Machine learning prediction models for different stages of non-small cell lung cancer based on tongue and tumor marker: a pilot study.

OBJECTIVE: To analyze the tongue feature of NSCLC at different stages, as well as the correlation between tongue feature and tumor marker, and investigate the feasibility of establishing prediction models for NSCLC at different stages based on tongue feature and tumor marker. METHODS: Tongue images were collected from non-advanced NSCLC patients (n = 109) and advanced NSCLC patients (n = 110), analyzed the tongue images to obtain tongue feature, and analyzed the correlation between tongue feature and tumor marker in different stages of NSCLC. On this basis, six classifiers, decision tree, logistic regression, SVM, random forest, naive bayes, and neural network, were used to establish prediction models for different stages of NSCLC based on tongue feature and tumor marker. RESULTS: There were statistically significant differences in tongue feature between the non-advanced and advanced NSCLC groups. In the advanced NSCLC group, the number of indexes with statistically significant correlations between tongue feature and tumor marker was significantly higher than in the non-advanced NSCLC group, and the correlations were stronger. Support Vector Machine (SVM), decision tree, and logistic regression among the machine learning methods performed poorly in models with different stages of NSCLC. Neural network, random forest and naive bayes had better classification efficiency for the data set of tongue feature and tumor marker and baseline. The models' classification accuracies were 0.767 ± 0.081, 0.718 ± 0.062, and 0.688 ± 0.070, respectively, and the AUCs were 0.793 ± 0.086, 0.779 ± 0.075, and 0.771 ± 0.072, respectively. CONCLUSIONS: There were statistically significant differences in tongue feature between different stages of NSCLC, with advanced NSCLC tongue feature being more closely correlated with tumor marker. Due to the limited information, single data sources including baseline, tongue feature, and tumor marker cannot be used to identify the different stages of NSCLC in this pilot study. In addition to the logistic regression method, other machine learning methods, based on tumor marker and baseline data sets, can effectively improve the differential diagnosis efficiency of different stages of NSCLC by adding tongue image data, which requires further verification based on large sample studies in the future.

miR-139-5p reverses stemness maintenance and metastasis of colon cancer stem-like cells by targeting E2-2.

Colon cancer stem cells (CCSCs) stand for a critical subpopulation of colon cancer cells that possess self-renewal and multilineage differentiation potentials and drive tumorigenicity. Due to their impact on treatment tolerance, CCSCs have been a hot research topic in the past few years. We have previously reported that miR-139-5p is a vital tumor repressive noncoding RNA whose level decreases in the clinical colon cancer samples with the increase of tumor malignancy. This research discovered that miR-139-5p targets the Wnt/ß-catenin/TCF7L2 downstream effector E2-2 in CCSCs. E2-2 is a pivot molecule in the negative feedback loop of miR-139-5p/Wnt/ß-catenin/TCF7L2. Its small interfering RNA reverses the stemness maintenance and epithelial-mesenchymal transition of colon cancer CSCs. This study provides a theoretical foundation for the clinical diagnosis and medical treatment of recurrent or metastatic colon cancer with miR-139-5p and its target E2-2.

Refinement and Evaluation of Modified Minimally Invasive Harvest Technique for Subepithelial Connective Tissue.

INTRODUCTION: The aim of this paper was to refine the modified minimally invasive single-incision technique (MSIT) into 6 steps that are easy to execute. The advantage of this modification was evaluated and compared with the traditional trap-door incision technique (TDIT). Several other harvesting techniques, suturing techniques, indications, contraindications, and limitations were also summarized. MATERIALS AND METHODS: A total of 40 patients presenting with multiple areas of gingival recession were recruited for this study. All patients were randomly assigned to either the MSIT or TDIT group. Standard periodontal instruments and crossed horizontal suspension sutures were used for both procedures. Harvesting and suturing time, verbal rating scale (VRS), and an early wound-healing index (EHI) were recorded. RESULTS: The total operating time, and particularly the suturing time, was shorter in the MSIT group (267.70 ±â€Š20.24 seconds) than the TDIT group (298.20 ±â€Š21.07 seconds), and the difference was statistically significant (P < 0.05). However, there was no significant difference in pain level between the 2 groups according to the VRS evaluation (P = 0.3658). One week postsurgery, the EHI of the MSIT group (2.00 ±â€Š0.95) was significantly lower than the TDIT group (2.85 ±â€Š1.15) (P < 0.05). DISCUSSION: The 6-step MSIT is more predictable and easy to execute, which decreases the challenge for both dentists and patients. Favorable outcomes occurred because of the streamlined minimally invasive procedure and favorable postoperative recovery.

Characterization and cytocompatibility of thermosensitive hydrogel embedded with chitosan nanoparticles for delivery of bone morphogenetic protein-2 plasmid DNA.

A novel injectable chitosan thermosensitive hydrogel was designed as a target multi-effect scaffold for endogenous repair of the periodontium. The hydrogel complex was designed by embedding chitosan nanoparticles (CSn) loaded with bone morphogenetic protein-2 plasmid DNA (pDNA-BMP2) into a chitosan (CS)-based hydrogel with α,ß-glycerophosphate (α,ß-GP), termed CS/CSn(pDNA-BMP2)-GP. Characterization, the in vitro release profile for pDNA-BMP2, and cytocompatibility to human periodontal ligament cells (HPDLCs), were then conducted. The average diameter of the CSn(pDNA-BMP2) was 270.1 nm with a polydispersity index (PDI) of 0.486 and zeta potential of +27.0 mv. A DNase I protection assay showed that CSn could protect the pDNA-BMP2 from nuclease degradation. Encapsulation efficiency and loading capacity of CSn(pDNA-BMP2) were more than 80 and 30 %, respectively. The sol-gel transition time was only 3 min when CSn(pDNA-BMP2) was added into the CS/α,ß-GP system. Scanning electron microscopy showed that CSn(pDNA-BMP2) was randomly dispersed in a network with regular holes and a porous structure. Weighting method showed the swelling ratio and degradation was faster in medium of pH 4.0 than pH 6.8. An in vitro pDNA-BMP2 release test showed that the cumulative release rate of pDNA-BMP2 was much slower from CS/CSn-GP than from CSn in identical release media. In release media with different pH, pDNA-BMP2 release was much slower at pH 6.8 than at pH 4.0. Three-dimensional culture with HPDLCs showed good cell proliferation and the Cell-Counting Kit-8 assay indicated improved cell growth with the addition of CSn(pDNA-BMP2) to CS/α,ß-GP. In summary, the CS/CSn(pDNA-BMP2)-GP complex system exhibited excellent biological properties and cytocompatibility, indicating great potential as a gene delivery carrier and tissue regeneration scaffold for endogenous repair of the periodontium.

Interleukin-17A stimulates migration of periodontal ligament fibroblasts via p38 MAPK/NF-κB -dependent MMP-1 expression.

Interleukin-17 (IL-17) is a cytokine secreted predominantly by Th17 cells. Although IL-17 is primarily associated with the induction of tissue inflammation, the other biological functions of IL-17, including its wound-healing functions, have yet to be thoroughly explored. Fibroblast proliferation and migration play essential roles in periodontal wound-healing responses. In this study, we report that IL-17A can increase the migration and expression of matrix metalloproteinase (MMP)-1 in human periodontal ligament (PDL) fibroblasts but has no effect on PDL fibroblast proliferation. IL-17A-induced MMP-1 expression led to cell migration, which was attenuated by pre-treatment with IL-17 receptor neutralizing antibody and small interfering RNA (siRNA) for MMP-1. The IL-17A-induced cell migration was also attenuated by its tissue inhibitor of matrix metalloproteinase (TIMP)-1. In addition, a p38 mitogen-activated protein kinase (MAPK) inhibitor (SB203580) inhibited IL-17A-induced increase of the migration and MMP-1 upregulation of PDL fibroblasts. The involvement of p38 MAPK in IL-17A-induced MMP-1 expression and cell migration was further confirmed by transfection of p38α siRNA. A nuclear factor kappaB (NF-κB) inhibitor (pyrrolidine dithiocarbamate) also suppressed the cell migration and MMP-1 expression enhanced by IL-17A. Moreover, transfection with p38α siRNA inhibited IL-17A-induced NF-κB nuclear translocation as well as NF-κB binding activity. Our results suggest that IL-17A enhances the migration of PDL fibroblasts by increasing MMP-1 expression through the IL-17 receptor, p38 MAPK, and NF-κB signal transduction pathways.

[Effect of integrated Chinese medical treatment (as maintenance therapy) on the survival time of patients with advanced non-small-cell lung cancer: a clinical study].

OBJECTIVE: To observe clinical effect of integrated Chinese medical (CM) treatment (as maintenance therapy) on the progression-free survival (PFS) and overall survival (OS) in patients with advanced non-small-cell lung cancer (NSCLC) after first-line chemotherapy. METHODS: The study was a prospective, randomized, controlled clinical trial. Totally 69 non-progressive advanced NSCLC patients treated with first-line chemotherapy were randomly assigned to the test group (34 cases) and the control group (35 cases). Patients in the control group were treated with one Western drug chemotherapy (Gemcitabine or Alimta or docetaxel). Those in the test group were treated with integrated CM treatment (CM decoction, CM Intravenous preparation, and point application). Each cycle consisted of 21 days. Treatment lasted till the disease progressed, or intolerable toxic/adverse reactions occurred, or patients refused to continue the treatment. Patients' life spans were regularly followed-up. RESULTS: (1) The median cycle of maintenance therapy was 2 cycles for two groups with no statistical difference (P =0.274). The median PFS was 12.43 weeks in the test group and 10.00 weeks in the control group, showing statistical difference (P =0.025). The middle survival time (MST) was 18.8 months in the test group and 16.73 months in the control group, showing no statistical difference (P =0.437). CONCLUSION: CM treatment (as maintenance therapy) showed quail effect to one Western drug chemotherapy in prolonging patients' life span.

[Retracted] Chronic oxymatrine treatment induces resistance and epithelial­mesenchymal transition through targeting the long non­coding RNA MALAT1 in colorectal cancer cells.

Following the publication of the above article, a concerned reader drew to the Editor's attention that certain of the cell migration and invasion assay data featured in Figs. 2B, 5C, 6B and C were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes that had either already been submitted elsewhere prior to the submission of this paper to Oncology Reports, or were under consideration for publication at around the same time (one of which has been retracted). In view of the fact that certain of these data had already apparently been submitted for publication prior to the submission of this article to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they agreed with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 39: 967­976, 2018; DOI: 10.3892/or.2018.6204].

Oral Decoctions Based on Qi-Yin Syndrome Differentiation After Adjuvant Chemotherapy in Resected Stage ΙΙΙA Non-Small Cell Lung Cancer: A Randomized Controlled Trial.

OBJECTIVE: Powerful adjuvant strategies are required to improve the survival of patients with completely resected stage ΙΙΙA non-small cell lung cancer (NSCLC). We aimed to compare the efficacy of traditional Chinese medicine (TCM) treatment versus observation after adjuvant chemotherapy in these patients. METHODS: Eligible patients were randomized 1:1 to receive either oral decoctions based on Qi-Yin syndrome differentiation (TCM group) or observation (observation group). The intervention lasted for 12 months. The primary endpoint was 1-year disease-free survival (DFS). Secondary endpoints were DFS, quality of life, regulatory T cells (Tregs), and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) on the surface of Tregs in peripheral blood. We used EORTC QLQ-LC43 to evaluate quality of life. RESULTS: Between Apr 29, 2019, and Nov 11, 2021, 75 patients were randomly assigned to oral decoctions based on Qi-Yin syndrome differentiation (n = 38) or observation (n = 37). The full analysis set included 35 patients in the TCM group and 35 in the observation group. After a median follow-up of 24.2 months, oral decoctions based on Qi-Yin syndrome differentiation improved DFS compared with observation (HR 0.378, 95% CI: 0.157-0.912; P = .03). One-year DFS was 82.1% in the TCM group and 61.9% in the observation group (P = .06). Three months after randomization, scores of total health, role function, emotional function, and social function in the TCM group were higher than those in the observation group (P < .01 for all), scores of fatigue, pain, insomnia, appetite loss, constipation, cough, and chest pain were lower than those in the observation group (P < .05 for all); there was no significant difference in the proportion of Tregs between the TCM group and the observation group (P = .58); the proportion of CTLA-4+Tregs in the TCM group was lower than that in the observation group (P = .046). There were no adverse events that occurred in both groups. CONCLUSIONS: Oral decoctions based on Qi-Yin syndrome differentiation after adjuvant chemotherapy prolonged DFS, reduced the risk of disease recurrence and metastasis, improved quality of life, and down-regulated the proportion of CTLA-4+Tregs in completely resected stage ΙΙΙA NSCLC patients. TRIAL REGISTRATION: Chinese Clinical Trial Register, No. ChiCTR1800019396. Date of registration: 9 November 2018.

SMAD2/3 Phosphorylation is correlated with matrix metalloproteinase 9 expression in human periapical lesions.

OBJECTIVE: The aim of this study was to investigate the presence of phosphorylated SMAD2/3 (P-SMAD2/3) in periapical lesions in humans and its possible correlation with matrix metalloproteinase 9 (MMP9) during the development of apical periodontitis. DESIGN: In this study, a total of 38 samples were collected, consisting of 16 healthy controls and 22 periapical lesions. These samples underwent fixation, dehydration, and embedding for further histologic and immunochemical analysis. The expression of phosphorylated SMAD2/3 and MMP9 was quantified using the average integrated optical density. Additionally, immunofluorescence analysis was conducted to investigate the colocalization of phosphorylated SMAD2/3 and MMP9. RESULTS: The study found that periapical lesions exhibited a stronger expression of MMP9 compared to healthy controls. Additionally, the expression of phosphorylated SMAD2/3 was observed to increase in the periapical granulomas and radicular cysts group, as compared to the normal group (P < 0.01). The results of the immunofluorescence test showed that phosphorylated SMAD2/3 was colocalized with MMP9. CONCLUSIONS: The study found that SMAD2/3 phosphorylation is correlated with matrix metalloproteinase 9 expression in human periapical lesions, suggesting its potential involvement in tissue destruction and immune cell infiltration in periapical lesions.

A lung cancer risk warning model based on tongue images.

Objective: To investigate the tongue image features of patients with lung cancer and benign pulmonary nodules and to construct a lung cancer risk warning model using machine learning methods. Methods: From July 2020 to March 2022, we collected 862 participants including 263 patients with lung cancer, 292 patients with benign pulmonary nodules, and 307 healthy subjects. The TFDA-1 digital tongue diagnosis instrument was used to capture tongue images, using feature extraction technology to obtain the index of the tongue images. The statistical characteristics and correlations of the tongue index were analyzed, and six machine learning algorithms were used to build prediction models of lung cancer based on different data sets. Results: Patients with benign pulmonary nodules had different statistical characteristics and correlations of tongue image data than patients with lung cancer. Among the models based on tongue image data, the random forest prediction model performed the best, with a model accuracy of 0.679 ± 0.048 and an AUC of 0.752 ± 0.051. The accuracy for the logistic regression, decision tree, SVM, random forest, neural network, and naïve bayes models based on both the baseline and tongue image data were 0.760 ± 0.021, 0.764 ± 0.043, 0.774 ± 0.029, 0.770 ± 0.050, 0.762 ± 0.059, and 0.709 ± 0.052, respectively, while the corresponding AUCs were 0.808 ± 0.031, 0.764 ± 0.033, 0.755 ± 0.027, 0.804 ± 0.029, 0.777 ± 0.044, and 0.795 ± 0.039, respectively. Conclusion: The tongue diagnosis data under the guidance of traditional Chinese medicine diagnostic theory was useful. The performance of models built on tongue image and baseline data was superior to that of the models built using only the tongue image data or the baseline data. Adding objective tongue image data to baseline data can significantly improve the efficacy of lung cancer prediction models.

Case report: Response to endocrine therapy in triple-negative breast cancer metastases with altered hormone receptors.

Triple-negative breast cancer refers to breast cancer patients with negative estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER2). Metastatic triple-negative breast cancer is predominantly treated with chemotherapy, but later-line treatment remains challenging. Breast cancer is highly heterogeneous, and the expression of hormone receptors is often inconsistent between primary and metastatic lesions. Here, we report a case of triple-negative breast cancer 17 years after surgery with lung metastases for 5 years that progressed to pleural metastases after multiple lines of chemotherapy. The pleural pathology suggested ER (+) and PR (+) and transformation to luminal A breast cancer. This patient received fifth-line letrozole endocrine therapy and achieved partial response (PR). The patient's cough and chest tightness improved after treatment, associated tumor markers decreased, and progression-free survival (PFS) exceeded 10 months. Our results may be of clinical relevance for patients with hormone receptor alterations in advanced triple-negative breast cancer and suggest that individualized regimens should be developed for breast cancer based on the molecular expression of tumor tissue at the primary and metastatic sites.

Multi-center randomized double-blind controlled clinical study of chemotherapy combined with or without traditional Chinese medicine on quality of life of postoperative non-small cell lung cancer patients.

BACKGROUND: Traditional Chinese medicine (TCM) is a widely applied complementary therapy for cancer patients. It can reduce the chemical drugs induced toxic effects to improve the quality of life (QOL). This study applies the highest quality of clinical trial methodology to examine the role of TCM in improving QOL of postoperative non-small-cell lung cancer patients. METHODS AND DESIGN: This study is a multi-center, randomized, placebo-controlled, double-blind trial. Four hundred eighty patients will be recruited into seven different research centers in China. These patients that meet the inclusion criteria will be randomized into either a treatment group or a placebo group. Each group will receive treatments of 3-weekly chemotherapy with TCM or placebo for four cycles. The primary outcome will involve the evaluation of QOL and the secondary outcome assessments will include two-year disease-free survival rate and disease-free survival. Other efficacy assessments are changes of TCM symptoms and toxicity. Side effects and safety profile of the therapy would be evaluated at the same time. The investigators expect that TCM therapy combined with chemotherapy is superior to chemotherapy solely in terms of QOL improvement and disease-free survival extension. "Intention-to-treat" analysis will include all randomized participants. DISCUSSION: The results from the clinical trial will provide evidence for the effectiveness of chemotherapy combined with or without TCM in QOL of postoperative NSCLC patients. TRIAL REGISTRATION: Clinical Trials.gov (Identifier: NCT01441752).

Mechanism underlying the effect of Liujunzi decoction on advanced-stage non-small cell lung cancer in patients after first-line chemotherapy.

OBJECTIVE: To further clarify the anticancer mechanisms of Liujunzi decoction and provide possible targets for the treatment of advanced-stage nonsmall cell lung cancer (NSCLC) by re-analyzing differential gene expression profile of peripheral blood mononuclear cells (PBMCs) from Liujunzi decoctiontreated NSCLC patients receiving first-line chemotherapy. METHODS: The PBMC gene expression microarray data set GSE61926 was retrieved from a high throughput gene expression database. Differentially expressed genes (DEGs) were screened by paired sample t-test and the multiple ratio method. Gene ontology and Kyoto encyclopedia of genes and genomes (KEGG) pathway analyses were performed using the DAVID database. The protein-protein interaction (PPI) network was constructed using interaction gene library retrieval tools and Cytoscape software. RESULTS: A total of 162 DEGs were identified, with 67 upregulated genes and 95 downregulated genes. The functional distribution of Gene Oncology (GO) genes showed that DEGs were mostly concentrated in extracellular regions, calcium ion binding, and transcriptase activity. KEGG pathway analysis showed that cytokine-cytokine receptor interactions were significantly enriched. PPI network analysis screened out the top 10 central protein-coding genes with the highest nodal degree: IL2, PIWIL4, DICER1, PIWIL2, SAA1, XCL1, IL22RA1, ARHGAP11A, DCP1A, and GDNF. Among them, the central protein-coding gene with the highest node degree was IL2. In addition, the central protein-coding genes with high node degrees and high molecular complex detection (MCODE) scores were PIWIL4, DICER1, PIWIL2, and DCP1A, all of which are related to tumor development. CONCLUSIONS: One signaling pathway and 10 central protein-coding genes related to anticancer mechanisms were screened by re-analysis of GSE61926 data. IL2, PIWIL4, DICER1, PIWIL2, and DCP1A may have important roles in the mechanism of Liujunzi decoction treatment against NSCLC. Our results suggest that the anticancer mechanism of Liujunzi decoction may be related to gene silencing by RNA and the biological processes of piwi-interacting RNA and other small RNAs.

Simultaneous development of pneumonitis and autoimmune diabetes secondary to immune checkpoint inhibitor treatment with durvalumab in an advanced small cell lung cancer patient: A case report.

RATIONALE: Immune checkpoint inhibitors (ICIs) have been widely used in the treatment of various types of cancers worldwide, which is the most significant breakthrough in cancer therapy in recent years. Despite their excellent benefits in anti-tumor efficacy, a subset of patients will experience various autoimmune toxicities, termed as immune-related adverse events (irAEs), which can affect almost any organ systems, but related to the pulmonary and pancreatic islets simultaneously has rarely been reported and discussed. PATIENT CONCERNS: In this report, we describe a rare case of a 65-year-old man patient with advanced small cell lung cancer (SCLC) who suffered general fatigue, dry cough, chest tightness, shortness of breath and polyuria-polydipsia syndrome after the eighth cycle treatment with programmed cell death ligand-1 (PD-L1) inhibitor durvalumab. DIAGNOSES: According to the results of laboratory tests, chest computed tomography and multidisciplinary discussion, the patient was eventually diagnosed with ICI-related pneumonitis and autoimmune diabetes mellitus. INTERVENTIONS: Multiple daily subcutaneous insulin injections, empirical anti-infection and immunosuppression treatment with corticosteroids were performed. OUTCOMES: After the cessation of durvalumab and comprehensive treatment, the patient's respiratory condition was relieved significantly and his blood glucose was well controlled with insulin therapy. LESSONS: With the widespread use of ICIs, there will be more patients developing these rare but severe irAEs in clinical practice, which should attract great attention of both clinicians and patients.

[Effect of Chinese medicine comprehensive regimen as the maintenance therapy on time to progression and quality of life of patients with advanced non-small-cell lung cancer].

OBJECTIVE: To observe the effect of Chinese medicine (CM) comprehensive regimen as the maintenance therapy (MT) on time to progression (TTP) and quality of life (QOL) of patients with advanced non-small-cell lung cancer (NSCLC). METHODS: The study was a prospective, randomized and controlled clinical trial. Fifty non-progressive patients with advanced NSCLC who responded to first-line therapy were randomized into the test group (25 cases, treated with CM comprehensive regimen: intravenous dripping of Chinese herbal preparation, oral administration of Chinese herbal decoction, and point application) and the control group [25 cases, treated with one of three single-agent maintenance chemotherapy regimens: pemetrexed (500 mg/m2, day 1), docetaxel (75 mg/m2, day 1), and gemcitabine (1000 mg/mi, day 1 and day 8) in the ratio of 1:1]. Each cycle consisted of 21 days. Cycles were repeated until the disease progressed, or intolerable toxic or adverse reaction occurred, or patients refused to continue the treatment. The primary end point was TTP and the secondary end point was QOL. QOL was evaluated using the European Organization for Research and Treatment of Cancer quality-of-life questionnaire QLQ-LC43 (EORTC QLQ-LC43). TTP of fifty patients and QOL of 43 patients had been statistically analyzed. RESULTS: (1) The TTP in the test group was prolonged for 23 days when compared with that of the control group, with insignificant difference (87 days vs 64 days, P=0.063). (2) The scores of domains in EORTC QLQ-LC43 were statistically significantly better in the test group than in the control group (P<0.05) except cognitive and social functions, the symptoms of dysphagia and pain in other parts. CONCLUSIONS: (1) The CM comprehensive regimen as MT had equivalent efficacy on TTP when compared with single-agent maintenance chemotherapy regimen. It was advantageous over improving the QOL. (2) It is necessary to enlarge the sample size to further confirm the therapeutic efficacy of CM comprehensive regimen as MT in treatment of patients with advanced NSCLC.

Expression of Matrix Metalloproteinases and Tissue Inhibitor of Matrix Metalloproteinases during Apical Periodontitis Development.

INTRODUCTION: Matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) are considered important mediators of the periapical immune response to infection. This study aimed to clarify the putative relationship between MMPs and TIMPs by elucidating the activity of MMP-1, MMP-2, MMP-8, MMP-9, TIMP-1, and TIMP-2 in the temporal development of apical periodontitis (AP) in mice. METHODS: AP was induced in the lower first molars of 30 male Kunming mice. The animals were randomly killed at 0, 7, 14, 28, 60, and 90 days after pulp exposure. The jaws were removed and subjected to quantitative real-time reverse transcription polymerase chain reaction, enzyme-linked immunosorbent assay, and immunohistochemical analysis. RESULTS: The MMP-1, MMP-2, MMP-8, MMP-9, TIMP-1, and TIMP-2 messenger RNA and protein expression levels increased with periapical inflammation progression (P < .05). The MMP-1, MMP-2, MMP-9, TIMP-1, and TIMP-2 messenger RNA and protein expression levels increased during the acute and chronic stages of periapical lesions, with less MMP-2 and MMP-9 expression levels at the chronic stage (P < .05). The MMP-8 expression increased at the chronic stage of inflammation (P < .05) but not at the acute stage. Immunostained MMP-2 and TIMP-1 were observed in all experimental periods. CONCLUSIONS: MMP-1, MMP-2, MMP-8, MMP-9, TIMP-1, and TIMP-2 were expressed in all periapical samples with varying levels between them. MMP expression could be related to TIMP expression in the temporal development of AP.

Hypoxia and Porphyromonas gingivalis-lipopolysaccharide synergistically induce NLRP3 inflammasome activation in human gingival fibroblasts.

OBJECTIVE: To investigate the effects of hypoxia and Porphyromonas gingivalis- lipopolysaccharide (P. gingivalis-LPS) on activation of the NACHT leucine-rich repeat protein 3 (NLRP3) inflammasome in human gingival fibroblasts (HGFs). DESIGN: Periodontitis was optimally simulated using a hypoxic concentration of 1%. HGFs were stimulated using P. gingivalis-LPS (1.0 µg/ml) in normoxia and hypoxia for 3 h and 6 h, respectively. The expression levels of genes and proteins of hypoxia-inducible factor-1α (HIF-1α), interleukin-1ß, gasdermin D (GSDMD) and the NLRP3 inflammasome, including NLRP3, apoptosis-associated speck-like protein containing CARD (ASC), caspase-1 and its activated forms, were measured using quantitative real-time polymerase chain reaction and western blot. ELISA was used to detect and determine levels of the inflammatory factor interleukin-1ß in cell supernatants. Lactate dehydrogenase (LDH) release assay, caspase-1 activity assay and Hoechst 33342/Propidium Iodide (PI) staining were performed to further verify the presence of pyroptosis. RESULTS: The NLRP3 inflammasome (i.e., NLRP3, ASC, caspase-1) was not affected by individual stimulation using P. gingivalis-LPS or hypoxia. However, the combination of both hypoxia and P. gingivalis-LPS stimulation significantly enhanced inflammasome activation and promoted the expression of interleukin-1ß, gasdermin D and HIF-1α at gene and protein levels; PI positive cells and the release of LDH were also elevated. CONCLUSION: Hypoxia and P. gingivalis-LPS synergistically induced NLRP3 inflammasome activation in HGFs, and subsequently high levels of interleukin-1ß and GSDMD-mediated pyroptosis can cause an HGF inflammatory response, which plays an important role in the pathogenesis of periodontitis.

Responses to crizotinib and cabozantinib in patient with lung adenocarcinoma harboring mesenchymal-epithelial transition factor exon 14 skipping mutation: A case report.

RATIONALE: Lung cancer is a leading cause of cancer-related mortality worldwide. Currently, targeted therapy has proved highly efficient in the treatment of advanced non-small cell lung cancer (NSCLC). Mesenchymal-epithelial transition factor (MET) is considered a validated molecular target in NSCLC. Given the low incidence of MET exon 14 skipping mutation, the planning of precision treatment for patients is a clinical problem that needs to be solved. In this report, we present a MET-positive case that benefited from crizotinib and cabozantinib treatment. PATIENT CONCERNS: A 77-year-old patient was diagnosed with lung adenocarcinoma in our hospital. Positron emission tomography-computed tomography (PET-CT) showed a right upper lobe mass (58 × 56 mm, SUVmax 15.6), right hilar enlarged lymph nodes, and multiple bone and left adrenal metastases (c-T3N1M1c). DIAGNOSES: MET exon 14 mutation (exon14, c.2888-1G>C) was examined using the lung puncture sample by next generation sequencing. Therefore, the patient was diagnosed with late-stage lung adenocarcinoma with MET exon14 skipping gene mutation. INTERVENTIONS: Crizotinib was given as the first-line treatment from August 2019. Considering the resistance of crizotinib, cabozantinib was given for second-line treatment. OUTCOMES: Crizotinib was administered (250 mg bid) for 8 months, and her disease achieved partial regression (PR) and progression-free survival (PFS), which lasted for 8 months. The patient also reached PR after the second-line treatment with cabozantinib, and is currently under follow-up, with an overall survival (OS) of >12 months. LESSONS: As MET exon 14 skipping mutation is rare in clinical practices, MET-TKIs (tyrosine kinase inhibitors) treatment can boost curative effects and improve prognosis of patients with advanced lung adenocarcinoma. This case report supports a rationale for the treatment of lung adenocarcinoma patients with a MET exon 14 skipping mutation and provides alternative treatment options for these types of NSCLC patients.

MMP9 protects against LPS-induced inflammation in osteoblasts.

The matrix metalloproteinase (MMP) family is widely involved in the destruction of the pulp and apical tissues in the inflammatory process. MMP9 is closely related to oral inflammation. Nevertheless, the specific function of MMP9 during oral inflammation, as well as its mechanism, is not well understood. Our previous studies found that in experimentally induced apical periodontitis, more severe inflammation occurred in MMP9 knockout mice compared with the wild type mice. Moreover, the pathology phenomenon of alveolar bone destruction was even more evident in MMP9 knockout mice compared with the wild type mice. We proposed that MMP9 has "anti-inflammatory" properties. We aimed to study the effects of MMP9 on inflammatory response as well as on bone formation and bone destruction. We found a specific relationship between MMP9 and inflammation. qRT-PCR and Western blot revealed that the production of IL-1ß, TNF-α, RANK, RANKL, TLR2, and TLR4 was reduced by MMP9 in LPS-stimulated MC3T3-E1 cells. Meanwhile, the expressions of OPG and OCN were increased by MMP9 in LPS-stimulated cells. MMP9 plays a protective role in LPS-induced inflammation, thereby providing new clues to the prevention and treatment of apical periodontitis.

[Regulatory effect of jianpi wenshen recipe in combining with chemotherapy on the blood level of estradiol in patients with lung cancer].

OBJECTIVE: To observe the regulatory effect of Jianpi Wenshen Recipe (JPWS), a Chinese herbal preparation for strengthening Pi and warming Shen, combined with chemotherapy on the level of estradiol (E2) in patients with mid-late non-small cell lung cancer (NSCLC), and to analyse the relationship between the changes of estradiol and tumor size. METHODS: Fifty-one NSCLC patients were randomized into three groups: 16 cases in the JPWS group treated with JPWS alone, 18 cases in the test group treated with combined therapy of JPWS plus chemotherapy, and 17 cases in the chemotherapy group treated with chemotherapy alone, all were treated for 2 months. The changes of blood E2 level and tumor size before and after treatment were compared. RESULTS: The disease control rate in the JPWS group and combined therapy group was 53.85% (7/13) and 80.00% (8/10), respectively, both were higher than that in the chemotherapy group (44.40%, 4/9), but the difference showed statistical insignificance (P > 0.05). E2 level was significantly lowered after treatment in the former two groups (all P < 0.05), and the change was in accordance with that of tumor size in 26 out of 31 patients (P < 0.01). CONCLUSION: JPWS combined with chemthherapy can stabilize the tumor size and down-regulate E2 levelo, with the change of E2 correlated with that of tumor size in patients. Hence, decreasing E2 is one of the mechanisms for JPWS in treating lung cancer.