Hironobu Sasano

Tohoku University, Japan

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Publications (865)2907.66 Total impact

  • Hironobu Sasano, Atsuko Kasajima
    12/2014; 111(12):2280-5.
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    ABSTRACT: The anti-tumor immune response was recently reported to play a critical role in the chemotherapeutic sensitivity of breast cancer. Therefore, we investigated the correlation between CD8+ and FOXP3+ tumor-infiltrating lymphocytes and the pathological complete response (pCR) following neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC), in conjunction with neoangiogenesis, basal and proliferation markers. CD8+ and FOXP3+ lymphocytes were assessed in biopsy specimens by double-staining immunohistochemistry, in combination with immunostaining of vasohibin-1, CD31, EGFR, CK5/6, and Ki-67. Earlier age, pre-menopausal status, smaller tumor size, and high Ki-67 were significantly associated with pCR, as in high CD8+, high CD8+/FOXP3+ ratio, and low vasohibin-1 positive ratio. Multivariate analysis did reveal that a high CD8+/FOXP3+ ratio was a strong predictor of pCR with an odds ratio of 5.32 (P = 0.005). High Ki-67 was also significantly associated with pCR (P = 0.002). TNBCs with a high CD8+/FOXP3+ ratio and high Ki-67 had the highest pCR rate (70 %) following NAC. However, the pCR rate of the patients with low CD8+/FOXP3+ ratio and low Ki-67 was only 5 %. The pCR rates of a high CD8+/FOXP3+ ratio and low Ki-67 patients and those with a low CD8+/FOXP3+ ratio and high Ki-67 were 24 and 21 %, respectively. TNBCs with a high CD8+/FOXP3+ ratio were more sensitive to anthracycline and taxane-based chemotherapeutic regimens, and the CD8+/FOXP3+ ratio in conjunction with Ki-67 could predict pCR following NAC in TNBC. This predictor may represent a new surrogate for testing the efficacy of investigational agents in the neoadjuvant setting.
    Breast Cancer Research and Treatment 11/2014; · 4.47 Impact Factor
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    ABSTRACT: The activating transcription factor 3 (ATF3) is a member of the cAMP-responsive element-binding (CREB) protein family of transcription factors. ATF3 is expressed in H295R human adrenocortical carcinoma cells and considered a rapid-responder gene to angiotensin-II stimulation. However, the functions of ATF3 in human adrenocortical tissues have remained unknown. In this study, we analyzed the localization and possible regulatory mechanisms of ATF3 in human adrenocortical cells and tissues. The expression levels of ATF3 mRNA were analyzed in 66 aldosterone-producing adenomas (APA) and 14 cortisol-producing adenomas (CPA) using real-time RT-PCR. To localize the ATF3 protein, we performed immunohistochemical analysis in 20 non-pathological adrenal glands, 9 adrenal glands with idiopathic hyperaldosteronism (IHA), 20 APA, and 5 CPA using a mouse monoclonal antibody against human ATF3. We showed that ATF3 mRNA levels were higher in APA compared to CPA (P = 0.0053). ATF3 was immunolocalized to the zona glomerulosa of non-pathological adrenal glands and adrenal glands with IHA, and diffusely detected in the tumor cells of APA and CPA. Subsequently, H295R cells were treated for 6 h with each inhibitor of Src kinase (SRC), PKC, JAK2, and calcium-dependent calmodulin kinase-II (CaMKII) in the presence or absence of angiotensin-II. The expression levels of ATF3 mRNA were increased by angiotensin-II (about 3.5-fold induction), but the magnitude of the induction was significantly decreased in the presence of an inhibitor for SRC (PP2) or CaMKII (KN93). These results suggest that ATF3 is a downstream target of SRC and CaMKII signaling, and may be involved in adrenocortical aldosterone synthesis.
    The Tohoku Journal of Experimental Medicine 11/2014; 234:249-254. · 1.37 Impact Factor
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    ABSTRACT: It has become important to evaluate the possible involvement of 3β-hydroxysteroid dehydrogenase type 1 (HSD3B1) and 2 (HSD3B2) isoforms in aldosterone-producing adenoma (APA). In this study, we studied 67 and 100 APA cases using real-time quantitative PCR (qPCR) and immunohistochemistry, respectively. Results of qPCR analysis demonstrated that HSD3B2 mRNA was significantly more abundant than HSD3B1 mRNA (P<0.0001), but only HSD3B1 significantly correlated with CYP11B2 (aldosterone synthase) (P<0.0001) and plasma aldosterone concentration (PAC) of the patients (P<0.0001). Results of immunohistochemistry subsequently revealed that HSD3B2 immunoreactivity was detected in the great majority of APA but a significant correlation was also detected between HSD3B1 and CYP11B2 (P<0.0001). In KCNJ5 mutated APA, CYP11B2 (P<0.0001) and HSD3B1 (P=0.011) were significantly higher than wild type APA. These results suggest that HSD3B1 is involved in aldosterone production, despite its lower levels of expression compared to HSD3B2, and also possibly associated withKCNJ5mutation in APA.
    Molecular and Cellular Endocrinology 10/2014; In Press(Online first). · 4.04 Impact Factor
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    ABSTRACT: Usually, benign tumors are not associated with an increased F-18 fluorodeoxyglucose (F-18 FDG) uptake on positron emission tomography (PET), although some exceptions have been reported in adrenal neoplasms. We present a rare case of adrenocortical oncocytoma associated with markedly increased FDG uptake, demonstrating a maximum standardized uptake value of 46.8. Histological examination demonstrated diffuse proliferation of tumor cells with eosinophilic and granular cytoplasm that were diffusely immunopositive for mitochondria and glucose transport protein 1, with focal and weak immunopositivity for 3β-hydroxysteroid dehydrogenase. Ultrastructural examination also revealed abundant mitochondria in the tumor cells. The tumor was diagnosed as adrenocortical oncocytoma and was considered benign according to Lin-Weiss-Bisceglia criteria. Diagnosis of adrenocortical oncocytoma can pose difficulties during both preoperative radiological and postoperative histopathological investigations.
    Endocrine Pathology 10/2014; · 1.60 Impact Factor
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    ABSTRACT: The great majority of the cases clinically diagnosed as primary aldosteronism (PA) have been caused by aldosterone-producing adenoma (APA) or idiopathic hyperaldosteronism (IHA). The differential diagnosis of both subtypes of PA is important due to the different therapeutic modes but clinically it is sometimes difficult. It is also important to understand the morphological features of these two subtypes with special emphasis upon differences of the status for aldosterone biosynthesis. In the last decade, molecular mechanisms of PA including the aberrant expression of G-protein coupled receptors (GPCRs), key regulators of the intracellular calcium signaling pathway and somatic mutations of ion channels, have been revealed and our understanding of the molecular pathways involved in excessive aldosterone production has been markedly advanced. In addition, newly developed monoclonal antibodies specific to the isoform of adrenal steroidogenic enzymes have demonstrated the novel profiles of adrenal steroidogenesis in PA. These novel findings indicate that the molecular mechanisms on the onset and pathophysiology of PA are more complicated than previously considered and further clarification of clinical relevance of these findings is required at this juncture.
    Pathology International 10/2014; · 1.72 Impact Factor
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    ABSTRACT: It is important to identify the sites of aldosterone biosynthesis in the adrenal glands, especially those involved in primary aldosteronism (PA). CYP11B2 catalyzes the last step of aldosterone biosynthesis but its close similarity to CYP11B1 has made it difficult to generate specific antibodies that distinguish between these two highly homologous cytochromes. We have recently produced specific monoclonal antibodies against CYP11B2. In addition, we have also produced the specific antibodies against 3BHSD 1/2, which is also the pivotal step in aldosterone biosynthesis. In 3BHSD, type 1 is the predominant form in idiopathic hyperaldosteronism (IHA) with diffuse glomerulosa hyperplasia but type 2 dominant in aldosterone producing adenoma (APA). Many of micro APA expressed 3BHSD2 and CYP11B2 with the absence of c17 and CYP11B1, which could explain the cause of hyperaldosteronism despite the small size of the lesions. In addition, many of the adrenals manifesting PA without discernible lesions demonstrated multiple clusters or nodules of cortical cells demonstrating the similar enzyme expression patterns as in micro APA. These results indicated that UMN or unilateral multiple nodules cases resulting in APA are much higher than previously considered.
    Pathology 10/2014; 46 Suppl 2:S14. · 2.66 Impact Factor
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    ABSTRACT: Adrenocortical carcinoma is a rare malignancy. Medical treatment including op'DDD or mitotane with or without platinum-based cytotoxic chemotherapy is frequently administered to the patients in an adjuvant setting following surgery or in advanced disease, because of aggressive clinical behavior in some cases. Potential roles of pathologists in determining the clinical algorithm of medical therapy are histopathological confirmation of adrenocortical carcinoma, both malignant features using the criteria of Weiss and adrenocortical origin applying immunohistochemistry of steroid factor-1 (SF-1); providing the relevant pathological information to determine the precise pathological stage in individual patients; and providing the accurate Ki67 labeling index of the patients. There are no established pathological surrogate markers for response to mitotane or op' DDD therapy available at this juncture but as in other malignancies, Ki67 LI could provide information as to the potential clinical response to platinum-based cytotoxic chemotherapy. Epidermal growth factor receptor (EGFR) is significantly overexpressed in adrenocortical carcinoma but the absence of gene mutations could limit the therapeutic application of anti-EGFR antibody and/or EGFR tyrosine kinase inhibitor in the patients.
    Endocrine Pathology 09/2014; · 1.60 Impact Factor
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    ABSTRACT: Corticotropin-releasing hormone (CRH), a major regulator of the stress response, regulates various biological functions through its interaction with CRH receptors 1 (CRHR1) and 2 (CRHR2). CRH, CRHR1, and CRHR2 have recently been reported in several types of carcinoma, but the significance of these proteins has remained largely unknown in human endometrial carcinoma.
    International journal of gynecological cancer : official journal of the International Gynecological Cancer Society. 09/2014;
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    ABSTRACT: Invasive lobular carcinoma (ILC) accounts for approximately 10% of all breast carcinomas and is characterized by higher levels of androgen receptor (AR) compared to invasive ductal carcinoma (IDC). Despite this potentially androgen responsive environment the combined importance of AR and androgen metabolism in non-neoplastic lobules and lobular carcinoma remains unknown. Therefore, in this study, we evaluated the status of pivotal androgen-producing enzymes, 17β-hydroxysteroid dehydrogenase type 5 (17βHSD5) and 5α-reductase type 1 (5αRed1), in 178 cases of ILC and surrounding histologically non-neoplastic lobular tissue using immunohistochemistry. AR prevalence was higher but androgenic enzymes lower in ILC than non-neoplastic lobules. In ILC cases the status of 5αRed1 and 17βHSD5 was inversely correlated with tumor size (p = 0.0053) and nuclear grade (p = 0.0440), and significantly associated with better overall survival of the patients (p = 0.0059). Based on these findings, we hypothesized that androgen signaling could act as a tumor suppressor. As previous studies suggested that androgens might partially act by increasing levels of the estrogen inactivating enzyme 17β-hydroxysteroid dehydrogenase type 2 (17βHSD2) in IDC tissues, this was reasonably considered a potential mechanism of androgen actions. Significantly positive correlation was detected between the status of androgenic enzymes and 17βHSD2 (p < 0.0001) and intratumoral 17βHSD2 was inversely correlated with tumor size in ILC (p = 0.0075). These correlations suggest one protective mode of androgen action could be through modulation of estrogen metabolism. Results of our present study indicated that androgen producing enzymes could play pivotal protective roles in AR-enriched ILC cases.This article is protected by copyright. All rights reserved.
    Cancer Science 09/2014; · 3.48 Impact Factor
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    ABSTRACT: Aromatase inhibitors (AI) are commonly used to treat postmenopausal estrogen-receptor (ER)-positive breast carcinoma. However, resistance to AI is sometimes acquired, and the molecular mechanisms underlying such resistance are largely unclear. Recent studies suggest that AI treatment increases androgen activity during estrogen deprivation in breast carcinoma, but the role of the androgen receptor (AR) in breast carcinoma is still a matter of controversy. The purpose of this study is to examine the potential correlation between the AR- and AI-resistant breast carcinoma. To this end, we performed immunohistochemical analysis of 21 pairs of primary breast carcinoma and corresponding AI-resistant recurrent tissue samples and established two stable variant cell lines from ER-positive T-47D breast carcinoma cell line as AI-resistance models and used them in in vitro experiments. Immunohistochemical analysis demonstrated that the expression of prostate-specific antigen (PSA) and Ki-67 were significantly higher and ER and progesterone receptor (PR) were lower in recurrent lesions compared to the corresponding primary lesions. Variant cell lines overexpressed AR and PSA and exhibited neither growth response to estrogen nor expression of ER. Androgen markedly induced the proliferation of these cell lines. In addition, the expression profile of androgen-induced genes was markedly different between variant and parental cell lines as determined by microarray analysis. These results suggest that in some cases of ER-positive breast carcinoma, tumor cells possibly change from ER-dependent to AR-dependent, rendering them resistant to AI. AR inhibitors may thus be effective in a selectd group of patients.
    The Journal of steroid biochemistry and molecular biology. 08/2014;
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    ABSTRACT: Calcium channel blockers can efficiently be used in the treatment of primary aldosteronism (PA) related hypertension, but details on the localization of calcium channels (CCs) in the human adrenal and its disorders, including PA, have remained unclear. Therefore, in this study we analyzed the known α subunits of L-, N-, and T-type CCs in 74 adrenocortical aldosterone-producing adenomas (APA) and 16 cortisol-producing adenomas (CPA) using quantitative RT-PCR (qPCR). We also examined the status of L-(CaV1.2, CaV1.3), N-(CaV2.2) and T-(CaV3.2) CC subunits in five non-pathological adrenals (NA), five idiopathic hyperaldosteronism (IHA) cases, and 50 APA using immunohistochemistry. After qPCR evaluation, only CaV1.2, CaV1.3, CaV2.2, and CaV3.2 mRNA levels could be detected in APA and CPA. Among those, only CaV3.2 mRNA levels were significantly correlated with plasma aldosterone levels (P=0.0031), CYP11B2 expression levels (P<0.0001) and the presence of KCNJ5 mutations (P=0.0019) in APA. The immunolocalization of CCs in NA and IHA was detected in the zona glomerulosa (ZG), with a predominance of CaV3.2 in APA. These findings suggest that different types of CC can be involved in calcium-related aldosterone biosynthesis.
    The Journal of Steroid Biochemistry and Molecular Biology 08/2014; pii: S0960-0760(14):00191-5. · 3.98 Impact Factor
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    ABSTRACT: The sebaceous gland is a major site of steroid synthesis in human skin, but details of the status of steroidogenic enzymes and their regulation in human sebaceous glands under normal and pathological conditions have rarely been reported. Therefore, in this study, we examined the status of steroidogenic enzymes, sex steroid receptors and transcription factors in human sebaceous glands under normal and pathological conditions to explore their possible roles in in situ steroid production in human skin. Immunohistochemical analysis was performed in a total of 59 human skin specimens, including 22 normal human sebaceous glands, 12 with sebaceous nevus, 12 with sebaceous gland hyperplasia, 3 with sebaceoma and 10 with sebaceous carcinoma. Immortalised human SZ95 sebocytes were treated with forskolin or vehicle for 3h, 6h, 12h or 24h, and the mRNA levels of steroidogenic enzymes were evaluated at each time point using quantitative RT-PCR (qPCR). The results of immunohistochemistry demonstrated the immunoreactivity of 3β-HSD1, CYP11A1, StAR, 17β-HSD5, CYP17A1, 5α-red1, PRB, AR and NGFI-B in normal human sebaceous gland, with lower levels of expression in pathological sebaceous glands. The results of the in vitro study also indicated that the expression levels of 3β-HSD1, CYP11A1, StAR, 5α-red1 and NGFI-B were elevated by forskolin. 3β-HSD1 and other steroidogenic enzymes were expressed in sebaceous glands resulting in in situ androgen and progesterone synthesis and their functions.
    The Journal of Steroid Biochemistry and Molecular Biology 07/2014; pii: S0960-0760(14):00134-4. · 3.98 Impact Factor
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    ABSTRACT: Title (in Japanese): 副腎腫瘍の病理診断 Authors: 笹野公伸 、サウロJ.A.フェリゾラ 、 中村保宏 Affiliation: Tohoku University Graduate School of Medicine Department of Pathology ( 東北大学大学院医学系研究科医科学専攻病理学講座病理診断学分野 ) Journal title (in Japanese): 臨床泌尿器科
    Japanese Journal of Clinical Urology 07/2014; 68(8):570-574.
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    ABSTRACT: CYP11B1 and CYP11B2 play pivotal roles in adrenocorticosteroids synthesis. We performed semi-quantitative immunohistochemical analysis of these proteins in adrenals from patients with primary aldosteronism using novel monoclonal antibodies. Clusters of cortical cells positive for CYP11B2 were detected in the zona glomerulosa (ZG) of normal adrenal gland (NA), idiopathic hyperaldosteronism (IHA) and the adjacent adrenal of aldosterone-producing adenoma (APA). In APA, heterogenous immunolocalization of CYP11B2 and diffuse immunoreactivity of CYP11B1 were detected in tumor cells, respectively. The relative immunoreactivity of CYP11B2 in the ZG of adjacent adrenal of APA was significantly lower than that of NA, IHA and APA tumor cells, suggestive of suppressed aldosterone biosynthesis in these cells. These findings did indicate the regulatory mechanisms of aldosterone biosynthesis were different between normal/hyperplastic and neoplastic aldosterone-producing cells in human adrenals. CYP11B2 immunoreactivity in the ZG could also serve as a potential immunohistochemical marker differentiating morphologically hyperplastic ZG of IHA and APA adjacent adrenal.
    Molecular and Cellular Endocrinology 07/2014; 392(1-2):73-79. · 4.04 Impact Factor
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    ABSTRACT: While the clinical benefit of androgen-based therapeutics in breast cancer has been known since the 1940s, we have only recently begun to fully understand the mechanisms of androgen action in breast cancer. Androgen signalling pathways can have either beneficial or deleterious effects in breast cancer depending on the breast cancer subtype and intracellular context. This review discusses our current knowledge of androgen signalling in breast cancer, including the relationship between serum androgens and breast cancer risk, the prognostic significance of androgen receptor (AR) expression in different breast cancer subtypes and the downstream molecular pathways mediating androgen action in breast cancer cells. Intracrine androgen metabolism is also discussed, and proposed as a potential mechanism that may explain some of the reported differences regarding dichotomous androgen actions in breast cancers. A better understanding of AR signalling in this disease is critical given the current resurgence in interest in utilising contemporary AR directed therapies for breast cancer and the need for biomarkers that will accurately predict clinical response.
    Endocrine Related Cancer 06/2014; · 5.26 Impact Factor
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    ABSTRACT: Androgens are well known to influence sebum synthesis and secretion. Various factors related to androgen biosynthesis are expressed in human sebaceous glands. In our present study, immunohistochemical analysis of 43 human skin specimens demonstrated that various androgen producing- and metabolizing-enzymes were functionally localized in sebocytes accumulating lipid droplets and that the exclusive expression of 17β-HSD2 in sebaceous glands was negatively correlated with that of PPARγ , which also significantly changed in an age dependent manner. We also demonstrated that the changes of 17β-HSD2 expression in human immortalized sebocytes (SZ95) influenced on the expressions of sebogenesis-related factors. In addition, the overexpression of 17β-HSD2 in SZ95 significantly increased the androstendione production and markedly decreased the amounts of testosterone and dihydrotestosterone when dehydroepiandrosterone was externally added. On the other hand, the phosphorylation of mammalian target of rapamycin, which is well known to induce the sebum secretion and the onset and/or aggravation of acne, was increased by the addition of testosterone with the presence of IGF-1 in hamster sebocytes. These results all indicated that local androgen biosynthesis and metabolism in human sebaceous glands could play a pivotal role in sebum synthesis and secretion.
    The Journal of endocrinology. 06/2014;
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    ABSTRACT: In this report, unique endocervical glandular lesions exhibiting gastric differentiation were examined in a patient with Peutz-Jeghers syndrome. The result of the human papillomavirus (HPV) in situ hybridization (ISH) for the hysterectomy specimens was negative, but they demonstrated a papillary mucinous adenocarcinoma at the proximal endocervix continuous to atypical lobular endocervical glandular hyperplasia. Both contained MUC6-positive neutral mucin in cytoplasm, and showed different immunoreactivity to p16, Ki-67, and p53. Moreover, they harbored the identical K-RAS gene mutation suggesting that there was a common origin. Somatic K-RAS mutation and defective function of p16 may have been involved in the tumorigenesis of these unusual mucinous neoplasms.
    Pathology International 06/2014; 64(6). · 1.72 Impact Factor
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    ABSTRACT: Aldosterone-producing adenoma is a major subtype of primary aldosteronism. The number of cases of these adenomas, which are below the detection limit of computed tomography but diagnosed by adrenal venous sampling, has recently been increasing. However, the pathophysiology of these adenomas, especially those manifesting clinically overt hyperaldosteronism despite their small size, remains unknown. Therefore, we examined the correlation between tumor size and the status of intratumoral steroidogenic enzymes involved in aldosterone biosynthesis using immunohistochemistry. Forty patients with surgically proven aldosterone-producing adenomas were retrospectively studied. Multidetector computed tomography, adrenal venous sampling, and laparoscopic adrenalectomy were performed in all of the patients studied. The tumor area at the maximum diameter of the sections was precisely measured by ImageJ software. The status of the steroidogenic enzymes was immunohistochemically analyzed, and the findings were evaluated according to the H-score system, based on both the number of immunopositive cells and relative immunointensity. Adrenal masses were not detected by computed tomography in 20 patients. Blood pressure, plasma aldosterone concentration, urinary aldosterone excretion, and the number of antihypertensive agents also decreased significantly after the surgery in these patients, as well as in the patients with adenomas detectable by computed tomography. Maximum tumor area obtained in the specimens was significantly correlated with preoperative plasma aldosterone concentration, urinary aldosterone excretion, and the H score of 11β-hydroxylase and was inversely correlated with the H score of aldosterone synthase. These results demonstrated that small adenomas could produce sufficient aldosterone to cause clinically overt primary aldosteronism because of the significantly higher aldosterone synthase expression per tumor area.
    Hypertension 05/2014; In press(Online first). · 6.87 Impact Factor
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    ABSTRACT: Androstenedione is a common precursor of sex steroids produced and secreted in the human adrenal gland and produced by 3β-hydroxysteroid dehydrogenase (3βHSD), 17β-hydroxylase/17,20-lyase (CYP17) and cytochrome b5 (CYB5A). 3βHSD is expressed in the zona glomerulosa (ZG) and fasciculata (ZF), CYP17 in the ZF and zona reticularis (ZR) and CYB5A in the ZR, respectively. We previously demonstrated the presence of cortical parenchymal cells co-expressing 3βHSD and CYB5A with hybrid features of both ZF and ZR in human adrenal cortex and hypothesized that these cells may play an important role in androstenedione production in human adrenal gland. Age-related morphologic development of these hybrid cells has, however, not been studied. Therefore, in this study, 48 human adrenal specimens from various age groups were retrieved. Double-immunohistochemical analyses were used in order to study the correlation between this hybrid cell type and age. In both male and female adrenal cortex, the means of total adrenocortical area, the area positive for CYB5A and its ratio reached highest peak in the 21–40-year-old (y.o.) group. The greatest overlap between 3βHSD and CYB5A in both total and relative area was present in the 13–20 y.o. group. For all the markers mentioned above, statistically significant differences were detected among the different age groups examined (p < 0.05). These findings indicated that both area and ratio of 3βHSD and CYB5A double positive cells, which could represent the hybrid cells of ZF and ZR, are correlated with human adrenal development and could subsequently influence age-related serum androstenedione levels. ------------ From: http://informahealthcare.com/doi/abs/10.3109/07435800.2014.895377
    Endocrine Research 05/2014; In press(Online first). · 1.03 Impact Factor

Publication Stats

14k Citations
2,907.66 Total Impact Points

Institutions

  • 1987–2014
    • Tohoku University
      • • Department of Pathology
      • • Department of Nephrology, Endocrinology and Vascular Medicine
      • • Division of Internal Medicine
      Japan
  • 2013
    • National Hospital Organization Kyushu Cancer Center
      Hukuoka, Fukuoka, Japan
    • Fudan University
      Shanghai, Shanghai Shi, China
    • Naha-Nishi Clinic
      Okinawa, Okinawa, Japan
  • 2008–2013
    • Kyoto University
      • • Department of Breast Surgery
      • • Department of Medicine and Clinical Science
      Kioto, Kyōto, Japan
    • Washington University in St. Louis
      • Alvin J. Siteman Cancer Center
      Saint Louis, MO, United States
  • 2005–2013
    • Prince Henry's Institute
      • Laboratory of Cancer Drug Discovery
      Melbourne, Victoria, Australia
    • Sendai Orthopaedic Hospital
      Sendai, Kagoshima, Japan
  • 2012
    • Akershus universitetssykehus
      Kristiania (historical), Oslo County, Norway
    • University of Toyama
      • Faculty of Medicine
      Тояма, Toyama, Japan
    • Monash University (Australia)
      • Department of Biochemistry and Molecular Biology
      Melbourne, Victoria, Australia
  • 1993–2012
    • Yokohama Rosai Hospital
      Yokohama, Kanagawa, Japan
  • 2011
    • Mitsubishi Nagoya Hospital
      Nagoya, Aichi, Japan
  • 2008–2011
    • Georgia Health Sciences University
      • Department of Physiology
      Augusta, GA, United States
  • 2010
    • Kyushu University
      • Graduate School of Medical Sciences
      Fukuoka-shi, Fukuoka-ken, Japan
  • 2009–2010
    • Hirosaki University
      • Department of Endocrinology and Metabolism
      Khirosaki, Aomori Prefecture, Japan
    • University of Bergen
      • Institute of Medicine
      Bergen, Hordaland Fylke, Norway
    • The University of Hong Kong
      • Department of Pathology
      Hong Kong, Hong Kong
  • 2005–2009
    • The Jikei University School of Medicine
      • • Department of Internal Medicine H
      • • Department of Pathology
      Tokyo, Tokyo-to, Japan
  • 2004–2009
    • The University of Tokyo
      • Department of Reproductive, Developmental and Aging Sciences
      Tokyo, Tokyo-to, Japan
    • Sendai University
      Sendai, Kagoshima, Japan
    • University of Hamamatsu
      Hamamatu, Shizuoka, Japan
  • 2004–2008
    • Northwestern University
      • • Feinberg School of Medicine
      • • Department of Obstetrics and Gynecology
      Evanston, IL, United States
  • 2003–2008
    • Akita University Hospital
      Akita, Akita, Japan
    • Tazuke Kofukai Medical Research Institute, Kitano Hospital
      Ōsaka, Ōsaka, Japan
  • 2004–2007
    • University Hospital Medical Information Network
      Edo, Tōkyō, Japan
  • 2006
    • Social Insurance Chukyo Hospital
      Nagoya, Aichi, Japan
  • 1998–2005
    • University of Texas Southwestern Medical Center
      • • Department of Obstetrics and Gynecology
      • • Division of Reproductive Endocrinology and Infertility
      Dallas, TX, United States
    • Tsukuba Research Institute
      Edo, Tōkyō, Japan
    • Hyogo Prefectural Amagasaki Hospital
      Amagasaki, Hyōgo, Japan
  • 2002–2003
    • Aomori Prefectural Central Hospital
      Aomori, Aomori Prefecture, Japan
  • 2000–2002
    • University of Illinois at Chicago
      • Department of Obstetrics and Gynecology (Chicago)
      Chicago, IL, United States
  • 2001
    • Fukushima Medical University
      Hukusima, Fukushima, Japan
  • 1999–2000
    • Hamamatsu University School of Medicine
      • School of Medicine
      Hamamatu, Shizuoka, Japan
    • University of Toronto
      Toronto, Ontario, Canada
  • 1997
    • Nagasaki University Hospital
      Nagasaki, Nagasaki, Japan
  • 1996
    • Alfred Hospital
      Melbourne, Victoria, Australia
    • Keio University
      Edo, Tōkyō, Japan
    • Hokkaido University Hospital
      Sapporo, Hokkaidō, Japan
    • Yamagata Prefectural Central Hospital
      Ямагата, Yamagata, Japan
  • 1994
    • Fujita Health University
      Nagoya, Aichi, Japan
  • 1988–1991
    • George Washington University
      • Department of Pathology
      Washington, D. C., DC, United States