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Estimation of the functional reserve of the remnant liver is important to reduce morbidity and mortality.To estimate the functional reserve of the remnant liver in patients with hepatocellular carcinoma (HCC).We reviewed the medical records of 199 patients who underwent resection of HCC. Hepatic clearance of the remnant liver was calculated using fusion images ofTwenty-seven (30%) patients had major complications and 23 (12%) developed PHLF. The incidence of major complications increased with increasing albumin-bilirubin (ALBI) grade. The area under the curve values for hepatic clearance of the remnant liver, liver to heart-plus-liver radioactivity at 15 min (LHL15), and ALBI score predicting PHLF were 0.868, 0.629, and 0.655, respectively. The area under the curve for hepatic clearance of the remnant liver, LHL15, and ALBI score predicting major complications were 0.758, 0.594, and 0.647, respectively. The risk factors for PHLF and major complications were hepatic clearance of the remnant liver and intraoperative bleeding.The measurement of hepatic clearance may predict PHLF and major complications for patients undergoing resection of HCC.

The associations between blood lipids, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides, and low-density lipoprotein cholesterol (LDL-C), and colorectal cancer risk are controversial. We evaluated potential causal relationships between blood lipids and colorectal cancer risk. Using the baseline data from the Japanese Consortium of Genetic Epidemiology studies, we estimated the single-nucleotide polymorphism (SNP)–exposure associations (n = 34,546 for TC, n = 50,290 for HDL-C, n = 51,307 for triglycerides, and n = 30,305 for LDL-C). We also estimated the SNP–outcome associations in another Japanese dataset (n = 7,936 colorectal cancer cases and n = 38,042 controls). We conducted Mendelian randomization (MR) analyses for the association between each blood lipid type and the risk of colorectal cancer using an inverse variance-weighted method. The total variances explained by the selected SNPs in TC (68 SNPs), HDL-C (50 SNPs), log-transformed triglycerides (26 SNPs), and LDL-C (35 SNPs) were 7.0%, 10.0%, 6.2%, and 5.7%, respectively. The odds ratios for colorectal cancer were 1.15 [95% confidence interval (CI), 1.01–1.32] per 1 standard deviation (SD; 33.3 mg/dL) increase in TC, 1.11 (95% CI, 0.98–1.26) per 1 SD (15.4 mg/dL) increase in HDL-C, 1.06 (95% CI, 0.90–1.26) per 1 SD (0.5 log-mg/dL) increase in log-transformed triglycerides, and 1.17 (95% CI, 0.91–1.50) per 1 SD (29.6 mg/dL) increase in LDL-C. Sensitivity analyses consistently suggested the positive association between TC and colorectal cancer, whereas results of each lipid component were inconsistent. In conclusion, this large MR study of a Japanese population showed a potentially causal association between high TC and colorectal cancer risk, although the association between each lipid component and colorectal cancer remained inconclusive. Prevention Relevance: In this large MR analysis of a Japanese population, a positive association was found between genetically predicted high total cholesterol (TC) levels and an increased risk of colorectal cancer. Therefore, lowering TC levels by lifestyle modifications or medications may be justified for the purpose of preventing colorectal cancer.

Health benefits of physical activity (PA) may be mediated by DNA methylation alterations. The purpose of the current study was to comprehensively identify CpG sites whose methylation levels were associated with accelerometer-assessed total PA in a general Japanese population.The study participants were from the baseline survey of Saga Japan Multi-institutional Collaborative Cohort. PA was objectively measured by a single-axis accelerometer for 7 d. We used a two-stage strategy. In the discovery stage, we performed a meta-analysis of two epigenome-wide association studies of total PA in 898 individuals (a combination of random sample ( n = 507) and case-control study sample ( n = 391)). Peripheral blood DNA methylation levels were measured using Infinium EPIC or HM450 arrays. In the replication stage, we subsequently examined whether CpG sites significantly associated ( P1 × 10 -5 ) with total PA were replicated in another sample ( n = 1711), in which methylation levels were measured by pyrosequencing. A multiple linear regression was performed to determine the cross-sectional association between total PA and methylation levels with adjustment for potential confounders, including body mass index. A fixed-effects model was used in the meta-analysis. Correlations between total PA-associated DNA methylation and several inflammatory markers, such as high-sensitivity C-reactive protein, were also conducted.In the meta-analysis, nine CpG sites were significantly associated with total PA ( P1 × 10 -5 ). Among the nine sites, one site cg07030336 (annotated to VTI1A/ZDHHC6 gene) was successfully replicated ( P = 0.009).The current study showed that greater accelerometer-assessed total PA was associated with higher DNA methylation levels at cg07030336 ( VTI1A/ZDHHC6 ) in the general population. In addition, we found a divergent relationship between the methylation levels at cg07030336 and several inflammatory biomarkers.

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.

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.

BACKGROUND Expression of NKG2D ligand (NKG2DL) plays a major role as a "danger signal" on stressed cells to promote removal of the latter by NKG2D-expressing cytotoxic lymphocytes. NKG2DL expression has been found in peripheral immune cells as well, such as in macrophages; however, the effect of this expression is yet to be determined. METHODS We determined instrumental variables (IVs; R2 0.05), and the results were consistent across the sensitivity analyses. CONCLUSIONS Our study provide novel evidence associating NKG2DL expression with Graves' disease, an autoimmune thyroiditis; direction of the effect indicated the immunoregulatory role of MICA expression in PBMCs, suggesting the importance of further functional assays in inflammatory diseases.

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 2 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.

Purpose 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. Methods 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. Results In multivariate analysis, microvascular invasion (HR 2.34, P = 0.0327, 95%CI 1.072–5.117), intraoperative blood loss (HR 2.27, P = 0.0313, 95%CI 1.077–4.797), and hepatic clearance of the remnant liver (HR 0.48, P = 0.0174, 95%CI 0.266–0.880) were independently associated with overall survival. Hepatic clearance of the remnant liver (HR 0.63, P = 0.0398, 95%CI 0.411–0.979) was independently associated with recurrence free survival. Conclusions 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 in patient with hepatocellular carcinoma.

Background: The use of heated tobacco products (HTP) has increased exponentially in Japan since 2016; however, their effects on health remain a major concern. Methods: Tsuruoka Metabolome Cohort Study participants (n = 11,002) were grouped on the basis of their smoking habits as never smokers (NS), past smokers (PS), combustible tobacco smokers (CS), and HTP users for Results: Ten of the 17 genes were significantly hypomethylated in CS and HTP users compared with NS, among which AHRR, F2RL3, and RARA showed intermediate characteristics between CS and NS; nonetheless, AHRR expression was significantly higher in CS than in the other three groups. Conversely, LRRN3 and GPR15 were more hypomethylated in HTP users than in NS, and GPR15 expression was markedly upregulated in all the groups when compared with that in NS. Conclusions: HTP users (switched from CS Impact: This study provides new insights into the molecular genetic effects on DNAm and transcriptome profiles in HTP users who switched from CS.

Background: Physician attire influences perceptions of care. This study was conducted to evaluate the impact of physician attire on perceptions of care by patients and families in a Japanese palliative care unit. Methods: From November 2018 to February 2020, patients and family members admitted to the Palliative Care Unit at Jichi Medical University Hospital were recruited and completed a survey consisting of 4 demographic questions and 15 questions regarding perceptions of care. A 7-point Likert scale (1 = strongly agree, 4 = neutral, 7 = strongly disagree) was used to judge attire (name tag, long sleeve white coat, short sleeve white coat, scrubs, scrub color, jeans, sneakers) addressing patient and overall impact on perception of care. Results: Of 203 patients admitted, 79 were enrolled. Surveys were received from 23 patients and 52 family members. Patients and families want physicians to wear name tags (median, interquartile range) (2, 1-2) and white coats (3, 2-4). Patients want to be addressed by surnames (2, 1.5-4). Patients and family members have neutral opinions about short sleeve white coats (4, 4-4) and scrubs (4, 4-4). Jeans were not liked (4, 4-6) while sneakers are acceptable (3, 2-4). The impact of attire on perceptions of care is significantly (p = .04) greater for patients (3, 2-4) than family members (4, 3-4). Conclusion: Patients and family members prefer their physicians to wear name tags and white coats and address patients by surnames. Physician attire has a significantly greater impact on perceptions of care for patients than family members in a palliative care unit.

Peptic ulcer disease (PUD) refers to acid-induced injury of the digestive tract, occurring mainly in the stomach (gastric ulcer; GU) or duodenum (duodenal ulcer; DU). We conducted a large-scale cross-ancestry meta-analysis of PUD combining genome-wide association studies with four Japanese and two European studies (52,032 cases and 905,344 controls), and discovered 25 novel loci highly concordant across ancestries. Based on these loci, an examination of similarities and differences in genetic architecture between GU and DU demonstrated that GU shared the same risk loci as DU, although with smaller genetic effect sizes and higher polygenicity than DU, indicating higher heterogeneity of GU.H. pylori(HP)-stratified analysis found an HP-related host genetic locus, marking its role in HP-mediated PUD etiology. Integrative analyses using bulk and single-cell transcriptome profiles highlighted the genetic factors of PUD to be enriched in the highly expressed genes in stomach tissues, especially in somatostatin-producing D cells. Our results provide genetic evidence that gastrointestinal cell differentiations and hormone regulations are critical in PUD etiology.

This study aimed to develop an ancestry-specific polygenic risk scores (PRSs) for the prediction of breast cancer events in Japanese females and validate it in a longitudinal cohort study.Using publicly available summary statistics of female breast cancer genome-wide association study (GWAS) of Japanese and European ancestries, we, respectively, developed 31 candidate genome-wide PRSs using pruning and thresholding (P + T) and LDpred methods with varying parameters. Among the candidate PRS models, the best model was selected using a case-cohort dataset (63 breast cancer cases and 2213 sub-cohorts of Japanese females during a median follow-up of 11.9 years) according to the maximal predictive ability by Harrell's C-statistics. The best-performing PRS for each derivation GWAS was evaluated in another independent case-cohort dataset (260 breast cancer cases and 7845 sub-cohorts of Japanese females during a median follow-up of 16.9 years).For the best PRS model involving 46,861 single nucleotide polymorphisms (SNPs; P + T method with PThis study developed a breast cancer PRS for Japanese females and demonstrated the usefulness of the PRS for breast cancer risk stratification.

A meta-analysis suggests a relationship between abnormal glucose metabolism and primary open-angle glaucoma (POAG); however, the causal association between them remains controversial. We therefore conducted a Mendelian randomization (MR) study to assess the causal association between genetically predicted glycemic traits and the risk of POAG.Two-sample MR design.We examined the genetically predicted measures of fasting glucose, hemoglobin A1c (HbA1c), and fasting C-peptide, in relation to POAG. For the single nucleotide polymorphism (SNP)-exposure analyses, we meta-analyzed the study-level genome-wide associations of fasting glucose levels (n = 17,289; n of SNPs = 34), HbA1c (n = 52,802; n of SNPs = 43), and fasting C-peptide levels (n=1666; n of SNPs = 17) from the Japanese Consortium of Genetic Epidemiology studies. We used summary statistics from the BioBank Japan projects (n = 3980 POAG cases and 18,815 controls) for the SNP-outcome association.We observed no association of genetically predicted HbA1c and fasting C-peptide with POAG. The MR inverse-variance-weighted (IVW) odds ratios (ORs) were 1.44 (95% confidence interval [CI], 0.78-2.65; P = .25) for HbA1c (per 1% increment) and 0.92 (95% CI, 0.56-1.53; P = .76) for fasting C-peptide (per 2-fold increment). A significant association between fasting glucose (per 10 mg/dL-increment) and POAG was observed according to the MR IVW analysis (OR = 1.48 [95% CI, 1.10-1.79, P = .009]); however, sensitivity analyses, including MR-Egger and weighted-median methods, did not support this association (P.10).We did not observe strong evidence to support the association between genetically predicted glycemic traits and POAG in the Japanese population.

In many epidemiological studies, the dust extinction coefficient measured by light detection and ranging (LIDAR) is used as an indicator of exposure to Asian dust. However, few reports on the relationship between the distribution of total suspended particles (TSPs) near the ground surface and the dust extinction coefficient exist. In this study, we examined the relationship between the concentrations of TSPs near the ground surface, substances indicative of mineral content, and air pollutants that may be transported with Asian dust and dust extinction coefficients in two regions: Imizu and Yurihama-Matsue, from March to May in 2011 and 2013. In both years, large dust extinction coefficients were observed in Imizu and Matsue on days when the concentrations of TSPs and mineral content indicators were high near the ground surface in Imizu and Yurihama, and Asian dust was expected to be highly suspended. In both regions, the concentrations of TSPs and mineral content indicators were significantly positively correlated with the dust extinction coefficient. The concentrations of all air pollutants analyzed were significantly positively correlated with the dust extinction coefficient in each region in 2013, but not in 2011. These results suggest that the dust extinction coefficient is a useful indicator of Asian dust near the ground surface; however, as harmful air pollutants occasionally move with Asian dust, it is necessary to monitor these pollutants near the ground surface when conducting an epidemiological study on the health effect of airborne particles.

Background Cardiovascular disease (CVD) is a major cause of mortality worldwide. High-sensitivity cardiac troponin T (hs-cTnT) is released into the bloodstream due to cardiomyocyte damage and is associated with a high CVD risk. This study aimed to investigate hs-cTnT-related genetic variation and to examine whether this is an associated risk factor for CVD in the Japanese general population. Methods This was a genome-wide association study (GWAS) based on a cohort from the 2013 Tohoku Medical Megabank Project community study. The GWAS was performed using a HumanOmniExpressExome BeadChip array with 914,035 autosomal single-nucleotide polymorphisms. The Framingham Risk Score and the Suita score were used to evaluate the future risk of CVD. Results The GWAS identified 10 loci reaching suggestive significance in the discovery cohort. A replication analysis confirmed that one of the 10 loci, rs7798496, is associated with elevated hs-cTnT levels. The combined P value in the discovery and replication cohorts for the association between the rs7798496 and hs-cTnT levels was 3.4 × 10−8, which indicates that the novel variant reached genome-wide significance. The rs7798496 loci was located at an intergenic region between the retinoblastoma gene product (RB)-associated Kruppell-associated box (KRAB) zinc finger, zinc finger protein 890, and pseudogene (ZNF890P). Logistic regression analysis revealed that the presence of the rs7798496 T allele was strongly associated with a high risk for CVD. Conclusions This study provides insights into a link between a novel genetic variant, T allele of rs7798269, and elevated hs-cTnT levels as a future risk for CVD in the general Japanese population.

Differences in individual eating habits may be influenced by genetic factors, in addition to cultural, social or environmental factors. Previous studies suggested that genetic variants within sweet taste receptor genes family were associated with sweet taste perception and the intake of sweet foods. The aim of this study was to conduct a genome-wide association study (GWAS) to find genetic variations that affect confection consumption in a Japanese population. We analysed GWAS data on confection consumption using 14 073 participants from the Japan Multi-Institutional Collaborative Cohort study. We used a semi-quantitative FFQ to estimate food intake that was validated previously. Association of the imputed variants with confection consumption was performed by linear regression analysis with adjustments for age, sex, total energy intake and principal component analysis components 1–3. Furthermore, the analysis was repeated adjusting for alcohol intake (g/d) in addition to the above-described variables. We found 418 SNP located in 12q24 that were associated with confection consumption. SNP with the ten lowest P-values were located on nine genes including at the BRAP, ACAD10 and aldehyde dehydrogenase 2 regions on 12q24.12-13. After adjustment for alcohol intake, no variant was associated with confections intake with genome-wide significance. In conclusion, we found a significant number of SNP located on 12q24 genes that were associated with confections intake before adjustment for alcohol intake. However, all of them lost statistical significance after adjustment for alcohol intake.

Traditional observational studies have reported a positive association between higher body mass index (BMI) and the risk of colorectal cancer (CRC). However, evidence from other approaches to pursue the causal relationship between BMI and CRC is sparse. A two‐sample Mendelian randomization (MR) study was undertaken using 68 single nucleotide polymorphisms (SNPs) from the Japanese genome‐wide association study (GWAS) and 654 SNPs from the GWAS catalogue for BMI as sets of instrumental variables. For the analysis of SNP‐BMI associations, we undertook a meta‐analysis with 36 303 participants in the Japanese Consortium of Genetic Epidemiology studies (J‐CGE), comprising normal populations. For the analysis of SNP‐CRC associations, we utilized 7636 CRC cases and 37 141 controls from five studies in Japan, and undertook a meta‐analysis. Mendelian randomization analysis of inverse‐variance weighted method indicated that a one‐unit (kg/m2) increase in genetically predicted BMI was associated with an odds ratio of 1.13 (95% confidence interval, 1.06‐1.20; P value, Traditional observational studies reported a positive association between higher body mass index (BMI) and colorectal cancer (CRC) risk. However, these studies suffer from biases such as reverse causality and confounding. This Mendelian randomization study consistently showed that the genetically predicted higher BMI was associated with an increased risk of CRC in Japanese populations.

Type 2 Diabetes (T2D) is an emerging public health problem in Asia. Although ethnic specific mtDNA polymorphisms have been shown to contribute to T2D risk, the functional effects of the mtDNA polymorphisms and the therapeutic potential of mitochondrial-derived peptides at the mtDNA polymorphisms are underexplored. Here, we showed an Asian-specific mitochondrial DNA variation m.1382A>C (rs111033358) leads to a K14Q amino acid replacement in MOTS-c, an insulin sensitizing mitochondrial-derived peptide. Meta-analysis of three cohorts (n = 27,527, J-MICC, MEC, and TMM) show that males but not females with the C-allele exhibit a higher prevalence of T2D. In J-MICC, only males with the C-allele in the lowest tertile of physical activity increased their prevalence of T2D, demonstrating a kinesio-genomic interaction. High-fat fed, male mice injected with MOTS-c showed reduced weight and improved glucose tolerance, but not K14Q-MOTS-c treated mice. Like the human data, female mice were unaffected. Mechanistically, K14Q-MOTS-c leads to diminished insulin-sensitization in vitro. Thus, the m.1382A>C polymorphism is associated with susceptibility to T2D in men, possibly interacting with exercise, and contributing to the risk of T2D in sedentary males by reducing the activity of MOTS-c.

An unprecedented radical polymerization of various (meth)acrylates, diethyl acrylamide, and 4-vinylpyridine initiated by Lewis pair (LP) catalysts, specifically PPh3/Cu(OTf)2 or PPh3/Sn(OTf)2, is r...

Formalin‐fixed paraffin‐embedded (FFPE) tissues are promising biological resources for genetic research. Recent improvements in DNA extraction from FFPE samples allowed the use of these tissues for multiple sequencing methods. However, fundamental research addressing the application of FFPE‐derived DNA for targeted‐bisulfite sequencing (TB‐seq) is lacking. Here, we evaluated the suitability of FFPE‐derived DNA for TB‐seq. We conducted TB‐seq using FFPE‐derived DNA and corresponding fresh frozen (FF) tissues of patients with kidney cancer and compared the quality of DNA, libraries, and TB‐seq statistics between the two preservation methods. The approximately 600‐bp average fragment size of the FFPE‐derived DNA was significantly shorter than that of the FF‐derived DNA. The sequencing libraries constructed using FFPE‐derived DNA and the mapping ratio were approximately 10 times and 10% lower, respectively, than those constructed using FF‐derived DNA. In the mapped data of FFPE‐derived DNA, duplicated reads accounted for > 60% of the obtained sequence reads, with lower mean on‐target coverage. Therefore, the standard TB‐seq protocol is inadequate for obtaining high‐quality data for epigenetic analysis from FFPE‐derived DNA, and technical improvements are necessary for enabling the use of archived FFPE resources.

Individual eating habits may be influenced by genetic factors, in addition to environmental factors. Previous studies suggested that adherence to Japanese food patterns was associated with a decreased risk of all-cause and cardiovascular disease mortality. We conducted a genome-wide association study (GWAS) in a Japanese population to find genetic variations that affect adherence to a Japanese food pattern. We analyzed GWAS data using 14,079 participants from the Japan Multi-Institutional Collaborative Cohort study. We made a Japanese food score based on six food groups. Association of the imputed variants with the Japanese food score was performed by linear regression analysis with adjustments for age, sex, total energy intake, alcohol intake (g/day), and principal components 1–10 omitting variants in the major histocompatibility region. We found one SNP in the 14q11.2 locus that was significantly associated with the Japanese food score with P values

Background Renal cell carcinoma (RCC) is the fourteenth most common cancer worldwide, accounting for approximately 4% of all cancers. More than 70% of RCC are clear cell RCC (ccRCC). To date, no reliable biomarkers for the detection of ccRCC have been identified. The aim of this study was to identify blood-based DNA methylation (DNAm) markers for the early detection and treatment of ccRCC. Results To identify ccRCC-associated DNAm markers, we performed targeted bisulfite sequencing (TB-seq) and an epigenome-wide association study (EWAS) using whole blood-derived DNA from 50 ccRCC patients and 50 healthy controls in the discovery phase. EWAS was performed using a linear regression model. The analysis was adjusted for age, sex, and the estimated cell-type composition. In the replication phase, the accuracy of the identified ccRCC-associated CpGs was verified in 48 independent ccRCC patients and 48 healthy controls. We identified six ccRCC-associated hypomethylated CpGs in PCBD2/MTND4P12 in the discovery phase (p −8); four were reproducible in the replication phase (p −8). The sum of the DNAm levels at the six CpGs was a valid indicator of ccRCC both in the discovery phase (area under the receiver operating characteristic curve [AUC-ROC] = 0.922) and in the replication phase (AUC-ROC = 0.871). Moreover, the results of cis-expression quantitative methylation analysis suggested that the DNAm levels of the ccRCC-associated CpGs affect the gene expression of transcription factor 7 (TCF7) and voltage-dependent anion-selective channel 1 (VDAC1), which are involved in cancer progression. Conclusions In this study, we identified six ccRCC-associated CpGs in PCBD2/MTND4P12 by EWAS using blood-based DNA. We found that the DNAm levels of the six CpGs in PCBD2/MTND4P12 may be a potential biomarker for early ccRCC detection, but the value as a biomarker needs to be investigated in future studies.

Hepatic surgery is a rapidly expanding component of abdominal surgery and is performed for a wide range of indications. The introduction of laparoscopic cholecystectomy in 1987 was a major change in abdominal surgery. Laparoscopic surgery was widely and rapidly adopted throughout the world for cholecystectomy initially and then applied to a variety of other procedures. Laparoscopic surgery became regularly applied to hepatic surgery, including segmental and major resections as well as organ donation. Many operations progressed from open surgery to laparoscopy to robot-assisted surgery, including colon resection, pancreatectomy, splenectomy thyroidectomy, adrenalectomy, prostatectomy, gastrectomy, and others. It is difficult to prove a data-based benefit using robot-assisted surgery, although laparoscopic and robot-assisted surgery of the liver are not inferior regarding major outcomes. When laparoscopic surgery initially became popular, many had concerns about its use to treat malignancies. Robot-assisted surgery is being used to treat a variety of benign and malignant conditions, and studies have shown no deterioration in outcomes. Robot-assisted surgery for the treatment of malignancies has become accepted and is now being used at more centers. The outcomes after robot-assisted surgery depend on its use at specialized centers, the surgeon’s personal experience backed up by extensive training and maintenance of international registries. Robot-assisted hepatic surgery has been shown to be associated with slightly less intraoperative blood loss and shorter hospital lengths of stay compared to open surgery. Oncologic outcomes have been maintained, and some studies show higher rates of R0 resections. Patients who need surgery for liver lesions should identify a surgeon they trust and should not be concerned with the specific operative approach used. The growth of robot-assisted surgery of the liver has occurred in a stepwise approach which is very different from the frenzy that was seen with the introduction of laparoscopic cholecystectomy. This approach allowed the identification of areas for improvement, many of which are at the nexus of engineering and medicine. Further improvements in robot-assisted surgery depend on the combined efforts of engineers and surgeons.

Naked mole-rats (NMRs) have a very low spontaneous carcinogenesis rate, which has prompted studies on the responsible mechanisms to provide clues for human cancer prevention. However, it remains unknown whether and how NMR tissues respond to experimental carcinogenesis induction. Here, we show that NMRs exhibit extraordinary resistance against potent chemical carcinogenesis induction through a dampened inflammatory response. Although carcinogenic insults damaged skin cells of both NMRs and mice, NMR skin showed markedly lower immune cell infiltration. NMRs harbour loss-of-function mutations in RIPK3 and MLKL genes, which are essential for necroptosis, a type of necrotic cell death that activates strong inflammation. In mice, disruption of Ripk3 reduced immune cell infiltration and delayed carcinogenesis. Therefore, necroptosis deficiency may serve as a cancer resistance mechanism via attenuating the inflammatory response in NMRs. Our study sheds light on the importance of a dampened inflammatory response as a non-cell-autonomous cancer resistance mechanism in NMRs.

Background While there are a variety of surgical options for hypertrophic cardiomyopathy, there are small number of reports of transapical septal myectomy. Furthermore, the characteristics and incidence of anomalous structures in the left ventricle in hypertrophic cardiomyopathy patients which can be identified with imaging studies are not clear. Methods We studied hypertrophic cardiomyopathy patients who underwent transapical septal myectomy from July 2013 to December 2019. We evaluated the frequency and characteristics of anomalous structures in the left ventricle which had been identified by preoperative examinations and studied their postoperative results. Results A total of 59 patients was included. The median age was 40 years. Sixteen patients (27.4%) were in New York Heart Association Functional Classification III or IV. The median peak intraventricular gradient at rest was 65 mmHg. By preoperative imaging studies, anomalous structures were detected in 56 cases (94.9%), of which 88% were successfully resected with myectomy. There were two perioperative deaths, while one late death caused by acute myocardial infarction occurred. The estimated 5-year survival rate was 95%. The intraventricular gradient had significantly decreased at the time of discharge, and no reoperation for recurrent obstruction was conducted. The left ventricular ejection fraction had significantly decreased after the operation, was however within the normal range. Left atrium volume index and tricuspid regurgitant velocity significantly improved. Conclusions Patients receiving transapical septal myectomy restored good hemodynamics from early postoperative period and showed improved subjective symptoms and good mid-term results. With multimodal imaging studies, we could accurately identify anomalous structures in hypertrophic cardiomyopathy patients and reliably treat them by transapical septal myectomy.

In recent years, lifestyle-related diseases such as hypertension and diabetes have been on the rise. These conditions can cause serious conditions such as myocardial and cerebral infarctions. Therefore, proper control of blood pressure and blood glucose levels is important issues in preventive medicine. Traditional fermented foods have been shown to have various functions, and their effects on lifestyle-related diseases have attracted particular attention. In this study, we investigated the effects of fermented soybeans and rice bran (OE-1) and supplements containing OE-1 on blood glucose levels and weight changes. We identified an inhibitory effect on elevated blood glucose levels upon administration of OE-1, and this effect was thought to be due to digestive enzyme inhibition. These effects of foods containing OE-1 are expected to have a positive effect on the prevention and improvement of lifestyle-related diseases as health foods.

In the Tohoku Medical Megabank project, genome and omics analyses of participants in two cohort studies were performed. A part of the data is available at the Japanese Multi Omics Reference Panel (jMorp; https://jmorp.megabank.tohoku.ac.jp) as a web-based database, as reported in our previous manuscript published in Nucleic Acid Research in 2018. At that time, jMorp mainly consisted of metabolome data; however, now genome, methylome, and transcriptome data have been integrated in addition to the enhancement of the number of samples for the metabolome data. For genomic data, jMorp provides a Japanese reference sequence obtained using de novo assembly of sequences from three Japanese individuals and allele frequencies obtained using whole-genome sequencing of 8,380 Japanese individuals. In addition, the omics data include methylome and transcriptome data from ∼300 samples and distribution of concentrations of more than 755 metabolites obtained using high-throughput nuclear magnetic resonance and high-sensitivity mass spectrometry. In summary, jMorp now provides four different kinds of omics data (genome, methylome, transcriptome, and metabolome), with a user-friendly web interface. This will be a useful scientific data resource on the general population for the discovery of disease biomarkers and personalized disease prevention and early diagnosis.

Intraoperative bleeding from the pelvic venous structures is one of the most serious complications of total pelvic exenteration with distal sacrectomy. The purpose of this study was to investigate the topographic anatomy of these veins and the potential source of the bleeding in cadaver dissections. We dissected seven cadavers, focusing on the veins in the surgical resection line for total pelvic exenteration with distal sacrectomy. The presacral venous plexus and the dorsal vein complex are thin-walled, plexiform, and situated on the line of resection. The internal iliac vein receives blood from the pelvic viscera and the perineal and the gluteal regions and then crosses the line of resection as a high-flow venous system. It has abundant communications with the presacral venous plexus and the dorsal vein complex. The anatomical features of the presacral venous plexus, the dorsal vein complex, and the internal iliac vein make them highly potential sources of bleeding. Surgical management strategies must consider the anatomy and hemodynamics of these veins carefully to perform this procedure safely.

Communicating accessory bile ducts are defined as ducts that communicate between major biliary channels but do not drain individual segments of the liver. The Couinaud Type A communicating accessory bile duct is a rare anomaly where an aberrant duct connects the right main hepatic duct to the common hepatic duct without segmental drainage. There are very few reports of this anomaly in the literature to date. A 75-year-old male who died of ischemic heart disease donated his body for cadaveric dissection, which included careful attention to the anatomy of the hepatic hilum. During dissection, it was found that the right hepatic duct was duplicated and an accessory duct drained directly into the common hepatic duct. Although rare and difficult to visualize even with modern preoperative imaging techniques, sound knowledge of this rare anatomic variation is imperative to avoid inadvertent intraoperative biliary injuries which can lead to severe morbidity. An aberrant bile duct from the right hepatic duct to the common hepatic duct (Couinaud Type A) is an uncommon accessory bile duct that one must be aware of when performing complex hepatobiliary procedures such as right liver resection for living-related donation. Detailed preoperative imaging and careful dissection with anticipation of anomalous anatomy are of the utmost importance for the safe conduct of hepatic surgery.

The overwhelming majority of participants in current genetic studies are of European ancestry. To elucidate disease biology in the East Asian population, we conducted a genome-wide association study (GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 320 independent signals in 276 loci for 27 diseases, with 25 novel loci (P < 9.58 × 10-9). East Asian-specific missense variants were identified as candidate causal variants for three novel loci, and we successfully replicated two of them by analyzing independent Japanese cohorts; p.R220W of ATG16L2 (associated with coronary artery disease) and p.V326A of POT1 (associated with lung cancer). We further investigated enrichment of heritability within 2,868 annotations of genome-wide transcription factor occupancy, and identified 378 significant enrichments across nine diseases (false discovery rate < 0.05) (for example, NKX3-1 for prostate cancer). This large-scale GWAS in a Japanese population provides insights into the etiology of complex diseases and highlights the importance of performing GWAS in non-European populations.

Background and Purpose— Environmental and genetic factors contribute to the development of ischemic stroke (IS). We recently developed a genome-wide polygenic risk score (PRS) for IS using case-control datasets from 4 large-scale observational studies conducted in Japan. Our objective in the present study was to confirm the association between the PRS and the risk of IS with data from an independent prospective cohort recruited from the general Japanese population. Methods— A total of 3038 subjects aged ≥40 years were followed up for 10 years (2002–2012). The genome-wide PRS was calculated using genotype data from >350 000 single-nucleotide polymorphisms. The PRS levels were divided into quintiles. High and low genetic risk groups were defined as top 60% and bottom 40% of PRS, respectively. The hazard ratio (HR) for the development of IS was estimated using a Cox proportional hazards model. Results— During the follow-up period, 91 cases developed first-ever IS. The age- and sex-adjusted HR for IS increased with higher PRS levels ( P for trend, 0.03). Subjects with the highest quintile level of PRS had a 2.44-fold (95% CI, 1.16–5.12) greater risk for IS than those with the lowest quintile level after adjusting for age and sex. A similar association was observed after adjusting for environmental risk factors ( P for trend, 0.03). As compared with low genetic risk group, the age- and sex-adjusted HR in high genetic risk group was 1.63 (95% CI, 1.04–2.55), which was comparable to the HR of hypertension (HR, 1.41), diabetes mellitus (HR, 1.72), and smoking (HR, 1.54). The age- and sex-adjusted HR increased with the number of environmental risk factors in both high and low genetic risk groups without significant interaction. Conclusions— A high genome-wide PRS was a significant risk factor for IS independent of environmental risk factors in a general Japanese population. This finding suggests that PRS may be useful to identify individuals at a high risk of IS.

In surgery, both antiperitoneal adhesion barriers and hemostats with high efficiency and excellent handling are necessary. However, antiadhesion and hemostasis have been examined separately. In this study, six different ultrapure alginate bilayer sponges with thicknesses of 10, 50, 100, 200, 300, and 500 μm were fabricated via lyophilization and subsequent mechanical compression. Compression significantly enhanced mechanical strength and improved handling. Furthermore, it had a complex effect on dissolution time and contact angle. Therefore, the 100 μm compressed sponge showed the highest hemostatic activity in the liver bleeding model in mice, whereas the 200 μm sponge demonstrated the highest antiadhesion efficacy among the compressed sponges in a Pean crush hepatectomy-induced adhesion model in rats. For the first time, we systematically evaluated the effect of sponge compression on foldability, fluid absorption, mechanical strength, hemostatic effect, and antiadhesion properties. The optimum thickness of an alginate bilayer sponge by compression balances antiperitoneal adhesion and hemostasis simultaneously.

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.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.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;Long-term echo follow-up demonstrates good results of mitral valve repair for extreme billowing and prolapsing valves using our strategy.

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.

BackgroundParadoxically, 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. Present study examines whether HP+ individuals have a lower likelihood of death from cancer than those who are HP-.Methods and findingsProspective cohort data (n = 4,982 subjects enrolled in the DAIKO study between 2008-2010) was used to assess whether anti-HP antibody status as a surrogate for past-present HP infection was associated with cancer incidence. The median age in the primary registry was 53 years-old (range 34-69 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; 99.97%). The number of HP+ and HP- individuals was 1,826 (37%) and 3,156 (63%), respectively. Anti-HP antibody distribution per birth year revealed that earlier birth year was associated with higher HP+ rates. To remove confounding factors associated with birth year, a birth year-matched cohort (n = 3,376) was generated for subsequent analyses. 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). Strikingly, we found that HP+ individuals who developed cancer had a better survival rate than would be expected based on cancer incidence. These results suggest that cancer patients who are HP+ may have a higher likelihood of survival than those who are HP-. 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.ConclusionsPotential systemic effects of HP+ status may contribute to reduced likelihood of death for patients with cancer.Data Availability StatementThe data cannot be shared publicly as data sharing is not permitted according to Japanese Government data protection policies. Requests for data analysis may be accepted anonymously and conditionally upon IRB approval from Iwate Medical University and Nagoya University Graduate School of Medicine.FundingThis study is supported by Grants-in-Aid for Scientific Research for Priority Areas of Cancer (No. 17015018); Grants-in-Aid for Innovative Areas (No. 221S0001); and the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant (No. 19K09130 and No. 16H06277 [CoBiA]) from the Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Competing interestsThe authors declare that no competing interests exist.Author summaryWhy was this study done?> Although HP infection is a major cause of gastric diseases including cancer, how HP infection affects prolonged survival of advanced gastric cancer patients is unknown.> Reports of studies carried out in different countries and regions revealed that advanced gastric cancer patients who are HP+ exhibited prolonged post-treatment survival, even though the genetic background of patients, HP strains, and cancer treatment procedures differed.> Since most advanced gastric cancer patients underwent gastrectomy, the favorable prognosis of HP+ patients after multidisciplinary treatment may be due to putative systematic mechanisms associated with HP infection.> If putative systemic mechanisms associated with HP infection reduce the likelihood of death due to cancer, the cancer survival rate in the HP+ population should be lower than that for the HP- population.What did the researchers do and find?> Using data from the DAIKO prospective cohort study in Nagoya, Japan, we analyzed the association between anti-HP antibody status, cumulative cancer incidence and all-cause and cancer-specific deaths.> The HP+ rate increased as birth year decreased. Thus, matching based on birth year between 1935 and 1975 was performed to correct for confounding factors associated with birth year.> Despite a significantly higher all-cancer incidence for HP+ individuals compared to those who were HP-, no difference in the all-cause and cancer death rate was observed between HP+ and HP- individuals.What do these findings mean?> HP+ individuals are less susceptible to death relative to their incidence of cancer.> Patients with advanced stage cancer who are HP+ may have a better treatment response/tolerance than those who are HP-.> Additional longitudinal analyses are warranted to evaluate the effect of HP+ status on prolonged survival of patients with advanced-stage cancer.