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Persistent infection with the carcinogenic human papillomavirus (HPV) is a prerequisite for the progression of cervical lesions and cancer. A growing body of research has focused on the functional role of the vaginal microbiota in the persistence of HPV infection. Understanding the microbial composition and structure in women with high-risk (hr)-HPV infection may help reveal associations between the vaginal microbiota and HPV infection, and identify potential biomarkers. Our study investigated the vaginal microbial community in women with and without hr-HPV infection, by using 16s rRNA gene sequencing. We found that microbial perturbations occurred in the early phase of hr-HPV infection. Lactobacillus and Sporolactobacillus were decreased, while bacteria related to bacterial vaginosis (BV), such as Gardnerella, Prevotella, Dialister, Slackia, Actinomyces, Porphyromonas, Peptoniphilus, Anaerococcus, Peptostreptococcus, Streptococcus, Ureaplasma, Megasphaera, and Mycoplasma were increased. Our results could offer insights into the correlations between hr-HPV and the vaginal microbiota in the early infection period, and provide indications that the predominance of some BV-associated bacteria during hr-HPV infection may increase the risk for cervical neoplasia.

Chaperone-mediated autophagy (CMA) is one of the three types of autophagy. In recent years, CMA has been shown to be associated with the pathogenesis of several types of cancer. However, whether CMA is involved in the pathogenesis of colorectal cancer (CRC) remains unclear. In this study, we investigated CMA activity in tissue specimens from CRC patients and mouse models of colitis-associated CRC (induced by administration of AOM plus DSS). In addition, we down-regulated CMA in CT26 colon carcinoma cells stably transfected with a vector expressing a siRNA targeting LAMP-2A, the limiting component in the CMA pathway, to explore the role of CMA in these cells. Apoptosis was detected using TUNEL assay, and the apoptosis-related proteins were detected using western blotting. Cell proliferation was assessed using MTT assay, Ki-67 labelling and western blotting for PCNA. We found that LAMP-2A expression was significantly increased in CRC patients and mouse models and varied according to the stage of the disease. Inhibition of CMA in CT26 cells facilitated apoptosis, as evidenced by increased TUNEL immunolabeling, increased expression of Bax and Bnip3, and decreased expression of Bcl-2. Cell proliferation assays showed that inhibition of CMA impeded the proliferation of CT26 cells. These data support the hypothesis that CMA is up-regulated in CRC, and inhibition of CMA may be a new therapeutic strategy for CRC patients.

We evaluated the efficacy and feasibility of the combination of gemcitabine plus vinorelbine in patients with platinum-based chemotherapy-refractory esophageal cancer. We enrolled 35 patients who received gemcitabine plus vinorelbine as second-line treatment after platinum-based chemotherapy failure between May 2009 and April 2012. Dosage: gemcitabine 1,000 mg/m2 plus vinorelbine 25 mg/m2; all drugs were administered on days 1 and 8 of a 21-day cycle, and this was continued until failure or unacceptable toxicity. A total of 125 cycles of treatment were administered, and all patients received at least two cycles of treatment (two to five cycles; median number of cycles: three). Thirty-two patients were evaluable for response. The response rate was 31.3%, and the disease control rate (partial response plus stable disease) was 62.5%. The progression-free survival (PFS) was 4.3 ± 0.2 months [95% confidence interval (CI), 4.0‐4.6], and the median overall survival (OS) was 7.3 ± 0.3 months (95% CI, 6.7‐7.8). In the subgroup analysis, median PFS was 4.0 ± 0.2 months (95% CI, 3.6‐4.3) in patients with high expression of miRNA-214, while it was 4.6 ± 0.3 months (95% CI, 4.1‐5.1) in patients with low expression of miRNA-214 (log rank = 0.023). Myelosuppression with neutropenia and thrombocytopenia was the most common side effect observed with this combination regimen, and higher than grade 3 neutropenia and thrombocytopenia were observed in 10 (31.3%) and 8 patients (25.0%), respectively. Grade 3 fatigue was the most common nonhematologic toxicity, which was observed in 2 (6.1%) patients. The combination of gemcitabine plus vinorelbine was well tolerated as second-line treatment for platinum-based chemotherapy-refractory esophageal cancer patients and appeared to provide enhanced clinical activity especially in patients with low expression of miRNA-214.

Bo Liu, Li Han, Junyan Liu, Shumei Han, Zhen Chen, Lixi Jiang Department of Internal Medicine Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Science, Ji’nan, People’s Republic of China Background: Cervical cancer is a major world health problem for women. Currently, cancer research focuses on improving therapy for cervical cancer using various treatment options such as co-delivery of chemotherapeutic agents by nanocarriers.Purpose: The aim of this study was to develop trans-activating transcriptional activator (TAT)-modified solid lipid nanoparticles (SLNs) for co-delivery of paclitaxel (PTX) and α-tocopherol succinate-cisplatin prodrug (TOS-CDDP) (TAT PTX/TOS-CDDP SLNs) in order to achieve synergistic antitumor activity against cervicalcancer.Methods: Lipid prodrug of CDDP (TOS-CDDP) and TAT-containing polyethylene glycol-distearoyl-phosphatidylethanolamine (TAT-PEG-DSPE) were synthesized. TAT PTX/TOS-CDDP SLNs were prepared by emulsification and solvent evaporation method. Physicochemical characteristics of SLNs such as size, morphology, and release profiles were explored. In vitro and in vivo studies were carried out to assess the efficacy of their antitumor activity in target cells.Results: TAT PTX/TOS-CDDP SLNs could be successfully internalized by HeLa cells and showed a synergistic effect in the suppression of cervical tumor cell growth. They exhibited high tumor tissue accumulation, superior antitumor efficiency, and much lower toxicity in vivo.Conclusion: The present study indicates that the co-delivery system provides a promising platform as a combination therapy for the treatment of cervical cancer, and possibly other types of cancer as well. Keywords: cervical cancer, lipid-based prodrug, combination therapy, solid lipid nanoparticles, cell-penetrating peptide

1-Aminocyclopropane-1-carboxylic acid synthase (ACS) and 1-aminocyclopropane-1-carboxylic acid oxidase (ACO) are encoded by multigene families and are involved in fruit ripening by catalyzing the production of ethylene throughout the development of fruit. However, there are no reports on ACS or ACO genes in mulberry, partly because of the limited molecular research background. In this study, we have obtained five ACS gene sequences and two ACO gene sequences from Morus Genome Database. Sequence alignment and phylogenetic analysis of MaACO1 and MaACO2 showed that their amino acids are conserved compared with ACO proteins from other species. MaACS1 and MaACS2 are type I, MaACS3 and MaACS4 are type II, and MaACS5 is type III, with different C-terminal sequences. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) expression analysis showed that the transcripts of MaACS genes were strongly expressed in fruit, and more weakly in other tissues. The expression of MaACO1 and MaACO2 showed different patterns in various mulberry tissues. MaACS and MaACO genes demonstrated two patterns throughout the development of mulberry fruit, and both of them were strongly up-regulated by abscisic acid (ABA) and ethephon.

Background and aims Advances in the treatment of cervical cancer over the last decade have predominantly involved the development of genes directed at molecular targets. Gene therapy is recognized to be a novel method for the treatment of cervical cancer. Genes can be administered into target cells via nanocarriers. This study aimed to develop systemically administrable nano-vectors. Floate (Fa) containing gene loaded nanoparticles (NPs) could target HeLa human cervical cancer cells through combination with receptors on the cells to increase the nuclear uptake of genetic materials. Methods Fa was linked onto Poly (ethylene glycol)-b-poly (D, L-lactide) (PEG-PLA) to form Fa-PEG-PLA, and the resulting material was used to load plasmids of enhanced green fluorescence protein (pEGFP) to obtain gene loaded nanoparticles (Fa-NPs/DNA). Physical-chemical characteristics, in vitro release and cytotoxicity of Fa-NPs/DNA were evaluated. The in vitro transfection efficiency of Fa-NPs/ DNA was evaluated in HeLa cells and human umbilical vein endothelial cells (HUVEC). PEG-PLA without Fa was used to load pEGFP from NPs/DNA as a control. Results Fa-NPs/DNA has a particle size of 183 nm and a gene loading quantity of 92%. After 72h of transfection, Fa-NPs/DNA displayed over 20% higher transfection efficiency than NPs/DNA and 40% higher than naked DNA in HeLa cells. However, in HUVECs, no significant difference appeared between Fa-NPs/DNA and NPs/DNA. Conclusions Fa-PEG-PLA NPs could function as excellent materials for gene loading. This nano-approach could be used as tumor cell targeted medicine for the treatment of cervical cancer.

Excess fluoride intake could induce apoptosis in the cells. As an essential micronutrient and cytoprotectant, zinc is involved in many types of apoptosis. Here, we studied the effects of zinc and ZIP1 on fluoride-induced apoptosis in mouse MC3T3-E1 cells and examined the underlying molecular mechanisms. Our study found that fluoride not only inhibited cell proliferation and increased the intracellular reactive oxygen species (ROS) but also induced cell apoptosis. Whereas pretreatment with zinc significantly attenuated fluoride-induced ROS production and partly protected cells against fluoride-induced apoptosis through MAPK/ERK signaling pathway. Our study also found that fluoride upregulated the expression of ZIP1 in a time-dependent manner. Moreover, overexpression of ZIP1 also inhibited fluoride-induced apoptosis by activation of PI3K/Akt pathway. This cytoprotective effect of zinc and ZIP1 may be new factors that affect the physiological activity of fluoride and need study further.

Ovarian cancer is a highly invasive and metastatic disease with poor prognosis, particularly if this disease is diagnosed at an advanced stage, which is often the case. Researchers have argued that ovarian cancer cells that have undergone epithelial-to-mesenchymal transition (EMT) acquire aggressive malignant properties; however, the relevant molecular mechanisms in this setting are poorly understood. In cancer cases, the transcription factor forkhead box protein C2 (FOXC2) has been detected, but the function of this factor in ovarian cancer tumorigenesis remains unclear. In the present study, FOXC2 was overexpressed in invasive ovarian cancer cell lines and tissues. The invasive potential of ovarian cancer cells was significantly increased by ectopic FOXC2 expres - sion but it was significantly decreased by RNA interference targeting FOXC2. E-cadherin and vimentin expression levels were modulated by FOXC2. These results indicated that FOXC2 was required for the maintenance of the mesenchymal phenotype after TGF-β1 induced EMT in human ovarian cancer cells. Thus, FOXC2 or its associated gene expression program may provide an effective target for anti-EMT-based therapies. These therapies can then be performed to treat inva- sive ovarian tumor.

Metastasis has become the main challenge for treatment of estrogen receptor alpha (ERα) negative breast cancer. Here, we found a negative correlation between miR-497 and estrogen-related receptor alpha (ERRα), a nuclear receptor overexpressed in ERα negative breast cancer. Targeted inhibition of ERRα by si-RNA increased miR-497 expression while overexpression of ERRα inhibited miR-497 expression. Further investigation showed that miR-497 targeted ERRα by binding to the 3'UTR region of ERRα. Luciferase assay and ChIP assay confirmed that ERα directly regulated the transcription of miR-497, suggesting that loss of ERα lowered miR-497 level in ERα negative breast cancer. Further, overexpression of miR-497 not only inhibited ERRα expression but also reduced MIF level and MMP9 activity, which led to significant decreases in cell proliferation, migration, and invasion of ERα negative breast cancer. Taken together, our findings suggested that, in ERα negative breast cancer, the low level of ERα reduced miR-497 expression, which promoted ERRα expression that enhanced cell proliferation, migration, and invasion by increasing MIF expression and MMP9 activity.

To investigate the optimal condition for in vitro cultivation of Trichomonas vaginalis for obtaining a better harvest of T. vaginalis.An isolate of T. vaginalis from clinical specimens was cultivated in three different media with initial inoculation of 9.0 x 10(4)/ml under pH 5.6.There was distinct difference after 96 h incubation in the cumulative harvest of T. vaginalis. The highest harvest was received in cysteine/liver/peptone/maltose medium, followed by the liver/peptone/maltose medium and soybean/liver/peptone/maltose medium.The cysteine/liver/peptone/maltose medium may be a suitable environment for in vitro multiplication of T. vaginalis.

Background The purpose of the present study was to examine the expression levels of microRNA-9 (miR-9) in osteosarcoma tissues and normal bone tissues, and investigate the relationships between miR-9 expression, clinicopathological features and the prognosis of patients with osteosarcoma. Methods The expression levels of miR-9 in osteosarcoma tissues and corresponding non-cancerous tissues were detected using a real-time quantitative assay. Differences in patient survival were determined using the Kaplan–Meier method and a log-rank test. A Cox proportional hazards regression analysis was used for univariate and multivariate analyses of prognostic values. Results Compared to non-cancerous bone tissues, the expression levels of miR-9 in osteosarcoma tissues were significantly elevated (P