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1.
Ann Hematol ; 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31493003

RESUMO

The prognostic significance of Wilms' tumor gene 1 (WT1) expression at diagnosis in adults with B cell precursor acute lymphoblastic leukemia (BCP-ALL) remains poorly understood. A total of 257 adults with Ph-negative BCP-ALL who were consecutively diagnosed and received at least 1 course of induction therapy at our institute were retrospectively analyzed. The WT1 expression patterns were significantly different among the molecularly and cytogenetically defined groups (E2A-PBX1, TEL-AML1, and MLL rearrangements; high hyperdiploidy and B-other). By considering the WT1 expression pattern and the relapse status, 2 cutoff values, 1.8% and 7.2%, were arbitrarily selected to place patients into WT1-low, WT1-inter, and WT1-high groups. In the B-other patients who achieved complete remission (CR), WT1-low and WT1-high patients had similar 3-year relapse-free survival (RFS), disease-free survival (DFS), and overall survival (OS) rates, which were all significantly lower than those of WT1-inter patients. The combined WT1-low/high expression group (n = 132) had significantly lower 3-year RFS, DFS, and OS rates compared with the WT1-inter group (n = 63) of B-other patients (RFS and DFS all P < 0.0001; OS P = 0.0018 and 0.0008). WT1 low/high expression as well as treating with chemotherapy only was independent poor prognostic factors for RFS, DFS, and OS in the B-other patients who achieved CR. Therefore, the molecularly and cytogenetically defined adult Ph-negative BCP-ALL groups have characteristic WT1 expression patterns, and WT1 low/high expression at diagnosis predicts poor outcome in B-other patients.

2.
J Immunother Cancer ; 7(1): 231, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31462297

RESUMO

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) are immunosuppressive cells that play an important role in immune evasion, PD-1/PD-L1 inhibitor tolerance and tumour progression. Therefore, MDSCs are potential targets for cancer immunotherapy. In this study, we screened an effective polymorphonuclear MDSC (PMN-MDSC) inhibitor from the Traditional Chinese Medicine Library and evaluated its synergistic antitumour effects with PD-1 inhibitor. METHODS: In the present study, we found that PMN-MDSCs accumulate heavily in the spleen and bone marrow of melanoma (B16-F10) tumour-bearing mice. Then, we determined the top 10 key proteins in the upregulated KEGG pathways of PMN-MDSCs in tumour-bearing mice through proteomics and Cytoscape analysis. The key proteins were then used as targets for the screening of PMN-MDSC inhibitors from the traditional Chinese Medicine Library (20000 compounds) through molecular docking and weight calculation of the docking score. Finally, the inhibitory effect of the inhibitor was verified through proteomics and metabolomics analysis in vitro and melanoma (B16-F10) and triple-negative breast cancer (4 T1) mouse tumour models in vivo. RESULTS: Traditional Chinese medicine saposhnikovia root extract Prim-O-glucosylcimifugin (POG) could bind well to the target proteins and inhibit the proliferation, metabolism and immunosuppressive ability of PMN-MDSCs by inhibiting arginine metabolism and the tricarboxylic acid cycle (TCA cycle). POG could also increase CD8 T-lymphocyte infiltration in the tumours and enhance the antitumour effect of PD-1 inhibitor in B16-F10 and 4 T1 mouse tumour models. CONCLUSIONS: POG was successfully screened from the traditional Chinese Medicine library as a PMN-MDSC inhibitor. POG exhibited a good synergistic antitumour effect with PD-1 inhibitor. This study provided a potential option for enhancing the efficacy of PD-1 inhibitors in clinical applications.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31424628

RESUMO

BACKGROUND: This study aimed to determine the impact of the pre- and post-minimal residual disease (MRD) status as well as the peri-transplant MRD kinetics on clinical outcomes in pediatric ALL patients who received haploidentical allografts. METHODS: A retrospective study (n = 166) was performed. MRD was determined using multiparameter flow cytometry. RESULTS: Pediatric ALL patients with pre-MRDneg had a lower cumulative incidences of relapse (CIR) compared to those with pre-MRDpos (19.7% vs. 41.2%, P = 0.009). Compared to post-MRDneg group, patients with post-MRDpos experienced higher CIR (81.0% vs. 15.9%, P < 0.001), inferior LFS (14.3% vs. 66.9%, P < 0.001) and OS (19.1% vs. 66.9%, P < 0.001). In regard to peri-MRD kinetics, compared with the MRD-decreasing group and MRDneg/MRDneg group, MRD-increasing group had higher CIR, lower probabilities of LFS and OS (P < 0.001). Compared to pre-MRDneg/post-MRDneg group, a higher CIR was found in the pre-MRDpos/post-MRDpos group (66.7% vs. 12.5%, P < 0.001), pre-MRDpos/post-MRDneg group (32.0% vs. 12.5%, P = 0.016), and pre-MRDneg/post-MRDpos group (91.7% vs. 12.5%, P < 0.001). A lower incidence of LFS and OS were found in pre-MRDpos/post-MRDpos group and pre-MRDneg/post-MRDpos group than in pre-MRDneg/post-MRDneg group (P < 0.05). Multivariate analyses confirmed the association of pre-MRD status, post-MRD status, and peri-MRD kinetics with outcomes (P < 0.05). CONCLUSIONS: The results indicate that, in the pediatric ALL subgroup, not only pre-MRD status or post-MRD status but also peri-SCT MRD dynamics, were associated with an increased CIR after haploidentical allografts. Patients are put into different risk group based on MRD kinetics versus single time MRD status. © 2019 International Clinical Cytometry Society.

4.
Cancer Med ; 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31364309

RESUMO

Acute myeloid leukemia (AML) with t(8;21) is a heterogeneous disease. Although the detection of minimal residual disease (MRD), which is indicated by RUNX1-RUNX1T1 transcript levels, plays a key role in directing treatment, risk stratification needs to be improved, and other markers need to be assessed. A total of 66 t(8;21) AML patients were tested for aldehyde dehydrogenase (ALDH) activity by flow cytometry at diagnosis, and 52 patients were followed up for a median of 20 (1-34) months. The median percentage of CD34+ALDH+, CD34+CD38-ALDH+, and CD34+CD38+ALDH+ cells among nucleated cells were 0.028%, 0.012%, and 0.0070%, respectively. The CD34+ALDH+-H, CD34+CD38-ALDH+-H, and CD34+CD38+ALDH+-H statuses (the percentage of cells that were higher than the individual cutoffs) were all significantly associated with a lower 2-year relapse-free survival (RFS) rate in both the whole cohort and adult patients (P = .015, .016, and .049; P = .014, .018, and .032). Patients with < 3-log reduction in the RUNX1-RUNX1T1 transcript level after the second consolidation therapy (defined as MRD-H) had a significantly lower 2-year RFS rate than patients with ≥ 3-log reduction (MRD-L) (P = .017). The CD34+ALDH+ status at diagnosis was then combined with the MRD status. CD34+ALDH+-L/MRD-H patients had similar 2-year RFS rates to both CD34+ALDH+-L/MRD-L and CD34+ALDH+-H/MRD-L patients (P = .50 and 1.0); and CD34+ALDH+-H/MRD-H patients had significantly lower 2-year RFS rate compared with CD34+ALDH+-L and/or MRD-L patients (P < .0001). Multivariate analysis showed that CD34+ALDH+-H/MRD-H was an independent adverse prognostic factor for relapse. In conclusion, ALDH status at diagnosis may improve MRD-based risk stratification in t(8;21) AML, and concurrent high levels of CD34+ALDH+ at diagnosis and MRD predict relapse.

5.
J Exp Clin Cancer Res ; 38(1): 285, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266540

RESUMO

BACKGROUND: Anti-angiogenic therapies demonstrate anti-tumor effects by decreasing blood supply to tumors and inhibiting tumor growth. However, anti-angiogenic therapy may leads to changes in tumor microenvironment and increased invasiveness of tumor cells, which in turn promotes distant metastasis and increased drug resistance. METHODS: The CO-IP assays, N-STORM and cytoskeleton analysis were used to confirm the mechanism that p-VEGFR2/VE-cadherin/ß-catenin/actin complex regulates vascular remodeling and improves the tumor microenvironment. 6-gingerol (6G), the major bioactive component in ginger, stabilized this complex by enhancing the binding of VEGFa to VEGFR2 with non-pathway dependent. Biacore, pull down and molecular docking were employed to confirm the interaction between 6G and VEGFR2 and enhancement of VEGFa binding to VEGFR2. RESULTS: Here, we report that microvascular structural entropy (MSE) may be a prognostic factor in several tumor types and have potential as a biomarker in the clinic. 6G regulates the structural organization of the microvascular bed to decrease MSE via the p-VEGFR2/VE-cadherin/ß-catenin/actin complex and inhibit tumor progression. 6G promotes the normalization of tumor vessels, improves the tumor microenvironment and decreases MSE, facilitating the delivery of chemotherapeutic agents into the tumor core and thereby reducing tumor growth and metastasis. CONCLUSIONS: This study demonstrated the importance of vascular normalization in tumor therapy and elucidated the mechanism of action of ginger, a medicinal compound that has been used in China since ancient times.

6.
Anim Biotechnol ; : 1-8, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253064

RESUMO

The study evaluated the effects of branched-chain volatile fatty acids (BCVFA) and fibrolytic enzyme (FE) on rumen development in calves. Forty Holstein male calves at the same ages (15 ± 2.5 days of age) and weights (45 ± 3.3 kg of body weight [BW]) were assigned randomly to four groups with a 2 × 2 factorial arrangement of treatments. Supplemental BCVFA (0 g/d or 18 g/d) and FE (0 g/d or 1.83 g/d) were fed to calves. Data were analyzed as a 2 × 2 factorial arrangement random design by the mixed procedure of SAS. The BCVFA × FE interaction was observed for ruminal propionate, blood growth hormone (GH) and insulin-like growth factor-1 (IGF-1), and GH receptor (GHR) and IGF-1 receptor (IGF-1R) expression in the rumen mucosa. Dry matter intake was higher for BCVFA addition. The higher average daily gain and ruminal volatile fatty acids were observed for BCVFA or FE addition. Stomach weight and the length and width of rumen papillae were higher for BCVFA addition. The higher expression of GHR, IGF-1R and 3-hydroxy-3-methylglutaryl-CoA synthase 1 in rumen mucosa, and blood GH and IGF-1 were observed with BCVFA or FE addition. Blood ß-hydroxybutyrate and acetoacetate were higher for BCVFA addition. The results indicated that rumen development was promoted by BCVFA, but was not affected with FE addition in calves.

7.
Plant Biotechnol J ; 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31094071

RESUMO

Salinity-induced accumulation of certain microRNAs accompanied by gaseous phytohormone ethylene production has been recognized as a mechanism of plant salt tolerance. MicroRNA319 (miR319) has been characterized as an important player in abiotic stress resistance in some C3 plants, such as Arabidopsis thaliana and rice. However, its role in the dedicated biomass plant switchgrass (Panicum virgatum L.), a C4 plant, has not been reported. Here, we show crosstalk between miR319 and ethylene (ET) for increasing salt tolerance. By overexpressing Osa-MIR319b and a target mimicry form of miR319 (MIM319), we showed that miR319 positively regulated ET synthesis and salt tolerance in switchgrass. By experimental treatments, we demonstrated that ET-mediated salt tolerance in switchgrass was dose-dependent, and miR319 regulated the switchgrass salt response by fine-tuning ET synthesis. Further experiments showed that the repression of a miR319 target, PvPCF5, in switchgrass also led to enhanced ethylene accumulation and salt tolerance in transgenic plants. Genome-wide transcriptome analysis demonstrated that overexpression of miR319 (OE-miR319) down-regulated the expression of key genes in the methionine (Met) cycle but promoted the expression of genes in ethylene synthesis. The results enrich our understanding of the synergistic effects of the miR319-PvPCF5 module and ethylene synthesis in the salt tolerance of switchgrass, a C4 bioenergy plant.

8.
FEMS Microbiol Lett ; 366(8)2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31070729

RESUMO

Lactic acid bacteria (LAB) are major probiotics in food supplements. Survival in gastrointestinal (GI) tract is important for the effective use of LAB as probiotics. Bile salt hydrolase (BSH), which catalyzes the conversion of conjugated bile salts into free bile salts, can significantly modulate the gut microbiome. Here, we hypothesize that BSH is important for LAB survival and adhesion in the gut. The aim of this study is to investigate the effect of BSH on the survival of LAB in the GI tract. A panel of bsh genes from murine gut microbiota were amplified, cloned and expressed into Lactobacillus plantarum, which were then administered to mice by gavage. Our data indicated that the survival of BSH-positive L. plantarum was significantly prolonged in the GI tract compared with wild type L. plantarum. Furthermore, BSH-positive strains exhibited increased adhesion to Caco-2 intestinal cells than BSH-deleted L. plantarum. Enhanced adhesion to intestinal cells of BSH positive LAB can therefore be an important criterion for selecting effective probiotic strains in food industry.

9.
Ann Hematol ; 98(7): 1733-1742, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31053879

RESUMO

Hepatic sinusoidal obstruction syndrome (SOS) has been rarely studied after haploidentical donor (HID) allogeneic hematopoietic stem cell transplantation (allo-HSCT). We performed a retrospective multicentre study on patients with SOS after allo-HSCT in China. The incidence, risk factors, and outcomes were compared between HID HSCT and matched related donor (MRD) HSCT. SOS developed in 0.4% of patients (HIDs: 0.4%, MRDs: 0.5%, p = 0.952) at a median time of 21.50 days (range, 1-55) after allo-HSCT (HIDs: 24 days, MRDs: 20 days, p = 0.316). For patients diagnosed with SOS, the 2-year cumulative incidence of relapse was 22.7% and 22.4% in patients receiving HID and MRD transplantation, respectively (p = 0.584). Overall survival (OS) at 2 year was 10.4% and 38.5% in the two groups (p = 0.113). The transplant-related mortality (TRM) at 100 days was 60.9% in the HID group and 38.5% in the MRD group (p = 0.178). According to the multivariate analyses, significant independent risk factors for the occurrence of SOS were delayed platelet engraftment (p = 0.007) and advanced disease status at the time of HSCT (p = 0.009). The outcomes of SOS after HID HSCT are similar to those after MRD HSCT.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Hepatopatia Veno-Oclusiva , Doadores de Tecidos , Condicionamento Pré-Transplante , Adolescente , Adulto , Aloenxertos , Criança , China/epidemiologia , Feminino , Seguimentos , Hepatopatia Veno-Oclusiva/epidemiologia , Hepatopatia Veno-Oclusiva/etiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco
10.
J Environ Sci (China) ; 81: 205-213, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30975323

RESUMO

Atmospheric particulate pollution in China has attracted much public attention. Occasionally, the particle number concentration increases sharply in a short time period, which is defined as a "particulate matter explosive increase". Heavy particulate matter pollution not only reduces visibility but also has an adverse effect on human health. Hence, there is an urgent need to discover the causes of particulate matter explosive increase. During this campaign, the particle number concentration and free radicals were measured at a tall building on the campus of Lanzhou University of Technology. Additionally, we examined a series of chemicals to reproduce the observed particulate matter explosive increase in a smog chamber to determine its potential factors. Then, we analyzed the mechanism of particulate matter explosive increase in the presence of free radicals. We found that, among the potential inorganic and organic sources analyzed, a mixture of organic and SO2 in the research region had a major effect on particulate matter explosive increase. Moreover, free radical oxidation has a large effect, especially in the formation of organic particulates.


Assuntos
Poluentes Atmosféricos/análise , Poluição do Ar/estatística & dados numéricos , Radicais Livres/química , Modelos Químicos , Material Particulado/análise , China , Poeira , Tamanho da Partícula
11.
Br J Haematol ; 185(5): 836-851, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30916375

RESUMO

Refinement of risk stratification in Philadelphia chromosome (Ph)-negative B-cell acute lymphoblastic leukaemia (ALL) might aid the identification of patients who are likely to relapse. Abnormal S100 calcium binding protein A16 (S100A16) has been implicated in various cancers, but its function remains unclear. We found S100A16 transcript levels were higher in 130 adults with newly-diagnosed Ph-negative B-cell ALL compared with 33 healthy controls. In 115 of 130 patients who achieved first complete remission, those with high S100A16 transcript levels displayed a lower 3-year cumulative incidence of relapse (CIR; 34% [21, 47%] vs. 40% [48, 72%]; P = 0·012) and higher 3-year relapse-free survival (RFS; 65% [53, 78%] vs. 35% [23, 46%]; P = 0·012), especially when receiving chemotherapy only. In multivariate analysis a low S100A16 transcript level was independently-associated with a higher CIR (Hazard ratio [HR] = 3·74 [1·01-13·82]; P = 0·048) and inferior RFS (HR = 5·78 [1·91, 17·84]; P < 0·001). Function analysis indicated that knockdown of S100A16 promoted proliferation and anti-apoptosis and reduced chemosensitivity. S100A16 over-expression revealed an opposite trend, especially in a xeno-transplant mouse model. Western blotting analysis showed upregulation of PI3K/AKT and ERK1/2 in S100A16-knockdown and S100A16-overexpression B-cell ALL cell lines respectively. Inhibition assays suggested these two signalling pathways participated in the S100A16-mediated proliferation and survival effects in B-cell ALL cell lines. Trial Registration: Registered in the Chinese Clinical Trial Registry [ChiCTR-OCH-10000940]; http://www.chictr.org.cn.

12.
Cancer Res ; 79(7): 1451-1464, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30760518

RESUMO

Quaking (QKI) is an alternative splicing factor that can regulate circRNA formation in the progression of epithelial-mesenchymal transition, but the mechanism remains unclear. High expression of QKI is correlated with short survival time, metastasis, and high clinical stage and pathology grade in hepatocellular carcinoma (HCC). Here we report that transcription of the QKI gene was activated by the Yin-Yang 1 (YY1)/p65/p300 complex, in which YY1 bound to the super-enhancer and promoter of QKI, p65 combined with the promoter, and p300 served as a mediator to maintain the stability of the complex. This YY1/p65/p300 complex increased QKI expression to promote the malignancy of HCC as well as an increased circRNA formation in vitro and in vivo. Hyperoside is one of several plant-derived flavonol glycoside compounds. Through virtual screening and antitumor activity analysis, we found that hyperoside inhibited QKI expression by targeting the YY1/p65/p300 complex. Overall, our study suggests that the regulatory mechanism of QKI depends on the YY1/p65/p300 complex and that it may serve as a potential target for treatment of HCC. SIGNIFICANCE: These findings identify the YY1/p65/p300 complex as a regulator of QKI expression, identifying several potential therapeutic targets for the treatment of HCC.

13.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(1): 141-148, 2019 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-30738461

RESUMO

OBJECTIVE: To study the value of flow cytometric scoring system in the diagnosis of myelodysplastic syndromes (MDS). METHODS: The phenotypes of erythroid and immature cells were analyzed retrospectively in 130 MDS patients, 19 healthy controls and 89 pathological controls, all of them were well clinically immunophenotyped. The 4-parameter scoring system reported in the literature was studied, including myeloblast-related cluster size, B-progenitor-related cluster size, lymphocyte to myeloblast CD45 ratio, and granulocyte to lymphocyte side scatter ratio. The two flow cytomatric parameters of the erythroid scoring system were analyzed, including CD36 coefficient of variation (CV) and CD71CV. According to our previous study, the percentage of CD117+CD105- myeloid progenitor cells and the proportion of CD105+ cells in CD117+ cells were selected to establish a two-parameter scoring system, and compared with the four-parameter scoring system and the erythroid scoring system. RESULTS: The sensitivity of the four-parameter scoring system and the erythroid scoring system for the diagnosis of low-risk MDS was 43.5% and 63.0%, and the specificity was 87.0% and 63.9%, respectively. After combining the two scoring systems, the sensitivity to diagnose low-risk MDS was 73.9% and the specificity was 62.0%. The sensitivity of the two-parameter scoring system for the diagnosis of low-risk MDS was 76.1% with a specificity of 81.5%. Combined with the four-parameter scoring system, the sensitivity was increased to 78.3%, but the specificity was reduced to 71.3%. After combining with the erythroid scoring system, the sensitivity reached 87.0%, but the specificity was reduced to 54.6%. CONCLUSION: Using the two-parameter scoring system alone can achieve great sensitivity and specificity in the diagnosis of low risk MDS.


Assuntos
Síndromes Mielodisplásicas , Endoglina , Citometria de Fluxo , Humanos , Imunofenotipagem , Síndromes Mielodisplásicas/diagnóstico , Proteínas Proto-Oncogênicas c-kit , Estudos Retrospectivos
14.
Leuk Lymphoma ; : 1-9, 2019 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-30773106

RESUMO

Acute myeloid leukemia (AML) patients with biallelic CEBPA (bi CEBPA) mutations are considered prognostically favorable, but 38-58% of them still relapse. Therefore, recognizing patients with a high risk of relapse is important. We retrospectively analyzed 83 bi CEBPA AML. Minimal residual disease (MRD) was detected by multiparameter flow cytometry (MFC). Patients with MRD positivity during consolidation chemotherapy had inferior 3-year CIR (55% vs. 36.7%; p = .037) and RFS (45% vs. 63.3%; p = .037) than those with MRD negativity. In patients with adverse cytogenetics, FLT3-ITD or MRD positivity, allogeneic hematopoietic stem cell transplantation (allo-HSCT) achieved superior 3-year CIR (0% vs. 52.8%; p = .006) and RFS (88.9% vs. 47.2%; p = .027) than did consolidation chemotherapy. Consolidation chemotherapy maintained a relatively favorable outcome (3-year CIR, 29%; 3-year RFS, 71%) in patients with intermediate cytogenetics, negative FLT3-ITD, and MRD negativity. Therefore, MFC-MRD could predict relapse and was complementary to genetics for risk stratification treatment in bi CEBPA AML.

15.
Am J Hematol ; 94(5): 512-521, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30680765

RESUMO

This study evaluated the effects of pretransplantation minimal residual disease (pre-MRD) on outcomes of patients with acute lymphoblastic leukemia (ALL) who underwent unmanipulated haploidentical stem cell transplantation (haplo-SCT). A retrospective study including 543 patients with ALL was performed. MRD was determined using multiparametric flow cytometry. Both in the entire cohort of patients and in subgroup cases with T-ALL or B-ALL, patients with positive pre-MRD had a higher incidence of relapse (CIR) than those with negative pre-MRD in MSDT settings (P < 0.01 for all). Landmark analysis at 6 months showed that MRD positivity was significantly and independently associated with inferior rates of relapse (HR, 1.908; P = 0.007), leukemia-free survival (LFS) (HR, 1.559; P = 0.038), and OS (HR, 1.545; P = 0.049). The levels of pre-MRD according to a logarithmic scale were also associated with leukemia relapse, LFS, and OS, except that cases with MRD <0.01% experienced comparable CIR and LFS to those with negative pre-MRD. A risk score for CIR was developed using the variables pre-MRD, disease status, and immunophenotype of ALL. The CIR was 14%, 26%, and 59% for subjects with scores of 0, 1, and 2-3, respectively (P < 0.001). Three-year LFS was 75%, 64%, and 42%, respectively (P < 0.001). Multivariate analysis confirmed the association of the risk score with CIR and LFS. The results indicate that positive pre-MRD, except for low level one (MRD < 0.01%), is associated with poor outcomes in patients with ALL who underwent unmanipulated haplo-SCT.

16.
Cell Death Dis ; 10(2): 43, 2019 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-30674871

RESUMO

Tumor progression is dependent on metabolic reprogramming. Metastasis and vasculogenic mimicry (VM) are typical characteristics of tumor progression. The relationship among metastasis, VM, and metabolic reprogramming remains unclear. In this study, we identified the novel role of Twist1, a VM regulator, in the transcriptional regulation of thymidine phosphorylase (TP) expression. TP promoted the extracellular metabolism of thymidine into ATP and amino acids through the pentose Warburg effect by coupling the pentose phosphate pathway and glycolysis. Moreover, Twist1 relied on TP-induced metabolic reprogramming to promote hepatocellular carcinoma (HCC) metastasis and VM formation mediated by VE-Cad, VEGFR1, and VEGFR2 in vitro and in vivo. The TP inhibitor tipiracil reduced the effect of TP on promoting HCC VM formation and metastasis. Hence, TP, when transcriptionally activated by Twist1, promotes HCC VM formation and metastasis through the pentose Warburg effect and contributes to tumor progression.

17.
Mol Cancer Ther ; 18(3): 541-555, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30642883

RESUMO

Pyrimethamine (Pyr), an antimalarial drug that targeting plasmodium dihydrofolate reductase (pDHFR), has been proved to have antitumor activity. However, its direct target on cancer cells remains unclear. Methotrexate (MTX) is a widely used anticancer drug that blocks human dihydrofolate reductase (hDHFR). In this work, we examined the anticancer effects of Pyr in vitro and in vivo Our results showed that hDHFR and pDHFR have similar secondary and three-dimensional structures and that Pyr can inhibit the activity of hDHFR in lung cancer cells. Although Pyr and MTX can inhibit the proliferation of lung cancer cells by targeting DHFR, only Pyr can inhibit the epithelial-mesenchymal transition (EMT), metastasis and invasion of lung cancer cells. These results indicated that hDHFR is not the only target of Pyr. We further found that thymidine phosphorylase (TP), an enzyme that is closely associated with the EMT of cancer cells, is also a target protein of Pyr. The data retrieved from the Cancer Genome Atlas (TCGA) database revealed that TP overexpression is associated with poor prognosis of patients with lung cancer. In conclusion, Pyr plays a dual role in antitumor proliferation and metastasis by targeting DHFR and TP. Pyr may have potential clinical applications for the treatment of lung cancer.

18.
Plant Cell Physiol ; 60(4): 788-801, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30590744

RESUMO

Plant mechanical strength contributes to lodging resistance and grain yield, making it an agronomically important trait in sorghum (Sorghum bicolor). In this study, we isolated the brittle culm 1 (bc1) mutant and identified SbBC1 through map-based cloning. SbBC1, a homolog of rice OsBC1 and Arabidopsis thaliana AtCOBL4, encodes a COBRA-like protein that exhibits typical structural features of a glycosylphosphatidylinositol-anchored protein. A single-nucleotide mutation in SbBC1 led to reduced mechanical strength, decreased cellulose content, and increased lignin content without obviously altering plant morphology. Transmission electron microscopy revealed reduced cell wall thickness in sclerenchyma cells of the bc1 mutant. SbBC1 is primarily expressed in developing sclerenchyma cells and vascular bundles in sorghum. RNA-seq analysis further suggested a possible mechanism by which SbBC1 mediates cellulose biosynthesis and cell wall remodeling. Our results demonstrate that SbBC1 participates in the biosynthesis of cellulose in the secondary cell wall and affects the mechanical strength of sorghum plants, providing additional genetic evidence for the roles of COBRA-like genes in cellulose biosynthesis in grasses.


Assuntos
Parede Celular/metabolismo , Celulose/metabolismo , Sorghum/metabolismo , Autoimunidade/fisiologia , Regulação da Expressão Gênica de Plantas , Proteínas Quinases Ativadas por Mitógeno/metabolismo
19.
Chin Med J (Engl) ; 131(23): 2808-2816, 2018 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-30511683

RESUMO

Background: Several studies have shown that detection of minimal residual disease (MRD) in acute myeloid leukemia (AML) is an independent prognostic factor. This study aimed to evaluate the significance of dynamic MRD pretransplantation on outcome of AML patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: We retrospectively analyzed 145 consecutive AML patients undergoing allo-HSCT in complete remission status between June 2013 and June 2016. MRD was determined with multiparameter flow cytometry after the first and second courses of chemotherapy and pre-HSCT. Results: In matched sibling donor transplantation (MSDT) settings, patients with positive MRD had higher cumulative incidence of relapse (CIR) than those without MRD after the first (32.3 ± 9.7% vs. 7.7 ± 3.1%, χ2 = 3.661, P = 0.055) or second course of chemotherapy (57.1 ± 3.6% vs. 12.5 ± 2.7%, χ2 = 8.759, P = 0.003) or pre-HSCT (50.0 ± 9.7% vs. 23.0 ± 3.2%, χ2 = 5.547, P = 0.019). In haploidentical SCT (haplo-SCT) settings, the MRD status at those timepoints had no significant impact on clinical outcomes. However, patients with persistent positive MRD from chemotherapy to pre-HSCT had higher CIR than those without persistent positive MRD both in MSDT and haplo-SCT settings. Patients with persistent positive MRD underwent MSDT had the highest relapse incidence, followed by those with persistent positive MRD underwent haplo-SCT, those without persistent MRD underwent haplo-SCT, and those without persistent MRD underwent MSDT (66.7 ± 9.2% vs. 38.5 ± 6.0% vs. 18.8 ± 8.7% vs. 12.0 ± 1.0%, χ2 = 20.763, P < 0.001). Multivariate analysis showed that persistent positive MRD before transplantation was associated with higher CIR (hazard ratio [HR] = 1.69, 95% confidence interval [CI]: 1.200-2.382, P = 0.003), worse leukemia-free survival (HR = 1.812, 95% CI: 1.168-2.812, P = 0.008), and overall survival (HR = 2.354, 95% CI: 1.528-3.627, P < 0.001). Conclusion: Our results suggest that persistent positive MRD before transplantation, rather than positive MRD at single timepoint, could predict poor outcome both in MSDT and haplo-SCT settings.

20.
Anim Biotechnol ; : 1-10, 2018 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-30570383

RESUMO

Cellular retinoic acid binding protein 2 (CRABP2) is essential to myoblast differentiation. However, there was no report about the function of CRABP2 gene in cattle. This study explored the association of CRABP2 gene polymorphisms with growth traits in cattle breeds by several methods, such as DNA sequencing, PCR, PCR-RFLP and forced PCR-RFLP. Two sequence variants were determined. There were 621 individuals in six cattle breeds from China for the experiment, and three breeds were used to test validation of polymorphisms and extent of linkage disequilibrium (LD). The results showed that both SNPs (SNP1, g.2458 G > T, SNP2, g.3878 G > A) were in intron1. Two SNPs were in low linkage disequilibrium. Association analysis suggested that SNP1 had the significant difference on growth traits with body height, height at hip cross and body slanting length (P < .05), while SNP2 showed a significant difference in growth traits with body height, height at hip cross and body slanting length(P < .05). The results of this investigation displayed that the CRABP2 gene is an available candidate gene and may be used for breed selection and conservation.

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