Phytosterol-mediated glycerosomes combined with peppermint oil enhance transdermal delivery of lappaconitine by modulating the lipid composition of the stratum corneum.

Although the introduction of glycerosomes has enriched strategies for efficient transdermal drug delivery, the inclusion of cholesterol as a membrane stabilizer has limited their clinical application. The current study describes the development and optimization of a new type of glycerosome (S-glycerosome) that is formed in glycerol solution with ß-sitosterol as the stabilizer. Moreover, the transdermal permeation properties of lappaconitine (LA)-loaded S-glycerosomes and peppermint oil (PO)-mediated S-glycerosomes (PO-S-glycerosomes) are evaluated, and the lipid alterations in the stratum corneum are analyzed via lipidomics. The LA-loaded S-glycerosomes prepared by the preferred formulation from the uniform design have a mean size of 145.3 ± 7.81 nm and an encapsulation efficiency of 73.14 ± 0.35%. Moreover, the addition of PO positively impacts transdermal flux, peaking at 0.4% (w/v) PO. Tracing of the fluorescent probe P4 further revealed that PO-S-glycerosomes penetrate deeper into the skin than S-glycerosomes and conventional liposomes. Additionally, treatment with PO-S-glycerosomes alters the isoform type, number, and composition of sphingolipids, glycerophospholipids, glycerolipids, and fatty acids in the stratum corneum, with the most notable effect observed for ceramides, the main component of sphingolipids. Furthermore, the transdermal administration of LA-loaded PO-S-glycerosomes improved the treatment efficacy of xylene-induced inflammation in mice without skin irritation. Collectively, these findings demonstrate the feasibility of ß-sitosterol as a stabilizer in glycerosomes. Additionally, the inclusion of PO improves the transdermal permeation of S-glycerosomes, potentially by altering the stratum corneum lipids.

Cobalt-free nickel-rich cathode materials based on Al/Mg co-doping of LiNiO2 for lithium ion battery.

To develop Co-free LiNiO2-based layered cathode materials is crucial for meeting the demands of the lithium-ion batteries with high energy density, long cycling life, and low cost. Herein, the LiNi1-x-yAlxMgyO2 materials are synthesized by the solid-solid interface elemental interdiffusion strategy. It is elucidated that the Mg2+ and Al3+ ions are mainly doped in the Li slabs and transition metal slabs, respectively, leading to the alteration of the crystal lattice. Furthermore, the incorporation of the Mg2+ ions may induce more Ni2+ ions formed in the transition metal slabs, which would have great impact on the electrochemical performance of the materials. The LiNi1-x-yAlxMgyO2 materials with optimized Mg/Al co-doping exhibit much better electrochemical performance than the pristine LiNiO2 and Al-doped LiNiO2 materials, including cycling stability and rate capability. The in-situ XRD characterization and structural analysis show that stabilization of the crystal structure, preservation of the integrity of the secondary particles, and enlargement of the interlayer spacing by the Mg/Al co-doping are the main factors responsible for the superior performance of the materials. The Mg/Al co-doping strategy might be the promising approach for the design of the cobalt-free nickel-rich materials.

Who really benefits from intraperitoneal chemotherapy for advanced ovarian cancer? A treatment-free survival analysis of the AICE trial.

OBJECTIVE: To investigate whether peritoneal disease extent can predict the survival benefit of intraperitoneal/intravenous (IP/IV) chemotherapy in ovarian cancer. DESIGN: A treatment-free survival (TFS) analysis. SETTING: Five-centre trial. POPULATION: An extended follow-up of the Additional Intraperitoneal Cisplatin and Etoposide in ovarian cancer (AICE) trial (NCT01669226), with data cut-off on 27 August 2020. Patients were categorised into subgroups with high tumour burden (HTB) and low tumour burden (LTB). METHODS: Overall survival (OS) was divided into time on protocol treatment exposure (T), time free of subsequent treatment or death (TFS) and time after the first subsequent therapy (REL). TFS analyses and quality-adjusted OS were calculated by multiplying the mean time in each health state by its assigned utility: quality-adjusted OS = ut  × T + TFS + urel  × REL. MAIN OUTCOME MEASURES: The area under each Kaplan-Meier curve was estimated using the 96-month restricted mean time, with threshold utility analyses used to illustrate quality-adjusted OS comparisons. RESULTS: In the HTB subgroup, the restricted mean TFS was 33.9 months and 18.7 months in the IP/IV and IV groups, respectively (p = 0.005), with a significant quality-adjusted OS gain (13.2-16.0 months). In the LTB subgroup, IP/IV therapy yielded no survival benefit in either TFS (p = 0.268) or quality-adjusted OS (range: 1.4-6.3 months). CONCLUSIONS: Both TFS and quality-adjusted OS was longer across all utility weight values with IP/IV than with standard IV therapy in the HTB subgroup, whereas patients in the LTB subgroup did not benefit from the therapy. The tumour burden of ovarian cancer should be assessed before deciding on IP/IV versus IV treatment.

Underlying Mechanisms for Low-Molecular-Weight Dissolved Organic Matter to Promote Translocation and Transformation of Chlorinated Polyfluoroalkyl Ether Sulfonate in Wheat.

Dissolved organic matter (DOM) such as fulvic acid (FA) and humic acid (HA) in soil considerably affects the fate of per- and polyfluoroalkyl substances (PFASs). However, the effect of DOM on their behavior in plants remains unclear. Herein, hydroponic experiments indicate that FA and HA reduce the accumulation of an emerging PFAS of high concern, 6:2 chlorinated polyfluoroalkyl ether sulfonate (6:2 Cl-PFESA), in wheat roots by reducing its bioavailability in the solution. Nevertheless, FA with low molecular weight (MW) promotes its absorption and translocation from the roots to the shoots by stimulating the activity and the related genes of the plasma membrane H+-ATPase, whereas high-MW HA shows the opposite effect. Moreover, in vivo and in vitro experiments indicate that 6:2 Cl-PFESA undergoes reductive dechlorination, which is regulated mainly using nitrate reductase and glutathione transferase. HA and FA, particularly the latter, promote the dechlorination of 6:2 Cl-PFESA in wheat by enhancing electron transfer efficiency and superoxide production. Transcriptomic analysis indicates that FA also stimulates catalytic activity, cation binding, and oxidoreductase activity, facilitating 6:2 Cl-PFESA transformation in wheat.

Paclitaxel and naringenin-loaded solid lipid nanoparticles surface modified with cyclic peptides with improved tumor targeting ability in glioblastoma multiforme.

The present work describes the systematic development of paclitaxel and naringenin-loaded solid lipid nanoparticles (SLNs) for the treatment of glioblastoma multiforme (GBM). So far only temozolomide therapy is available for the GBM treatment, which fails by large amount due to poor brain permeability of the drug and recurrent metastasis of the tumor. Thus, we investigated the drug combination containing paclitaxel and naringenin for the treatment of GBM, as these drugs have individually demonstrated significant potential for the management of a wide variety of carcinoma. A systematic product development approach was adopted where risk assessment was performed for evaluating the impact of various formulation and process parameters on the quality attributes of the SLNs. I-optimal response surface design was employed for optimization of the dual drug-loaded SLNs prepared by micro-emulsification method, where Percirol ATO5 and Dynasan 114 were used as the solid lipid and surfactant, while Lutrol F188 was used as the stabilizer. Drug loaded-SLNs were subjected to detailed in vitro and in vivo characterization studies. Cyclic RGD peptide sequence (Arg-Gly-Asp) was added to the formulation to obtain the surface modified SLNs which were also evaluated for the particle size and surface charge. The optimized drug-loaded SLNs exhibited particle size and surface charge of 129 nm and 23 mV, drug entrapment efficiency >80% and drug loading efficiency >7%. In vitro drug release study carried out by micro dialysis bag method indicated more than 70% drug was release observed within 8 h time period. In vivo pharmacokinetic evaluation showed significant improvement (p < 0.05) in drug absorption parameters (Cmax and AUC) from the optimized SLNs over the free drug suspension. Cytotoxicity evaluation on U87MG glioma cells indicated SLNs with higher cytotoxicity as compared to that of the free drug suspension (p < 0.05). Evaluation of uptake by florescence measurement indicated superior uptake of SLNs tagged with dye over the plain dye solution. Overall, the dual drug-loaded SLNs showed better chemoprotective effect over the plain drug solution, thus construed superior anticancer activity of the developed nanoformulation in the management of glioblastoma multiforme.

A preoperative prediction model for predicting coexisting adnexa malignancy of patients with G1/G2 endometrioid endometrial cancer.

OBJECTIVE: To identify the predictors of coexisting adnexa malignancy (CAM) before surgery for patients with G1/G2 endometrioid endometrial cancer (EEC). METHODS: Patients with G1/G2 EEC who received surgery in Fudan University Shanghai Cancer Center from 1996 to 2017 were enrolled. Univariate and multivariate logistic regression were performed to identify the predictors for CAM, and the nomogram was constructed and evaluated the discrimination and calibration. RESULTS: Among the 1511 patients in the study cohort, 66 (4.4%) coexisted adnexa malignancy (51 metastatic and 15 synchronous primaries). In the univariate logistic regression analysis, CA125 level (>35 U/ml), histologic grades, myometrial invasion depth in magnetic resonance imaging (MRI), adnexal involvement in MRI/surgical exploration (SEP) were found to be significant predictors for CAM (P < .001, 0.047, 0.011, <0.001, respectively). The multivariate analysis demonstrated that high CA125 level (P < .001; OR: 2.945; 95%CI: 1.700-5.101), deep myometrial invasion (P = .011; OR: 2.194; 95%CI: 1.200-4.011), and suspected adnexal involvement in MRI/SEP (P < .001; OR: 11.524; 95%CI: 6.726-19.744) were independent predictors for CAM (AUC = 0.786). In 338 patients with MMR results, eighty-seven (25.7%) were detected MSI-high. There were 5.7% (5/87) patients diagnosed with CAM in the MSI-high group compared with 4.4% (11/251) in the MSS group. CONCLUSIONS: A nomogram with pre- and intra-operative factors was constructed to predict CAM in G1/G2 EEC patients, which may help clinicians in decision-making for ovarian preservation for these patients.

Temperature-sensitive gel-loaded composite nanomedicines for the treatment of cervical cancer by vaginal delivery.

In this study, toad venom (TV) and realgar were loaded into a poloxamer 188/407 (F127/F188)-based temperature-sensitive in situ gel (TISG) and encapsulated in solid lipid nanoparticles (TV-SLN) or ground nano-realgar (NR) to improve drug release and reduce local irritation after vaginal administration. The combination of TV-SLN and NR (TV-SLN/NR) greatly enhanced the inhibition of tumor cell proliferation and was most effective at a dose ratio of 2:3 (w/w). After TV-SLN/NR treatment, S and G0/G1 phase arrest were observed in HeLa and SKOV-3 cells and the inhibitory effects on proliferation were stronger than those in the conventional powder group. The gelation temperature of TV-SLN and NR-loaded TISG (TV-SLN/NR-TISG) using the selected formulation was 33 ± 0.91 °C. The cumulative release of the drug increased as the dissolution of gel progressed, showing a linear relationship (r > 0.99). TV-SLN/NR-TISG enabled the sustained release of cargo by adhesion to the vaginal mucosa and showed excellent biocompatibility during continuous administration for 7 days. We specifically demonstrated the effectiveness of the TISG for the vaginal delivery of TV-SLN and NR, supporting its important clinical implications for the treatment of cervical cancer.

Correction: Prognostic and diagnostic significance of lncRNAs expression in cervical cancer: a systematic review and meta-analysis.

[This corrects the article DOI: 10.18632/oncotarget.18323.].

Prognostic and diagnostic significance of lncRNAs expression in cervical cancer: a systematic review and meta-analysis.

Long noncoding RNAs (lncRNAs) have been reported to be abnormally expressed in cervical cancer (CC) and presumably serve as diagnostic or prognostic markers. We thus performed a systematic review and meta-analysis to evaluate the clinical values of dysregulated lncRNAs in CC. A literature search was performed using the electronic databases PubMed, Embase, and Web of Science. A total of 22 relevant studies were eligible, including 21 on clinicopathological features, 18 on prognosis, and 4 on diagnosis. For clinicopathological features, HOTAIR expression was positively associated with tumor size (odds ratio [OR]=2.19, 95% confidence interval [CI] 1.42-3.38, P=0.000) and lymph node metastasis (OR=6.04, 95% CI 3.51-10.42, P=0.000). For the prognostic values, up-regulated HOTAIR had an unfavorable impact on overall survival ([OS]; hazard ratio [HR]=1.94, 95%CI 1.17-3.22, P=0.011) and disease-free survival (HR=2.61, 95%CI 1.35-5.05, P=0.004), and high PVT1 expression was correlated with shorter OS (HR=1.66, 95%CI 1.21-2.29, P=0.002). For the diagnostic values, the pooled result showed an area under the curve (AUC) of 0.85, with 85% sensitivity and 81% specificity in discriminating patients with CC from healthy controls. Overall, we conclude that lncRNAs might serve as promising indicators for prognostic and diagnostic evaluation of patients with CC.

Preparation and in vitro anti-tumor properties of toad venom extract-loaded solid lipid nanoparticles.

In this study, we prepared solid lipid nanoparticles (TV-SLNs) loaded with toad venom extract and investigated their anti-tumor effects in vitro in HeLa and SKOV-3 cells. TV-SLNs were prepared using a cold homogenization technique, and the formulation was optimized by central composite design and response surface methods. The anti-tumor activities of TV-SLNs were evaluated by analyzing cell division and cell cycle distribution by using the MTT assay and flow cytometry. After incubation with TV-SLNs, the growth of both HeLa and SKOV-3 cells was inhibited significantly. The percentage of HeLa cells in G0/G1 phase decreased, whereas that in the S and G2/M phases increased. Thus, the S and G2/M phases were blocked after the incubation of HeLa cells with TV-SLNs for 24 h. In contrast, the percentage of SKOV-3 cells in G0/G1 phase increased and then decreased in S and G2/M phases, with the G0/G1 phase being blocked after incubation with TV-SLNs for 24 h. Our results demonstrate that TV-SLNs inhibited the fissiparism of HeLa and SKOV-3 cells in a time-and dose-dependent manner. TV-SLNs may be effective as a novel TV vaginal delivery system for the treatment of cervical and ovarian cancers.

[Expression of A-kinase anchor protein 95, cyclin E2, and connexin 43 in lung cancer tissue, clinical significance of their expression, and their expression correlation].

OBJECTIVE: To study the expression of A-kinase anchor protein 95 (AKAP95), cyclin E(2), and connexin 43 (Cx43) in lung cancer tissue, the clinical significance of their expression, and the expression correlation among the three proteins. METHODS: Fifty-one samples of lung cancer tissue were examined by immunohistochemistry to measure the expression of AKAP95, cyclin E2, and Cx43. RESULTS: The positive rate of AKAP95 expression in lung cancer tissue was significantly higher than that in paracancerous tissue (82.35% vs 33.33%, P < 0.05); AKAP95 expression was associated with the cell differentiation and histopathological type of lung cancer (P < 0.05). The positive rate of cyclin E(2) expression in lung cancer tissue was significantly higher than that in paracancerous tissue (43.14% vs 13.33%, P < 0.05); cyclin E(2) expression was associated with the lymph node metastasis and histopathological type of lung cancer (P < 0.05). The positive rate of Cx43 expression in lung cancer tissue was lower than that in paracancerous tissue (60.78% vs 80.00%); Cx43 expression was associated with the cell differentiation, lymph node metastasis, and histopathological type of lung cancer (P < 0.05). There was correlation between each two of AKAP95 expression, cyclin E(2) expression, and Cx43 expression in lung cancer tissue. CONCLUSION: High expression of AKAP95 and cyclin E(2) plays an important role in the occurrence and development of lung cancer. AKAP95 expression is associated with the cell differentiation and histopathological type of lung cancer, and cyclin E2 expression is associated with lymph node metastasis and histopathological type. There is correlation between each two of AKAP95 expression, cyclin E(2) expression, and Cx43 expression in lung cancer tissue.