Showing papers by "Kumamoto University published in 2012"
Shiga University of Medical Science1, Kumamoto University2, Tohoku University3, Osaka Medical College4, Nippon Medical School5, Wakayama Medical University6, Hyogo College of Medicine7, Kawasaki Medical School8, Kagoshima University9, National Institute of Advanced Industrial Science and Technology10, Tokyo Dental College11, Gunma University12, Memorial Hospital of South Bend13, University of Tokyo14
TL;DR: The JDS extensively evaluated the usefulness and feasibility of more extended use of HbA1c in the diagnosis of diabetes based on Japanese epidemiological data, and then the ‘Report of the Committee on the Classification and Diagnostic Criteria of Diabetes Mellitus’ was published in the Journal of Diabetes Investigation5 and Diabetology International.
Abstract: In 1999, the Japan Diabetes Society (JDS) launched the previous version of the diagnostic criteria of diabetes mellitus, in which JDS took initiative in adopting glycated hemoglobin (HbA1c) as an adjunct to the diagnosis of diabetes. In contrast, in 2009 the International Expert Committee composed of the members of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) manifested the recommendation regarding the use of HbA1c in diagnosing diabetes mellitus as an alternative to glucose measurements based on the updated evidence showing that HbA1c has several advantages as a marker of chronic hyperglycemia2–4. The JDS extensively evaluated the usefulness and feasibility of more extended use of HbA1c in the diagnosis of diabetes based on Japanese epidemiological data, and then the ‘Report of the Committee on the Classification and Diagnostic Criteria of Diabetes Mellitus’ was published in the Journal of Diabetes Investigation5 and Diabetology International6. The new diagnostic criterion in Japan came into effect on 1 July 2010. According to the new version of the criteria, HbA1c (JDS) ≥6.1% is now considered to indicate a diabetic type, but the previous diagnosis criteria of high plasma glucose (PG) levels to diagnose diabetes mellitus also need to be confirmed. Those are as follows: (i) FPG ≥126 mg/dL (7.0 mmol/L); (ii) 2‐h PG ≥200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test; or (iii) casual PG ≥200 mg/dL (11.1 mmol/L). If both PG criteria and HbA1c in patients have met the diabetic type, those patients are immediately diagnosed to have diabetes mellitus5,6.
825 citations
University of Toronto1, German Cancer Research Center2, Harvard University3, Broad Institute4, University of British Columbia5, Heidelberg University6, Memorial Sloan Kettering Cancer Center7, Vanderbilt University8, Sanford-Burnham Institute for Medical Research9, Medical University of Vienna10, Curie Institute11, University of Lausanne12, Seoul National University13, Johns Hopkins University14, University of Lyon15, University of Pittsburgh16, University of Michigan17, University of Alabama at Birmingham18, Catholic University of the Sacred Heart19, Erasmus University Rotterdam20, Boston Children's Hospital21, University of Washington22, Masaryk University23, Hamilton Health Sciences24, McMaster University25, Duke University26, McGill University27, McGill University Health Centre28, Newcastle University29, University of California, San Francisco30, University of Debrecen31, Tohoku University32, Saint Louis University33, Washington University in St. Louis34, University of California, Los Angeles35, Emory University36, University of Cincinnati37, Kumamoto University38, Semmelweis University39, University of Arkansas for Medical Sciences40, University of Naples Federico II41, Chonnam National University42, University of São Paulo43, University of Colorado Denver44, University of Ulsan45, University of Calgary46, Stanford University47
TL;DR: Somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas are reported, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Groups 4, which suggest future avenues for rational, targeted therapy.
Abstract: Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy.
749 citations
Duke University1, Uppsala University2, University of Kentucky3, University of Alberta4, Katholieke Universiteit Leuven5, Auckland City Hospital6, Flinders University7, Merck & Co.8, University of Tennessee Health Science Center9, University of Perugia10, University of Freiburg11, University of Barcelona12, Ufuk University13, Henry Ford Health System14, Peking Union Medical College15, Leiden University16, Cleveland Clinic17, Pierre-and-Marie-Curie University18, University of São Paulo19, Kumamoto University20, University of Basel21, University of Chile22, University of Sheffield23, University of Ferrara24, Thomas Jefferson University25, Charles University in Prague26
TL;DR: In patients with acute coronary syndromes, the addition of vorapaxar to standard therapy did not significantly reduce the primary composite end point but significantly increased the risk of major bleeding, including intracranial hemorrhage.
Abstract: In patients with acute coronary syndromes, the addition of vorapaxar to standard therapy did not significantly reduce the primary composite end point but significantly increased the risk of major bleeding, including intracranial hemorrhage. (Funded by Merck; TRACER ClinicalTrials.gov number, NCT00527943.).
690 citations
TL;DR: KW-0761 demonstrated clinically meaningful antitumor activity in patients with relapsed ATL, with an acceptable toxicity profile, and further investigation of KW-761 for treatment of ATL and other T-cell neoplasms is warranted.
Abstract: Purpose Adult T-cell leukemia-lymphoma (ATL) is usually resistant to conventional chemotherapies, and there are few other treatment options. Because CC chemokine receptor 4 (CCR4) is expressed on tumor cells from most patients with ATL, KW-0761, a humanized anti-CCR4 monoclonal antibody, which markedly enhances antibody-dependent cellular cytotoxicity, was evaluated in the treatment of patients with relapsed ATL. Patients and Methods A multicenter phase II study of KW-0761 for patients with relapsed, aggressive CCR4-positive ATL was conducted to evaluate efficacy, pharmacokinetic profile, and safety. The primary end point was overall response rate, and secondary end points included progression-free and overall survival from the first dose of KW-0761. Patients received intravenous infusions of KW-0761 once per week for 8 weeks at a dose of 1.0 mg/kg. Results Of 28 patients enrolled onto the study, 27 received at least one infusion of KW-0761. Objective responses were noted in 13 of 26 evaluable patients, i...
563 citations
TL;DR: This is the first report on the occurrence of bisphenols, other than BPA, in indoor dust, and the estimated median daily intake of ∑BPs through dust ingestion in the U.S., China, Japan, and Korea was 12.6 ng/kg body weight (bw)/day for toddlers and 1.13 ng/ kg bw/day for adults.
Abstract: Bisphenol A has been reported to be a ubiquitous contaminant in indoor dust, and human exposure to this compound is well documented. Information on the occurrence of and human exposure to other bisphenol analogues is limited. In this study, eight bisphenol analogues, namely 2,2-bis(4-hydroxyphenyl)propane (BPA), 4,4′-(hexafluoroisopropylidene)diphenol (BPAF), 4,4′-(1-phenylethylidene)bisphenol (BPAP), 2,2-bis(4-hydroxyphenyl)butane (BPB), 4,4′-dihydroxydiphenylmethane (BPF), 4,4′-(1,4-phenylenediisopropylidene)bisphenol (BPP), 4,4′- sulfonyldiphenol (BPS), and 4,4′-cyclohexylidenebisphenol (BPZ), were determined in indoor dust samples (n = 156) collected from the United States (U.S.), China, Japan, and Korea. Samples were extracted by solid–liquid extraction, purified by automated solid phase extraction methods, and determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The total concentrations of bisphenols (∑BPs; sum of eight bisphenols) in dust were in the range of 0.026–111 μg/g (geo...
463 citations
TL;DR: It is found that treatment of cells with tert-butylhydroquinone accelerated the Keap1 degradation and this results indicate that Nrf2 accumulation is the dominant cause to provoke the liver damage in the autophagy-deficient mice.
Abstract: The Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) system is essential for cytoprotection against oxidative and electrophilic insults. Under unstressed conditions, Keap1 serves as an adaptor for ubiquitin E3 ligase and promotes proteasomal degradation of Nrf2, but Nrf2 is stabilized when Keap1 is inactivated under oxidative/electrophilic stress conditions. Autophagy-deficient mice show aberrant accumulation of p62, a multifunctional scaffold protein, and develop severe liver damage. The p62 accumulation disrupts the Keap1-Nrf2 association and provokes Nrf2 stabilization and accumulation. However, individual contributions of p62 and Nrf2 to the autophagy-deficiency–driven liver pathogenesis have not been clarified. To examine whether Nrf2 caused the liver injury independent of p62, we crossed liver-specific Atg7::Keap1-Alb double-mutant mice into p62- and Nrf2-null backgrounds. Although Atg7::Keap1-Alb::p62−/− triple-mutant mice displayed defective autophagy accompanied by the robust accumulation of Nrf2 and severe liver injury, Atg7::Keap1-Alb::Nrf2−/− triple-mutant mice did not show any signs of such hepatocellular damage. Importantly, in this study we noticed that Keap1 accumulated in the Atg7- or p62-deficient mouse livers and the Keap1 level did not change by a proteasome inhibitor, indicating that the Keap1 protein is constitutively degraded through the autophagy pathway. This finding is in clear contrast to the Nrf2 degradation through the proteasome pathway. We also found that treatment of cells with tert-butylhydroquinone accelerated the Keap1 degradation. These results thus indicate that Nrf2 accumulation is the dominant cause to provoke the liver damage in the autophagy-deficient mice. The autophagy pathway maintains the integrity of the Keap1-Nrf2 system for the normal liver function by governing the Keap1 turnover.
392 citations
TL;DR: In this article, the authors identify populations of progenitor cells that are Tie2 positive (Tie2+) and disialoganglioside 2 positive (GD2+), in the nucleus pulposus from mice and humans.
Abstract: Despite the high prevalence of intervertebral disc disease, little is known about changes in intervertebral disc cells and their regenerative potential with ageing and intervertebral disc degeneration. Here we identify populations of progenitor cells that are Tie2 positive (Tie2+) and disialoganglioside 2 positive (GD2+), in the nucleus pulposus from mice and humans. These cells form spheroid colonies that express type II collagen and aggrecan. They are clonally multipotent and differentiated into mesenchymal lineages and induced reorganization of nucleus pulposus tissue when transplanted into non-obese diabetic/severe combined immunodeficient mice. The frequency of Tie2+ cells in tissues from patients decreases markedly with age and degeneration of the intervertebral disc, suggesting exhaustion of their capacity for regeneration. However, progenitor cells (Tie2+GD2+) can be induced from their precursor cells (Tie2+GD2-) under simple culture conditions. Moreover, angiopoietin-1, a ligand of Tie2, is crucial for the survival of nucleus pulposus cells. Our results offer insights for regenerative therapy and a new diagnostic standard.
342 citations
TL;DR: iRhom2 is identified as a regulator of innate immunity that may be an important target for modulating sepsis and pathogen defense and was critical for TACE maturation and trafficking to the cell surface in hematopoietic cells.
Abstract: Innate immune responses are vital for pathogen defense but can result in septic shock when excessive. A key mediator of septic shock is tumor necrosis factor–α (TNFα), which is shed from the plasma membrane after cleavage by the TNFα convertase (TACE). We report that the rhomboid family member iRhom2 interacted with TACE and regulated TNFα shedding. iRhom2 was critical for TACE maturation and trafficking to the cell surface in hematopoietic cells. Gene-targeted iRhom2-deficient mice showed reduced serum TNFα in response to lipopolysaccharide (LPS) and could survive a lethal LPS dose. Furthermore, iRhom2-deficient mice failed to control the replication of Listeria monocytogenes. Our study has identified iRhom2 as a regulator of innate immunity that may be an important target for modulating sepsis and pathogen defense.
301 citations
TL;DR: It is suggested that several CVD-associated SNPs in the 9p21 locus affect the expression of ANRIL, which, in turn modulate cell growth, possibly via CDKN2A/B regulation.
294 citations
Wellcome Trust Sanger Institute1, Dresden University of Technology2, National Institutes of Health3, Genome Canada4, Technische Universität München5, Regeneron6, Texas A&M University7, University of Texas at Austin8, Mount Sinai Hospital9, Erasmus University Medical Center10, University of Manitoba11, Katholieke Universiteit Leuven12, Children's Hospital Oakland Research Institute13, University of California14, Goethe University Frankfurt15, National Institute on Drug Abuse16, University of Calgary17, European Bioinformatics Institute18, Charité19, University of Cambridge20, University of British Columbia21, Ottawa Hospital Research Institute22, Kumamoto University23, Max Planck Society24
TL;DR: The IKMC materials considerably enhance functional gene annotation of the mammalian genome and will have a major impact on future biomedical research.
Abstract: In 2007, the International Knockout Mouse Consortium (IKMC) made the ambitious promise to generate mutations in virtually every protein-coding gene of the mouse genome in a concerted worldwide action. Now, 5 years later, the IKMC members have developed high-throughput gene trapping and, in particular, gene-targeting pipelines and generated more than 17,400 mutant murine embryonic stem (ES) cell clones and more than 1,700 mutant mouse strains, most of them conditional. A common IKMC web portal (www.knockoutmouse.org) has been established, allowing easy access to this unparalleled biological resource. The IKMC materials considerably enhance functional gene annotation of the mammalian genome and will have a major impact on future biomedical research.
285 citations
TL;DR: In this article, the authors investigated the efficacy and safety of TAS-102 (35 mg/m 2 given orally twice a day in a 28-day cycle [2-week cycle of 5 days of treatment followed by a 2-day rest period, and then a 14-day period] or placebo; all patients received best supportive care.
Abstract: Summary Background Treatments that confer survival benefit are needed in patients with heavily pretreated metastatic colorectal cancer. The aim of this trial was to investigate the efficacy and safety of TAS-102—a novel oral nucleoside antitumour agent. Methods Between August 25, 2009, and April 12, 2010, we undertook a multicentre, double-blind, randomised, placebo-controlled phase 2 trial in Japan. Eligible patients were 20 years or older; had confirmed colorectal adenocarcinoma; had a treatment history of two or more regimens of standard chemotherapy; and were refractory or intolerant to fluoropyrimidine, irinotecan, and oxaliplatin. Patients had to be able to take oral drugs; have measurable lesions; have an Eastern Cooperative Oncology Group performance status of between 0 and 2; and have adequate bone-marrow, hepatic, and renal functions within 7 days of enrolment. Patients were randomly assigned (2:1) to either TAS-102 (35 mg/m 2 given orally twice a day in a 28-day cycle [2-week cycle of 5 days of treatment followed by a 2-day rest period, and then a 14-day rest period]) or placebo; all patients received best supportive care. Randomisation was done with minimisation methods, with performance status as the allocation factor. The randomisation sequence was generated with a validated computer system by an independent team from the trial sponsor. Investigators, patients, data analysts, and the trial sponsor were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. Safety analyses were done in the per-protocol population. The study is in progress and is registered with Japan Pharmaceutical Information Center, number JapicCTI-090880. Findings 112 patients allocated to TAS-102 and 57 allocated to placebo made up the intention-to-treat population. Median follow-up was 11·3 months (IQR 10·7–14·0). Median overall survival was 9·0 months (95% CI 7·3–11·3) in the TAS-102 group and 6·6 months (4·9–8·0) in the placebo group (hazard ratio for death 0·56, 80% CI 0·44–0·71, 95% CI 0·39–0·81; p=0·0011). 57 (50%) of 113 patients given TAS-102 in the safety population had neutropenia of grade 3 or 4, 32 (28%) leucopenia, and 19 (17%) anaemia. No patient given placebo had grade 3 or worse neutropenia or leucopenia; three (5%) of 57 had grade 3 or worse anaemia. Serious adverse events occurred in 21 (19%) patients in the TAS-102 group and in five (9%) in the placebo group. No treatment-related deaths occurred. Interpretation TAS-102 has promising efficacy and a manageable safety profile in patients with metastatic colorectal cancer who are refractory or intolerant to standard chemotherapies. Funding Taiho Pharmaceutical.
TL;DR: It is found that the D1 dopamine receptor (DA1) in the dorsal fan-shaped body (dFSB) mediates the arousal effect of dopamine in Drosophila and suggests that a local dopamine pathway regulates sleep.
Abstract: Dopamine signaling is known to influence sleep and arousal in Drosophila. Here the authors identify the circuitry underlying the effect of dopamine on arousal, which involves D1 dopamine receptors in the dorsal fan-shaped body as the target of dopaminergic projections.
TL;DR: It is reported that enzymatically generated hydrogen sulfide anion (HS(-)) regulates the metabolism and signaling actions of various electrophiles and acts as a unique mechanism for regulating electrophile-mediated redox signaling.
Abstract: Hydrogen sulfide anion reacts with cellular electrophiles, including 8-nitro-cGMP, and sulfhydration products inhibit S-guanylation–dependent H-Ras activation in cardiac inflammatory injury models.
TL;DR: A DPP-4 inhibitor, DFS, exhibited antiatherogenic effects through augmenting GLP-1 activity in macrophages and endothelium, and sustained endothelial nitric oxide synthase phosphorylation and decreased endothelial senescence and apoptosis compared with GLp-1 alone.
TL;DR: Peripheral endothelial dysfunction independently correlated with future cardiovascular events, adding incremental clinical significance for risk stratification in patients with HFNEF.
TL;DR: Transient electron densities indicate that deprotonation and an accompanying C2′-endo to C3″-endo conversion of the nucleophile 3′-OH are rate limiting and may be an unappreciated feature of the two-metal-ion mechanism.
Abstract: DNA synthesis has been extensively studied, but the chemical reaction itself has not been visualized Here we follow the course of phosphodiester bond formation using time-resolved X-ray crystallography Native human DNA polymerase η, DNA and dATP were co-crystallized at pH 60 without Mg2+ The polymerization reaction was initiated by exposing crystals to 1 mM Mg2+ at pH 70, and stopped by freezing at desired time points for structural analysis The substrates and two Mg2+ ions are aligned within 40 s, but the bond formation is not evident until 80 s From 80 to 300 s structures show a mixture of decreasing substrate and increasing product of the nucleotidyl-transfer reaction Transient electron densities indicate that deprotonation and an accompanying C2′-endo to C3′-endo conversion of the nucleophile 3′-OH are rate limiting A third Mg2+ ion, which arrives with the new bond and stabilizes the intermediate state, may be an unappreciated feature of the two-metal-ion mechanism Atomic-resolution time courses of phosphodiester bond formation catalysed by DNA polymerase η reveal transient intermediate states and an unexpected third metal ion in the reaction mechanism Chemists would like to be able to determine the structures of true transition states in chemical reactions, but the high energy and unstable nature of transition states had made this goal unattainable Using a repair reaction catalysed by DNA polymerase η (Pol η) as their model, Wei Yang and colleagues have extended the use of flash–freeze technology to observe DNA synthesis in real time and at atomic resolution using X-ray crystallography to analyse the trapped covalent intermediates Pol η is particularly well suited to this approach because it has a slow rate of reaction and a relatively rigid catalytic centre The observed reaction intermediates reveal several unanticipated transient states, and implicate an unexpected third magnesium ion in the reaction mechanism
TL;DR: In conclusion, the esterase expression and hydrolyzing pattern of dog plasma were found to be closest to that of human plasma, and should be considered when selecting model animals for preclinical studies.
TL;DR: Because cholinergic deficits are prominent in dementia with Lewy bodies, the effects of a cholinesterase inhibitor, donepezil, in such patients in a randomized, double‐blind, placebo‐controlled exploratory phase 2 trial are investigated.
Abstract: Objective Because cholinergic deficits are prominent in dementia with Lewy bodies (DLB), we investigated the effects of a cholinesterase inhibitor, donepezil, in such patients in a randomized, double-blind, placebo-controlled exploratory phase 2 trial. Methods One-hundred forty patients with DLB, recruited from 48 specialty centers in Japan, were randomly assigned to receive placebo or 3, 5, or 10 mg of donepezil hydrochloride daily for 12 weeks (n = 35, 35, 33, and 37, respectively). Effects on cognitive function were assessed using the Mini-Mental State Examination (MMSE) and several domain-specific neuropsychological tests. Changes in behavior were evaluated using the Neuropsychiatric Inventory, caregiver burden using the Zarit Caregiver Burden Interview, and global function using the Clinician's Interview-Based Impression of Change-plus Caregiver Input (CIBIC-plus). Safety measures included the Unified Parkinson's Disease Rating Scale part III. Results Donepezil at 5 and 10 mg/day was significantly superior to placebo on both the MMSE (5 mg: mean difference, 3.8; 95% confidence interval [CI], 2.3-5.3; p Interpretation Donepezil at 5 and 10mg/day produces significant cognitive, behavioral, and global improvements that last at least 12 weeks in DLB patients, reducing caregiver burden at the highest dose. Donepezil is safe and well tolerated.
TL;DR: It is found that CD44, a cell surface marker for cancer stem cells, interacts with pyruvate kinase M2 (PKM2) and thereby enhances the glycolytic phenotype of cancer cells that are either deficient in p53 or exposed to hypoxia.
Abstract: An increased glycolytic flux accompanied by activation of the pentose phosphate pathway (PPP) is implicated in chemoresistance of cancer cells. In this study, we found that CD44, a cell surface marker for cancer stem cells, interacts with pyruvate kinase M2 (PKM2) and thereby enhances the glycolytic phenotype of cancer cells that are either deficient in p53 or exposed to hypoxia. CD44 ablation by RNA interference increased metabolic flux to mitochondrial respiration and concomitantly inhibited entry into glycolysis and the PPP. Such metabolic changes induced by CD44 ablation resulted in marked depletion of cellular reduced glutathione (GSH) and increased the intracellular level of reactive oxygen species in glycolytic cancer cells. Furthermore, CD44 ablation enhanced the effect of chemotherapeutic drugs in p53-deficient or hypoxic cancer cells. Taken together, our findings suggest that metabolic modulation by CD44 is a potential therapeutic target for glycolytic cancer cells that manifest drug resistance.
TL;DR: Zr(IV) loaded ligand exchange adsorbent is to be an effective means to treat arsenic(V) contaminated water efficiently and able to safeguard the human health.
TL;DR: This review will summarize and discuss recent progress and topics in p97 functions and the relationship to its associated diseases.
TL;DR: It is found that the loss of LSD1 function, either by short interfering RNA or by selective inhibitors in adipocytes, induces a number of regulators of energy expenditure and mitochondrial metabolism such as PPARγ coactivator-1α resulting in the activation of mitochondrial respiration.
Abstract: Environmental factors such as nutritional state may act on the epigenome that consequently contributes to the metabolic adaptation of cells and the organisms. The lysine-specific demethylase-1 (LSD1) is a unique nuclear protein that utilizes flavin adenosine dinucleotide (FAD) as a cofactor. Here we show that LSD1 epigenetically regulates energy-expenditure genes in adipocytes depending on the cellular FAD availability. We find that the loss of LSD1 function, either by short interfering RNA or by selective inhibitors in adipocytes, induces a number of regulators of energy expenditure and mitochondrial metabolism such as PPARγ coactivator-1α resulting in the activation of mitochondrial respiration. In the adipose tissues from mice on a high-fat diet, expression of LSD1-target genes is reduced, compared with that in tissues from mice on a normal diet, which can be reverted by suppressing LSD1 function. Our data suggest a novel mechanism where LSD1 regulates cellular energy balance through coupling with cellular FAD biosynthesis.
TL;DR: IL-17A signaling, not IL-17F, has an antifibrogenic effect via the upregulation of miR-129-5p and the downregulation of connective tissue growth factor and α1(I) collagen, which may lead to a new therapeutic approach for this disease.
Abstract: Among IL-17 families, IL-17A and IL-17F share amino acid sequence similarity and bind to IL-17R type A. IL-17 signaling is implicated in the pathogenesis of various autoimmune diseases, but its role in the regulatory mechanism of extracellular matrix expression and its contribution to the phenotype of systemic sclerosis (SSc) both remain to be elucidated. This study revealed that IL-17A expression was significantly increased in the involved skin and sera of SSc patients, whereas the IL-17F levels did not increase. In contrast, the expression of IL-17R type A in SSc fibroblasts significantly decreased in comparison with that in normal fibroblasts, due to the intrinsic TGF-β1 activation in these cell types. Moreover, IL-17A, not IL-17F, reduced the protein expression of α1(I) collagen and connective tissue growth factor. miR-129-5p, one of the downregulated microRNAs in SSc fibroblasts, increased due to IL-17A and mediated the α1(I) collagen reduction. These results suggest that IL-17A signaling, not IL-17F, has an antifibrogenic effect via the upregulation of miR-129-5p and the downregulation of connective tissue growth factor and α1(I) collagen. IL-17A signaling is suppressed due to the downregulation of the receptor by the intrinsic activation of TGF-β1 in SSc fibroblasts, which may amplify the increased collagen accumulation and fibrosis characteristic of SSc. Increased IL-17A levels in the sera and involved skin of SSc may be due to negative feedback. Clarifying the novel regulatory mechanisms of fibrosis by the cytokine network consisting of TGF-β and IL-17A may lead to a new therapeutic approach for this disease.
TL;DR: It is indicated that blastocyst complementation can be extended to generate PSC-derived kidneys, and this system may provide novel insights into renal organogenesis.
Abstract: Because a shortage of donor organs has been a major obstacle to the expansion of organ transplantation programs, the generation of transplantable organs is among the ultimate goals of regenerative medicine. However, the complex cellular interactions among and within tissues that are required for organogenesis are difficult to recapitulate in vitro . As an alternative, we used blastocyst complementation to generate pluripotent stem cell (PSC)–derived donor organs in vivo . We hypothesized that if we injected PSCs into blastocysts obtained from mutant mice in which the development of a certain organ was precluded by genetic manipulation, thereby leaving a niche for organ development, the PSC-derived cells would developmentally compensate for the defect and form the missing organ. In our previous work, we showed proof-of-principle findings of pancreas generation by injection of PSCs into pancreas-deficient Pdx1 −/− mouse blastocysts. In this study, we have extended this technique to kidney generation using Sall1 −/− mouse blastocysts. As a result, the defective cells were totally replaced, and the kidneys were entirely formed by the injected mouse PSC-derived cells, except for structures not under the influence of Sall1 expression (ie, collecting ducts and microvasculature). These findings indicate that blastocyst complementation can be extended to generate PSC-derived kidneys. This system may therefore provide novel insights into renal organogenesis.
TL;DR: It is suggested that CD44s plays a critical role in the TGF-β-mediated mesenchymal phenotype and therefore represents a potential therapeutic target for HCC.
Abstract: The prognosis for individuals diagnosed with hepatocellular carcinoma (HCC) remains poor because of the high frequency of invasive tumor growth, intrahepatic spread, and extrahepatic metastasis. Here, we investigated the role of the standard isoform of CD44 (CD44s), a major adhesion molecule of the extracellular matrix and a cancer stem cell marker, in the TGF-β-mediated mesenchymal phenotype of HCC. We found that CD44s was the dominant form of CD44 mRNA expressed in HCC cells. Overexpression of CD44s promoted tumor invasiveness and increased the expression of vimentin, a mesenchymal marker, in HCC cells. Loss of CD44s abrogated these changes. Also in the setting of CD44s overexpression, treatment with TGF-β1 induced the mesenchymal phenotype of HCC cells, which was characterized by low E-cadherin and high vimentin expression. Loss of CD44s inhibited TGF-β-mediated vimentin expression, mesenchymal spindle-like morphology, and tumor invasiveness. Clinically, overexpression of CD44s was associated with low expression of E-cadherin, high expression of vimentin, a high percentage of phospho-Smad2-positive nuclei, and poor prognosis in HCC patients, including reduced disease-free and overall survival. Together, our findings suggest that CD44s plays a critical role in the TGF-β-mediated mesenchymal phenotype and therefore represents a potential therapeutic target for HCC.
TL;DR: It is suggested that two different assemblies of Notch receptors coordinate the numbers and distribution of the major epithelial cell types in the conducting airway during lung organogenesis and that maintenance of Hes1 expression in epithelial cells is key to the regulation of pNEB size.
Abstract: In the developing lung, it is thought that the terminal buds of elongating airways contain a population of multipotent epithelial progenitors. As the bronchial tree extends, descendants of these cells give rise to lineage-restricted progenitors in the conducting airways via Notch signaling, which is involved in the establishment of epithelial Clara, ciliated and pulmonary neuroendocrine (NE) cell populations. However, the precise molecular details of this selection process are still emerging. Our stepwise removal of the three Notch receptors from the developing lung epithelium reveals that, whereas Notch2 mediates the Clara/ciliated cell fate decision with negligible contributions from Notch1 and Notch3, all three Notch receptors contribute in an additive manner to regulate the abundance of NE cells and the size of the presumptive pulmonary neuroepithelial body (pNEB) as a result of mutual interactions between NE cells and the Notch-dependent, SSEA-1(+), CC10(-) cell population surrounding the pNEB (SPNC cells). Ectopic expression of the Notch1 or Notch2 intracellular domain was sufficient to induce SSEA-1(+) cells and to suppress pNEB formation without expending Clara cells. We provide evidence that the additive functions of Notch receptors, together with other signaling pathways, maintains the expression of Hes1, a key regulator of NE cell fate, and that maintenance of Hes1 expression in epithelial cells is key to the regulation of pNEB size. These results suggest that two different assemblies of Notch receptors coordinate the numbers and distribution of the major epithelial cell types in the conducting airway during lung organogenesis.
TL;DR: miR-200b regulates ZEB2 expression and thus controls metastasis in gastric cancer patients and is associated with significantly reduced cellular proliferation, and inhibition of cellular migration and invasion.
Abstract: Background
The microRNA-200 (miR-200) family has been reported to induce epithelial differentiation and suppress epithelial–mesenchymal transition (EMT) by inhibiting translation of zinc finger E-box-binding homeobox (ZEB) 1 and 2 mRNAs in several types of cancers. This study aimed to clarify the role of miR-200b in regulating EMT and promoting cellular proliferation, invasion, and migration in gastric cancer.
TL;DR: Critical and distinct roles for Sall4 are demonstrated in development of embryonic germ cells and differentiation of postnatal spermatogonial progenitor cells (SPCs), suggesting that transcription factors required for embryonic tissue development postnatally take on distinct roles through interaction with opposing factors, which hence define properties of the adult stem cell compartment.
TL;DR: Using exome sequencing, it is determined that mutations in the UVSSA gene (formerly known as KIAA1530) cause UVSS-A, which interacts with TC-NER machinery and stabilizes the ERCC6 complex; it also facilitates ubiquitination of RNA polymerase IIo stalled at DNA damage sites.
Abstract: UV-sensitive syndrome (UVSS) is a genodermatosis characterized by cutaneous photosensitivity without skin carcinoma1, 2, 3, 4. Despite mild clinical features, cells from individuals with UVSS, like Cockayne syndrome cells, are very UV sensitive and are deficient in transcription-coupled nucleotide-excision repair (TC-NER)2, 4, 5, which removes DNA damage in actively transcribed genes6. Three of the seven known UVSS cases carry mutations in the Cockayne syndrome genes ERCC8 or ERCC6 (also known as CSA and CSB, respectively)7, 8. The remaining four individuals with UVSS, one of whom is described for the first time here, formed a separate UVSS-A complementation group1, 9, 10; however, the responsible gene was unknown. Using exome sequencing11, we determine that mutations in the UVSSA gene (formerly known as KIAA1530) cause UVSS-A. The UVSSA protein interacts with TC-NER machinery and stabilizes the ERCC6 complex; it also facilitates ubiquitination of RNA polymerase IIo stalled at DNA damage sites. Our findings provide mechanistic insights into the processing of stalled RNA polymerase and explain the different clinical features across these TC-NER–deficient disorders.
TL;DR: In this article, short-chain fatty acids accumulated in waste activated sludge (WAS) fermentation was adopted as an alternative extra carbon source for bio-hydrogen production in microbial electrolysis cells (MECs).