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Although pyroptosis is critical for macrophages against pathogen infection, its role and mechanism in cancer cells remains unclear. PD-L1 has been detected in the nucleus, with unknown function. Here we show that PD-L1 switches TNFα-induced apoptosis to pyroptosis in cancer cells, resulting in tumour necrosis. Under hypoxia, p-Stat3 physically interacts with PD-L1 and facilitates its nuclear translocation, enhancing the transcription of the gasdermin C (GSDMC) gene. GSDMC is specifically cleaved by caspase-8 with TNFα treatment, generating a GSDMC N-terminal domain that forms pores on the cell membrane and induces pyroptosis. Nuclear PD-L1, caspase-8 and GSDMC are required for macrophage-derived TNFα-induced tumour necrosis in vivo. Moreover, high expression of GSDMC correlates with poor survival. Antibiotic chemotherapy drugs induce pyroptosis in breast cancer. These findings identify a non-immune checkpoint function of PD-L1 and provide an unexpected concept that GSDMC/caspase-8 mediates a non-canonical pyroptosis pathway in cancer cells, causing tumour necrosis.Hou et al. show that following hypoxia PD-L1 translocates into the nucleus to enhance transcription of GSDMC, which is then cleaved and activated by caspase-8 to cause pyroptosis in cancer cells.

Several poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are approved by FDA to treat cancer with BRCA mutations. BRCA mutations are considered to fuel a PARPi killing effect by inducing apoptosis. However, resistance to PARPi is frequently observed in the clinic due to an incomplete understanding on the molecular basis of PARPi function and a lack of good markers, beyond BRCA mutations, to predict response. Here, we show that gasdermin C (GSDMC) sensitized tumor cells to PARPi in vitro and in immunocompetent mice and caused durable tumor regression in an immune-dependent manner. A high expression level of GSDMC predicted better response to PARPi treatment in patients with triple-negative breast cancer (TNBC). PARPi treatment triggered GSDMC/caspase-8-mediated cancer cell pyroptosis (CCP) that enhanced PARPi killing of tumor cells. GSDMC-mediated CCP increased memory CD8+ T cell population in lymph node (LN), spleen, and tumor and, thus, promoted cytotoxic CD8+ T cell infiltration in the tumor microenvironment. T cell-derived granzyme B (GZMB) activated caspase-6, which subsequently cleaved GSDMC to induce pyroptosis. Interestingly, IFN-γ induced GSDMC expression, which, in turn, enhanced the cytotoxicity of PARPi and T cells. Importantly, GSDMC promoted tumor clearance independent of BRCA deficiency in multiple cancer types with PARPi treatment. This study identifies a general marker and target for PARPi therapy and offers insights into the mechanism of PARPi function.

Triple-negative breast cancer (TNBC), which lacks estrogen receptor α (ERα), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) expression, is closely related to basal-like breast cancer. Previously, we and others report that cyclin E/cyclin-dependent kinase 2 (CDK2) phosphorylates enhancer of zeste homolog 2 (EZH2) at T416 (pT416-EZH2). Here, we show that transgenic expression of phospho-mimicking EZH2 mutant EZH2 T416D in mammary glands leads to tumors with TNBC phenotype. Coexpression of EZH2 T416D in mammary epithelia of HER2/Neu transgenic mice reprograms HER2-driven luminal tumors into basal-like tumors. Pharmacological inhibition of CDK2 or EZH2 allows re-expression of ERα and converts TNBC to luminal ERα-positive, rendering TNBC cells targetable by tamoxifen. Furthermore, the combination of either CDK2 or EZH2 inhibitor with tamoxifen effectively suppresses tumor growth and markedly improves the survival of the mice bearing TNBC tumors, suggesting that the mechanism-based combination therapy may be an alternative approach to treat TNBC. EZH2 phosphorylation by CDK2 promotes progression of triple-negative breast cancer (TNBC). Here, the authors show that this signaling axis downregulates ERα, and thus combinatorial blockade of CDK2 and EZH2 sensitizes TNBC cells to tamoxifen.

Clopidol is one of the most widely used anti-coccidiosis drugs. Its residues in poultry products and the environment pose a serious threat to human health. In this work, microwave-assisted synthesis of magnetic ionic liquid/gold nanoparticles (MIL-Au NPs) as the SERS substrates were first designed for sensitive and reliable determination of clopidol residue in egg samples. The experiment shows that MIL(1-methyl-3-hexyl imidazole ferric tetrachloride ([C6mim]FeCl4)) and microwave play a key role in the dispersion and morphology of Au NPs. Under the optimal conditions, the as-prepared MIL-Au NPs were applied to the SERS detection of clopidol in methanol and egg solution and its detection limits can be as low as to 0.5 μg/kg (equal to 0.5 ppb) in both solutions. The standard curves with regression coefficients of 0.9298 and 0.93496 were constructed in the linear range of 100–1000 ppb and 0.5–50 ppb for clopidol in egg solutions. Moreover, satisfactory recoveries (97.5–103.2%) were obtained for egg samples. The developed SERS method provides a way for quantitation of clopidol and can be applied for the convenient, reliable, and highly sensitive detection of antibiotic residues in food and environment, which has great potential in food safety and biological monitoring.

Canonically PD-L1 functions as the inhibitory immune checkpoint on cell surface. Recent studies have observed PD-L1 expression in the nucleus of cancer cells. But the biological function of nuclear PD-L1 (nPD-L1) in tumor growth and antitumor immunity is unclear. Here we enforced nPD-L1 expression and established stable cells. nPD-L1 suppressed tumorigenesis and aggressiveness in vitro and in vivo. Compared with PD-L1 deletion, nPD-L1 expression repressed tumor growth and improved survival more markedly in immunocompetent mice. Phosphorylated AMPKα (p-AMPKα) facilitated nuclear PD-L1 compartmentalization and then cooperated with it to directly phosphorylate S146 of histone variant macroH2A1 (mH2A1) to epigenetically activate expression of genes of cellular senescence, JAK/STAT, and Hippo signaling pathways. Lipoic acid (LA) that induced nuclear PD-L1 translocation suppressed tumorigenesis and boosted antitumor immunity. Importantly, LA treatment synergized with PD-1 antibody and overcame immune checkpoint blockade (ICB) resistance, which likely resulted from nPD-L1-increased MHC-I expression and sensitivity of tumor cells to interferon-γ. These findings offer a conceptual advance for PD-L1 function and suggest LA as a promising therapeutic option for overcoming ICB resistance.

The Second Oil Production Plant of Xinjiang Oilfield produces a large amount of highly emulsified crude oil, which has a serious impact on the subsequent oil–water separation. At present, the concentration of demulsifier has increased to 2000 mg/L, but the demulsification effect is still poor. In this paper, the source and physical properties of highly emulsified crude oil are investigated firstly. The results show that highly emulsified crude oil is composed of three kinds of liquid: (1) conventional water flooding (WF); (2) chemical flooding (CF); (3) fracturing backflow fluid (FB). Among them, high zeta potential, low density difference, high viscosity, and small emulsion particles are responsible for the difficulty in the demulsification of the WF emulsion, while the high pH value is the reason why the CF emulsion is difficult to demulsify. Therefore, systematic experiments were implemented to investigate the optimal demulsification approach towards the three liquids above. As for the WF emulsion, it was necessary to raise the temperature to 70 °C and the concentration of the demulsifier to 200 mg/L. Moreover, it was only necessary to add 200 mg/L of demulsifier to break the CF emulsion after adjusting the pH value to 7, while no extra treatments were needed to break the FB emulsion. We hope this study can provide a new insight for the treatment of emulsions in the later stage of oilfield development.

Programmed death ligand 1 (PD-L1) has been recently shown to be a major obstacle to antiviral immunity by binding to its receptor programmed death 1 (PD-1) on specific IFN-γ producing T cells in chronic hepatitis B. Currently, IFN-α is widely used to treat hepatitis B virus (HBV) infection, but its antiviral effect vary greatly and the mechanism is not totally clear. We found that IFN-α/γ induced a marked increase of PD-L1 expression in hepatocytes. Signal and activators of transcription (Stat1) was then identified as a major transcription factor involved in IFN-α/γ-mediated PD-L1 elevation both in vitro and in mice. Blockage of the PD-L1/PD-1 interaction by a specific mAb greatly enhanced HBV-specific T cell activity by the gp96 adjuvanted therapeutic vaccine, and promoted HBV clearance in HBV transgenic mice. Our results demonstrate the IFN-α/γ-Stat1-PD-L1 axis plays an important role in mediating T cell hyporesponsiveness and inactivating liver-infiltrating T cells in the hepatic microenvironment. These data raise further potential interest in enhancing the anti-HBV efficacy of IFN-α and therapeutic vaccines.

Laser-induced graphene (LIG) has been widely used in flexible sensors due to its excellent mechanical properties and high conductivity. In this paper, a flexible pressure sensor prepared by bionic micro/nanostructure design and LIG mass fraction regulation is reported. First, prepared LIG and conductive carbon paste (CCP) solutions were mixed to obtain a conductive polymer. After the taro leaf structure was etched on the surface of the aluminum alloy plate by Nd:YAG laser processing, the conductive polymer was evenly coated on the template. Pressure sensors were packaged with a stencil transfer printing combined with an Ecoflex flexible substrate. Finally, the effects of different laser flux and the proportion of LIG in the composite on the sensitivity of the sensor are discussed. The results show that when the laser flux is 71.66 J·cm−2 and the mass fraction of LIG is 5%, the sensor has the best response characteristics, with a response time and a recovery time of 86 ms and 101 ms, respectively, with a sensitivity of 1.2 kPa−1 over a pressure range of 0–6 kPa, and stability of 650 cycle tests. The LIG/CCP sensor with a bionic structure demonstrates its potential in wearable devices.

The air-suction precision seed-metering device is prone to the instability of the seed adsorption state, which arises from blockage of the suction hole and leads to uneven seeding. This paper analyzed and determined key structural parameters of the seed-metering plate, then established an adsorption mechanics model of the seed during the migration process and designed the key structure of the air-suction seed-metering device with the aim of improving the uniformity of high-speed direct seeding of vegetables. Furthermore, we used the DEM-CFD coupling method to analyze the influence of the law of seeds on the change of the flow field with different hole types. Results showed that the turbulent kinetic energy (202.65 m2∙s−2) and the coupling force to the seeds (0.029 N) of the B-type hole are the largest, which is the best fluid domain structure for the suction hole of the seed-metering plate. Moreover, we used Adams to analyze the meshing process between the knock-out wheel and the seed-metering plate, affirming the rationality of the knock-out wheel design. Finally, in order to improve the working efficiency of the seed-metering device, we performed one-factor and response surface experiments of seeding performance using the air-suction seed-metering device designed with the optimized structure as the experimental object. Analysis of the influence of weights across each factor on the experimental performance evaluation indicators revealed an optimal combination of seeding performance parameters in the air-suction seed-metering device, namely a seed-throwing angle of 13°, a working speed of 14.5 km/h, and negative pressure of 3.1 kPa. Results from verification experiments revealed the corresponding experimental indicators, namely qualified, multiple, and missing indexes of 95.9, 1.2%, and 2.9%, respectively.