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1.
Artigo em Inglês | MEDLINE | ID: mdl-31983279

RESUMO

An Ir(III) polypyridyl complex-conjugated 14-mer oligonucleotide (IrIII-DNA) was synthesized and its hybridization properties with single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) were evaluated by UV-melting experiments. The stabilities of the duplexes of IrIII-DNA with 14-, 20-, and 26-mer ssDNAs were higher than those of the unconjugated oligonucleotides. The triplex of IrIII-DNA with 14-mer dsDNA was also stabilized. However, the triplexes of IrIII-DNA with 20- and 26-mer dsDNAs, flanked by 3 and 6 base pairs at the both ends of 14-mer dsDNA target, were destabilized. This is presumably because of steric repulsion between the Ir(III) complex and the protruding 3- and 6-mer dsDNA moieties which are inflexible compared to ssDNA.

2.
Molecules ; 25(2)2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31952133

RESUMO

The post-synthetic modification of an oligonucleotide is a powerful strategy for the synthesis of various analogs of the oligonucleotide, aiming to achieve the desired functions. In this study, we synthesized the thymidine phosphoramidite of 2'-N-pentafluorophenoxycarbonyl-2'-amino-LNA, which was introduced into oligonucleotides. Oligonucleotides containing a 2'-N-pentafluorophenoxycarbonyl-2'-amino-LNA unit could be isolated under ultra-mild deprotection conditions (50 mM K2CO3 in MeOH at room temperature for 4 h). Moreover, by treatment with various amines as a post-synthetic modification, the oligonucleotides were successfully converted into the corresponding 2'-N-alkylaminocarbonyl-2'-amino-LNA (2'-urea-LNA) derivatives. The duplex- and triplex-forming abilities of the synthesized oligonucleotides were evaluated by UV-melting experiments, which showed that 2'-urea-LNAs could stabilize the nucleic acid complexes, similar to the proto-type, 2'-amino-LNA. Thus, 2'-urea-LNAs could be promising units for the modification of oligonucleotides; the design of a substituent on urea may aid the formation of useful oligonucleotides. In addition, pentafluorophenoxycarbonyl, an amino moiety, acted as a precursor of the substituted urea, which may be applicable to the synthesis of oligonucleotide conjugates.

3.
Phys Rev Lett ; 123(12): 123201, 2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31633947

RESUMO

Femtosecond laser pulses have opened new frontiers for the study of ultrafast phase transitions and nonequilibrium states of matter. In this Letter, we report on structural dynamics in atomic clusters pumped with intense near-infrared (NIR) pulses into a nanoplasma state. Employing wide-angle scattering with intense femtosecond x-ray pulses from a free-electron laser source, we find that highly excited xenon nanoparticles retain their crystalline bulk structure and density in the inner core long after the driving NIR pulse. The observed emergence of structural disorder in the nanoplasma is consistent with a propagation from the surface to the inner core of the clusters.

4.
J Org Chem ; 84(21): 13336-13344, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31565938

RESUMO

2',4'-Bridged nucleic acid (2',4'-BNA) analogues are used for therapeutic oligonucleotides, owing to their excellent hybridizing ability with complementary RNA and high resistance toward enzymatic degradation. We developed 2',4'-BNA analogues with oxygen atoms at 6'-positions (e.g., EoNA and EoDNAs) and demonstrated that the presence of 6'-oxygen atoms in the bridge structure could show positive effect on the properties of the modified oligonucleotides. Herein, we designed and synthesized 7'-methyl derivatives of methyleneoxy-bridged 2'-deoxyribonucleic acid (MoDNA), possessing a five-membered bridge with 6'-oxygen atom via radical cyclization for the bridge construction. The synthesized monomers were incorporated into the oligonucleotides by solid-phase oligonucleotide synthesis. The MoDNA-modified oligonucleotides showed high affinity toward single-stranded RNA and double-stranded DNA, as well as excellent resistance toward nuclease compared with the corresponding natural oligonucleotide.

5.
J Chem Phys ; 151(10): 104302, 2019 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-31521098

RESUMO

Carbon 1s photoelectron angular distributions of an iodomethane molecule were measured relative to the recoil-frame determined by the momentum correlation between I+ and CH3 + at photoelectron energies of 3, 6.1, and 12 eV. The energy dependent behavior of the recoil-frame photoelectron angular distributions is reproduced reasonably well by the time-dependent density functional theory with B-spline methods. We discuss potential applications of the fully differential photoelectron angular distribution measurements in the molecular frame to three-dimensional molecular structural determinations identifying the directions and lengths of the bonds.

6.
Curr Protoc Nucleic Acid Chem ; 78(1): e91, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31529781

RESUMO

This unit describes postsynthetic modification of oligonucleotides (ONs) containing 2'-deoxy-5-trifluoromethyluridine and 2'-deoxy-5-trifluoromethylcytidine. In ONs, the trifluoromethyl group at the C5 position of pyrimidine bases is converted into a variety of carboxylic acid equivalents using alkaline and amine solutions. In addition, treating fully protected and controlled pore glass (CPG)-attached ONs with methylamine and sodium hydroxide aqueous solution results in deprotection of all protecting groups (except the 4,4'-dimethoxytrityl group), cleavage from CPG, and simultaneous conversion of the trifluoromethyl group to afford the corresponding ONs containing 5-substituted pyrimidine bases. © 2019 by John Wiley & Sons, Inc.

7.
Chem Pharm Bull (Tokyo) ; 67(9): 1015-1018, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474724

RESUMO

Thiocyanation of aromatic compounds has been investigated using the combination of 1-chloro-1,2-benziodoxol-3-(1H)-one (1) and (trimethylsilyl)isothiocyanate (TMSNCS). The reaction with electron rich aromatic compounds proceeded smoothly to provide the thiocyanated products in high yield, while electron deficient heteroaromatic compounds were not suitable for this reaction. In these reactions, the regioselectivity was generally high. Transformations of the products were also investigated to demonstrate the utility of the reaction. Based on NMR experiments, we propose that thiocyanogen chloride is generated in situ as an active species.


Assuntos
Derivados de Benzeno/química , Compostos Heterocíclicos/química , Isotiocianatos/química , Compostos de Trimetilsilil/química , Iodo/química , Estereoisomerismo
8.
Pathol Int ; 69(7): 392-397, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31328350

RESUMO

Epstein-Barr virus (EBV) infection is associated with pathogenesis of various cancers, including extranodal natural killer/T-cell lymphoma, nasal type (ENKL). ENKL tumor cells are positive for EBV-encoded RNA1 (EBER1), which is the most useful marker to identify ENKL tumor cells in histopathology. Currently, EBER1 in situ hybridization (ISH) is recommended to evaluate bone marrow (BM) involvement of ENKL. However, the actual burden of EBER1-positive cells in normal BM specimens remains unclear. In the present study, we performed EBER1 ISH on 111 BM specimens, which were obtained during an initial staging procedure in patients with EBV-negative cancers and were also negative for BM involvement. One or more EBER1-positive cells per whole specimen were observed in 38 specimens (34%). The number of EBER1-positive cells was distributed as follows: single positive cell, n = 17; two positive cells, n = 13; three positive cells, n = 3; and four positive cells, n = 5. These findings suggest that four or fewer EBER1-positive cells can be observed in BM specimens of patients with non-EBV-related cancers. The clinical implications of a small number of EBER1-positive cells in BM specimens of patients with ENKL should be evaluated in further studies.

9.
Int J Hematol ; 110(3): 340-346, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31187439

RESUMO

We analyzed the clinicopathologic characteristics of 136 intestinal diffuse large B-cell lymphomas (DLBCLs) among 126 patients. The DLBCL sites were categorized as: duodenum (n = 23), ileocecal region (n = 63), other small intestine (n = 29), rectum (n = 7), and other large intestine (n = 14). Patients with DLBCLs of the ileocecal region or other small intestine frequently underwent surgery for ileus or perforations (P < 0.001), were predominantly male (P = 0.042), and had a higher incidence of limited-stage disease (P = 0.001), lower International Prognostic Index (P = 0.015), and lower incidence of lactate dehydrogenase elevation (P = 0.007) than those with DLBCLs of other regions. Half of the intestinal DLBCLs exhibited the germinal center B-cell phenotype. A low-grade B-cell lymphoma background was found in 21% of the cases; the prevalence was significantly lower in the ileocecal region (13%, P = 0.025), suggesting a higher incidence of de novo DLBCLs. Intestinal follicular lymphoma (FL) and mucosa-associated lymphoid tissue (MALT) lymphoma backgrounds were observed in 10% and 0% of the cases, respectively. Five percent (5/107) of intestinal DLBCL cases were Epstein-Barr virus-encoded RNA-1 positive. The clinicopathologic characteristics of the DLBCLs differed by region. Histologic transformation of intestinal FL was observed in around 10% of the intestinal DLBCL cases.


Assuntos
Neoplasias Intestinais , Linfoma Difuso de Grandes Células B , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Neoplasias Intestinais/metabolismo , Neoplasias Intestinais/patologia , Intestinos/patologia , Linfoma de Zona Marginal Tipo Células B/metabolismo , Linfoma de Zona Marginal Tipo Células B/patologia , Linfoma Folicular/metabolismo , Linfoma Folicular/patologia , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade
10.
Ann Hematol ; 98(10): 2463-2465, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31240468
11.
J Org Chem ; 84(14): 9093-9100, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31241329

RESUMO

The synthesis of 6'S-Me-2'-O,4'-C-ethylene-bridged 5-methyluridine (6'S-Me-ENA-T) was achieved using visible light-mediated stereoselective radical cyclization as a key step. This is the first example of a method for constructing a 2',4'-bridged structure from a 4'-carbon radical intermediate. The 6'S-Me-ENA-T monomer was successfully incorporated into oligonucleotides, and their properties were examined. The oligonucleotides containing 6'S-Me-ENA-T exhibited a highly selective hybridization affinity toward single-stranded RNA and an excellent enzymatic stability, compared to the corresponding LNA- and ENA-modified oligonucleotides.

12.
Nat Commun ; 10(1): 2186, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31097703

RESUMO

The increasing availability of X-ray free-electron lasers (XFELs) has catalyzed the development of single-object structural determination and of structural dynamics tracking in real-time. Disentangling the molecular-level reactions triggered by the interaction with an XFEL pulse is a fundamental step towards developing such applications. Here we report real-time observations of XFEL-induced electronic decay via short-lived transient electronic states in the diiodomethane molecule, using a femtosecond near-infrared probe laser. We determine the lifetimes of the transient states populated during the XFEL-induced Auger cascades and find that multiply charged iodine ions are issued from short-lived (∼20 fs) transient states, whereas the singly charged ones originate from significantly longer-lived states (∼100 fs). We identify the mechanisms behind these different time scales: contrary to the short-lived transient states which relax by molecular Auger decay, the long-lived ones decay by an interatomic Coulombic decay between two iodine atoms, during the molecular fragmentation.

13.
Rinsho Ketsueki ; 60(2): 87-92, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-30842385

RESUMO

Primary central nervous system lymphoma (PCNSL) is a rare, aggressive type of non-Hodgkin lymphoma with a poor prognosis and no defined optimal therapeutic strategies. We retrospectively analyzed the survival of six PCNSL patients who were treated with high-dose methotrexate (HDMTX) -based chemotherapy combined with rituximab. The median age at diagnosis was 71 (range, 54-75) years, and the ECOG performance status was ≥3 in four patients. The histopathological findings revealed that all patients had diffuse large B-cell lymphoma. Objective response was obtained in all patients (five, complete response; one, partial response). Three patients had severe non-hematological toxicities: one had pulmonary thromboembolism, one had sepsis, and one developed acute epididymitis. However, each patient recovered and their symptoms could be managed. The median follow-up was 28.8 (range, 13.4-65.5) months. Five patients were still alive and disease-free, and one patient relapsed 62.2 months after the diagnosis. Therefore, the addition of rituximab to HDMTX may improve outcomes. Further clinical investigation is necessary to establish standardized initial therapies for PCNSL, particularly in elderly patients.


Assuntos
Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Metotrexato/uso terapêutico , Rituximab/uso terapêutico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
14.
Expert Opin Biol Ther ; 19(3): 197-209, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30658046

RESUMO

INTRODUCTION: Peripheral T-cell lymphoma (PTCL) is a relatively rare, heterogeneous group of mature T-cell neoplasms generally associated with poor prognosis, partly because of refractoriness against conventional cytotoxic chemotherapies. To improve the outcome of patients with PTCL, the clinical development of several novel agents is currently under investigation. AREAS COVERED: Since the first approval of pralatrexate (dihydrofolate reductase inhibitor) by the US Food and Drug Administration, belinostat, romidepsin (histone deacetylase inhibitors), and brentuximab vedotin (anti-CD30 antibody-drug conjugate) have been approved in the US, and many other countries. In addition, mogamulizumab (anti-CC chemokine receptor 4 antibody), chidamide (histone deacetylase inhibitor), and forodesine (purine nucleoside phosphorylase inhibitor) have been approved in Asian countries, including China, and Japan. In this review, we have summarized the available data regarding these approved agents and new agents currently under development for PTCL. EXPERT OPINION: Novel agents will be a promising therapeutic option in selected patients with relapsed/refractory PTCL and will change the daily clinical practice in the treatment of PTCL. However, these are not a curative option when used as a single agent. Further clinical developments are expected, comprising 1) combination therapies of new agents with cytotoxic chemotherapies; 2) 'novel-novel' combinations; 3) immune therapies, including chimeric antigen receptor T-cell therapy; and 4) predictive marker analysis.


Assuntos
Antineoplásicos/uso terapêutico , Linfoma de Células T Periférico/tratamento farmacológico , Aminopterina/análogos & derivados , Aminopterina/uso terapêutico , Aminopiridinas/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Benzamidas/uso terapêutico , China , Depsipeptídeos/uso terapêutico , Aprovação de Drogas , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Ácidos Hidroxâmicos/uso terapêutico , Imunoconjugados/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Sulfonamidas/uso terapêutico
15.
PLoS Genet ; 14(10): e1007651, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30286074

RESUMO

Beetle horns are attractive models for studying the evolution of novel traits, as they display diverse shapes, sizes, and numbers among closely related species within the family Scarabaeidae. Horns radiated prolifically and independently in two distant subfamilies of scarabs, the dung beetles (Scarabaeinae), and the rhinoceros beetles (Dynastinae). However, current knowledge of the mechanisms underlying horn diversification remains limited to a single genus of dung beetles, Onthophagus. Here we unveil 11 horn formation genes in a rhinoceros beetle, Trypoxylus dichotomus. These 11 genes are mostly categorized as larval head- and appendage-patterning genes that also are involved in Onthophagus horn formation, suggesting the same suite of genes was recruited in each lineage during horn evolution. Although our RNAi analyses reveal interesting differences in the functions of a few of these genes, the overwhelming conclusion is that both head and thoracic horns develop similarly in Trypoxylus and Onthophagus, originating in the same developmental regions and deploying similar portions of appendage patterning networks during their growth. Our findings highlight deep parallels in the development of rhinoceros and dung beetle horns, suggesting either that both horn types arose in the common ancestor of all scarabs, a surprising reconstruction of horn evolution that would mean the majority of scarab species (~35,000) actively repress horn growth, or that parallel origins of these extravagant structures resulted from repeated co-option of the same underlying developmental processes.


Assuntos
Besouros/genética , Larva/genética , Animais , Evolução Biológica , Regulação da Expressão Gênica no Desenvolvimento/genética , Cornos/anatomia & histologia , Cornos/embriologia , Fenótipo , Interferência de RNA , Especificidade da Espécie
16.
J Org Chem ; 83(18): 10701-10708, 2018 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-30136574

RESUMO

A concise approach for the synthesis of the 5'-carba analogs of nucleoside 5'-phosphates from 2'-deoxy-5'- O-phthalimidonucleosides by a visible-light-mediated deformylative 1,4-addition was developed. This method enabled rapid and facile generation of 4'-carbon radicals of nucleosides. Moreover, this synthetic strategy was applicable to the 5'-carba analogs of nucleoside 5'-phosphates as well as other 5'-carba nucleosides bearing methoxycarbonyl, cyano, and N-methylsulfamoyl groups.

17.
Clin Neurol Neurosurg ; 172: 174-176, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30031255

RESUMO

The term cerebral small vessel disease (SVD) refers to a group of pathological processes with various etiologies that affect the small arteries, arterioles, venules, and capillaries of the brain. SVD occurs in approximately 5% of patients. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL),a recessive form of heritable SVD, is caused by a mutation in the high temperature requirement A serine peptidase (HTRA1) gene. Recently, heterozygous mutations in HTRA1 were identified in patients with symptomatic SVD. We identified two families harboring HTRA1 (p.S284 N and p.V216 M) heterozygous mutations with symptoms that mimicked common symptoms of CARASIL.


Assuntos
Alopecia/genética , Encéfalo/patologia , Infarto Cerebral/genética , Transtornos Cerebrovasculares/genética , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Leucoencefalopatias/genética , Doenças da Coluna Vertebral/genética , Doenças de Pequenos Vasos Cerebrais/genética , Doenças de Pequenos Vasos Cerebrais/patologia , Transtornos Cerebrovasculares/patologia , Heterozigoto , Humanos , Leucoencefalopatias/patologia , Masculino , Pessoa de Meia-Idade , Linhagem , Serina Endopeptidases/genética
18.
Phys Rev Lett ; 120(22): 223201, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29906148

RESUMO

We show that electron and ion spectroscopy reveals the details of the oligomer formation in Ar clusters exposed to an x-ray free electron laser (XFEL) pulse, i.e., chemical dynamics triggered by x rays. With guidance from a dedicated molecular dynamics simulation tool, we find that van der Waals bonding, the oligomer formation mechanism, and charge transfer among the cluster constituents significantly affect ionization dynamics induced by an XFEL pulse of moderate fluence. Our results clearly demonstrate that XFEL pulses can be used not only to "damage and destroy" molecular assemblies but also to modify and transform their molecular structure. The accuracy of the predictions obtained makes it possible to apply the cluster spectroscopy, in connection with the respective simulations, for estimation of the XFEL pulse fluence in the fluence regime below single-atom multiple-photon absorption, which is hardly accessible with other diagnostic tools.

19.
Bioorg Med Chem ; 26(14): 3875-3881, 2018 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-29861173

RESUMO

3',4'-Ethyleneoxy-bridged 5-methyluridine derivatives with methyl groups in the bridge, (R)-Me-3',4'-EoNA-T and (S)-Me-3',4'-EoNA-T, were synthesized, and these two analogs and unsubstituted 3',4'-EoNA-T were successfully incorporated into a 2',5'-linked oligonucleotide (isoDNA). Their duplex-forming ability with complementary DNA and complementary RNA, and triplex-forming ability with double-stranded DNA, were evaluated by UV-melting experiments. The results indicated that isoDNAs, including these 3',4'-EoNA analogs, could hybridize exclusively with complementary RNA. In particular, 3',4'-EoNA-T and (R)-Me-3',4'-EoNA-T modifications within isoDNA could stabilize the duplexes with complementary RNA compared with unmodified or 3',4'-BNA-modified isoDNAs.


Assuntos
Oligonucleotídeos/síntese química , Uridina/análogos & derivados , Conformação de Ácido Nucleico , Oligonucleotídeos/química , Raios Ultravioleta , Uridina/química
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