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2.
Nat Commun ; 10(1): 3789, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31439836

RESUMO

ProMyelocyticLeukemia (PML) protein can polymerize into a mega-Dalton nuclear assembly of 0.1-2 µm in diameter. The mechanism of PML nuclear body biogenesis remains elusive. Here, PMLRBCC is successfully purified. The gel filtration and ultracentrifugation analysis suggest a previously unrecognized sequential oligomerization mechanism via PML monomer, dimer, tetramer and N-mer. Consistently, PML B1-box structure (2.0 Å) and SAXS characterization reveal an unexpected networking by W157-, F158- and SD1-interfaces. Structure-based perturbations in these B1 interfaces not only impair oligomerization in vitro but also abolish PML sumoylation and nuclear body biogenesis in HeLaPml-/- cell. More importantly, as demonstrated by in vivo study using transgenic mice, PML-RARα (PR) F158E precludes leukemogenesis. In addition, single cell RNA sequencing analysis shows that B1 oligomerization is an important regulator in PML-RARα-driven transactivation. Altogether, these results not only define a previously unrecognized B1-box oligomerization in PML, but also highlight oligomerization as an important factor in carcinogenesis.

4.
Fish Shellfish Immunol ; 92: 265-275, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31202962

RESUMO

The application of probiotics as an eco-friendly alternative to antibiotics is an emerging strategy for sustainable aquaculture. In the present study, Rummeliibacillus stabekisii was isolated from the gut of Nile tilapia, and the effects of R. stabekisii on the growth, innate immunity, disease resistance, and gut microbiota of Nile tilapia (Oreochromis niloticus) were investigated. The results showed significantly increased weight gain (WG), feed conversion ratio (FCR), and feed efficiency (FE) in Nile tilapia fed R. stabekisii for 8 weeks compared to those in fish fed a control diet. Intestinal digestive enzymes such as protease, cellulase, and xylanase were also significantly increased in the R. stabekisii-administered groups. Enhanced cumulative survival was exhibited in fish fed R. stabekisii after challenge with Aeromonas hydrophila and Streptococcus iniae. Immune parameters such as the phagocytic activity, respiratory bursts, and superoxide dismutase of head kidney leukocytes; serum lysozyme activity; and expression of the cytokine genes interleukin-1ß, tumor necrosis factor-α, transforming growth factor-ß, and heat shock protein 70 were significantly elevated in fish fed R. stabekisii. Administration of R. stabekisii considerably increased the abundance of potential probiotics (Bacillus and Lactobacillus spp.) and reduced abundances of potential pathogenic bacteria (Streptococcus and Staphylococcus spp.) in fish intestines. The present study indicated that dietary supplementation with R. stabekisii improved the growth, immunity, disease resistance, and gut microflora of Nile tilapia. This research is the first study reporting that the genus Rummeliibacillus is a potential probiotic in animals, suggesting that R. stabekisii can be used as a feed additive to enhance the growth and health status in tilapia.

5.
Cell Res ; 29(6): 427-428, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31086254
6.
Lancet Haematol ; 6(6): e328-e337, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31126528

RESUMO

BACKGROUND: Anthracycline dose optimisation in the treatment of diffuse large B-cell lymphoma has rarely been tested. We aimed to find out whether R-CEOP70 was non-inferior to R-CHOP50 with less cardiotoxicity, and whether R-CEOP90 had a superior efficacy to R-CHOP50 or R-CEOP70 with acceptable toxic effects. METHODS: In this multicentre, phase 3, randomised, controlled study (NHL-001), patients with newly diagnosed diffuse large B-cell lymphoma or follicular lymphoma grade 3B were enrolled from 20 centres of the Multicenter Hematology-Oncology Programs Evaluation System in China. Young patients (16-60 years) were randomly assigned 1:1:1 (block size of six) to six courses of R-CHOP50, R-CEOP70, or R-CEOP90, and older patients (61-80 years) were assigned 1:1 (block size of four) to R-CHOP50 or R-CEOP70. Patients were randomly assigned using computer-assisted permuted-block randomisation. Investigators and patients were not masked to treatment assignment. In the R-CHOP50 group, patients were given rituximab 375 mg/m2 intravenously on day 0, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 (maximum dose 2 mg) intravenously on day 1, and prednisone 60 mg/m2 (maximum dose 100 mg) orally from day 1-5; in the R-CEOP70 group, epirubicin 70 mg/m2 replaced doxorubicin; and in the R-CEOP90 group, high dose epirubicin 90 mg/m2 replaced doxorubicin. All patients received two additional courses of rituximab 375 mg/m2 intravenously every 21 days. Consolidation radiotherapy was given to patients with bulky disease at diagnosis or residual disease at the end of treatment. The primary endpoint was 2-year progression-free survival. The non-inferiority margin for R-CEOP70 versus R-CHOP50 was defined by hazard ratio [HR] as the upper limit of its 95% CI being no greater than 1·50. Analysis of efficacy and safety were of the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01852435. FINDINGS: From May 15, 2013, to March 16, 2016, a total of 648 patients were enrolled, including 404 (62%) young patients (R-CHOP50 [n=135], R-CEOP70 [n=134], or R-CEOP90 [n=135]), and 244 (38%) older patients (R-CHOP50 [n=122] or R-CEOP70 [n=122]). Four patients were excluded from the study for consent withdrawal and one patient for misdiagnosis before treatment. The 2-year progression-free survival in the R-CHOP50 group was 72·5% (95% CI 66·6-77·6) and in the R-CEOP70 group was 72·4% ([66·5-77·5]; HR 1·00 [0·73-1·38]; p=0·99). The non-inferiority was met and adverse events were similar between the two groups. Fewer patients in the R-CEOP70 group (14 [13%] of 110) presented with over 10% decrease in left ventricular ejection fraction (LVEF) than those in the R-CHOP50 group (31 [29%] of 108) at 3 years after remission. For young patients, the 2-year progression-free survival in the R-CEOP90 group was 88·8% (82·1-93·1) and was significantly improved compared with the R-CHOP50 group (75·9% [67·7-82·3]; 0·44 [0·25-0·76]; p=0·0047) and the R-CEOP70 group (77·4% [69·4-83·7%]; 0·49 [0·27-0·86]; p=0·017). Grade 3-4 neutropenia occurred more frequently in the R-CEOP90 group (97 [72%] of 134) than in the R-CHOP50 group (87 [65%] of 133) and R-CEOP70 group (84 [63%] of 133) in young patients but without further increase of clinically significant infections. Fewer patients in the R-CEOP70 group (7 [11%] of 66) and in the R-CEOP90 group (10 [13%] of 79) presented with more than 10% decrease in LVEF than those in the R-CHOP50 group (17 [26%] of 66) at 3 years after remission. INTERPRETATION: R-CEOP70 could serve as an alternative regimen to R-CHOP50 with mild long-term cardiotoxicity. Young patients with diffuse large B-cell lymphoma might benefit from high-dose epirubicin. Epirubicin is an alternative drug to doxorubicin in regular R-CHOP with mild long-term cardiotoxicity. FUNDING: National Natural Science Foundation of China, National Key Research and Development Program, Shanghai Commission of Science and Technology, Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support, Multicenter Clinical Research Project by Shanghai Jiao Tong University School of Medicine, Clinical Research Plan of Shanghai Hospital Development Center, and Chang Jiang Scholars Program.

8.
Bioinformatics ; 2019 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-31134279

RESUMO

SUMMARY: We describe a novel computational method for genotyping repeats using sequence graphs. This method addresses the long-standing need to accurately genotype medically important loci containing repeats adjacent to other variants or imperfect DNA repeats such as polyalanine repeats. Here we introduce a new version of our repeat genotyping software, ExpansionHunter, that uses this method to perform targeted genotyping of a broad class of such loci. AVAILABILITY AND IMPLEMENTATION: ExpansionHunter is implemented in C++ and is available under the Apache License Version 2.0. The source code, documentation, and Linux/macOS binaries are available at https://github.com/Illumina/ExpansionHunter/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

9.
JAMA Netw Open ; 2(5): e193348, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31050781

RESUMO

Importance: Thyrotoxic periodic paralysis (TPP) is a potentially lethal complication of hyperthyroidism. However, only 1 specific susceptibility locus for TPP has been identified. Additional genetic determinants should be detected so that a prediction model can be constructed. Objective: To investigate the genetic architecture of TPP and distinguish TPP from Graves disease cohorts. Design, Setting, and Participants: This population-based case-control study used a 2-stage genome-wide association study to investigate the risk loci of TPP and weighted genetic risk score to construct a TPP prediction model with data from a Chinese Han population recruited in hospitals in China from March 2003 to December 2015. The analysis was conducted from November 2014 to August 2016. Main Outcomes and Measures: Loci specifically associated with TPP risk and those shared with Graves disease and prediction model of joint effects of TPP-specific loci. Results: A total of 537 patients with TPP (mean [SD] age, 35 [11] years; 458 male) 1519 patients with Graves disease and no history of TPP (mean [SD] age, 38 [13] years; 366 male), and 3249 healthy participants (mean [SD] age, 46 [10] years; 1648 male) were recruited from the Han population by hospitals throughout China. Two new TPP-specific susceptibility loci were identified: DCHS2 on 4q31.3 (rs1352714: odds ratio [OR], 1.58; 95% CI, 1.35-1.85; P = 1.24 × 10-8) and C11orf67 on 11q14.1 (rs2186564: OR, 1.50; 95% CI, 1.29-1.74; P = 2.80 × 10-7). One previously reported specific locus was confirmed on 17q24.3 near KCNJ2 (rs312729: OR, 2.08; 95% CI, 1.83-2.38; P = 8.02 × 10-29). Meanwhile, 2 risk loci (MHC and Xq21.1) were shared by Graves disease and TPP. After 2 years of treatment, the ratio of persistent thyrotropin receptor antibody positivity was higher in patients with TPP than in patients with Graves disease and no history of TPP (OR, 3.82; 95% CI, 2.04-7.16; P = 7.05 × 10-6). The prediction model using a weighted genetic risk score and 11 candidate TPP-specific single-nucleotide polymorphisms had an area under the curve of 0.80. Conclusions and Relevance: These findings provide evidence that TPP is a novel molecular subtype of Graves disease. The newly identified loci, along with other previously reported loci, demonstrate the growing complexity of the heritable contribution to TPP pathogenesis. A complete genetic architecture will be helpful to understand the pathophysiology of TPP, and a useful prediction model could prevent the onset of TPP.

10.
Proc Natl Acad Sci U S A ; 116(19): 9543-9551, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-30988175

RESUMO

Relapsed and refractory (R/R) multiple myeloma (MM) patients have very poor prognosis. Chimeric antigen receptor modified T (CAR T) cells is an emerging approach in treating hematopoietic malignancies. Here we conducted the clinical trial of a biepitope-targeting CAR T against B cell maturation antigen (BCMA) (LCAR-B38M) in 17 R/R MM cases. CAR T cells were i.v. infused after lymphodepleting chemotherapy. Two delivery methods, three infusions versus one infusion of the total CAR T dose, were tested in, respectively, 8 and 9 cases. No response differences were noted among the two delivery subgroups. Together, after CAR T cell infusion, 10 cases experienced a mild cytokine release syndrome (CRS), 6 had severe but manageable CRS, and 1 died of a very severe toxic reaction. The abundance of BCMA and cytogenetic marker del(17p) and the elevation of IL-6 were the key indicators for severe CRS. Among 17 cases, the overall response rate was 88.2%, with 13 achieving stringent complete response (sCR) and 2 reaching very good partial response (VGPR), while 1 was a nonresponder. With a median follow-up of 417 days, 8 patients remained in sCR or VGPR, whereas 6 relapsed after sCR and 1 had progressive disease (PD) after VGPR. CAR T cells were high in most cases with stable response but low in 6 out of 7 relapse/PD cases. Notably, positive anti-CAR antibody constituted a high-risk factor for relapse/PD, and patients who received prior autologous hematopoietic stem cell transplantation had more durable response. Thus, biepitopic CAR T against BCMA represents a promising therapy for R/R MM, while most adverse effects are clinically manageable.

11.
Theranostics ; 9(4): 1115-1124, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30867819

RESUMO

Rationale: Epstein-Barr virus (EBV) is associated with multiple malignancies with expression of viral oncogenic proteins and chronic inflammation as major mechanisms contributing to tumor development. A less well-studied mechanism is the integration of EBV into the human genome possibly at sites which may disrupt gene expression or genome stability. Methods: We sequenced tumor DNA to profile the EBV sequences by hybridization-based enrichment. Bioinformatic analysis was used to detect the breakpoints of EBV integrations in the genome of cancer cells. Results: We identified 197 breakpoints in nasopharyngeal carcinomas and other EBV-associated malignancies. EBV integrations were enriched at vulnerable regions of the human genome and were close to tumor suppressor and inflammation-related genes. We found that EBV integrations into the introns could decrease the expression of the inflammation-related genes, TNFAIP3, PARK2, and CDK15, in NPC tumors. In the EBV genome, the breakpoints were frequently at oriP or terminal repeats. These breakpoints were surrounded by microhomology sequences, consistent with a mechanism for integration involving viral genome replication and microhomology-mediated recombination. Conclusion: Our finding provides insight into the potential of EBV integration as an additional mechanism mediating tumorigenesis in EBV associated malignancies.

12.
J Am Chem Soc ; 141(12): 4791-4794, 2019 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-30862159

RESUMO

Electrocatalytic reduction of carbon dioxide (CO2ER) to reusable carbon resources is a significant step to balance the carbon cycle. This Communication describes a seed-mediated growth method to synthesize ultrathin Pd-Au alloy nanoshells with controllable alloying degree on Pd nanocubes. Specifically, Pd@Pd3Au7 nanocrystals (NCs) show superior CO2ER performance, with a 94% CO faraday efficiency (FE) at -0.5 V vs reversible hydrogen electrode and approaching 100% CO FE from -0.6 to -0.9 V. The enhancement primarily originates from ensemble and ligand effects, i.e., appropriately proportional Pd-Au sites and electronic back-donation from Au to Pd. In situ attenuated total reflection infrared spectra and density functional theory calculations clarify the reaction mechanism. This work may offer a general strategy for the synthesis of bimetallic NCs to explore the structure-activity relationship in catalytic reactions.

13.
ACS Appl Mater Interfaces ; 11(14): 13538-13544, 2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30896153

RESUMO

Electrochromic devices with tunable infrared radiation can meet the steadily growing demands in energy saving and thermal camouflage applications. Here, a mid-infrared radiation modulator based on flexible multilayer graphene thin films gated by nonvolatile ionic liquid on both rigid and flexible substrates is designed. The thermal emissivity of the device decreases nearly 80% within 2 s with the accumulation of anions in the multilayer graphene. The effective reduction of the emissivity results from the dramatic decrease in film's intraband absorption of graphene according to the Drude model. It has been demonstrated that with electrical control the film's mid-infrared radiation is capable of adapting to different backgrounds for thermal camouflage applications. Moreover, a sandwiched structure with stacked graphene films is designed to realize structural flexibility and double-sided radiation control for a wide range of potential applications, including energy-efficient buildings, infrared sources, and electrochromic displays.

14.
Cell Death Differ ; 26(11): 2430-2446, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30824836

RESUMO

TAMM41, located within the congenital heart diseases (CHD) sensitive region of 3p25 deletion syndrome, is a mitochondrial membrane maintenance protein critical for yeast survival, but its function in higher vertebrates remains unknown. Via in vivo zebrafish model, we found that tamm41 is highly expressed in the developing heart and deficiency of which led to heart valve abnormalities. Molecular mechanistic studies revealed that TAMM41 interacts and modulates the PINK1-PARK2 dependent mitophagy pathway, thereby implicating TAMM41 in heart valve development during zebrafish embryonic cardiogenesis. Furthermore, through screening of the congenital heart diseases (CHD) sensitive region of 3p25 deletion syndrome among 118 sporadic atrioventricular septal defect (AVSD) patients, we identified three cases carrying heterozygous pathogenic intronic variants of TAMM41. All three cases lacked normal full-length TAMM41 transcripts, most likely due to specific expression of the mutant allele. Collectively, our studies highlight essential roles for TAMM41-dependent mitophagy in development of the heart and provide novel insights into the etiology of AVSD.

15.
Hum Genet ; 138(4): 307-326, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30820706

RESUMO

Genome-wide association studies have reported 56 independently associated colorectal cancer (CRC) risk variants, most of which are non-coding and believed to exert their effects by modulating gene expression. The computational method PrediXcan uses cis-regulatory variant predictors to impute expression and perform gene-level association tests in GWAS without directly measured transcriptomes. In this study, we used reference datasets from colon (n = 169) and whole blood (n = 922) transcriptomes to test CRC association with genetically determined expression levels in a genome-wide analysis of 12,186 cases and 14,718 controls. Three novel associations were discovered from colon transverse models at FDR ≤ 0.2 and further evaluated in an independent replication including 32,825 cases and 39,933 controls. After adjusting for multiple comparisons, we found statistically significant associations using colon transcriptome models with TRIM4 (discovery P = 2.2 × 10- 4, replication P = 0.01), and PYGL (discovery P = 2.3 × 10- 4, replication P = 6.7 × 10- 4). Interestingly, both genes encode proteins that influence redox homeostasis and are related to cellular metabolic reprogramming in tumors, implicating a novel CRC pathway linked to cell growth and proliferation. Defining CRC risk regions as one megabase up- and downstream of one of the 56 independent risk variants, we defined 44 non-overlapping CRC-risk regions. Among these risk regions, we identified genes associated with CRC (P < 0.05) in 34/44 CRC-risk regions. Importantly, CRC association was found for two genes in the previously reported 2q25 locus, CXCR1 and CXCR2, which are potential cancer therapeutic targets. These findings provide strong candidate genes to prioritize for subsequent laboratory follow-up of GWAS loci. This study is the first to implement PrediXcan in a large colorectal cancer study and findings highlight the utility of integrating transcriptome data in GWAS for discovery of, and biological insight into, risk loci.


Assuntos
Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Neoplasias Colorretais/epidemiologia , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Frequência do Gene , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Valor Preditivo dos Testes , Prognóstico , Fatores de Risco
16.
ACS Appl Mater Interfaces ; 11(9): 8982-8991, 2019 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-30702860

RESUMO

A phase change material (PCM) essentially making up hexadecyl acrylate-grafted graphene (HDA- g-GN) was fabricated via a solvent-free Diels-Alder (DA) reaction. The novel material exhibits multiresponsive, enhanced thermal and electrical conductivities and valid thermal enthalpy. In addition, the optimum DA reaction conditions were explored. A variety of characterization techniques were used to study the thermal, crystalline, and structural properties of HDA- g-GN. The melting and crystallizing enthalpies of HDA- g-GN were as high as 57 and 55 J/g, respectively. Furthermore, the melting and freezing points of HDA- g-GN were 29.5 and 32.7 °C, respectively. The thermal conductivity of HDA- g-GN reached 3.957 W/(m K), which is well above that of HDA itself and the previously reported PCMs. HDA- g-GN exhibited an excellent electric conductivity of 219 S/m. Compared to HDA, the crystalline activation energy of HDA- g-GN decreased from 397 to 278 kJ/mol (Kissinger model) and 373 to 259 kJ/mol (Ozawa model). Moreover, HDA- g-GN exhibited excellent thermal stability, shape stability, and thermal reliability. More importantly, HDA- g-GN can be employed to realize high-performance light-to-thermal and electron-to-thermal energy conversion and storage, which provides wide application prospects in energy-saving buildings, battery thermal management system, bioimaging, biomedical devices, as well as real-time and time-resolved applications.

18.
J Am Chem Soc ; 141(7): 2911-2915, 2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30715865

RESUMO

The role of surface hydroxyls is significant for understanding catalytic performance of metallic oxides for CO2 electroreduction reaction (CO2ER). This Communication describes, employing SnO x as a model system, how to moderate coverage of hydroxyl to derive a stable Sn branches catalyst for CO2ER with a 93.1% Faradaic efficiency (FE) of carbonaceous products. With use of in situ attenuated total reflection surface enhanced infrared adsorption spectroscopy (ATR-SEIRAS) and density functional theory (DFT) calculations, we found that a proper amount of surface hydroxyls offered effective sites to boost CO2 adsorption via hydrogen bond. However, a higher surface coverage of hydroxyls leads to self-reduction of Sn-OH. We also explained the competition between self-reduction and CO2 reduction over Sn-based catalysts. The findings revealed the quantitative correlation between surface coverage of hydroxyl and CO2ER activity and suggested a logical extension to other metal oxide catalysts for CO2ER.

19.
Blood ; 133(15): 1630-1643, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30803991

RESUMO

Since the comprehensive recommendations for the management of acute promyelocytic leukemia (APL) reported in 2009, several studies have provided important insights, particularly regarding the role of arsenic trioxide (ATO) in frontline therapy. Ten years later, a European LeukemiaNet expert panel has reviewed the recent advances in the management of APL in both frontline and relapse settings in order to develop updated evidence- and expert opinion-based recommendations on the management of this disease. Together with providing current indications on genetic diagnosis, modern risk-adapted frontline therapy, and salvage treatment, the review contains specific recommendations for the identification and management of the most important complications such as the bleeding disorder APL differentiation syndrome, QT prolongation, and other all-trans retinoic acid- and ATO-related toxicities, as well as recommendations for molecular assessment of the response to treatment. Finally, the approach to special situations is also discussed, including management of APL in children, elderly patients, and pregnant women. The most important challenges remaining in APL include early death, which still occurs before and during induction therapy, and optimizing treatment in patients with high-risk disease.

20.
Proc Natl Acad Sci U S A ; 116(6): 2220-2225, 2019 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-30659143

RESUMO

Homoharringtonine (HHT), a known protein synthesis inhibitor, has an anti-myeloid leukemia effect and potentiates the therapeutic efficacy of anthracycline/cytarabine induction regimens for acute myelogenous leukemia (AML) with favorable and intermediate prognoses, especially in the t(8;21) subtype. Here we provide evidence showing that HHT inhibits the activity of leukemia-initiating cells (Lin-/Sca-1-/c-kit+; LICs) in a t(8;21) murine leukemia model and exerts a down-regulating effect on MYC pathway genes in human t(8;21) leukemia cells (Kasumi-1). We discovered that NF-κB repressing factor (NKRF) is bound directly by HHT via the second double-strand RNA-binding motif (DSRM2) domain, which is the nuclear localization signal of NKRF. A series of deletion and mutagenesis experiments mapped HHT direct binding sites to K479 and C480 amino acids in the DSRM2 domain. HHT treatment shifts NKRF from the nucleus (including nucleoli) to the cytoplasm by occupying the DSRM2 domain, strengthens the p65-NKRF interaction, and interferes with p65-p50 complex formation, thereby attenuating the transactivation activity of p65 on the MYC gene. Moreover, HHT significantly decreases the expression of KIT, a frequently mutated and/or highly expressed gene in t(8;21) AML, in concert with MYC down-regulation. Our work thus identifies a mechanism of action of HHT that is different from, but acts in concert with, the known mode of action of this compound. These results justify further clinical testing of HHT in AML.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Genes myc , Mepesuccinato de Omacetaxina/farmacologia , Proteínas Repressoras/metabolismo , Animais , Sítios de Ligação , Biomarcadores Tumorais , Linhagem Celular Tumoral , Cromossomos Humanos Par 21 , Cromossomos Humanos Par 8 , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Mepesuccinato de Omacetaxina/química , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Camundongos , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Proteínas Repressoras/química , Fator de Transcrição RelA/metabolismo , Transcrição Genética , Translocação Genética , Ensaios Antitumorais Modelo de Xenoenxerto
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