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*

Psoriasis is an incurable chronic inflammatory disease that requires new interventions. Here, we found that fibroblasts exacerbate psoriasis progression by promoting macrophage recruitment via CCL2 secretion by single-cell multi-omics analysis. The natural small molecule celastrol was screened to interfere with the secretion of CCL2 by fibroblasts and improve the psoriasis-like symptoms in both murine and cynomolgus monkey models. Mechanistically, celastrol directly bound to the low-density lipoprotein receptor-related protein 1 (LRP1) β-chain and abolished its binding to the transcription factor c-Jun in the nucleus, which in turn inhibited CCL2 production by skin fibroblasts, blocked fibroblast-macrophage crosstalk, and ameliorated psoriasis progression. Notably, fibroblast-specific LRP1 knockout mice exhibited a significant reduction in psoriasis like inflammation. Taken together, from clinical samples and combined with various mouse models, we revealed the pathogenesis of psoriasis from the perspective of fibroblast-macrophage crosstalk, and provided a foundation for LRP1 as a novel potential target for psoriasis treatment.

Insufficient alveolar bone thickness increases the risk of periodontal dehiscence and fenestration, especially in orthodontic tooth movement. Abaloparatide (ABL), a synthetic analog of human PTHrP (1-34) and a clinical medication for treating osteoporosis, has recently demonstrated its potential in enhancing craniofacial bone formation. Herein, we show that intraoral submucosal injection of ABL, when combined with mechanical force, promotes in situ alveolar bone thickening. The newly formed bone is primarily located outside the original compact bone, implying its origin from the periosteum. RNA sequencing of the alveolar bone tissue revealed that the focal adhesion (FA) pathway potentially mediates this bioprocess. Local injection of ABL alone enhances cell proliferation, collagen synthesis, and phosphorylation of focal adhesion kinase (FAK) in the alveolar periosteum; when ABL is combined with mechanical force, the FAK expression is upregulated, in line with the accomplishment of the ossification. In vitro, ABL enhances proliferation, migration, and FAK phosphorylation in periosteal stem cells. Furthermore, the pro-osteogenic effects of ABL on alveolar bone are entirely blocked when FAK activity is inhibited by a specific inhibitor. In summary, abaloparatide combined with mechanical force promotes alveolar bone formation via FAK-mediated periosteal osteogenesis. Thus, we have introduced a promising therapeutic approach for drug-induced in situ alveolar bone augmentation, which may prevent or repair the detrimental periodontal dehiscence, holding significant potential in dentistry.
Osteogenesis/drug effects* ; Periosteum/cytology* ; Parathyroid Hormone-Related Protein/administration & dosage* ; Animals ; Focal Adhesion Protein-Tyrosine Kinases/metabolism* ; Alveolar Process/drug effects* ; Cell Proliferation/drug effects* ; Phosphorylation ; Rats ; Male ; Humans ; Focal Adhesion Kinase 1/metabolism* ; Cell Movement/drug effects*

Objective:To understand the epidemiological characteristics and spatiotemporal distribution of viral encephalitis in children and adolescents in Henan Province from 2012 to 2023.Methods:The information about viral encephalitis cases from October 1, 2012 to July 26, 2023 were collected from Zhengzhou Children's Hospital (National Children's Regional Medical Center),Henan Provincial Children's Hospital for the analyses on temporal distribution the cases, the severe illness rate, age distribution, pathogen type and imaging findings of the cases.Results:A total of 6 276 cases of viral encephalitis were included in this study after excluding cases with incomplete information. The cases mainly originated from Zhengzhou (38.96%), followed by Zhoukou (9.93%), Xuchang (8.68%), Zhumadian (7.90%) and Pingdingshan (7.39%). The cases in boys accounted for 62.13% and the cases in girls accounted for 37.87%. Most cases (72.45%) occurred in age group 7-13 years. The overall rate of severe illness cases was 4.51% from 2012 to 2023. There were significant differences in severe illness cases among different areas and years ( χ2=5.33, P=0.021; χ2=48.14, P<0.001). Enteroviruses were mainly detected (31.57%), in which Coxsackie virus was predominant (58.37%). Imaging findings showed that cerebral hemisphere damage was most common in children and adolescents with viral encephalitis (54.93%). Conclusions:From 2012 to 2023, more cases of viral encephalitis occurred in boys in Henan. Children and adolescents aged 7-13 years were the main affected group. The prevention of enteroviruses infection, especially Coxsackie virus, needs to be strengthened. Special attention should be paid to the prevention of cerebral hemisphere damage after viral encephalitis diagnosis.

ObjectiveTo investigate the effect of multi-target transcranial direct current stimulation (tDCS) and single-target tDCS on the performance of working memory-postural control dual-task in healthy adults, and to compare the regulatory effect of the two stimulation protocols. MethodsFrom November, 2020 to February, 2021, 19 healthy adults in Shanghai University of Sport were recruited and randomly accepted multi-target tDCS, single-target tDCS and sham stimulation with at least one week interval between any two stimulation protocols. The target areas of multi-target tDCS included left dorsal lateral prefrontal cortex (L-DLPFC) and bilateral primary motor cortex (M1), and single-tDCS only applied to L-DLPFC. Before and after stimulation, participants completed walking and standing balance tests under single task and dual-task conditions with the second task being a N-back task. The dual-task postural control performance, dual-task cost (DTC) and working memory performance were observed before and after stimulation. ResultsSignificant differences were observed among three stimulation protocols in the changes of stride variability (F = 3.792, P = 0.029), DTC of stride variability (F = 3.412, P = 0.040) and velocity of center of pressure (Vcop) (F = 3.815, P = 0.029). The stride variability (P = 0.047) and Vcop (P = 0.015) were significantly lower and the decrease in DTC of stride variability tended to be significant (P = 0.073) following multi-target tDCS, as compared to sham stimulation. Single-target tDCS significantly decreased the changes of stride variability (P = 0.011), DTC of stride variability (P = 0.014) and Vcop (P = 0.025), as compared to sham stimulation. Compared with single target tDCS, multi-target tDCS reduced the changes of the dual-task cost of the area of center of pressure (P = 0.035). Moreover, no significant difference was observed among the three stimulation protocols in the changes of each measure in the working memory test (P > 0.05). ConclusionBoth multi-target tDCS and single-target tDCS can improve the performance of working memory-postural control dual-task in healthy adults, and compared with single-target tDCS, multi-target tDCS has some advantages in regulating postural control.

In recent years, the incidence of obesity has been rapidly increasing, greatly elevating the incidence of hypertension, heart disease, non-alcoholic fatty liver disease, and other diseases. Reducing the incidence of obesity has become the focus of global concern. There is an urgent need to find effective and safe treatment method. More and more evidence support the efficacy of auricular acupoint therapy for obesity. It has the advantages of safety, effectiveness, convenience, and cheap. This article intends to discuss the research status of auricular acupoint therapy for obesity based on theoretical development, mechanism exploration, and technical innovation in order to promote the clinical application of auricular acupoint therapy for obesity. At present, with the help of multiple disciplines, inheriting and enriching the theoretical connotation of auricular point therapy for obesity, confirming its clinical effectiveness and safety, clarifying its effect mechanism in the treatment of obesity, and improving the traditional auricular acupoint therapy are feasible directions to promote auricular point therapy in the treatment of obesity, and it can make auricular point therapy have a broader application prospect.

Major depressive disorder (MDD) has become an increasingly serious public health issue, characterized by high incidence and high disability rates. It often coexists with other mental health problems and physical diseases, with a significant negative impact on patients' quality of life. In clinical practice, MDD is considered a heterogeneous disease. The complexity of the pathological mechanisms and the variability in treatment responses lead to a lack of clear therapeutic targets, which complicates the treatment process. In recent years, with advancements in neuroscience, the crucial role of microglia in the pathogenesis of MDD has been revealed. As the main immune cells in the brain, microglia are not only involved in the regulation of neuroinflammation but also play important roles in neurogenesis and neuronal regulation in MDD. This article mainly discusses the role of microglia in the pathophysiological mechanisms of MDD, aiming to provide a theoretical basis for microglia as a potential target for the treatment of MDD.

【Objective】 To explore the diagnostic value of platelet long non-coding RNA (lncRNA) as a biomarker for early screening of lung adenocarcinoma (LUAD). 【Methods】 The GSE183635 and GSE89843 datasets, which contained the platelet transcriptome of LUAD and healthy controls, were used for differential analysis, and the intersection of the differentially expressed lncRNA(DElncRNA) of the two datasets was taken. The expression levels of DElncRNA in LUAD tissues and normal control tissues were analyzed using GEPIA2. The expression levels of LINC01088 in platelets of 51 healthy controls and 54 LUAD patients were detected by quantitative Real-time PCR (qRT-PCR), and the diagnostic ability of each index was evaluated by ROC curve. 【Results】 8 DElncRNAs and 1 265 DElncRNAs were obtained from GSE183635 and GSE89843 datasets, respectively. The key DElncRNA LINC01088 was selected after intersection. GEPIA2 analysis showed that the expression level of LINC01088 in LUAD tissues was lower than that in normal lung tissues (P<0.05). Platelet LINC01088 was significantly downregulated in patients with LUAD and early-stage LUAD than in healthy controls(P<0.001). The area under the curve (AUC) of platelet LINC01088 in the diagnosis of LUAD was 0.755, the sensitivity was 81.1%, and the specificity was 67.9%. The AUC for early LUAD diagnosis was 0.727, the sensitivity was 80.0%, and the specificity was 67.9%. The AUC of the combined diagnostic model composed of platelet LINC01088 and carcinoembryonic antigen (CEA) for LUAD diagnosis was 0.807, the sensitivity was 89.2%, and the specificity was 71.4%. The AUC for early LUAD was 0.770, the sensitivity was 86.7%, and the specificity was 71.4%. The combined diagnostic model of platelet LINC01088 and CEA was superior to CEA in the diagnosis of LUAD and early LUAD (Z=-2.288, -2.34, both P<0.05). 【Conclusion】 LINC01088 is down-regulated in platelets of LUAD patients. Platelet LINC01088 may be a biomarker for early screening and diagnosis of LUAD.

At present,pharmaceutical services for Alzheimer's disease (AD) patients are mostly based on the western medication therapy management (MTM) model,which includes conducting drug treatment evaluations for patients,identifying drug treatment issues,proposing drug treatment recommendations,restructuring drug treatment checklists,follow-up visiting and recording,etc.However,in recent years,more and more domestic clinical practices have proven that individualized treatment with dialectical treatment of traditional Chinese medicine can effectively prevent and delay the occurrence and development of AD,while the MTM pharmaceutical service model has some limitations when facing such AD patients.Therefore,it is necessary to explore a new pharmaceutical service model with Chinese medicine characteristics for AD MTM,so as to provide pharmaceutical services for patients receiving individualized treatment of AD through the combination of traditional Chinese and Western medicine.Combining the traditional Chinese medicine sequential therapy of AD with the MTM concept,MTM was conducted on a typical outpatient AD patient,which effectively solved the medication related problems of the patient and ensured the medication safety and efficacy.

Objective To compare image quality of 3.0T and 5.0T MR cholangiopancreatography(MRCP).Methods Eighteen patients with bile duct dilation(bile duct dilation group)and 7 healthy volunteers(healthy group)were prospectively enrolled.MRCP was performed with 3.0T and 5.0T scanners,respectively,and the ability for displaying details of bile duct tree,signal-to-noise ratio(SNR)and image artifacts were compared between 3.0T and 5.0T MRCP.Results In bile duct dilation group,the number of branches,total branch length and the maximum branch length of bile duct tree on 5.0T MRCP were all greater than those on 3.0T MRCP(all P＜0.05).In healthy group,the number of branches and total branch length of bile duct tree on 5.0T MRCP were both greater than those on 3.0T MRCP(both P＜0.05).In both groups,the SNR of 5.0T MRCP was greater than that of 3.0T MRCP,but the difference was not significant(both P＞0.05).No significant difference of image artifacts was found between 3.0T and 5.0T MRCP(P=0.054).Conclusion 5.0T MRCP might display better anatomical details of bile duct tree than 3.0T MRCP,with SNR and image artifacts comparable to 3.0T MRCP.