Serum biomarker monitoring is essential for management of germ-cell tumors (GCT). However, not all GCT are positive for conventional tumor markers. We examined whether serum N-glycan-based biomarkers can be applied for detection and prognosis in patients with GCT. We performed a comprehensive N-glycan structural analysis of sera from 54 untreated GCT patients and 103 age-adjusted healthy volunteers using glycoblotting methods and mass spectrometry. Candidate N-glycans were selected from those with the highest association; cutoff concentration values were established, and an N-glycan score was created based on the number of positive N-glycans present. The validity of this score for diagnosis and prognosis was analyzed using a receiver operating characteristic (ROC) curve. We identified five candidate N-glycans significantly associated with GCT patients. The accuracy of the N-glycan score for GCT was significant with an area-under-the-curve (AUC) value of 0.87. Diagnostically, the N-glycan score detected 10 of 12 (83%) patients with negative conventional tumor markers. Prognostically, the N-glycan score comprised four candidate N-glycans. The predictive value of the prognostic N-glycan score was significant, with an AUC value of 0.89. A high value prognostic N-glycan score was significantly associated with poor prognosis. Finally, to identify a potential carrier protein, immunoglobulin (Ig) fractions of sera were subjected to N-glycan analysis and compared to whole sera. Candidate N-glycans in Ig-fractions were significantly decreased; therefore, the carrier protein for candidate N-glycans is likely not an immunoglobulin. In summary, our newly developed N-glycan score seems to be a practical diagnostic and prognostic method for GCT.

Suppression of gastric acid by proton pump inhibitors is associated with the increase of Lactobacillus in human gut microbiota. Gastric acid secretion is also suppressed by Helicobacter pylori infection and following atrophic gastritis. However, few studies have examined the association between H. pylori infection and Lactobacillus species in gut microbiota particularly in Japan.

This cross-sectional study sought to determine the neck-shoulder stiffness/low back pain (NSS/LBP) comorbidity rate in a Japanese community population and to compare the quality of life (QOL) in individuals with comorbid NSS/LBP, asymptomatic individuals, and those with symptoms of NSS or LBP alone.

Owing to increasing medical expenses, researchers have attempted to detect clinical signs and preventive measures of diseases using electronic health record (EHR). In particular, time-series EHRs collected by periodic medical check-up enable us to clarify the relevance among check-up results and individual environmental factors such as lifestyle. However, usually such time-series data have many missing observations and some results are strongly correlated to each other. These problems make the analysis difficult and there exists strong demand to detect clinical findings beyond them. We focus on blood test values in medical check-up results and apply a time-series analysis methodology using a state space model. It can infer the internal medical states emerged in blood test values and handle missing observations. The estimated models enable us to predict one's blood test values under specified condition and predict the effect of intervention, such as changes of body composition and lifestyle. We use time-series data of EHRs periodically collected in the Hirosaki cohort study in Japan and elucidate the effect of 17 environmental factors to 38 blood test values in elderly people. Using the estimated model, we then simulate and compare time-transitions of participant's blood test values under several lifestyle scenarios. It visualizes the impact of lifestyle changes for the prevention of diseases. Finally, we exemplify that prediction errors under participant's actual lifestyle can be partially explained by genetic variations, and some of their effects have not been investigated by traditional association studies.

Cigarette smoking affects the oral microbiome, which is related to various systemic diseases. While studies that investigated the relationship between smoking and the oral microbiome by 16S rRNA amplicon sequencing have been performed, investigations involving metagenomic sequences are rare. We investigated the bacterial species composition in the tongue microbiome, as well as single-nucleotide variant (SNV) profiles and gene content of these species, in never and current smokers by utilizing metagenomic sequences. Among 234 never smokers and 52 current smokers, beta diversity, as assessed by weighted UniFrac measure, differed between never and current smokers (pseudo-F = 8.44, R2 = 0.028, p = 0.001). Among the 26 species that had sufficient coverage, the SNV profiles of Actinomyces graevenitzii, Megasphaera micronuciformis, Rothia mucilaginosa, Veillonella dispar, and one Veillonella sp. were significantly different between never and current smokers. Analysis of gene and pathway content revealed that genes related to the lipopolysaccharide biosynthesis pathway in Veillonella dispar were present more frequently in current smokers. We found that species-level tongue microbiome differed between never and current smokers, and 5 species from never and current smokers likely harbor different strains, as suggested by the difference in SNV frequency.

This study aimed (1) to assess serum trace elements concentrations and hematological parameters, (2) to evaluate the sex differences in the associations between serum trace elements levels and hematological parameters, and (3) to identify the associations between serum trace elements concentrations and risk of anemia among Japanese community dwellers. This is a community-based cross-sectional study that utilized the data of the 2014 Iwaki Health Promotion Project. Participants were 1176 community dwellers (>18 years) residing in the Iwaki District, Aomori Prefecture, Japan. We assessed the data of serum trace elements concentrations of cadmium (Cd), cobalt (Co), copper (Cu), selenium (Se), zinc (Zn), and iron (Fe) as well as the hematological parameters of red blood cells (RBC) counts, hemoglobin, packed cells volume (PCV), mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH). Serum concentrations of Zn (871.5 μg/L vs. 900.1 μg/L) and Fe (946.8 μg/L vs. 1096.1 μg/L) were significantly lower in females than in males, while serum concentrations of Co (0.4 μg/L vs. 0.3 μg/L) and Cu (1062.4 μg/L vs. 965.3 μg/L) were significantly higher in females. By multivariate linear regression, serum Se concentration was significantly, positively associated with PCV (β = 1.04; 95% confidence interval (CI): 0.17, 1.92; p = 0.016) among the study participants. Serum Zn also had positive associations with hemoglobin (β = 0.42; 95% CI: 0.07, 0.77; p = 0.020), PCV (β = 1.79; 95% CI: 0.78, 2.81; p < 0.001), and RBCs count (β = 15.56; 95% CI: 7.31, 31.69; p = 0.002). On the other hand, serum Co concentration was negatively associated with the hematological parameters, particularly in females. Moreover, serum Zn concentration had a decreased risk of anemia (lowest vs. highest quartiles: odds ratio (OR) = 0.42; 95% CI: 0.23, 0.76; p = 0.005) while higher Co concentrations had an increased risk of anemia (lowest vs. highest quartiles: OR = 1.95; 95% CI: 1.04, 3.67; p = 0.037). However, no significant association was found between serum Cu level and hematological parameters. There were substantial sex differences in serum trace elements, implying that trace elements metabolism differed between males and females. Zn can play a protective role in the development of anemia. Surprisingly, increased Co concentration increased the risk of anemia among our study population, which called for further studies to confirm and to consider for speciation analysis.

For large-scale metabolomics, such as in cohort studies, normalization protocols using quality control (QC) samples have been established when using data from gas chromatography and liquid chromatography coupled to mass spectrometry. However, normalization protocols have not been established for capillary electrophoresis-mass spectrometry metabolomics. In this study, we performed metabolome analysis of 314 human plasma samples using capillary electrophoresis-mass spectrometry. QC samples were analyzed every 10 samples. The results of principal component analysis for the metabolome data from only the QC samples showed variations caused by capillary replacement in the first principal component score and linear variation with continuous measurement in the second principal component score. Correlation analysis between diagnostic blood tests and plasma metabolites normalized by the QC samples was performed for samples from 188 healthy subjects who participated in a Japanese population study. Five highly correlated pairs were identified, including two previously unidentified pairs in normal healthy subjects of blood urea nitrogen and guanidinosuccinic acid, and gamma-glutamyl transferase and cysteine glutathione disulfide. These results confirmed the validity of normalization protocols in capillary electrophoresis-mass spectrometry using large-scale metabolomics and comprehensive analysis.

The aim of this work was to investigate the effect of age on the association between daily gait speed (DGS) and abdominal obesity defined by visceral fat area (VFA). A cross-sectional study was performed using data from an annual community-based health check-up. A total of 699 participants aged 20-88 years were enrolled in this analysis. DGS was assessed using tri-axial accelerometers worn for ≥ 7 days with at least 10 measuring hours each day. VFA was measured using a visceral fat meter. Since DGS differed significantly with age, the participants were divided into two groups: younger adults (YA), aged 20-49 years, and older adults (OA), aged 50-88 years. The association between DGS and VFA differed significantly with age (r = 0.099 for YA and r =  - 0.080 for OA; test for difference between correlation coefficients, P = 0.023). In OA, the adjusted odds ratio of abdominal obesity (VFA ≥ 100 cm2) was 0.40 (95% confidence interval 0.18, 0.88, P = 0.022) for the highest DGS quartile (DGS ≥ 1.37 m/s) compared to that for the lowest quartile (DGS < 1.11 m/s), whereas no significant association was found in YA. These data could aid in raising awareness of the self-management of obesity via DGS monitoring, especially in OA.

Atomic oxygen (AO) is the main component of the residual atmosphere in a low Earth orbit. AO with a translational energy of 5 eV colliding with artificial satellites forms nano- and microscale protrusions on polymeric materials. This study investigated the influences of AO (fluence and velocity distribution) and a polymer's chemical structure on such surface morphologies. The correlations between samples' mass losses and positions in the irradiation field of an AO beam were analyzed with polyimide (Kapton) films, a standard reference material for AO fluence measurements. The characterizations of polyethylene (PE), polypropylene (PP), and polystyrene (PS) films were studied using gel permeation chromatography and X-ray diffraction. The sample surfaces were observed using a field emission scanning electron microscope. Nanoscale protrusions were formed on all the samples and were larger but fewer with increasing AO fluence. The numerical density of protrusions formed on PE and PP was lower than that on PS. However, the erosion yields and functional groups of PE, PP, and PS were similar per FT-IR spectra.

White matter lesions (WML) commonly occur in older brains and are quantifiable on MRI, often used as a biomarker in Aging research. Although algorithms are regularly proposed that identify these lesions from T2-fluid-attenuated inversion recovery (FLAIR) sequences, none so far can estimate lesions directly from T1-weighted images with acceptable accuracy. Since 3D T1 is a polyvalent and higher-resolution sequence, it could be beneficial to obtain the distribution of WML directly from it. However a serious difficulty, both for algorithms and human, can be found in the ambiguities of brain signal intensity in T1 images. This manuscript shows that a cross-domain ConvNet (Convolutional Neural Network) approach can help solve this problem. Still, this is non-trivial, as it would appear to require a large and varied dataset (for robustness) labelled at the same high resolution (for spatial accuracy). Instead, our model was taught from two-dimensional FLAIR images with a loss function designed to handle the super-resolution need. And crucially, we leveraged a very large training set for this task, the recently assembled, multi-sites Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD) cohort. We describe the two-step procedure that we followed to handle such a large number of imperfectly labeled samples. A large-scale accuracy evaluation conducted against FreeSurfer 7, and a further visual expert rating revealed that WML segmentation from our ConvNet was consistently better. Finally, we made a directly usable software program based on that trained ConvNet model, available at https://github.com/bthyreau/deep-T1-WMH.

Germ cell tumors are highly susceptible to chemotherapy; however, there is a lack of established treatments for consistently relapsing germ cell tumor. Therefore, in this phase II study, we evaluated the efficacy and safety of nivolumab for relapsed germ cell tumor.

The gut microbiota is reported to be related to obesity, and visceral fat is reported to be strongly associated with cardiovascular disease and overall mortality. However, the association between the gut microbiota and obesity has mainly been studied using body mass index (BMI) as a proxy for obesity. We investigated the relationship of both visceral fat and BMI with the gut microbiota stratified by sex in a population-based cross-sectional study of Japanese men and women 20-76 years of age (n = 1001). Women with a higher visceral fat area (VFA) harboured a higher relative abundance of the Firmicutes phylum (P for trend <0.001) and a lower relative abundance of the Bacteroidetes phylum (P for trend 0.030), whereas men with higher VFA harboured a lower relative abundance of the Firmicutes phylum (P for trend 0.076) and a higher relative abundance of the Bacteroidetes phylum (P for trend 0.013). Similar results were obtained using BMI as an index, but the differences were not significant in men. At the genus level, Blautia was the only gut microbe significantly and inversely associated with VFA regardless of sex. In conclusion, at the genus level we found that Blautia was the only gut microbe significantly and inversely associated with VFA, regardless of sex.

Oral frailty or the loss of oral functionality can be a symptomatic precursor of overall frailty. Previous studies have suggested that decreased tongue pressure causes a decline in ingesting and swallowing function and poor nutrition. This study investigated what factor(s) contribute to tongue pressure, thereby leading to frailty.

The aim of this study was to confirm determinative factors for plasma Aβ and its association with cognitive function.

The burden of dementia is growing rapidly and has become a medical and social problem in Japan. Prospective cohort studies have been considered an effective methodology to clarify the risk factors and the etiology of dementia. We aimed to perform a large-scale dementia cohort study to elucidate environmental and genetic risk factors for dementia, as well as their interaction.

Atomic oxygen (AO) is one of the dominant components of the residual atmosphere in low Earth orbit. AO collides with spacecraft with a translational energy of 5 eV, forming nanoscale protrusions on polymeric materials. To clarify the influences of a polymer's chemical structure on the formation of AO-induced microstructures, this study investigated the size of free-volume holes and the layer thickness that interacted with AO for polyethylene (PE), polypropylene (PP), and polystyrene (PS) by positron annihilation lifetime spectroscopy. The injection energies of positrons varied from 1.3 to 10 keV to adjust the injection depth (range) into the polymers (40 nm-1.6 μm). For the pristine films, the lifetime of ortho-positronium (o-Ps, τ3) was longer in the order of PS, PP, and PE regardless of the injection energy of positrons, showing the different sizes of free-volume holes with radii of 0.29, 0.31, and 0.32 nm, respectively. The fraction of the decay component corresponding to o-Ps in all decay components (relative intensity of o-Ps, I3) was used to investigate the chemical change induced by AO exposure. The I3 values for the three polymers were decreased by AO exposure of (2-5) × 1018 atoms/cm2 or more at a depth of 40-48 nm, obtained by 1.3 keV positrons. This indicates that AO formed polar groups (i.e., an oxidized layer) on the polymer surfaces. The maximum depths of such chemical change for PE and PP were deeper than that for PS. The different sizes of free-volume holes would affect the diffusion or ballistic penetration of AO, resulting in the difference in the oxidized layers' thicknesses and surface morphologies.

Nanoparticle-based drug delivery systems (DDS) have been developed as effective diagnostic and low-dose imaging agents. Nano-imaging agents with particles greater than 100 nm are difficult to accumulate in pancreatic cancer cells, making high-intensity imaging of pancreatic cancer challenging. Peptides composed of histidine and glycine were designed and synthesized. Additionally, aqueous peptide solutions were irradiated with γ-rays to produce peptide nanogels with an average size of 25-53 nm. The mechanisms underlying radiation-mediated peptide crosslinking were investigated by simulating peptide particle formation based on rate constants. The rate constants for reactions between peptides and reactive species produced by water radiolysis were measured using pulse radiolysis. HGGGHGGGH (H9, H-histidine; G-glycine) particles exhibited a smaller size, as well as high formation yield, stability, and biodegradability. These particles were labeled with fluorescent dye to change their negative surface potential and enhance their accumulation in pancreatic cancer cells. Fluorescent-labeled H9 particles accumulated in PANC1 human pancreatic cancer cells, demonstrating that these particles are effective nano-imaging agents for intractable cancers.

In this study, we investigated the impact of single nucleotide polymorphisms in solute carrier (SLC) transporters, that is, SLC22A7 c.1586 + 206A > G, SLC22A2 c.808G > T, SLC22A3 c.1233G > A, SLC47A1 c.922-158G > A, and SLC47A2 c.-130G > A, on serum creatinine (SCr) concentrations. This cross-sectional study included residents who participated as volunteers in a health promotion study. Lifestyle data, blood chemical analysis data, and SLC gene polymorphism information were collected from each participant. Univariate analyses were carried out to determine differences between groups and correlations in SCr. Stepwise multiple regression analysis was performed to confirm the independence of factors that were significantly different in the univariate analyses. In multiple regression analyses, muscle mass, serum cystatin C concentrations, body fat percentage, serum albumin concentrations, and SLC47A2 c.-130G/G had the highest contribution to SCr concentrations, in that order (standardized regression coefficients = .505, .332, -.234, .123, and .084, respectively). The final model explained 72.2% of the variability in SCr concentrations. The SLC47A2 c.-130G > A polymorphism may affect creatinine dynamics in the proximal tubules. Further studies are needed to determine the effects of SLC transporter gene polymorphisms on SCr concentrations in patients with various diseases in real-world clinical settings.

Sex-specific differences in the incidence of urinary bladder carcinomas are well known, and the possible involvement of sex steroids has been proposed. We previously reported the association of the loss of androgen receptors and androgen-producing enzymes with tumor progression of urinary bladder cancer patients. Clinically, the selective estrogen receptor modulators (SERMs) were reported to suppress the progression of these tumors but the status of estrogen receptors (ERs) has not been well studied in patients with bladder urinary cancer. Moreover, not only ERs but also estrogen-related enzymes, such as aromatase, steroid sulfatase (STS), and estrogen sulfotransferase (EST), have been reported in the biological/clinical behavior of various hormone-dependent carcinomas but not studied in urinary bladder carcinoma. Therefore, in this study, we immunolocalized ERs as well as estrogen metabolizing enzymes in urinary bladder carcinoma and performed immunoblotting and cell proliferation assays using the bladder urothelial carcinoma cell line, T24. The results revealed that the loss of STS and aromatase was significantly correlated with advanced stages of the carcinoma. In vitro studies also revealed that T24 cell proliferation rates were significantly ameliorated after treatment with estradiol or diarylpropionitrile (DPN). EST and aromatase were also significantly correlated with the nuclear grade of the carcinoma. The results of our present study, for the first time, demonstrated that biologically active estrogens that bind to ERs could suppress tumor progression and the inactive ones could promote its progression and the potential clinical utility of SERM treatment in selective patients with urinary bladder carcinoma.

Normal-high HbA1c levels are a risk factor for attenuated pain sensation in normoglycemic subjects. It is unclear, however, what mechanisms underlie the pathogenesis of attenuated pain sensation in such a population. We, therefore, explored the relationship between oxidative stress (OS) and pain sensation in a rural Japanese population. A population-based study of 894 individuals (average age 53.8 ± 0.5 years) and 55 subjects with impaired fasting glucose (IFG) were enrolled in this study. Individuals with diabetes were excluded. Relationships between pain threshold induced by intraepidermal electrical stimulation (PINT) and clinico-hematological parameters associated with OS were evaluated. Univariate linear regression analyses revealed age, BMI, HbA1c, the OS biomarker urine 8-hydroxy-2'-deoxyguanosine (8-OHdG), systolic blood pressure, and decreased Achilles tendon reflex on the PINT scores. Adjustments for age, gender, and multiple clinical measures confirmed a positive correlation between PINT scores and urine 8-OHdG (β = 0.09, p < 0.01). Urine 8-OHdG correlated positively with higher HbA1c levels and age in the normoglycemic population. Unlike in the normoglycemic population, both inflammation and OS were correlated with elevated PINT scores in IFG subjects. OS may be a major contributing factor to elevated PINT scores in a healthy Japanese population.