Immunogenic Cell Death-Relevant Damage-Associated Molecular Patterns and Sensing Receptors in Triple-Negative Breast Cancer Molecular Subtypes and Implications for Immunotherapy.

Objectives: Triple-negative breast cancer (TNBC) is defined as a highly aggressive type of breast cancer which lacks specific biomarkers and drug targets. Damage-associated molecular pattern (DAMP)-induced immunogenic cell death (ICD) may influence the outcome of immunotherapy for TNBC patients. This study aims to develop a DAMPs gene signature to classify TNBC patients and to further predict their prognosis and immunotherapy outcome. Methods: We identified the DAMPs-associated subtypes of 330 TNBCs using K-means analysis. Differences in immune status, genomic alterations, and predicted immunotherapy outcome were compared among each subtype. Results: A total of 330 TNBCs were divided into three subtypes according to DAMPs gene expression: the nuclear DAMPs subtype, featuring the upregulation of nuclear DAMPs; the inflammatory DAMPs subtype, characterized by the gene set enrichment of the adaptive immune system and cytokine signaling in the immune system; and the DAMPs-suppressed subtype, having the lowest level of ICD-associated DAMPs. Among them, the inflammatory subtype patients had the most favorable survival, while the DAMPs-suppressed subtype was associated with the worst prognosis. The DAMPs subtyping system was successfully validated in the TCGA cohort. Furthermore, we systemically revealed the genomic alterations among the three DAMPs subtypes. The inflammatory DAMPs subtype was predicted to have the highest response rate to immunotherapy, suggesting that the constructed DAMPs clustering had potential for immunotherapy efficacy prediction. Conclusion: We established a novel ICD-associated DAMPs subtyping system in TNBC, and DAMPs expression might be a valuable biomarker for immunotherapy strategies. Our work could be helpful to the development of new immunomodulators and may contribute to the development of precision immunotherapy for TNBC.

Efficacy and safety of multi-kinase inhibitors in patients with radioiodine-refractory differentiated thyroid cancer: a systematic review and meta-analysis of clinical trials.

OBJECTIVES: Radioiodine-refractory differentiated thyroid cancer (RAI-rDTC) has frequently been associated with poor prognosis. We conducted a meta-analysis of published randomized controlled trials to evaluate multi-kinase inhibitors' efficacy and safety profile treatment. METHODS: A comprehensive search was conducted using PubMed, Embase, Cochrane, and Medline databases. The quality of literature and trial risk of bias was assessed using the Cochrane risk of bias tool, while the results of progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated using RevMan5.3 software. RESULTS: Treatment with MKIs significantly improved PFS and OS, but AEs were significantly higher than those in the control group (P < 0.01). The studies demonstrated the median PFS (HR 0.30, 95% CI: 0.18-0.50, P < 0.00001) and OS (HR 0.70, 95% CI: 0.57-0.88, P = 0.002) in RAI-rDTC patients treated with MKIs, and the median PFS of papillary thyroid carcinoma (HR0.28, 95% CI: 0.22-0.37, P < 0.00001) along with follicular thyroid carcinoma (HR0.14, 95%CI 0.09-0.24, P < 0.00001) were extended. CONCLUSION: MKIs significantly prolonged PFS and OS in patients with RAI-rDTC (P < 0.01). Our recommendation is to use MKIs carefully in patients after evaluating their health status to maximize treatment benefits and minimize adverse effects.

PPM1A as a key target of the application of Jiawei­Maxing­Shigan decoction for the attenuation of radiation­induced epithelial­mesenchymal transition in type II alveolar epithelial cells.

Radiation­induced lung tissue injury is an important reason for the limited application of radiotherapy on thoracic malignancies. Previously, we reported that administration of Jiawei­Maxing­Shigan decoction (JMSD) attenuated the radiation­induced epithelial­mesenchymal transition (EMT) in alveolar epithelial cells (AECs) via TGF­ß/Smad signaling. The present study aimed to examine the role of protein phosphatase Mg2+/Mn2+­dependent 1A (PPM1A) in the anti­EMT activity of JMSD on AECs. The components in the aqueous extract of JMSD were identified by high­performance liquid chromatography coupled with electrospray mass spectrometry. Primary rat type II AECs were treated with radiation (60Co γ­ray at 8 Gy) and JMSD­medicated serum. PPM1A was overexpressed and knocked down in the AECs via lentivirus transduction and the effects of JMSD administration on the key proteins related to TGF­ß1/Smad signaling were measured by western blotting. It was found that radiation decreased the PPM1A expression in the AECs and JMSD­medicated serum upregulated the PPM1A expressions in the radiation­induced AECs. PPM1A overexpression increased the E­cadherin level but decreased the phosphorylated (p­)Smad2/3, vimentin and α­smooth muscle actin (α­SMA) levels in the AECs. By contrast, the PPM1A knockdown decreased the E­cadherin level and increased the p­Smad2/3, vimentin and α­SMA levels in the AECs and these effects could be blocked by SB431542 (TGF­ß1/Smad signaling inhibitor). JMSD administration increased the E­cadherin level and decreased the p­Smad2/3, vimentin and α­SMA levels in the AECs; however, these effects could be blocked by siPPM1A­2. In conclusion, PPM1A is a key target of JMSD administration for the attenuation of the radiation­induced EMT in primary type II AECs via the TGF­ß1/Smad pathway.