BACKGROUND: Oral squamous cell carcinoma (OSCC) is a prevalent type of cancer with a high mortality rate in its late stages. One of the major challenges in OSCC treatment is the resistance to epidermal growth factor receptor (EGFR) inhibitors. Therefore, it is imperative to elucidate the mechanism underlying drug resistance and develop appropriate precision therapy strategies to enhance clinical efficacy. METHODS: To evaluate the efficacy of the combination of the Ca 2+ /calmodulin-dependent protein kinase II (CAMK2) inhibitor KN93 and EGFR inhibitors, we performed in vitro and in vivo experiments using two FAT atypical cadherin 1 ( FAT1 )-deficient (SCC9 and SCC25) and two FAT1 wild-type (SCC47 and HN12) OSCC cell lines. We assessed the effects of EGFR inhibitors (afatinib or cetuximab), KN93, or their combination on the malignant phenotype of OSCC in vivo and in vitro . The alterations in protein expression levels of members of the EGFR signaling pathway and SRY-box transcription factor 2 (SOX2) were analyzed. Changes in the yes-associated protein 1 (YAP1) protein were characterized. Moreover, we analyzed mitochondrial dysfunction. Besides, the effects of combination therapy on mitochondrial dynamics were also evaluated. RESULTS: OSCC with FAT1 mutations exhibited resistance to EGFR inhibitors treatment. The combination of KN93 and EGFR inhibitors significantly inhibited the proliferation, survival, and migration of FAT1 -mutated OSCC cells and suppressed tumor growth in vivo . Mechanistically, combination therapy enhanced the therapeutic sensitivity of FAT1 -mutated OSCC cells to EGFR inhibitors by modulating the EGFR pathway and downregulated tumor stemness-related proteins. Furthermore, combination therapy induced reactive oxygen species (ROS)-mediated mitochondrial dysfunction and disrupted mitochondrial dynamics, ultimately resulting in tumor suppression. CONCLUSION Combination therapy with EGFR inhibitors and KN93 could be a novel precision therapeutic strategy and a potential clinical solution for EGFR-resistant OSCC patients with FAT1 mutations.
Humans ; ErbB Receptors/metabolism* ; Mouth Neoplasms/metabolism* ; Cell Line, Tumor ; Animals ; Drug Resistance, Neoplasm/genetics* ; Cadherins/metabolism* ; Carcinoma, Squamous Cell/metabolism* ; Mice ; Mutation/genetics* ; Mice, Nude ; Protein Kinase Inhibitors/therapeutic use* ; Cetuximab/pharmacology* ; Afatinib/therapeutic use* ; Cell Proliferation/drug effects* ; Signal Transduction/drug effects*

Acute liver failure (ALF) is a life-threatening condition associated with macrophage-mediated inflammatory responses. Effective therapies and drugs are still lacking to date. Here, we reveal that a derivative of xanthohumol, CAM12203, alleviates lipopolysaccharide (LPS) + d-galactosamine (D-GalN)-induced ALF through limiting macrophage-mediated inflammation, with the most significant impact on interleukin-1β (IL-1β) transcription. Through biotin labeling-mediated pull-down and LC-MS/MS analysis, diacylglycerol kinase ζ (DGKζ), a lipid-metabolizing kinase, is identified as the direct target of CAM12203. Mechanistically, DGKζ is induced in macrophages upon inflammatory stimuli and is upregulated observed on clinical liver failure samples. Its product phosphatidic acid (PA) boosts phospholipase C (PLC)-inositol 1,4,5-trisphosphate (IP₃)-Ca²⁺ signaling and subsequent janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) cascade, ultimately promoting IL-1β production and liver failure. DGKζ knockdown/ablation or inhibition significantly impairs the DGKζ-STAT3-IL-1β pathway along with ALF progression. Finally, CAM12203 is confirmed to be a new DGKζ inhibitor and acts against inflammation in a DGKζ-reliant manner. Taken together, CAM12203 inhibits IL-1β transcription in macrophages by binding to DGKζ and blocking the DGKζ-STAT3 axis, thereby exerting an ameliorative effect on ALF. These results not only highlight CAM12203 as a promising lead compound for ALF treatment, but also define DGKζ as a novel therapeutic target.

T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive hematologic malignancy with a poor prognosis, despite advancements in treatment. Many patients struggle with relapse or refractory disease. Investigating the role of the super-enhancer (SE) regulated gene ubiquitin-specific protease 20 (USP20) in T-ALL could enhance targeted therapies and improve clinical outcomes. Analysis of histone H3 lysine 27 acetylation (H3K27ac) chromatin immunoprecipitation sequencing (ChIP-seq) data from six T-ALL cell lines and seven pediatric samples identified USP20 as an SE-regulated driver gene. Utilizing the Cancer Cell Line Encyclopedia (CCLE) and BloodSpot databases, it was found that USP20 is specifically highly expressed in T-ALL. Knocking down USP20 with short hairpin RNA (shRNA) increased apoptosis and inhibited proliferation in T-ALL cells. In vivo studies showed that USP20 knockdown reduced tumor growth and improved survival. The USP20 inhibitor GSK2643943A demonstrated similar anti-tumor effects. Mass spectrometry, RNA-Seq, and immunoprecipitation revealed that USP20 interacted with hypoxia-inducible factor 1 subunit alpha (HIF1A) and stabilized it by deubiquitination. Cleavage under targets and tagmentation (CUT&Tag) results indicated that USP20 co-localized with HIF1A, jointly modulating target genes in T-ALL. This study identifies USP20 as a therapeutic target in T-ALL and suggests GSK2643943A as a potential treatment strategy.

OBJECTIVES: To develop an E-selectin-targeting nanomedicine delivery system that competitively inhibits E-selectin-neutrophil ligand binding to block neutrophil adhesion to vessels and suppress their recruitment to the lesion sites. METHODS: Doxorubicin hydrochloride (DOX)-loaded liposomes (IEL-Lip/DOX) conjugated with E-selectin-affinity peptide IELLQARC were developed using a post-insertion method. Two formulations [2-1P: Mol(PC): Mol(DPI)=100:1; 2-3P: 100:3] were prepared and their modification density and in vitro release characteristics were determined. Their targeting efficacy was assessed in a cell model of LPS-induced inflammation, a mouse model of acute lung injury (ALI), a rat femoral artery model of physical injury-induced inflammation, and a zebrafish model of local inflammation. RESULTS: The prepared IEL-Lip/DOX 2-1P and 2-3P had peptide modification densities of 4.76 and 7.57 pmoL/cm², respectively. Compared with unmodified liposomes, IEL-Lip/DOX exhibited significantly reduced 48-h cumulative release rates at pH 5.5. In the inflammation cell model, IEL-Lip/DOX showed increased uptake by activated inflammatory endothelial cells, and 2-1P exhibited a higher trans-endothelial ability. In ALI mice, the fluorescence intensity of IEL-Lip/Cy5.5 increased significantly in lung tissues by 53.71% [Z-(2-1P)] and 93.41% [Z-(2-3P)], and 2-1P had an increased distribution by 24.19% in the inflammatory lung tissue compared to normal mouse lung tissue. In rat femoral artery models, 2-1P had greater injured/normal vessel fluorescence intensity contrast. In the zebrafish models, both 2-1P and 2-3P showed increased aggregation at the site of inflammation. CONCLUSIONS This E-selectin-targeting nanomedicine delivery system efficiently targets activated inflammatory endothelial cells to increase drug concentration at the inflammatory site, which sheds light on new strategies for treating neutrophil-mediated inflammatory diseases and practicing the concept of "one drug for multiple diseases".
Animals ; Liposomes ; Rats ; Nanomedicine ; E-Selectin ; Drug Delivery Systems ; Inflammation/drug therapy* ; Mice ; Doxorubicin/analogs & derivatives* ; Zebrafish ; Acute Lung Injury/drug therapy*

Comfortable supragingival scaling uses ultrasonic cleaning with sedation and minimally invasive techniques to minimize the negative emotions of patients and improve patient compliance. At present, there is still much room for optimization of the environment, equipment, and operation steps for the development of comfortable supragingival scaling. On this basis, the Department of Periodontology, College of Stomatology, Xi'an Jiaotong University proposed a 16-step new model of comfortable supragingival scaling. The new model incorporates adjustments to the previous model concerning the environment, equipment, operational procedures, process links and services, comprising 16 steps for optimization and innovation. Clinical practice has confirmed that the 16-step new model of comfortable supra-gingival scaling can significantly improve patient satisfaction and adherence to medical treatment, and it has good promotional value.
Humans ; Dental Scaling/instrumentation* ; Patient Satisfaction ; Patient Compliance ; Gingiva

Bone formation and deposition are initiated by sensory nerve infiltration in adaptive bone remodeling. Here, we focused on the role of Semaphorin 3A (Sema3A), expressed by sensory nerves, in mechanical loads-induced bone formation and nerve withdrawal using orthodontic tooth movement (OTM) model. Firstly, bone formation was activated after the 3rd day of OTM, coinciding with a decrease in sensory nerves and an increase in pain threshold. Sema3A, rather than nerve growth factor (NGF), highly expressed in both trigeminal ganglion and the axons of periodontal ligament following the 3rd day of OTM. Moreover, in vitro mechanical loads upregulated Sema3A in neurons instead of in human periodontal ligament cells (hPDLCs) within 24 hours. Furthermore, exogenous Sema3A restored the suppressed alveolar bone formation and the osteogenic differentiation of hPDLCs induced by mechanical overload. Mechanistically, Sema3A prevented overstretching of F-actin induced by mechanical overload through ROCK2 pathway, maintaining mitochondrial dynamics as mitochondrial fusion. Therefore, Sema3A exhibits dual therapeutic effects in mechanical loads-induced bone formation, both as a pain-sensitive analgesic and a positive regulator for bone formation.
Humans ; Bone Remodeling ; Cell Differentiation ; Osteogenesis ; Semaphorin-3A/pharmacology* ; Trigeminal Ganglion/metabolism*

Bone formation and deposition are initiated by sensory nerve infiltration in adaptive bone remodeling.Here,we focused on the role of Semaphorin 3A(Sema3A),expressed by sensory nerves,in mechanical loads-induced bone formation and nerve withdrawal using orthodontic tooth movement(OTM)model.Firstly,bone formation was activated after the 3rd day of OTM,coinciding with a decrease in sensory nerves and an increase in pain threshold.Sema3A,rather than nerve growth factor(NGF),highly expressed in both trigeminal ganglion and the axons of periodontal ligament following the 3rd day of OTM.Moreover,in vitro mechanical loads upregulated Sema3A in neurons instead of in human periodontal ligament cells(hPDLCs)within 24 hours.Furthermore,exogenous Sema3A restored the suppressed alveolar bone formation and the osteogenic differentiation of hPDLCs induced by mechanical overload.Mechanistically,Sema3A prevented overstretching of F-actin induced by mechanical overload through ROCK2 pathway,maintaining mitochondrial dynamics as mitochondrial fusion.Therefore,Sema3A exhibits dual therapeutic effects in mechanical loads-induced bone formation,both as a pain-sensitive analgesic and a positive regulator for bone formation.

Bone formation and deposition are initiated by sensory nerve infiltration in adaptive bone remodeling.Here,we focused on the role of Semaphorin 3A(Sema3A),expressed by sensory nerves,in mechanical loads-induced bone formation and nerve withdrawal using orthodontic tooth movement(OTM)model.Firstly,bone formation was activated after the 3rd day of OTM,coinciding with a decrease in sensory nerves and an increase in pain threshold.Sema3A,rather than nerve growth factor(NGF),highly expressed in both trigeminal ganglion and the axons of periodontal ligament following the 3rd day of OTM.Moreover,in vitro mechanical loads upregulated Sema3A in neurons instead of in human periodontal ligament cells(hPDLCs)within 24 hours.Furthermore,exogenous Sema3A restored the suppressed alveolar bone formation and the osteogenic differentiation of hPDLCs induced by mechanical overload.Mechanistically,Sema3A prevented overstretching of F-actin induced by mechanical overload through ROCK2 pathway,maintaining mitochondrial dynamics as mitochondrial fusion.Therefore,Sema3A exhibits dual therapeutic effects in mechanical loads-induced bone formation,both as a pain-sensitive analgesic and a positive regulator for bone formation.

Objective To investigate the safety of regular plasma donors aged 55 to 60,so as to provide reference for retention and recruitment of elderly plasma donors in China.Methods Plasma donors from 9 blood products manufacturing enterprises from 2018 to 2020 and the local general population were selected as the research objects.The total protein level,albumin and globulin ratio(ALB/GLB,A/G)and adverse reactions of plasma donation of regular plasma donors and local general population were retrospectively analyzed.Results The total protein level(g/L)and A/G of plasma donors aged 56 to 60 and the general population were 61.21±5.62 vs 60.04±6.93 and 1.610±0.299 vs 1.635±0.330,respectively,and the differences were statistically significant.The total protein level of regular plasma donors was higher than that of general popu-lation,but A/G was slightly lower than that of general population.From 2018 to 2020,there were a total of 23 056 302 plas-ma donations in 108 plasma stations,and adverse reactions occurred in 20 932 donations,with a total incidence of 0.09%,with no serious adverse reactions.Conclusion It is safe for regular plasma donors aged 55 to 60 to donate plasma,and the retention of them can alleviate the pressure of plasma supply.

[Abstract] [Objective] To establish a new centrifugal-membrane hybrid plasmapheresis (CMHP) model, and observe its clinical efficacy, safety and advantages in the treatment of hyperlipidemia by comparing with centrifugation therapeutic plasma exchange (cTPE). [Methods] A retrospective analysis was performed on 47 patients with hyperlipidemia treated in our department from August 2021 to September 2023, with a total of 60 treatments. They were divided into two groups: CMHP group with 37 patients and 46 treatments; cTPE group included 10 patients with 14 treatments. In the CMHP group, the plasma was separated by a blood cell separator and the plasma components were separated by a two-stage membrane plasma component separator. In the cTPE group, the plasma was separated by a blood cell separator for therapeutic plasma exchange. The clinical efficacy, safety and advantages of the two groups were compared. [Results] The reduction ratios of total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C) before and after treatment in CMHP group were 68.56%[59.81%, 73.42%], 65.80%[55.55%, 75.98%] and 46.57%[36.02%, 54.83%] and 66.67%[43.48%, 76.24%] respectively, with statistically significant difference (P<0.001). The decrease ratios of TC, TG and HDL-C before and after treatment in cTPE group were 42.52%[29.67%, 49.85%], 52.32%[38.43%, 67.07%] and 22.36%[8.51%, 33.65%], respectively, and the difference was statistically significant (P<0.05). The plasma treatment multiple was 1.48 (0.29) in CMHP group, which was significantly higher than 0.87 (0.26) in cTPE group, with a statistically significant difference (P<0.001), resulting in higher TC and HDL-C reduction ratios in CMHP group than in cTPE group, with a statistically significant difference (P<0.001), while there was no significant difference in TG reduction rate between the two groups (P>0.05). At the same time, the cTPE group required 1 520.00 mL[1 462.50 mL, 2 000.00 mL] plasma input, while the CMHP group achieved zero blood input. The adverse reaction ratio was 6.52%(3/46) in CMHP group and 7.14%(1/14) in cTPE group, and the difference was not statistically significant (P>0.05). [Conclusion] Compared with cTPE, CMHP can better reduce blood lipid levels without any blood products, avoid the spread of blood infectious diseases, and have a low incidence of adverse reactions, so it has a good clinical application prospect.