Network pharmacology and transcriptomics reveal the mechanisms of FFBZL in the treatment of oral squamous cell carcinoma.

Background: FFBZL is composed of three herbs: Scutellaria barbata D. Don (SBD), Astragali Radix (AR), and Ligusticum chuanxiong Hort (CX). FFBZL has been reported to be effective in the treatment of oral squamous cell carcinoma (OSCC). However, the molecular mechanism involved remains unclear. Based on network pharmacology combined with bioinformatics and molecular docking, the effect and molecular mechanism of action of FFBZL in treating OSCC were explored. Materials and methods: This study employed an integrated approach using various databases and literature sources to identify the effective components of FFBZL, with a specific emphasis on screening active ingredients that align with traditional Chinese medicine principles. The TCMSP, ETCM, and SymMap databases were utilized to collect information on the active constituents and targets of FFBZL, while the PharmMapper database was used to predict targets. Key components were selected based on the degree value of the 'active component-target' network. Transcriptome data for OSCC samples were obtained from the TCGA and GEO databases. Differential gene expression analysis was conducted to identify targets associated with OSCC, and these targets were subsequently aligned with targets of the effective components of FFBZL to identify common targets. Subsequently, the STRING database was utilized to construct a protein‒protein interaction (PPI) network of these common targets, which was subsequently visualized using Cytoscape. Next, 71 targets were rescreened using the PPI network, and GO and KEGG enrichment analyses were performed; the PI3K-Akt signaling pathway was the top-ranking pathway related to cell apoptosis. Next, the expression of 19 genes enriched in the PI3K-Akt signaling pathway was analyzed using OSCC transcriptome data from the TCGA and GEO databases. The targets were subsequently mapped to the PI3K-Akt signaling pathway using the KEGG database, and the GSEA algorithm was used to assess the overall expression trend of the genes in this pathway. The 71 common targets were subsequently imported into the STRING database and visualized using Cytoscape. The DEGREE and MCC algorithms were used to select the corresponding targets within the PPI network. The intersection of these targets and the 19 targets mapped to the PI3K-Akt signaling pathway led to the identification of 6 key targets associated with cell apoptosis: GSK3B, PIK3CA, FN1, MET, SPP1, and MAPK3. Subsequently, the UALCAN database was utilized to analyze the expression levels and survival associations of the key genes related to cell apoptosis, and the transcriptome data from the GEO database were used to assess the correlations among the 6 key genes. Finally, molecular docking studies were conducted to explore the relationships between these targets and the active components with predicted associations. Results: This study identified six key components of FFBZL (quercetin, wogonin, carthamidin, scutellarein, senkyunolide K and astragalosidei: astragaloside I) as well as 820 potential target genes of these components. Intersection of these targets with those related to OSCC yielded 151 common targets. GO and KEGG enrichment analyses revealed that most of the top-ranked functions and pathways were associated with apoptosis, with the PI3K-Akt signaling pathway playing a critical role. Transcriptome analysis of data from the TCGA and GEO databases indicated that the genes enriched in the PI3K-Akt signaling pathway were strongly upregulated, and the GSEA algorithm indicated an overall upregulation trend for the PI3K-Akt signaling pathway. By intersecting the targets with the 19 genes mapped to the PI3K-Akt signaling pathway using the DEGREE and MCC algorithms, six key targets related to cell apoptosis were identified. The mRNA and protein expression levels of most these targets in head and neck squamous cell carcinoma were higher than those in normal tissues. Survival analysis revealed that low expression of SPP1 and FN1 was associated with increased patient survival time. Additionally, the molecular docking results indicated strong binding potential between the six identified key components and the six key targets.

Innovated surgery incision for patients of congenital malformation of the middle and outer ear with infection (CMMOEI).

BACKGROUND: It is the challenging clinical issue of combining debridement of infected lesions and retaining the blood skin flap for auricle reconstruction in patients of Congenital Malformation of the Middle and Outer Ear with Infection (CMMOEI). AIMS/OBJECTIVES: To innovate and introduce an surgery incision to solve the challenging clinical issue of a combined debridement of infection yet retaining a well vascularized skin flap for auricle reconstruction in patients with CMMOEI. MATERIAL AND METHODS: A combined innovated incision of ear sulcus and prefabricated earlobe was used for 23 cases (23 ears) with CMMOEI, The success in the management of the encountered infections, and the short and moderate-term outcome of the innovated incision to preserve a well-vascularized skin flap for subsequent auricle reconstruction were reviewed. The 23 cases include 10 males and 13 females, aged 4-14 years (mean 8.4 years), 7 left ears and 16 right ears. 14 ears stenosis and 9 ears atresia of the outer ear canals. RESULTS: In all 23 cases, the infections were successfully cleared without recurrence or complication with 2-year follow-up. The local skin flap and its blood supply were well preserved for subsequent auricle reconstruction. CONCLUSIONS AND SIGNIFICANCE: The new incision can facilitate clearance of infection in CMOMEI patients, and preserve the retroauricular tissues for subsequent harvesting of a well-vascularized skin flap for subsequent auricle reconstruction.

Pure tone audiometry is a new method for evaluating congenital malformation of the middle and outer ear (CMMOE).

Background: The preoperative evaluation of Congenital Malformation of the Middle and Outer Ear (CMMOE) is very important. Jahrsdoerfer score commonly used at present, based on CT scanning images of the temporal bone, is often unable to accurately evaluate deformity and hearing level.Aims/Objectives: To investigate and promote a straightforward and easily accessible assessment method, pure tone audiometry, for the evaluation of CMMOE.Material and Methods: A total of 223 cases (244 ears) CMMOE with hearing data were retrospectively analyzed. Among them, 180 cases (197 ears) underwent exploratory tympanoplasty with clear conditions: ossicle numbers in 136 cases (147 ears) and morphology in 128 cases (138 ears) and vestibular window development in 137 cases (146 ears), and CT scans of temporal bone in 113 cases (120 ears). 1). The correlation was analyzed between ossicle numbers, ossicle morphology, Jahrsdoerfer score groups and their corresponding Average Air-Conduction Threshold of pure tone (AACT) at 0.5-4 KHz. 2) The AACT difference is compared among the above groups respectively and between the developed and undeveloped groups of vestibular window at 0.5-4 KHz and each frequency of 0.125-8 KHz. Spearman method was used for correlation analysis (calculating coefficient r and p values). For the data followed a normal distribution, a one-way analysis of variance (ANOVA) and t-test were employed, otherwise, Kruskal Wallis multiple local rank coincidence test and Wilcoxon rank sum test were used. p <0 .05 was considered statistically significant.Results: 1) The correlation coefficients between the groups of ossicle number scores, ossicle morphology scores, Jahrsdoerfer scores and their corresponding AACT are r = -0.187 (p <0 .05), r = -0.073 (p >0 .05) and r = -0.079 (p > 0.05), respectively. 2) Comparison of AACT difference based on ossicle number or morphological scores and Jahrsdoerfer scores with p > 0.05 among all groups, respectively. The AACT difference between the developed and undeveloped vestibular window groups is 5.5 (63.5/69.0) dB HL(p < .05) at 0.5-4KHz, out of 0.125-8 KHz frequency 1, 2, 4 KHz were 5.7 (65.0/70.7) dB HL, 8.4 (60.7/69.1) dB HL and 2 (61.5/63.5) dB HL, respectively, all p < 0.05, the other frequencies with all p > 0.05.Conclusions and Significance: 1) Ossicle number was correlated with AACT, but not for ossicle morphology and Jahrsdoerfer scores. 2) There was no significant difference in AACT corresponding to ossicle number or morphology scores and Jahrsdoerfer scores groups, but the patients with undeveloped vestibular window had poorer hearing than those with developed ones. Therefore, the AACT can evaluate the development of ossicle and vestibular window, and more directly reflect the hearing level than Jahrsdoerfer score. Pure tone audiometry is simple, widely used, and easily accessible, which making it a new assessment method of CMMOE.

New strategies and methods for reconstruction of the outer ear canal (OEC).

Background: The incidence of re-stenosis or re-atresia after reconstruction of the Outer Ear Canal (OEC) in patients with Congenital Malformation of the Middle and Outer Ear (CMMOE) is very high (up to 48%), and it has been a difficult problem for otologists not being able to solve.Aims/Objectives: To explore new strategies and methods to improve re-stenosis or re-atresia after reconstruction of the OEC in patients with CMMOE.Material and Methods: According to the characteristics of reconstructed OEC (r-OEC) re-stenosis or re-atresia summarized by us, a number of new prevention strategies and methods have been proposed and related patent products have been designed, including the improvement of covering epithelium types and skin grafting methods (7 types), simulated drum ring function to prevent the formation of negative pressure in the cavity, and strengthen postoperative support to reduce skin shrinkage and bone hyperplasia. The postoperative effects of different ages and preoperative OEC malformations are statistically analyzed.Results: The incidence of re-stenosis/re-atresia is 14.3% (5/35) in the thin sectional skin of the temporal scalp overlap splicing skin grafting, which was significantly better than 45.5% (15/33) in the whole piece mosaic splicing and barrel skin grafting from the inner thin sectional thigh skin and overlay splicing other methods, including the inner thigh thin sectional skin, chest medium thick skin and subcutaneous pedicle + chest medium thick skin (p<0.05). The patent artificial drum ring and the model stent of the OEC have obvious effects. The mean operation age of postoperative atresia, stenosis, and good groups are 9.3, 13.1, and 12.5 years old, respectively. The proportion of preoperative atresia is 91.3%, 85.7%, and 57.7%, respectively. The total incidence of re-atresia and re-stenosis of r-OEC for two groups of atresia and stenosis of OEC before surgery is 40.5% (49/121) and 13.3% (8/60), respectively.Conclusions and Significance: The best result is found in overlapping the splicing thin sectional skin of the temporal scalp, combined with artificial drum ring implantation, effective support of postoperative model stent of OEC and post-pubertal surgery selection are new and effective strategies and methods to prevent re-stenosis or re-atresia of r-OEC. Atresia or stenosis of the OEC before the operation is the influence factor of the postoperative effect.

Precise selection of bone conduction hearing devices for congenital malformation of the middle and outer ear (CMMOE).

Background: No selection criteria for the four bone conduction hearing devices yet.Aims/Objectives: To compare effectiveness of four bone conduction hearing devices in patients with bilateral Congenital Malformation of the Middle and Outer Ear (CMMOE).Material and Methods: 24 Patients (25 ears) were divided into five groups: 1) Bone Anchored Hearing Aid softband (BAHA-s), 2) BAHA implant (BAHA-i nested within group 1), 3) Vibration Sound Bridge implant (VSB-i), 4) Bone Bridge implant (BB-i), and 5) Bone Conduction Hearing Aid softband (BCHA-s). One patient implanted VSB and BB. Auditory parameters were compared: 1. Communication, 2. Average Air Conduction Thresholds (ACT) of pure tone, 3. Sentence Recognition Scores in quiet (SRS-q) and noisy (SRS-n) settings. The one-way analysis of variance (ANOVA) were employed to compare the differences in ACT and SRS-q/n among the groups, a statistical significance level of P < 0.05 was applied.Results: After hearing aid usage, all 24 patients (25 ears) reached or approached the normal in communication (i.e. from difficult to smooth), average ACT and SRS-q/SRS-n (no difference among groups, p > 0 .05). However, there was the difference in the optimal frequency of ACT and the absolute value of SRS-q/SRS-n for VSB/BAHA implants was higher than that for BB and BAHA softband.Conclusions and Significance: The precise selection of the four hearing devices mainly depends on patient's hearing level, the optimal frequency of ACT and absolute values of SRS-q/SRS-n.

Study of hearing features of Congenital Malformation of the Middle and Outer Ear (CMMOE).

Background: There is no study on the hearing features of congenital malformation of middle and outer ears (CMMOE), including classification, grades, and frequency characteristics, which play a decisive role in the selection of precise hearing solutions for patients. Aims/Objectives: To analyze the hearing features of CMMOE and provide guidance for clinical practice.Material and Methods: 298 cases (351 ears) with CMMOE were retrospectively analyzed for the features of 0.5 ∼ 4KHz pure tone hearing, including the classification, grades and frequency characteristics. Results: We observed conductive deafness in 84.3% (296/351), mixed deafness in 15.7% (55/351), and 0% (0/351) sensorineural deafness. Grades measured by average Air Conduction Thresholds (ACT) of pure tone: Mild deafness (26-40dB HL) 0.6% (2/351), moderate deafness (41-55dB HL) 10.3% (36/351), moderate to severe deafness (56-70dB HL) 46.1%(162/351), severe deafness (71-90dB HL) 39.9%(140/351), extremely severe deafness (> 90 dB HL) 3.1%(11/351). The average ACT of 296 ears conductive deafness was 67 ± 10 dB HL, of which 56-80dB HL accounted for 78.1% (274/351). In 55 ears with mixed deafness, 32 ears (32/55 = 58.2%) increased Bone Conduction Threshold (BCT) at a single frequency, and out of 32 ears, 31ears (31/55 = 56.4%) ≤40dB HL, 25(25/32 = 78.1%) ears at 2KHz. In 55 ears with mixed deafness, 87.3% (48/55) increased BCT at 2KHz, and the average BCT was 35 ± 10dB HL. Conclusions and Significance: CMMOE result mainly in conductive deafness, moderate to severe and severe deafness. In mixed deafness, the BCT increased mainly at a single frequency, 2KHz and ≤40dB HL. These data suggest that bone-conductive hearing devices are a good solution for CMMOE hearing impairment.

Metabolomic profiling of Marek's disease virus infection in host cell based on untargeted LC-MS.

Marek's disease (MD) caused by Marek's disease virus (MDV), poses a serious threat to the poultry industry by inducing neurological disease and malignant lymphoma in infected chickens. However, the underlying mechanisms how MDV disrupts host cells and causes damage still remain elusive. Recently, the application of metabolomics has shown great potential for uncovering the complex mechanisms during virus-host interactions. In this study, chicken embryo fibroblasts (CEFs) infected with MDV were subjected to ultrahigh-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UHPLC-QTOF-MS) and multivariate statistical analysis. The results showed that 261 metabolites were significantly altered upon MDV infection, with most changes occurring in amino acid metabolism, energy metabolism, nucleotide metabolism, and lipid metabolism. Notably, MDV infection induces an up-regulation of amino acids in host cells during the early stages of infection to provide the energy and intermediary metabolites necessary for efficient multiplication of its own replication. Taken together, these data not only hold promise in identifying the biochemical molecules utilized by MDV replication in host cells, but also provides a new insight into understanding MDV-host interactions.

[Effects of mouth opening breathing for different reasons on maxillofacial development in children].

Objective:To explore the effects of mouth opening breathing for different reasons on children's maxillofacial development. Methods:One hundred and fifty-one children were selected as the research objects of this experiment. They were divided into 49 cases of adenoid hypertrophy group（group A）, 52 cases of tonsillar hypertrophy group（group B） and 50 cases of adenoid with tonsillar hypertrophy group（Group C）. Healthy children in the same period were selected as the control group, a total of 45 cases. The reflex nasopharyngeal measurement parameters, facial development indexes and cephalometric parameters of group A, group B, group C and control group were analyzed, and the incidence of Angle ClassⅡand Angle Class Ⅲ in group A, group B and group C were studied. Results:Compared with the control group, the reflex nasopharyngeal measurement parameters in group A, group B and group C was significantly different（P<0.05）, and the cephalometric parameters changed with variation in groups（P<0.05）. The incidence of Angle Class Ⅱ facial pattern in group A and group C was higher, but the incidence of Angle Class Ⅲ facial pattern in group B and group C was higher（P<0.05）. Conclusion:Adenoid hypertrophy leads to mandibular retraction; tonsil hypertrophy leads to anterior mandibular arch; adenoid hypertrophy and tonsil hypertrophy are easy to lead to clockwise rotation of the mandible. In clinical practice, to avoid children's uncoordinated maxillofacial development, we should correct the maxillofacial situation of children as soon as possible.

An immune indicator based on BTK and DPEP2 identifies hot and cold tumors and clinical treatment outcomes in lung adenocarcinoma.

In lung adenocarcinoma (LUAD), immune heterogeneity of hot and cold tumors has been recognized as one of the major factors affecting immunotherapy and other common treatments. However, there is still a lack of biomarkers that can effectively identify the immunophenotype of cold and hot tumors. First, the immune signatures were obtained based on literature mining, including macrophage/monocyte, IFN-γ response, TGF-ß response, IL12 response, lymphocyte activation, and ECM/Dve/immune response. Subsequently, LUAD patients were further clustered into different immune phenotypes based on these immune signatures. Next, the key genes related to the immune phenotypes were screened by WGCNA analysis, univariate analysis, and lasso-cox analysis, and the risk signature was established via the key genes. In additional, we compared the clinicopathological characteristics, drug sensitivity, the abundance of immune infiltration, and the efficacy of immunotherapy and commonly used therapies between patients in the high- and low-risk groups in LUAD. LUAD patients were divided into immune hot phenotype and immune cold phenotype groups. The clinical presentation showed that patients with the immune hot phenotype had higher immunoactivity (including higher MHC, CYT, immune, stromal, ESTIMATE scores, higher abundance of immune cell infiltration, higher abundance of TIL, and enrichment of immune-enriched subtypes) and better survival outcomes than those with the immune cold phenotype. Subsequently, WGCNA analysis, univariate analysis, and lasso-cox analysis identified the genes highly associated with the immune phenotype: BTK and DPEP2. The risk signature, consisting of BTK and DPEP2, is highly correlated with the immune phenotype. High-risk scores were enriched in patients with immune cold phenotype and low-risk scores were enriched in patients with immune hot phenotype. Compared to the high-risk group, the low-risk group had better clinical performance, higher drug sensitivity, and a higher degree of immunoactivity, as well as better efficacy in receiving immunotherapy and common adjuvant therapy. This study developed an immune indicator consisting of BTK and DPEP2 based on the heterogeneity of hot and cold Immunophenotypes of the tumor microenvironment. This indicator has good efficacy in predicting prognosis and assessing the efficacy of immunotherapy, chemotherapy, and radiotherapy. It has the potential to facilitate personalized and precise treatment of LUAD in the future.

Long-Term Exposure to Dust and Noise Can Increase the Risk of Hypertension-A Population Based, Cross-sectional Study.

OBJECTIVE: The aim of the study is to assess whether occupational groups exposed to dust and noise increase their risk of developing hypertension and to identify associated risk factors. METHODS: Logistic regression analysis was used to analyze the influence of exposure factors on the occurrence of hypertension, and confounding factors were adjusted to identify independent effects. Stratified analysis and smoothed curve fitting were used to explore the effects in different populations. RESULTS: Combined dust + noise exposure significantly increased the risk of hypertension in workers (model 1: odds ratio [OR], 2.75; model 2: OR, 2.66; model 3: OR, 2.85). Further analysis showed that when exposed to dust and noise for more than 17 years, the risk of hypertension increased by 15%. CONCLUSIONS: The combined exposure of dust and noise significantly increases the risk of hypertension among occupational groups, especially among workers who have worked for more than 17 years.

Analysis of the effectiveness of hearing solutions for congenital malformation of the middle and outer ear (CMMOE).

BACKGROUND: There are no reports about comprehensive comparative analysis of the effects after various hearing surgery solutions for congenital malformation of the middle and outer ear (CMMOE). AIMS/OBJECTIVES: To analyze the improvement of Average Air-Conduction Threshold (AACT) of pure tone after various hearing surgery solutions for CMMOE and provide a reference for the selection of accurate hearing solutions. MATERIALS AND METHODS: A retrospective analysis of 159 cases (170 ears) with CMMOE submitted to various ear surgery solutions, including: (1) Three situations of outer ear canal (OEC): ① atresia 85 ears, ② stenosis 28 ears, and ③ normal 57 ears. (2) Three commonly used hearing solutions: eardrum repair 53 ears, Porp 44 ears and Piston 32 ears implantation. (3) Three OEC situations with different hearing solutions: type I. Reconstruction of OEC (r-OEC), type II. r-OEC and/or different tympanoplasty, including ① eardrum repair, ② release of ossicular chain, ③ Porp implantation, and ④ Torp implantation, type III. Piston implantation with fenestration of the inner ear. Compare AACT of postoperative short term (0.5 years) or long term (0.5-10 years) and preoperative in the speech frequency range of 0.5-4 kHz to assess efficacy. If the sample number ≥10, and not subject to normal distribution, the Kruskal-Wallis multi-sample rank sum test is used for the comparison of multiple groups and Wilcoxon's rank sum test for two groups, with P < 0.05 being statistically significant. If the sample size <10, the standard of clinical efficacy is one frequency improvement value ≥15 dB HL, or 10 dB HL ≤2 frequency improvements <15 dB HL at 0.125-8 KHz. RESULTS: Intra-group comparison of AACT: (1) three situations of OEC: atresia, stenosis and normal all had P < 0.05 postoperatively in short term, while in long term only the normal group had P < 0.05. (2) Three commonly used hearing solutions: eardrum repair, Porp and Piston implantation all had P < 0.05 in short and long terms, except for eardrum repair P >0 .05 in long term. (3) Three OEC situations with different hearing solutions: 1) Atresia of OEC: Porp and Piston implantation, r-OEC and release of ossicular chain were effective in short term and were not effective in long term, and the eardrum repair was not effective in both short and long term. 2) Stenosis of OEC: eardrum repair, Porp and Piston implantation were effective in short and long term. r-OEC P >0 .05 for short and long term, Torp implantation was not effective in long term, 3) Normal of OEC: Porp, Torp and Piston implantation were all P < 0.05 in short and long term except for Torp >0.05 in long term, and release of ossicular chain is both short and long term clinically effective. The AACT values of postoperative in long term for three groups of atresia, stenosis, normal of OEC are over 58.7 dB HL (except Porp implantation 52.5 dB HL), 51.3 dB HL (except Porp implantation 42.5 dB HL), and 37.5 dB HL (except Torp implantation are 32.6 dB HL), respectively. CONCLUSIONS AND SIGNIFICANCE: Intra-group comparison of AACT. (1) Three groups of the atresia, stenosis and normal of OEC are all effective in short term, while in long term only the normal group is effective. (2) The three most commonly used surgical solutions of eardrum repair, Porp and Piston implantation are effective in short and long terms, except for long term eardrum repair. (3) Three OEC situations with different hearing solutions: some of surgical solutions were effective in short term or long term for CMMOE, but based on the AACT values of postoperative in long term for three OEC situations, it is better to choose a hearing device for atresia of OEC, comprehensive review of surgical or hearing device for stenosis of OEC. Surgery can be considered for normal OEC.

Surgical Treatment is Still Recommended for Patients Over 75 Years with IA NSCLC: A Predictive Model Based on Surveillance, Epidemiology and End Results Database.

BACKGROUND: To determine the populations who suitable for surgical treatment in elderly patients (age ≥ 75 y) with IA stage. METHODS: The clinical data of NSCLC patients diagnosed from 2010 to 2015 were collected from the SEER database and divided into surgery group (SG) and no-surgery groups (NSG). The confounders were balanced and differences in survival were compared between groups using PSM (Propensity score matching, PSM). Cox regression analysis was used to screen the independent factors that affect the Cancer-specific survival (CSS). The surgery group was defined as the patients who surgery-benefit and surgery-no benefit according to the median CSS of the no-surgery group, and then randomly divided into training and validation groups. A surgical benefit prediction model was constructed in the training and validation group. Finally, the model is evaluated using a variety of methods. RESULTS: A total of 7297 patients were included. Before PSM (SG: n = 3630; NSG: n = 3665) and after PSM (SG: n = 1725, NSG: n = 1725) confirmed that the CSS of the surgery group was longer than the no-surgery group (before PSM: 82 vs. 31 months, P < .0001; after PSM: 55 vs. 39 months, P < .0001). Independent prognostic factors included age, gender, race, marrital, tumor grade, histology, and surgery. In the surgery cohort after PSM, 1005 patients (58.27%) who survived for more than 39 months were defined as surgery beneficiaries, and the 720 patients (41.73%) were defined surgery-no beneficiaries. The surgery group was divided into training group 1207 (70%) and validation group 518 (30%). Independent prognostic factors were used to construct a prediction model. In training group (AUC = .678) and validation group (AUC = .622). Calibration curve and decision curve prove that the model has better performance. CONCLUSIONS: This predictive model can well identify elderly patients with stage IA NSCLC who would benefit from surgery, thus providing a basis for clinical treatment decisions.

Relationship between lymphocyte to monocyte ratio and brain metastasis in non-smalll cell lung cancer patients.

OBJECTIVE: To observe whether there is an association between the lymphocyte/monocyte ratio (LMR) and the occurrence of brain metastases in non-small cell lung cancer (BM-NSCLC) patients. METHOD: Retrospective collection of patients' information meeting the standards of nano-excretion, was done from January 2016 to September 2021. We calculated the odds ratio (OR) and 95% confidence interval (CI) of LMR versus BM-NSCLC using multivariate logistic regression, and stratified analysis was performed. The linear or nonlinear relationships that exist between the two were explored by generalized additive model and smoothed curve fitting. RESULTS: In all three models, LMR was negatively associated with BM-NSCLC (Model 1: OR, 0.72; 95% CI, 0.57-0.9; P=0.0037. Model 2: OR, 0.64; 95% CI, 0.50-0.82; P=0.0005. Model 3: OR, 0.62; 95% CI, 0.47-0.81; P=0.0005). This negative association was shown to be significant in patients with adenocarcinoma (ADC), who were, female, and in T2-T4 stages, and N1-N3 stages (ADC: OR, 0.59; 95% CI, 0.44-0.80; P=0.0006. female: OR, 0.37; 95% CI, 0.20-0.68; P=0.0013. T2-T4: OR, 0.59; 95% CI, 0.43-0.82; P=0.0014; N1-N3: OR, 0.62; 95% CI, 0.45-0.86; P=0.0042), according to subgroup analysis. CONCLUSION: After controlling for relevant confounders, this study demonstrated that increased LMR levels in NSCLC patients were substantially and inversely connected to their likelihood of BM, particularly in patients with ADC, who were female, or had T2-T4, and N1-N3 stages.

Development and Validation of Machine Learning Models to Predict Epidermal Growth Factor Receptor Mutation in Non-Small Cell Lung Cancer: A Multi-Center Retrospective Radiomics Study.

OBJECTIVE: To develop and validate a generalized prediction model that can classify epidermal growth factor receptor (EGFR) mutation status in non-small cell lung cancer patients. METHODS: A total of 346 patients (296 in the training cohort and 50 in the validation cohort) from four centers were included in this retrospective study. First, 1085 features were extracted using IBEX from the computed tomography images. The features were screened using the intraclass correlation coefficient, hypothesis tests and least absolute shrinkage and selection operator. Logistic regression (LR), decision tree (DT), random forest (RF), and support vector machine (SVM) were used to build a radiomics model for classification. The models were evaluated using the following metrics: area under the curve (AUC), calibration curve (CAL), decision curve analysis (DCA), concordance index (C-index), and Brier score. RESULTS: Sixteen features were selected, and models were built using LR, DT, RF, and SVM. In the training cohort, the AUCs was .723, .842, .995, and .883; In the validation cohort, the AUCs were .658, 0567, .88, and .765. RF model with the best AUC, its CAL, C-index (training cohort=.998; validation cohort=.883), and Brier score (training cohort=.007; validation cohort=0.137) showed a satisfactory predictive accuracy; DCA indicated that the RF model has better clinical application value. CONCLUSION: Machine learning models based on computed tomography images can be used to evaluate EGFR status in patients with non-small cell lung cancer, and the RF model outperformed LR, DT, and SVM.

Relationship Between Neutrophil-To-Lymphocyte Ratio and Brain Metastasis in Non-Small Cell Lung Cancer Patients.

OBJECTIVE: To investigate the relationship between the neutrophil-to-lymphocyte ratio (NLR) of patients with non-small cell lung cancer (NSCLC) and their risk of developing brain metastases after adjusting for confounding factors. METHODS: A retrospective observational study of the general data of patients with NSCLC diagnosed from January 2016 to December 2020. Multivariate logistic regression was used to calculate the dominance ratio (OR) with 95% confidence interval (CI) for NLR and NSCLC brain metastases with subgroup analysis. Generalized summation models and smoothed curve fitting were used to identify whether there was a nonlinear relationship between them. RESULTS: In all 3 models, NLR levels were positively correlated with NSCLC brain metastasis (model 1: OR: 1.12, 95% CI: 1.01-1.23, P = .025; model 2: OR: 1.16, 95% CI: 1.04-1.29, P = .007; model 3: OR: 1.20, 95% CI: 1.05-1.37, P = .006). Stratified analysis showed that this positive correlation was present in patients with adenocarcinoma (LUAD) and female patients (LUAD: OR: 1.30, 95% CI: 1.10-1.54, P = .002; female: OR: 1.52, 95% CI: 1.05-2.20, P = .026), while there was no significant correlation in patients with squamous carcinoma (LUSC) and male patients (LUSC: OR:0.76,95% CI:0.38- 1.53, P = .443; male: OR:1.13, 95% CI:0.95-1.33, P = .159). CONCLUSION: This study showed that elevated levels of NLR were independently associated with an increased risk of developing brain metastases in patients with NSCLC, and that this correlation varied by TYPE and SEX, with a significant correlation in female patients and patients with LUAD.

Protein Tyrosine Phosphatase SHP2 Suppresses Host Innate Immunity against Influenza A Virus by Regulating EGFR-Mediated Signaling.

Influenza A virus (IAV) is a highly contagious pathogen, causing acute respiratory illnesses in human beings and animals and frequently giving rise to epidemic outbreaks. Evasion by IAV of host immunity facilitates viral replication and spread, which can be initiated through various mechanisms, including epidermal growth factor receptor (EGFR) activation. However, how EGFR mediates the suppression of antiviral systems remains unclear. Here, we examined host innate immune responses and their relevant signaling to EGFR upon IAV infection. IAV was found to induce the phosphorylation of EGFR and extracellular signal-regulated kinase (ERK) at an early stage of infection. Inhibition of EGFR or ERK suppressed the viral replication but increased the expression of type I and type III interferons (IFNs) and interferon-stimulated genes (ISGs), supporting the idea that IAV escapes from antiviral innate immunity by activating EGFR/ERK signaling. Meanwhile, IAV infection also induced the activation of Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2). Pharmacological inhibition or small interfering RNA (siRNA)-based silencing of SHP2 enhanced the IFN-dependent antiviral activity and reduced virion production. Furthermore, knockdown of SHP2 attenuated the EGFR-mediated ERK phosphorylation triggered by viral infection or EGF stimulation. Conversely, ectopic expression of constitutively active SHP2 noticeably promoted ERK activation and viral replication, concomitant with diminished immune function. Altogether, the results indicate that SHP2 is crucial for IAV-induced activation of the EGFR/ERK pathway to suppress host antiviral responses.IMPORTANCE Viral immune evasion is the most important strategy whereby viruses evolve for their survival. This work shows that influenza A virus (IAV) suppressed the antiviral innate immunity through downregulation of IFNs and ISGs by activating EGFR/ERK signaling. Meanwhile, IAV also induced the activation of protein tyrosine phosphatase SHP2, which was found to be responsible for modulating the EGFR-mediated ERK activity and subsequent antiviral effectiveness both in vitro and in vivo The results suggest that SHP2 is a key signal transducer between EGFR and ERK and plays a crucial role in suppressing host innate immunity during IAV infection. The finding enhances our understanding of influenza immune evasion and provides a new therapeutic approach to viral infection.

Modulation of Mitochondrial Dynamics in Neurodegenerative Diseases: An Insight Into Prion Diseases.

Mitochondrial dysfunction is a common and prominent feature of prion diseases and other neurodegenerative disorders. Mitochondria are dynamic organelles that constantly fuse with one another and subsequently break apart. Defective or superfluous mitochondria are usually eliminated by a form of autophagy, referred to as mitophagy, to maintain mitochondrial homeostasis. Mitochondrial dynamics are tightly regulated by processes including fusion and fission. Dysfunction of mitochondrial dynamics can lead to the accumulation of abnormal mitochondria and contribute to cellular damage. Neurons are among the cell types that consume the most energy, have a highly complex morphology, and are particularly dependent on mitochondrial functions and dynamics. In this review article, we summarize the molecular mechanisms underlying the mitochondrial dynamics and the regulation of mitophagy and discuss the dysfunction of these processes in the progression of prion diseases and other neurodegenerative disorders. We have also provided an overview of mitochondrial dynamics as a therapeutic target for neurodegenerative diseases.