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Post-COVID-19 syndrome may be associated with the abnormal immune status. Compared with the unexposed age-matched elder group, PD-1 in the CD8 + T cells from recovered COVID-19 patients was significantly lower. IFN-γ in the plasma of COVID-19 convalescent patients was increased, which inhibited PD-1 expression in CD8 + T cells from COVID-19 convalescent patients. scRNA-seq bioinformatics analysis revealed that AKT/GSK3β may regulate the INF-γ/PD-1 axis in CD8 + T cells from COVID-19 convalescent patients. In parallel, an IFN-γ neutralizing antibody reduced AKT and increased GSK3β in PBMCs. An AKT agonist (SC79) significantly decreased p-GSK3β. Moreover, AKT decreased PD-1 on CD8 + T cells, and GSK3β increased PD-1 on CD8 + T cells according to flow cytometry analysis. Collectively, we demonstrated that recovered COVID-19 patients may develop long COVID. Increased IFN-γ in the plasma of recovered Wuhan COVID-19 patients contributed to PD-1 downregulation on CD8 + T cells by regulating the AKT/GSK3β signaling pathway.

Brachytherapy (BT) consists in the insertion of radioactive implants directly into the tissue through an applicator, in order to kill tumor cells. This is for the tumor tissue to receive a higher dose, whereas the surrounding normal tissues receive a lower dose of radiation because of the rapid fall of the dose. Because of the special anatomical position of the cervix, smaller organ mobility, and higher tolerable doses of radiotherapy in the vagina and uterus, BT has been most widely used to treat cervical cancer and is an important part of radical radiotherapy for this type of cancer. Furthermore, it is closely related to the prognosis of patients. However, the treatment process, including target area delineation, applicator reconstruction, plan design, and optimization, is time-consuming, which may lead to changes in patient's bladder filling or gastrointestinal peristalsis. Therefore, this not only yields a poor patient experience, but may also affect the accuracy of the treatment and prognosis. With the development of computer hardware, deep learning has been gradually applied in different fields and different networks have been developed to solve various problems. By combining deep learning technology with three-dimensional BT technology, the automation of BT planning can be realized, which, in turn, can significantly shorten the treatment time, alleviate the pain of the patient, and improve treatment efficacy. This article summarizes and gives the prospects of the application of artificial intelligence in the context of BT for cervical cancer.

Background The most prevalent mesenchymal-derived gastrointestinal cancers are gastric stromal tumors (GSTs), which have the highest incidence (60–70%) of all gastrointestinal stromal tumors (GISTs). However, simple and effective diagnostic and screening methods for GST remain a great challenge at home and abroad. This study aimed to build a GST early warning system based on a combination of machine learning algorithms and routine blood, biochemical and tumour marker indicators. Methods In total, 697 complete samples were collected from four hospitals in Gansu Province, including 42 blood indicators from 318 pretreatment GST patients, 180 samples of gastric polyps and 199 healthy individuals. In this study, three algorithms, gradient boosting machine (GBM), random forest (RF), and logistic regression (LR), were chosen to build GST prediction models for comparison. The performance and stability of the models were evaluated using two different validation techniques: 5-fold cross-validation and external validation. The DeLong test assesses significant differences in AUC values by comparing different ROC curves, the variance and covariance of the AUC value. Results The AUC values of both the GBM and RF models were higher than those of the LR model, and this difference was statistically significant ( P  < 0.05). The GBM model was considered to be the optimal model, as a larger area was enclosed by the ROC curve, and the axes indicated robust model classification performance according to the accepted model discriminant. Finally, the integration of 8 top-ranked blood indices was proven to be able to distinguish GST from gastric polyps and healthy people with sensitivity, specificity and area under the curve of 0.941, 0.807 and 0.951 for the cross-validation set, respectively. Conclusion The GBM demonstrated powerful classification performance and was able to rapidly distinguish GST patients from gastric polyps and healthy individuals. This identification system not only provides an innovative strategy for the diagnosis of GST but also enables the exploration of hidden associations between blood parameters and GST for subsequent studies on the prevention and disease surveillance management of GST. The GST discrimination system is available online for free testing of doctors and high-risk groups at https://jzlyc.gsyy.cn/bear/mobile/index.html .

BackgroundImmune-checkpoint inhibitors (ICIs) remain ineffective in a large group of non-small cell lung cancer (NSCLC) patients. Mucosal-associated invariant T (MAIT) cells, a population of unconventional innate-like T lymphocytes abundant in the human body, play important roles in human malignancies. Little is known about the immune characteristics of MAIT cells in NSCLC and correlation with prognosis and response rate of ICIs treatment.MethodsTo investigate the distribution, activation status, and function of MAIT cells in NSCLC patients and their correlations with anti-PD-1 immunotherapy, MAIT cells in peripheral blood, tumor and paratumor samples from NSCLC patients with or without anti-PD-1 immunotherapy were analyzed using flow cytometry and single-cell RNA-sequencing.ResultsMAIT cells were enriched in the tumor lesions of NSCLC patients migrating from peripheral blood via the CCR6-CCL20 axis. Both peripheral and tumor-infiltrating MAIT cells displayed an exhausted phenotype with upregulated PD-1, TIM-3, and IL-17A while less IFN-γ. Anti-PD-1 therapy reversed the function of circulating MAIT cells with higher expression of IFN-γ and granzyme B. Subcluster MAIT-17s (defined as cells highly expressing exhausted and Th17-related genes) mainly infiltrated in the non-responsive tissues, while the subcluster MAIT-IFNGRs (cells expressing genes related to cytotoxic function) were mainly enriched in responsive tissues. Moreover, we found predictive value of circulating MAIT cells for anti-PD-1 immunotherapy in NSCLC patients.ConclusionsMAIT cells shifted to an exhausted tumor-promoting phenotype in NSCLC patients and the circulating MAIT subset could be a predictor for patients who respond to anti-PD-1 immunotherapy.

Proline and its synthesis enzyme pyrroline-5-carboxylate reductase 1 (PYCR1) are implicated in epithelial-mesenchymal transition (EMT), yet how proline and PYCR1 function in allergic asthmatic airway remodeling via EMT has not yet been addressed. In the present study, increased levels of plasma proline and PYCR1 were observed in asthmatic patients. Similarly, proline and PYCR1 in lung tissues were higher in a murine allergic asthma model induced by house dust mites (HDMs). Pycr1 knockout (KO) decreased proline in lung tissues, with reduced airway remodeling and EMT. Mechanistically, loss of Pycr1 restrained HDM-induced EMT by modulating mitochondrial fission, metabolic reprogramming, and the AKT/mTOR1 and WNT3a/β-catenin signaling pathways in airway epithelial cells. Therapeutic inhibition of PYCR1 in wild-type mice disrupted HDM-induced airway inflammation and remodeling. Deprivation of exogeneous proline partially relieved HDM-induced airway remodeling to some extent. Collectively, this study illuminates that proline and PYCR1 involved with airway remodeling in allergic asthma could be viable targets for asthma treatment.

Bronchoalveolar lavage fluid (BALF) exosomes possess different properties in different diseases, which are mediated through microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), among others. By sequencing the differentially expressed lncRNAs in BALF exosomes, we seek potential targets for the diagnosis and treatment of acute lung injury (ALI). Considering that human and rat genes are about 80% similar, ALI was induced using lipopolysaccharide in six male Wistar rats, with six rats as control (all weighing 200 ± 20 g and aged 6-8 weeks). BALF exosomes were obtained 24 h after ALI. The exosomes in BALF were extracted by ultracentrifugation. The differential expression of BALF exosomal lncRNAs in BALF was analyzed by RNA sequencing. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to predict the functions of differentially expressed lncRNAs, which were confirmed by reverse transcription-polymerase chain reaction. Compared with the control group, the ALI group displayed a higher wet/dry ratio, tumor necrosis factor-α levels, and interleukin-6 levels (all < 0.001). The airway injection of exosomes in rats led to significant infiltration by neutrophils. A total of 2,958 differentially expressed exosomal lncRNAs were identified, including 2,524 upregulated and 434 downregulated ones. Five lncRNAs confirmed the reliability of the sequencing data. The top three GO functions were phagocytic vesicle membrane, regulation of receptor biosynthesis process, and I-SMAD binding. Salmonella infection, Toll-like receptor signaling pathway, and osteoclast differentiation were the most enriched KEGG pathways. The lncRNA-miRNA interaction network of the five confirmed lncRNAs could be predicted using miRDB. BALF-derived exosomes play an important role in ALI development and help identify potential therapeutic targets related to ALI.

Pancreatic cancer is a highly aggressive disease with poor prognosis. N6-methyladenosine (m6A) is critical for post-transcriptional modification of messenger RNA (mRNA) and long non-coding RNA (lncRNA). However, the m6A-associated lncRNAs (m6A-lncRNA) and their values in predicting clinical outcomes and immune microenvironmental status in pancreatic cancer patients remain largely unexplored. This study aimed to evaluate the importance of m6A-lncRNA and established a m6A-lncRNA signature for predicting immunotherapeutic response and prognosis of pancreatic cancer. The m6A-lncRNA co-expression networks were constructed using data from the TCGA and GTEx database. Based on the least absolute shrinkage and selection operator (LASSO) analysis, we constructed an 8 m6A-lncRNA signature risk model, and selection operator (LASSO) analysis, and stratified patients into the high- and low-risk groups with significant difference in overall survival (OS) (HR = 2.68, 95% CI = 1.74–4.14, P < 0.0001). Patients in the high-risk group showed significantly reduced OS compared to patients in the low-risk group ( P < 0.001). The clinical characteristics and m6A-lncRNA risk scores were used to construct a nomogram which accurately predicted the OS in pancreatic cancer. TIMER 2.0 were used to investigate tumor immune infiltrating cells and its relationship with pancreatic cancer. CIBERSORT analysis revealed increased higher infiltration proportions of M0 and M2 macrophages, and lower infiltration of naive B cell, CD8 + T cell and Treg cells in the high-risk group. Compared to the low-risk group, functional annotation using ssGSEA showed that T cell infiltration and the differential immune-related check-point genes are expressed at low level in the high-risk group ( P < 0.05). In summary, our study constructed a novel m6A-associated lncRNAs signature to predict immunotherapeutic responses and provided a novel nomogram for the prognosis prediction of pancreatic cancer.

Background The microtubule-dependent molecular motor protein Kinesin Family Member 2A (KIF2A) is down-regulated in asthmatic human airway epithelium. However, little is known about the roles of KIF2A as well as the possible underlying mechanisms in asthma. Methods House dust mite (HDM) extract was administered to establish a murine model of asthma. The expression of KIF2A, IL-33 and the autophagy pathways were detected. The plasmid pCMV-KIF2A was used to overexpress KIF2A in the airway epithelial cells in vitro and in vivo. IL-4, IL-5, IL-33 and other cytokines in bronchoalveolar lavage fluid (BALF) and lung tissues homogenates were measured. Results In response to the challenge of house dust mite (HDM) in vitro and in vivo, airway epithelial cells displayed decreased production of KIF2A. Meanwhile, autophagy and IL-33 were increased in HMD-treated epithelial cells. Mechanistically, KIF2A decreased autophagy via suppressing mTORC1 pathway in HDM-treated epithelial cells, which contributed to the reduced production of IL-33. Moreover, in vivo KIF2A transfection reduced IL-33 and autophagy in the lung, leading to the attenuation of allergic asthma. Conclusion KIF2A suppressed mTORC1-mediated autophagy and decreased the production of epithelial-derived cytokine IL-33 in allergic airway inflammation. These data indicate that KIF2A may be a novel target in allergic asthma.

Objective The IL‐33/ST2 axis has been extensively investigated in type 2 eosinophilic inflammation. Here, we aimed to investigate the role of the IL‐33/ST2 axis in neutrophil‐dominant allergic airway inflammation. Methods House‐dust mite (HDM) extract and lipopolysaccharide (LPS) were administered to establish a murine model of neutrophil‐dominant allergic airway inflammation. The formation of neutrophilic extracellular traps (NETs) in the lung tissues was demonstrated by immunofluorescence imaging. Mature IL‐33 in bronchoalveolar lavage fluid (BALF) was detected by Western blotting. The neutrophilic chemokine KC produced by bone marrow‐derived macrophages (BMDMs) or primary alveolar epithelial cells was measured with a commercial ELISA kit. Results In the present study, we observed neutrophilic inflammation and tight junction damage in the lungs of mice sensitised with HDM and LPS. Furthermore, sensitisation with HDM and LPS resulted in the formation of NETs, accompanied by increased levels of mature IL‐33 in the BALF. Moreover, LPS damaged the epithelial tight junction protein occludin directly or indirectly by inducing NET formation. Surprisingly, IL‐33 deficiency augmented neutrophilia and epithelial barrier injury in the lungs of mice after sensitisation with HDM and LPS. Similarly, the absence of ST2 exacerbated the neutrophilic inflammatory response, decreased the expression of occludin and exacerbated the severity of neutrophil‐dominant allergic airway inflammation in an HDM/LPS‐induced mouse model. Mechanistically, BMDMs and alveolar epithelial cells from IL‐33‐ or ST2‐deficient mice tended to produce higher levels of the neutrophilic chemokine KC. Conclusions These results demonstrated that the IL‐33/ST2 axis may play a protective role in neutrophil‐dominant allergic airway inflammation. Most research on the IL‐33/ST2 axis has been conducted in type 2 immunity‐mediated eosinophilic asthma, but less research has focused on neutrophilic asthma. In this study, we found that IL‐33/ST2 axis deficiency aggravated neutrophil‐dominant allergic airway inflammation induced by house‐dust mite and lipopolysaccharide coexposure, which may account for the more proinflammatory status of IL‐33/ST2 axis‐deficient macrophages and lung epithelial cells.

To investigate the relationship of preoperative high-sensitivity cardiac troponin T (hs-cTnT) with early postoperative hypoxemia (EPH) following off-pump coronary artery bypass grafting (OPCAB). Records of patients undergoing OPCAB between 2018 and 2022 were reviewed. Baseline characteristics and postoperative arterial blood gas analysis were derived from the cardiovascular surgery electronic medical records. Preoperative hs-cTnT levels were measured routinely in all patients. Logistic regression analyses were performed to test the association of preoperative hs-cTnT with EPH. A total of 318 OPCAB patients were included, who had a preoperative hs-cTnT test available for review. Before surgery, 198 patients (62%) had a rise in hs-cTnT level (≥14 ng/L) and 127 patients (40%) had a more severe hs-cTnT level (≥25 ng/L). The preoperative hs-cTnT level was associated with EPH (odds ratio per ng/L, 1.86; 95% confidence interval 1.30–2.68; p < 0.001), prolonged intensive care unit stay (odds ratio, 1.58; 95% confidence interval 1.08–2.32; p = 0.019), and delayed extubating time (odds ratio, 1.63; 95% confidence interval 1.15–2.34; p = 0.007). On multivariable analysis, adjusted for BMI, hypertension, smoking status, serum creatinine, and cardiac function, preoperative hs-cTnT remained an independent factor associated with EPH. Elevation of hs-cTnT concentrations are significantly associated with EPH after OPCAB. Review of presurgical hs-cTnT concentration may help identify patients who would benefit from OPCAB to improve surgical risk assessment.