Propolis Extract Regulates microRNA Expression in Glioblastoma and Brain Cancer Stem Cells.

BACKGROUND: Grade IV gliomas are classified as glioblastoma (GBM), which is the most malignant brain cancer type. Various genetic and epigenetic mechanisms play a role in the initiation and progression of GBM. MicroRNAs (miRNAs) are small, non-coding RNA molecules that belong to the main epigenetic regulatory RNA class that plays different roles in either physiological or pathological conditions, including GBM pathogenesis regulating expression levels of the target genes. Brain Cancer Stem Cells (BCSCs) are responsible for poor prognosis, including therapy resistance and relapse. Epigenetic regulation mediated by miRNAs is also a critical component of BCSC selfrenewal and differentiation properties. Propolis is a resinous substance collected by honey bees from various plant sources. The flavonoid content of propolis varies depending on the collection region and the extraction method. Although there are studies that include the effects of different originated-propolis on the miRNA expression levels of the glioblastoma cells, the impact on the BCSCs has not been studied yet. OBJECTIVE: This study aims to evaluate the effects of propolis obtained from Aydin, a city in western Turkey, on miRNA expression levels of BCSCs and GBM cells. METHODS: Aydin propolis was dissolved in 60% ethanol, and after evaporation, distilled water was added to prepare the propolis stock solution. The flavonoids content of the Aydin propolis was determined by MS Q-TOF analysis. Commercially obtained U87MG and BCSCs were used as in-vitro brain cancer models. Cytotoxic and apoptotic effects of Aydin propolis were determined via WST-1 assay and Annexin V test, respectively. The miRNA expression profile was investigated using the real-time qRT-PCR method. The fold changes were calculated by the2-ΔΔCt method. The miRNA-mRNA-pathway interactions, including significantly altered miRNAs, were determined using different bioinformatics tools and databases. RESULTS: Quercetin 3-methyl ether was the main component of the Aydin propolis. Aydin propolis did not show significant cytotoxic and apoptotic effects on both GBM and BCSCs up to 2mg/ml concentration. Aydin propolis treatment decreased the expression of nine miRNAs in the U87MG and five miRNAs in the BCSCs. Moreover, ten miRNAs have upregulated from 2.22 to 10.56 folds in propolis treated GBM cells compared to the control group significantly (p<0.05). In the study, the potential roles of two new miRNAs, whose regulations in glioma were not previously defined, were identified. One of them was miR-30d-5p, a novel potential oncomiR in GBM, which was 2.46 folds downregulated in Aydin propolis treated GBM cells. The other one is miR-335-5p, which is a potential tumor suppressor miR in GBM, that was 5.66 folds upregulated in Aydin propolis treated GBM cells. FOXO pathway, its upstream and downstream regulators, and critically neuronal developmental regulators, NOTCH and WNT pathways, were determined as the most deregulated pathways in Aydin propolis treated cells. CONCLUSION: The determination of the anti-cancer effect of Aydin propolis on the miRNA expression of GBM, especially on cancer stem cells, may contribute to the elucidation of brain cancer genetics by supporting further analyses.

Investigation the effect of Hypericum perforatum on corneal alkali burns.

Purpose: To investigate the effect of Hypericum perforatum on corneal alkali burn. Methods: We studied 45 250 g weighing, 4 months old Wistar albino rats. Alkaline burns were performed in the corneas of all experimental animals with 2 mol/L NaOH after general anaesthesia. Rats were divided into five groups according to the subsequent process applied to them: group 1 was the topical Hypericum perforatum group, group 2 was the topical pure olive oil group, group 3 was the oral Hypericum perforatum group, group 4 was the oral pure olive oil group, and group 5 was the control untreated group. Rats were sacrificed under general anaesthesia on the 14 day. The rate of corneal inflammation, neovascularization, fibroblastic activity, and cluster of differentiation 31 (CD31) staining was investigated. Result: There were 45 rats at the beginning of the study. One rat in groups 1, 2, and 3 died during the study; therefore, 42 rats could be evaluated. There were 8 rats in group 1, 8 rats in group 2, 8 rats in group 3, and 9 rats in group 4. We found less corneal neovascularization (CNV), inflammation, and fibroblastic activity in group 1 and group 2 than in the other groups (p ˂ 0.001 for all parameters). CNV, inflammation, fibroblastic activity, and CD31 staining rates were lower in group 1 than in group 2 (p ˂ 0.001 for all parameters). There was no difference between groups 3, 4, and 5 (respectively, p = 0.436, 0.634, and 0.750). Conclusions: We found that both topical Hypericum perforatum oily extract and olive oil have anti-inflammatory, anti-angiogenic, and anti-fibroblastic effects when applied after corneal alkali burns in rat corneas. Further studies should be conducted in this field.

Bimonthly regimen of high-dose leucovorin, infusional 5-fluorouracil, docetaxel, and cisplatin (modified DCF) in advanced gastric adenocarcinoma.

BACKGROUND: The combination of docetaxel, cisplatin, and 5-fluorouracil (DCF) is an effective but highly toxic regimen for the treatment of advanced gastric cancer. To improve tolerability while maintaining the efficacy of the DCF regimen, we developed a modified DCF regimen including an infusional 5-fluorouracil administration according to the de Gramont regimen. METHODS: In this study, 70 patients with advanced gastric cancer were treated. Each 2-week cycle consisted of docetaxel (60 mg/m(2)), cisplatin (50 mg/m(2)), a 5-fluorouracil (400 mg/m(2)) i.v. bolus, and 5-fluorouracil (2,400 mg/m(2)) i.v. over 46 h plus leucovorin (400 mg/m(2)) i.v. over 2 h. RESULTS: The median progression-free survival and overall survival were 9.0 months (95% CI, 7.1-10.9) and 10.8 months (95% CI, 7.4-14.2), respectively; the 1-year and 2-year overall survival rates were 46.3 and 18.4%, respectively. Twenty-nine (41.4%) partial responses, 19 (27.1%) stable disease, and 22 (31.4%) progression of disease were observed. Grade 3-4 toxicities included neutropenia (37.1%), febrile neutropenia (15.7%), thrombocytopenia (10.0%), anemia (8.6%), nausea and vomiting (10.0%), stomatitis (5.7%), infection (8.6%), and diarrhea (2.9%). CONCLUSIONS: Our results show that a de Gramont-based DCF regimen may have tolerable toxicities and be an effective and convenient palliative treatment for advanced gastric cancer.

Bimonthly regimen of high-dose leucovorin, infusional 5-fluorouracil, epirubicin and cisplatin (modified ECF) as adjuvant chemotherapy in resected gastric adenocarcinoma.

BACKGROUND: The administration of the de Gramont regimen in combination with cisplatin and epirubicin (modified ECF) has previously been reported as a treatment for advanced gastric cancer, but here we report this regimen combination in an adjuvant setting for the first time. METHODS: Forty-eight patients with curatively resected gastric cancer were treated. Each 2-week cycle consisted of epirubicin (50 mg/m(2)), cisplatin (50 mg/m(2)), 5-fluorouracil (5-FU) IV bolus (400 mg/m(2)) and 5-FU IV (2,400 mg/m(2)) over 46 h plus leucovorin IV (400 mg/m(2)) over 2 h. Postoperative chemoradiotherapy was also administered to the patients when indicated. We retrospectively reviewed the patients who were treated with modified ECF. RESULTS: The median disease-free survival (DFS) was 40.7 months and the 1-, 3- and 5-year DFS rates were 78.5, 55.7 and 44.6%, respectively. The most common grade 3-4 toxicities were hematological and gastrointestinal. CONCLUSION: A modified ECF regimen may be an effective and convenient treatment with tolerable toxicities for the adjuvant treatment of gastric cancer. It may provide an alternative regimen to the standard ECF when a continuous ambulatory infusion pump is not feasible or not preferred by the patient.

Idiopathic chylous ascites treated with total parenteral nutrition and octreotide. A case report and review of the literature.

Chylous ascites is the accumulation of lipid-rich lymph in the peritoneal cavity. The usual cause in adults is lymphatic obstruction or leakage caused by malignancy. Non-malignant causes include postoperative trauma, cirrhosis, tuberculosis, pancreatitis and filariasis. A variety of treatment options have been proposed for the management of chylous ascites; however, their effectiveness in idiopathic or primary form is unknown. Here we report a case of chylous acid rapidly resolved with the treatment of fasting, total parenteral nutrition and somatostatin analogue.

Evaluation of the efficacy of modified De Gramont and modified FOLFOX4 regimens for adjuvant therapy of locally advanced rectal cancer.

OBJECTIVE: To evaluate the efficacy of modified De Gramont (mDG) and FOLFOX4 (mFOLFOX4) regimens in patients with locally advanced rectal cancer (LARC). METHODS: Patients that received adjuvant chemotherapy (CT) for the treatment of LARC (stage II and III) were retrospectively evaluated. RESULTS: A total of 231 patients were examined. Median age was 58 (range, 18-83) and, of these patients, 36 (15.6%) had stage II and 195 (84.4%) had stage III disease. While the patients with stage II disease received only mDG regimen (36, 100.0%), of the patients with stage III disease, 71 (36.5%) received mDG and 124 (63.5%) received mFOLFOX4 regimen. Patients with stage III disease showed recurrences more often, but this difference was not statistically significant. Similarly, for the patients with stage III disease, there was no statistically significant relation between the adjuvant CT regimen received and the rate of recurrence. In patients with stage II disease, who received mDG, median DFS was 101 months and median OS was 106 months. For the patients with stage III disease, the patients that received mDG showed a median DFS of 78 months and a median OS of 96 months, while the patients that received mFOLFOX4 had a median DFS of 51 months and a median OS of 78 months. Although, for the patients with stage III disease, there are major differences between the two different regimens of CT in terms of DFS and OS, this difference was not statistically significant.When the results were evaluated from the perspective of toxicity, the patients that received mFOLFOX4 showed more toxicity. Neurotoxicity, which was seen in the patients that were given mFOLFOX4, was the most prominent toxicity. CONCLUSIONS: mDG and mFOLFOX4 regimens are applicable regimens as adjuvant CT for the treatment of LARC.

Irinotecan combined with infusional 5-fluorouracil and high-dose leucovorin for the treatment of advanced gastric carcinoma as the first-line chemotherapy.

BACKGROUND: Because of insufficient activity and high toxicity of current chemotherapy regimens in advanced gastric cancer (AGC), there is a need for newer regimens. METHODS: Twenty-five chemonaive patients with AGC have been treated with FOLFIRI regimen consisting of irinotecan 180 mg/m(2) over 30 min on day 1 combined with leucovorin 200 mg/m(2) over 2 h followed by 5-fluorouracil 400 mg/m(2) as bolus and 600 mg/m(2) as a 22-hour infusion on day 1 and 2. The treatment was administered every 14th day until progression or intolerable toxicity. RESULTS: Twenty-five patients (17 male, 8 female; 22 patients with PS 0-1 and 3 patients with PS 2), median age 54 (range 25-77), received a total of 230 courses of chemotherapy (median 9; range 1-18). Objective responses were observed in 9 patients (36%), all being partial. Median progression-free survival, 1- and 2-year progression-free survival rates were 8.6 months, 28.4% and 15.3%, respectively. Median overall survival, 1- and 2-year overall survival rates were 11.6 months, 48.0% and 17.8%, respectively. As serious adverse events, grade 3-4 neutropenia was observed in 5 patients (20.0%), grade 3 diarrhea in 4 patients (16.0%). No treatment-related death occurred. CONCLUSION: FOLFIRI regimen is an active regimen with acceptable toxicity for the treatment of AGC.

Gemcitabine combined with infusional 5-fluorouracil and high-dose leucovorin for the treatment of advanced carcinoma of the pancreas.

BACKGROUND: 5-Fluorouracil (5-FU) and gemcitabine are the major active drugs in the treatment of pancreatic cancer. METHODS: Twenty-two patients with advanced pancreas cancer were treated with a new chemotherapy regimen consisting of infusional 5-FU and high-dose leucovorin with gemcitabine (GEMFUFOL). RESULTS: A total of 200 cycles of chemotherapy were administered. The response rate was 27.3%, all responses being partial. The median survival time and 1-year survival rate were, respectively, 13 months and 60.4%. The toxicity was very low and severe hematological toxicity was exceptional. CONCLUSION: The GEMFUFOL regimen can be an active regimen for the treatment of advanced pancreatic cancer and has a low toxicity.