Targeting of the PD-1/PD-L1 immunologic checkpoint is believed to have provided a real breakthrough in the field of cancer therapy in recent years. Due to the intrinsic limitations of antibodies, the discovery of small-molecule inhibitors blocking PD-1/PD-L1 interaction has gradually opened valuable new avenues in the past decades. In an effort to discover new PD-L1 small molecular inhibitors, we carried out a structure-based virtual screening strategy to rapidly identify the candidate compounds. Ultimately, CBPA was identified as a PD-L1 inhibitor with a K_D value at the micromolar level. It exhibited effective PD-1/PD-L1 blocking activity and T-cell-reinvigoration potency in cell-based assays. CBPA could dose-dependently elevate secretion levels of IFN-γ and TNF-α in primary CD4⁺ T cells in vitro. Notably, CBPA exhibited significant in vivo antitumor efficacy in two different mouse tumor models (a MC38 colon adenocarcinoma model and a melanoma B16F10 tumor model) without the induction of observable liver or renal toxicity. Moreover, analyses of the CBPA-treated mice further showed remarkably increased levels of tumor-infiltrating CD4⁺ and CD8⁺ T cells and cytokine secretion in the tumor microenvironment. A molecular docking study suggested that CBPA embedded relatively well into the hydrophobic cleft formed by dimeric PD-L1, occluding the PD-1 interaction surface of PD-L1. This study suggests that CBPA could work as a hit compound for the further design of potent inhibitors targeting the PD-1/PD-L1 pathway in cancer immunotherapy.

Background: Uterine carcinosarcoma (UCS) is a type of rare and aggressive tumor. The standard treatment for UCS involves surgical treatment followed by radiochemotherapy. Clinical outcomes of UCS patients are poor due to high metastasis and relapse rate. Therefore, new targeted therapy strategies for UCS are needed. Because UCS is highly heterogenous, it is critical to identify and develop prognostic biomarkers to distinguish molecular subtypes of UCS for better treatment guidance. Methods: Using gene expression profiles and clinical follow-up data, we developed an online consensus survival analysis tool named OSucs. This web tool allows researchers to conveniently analyze the prognostic abilities of candidate genes in UCS. Results: To test the reliability of this server, we analyzed five previously reported prognostic biomarkers, all of which showed significant prognostic impacts. In addition, ETV4 (ETS variant transcription factor 4), ANGPTL4 (Angiopoietin-like protein 4), HIST1H1C (Histone cluster 1 H1 family member c) and CTSV (Cathepsin V) showed prognostic potential in a molecular subtype-specific manner. Conclusion: We built a platform for researchers to analyze if genes have prognostic potentials in UCS.

The Farnesoid X receptor (FXR) has recently been identified as being closely associated with the progression of primary hepatocellular carcinoma. Cancer stem cells (CSCs) play a crucial role in tumor initiation, progression, invasion, metastasis, recurrence, and drug resistance. The elucidation of the role and regulatory mechanism of FXR in CSCs is therefore deemed significant. Here, bioinformatics analysis has revealed a downregulation of FXR in hepatocellular carcinoma (HCC), which showed a negative correlation with HCC malignancy. This result was further confirmed through clinical sample analysis. Subsequently, CSCs were isolated from HCC cell lines and exhibited a significant decrease in the expression of FXR. The activation of FXR resulted in a remarkable inhibition of the proliferation, invasion, and tumorigenicity of CSCs. Furthermore, activated FXR prominently upregulated the expression of SOCS3 while suppressing STAT3 phosphorylation in CSCs. To further investigate this discovery, we established a DEN-induced HCC model in mice and observed that FXR-deficient mice exhibited heightened susceptibility to HCC. This was accompanied by decreased expression levels of SOCS3 and elevated expression and phosphorylation levels of STAT3, as well as significantly enhanced HCC CSCs markers and stemness-related genes expression in DEN-induced HCC tissues of FXR-deficient mice. Additionally, we also found a significant upregulation of CSCs markers and stemness-related genes within HCC clinical samples. Based on these findings, we postulated that targeted regulation of SOCS3 by FXR inhibits STAT3 phosphorylation, thereby exerting an inhibitory effect on CSCs.

At the beginning of the 2019 coronavirus disease (COVID-19) pandemic, airway allergic diseases such as asthma and allergic rhinitis (AR) were considered as risk factors for COVID-19, as they would aggravate symptoms. With further research, more and more literature has shown that airway allergic disease may not be a high-risk factor, but may be a protective factor for COVID-19 infection, which is closely related to its low-level expression of the ACE2 receptor and the complex cytokines network as underlying molecular regulatory mechanisms. In addition, steroid hormones and age factors could not be ignored. In this review, we have summarized some current evidence on the relationship between COVID-19 and allergic rhinitis to highlight the underlying mechanisms of COVID-19 infection and provide novel insights for its prevention and treatment. The key findings show that allergic rhinitis and its related molecular mechanisms may have a protective effect against COVID-19 infection.

BackgroundPTEN is a tumor suppressor gene, which is often inactivated through mutation and/or deletion in diverse human tumors. In the cytoplasm, PTEN negatively regulates the phosphatidylinositol 3′ kinase (PI3K) signaling pathway, while PTEN also shuttles to the nucleus, where PTEN stabilizes genome and/or participates in DNA repairment after damage. PTEN’s subcellular localization seems to be regulated by various factors. MethodsU87MG cells with expressing Wild-type-PTEN (WT-PTEN) and K13E-PTEN mutant were engineered respectively. The relationship between UV radiation and PTEN’s subcellular localization were elucidated using nuclear and cytosolic fractionation and fluorescence co-localization assay. Related signaling pathways were studied with western blot assays.ResultsHere, we demonstrated that UV irradiation could promote nuclear translocation of both WT-PTEN and K13E-PTEN mutant in a dose-dependent manner, but WT PTEN had a higher level of nuclear accumulation after inducing by UV-irradiation compared to K13E-PTEN. In contrast, the cytoplasmic-nuclear translocation of exogenous PTEN was critical to its tumor-suppressing functions that made U87MG cells more sensitive to the UV irradiation. ConclusionOur findings may have implications for further revealing the function of nuclear PTEN and provide insights for clinical treatment of PTEN-deficient tumors.

Mitochondria produce signals besides energy and metabolites that influence plant growth and fitness. However, how mitochondrial signals are relayed to other cellular compartments is largely unknown. By applying poly(A)-site RNA-sequencing (PAS-seq) to wildtype Arabidopsis seedlings and a mutant in the histone demethylase JMJ30 treated with the mitochondrial electron transfer chain inhibitor antimycin A (AA), we identified a previously undefined mitochondrion-to-nucleus communication pathway by which mitochondrial functional state regulates co-transcriptionally alternative polyadenylation (APA) of nuclear mRNA. We observed a global shortening of 3′ untranslated regions (UTRs) as a molecular signature of AA-activated mitochondrial retrograde response (MRR), which contributed in part to translational regulation of auxin response and cell wall biogenesis. JMJ30 regulated AA-induced 3′ UTR shortening, resulting in more transcripts with shortened 3′ UTRs upon AA treatment in a JMJ30 gain-of-function mutant and overexpression lines. We also report on the JMJ30-interacting protein CPSF30, a cleavage and polyadenylation specificity factor that recruits JMJ30 to modulate H3K27me3 status at its target loci. Our study illustrates how epigenetic modification and APA coordinate mitochondrion-to-nucleus communication to allow cells to rapidly respond to changes in mitochondrial functional state and shape plant growth and fitness. One-sentence summary Epigenetic modification and APA coordinate mitochondrion-to-nucleus communication to allow cells to rapidly respond to changes in mitochondrial functional state and shape plant growth and fitness.