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The efficacy of combination immunotherapy has been limited by tumor specificity and immune‐related adverse events (irAEs). Herein, we report the development of polymeric STING pro‐agonists (PSPA), whose sono‐immunotherapeutic efficacy is activated by sono‐irradiation and elevated glutathione (GSH) within the tumor microenvironment (TME). PSPA is composed of sonosensitizers (semiconducting polymer) and STING agonists (MSA‐2) via the GSH‐activatable linkers. Under sono‐irradiation, PSPA serves as a sonosensitizer to generate 1O2 and induce immunogenic cell death (ICD) of malignant tumor cells. Furthermore, MSA‐2 is released specifically in tumor microenvironment with highly expressed GSH, minimizing off‐target side effects. The activation of the STING pathway elevates the interferon‐β level and synergizes with SDT to enhance the anti‐tumor response. Therefore, this work proposes a universal approach for spatiotemporal regulation of cancer sono‐immunotherapy. [ABSTRACT FROM AUTHOR]

Although great advances have been made over the past decades, therapeutics for osteosarcoma are quite limited. We performed long‐read RNA sequencing and tandem mass tag (TMT)‐based quantitative proteome on osteosarcoma and the adjacent normal tissues, next‐generation sequencing (NGS) on paired osteosarcoma samples before and after neoadjuvant chemotherapy (NACT), and high‐throughput drug combination screen on osteosarcoma cell lines. Single‐cell RNA sequencing data were analyzed to reveal the heterogeneity of potential therapeutic target genes. Additionally, we clarified the synergistic mechanisms of doxorubicin (DOX) and HDACs inhibitors for osteosarcoma treatment. Consequently, we identified 2535 osteosarcoma‐specific genes and several alternative splicing (AS) events with osteosarcoma specificity and/or patient heterogeneity. Hundreds of potential therapeutic targets were identified among them, which showed the core regulatory roles in osteosarcoma. We also identified 215 inhibitory drugs and 236 synergistic drug combinations for osteosarcoma treatment. More interestingly, the multiomic analysis pointed out the pivotal role of HDAC1 and TOP2A in osteosarcoma. HDAC inhibitors synergized with DOX to suppress osteosarcoma both in vitro and in vivo. Mechanistically, HDAC inhibitors synergized with DOX by downregulating SP1 to transcriptionally modulate TOP2A expression. This study provided a comprehensive view of molecular features, therapeutic targets, and synergistic drug combinations for osteosarcoma. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy has shown tremendous potential to train the intrinsic immune system against malignancy in the clinic. However, the extracellular matrix (ECM) in tumor microenvironment is a formidable barrier that not only restricts the penetration of therapeutic drugs but also prevents the infiltration of antitumor immune cells. We herein report a semiconducting polymer‐based ECM nanoremodeler (SPNcb) to combine photodynamic antitumor activity with cancer‐specific inhibition of collagen‐crosslinking enzymes (lysyl oxidase (LOX) family) for activatable cancer photo‐immunotherapy. SPNcb is self‐assembled from an amphiphilic semiconducting polymer conjugated with a LOX inhibitor (β‐aminopropionitrile, BAPN) via a cancer biomarker (cathepsin B, CatB)‐cleavable segment. BAPN can be exclusively activated to inhibit LOX activity in the presence of the tumor‐overexpressed CatB, thus blocking collagen crosslinking and decreasing ECM stiffness. Such an ECM nanoremodeler synergizes immunogenic phototherapy and checkpoint blockade immunotherapy to improve the tumor infiltration of cytotoxic T cells, inhibiting tumor growth and metastasis. [ABSTRACT FROM AUTHOR]

Papillary thyroid carcinoma (PTC) commonly presents with lymph node metastasis, which may be associated with worsened prognosis. This study aimed to comprehensively evaluate the risk factors of lymph node metastasis in PTC based on preoperative clinical and imaging data and to construct a nomogram model to predict the risk of lymph node metastasis. A total of 989 patients with PTC were enrolled and randomly divided into training and validation cohorts in an 8:2 ratio. Independent risk factors for lymph node metastasis in PTC were analyzed using univariate and stepwise multivariate logistic regression. An importance analysis of independent risk factors affecting lymph node metastasis was performed according to the random forest method. Subsequently, a nomogram to predict lymph node metastasis was constructed, and the predictive effect of the nomogram was evaluated using receiver operating characteristic analysis and calibration curves. Univariate regression analysis revealed that age, sex, body weight, systolic blood pressure, free triiodothyronine, nodule location, nodule number, Thyroid Imaging Reporting and Data System (TI-RADS) grade on color Doppler ultrasound, enlarged lymph node present on imaging, and nodule diameter could affect lymph node metastasis in PTC. Stepwise multivariate regression analysis showed that sex, age, enlarged lymph node present on imaging, nodule diameter, and color Doppler TI-RADS grade were independent risk factors for lymph node metastasis in PTC. Combining these five independent risk factors, a nomogram prediction model was constructed. The area under the curve (AUC) of the nomogram in the training and validation cohorts was 0.742 and 0.765, respectively, with a well-fitted calibration curve. Our study showed that independent risk factors for lymph node metastasis in PTC were sex, age, enlarged lymph node present on imaging, nodule diameter, and color Doppler TI-RADS grade. The nomogram constructed based on these independent risk factors can better predict the risk of lymph node metastasis. [ABSTRACT FROM AUTHOR]

Objective: Taraxasterol (TS) is the main active compound of Taraxacum, which plays a significant role in the treatment of diabetes in many classic prescriptions. However, the mechanisms of TS in the treatment of diabetes remain unclear. This study aimed to investigate the underlying mechanism of TS in hepatic gluconeogenesis and glycogen synthesis in HepG2 cells with insulin resistance (IR). Methods: Molecular docking was conducted by using Discovery Studio (DS) to predict the target of TS in the treatment of diabetes. Then we treated HepG2 cells with glucosamine for 18 h. After the cells were treated with TS, the glucose consumption was examined. Oil red O staining was used to detect the lipid accumulation of HepG2 cells, and cellular glucose uptake levels were assessed using fluorescent 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino)-2-deoxy-D-glucose. The expression of the related proteins of the PI3K/Akt signaling pathway in the HepG2 cells was evaluated by western blot assay. Results: The molecular docking analysis revealed a good binding pose between the insulin receptor and TS. Furthermore, TS administration significantly enhanced glucose uptake and consumption, and reduced lipid accumulation in HepG2 cells with IR. The results of pharmacological mechanism study showed that TS up-regulated glycogenesis by PI3K/Akt/GSK3-motivated GS activation, and down-regulated gluconeogenesis by PI3K/Akt/FoxO1 expression of PEPCK and G6Pase in HepG2 cells with IR. Conclusions: Molecular docking and in vitro experimental results indicate that TS suppresses hepatic gluconeogenesis and augments glycogen synthesis by the PI3K/Akt signaling pathway, and it may have similar effects as insulin in regulating blood glucose. [ABSTRACT FROM AUTHOR]

Objectives: To explore the efficacy of induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT) in stage II nasopharyngeal carcinoma (NPC) treated with intensity‐modulated radiotherapy (IMRT). Methods: Totally, 450 eligible patients with staged II NPC on the basis of the 8th edition of the AJCC/UICC TNM staging system were eventually included from January 2010 to September 2020. The one‐to‐one propensity score‐matched (1:1 PSM) analysis was employed to balance variables. We conducted univariate and multivariate analysis of survival to identify prognostic factors and demonstrated the findings in the matching cohort. Results: In total, 141 pairs were selected by 1:1 PSM. IC + CCRT group in the matched data decreased 5‐year progression‐free survival (PFS, 75.5% vs. 88.0%, p = 0.032) and distant metastasis‐free survival (DMFS, 86.0% vs. 96.5%, p = 0.009). There was no significant difference in 5‐year overall survival (OS, 93.8% vs. 95.6%, p = 0.192) and locoregional relapse‐free survival (LRRFS, 87.1% vs. 94.3%, p = 0.169) compared with RT/CCRT. Multivariate analysis indicated that IC + CCRT was associated with significantly poor PFS (p = 0.024) and DMFS (p = 0.010). High neutrophil‐to‐lymphocyte ratio (>4.1) was negatively associated with OS (p = 0.034), PFS (p = 0.017) and DMFS (p = 0.001). Conclusion: Adding IC to CCRT or IMRT alone has decreased PFS and DMFS, therefore, IC should not be recommended in stage II NPC patients. No significant differences in OS and LRRFS were observed in stage II disease. [ABSTRACT FROM AUTHOR]