ヌクレオシドトランスポーターと抗腫瘍性ヌクレオシドに対する感受性との関連性

金沢大学がん進展制御研究所抗腫瘍性ヌクレオシドはヌクレオシドトランスポーター(NT)によって細胞内に輸送される。本研究では、薬剤感受性とNT機能の関連性を検討した。培養がん細胞では促進拡散輸送系(ENT)1-3のmRNAは恒常的にその発現が観察されたが、ENT4は特に大腸がん細胞株で高頻度に発現が観察された。能動的輸送系(CNT)は組織特異性や恒常的発現などは観察されず、ENTに比較して低発現であった。また、8種類のヒトがん細胞を用い、抗腫瘍性ヌクレオシドの薬剤感受性と薬剤輸送量を検討した結果、NTのmRNAの発現量とヌクレオシドの細胞内輸送量に関連性は認められなかった。しかしながら、NTの阻害剤を用いて細胞内輸送量を制限すると、薬剤感受性が低下し、細胞内輸送量と薬剤感受性との間に明らかな関連性が認められた。更に薬剤感受性との関連性をより明確にするためにGFPとの融合蛋白質としてENT1-4を培養がん細胞株に強制発現させた結果、ENT1および2は従来までの報告通り細胞膜への局在性が観察された。しかしながら、ENT3および4は細胞膜上ではなく細胞内の小器官で発現が認められた。つまり、薬剤が細胞内に輸送された後の細胞内での分布に関与し、細胞膜での輸送活性や薬剤感受性には関与しないことが示唆された。そこで、強制発現細胞株での薬剤感受性を検討した結果、ENT1およびENT2の強制発現細胞株では薬剤の感受性が増強した。しかし、ENT3やENT4を発現した細胞株では薬剤の感受性に変化は認められなかった。ENT3およびENT4が細胞内小器官に発現し、そのヌクレオシドの輸送能にいかなる生物学的意義があるのかは不明ではあるが、抗腫瘍性ヌクレオシドの細胞内輸送(薬剤感受性)とは直接関係しないことが明らかとなった。これらの結果の一部は現在、論文として投稿準備中である。研究課題/領域番号:15790071, 研究期間(年度):2003 – 2004出典：「ヌクレオシドトランスポーターと抗腫瘍性ヌクレオシドに対する感受性との関連性」研究成果報告書　課題番号15790071（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-15790071/)を加工して作

From symplectic cohomology to Lagrangian enumerative geometry

We build a bridge between Floer theory on open symplectic manifolds and the enumerative geometry of holomorphic disks inside their Fano compactifications, by detecting elements in symplectic cohomology which are mirror to Landau-Ginzburg potentials. We also treat the higher Maslov index versions of LG potentials. We discover a relation between higher disk potentials and symplectic cohomology rings of anticanonical divisor complements (themselves related to closed-string Gromov-Witten invariants), and explore several other applications to the geometry of Liouville domains.Comment: 47 pages, 13 figures; v2: reference fixes, minor correction

Increased isoprostane levels in oleic acid-induced lung injury

The present study was performed to examine a role of oxidative stress in oleic acid-induced lung injury model. Fifteen anesthetized sheep were ventilated and instrumented with a lung lymph fistula and vascular catheters for blood gas analysis and measurement of isoprostanes (8-epi prostaglandin F2 alpha). Following stable baseline measurements, oleic acid (0.08 ml/kg) was administered and observed 4 h. Isoprostane was measured by gas chromatography mass spectrometry with the isotope dilution method. Isoprostane levels in plasma and lung lymph were significantly increased 2 h after oleic acid administration and then decreased at 4 h. The percent increases in isoprostane levels in plasma and lung lymph at 2 h were significantly correlated with deteriorated oxygenation at the same time point, respectively. These findings suggest that oxidative stress is involved in the pathogenesis of the pulmonary fat embolism-induced acute lung injury model in sheep and that the increase relates with the deteriorated oxygenation.ArticleBIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS. 388(2):297-300 (2009)journal articl

Balloon Enteroscopy-Assisted Endoscopic Retrograde Cholangiopancreatography for the Treatment of Common Bile Duct Stones in Patients with Roux-en-Y Gastrectomy: Outcomes and Factors Affecting Complete Stone Extraction

Background: Endoscopic retrograde cholangiopancreatography (ERCP) for extraction of common bile duct (CBD) stones in patients with Roux-en-Y gastrectomy (RYG) remains technically challenging. Methods: Seventy-nine RYG patients (median 79 years old) underwent short-type double-balloon enteroscopy-assisted ERCP (sDBE-ERCP) for CBD stones at three referral hospitals from 2011-2020. We retrospectively investigated the treatment outcomes and potential factors affecting complete stone extraction. Results: The initial success rates of reaching the papilla of Vater, biliary cannulation, and biliary intervention, including complete stone extraction or biliary stent placement, were 92%, 81%, and 78%, respectively. Of 57 patients with attempted stone extraction, complete stone extraction was successful in 74% for the first session and ultimately in 88%. The adverse events rate was 5%. The multivariate analysis indicated that the largest CBD diameter >= 14 mm (odds ratio (OR), 0.04; 95% confidence interval (CI), 0.01-0.58; p = 0.018) and retroflex position (OR, 6.43; 95% CI, 1.12-36.81; p = 0.037) were independent predictive factors affecting complete stone extraction achievement. Conclusions: Therapeutic sDBE-ERCP for CBD stones in a relatively elderly RYG cohort, was effective and safe. A larger CBD diameter negatively affected complete stone extraction, but using the retroflex position may be useful for achieving complete stone clearance

Low Tongue Strength and the Number of Teeth Present Are Associated with Cognitive Decline in Older Japanese Dental Outpatients: A Cross-Sectional Study

福岡歯科大学2020年

The DsbA-L gene is associated with respiratory function of the elderly via its adiponectin multimeric or antioxidant properties

Oxidative stress and inflammation play a key role in the age-related decline in the respiratory function. Adipokine in relation to the metabolic and inflammatory systems is attracting growing interest in the field of respiratory dysfunction. The present clinical and experimental studies investigated the role of the disulfide bond-forming oxidoreductase A-like protein (DsbA-L) gene, which has antioxidant and adiponectin multimeric (i.e. activation) properties, on the respiratory function of the elderly. We performed a retrospective longitudinal genotype-phenotype relationship analysis of 318 Japanese relatively elderly participants (mean age ± standard deviation: 67.0 ± 5.8 years) during a health screening program and an in vitro DsbA-L knock-down evaluation using 16HBE14o-cells, a commonly evaluated human airway epithelial cell line. The DsbA-L rs1917760 polymorphism was associated with a reduction in the ratio of forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) and %FEV1 and with the elevation of the prevalence of FEV1/FVC < 70%. We also confirmed that the polymorphism was associated with a decreased respiratory function in relation to a decrease in the ratio of high-molecular-weight adiponectin/total adiponectin (as a marker of adiponectin multimerization) and an increase in the oxidized human serum albumin (as an oxidative stress marker). Furthermore, we clarified that DsbA-L knock-down induced oxidative stress and up-regulated the mucus production in human airway epithelial cells. These findings suggest that the DsbA-L gene may play a role in protecting the respiratory function of the elderly, possibly via increased systemic adiponectin functions secreted from adipocytes or through systemic and/or local pulmonary antioxidant properties

Acceleration of small bowel motility after oral administration of dai-kenchu-to (TJ-100) assessed by cine magnetic resonance imaging.

Dai-kenchu-to (TJ-100) is an herbal medicine used to shorten the duration of intestinal transit by accelerating intestinal movement. However, intestinal movement in itself has not been evaluated in healthy volunteers using radiography, fluoroscopy, and radioisotopes because of exposure to ionizing radiation. The purpose of this study was to evaluate the effect of TJ-100 on intestinal motility using cinematic magnetic resonance imaging (cine MRI) with a steady-state free precession sequence. Ten healthy male volunteers received 5 g of either TJ-100 or lactose without disclosure of the identity of the substance. Each volunteer underwent two MRI examinations after taking the substances (TJ-100 and lactose) on separate days. They drank 1200 mL of tap water and underwent cine MRI after 10 min. A steady-state free precession sequence was used for imaging, which was performed thrice at 0, 10, 20, 30, 40, and 50 min. The bowel contraction frequency and distention score were assessed. Wilcoxon signed-rank test was used, and differences were considered significant at a P-value <0.05. The bowel contraction frequency tended to be greater in the TJ-100 group and was significantly different in the ileum at 20 (TJ-100, 8.95 ± 2.88; lactose, 4.80 ± 2.92; P < 0.05) and 50 min (TJ-100, 9.45 ± 4.49; lactose, 4.45 ± 2.65; P < 0.05) between the groups. No significant differences were observed in the bowel distention scores. Cine MRI demonstrated that TJ-100 activated intestinal motility without dependence on ileum distention

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target