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Detecting molecular targets in specimens from patients with lung cancer is essential for targeted therapy. Recently, we developed a highly sensitive, rapid-detection device (an immuno-wall device) that utilizes photoreactive polyvinyl alcohol immobilized with antibodies against a target protein via a streptavidin–biotin interaction. To evaluate its performance, we assayed epidermal growth factor receptor ( EGFR ) mutations, such as E746_A750 deletion in exon 19 or L858R substitution in exon 21, both of which are common in non-small cell lung cancer and important predictors of the treatment efficacy of EGFR tyrosine kinase inhibitors. The results showed that in 20-min assays, the devices detected as few as 1% (E746_A750 deletion) and 0.1% (L858R substitution) of mutant cells. Subsequent evaluation of detection of the mutations in surgically resected lung cancer specimens from patients with or without EGFR mutations and previously diagnosed using commercially available, clinically approved genotyping assays revealed diagnostic sensitivities of the immuno-wall device for E746_A750 deletion and L858R substitution of 85.7% and 87.5%, respectively, with specificities of 100% for both mutations. These results suggest that the immuno-wall device represents a good candidate next-generation diagnostic tool, especially for screening of EGFR mutations.

Foot disorders in older individuals compromise balance and contribute to postural and gait instabilities, causing a decrease in the activities of daily living and quality of life. In this cross-sectional study, we analyzed the foot-related data of 160 frail older participants who attended day service centers in A prefecture in Japan to determine the prevalence of foot problems and their associations with toe grip strength and walking speed in frail older people. Multiple regression analysis was used to identify foot-related variables that correlated with toe grip strength and walking speed. The prevalence rates of skin dryness (Support level 88.2%, Care level 85.2% for men; Support level 84.9%, Care level 93% for women) and suspected and existing fungal infections in nails (Support level 94.1%, Care level 92.6% for men; Support level 98.1%, Care level 95.2% for women) were high in both sexes regardless of the level of care required. Furthermore, in both sexes, the prevalence rates of toe and arch deformities were significantly increased in the people who required care. Regression analysis revealed that some right-sided foot-related problems were significantly associated with right toe grip strength and walking speed. The decrease in toe grip strength was significantly associated with walking speed. Our study provides evidence that some specific conditions were associated with toe grip force and walking speed. This finding can contribute to future strategies to protect foot health in community-dwelling older individuals.

Grainyhead-like 2 (GRHL2) is a transcription factor that suppresses epithelial-to-mesenchymal transition (EMT). It has been previously shown that GRHL2 can confer both oncogenic and tumor-suppressive roles in human cancers, including breast, pancreatic and colorectal cancers. However, its role in lung cancer remains elusive. In the present study, a meta-analysis of multiple gene expression datasets with clinical data revealed that GRHL2 expression was increased in lung cancer compared with that in the normal tissues. Copy number analysis of GRHL2, performed using datasets of whole exome sequencing involving 151 lung cancer cell lines, revealed frequent amplifications, suggesting that the increased GRHL2 expression may have resulted from gene amplification. A survival meta-analysis of GRHL2 using The Cancer Genome Atlas (TCGA) dataset showed no association of GRHL2 expression with overall survival. GRHL2 expression was found to be associated with EMT status in lung cancer in TCGA dataset and lung cancer cell lines. GRHL2 knockdown induced partial EMT in the hTERT/Cdk4-immortalized normal lung epithelial cell line HBEC4KT without affecting proliferation measured by CCK-8 assays. In addition, GRHL2 silencing caused three lung cancer cell lines, H1975, H2009 and H441, to undergo partial EMT. However, the proliferative effects differed significantly. GRHL2 silencing promoted proliferation but not colony formation in H1975 cells whilst suppressing colony formation without affecting proliferation in H2009 cells, but it did not affect proliferation in H441 cells. These results suggest cell type-dependent effects of GRHL2 knockdown. Downstream, GRHL2 silencing enhanced the phosphorylation of AKT and ERK, assessed by western blotting with phospho-specific antibodies, in HBEC4KT, H1975 and H2009 cell lines but not in the H441 cell line. By contrast, transient GRHL2 overexpression did not affect A549 cell proliferation, which lack detectable endogenous expression of the GRHL2 protein. However, GRHL2 overexpression did suppress E-cadherin expression in A549 cells. These results suggested that GRHL2 does not only function as a tumor suppressor of EMT but can also behave as an oncogene depending on the lung cancer cell-type context.

Introduction Patients with rheumatoid arthritis (RA) treated with abatacept (ABT) are at increased risk for vaccine-preventable infections. The aim of the present study is to evaluate the humoral response to 23-valent pneumococcal polysaccharide (PPSV23) vaccination in RA patients receiving ABT. Methods The immunogenicity study was nested within a randomized, double-blind placebo-controlled study, designed to evaluate the efficacy of the PPSV23. PPSV23 was given to 111 RA patients, who were classified into three groups: RA control (n = 35), methotrexate (MTX) alone (n = 55), and ABT (n = 21). Before and 4–6 weeks after vaccination, we measured the patients’ concentrations of antibodies against pneumococcal serotypes 6B and 23F using an enzyme-linked immunosorbent assay and determined their antibody functionality using a multiplexed opsonophagocytic killing assay, reported as the opsonization index (OI). Results The pneumococcal serotype-specific IgG concentrations and OIs were both significantly increased in all treatment groups in response to PPSV23 vaccination. In the ABT group, the IgG responses for the 6B serotype were lower compared with those in the MTX alone or control groups, whereas the OI responses were similar to those in the other two groups. In a subgroup analysis, the pneumococcal serotype-specific IgG responses were significantly lower in both serotypes (6B and 23F) in the ABT/MTX group; however, the OI responses in the ABT group were not different from the control group. There was no association between the pneumococcal serotype-specific IgG and OI responses for the 6B serotype in patients receiving ABT in contrast to the control or MTX alone patients. No severe adverse effects were observed in any of the treatment groups. Conclusions OI responses indicate antibody functionality rather than simply their amount, so the similarity of these measurements between all three groups suggests that RA patients receiving ABT still benefit from receiving the PPSV23 vaccination, even though they produce less IgG in response to it. The results suggest an influence of ABT on the humoral response to PPSV23 vaccination under MTX treatment; however, preserved opsonin responses are expected in RA patients treated with ABT plus MTX. Trial registration University Hospital Medical Information Network Clinical Trials Registry: UMIN000009566. Registered 12 December 2012.

Purpose  Less-invasive early diagnosis of lung cancer is essential for improving patient survival rates. The purpose of this study is to demonstrate that serum comprehensive miRNA profile is high sensitive biomarker to early-stage lung cancer in direct comparison to the conventional blood biomarker using next-generation sequencing (NGS) technology combined with automated machine learning (AutoML). Methods We first evaluated the reproducibility of our measurement system using Pearson’s correlation coefficients between samples derived from a single pooled RNA sample. To generate comprehensive miRNA profile, we performed NGS analysis of miRNAs in 262 serum samples. Among the discovery set (57 patients with lung cancer and 57 healthy controls), 1123 miRNA-based diagnostic models for lung cancer detection were constructed and screened using AutoML technology. The diagnostic faculty of the best performance model was evaluated by inspecting the validation samples (74 patients with lung cancer and 74 healthy controls). Results The Pearson’s correlation coefficients between samples derived from the pooled RNA sample ≥ 0.98. In the validation analysis, the best model showed a high AUC score (0.98) and a high sensitivity for early stage lung cancer (85.7%, n  = 28). Furthermore, in comparison to carcinoembryonic antigen (CEA), a conventional blood biomarker for adenocarcinoma, the miRNA-based model showed higher sensitivity for early-stage lung adenocarcinoma (CEA, 27.8%, n  = 18; miRNA-based model, 77.8%, n  = 18). Conclusion The miRNA-based diagnostic model showed a high sensitivity for lung cancer, including early-stage disease. Our study provides the experimental evidence that serum comprehensive miRNA profile can be a highly sensitive blood biomarker for early-stage lung cancer.

Obesity‐related liver disease remains a critical global health challenge, underscoring the need to elucidate the molecular mechanisms underlying hepatic inflammation and metabolic dysfunction, and to identify novel therapeutic targets. This study aimed to determine whether erythropoietin (EPO) modulates soluble epoxide hydrolase (sEH) and lipid mediator pathways to ameliorate hepatic inflammation and metabolic dysfunction in high‐fat diet (HFD)‐induced obese mice. Male C57BL/6 mice were fed HFD with or without EPO treatment, and metabolic phenotyping, including glucose tolerance testing and homeostasis model assessment of insulin resistance, was performed. Hepatic histology and quantitative real‐time polymerase chain reaction were conducted, together with flow cytometry to assess macrophage polarization, western blotting for sEH, and targeted liquid chromatography–tandem mass spectrometry profiling of cytochrome P450 epoxygenase‐derived epoxides. EPO treatment improved glucose metabolism, reduced hepatic steatosis, lowered Ccr2, Mcp1, and Tnfα expression, promoted a shift of hepatic macrophages toward an M2 (anti‐inflammatory) phenotype, downregulated hepatic sEH protein levels, and increased both hepatic and plasma concentrations of epoxygenase‐derived epoxides. These findings indicate that EPO suppresses hepatic sEH and favors pro‐resolving lipid mediator signaling, suggesting a potential therapeutic avenue for obesity‐related hepatic inflammation. Erythropoietin administration suppresses hepatic soluble epoxide hydrolase (sEH) expression, leading to increased CYP‐derived epoxides. This is associated with a shift in hepatic macrophage polarization characterized by reduced M1 markers and increased M2 markers, along with reduced hepatic inflammation, suppressed hepatic lipogenesis, and attenuated hepatic steatosis in high‐fat diet‐induced obesity. This graphic was created using BioRender.com.

Introduction In rheumatoid arthritis (RA) patients receiving immunosuppressive treatments, vaccination against Streptococcus pneumoniae is recommended. The objective of the study was to evaluate the effects of tacrolimus (TAC) on immune response following administration of a 23-valent pneumococcal polysaccharide vaccine (PPSV23) in patients with established RA. Methods Patients with RA ( n  = 133) were vaccinated with PPSV23. Patients were classified into TAC ( n  = 29), methotrexate (MTX) ( n  = 55), control ( n  = 35), and TAC/MTX ( n  = 14) treatment groups. We measured the concentrations of pneumococcal serotypes 6B and 23F by using an enzyme-linked immunosorbent assay and determined antibody functionality by using a multiplexed opsonophagocytic killing assay, reported as the opsonization index (OI), before and 4 to 6 weeks after vaccination. A positive antibody response was defined as at least a twofold increase in the IgG concentration or as at least a 10-fold increase in the OI. Results IgG concentrations and OIs were significantly increased in all treatment groups after PPSV23 vaccination. The TAC treatment group appears to respond in a manner similar to that of the RA control group in terms of 6B and 23F serotype concentration and function. In contrast, the MTX group had the lowest immune response. Patients who received a combination of TAC and MTX (TAC/MTX) also had a diminished immune response compared with those who received TAC alone. Conclusions TAC monotherapy does not appear to impair PPSV23 immunogenicity in patients with RA, whereas antibody production and function may be reduced when TAC is used with MTX. Thus, PPSV23 administration during ongoing TAC treatment should be encouraged for infection-prone TAC-treated patients with rheumatic diseases. Trial registration University Hospital Medical Information Network Clinical Trials Registry: UMIN000009566 . Registered 12 December 2012.

Maternal obesity and malnutrition during gestation and lactation have been recognized to increase the risk of obesity and metabolic disorders in the offspring across their lifespan. However, the gestational period during which malnutrition exerts a decisive effect is unclear. Brown adipose tissue (BAT) plays a critical role in energy metabolism owing to its high efficiency in oxidizing glucose and fatty acids. This study aimed to determine the impact of maternal high-fat diet (HFD) consumption only during pregnancy on BAT and energy metabolism in offspring mice. Dams were fed an HFD or a normal chow diet from embryonic day 2.5. HFD consumption during pregnancy induced glucose intolerance and hypertension in dams. In the offspring of HFD-fed dams, maternal HFD lowered fetal weight without affecting placental weight, whereas HFD consumption after birth exacerbated oxygen consumption and cold-induced thermogenesis at 12 months of age, accompanied by increased lipid droplet size in BAT. These data demonstrate that HFD consumption only during pregnancy exerts a long-lasting effect on BAT. Collectively, these findings indicate the importance of nutrition during pregnancy with respect to the energy metabolism of the offspring, and pregnant women should thus ensure proper nutrition during pregnancy to ensure normal energy metabolism in the offspring.

This study aims to evaluate the impact of early steroid discontinuation on total dosage and outcomes in pediatric immunoglobulin A (IgA) vasculitis patients with uncontrolled abdominal pain. This retrospective cohort study included children younger than 16 years with newly diagnosed IgA vasculitis hospitalized for abdominal pain who received their first dose of steroids between April 1, 2013, and March 31, 2019, at 14 hospitals. Patients were divided into two groups: the standard (STD) group, which received steroid therapy for at least 8 consecutive days, and the early discontinuation attempt (EDA) group, which attempted discontinuation within 7 days. EDA was further divided into two subgroups: the early discontinuation (ED) group, which completed steroid treatment within a week, and the readministration (RA) group, which required readministration. Total steroid dosage, duration of therapy, hospital stay, and complications were compared. A total of 272 patients were analyzed: STD ( n  = 190) and EDA ( n  = 82). There were no significant differences in baseline characteristics. EDA had a shorter hospital stay (8.5 vs. 15.0 days, p  < 0.01), fewer total steroid days (6 vs. 17.5 days, p  < 0.01), and lower total steroid dosage (5.4 mg/kg vs. 15.4 mg/kg, p  < 0.01) compared to STD, with no significant differences in complications. Among EDA patients, 22 (27%) required steroid readministration due to symptom recurrence; however, symptoms resolved in all RA patients, with lower total steroid dosage and duration compared to STD, without prolonging hospital stay. Conclusion : Discontinuing steroids within 7 days for abdominal pain in children with IgA vasculitis reduces total steroid dosage without increasing complications, even with occasional readministration. Clinical trial registration : Approval no. 2019–0394. What is known: • Steroids have been reported to be effective for abdominal pain in pediatric IgA vasculitis. . • Steroids should be tapered gradually to reduce the risk of symptom flare-up in pediatric IgA vasculitis. . What is new: • Early discontinuation of steroids reduced total dosage and hospital stay without increasing complications in pediatric IgA vasculitis. .