Nanoparticle (NP)-mediated APOC1 silencing to inhibit MAPK/ERK and NF-κB pathway and suppress breast cancer growth and metastasis.

Breast cancer is one of the most common malignant tumors with high mortality and poor prognosis in women. There is an urgent need to discover new therapeutic targets for breast cancer metastasis. Herein, we identified that Apolipoprotein C1 (APOC1) was up-regulated in primary tumor of breast cancer patient that recurrence and metastasis by immunohistochemistry (IHC). Kaplan-Meier Plotter database showed that high levels of APOC1 in breast cancer patients were strongly associated with worse overall survival (OS) and relapse-free survival (RFS). Mechanistically, APOC1 silencing significantly inhibits MAPK/ERK kinase pathway and restrains the NF-κB to decrease the transcription of target genes related to growth and metastasis in vitro. Based on this regulatory mechanism, we developed these findings into potential therapeutic drugs, glutathione (GSH) responsive nano-particles (NPs) were used for systemic APOC1 siRNA delivery, NPs (siAPOC1) silenced APOC1 expression, and subsequently resulted in positive anti-tumor effects in orthotopic and liver metastasis models in vivo. Taken together, GSH responsive NP-mediated siAPOC1 delivery was proved to be effective in regulating growth and metastasis in multiple tumor models. These findings show that APOC1 could be a potential biomarker to predict the prognosis of breast cancer patients and NP-mediated APOC1 silencing could be new strategies for exploration of new treatments for breast cancer metastasis.

Remodeling Serine Synthesis and Metabolism via Nanoparticles (NPs)-Mediated CFL1 Silencing to Enhance the Sensitivity of Hepatocellular Carcinoma to Sorafenib.

Tyrosine kinase inhibitors represented by sorafenib are the first-line treatment for hepatocellular carcinoma (HCC), but the low response rate of HCC patient has become a clinical pain-point. Emerging evidences have revealed that metabolic reprogramming plays an important role in regulating the sensitivity of tumor cells to various chemotherapeutics including sorafenib. However, the underlying mechanisms are very complex and are not fully elucidated. By comparing the transcriptome sequencing data of sorafenib-sensitive and -insensitive HCC patients, it is revealed that cofilin 1 (CFL1) is highly expressed in the tumor tissues of sorafenib-insensitive HCC patients and closely correlated with their poor prognosis. Mechanically, CFL1 can promote phosphoglycerate dehydrogenase transcription and enhance serine synthesis and metabolism to accelerate the production of antioxidants for scavenging the excessive reactive oxygen species induced by sorafenib, thereby impairing the sorafenib sensitivity of HCC. To translate this finding and consider the severe side effects of sorafenib, a reduction-responsive nanoplatform for systemic co-delivery of CFL1 siRNA (siCFL1) and sorafenib is further developed, and its high efficacy in inhibiting HCC tumor growth without apparent toxicity is demonstrated. These results indicate that nanoparticles-mediated co-delivery of siCFL1 and sorafenib can be a new strategy for the treatment of advanced HCC.

Survival, treatment pattern, and treatment outcome in patients with cervical cancer metastatic to distant lymph nodes.

Background: Cervical cancer with nodal involvement beyond the pelvis was considered as distant nodal metastasis in the previous International Federation of Gynecology and Obstetrics staging system. With the improvement of cancer-directed therapies, some of these patients can receive curative treatment. Classifying them as distant metastasis may result in underestimation of their prognosis as well as undertreatment. However, limited research has been conducted on the survival and treatment pattern in distant lymphatic metastatic cervical cancer. Objective: To investigate the survival, treatment pattern, and treatment outcome of patients with cervical cancer metastasized to distant lymph nodes (DLN) beyond the pelvis. Methods: Patients with stage III-IV cervical cancer from 1988 to 2016 were identified using the Surveillance, Epidemiology, and End Results program. The cancer cause-specific survival (CSS) was analyzed using the Kaplan-Meier method, log-rank test, multivariable Cox proportional hazard regression, subgroup analysis, and propensity score-matched analysis. Results: Of 17783 patients with stage III-IV cervical cancer, patients with distant nodal disease beyond the pelvis (n=1883; included para-aortic lymph nodes metastasis) had superior survival compared to those with pelvic organ invasion or with distant organ(s) metastasis (5-year CSS, 32.3%, 26.3%, and 11.5%, respectively; adjusted P<0.001). The T stage significantly affected the survival of patients with positive DLN (5-year CSS for T1, T2, and T3: 47.3%, 37.0%, and 19.8%, respectively, adjusted P<0.01). For patients with positive DLN, combination radiotherapy (external beam radiotherapy [EBRT] with brachytherapy) prolonged CSS compared to EBRT alone (5-year CSS, 38.0% vs 21.7%; propensity score-adjusted HR, 0.60; 95% CI 0.51-0.72; P<0.001). Despite the superiority of combination radiotherapy, EBRT was the most frequently used treatment after 2004 (483/1214, 39.8%), while the utilization of combination radiotherapy declined from 37.8% (253/669) during 1988 through 2003 to 25.2% (306/1214) during 2004 through 2016. Conclusion: Patients with cervical cancer metastasized to DLN have favorable survival compared to those with pelvic organ invasion or with distant organ(s) metastasis. Their prognosis is significantly affected by local tumor burden and local treatment. Adequate and aggressive local radiotherapy, such as image-guided brachytherapy, can be considered for these patients to achieve better outcomes.

Towards improving the biocompatibility of prosthetic eyes.

Prosthetic eyes are currently manufactured using Poly(methyl methacrylate) (PMMA) which is not an ideal material because it is hydrophobic. While significant research has investigated the benefits of hydrophilic materials for contact lenses, no such research has been carried out on hydrophilic materials for prosthetic eyes until now. In this study, different derivatives of Poly(ethylene glycol) (PEG) monomer and methyl methacrylate (MMA) monomer were grafted to PMMA using copolymerisation. The resulting matrixes were evaluated by water contact angle measurement, 24 h water absorption testing, and colour-difference measurement when exposed to ultraviolet light. The contact angle and water absorption results indicated that ethylene glycol dimethacrylate (EGDMA) grafted PMMA matrix had a better hydrophilic performance than the other matrixes tested. EGDMA is already a minor constituent of the PMMA matrix currently used for manufacturing prosthetic eyes but when the proportion of EGDMA monomer to MMA monomer used in the manufacturing process was increased to 50/50 the hydrophilicity of the matrix was significantly improved. EGDMA-grafted PMMA is inexpensive and comes as a liquid monomer that is easily mixed with the PMMA monomer that ocular prosthetists are familiar with. The mixture requires no special handling beyond the normal safety precautions that apply when using PMMA monomers. In-vitro testing shows that EGDMA-grafted PMMA significantly improves the wettability of PMMA currently used for the manufacture of prosthetic eyes and has the potential to significantly improve wearing comfort and socket health.

Development and Validation of an RNA-Binding Protein-Based Prognostic Model for Ovarian Serous Cystadenocarcinoma.

Ribonucleic acid-binding proteins (RBPs) are reportedly involved in tumor progression and recurrence; however, the functions and mechanisms of action of RBPs in ovarian serous cystadenocarcinoma (OSC) are not known. To address these issues, gene expression profiles of OSC tissues from The Cancer Genome Atlas (TCGA) and normal tissues from the Genotype-Tissue Expression database were compared in order to identify RBPs that are differentially expressed in OSC. We also analyzed the biological functions of these RBPs and their relationship to clinical outcome. There were 190 RBPs that were differentially expressed between OSC and normal tissues, including 93 that were upregulated and 97 that were downregulated. Five of the RBPs were used to construct a prediction model that was evaluated by univariate and multivariate Cox regression analyses. TCGA data were randomly divided into training and test cohorts, and further categorized into high- and low-risk groups according to risk score in the model. The overall survival (OS) of the high-risk group was shorter than that of the low-risk group (training cohort P = 0.0007596; test cohort P = 0.002219). The area under the receiver operating characteristic curve of the training and test cohorts was 0.701 and 0.638, respectively, demonstrating that the model had good predictive power. A nomogram was established to quantitatively describe the relationship between the five prognostic RBPs and OS in OSC, which can be useful for developing individualized management strategies for patients.