-
[show abstract]
[hide abstract]
ABSTRACT: Extrahepatic bile duct (EBD) carcinoma is a relatively rare neoplasm worldwide, and its prognostic outcome remains unfavorable. Therefore, it is necessary to investigate molecular biologic features of EBD carcinomas. Focal adhesion kinase (FAK) plays a pivotal role in cell adhesion, survival, migration, and signal transduction, but FAK expression in EBD carcinomas has not been evaluated. We measured FAK expression in 76 EBD carcinomas using immunohistochemistry and evaluated its correlation with tumor progression, clinicopathologic factors, and patient outcome. FAK was expressed specifically in the cytoplasm of all normal biliary epithelia (100%). Most dysplastic epithelia also showed positive FAK expression except for 2 cases (92%), whereas EBD carcinomas showed positive FAK expression in 53 (77%) of 76 cases (P < .001, versus normal epithelia). FAK expression tended to be gradually reduced along as dysplasia progressed to carcinoma. Although FAK expression had no association with clinicopathologic factors, the positive FAK expression group showed significantly better survival than the negative FAK expression group (P < .05). However, FAK expression was not an independent prognostic factor by multivariate analysis. In conclusion, FAK expression was significantly lower in EBD carcinomas than in normal biliary epithelia and decreased expression of FAK seemed to be indicative of a poor prognosis, suggesting that FAK might play an inhibitory role for tumor progression in EBD carcinomas. It is important to notice the role of FAK in tumor progression when treatments targeting FAK are performed.
Human pathology 02/2010; 41(6):859-66. · 3.03 Impact Factor
-
Mitsuki Kubo,
Kensuke Egashira, Takahiro Inoue,
Jun-ichiro Koga,
Shinichiro Oda,
Ling Chen,
Kaku Nakano,
Tetsuya Matoba,
Yoshiaki Kawashima,
Kaori Hara,
Hiroyuki Tsujimoto,
Katsuo Sueishi,
Ryuji Tominaga,
Kenji Sunagawa
[show abstract]
[hide abstract]
ABSTRACT: Recent clinical studies of therapeutic neovascularization using angiogenic growth factors demonstrated smaller therapeutic effects than those reported in animal experiments. We hypothesized that nanoparticle (NP)-mediated cell-selective delivery of statins to vascular endothelium would more effectively and integratively induce therapeutic neovascularization.
In a murine hindlimb ischemia model, intramuscular injection of biodegradable polymeric NP resulted in cell-selective delivery of NP into the capillary and arteriolar endothelium of ischemic muscles for up to 2 weeks postinjection. NP-mediated statin delivery significantly enhanced recovery of blood perfusion to the ischemic limb, increased angiogenesis and arteriogenesis, and promoted expression of the protein kinase Akt, endothelial nitric oxide synthase (eNOS), and angiogenic growth factors. These effects were blocked in mice administered a nitric oxide synthase inhibitor, or in eNOS-deficient mice.
NP-mediated cell-selective statin delivery may be a more effective and integrative strategy for therapeutic neovascularization in patients with severe organ ischemia.
Arteriosclerosis Thrombosis and Vascular Biology 04/2009; 29(6):796-801. · 6.37 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Reactive oxygen species (ROS) is increased in myocardium after myocardial infarction (MI), which may play a causal role in cardiac remodelling. However, there is scant direct and longitudinal evidence that systemic oxidative stress is enhanced accompanying an increase of ROS in myocardium. The authors conducted a comprehensive investigation of ROS markers by simultaneously sampling urine, blood and myocardium and in vivo ESR for the heart at different stages of post-MI cardiac remodelling in mouse with permanent occlusion of left coronary artery. Systemic oxidative markers increased at early days after MI and were normalized later. In contrast, TBARS and 4-hexanoyl-Lys staining were increased in non-infarct myocardium at day 28. The enhancement of ESR signal decay of methoxycarbonyl-PROXYL measured at the chest was associated with the progression of left ventricle dilatation and dysfunction. This study provided the direct evidence that redox alteration and production of ROS occurred in myocardium during the progression of cardiac remodelling and failure; however, ROS marker levels in blood and urine do not reflect the production of ROS from failing myocardium.
Free radical research 01/2009; 43(1):37-46. · 2.22 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Gallbladder carcinoma (GC) is a relatively uncommon malignancy and is often caused by diagnostic difficulties in distinguishing the extension of carcinoma in situ (CIS) from invasive carcinoma along Rokitansky-Aschoff sinuses (RAS). The laminin-5, a heterotrimer, is composed of alpha-3, beta-3 and gamma-2 chains. The gamma-2 chain is expressed in various invasive carcinoma cells. There are numerous reports that have described that laminin-5-gamma-2 is associated with tissue invasion in many organs. However, few studies are found in gallbladder carcinoma. To clarify the relationship between laminin-5-gamma-2 chain (LN-5) expression and the development of GCs, we performed an immunohistochemical study of 93 GCs. Cases were classified into three groups: CIS with/without the extension along RAS (Group A; n=17), carcinoma invading mucosa or muscular layer (Group B; n=5) and carcinoma invading beyond perimuscular connective tissue (Group C; n=71). The immunohistochemical intracytoplasmic expression was detected in the invasive fronts of the tumor. In the invasive components of Group B and C, LN-5 was expressed in 100 and 97% of cases, respectively, whereas in the CIS lesions of GCs, expression was not observed in Group A. LN-5 expression in the GCs tended to increase as tumors developed, which may be an indicator of the potential invasiveness of the tumor. Our results indicate that, in GCs, a strong intracytoplasmic expression of LN-5 was identified in the cancer cells whether in situ they extend along RAS or invading stroma.
Oncology Reports 08/2008; 20(1):33-9. · 1.84 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Intraductal papillary mucinous neoplasms (IPMN) are known to show a transition from adenoma to carcinoma accompanied by several molecular abnormalities. ATM-Chk2-p53 DNA damage checkpoint activation, which is involved in prevention of the progression of several tumors, was analyzed to evaluate the role of the DNA damage checkpoint in the progression of IPMNs.
One hundred and twenty-eight IPMNs were classified into four groups (intraductal papillary mucinous adenoma, borderline IPMN, noninvasive intraductal papillary mucinous carcinoma, and invasive intraductal papillary mucinous carcinoma) and stained immunohistochemically using antibody for Thr(68)-phosphorylated Chk2. Expression of ATM, Chk2, and p21(WAF1) and accumulation of p53 were also analyzed.
Chk2 phosphorylation was shown in all adenomas and showed a significant decreasing trend with the progression of atypia (P < 0.0001 by the Cochran-Armitage test for trend). Expression of p21(WAF1) also exhibited a decreasing tendency (P < 0.0001), reflecting DNA damage checkpoint inactivation. p53 accumulation was mostly detected in malignant IPMNs. It was suggested that the DNA damage checkpoint provides a selective pressure for p53 mutation.
Our findings indicate that DNA damage checkpoint activation occurs in the early stage of IPMNs and prevents their progression. It is suggested that disturbance of the DNA damage checkpoint pathway due to Chk2 inactivation or p53 mutation contributes to the carcinogenesis of IPMNs.
Clinical Cancer Research 08/2007; 13(15 Pt 1):4371-7. · 7.74 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Tumor necrosis factor (TNF)-alpha induced in damaged myocardium has been considered to be cardiotoxic. TNF-alpha initiates its biological effects by binding two distinct receptors: R1 (p55) and R2 (p75). Although TNF-alpha has been shown to be cardiotoxic via R1-mediated pathways, little is known about the roles of R2-mediated pathways in myocardial infarction (MI). We created MI in R1 knockout (R1KO), R2KO, and wild-type (WT) mice by ligating the left coronary artery. Functional, histological, and biochemical analyses were performed 4 wk after ligation. Although infarct size was not different among WT, R1KO, and R2KO mice, post-MI survival was significantly improved in R1KO but not R2KO mice. R1KO significantly ameliorated contractile dysfunction after MI, whereas R2KO significantly exaggerated ventricular dilatation and dysfunction. Myocyte hypertrophy and interstitial fibrosis in noninfarct myocardium was exacerbated in R2KO but not in R1KO mice. Expression of R1, which was not affected by MI and was nullified in R1KO mice, was significantly upregulated in R2KO mice. In contrast, expression of R2, which was significantly upregulated by MI and was nullified in R2KO mice, was unaffected in R1KO mice. Meanwhile, TNF-alpha expression, which was significantly upregulated in noninfarct myocardium after MI, was not affected by R1KO or R2KO. However, transcript levels of IL-6, IL-1beta, transforming growth factor-beta, and monocyte chemotactic protein-1, which were significantly upregulated after MI, were significantly downregulated in R1KO mice. In contrast, transcript levels of IL-6 and IL-1beta were significantly further upregulated in R2KO mice. TNF-alpha is toxic via R1 and protective via R2 in a murine model of MI. Selective blockade of R1 may be a candidate therapeutic intervention for MI.
AJP Heart and Circulatory Physiology 08/2007; 293(1):H743-53. · 3.71 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A case of solid pancreatic hamartoma in a 58-year-old Japanese woman is presented. She had no symptoms, and a pancreatic mass was incidentally found on screening ultrasonography 4 months before admission. The patient was not alcoholic and had no history of pancreatitis. Physical examination and laboratory data were unremarkable. Preoperative imaging demonstrated a nodule in the body of the pancreas, measuring 2.0 cm in maximum diameter, which showed marked delayed enhancement during dynamic CT. The patient underwent a distal pancreatectomy under the preoperative diagnosis of pancreatic endocrine tumor and had an uneventful postoperative course. A well-demarcated solid nodule, 1.9 cm in diameter, was evident in the body of the pancreas. Microscopically, the lesion was composed of non-neoplastic, disarranged acinar cells and ducts embedded in a sclerotic stroma with elongated spindle cells, lacking discrete islets. The stromal spindle cells were immunoreactive for CD34 and CD117. The histological diagnosis was solid hamartoma of the pancreas. There was no recurrence 5 months after surgery. Herein is reported a case of solid hamartoma of the pancreas and review of the literature. A search through the literature found only two cases of solid hamartoma of the pancreas, among the 14 cases previously reported as pancreatic hamartoma.
Pathology International 06/2007; 57(5):276-80. · 1.62 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Intraductal papillary mucinous neoplasm (IPMN) is a well-established entity in pancreatic neoplasms and a precursor of infiltrating adenocarcinoma. Fascin, an actin-bundling protein involved in cellular motility, is upregulated in many human neoplasms. Its overexpression in pancreatic intraepithelial neoplasia, a pre-cancerous lesion sharing many characteristics with IPMN, has been reported. However, fascin expression in IPMN remains unknown. The aim of this study was to investigate fascin expression in IPMNs and to elucidate its relationship to clinicopathological features, including histological grade and phenotypic subclassification. We evaluated fascin expression by immunohistochemistry in 116 surgical specimens, followed by quantitative analysis of fascin mRNA expression using a laser microdissection system and real-time reverse-transcriptase polymerase chain reaction in eight frozen samples. Fascin expression was significantly higher in borderline neoplasms (25/29, 86%) and carcinomas (37/42, 88%) than in adenomas (23/45, 51%) (P<0.05, respectively), but no difference was observed between borderline neoplasms and carcinomas. With regard to the subclassification, intestinal-type neoplasms (35/39, 90%) were more frequently positive for fascin than gastric-type neoplasms (36/59, 61%) (P<0.05). Two oncocytic-type neoplasms were both fascin-negative. Fascin mRNA expression seemed to be higher in moderately to severely dysplastic epithelium than in mildly dysplastic epithelium (not statistically significant), supporting the immunohistochemical experiments. Our findings suggest that fascin overexpression is involved in the progression of IPMN. Fascin could become a new therapeutic target for inhibition of their progression.
Modern Pathology 05/2007; 20(5):552-61. · 4.79 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Pyloric-gland type adenoma of the gallbladder is formed by proliferation of glands resembling pyloric glands, morphologically. No previous report has described the cellular phenotype and differentiation of pyloric-gland type adenoma of the gallbladder, using CD10 as a marker of proper biliary phenotype. Immunostainings were performed for mucin markers such as MUC5AC, human gastric mucin (HGM) for gastric foveolar type epithelium, MUC6, M-GGMC-1 for pyloric-gland type and MUC2 for intestinal goblet-cell type, and for CD10 as a proper biliary type marker on 58 pyloric-gland type adenomas of the gallbladder, as well as for p53, Ki-67 and CDX2. The percentage (X) of reactive cells in relation to the total number of tumor cells was estimated semi-quantitatively, and divided into four categories: X=0% (negative), 0%<X<10%, 10%<or=X<30%, and X>or=30%. CDX2 expression was considered to be positive when the percentage of positively stained cells was >or=10%. Out of the 58 pyloric-gland type adenomas, >or=30% of adenoma cells were positive for MUC5AC in 22 (38%) tumors, HGM in 29 (50%), MUC6 in 58 (100%), M-GGMC-1 in 54 (93%), MUC2 in none (0%), and CD10 in 20 (34%). MUC6 (P<0.001) and M-GGMC-1 (P<0.001) mucins were detected more frequently in pyloric-gland type adenomas, and CD10 expression was significantly decreased, compared with normal gallbladder epithelium (P=0.006). P53 overexpression was not found in any of the 58 tumors, including two adenomas with carcinomatous foci. The mean number of Ki-67-positive cells was 10.3+/-5.8%. CDX2 expression was judged as negative in all 58 pyloric-gland type adenomas. In pyloric-gland type adenomas of the gallbladder, expression of pyloric-gland type mucins was observed with a high frequency, whereas intestinal goblet-cell mucins were rarely seen. In addition, co-expression of gastric foveolar type mucins and CD10 was also demonstrated. Pyloric-gland type adenomas of the gallbladder show a differentiation toward pyloric glands in terms of immunohistochemistry, as well as morphology, accompanied by co-expression of gastric foveolar and native biliary phenotypes.
Oncology Reports 04/2007; 17(4):721-9. · 1.84 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Tumor necrosis factor (TNF)-alpha induced in damaged myocardium has been considered to be cardiotoxic. However, the negative results of RENEWAL and ATTACH prompt us to reconsider the role of TNF-alpha in cardiovascular diseases. The present study aimed to evaluate the effects of soluble TNF receptor treatment on myocardial infarction (MI).
An adenovirus encoding a 55-kDa TNF receptor-IgG fusion protein (AdTNFR1) was used to neutralize TNF-alpha, and an adenovirus encoding LacZ (AdLacZ) served as control. In the pre-MI treatment protocol, mice were given an intravenous injection of AdTNFR1 or AdLacZ 1 week before left coronary artery ligation to induce MI. In the post-MI treatment protocol, mice were treated with AdTNFR1 or AdLacZ 1 week after left coronary ligation.
Treatment with AdTNFR1 neutralized bioactivity of TNF-alpha that was activated after MI and prevented apoptosis of infiltrating cells in infarct myocardium. However, pre-MI treatment with AdTNFR1 promoted ventricular rupture by reducing fibrosis with further activation of matrix metalloproteinase (MMP)-9. Post-MI treatment with AdTNFR1 exacerbated ventricular dysfunction and remodeling, with enhanced fibrosis of non-infarct myocardium with further MMP-2 activation.
Both pre- and post-MI treatments with AdTNFR1 were deleterious in a mouse MI model. Thus, TNF-alpha may play not only toxic but also protective roles in MI.
Cardiovascular Research 04/2007; 73(4):794-805. · 6.06 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Extrahepatic bile duct carcinomas (EBDCs) still result in an unfavorable prognostic outcome, and little is known about their biological aggressiveness. Recently, UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyl transferase-3 (GalNAc-T3) was reported to be associated with differentiation and malignant potential of human carcinomas. Here, we investigated 61 EBDCs for their detailed clinicopathological features and GalNAc-T3 expression by immunohistochemistry, and then evaluated the relationships between the clinicopathological features and GalNAc-T3 expression patterns. Most of the EBDCs were massively invasive tumors with frequent vascular or perineural invasion and lymph node metastases. GalNAc-T3 expression was detected in all 61 EBDCs, and the expression patterns could be classified into granular and diffuse types. All four noninvasive or minimally invasive EBDCs were the granular type. Among the 58 minimally or massively invasive EBDCs, the GalNAc-T3 expression pattern at the luminal surface was the granular type in 38 cases (66%) and diffuse type in 20 cases (34%), while the expression pattern at the invasive front was the granular type in 26 cases (45%) and diffuse type in 32 cases (55%). Among the 38 cases with granular-type expression at the luminal surface, 26 cases (68%) remained the granular type and 12 cases (32%) became the diffuse type at the invasive front. All 20 cases with diffuse-type expression at the luminal surface remained the diffuse type at the invasive front. Diffuse-type GalNAc-T3 expression at the invasive front was significantly associated with lymph node metastasis (P<0.05). There were no significant correlations between the GalNAc-T3 expression patterns and other clinicopathological factors, including tumor differentiation, depth of invasion or overall survival. In conclusion, EBDCs alter their GalNAc-T3 expression pattern during tumor growth, and the difference in the GalNAc-T3 expression pattern may be associated with lymph node metastasis. Clinically, preoperative evaluation of GalNAc-T3 expression is considered to be useful for decisions regarding operative procedures.
Modern Pathology 02/2007; 20(2):267-76. · 4.79 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Serous oligocystic adenoma (SOA), a rare pancreatic neoplasm, is generally a benign lesion without the necessity of surgery. Preoperatively, it is difficult to discriminate SOA from mucinous cystic neoplasm (MCN), which essentially needs surgical treatment. The purpose of this study was to evaluate the cyst wall thickness of SOAs and MCNs for preoperative differential diagnosis.
We experienced three cases of SOAs with typical histopathological features. The cyst wall thickness of the SOAs was evaluated in the area protruding out of the pancreas and was compared with that of 13 MCNs histopathologically. The same evaluation and comparison were conducted on preoperative computed tomography (CT) images retrospectively.
The SOAs had a uniformly thin cyst wall measuring less than 1 mm. In contrast, the largest area of a cyst wall in MCNs ranged from 2.5 to 10.0 mm. On CT images, all but one of the MCNs showed a detectable cyst wall, while the cyst walls were hardly recognizable in two of the three SOAs.
For preoperative differentiation between SOAs and MCNs, the evaluation of cyst wall thickness may be an important tool and may contribute to the decision of treatment strategy.
Journal of Gastrointestinal Cancer 02/2007; 38(1):52-8.
-
Takashi Okafuji,
Hidetake Yabuuchi,
Shuji Sakai,
Hiroyasu Soeda,
Yoshio Matsuo, Takahiro Inoue,
Masamitsu Hatakenaka,
Naoki Takahashi,
Syoji Kuroki,
Eriko Tokunaga,
Hiroshi Honda
[show abstract]
[hide abstract]
ABSTRACT: To characterize MR imaging features of pure mucinous carcinoma of the breast.
MR images obtained from 16 women (age range, 29-81; mean age, 57 years) with pure mucinous carcinoma of the breast determined at surgery were reviewed. The MR findings used were shape, margin, internal mass enhancement, kinetic curve pattern on dynamic study, signal intensity on short time inversion recovery (STIR) T2-weighted images, and non-mass-like enhancement around the main tumor. Non-mass-like enhancement was compared with the presence of extensive intraductal component (EIC) on histopathological findings.
Eleven tumors (69%) had lobular contour, and nine tumors (56%) had smooth margin. Eight tumors (50%) showed rim enhancement and six tumors (38%) showed heterogeneous enhancement. Fourteen tumors (88%) showed a persistent enhancing pattern on kinetic curve. Fifteen tumors exhibited homogenous strongly high signal intensity on STIR T2-weighted images. In six cases with EIC, five cases had non-mass-like enhancement around the main mass.
MR findings such as lobular shape, rim or heterogeneous enhancement, persistent pattern on kinetic curve, and homogeneous strongly high signal intensity on STIR T2-weighted images may be useful in diagnosing pure mucinous carcinoma. Moreover, linear-ductal enhancement around main mass may indicate presence of EIC.
European Journal of Radiology 01/2007; 60(3):405-13. · 2.61 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: NF-kappaB is a key transcription factor that regulates inflammatory processes. In the present study, we tested the hypothesis that blockade of NF-kappaB ameliorates cardiac remodeling and failure after myocardial infarction (MI). Knockout mice with targeted disruption of the p50 subunit of NF-kappaB (KO) were used to block the activation of NF-kappaB. MI was induced by ligation of the left coronary artery in male KO and age-matched wild-type (WT) mice. NF-kappaB was activated in noninfarct as well as infarct myocardium in WT+MI mice, while the activity was completely abolished in KO mice. Blockade of NF-kappaB significantly reduced early ventricular rupture after MI and improved survival by ameliorating congestive heart failure. Echocardiographic and pressure measurements revealed that left ventricular fractional shortening and maximum rate of rise of left ventricular pressure were significantly increased and end-diastolic pressure was significantly decreased in KO+MI mice compared with WT+MI mice. Histological analysis demonstrated significant suppression of myocyte hypertrophy as well as interstitial fibrosis in the noninfarct myocardium of KO+MI mice. Blockade of NF-kappaB did not ameliorate expression of proinflammatory cytokines in infarct or noninfarct myocardium. In contrast, phosphorylation of c-Jun NH2-terminal kinase was almost completely abolished in KO+MI mice. The present study demonstrates that targeted disruption of the p50 subunit of NF-kappaB reduces ventricular rupture as well as improves cardiac function and survival after MI. Blockade of NF-kappaB might be a new therapeutic strategy to attenuate cardiac remodeling and failure after MI.
AJP Heart and Circulatory Physiology 10/2006; 291(3):H1337-44. · 3.71 Impact Factor
-
Fumi Sawada,
Rie Yoshimura,
Kenichi Ito,
Kazuhiko Nakamura,
Hajime Nawata,
Kazuhiro Mizumoto,
Shuji Shimizu, Takahiro Inoue,
Takashi Yao,
Masazumi Tsuneyoshi,
Atushi Kondo,
Naohiko Harada
[show abstract]
[hide abstract]
ABSTRACT: This report describes an extremely rare adult case of an omphalomesenteric cyst resected by laparoscopic-assisted surgery. A 29-years-old Japanese man was referred and admitted to Kyushu University Hospital because of an abdominal mass and an elevated serum CEA (carcinoembryonic antigen) level (21.3 ng/mL) in August 2001. Abdominal CT and US demonstrated a cystic mass with septum and calcification. Laparoscopy showed a large mass to be attached to his abdominal wall, measuring 110 mm x 70 mm x 50 mm and filled with mucus. The mass was resected by laparoscopic-assisted surgery. The histological findings of its wall showed fibromuscular tissue, adipose tissue, calcification, and an intestinal structure. It was finally diagnosed to be an omphalomesenteric cyst.
World Journal of Gastroenterology 03/2006; 12(5):825-7. · 2.47 Impact Factor
