Background: Nasopharyngeal carcinoma (NPC) is characterized by high programmed death-ligand 1 (PD-L1) expression and abundant infiltration of non-malignant lymphocytes, which renders patients potentially suitable candidates for immune checkpoint blockade therapies. Palate, lung, and nasal epithelium clone (PLUNC) inhibit the growth of NPC cells and enhance cellular apoptosis and differentiation. Currently, the relationship between PLUNC (as a tumor-suppressor) and PD-L1 in NPC is unclear. Methods: We collected clinical samples of NPC to verify the relationship between PLUNC and PD-L1. PLUNC plasmid was transfected into NPC cells, and the variation of PD-L1 was verified by western blot and immunofluorescence. In NPC cells, we verified the relationship of PD-L1, activating transcription factor 3 (ATF3), and β-catenin by western blot and immunofluorescence. Later, we further verified that PLUNC regulates PD-L1 through β-catenin. Finally, the effect of PLUNC on β-catenin was verified by co-immunoprecipitation (Co-IP). Results: We found that PLUNC expression was lower in NPC tissues than in paracancer tissues. PD-L1 expression was opposite to that of PLUNC. Western blot and immunofluorescence showed that β-catenin could upregulate ATF3 and PD-L1, while PLUNC could downregulate ATF3/PD-L1 by inhibiting the expression of β-catenin. PLUNC inhibits the entry of β-catenin into the nucleus. Co-IP experiments demonstrated that PLUNC inhibited the interaction of DEAD-box helicase 17 (DDX17) and β-catenin. Conclusions PLUNC downregulates the expression of PD-L1 by inhibiting the interaction of DDX17/β-catenin in NPC.

Background: Nasopharyngeal carcinoma (NPC) is characterized by high programmed death-ligand 1 (PD-L1) expression and abundant infiltration of non-malignant lymphocytes, which renders patients potentially suitable candidates for immune checkpoint blockade therapies. Palate, lung, and nasal epithelium clone (PLUNC) inhibit the growth of NPC cells and enhance cellular apoptosis and differentiation. Currently, the relationship between PLUNC (as a tumor-suppressor) and PD-L1 in NPC is unclear. Methods: We collected clinical samples of NPC to verify the relationship between PLUNC and PD-L1. PLUNC plasmid was transfected into NPC cells, and the variation of PD-L1 was verified by western blot and immunofluorescence. In NPC cells, we verified the relationship of PD-L1, activating transcription factor 3 (ATF3), and β-catenin by western blot and immunofluorescence. Later, we further verified that PLUNC regulates PD-L1 through β-catenin. Finally, the effect of PLUNC on β-catenin was verified by co-immunoprecipitation (Co-IP). Results: We found that PLUNC expression was lower in NPC tissues than in paracancer tissues. PD-L1 expression was opposite to that of PLUNC. Western blot and immunofluorescence showed that β-catenin could upregulate ATF3 and PD-L1, while PLUNC could downregulate ATF3/PD-L1 by inhibiting the expression of β-catenin. PLUNC inhibits the entry of β-catenin into the nucleus. Co-IP experiments demonstrated that PLUNC inhibited the interaction of DEAD-box helicase 17 (DDX17) and β-catenin. Conclusions PLUNC downregulates the expression of PD-L1 by inhibiting the interaction of DDX17/β-catenin in NPC.

Background: Nasopharyngeal carcinoma (NPC) is characterized by high programmed death-ligand 1 (PD-L1) expression and abundant infiltration of non-malignant lymphocytes, which renders patients potentially suitable candidates for immune checkpoint blockade therapies. Palate, lung, and nasal epithelium clone (PLUNC) inhibit the growth of NPC cells and enhance cellular apoptosis and differentiation. Currently, the relationship between PLUNC (as a tumor-suppressor) and PD-L1 in NPC is unclear. Methods: We collected clinical samples of NPC to verify the relationship between PLUNC and PD-L1. PLUNC plasmid was transfected into NPC cells, and the variation of PD-L1 was verified by western blot and immunofluorescence. In NPC cells, we verified the relationship of PD-L1, activating transcription factor 3 (ATF3), and β-catenin by western blot and immunofluorescence. Later, we further verified that PLUNC regulates PD-L1 through β-catenin. Finally, the effect of PLUNC on β-catenin was verified by co-immunoprecipitation (Co-IP). Results: We found that PLUNC expression was lower in NPC tissues than in paracancer tissues. PD-L1 expression was opposite to that of PLUNC. Western blot and immunofluorescence showed that β-catenin could upregulate ATF3 and PD-L1, while PLUNC could downregulate ATF3/PD-L1 by inhibiting the expression of β-catenin. PLUNC inhibits the entry of β-catenin into the nucleus. Co-IP experiments demonstrated that PLUNC inhibited the interaction of DEAD-box helicase 17 (DDX17) and β-catenin. Conclusions PLUNC downregulates the expression of PD-L1 by inhibiting the interaction of DDX17/β-catenin in NPC.

BACKGROUND: The effects of human umbilical cord-derived mesenchymal stem cell (UC-MSC) treatment on coronavirus disease 2019 (COVID-19) patients have been preliminarily characterized. However, real-world data on the safety and efficacy of intravenous transfusions of MSCs in hospitalized COVID-19 patients at the convalescent stage remain to be reported. METHODS: This was a single-arm, multicenter, real-word study in which a contemporaneous external control was included as the control group. Besides, severe and critical COVID-19 patients were considered together as the severe group, given the small number of critical patients. For a total of 110 patients, 21 moderate patients and 31 severe patients were enrolled in the MSC treatment group, while 26 moderate patients and 32 severe patients were enrolled in the control group. All patients received standard treatment. The MSC treatment patients additionally received intravenous infusions of MSCs at a dose of 4 × 10 7 cells on days 0, 3, and 6, respectively. The clinical outcomes, including adverse events (AEs), lung lesion proportion on chest computed tomography, pulmonary function, 6-min walking distance (6-MWD), clinical symptoms, and laboratory parameters, were measured on days 28, 90, 180, 270, and 360 during the follow-up visits. RESULTS: In patients with moderate COVID-19, MSC treatment improved pulmonary function parameters, including forced expiratory volume in the first second (FEV1) and maximum forced vital capacity (VCmax) on days 28 (FEV1, 2.75 [2.35, 3.23] vs . 2.11 [1.96, 2.35], P  = 0.008; VCmax, 2.92 [2.55, 3.60] vs . 2.47 [2.18, 2.68], P  = 0.041), 90 (FEV1, 2.93 [2.63, 3.27] vs . 2.38 [2.24, 2.63], P  = 0.017; VCmax, 3.52 [3.02, 3.80] vs . 2.59 [2.45, 3.15], P  = 0.017), and 360 (FEV1, 2.91 [2.75, 3.18] vs . 2.30 [2.16, 2.70], P  = 0.019; VCmax,3.61 [3.35, 3.97] vs . 2.69 [2.56, 3.23], P  = 0.036) compared with the controls. In addition, in severe patients, MSC treatment notably reduced the proportion of ground-glass lesions in the whole lung volume on day 90 ( P  = 0.045) compared with the controls. No difference in the incidence of AEs was observed between the two groups. Similarly, no significant differences were found in the 6-MWD, D-dimer levels, or interleukin-6 concentrations between the MSC and control groups. CONCLUSIONS: Our results demonstrate the safety and potential of MSC treatment for improved lung lesions and pulmonary function in convalescent COVID-19 patients. However, comprehensive and long-term studies are required to confirm the efficacy of MSC treatment. TRIAL REGISTRATION Chinese Clinical Trial Registry, ChiCTR2000031430.
Humans ; COVID-19/therapy* ; Female ; Male ; Mesenchymal Stem Cell Transplantation/adverse effects* ; Middle Aged ; Adult ; Umbilical Cord/cytology* ; Mesenchymal Stem Cells/cytology* ; SARS-CoV-2 ; Aged ; Treatment Outcome

Extensive epigenetic reprogramming involves in memory CD8+ T-cell differentiation. The elaborate epigenetic rewiring underlying the heterogeneous functional states of CD8+ T cells remains hidden. Here, we profile single-cell chromatin accessibility and map enhancer-promoter interactomes to characterize the differentiation trajectory of memory CD8+ T cells. We reveal that under distinct epigenetic regulations, the early activated CD8+ T cells divergently originated for short-lived effector and memory precursor effector cells. We also uncover a defined epigenetic rewiring leading to the conversion from effector memory to central memory cells during memory formation. Additionally, we illustrate chromatin regulatory mechanisms underlying long-lasting versus transient transcription regulation during memory differentiation. Finally, we confirm the essential roles of Sox4 and Nrf2 in developing memory precursor effector and effector memory cells, respectively, and validate cell state-specific enhancers in regulating Il7r using CRISPR-Cas9. Our data pave the way for understanding the mechanism underlying epigenetic memory formation in CD8+ T-cell differentiation.
CD8-Positive T-Lymphocytes/metabolism* ; Cell Differentiation ; Chromatin/immunology* ; Animals ; Mice ; Immunologic Memory ; Epigenesis, Genetic ; SOXC Transcription Factors/immunology* ; NF-E2-Related Factor 2/immunology* ; Mice, Inbred C57BL ; Gene Regulatory Networks ; Enhancer Elements, Genetic

Objective To analyze the short-term clinical efficacy and prognosis of one-stop transcatheter aortic valve replacement (TAVR)+percutaneous coronary intervention (PCI) in the treatment of aortic valve disease with coronary heart disease. Methods The clinical data of patients with aortic valve disease complicated with coronary heart disease who underwent one-stop TAVR+PCI treatment at the Department of Cardiovascular Surgery, the Second Hospital of Hebei Medical University from January 2018 to June 2023 were retrospective analyzed. The preoperative and postoperative clinical data were compared, and 1-month follow-up results were recorded. Results A total of 37 patients were enrolled, including 22 males and 15 females, with an average age of 69.14±6.47 years. Thirty-six patients recovered and were discharged after the surgery, and 1 (2.7%) patient died during the surgery. Self-expanding TAVR valves were implanted through the femoral artery in all patients. One coronary artery was opened by PCI in 35 (94.6%) patients, and two coronary arteries were opened by PCI in 2 (5.4%) patients. All PCI opened arteries had a stenosis>70%. During the postoperative hospitalization, the complications included pulmonary infection in 11 (30.6%) patients, severe pneumonia in 10 (27.8%) patients, liver function injury in 14 (38.9%) patients, renal function injury in 5 (13.9%) patients, cerebral infarction in 1 (2.8%) patient, atrial fibrillation in 1 (2.8%) patient, ventricular premature beats in 2 (5.6%) patients, atrioventricular block in 2 (5.6%) patients, and complete left bundle branch block in 5 (13.9%) patients. The median postoperative ventilation assistance time was 12.0 (0.0, 17.0) h, the ICU monitoring time was 1.0 (0.0, 2.0) d, and the postoperative hospitalization time was 5.0 (4.0, 7.0) d. There was a significant improvement in the New York Heart Association cardiac function grading after surgery (P<0.001). After surgery, there were 21 (58.3%) patients had minor perivalve leakage, 6 (16.7%) patients had minor to moderate perivalve leakage, and no moderate or above degree of perivalve leakage. After one month of postoperative follow-up, 36 patients showed significant improvement in heart function. There were no patients with recurrent acute coronary syndrome, re-PCI, or cardiovascular system disease related re-hospitalization. Conclusion The one-stop TAVR+PCI treatment for patients with aortic valve disease and coronary heart disease can obtain satisfactory short-term clinical efficacy, which is worth further trying and studying.

Objective:To evaluate the effects of different types of psychological interventions on the fear of cancer recurrence through a network Meta-analysis.Methods:Randomized controlled trials on the effects of different types of psychological interventions on the fear of cancer recurrence were retrieved from PubMed, PsycINFO, Web of Science, The Cochrane Library, Embase, EBSCO, China Biomedical Literature Database, CNKI, Wanfang Database and Vip Database. The retrieval period was from the establishment of the database to December, 31 2022. Two researchers conducted literature screening, extraction and quality evaluation, and used Stata14.0 software to conduct network Meta-analysis.Results:A total of 29 pieces of research involving 3 068 cancer patients and 11 psychological intervention measures. The results of network Meta-analysis showed that narrative therapy, PERMA(Positive, Engagement, Relationship, Meaning, Accomplishment) happiness theory model, acceptance and commitment therapy and cognitive behavior therapy had statistically significant differences in the intervention effect on the fear of cancer recurrence compared with conventional nursing ( SMD values were -1.93--0.83, all P<0.05); there was no significant difference among narrative therapy, PERMA happiness model, acceptance and commitment therapy and gratitude-expansion behavior theory (all P>0.05). The results of the cumulative probability map showed the best intervention was narrative therapy. Conclusions:The results of this study suggest that narrative therapy, acceptance and commitment therapy, and cognitive behavior therapy may be effective psychological intervention measures to improve the fear of cancer recurrence. However, more studies are still needed for further verification.

BACKGROUND:In recent years,increasing studies have focused on the abnormal proliferation and differentiation of acinous cells in the meibomian gland,suggesting that this process is closely related to the occurrence and development of dry eye.Structural and functional abnormalities such as blockage of the lumen of the meibomian gland and atrophy of the glands can cause or exacerbate dry eye.Therefore,the study of changes in the meibomian glands in dry eyes is important for understanding the pathogenesis of dry eyes in depth and finding new targets for the treatment and prevention of dry eyes. OBJECTIVE:To investigate the changes of the meibomian gland in a mouse model of aqueous deficient dry eyes. METHODS:Thirty-two female C57/B6 mice at 6-8 weeks were selected and randomly divided into experimental and control groups with 16 mice in each group.The mice in the experimental group were constructed by removing both the extra-orbital and intra-orbital lacrimal glands,while those in the control group were not treated.After 2 weeks of normal feeding,the corneal changes of both groups were observed under a slit lamp,and the tear secretion of both groups was measured.The meibomian glands of the two groups of mice were removed after decapitation.The changes in the gross morphology of the meibomian glands were observed and the meibomian glands were made into frozen sections.Hematoxylin-eosin staining was used to observe the structure of the meibomian glands,oil red staining was used to evaluate the function of the meibomian glands,and immunofluorescence staining and RT-qPCR were used to observe the expression of cytokeratin 14,Ki67 and abnormally differentiated small proline-rich protein 1B in the meibomian glands of mice. RESULTS AND CONCLUSION:Two weeks after modeling,lamellar defects were seen in the corneas of the experimental mice,and neovascularization of the limbal corneal was generated and invaded the central cornea.(2)Tear secretion volume was significantly reduced in the experimental group compared with the control group(P<0.05).Microscopic findings showed that the ducts of the meibomian glands in the experimental group were interrupted and atrophied,and their arrangement was disorganized.Hematoxylin-eosin staining results showed a significant increase in lipid vacuoles in the meibomian glands of the experimental mice compared with the control group.Lipid deposition was seen in oil red staining in the experimental group.Immunofluorescence and RT-qPCR results showed a significant increase in the expression of cytokeratin 14,Ki67 and small proline-rich protein 1B in the meibomian glands of mice in the experimental group compared with the control group(P<0.05).To conclude,aqueous deficient dry eye can lead to compensatory hypertrophy,increased proliferation,and abnormal lipid metabolism in the meibomian gland,as well as abnormal differentiation of the meibomian gland.

Objective To investigate the possible mechanism of action of Jinqi Qingshu granules(JQQSG)in the treatment of community-acquired pneumonia(CAP)by network pharmacology and molecular docking technology.Methods The TCMSP database and SwissTargetPrediction database were used to obtain and screen the active ingredients and targets of JQQSG,and GeneCards,OMIM,TTD,and DisGeNET databases were used to search for the predicted targets of CAP,and the two targets were mapped and then imported into STRING database to construct a PPI network to screen the key targets,and then the GO and KEGG pathway enrichment were analyzed by the DAVID database,and molecular docking was carried out by the AutoDock Tools software.Results 209 active ingredients and 1 041 targets of JQQSG were obtained after screening;312 targets were co-activated with CAP,and 64 core targets were obtained after PPI network screening.571 biological processes,68 cellular components,and 199 molecular functions were analyzed by GO enrichment,and 165 KEGG pathways were analyzed by KEGG pathway enrichment,mainly involved in protein action,apoptosis and MAPK signaling pathway.Molecular docking suggests that the core target and the core components all have good binding ability.Conclusion The mechanism of action of JQQSG in the treatment of CAP may be related to its regulation of Akt,MAPK signaling pathway,improvement of oxidative stress,and other pathways to exert anti-inflammatory and antioxidant effects,which could lay the foundation for further in-depth study of its specific mechanism of action.

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) technology has the characteristics of high specificity and high throughput, making it rapidly applied and developed in the field of clinical testing. Its application in the monitoring of therapeutic drugs can effectively improve the quantitative accuracy and sensitivity, and formulate a personalized and optimal dosing plan for patients. However, this technology still faces some challenges, and automation, quality control, and quantitative traceability will be the future development direction.