Immune signatures of the POLE mutation in endometrial carcinomas: a systematic study based on TCGA data and clinical cohort validation.

Background: POLE is a critical biomarker for endometrial cancer (ECs) prognosis and therapeutic decision. However, the immune infiltration and immunotherapy-related gene expression in the tumor microenvironment (TME) of POLE-mutated ECs remain unresolved. Methods: The TCGA database was used to characterize the TME of POLE mutants, which primarily included immune cells and co-expression genes. We used immunohistochemistry (IHC) to determine immune cell abundance and PD-L1 expression in 104 EC tissues, including 11 POLE mutants and 93 wild-type. Results: The bioinformatic study found significant differences in gene expression of the chemokine family, immune-cell markers, and lysozyme in POLE mutants, along with immune response activation. In POLE-mutated ECs, the abundance of CD4+T, CD8+T, M1 macrophages, and dendritic cells increased considerably. Furthermore, POLE mutations may enhance immune cell recruitment or activation and lymphocyte homing in ECs. POLE mutants also had increased expression of immune-checkpoint suppressor genes such as PD-L1, CTLA-4, TIM-3, and others. The tumor mutation burden (TMB) was higher in ECs with POLE mutation. In the validation cohort, we discovered that POLE mutations were related to the immune infiltration abundance of CD8+, CD4+, and Foxp3+ cells and PD-L1 expression by IHC. The prognosis of TCGA-ECs showed that the survival time of the CD8, CD4, PD-L1, or Foxp3 over-expression subgroup of the POLE mutants was significantly prolonged compared to the down-regulation subgroup or the POLE wild-type. Conclusion: The infiltration abundance of CD8+ T, CD4+ T, Foxp3+ T cells, and the expression of PD-L1 harbor crucial value for the prognosis or individualized therapy of POLE-mutated ECs.

CXCL9 correlates with antitumor immunity and is predictive of a favorable prognosis in uterine corpus endometrial carcinoma.

Background: The C-X-C motif chemokine ligand-9 (CXCL9) is related to the progression of multiple neoplasms. Yet, its biological functions in uterine corpus endometrioid carcinoma (UCEC) remain shrouded in confusion. Here, we assessed the prognostic significance and potential mechanism of CXCL9 in UCEC. Methods: Firstly, bioinformatics analysis of the public cancer database, including the Cancer Genome Atlas / the Genotype-Tissue Expression project (TCGA+ GTEx, n=552) and Gene Expression Omnibus (GEO): GSE63678 (n=7), were utilized for the CXCL9 expression-related analysis in UCEC. Then, the survival analysis of TCGA-UCEC was performed. Futher, the gene set enrichment analysis (GSEA) was carried out to reveal the potential molecular signaling pathway in UCEC associated with CXCL9 expression. Moreover, the immunohistochemistry (IHC) assay of our validation cohort (n=124) from human specimens were used to demonstrate the latent significance of CXCL9 in UCEC. Results: The bioinformatics analysis suggested that CXCL9 expression was significantly upregulated in UCEC patients; and hyper-expression of CXCL9 was related to prolonged survival. the GSEA enrichment analysis showed various immune response-related pathways, including T/NK cell, lymphocyte activation, cytokine-cytokine receptor interaction network, and chemokine signaling pathway, mediated by CXCL9. In addition, the cytotoxic molecules (IFNG, SLAMF7, JCHAIN, NKG7, GBP5, LYZ, GZMA, GZMB, and TNF3F9) and the immunosuppressive genes (including PD-L1) were positively related to the expression of CXCL9. Further, the IHC assay indicated that the CXCL9 protein expression was mainly located in intertumoral and significantly upregulated in the UCEC patients; UCEC with high intertumoral CXCL9 cell abundance harbored an improved prognosis; a higher ratio of anti-tumor immune cells (CD4+, CD8+, and CD56+ cell) and PD-L1 was found in UCEC with CXCL9 high expression. Conclusion: Overexpressed CXCL9 correlates with antitumor immunity and is predictive of a favorable prognosis in UCEC. It hinted that CXCL9 may serve as an independent prognostic biomarker or therapeutic target in UCEC patients, which augmented anti-tumor immune effects to furnish survival benefits.

The insulin long-acting chitosan - Polyethyleneimine nanoparticles to treat the type 2 diabetes mellitus and prevent the associated complications.

Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder, which is ultimately treated by the insulin (INS). However, the subcutaneous (s. c.) injection of insulin solution faces the problems of pain and unsatisfactory patient compliance. In this study, the long-acting formulations of insulin are propsed to treat the T2DM and prevent the associated complications. The chitosan (CS) and/or branched polyethyleneimine (bPEI) nanoparticles (bPEI-INS NPs, CS-bPEI-INS NPs) were constructed to load insulin. The long -acting nanoparticles successfully achieved the sustained release of the INS in vitro and in vivo. After s. c. administration, the CS-bPEI-INS NPs greatly improved the INS bioavailability. As a result, the CS-bPEI-INS NPs produced sustained glucose-lowering effects, promising short-term and long-term hypoglycemic efficacy in the T2DM model. Furthermore, the treatment of the CS-bPEI-INS NPs greatly protected the islet in the pancreas and prevented the associated complications of the T2DM, such as cardiac fibrosis in the myocardial interstitium and the perivascular area. In a word, the CS-bPEI-INS NPs was an encouraging long-acting formulation of insulin and had great potential in the treatment of T2DM.

CENPF/CDK1 signaling pathway enhances the progression of adrenocortical carcinoma by regulating the G2/M-phase cell cycle.

BACKGROUND: Adrenocortical carcinoma (ACC) is an aggressive and rare malignant tumor and is prone to local invasion and metastasis. And, overexpressed Centromere Protein F (CENPF) is closely related to the oncogenesis of various neoplasms, including ACC. However, the prognosis and exact biological function of CENPF in ACC remains largely unclear. METHODS: In the present essay, the expression patterns and prognostic value of CENPF in ACC were investigated in clinical specimens and public cancer databases, including GEO and TCGA. The potential signaling mechanism of CENPF in ACC was studied based on gene-set enrichment analysis (GSEA). Furthermore, a small RNA interference experiment was conducted to probe the underlying biological function of CENPF in the human ACC cell line, SW13 cells. Lastly, two available therapeutic strategies, including immunotherapy and chemotherapy, have been further explored. RESULTS: The expression of CENPF in human ACC samples, GEO, and TCGA databases depicted that CENPF was overtly hyper-expressed in ACC patients and positively correlated with tumor stage. The aberrant expression of CENPF was significantly correlated with unfavorable overall survival (OS) in ACC patients. Then, the GSEA analysis declared that CENPF was mainly involved in the G2/M-phase mediated cell cycle and p53 signaling pathway. Further, the in vitro experiment demonstrated that the interaction between CENPF and CDK1 augmented the G2/M-phase transition of mitosis, cell proliferation and might induce p53 mediated anti-tumor effect in human ACC cell line, SW13 cells. Lastly, immune infiltration analysis highlighted that ACC patients with high CENPF expression harbored significantly different immune cell populations, and high TMB/MSI score. The gene-drug interaction network stated that CENPF inhibitors, such as Cisplatin, Sunitinib, and Etoposide, might serve as potential drugs for the therapy of ACC. CONCLUSION: The result points out that CENPF is significantly overexpressed in ACC patients. The overexpressed CENPF predicts a poor prognosis of ACC and might augment the progress of ACC. Thus, CENPF and related genes might serve as a novel prognostic biomarker or latent therapeutic target for ACC patients.

EMS1/DLL4-Notch Signaling Axis Augments Cell Cycle-Mediated Tumorigenesis and Progress in Human Adrenocortical Carcinoma.

Adrenocortical carcinoma (ACC) is a rare malignant neoplasm that is prone to local invasion and metastasis. Meanwhile, overexpressed endothelial cell-specific molecule 1 (ESM1) is closely related to tumorigenesis of multitudinous tumors. However, the prognosis value and biological function of ESM1 in ACC remains undefined. In the current essay, the assessment in human ACC samples and multiple public cancer databases suggested that ESM1 was significantly overexpressed in ACC patients. The abnormal expression of ESM1 was evidently correlated with dismal overall survival (OS) in ACC patients. Then, the gene-set enrichment analysis (GSEA) was applied to unravel that ESM1 was mostly involved in cell cycle and Notch4 signaling pathway. Furthermore, in vitro experiment, RNA interference of ESM1 was carried out to state that ESM1 augments CDK1 and p21-mediated G2/M-phase transition of mitosis, cell proliferation via DLL4-Notch signaling pathway in human ACC cell line, SW13 cells. Additionally, two possible or available therapeutic strategies, including immunotherapy and chemotherapy, have been further explored. Immune infiltration analysis highlighted that no significant difference was found in ACC patients between EMS1high and EMS1low group for immune checkpoint-related genes. In addition, the overexpression of ESM1 might trigger the accumulation of tumor mutation burden (TMB) during the cell cycle of DNA replication in ACC. The gene-drug interaction network then indicated that ESM1 inhibitors, such as cisplatin, might serve as potential drugs for the therapy of ACC. Collectively, the results asserted that ESM1 and related regulators might act as underlying prognostic biomarkers or novel therapeutic targets for ACC.

The Antibacterial Effects of Supermolecular Nano-Carriers by Combination of Silver and Photodynamic Therapy.

The over-use of antibiotics has promoted multidrug resistance and decreased the efficacy of antibiotic therapy. Thus, it is still in great need to develop efficient treatment strategies to combat the bacteria infection. The antimicrobial photodynamic therapy (aPDT) and silver nanoparticles have been emerged as effective antibacterial methods. However, the silver therapy may induce serious damages to human cells at high concentrations and, the bare silver nanoparticles may rapidly aggregate, which would reduce the antibacterial efficacy. The encapsulation of sliver by nano-carrier is a promising way to avoid its aggregation and facilitates the co-delivery of drugs for combination therapy, which does not require high concentration of sliver to exert antibacterial efficacy. This work constructed a self-assembled supermolecular nano-carrier consisting of the photosensitizers (PSs), the anti-inflammatory agent and silver. The synthesized supermolecular nano-carrier produced reactive oxygen species (ROS) under the exposure of 620-nm laser. It exhibited satisfying biocompatibility in L02 cells. And, this nano-carrier showed excellent antibacterial efficacy in Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) as indicated by bacterial growth and colony formation. Its antibacterial performance is further validated by the bacteria morphology through the scanning electron microscope (SEM), showing severely damaged structures of bacteria. To summary, the supermolecular nano-carrier TCPP-MTX-Ag-NP combining the therapeutic effects of ROS and silver may serve as a novel strategy of treatment for bacterial infection.

Doxorubicin-loaded hydrogen peroxide self-providing copper nanodots for combination of chemotherapy and acid-induced chemodynamic therapy against breast cancer.

In recent years, chemodynamic therapy (CDT) has gained increasing interest in cancer treatment. In contrast to photodynamic therapy and sonodynamic therapy, extrinsic excitations such as laser or ultrasound are not required in CDT. As a result, the CDT performance is not limited by the penetration depth of the external irritation. However, CDT relies heavily on hydrogen peroxide (H2O2) in the tumour microenvironment (TME). Insufficient H2O2 in the TME limits the CDT performance, and the most reported methods to produce H2O2 in the TME are dependent on oxygen supply, which is restricted by the hypoxic TME. In this study, H2O2 self-providing copper nanodots were proposed, and the drug doxorubicin (DOX) was successfully loaded to construct DOX-nanodots. Our results showed that the nanodots produced H2O2 in the weakly acidic TME due to the peroxo group and further generated the most active hydroxyl radical (OH) through the Fenton-like reaction. This process was pH-dependent and did not occur in a neutral environment. In addition to OH, the nanodots also produced singlet oxygen (1O2) and superoxide anions (O2-) in the cancer cells. The copper nanodots performed promising CDT against breast cancer in vitro and in vivo, with enhanced cell apoptosis and decreased cell proliferation. The combination of chemotherapy and CDT using DOX-nanodots further improved the therapeutic effects. The treatments showed good biocompatibility with no obvious toxicity in major tissues, possibly due to the specific OH generation in the weakly acidic TME. In summary, the H2O2 self-providing copper nanodots in combination with DOX showed promising cancer-curing effects due to the oxygen-independent and tumour-specific production of reactive oxygen species and the cooperation of chemotherapy.

Bismuth chelate as a contrast agent for X-ray computed tomography.

BACKGROUNDS: Due to the unexpected side effects of the iodinated contrast agents, novel contrast agents for X-ray computed tomography (CT) imaging are urgently needed. Nanoparticles made by heavy metal elements are often employed, such as gold and bismuth. These nanoparticles have the advantages of long in vivo circulation time and tumor targeted ability. However, due to the long residence time in vivo, these nanoparticles may bring unexpected toxicity and, the preparation methods of these nanoparticles are complicated and time-consuming. METHODS: In this investigation, a small molecular bismuth chelate using diethylenetriaminepentaacetic acid (DPTA) as the chelating agent was proposed to be an ideal CT contrast agent. RESULTS: The preparation method is easy and cost-effective. Moreover, the bismuth agent show better CT imaging for kidney than iohexol in the aspect of improved CT values. Up to 500 µM, the bismuth agent show negligible toxicity to L02 cells and negligible hemolysis. And, the bismuth agent did not induce detectable morphology changes to the main organs of the mice after intravenously repeated administration at a high dose of 250 mg/kg. The pharmacokinetics of the bismuth agent follows the first-order elimination kinetics and, it has a short half-life time of 0.602 h. The rapid clearance from the body promised its excellent biocompatibility. CONCLUSIONS: This bismuth agent may serve as a potential candidate for developing novel contrast agent for CT imaging in clinical applications.

The use of amphiphilic copolymer in the solid dispersion formulation of nimodipine to inhibit drug crystallization in the release media: Combining nano-drug delivery system with solid preparations.

Solid dispersion is a widely used method to improve the dissolution and oral bioavailability of water-insoluble drugs. However, due to the strong hydrophobicity, the drug crystallization in the release media after drug dissolution and the resulted decreased drug absorption retards the use of solid dispersions. It is widely known that the amphiphilic copolymer can encapsulate the hydrophobic compounds and help form stable nano-dispersions in water. Inspired by this, we tried to formulate the solid dispersion of nimodipine by using amphipathic copolymer as one of the carriers. Concerning the solid dispersions, there are many important points involved in these formulations, such as the miscibility between the drug and the carriers, the storage stability of solid dispersions, the dissolution enhancement and so on. In this study, a systemic method is proposed. In details, the supersaturation test and the glass transition temperature (Tg) measurement to predict the crystallization inhibition, the ratios of different components and the storage stability, the interactions among the components were investigated in detail by nuclear magnetic resonance (1H NMR) and isothermal titration calorimetry (ITC) and, the final dissolution and oral bioavailability enhancement. It was found that the amphiphilic copolymer used in the solid dispersion encouraged the formation the drug loading micelles in the release media and, finally, the problem of drug crystallization in the dissolution process was successfully solved.

Percutaneous imaging-guided cryoablation for lung cancer.

Percutaneous cryoablation under imaging guidance has been proved to be a safe and effective method for ablation and debulking of tumors, providing radical cure or palliation, as the case may be, for patients with different stages of disease. The local control rate is high with cryoablation, and the complications are usually controllable, making it a reasonable choice in lung cancer treatment. In this paper the technique and mechanism of action of cryoablation are summarized, and studies performed on the application of percutaneous cryoablation in various stages of lung cancer are reviewed. Its emerging application in the treatment of pure ground-glass nodules (GGNs) is also introduced.