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We developed and validated a new staging system that includes metabolic information from pretreatment [18F]Fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) for predicting disease-specific survival (DSS) in gastric cancer (GC) patients. Overall, 731 GC patients undergoing preoperative [18F]FDG PET/CT were enrolled and divided into the training (n = 543) and validation (n = 188) cohorts. A metabolic score (MS) was developed by combining the maximum standardized uptake value (SUVmax) of the primary tumor (T_SUVmax) and metastatic lymph node (N_SUVmax). A new staging system incorporating the MS and tumor-node-metastasis (TNM) stage was developed using conditional inference tree analysis. The MS was stratified as follows: score 1 (T_SUVmax ≤ 4.5 and N_SUVmax ≤ 1.9), score 2 (T_SUVmax > 4.5 and N_SUVmax ≤ 1.9), score 3 (T_SUVmax ≤ 4.5 and N_SUVmax > 1.9), and score 4 (T_SUVmax > 4.5 and N_SUVmax > 1.9) in the training cohort. The new staging system yielded five risk categories: category I (TNM I, II and MS 1), category II (TNM I, II and MS 2), category III (TNM I, II and MS ≥ 3), category IV (TNM III, IV and MS ≤ 3), and category V (TNM III, IV and MS 4) in the training cohort. DSS differed significantly between both staging systems; the new staging system showed better prognostic performance in both training and validation cohorts. The MS was an independent prognostic factor for DSS, and discriminatory power of the new staging system for DSS was better than that of the conventional TNM staging system alone.

The FKBP5 gene is known to have an important role in alcohol use disorder (AUD) in response to stress and has been reported to affect stress responses by interacting with childhood trauma. This study investigated the effects of the FKBP5 polymorphism rs1360780 and childhood trauma on trait resilience in male patients with AUD. In addition, allele-specific associations between FKBP5 DNA methylation and resilience were examined. In total, 297 men with AUD were assessed for alcohol use severity, childhood trauma, resilience, and impulsivity. Genotyping for FKBP5 rs1360780 and DNA methylation were analyzed. The effects of the rs1360780 single nucleotide polymorphism (SNP) and clinical variables on resilience were tested using linear regression analysis. Possible associations between FKBP5 DNA methylation and resilience were tested with partial correlation analysis. The rs1360780 risk allele, a low education level, and high impulsivity were associated with diminished resilience, whereas no significant main or interaction effect of childhood trauma with the SNP rs1360780 genotype on resilience was shown. No significant association between FKBP5 DNA methylation and resilience was found. The present study demonstrated the involvement of the rs1360780 risk allele in trait resilience in men with AUD, suggesting that the genetic vulnerability of FKBP5 may influence resilience related to AUD.

Cerebrovascular disease is a potential risk factor for Alzheimer's disease (AD). Although acute cerebral hypoperfusion causes neuronal necrosis and infarction, chronic cerebral hypoperfusion induces apoptosis in neurons, but its effects on the cognitive impairment are not clear. The purpose of this study was to evaluate the effects of chronic cerebral hypoperfusion on AD pathology and cerebral glucose metabolism. A model of chronic cerebral hypoperfusion was established by ligating the common carotid arteries bilaterally in adult male rats (CAL group). Sham-operated rats underwent the same procedures without artery ligation (control group). At 12 weeks after ligation, expression levels of amyloid-β (Aβ) and hyperphosphorylated tau (p-tau), as well as the regional cerebral glucose metabolism, were evaluated using Western blots and positron emission tomography with fluorine-18 fluorodeoxyglucose, respectively. The expression levels of Aβ in the frontal cortex and hippocampus and of p-tau in the temporal cortex were significantly higher in the CAL group than those in the control group. The cerebral glucose metabolism of the amygdala, entorhinal cortex, and hippocampus was significantly decreased in the CAL group compared to that in the control. These results suggest that chronic cerebral hypoperfusion can induce AD pathology and may play a significant role in AD development.

[18F]Fluorodeoxyglucose ([18F]FDG) Positron emission tomography/computed tomography (PET/CT) is commonly used for rectal cancer staging, but improved diagnostic methods for nodal metastases are needed. We aimed to evaluate whether the combination model of the metabolic tumor volume of primary tumor (T_MTV) and maximum standardized uptake value of lymph node (N_SUVmax) on pretreatment [18F]FDG PET/CT could improve nodal metastases prediction in rectal cancer. We enrolled a total of 166 rectal cancer patients who underwent pretreatment [18F]FDG PET/CT and surgical resection without neoadjuvant treatment between January 2009 and August 2016. Visual and semiquantitative PET/CT parameters were obtained. Associations between clinicopathological, PET/CT-derived variables and nodal metastases were evaluated by logistic regression analysis. Nodal metastases were confirmed histologically in 68 of the 166 patients (41%). Uni- and multivariate analyses demonstrated T_MTV and N_SUVmax were independent predictive factors for nodal metastases. The c-statistics of the combination model was 0.806 (Standard Error, 0.034; 95% Confidence Interval, 0.737–0.863), which showed significant improvement compared to T_MTV (0.698, P = 0.0002) or N_SUVmax (0.720, P = 0.0008) alone. T_MTV and N_SUVmax are independently correlated with nodal metastases. Furthermore, the combination model showed improved performance for risk prediction; thus, [18F]FDG PET/CT might have a role in rectal cancer staging and treatment planning.

We aimed to investigate the prognostic value of the metabolic parameters of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) in classical rectal adenocarcinoma (CRAC). We retrospectively reviewed 149 patients with CRAC who underwent preoperative 18F-FDG PET/CT at initial diagnosis followed by curative surgical resection. 18F-FDG PET/CT metabolic parameters including maximum standardized uptake value (SUVmax), metabolic tumour volume (MTV), and total lesion glycolysis (TLG) for disease-free survival (DFS) and overall survival (OS) were evaluated for prognostic significance by univariate and multivariate analyses, along with conventional risk factors including pathologic T (pT) stage, lymph node (LN) metastasis, lymphovascular invasion (LVI), perineural invasion (PNI), and preoperative carcinoembryonic antigen (CEA) level. On univariate analysis, high pT stage, positive LN metastasis, LVI, PNI, MTV, and TLG were significant prognostic factors affecting DFS (all P

Alcohol use disorder (AUD) is a chronic and relapsing disease with a substantial genetic influence. Given the recent discovery of the association of PPM1G methylation with alcohol use disorder (AUD) from a genome-wide methylation study, we sought to verify and extend the previous work of AUD-related impulsivity in a Korean population with AUD. A total of 244 men with AUD were assessed for psychological characteristics and behavioral impulsivity using stop signal task (response inhibition) and Balloon Analog Risk Task (risk-taking). Leukocyte DNA methylation at PPM1G was quantified using pyrosequencing. The effects of PPM1G methylation on severity of problematic drinking measured by Alcohol Use Disorder Identification Test (AUDIT) and multidimensional impulsivity were tested using linear regression analyses. Hypermethylation of PPM1G was significantly associated with risk-taking propensity among men with AUD. No significant association of PPM1G methylation was found to be associated with AUDIT scores and response inhibition. Our findings indicate that altered methylation of PPM1G may influence the impulsive choice of risk-taking in AUD. Further research is required in order to determine the role of PPM1G in the pathophysiology of AUD and multidimensional impulsivity.

Early life stress (ELS) leads to increased susceptibility to serious psychiatric problems such as alcohol dependence, but the mechanisms through which ELS affects alcohol dependence are unclear. We investigated the mediating role of multi-dimensional impulsivity in the associations between ELS and alcohol dependence. 330 male patients with alcohol dependence (mean age = 48.39) completed self-rating scales of ELS and several self-report measures of impulsivity as well as balloon analogue risk task (BART). After classifying different dimensions of impulsivity using factor analysis, structural equation modeling was conducted to test the mediation effects of impulsivity between ELS and alcohol dependence severity and social onset of hazardous drinking. Among the participants, 64.8%, 42.1% and 47.9% reported at least one episode of childhood maltreatment, sexual abuse and parental conflict, respectively. Response impulsivity-sensation seeking, reflection impulsivity and aggression partially mediated the association between ELS and severity of alcohol dependence (CFI = 0.902 and RMSEA = 0.079). Reflection impulsivity dimension partially mediated the association between ELS and social onset of hazardous drinking (CFI = 0.939, RMSEA = 0.091). These finding imply that stabilizing vulnerabilities such as reflection impulsivity via intervention programs that target young individuals with ELS may be helpful in delaying the onset of hazardous drinking and prevent alcohol dependence.

A glucose-reactive enzyme-based biofuel cell system (EBFC) was recently introduced in the scientific community for biomedical applications, such as implantable artificial organs and biosensors for drug delivery. Upon direct contact with tissues or organs, an implanted EBFC can exert effects that damage or stimulate intact tissue due to its byproducts or generated electrical cues, which have not been investigated in detail. Here, we perform a fundamental cell culture study using a glucose dehydrogenase (GDH) as an anode enzyme and bilirubin oxidase (BOD) as a cathode enzyme. The fabricated EBFC had power densities of 15.26 to 38.33 nW/cm2 depending on the enzyme concentration in media supplemented with 25 mM glucose. Despite the low power density, the GDH-based EBFC showed increases in cell viability (~150%) and cell migration (~90%) with a relatively low inflammatory response. However, glucose oxidase (GOD), which has been used as an EBFC anode enzyme, revealed extreme cytotoxicity (~10%) due to the lethal concentration of H2O2 byproducts (~1500 µM). Therefore, with its cytocompatibility and cell-stimulating effects, the GDH-based EBFC is considered a promising implantable tool for generating electricity for biomedical applications. Finally, the GDH-based EBFC can be used for introducing electricity during cell culture and the fabrication of organs on a chip and a power source for implantable devices such as biosensors, biopatches, and artificial organs.

Alcohol use disorder (AUD) is a chronic and relapsing disease with a substantial genetic influence. Given the recent discovery of the association of PPM1G methylation with alcohol use disorder (AUD) from a genome-wide methylation study, we sought to verify and extend the previous work of AUD-related impulsivity in a Korean population with AUD. A total of 244 men with AUD were assessed for psychological characteristics and behavioral impulsivity using stop signal task (response inhibition) and Balloon Analog Risk Task (risk-taking). Leukocyte DNA methylation at PPM1G was quantified using pyrosequencing. The effects of PPM1G methylation on severity of problematic drinking measured by Alcohol Use Disorder Identification Test (AUDIT) and multidimensional impulsivity were tested using linear regression analyses. Hypermethylation of PPM1G was significantly associated with risk-taking propensity among men with AUD. No significant association of PPM1G methylation was found to be associated with AUDIT scores and response inhibition. Our findings indicate that altered methylation of PPM1G may influence the impulsive choice of risk-taking in AUD. Further research is required in order to determine the role of PPM1G in the pathophysiology of AUD and multidimensional impulsivity.

[18F]Fluorodeoxyglucose ([18F]FDG) Positron emission tomography/computed tomography (PET/CT) is commonly used for rectal cancer staging, but improved diagnostic methods for nodal metastases are needed. We aimed to evaluate whether the combination model of the metabolic tumor volume of primary tumor (T_MTV) and maximum standardized uptake value of lymph node (N_SUVmax) on pretreatment [18F]FDG PET/CT could improve nodal metastases prediction in rectal cancer. We enrolled a total of 166 rectal cancer patients who underwent pretreatment [18F]FDG PET/CT and surgical resection without neoadjuvant treatment between January 2009 and August 2016. Visual and semiquantitative PET/CT parameters were obtained. Associations between clinicopathological, PET/CT-derived variables and nodal metastases were evaluated by logistic regression analysis. Nodal metastases were confirmed histologically in 68 of the 166 patients (41%). Uni- and multivariate analyses demonstrated T_MTV and N_SUVmax were independent predictive factors for nodal metastases. The c-statistics of the combination model was 0.806 (Standard Error, 0.034; 95% Confidence Interval, 0.737–0.863), which showed significant improvement compared to T_MTV (0.698, P = 0.0002) or N_SUVmax (0.720, P = 0.0008) alone. T_MTV and N_SUVmax are independently correlated with nodal metastases. Furthermore, the combination model showed improved performance for risk prediction; thus, [18F]FDG PET/CT might have a role in rectal cancer staging and treatment planning.

Although PMMA-based biomaterials are widely used in clinics, a major hurdle, namely, their poor antimicrobial (i.e., adhesion) properties, remains and can accelerate infections. In this study, carboxylated multiwalled carbon nanotubes (CNTs) were incorporated into poly(methyl methacrylate) (PMMA) to achieve drug-free antimicrobial adhesion properties. After characterizing the mechanical/surface properties, the anti-adhesive effects against 3 different oral microbial species (Staphylococcus aureus, Streptococcus mutans, and Candida albicans) were determined for roughened and highly polished surfaces using metabolic activity assays and staining for recognizing adherent cells. Carboxylated multiwalled CNTs were fabricated and incorporated into PMMA. Total fracture work was enhanced for composites containing 1 and 2% CNTs, while other mechanical properties were gradually compromised with the increase in the amount of CNTs incorporated. However, the surface roughness and water contact angle increased with increasing CNT incorporation. Significant anti-adhesive effects (35~95%) against 3 different oral microbial species without cytotoxicity to oral keratinocytes were observed for the 1% CNT group compared to the PMMA control group, which was confirmed by microorganism staining. The anti-adhesive mechanism was revealed as a disconnection of sequential microbe chains. The drug-free antimicrobial adhesion properties observed in the CNT-PMMA composite suggest the potential utility of CNT composites as future antimicrobial biomaterials for preventing microbial-induced complications in clinical settings (i.e., Candidiasis).

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

Este artículo se encuentra disponible en la página web de la revista en la siguiente URL: https://www.nature.com/articles/s41598-018-23939-6 Restoration of hard tissue in conjunction with adhesive is a globally challenging issue in medicine and dentistry. Common clinical therapies involving application of adhesive and substitute material for functional or anatomical recovery are still suboptimal. Biomaterials with bioactivity and inhibitory effects of enzyme-mediated adhesive degradation can render a solution to this. Here, we designed a novel copper-doped bioactive glass nanoparticles (CuBGn) to offer multifunction: metalloproteinases (MMP) deactivation and remineralization and incorporated the CuBGn in resin-dentin adhesive systems, which showed most common failure of MMP mediated adhesive degradation among hard tissue adhesives, to evaluate proposed therapeutic effects. A sol-gel derived bioactive glass nanoparticles doping 10 wt% of Cu (Cu-BGn) for releasing Cu ions, which were well-known MMP deactivator, were successfully created and included in light-curing dental adhesive (DA), a filler-free co-monomer resin blend, at different concentrations (up to 2 wt%). These therapeutic adhesives (CuBGn-DA) showed enhanced (a)cellular bioactivity, cytocompatibility, microtensile bond strength and MMP deactivationability. In conclusion, the incorporation of Cu ions releasing nano-bioactive glass demonstrated multifunctional properties at the resin-dentin interface; MMP deactivation and remineralization, representing a suitable strategy to extend the longevity of adhesive-hard tissue (i.e. resin-dentin) interfaces.

Telomere length has been suggested to be a cellular marker for age-related diseases as well as psychosocial stress. The present study investigated whether telomere length is associated with post-traumatic stress disorder (PTSD) among veterans exposed to combat trauma in the Vietnam War. The potentially associated factors on cellular aging were considered. Korean male veterans with (n = 122) and without (n = 120) PTSD were included and leukocyte telomere length was measured with a quantitative PCR-based technique. As a whole, no significant difference in telomere length was found between PTSD and non-PTSD groups. In linear regression analysis stratified by trauma levels, among veterans exposed to severe combat (n = 45), PTSD status (B = −1.176, t = −2.259, p = 0.029), antidepressant use (B = 0.168, t = 2.528, p = 0.015), and education level (B = 0.019, t = 2.369, p = 0.023) affected telomere length. However, among veterans with light-to-moderate combat exposure (n = 197), only age (B = −0.007, t = −2.434, p = 0.016) and education level (B = 0.010, t = 2.295, p = 0.023) were associated with telomere length. In the Post-hoc analysis, antidepressant use was associated with longer telomere length in subjects exposed to severe combat. Our exploratory results suggest that PTSD status in combination with severe trauma may be associated with accelerated telomere shortening, and that antidepressant use may have a protective effect on telomere dynamics.

Evidence from literature supports the existence of associations between serotonin-related genetic variants and obsessive-compulsive disorder (OCD), but few studies have explored the involvement of serotonin receptor type 3 genes (HTR3) in OCD. To identify whether HTR3 variability affects an individual’s susceptibility to OCD, we examined 10 HTR3 variants in 596 individuals with OCD and 599 controls. A significant difference existed in the genotypic distribution of the HTR3B variant rs1176744 between individuals with OCD and controls (odds ratio [OR] = 0.74, 95% confidence interval [CI] = 0.60–0.91, P = 0.0043). A protective haplotype in HTR3B was also associated with OCD (OR = 0.77, CI = 0.63–0.95, permutated P = 0.0179). Analyses of OCD sub-phenotypes demonstrated significant associations between rs3758987 and early onset OCD in male subjects (OR = 0.49, CI = 0.31–0.79, P = 0.0031) and among rs6766410, rs6443930, and the cleaning dimension in female subjects (OR = 0.36, CI = 0.18–0.69, P = 0.0016 and OR = 0.47, CI = 0.29–0.79, P = 0.0030, respectively). Additionally, rs6766410 was related to contamination-based disgust in OCD (P = 0.0044). These results support that common HTR3 variants are involved in OCD and some of its clinical phenotypes.