MYEOV overexpression induced by demethylation of its promoter contributes to pancreatic cancer progression via activation of the folate cycle/c-Myc/mTORC1 pathway.

BACKGROUND: While molecular targeted drugs and other therapies are being developed for many tumors, pancreatic cancer is still considered to be the malignant tumor with the worst prognosis. We started this study to identify prognostic genes and therapeutic targets of pancreatic cancer. METHODS: To comprehensively identify prognostic genes in pancreatic cancer, we investigated the correlation between gene expression and cancer-specific prognosis using transcriptome and clinical information datasets from The Cancer Genome Atlas (TCGA). In addition, we examined the effects of the suppression of candidate prognostic genes in pancreatic cancer cell lines. RESULT: We found that patients with high expression levels of MYEOV, a primate-specific gene with unknown function, had significantly shorter disease-specific survival times than those with low expression levels. Cox proportional hazards analysis revealed that high expression of MYEOV was significantly associated with poor survival and was an independent prognostic factor for disease-specific survival in pancreatic cancer patients. Analysis of multiple cancer samples revealed that the MYEOV promoter region is methylated in noncancer tissues but is demethylated in tumors, causing MYEOV overexpression in tumors. Notably, the knockdown of MYEOV suppressed the expression of MTHFD2 and other folate metabolism-related enzyme genes required for the synthesis of amino acids and nucleic acids and also restored the expression of c-Myc and mTORC1 repressors. CONCLUSION: There is a significant correlation between elevated MYEOV expression and poor disease-specific survival in pancreatic cancer patients. MYEOV enhances the activation of several oncogenic pathways, resulting in the induction of pancreatic cancer cell proliferation. Overall, MYEOV acts as an oncogene in pancreatic cancer. Furthermore, MYEOV may be a prognostic biomarker and serve as an 'actionable' therapeutic target for pancreatic cancers.

Dead or alive? Pitfall of survival analysis with TCGA datasets.

We often encounter situations in which data from the TCGA that have been analyzed in papers we read or reviewed cannot be reproduced, even when TCGA datasets are used, especially in survival analyses. Therefore, we attempted to confirm the data source for TCGA survival analysis and found that several websites used to analyze the survival data of TCGA datasets inappropriately handle the survival data, causing differences in statistical analyses. This causes the misinterpretation of results because figures of survival analysis results in several papers are sometimes exactly as generated by these sites, and the results depend on only the tools provided by these sites. We would like to make this situation widely known and raise the problem for scientific soundness.

Early dynamics of circulating tumor DNA predict chemotherapy responses for patients with esophageal cancer.

We investigated whether early circulating tumor DNA (ctDNA) changes, measured using digital PCR (dPCR), can predict later chemotherapy responses in esophageal squamous cell cancer (ESCC). We compared the dynamics of ctDNA and tumor volumes during chemotherapy in 42 ESCC. The accuracy of predictions of later chemotherapy responses was evaluated by the ratio of the variant allele frequency of ctDNA (post-/pre-ctDNA) and the total tumor volume (post-/pre-volume) before and after an initial chemotherapy cycle using a receiver-operating characteristic curve analysis. Total positive and negative objective responses (ORs) were defined as either >50 or ≤50% reductions, respectively, in the total tumor volume at the end of first-line chemotherapy. Mutation screening of 43 tumors from 42 patients revealed 96 mutations. The pretreatment dPCR-ctDNA data were informative in 38 patients, using 70 selected mutations (1-3 per patient). The areas under the curve (AUCs) for the post-/pre-volume and post-/pre-ctDNA levels used in predicting the total OR were 0.85 and 0.88, respectively. The optimal cutoff value of post-/pre-ctDNA was 0.13. In 20 patients with post-/pre-volume ≥50%, the total OR could be predicted by the post-/pre-ctDNA with high accuracy; the AUC by post-/pre-ctDNA was higher than that by post-/pre-volume (0.85 versus 0.76, respectively). Patients with low post-/pre-ctDNA (n = 18) had a significantly better overall survival rate than those with high post-/pre-ctDNA (n = 20; P = 0.03). Early ctDNA changes after an initial cycle of chemotherapy predict later responses to treatment with high accuracy in ESCC patients.

Genetic analyses of a secondary poroma and trichoblastoma in a HRAS-mutated sebaceous nevus.

A sebaceous nevus is a congenital skin hamartoma caused by postzygotic HRAS or KRAS mosaic mutations. With age, affected individuals may develop secondary tumors within a sebaceous nevus. RAS mutations are harbored from the onset of sebaceous nevus, and further mutations can be expected to be required in order to explain the initiation of secondary tumors. However, genetic analyses of the secondary tumors have not been conducted. Herein, we describe the rare coexistence of a poroma and a trichoblastoma arising in a sebaceous nevus. This is the first report of an investigation of multiple genes in a secondary tumor in an SN. First, HRAS c.37G>C, which is the common mutation in sebaceous nevus, was detected in all three lesions (sebaceous nevus, poroma, and trichoblastoma). Next, to elucidate the potential second-hit mutations in the secondary poroma and trichoblastoma, we applied a panel sequencing for skin cancers that was newly developed in our institution. Our comparison of the mutational profile of 95 skin cancer-related genes in each of the three lesions newly revealed TP53 p.R158P in the poroma and NOTCH2 p.G329S in the trichoblastoma. TP53 p.R158P has been determined as a pathogenic mutation in other tumors, and NOTCH2 p.G329S was a novel mutation. We identified two novel mutations that may have contributed to the pathogenesis of the secondary tumor's development. The roles of the mutations remain unclear.

Utilization of adzuki bean extract as a natural antioxidant in cured and uncured cooked pork sausages.

A commercial adzuki bean extract (AE) was evaluated for antioxidant effectiveness in cured and uncured cooked pork sausages. TBARS values, instrumental color evaluation and sensory panel scores were assessed. For uncured sausages, AE at 0.2% was equally effective as 0.1% butylated hydroxytoluene (BHT) in reducing TBARS values. Similarly, AE at 0.2% significantly (P<0.01) reduced the TBARS in cured sausages. Incorporation of 0.2% AE into sausages produced higher (P<0.05) CIE lab color a* value and lower (P<0.05) L* and b* values. Sensory panels did not detect any difference in color, odor, taste, flavor, and overall acceptance in uncured pork sausages with addition of 0.2% AE. However, there were adverse changes in the color and odor of cured sausages, even though the taste, flavor, and overall acceptance were similar. Therefore, the results suggest that AE is a potential antioxidant.

Low pre-radiotherapy prostate-specific antigen level is a significant predictor of treatment success for postoperative radiotherapy in patients with prostate cancer.

BACKGROUND: The optimal role of postoperative radiotherapy for patients with prostate cancer remains undefined. MATERIALS AND METHODS: The medical records of 70 patients (median age: 66 years), who had received radical radiotherapy (RT) between the years 1996 and 2004 after radical prostatectomy (RP), were analyzed. Fifteen patients had received immediate adjuvant RT, while the other 55 patients had received salvage therapy. Hormonal therapy had been performed in 28 patients before RT and continued in two of them concurrently with RT. A median dose of 60 Gy was delivered to the prostate bed. Pelvic node irradiation was performed in all patients. RESULTS: After a median follow-up period of 23 months, 21 patients had experienced biochemical failure. Actuarial 3- and 5-year biochemical relapse-free survival estimates were 67.4%. No patient had local failure, although distant metastases with biochemical failure were found in five patients. On univariate analysis, the following were significant for biochemical failures: seminar vesicle involvement, serum PSA level >1 ng/ml before RT, pathological pelvic node involvement, RT indication (adjuvant vs. salvage) and Gleason score. However, only the serum PSA level before RT was significant on multivariate analysis. CONCLUSION: Postoperative RT with a pre-RT PSA level <0.1 ng/ml seemed to be effective in patients with prostate cancer.

Development of food grade media for the preparation of Lactobacillus plantarum starter culture.

Based on MRS medium, two types of food grade (FG) culture media (FG medium I and FG medium II) for the preparation of a concentrated starter culture of Lactobacillus plantarum NRIC 0380 to manufacture a new type of instant Chinese noodle, the fermented instant Chinese noodle, were developed using FG materials. FG medium I, which is for normal static culture, contains table sugar (sucrose), Yeast peptone standard type F, Sunsoft Q-17S (emulsifier), sodium acetate, trisodium citrate and MnSO(4).4-5H(2)O. FG medium II was designed to be used for the pH-controlled jar fermentor culture conditions. Therefore, sodium acetate and trisodium citrate as a buffer to prevent acidification of medium were omitted from FG medium I. When L. plantarum NRIC 0380 was cultured under the pH-controlled jar fermentor culture conditions, the kinetics of growth, sugar consumption and lactic acid production in FG medium II were quite similar to those observed in the Difco Lactobacilli MRS Broth. Furthermore, growths of many lactobacilli strains isolated from various fermented foods in FG medium I were also quite similar to those observed in MRS medium. Therefore, simple and practical FG media for the culture of lactobacilli were successfully established.

Hemostatic abnormalities and changes following bone marrow transplantation.

Hemostatic parameters were examined in 39 patients who underwent allogeneic bone marrow transplantation (BMT). Twenty-six patients survived and 13 patients died within 6 months after BMT. The main causes of death were acute graft-versus-host disease (GVHD: n=6), veno-occlusive disease (VOD: n=2), and thrombotic microangiopathy (TMA: n=2). Plasma levels of D-dimer and thrombomodulin (TM) were significantly elevated in the non-survivor group. Plasma levels of soluble fibrin (SF) and Fas were significantly elevated in the non-survivor group at 1 to 4 weeks after BMT. Plasma levels of thrombin-antithrombin complex (TAT), D-dimer, and tissue plasminogen activator-plasminogen activator inhibitor-1 complex (tPA-PAI-1 complex) were significantly elevated in patients with complications after BMT. Plasma levels of TAT, D-dimer, and tPA-PAI-1 complex were significantly elevated in patients with GVHD. These results suggest that abnormalities of hemostatic parameters might predict poor outcomes or complications in patients with BMT.