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Background: Noninvasive brain stimulation (NBS) using repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) has recently been adopted for modulating motor function in stroke patients. Objective:We investigated the effect of simultaneous dual-mode stimulation using rTMS and tDCS over the bilateral primary motor cortices (M1) to assess its efficacy as compared to single stimulation using rTMS for the recovery of motor function in subacute stroke patients. Methods: Thirty subacute stroke patients were recruited in this study. In the dual-mode stimulation group, 10 Hz rTMS (90% of resting motor threshold, 1,000 pulses) was applied over the ipsilesional M1 for 20 minutes with the simultaneous application of cathodal tDCS (2 mA) on the contralesional M1. The single stimulation group underwent 10 Hz rTMS without tDCS. Ten daily sessions were conducted for two consecutive weeks. The total Fugl-Meyer (FMA-T), upper limb (FMA-UL), and lower limb (FMA-LL) scores were measured before, after, and two months later. Results: The FMA-T and FMA-UL were significantly improved over time in both the dual and single stimulation group (p < 0.05). However, there were significant group and time interaction effects in both the FMA-T and FMA-UL (p < 0.05). Post-hoc analysis showed that the mean changes in the FMA-T and FMA-UL were significantly better in the dual-mode stimulation group. Conclusion: Dual-mode NBS with the simultaneous application of 10 Hz rTMS and cathodal tDCS over the bilateral M1s was safe and superior to 10 Hz rTMS alone for improving motor function in subacute stroke patients. [ABSTRACT FROM AUTHOR]

Gastric cancer is the second leading cause of cancer-related deaths worldwide. In advanced and metastatic gastric cancer, the conventional chemotherapy with limited efficacy shows an overall survival period of about 10 months. Patient specific and effective treatments known as personalized cancer therapy is of significant importance. Advances in high-throughput technologies such as microarray and next generation sequencing for genes, protein expression profiles and oncogenic signaling pathways have reinforced the discovery of treatment targets and personalized treatments. However, there are numerous challenges from cancer target discoveries to practical clinical benefits. Although there is a flood of biomarkers and target agents, only a minority of patients are tested and treated accordingly. Numerous molecular target agents have been under investigation for gastric cancer. Currently, targets for gastric cancer include the epidermal growth factor receptor family, mesenchymal-epithelial transition factor axis, and the phosphatidylinositol 3-kinase--AKT--mammalian target of rapamycin pathways. Deeper insights of molecular characteristics for gastric cancer has enabled the molecular classification of gastric cancer, the diagnosis of gastric cancer, the prediction of prognosis, the recognition of gastric cancer driver genes, and the discovery of potential therapeutic targets. Not only have we deeper insights for the molecular diversity of gastric cancer, but we have also prospected both affirmative potentials and hurdles to molecular diagnostics. New paradigm of transdisciplinary team science, which is composed of innovative explorations and clinical investigations of oncologists, geneticists, pathologists, biologists, and bio-informaticians, is mandatory to recognize personalized target therapy. [ABSTRACT FROM AUTHOR]

We recently proposed a metabolic engineering strategy for l-ornithine production based on the hypothesis that an increased intracellular supply of N-acetylglutamate may further enhance l-ornithine production in a well-defined recombinant strain of Corynebacterium glutamicum. In this work, an argJ-deficient arginine auxotrophic mutant of C. glutamicum is suppressed by a different locus of C. glutamicum ATCC13032. Overexpression of the NCgl1469 open reading frame (ORF), exhibiting N-acetylglutamate synthase (NAGS) activity, was able to complement the C. glutamicum arginine-auxotrophic argJ strain and showed increased NAGS activity from 0.03 to 0.17 units mg protein. Additionally, overexpression of the NCgl1469 ORF resulted in a 39% increase in excreted l-ornithine. These results indicate that the intracellular supply of N-acetylglutamate is a rate-limiting step during l-ornithine production in C. glutamicum. [ABSTRACT FROM AUTHOR]

Background: The aim of this clinical study was to evaluate the efficacy of combination chemotherapy of oxaliplatin, leucovorin and continuous-infusion 5-fluorouracil (5-FU) for advanced gastric cancer. Methods: Patients with previously untreated gastric cancer with measurable disease received oxaliplatin (100 mg/m2, day 1), followed by leucovorin (100 mg/m2, day 1) and 5-FU (2,400 mg/m2, days 1–2), which was repeated every 2 weeks. The primary endpoint was overall response rate (ORR) and secondary endpoints were progression-free survival (PFS), overall survival (OS) and toxicity. Results: Forty-eight patients were enrolled, and 45 were evaluable for response. A total of 320 cycles of chemotherapy were administered (median 6 cycles per patient). One complete response (2.1%) and 19 partial responses (39.6%) were noted, resulting in an ORR of 41.7% (95% confidence interval, CI: 27.7–55.6%) by intent-to-treat analysis. With a median follow-up duration of 22 months, the median PFS was 5.3 (95% CI: 2.8–7.8) months and the median OS was 13.6 (95% CI: 9.3–17.9) months. There was 1 treatment-related death, and the most common grade 3/4 toxicity was neutropenia (36.1%). Three patients discontinued treatment because of serum creatinine elevation. Conclusion: This study reaffirms the efficacy of oxaliplatin in advanced gastric cancer, but its dose of 100 mg/m2 remains to be reconsidered in Korean patients. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: We conducted a phase II study to assess the efficacy and tolerability of docetaxel and epirubicin as salvage chemotherapy in advanced/metastatic gastric cancer patients with documented progression after 5-fluorouracil/platinum-based combination chemotherapy. Methods: Docetaxel 75 mg/m2 and epirubicin 50 mg/m2 were administered on days 1 and 2, respectively, every 3 weeks. Treatment continued until progression of disease or until a life-threatening adverse event occurred. The primary objectives of this study were to evaluate the safety profile and response rate to this treatment regimen. Results: Thirty-four patients were enrolled in the study. Twenty-six patients had locally advanced or metastatic disease at the time of diagnosis, and 8 patients had recurrent disease after surgical resection of the primary tumor. A total of 157 chemotherapy cycles were administered. Seven (21.8%) patients had a partial response and 12 (37.5%) patients had stable disease. The median time to progression and overall survival were 4.1 and 13.4 months, respectively. Grade III/IV hematologic toxicities included neutropenia in 16 patients (47%) and febrile neutropenia in 8 patients (24%). Nonhematologic toxicities were rare. Conclusion: A combination of chemotherapy with docetaxel and epirubicin showed moderate activity as salvage treatment in advanced/metastatic gastric cancer, especially in patients who had responded to prior chemotherapy. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Studies the expression of genes encoding group I alcohol dehydrogenases in the yeast Pichia stipitis. Regulation PsADH1 expression and dependence on oxygen limitation; Effect of heme addition on ADH1 expression in oxygen-limited cells; Effect of PsADH1 disruption on PsADH2 expression; Promoter region of PsADH1.

It was previously shown that fruiting bodies of the mushroom, Flammulina velutipes, exert anti-tyrosinase activity by producing a triacylglycerol characterized as 1′,3′-dilinolenoyl-2′-linoleoylglycerol (LnLLn). In this study, we provide evidence that the mycelia of F. velutipes grown on glucose, but not on glycerol, exhibit anti-tyrosinase activity. To identify genes possibly involved in the process of expressing anti-tyrosinase activity in F. velutipes, a reverse transcription-polymerase chain reaction (RT-PCR) method that involves annealing control primers (ACPs) was employed. Using 120 ACPs, a total of 84 differentially expressed genes (DEGs) in F. velutipes mycelia with anti-tyrosinase activity were cloned and sequenced. Basic Local Alignment Search Tool (BLAST) searches revealed that 72 of the genes have known sequence homology. Of these, three genes involved in the synthesis and modification of fatty acids were selected and further quantified by real-time RT-PCR. These genes involved in fatty acid-biosynthetic processes can be potential candidates for further studies related to the development of a new anti-browning agent. [ABSTRACT FROM AUTHOR]

Purpose: To identify baseline prognostic factors for survival in patients with disease progression, during or after chemotherapy for the treatment of advanced gastric or gastroesophageal junction (GEJ) cancer. Materials and Methods: We pooled data from patients randomized between 2009 and 2012 in 2 phase III, global double-blind studies of ramucirumab for the treatment of advanced gastric or GEJ adenocarcinoma following disease progression on first-line platinum- and/or fluoropyrimidine-containing therapy (REGARD and RAINBOW). Forty-one key baseline clinical and laboratory factors common in both studies were examined. Model building started with covariate screening using univariate Cox models (significance level=0.05). A stepwise multivariable Cox model identified the final prognostic factors (entry+exit significance level=0.01). Cox models were stratified by treatment and geographic region. The process was repeated to identify baseline prognostic quality of life (QoL) parameters. Results: Of 1,020 randomized patients, 953 (93%) patients without any missing covariates were included in the analysis. We identified 12 independent prognostic factors of poor survival: 1) peritoneal metastases; 2) Eastern Cooperative Oncology Group (ECOG) performance score 1; 3) the presence of a primary tumor; 4) time to progression since prior therapy <6 months; 5) poor/unknown tumor differentiation; abnormally low blood levels of 6) albumin, 7) sodium, and/or 8) lymphocytes; and abnormally high blood levels of 9) neutrophils, 10) aspartate aminotransferase (AST), 11) alkaline phosphatase (ALP), and/or 12) lactate dehydrogenase (LDH). Factors were used to devise a 4-tier prognostic index (median overall survival [OS] by risk [months]: high=3.4, moderate=6.4, medium=9.9, and low=14.5; Harrell's C-index=0.66; 95% confidence interval [CI], 0.64-0.68). Addition of QoL to the model identified patient-reported appetite loss as an independent prognostic factor. Conclusions: The identified prognostic factors and the reported prognostic index may help clinical decision-making, patient stratification, and planning of future clinical studies. [ABSTRACT FROM AUTHOR]

Purpose: Gastric cancer is the second leading cause of cancer-related death worldwide. Although surgery is the standard curative treatment for gastric cancer, relapse occurs in a large number of patients, except in the case of early diagnosed gastric cancer. Following previous studies that identified endoplasmic reticulum oxidoreductin 1-? (ERO1L) as a potential marker for gastric cancer, we investigated the functional role of ERO1L in gastric cancer. Materials and Methods: For validation of microarray data, the mRNA expression level of ERO1L was measured by quantitative real-time reverse transcription polymerase chain reaction in 56 independent stage III gastric cancer patients. Immunohistochemical staining was performed to examine the protein expression level of ERO1L in 231 gastric cancer patients. Correlation between gene expression and cancer prognosis was evaluated. Results: Patients with high ERO1L expression had poorer survival than those with low expression (p < 0.01). Functional assays demonstrated that ERO1L knockdown inhibited cell proliferation, migration, invasion, and chemoresistance. In addition, involvement of inactivation of Akt and JNK signaling in molecular mechanisms of ERO1L inhibition was demonstrated. Conclusion: High expression of ERO1L is associated with poor prognosis of patients with gastric cancer. These results indicate that ERO1L expression may be a clinically promising therapeutic target for prevention of gastric cancer. [ABSTRACT FROM AUTHOR]

Purpose This study was conducted to validate the survival benefit of metastasectomy plus chemotherapy over chemotherapy alone for treatment of Krukenberg tumors from gastric cancer and to identify prognostic factors for survival. Materials and Methods Clinical data from 216 patients with Krukenberg tumors from gastric cancer were collected. Patients were divided into two arms according to treatment modality: arm A, metastasectomy plus chemotherapy and arm B, chemotherapy alone. Results Overall survival (OS) was significantly increased in arm A relative to arm B for patients initially diagnosed with stage IV gastric cancer (18.0 months vs. 8.0 months; p < 0.001) and those with recurrent Krukenberg tumors (19.0 months vs. 9.0 months; p=0.002), respectively. Metastasectomy (hazard ratio [HR], 0.458; 95% confidence interval [CI], 0.287 to 0.732; p=0.001), signet-ring cell pathology (HR, 1.583; 95% CI, 1.057 to 2.371; p=0.026), and peritoneal carcinomatosis (HR, 3.081; 95% CI, 1.610 to 5.895; p=0.001) were significant prognostic factors for survival. Conclusion Metastasectomy plus chemotherapy offers superior OS when compared to palliative chemotherapy alone in gastric cancer with Krukenberg tumor. Prolonged survival applies to all patients, regardless of gastric cancer stage. Metastasectomy, signet-ring cell pathology, and peritoneal carcinomatosis were prognostic factors for survival. Future prospective randomized trials are needed to confirm the optimal treatment strategy for Krukenberg tumors from gastric cancer. [ABSTRACT FROM AUTHOR]

Purpose The purpose of this study is to retrospectively compare the efficacy and tolerability between three regimens for first-line chemotherapy--gemcitabine plus capecitabine (GEM-X), gemcitabine plus erlotinib (GEM-T), and gemcitabine monotherapy (GEM)--in patients with advanced pancreatic cancer. Materials and Methods There was a total of 127 patients who underwent chemotherapy for pancreatic cancer between January 2007 and November 2011 at our institution. Patients were treated with either GEM (gemcitabine 1,000 mg/m2 on days 1, 8, and 15 every 4 weeks), GEM-T (gemcitabine 1,000 mg/m2 on days 1 and 8 every 3 weeks and erlotinib 100 mg daily), or GEM-X (gemcitabine 1,000 mg/m2 on days 1 and 8 every 3 weeks and capecitabine 850 mg/m2 twice daily for 2 weeks followed by 1 week's rest) as the first-line treatment. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and toxicity were evaluated. Results The patient population was divided into groups depending on their first-line treatment: GEM (n=47), GEM-T (n=44), and GEM-X (n=36). GEM-X significantly improved ORR (21.2% vs. 12.7% and 15.9%), PFS (8.9 vs. 5.2 and 3.9 months; p < 0.001), and OS (12.1 vs. 10.4 and 9.9 months; p = 0.03) compared to GEM and GEM-T, respectively. There were higher incidences of some non-hematologic adverse events with GEM-X and GEM-T compared to GEM, but most were grade 1 or 2. Conclusion GEM-X presented better clinical efficacy and acceptable tolerability than GEM-T and GEM in advanced pancreatic cancers. It is worthy to further investigate which agent has a clinical advantage as a combination drug with gemcitabine in pancreatic cancer and to explore the predictive markers leading to personalize anti-cancer treatment. [ABSTRACT FROM AUTHOR]

Although gastric cancer is quite common in Korea, the treatment outcome is relatively favorable compared to those in western countries. However, there are currently no Korean multidisciplinary guidelines for gastric cancer. Experts from related societies developed guidelines de novo to meet Korean circumstances and requirements, including 23 recommendation statements for diagnosis (n=9) and treatment (n=14) based on relevant key questions. The quality of the evidence was rated according to the GRADE evidence evaluation framework: the evidence levels were based on a systematic review of the literature, and the recommendation grades were classified as either strong or weak. The applicability of the guidelines was considered to meet patients' view and preferences in the context of Korea. The topics of the guidelines cover diagnostic modalities (endoscopy, endoscopic ultrasound, and radiologic diagnosis), treatment modalities (surgery, therapeutic endoscopy, chemotherapy, and radiotherapy), and pathologic evaluation. An external review of the guidelines was conducted during the finalization phase. [ABSTRACT FROM AUTHOR]

Gastric cancer is the most common cancer in Asia and most developing countries. Despite the use of multimodality therapeutics, it remains the second leading cause of cancer death in the world. To identify the molecular underpinnings of gastric cancer in the Asian population, we applied an RNA-sequencing approach to gastric tumor and noncancerous specimens, generating 680 million informative short reads to quantitatively characterize the entire transcriptome of gastric cancer (including mRNAs and miRNAs). A multilayer analysis was then developed to identify multiple types of transcriptional aberrations associated with different stages of gastric cancer, including differentially expressed mRNAs, recurrent somatic mutations, and key differentially expressed miRNAs. Through this approach, we identified the central metabolic regulator AMP-activated protein kinase (AMPK)a as a potential functional target in Asian gastric cancer. Furthermore, we experimentally showed the translational relevance of this gene as a potential therapeutic target for early-stage gastric cancer in Asian patients. Together, our findings not only provide a valuable information resource for identifying and elucidating the molecular mechanisms of Asian gastric cancer, but also represent a general integrative framework to develop more effective therapeutic targets. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer continues to be one of the deadliest cancers in the world and therefore identification of new drugs targeting this type of cancer is thus of significant importance. The purpose of this study was to identify and validate a therapeutic agent which might improve the outcomes for gastric cancer patients in the future. Methodology/Principal Findings: Using microarray technology, we generated a gene expression profile of human gastric cancer-specific genes from human gastric cancer tissue samples. We used this profile in the Broad Institute's Connectivity Map analysis to identify candidate therapeutic compounds for gastric cancer. We found the histone deacetylase inhibitor vorinostat as the lead compound and thus a potential therapeutic drug for gastric cancer. Vorinostat induced both apoptosis and autophagy in gastric cancer cell lines. Pharmacological and genetic inhibition of autophagy however, increased the therapeutic efficacy of vorinostat, indicating that a combination of vorinostat with autophagy inhibitors may therapeutically be more beneficial. Moreover, gene expression analysis of gastric cancer identified a collection of genes (ITGB5, TYMS, MYB, APOC1, CBX5, PLA2G2A, and KIF20A) whose expression was elevated in gastric tumor tissue and downregulated more than 2-fold by vorinostat treatment in gastric cancer cell lines. In contrast, SCGB2A1, TCN1, CFD, APLP1, and NQO1 manifested a reversed pattern. Conclusions/Significance: We showed that analysis of gene expression signature may represent an emerging approach to discover therapeutic agents for gastric cancer, such as vorinostat. The observation of altered gene expression after vorinostat treatment may provide the clue to identify the molecular mechanism of vorinostat and those patients likely to benefit from vorinostat treatment. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to evaluate the outcome of adjuvant therapy on the overall survival (OS) and disease-free survival (DFS) after curative resection (RO) of patients with TNM stage II gallbladder (GB) cancer. Methods: A total of 160 patients who had received curative resection (RO) between January 2000 and December 2009 were retrospectively reviewed. Among 61 stage II GB cancer patients, 43 received adjuvant therapy, while 18 others received surgery alone. The median follow-up period was 27.3 months (range 2.2-98.9 months). Results: OS was not significantly different among the adjuvant therapies (p = 0.180), but DFS was (p = 0.033). The 3-year OS and DFS from surgery alone, adjuvant chemotherapy, adjuvant radiotherapy, and adjuvant concurrent chemo-radiotherapy were 64, 78, 36 and 36%, and 56, 69, 14 and 47%, respectively. Overall, the chemotherapy group had a better prognosis, although there were no significant differences. Conclusions: The data from this study do not provide evidence that adjuvant therapy is an effective treatment option for curative resected GB cancer. A large randomized controlled study is necessary to confirm the efficacy of adjuvant therapy. Newer adjuvant studies should be focused on gemcitabine-based chemotherapy or chemo-radiotherapy with molecular-based target agents. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Despite many attempts to establish pre-treatment prognostic markers to understand the clinical biology of esophageal adenocarcinoma (EAC), validated clinical biomarkers or parameters remain elusive. We generated and analyzed tumor transcriptome to develop a practical biomarker prognostic signature in EAC. Methodology/Principal Findings: Untreated esophageal endoscopic biopsy specimens were obtained from 64 patients undergoing surgery and chemoradiation. Using DNA microarray technology, genome-wide gene expression profiling was performed on 75 untreated cancer specimens from 64 EAC patients. By applying various statistical and informatical methods to gene expression data, we discovered distinct subgroups of EAC with differences in overall gene expression patterns and identified potential biomarkers significantly associated with prognosis. The candidate marker genes were further explored in formalin-fixed, paraffin-embedded tissues from an independent cohort (52 patients) using quantitative RT-PCR to measure gene expression. We identified two genes whose expression was associated with overall survival in 52 EAC patients and the combined 2-gene expression signature was independently associated with poor outcome (P<0.024) in the multivariate Cox hazard regression analysis. Conclusions/Significance: Our findings suggest that the molecular gene expression signatures are associated with prognosis of EAC patients and can be assessed prior to any therapy. This signature could provide important improvement for the management of EAC patients. [ABSTRACT FROM AUTHOR]

This open-label, multicenter phase II study was conducted to investigate the efficacy and safety of capecitabine plus gemcitabine combination chemotherapy as first-line treatment in patients with locally advanced or metastatic pancreatic cancer. We enrolled 63 patients who received capecitabine 830 mg/m2 orally twice daily on days 1–21 plus gemcitabine 1000 mg/m2 as a 30-min infusion on days 1, 8 and 15 every 4 weeks for up to six cycles. A total of 14 patients had partial responses giving an overall response rate of 22% (95% confidence interval [CI] 13–34%) in the intent-to-treat population. The median time to progression and overall survival were 3.9 months (95% CI 3.5–5.7) and 7.5 months (95% CI 5.0–10.0), respectively, and 1-year survival rate was 27.1% in the intent-to-treat population. Capecitabine plus gemcitabine was well tolerated. Grade 3 hematological adverse events were neutropenia (21%) and thrombocytopenia (2%); the only grade 4 hematological events were anemia (2%) and neutropenia (6%). Non-hematological adverse events were mainly gastrointestinal events and hand–foot syndrome, which affected 16% of patients. Grade 3/4 non-hematological events were infrequent. The combination of capecitabine plus gemcitabine appears to be active and well tolerated as first-line treatment in patients with advanced/metastatic pancreatic cancer. [ABSTRACT FROM AUTHOR]

Determines whether homology-dependent gene silencing or cosuppression mechanisms underlie copy number control of Ty1 retrotransposition. Introduction of an active Ty1 element into a naive strain; Suggestion that Ty1 cosuppression can occur posttranscriptionally, either prior to or during reverse transcription; Ty1-less derivatives; Evidence that additional chromosomal Ty1 elements affect Ty1 transposition.