Metformin alleviates benzo[a]pyrene-induced alveolar injury by inhibiting necroptosis and protecting AT2 cells.

Exposure to benzo[a]pyrene (B[a]P) has been linked to lung injury and carcinogenesis. Airway epithelial cells express the B[a]P receptor AHR, so B[a]P is considered to mainly target airway epithelial cells, whereas its potential impact on alveolar cells remains inadequately explored. Metformin, a first-line drug for diabetes, has been shown to exert anti-inflammatory and tissue repair-promoting effects under various injurious conditions. Here, we explored the effect of chronic B[a]P exposure on alveolar cells and the impact of metformin on B[a]P-induced lung injury by examining the various parameters including lung histopathology, inflammation, fibrosis, and related signal pathway activation. MLKL knockout (Mlkl-/-) and AT2-lineage tracing mice (SftpcCre-ERT2;LSL-tdTomatoflox+/-) were used to delineate the role of necroptosis in B[a]P-induced alveolar epithelial injury and repair. Mice receiving weekly administration of B[a]P for 6 weeks developed a significant alveolar damaging phenotype associated with pulmonary inflammation, fibrosis, and activation of the necroptotic cell death pathway. These effects were significantly relieved in MLKL null mice. Furthermore, metformin treatment, which were found to promote AMPK phosphorylation and inhibit RIPK3, as well as MLKL phosphorylation, also significantly alleviated B[a]P-induced necroptosis and lung injury phenotype. However, the protective efficacy of metformin was rendered much less effective in Mlkl null mice or by blocking the necroptotic pathway with RIPK3 inhibitor. Our findings unravel a potential protective efficacy of metformin in mitigating the detrimental effects of B[a]P exposure on lung health by inhibiting necroptosis and protecting AT2 cells.

A ribosomal gene panel predicting a novel synthetic lethality in non-BRCAness tumors.

Poly (ADP-ribose) polymerase (PARP) inhibitors are one of the most exciting classes of targeted therapy agents for cancers with homologous recombination (HR) deficiency. However, many patients without apparent HR defects also respond well to PARP inhibitors/cisplatin. The biomarker responsible for this mechanism remains unclear. Here, we identified a set of ribosomal genes that predict response to PARP inhibitors/cisplatin in HR-proficient patients. PARP inhibitor/cisplatin selectively eliminates cells with high expression of the eight genes in the identified panel via DNA damage (ATM) signaling-induced pro-apoptotic ribosomal stress, which along with ATM signaling-induced pro-survival HR repair constitutes a new model to balance the cell fate in response to DNA damage. Therefore, the combined examination of the gene panel along with HR status would allow for more precise predictions of clinical response to PARP inhibitor/cisplatin. The gene panel as an independent biomarker was validated by multiple published clinical datasets, as well as by an ovarian cancer organoids library we established. More importantly, its predictive value was further verified in a cohort of PARP inhibitor-treated ovarian cancer patients with both RNA-seq and WGS data. Furthermore, we identified several marketed drugs capable of upregulating the expression of the genes in the panel without causing HR deficiency in PARP inhibitor/cisplatin-resistant cell lines. These drugs enhance PARP inhibitor/cisplatin sensitivity in both intrinsically resistant organoids and cell lines with acquired resistance. Together, our study identifies a marker gene panel for HR-proficient patients and reveals a broader application of PARP inhibitor/cisplatin in cancer therapy.

Construction and validation of a novel aging-related gene signature and prognostic nomogram for predicting the overall survival in ovarian cancer.

BACKGROUND: Ovarian cancer (OC) is the most lethal gynecological malignancy. The objective of this study was to establish and validate an individual aging-related gene signature and a clinical nomogram that can powerfully predict independently the overall survival rate of patients with ovarian cancer. METHODS: Data on transcriptomic profile and relevant clinical information were retrieved from The Cancer Genome Atlas (TCGA) database as a training group, and the same data from three public Gene Expression Omnibus (GEO) databases as validation groups. Univariate Cox regression analysis, lasso regression analysis, and multiple multivariate Cox analysis were analyzed sequentially to select the genes to be included in the aging-associated signature. A risk scoring model was established and verified, the predictive value of the model was evaluated, and a clinical nomogram was established. RESULTS: We found eight genes that were most relevant to prognosis and constructed an eight-mRNA signature. Based on the model, each OC patient's risk score was able to be calculated and patients were split into groups of low and high risks with a distinct outcome. Survival analysis confirmed that the outcome of patients in the high-risk group was dramatically shorter than that of those in the low-risk group, and the eight-mRNA signature can be considered as a powerful and independent predictor that could predict the outcome of OC patient. Additionally, the risk score and age can be used to construct a clinical nomogram as a simpler tool for predicting prognosis. We also explored the association between the risk score and immunity and drug sensitivity. CONCLUSION: This study suggested that the aging-related gene signature could be used as an intervention point and latent prognostic predictor in OC, which may provide new perceptions for postoperative treatment strategies.

Development of an Interferon Gamma Response-Related Signature for Prediction of Survival in Clear Cell Renal Cell Carcinoma.

BACKGROUND: Interferon plays a crucial role in the pathogenesis and progression of tumors. Clear cell renal cell carcinoma (ccRCC) represents a prevalent malignant urinary system tumor. An effective predictive model is required to evaluate the prognosis of patients to optimize treatment. MATERIALS AND METHODS: RNA-sequencing data and clinicopathological data from TCGA were involved in this retrospective study. The IFN-γ response genes with significantly different gene expression were screened out. Univariate Cox regression, LASSO regression and multivariate Cox regression were used to establish a new prognostic scoring model for the training group. Survival curves and ROC curves were drawn, and nomogram was constructed. At the same time, we conducted subgroup analysis and experimental verification using our own samples. Finally, we evaluated the relatedness between the prognostic signature and immune infiltration landscapes. In addition, the sensitivity of different risk groups to six drugs and immune checkpoint inhibitors was calculated. RESULTS: The IFN-γ response-related signature included 7 genes: C1S, IFI44, ST3GAL5, NUP93, TDRD7, DDX60, and ST8SIA4. The survival curves of the training and testing groups showed the model's effectiveness (P = 4.372e-11 and P = 1.08e-08, respectively), the ROC curves showed that the signature was stable, and subgroup analyses showed the wide applicability of the model (P<0.001). Multivariate Cox regression analysis showed that the risk model was an independent prognostic factor of ccRCC. A high-risk score may represent an immunosuppressive microenvironment, while the high-risk group exhibited poor sensitivity to drugs. CONCLUSION: Our findings strongly indicate that the IFN-γ response-related signature can be used as an effective prognostic indicator of ccRCC.

Anti-tumour effect of in situ vaccines combined with VEGFR inhibitors in the treatment of metastatic cervical cancer.

Cervical cancer is the fourth most common malignant tumor in the world, for advanced cervical cancer, more than 30% of patients continue to have tumor and relapse or metastasis after the traditional treatment (concurrent chemoradiotherapy), and the response rate of immune checkpoint inhibitor (PD-1) is less 15%, so additional approaches are required. In situ vaccine is a very promising immunotherapy strategy. In the preclinical study, the combination of CPG and anti-Ox40 antibody can completely resolve injection site tumours and distant tumours and leads to the recovery of most mice with lymphoma. However, our early exploration process found that the effect of CpG + OX40 in the treatment of advanced cervical cancer is not ideal. Hence, we explored the anti-tumor effect of CpG + OX40 combined with anti-angiogenic therapy for the first time. The results showed that the combination significantly inhibited the proliferation of primary and secondary tumor volume and prolonged the survival time of mice, compared with the control group, CD3+, CD4 + and CD8 + T cells in the combined group showed an increasing trend. In addition, in terms of metabolism, the anti-vascular effect of anlotinib can significantly reduce the blood supply and metabolic level of tumor, the expression of Ki67 and CD31 in the control group was significantly higher than that in each administration group. In conclusion, our preclinical research results showed that the combination of in situ vaccine and anti-angiogenic therapy has a good anti-tumor effect, and may potentially offer an effective treatment option for patients with advanced cervical cancer.