BACKGROUND:In February 2013, Japanese national health insurance coverage for Helicobacter pylori eradication was expanded to patients with H. pylori-positive, endoscopically diagnosed chronic gastritis. This policy broadened access to eradication treatment, but its relationship with subsequent population-level gastric cancer trends requires cautious interpretation. AIM:To describe national trends in gastric cancer mortality and incidence before and after the 2013 insurance expansion, with attention to age-specific patterns, endoscopic screening, treatment uptake, and alternative explanations. METHODS:We examined publicly available national mortality data from the Ministry of Health, Labour and Welfare and cancer incidence data from the National Cancer Center. Calendar-year trends in annual gastric cancer deaths, incident cases, and age-specific deaths were evaluated descriptively. The 2013 policy change was treated as a major contextual event rather than as a causal intervention with an internally estimated counterfactual. RESULTS:Annual gastric cancer deaths declined from 48,427 in 2013 to 37,394 in 2024, a 25.2% reduction in crude annual deaths. Incidence also decreased after a later peak, with available national incidence data showing fewer new cases by 2021. Age-specific analyses showed pronounced decreases in deaths among people younger than 80 years, whereas deaths among those aged 80 years or older continued to increase. CONCLUSION:After the 2013 expansion of insurance coverage for H. pylori eradication, gastric cancer mortality and incidence in Japan declined at the population level. These ecological trends are compatible with a contribution from increased eradication therapy and endoscopy-linked detection, but causality cannot be established from aggregate data alone. Age-standardized, claims-linked, stage-specific, and treatment-linked analyses are needed to quantify the independent policy effect.

Background: Japan became the world's first country to cover Helicobacter pylori eradication for chronic gastritis under its National Health Insurance (NHI) system in February 2013. Thereafter, H. pylori eradication dramatically increased and gastric cancer deaths began to decrease in Japan. However, the details of gastric cancer deaths and its prevention in the very elderly have not been fully elucidated. Methods: We analyzed the temporal trend of gastric cancer deaths referencing data from Ministry of Health, Labour and Welfare reports and "Cancer Statistics in Japan-2021" and assessed the numbers of H. pylori test and gastric cancer screening using a national database and a report of cancer screening in Shimane Prefecture, respectively. Results: Although gastric cancer deaths in total population have clearly decreased since 2013, those in people aged 80 years and older are still increasing. People aged 80 years and older represent 9% of the total population and accounted for half of all gastric cancer deaths in 2020. The numbers of H. pylori eradication and gastric cancer screening in people aged 80 years and older were 25% and 25% of those in other generations, respectively. Conclusion: In spite of a dramatic increase in H. pylori eradication and a clear decrease in gastric cancer deaths in Japan, gastric cancer deaths in people aged 80 years and older are increasing. This might be due to fewer H. pylori eradication in the elderly than in other generations, indicating the difficulty of gastric cancer prevention in the very elderly.

Isolation of colon CICs as SP cells and the expression of OR7C1

OR7C1 gene overexpression experiments

Establishment of CIC-targeting immunotherapy using antigenic peptide derived from OR7C1.

Summary of the OR7C1 peptides carrying HLA-A24 binding motief.

Supplementary Figures S1-S6 from A Novel FRET-Based Biosensor for the Measurement of BCR-ABL Activity and Its Response to Drugs in Living Cells

Supplemental Materials and Methods and figure legends

A virulence bacterium, Helicobacter pylori, evolved parallel to its host human, therefore, can work as a marker for tracing the human migration. We found H. pylori strains indigenous in the southernmost islands of Japanese Archipelago, Okinawa, and defined them as hspOkinawa and hpRyukyu. Genome data of the strains revealed that hspOkinawa diverged from other East Asian strains about 20,000 years ago, and that hpRyukyu diverged about 45,000 years ago. The closest strains of hpRyukyu were found from Afghanistan, Punjab, and Nepal, which suggest this strain originated in the central Asia and traveled across the Eurasian continent during Paleolithic era. The divergence date of hpRyukyu corresponds with human fossil records in Okinawa. Although it is controversial from human DNA analyses whether descendants of the Paleolithic migrants remain in the modern Japanese population, this study reveals that the bacterium of Paleolithic origin remains in the stomachs of current Japanese.

Starting on 12 April 2021, Japan began administering coronavirus disease 2019 vaccines to senior citizens aged ≥65 years. As of September 2021, >80% of them already completed two doses of vaccination. As a result, the new cases of infections among older adults have decreased and the incident of clusters in long-term care facilities (LTCFs) have dramatically reduced. Coronavirus disease 2019 vaccine booster shots are considered in Japan at this point due to the waning immunity. To determine who should receive the booster shot, it is necessary to investigate the antibody response by the different age group and situation. We compared the serological response induced by two doses of the mRNA vaccine, BNT162b2, between LTCF residents and healthcare workers (HCWs). Written informed consent was obtained from all participants. If residents lacked the capacity to consent, the responsible guardian's permission was obtained. This study was approved by Health Sciences University of Hokkaido Research Ethics Boards (20N037045). A total of 75 residents of a LTCF and 69 HCWs of the LTCF and the affiliated hospital were included in the present study. Those previously infected with SARS-Cov-2 were excluded from this study. Almost all residents had more than two comorbidities and required assistance for activities of daily living. Four groups were compared: group 1: HCWs aged ≤64 years; group 2: HCWs aged between 65 and 84 years; group 3: LTCF residents aged between 65 and 84 years; and group 4: LTCF residents aged ≥85 years. Blood samples were collected at 28–45 days after the second injection using the BNT162b2 mRNA vaccine. The quantitative enzyme-linked immunosorbent assay test to measure an anti-SARS-Cov-2 immunoglobulin G antibody to S1 protein was carried out by using the Vitros Immunodiagnostic Product anti-SARS-Cov-2 S1 Quant immunoglobulin G test (Ortho Clinical Diagnostics, Raritan, NJ, USA) according to the manufacturer's instructions. Results were expressed as binding activity units per mL (BAU/mL; positive threshold: 17.8 BAU/mL; upper limit: 4000 BAU/mL). For comparative analysis of antibody levels between four groups, the Kruskal–Wallis test followed by the Mann–Whitney U-test, using the Bonferroni correction with adjustment of the probability (P < 0.05 / 4 = 0.0125) was carried out. After vaccination, all residents tested positive for antibodies, except two residents. However, the median antibody titers were eightfold and fivefold lower in group 3 (median antibody titer 127 BAU/mL) and group 4 (median antibody titer: 200 BAU/mL), respectively, compared with those of group 1 (median antibody titer 1095 BAU/mL; P = 7.25465E-08 and 1.11602E-14, respectively; Fig. 1). Compared with the median antibody titers of group 1, those of group 2 tended to be lower, but the difference was not significant (P = 0.26341; Fig. 1). However, the median antibody titers of group 2 were higher than those of group 3 (P = 0.000415; Fig. 1). The present study found that serological response to two doses of the mRNA vaccine, BNT162b2, in LTCF residents was significantly lower than those in HCWs aged between 65 and 84 years, as well as in HCWs aged <64 years. This finding is in accordance with previous studies that compared the response to the vaccination in LTCFs and HCWs.1, 2 In addition, the present study showed that the serological response of older HCWs did not show any significant difference compared with that of younger HCWs, in accordance with previous studies that examined the response to the vaccination among older adults.3, 4 These results suggest that LTCF residents are thought to be immunocompromised by a variety of factors in addition to aging, such as comorbidity, malnutrition and inactivity,5 and that LTCF residents should be included in the target population for the third booster vaccine. Limitations include the small sample size, possible selection bias, failure to identify factors other than aging and failure to investigate cellular immunity. This work was supported, in part, by the Grant from Advanced Research Promotion Center, Health Sciences University of Hokkaido. We thank Ortho Clinical Diagnostics to lent us Vitros XT7600 integrated system. We thank Yoko Tsukamoto, PhD, School of Nursing & Social Services, Health Sciences University of Hokkaido, for support in drafting of the manuscript. LCDR Thompson did not receive any compensation. The authors declare no conflict of interest.

Background Several reports suggest that the microbiome of the digestive system affects vaccine efficacy and that the severity of coronavirus disease (COVID-19) is associated with decreased diversity of the oral and/or intestinal microbiome. The present study examined the effects of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine on the oral microbiome. Methods Forty healthy Japanese oral healthcare personnel were recruited, and unstimulated saliva was collected before vaccination, after the 1st vaccination, and after the 2nd vaccination. Genomic DNA was extracted from saliva samples, and PCR amplicons of the 16S rRNA gene were analyzed using next-generation sequencing. Microbial diversity and composition were analyzed using Quantitative Insights into Microbial Ecology 2. In addition, alterations in microbial function were assessed using PICRUSt2. Results SARS-CoV-2 mRNA vaccination significantly increased oral bacterial diversity and significantly decreased the proportion of the genus Bacteroides . Conclusions The SARS-CoV-2 mRNA vaccine alters the oral microbiome; accordingly, vaccination might have beneficial effects on oral health.

Background Most peptic ulcer cases are associated with Helicobacter pylori (H. pylori) infection or the use of nonsteroidal anti-inflammatory drugs (NSAIDs). H. pylori eradication therapy is recommended for the treatment of H. pylori-positive peptic ulcers. We aimed to assess and validate the cumulative economic and health effects of H. pylori eradication strategy for the treatment of peptic ulcers compared with PPI therapy strategy. Materials and Methods We developed a cohort state-transition model for H. pylori eradication strategy and PPI therapy strategy over a lifetime horizon from a healthcare payer perspective. We targeted two hypothetical cohorts of H. pylori-positive patients with gastric and duodenal ulcers aged 20, 30, 40, 50, 60, 70, and 80. The main outcomes were costs, quality-adjusted life-years (QALYs), life expectancy life-years (LYs), incremental cost-effectiveness ratios, ulcer recurrence cases, and ulcer-associated deaths. One-way and probabilistic sensitivity analyses were conducted to assess the impact of uncertainty. Results In the base-case analysis, H. pylori eradication strategy was less costly with greater benefits than PPI therapy strategy in all age groups. Cost-effectiveness was not sensitive to any variables in all age groups. Sensitivity analyses showed strong robustness of the results. From 2000 to 2020, H. pylori eradication strategy saved US$14.07 billion over a lifetime, increased 8.65 million QALYs and 1.23 million LYs over a lifetime, and prevented 551,298 ulcer recurrence cases and 59,465 ulcer-associated deaths, compared with PPI therapy strategy. Conclusions H. pylori eradication strategy not only has contributed significantly to preventing ulcer recurrence and reducing ulcer-associated deaths but also has resulted in great cost savings. All over the world, H. pylori eradication strategy is likely to have yielded a comparable magnitude of economic and health benefits, depending on the epidemiology of H. pylori-related peptic ulcers and the healthcare environment in each country.

BACKGROUND:Helicobacter pylori (H. pylori) eradication reduces gastric cancer risk. Since 2013, a population-wide H. pylori eradication strategy for patients with chronic gastritis has begun to prevent gastric cancer in Japan. The aim of this study was to evaluate the economic and health effects of H. pylori eradication strategy in national gastric cancer prevention program.MATERIALS AND METHODS:We developed a cohort state-transition model for H. pylori eradication and no eradication over a lifetime horizon from a healthcare payer perspective, and performed one-way and probabilistic sensitivity analyses. We targeted a hypothetical cohort of H. pylori-positive patients aged 20, 30, 40, 50, 60, 70, and 80. The main outcomes were costs, quality-adjusted life-years (QALYs), life expectancy life-years (LYs), incremental cost-effectiveness ratios, gastric cancer cases, and deaths from gastric cancer.RESULTS:H. pylori eradication was more effective and cost-saving for all age groups than no eradication. Sensitivity analyses showed strong robustness of the results. From 2013-2019 for 8.50 million patients, H. pylori eradication saved US$3.75 billion, increased 11.11 million QALYs and 0.45 million LYs, and prevented 284,188 cases and 65,060 deaths. For 35.59 million patients without eradication, H. pylori eradication has the potential to save US$14.82 billion, increase 43.10 million QALYs and 1.66 million LYs, and prevent 1,084,532 cases and 250,256 deaths.CONCLUSIONS:National policy using population-wide H. pylori eradication to prevent gastric cancer has significant cost savings and health impacts for young-, middle-, and old-aged individuals in Japan. The findings strongly support the promotion of H. pylori eradication strategy for all age groups in high-incidence countries.

Background: Helicobacter pylori (H. pylori) infection causes chronic atrophic gastritis, a common stage of progression to gastric cancer. In February 2013, the Ministry of Health, Labour, and Welfare approved H. pylori eradication in patients with chronic gastritis under the Japanese National Health Insurance System in Japan. The economic and health effects of H. pylori eradication on national health policy have not been established. We aimed to assess the cost-effectiveness of H. pylori eradication compared to no eradication, and estimate health outcomes of adopting the Japanese National Health Insurance System from 2013.Methods: We developed decision trees with Markov models for two strategies, H. pylori eradication and no eradication from a healthcare payer perspective over a lifetime horizon, and performed Markov cohort analyses. We based national census by age and Japanese cancer statistics. Main outcomes were costs, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios, gastric cancer cases and deaths. Findings: H. pylori eradication was more cost-effective than no eradication at a US$50,000 willingness-to-pay threshold. One-way and probabilistic sensitivity analyses showed robustness of excellent cost-effectiveness results. From 2013-2017, H. pylori eradication resulted in health gains of 8.1 million QALYs and healthcare cost-savings of US$24.7 billion over a lifetime. H. pylori eradication was also predicted to reduce 52,831 gastric cancer cases and save 16,885 lives from 2013-2017. For estimated 38.8 million H. pylori-infected cases in 2020, H. pylori eradication would be expected to increase 44 million potential QALYs, reduce $US125 billion healthcare costs, prevent 1.2 million gastric cancer cases, and save 382,342 lives over a lifetime. Interpretation: In conclusion, H. pylori eradication generates significant health gains and healthcare cost-savings, and reduces gastric cancer incidence and deaths. These findings strongly support a widespread expansion of H. pylori eradication in H. pylori-infected individuals of all ages to prevent gastric cancer. Funding: No funding.Declaration of Interests: The author has no conflicts of interest to declare.Ethics Approval Statement: As this was a modeling study with all inputs and parameters derived from the published literature and Japanese statistics, ethics approval was not required.

Background/Aim: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been affecting Hokkaido, Japan since late February 2020 until present. The aim of this study was to report the relationship between anti-SARS-CoV-2 antibody-positive and SARS-CoV-2 PCR-positive cases by analyzing anti-SARS-CoV-2 antibodies (IgG and total-Ig). Patients and Methods: Serum samples were collected from care workers and nurses in two nursing homes and two hospitals which underwent virus outbreak. All people were confirmed to be SARS-CoV-2-positive by RT-qPCR and their sera was analyzed for anti-SARS-CoV-2 antibodies (IgG and total-Ig). Results: Although 34 out of 43 samples (79.1%) showed enough amount of anti-SARS-CoV-2 antibodies, 9 RT-qPCR -positive samples (20.9%) showed absence of anti-SARS-CoV-2 antibodies in their sera. Conclusion: The results that 20.9% of RT-qPCR-positive samples with SARS-CoV-2 showed absence of anti-SARS-CoV-2 antibodies provides a possibility that the innate immune reaction could eliminate the virus without activating adaptive immune reaction.

In 2020, the worldwide incidence and mortality of colorectal cancer (CRC) were third and second, respectively. As the 5-y survival rate is low when CRC is diagnosed at an advanced stage, a reliable method to predict CRC susceptibility is important for preventing the onset and development and improving the prognosis of CRC. Therefore, we focused on the normal colonic mucosa to investigate changes in gene expression that may induce subsequent genetic alterations that induce malignant transformation. Comprehensive gene expression profiling in the normal mucosa adjacent to colon cancer (CC) compared with tissue from non-colon cancer patients was performed. PCR arrays and qRT-PCR revealed that the expression of 5 genes involved in the immune response, including MYD88, was increased in the normal mucosa of CC patients. The expression levels of MYD88 were strikingly increased in precancerous normal mucosa specimens, which harbored no somatic mutations, as shown by immunohistochemistry. Microarray analysis identified 2 novel RNA-controlling molecules, EXOSC3 and CNOT4, that were significantly upregulated in the normal mucosa of CC patients and were clearly visualized in the nuclei. Forced expression of EXOSC3 and CNOT4 in human colonic epithelial cells increased the expression of IFNGR1, MYD88, NFκBIA, and STAT3 and activated ERK1/2 and JNK in 293T cells. Taken together, these results suggested that, in the inflamed mucosa, EXOSC3- and CNOT4-mediated RNA stabilization, including that of MYD88, may trigger the development of cancer and can serve as a potential predictive marker and innovative treatment to control cancer development.

In February 2013, Japan became the first country in the world to cover Helicobacter pylori eradication for chronic gastritis under its National Health Insurance (NHI) system. Now that eradication therapy is covered by NHI, its usage has increased dramatically, and gastric cancer deaths have begun to decrease. We undertook a detailed epidemiological analysis to investigate effects of expanded NHI coverage for H. pylori eradication therapy on gastric cancer deaths in specific age groups. Numbers of gastric cancer deaths were determined by referencing data from Ministry of Health, Labour and Welfare reports and "Cancer Statistics in Japan - 2018" published by the Foundation for Promotion of Cancer Research. Gastric cancer deaths across all age groups have been clearly decreasing since 2013, but deaths of people aged 80 years and older are still increasing. The number of gastric cancer deaths in people aged in their 80s was 2 times higher than in people aged in their 70s and 4 times higher than in people aged in their 60s. The number of people in their 80s who had an endoscopy was less than half that of people in their 60s and 70s. The eradication therapy has increased dramatically, and gastric cancer deaths are clearly decreasing in Japan. However, this decrease in deaths has not extended to elderly adults aged in their 80s, which suggests that measures to prevent gastric cancer in people aged 80 years and older will be critical to achieving the mission of eliminating gastric cancer in Japan.

Although epidemiological studies have shown a relationship between periodontal disease and pancreatic cancer, the molecular mechanisms involved remain unclear. In this study, the effects of systemic administration of Porphyromonas gingivalis lipopolysaccharide (PG-LPS) on gene expression were comprehensively explored in mouse pancreas that did not demonstrate any signs of inflammation. PG-LPS was prepared in physiological saline and intraperitoneally administered to male mice at a concentration of 5 mg/kg every 3 days for 1 month. After extracting total RNA from the excised mice pancreas, a comprehensive DNA microarray analysis of gene expression was performed. Tissue specimens were also subjected to hematoxylin–eosin staining and immunohistochemistry using anti-regenerating islet-derived 3A and G (Reg3A/G) antibody. ImageJ software was used to quantify the area of Reg3A/G positive cells in pancreatic islets by binarizing image date followed by area extraction. The results were compared using Mann–Whitney U test. Data are presented as mean ± standard deviation (SD) with p < 0.05 considered as significant. Reg3G, a gene related to pancreatic cancer, was one of the 10 genes with the highest levels of expression in the pancreas stimulated with PG-LPS. The comprehensive analysis revealed a 73-fold increase in Reg3G expression level in the PG-LPS group when compared with the control group; in addition, the expression level of Reg3A was increased by 11-fold in the PG-LPS group. Image analysis showed that the ratio of Reg3A/G positive cells was higher in the PG-LPS group than the control. Immunostaining showed the presence of Reg3A/G-positive cells in the alpha-cell equivalent areas around the islets of Langerhans in the PG-LPS group. These results support the notion that periodontal disease may be a risk factor for pancreatic cancer.

We investigated the positive detection rates for hepatitis B surface antigens (HBsAg) and hepatitis C (HCV) antibodies as well as the elevation of AST and ALT in patients who were to undergo oral surgery. Our results revealed positive rates of 1.1% and 1.5% for HBsAgs and HCV antibodies, respectively. Patients older than 40 years had a higher proportion of positive HBsAg or HCV antibody results than did patients younger than 40 years. The rate of AST and ALT elevation was 7.3%. There were some missing data on viral infection in patient referral documents or interview sheets, suggesting a perception gap existed with respect to the seriousness of viral hepatitis among dental doctors and patients. These findings suggest that designating a hepatitis medical care coordinator might help not only in understanding patients' infection status but also in collaborating with hepatologists in the field of oral surgery.

BACKGROUND:Helicobacter pylori (H. pylori) gastritis could cause dyspepsia, and eradication is recommended as the first-line treatment. Patients who continuously have their symptoms under control > 6 months after eradication are defined as having H. pylori-associated dyspepsia (HPD), whereas patients who do not benefit from successful eradication are defined as having functional dyspepsia.OBJECTIVES:We assessed changes in dyspeptic symptoms after successful eradication of H. pylori by using a questionnaire.METHODS:We studied H. pylori-infected dyspeptic participants with abdominal symptom scores > 4 points on the Global Overall Symptom (GOS) scoring items and received eradication therapy. We evaluated their symptoms using the GOS questionnaire before their eradications, at 1-month and at 1-year check-ups after eradication therapy.RESULTS:Thirty dyspeptic participants (mean age 59.6 ± 15.3 years) answered every questionnaire. Fourteen participants (46.7%) had HPD, whereas 16 participants (53.3%) were non-HPD patients. The questionnaire at 1 month showed sensitivity of 64.3% (9/14) and specificity of 56.3% (9/16) for HPD. Approximately 60% of H. pylori-infected dyspepsia participants were identified as having HPD or non-HPD within 1 month after their eradications.CONCLUSIONS:Approximately 60% of HPD participants improved at 1 month after eradication. The questionnaire at 1 month helped diagnose HPD in advance and guided next treatment choice.