Glutathione-S-transferase P1-1 protects aberrant crypt foci from apoptosis induced by deoxycholic acid

BACKGROUND & AIMS: Aberrant crypt foci, precursors of colonic adenoma, are frequently positive for glutathione-S-transferase P1-1. Because deoxycholic acid is an apoptosis-inducing xenobiotic in the colon, we examined the possibility that aberrant crypt foci, through the cytoprotecting function of glutathione-S-transferase P1-1, resist deoxycholic acid-induced apoptosis, thereby surviving to become adenomas and subsequently cancer. METHODS: Glutathione-S-transferase P1-1 or cyclooxygenase-2 expression and the percentage of apoptotic cells in aberrant crypt foci were examined by immunohistochemistry and by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling, respectively. Glutathione-S-transferase P1-1 was transfected into colon cancer cells (M7609) and human lung fibroblasts, and deoxycholic acid-induced apoptosis was evaluated by a dye-uptake assay and flow cytometry. Binding of deoxycholic acid to glutathione-S-transferase P1-1 was analyzed by circular dichroism and immunoprecipitation. Caspase activities were determined by colorimetric protease assay, and sulindac binding to glutathione-S-transferase P1-1 was determined by inhibition assay of glutathione-S-transferase P1-1 activity. RESULTS: Aberrant crypt foci showed positive immunostaining for glutathione-S-transferase P1-1 but negative staining for cyclooxygenase-2. The percentage of apoptotic cells in aberrant crypt foci was significantly lower than in healthy epithelium, and the difference became more apparent with deoxycholic acid treatment. The impaired sensitivity of aberrant crypt foci to deoxycholic acid was restored by the glutathione-S-transferase P1-1-specific inhibitor gamma-glutamyl-S-(benzyl)cysteinyl-R-phenylglycine diethylester. By transfection of glutathione-S-transferase P1-1, M7609 cells became more resistant to deoxycholic acid-induced apoptosis than mock transfectants. Direct binding of glutathione-S-transferase P1-1 to deoxycholic acid was proven by circular dichroism and by immunoprecipitation. The aberrant crypt foci in adenoma patients treated with sulindac, which was shown to bind to glutathione-S-transferase P1-1, underwent apoptosis in 4 days and mostly regressed in 2-3 months. CONCLUSIONS: Glutathione-S-transferase P1-1 protects aberrant crypt foci from deoxycholic acid-induced apoptosis and may play a pivotal role in early colon carcinogenesis.     

Image-guided bronchoscopy for histopathologic diagnosis of pure ground glass opacity: a case report

Guided bronchoscopy has been found to be useful for the diagnosis of solid peripheral pulmonary lesions (PPLs) but more evidence on ground glass opacities (GGOs), especially those without a solid component, are lacking. A 69-year-old male, asymptomatic, heavy smoker was referred to our department for non-surgical diagnosis of a focal pure GGO in the right upper lobe that was found incidentally on computed tomography (CT). Transbronchial biopsy (TBB) with the aide of endobronchial ultrasound with a guide sheath (EBUS-GS), virtual bronchoscopic navigation (VBN), and fluoroscopy was performed for sampling. There were no complications after the procedure. The diagnosis of adenocarcinoma with lepidic growth pattern was established from the fourth and fifth TBB specimens and was confirmed on subsequent surgical resection. Image-guided bronchoscopy with TBB was successful for the diagnosis of a pure GGO. Use of a larger biopsy device may be helpful for the histopathologic diagnosis of lung adenocarcinoma with lepidic growth.     

Industrial separation of oxygen isotopes by oxygen distillation

¹⁸O‐labeled water (Water‐¹⁸O) is a widely used starting material of ¹⁸F‐labeled diagnostic agents in positron emission tomography (PET). Conventionally, Water‐¹⁸O has been separated from other stable oxygen isotope species (¹⁶O, ¹⁷O) by water distillation or nitric oxide distillation. However, conventional methods are costly and may have safety issues. In 2004, we developed the first unit of our novel oxygen isotope separation process by cryogenic oxygen distillation to overcome these issues. To meet the needs of the market, we built a second unit in 2013 and a third in 2016. We are now operating three commercially viable separation units with a total capacity of 600 kg of Water‐¹⁸O per year.     

A Prospective Analysis of Efficacy and Long-Term Outcome of Radiation Therapy for Gastric Mucosa-Associated Lymphoid Tissue Lymphoma

Background/Aims: Few studies exist on the efficacy and long-term outcome of radiation therapy (RT) for gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Methods: Twenty-two patients with stage I or stage II(1) disease were prospectively evaluated, including 14 patients without Helicobacter pylori(H. pylori) infection and 8 patients with persistent lymphoma after H. pylori eradication. RT dose was 30 Gy in daily fractions of 1.5 Gy. All patients underwent endoscopic and histological follow-up regularly. Results: The study included 22 patients with a mean age of 63 years. The t(11;18)(q21;q21) translocation occurred in 8 of the 22 cases. All patients showed complete remission without any serious toxicity. At a median follow-up evaluation 74 months (range 27-159) after completion of RT, the overall and relapse-free survival rates after 5 years were 91 and 84%, respectively. Although no patient showed local recurrence of lymphoma, distant recurrence was detected in 3 patients, all of whom were H. pylori negative; MALT lymphoma relapsed in two patients with the t(11;18)(q21;q21) translocation, and diffuse large-cell lymphoma developed in one patient without the translocation. Conclusion: RT provides excellent local control of the gastric MALT lymphoma. However, continuous follow-up is mandatory as relapse may occur in other sites.     

Neuroendocrine carcinoma of the stomach: clinicopathological and immunohistochemical evaluation

Neuroendocrine carcinoma (NEC) of the stomach is an uncommon disease. Because of its rarity, the clinicopathological features are unclear, and there is no consensus on the optimal treatment strategy. This study included five consecutive patients with gastric NEC who underwent surgery from July 2001 to August 2011. Clinical presentation, tumor location, tumor morphology and size, pathology and immunohistochemistry results, and treatment outcome were analyzed retrospectively and discussed. The study cohort of four men and one woman ranged in age from 52 to 84 years, with a median age of 72 years. Positive rates of neuroendocrine markers were 40 % for chromogranin A, 60 % for synaptophysin, 60 % for CD56, 40 % for neuron-specific enolase, and 100 % for p53 protein. Median number of lymph node metastases per patient was 10, with severe lymphatic and venous infiltration, and high Ki-67 labeling index (60–90 %) reported for all patients. Median tumor size was 6 cm. Stage IV disease was diagnosed in three patients; the other two patients showed stage IIIA tumors. After a mean follow-up of 29.8 months, two of the five patients had died of the disease. Although rare, gastric NECs deserve particular attention because of their strong malignant potential associated with an extremely poor prognosis. Such carcinomas demand an aggressive surgical approach followed by chemotherapy and multimodality adjuvant therapy.