Hironobu Sasano

Tohoku University, Miyagi, Japan

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Publications (900)3106.16 Total impact

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    ABSTRACT: Genetic analyses have revealed an important association between P/Q-type calcium channel activities and hereditary neurological disorders. The P/Q-type channels are composed principally of heterologous multimeric subunits including CaV2.1 and CaVβ4. Of these, the β4 subunit is thought to play a significant role in channel physiology, because a mouse line mutant in that subunit (the lethargic mouse: lh) exhibits a severe ataxic phenotype. The aim of the present study was to elucidate the physiological importance of the β4 subunit. ECG analysis showed that the T wave was high in 8-week-old lh mutants; this may be associated with hyperkalemia. Upon pharmacological ECG analysis, 2-3-week-old lh mutants exhibited reduced responses to a β-blocker and a muscarinic receptor antagonist. Analysis of heart rate variability revealed that the R-R interval was unstable in lh mutants and that both the low- and high-frequency components had increased in extent, indicating that the tonus of both the sympathetic and parasympathetic nervous systems was modified. Thus, our present study revealed that the β4 subunit played a significant role in regulation of sympathetic and parasympathetic nerve activities. Copyright © 2015 Elsevier Inc. All rights reserved.
    Biochemical and Biophysical Research Communications 04/2015; DOI:10.1016/j.bbrc.2015.03.112 · 2.28 Impact Factor
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    ABSTRACT: Thymidylate synthase (TS) is an enzyme involved in DNA synthesis, and it is a target for 5-fluorouracil. Previous studies have demonstrated that TS is a potent estrogen-induced gene in breast carcinoma cells, suggesting the importance of TS in estrogen-receptor (ER)-positive breast carcinoma. TS immunolocalization has been reported previously, but the clinicopathological significance of TS in ER-positive breast carcinoma still remains unclear. We immunolocalized TS in 178 breast carcinoma tissues in total, and examined its significance according to the ER-status. TS status was positive in 58% of ER-positive ductal carcinoma in situ (DCIS) cases, and it was significantly associated with the Ki-67 and progesterone receptor (PR). Moreover, in ER-positive DCIS patients who received aromatase inhibitor (AI) before surgery, TS immunoreactivity was significantly decreased after AI treatment. In ER-positive invasive ductal carcinoma (IDC) cases, TS status was significantly associated with PR, and it turned out an independent favorable prognostic factor for recurrence of the patients by multivariate analysis. On the other hand, TS status was positively correlated with pathological T factor in ER-negative IDC cases, and tended to have a worse prognosis for disease-free survival of the patients. These results suggest that TS expression is mainly regulated by estrogen in ER-positive breast carcinoma and is associated with estrogen-mediated proliferation. TS status is a favorable prognostic factor in ER-positive IDC patients, which is different from the ER-negative cases.
    Histology and histopathology 04/2015; DOI:10.14670/HH-11-619 · 2.24 Impact Factor
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    ABSTRACT: Krüppel-like factor 15 (KLF15) is a transcription factor that is involved in various biological processes, including cellular proliferation, differentiation and death. In addition, KLF15 has recently been implicated in the development of several human malignancies, including breast cancer. In vitro breast cancer studies have pointed at a putative role in the regulation of cell proliferation. As yet, however, KLF15 expression analyses in primary human breast cancers have not been reported. Here, we set out to investigate the clinical and biological significance of KLF15 expression in human breast cancers. KLF15 expression was evaluated by immunohistochemistry in 54 primary invasive ductal breast carcinomas, and its status was correlated with various clinicopathological parameters. We also assessed KLF15 expression in vitro in 4 breast cancer-derived cell lines using Western blotting, and examined the effects of exogenous KLF15 expression on cell cycle progression using flow cytometry. Concomitant (changes in) p21, p27 and TOPO2A expression levels were examined using real-time RT-PCR and immunocytochemistry, respectively. In ~90 % of the primary breast carcinoma tissues tested, KLF15 was found to be expressed and localized in either the cytoplasm, the nucleus or both. Predominant nuclear immunoreactivity was found to be associated with clinicopathological factors predicting a better clinical outcome (i.e., ER positive, HER2 negative, low grade, low Ki-67 expression). The breast cancer-derived cell lines tested showed a low KLF15 expression with a predominant cytoplasmic localization. Subsequent exogenous KLF15 over-expression resulted in a predominant nuclear localization and a concomitant decreased cellular proliferation and an arrest at the G0/G1 phase of the cell cycle. In addition, we found that nuclear KLF15 expression results in up-regulation of p21, a pivotal suppressor of the G1 to S phase transition of the cell cycle. Our results indicate that nuclear KLF15 expression suppresses breast cancer cell proliferation at least partially through p21 up-regulation and subsequent cell cycle arrest. This is a first study addressing the role of KLF15 in breast cancer development.
    04/2015; DOI:10.1007/s13402-015-0226-8
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    ABSTRACT: New molecular markers related to prognosis and/or clinical outcome have been extensively studied in breast cancer. In particular, microRNA (miRNA) has attracted the interest of both basic and clinical investigators as one of the promising molecular markers of breast cancer patients. MiRNAs are a class of short noncoding RNAs that regulate mRNAs at posttranscriptional level and are deregulated in various human malignancies. Previous studies have reported that miRNAs were stably conserved in 10% formalin-fixed paraffin-embedded tissues without significant degradation, in contrast to more fragile RNA. Therefore, in this study, we examined 21 surgical breast cancer specimens using the Human Cancer microRNA PCR Array system (QIAGEN) to explore potential molecular targets of miRNAs. Profiling of miRNA expression in archival materials demonstrated that a group of deregulated miRNAs was associated with clinicopathological parameters of the patients, such as Ki-67, HER2, ER and PR. For instance, an abundant expression of multiple let-7 miRNA family, also known as tumor suppressor, was detected in low Ki-67 and HER2 groups. Elevated expression of 8 miRNAs overlapped between Ki-67+/HER2+/ER+/PR+ groups, including several known oncogenic miRNAs such as miR-148b, miR-15b, miR-200c, miR-150, miR-191, miR-96, miR-25 and miR-21. These results all indicated that when analyzing miRNAs in surgical pathology specimens of breast cancer as a biomarker, they should be examined as a cluster through miRNA profiling, rather than relying on the analysis of a single miRNA.
    The International journal of biological markers 04/2015; DOI:10.5301/jbm.5000141 · 1.36 Impact Factor
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    ABSTRACT: The pre-B lymphocyte protein 3 (VPREB3) is expressed during B-cell differentiation and in subsets of mature B-lymphocytes and is mainly found in bone marrow and lymphoid tissue germinative centers. So far, its function in B-cells remains to be clarified. The mRNA of VPREB3 was previously detected in aldosterone-producing adenomas (APA), however further information about this protein in human adrenocortical cells and tissues is currently unavailable. Therefore, in the present study we for the first time investigate the protein expression of VPREB3 in human adrenocortical tissues. In addition, we approach the previously suggested similarities in expression patterns of aldosterone-producing cells and Purkinje neurons. Immunohistochemical analysis of VPREB3 was performed in 13 non-pathological adrenals (NA), 6 adrenal glands with idiopathic hyperaldosteronism (IHA), 18 APA, 5 cortisol-producing adenomas (CPA) and 5 non-pathological human cerebellum specimens. The mRNA levels of VPREB3, steroidogenic-enzymes and other aldosterone biosynthesis markers were detected in 53 APA samples using real-time RT-PCR (qPCR) and compared to the clinical data of APA patients. In our results, the VPREB3 protein was diffusely detected in APA, partially or weakly detected in CPA, and immunolocalized in the zona glomerulosa of NA and IHA, as well as in the cytoplasm of cerebellar Purkinje cells. In APA, VPREB3 mRNA levels were significantly correlated to plasma aldosterone (P=0.026; R=0.30), KCNJ5 mutations (P=0.0061; mutated 34:19 wild-type), CYP11B2 (P<0.0001; R=0.65), Purkinje cell protein 4 (PCP4; P<0.0001; R=0.53) and voltage-dependent calcium channels CaV1.3 (P=0.023; R=0.31) and CaV3.2 (P=0.0019; R=0.42). Based on our data, we hypothesize a possible role for VPREB3 in aldosterone biosynthesis, and present ideas for future functional studies.
    Endocrine Pathology 04/2015; DOI:10.1007/s12022-015-9366-7 · 1.64 Impact Factor
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    ABSTRACT: Background Definitive chemoradiotherapy (dCRT) has recently become one of the most effective therapies for the treatment of esophageal squamous cell carcinoma (ESCC). However, it is also true this treatment has not been effective in all patients. Therefore, it is very important to evaluate the surrogate marker of dCRT in order to improve clinical outcomes of patients with ESCC. On the other hand, our previous study had suggested that murine double minute 2 (MDM2) and p16 were associated with chemoradioresistance in ESCC. Methods We selected pretreatment biopsy specimens of ESCC patients from our prospective clinical study on dCRT. Seventy-nine cases histologically diagnosed as ESCC were used. We immunohistochemically investigated these specimens using antibodies against MDM2, p53, p16, and Ki-67. Results The patients included 68 males and 11 females with a mean age of 63.3 years. The number of patients in each clinical stage was as follows: 22 in c-Stage I; 17 in c-Stage II; and 40 in c-Stage III. cT, cN, and cStage were significantly more advanced in the Failure group (including patients with persistent and recurrent disease after dCRT) than in the complete response (CR) group (patients with persistent CR after dCRT). The clinical stage inversely correlated with the CR rate and the rescue rate after failure. The overall survival rate was significantly worse in the patients with advanced cT, cN, and cStage levels, and in the Failure group. MDM2 positivity was significantly higher in the Failure group than in the CR group in cStageIII (P = 0.014). The number of patients with an absence of p16 immunoreactivity was significantly higher in the Failure group than in the CR group in cStageIII (P = 0.010) but not in cStageI or cStageII. Moreover, the overall survival with a Ki-67 ≥ 33.7% was significantly better than that with <33.7% for patients in cStageIII (P = 0.024). Conclusions The results of this study suggested that MDM2 and p16 are predictive markers for chemoradioresistance in cStageIII ESCC and Ki-67 is a prognostic marker following dCRT in cStageIII ESCC. These issues could contribute to the formulation of treatment strategy for patients with advanced ESCC.
    BMC Cancer 03/2015; 15(1). DOI:10.1186/s12885-015-1222-0 · 3.32 Impact Factor
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    ABSTRACT: Adrenal venous sampling is currently the only reliable method to distinguish unilateral from bilateral diseases in primary aldosteronism. In this study, we attempted to determine whether peripheral plasma levels of 18-oxocortisol (18oxoF) and 18-hydroxycortisol could contribute to the clinical differentiation between aldosteronoma and bilateral hyperaldosteronism in 234 patients with primary aldosteronism, including computed tomography (CT)-detectable aldosteronoma (n=113) and bilateral hyperaldosteronism (n=121), all of whom underwent CT and adrenal venous sampling. All aldosteronomas were surgically resected and the accuracy of diagnosis was clinically and histopathologically confirmed. 18oxoF and 18-hydroxycortisol were measured using liquid chromatography tandem mass spectrometry. Receiver operating characteristic analysis of 18oxoF discrimination of adenoma from hyperplasia demonstrated sensitivity/specificity of 0.83/0.99 at a cut-off value of 4.7 ng/dL, compared with that based on 18-hydroxycortisol (sensitivity/specificity: 0.62/0.96). 18oxoF levels above 6.1 ng/dL or of aldosterone >32.7 ng/dL were found in 95 of 113 patients with aldosteronoma (84%) but in none of 121 bilateral hyperaldosteronism, 30 of whom harbored CT-detectable unilateral nonfunctioning nodules in their adrenals. In addition, 18oxoF levels below 1.2 ng/dL, the lowest in aldosteronoma, were found 52 of the 121 (43%) patients with bilateral hyperaldosteronism. Further analysis of 27 patients with CT-undetectable micro aldosteronomas revealed that 8 of these 27 patients had CT-detectable contralateral adrenal nodules, the highest values of 18oxoF and aldosterone were 4.8 and 24.5 ng/dL, respectively, both below their cut-off levels indicated above. The peripheral plasma 18oxoF concentrations served not only to differentiate aldosteronoma but also could serve to avoid unnecessary surgery for nonfunctioning adrenocortical nodules concurrent with hyperplasia or microadenoma. © 2015 American Heart Association, Inc.
    Hypertension 03/2015; DOI:10.1161/HYPERTENSIONAHA.114.04453 · 7.63 Impact Factor
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    ABSTRACT: Pancreatic neuroendocrine tumor (PNET) has been reported to express progesterone receptor (PR) and its expression is demonstrated as a favorable prognostic factor in these patients. We examined the status of PR isoforms, PRA and PRB, in human PNET cell line and their association with cell proliferation of the tumor cells which is closely related to the clinical outcome of PNET patients. Quantitative RT-PCR and cell proliferation assay was performed following the treatment of the cells with progesterone and RU486 as PR antagonist in nontransfected and PRA transfected cells of NET cell line, QGP-1 which expressed PRB in its native state. PRA, PRB and cyclin D1 (CCND1) were immunolocalized in 87 PNET cases and the results were compared with clinicopathological parameters. CCND1, c-Fos and c-Jun mRNA were all significantly increased by the treatment with progesterone in QGP-1 cell line with PRB expression than PRA transfected cells (p = 0.02, p = 0.007, p = 0.001; respectively). The proliferative activity of QGP-1 with PRB expression, was also significantly stimulated by the administration of progesterone (p = 0.008). PRA immunoreactivity was significantly decreased in higher grade PNET (p = 0.04) whereas CCND1 significantly elevated in higher grade PNET (p = 0.035). Results of our present study demonstrated that PRA could play an inhibitory role in cell proliferation of PNET possibly through inhibiting PRB mediated signals under the presence of progesterone, which could result in decreased CCND1 expression. In addition, the status of PRA in tumor cells could be the prognostic factor in PNET. © 2015 S. Karger AG, Basel.
    Neuroendocrinology 03/2015; Online first. DOI:10.1159/000381455 · 4.93 Impact Factor
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    ABSTRACT: An inhibitory mechanism toward gastrin hypersecretion is significantly different between G-cell hyperplasia and gastrinoma despite the common clinical manifestations; hypergastrinemia and its related persistent gastric ulcers. We recenlty studied the G-cell, d-cell and ECL-cell density in a case of G-cell hyperplasia. The 70-year-old patient has been treated for persistent gastric ulcers with a markedly increased plasma gastrin (5600 pg/mL). The stomach was surgically resected because of the obstruction associated with ulcer scars. The number of G-cells in the pyloric glands was quantified on the surgical specimens and G-cell hyperplasia was histolopathologically identified. Immunostainig of histidine decarboxylate revealed the presence of ECL-cell hyperplasia in the pyloric glands and its density was significantly and positively correlated with G-cell density. Somatostatin immunoreactive cells (d-cells) increased in their number in the oxyntic glands. These results all indicated that hypersecretion of gastrin in G-cell hyperplasia could induce ECL-cell proliferation in a paracrinal manner. In addition, relatively non-prominent endocrinological features in the G-cell hyperplasia compared to gastrinoma could be also related to the paracrinal somatostatin inhibitory effects upon ECL-cells in the pyloric glands. © 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.
    Pathology International 03/2015; 65(5). DOI:10.1111/pin.12276 · 1.59 Impact Factor
  • Hironobu Sasano, Samaneh Yazdani, Atsuko Kasajima
    Nippon rinsho. Japanese journal of clinical medicine 03/2015; 73 Suppl 3:321-6.
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    ABSTRACT: We report a rare case of lymphangitis carcinomatosa in a 66-year-old man with a relatively long survival of 18 months following chemotherapy.The patient initially presented with dyspnea and lower abdominal pain.Subsequent colonoscopy detected adenocarcinoma of the descending colon, and computed tomography(CT)demonstrated indications of lymphangitis carcinomatosa of the lung.Therefore, the patient was diagnosed with pulmonary metastasis due to colon cancer and administered chemotherapy.The performance status(PS)of patients with lymphangitis carcinomatosa is usually dismal.This patient's PS was also poor, but dyspnea markedly improved following chemotherapy, and a subsequent CT revealed disappearance of radiological findings of lymphangitis carcinomatosa.However, subsequent immunocytochemistry analysis using the cell transfer method in bronchoalveolar lavage fluid specimens revealed diffuse positivity for cytokeratin(CK)7, while the colon carcinoma was negative for CK7.The difference in CK7 immunoreactivity between the bronchoalveolar lavage fluid and biopsy specimen of the colon indicated that the lymphangitis carcinomatosa in this patient could be reasonably postulated to be caused by a synchronous primary pulmonary adenocarcinoma with intestinal differentiation.However, an autopsy could not be performed to test this hypothesis.
    Gan to kagaku ryoho. Cancer & chemotherapy 03/2015; 42(3):371-374.
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    ABSTRACT: The clinical outcome for esophageal squamous cell carcinoma (ESCC) patients is often poor because of the invasive nature of this tumor type. AT-rich interactive domain 1A (ARID1A) functions as a tumor suppressor, and its gene mutation has been reported in various human malignancies. ARID1A is a non-catalytic subunit of the SWItch/Sucrose Non Fermentable (SWI/SNF) chromatin-remodeling complex that regulates gene transcription. Decreased expression of ARID1A protein has been reported to decrease the expression of E-cadherin, an adhesion protein. However, the correlation between ARID1A and E-cadherin expression status in ESCC remains largely unknown. To address this issue, we examined the expression of ARID1A and E-cadherin in tumor specimens excised from 83 ESCC patients using immunohistochemical analysis. The intensity of the ARID1A immunoreactivity was significantly lower in tumors with a growth pattern characterized by ill-defined borders than that in tumors with an expansive growth pattern having a well-demarcated border or tumors with an intermediate growth pattern. Thus, decreased ARID1A immunoreactivity correlated with infiltrative growth of ESCC. In contrast, E-cadherin status did not correlate with the infiltrative growth pattern of ESCC. Moreover, ARID1A expression status did not significantly correlate with any of other clinicopathological factors, E-cadherin expression levels, or the clinical outcome of the patients. On the other hand, the patients with tumors expressing low levels of E-cadherin exhibited significantly lower survival rates than those with high expression. In conclusion, reduced ARID1A expression in tumor tissues contributes to infiltrative growth of ESCC, irrespective of E-cadherin expression levels.
    The Tohoku Journal of Experimental Medicine 03/2015; 235(3):185-191. DOI:10.1620/tjem.235.185 · 1.28 Impact Factor
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    ABSTRACT: Glioblastoma is the most malignant human brain tumor and has a dismal prognosis; however, some patients show long-term survival. The interaction between the costimulatory molecule OX40 and its ligand OX40L generates key signals for T-cell activation. The augmentation of this interaction enhances antitumor immunity. In this present study, we explored whether OX40 signaling is responsible for antitumor adaptive immunity against glioblastoma and also established therapeutic antiglioma vaccination therapy. Tumor specimens were obtained from patients with primary glioblastoma (n = 110) and grade III glioma (n = 34). Quantitative polymerase chain reaction (PCR), flow cytometry, and immunohistochemistry were used to analyze OX40L expression in human glioblastoma specimens. Functional consequences of OX40 signaling were studied using glioblastoma cell lines, mouse models of glioma, and T cells isolated from human subjects and mice. Cytokine production assay with mouse regulatory T cells was conducted under hypoxic conditions (1.5% O2). OX40L mRNA was expressed in glioblastoma specimens and higher levels were associated with prolonged progression-free survival of patients with glioblastoma, who had undergone gross total resection. In this regard, OX40L protein was expressed in A172 human glioblastoma cells and its expression was induced under hypoxia, which mimics the microenvironment of glioblastoma. Notably, human CD4 T cells were activated when cocultured in anti-CD3-coated plates with A172 cells expressing OX40L, as judged by the increased production of interferon-γ. To confirm the survival advantage of OX40L expression, we then used mouse glioma models. Mice bearing glioma cells forced to express OX40L did not die during the observed period after intracranial transplantation, whereas all mice bearing glioma cells lacking OX40L died. Such a survival benefit of OX40L was not detected in nude mice with an impaired immune system. Moreover, compared with systemic intraperitoneal injection, the subcutaneous injection of the OX40 agonist antibody together with glioma cell lysates elicited stronger antitumor immunity and prolonged the survival of mice bearing glioma or glioma-initiating cell-like cells. Finally, OX40 triggering activated regulatory T cells cultured under hypoxia led to the induction of the immunosuppressive cytokine IL10. Glioblastoma directs immunostimulation or immunosuppression through OX40 signaling, depending on its microenvironment.
    Molecular Cancer 02/2015; 14(1):41. DOI:10.1186/s12943-015-0307-3 · 5.40 Impact Factor
  • Atsuko Kasajima, Samaneh Yazdani, Hironobu Sasano
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    ABSTRACT: Histopathology of pancreatic neuroendocrine tumors (PNETs) typically displays characteristic features. However, pathologists may encounter histological variants that may resemble other pancreatic tumors. Immunohistochemistry is a powerful tool in confirming neuroendocrine differentiation and differentiating PNETs with other pancreatic neoplasms. Histopathological features could be associated with inherited syndromes. Once the pathology diagnosis of neuroendocrine tumor was made, an accurate grading based on World Health Organization (WHO) classification is required. This review will focus on histology variants, immunohistochemistry and WHO classification of PNET. © 2015 Japanese Society of Hepato-Biliary-Pancreatic Surgery.
    Journal of Hepato-Biliary-Pancreatic Sciences 02/2015; DOI:10.1002/jhbp.208
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    ABSTRACT: Obesity is a risk factor for postmenopausal breast cancer and the majority of these cancers are estrogen dependent. Aromatase converts androgens into estrogens and its increased expression in breast adipose stromal cells (ASC) is a major driver of estrogen receptor-positive breast cancer. In particular, obesity-associated and tumor-derived factors, such as prostaglandin E2 (PGE2), have been shown to drive the expression of aromatase by stimulating the activity of the proximal promoter II (PII). The tumor-suppressor p53 is a key regulator of cell-cycle arrest and apoptosis and is frequently mutated in breast cancer. Mutations in p53 are rare in tumor-associated ASCs. Therefore, it was hypothesized that p53 is regulated by PGE2 and involved in the PGE2-mediated regulation of aromatase. Results demonstrate that PGE2 causes a significant decrease in p53 transcript and nuclear protein expression, as well as phosphorylation at Ser15 in primary human breast ASCs. Stabilization of p53 with RITA leads to a significant decrease in the PGE2-stimulated aromatase mRNA expression and activity, and PII activity. Interaction of p53 with PII was demonstrated and this interaction is decreased in the presence of PGE2. Moreover, mutation of the identified p53 response element leads to an increase in the basal activity of the promoter. Immunofluorescence on clinical samples demonstrates that p53 is decreased in tumor-associated ASCs compared with ASCs from normal breast tissue, and that there is a positive association between perinuclear (inactive) p53 and aromatase expression in these cells. Furthermore, aromatase expression is increased in breast ASCs from Li-Fraumeni patients (germline TP53 mutations) compared with non-Li-Fraumeni breast tissue. Overall, our results demonstrate that p53 is a negative regulator of aromatase in the breast and its inhibition by PGE2 provides a novel mechanism for aromatase regulation in obesity and breast cancer. Cancer Res; 75(4); 1-11. ©2014 AACR. ©2014 American Association for Cancer Research.
    Cancer Research 01/2015; 75(4). DOI:10.1158/0008-5472.CAN-14-2164 · 9.28 Impact Factor
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    ABSTRACT: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) has demonstrated a promising therapeutic response in lung adenocarcinoma patients with EGFR gene mutations. However, the predictive factors for this therapy have not been established, except for the EGFR gene mutation status of carcinoma cells. We first performed microarray analysis in EGFR-TKI-sensitive lung adenocarcinoma cell lines. The results indicated anterior gradient 2 (AGR2) as a potential surrogate marker of EGFR-TKI. Therefore, we then evaluated the correlation between the status of AGR2 immunoreactivity and clinicopathological factors including overall survival (OS), progression-free survival (PFS) and clinical response to EGFR-TKI, in 147 cases of surgically resected lung adenocarcinoma. The biological significance of AGR2 was further evaluated by transfecting small interfering RNA (siRNA) against AGR2 in these cells. The status of AGR2 immunoreactivity was significantly higher in lung adenocarcinoma cases with EGFR gene mutations than in those with the wild type (p<0.0001), but there were no significant differences in OS, PFS and response of EGFR-TKI between the AGR2 high and low carcinoma cases. Knockdown of AGR2 gene expression following siRNA transfection resulted in a significantly lower response to EGFR-TKI in EGFR-mutated PC-3. AGR2 could serve as an adjunctive surrogate protein marker possibly reflecting EGFR gene mutations in lung adenocarcinoma patients. Results from in vitro analysis indicated that AGR2 could be a potential clinical biomarker of EGFR-TKI therapeutic sensitivity in lung adenocarcinoma cells.
    The International journal of biological markers 01/2015; DOI:10.5301/jbm.5000131 · 1.36 Impact Factor
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    ABSTRACT: A 39-year-old Japanese woman presented with typical clinical symptoms of Cushing's syndrome, including amenorrhea and hirsutism, for 2 years. The results of her initial endocrine evaluation were consistent with ACTH-independent Cushing's syndrome due to bilateral adrenal masses (diameters of 3.1 cm and 2.4 cm on the right and left, respectively). Serum dehydroepiandrosterone levels were 6,901 ng/mL (normal range 230-2,660 ng/mL). Bilateral laparoscopic adrenalectomies were performed (left adrenalectomy first and right adrenalectomy 3 months later). Following the left adrenalectomy, the results of the endocrine evaluations were still consistent with a diagnosis of ACTH-independent Cushing's syndrome. Serum dehydroepiandrosterone sulphate levels, however, were below the normal range (143 ng/mL). Unexpectedly, the patient's menstruation resumed 2.5 months after the left adrenalectomy. Pathological examination of the resected glands showed bilateral adrenocortical adenomas, one on the left with a diameter of 3 cm, and two on the right with diameters of 0.7 cm and 1.3 cm. Immunohistochemical analysis revealed side chain cleavage, 17α-hydroxylase, 3β-hydroxysteroid dehydrogenase, and 21-hydroxylase immunoreactivity in each adenoma. Dehydroepiandrosterone-sulfotransferase immunoreactivity was pronounced in the left adenoma, less pronounced in one of the right adenoma and weak in the other right adenoma. These results were consistent with clinical endocrine findings. Ours is the first case of a patient with bilateral cortisol-secreting adenomas with unilateral oversecretion of dehydroepiandrosterone sulphate. Resumption of menstruation after the correction of the dehydroepiandrosterone-sulphate excess, despite persistent cortisol excess, indicates the importance of adrenal androgens for the regulation of the menstrual cycle.
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    ABSTRACT: Assessment of the microvessel density (MVD) may yield important information leading to an effective antiangiogenic treatment for hepatocellular carcinoma (HCC). The intratumoral MVD of 136 HCC patients was retrospectively evaluated using CD34. The correlation between the MVD and clinicopathological findings was assessed. In addition, the prognostic factors influencing the two-year disease-free survival (DFS) and overall survival (OS) were analyzed. The MVD of each tumor size group (<2, 2-5 and >5 cm) was 196±51, 181±63 and 147±69 (P=0.004). The MVD of each histological grade (well-, moderately- and poorly-differentiated) was 200±56, 184±61 and 114±55 (P<0.001). The optimum cut-off values of the MVD for the two-year DFS and OS were 118.3 and 112.7, respectively. For the two-year DFS, high tumor marker levels[AFP>100 ng/ml and PIVKA-II>100 mAU/ml] (P=0.016 and P=0.008), poorly-differentiated HCC (P=0.005), a high Ki-67 index [>20 %] (P=0.006), a large tumor size [>5 cm] (P<0.001), vascular invasion (P<0.001), high TNM stage [III/IV] (P<0.001) and a low MVD (P<0.001) were the significant unfavorable prognostic factors. For the OS, a high Ki-67 index (P=0.009), a large tumor size (P=0.005), vascular invasion (P=0.003), high TNM stage (P<0.001) and a low MVD (P<0.001) were the significant risk factors for death. By the multivariate analysis, a low MVD was identified as an independent predictor of the two-year DFS (P=0.032, hazard ratio: 0.513, 95% confidence interval: 0.279-0.943) as well as the OS (P=0.011, hazard ratio: 0.415, 95% confidence interval: 0.210-0.820). A low MVD can be used to predict an unfavorable prognosis in HCC patients. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Hepatology Research 01/2015; DOI:10.1111/hepr.12487 · 2.22 Impact Factor
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    ABSTRACT: Prediction of subsequent risks of breast carcinoma (BC) development in intraductal papilloma (IDP) has remained controversial with the exception of atypical papilloma (AP). The potential value of immunohistochemistry (IHC) of cytokeratin 5/6 [CK5/6] and p63 have been proposed but its standardization has also remained controversial. We studied 17 patients initially diagnosed as IDP or AP who subsequently developed BC with 34 age-matched controls. We compared histological features, results of IHC (estrogen receptor [ER], progesterone receptor [PR], human epidermal growth factor receptor 2 [HER2], p63, CK5/6, Ki67), and ultrasound findings. Univariate conditional logistic regression analysis revealed that the status of both CK5/6 and p63/CK5/6 were significantly associated with subsequent BC development (P < 0.05). BC development in CK5/6 positive patients was 17.9% and p63/CK5/6 double positive patients 8.6%, respectively. Ultrasound evaluation was not significantly associated with any of the parameters examined and subsequent carcinoma development. Despite CK5/6 positivity, the subsequent incidence of BC development was nearly 20%. However p63/CK5/6 double positive status could predict a significantly lower subsequent carcinoma incidence, indicating a more accurate prognostic utility. Combining p63/CK5/6 with histological findings could be easily applied and could predict the subsequent BC development of the patients diagnosed as IDP at biopsy. © 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.
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    ABSTRACT: Chapter title (in Japanese): 原発性アルドステロン症の最近の進歩:アルドステロン合成の場の同定と遺伝子変異 Author affiliations (in Japanese): 東北大学大学院医学系研究科病理診断学分野教授 笹野公伸 同 病理診断学分野 サウロJ.A.フェリゾラ 同 病理診断学分野 中村保宏 東北大学病院腎臓・高血圧・内分泌科講師 佐藤文俊 Key words: primary aldosteronism, CYP11B1, CYP11B2, 3βHSD1 (HSD3B1), 3βHSD2 (HSD3B2), KCNJ5, Purkinje cell protein 4 (PCP4), metallothionein 3 (MT3), GnRH Abstract(動向): アルドステロンは副腎皮質球状層で合成、分泌される鉱質コルチコイドであり陸上動物の血圧維持、水電解質代謝で欠かせない役割を果たしている。一方アルドステロン受容体は従来のように腎臓、大腸上皮以外にも種々の臓器で発現、分布していることが示され、アルドステロンが直接作用を及ぼしていることも明らかにされた。一方アルドステロン過剰に基づく高血圧、すなわち原発性アルドステロン症は全ての高血圧患者の5~10%を占めることが推定されてきた、加えてこれらの患者ではアルドステロンの直接作用から同じ血圧でも種々の臓器障害を生じやすく、早期発見/早期治療を含む臨床的対応が強く求められている。 このように関心が高くなってきたアルドステロンであるが、近年その合成、代謝制御の機序としてアルドステロン産生腺腫における遺伝子変異が関与している可能性が示され、さらにこの遺伝子変異の多くは細胞内カルシウム代謝を介してアルドステロン合成、分泌を促進されること判明してきた。さらにこれらのカルシウム代謝に関係する種々の因子が網羅的遺伝子解析で明らかになってきて、原発性アルドステロン症患者における内分泌代謝異常の詳細がかなりわかるようになってきた。一方アルドステロン合成に関与する特異的なステロイド合成経路もその病変における局在も含めて明らかにされてきていて、個々の患者における病態の理解がかなり深まってきた。そこで本稿では、これらの原発性アルドステロン症患者を中心にアルドステロン合成の制御機序、局在性に関する最近の動向について概説する。 Editors (in Japanese): 寺内康夫 ( 横浜市立大学教授 ) 伊藤裕 ( 慶應義塾大学教授 ) 石橋俊 ( 自治医科大学教授 )
    Annual Review OnLine 2015 - Endocrinology, Diabates and Metabolism ( 糖尿病・代謝・内分泌 ), 2015 edited by Yasuo Terauchi, Hiroshi Itoh, Shun Ishibashi, 01/2015: chapter Recent advances in primary aldosteronism: identifying the sites of aldosterone synthesis and related genetic mutations: pages 177-182; Chugai Medical Co. ( 中外医学社 )., ISBN: 9784498123533

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  • 1997–2015
    • Tohoku University
      • • Department of Anatomic Pathology
      • • Department of Pathology
      • • Division of Internal Medicine
      Miyagi, Japan
  • 2013
    • Kyoto University
      • Division of Pharmaceutical Sciences
      Kioto, Kyōto, Japan
    • Sendai National College of Technology
      Sendai, Kagoshima, Japan
    • Fudan University
      • Department of Obstetrics and Gynecology
      Shanghai, Shanghai Shi, China
  • 1998–2013
    • University of Texas Southwestern Medical Center
      • • Department of Obstetrics and Gynecology
      • • Division of Reproductive Endocrinology and Infertility
      Dallas, Texas, United States
    • Hyogo Prefectural Amagasaki Hospital
      Amagasaki, Hyōgo, Japan
  • 2012
    • St. Luke's International Hospital
      Edo, Tōkyō, Japan
  • 1999–2012
    • Yokohama Rosai Hospital
      Yokohama, Kanagawa, Japan
    • University of Toronto
      • Saint Michael's Hospital
      Toronto, Ontario, Canada
  • 2011
    • Mitsubishi Nagoya Hospital
      Nagoya, Aichi, Japan
  • 2009
    • The University of Hong Kong
      • Department of Pathology
      Hong Kong, Hong Kong
  • 2003–2009
    • Hirosaki University
      • Department of Endocrinology and Metabolism
      Khirosaki, Aomori Prefecture, Japan
    • University of Illinois at Chicago
      • Department of Obstetrics and Gynecology (Chicago)
      Chicago, Illinois, United States
    • Baker IDI Heart and Diabetes Institute
      Melbourne, Victoria, Australia
    • Akita University
      Akita, Akita, Japan
  • 2008
    • Georgia Health Sciences University
      • Department of Physiology
      Augusta, GA, United States
    • Akita University Hospital
      Akita, Akita, Japan
  • 2004–2008
    • The Jikei University School of Medicine
      • • Department of Internal Medicine H
      • • Department of Pathology
      Tokyo, Tokyo-to, Japan
    • Northwestern University
      • Department of Obstetrics and Gynecology
      Evanston, IL, United States
    • Kumamoto University
      • Department of Obstetrics and Gynecology
      Kumamoto, Kumamoto, Japan
  • 2007
    • Novartis
      Bâle, Basel-City, Switzerland
  • 2004–2007
    • Sendai University
      Sendai, Kagoshima, Japan
  • 2001–2006
    • Fukushima Medical University
      • Department of Obstetrics and Gynecology
      Hukusima, Fukushima, Japan
  • 2005
    • Prince Henry's Institute
      Melbourne, Victoria, Australia
    • Sendai Orthopaedic Hospital
      Sendai, Kagoshima, Japan
  • 1996–2003
    • Keio University
      Edo, Tōkyō, Japan
    • Hokkaido University Hospital
      Sapporo, Hokkaidō, Japan
    • Nippon Kayaku Co., Ltd.
      Edo, Tōkyō, Japan
    • University of Oulu
      • Department of Clinical Chemistry
      Uleoborg, Northern Ostrobothnia, Finland
  • 2002
    • Aomori Prefectural Central Hospital
      Aomori, Aomori Prefecture, Japan
  • 1996–2001
    • Fujita Health University
      Nagoya, Aichi, Japan
  • 2000
    • Fukuoka University
      • Department of Internal Medicine
      Hukuoka, Fukuoka, Japan
  • 1995
    • University of California, Davis
      Davis, California, United States
    • Kyushu University
      • Department of Molecular Biology
      Hukuoka, Fukuoka, Japan
  • 1988–1990
    • George Washington University
      • Department of Pathology
      Washington, Washington, D.C., United States
  • 1985–1988
    • Cornell University
      • Department of Pediatrics
      Итак, New York, United States