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Whether tobacco carcinogens enable exposed cells immune escape resulting in carcinogenesis, and why patients who smoke respond better to immunotherapies than non-smokers, remains poorly understood. Here we report that cigarette smoke and the carcinogen benzo(a)pyrene (BaP) induce PD-L1 expression on lung epithelial cells in vitro and in vivo, which is mediated by aryl hydrocarbon receptor (AhR). Anti-PD-L1 antibody or deficiency in AhR significantly suppresses BaP-induced lung cancer. In 37 patients treated with anti-PD-1 antibody pembrolizumab, 13/16 (81.3%) patients who achieve partial response or stable disease express high levels of AhR, whereas 12/16 (75%) patients with progression disease exhibit low levels of AhR in tumor tissues. AhR inhibitors exert significant antitumor activity and synergize with anti-PD-L1 antibody in lung cancer mouse models. These results demonstrate that tobacco smoke enables lung epithelial cells to escape from adaptive immunity to promote tumorigenesis, and AhR predicts the response to immunotherapy and represents an attractive therapeutic target. Lung cancer patients who smoke show a better response to immunotherapy than non-smokers. Here, the authors show that tobacco smoke induces PD-L1 expression on lung epithelial cells via AhR that is associated with benefits of PD-1 inhibitor in patients, shedding new lights on lung carcinogenesis and immunotherapy.

for a deeper understanding of the deformation failure behavior of jointed rock, numerical compression simulations are carried out on a rock specimen containing non-persistent joints under confining pressure with the bonded-particle model. The microscopic parameters which can reflect the macroscopic mechanical properties and failure behavior of artificial jointed specimens are firstly calibrated. Then, the influence of joint inclination and confining pressure on stress — strain curves, crack patterns, and contact force distributions of jointed rock are investigated. The simulation results show that both the compressive strength and elastic modulus of the specimens increase with increasing confining pressure, and these two mechanical parameters decrease first and then increase with the increase of joints inclination. The sensitivity of strength and elastic modulus to confining pressure is not the same in different joints inclinations, which has the least impact on specimens with α =90°. Under low confining pressure, the failure modes are controlled by the joint inclination. As the confining pressure increased, the initiation and propagation of tensile crack are gradually inhibited, and the failure mode is transferred from tensile failure to shear-compression failure. Finally, the reinforcement effect of prestressed bolt support on engineering fractured rock mass is discussed.

Circulating adiponectin (APN) levels decrease with age and obesity. On the other hand, a reduction in APN levels is associated with neurodegeneration and neuroinflammation. We previously showed that aged adiponectin knockout (APN−/−) mice developed Alzheimer’s like pathologies, cerebral insulin resistance, and cognitive impairments. More recently, we also demonstrated that APN deficiency increased Aβ-induced microglia activation and neuroinflammatory responses in 5xFAD mice. There is compelling evidence that deregulated insulin activities or cerebral insulin resistance contributes to neuroinflammation and Alzheimer’s disease (AD) pathogenesis. Here, we demonstrated that APN levels were reduced in the brain of AD patients and 5xFAD mice. We crossbred 5xFAD mice with APN−/− mice to generate APN-deficient 5xFAD (5xFAD;APN−/−). APN deficiency in 5xFAD mice accelerated amyloid loading, increased cerebral amyloid angiopathy, and reduced insulin-signaling activities. Pharmacokinetics study demonstrated adipoRon (APN receptor agonist) was a blood–brain barrier penetrant. AdipoRon improved neuronal insulin-signaling activities and insulin sensitivity in vitro and in vivo. Chronic adipoRon treatment improved spatial memory functions and significantly rescued neuronal and synaptic loss in 5xFAD and 5xFAD;APN−/− mice. AdipoRon lowered plaque and Aβ levels in AD mice. AdipoRon also exerted anti-inflammatory effects by reducing microglial and astrocytes activation as well as suppressing cerebral cytokines levels. The microglial phagocytic activity toward Aβ was restored after adipoRon treatment. Our results indicated that adipoRon exerts multiple beneficial effects providing important therapeutic implications. We propose chronic adipoRon administration as a potential treatment for AD.

Spermidine has therapeutic effects in many diseases including as heart diastolic function, myopathic defects and neurodegenerative disorders via autophagy activation. Autophagy has been found to mitigate cell apoptosis in intervertebral disc degeneration (IDD). Accordingly, we theorize that spermidine may have beneficial effects on IDD via autophagy stimulation. In this study, spermidine's effect on IDD was evaluated in tert‐butyl hydroperoxide (TBHP)‐treated nucleus pulposus cells of SD rats in vitro as well as in a puncture‐induced rat IDD model. We found that autophagy was actuated by spermidine in nucleus pulposus cells. In addition, spermidine treatment weakened the apoptotic effects of TBHP in nucleus pulposus cells. Spermidine increased the expression of anabolic proteins including Collagen‐II and aggrecan and decreased the expression of catabolic proteins including MMP13 and Adamts‐5. Additionally, autophagy blockade using 3‐MA reversed the beneficial impact of spermidine against nucleus pulposus cell apoptosis. Autophagy was thus important for spermidine's therapeutic effect on IDD. Spermidine‐treated rats had an accentuated T2‐weighted signal and a diminished histological degenerative grade than vehicle‐treated rats, showing that spermidine inhibited intervertebral disc degeneration in vivo. Thus, spermidine protects nucleus pulposus cells against apoptosis through autophagy activation and improves disc, which may be beneficial for the treatment of IDD.

Ultrasound probe calibration is crucial for precise spatial mapping in ultrasound-guided surgical navigation and free-hand 3D ultrasound imaging as it establishes the rigid-body transformation between the ultrasound image plane and an external tracking sensor. However, the existing methods often rely on manual feature point selection and exhibit limited robustness to outliers, resulting in reduced accuracy, reproducibility, and efficiency. To address these limitations, we propose a fully automated calibration framework that leverages the geometric priors of an N-wire phantom to achieve reliable recognition. The method incorporates a robust feature point extraction algorithm and integrates a hybrid outlier rejection strategy based on the Random Sample Consensus (RANSAC) algorithm. The experimental evaluations demonstrate sub-millimeter accuracy (<0.6 mm) across varying imaging depths, with the calibration process completed in under two minutes and exhibiting high repeatability. These results suggest that the proposed framework provides a robust, accurate, and time-efficient solution for ultrasound probe calibration, with strong potential for clinical integration.

Red wine consists of a large amount of compounds such as resveratrol, which exhibits chemopreventive and therapeutic effects against several types of cancers by targeting cancer driver molecules. In this study, we tested the anti‐lung cancer activity of 11 red wine components and reported that a natural polyphenol compound ellagic acid (EA) inhibited lung cancer cell proliferation at an efficacy approximately equal to that of resveratrol. EA markedly increased the expression of the autophagosomal marker LC3‐II as well as inactivation of the mechanistic target of rapamycin signalling pathway. EA elevated autophagy‐associated cell death by down‐regulating the expression of cancerous inhibitor of protein phosphatase 2A (CIP2A), and CIP2A overexpression attenuated EA‐induced autophagy of lung cancer cells. Treating tumour‐bearing mice with EA resulted in significant inhibition of tumour growth with suppression of CIP2A levels and increased autophagy. In addition, EA potentiated the inhibitory effects of the natural compound celastrol on lung cancer cells in vitro and in vivo by enhancing autophagy and down‐regulating CIP2A. These findings indicate that EA may be a promising chemotherapeutic agent for lung cancer, and that the combination of EA and celastrol may have applicability for the treatment of this disease.

Hypertrophic scars (HTS) and keloids are challenging problems. Their pathogenesis results from an overproduction of fibroblasts and excessive deposition of collagen. Studies suggest a possible anti-scarring effect of basic fibroblast growth factor (bFGF) during wound healing, but the precise mechanisms of bFGF are still unclear. In view of this, we investigated the therapeutic effects of bFGF on HTS animal model as well as human scar fibroblasts (HSF) model. We show that bFGF promoted wound healing and reduced the area of flattened non-pathological scars in rat skin wounds and HTS in the rabbit ear. We provide evidence of a new therapeutic strategy: bFGF administration for the treatment of HTS. The scar elevation index (SEI) and epidermal thickness index (ETI) was also significantly reduced. Histological reveal that bFGF exhibited significant amelioration of the collagen tissue. bFGF regulated extracellular matrix (ECM) synthesis and degradation via interference in the collagen distribution, the α-smooth muscle actin (α-SMA) and transforming growth factor-1 (TGF-β1) expression. In addition, bFGF reduced scarring and promoted wound healing by inhibiting TGFβ1/SMAD-dependent pathway. The levels of fibronectin (FN), tissue inhibitor of metalloproteinase-1 (TIMP-1) collagen I, and collagen III were evidently decreased, and matrix metalloproteinase-1 (MMP-1) and apoptosis cells were markedly increased. These results suggest that bFGF possesses favorable therapeutic effects on hypertrophic scars in vitro and in vivo, which may be an effective cure for human hypertrophic scars.

Background Obesity may impact surgical outcomes of gastrectomy. Whether visceral fat area (VFA) is a better obesity parameter than body mass index (BMI) is still controversial. The aim of this study is to compare the accuracy and effectiveness of VFA and BMI in predicting the short-term surgical outcomes of gastrectomy. Methods Patients who were diagnosed with gastric cancer were measured for BMI and VFA preoperatively and then divided into a VFA-H (VFA-high) group and VFA-L (VFA-low) group, at the cutoff point of 100 cm 2 , and a BMI-H (BMI-high) group and BMI-L (BMI-low) group, at the cutoff point of 25 kg/m 2 . The short-term surgical outcomes were compared between the different groups. Results In total, 276 patients were enrolled in this study; 55 (19.9%) patients were classified into the BMI-H group, and 122 (44.2%) patients were classified into the VFA-H group. There was a significant correlation between BMI and VFA ( r  = 0.652, p  < 0.001). Compared with the VFA-L group, the VFA-H group had a higher incidence of postoperative complications (31.1% vs. 13.0%; p  < 0.001), longer operation duration (270.0 (235.0–305.0) vs. 255.0 (223.8–295.0), p  = 0.046), and more blood loss (100.0 (100.0–150.0) vs. 80.0 (80.0–100.0), p  < 0.001), while the BMI-H group had more blood loss than the BMI-L group (100.0 (100.0–120.0) vs. 100.0(80.0–100.0), p  = 0.006). Logistic regression showed that VFA was an independent risk factor for postoperative complications (odds ratio 2.813, 95% CI 1.523–5.194; p  = 0.001). Conclusion For gastric cancer patients, VFA is superior to BMI in accurately and effectively illuminating the impact of obesity on short-term surgical outcomes. Trial Registration Clinicaltrials.gov : NCT02800005.

A sound understanding of the influence of cyclic loading on mechanical properties of rock is of great importance for the management and optimization of engineering rock mass structures such as nuclear waste repositories and geothermal resources. In the present manuscript, we first performed a series of conventional uniaxial compressive tests and fatigue failure tests (i.e. cyclic loading tests) on sandstone samples from Sichuan Province, China. The experimental results show that the fatigue failure of sandstone is achieved once the cumulative axial deformation under cyclic loading reaches the axial strain that corresponds to the post-peak phase of the stress–strain curve from a conventional uniaxial test. Based on our laboratory data, and considering that the fatigue process is characterized by local material degradation as well as irreversible deformation that accumulates during each loading cycle, we propose here a two-dimensional meso-scale elasto-plastic damage model to simulate the fatigue behavior of rock during cyclic loading. We then performed a suite of numerical simulations using this model to better understand the fatigue process in sandstone. The results of our numerical modeling show that the ratios of maximum stress and stress amplitude to the uniaxial compressive strength are the most important factors affecting the fatigue life of sandstone. A larger maximum stress and/or stress amplitude results in a shorter fatigue life for the numerical sandstone specimen. However, we find no significant correlation between sample homogeneity and fatigue life. Importantly, our modeled results show that specimen failure occurs once the cumulative axial deformation under cyclic loading reaches the axial strain that corresponds to the post-peak phase of the stress–strain curve from a conventional uniaxial test simulation, in accordance with our laboratory testing. Therefore, the model presented herein provides a new platform to investigate the fatigue failure of rocks.

Autophagy and apoptosis are two key cell fate determination pathways, which play vital roles in the interaction between viruses and host cells. Previous research had confirmed that one strain of fish rhabdoviruses, Siniperca chuatsi rhabdovirus (SCRV), could induce apoptosis and autophagy after infection. In the current study, we continued to analyze the interaction of autophagy and apoptosis in SCRV-infected EPC cell lines after treatment with different autophagy or apoptosis inhibitors. We found that SCRV infection could activate the mitochondrial apoptotic pathway by the detection of the activities of the caspase-3 and caspase-9 and by flow cytometry analysis in JC-1-stained cells, respectively. Furthermore, no significant autophagy-related factors were disturbed in SCRV-infected cell after apoptosis inhibitor Z-VAD-FMK treatment, while autophagy inducer rapamycin could obviously delay the occurrence of CPE and cell death. Meanwhile, rapamycin was able to reduce the proportion of apoptotic cells. Besides that, rapamycin could disturb the expression of p62 and LC3B-II, and the transcription level of SCRV nucleoprotein mRNA. The progeny virus titers did not show a big difference between the rapamycin treatment or without it. Collectively, our data preliminarily confirmed that SCRV-activated autophagy could delay apoptosis in EPC cells and may not affect virus production. Further study may need to focus on the crosstalk regulation and its roles on the SCRV infection.