Oteseconazole versus fluconazole for the treatment of severe vulvovaginal candidiasis: a multicenter, randomized, double-blinded, phase 3 trial.

Vulvovaginal candidiasis (VVC) is a common condition among women. Fluconazole remains the dominant treatment option for VVC. Oteseconazole is a highly selective inhibitor of fungal CYP51. This randomized, double-blinded, phase 3 trial was conducted to evaluate the efficacy and safety of oteseconazole compared with fluconazole in treating severe VVC. Female subjects presenting with vulvovaginal signs and symptoms score of ≥7 and positive Candida infection determined by potassium hydroxide test or Gram staining were randomly assigned to receive oteseconazole (600 mg on D1 and 450 mg on D2) or fluconazole (150 mg on D1 and D4) in a 1:1 ratio. The primary endpoint was the proportion of subjects achieving therapeutic cure [defined as achieving both clinical cure (absence of signs and symptoms of VVC) and mycological cure (negative culture of Candida species)] at D28. A total of 322 subjects were randomized and 321 subjects were treated. At D28, a statistically significantly higher proportion of subjects achieved therapeutic cure in the oteseconazole group than in the fluconazole group (66.88% vs 45.91%; P = 0.0002). Oteseconazole treatment resulted in an increased proportion of subjects achieving mycological cure (82.50% vs 59.12%; P < 0.0001) and clinical cure (71.25% vs 55.97%; P = 0.0046) compared with fluconazole. The incidence of treatment-emergent adverse events was similar between the two groups. No subjects discontinued study treatment or withdrew study due to adverse events. Oteseconazole showed statistically significant and clinically meaningful superiority over fluconazole for the treatment of severe VVC and was generally tolerated.

Pegylated liposomal doxorubicin in partially platinum-sensitive, platinum-resistant, or platinum-refractory ovarian cancer: a prospective study.

BACKGROUND: This study aimed to evaluate the efficacy and safety of pegylated liposomal doxorubicin (PLD) for patients with partially platinum-sensitive, platinum-resistant, or platinum-refractory ovarian cancer. METHODS: Patients with partially platinum-sensitive, platinum-resistant, or platinum-refractory ovarian cancer were recruited in this prospective, open-label, single-arm, multicenter study. Eligible patients were given 4-6 cycles of PLD (40 mg/m2 on day 1, every 4 weeks). The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), quality of life, and safety. Exploratory endpoints included the change trend of CA125 and platinum-free interval. RESULTS: Between June 2017 and November 2020, 167 eligible patients were included in the full analysis set. The median PFS and OS were 6.8 months (95% CI, 4.4-9.3 months) and 19.1 months (95% CI, 15.0-23.3 months), respectively. The ORR and DCR were 32.3% and 60.5%, respectively. The ORR (62.3 vs 22.5%) and DCR (84.9 vs 60.7%) of patients with a CA125 decrease after the first cycle were significantly higher than those without a CA125 decrease (all P < .05). Grade ≥ 3 and serious adverse events were reported in 9.9% and 3.9% of patients, respectively. No treatment-related death was observed. CONCLUSION: PLD showed promising efficacy and manageable tolerability in patients with partially platinum-sensitive, platinum-resistant, or platinum-refractory ovarian cancer.ClinicalTrials.gov Identifier: Chinese Clinical Trial Registry, ChiCTR1900022962.

MCM10: An effective treatment target and a prognostic biomarker in patients with uterine corpus endometrial carcinoma.

Molecular profiling has been applied for uterine corpus endometrial carcinoma (UCEC) management for many years. The aim of this study was to explore the role of MCM10 in UCEC and construct its overall survival (OS) prediction models. Data from TCGA, GEO, cbioPotal and COSMIC databases and the methods, such as GO, KEGG, GSEA, ssGSEA and PPI, were employed to bioinformatically detect the effects of MCM10 on UCEC. RT-PCR, Western blot and immunohistochemistry were used to validate the effects of MCM10 on UCEC. Based on Cox regression analysis using the data from TCGA and our clinical data, two OS prediction models for UCEC were established. Finally, the effects of MCM10 on UCEC were detected in vitro. Our study revealed that MCM10 was variated and overexpressed in UCEC tissue and involved in DNA replication, cell cycle, DNA repair and immune microenvironment in UCEC. Moreover, silencing MCM10 significantly inhibited the proliferation of UCEC cells in vitro. Importantly, based on MCM10 expression and clinical features, the OS prediction models were constructed with good accuracy. MCM10 could be an effective treatment target and a prognostic biomarker for UCEC patients. The OS prediction models might help establish the strategies of follow-up and treatment for UCEC patients.

UBP43 promotes epithelial ovarian carcinogenesis via activation of ß-catenin signaling pathway.

Dysregulation of the deubiquitinating protease, UBP43, has been implicated in many human diseases, including cancer. Here, we evaluated the functional significance and mechanism of action of UBP43 in epithelial ovarian cancer. We found that UBP43 was significantly upregulated in the tumor tissues of patients with epithelial ovarian cancer. Similar results were observed in OVCAR-3, Caov-3, TOV-112D, A2780, and SK-OV-3 cells. Furthermore, in vitro functional assays of A2780 and TOV-112D cells demonstrated that UBP43 overexpression promoted cell proliferation, migration, and invasion. Upregulation of UBP43 might result in epithelial-mesenchymal transition by inducing the nuclear transport of ß-catenin, which was accompanied by enhanced N-cadherin but decreased E-cadherin expression. These malignant phenotypes were reversed by UBP43 silencing. Further investigation revealed that the knockdown of UBP43 inhibited cell proliferation by inducing a cell cycle arrest at the G2/M phase. The oncogenic characteristics of UBP43 were validated in a subcutaneous xenograft mouse model. In vivo, tumor growth was delayed in the UBP43-silenced group but accelerated after UBP43 overexpression. Finally, we demonstrated that ß-catenin is a key protein in the UBP43-mediated malignant development of epithelial ovarian cancer. Specifically, overexpression of UBP43 decreased the ubiquitination degradation of ß-catenin and enhanced its protein stability. Also, we observed that the downstream genes of beta-catenin such as cyclin D1, MMP2, and MMP9 were upregulated due to UBP43 overexpression. Thus, we concluded that UBP43 promoted epithelial ovarian cancer tumorigenesis and metastasis through activation of the ß-catenin pathway, suggesting that UBP43 may be a potential therapeutic target for this intractable disease.

In Vitro Antifungal Activity of Azoles and Other Antifungal Agents Against Pathogenic Yeasts from Vulvovaginal Candidiasis in China.

BACKGROUND: Vulvovaginal candidiasis (VVC) is a public health issue worldwide. Little is known of the optimal treatment of recurrent VVC (RVVC) has not been established. OBJECTIVE: Through the in vitro antifungal susceptibility profiling of VVC isolates, we hope to foster significant improvements in the control and treatment of this disease. METHODS: Candida isolates from VVC patients were collected from 12 hospitals in 10 cities across China. Species were identified by phenotype analysis and DNA sequencing. Species were identified by phenotype analysis and DNA sequencing. Susceptibilities to 11 drugs were determined by Clinical and Laboratory Standards Institute broth microdilution. RESULTS: 543 strains were isolated from those VVC patients enrolled in this study, of which, 15.7% were from RVVC. The most commonly identified species was C. albicans (460, 84.71%), and the most commonly non-albicans Candida spp. (NAC) was C. glabrata (47, 8.66%). NAC also included C. Krusei, Meyerozyma Guillermondii, Meyerozyma Caribbica, C. Tropicalis, C. Parapsilosis, and C. Nivariensis. Most C. albicans isolates were susceptible to caspofungin (99.8%), followed by fluconazole (92%) and voriconazole (82.6%). The proportion of C. albicans strains with wild type (WT) MICs that were susceptible to amphotericin B and caspofungin were 98%, followed by posaconazole at 95%, itraconazole at 86%, fluconazole at 74% and voriconazole at 54%. The fluconazole MICs for C. albicans were lower than those for NAC (P < 0.05), while the itraconazole MICs showing no significant difference (P > 0.05). The susceptible rate of uncomplicated VVC to fluconazole was 92%. The proportion of WT strains to fluconazole in RVVC was much lower than that in other types of VVC (67 vs. 77%, P < 0.05). However, the proportions of WT strains to itraconazole in RVVC was over 85%, which was much higher than that to fluconazole (87 vs. 67%, P < 0.05). CONCLUSIONS: C. albicans was still the predominant pathogen for VVC in China, while C. glabrata was the main species in NAC. Fluconazole could still be used as an empirical treatment for uncomplicated VVC. However, fluconazole may not be the first choice for the therapy of RVVC. In such cases, itraconazole appears to be the more appropriate treatment. As for VVC caused by NAC, nonfluconazole drugs, such as itraconazole, may be a good choice.

Neoadjuvant chemotherapy for patients with international federation of gynecology and obstetrics stages IB3 and IIA2 cervical cancer: a multicenter prospective trial.

BACKGROUND: Preoperative neoadjuvant chemotherapy (NACT) has been widely used in developing countries for the treatment of patients with International Federation of Gynecology and Obstetrics (FIGO) stages IB3 and IIA2 cervical cancer. However, the effectiveness of NACT and treatment options for NACT-insensitive patients have been concerning. This study will assess prognostic differences between NACT and primary surgery treatment (PST), determine factors associated with prognosis, and explore better adjuvant treatment modalities for NACT-insensitive patients. METHODS: This study analyzed clinical characteristics, pathological characteristics, treatment options, and follow-up information of 774 patients with FIGO stages IB3 and IIA2 cervical cancer from 28 centers from January 2016 to October 2019 who participated in a multicenter, prospective, randomized controlled trial. RESULTS: For patients undergoing NACT, the 5-year OS and PFS rate was 85.8 and 80.5% respectively. They were similar in the PST group. There was no significant difference in OS and PFS between clinical response (CR)/partial response (PR) groups and stable disease (SD)/progressive disease (PD) groups. Apart from deep cervical invasion (p = 0.046) affecting OS for patients undergoing NACT, no other clinical and pathological factors were associated with OS. 97.8% of NACT-insensitive patients opted for surgery. If these patients did not have intermediate- or high-risk factors, whether they had undergone postoperative adjuvant therapy was irrelevant to their prognosis, whereas for patients with intermediate- or high-risk factors, adjuvant chemotherapy resulted in better PFS (chemotherapy vs. no therapy, p < 0.001; chemotherapy vs. radiotherapy, p = 0.019) and OS (chemotherapy vs. no therapy, p < 0.001; chemotherapy vs. radiotherapy, p = 0.002). CONCLUSIONS: NACT could be a choice for patients with FIGO stages IB3 and IIA2 cervical cancer. The main risk factor influencing prognosis in the NACT group is deep cervical invasion. After systematic treatment, insensitivity to NACT does not indicate a poorer prognosis. For NACT-insensitive patients, Chinese prefer surgery. Postoperative adjuvant therapy in patients with no intermediate- or high-risk factors does not improve prognosis, and chemotherapy in patients with intermediate- and high-risk factors is more effective than radiation therapy and other treatments. TRIAL REGISTRATION: The study was prospectively registered on ClinicalTrials.gov (NCT03308591); date of registration: 12/10/2017.

MicroRNA-612 inhibits cervical cancer progression by targeting NOB1.

Recently, many studies have shown that microRNA (miR)-612 is involved in cancer progression. However, the role of miR-612 in cervical cancer remains unclear. The present study aims to investigate the biological effects of miR-612 on cervical cancer. The expression of miR-612 in cervical cancer tissues and cell lines was analysed by quantitative reverse transcription-polymerase chain reaction. The effect of miR-612 cell proliferation, migration, invasion and apoptosis was studied by appropriate methods. Protein expression was determined by Western blot analyses. Bioinformatics analysis and luciferase reporter assays were performed to clarify the relationship between miR-612 and nin one binding protein (NOB1). A xenograft model was established to examine the role of miR-612 in vivo tumorigenesis. Cervical cancer tissues and cell lines showed down-regulation of miR-612 expression, which was associated with the Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) stage and lymph node metastasis. Functional assays revealed that miR-612 overexpression significantly suppressed cervical cancer cell proliferation, migration and invasion in vitro and delayed tumour growth in vivo. Mechanically, miR-612 targeted NOB1 in cervical cancer cells, revealing a negative correlation between miR-612 and NOB1in cervical cancer samples. NOB1 overexpression partially reversed the inhibitory effects of miR-612 overexpression in cervical cancer cells. Taken together, these findings indicate that miR-612 functions as a tumour suppressor in cervical cancer and suggest that miR-612 may be a potential target in the therapeutic intervention of this malignancy.

Dysregulated Expression of Long Noncoding RNAs in Endometriosis.

Endometriosis is a common debilitating gynecologic disease. Almost 10% of reproductive-age women are affected by this disease; they commonly suffer pelvic pain and/or infertility. Early diagnosis of this multifactorial disease remains difficult because its etiology is not clear and the early symptoms are nonspecific. In addition, many reproductive-age women are unwilling to undergo invasive laparoscopic surgery because of the possibility of decreasing fertility. Thus, identifying biomarkers for the early diagnosis of endometriosis a key focus of current research. Long noncoding RNAs (lncRNAs) are a class of noncoding transcripts that have length of > 200 nucleotides and lack protein-coding ability but still influence gene expression in various ways. With advances in genome-wide analysis, researchers have determined that lncRNAs play an important role in many human diseases, particularly tumors. Moreover, the role of lncRNAs in the pathogenesis of endometriosis has been continually recognized. In this review, we discuss the status of current research on dysregulated lncRNAs and their roles in the pathogenesis of endometriosis. We aim to stimulate new investigations toward the identification of lncRNAs as biomarkers for the early diagnosis and therapy of this long-term gynecological disease.

Identification of mRNAs related to endometrium function regulated by lncRNA CD36-005 in rat endometrial stromal cells.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder in women of reproductive age and is commonly complicated by adverse endometrial outcomes. Long non-coding RNAs (lncRNAs) are a class of non-protein-coding transcripts that are more than 200 nucleotides in length. Accumulating evidence indicates that lncRNAs are involved in the development of various human diseases. Among these lncRNAs, lncRNA CD36-005 (CD36-005) is indicated to be associated with the pathogenesis of PCOS. However, the mechanisms of action of CD36-005 have not yet been elucidated. METHODS: This study determined the CD36-005 expression level in the uteri of PCOS rat model and its effect on the proliferation activity of rat primary endometrial stromal cells. RNA sequencing (RNA-seq) and bioinformatics analysis were performed to detect the mRNA expression profiles and the biological pathways in which these differentially expressed mRNAs involved, after CD36-005 overexpression in the primary endometrial stromal cells. The differential expression of Hmgn5, Nr5a2, Dll4, Entpd1, Fam50a, and Brms1 were further validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: CD36-005 is highly expressed in the uteri of PCOS rat model and promotes the proliferation of rat primary endometrial stromal cells. A total of fifty-five mRNAs differentially expressed were identified in CD36-005 overexpressed stromal cells. Further analyses identified that these differentially expressed mRNAs participate in many biological processes and are associated with various human diseases. The results of qRT-PCR validation were consistent with the RNA-seq data. CONCLUSIONS: These data provide a list of potential target mRNA genes of CD36-005 in endometrial stromal cells and laid a foundation for further studies on the molecular function and mechanism of CD36-005 in the endometrium.

Relationship between RAS Association Domain Family Protein 1A Promoter Methylation and the Clinicopathological Characteristics in Patients with Ovarian Cancer: A Systematic Meta-Analysis.

BACKGROUND: To investigate the relationship between RAS association domain family protein 1A (RASSF1A) promoter methylation and the clinical features, and the survival of ovarian cancer patients. METHODS: A comprehensive literature search was conducted in the PubMed, Embase, EBSCO, and Cochrane Library databases. The overall ORs with their 95% CIs were calculated in this meta-analysis. RESULTS: Finally 17 relevant publications with 1,108 ovarian cancer samples were available for the current meta-analysis. RASSF1A promoter methylation had a significantly higher level in ovarian cancer than in low malignant potential (LMP) tumors. No significant relationship was observed between RASSF1A promoter methylation and the clinicopathological characteristics in ovarian cancer. Two studies reported that RASSF1A promoter methylation was not correlated with the survival of patients with ovarian cancer. CONCLUSIONS: Our findings suggest that the use of RASSF1A promoter methylation could distinguish ovarian cancer and LMP tumors. -RASSF1A promoter methylation may not be correlated with the clinical features and the survival of ovarian cancer patients. More studies with large sample sizes are essential in the future.

Irreversible electroporation in the eradication of rabbit VX2 cervical tumors.

The aim of this study was to evaluate the effects of irreversible electroporation (IRE) on the eradication of rabbit VX2 cervical tumors. A VX2 cervical cancer model was first made in 20 New Zealand rabbits. IRE ablation was performed for the cervical cancers of 15 rabbits when the diameter of the tumor was about 1.0-1.5 cm. The control group (n = 5) did not receive IRE ablation. The gross pathology, ultrasound, computed tomography, hematoxylin and eosin, terminal deoxynucleotidyl transferase dUTP nick end labeling assay, and proliferating cell nuclear antigen immunohistochemical staining were performed to evaluate the efficacy of IRE on cervical cancer. All the rabbits tolerated the IRE ablation without serious complications. The tumors treated by IRE slightly increased in size during the first two days, but decreased gradually. IRE caused tumor cell death efficiently, mainly through cell apoptosis; however, it did not induce complete tumor ablation in our study. The results suggested that IRE could eradicate rabbit VX2 cervical tumors efficiently. However, the optimal IRE parameters remain to be determined.

Irreversible electroporation of the uterine cervix in a rabbit model.

The aim of this study was to evaluate the effects of irreversible electroporation (IRE) on the uterine cervix in a rabbit model. IRE ablation was performed in the cervices of 48 New Zealand rabbits, with one ablation lesion in each animal. Gross pathology, transmission electron microscopy, hematoxylin and eosin (H&E), Masson's trichrome (MT) stain, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays were performed at pre-set time points (0 h, 12 h, 1 d, 2 d, 4 d, 7 d, 14 d, and 28 d post-IRE). All the rabbits tolerated the IRE ablation without serious complications. IRE caused complete cell death of the ablated cervix via cell apoptosis. However, fast recovery of the cervix was observed from 7 d post-IRE, with the signs of collagen fibers hyperplasia, the disappearance of the necrotic cells and muscle fibers, and regeneration and extension of the cervical epithelium. At 28 d post-IRE, the ablated cervices recovered to almost normal. Our study suggested that IRE might be an efficient and safe technology to treat cervical tumors, without causing serious cervical damage.

miR-494 suppresses tumor growth of epithelial ovarian carcinoma by targeting IGF1R.

A growing body of evidence suggests that microRNA-494 (miR-494) could act as tumor-suppressive or oncogenic microRNAs (miRNAs) in different types of tumors. However, the biological roles and underlying mechanisms of miR-494 remain unknown in human epithelial ovarian carcinoma (EOC). Therefore, the aims of this study were to investigate the miR-494 expression and the significance of its clinical diagnosis in patients suffering EOC and to analyze its role and underlying molecular mechanism on the carcinogenesis of EOC. Here, we found that miR-494 was significantly decreased in EOC cell lines and tissues and its expression was negatively correlated with advanced International Federation of Gynecology and Obstetrics (FIGO) stage, high pathological grade, and lymph node metastasis (all P < 0.01). Functional studies showed that overexpression of miR-494 in EOC cells could remarkably inhibit proliferation, colony formation, migration, and invasion and induce cell apoptosis, G0/G1 phase arrest. An in vivo analysis revealed that the overexpression of miR-494 suppressed tumor growth in a nude mouse xenograft model system. Bioinformatic assay and dual-luciferase assay confirmed that insulin-like growth factor 1 receptor (IGF1R) was as a direct target of miR-494 in EOC cells. Western blot assay showed that overexpression of miR-494 inhibited IGF1R expression and its downstream signal protein expression. In addition, downregulation of IGF1R has similar effects with miR-494 overexpression on EOC cells and overexpression of IGF1R effectively rescued the inhibition of overexpressed miR-494 in EOC cells. These data suggested that miR-494 functions as a tumor suppressor in EOC by targeting IGF1R.

Nedd4L expression is decreased in ovarian epithelial cancer tissues compared to ovarian non-cancer tissue.

AIM: Recent studies have demonstrated that the neural precursor cell expressed, developmentally downregulated 4-like (Nedd4L) gene plays a role in the progression of various cancers. However, reports describing Nedd4L expression in ovarian cancer tissues are limited. MATERIAL AND METHODS: A cohort (n = 117) of archival formalin-fixed, paraffin embedded resected normal ovarian epithelial tissues (n = 10), benign ovarian epithelial tumor tissues (n = 10), serous borderline ovarian epithelial tumor tissues (n = 14), mucous borderline ovarian epithelial tumor tissues (n = 11), and invasive ovarian epithelial cancer tissues (n = 72) were assessed for Nedd4L protein expression using immunohistochemistry. RESULTS: Nedd4L protein expression was significantly decreased in invasive ovarian epithelial cancer tissues compared to non-cancer tissues (P < 0.05). Decreased Nedd4L protein expression correlated with clinical stage, pathological grade, lymph node metastasis and survival (P < 0.05). CONCLUSION: Nedd4L protein expression may be an independent prognostic marker of ovarian cancer development.

Sclerosing Stromal Ovarian Tumor Combined with Early Onset Severe Preeclampsia. A Case Report.

BACKGROUND: Sclerosing stromal tumor (SST) of the ovary is an extremely rare, benign, sex cord-stromal tumor. The tumor consists of cells with the multilineage potential of undifferentiated mesenchymal cells and the ability to secrete estrogen or androgen. Current research suggests that the tumor originates in the ovarian cortex. SSTs of the ovary are predominantly found in young women aged 20-30 years; information describing SST during pregnancy is limited. CASE: We report a case of SST of the ovary combined with early onset severe preeclampsia. CONCLUSION: We document the clinical and pathological characteristics of the patient's disease, including the effects on the pregnancy and fetus.

A de novo germline mutation of APC for inheritable colon cancer in a Chinese family using multigene next generation sequencing.

Inheritable colorectal cancers (CRC) accounted for about 20% of the CRC cases, such as hereditary nonpolyposis colorectal cancer (HNPCC), Gardner syndrome and familial adenomatous polyposis (FAP). A four-generation Han Chinese family was found affected with polyposis in colons. Inferred from the pedigree structure, the disease in this family showed an autosomal dominant inheritance model. To locate the causal mutations in this family, genomic DNAs were extracted and the next generation sequencing for 5 genes relating to colon cancer performed by Ion Torrent Personal Genome Machine with a 314 chip. The reads were aligned with human reference genome hg19 to call variants in the 5 genes. After analysis, 14 variants were detected in the sequenced sample and 13 been collected in dbSNP database and assigned with a rs identification number. In these variants, 9 were synonymous, 4 missense and 1 non-sense. In them, 2 rare variants (c.694C>T in APC and c.1690A>G in MSH2) might be the putative causal mutations for familial adenomatous polyposis (FAP) since the rarity of the mutated allele in normal controls. c.694C>T was detected in only affected members and generated a premature stop codon in APC. It should be a de novo germline mutation making APC containing this stop codon as targets for nonsense-mediated mRNA decay (NMD). c.1690A>G in MSH2 was not only detected in affected members, but also in normal ones in the family. Functional prediction revealed that the amino acid affected by this variant had no effect on the function of MSH2. Here, we report a de novo germline mutation of APC as the causal variant in a Chinese family with inheritable colon cancer by the next generation sequencing.

In vitro and in vivo anti-cancer activity of formononetin on human cervical cancer cell line HeLa.

Worldwide, cervical cancer (CC) is the third most common malignancy in women, and it remains a leading cause of cancer-related death of women. Genomic studies indicate that phosphoinositide 3-kinase (PI3K)/AKT signaling is one of the most frequently deregulated pathways in several human cancers, including CC. This signaling pathway has an important role in cancer cell proliferation, survival, motility, and metabolism, and therefore could be an attractive therapeutic target. In a previous study, we used a sensitive and high-speed homogeneous assay for the detection of kinase activity and for screening of PI3K/AKT signaling inhibitors in a high-throughput screening (HTS) format and then obtain formononetin, as an O-methylated isoflavone existed in a number of plants and herbs like Astragalus membranaceus. We showed that formononetin inhibited the phosphorylation of AKT and induced the apoptosis of CC cell line HeLa in a dose-dependent manner. Furthermore, formononetin suppressed xenograft tumor growth in nude mice. Our results indicated that formononetin may be used as an anti-cancer drug for cervical cancer in the future.

[Pro-apoptotic effects of curcumin associated with CIK cells against ovarian carcinoma cells].

OBJECTIVE: To observe the pro-apoptotic effects of Curcumin associated with CIK cells against SKOV3 cells of ovarian carcinoma and discusses the possible molecular mechanisms. METHODS: CIK cells were induced from umbilicus cord blood. The apoptotic morphology of SKOV3 cells was observed under electron microscope after treated with Cur, CIK cells and Cur associated with CIK cells. The levels of Fas protein on surface of ovarian cancer cells and FasL protein on surface of CIK cells after Curcumin treatment were determined by Western blot. The inhibition rates on proliferation of CIK cells and Cur associated with CIK cells after addition of FasL monoclonal antibody were detected by (thiazolyl blue tetrazolium bromide) MTT. RESULTS: The changes of apoptotic morphology in the group of Cur associated with CIK cells were most obvious compared with that in the group of Cur or CIK cells alone. Cur could promote the expression of Fas on surface of SKOV3 cells and FasL on membranes of CIK cells. The inhibition rates on proliferation in the group of CIK cells and Cur associated with CIK cells could be restrained obviously after an addition of anti-FasmAb. CONCLUSION: The pro-apoptotic effects of SKOV3 cells increase with the combined use of Cur and CIK cells. The mechanism may be that Cur can promote the expression of Fas protein on cell surface of SKOV3 cells and FasL protein on cell membrane of CIK cells so as to up-regulate the expression of Fas protein in SKOV3 cells and lead ultimately to the a higher expression of Caspase3.

[Inhibition of GRP78 expression reverses cisplatin resistance in human ovarian cancer].

OBJECTIVE: To explore the effects of GRP78 suppression on the sensitivity to cisplatin and elucidate the role and mechanism of GRP78 in ovarian cancer cisplatin resistance. METHODS: The GRP78 siRNA expression plasmid was constructed to suppress GRP78 expression. Cell viability was detected by methyl thiazolyl tetrazolium (MTT) assay. Endoplasmic reticulum stress-related apoptosis related protein expressions were detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. And cell apoptosis was detected by flow cytometry. RESULTS: The expressions of GRP78, CHOP and cleaved-caspase 4 were induced significantly by cisplatin (6 mg/L) in SKOV3 cells. And the expression of GRP78 was induced significantly by cisplatin in SKOV3/DDP cells. But the expressions of CHOP and cleaved-caspase 4 showed no significant difference. Inhibition of GRP78 expression and cisplatin combined treatment significantly increased the expressions of cleaved-caspase 4 and cleaved-caspase 3 in SKOV3/DDP cells. Inhibition of GRP78 expression reduced the cisplatin-induced up-regulations of p-Akt and p-mTOR and induced XBP1 mRNA shear expression and CHOP mRNA expression. CONCLUSION: Inhibition of GRP78 expression reverses cisplatin resistance in SKOV3/DDP cells. The mechanism may be through the activity of Akt/mTOR signaling pathway, CHOP expression levels and caspase activity.

[Expression and role of glucose-regulated protein 78 in ovarian serous adenocarcinoma].

OBJECTIVE: To explore the expression and role of glucose-regulated protein 78 in ovarian serous adenocarcinoma. METHODS: The surgical specimens were collected from 126 cases of serous ovarian tumors and 30 cases of normal ovarian tissue. And the mRNA and protein expressions of GRP78 were detected by immunohistochemistry, reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. RESULTS: The results of immunohistochemistry showed that GRP78 positive cells in ovarian serous adenocarcinoma were significantly higher than those in normal ovarian and ovarian serous cystadenoma tissues (P < 0.05). In ovarian serous adenocarcinoma, GRP78 expression was not associated with pathological grade, age and clinical staging (P > 0.05). And the mRNA expressions of GRP78 in normal ovarian tissue, ovarian serous cystadenoma and ovarian serous cystadenocarcinoma were 0.134 ± 0.021, 0.121 ± 0.032 and 0.685 ± 0.085 respectively. Protein expressions of GRP78 in normal ovarian tissue, ovarian serous cystadenoma and ovarian serous cystadenocarcinoma were 0.211 ± 0.042, 0.193 ± 0.032 and 0.770 ± 0.074 respectively. GRP78 mRNA and protein expression had no difference between different pathological grades of ovarian serous cystadenocarcinoma (P > 0.05). CONCLUSION: GRP78 is highly expressed in ovarian serous adenocarcinoma. And its differential expression between ovarian benign and malignant tumors is significant and correlated with the occurrence and progression of ovarian cancer.