RESUMO
Radiation therapy, a mainstay of treatment for head and neck cancer, is not always curative due to the development of treatment resistance; additionally, multi-institutional trials have questioned the efficacy of concurrent radiation with cetuximab, the epidermal growth factor receptor (EGFR) inhibitor. We unraveled a mechanism for radiation resistance; that is, radiation induces EGFR, which phosphorylates TRIP13 (thyroid hormone receptor interactor 13) on tyrosine 56. Phosphorylated (phospho-)TRIP13 promotes non-homologous end joining (NHEJ) repair to induce radiation resistance. NHEJ is the main repair pathway for radiation-induced DNA damage. Tumors expressing high TRIP13 do not respond to radiation but are sensitive to cetuximab or cetuximab combined with radiation. Suppression of phosphorylation of TRIP13 at Y56 abrogates these effects. These findings show that EGFR-mediated phosphorylation of TRIP13 at Y56 is a vital mechanism of radiation resistance. Notably, TRIP13-pY56 could be used to predict the response to radiation or cetuximab and could be explored as an actionable target.
Assuntos
Neoplasias de Cabeça e Pescoço , ATPases Associadas a Diversas Atividades Celulares/metabolismo , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Cetuximab/metabolismo , Cetuximab/farmacologia , Reparo do DNA por Junção de Extremidades , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , FosforilaçãoRESUMO
This study aimed to determine the association between the progressive contraction of the posterior pharyngeal wall and dysphagia in postoperative patients with tongue cancer. A videofluoroscopic swallowing study (VFSS) was performed in 34 patients after tongue cancer surgery. Images were analyzed using a two-dimensional video measurement software. Cases in which the processes on the posterior pharyngeal wall moved downward from the 2nd to 4th vertebral regions were defined as "normal type", other cases were defined as "abnormal type". Twenty-four patients showed normal movement of the posterior pharyngeal wall, whereas 10 patients showed the abnormal type. The results showed that there was a significant difference in dysphagia scores between the postoperative swallowing type and swallowing dysfunction score. This implies that dysphagia is related to the movement of the posterior pharyngeal wall after tongue cancer surgery. Furthermore, the extent of resection and stage were significantly different between the normal and abnormal groups in the posterior pharyngeal wall movement. There was also a significant difference between the two groups in terms of the following: whether the tongue base was included in the excision range (p < 0.01), whether neck dissection was performed (p < 0.01), or whether reconstruction was not performed (p < 0.01). VFSS results showed that posterior pharyngeal wall movement was altered after surgery in patients with tongue cancer who had severe dysphagia.
Assuntos
Transtornos de Deglutição , Deglutição , Fluoroscopia , Neoplasias da Língua , Humanos , Transtornos de Deglutição/diagnóstico por imagem , Transtornos de Deglutição/etiologia , Faringe/diagnóstico por imagem , Língua , Neoplasias da Língua/cirurgiaRESUMO
BACKGROUND: Polymorphous adenocarcinoma is a common intraoral minor salivary gland carcinoma in Western countries but is extremely rare in Japan. The current study aimed to characterize the clinicopathological features and status of molecular alterations of polymorphous adenocarcinoma-associated genes, such as PRKD1/2/3, ARID1A, and DDX3X, in a large cohort of Japanese patients with polymorphous adenocarcinoma. METHODS: We examined the cases of 36 Japanese patients with salivary gland polymorphous adenocarcinoma and 26 cases involving histopathological mimics. To detect gene splits, fluorescence in situ hybridization was carried out for polymorphous adenocarcinoma-associated genes. Additionally, we applied a SNaPshot multiplex assay to identify PRKD1 hotspot mutations. RESULTS: This study revealed the indolent clinical course of polymorphous adenocarcinoma with a high 10-year overall survival rate (92.9%), accompanied by occasional local recurrences and cervical lymph node metastasis (23.3%). Twenty cases (55.6%) of polymorphous adenocarcinoma (but none of the mimics) exhibited alterations in at least one polymorphous adenocarcinoma-associated gene. Rearrangement of polymorphous adenocarcinoma-associated genes and PRKD1 E710D were identified in 17 (47.2%) and 4 (11.1%) cases, respectively; one case showed coexisting PRKD3 split and PRKD1 E710D. In the multivariate analysis, high clinical stage (p = 0.0005), the presence of prominent nucleoli (p = 0.0003), and ARID1A split positivity (p = 0.004) were independent risk factors for disease-free survival. CONCLUSION: Japanese patients with polymorphous adenocarcinoma showed clinicopathological features similar to those reported in Western countries. This study disclosed that polymorphous adenocarcinoma-associated genetic alterations were common and specific findings in polymorphous adenocarcinomas. The diagnostic role and possible prognostic significance of polymorphous adenocarcinoma-associated genetic alterations in polymorphous adenocarcinomas were suggested.
Assuntos
Adenocarcinoma , Neoplasias das Glândulas Salivares , Adenocarcinoma/patologia , Biomarcadores Tumorais/genética , Humanos , Hibridização in Situ Fluorescente , Japão , Neoplasias das Glândulas Salivares/genética , Neoplasias das Glândulas Salivares/patologia , Glândulas Salivares/patologiaRESUMO
The expression of programmed death ligand-1 (PD-L1) is controlled by complex mechanisms. The elucidation of the molecular mechanisms of PD-L1 expression is important for the exploration of new insights into PD-1 blockade therapy. Detailed mechanisms of the in situ expression of PD-L1 in tissues of oral squamous cell carcinomas (OSCCs) have not yet been clarified. We examined the mechanisms of PD-L1 expression focusing on the phosphorylation of downstream molecules of epidermal growth factor (EGF) and interferon gamma (IFN-γ) signaling in vitro and in vivo by immunoblotting and multi-fluorescence immunohistochemistry (MF-IHC), respectively. The in vitro experiments demonstrated that PD-L1 expression in OSCC cell lines is upregulated by EGF via the EGF receptor (EGFR)/PI3K/AKT pathway, the EGFR/STAT1 pathway, and the EGFR/MEK/ERK pathway, and by IFN-γ via the JAK2/STAT1 pathway. MF-IHC demonstrated that STAT1 and EGFR phosphorylation was frequently shown in PD-L1-positive cases and STAT1 phosphorylation was correlated with lymphocyte infiltration and EGFR phosphorylation. Moreover, the phosphorylation pattern of the related molecules in PD-L1-positive cells differed among the cases investigated. These findings indicate that PD-L1 expression mechanisms differ depending on the tissue environment and suggest that the examination of the tissue environment and molecular alterations of cancer cells affecting PD-L1 expression make it necessary for each patient to choose the appropriate combination drugs for PD-1 blockade cancer treatment.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Fator de Crescimento Epidérmico , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Interferon gama/uso terapêutico , Neoplasias Bucais/metabolismo , Fosfatidilinositol 3-Quinases , Receptor de Morte Celular Programada 1 , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
OBJECTIVE: This study aimed to elucidate the oral hygiene status and the factors associated with poor oral hygiene among patients with schizophrenia. METHODS: The relationships of oral hygiene status (calculus index [CI], debris index [DI]), the mean number of decayed-missing-filled teeth (mean DMFT), and Revised Oral Assessment Guide (ROAG) with related factors (hospitalization, chlorpromazine equivalents [CPZE], age, Barthel Index [BI], frequency of cleaning teeth, and self-oral hygiene ability) among 249 hospitalized schizophrenic patients were investigated. RESULTS: The results for oral hygiene status were as follows: median (range); CI 0.5 (0-6.0), DI 1.7 (0-6.0), ROAG 10.0 (7.0-15.0); and mean DMFT 21.7 ± 7.3. The average CPZE was 524.4 ± 353.6 mg (mean ± SD), and the BI was 76.4 ± 30.7. There was a negative correlation between BI and DI (r = -0.34), and a positive correlation between age and mean DMFT (r = 0.57). Male patients tended to have worse oral conditions (ROAG) than females. The least-squares multiple regression analysis revealed that BI for DI, age for mean DMFT, sex for ROAG, and self-oral hygiene ability for CI, DI, and mean DMFT were factors related to oral health status. CONCLUSION: Patients with schizophrenia tended to have poor oral hygiene. BI, being male, and low activities of daily living were associated with poor oral hygiene. Furthermore, advanced age was associated with an increased risk of dental caries.
Assuntos
Cárie Dentária , Esquizofrenia , Perda de Dente , Feminino , Humanos , Masculino , Saúde Bucal , Higiene Bucal , Índice CPO , Cárie Dentária/etiologia , Cárie Dentária/complicações , Esquizofrenia/complicações , Clorpromazina , Atividades Cotidianas , PrevalênciaRESUMO
Immunotherapy with immune-checkpoint therapy has recently been used to treat oral squamous cell carcinomas (OSCCs). However, improvements in current immunotherapy are expected because response rates are limited. Transforming growth factor-ß (TGF-ß) creates an immunosuppressive tumor microenvironment (TME) by inducing the production of regulatory T-cells (Tregs) and cancer-associated fibroblasts and inhibiting the function of cytotoxic T-lymphocytes (CTLs) and natural killer cells. TGF-ß may be an important target in the development of novel cancer immunotherapies. In this study, we investigated the suppressive effect of TGF-ß on CTL function in vitro using OSCC cell lines and their specific CTLs. Moreover, TGFB1 mRNA expression and T-cell infiltration in 25 OSCC tissues were examined by in situ hybridization and multifluorescence immunohistochemistry. We found that TGF-ß suppressed the function of antigen-specific CTLs in the priming and effector phases in vitro. Additionally, TGF-ß inhibitor effectively restored the CTL function, and TGFB1 mRNA was primarily expressed in the tumor invasive front. Interestingly, we found a significant negative correlation between TGFB1 mRNA expression and the CD8+ T-cell/Treg ratio and between TGFB1 mRNA expression and the Ki-67 expression in CD8+ T-cells, indicating that TGF-ß also suppressed the function of CTLs in situ. Our findings suggest that the regulation of TGF-ß function restores the immunosuppressive TME to active status and is important for developing new immunotherapeutic strategies, such as a combination of immune-checkpoint inhibitors and TGF-ß inhibitors, for OSCCs.
Assuntos
Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia Adotiva/métodos , Neoplasias Bucais/terapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Linfócitos T Citotóxicos/efeitos dos fármacos , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Microambiente Tumoral/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Fibroblastos Associados a Câncer/citologia , Fibroblastos Associados a Câncer/imunologia , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Interferon gama/análise , Interferon gama/metabolismo , Antígeno Ki-67/metabolismo , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Linfócitos do Interstício Tumoral/citologia , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/metabolismo , RNA Mensageiro/metabolismo , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Sais de Tetrazólio/farmacologia , Fator de Crescimento Transformador beta/antagonistas & inibidores , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta1/análise , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/metabolismo , Adulto JovemRESUMO
PURPOSE: In this study, particulate cancellous bone marrow was harvested from the tibia for alveolar bone grafting, and postoperative complications at the donor site were compared between patients aged 10 years or older (29 tibias) and those aged younger than 10 years (42 tibias). PATIENTS AND METHODS: Enrolled patients were those who underwent tibial bone graft harvesting at the Department of Oral and Maxillofacial Surgery, Aichi Gakuin University, during a period of 3 years and 1 month from March 2012 through March 2015. We examined clinical findings at the time of harvesting and changes in symptoms during hospital admission in study 1. Follow-up examinations and survey questionnaires on symptoms also were investigated to clarify medium- to long-term postoperative outcomes in study 2. RESULTS: In both age groups, medium- to long-term postoperative findings showed no apparent adverse events, except for acceptable levels of scar tissue. Clinical findings on harvesting and early postoperative findings showed that intraoperative blood loss, early postoperative pain, and gait disorders were similar between the group aged younger than 10 years and the group aged 10 years or older. However, the latter group needed a considerably longer time for ambulation and weight-bearing pain to disappear and for every movement in daily activities to return to normal. Regarding patients with a bilateral alveolar cleft, we found no significant difference between the first and second harvesting in the factors affecting postoperative morbidity. CONCLUSIONS: Our findings suggest that tibial bone graft harvesting is safe and requires a shorter recovery period even in patients aged between 8 and 10 years.
Assuntos
Enxerto de Osso Alveolar/métodos , Transplante de Medula Óssea/métodos , Transplante Ósseo/métodos , Complicações Pós-Operatórias/etiologia , Tíbia/transplante , Coleta de Tecidos e Órgãos/métodos , Adolescente , Fatores Etários , Enxerto de Osso Alveolar/efeitos adversos , Transplante de Medula Óssea/efeitos adversos , Transplante Ósseo/efeitos adversos , Criança , Feminino , Seguimentos , Humanos , Masculino , Avaliação de Resultados em Cuidados de Saúde , Complicações Pós-Operatórias/prevenção & controle , Coleta de Tecidos e Órgãos/efeitos adversosRESUMO
OBJECTIVE: The defect volume measured on computed tomography (CT) for secondary bone graft (SBG) is well correlated to the actual amount of particulate cancellous bone and marrow (PCBM) transplanted in unilateral cleft lip and palate (UCLP) patients. However, the validity of such measurements have not been completely verified due to lack of evaluation of treatment results. The objective of this study was to propose an estimation method by CT based on the data of successfully treated patients. For this purpose, the association was initially verified between the weight of transplanted PCBM and the defect volume measured on CT using the results of successfully treated patients. METHODS: Treatment results were evaluated 1 year after SBG by intraoral radiography in 50 UCLP patients. For the patients with good results, the correlation was investigated between the defect volume on CT and the transplanted PCBM weight, and a method was proposed based on PCBM density, calculated as PCBM weight divided by defect volume on CT. RESULTS: In successfully treated patients showing level 3 or 4 alveolar resorption, a strong correlation (r = .87) was found between the volume on CT and the PCBM weight. Level 4 results were observed in 22 of 23 (95.7%) patients who had calculated PCBM densities of more than 6 g/cm3. CONCLUSIONS: Volume estimation on preoperative CT was confirmed to have sufficient validity. The weight of PCBM transplanted should be greater than the defect volume on CT multiplied by 6.
Assuntos
Alveoloplastia/métodos , Transplante Ósseo/métodos , Osso Esponjoso/diagnóstico por imagem , Osso Esponjoso/transplante , Fenda Labial/diagnóstico por imagem , Fenda Labial/cirurgia , Fissura Palatina/diagnóstico por imagem , Fissura Palatina/cirurgia , Tomografia Computadorizada por Raios X/métodos , Adolescente , Medula Óssea/diagnóstico por imagem , Criança , Feminino , Humanos , Masculino , Resultado do TratamentoRESUMO
Desmin is a type III intermediate filament (IF) component protein expressed specifically in muscular cells. Desmin is phosphorylated by Aurora-B and Rho-kinase specifically at the cleavage furrow from anaphase to telophase. The disturbance of this phosphorylation results in the formation of unusual long bridge-like IF structures (IF-bridge) between two post-mitotic (daughter) cells. Here, we report that desmin also serves as an excellent substrate for the other type of mitotic kinase, Cdk1. Desmin phosphorylation by Cdk1 loses its ability to form IFs in vitro. We have identified Ser6, Ser27, and Ser31 on murine desmin as phosphorylation sites for Cdk1. Using a site- and phosphorylation-state-specific antibody for Ser31 on desmin, we have demonstrated that Cdk1 phosphorylates desmin in entire cytoplasm from prometaphase to metaphase. Desmin mutations at Cdk1 sites exhibit IF-bridge phenotype, the frequency of which is significantly increased by the addition of Aurora-B and Rho-kinase site mutations to Cdk1 site mutations. In addition, Cdk1-induced desmin phosphorylation is detected in mitotic muscular cells of murine embryonic/newborn muscles and human rhabdomyosarcoma specimens. Therefore, Cdk1-induced desmin phosphorylation is required for efficient separation of desmin-IFs and generally detected in muscular mitotic cells in vivo.
Assuntos
Proteína Quinase CDC2/metabolismo , Desmina/metabolismo , Filamentos Intermediários/metabolismo , Mitose , Músculo Esquelético/embriologia , Músculo Esquelético/metabolismo , Rabdomiossarcoma/metabolismo , Animais , Animais Recém-Nascidos , Humanos , Camundongos , Proteínas Mutantes/metabolismo , Fosforilação , Fosfosserina/metabolismo , Rabdomiossarcoma/patologiaRESUMO
In recent years, intraoperative surgical guides have been widely used in oral and maxillofacial surgery to navigate the resection sites. However, most of them are designed for segmental mandibulectomy and determine only the anterior-posterior cutting sites. In the case of marginal mandibulectomy, the depth and angle of the resection need to be considered in addition to the anterior-posterior cutting site. This report describes a method for creating a translucent mandible model with a colored tumor that enables visualization of the tumor depth and a surgical guide for marginal mandibulectomy with a planned resection angle. If accurate surgical planning and intraoperative navigation are established using this method, personalized surgery is realized according to tumor features and hence avoids over- or under-resection.
RESUMO
This study aimed to analyze post-coronectomy complications, chronological root survival rate (success rate) using Kaplan-Meier analysis, and postoperative radiographic signs for root extraction. A total of 555 mandibular third molar coronectomies were clinically and radiologically evaluated (mean follow-up period, 27.2 months; range, 1 month to 10.5 years). Complications were observed in 22 (4.0%) cases. Temporary inferior alveolar nerve damage was observed in one (0.2%) case, and 21 (3.8%) retained roots required extraction between 1 and 64 months after coronectomy due to dry socket (two cases, 0.4%), primary non-wound closure (10 cases, 1.8%), secondary root exposure (seven cases, 1.3%), and submucosal root eruption (two cases, 0.4%). Residual enamel after coronectomy was more significantly found on 13 (61.9%) of 21 extracted roots than on 30 (5.6%) of 534 surviving roots. Kaplan-Meier analysis revealed an overall survival rate of 93.8% at 5 years and 92.2% at 10 years. The 5-year survival rates differed significantly (p < 0.001) between the enamel-free (97.0%) and residual enamel-attached (58.3%) roots. The Cox proportional hazards model showed a hazard ratio of 20.87 (95% confidence interval, 8.58-50.72). The long-term outcomes of coronectomy were satisfactory, and a higher success rate is expected when the enamel is completely removed during coronectomy.
RESUMO
Congenital tooth agenesis is caused by the impairment of crucial genes related to tooth development, such as Wnt signaling pathway genes. Here, we investigated the genetic causes of sporadic congenital tooth agenesis. Exome sequencing, followed by Sanger sequencing, identified a novel single-nucleotide deletion in WNT10A (NC_000002.12(NM_025216.3):c.802del), which was not found in the healthy parents of the patient. Thus, we concluded that the variant was the genetic cause of the patient's agenesis.
RESUMO
Background: Postoperative swelling is a common complication of orthognathic surgery. The authors used three-dimensional (3D) image analysis and body surface temperature to determine the effects of compression taping (CT) and Kinesio taping (KT) by the epidermis, dermis, and fascia method (EDF-KT) on postoperative swelling. Materials and methods: The authors conducted a prospective, parallel-group, randomized controlled trial. Among the 162 patients diagnosed with jaw deformity and who underwent orthognathic surgery from August 2020 to October 2022, 105 patients (men: 36, women: 69, mean age: 28.27±8.92) underwent Le Fort type I + sagittal split ramus osteotomy (SSRO) or SSRO and were included in this study. Patients were randomly divided into three groups: EDF-KT group (n=31), CT group (n=41), and no tape group (control group, n=30). All taping was performed immediately postoperatively and removed on postoperative day (POD) 5. Three-dimensional images of the participants' faces were obtained preoperatively and at PODs 3, 7, 30, and 90 using a hand-held 3D imaging system and infrared thermography. Results: No significant difference was observed in postoperative swelling and postoperative body surface temperature between the groups at each time point. The CT group showed a trend towards reduced swelling on PODs 3 and 7 and a trend toward residual swelling on POD 90. The EDF-KT group showed a trend towards an increase in postoperative body surface temperature. Conclusion: CT taping may not be appropriate for postoperative swelling control, suggesting that EDF-KT may affect body surface temperature. Further validation of the efficacy of KT for jaw deformities is needed.
RESUMO
Smoking affects wound healing and is associated with dental implant failure. Heated tobacco products (HTPs) appear to be less harmful than conventional cigarettes (CCs); however, there is limited analytical data to support this claim. This study aimed to compare HTPs and CCs for their impact on wound healing using L929 mouse fibroblast cells and evaluate whether HTPs also lead to failure in implant therapy. Materials and methods: Cigarette smoke extract (CSE) was obtained from CCs (Marlboro, Philip Morris) and HTPs (Marlboro Heat Sticks Regular for IQOS, Philip Morris) and initiated a wound-healing assay with a cell-free area created in the centre of a titanium plate by sticking a 2-mm-width line tape. The L929 mouse fibroblast cells were exposed with 2.5 and 5% CSE from HTPs and CCs and then seeded in the titanium plate. A scratch wound-healing assay was initiated when all samples were at 80% confluence. The number of cells migrating to the wound site was counted after 12, 24, and 48 h. Results: Cell migration decreased after CSE exposure from both CCs and HTPs. At each time-point with 2.5% CSE, cell migration in the HTP group was less than that of the CC group. There were significant differences between the 2.5% CC and 2.5% HTP groups and the 5% CC and 5% HTP groups after 24 h. HTPs and CCs had similar effects in the wound-healing assay. Conclusion: Therefore, HTP use may be a risk factor for poor dental implant healing.
RESUMO
Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) is a low-grade B-cell lymphoma. MALT lymphomas involving the sublingual gland are extremely rare. Herein, we report a case of MALT lymphoma of the sublingual gland. Additionally, we discuss challenging diagnostic aspects as well as current treatment strategies.
RESUMO
INTRODUCTION: Heated tobacco products (HTPs) appear to be less harmful to health than conventional cigarettes (CCs). However, limited analytical data are available to support this claim. This study aimed to compare the cytotoxic, genotoxic, and toxicogenomic effects of HTPs and CCs in carcinogenesis via multistep gene mutations in the oral mucosal cells. METHODS: Cigarette smoke extract (CSE) was obtained from HTPs and CCs. Primary human oral keratinocytes (HOKs) were treated with 5% and 20% CSE from HTPs and CCs. Cell survival rate assays were performed after 6, 12, and 24 h. After 6 h, DNA double-strand breaks (DSBs) were evaluated using anti-γH2AX antibodies with immunohistochemistry. mRNAs expressions of mediator of DNA damage checkpoint 1 (MDC1) and ataxia telangiectasia and Rad3-related protein (ATR), were analyzed. Expressions of miR-22 and miR-185 were analyzed because miR-22 targets MDC1 and miR-185, ATR. RESULTS: The HOKs had equivalent survival rates after exposure to the same concentrations of CSE from CCs and HTPs. HTPs increased foci formation of γH2AX in HOKs, as did CCs (without CSE vs 20% HTP, p<0.05; without CSE vs 20% CC, p<0.05). Expressions of MDC1 and ATR decreased in cells exposed to CSE from CCs and HTPs (MDC1: without CSE vs 20% HTP, p<0.05; without CSE vs 20% CC, p<0.05; ATR: without CSE vs 20% HTP, p<0.05; without CSE vs 20% CC, p<0.05). Expressions of miR-22 and miR-185 were not significantly increased when exposed to CSE from CCs or HTPs. CONCLUSIONS: HTPs and CCs had similar cytotoxic effects. HTPs are genotoxic, can cause DSBs, and have toxicogenomic damage because they inhibit the MDC1 and ATR-CHK1 DNA repair pathways in the oral mucosa. The miRNA-mRNA axis was not related to these inhibitions.
RESUMO
OBJECTIVE: The objective of this study was to assess the efficacy of a tobacco cessation intervention conducted by different dental specialists directed at a group of patients with tobacco-related oral diseases or undergoing implant treatment. METHODS: The study design was a multicentre, nonrandomized prospective cohort study to examine the effects of smoking cessation. The target patients were current smokers (aged ≥20 years) with an oral potentially malignant disorder or periodontitis and those seeking dental implants. A total of 74 patients were enrolled in the study. All dental specialists who participated in the trial completed an e-learning Japan Smoking Cessation Training Outreach Project (J-STOP) tobacco cessation education programme. Nicotine dependence was evaluated by the Fagerstrom Test for Nicotine Dependence. Cessation status was verified biochemically by measurement of salivary cotinine or exhaled carbon monoxide. Tobacco cessation intervention was implemented for 8 weeks with or without nicotine replacement therapy with follow-up for 12 months. RESULTS: A total of 61 patients agreed to the tobacco cessation intervention. The mean biochemically confirmed tobacco abstinence rate was 37.7% at month 3, 34.4% at month 6, and 32.8% at month 12. The highest rate of biochemically confirmed tobacco abstinence at month 12 was among patients receiving implant treatment (42.9%) followed by patients with oral potentially malignant disorder (37.1%), and those with periodontitis (21.1%). CONCLUSION: This interventional study demonstrates the challenges encountered and the feasibility of tobacco cessation intervention among Japanese patients attending dental specialists who had completed an e-learning course on smoking cessation. Making tobacco cessation an integral part of patient management by dental specialists requires further evaluation.
Assuntos
Abandono do Hábito de Fumar , Abandono do Uso de Tabaco , Humanos , Japão , Estudos Prospectivos , Fumar , Dispositivos para o Abandono do Uso de TabacoRESUMO
Regulatory T-cells (Tregs) play a major role in suppressing anti-tumor immune responses. Mogamulizumab, an anti-CC chemokine receptor type 4 (CCR4) monoclonal antibody, depletes effector Tregs (eTregs). However, the clinical efficacy of mogamulizumab was limited in phase Ia/Ib studies for solid tumors (NCT01929486); the finding suggests that mogamulizumab may also deplete beneficial CCR4+CD8+ T-cells in patients. Therefore, we focused on CTLs and aimed to identify a way to protect CCR4+ CTLs. Here, we evaluated the association of CCR4 expression in cytotoxic T-lymphocytes (CTLs) with antigen and cytokine stimulations and kinase inhibition using cytomegalovirus antigen instead of tumor antigen. CCR4 expression in CTLs was induced by antigen stimulation (mean 3.14-29.0%), enhanced by transforming growth factor-ß1 (TGF-ß1) (mean 29.0-51.2%), and downregulated by trametinib with (mean 51.2-11.4%) or without TGF-ß1 treatment (mean 29.0-6.98%). Phosphorylation of ERK in CD8+ T-cells was suppressed by trametinib. Regarding the effect on immunological function of CTL, trametinib reduced cytokine production but not affected cytotoxicity. Importantly, trametinib alleviated CTL reduction by anti-CCR4 antibody without affecting eTreg depletion because CCR4 expression in eTregs was not downregulated. In conclusion, combination therapy with trametinib may improve the clinical efficacy of mogamulizumab.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Humanos , Linfócitos T Reguladores , Fator de Crescimento Transformador beta1/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T Citotóxicos/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/metabolismo , Receptores CCR4/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismoRESUMO
BACKGROUND/AIM: This study investigated the utility of C-C motif chemokine ligand 20 (CCL20) expression in saliva as a biomarker for oral squamous cell carcinoma (OSCC) and also examined the associated microbiome. MATERIALS AND METHODS: The study group included patients with OSCC or oral potentially malignant disorder (OPMD), and healthy volunteers (HVs). microarray and qRT-PCR were used to compare salivary CCL20 expression levels among groups. Data on CCL20 levels in oral cancer tissues and normal tissues were retrieved from a public database and examined. Furthermore, next-generation sequencing was used to investigate the salivary microbiome. RESULTS: A significant increase in the expression level of CCL20 was observed in both OSCC tissues and saliva from patients with oral cancer. Fusobacterium was identified as the predominant bacteria in OSCC and correlated with CCL20 expression level. OSCC screening based on salivary CCL20 expression enabled successful differentiation between patients with OSCC and HVs. CONCLUSION: CCL20 expression may be a useful biomarker for OSCC.