Norimichi Nemoto

Nihon University, Edo, Tōkyō, Japan

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Publications (108)201.65 Total impact

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    ABSTRACT: The MYC transcription factor plays a crucial role in the regulation of cell cycle progression, apoptosis, angiogenesis, and cellular transformation. Due to its oncogenic activities and over expression in a majority of human cancers, it is an interesting target for novel drug therapies. MYC binding to the E-box (5’-CACGTGT-3’) sequence at gene promoters contributes to more than 4,000 MYC-dependent transcripts. Owing to its importance in MYC regulation, we designed a novel sequence-specific DNA-binding Pyrrole-Imidazole (PI) polyamide, Myc-5, that recognizes E-box consensus sequence. Bioinformatics analysis revealed that Myc-5 binding sequence appeared in 5′ MYC binding E-box sequences at the eIF4G1, CCND1 and CDK4 gene promoters. Furthermore Chromatin immunoprecipitation (ChIP) coupled with detection by qPCR demonstrated that Myc-5 has the ability to inhibit MYC-binding at the target gene promoters and thus cause down-regulation at m-RNA level and protein expression of its target gene in human Burkitt's lymphoma model cell line, P493.6, carrying an inducible MYC repression system and K562 (human chronic myelogenous leukaemia) cell lines. Single intravenous injection of Myc-5 at 7.5 mg/kg dose caused a significant tumor-growth inhibition in a MYC-dependent tumor xenograft model without evidence of toxicity. We report here a compelling rationale for the identification of a PI polyamide that inhibits a part of an E-box-mediated MYC downstream gene expression and is a model for showing that phenotype-associated MYC downstream gene targets consequently inhibits MYC dependent tumor growth.This article is protected by copyright. All rights reserved.
    Cancer Science 01/2015; DOI:10.1111/cas.12610 · 3.53 Impact Factor
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    ABSTRACT: Apocrine carcinoma is categorized as a special type of breast carcinoma because of its specific morphological features. To clarify the characteristics of apocrine carcinoma from the point of view of the mitochondrial profile, we conducted a comparative study between apocrine and non-apocrine carcinomas. The expressions of mitochondrial related factors (PGC1α, Nrf1, Nrf2, mtTFA and COX4) were examined in a testing set of breast cancer tissue. Apocrine carcinomas showed a clear tendency towards higher mRNA expression levels of PGC1α than non-apocrine carcinomas. The expression of the selected factor, PGC1α, as well as that of p62 was further examined. The results revealed that apocrine carcinomas showed a higher immunohistochemical positivity rate for PGC1α (21.3% vs. 3.2%; P = 0.008), and that the mRNA expression level of PGC1α was significantly higher in apocrine carcinoma than in non-apocrine carcinoma (P = 0.007). The immunohistochemical positivity rate for p62 protein was also higher in apocrine carcinomas (44.7% vs. 21.0%; P = 0.015), although no significant difference in the p62 mRNA expression level was detected between the two types of carcinoma (P = 0.633). In conclusion, this study revealed that apocrine carcinoma overexpressed PGC1α contributing to mitochondrial biogenesis, and also p62 protein accumulation.
    Pathology International 01/2015; 65(1). DOI:10.1111/pin.12235 · 1.59 Impact Factor
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    ABSTRACT: Undifferentiated (anaplastic) carcinoma with rhabdoid features is a rare and aggressive subtype of pancreatic carcinoma. Here, we report the clinical, histological, and immunohistochemical phenotypes in six autopsy cases of anaplastic carcinoma with rhabdoid features. The patients ranged between 44 and 76 years of age (median, 61 years) and consisted of four males and two females. All patients except one case died within 3 months of diagnosis, as these tumors were found at an advanced stage and were chemoresistant. At autopsy, tumor masses measuring 4-22 cm in maximum diameter were mainly located in the pancreatic body and tail. Microscopically, all cases showed anaplastic carcinoma with rhabdoid features that were discohesive with round to polygonal eosinophilic cytoplasm with occasional inclusions, and that had vesicular nuclei, and prominent nucleoli. Immunohistochemistry showed that the rhabdoid cells, particularly the inclusions, were strongly positive for pan-cytokeratin (AE1/AE3) and vimentin. Meanwhile, downregulation or aberrant cytoplasmic localization with focal aggregation of E-cadherin, β-catenin, and EMA were frequently observed in the rhabdoid cells. Moreover, the intracytoplasmic inclusions were labeled with selective autophagy-related molecules including p62/SQSTM1, ubiquitin, and kelch-like ECH-associated protein 1 (KEAP1). In addition, nuclear factor erythroid 2-related factor 2 (NRF2) and overexpression of its target molecule multidrug resistance-associated protein 1 (MRP1) were commonly observed in the rhabdoid cells. Therefore, these results suggest that p62-mediated aggregation of ubiquitinated intermediate filaments and membranous proteins is an important phenomenon in the rhabdoid phenotype. Indeed, the ubiquitinated aggregates of p62 and KEAP1 would induce activation of NRF2 and upregulation of MRP1, leading to potential chemoresistance of anaplastic carcinoma with rhabdoid features.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 07/2014; 465(5). DOI:10.1007/s00428-014-1631-5 · 2.56 Impact Factor
  • Acta histochemica et cytochemica official journal of the Japan Society of Histochemistry and Cytochemistry 01/2014; 47(5):219-229. DOI:10.1267/ahc.14024 · 1.22 Impact Factor
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    ABSTRACT: Anaplastic sarcoma of the kidney (ASK) is a relatively newly recognized pediatric renal tumor. The present patient, a 13-year-old boy with a large renal mass, underwent surgery. Pathological findings showed proliferation of short spindle-shaped cells with anaplastic features including multiple foci in hyaline cartilage. Complex chromosomal abnormalities were detected in the tumor cells. Postoperative chemotherapy with the regimen for Ewing's sarcoma achieved complete remission but the tumor recurred and the patient died during re-induction chemotherapy. Autopsy indicated the cause of death as duodenal hemorrhage. Because there were no viable tumor cells, the recurrent tumor was considered to have been completely cured by chemotherapy. ASK is a very rare tumor, of unknown pathogenesis, and no standard treatment has yet been established, but the tumor cells may be responsive to chemotherapy. Further study is needed to establish the optimal treatment strategy.
    Pediatrics International 10/2013; 55(5):e129-32. DOI:10.1111/ped.12167 · 0.73 Impact Factor
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    ABSTRACT: The polymeric immunoglobulin receptor (pIgR) is a type I transmembrane protein that is expressed on the surfaces of glandular epithelial cells. The extracellular portion of the pIgR is composed of 6 different domains. Domain 6 is involved in the enzymatic cleavage and release of the pIgR into the intestinal lumen as a free secretory component (fSC). A highly conserved 9-amino acid sequence is present in this region in various species. Although mutations in domain 6 are associated with particular diseases, such as IgA nephropathy and Epstein Barr virus-related nasopharyngeal cancer, and the glutamic acid residues in the conserved 9-amino acid sequence are expected to be indispensable for the secretion of fSC, the importance of these residues has not been examined. In the present study, we attempted to examine the role of these residues in the enzymatic cleavage of the pIgR. The enzymatic cleavage of the pIgR was not affected by the presence of an alanine to valine substitution at position 580 or glutamine to alanine substitutions at positions 606 and/or 607, or the deletion of the whole 9-amino acid conserved sequence. Intriguingly, the 10-amino acid sequences flanking the N- and C-terminal ends of the conserved 9-amino acid sequence had opposite effects on pIgR cleavage. Namely, the N-terminal and C-terminal sequences enhanced and reduced pIgR cleavage efficiency, respectively. These results indicated that the pIgR can be divided into several functionally distinct regions. This article is protected by copyright. All rights reserved.
    Scandinavian Journal of Immunology 06/2013; 78(4). DOI:10.1111/sji.12093 · 1.88 Impact Factor
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    ABSTRACT: In patients with inoperable advanced non-small cell lung carcinomas (NSCLCs), histological subtyping using small-mount biopsy specimens was often required to decide the indications for drug treatment. The aim of this study was to assess the utility of highly sensitive mRNA quantitation for the subtyping of advanced NSCLC using small formalin fixing and paraffin embedding (FFPE) biopsy samples. Cytokeratin (CK) 6, CK7, CK14, CK18, and thyroid transcription factor (TTF)-1 mRNA expression levels were measured using semi-nested real-time quantitative (snq) reverse-transcribed polymerase chain reaction (RT-PCR) in microdissected tumor cells collected from 52 lung biopsies. Our results using the present snqRT-PCR method showed an improvement in mRNA quantitation from small FFPE samples, and the mRNA expression level using snqRT-PCR was correlated with the immunohistochemical protein expression level. CK7, CK18, and TTF-1 mRNA were expressed at significantly higher levels (P<0.05) in adenocarcinoma (AD) than in squamous cell carcinoma (SQ), while CK6 and CK14 mRNA expression was significantly higher (P<0.05) in SQ than in AD. Each histology-specific CK, particularly CK18 in AD and CK6 in SQ, were shown to be correlated with a poor prognosis (P=0.02, 0.02, respectively). Our results demonstrated that a quantitative CK subtype mRNA analysis from lung biopsy samples can be useful for predicting the histology subtype and prognosis of advanced NSCLC.
    Acta histochemica et cytochemica official journal of the Japan Society of Histochemistry and Cytochemistry 04/2013; 46(2):85-96. DOI:10.1267/ahc.12024 · 1.22 Impact Factor
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    ABSTRACT: A 14-year-old girl with acute lymphocytic leukemia complained of right flank pain and fever. As her fever was prolonged, she underwent renal biopsy and was diagnosed with mucormycosis. We performed right nephrectomy, and subsequent pathological examination of her tissue specimen also detected mucormycosis. Here, we report a rare case of renal mucormycotic abscess.
    01/2013; 66(4):345-7.
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    ABSTRACT: PROBLEM: Toll-like receptors (TLRs) are innate immune receptors that mediate the pattern recognition of, and response toward, pathogens and host-derived danger signals. We reported that cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase (mPGES) mRNA were expressed in cases of endometriosis. The relationship between COX-2, mPGES-1, and TLR4 in endometriotic lesions has yet to be determined. METHOD OF STUDY: Endometriosis samples were obtained from 37 patients with endometrial cysts. Endometrial tissues were obtained from patients undergoing surgical procedures for benign gynecological conditions. COX-2, mPGES-1, and TLR4 mRNA expressions were examined by real-time quantitative reverse transcription PCR (qRT-PCR) and mPGES-1, and TLR4 protein localization was examined by immunohistochemistry. RESULTS: TLR4 proteins were mostly located to the glandular epithelium. The immunoreactivities of TLR4 and mPGES-1 from endometriosis lesions were significantly higher than those in eutopic endometrium in the proliferative phase. The expression levels of mPGES-1 mRNA in peritoneal endometriosis were higher than those in eutopic endometrium in the proliferative phase. The expression of TLR4 mRNA correlates with that of mPGES-1 mRNA and not with that of COX-2 in endometriotic lesions. CONCLUSION: Relationship between TLR4 and mPGES-1 mRNA in endometriotic lesions indicate that innate immunity may play an important role in the pathogenesis of endometriosis.
    American Journal Of Reproductive Immunology 12/2012; 69(3). DOI:10.1111/aji.12056 · 3.32 Impact Factor
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    ABSTRACT: Pemetrexed inhibits three key folate enzymes: thymidylate synthetase (TYMS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT). The relationship between the clinical efficacy of pemetrexed and the expression of folate enzymes in lung cancer cells is unknown. The purpose of this study was to determine whether TYMS, DHFR, and GARFT expression affect the therapeutic efficacy of pemetrexed. Participants (n=50) were patients with advanced non-small cell lung cancer (NSCLC) treated with pemetrexed. Samples were obtained by tumor biopsy before treatment. We isolated cancer cells from formalin-fixed paraffin-embedded tissues using laser microdissection, and mRNA levels were analyzed using real-time reverse transcription polymerase chain reaction. Protein expression was evaluated using immunohistochemistry. We assessed the association between TYMS, DHFR, and GARFT expression and the therapeutic efficacy of pemetrexed. The median age was 66.8 years. Compared to healthy tissues, the relative TYMS mRNA expression ranged from 0.001 to 41.613 (mean 4.638±1.357), and was significantly lower in responders compared to non-responders (1.671±0.844 versus 5.978±1.895, p=0.0142). Progression-free survival was prolonged in patients with lower TYMS mRNA expression compared to those with higher TYMS mRNA expression, but the difference was not statistically significant (18.0 versus 13.3 weeks, p=0.3001). DHFR and GARFT mRNA expression did not correlate with the efficacy of pemetrexed. We specifically analyzed TYMS, DHFR, and GARFT mRNA expression levels in lung cancer cells from biopsy specimens using laser microdissection. TYMS mRNA expression affected the therapeutic efficacy of pemetrexed and could therefore constitute a useful predictive biomarker for NSCLC patients receiving pemetrexed.
    Anticancer research 10/2012; 32(10):4589-96. · 1.87 Impact Factor
  • European Journal of Cancer 07/2012; 48:S241. DOI:10.1016/S0959-8049(12)71617-9 · 4.82 Impact Factor
  • European Journal of Cancer 07/2012; 48:S237-S238. DOI:10.1016/S0959-8049(12)71603-9 · 4.82 Impact Factor
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    ABSTRACT: Molecule targeting therapy using somatostatin (SS) analogues has become a widely accepted modality to treat neuroendocrine tumors (NETs), particularly gastrointestinal (GI) and pancreatic endocrine tumors. On the other hand, little is known about the expression of somatostatin receptor (SSTR) subtypes in neuroendocrine carcinomas (NECs). We investigated the expression of SSTR subtypes (SSTR-1, 2A, 3, 4 and 5) using real-time reverse transcription polymerase chain reaction (RT-PCR) method and immunohistochemistry in 32 neuroendocrine neoplasms (9 NET G1, 2 NET G2, 18 NECs G3 and 3 mixed NEC G3) of various primary sites. Expression of more than two SSTR subtypes was detected in all neuroendocrine neoplasms examined. Expression of SSTR-2A mRNA was significantly higher than other subtypes. In addition, mRNA expression of SSTR-3 and SSTR-5 was significantly low or below the detection level except for gastroduodenal NET G1. No significant difference of the expression of SSTR subtypes was observed between the NET and NEC groups. The expression of protein and mRNA was generally well correlated. In conclusion, NECs would be a good candidate for molecule targeting therapy using SS analogues, and the expression of SSTR-2A can be useful as a biomarker of neuroendocrine differentiation. We have demonstrated that NEC G3 small cell type shows a different expression profile of SSTR subtypes compared with NET and NEC non-small cell type.
    ACTA HISTOCHEMICA ET CYTOCHEMICA 06/2012; 45(3):167-76. DOI:10.1267/ahc.12006 · 1.22 Impact Factor
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    ABSTRACT: We describe herein a 39-year-old woman with tumor recurrence in the residual pancreas and metastasis to the lymph node about 5 years after an eneclation for insulinoma in the body of the pancreas. A certain day in the morning in June 2002, she was immediately admitted to our hospital due to impairment of consciousness based hypoglycemia. On diagnostic imaging including an arterial stimulation venous sampling, localization of the recurrent lesions was not identified. In October 2002, we underwent laparotomy for the purpose of localization of the recurrent lesions and treatment. During the operation, peripheral blood glucose level, portal blood glucose level and portal insulin level were measured periodically. The mobilization started from the tail of the pancreas. Blood glucose levels were gradually elevated during the mobilization. The pancreas was mobilized to the right edge of the portal vein and was resected. Histopathological diagnosis was recurrent insulinoma in a peripancreatic lymph node and intra-pancreatic subcapsular tumor embolization. Postoperative course was uneventful. More than 8 years after surgery, she is doing well without signs of recurrence.
    Gan to kagaku ryoho. Cancer & chemotherapy 11/2011; 38(12):2023-6.
  • European Journal of Cancer 09/2011; 47. DOI:10.1016/S0959-8049(11)72445-5 · 4.82 Impact Factor
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    ABSTRACT: A 74-year-old man with anemia visited our hospital. When he was 42 years old, he was diagnosed with duodenal ulcer and underwent gastrectomy with Billroth II construction. A gastrointestinal endoscopic examination revealed an ulcerative lesion at the remnant stomach, and the pathological examination of the biopsy specimen showed moderate to poorly differentiated adenocarcinoma. Abdominal CT scan revealed liver and para-aortic lymphnode metastases. He received daily oral administration of S-1 at a dose of 100 mg/body, bid, 4 weeks on and 2 weeks off. After 4 courses of S-1, CT scan showed a complete response of the liver and also para-aortic lymphnode metastasis. He underwent total remnant gastrectomy with D2 dissection. Histological examination revealed no residual cancer cells in the surgically removed stomach and lymphnode, and he was diagnosed a complete pathological response (Grade 3). He refused adjuvant S-1, but is in good health without recurrence 2 years after the operation.
    Gan to kagaku ryoho. Cancer & chemotherapy 07/2011; 38(7):1191-5.
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    Journal of Neurology 02/2011; 258(7):1351-3. DOI:10.1007/s00415-011-5917-0 · 3.84 Impact Factor
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    ABSTRACT: We carried out a histopathologic study of pilomatrixoma, a benign skin tumor, and also examined apoptosis and hair differentiation with the aim to understand the presence of amorphous debris and cyst formation in the tumor. Among 16 cases of pilomatrixoma examined, 11 were at the early regressive stage and 5 were at the late regressive stage according to the classification by Kaddu et al. In the former cases, tumor nests were basically composed of basophilic, transitional, and shadow cells. Cyst formation was evident in all cases and squamoid epithelium was observed in 4 cases at the early regressive stage. Amorphous debris was found in all cases including those at the late regressive stage. Immunohistochemical analysis revealed positive reaction products for β-catenin and Lef-1 in basophilic and transitional cells, although their distribution differed. Immunoreactivity for β-catenin was observed in the lower transitional cells, whereas immunoreactivity for Lef-1 was also evident in the upper transitional cells. Positive reactions for hair keratins were found in the cytoplasm of transitional and shadow cells, but not in the amorphous debris. Examination by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) method revealed positive reactions in transitional and some shadow cells. These results suggest that in pilomatrixoma, production of hair keratin and induction of apoptosis may occur at the same time, and that unlike the normal hair follicle irregular expression of β-catenin and Lef-1 results in the appearance of amorphous debris and cyst formation.
    The American Journal of dermatopathology 02/2011; 33(1):60-4. DOI:10.1097/DAD.0b013e3181e07891 · 1.30 Impact Factor
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    ABSTRACT: We report a rare autopsy case of disseminated strongyloidiasis combined with cytomegalovirus co-infection involving a 68-year-old man, who was originally from Okinawa Prefecture in southern Japan, where strongyloidiasis occurs sporadically among the elderly. This patient was admitted with a diagnosis of drug eruption and hypereosinophilic syndrome. He was administered steroid therapy, but suffered complications of fever, respiratory distress, and pulmonary hemorrhaging. The autopsy findings showed disseminated strongyloidiasis in the alveolar spaces and the intestine and cytomegalovirus inclusion body foci in the lungs.
    01/2011; 64(2):150-2.
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    ABSTRACT: Invasive pulmonary aspergillosis (IPA) is an important and fatal complication in the patients with neutropenic or immunosuppressed condition. In spite of intensive treatment with anti-fungal drugs, the prognosis of the patients who have been suffered from IPA is extremely poor. This case was an 85-year-old Japanese man who was diagnosed as idiopathic thrombocytopenic purpura (ITP). He underwent high-dose corticosteroids and gamma-globulin therapy. During the hospitalization, he complained respiratory symptoms, and the abnormal shadow suggesting pulmonary infiltration and cavitation was pointed out on chest imaging. He was diagnosed as IPA because of high level of serum beta-D-glucan and positive for aspergillus antigen. Although he underwent intensive care with anti-fungal drug administration and artificial respiration, he died of respiratory distress on the 68th hospitalization. Postmortem examination disclosed severe bronchopneumonia, cavitation and pulmonary arterial thrombi in both lungs. Histological examination showed widely distributed epitheloid cell granulomata with central necrosis containing aspergillus hyphae, and vasodestructive growth of fungus with occasional organized thrombi.
    Rinsho byori. The Japanese journal of clinical pathology 08/2010; 58(8):786-91.