Evolutionary Dynamics-Driven Learning of Optimal Decisions for Nonlinear System: Extend-Policy Iterative Algorithm.

An extend-policy iterative algorithm is proposed for solving the ecological evolving-lung cancer cells growth inhibition optimal drug delivery scheme. With the analysis of the cell proliferation-apoptosis process of lung cancer cells with primitive immune system and external drug interventions, such as chemotherapeutic drugs and immunological agents, a model of ecological containment of lung cancer cells mimicking injection labeling is constructed. The HJB equation for biological tissue damage has also been established by considering the concentration of lung cancer cells in the blood and the amount of drug administered. The final simulation experiment proved the effectiveness of the drug delivery scheme.

Human periodontal ligament stem cell sheets activated by graphene oxide quantum dots repair periodontal bone defects by promoting mitochondrial dynamics dependent osteogenic differentiation.

BACKGROUND: Bone defects in the maxillofacial region restrict the integrity of dental function, posing challenges in clinical treatment. Bone tissue engineering (BTE) with stem cell implants is an effective method. Nanobiomaterials can effectively enhance the resistance of implanted stem cells to the harsh microenvironment of bone defect areas by promoting cell differentiation. Graphene oxide quantum dots (GOQDs) are zero-dimensional nanoscale derivatives of graphene oxide with excellent biological activity. In the present study, we aimed to explore the effects of GOQDs prepared by two methods (Y-GOQDs and B-GOQDs) on the osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs), as well as the effect of gelatin methacryloyl (GelMA)-encapsulated GOQD-induced hPDLSC sheets on the repair of mandibular periodontal defects in rats. We also explored the molecular biological mechanism through which GOQD promotes bone differentiation. RESULTS: There were significant differences in oxygen-containing functional groups, particle size and morphology between Y-GOQDs and B-GOQDs. Y-GOQDs promoted the osteogenic differentiation of hPDLSCs more effectively than did B-GOQDs. In addition, GelMA hydrogel-encapsulated Y-GOQD-induced hPDLSC cell sheet fragments not only exhibited good growth and osteogenic differentiation in vitro but also promoted the repair of mandibular periodontal bone defects in vivo. Furthermore, the greater effectiveness of Y-GOQDs than B-GOQDs in promoting osteogenic differentiation is due to the regulation of hPDLSC mitochondrial dynamics, namely, the promotion of fusion and inhibition of fission. CONCLUSIONS: Overall, Y-GOQDs are more effective than B-GOQDs at promoting the osteogenic differentiation of hPDLSCs by regulating mitochondrial dynamics, which ultimately contributes to bone regeneration via the aid of the GelMA hydrogels in vivo.

Accelerated corrosion of 316L stainless steel in a simulated oral environment via extracellular electron transfer and acid metabolites of subgingival microbiota.

316L stainless steel (SS) is widely applied as microimplant anchorage (MIA) due to its excellent mechanical properties. However, the risk that the oral microorganisms can corrode 316L SS is fully neglected. Microbiologically influenced corrosion (MIC) of 316L SS is essential to the health and safety of all patients because the accelerated corrosion caused by the oral microbiota can trigger the release of Cr and Ni ions. This study investigated the corrosion behavior and mechanism of subgingival microbiota on 316L SS by 16S rRNA and metagenome sequencing, electrochemical measurements, and surface characterization techniques. Multispecies biofilms were formed by the oral subgingival microbiota in the simulated oral anaerobic environment on 316L SS surfaces, significantly accelerating the corrosion in the form of pitting. The microbiota samples collected from the subjects differed in biofilm compositions, corrosion behaviors, and mechanisms. The oral subgingival microbiota contributed to the accelerated corrosion of 316L SS via acidic metabolites and extracellular electron transfer. Our findings provide a new insight into the underlying mechanisms of oral microbial corrosion and guide the design of oral microbial corrosion-resistant materials.

[Three-dimensional assessment and study on temporomandibular joint and the maxillary characteristics of skeletal Class â ¢ mandibular deviation patients].

PURPOSE: To study the temporomandibular joint morphology and position and the maxillary characteristics of skeletal Class Ⅲ mandibular deviation patients with vertical disproportion in bilateral gonions. METHODS: Overall 79 adult patients with skeletal Class Ⅲ malocclusions were selected. Craniofacial spiral CT scanning was performed, and three-dimensional reconstruction of the temporomandibular joint(TMJ) was carried out by using ProPlan CMF3.0 three-dimensional analysis software. The patients were divided into two groups according to the deviation degree of the mentum: symmetric group (the S group: n=24) and deviation group (n=55). The deviation group was divided into two subgroups according to whether there was vertical disproportion in bilateral gonions, i.e., ASV group: there were vertical differences in bilateral gonions(n=27), and ASNV group: there was no vertical difference in bilateral gonions (n=28). Seven condylar morphological and position indicators and nine maxilla-related indicators were measured. SPSS 22.0 software package was used for statistical analysis. RESULTS: In deviation group, the condylar length on the deviated side was shorter than the opposite side, the difference value between the two sides was greater than the symmetric group, and there were asymmetry and different degrees of disproportion in the three-dimensional direction in the maxilla. In ASV group, the angle of the condylar axis to the horizontal plane on the deviated side was smaller and the anteroposterior diameter of the condyle was smaller. In ASV group, the mediolateral dimension of condyle on the deviated side were smaller. From variance analysis and multiple comparisons, the difference of condylar length on both sides in ASV group and ASNV group was greater than that in the symmetric group. There were asymmetries in the maxillae in ASV group and ASNV group, and the maxillary width on the deviated side was greater than that on non-deviated side. Transverse maxillary disproportion was more likely to occur in the ASNV group. The vertical maxillary disproportion on both sides in ASV group was larger than that in ASNV group and S group, and the deviated side was smaller than the opposite side. CONCLUSIONS: The TMJ morphology and position of skeletal Class Ⅲ mandibular deviation patients with vertical disproportion in bilateral gonions and the maxillary asymmetry in the three-dimensional direction require attention in the diagnosis and conceptual design of surgical-orthodontic treatment.

Differences in Predicted Therapeutic Outcome of Mandibular Advancement Determined by Remotely Controlled Mandibular Positioner in Canadian and Chinese Apneic Patients.

Background: In-lab mandibular protrusive titration using a remotely controlled mandibular positioner (RCMP) could predict the success rate of mandibular advancement device (MAD) and reliably determine the Optimal Protrusive Position (OPP) for obstructive sleep apnea (OSA) patients. The aim of this study was to compare MAD success rate using in-lab RCMP manual titration performed in Caucasian and Chinese OSA patients. Methods: Manual RCMP titration was performed during an in-lab sleep study using the same procedure that had been previously reported in untreated Caucasian and Chinese OSA patients. Success rate was determined according to classical success criteria or to those previously used for RCMP titration. Results: A total of 160 subjects were included in this study, and conclusive data were obtained from 141 (71 Chinese and 70 Caucasian OSA patients). Chinese patients were significantly younger, with lower BMI and more severe OSA disease than the Canadian counterparts. Among patients with predicted success, the OPP expressed in % of full protrusion position did not differ between the two ethnic groups. Chinese ethnicity, younger age and lower baseline AHI were significant determinants of RCMP success. In a multivariate analysis, only ethnicity and AHI were found to significantly account for success, the odds ratio for success in Chinese compared to Caucasians corrected for AHI being 3.7 and 4.6 depending on criteria used to define success. Conclusion: Although the OSA disease was more severe in Chinese patients, the predicted success rate of MAD according to RCMP titration was higher in Chinese than in Caucasians. This study was registered on ClinicalTrials.gov (NCT03231254).

Diagnosis and treatment of MN1 C-terminal truncation syndrome.

BACKGROUND: MN1 C-terminal truncation (MCTT) is a rare syndrome; only 27 cases have been reported. We report the first case of an 8-year-old girl with MCTT syndrome complicated with moderate obstructive sleep apnea (OSA). METHODS: MCTT syndrome was diagnosed by whole-exome sequencing (WES) and validated by Sanger sequencing. The patient received 2 years of treatment with continuous positive airway pressure (CPAP) to relieve sleep apnea and hypoxia, and a reverse sector fan-shaped expander for maxillary expansion. RESULTS: WES revealed a de novo MN1 variant, c.3760C>T (p.[Q1254*]). An arachnoid cyst was found in the right occipital brain. The patient presented mild symptoms of classic MCTT syndrome. The patient did not experience hearing loss and only mild intellectual disability. Radiological examinations showed cleft secondary palate, narrow upper arch, narrow upper airway, and mandibular skeletal retrusion. Polysomnography indicated moderate OSA, with an apnea/hypopnea index of 6.8, which decreased to 1 after CPAP during the night. Two-year maxillary expansion widened the upper arch, and the cleft secondary palate became visible. The mandible moved forward spontaneously, resulting in the improvement of profile and upper airway widening. General physical conditions, such as motor delay, muscle weakness, and developmental delay, were significantly improved two years later. CONCLUSION: In conclusion, we discovered a MN1 variant [NM_002430.2: c.3760C>T, p.Q1254*] that causes mild MCTT symptoms compared to other MN1 variants. For patients with MCTT complicated with OSA, multidisciplinary combination therapy can improve maxillofacial development, widen the upper airway and relieve sleep apnea, improving the general physical condition.

Identification of Hypoxia-Related Molecular Classification and Associated Gene Signature in Oral Squamous Cell Carcinoma.

The high heterogeneity of oral squamous cell carcinoma (OSCC) is the main obstacle for individualized treatment. Recognizing the characteristics of different subtypes and investigating the promising strategies for each subclass are of great significance in precise treatment. In this study, we systematically evaluated hypoxia-mediated patterns together with immune characteristics of 309 OSCC patients in the TCGA training set and 97 patients in the GSE41613 testing set. We further identified two different hypoxia subtypes with distinct immune microenvironment traits and provided treatment programs for the two subclasses. In order to assess hypoxia level individually, we finally constructed a hypoxia-related risk score, which could predict the clinical outcome and immunotherapy response of OSCC patients. In summary, the recognition of different hypoxia patterns and the establishment of hypoxia-related risk score might enhance our understanding of the tumor microenvironment of OSCC and provide more personalized treatment strategies in the future.

[Correlation between social psychology and personality characteristics and treatment options for adult patients with skeletal malocclusion].

OBJECTIVE: This study aims to explore factors affecting the dental aesthetic social psychology of patients with skeletal malocclusion and to measure the relationship between the objective orthodontic requirements and the subjective treatment requirements of patients. This work provides a reference for doctors to measure patients' orthodontic treatment needs. METHODS: Adult patients with skeletal malocclusion were chosen as the research object. Questionnaire survey was used to analyze factors influencing the psychosocial impact of dental aesthetics questionnaire (PIDAQ), index of orthodontic treatment need (IOTN), and Eysenck personality questionnaire-revised short scale for Chinese (EPQ-RSC). The relationship among PIDAQ, IOTN, EPQ-RSC, and treatment options was also evaluated. RESULTS: Seventy-two valid questionnaires were collected from adult patients with skeletal malocclusion. 1) The PIDAQ scores significantly differed among different occupations (P<0.05) but were not affected by other general conditions such as gender and age. 2) Patients of different dental health component (DHC) grade and ages had different AC self-assessment scores (P<0.01, P<0.05). The AC self-assessment score was positively correlated with the PIDAQ score (P<0.05). 3) Males accounted for a higher proportion of patients who received treatment. Younger patients (18-28 years old) were more likely to receive treat-ment when their own dental aesthetics were poor. People with the higher monthly expenditure accounted for the larger proportion of surgical patients. 4) The PIDAQ score had no significant effects on the choice of opera-tion (P>0.05). People with low educational level were more likely to receive surgery if their psychosocial impacts of dental aes-thetics were serious. 5) The score of psychoticism scale of EPQ-RSC and the educa-tional level had a mutual influence on the PIDAQ score (P<0.01). Moreover, the neuroticism scale and AC self-assessment scores had a mutual influence on the PIDAQ score (P<0.05). However, this study did not find a correlation between personality traits and treatment options. CONCLUSIONS: Many factors, such as personal natural conditions, subjective aesthetic evaluation of teeth, and psychosocial impacts of dental aesthetics, affect patients' treatment options. Personality characteristics can play a certain role in dental aesthetics social psychology.

MicroRNA­21 serves an important role during PAOO­facilitated orthodontic tooth movement.

Periodontal accelerate osteogenesis orthodontics (PAOO) is an extension of described techniques that surgically alter the alveolar bone; however, the specific mechanism underlying the technique is not completely understood. The aim of the present study was to evaluate the roles of microRNA (miR)­21 during PAOO. Sprague­Dawley rats were divided into the following four groups: i) Group tooth movement (TM), underwent TM and were administered normal saline (NS); ii) Group PAOO, underwent PAOO + TM and were administered NS; iii) Group agomiR­21, underwent PAOO + TM and were administered agomiR­21; and iv) Group antagomiR­21, underwent PAOO + TM and were administered antagomiR­21. To validate the rat model of PAOO, morphological analyses were performed and measurements were collected. Reverse transcription­quantitative PCR, western blotting and immunohistochemical staining were performed to examine the expression levels of programmed cell death 4 (PDCD4), activin A receptor type 2B (ACVR2b), receptor activator of NF­κΒ ligand (RANKL) and C­Fos. Dual­luciferase reporter assays were performed to validate PDCD4 as a target of miR­21 in vitro. Following 7 days of treatment, the TM distance of group PAOO was longer compared with groups TM and antagomiR­21 (P<0.05), but shorter compared with group agomiR­21 (P<0.05). Tartrate­resistant acid phosphatase staining indicated that following treatment with agomiR­21, osteoclast activity was notably increased, whereas the mRNA and protein expression levels of PDCD4 were notably decreased compared with group PAOO. The mRNA and protein expression levels of RANKL and C­Fos in group agomiR­21 were notably increased compared with group PAOO, whereas group antagomiR­21 displayed the opposite pattern (P<0.05). With regard to ACVR2b, no significant differences were observed among the group agomiR­21 and antagomiR­21 compared with group PAOO. Bioinformatics analysis predicted that PDCD4 was a potential target gene of miR­21, and dual­luciferase reporter assays demonstrated that miR­21 directly targeted PDCD4. In conclusion, the present study demonstrated that miR­21 serves an important role during PAOO­mediated orthodontic TM.

[Meta-analysis of the condylar position with mandibular deviation].

PURPOSE: This study was aimed to analyze the differences of condylar position between the mandibular deviation and the individual normal occlusion. METHODS: Databases of PubMed,Embase,CNKI ,Wanfang ,VIP and CBL were searched for the relevant articles about condylar position with mandibular deviation. The deadline was June 2017.Data quality evaluation and extraction were independently conducted by two authors. Then meta analysis was performed using Rev Man 5.3 software. RESULTS: Six articles on controlled study of the condylar position in patients with mandibular deviation and individuals with normal occlusion were included. 122 patients had mandibular deviation and 110 had normal occlusion. Meta analysis results showed that the condylar superior space[MD=-0.38,95%CI(-0.74,-0.01),P=0.04]and anterior space[MD=-0.72,95%CI(-0.99,-0.04),P＜0.00001]of the deviation side in mandibular deviation group were significantly greater than that of the opposite side; The condylar posterior space[MD=-0.35,95%CI(0.25,0.45),P＜0.00001]of the deviation side in mandibular deviation group was significantly smaller than that of the opposite side. The condylar posterior space of deviation side[MD=-0.58,95%CI(-0.88,-0.28),P=0.0002],opposite side[MD=-0.30,95%CI(-0.59,-0.00),P=0.05] and the anterior space of opposite side[MD=-0.85,95%CI(-1.58,-0.13),P=0.02] in the mandibular deviation group was significantly smaller than that in the individuals with normal occlusion; the differences were statistically significant. There was no significant difference in the condylar superior space between the deviation side[MD=-0.56,95%CI(-1.14,0.02),P=0.06] and the opposite side[MD=-0.58,95%CI(-1.27,0.10),P=0.10] and the anterior space[MD=-0.05,95%CI(-0.35,0.46),P=0.80]in deviation side in the mandibular deviation group ,comparing with individuals with normal occlusion. CONCLUSIONS: The condylar position of deviation side in patients with mandibular deviation is posterior and inferior, comparing with the opposite side. The condylar position of deviation side in patients with mandibular deviation is posterior, comparing with the individuals with normal occlusion.

[The relationship between labial-lingual inclination and the thickness of the alveolar bone in the mandibular central incisors assessed with cone-beam computed tomography].

PURPOSE: To investigate the alveolar bone thickness of mandibular central incisors with different labial-lingual inclinations by cone-beam computed tomography (CBCT). METHODS: CBCT and lateral cephalometric images of 60 patients were chosen. The data was respectively classified into 3 groups by L1-MP: lingual inclination group (L1-MP<85.6°); normal group (L1-MP 85.6°-99.6°), and labial inclination group(L1-MP>99.6°). Three-dimensional reconstruction was made for CBCT, and the sagittal images of the largest alveolar bone area along the tooth axis were chosen. The central incisor roots were divided into 4 sections from cementoenamel junction to root apex, then the labial and lingual alveolar bone thickness were measured and added up to get total alveolar bone thickness, and the occurrence of fenestration and dehiscence were recorded. The data was analyzed with SPSS 17.0 software package. RESULTS: The alveolar bone thickness on lingual side and the total bone thickness were significantly different between every 2 sections of all the measured zone. The average values of bone thickness on labial side were thinner than that on lingual side in sections of middle 1/2, root apex 1/4 and root apex. The total bone and lingual bone were thinner in lingual inclination group than in labial inclination group at root apex, root apex 1/4 and middle 1/2. Labial and lingual inclination group were more likely to develop dehiscence (P<0.05). CONCLUSIONS: Lingual and total alveolar bone of central incisors become increasingly thinner from root apex area to cementoenamel junction. The total bone and lingual bone are thinner in lingual inclination group than in labial inclination group. Labial or lingual inclined incisors have higher incidence of dehiscence.

MicroRNA expression profile of surgical removed mandibular bone tissues from patients with mandibular prognathism.

BACKGROUND: Mandibular prognathism (MP) or skeletal class III malocclusion with a prognathic mandible is one of the most severe facial deformities. Recent work has revealed certain circulating microRNAs (miRNAs) are associated with MP, we conducted this study to characterize the miRNAs expression profile in surgically removed mandibular bone tissue in patients with MP and explored the role of miRNA regulation in the pathogenesis of MP. METHODS: Affymetrix GeneChip miRNA 3.0 Array was used to examine the miRNA expression in mandibular bone tissues from MP patients and control subjects. A variety of bioinformatic approaches were used to predict the target genes of the miRNAs, find the potential functions and pathways of the target genes, analyze their intersection with differentially expressed mRNAs, and establish miRNA-gene network. RESULTS: Eleven upregulated and 11 downregulated miRNAs with a fold change ≥ 2 and a P value <0.05 were identified in bone specimens of MP patients. A total of 3569 genes were predicted as targets of hsa-miR-10a-5p, hsa-miR-150-5p, hsa-miR-192-5p, hsa-miR-194-5p, hsa-miR-197-3p, hsa-miR-30 d-5p, hsa-miR-342-5p and hsa-miR-629-5p, hsa-miR-1202, and hsa-miR-638. The target genes were predicted to be involved in biological functions and signaling pathways related to osteogenesis. Hsa-miR-30 d-5p was the key node of miRNA-gene network. CONCLUSIONS: Our results indicated a possible association between the differentially expressed miRNAs and MP pathogenesis, and the precise mechanisms are needed to be further validated.

[The relationship between maxillary anterior impacted teeth and sagittal facial type].

PURPOSE: To investigate the relationship between impaction of maxillary anterior teeth and sagittal facial type and evaluate the dentofacial morphological characteristics of patients with maxillary teeth impaction. METHODS: Totally 90 patients with maxillary anterior teeth impaction were divided into 3 groups (one incisor impaction, one canine impaction and two canines impaction), and their cephalometric films were measured and analyzed. They were further divided into Class I, II and III facial types according to ANB and the constituent ratio were calculated. SPSS 17.0 software package was applied for Student's t test and chi-square test. RESULTS: SNA, A'-Ptm' and L1-NB were smaller than the normal value in the 3 groups. Convexity, L1-MP, ANB and Wits appraisal were smaller while AB plane angle, U1-NA and U1-NA were greater than the normal value in groups of one and two canines impaction; S'-Ptm', L1-NB were smaller while U1-L1 was greater than normal value in group of two canines impaction; Among the 3 groups, ANB and Wits appraisal were the smallest while AB plane angle was the greatest in group of two canines impaction. The sagittal facial type of 90 patients was mainly Class I (50%), but Class III in group of two canines impaction increased to 40%. CONCLUSIONS: Impacted maxillary anterior teeth might result in short maxillary basal bone. One canine impaction has the greatest influence than one incisor impaction on sagittal position of jaws. Two canines impaction has the greatest impact on sagittal facial type and tends to be Class III facial type.

[Effect of rapamycin combined with cisplatin on head and neck squamous cancer cells regulated by CCL19].

OBJECTIVE: To investigate the synergistic effects of rapamycin and cisplatin on head and neck squamous cancer cells regulated by chemokine (C-C motif) ligand 19 (CCL19). METHODS: The role of rapamycin and cisplatin was detected on cell-cycle and apoptosis in CCL19 induced PCI-4B and PCI-37B cells by methyl thiazolyl tetrazolium (MTT) and flow cytometry (FCM). Dose-effect relationship parameters and combination index (CI) were calculated on the median-effect equation and multiple drug effect equation using computer software CalcuSyn. Statistical analysis was performed by the unpaired student's t-test. RESULTS: Rapamycin and cisplatin could respectively increase the growth arrest, the proportion of G(1) phase and apoptosis of CCL19 induced cancer cells (P < 0.05). Under inhibitory concentration 50% (IC(50)), CI was less than 1, and in IC(75), it was more than 1 in PCI-4B cells. In PCI-37B cells, under IC(75), CI was less than 1, and in IC(90), it was more than 1. CONCLUSIONS: Rapamycin and cisplatin can inhibit CCL19-regulated PCI-4B and PCI-37B cells' survival. The two drugs have synergistic effects when used in combination.

Chemokine receptor 7 promotes cell migration and adhesion in metastatic squamous cell carcinoma of the head and neck by activating integrin αvß3.

The mechanisms leading to squamous cell carcinoma of the head and neck (SCCHN) metastasis are incompletely understood. Although evidence shows that the chemokine receptor 7 (CCR7) and its ligand CCL19 may regulate tumor dissemination, their role in SCCHN is not clearly defined. CCR7 has been shown to regulate integrins, which facilitate adhesion of cancer cells to and/or migration through the extracellular matrix (ECM). To investigate the relationship between CCR7 and integrin αvß3 in metastatic SCCHN, we used adhesion and migration assays, immunofluorescence staining and western blotting to determine whether integrin αvß3 can be activated by CCL19 in the metastatic SCCHN cell line PCI-37B, which was pre-incubated with CCL19 or the integrin αvß3 inhibitor, IS201. Our results demonstrate that CCR7 favors PCI-37B cell adhesion and migration, induces reorganization of the actin cytoskeleton and induces integrin αvß3 phosphorylation. The integrin αvß3 inhibitor, IS201, blocked all of these effects. CCR7 and integrin αvß3 expression significantly and positively correlated with tumor size, clinical stage and nodal metastasis. Taken together, our data indicate that CCR7 regulates cell adhesion and migration via integrin αvß3 in metastatic SCCHN. These results should provide the groundwork for new strategies aimed at preventing SCCHN metastasis.

NF-κB participates in chemokine receptor 7-mediated cell survival in metastatic squamous cell carcinoma of the head and neck.

Metastatic squamous cell carcinoma of the head and neck (SCCHN) has been shown to express chemokine receptor 7 (CCR7), which activates phosphoinositide-3 kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) signal pathway to promote the invasion and survival of SCCHN cells. Since nuclear factor-kappa B (NF-κB) is shown to be the downstream signal molecule of PI3K/Akt in many tumors, we investigated whether it also exists in the CCR7 pathway in SCCHN, and the relationship between NF-κB and PI3K/Akt/mTOR, and the role it plays in SCCHN. We assayed the phosphorylation of the inhibitor of NF-κB (IκBα), the NF-κB DNA-binding capacity and location. The results showed that the interaction between CCR7 and the ligand for CCR7, CCL19, induces phosphorylation of IκBα, causes NF-κB to translocate to the nucleus and raises the DNA-binding capacity of NF-κB. The phosphorylation and DNA-binding capacity were abolished by the inhibition of CCR7, PI3K, Akt and mTOR. Further research demonstrated that inhibitors of NF-κB and CCR7-PI3K attenuate the survival of CCR7-mediated cells, causing decreased viability, increased apoptosis and increased cell cycle arrest in SCCHN cells. In clinical samples from 78 patients, immunohistochemical assay also showed that CCR7 and NF-κB are not only highly expressed in SCCHN, but also correlated with each other, and related to lymph node metastasis and clinical stage. Together, our data indicate that NF-κB is activated by CCR7 via PI3K/Akt/mTOR, and this signal pathway plays an important role in regulating the cell survival and prognosis of SCCHN.

CCL19-induced chemokine receptor 7 activates the phosphoinositide-3 kinase-mediated invasive pathway through Cdc42 in metastatic squamous cell carcinoma of the head and neck.

Metastatic squamous cell carcinoma of the head and neck (SCCHN) has been shown to express chemokine receptor 7 (CCR7), which activates phosphoinositide-3 kinase (PI3K) to promote invasion and survival of SCCHN cells. We hypothesized that Cdc42 might be involved in the CCR7-PI3K pathway. Adhesion assays, migration assays, immunofluorescence staining, Western blotting and immunohistochemical analysis were used to find whether Cdc42 can be activated by CCL19 (the CCR7 ligand) and its role in SCCHN. Results showed that CCL19 induced polarized localization of Cdc42 and actin polymerization in the leading edge of migrating cells. The level of activated membrane-bound Cdc42 was elevated, as measured by the GTPase activity pull-down assay. The increased membrane localization and membrane-bound activity of Cdc42 were abolished by CCR7 and PI3K inhibition, indicating the involvement of Cdc42 in the CCR7-PI3K cascade. Knockdown of Cdc42 by small interfering RNA (siRNA) led to significant reduction in the activation of Rac, filamentous actin (F-actin) accumulation as well as in the migration and invasion induced by CCL19. Taken together, our data indicate the important role played by Cdc42 in CCL19-induced migration and invasion of SCCHN cells.

The chemokine receptor 7 regulates cell adhesion and migration via beta1 integrin in metastatic squamous cell carcinoma of the head and neck.

Migration and adhesion of tumor cells are essential prerequisites for the formation of metastases in malignant diseases. Chemokine receptor 7 (CCR7) has been shown to regulate integrin which can then facilitate adhesion of cancer cells to and/or migration through the extracellular matrix (ECM). In order to identify the connection between CCR7 and beta1 integrin, and the influence on cell adhesion and migration in metastatic squamous cell carcinoma of the head and neck (SCCHN). We use adhesion assays, migration assay, immunofluorescence staining, western blotting, and immunohistochemical analysis to find whether beta1 integrin can be activated by CCL19 (CCR7's ligand) and its role in SCCHN. The experiments were performed in the metastatic SCCHN cell line PCI-37B after pre-incubation of the cells with CCL19 and beta1 integrin inhibitors RGD-peptide. Our results demonstrate that CCR7 favours PCI-37B cell adhesion and migration, and induces reorganization of the actin cytoskeleton and up-expression of beta1 integrin protein. beta1 integrin inhibitor RGD-peptide can block all these effects. Taken together, our data indicate that CCR7 regulate cell adhesion and migration via beta1 integrin in metastatic SCCHN, and these results can provide a basis for new strategies in preventing metastases of SCCHN.

[The effect of CCL19 on the viability of head and neck squamous cancer cells].

PURPOSE: To study the role of CCL19 on the viability,cell-cycle and apoptosis of head and neck squamous cancer cells. METHODS: We assayed the growth arrest induced by cisplatin in 4A cells and 4B cells by MTT, detected the role of CCL19 on the effect of cisplatin and observed the change of morphology by transmission electron microscope, evaluated cell-cycle and apoptosis of 4B cell pretreated by CCL19 and cisplatin via FCM. Statistical differences between the two groups were evaluated using the unpaired Student's t test. All statistical analyses were performed with SPSS 11.0 software package. RESULTS: The growth arrest of 4B cell by cisplatin was significantly higher than 4A(P<0.05). CCL19 could protect 4B cell against inhibition, but no effect on 4A. CCL19 contributed to 4B by promoting to normal morphology, reducing G1 phase arrest, inhibiting apoptosis. CONCLUSIONS: Cisplatin works better in 4B cell than in 4A cell, and CCL19 can inhibit its effect, which provide a new way to treat head and neck squamous cancer. Supported by National Natural Science Foundation of China (Grant No.30672331) and Foundation of Liaoning Provincial Educational Commission (Grant No.2009A755).

Mammalian target of rapamycin (mTOR) is involved in the survival of cells mediated by chemokine receptor 7 through PI3K/Akt in metastatic squamous cell carcinoma of the head and neck.

Metastatic squamous cell carcinoma (SCC) of the head and neck expresses chemokine receptor 7 (CCR7), which activates phosphoinositide-3 kinase (PI3K) to promote invasion and survival of SCC cells in the head and neck. We hypothesised that mammalian target of rapamycin (mTOR) may be the downstream molecule of the CCR7-PI3K pathway. Results have shown that interaction between CCR7 and its ligand CCL19 induces the phosphorylation of mTOR and its target p70s6k. This phosphorylation is abolished by inhibition of CCR7 and PI3K/Akt, indicating that mTOR is involved in the CCR7-PI3K cascade. The inhibitors of mTOR and CCR7-PI3K also lead to a significant increase in CCL19-induced death, apoptosis, and cell-cycle arrest of metastatic SCC cells in the head and neck. Taken together, our data indicate the important part played by mTOR in CCR7-induced survival of such SCC cells.