Kon A.,University of Tokyo |
Shih L.-Y.,Chang Gung Memorial Hospital |
Minamino M.,University of Tokyo |
Sanada M.,University of Tokyo |
And 45 more authors.
Nature Genetics | Year: 2013
Cohesin is a multimeric protein complex that is involved in the cohesion of sister chromatids, post-replicative DNA repair and transcriptional regulation. Here we report recurrent mutations and deletions involving multiple components of the cohesin complex, including STAG2, RAD21, SMC1A and SMC3, in different myeloid neoplasms. These mutations and deletions were mostly mutually exclusive and occurred in 12.1% (19/157) of acute myeloid leukemia, 8.0% (18/224) of myelodysplastic syndromes, 10.2% (9/88) of chronic myelomonocytic leukemia, 6.3% (4/64) of chronic myelogenous leukemia and 1.3% (1/77) of classical myeloproliferative neoplasms. Cohesin-mutated leukemic cells showed reduced amounts of chromatin-bound cohesin components, suggesting a substantial loss of cohesin binding sites on chromatin. The growth of leukemic cell lines harboring a mutation in RAD21 (Kasumi-1 cells) or having severely reduced expression of RAD21 and STAG2 (MOLM-13 cells) was suppressed by forced expression of wild-Type RAD21 and wild-Type RAD21 and STAG2, respectively. These findings suggest a role for compromised cohesin functions in myeloid leukemogenesis. © 2013 Nature America, Inc. All rights reserved.
PubMed | Clinical Data, Tohoku University, Jumonji University, University of Tokyo and 6 more.
Type: Journal Article | Journal: BMJ open | Year: 2016
To evaluate the impact of the 2011 great east Japan earthquake on body mass index (BMI) of preschool children.Retrospective cohort study and ecological study.Affected prefectures (Fukushima, Miyagi and Iwate) and unaffected prefectures in northeast Japan.The cohort study assessed 2033 and 1707 boys and 1909 and 1658 girls in 3 affected prefectures and unaffected prefectures, respectively, all aged 3-4years at the time of the earthquake. The ecological study examined random samples of schoolchildren from the affected prefectures.The cohort study compared postdisaster changes in BMIs and the prevalence of overweight and obese children. The ecological study evaluated postdisaster changes in the prevalence of overweight children.1month after the earthquake, significantly increased BMIs were observed among girls (+0.087kg/m(2) vs unaffected prefectures) in Fukushima and among boys and girls (+0.165 and +0.124kg/m(2), respectively vs unaffected prefectures) in Iwate. 19months after the earthquake, significantly increased BMIs were detected among boys and girls (+0.137 and +0.200kg/m(2), respectively vs unaffected prefectures) in Fukushima, whereas significantly decreased BMIs were observed among boys and girls (-0.218 and -0.082kg/m(2), respectively vs unaffected prefectures) in Miyagi. 1month after the earthquake, Fukushima, Miyagi and Iwate had a slightly increased prevalence of overweight boys, whereas Fukushima had a slightly decreased prevalence of overweight girls, compared with the unaffected prefectures. The ecological study detected increases in the prevalence of overweight boys and girls in Fukushima who were 6-11 and 6-10years of age, respectively.These results suggest that in the affected prefectures, preschool children gained weight immediately after the earthquake. The long-term impact of the earthquake on early childhood growth was more variable among the affected prefectures, possibly as a result of different speeds of recovery.
PubMed | Center for Clinical Research and Development, Tokyo Women's Medical University, Fukushima Medical University, Nagoya University and 10 more.
Type: Journal Article | Journal: Clinical and experimental nephrology | Year: 2016
Transition of adolescent and young adult (AYA) patients with childhood-onset chronic kidney diseases (C-CKD) from pediatric to adult renal services has received increasing attention. However, information on transition of Japanese patients with C-CKD is limited.The Transition Medicine Working Group, in collaboration with the Japanese Society for Nephrology, the Japanese Society for Pediatric Nephrology and the Japanese Society of Pediatric Urology, conducted a retrospective cross-sectional study in 2014 on issues concerning the transition of Japanese patients with C-CKD.Few institutions in Japan had transition programs and/or transition coordinators for patients with C-CKD. Refusal to transfer by patients or their families, lack of concern about transition and inability to decide on transfer were common reasons for non-transfer of patients still followed by pediatric renal services. Around 25% of patients who had ended or interrupted follow-up by pediatric renal services presented to adult renal services because of symptoms associated with C-CKD. Patients with various types of childhood-onset nephrourological diseases were transferred from pediatric to adult renal services. IgA nephropathy, minimal change nephrotic syndrome and congenital anomalies of the kidney and urinary tract were the most frequent primary kidney diseases in adult patients with C-CKD.These survey results indicate the need for introduction of transitional care for Japanese AYA patients with C-CKD. Consensus guidelines for the optimal clinical management of AYA patients with C-CKD are required to ensure the continuity of care from child to adult renal services.
PubMed | Shinshu University, Shizuoka Cancer Center, Gifu University, Kitakyushu Municipal Medical Center and 17 more.
Type: | Journal: Journal of gastroenterology | Year: 2016
Although radical surgery is routinely performed for patients who do not meet the curative criteria for endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) due to the risk of lymph node metastasis (LNM), this standard therapeutic option may be excessive given the lower number of patients with LNM. Therefore, we aimed to investigate long-term outcomes and validate risk factors predicting recurrence after ESD.Of 15,785 patients who underwent ESD for EGC at 19 institutions between 2000 and 2011, 1969 patients not meeting the curative criteria were included in this multi-center study. Based on the treatment strategy after ESD, patients were divided into radical surgery (n=1064) and follow-up (no additional treatment, n=905) groups.Overall survival (OS) and disease-specific survival (DSS) were significantly higher in the radical surgery group than in the follow-up group (p<0.001 and p=0.012, respectively). However, the difference in 3-year DSS between the groups (99.4 vs. 98.7%) was rather small compared with the difference in 3-year OS (96.7 vs. 84.0%). LNM was found in 89 patients (8.4%) in the radical surgery group. Lymphatic invasion was found to be an independent risk factor for recurrence in the follow-up group (hazard ratio 5.23; 95% confidence interval 2.01-13.6; p=0.001).This multi-center study, representing the largest cohort to date, revealed a large discrepancy between OS and DSS in the two groups. Since follow-up with no additional treatment after ESD may be an acceptable option for patients at low risk, further risk stratification is needed for appropriate individualized treatment strategies.
News Article | November 28, 2016
Tohoku University Graduate School of Medicine and Tohoku Medical Megabank Organization (ToMMo) are pleased to announce the published results of a study into why air pollutants cause some people to be more susceptible to atopic dermatitis, a kind of skin inflammation. "We have discovered that AhR, a transcription factor activated by air pollutants, causes hypersensitivity to itch, through the expression of neurotrophic factor artemin," says Dr. Masayuki Yamamoto, who led the research team with Drs. Takanori Hidaka and Eri Kobayashi. "Scratching makes things worse because the skin barrier gets disrupted and sensitization to antigens is enhanced. That's why some people are predisposed to atopic dermatitis." While the correlation between air pollution and the prevalence and severity of atopic dermatitis is well known, the underlying mechanism behind it was not widely understood, until now. Itch causes scratching, which disrupts the skin barrier function, making it easy for antigens to penetrate. This results in the patients being sensitized to antigens and predisposed to allergic diseases such as asthma. This is known as "the allergic march," and is observed in patients with atopic dermatitis. In human clinical samples, high levels of AhR activation and artemin expression are observed in atopic dermatitis patients but not in healthy individuals. This is also consistent with the findings in a similar study of mice, and further supports the notion that chronic activation of AhR is an important environmental factor causing atopic dermatitis. Currently, steroid drugs are used as a symptomatic treatment for atopic dermatitis. However, in some cases, the itch remains. The research team believes that control of the itch is important and hopes that with the results of this study, new treatments using inhibitors of AhR and/or artemin can be found.
Hirotsu Y.,Tohoku Medical Megabank Organization |
Katsuoka F.,Tohoku Medical Megabank Organization |
Funayama R.,Tohoku University |
Nagashima T.,Tohoku University |
And 4 more authors.
Nucleic Acids Research | Year: 2012
NF-E2-related factor 2 (Nrf2) is a key transcription factor that is critical for cellular defense against oxidative and xenobiotic insults. Nrf2 heterodimerizes with small Maf (sMaf) proteins and binds to antioxidant response elements (AREs) to activate a battery of cytoprotective genes. However, it remains unclear to what extent the Nrf2-sMaf heterodimers contribute to ARE-dependent gene regulation on a genome-wide scale. We performed chromatin immunoprecipitation coupled with high-throughput sequencing and identified the binding sites of Nrf2 and MafG throughout the genome. Compared to sites occupied by Nrf2 alone, many sites co-occupied by Nrf2 and MafG exhibit high enrichment and are located in species-conserved genomic regions. The ARE motifs were significantly enriched among the recovered Nrf2-MafG-binding sites but not among the Nrf2-binding sites that did not display MafG binding. The majority of the Nrf2-regulated cytoprotective genes were found in the vicinity of Nrf2-MafG-binding sites. Additionally, sequences that regulate glucose metabolism and several amino acid transporters were identified as Nrf2-MafG target genes, suggesting diverse roles for the Nrf2-MafG heterodimer in stress response. These data clearly support the notion that Nrf2-sMaf heterodimers are complexes that regulate batteries of genes involved in various aspects of cytoprotective and metabolic functions through associated AREs. © 2012 The Author(s).
De Aguiar Vallim T.Q.,University of California at Los Angeles |
Tarling E.J.,University of California at Los Angeles |
Ahn H.,University of California at Los Angeles |
Hagey L.R.,University of California at San Diego |
And 6 more authors.
Cell Metabolism | Year: 2015
Summary Specific bile acids are potent signaling molecules that modulate metabolic pathways affecting lipid, glucose and bile acid homeostasis, and the microbiota. Bile acids are synthesized from cholesterol in the liver, and the key enzymes involved in bile acid synthesis (Cyp7a1, Cyp8b1) are regulated transcriptionally by the nuclear receptor FXR. We have identified an FXR-regulated pathway upstream of a transcriptional repressor that controls multiple bile acid metabolism genes. We identify MafG as an FXR target gene and show that hepatic MAFG overexpression represses genes of the bile acid synthetic pathway and modifies the biliary bile acid composition. In contrast, loss-of-function studies using MafG+/- mice causes de-repression of the same genes with concordant changes in biliary bile acid levels. Finally, we identify functional MafG response elements in bile acid metabolism genes using ChIP-seq analysis. Our studies identify a molecular mechanism for the complex feedback regulation of bile acid synthesis controlled by FXR. © 2015 Elsevier Inc.
Yamada T.,University of Tsukuba |
Yamada T.,RIKEN |
Abei M.,University of Tsukuba |
Danjoh I.,Tohoku Medical Megabank Organization |
And 4 more authors.
BMC Cancer | Year: 2015
Backgrounds: Cancer stem cell (CSC) research has highlighted the necessity of developing drugs targeting CSCs. We investigated a hepatocellular carcinoma (HCC) cell line that not only has CSC hierarchy but also shows phenotypic changes (population changes) upon differentiation of CSC during culture and can be used for screening drugs targeting CSC. Methods: Based on a hypothesis that the CSC proportion should decrease upon its differentiation into progenitors (population change), we tested HCC cell lines (HuH-7, Li-7, PLC/PRF/5, HLF, HLE) before and after 2 months culture for several markers (CD13, EpCAM, CD133, CD44, CD90, CD24, CD166). Tumorigenicity was tested using nude mice. To evaluate the CSC hierarchy, we investigated reconstructivity, proliferation, ALDH activity, spheroid formation, chemosensitivity and microarray analysis of the cell populations sorted by FACS. Results: Only Li-7 cells showed a population change during culture: the proportion of CD13 positive cells decreased, while that of CD166 positive cells increased. The high tumorigenicity of the Li-7 was lost after the population change. CD13(+)/CD166(-) cells showed slow growth and reconstructed the bulk Li-7 populations composed of CD13(+)/CD166(-), CD13(-)/CD166(-) and CD13(-)/CD166(+) fractions, whereas CD13(-)/CD166(+) cells showed rapid growth but could not reproduce any other population. CD13(+)/CD166(-) cells showed high ALDH activity, spheroid forming ability and resistance to 5-fluorouracil. Microarray analysis demonstrated higher expression of stemness-related genes in CD166(-) than CD166(+) fraction. These results indicated a hierarchy in Li-7 cells, in which CD13(+)/CD166(-) and CD13(-)/CD166(+) cells serve as slow growing CSCs and rapid growing progenitors, respectively. Sorafenib selectively targeted the CD166(-) fraction, including CD13(+) CSCs, which exhibited higher mRNA expression for FGF3 and FGF4, candidate biomarkers for sorafenib. 5-fluorouracil followed by sorafenib inhibited the growth of bulk Li-7 cells more effectively than the reverse sequence or either alone. Conclusions: We identified a unique HCC line, Li-7, which not only shows heterogeneity for a CD13(+) CSC hierarchy, but also undergoes a "population change" upon CSC differentiation. Sorafenib targeted the CSC in vitro, supporting the use of this model for screening drugs targeting the CSC. This type of "heterogeneous, unstable" cell line may prove more useful in the CSC era than conventional "homogeneous, stable" cell lines. © Yamada et al.
PubMed | Tajimi Iwase Eye Clinic, Jikei University School of Medicine, Chiyoda Corporation, Tohoku Medical Megabank Organization and 2 more.
Type: | Journal: Clinical ophthalmology (Auckland, N.Z.) | Year: 2017
We have shown a decrease in mean intraocular pressure (IOP) by switching to travoprost/timolol fixed combination (TTFC) in subjects receiving prostaglandin analogue (PGA) monotherapy and requiring additional medication in a previous report. For analyzing factors affecting IOP reduction, baseline IOP and preceding PGA were selected as statistically and clinically significant factors. In this report, we examine IOP-lowering effect and adverse drug reactions by preceding PGA.Patients with primary open angle glaucoma or ocular hypertension who received monotherapy with one of four PGAs (travoprost, latanoprost, tafluprost, or bimatoprost) for at least 3 months at 26 institutions and were determined to require additional medication by their primary physician were included. IOP reduction and adverse events were examined at 4, 8, and 12 weeks for each of four PGAs after switching to TTFC.In total, 157 patients who could be followed up for at least 4 weeks after switching to TTFC were included in the efficacy analysis. Multiple regression analysis was performed, and baseline IOP and PGA were found to be significant factors to IOP reduction. IOP reduction at week 12, adjusted with the regression model, was -3.5, -1.8, and -1.4 mmHg in the tafluprost, latanoprost, and travoprost groups, whereas it was -0.5 mmHg in the bimatoprost group. Along with differences in baseline IOP between groups, an IOP-lowering effect of >1 mmHg was noted in the tafluprost, latanoprost, and travoprost groups after the switch. IOP was maintained at 13.8-14.8 mmHg throughout the follow-up period. No serious adverse events or noteworthy issues were observed in any group after the switch.Clinically significant IOP-reducing effects of TTFC were observed in the latanoprost, travoprost, and tafluprost groups when switching from each PGA monotherapy, while there were some differences in effects between groups, with minimal safety concerns.
PubMed | Tohoku Medical Megabank Organization, Tohoku University and University of Tokyo
Type: Journal Article | Journal: PloS one | Year: 2016
Although sphingosine 1-phosphate (S1P) has been reported to play an important role in cancer pathophysiology, little is known about S1P and hepatocellular carcinoma (HCC). To clarify the relationship between S1P and HCC, 77 patients with HCC who underwent surgical treatment were consecutively enrolled in this study. In addition, S1P and its metabolites were quantitated by LC-MS/MS. The mRNA levels of sphingosine kinases (SKs), which phosphorylate sphingosine to generate S1P, were increased in HCC tissues compared with adjacent non-HCC tissues. Higher mRNA levels of SKs in HCC were associated with poorer differentiation and microvascular invasion, whereas a higher level of SK2 mRNA was a risk factor for intra- and extra-hepatic recurrence. S1P levels, however, were unexpectedly reduced in HCC compared with non-HCC tissues, and increased mRNA levels of S1P lyase (SPL), which degrades S1P, were observed in HCC compared with non-HCC tissues. Higher SPL mRNA levels in HCC were associated with poorer differentiation. Finally, in HCC cell lines, inhibition of the expression of SKs or SPL by siRNA led to reduced proliferation, invasion and migration, whereas overexpression of SKs or SPL enhanced proliferation. In conclusion, increased SK and SPL mRNA expression along with reduced S1P levels were more commonly observed in HCC tissues compared with adjacent non-HCC tissues and were associated with poor differentiation and early recurrence. SPL as well as SKs may be therapeutic targets for HCC treatment.