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Background: Iron is essential for cell replication, metabolism and growth. Because neoplastic cells have high iron requirements due to their rapid proliferation, iron depletion may be a novel therapeutic strategy for cancer. Deferasirox (DFX), a novel oral iron chelator, has been successful in clinical trials in iron-overload patients and has been expected to become an anticancer agent. However, no studies have investigated the effects of DFX on pancreatic cancer. This study aimed to elucidate the effects of DFX against pancreatic cancer.Methods: The effects of DFX on cell cycle, proliferation, and apoptosis were examined in three human pancreatic cancer cell lines: BxPC-3, HPAF-II, and Panc 10.05. The effect of orally administered DFX on the growth of BxPC-3 pancreatic cancer xenografts was also examined in nude mice. Additionally, microarray analysis was performed using tumors excised from xenografts.Results: DFX inhibited pancreatic cancer cell proliferation in a dose-dependent manner. A concentration of 10 μM DFX arrested the cell cycle in S phase, whereas 50 and 100 μM DFX induced apoptosis. In nude mice, orally administered DFX at 160 and 200 mg/kg suppressed xenograft tumor growth with no serious side effects (n = 5; average tumor volumes of 674 mm(3) for controls vs. 327 mm(3) for 160 mg/kg DFX, p <0.05; average tumor volumes of 674 mm(3) for controls vs. 274 mm(3) for 200 mg/kg DFX, p <0.05). Importantly, serum biochemistry analysis indicated that serum levels of ferritin were significantly decreased by the oral administration of 160 or 200 mg/kg DFX (n = 5; average serum ferritin of 18 ng/ml for controls vs. 9 ng/ml for 160 mg/kg DFX, p <0.05; average serum ferritin of 18 ng/ml for controls vs. 10 ng/ml for 200 mg/kg DFX, p <0.05). Gene expression analysis revealed that most genes in pancreatic adenocarcinoma signaling, especially transforming growth factor-ß1 (TGF-ß1), were downregulated by DFX.Conclusions: DFX has potential as a therapeutic agent for pancreatic cancer. Iron depletion was essential for the antiproliferative effect of DFX in a preclinical model, and DFX acted through the suppression of TGF-ß signaling. [ABSTRACT FROM AUTHOR]

Background: Adenylate kinase is a key enzyme in the high-energy phosphoryl transfer reaction in living cells. An isoform of this enzyme, adenylate kinase 4 (AK4), is localized in the mitochondrial matrix and is believed to be involved in stress, drug resistance, malignant transformation in cancer, and ATP regulation. However, the molecular basis for the AK4 functions remained to be determined. Methods: HeLa cells were transiently transfected with an AK4 small interfering RNA (siRNA), an AK4 short hairpin RNA (shRNA) plasmid, a control shRNA plasmid, an AK4 expression vector, and a control expression vector to examine the effect of the AK4 expression on cell proliferation, sensitivity to anti-cancer drug, metabolome, gene expression, and mitochondrial activity. Results: AK4 knockdown cells treated with short hairpin RNA increased ATP production and showed greater sensitivity to hypoxia and anti-cancer drug, cis-diamminedichloro-platinum (II) (CDDP). Subcutaneous grafting AK4 knockdown cells into nude mice revealed that the grafted cells exhibited both slower proliferation and reduced the tumor sizes in response to CDDP. AK4 knockdown cell showed a increased oxygen consumption rate with FCCP treatment, while AK4 overexpression lowered it. Metabolome analysis showed the increased levels of the tricarboxylic acid cycle intermediates, fumarate and malate in AK4 knockdown cells, while AK4 overexpression lowered them. Electron microscopy detected the increased mitochondrial numbers in AK4 knockdown cells. Microarray analysis detected the increased gene expression of two key enzymes in TCA cycle, succinate dehydrogenase A (SDHA) and oxoglutarate dehydrogenease L (OGDHL), which are components of SDH complex and OGDH complex, supporting the metabolomic results. Conclusions: We found that AK4 was involved in hypoxia tolerance, resistance to anti-tumor drug, and the regulation of mitochondrial activity. These findings provide a new potential target for efficient anticancer therapies by controlling AK4 expression. [ABSTRACT FROM AUTHOR]

Background/Aims: Intralesional steroid injections have been administered as prophylaxis for stenosis after esophageal endoscopic submucosal dissection. However, this method carries a risk of potential complications such as perforation because a fine needle is used to directly puncture the postoperative ulcer. We devised a new method of steroid intralesional infusion using a spray tube and evaluated its efficacy and safety. Methods: Intralesional steroid infusion using a spray tube was performed on 27 patients who underwent endoscopic submucosal dissection for superficial esophageal cancer with three-quarters or more of the lumen circumference resected. The presence or absence of stenosis, complications, and the number of endoscopic balloon dilations (EBDs) performed were evaluated after treatment. Results: Although stenosis was not observed in 22 of the 27 patients, five patients had stenosis and dysphagia requiring EBD. The stenosis in these five patients was relieved after four EBDs. No complications related to intralesional steroid infusion using the spray tube were observed. Conclusions: Intralesional steroid infusion using a spray tube is a simple and safe technique that is adequately effective in preventing stenosis (clinical trial number, UMIN000037567). [ABSTRACT FROM AUTHOR]

We develop “autologous bone marrow cell infusion (ABM i) therapy” for the treatment of human decompensated liver cirrhosis and confirm the efficacy and safety of this treatment in multicenter clinical studies. With the goal of further expanding the applications of ABM i, we first cultured human bone marrow cells and then determined whether a cell fraction found to be effective in improving liver fibrosis can be amplified. Cells harvested after two passages (P2 cells) consistently contained approximately 94 % mesenchymal stem cells (MSCs); conversely, the cells harvested after only medium change (P0 cells) contained many macrophages. MSCs (2.8 × 10 8) in P2 cells were harvested from 3.8 × 10 8 bone marrow-derived mononuclear cells after 22 days. DNA-chip analysis also showed during the culturing step that bone marrow-derived cells decreased with macrophage phenotype. The infused 5 × 10 5 P2 cells significantly improved liver fibrosis in the nonobese diabetic/severe combined immunodeficient (NOD-SCID) mouse carbon tetrachloride (CCl 4) liver cirrhosis model and induced the expression of matrix metalloproteinase (MMP)-9 and suppressed expressions of alpha smooth muscle actin (αSMA), tumor necrosis factor alpha (TNFα) and transforming growth factor beta (TGFβ) in the liver. Cultured human bone marrow-derived cells (P2 cells) significantly inhibited liver fibrosis. The increase of MMP-9 and suppressed activation of hepatic stellate cells (HSCs) through the regulation of humoral factors (TNFα and TGFβ) contribute to the improvement of liver fibrosis by MSCs comprising about 94 % of P2 cells. MSCs in cultured human bone marrow-derived mono-nuclear cells (BM-MNCs) proliferate sufficiently in cell therapy, so we believe our cultured bone marrow-derived cell therapy can lead to expanded clinical applications and enable outpatient therapy. [ABSTRACT FROM AUTHOR]

Objective: Unusual or unexpected effect of treatment. Background: This is a case report validating our previous studies showing clinical benefit of balloon-occluded retrograde transvenous obliteration (BRTO) in improving hepatic function and outcomes in patients with a low liver stiffness (LS) and with procedural indication of encephalopathy. Here, we present the case of a woman in her late 60s suffering from hepatitis C virus-related decompensated liver cirrhosis with refractory encephalopathy. Case Report: The patient presented with a Child-Pugh score of 11, Model for End-Stage Liver Disease-Sodium (MELD-Na) score of 16, and LS of 21.5 kPa. BRTO was expected to improve both the intractable encephalopathy and hepatic function and prolong her vital prognosis. Portosystemic shunt (PSS) occlusion induced drastic changes in the portal-splenic vein hemodynamics, resulting in dramatically improved Child-Pugh and MELD-Na scores. This status was maintained for 1 year postoperatively. However, her LS increased 1 month postoperatively and declined steadily thereafter. The postoperative levels of hepatic fibrosis markers, including Mac-2 binding protein glycosylation isomer, decreased markedly. No ascites, pleural effusion, esophagogastric varices, or relapse of encephalopathy were observed during a 1-year postoperative follow-up period. Conclusions: Liver failure caused mainly by the advanced development of PSSs (as in our case), rather than hepatic parenchymal cell dysfunction, is considered reversible and controllable via PSS occlusion. We herein propose a novel concept, "portal-systemic liver failure," to describe liver failure with a non-stiff liver and giant PSSs, as in the present case. In patients with "portal-systemic liver failure," BRTO could potentially improve the prognosis in association with improved hepatic reserve and fibrosis. [ABSTRACT FROM AUTHOR]

Objective: Unusual clinical course Background: The appearance of direct acting antivirals (DAAs) has produced a major paradigm shift in hepatitis C virus (HCV) infection treatment, and virus elimination has become possible in most patients. Improvement of the model for end-stage liver disease (MELD) score by elimination of HCV has been reported, but for decompensated liver cirrhosis, it is also important to overcome various complications before antiviral treatment. Case Report: A 72-year-old male, who had been treated for HCV-related liver cirrhosis was referred to our hospital for treatment of refractory hepatic encephalopathy. At that time, his Child-Pugh score was 10 and class was C. On contrast-enhanced computed tomography (CT), a splenorenal shunt, splenomegaly, and splenic artery aneurysm were noted. The disease was also complicated by cytopenia associated with hypersplenism, and embolization of the splenic artery aneurysm and partial splenic embolization (PSE) were concomitantly performed. One month after the PSE, balloon occluded retrograde transvenous obliteration (BRTO) for refractory hepatic encephalopathy was performed. Hepatic functional reserve improved compared with that at the first examination, and SOF/LDV therapy was initiated. Fortunately, no adverse effect occurred during treatment, and sustained virologic response (SVR) was achieved. Hepatic functional reserve further improved thereafter. At the time of this report, a Child-Pugh A status was being maintained without administration of a branched chain amino acid preparation, drugs for hyperammonemia, or diuretics. Conclusions: We encountered a patient with decompensated liver cirrhosis accompanied by complications of hypersplenism, hepatic encephalopathy, and splenic artery aneurysm. These complications were overcome by treatment with PSE and BRTO, which led to DAAs treatment and a marked improvement of hepatic function. [ABSTRACT FROM AUTHOR]