to 0.52 ± 0.17 units/kg (p < 0.01) after 24 weeks. HbA1c value was particularly reduced in subjects with preserved C-peptide index. IPRA significantly reduced body weight by –1.4 ± 1.4 kg (p < 0.01) 16 weeks after starting treatment, with no further weight loss after 24 weeks. There were no instances of diabetic ketoacidosis or severe hypoglycemia. IPRA exerted beneficial effects on glycemic control without any severe adverse effects, and should be safe and effective when used in patients with type 1 DM with understanding of correspondence in sick day.

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  • Natsuko Watanabe, Jaeduk Yoshimura Noh, Takashi Akamizu, Masanobu Yama ...
    Type: Original
    Article ID: EJ21-0238
    Published: 2021
    [Advance publication] Released: July 29, 2021
    JOURNAL FREE ACCESS ADVANCE PUBLICATION
    Supplementary material

    To clarify the actual administration of thiamazole (MMI), the first choice of antithyroid drugs, the actual therapy provided by the Japan Thyroid Association (JTA) members for the following conditions was surveyed. The subjects included adult patients, pregnant women, and pediatric patients with Graves’ disease who visited each medical institution from September 2019 to February 2020. Initial doses, frequency of administration, maintenance doses, maximum doses, consultation intervals for pregnant women, and dosages administrated to breastfeeding mothers were surveyed. The total number of cases collected was 11,663. Administration of 15 mg once a day was the most common initial therapy, constituted 74.4% (2,526/3,397 cases) of adults, 33.8% (44/130) of pregnant women, and 50.8% (61/120) of children. The maintenance dose before discontinuation was equivalent to 2.5 mg/day in 52.3% (3,147/6,015). The most common maximum dose for adults and children was 30 mg/day, administrated to 57.5% of adults (223/388) and 59.6% (28/47) of children; for pregnant women, it was 15 mg/day, administrated to 71.1% (27/38). The most common consultation interval for pregnant women was every four weeks (32.1%, 341/1,063). In lactating mothers, the dose was 10 mg/day or less in 366 of 465 cases (78.7%). Breastfeeding was also allowed 4–6 hours after the administration of 15–20 mg/day in 69 patients (14.8%). Breastfeeding was prohibited in 26 patients (5.6%). In conclusion, initial MMI therapy was started with 15 mg once a day in most patients, and MMI was also administrated to lactating mothers following the Graves’ disease treatment guidelines by the JTA.

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  • Tetsuo Nishikawa, Fumitoshi Satoh, Yuichi Takashi, Toshihiko Yanase, H ...
    Type: Original
    Article ID: EJ21-0278
    Published: 2021
    [Advance publication] Released: July 22, 2021
    JOURNAL FREE ACCESS ADVANCE PUBLICATION

    A commutability confirmation test for the blood aldosterone measurement was performed on liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) as a designated comparison method (DCM) and four chemiluminescent enzyme immunoassay (CLEIA) measurement procedures based on metrological traceability. A conventional radioimmunoassay (RIA) and two measurement procedures of CLEIA which obtains RIA equivalent values were also compared. The relationship between the DCM value and the CLEIA value with respect to 120 pg/mL of the RIA value, which is the screening criterion of primary aldosteronism (PA) was clarified. For the correlation test, 75 samples of patient serum and plasma were used. Regression analysis revealed that the standardized LC-MS/MS and four CLEIA measurement procedures were in good agreement. This is the effect of measurement specificity and calibration using by certified reference material (CRM). The median of the LC-MS/MS corresponding to 120 pg/mL of RIA was 48.5 pg/mL. In the mean of standardized four CLEIA values corresponding to the 48.5 pg/mL of LC-MS/MS value was 47.51 pg/mL and the standard deviation (SD) was 2.93 pg/mL. However, the correlation between the RIA value and the RIA equivalent of the two measurement procedures by CLEIA differed depending on the measurement procedure. This is due to the influence of RIA measurement performance. Standardized CLEIA measurements are suitable for routine measurement procedure. When converting the LC-MS/MS equivalent value by the standardized CLEIA to the conventional RIA value, it is necessary to use the conversion formula.

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  • Nao Shibata, Hiromi Nyuzuki, Sunao Sasaki, Yohei Ogawa, Masayasu Okada ...
    Type: Note
    Article ID: EJ21-0117
    Published: 2021
    [Advance publication] Released: July 17, 2021
    JOURNAL FREE ACCESS ADVANCE PUBLICATION

    Human chorionic gonadotropin (hCG)-producing tumors cause peripheral precocious puberty (PP) in boys, but generally not in girls. Homology between LH and hCG activates the LH receptor in testicular Leydig cells, increases testosterone production, and causes virilization. However, since FSH action is required for follicle development, hCG action alone does not increase estradiol (E2) production and does not cause feminization. Only a few cases of peripheral PP with hCG tumors in girls have been reported. We describe the case of a 7-year-old Japanese girl with peripheral PP associated with an hCG-producing tumor. She had prolonged vomiting, loss of appetite, and Tanner stage III breast development. Although no apparent increase in growth rate, bone age was advanced at 9.8 years. Serum E2 was slightly elevated and LH and FSH were below the measurement sensitivity, and abdominal ultrasonography and computed tomography images showed no abnormal findings in the uterus or ovaries. Subsequently, she developed visual field disturbance and loss of consciousness, and brain magnetic resonance imaging revealed an intracranial tumor. Based on pathological findings and abnormally high serum hCG-β level (48,800 IU/L), intracranial choriocarcinoma was diagnosed. 2.5 months after the start of chemotherapy, the hCG-β level became almost negative and the breast development disappeared synchronously. Tissue immunostaining of the tumor showed strong positivity for aromatase and hCG, indicating that the choriocarcinoma cells themselves may have produced estrogen via aromatase. This unique case highlights the possibility that hCG-producing tumors can cause peripheral PP in girls as well as boys.

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  • Minoru Kihara, Akira Miyauchi, Mitsuyoshi Hirokawa, Hiroo Masuoka, Tak ...
    Type: Original
    Article ID: EJ21-0252
    Published: 2021
    [Advance publication] Released: July 16, 2021
    JOURNAL FREE ACCESS ADVANCE PUBLICATION
    Supplementary material

    Some thyroid tumors that are cytologically diagnosed as benign may be pathologically diagnosed as malignant. Here, we investigated the long-term outcomes of patients with thyroid tumors with benign cytology, and the factors for malignancy. We retrospectively reviewed the cases of 3,102 patients with thyroid tumors >1 cm cytologically diagnosed as benign at our hospital during a 1-year period from January 2007. The median follow-up duration for all patients was 68.7 (range 0.0–168.7) months. Immediate surgery and delayed surgery were performed in 393 and 148 patients, respectively. Eventually, 541 (17.4%) of the 3,102 patients underwent a thyroidectomy, and 2,561 (82.6%) were observed without surgery. Among the surgically treated patients, the tumors of 525 (97.0%) and 16 (3.0%) were pathologically diagnosed as benign and malignant, respectively. There was no significant difference in age, gender, tumor size, serum thyroglobulin level at surgery, or the tumor volume-doubling rate (TV-DR) between the benign and malignant cases. Only the ultrasonographic findings based on our hospital’s classification system were directly and significantly linked to pathological diagnosis (p < 0.01). Among the tumors of the 667 patients who were followed without surgery for >10 years, 89.9% remained unchanged and 7.2% were reduced in size. Ultrasonographic evaluation provides important information for therapeutic decision-making regarding surgery versus observation for cytologically benign tumors.

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  • Desheng Wu, Jin Guo, Benquan Qi, Heng Xiao
    Type: Original
    Article ID: EJ21-0176
    Published: 2021
    [Advance publication] Released: July 15, 2021
    JOURNAL FREE ACCESS ADVANCE PUBLICATION

    Chronic pancreatitis (CP) is a chronic inflammatory and fibrotic disease of the pancreas, and activated pancreatic stellate cells (PSCs) play a vital role in the progression of pancreatic fibrosis in CP. It has been reported that long non-coding RNA small nucleolar RNA host gene 11 (SNHG11) is highly expressed in chronic pancreatitis (CP) patients. However, the role of SNHG11 in CP progression is unclear. The purport of the study was to survey the role of SNHG11 in CP. We employed transforming growth factor (TGF)-beta1 (TGF-β1) to activate human pancreatic stellate cells (PSCs). Expression of SNHG11 was assessed with qRT-PCR. Loss-of-function experiments were executed to evaluate the effects of SNHG11 on the proliferation and migration of TGF-β1-treated PSCs. Some protein levels were detected by western blotting. The regulatory mechanism of SNHG11 was verified by the dual-luciferase reporter and RIP assays. As a result, SNHG11 was upregulated in plasma of CP patients and TGF-β1-treated PSCs. Also, SNHG11 inhibition reduced TGF-β1-induced proliferation, migration, and ECM accumulation in PSCs. Mechanistically, SNHG11 regulated leukemia inhibitory factor (LIF) expression by sponging miR-34b. Furthermore, miR-34b inhibitor abolished SNHG11 silencing-mediated effects on TGF-β1-treated PSC proliferation, migration, and ECM accumulation. LIF overexpression counteracted the repressive influence of miR-34b mimic on proliferation, migration, and ECM accumulation of TGF-β1-treated PSCs. In conclusion, SNHG11 knockdown reduced TGF-β1-induced PSC proliferation, migration, and ECM accumulation by the miR-34b/LIF axis.

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  • Tomohiro Suzuki, Mayuko Hayashi, Tetsuro Komatsu, Akiko Tanioka, Masah ...
    Type: Original
    Article ID: EJ21-0255
    Published: 2021
    [Advance publication] Released: July 15, 2021
    JOURNAL FREE ACCESS ADVANCE PUBLICATION

    α-Ketoglutarate (α-KG) also known as 2-oxoglutarate (2-OG) is an intermediate metabolite in the tricarboxylic acid (TCA) cycle and is also produced by the deamination of glutamate. It is an indispensable cofactor for a series of 2-oxoglutarate-dependent oxygenases including epigenetic modifiers such as ten-eleven translocation DNA demethylases (TETs) and JmjC domain-containing histone demethylases (JMJDs). Since these epigenetic enzymes target genomic DNA and histone in the nucleus, the nuclear concentration of α-KG would affect the levels of transcription by modulating the activity of the epigenetic enzymes. Thus, it is of great interest to measure the nuclear concentration of α-KG to elucidate the regulatory mechanism of these enzymes. Here, we report a novel fluorescence resonance energy transfer (FRET)-based biosensor with multiple nuclear localization signals (NLSs) to measure the nuclear concentration of α-KG. The probe contains the α-KG-binding GAF domain of NifA protein from Azotobacter vinelandii fused with EYFP and ECFP. Treatment of 3T3-L1 preadipocytes expressing this probe with either dimethyl-2-oxoglutarate (dimethyl-2-OG), a cell-permeable 2-OG derivative, or citrate elicited time- and dose-dependent changes in the FRET ratio, proving that this probe functions as an α-KG sensor. Measurement of the nuclear α-KG levels in the 3T3-L1 cells stably expressing the probe during adipocyte differentiation revealed that the nuclear concentration of α-KG increased in the early stage of differentiation and remained high thereafter. Thus, this nuclear-localized α-KG probe is a powerful tool for real-time monitoring of α-KG concentrations with subcellular resolution in living cells and is useful for elucidating the regulatory mechanisms of epigenetic enzymes.

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  • Yuri Ishiuchi-Sato, Taku Nedachi
    Type: Original
    Article ID: EJ21-0275
    Published: 2021
    [Advance publication] Released: July 14, 2021
    JOURNAL FREE ACCESS ADVANCE PUBLICATION

    Evidence suggests that exercise can regulate skin functions such as promoting wound healing and inhibiting aging. Physical exercise modulates the secretion of proteins and peptides from skeletal muscles, called myokines, which play a role in transmitting exercise signals throughout the body. Therefore, exercise-regulated myokines may play a role in controlling skin functions; however, the precise mechanisms remain elusive. In this study, we focused on the recently identified CXC motif chemokine ligand 10 (CXCL10), an exercise-reduced myokine, and attempted to elucidate its role in regulating collagen synthesis in dermal fibroblasts. Mouse C2C12 myotubes were stimulated with or without electrical pulse stimulation (EPS) to induce contraction for 24 h, and conditioned medium was collected (EPS-CM or Ctrl-CM, respectively). The reduction in CXCL10 concentration by EPS was confirmed using ELISA. Next, mouse dermal fibroblasts were isolated from the dorsal skin of C57BL6/J mice (2 weeks old) and were stimulated with Ctrl-CM or EPS-CM for 24 h. EPS-CM treatment significantly increased collagen production compared to Ctrl-CM treatment. Even in the Ctrl-CM condition, the addition of an antagonist for CXCR3 (CXCL10 receptor) increased collagen production. In contrast, recombinant CXCL10 abolished EPS-CM-dependent collagen induction. Overall, this study raises the possibility that CXCL10 secretion from skeletal muscles may control collagen production in mouse dermal fibroblasts.

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  • Cyndy Liu, Tae Nakano-Tateno, Motoyasu Satou, Constance Chik, Toru Tat ...
    Type: Review
    Article ID: EJ21-0106
    Published: 2021
    [Advance publication] Released: July 10, 2021
    JOURNAL FREE ACCESS ADVANCE PUBLICATION

    Pituitary adenomas are benign tumours that can cause an individual various clinical manifestations including tumour mass effects and/or the diverse effects of abnormal pituitary hormone secretion. Given the morbidity and limited treatment options for pituitary adenomas, there is a need for better biomarkers and treatment options. One molecule that is of specific interest is the signal transducer and activator of transcription 3 (STAT3), a transcription factor that plays a critical role in mediating cytokine-induced changes in gene expression. In addition, STAT3 controls cell proliferation by regulating mitochondrial activity. Not only does activation of STAT3 play a crucial role in tumorigenesis, including pituitary tumorigenesis, but a number of studies also demonstrate pharmacological STAT3 inhibition as a promising treatment approach for many types of tumours, including pituitary tumours. This review will focus on the role of STAT3 in different pituitary adenomas, in particular, growth hormone-producing adenomas and null cell adenomas. Furthermore, how STAT3 is involved in the cell proliferation and hormone regulation in pituitary adenomas and its potential role as a molecular therapeutic target in pituitary adenomas will be summarized.

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  • Hiroki Ehara, Yoshimasa Takafuji, Kohei Tatsumi, Kiyotaka Okada, Yuya ...
    Type: Original
    Article ID: EJ21-0142
    Published: 2021
    [Advance publication] Released: July 09, 2021
    JOURNAL FREE ACCESS ADVANCE PUBLICATION

    Muscle wasting is a complication in patients with diabetes and leads to a reduced quality of life. However, the detailed mechanisms of diabetes-induced muscle wasting remain unknown. Plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor that suppresses plasminogen activator activity, is involved in the pathophysiology of various diseases, including diabetes. In the present study, we examined the role of endogenous PAI-1 in the decrease in muscle mass and the impaired grip strength induced by the diabetic state by employing streptozotocin (STZ)-treated PAI-1-deficient female mice. The analyses of skeletal muscles and grip strength were performed in PAI-1-deficient and wild-type mice 4 weeks after the induction of a diabetic state by STZ administration. PAI-1 deficiency did not affect muscle mass in the lower limbs measured by quantitative computed tomography or tissue weights of the tibialis anterior, gastrocnemius and soleus muscles of female mice with or without STZ treatment. On the other hand, PAI-1 deficiency significantly aggravated grip strength decreased by STZ in female mice. PAI-1 deficiency did not affect the mRNA levels of Pax7, MyoD, myogenin or myosin heavy chain in either the tibialis anterior or soleus muscles of female mice with or without STZ treatment. In conclusion, we revealed for the first time that PAI-1 deficiency aggravates grip strength impaired by the diabetic state in female mice, although it did not affect diabetes-decreased muscle mass.

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  • Daisuke Watanabe, Hideaki Yagasaki, Hiromune Narusawa, Tomohiro Saito, ...
    Type: Original
    Article ID: EJ21-0353
    Published: 2021
    [Advance publication] Released: July 08, 2021
    JOURNAL FREE ACCESS ADVANCE PUBLICATION

    Congenital hypothyroidism (CH) is considered the most common congenital endocrine disorder of genetic origin. Next generation sequencing (NGS) is the standard method for identifying genetic mutations, but it is an expensive and complex technique. Therefore, we propose to use Sanger sequencing to identify selected variants of the four most common CH-causative genes: DUOX2, TG, TSHR, and PAX8. To analyze the performance of Sanger sequencing, we compared its variant detection ability with that of a CH NGS panel containing 53 genes. We performed Sanger sequencing of selected variants and panel NGS analysis of 25 Japanese patients with CH. Sanger sequencing identified nine variants in seven patients, while NGS identified 24 variants in 14 patients. Of these, eight, five, eight, two, and one were found to be potentially pathogenic in DUOX2, TSHR, TG, UBR1, and TPO genes, respectively. The percentage of detectable variants using Sanger sequencing compared with NGS was 37.5% (9/24 variants), whereas the percentage of detectable cases carrying variants using Sanger sequencing compared with NGS was 50% (7/14 patients). We proposed a system for screening commonly identified CH-related variants by Sanger sequencing. Sanger sequencing could therefore identify about a third of CH-causative variants, so is considered an effective and efficient form of pre-screening before NGS.

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  • Daisuke Miyamori, Marenao Tanaka, Masato Furuhashi, Hirofumi Ohnishi, ...
    Type: Original
    Article ID: EJ20-0823
    Published: 2021
    [Advance publication] Released: July 07, 2021
    JOURNAL FREE ACCESS ADVANCE PUBLICATION
    Supplementary material

    Levels of alanine aminotransferase (ALT) and γ-glutamyl transferase (GGT) have been reported to be associated with increased risk of diabetes mellitus (DM). However, whether a combination of levels of ALT and GGT predicts new onset of DM better than does ALT or GGT alone in both males and females has not fully been addressed. We investigated the relationship between the combination of ALT and GGT and DM development during a 10-year follow-up period in 13,919 subjects (male/female: 8,983/4,936; age 48 ± 10 years) who received health examinations. During the 10-year period, 617 males (6.9%) and 153 females (3.1%) had new onset of DM. Multivariable Cox proportional hazard models with a restricted cubic spline showed that hazard ratios (HRs) of DM development increased with higher levels of ALT and GGT at baseline in both sexes after adjustment of confounding factors. When divided into 4 subgroups of high (H-) and low (L-) levels of ALT (male/female: 27/21 U/L) and GGT (male/female: 43/23 U/L) using cutoff values shown by receiver operating characteristic curve analyses, the adjusted HR in the H-ALT/H-GGT group was significantly higher than HR in the L-ALT/L-GGT group as the reference in males (HR [95% confidence interval]: 1.73[1.36–2.20], p < 0.001) but was not significantly higher in females (1.50 [0.97–2.33], p = 0.065). The addition of the combination of H-ALT/H-GGT to traditional risk factors with and without H-ALT or H-GGT alone significantly improved the discriminatory capability for predicting development of DM. In conclusion, the combination of H-ALT/H-GGT efficiently predicts development of DM in male individuals but not significantly in female individuals.

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  • Yasuhiro Ito, Mitsuyoshi Hirokawa, Kazuyoshi Kousaka, Mitsuru Ito, Min ...
    Type: Original
    Article ID: EJ21-0143
    Published: 2021
    [Advance publication] Released: July 06, 2021
    JOURNAL FREE ACCESS ADVANCE PUBLICATION

    Hyalinizing trabecular tumor (HTT) of the thyroid is a mostly benign disease. Its cytological and pathological diagnosis is often difficult, because HTT cells and papillary thyroid carcinoma (PTC) cells share similar features (e.g., intranuclear cytoplasmic inclusions and nuclear grooves). At our institution, 38 patients were diagnosed as or highly suspected of having HTT without the possibility of PTC, based on cytology: 19 of these patients underwent immediate surgery (surgery group) and the remaining 19 underwent active surveillance without surgery (AS group). The surgery-group patients’ tumor sizes were significantly larger (p < 0.0001) than those in the AS group. During AS (median 38 months), only one patient (5%) showed tumor enlargement by ≥3 mm; the AS was continued. Of the 34 patients pathologically diagnosed with HTT, 22 (65%) were cytologically diagnosed or highly suspected as having HTT without the possibility of PTC. Of the nine patients who were suspected to have HTT but PTC was possible and surgery was performed, two (22%) and seven (78%) were pathologically diagnosed as having PTC and HTT, respectively. Five patients were cytologically diagnosed with PTC, but pathologically diagnosed as having HTT. No patients showed HTT recurrence during postoperative follow-up (median 60 months). These findings suggest that (1) active surveillance can be a valid strategy for managing tumors that are cytologically diagnosed as HTT with no possibility of PTC; (2) surgery is recommended for tumors suspected of being HTT but may be PTC, and (3) the prognosis of HTT in both the AS and surgery groups was excellent.

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  • Takaaki Oba, Kazuma Maeno, Masatsugu Amitani, Tadafumi Shimizu, Koichi ...
    Type: Original
    Article ID: EJ21-0237
    Published: 2021
    [Advance publication] Released: July 02, 2021
    JOURNAL FREE ACCESS ADVANCE PUBLICATION

    Poorly differentiated thyroid cancer (PDTC) is a distinct but rare type of thyroid cancer with intermediate biological behavior between differentiated and anaplastic thyroid cancers. PDTC was first defined in 2005 in Japan, but the diagnostic criteria changed in 2015, requiring the tumor to have more than 50% of poorly differentiated components for diagnosis. Because only six years have passed since the PDTC definition change, prognostic factors for long-term survival who meet the latest criteria have not been determined. Neutrophil-to-lymphocyte ratio (NLR) is a prognostic marker in various solid malignancies. However, its impact on PDTC remains unclear. This study aimed to evaluate the significance of NLR as a prognostic factor for patients with PDTC diagnosed based on the latest criteria. In total, 28 PDTC cases (4.4%) of 637 thyroid cancer patients who underwent surgery between 2002 and 2012 were retrospectively analyzed. The median follow-up period was 120 months (range, 7–216 months). Of the 13 deaths (46.4%), 9 patients (32.1%) died from PDTC. The median preoperative NLR was 2.7 (0.67–8.62), and the NLR cut-off value determined by the receiver operating characteristic curve was 2.88. Patients with a high NLR (>2.88) showed significantly worse disease-specific survival (hazard ratio [HR] 4.67, p = 0.036) and overall survival (HR 4.94, p = 0.007) than those with a low NLR (≤2.88). Multivariate analysis revealed that a high NLR independently predicted a worse prognosis (HR 6.06, p = 0.0087). In conclusion, NLR is a useful prognostic marker for patients with PDTC.

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  • Atsuhito Suyama, Nahoko Iwata, Yoshiaki Soejima, Yasuhiro Nakano, Koic ...
    Type: Original
    Article ID: EJ21-0223
    Published: 2021
    [Advance publication] Released: June 26, 2021
    JOURNAL FREE ACCESS ADVANCE PUBLICATION

    The functional role of the transcription factors NR5A1 and NR5A2 and their interaction with Clock gene and bone morphogenetic proteins (BMPs) were investigated in human granulosa KGN cells. Treatment with BMP-15 and GDF-9 suppressed forskolin (FSK)-induced steroidogenesis as shown by the mRNA expression levels of StAR and P450scc but not the mRNA expression level of P450arom. Of interest, treatment with BMP-15 and GDF-9 also suppressed FSK-induced NR5A2 mRNA expression. Treatment with BMP-15 suppressed NR5A2 mRNA and protein expression but increased Clock mRNA and protein expression levels by granulosa cells. The mRNA expression levels of NR5A1, but not those of NR5A2, were positively correlated with the levels of Clock mRNA, while the mRNA levels of Id-1, the target gene of BMP signaling, were positively correlated with those of NR5A1 but not with those of NR5A2. It was also demonstrated that the mRNA expression levels of NR5A1 were positively correlated with those of P450arom and 3βHSD, whereas the mRNA expression level of NR5A2 was correlated with those of StAR and P450scc. Furthermore, inhibition of Clock gene expression by siRNA attenuated the expression of NR5A1, and the mRNA levels of Clock gene were significantly correlated with those of NR5A1. Collectively, the results suggested a novel mechanism by which Clock gene expression induced by BMP-15 is functionally linked to the expression of NR5A1, whereas NR5A2 expression is suppressed by BMP-15 in granulosa cells. The interaction between Clock NR5A1/NR5A2 and BMP-15 is likely to be involved in the fine-tuning of steroidogenesis by ovarian granulosa cells.

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  • Akihiro Ohmoto, Yasuyuki Shigematsu, Naoki Fukuda, Xiaofei Wang, Tetsu ...
    Type: Original
    Article ID: EJ21-0277
    Published: 2021
    [Advance publication] Released: June 26, 2021
    JOURNAL FREE ACCESS ADVANCE PUBLICATION

    Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis. While mitotane is the only agent approved for ACC, clinical data are scarce, especially in the Asian population. We reviewed 10 patients with ACC who received mitotane as a single agent or in combination with other agents in our institution. Patient characteristics, clinical outcomes, and toxicities were analyzed. Mitotane was administered to 2 patients as an adjuvant therapy and to 8 patients for systemic control. In the latter 8 patients, 1 patient had locally advanced disease and 1 had metastatic disease at the time of initial diagnosis, whereas the other 6 patients experienced metastatic relapse at mitotane initiation. The administered regimen was mitotane alone in 7 patients, and mitotane plus cytotoxic chemotherapy in 3 patients. The initial daily mitotane dose was 3.0 g in 2 patients, 1.5 g in 7 patients, and 1.0 g in 1 patient. The median duration of treatment was 3.7 (range, 0.7–22.1) months. In 8 systemic cases, the median overall survival from chemotherapy initiation was 7.2 months, and only 1 patient survived over 1 year. The median interval from mitotane termination to death in systemic cases was 2.8 months, and the cause was progressive disease in 4 patients and toxicity (hallucination, mycobacteriosis, or liver injury) in 3 patients. As a second-line regimen, 2 systemic cases and 1 adjuvant case were enrolled in clinical trials. Our analysis exhibited extremely poor prognosis under mitotane-based regimens, and further treatment strategies are warranted to improve outcomes.

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  • Naoki Edo, Koji Morita, Chisato Ishiwata, Rina Nakajima, Yohei Sayama, ...
    Type: Original
    Article ID: EJ21-0140
    Published: 2021
    [Advance publication] Released: June 23, 2021
    JOURNAL FREE ACCESS ADVANCE PUBLICATION

    Serum dehydroepiandrosterone sulfate (DHEA-S) levels reflect the state of adrenocorticotropic hormone (ACTH) secretion. However, it is difficult to use serum DHEA-S to diagnose hypothalamic-pituitary-adrenal (HPA) axis insufficiency due to its non-normal and highly skewed distribution. In this study, we focused on HPA insufficiency caused by hypothalamic and/or pituitary dysfunction and evaluated the usefulness of the standard deviation score of log-transformed DHEA-S (ln DHEA-S SD score), which was calculated from the established age- and sex-specific reference values. We retrospectively reviewed the medical records of 94 patients suspected of having HPA insufficiency, in whom serum DHEA-S measurement and the rapid ACTH stimulation test were performed, and included 65 patients who met our criteria in this study. The ln DHEA-S SD scores were distributed more normally than measured DHEA-S levels and were significantly higher in patients with a peak cortisol level ≥18 μg/dL than in those below this value, suggesting that this score is a legitimate and strong indicator of adrenocortical function. The optimal cut-off value for impaired HPA function was –0.853, with a sensitivity of 70.3% and a specificity of 100%. Among the 37 patients whose peak cortisol levels were below 18 μg/dL, 11 patients with ln DHEA-S scores ≥–0.853 exhibited significantly higher basal ACTH and basal and peak cortisol levels than the 26 patients with scores <–0.853. Thus, this score plays a supportive role in evaluating HPA axis function, particularly in patients with borderline cortisol responses to ACTH.

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  • Makoto Fujishima, Akira Miyauchi, Yasuhiro Ito, Takumi Kudo, Takuya No ...
    Type: Original
    Article ID: EJ21-0128
    Published: 2021
    [Advance publication] Released: June 15, 2021
    JOURNAL FREE ACCESS ADVANCE PUBLICATION

    Identification of the parathyroid glands during surgery is crucial for preventing postoperative hypoparathyroidism. Kikumori et al. reported that the aspartate aminotransferase (AST)/lactate dehydrogenase (LDH) ratio for the saline suspension of a suspicious tissue can differentiate parathyroid tissue from other tissues. The aim of this study was to evaluate the utility of this method and investigate the appropriate time for measurement. We obtained 465 tissue specimens during thyroidectomy of 102 patients with papillary thyroid carcinoma (PTC), and 422 specimens (129 parathyroid, 92 PTC, and 201 other tissues) with measurable AST and LDH were analyzed. Small pieces of the tissues were immersed in saline and sent for measurement of AST and LDH. The assay was performed immediately after thyroidectomy for 245 specimens (the same-day group) and during the next morning for the remaining 177 specimens (the next-day group). The accuracy of diagnosing parathyroid tissue was significantly better in the same-day group than in the next-day group. A cut-off value of 0.18 gave the best diagnostic precision, with an area under the receiver operating characteristic curve of 0.95 and 88.7% sensitivity and specificity in the same-day group. When the cut-off value was set to 0.20, the specificity for excluding carcinomatous tissues was 100%. When measured on the day of the surgery, the AST/LDH ratio for the saline suspension of the surgical specimens is useful for discriminating parathyroid tissues from other tissues. This method can be utilized at most hospitals where intraoperative frozen sections or rapid parathyroid hormone assays are not available.

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  • Yasufumi Enyama, Yumie Takeshita, Takeo Tanaka, Saori Sako, Takehiro K ...
    Type: Original
    Article ID: EJ20-0623
    Published: 2021
    [Advance publication] Released: June 11, 2021
    JOURNAL FREE ACCESS ADVANCE PUBLICATION

    This randomized, open-label, and parallel-group study aimed to investigate the effects of altering the timing of carbohydrate intake at breakfast or dinner on blood glucose fluctuations and energy metabolism. A total of 43 participants with type 2 diabetes were assigned to either the breakfast or dinner group. Participants were provided an isocaloric carbohydrate-restricted diet constituting 10% carbohydrate only at breakfast or dinner for 2 days during the study. Glucose fluctuations were compared using a continuous glucose monitoring system (iPro2) and body composition, energy expenditure, blood biochemistry, and endocrine function changes. The carbohydrate restriction either at breakfast or dinner significantly decreased postprandial glucose excursion and mean 24-h blood glucose levels. The incremental blood glucose area under the curve (AUC) for 2 h (iAUC0-2h) at lunch significantly increased in the breakfast group, whereas no significant differences were observed in the iAUC0-2h between breakfast and lunch in the dinner group. Carbohydrate restriction reduced diet-induced thermogenesis at breakfast (intragroup comparison; 223 ± 117 to 109 ± 104 kcal, p = 0.002) but did not affect diet-induced thermogenesis at dinner. However, fasting plasma free fatty acids were comparable in both groups, prelunch free fatty acids increased significantly only in the breakfast group (0.20 ± 0.09 to 0.63 ± 0.19 mEq/L, p < 0.001). Carbohydrate restriction in the diet once daily decreases mean 24-h blood glucose levels and exerts unique metabolic effects depending on the timing.

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