Genki Tanaka

Augmented Pentose Phosphate Pathway Plays Critical Roles in Colorectal Carcinomas

Glycolysis and the pentose phosphate pathway (PPP) are preferentially activated in cancer cells. Accumulating evidence indicated the significance of the altered glucose metabolism in cancer, but the implication for oncotherapy remains unclear. Here we report that the synthesis of glycolytic and PPP enzymes is almost ubiquitously augmented in colorectal carcinoma (CRC) specimens. The mammalian target of rapamycin (mTOR) inhibitor INK128 (300 nM) and phytochemical Avemar (1 mg/ml) inhibited the synthesis of PPP enzymes in CRC cell lines. INK128 (150-600 nM) and resveratrol (75-300 μM) inhibited aerobic glycolysis in the cell lines. INK128 (300 nM) and Avemar (1 mg/ml) decreased the NADPH/NADP+ ratio as well as the GSH/GSSG ratio in the cell lines. Finally, per os administration of INK128 (0.8 mg/kg) or Avemar (1 g/kg) suppressed tumor growth and delayed tumor formation by transplantable CRC specimens derived from patients. Taken together, pharmacological inhibition of the mTOR-PPP axis is a promising therapeutic strategy against CRCs.

Usefulness of Intraoperative Observation Using a Fluorescence Imaging Instrument for Patients With Nonocclusive Mesenteric Ischemia

The authors evaluated the usefulness of intraoperative photodynamic eye (PDE) observation in patients with nonocclusive mesenteric ischemia (NOMI). Between February 2012 and July 2013, 6 patients who had undergone emergency surgery for NOMI were enrolled. Intraoperative PDE observation was performed to decide the adequate length of bowel resection including all skipped dark spots, which could not be detected as ongoing mucosal ischemic changes under visible light observation. All ongoing mucosal ischemic changes were easily detected as dark spots using PDE observation in all 6 patients. The mean length of adequate ileal resection (92 ± 48 cm) was significantly longer than that of ischemic ileum (85 ± 50 cm) (mean ± SD) (P = 0.043). After resection of an adequate length of bowel, all the patients had a good course until discharge without incidents due to residual bowel ischemia, except for 1patient who died. PDE observation is useful for deciding the adequate length of bowel to resect, including ongoing mucosal ischemic changes that cannot be detected under visible light observation. In patients with NOMI, resection of an adequate length of bowel is necessary to prevent postoperative incidents due to residual bowel ischemia.

Dual pharmacological inhibition of glutathione and thioredoxin systems synergizes to kill colorectal carcinoma stem cells

NRF2 stabilizes redox potential through genes for glutathione and thioredoxin antioxidant systems. Whether blockade of glutathione and thioredoxin is useful in eliminating cancer stem cells remain unknown. We used xenografts derived from colorectal carcinoma patients to investigate the pharmacological inhibition of glutathione and thioredoxin systems. Higher expression of five glutathione S‐transferase isoforms (GSTA1, A2, M4, O2, and P1) was observed in xenograft‐derived spheroids than in fibroblasts. Piperlongumine (2.5–10 μmol/L) and auranofin (0.25–4 μmol/L) were used to inhibit glutathione S‐transferase π and thioredoxin reductase, respectively. Piperlongumine or auranofin alone up‐regulated the expression of NRF2 target genes, but not TP53 targets. While piperlongumine showed modest cancer‐specific cell killing (IC50 difference between cancer spheroids and fibroblasts: P = 0.052), auranofin appeared more toxic to fibroblasts (IC50 difference between cancer spheroids and fibroblasts: P = 0.002). The synergism of dual inhibition was evaluated by determining the Combination Index, based on the number of surviving cells with combination treatments. Molar ratios indicated synergism in cancer spheroids, but not in fibroblasts: (auranofin:piperlongumine) = 2:5, 1:5, 1:10, and 1:20. Cancer‐specific cell killing was achieved at the following drug concentrations (auranofin:piperlongumine): 0.25:2.5 μmol/L, 0.5:2.5 μmol/L, or 0.25:5 μmol/L. The dual inhibition successfully decreased CD44v9 surface presentation and delayed tumor emergence in nude mouse. However, a small subpopulation persistently survived and accumulated phosphorylated histone H2A. Such “persisters” still retained lesser but significant tumorigenicity. Thus, dual inhibition of glutathione S‐transferase π and thioredoxin reductase could be a feasible option for decreasing the tumor mass and CD44v9‐positive fraction by disrupting redox regulation.

The preoperative globulin-to-albumin ratio, a novel inflammation-based prognostic system, predicts survival after potentially curative liver resection for patients with hepatocellular carcinoma

Although the globulin‐to‐albumin ratio (GAR) is useful for prognostication of patients with various cancers, its relationship with hepatocellular carcinoma (HCC) remains unclear. The study aims to investigate the relationship between GAR and postoperative survival among patients with HCC undergoing potentially curative liver resection (LR).

A case of obstructive jaundice due to early carcinoma of the cystic duct protruding into the common bile duct

Highlights • An extremely rare early cystic duct carcinoma.• The protruding part was the cause of jaundice.• There is a significant interesting macro findings in the removed sample.• The only small part of the invasive part which reach fibro-muscular layer is revealed by the pathological findings.

Preoperative globulin-to-albumin ratio predicts outcome after curative resection in patients with gastric cancer

The globulin‐to‐albumin ratio (GAR) is useful for prognostication of patients with various cancers. However, the significance of GAR in gastric cancer (GC) remains unclear. Our purpose was to investigate the relationship between the GAR and outcome after curative resection in GC patients.