Fraxetin reduces endometriotic lesions through activation of ER stress, induction of mitochondria-mediated apoptosis, and generation of ROS.

BACKGROUND: Fraxetin, a phytochemical obtained from Fraxinus rhynchophylla, is well known for its anti-inflammatory and anti-fibrotic properties. However, fraxetin regulates the progression of endometriosis, which is a benign reproductive disease that results in low quality of life and infertility. HYPOTHESIS/PURPOSE: We hypothesized that fraxetin may have therapeutic effects on endometriosis and aimed to elucidate the underlying mechanisms of mitochondrial function and tiRNA regulation. STUDY DESIGN: Endometriotic animal models and cells (End1/E6E7 and VK2/E6E7) were used to identify the mode of action of fraxetin. METHODS: An auto-implanted endometriosis animal model was established and the effects of fraxetin on lesion size reduction were analyzed. Cell-based assays including proliferation, cell cycle, migration, apoptosis, mitochondrial function, calcium efflux, and reactive oxygen species (ROS) were performed. Moreover, fraxetin signal transduction was demonstrated by western blotting and qPCR analyses. RESULTS: Fraxetin inhibited proliferation and migration by inactivating the P38/JNK/ERK mitogen-activated protein kinase (MAPK) and AKT/S6 pathways. Fraxetin dissipates mitochondrial membrane potential, downregulates oxidative phosphorylation (OXPHOS), and disrupts redox and calcium homeostasis. Moreover, it triggered endoplasmic reticulum stress and intrinsic apoptosis. Furthermore, we elucidated the functional role of tiRNAHisGTG in endometriosis by transfection with its inhibitor. Finally, we established an endometriosis mouse model and verified endometriotic lesion regression and downregulation of adhesion molecules with inflammation. CONCLUSION: This study suggests that fraxetin is a novel therapeutic agent that targets mitochondria and tiRNAs. This is the first study to demonstrate the mechanisms of tiRNAHisGTG with mitochondrial function and cell fates and can be applied as a non-hormonal method against the progression of endometriosis.

Alpinumisoflavone Activates Disruption of Calcium Homeostasis, Mitochondria and Autophagosome to Suppress Development of Endometriosis.

Alpinumisoflavone is an isoflavonoid extracted from the Cudrania tricuspidate fruit and Genista pichisermolliana. It has various physiological functions, such as anti-inflammation, anti-proliferation, and apoptosis, in malignant tumors. However, the effect of alpinumisoflavone is still not known in chronic diseases and other benign reproductive diseases, such as endometriosis. In this study, we examined the cell death effects of alpinumisoflavone on the endometriosis cell lines, End1/E6E7 and VK2/E6E7. Results indicated that alpinumisoflavone inhibited cell migration and proliferation and led to cell cycle arrest, depolarization of mitochondria membrane potential, apoptosis, and disruption of calcium homeostasis in the endometriosis cell lines. However, the cellular proliferation of normal uterine epithelial cells was not changed by alpinumisoflavone. The alteration in Ca2+ levels was estimated in fluo-4 AM-stained End1/E6E7 and VK2/E6E7 cells after alpinumisoflavone treatment with or without calcium inhibitor, 2-aminoethoxydiphenyl borate (2-APB). The results indicated that a combination of alpinumisoflavone and a calcium inhibitor reduced the calcium accumulation in the cytosol of endometriosis cells. Additionally, alpinumisoflavone decreased oxidative phosphorylation (OXPHOS) in the endometriotic cells. Moreover, protein expression analysis revealed that alpinumisoflavone inactivated AKT signaling pathways, whereas it increased MAPK, ER stress, and autophagy regulatory proteins in End1/E6E7 and VK2/E6E7 cell lines. In summary, our results suggested that alpinumisoflavone could be a promising effective management agent or an adjuvant therapy for benign disease endometriosis.

Efficacy and safety of intravenous administration of high-dose selenium for preventing chemotherapy-induced peripheral neuropathy in platinum-sensitive recurrent ovarian, fallopian or primary peritoneal cancer: study protocol for a phase III, double-blind, randomized study.

BACKGROUND: The second-line chemotherapy using paclitaxel, carboplatin, and bevacizumab for treating platinum-sensitive recurrent ovarian, fallopian or primary peritoneal cancer frequently cause chemotherapy-induced peripheral neuropathy (CIPN), which is significantly associated with deterioration of quality of life. Despite the potential of some agents to prevent and treat CIPN, and there is still a lack of evidence of the effect. Although selenium has been suggested as an antioxidant candidate to prevent CIPN, there are insufficient data regarding its effect due to its low dose by oral administration. Thus, we hypothesized intravenous administration of high-dose selenium (2,000 µg/day) at each cycle of the second-line chemotherapy would prevent and reduce CIPN in patients with platinum-sensitive recurrent ovarian, fallopian or primary peritoneal cancer. METHOD: This trial is an investigator-initiated, phase III, double-blinded, randomized controlled trial to evaluate the efficacy and safety of intravenous administration of high-dose selenium (2,000 µg/day) for preventing CIPN in patients with platinum-sensitive recurrent ovarian, fallopian or primary peritoneal cancer who receive paclitaxel, carboplatin, and bevacizumab. A total of 68 patients will be randomly assigned to the experimental and control groups at a 1:1 ratio. As the primary endpoint, the incidence rate of CIPN three months after six cycles of chemotherapy will be compared between the two groups according to the combined criteria of neuropathy using the World Health Organization-CIPN criteria and Common Terminology Criteria for Adverse Events version 5.0. As secondary endpoints, we will compare adverse events, patient-reported quality of life, and requirement of concomitant drugs for reducing CIPN between the two groups. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04201561.

Selection of patients with ovarian cancer who may show survival benefit from hyperthermic intraperitoneal chemotherapy: A systematic review and meta-analysis.

BACKGROUND: The use of hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery has been extensively studied in patients with peritoneal carcinomatosis from various malignancies. However, the effectiveness of HIPEC for ovarian cancer is still controversial. Therefore, we performed this meta-analysis to identify patients with ovarian cancer who can obtain survival benefit from HIPEC. METHODS: Articles regarding HIPEC in the MEDLINE, EMBASE, and Cochrane Library were searched till December 2018. In total, 13 case-control studies and two randomized controlled trials were included in this meta-analysis. We investigated the effect of HIPEC on disease-free survival (DFS) and overall survival (OS), and performed subgroup analyses based on the study design, adjustment of confounding variables, and quality of the study. RESULTS: HIPEC improved both DFS (hazard ratio [HR], 0.603; 95% confidence interval [CI], 0.513-0.709) and OS (HR, 0.640; 95% CI, 0.519-0.789). In cases of primary disease, HIPEC improved DFS (HR, 0.580; 95% CI, 0.476-0.706) and OS (HR, 0.611; 95% CI, 0.376-0.992). Subgroup analyses revealed that HIPEC did not improve OS but improved DFS of patients with residual tumors ≤1 cm or no visible tumors. In cases of recurrent disease, HIPEC was associated with better OS (HR, 0.566; 95% CI, 0.379-0.844) but not with DFS. Subgroup analyses also revealed similar tendencies. However, HIPEC improved DFS of patients with residual tumors ≤1 cm or no visible tumors, while it improved OS of only those with residual tumors ≤1 cm. CONCLUSIONS: HIPEC may improve DFS of patients with ovarian cancer when residual tumors were ≤1 cm or not visible. It may also improve OS of only patients with recurrent disease whose residual tumors were ≤1 cm.

Development and Validation of Ovarian Symptom Index-18 and Neurotoxicity-4 for Korean Patients with Ovarian, Fallopian Tube, or Primary Peritoneal Cancer.

PURPOSE: The purpose of this study was to develop Korean versions of the National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy (NCCN-FACT) Ovarian Symptom Index-18 (NFOSI-18) and FACT/Gynecologic Oncology Group (FACT-GOG) Neurotoxicity 4-item (NTX-4), evaluating their reliability and reproducibility. MATERIALS AND METHODS: In converting NFOSI-18 and NTX-4, the following steps were performed: forward translation, backward translation, expert review, pretest of preliminary format, and finalization of Korean versions (K-NFOSI-18 and K-NTX-4). Patients were enrolled from six institutions where each had completed chemotherapy for ovarian, tubal, or peritoneal cancer at least 1 month earlier. In addition to demographics obtained by questionnaire, all subjects were assessed via K-NFOSI-18, K-NTX-4, and a Korean version of the EuroQoL-5 Dimension. Internal structural validity and reliability were evaluated using item internal consistency, item discriminant validity, and Cronbach's α. To evaluate test-retest reliability, K-NFOSI-18 and K-NTX-4 were readministered after 7-21 days, and intraclass correlation coefficients (ICCs) were calculated. RESULTS: Of the 250 women enrolled during the 3-month recruitment period, 13 withdrew or did not respond, leaving 237 (94.8%) for the analyses. Mean patient age was 54.3±10.8 years. Re-testing was performed in 190 patients (80.2%). The total K-NFOSI-18 and K-NTX-4 scores were 49 (range, 20 to 72) and 9 (range, 0 to 16), respectively, with high reliability (Cronbach's α=0.84 and 0.89, respectively) and reproducibility (ICC=0.77 and 0.84, respectively) achieved in retesting. CONCLUSION: Both NFOSI-18 and NTX-4 were successfully developed in Korean with minimal modification. Each Korean version showed high internal consistency and reproducibility.

Effects of a Web-Based Self-Management Program on the Behavior and Blood Glucose Levels of Women with Gestational Diabetes Mellitus.

Background:Women diagnosed with gestational diabetes mellitus suffer from anxiety and depression, which make controlling blood glucose levels difficult.Introduction:This quasi-experimental study uses a nonequivalent control group pretest-posttest design to investigate the effects of a web-based self-care program on self-care behaviors, anxiety, depression, and blood glucose in patients with gestational diabetes mellitus.Methods:The subjects of the study were outpatients being treated in the Department of Endocrinology at Hospital G, located in Seoul near University C, from July 15, 2015, to December 31, 2016. The experimental and control groups contained 22 participants each. The experimental group received a 12-week web-based program and one session of nutrition education; the control group received nutrition education. Using the SPSS program, pre-post changes in blood glucose, anxiety, depression, and self-care behaviors were examined between the two groups by a repeated-measures ANOVA.Results:After the 12 weeks intervention, self-care behaviors increased in both groups, and blood glucose monitoring increased in the experimental group (p = 0.001). Anxiety in the experimental group decreased by 5.1 points but increased by 1.0 point in the control group (p = 0.048). Depression increased in both groups. Glycated hemoglobin (HbA1C) levels decreased in the experimental group but increased in the control group (p = 0.001).Discussion:In addition to reducing HbA1C and anxiety, the web-based self-care program was effective in increasing the frequency of daily blood glucose monitoring in patients with gestational diabetes mellitus.Conclusions:This study will be helpful in informing an anxiety intervention program, blood glucose control, and healthy self-care behaviors in women with gestational diabetes mellitus.

Effect of Red Ginseng on Genotoxicity and Health-Related Quality of Life after Adjuvant Chemotherapy in Patients with Epithelial Ovarian Cancer: A Randomized, Double Blind, Placebo-Controlled Trial.

We evaluated the effect of red ginseng on toxicity, health-related quality of life (HRQL) and survival after adjuvant chemotherapy in patients with epithelial ovarian cancer (EOC). A total of 30 patients with EOC were randomly assigned to placebo (n = 15) and red ginseng groups (n = 15). All patients took placebo or red ginseng (3000 mg/day) for three months. Then, we compared changes of genotoxicity, HRQL and survival between the two groups. As a result, red ginseng reduced micronuclei yield in comparison with placebo despite no difference of binucleated cells index. Although red ginseng increased serum levels of alanine aminotransferase and aspartate aminotransferase significantly, they were within the normal value. Moreover, there were no differences in adverse events between placebo and red ginseng groups. In terms of HRQL, red ginseng was associated with improved emotional functioning and decreased symptoms of fatigue, nausea and vomiting, and dyspnea, reduced anxiety and interference affecting life and improved daytime somnolence. However, there was no effect of red ginseng on prognosis of EOC. Conclusively, red ginseng may be safe and effective to reduce genotoxicity and improve HRQL despite no benefit of survival in patients with EOC who received chemotherapy.

Genistein as a Potential Anticancer Agent against Ovarian Cancer.

Genistein is known as the major component of isoflavone, which is present in high-soy diets. Genistein has received much attention because of its chemopreventive and therapeutic effects on various types of cancers. Numerous studies have shown that genistein has antineoplastic effects against ovarian cancer. Several epidemiological studies have shown that women who have high consumption of isoflavones have a relatively low incidence of ovarian cancer. Genistein inhibits ovarian carcinogenesis by pleiotropic mechanisms. A higher affinity to estrogen receptor ß is one probable explanation for its ability to reduce the risk of ovarian cancer. Genistein also targets multiple cellular signal transduction pathways associated with cell cycle regulation and apoptosis. In addition, genistein has been suggested to have antiangiogenic and antioxidant activities. Herein, we summarize recent results from epidemiological and experimental studies to identify the role of genistein in ovarian cancer. Further studies are needed to achieve conclusive results and determine the clinical applications of genistein.

Matched-case comparison for the efficacy of neoadjuvant chemotherapy before surgery in FIGO stage IB1-IIA cervical cancer.

OBJECTIVE: To evaluate whether neoadjuvant chemotherapy before surgery (NCS) is more efficient than primary surgical treatment (PST) for improving clinical outcomes in FIGO stage IB1-IIA cervical cancer. METHODS: We conducted a matched-case comparison where 61 patients treated with NCS were matched to 183 treated with PST. We compared intermediate- and high-risk factors, the need of adjuvant radiotherapy, disease recurrence and survivals between NCS and PST. Patients with ≥2 intermediate- or ≥1 high-risk factors received adjuvant concurrent chemoradiation using cisplatin-based chemotherapy. RESULTS: NCS reduced more definitely intermediate- and high-risk factors than PST in stage IIA disease in spite of little difference of them in stage IB disease (large tumor size, 25% vs. 52.4%; deep stromal invasion, 57.1% vs. 82.1%; lymphovascular space invasion, 35.7% vs. 65.5%; parametrial invasion, 17.9% vs. 41.7%; p<0.05). Moreover, ≥2 intermediate-risk factors were less common in NCS than PST despite no difference of the number of high-risk factors between the 2 treatments, which decreased the need of adjuvant radiotherapy in patients with stage IIA disease who received NCS (46.4% vs. 84.5%, p<0.01). Although there were no differences in progression-free survival and disease recurrence between the 2 treatments, NCS led to poorer overall survival than PST in stage IIA disease with no difference of it in stage IB disease. CONCLUSIONS: The efficacy between NCS and PST may be similar in FIGO stage IB cervical cancer. However, NCS can lead to poor prognosis despite the reduction of intermediate-risk factors and the need of adjuvant radiotherapy in FIGO stage IIA disease.

Effects of a relaxation breathing exercise on anxiety, depression, and leukocyte in hemopoietic stem cell transplantation patients.

This study was performed to investigate the effects of a relaxation breathing exercise on anxiety, depression, and leukocyte count in patients who underwent allogenic hemopoietic stem cell transplantation. Thirty-five patients were randomly selected, with 18 assigned to an exercise group and 17 assigned to a control group. The exercise intervention was applied to the exercise group for 30 minutes every day for 6 weeks. It consisted of physical exercises combined with relaxation breathing. Anxiety was measured by the State-Trait Anxiety Inventory and depression was measured by the Beck Depression Inventory. The total number of leukocytes was calculated from total and differential counts of peripheral white blood cells. The exercise group had a greater decrease in anxiety and depression than did the control group, but the total number of leukocytes did not significantly differ between the two groups. These findings indicate that a relaxation breathing exercise would improve anxiety and depression levels in patients who undergo allogenic hemopoietic stem cell transplantation, but would not affect the number of leukocytes.

Effects of a relaxation breathing exercise on fatigue in haemopoietic stem cell transplantation patients.

AIM: Our purpose was to investigate the effect of a relaxation breathing exercise on fatigue in allogenic haemopoietic stem cell transplantation patients. BACKGROUND: Exercise is a promising approach in ameliorating the fatigue associated with cancer and its treatment. DESIGN: A randomized design with control, experimental groups being assessed pre- and postintervention. METHODS: Thirty-five patients were randomly selected, with 18 assigned to an exercise group and 17 to a control group. The exercise intervention lasted for 30 minutes every day for six weeks. It consisted of physical exercise combined with relaxation breathing exercise. Fatigue was measured by the revised version of the Piper Fatigue Scale. RESULTS: The exercise group had a greater decrease in fatigue than the control group. CONCLUSION: These findings indicate that a relaxation breathing exercise would improve fatigue in allogenic haemopoietic stem cell transplantation patients. RELEVANCE TO CLINICAL PRACTICE: A relaxation breathing exercise by a nurse can improve fatigue in allogenic haemopoietic stem cell transplantation patients.