Biomedical subjects

Atsushi Takahashi

Publications and source records attributed to Atsushi Takahashi.

At least 19 recordsLinked to original sources

PubMed2025

Stratifying Lung Adenocarcinoma Risk with Multi-ancestry Polygenic Risk Scores in East Asian Never-Smokers.

BACKGROUND: Lung adenocarcinoma (LUAD) in never-smokers is a major public health burden, especially among East Asian women. Polygenic risk scores (PRSs) are promising for risk stratification but are primarily developed in European-ancestry populations. We aimed to develop and validate single- and multi-ancestry PRSs for East Asian never-smokers to improve LUAD risk prediction. METHODS: PRSs were developed using genome-wide association study summary statistics from East Asian (8,002 cases; 20,782 controls) and European (2,058 cases; 5,575 controls) populations. Single-ancestry models included PRS-25, PRS-CT, and LDpred2; multi-ancestry models included LDpred2+PRS-EUR128, PRS-CSx, and CT-SLEB. Performance was evaluated in independent East Asian data from the Female Lung Cancer Consortium (FLCCA) and externally validated in the Nanjing Lung Cancer Cohort (NJLCC). We assessed predictive accuracy via AUC, with 10-year and (age 30-80) absolute risks estimates. RESULTS: The best multi-ancestry PRS, using East Asian and European data via CT-SLEB (clumping and thresholding, super learning, empirical Bayes), outperformed the best East Asian-only PRS (LDpred2; AUC=0.629, 95% CI:0.618,0.641), achieving an AUC of 0.640 (95% CI:0.629,0.653) and odds ratio of 1.71 (95% CI:1.61,1.82) per SD increase. NJLCC Validation confirmed robust performance (AUC =0.649, 95% CI: 0.623, 0.676). The top 20% PRS group had a 3.92-fold higher LUAD risk than the bottom 20%. Further, the top 5% PRS group reached a 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year LUAD risk at age 50 (0.42%) by age 41, nine years earlier. CONCLUSIONS: Multi-ancestry PRS approaches enhance LUAD risk stratification in East Asian never-smokers, with consistent external validation, suggesting future clinical utility.

East Asian never smokers↗

PubMed2007

A functional SNP in ITIH3 is associated with susceptibility to myocardial infarction.

Myocardial infarction (MI) results from complex interactions of multiple genetic and environmental factors. To disclose genetic backgrounds of MI, we performed a large-scale, case-control association study using 52,608 gene-based single-nucleotide polymorphism (SNP) markers, and identified a candidate SNP located on chromosome 3p21.2-p21.1. Subsequent linkage-disequilibrium mapping indicated very significant association between MI and a SNP in exon 2 of the inter-alpha (globulin) inhibitor 3 gene (ITIH3; chi(2) = 24.88, P = 6.1 x 10(-7), 3,353 affected individuals versus 3,807 controls). In vitro functional analyses showed that this SNP enhanced the transcriptional level of the ITIH3 gene. Furthermore, we found expression of the ITIH3 protein in the vascular smooth muscle cells and macrophages in the human atherosclerotic lesions, suggesting ITIH3 SNP to be a novel genetic risk factor of MI.

Alpha-Globulins↗

PubMed2007

Functional single-nucleotide polymorphisms in the secretogranin III (SCG3) gene that form secretory granules with appetite-related neuropeptides are associated with obesity.

CONTEXT: Genetic factors are important for the development of obesity. However, the genetic background of obesity still remains unclear. OBJECTIVE: Our objective was to search for obesity-related genes using a large number of gene-based single-nucleotide polymorphisms (SNPs). DESIGN AND SETTING: We conducted case-control association analyses using 94 obese patients and 658 controls with 62,663 SNPs selected from the SNP database. SNPs that possessed P < or = 0.02 were further analyzed using 796 obese and 711 control subjects. One SNP (rs3764220) in the secretogranin III (SCG3) gene showed the lowest P value (P = 0.0000019). We sequenced an approximately 300-kb genomic region around rs3764220 and discovered SNPs for haplotype analyses. SCG3 was the only gene within a haplotype block that contained rs3764220. The functions of SCG3 were studied. PATIENTS: Obese subjects (body mass index > or = 30 kg/m(2), n = 890) and control subjects (general population; n = 658, body mass index < or = 25 kg/m(2); n = 711) were recruited for this study. RESULTS: Twelve SNPs in the SCG3 gene including rs3764220 were in almost complete linkage disequilibrium and significantly associated with an obesity phenotype. Two SNPs (rs16964465, rs16964476) affected the transcriptional activity of SCG3, and subjects with the minor allele seemed to be resistant to obesity (odds ratio, 9.23; 95% confidence interval, 2.77-30.80; chi(2) = 19.2; P = 0.0000067). SCG3 mRNA and immunoreactivity were detected in the paraventricular nucleus, lateral hypothalamic area, and arcuate nucleus, and the protein coexisted with orexin, melanin-concentrating hormone, neuropeptide Y, and proopiomelanocortin. SCG3 formed a granule-like structure together with these neuropeptides. CONCLUSIONS: Genetic variations in the SCG3 gene may influence the risk of obesity through possible regulation of hypothalamic neuropeptide secretion.

Adult↗

PubMed2007

Retinal circulatory changes associated with interferon-induced retinopathy in patients with hepatitis C.

PURPOSE: To evaluate the effect of interferon (IFN) therapy on retinal microcirculation. METHODS: Thirty-six patients with chronic hepatitis C who were treated with high-dose IFN were included in this prospective study. The changes in vessel diameter and blood velocity were measured, and the retinal blood flow (RBF) and wall shear rate (WSR) were calculated in the retinal arteries before and 2, 4, 8, 16, and 24 weeks after IFN therapy by using laser Doppler velocimetry. RESULTS: Retinal blood velocity, RBF, and WSR significantly (P < 0.0001) increased in all patients, as early as 2 weeks after IFN therapy. The increase in RBF was independently correlated with a decrease in the red blood cell count. In 22 (61%) of the 36 patients asymptomatic retinopathy developed during treatment. In patients with retinopathy, the blood velocity and WSR increased, but the vessel diameter did not change, whereas the vessel diameter increased but the blood velocity and WSR did not change in patients without retinopathy 2 weeks after IFN therapy. Multiple logistic regression analysis showed that patient age and the change in WSR at week 2 were risk factors for the development of IFN-induced retinopathy. CONCLUSIONS: RBF increases in association with IFN therapy in patients with chronic hepatitis C. In addition, the increased WSR in patients with retinopathy indicates that retinal vascular endothelial dysfunction may be associated with IFN-induced retinopathy, because wall shear stress should be constant under physiologic conditions.

Adult↗

PubMed2007

[Case of acute hepatitis associated with Basedow's disease].

A 20-year-old woman given a diagnosis of hyperthyroidism (Basedow's disease) had been subsequently treated with methimazole since 1999. As she could not be made euthyroid, surgery was planned to relieve the symptoms. Because of liver dysfunction after discontinuation of methimazole and administration of iodine, she was admitted to the hospital. She was negative for hepatitis A, B and C virus serologies, but positive for anti-nuclear antibodies. A liver biopsy, which showed features of chronic active hepatitis, led to the diagnosis of autoimmune hepatitis (AIH). Interestingly, normalization of serum T4 correlated with improvement of serum aminotransferases. This leads us to speculate that this patient's liver dysfunction may have been AIH exacerbated by the liver dysfunction of hyperthyroidism rather than acute deterioration of AIH itself.

Adult↗

PubMed2006

A genomewide linkage analysis of Kawasaki disease: evidence for linkage to chromosome 12.

Kawasaki disease (KD) is an acute systemic vasculitis syndrome that primarily affects infants and young children. The cause of KD is largely unknown, but its higher incidence in the Asian population and increased risk in patients' families suggests the existence of underlying genetic factors. To determine the loci of a susceptibility gene for KD, a genomewide linkage analysis with affected sib pairs was performed on 78 family samples collected from all over Japan. Multipoint linkage analysis using MAPMAKER/SIBS 2.0 identified evidence of linkage on 12q24 [maximum lod score (MLS) = 2.69]. Possible linkage (MLS > 1.0) was also found on 4q35, 5q34, 6q27, 7p15, 8q24, 18q23, 19q13, Xp22, and Xq27. This is the first large-scale study of the genetic susceptibility to KD, and our results, combined with the accumulated knowledge of the human genome, could greatly promote research on identification of the molecular pathogenesis of KD.

Chromosome Mapping↗

PubMed2006

A recovery case of acute-onset autoimmune hepatitis presenting as fulminant hepatic failure [corrected], who received living donor-liver transplantation.

A 23-year-old woman was admitted to our hospital with jaundice and hepatic coma. She had taken a weight-loss supplement for one month before admission. Her clinical and laboratory findings were consistent with fulminant hepatic failure and fulfilled the criteria of autoimmune hepatitis. Despite corticosteroid pulse therapy and plasma exchange, her symptoms and laboratory findings deteriorated. Her condition improved after she received a living donor-liver transplant from her sister. Autoimmune hepatitis usually follows a chronic course, but it should be considered a type of fulminant hepatic failure and treated promptly.

Acute Disease↗

PubMed2006

Identification of a novel non-coding RNA, MIAT, that confers risk of myocardial infarction.

Through a large-scale case-control association study using 52,608 haplotype-based single nucleotide polymorphism (SNP) markers, we identified a susceptible locus for myocardial infarction (MI) on chromosome 22q12.1. Following linkage disequilibrium (LD) mapping, haplotype analyses revealed that six SNPs in this locus, all of which were in complete LD, showed markedly significant association with MI (chi2=25.27, P=0.0000005; comparison of allele frequency, 3,435 affected individuals versus 3,774 controls, in the case of intron 1 5,338 C>T; rs2331291). Within this locus, we isolated a complete cDNA of a novel gene, designated myocardial infarction associated transcript (MIAT). MIAT has five exons, and in vitro translation assay showed that MIAT did not encode any translational product, indicating that this is likely to be a functional RNA. In vitro functional analyses revealed that the minor variant of one SNP in exon 5 increased transcriptional level of the novel gene. Moreover, unidentified nuclear protein(s) bound more intensely to risk allele than non-risk allele. These results indicate that the altered expression of MIAT by the SNP may play some role in the pathogenesis of MI.

Alleles↗

PubMed2006

CD8-positive T cell-induced liver damage was found in a patient with polymyositis.

We describe a case of polymyositis (PM) with liver injury that occurred in a patient with rheumatoid arthritis (RA). A 74-year-old woman who had a 12-year history of RA was admitted to our hospital because of muscle weakness and liver dysfunction. CD8-positive T cell infiltration was found in the interstitium of both the liver and muscle. In addition to the administration of a large amount of prednisolone (PSL), high-dose intravenous immunoglobulin (IVIG) successfully improved myositis and hepatitis. Our case indicates the pathogenic potential of CD8-positive T cells in PM-associated liver injury.

Aged↗

PubMed2006

Expression of nonmuscle cofilin-1 and steroid responsiveness in severe asthma.

BACKGROUND: Glucocorticoids are the mainstay of asthma therapy; however, a proportion of patients with asthma has a severe form of the disease that fails to respond to therapy. Understanding the molecular mechanisms behind glucocorticoid-insensitive asthma is therefore of clinical importance. Evidence in glucocorticoid-unresponsive Henrietta Lack (HeLa) cells indicated that cofilin-1 could act as an inhibitor of glucocorticoid function. OBJECTIVE: To determine whether cofilin-1 expression is abnormally expressed in cells from patients with severe glucocorticoid-insensitive asthma and examine the effect of cofilin-1 overexpression on glucocorticoid function. METHODS: Peripheral blood CD4(+) T cells were purified from 16 subjects with severe glucocorticoid-insensitive asthma and 16 subjects with mild glucocorticoid-sensitive asthma, and cofilin-1 expression was determined by quantitative real-time RT-PCR and Western blotting. The effect of dexamethasone on cofilin-1 expression was determined in Jurkat T cells, and the effect of cofilin-1 overexpression on anti-CD3/CD28-stimulated IL-2 release was measured. RESULTS: Peripheral blood CD4(+) T cells from subjects with severe glucocorticoid-insensitive asthma are less responsive to dexamethasone than cells from subjects with mild glucocorticoid-sensitive asthma. Cells from these patients express significantly (P < .05) higher levels of cofilin-1 than cells from subjects with mild asthma. Dexamethasone did not affect cofilin-1 expression in Jurkat T cells. Functionally, dexamethasone suppression of anti-CD3/CD28-stimulated IL-2 was attenuated in Jurkat cells overexpressing cofilin-1. CONCLUSION: These results suggest that increased cofilin-1 expression may be important in the regulation of glucocorticoid sensitivity in peripheral blood lymphocytes of patients with severe treatment-insensitive asthma. CLINICAL IMPLICATIONS: Understanding the mechanisms of enhanced cofilin-1 expression may lead to the development of new therapies for severe treatment-insensitive asthma.

Adult↗

PubMed2006

Removal of more lymph nodes may provide better outcome, as well as more accurate pathologic findings, in patients with bladder cancer--analysis of role of pelvic lymph node dissection.

OBJECTIVES: To examine the role of pelvic lymph node dissection (PLND) in patients who underwent radical cystectomy for bladder cancer. The diagnostic and therapeutic role of PLND is still controversial in bladder cancer. The extent of PLND and the necessary number of lymph nodes to remove have not been defined. METHODS: This retrospective review included 146 patients with refractory superficial and muscle-invasive disease treated with radical cystectomy, regional PLND (internal iliac, external iliac, and obturator nodes) and urinary diversion from January 1990 to December 2002. RESULTS: Lymph node metastases were detected in 25 patients (17.1%). The average number of nodes removed in the node-positive and node-negative patients was 13.9 and 14.2, respectively. Although no difference was found in disease-specific survival in the node-negative patients when stratified by the number of nodes removed (13 or more versus less than 13), a significant survival advantage was found in the node-positive patients with 13 or more nodes removed versus less than 13 nodes removed. The patients with four or more positive nodes had a worse outcome than those with less than four positive nodes. However, even if the patients had less than four positive nodes, the survival of patients with less than 13 nodes removed was as poor as that of the patients with four or more positive nodes. CONCLUSIONS: In this series, the removal of 13 or more pelvic lymph nodes was essential for more accurate pathologic examination to predict patient outcome and contributed to an increased chance of survival.

Adult↗

PubMed2006

Efficient pyrrole synthesis using double nucleophilic addition to alpha,beta-unsaturated imines with plural nucleophiles.

[reaction: see text] 2,3,5-Trisubstituted pyrroles were prepared in a regioselective manner using the double nucleophilic addition of alpha,alpha-dialkoxy ketene silyl acetals and ketene sily thioacetals or trimethylsilyl cyanide to alpha,beta-unsaturated imines followed by acid-promoted cyclization and oxidation with DDQ. Using this methodology an imidazole glycerol phosphate dehydratase inhibitor (IGPDI) possessing a monopyrrole aldehyde moiety was synthesized.

Catalysis↗

PubMed2006

A functional SNP in PSMA6 confers risk of myocardial infarction in the Japanese population.

Inflammation is now considered critical in the pathogenesis of myocardial infarction. One of the mechanisms regulating the inflammatory process is the ubiquitin-proteasome system. We investigated whether variants of the 20S proteasome are associated with susceptibility to myocardial infarction and found a common SNP (minor allele frequency of 0.35) in the proteasome subunit alpha type 6 gene (PSMA6) conferring risk of myocardial infarction in the Japanese population (chi(2) = 21.1, P = 0.0000044, 2,592 affected individuals versus 2,851 controls). We replicated this association in another panel of myocardial infarction and control subjects, although its relevance to other ethnic groups remains to be clarified. The SNP, located in the 5' untranslated region of exon 1 in this gene, enhanced the transcription of PSMA6. Moreover, suppression of PSMA6 expression using short interfering RNA in cultured cells reduced activation of the transcription factor NF-kappaB by stabilizing phosphorylated IkappaB. Our results implicate this PSMA6 SNP as a previously unknown genetic risk factor for myocardial infarction.

Alleles↗

PubMed2006

Modified and bilateral retroperitoneal lymph node dissection for testicular cancer: peri- and postoperative complications and therapeutic outcome.

OBJECTIVE: To characterize surgical invasiveness and morbidity and to verify therapeutic efficacy, we reviewed perioperative and postoperative courses and therapeutic outcomes of patients who underwent retroperitoneal lymph node dissection (RPLND) for testicular germ cell cancers. METHODS: The study included 31 patients who underwent retroperitoneal lymph node dissection. A modified template was used if retroperitoneal metastasis was limited to the areas below the level of the renal hilus and above the level of the inferior mesenteric artery (IMA). Perioperative and postoperative courses and complications were reviewed as well as therapeutic outcomes. RESULTS: Overall, 27 perioperative and postoperative complications were observed in 15 patients (48.4%). Superficial surgical site infection and paralytic ileus were seen most frequently. All of them were resolved without special additional treatments; however, patients who underwent retrocrural dissection had a tendency to have severe symptomatic complications such as chylothorax, phrenic nerve palsy and orthostatic hypotension. Antegrade ejaculation was preserved in 94.1% of patients with modified template dissection, whereas no patients with additional dissection below the level of the IMA had the function preserved. One patient (3.2%) developed a postoperative recurrent disease in the retroperitoneum, which was outside the dissection field, as well as in the mediastinum. CONCLUSIONS: Although RLND had high morbidity, most peri- and postoperative complications were manageable conservatively. Modified template dissection enabled patients to preserve antegrade ejaculation without compromising its therapeutic efficacy, if the disease extension allowed us to use the template.

Adolescent↗

PubMed2006

A case of primary biliary cirrhosis complicated by Behçet's disease and palmoplantar pustulosis.

A 46-year-old woman was diagnosed with palmoplantar pustulosis (PPP) at the Department of Dermatology, Fukushima Medical University Hospital in 2000, and was treated with ointment. However, because liver dysfunction developed in 2003, she was referred to our department, where primary biliary cirrhosis (PBC) was also diagnosed on the basis of clinical findings. One year later, at the age of 49, she developed manifestations of Behçet's disease (BD), including erythema nodosum in the lower extremities. Because she had a history of uveitis, recurrent oral ulceration was present, and the HLA typing was positive for B51, BD was additionally diagnosed. Liver function normalized within three months of the start of treatment with ursodesoxycholic acid (UDCA). This is the first case of PBC associated with BD and PPP.

Adult↗

PubMed2006

Murine androgen-independent neuroendocrine carcinoma promotes metastasis of human prostate cancer cell line LNCaP.

BACKGROUND: Although neuroendocrine (NE) cells in prostate cancer have been speculated to accelerate the growth and progression of surrounding cancer cells, the evidence is as yet inconclusive. We investigated the effect of an NE allograft (NE-10) and its cell line, NE-CS, which were established from the prostate of the LPB-Tag 12T-10 transgenic mouse, on human prostate cancer cell line LNCaP. METHODS: The proliferation and pulmonary metastasis of LNCaP xenografts in athymic mice with and without NE-10 allografts were evaluated. Boyden chamber assay and microarray analysis were performed to investigate changes in invasion/migration and mRNA of LNCaP cells under the influence of the NE cells, respectively. RESULTS: NE-10 did not influence the proliferation of LNCaP. The pulmonary metastasis of LNCaP with NE-10 significantly increased compared to mice without it. The NE-CS cells accelerated the in vitro invasion/migration of adenocarcinoma cells. Increased expression of mRNA of gelsolin was observed in LNCaP cells incubated with the supernatant of NE-CS cells. CONCLUSIONS: The NE-10 allograft promotes pulmonary metastasis of subcutaneously inoculated LNCaP cells by facilitating cell invasion. Secretions from NE cells upregulate the expression of gelsolin, which is an actin-binding protein, resulting in acceleration of the migration of LNCaP cells.

Adenocarcinoma↗

PubMed2006

Association of VKORC1 and CYP2C9 polymorphisms with warfarin dose requirements in Japanese patients.

Warfarin is the most commonly used oral anticoagulant for treatment of thromboembolism, but adjustment of the dose appropriate to each patient is not so easy because of the large inter-individual variation in dose requirement. We analyzed single nucleotide polymorphism (SNP) genotypes of the VKORC1 and CYP2C9 genes using DNA from 828 Japanese patients treated with warfarin, and investigated association between SNP genotype and warfarin-maintenance dose. Five SNPs in VKORC1, 5' flanking-1413A > G, intron 1-136T > C, intron 2+124C > G, intron 2+837T > C and exon 3 343G > A, were in absolute linkage disequilibrium, and showed a significant association with daily warfarin dose of these patients. The median warfarin dose of patients with homozygosity for the minor allele was 4.0 mg/day, which is significantly higher than those heterozygous for the minor allele (3.5 mg/day) or those homozygous for the major allele (2.5 mg/day; P = 5.1 x 10(-11) in the case of intron 1-136T > C SNP). We then genotyped the CYP2C9 gene for the Japanese common genetic variant, CYP2C9*3 and, based on the genotype of these two genes, classified patients into three categories, which we call "warfarin-responsive index." The median warfarin daily dose varied significantly in this classification according to the warfarin-responsive index (2.0 mg/day for index 0 group, 2.5 mg/day for index 1 group, and 3.5 mg/day for index 2 group; P = 4.4 x 10(-13)). Thus, analysis of the combination of VKORC1 and CYP2C9 genotypes should identify warfarin-sensitive patients who require a lower dose of drug, allowing personalized warfarin treatment.

Anticoagulants↗

PubMed2006

Effect of systemic administration of simvastatin on retinal circulation.

OBJECTIVE: To investigate the effect of systemic administration of simvastatin on the retinal circulation. METHODS: The effects of systemic administration of simvastatin on the retinal circulation after 90 minutes and after 7 days were studied in a placebo-controlled, double-masked, clinical trial among 12 healthy men. We used laser Doppler velocimetry to measure vessel diameter and blood velocity and calculated the blood flow in retinal arteries and veins. We also measured the intraocular pressure and the plasma nitrite/nitrate levels, the stable end products of nitric oxide metabolism. RESULTS: There were no significant changes in any retinal circulatory parameters at 90 minutes after administration of simvastatin. Daily administration of simvastatin for 7 days significantly increased blood velocity and blood flow in retinal arteries and veins but did not significantly change vessel diameter. The intraocular pressure significantly decreased at 90 minutes and at 7 days after administration of simvastatin. Simvastatin also significantly increased the plasma nitrite/nitrate levels. CONCLUSION: Simvastatin induced an increase in blood velocity and blood flow in retinal arteries and veins, increased the plasma nitrite/nitrate levels, and decreased the intraocular pressure, probably through the increase in nitric oxide.

Administration, Oral↗