Atorvastatin, etanercept and the nephrogenic cardiac sympathetic remodeling in chronic renal failure rats.

BACKGROUND: Chronic renal failure (CRF) patients are predisposed to arrhythmias, while the detailed mechanisms are unclear. We hypothesized the chronic inflammatory state of CRF patients may lead to cardiac sympathetic remodeling, increasing the incidence of ventricular arrhythmia (VA) and sudden cardiac death. And explored the role of atorvastatin and etanercept in this process. METHODS: A total of 48 rats were randomly divided into sham operation group (Sham group), CRF group, CRF + atorvastatin group (CRF + statin group), and CRF + etanercept group (CRF + rhTNFR-Fc group). Sympathetic nerve remodeling was assessed by immunofluorescence of growth-associated protein 43 (GAP-43) and tyrosine hydroxylase positive area fraction. Electrophysiological testing was performed to assess the incidence of VA by assessing the ventricular effective refractory period and ventricular fibrillation threshold. The levels of tumor necrosis factor-alpha (TNF-α) and interleukin-1beta were determined by Western blotting and enzyme-linked immunosorbent assay. RESULTS: Echocardiogram showed that compared with the Sham group, left ventricular end-systolic diameter and ventricular weight/body weight ratio were significantly higher in the CRF group. Hematoxylin-eosin and Masson staining indicated that myocardial fibers were broken, disordered, and fibrotic in the CRF group. Western blotting, enzyme-linked immunosorbent assay, immunofluorescence and electrophysiological examination suggested that compared with the Sham group, GAP-43 and TNF-α proteins were significantly upregulated, GAP-43 and tyrosine hydroxylase positive nerve fiber area was increased, and ventricular fibrillation threshold was significantly decreased in the CRF group. The above effects were inhibited in the CRF + statin group and the CRF + rhTNFR-Fc group. CONCLUSIONS: In CRF rats, TNF-α was upregulated, cardiac sympathetic remodeling was more severe, and the nephrogenic cardiac sympathetic remodeling existed. Atorvastatin and etanercept could downregulate the expression of TNF-α or inhibit its activity, thus inhibited the above effects, and reduced the occurrence of VA and sudden cardiac death.

Lipid droplets-related Perilipin-3: potential immune checkpoint and oncogene in oral squamous cell carcinoma.

BACKGROUND: Lipid droplets (LDs) as major lipid storage organelles are recently reported to be innate immune hubs. Perilipin-3 (PLIN3) is indispensable for the formation and accumulation of LDs. Since cancer patients show dysregulated lipid metabolism, we aimed to elaborate the role of LDs-related PLIN3 in oral squamous cell carcinoma (OSCC). METHODS: PLIN3 expression patterns (n = 87), its immune-related landscape (n = 74) and association with B7-H2 (n = 51) were assessed by immunohistochemistry and flow cytometry. Real-time PCR, Western blot, Oil Red O assay, immunofluorescence, migration assay, spheroid-forming assay and flow cytometry were performed for function analysis. RESULTS: Spotted LDs-like PLIN3 staining was dominantly enriched in tumor cells than other cell types. PLIN3high tumor showed high proliferation index with metastasis potential, accompanied with less CD3+CD8+ T cells in peripheral blood and in situ tissue, conferring immunosuppressive microenvironment and shorter postoperative survival. Consistently, PLIN3 knockdown in tumor cells not only reduced LD deposits and tumor migration, but benefited for CD8+ T cells activation in co-culture system with decreased B7-H2. An OSCC subpopulation harbored PLIN3highB7-H2high tumor showed more T cells exhaustion, rendering higher risk of cancer-related death (95% CI 1.285-6.851). CONCLUSIONS: LDs marker PLIN3 may be a novel immunotherapeutic target in OSCC.

IL-36 antagonism blunts the proliferation and migration of oral squamous cell carcinoma cells.

IL-36 is known to mediate inflammation and fibrosis. Nevertheless, IL-36 signalling axis has also been implicated in cancer, although understanding of exact contribution of IL-36 to cancer progression is very limited, partly due to existence of multiple IL-36 ligands with agonistic and antagonistic function. Here we explored the role of IL-36 in oral squamous cell carcinoma (OSCC). Firstly, we analyzed expression of IL-36 ligands and receptor and found that the expression of IL-36γ was significantly higher in head and neck cancer (HNSCC) than that of normal tissues, and that the high expression of IL-36γ predicted poor clinical outcomes. Secondly, we investigated the direct effect of IL-36γ on OSCC cells and found that IL-36γ stimulated proliferation of OSCC cells with high expression of IL-36R expression. Interestingly, IL-36γ also promoted migration of OSCC cells with low to high IL-36R expression. Critically, both proliferation and migration of OSCC cells induced by IL-36γ were abrogated by anti-IL-36R mAb. Fittingly, RNA sequence analysis revealed that IL-36γ regulated genes involved in cell cycle and cell division. In summary, our results showed that IL-36γ can be a tumor-promoting factor, and targeting of IL-36R signalling may be a beneficial targeted therapy for patients with abnormal IL-36 signalling.

Biotransformation of antioxidant eriocitrin into characteristic metabolites by the gut microbiota.

Eriocitrin is a flavonoid glycoside with strong antioxidant capacity that has a variety of pharmacological activities, such as hypolipidemic, anticancer and anti-inflammatory effects. We found that the gut microbiota could rapidly metabolize eriocitrin. By using LC/MSn-IT-TOF, we identified three metabolites of eriocitrin metabolized in the intestinal microbiota: eriodictyol-7-O-glucoside, eriodictyol, and dihydrocaffeic acid. By comparing these two metabolic pathways of eriocitrin (the gut microbiota and liver microsomes), the intestinal microbiota may be the primary metabolic site of eriocitrin metabolism. These findings provide a theoretical foundation for the study of pharmacologically active substances.

Repurposing fluphenazine as an autophagy modulator for treating liver cancer.

Hepatocellular carcinoma (HCC) is a common malignant tumor of the digestive system with a low early diagnosis rate. Owing to the side effects, tolerance, and patient contraindications of existing therapies, effective drug treatments for HCC remain a major clinical challenge. However, using approved or investigational drugs not initially intended for cancer therapy is a promising strategy for resolving this problem because their safety have been tested in clinic. Therefore, this study evaluated differentially expressed genes between liver cancer and normal tissues in a cohort of patients with HCC from The Cancer Genome Atlas and applied them to query a connectivity map to identify candidate anti-HCC drugs. As a result, fluphenazine was identified as a candidate for anti-HCC therapy in vitro and in vivo. Fluphenazine suppressed HCC cell proliferation and migration and induced cell cycle arrest and apoptosis, possibly owing to disrupted lysosomal function, blocking autophagy flux. Additionally, in vivo studies demonstrated that fluphenazine suppresses HCC subcutaneous xenografts growth without causing severe side effects. Strikingly, fluphenazine could be used as an analgesic to alleviate oxaliplatin-induced pain as well as pain related anxiety-like behavior. Therefore, fluphenazine could be a novel liver cancer treatment candidate.

ARV-825 Showed Antitumor Activity against BRD4-NUT Fusion Protein by Targeting the BRD4.

Objective: The bromodomain-containing 4 (BRD4) is a member of the bromodomain and extra terminal domain (BET) family, which is an important epigenetic reader. It is currently a promising oncology target. In some tumors, BET bromodomain inhibitors have demonstrated promising results. Proteolysis-targeting methods (PROTAC), which rapidly and effectively degrade BRD4, have displayed considerable potential in the treatment of tumors in recent years. The purpose of this study is to examine the potential impact of BRD4 PROTAC compounds ARV-825 on oncogene BRD4-NUT fused protein in NUT carcinoma. Methods: The effectiveness of ARV-825 was evaluated at the cellular level using the cell counting kit 8 test, wound healing, cell transfection, western blotting analysis, and RNA sequencing. The effectiveness of ARV-825 was also examined in vivo using a xenograft model. Results: The BRD4-NUT fusion gene was overexpressed in 3T3 cells, and the pathogenic fusion gene was simulated. The results showed that the overexpression of BRD4-NUT could promote the proliferation and migration of 3T3 cells, but the expression of BRD4 protein was degraded after the addition of the novel cereblon-based PROTAC compound ARV-825 against BRD4, resulting in inhibition of BRD4-NUT 3T3 cell proliferation and migration. Further RNA-seq analysis showed that overexpression of BRD4-NUT was accompanied by increased expression of gene (e.g., Myc, E2F, TRAFs, Wnt, Gadd45g, and Sox6) with significantly enriched pathway (e.g., small cell lung cancer, NF-kappa B signaling pathway, and breast cancer), promoted cell cycle from G 1 phase to S phase, and increased cell proliferation and migration, activated the antiapoptosisi signal, led to abnormal cell growth, and ultimately led to tumorigenesis. The addition of ARV-825 effectively rescued this process and effectively inhibited cell vitality, proliferation, and migration. In vivo studies demonstrated that treatment with ARV-825 greatly suppressed tumor growth without causing harmful side effects and downregulated the BRD4-NUT expression level. Conclusion: Through the induction of BRD4 protein degradation, ARV-825 can successfully limit BRD4-NUT 3T3 cell proliferation in vitro and in vivo. These findings suggested that the BRD4 inhibitor ARV-825 would be an effective therapeutic strategy for treating NUT carcinoma that with the genetic feature of BRD4-NUT fusion event.

CD45- erythroid progenitor cells promote lymph node metastasis in gastric cancer by inducing a hybrid epithelial/mesenchymal state in lymphatic endothelial cells.

BACKGROUND AND AIMS: Specific mechanisms of lymph node (LN) metastasis in early-stage gastric cancer (GC) have not been elucidated. The role of anemia, a vital clinical feature of GC, in LN metastasis is also unclear. Since the number of erythroid progenitor cells (EPCs) is increased in chronic anemia, we investigated its association with LN metastasis in GC. METHODS: Flow cytometry and immunofluorescence analyses were performed to sort and study EPCs from the circulation and tumors of patients with stage I-III GC. The effect of these EPCs on the activation of T and B cells and on the functions of lymphatic endothelial cells (LECs) was determined, and their ability to promote LN metastasis was evaluated using a footpad-popliteal LN metastasis model based on two human adenocarcinoma GC cell lines in nude mice. The prognostic value of EPCs was also analyzed. RESULTS: The proportion of CD45- EPCs was higher in the mononuclear cells in the circulation, tumors, and LNs of GC patients with LN metastasis (N+) than in those of GC patients without LN metastasis (N0). In N+ patients, CD45- EPCs were more abundant in metastatic LNs than in non-metastatic LNs. Lymphatic vessel endothelial hyaluronan receptor 1 immunoreactivity in tumors revealed that CD45- EPCs were positively associated with nodal stages and lymph vessel density. Furthermore, CD45- EPCs increased LEC proliferation and migration through their S100A8/A9 heterodimer-induced hybrid epithelial/mesenchymal (E/M) state; however, they did not influence the invasion and tubulogenesis of LECs or T and B cell proliferation. CD45- EPCs promoted LN metastasis in vivo; the S100A8/A9 heterodimer mimicked this phenomenon. Finally, CD45- EPCs predicted the overall and disease-free survival of stage I-III GC patients after radical resection. CONCLUSIONS: The CD45- EPCs accumulated in GC tissues and metastatic LNs and promoted LN metastasis via the S100A8/9-induced hybrid E/M state of LECs, which was the specific mechanism of LN metastasis in the early stages of GC.

Effects of cancer-associated fibroblasts deletion using HSVtk suicide system in OSCC.

OBJECTIVE: To evaluate the biological characteristics of oral cancer cells co-cultured with cancer-associated fibroblasts (CAFs)-HSVtk and to assess the reliability of the CAFs-HSVtk suicide system in a co-culture model. METHODS: CAFs were lentivirus-transfected with PCDH-HSVtk. Ganciclovir (GCV) was added and the survival rates of the CAFs-HSVtk were measured. In parallel with the selective elimination of CAFs, comparison was made of the effects of CAF-HSVtk on tumor cell proliferation/migration in a CAFs-tumor co-cultural system. Cell death of co-cultured oral cancer cells was evaluated by flow cytometry. RESULTS: Q-PCR analysis showed that the expression of HSVtk in the CAFs-HSVtk group was significantly higher than in the control group (p < 0.01). The survival rates of CAFs-HSVtk with GCV were significantly reduced (p < 0.01). Following selective depletion of CAFs-HSVtk, the growth and migration rates of oral cancer cells co-cultured with CAFs-HSVtk were reduced in a mixture ratio of 1:2 (p < 0.01, p < 0.01). CONCLUSIONS: Enhanced proliferation and migration rates of oral cancer cells in co-culture were seriously impaired after deleting CAFs using the HSVtk suicide system, while oral tumor cell death was not affected. Therefore, CAFs-HSVtk can be utilized as a valid model for CAF signature identification.

Betaine regulates adipogenic and osteogenic differentiation of hAD-MSCs.

BACKGROUND: With an ageing population, the incidence of bone loss and obesity are increasing. Numerous studies emphasized the multidirectional differentiation ability of mesenchymal stem cells (MSCs), and reported betaine modulated the osteogenic differentiation and adipogenic differentiation of MSCs in vitro. We wondered how betaine affected the differentiation of hAD-MSCs and hUC-MSCs. METHODS AND RESULTS: ALP staining and alizarin red S (ARS) staining were proved 10 mM betaine significantly increased the number of ALP-positive cells and plaque calcified extracellular matrices, accompanying by the up-regulation of OPN, Runx-2 and OCN. Oil red O staining demonstrated the number and size of lipid droplets were reduced, the expression of adipogenic master genes such as PPARγ, CEBPα and FASN were down-regulated simultaneously. For further investigating the mechanism of betaine on hAD-MSCs, RNA-seq was performed in none-differentiation medium. The Gene Ontology (GO) analysis showed fat cell differentiation and bone mineralization function terms were enriched, and KEGG showed PI3K-Akt signaling pathway, cytokine-cytokine receptor interaction and ECM-receptor interaction pathways were enriched in betaine treated hAD-MSCs, demonstrated betaine had a positive inducing effect on osteogenic of hAD-MSCs in the non-differentiation medium in vitro, which is opposite to the effect on adipogenic differentiation. CONCLUSIONS: Our study demonstrated that betaine promoted osteogenic and compromised adipogenic differentiation of hUC-MSCs and hAD-MSCs upon low concentration administration. PI3K-Akt signaling pathway, cytokine-cytokine receptor interaction and ECM-receptor interaction were significantly enriched under betaine-treated. We showed hAD-MSCs were more sensitive to betaine stimulation and have a better differentiation ability than hUC-MSCs. Our results contributed to the exploration of betaine as an aiding agent for MSCs therapy.

GLP-1 receptor agonists for the treatment of obesity: Role as a promising approach.

Obesity is a complex disease characterized by excessive fat accumulation which is caused by genetic, environmental and other factors. In recent years, there has been an increase in the morbidity, disability rate,and mortality due to obesity, making it great threat to people's health and lives, and increasing public health care expenses. Evidence from previous studies show that weight loss can significantly reduce the risk of obesity-related complications and chronic diseases. Diet control, moderate exercise, behavior modification programs, bariatric surgery and prescription drug treatment are the major interventions used to help people lose weight. Among them, anti-obesity drugs have high compliance rates and cause noticeable short-term effects in reducing obese levels. However, given the safety or effectiveness concerns of anti-obesity drugs, many of the currently used drugs have limited clinical use. Glucagon-like peptide-1 receptor (GLP-1R) agonists are a group of drugs that targets incretin hormone action, and its receptors are widely distributed in nerves, islets, heart, lung, skin, and other organs. Several animal experiments and clinical trials have demonstrated that GLP-1R agonists are more effective in treating or preventing obesity. Therefore, GLP-1R agonists are promising agents for the treatment of obese individuals. This review describes evidence from previous research on the effects of GLP-1R agonists on obesity. We anticipate that this review will generate data that will help biomedical researchers or clinical workers develop obesity treatments based on GLP-1R agonists.

Effect of intradiscal local anesthetic injection on intraoperative pain during percutaneous transforaminal endoscopic discectomy: A retrospective study.

OBJECTIVE: Patients undergoing percutaneous transforaminal endoscopic discectomy (PTED) often complain of unbearable intraoperative pain. This study is to observe clinical effectiveness and safety of intradiscal local anesthetic injection for intraoperative pain relief. METHODS: Total 268 patients who underwent PTED were analyzed. Patients were divided into intradiscal saline injection group (group C) and intradiscal local anesthetic injection group (group L). Intradiscal mixture was consisted of saline or local anesthetic + methylene blue, the amount of injected mixture was 3 mL. Demographic data, visual analog scale (VAS) and Quebec Back Pain Disability Scale (QBPDS) scores, mean arterial pressure (MAP) and heart rate (HR), total dosage of fentanyl, satisfaction rate of anesthesia and complications were collected at different timepoints. RESULTS: Compared with group C (3.94 ± 0.57), there was a significant reduction of VAS in group L (2.83 ± 0.28) during fibrous annular operation phase (T2). Group L had a lower total dosage of fentanyl (71 [63, 78] µg) and a higher anesthesia satisfaction rate (95.3%) than group C (82 [70, 132] µg and 73.6%, respectively) (P < 0.001). MAP and HR were lower in group L than in group C at T2 (P < 0.001). Baseline characteristics and QBPDS scores showed no meaningful intergroup differences. Four cases of complications were reported in this study. CONCLUSION: Intradiscal local anesthetic injection significantly alleviated intraoperative back pain and increased the satisfaction rate of anesthesia, without severe complications, indicating that this technique is a feasible method for intraoperative back pain relief for patients undergoing PTED.

[Gene Mutation and Clinical Characteristics of Patients with Acute Leukemia].

OBJECTIVE: To investigate the characteristics of gene mutation, clinical characteristics and significance in acute leukemia (AL) patients. METHODS: The clinical data of 102 AL patients in Hebei General Hospital from September 2016 to September 2020 were collected and analyzed retrospectively, including the characteristics of gene mutation, age, peripheral blood cells, bone marrow blasts, leukemia subtypes and myeloperoxidase (MPO). RESULTS: The total gene mutation rate was 87.25% (89/102) in all 102 patients. A total of 275 gene mutations were detected, with an average of 2.70 gene mutations per patient. The most frequent mutations of 102 patients were as follows: CEBPA (6.91%), NPM1 and ASXL1(6.18%), TET2 (5.82%), DNMT3A (5.45%), IDH2 and FLT3-ITD (5.09%). Gene mutations often occurred simultaneously. CEBPA mutation occurred in 10 cases of M2 subtype, while TET2 mutation occurred in 9 cases of M2 subtype. Among the most common gene mutations in MPO low expression group, mutation rates of NPM1, DNMT3A, IDH2, SF related gene mutation and RUNX1 were significantly different than those in MPO high expression group (all P<0.05). Univariate analysis showed that age, NPM1, DNMT3A and FLT3-ITD had significant effects on leukocyte level. Logistic regression analysis showed that patients with positive NPM1 mutations may had higher leukocyte levels (p=0.038), and those with positive DNMT3A mutations may had higher platelet levels (p=0.042). CONCLUSION: The incidence of gene mutation in patients with AL is high, and it often occurs simultaneously. CEBPA and TET2 gene mutations are more common in M2 subtype. In patients with MPO low expression, the most common gene mutations are NPM1, DNMT3A and IDH2. AL patients with NPM1 gene mutation had higher white blood cell levels, while with DNMT3A gene mutation had higher platelet levels.

Halofuginone inhibits tumor migration and invasion by affecting cancer-associated fibroblasts in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is the most common malignant tumor in the oral and maxillofacial regions, with a high rate of metastasis. Cancer-associated fibroblasts (CAFs) play critical roles in tumor growth, metastasis and invasion, making them attractive therapeutic targets for cancer treatment. As an old anti-coccidiosis drug for poultry, Halofuginone (HF) has also been reported to possess anti-fibrosis and anti-cancer activities in the recent decades. However, whether it works by targeting CAFs in OSCC, and the mechanisms involved remain unclear. In the present study, we observed HF dose-dependently inhibits OSCC-derived CAF viability and proliferation. Meanwhile, HF decreased the expressions of α-SMA, FSP-1 and PDGFRß, markers of the malignant phenotype of CAFs, both at mRNA and protein levels. Furthermore, functional studies demonstrated that HF dramatically attenuates the promotion effect of CAFs on OSCC cell migration and invasion. Mechanistically, the inhibition of MMP2 secretion and the upstream TGF-ß/Smad2/3 signaling pathway played an important role in these processes. In the orthotopic transplanted tongue carcinoma in mice model, we confirmed that HF administration inhibited tumor growth and lymph node metastasis (LNM) with reduced CAF population, MMP2 expression and collagen deposition in tumor. Altogether, these results indicate that HF can inhibit the migration and invasion of OSCC by targeting CAFs, which will provide new ideas for the treatment of OSCC.

Identification and validation of immune and prognosis-related genes in hepatocellular carcinoma: A review.

PURPOSE: Bioinformatics methods were used to identify the key genes associated with the immune microenvironment of hepatocellular carcinoma (HCC) to construct an immune risk prognostic model (IRPM) and to study the correlation between IRPM's risk groups and immune characteristics of patients with HCC. METHODS: HCC transcriptome sequencing information was searched for immune-related genes (IRGs) that were regularly expressed in cancer tissues. The IRGs, which were strongly linked to overall survival were screened; the prognostic characteristics model was constructed using Cox regression analysis. IRPM's independent prognostic value was explored; Kaplan-Meier survival and receiver-operating characteristic curves were used to determine the model prediction ability in the led-to queue. RESULTS: Patients in the high-risk group (HRG) showed significantly poor outcomes. Gene Set Enrichment Analysis revealed factors involved in both the HRG and low risk group. Immune-related hub genes (IRHGs) and drug sensitivity expression levels revealed that all IRHGs were correlated with drug sensitivity for certain chemotherapy drugs. CONCLUSION: The study results may serve as a reference for improving prognosis, early screening, and immunotherapy in patients with HCC.

A simple method for eyelid reconstruction with an advancement flap after resection of a minor nevus on the eyelid margin.

We developed a simple and effective method for eyelid reconstruction after resection of a minor nevus on the eyelid margin. With a vertical advancement flap to repair the defect, all patients were satisfied with the cosmetic and functional results of the eyelids, and no significant complications occurred.

Identification of Biological Functions and Prognostic Value of NNMT in Oral Squamous Cell Carcinoma.

BACKGROUND: Nicotinamide N-methyltransferase (NNMT) is a metabolic enzyme that catalyzes the methylation of nicotinamide (NAM) to generate 1-methyl nicotinamide (MNAM). Although previous studies have shown that NNMT is frequently dysregulated to promote the onset and progression of many malignancies, its expression profile, prognostic value and function in oral squamous cell carcinoma (OSCC) are still unknown. METHODS: We used untargeted metabolomics based on mass spectrometry to analyze potential metabolite differences between tumors and matched adjacent normal tissues in 40 OSCC patients. Immunohistochemistry (IHC) was used to analyze the NNMT expression profile in OSCC, and the diagnostic and prognostic values of NNMT were evaluated. Next, qPCR and Western blot were used to compare the expression of NNMT in five OSCC cell lines. Stable transfected cell lines were constructed, and functional experiments were carried out to elucidate the effects of NNMT on the proliferation and migration of OSCC cells. Finally, gene set enrichment analysis (GSEA) was performed using The Cancer Genome Atlas (TCGA) data to investigate the potential functional mechanisms of NNMT in OSCC. RESULTS: We found that the nicotinamide metabolic pathway was abnormally activated in OSCC tumor tissues compared with normal tissues. NNMT was expressed ubiquitously in tumor cells (TCs) and fibroblast-like cells (FLCs) but was absent in tumor-infiltrating lymphocytes (TILs). OSCC patients with highly expressed NNMT in TCs had higher risk of lymph node metastasis and showed a worse pattern of invasion (POI). Moreover, patients with highly expressed NNMT were also susceptible to postoperative recurrence. Highly expressed NNMT can independently predict shorter disease-free survival and recurrence-free survival. Functionally, we demonstrated that the ectopic expression of NNMT promoted OSCC tumor cell proliferation and migration in vitro. Conversely, silencing exerted significantly opposite effects in vitro. In addition, GSEA showed that highly expressed NNMT was mainly enriched in the epithelial-mesenchymal transformation (EMT) pathway, which displayed a significant positive correlation with the six classic EMT markers. CONCLUSIONS: Our study uncovered that NNMT may be a critical regulator of EMT in OSCC and may serve as a prognostic biomarker for OSCC patients. These findings might provide novel insights for future research in NNMT-targeted OSCC metastasis and recurrence therapy.

OXTRHigh stroma fibroblasts control the invasion pattern of oral squamous cell carcinoma via ERK5 signaling.

The Pattern Of Invasion (POI) of tumor cells into adjacent normal tissues clinically predicts postoperative tumor metastasis/recurrence of early oral squamous cell carcinoma (OSCC), but the mechanisms underlying the development of these subtypes remain unclear. Focusing on the highest score of POIs (Worst POI, WPOI) present within each tumor, we observe a disease progression-driven shift of WPOI towards the high-risk type 4/5, associated with a mesenchymal phenotype in advanced OSCC. WPOI 4-5-derived cancer-associated fibroblasts (CAFsWPOI4-5), characterized by high oxytocin receptor expression (OXTRHigh), contribute to local-regional metastasis. OXTRHigh CAFs induce a desmoplastic stroma and CCL26 is required for the invasive phenotype of CCR3+ tumors. Mechanistically, OXTR activates nuclear ERK5 transcription signaling via Gαq and CDC37 to maintain high levels of OXTR and CCL26. ERK5 ablation reprograms the pro-invasive phenotype of OXTRHigh CAFs. Therefore, targeting ERK5 signaling in OXTRHigh CAFs is a potential therapeutic strategy for OSCC patients with WPOI 4-5.

Clinical Analysis of Primary Tracheobronchial Tumors in Children and Evaluation of the Predicting Models for Mucoepidermoid Carcinoma.

OBJECTIVE: To determine the clinical characteristics and prognosis of primary tracheobronchial tumors (PTTs) in children, and to explore the most common tumor identification methods. METHODS: The medical records of children with PTTs who were hospitalized at the Children's Hospital of Chongqing Medical University from January 1995 to January 2020 were reviewed retrospectively. The clinical features, imaging, treatments, and outcomes of these patients were statistically analyzed. Machine learning techniques such as Gaussian naïve Bayes, support vector machine (SVM) and decision tree models were used to identify mucoepidermoid carcinoma (ME). RESULTS: A total of 16 children were hospitalized with PTTs during the study period. This included 5 (31.3%) children with ME, 3 (18.8%) children with inflammatory myofibroblastic tumors (IMT), 2 children (12.5%) with sarcomas, 2 (12.5%) children with papillomatosis and 1 child (6.3%) each with carcinoid carcinoma, adenoid cystic carcinoma (ACC), hemangioma, and schwannoma, respectively. ME was the most common tumor type and amongst the 3 ME recognition methods, the SVM model showed the best performance. The main clinical symptoms of PPTs were cough (81.3%), breathlessness (50%), wheezing (43.8%), progressive dyspnea (37.5%), hemoptysis (37.5%), and fever (25%). Of the 16 patients, 7 were treated with surgery, 8 underwent bronchoscopic tumor resection, and 1 child died. Of the 11 other children, 3 experienced recurrence, and the last 8 remained disease-free. No deaths were observed during the follow-up period. CONCLUSION: PTT are very rare in children and the highest percentage of cases is due to ME. The SVM model was highly accurate in identifying ME. Chest CT and bronchoscopy can effectively diagnose PTTs. Surgery and bronchoscopic intervention can both achieve good clinical results and the prognosis of the 11 children that were followed up was good.

Lateral epicondyle osteotomy approach vs. olecranon osteotomy approach: an anatomic study of cadavers.

BACKGROUND: Exposure of the articular surface is the key to successful open reduction and internal fixation treatment for coronal shear fractures of the distal humerus. The olecranon osteotomy approach has previously been described as one of the most effective exposure approaches. Nevertheless, this approach cannot expose the anterior trochlea, and it is impossible to reduce and fix the capitellum under direct vision. The purpose of this study was to compare the exposure of the articular surface of the distal humerus between the lateral epicondyle osteotomy approach (group L) and the olecranon osteotomy approach (group O). METHODS: Each approach was performed on 8 freshly frozen upper limbs of adult cadavers. After each approach was completed, a 0.5-mm Kirschner wire is inserted along the edge to mark the visible part of the articular surface. Then, the soft tissue of each elbow is removed, and a surface-scanning system is used to create a digital 3-dimensional model. The visible part of the articular surface obtained by each surgical approach was mapped and quantified using markers created by Kirschner wires. RESULTS: The lateral epicondyle osteotomy approach and the olecranon osteotomy approach exposed 0.8 ± 0.0 and 0.6 ± 0.0 of the distal humeral articular surface (P < .001), 1.0 ± 0.0 and 0.3 ± 0.1 of the capitellum (P < .001), 0.6 ± 0.0 and 0.7 ± 0.0 of the trochlea (P < .001), 0.7 ± 0.0 and 0.5 ± 0.1 of the anterior trochlea (P < .001), and 0.5 ± 0.0 and 1.0 ± 0.0 of the posterior trochlea, respectively (P < .001). CONCLUSION: Compared with the olecranon osteotomy approach, the lateral epicondyle osteotomy approach could more fully expose the total articular surface of the distal humerus, capitellum, and anterior trochlea, but the olecranon osteotomy approach could more fully expose the trochlea and posterior trochlea.