Cocktail hepatocarcinoma therapy by a super-assembled nano-pill targeting XPO1 and ATR synergistically.

Intensive cancer treatment with drug combination is widely exploited in the clinic but suffers from inconsistent pharmacokinetics among different therapeutic agents. To overcome it, the emerging nanomedicine offers an unparalleled opportunity for encapsulating multiple drugs in a nano-carrier. Herein, a two-step super-assembled strategy was performed to unify the pharmacokinetics of a peptide and a small molecular compound. In this proof-of-concept study, the bioinformatics analysis firstly revealed the potential synergies towards hepatoma therapy for the associative inhibition of exportin 1 (XPO1) and ataxia telangiectasia mutated-Rad3-related (ATR), and then a super-assembled nano-pill (gold nano drug carrier loaded AZD6738 and 97-110 amino acids of apoptin (AP) (AA@G)) was constructed through camouflaging AZD6738 (ATR small-molecule inhibitor)-binding human serum albumin onto the AP-Au supramolecular nanoparticle. As expected, both in vitro and in vivo experiment results verified that the AA@G possessed extraordinary biocompatibility and enhanced therapeutic effect through inducing cell cycle arrest, promoting DNA damage and inhibiting DNA repair of hepatoma cell. This work not only provides a co-delivery strategy for intensive liver cancer treatment with the clinical translational potential, but develops a common approach to unify the pharmacokinetics of peptide and small-molecular compounds, thereby extending the scope of drugs for developing the advanced combination therapy.

One Stone, Two Birds: A Peptide-Au(I) Infinite Coordination Supermolecule for the Confederate Physical and Biological Radiosensitization in Cancer Radiation Therapy.

Over half of cancer patients are subjected to radiotherapy, but owing to the deficient amount of reactive oxygen radicals (ROS) and DNA double-strand breaks (DSBs), a fair number of them suffer from radiotherapy resistance and the subsequent short-term survival opportunity. To overcome it, many successes have been achieved in radiosensitizer discovery using physical strategy and/or biological strategy, but significant challenges remain regarding developing clinically translational radiosensitizers. Herein, a peptide-Au(I) infinite coordination supermolecule termed PAICS is developed that combined both physical and biological radiosensitization and possessed pharmaceutical characteristics including adequate circulatory stability, controllable drug release, tumor-prioritized accumulation, and the favorable body eliminability. As expected, monovalent gold ion endowed this supermolecule with high X-ray absorption and the subsequent radiosensitization. Furthermore, a peptide targeting CRM1, is assembled into the supermolecule, which successfully activates p53 and apoptosis pathway, thereby further sensitizing radiotherapy. As a result, PAICS showed superior ability for radiotherapy sensitization in vivo and maintained a favorable safety profile. Thus, the PAICS reported here will offer a feasible solution to simultaneously overcome both the pharmaceutical obstacles of physical and biological radiosensitizers and will enable the development of a class of nanomedicines for tumor radiotherapy sensitization.

3D Collagen Fiber Concentration Regulates Treg Cell Infiltration in Triple Negative Breast Cancer.

Background: Triple negative breast cancer (TNBC) is characterized by poor prognosis and a lack of effective therapeutic agents owing to the absence of biomarkers. A high abundance of tumor-infiltrating regulatory T cells (Tregs) was associated with worse prognosis in malignant disease. Exploring the association between Treg cell infiltration and TNBC will provide new insights for understanding TNBC immunosuppression and may pave the way for developing novel immune-based treatments. Materials and Methods: Patients from TCGA were divided into Treg-high (Treg-H) and Treg-low (Treg-L) groups based on the abundance of Tregs according to CIBERSORT analysis. The association between expression level of Tregs and the clinical characteristics as well as prognosis of breast cancer were evaluated. Next, a Treg-related prognostic model was established after survival-dependent univariate Cox and LASSO regression analysis, companied with an external GEO cohort validation. Then, GO, KEGG and GSEA analyses were performed between the Treg-H and Treg-L groups. Masson and Sirius red/Fast Green staining were applied for ECM characterization. Accordingly, Jurkat T cells were encapsulated in 3D collagen to mimic the ECM microenvironment, and the expression levels of CD4, FOXP3 and CD25 were quantified according to immunofluorescence staining. Results: The expression level of Tregs is significantly associated with the clinical characteristics of breast cancer patients, and a high level of Treg cell expression indicates a poor prognosis in TNBC. To further evaluate this, a Treg-related prognostic model was established that accurately predicted outcomes in both TCGA training and GEO validation cohorts of TNBC patients. Subsequently, ECM-associated signaling pathways were identified between the Treg-H and Treg-L groups, indicating the role of ECM in Treg infiltration. Since we found increasing collagen concentrations in TNBC patients with distant migration, we encapsulated Jurkat T cells within a 3D matrix with different collagen concentrations and observed that increasing collagen concentrations promoted the expression of Treg biomarkers, supporting the regulatory role of ECM in Treg infiltration. Conclusion: Our results support the association between Treg expression and breast cancer progression as well as prognosis in the TNBC subtype. Moreover, increasing collagen density may promote Treg infiltration, and thus induce an immunosuppressed TME.

A Novel Necroptosis-Related lncRNA Signature Predicts the Prognosis of Lung Adenocarcinoma.

Background: Necroptosis is closely related to the tumorigenesis and development of cancer. An increasing number of studies have demonstrated that targeting necroptosis could be a novel treatment strategy for cancer. However, the predictive potential of necroptosis-related long noncoding RNAs (lncRNAs) in lung adenocarcinoma (LUAD) still needs to be clarified. This study aimed to construct a prognostic signature based on necroptosis-related lncRNAs to predict the prognosis of LUAD. Methods: We downloaded RNA sequencing data from The Cancer Genome Atlas database. Co-expression network analysis, univariate Cox regression, and least absolute shrinkage and selection operator were adopted to identify necroptosis-related prognostic lncRNAs. We constructed the predictive signature by multivariate Cox regression. Kaplan-Meier analysis, time-dependent receiver operating characteristics, nomogram, and calibration curves were used to validate and evaluate the signature. Subsequently, we used gene set enrichment analysis (GSEA) and single-sample gene set enrichment analysis (ssGSEA) to explore the relationship between the predictive signature and tumor immune microenvironment of risk groups. Finally, the correlation between the predictive signature and immune checkpoint expression of LUAD patients was also analyzed. Results: We constructed a signature composed of 7 necroptosis-related lncRNAs (AC026355.2, AC099850.3, AF131215.5, UST-AS2, ARHGAP26-AS1, FAM83A-AS1, and AC010999.2). The signature could serve as an independent predictor for LUAD patients. Compared with clinicopathological variables, the necroptosis-related lncRNA signature has a higher diagnostic efficiency, with the area under the receiver operating characteristic curve being 0.723. Meanwhile, when patients were stratified according to different clinicopathological variables, the overall survival of patients in the high-risk group was shorter than that of those in the low-risk group. GSEA showed that tumor- and immune-related pathways were mainly enriched in the low-risk group. ssGSEA further confirmed that the predictive signature was significantly related to the immune status of LUAD patients. The immune checkpoint analysis displayed that low-risk patients had a higher immune checkpoint expression, such as CTLA-4, HAVCR2, PD-1, and TIGIT. This suggested that immunological function is more active in the low-risk group LUAD patients who might benefit from checkpoint blockade immunotherapies. Conclusion: The predictive signature can independently predict the prognosis of LUAD, helps elucidate the mechanism of necroptosis-related lncRNAs in LUAD, and provides immunotherapy guidance for patients with LUAD.

CMTM7 as a novel molecule of ATG14L-Beclin1-VPS34 complex enhances autophagy by Rab5 to regulate tumorigenicity.

BACKGROUND: CMTM7 is a tumor suppressor that positively regulates EGFR degradation by promoting Rab5 activation, and plays a vital role in tumor progression. Rab5 forms complexes with Beclin1 and VPS34, and acts in the early stage of autophagy. However, the affects of CMTM7 on autophagy and its mechanism are still unclear. METHODS: The effect of CMTM7 on autophagy induction was confirmed by western blotting, confocal microscopy and transmission electron microscopy. Co-immunoprecipitation was used to analyse the interaction of CMTM7 with autophagy initiation complex and Rab5. The xenograft model in nude mice was used to elucidate the function of CMTM7 in tumorigenicity and autophagy in vivo. RESULTS: In this study, we first demonstrated that CMTM7 facilitated the initiation of autophagosome formation, which consequently promoted the subsequent multistage process of autophagic flux, i.e. from autophagosome assembly till autolysosome formation and degradation. Confocal and co-immunoprecipitation showed that CMTM7 interacted with Rab5, VPS34, Beclin1, and ATG14L, but not with ULK1, UVRAG and LC3B. CMTM7 also increased the activity of ATG14L-linked VPS34 complex and its association with Rab5. Both in vitro and in vivo experiments demonstrated that knockdown of CMTM7 enhanced tumor growth by impairing autophagy. CONCLUSION: These findings highlighted the role of CMTM7 in the regulation of autophagy and tumorigenicity, revealing it as a novel molecule that is associated with the interaction of Rab5 and ATG14L-Beclin1-VPS34 complex. Video Abstract.

Dual effects of active ERK in cancer: A potential target for enhancing radiosensitivity.

Ionizing radiation (IR) is an important cancer treatment approach. However, radioresistance eventually occurs, resulting in poor outcomes in patients with cancer. Radioresistance is associated with multiple signaling pathways, particularly pro-survival signaling pathways. The extracellular signal-regulated kinase 1/2 (ERK1/2) cascade is an important signaling pathway that initiates several cellular processes and is regulated by various stimuli, including IR. Although numerous studies have demonstrated the pro-survival effects of active ERK, activation of ERK has also been associated with cell death, indicating that radiosensitization may occur by ERK stimulation. In this context, the present review describes the associations between ERK signaling, cancer and IR, and discusses the association between ERK and its pro-survival function in cancer cells, including stimuli, molecular mechanisms, clinical use of inhibitors and underlying limitations. Additionally, the present review introduces the view that active ERK may induce cell death, and describes the potential factors associated with this process. This review describes the various outcomes induced by active ERK to prompt future studies to aim to enhance radiosensitivity in the treatment of cancer.

Hypoxia-induced autophagy promotes EGFR loss in specific cell contexts, which leads to cell death and enhanced radiosensitivity.

Treatment failure through radioresistance of tumors is associated with activation of the epidermal growth factor receptor (EGFR). Tumor cell proliferation, DNA-repair, hypoxia and metastases-formation are four mechanisms in which EGFR signaling has an important role. However, the effect of hypoxia on EGFR expression is still controversial. In this study, we demonstrated that hypoxia enhanced EGFR expression and sustained cell survival in SiHa, CAL 27 and A549 cells at both low and high cell desnities, while in MCF-7, MDA-MB-231 and HeLa cells, EGFR and cell survival were regulated by hypoxic treatment in a cell-density dependent manner: upregulated at low cell density and downregulated at high cell density. In MCF-7 and HeLa xenografts in nude mice, EGFR expression varied inversely with the pimonidazole level that was used as an indicator of hypoxia, accordant with the effect of hypoxia at high cell density in vitro. Hypoxia induced more remarkable cell autophagy at high cell density than at low cell density. Autophagy inhibitor 3MA, rather than proteasome inhibitor MG132 inhibited hypoxia-mediated EGFR loss and shifted cell death to cell survival in HeLa cells. The MCF7 cells' sensitivity to ionizing radiation (IR) under hypoxia was also conditional on the cell densities when the hypoxia treatment was introduced, inversely associated with the expression levels of EGFR. Altogether, hypoxia can decrease EGFR expression in some cell lines by enhancing autophagy at high cell density, leading to cell death and hypersensitivity to radiotherapy. This study may help to understand how hypoxia influences EGFR expression and radiosensitivity.

The efficacy and safety comparison of surgical treatments for stress urinary incontinence: A network meta-analysis.

AIMS: Stress urinary incontinence (SUI) is a common problem worldwide. Mainstream surgical procedures include tension-free vaginal tape (TVT), transobturator tape (TOT), tension-free vaginal tape-obturator (TVT-O), tension-free vaginal tape SECUR (TVT-S), and adjustable single-incision sling (Ajust). The aim of this study was to compare the efficacy and safety of these surgical procedures and assess which surgery is most optimal for SUI by adopting a network meta-analysis (NMA). METHODS: Electronic databases including PubMed, Cochrance Library, and Embase database were researched systematically, until March 21, 2017. The randomized controlled trials (RCTs) that compared the efficacy and safety of TVT, TOT, TVT-O, TVT-S, and Ajust were identified. The studies were included in the analysis when met the predefined inclusion criteria. After demographic and outcome data extraction, a network meta-analysis was conducted with software R 3.3.2 and STATA 14.0. Objective cure rate, subjective cure rate, postoperative complication rate, bladder perforation, tape erosion, urinary retention, and postoperative pain were considered as outcomes, and the outcomes were displayed as odds ratios (ORs) and 95% credible intervals (CrI). The consistency of direct and indirect evidence was assessed by node splitting. The ranks based on probabilities of intervention for the different endpoints were performed. RESULTS: Fourty-five RCTs with 7295 participants were analyzed. The NMA results revealed that, TVT, TOT, and Ajust had a higher objective cure rate than TVT-O and TVT-S (TVT-O: OR = 0.76, 95%CI [0.61, 0.94]; TVT-S: OR = 0.41, 95%CI [0.28, 0.60]). TVT, TOT, and TVT-O had a superior subjective cure rate than TVT-S and Ajust (Ajust: OR = 0.45, 95%CI [0.20, 0.91]; TVT-S: OR = 0.29, 95%CI [0.15, 0.56]). With TVT as the reference, TVT-S had a statistically lower postoperative complication rate (TVT-S: OR = 0.39, 95%CI [0.16, 0.89]). TVT-O, TVT-S, and TOT had a significantly lower bladder perforation rate (TOT: OR = 0.076, 95%CI [0.0060, 0.37]; TVT-O: OR = 4.1e-17, 95%CI [6.1e-48, 0.0032]; TVT-S: OR = 3.8e-17, 95%CI [1.8e-48, 0.0052]). There were no obvious differences between the five treatments for tape erosion. TVT-O exhibited a less postoperative retention (TVT-O: OR = 0.35, 95%CI [0.16, 0.74]). Probabilities of ranking results indicated that TOT was the treatment with best ranking in efficacy and a relatively high safety. CONCLUSIONS: Our study recommend TOT as the optimal regimen for SUI with high efficacy and moderate safety when compared with TVT, TVT-O, TVT-S, and Ajust interventions. However, with the limitation of our study, additional high-quality studies are needed to further evaluate the outcomes.