Kasumigaura Medical Center

Asthma heterogeneity remains a major barrier in precision medicine. Although elevated total serum immunoglobulin E (IgE) is a hallmark of asthma, even in nonatopic patients, its causal role in asthma pathogenesis is debated. We hypothesized that genetic predisposition to increased IgE defines a distinct asthma endotype. A genome-wide association study of total serum IgE in 1,287 non-asthmatic Japanese adults was used to construct IgE polygenic risk scores (IgE_PRS). Applying IgE_PRS to 745 patients with asthma, we performed cluster analysis incorporating age at onset, total IgE levels, IgE_PRS, and percent predicted forced expiratory volume in 1s (pFEV1), identifying four distinct adult asthma phenotypes. Notably, one cluster had the highest IgE_PRS and adult-onset-predominant type 2 inflammation. Conversely, the second cluster displayed the highest IgE levels but average IgE_PRS. The remaining two clusters comprised patients with lower IgE_PRS. One cluster was characterized by eosinophilia and smoking-related airflow limitation, whereas the other exhibited a type 2 low phenotype. In a 10-year retrospective cohort, over 30% of newly diagnosed asthma cases fell into the genetically predisposed high-IgE_PRS cluster. These findings reveal a distinct adult-onset-predominant asthma phenotype driven by genetically determined IgE production, offering new avenues for endotype-driven diagnosis and personalized therapy.

Abstract Background The activated endothelin pathway, inadequate prostacyclin IP receptor pathway and impaired bone morphogenetic protein (BMP) signaling pathway play an important role in the development of pulmonary arterial hypertension (PAH). The pulmonary artery smooth muscle cells (PASMCs) of pulmonary arteriole in patients with PAH indicate abnormally activated p38MAPK and abnormal outgrowth. We have reported that dual specificity protein phosphatase 1 (DUSP1), which inactivates p38MAPK, is downregulated in the lungs of PAH patients, and that IP receptor agonist upregulates DUSP1 expression and suppresses abnormal PASMC proliferation. The relationship between the BMP pathway, the IP receptor pathway, and the endothelin pathway is complicated and has not been clarified. Purpose The purpose of this study is to confirm the association of DUSP1 in the inhibition of cell proliferation by the BMP signaling pathway. Methods We stimulated purchased human PASMCs by endothelin 1 (ET-1), a non-prostanoid IP receptor agonist MRE-269, BMP2, or combination of them in vitro. Quantitative PCR was performed to quantify mRNA expression. Results ET-1 alone did not alter the expression of DUSP1. DUSP1 was induced independently by either BMP2 alone or MRE-269 alone. The combination of ET-1 with BMP2 and ET-1 with MRE-269 further accelerated the expression of DUSP1 induced by BMP2 alone and MRE-269 alone. ET-1 alone, BMP2 alone, and MRE-269 alone had no effect on cyclin D1 expression. The combination of ET-1 and BMP2 significantly enhanced cyclin D1 expression, while the combination of ET-1 and MRE-269 significantly suppressed it. BMP2 did not affect the expression of MSK1, whereas MRE-269 decreased that. Conclusions Here we report that BMP2 alone and in combination with ET-1 induces DUSP1, suggesting a novel mechanism of anti-proliferative effect of the BMP pathway. Since activated p38MAPK promotes cyclin D1 and cell proliferation and induce DUSP1 expression through MSK1 forming negative feedback system, the difference in expression of cyclin D1 and MSK1 by BMP2 and MRE-269 suggests that the expression of DUSP1 by MRE-269 is not through the negative feedback system, and that the accelerated expression of DUSP1 by the combination of ET-1 and BMP2 is through it. The importance of combined use of endothelin receptor antagonists in therapy targeting the BMP/TGF system was also suggested.

Atmospheric deposition affects both aquatic and terrestrial ecosystems. In this study, the atmospheric deposition of nitrogen (N) and phosphorus (P) was investigated in Lake Kasumigaura, Japan's second-largest lake, for approximately seven years. Seasonal variations in the total N (TN) and total P (TP) fluxes tended to be higher in spring and lower from fall to winter. The annual variations could be categorized into three distinct periods in conjunction with the precipitation trend. The estimated annual fluxes based on these three periods showed that the TN flux was accurately predicted. A comparison of the results of this study with those of studies conducted around 1980 reveals that the concentration of dissolved inorganic N in wet deposition has declined. This suggests that decreased N oxide (NOX) concentrations due to air pollution control measures contribute to the decrease in the nitrate (NO3-N) flux in atmospheric deposition. Despite the reduction in N fluxes from atmospheric deposition, monthly calculations of the impact of atmospheric deposition on Lake Kasumigaura revealed that the total inflow load reached a maximum of 17% for TN and 26% for TP.

Abstract Rationale: Elevated total serum IgE levels are associated with asthma independent of allergen sensitization, suggesting a role for genetic factors regulating IgE levels in asthma pathogenesis. This study aimed to characterize asthma phenotypes in adults that are influenced by genetic factors associated with elevated total IgE levels. Methods: This study population comprised Japanese adult healthy controls (N=1379) and adult asthma patients (N=750). We performed a genome-wide association study (GWAS) of total IgE levels in healthy adults without asthma or atopic dermatitis and developed a polygenic risk score (IgE_PRS) for total serum IgE using PRSice-2 with clumping and thresholding method. This IgE_PRS was then calculated in adult asthma patients using the same SNP set. A two-step cluster analysis was performed in asthma patients based on total serum IgE, pFEV1, age at asthma onset, and IgE_PRS to delineate distinct clusters. In addition, we evaluated the distribution of these clusters among newly diagnosed asthma cases in a 10-year prospective cohort of Japanese healthy adults (N=1303) using a decision tree model to validate the cluster distribution. Results: IgE_PRS was derived from 16,169 SNPs, and showed the strongest association with total IgE levels (p=0.0018, r2=0.017) but not with allergen sensitization (p=0.595) in healthy adults. Total IgE levels were significantly elevated in asthmatic patients compared to healthy controls (p=2.4×10-25), while IgE_PRS levels were not significantly different between groups (p=0.235). The two-step cluster analysis of asthmatic patients identified four distinct subgroups, two of which had significantly higher IgE_PRS compared to healthy controls. Cluster 1 (N=194), with the highest IgE_PRS, was characterized by adult-onset allergic asthma, elevated total IgE levels, high allergen sensitization (75.3%), mild airflow obstruction, and a predominance of females (64.4%). Cluster 2 (N=172), with the second highest IgE_PRS, included individuals with adult-onset asthma, moderate to severe airflow obstruction, and a high prevalence of smoking (52.3%). Of 79 newly diagnosed asthma cases, 26.6% were classified in the highest IgE_PRS cluster. Conclusions: Our findings reveal a distinct phenotype of adult-onset asthma characterized by a genetic predisposition to elevated total IgE levels. This study highlights the potential of IgE_PRS-driven clustering to identify asthma endotypes that may be particularly influenced by genetic susceptibility to high IgE levels, with implications for more tailored therapeutic approaches.

Abstract This study presents results of circulation and residence time in lakes influenced by wind‐induced mixing investigated with numerical simulations. The study area is Lake Kasumigaura, a continuous lake system primally consisting of two lakes, West Lake and North Lake. Although metrological conditions and depths are similar for both lakes, the surface area and shape of the lakes are very different. A numerical model resolves the primary features of the wind‐driven circulation in the lake system and is forced by observed river discharges and wind stress. A passive tracer released from the river mouths is used to estimate the residence time and evaluate mixing processes. Wind‐driven flow dominates the kinetic energy in the lakes and induces chaotic motions leading to tracer dispersion which is largely influenced by the shape of the lakes. Results indicate that the residence time is much longer in the well‐mixed middle basin of West Lake than North Lake. The estimated horizontal tracer diffusivity is approximately three times larger for the large West Lake than for the small‐narrow North Lake. This study suggests that the surface area and shape of lakes in which the flow is predominantly wind driven largely influences circulation, water exchange processes and residence times in lakes.

This study aimed to investigate prognostic factors for predicting the survival of patients with extensive-disease-stage small-cell lung cancer treated with chemoimmunotherapy. Patients were classified according to overall survival (OS): favorable corresponded to an OS ≥ 24 months, moderate corresponded to an OS of 6-24 months, and poor corresponded to an OS < 6 months. Multivariate Cox regression analyses were used to evaluate prognostic factors. Of 130 patients, the proportions of performance status decline and liver metastasis were significantly higher in the poor-prognosis group. With regard to the laboratory findings, neutrophil/lymphocyte ratios and albumin levels differed significantly among the groups. Multivariate analysis showed that the independent prognostic factors for OS were liver metastasis and decreased albumin levels (<3.5 mg/dL). After classifying the patients into three groups according to the quantities of these prognostic factors, the OS differed significantly among the groups (18.3 vs. 13.5 vs. 3.8 months; p < 0.001). The incidence of immune-related adverse events (irAEs) was higher in patients without these prognostic factors than in those with both (36% vs. 5%; p = 0.01). Liver metastasis and decreased albumin levels are independent unfavorable prognostic factors. Patients with both prognostic factors showed unfavorable OS; however, patients without these factors may have a favorable prognosis but be at greater risk of irAEs.

【目的】小児に用いた光学式バイオメトリーで取得された眼球生体パラメータから調節麻痺下における等価球面度数（SE）とSEの左右差（不同視差）を予測すること。

To elucidate the mechanism by which cigarette smoking causes vascular damage, we examined the relationship between cumulative cigarette consumption and abdominal obesity, and the possible mediating effect of smoking on arterial stiffness. Cross-sectional data from 19499 never smokers and 5406 current smokers receiving health screening was analyzed. Abdominal obesity was assessed by ABSI, and arterial stiffness by CAVI. High CAVI was defined as CAVI ≥ 9.0. Current smoker showed higher ABSI than never smokers after propensity score matching. Cumulative cigarette consumption expressed in pack-years correlated with ABSI (Rs: 0.312 in men, 0.252 in women), and was also extracted as an independent factor associated with ABSI by multiple regression analysis. A linear relationship between pack-year and CAVI was observed (Rs: 0.544 in men, 0.423 in women). Pack-year had almost equal discriminatory power in predicting high CAVI in both sexes (C-statistic: 0.774 in men, 0.747 in women), and the best cut-offs of pack-year for high CAVI were 24.5 in men and 14.7 in women. Bivariate logistic regression models revealed that the association between pack-year higher than cut-off and high CAVI was independent of traditional risks. A mediating effect of ABSI (mediation rate: 9.9% in men and 11.2% in women), but not waist circumference (WC), on the association of pack-year with CAVI was observed, after adjusting for traditional risks. Cumulative cigarette smoking in pack-years was independently associated with ABSI. ABSI partially mediates the association between pack-year and CAVI, suggesting that abdominal obesity partially mediates smoking-related vascular dysfunction.