Comparative analysis of the clinical efficacy and reproductive outcomes of the hysteroscopic tissue removal system (MyoSure) and hysteroscopic electroresection in the treatment of benign intrauterine lesions.

OBJECTIVE: To compare and analyze the clinical efficacy and reproductive outcomes of the hysteroscopic tissue removal system (MyoSure) and hysteroscopic electroresection in the treatment of benign intrauterine lesions in women of reproductive age. METHODS: This is a retrospective study of patients with benign intrauterine lesions treated with MyoSure or hysteroscopic electroresection. The primary outcomes were operative time and resection completeness, and reproductive outcomes were followed up and compared. Secondary outcomes included perioperative adverse events and postoperative adhesions seen during second-look hysteroscopy. Data analysis was performed using χ2 and Fisher tests for qualitative variables and Student t-test for quantitative variables. RESULTS: The operative times of patients with type 0 or I myoma, endometrial polyps, or retained products of conception in the MyoSure group were shorter than those in the electroresection group but were not significantly different for patients with type II myomas. The complete resection rate was lower in the MyoSure group than in the electroresection group. The degree of decrease in the American Fertility Society score of intrauterine adhesion in the MyoSure group was significantly higher (2.90 ± 1.29 points vs 1.31 ± 0.89 points, P = 0.025). The time to pregnancy and the pregnancy rate were higher in the MyoSure group (13.14 ± 7.85 months vs 16.26 ± 8.22 months, P = 0.040; 65.12% vs 54.55%, P = 0.045), but there was no significant difference in the term live birth rate, premature birth rate, or abortion rate between the two groups. CONCLUSION: MyoSure has advantages of a shortened operative time and improvement in reproductive outcomes such as pregnancy rate. However, for type II myomas, MyoSure has limitations, and a comprehensive evaluation before the procedure is required.

Polydopamine-coated thalidomide nanocrystals promote DSS-induced murine colitis recovery through Macrophage M2 polarization together with the synergistic anti-inflammatory and anti-angiogenic effects.

High levels of proinflammatory cytokines, macrophage polarization status and immune-mediated angiogenesis play pivotal roles in the pathogenesis of inflammatory bowel disease (IBD). Thalidomide, an anti-inflammatory, immunomodulatory and antiangiogenic agent, is used off-label for treatment of IBD. The therapeutic potential of thalidomide is limited by its poor solubility and side effects associated with its systemic exposure. To address these issues and promote its therapeutic effects on IBD, thalidomide nanocrystals (Thali NCs) were prepared and coated with polydopamine (PDA), a potential macrophage polarization modulator, to form PDA coated Thali NCs (Thali@PDA). Thali@PDA possessed a high drug loading and displayed average particle size of 764.7 ± 50.30 nm. It showed a better anti-colitis effect than bare thalidomide nanocrystals at the same dose of thalidomide. Synergistic effects of polydopamine on anti-inflammatory and anti-angiogenic activities of thalidomide were observed. Furthermore, PDA coating could direct polarization of macrophages towards M2 phenotype, which boosted therapeutic effects of Thali@PDA on IBD. Upon repeated dosing of Thali@PDA for one week, symptoms of IBD in mice were significantly relieved, and histomorphology of the colitis colons were normalized. Key proinflammatory cytokine levels in the inflamed intestines were significantly decreased. Toxicity study also revealed that Thali@PDA is a safe formulation.

Impact of examined lymph node number on accurate nodal staging and long-term survival of resected Siewert type II-III adenocarcinoma of the esophagogastric junction: A large population-based study.

Background: We aimed to investigate the association between the number of examined lymph nodes (ELNs) and accurate nodal staging and long-term survival in Siewert type II-III Adenocarcinoma of the Esophagogastric Junction (AEG) by using large population-based databases and determined the optimal ELN number threshold. Methods: Data on Stage I-III Siewert type II-III AEG patients from 2010 to 2014 respectively from the United States (US) SEER database and a Chinese large medical center institutional registry were analyzed for correlation between the ELN number and stage migration (node negative-to-positive) and overall survival (OS) by using multivariable-adjusted logistic and Cox regression models, respectively. The series of odds ratios (ORs), and hazard ratios (HRs) were fitted with a LOWESS smoother, and the structural breakpoints were determined by Chow test. The selected optimal cut point was then validated with the 2015 to 2016 SEER database. Results: Both the US cohort(n=1387) and China cohort(n=981) showed significantly increases from node-negative to node-positive disease (ORtheUS1.032,95%CI 1.017-1.046;ORChina1.034,95%CI 1.002-1.065) and enhancements in overall survival (HRtheUS0.970,95%CI 0.961-0.979;HRChina0.960,95%CI 0.940-0.980) with the increasing ELN number after controlling for confounders. Associations for both stage migration and overall survival were still significant in most subgroups' stratification. Cut point analysis showed a threshold ELN number of 18, which was validated both in the cohorts where it originated and in an independent SEER data cohort(n=379). Conclusions: More ELNs are associated with accurate nodal staging(negative-to-positive) as well as higher overall survival in resected Siewert types II-III AEG, We recommend 18 ELNs as the optimal cut point for the quality assessment of postoperative lymph node examination or prognostic stratification in clinical practice.

Impact of examined lymph node number on lymph node status and prognosis in FIGO stage IB-IIA cervical squamous cell carcinoma: A population-based study.

Objective: We aimed to investigate the association of examined lymph node (ELN) number with lymph node status and long-term survival in FIGO stage IB-IIA cervical squamous cell carcinoma(CSCC) and to determine the minimum number of ELN associated with survival improvement. Method: Data from the Surveillance, Epidemiology, and End Results Program (SEER) database of FIGO stage IB-IIA CSCC patients undergoing hysterectomy and pelvic lymphadenectomy in 2004-2016 were analyzed to explore the relationship between ELN number and lymph node status and overall survival (OS) by using the multivariable approach. The estimated probability of falsely identifying a patient as node-negative and the hazard ratios (HRs) for each ELN was fitted with a LOWESS smoother, and the structural breakpoints were determined. X-tile software was used to determine the optimal cutoff value for ELNs. Results: A total of 2627 patients were analyzed. The optimal cutoff value of the ELN number was identified as 7 based on the results of X-tile software. The structural breakpoints according to the associations between the number of ELNs and the estimated risk of false-negative lymph node dissection and HRs for overall survival were 9 and 8, respectively. The multivariate analysis indicated that ELN number was an independent prognostic factor for OS, both as a continuous or categorical variable. To further explore the effect of more ELNs on survival, another cutoff value of 17 was chosen to compare the survival curves of patients. The multivariate-adjusted COX model showed that patients with ELN<8 had a significantly higher risk of death than those with ELN8-17 (HR=1.447, 95% CI =1.075-1.947, p=0.015), but there was no significant difference in overall survival between patients with ELN>17 and patients with ELN8-17 (HR=0.822, 95%CI =0.665-1.016, p=0.070). Conclusion: A sufficient number of ELNs was associated with better long-term survival in FIGO stage IB-IIA CSCC. At least 8 ELNs need to be examined for prognostic stratification. Excessive lymph node dissection (ELN>17) may not confer additional survival benefits.

Model based on preoperative clinical characteristics to predict lymph node metastasis in patients with gastric cancer.

Background: The risk factors of lymph node metastasis (LNM) in gastric cancer (GC) remain controversial. We aimed to identify risk factors of LNM in GC and construct a predictive model. Methods: A total of 1,337 resectable GC patients who underwent radical D2 lymphadenectomy at the first affiliated Hospital of Anhui Medical University from January 2011 to January 2014 were retrospectively analyzed and randomly divided into training and validation cohorts (n = 1,003 and n = 334, respectively) in a 3:1 ratio. Collecting indicators include age, gender, body mass index (BMI), tumor location, pathology, histological grade, tumor size, preoperative neutrophils to lymphocytes ratio (NLR), platelets to lymphocytes ratio (PLR), fibrinogen to albumin ratio (FAR), carcinoembryonic antigen (CEA), cancer antigen19-9 (CA19-9) and lymph nodes status. Significant risk factors were identified through univariate and multivariate logistic regression analysis, which were then included and presented as a nomogram. The performance of the model was assessed with receiver operating characteristic curves (ROC curves), calibration plots, and Decision curve analysis (DCA), and the risk groups were divided into low-and high-risk groups according to the cutoff value which was determined by the ROC curve. Results: BMI, histological grade, tumor size, CEA, and CA19-9 were enrolled in the model as independent risk factors of LNM. The model showed good resolution, with a C-index of 0.716 and 0.727 in the training and validation cohort, respectively, and good calibration. The cutoff value for predicted probability is 0.594, the proportion of patients with LNM in the high-risk group was significantly higher than that in the low-risk group. Decision curve analysis also indicated that the model had a good positive net gain. Conclusions: The nomogram-based prediction model developed in this study is stable with good resolution, reliability, and net gain. It can be used by clinicians to assess preoperative lymph node metastasis and risk stratification to develop individualized treatment plans.

Effect of (NH4)2ZrF6, Voltage and Treating Time on Corrosion Resistance of Micro-Arc Oxidation Coatings Applied on ZK61M Magnesium Alloys.

The effects of (NH4)2ZrF6 concentration, voltage and treating time on the corrosion resistance of ZK61M magnesium alloy micro-arc oxidation coatings were studied by orthogonal experiments. The SEM result shows that the surface roughness and porosity of MAO coatings increased with (NH4)2ZrF6 concentration, voltage and treating time as a whole, except the porosity decreased with treating time. EDS, XRD and XPS analysis show that (NH4)2ZrF6 was successfully incorporated into coatings by reactive incorporation, coatings are dominantly composed of ZrO2, MgO, MgF2 and amorphous phase Mg phosphate. Potentiodynamic polarization was used to evaluate the corrosion property of coatings. When the concentration of (NH4)2ZrF6 is 6 g/L, the voltage is 450 V, and the treating time is 15 min, the coating exhibits the best corrosion resistance which corrosion current density is four magnitudes lower than substrate attributed to the incorporation of ZrO2 and the deposition of MgF2 in the micropores.

Self-assembled FeS-based cascade bioreactor with enhanced tumor penetration and synergistic treatments to trigger robust cancer immunotherapy.

Major challenges for cancer treatment are how to effectively eliminate primary tumor and sufficiently induce immunogenic cell death (ICD) to provoke a robust immune response for metastasis control. Here, a self-assembled cascade bioreactor was developed to improve cancer treatment with enhanced tumor penetration and synergistic therapy of starvation, chemodynamic (CDT) and photothermal therapy. Ultrasmall FeS-GOx nanodots were synthesized with glucose oxidase (GOx) as template and induced by paclitaxel (PTX) to form self-assembling FeS-GOx@PTX (FGP) via hydrophobic interaction. After accumulated at tumor sites, FGP disassembles to smaller FeS-GOx for enhanced deep tumor penetration. GOx maintains high enzymatic activity to catalyze glucose with assistant of oxygen to generate hydrogen peroxide (H2O2) as starvation therapy. Fenton reaction involving the regenerated H2O2 in turn produced more hydroxyl radicals for enhanced CDT. Following near-infrared laser at 808 nm, FGPs displayed pronounced tumor inhibition in vitro and in vivo by the combination therapy. The consequent increased exposure to calreticulin amplified ICD and promoted dendritic cells maturation. In combination with anti-CTLA4 checkpoint blockade, FGP can absolutely eliminate primary tumor and avidly inhibit distant tumors due to the enhanced intratumoral infiltration of cytotoxic T lymphocytes. Our work presents a promising strategy for primary tumor and metastasis inhibition.

The Emerging Role of Non-coding RNAs in Drug Resistance of Ovarian Cancer.

Ovarian cancer is one of the most common gynecological malignancies with highest mortality rate among all gynecological malignant tumors. Advanced ovarian cancer patients can obtain a survival benefit from chemotherapy, including platinum drugs and paclitaxel. In more recent years, the administration of poly-ADP ribose polymerase inhibitor to patients with BRCA mutations has significantly improved the progression-free survival of ovarian cancer patients. Nevertheless, primary drug resistance or the acquisition of drug resistance eventually leads to treatment failure and poor outcomes for ovarian cancer patients. The mechanism underlying drug resistance in ovarian cancer is complex and has not been fully elucidated. Interestingly, different non-coding RNAs (ncRNAs), such as circular RNAs, long non-coding RNAs and microRNAs, play a critical role in the development of ovarian cancer. Accumulating evidence has indicated that ncRNAs have important regulatory roles in ovarian cancer resistance to chemotherapy reagents and targeted therapy drugs. In this review, we systematically highlight the emerging roles and the regulatory mechanisms by which ncRNAs affect ovarian cancer chemoresistance. Additionally, we suggest that ncRNAs can be considered as potential diagnostic and prognostic biomarkers as well as novel therapeutic targets for ovarian cancer.

Surface Decoration via Physical Interaction of Cupric Diethyldithiocarbamate Nanocrystals and Its Impact on Biodistribution and Tumor Targeting.

The vascular wall is the first physiologic barrier that circulating nanoparticles (NPs) encounter, which also is a key biological barrier to cancer drug delivery. NPs can continually scavenge the endothelium for biomarkers of cancer, and the chance of NPs' extravasation into the tumors can be enhanced. Here, we envision P-selectin as a target for specific delivery of drug nanocrystals to tumors. The cupric diethyldithiocarbamate nanocrystals (CuET NCs) were first prepared by an antisolvent method, and then nanocrystals were coated with fucoidan via physical interaction. The fucoidan-coated CuET nanocrystals (CuET@Fuc) possess high drug loading and have the ability to interact with human umbilical vein endothelial cells expressing P-selectin, which transiently enhances the endothelial permeability and facilitates CuET@Fuc extravasation from the peritumoral vascular to achieve higher tumor accumulation of drugs than bare CuET NCs. The CuET NC shows poorer anticancer efficacy than CuET@Fuc at the same dose of CuET. Upon repeated dosing of CuET@Fuc for 2 weeks, no mortality was observed in treated melanoma-bearing mice, while the mortality in the control group and excipient-treated groups reached 23%. The growth rate of melanoma in the CuET@Fuc-treated group was significantly lower than those in other groups. Furthermore, an acute toxicity study revealed that CuET@Fuc is a safe formulation for cancer treatment.

Clinical analysis of the MyoSure hysteroscopic tissue removal system of endometrial polyps in women with an intact hymen.

BACKGROUND: To investigate the clinical efficacy of the MyoSure hysteroscopic tissue removal system in the treatment of endometrial and cervical polyps in women with an intact hymen. METHODS: Retrospective analysis was performed on the clinical data of 32 patients treated with the MyoSure hysteroscopic tissue removal system for endometrial and cervical polyps. RESULTS: All the patients successfully completed the procedure. No intraoperative complications, such as cervical trauma, uterine perforation or TURP syndrome, were reported. The surgical time ranged from 5 to 35 min, with an average time of 19.3 min, and the intraoperative blood loss ranged from 2 to 50 ml with an average blood loss of 10.8 ml. After surgery, all patients were shown to have intact hymens. No residual polyp tissues were observed under the microscope, and abnormal uterine bleeding was relieved. CONCLUSIONS: The MyoSure hysteroscopic tissue removal system can be a safe and effective treatment for endometrial and cervical polyps in women with an intact hymen.

Mitochondria targeted nanoparticles to generate oxygen and responsive-release of carbon monoxide for enhanced photogas therapy of cancer.

Carbon monoxide (CO) based gas therapy has been an emerging strategy for cancer treatment. However, the uncontrolled release of CO and limited therapeutic efficacy of monotherapy are two major obstacles for clinical application. To overcome these issues, human serum albumin (HSA) nanoparticles combined with manganese dioxide (MnO2) were developed to deliver a photosensitizer (IR780) and CO donor (MnCO) for a synergistic therapy combining CO gas therapy and phototherapy. The nanoparticles (HIM-MnO2) formed catalyze hydrogen peroxide to produce oxygen for hypoxia relief. With laser irradiation, it can increase the generation of reactive oxygen species for the enhancement of photodynamic therapy (PDT). Furthermore, the generated heat of photothermal therapy (PTT) induced by nanoparticles could trigger the release of CO to achieve a therapeutic window for enhanced gas therapy. Due to the co-localization of IR780 in mitochondria, HIM-MnO2 could accumulate in mitochondria for the synergistic therapy combining CO gas therapy and phototherapy, and could oxidize the mitochondrial membrane and induce more apoptosis. After intravenous injection into tumor bearing mice, HIM-MnO2 could accumulate at tumor sites and with laser irradiation, tumor growth was significantly inhibited due to the enhanced PDT, PTT, and CO gas therapy. This study provides a strategy with oxygen generating and thermal-responsive CO release to combine phototherapy and CO gas therapy for cancer treatment.

Multi-Omics Analysis of the Therapeutic Value of MAL2 Based on Data Mining in Human Cancers.

Recent studies have reported that T-cell differentiation protein 2 (MAL2) is an important regulator in cancers. Here, we downloaded data from multiple databases to analyze MAL2 expression and function in pan-cancers, especially in ovarian cancer (OC). Gene Expression Profiling Interactive Analysis (GEPIA) databases was used to examine MAL2 expression in 13 types of cancer. Kaplan-Meier plotter database was used to analyze the overall survival rate of MAL2 in pan-cancers. The Catalog of Somatic Mutations in Cancer (COSMIC), cBioPortal, and UCSC databases were used to examine MAL2 mutation in human cancers. Metascape, STRING, and GeneMANIA websites were used to explore MAL2 function in OC. Furthermore, ggplot2 package and ROC package were performed to analyze hub gene expression and undertake receiver operating characteristic (ROC) analysis. Drug sensitivity of MAL2 in OC was examined by the GSCALite database. In order to verify the results from databases above, real-time quantitative polymerase chain reaction (qRT-PCR) and western blotting were conducted to detect the expression of MAL2 in OC cells. CRISPR/Cas9 system was used to knockout the MAL2 gene in the OC cell lines HO8910 and OVCAR3, using specific guide RNA targeting the exons of MAL2. Then, we performed proliferation, colony formation, migration, and invasion assays to investigate the impact of MAL2 in OC cell lines in vivo and in vitro. Epithelial-mesenchymal transition (EMT)-associated biomarkers were significantly altered in vitro via western blotting and qRT-PCR. Taken together, we observed that MAL2 was remarkably dysregulated in multiple cancers and was related to patient overall survival (OS), mutation, and drug sensitivity. Furthermore, experimental results showed that MAL2 deletion negatively regulated the proliferation, migration, invasion, and EMT of OC, indicating that MAL2 is a novel oncogene that can activate EMT, significantly promote both the proliferation and migration of OC in vitro and in vivo, and provide new clues for treatment strategies.

Blockade of Platelets Using Tumor-Specific NO-Releasing Nanoparticles Prevents Tumor Metastasis and Reverses Tumor Immunosuppression.

The tumor microenvironment maintains a sufficient immunosuppressive state owing to the existence of the immunosuppressive factors. The most prominent such factor is transforming growth factor ß (TGF-ß), which is mainly provided by platelets. Moreover, platelets have been shown to be the main accomplice in assisting tumor metastasis. Therefore, blocking tumor-associated platelets is endowed with functions of enhancing immunity and reducing metastasis. Herein, we designed a tumor microenvironment-responsive nitric oxide (NO) release nanoparticle, Ptx@AlbSNO, which was able to specifically and safely co-deliver the antiplatelet agent NO and the chemotherapeutic agent paclitaxel (Ptx) into tumor tissues and inhibit platelet-tumor cell interactions. We discovered that Ptx@AlbSNO could successfully block tumor-specific platelet functions, thereby suppressing the process of tumor epithelial-mesenchymal transition (EMT), preventing platelet adhesion around circulating tumor cells (CTCs) and reducing distant metastasis. In vivo studies demonstrate that the co-delivery of NO and Ptx can suppress primary tumor growth. With the ability to effectively inhibit activated platelets and TGF-ß secretion in tumors, Ptx@AlbSNO can enhance intratumoral immune cell infiltration to reverse the immunosuppressive tumor microenvironment.

circCELSR1 facilitates ovarian cancer proliferation and metastasis by sponging miR-598 to activate BRD4 signals.

BACKGROUND: Ovarian cancer is one of the most common gynecologic cancers and has high mortality rate due to the lack of early diagnosis method and efficient therapeutic agents. circCELSR1 is up-regulated in ovarian cancer, but its role and mechanisms in ovarian cancer are unclear. METHODS: Gene expression of circCELSR1, miR-598 and BRD4 in ovarian cells was examined by qRT-PCR. Protein level was determined by Western blotting. Bioinformatic analysis and luciferase assay determined the molecular binding among circCELSR1, miR-598 and BRD4 3' UTR. Cell proliferation, migration, invasion and apoptosis were determined by colony formation, wound healing assay, transwell assay and flow cytometry analysis, respectively. An abdominal cavity metastasis nude mice model was used to determine the in vivo function of circCELSR1. RESULTS: circCELSR1 and BRD4 were promoted, but miR-598 was suppressed in various ovarian cancer cells. circCELSR1 bound to miR-598 and promoted expression of its downstream target BRD4. Knockdown of circCELSR1 suppressed proliferation, migration, invasion and epithelial-mesenchymal transition (EMT), but promoted apoptosis in ovarian cancer cells, and these effects were reversed by miR-598 inhibition or BRD4 overexpression. circCELSR1 inhibition decreased the expression of BRD4 and its downstream proliferation/migration related genes by targeting miR-598. Furthermore, knockdown of circCELSR1 suppressed ovarian cancer growth and metastasis in nude mice. CONCLUSION: Knockdown of circCELSR1 inhibited BRD4-mediated proliferation/migration related signaling via sponging miR-598, thereby repressing ovarian cancer progression. This study provides a new regulatory mechanism of ovarian cancer may facilitate the development of therapeutic agents for ovarian cancer.

lncRNA ABHD11-AS1, regulated by the EGFR pathway, contributes to the ovarian cancer tumorigenesis by epigenetically suppressing TIMP2.

OBJECTIVE: Epithelial ovarian cancer (EOC) is a common gynecologic malignancy characterized by extensive peritoneal metastasis and high mortality rate. ABHD11 Antisense RNA1 (ABHD11-AS1) has recently been identified as a regulator of growth and metastasis in multiple tumors, including EOC. However, the biological function and potential mechanism of ABHD11-AS1 in EOC remains poorly understood. METHODS: Immunohistochemistry, western blot, and qRT-PCR analysis were used to determine the expression pattern of ABHD11-AS1 and epidermal growth factor receptor (EGFR) in both EOC tissues and cell lines, respectively. Colony formation, transwell and wound healing assays were performed to evaluate the roles of EGFR and ABHD11-AS1 on the capacity of cell proliferation, migration, and invasion. Western blot analysis was performed to measure the regulation of EGFR pathway on STAT3. Moreover, chromatin immunoprecipitation was employed to demonstrate the interaction between ABHD11-AS1 and STAT3. RNA immunoprecipitation was subjected to prove the direct binding between ABHD11-AS1 and EZH2. Immunofluorescence staining was performed to measure the expression and localization of TIMP2. EOC mouse model was conducted for validating the role of ABHD11-AS1 in vivo. RESULTS: EGFR and ABHD11-AS1 were highly expressed in EOC tissues and cell lines. Knockdown of EGFR or ABHD11-AS1 inhibited cell growth, migration, and invasion of EOC cells. Expression of ABHD11-AS1 was regulated by the activation of EGFR signaling pathway, mediated by STAT3. Besides, ABHD11-AS1 was shown to silence TIMP2 by binding to chromatin-modifying enzyme EZH2. Furthermore, inhibition of EGFR pathway or ABHD11-AS1 repressed the tumor growth of EOC. CONCLUSION: We defined the regulatory relationship between the EGFR signaling pathway, ABHD11-AS1, EZH2, and TIMP2 suggesting that ABHD11-AS1 may act as an oncogene and a potential target for antitumor therapies in ovarian cancer.

A modified hydrophobic ion-pairing complex strategy for long-term peptide delivery with high drug encapsulation and reduced burst release from PLGA microspheres.

Poor encapsulation and high initial burst were two major obstacles for the water-soluble peptide drug loaded microspheres preparation using the industrial emulsification method. In the present study, we hypothesized that the hydrophobic ion-pairing (HIP) complex strategy with a further healing of the pores within the microspheres may improve drug encapsulation and initial burst release. DSS was chosen as the most suitable one among the three test ion-pairing agents (SDS, DSS and STC) due to its high binding efficiency with drug and reversible dissociation capacity in presence of counter ions. The formation of HIP complex between octreotide acetate and DSS successfully reversed the highly water-soluble nature of the drug. A specific S/O/W method was adopted to encapsulate such drug containing HIP complex. The encapsulation efficiency of the drug was greatly improved compared with the conventional W1/O/W2 method (from 44% to 90%). Under the optimal healing conditions (the healing time 6 h, temperature 40 °C and 4% DEP content), the pores within the microspheres were effectively healed. Initial burst amount of octreotide acetate in S/O/W microspheres decreased to 3.56%. The pore healing effect was further confirmed by the scanning electron microscopy and fluorescence microscopy results. In the process of testing the drug release performance of such new strategy in vitro and in vivo, a more satisfactory single phase release profile with sustained and steady drug release was observed. These results suggested that the modified HIP strategy could be a promising platform for water-soluble peptide encapsulation with high encapsulation efficiency, low initial burst and stable drug release mechanism.

Glutathione depletion and dual-model oxygen balance disruption for photodynamic therapy enhancement.

Photodynamic therapy (PDT) is a prospective approach to cure tumor diseases. However, tumor micro-environment is notably characterized with severe hypoxia and high expression of glutathione (GSH), which seriously limit its clinical application. Here, based on the characteristics of perfluorocarbon (PFC) to dissolve substantial oxygen (O2) and the sensitivity of reductive GSH to S-NO group, we designed GSH depletion and dual-model O2 supply strategies to promote PDT enhancement. The PFC nanoliposomes (FI@Lip) and biocompatible NO donor S-nitrosated human serum albumin (HSA-SNO) were combined to synergistically combat the obstacle of tumor micro-environment, reducing GSH concentration and increasing singlet oxygen (1O2) generation. In vitro, after irradiation with NIR laser, the PFC in FI@Lip dissolved more O2 to increase 1O2 generation. In addition, with co-delivery of HSA-SNO, it can effectively promote GSH depletion to recover 1O2 level and release NO concurrently to inhibit mitochondrial respiration. This combination strategy of FI@Lip and HSA-SNO obviously relieved intracellular hypoxia and decreased GSH to increase more toxic 1O2 generation for PDT enhancement. The present work will play as an enlightening role in PDT design and clinical application in the near future.

M2-like tumor-associated macrophages-secreted EGF promotes epithelial ovarian cancer metastasis via activating EGFR-ERK signaling and suppressing lncRNA LIMT expression.

Background: Ovarian cancer (OC) is the gynecologic malignant tumor with high mortality. Accumulating evidence indicates that M2-like tumor-associated macrophages (TAMs) can secret EGF to participate in ovarian cancer growth, migration, and metastasis. An EGF-downregulated lncRNA, LIMT (lncRNA inhibiting metastasis), was identified as a critical regulator of mammary cell migration and invasion. Nevertheless, whether EGF secreted from M2-like TAMs regulates LIMT expression in ovarian cancer progression remains largely unknown. Methods: The human OC cell lines OV90 and OVCA429 were recruited in this study. The differentiation of the human monocyte cell line THP-1 into M2-like TAMs was confirmed using flow cytometry within the application of phorbol 12-myristate 13-acetate (PMA). ELISA was performed to detect EGF concentration in co-culture system of M2-like TAMs and OC cell lines. Moreover, CCK-8, flow cytometry and immunofluorescence staining of Ki67 were performed to assess the capacity of cell proliferation. Besides, cell migration and invasion were determined by wound healing and transwell assays. Furthermore, the expression levels of epithelial-mesenchymal transition (EMT) markers and EGFR/ERK signals were analyzed by qRT-PCR and western blot. Female athymic nude mice (8-12 weeks of age; n = 8 for each group) were recruited for in vivo study. Results: In the present study, THP-1 cells exhibited the phenotype markers of M2-like TAMs with low proportion of CD14+ marker and high proportion of CD68+, CD204+, CD206+ markers within the application of PMA. After co-culturing with M2-like TAMs, EGF concentration in the supernatants was significantly increased in a time-dependent manner. Besides, OC cells presented better cell viability, higher cell proliferation, and stronger migration and invasion. The expression of EMT-related markers N-cadherin, Vimentin and EGFR/ERK signals were markedly up-regulated, while E-cadherin was significantly decreased. However, these effects induced by co-culture system were reversed by the application of AG1478 (an EGFR inhibitor) or LIMT overexpression. Furthermore, the endogenous expression of LIMT was decreased in OC cell lines compared with the control group. Also, the in vivo experiments verified that the inhibition of EGFR signaling by AG1478 or overexpression of LIMT effectively repressed the tumor growth. Conclusion: Taken together, we demonstrated that EGF secreted by M2-like TAMs might suppress LIMT expression via activating EGFR-ERK signaling pathway to promote the progression of OC.