[show abstract][hide abstract] ABSTRACT: Nucleus accumbens-associated protein 1 (NAC1) is overexpressed in various carcinomas including ovarian, cervical, breast, and pancreatic carcinomas. High expression of NAC1 is considered to have adverse effects on prognosis through negative regulation of growth arrest and DNA-damage-inducible 45-γ interacting protein 1 (GADD45GIP1) in ovarian and cervical carcinomas. In the present study, the expression of NAC1 in pancreatic ductal adenocarcinoma (PDA) was measured using immunohistochemistry and computer-assisted image analysis in order to investigate its correlation with various clinicopathological parameters and prognosis. Patients with low-NAC1 PDA had worse overall survival (P = 0.0010) and a shorter disease-free survival (P = 0.0036) than patients with high-NAC1 PDA. This was a clinical effect opposite to that reported in ovarian and cervical carcinomas. Furthermore, knockdown of NAC1 in pancreatic carcinoma cell lines did not increase expression of the GADD45GIP1 protein. These results indicate that the gene(s) regulated by NAC1 vary depending on the types of carcinoma or originating tissue, and that low expression of NAC1 predicts poor prognosis for patients with PDA.
Pathology International 12/2012; 62(12):802-10. · 1.72 Impact Factor
[show abstract][hide abstract] ABSTRACT: Hypoxia has been shown to promote metastasis of cancer cells through induction of epithelial-mesenchymal transition (EMT). It is also known to cause generation of reactive oxygen species (ROS). We investigated here the role of ROS in hypoxia-induced EMT and whether attenuation of ROS by antioxidants suppresses hypoxia-induced EMT and metastasis of human pancreatic cancer cells in a xenograft nude mouse model. PANC-1 and MiaPaCa-2 cells exposed to hypoxia (1 % O(2)) showed increased ROS generation and characteristic changes of EMT such as morphological changes, enhanced invasiveness, and upregulation of EMT regulators, SLUG, SNAI1 and TWIST. The antioxidants N-acetylcysteine (NAC) and ebselen significantly suppressed EMT and the expression of EMT regulators during hypoxia. NAC abrogated activation of HIF-1α and NF-κB, both of which were found to play an active role in hypoxia-induced EMT. Administration of NAC to nude mice with orthotopic tumors suppressed the expression of EMT regulators in hypoxic areas and significantly inhibited hepatic metastasis. Together, the present findings demonstrate that attenuation of ROS by antioxidants suppresses hypoxia-induced EMT and metastatic phenotype, suggesting that antioxidants may be of therapeutic value in treating pancreatic cancers.
Clinical and Experimental Metastasis 07/2012; · 3.46 Impact Factor
[show abstract][hide abstract] ABSTRACT: A 73-year-old man was diagnosed with superficial esophageal cancer, and endoscopic mucosal resection was performed. Histologically,
the lesion was found to be a squamous cell carcinoma invading the muscularis mucosae without vascular invasion. The patient
was followed without being given adjuvant therapy, and lymph node recurrence along the lesser curvature of the stomach was
found after 2.5 years. He underwent laparoscopic removal of the metastatic lymph node and cholecystectomy for cholecystolithiasis.
He had two courses of adjuvant chemotherapy and showed no recurrence during 3 years of observation. Although the effectiveness
of surgical resection for nodal recurrence of esophageal cancer remains controversial, this case highlights the possibility
of salvage resection using minimally invasive surgery.
[show abstract][hide abstract] ABSTRACT: Despite efforts to improve surgical techniques, serious complications still sometimes occur. Use of a physiological posterior mediastinal pathway has increased given advances such as automated anastomotic devices and a reduction in the incidence of anastomotic sufficiency. Until now the gastric conduit created has been protected by an echo probe cover and, sown to the ventral side of polyester tape placed through the abdomen to the neck, and then blindly elevated to the neck. We report on a new method of gastric conduit elevation.
Two 60-cm lengths polyester tape are ligated at both ends to form a loop. An echo probe cover of 10 cm in diameter and 50 cm in length is prepared and the tip cut off, forming a cylinder. The knots in the previously looped polyester tape are inserted into the echo probe cover. The looped polyester tape and echo probe cover is ligated with silk approximately 5 cm in front of the knots on both sides. After dissection is carried out according to practice, the previously crafted polyester tape is inserted into the chest cavity. One end of polyester tape is fixed to the distal esophageal stump with the clips, with the opposite end fixed to the proximal esophageal stump. The echo probe cover that connects the proximal esophagus and distal esophagus is monitored for the presence of creases along the long axis to ensure there are no twists in the echo probe cover. We carry out a laparoscopic-assisted perigastric lymph node dissection, make a small skin incision, and guide part of the thoracic esophagus and stomach outside the body. Either one of the two lengths of polyester tape is connected to the gastric conduit. By pulling up this length of polyester tape from the neck, the gastric conduit can pass through the echo probe cover and be elevated to the neck.
No perioperative complications such as bleeding or difficulty of the gastric conduit elevation were recognized with this method.
This method is considered to serve as a useful technique for gastric conduit elevation.
World Journal of Surgical Oncology 01/2012; 10:20. · 1.09 Impact Factor
[show abstract][hide abstract] ABSTRACT: Innate adjuvant receptors are expressed in immune cells and some types of cancers. If antitumor therapies targeting these receptors are established, it is likely that they will be therapeutically beneficial because antitumor effects and immune-cell activation can be induced simultaneously. In this study, we tested this possibility of using an innate adjuvant receptor ligand, polyinosinic-polycytidylic acid [poly(I:C)], to treat human breast cancer cell lines. Three breast cancer cell lines (MCF-7, MDA-MB-231, and BT-549) were used in this study. Poly(I:C) was transfected into these cancer cells to stimulate melanoma differentiation-associated gene (MDA) 5, which is a cytoplasmic adjuvant receptor. Poly(I:C) transfection significantly reduced the viability of all cell lines in a manner partially dependent on MDA5. Flow cytometeric analyses and immunoblot assays revealed that the antitumor effect depended on both caspase-dependent apoptosis and c-Myc- and cyclinD1-dependent growth arrest. Interestingly, poly(I:C) transfection was accompanied by autophagy, which is thought to protect cancer cells from apoptosis after poly(I:C) transfection. In a xenograft mouse model, local transfection of poly(I:C) significantly inhibited the growth of xenografted MDA-MB-231 cells. Our findings indicate that cytoplasmic delivery of poly(I:C) can induce apoptosis and growth arrest of human breast cancer cells, and that therapy-associated autophagy prevents apoptosis. The results of this study suggest that the innate adjuvant receptors are promising targets and that their ligands could serve as antitumor reagents, which have the potential to simultaneously induce antitumor effects and activate immune cells.
Breast Cancer Research and Treatment 12/2011; 134(1):89-100. · 4.47 Impact Factor
[show abstract][hide abstract] ABSTRACT: Previously, we reported that PSK induces apoptosis and growth inhibition in HL60 cells. In this study, we tried to clarify the mechanism of how PSK induces apoptosis. Because several reports suggested that apoptosis of HL60 cells is mediated by activation of p38MAPK, we examined whether p38MAPK is involved in PSK-induced apoptosis. First, we found that PSK induced p38MAPK phosphorylation, which is considered as its activation. Next, we demonstrated that SB203580, inhibitor of p38MAPK, inhibited PSK-induced apoptosis. These results suggest that p38MAPK plays an important role in PSK-induced apoptosis.
Gan to kagaku ryoho. Cancer & chemotherapy 11/2011; 38(12):1915-7.
[show abstract][hide abstract] ABSTRACT: Protein-bound polysaccharide-K (PSK) is extracted from Coriolus versicolor (CM101), and is clinically used in combination therapy for gastrointestinal cancer and small cell lung carcinoma. PSK is a biological response modifier (BRM), and its mechanism of action is partly mediated, by modulating host immune systems, such as the activation of immune effector cells and the neutralization of transforming growth factor-beta (TGFβ) activity. Direct inhibition of tumor cell proliferation has been reported as another mechanism, but how PSK induces such an effect remains to be elucidated. Here, the anti-proliferative activity of PSK was examined using seven different human malignant cell lines (WiDr, HT29, SW480, KATOIII, AGS, HL60 and U937), and PSK was found to inhibit the proliferation of HL-60 cells most profoundly. Therefore, HL-60 cells were used to clarify the mechanism of anti-proliferative activity. Caspase-3 activation followed by apoptosis are involved at least in part in the PSK-induced anti-proliferative activity against HL-60 cells.
Anticancer research 09/2011; 31(9):2733-8. · 1.71 Impact Factor
[show abstract][hide abstract] ABSTRACT: We report the method of anastomosis based on a hemi-double stapling technique (hereinafter, HDST) using a trans-oral anvil delivery system (EEA OrVil) for reconstructing the esophagus and lifted jejunum following laparoscopic total gastrectomy or proximal gastric resection. As a basic technique, end-to-side anastomosis was used for the cut-off stump of the esophagus and lifted jejunum. After the gastric lymph node dissection, the esophagus was cut off obliquely to the long axis using an automated stapler. EEA OrVil was orally, and a small hole was created at the tip of the obliquely cut-off stump with scissors to let the valve tip pass through. When it was confirmed that the automated stapler and center rod were made completely linear, the anvil and the main unit were connected with each other and firing was carried out. Then, HDST-based anastomosis was completed. The method may safe laparoscopic anastomosis between the esophagus and reconstructed intestine.
[show abstract][hide abstract] ABSTRACT: Here we report the method of anastomosis based on double stapling technique (hereinafter, DST) using a trans-oral anvil delivery system (EEATM OrVilTM) for reconstructing the esophagus and lifted jejunum following laparoscopic total gastrectomy or proximal gastric resection. As a basic technique, laparoscopic total gastrectomy employed Roux-en-Y reconstruction, laparoscopic proximal gastrectomy employed double tract reconstruction, and end-to-side anastomosis was used for the cut-off stump of the esophagus and lifted jejunum. We used EEATM OrVilTM as a device that permitted mechanical purse-string suture similarly to conventional EEA, and endo-Surgitie. After the gastric lymph node dissection, the esophagus was cut off using an automated stapler. EEATM OrVilTM was orally and slowly inserted from the valve tip, and a small hole was created at the tip of the obliquely cut-off stump with scissors to let the valve tip pass through. Yarn was cut to disconnect the anvil from a tube and the anvil head was retained in the esophagus. The end-Surgitie was inserted at the right subcostal margin, and after the looped-shaped thread was wrapped around the esophageal stump opening, assisting Maryland forceps inserted at the left subcostal and left abdomen were used to grasp the left and right esophageal stump. The surgeon inserted anvil grasping forceps into the right abdomen, and after grasping the esophagus with the forceps, tightened the end Surgitie, thereby completing the purse-string suture on the esophageal stump. The main unit of the automated stapler was inserted from the cut-off stump of the lifted jejunum, and a trocar was made to pass through. To prevent dropout of the small intestines from the automated stapler, the automated stapler and the lifted jejunum were fastened with silk thread, the abdomen was again inflated, and the lifted jejunum was led into the abdominal cavity. When it was confirmed that the automated stapler and center rod were made completely linear, the anvil and the main unit were connected with each other and firing was carried out. Then, DST-based anastomosis was completed with no dog-ear. The method may facilitate safe laparoscopic anastomosis between the esophagus and reconstructed intestine. This is also considered to serve as a useful anastomosis technique for upper levels of the esophagus in laparotomy.
World Journal of Surgical Oncology 01/2011; 9:55. · 1.09 Impact Factor
[show abstract][hide abstract] ABSTRACT: Although PSK is an antitumor drug with immunomodulating effects, it has also been shown to have a direct action on cancer cells. This study analyzed the mechanism of the direct action of PSK on cancer cells, focused on the apoptosis-inducing effect. First, the cell growth inhibitory effect of PSK was examined using seven cancer cell lines, and HL60 cells were found to be strongly inhibited. Next, using HL60 cells, the apoptosis-inducing effect of PSK was examined using Annexin-V/Propidium iodide immunostaining and DNA fragmentation. The results indicated that PSK induced the apoptosis of HL60 cells. When the effect of PSK on protein expression of apoptosis-related factors was analyzed using an apoptosis array, over-expression of pro-caspase-3 and under-expression of factors such as cIAP-1, and cIAP-2 were observed. Furthermore, FACS analysis confirmed an increase in percentage of cells expressing activated caspase-3. These findings suggest that PSK induces apoptosis of HL60 cells and inhibits cell proliferation.
Gan to kagaku ryoho. Cancer & chemotherapy 11/2010; 37(12):2255-7.
[show abstract][hide abstract] ABSTRACT: We assessed the expression of cytokeratin (CK) and apomucin (MUC) in ampullary carcinoma (AC) to develop a system for the classification of ACs on the basis of their clinical significance.
We studied the expressions of CK7, CK20, MUC1, MUC2, MUC5AC, and MUC6 in 43 patients with ACs. Clinical data were obtained retrospectively by examining surgically resected ACs of the patients.
We classified the cases into 3 groups: tumors expressing CK20 and lacking MUC1 (intestinal type [I-type], 26%), tumors expressing MUC1 and lacking CK20 (pancreatobiliary type [PB-type], 35%), and those expressing or lacking both CK20 and MUC1 (other type [O-type], 39%). Eight (73%) of 11 I-type carcinomas, 3 (20%) of 15 PB-type carcinomas, and 4 (24%) of 17 O-type carcinomas were classified as pT1. The number of I-type carcinomas in the early tumor stages was significantly higher than the number of PB- and O-type carcinomas (p = 0.014 and p = 0.018, respectively). The 5-year survival rates for pT1, pT2, and pT3 tumors were 76%, 33%, and 22%, respectively (p < 0.001). Rates of MUC5AC and MUC6 coexpression for I-type, PB-type, and O-type tumors were 18%, 13%, and 53%, respectively. There was a significant correlation between MUC5AC and MUC6 coexpression and O-type characteristics (p = 0.031). The five-year survival rates for O-type ACs with and without MUC5AC and MUC6 coexpression were 71% and 17%, respectively (p = 0.048).
The immunohistochemical subtypes based on CK and MUC expression correlated with tumor progression. Gastric MUC5AC and MUC6 coexpression correlated with better prognosis for O-type ACs.
[show abstract][hide abstract] ABSTRACT: High-mobility group box 1, a ubiquitous nonhistone chromosomal protein, is passively released from necrotic cells and actively secreted by inflammatory cells. Extracellular high-mobility group box 1 has recently been recognized to be a mediator of hepatic ischemia-reperfusion injury; however, the kinetics of high-mobility group box 1 during hepatic ischemia-reperfusion and the role of high-mobility group box 1 in ischemia-reperfusion injury still remain poorly understood. This study was designed to assess the localization and the kinetics of high-mobility group box 1 during hepatic ischemia-reperfusion injury and the effects of high-mobility group box 1 adsorption column in hepatic ischemia-reperfusion injury.
A prospective, randomized animal study.
University medical center research laboratory.
Male Sprague-Dawley rats.
The animals underwent 70% partial hepatic ischemia for 60 or 90 mins and were then reperfused. To investigate the high-mobility group box 1 levels in the serum and in the liver, the animals were killed at predetermined periods. As a lethal model, global hepatic ischemia-reperfusion was induced by portal triad cross-clamping for 30 mins. Hemoperfusion therapy using a cellulofine sulfate bead column (high-mobility group box 1 adsorption column) was performed during global hepatic ischemia.
During 60 mins of 70% hepatic ischemia, nuclear high-mobility group box 1 was translocated to the cytoplasm in hepatocytes; however, serum high-mobility group box 1was not increased. Immediately after reperfusion, the serum high-mobility group box 1 was significantly increased (p < .05). High-mobility group box 1 mediated ischemia-reperfusion injury in not only liver but also the remote organ, lung. Removal of excess high-mobility group box 1 in blood using an adsorption column significantly improved animal survival (p < .03) and liver and lung injuries.
High-mobility group box 1 plays an important role in the systemic as well as local pathogenesis of hepatic ischemia-reperfusion injury. The removal of excessive high-mobility group box 1 with adsorption column was beneficial and promising option in ischemia-related liver injuries.
Critical care medicine 12/2009; 38(3):879-85. · 6.37 Impact Factor
[show abstract][hide abstract] ABSTRACT: Mitochondrial transcription factor A (mtTFA) is a member of the HMG (high mobility group)-box protein family. We previously showed that mtTFA preferentially binds to both cisplatin-damaged and oxidatively damaged DNA. In this study, we found that expression levels of both mtTFA and the mitochondrial antioxidant protein thioredoxin2 (TRX2) are upregulated in cisplatin-resistant cell lines. In addition, TRX2 directly interacts with mtTFA and enhances its damaged DNA binding activity. The interaction between mtTFA and TRX2 requires the HMG box 1 motif of mtTFA. Furthermore, when amino acid substitutions were introduced at either C49G or C246stop, TRX2 interacted with mtTFA. However, the interaction of TRX2 with mtTFA was enhanced when both mutations (C49G and C246stop) were introduced. Binding to cisplatin-damaged DNA was similar among mutant mtTFA proteins. By contrast, binding to oxidized DNA was significantly enhanced when double mutations were introduced. These results suggest that TRX2 not only functions as an antioxidant, but also supports mtTFA functions.
International Journal of Oncology 12/2009; 35(6):1435-40. · 2.66 Impact Factor
[show abstract][hide abstract] ABSTRACT: Combination chemotherapy with oxaliplatin plus 5-fluorouracil/leucovorin (FOLFOX) has become a standard regimen for colorectal cancer. An increase of adverse events with combination chemotherapy is predicted in elderly patients, and it remains controversial whether they should receive the same chemotherapy as younger patients. Accordingly, this study of modified FOLFOX6 (mFOLFOX6) therapy was performed to compare its safety between elderly and non-elderly patients.
We prospectively studies 14 non-elderly patients aged <70 years old and 8 elderly patients aged >or= 70 years with unresectable advanced/recurrent colorectal cancer who received mFOLFOX6 therapy during the period from March 2006 to March 2007. Adverse events and the response to treatment were compared between the elderly and non-elderly groups.
The main adverse events were neutropenia and peripheral neuropathy, which occurred in 62.5% (>or= grade 3) and 87.5% (>or= grade 1) of elderly patients. The grade and frequency of adverse events were similar in the elderly and non-elderly groups. In some patients with neutropenia, treatment could be continued without reducing the dose of oxaliplatin by deleting bolus 5-fluorouracil. A correlation was found between the cumulative dose of oxaliplatin and the severity of neuropathy, and there were 2 elderly and 3 younger patients in whom discontinuation of treatment was necessary due to peripheral neuropathy. The median number of treatment cycles was 10.0 and 9.5 in the non-elderly and elderly groups, respectively. The response rate was 60.0% in the non-elderly and 50.0% in the elderly group, while the disease control rate was 100% and 83.3% respectively, showing no age-related difference.
mFOLFOX6 therapy was well-tolerated and effective in both non-elderly and elderly patients. However, discontinuation of treatment was sometimes necessary due to peripheral neuropathy, which is dose-limiting toxicity of this therapy.
Journal of Experimental & Clinical Cancer Research 08/2009; 28:109. · 3.07 Impact Factor
[show abstract][hide abstract] ABSTRACT: Fractalkine (CX3CL1) is the only CX3C chemokine that can chemoattract natural killer (NK) cells, CD8+ T cells, monocytes, and dendritic cells. Although experimental studies have demonstrated that Fractalkine expression by tumor cells is related to the infiltrating lymphocytes and initiates antitumor immunity, the clinical significance of Fractalkine remains to be elucidated in gastric adenocarcinoma.
Tissue sections from 158 patients with curatively resected T2 or T3 gastric adenocarcinoma were immunohistochemically stained for Fractalkine. Furthermore, to evaluate CD8+ T cells and NK cells infiltration, antibodies to CD8 and CD57 protein were respectively used for immunohistochemistry.
A significant direct correlation was observed between the Fractalkine scores and the number of CD8+ T cells and NK cells using the Spearman rank correlation coefficient test (P = .0080, .0031, respectively). Furthermore, the high Fractalkine expression group (n = 67) showed a significantly better prognosis than the low Fractalkine expression group (n = 91) regarding the disease-free survival (P = .0016). In a multivariate analysis, the Fractalkine expression was identified as one of the independent prognosticators for disease-free survival (risk ratio, 2.5; P = .0147).
These data suggest that the expression of Fractalkine by tumor cells enhances the recruitment of CD8+ T cells and NK cells and induces both innate and adaptive immunity, thereby yielding a better prognosis in gastric adenocarcinoma. Fractalkine is a new independent predictor of the prognosis and can be a novel candidate for development of a more effective therapeutic strategy for gastric adenocarcinomas.
Annals of Surgical Oncology 07/2008; 15(6):1775-82. · 4.12 Impact Factor
[show abstract][hide abstract] ABSTRACT: Peroxisome proliferator-activated receptor-gamma (PPARgamma), a member of the nuclear receptor superfamily, is widely expressed in adipocytes and other tissues, including the liver. Several reports have shown that PPARgamma activation induced cell-cycle arrest and apoptosis in tumor cells. We investigated the role of the PPARgamma/ligand system and the effect of the PPARgamma agonist during liver regeneration.
Expression of PPARgamma and serum levels of 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) by enzyme immunoassay were evaluated in rats following partial hepatectomy (PH group). Further, the effect of the PPARgamma agonist, pioglitazone, on liver regeneration (PH + PGZ group) was evaluated by proliferating cell nuclear antigen labeling index, relative liver weight, and expression of cell-cycle regulators.
The number of PPARgamma-stained hepatocytes decreased at 24 h (PH, 15.8 +/- 2.2%; sham, 35.5 +/- 2.4%; P < 0.001) and increased in the late phase of liver regeneration compared to the sham-operated group (P < 0.001 at 48-120 h). The peaks of serum 15d-PGJ2 (627.0 +/- 91.1 pg/ml) and PPARgamma expression (90.6 +/- 3.1%) coincided in the late phase of liver regeneration. Also, oral administration of pioglitazone inhibited hepatocyte proliferation, in terms of the proliferating cell nuclear antigen (PCNA) labeling index and p27 expression during the late phase of liver regeneration, and caused a transient reduction in liver mass when compared to the PH group.
These results indicate that the PPARgamma/ligand system may be one of the key negative regulators of hepatocyte proliferation and may be responsible for the inhibition of liver growth in the late phase of liver regeneration.
Journal of Gastroenterology and Hepatology 06/2008; 23(6):930-7. · 3.33 Impact Factor