Periodontitis and postoperative inflammation in gastric cancer patients: Propensity score analysis.

OBJECTIVE: The objective of this study was to clarify the association between preoperative periodontitis and postoperative systemic inflammation in patients with gastric cancer. SUBJECTS AND METHODS: This retrospective cohort study analyzed data from 140 gastric cancer patients who underwent surgery at Hiroshima University Hospital between May 2019 and May 2022. Periodontal inflamed surface area (PISA) scores were determined to assess periodontitis severity using modified Nesse's methods. Propensity score matching was used to compare patients with high and low PISA scores (> or < the median PISA score of 92.4, respectively). Propensity scores were calculated using a logistic regression model, based on 17 clinical parameters: age, sex, smoking, alcohol consumption, hypertension, diabetes, dyslipidemia, cardiovascular disease, stroke, clinical stage, surgical procedure, surgical approach, neoadjuvant chemotherapy, surgery duration, blood loss during surgery, remaining teeth, and denture use. RESULTS: Thirty-seven patients were propensity-score-matched. Participants with high PISA scores had a higher incidence of surgical site infection (10.5%) than those with low PISA scores (5.3%). Moreover, participants with high PISA scores had significantly higher C-reactive protein levels on postoperative days 1 than those with low PISA scores. CONCLUSION: Preoperative periodontitis may determine the level of postoperative systemic inflammation in patients with gastric cancer.

Effectiveness of e-learning to promote oral health education: A systematic review and meta-analysis.

BACKGROUND: In recent times during and after the COVID-19 pandemic, e-learning is increasingly being used to give oral health education. However, the efficacy of e-learning in improving and promoting the oral hygiene and oral health knowledge, attitude and practice is unclear. Therefore, this systematic review and meta-analysis aim to clarify the effectiveness of e-learning compared to other conventional education methods for providing oral health. METHODS: An electronic database search was performed on PubMed-Medline, Scopus, and CENTRAL (Central Register Cochrane of Controlled trials). Randomized controlled trials (RCTs), including cluster or group RCTs, were collected in this study. The risk of bias was assessed with the Cochrane Handbook for Systematic Reviews of Interventions. Five different meta-analyses were conducted for plaque index, gingival index, oral health knowledge, oral health attitude, and oral health practice using a random effects model. RESULTS: A total of 282 articles were found through the database search; 19 articles were included in the qualitative synthesis and 9 articles in the quantitative synthesis. The meta-analysis found that compared with conventional education, e-learning exhibited no positive effect. However, the use of e-learning was superior to conventional education methods for oral health practice for adults in subgroup analysis. CONCLUSIONS: This paper could not indicate the effectiveness of e-learning in comparison with conventional education for oral health in total. However, for adults, it may be effective to get the oral health practice compared to the conventional education. Our study limitation is that there are only few studies that have assessed the effectiveness of e-learning. Therefore, numerous further high-quality studies should be conducted regarding the efficacy of e-learning compared with conventional education methods for oral health promotion.

Efficacy of Low-Level Laser Therapy for Oral Mucositis in Hematologic Patients Undergoing Transplantation: A Single-Arm Prospective Study.

Oral mucositis significantly affects the quality of life in hematologic cancer patients undergoing hematopoietic stem cell transplantation. Despite global evidence supporting the efficacy of low-level laser therapy (LLLT) for mucositis prevention, its clinical adoption in Japan is limited. This study aimed to fill this gap by evaluating the safety and efficacy of LLLT in a Japanese patient population. In a single-group, non-blinded, exploratory trial, we compared 21 LLLT-treated patients against a historical control of 96 patients. The primary endpoint was the incidence of Grade ≥ 2 mucositis, based on NCI-CTCAE ver. 4.0. The LLLT group showed a significantly lower incidence of Grade ≥ 2 mucositis (23.8%) compared to the control group (64.6%) (p = 0.0006). Furthermore, Grade ≥ 2 mucositis correlated with increased oral dryness and longer hospital stays. Our study confirms the efficacy of LLLT in reducing the onset of severe oral mucositis among Japanese hematologic cancer patients, advocating for its clinical introduction as a preventive measure in Japan.

Development and evaluation of the "Toothbrushing Timer with Information on Toothbrushes" application: A prospective cohort pilot study.

OBJECTIVES: For people, it is challenging to be conscious of the appropriate toothbrushing time to maintain good oral health in daily life. The aim of this study was to preliminarily examine the utility of an application (app) that combines a toothbrushing timer and information on toothbrushes. MATERIALS AND METHODS: We developed the "Toothbrushing Timer with Information on Toothbrushes" app to help users ensure appropriate toothbrushing time and learn about the beneficial characteristics of toothbrushes. A total of 18 participants were registered for the study. At baseline (T0) and after 1 month (T1) of app usage, study participants answered a digital questionnaire that comprised three questions on oral health practice, self-efficacy in oral hygiene, and quality of life related to oral health (Oral Health Impact Profile-14 [OHIP-14]). RESULTS: Five participants were excluded from the analysis as they did not answer the digital questionnaire. Finally, 13 participants completed the survey with a follow-up of 1 month. The 13 participants were grouped into health professionals (n = 8) and non-health professionals (n = 5). The total scores for oral health practice and self-efficacy related to oral hygiene increased after a month of app usage in health professional and non-health professional groups. However, there were no significant differences between T0 and T1 in either group. The total score of OHIP-14 was lower at T1 than at T0 in both groups. Therefore, participants showed better oral health practice, self-efficacy in oral hygiene, and quality of life related to oral health at T1 compared with that at T0. CONCLUSIONS: Our app showed positive results for the users and is useful in maintaining and promoting oral health awareness and practice. However, our pilot study lacks sufficient power and did not yield significant differences. Therefore, high-quality clinical trials with larger sample sizes are warranted for further improvement and evaluation.

Head and neck cancer patients show poor oral health as compared to those with other types of cancer.

PURPOSE: Several studies have found associations between periodontitis and various types of cancer. Since the site of head and neck cancer (HNC) has contiguity or proximity to the oral cavity, it may be particularly influenced by oral inflammation. This study aimed to determine whether HNC patients have poor oral health as compared to those with other types of cancer. METHODS: This study retrospectively examined oral environmental factors including periodontal inflamed surface area (PISA), a new periodontal inflammatory parameter. A total of 1030 cancer patients were divided into the HNC (n = 142) and other cancer (n = 888) groups. Furthermore, the HNC group was divided into high (n = 71) and low (n = 71) PISA subgroups, and independent risk factors affecting a high PISA value were investigated. RESULTS: Multivariate logistic regression analysis showed that number of missing teeth (odds ratio 1.72, 95% CI 1.15-2.56, P < 0.01), PISA (odds ratio 1.06, 95% CI 1.03-1.06, P < 0.05), and oral bacterial count (odds ratio 1.02, 95% CI 1.01-1.03, P < 0.01) were independent factors related to HNC. In addition, multivariate logistic regression analysis indicated that current smoker (odds ratio 7.51, 95% CI 1.63-34.71, P < 0.01) and presence of untreated dental caries (odds ratio 3.33, 95% CI 1.23-9.00, P < 0.05) were independent risk factors affecting high PISA values in HNC patients. CONCLUSION: HNC patients have higher levels of gingival inflammation and poor oral health as compared to patients with other types of cancer, indicating that prompt oral assessment and an effective oral hygiene management plan are needed at the time of HNC diagnosis.

ACE2 expression and spike S1 protein-mediated immune responses in oral mucosal cells.

OBJECTIVES: ACE2, known as a host receptor involved with SARS-CoV-2 infection, binds to viral spike proteins for host cell entry. However, details regarding its induction and function in oral mucosal cells remain unknown. MATERIALS AND METHODS: We examined ACE2 expression and its induction by transfected mimic nucleotides and pro-inflammatory cytokines in oral keratinocytes (RT7) and fibroblasts (GT1). Subsequently, the effects of viral spike S1 protein via ACE2 on CXCL10 expression induced by pro-inflammatory cytokines in both cells were examined. RESULTS: ACE2 was constitutively expressed in RT7 and GT1. Transfected Poly(I:C) and Poly(dA:dT) increased ACE2 expression in those cells, while knockdown of RIG-I decreased ACE2 expression induced by those transfected ds nucleotides. IFN-γ and TNF-α enhanced transfected ds nucleotides-induced ACE2 expression in RT7 but not GT1. S1 protein alone did not affect CXCL10 expression in either cell type, whereas it enhanced IFN-ß-induced CXCL10 in both, while immune responses of IFN-γ- and TNF-α-induced CXCL10 enhanced by S1 protein were different between RT7 and GT1. Finally, knockdown of ACE2 decreased cytokines and S1 protein mediated-CXCL10 levels in both cells. CONCLUSIONS: ACE2 in oral mucosal cells may contribute to development of infection and inflammation in cooperation with pro-inflammatory cytokines following SARS-CoV-2 invasion.

Association between human papillomavirus and oral cancer: a literature review.

HPV plays a vital role in the development of cervical cancers and oropharyngeal cancers, but it is controversial whether HPV is involved in oral cancer development and to what extent. In this review, the clinical characteristics, diagnosis, treatment, and prognosis of HPV-positive oral cancers are summarized, and the mechanisms of HPV-related oral cancer development are discussed. HPV DNA positivity rates are 20-30% in oral squamous cell carcinoma (OSCC), and HPV16 is the most common high-risk HPV. E6/E7 mRNA positivity rates are 2-6% in OSCC. Detection of both high-risk HPV DNA and E6/E7 mRNA is recommended to determine the presence of active HPV, in agreement with high-risk HPV infection in OSCC. Surgical treatment is the first-line therapy for HPV-positive and -negative oral cancer, but there is no unified view about the prognosis of HPV-positive OSCC patients. HPV16 may play a vital role in malignant transformation in oral epithelial dysplasia, and a model of synergistic carcinogenic impact of HPV and tobacco smoking is predicted. Additionally, it is hypothesized that there are different HPV-associated oral cancers, such as integrated HPV DNA-positive OSCC with stable E6/E7 expression and episomal HPV DNA-positive OSCC. In summary, the role of HPV in oral carcinogenesis seems to be limited because of the low E6/E7 positivity in OSCCs; however, episomal HPV DNA may play a vital role in the malignant transformation of HPV-positive oral premalignant lesions. Further investigation is required to promote new insights into the role of episomal HPV DNA in oral carcinogenesis.

LL-37-dsRNA Complexes Modulate Immune Response via RIG-I in Oral Keratinocytes.

Recognition of nucleic acids as pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) promotes an inflammatory response. On the other hand, LL-37, an antimicrobial peptide, is a multifunctional modulator of immune response, though whether it modulates inflammatory responses induced by nucleic acids in oral keratinocytes is unknown. In this study, we firstly investigated the effect of LL-37 on CXCL10 induced by DAMPs and PAMPs in immortalized oral keratinocytes, RT7. Furthermore, the effects of LL-37 on translocation of exogenous nucleic acids into cytoplasm as well as cytosolic receptor, RIG-I on immune responses mediated by LL-37-nucleic acid complexes were examined. From these results, LL-37 enhanced necrotic cell supernatant (NCS)-induced CXCL10 expression in RT7, while the response was decreased by RNase. Complexes of LL-37 and double-stranded (ds) RNA, Poly(I:C) enhanced CXCL10 expression in comparison with each alone, which were associated with NF-κB activation. Furthermore, LL-37 was shown to bind with ds nucleotides and translocate into cytoplasm. Knockdown of RIG-I decreased expression of CXCL10 induced by LL-37-Poly(I:C) complexes, and RIG-I were co-localized with Poly(I:C) entered by LL-37 in cytoplasm. LL-37 modulates dsRNA-mediated inflammatory response via RIG-I in oral keratinocytes, which may play an important role in the pathogenesis of oral inflammatory diseases.

Associations between Oral Human Herpesvirus-6 and -7 and Periodontal Conditions in Older Adults.

BACKGROUND: The associations between oral human herpesvirus-6 (HHV-6) and HHV-7, periodontal conditions, and lifestyle-related diseases, such as hypertension, diabetes, and dyslipidemia, have not been fully investigated in older adults. METHODS: Seventy-four older patients who visited Hiroshima University Hospital were enrolled. Tongue swab samples were employed, and a real-time polymerase chain reaction was performed to detect HHV-6 and HHV-7 DNA. Dental plaque accumulation, probing pocket depth, and bleeding on probing (BOP) (i.e., a sign of periodontal inflammation) were examined. The periodontal inflamed surface area (PISA) value (i.e., an indicator of the severity of periodontitis) was also examined. RESULTS: Of the 74 participants, one participant (1.4%) was HHV-6 DNA-positive and 36 participants (48.6%) were HHV-7 DNA-positive. A significant association between HHV-7 DNA and probing depth was found (p = 0.04). The HHV-7 DNA-positive participants had a higher positive rate of a ≥6-mm periodontal pocket with BOP (25.0%) than the HHV-7 DNA-negative participants (7.9%). Additionally, the HHV-7 DNA-positive participants had a higher PISA value than the HHV-7 DNA-negative participants. However, there was no significant association between HHV-7 and the PISA value (p = 0.82). No significant association was found between HHV-7 and lifestyle-related diseases (p > 0.05). CONCLUSIONS: Oral HHV-7 infection is associated with a deep periodontal pocket.

Physical Properties and Antimicrobial Release Ability of Gentamicin-Loaded Apatite Cement/α-TCP Composites: An In Vitro Study.

Apatite cement (AC), which has excellent osteoconductive ability, and alpha-tricalcium phosphate (α-TCP), which can be used for bone replacement, are useful bone substitute materials. The objective of this study was to clarify the physical properties and antimicrobial release ability of antibiotic-loaded AC/α-TCP composites in vitro. Gentamicin-loaded, rapid setting AC/α-TCP composites were prepared in 2 mixing ratios (10:3 and 10:6). The cement paste of AC/α-TCP composites was prepared in a plastic mold and dried in a thermostatic chamber at 37 °C and 100% relative humidity for 24 h. A diametral tensile strength test, powder X-ray diffraction analysis, and gentamicin release test were performed. The diametral tensile strengths of the AC/α-TCP composites were significantly less than that of AC alone. Powder X-ray diffraction patterns exhibited the characteristic peaks of hydroxyapatite in the AC/α-TCP composites and gentamicin-loaded AC/α-TCP composites. The concentration of the released gentamicin was maintained above the minimum inhibitory concentration of Staphylococcus aureus until Day 30 in both the gentamicin-loaded AC/α-TCP composites (10:3 and 10:6). Our results suggest that a gentamicin-loaded AC/α-TCP composite has potential as a drug delivery system. Further study is essential to investigate the antimicrobial activity and safety of the gentamicin-loaded AC/α-TCP composites in animal models.

Effects of CEACAM1 in oral keratinocytes on HO-1 expression induced by Candida ß-glucan particles.

OBJECTIVE: Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a member of the carcinoembryonic antigen family. Although its expression has been found in chronic oral inflammatory epithelium, this study aimed to know whether CEACAM1 in oral keratinocytes participates in host immune response against Candida albicans . METHODOLOGY: We investigated CEACAM1 expression in oral keratinocytes induced by C. albicans as well as by Candida cell wall component ß-glucan particles (ß-GPs). Furthermore, the effects of CEACAM1 on ß-GPs-induced heme oxygenase-1 (HO-1) expression and its related signals were examined. RESULTS: Fluorescence staining showed CEACAM1 expression in oral keratinocytes (RT7) cells, whereas quantitative reverse transcription (RT)-PCR indicated that both live and heat-killed C. albicans increased CEACAM1 mRNA expression in RT7 cells. Examinations using quantitative RT-PCR and western blotting indicated that CEACAM1 expression was also increased by ß-GPs derived from C. albicans . Specific siRNA for CEACAM1 decreased HO-1 expression induced by ß-GPs from C. albicans as well as the budding yeast microorganism Saccharomyces cerevisiae . Moreover, knockdown of CEACAM1 decreased ß-GPs-induced ROS activity in the early phase and translocation of Nrf2 into the nucleus. CONCLUSION: CEACAM1 in oral keratinocytes may have a critical role in regulation of HO-1 for host immune defense during Candida infection.

Prevalence of oral Epstein-Barr virus and Porphyromonas gingivalis and their association with periodontal inflamed surface area: A cross-sectional study.

We previously reported that oral herpesviruses, such as Epstein-Barr virus (EBV), are associated with periodontitis. However, the relationship between oral EBV or dual oral EBV and Porphyromonas gingivalis infections and periodontal inflammation severity remains unclear. We conducted this study to determine the relationship between oral EBV and P gingivalis prevalence and the periodontal inflamed surface area (PISA) in middle-aged and older adults. We analyzed 205 patients (median age, 70 years) who visited Hiroshima University Hospital. Tongue swab samples were used to investigate the presence of EBV and P gingivalis DNA using real-time PCR. Probing pocket depth and bleeding on probing were measured at 6 sites per tooth. PISA scores were calculated based on the results of probing pocket depth and bleeding on probing. Propensity scores were calculated via logistic regression analysis of 8 clinical factors: age, sex, smoking status, remaining teeth, denture use, hypertension, diabetes, and hyperlipidemia. EBV DNA was present in 41 of the 205 participants (20.0%). Thirty-seven EBV-positive or -negative participants in 74 matched pairs after propensity-score matching were examined via univariate analysis. EBV-positive participants exhibited higher plaque control record scores and PISAs than did EBV-negative participants. EBV DNA was significantly associated with plaque control record scores and PISA (both P = .04). Of the 205 participants, 111 were positive for P gingivalis (54.1%). Nineteen participants (9.3%) were infected with both oral EBV and P gingivalis. Logistic regression analysis revealed that dual infection with EBV and P gingivalis was significantly associated with diabetes (odds ratio = 3.37, 95% confidence interval: 1.13-10.1; P = .03). Oral EBV prevalence is associated with oral hygiene and the spread of inflamed periodontal tissue. Diabetes may be a risk factor for dual infection with oral EBV and P gingivalis.

Sunitinib promotes apoptosis via p38 MAPK activation and STAT3 downregulation in oral keratinocytes.

OBJECTIVE: Sunitinib, a targeted cancer drug, inhibits tyrosine kinases receptors and is widely used as first-line treatment for metastatic renal cell carcinoma. Patients undergoing chemotherapy with sunitinib frequently have oral mucosal complications, such as oral stomatitis, though cytotoxic effects of the drug on oral keratinocytes remain unknown. METHODS: The effects of sunitinib on immortalized oral keratinocytes, RT7 cells, in regard to cell injury and apoptosis, as well as apoptosis-mediated signaling pathways were investigated. RESULTS: Sunitinib treatment caused a significant increase in lactate dehydrogenase (LDH) in RT7 cells and primary oral keratinocytes. Additionally, the drug induced apoptosis-related events, such as DNA fragmentation, decreased anti-apoptotic Bcl-2 protein expression, and induction of cleaved PARP and caspase 3/9 in RT7 cells. Furthermore, phosphorylation of p38 MAPK, but not of ERK or JNK, was increased. On the contrary, constitutive phosphorylated STAT3 was decreased by sunitinib treatment, which was recovered by exposure to SB203580, a p38 MAPK inhibitor. Finally, SB203580 was found to reduce sunitinib-induced cell injury and apoptosis. CONCLUSION: The present results indicate that sunitinib promotes cell injury and apoptosis in oral keratinocytes via p38 activation and STAT3 downregulation. Sunitinib-mediated oral complications may be associated with cytotoxic effects of the drug on oral keratinocytes.

Analysis of the Deflection, Bristle Splaying, and Abrasion of a Single Tuft of a Polybutylene Terephthalate Toothbrush after Use: A Randomized Controlled Trial.

The aim of this study is to clarify the deflection, splaying, and abrasion of single tufts of polybutylene terephthalate (PBT) toothbrushes after use. A single-center randomized controlled trial is performed. The changes in deflection, bristle splaying, and abrasion are investigated for the middle single tuft of the top line (top-middle tuft) and the middle single tuft of the bottom line (bottom-middle tuft) of PBT toothbrushes with medium stiffness after 1 month, 2 months, and 3 months of use by 34 participants. A soft-material bending-resistance tester is used to assess the deflection of the single tufts. The deflection value of the top-middle tuft significantly increased after 1 month of use compared with the baseline. In contrast, the deflection of the bottom-middle tuft significantly increased after 3 months of use compared with the baseline and after 1 month and 2 months of use. Importantly, the change in deflection was distinctly different between the top- and bottom-middle tufts. The bristle splaying of both tufts significantly increased after use, but a significant change in bristle abrasion was not found. The bending stiffness of the top tuft of a PBT toothbrush may decrease more rapidly than that of the bottom tuft with use.

Co-Infection of Oral Candida albicans and Porphyromonas gingivalis Is Associated with Active Periodontitis in Middle-Aged and Older Japanese People.

Background and Objectives: Candida albicans can be detected in subgingival sites of patients with periodontitis. However, the association between oral Candida albicans and periodontitis has not been fully elucidated in Japanese adults. The aim of this study is to clarify the relationship between oral Candida albicans infection/co-infection of oral C. albicans and Porphyromonas gingivalis and periodontitis among middle-aged and older Japanese people. Materials and Methods: Eighty-six patients (mean age 70.4 years) who visited the Hiroshima University Hospital from April to September 2021 were investigated in this study. Oral swab samples were collected from the tongue surface. C. albicans and P. gingivalis DNA was detected by real-time PCR using specific DNA primer sets. C. albicans-positive participants were classified into two groups according to the presence or absence of intron insertion of C. albicans DNA by PCR analysis. Results: C. albicans was detected in 22 (25.6%) of the 86 patients. Patients in their 80s recorded a higher C. albicans-positive rate (35.3%) compared with other participants. However, there was no significant association between the C. albicans positivity rate and clinical parameters such as sex, age, systemic disease, denture use, or oral health status. Of the 22 C. albicans-positive participants, 10 participants (45.5%) had C. albicans with intron insertion; 70% of participants who had C. albicans with intron insertion exhibited ≥6 mm probing depth. C. albicans/P. gingivalis co-infection was found in 12 patients (14%). Importantly, binomial logistic regression analysis revealed that C. albicans/P. gingivalis co-infection was significantly associated with ≥6 mm periodontal pockets with bleeding on probing (p = 0.02). Conclusions: Co-infection of C. albicans and P. gingivalis is involved in active periodontitis in middle-aged and older people.

Expression of anti-fungal peptide, ß-defensin 118 in oral fibroblasts induced by C. albicans ß-glucan-containing particles.

OBJECTIVE: Although oral fibroblasts are thought to have the potential to enhance host defenses against Candida albicans , it is unknown whether they are able to recognize Candida cell components to increase the expression of antifungal peptides, such as defensin factors, against Candida infection. METHODOLOGY: We performed expression profiles of defensin genes induced by heat-killed C. albicans in oral immortalized fibroblasts (GT1) using cDNA microarray analysis. From those results, quantitative RT-PCR was used to examine the effects of Candida ß-glucan-containing particles (ß-GPs) on ß-Defensin 118 (DEFB 118) expression in oral mucosal cells. Furthermore, the antifungal activities of recombinant DEFB 118 against C. albicans and C. glabrata were investigated using fungicidal assays. RESULTS: Microarray analysis showed that DEFB118, ß-Defensin 129 (DEFB129), and α-Defensin 1 (DEFA1) genes were induced by heat-killed C. albicans and that their mRNA expressions were also significantly increased by live as well as heat-killed C. albicans . Next, we focused on DEFB118, and found that GT1, primary fibroblasts, and RT7 (oral immortalized keratinocytes) constitutively expressed DEFB118 mRNA expression in RT-PCR. Furthermore, C. albicans ß-GPs significantly increased the expression of DEFB118 mRNA in GT1 and primary fibroblasts. Although DEFB118 mRNA expression in RT7 was significantly induced by both live and heat-killed C. albicans, C. albicans ß-GPs failed to have an effect on that expression. Finally, recombinant DEFB118 significantly decreased the survival of both strains of C. albicans in a dose-dependent manner, whereas no effects were seen for both C. glabrata strains. CONCLUSION: DEFB118, induced by C. albicans ß-GPs from oral fibroblasts, may play an important role in oral immune responses against C. albicans infection.

Periodontal inflamed surface area in oral cavity associated with febrile neutropenia in patients with hematologic malignancy undergoing chemotherapy.

Febrile neutropenia (FN) is an infectious complication that develops during chemotherapy. Although the oral cavity can be an important infection route, it is unknown whether the oral environment is associated with FN. The present study examined the relationship between the oral environment using periodontal inflamed surface area (PISA), a new periodontal disease parameter, and FN in hematologic cancer patients undergoing chemotherapy. In this retrospective cohort study, 157 patients were divided into FN onset during chemotherapy (n = 75) and the FN negative groups (n = 82). The associations of risk factors related to the intraoral environment were assessed. Logistic regression analysis showed that types of blood cancer (odds ratio 1.98; P < 0.01), use of a high-risk regimen (odds ratio 4.44; P < 0.05), prophylaxis treatment with human granulocyte colony-stimulating factor (G-CSF) (odds ratio 4.15; P < 0.01) and PISA (odds ratio 1.02; P < 0.01) were independent factors associated with FN onset. Finally, propensity score matching was performed between two groups; 37 matched pairs were generated. PISA was significantly higher in the FN group than the FN negative group. There was a significant relationship between PISA and FN onset (P = 0.035). The present findings indicate that periodontitis treatment before starting cancer treatment is recommended as supportive care for preventing FN onset during chemotherapy.

Two PARP13 isoforms are associated with induction of antiviral factors in oral mucosal cells.

Innate immune systems in the oral cavity have important roles in the host defense against viral invasion of oral mucosa. Poly(ADP­ribose) polymerase 13 (PARP13), which has a strong antiviral ability, has been reported to possess two isoforms; a full­length protein, zinc­finger antiviral protein long (ZAPL), and a shorter protein (ZAPS). However, the expression and function of these two isoforms in oral mucosa remain unknown. In the present study, the expression levels of ZAPL and ZAPS induced by transfected double­stranded (ds) RNA, Poly(I:C), and dsDNA, Poly(dA:dT), in immortalized oral keratinocytes and fibroblasts (RT7 and GT1 cell lines, respectively) were investigated. Subsequently, the effects of the knockdown of ZAPL and ZAPS on transfected nucleotide­induced antiviral factors were examined. The results demonstrated constitutive expression of ZAPL and ZAPS in RT7 and GT1 cells, and their expression in both cell types was notably increased by transfection of Poly(I:C) and Poly(dA:dT) when compared with no transfection. Specific knockdown of ZAPL and ZAPS in RT7 cells decreased IFN­ß and C­X­C motif chemokine ligand 10 (CXCL10) expression induced by transfected Poly(I:C) and Poly(dA:dT). On the other hand, knockdown of ZAPL and ZAPS in GT1 cells decreased the expression of CXCL10 induced by the transfected nucleotides, whereas that had no effect on IFN­ß expression induced by Poly(dA:dT). Their knockdown was also associated with transfected nucleotides­induced IFN regulatory factor 3 phosphorylation in both cell types. Taken together, these results indicate that ZAPL and ZAPS, isoforms of PARP13, in oral mucosal cells participate in host defense against viral infection of oral mucosa.

Immune response to cytosolic DNA via intercellular receptor modulation in oral keratinocytes and fibroblasts.

OBJECTIVE: Double-strand (ds) DNA-enveloped viruses can cause oral infection. Our aim is to investigate whether oral mucosal cells participate in immune response against cytosolic dsDNA invasion. METHODS: We examined the response to transfected herpes simplex virus (HSV) dsDNA via intracellular receptors in oral keratinocytes (RT7) and fibroblasts (GT1), and the effect of TNF-α on those responses. RESULTS: Transfected dsDNA increased CXCL10 expression via NF-κB activation in both cell types, while those responses were inhibited by knockdown of RIG-I, an RNA sensor. Although IFI16, a DNA sensor, was expressed in the nuclei of both types, its knockdown decreased transfected dsDNA-induced CXCL10 expression in GT1 but not RT7 cells. IFI16 in GT1 cells was translocated into cytoplasm from nuclei, which was attributed to immune response to cytosolic dsDNA. TNF-α enhanced transfected dsDNA-induced CXCL10, and knockdown of IFI16 decreased TNF-α and dsDNA-driven CXCL10 expression in both RT7 and GT1 cells. Finally, the combination of TNF-α and transfected dsDNA resulted in translocation of IFI16 from nuclei to cytoplasm in RT7 cells. CONCLUSION: RIG-I and IFI16 in oral mucosal cells may play important roles in host immune response against DNA viral infection, while TNF-α contributes to development of an antiviral system via those intracellular receptors.

Melatonin enhances cisplatin-induced cell death through inhibition of DERL1 in mesenchymal-like CD44high OSCC cells.

BACKGROUND: Melatonin is a hormone that is primarily produced in the pineal gland and is involved in wide range of biological functions. However, the impact of melatonin on chemotherapy-induced cell death remains to be elucidated in oral squamous cell carcinoma (OSCC) cells. The objective of this study was to clarify the role of melatonin in cisplatin-induced cytotoxicity in CD44high OSCC cells. METHODS: CD44high OSCC cells were cultured on fibronectin-coated hydrogel. A lactate dehydrogenase cytotoxicity assay was performed to evaluate cisplatin-induced cell death. The effect of melatonin on cisplatin-induced cell death and Derlin-1 (DERL1) endoplasmic reticulum membrane protein expression was investigated. RESULTS: CD44high OSCC cells exhibited mesenchymal-like features when cultured on fibronectin-coated hydrogel. Mesenchymal-like CD44high OSCC cells demonstrated strong resistance to cisplatin-induced cell death compared with epithelial-like CD44high OSCC cells. DERL1 mRNA and DERL1 protein expression levels were significantly higher in mesenchymal-like CD44high cells compared with epithelial-like CD44high cells. Cisplatin-induced cell death was significantly enhanced after DERL1 siRNA knockdown, suggesting that DERL1 is involved in resistance to cisplatin-induced cell death. Melatonin significantly inhibited DERL1 expression and enhanced cisplatin-induced cell death in mesenchymal-like CD44high cells. miR-181c-5p expression was significantly upregulated in the presence of melatonin. Furthermore, melatonin-inhibited DERL1 expression was significantly recovered by miR-181c-5p inhibitor. In addition, melatoninenhanced cisplatin-induced cell death was attenuated by miR-181c-5p inhibitor. These results suggest that melatonin-induced miR-181c-5p enhances cisplatin-induced cell death through inhibition of DERL1 in mesenchymal-like CD44high cells. CONCLUSIONS: Melatonin plays a vital role in promoting cisplatin-induced cytotoxicity in mesenchymal-like CD44high OSCC cells.