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Atsushi Otsuka,
Motoaki Ozaki,
Yuri Horiguchi,
Yozo Murata,
Kimiko Kumano,
Reiko Nogami, Masamichi Goto,
Andrew F Walls,
Norihisa Ishii,
Yoshiki Miyachi,
Kenji Kabashima
Acta Dermato-Venereologica 04/2012;
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Suguru Yonezawa,
Shinichi Kitajima,
Michiyo Higashi,
Masahiko Osako,
Michiko Horinouchi,
Seiya Yokoyama,
Sho Kitamoto,
Norishige Yamada,
Yukihiro Tamura,
Takeshi Shimizu,
Mineo Tabata, Masamichi Goto
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ABSTRACT: Isolated cancer cells of non-solid type poorly differentiated adenocarcinoma (por2) or signet-ring cell carcinoma (sig) are frequently seen in scirrhous gastric cancers with a very poor prognosis. These cells are often scattered in granulation tissue or desmoplastic fibrotic tissue and tend to be overlooked in routine pathological examination. We aimed to raise a novel antibody that can identify the isolated cancer cells easily.
Because the MUC1 cytoplasmic tail domain (CTD) has many biological roles including tumor progression and cell adhesion disturbance and is expected to be expressed in isolated cancer cells, we raised a novel monoclonal antibody (MAb) MUC1-014E against an intracellular nonrepeating 19-amino-acid sequence (RYVPPSSTDRSPYEKVSAG: N-1217-1235-C) of the MUC1 CTD, using a synthetic peptide including the 7-amino-acid epitope (STDRSPY: N-1223-1229-C).
In the immunohistochemical staining of 107 gastrectomy specimens including 48 por2 and 31 sig lesions, the MAb MUC1-014E showed high rates of positive staining (≥5% of carcinoma cells stained) for por2 (100%) and sig (97%), and of the highest intensity staining (4+, ≥75% of carcinoma cells stained) for por2 (100%) and sig (90%). In the 89 biopsy specimens including 82 por2 and 38 sig lesions, the MAb MUC1-014E showed high rates of positive staining for por2 (100%) and sig (100%) and of 4+ staining for por2 (87%) and sig (84%). All the rates were significantly higher than those with cytokeratins (AE1/AE3 or CAM5.2).
The MAb MUC1-014E is very useful for accurate detection of isolated cancer cells in scirrhous gastric cancers.
Gastric Cancer 01/2012; 15(4):370-81. · 2.42 Impact Factor
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Yukihiro Tamura,
Michiyo Higashi,
Sho Kitamoto,
Seiya Yokoyama,
Masahiko Osako,
Michiko Horinouchi,
Takeshi Shimizu,
Mineo Tabata,
Surinder K Batra, Masamichi Goto,
Suguru Yonezawa
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ABSTRACT: We have previously reported that MUC4 expression is a poor prognostic factor in various carcinomas. Our previous study also showed that MUC1 expression in gastric cancers, including the early and advanced stages is a poor prognostic factor. In the present study, the expression profiles of MUC4 and MUC1 were examined by immunohistochemistry (IHC) using two anti-MUC4 monoclonal antibodies (MAbs), 8G7 and 1G8, and anti-MUC1 MAb DF3 in 104 gastrectomy specimens of early gastric adenocarcinoma with submucosal invasion (pT1b2), including 197 histological subtype lesions. Before the IHC study of the human specimens, we evaluated the specificity of the two MAbs by Western blotting and IHC of two MUC4 mRNA expressing gastric cancer cell lines. MAb 8G7 reacted clearly, whereas MAb 1G8 did not show any reactivity, in either Western blotting or IHC. In the IHC of the gastric cancers, the expression rates of MUC4/8G7 detected by MAb 8G7, MUC4/1G8 detected by MAb 1G8 and MUC1/DF3 detected by MAb DF3 in well differentiated types (70%, 38/54; 67%, 36/54; 52%, 28/54) were significantly higher than those in poorly differentiated types (18%, 10/55; 36%, 20/55; 13%, 7/55) (P<0.0001; P = 0.0021; P<0.0001), respectively. The MUC4/8G7 expression was related with lymphatic invasion (r = 0.304, P = 0.033). On the other hand, the MUC4/1G8 expression was related with lymphatic invasion (r = 0.395, P = 0.001) and lymph node metastasis (r = 0.296, P = 0.045). The MUC1/DF3 expression was related with lymphatic invasion (r = 0.357, P = 0.032) and venous invasion (r = 0.377, P = 0.024). In conclusion, the expression of MUC4 as well as MUC1 in early gastric cancers is a useful marker to predict poor prognostic factors related with vessel invasion.
PLoS ONE 01/2012; 7(11):e49251. · 4.09 Impact Factor
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ABSTRACT: Mucins are high molecular weight glycoproteins that play important roles in carcinogenesis and tumor invasion. Our immunohistochemical studies demonstrated that MUC1 or MUC4 expression is related to the aggressive behavior and poor outcome of human neoplasms. MUC2 is expressed in indolent pancreatobiliary neoplasms, but these tumors sometimes show invasive growth with MUC1 expression in invasive areas. MUC5AC shows de novo high expression in many types of precancerous lesions of pancreatobiliary cancers and is an effective marker for early detection of the neoplasms. The combination of MUC1, MUC2, MUC4 and MUC5AC expression may be useful for early detection and evaluation of the potential for malignancy of pancreatobiliary neoplasms. Regarding the mechanism of mucin expression, we have recently reported that expression of the mucin genes is regulated epigenetically in cancer cell lines, using quantitative MassARRAY analysis, methylation-specific polymerase chain reaction analysis and chromatin immunoprecipitation analysis, with confirmation by the treatment with 5-aza-2'-deoxycytidine and trichostatin A. We have also developed a monoclonal antibody against the MUC1 cytoplasmic tail domain, which has many biological roles. Based on all of the above findings, we suggest that translational research into mucin gene expression mechanisms, including epigenetics, may provide new tools for early and accurate detection of human neoplasms.
Pathology International 12/2011; 61(12):697-716. · 1.62 Impact Factor
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Norihisa Ishii,
Yutaka Ishida,
Yoshiko Okano,
Motoaki Ozaki,
Masaich Gidoh,
Kimiko Kumano, Masamichi Goto,
Reiko Nogami,
Kentaro Hatano,
Akatsuki Yamada,
Rie Roselyne Yotsu
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ABSTRACT: Treatment of erythema nodosum leprosum (ENL, type 2 reaction) using thalidomide provides effective alternative choice to steroid therapy. Yet, the Japanese National Health Insurance approves thalidomide prescription only for the treatment of multiple myeloma under the Thalidomide Education and Risk Management System (TERMS). Benefit of thalidomide therapy for patients with ENL is already an established fact based on various reports from other countries, but limited experiences and standards in Japan have hindered application of the medication to our patients. This led us to compose a local guideline. Based on and following the TERMS, we suggest starting thalidomide from 50-100 mg/day and then onwards adjusting the dose according to the symptoms of each patient, not to exceed the maximum recommended dose of 300 mg/day, for the treatment of ENL.
Nihon Hansenbyo Gakkai zasshi = Japanese journal of leprosy: official organ of the Japanese Leprosy Association 09/2011; 80(3):275-85.
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ABSTRACT: Mucins are high molecular weight glycoproteins that play important roles in diagnostic and prognostic prediction and in carcinogenesis and tumor invasion. Regulation of expression of mucin genes has been studied extensively, and signaling pathways, transcriptional regulators, and epigenetic modification in promoter regions have been described. Detection of the epigenetic status of cancer-related mucin genes is important for early diagnosis of cancer and for monitoring of tumor behavior and response to targeted therapy. Effects of micro-RNAs on mucin gene expression have also started to emerge. In this review, we discuss the current views on epigenetic mechanisms of regulation of mucin genes (MUC1, MUC2, MUC3A, MUC4, MUC5AC, MUC5B, MUC6, MUC16, and MUC17) and the possible clinical applications of this epigenetic information.
Clinical epigenetics. 08/2011; 2(2):85-96.
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ABSTRACT: Cavernous angiomas or hemangiomas and malignant lymphomas rarely involve the cavernous sinus. We report the case of a 72-year-old man with right circumorbital pain and right oculomotor nerve dysfunction because of a mass in the right cavernous sinus. It was removed via a transsphenoidal approach and histological examination revealed the mass was a cavernous hemangioma containing atypical large B cells in some sinusoidal vessels; no other evidence of lymphoma was detected on (18)F-2-fluoro-2-deoxy-D-glucose positron-emission tomography or bone marrow biopsy. The patient underwent gamma knife radiosurgery (GKS) of the right cavernous sinus, but no systemic chemotherapy was administered. Although good local control was achieved, the patient developed a systemic diffuse large B-cell lymphoma (DLBCL) 1.5 years after the GKS. The atypical lymphocytes of the cavernous hemangioma and biopsied lymph nodes expressed multiple myeloma oncogene-1 protein. This is a rare case of DLBCL occurring within a cavernous sinus that was diagnosed as hemangioma of the cavernous sinus by neuroimaging, surgical findings, and rapid-freezing histological diagnosis. The case indicates a importance of surgical sampling and detailed histopathological analysis.
Brain Tumor Pathology 07/2011; 28(4):353-8. · 1.19 Impact Factor
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ABSTRACT: Buruli ulcer is a skin disease caused by Mycobacterium ulcerans (M. ulcerans). In this review, we introduce our recent studies and other important works. Lesions of Buruli ulcer are usually painless, despite the extensive tissue necrosis. We have reported that mice inoculated with M ulcerans show nerve degeneration and absence of pain, but the mechanism evoking the nerve damage have not been clarified. In order to define whether mycolactone, a toxic lipid produced by M. ulcerans, can induce nerve damages, we have injected mycolactone A/B to BALB/c mouse footpads. Mycolactone induced footpad swelling, and sensory test showed hyperesthesia on day 7 and 14, recovery on day 21, and hypoesthesia on days 28 and 42. Histologically, nerve bundles showed hemorrhage, neutrophilic infiltration, and loss of Schwann cell nuclei on days 7 and 14. Semithin section studies revealed vacuolar change of Schwann cells started on day 14, which subsided by day 42, but myelinated fiber density remained low. This study suggests that mycolactone directly damages nerves and is responsible for the absence of pain characteristic of Buruli ulcer. In the human lesions, presence of neuritis is reported (Rondini S, 2006), and murine studies showed "autoamputation" (Addo P, 2005). In order to prevent the serious deformities evoked by Buruli ulcer, further studies are necessary.
Nihon Hansenbyo Gakkai zasshi = Japanese journal of leprosy: official organ of the Japanese Leprosy Association 02/2011; 80(1):5-10.
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ABSTRACT: A 7-month-old girl with acute myeloid leukemia (AML) developed acute respiratory distress syndrome (ARDS) during the pancytopenic period after induction chemotherapy. Respiratory failure did not improve despite intensive treatments. Eventually, hemophagocytic lymphohistiocytosis (HLH) was diagnosed based on hemophagocytosis in bone marrow, and high soluble interleukin-2 receptor (sIL-2R) and ferritin levels. Even after cyclosporin A was started against HLH, she did not recover. Autopsy showed macrophage proliferation in bone marrow and lymph nodes. HLH should be considered, even in the pancytopenic period after chemotherapy, when patients develop ARDS that does not respond to supportive therapies.
Pediatric Hematology and Oncology 11/2010; 28(3):244-8. · 0.89 Impact Factor
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ABSTRACT: High de novo expression of MUC5AC (a gastric-type secreted mucin) is observed in many types of pancreatobiliary neoplasms, including precursor lesions. In this study, we show that the DNA methylation pattern is intimately correlated with MUC5AC expression in ten cancer cell lines (breast, lung, pancreas, and colon).
The CpG methylation status of the MUC5AC promoter from -3855 to +321 was mapped using MassARRAY analysis, which utilizes base-specific cleavage of nucleic acids. ChIP assays and micro-RNA (miRNA) microarray expression profiling were also carried out in both MUC5AC-positive cells and in those with no or low MUC5AC expression.
In the distal region from -3718 to -3670 of the promoter, MUC5AC-negative cancer cells (e.g., MDA-MB-453) were highly methylated, whereas MUC5AC-positive cells (e.g., MCF-7) had low methylation levels. The modification status of histone H3 lysine 9 (H3-K9) was also closely related to MUC5AC expression. Expression levels of miRNAs in the cancer cells were not correlated with MUC5AC expression.
Our results indicate that MUC5AC is regulated by CpG methylation and histone H3-K9 modification of the MUC5AC promoter distal region, but not by miRNAs. An understanding of the epigenetic regulation of MUC5AC may be of importance for the diagnosis of carcinogenic risk in the pancreatobiliary system.
Journal of hepato-biliary-pancreatic sciences. 11/2010; 17(6):844-54.
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ABSTRACT: MUC17 glycoprotein is a membrane-associated mucin that is mainly expressed in the digestive tract. It has been suggested that MUC17 expression is correlated with the malignancy potential of pancreatic ductal adenocarcinomas (PDACs). In the present study, we provided the first report of the MUC17 gene expression through epigenetic regulation such as promoter methylation, histone modification and microRNA (miRNA) expression. Near the transcriptional start site, the DNA methylation level of MUC17-negative cancer cell lines (e.g. PANC1) was high, whereas that of MUC17-positive cells (e.g. AsPC-1) was low. Histone H3-K9 (H3-K9) modification status was also closely related to MUC17 expression. Our results indicate that DNA methylation and histone H3-K9 modification in the 5' flanking region play a critical role in MUC17 expression. Furthermore, the hypomethylation status was observed in patients with PDAC. This indicates that the hypomethylation status in the MUC17 promoter could be a novel epigenetic marker for the diagnosis of PDAC. In addition, the result of miRNA microarray analysis showed that five potential miRNA candidates existed. It is also possible that the MUC17 might be post-transcriptionally regulated by miRNA targeting to the 3'-untranslated region of its mRNA. These understandings of the epigenetic changes of MUC17 may be of importance for the diagnosis of carcinogenic risk and the prediction of outcomes for cancer patients.
Glycobiology 10/2010; 21(2):247-56. · 3.58 Impact Factor
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ABSTRACT: Only limited data are available regarding mucin antigen expression in adenocarcinoma of the uterine cervix.
Fifty-two patients with mucinous adenocarcinoma of the endocervical type were enrolled for making clear implication of the mucin antigens. The expression of mucin antigens in hysterectomized specimens were determined immunohistochemically. Clinicopathological characteristics and prognosis included International Federation of Gynecology and Obstetrics (FIGO) stage, histological grade, nodal and ovarian metastases, overall and disease-free survivals. The relationships of the expression of mucin antigens to various variables were investigated using uni- and multivariate analyses.
The majority of mucinous adenocarcinoma showed overexpression of MUC1 and MUC16. Overexpression of both MUC1 and MUC16 was associated with lower survival rates. Particularly, overexpression of MUC1 was associated with a lower disease-free survival rate and lymph node metastasis. However, absence of expression of MUC1 and/or MUC16 was associated with longer overall and disease-free survival. In cases classified as FIGO stage Ib (n = 35), after adjusting for patient age at diagnosis and stratifying by histological grade, MUC1 and/or MUC 16 overexpression was an independent prognostic factor for overall survival (hazard ratio [HR] = 6.16, 95% confidence interval [CI] = 1.01-118.5, P < 0.05). After stratifying by ovarian metastasis, MUC1 and/or MUC 16 overexpression was also an independent prognostic factor for disease-free survival (HR = 5.50, 95% CI = 0.82-87.4, P < 0.05).
The expressions of MUC1 and/or MUC16 may be available as independent prognostic factors for the endocervical type of mucinous adenocarcinoma.
Journal of Obstetrics and Gynaecology Research 06/2010; 36(3):588-97. · 0.94 Impact Factor
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ABSTRACT: Mucins are high molecular weight glycoproteins that play important roles in carcinogenesis and tumor invasion. We have described, for the first time, that pancreatic ductal adenocarcinomas (PDACs) with an aggressive behavior and a poor outcome expressed MUC1 (pan-epithelial membrane-associated mucin) but did not express MUC2 (intestinal-type secreted mucin), whereas intraductal papillary mucinous neoplasms (IPMNs) with indolent behavior and a favorable outcome did not express MUC1 but did express MUC2. These expression profiles of MUC1 and MUC2 related to the prognoses of the patients were also observed in biliary neoplasms such as intrahepatic cholangiocarcinoma (ICC)-mass-forming type (MF), mucin-producing bile duct tumor (MPBT), and extrahepatic bile duct carcinoma (EHBDC). We also found recently that high expression of MUC4 (tracheobronchial membrane-associated mucin) in PDACs, ICCs-MF, and EHBDCs was a new independent poor prognostic factor, although MUC4 was not expressed in normal pancreatobiliary tissue. High de novo expression of MUC5AC (gastric-type secreted mucin) was observed in many types of pancreatobiliary neoplasms, including all grades of pancreatic intraepithelial neoplasia (PanIN) and biliary intraepithelial neoplasia (BilIN), and all types of IPMNs and MPBTs, as well as PDACs and ICCs-MF, although MUC5AC was not expressed in normal pancreatobiliary tissue. The combined status of MUC1, MUC2, MUC4, and MUC5AC expression may be useful for the early detection of pancreatobiliary neoplasms and evaluation of their malignancy. In regard to the mechanism of mucin expression, we have recently reported that MUC1, MUC2, MUC4, and MUC5AC gene expression is regulated by epigenetics (DNA methylation and histone H3 lysine 9 modification) in cancer cell lines, including PDAC cells. Translational research of mucin gene expression mechanisms, including epigenetics, in pancreatobiliary neoplasms may give us new tools for the early and accurate detection of these neoplasms.
Journal of hepato-biliary-pancreatic sciences. 09/2009; 17(2):108-24.
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ABSTRACT: Benign tumors and tumor-like conditions in the ampullary area are uncommon, and there are extremely rare cases of adenomyoma (AM) and adenomyomatous hyperplasia (AMH). Surgical treatment is necessary if these lesions cause biliary obstruction. In addition, the differential diagnosis of AM and AMH from carcinoma is often difficult by standard endoscopic biopsy and cytopathological analysis that may show differential findings, resulting in unnecessary surgeries sometimes being performed.
Immunohistochemical (IHC) analysis of periampullary AM and AMH was performed.
For both types of lesions, epithelial glandular cells (EGCs) showed diffuse expression of MUC6 and focal expression of HIK1083, mainly in the inner region, and focal expression of MUC5AC, mainly at the surface. The EGCs showed no expression of MUC1 or MUC4, both of which were identified as malignant tumor markers in our previous series of mucin expression studies in pancreatobiliary tumors. The expression of CK7, which was diffusely positive in normal periampullary mucosa, was decreased in the EGCs of AM and AMH.
A combined evaluation of IHC findings may be effective in the detection of AM and AMH, and also in distinguishing benign periampullary lesions, such as AM and AMH, from ampulla of Vater adenocarcinoma, thus avoiding excessive surgery.
Journal of hepato-biliary-pancreatic sciences. 09/2009; 17(3):275-83.
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ABSTRACT: Prevention of paraplegia remains an important issue in repair of descending thoracic and thoracoabdominal aneurysms. Therefore, we investigated the protective effect of sivelestat sodium hydrate (ONO-5046) on ischemia-induced spinal cord damage in a rabbit model. Twenty New Zealand white rabbits were divided into two equal groups; ONO-5046 (1.6 mg/kg)+isotonic NaCl (30 ml) was administered selectively to the spinal cord via the lumbar arteries for the first 3 min during 30 min of infra-renal aorta clamping in the experimental group (group E), whereas NaCl was given alone in the control group (group C). Motor function of the lower limbs was assessed two days later by Tarlov criteria. The number of intact motor neurons in the anterior segment of the cord (L5 level) was counted after hematoxylin-eosin staining and the number of apoptotic motor neurons after TUNEL staining. Motor function of the lower limbs in group E was significantly better (P=0.003) than that in group C. The number of intact motor neurons was greater and of apoptotic motor neurons was less in group E than C. Selective infusion of sivelestat sodium hydrate directly into the spinal cord via the lumbar arteries significantly attenuated functional and morphological ischemia-induced spinal cord injury.
Interactive cardiovascular and thoracic surgery 04/2009; 8(6):606-9.
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ABSTRACT: This review article describes morphological aspects, gene abnormalities, and mucin expression profiles in precursor lesions such as pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), and mucinous cystic neoplasm (MCN) of the pancreas, as well as their relation to pancreatic ductal adenocarcinoma (PDAC). The gene abnormalities in precursors of PDAC are summarized as follows: (1) KRAS mutation and p16/CDKN2A inactivation are early events whose frequencies increase with the dysplasia grade in both PanIN and IPMN; (2) TP53 mutation and SMAD4/DPC4 inactivation are late events observed in PanIN3 or carcinomatous change of IPMN in both PanIN and IPMN, although the frequency of the TP53 mutation is lower in IPMN than in PDAC; and (3) also in MCN, KRAS mutation is an early event whose frequency increases with the dysplasia grade, whereas TP53 mutation and SMAD4/DPC4 inactivation are evident only in the carcinoma. The mucin expression profiles in precursors of PDAC are summarized as follows: (1) MUC1 expression increases with the PanIN grade, and is high in PDAC; (2) the expression pattern of MUC2 differs markedly between the major subtypes of IPMN with different malignancy potentials (i.e., IPMN-intestinal type with MUC2+ expression and IPMN-gastric type with MUC2- expression); (3) MUC2 is not expressed in any grade of PanINs, which is useful for differentiating PanIN from intestinal-type IPMN; (4) de novo expression of MUC4, which appears to increase with the dysplasia grade; and (5) high de novo expression of MUC5AC in all grades of PanINs, all types of IPMN, MCN, and PDAC.
Gut and liver 12/2008; 2(3):137-54. · 0.83 Impact Factor
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ABSTRACT: Mucins are high molecular weight glycoproteins that play important roles in carcinogenesis or tumor invasion. To clarify the relationship of the expression patterns of mucins in human neoplasms with their biological behavior, we examined the expression profiles of MUC1, MUC2, and MUC4 mucins in various human neoplasms using immunohistochemistry and in situ hybridization, and compared them with clinicopathologic factors including outcome of the patients. MUC1 or MUC4 expression is related with the aggressive behavior of human neoplasms and a poor outcome of the patients. In contrast, MUC2 expression tends to be related with the indolent behavior of human neoplasms and a favorable outcome of the patients, although indolent pancreatobiliary neoplasms sometimes show invasive growth with MUC1 expression in the invasive areas. The expression of MUC2 mucin in indolent pancreatobiliary neoplasms coincided with expression of MUC2 mRNA. Our recent studies to clarify the MUC2 gene regulation mechanism disclosed that DNA methylation and histone modification in the 5' flanking region of the MUC2 promoter may play an important role. Further studies of the epigenetics also in MUC1 and MUC4 gene expression may be needed to understand the relationship between the expression of mucins in human neoplasms with their biological behavior.
Proteomics 08/2008; 8(16):3329-41. · 4.43 Impact Factor
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ABSTRACT: Buruli ulcer is a chronic skin disease caused by Mycobacterium ulcerans, which produces a toxic lipid mycolactone. Despite the extensive necrosis and tissue damage, the lesions are painless. This absence of pain prevents patients from seeking early treatment and, as a result, many patients experience severe sequelae, including limb amputation. We have reported that mice inoculated with M. ulcerans show loss of pain sensation and nerve degeneration. However, the molecules responsible for the nerve damage have not been identified. In order to clarify whether mycolactone alone can induce nerve damage, mycolactone A/B was injected to footpads of BALB/c mice. A total of 100 microg of mycolactone induced footpad swelling, redness, and erosion. The von Frey sensory test showed hyperesthesia on day 7, recovery on day 21, and hypoesthesia on day 28. Histologically, the footpads showed epidermal erosion, moderate stromal edema, and moderate neutrophilic infiltration up to day 14, which gradually resolved. Nerve bundles showed intraneural hemorrhage, neutrophilic infiltration, and loss of Schwann cell nuclei on days 7 and 14. Ultrastructurally, vacuolar change of myelin started on day 14 and gradually subsided by day 42, but the density of myelinated fibers remained low. This study demonstrated that initial hyperesthesia is followed by sensory recovery and final hypoesthesia. Our present study suggests that mycolactone directly damages nerves and is responsible for the absence of pain characteristic of Buruli ulcer. Furthermore, mice injected with 200 microg of mycolactone showed pulmonary hemorrhage. This is the first study to demonstrate the systemic effects of mycolactone.
Infection and immunity 06/2008; 76(5):2002-7. · 4.21 Impact Factor
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ABSTRACT: MUC1 is a transmembrane mucin that is highly expressed in various cancers and correlates with malignant potential. Important cancer-related genes such as p16 and E-cadherin are controlled epigenetically; however, MUC1 has been overlooked in epigenetics. Herein, we provide the first report that MUC1 gene expression is regulated by DNA methylation and histone H3 lysine 9 (H3-K9) modification of the MUC1 promoter. The recently developed MassARRAY assay was performed to investigate the DNA methylation status of 184 CpG sites from -2,753 to +263. Near the transcriptional start site, the DNA methylation level of MUC1-negative cancer cell lines (e.g., MDA-MB-453) was high, whereas that of MUC1-positive cell lines (e.g., MCF-7) was low. Histone H3-K9 modification status was also closely related to MUC1 gene expression. Furthermore, MUC1 mRNA expression in MUC1-negative cells was restored by treatment with the DNA methylation inhibitor 5-aza-2'-deoxycytidine. Our results indicate that DNA methylation and histone H3-K9 modification in the 5' flanking region play a critical role in MUC1 gene expression, and this study defines MUC1 as a new member of the class of epigenetically controlled genes. An understanding of the epigenetic changes of MUC1 may be of importance for diagnosis of carcinogenic risk and prediction of outcome for cancer patients.
Cancer Research 05/2008; 68(8):2708-16. · 7.86 Impact Factor
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Yoshihiro Yoshida,
Shinya Ikematsu,
Hisako Muramatsu,
Harutoshi Sakakima,
Nobuhisa Mizuma,
Fumiyo Matsuda,
Ken Sonoda,
Fujio Umehara,
Ryuichi Ohkubo,
Eiji Matsuura, Masamichi Goto,
Mitsuhiro Osame,
Takashi Muramatsu
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ABSTRACT: This study was to clarify the roles of midkine (MK) in the brain.
We determined cerebrospinal fluid MK levels in patients with neurological disorders by enzyme-linked immunoassay and immunostained autopsied brain samples in patients with meningitis.
MK levels were 0.37+/-0.21 ng/ml in controls (n=46, mean +/- S.D.), 0.67+/-0.19 ng/ml in patients with cerebral infarction (n=8), 1.78+/-1.32 ng/ml in patients with meningitis (n=25; ANOVA and post-hoc Fisher's PLSD test, p<0.0001), 0.31+/-0.25 ng/ml in patients with human T-lymphotrophic virus type I-associated myelopathy/tropical spastic paraparesis (n=29), and 0.42+/-0.17 ng/ml in patients with amyotrophic lateral sclerosis (n=8). The regression equations were Y=0.005X+0.498 (Y, CSF MK level; X, cell number) and Y=0.007X+0.326 (Y, MK level; X, protein level) for all CSF samples. Autopsy brain samples from patients with meningitis expressed MK weakly in mononuclear cells on immunohistochemical examination. Western blot and polymerase chain reaction analyses showed that leukocytes were MK positive. CSF MK levels were not high in patients with cerebral infarction but were increased in patients with meningitis. CSF MK levels were high in normal controls, compared to those of other cytokines. MK was expressed in choroid plexus of normal brain and released there.
Our findings suggested that MK may maintain normal adult brain as a neurotrophic factor, and that MK may be released from leucocytes in brain of patients with meningitis as an immunological mediator.
Internal Medicine 01/2008; 47(2):83-9. · 0.94 Impact Factor
