The BRD4 inhibitor JQ1 suppresses tumor growth by reducing c-Myc expression in endometrial cancer.

BACKGROUND: Endometrial cancer (EC) is the most common gynecological malignancy in developed countries. Efficacy of the bromodomain 4 (BRD4) inhibitor JQ1 has been reported for the treatment of various human cancers, but its potential impact on EC remains unclear. We therefore aimed to elucidate the function of BRD4 and the effects of JQ1 in EC in vivo and in vitro. METHODS: The mRNA expression of BRD4 was evaluated using datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). BRD4 protein expression in EC tissues was measured using immunohistochemistry (IHC) assays. The effects of JQ1 on EC were determined by using MTT and colony formation assays, flow cytometry and xenograft mouse models. The underlying mechanism was also examined by western blot and small interfering RNA (siRNA) transfection. RESULTS: BRD4 was overexpressed in EC tissues, and the level of BRD4 expression was strongly related to poor prognosis. The BRD4-specific inhibitor JQ1 suppressed cell proliferation and colony formation and triggered cell apoptosis, cell cycle arrest, and changes in the expression of proteins in related signaling pathways. Moreover, JQ1 decreased the protein expression of BRD4 and c-Myc, and knockdown of BRD4 or c-Myc reduced the viability of EC cells. Intraperitoneal administration of JQ1 (50 mg/kg) significantly suppressed the tumorigenicity of EC cells in a xenograft mouse model. CONCLUSION: Our results demonstrate that BRD4 is a potential marker of EC and that the BRD4 inhibitor JQ1 is a promising chemotherapeutic agent for the treatment of EC.

The gene signature of tertiary lymphoid structures within ovarian cancer predicts the prognosis and immunotherapy benefit.

Ovarian cancer (OC) has the lowest survival rate among gynecologic malignancies. Ectopic lymphocyte aggregates, namely tertiary lymphoid structures (TLSs), have been reported as positive biomarkers for tumor prognosis. However, the related gene signature of tertiary lymphoid structure in ovarian cancer was less understood. Therefore, this study first exhibited the organizational patterns of tertiary lymphoid structure by H&E staining and immunohistochemistry (IHC), and confirmed the improved survival values of tertiary lymphoid structure and quantified tumor-infiltrating lymphocytes (CD20+ B cells and CD8+ T cells) in ovarian cancer patients. Secondly, we collected the genes involved in tertiary lymphoid structure from databases. By the univariate regression analysis, the tertiary lymphoid structure gene signature (CETP, CCR7, SELL, LAMP3, CCL19, CXCL9, CXCL10, CXCL11, and CXCL13) with prognostic value, characteristically of ovarian cancer, was constructed in the TCGA dataset and validated in the GSE140082 dataset. Thirdly, by performing CIBERSORT and Tumor Immune Dysfunction and Exclusion (TIDE) analysis, we found that the high expression of this gene signature was positively correlated with developed immune infiltration and reduced immune escape. The improved IPS score and application in the IMvigor210 dataset received PD-L1 proved the predictive value of immunotherapy for this gene signature. Furthermore, this signature showed a better correlation between tumor mutation burden and classical checkpoint genes. In conclusion, Tertiary lymphoid structure plays important role in tumor immunity and the gene signature can be evaluated as a biomarker for predicting prognosis and guiding immunotherapy in ovarian cancer.

Corrigendum: Targeting ACLY Attenuates Tumor Growth and Acquired Cisplatin Resistance in Ovarian Cancer by Inhibiting the PI3K-AKT Pathway and Activating the AMPK-ROS Pathway.

[This corrects the article DOI: 10.3389/fonc.2021.642229.].

Roles of NPAS2 in circadian rhythm and disease.

NPAS2, a circadian rhythm gene encoding the neuronal PAS domain protein 2 (NPAS2), has received widespread attention because of its complex functions in cells and diverse roles in disease progression, especially tumorigenesis. NPAS2 binds with DNA at E-box sequences and forms heterodimers with another circadian protein, brain and muscle ARNT-like protein 1 (BMAL1). Nucleotide variations of the NPAS2 gene have been shown to influence the overall survival and risk of death of cancer patients, and differential expression of NPAS2 has been linked to patient outcomes in breast cancer, lung cancer, non-Hodgkin's lymphoma, and other diseases. Here, we review the latest advances in our understanding of NPAS2 with the aim of drawing attention to its potential clinical applications and prospects.

GABPA Expression in Endometrial Carcinoma: A Prognostic Marker.

BACKGROUND: GA-binding protein A (GABPA), a transcription factor, is broadly involved in physiological and pathological processes. Several studies have investigated the relationship between GABPA expression level and outcomes of various malignancies. However, the function and clinicopathological significance of GABPA in endometrial carcinoma (EC) remain obscure. METHODS: The GABPA mRNA expression in EC tissues and adjacent nonneoplastic tissues in the TCGA database was involved in our study. The protein expression of GABPA in 107 EC tissues and 15 normal endometrial tissues was detected by immunohistochemistry. RESULTS: The GABPA expression was significantly downregulated in EC tissues compared with its expression in normal tissues (P < 0.001). The expression of GABPA was markedly correlated with type II EC (P < 0.01) and grade 3 EC (P < 0.05). A tendency has been observed that patients with low GABPA levels had relatively poorer overall survival (OS) (P = 0.036) and disease-free survival (DFS) (P = 0.016) than patients with high GABPA levels. The multivariate Cox proportional hazard model showed that lower expression of GABPA was an independent poor prognostic factor for OS (P = 0.043) and DFS (P = 0.045). Similar correlation between low expression levels of GABPA and unfavorable prognosis has also been found in type II or grade 3 EC. IHC analysis showed EC tissues had low expression of GABPA, which indicated relatively poor prognosis. Moreover, we identified that the GABPA mRNA expression was negatively correlated with its methylation level (R = -0.2512, P < 0.001) which is one of the mechanisms for the silencing of GABPA gene. CONCLUSION: GABPA may act as an independent predictor of clinical prognosis and serve as a potential target gene for EC therapy.

Targeting ACLY Attenuates Tumor Growth and Acquired Cisplatin Resistance in Ovarian Cancer by Inhibiting the PI3K-AKT Pathway and Activating the AMPK-ROS Pathway.

Background: Ovarian cancer is the most lethal female genital malignancy. Although cisplatin is the first-line chemotherapy to treat ovarian cancer patients along with debulking surgeries, its efficacy is limited due to the high incidence of cisplatin resistance. ATP citrate lyase (ACLY) has been shown to be a key metabolic enzyme and is associated with poor prognosis in various cancers, including ovarian cancer. Nevertheless, no studies have probed the mechanistic relationship between ACLY and cisplatin resistance. Methods: Survival analysis was mainly carried out online. Bioinformatic analysis was performed in R/R studio. Proliferative activity was measured by MTT and colony formation assays. Cell cycle and apoptosis analysis were performed by flow cytometry. The acquired-cisplatin-resistant cell line A2780/CDDP was generated by exposing A2780 to cisplatin at gradually elevated concentrations. MTT assay was used to calculate IC50 values of cisplatin. A xenograft tumor assay was used test cell proliferation in vivo. Results: Higher expression of ACLY was found in ovarian cancer tissue and related to poor prognosis. Knockdown of ACLY in A2780, SKOV3, and HEY cells inhibited cell proliferation, caused cell-cycle arrest by modulating the P16-CDK4-CCND1 pathway, and induced apoptosis probably by inhibiting p-AKT activity. Bioinformatic analysis of the GSE15709 dataset revealed upregulation of ACLY and activation of PI3K-AKT pathway in cells with acquired cisplatin resistance, in line with observations on A2780/CDDP cells that we generated. Knockdown of ACLY alleviated cisplatin resistance, and works synergistically with cisplatin treatment to induce apoptosis in A2780/CDDP cells by inhibiting the PI3K-AKT pathway and activating AMPK-ROS pathway. The ACLY-specific inhibitor SB-204990 showed the same effect. In A2780/CDDP cells, AKT overexpression could attenuate cisplatin re-sensitization caused by ACLY knockdown. Conclusions: Knockdown of ACLY attenuated cisplatin resistance by inhibiting the PI3K-AKT pathway and activating the AMPK-ROS pathway. These findings suggest that a combination of ACLY inhibition and cisplatin might be an effective strategy for overcoming cisplatin resistance in ovarian cancer.

Overexpression of Nucleolin is a Potential Prognostic Marker in Endometrial Carcinoma.

PURPOSE: Nucleolin (NCL) is a multifunctional protein with oncogenic properties. NCL expression levels have been linked to the outcomes of various malignancies, but the clinical value of NCL in patients with endometrial carcinoma (EC) remains unclear. Here, the expression of NCL in EC tissues and its associations with patient outcomes were assessed. PATIENTS AND METHODS: Data on NCL mRNA expression in EC and adjacent nonneoplastic tissues from The Cancer Genome Atlas (TCGA) were analyzed. In addition, NCL protein expression in 82 endometroid endometrial adenocarcinoma tissues and 15 non-malignant tissues was detected by immunohistochemistry. RESULTS: Elevated NCL expression was markedly correlated with serous endometrial carcinoma (P<0.001), advanced stage (P=0.029), and grade 3 (P<0.001). High NCL levels were associated with poorer overall survival (OS) and disease-free survival (DFS) compared with intermediate or low NCL levels (OS: P=0.001, DFS: P=0.006). The multivariate Cox proportional hazards model showed that NCL expression was an independent poor prognostic factor for DFS (HR=1.282, CI=1.027-1.601, P=0.028). A similar correlation between high expression levels of NCL and unfavorable DFS was found in endometrioid endometrial adenocarcinoma (HR=1.411, CI=1.083-1.840, P=0.011). Positive extra-nuclear NCL expression (HR=3.377, 95% CI=1.029-11.186, P=0.046) and low nuclear NCL expression (HR=0.233, 95% CI=0.068-0.796, P=0.020) were independent prognostic factors for DFS in endometrioid endometrial adenocarcinoma. CONCLUSION: Heterotopic NCL is a potential prognostic biomarker for EC. Inhibiting the distribution of NCL from the nucleus to the cytoplasm and membrane may be a promising therapeutic strategy to improve outcomes in patients with EC with high NCL expression.

Rimonabant potentiates the antifungal activity of amphotericin B by increasing cellular oxidative stress and cell membrane permeability.

Amphotericin B (AmB) is a very effective antifungal agent, and resistance in clinical isolates is rare. However, clinical treatment with AmB is often associated with severe side effects. Reducing the administration dose of AmB by combining it with other agents is a promising strategy to minimize this toxicity. In this study, we screened a small compound library and observed that the anti-obesity drug rimonabant exhibited synergistic antifungal action with AmB against Candida species and Cryptococcus neoformans. Moreover, the combination of AmB and rimonabant exhibited synergistic or additive effects against Candida albicans biofilm formation and cell viability in preformed biofilms. The effects of this combination were further confirmed in vivo using a murine systemic infection model. Exploration of the mechanism of synergy revealed that rimonabant enhances the fungicidal activity of AmB by increasing cellular oxidative stress and cell membrane permeability. These findings provide a foundation for the possible development of AmB-rimonabant polytherapies for fungal infections.

Association between BRCA mutations and endometrial carcinoma: a systematic review with meta-analysis.

PURPOSE: To first investigate on the association between BRCA mutations and endometrial carcinoma. To first evaluate the contribution of tamoxifen use and risk-reducing bilateral salping-oophenrectomy (BSO) on endometrial carcinoma in BRCA carriers. METHODS: A systematic search of electronic databases including the PubMed and EMBASE was conducted to identify publications exploring the association between BRCA mutations and endometrial carcinoma. Finally, single rate meta-analysis and diagnostic meta-analysis were performed. RESULTS: 11 retrospective studies and 3 prospective studies were included in the meta-analysis, single rate meta-analysis was performed on retrospective studies and prospective studies respectively. We got that incidence of BRCA mutations in patients with endometrial carcinoma is about 0.035, the incidence of endometrial carcinoma in BRCA carriers is about 0.004. Diagnostic meta-analysis performed on prospective studies found that tamoxifen increased incidence of endometrial carcinoma in BRCA carriers. CONCLUSIONS: The incidence of BRCA mutations in patients with endometrial carcinoma is about 0.035 according to present studies, the incidence of endometrial carcinoma in BRCA carriers is about 0.004. Tamoxifen use is a certain risk factor for subsequent endometrial carcinoma, while history of breast cancer or risk-reducing BSO is not associated with incidence of follow-up endometrial carcinoma. The necessity and rationality of prophylactic hysterectomy for BRCA carriers remained to be discussed.

A comparison between laparoscopy and hysteroscopy approach in treatment of cesarean scar pregnancy.

The aim of the study was to compare the efficacy of laparoscopy and hysteroscopy for the treatment of cesarean scar pregnancy (CSP) and analyze the clinical factors associated with successful selection for hysteroscopic or laparoscopic treatment of CSP.We retrospectively studied 112 cases of CSP that were treated by laparoscopy and/or hysteroscopy in our hospital from December 2014 to December 2017. In total, 72 of these patients underwent ultrasound-guided curettage and hysteroscopic resection without uterine scar defect repair. Fourty of these patients underwent laparoscopic resection and repair of the uterine scar defect. We analyzed the different clinical variables between the 2 groups and identified the clinical factors which could predict the need for the laparoscopic repair of uterine scar defect. Results showed that laparoscopy and hysteroscopy were safe ways to treat CSP, and no patient underwent hysterectomy. The ß-hCG level in both of the 2 groups decreased to normal 4 to 8 weeks after surgery. There were significant differences between the hysteroscopy group and laparoscopy uterine scar repair group in terms of days of amenorrhea, gestational sac diameter, myometrial thickness, operation time, intraoperative blood loss, and hospitalization duration (P < .05). Logistic regression analysis showed that the days of amenorrhea, gestational sac diameter and myometrial thickness were independent risk factors for CSP treated by minimally invasive surgery, which were also shown by ROC curve analysis to be predictors of the need for the repair of the uterine scar defect, with optimal cutoffs of 52.50 days, 3.25 cm, and 2.05 mm, respectively; and the areas under their corresponding ROC were 0.721, 0.851, and 0.927, respectively.We conclude that laparoscopy and hysteroscopy are safe and efficient minimally invasive procedures for the treatment of CSP. The days of amenorrhea, gestational sac diameter and myometrial thickness may be key factors associated with successful selection for hysteroscopic or laparoscopic treatment of CSP.

Full-term pregnancy in a rudimentary horn with a live fetus: A case report.

INTRODUCTION: Rudimentary horns and unicornuate uteri, 2 types of Mullerian duct abnormalities, often lack obvious symptoms. Ultrasonography (US) and magnetic resonance imaging (MRI) are alternative examinations but have low accuracy. Full-term rudimentary horn pregnancies are rather rare but life-threatening. PATIENT CONCERNS: A 30-year-old Chinese woman complained of lower abdominal pain one year after a full-term unicornate uterus pregnancy and a rudimentary horn pregnancy successively. DIAGNOSIS: Uterine dysplasia (right rudimentary uterine horn and left unicornate uterus), hematometra and right fallopian tube effusion were diagnosed. INTERVENTIONS: We performed laparoscopic hysterectomy (rudimentary horn), right salpingectomy, pelvic adhesion release and hysteroscopy. OUTCOMES: The patient has not complained of specific discomfort during the one-year follow-up so far. CONCLUSION: The reported case was a rare full-term rudimentary horn pregnancy. The degree of development of the rudimentary horn, such as the endometrial function, muscle layer thickness, and uterine shape and size, is closely related to pregnancy outcome. The rudimentary horn with a functional endometrium must be disposed of once it is definitely diagnosed. Pregnancy in the rudimentary horn with a weak muscular layer should be treated as soon as possible. Detailed and scientific prenatal examination is important.

Novel Nanocomplexes Targeting STAT3 Demonstrate Promising Anti-Ovarian Cancer Effects in vivo.

BACKGROUND: Cationic solid lipid nanoparticles (SLN) have attracted intensive interest as an effective gene delivery system for its high biocompatibility, stability and low cytotoxicity. In our previous study, we successfully prepared SLN-STAT3 decoy ODN complexes and made a primary study on its antitumor behavior in ovarian cancer cells in vitro. However, there is little information available so far about the effect of SLN-STAT3 decoy ODN complexes on ovarian cancer in vivo, either little information about the pharmacological toxicology in vivo. MATERIAL AND METHODS: We applied nanotechnology to improve the gene delivery system and synthesize SLN-STAT3 decoy ODN complexes. Xenograft mouse models were established to assess the antitumor effects of SLN-STAT3 decoy ODN on the tumor growth of ovarian cancer in vivo. To analyze the mechanisms of SLN-STAT3 decoy ODN, we investigated apoptosis, autophagy, epithelial-mesenchymal transition (EMT) in tumor tissues of nude mice and investigated the effects and toxicology of SLN-STAT3 decoy ODN complexes on the vital organs of nude mice. RESULTS: The results showed that SLN-STAT3 decoy ODN complexes markedly inhibited tumor growth in vivo. SLN-STAT3 decoy ODN complexes could induce cell apoptosis through downregulating Bcl-2, survivin and pro caspase 3, but upregulating Bax and cleaved caspase 3. These complexes could also regulate autophagy through upregulating LC3A-II, LC3B-II and beclin-1, but downregulating p-Akt and p-mTOR. Moreover, these complexes could inhibit cancer cell invasion through reversing EMT. Besides, SLN-STAT3 decoy ODN complexes showed no obvious toxicity on vital organs and hematological parameters of nude mice. CONCLUSION: The molecular mechanisms that SLN-STAT3 decoy ODN complexes inhibit tumor growth involved activating the apoptotic cascade, regulating autophagy, and reversing EMT program; and these complexes showed no obvious toxicity on nude mice. Our study indicated that the nanocomplexes SLN-STAT3 decoy ODN might be a promising therapeutic approach for ovarian cancer treatment.

Exosomes derived from human umbilical cord mesenchymal stem cells inhibit vein graft intimal hyperplasia and accelerate reendothelialization by enhancing endothelial function.

BACKGROUND: In our previous research, we found that mesenchymal stem cell (MSC) transplantation therapy can inhibit intimal hyperplasia and enhance endothelial function in arterialized vein grafts in rats. However, whether MSC-derived exosomes (MSC-exosomes) can reduce neointimal formation and its possible mechanism is still unclear. METHODS: The primary human umbilical cord MSCs (hucMSCs) and human umbilical vein endothelial cells (HUVECs) were isolated and characterized by flow cytometry and immunofluorescence. The exosomes derived from hucMSCs (hucMSC-exosomes) were identified by transmission electron microscopy and western blots. hucMSC-exosomes were intravenously injected into a rat model of vein grafting, and its effect on vein grafts reendothelialization and intimal hyperplasia was assessed by physical, histological, immunohistochemistry, and immunofluorescence examinations. The effects of hucMSC-exosomes on endothelial cells were evaluated by integrated experiment, EdU staining, scratch assay, and Transwell assay. The expression levels of key gene and pathways associated with the biological activity of vascular endothelial cells were evaluated following the stimulation of hucMSC-exosomes. RESULTS: We successfully isolated and characterized primary hucMSCs and hucMSC-exosomes and primary HUVECs. We verified that the systemic administration of hucMSC-exosomes accelerates reendothelialization and decreases intimal hyperplasia of autologous vein graft in a rat model. We also identified that hucMSC-exosomes can be uptaken by endothelial cells to stimulate cell proliferative and migratory activity in vitro. Furthermore, we detected that vascular endothelial growth factor (VEGF) plays an important part in hucMSC-exosome-mediated proliferation and migration in HUVECs. In addition, we also provided evidence that the signalling pathways of PI3K/AKT and MAPK/ERK1/2 take part in hucMSC-exosome-induced VEGF regulation. CONCLUSION: Our data suggest that hucMSC-exosomes exert a vasculoprotective role in the setting of vein graft disease, which may provide a new clue to protect against vein graft failure in the future.

Clinicopathological factors and prognosis analysis of 39 cases of non-gestational ovarian choriocarcinoma.

PURPOSE: Non-gestational ovarian choriocarcinoma (NGOC) is a rare malignant germ cell tumor. Through literature review and cases collection, we aim to analyze prognostic factors for NGOC and summarize its clinicopathological characteristics to guide the individualized treatment. METHODS: We searched PubMed database, Cochrane library, and Google Scholar for cases published between January 1, 1967 and July 31, 2018 using various search terms. We retrieved patients' clinicopathological characteristics, treatment, and prognosis information from included studies. These patients were divided into two groups: died (case group) or alive (control group) group. We summarized and compared their clinical (age, symptoms, R0 resection, serum HCG levels, chemotherapy regimen) and pathological (pure vs non-pure type, tumor size, tumor location, metastasis sites, stage) features by statistical analysis. RESULTS: Only 39 patients were retrieved from 36 studies in total. The median age was 30 years (range 12- to 65-years old). The peak incidence was in the adolescent age 12-25 years. Median follow-up was 20.3 months (range 1-84 months). 9 (23%) patients died; 24 (62%) patients were alive; 6 (15%) were lost to follow-up. Upon univariate analysis, we found age had a poor impact on overall survival (OS) in NGOC, HR - 0.057, 95% CI - 0.111 to - 0.004. Pure type NGOC has a better OS than mixed type, HR - 2.621, 95% CI - 4.577 to - 0.666. R0 resection is a good prognostic factor for OS, HR 2.967, 95% CI 0.709-5.224. CONCLUSION: Clinicians should try to achieve R0 resection to improve the prognosis for NGOC patients even among advanced patients.

Akt/mTOR-Mediated Autophagy Confers Resistance To BET Inhibitor JQ1 In Ovarian Cancer.

BACKGROUND: Bromodomain and extra-terminal domain inhibitors like JQ1 have proved to be promising epigenetic agents for the treatment of malignant ovarian carcinoma. However, the resistance of ovarian cancer cells to BET inhibitors has not been elucidated. In this study, we investigated the potential mechanisms underlying the resistance of ovarian cancer cell lines to the BET inhibitor JQ1. MATERIALS AND METHODS: We evaluated the apoptotic and proliferative response of four ovarian cancer cell lines to JQ1. The cell lines were designated as resistant (A2780 and HO-8910) and sensitive groups (SKOV-3 and HEY). Further experiments detected the different levels of JQ1-induced autophagy. Anti-tumour effect of the combination of JQ1 and autophagy inhibitors was tested both in vitro and in vivo. RESULTS: In the JQ1-sensitive group, JQ1 effectively inhibited proliferation and apoptosis in a concentration-dependent manner. Conversely, JQ1 showed modest inhibition of proliferation and negligible apoptosis in the resistant group. We detected increased LC3-II lipidation, autophagosome formation, upregulation of Beclin-1 and ATG5, and downregulation of P62/SQSTM1 in the resistant group. Inhibition of JQ1-induced autophagy by pharmacologic inhibitors 3-MA and CQ enhanced the inhibition of proliferation and significantly increased the apoptosis in the JQ1-resistant group, which was also verified by in vivo experiments, indicating that JQ1-induced autophagy played a cytoprotective role. Inactivation of Akt (Ser473)/mTOR(Ser2448) pathway was associated with JQ1-induced autophagy in the resistant group. Overexpression of Akt1 suppressed autophagy and increased the anti-tumour effect of JQ1. CONCLUSION: These findings revealed that JQ1-induced pro-survival autophagy might be a potential mechanism in the resistance of ovarian cancer cells to BET inhibition by JQ1. Combination of JQ1 and autophagy inhibitors could be an effective therapeutic strategy for overcoming BET inhibitor resistance in ovarian cancer.

Primary malignant melanoma of the female genital tract synchronously involving the vulva and uterine cervix: A case report.

RATIONALE: Primary melanomas of the female genital tract are rare and usually occur in the vulva and vagina. Involvement of the cervix, uterus, and ovary are extremely rare. Surgery and adjuvant therapy remain the mainstay of treatment. The majority of patients experience poor long-term survival. This report aimed at highlighting an extremely rare case of primary melanoma of the female genitalia, synchronously involving the vulva and uterine cervix. PATIENT CONCERNS: A 58-year-old multiparous female presented with postmenopausal bleeding for 10 days. DIAGNOSES: Speculum examination and histologic analysis of the surgical specimens revealed synchronous involvement of the vulva and uterine cervix by malignant melanoma. According to the American Joint Committee on Cancer stage grouping for melanoma, this tumor was at stage V. INTERVENTIONS: The patient subsequently underwent radical surgery and postoperative chemotherapy. OUTCOMES: She has been on regular follow-up, and is now free of disease for 50 months after the operation. LESSONS: Primary melanomas of the female genital tract have biologically aggressive characteristics. Optimal management consists of individualized surgery and adjuvant therapy. However, early recognition and prompt intervention offer maximal benefit from treatment.

Curcumin induces apoptotic cell death and protective autophagy by inhibiting AKT/mTOR/p70S6K pathway in human ovarian cancer cells.

PURPOSE: Curcumin (Cur), a yellow-colored dietary flavor from the plant (Curcuma longa), has been demonstrated to potentially resist diverse diseases, including ovarian cancer, but drug resistance becomes a major limitation of its success clinically. The key molecule or mechanism associated with curcumin resistance in ovarian cancer still remains unclear. The aim of our study was to investigate the effects of curcumin on autophagy in ovarian cancer cells and elucidate the underlying mechanism. METHODS: In our study, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), EdU proliferation assay and colony-forming assay were used to assess cell viability. Apoptosis was detected by western blot and flow cytometric analysis of apoptosis. Autophagy was defined by both electron microscopy and immunofluorescence staining markers such as microtubule-associated protein 1 light chain 3 (LC3). Plasmid construction and shRNA transfection helped us to confirm the function of curcumin. RESULTS: Curcumin reduced cell viability and induced apoptotic cell death by MTT assay in human ovarian cancer cell lines SK-OV-3 and A2780 significantly. Electron microscopy, western blot and immunofluorescence staining proved that curcumin could induce protective autophagy. Moreover, treatment with autophagy-specific inhibitors or stable knockdown of LC3B by shRNA could markedly enhance curcumin-induced apoptosis. Finally, the cells transiently transfected with AKT1 overexpression plasmid demonstrated that autophagy had a direct relationship with the AKT/mTOR/p70S6K pathway. CONCLUSIONS: Curcumin can induce protective autophagy of human ovarian cancer cells by inhibiting the AKT/mTOR/p70S6K pathway, indicating the synergistic effects of curcumin and autophagy inhibition as a possible strategy to overcome the limits of current therapies in the eradication of epithelial ovarian cancer.

The association between BMI and body weight perception among children and adolescents in Jilin City, China.

OBJECTIVES: We evaluated the association between BMI and body weight perception in a sample of children and adolescents. METHODS: A cross-sectional school-based study was conducted among 7-18 year-olds (N = 9727) from 4 districts in Jilin City, China. We calculated BMI from measured weight and height and assessed body weight perception using a single questionnaire item. We analyzed these data using SPSS version 20.0. RESULTS: Approximately 19.8% of these youth perceived themselves as underweight, 57.8% as normal weight, and 22.4% as overweight. In reality, 4.9% were underweight, 64.3% were normal weight, and 30.8% were overweight. Furthermore, approximately 66.4% of these Chinese youth correctly perceived their body image, 28.2% underestimated their true body image, and 5.4% overestimated their weight status. Girls were more likely than boys to overestimate their weight (χ2 = 135.4, p < 0.05). Adolescents 13-18 years old were more likely than children 7-12 years old to overestimate their weight (χ2 = 248.4, p < 0.05). Senior high school students were the most likely to overestimate their weight (χ2 = 297.6, p < 0.05). Kappa tests revealed significant differences in consistency analysis of BMI and body weight perception (Kappa = 0.352, p < 0.05). Kappa < 0.4, the consistency of BMI and body weight perception was poor. CONCLUSIONS: A mismatch existed between BMI and body weight perception among these children and adolescents. Thus, schools and parents should take steps to help them improve weight management and overall health awareness.

Smoking, leisure-time exercise and frequency of self-reported common cold among the general population in northeastern China: a cross-sectional study.

BACKGROUND: Physical activity (PA) and smoking have been reported to be associated with the duration and severity of common cold symptoms. However, few studies have addressed the associations between the frequency of leisure-time exercise, cigarette smoking status and the frequency of the common cold in a cold area. This study was designed to investigate these issues in northeastern China. METHODS: This cross-sectional study included individuals who participated in a regular health examination conducted in Jilin Province, China. Information on episodes of the common cold, the frequency of leisure-time exercise and cigarette smoking status in the past year were collected by self-administered health questionnaires. Ordinal logistic regression models were used to analyse the associations between the frequency of leisure-time exercise, cigarette smoking status and the retrospective frequency of common cold. RESULTS: A total of 1413 employees participated in the study, with an average age of 38.92 ± 9.04 years and 44.4% of them were male. Of all participants, 80.8% reported having experienced the common cold in the past year. After adjustment, the risk of suffering from the common cold more than once (odds ratios (ORs), 1.59; 95% confidence interval (CI), 1.27-1.99) in passive smokers was 1.59 times as high as that in non-smokers. Nevertheless, the results of the adjusted analysis showed no statistically significant relation between current smoking and the frequency of the common cold. A high frequency of leisure-time exercise (≥3 days/week) was associated with a 26% reduced risk of having at least one episode of the common cold (OR, 0.74; 95% CI, 0.55-0.98) compared with a low frequency group (< 4 days/month). For current and passive smokers, the protective effect of a high frequency of leisure-time exercise appears not to be obvious (current smokers: OR, 0.68; 95% CI, 0.33-1.43; passive smokers: OR, 1.15; 95% CI, 0.69-1.93). CONCLUSION: Passive smoking was associated with a higher risk of having self-reported common cold at least once, while a high frequency of leisure-time exercise was related to a lower risk of reporting more than one episode of the disease in Chinese.

Gender-specific association of metabolic syndrome and its components with arterial stiffness in the general Chinese population.

OBJECTIVES: Metabolic syndrome (MS) is considered to be a cluster of interrelated risk factors for metabolism, which may increase arterial stiffness and cardiovascular morbidity. The cardio-ankle vascular index (CAVI) is a reliable indicator of arterial stiffness and early arteriosclerosis. The main objective of this study is to evaluate the gender-specific relationship between MS and CAVI in the general Chinese population. METHODS: A total of 1,301 subjects aged 20 to 60 years participated in this study. CAVI was measured noninvasively using a Vasera VS-1000 device. Blood samples and waist circumference were examined to identify metabolic syndrome according to the criteria set forth in the 2009 Joint Scientific Statement. RESULTS: The prevalence of MS in the study subjects was 17.4% (30.7% in males and 7.0% in females, P < 0.001). CAVI values were significantly higher in MS subjects than in non-MS subjects and increased linearly as the number of MS components increased in females, but not in males. Using multiple regression analysis, we found that BMI was correlated with CAVI in the overall population and in both genders, and that high-density lipoprotein cholesterol (HDL-C) was associated with CAVI in males, while the number of MS components was related to CAVI in females. CAVI values increased linearly with age in both genders (P-trend < 0.001 for both), and this correlation was stronger in males than in females. CONCLUSIONS: There are gender-specific differences in the association of MS and CAVI. First, the effects of the number of MS components on CAVI are stronger in females than in males. Second, the effect of each MS component on arterial stiffness may differ in relation to gender. In addition, aging affects arterial stiffness more severely in males, and the increase in arterial stiffness tends to occur at a younger age in males than in females. Larger samples and longitudinal studies are needed to further confirm our results in the future.