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Abstract Aim Central liver resections are considered to be high‐risk procedures due to postoperative biliary complications. However, anatomical aspect‐related causes are underreported. Focusing upon right anterior sectionectomy (H58) and central bisectionectomy (H458), we assessed risk factors for postoperative biliary complications. Methods We retrospectively reviewed patients who underwent H58 or H458 in our hospital between April 2008 and June 2023 (n = 58). We conducted univariate and multivariate analysis of risk factors of postoperative biliary complications among perioperative factors and anatomical factors including the branching type of the right posterior hepatic duct (RPHD) and the length of the right hepatic duct (RHD). Results Twenty‐six patients (44.8%) had postoperative biliary complications. Potent risk factors in univariate analysis were the tumor proximity to the right anterior Glissonean branch and longer RHD (both P 10 mm; its hazard (95% CI) was 5.83 (0.95–35.7). Conclusion Anatomical factors of RPHD and RHD influenced postoperative biliary complications in this cohort. The supraportal with RHD type was most common anatomy but considered to be hazardous if the RHD was >10 mm.

Background: Genetic epidemiological evidence for the kidney function traits in East Asian populations, including Japanese, remain still relatively unclarified. Especially, the number of genome-wide association studies (GWASs) for kidney traits reported still remains limited, and the sample size of each independent study is relatively small. Given the genetic variability between ancestries/ethnicities, implementation of GWAS with sufficiently large sample sizes in specific population of Japanese is considered meaningful. Methods: We conducted the GWAS meta-analyses of kidney traits by leveraging the GWAS summary data of the representative large genome cohort studies with about 200,000 Japanese participants (n = 202,406 for estimated glomerular filtration rate [eGFR] and n = 200,845 for serum creatinine [SCr]). Results: In the present GWAS meta-analysis, we identified 110 loci with 169 variants significantly associated with eGFR (on chromosomes 1–13 and 15–22; P < 5 × 10−8), whereas we also identified 112 loci with 176 variants significantly associated with SCr (on chromosomes 1–22; P < 5 × 10−8), of which one locus (more than 1 Mb distant from known loci) with one variant (CD36 rs146148222 on chromosome 7) for SCr was considered as the truly novel finding. Conclusion: The present GWAS meta-analysis of the largest genome cohort studies in Japanese subjects provided some original genomic loci associated with kidney function, which may contribute to the possible development of personalized prevention of kidney diseases based on genomic information in the near future.

Abstract Background Biological age, especially epigenetic age derived from the epigenetic clock, is a significant measure of aging, considering the differences in aging rates among individuals. The epigenetic clock, a machine learning-based algorithm, uses DNA methylation states to estimate biological age. Previous studies have reported inconsistent associations between physical activity (PA) and the epigenetic clock, especially second-generation clocks such as PhenoAge and GrimAge. This study aimed to clarify this relationship using cross-sectional data from Japanese participants aged 40–69. Methods We used two datasets from the Saga J-MICC study, of which 867 samples were available for analysis. DNA methylation data from peripheral blood samples were used to calculate the epigenetic age using the epigenetic clocks PhenoAge and GrimAge. PA and sedentary time were measured using a single-axis accelerometer, while self-reported PA, sedentary time, and covariates were assessed using a self-administered questionnaire. The association between PA or sedentary time and epigenetic age acceleration was assessed using multiple linear regression. Results Pearson's correlation coefficients between accelerometer-based and self-reported PA variables ranged from 0.09 to 0.20. Multivariable regression analysis showed that accelerometer-based PA and sedentary time were associated with epigenetic age decelerations and accelerations, respectively. However, self-reported PA was not associated with the epigenetic age accelerations. Conclusions These results indicate that reducing sedentary time and increasing PA were associated with slowing both PhenoAge and GrimAge, even in East Asian populations with different exercise habits, body shapes, and lifestyles. This study highlights the potential of objective second-generation epigenetic age acceleration as an outcome index for healthcare interventions and clinical applications.

Abstract Background Pancreaticoduodenectomy is a highly difficult and invasive type of gastrointestinal surgery. Prevention of postoperative pancreatic fistula is important, and this may be possible by the stapler method. Methods STRAP-PD is a single center randomized controlled trial. We compare a method of transecting the pancreatic parenchyma in pancreaticoduodenectomy using a surgical stapler device with a conventional transecting method using energy devices (e.g., scalpel, ultrasonic coagulator and incision devices). Patients with soft pancreas who are scheduled to undergo pancreaticoduodenectomy are randomized to arm A (conventional method) or arm B (stapler method). We aim to examine the safety and usefulness of dissection by the automatic suture device, with attention to the rate of pancreatic fistula ISGPF grade B or C and to postoperative complications. This is a single-center randomized study, which began in September 2023 at Wakayama Medical University Hospital. Discussion Pancreatic parenchymal transection is typically performed either by direct incision using a scalpel or by employing energy devices such as ultrasonic coagulating cutting devices during pancreaticoduodenectomy. In a prospective pilot study, we conducted pancreatic parenchymal transection in 20 consecutive normal pancreatic cases during pancreaticoduodenectomy, observing postoperative pancreatic fistula grade B in one case (5%). Traditional methods involving scalpel incision or the use of ultrasonic coagulating cutting devices have been historically favored but perceived as technically challenging, and they have been reliant upon the surgeon's skill. Notably, relatively high incidences of postoperative pancreatic fistula among patients with soft pancreas have also been observed. Our proposed stapler method may therefore be a useful method responsible for reducing the development of pancreatic fistula. This method would be as part of minimally-invasive surgery for pancreaticoduodenectomy. It uses an endoscopic linear stapler to cut the pancreatic parenchyma, so it is likely to be more convenient than conventional methods and can be used universally. Trial registration University Hospital Medical Information Network Clinical Trials Registry, UMIN000052089. the Registration Date on 1st September 2023.

Background: Heated tobacco products (HTPs) have gained global popularity, but their health risks remain unclear. Therefore, the current study aimed to identify plasma metabolites associated with smoking and HTP use in a large Japanese population to improve health risk assessment. Methods: Metabolomics data from 9,922 baseline participants of the Tsuruoka Metabolomics Cohort Study (TMCS) were analyzed to determine the association between smoking habits and plasma metabolites. Moreover, alterations in smoking-related metabolites among HTP users were examined based on data obtained from 3,334 participants involved from April 2018 to June 2019 in a follow-up survey. Results: Our study revealed that cigarette smokers had metabolomics profiles distinct from never smokers, with 22 polar metabolites identified as candidate biomarkers for smoking. These biomarker profiles of HTP users were closer to those of cigarette smokers than those of never smokers. The concentration of glutamate was higher in cigarette smokers, and biomarkers involved in glutamate metabolism were also associated with cigarette smoking and HTP use. Network pathway analysis showed that smoking was associated with the glutamate pathway, which could lead to endothelial dysfunction and atherosclerosis of the vessels. Conclusion: Our study showed that the glutamate pathway is affected by habitual smoking. These changes in the glutamate pathway may partly explain the mechanism by which cigarette smoking causes cardiovascular disease. HTP use was also associated with glutamate metabolism, indicating that HTP use may contribute to the development of cardiovascular disease through mechanisms similar to those in cigarette use.

Abstract Background Central pain, characterized by neuropathic pain, can manifest due to injury to the superior spinothalamic tract. The brainstem includes sensory and motor pathways as well as nuclei of the cranial nerves, and therefore cancer metastasis in the region requires early intervention. Although stereotactic radiosurgery (SRS) is commonly employed for the treatment of brain metastasis, it poses risks of late complications like radiation necrosis (RN). RN exacerbates the progression of brain lesions within the irradiated area, and in the brainstem, it can damage multiple nerves, including the superior spinothalamic tract. Central neuropathic pain is often intractable and empirically managed with a combination of conventional drugs, such as serotonin-norepinephrine reuptake inhibitors (SNRIs) and anticonvulsants. However, their efficacy is often limited, leading to a decline in performance status (PS) and quality of life (QOL). Case presentation We present the case of a 53-year-old man diagnosed with stage IV lung cancer, referred to our palliative care team for managing severe central pain resulting from SRS-related RN in the pons. Despite administration of opioids, including oxycodone and hydromorphone, and adjuvant analgesics, the patient continued to require frequent use of immediate-release opioids. The addition of methadone alone proved successful in achieving optimal pain control. Conclusions Provided that RN in the brainstem can lead to intractable neuropathic pain, it is advisable to avoid SRS for brainstem metastasis when possible. Add-on methadone should be considered as a viable pain management medication for patients experiencing unresolved central pain.

The Tsuruoka Metabolomics Cohort Study (TMCS) is an ongoing population-based cohort study being conducted in the rural area of Yamagata Prefecture, Japan. This study aimed to enhance the precision prevention of multi-factorial, complex diseases, including non-communicable and aging-associated diseases, by improving risk stratification and prediction measures. At baseline, 11,002 participants aged 35–74 years were recruited in Tsuruoka City, Yamagata Prefecture, Japan, between 2012 and 2015, with an ongoing follow-up survey. Participants underwent various measurements, examinations, tests, and questionnaires on their health, lifestyle, and social factors. This study uses an integrative approach with deep molecular profiling to identify potential biomarkers linked to phenotypes that underpin disease pathophysiology and provide better mechanistic insights into social health determinants. The TMCS incorporates multi-omics data, including genetic and metabolomic analyses of 10,933 participants, and comprehensive data collection ranging from physical, psychological, behavioral, and social to biological data. The metabolome is used as a phenotypic probe because it is sensitive to changes in physiological and external conditions. The TMCS focuses on collecting outcomes for cardiovascular disease, cancer incidence and mortality, disability and functional decline due to aging and disease sequelae, and the variation in health status within the body represented by omics analysis that lies between exposure and disease. It contains several sub-studies on aging, heated tobacco products, and women’s health. This study is notable for its robust design, high participation rate (89%), and long-term repeated surveys. Moreover, it contributes to precision prevention in Japan and East Asia as a well-established multi-omics platform.

The increased demand for efficient computation in data analysis encourages researchers in biomedical science to use workflow systems. Workflow systems, or so-called workflow languages, are used for the description and execution of a set of data analysis steps. Workflow systems increase the productivity of researchers, specifically in fields that use high-throughput DNA sequencing applications, where scalable computation is required. As systems have improved the portability of data analysis workflows, research communities are able to share workflows to reduce the cost of building ordinary analysis procedures. However, having multiple workflow systems in a research field has resulted in the distribution of efforts across different workflow system communities. As each workflow system has its unique characteristics, it is not feasible to learn every single system in order to use publicly shared workflows. Thus, we developed Sapporo, an application to provide a unified layer of workflow execution upon the differences of various workflow systems. Sapporo has two components: an application programming interface (API) that receives the request of a workflow run and a browser-based client for the API. The API follows the Workflow Execution Service API standard proposed by the Global Alliance for Genomics and Health. The current implementation supports the execution of workflows in four languages: Common Workflow Language, Workflow Description Language, Snakemake, and Nextflow. With its extensible and scalable design, Sapporo can support the research community in utilizing valuable resources for data analysis.

Abstract It is important to assess the prognosis and intervene before and after surgery in patients with hepatocellular carcinoma. This study aims to elucidate the association of outcomes and residual liver function after hepatectomy. A total of 176 patients who underwent the initial resection for hepatocellular carcinoma between January 2011 and March 2021 at Jichi Medical University were included. Hepatic clearance of the remnant liver was measured using 99mTc-galactosyl serum albumin scintigraphy. The log-rank test was used to analyze survival using the Kaplan–Meier method. Hazard ratios (HR) and 95% confidence intervals (CI) for overall survival were calculated using Cox’s proportional hazard model. In multivariate analysis, microvascular invasion, intraoperative blood loss, and hepatic clearance of the remnant liver were independently associated with overall survival. Hepatic clearance of the remnant liver was independently associated with recurrence free survival. This is the first report to show that lower residual liver function is associated with shorter survival in patients with hepatocellular carcinoma undergoing hepatectomy. Preoperative determination of remnant liver function may allow assessment of prognosis in patients planned to undergo resection of hepatocellular carcinoma. Preservation of liver functional reserve may be crucial for improved long-term outcomes after hepatectomy.

Background: Flow-mediated dilation (FMD) measures vascular endothelial function by evaluating the vasodilatory response of blood vessels to increased blood flow. Nevertheless, the association between FMD and stroke incidence in a general population remains unclear. This study investigated the association between vascular endothelial function and stroke incidence in the general Japanese population. Methods: Based on cohort data from the Tohoku Medical Megabank Community-based Cohort Study, participants aged ≥18 years were recruited from Iwate Prefecture, with the final sample comprising 2952 subjects. Results: The FMD level was 0.5%–27.1%, with a median of 5.0% (interquartile, 4.2%–11.3%). The mean follow-up period was 5.5 ± 1.8 years (range, 0.6–6.9 years). After dividing the participants into two subgroups according to the median FMD value, a multivariate Cox regression analysis adjusting for gender, age, smoking, alcohol consumption, systolic blood pressure, low-density lipoprotein cholesterol, estimated glomerular filtration rate, N-terminal pro-brain natriuretic peptide, high-sensitivity cardiac troponin T and hemoglobin A1c revealed that a lower FMD value was strongly associated with incidences of total stroke (hazard ratio[HR] = 2.13, 95% confidence interval[CI] = 1.48–3.07, p

Abstract Observational studies suggest that abnormal glucose metabolism and insulin resistance contribute to colorectal cancer; however, the causal association remains unknown, particularly in Asian populations. A two-sample Mendelian randomisation analysis was performed to determine the causal association between genetic variants associated with elevated fasting glucose, haemoglobin A1c (HbA1c), and fasting C-peptide and colorectal cancer risk. In the single nucleotide polymorphism (SNP)-exposure analysis, we meta-analysed study-level genome-wide associations of fasting glucose (~ 17,289 individuals), HbA1c (~ 52,802 individuals), and fasting C-peptide (1,666 individuals) levels from the Japanese Consortium of Genetic Epidemiology studies. The odds ratios of colorectal cancer were 1.01 (95% confidence interval [CI], 0.99–1.04, P = 0.34) for fasting glucose (per 1 mg/dL increment), 1.02 (95% CI, 0.60–1.73, P = 0.95) for HbA1c (per 1% increment), and 1.47 (95% CI, 0.97–2.24, P = 0.06) for fasting C-peptide (per 1 log increment). Sensitivity analyses, including Mendelian randomisation-Egger and weighted-median approaches, revealed no significant association between glycaemic characteristics and colorectal cancer (P > 0.20). In this study, genetically predicted glycaemic characteristics were not significantly related to colorectal cancer risk. The potential association between insulin resistance and colorectal cancer should be validated in further studies.

Objectives: We describe our method and results of mitral valve repair up to 20 years in a defined group of patients with mitral regurgitation caused by an extreme billowing and prolapsing valve. Methods: An extreme billowing and prolapsing valve was defined by the presence of excess tissue on both leaflets and prolapse of 2 or more of the 3 segments of each leaflet. Among 1344 consecutive patients who underwent mitral valve repair for degenerative mitral regurgitation between 1991 and 2012 at the Sakakibara Heart Institute, 73 patients met our definition of an extreme billowing and prolapsing valve. From these 73 patients, 67 patients who underwent mitral valve repair based on the surgical strategy we developed in July 1996 were enrolled in this study. Our strategy of mitral valve repair for extreme billowing and prolapsing valves consists of (1) volume reduction of the leaflets, (2) physiologic remodeling annuloplasty for long anterior leaflet, and (3) wide usage of artificial chordae. Results: Mean age of the patients was 46.6 ± 12.9 years. There were no hospital deaths and 6 late deaths in this series. Kaplan–Meier survival at 10 years was 96.8 ± 2.2%. There were 2 reoperations. Cumulative incidence rate of mitral valve reoperation and moderate or severe mitral regurgitation at 10 years was 1.8 ± 1.8% and 11.2 ± 4.0%. Number of artificial chordal replacement was associated with decreased risk of recurrent moderate mitral regurgitation (hazard ratio, 0.60; P = .03). Conclusions: Long-term echo follow-up demonstrates good results of mitral valve repair for extreme billowing and prolapsing valves using our strategy.

Naked mole rats are found to be resistant to cancer development through dampened inflammatory response due to genetically determined impaired necroptosis, with essential necroptosis genes RIPK3 and MLKL containing mutations causing premature stop codons.

Background: The Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study was launched in 2013 to evaluate the complex interactions of genetic and environmental factors in multifactorial diseases. The present study describes the maternal baseline profile and perinatal data of participating mothers and infants. Methods: Expectant mothers living in Miyagi Prefecture were recruited from obstetric facilities or affiliated centers between 2013 and 2017. Three sets of self-administered questionnaires were collected, and the medical records were reviewed to obtain precise information about each antenatal visit and each delivery. Biospecimens, including blood, urine, umbilical cord blood, and breast milk, were collected for the study biobank. The baseline maternal sociodemographic characteristics, results of screening tests, and obstetric outcomes were analyzed according to the maternal age group. Results: A total of 23,406 pregnancies involving 23,730 fetuses resulted in 23,143 live births. Younger maternal participants had a tendency toward a higher incidence of threatened abortion and threatened premature labor, while older age groups exhibited a significantly higher rate of low lying placenta, placenta previa, gestational diabetes, and hypertensive disorders of pregnancy. Conclusions: The present study clearly shows the distribution of maternal baseline characteristics and the range of perinatal outcomes according to maternal age group. This cohort study can provide strategic information for creating breakthroughs in the pathophysiology of perinatal, developmental, and noncommunicable diseases by collaborative data visiting or sharing.

Paradoxically, patients with advanced stomach cancer who are Helicobacter pylori-positive (HP+) have a higher survival rate than those who are HP-. This finding suggests that HP infection has beneficial effects for cancer treatment. The present study examines whether HP+ individuals have a lower likelihood of death from cancer than those who are HP-. Prospective cohort data (n = 4,982 subjects enrolled in the DAIKO study between 2008-2010) were used to assess whether anti-HP antibody status was associated with cancer incidence. The median age in the primary registry was 53 years-old (range 35-69 years-old). Over the 8-year observation period there were 234 (4.7%) cancer cases in the cohort and 88 (1.8%) all-cause deaths. Urine anti-HP antibody data was available for all but one participant (n = 4,981; 99.98%). The number of HP+ and HP- individuals was 1,825 (37%) and 3,156 (63%), respectively. Anti-HP antibody distribution per birth year revealed that earlier birth year was associated with higher HP+ rates. With a birth year-matched cohort (n = 3,376), all-cancer incidence was significantly higher in HP+ individuals than those who were HP- (p = 0.00328), whereas there was no significant difference in the cancer death rate between HP+ and HP- individuals (p = 0.888). Cox regression analysis for prognostic factors revealed that the hazards ratio of HP+ was 1.59-fold (95%CI 1.17-2.26) higher than HP- in all-cancer incidence. Potential systemic effects of HP+ status may contribute to reduced likelihood of death for patients after an initial diagnosis of cancer.

Rheumatoid arthritis is an inflammatory autoimmune disease, characterized by autoantibody production, synovial inflammation, and joint destruction. Its pathogenesis is due to environmental factors and genetic backgrounds. Bruton's tyrosine kinase is a cytoplasmic non-receptor tyrosine kinase, expressed in most hematopoietic cell lineages, except T cells and plasma cells, and regulates various immune-related signaling pathways, thereby playing a crucial role in pathogenesis. Thus, inhibiting Bruton's tyrosine kinase may prove beneficial in treating autoimmune diseases. In the present study, we characterized Bruton's tyrosine kinase inhibitor, TAS5315, in vitro and evaluated its therapeutic effects in experimental arthritis models. TAS5315 markedly inhibited Bruton's tyrosine kinase enzyme activity and suppressed the B-cell receptor signaling pathway in Ramos cells. Moreover, it suppressed the expression of CD69, CD86, and MHC class II in mouse B lymphocytes and the production of TNF-α and MIP-1α in mouse macrophages and decreased bone resorption activity in mouse osteoclasts. Furthermore, it ameliorated the pathological changes in two rodent models of collagen-induced arthritis in vivo. TAS5315 improved bone mineral density and bone intensity. Thus, these results suggest that TAS5315 could be a promising therapeutic option for the treatment of rheumatoid arthritis.

Databases: Integrating megadata for disease research A database integrating 1.3 trillion genome cohort data entries from 157,191 individuals in Japan will facilitate research into the gene-environment interactions underlying common diseases. The Tohoku Medical Megabank integrated database called dbTMM was developed by Soichi Ogishima, Masayuki Yamamoto and colleagues at Tohoku University in Japan. It incorporates the genome, metabolome, proteome, clinical, sociodemographic, lifestyle and environmental data from 84,073 adults, and 73,529 pregnant women and their families, including children. Blood and urine samples were collected from participants and analysed, then obtained genome/multiomics data were stored in dbTMM. Users can stratify the entire population into smaller populations based on multiple data variables, including whole genome variants, to search for statistically significant differences that might warrant further research. The dbTMM is expected to help clarify the genes and gene-environment interactions underlying common diseases and improve disease risk prediction.

Introduction: Xanthine oxidoreductase (XOR) has been identified as a critical source of reactive oxygen species in various pathophysiological conditions, including hypertension, endothelial dysfunction and atherosclerosis. This study investigated the association between XOR and renal function in a general Japanese population. Methods: The Iwate Tohoku Medical Megabank Organization pooled individual participant data from a community-based cohort study in Iwate prefecture. Chronic kidney disease (CKD) was estimated using the estimated glomerular filtration rate of cystatin C (eGFRcys). Individuals with a history of hyperuricemia or severe renal dysfunction (eGFRcys < 15 ml/min/1.73 m2 or undergoing dialysis) were excluded from the study. We performed a multinominal multivariate logistic analysis adjusted for age, blood pressure, uric acid, glycated hemoglobin A1c, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol to associate XOR activity and renal function. Results: The present study included 4,248 participants (male/female: 1,373/2,875, age: 62.9 ± 11.7 years). When participants were divided according to XOR quartiles, blood pressure, body mass index, uric acid, low-density lipoprotein cholesterol and glycated hemoglobin A1c were highest in the highest XOR quartile (all p < 0.001). The XOR activity was significantly higher in the subgroup with CKD stage G3 and G4 (G1 vs. G2 vs. G3-G4: 44.8 ± 40.5 vs 52.0 ± 42.9 vs. 54.1 ± 43.9 pmol / h / mL, p = 0.02). The higher XOR activity was significantly associated with an increase of CKD stage: the odd ratios (95% confidence intervals) per 1 pmol/h/mL increase in XOR activity with CKD stage G1 as a reference were 1.37 (1.13-1.73) in G2 and 1.51 (1.30-1.84) in G3-G4. Conclusion: The present study concluded that high XOR activity was associated with the severity of CKD in a general Japanese population, suggesting that upregulated XOR activity may be involved in advanced renal dysfunction.

Elevated levels of circulating high-sensitivity cardiac troponin T (hs-cTnT) are associated with cardiovascular disease. This study aimed to examine whether hs-cTnT levels are associated with incident stroke in the elderly population.The Iwate Tohoku Medical Megabank Organization pooled participant data for a community-based cohort study (n = 15,063, 69.6 ± 3.4 years), with a mean follow-up period of 5.23 years for all-cause death and incident stroke. The follow-up revealed 316 incident strokes, including atherothrombotic (n = 98), cardioembolic (n = 54), lacunar (n = 63), hemorrhagic (n = 101), and 178 all-cause deaths. Participants were classified into quartiles according to hs-cTnT levels (Q1 ≦ 4 ng/L, Q2: 5–6 ng/L, Q3: 7–9 ng/L, and Q4 > 9 ng/L). After adjusting for sex, age, smoking, drinking, systolic blood pressure, estimated glomerular filtration rate, N-terminal pro-brain natriuretic peptide, hemoglobin A1c, and lipid profile, a Cox proportional hazard model showed that higher hs-cTnT levels were associated with ischemic stroke (Q1 vs. Q4, hazard ratio [HR] = 2.24, 95 % confidence interval [CI] = 1.12–4.51, p = 0.023). The incident of total stroke was not associated with hs-cTnT levels (Q1 vs. Q4, HR 1.39, 95 % CI = 0.89–1.74, p = 0.145). Numerical differences were highest regarding incident lacunar stroke subtypes; however, this association was not statistically significant.Higher hs-cTnT concentrations were associated with ischemic stroke in the elderly Japanese population.

Background: Bone metabolic dysregulation plays an important role in the pathogenesis of atherosclerosis; however, whether its markers contribute to coronary artery disease (CAD) risk in the general population remains unclear. Therefore, this study aimed to analyze the association between bone metabolic markers and CAD risk score in the general Japanese population. Methods: The Iwate Medical Megabank Organization collected individual participant data during a community-based cohort study in the Iwate prefecture (n = 5,095, age = 58.9 ± 12.4 years). Participants with osteoporosis, chronic kidney disease, malignant disease, or primary wasting disease were excluded from the study. The present study measured the levels of circulating bone metabolic markers, including total type I collagen N-terminal propeptide (TP1NP), bone-type alkaline phosphatase, cross-linked N-telopeptide of type 1 collagen (NTX), and intact parathyroid hormone. CAD risk and atherosclerosis were evaluated using the Suita score and brachial–ankle pulse wave velocity (baPWV) measurement, respectively. Results: Among the bone metabolic markers, TP1NP was strongly associated with a high Suita score (≥56 points) (OR = 0.77, 95% CI = 0.69–0.82, P 1,400 cm/s). Conclusions: This study demonstrated that TP1NP levels decreased in participants with high Suita scores and high baPWV, suggesting that TP1NP downregulation may indicate future CAD risk and atherosclerosis progression in the general Japanese population.

Abstract Background Social isolation and mental health issues have become a severe problem in disaster areas in the Great East Japan Earthquake. This study examined whether the combination of the house damage and social isolation or the combination of the death of family members and social isolation is associated with depressive symptoms among survivors using the baseline study data of the Tohoku Medical Megabank Project Community-Based Cohort Study (TMM CommCohort Study). Methods We used cross-sectional data from a baseline survey of 48,958 participants (18,423 males, 30,535 females; aged 60.1 ± 11.2 years) to examine the association between social isolation measured by the Lubben social network scale 6 (LSNS-6) and depressive symptoms measured by the Center for Epidemiological Studies-Depressive Scale (CES-D). The presence of social isolation and depressive symptoms was defined by an LSNS-6 score of

Abstract Preterm birth is known to be associated with chronic disease risk in adulthood whereby epigenetic memory may play a mechanistic role in disease susceptibility. Gestational age (GA) is the most important prognostic factor for preterm infants, and numerous DNA methylation alterations associated with GA have been revealed by epigenome-wide association studies. However, in human preterm infants, whether the methylation changes relate to transcription in the fetal state and persist after birth remains to be elucidated. Here, we identified 461 transcripts associated with GA (range 23–41 weeks) and 2093 candidate CpG sites for GA-involved epigenetic memory through analysis of methylome (110 cord blood and 47 postnatal blood) and transcriptional data (55 cord blood). Moreover, we discovered the trends of chromatin state, such as polycomb-binding, among these candidate sites. Fifty-four memory candidate sites showed correlation between methylation and transcription, and the representative corresponding gene was UCN, which encodes urocortin.

Abstract Background Gallbladder neuroendocrine neoplasm is a rare disease that is divided into neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs). Clear cell NETs of the gallbladder are extremely rare. We report the case of a patient with polypoid clear cell NET G1 of the gallbladder who underwent laparoscopic cholecystectomy. Case presentation A 10-mm pedunculated polyp in the gallbladder neck was detected on a follow-up abdominal ultrasound in a 60-year-old man with chronic hepatitis and hepatitis B without medication. Six months later, an abdominal ultrasound revealed that the tumor had enlarged to 12 mm in size. He was asymptomatic and had no abnormalities in other laboratory examinations, including the tumor markers, carcinoembryonic antigen and CA19-9. Abdominal ultrasound showed a 12-mm polyp in the neck of the gallbladder with perfusion and focal thickening of the gallbladder wall. A gallbladder stone was also seen in the fundus. An enhanced computed tomography scan and magnetic resonance imaging revealed a polypoid lesion and gallbladder stone located at the neck of the gallbladder and the fundus, respectively. Malignancy could not be excluded, and hence, a laparoscopic cholecystectomy was performed. Pathologically, a pedunculated polyp (14 × 11 × 15 mm) was observed in the neck of the gallbladder, and the polypoid lesion comprised nests or trabecular growths of clear NET cells in the lamina propria (ENETS: T1N0M0; AJCC: T1aN0M0). Immunohistochemical staining with synaptophysin, chromogranin A, and CD56 was confined to the tumor. The pathological diagnosis was clear cell NET G1 of the gallbladder. Although clear cell NET is often described as a distinct manifestation of von Hippel-Lindau disease (VHL), the patient had no past medical or family history of VHL. Until his one-and-a-half-year follow-up, the patient was doing well and without any signs of recurrence. Conclusion We report an extremely rare case of gallbladder clear cell NET G1. When NET G1 is incidentally identified in a gallbladder surgical specimen, clinical information and pathological findings should be considered as references.

Abstract Background Methotrexate (MTX) is a frequently used drug in the treatment of rheumatoid arthritis (RA), but occurrences of lymphoproliferative disorders (LPD) have been reported in patients undergoing an MTX regimen. Almost half of the patients with methotrexate-associated lymphoproliferative disorders (MTX-LPD) have extranodal lesions; moreover, although extremely rare, digestive tract perforations resulting from the extranodal lesions of MTX-LPD have also been reported. Case presentation We describe the case of an 81-year-old woman with RA who had been prescribed MTX at 6 mg per week for the past 11 years. She was admitted to our hospital with occasional abdominal pain and was first diagnosed with enteritis. Her abdominal pain did not improve, and a computed tomography scan showed abdominal effusion and free air in the abdominal cavity. She was diagnosed with a digestive tract perforation and underwent emergency surgery. The perforation site was identified in the jejunum, and she underwent small intestinal resection around the perforated region. The pathological findings showed an ulcer in the jejunum and infiltration of large atypical lymphocytes around the perforated region. An immunohistochemical examination revealed the expression of a cluster of differentiation 20 and latent membrane protein 1. Considering the patient’s history of RA treated with MTX, she was diagnosed as having Epstein–Barr virus (EBV)-related MTX-LPD with a histological diagnosis of EBVMCU. MTX was discontinued after the surgery, and her soluble interleukin-2 receptor (sIL-2R) levels had returned to normal 1 year later. She has had a good course for the 2 years since surgery and remains asymptomatic with no recurrence of MTX-LPD, as confirmed by the sIL-2R levels. Conclusion We experienced a rare case of the jejunum perforation induced by MTX-LPD. Since only a few cases have been reported of a patient with small intestinal perforation induced by MTX-LPD, further research is necessary to evaluate the clinicopathological features of MTX-LPD. The patient had disease remission after surgery and by discontinuing MTX treatment; our case did not require chemotherapy. EBV-positive patients, especially those with a pathological presentation of EBVMCU, could have a higher likelihood of remission, which could have been a factor in the present case.

Background: We established a community-based cohort study to assess the long-term impact of the Great East Japan Earthquake on disaster victims and gene-environment interactions on the incidence of major diseases, such as cancer and cardiovascular diseases. Methods: We asked participants to join our cohort in the health check-up settings and assessment center based settings. Inclusion criteria were aged 20 years or over and living in Miyagi or Iwate Prefecture. We obtained information on lifestyle, effect of disaster, blood, and urine information (Type 1 survey), and some detailed measurements (Type 2 survey), such as carotid echography and calcaneal ultrasound bone mineral density. All participants agreed to measure genome information and to distribute their information widely. Results: As a result, 87,865 gave their informed consent to join our study. Participation rate at health check-up site was about 70%. The participants in the Type 1 survey were more likely to have psychological distress than those in the Type 2 survey, and women were more likely to have psychological distress than men. Additionally, coastal residents were more likely to have higher degrees of psychological distress than inland residents, regardless of sex. Conclusion: This cohort comprised a large sample size and it contains information on the natural disaster, genome information, and metabolome information. This cohort also had several detailed measurements. Using this cohort enabled us to clarify the long-term effect of the disaster and also to establish personalized prevention based on genome, metabolome, and other omics information.

Abstract Background Adhesion formation after hepatectomy creates problems for repeat hepatectomy. This study aimed to compare the effectiveness of a spray (AdSpray) and sheet adhesion barrier (Seprafilm) in a rat hepatectomy-induced adhesion model. Methods Thirty male Sprague-Dawley rats underwent partial resection of the left lateral liver lobe. They were randomly assigned to control (n = 10), AdSpray (n = 10), and Seprafilm groups. Seven days after surgery, the animals were sacrificed, and adhesions at the hepatic resection surface were blindly evaluated. Results In the control group, adhesions were formed in all 10 animals (100%), with a 69% adhesion extent (mean). In the AdSpray group, the incidence of adhesions (40%) and the adhesion extent (mean, 10%) were significantly lower than in the control group (incidence; p = 0.0147, adhesion extent; p = 0.0007). In the Seprafilm group, the incidence of adhesions was 70%. The adhesion extent of Seprafilm (mean, 30%) was significantly lower than in the control group (p = 0.0492). No significant differences were observed between the AdSpray and Seprafilm groups. As for histopathological examination, animals in the AdSpray group showed a similar healing profile to that of the control group without delayed healing and regeneration of mesothelial cells. In contrast, the Seprafilm group showed ongoing foreign body reaction to Seprafilm, and regeneration of mesothelial cells was immature at 7 days. Conclusions Both the spray-type gel and sheet adhesion barriers significantly reduced adhesion formation after hepatectomy. The spray-type adhesion barrier caused no adverse events and induced favorable healing. These adhesion barriers may be effective in hepatectomy. Further animal studies and clinical trials are required to determine their benefits in clinical use.

Previous genome-wide association studies have identified risk loci for pancreatic cancer but were centered on individuals of European ancestry. Here the authors identify GP2 gene variants associated with pancreatic cancer susceptibility in populations of East Asian ancestry.

Abstract Background Studies on the adverse effects of Asian dust (AD) on respiratory function in children are scarce. The objective of this study was to examine the association between AD and respiratory function by measuring peak expiratory flow rates (PEFRs) in asthmatic children. Methods The study was carried out from March to May from 2014 through 2016. One hundred ten children with bronchial asthma were recruited from four hospitals in the Goto Islands and south Nagasaki area in Nagasaki prefecture. The parents were asked to record their children’s PEFRs every morning/evening and clinical symptoms in an asthma diary. AD was assessed from light detection and ranging data, and a linear mixed-effects model was used to estimate the effects of AD on daily PEFR. Time-stratified case-crossover analyses were performed to examine the association between AD and asthma attacks defined by reduction levels in PEFR. Results AD was detected on 11 days in the Goto Islands, and on 23 days in the south Nagasaki area. After adjusting for age, sex, temperature, and daily oxidants, we found a consistent association between AD and a 1.1% to 1.7% decrease in PEFR in the mornings and a 0.7% to 1.3% decrease in the evenings at a lag of 0 to 5 days. AD was not associated with the number of asthma attacks, respiratory symptoms, or other symptoms at any lag days examined. Conclusions Exposure to AD was associated with reduced PEFR, although the effects were not large enough to induce clinically apparent symptoms, in clinically well-controlled asthmatic children.

Few studies have investigated the interactions between HDL-C-related SNPs identified by genome-wide association (GWA) study and physical activity (PA) on HDL-C. First, we conducted a sex-stratified GWA study in a discovery sample (2,231 men and 2,431 women) and replication sample (2,599 men and 3,109 women) to identify SNPs influencing log-transformed HDL-C in Japanese participants in the baseline survey of the Japan Multi-Institutional Collaborative Cohort Study. We also replicated previously reported HDL-C-related SNPs in a combined (discovery plus replication) sample (4,830 men and 5,540 women). We then analyzed the interactions of the HDL-C-related SNPs with PA on HDL-C. The sex-stratified GWA analyses identified 11 and 10 HDL-C-related SNPs in men and women as targets for an interaction analysis. Among these, only one interaction of ABCA1 rs1883025 with PA was statistically significant in men, after Bonferroni correction [P-interaction = 0.001 (α = 0.05/21 = 0.002)]. The per-major-allele (C allele) increase in log-transformed HDL-C was lost in men with low PA (β = 0.008) compared with those with medium (β = 0.032) or high PA (β = 0.034). These findings suggest that the benefit of carrying a C allele of ABCA1 rs1883025 on enhancing HDL-C may be attenuated in inactive men.

Focusing on the components of fine particulate matter, i.e., PM2.5, we have analyzed the factors that led to the high concentrations of each chemical component in PM2.5 during our observations in Fukuoka, Japan in spring 2020. The backward trajectory showed that air masses reached Fukuoka via the Yellow Sea and the southern part of South Korea when PM2.5 and each chemical component were high in concentrations. On the other hand, diurnal variations in ozone were also observed, suggesting that both transboundary and local air pollution are involved. Air masses reached the southern part of the Kyushu region when only sulfate concentrations were high. A volcano eruption led the high sulfate concentration. When only polycyclic aromatic hydrocarbons (PAHs) concentrations were high, air masses often reached the northern part of Kyushu, indicating that there may be a specific local source for PAHs.

Thousands of genetic loci are known to associate with human height, but these are mainly based on studies in European ancestry populations. Here, Akiyama et al. construct a genotype reference panel for the Japanese population followed by GWAS and report 573 height associated variants in 191,787 Japanese.

More than 170 genetic loci have been linked to prostate cancer risk, primarily based on genome-wide association studies (GWAS) in European population. Here, the authors performed a GWAS on a Japanese cohort of prostate cancer patients, finding 12 new susceptibility loci, and identifying a polygenic risk for Japanese prostate cancer.

Mechanical thrombectomy has become the most effective treatment for intracranial artery occlusion; however, it is difficult to recanalize acute arterial occlusion resulting from atherothrombotic causes. We describe a 44-year-old man diagnosed with cerebral infarction associated with acute right middle cerebral artery occlusion. During emergency mechanical thrombectomy, atheromatous disease was identified by deployment of a stent retriever. The stent retriever was reinserted within a microcatheter and retrieved. After the procedure, the right middle cerebral artery was recanalized, although severe stenosis persisted. We recommend mild angioplasty with a stent retriever for patients with atherothrombotic intracranial artery occlusion as an optional treatment for avoiding damage to the vessel wall, and plaque shift to the perforating arteries.

Abstract Background Genotype imputation from single-nucleotide polymorphism (SNP) genotype data using a haplotype reference panel consisting of thousands of unrelated individuals from populations of interest can help to identify strongly associated variants in genome-wide association studies. The Tohoku Medical Megabank (TMM) project was established to support the development of precision medicine, together with the whole-genome sequencing of 1070 human genomes from individuals in the Miyagi region (Northeast Japan) and the construction of the 1070 Japanese genome reference panel (1KJPN). Here, we investigated the performance of 1KJPN for genotype imputation of Japanese samples not included in the TMM project and compared it with other population reference panels. Results We found that the 1KJPN population was more similar to other Japanese populations, Nagahama (south-central Japan) and Aki (Shikoku Island), than to East Asian populations in the 1000 Genomes Project other than JPT, suggesting that the large-scale collection (more than 1000) of Japanese genomes from the Miyagi region covered many of the genetic variations of Japanese in mainland Japan. Moreover, 1KJPN outperformed the phase 3 reference panel of the 1000 Genomes Project (1KGPp3) for Japanese samples, and IKJPN showed similar imputation rates for the TMM and other Japanese samples for SNPs with minor allele frequencies (MAFs) higher than 1%. Conclusions 1KJPN covered most of the variants found in the samples from areas of the Japanese mainland outside the Miyagi region, implying 1KJPN is representative of the Japanese population’s genomes. 1KJPN and successive reference panels are useful genome reference panels for the mainland Japanese population. Importantly, the addition of whole genome sequences not included in the 1KJPN panel improved imputation efficiencies for SNPs with MAFs under 1% for samples from most regions of the Japanese archipelago.

Abstract Background The Tohoku Medical Megabank project aims to create a next-generation personalized healthcare system by conducting large-scale genome-cohort studies involving three generations of local residents in the areas affected by the Great East Japan Earthquake. We collected medical and genomic information for developing a biobank to be used for this healthcare system. We designed a questionnaire-based pedigree-creation software program named “f-treeGC,” which enables even less experienced medical practitioners to accurately and rapidly collect family health history and create pedigree charts. Results f-treeGC may be run on Adobe AIR. Pedigree charts are created in the following manner: 1) At system startup, the client is prompted to provide required information on the presence or absence of children; f-treeGC is capable of creating a pedigree up to three generations. 2) An interviewer fills out a multiple-choice questionnaire on genealogical information. 3) The information requested includes name, age, gender, general status, infertility status, pregnancy status, fetal status, and physical features or health conditions of individuals over three generations. In addition, information regarding the client and the proband, and birth order information, including multiple gestation, custody, multiple individuals, donor or surrogate, adoption, and consanguinity may be included. 4) f-treeGC shows only marriages between first cousins via the overlay function. 5) f-treeGC automatically creates a pedigree chart, and the chart-creation process is visible for inspection on the screen in real time. 6) The genealogical data may be saved as a file in the original format. The created/modified date and time may be changed as required, and the file may be password-protected and/or saved in read-only format. To enable sorting or searching from the database, the file name automatically contains the terms typed into the entry fields, including physical features or health conditions, by default. 7) Alternatively, family histories are collected using a completed foldable interview paper sheet named “f-sheet”, which is identical to the questionnaire in f-treeGC. Conclusions We developed a questionnaire-based family tree-creation software, named f-treeGC, which is fully compliant with international recommendations for standardized human pedigree nomenclature. The present software simplifies the process of collecting family histories and pedigrees, and has a variety of uses, from genome cohort studies or primary care to genetic counseling.

Epigenomics: Finding DNA modifications that predict disease Patterns of chemical modifications on DNA can predict the risk of certain diseases, but the challenge is knowing where to look for them. Atsushi Shimizu from Iwate Medical University in Japan and his colleagues determined the location of these modifications, methyl groups added to DNA’s cytosine bases, in over hundred healthy people and found two million regions that vary widely between individuals. They used previous data to show that these regions are far more likely to change during the course of disease than genomic loci that are unchanged in all subjects. Current methods to look for disease-specific methylation changes can only profile at most 20% of the genome and Shimizu’s work will help focus on the 20% that matter for identifying disease risk and lead to better diagnosis and prognosis.

Rail corrugation is a periodic rail surface roughness that is formed as the rolling stock runs repeatedly on the rail. The rail corrugation occurs in various track alignment and track structures, but the generation mechanism and wavelength determination mechanism are often unknown. Therefore, in this paper, in order to measure the rail surface roughness of rail corrugation in detail, we have developed a trolley that can measure rail surface roughness continuously regardless of moving speed of the device. At that time, the asymmetrical chord method widely used in track geometry cars was adopted as a measurement method of the rail surface roughness in the longitudinal direction of the track. In this way, we considered to measure the rail surface roughness with any wavelength with high accuracy, and verified the measurement accuracy. Finally, we indicated that measurement cases at commercial lines, and the prospect of how to use the developed trolley.

Coincident profiles from the space-borne and ground-based lidar measurements provide a unique opportunity to estimate the planetary boundary layer height (PBLH). In this study, PBLHs derived from the Cloud-Aerosol Lidar with Orthogonal Polarization (CALIOP) were assessed by comparing them with those obtained from the ground-based lidar at Seoul National University (SNU) in Korea for both day and night from 2006 to 2019, and sounding data. CALIOP-derived PBLHs using wavelet covariance transform (WCT) are generally higher than those derived from the SNU lidar for both day and night. The difference in PBLH tends to increase as the signal-to-noise ratio for CALIOP decreases. The difference also increases as aerosol optical depth increases, implying that the PBLH estimated from CALIOP could be higher than that determined from the SNU lidar because of the signal attenuation within the aerosol layer under optically thick aerosol layer conditions. The higher PBLH for CALIOP in this study is mainly attributed to multiple aerosol layers. After eliminating multilayer cases, the PBLHs estimated from both the lidars showed significantly improved agreement: a mean difference of 0.09 km (R = 0.81) for daytime and 0.25 km (R = 0.51) for nighttime. The results from this study suggest that PBL detection using CALIOP is reliable for daytime if multilayer cases are removed. For nighttime, PBLHs derived from the SNU lidar and CALIOP showed a relatively large difference in frequency distribution compared with sounding data. It suggests that further investigations are needed for nighttime PBLHs, such as investigations about discriminating the residual layer and the difference between lidar-derived PBLH based on the aerosol layer and thermally derived PBLH from radiosonde data for the stable boundary layer during the nighttime.

Two polarization-sensitive lidars were operated continuously to monitor the three-dimensional distribution of small volcanic ash particles around Sakurajima volcano, Kagoshima, Japan. Here, we estimated monthly averaged extinction coefficients of particles between the lidar equipment and the vent and compared our results with monthly records of volcanic activity reported by the Japan Meteorological Agency, namely the numbers of eruptions and explosions, the density of ash fall, and the number of days on which ash fall was observed at the Kagoshima observatory. Elevated extinction coefficients were observed when the surface wind direction was toward the lidar. Peaks in extinction coefficient did not always coincide with peaks in ash fall density, and these differences likely indicate differences in particle size.

Ground-based remote sensing equipment have the potential to be used for the nowcasting of the tephra hazard from volcanic eruptions. To do so raw data from the equipment first need to be accurately transformed to tephra-related physical quantities. In order to establish these relations for Sakurajima volcano, Japan, we propose a methodology based on high-resolution simulations. An eruption that occurred at Sakurajima on 16 July 2018 is used as the basis of a pilot study. The westwards dispersal of the tephra cloud was ideal for the observation network that has been installed near the volcano. In total, the plume and subsequent tephra cloud were recorded by 2 XMP radars, 1 lidar and 3 optical disdrometers, providing insight on all phases of the eruption, from plume generation to tephra transport away from the volcano. The Weather Research and Forecasting (WRF) and FALL3D models were used to reconstruct the transport and deposition patterns. Simulated airborne tephra concentration and accumulated load were linked, respectively, to lidar backscatter intensity and radar reflectivity. Overall, results highlight the possibility of using such a high-resolution modelling-based methodology as a reliable complementary strategy to common approaches for retrieving tephra-related quantities from remote sensing data.

The naked mole-rat exhibits an exceptional resistance to cancer. Here, the authors show that induced pluripotent stem cells derived from the naked mole-rat lack teratoma-forming tumorigenicity due to a naked mole-rat-specific ARF-dependent tumour-suppression mechanism.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Genome-wide association studies (GWAS) have identified greater than 30 variants associated with ovarian cancer, but most of these variants were investigated in European populations. Here, we integrated GWAS and subsequent functional analyses to identify the genetic variants with potential regulatory effects. We conducted GWAS for ovarian cancer using 681 Japanese cases and 17,492 controls and found that rs137672 on 22q13.1 exhibited a strong association with a P-value of 1.05 × 10(-7) and an odds ratio of 0.573 with a 95% confidence interval of 0.466-0.703. In addition, three previously reported SNPs, i.e., rs10088218, rs9870207 and rs1400482, were validated in the Japanese population (P < 0.05) with the same risk allele as noted in previous studies. Functional studies including regulatory feature analysis and electrophoretic mobility shift assay (EMSA) revealed two regulatory SNPs in 22q13.1, rs2072872 and rs6509, that affect the binding affinity to some nuclear proteins in ovarian cancer cells. The plausible regulatory proteins whose motifs could be affected by the allele changes of these two SNPs were also proposed. Moreover, the protective G allele of rs6509 was associated with a decreased SYNGR1 expression level in normal ovarian tissues. Our findings elucidated the regulatory variants in 22q13.1 that are associated with ovarian cancer risk.

Granulomatosis with polyangiitis (GPA) is known as anti-neutrophil cytoplasmic antibody- (ANCA-) associated small vessel vasculitis and typically manifests as pulmonary-renal syndrome, but the disease is not limited to pulmonary or renal systems. The inflammation can involve whole body organs. In addition, the ANCA titer does not always become positive. Here, we describe the case of a 91-year-old man who presented with umbilical pain and fever of unknown origin. Only the increased computed tomography value of the greater omentum suggested intra-abdominal inflammation; however, serological examinations, including the ANCA level, could not reveal the focus or cause of symptoms. Finally, the histopathological examination of specimens surgically excised from the greater omentum demonstrated GPA limited to the greater omentum. This report reminds physicians to consider GPA in the differential diagnosis of acute abdominal pain or fever of unknown origin.

Recently, many autologous tumor antigens have been examined for their potential use in cancer immunotherapy. However, the success of cancer vaccines in clinical trials has been limited, partly because of the limitations of using single, short peptides in most attempts. With this in mind, we aimed to develop multivalent synthetic long peptide (SLP) vaccines containing multiple cytotoxic T-lymphocyte (CTL) epitopes. However, to confirm whether a multivalent vaccine can induce an individual epitope-specific CTL, the only viable screening strategies currently available are interferon-gamma (IFN-γ enzyme-linked immunospot (ELISPOT) assays using human peripheral blood mononuclear cells, or expensive human leukocyte antigen (HLA)-expressing mice. In this report, we evaluated the use of our developed murine-20S immunoproteasome (i20S) digestion assay, and found that it could predict the results of IFN-γ ELISPOT assays. Importantly, the murine-i20S digestion assay not only predicted CTL induction, but also antitumor activity in an HLA-expressing mouse model. We conclude that the murine-i20S digestion assay is an extremely useful tool for the development of "all functional" multivalent SLP vaccines.

Introduction. Annular pancreas is a rare congenital abnormality characterized by a ring of pancreatic tissue surrounding the descending portion of the duodenum. Annular pancreas coexisting with replaced common hepatic artery which is also a rare anatomical variation has not been reported previously. Case Presentation. A 53-year-old man visited our hospital complaining of epigastric pain. Based on radiological examinations, he was diagnosed as having pancreatitis, annular pancreas, and hepatomesenteric trunk. One month later, obstructive jaundice developed. Endoscopic examination revealed ampullary region carcinoma. We performed pancreaticoduodenectomy using the “artery-first” approach. Discussion. Both annular pancreas and common hepatic artery anomaly are rare. High-quality preoperative imaging and awareness of such rare conditions are necessary for operative safety. Although the embryological relationship between these anomalies is uncertain, the present case may suggest some relevance between the two. Conclusion. The “artery-first” approach may be a useful method for pancreaticoduodenectomy in patients who have an anatomical abnormality.

[This corrects the article DOI: 10.1371/journal.pone.0199249.].