Insulin-like growth factor 2 mRNA-binding protein 3 enhanced melanoma migration through regulation of AKT1 and RELA expression.

IMP-3 expression is a poor prognostic factor of melanomas and it promotes melanoma cell migration and invasion by a pathway modulating HMGA2 mRNA expression. We tried to identify other putative targets of IMP-3. We identified putative IMP-3-binding RNAs, including AKT1, MAPK3, RB1 and RELA, by RNA immunoprecipitation coupled with next-generation sequencing. IMP-3 overexpression increased AKT and RELA levels in MeWo cells. siRNAs against AKT1 and RELA inhibited MeWo/Full-length IMP-3 cell migration. IMP-3 knockdown of A2058 cells decreased AKT1 and RELA expression and lowered migration ability. Co-transfection of A2058 cells with AKT1- or RELA-expressing plasmids with IMP-3 siRNA restored the inhibitory effects of IMP-3 knockdown on migration. HMGA2 did not influence AKT1 and RELA expression in melanoma cells. Human melanoma samples with high IMP-3 levels also showed high HMGA2, AKT1 and RELA expression. Our results show that IMP-3 enhances melanoma cell migration through the regulation of the AKT1 and RELA axis.

Baseline and interim [18F]FDG-PET/MRI to assess treatment response and survival in patients with M0 esophageal squamous cell carcinoma treated by curative-intent therapy.

BACKGROUND: To investigate the value of [18F]FDG-PET/MRI in predicting treatment response and survival in patients with primary M0 esophageal squamous cell carcinoma. METHODS: Patients with esophageal squamous cell carcinoma received [18F]FDG-PET/MRI at baseline and during neoadjuvant or definitive chemoradiotherapy. The treatment response was classified according to the Response Evaluation Criteria for Solid Tumors 1.1. We used Kaplan-Meier and Cox regression analyses to assess the association between PET/MRI parameters and overall survival (OS) or progression-free survival (PFS). RESULTS: We included 40 M0 patients in the final analysis. The volume transfer constant (Ktrans) from baseline PET/MRI (area under the curve (AUC) = 0.688, P = 0.034) and total lesion glycolysis (TLG) from baseline PET/MRI (AUC = 0.723, P = 0.006) or interim PET/MRI (AUC = 0.853, P < 0.001) showed acceptable AUC for predicting treatment response. The TLG from interim PET/MRI (interim TLG, P < 0.001) and extracellular volume fraction (Ve) on interim PET/MRI (interim Ve, P = 0.001) were identified as independent prognostic factors for OS. Baseline Ve (P = 0.044) and interim TLG (P = 0.004) were significant predictors of PFS. The c-indices of the prognostic models combining interim TLG with Ve for predicting OS, and baseline Ve and interim TLG for predicting PFS were 0.784 and 0.699, respectively. These values were significantly higher than the corresponding c-indices of the TNM staging system (P = 0.002 and P = 0.047, respectively). CONCLUSIONS: Combining the baseline and interim [18F]FDG-PET/MRI qualitative imaging parameters aids in predicting the prognosis of patients with M0 esophageal squamous cell carcinoma. TRIAL REGISTRATION: The study was registered at Clinicaltrials.gov (identifier: NCT05855291 and NCT05855278).

Impact of public health measures and new introducing variants on Respiratory syncytial virus recrudescence in Taiwan during the COVID-19 pandemic.

OBJECTIVES: Respiratory syncytial virus (RSV) causes clinically significant distress in children and adults. Non-pharmaceutical interventions against SARS-CoV-2 have affected the seasonal activity of common respiratory pathogens. This seems exceptionally true regarding RSV's seasonal circulation, hence we have investigated the changes in the epidemiology of RSV in Taiwan during the pandemic. MATERIALS: A prospective surveillance of RSV among hospitalized children was carried out between 2020 and 2022 in central Taiwan. Of all PCR-detected RSV, genotype and evolutionary analysis were further investigated. Demographics and clinical features were compared between each outbreak. RESULTS: Throughout the consecutive three years of the SARS-CoV-2 pandemic, RSV outbreaks took place in Taiwan first in 2020 and a second time in 2022. We enrolled 80 and 105 hospitalized child cases, in each surge respectively. The RSV G protein genomic analysis revealed that RSV ON1 and RSV BA9 were separately contributing to these two outbreaks, and evolutionary evidence indicated these RSV variants are new to Taiwan, with their own featured sets of mutations. Clinically, a shift in age of RSV infected children was found, but the clinical severity was not worse and remained independent of RSV genotype. CONCLUSIONS: There were two delayed RSV surges after the relaxation of public measures during the pandemic in Taiwan, and both outbreaks were driven by new RSV genetic variants rather than cryptic circulation of the previous genetic clusters in Taiwan. These findings highlight the importance of continued surveillance on the trend and evolution of RSV after the COVID-19 pandemic.

Prenatal and early-life antibiotic exposure and the risk of atopic dermatitis in children: A nationwide population-based cohort study.

BACKGROUND: Atopic dermatitis (AD) contributes to substantial social and financial costs in public health care systems. Antibiotic exposure during pregnancy has been proposed as a risk factor, but findings remain inconsistent. The aim of this study was to investigate the association between prenatal antibiotic use and childhood AD. METHODS: We performed a population-based cohort study using data collected from the Taiwan Maternal and Child Health Database from 2009 to 2016. Associations were determined using Cox proportional hazards model and were adjusted for several potential covariates, including maternal atopic disorders and gestational infections. Children with and without maternal predispositions of atopic diseases and postnatal antibiotic/acetaminophen exposures within 1 year were stratified to identify the subgroups at risk. RESULTS: A total of 1,288,343 mother-child pairs were identified and 39.5% received antibiotics prenatally. Maternal antibiotic use during pregnancy was slightly positively associated with childhood AD (aHR 1.04, 95% CI 1.03-1.05), especially in the first and second trimesters. An apparent dose-response pattern was observed with an 8% increased risk when the exposure was ≥5 courses prenatally (aHR 1.08, 95% CI 1.06-1.11). Subgroup analysis showed the positive association remained significant regardless of postnatal infant antibiotic use, but the risk attenuated to null in infants who were not exposed to acetaminophen (aHR 1.01, 95% CI 0.96-1.05). The associations were higher in children whose mothers were without AD compared to those whose mothers were with AD. In addition, postnatal antibiotic or acetaminophen exposure of infants was associated with an increased risk of developing AD after 1 year of age. CONCLUSION: Maternal antibiotic use during pregnancy was associated with an increased risk of childhood AD in a dose-related manner. Further research may be warranted to investigate this variable using a prospectively designed study, and also to examine whether or not this association is specifically related to pregnancy.

Clinical characteristics and differential cytokine expression in hospitalized Taiwanese children with respiratory syncytial virus and rhinovirus bronchiolitis.

BACKGROUND: Viral bronchiolitis presents a heterogeneous spectrum. In this study, we investigated the clinical characteristics and the cytokines/chemokines profiles among respiratory syncytial virus (RSV), rhinovirus (RV), and their dual infection in Taiwanese children with viral bronchiolitis. METHOD: This study was conducted between October 2014 and June 2017. Viral etiology was identified using a Luminex respiratory virus panel and blood cytokines were evaluated using a MILLIPLEX MAP Human Cytokine/Chemokine Panel. Cytokine/Chemokine expressions were compared by clinical severity, steroid treatment, and viral entities. RESULTS: A total of 184 patients were evaluated; at least one respiratory virus was identified in 163 (88.6%) patients. RSV and RV were the two leading viral etiologies, with 25.5% and 17.3%, respectively. RV bronchiolitis has a comparable severity to RSV but is more common in children of an older age with a history of recurrent wheezing and blood eosinophilia. Decreased tumor necrosis factor-alpha (TNF-α) and interferon gamma (INF-γ) levels were correlated with clinical severity. Patients infected with RV exhibited higher levels of Interleukin (IL)-22, IL-23, IL-25, IL-31, and IL-33 (p < 0.05), whereas those with RSV had higher levels of TNF-α, INF-γ, and IL-10 (p < 0.05). Systemic steroid treatment was associated with higher expressions of IL-4, IL-8, IL-13, and MIP-1α levels (p < 0.05). Cluster analysis revealed a high correlation of IL-33 and IL-31(R2 = 0.9731, p < 0.0001). CONCLUSION: Different viral infections elicited the characteristic clinical presentation and immune profiles in bronchiolitis. Our findings also highlight the role of the IL-33/IL-31 axis in the immunopathogenesis of bronchiolitis.

Genome-wide association study reveals ethnicity-specific SNPs associated with ankylosing spondylitis in the Taiwanese population.

BACKGROUND: Ankylosing spondylitis (AS) is an autoimmune disease affecting mainly spine and sacroiliac joints and adjacent soft tissues. Genome-wide association studies (GWASs) are used to evaluate genetic associations and to predict genetic risk factors that determine the biological basis of disease susceptibility. We aimed to explore the race-specific SNP susceptibility of AS in Taiwanese individuals and to investigate the association between HLA-B27 and AS susceptibility SNPs in Taiwan. METHODS: Genotyping data were collected from a medical center participating in the Taiwan Precision Medicine Initiative (TPMI) in the northern district of Taiwan. We designed a case-control study to identify AS susceptibility SNPs through GWAS. We searched the genome browser to find the corresponding susceptibility genes and used the GTEx database to confirm the regulation of gene expression. A polygenic risk score approach was also applied to evaluate the genetic variants in the prediction of developing AS. RESULTS: The results showed that the SNPs located on the sixth chromosome were related to higher susceptibility in the AS group. There was no overlap between our results and the susceptibility SNPs found in other races. The 12 tag SNPs located in the MHC region that were found through the linkage disequilibrium method had higher gene expression. Furthermore, Taiwanese people with HLA-B27 positivity had a higher proportion of minor alleles. This might be the reason that the AS prevalence is higher in Taiwan than in other countries. We developed AS polygenic risk score models with six different methods in which those with the top 10% polygenic risk had a fivefold increased risk of developing AS compared to the remaining group with low risk. CONCLUSION: A total of 147 SNPs in the Taiwanese population were found to be statistically significantly associated with AS on the sixth pair of chromosomes and did not overlap with previously published sites in the GWAS Catalog. Whether those genes mapped by AS-associated SNPs are involved in AS and what the pathogenic mechanism of the mapped genes is remain to be further studied.

Genome-wide analyses identify novel risk loci for cluster headache in Han Chinese residing in Taiwan.

BACKGROUND: Cluster headache is a highly debilitating neurological disorder with considerable inter-ethnic differences. Genome-wide association studies (GWAS) recently identified replicable genomic loci for cluster headache in Europeans, but the genetic underpinnings for cluster headache in Asians remain unclear. The objective of this study is to investigate the genetic architecture and susceptibility loci of cluster headache in Han Chinese resided in Taiwan. METHODS: We conducted a two-stage genome-wide association study in a Taiwanese cohort enrolled from 2007 through 2022 to identify the genetic variants associated with cluster headache. Diagnosis of cluster headache was retrospectively ascertained with the criteria of International Classification of Headache Disorders, third edition. Control subjects were enrolled from the Taiwan Biobank. Genotyping was conducted with the Axiom Genome-Wide Array TWB chip, followed by whole genome imputation. A polygenic risk score was developed to differentiate patients from controls. Downstream analyses including gene-set and tissue enrichment, linkage disequilibrium score regression, and pathway analyses were performed. RESULTS: We enrolled 734 patients with cluster headache and 9,846 population-based controls. We identified three replicable loci, with the lead SNPs being rs1556780 in CAPN2 (odds ratio = 1.59, 95% CI 1.42‒1.78, p = 7.61 × 10-16), rs10188640 in MERTK (odds ratio = 1.52, 95% CI 1.33‒1.73, p = 8.58 × 10-13), and rs13028839 in STAB2 (odds ratio = 0.63, 95% CI 0.52‒0.78, p = 2.81 × 10-8), with the latter two replicating the findings in European populations. Several previously reported genes also showed significant associations with cluster headache in our samples. Polygenic risk score differentiated patients from controls with an area under the receiver operating characteristic curve of 0.77. Downstream analyses implicated circadian regulation and immunological processes in the pathogenesis of cluster headache. CONCLUSIONS: This study revealed the genetic architecture and novel susceptible loci of cluster headache in Han Chinese residing in Taiwan. Our findings support the common genetic contributions of cluster headache across ethnicities and provide novel mechanistic insights into the pathogenesis of cluster headache.

The effective distance and cooling rate of liquid nitrogen-based adjunctive cryotherapy for bone tumors ex vivo.

BACKGROUND: Liquid nitrogen (LN) has been used as an adjuvant cryotherapy for bone tumors including giant-cell tumor of the bone (GCTB) to remove residual tumor cells after curettage. This study evaluated variables related to the efficacy of LN-based cryoablation in the context of adjuvant treatment of GCTB using porcine femur bone model. METHODS: A porcine femur bone model was adopted to simulate intralesional cryotherapy. A LN-holding cavity (point 1, nadir) in the medial epicondyle, 4 holes (points 2-5) in the shaft situated 5, 10, 15, and 20 mm away from the proximal edge of the cavity, and 2 more holes (points 6 and 7) in the condyle cartilage (10 and 20 mm away from the distal edge of the cavity) were made. The cooling rate was compared between the 5 points. The cellular morphological changes and DNA damage in the GCTB tissue attributable to LN-based cryotherapy were determined by H&E stain and TUNEL assay. Cartilage tissue at points 6 and 7 was examined for the extent of tissue injury after cryotherapy. RESULTS: The temperature kinetics at points 1, 2 reached the reference target and were found to be significantly better than the reference (both p < 0.05). The target temperature kinetics were not achieved at points 4 and 5, which showed a significantly lower cooling rate than the reference (both p < 0.001) without reaching the -60°C target. Compared with untreated samples, significantly higher proportion of shrunken or apoptotic cells were found at points 1-3; very small proportion were observed at points 4, 5. Significantly increased chondrocyte degeneration was observed at point 6, and was absent at point 7. CONCLUSION: The cryotherapy effective range was within 5 mm from nadir. Complications were restricted to within this distance. The cooling rate was unchanged after three repeated cycles of cryotherapy.

Sintering Nano-Silver Paste by Resistive Joule Heating Process for 2G HTS Tape Joints.

Developing a joining technology for 2G HTS tapes without significantly reducing their superconducting property is crucial for numerous applications (MRI, motor/generator, power transmission, etc.). In this study, low sintering temperature (~230 °C) nano-silver paste was used as solder to join two 2G HTS tapes. In addition, two heating methods, i.e., furnace heating (heat flux outside-in) and resistive Joule heating (heat flux inside-out), were studied. This study indicates that the heat flux from internal by resistive Joule heating method shows less deteriorating impact to the 2G RE-Ba-Cu-O tape (RE: rare earth element) during the sintering process with the best specific resistance of 0.074 µΩ∙cm2 and Ic retention percentage of 99% (i.e., Ic reduced from 100 A before joining to 99 A after joining). This study indicates that nano-silver paste together with resistive Joule heating can possibly be used as soldering materials to join 2G HTS tapes.

Predictability of the preoperative lateral fulcrum radiograph of success in one-level vertebroplasty to treat painful osteoporotic vertebral fracture.

BACKGROUND: Restoration of height or angle has been reported following vertebroplasty (VP). The purpose of the study was to investigate the predictive value of the preoperative lateral fulcrum radiograph (LFR) of success in one-level VP for painful osteoporotic vertebral fracture. METHODS: From January 2017 to January 2018, 71 patients (mean age, 76 years) receiving VP were retrospectively analyzed. Painful vertebra was defined as pseudarthrosis or edematous change in magnetic resonance imaging (MRI) scan. Fulcrum flexibility (FF) and fulcrum restoration index (FRI) of the vertebral wedge angle (VWA), regional kyphotic angle (RKA), and anterior vertebral body height (AVBH) were investigated. Back pain was evaluated using a visual analogue scale. RESULTS: The 30 males and 41 females were followed for an average of 21 months. The sensitivity of LFR and MRI to detect pseudarthrosis was 92% and 97%, respectively. Preoperative FF of VWA, RKA, and AVBH was 52.4%, 58.3%, and 60%, respectively, indicating similar potential restoration ability. Postoperative average FRI for VWA, RKA, and AVBH was 1.29 ± 2.98, 0.46 ± 1.16, and 1.04 ± 1.68, respectively. Final average FRI was 0.94 ± 2.96, -0.03 ± 2.25, and 0.6 ± 2.04, respectively. VWA and AVBH had better immediate restoration, and VWA had better final maintenance. All parameters progressive lost significant levels of restoration to similar degrees but without increase in back pain. CONCLUSION: LFR can help with evaluation for pseudarthrosis and the restoration effect of VP. VP had better immediate restoration of VWA and AVBH and better final VWA maintenance.

Predicting the risk of interval distant metastases in patients with esophageal squamous cell carcinoma undergoing chemoradiotherapy.

BACKGROUND: This study was conducted to identify risk factors for distant interval metastases (IM) in patients with esophageal squamous cell carcinoma (ESCC) who underwent chemoradiotherapy (CRT). METHODS: We retrospectively reviewed the clinical records of 358 patients with ESCC treated with CRT between 2006 and 2017. Distant IM were defined as systemic metastases developing during or shortly after CRT and identified during the restaging work-up period. A risk prediction nomogram for distant IM was developed based on independent pretreatment risk factors identified using multivariable logistic regression analysis. RESULTS: Distant IM occurred in 26 (7.3%) patients and had a significant adverse impact on survival (median survival: 8.7 months). The most common site of distant IM was the lung (n = 9), followed by non-regional lymph nodes (n = 8) and the bone (n = 8). Multivariable logistic regression analysis revealed that high baseline tumor SUVmax values were independently associated with an increased risk of distant IM (odds ratio [OR] = 1.059, p = 0.019), whereas older age was an independent protective factor (OR = 0.946, p = 0.032). A nomogram based on age, tumor SUVmax, tumor length, and the chemotherapy regimen showed a good predictive performance (c-statistic = 0.761), which was internally validated using 200 bias-corrected bootstrap replicates (c-statistic = 0.71). CONCLUSION: Distant IM were identified in 7.3% of patients with ESCC undergoing CRT. The nomogram described in our study may prove useful to predict the risk of distant IM in this patient group.

Delayed respiratory syncytial virus outbreak in 2020 in Taiwan was correlated with two novel RSV-A genotype ON1 variants.

BACKGROUND: Human respiratory syncytial virus (RSV) is a leading pathogen of acute respiratory tract disease among infants and young children. Compared with previous seasons, RSV outbreaks in Taiwan during the 2020-2021 season were delayed because of COVID-19 mitigation measures. We conducted this study to determine the association of viral factors with clinical characteristics of preschool children with RSV infection. METHODS: We performed a molecular epidemiology analysis of RSV among inpatient preschool children in Taiwan. In 80 nasopharyngeal samples positive for RSV, we sequenced and analyzed viral genotypes according to patient data. Patients' clinical data were obtained from medical files, and their clinical profiles were compared with those of RSV cases recorded during the 2014-2017 seasons. RESULTS: Phylogenetic analysis revealed that among the RSV-positive samples, all RSV strains identified during the 2020-2021 season belonged to the ON1 genotype. Most of the Taiwan ON1 strains were categorized into two well-supported clusters with distinct G protein amino acid substitution patterns that had never been demonstrated previously. Furthermore, the proportion of cases among children aged >24 months increased (P < 0.001). Compared with patients infected during the 2014-2017 seasons, patients infected during the 2020-2021 season were hospitalized for shorter days from hospital admission to dereference (P = 0.004) and had a greater need for oxygen supplements (P = 0.021) and systemic steroid therapy (P = 0.026). CONCLUSION: The delayed 2020-2021 RSV outbreak in Taiwan was caused by two novel RSV ON1.1 variants. How the change in RSV epidemiology affects future RSV outbreaks warrants exploration.

Epidemiology of Meckel's diverticulum: A nationwide population-based study in Taiwan: Characteristics of the cases from surgery between 1996 and 2013.

ABSTRACT: The diverse presentation of Meckel's diverticulum (MD) is a diagnostic challenge for clinicians and most previous studies consist of single institutional case series. The aim of this study was to review the related diagnoses of MD and to investigate the epidemiological characteristics using Taiwan's National Health Insurance Research Database.We conducted an observational study using a population-based database. Patients diagnosed with MD who concurrently received intestinal surgery were identified. We analyzed the patients' demographic characteristics and relevant diagnoses using χ2 test and 2-sample t test.We identified 2453 newly diagnosed MD patients from 1996 to 2013 and 1227 patients (50%) with intestinal obstruction, gastrointestinal bleeding, and acute appendicitis (acute abdominal pain) were defined as symptomatic. The male to female ratio was 2.4:1 with half of the patients experiencing symptomatic MD before the age of 20 years' old. The age-specific and annual incidence were calculated for all MD and symptomatic MD. Among the symptomatic MD patients, intestinal obstruction was present in 583 (48%), acute appendicitis was present in 464 (38%), and gastrointestinal bleeding was present in 283 (23%) patients. Intestinal obstruction was the most common preoperative diagnosis in the 0 to 10 years and >20 years' age groups, and acute appendicitis (acute abdominal pain) was the most common diagnosis in the 11 to 20 years' age group.This population-based 18 years' epidemiologic study described the distributions of MD symptoms among different age groups, which may help clinicians gain a better understanding of this diagnostically challenging gastrointestinal anomaly.

Acute Effects of Different Exercise Intensities on Executive Function and Oculomotor Performance in Middle-Aged and Older Adults: Moderate-Intensity Continuous Exercise vs. High-Intensity Interval Exercise.

A wealth of evidence has shown that a single bout of aerobic exercise can facilitate executive function. However, none of current studies on this topic have addressed whether the magnitude of the acute-exercise benefit on executive function and oculomotor performance is influenced by different aerobic exercise modes. The present study was thus aimed toward an investigation of the acute effects of high-intensity interval exercise (HIIE) vs. moderate-intensity continuous exercise (MICE) on executive-related oculomotor performance in healthy late middle-aged and older adults. Using a within-subject design, twenty-two participants completed a single bout of 30 min of HIIE, MICE, or a non-exercise-intervention (REST) session in a counterbalanced order. The behavioral [e.g., reaction times (RTs), coefficient of variation (CV) of the RT], and oculomotor (e.g., saccade amplitude, saccade latency, and saccadic peak velocity) indices were measured when participants performed antisaccade and prosaccade tasks prior to and after an intervention mode. The results showed that a 30-min single-bout of HIIE and MICE interventions shortened the RTs in the antisaccade task, with the null effect on the CV of the RT in the late middle-aged and older adults. In terms of oculomotor metrics, although the two exercise modes could not modify the performance in terms of saccade amplitudes and saccade latencies, the participants' saccadic peak velocities while performing the oculomotor paradigm were significantly altered only following an acute HIIE intervention. The present findings suggested that a 30-min single-bout of HIIE and MICE interventions modulated post-exercise antisaccade control on behavioral performance (e.g., RTs). Nevertheless, the HIIE relative MICE mode appears to be a more effective aerobic exercise in terms of oculomotor control (e.g., saccadic peak velocities) in late middle-aged and older adults.

Cardiovascular and metabolic risk of antipsychotics in children and young adults: a multinational self-controlled case series study.

AIMS: The risk of antipsychotic-associated cardiovascular and metabolic events may differ among countries, and limited real-world evidence has been available comparing the corresponding risks among children and young adults. We, therefore, evaluated the risks of cardiovascular and metabolic events in children and young adults receiving antipsychotics. METHODS: We conducted a multinational self-controlled case series (SCCS) study and included patients aged 6-30 years old who had both exposure to antipsychotics and study outcomes from four nationwide databases of Taiwan (2004-2012), Korea (2010-2016), Hong Kong (2001-2014) and the UK (1997-2016) that covers a total of approximately 100 million individuals. We investigated three antipsychotics exposure windows (i.e., 90 days pre-exposure, 1-30 days, 30-90 days and 90 + days of exposure). The outcomes were cardiovascular events (stroke, ischaemic heart disease and acute myocardial infarction), or metabolic events (hypertension, type 2 diabetes mellitus and dyslipidaemia). RESULTS: We included a total of 48 515 individuals in the SCCS analysis. We found an increased risk of metabolic events only in the risk window with more than 90-day exposure, with a pooled IRR of 1.29 (95% CI 1.20-1.38). The pooled IRR was 0.98 (0.90-1.06) for 1-30 days and 0.88 (0.76-1.02) for 31-90 days. We found no association in any exposure window for cardiovascular events. The pooled IRR was 1.86 (0.74-4.64) for 1-30 days, 1.35 (0.74-2.47) for 31-90 days and 1.29 (0.98-1.70) for 90 + days. CONCLUSIONS: Long-term exposure to antipsychotics was associated with an increased risk of metabolic events but did not trigger cardiovascular events in children and young adults.

Genome-Wide Meta-analysis Identifies Genetic Variants Associated With Glycemic Response to Sulfonylureas.

OBJECTIVE: Sulfonylureas, the first available drugs for the management of type 2 diabetes, remain widely prescribed today. However, there exists significant variability in glycemic response to treatment. We aimed to establish heritability of sulfonylurea response and identify genetic variants and interacting treatments associated with HbA1c reduction. RESEARCH DESIGN AND METHODS: As an initiative of the Metformin Genetics Plus Consortium (MetGen Plus) and the DIabetes REsearCh on patient straTification (DIRECT) consortium, 5,485 White Europeans with type 2 diabetes treated with sulfonylureas were recruited from six referral centers in Europe and North America. We first estimated heritability using the generalized restricted maximum likelihood approach and then undertook genome-wide association studies of glycemic response to sulfonylureas measured as HbA1c reduction after 12 months of therapy followed by meta-analysis. These results were supported by acute glipizide challenge in humans who were naïve to type 2 diabetes medications, cis expression quantitative trait loci (eQTL), and functional validation in cellular models. Finally, we examined for possible drug-drug-gene interactions. RESULTS: After establishing that sulfonylurea response is heritable (mean ± SEM 37 ± 11%), we identified two independent loci near the GXYLT1 and SLCO1B1 genes associated with HbA1c reduction at a genome-wide scale (P < 5 × 10-8). The C allele at rs1234032, near GXYLT1, was associated with 0.14% (1.5 mmol/mol), P = 2.39 × 10-8), lower reduction in HbA1c. Similarly, the C allele was associated with higher glucose trough levels (ß = 1.61, P = 0.005) in healthy volunteers in the SUGAR-MGH given glipizide (N = 857). In 3,029 human whole blood samples, the C allele is a cis eQTL for increased expression of GXYLT1 (ß = 0.21, P = 2.04 × 10-58). The C allele of rs10770791, in an intronic region of SLCO1B1, was associated with 0.11% (1.2 mmol/mol) greater reduction in HbA1c (P = 4.80 × 10-8). In 1,183 human liver samples, the C allele at rs10770791 is a cis eQTL for reduced SLCO1B1 expression (P = 1.61 × 10-7), which, together with functional studies in cells expressing SLCO1B1, supports a key role for hepatic SLCO1B1 (encoding OATP1B1) in regulation of sulfonylurea transport. Further, a significant interaction between statin use and SLCO1B1 genotype was observed (P = 0.001). In statin nonusers, C allele homozygotes at rs10770791 had a large absolute reduction in HbA1c (0.48 ± 0.12% [5.2 ± 1.26 mmol/mol]), equivalent to that associated with initiation of a dipeptidyl peptidase 4 inhibitor. CONCLUSIONS: We have identified clinically important genetic effects at genome-wide levels of significance, and important drug-drug-gene interactions, which include commonly prescribed statins. With increasing availability of genetic data embedded in clinical records these findings will be important in prescribing glucose-lowering drugs.

Connecting MHC-I-binding motifs with HLA alleles via deep learning.

The selection of peptides presented by MHC molecules is crucial for antigen discovery. Previously, several predictors have shown impressive performance on binding affinity. However, the decisive MHC residues and their relation to the selection of binding peptides are still unrevealed. Here, we connected HLA alleles with binding motifs via our deep learning-based framework, MHCfovea. MHCfovea expanded the knowledge of MHC-I-binding motifs from 150 to 13,008 alleles. After clustering N-terminal and C-terminal sub-motifs on both observed and unobserved alleles, MHCfovea calculated the hyper-motifs and the corresponding allele signatures on the important positions to disclose the relation between binding motifs and MHC-I sequences. MHCfovea delivered 32 pairs of hyper-motifs and allele signatures (HLA-A: 13, HLA-B: 12, and HLA-C: 7). The paired hyper-motifs and allele signatures disclosed the critical polymorphic residues that determine the binding preference, which are believed to be valuable for antigen discovery and vaccine design when allele specificity is concerned.

Acute effects of high-intensity interval training and moderate-intensity continuous exercise on BDNF and irisin levels and neurocognitive performance in late middle-aged and older adults.

The purposes of the present study were (1) to explore and compare the acute effects of high-intensity interval training (HIIT) and moderate-intensity continuous exercise (MICE) on neurocognitive performance and molecular biomarkers in late middle-aged and older adults, and (2) to examine the relationships of HIIT/MICE exercise-induced neurocognitive changes with changes in circulating irisin and BDNF levels elicited by different acute exercise modes. Using a within-subject design, twenty-one participants completed an acute bout of 30 min of HIIT, MICE, or a non-exercise-intervention (REST) session in a counterbalanced order. The neuropsychological [i.e., accuracy rate (AR) and reaction time (RT)] and neurophysiological [i.e., event-related potential (ERP) P3 latency and amplitude] indices were simultaneously measured when the participants performed a working memory task at baseline and after an intervention mode. Blood samples were also taken before and after the intervention mode. The results showed that, although ARs were significantly increased only via the MICE intervention mode, the acute HIIT and MICE interventions improved RT performance and increased ERP P3 amplitudes in the late middle-aged and older adults under consideration. Serum BDNF levels were significantly increased with the acute HIIT and MICE interventions, and significant irisin level increases were only observed following the HIIT intervention. However, changes in the levels of Irisin and BDNF pre- and post-intervention were not correlated with changes in neurocognitive performance, with the exception of the correlation between the changes in irisin levels and RTs with acute exercise in the MICE intervention mode. The present findings suggested similar beneficial effects on neurocognitive performance (i.e., RTs and ERP P3 amplitudes) and peripheral BDNF levels following MICE and HIIT interventions in the middle-aged and older adults. In terms of ARs and irisin, the two acute exercise modes appear to induce divergent effects. Irisin may play a potential facilitating role in the neuropsychological (e.g., RT) performance of working memory in such a group. However, the mechanisms remain to be determined.

Synthesis of Fe1-xS Nanoparticles with Various Superstructures by a Simple Thermal Decomposition Route and Their Magnetic Properties.

Pyrrhotite nanoparticles with 5C and 3C superstructures were synthesized via a simple one-step thermal decomposition method in which hexadecylamine was used as a solvent at various reaction temperatures (TR). Structural analysis showed that at TR = 360 °C, almost uniform in size and shape Fe7S8 nanoparticles with 3C superstructure are formed, and an increase in the reaction temperature leads to the formation of Fe9S10 nanoparticles (5C superstructure), herewith a significant increase in the size of nanoparticles is observed. High-temperature magnetic measurements in 5 repeated heating-cooling cycles revealed that after the first heating branch in the Fe9S10 samples, the λ-Peak transition disappears, and the magnetization has a Weiss-type behavior characteristic of the Fe7S8 sample. The change in the behavior of magnetization can be explained by the redistribution of iron vacancies, which changes the initial phase composition of nanoparticles.