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Find video protocols related to scientific articles indexed in Pubmed.
Hepatitis C Virus-specific T-cell Response Correlates with Hepatitis Activity and Donor IL28B Genotype Early after Liver Transplantation.
Acta Med. Okayama
PUBLISHED: 10-24-2014
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It is not known how the immune system targets hepatitis C virus (HCV)-infected HLA-mismatched hepatocytes under immune-suppressed conditions after orthotopic liver transplantation (OLT). In addition, the relationship between the HCV-specific immune response and IL28B variants as predictors of HCV clearance has not been well-characterized. We determined the IL28B polymorphisms for 57 post-OLT HCV carriers, and we assessed the HCV-specific immune responses by measuring the peripheral blood mononuclear cell-derived HCV-specific interferon-gamma (IFN-?) response using an enzyme-linked immunospot assay. At 1-3 years after OLT, patients with no active hepatitis showed higher total spots on the immunospot assay. At?3 years after OLT, patients with resolved HCV showed higher levels of core, NS3, NS5A, and total spots compared to the chronic hepatitis patients. The IL28B major genotype in the donors correlated with higher spot counts for NS5A and NS5B proteins at 1-3 years after OLT. In the post-OLT setting, the HCV-specific immune response could be strongly induced in patients with no active hepatitis with an IL28B major donor or sustained virological response. Strong immune responses in the patients with no active hepatitis could only be maintained for 3 years and diminished later. It may be beneficial to administer IFN treatment starting 3 years after OLT, to induce the maximum immunological effect.
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Generation and characterization of MafA-Kusabira Orange mice.
Endocr. J.
PUBLISHED: 10-03-2014
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MafA and MafB are basic leucine zipper transcription factors expressed in mature pancreatic ?- and ?-cells, respectively. MafA is not only an insulin gene transcription factor but is also critical for the maturation and maintenance of ?-cell function, whereas MafB is expressed in immature ?-cells during development and in compromised ?-cells in diabetes. In this study, we developed a mouse model to easily trace the promoter activity of MafA in ?-cells as a tool for studying ?-cell differentiation, maturation, regeneration and function using the expression of the fluorescent protein Kusabira Orange (KOr) driven by the BAC-mafA promoter. The expression of KOr was highly restricted to ?-cells in the transgenic pancreas. By crossing MafA-KOr mice with MafB(GFP/+) reporter mice, simultaneous monitoring of MafA and MafB expressions in the isolated islets was successfully performed. This system can be a useful tool for examining dynamic changes in the differentiation and function of pancreatic islets by visualizing the expressions of MafA and MafB.
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Selective methioninase-induced trap of cancer cells in S/G2 phase visualized by FUCCI imaging confers chemosensitivity.
Oncotarget
PUBLISHED: 09-20-2014
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A major impediment to the response of tumors to chemotherapy is that the large majority of cancer cells within a tumor are quiescent in G0/G1, where cancer cells are resistant to chemotherapy. To attempt to solve this problem of quiescent cells in a tumor, cancer cells were treated with recombinant methioninase (rMETase), which selectively traps cancer cells in S/G2. The cell cycle phase of the cancer cells was visualized with the fluorescence ubiquitination-based cell cycle indicator cell cycle indicator (FUCCI). At the time of rMETase-induced S/G2-phase blockage, identified by the cancer cells' green fluorescence by FUCCI imaging, the cancer cells were administered S/G2-dependent chemotherapy drugs, which interact with DNA or block DNA synthesis such as doxorubicin, cisplatin, or 5-fluorouracil. Treatment of cancer cells with drugs only, without rMETase-induced S/G2 phase blockage, led to the majority of the cancer-cell population being blocked in G0/G1 phase, identified by the cancer cells becoming red fluorescent in the FUCCI system. The G0/G1 blocked cells were resistant to the chemotherapy. In contrast, trapping of cancer cells in S/G2 phase by rMETase treatment followed by FUCCI-imaging-guided chemotherapy was highly effective in killing the cancer cells.
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Percutaneous radiofrequency ablation for pulmonary metastases from esophageal cancer: retrospective evaluation of 21 patients.
J Vasc Interv Radiol
PUBLISHED: 08-22-2014
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To evaluate retrospectively outcomes after radiofrequency (RF) ablation for pulmonary metastases from esophageal cancer.
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MafA is required for postnatal proliferation of pancreatic ?-cells.
PLoS ONE
PUBLISHED: 08-15-2014
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The postnatal proliferation and maturation of insulin-secreting pancreatic ?-cells are critical for glucose metabolism and disease development in adults. Elucidation of the molecular mechanisms underlying these events will be beneficial to direct the differentiation of stem cells into functional ?-cells. Maturation of ?-cells is accompanied by increased expression of MafA, an insulin gene transcription factor. Transcriptome analysis of MafA knockout islets revealed MafA is required for the expression of several molecules critical for ?-cell function, including Glut2, ZnT8, Granuphilin, Vdr, Pcsk1 and Urocortin 3, as well as Prolactin receptor (Prlr) and its downstream target Cyclin D2 (Ccnd2). Inhibition of MafA expression in mouse islets or ?-cell lines resulted in reduced expression of Prlr and Ccnd2, and MafA transactivated the Prlr promoter. Stimulation of ?-cells by prolactin resulted in the phosphorylation and translocation of Stat5B and an increased nuclear pool of Ccnd2 via Prlr and Jak2. Consistent with these results, the loss of MafA resulted in impaired proliferation of ?-cells at 4 weeks of age. These results suggest that MafA regulates the postnatal proliferation of ?-cells via prolactin signaling.
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Enlarging lymphoepithelial cyst of the pancreas during 12 months of observation: report of a case.
Surg. Today
PUBLISHED: 07-09-2014
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Pancreatic lymphoepithelial cysts (LECs) are rare benign pancreatic cystic lesions, the etiology of which is unknown. We report a case of a pancreatic LEC, discovered incidentally in a 63-year-old man during a follow-up clinic visit for an abdominal aneurysm. Computed tomography showed a multilocular cyst, 60-mm diameter in the body of the pancreas. This cyst increased from 6.0 to 6.5 cm during 12 months of observation. Part of the cyst was also visualized on positron emission tomography imaging. Since a pancreatic cystic neoplasm could not be ruled out, we performed distal pancreatectomy and postoperative pathological examination confirmed that the lesion was an LEC of the pancreas. Despite the conclusive postoperative findings, resection is unavoidable when a true pancreatic neoplasm cannot be excluded.
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Management of peritoneal effusion by sealing with a self-assembling nanofiber polypeptide following pelvic surgery.
Hepatogastroenterology
PUBLISHED: 06-06-2014
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PuraMatrix is a synthetic material consisting of 16-amino acid peptides that self-assemble into nanofibers, previously used as a scaffold for functional cell cultures. We conducted a clinical study to determine the safety and sealing properties of PuraMatrix in post-operative lymphorrhea following pelvic surgery in humans.
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Fluorescence virus-guided capturing system of human colorectal circulating tumour cells for non-invasive companion diagnostics.
Gut
PUBLISHED: 05-30-2014
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Molecular-based companion diagnostic tests are being used with increasing frequency to predict their clinical response to various drugs, particularly for molecularly targeted drugs. However, invasive procedures are typically required to obtain tissues for this analysis. Circulating tumour cells (CTCs) are novel biomarkers that can be used for the prediction of disease progression and are also important surrogate sources of cancer cells. Because current CTC detection strategies mainly depend on epithelial cell-surface markers, the presence of heterogeneous populations of CTCs with epithelial and/or mesenchymal characteristics may pose obstacles to the detection of CTCs.
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Spatial-temporal FUCCI imaging of each cell in a tumor demonstrates locational dependence of cell cycle dynamics and chemoresponsiveness.
Cell Cycle
PUBLISHED: 05-08-2014
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The phase of the cell cycle can determine whether a cancer cell can respond to a given drug. We report here on the results of monitoring of real-time cell cycle dynamics of cancer cells throughout a live tumor intravitally using a fluorescence ubiquitination cell cycle indicator (FUCCI) before, during, and after chemotherapy. In nascent tumors in nude mice, approximately 30% of the cells in the center of the tumor are in G?/G? and 70% in S/G?/M. In contrast, approximately 90% of cancer cells in the center and 80% of total cells of an established tumor are in G?/G? phase. Similarly, approximately 75% of cancer cells far from (> 100 µm) tumor blood vessels of an established tumor are in G?/G?. Longitudinal real-time imaging demonstrated that cytotoxic agents killed only proliferating cancer cells at the surface and, in contrast, had little effect on quiescent cancer cells, which are the vast majority of an established tumor. Moreover, resistant quiescent cancer cells restarted cycling after the cessation of chemotherapy. Our results suggest why most drugs currently in clinical use, which target cancer cells in S/G?/M, are mostly ineffective on solid tumors. The results also suggest that drugs that target quiescent cancer cells are urgently needed.
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Assistant-based standardization of prone position thoracoscopic esophagectomy.
Acta Med. Okayama
PUBLISHED: 04-19-2014
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Thoracoscopic esophagectomy in the prone position (TEPP) might enable solo-surgery in cases requiring resection of the esophagus and the surrounding lymph nodes due to the associated advantages of good exposure of the surgical field and ergonomic considerations for the surgeon. However, no one approach can be for all patients requiring extensive lymphadenectomy. We recently developed an assistant-based procedure to standardize exposure of the surgical field. Patients were divided into 1 of 2 groups:a pre-standardization group (n=37) and a post-standardization group (n=28). The thoracoscopic operative time was significantly shorter (p=0.0037) in the post-standardization group (n=28; 267 ± 31 min) than in the pre-standardization group (n=37;301 ± 53 min). Further, learning curve analysis using the moving average method showed stabilization of the thoracoscopic operative time after the standardization. No significant differences were found in the number of mediastinal lymph nodes dissected or intraoperative blood loss between the 2 groups. There were also no significant differences in the complication rate. Assistant-based surgery and standardization of the procedure resulted in a well-exposed and safe surgical field. TEPP decreased the operative time, even in patients requiring extensive lymphadenectomy.
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Intussusception due to rectal adenocarcinoma in a young adult: a case report.
World J. Gastroenterol.
PUBLISHED: 04-09-2014
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An intussusception due to colonic adenocarcinoma has sometimes been reported. However, to the best of our knowledge, reports of intussusception due to rectal adenocarcinoma are extremely rare. In this report, the case of a young man with rectal adenocarcinoma causing intussusception is described. A 24-year-old man visited a hospital complaining of abdominal pain, and an upper rectal cancer was diagnosed by colonoscopy. Computed tomography showed intussusception caused by a large tumor in the pelvis and absence of distant metastases. Locally advanced rectal cancer causing intussusception was diagnosed, and a low anterior resection was performed. Intraoperatively, repair of the invagination could not be accomplished easily; therefore, the repair was abandoned. Instead, the tumor was removed en bloc to avoid dissemination of the cancer. Histopathologically, the tumor was diagnosed as a poorly differentiated adenocarcinoma, pStage IIA. The patient has no evidence of recurrence at 10 mo after the operation.
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Establishment of a pancreatic stem cell line from fibroblast-derived induced pluripotent stem cells.
Biomed Eng Online
PUBLISHED: 04-02-2014
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For cell therapies to treat diabetes, it is important to produce a sufficient number of pancreatic endocrine cells that function similarly to primary islets. Induced pluripotent stem (iPS) cells represent a potentially unlimited source of functional pancreatic endocrine cells. However, the use of iPS cells for laboratory studies and cell-based therapies is hampered by their high tumorigenic potential and limited ability to generate pure populations of differentiated cell types in vitro. The purpose of this study was to establish a pancreatic stem cell line from iPS cells derived from mouse fibroblasts.
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Frequency of regulatory T-cell and hepatitis C viral antigen-specific immune response in recurrent hepatitis C after liver transplantation.
Transpl. Immunol.
PUBLISHED: 03-06-2014
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Regulatory T (Treg) and type 1 regulatory T (Tr1) cells facilitate hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (OLT). However, their frequencies and effects on HCV-specific immune responses have not been well investigated.
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Outcomes of living donor liver transplantation for hepatitis C virus-positive recipients in Japan: results of a nationwide survey.
Transpl. Int.
PUBLISHED: 02-17-2014
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A nationwide survey of living donor liver transplantation (LDLT) for hepatitis C virus (HCV)-positive recipients was performed in Japan. A total of 514 recipients are reported and included in the study. The cumulative patient survival rate at 5 and 10 years was 72% and 63%, respectively. Of the 514 recipients, 142 patients (28%) died until the end of the observation, among which the leading cause was recurrent hepatitis C (42 cases). According to Cox regression multivariate analysis, donor age (>40), non-right liver graft, acute rejection episode, and absence of a sustained virologic response were independent prognostic factors. Of the 514 recipients, 361 underwent antiviral treatment mainly with pegylated-interferon and ribavirin (preemptive treatment in 150 patients and treatment for confirmed recurrent hepatitis in 211). The dose reduction rate and discontinuation rate were 40% and 42%, respectively, with a sustained virologic response rate of 43%. In conclusion, patient survival of HCV-positive recipients after LDLT was good, with a 10-year survival of 63%. Right liver graft might be preferable for HCV-positive recipients in an LDLT setting.
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Generation of hepatocyte-like cells from human induced pluripotent stem (iPS) cells by co-culturing embryoid body cells with liver non-parenchymal cell line TWNT-1.
J Coll Physicians Surg Pak
PUBLISHED: 02-05-2014
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To generate a homogeneous population of patient-specific hepatocyte-like cells (HLCs) from human iPS cells those show the morphologic and phenotypic properties of primary human hepatocytes.
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Invading cancer cells are predominantly in G0/G1 resulting in chemoresistance demonstrated by real-time FUCCI imaging.
Cell Cycle
PUBLISHED: 01-20-2014
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Invasive cancer cells are a critical target in order to prevent metastasis. In the present report, we demonstrate real-time visualization of cell cycle kinetics of invading cancer cells in 3-dimensional (3D) Gelfoam® histoculture, which is in vivo-like. A fluorescence ubiquitination cell cycle indicator (FUCCI) whereby G0/G1 cells express a red fluorescent protein and S/G2/M cells express a green fluorescent protein was used to determine the cell cycle position of invading and non-invading cells. With FUCCI 3D confocal imaging, we observed that cancer cells in G0/G1 phase in Gelfoam® histoculture migrated more rapidly and further than cancer cells in S/G2/M phases. Cancer cells ceased migrating when they entered S/G2/M phases and restarted migrating after cell division when the cells re-entered G0/G1. Migrating cancer cells also were resistant to cytotoxic chemotherapy, since they were preponderantly in G0/G1, where cytotoxic chemotherapy is not effective. The results of the present report suggest that novel therapy targeting G0/G1 cancer cells should be developed to prevent metastasis.
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Oncolytic adenovirus-induced autophagy: tumor-suppressive effect and molecular basis.
Acta Med. Okayama
PUBLISHED: 12-21-2013
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Autophagy is a catabolic process that produces energy through lysosomal degradation of intracellular organelles. Autophagy functions as a cytoprotective factor under physiological conditions such as nutrient deprivation, hypoxia, and interruption of growth factors. On the other hand, infection with pathogenic viruses and bacteria also induces autophagy in infected cells. Oncolytic virotherapy with replication-competent viruses is thus a promising strategy to induce tumor-specific cell death. Oncolytic adenoviruses induce autophagy and subsequently contribute to cell death rather than cell survival in tumor cells. We previously developed a telomerase-specific replication-competent oncolytic adenovirus, OBP-301, which induces cell lysis in tumor cells with telomerase activities. OBP-301-mediated cytopathic activity is significantly associated with induction of autophagy biomarkers. In this review, we focus on the tumor-suppressive role and molecular basis of autophagic machinery induced by oncolytic adenoviruses. Addition of tumor-specific promoters and modification of the fiber knob of adenoviruses supports the oncolytic adenovirus-mediated autophagic cell death. Autophagy is cooperatively regulated by the E1-dependent activation pathway, E4-dependent inhibitory pathway, and microRNA-dependent fine-tuning. Thus, future exploration of the functional role and molecular mechanisms underlying oncolytic adenovirus-induced autophagy would provide novel insights and improve the therapeutic potential of oncolytic adenoviruses.
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[A case of local recurrence of rectal carcinoma 10 years after initial surgery].
Gan To Kagaku Ryoho
PUBLISHED: 12-17-2013
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Here, we report an extremely rare case of local recurrence of rectal cancer 10 years after initial tumor resection. A 53-year-old man underwent abdominoperineal resection for advanced rectal cancer at a local hospital. The tumor was graded as pStage II (pA, pN0, pH0, pP0, pM0, curA)as per the Japanese Classification of Colorectal Carcinoma, seventh edition, and diagnosed as a moderately differentiated adenocarcinoma on histopathological examination. Subsequently, the patient received adjuvant chemotherapy for 5 years. Although the patient lived without any recurrences after adjuvant chemotherapy, unfortunately, blood examination showed a high carcinoembryonic antigen(CEA)level 10 years after the initial surgical treatment. Computed tomography(CT)and positron emission tomography(PET)/CT revealed a perineal tumor, 40mm in size, without other distant metastases. On diagnosis of local recurrence of rectal cancer, the patient underwent surgical tumor resection at Okayama University Hospital. The tumor was determined to be a well- to moderately differentiated adenocarcinoma by histopathological examination, suggesting local recurrence of the primary rectal adenocarcinoma. Moreover, the radial margin was free of cancer. The patient is now doing well without any re-recurrence 30 months after the second surgical treatment, without any adjuvant chemotherapy.
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Advances in adenovirus-mediated p53 cancer gene therapy.
Expert Opin Biol Ther
PUBLISHED: 10-11-2013
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The tumor suppressor p53 gene regulates diverse cellular processes, such as cell-cycle arrest, senescence, apoptosis and autophagy, and it is frequently inactivated by genetic alterations in ? 50% of all types of human cancers. To restore wild-type p53 function in p53-inactivated tumors, adenovirus-mediated p53 gene therapy has been developed as a promising antitumor strategy in preclinical experiments and clinical studies.
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A Genetically Engineered Oncolytic Adenovirus Decoys and Lethally Traps Quiescent Cancer Stem-like Cells in S/G2/M Phases.
Clin. Cancer Res.
PUBLISHED: 09-30-2013
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Because chemoradiotherapy selectively targets proliferating cancer cells, quiescent cancer stem-like cells are resistant. Mobilization of the cell cycle in quiescent leukemia stem cells sensitizes them to cell death signals. However, it is unclear that mobilization of the cell cycle can eliminate quiescent cancer stem-like cells in solid cancers. Thus, we explored the use of a genetically-engineered telomerase-specific oncolytic adenovirus, OBP-301, to mobilize the cell cycle and kill quiescent cancer stem-like cells.
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[A long-term control of gastrointestinal stromal tumor with sunitinib].
Gan To Kagaku Ryoho
PUBLISHED: 09-20-2013
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The patient was a 70-year-old woman with gastrointestinal stromal tumor(GIST)of the small intestine, accompanied by liver metastasis. Multiple liver metastases were pointed out 3 months after R0 surgery(jejunectomy and hepatectomy). Although she was given radiofrequency ablation(RFA)therapy and imatinib, metastatic tumors progressed. In a further examination at our institution 21 months after R0 surgery, multiple liver, bone, and lung metastases were indicated, and she was given sunitinib once daily at a 50mg in 6-week courses, with 4 weeks on and 2 weeks off treatment. Although sunitinib dosage was decreased to 25mg/day because of adverse events, 21 courses of this treatment were administered, and it took 137 weeks to progress her disease with this sunitinib treatment. At our institution, seven cases of GIST were treated with sunitinib, and the median time to progression was 30-weeks. That was almost the same result as for Japan and international clinical trials. Sunitinb treatment may be one of the most important therapeutic options for unresectable imatinib-resistant GIST.
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Quantitative assessment of Pdx1 promoter activity in vivo using a secreted luciferase reporter system.
Endocrinology
PUBLISHED: 09-12-2013
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The luciferase reporter system is useful for the assessment of various biological processes in vivo. The transcription factor pancreatic and duodenal homeobox 1 (Pdx1) is critical for the formation and the function of pancreatic ?-cells. A novel reporter system using secreted Gaussia princeps luciferase (GLuc) under the control of a Pdx1 promoter was generated and activated in rat and mouse ?-cell lines. This Pdx1-GLuc construct was used as a transgene for the generation of reporter mice to monitor Pdx1 promoter activity in vivo via the measurement of secreted GLuc activity in a small aliquot of blood. Significantly increased plasma GLuc activity was observed in Pdx1-GLuc mice. Analysis of Pdx1-GLuc mice by bioluminescence imaging, GLuc reporter assays using homogenates of various organs, and immunohistochemistry revealed that GLuc expression and activity were exponentially higher in pancreatic ?-cells than in pancreatic non-?-cells, the duodenum, and other organs. In addition, GLuc activity secreted into the culture medium from islets isolated from Pdx1-GLuc mice correlated with the number of islets. The transplantation of Pdx1-GLuc islets into severe combined immunodeficiency mice elevated their plasma GLuc activity. Conversely, a partial pancreatectomy in Pdx1-GLuc mice reduced plasma GLuc activity. These results suggest that a secreted luciferase reporter system in vivo enables not only the monitoring of promoter activity but also a quantitative and minimally invasive assessment of physiological and pathological changes in small cell masses, such as pancreatic ?-cells.
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Serial changes of serum growth factor levels and liver regeneration after partial hepatectomy in healthy humans.
Int J Mol Sci
PUBLISHED: 08-28-2013
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This study aimed to investigate the associations of the serial changes of serum levels of various growth factors with liver regeneration after hepatectomy in healthy liver donors. Sixteen healthy liver donors who underwent conventional liver resection were included. Serum levels of various growth factors before hepatectomy and on postoperative day (POD) 1, 3, 5 and 7 were measured. Liver volume data calculated by multi-detector computed tomography using workstation. The ratio of remnant liver volume on POD 0 to liver volume before the operation was 51% ± 20%. The ratio of liver volume on POD 14 to liver volume on POD 0 were inversely correlated with remnant liver volume on POD 0 (r = -0.91). The ratio of liver volume on POD 14 to liver volume on POD 0 were significantly correlated with serum hepatocyte growth factor (HGF) levels on POD 1 (r = 0.54), serum leptin levels on POD 1 (r = 0.54), and serum macrophage colony-stimulating factor (M-CSF) levels on POD 5 (r = 0.76) and POD 7 (r = 0.80). These results suggest that early-phase elevation of serum levels of HGF, leptin and M-CSF may be associated with the acceleration of liver regeneration after hepatectomy in humans.
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Estrogen receptor (ER) mRNA expression and molecular subtype distribution in ER-negative/progesterone receptor-positive breast cancers.
Breast Cancer Res. Treat.
PUBLISHED: 08-11-2013
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We examined estrogen receptor (ER) mRNA expression and molecular subtypes in stage I-III breast cancers that are progesterone receptor (PR) positive but ER and HER2 negative by immunohistochemistry (IHC) or fluorescent in situ hybridization. The ER, PR, and HER2 status was determined by IHC as part of routine clinical assessment (N = 501). Gene expression profiling was done with the Affymetrix U133A gene chip. We compared expressions of ESR1 and MKI67 mRNA, distribution of molecular subtypes by the PAM50 classifier, the sensitivity to endocrine therapy index, and the DLDA30 chemotherapy response predictor signature among ER/PR-positive (n = 223), ER-positive/PR-negative (n = 73), ER-negative/PR-positive (n = 20), and triple-negative (n = 185) cancers. All patients received neoadjuvant chemotherapy with an anthracycline and taxane and had adjuvant endocrine therapy only if ER or PR > 10 % positive. ESR1 expression was high in 25 % of ER-negative/PR-positive, in 79 % of ER-positive/PR-negative, in 96 % of ER/PR-positive, and in 12 % of triple-negative cancers by IHC. The average MKI67 expression was significantly higher in the ER-negative/PR-positive and triple-negative cohorts. Among the ER-negative/PR-positive patients, 15 % were luminal A, 5 % were Luminal B, and 65 % were basal like. The relapse-free survival rate of ER-negative/PR-positive patients was equivalent to ER-positive cancers and better than the triple-negative cohort. Only 20-25 % of the ER-negative/PR-positive tumors show molecular features of ER-positive cancers. In this rare subset of patients (i) a second RNA-based assessment may help identifying the minority of ESR1 mRNA-positive, luminal-type cancers and (ii) the safest clinical approach may be to consider both adjuvant endocrine and chemotherapy.
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Poor prognosis of KRAS or BRAF mutant colorectal liver metastasis without microsatellite instability.
J Hepatobiliary Pancreat Sci
PUBLISHED: 08-07-2013
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The discovery of practical biomarkers is important to realize personalized medicine for patients with malignant neoplasias, including colorectal cancer (CRC).
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Risk factors for organ/space surgical site infection after hepatectomy for hepatocellular carcinoma in 359 recent cases.
J Hepatobiliary Pancreat Sci
PUBLISHED: 08-07-2013
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Surgical site infections (SSIs), particularly organ/space SSIs, remain a common cause of major morbidity after hepatectomy for hepatocellular carcinoma (HCC).
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Antitumor effects of telomerase-specific replication-selective oncolytic viruses for adenoid cystic carcinoma cell lines.
Oncol. Rep.
PUBLISHED: 07-01-2013
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We evaluated the antitumor effect of a telomerase-specific replication-selective adenovirus (Telomelysin, OBP-301) for adenoid cystic carcinoma (ACC) in vitro and in vivo. Adenovirus E1 gene expression was controlled by human telomerase reverse transcription (hTERT). Infection of ACC cells by OBP-301 induced high E1A mRNA expression and subsequent oncolytic cell death in a dose-dependent manner. Using OBP-401 (TelomeScan), a genetically engineered adenovirus that carries the GFP gene under the control of the cytomegalovirus (CMV) promoter at the deleted E3 region of OBP-301, ACC cells expressed bright GFP fluorescence as early as 12 h after OBP-401 infection. The fluorescence intensity gradually increased in a time-dependent manner, followed by rapid cell death due to the cytopathic effect of OBP-401, as evidenced by the floating, highly light-refractive cells using phase-contrast microscopy. Effects of intratumorally injected OBP-401 against established Acc2 xenograft tumors were seen in BALB/c nu/nu mice. The levels of GFP expression following ex vivo infection of OBP-401 may be of value as a positive predictive marker for the outcome of telomerase-specific virotherapy. Our data clearly indicated that telomerase-specific oncolytic adenoviruses have significant therapeutic potential against human ACC in vitro and in vivo. These results suggest that treatment with OBP-301 and OBP-401 may improve the quality of life of oral cancer patients.
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Early detection of metachronous bile duct cancer in Lynch syndrome: report of a case.
Surg. Today
PUBLISHED: 06-03-2013
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Lynch syndrome is an autosomal dominant disease associated with a high incidence of colorectal, endometrial, stomach, ovarian, pancreatic, ureter and renal pelvis, bile duct and brain tumors. The syndrome can also include sebaceous gland adenomas and keratoacanthomas, and carcinoma of the small bowel. The lifetime risk for bile duct cancer in patients with Lynch syndrome is approximately 2 %. The present report describes a case of Lynch syndrome with metachronous bile duct cancer diagnosed at an early stage. The patient was a 73-year-old Japanese male who underwent a successful left lobectomy of the liver, and there was no sign of recurrence for 2 years postoperative. However, this patient harbored a germline mutation in MLH1, which prompted diagnostic examinations for noncolorectal tumors when a periodic surveillance blood examination showed abnormal values of hepatobiliary enzymes. Although most patients with bile duct cancer are diagnosed at an advanced stage, the bile duct cancer was diagnosed at an early stage in the present patient due to the observation of the gene mutation and the preceding liver tumor. This case illustrates the importance of continuous surveillance for extracolonic tumors, including bile duct cancer, in patients with Lynch syndrome.
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CD14 upregulation as a distinct feature of non-alcoholic fatty liver disease after pancreatoduodenectomy.
World J Hepatol
PUBLISHED: 05-15-2013
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To investigate the pathogenesis of non-alcoholic fatty liver disease (NAFLD) after pancreatoduodenectomy (PD).
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Successfully treated pneumatosis cystoides intestinalis with pneumoperitoneum onset in a patient administered ?-glucosidase inhibitor.
Acta Med. Okayama
PUBLISHED: 04-23-2013
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An 80-year-old woman, who had been administered ?-glucosidase inhibitor for diabetes, was brought to the hospital with the sensation of abdominal fullness and pain. Abdominal computed tomography indicated pneumatosis cystoides intestinalis (PCI) in the small intestinal wall, with free air within the abdomen. A blood examination showed no increases in white blood cells or C-reactive protein level. The patients condition improved with conservative therapy. PCI with pneumoperitoneum induced by ?-glucosidase inhibitor is rare, with only 27 cases (excluding the present case) reported in Japan to date. In PCI with pneumoperitoneum, differentiation from gastrointestinal perforation is important and following the clinical symptoms over time is vital.
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Living donor liver transplantation to a survivor of liver resection for hepatocellular carcinoma with major portal vein invasion.
Acta Med. Okayama
PUBLISHED: 04-23-2013
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We present a case of living donor liver transplantation to a 3-year disease-free survivor of liver resection for hepatocellular carcinoma (HCC) with major portal vein invasion. A 48-year-old man had HCC in the right lobe with a portal venous tumor thrombus extending into the left portal vein. An extended right lobectomy with thrombectomy was performed to remove the thrombus. Three years after liver resection, the patient experienced liver failure, with massive ascites and jaundice due to the formation of a thrombus in the main and left portal veins. During the 3 years after liver resection, no metastasis or recurrence of HCC had been detected, and tumor markers had been within normal ranges. The portal venous thrombus did not show any arterial enhancement under contrast-enhanced computed tomography, suggesting that the co-existence of any HCC component in the portal venous thrombus may have been negative. Based on these findings, living donor liver transplantation was performed using a right lobe graft from the patients son. The patient is alive at 87 months after the transplantation, with no evidence of HCC recurrence.
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The Maximum standardized uptake value is more reliable than size measurement in early follow-up to evaluate potential pulmonary malignancies following radiofrequency ablation.
Acta Med. Okayama
PUBLISHED: 04-23-2013
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We retrospectively evaluated the accumulation of fluorodeoxy glucose (FDG) in pulmonary malignancies without local recurrence during 2-year follow-up on positron emission tomography (PET)/computed tomography (CT) after radiofrequency ablation (RFA). Thirty tumors in 25 patients were studied (10 non-small cell lung cancers;20 pulmonary metastatic tumors). PET/CT was performed before RFA, 3 months after RFA, and 6 months after RFA. We assessed the FDG accumulation with the maximum standardized uptake value (SUVmax) compared with the diameters of the lesions. The SUVmax had a decreasing tendency in the first 6 months and, at 6 months post-ablation, FDG accumulation was less affected by inflammatory changes than at 3 months post-RFA. The diameter of the ablated lesion exceeded that of the initial tumor at 3 months post-RFA and shrank to pre-ablation dimensions by 6 months post-RFA. SUVmax was more reliable than the size measurements by CT in the first 6 months after RFA, and PET/CT at 6 months post-RFA may be more appropriate for the assessment of FDG accumulation than that at 3 months post-RFA.
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Dynamic color-coded fluorescence imaging of the cell-cycle phase, mitosis, and apoptosis demonstrates how caffeine modulates cisplatinum efficacy.
J. Cell. Biochem.
PUBLISHED: 03-21-2013
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Caffeine enhances the effect of certain anticancer drugs, but the mechanism of modulation is poorly understood. In this study, modulation of cisplatinum efficacy induced by caffeine was visualized at the subcellular level by real-time fluorescent-protein imaging. Mitotic and apoptotic changes were observed by imaging 143B human osteosarcoma dual-color cells, in which GFP is expressed in the nucleus and RFP is expressed in the cytoplasm. Modulation of the cell cycle was imaged using time-lapse imaging of HeLa cells expressing a fluorescent ubiquitination-based cell cycle indicator (FUCCI) in the nucleus. Clonogenic assays showed that caffeine increased the inhibition by cisplatinum on cell proliferation. Subcellular imaging demonstrated that cisplatinum decreased mitosis and induced apoptosis in 143B cells. The combination of cisplatinum and caffeine enhanced mitosis and subsequently increased apoptosis. Time-lapse imaging showed that cisplatinum strongly induced cell-cycle arrest in the S/G2 phase in HeLa-FUCCI cells. Caffeine overcame the cell-cycle arrest induced by cisplatinum, thereby increasing its efficacy, since cisplatinum is ineffective against quiescent cells. The data in this report indicate that caffeine modulates the cell cycle in cancer cells, thereby enhancing efficacy of cell-cycle-dependent anticancer drugs such as cisplatinum.
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[Development of a detection system for circulating tumor cells in peripheral blood using a next generation conditionally-replicating adenovirus].
Yakugaku Zasshi
PUBLISHED: 03-02-2013
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An easy and sensitive detection method for circulating tumor cells (CTC) is expected to be developed because CTC are a promising biomarker for early diagnosis of tumors and prognosis prediction of tumor patients. Our group has already developed a CTC detection method using a conditionally replicating adenovirus (Ad) which efficiently replicates and expresses GFP in telomerase-positive tumor cells. However, malignant tumor cells express much low levels of coxsackievirus and adenovirus receptor (CAR), leading to inefficient infection with a conventional conditionally replicating Ad. In addition, a tiny fraction of normal blood cells, including lymphocytes, express GFP following infection. To overcome these problems, we have developed a next-generation conditionally replicating Ad. The next-generation conditionally replicating Ad possesses the fiber protein derived from Ad serotype 35, leading to efficient infection in both CAR-positive and -negative tumor cells, because the fiber protein of Ad serotype 35 binds to CD46, which is expressed on almost all human cells. Furthermore, sequences complementary to blood cell-specific miRNA (miR-142-3p) were inserted into the 3 untranslated region of the E1 gene and GFP gene, leading to the suppression of GFP expression in normal blood cells. In this symposium, we will not only introduce the importance of CTC as a biomarker and conventional CTC detection methods but also show our data of the novel CTC detection using the next-generation conditionally replicating Ad.
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First successful case of simultaneous liver and kidney transplantation for patients with chronic liver and renal failure in Japan.
Hepatol. Res.
PUBLISHED: 03-01-2013
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Establishment of a preferential liver allocation rule for simultaneous liver and kidney transplantation (SLK) and revisions of laws regarding organ transplants from deceased donors have paved the way for SLK in Japan. Very few cases of SLK have been attempted in Japan, and no such recipients have survived for longer than 40 days. The present report describes a case of a 50-year-old woman who had undergone living donor liver transplantation at the age of 38 years for management of post-partum liver failure. After the first transplant surgery, she developed hepatic vein stenosis and severe hypersplenism requiring splenectomy. She was then initiated on hemodialysis (HD) due to the deterioration of renal function after insertion of a hepatic vein stent. She was listed as a candidate for SLK in 2011 because she required frequent plasma exchange for hepatic coma. When her Model for End-stage Liver Disease score reached 46, the new liver was donated 46 days after registration. The reduced trisegment liver and the kidney grafts were simultaneously transplanted under veno-venous bypass and intraoperative HD. The hepatic artery was reconstructed prior to portal reconstruction in order to shorten anhepatic time. Although she developed subcapsular bleeding caused by hepatic contusion on the next day, subsequent hemostasis was obtained by transcatheter embolization. Thereafter, her recovery was uneventful, except for mild rejection and renal tubular acidosis of the kidney graft. This case highlights the need to establish Japanese criteria for SLK.
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Peptide vaccines for hepatocellular carcinoma.
Hum Vaccin Immunother
PUBLISHED: 02-28-2013
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Immunotherapy is a potentially attractive treatment option for patients with hepatocellular carcinoma (HCC). We have reported that glypican-3 (GPC3) is an ideal target for anticancer immunotherapy against HCC because its expression is specifically detected in > 80% of HCCs, even during the early stages. Further, increased GPC3 expression is correlated with a poor prognosis. Based on results obtained from a preclinical study using mice, we conducted a phase I clinical trial using a GPC3-derived peptide vaccine. Phase I results showed that the GPC3-derived peptide vaccine was well tolerated. Furthermore, this was the first study to show that the frequency of peptide-specific cytotoxic T lymphocytes was correlated with overall survival in patients with HCC receiving a peptide vaccine. Next, we conducted a phase II clinical trial using the GPC3-derived peptide vaccine in patients with HCC after surgery or radiofrequency ablation (adjuvant setting). We are currently evaluating a third trial involving liver biopsies removed from patients with advanced HCC before and after GPC3-derived peptide vaccination. We expect that the results of these trials will result in future drug development.
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Peptide intra-tumor injection for cancer immunotherapy: enhancement of tumor cell antigenicity is a novel and attractive strategy.
Hum Vaccin Immunother
PUBLISHED: 02-14-2013
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One of the problems in antigen-specific cancer immunotherapy is the low density of the tumor antigen-derived peptide endogenously presented on tumor cell surface major histocompatibility complex class I molecules. To overcome this, we are engaged in research on peptide intra-tumor injection to enhance tumor cell antigenicity. In in vivo studies using immunodeficient mice, the peptide injected into a solid mass of subcutaneous tumor was revealed to be loaded onto human leukocyte antigen class I molecules of tumor cells. In a peptide vaccine model and an adoptive cell transfer model using C57BL/6 mice, peptide intra-tumor injection was effective in terms of tumor growth inhibition and prolongation of survival time. Moreover, an antigen-spreading effect was detected after peptide intra-tumor injection. Peptide intra-tumor injection is an effective method of enhancing tumor cell antigenicity. It can induce additional peptide loading onto tumor cells, making tumor cells more antigenic for specific cytotoxic T-lymphocyte activity. Peptide intra-tumor injection may be a useful option for improvement of antigen-specific immunotherapy against solid tumors.
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Risk factors for acute renal injury in living donor liver transplantation: evaluation of the RIFLE criteria.
Transpl. Int.
PUBLISHED: 02-06-2013
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Acute renal injury (ARI) is a serious complication after liver transplantation. This study investigated the usefulness of the RIFLE criteria in living donor liver transplantation (LDLT) and the prognostic impact of ARI after LDLT. We analyzed 200 consecutive adult LDLT patients, categorized as risk (R), injury (I), or failure (F), according to the RIFLE criteria. ARI occurred in 60.5% of patients: R-class, 23.5%; I-class, 21%; and F-class, 16%. Four patients in Group-A (normal renal function and R-class) and 26 patients in Group-B (severe ARI: I- and F-class) required renal replacement therapy (P < 0.001). Mild ARI did not affect postoperative prognosis regarding hospital mortality rate in Group A (3.2%), which was superior to that in Group B (15.8%; P = 0.0015). Fourteen patients in Group B developed chronic kidney disease (KDIGO stage 3/4). The 1-, 5- and 10-year survival rates were 96.7%, 90.6%, and 88.1% for Group A and 71.1%, 65.9%, and 59.3% for Group B, respectively (P < 0.0001). Multivariate analysis revealed risk factors for severe ARI as MELD ? 20 [odds ratio (OR) 2.9], small-for-size graft (GW/RBW <0.7%; OR 3.1), blood loss/body weight >55 ml/kg (OR 3.7), overexposure to calcineurin inhibitor (OR 2.5), and preoperative diabetes mellitus (OR 3.2). The RIFLE criteria offer a useful predictive tool after LDLT. Severe ARI, defined beyond class-I, could have negative prognostic impact in the acute and late postoperative phases. Perioperative treatment strategies should be designed and balanced based on the risk factors for the further improvement of transplant prognosis.
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Which patients respond best to hepatitis B vaccination after a hepatitis B virus-related liver transplantation?
J. Gastroenterol.
PUBLISHED: 01-31-2013
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A combination of hepatitis B immunoglobulin and nucleos(t)ide analogues is the current standard of care for controlling hepatitis B recurrence after orthotopic liver transplantation (OLT). However, frequent immunoglobulin treatment is expensive and inconvenient. This study investigated the efficacy of hepatitis B virus (HBV) vaccination in preventing the recurrence of hepatitis B after living donor OLT.
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Telomelysin shows potent antitumor activity through apoptotic and non-apoptotic cell death in soft tissue sarcoma cells.
Cancer Sci.
PUBLISHED: 01-21-2013
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This study investigated the pathway underlying the antitumor activity of telomelysin, a telomerase-dependent, replication-selective oncolytic adenovirus, in soft tissue sarcoma cells. Treatment with telomelysin alone resulted in simultaneous induction of apoptosis and autophagy, whereas cotreatment with telomelysin and 3-methyladenine significantly reduced cell viability and increased apoptosis and the cellular ATP level compared to treatment with telomelysin alone, indicating that telomelysin-mediated autophagy is a death-protective but not death-promoting process. Cotreatment with Z-Val-Ala-Asp-CH2F significantly increased cellular ATP depletion compared to telomelysin-alone treatment while inhibiting telomelysin-induced apoptosis and having no significant effect on cell viability, indicating that it promotes transition from apoptotic to necrotic cell death.
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Advanced hepatocellular carcinoma with lymph node metastases showing epithelial to mesenchymal transition effectively treated with systemic chemotherapy: Report of a case.
Hepatol. Res.
PUBLISHED: 01-21-2013
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We present a case in which combination chemotherapy was used to successfully treat hepatocellular carcinoma (HCC) with rapid progression of lymph node (LN) metastases after liver resection. In addition, epithelial to mesenchymal transition (EMT) markers were examined immunohistochemically. A 43-year-old man who had been diagnosed with HCC showed an enlarged LN near the hepatic artery proper. After extended left lobectomy with lymphadenectomy in the hepatoduodenal ligament, he experienced rapid progression of metastases to the para-aortic and mediastinal LN. Partial remission was achieved after induction and maintenance of combination chemotherapy using etoposide, carboplatin, epirubicin and 5-fluorouracil. As a consequence of this treatment, the patient survived 10?months. Immunohistochemical studies demonstrated that HCC cells in the metastatic LN showed low expression of E-cadherin and high expression of N-cadherin and vimentin, indicating EMT. Combination chemotherapy may prove effective for patients with HCC accompanied by LN metastases that show features of EMT.
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In vivo imaging of transplanted islets labeled with a novel cationic nanoparticle.
PLoS ONE
PUBLISHED: 01-16-2013
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To monitor pancreatic islet transplantation efficiency, reliable noninvasive imaging methods, such as magnetic resonance imaging (MRI) are needed. Although an efficient uptake of MRI contrast agent is required for islet cell labeling, commercially-available magnetic nanoparticles are not efficiently transduced into cells. We herein report the in vivo detection of transplanted islets labeled with a novel cationic nanoparticle that allowed for noninvasive monitoring of islet grafts in diabetic mice in real time. The positively-charged nanoparticles were transduced into a ?-cell line, MIN6 cells, and into isolated islets for 1 hr. MRI showed a marked decrease in the signal intensity on T1- and T2-weighted images at the implantation site of the labeled MIN 6 cells or islets in the left kidneys of mice. These data suggest that the novel positively-charged nanoparticle could be useful to detect and monitor islet engraftment, which would greatly aid in the clinical management of islet transplant patients.
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Dual programmed cell death pathways induced by p53 transactivation overcome resistance to oncolytic adenovirus in human osteosarcoma cells.
Mol. Cancer Ther.
PUBLISHED: 01-11-2013
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Tumor suppressor p53 is a multifunctional transcription factor that regulates diverse cell fates, including apoptosis and autophagy in tumor biology. p53 overexpression enhances the antitumor activity of oncolytic adenoviruses; however, the molecular mechanism of this occurrence remains unclear. We previously developed a tumor-specific replication-competent oncolytic adenovirus, OBP-301, that kills human osteosarcoma cells, but some human osteosarcoma cells were OBP-301-resistant. In this study, we investigated the antitumor activity of a p53-expressing oncolytic adenovirus, OBP-702, and the molecular mechanism of the p53-mediated cell death pathway in OBP-301-resistant human osteosarcoma cells. The cytopathic activity of OBP-702 was examined in OBP-301-sensitive (U2OS and HOS) and OBP-301-resistant (SaOS-2 and MNNG/HOS) human osteosarcoma cells. The molecular mechanism in the OBP-702-mediated induction of two cell death pathways, apoptosis and autophagy, was investigated in OBP-301-resistant osteosarcoma cells. The antitumor effect of OBP-702 was further assessed using an orthotopic OBP-301-resistant MNNG/HOS osteosarcoma xenograft tumor model. OBP-702 suppressed the viability of OBP-301-sensitive and -resistant osteosarcoma cells more efficiently than OBP-301 or a replication-deficient p53-expressing adenovirus (Ad-p53). OBP-702 induced more profound apoptosis and autophagy when compared with OBP-301 or Ad-p53. E1A-mediated miR-93/106b upregulation induced p21 suppression, leading to p53-mediated apoptosis and autophagy in OBP-702-infected cells. p53 overexpression enhanced adenovirus-mediated autophagy through activation of damage-regulated autophagy modulator (DRAM). Moreover, OBP-702 suppressed tumor growth in an orthotopic OBP-301-resistant MNNG/HOS xenograft tumor model. These results suggest that OBP-702-mediated p53 transactivation is a promising antitumor strategy to induce dual apoptotic and autophagic cell death pathways via regulation of miRNA and DRAM in human osteosarcoma cells.
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Multicenter phase II study of S-1 and docetaxel combination chemotherapy for advanced or recurrent gastric cancer patients with peritoneal dissemination.
Cancer Chemother. Pharmacol.
PUBLISHED: 01-10-2013
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Peritoneal dissemination is the most frequent and life-threatening mode of metastasis and recurrence in patients with gastric cancer. A multicenter phase II study was designed to evaluate the efficacy and tolerability of S-1 and docetaxel combination chemotherapy regimen for the treatment of advanced or recurrent gastric cancer patients with peritoneal dissemination.
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Antiproliferative effect of a novel mTOR inhibitor temsirolimus contributes to the prolonged survival of orthotopic esophageal cancer-bearing mice.
Cancer Biol. Ther.
PUBLISHED: 01-04-2013
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Esophageal squamous cell carcinoma (ESCC) remains one of the most aggressive cancers with poor prognosis regardless of a several reports that indicate a better therapeutic efficacy using some new chemotherapeutic agents. Recent drug development has contributed to an improved specificity to suppress mTOR activity by which many types of malignancies can be explosively progressed. Temsirolimus (CCI-779, TricelTM) is one of recently synthesized analogs of rapamycin and has provided better outcomes for patients with renal cell carcinoma. In this study, we experimentally evaluated an efficacy of targeting mTOR by temsirolimus for ESCC treatment, with an assessment of its survival advantage using an advanced ESCC animal model. First, we confirmed that the expression of phosphorylated mTOR was increased in 46 of 58 clinical ESCC tumor tissues (79.3%) and appeared to get strengthened with tumor progression. All of ESCC cell lines used in this study revealed an increase of mTOR phosphorylation, accompanied with the upregulation of hypoxia inducible factor-I ? (HIF-1?), one of the critical effectors regulated by mTOR. Temsirolimus treatment apparently suppressed the activation of mTOR and its downstream effectors, resulting in the reduced ability of ESCC cell proliferation. Finally, the weekly administration of temsirolimus significantly diminished the size of subcutaneous tumors (vehicle, 3261.6 ± 722.0; temsirolimus, 599.2 ± 122.9; p = 0.007) in nude mice and effectively prolonged orthotopic esophageal cancer-bearing mice (median survival periods: control, 31 d; temsirolimus, 43 d; p = 0.0024). These data suggests that targeting mTOR by temsirolimus may become a therapeutic alternative for esophageal cancer, with a contribution to a better outcome.
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Development of a clinically-precise mouse model of rectal cancer.
PLoS ONE
PUBLISHED: 01-01-2013
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Currently-used rodent tumor models, including transgenic tumor models, or subcutaneously growing tumors in mice, do not sufficiently represent clinical cancer. We report here development of methods to obtain a highly clinically-accurate rectal cancer model. This model was established by intrarectal transplantation of mouse rectal cancer cells, stably expressing green fluorescent protein (GFP), followed by disrupting the epithelial cell layer of the rectal mucosa by instilling an acetic acid solution. Early-stage tumor was detected in the rectal mucosa by 6 days after transplantation. The tumor then became invasive into the submucosal tissue. The tumor incidence was 100% and mean volume (±SD) was 1232.4 ± 994.7 mm(3) at 4 weeks after transplantation detected by fluorescence imaging. Spontaneous lymph node metastasis and lung metastasis were also found approximately 4 weeks after transplantation in over 90% of mice. This rectal tumor model precisely mimics the natural history of rectal cancer and can be used to study early tumor development, metastasis, and discovery and evaluation of novel therapeutics for this treatment-resistant disease.
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[Prolonged complete response obtained by radiation and chemotherapy with paclitaxel in a case of recurrent gastric cancer in the rectovesical pouch].
Gan To Kagaku Ryoho
PUBLISHED: 12-29-2011
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The case is a 75-year-old man, who underwent curative resection for the upper part of stomach cancer (Stage II), and was without a recurrence for two years. The patient had been well until September 2006, when CT examination revealed a 5 cm tumor in the rectovesical pouch. The tumor was histologically diagnosed as a peritoneal metastasis of gastric cancer through CT-guided percutaneous needle biopsy. Chemotherapy with S-1 was initiated, but it resulted in progressive disease. To locally control the growing tumor and avoid rectal stenosis, irradiation was applied for a total of 56 Gy in December 2007 and then followed by chemotherapy with paclitaxel. He obtained a complete response 7-month later, and remains CR for 3 years by receiving paclitaxel chemotherapy. Although chemotherapy is of choice for gastric cancer recurrence, in some cases radiotherapy can play an important role in local control even in peritoneal metastasis.
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The usefulness of pre-radiofrequency ablation SUV(max) in 18F-FDG PET/CT to predict the risk of a local recurrence of malignant lung tumors after lung radiofrequency ablation.
Acta Med. Okayama
PUBLISHED: 12-23-2011
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The aim of the present study was to assess the diagnostic usefulness of Fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in the prediction of local recurrence of malignant lung tumors by analyzing the pre-radiofrequency ablation (RFA) maximal standardized uptake value (SUV(max)). We performed a historical cohort study of consecutive malignant lung tumors treated by RFA from January 2007 to May 2008 at Okayama University Hospital. We selected only lung tumors examined by PET/CT within 90 days before RFA and divided them (10 primary and 29 metastatic) into 3 groups according to their tertiles of SUV(max). We calculated recurrence odds ratios in the medium group and the high group compared to the low group using multivariate logistic analysis. After we examined the relationship between SUV(max) and recurrence in a crude model, we adjusted for some factors. Tumors with higher SUV(max) showed higher recurrence odds ratios (medium group; 1.84, high group; 4.14, respectively). The tumor size also increased the recurrence odds ratio (2.67); we thought this was mainly due to selection bias because we excluded tumors less than 10mm in diameter. This study demonstrated the pre-RFA SUV(max) in PET/CT may be a prognostic factor for local recurrence of malignant lung tumors.
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F-18 FDG PET/CT contributes to more accurate detection of lymph nodal metastasis from actively proliferating esophageal squamous cell carcinoma.
Clin Nucl Med
PUBLISHED: 09-06-2011
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Evaluating the status of disease progression is critical for planning a therapeutic strategy for esophageal cancer. In this regard, F-18 fluorodeoxyglucose-labeled positron emission tomography (PET) is one of the most useful diagnostic modalities. However, there is room to improve its diagnostic performance, such as distinguishing lymph nodal metastases from false positives. In this study, we examined the diagnostic accuracy of fluorodeoxyglucose PET accompanied by computed tomography imaging (PET/CT) to detect regional lymph nodal metastasis from esophageal squamous cell carcinoma (ESCC).
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[Bacteria isolated from surgical infections and its susceptibilities to antimicrobial agents--special references to bacteria isolated between April 2009 and March 2010].
Jpn J Antibiot
PUBLISHED: 08-25-2011
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Bacteria isolated from surgical infections during the period from April 2009 to March 2010 were investigated in a multicenter study in Japan, and the following results were obtained. In this series, 671 strains including 16 strains of Candida spp. were isolated from 174 (79.1%) of 220 patients with surgical infections. Four hundred and eleven strains were isolated from primary infections, and 244 strains were isolated from surgical site infection. From primary infections, anaerobic Gram-negative bacteria were predominant, followed by aerobic Gram-negative bacteria, while from surgical site infection aerobic Gram-positive bacteria were predominant, followed by anaerobic Gram-negative bacteria. Among aerobic Gram-positive bacteria, the isolation rate of Enterococcus spp. was highest, followed by Streptococcus spp., and Staphylococcus spp. in this order, from primary infections, while Enterococcus spp. was highest, followed by Staphylococcus spp. from surgical site infection. Among aerobic Gram-negative bacteria, Escherichia coli was the most predominantly isolated from primary infections, followed by Klebsiella pneumoniae, Enterobacter cloacae and Pseudomonas aeruginosa, in this order, and from surgical site infection, E. coli was most predominantly isolated, followed by P. aeruginosa and E. cloacae. Among anaerobic Gram-positive bacteria, the isolation rate of Eggerthella lenta was the highest from primary infections, followed by Parvimonas micra, Streptococcus constellatus and Finegoldia magna, and from surgical site infection, E. lenta was most predominantly isolated. Among anaerobic Gram-negative bacteria, the isolation rate of Bilophila wadsworthia was the highest from primary infections, followed by Bacteroides fragilis, Bacteroides ovatus and Bacteroides thetaiotaomicron, and from surgical site infection, B. fragilis was most predominantly isolated, followed by B. ovatus, B. wadsworthia and B. thetaiotaomicron, in this order. In this series, we noticed no vancomycin-resistant Gram-positive cocci, nor multidrug-resistant P. aeruginosa. We should carefully follow up B. wadsworthia which was resistant to various antibiotics, and also Bacteroides spp. which was resistant to many beta-lactam antibiotics.
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Tumor-selective, adenoviral-mediated GFP genetic labeling of human cancer in the live mouse reports future recurrence after resection.
Cell Cycle
PUBLISHED: 08-15-2011
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We have previously developed a telomerase-specific replicating adenovirus expressing GFP (OBP-401), which can selectively label tumors in vivo with GFP. Intraperitoneal (i.p.) injection of OBP-401 specifically labeled peritoneal tumors with GFP, enabling fluorescence visualization of the disseminated disease and real-time fluorescence surgical navigation. However, the technical problems with removing all cancer cells still remain, even with fluorescence-guided surgery. In this study, we report imaging of tumor recurrence after fluorescence-guided surgery of tumors labeled in vivo with the telomerase-dependent, GFP-containing adenovirus OBP-401.. Recurrent tumor nodules brightly expressed GFP, indicating that initial OBP-401-GFP labeling of peritoneal disease was genetically stable, such that proliferating residual cancer cells still express GFP. In situ tumor labeling with a genetic reporter has important advantages over antibody and other non-genetic labeling of tumors, since residual disease remains labeled during recurrence and can be further resected under fluorescence guidance.
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Radiofrequency ablation for hepatocellular carcinoma induces glypican-3 peptide-specific cytotoxic T lymphocytes.
Int. J. Oncol.
PUBLISHED: 07-09-2011
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Glypican-3 (GPC3), a carcinoembryonic antigen, is an ideal target for anticancer immunotherapy against hepatocellular carcinoma (HCC). In this study, we attempted to compare the induction of the GPC3-specific T-cell-mediated immune response after locoregional therapies in HCC patients and tumor-bearing mice. Twenty-seven HCC patients treated with locoregional therapies, including radiofrequency ablation (RFA), surgical resection and transcatheter arterial chemo-embolization (TACE), were prospectively enrolled in this study. Additionally, we performed RFA experiments using a mouse model. GPC3-specific T-cell response was investigated pre-treatment and post-treatment by an interferon-? enzyme-linked immunospot assay using peripheral blood mononuclear cells from HCC patients and lymph node cells from tumor-bearing mice. Circulating GPC3-specific cytotoxic T lymphocytes (CTLs) were increased in 5 of 9 patients after RFA and in 4 of 9 patients after TACE, but in only 1 of 9 patients after surgical resection. All 7 patients with GPC3-expressing HCCs exhibited an increase in GPC3-specific CTLs after RFA or TACE, whereas none of the 7 patients did after surgical resection. The number of increased GPC3-specific CTLs after RFA was significantly larger than that after surgical resection (P=0.023). Similarly, the frequency of GPC3-specific CTLs after RFA was significantly greater than that after surgical resection in the mouse model (P=0.049). We validated for the first time the stronger effect on the immune system brought by RFA compared with surgical resection for HCC patients and tumor-bearing mice. Combined treatment of RFA and immunotherapy is a reasonable strategy against HCC.
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Expansion of CpG methylation in the SFRP2 promoter region during colorectal tumorigenesis.
Acta Med. Okayama
PUBLISHED: 06-29-2011
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Secreted frizzled-related protein 2, (SFRP2) is a Wnt inhibitor whose promoter CpGs were recently found to be methylated at high frequency in colorectal cancers (CRCs). We hypothesized that the pattern of SFRP2 methylation may differ throughout the promoter during progressive tumorigenesis. Using combined bisulfite restriction analysis (COBRA), two methylation-sensitive regions (Regions A and B) of the SFRP2 promoter were investigated in 569 specimens of colorectal tissue:222 CRCs, 103 adenomatous polyps (APs), 208 normal colonic mucosa from CRC patients (N-Cs), and 36 normal colonic mucosa from subjects with no evidence of colorectal neoplasia at colonoscopy (N-Ns). Extensive (including both Regions A and B) and partial (either Region A or B) SFRP2 methylation levels were found in 61.7% and 24.8% of CRCs, 8.7% and 37.9% of APs, 3.9% and 39.9% of N-Cs, and 0% and 30.6% of N-Ns, respectively. Extensive methylation of the SFRP2 promoter was present primarily in CRCs, while partial methylation was common in APs. Whereas APs with the KRAS mutant showed no correlation to any pattern of SFRP2 methylation, extensive methylation of the SFRP2 promoter was significantly associated with KRAS mutant CRCs (p?.0001), suggesting that genetic alteration in the RAS-RAF pathway might precede the spread of CpG methylation through the SFRP2 promoter, which is observed in over 60% of advanced colorectal tumors.
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A novel molecular therapy using bioengineered adenovirus for human gastrointestinal cancer.
Acta Med. Okayama
PUBLISHED: 06-29-2011
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Replication-selective tumor-specific viruses constitute a novel approach for treatment of neoplastic disease. These vectors are designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. Human telomerase is highly active in more than 85? of primary cancers, regardless of their tissue origins, and its activity correlates closely with human telomerase reverse transcriptase (hTERT) expression. We constructed an attenuated adenovirus 5 vector (Telomelysin, OBP-301), in which the hTERT promoter element drives expression of E1 genes. Since only tumor cells that express telomerase activity would activate this promoter, the hTERT proximal promoter would allow for preferential expression of viral genes in tumor cells, leading to selective viral replication and oncolytic cell death. Lymphatic invasion is a major route for cancer cell dissemination, and adequate treatment of locoregional lymph nodes is required for curative treatment in patients with gastrointestinal tumors. We demonstrated that intratumoral injection of Telomelysin mediates effective in vivo purging of metastatic tumor cells from regional lymph nodes. Moreover, using noninvasive whole-body imaging, we found that intratumoral injection of Telomelysin followed by regional irradiation induces a substantial antitumor effect, resulting from tumor cell-specific radiosensitization, in an orthotopic human esophageal cancer xenograft model. These results illustrate the potential of oncolytic virotherapy as a promising strategy in the management of human gastrointestinal cancer.
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A prognostic model and treatment strategy for intrahepatic recurrence of hepatocellular carcinoma after curative resection.
World J Surg
PUBLISHED: 06-03-2011
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The aim of this study was to evaluate the prognostic factors for intrahepatic recurrence of hepatocellular carcinoma (HCC) after curative resection.
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Inhibition of mTOR by temsirolimus contributes to prolonged survival of mice with pleural dissemination of non-small-cell lung cancer cells.
Cancer Sci.
PUBLISHED: 06-02-2011
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Temsirolimus (CCI-779), a recently synthesized analogue of rapamycin, specifically inhibits mTOR and has been approved for clinical use in renal cell carcinoma. Recent reports have indicated the growth inhibitory effect of temsirolimus in some cancers including non-small-cell lung carcinoma (NSCLC). In this study, we aimed to explore the potential therapeutic use of temsirolimus as a treatment for NSCLC. Using cultured NSCLC cells (A549, H1299, and H358), we determined the effect of temsirolimus on cell proliferation and its antitumor effects on subcutaneous tumors, as well as its contribution to the survival of mice having pleural dissemination of cancer cells, mimicking advanced NSCLC. Temsirolimus suppressed proliferation of NSCLC cells in a dose-dependent manner, with an IC(50) of <1 nM. Western blot analysis revealed that temsirolimus treatment specifically inhibited the phosphorylation of mTOR and its downstream effectors in 1 h, accompanied by an increased cell population in the G(0) /G(1) phase, but according to flow cytometry, the cell population did not increase in the sub-G(0) phase. When NSCLC subcutaneous tumor-bearing mice were treated with temsirolimus, tumor volume was significantly reduced (tumor volume on day 35: vehicle vs temsirolimus = 1239 vs 698 cm(3) ; P < 0.05). Furthermore, prolonged survival was observed in pleural disseminated tumor-bearing mice with temsirolimus treatment (median survival: vehicle vs temsirolimus = 53.5 vs 72.5 days; P < 0.05). These results suggest that temsirolimus could be useful for NSCLC treatment, due to its antiproliferative effect, and could be a potential treatment for advanced NSCLC, giving prolonged survival.
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Telomerase-specific oncolytic virotherapy for human gastrointestinal cancer.
Expert Rev Anticancer Ther
PUBLISHED: 04-21-2011
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Replication-selective tumor-specific viruses present a novel approach for treatment of neoplastic disease. These vectors are designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. Human telomerase is highly active in more than 85% of primary cancers, regardless of their tissue origins, and its activity correlates closely with human telomerase reverse transcriptase (hTERT) expression. We constructed an attenuated adenovirus 5 vector (OBP-301), in which the hTERT promoter element drives the expression of E1 genes. Since only tumor cells that express telomerase activity are able to activate this promoter, the hTERT proximal promoter allows for preferential expression of viral genes in tumor cells, leading to selective viral replication and oncolytic cell death. Lymphatic invasion is a major route for cancer cell dissemination, and adequate treatment of locoregional lymph nodes is required for curative treatment in patients with gastrointestinal tumors. In this article we show that intratumoral injection of OBP-301 mediates effective in vivo purging of metastatic tumor cells from regional lymph nodes, which may help optimize treatment of human gastrointestinal malignancies.
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Leukoencephalopathy syndrome after living-donor liver transplantation.
Exp Clin Transplant
PUBLISHED: 04-02-2011
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Leukoencephalopathy syndrome is a neurologic complication after organ transplantation caused predominantly by the neurotoxic effects of immunosuppressive agents on cerebral white matter. We determined the incidence and features of leukoencephalopathy syndrome in recipients after living-donor liver transplantations.
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Glutamine depletion induces murine neonatal melena with increased apoptosis of the intestinal epithelium.
World J. Gastroenterol.
PUBLISHED: 03-11-2011
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To investigate the possible biological outcome and effect of glutamine depletion in neonatal mice and rodent intestinal epithelial cells.
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Enhanced safety profiles of the telomerase-specific replication-competent adenovirus by incorporation of normal cell-specific microRNA-targeted sequences.
Clin. Cancer Res.
PUBLISHED: 02-23-2011
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Oncolytic adenoviruses (Ad) have been actively pursued as potential agents for cancer treatment. Among the various types of oncolytic Ads, the telomerase-specific replication-competent Ad (TRAD), which possesses an E1 gene expression cassette driven by the human telomerase reverse transcriptase promoter, has shown promising results in human clinical trials; however, the E1 gene is also slightly expressed in normal cells, leading to replication of TRAD and cellular toxicity in normal cells.
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Preclinical evaluation of telomerase-specific oncolytic virotherapy for human bone and soft tissue sarcomas.
Clin. Cancer Res.
PUBLISHED: 02-16-2011
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Tumor-specific replication-selective oncolytic virotherapy is a promising antitumor therapy for induction of cell death in tumor cells but not of normal cells. We previously developed an oncolytic adenovirus, OBP-301, that kills human epithelial malignant cells in a telomerase-dependent manner. Recent evidence suggests that nonepithelial malignant cells, which have low telomerase activity, maintain telomere length through alternative lengthening of telomeres (ALT). However, it remains unclear whether OBP-301 is cytopathic for nonepithelial malignant cells. Here, we evaluated the antitumor effect of OBP-301 on human bone and soft tissue sarcoma cells.
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MicroRNAs as potential target gene in cancer gene therapy of gastrointestinal tumors.
Expert Opin Biol Ther
PUBLISHED: 01-12-2011
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MicroRNA (miRNA) is a small non-coding RNA, which negatively regulates the expression of many target genes, thereby contributing to the modulation of diverse cell fates. Recent advances in molecular biology have revealed the potential role of miRNAs in tumor initiation, progression and metastasis. Aberrant regulation of miRNAs has been frequently reported in a variety of cancers, including gastrointestinal tumors, suggesting that cancer-related miRNAs are promising as novel biomarkers for tumor diagnosis and are potential target genes for cancer gene therapy against gastrointestinal tumors.
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Efficient virotherapy for osteosarcoma by telomerase-specific oncolytic adenovirus.
J. Cancer Res. Clin. Oncol.
PUBLISHED: 01-04-2011
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A telomerase-specific oncolytic adenovirus, Telomelysin, can selectively kill cancer cells, and be attenuated in normal cells. We herein describe the oncolytic effect of Telomelysin on human osteosarcoma both in vitro and in vivo.
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Telomerase-dependent oncolytic adenovirus sensitizes human cancer cells to ionizing radiation via inhibition of DNA repair machinery.
Cancer Res.
PUBLISHED: 11-02-2010
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The inability to repair DNA double-strand breaks (DSB) leads to radiosensitization, such that ionizing radiation combined with molecular inhibition of cellular DSB processing may greatly affect treatment of human cancer. As a variety of viral products interact with the DNA repair machinery, oncolytic virotherapy may improve the therapeutic window of conventional radiotherapy. Here, we describe the mechanistic basis for synergy of irradiation and OBP-301 (Telomelysin), an attenuated type-5 adenovirus with oncolytic potency that contains the human telomerase reverse transcriptase promoter to regulate viral replication. OBP-301 infection led to E1B55kDa viral protein expression that degraded the complex formed by Mre11, Rad50, and NBS1, which senses DSBs. Subsequently, the phosphorylation of cellular ataxia-telangiectasia mutated protein was inhibited, disrupting the signaling pathway controlling DNA repair. Thus, tumor cells infected with OBP-301 could be rendered sensitive to ionizing radiation. Moreover, by using noninvasive whole-body imaging, we showed that intratumoral injection of OBP-301 followed by regional irradiation induces a substantial antitumor effect, resulting from tumor cell-specific radiosensitization, in an orthotopic human esophageal cancer xenograft model. These results illustrate the potential of combining oncolytic virotherapy and ionizing radiation as a promising strategy in the management of human cancer.
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Preclinical evaluation of differentially targeting dual virotherapy for human solid cancer.
Mol. Cancer Ther.
PUBLISHED: 05-25-2010
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Multimodal approaches combining drugs that differentially function is the most popular regimen for treating human cancer. Understanding the molecular mechanisms underlying the synergistic, potentiative, and antagonistic effects of drug combinations could facilitate the discovery of novel efficacious combinations. We previously showed that telomerase-specific replication-competent adenovirus (Telomelysin, OBP-301), in which the human telomerase reverse transcriptase promoter controls the adenoviral E1 gene expression, induces a selective antitumor effect in human cancer cells. Here, using E1-deleted replication-deficient adenovirus expressing the p53 tumor suppressor gene (Advexin, Ad-p53) and OBP-301, we investigate how these adenoviruses that kill tumor cells with different mechanisms could work in combination on human cancer. We found that E1-deficient Ad-p53 could kill cancer cells more efficiently in the presence of OBP-301 than Ad-p53 alone or OBP-301 alone, because Ad-p53 could become replication-competent by being supplied adenoviral E1 from coinfected OBP-301 in trans. Ad-p53 plus OBP-301 induced high levels of p53 protein expression without p21 induction, resulting in apoptotic cell death documented by active caspase-3 expression with a cytometric bead array and an increased subdiploid apoptotic fraction of the cell cycle. For in vivo evaluation, nude mice xenografted with human lung tumors received intratumoral injection of OBP-301 and/or Ad-p53. Analysis of the growth of implanted tumors showed an enhanced antitumor effect in combination therapy. Our data show that Ad-p53 in combination with OBP-301 induces not only oncolytic but also apoptotic cancer cell death and enhances antitumor activity in vitro and in vivo, providing potential merits as a multimodal treatment for human cancer.
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In vivo biological purging for lymph node metastasis of human colorectal cancer by telomerase-specific oncolytic virotherapy.
Ann. Surg.
PUBLISHED: 05-21-2010
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The aim of this study was to develop a less invasive way of targeting lymph node metastasis for the treatment of human gastrointestinal cancer. Lymphatic invasion is a major route for cancer cell dissemination, and adequate treatment of locoregional lymph nodes is required for curative treatment in patients with malignancies.
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Portal/splenic vein thrombosis following splenectomy in gastric cancer surgery.
Asian J Surg
PUBLISHED: 05-17-2010
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Although splenectomy is often performed along with en bloc node dissection in gastric cancer surgery, portal/splenic vein thrombosis (PSVT) has been rarely reported. We recently encountered a case of PSVT after a splenectomy was performed during gastric cancer surgery. A 53-year-old woman underwent total gastrectomy, splenectomy, and en bloc regional lymph node dissection for gastric cancer. An uneventful postoperative course ended with abrupt development of a fever and general fatigue. Laboratory tests showed elevated levels of liver transaminases and fibrinogen degenerative products. Contrast-enhanced computed tomography revealed splenic vein thrombosis and partial liver infarction. Immediate anticoagulant treatment resulted in clinical improvement and partial thrombolysis in 2 months. PSVT after splenectomy in haematological disorders has been recognized as a possibly lethal complication. However, it has been underappreciated in cases of splenectomy for gastric cancer. The present case demonstrates the importance of considering PSVT as a possible complication of splenectomy in gastric cancer surgery.
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A phase I study of telomerase-specific replication competent oncolytic adenovirus (telomelysin) for various solid tumors.
Mol. Ther.
PUBLISHED: 11-24-2009
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A phase I clinical trial was conducted to determine the clinical safety of Telomelysin, a human telomerase reverse transcriptase (hTERT) promoter driven modified oncolytic adenovirus, in patients with advanced solid tumors. A single intratumoral injection (IT) of Telomelysin was administered to three cohorts of patients (1 x 10(10), 1 x 10(11), 1 x 10(12) viral particles). Safety, response and pharmacodynamics were evaluated. Sixteen patients with a variety of solid tumors were enrolled. IT of Telomelysin was well tolerated at all dose levels. Common grade 1 and 2 toxicities included injection site reactions (pain, induration) and systemic reactions (fever, chills). hTERT expression was demonstrated at biopsy in 9 of 12 patients. Viral DNA was transiently detected in plasma in 13 of 16 patients. Viral DNA was detectable in four patients in plasma or sputum at day 7 and 14 post-treatment despite below detectable levels at 24 h, suggesting viral replication. One patient had a partial response of the injected malignant lesion. Seven patients fulfilled Response Evaluation Criteria in Solid Tumors (RECIST) definition for stable disease at day 56 after treatment. Telomelysin was well tolerated. Evidence of antitumor activity was suggested.
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Selective metastatic tumor labeling with green fluorescent protein and killing by systemic administration of telomerase-dependent adenoviruses.
Mol. Cancer Ther.
PUBLISHED: 11-03-2009
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We previously constructed telomerase-dependent, replication-selective adenoviruses OBP-301 (Telomelysin) and OBP-401 [Telomelysin-green fluorescent protein (GFP); TelomeScan], the replication of which is regulated by the human telomerase reverse transcriptase promoter. By intratumoral injection, these viruses could replicate within the primary tumor and subsequent lymph node metastasis. The aim of the present study was to evaluate the possibility of systemic administration of these telomerase-dependent adenoviruses. We assessed the antitumor efficacy of OBP-301 and the ability of OBP-401 to deliver GFP in hepatocellular carcinoma (HCC) and metastatic colon cancer nude mouse models. We showed that i.v. administration of OBP-301 significantly inhibited colon cancer liver metastases and orthotopically implanted HCC. Further, we showed that OBP-401 could visualize liver metastases by tumor-specific expression of the GFP gene after portal venous or i.v. administration. Thus, systemic administration of these adenoviral vectors should have clinical potential to treat and detect liver metastasis and HCC.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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