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.

Heterozygous loss-of-function variants of FOXP4 are associated with neurodevelopmental disorders (NDDs) that exhibit delayed speech development, intellectual disability, and congenital abnormalities. The etiology of NDDs is unclear. Here we found that FOXP4 and N-cadherin are expressed in the nuclei and apical end-feet of radial glial cells (RGCs), respectively, in the mouse neocortex during early gestation. Knockdown or dominant-negative inhibition of Foxp4 abolishes the apical condensation of N-cadherin in RGCs and the integrity of neuroepithelium in the ventricular zone (VZ). Inhibition of Foxp4 leads to impeded radial migration of cortical neurons and ectopic neurogenesis from the proliferating VZ. The ectopic differentiation and deficient migration disappear when N-cadherin is over-expressed in RGCs. The data indicate that Foxp4 is essential for N-cadherin-based adherens junctions, the loss of which leads to periventricular heterotopias. We hypothesize that FOXP4 variant-associated NDDs may be caused by disruption of the adherens junctions and malformation of the cerebral cortex.
Mice ; Animals ; Ependymoglial Cells/physiology* ; Cadherins ; Neurons/metabolism* ; Cerebral Cortex/metabolism* ; Cell Differentiation ; Cell Movement

BACKGROUND On March 2022, the United States Food and Drug Administration(FDA) announced the approval of radiolabeled drug lutetium Lu 177 vipivotide tetraxetan for treatment of adult patients with prostate specific membrane antigen(PSMA)-positive metastatic castration-resistant prostate cancer who have been treated with androgen-receptor pathway inhibition and taxane-based chemotherapy. As PSMA is barely expressed on non-prostatic tissue, it has a very low background accumulation in healthy tissue, consequently, avoiding severe adverse drug reaction of lutetium Lu 177 vipivotide tetraxetan. A multicenter phase Ⅲ VISION study(NCT 03511664) showed that about 30% of patients with evaluable disease at baseline demonstrated an overall response with lutetium Lu 177 vipivotide tetraxetan plus standard care, compared to only 2% in the control arm. The high efficacy and mild adverse drug reaction of lutetium Lu 177 vipivotide tetraxetan cause opportunities for the healthcare systems and represent an important next step towards novel oncotherapy, but also cause great challenges in its clinical use due to lack of practical experience. Currently, data on the large sample and real-world comprehensive safety of lutetium Lu 177 vipivotide tetraxetan are still limited. Therefore, it is necessary to employ data mining algorithms to seek out the potential adverse event signals of lutetium Lu 177 vipivotide tetraxetan by post-marketing monitoring. METHODS FDA Adverse Event Reporting System(FAERS) is a publicly available, voluntary, and spontaneous reporting database. In the present study, the adverse events reported from the second quarter of 2022 to the fourth quarter of 2022 with lutetium Lu 177 vipivotide tetraxetan from FAERS were retrospectively analyzed. Seven types of datasets, including patient demographic and administrative information(DEMO), drug information(DRUG), therapy start dates and end dates for reported drugs(THER), adverse event results(OUTC), adverse event sources(PRSP), coded for the adverse events(REAC), and indications for use/diagnosis(INDI) were used. The reports of lutetium Lu 177 vipivotide tetraxetan were identified using generic name(LUTETIUM LU-177 VIPIVOTIDE TETRAXETAN in prod_ai column) and trade name(PLUVICTO in drug name column) in the DRUG dataset. The adverse event reports with the role_cod as the primary suspected(PS) were chose. Next, the report characteristics, demographic characteristics and onset time of lutetium Lu 177 vipivotide tetraxetan-associated adverse events were analyzed. The adverse events were coded using preferred terms(PT) derived from the standardized Medical Dictionary for Regulatory Activities 25.1(MedDRA), which contained 27 system organ classes(SOCs). Four algorithms, including reporting odds ratio(ROR), proportional reporting ratio(PRR), Bayesian confidence propagation neural network(BCPNN) and multi-item gamma Poisson shrinker(MGPS) were used to detect the signals. All the four data mining algorithms were based on the disproportionality analysis. An adverse event signal was detected only when it conformed to all of the four algorithms criteria simultaneously. RESULTS A total of 634 reports associated with lutetium Lu 177 vipivotide tetraxetan were considered. As a whole, the number of reports had increased gradually month-on-month, and 568(89.6%) reports occurred in the United States. The most common age and body weight groups were 61-80 years(75.4%) and 61-80 kg(50.9%), respectively. Most reports occurred within 30 d after administration of lutetium Lu 177 vipivotide tetraxetan, accounting for 41.5%. Based on 4 algorithms of ROR, PRR, BCPNN and MGPS, six effective signals at the PT level were detected, including anaemia(PT: 10002034), thrombocytopenia(PT: 10043554), laboratory test abnormal(PT: 10023547), platelet count decreased(PT: 10035528), full blood count decreased(PT: 10017413) and dry mouth(PT: 10013781). CONCLUSION When using lutetium Lu 177 vipivotide tetraxetan, it is important to strengthen clinical monitoring within one month and pay attentions to laboratory results including complete blood cell and platelet count. This study might provide powerful support for clinical monitoring of lutetium Lu 177 vipivotide tetraxetan.

Objective: To explore the influencing factors of cognitive impairment in patients with silicosis, and to analyze the effect of brain-derived neurotrophic factor (BDNF) on cognitive function. Methods: In March 2021, 484 silicosis patients from April 2018 to April 2020 were included in the study. The Montreal Cognitive Assessment Scale of Chinese version was used to evaluate their cognitive function, and they were divided into the cognitive impairment group (n=282) and the non cognitive impairment group (n=202) , another 30 healthy persons from body check were served as control group. The concentrations of BDNF were compared between the three groups. And the receiver operating characteristic (ROC) curve was drawed to analyze the value of BDNF in predicting cognitive impairment in silicosis patients. And the logistic regression analysis was used to explore the risk factors of cognitive impairment. Results: The incidence of cognitive impairment in silicosis patients was 58.26% (282/484) . The level of BDNF in the cognitive impairment group[ (10.32±2.11) mg/L] was significantly lower than that in the non cognitive impairment group[ (13.43±3.45) mg/L] (t=-12.27, P<0.001) . The results of ROC curve analysis showed that the area unde the curve of BDNF in predicting cognitive impairment of silicosis patients was 0.763 (95%CI: 0.613-0.874, P=0.024) , the cut off value was 10 mg/L, the sensitivity was 0.88, and the specificity was 0.84. Logistic regression analysis showed that the level of BDNF (≤10 mg/L) , age (≥65 years old) , course of disease (≥5 years) and diabetes mellitus were the risk factors of cognitive impairment in silicosis patients (OR=2.346, 95%CI: 1.654-3.103; OR=1.757, 95%CI: 1.214-1.998; OR=1.346, 95%CI: 1.112-1.564; OR=1.165, 95%CI: 1.102-1.542, P=0.001, 0.012, 0.027, 0.036) . Conclusion: BDNF may be one of the indicator to predict the risk of cognitive impairment in patients with silicosis.
Aged ; Brain-Derived Neurotrophic Factor ; Cognitive Dysfunction/etiology* ; Diabetes Mellitus, Type 2 ; Humans ; ROC Curve ; Silicosis/complications*

Objective:To explore the effects of competency-based diversified training on the bedside nursing comprehensive ability aand transition shock of newly recruited nurses.Methods:A total of 62 newly recruited nurses from the Second Affiliated Hospital of Zhengzhou University in June 2018 were selected as the control group, and 70 newly recruited nurses from June 2019 were selected as the experimental group by cluster sampling. The control group received routine pre-job training, and the experimental group received diversified training based on the control group. After one year of training, the differences in the scores of bedside nursing comprehensive ability, post competency and transition shock between the two groups of nurses were analyzed.Results:After 1 year of training, the total scores and the scores of nursing problems, nursing evaluation, nursing plan, nursing theory, nursing operation and bedside nursing comprehensive ability in the experimental group were 12.20±1.76, 24.29±2.38, 13.54±1.88, 9.77±1.35, 15.14±2.30 and 79.24±6.59, which were all higher than those of the control group (10.26±1.55,22.31±1.84,10.45±1.58, 8.56±1.80, 13.27±2.38 and 69.82±4.09), the differences were statistically significant ( t value was 4.582-13.679, P<0.05). The total scores and the scores of each dimension of the Post-competency the experimental group were 31.46 ±4.32, 51.03± 4.64, 20.27± 3.78, 17.86±3.99, 58.43± 4.44, 179.37±9.97, which were all higher than those of the control group 24.76±4.12, 40.56±5.55, 16.61±2.88, 15.15± 2.96, 49.74±3.07, 146.66±17.98, the differences were statistically significant ( t value was 4.466-13.197, P<0.05). The scores of psychological knowledge, skills, social culture and development and the total scores of Transition shock in the experimental group were 30.90±3.15, 19.69±2.74, 32.17±3.06, 103.81±12.24, which were all higher than those in the control group (25.69±2.76, 15.92±3.24, 27.50±4.15, 88.32±11.54), the differences were statistically significant ( t value was 7.237-10.040, P<0.05). Conclusions:competency-based diversified training can effectively improve the bedside nursing comprehensive ability and post competency, reduce their transition shock, and has strong clinical reference significance.

Objective:To investigate radiation-induced somatic mutations and variations and provide theoretical basis for clarifying radiation-induced genetic changes and long-term effects by whole-genome sequencing analysis of the genetic variations of the victim of the " 5.7" 192Ir radiation accident in Nanjing. Methods:Normal back skin tissue, irradiated bone and soft tissues, and peripheral blood were collected from the victim 2 047 days post-irradiation. DNA of these samples was extracted and sequenced with high-throughput genomics and analyzed by bioinformatics method. The genetic variations of between irradiated and normal tissues were compared.Results:Compared with normal back skin tissue, there are large amounts of genetic variations in the irradiated bone and soft tissues and peripheral blood, including base substitution (transition, transversion), small insertion, small deletion, copy number variation (gain, loss) and structure variation (large deletion, large duplication, inversion, intra-chromosomal translocation, inter-chromosomal translocation). There were 10 666 genetic variations in the irradiated bone and soft tissues and 11 233 genetic variations in peripheral blood, where thousands of genes were involved in. These variations occurred in the exons, introns, UTR′3, UTR′5, splicing sites, within 5 kb upstream of transcription initiation site, within 5 kb downstream of transcription termination site, ncRNA and intergenic region. All chromosomes had genetic variations.Conclusions:There were a large number of genetic variations in the irradiated tissues and blood of the victim at 2 047 days after irradiation, which may affect the body function and cause the long-term effects.

Objective:To investigate the effect of ionizing radiation on the ferroptosis of skin cells and the potential therapeutic strategy of ferroptosis inhibitor Ferrostatin-1 (Fer-1) on irradiated skin cells.Methods:HaCaT cells were pre-treated with Fer-1 before X-ray irradiation. After irradiation, CCK-8 assay and LDH release assay were used to detect cell viability and cell death, flow cytometry was used to detect the lipid peroxidation levels, crystal violet staining assay was used to detect colony forming ability, and the expressions of ferroptosis related proteins ACSL4 and GPX4 were detected by Western blot.Results:The cell viability of HaCaT cells was significantly decreased ( t=5.63, 8.74, P<0.05) and the release of LDH was significantly increased ( t=3.98, 5.08, 9.27, P<0.05) after different doses of X-ray irradiation. The cell viability was improved ( t=5.79, P<0.05) and the release of LDH was reduced ( t=12.36, 11.96, 18.13, 9.96, P<0.05) after the pre-treatment with Fer-1. The lipid peroxidation levels of HaCaT cells were significantly increased ( t=9.59, P<0.05) and the clonogenic survival ability were reduced ( t=4.26, P<0.05) after 10 Gy X-ray irradiation, while Fer-1 pre-treatment reduced ( t=6.48, 17.04, P<0.05) the increase of lipid peroxidation level induced by X-ray irradiation and also effectively restore ( t=3.96, P<0.05) the clonogenic survival ability. The expressions of ACSL4 and GPX4 were decreased after 10 Gy X-ray irradiation, while they recovered to normal level ( t=5.23, 7.16, 4.78, 8.29, 6.43, P<0.05) after the pre-treatment with Fer-1. Conclusions:Ferroptosis inhibitor Fer-1 alleviates the progress of radiation-induced skin injury by inhibiting ferroptosis after ionizing radiation at the cellular level, which provides a potential strategy for the protection of radiation injury.

Objective: Comparing the benefit of Abidor, lopinavir/ritonavir and recombinant interferon α-2b triple combination antiviral therapy and lopinavir/ritonavir and interferon dual combination antiviral therapy to hospitalized novel coronavirus pneumonia 2019 in Zhejiang province. Methods: A multi-center prospective study was carried out to compare the effect of triple combination antiviral therapy with dual combination antiviral therapy in 15 medical institutions of Zhejiang Province. All patients were treated with recombinant interferon α-2b (5 million U, 2 times/d) aerosol inhalation. 196 patients were treated with abidol (200 mg, 3 times/d) + lopinavir / ritonavir (2 tablets, 1 time/12 h) as the triple combination antiviral treatment group. 41 patients were treated with lopinavir / ritonavir (2 tablets, 1 time/12 h) as the dual combination antiviral treatment group. The patients who received triple combination antiviral therapy were divided into three groups: within 48 hours, 3-5 days and > 5 days after the symptom onset. To explore the therapeutic effects of triple combination antiviral drugs and dual combination antiviral drugs, as well as triple combination antiviral drugs with different antiviral initiate time. SPSS17.0 software was used to analyze the data. Results: The time of virus nucleic acid turning negative was (12.2 ± 4.7) days in the triple combination antiviral drug group, which was shorter than that in the dual combination antiviral drug group [(15.0 ± 5.0) days] (t = 6.159, P < 0.01 ). The length of hospital stay [12 (9, 17) d] in the triple combination antiviral drug group was also shorter than that in the dual combination antiviral drug group [15 (10, 18) d] (H = 2.073, P < 0.05). Comparing the antiviral treatment which was started within 48 hours, 3-5 days and > 5 days after the symptom onset of triple combination antiviral drug group, the time from the symptom onset to the negative of viral shedding was 13 (10,16.8), 17 (13,22) and 21 (18-24) days respectively (Z = 32.983, P < 0.01), and the time from antiviral therapy to the negative of viral shedding was (11.8±3.9) , (13.5±5.1) and (11.2±4.3) d. The differences among the three groups were statistically significant (Z=32.983 and 6.722, P<0.01 or<0.05). Conclusions The triple combination antiviral therapy of Abidor, Lopinavir/Litonavir and recombinant interferon α-2b showed shorter viral shedding time and hospitalization time compared with the dual combination antiviral therapy. The earlier the time to initiate triple antiviral treatment, the shorter the time of virus shedding.