Periostin promotes ovarian cancer metastasis by enhancing M2 macrophages and cancer-associated fibroblasts via integrin-mediated NF-κB and TGF-ß2 signaling.

BACKGROUND: Ovarian cancer has the highest mortality among gynecological cancers due to late diagnosis and lack of effective targeted therapy. Although the study of interplay between cancer cells with their microenvironment is emerging, how ovarian cancer triggers signaling that coordinates with immune cells to promote metastasis is still elusive. METHODS: Microarray and bioinformatics analysis of low and highly invasive ovarian cancer cell lines were used to reveal periostin (POSTN), a matrix protein with multifunctions in cancer, with elevated expression in the highly invasive cells. Anchorage independent assay, Western blot, RNA interference, confocal analysis and neutralizing antibody treatment were performed to analyze the effects of POSTN on tumor promotion and to explore the underlying mechanism. Chemotaxis, flow cytometry and cytokine array analyses were undertaken to analyze the involvement of POSTN in cancer-associated fibroblast (CAF) and macrophage modulation. Correlations between POSTN expression levels and clinical characteristics were analyzed using the Oncomine, commercial ovarian cancer cDNA and China Medical University Hospital patient cohort. In vivo effect of POSTN on metastasis was studied using a mouse xenograft model. RESULTS: Expression of POSTN was found to be elevated in highly invasive ovarian cancer cells. We observed that POSTN was co-localized with integrin ß3 and integrin ß5, which was important for POSTN-mediated activation of ERK and NF-κB. Ectopic expression of POSTN enhanced whereas knockdown of POSTN decreased cancer cell migration and invasion in vitro, as well as tumor growth and metastasis in vivo. POSTN enhanced integrin/ERK/NF-κB signaling through an autocrine effect on cancer cells to produce macrophage attracting and mobilizing cytokines including MIP-1ß, MCP-1, TNFα and RANTES resulting in increased chemotaxis of THP-1 monocytes and their polarization to M2 macrophages in vitro. In agreement, tumors derived from POSTN-overexpressing SKOV3 harbored more tumor-associated macrophages than the control tumors. POSTN induced TGF-ß2 expression from ovarian cancer cells to promote activation of adipose-derived stromal cells to become CAF-like cells expressing alpha smooth muscle actin and fibroblast activation protein alpha. Consistently, increased CAFs were observed in POSTN overexpressing SKOV3 cells-derived metastatic tumors. In clinical relevance, we found that expression of POSTN was positively correlated with advanced-stage diseases and poor overall survival of patients. CONCLUSIONS: Our study revealed a POSTN-integrin-NF-κB-mediated signaling and its involvement in enhancing M2 macrophages and CAFs, which could potentially participate in promoting tumor growth. Our results suggest that POSTN could be a useful prognosis marker and potential therapeutic target.

Factors related to changes in resilience and distress in women with endometrial cancer.

The purpose of the study is to explore changes in resilience and physical and psychological distress and their related factors over time in women with endometrial cancer. This study adopted a repeated measures design using purposive sampling and was conducted in a hospital in Taiwan. Data were collected before surgery, 2 weeks after surgery, and 3 months after surgery. The measured variables consisted of demographic and disease characteristics, social support, resilience, and physical and psychological distress. A total of 48 women participated in the study, of whom 42 (mean age = 54.2 years old) completed all of the questionnaires. The results showed that resilience and physical distress in women with endometrial cancer was not statistically significantly changed over time. Rather, their psychological distress was significantly alleviated 2 weeks and 3 months after surgery as compared to before surgery. Women with less social support showed a lower level of resilience. In addition, those with a lower level of resilience experienced greater psychological distress. Compared with those who received only surgical treatment, women who had undergone surgery combined with chemotherapy and radiotherapy had more physical distress. Clinical medical staff should conduct continuing assessments of the resilience, physical distress, and psychological distress of women with endometrial cancer. Interventions related to resilience-enhancing and self-care should be implemented to avoid worsening or to improve women's resilience and distress.

Evaluation of a Simple and Safe Tumor Drilling Technique to Potentiate the Effect of Intraperitoneal Chemotherapy in the Treatment of Recurrent Epithelial Ovarian, Tubal, and Peritoneal Cancer: A Matched Retrospective Cohort Study.

Frontline intraperitoneal chemotherapy (IPCT) in the treatment of epithelial ovarian cancer has been well established. However, the role of second-line IPCT is yet to be confirmed. With a view to implementing IPCT to treat recurrent disease, a prerequisite is to perform a cytoreductive procedure to minimize residual tumor size. However, the role of cytoreductive procedure is still in debate due to a higher chance of complications. A matched retrospective cohort study was conducted. From 2008 to 2015, we adopted a relatively simple and safe tumor drilling technique to maximize tumor exposure to second-line IPCT. Patients who received tumor drilling followed by second-line IPCT constituted the cohort group. Concurrently, patients who received standard second-line systemic chemotherapy were selected as the comparison group. After propensity score matching, 85 patients in each group entered into the final analysis. The median progression-free survival was 7.3 months (95% confidence interval [CI], 6.2-7.8) for the cohort group versus 4.1 months (95% CI, 4.0-4.3) for the comparison group (hazard ratio = 0.25 [95% CI, 0.17-0.36]; P < .001, by log-rank test). The median overall survival was 33.6 months (32.1-36.6) for the cohort group versus 25.9 months (20.5-26.9) for the comparison group (hazard ratio = 0.33 [95% CI, 0.23-0.48]; P < .001, by log-rank test). Toxicities in the cohort group were not different from those that were published in reports of IPCT for ovarian cancer. The most commonly observed toxicity was gastrointestinal origin (51.7%), and it may be attributed to the intraperitoneal pharmacokinetic clearance of cisplatin and taxol and we also discussed the mechanism of gastrointestinal toxicity. Tumor drilling followed by second-line IPCT may confer a survival advantage over standard second-line systemic chemotherapy in the treatment of recurrent ovarian cancer.

188Re-Liposome Can Induce Mitochondrial Autophagy and Reverse Drug Resistance for Ovarian Cancer: From Bench Evidence to Preliminary Clinical Proof-of-Concept.

Despite standard treatment, about 70% of ovarian cancer will recur. Cancer stem cells (CSCs) have been implicated in the drug-resistance mechanism. Several drug resistance mechanisms have been proposed, and among these, autophagy plays a crucial role for the maintenance and tumorigenicity of CSCs. Compared to their differentiated counterparts, CSCs have been demonstrated to display a significantly higher level of autophagy flux. Moreover, mitophagy, a specific type of autophagy that selectively degrades excessive or damaged mitochondria, is shown to contribute to cancer progression and recurrence in several types of tumors. Nanomedicine has been shown to tackle the CSCs problem by overcoming drug resistance. In this work, we developed a nanomedicine, 188Re-liposome, which was demonstrated to target autophagy and mitophagy in the tumor microenvironment. Of note, the inhibition of autophagy and mitophagy could lead to significant tumor inhibition in two xenograft animal models. Lastly, we presented two cases of recurrent ovarian cancer, both in drug resistance status that received a level I dose from a phase I clinical trial. Both cases developing drug resistance showed drug sensitivity to 188Re-liposome. These results suggest that inhibition of autophagy and mitophagy by a nanomedicine may be a novel strategy to overcome drug resistance in ovarian cancer.

Discovering the Deregulated Molecular Functions Involved in Malignant Transformation of Endometriosis to Endometriosis-Associated Ovarian Carcinoma Using a Data-Driven, Function-Based Analysis.

The clinical characteristics of clear cell carcinoma (CCC) and endometrioid carcinoma EC) are concomitant with endometriosis (ES), which leads to the postulation of malignant transformation of ES to endometriosis-associated ovarian carcinoma (EAOC). Different deregulated functional areas were proposed accounting for the pathogenesis of EAOC transformation, and there is still a lack of a data-driven analysis with the accumulated experimental data in publicly-available databases to incorporate the deregulated functions involved in the malignant transformation of EOAC. We used the microarray gene expression datasets of ES, CCC and EC downloaded from the National Center for Biotechnology Information Gene Expression Omnibus (NCBI GEO) database. Then, we investigated the pathogenesis of EAOC by a data-driven, function-based analytic model with the quantified molecular functions defined by 1454 Gene Ontology (GO) term gene sets. This model converts the gene expression profiles to the functionome consisting of 1454 quantified GO functions, and then, the key functions involving the malignant transformation of EOAC can be extracted by a series of filters. Our results demonstrate that the deregulated oxidoreductase activity, metabolism, hormone activity, inflammatory response, innate immune response and cell-cell signaling play the key roles in the malignant transformation of EAOC. These results provide the evidence supporting the specific molecular pathways involved in the malignant transformation of EAOC.

Front-line intraperitoneal versus intravenous chemotherapy in stage III-IV epithelial ovarian, tubal, and peritoneal cancer with minimal residual disease: a competing risk analysis.

BACKGROUND: In the analysis of survival data for cancer patients, the problem of competing risks is often ignored. Competing risks have been recognized as a special case of time-to-event analysis. The conventional techniques for time-to-event analysis applied in the presence of competing risks often give biased or uninterpretable results. METHODS: Using a prospectively collected administrative health care database in a single institution, we identified patients diagnosed with stage III or IV primary epithelial ovarian, tubal, and peritoneal cancers with minimal residual disease after primary cytoreductive surgery between 1995 and 2012. Here, we sought to evaluate whether intraperitoneal chemotherapy outperforms intravenous chemotherapy in the presence of competing risks. Unadjusted and multivariable subdistribution hazards models were applied to this database with two types of competing risks (cancer-specific mortality and other-cause mortality) coded to measure the relative effects of intraperitoneal chemotherapy. RESULTS: A total of 1263 patients were recruited as the initial cohort. After propensity score matching, 381 patients in each arm entered into final competing risk analysis. Cumulative incidence estimates for cancer-specific mortality were statistically significantly lower (p = 0.017, Gray test) in patients receiving intraperitoneal chemotherapy (5-year estimates, 34.5%; 95% confidence interval [CI], 29.5-39.6%, and 10-year estimates, 60.7%; 95% CI, 52.2-68.0%) versus intravenous chemotherapy (5-year estimates, 41.3%; 95% CI, 36.2-46.3%, and 10-year estimates, 67.5%, 95% CI, 61.6-72.7%). In subdistribution hazards analysis, for cancer-specific mortality, intraperitoneal chemotherapy outperforms intravenous chemotherapy (Subdistribution hazard ratio, 0.82; 95% CI, 0.70-0.96) after correcting other covariates. CONCLUSIONS: In conclusion, results from this comparative effectiveness study provide supportive evidence for previous published randomized trials that intraperitoneal chemotherapy outperforms intravenous chemotherapy even eliminating the confounding of competing risks. We suggest that implementation of competing risk analysis should be highly considered for the investigation of cancer patients who have medium to long-term follow-up period.

Second-Line Intraperitoneal Chemotherapy for Recurrent Epithelial Ovarian, Tubal and Peritoneal Cancer: A Propensity Score-Matching Study.

BACKGROUND: The superiority of frontline intraperitoneal (IP) over intravenous (IV) chemotherapy is well established in the treatment of epithelial ovarian cancer. However, the role of IP chemotherapy in the second-line setting has rarely been investigated. METHODS: Consecutive patients diagnosed with recurrent epithelial, tubal and peritoneal cancers between January 2000 and December 2012 were recruited using a propensity score-matching technique to adjust relevant risk factors. RESULTS: In total, 310 patients were included in the final analysis (94 for platinum-refractory/resistant disease and 216 for platinum-sensitive disease). IP chemotherapy demonstrated significantly longer median progression-free survival than IV chemotherapy (4.9 vs. 2.4 months, p < 0.001, for platinum-refractory/resistant disease, and 9.8 vs. 6.9 months, p < 0.001, for platinum-sensitive disease). CONCLUSIONS: Second-line IP chemotherapy confers longer progression-free survival than IV chemotherapy. Large-scale clinical trials should be conducted to validate the true efficacy.

Gene Set-Based Functionome Analysis of Pathogenesis in Epithelial Ovarian Serous Carcinoma and the Molecular Features in Different FIGO Stages.

Serous carcinoma (SC) is the most common subtype of epithelial ovarian carcinoma and is divided into four stages by the Federation of Gynecologists and Obstetrics (FIGO) staging system. Currently, the molecular functions and biological processes of SC at different FIGO stages have not been quantified. Here, we conducted a whole-genome integrative analysis to investigate the functions of SC at different stages. The function, as defined by the GO term or canonical pathway gene set, was quantified by measuring the changes in the gene expressional order between cancerous and normal control states. The quantified function, i.e., the gene set regularity (GSR) index, was utilized to investigate the pathogenesis and functional regulation of SC at different FIGO stages. We showed that the informativeness of the GSR indices was sufficient for accurate pattern recognition and classification for machine learning. The function regularity presented by the GSR indices showed stepwise deterioration during SC progression from FIGO stage I to stage IV. The pathogenesis of SC was centered on cell cycle deregulation and accompanied with multiple functional aberrations as well as their interactions.

Gene Set-Based Integrative Analysis Revealing Two Distinct Functional Regulation Patterns in Four Common Subtypes of Epithelial Ovarian Cancer.

Clear cell (CCC), endometrioid (EC), mucinous (MC) and high-grade serous carcinoma (SC) are the four most common subtypes of epithelial ovarian carcinoma (EOC). The widely accepted dualistic model of ovarian carcinogenesis divided EOCs into type I and II categories based on the molecular features. However, this hypothesis has not been experimentally demonstrated. We carried out a gene set-based analysis by integrating the microarray gene expression profiles downloaded from the publicly available databases. These quantified biological functions of EOCs were defined by 1454 Gene Ontology (GO) term and 674 Reactome pathway gene sets. The pathogenesis of the four EOC subtypes was investigated by hierarchical clustering and exploratory factor analysis. The patterns of functional regulation among the four subtypes containing 1316 cases could be accurately classified by machine learning. The results revealed that the ERBB and PI3K-related pathways played important roles in the carcinogenesis of CCC, EC and MC; while deregulation of cell cycle was more predominant in SC. The study revealed that two different functional regulation patterns exist among the four EOC subtypes, which were compatible with the type I and II classifications proposed by the dualistic model of ovarian carcinogenesis.

The risk of irritable bowel syndrome in patients with endometriosis during a 5-year follow-up: a nationwide population-based cohort study.

PURPOSE: Studies have suggested that endometriosis may coexist with irritable bowel syndrome (IBS). Using a population-based cohort study, we followed subjects for a 5-year period to identify the risk of IBS after a diagnosis of endometriosis. METHODS: This cohort study used the Taiwan National Health Insurance Database as a source of subjects. A total of 6076 patients with endometriosis from 2000 to 2005 were identified. Their data were compared with those of 30,380 age-matched controls without endometriosis who were randomly selected from the same database. All subjects were tracked for 5 years from the date of cohort entry to identify the risk of IBS. The Cox model was used to evaluate the 5-year event occurrence of IBS. RESULTS: Nine hundred twenty-six patients were diagnosed with IBS, including 256 in the case cohort (4.2%) and 670 in the control cohort (2.2%). The Kaplan-Meier survival curves demonstrated significantly lower event-free rates in the case cohort than in the control cohort (P = 0.001). After adjusting for urbanization level, monthly income, residential region and comorbidities, the hazard ratio (HR) within 5 years revealed a 1.79-fold (95% confidence interval [CI] 1.55-2.07) greater risk among the cases than the controls. The HR was higher within the first year of follow-up (HR 1.90, 95% CI 1.42-2.55) and in those women aged 25-34 years (HR 2.17, 95% CI 1.61-2.92). CONCLUSIONS: The risk of IBS among endometriosis patients persisted over 5 years of follow-up. The association detected in this study might have proceeded through shared risk and pathogenic factors.

Increased association between endometriosis and endometrial cancer: a nationwide population-based retrospective cohort study.

OBJECTIVE: Association between endometriosis and ovarian cancer has been well established. Nonetheless, endometriosis may also be associated with endometrial cancer because of shared etiological mechanisms of both estrogen stimulation and chronic inflammation; however, the association between these 2 disorders has rarely been investigated. METHODS: The National Health Insurance Research Databases in Taiwan were retrieved and analyzed. The case cohort consisted of patients with a diagnosis of endometriosis between January 1997 and December 2000 (N = 15,488). For the construction of control cohort, 8 age- and sex-matched control patients for every patient in the case cohort were selected using a random sampling method (n = 123,904). All subjects were tracked for 10 years from the date of entry to identify whether they had developed endometrial cancer. The Cox proportional hazards regression model was used to evaluate 10-year event occurrence of endometrial cancer. RESULTS: During the 10-year follow-up period, 392 participants developed endometrial cancer, with 104 (0.7%) distributed in the case cohort and 288 (0.2%) in the control cohort. Multivariable Cox regression modeling demonstrates a higher risk for developing endometrial cancer in the case cohort than in the control cohort (adjusted hazard ratio [aHR], 2.83; 95% confidence interval [CI], 1.495.35; P < 0.01). Age at diagnosis of endometriosis shows a moderator effect: when 40 years or younger, the risk for developing endometrial cancer was comparable between the case cohort and the control cohort (aHR, 1.42; 95% CI, 0.55-3.70; P = 0.226), whereas when older than 40 years, the risk for developing endometrial cancer was higher in the former group than in the latter group (aHR, 7.08; 95% CI, 2.33-21.55; P = 0.007). CONCLUSIONS: Patients diagnosed with endometriosis may harbor an increased risk for developing endometrial cancer in their later life. Closer monitoring is advised for this patient population.

Global distribution pattern of histological subtypes of epithelial ovarian cancer: a database analysis and systematic review.

BACKGROUND: Epithelial ovarian cancer is basically a heterogeneous disease with different chemosensitivity and distinct molecular alternations for each histological subtype. In order to assess whether the results of clinical trials can be extrapolated to a new country, it is critical to first examine whether the relative frequencies is homogenous across countries. METHODS: Cancer registry database from a single institution in Taiwan combined with systematic review of the global literature on the relative frequencies of histological subtypes between 2003 and 2012 was provided. RESULTS: Of 175 titles identified, 41 studies met inclusion/exclusion criteria. Globally, for each subtype, the median value of relative frequencies for serous subtype was 45.0%, with the Philippines (16.0%), Indonesia (22.7%), and Brazil (30.1%) as the three lowest countries and South Africa (68.0%), Greece (71.5%), and India (86.7%) as the three highest countries; for mucinous subtype, 11.4%, Italy (3.0%), Australia (3.4%), and Japan (5.4%) were the three lowest countries, while Indonesia (29.1%), Singapore (30.3%), and South Korea (38.6%) were the three highest countries; for endometrioid subtype, 12.6%, India (1.6%), Greece (5.7%), and Portugal (7.6%) were the three lowest countries, while Taiwan (24.8%), Egypt (25.0%), and Austria (25.5%) were the three highest countries; and for clear cell subtype, 5.3%, Pakistan (1.0%), Iran (2.0%), and Brazil (2.1%) were the three lowest countries while Thailand (16.0%), Taiwan (16.8%), and Spain (18.8%) were the three highest countries. CONCLUSIONS: Relative frequencies of subtypes were not homogenous across countries. This diversity may reflect the geographical and ethnic variations. Globally, epithelial ovarian cancer is a heterogeneous disease with a heterogeneous distribution pattern.

MicroRNA-138 suppresses ovarian cancer cell invasion and metastasis by targeting SOX4 and HIF-1α.

Metastasis is the major factor affecting patient survival in ovarian cancer. However, its molecular mechanisms remain unclear. Our study used isogenic pairs of low- and high-invasive ovarian cancer cell lines to demonstrate the downregulation of miRNA-138 in the highly invasive cells, and its functioning as an inhibitor of cell migration and invasion. An orthotopic xenograft mouse model further demonstrated that the expression of miRNA-138 inhibited ovarian cancer metastasis to other organs. Results indicated that miR-138 directly targeted SRY-related high mobility group box 4 (SOX4) and hypoxia-inducible factor-1α (HIF-1α), and overexpression of SOX4 and HIF-1α effectively reversed the miR-138-mediated suppression of cell invasion. Epidermal growth factor receptor acted as the downstream molecule of SOX4 by way of direct transcriptional control, whereas Slug was the downstream molecule of HIF-1α by way of proteasome-mediated degradation. Analysis of human ovarian tumors further revealed downregulation of miR-138 and upregulation of SOX4 in late-stage tumors. Patients with miR-138(low)/SOX(high) signature are predominant in late stage and tend to have malignant phenotypes including lymph nodes metastasis, larger ascites volume and higher tumor grade. Our study demonstrates the role and clinical relevance of miR-138 in ovarian cancer cell invasion and metastasis, providing a potential therapeutic strategy for suppression of ovarian cancer metastasis by targeting SOX4 and HIF-1α pathways.

Electrotransfer of the epinecidin-1 gene into skeletal muscle enhances the antibacterial and immunomodulatory functions of a marine fish, grouper (Epinephelus coioides).

Electrotransfer of plasmid DNA into skeletal muscle is a common non-viral delivery system for the study of gene function and for gene therapy. However, the effects of epinecidin-1 (epi) on bacterial growth and immune system modulation following its electrotransfer into the muscle of grouper (Epinephelus coioides), a marine fish species, have not been addressed. In this study, pCMV-gfp-epi plasmid was electroporated into grouper muscle, and its effect on subsequent infection with Vibrio vulnificus was examined. Over-expression of epi efficiently reduced bacterial numbers at 24 and 48 h after infection, and augmented the expression of immune-related genes in muscle and liver, inducing a moderate innate immune response associated with pro-inflammatory infiltration. Furthermore, electroporation of pCMV-gfp-epi plasmid without V. vulnificus infection induced moderate expression of certain immune-related genes, particularly innate immune genes. These data suggest that electroporation-mediated gene transfer of epi into the muscle of grouper may hold potential as an antimicrobial therapy for pathogen infection in marine fish.

Novel cancer treatment paradigm targeting hypoxia-induced factor in conjunction with current therapies to overcome resistance.

Chemotherapy, radiotherapy, targeted therapy, and immunotherapy are established cancer treatment modalities that are widely used due to their demonstrated efficacy against tumors and favorable safety profiles or tolerability. Nevertheless, treatment resistance continues to be one of the most pressing unsolved conundrums in cancer treatment. Hypoxia-inducible factors (HIFs) are a family of transcription factors that regulate cellular responses to hypoxia by activating genes involved in various adaptations, including erythropoiesis, glucose metabolism, angiogenesis, cell proliferation, and apoptosis. Despite this critical function, overexpression of HIFs has been observed in numerous cancers, leading to resistance to therapy and disease progression. In recent years, much effort has been poured into developing innovative cancer treatments that target the HIF pathway. Combining HIF inhibitors with current cancer therapies to increase anti-tumor activity and diminish treatment resistance is one strategy for combating therapeutic resistance. This review focuses on how HIF inhibitors could be applied in conjunction with current cancer treatments, including those now being evaluated in clinical trials, to usher in a new era of cancer therapy.

The role of secondary cytoreductive surgery in patients with recurrent epithelial ovarian, tubal, and peritoneal cancers: a comparative effectiveness analysis.

Background. All published reports concerning secondary cytoreductive surgery for relapsed ovarian cancer have essentially been observational studies. However, the validity of observational studies is usually threatened from confounding by indication. We sought to address this issue by using comparative effectiveness methods to adjust for confounding. Methods. Using a prospectively collected administrative health care database in a single institution, we identified 1,124 patients diagnosed with recurrent epithelial, tubal, and peritoneal cancers between 1990 and 2009. Effectiveness of secondary cytoreductive surgery using the conventional Cox proportional hazard model, propensity score, and instrumental variable were compared. Sensitivity analyses for residual confounding were explored using an array approach. Results. Secondary cytoreductive surgery prolonged overall survival with a hazard ratio (95% confidence interval) of 0.76 (range 0.66-0.87), using the Cox proportional hazard model. Propensity score methods produced comparable results: 0.75 (range 0.64-0.86) by nearest matching, 0.73 (0.65-0.82) by quintile stratification, 0.71 (0.65-0.77) by weighting, and 0.72 (0.63-0.83) by covariate adjustment. The instrumental variable method also produced a comparable estimate: 0.75 (range 0.65-0.86). Sensitivity analyses revealed that the true treatment effects may approach the null hypothesis if the association between unmeasured confounders and disease outcome is high. Conclusions. This comparative effectiveness study provides supportive evidence for previous reports that secondary cytoreductive surgery may increase overall survival for patients with recurrent epithelial, tubal, and peritoneal cancers.

A Cationic Amphipathic Tilapia Piscidin 4 Peptide-Based Antimicrobial Formulation Promotes Eradication of Bacterial Vaginosis-Associated Bacterial Biofilms.

Bacterial vaginosis (BV) is prevalent among women of reproductive age and has a high rate of recurrence, which can be largely attributed to ineffective BV biofilm eradication by current first-line antibiotics. In this study, we report that the Nile tilapia piscidin 4 (TP4) exhibits broad-spectrum antimicrobial and antibiofilm activity against BV-associated bacteria, but not beneficial lactobacilli. In addition, BV-associated Gardnerella vaginalis remains susceptible to TP4 even after continual exposure to the peptide for up to 22 passages. Gardnerella vaginalis and Streptococcus anginosus are both biofilm-forming BV-associated bacteria, and we found that combining TP4 peptide and disodium EDTA with the biofilm-disrupting agent, chitosan, can eradicate biofilms formed by single or mixed G. vaginalis and S. anginosus. In addition, long-term storage of TP4 peptide in chitosan did not diminish its bactericidal activity toward G. vaginalis. Preformulation studies were performed using High performance liquid chromatography (HPLC) and Circular Dichroism (CD). The long-term stability of TP4 peptide was assessed under various conditions, such as different temperatures and ionic strengths, and in the presence of H2O2 and lactic acid. When exposed to sodium dodecyl sulfate (SDS), TP4 maintained its secondary structure at various temperatures, salt and disodium EDTA concentrations. Furthermore, the TP4 microbicide formulation significantly reduced the colonization density of BV-associated bacteria in mice infected with single or mixed bacteria (G. vaginalis and S. anginosus). The TP4 microbicide formulation showed biocompatibility with beneficial human vaginal lactobacilli and female reproductive tissues in C57BL/6 mice. These results suggest that the TP4 microbicide formulation could be a promising topical microbicide agent for BV treatment.

Changes in Depression and Sleep Quality and Associated Factors in Women Receiving Chemotherapy for Ovarian Cancer: An Observational Study.

BACKGROUND: Although women with ovarian cancer experience depression and poor sleep quality, little is known about how various factors, particularly self-efficacy, might be associated with these conditions. OBJECTIVES: The aim of this study was to examine the prevalence of and changes in depression and sleep quality and the factors associated with these conditions in a cohort of women with ovarian cancer before, during, and after chemotherapy. METHODS: A prospective repeated-measures design was adopted in this study. Participants were women with ovarian cancer who were expected to receive 4 to 6 cycles of chemotherapy and were recruited at a medical center in Taiwan. The participants were asked to complete a questionnaire that included the Symptom Distress Scale, Center for Epidemiologic Studies Depression Scale, General Self-efficacy Scale, and Pittsburgh Sleep Quality Index. The data were collected before, during, and after the course of chemotherapy. RESULTS: Overall, 24.6% to 36.9% of women were at risk for depression; 75.4% to 80.0% of women had poor sleep quality. There were no significant changes in depressive symptoms and sleep quality throughout the course of chemotherapy. More severe depressive symptoms were associated with higher levels of symptom distress and lower self-efficacy. Poorer sleep quality was associated with higher levels of symptom distress. CONCLUSIONS: Among participants, more depressive symptoms and poorer sleep quality were associated with higher levels of symptom distress or lower self-efficacy. IMPLICATIONS FOR PRACTICE: Healthcare providers should continuously assess depression and sleep quality in women with ovarian cancer. These symptoms may be improved by strengthening self-efficacy and relieving symptom distress.

Synergistic therapeutic effect of low-dose bevacizumab with cisplatin-based chemotherapy for advanced or recurrent cervical cancer.

BACKGROUND: Cisplatin-based chemotherapy (CBC) is highly efficacious for advanced cervical cancer; its efficacy can be enhanced by combining with 15 mg/kg (standard dose) bevacizumab (BEV). However, this standard dose is associated with various adverse events (AEs). Therefore, in this retrospective study, we analyzed the survival outcomes and AEs in patients with advanced or recurrent cervical cancer treated with CBC in combination with BEV 7.5 mg/kg. METHODS: Registered patient data were retrieved between October 2014 and September 2019, and 64 patients with advanced or recurrent cervical cancer treated with CBC + BEV (n = 21) or CBC alone (n = 43) were analyzed. The primary endpoints were progression-free survival (PFS) and overall survival (OS); the secondary endpoints were the frequency and severity of AEs. The Cox proportional-hazards model was applied to explore prognostic factors associated with PFS and OS. RESULTS: The 1-, 2-, and 3-year PFS rates (95% CI) were 36.24% (22.0-50.5), 20.7% (9.8-34.2), and 17.7% (7.7-31.1) for the CBC group; and 71.4% (47.1-86.0), 51.0% (27.9-70.1), and 51.0% (27.9-70.1) for the CBC + BEV group, respectively. The 1-, 2-, and 3-year OS rates were 62.6% (46.4-75.18), 32.4% (18.8-46.9), and 23.2% (11.2-37.6) for the CBC group; and 85.7% (61.9-95.1), 66.6% (42.5-82.5), and 55.5% (27.1-76.7) for the CBC + BEV group, respectively. The CBC + BEV group presented higher PFS and OS rates, p = 0.003 and p = 0.005, respectively. Proteinuria (6 vs 9, p = 0.025) and hypertension (0 vs 10, p < 0.001) were less common, but anemia was more common in the CBC group (35 vs 11, p = 0.021). CONCLUSION: Overall, CBC + BEV significantly improved the PFS and OS compared with CBC alone. CBC + BEV also prevents severe AEs and hence is an efficacious and safe therapeutic option.