Nuclear translocation of Axl contributes to the malignancy of oral cancer cells.

Background/purpose: Dysregulation of receptor tyrosine kinases is implicated in cancer development. This study aimed to investigate the nuclear translocation of Axl, a membrane protein and receptor tyrosine kinase in cancer malignancy. Materials and methods: We examined Axl's entry into the cell nucleus and validated it with the nuclear export inhibitor leptomycin. Transfection experiments with mutated nuclear localization signals were conducted to assess the impact of reduced nuclear Axl levels on cancer cell malignancy. Additionally, we evaluated the effects of decreased nuclear Axl on sensitivity to radiation and cisplatin, a chemotherapeutic drug. Results: In the present study, we observed nuclear translocation of Axl in cancer cells. Reducing nuclear Axl levels led to a decrease in cancer cell malignancy. This nuclear translocation was further validated using a nuclear export inhibitor, leptomycin. Additionally, transfection experiments with mutated nuclear localization signals confirmed the functional significance of Axl's nuclear localization. Notably, decreased nuclear Axl levels also increased the sensitivity of cancer cells to radiation and cisplatin treatment. Conclusion: This study suggests that Axl's nuclear translocation plays a significant role in cancer malignancy. Targeting Axl's nuclear localization could offer a potential strategy to inhibit cancer progression and improve the efficacy of radiation and chemotherapy treatments.

MiR-34a functions as a tumor suppressor in oral cancer through the inhibition of the Axl/Akt/GSK-3ß pathway.

Background/purpose: Oral cancer is a prevalent malignancy affecting men globally. This study aimed to investigate the regulatory role of miR-34a in oral cancer cells through the Axl/Akt/glycogen synthase kinase-3ß (GSK-3ß) pathway and its impact on cellular malignancy. Materials and methods: We examined the effects of miR-34a overexpression on the malignancy of oral cancer cells. Multiple oral cancer cell lines were assessed to determine the correlation between endogenous miR-34a and Axl levels. Transfection experiments with miR-34a were conducted to analyze its influence on Axl mRNA and protein expression. Luciferase reporter assays were performed to investigate miR-34a's modulation of Axl gene transcription. Manipulation of miR-34a expression was utilized to demonstrate its regulatory effects on oral cancer cells through the Axl/Akt/GSK-3ß pathway. Results: Overexpression of miR-34a significantly suppressed the malignancy of oral cancer cells. We observed an inverse correlation between endogenous miR-34a and Axl levels across multiple oral cancer cell lines. Transfection of miR-34a resulted in decreased Axl mRNA and protein expression, and luciferase reporter assays confirmed miR-34a-mediated modulation of Axl gene transcription. The study revealed regulatory effects of miR-34a on oral cancer cells through the Axl/Akt/GSK-3ß pathway, leading to alterations in downstream target genes involved in cellular proliferation and tumorigenesis. Conclusion: Our findings highlight the significance of the miR-34a/Axl/Akt/GSK-3ß signaling axis in modulating the malignancy of oral cancer cells. Targeting miR-34a may hold therapeutic potential in oral cancer treatment, as manipulating its expression can attenuate the aggressive behavior of oral cancer cells via the Axl/Akt/GSK-3ß pathway.

Silibinin alleviates inflammation-induced bone loss by modulating biological interaction between human gingival fibroblasts and monocytes.

BACKGROUND: Silibinin has shown various pharmacological effects that could be attributed to its antioxidant, anti-inflammatory, and immunoregulatory properties. However, the therapeutic potential of silibinin for periodontitis has not been investigated. METHODS: The therapeutic effects of silibinin in ligation-induced experimental periodontitis were investigated using biochemical, histological, and immunohistochemical methods. The effects of silibinin on the osteoclastogenesis of RAW264.7 cells were investigated using TRAP staining, quantitative polymerase chain reaction (qPCR), pit formation, and immunoblotting. Moreover, its effects on inflammatory cytokine production, RANKL expression, and oxidative stress in lipopolysaccharide (LPS)-stimulated human gingival fibroblasts (HGFs) were evaluated using qPCR and flow cytometry. A coculture system was established to elucidate the effects of silibinin on the crosstalk between LPS-stimulated HGFs and undifferentiated monocytes. RESULTS: Silibinin significantly reduced the alveolar bone loss, decreased the gingival inflammation and RANKL expression, and decreased the RANKL/osteoprotegerin ratio in gingival tissues in experimental periodontitis. The in vitro results showed that silibinin inhibited RANKL-induced osteoclast differentiation and function of RAW264.7 cells and suppressed RANKL-induced nuclear factor of activated T cells 1 (NFATc1) induction and translocation through the nuclear factor-κB and mitogen-activated protein kinase signaling pathways. Silibinin decreased the inflammatory cytokine level and oxidative stress production in LPS-stimulated HGFs; significantly suppressed membrane-bound RANKL expression on LPS-stimulated HGFs; and significantly disrupted TRAP+ cell differentiation in the coculture system. CONCLUSIONS: Silibinin effectively inhibits inflammation-induced bone loss in experimental periodontitis based on the regulation of stimulated HGFs by inhibiting the expression of inflammatory and osteoclastogenic mediators. Collectively, targeting the inflamed HGF resolution that mediates osteogenesis may use silibinin as a potential drug-repurposing candidate for modulating alveolar bone destruction in periodontitis. SUMMARY: Silibinin effectively inhibits inflammation-induced bone loss in experimental periodontitis based on the regulation of stimulated HGFs by inhibiting the expression of inflammatory and osteoclastogenic mediators.

Effectiveness of different root-end filling materials in modern surgical endodontic treatment: A systematic review and network meta-analysis.

Background/purpose: There is controversial evidence on the best choice for root-end filling materials in follow-up periods and treatment protocols. The purpose of this study was to evaluate the effectiveness of different root-end filling materials in modern surgical endodontic treatment. Materials and methods: A total of 16 studies with a minimum follow-up of 12-months were qualified to be reviewed, involving randomized control trials and observational studies in PubMed, Cochrane library and Scopus until September 1, 2021. The outcome of modern surgical endodontic treatment was assessed based on clinical and radiographic success. Direct comparisons were combined to estimate indirect comparisons, and the estimated effect size was analyzed using the odds ratio (OR). The comparative effectiveness of all materials for target outcomes were shown as P-score. Results: Within this network meta-analysis, mineral trioxide aggregate (MTA) had superior effects among all root-end filling materials at 12-months follow-up. (MTA: OR, 2.03; 95% CI, 0.84-4.91; P-score, 0.86; reference material, gutta-percha). In further sensitivity analyses, MTA, calcium silicate-based root repair material (RRM) and super EBA cement (Super EBA) were associated with significantly higher success rates at 12-months follow-up. (MTA: OR, 5.62; 95% CI, 1.58-19.99; P-score, 0.88; RRM: OR, 5.23; 95% CI, 1.05-25.98; P-score, 0.74; Super EBA: OR, 3.99; 95% CI, 1.06-15.04; P-score, 0.54; reference material, gutta-percha). Conclusion: MTA remains the best choice for root-end filling materials of modern surgical endodontic treatment at the 12-month follow-up. Comparative randomized clinical trials in the long-term follow-up are warranted in future investigations.

Obesity-associated leptin promotes chemoresistance in colorectal cancer through YAP-dependent AXL upregulation.

Obesity results from an imbalance between caloric intake and energy expenditure, and it is highly associated with colorectal carcinogenesis and therapeutic resistance in patients with colorectal cancer (CRC). Dysregulation of adipokine production in obesity has been reported to cause malignant behaviors in CRC. Leptin, which is the principal hormone secreted by adipocytes and an obesity-associated adipokine, is significantly overexpressed in CRC tissues. However, the effect of leptin on chemoresistance in CRC is unclear. Therefore, the aim of this study was to clarify the role of leptin and the underlying mechanisms in mediating 5-fluorouracil (5-FU) resistance in CRC. We used palmitate to artificially generate obese adipocytes. As expected, lipid accumulation was significantly increased in obese adipocytes. We demonstrated that CRC cells incubated with conditioned media (CM) harvested from obese adipocytes were associated with increased resistance to 5-FU. Notably, this increase in resistance to 5-FU was through the elevated production and secretion of leptin. Leptin could further stimulate the expression of AXL and activate its downstream signaling molecule, PLCγ, thereby resulting in an increased expression of p-glycoprotein (P-gp) in CRC cells. Mechanistically, leptin induced AXL expression via the inhibition of AMPK and subsequent increase in YAP activation and nuclear translocation. In addition, nuclear YAP interacted with TEAD and promoted the occupancy of TEAD on the AXL promoter, thereby stimulating AXL promoter activity after leptin treatment. Furthermore, leptin neutralization rescued the sensitivity of CRC tumors to 5-FU in mice fed on a high-fat diet (HFD). These results indicated that leptin mediated 5-FU resistance through YAP-dependent AXL overexpression in CRC.

Dysregulation of the miR-30a/BiP axis by cigarette smoking accelerates oral cancer progression.

BACKGROUND: Cigarette smoking is the most significant cause of oral cancer progression. Cigarette smoke condensate (CSC) has been shown to induce endoplasmic reticulum (ER) stress. Binding immunoglobulin protein (BiP) being as an ER stress regulator, has been reported to be implicated in malignant behaviors. Therefore, the aim of this study was to investigate the role of the ER stress-responsive protein, BiP, in CSC-induced oral squamous cell carcinoma (OSCC) malignancy. METHODS: The biological role of BiP in CSC-induced tumor progression was investigated in OSCC cells (YD38 and SCC25) and in a tumor xenograft mouse model. The expressions of related genes were investigated using quantitative RT-PCR and Western blot analysis. Cell migration and invasion were assessed using scratch wound healing and Transwell invasion assays. The effects of conditioned media from OSCC cells on the angiogenic activities of endothelial cells were analyzed using a tube formation assay. The interaction between miR-30a and BiP mRNA was detected using a luciferase reporter assay. RESULTS: Our results demonstrated that CSC increased the expression of BiP in time- and dose-dependent manners in YD38 and SCC25 cells, and that silencing BiP abrogated CSC-induced cell invasion and tumor-associated angiogenesis. Notably, the putative miR-30a binding site was observed in the 3'untranslated region (UTR) of BiP mRNA, and miR-30a suppressed BiP expression by targeting 3'UTR of BiP transcript. In addition, CSC increased the expression of BiP in OSCC cells by downregulating miR-30a. We also showed that BiP promoted invasion and tumor-associated angiogenesis by increasing the production and secretion of vascular endothelial growth factor in CSC-exposed OSCC cells. Moreover, BiP inhibition suppressed OSCC growth and reduced tumor vessel density in tumor-bearing mice administered with CSC. CONCLUSIONS: These observations suggest that epigenetic regulation of BiP via miR-30a downregulation is involved in CSC-induced OSCC progression.

YAP-Dependent BiP Induction Is Involved in Nicotine-Mediated Oral Cancer Malignancy.

Cigarette smoking is a significant risk factor for the development and progression of oral cancer. Previous studies have reported an association between nicotine and malignancy in oral cancer. Recent studies have also demonstrated that nicotine can induce endoplasmic reticulum (ER) stress in tumor cells. Binding immunoglobulin protein (BiP) acts as a master regulator of ER stress and is frequently overexpressed in oral cancer cell lines and tissues. However, the effect of nicotine on BiP in oral cancer is unknown. Therefore, this study aimed to evaluate the role of BiP and its underlying regulatory mechanisms in nicotine-induced oral cancer progression. Our results showed that nicotine significantly induced the expression of BiP in time- and dose-dependent manners in oral squamous cell carcinoma (OSCC) cells. In addition, BiP was involved in nicotine-mediated OSCC malignancy, and depletion of BiP expression remarkably suppressed nicotine-induced malignant behaviors, including epithelial-mesenchymal transition (EMT) change, migration, and invasion. In vivo, BiP silencing abrogated nicotine-induced tumor growth and EMT switch in nude mice. Moreover, nicotine stimulated BiP expression through the activation of the YAP-TEAD transcriptional complex. Mechanistically, we observed that nicotine regulated YAP nuclear translocation and its interaction with TEAD through α7-nAChR-Akt signaling, subsequently resulting in increased TEAD occupancy on the HSPA5 promoter and elevated promoter activity. These observations suggest that BiP is involved in nicotine-induced oral cancer malignancy and may have therapeutic potential in tobacco-related oral cancer.

Correction to: Gamma synuclein is a novel nicotine responsive protein in oral cancer malignancy.

[This corrects the article DOI: 10.1186/s12935-020-01401-w.].

MiR-944/CISH mediated inflammation via STAT3 is involved in oral cancer malignance by cigarette smoking.

The cytokine-inducible Src homology 2-containing protein (CISH) is an endogenous suppressors of signal transduction and activator of transcription (STAT) and acts as a key negative regulator of inflammatory cytokine responses. Downregulation of CISH has been reported to associate with increased activation of STAT and enhanced inflammatory pathways. However, whether microRNAs (miRNAs) play a crucial role in CISH/STAT regulation in oral squamous cell carcinoma (OSCC) remains unknown. The expression of CISH on OSCC patients was determine by quantitative real-time PCR (qRT-PCR) and immunohistochemistry. Specific targeting by miRNAs was determined by software prediction, luciferase reporter assay, and correlation with target protein expression. The functions of miR-944 and CISH were accessed by transwell migration and invasion analyses using gain- and loss-of-function approaches. Enzyme-linked immunosorbent assay (ELISA) and qRT-PCR were used to evaluate the pro-inflammation cytokines expression under the miR-944, CISH, NNK or combinations treatment. We found that the CISH protein, which modulates STAT3 activity, as a direct target of miR-944. CISH protein was significantly down-regulated in OSCC patients and cell lines and its level was inversely correlated with miR-944 expression. The miR-944-induced STAT3 phosphorylation, pro-inflammation cytokines secretion, migration and invasion were abolished by CISH restoration, suggesting that the oncogenic activity of miR-944 is CISH dependent. Furthermore, tobacco extract (NNK) may contribute to miR-944 induction and STAT3 activation. Antagomir-mediated inactivation of miR-944 prevented the NNK-induced STAT3 phosphorylation and pro-inflammation cytokines secretion. Altogether, these data demonstrate that NNK-induced miR944 expression plays an important role in CISH/STAT3-mediated inflammatory response and activation of tumor malignancy.

Gamma synuclein is a novel nicotine responsive protein in oral cancer malignancy.

BACKGROUND: The mechanisms of neuronal protein γ-synuclein (SNCG) in the malignancy of oral squamous cell carcinoma (OSCC) are not clear. This study tested the hypothesis that SNCG is involved in nicotine-induced malignant behaviors of OSCC. The effect of nicotine on SNCG expression and epithelial-to-mesenchymal transition (EMT) markers were examined. METHODS: Short hairpin RNA (shRNA) and an antagonist specific for α7-nicotine acetylcholine receptors (α7-nAChRs) were used to examine the role of α7-nAChRs in mediating the effects of nicotine. Knockdown of SNCG in nicotine-treated cells was performed to investigate the role of SNCG in cancer malignancy. The in vivo effect of nicotine was examined using a nude mouse xenotransplantation model. RESULTS: Nicotine increased SNCG expression in a time- and dose-dependent manner. Nicotine treatment also increased E-cadherin and ZO-1 and decreased fibronectin and vimentin expression. After specific knockdown of α7-nAChRs and inhibition of the PI3/AKT signal, the effect of nicotine on SNCG expression was attenuated. Silencing of SNCG abolished nicotine-induced invasion and migration of OSCC cells. The xenotransplantation model revealed that nicotine augmented tumor growth and SNCG expression. CONCLUSION: Nicotine upregulated SNCG expression by activating the α7-nAChRs/PI3/AKT signaling that are participated in nicotine-induced oral cancer malignancy.

The prognostic factors of recurrence and survival in female patients with lung adenocarcinoma and breast cancer.

BACKGROUND: The aim of this study was to verify the predictors of recurrence and survival in lung adenocarcinoma patients with experiences of breast cancer therapies. METHODS: We retrospectively reviewed consecutive patients who were treated at our hospital for lung adenocarcinoma from 2004/01 to 2014/03. The patients were divided into groups of those with lung adenocarcinoma alone and those with lung and breast cancer. Kaplan-Meier plots and log-rank tests were used to estimate outcomes. RESULTS: 54 patients with lung adenocarcinoma and breast cancer were compared with 457 patients with single primary lung adenocarcinomas. After propensity score matching with control of age, operation type, smoking status and pathologic stage, tumor differentiation, recurrence rate and tumor size were significantly different between two groups. The significant predictors for recurrence included undergone chemotherapy (HR = 25, p < 0.001), moderate/poor differentiation (HR = 8.125, p = 0.012), tumor size ≧ 2 cm (HR = 15, p < 0.001), LVSI (HR = 13.67, p = 0.031) and GGO ratio < 50% (HR = 14.667, p = 0.014). The significant prognostic factors for survival were accepted chemotherapy (HR = 6.182, p = 0.021), LVSI (HR = 22, p = 0.012) and GGO ratio < 50% (HR = 9.143, p = 0.045). Kaplan-Meier analysis revealed that patients with lung adenocarcinoma and breast cancer had a better 5-year disease-free survival (p = 0.009), while the Her2-negative patients obtained a better overall survival (p = 0.038). CONCLUSIONS: In patients with breast cancer and lung adenocarcinoma, independent risk factors of recurrence were undergone chemotherapy, moderate/poor differentiation, tumor size ≧ 2 cm, LVSI and GGO ratio < 50%. Only undergone chemotherapy, LVSI and GGO ratio < 50% were significant poor predictors for survival. However, patients with metachronous lung adenocarcinoma and breast cancer had better disease-free survival and less tumor recurrence than patients with lung adenocarcinoma alone.

α7-Nicotine acetylcholine receptor mediated nicotine induced cell survival and cisplatin resistance in oral cancer.

OBJECTIVE: To investigate the effect of nicotine on cell survival and cisplatin resistance in oral cancer and the possible involvement of α7-nicotinic acetylcholine receptors (α7-nAChRs). DESIGN: The effects of nicotine on cell survival and cisplatin-induced apoptosis were assessed. Knockdown of α7-nAChRs by short hairpin RNA and the specific antagonist methyllycaconitine (MLA) was used to examine the involvement of α7-nAChRs in modulating the effects of nicotine. Apoptosis signal molecules were examined in nicotine- and cisplatin-treated cells. RESULTS: Nicotine increased the survival of the oral cancer cells YD8 and OEC-M1 in a dose- and time-dependent manner. Nicotine treatment accelerated cell cycle progression in the oral cancer cells, and significantly reduced cisplatin-induced cell apoptosis. In the α7-nAChR-silenced cells, the prosurvival effect of nicotine in the cisplatin-treated cells was attenuated. Co-treatment of cisplatin and nicotine attenuated the effect of cisplatin on Bcl-2 expression. In addition, the effect of nicotine on cell survival under cisplatin treatment was attenuated with the addition of the Bcl-2 inhibitor ABT-737. CONCLUSIONS: Treating oral cancer cells with nicotine increased cell survival and cisplatin resistance, in which α7-nAChRs were involved.

Macrophage phenotypes and Gas6/Axl signaling in apical lesions.

BACKGROUND/PURPOSE: Macrophages participate in the periapical inflammation with pro-inflammatory M1 cells and anti-inflammatory M2 cells. Gas6/Axl signal is the responsible pathway for the activation of M1 and polarization of M2. The aim of this study was to compare the number of CD16+ M1 cells, CD206+ M2 cells, and Gas6/Axl expression between apical granulomas and radicular cysts. MATERIALS AND METHODS: Twenty-four cases of granuloma and twenty of cysts were submitted to immunohistochemistry using anti-CD16 and anti-CD206 antibodies for determining M1 and M2 macrophages and investigating the cells with positive Gas6 and Axl expression. RESULTS: There were more numerous of M1 macrophages in radicular cysts (175.9 ±â€¯87.7) compared to apical granuloma (116.6 ±â€¯55.8), and M2 macrophages was higher in cysts (204.0 ±â€¯97.6) than granuloma (152.9 ±â€¯64.6). The level of Gas6/Axl expression were similar. There was a significant different in M1 macrophage (P = 0.014) between two diagnosis. In patients with or without root resorption, the number of M1 were 194.6 ±â€¯57.2 compared with 139.1 ±â€¯79.6. The number of M2 were 241.7 ±â€¯81.4 and 164.6 ±â€¯77.1. The expression of Axl was stronger in root resorption patients (191.1 ±â€¯43.6), but the tendency in Gas6 expression was similar. Significant differences were noted in high M2 infiltration and Axl positive lesions. CONCLUSION: It appears that macrophages associated with significantly higher numbers in radicular cysts than apical granuloma. Meanwhile, macrophages and Axl receptor was intensively expressed in patients with root resorption, related to severe inflammation.

OCT4B mediates hypoxia-induced cancer dissemination.

Hypoxia, the reduction of oxygen levels in cells or tissues, elicits a set of genes to adjust physiological and pathological demands during normal development and cancer progression. OCT4, a homeobox transcription factor, is essential for self-renewal of embryonic stem cells, but little is known about the role of OCT4 in non-germ-cell tumorigenesis. Here, we report that hypoxia stimulates a short isoform of OCT4, called OCT4B, via a HIF2α-dependent pathway to induce the epithelial-mesenchymal transition (EMT) and facilitate cancer dissemination. OCT4B overexpression decreased epithelial barrier properties, which led to an increase in cell migration and invasion in lung cancer cells. OCT4B knockdown attenuated HIF2α-induced EMT and inhibited cancer dissemination in cell-line and animal models. We observed that OCT4B bound the SLUG promoter and enhanced its expression, and SLUG silencing inhibited OCT4B-mediated EMT, accompanied with decreased cell migration and invasion. Correlation analysis revealed that OCT4B expression was significantly associated with the SLUG level in lung tumors. These results provide novel insights into OCT4B-mediated oncogenesis in cancer dissemination.

Plasma Growth Arrest-Specific 6 Protein and Genetic Variations in the GAS6 Gene in Patients with Metabolic Syndrome.

BACKGROUND: Growth arrest-specific 6 (Gas6) is a vitamin K-dependent protein secreted by immune cells, endothelial cells, vascular smooth muscle cells, and adipocytes. Recent studies indicate that Gas6 and receptors of the TAM (Tyro3, Axl, and Mer) family may be involved in the pathogenesis of obesity, systemic inflammation, and insulin resistance. The aim of this study was to investigate the association between plasma Gas6 protein and the c.843 + 7G>A Gas6 polymorphism in metabolic syndrome (MetS). METHODS: Two hundred five adults (88 men and 117 women) were recruited in this study. Plasma Gas6 concentration, general, and biochemical data were measured. All subjects were genotyped for the c.843 + 7G>A Gas6 polymorphism. RESULTS: Plasma Gas6 concentrations decreased in parallel with various MetS components in all groups (P = 0.017 for trend). Patients in the second and third tertiles of Gas6 level had higher high-density lipoprotein cholesterol (HDL-C) levels than those in the first tertile overall and in the female group. Plasma Gas6 levels were significantly positively correlated with HDL-C level and negatively with fasting glucose level in the female patients. The A allele and genotype AA in single nucleotide polymorphism c.843 + 7G>A were less frequent in the subjects with MetS compared to those without MetS. CONCLUSIONS: Our results demonstrated a positive correlation between Gas6 protein values and HDL-C and reinforce the association with fasting glucose. In addition, the presence of c.843 + 7G>A Gas6 polymorphisms, especially the AA genotype, had an association with MetS. The potential role of the Gas6/TAM system in MetS deserves further investigation.

Axl Involved in Mineral Trioxide Aggregate Induces Macrophage Polarization.

INTRODUCTION: In this study, we examined the effect of mineral trioxide aggregate (MTA) on macrophage polarization and the potential involvement of Axl/nuclear factor kappa B (NF-κB) signaling in mediating the effect of MTA. METHODS: The human monocyte cell line THP-1 was cultured with MTA solution for 1, 2, or 3 days, and the population change of M2 macrophages was analyzed by flow cytometry. Expression of M2 cytokines was examined by enzyme-linked immunosorbent assay. Phagocytosis and angiogenesis-induction ability were also assayed. The involvement of Axl/NF-κB signaling in MTA-treated cells was examined by analyzing phosphorylation status of Axl, Akt, IKKα/ß, and IκBα. Specific inhibitors for Axl/Akt/NF-κB signaling were added to MTA-treated THP-1 cells, and their cytokine expression change was examined. RESULTS: Flow cytometry analysis showed that MTA treatment increased CD206＋ cells in a time-dependent way. After MTA treatment, the expression of M2-related cytokines was up-regulated. MTA also enhanced phagocytic ability and the ability of THP-1 cells to induce angiogenesis. Treatment of MTA led to activate Axl/Akt/NF-kB signal axis by phosphorylation of Axl, Akt, IKKα/ß, IκBα, and p65. In addition, MTA-induced interleukin 10, transforming growth factor beta, and vascular endothelial growth factor expression was suppressed as specific inhibitors were added. CONCLUSIONS: Our findings indicate that MTA is able to induce macrophage polarization toward the M2 phenotype, with up-regulation of interleukin 10, transforming growth factor beta, and vascular endothelial growth factor, and that Axl/Akt/NF-κB signaling participates in this process. These results provide the cellular and molecular basis of MTA's anti-inflammatory action in clinical applications.

Periodontal status of tooth adjacent to implant with peri-implantitis.

OBJECTIVES: To evaluate the relationship between peri-implantitis and the periodontal health of the adjacent tooth, the periodontal status of the teeth adjacent and contralateral to the implants with and without peri-implantitis. METHODS: Fifty-three subjects with existing dental implants and chronic periodontitis were examined in this cross-sectional study. Seventy implants were categorized into peri-implantitis (n = 42) and healthy/mucositis (n = 28) groups. The periodontal and peri-implant status, including probing depth (PD), clinical attachment level (CAL), and gingival recession (GR) were measured at 6 sites around the implants and the teeth adjacent and contralateral to those implants. In total 560 sites of the 70 teeth/implant sets, the association between the periodontal status at the near and away sites of the teeth (according to implant) and the implant status (without/with peri-implantitis) was examined. RESULTS: A significantly different mean PD (5.01 ±â€¯1.69, 4.42 ±â€¯1.8, 3.55 ±â€¯0.88, and 3.71 ±â€¯1.07 mm, p < 0.001) and CAL (6.02 ±â€¯2.36, 4.89 ±â€¯2.04, 4.35 ±â€¯1.11, and 4.35 ±â€¯1.5 mm, p < 0.001) were noted at the near sites of the teeth adjacent to the implants with peri-implantitis when compared with the away sites of adjacent and contralateral teeth and the near sites of contralateral teeth. With generalized estimating equation (GEE), the presence of peri-implantitis (ß â€¯= 1.041 mm, confidence interval = 0.646-1.435, and p < 0.001; ß â€¯= 0.857 mm, confidence interval = 0.279-1.434, and p < 0.004) and tooth location (ß â€¯= 0.65 mm, confidence interval = 0.4-0.9, and p < 0.001; ß â€¯= 0.682 mm, confidence interval = 0.34-1.024, and p < 0.001) were significantly associated with the values of the PD and CAL of the teeth. Moreover, the factor of examining sites (i.e. near and away sites of the tooth) was significantly associated with CAL (ß = 0.304 mm, confidence interval = 0.019-0.588, and p = 0.036) and GR (ß = 0.136 mm, confidence interval = 0.02-0.252, and p = 0.022). CONCLUSION: The existence of peri-implantitis, the tooth location, and the examining site are significantly associated with the periodontal measurements of the remaining teeth. CLINICAL SIGNIFICANCE: Peri-implant health is related to the periodontal health of the natural teeth close to the dental implant.

The role of Thyroid Transcription Factor-1 and Tumor differentiation in Resected Lung Adenocarcinoma.

To investigate the role of thyroid transcription factor-1 (TTF-1) and tumor differentiation in resected lung adenocarcinoma. A total of 520 patients with clinical early stage lung adenocarcinoma who underwent surgical resection were reviewed retrospectively. Clinical data and outcomes were evaluated with an average follow-up of 117 months. The results were validated via lung cancer cell line studies. The clinical parameters did not differ between relapse and nonrelapse patients. Exceptions were tumor differentiation, lymphovascular space invasion, F18-fluorodeoxyglucose maximum standard uptake value, tumor size, and pathological stage (p < 0.001). Poor tumor differentiation was the independent prognostic factor (odds ratio: 2.937, p = 0.026). The expression of TTF-1 was correlated with tumor differentiation in resected lung adenocarcinoma patients (p < 0.001). Five-year survival was 60.0% for score 1 TTF-1 expression patients, 80.1% for score 2 TTF-1 expression patients, and 86.1% for score 3 TTF-1 expression group patients. The lung cancer cell line study of knockdown and overexpression of TTF-1 revealed TTF-1 mediated High Mobility Group AT-Hook 2 (HMGA2) protein involved with epithelium-mesenchymal transformation. The chromatin immunoprecipitation revealed TTF-1 regulated HMGA2 via direct binding. TTF-1/HMGA2 axis was associated with tumor differentiation and mediated the aggressiveness of the tumor and prognosis.

A novel potential biomarker for metabolic syndrome in Chinese adults: Circulating protein disulfide isomerase family A, member 4.

BACKGROUND/OBJECTIVES: Protein disulfide isomerase (PDI) family members are specific endoplasmic reticulum proteins that are involved in the pathogenesis of numerous diseases including neurodegenerative diseases, cancer and obesity. However, the metabolic effects of PDIA4 remain unclear in humans. The aims of this study were to investigate the associations of serum PDIA4 with the metabolic syndrome (MetS) and its components in Chinese adults. SUBJECTS/METHODS: A total of 669 adults (399 men and 270 women) were recruited. Serum PDIA4 concentrations and biochemical variables were recorded. Insulin sensitivity and ß-cell function were examined by homeostasis model assessment. MetS was defined based on the modified National Cholesterol Education Program Adult Treatment Panel III criteria for Asia Pacific. RESULTS: The participants with MetS had significantly higher serum PDIA4 levels than those without MetS (P<0.001). After adjustments, the individuals with the highest PDIA4 tertile were associated with a higher risk of MetS than those with the lowest tertile (OR = 4.83, 95% CI: 2.71-8.60). The concentration of PDIA4 showed a stepwise increase with the components of MetS (P<0.001 for trend). The individuals with the highest PDIA4 tertile were significantly associated with waist circumference (OR = 2.41, 95% CI 1.34-4.32), blood pressure (OR = 2.71, 95% CI 1.57-4.67), fasting glucose concentration (OR = 3.17, 95% CI 1.80-5.57), and serum triglycerides (OR = 4.12, 95% CI 2.30-7.37) than those with the lowest tertile. At cutoff point of 15.24 ng/ml, the diagnostic sensitivity and specificity of PDIA4 for the metabolic syndrome were 67 and 72%, respectively, in male patients and 60 and 78%, respectively, in female patients. Finally, the result showed that PDIA4 had a significantly higher area under the curve compared with blood pressure to detect MetS using receiver operating characteristic analysis. CONCLUSIONS: Serum PDIA4 concentrations are closely associated to MetS and its components in Chinese adults.

Melatonin exerts anti-oral cancer effect via suppressing LSD1 in patient-derived tumor xenograft models.

Aberrant activation of histone lysine-specific demethylase (LSD1) increases tumorigenicity; hence, LSD1 is considered a therapeutic target for various human cancers. Although melatonin, an endogenously produced molecule, may defend against various cancers, the precise mechanism involved in its anti-oral cancer effect remains unclear. Patient-derived tumor xenograft (PDTX) models are preclinical models that can more accurately reflect human tumor biology compared with cell line xenograft models. Here, we evaluated the anticancer activity of melatonin by using LSD1-overexpressing oral cancer PDTX models. By assessing oral squamous cell carcinoma (OSCC) tissue arrays through immunohistochemistry, we examined whether aberrant LSD1 overexpression in OSCC is associated with poor prognosis. We also evaluated the action mechanism of melatonin against OSCC with lymphatic metastases by using the PDTX models. Our results indicated that melatonin, at pharmacological concentrations, significantly suppresses cell proliferation in a dose- and time-dependent manner. The observed suppression of proliferation was accompanied by the melatonin-mediated inhibition of LSD1 in oral cancer PDTXs and oral cancer cell lines. In conclusion, we determined that the beneficial effects of melatonin in reducing oral cancer cell proliferation are associated with reduced LSD1 expression in vivo and in vitro.