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Cancer immunotherapy involves blocking the interactions between the PD-1/PD-L1 immune checkpoints with antibodies. This has shown unprecedented positive outcomes in clinics. Particularly, the PD-L1 antibody therapy has shown the efficiency in blocking membrane PD-L1 and efficacy in treating some advanced carcinoma. However, this therapy has limited effects on many solid tumors, suspecting to be relevant to PD-L1 located in other cellular compartments, where they play additional roles and are associated with poor prognosis. In this review, we highlight the advances of 3 current strategies on PD-1/PD-L1 based immunotherapy, summarize cellular distribution of PD-L1, and review the versatile functions of intracellular PD-L1. The intracellular distribution and function of PD-L1 may indicate why not all antibody blockade is able to fully stop PD-L1 biological functions and effectively inhibit tumor growth. In this regard, gene silencing may have advantages over antibody blockade on suppression of PD-L1 sources and functions. Apart from cancer cells, PD-L1 silencing on host immune cells such as APC and DC can also enhance T cell immunity, leading to tumor clearance. Moreover, the molecular regulation of PD-L1 expression in cells is being elucidated, which helps identify potential therapeutic molecules to target PD-L1 production and improve clinical outcomes. Based on our understandings of PD-L1 distribution, regulation, and function, we prospect that the more effective PD-L1-based cancer immunotherapy will be combination therapies.

Bolted connections have been widely applied in engineering structures, loosening will happen when bolted connections are subjected to continuous cyclic load, and a significant rotation between the nut and the bolt can be observed. Combining deep learning with machine vision, a bolt loosening detection method based on the fifth version of You Only Look Once (YOLOv5) is proposed, and the rotation of the nut is identified to detect the bolt loosening. Two different circular markers are added to the bolt and the nut separately, and then YOLOv5 is used to identify the circular markers, and the rotation angle of the nut against the bolt is calculated according to the center coordinate of each predicted box. A bolted connection structure is adopted to illustrate the effectiveness of the method. First, 200 images containing bolts and circular markers are collected to make the dataset, which is divided into a training set, verification set and test set. Second, YOLOv5 is used to train the model; the precision rate and recall rate are respectively 99.8% and 100%. Finally, the robustness of the proposed method in different shooting environments is verified by changing the shooting distance, shooting angle and light condition. When using this method to detect the bolt loosening angle, the minimum identifiable angle is 1°, and the maximum detection error is 5.91% when the camera is tilted 45°. The experimental results show that the proposed method can detect the loosening angle of the bolted connection with high accuracy; especially, the tiny angle of bolt loosening can be identified. Even under some difficult shooting conditions, the method still works. The early stage of bolt loosening can be detected by measuring the rotation angle of the nut against the bolt.

ObjectivesNight-shift work exposure is proposed to link to a wide range of health issues, especially cancer incidence, cancer-specific death, and all-cause death. However, the epidemiological associations among night-shift work exposure, breast cancer, breast cancer-specific death, and all-cause mortality remain inconclusive.MethodsWe performed an updated systematic review and meta-analysis to confirm potential associations among night-shift work exposure, breast cancer, and all-cause mortality.ResultsA total of 31 prospective cohort studies, involving 9.3 million participants, 31,244 incident breast cancer cases, 12,728 cancer-related deaths, 7882 cardiovascular deaths, and 30,807 all-cause mortalities were included. Overall, the summary RR of incident breast cancer in females for an increase of night-shift work was 1.029 (95% CI 1.003–1.055). Compared with standard day workers, night-shift workers had a statistically significantly increased RR (1.086, 95% CI 1.032–1.142) for breast cancer incidence in the subgroup of > 10 years exposure. Furthermore, a positive association was revealed in subgroup studies of rotating night-shift work (RR = 1.053, 95% CI 1.018–1.090). A significant increased risk of cardiovascular mortality was demonstrated in the night-shift work group (RR = 1.031; 95% CI 1.006–1.057).ConclusionOur systematic review and meta-analysis provided convincing evidence supporting positive associations among night-shift work exposure, breast cancer incidence, and cardiovascular mortality. Taken together, night-shift work exposure significantly increased the risk of breast cancer morbidity by 2.9% for total, 8.6% for the subgroup of more than 10 years night-shift work, and 5.3% for rotating night-shift work. In addition, night-shift work increased the risk of cardiovascular mortality by 3.1%.

Objective: This study evaluated the effects of glutamic acid (Glu) and glutamine (Gln) on the intestinal development of layer chicks with lipopolysaccharide (LPS)-induced damage.Methods: A total of 240 healthy 0-d-old Hy-Line Brown chicks were randomly assigned to 4 treatments, each with 6 replicates. At 8 and 11 d of age, all birds (except for the control group) received two administrations of LPS. The LPS-challenged birds were divided into three dietary treatment groups: a basal diet (without additives), a 0.05% Glu-supplemented diet, and a 0.20% Gln-supplemented diet.Results: The LPS challenge induced intestinal injury and suppressed intestinal development in layer chicks, as evidenced by reduced growth performance, poor intestinal parameters, and morphology (p<0.05). Compared to the LPS group, dietary supplementation with 0.05% Glu and 0.20% Gln enhanced average daily gain (ADG), average daily feed intake, body weight (BW), and intestinal development parameters (including length, weight, villus height, and villus height/crypt depth) of duodenum, jejunum and ileum (p<0.05). These results could be attributed to upregulated mRNA expression levels of Mucin-2, Ecadherin, Dclk-1, Vil-1, Lysozyme, ChgA, Lgr-5, Bmi-1, ATP5F1AZ, and β-catenin (p<0.05). Furthermore, dietary supplementation with 0.20% Gln outperformed 0.05% Glu in enhancing BW, ADG, and ileum parameters (weight, length, epithelial cell count, and energy metabolism) (p<0.05). Additionally, intestinal organoids supplemented with 10 μM Gln had higher mean area, E-cadherin gene expression, and ATP content compared with those treated with 5 μM Glu in vitro (p<0.05).Conclusion: Dietary supplementation with 0.05% Glu and 0.20% Gln could improve growth performance, intestinal development, and repair intestinal damage in layer chicks through enhanced epithelial proliferation and differentiation. Moreover, 0.20% Gln performed better than 0.05% Glu, which may be attributed to superior energy metabolism.

Bladder cancer (BC) is the most common urologic malignancy, facing enormous diagnostic challenges. Urinary extracellular vesicles (EVs) are promising source for developing diagnostic markers for bladder cancer because of the direct contact between urine and bladder. This study pioneers urinary EV N-glycomics for bladder cancer diagnosis. We have generated a comprehensive N-glycome landscape of urinary EVs through high-throughput N-glycome analysis, identifying a total of 252 N-glycans from 333 individuals. In bladder cancer patients, urinary EVs exhibit decreased fucosylation and increased sialylation level. An Eight N-glycan diagnostic model demonstrates strong performance in both validation cohorts, achieving ROC AUC values of 0.88 and 0.86, respectively. Furthermore, this model successfully differentiates both non-muscle invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) from healthy individuals, underscoring the model’s superiority. Moreover, urinary EVs N-glycoproteomic analysis reveals that the glycoproteins carrying cancer-associated N-glycan signatures are closely associated with immune activities. The N-glycome comparative analysis of EVs and their source cells indicate that the glycosylation profiles of EVs do not completely match the glycosylation backgrounds of their source cells. In summary, our study establishes urinary EV N-glycomics as a non-invasive BC screening tool and provide a framework for EV glycan biomarker discovery across cancers. Bladder cancer diagnosis lacks non-invasive biomarkers. Here, the authors discover urinary extracellular vesicle (EV) glycan signatures that distinguish bladder cancer patients from healthy controls, paving the way for EV-based liquid biopsy.

The manifestation of acute kidney injury (AKI) is associated with poor patient outcomes, with treatment options limited to hydration or renal replacement therapies. The onset of AKI is often associated with a surfeit of reactive oxygen species. Here, it is shown that selenium‐doped carbon quantum dots (SeCQDs) have broad‐spectrum antioxidant properties and prominent renal accumulation in both healthy and AKI mice. Due to these properties, SeCQDs treat or prevent two clinically relevant cases of AKI induced in murine models by either rhabdomyolysis or cisplatin using only 1 or 50 µg per mouse, respectively. The attenuation of AKI in both models is confirmed by blood serum measurements, kidney tissue staining, and relevant biomarkers. The therapeutic efficacy of SeCQDs exceeds amifostine, a drug approved by the Food and Drug Administration that also acts by scavenging free radicals. The findings indicate that SeCQDs show great potential as a treatment option for AKI and possibly other ROS‐related diseases. The specific renal accumulation and excellent antioxidant properties of SeCQDs allows prevention and treatment of acute kidney injury.

Aim. Atherosclerosis is the major cause of acute coronary syndrome (ACS) which is a significant contributor to both morbidity and mortality in the world. The microbiome-derived metabolite trimethylamine-N-oxide (TMAO) has aroused great interest and controversy as a risk factor of atherosclerosis. Therefore, in this study, we aimed at investigating whether plasma TMAO can be a risk factor of atherosclerosis in coronary artery of patients with ACS and how this relates to lipids and proinflammatory cytokines in plasma. Methods. We enrolled consecutive patients with ACS who underwent percutaneous coronary intervention (PCI). Gensini scoring was used to evaluate angiographic atherosclerosis in the coronary artery of the patients. 13 patients were divided into low (Gensini score<25), 33 into intermediate (Gensini score 25-50), and 81 into severe atherosclerosis (Gensini score ≥50). Plasma TMAO, vasculitis factors, and cardiovascular biomarkers were measured by clinical biochemistry, intima-media thickness (IMT) of carotid artery was determined by the Color Doppler ultrasound, and the atherosclerotic lesion in coronary artery was assessed in PCI. Results. Plasma TMAO concentrations were positively associated with Gensini score (OR=0.629, p<0.001) and Gensini subgroup (R=0.604, p<0.001). Plasma TMAO concentrations in patients with severe coronary atherosclerosis were higher than those of patients with moderate coronary atherosclerosis, and the plasma TMAO concentrations of patients with moderate coronary atherosclerosis were higher than those of patients with mild coronary atherosclerosis, the difference was statistically significant [4.73 (3.13, 4.62) versus 1.13 (0.63, 3.34) versus 0.79 (0.20, 1.29), p<0.001], respectively. Furthermore, ROC analysis showed that plasma TMAO could identify the severity of atherosclerosis (p<0.001). The AUC of TMAO for severe atherosclerosis was 0.852 (95%CI=0.779−0.925). The sensitivity and specificity of TMAO for identifying severe atherosclerosis are 96.3% and 63.0% when the cut-off value of TMAO was set at 1.2715 pg/ml. Furthermore, logistic regression analysis showed plasma TMAO concentrations were positively associated with severity of atherosclerosis in coronary artery (OR=1.934, 95%CI=1.522−2.459, p<0.001). For all that, negatively association was observed between TMAO and age (OR=−0.224, p<0.05), B-type natriuretic peptide (BNP) (OR=−0.175, p<0.05), and interleukin-8 (IL-8) (OR=−0.324, p<0.001), while positive association was observed between TMAO and nitric oxide (NO) (OR=0.234, p<0.01). However, there is no obvious association was observed between Gensini score and cardiovascular biomarkers, vasculitis factors, and carotid IMT, respectively. Conclusion. Our cross-sectional observation suggested that plasma TMAO concentrations positively associated with coronary atherosclerosis in ACS patients and serve as a risk factor for severe atherosclerosis. Plasma TMAO also correlated with age, BNP, IL-8, and NO. However, no obvious association was found between atherosclerosis with vasculitis factors and cardiovascular biomarkers in this study, and there was no conclusive evidence showing TMAO enhance atherosclerosis via regulation of inflammation or lipid.

Overcoming immunosuppression in the tumor microenvironment (TME) is crucial for developing novel cancer immunotherapies. Here, we report that IL-16 administration enhances the polarization of T helper 1 (Th1) cells by inhibiting glutamine catabolism through the downregulation of glutaminase in CD4 + T cells and increases the production of Th1 effector cytokine IFN-γ, thus improving anti-tumor immune responses. Moreover, we find that establishing an IL-16-dependent, Th1-dominant TME relies on mast cell-produced histamine and results in the increased expression of the CXCR3 ligands in tumor-associated macrophages (TAM), thereby improving the therapeutic effectiveness of immune checkpoint blockade (ICB). Cancer patients exhibit impaired production of IL-16, which correlates with poorer prognosis. Additionally, low IL-16 production is associated with unresponsiveness to immunotherapy in cancer patients. Collectively, our findings provided new insights into the biological function of IL-16, emphasizing its potential clinical significance as a therapeutic approach to augment anti-tumor immunity and sensitize ICB-based cancer immunotherapy. Overcoming the suppressive tumor microenvironment (TME) is crucial to improving the efficacy of cancer therapy. Here the authors show that, in mouse cancer models, administration of exogenous IL-16 establishes a Th1-dominant TME via regulation of glutamine catabolism and triggers a Th1 cell-macrophage crosstalk, enhancing anti-tumor immune responses and the efficacy of immunotherapy.

During the past two decades, aggregation-induced emission luminogens (AIEgens) have been intensively exploited for biological and biomedical applications. Although a series of investigations have been performed in non-primate animal models, there is few pilot studies in non-human primate animal models, strongly hindering the clinical translation of AIE luminogens (AIEgens). Herein, we present a systemic and multifaceted demonstration of an optical imaging-guided surgical operation via AIEgens from small animals (e.g., mice and rabbits) to rhesus macaque, the typical non-human primate animal model. Specifically, the folic conjugated-AIE luminogen (folic-AIEgen) generates strong and stable fluorescence for the detection and surgical excision of sentinel lymph nodes (SLNs). Moreover, with the superior tumor/normal tissue ratio and rapid tumor accumulation, folic-AIEgen successfully images and guides the precise resection of invisible cancerous metastases. Taken together, the presented strategies of folic-AIEgen based fluorescence intraoperative imaging and visualization-guided surgery show potential for clinical applications. Most applications of aggregation-induced emission luminogens (AIEgens) have been limited in small animal models. Here, the authors show the versatility of AIEgens-based imaging-guided surgical operation from small animals to rhesus macaque, in support of the clinical translation of AIEgens.

Combination therapy has become a promising strategy for promoting the outcomes of anti‐programmed death ligand‐1 (αPD‐L1) therapy in lung cancer. Among all, emerging strategies targeting cancer metabolism have shown great potency in treating cancers with immunotherapy. Here, alteration in glucose and copper metabolisms is found to synergistically regulate PD‐L1 expression in lung cancer cells. Thus, an intelligent biomimetic nano‐delivery system is synthesized by camouflaging lung cancer cell membranes onto glucose oxidase‐loaded Cu‐LDHs (CMGCL) for cancer metabolism targeted interference. Such novel nanomedicine is able to induce lung cancer cell cuproptosis and PD‐L1 upregulation significantly via self‐amplified cascade reactions. Meanwhile, with a decent cancer cell membrane coating, CMGCL exhibited great biosafety, tumor‐targeted efficiency and anti‐tumor effects in LLC lung tumor‐bearing mice models. Additionally, a combination of CMGCL can sensitize the therapeutic effects of αPD‐L1, substantially promoting tumor inhibition in both subcutaneous and lung metastasis LLC‐bearing mice models. Overall, these findings highlight the potential connections between glucose metabolism and cell cuproptosis, offering a promising approach for treating lung cancer by integrating starvation, cuproptosis, and immunotherapy. An intelligent biomimetic nanomedicine is synthesized by camouflaging lung cancer cell membranes onto glucose oxidase‐loaded Cu‐LDHs (CMGCL) for cancer metabolism targeted interference. The CMGCL can achieve great tumor targeting efficacy and upregulate programmed death ligand‐1 (PD‐L1) expression on LLC cells by simultaneously inducing glucose starvation and cuproptosis, thus effectively sensitizing αPD‐L1 therapy against subcutaneous or lung metastatic LLC tumors.