The Tohoku Journal of Experimental Medicine
Online ISSN : 1349-3329
Print ISSN : 0040-8727
ISSN-L : 0040-8727
Volume 242, Issue 2
June
Displaying 1-11 of 11 articles from this issue
Invited Review
  • Tohru Fujiwara
    Article type: Invited Review
    2017 Volume 242 Issue 2 Pages 83-91
    Published: 2017
    Released on J-STAGE: May 31, 2017
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    The development of mature blood cell from hematopoietic stem cells is regulated by transcription factors that coordinate the expression of lineage-specific genes. GATA transcription factors are zinc finger DNA-binding proteins that play crucial roles in various biological processes, including hematopoiesis. Among GATA family proteins, GATA-1, GATA-2, and GATA-3 are essential for hematopoiesis. GATA-1 functions to promote development of erythrocytes, megakaryocytes, eosinophils, and mast cells. Mutations in GATA-1 are associated with acute megakaryoblastic leukemia (AMKL), congenital erythroid hypoplasia (Diamond-Blackfan anemia; DBA), and X-linked anemia and/or thrombocytopenia. Conversely, GATA-2 functions early in hematopoiesis and is required for maintenance and expansion of hematopoietic stem cells (HSCs) and/or multipotent progenitors. GATA-2 mutations are associated with immunodeficiency, lymphedema, myelodysplastic syndrome (MDS), and leukemia. Furthermore, decreased GATA-2 expression may contribute to the pathophysiology of aplastic anemia. GATA-3 has an important role in T cell development, and has been suggested to be involved in the pathophysiology of acute lymphoblastic leukemias. This review summarizes current knowledge on hematological disorders associated with GATA-1 and GATA-2 mutations.

Regular Contribution
  • Na Hu, Xiao-Peng Fan, Yu-Chen Fan, Long-Yan Chen, Chen-Yang Qiao, Li-Y ...
    Article type: Regular Contribution
    2017 Volume 242 Issue 2 Pages 93-100
    Published: 2017
    Released on J-STAGE: June 06, 2017
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    Aberrant DNA methylation, which can be detected in circulating cell-free DNA (cfDNA), is one of the major epigenetic alterations in hepatocellular carcinoma (HCC). UBE2Q1, a putative member of the ubiquitin-conjugating enzyme family, might play substantial roles in tumorigenesis. However, the methylation status of the UBE2Q1 gene in HCC remains unknown. We aimed to determine the methylation status of the UBE2Q1 gene promoter and to evaluate its potential clinical significance for HCC detection. The methylation-specific polymerase chain reaction (MSP) assay was used to detect the UBE2Q1 gene methylation status in serum samples from 80 patients with hepatitis B virus (HBV)-related HCC, 40 patients with liver cirrhosis (LC), 40 patients with chronic hepatitis B (CHB), and 20 healthy controls (HCs). Significantly lower methylation frequencies were detected in HCC patients (33.75%) compared with LC patients (55.00%, p = 0.026) and CHB patients (60.00%, p = 0.006) and HCs (65.00%, p = 0.011). Hypomethylation of the UBE2Q1 gene was negatively associated with the tumor node metastasis stage (rs = −0.30, p = 0.008). The UBE2Q1 gene methylation status combined with alpha fetoprotein using cut-off points of 20, 200 and 400 ng/ml showed sensitivity and specificity values of 58.8% and 75.0%, 53.8% and 87.5%, and 37.5% and 88.7%, respectively, and yielded a significantly increased area under the ROC curve (0.720, 0.760 and 0.694, respectively) for discriminating HCC from LC and CHB. Our study results suggest that hypomethylation of the UBE2Q1 gene promoter is a potential biomarker for detecting HBV-associated HCC.

  • Guorong Zhang, Zhiqiang Liu, Yan Chen, Yihang Zhang
    Article type: Regular Contribution
    2017 Volume 242 Issue 2 Pages 101-108
    Published: 2017
    Released on J-STAGE: June 07, 2017
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    Hepatoma-derived growth factor (HDGF) is a heparin-binding protein possessing mitogenic activity and could be secreted from necrotic cells passively or actively, thereby functioning as a damage-associated molecular pattern (DAMP). The high expression of HDGF in non-small cell lung cancer (NSCLC) tissues is associated with unfavorable prognosis. However, the clinical significance of serum HDGF has not been elucidated in NSCLC yet. In the present study, we compared the serum levels of HDGF in 235 patients with NSCLC (141 adenocarcinoma and 94 squamous cell carcinoma cases) with those in 40 healthy subjects. Moreover, we explored the correlation between serum HDGF levels and clinicopathologic factors or the overall survival rates. We thus found that the serum HDGF levels were significantly higher in NSCLC patients than those in healthy subjects (P < 0.001). Moreover, there was no significant difference in the serum HDGF levels between adenocarcinoma and squamous cell carcinoma. Importantly, the higher serum levels of HDGF were significantly associated with bone metastasis and with lower overall survival rates. Thus, serum HDGF was identified as an independent prognostic factor indicating poor prognosis of NSCLC. Using A549 human lung adenocarcinoma cell line, we demonstrated that an autophagy inhibitor, chloroquine, could inhibit the HDGF secretion, while quercetin, an autophagy inducer derived from a traditional Chinese drug, could facilitate HDGF secretion. In conclusion, high serum levels of HDGF were significantly correlated to bone metastasis and poorer prognosis of NSCLC. We suggest that anti-HDGF therapy is potential to protect NSCLC patients with advanced stages from bone metastasis.

Case
  • Masaru Ando, Akihiko Goto, Mari Yamasue, Yuko Usagawa, Hiroaki Oka, Ta ...
    Article type: Case
    2017 Volume 242 Issue 2 Pages 109-114
    Published: 2017
    Released on J-STAGE: June 07, 2017
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    Granulomatosis with polyangiitis (GPA) is a systemic disease characterized by necrotizing, granulomatous vasculitis of the upper and lower respiratory tracts and glomerulonephritis, and is classified as a classical or limited form. The classical form of GPA demonstrates the involvement of the upper respiratory tract, sinuses, lungs and kidneys, whereas the limited form is characterized by the lack of the renal involvement with female predominance. On the other hand, mixed connective tissue disease (MCTD) shows the clinical and laboratorial features of systemic lupus erythematosus, systemic sclerosis and polymyositis, along with high titers of anti-ribonucleoprotein antibodies and is characterized by good response to corticosteroid therapy and favorable prognosis. We herein report a patient with a history of MCTD that developed into a limited form of GPA (pulmonary-limited GPA). A 39-year-old woman suffered from persistent cough, left back pain and appetite loss. At 21 years of age she was diagnosed with MCTD, but the persistent administration of prednisolone or immunosuppressants was not needed. On admission, high-resolution chest computed tomography showed bilateral, multiple, poorly circumscribed nodules and masses, some of which showed cavitation. A surgical lung biopsy demonstrated granulomas with vasculitis surrounding the necrotic lesions. She was diagnosed with pulmonary-limited GPA. In conclusion, we should recognize that GPA may develop during the disease course of MCTD even after prolonged disease remission. To prevent progression to an irreversible state, physicians should consider a surgical lung biopsy for the diagnosis in patients suspected of having pulmonary-limited GPA.

  • Masashi Uehara, Yukio Nakamura, Jun Takahashi, Mikio Kamimura, Shota I ...
    Article type: Case
    2017 Volume 242 Issue 2 Pages 115-120
    Published: 2017
    Released on J-STAGE: June 16, 2017
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    Osteogenesis imperfecta (OI) is an inherited bone disorder that causes fractures due to impaired production of collagen type I. In recent years, denosumab, a human monoclonal antibody against receptor activator of nuclear factor κB ligand (RANKL), has become widely used as an anti-osteoclastic agent for osteoporosis. This study investigated osteoporotic cases of OI to examine effects of denosumab on bone fragility. This was a retrospective, consecutive case series that included 3 female patients aged 42, 40, and 14 years, respectively. One patient carries a point mutation (c.G769A) in the COL1A1 gene, encoding collagen type I alpha 1 chain, which causes an amino-acid substitution (p.G257R). By contrast, no mutation was found in the analyzed regions of the OI responsive genes in another two patients (mother and daughter). These three patients underwent subcutaneous injection of denosumab every 6 months. All patients underwent dual-energy X-ray absorptiometry for bone mineral density (BMD) measurement of the lumbar 1-4 spine (L-BMD) and bilateral hips (H-BMD) before and during treatment. BMD and laboratory data were evaluated before, between 2 and 4 months, and at 6, 12, 18, and 24 months of therapy. No fractures or severe side effects, such as hypocalcemia, were observed during denosumab treatment. Both L-BMD and H-BMD were increased by denosumab. At 24 months, the mean percentage changes in L-BMD and H-BMD were 14.7% and 15.1%, respectively. In conclusion, no bone fragility fractures occurred during 2 years of denosumab administration in OI patients. Denosumab therefore is a good therapeutic option in the OI patients.

Regular Contribution
  • Feng Wang, Minghui Zhao, Zhaoli Han, Dai Li, Shishuang Zhang, Yongqian ...
    Article type: Regular Contribution
    2017 Volume 242 Issue 2 Pages 121-128
    Published: 2017
    Released on J-STAGE: June 08, 2017
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    Dementia is one of the most common geriatric diseases, and mild cognitive impairment (MCI) is considered to be incipient dementia. MCI patients have elevated risk of progressing to dementia. Multiple metabolic abnormalities have an unconfirmed effect on MCI risk, and taking adequate measures against metabolic abnormalities might prevent the developing of MCI. Thus, the present study explored the association of MCI risk with common metabolic abnormalities, such as hyperglycemia, hypoglycemia, hyperlipidemia and hypouricemia, and to provide the basis for MCI prevention. A total of 1,262 elderly outpatients with normal cognitive function and without confirmed diabetes mellitus, hyperlipoidemia and gout were enrolled. During the five-year follow-up period, 142 subjects were diagnosed with MCI according to Mini Mental State Examination and Montreal Cognitive Assessment. Furthermore, annual blood glucose, glycated hemoglobin, lipids and uric acid values were obtained, and mean of each indicator was calculated. Only mean values were included in the study to reflect long-term effect of metabolic abnormalities on MCI risk. Thus, the increased risk of MCI was associated with the mean values of blood glucose < 4.7 mmol/L (RR: 1.57, 95% CI: 1.14-2.32), blood glucose ≥ 6.3 mmol/L (RR: 1.49, 95% CI: 1.03-2.39), glycated hemoglobin ≥ 5.9% (RR: 2.28, 95% CI: 1.59-3.91), triglycerides ≥ 2.0 mmol/L (RR: 2.79, 95% CI: 2.14-3.79), total cholesterol ≥ 5.5 mmol/L (RR: 2.37, 95% CI: 1.69-3.39) and uric acid ≤ 380 μmol/L (RR: 1.62, 95% CI: 1.08-2.51). In conclusion, long-term subclinical hyperglycemia, hypoglycemia, hyperlipidemia, and hypouricemia are independent risk factors for MCI in elderly people.

  • Yuquan Wu, Juan Xu, Jing Xu, Jun Cheng, Demin Jiao, Chun Zhou, Yi Dai, ...
    Article type: Regular Contribution
    2017 Volume 242 Issue 2 Pages 129-136
    Published: 2017
    Released on J-STAGE: June 14, 2017
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    MicroRNAs (miRNAs) are short noncoding RNA that participate in posttranscriptional gene regulation. However, little is understood about the roles of miRNAs in Alzheimer’s disease (AD). In this study, we used next-generation sequencing on RNA extracted from the serum samples of 20 AD patients and 20 controls, yielding a total of 72 miRNAs with significantly changed expression levels. Among these candidates, we selected 9 miRNAs with most significant alteration in disease, and validated their expression levels using RT-qPCR analysis on serum samples from 45 AD patients and 40 control subjects. Thus, the serum levels of miR-146a-5p, 106b-3p, 195-5p, 20b-5p, and 497-5p were significantly higher, while those of miR-125b-3p, 29c-3p, 93-5p and 19b-3p were significantly lower in AD patients, compared with control subjects. Two miRNAs, miR-29c-3p and miR-19b-3p, were selected because both RNA deep-sequencing and q-PCR methods indicated lower serum levels of these miRNAs in AD patients. Computational analysis predicted that 3′-untranslated region of signal transduction and activator of transcription 3 (STAT3) mRNA is targeted both by miR-29c-3p and miR-19b-3p. Using SH-SY5Y human neuroblastoma cells, we showed that transfection with miR-29c-3p or miR-19b-3p inhibitor significantly increased STAT3 phosphorylation. Furthermore, Water maze test, which assesses the learning and memory deficits in rodents, showed that escape latency was significantly shorter in AD rats with overexpression of miR-29c-3p or miR-19b-3p than in control AD rats. These results suggest that miR-29c-3p or miR-19b-3p may contribute to the cognitive function. In conclusion, the serum levels of miR-29c-3p and miR-19b-3p are helpful biomarkers for AD.

  • Hak-Ryul Kim, Byoung-Ryun Kim, Rae-Kil Park, Kwon-Ha Yoon, Eun-Taik Je ...
    Article type: Regular Contribution
    2017 Volume 242 Issue 2 Pages 137-142
    Published: 2017
    Released on J-STAGE: June 14, 2017
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    Malignancy and tuberculosis are common causes of lymphocytic exudative pleural effusion. However, it is occasionally difficult to differentiate malignant pleural effusion from tuberculous pleural effusion. Vascular endothelial growth factor (VEGF) is a critical cytokine in the pathogenesis of malignant pleural effusion. Endocan is a dermatan sulfate proteoglycan that is secreted by endothelial cells. Importantly, endocan mediates the vascular growth-promoting action of VEGF. The aim of this study was to evaluate the diagnostic significance of VEGF and endocan in pleural effusion. We thus measured the levels of VEGF and endocan in the pleural effusion and serum samples of patients with lung cancer (n = 59) and those with tuberculosis (n = 32) by enzyme-linked immunosorbent assay. Lung cancer included 40 cases of adenocarcinoma, 13 of squamous cell carcinoma, and 6 of small cell carcinoma. Pleural effusion VEGF levels were significantly higher in the malignant group than in the tuberculosis group (2,091.47 ± 1,624.80 pg/mL vs. 1,291.05 ± 1,100.53 pg/mL, P < 0.05), whereas pleural effusion endocan levels were similar between the two groups (1.22 ± 0.74 ng/mL vs. 0.87 ± 0.53 ng/mL). The areas under the curve of VEGF and endocan were 0.73 and 0.52, respectively. Notably, the VEGF levels were similar in malignant pleural effusion, irrespective of the histological type of lung cancer. Moreover, no significant difference was found in the serum VEGF and endocan levels between patients with lung cancer and those with tuberculosis. In conclusion, high VEGF levels in pleural effusion are suggestive of malignant pleural effusion.

  • Zhiqi Ma, Yaoshu Teng, Xiang Liu, Jing Li, Jiangwei Mo, Min Sha, Yong ...
    Article type: Regular Contribution
    2017 Volume 242 Issue 2 Pages 143-150
    Published: 2017
    Released on J-STAGE: June 14, 2017
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    Long non-coding RNAs (lncRNAs) have been proved to play important roles in a variety of human immune diseases. However, their pathological effects on the development of allergic rhinitis (AR) have not been clearly understood. The aim of this study was to determine the expression profile of lncRNAs in nasal mucosa of AR patients by lncRNA microarray and to predict potential roles of specific lncRNAs in the pathogenic mechanisms of AR by analysis of lncRNA-mRNA co-expression network, Gene Ontology (GO) and pathway. The lncRNA microarray analysis showed that a total of 2,259 lncRNAs (1,033 up-regulated and 1,226 down-regulated) and 704 mRNAs (157 up-regulated and 547 down-regulated) were significantly differentially expressed in the nasal mucosa samples from 4 AR patients as compared to those from 4 non-allergic subjects (fold change > 2; P < 0.05). In addition, the lncRNA-mRNA co-expression network contained 143 network nodes including 76 lncRNAs and 67 mRNAs, in which 117 significant correlation pairs presented as positive, and 108 pairs presented as negative. The results from GO and pathway analysis indicated that the lncRNAs–coexpressed mRNAs were enriched in several biological processes and cellular signaling pathways related to AR development, such as positive regulation of interleukin-13 secretion, Fc epsilon RI signaling pathway and NF-kappa B signaling pathway. To summary, our study provides important information on the molecular mechanisms and biological functions of these AR-related lncRNAs, which could be utilized for developing novel therapeutic strategies for AR.

  • Seon-Cheol Park, Min-Soo Lee, Sang Woo Hahn, Shigenobu Kanba, Mian-Yoo ...
    Article type: Regular Contribution
    2017 Volume 242 Issue 2 Pages 151-156
    Published: 2017
    Released on J-STAGE: June 20, 2017
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    The Research on Asian Psychotropic Prescription Patterns for Antidepressants (REAP-AD) study aimed to survey and review antidepressant prescribing patterns in different clinical settings in Asian countries/areas. The REAP-AD study collected comprehensive data for psychiatric patients prescribed antidepressants in 10 Asian countries/areas during the period from March to June 2013. Depressive disorders have been an important issue closely associated with ill-health and disability in the realm of mental health. Impaired concentration was found to be a consistent symptom in depressive disorders regardless of clinical course, and a predictor of poor treatment outcome. In this work we aimed to identify clinical characteristics independently associated with impaired concentration in patients with depressive disorders, using data from the REAP-AD study. A total of 336 depressive disorder patients with impaired concentration and 786 depressive disorder patients without impaired concentration were recruited from 40 centers in 10 Asian countries/areas. A binary logistic regression model was fitted to identify the independent correlates of impaired concentration in patients with depressive disorders. After adjusting the effects of covariates, the binary logistic model showed that impaired concentration was independently associated with higher rates of loss of interest (P < 0.0001), fatigue (P < 0.0001), low self-confidence (P < 0.0001) and appetite disturbance (P < 0.0001) and with a lower rate of adjunctive antipsychotic prescription (P = 0.007). Our findings suggest that impaired concentration and its associated depressive symptom profiles constitute a unitary depressive symptom cluster that is also an intervening variable for poor social function.

  • Hisashi Yoshimoto, Ayumi Takayashiki, Ryohei Goto, Go Saito, Kyoko Kaw ...
    Article type: Regular Contribution
    2017 Volume 242 Issue 2 Pages 157-163
    Published: 2017
    Released on J-STAGE: June 22, 2017
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    Alcohol-related injuries in college students are a major public health problem worldwide. We clarified the association between excessive drinking and alcohol-related injuries in Japanese college students. This was a cross-sectional study with a self-administered questionnaire. From January to March 2013, we sampled all college students and graduate students aged 20 years or older during annual health examinations at three colleges in Mie Prefecture in Japan. The questionnaire assessed the frequency of alcohol drinking, amount of alcohol consumed per day, binge drinking during the past year, alcohol-related injuries during the past year, and demographic data. Logistic regression analysis was conducted on the association between excessive alcohol use and alcohol-related injuries. A total of 2,842 students underwent health examinations, of whom 2,177 (76.6%) completed the questionnaire. Subjects included 1,219 men (56.0%) and 958 women (44.0%). Eighty-eight men (7.2%) and 93 women (9.7%) were classified as excessive weekly drinkers, while 693 men (56.8%) and 458 women (47.8%) were determined to be binge drinkers. Eighty-one men (6.6%) and 26 women (2.7%) had experienced alcohol-related injuries during the past year. In the logistic regression analysis, binge drinkers (odds ratio 25.6 [8.05-81.4]) and excessive weekly drinkers (odds ratio 3.83 [2.41-6.09]) had a history of significantly more alcohol-related injuries, even after adjusting for age and sex. In conclusion, alcohol-related injuries in college students in Japan were strongly associated with excessive drinking. As a strategy for preventing such injuries in this population, an interventional study is required to identify effective methods for reducing excessive alcohol use.

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