Combination therapy with WEE1 inhibition and trifluridine/tipiracil against esophageal squamous cell carcinoma.

Despite advanced therapeutics, esophageal squamous cell carcinoma (ESCC) remains one of the deadliest cancers. Here, we propose a novel therapeutic strategy based on synthetic lethality combining trifluridine/tipiracil and MK1775 (WEE1 inhibitor) as a treatment for ESCC. This study demonstrates that trifluridine induces single-strand DNA damage in ESCC cells, as evidenced by phosphorylated replication protein 32. The DNA damage response includes cyclin-dependent kinase 1 (CDK1) (Tyr15) phosphorylation as CDK1 inhibition and a decrease of the proportion of phospho-histone H3 (p-hH3)-positive cells, indicating cell cycle arrest at the G2 phase before mitosis entry. The WEE1 inhibitor remarkedly suppressed CDK1 phosphorylation (Try15) and reactivated CDK1, and also increased the proportion of p-hH3-positive cells, which indicates an increase of the number of cells into mitosis. Trifluridine combined with a WEE1 inhibitor increased trifluridine-mediated DNA damage, namely DNA double-strand breaks, as shown by increased γ-H2AX expression. Moreover, the combination treatment with trifluridine/tipiracil and a WEE1 inhibitor significantly suppressed tumor growth of ESCC-derived xenograft models. Hence, our novel combination treatment with trifluridine/tipiracil and a WEE1 inhibitor is considered a candidate treatment strategy for ESCC.

Cross-Cultural Validity of a Dietary Questionnaire for Studying Dental Caries in Japanese Children.

This study examines the cross-cultural validity of the Japanese version of the Food Frequency Questionnaire (FFQ), designed for studies on dental caries to assess dietary intake in Japanese children. Parent-reported dietary data were collected (274 children, 3-6 years old) using the 38-item FFQ, whose reliability and validity have been demonstrated in adults. Factor analysis was used to determine dimensionality. Dietary cariogenicity scores were compared with the levels of plaque mutans streptococci, and the decayed, missing, and filled teeth (dmft) index to evaluate the criterion validity using Pearson's correlation coefficient (r) and the Kruskal-Wallis test. The FFQ showed good criterion validity, assessed through its relationship with the dmft index (r = 0.119; p = 0.05) and Dentocult SM score (r = 0.124; p = 0.04). Factor analysis revealed six questionnaire subscales. Internal consistency was from low to acceptable (Cronbach's alpha = 0.64 for the total scale, 0.39-0.53 for each subscale). Children with a higher SM score were more likely to have higher dietary cariogenicity scores (p = 0.01; Kruskal-Wallis test). These results confirm the validity of the Japanese version of the FFQ for children, which can be used to track dietary structure dynamics regarding cariogenicity from childhood to adulthood.

Broadening the Dental Hygiene Students' Perspectives on the Oral Health Professionals: A Text Mining Analysis.

Professional identity formation, an important component of education, is influenced by participation, social relationships, and culture in communities of practice. As a preliminary investigation of dental hygienists' professional identity formation, this study examined changes in the dental hygiene students' perceptions of oral health professionals over the three years of their undergraduate program. At a Japanese dental hygiene school, 40 students participated in surveys with open-ended questions about professional groups several times during their studies. The text data were analyzed through content analysis with text mining software. The themes that characterized their dental hygienist profession perceptions in their programs each year were identified as: "Supporters at the dental clinic"; "Engagement with interprofessional care" and "Improved problem-solving skills for clinical issues regarding the oral region"; and "Active contribution to general health" and "Recognition of the roles considering relationships" (in the first, second, and third years, respectively). The students acquired professional knowledge and recognized the significance and roles of oral health professionals in practice. They gained more learning experiences in their education, including clinical placements and interprofessional education. This study provides insight into curriculum development for professional identity formation in dental hygiene students.

HER2 G776S mutation promotes oncogenic potential in colorectal cancer cells when accompanied by loss of APC function.

Clinical cancer genome sequencing detects oncogenic variants that are potential targets for cancer treatment, but it also detects variants of unknown significance. These variants may interact with each other to influence tumor pathophysiology, however, such interactions have not been fully elucidated. Additionally, the effect of target therapy for those variants also unclarified. In this study, we investigated the biological functions of a HER2 mutation (G776S mutation) of unknown pathological significance, which was detected together with APC mutation by cancer genome sequencing of samples from a colorectal cancer (CRC) patient. Transfection of the HER2 G776S mutation alone slightly increased the kinase activity and phosphorylation of HER2 protein, but did not activate HER2 downstream signaling or alter the cell phenotype. On the other hand, the HER2 G776S mutation was shown to have strong oncogenic potential when loss of APC function was accompanied. We revealed that loss of APC function increased Wnt pathway activity but also increased RAS-GTP, which increased ERK phosphorylation triggered by HER2 G776S transfection. In addition, afatinib, a pan-HER tyrosine kinase inhibitor, suppressed tumor growth in xenografts derived from HER2 G776S-transfected CRC cells. These findings suggest that this HER2 mutation in CRC may be a potential therapeutic target.

Impact of Dietary Patterns on Plaque Acidogenicity and Dental Caries in Early Childhood: A Retrospective Analysis in Japan.

This study aimed to assess the relationship of dietary patterns, such as frequency, timing, and cariogenicity of food/beverage consumption, with plaque acidogenicity and early childhood caries (ECC) in Japan. A total of 118 children aged 1-4 years who had visited the pediatric dental clinic were enrolled. We retrospectively reviewed their records to collect data including age, sex, medical history, medication, caries status, and plaque acidogenicity level at the first dental visit. The plaque acidogenicity level was measured using Cariostat®. Dietary data were collected from 3-day dietary records, and the dietary cariogenicity score was calculated from these data. Children with ECC or high plaque acidogenicity consumed between-meal sugars more frequently than did their counterparts (p = 0.002 and p = 0.006, respectively). Children with ECC or high plaque acidogenicity drank juices between meals more frequently than at mealtimes (p = 0.02). Frequent consumption of between-meal sugars was associated with higher plaque acidogenicity and ECC, and frequent breast/bottle feeding was associated with ECC. No differences were found in the dietary cariogenicity scores between these groups. Therefore, the frequency and timing of sugar consumption, might affect plaque acidogenicity and ECC, and reducing the frequency of sugar intake could prevent ECC.

What impact does postgraduate clinical training have on empathy among Japanese trainee dentists?

BACKGROUND: Enhancing empathy in healthcare education is a critical component in the development of a relationship between healthcare professionals and patients that would ensure better patient care; improved patient satisfaction, adherence to treatment, patients' medication self-efficacy, improved treatment outcomes, and reduced patient anxiety. Unfortunately, however, the decline of empathy among students has been frequently reported. It is especially common when the curriculum transitions to a clinical setting. However, some studies have questioned the significance and frequency of this decline. Thus, the purpose of this study was to determine the impact of postgraduate clinical training on dental trainees' empathy from cognitive, behavioral, and patients' perspective. METHODS: This study included 64 trainee dentists at Okayama University Hospital and 13 simulated patients (SPs). The trainee dentists carried out initial medical interviews with SPs twice, at the beginning and the end of their clinical training. The trainees completed the Japanese version of the Jefferson Scale of Empathy for health professionals just before each medical interview. The SPs evaluated the trainees' communication using an assessment questionnaire immediately after the medical interviews. The videotaped dialogue from the medical interviews was analyzed using the Roter Interaction Analysis System. RESULTS: No significant difference was found in the self-reported empathy score of trainees at the beginning and the end of the clinical training (107.73 [range, 85-134] vs. 108.34 [range, 69-138]; p = 0.643). Considering the results according to gender, male scored 104.06 (range, 88-118) vs. 101.06 (range, 71-122; p = 0.283) and female 109.17 (range, 85-134) vs. 111.20 (range, 69-138; p = 0.170). Similarly, there was no difference in the SPs' evaluation of trainees' communication (10.73 vs. 10.38, p = 0.434). Communication behavior in the emotional responsiveness category for trainees in the beginning was significantly higher than that at the end (2.47 vs. 1.14, p = 0.000). CONCLUSIONS: Overall, a one-year postgraduate dental training program neither reduced nor increased trainee dentists' empathy levels. Providing regular education support in this area may help trainees foster their empathy.

Synthetic Lethality with Trifluridine/Tipiracil and Checkpoint Kinase 1 Inhibitor for Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a disease characterized by a high mutation rate of the TP53 gene, which plays pivotal roles in the DNA damage response (DDR) and is regulated by checkpoint kinase (CHK) 2. CHK1 is another key DDR-related protein, and its selective inhibition is suggested to be particularly sensitive to TP53-mutated cancers, because a loss of both pathways (CHK1 and/or CHK2-p53) is lethal due to the serious impairment of DDR. Such a therapeutic strategy is termed synthetic lethality. Here, we propose a novel therapeutic strategy based on synthetic lethality combining trifluridine/tipiracil and prexasertib (CHK1 inhibitor) as a treatment for ESCC. Trifluridine is a key component of the antitumor drug combination with trifluridine/tipiracil (an inhibitor of trifluridine degradation), also known as TAS-102. In this study, we demonstrate that trifluridine increases CHK1 phosphorylation in ESCC cells combined with a reduction of the S-phase ratio as well as the induction of ssDNA damage. Because CHK1 phosphorylation is considered to be induced as DDR for trifluridine-mediated DNA damage, we examined the effects of CHK1 inhibition on trifluridine treatment. Consequently, CHK1 inhibition by short hairpin RNA or treatment with the CHK1 inhibitor, prexasertib, markedly enhanced trifluridine-mediated DNA damage, represented by an increase of γH2AX expression. Moreover, the combination of trifluridine/tipiracil and CHK1 inhibition significantly suppressed tumor growth of ESCC-derived xenograft tumors. Furthermore, the combination of trifluridine and prexasertib enhanced radiosensitivity both in vitro and in vivo Thus, the combination of trifluridine/tipiracil and a CHK1 inhibitor exhibits effective antitumor effects, suggesting a novel therapeutic strategy for ESCC.

Experimental model for the irradiation-mediated abscopal effect and factors influencing this effect.

Radiotherapy (RT) is the primary treatment for cancer. Ionizing radiation from RT induces tumor damage at the irradiated site, and, although clinically infrequent, may cause regression of tumors distant from the irradiated site-a phenomenon known as the abscopal effect. Recently, the abscopal effect has been related to prolongation of overall survival time in cancer patients, though the factors that influence the abscopal effect are not well understood. The aim of this study is to clarify the factors influencing on abscopal effect. Here, we established a mouse model in which we induced the abscopal effect. We injected MC38 (mouse colon adenocarcinoma) cells subcutaneously into C57BL/6 mice at two sites. Only one tumor was irradiated and the sizes of both tumors were measured over time. The non-irradiated-site tumor showed regression, demonstrating the abscopal effect. This effect was enhanced by an increase in the irradiated-tumor volume and by administration of anti-PD1 antibody. When the abscopal effect was induced by a combination of RT and anti-PD1 antibody, it was also influenced by radiation dose and irradiated-tumor volume. These phenomena were also verified in other cell line, B16F10 cells (mouse melanoma cells). These findings provide further evidence of the mechanism for, and factors that influence, the abscopal effect in RT.

Dentist gender-related differences in patients' oral health behaviour.

This study aimed at determining whether oral health behavior differs between patients regularly checked by male and female dentists. The analysis was based on a cross-sectional survey of 354 Japanese community residents (median age = 54 years; 145 men and 209 women) conducted in a municipality from January to February 2017. Data on demographic characteristics and factors associated with oral health behavior were obtained through self-administered questionnaires. The association between regular dentist gender and patients' regular dental care check-up and interdental cleaning performance was examined after adjusting for potential confounders. Among respondents, 88.7% and 11.3% reported having male and female regular dentists, respectively. In a multivariate logistic regression model, patients regularly checked by female dentists had an increased likelihood of visiting their dentist for dental care check-up at least once every year (odds ratio [OR] = 2.23, 95% confidence interval [CI] = 1.09-4.55)and using an interdental cleaner (OR = 2.62, 95% CI = 1.03-6.71) compared to those regularly checked by male dentists. Patients regularly checked by female dentists tended to have more preventive oral health behaviors than those regularly checked by male dentists. These findings suggest that dentist gender has important clinical implications for patients' oral health behavior.

Protective effects of Alda-1, an ALDH2 activator, on alcohol-derived DNA damage in the esophagus of human ALDH2*2 (Glu504Lys) knock-in mice.

Alcohol consumption is the key risk factor for the development of esophageal squamous cell carcinoma (ESCC), and acetaldehyde, a metabolite of alcohol, is an alcohol-derived major carcinogen that causes DNA damage. Aldehyde dehydrogenase2 (ALDH2) is an enzyme that detoxifies acetaldehyde, and its activity is reduced by ALDH2 gene polymorphism. Reduction in ALDH2 activity increases blood, salivary and breath acetaldehyde levels after alcohol intake, and it is deeply associated with the development of ESCC. Heavy alcohol consumption in individuals with ALDH2 gene polymorphism significantly elevates the risk of ESCC; however, effective prevention has not been established yet. In this study, we investigated the protective effects of Alda-1, a small molecule ALDH2 activator, on alcohol-mediated esophageal DNA damage. Here, we generated novel genetically engineered knock-in mice that express the human ALDH2*1 (wild-type allele) or ALDH2*2 gene (mutant allele). Those mice were crossed, and human ALDH2*1/*1, ALDH2*1/*2 and ALDH2*2/*2 knock-in mice were established. They were given 10% ethanol for 7 days in the presence or absence of Alda-1, and we measured the levels of esophageal DNA damage, represented by DNA adduct (N2-ethylidene-2'-deoxyguanosine). Alda-1 significantly increased hepatic ALDH2 activity both in human ALDH2*1/*2 and/or ALDH2*2/*2 knock-in mice and reduced esophageal DNA damage levels after alcohol drinking. Conversely, cyanamide, an ALDH2-inhibitor, significantly exacerbated esophageal DNA adduct level in C57BL/6N mice induced by alcohol drinking. These results indicate the protective effects of ALDH2 activation by Alda-1 on esophageal DNA damage levels in individuals with ALDH2 gene polymorphism, providing a new insight into acetaldehyde-mediated esophageal carcinogenesis and prevention.