Objective To explore the role and molecular mechanism of major vault protein (MVP) in tumor-associated macrophages in the occurrence and development of liver cancer. Methods The expression of MVP in macrophages was analyzed by bioinformatics method and multi-fluorescent immunohistochemical staining. Mice with MVP deficiency in macrophages were constructed by Cre/LoxP recombinant enzyme system. The proliferation and migration abilities of tumor cells were detected by cloning formation and Transwell migration assays. The effect of MVP in macrophages on tumorigenesis and development was investigated by mouse primary liver cancer model and subcutaneous tumor transplantation model. The effect of MVP on the tumor microenvironment was investigated by multi-fluorescent immunohistochemical staining. The effect of MVP on CD8⁺ T cells was detected by cell co-culture, flow cytometry, qPCR, and ELISA. Results The high expression of MVP in tumor-associated macrophages. The downregulation of the expression of MVP in tumor-associated macrophages compared with para-carcinoma tissues. MVP deficiency in macrophages promoted the proliferation and migration of tumor cells (P<0.05), promoted the development of tumor in vivo (P<0.05), formed an immunosuppressive microenvironment and weakened CD8⁺ T cell-mediated anti-tumor immunity (P<0.05). Conclusion MVP deficiency in macrophages can promote the occurrence and development of liver cancer by suppressing the function of CD8⁺ T cells.

Oral lichen planus (OLP) is a common chronic inflammatory disease and potentially malignant disorder of the oral mucosa. Clinical manifestations include bilateral symmetrical distributions of pearly white reticular streaks, and its subtype erosive oral lichen planus (EOLP) is often accompanied by local congestion, erosion, obvious pain, and other symptoms, which affects the patient's eating and swallowing. Oral hygiene and environmental factors, lifestyle and dietary factors, psychological factors, medication factors, and systemic disease factors all contribute to the recurrence of EOLP lesions, which increases the cancer potential of this condition. Therefore, measures to prevent the recurrence and cancerous transformation of EOLP have attracted much attention. In the clinical treatment strategy for EOLP, attention should be given to its influencing factors for comprehensive management. Patients should be provided with multidisciplinary and multifaceted oral comprehensive management measures across the following strategies: maintaining a good oral hygienic environment, dietary therapies and healthy living habits, psychological therapies, systemic/local therapeutic guidance, and active follow-up and treatment of systemic diseases. This article provides multidisciplinary and multifaceted comprehensive oral management measures for patients with the goal of cancer prevention, minimizing recurrence, and improving the quality of life of patients.

Studies have suggested that the nucleus accumbens (NAc) is implicated in the pathophysiology of major depression; however, the regulatory strategy that targets the NAc to achieve an exclusive and outstanding anti-depression benefit has not been elucidated. Here, we identified a specific reduction of cyclic adenosine monophosphate (cAMP) in the subset of dopamine D1 receptor medium spiny neurons (D1-MSNs) in the NAc that promoted stress susceptibility, while the stimulation of cAMP production in NAc D1-MSNs efficiently rescued depression-like behaviors. Ketamine treatment enhanced cAMP both in D1-MSNs and dopamine D2 receptor medium spiny neurons (D2-MSNs) of depressed mice, however, the rapid antidepressant effect of ketamine solely depended on elevating cAMP in NAc D1-MSNs. We discovered that a higher dose of crocin markedly increased cAMP in the NAc and consistently relieved depression 24 h after oral administration, but not a lower dose. The fast onset property of crocin was verified through multicenter studies. Moreover, crocin specifically targeted at D1-MSN cAMP signaling in the NAc to relieve depression and had no effect on D2-MSN. These findings characterize a new strategy to achieve an exclusive and outstanding anti-depression benefit by elevating cAMP in D1-MSNs in the NAc, and provide a potential rapid antidepressant drug candidate, crocin.

This article reviews relevant literature on the prevention and treatment of cancer with hesperidin published in the past 10 years by searching electronic databases such as China National Knowledge Infrastructure（CNKI）， Wanfang， and PubMed， and summarizes the research progress on the anticancer mechanism of hesperidin. Hesperidin has a wide range of pharmacological effects， including anti-inflammatory， antioxidant， antibacterial， antiviral， anticancer， immune-regulatory， anti-radiation， neuroprotective and cardiovascular protective properties and so on. Its anticancer mechanisms mainly include inhibiting cancer cell proliferation， promoting apoptosis， reducing angiogenesis， inhibiting invasion and migration of cancer cells， regulating immunity and autophagy， and exerting antioxidant and anti-inflammatory effects. As a broad-spectrum anticancer drug， hesperidin manifests chemo-preventive and therapeutic effects across various cancers， contingent upon its multifaceted anticancer mechanisms. Furthermore， this article summarizes the synergistic effects of hesperidin in combination with cisplatin， doxorubicin， cyclophosphamide and paclitaxel. It elucidates that hesperidin can enhance the cytotoxicity of these anticancer drugs against cancer cells while mitigating drug resistance and adverse side effects. Nonetheless， the clinical use is somewhat constrained due to its poor water solubility and limited bioavailability. Therefore， this article also outlines the current strategies for enhancing hesperidin's bioavailability， including structural modification， combination with other chemical substances， and utilization of nano drug carriers.The discovery of derivatives of hesperidin not only preserves the anticancer efficacy of hesperidin, but also effectively overcomes the shortcomings of poor water solubility and low bioavailability of hesperidin, effectively predicting the good application prospects of hesperidin and its derivatives.

Objective:To Constructing a nomogram based on clinical, ultrasound and BRAF V600E gene for predicting cervical lymph node metastasis in patients with papillary thyroid carcinoma (PTC).Methods:The clinical data of 287 patients with PTC (374 malignant nodules) from December 2019 to December 2021 in the First Affiliated Hospital of Hunan Normal University were analyzed retrospectively. Among them, there were 205 nodes with cervical lymph node metastasis and 169 nodes without cervical lymph node metastasis. The echo type, capsule, boundary, shape, number, diameter, location, cystic and solid properties, aspect ratio, blood flow signal, echo distribution, ultrasonic classification, microcalcification and enlarged lymph nodes were observed by ultrasound. The mutation of BRAF V600E gene was detected by fluorescence polymerase chain reaction. The nomograph model for predicting neck lymph node metastasis in patients with PTC was constructed and validated by R3.6.3 software.Results:Univariate analysis result showed that gender, age, microcalcifications, aspect ratio, morphology, blood flow signal, diameter, echo distribution, enlarged lymph nodes, ultrasound classification and BRAF V600E gene were the risk factors for cervical lymph node metastasis in patients with PTC ( P<0.05 or <0.01). Multivariate Logistic regression analysis result showed that age (<40 years old), ultrasonic classification (≥4a) and diameter (>1 cm) were independent risk factors for cervical lymph node metastasis in patients with PTC ( OR = 2.847, 1.436 and 2.475; 95% CI 1.827 to 4.436, 1.075 to 1.918 and 1.505 to 4.069; P<0.01 or <0.05). The age, ultrasonic classification and diameter were included as predictors for constructing the nomogram model. The receiver operating characteristic curve analysis result shows that the area under the curve predicted by the nomogram model for neck lymph node metastasis in patients with PTC was 0.692 (95% CI 0.631 to 0.753). Conclusions:Nomogram based on age, ultrasonic classification and diameter is of high value in predicting neck lymph node metastasis in patients with PTC.

Oral squamous cell carcinoma (OSCC) escape from the immune system is mediated through several immunosuppressive phenotypes that are critical to the initiation and progression of tumors. As a hallmark of cancer, DNA damage repair is closely related to changes in the immunophenotypes of tumor cells. Although flap endonuclease-1 (FEN1), a pivotal DNA-related enzyme is involved in DNA base excision repair to maintain the stability of the cell genome, the correlation between FEN1 and tumor immunity has been unexplored. In the current study, by analyzing the clinicopathological characteristics of FEN1, we demonstrated that FEN1 overexpressed and that an inhibitory immune microenvironment was established in OSCC. In addition, we found that downregulating FEN1 inhibited the growth of OSCC tumors. In vitro studies provided evidence that FEN1 knockdown inhibited the biological behaviors of OSCC and caused DNA damage. Performing multiplex immunohistochemistry (mIHC), we directly observed that the acquisition of critical immunosuppressive phenotypes was correlated with the expression of FEN1. More importantly, FEN1 directly or indirectly regulated two typical immunosuppressive phenotype-related proteins human leukocyte antigen (HLA-DR) and programmed death receptor ligand 1 (PD-L1), through the interferon-gamma (IFN-γ)/janus kinase (JAK)/signal transducer and activator transcription 1 (STAT1) pathway. Our study highlights a new perspective on FEN1 action for the first time, providing theoretical evidence that it may be a potential immunotherapy target for OSCC.
Humans ; Carcinoma, Squamous Cell/pathology* ; DNA ; Down-Regulation ; Flap Endonucleases/metabolism* ; Head and Neck Neoplasms ; Interferon-gamma/metabolism* ; Mouth Neoplasms/pathology* ; Phenotype ; Squamous Cell Carcinoma of Head and Neck ; Tumor Microenvironment ; Janus Kinases/metabolism*

Objective:To construct a prognosis associated micro RNA(miRNA) prediction model based on bioinformatics analysis and evaluate its application value in pancreatic cancer patients.Methods:The retrospective cohort study was conducted. The clinicopathological data of 171 pancreatic cancer patients from the Cancer Genome Atlas (TCGA) (https: //cancergenome.nih.gov/) between establishment of database and September 2017 were collected. There were 93 males and 78 females, aged from 35 to 88 years, with a median age of 65 years. Of the 171 patients, 64 had complete clinicopathological data. Patients were allocated into training dataset consisting of 123 patients and validation dataset consisting of 48 patients using the random sampling method, with a ratio of 7∶3. The training dataset was used to construct a prediction model, and the validation dataset was used to evaluate performance of the prediction model. Nine pairs of miRNA sequencing data (GSE41372) of pancreatic cancer and adjacent tissues were downloaded from Gene Expression Omnibus database. The candidate miRNAs were selected from differentially expressed miRNAs in pancreatic cancer and adjacent tissues for LASSO-COX regression analysis based on the patients of training dataset. A prognosis associated miRNA prediction model was constructed upon survival associated miRNAs which were selected from candidate differentially expressed miRNAs. The performance of prognosis associated miRNA prediction model was validated in training dataset and validation dataset, the accuracy of model was evaluated using the area under curve (AUC) of the receiver operating characteristic curves and the efficiency was evaluated using the consistency index (C-index). Observation indicarors: (1) survival of patients; (2) screening results of differentially expressed miRNAs; (3) construction of prognosis associated miRNA model; (4) validation of prognosis associated miRNA model; (5) comparison of clinicopathological factors in pancreatic cancer patients; (6) analysis of factors for prognosis of pancreatic cancer patients; (7) comparison of prediction performance between prognosis associated miRNA model and the eighth edition TNM staging. Measurement data with normal distribution were represented as Mean± SD, comparison between groups was analyzed by the student- t test, and comparison between multiple groups was analyzed by the AVONA. Measurement data with skewed data were represented as M (range), and comparison between groups was analyzed using the Mann-Whitney U test. Count data were described as absolute numbers or percentages, and comparison between groups was conducted using the chi-square test. Ordinal data were analyzed using the rank sum test. Correlation analysis was conducted based on count data to mine the correlation between prognosis associated miRNA model and clinicopathological factors. COX univariate analysis and multivariate analysis were applied to evaluate correlation with the results described as hazard ratio ( HR) and 95% confidence interval ( CI). HR<1 indicated the factor as a protective factor, HR>1 indicated the factor as a risk factor, and HR equal to 1 indicated no influence on survival. The Kaplan-Meier method was used to draw survival curve and calculate survival rates, and the Log-rank test was used for survival analysis. Results:(1) Survival of patients: 123 patients in the training dataset were followed up for 31-2 141 days, with a median follow-up time of 449 days. The 3- and 5-year survival rates were 16.67% and 8.06%. Forty-eight patients in the validation dataset were followed up for 41-2 182 days, with a median follow-up time of 457 days. The 3- and 5-year survival rates were 15.63% and 9.68%. There was no significant difference in the 3- or 5-year survival rates between the two groups ( χ2=0.017, 0.068, P>0.05). (2) Screening results of differentially expressed miRNAs. Results of bioinformatics analysis showed that 102 candidate differentially expressed miRNAs were selected, of which 63 were up-regulated in tumor tissues while 39 were down-regulated. (3) Construction of prognosis associated miRNA model: of the 102 candidate differentially expressed miRNAs, 5 survival associated miRNAs were selected, including miR-21, miR-125a-5p, miR-744, miR-374b, miR-664. The differential expression patterns of pancreatic cancer to adjacent tissues were up-regulation, up-regulation, down-regulation, up-regulation, and down-regulation, respectively, with the fold change of 4.00, 3.43, 3.85, 2.62, and 2.35. A prognostic expression equation constructed based on 5 survival associated miRNAs = 0.454×miR-21 expression level-0.492×miR-125a-5p expression level-0.49×miR-744 expression level-0.419×miR-374b expression level-0.036×miR-664 expression level. (4) Validation of prognosis associated miRNA model: The C-index of prognosis associated miRNA model was 0.643 and 0.642 for the training dataset and validation dataset, respectively. (5) Comparison of clinicopathological factors in pancreatic cancer patients: results of COX analysis showed that the prognosis associated miRNA model was highly related with pathological T stage and location of pancreatic cancer ( Z=45.481, χ2=10.176, P<0.05). (6) Analysis of factors for prognosis of pancreatic cancer patients: results of univariate analysis showed that pathological N stage, radiotherapy, molecular targeted therapy, score of prognosis associated miRNA model were related factors for prognosis pf pancreatic cancer patients ( HR=2.471, 0.290, 0.172, 2.001, 95% CI: 1.012-6.032, 0.101-0.833, 0.082-0.364, 1.371-2.922, P<0.05). Results of multivariate analysis showed that molecular targeted therapy was an independent protective factor for prognosis of pancreatic cancer patients ( HR=0.261, 95% CI: 0.116-0.588, P<0.05) and score of prognosis associated miRNA model≥1.16 was an independent risk factor for prognosis of pancreatic cancer patients ( HR=1.608, 95% CI: 1.091-2.369, P<0.05). (7) Comparison of prediction performance between prognosis associated miRNA model and the eighth edition TNM staging: in the training dataset, there was a significant difference in the prediction probability for 3- and 5-year survival of pancreatic cancer patients between prognosis associated miRNA model and the eighth edition TNM staging ( Z=-1.671, -1.867, P<0.05). The AUC of the prognosis associated miRNA model and the eight edition TNM staging for 3- and 5-year survival prediction was 0.797, 0.935 and 0.737 , 0.703, with the 95% CI of 0.622-0.972, 0.828-1.042 and 0.571-0.904 , 0.456-0.951. The C-index was 0.643 and 0.534. In the validation dataset, there was a significant difference in the prediction probability for 3- and 5-year survival of pancreatic cancer patients between prognosis associated miRNA model and the eighth edition TNM staging ( Z=-1.729, -1.923, P<0.05). The AUC of the prognosis associated miRNA model and the eight edition TNM staging was 0.750, 0.873 and 0.721 , 0.703, with the 95% CI of 0.553-0.948, 0.720-1.025 and 0.553-0.889, 0.456-0.950, respectively. The C-index was 0.642 and 0.544. Conclusions:A prognosis associated miRNA prediction model can be constructed based on 5 survival associated miRNAs in pancreatic cancer patients, as a complementation to current TNM staging and other clinicopathological parameters, which provides individual and accurate prediction of survival for reference in the clinical treatment.

OBJECTIVE：To preliminarily optimize the preparation technology of Ligustrazine pellicle ，and to study its in vitro percutaneous permeation characteristics. METHODS ：With the amounts of PVA- 124，ethyl alcohol ，glycerin，tween-80 and azone as factors ，single factor experiment was used to optimize the Ligustrazine pellicle matrix formulation ；modified scoring standard was used to evaluate the film formation time ，film formation ability ，ductility，uniformity and the presence of bubble. On the basis of the optimal matrix formulation ，the pellicle with different loading amount of ligustrazine （300，250，200，150，100，50 mg/mL） was prepared and its maximum loading amount was investigated. HPLC method was adopted to determine the content of ligustrazine，and methodology investigation was conducted. Isolated back skin of rats were collected ，the percutaneous permeation test was conducted for high ，medium and low loading amount （100，75，50 mg/mL）of Ligustrazine pellicle. At 15，30，45，60， 75，90，120，150，180 min，the sample was taken and the permeation rate of ligustrazine was calculated. RESULTS ：When the amounts of PVA- 124，ethyl alcohol，glycerin，tween-80 and azone were 2.5 g，7.0 mL，1.97 mL，0.07 mL，0.28 mL（in terms of 50 mL formulation amount ），the optimal matrix formulation of Ligustrazine pellicle was obtained. The maximum drug loading amount of ligustrazine was 100 mg/mL. The linear ranges of ligustrazine was 3.125-100 μg/mL. The specificity，precision， reproducibility，recovery and stability investigation of content determination method of ligustrazine were all in line with the requirements（RSD＜2％）. The permeation rate of high ，medium and low loading amount of Ligustrazine pellicle were 608.42， 384.19，158.20 μg（/ cm2·h）. CONCLUSIONS ：According to the optimized formulation ，the prepared Ligustrazine pellicle had a short film forming time ，stable and re liable quality ； the drug-loading amount was up to 100 mg/mL. The pellicle with drug-loading amount of 75 mg/mL had reached the penetration rate range of effective plasma concentration of ligustrazine treatment.

Objective:To investigate the expression and clinical significance of long non-coding RNA (lncRNA) H19 and lncRNA maternally expressed gene 3 (MEG3) in the serum of patients with gastric cancer (GC).Methods:A total of 87 GC patients admitted to the First People′s Hospital of Suqian (July 2017 to August 2018) were selected as the GC group, 51 patients with benign tumors as the benign tumor group, and 40 healthy people with physical examination as the healthy control group. The expression levels of lncRNA H19 and lncRNA MEG3 in serum were measured; the relationship between the expression levels of the two and clinicopathological features and prognosis of patients with GC was analyzed.Results:The levels of serum lncRNA H19 in healthy control group, benign tumor group and GC group were gradually increased, and lncRNA MEG3 level was gradually decreased ( P<0.05); the serum lncRNA H19 level in GC group was related to tumor invasion depth, tumor node metastasis (TNM) stage and lymph node metastasis. The level of lncRNA MEG3 was related to the degree of differentiation, TNM stage and lymph node metastasis ( P<0.05). Among the 87 GC patients , 63 patients were followed up for 13-32 months with an average of (23.54±4.18)months. Kaplan Meier survival curve showed that the overall survival rate of high serum lncRNA H19 group and low serum lncRNA MEG3 level group was significantly lower than that of low serum lncRNA H19 level group and high serum lncRNA H19 level group. Multivariate Cox regression analysis showed that lncRNA H19 ( HR=3.442, 95% CI=0.089-23.421) was an independent prognostic factor for GC patients, and lncRNA MEG3 ( HR=4.386, 95% CI=0.934-20.596) was a protective factor ( P<0.05); receiver operating characteristic (ROC) curve showed that the sensitivity, specificity and accuracy of serum lncRNA H19+ lncRNA MEG3 [area under curve (AUC)=0.922, 95% CI=0.861-0.962] were higher than those of serum lncRNA H19 (AUC=0.840, 95% CI=0.771-0.904) and lncRNA MEG3 (AUC=0.830, 95% CI=0.753-0.890). Conclusions:The level of serum lncRNA H19 in GC patients is significantly increased, and the level of lncRNA MEG3 is significantly reduced, which is closely related to tumor occurrence, development and prognosis. Combined detection of the two can enhance the diagnostic value of GC.

Tooth decay is prevalent, and secondary caries causes restoration failures, both of which are related to demineralization. There is an urgent need to develop new therapeutic materials with remineralization functions. This article represents the first review on the cutting edge research of poly(amido amine) (PAMAM) in combination with nanoparticles of amorphous calcium phosphate (NACP). PAMAM was excellent nucleation template, and could absorb calcium (Ca) and phosphate (P) ions via its functional groups to activate remineralization. NACP composite and adhesive showed acid-neutralization and Ca and P ion release capabilities. PAMAM+NACP together showed synergistic effects and produced triple benefits: excellent nucleation templates, superior acid-neutralization, and ions release. Therefore, the PAMAM+NACP strategy possessed much greater remineralization capacity than using PAMAM or NACP alone. PAMAM+NACP achieved dentin remineralization even in an acidic solution without any initial Ca and P ions. Besides, the long-term remineralization capability of PAMAM+NACP was established. After prolonged fluid challenge, the immersed PAMAM with the recharged NACP still induced effective dentin mineral regeneration. Furthermore, the hardness of pre-demineralized dentin was increased back to that of healthy dentin, indicating a complete remineralization. Therefore, the novel PAMAM+NACP approach is promising to provide long-term therapeutic effects including tooth remineralization, hardness increase, and caries-inhibition capabilities.
Amines ; pharmacology ; Calcium ; Calcium Phosphates ; chemistry ; pharmacology ; Dentin ; chemistry ; Humans ; Nanocomposites ; chemistry ; Nanoparticles ; Tooth Remineralization ; methods