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1.
Acta Neuropathol Commun ; 8(1): 8, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32019606

RESUMO

Diffuse midline glioma, H3 K27M-mutant is a lethal brain tumor located in the thalamus, brain stem, or spinal cord. H3 K27M encoded by the mutation of a histone H3 gene such as H3F3A plays a pivotal role in the tumorigenesis of this type of glioma. Although several studies have revealed comprehensive genetic and epigenetic profiling, the prognostic factors of these tumors have not been identified to date. In various cancers, oncogenic driver genes have been found to exhibit characteristic copy number alterations termed mutant allele specific imbalance (MASI). Here, we showed that several diffuse midline glioma, H3 K27M-mutant exhibited high variant allele frequency (VAF) of the mutated H3F3A gene using droplet digital polymerase chain reaction (ddPCR) assays. Whole-genome sequencing (WGS) revealed that these cases had various copy number alterations that affected the mutant and/or wild-type alleles of the H3F3A gene. We also found that these MASI cases showed a significantly higher Ki-67 index and poorer survival compared with those in the lower VAF cases (P < 0.05). Our results indicated that the MASI of the H3F3A K27M mutation was associated with the aggressive phenotype of the diffuse midline glioma, H3 K27M-mutant via upregulation of the H3 K27M mutant protein, resulting in downregulation of H3K27me3 modification.

2.
Am J Infect Control ; 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31519478

RESUMO

Our infection control team initiated active screening for multidrug-resistant organisms (MDROs) among children who had been hospitalized abroad before their admission to our hospital. MDROs were detected in 19 of 34 cases (56%), including 3 isolates of Enterobacteriaceae harboring carbapenemase genes still rare in Japan. Early recognition of MDROs by screening this population may be required to avoid the introduction of new modes of resistance into the hospital environment.

3.
Cancer Res ; 79(19): 4814-4827, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31431463

RESUMO

Gliomas are classified by combining histopathologic and molecular features, including isocitrate dehydrogenase (IDH) status. Although IDH-wild-type diffuse astrocytic glioma (DAG) shows a more aggressive phenotype than IDH-mutant type, lack of knowledge regarding relevant molecular drivers for this type of tumor has hindered the development of therapeutic agents. Here, we examined human IDH-wild-type DAGs and a glioma mouse model with a mosaic analysis with double markers (MADM) system, which concurrently lacks p53 and NF1 and spontaneously develops tumors highly comparable with human IDH-wild-type DAG without characteristic molecular features of glioblastoma (DAG-nonMF). During tumor formation, enhancer of zeste homolog (EZH2) and the other polycomb repressive complex 2 (PRC2) components were upregulated even at an early stage of tumorigenesis, together with an increased number of genes with H3K27me3 or H3K27me3 and H3K4me3 bivalent modifications. Among the epigenetically dysregulated genes, frizzled-8 (Fzd8), which is known to be a cancer- and stem cell reprogramming-related gene, was gradually silenced during tumorigenesis. Genetic and pharmacologic inhibition of EZH2 in MADM mice showed reactivation of aberrant H3K27me3 target genes, including Fzd8, together with significant reduction of tumor size. Our study clarifies a pathogenic molecular pathway of IDH-wild-type DAG-nonMF that depends on EZH2 activity and provides a strong rationale for targeting EZH2 as a promising therapeutic approach for this type of glioma. SIGNIFICANCE: EZH2 is involved in the generation of IDH-wild-type diffuse astrocytic gliomas and is a potential therapeutic target for this type of glioma. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/19/4814/F1.large.jpg.

4.
Neuropediatrics ; 50(3): 160-163, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30939600

RESUMO

PURPOSE: This study was aimed to assess the accurate incidence of renal stones in severely disabled children treated with topiramate (TPM). METHOD: We reviewed the medical records of severely disabled children with epilepsy under 15 years old who underwent radiological examinations to investigate urinary stones. The study enrolled 26 patients who were divided into two groups. One group had been treated with TPM for at least 1 year and the other had not been treated with TPM, zonisamide, acetazolamide, or other diuretic drugs. We collected parameters from the medical records and compared the groups. RESULTS: All participants were evaluated radiologically, with computed tomography (CT) in two patients, ultrasonography in 22 patients, and both in two. No patient had any morphological abnormality of the kidneys and history of urinary tract infection. There were no significant differences in sex, age, body weight, or feeding manner between the groups, while the incidence of renal stones or calcifications was significantly higher in the TPM-treated group (60 vs. 0%; p = 0.00241). CONCLUSION: There is a high incidence of renal stone formation in severely disabled children treated with TPM.


Assuntos
Anticonvulsivantes/efeitos adversos , Crianças com Deficiência , Epilepsia/tratamento farmacológico , Cálculos Renais/induzido quimicamente , Índice de Gravidade de Doença , Topiramato/efeitos adversos , Adolescente , Criança , Pré-Escolar , Epilepsia/diagnóstico , Epilepsia/epidemiologia , Feminino , Humanos , Incidência , Cálculos Renais/diagnóstico , Cálculos Renais/epidemiologia , Masculino , Estudos Retrospectivos
5.
Gan To Kagaku Ryoho ; 46(2): 327-329, 2019 Feb.
Artigo em Japonês | MEDLINE | ID: mdl-30914549

RESUMO

A 71-year-old man underwent low anterior resection for rectal cancer 10 years prior. He underwent resection of liver metastasis once and that of lung metastases multiple times after the primary surgery. Computed tomography revealed a mass measuring 22mm in size in the pancreatic body 10 years after the rectal resection. We inspected it before surgery by performing EUS-FNA. On suspicion of metastasis of rectal cancer or primary pancreatic cancer, we performed distal pancreatectomy. The pancreatic tumor was diagnosed as metastasis of the rectal cancer. There were multiple metastases in the resected specimen that we were unable to indicate at the preoperative inspection. Resectable pancreatic metastasis from colorectal cancer is rare, but some patients with long-term survival have been reported. If a patient is tolerant to pancreatectomy and has no metastasis in other organs, the patient should be considered as a good candidate for pancreatectomy.


Assuntos
Neoplasias Pancreáticas , Neoplasias Retais , Idoso , Humanos , Masculino , Pancreatectomia , Neoplasias Pancreáticas/secundário , Neoplasias Pancreáticas/cirurgia , Neoplasias Retais/patologia , Resultado do Tratamento
6.
Gan To Kagaku Ryoho ; 46(3): 523-525, 2019 Mar.
Artigo em Japonês | MEDLINE | ID: mdl-30914602

RESUMO

We report a case of colostomy-free, long-term survival following 5-FU/CDDP for the local recurrence of anal cancer after chemoradiation therapy(CRT). The patient was a 48-year-old woman who was diagnosed with cStage ⅢA anal cancer. She was treated with CRT(5-FU/MMC plus 59 Gy)and achieved a complete response upon treatment completion. A local recurrence was detected on the left-side wall of her rectum after 6 months. We recommended abdominoperineal resection but the patient refused operation. The patient was treated with chemotherapy consisting of 5-FU(1,000mg/m / 2/day)on days 1-5 and CDDP(100mg/m / 2/day)on day 2. Grade 3 peripheral neuropathy appeared following the completion of 5 courses. Therefore, the dose was reduced to 60%. Twenty-five courses of this treatment were continued and chemotherapy was completed. The patient has been alive with no sign of recurrence for 6 years and 8 months from the initial treatment. CRT for anal cancer is becoming a standard therapy but local recurrence is possible. In these cases, abdominoperineal resection is required. Chemotherapy with 5-FU/CDDP in cases of recurrence can be a colostomy-free option.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias do Ânus , Quimiorradioterapia , Recidiva Local de Neoplasia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Ânus/tratamento farmacológico , Neoplasias do Ânus/radioterapia , Colostomia , Feminino , Fluoruracila , Humanos , Pessoa de Meia-Idade
7.
Cell Rep ; 26(9): 2274-2281.e5, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30811978

RESUMO

RET finger protein (RFP) forms a complex with histone deacetylase 1, resulting in aberrant deacetylation of H3K27ac and dysregulation of cis-regulatory elements. We evaluated the modulatory effects of RFP knockdown on cis-regulatory elements, gene expression, and chemosensitivity to temozolomide both in glioblastoma cells and in an intracranial glioblastoma model. The combination of RFP knockdown and temozolomide treatment markedly suppressed the glioblastoma cell growth due to oxidative stress and aberrant cell cycle and increased survival time in mice with glioblastoma. ChIP-seq and RNA-seq revealed that RFP knockdown increased or decreased activity of numerous cis-regulatory elements that lie adjacent to genes that control functions such as apoptosis, mitosis, DNA replication, and cell cycle: FOXO1, TBP2, and PARPBP. This study suggests that RFP contributes to chemoresistance via aberrant deacetylation of histone H3 at K27, whereas dysregulation of RFP-associated cis-regulatory elements in glioma and RFP knockdown combined with temozolomide is an effective treatment strategy for lethal glioma.

8.
J Pediatric Infect Dis Soc ; 8(2): 166-169, 2019 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-30010914

RESUMO

In this quasi-experimental study that included 3489 blood culture bottles, interventions that included the distribution of simple weight-stratified guidelines for recommended blood volume and monthly feedback to physicians were effective in optimizing blood volume for culture in a pediatric intensive care unit.


Assuntos
Hemocultura/métodos , Determinação do Volume Sanguíneo/métodos , Retroalimentação , Unidades de Terapia Intensiva Pediátrica , Bactérias/isolamento & purificação , Técnicas Bacteriológicas/métodos , Fungos/isolamento & purificação , Humanos
9.
Am J Physiol Renal Physiol ; 316(2): F263-F273, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30520657

RESUMO

Zinc (Zn2+) is the second most abundant trace element, but is considered a micronutrient, as it is a cofactor for many enzymes and transcription factors. Whereas Zn2+ deficiency can cause cognitive immune or metabolic dysfunction and infertility, excess Zn2+ is nephrotoxic. As for other ions and solutes, Zn2+ is moved into and out of cells by specific membrane transporters: ZnT, Zip, and NRAMP/DMT proteins. ZIP10 is reported to be localized at the apical membrane of renal proximal tubules in rats, where it is believed to play a role in Zn2+ import. Renal regulation of Zn2+ is of particular interest in light of growing evidence that Zn2+ may play a role in kidney stone formation. The objective of this study was to show that ZIP10 homologs transport Zn2+, as well as ZIP10, kidney localization across species. We cloned ZIP10 from dog, human, and Drosophila ( CG10006), tested clones for Zn2+ uptake in Xenopus oocytes and localized the protein in renal structures. CG10006, rather than foi (fear-of-intimacy, CG6817) is the primary ZIP10 homolog found in Drosophila Malpighian tubules. The ZIP10 antibody recognizes recombinant dog, human, and Drosophila ZIP10 proteins. Immunohistochemistry reveals that ZIP10 in higher mammals is found not only in the proximal tubule, but also in the collecting duct system. These ZIP10 proteins show Zn2+ transport. Together, these studies reveal ZIP10 kidney localization, a role in renal Zn2+ transport, and indicates that CG10006 is a Drosophila homolog of ZIP10.


Assuntos
Proteínas de Transporte de Cátions/metabolismo , Clonagem Molecular , Proteínas de Drosophila/metabolismo , Túbulos Renais Coletores/metabolismo , Túbulos Renais Proximais/metabolismo , Túbulos de Malpighi/metabolismo , Zinco/metabolismo , Animais , Transporte Biológico , Proteínas de Transporte de Cátions/genética , Cães , Proteínas de Drosophila/genética , Humanos , Especificidade da Espécie , Xenopus laevis
10.
J Glob Antimicrob Resist ; 17: 157-159, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30553930

RESUMO

OBJECTIVES: Here we describe a clinical isolate of Klebsiella pneumoniae ST11 harbouring both blaKPC-2 and rmtB genes in Japan. METHODS: A carbapenem- and aminoglycoside-resistant K. pneumoniae was isolated from an inpatient in Japan. Whole-genome sequencing (WGS) was performed using an Illumina next-generation sequencer. RESULTS: Minimum inhibitory concentrations (MICs) of meropenem and amikacin were ≥512µg/mL. WGS analysis revealed that the isolate harboured both blaKPC-2 and rmtB. The genetic environments of blaKPC-2 and rmtB consisted of IS6-orfA-orfB-IS481-blaKPC-2-ISKpn6-korC-orfC-orfD-rep-tnp-Tn3-IS6 and IS6-IS91-orfE-orfF-blaTEM-1-rmtB-orfG-IS6, respectively. These genetic environments are similar (>99% identity) to those of K. pneumoniae WCHKP040035 (accession no. CP028796) isolated in a Chinese hospital. The blaKPC-2 and rmtB genes were located on a 130-kb IncFII plasmid. CONCLUSIONS: This is the first report of a K. pneumoniae clinical isolate from Japan co-harbouring blaKPC-2 and rmtB on a 130-kb plasmid.

11.
Conf Proc IEEE Eng Med Biol Soc ; 2018: 1891-1894, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30440766

RESUMO

Powered prostheses with low degree of freedom (DoF) have been developed for people with disabilities to assist daily tasks. These prostheses neglect the user's compensatory movements caused by the low degree of freedom. We assume that the movements can be reduced by well-designed controller of the devices. This paper explores an optimal control gain of the powered prosthesis to prevent the user from compensatory movements through experiments. In the experiments, we developed 1-DoF hand prosthesis with a position-controlled servo, which includes the constant gain as a feed-forward term. The compensatory movements are regarded as a joint torque at a shoulder (abduction/adduction). 4 intact subjects performed a pick-and-place task, using the prosthesis with several control gains. The empirical results show that there was the optimal gain for each subject, which reduces their compensatory movement.


Assuntos
Membros Artificiais , Movimento , Desenho de Prótese , Articulação do Ombro , Articulação do Punho , Humanos , Torque
12.
J Med Microbiol ; 67(8): 1047-1049, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29972350

RESUMO

The mcr-1 gene encodes a phosphoethanolamine transferase, which confers resistance to colistin by transferring phosphoethanolamine to lipid A. This study describes the emergence of a colistin- and carbapenem-resistant clinical isolate of Escherichia coli harbouring mcr-1 and blaNDM-5 genes, located on 90 and 150 Kb plasmids, respectively. The isolate belonged to ST132. This is the first report of a clinical isolate in Japan co-harbouring mcr-1 and blaNDM-5.


Assuntos
Farmacorresistência Bacteriana , Proteínas de Escherichia coli/genética , Escherichia coli/genética , Escherichia coli/isolamento & purificação , Plasmídeos/análise , beta-Lactamases/genética , Antibacterianos , Carbapenêmicos/farmacologia , Pré-Escolar , Colistina/farmacologia , Escherichia coli/classificação , Infecções por Escherichia coli/microbiologia , Genótipo , Humanos , Japão , Masculino , Tipagem Molecular
13.
J Med Chem ; 61(14): 6339-6349, 2018 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-29936834

RESUMO

We designed and synthesized vitamin D analogues with an electrophile as covalent modifiers for the vitamin D receptor (VDR). Novel vitamin D analogues 1-4 have an electrophilic enone group at the side chain for conjugate addition to His301 or His393 in the VDR. All compounds showed specific VDR-binding potency and agonistic activity. Covalent bond formations of 1-4 with the ligand-binding domain (LBD) of VDR were evaluated by electrospray ionization mass spectrometry. All compounds were shown to covalently bind to the VDR-LBD, and the abundance of VDR-LBD corresponding conjugate adducts of 1-4 increased with incubation time. Enone compounds 1 and 2 showed higher reactivity than the ene-ynone 3 and dienone 4 compounds. Furthermore, we successfully obtained cocrystals of VDR-LBD with analogues 1-4. X-ray crystallographic analysis showed a covalent bond with His301 in VDR-LBD. We successfully synthesized vitamin D analogues that form a covalent bond with VDR-LBD.


Assuntos
Desenho de Drogas , Histidina , Receptores de Calcitriol/química , Receptores de Calcitriol/metabolismo , Humanos , Ligantes , Modelos Moleculares , Ligação Proteica , Domínios Proteicos
14.
Brain Tumor Pathol ; 35(2): 106-113, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29550880

RESUMO

The IDH-mutant and 1p/19q co-deletion (1p19q codel) provides significant diagnostic and prognostic value in lower-grade gliomas. As ATRX mutation and 1p19q codel are mutually exclusive, ATRX immunohistochemistry (IHC) may substitute for 1p19q codel, but this has not been comprehensively examined. In the current study, we performed ATRX-IHC in 78 gliomas whose ATRX statuses were comprehensively determined by whole exome sequencing. Among the 60 IHC-positive and 18 IHC-negative cases, 86.7 and 77.8% were ATRX-wildtype and ATRX-mutant, respectively. ATRX mutational patterns were not consistent with ATRX-IHC. If our cohort had only used IDH status and IHC-based ATRX expression for diagnosis, 78 tumors would have been subtyped as 48 oligodendroglial tumors, 16 IDH-mutant astrocytic tumors, and 14 IDH-wildtype astrocytic tumors. However, when the 1p19q codel test was performed following ATRX-IHC, 8 of 48 ATRX-IHC-positive tumors were classified as "1p19q non-codel" and 3 of 16 ATRX-IHC-negative tumors were classified as "1p19q codel"; a total of 11 tumors (14%) were incorrectly classified. In summary, we observed dissociation between ATRX-IHC and actual 1p19q codel in 11 of 64 IDH-mutant LGGs. In describing the complex IHC expression of ATRX somatic mutations, our results indicate the need for caution when using ATRX-IHC as a surrogate of 1p19q status.


Assuntos
Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Deleção de Genes , Expressão Gênica , Glioma/diagnóstico , Glioma/genética , Imuno-Histoquímica , Proteína Nuclear Ligada ao X/genética , Proteína Nuclear Ligada ao X/metabolismo , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Sequenciamento Completo do Exoma , Adulto Jovem
15.
Brain Tumor Pathol ; 35(2): 97-105, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29460200

RESUMO

Detection of mutations in the isocitrate dehydrogenase 1 (IDH1) gene is useful for accurate diagnosis of lower grade gliomas, as described in the 2016 World Health Organization classification of tumors of the central nervous system. Conventional analysis tools, including Sanger DNA sequencing and immunohistochemistry, might fail to detect a small fraction of mutant IDH1 owing to their limited sensitivity. Considering that lower grade gliomas are infiltrative in nature, a highly sensitive detection assay for IDH1 mutation is required for their accurate diagnosis. In this study, we successfully established a droplet digital PCR (ddPCR) system to detect a small fraction of IDH1 mutation. We could detect 0.05% of mutant IDH1 allele in 30 ng DNA. Using this assay, we could detect a small fraction of mutant IDH1 in a glioma case, identified as a wildtype tumor according to the conventional assays. Additionally, in a small amount of DNA derived from the cerebrospinal fluid, we could detect an IDH1 mutation. In conclusion, the ddPCR system is useful to identify a small fraction of IDH1 mutation in diffuse infiltrative gliomas. This might be useful for precision medicine of these gliomas in the near future and also for the non-invasive diagnosis of these gliomas.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/diagnóstico , Glioma/classificação , Glioma/diagnóstico , Isocitrato Desidrogenase/análise , Isocitrato Desidrogenase/genética , Mutação , Reação em Cadeia da Polimerase/métodos , Adulto , Alelos , Neoplasias Encefálicas/patologia , DNA de Neoplasias/genética , Feminino , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Sensibilidade e Especificidade
16.
J Phys Condens Matter ; 30(12): 125802, 2018 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-29443003

RESUMO

We demonstrate how micromagnetic simulations can be employed in order to characterize and analyze the magnetic microstructure of nanocomposites. For the example of nanocrystalline Nd-Fe-B, which is a potential material for future permanent-magnet applications, we have compared three different models for the micromagnetic analysis of this material class: (i) a description of the nanocomposite microstructure in terms of Stoner-Wohlfarth particles with and without the magnetodipolar interaction; (ii) a model based on the core-shell representation of the nanograins; (iii) the latter model including a contribution of superparamagnetic clusters. The relevant parameter spaces have been systematically scanned with the aim to establish which micromagnetic approach can most adequately describe experimental data for this material. According to our results, only the last, most sophisticated model is able to provide an excellent agreement with the measured hysteresis loop. The presented methodology is generally applicable to multiphase magnetic nanocomposites and it highligths the complex interrelationship between the microstructure, magnetic interactions, and the macroscopic magnetic properties.

17.
Apoptosis ; 22(11): 1353-1361, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28951984

RESUMO

In previous clinical trials, we showed that remote ischemic preconditioning (rIPC) reduced myocardial damage in children undergoing treatment for congenital heart defects and postoperative renal failure in patients undergoing abdominal aortic aneurysm surgery. In rabbit experiments, pre-treatment with plasma and plasma dialysate (obtained using 15-kDa cut-off dialysis membrane) from donor rabbits subjected to rIPC similarly protected against cardiac infarction. However, the protective substances containing in rIPC plasma have been unknown. In the present study, we showed that rIPC plasma exerted anti-apoptotic and anti-oxidative effects on human neural stem cells under oxygen glucose deprivation (OGD) that mimics brain ischemia. Additionally, we applied the sample to the liquid chromatography integrated with mass spectrometry to identify candidate key molecules in the rIPC plasma and determine its role in protecting neural stem cells from OGD-induced cell death. Thioredoxin increased significantly after rIPC compared to pre-IPC. Pretreatment with thioredoxin, the antioxidant protein, markedly protected human neural stem cells from OGD-induced cell death. The effect of thioredoxin on brain ischemia in animals should be further evaluated. However, the present study first evaluated the effect of rIPC in the ischemic cellular model.


Assuntos
Antioxidantes/farmacologia , Proteínas Sanguíneas/farmacologia , Meios de Cultura/farmacologia , Precondicionamento Isquêmico , Células-Tronco Neurais/efeitos dos fármacos , Tiorredoxinas/farmacologia , Adulto , Antioxidantes/isolamento & purificação , Apoptose/efeitos dos fármacos , Apoptose/genética , Proteínas Sanguíneas/isolamento & purificação , Hipóxia Celular , Linhagem Celular Transformada , Glucose/deficiência , Glucose/farmacologia , Voluntários Saudáveis , Humanos , Marcação In Situ das Extremidades Cortadas , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Estresse Oxidativo , Oxigênio/farmacologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Tiorredoxinas/isolamento & purificação
18.
J Med Chem ; 60(20): 8394-8406, 2017 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-28954197

RESUMO

Vitamin D receptor (VDR) antagonists can be classified into two categories: the first category of VDR antagonists, which do not stabilize the helix 11-12, and the second category of antagonists, which destabilize the helix 6-7 region. To elucidate the mechanism underlying the first category antagonists by using the crystal structure, we designed and synthesized several VDR ligands with a p-hydroxyphenyl group at the C25-position. Of these, 22S-butyl-25-carbonyl analogue 5b and 25-di-p-hydoroxyphenyl analogues 6a,b showed strong antagonistic activity. We succeeded in cocrystallizing the ligand-binding domain of VDR complexed with 5b and found that the structure showed an alternative conformation of the helix 11-12 that explained the mechanism of the first category antagonists. Taking the present and previous studies together, we could elucidate the mechanisms underlying first and second categories antagonists based on individual crystal structures. This study provides significant insights into antagonism against not only VDR but also nuclear receptors.


Assuntos
Receptores de Calcitriol/antagonistas & inibidores , Vitamina D/análogos & derivados , Animais , Linhagem Celular , Cristalografia por Raios X , Humanos , Ligantes , Estrutura Molecular , Receptores de Calcitriol/química , Análise Espectral/métodos , Vitamina D/química , Vitamina D/farmacologia
19.
J Pathol ; 243(4): 468-480, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28888050

RESUMO

In the progression of glioma, tumour cells often exploit the perivascular microenvironment to promote their survival and resistance to conventional therapies. Some of these cells are considered to be brain tumour stem cells (BTSCs); however, the molecular nature of perivascular tumour cells has not been specifically clarified because of the complexity of glioma. Here, we identified CD109, a glycosylphosphatidylinositol-anchored protein and regulator of multiple signalling pathways, as a critical regulator of the progression of lower-grade glioma (World Health Organization grade II/III) by clinicopathological and whole-genome sequencing analysis of tissues from human glioma. The importance of CD109-positive perivascular tumour cells was confirmed not only in human lower-grade glioma tissues but also in a mouse model that recapitulated human glioma. Intriguingly, BTSCs isolated from mouse glioma expressed high levels of CD109. CD109-positive BTSCs exerted a proliferative effect on differentiated glioma cells treated with temozolomide. These data reveal the significance of tumour cells that populate perivascular regions during glioma progression, and indicate that CD109 is a potential therapeutic target for the disease. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Antígenos CD/metabolismo , Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Proteínas de Neoplasias/metabolismo , Células-Tronco Neoplásicas/metabolismo , Animais , Antígenos CD/genética , Antineoplásicos Alquilantes/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Proliferação de Células/efeitos dos fármacos , Dacarbazina/análogos & derivados , Dacarbazina/farmacologia , Progressão da Doença , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Regulação Neoplásica da Expressão Gênica , Glioma/tratamento farmacológico , Glioma/genética , Glioma/patologia , Humanos , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/deficiência , Proteínas de Neoplasias/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Transdução de Sinais , Temozolomida , Fatores de Tempo , Células Tumorais Cultivadas , Microambiente Tumoral
20.
Brain Tumor Pathol ; 34(2): 91-97, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28353033

RESUMO

IDH1 gene mutation has been demonstrated to be an oncogenic driver in a majority of lower-grade gliomas (LGGs). In contrast to other central nervous neoplasms and normal brain tissue without IDH1 mutation, almost 80% of LGGs exhibit IDH1 mutation. Therefore, expeditious detection of IDH1 mutation is useful, not only for intraoperative diagnosis of these gliomas but also for determination of the border between the tumor and normal brain tissue. In this study, we established a rapid genotyping assay with a simple DNA extraction method, involving only incubation of the tumor specimen with Tris-EDTA buffer, which can be easily performed in an operating room. In all 11 tested cases, we could identify the IDH1 status within 90-100 min intraoperatively. In a case of anaplastic astrocytoma, IDH-mutant, we could detect the tumor border by IDH1 profiling. In addition, with this assay, we could detect IDH1 mutation using cell-free tumor DNA derived from cerebrospinal fluid in a case of glioblastoma, IDH-mutant. Considering that clinical trials of mutated IDH1 inhibitors are ongoing, less-invasive intraoperative IDH1 gene profiling might be useful for decision making of the overall treatment strategy of LGGs. Our assay might be a useful tool for precision medicine and surgery of IDH1-mutant gliomas.


Assuntos
Neoplasias Encefálicas/genética , Técnicas de Genotipagem/métodos , Glioma/genética , Isocitrato Desidrogenase/genética , Mutação , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/terapia , Glioma/diagnóstico , Glioma/terapia , Humanos , Período Intraoperatório
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