KEYNOTE-434 part B: A phase 1 study evaluating the combination of epacadostat, pembrolizumab, and chemotherapy in Japanese patients with previously untreated advanced non-small-cell lung cancer.

BACKGROUND: Pembrolizumab plus epacadostat (indoleamine 2,3-dioxygenase-1 inhibitor) was well tolerated in Japanese patients with advanced solid tumors in part A of the nonrandomized, open-label, phase 1 KEYNOTE-434 study (NCT02862457). We report results from part B, which evaluated epacadostat plus pembrolizumab and chemotherapy in Japanese patients with advanced non-small-cell lung cancer (NSCLC). METHODS: Eligible patients aged ≥ 20 years had histologically or cytologically confirmed stage IIIB or IV NSCLC with no prior systemic therapy, and ECOG performance status of 0 or 1. Patients received epacadostat 100 mg orally twice-daily, pembrolizumab 200 mg intravenously every-3-weeks for ≤ 35 cycles, and 4 cycles of chemotherapy (cohort 1: cisplatin plus pemetrexed, non-squamous; cohort 2: carboplatin plus pemetrexed, non-squamous; cohort 3: carboplatin plus paclitaxel, squamous or non-squamous). Primary endpoint was incidence of dose-limiting toxicities (DLTs). Following unfavorable results from other studies, a protocol amendment removed epacadostat from the treatment combination. RESULTS: Of 19 patients, 7 were enrolled in cohort 1, and 6 each in cohorts 2 and 3. Median follow-up was 13.7 (range, 4.2-27.8) months. Five of 17 (29%) DLT-evaluable patients experienced ≥ 1 DLT (cohort 1, n = 1; cohorts 2 and 3, n = 2 each); most commonly maculopapular rash (grade 3, n = 3) and increased alanine aminotransferase (grade 2, n = 1; grade 3, n = 2). All patients experienced treatment-related adverse events (AEs); 58% experienced grade 3 or 4 treatment-related AEs. Objective response rate was 47%. CONCLUSION: The combination of epacadostat plus pembrolizumab and chemotherapy was found to be tolerable in Japanese patients with advanced NSCLC. TRIAL REGISTRATION: ClinicalTrials.gov , NCT02862457.

A Systematic Review of Treatment-Related Adverse Events for Combination Therapy of Multiple Tyrosine Kinase Inhibitor and Immune Checkpoint Inhibitor.

BACKGROUND: Combination therapy with multiple tyrosine kinase inhibitors (multi-TKIs) and immune checkpoint inhibitors (ICIs) has been increasingly tested in clinical studies. This study aimed to investigate the effect of the addition of ICI to multi-TKIs on the profile of treatment-related adverse events. METHODS: An electronic database search was performed using PubMed and Web of Science to identify published clinical studies on multi-TKI monotherapy and multi-TKI plus ICI combination therapy from July 20, 2005 to July 1, 2023. The incidence rate of common adverse events caused by multi-TKI monotherapy and multi-TKI plus ICI combination therapy was obtained and compared from the viewpoints of (1) relative risk for the combination therapy vs sunitinib, (2) adverse event incidence rate by clinical trial, and (3) pooled incidence rate. The quality of the evidence was assessed with the Cochrane risk of bias tool. Meta-analysis used random effects models. RESULTS: This systematic review identified 83 clinical studies involving 7951 patients. The combination therapy of multi-TKI and ICI was associated with an increased risk of diarrhea (relative risk [RR]: 1.24, 95% confidence interval [CI]: 1.15-1.33, P < .001), hypothyroidism (RR: 1.44, 95% CI: 1.11-1.87, P = .0064) and rash (RR: 1.71, 95% CI: 1.18-2.47, P = .0045) compared with multi-TKI monotherapy. The addition of ICI was suggested to decrease the risk of adverse events related to performance status. CONCLUSION: Our study identified an increased risk of treatment-related adverse events associated with multi-TKI plus ICI combination therapy. This would help optimize the management of toxicities caused by multi-TKI plus ICI combination therapy.

siRNA potency enhancement via chemical modifications of nucleotide bases at the 5'-end of the siRNA guide strand.

Small interfering RNAs (siRNAs) can be utilized not only as functional biological research tools but also as therapeutic agents. For the clinical use of siRNA as drugs, various chemical modifications have been used to improve the activity of siRNA drugs, and further chemical modifications are expected to improve the utility of siRNA therapeutics. As the 5' nucleobase of the guide strand affects the interaction between an siRNA and AGO2 and target cleavage activity, structural optimization of this specific position may be a useful strategy for improving siRNA activity. Here, using the in silico model of the complex between human AGO2 MID domain and nucleoside monophosphates, we screened and synthesized an original adenine-derived analog, 6-(3-(2-carboxyethyl)phenyl)purine (6-mCEPh-purine), that fits better than the natural nucleotide bases into the MID domain of AGO2. Introduction of the 6-mCEPh-purine analog at the 5'-end of the siRNA guide strand significantly enhanced target knockdown activity in both cultured cell lines and in vivo animal models. Our findings can help expand strategies for rationally optimizing siRNA activity via chemical modifications of nucleotide bases.

The relationship between bone density and the oral function in older adults: a cross-sectional observational study.

BACKGROUND: Falls among older adults with a low bone density can lead to a bedridden state. Declining bone density increases the risk of falls resulting fractures in older adults. A person's physical performance is known to be closely related to bone density, and a relationship between the physical performance and the oral function is also known to exist. However, there currently is a lack of evidence regarding the relationship between bone density and the oral function. We assessed the relationship between the bone density and the both the oral function and physical performance among older adults. PATIENTS AND METHODS: 754 older adults aged 65 years or older who independently lived in rural regions and who were not taking any medications for osteoporosis participated. We checked all participants for osteoporosis using an ultrasonic bone density measuring device. Regarding the oral function, we evaluated the following factors: remaining teeth, occlusal support, masticatory performance, occlusal force, and tongue pressure. We also evaluated body mass index (BMI) and skeletal muscle mass Index as clinical characteristics. The normal walking speed, knee extension force and one-leg standing test were evaluated as physical performance. For the statistical analyses, we used the Mann-Whitney U test, chi-square test, the Kruskal-Wallis, and a multiple regression analysis. RESULTS: Eighty-one percent of the females and 58% of the males had osteoporosis or a decreased bone mass. The occlusal force, masticatory performance and the tongue pressure showed significant association with the bone density. The participants physical performance showed a significant association with their bone states except for walking speed. According to a multiple regression analysis, clinical characteristics (sex, age, BMI), one-leg standing and occlusal force showed independent associations with the bone density. It was suggested that the bone density tends to increase if the occlusal force is high and/or the one-leg standing test results are good. CONCLUSIONS: The bone density in the older adults showed a significant relationship not only with clinical characteristics or physical performance, but also with occlusal force. It may also be effective to confirm a good oral function in order to maintain healthy living for older adults.

Relationship between oral environment and frailty among older adults dwelling in a rural Japanese community: a cross-sectional observational study.

BACKGROUND: Oral functions are known to decline with aging. However, there is limited evidence that supports the relationship between oral health and frailty. This study aimed to clarify the relationship between oral hygiene conditions, measured by remaining teeth and mucosa, and frailty among elderly people dwelling in a Japanese rural community. METHODS: We surveyed self-reliant elderly individuals aged ≥65 years who were dwelling in the Sasayama-Tamba area of Hyogo, Japan. Frailty was evaluated according to the total score of the Kihon Checklist (KCL). Based on the KCL score, elderly participants were divided into three groups: robust, pre-frail, and frail. The items measured to evaluate oral environment included the number of remaining teeth, denture usage condition, oral hygiene status, dry mouth condition, and salivary bacterial count. For statistical analysis, Fisher's exact test, one-way analysis of variance, and multiple comparison technique were used. RESULTS: Of 308 elderly participants, 203 (65.9%), 85 (27.6%), and 20 (6.5%) belonged to the robust, pre-frail, and frail groups, respectively. The proportion of participants who were judged to have poor hygiene was significantly higher in the frail group than in the other two groups. The bacterial count was significantly smaller in the frail group than in the robust group, and the frail group had fewer number of remaining teeth than the other two groups, suggesting that the number of remaining teeth may be associated with bacterial count. CONCLUSION: In elderly adults, physical frailty may affect the oral hygiene status and condition of the remaining teeth.

Ultrastructural and immunocytochemical characterization of ameloblast-enamel adhesion at maturation stage in amelogenesis in Macaca fuscata tooth germ.

Maturation-stage ameloblasts are firmly bound to the tooth enamel by a basal lamina-like structure. The mechanism underlying this adhesion, however, remains to be fully clarified. The goal of this study was to investigate the mechanism underlying adhesion between the basal lamina-like structure and the enamel in monkey tooth germ. High-resolution immunogold labeling was performed to localize amelotin and laminin 332 at the interface between ameloblasts and tooth enamel. Minute, electron-dense strands were observed on the enamel side of the lamina densa, extending into the degrading enamel matrix to produce a well-developed fibrous layer (lamina fibroreticularis). In un-demineralized tissue sections, mineral crystals smaller than those in the bulk of the enamel were observed adhering to these strands where they protruded into the surface enamel. Immunogold particles reactive for amelotin were preferentially localized on these strands in the fibrous layer. On the other hand, those for laminin 332 were localized solely in the lamina densa; none were observed in the fibrous layer. These results suggest that the fibrous layer of the basal lamina-like structure is partly composed of amelotin molecules, and that these molecules facilitate ameloblast-enamel adhesion by promoting mineralization of the fibrous layer during the maturation stage of amelogenesis.

Ultrastructural immunolocalization of laminin 332 (laminin 5) at dento-gingival interface in Macaca fuscata monkey.

Although laminin 332 (laminin 5), an extracellular matrix molecule involved in cell adhesion and migration, has been localized at the interface between the tooth enamel and junctional epithelium, its ultrastructural localization remains to be fully clarified. The purpose of the present study was to investigate the ultrastructural distribution of laminin 332 at the dento-gingival interface in Japanese monkey (Macaca fuscata) using pre- and post-embedding immunoelectron microscopy. Pre-embedding immunoelectron microscopy revealed a broad band of internal basal lamina together with supplementary lamina densa, and both showed immunolabeling for laminin 332. Immunoreaction products for laminin 332 were observed in the rough-surfaced endoplasmic reticulum of the junctional epithelial cells close to the tooth enamel. Post-embedding immunoelectron microscopy revealed an increase in the number of immunogold particles toward the coronal portion, resulting in a large accumulation of particles on the basal lamina, preferentially on the lamina densa. Concomitantly the dental cuticle at the dento-gingival interface was sporadically, but specifically, immunogold-labeled with anti-laminin 332 antibody. These data suggest that junctional epithelium actively produces laminin 332, and that the products accumulate at the dento-gingival interface during cell migration coronally towards the gingival sulcus.

[Prevalence of HIV and sexually transmitted infections and characteristics of men who have sex with men at a community-based center in Yokohama, Japan].

OBJECTIVES: To investigate the characteristics of men who have sex with men (MSM) in a sample of men who sought voluntary testing and counseling (VCT) for human immunodeficiency virus (HIV) and sexually transmitted infections (STIs) in a community-based center in Yokohama, Japan. The prevalence of HIV/STIs and the incidence rate of HIV were also assessed. METHODS: We investigated VCT records of 449 clients who received free anonymous night VCT services between 2008 and 2011. The tests included rapid HIV antibody, Treponema pallidum antibody (TP Ab), and hepatitis B surface antigen (HBs Ag) tests. We also analyzed VCT records of 82 clients who had at least two tests at our center to estimate the HIV incidence rate. RESULTS: The number of MSM who visited the community center for the first time was 423. Those who resided in Kanagawa Prefecture accounted for 78.5% of the sample, and 30.5% had never been tested for HIV previously. The rate of consistent condom use in the past six months was 44.9%. The results revealed that 3.1%, 10.2%, and 1.7% of MSM tested positive for HIV, TP Ab, and HBs Ag respectively. There was no significant difference in age, residence, previous HIV-testing rates, and the rate of consistent condom use in the past six months between subjects who underwent multiple HIV tests at the community center and those who did not undergo any test after the first visit. HIV-positive individuals were all referred to hospitals nearby. Of 82 repeat HIV testers, one was a seroconverter, indicating an incidence rate of 1.00 per 100 person-years (95% confidence interval, 0.00-5.58). CONCLUSION: Our VCT services were accepted by MSM with a high risk of HIV/STIs infection. HIV prevalence was higher than that at local health centers. The HIV incidence rate was equivalent to the previous study that estimated HIV incidence rate from national and sentinel surveillance data. Creating and sustaining alternative VCT venues targeting MSM with high risk of HIV/STIs infection should be considered in other prefectures in Japan to facilitate the early detection and treatment of HIV/STIs.

Migrants' access to COVID-19 vaccination in Japan: Progress and challenges.

Objectives: This study aimed to review the progress and challenges of COVID-19 vaccine roll-out for migrants in Japan and discuss the approaches to address the challenges and better prepare for future waves of COVID-19 and other pandemics. Methods: We conducted a literature review using an assessment framework which we developed building upon existing frameworks and tools on access to health services and COVID-19 vaccination among migrants. Results: COVID-19 vaccination coverage among foreigners might be lower than that of nationals although the data on foreigners were not widely available. A gap appeared to exist between the government's efforts to disseminate vaccine-related information through multi-lingual websites and migrant communities as recipients. A series of barriers for migrants were identified at different stages of the vaccination process. While efforts were made by different units of local governments, NGOs, migrant communities, and international exchange associations, linkages across sectors and scaling-up appeared to be an issue. No foreigners were explicitly excluded from the entitlements of COVID-19 vaccination. The national level guidance, however, allowed sub-national levels to make a decision on whether or not undocumented foreigners should be reported to the immigration office or law enforcement when providing the services. In consequence, units in charge of public health and vaccination of some municipalities did not offer vaccination to those in need. Conclusion: Migrants, especially those unregistered face various barriers in accessing COVID-19 vaccination. It is critical to assess and address challenges concerning channels of information dissemination, pathways to access services, obstacles for vulnerable migrants, and data for evidence-based actions.

Effect of single-dose amoxicillin on rat incisor odontogenesis: a morphological study.

The effect of exposure to amoxicillin on tooth development remains to be elucidated. The purpose of this study was to investigate the effect of amoxicillin on rat incisor odontogenesis. Male Wistar rats weighing approximately 100 g were given a single intraperitoneal injection of 3.0 g/kg body weight amoxicillin. One week after injection, the rats were fixed, and the lower incisors were demineralized and prepared into paraffin sections for light microscopy (LM) and immunohistochemistry. Undemineralized samples were embedded in resin and ground for processing for contact microradiography (CMR) and scanning electron microscopy (SEM). Serum calcium, phosphate, and magnesium concentrations were measured. At 1 week after amoxicillin administration, LM, CMR, and SEM revealed a clear increase in the area of interglobular dentin, representing disruption of mineralization by odontoblasts. Immunohistochemistry demonstrated moderate levels of the small integrin-binding ligand N-linked glycoprotein family dentin matrix protein 1 in large areas of interglobular dentin. On the other hand, no morphological alteration or hypomineralization was observed in the enamel. Serum calcium values showed no significant differences between the control and experimental rats during the experimental period although both serum phosphate and magnesium levels increased at day 1 after amoxicillin injection. The results suggest that a single dose of amoxicillin specifically affects normal tooth dentin mineralization, but not enamel mineralization in rat incisor odontogenesis. The present results further our understanding of the clinical association between dentin abnormality and amoxicillin exposure during tooth development.

Hepatocellular carcinoma diagnosis using a novel electrochemiluminescence immunoassay targeting serum IgM-free AIM.

BACKGROUND: Recent increases in the number of patients with non-alcoholic steatohepatitis (NASH) warrant the identification of biomarkers for early detection of hepatocellular carcinoma (HCC) associated with NASH (NASH-HCC). IgM-free apoptosis inhibitor of macrophage (AIM), which generally associates with IgM in blood and exerts its biological function by dissociation from IgM, may serve as an effective biomarker for NASH-HCC. Here, we established a fully automatic and high-throughput electrochemiluminescence immunoassay (ECLIA) to measure IgM-free AIM and investigated its efficacy in diagnosing NASH-HCC and viral HCC. METHODS: IgM-free AIM levels were measured in 212 serum samples from patients with, or without, HCC related to NASH, hepatitis B virus, and hepatitis C virus, using ECLIA. We also developed an ECLIA for measuring both IgM-free and IgM-bound AIM and investigated the existing form of AIM in blood by size-exclusion chromatography. RESULTS: IgM-free AIM levels were significantly higher in the HCC group than in the non-HCC group, regardless of the associated pathogenesis. Moreover, the area under the receiver operating curve for IgM-free AIM was greater than that for conventional HCC biomarkers, alpha-fetoprotein or des-γ-carboxy prothrombin, regardless of the cancer stage. ECLIA counts of IgM-free AIM derived from samples fractionated by size-exclusion chromatography were significantly higher in patients with NASH-HCC than in healthy volunteers and in patients with non-alcoholic fatty liver and NASH. CONCLUSIONS: Serum IgM-free AIM may represent a universal HCC diagnostic marker superior to alpha-fetoprotein or des-γ-carboxy prothrombin. Our newly established ECLIA could contribute to further clinical studies on AIM and in vitro HCC diagnosis.

The Association of Dietary Intake, Oral Health, and Blood Pressure in Older Adults: A Cross-Sectional Observational Study.

Hypertension is related to impaired mastication that causes malnutrition, declining the general health of older adults. This study assessed the role of dietary intake in the relationship between oral health and blood pressure. Eight hundred ninety-four adults aged ≥65 years who independently lived in rural regions of Japan participated in this study. Hypertension was classified according to the guidelines of the Japanese Society of Hypertension. The oral condition was evaluated by analyzing the remaining teeth, occlusal force, posterior occlusal support, masticatory performance, oral moisture, and oral bacterial level. Dietary intake was assessed using a brief self-administered dietary history questionnaire. Mann-Whitney U, chi-square, Kruskal-Wallis tests, and logistic regression analyses were used to elucidate the factors related to hypertension. Normotensive, hypertensive, and history of hypertension were observed in 30.9%, 23.8%, and 45.3% of the participants, respectively. The factors significantly associated with the hypertension were age, body mass index, posterior occlusal support condition, and sodium-to-potassium ratio related to salt intake and/or vegetable intake. Participants without posterior occlusion significantly had higher risk of hypertension (odds ratio = 1.72). This study suggested that there was an association between oral health and hypertension, while the loss of occlusal support may influence nutritional intake conditions.

Predictability of Severe Adverse Events in Phase 3 Trials from Safety Information on Phase 1 Trials in Oncology Drug Development.

PURPOSE: Safety information obtained in phase 1 trials is becoming increasingly important with the recent changes in the development strategy of oncology drugs, including the skipping of phase 2 or 3 trials before regulatory approval. This study aimed to investigate the predictive factors for severe adverse events (AEs) in phase 3 trials based on phase 1 trial data. METHODS: The data on phase 1 and phase 3 trials applied for their marketing approval of the newly approved anticancer drugs in Japan were used for analysis. Regression analyses were performed to investigate factors related to the predictability of the occurrence of severe AEs in phase 3 trials based on phase 1 trial data. RESULTS: Thirty-two drugs (80 phase 1 trials and 40 phase 3 trials) were selected for the analyses. As a result of multivariate regression analyses, immune therapy agents (P = 0.009) and a pair of monotherapy in the phase 1 trials and combination therapy in the phase 3 trials (P = 0.017) were associated with low predictability of severe AEs in the phase 3 trials; signal inhibitor agents (P = 0.002) and large number of subjects in phase 1 trials (P = 0.008) were associated with high predictability. A significant relationship between the actual number of subjects in phase 1 trials and the predictability of severe AEs was observed when trials for immune checkpoint inhibitors were excluded (P < 0.001). CONCLUSION: These results should be effectively utilized for the strategic design of early-stage oncology drug development.

Perilipin overexpression in mice protects against diet-induced obesity.

Perilipin A is the most abundant phosphoprotein on adipocyte lipid droplets and is essential for lipid storage and lipolysis. Perilipin null mice exhibit diminished adipose tissue, elevated basal lipolysis, reduced catecholamine-stimulated lipolysis, and increased insulin resistance. To understand the physiological consequences of increased perilipin expression in vivo, we generated transgenic mice that overexpressed either human or mouse perilipin using the adipocyte-specific aP2 promoter/enhancer. Phenotypes of female transgenic and wild-type mice were characterized on chow and high-fat diets (HFDs). When challenged with an HFD, transgenic mice exhibited lower body weight, fat mass, and adipocyte size than wild-type mice. Expression of oxidative genes was increased and lipogenic genes decreased in brown adipose tissue of transgenic mice. Basal and catecholamine-stimulated lipolysis was decreased and glucose tolerance significantly improved in transgenic mice fed a HFD. Perilipin overexpression in adipose tissue protects against HFD-induced adipocyte hypertrophy, obesity, and glucose intolerance. Alterations in brown adipose tissue metabolism may mediate the effects of perilipin overexpression on body fat, although the mechanisms by which perilipin overexpression alters brown adipose tissue metabolism remain to be determined. Our findings demonstrate a novel role for perilipin expression in adipose tissue metabolism and regulation of obesity and its metabolic complications.

Factors associated with access to HIV testing among international students in Japanese language schools in Tokyo.

Japan has been recognized for its excellent universal health coverage system. However, the migrant population faces many barriers in accessing health services in Japan. Japan hosts around 260,000 international students, mostly from developing countries. Among them, language school students tripled from 2011 to 2017, against the backdrop of labor shortage in Japan. Most of these students are also engaged as cheap laborers and are vulnerable populations with poor access to health services. Several socio-economic and behavioral factors may increase their vulnerability to HIV and prevent them from accessing HIV testing in Japan. We examined the factors associated with access to HIV testing among international students in language schools in Tokyo. We conducted a cross-sectional study among international students studying in Japanese language schools in Tokyo. We collected data from 769 Chinese, Vietnamese, and Nepalese students using a self-administered questionnaire. We measured their access to HIV testing through questions on their knowledge of where to receive HIV testing and utilization of HIV testing. Bivariate and multivariable logistic regression models were used to analyze the data. Nepalese students were less likely to know where to receive HIV testing in Japan than Chinese students (AOR = 0.12, 95% CI 0.01-0.96). Students who did not need Japanese language interpreters during visits to health facilities were more likely to know where to receive HIV testing (AOR = 1.93, 95% CI 1.14-3.25). Students who did not have knowledge of free and anonymous HIV testing in Japan were also less likely to know where to receive HIV testing in Japan (AOR = 0.18, 95% CI 0.08-0.42). Students who did not have knowledge of free and anonymous HIV testing (OR = 0.05, 95% CI 0.02-0.10) and who had not utilized HIV testing in their home country (OR = 0.12, 95% CI 0.06-0.27) were less likely to utilize HIV testing in Japan. Factors associated with access to HIV testing among Japanese language school students in Tokyo are nationality, need for Japanese language interpreters, perceived access to doctors/health workers, utilization of HIV testing in the home country, and knowledge of free and anonymous HIV testing. These findings may help to design interventions for improving access to HIV testing among international students in Japan.

Development of Prodrug Type Circular siRNA for In Vivo Knockdown by Systemic Administration.

siRNAs are being developed as a novel therapeutic modality; however, problems impeding their application in extrahepatic tissues persist, including inadequate stability in biological environments and inefficient drug delivery system to target tissues. Thus, technological improvements that enable robust silencing of target messenger RNA (mRNA) in extrahepatic tissues are necessary. We developed prodrug type covalently closed siRNA (circular siRNA) as a novel nucleic acid agent to knockdown target genes in extrahepatic tissues by systemic administration without drug delivery components. Circular siRNA, which is chemically synthesizable, can assume optimal structures for efficient knockdown using its cleavable linker; namely, circular and linear structure in extracellular and intracellular environment, respectively. In this study, we investigated circular siRNA physicochemical properties, knockdown mechanism, and characteristics in vitro, as well as pharmacokinetics, accumulation, knockdown activity, and safety in vivo. Our circular siRNA exhibited higher stability against serum and exonucleases, increased cellular uptake, and stronger knockdown activity without transfection reagent in vitro than linear siRNA. Furthermore, after systemic administration to mice, circular siRNA showed prolonged circulation and improved knockdown activity in the liver, kidney, and muscle, without causing adverse effects. Circular siRNA may represent an additional platform for RNAi therapeutics, providing alternate solutions for disease treatment.

Clinical relevance of increased serum preneoplastic antigen in hepatitis C-related hepatocellular carcinoma.

BACKGROUND: The prognosis of hepatocellular carcinoma (HCC) patients remains poor despite advances in treatment modalities and diagnosis. It is important to identify useful markers for the early detection of HCC in patients. Preneoplastic antigen (PNA), originally reported in a rat carcinogenesis model, is increased in the tissues and serum of HCC patients. AIM: To determine the diagnostic value of PNA for discriminating HCC and to characterize PNA-positive HCC. METHODS: Patients with hepatitis C virus (HCV)-related hepatic disorders were prospectively enrolled in this study, which included patients with hepatitis, with cirrhosis, and with HCC. A novel enzyme-linked immunosorbent assay was developed to measure serum PNA concentrations in patients. RESULTS: Serum PNA concentrations were measured in 89 controls and 141 patients with HCV infections (50 hepatitis, 44 cirrhosis, and 47 HCC). Compared with control and non-HCC patients, PNA was increased in HCC. On receiver operating characteristic curve analysis, the sensitivity of PNA was similar to the HCC markers des-γ-carboxy-prothrombin (DCP) and α-fetoprotein (AFP), but the specificity of PNA was lower. There was no correlation between PNA and AFP and a significant but weak correlation between PNA and DCP in HCC patients. Importantly, the correlations with biochemical markers were completely different for PNA, AFP, and DCP; glutamyl transpeptidase was highly correlated with PNA, but not with AFP or DCP, and was significantly higher in PNA-high patients than in PNA-low patients with HCV-related HCC. CONCLUSION: PNA may have the potential to diagnose a novel type of HCC in which glutamyl transpeptidase is positively expressed but AFP or DCP is weakly or negatively expressed.

Does Oral Hypofunction Promote Social Withdrawal in the Older Adults? A Longitudinal Survey of Elderly Subjects in Rural Japan.

It is often assumed that oral hypofunction is associated with social withdrawal in older adults because decreased motor function is related to decreased oral function. However, few studies have examined the relationship between social withdrawal in older adults and oral function. This longitudinal study aimed to clarify the relationship between changes in the level of social withdrawal and oral function in independent older adults. Participants were 427 older adults aged 65 years or older who took part in a self-administered questionnaire from 2016 to 2017 (baseline), and again two years later (follow-up). At baseline, 17 items related to oral function and confounding factors related to withdrawal, physical condition, physical function, and cognitive function were evaluated. A Cox proportional hazard model was used to examine the oral functions that negatively impact social withdrawal. The following factors were significantly associated with the worsening of social withdrawal: the number of remaining teeth, gingival condition, occlusal force, masticatory efficiency, and items related to swallowing and dry mouth. Older adults with cognitive issues who walk slowly and have a weak knee extension muscle were also significantly more likely to have oral frailty. Those who were found to have oral frailty at baseline were 1.8 times more likely to develop withdrawal compared to those with robust oral function. The results indicated that the worsening of withdrawal was associated with oral hypofunction at baseline. Since oral hypofunction was associated with the worsening of social withdrawal in older adults, it is important to maintain older adults' oral function.

Ultrastructural study of tissues surrounding replanted teeth and dental implants.

OBJECTIVES: The aim of this study was to describe the ultrastructure of the dentogingival border at replanted teeth and implants. MATERIAL AND METHODS: Wistar rats (8 weeks old) were divided into groups for replantation and implantation experiments. In the former, the upper right first molars were extracted and then immediately replanted. In the latter, pure titanium implants were used. All tissues were fixed, demineralized and embedded in epoxy resin for ultrastructural observations. RESULTS: One week after replantation, the junctional epithelium was lost, and the oral sulcular epithelium covered the enamel surface. The amount of the epithelium increased in 2 weeks, and resembled the junctional epithelium, and the internal basal lamina and hemidesmosomes were formed in 4 weeks. One week after implantation, peri-implant epithelium was formed, and in 2 and 4 weeks, this epithelium with aggregated connective tissue cells were observed. In 8 weeks, the peri-implant epithelium receded, and aligned special cells with surrounding elongated fibroblasts and bundles of collagen fibers appeared to seal the implant interface. CONCLUSION: In replantation of the tooth, the internal basal lamina remained at the surface of the enamel of the replanted tooth, which is likely to be related to regeneration of the junctional epithelium and the attachment apparatus at the epithelium-tooth interface. Following implantation, a layer of cells with characteristics of connective tissue cells, but no junctional epithelium and attachment apparatus, was formed to seal the site of the implant.