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1.
J Clin Lab Anal ; 34(5): e23172, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31907990

RESUMO

BACKGROUND: In previous research, we found diabetes rather than obesity was an independent risk factor of breast cancer. However, why diabetes could lead to increased risk of breast cancer patients remains elusive. Long non-coding RNAE330013P06 has been shown to be upregulated in diabetes, and long non-coding RNAs generally promote progression of cancer. METHODS: About 200 specimens of breast patients were obtained in previous clinical trial; 34 samples diagnosed as type 2 diabetes in breast cancer patient were enrolled in this research. Blood samples from 36 patients diagnosed as breast cancer without diabetes; 35 diabetic patients and 35 healthy peoples were obtained as control. All blood samples were measured by quantitative real-time PCR (qRT-PCR). Invasion and migration were tested by Transwell assay. Cell proliferation assay was tested by CCK-8. Protein analysis was determined by Western blot. RESULTS: Compared with breast cancer patients without diabetes, diabetic patients without breast cancer and healthy peoples, LncRNAE330013P06 was upregulated in breast cancer patient with diabetes. Furthermore, of 34 breast patients, high LncRNAE330013P06 expression was significantly associated with family history, tumor-node-metastasis stage and lymph node metastasis. E33 promoted cancer cell growth in vitro via downregulation of P53. CONCLUSION: Upregulation of LncRNAE330013P06 driven by type 2 diabetes is one of the factors which promoted progression of breast cancer.

2.
Adv Mater ; 32(6): e1905658, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31830338

RESUMO

Lithium-sulfur (Li-S) batteries are strongly considered as next-generation energy storage systems because of their high energy density. However, the shuttling of lithium polysulfides (LiPS), sluggish reaction kinetics, and uncontrollable Li-dendrite growth severely degrade the electrochemical performance of Li-S batteries. Herein, a dual-functional flexible free-standing carbon nanofiber conductive framework in situ embedded with TiN-VN heterostructures (TiN-VN@CNFs) as an advanced host simultaneously for both the sulfur cathode (S/TiN-VN@CNFs) and the lithium anode (Li/TiN-VN@CNFs) is designed. As cathode host, the TiN-VN@CNFs can offer synergistic function of physical confinement, chemical anchoring, and superb electrocatalysis of LiPS redox reactions. Meanwhile, the well-designed host with excellent lithiophilic feature can realize homogeneous lithium deposition for suppressing dendrite growth. Combined with these merits, the full battery (denoted as S/TiN-VN@CNFs || Li/TiN-VN@CNFs) exhibits remarkable electrochemical properties including high reversible capacity of 1110 mAh g-1 after 100 cycles at 0.2 C and ultralong cycle life over 600 cycles at 2 C. Even with a high sulfur loading of 5.6 mg cm-2 , the full cell can achieve a high areal capacity of 5.5 mAh cm-2 at 0.1 C. This work paves a new design from theoretical and experimental aspects for fabricating high-energy-density flexible Li-S full batteries.

3.
Ecotoxicol Environ Saf ; 188: 109898, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31711775

RESUMO

Gamma-aminobutyric acid (GABA) plays a critical role in regulation of gonadotropin-releasing hormone (GnRH) through GABAA receptor (GABAAR). Nitric oxide (NO) production has correlation with GABA and regulates GnRH secretion. This study was performed to examine the mechanisms by which manganese (Mn) accelerate puberty onset involves GABAAR/NO pathway in the preoptic area-anterior hypothalamus (POA-AH) in immature female rats. First, female rats received daily dose of MnCl2 0 (saline), 2.5, 5 and 10 mg/kg b.w by oral gavage during postnatal day (PND) 21-32. Animals administered with 10 mg/kg MnCl2 exhibited earlier puberty onset age and advanced ovary and uterus development than these in saline-treatment group. Furthermore, we found that decrease of GABAAR result in elevated production of nitric oxide synthase1 (NOS1), NO and GnRH in the POA-AH. Second, we recorded the neuronal spikes alternation after perfusion with GABAAR inhibitor bicuculline (BIC), GABAAR agonist isoguvacine (isog), and MnCl2 from the POA-AH in acute brain slices of PND21 rats. Spontaneous firing revealed a powerful GABAAR-mediated action on immature POA-AH and confirm that MnCl2 has a significant effect on GABAAR. Third, we revealed that decrease in NOS1 and NO production by treatment with isog-alone or isog+MnCl2 contribute to the decrease of GnRH in the POA-AH and a delayed puberty onset age compared to treatment with MnCl2-alone. Together, these results suggested that excessive exposure to MnCl2 stimulates NO production through decreased GABAAR in the POA-AH to advance puberty onset in immature female rats.


Assuntos
Envelhecimento/efeitos dos fármacos , Cloretos/toxicidade , Disruptores Endócrinos/toxicidade , Óxido Nítrico/metabolismo , Área Pré-Óptica/efeitos dos fármacos , Receptores de GABA-A/metabolismo , Maturidade Sexual/efeitos dos fármacos , Envelhecimento/metabolismo , Animais , Feminino , Hormônio Liberador de Gonadotropina/metabolismo , Compostos de Manganês , Neurônios/efeitos dos fármacos , Ovário/efeitos dos fármacos , Ovário/crescimento & desenvolvimento , Área Pré-Óptica/crescimento & desenvolvimento , Área Pré-Óptica/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Útero/diagnóstico por imagem , Útero/efeitos dos fármacos , Desmame
4.
Huan Jing Ke Xue ; 40(9): 4000-4008, 2019 Sep 08.
Artigo em Chinês | MEDLINE | ID: mdl-31854862

RESUMO

In order to recognize the risk of odorous compounds and its driving mechanisms in water source reservoirs, the water quality, plankton, and odorous compounds of 17 provincial water source reservoirs in Jiangsu Province were investigated during a high-risk period of odorous compounds. A high eutrophication status, such as high algal biomass and low transparency, were widely observed in our study reservoirs. In addition, 2-methylisoborneol (MIB) exceeded the standard in some water layers of one-third of the reservoirs, of which the average concentration was (13.7±20.7) ng·L-1. Geosmin (GSM) was also detected in several reservoirs, although the maximum concentration of 4.6 ng·L-1 did not exceed the drinking water quality standard. With respect to the relationships between odorous compounds and environmental conditions, significant correlation (P<0.05) was noted between the MIB concentration and eutrophication indicators, including chlorophyll-a, Secchi depth, suspended solids, and comprehensive nutrition state index (TLI), particularly for chlorophyll-a and TLI (P<0.01). These results indicate that the risk of odorous compounds in water source reservoirs depend largely on the eutrophic status. Therefore, nutrient reduction, improvement in vegetation coverage of the reservoir basin, reasonable fishing practices are considered as effective strategies to avoid the risk of the odorous compounds in reservoirs.

5.
Huan Jing Ke Xue ; 40(9): 4023-4032, 2019 Sep 08.
Artigo em Chinês | MEDLINE | ID: mdl-31854865

RESUMO

Twelve lakes and reservoirs with different water depths and different water residence times were studied to identify the applicability of bioavailable phosphorus of sediments in indicating trophic levels. Water and sediment samples were collected in these 12 lakes and reservoirs to analyze the relationship of nutrient levels between the sediment and the water column. Sodium hydroxide extracted phosphorus (NaOH-P) determined using the SMT classification method is defined as the bioavailable phosphorus of sediment. The results showed that total phosphorus levels in sediments in different lakes and reservoirs ranged from 225 to 760 mg·kg-1 (mean value 502 mg·kg-1); the NaOH-P levels in sediments ranged from 86 to 584 mg·kg-1 (mean value 263 mg·kg-1); the total phosphorus concentrations in the water was 0.02-0.35 mg·L-1 (mean value 0.11 mg·L-1), and the chlorophyll a concentrations in the water were 3-349 µg·L-1 (mean value 51 µg·L-1). It was found that NaOH-P was more effective than total phosphorus in indicating the trophic status of the lakes and reservoirs. However, the NaOH-P levels were significantly related to the phosphorus concentrations in the water column only in shallow water with a long residence time. It was revealed that water residence time and water depth are two key factors that affect the relationship of the phosphorus content between the sediment and the water column. In deep waters or waters with short residence time, the NaOH-P content in the sediment hardly influenced the phosphorus concentration in the water columns, even at high levels. However, in shallow waters with long residence time, the sediment acted as both sources and sinks and frequently exchanged nutrients with the overlying water, especially during bloom periods in summer. Thus NaOH-P could be a potential risk of eutrophication in such waters.


Assuntos
Eutrofização , Lagos , Fósforo , Poluentes Químicos da Água , China , Clorofila A , Monitoramento Ambiental , Sedimentos Geológicos
6.
Chem Commun (Camb) ; 55(68): 10088-10091, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31380863

RESUMO

Trace ethanol is applied as a cheap and effective electrolyte additive for reducing the activation voltage of Li2S cathodes in lithium-ion-sulfur batteries. Because Li2S can dissolve in ethanol, the solid-solid phase reaction in the first stage of the activation process converts into a liquid-solid phase reaction, which expedites the transport of electrons and lithium ions and reduces the activation voltage of Li2S. This strategy can be extended to other solvents that can dissolve Li2S.

7.
Small ; 15(14): e1805479, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30730107

RESUMO

Rapidly developed Na-ion batteries are highly attractive for grid energy storage. Nevertheless, the safety issues of Na-ion batteries are still a bottleneck for large-scale applications. Similar to Li-ion batteries (LIBs), the safety of Na-ion batteries is considered to be tightly associated with the electrolyte and electrode/electrolyte interphase. Although the knowledge obtained from LIBs is helpful, designing safe electrolytes and obtaining stable interphases in Na-ion batteries is still a huge challenge. Therefore, it is of significance to investigate the key factors and develop new strategies for the development of high-safety Na-ion batteries. This comprehensive review introduces the recent efforts from nonaqueous electrolytes and interphase aspects of Na-ion batteries, proposes their design strategies and requirements for improving safety characteristics, and discusses the potential issues for practical applications. The insight to formulate safe electrolytes and design the stable interphase for Na-ion batteries with high safety is intended to be provided herein.

8.
IEEE Trans Biomed Eng ; 66(9): 2651-2662, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30668450

RESUMO

In this study, we explore the use of low rank and sparse constraints for the noninvasive estimation of epicardial and endocardial extracellular potentials from body-surface electrocardiographic data to locate the focus of premature ventricular contractions (PVCs). The proposed strategy formulates the dynamic spatiotemporal distribution of cardiac potentials by means of low rank and sparse decomposition, where the low rank term represents the smooth background and the anomalous potentials are extracted in the sparse matrix. Compared to the most previous potential-based approaches, the proposed low rank and sparse constraints are batch spatiotemporal constraints that capture the underlying relationship of dynamic potentials. The resulting optimization problem is solved using alternating direction method of multipliers. Three sets of simulation experiments with eight different ventricular pacing sites demonstrate that the proposed model outperforms the existing Tikhonov regularization (zero-order, second-order) and L1-norm based method at accurately reconstructing the potentials and locating the ventricular pacing sites. Experiments on a total of 39 cases of real PVC data also validate the ability of the proposed method to correctly locate ectopic pacing sites.

9.
Eur J Pharmacol ; 843: 145-153, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30423319

RESUMO

Apatinib is a tyrosine kinase inhibitor that selectively targets vascular endothelial growth factor receptor-2 (VEGFR-2). Although apatinib has shown promising anti-tumor activity against several types of tumor, its role and underlying mechanism against non-Hodgkin lymphoma (NHL) remain to be explored. Here, we report that apatinib dramatically inhibited in vitro the proliferation of various human NHL cell lines, including Burkitt lymphoma (BL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL), in a dose-dependent manner. Moreover, administration of apatinib markedly delayed tumor growth in vivo in a xenograft mouse model derived from human DLBCL OCI-ly3 cells, in association with significantly prolonged survival of tumor-bearing mice. Mechanistically, apatinib suppressed activation of VEGFR2 (manifested by reduced VEGFR2 phosphorylation), accompanied by inhibition of the Ras pathway (reflected by down-regulation Ras, Raf, pMEK1/2, pERK1/2) in OCI-ly1 (GCB subtype of DLBCL) and SU-DHL2 (ABC subtype of DLBCL) cells. Of note, apatinib sharply impaired angiogenesis in vivo in tumor tissues. Together, these results indicate that apatinib displays a marked cytotoxic activity against various types of NHL cells (including BL, MCL, and GCB- or ABC-DLBCL) both in vitro and in vivo. They also suggest that anti-NHL activity of apatinib might be associated with inhibition of tumor cell growth and induction of apoptosis as well as anti-angiogenesis by targeting VEGFR2 and its downstream Ras/Raf/MEK/ERK pathway.


Assuntos
Antineoplásicos , Linfoma não Hodgkin/tratamento farmacológico , Inibidores de Proteínas Quinases , Piridinas , Proteínas ras/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Humanos , Linfoma não Hodgkin/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
10.
Nanoscale ; 10(38): 18407-18414, 2018 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-30256369

RESUMO

In this work, a ternary confined-functional sulfur composite with a Host-Sulfur-Container structure is designed and synthesized for high performance lithium sulfur batteries. The host in this unique architecture is porous carbon, which contains interconnected macropore tunnels and meso/micropores on the macropore tunnel walls. These hierarchical pores exhibit a synergistic effect to adsorb sulfur in their spaces and provide more nucleation sites to direct the uniform coating of sulfur. Moreover, the interconnected porous structure can facilitate electron transfer and also ensure high sulfur utilization. Furthermore, the poly(3,4-ethylenedioxythiophene) layer container improves the conductivity of the electrode, prevents the diffusion of dissolved polysulfide, and prevents volume expansion during the charge-discharge processes. As a result, the electrode with the poly(3,4-ethylenedioxythiophene)/sulfur/porous carbon composite and Host-Sulfur-Container architecture maintains a reversible capacity of 831.9 mA h g-1 after 200 cycles at a current density of 0.5 C and presents long-term cycling stability with 0.088% capacity decay per cycle over 500 cycles at 1 C. This indicates that the prepared Host-Sulfur-Container composite is a promising cathode material for lithium-sulfur batteries, and its hierarchical tunnel pore carbon host with meso/micropores inside shows great potential in the energy storage field.

11.
ACS Appl Mater Interfaces ; 10(26): 22201-22209, 2018 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-29898366

RESUMO

The notorious lithium (Li) dendrites and the low Coulombic efficiency (CE) of Li anode are two major obstacles to the practical utilization of Li metal batteries (LMBs). Introducing a dendrite-suppressing additive into nonaqueous electrolytes is one of the facile and effective solutions to promote the commercialization of LMBs. Herein, Li difluorophosphate (LiPO2F2, LiDFP) is used as an electrolyte additive to inhibit Li dendrite growth by forming a vigorous and stable solid electrolyte interphase film on metallic Li anode. Moreover, the Li CE can be largely improved from 84.6% of the conventional LiPF6-based electrolyte to 95.2% by the addition of an optimal concentration of LiDFP at 0.15 M. The optimal LiDFP-containing electrolyte can allow the Li||Li symmetric cells to cycle stably for more than 500 and 200 h at 0.5 and 1.0 mA cm-2, respectively, much longer than the control electrolyte without LiDFP additive. Meanwhile, this LiDFP-containing electrolyte also plays an important role in enhancing the cycling stability of the Li||LiNi1/3Co1/3Mn1/3O2 cells with a moderately high mass loading of 9.7 mg cm-2. These results demonstrate that LiDFP has extensive application prospects as a dendrite-suppressing additive in advanced LMBs.

12.
Chem Commun (Camb) ; 54(35): 4453-4456, 2018 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-29652062

RESUMO

We prepare a totally nonflammable phosphate-based electrolyte composed of 5 mol L-1 (M) Li bis(fluorosulfonyl) imide (LiFSI) in a trimethyl phosphate (TMP) solvent. The concentrated 5 M LiFSI/TMP electrolyte shows good compatibility with graphite and no Al corrosion. More attractively, such a concentrated electrolyte can effectively suppress the growth of Li dendrites in Li metal batteries because of a stable LiF-rich SEI layer. Therefore, this highly concentrated electrolyte is promising for safe Li batteries.

13.
IEEE J Transl Eng Health Med ; 6: 1800212, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29531867

RESUMO

The prominent advantage of meshfree method, is the way to build the representation of computational domain, based on the nodal points without any explicit meshing connectivity. Therefore, meshfree method can conveniently process the numerical computation inside interested domains with large deformation or inhomogeneity. In this paper, we adopt the idea of meshfree representation into cardiac medical image analysis in order to overcome the difficulties caused by large deformation and inhomogeneous materials of the heart. In our implementation, as element-free Galerkin method can efficiently build a meshfree representation using its shape function with moving least square fitting, we apply this meshfree method to handle large deformation or inhomogeneity for solving cardiac segmentation and motion tracking problems. We evaluate the performance of meshfree representation on a synthetic heart data and an in-vivo cardiac MRI image sequence. Results showed that the error of our framework against the ground truth was 0.1189 ± 0.0672 while the error of the traditional FEM was 0.1793 ± 0.1166. The proposed framework has minimal consistency constraints, handling large deformation and material discontinuities are simple and efficient, and it provides a way to avoid the complicated meshing procedures while preserving the accuracy with a relatively small number of nodes.

14.
Nanomaterials (Basel) ; 8(3)2018 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-29562687

RESUMO

In this paper, we come up with a wavelength tunable absorber which is made up of periodically elliptical graphene arrays in the far-infrared and terahertz regions. Through simulation, we find that we can increase the length of long axis of the ellipse, raise the incidence angles of TM- and TE-polarization (TM- and TE-polarization indicate the direction of the incident electric field along the direction of the x and the y axis, respectively.) within certain limits, and increase the chemical potential of graphene, so as to enhance the absorption of light in the elliptical graphene arrays. We also compare the absorption spectra of the original structure and the complementary structure, and find that the absorption of the original structure is higher than that of the complementary structure. In the end, we study the changes in the absorption rate of the double layer structure of the elliptical array with the increase in the thickness of SiO2. The elliptical array structure can be applied to tunable spectral detectors, filters and sensors at far-infrared and terahertz wavelengths.

15.
Oncol Lett ; 15(1): 75-82, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29387211

RESUMO

Data from clinical trials suggest that polyethylene glycol-conjugated asparaginase (PEG asparaginase) should be recommended as a replacement for Escherichia coli (E. coli) asparaginase in the treatment of pediatric acute lymphoblastic leukemia (ALL) due to its prolonged effect, similar safety profile and convenience. The present study investigated the efficacy and safety of PEG asparaginase in adolescents and adults with newly diagnosed ALL. The clinical data of 122 patients, ≥14 years old with de novo ALL, who received either PEG asparaginase or E. coli asparaginase as part of an induction regimen, were retrospectively analyzed. The results revealed that PEG asparaginase had a comparable complete remission rate (95.65 vs. 90.79%), median overall survival time (14.07 vs. 16.29 months) and median relapse-free survival time (10.00 vs. 8.57 months) with E. coli asparaginase. In addition, patients <35 years old receiving PEG asparaginase obtained a higher median RFS time compared with those receiving E. coli asparaginase (10.93 vs. 8.97 months; P=0.037). Patients treated with E. coli asparaginase exhibited a significantly higher incidence of central nervous system leukemia (CNSL) compared with those treated with PEG asparaginase (27.63 vs. 10.87%; P=0.028) during the consolidation phase. Toxic events, including allergy, grade III-IV liver dysfunction, renal function damage and pancreatic lesions were similar between the two groups. A longer duration of coagulation dysfunction (9.80±5.51 vs. 6.80±4.21 days; P=0.002) and agranulocytosis (18.89±8.79 vs. 12.03±8.34 days; P<0.01), and a higher incidence of grade IV-V infections (22.73 vs. 7.25%; P=0.018) were observed in the PEG asparaginase group. However, these did not increase bleeding events or infection-associated mortalities. When taking the convenience and superior efficacy in preventing CNSL into consideration, PEG asparaginase is a candidate for first-line treatment of adolescent and adult ALL. A larger prospective clinical trial is required to further confirm this point of view.

16.
Oncol Rep ; 38(4): 2205-2210, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28791365

RESUMO

Fibroblast growth factor 8 (FGF8), a member of the fibroblast growth factor (FGF) family, is upregulated in several human cancers, including HCC (HCC). Previous studies have demonstrated that FGF8 increased cell growth and invasion of tumor cells. In the present study we investigated whether FGF8 is involved in the cell proliferation and resistance to several drugs in human HCC cells. We stably overexpressed FGF8 by lentiviral transfection. In addition, we also added recombinant FGF8 instead of stably overexpressing FGF8 in human HCC cells. Stable overexpression of FGF8 or exogenous recombinant FGF8 resulted in significantly enhanced cell proliferation in human HCC cells. With the use of CellTiter-Glo assay for the determination of cell viability, we found that FGF8 increased the resistance to epidermal growth factor receptor (EGFR) inhibitors in human HCC cells. Additionally, the expression of EGFR was also upregulated by stably overexpressing FGF8 or exogenous recombinant FGF8. Yes-associated protein 1 (YAP1) was reported to upregulate the expression of EGFR. Moreover, we also found that FGF8 increased the expression of YAP1 and knockdown of YAP1 eliminated the upregulation of EGFR and the resistance to EGFR inhibition induced by FGF8. Our study provides evidence that FGF8 plays an important role in the resistance to EGFR inhibition of human HCC cells.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Carcinoma Hepatocelular/tratamento farmacológico , Receptores ErbB/genética , Fator 8 de Crescimento de Fibroblasto/genética , Neoplasias Hepáticas/tratamento farmacológico , Fosfoproteínas/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição , Ativação Transcricional/efeitos dos fármacos
18.
Target Oncol ; 12(5): 677-687, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28710745

RESUMO

BACKGROUND: Leukemia stem cells (LSCs) are considered to be the cause of treatment failure and relapse in acute myeloid leukemia (AML). Overexpression of the Bcl-2 family of anti-apoptotic proteins such as Bcl-2, Bcl-xl, and Mcl-1 accounts for survival and self-renewal of LSCs. AT101 binds to the BH3 motif of all Bcl-2 family anti-apoptotic proteins and demonstrates anti-tumor activity in multiple types of tumor. Thus, we hypothesized that this agent might have the potential to deplete LSCs. OBJECTIVE: The present study aims to investigate if and by what mechanism AT101 is able to target AML stem-like cells. METHODS: As LSCs and hematopoietic stem cells (HSCs) are enriched in CD34+CD38- populations, CD34+CD38- cells from KG1α and Kasumi-1 cell lines as well as CD34+ blasts from AML patients were used as LSC models, while CD34+ cells from healthy donors were used as normal hematopoietic cells. Cell proliferation and apoptosis were assessed by a cell counting kit-8 (CCK8) assay and an Annexin V/PI assay using flow cytometry, respectively. Colony-forming units experiments were performed to monitor the stemness features of AML cells. Western blot and quantitative real-time polymerase chain reaction (qPCR) analysis were performed to examine the levels of proteins and mRNAs related to either the intrinsic apoptotic pathway or DNA damage response. RESULTS: AT101 inhibited proliferation and induced apoptosis in CD34+CD38- KG1α and Kasumi-1 cells in a dose- and time-dependent manner. Exposure to AT101 for 24 h resulted in apoptosis in primary CD34+ AML blasts (EC50 [concentration needed for a 50% maximal effect] = 2.45-76.00 µmol/L), while it only had a modest effect on normal CD34+ hematopoietic cells. Mechanistically, AT101 activated the intrinsic apoptotic pathway by inhibition of Bcl-2 anti-apoptotic proteins, reflected by a decrease in mitochondrial membrane potential. Moreover, AT101 caused DNA damage (e.g., increased γH2AX phosphorylation), which might also contribute to its anti-leukemic effects. Interestingly, the ex vivo efficacy of AT101 in primary AML samples significantly correlated to hyperleukocytosis and FLT3-ITD mutations. AT101 was also effective against CD34+ blasts isolated from elderly patients and patients who did not achieve complete remission after induction therapy. CONCLUSIONS: AT101 effectively eliminates LSCs in vitro through the induction of DNA damage and activation of the intrinsic apoptotic pathway. AT101 is effective towards leukemic cells from patients with adverse prognostic factors, suggesting that AT101 could have the potential as an alternative salvage therapy for the treatment of relapsed and refractory AML.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Gossipol/análogos & derivados , Leucemia Mieloide Aguda , Células-Tronco Neoplásicas/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Gossipol/farmacologia , Humanos , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores
19.
Pharmacogenomics ; 18(13): 1259-1270, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28745928

RESUMO

AIM: To investigate the combined action of decitabine (DAC) with chidamide (CS055) on acute lymphoblastic leukemia (ALL) cells. MATERIALS & METHODS: ALL cell lines as well as primary cells from 17 ALL patients were subjected to different treatments and thereafter cell counting Kit-8 (CCK-8) assay, flow cytometry and western blot were employed to determine IC50, apoptosis and checkpoint kinase 1 and γH2A.X expression. RESULTS: Low-dose DAC combined with CS055 could effectively kill ALL cells by the reduction of cell viability and induction of apoptosis. This was also observed in primary cells from 17 ALL patients, especially for those with p16 gene deletion. Suppression of checkpoint kinase 1 phosphorylation and upregulation of γH2A.X expression was demonstrated to participate in DAC plus CS055-induced apoptosis. CONCLUSION: Low-dose DAC could enhance chidamide-induced apoptosis in adult ALL, especially for patients with p16 gene deletion through DNA damage.


Assuntos
Aminopiridinas/uso terapêutico , Antimetabólitos Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Azacitidina/análogos & derivados , Benzamidas/uso terapêutico , Inibidor p16 de Quinase Dependente de Ciclina/genética , Dano ao DNA/efeitos dos fármacos , Inibidores de Histona Desacetilases/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Adulto , Azacitidina/administração & dosagem , Linhagem Celular Tumoral , Decitabina , Feminino , Deleção de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adulto Jovem
20.
Int Immunopharmacol ; 50: 146-151, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28662433

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is a common and aggressive subtype of non-Hodgkin's lymphomas, with limited treatment options in refractory and relapsed patients. Growing evidence supports the notion that CD8+ T cell immunity could be utilized to eliminate B cell lymphomas. CXCR5+CD8+ T cell is a novel cell subtype and share CXCR5 expression with CD19+ tumor cells. In this study, we investigated the frequency and function of existing CXCR5+CD8+ T cells in DLBCL patients. We found that DLBCL patients as a group demonstrated significantly higher level of CXCR5+CD8+ T cells than healthy individuals, with huge variability in each patient. Using anti-CD3/CD28-stimulated CD8+ T cells as effector (E) cells and autologous CD19+ tumor cells as target (T) cells, at high E:T ratio, no difference between the intensities of CXCR5+CD8+ T cell- and CXCR5-CD8+ T cell-mediated cytotoxicity were observed. However, at intermediate and low E:T ratios, the CXCR5+CD8+ T cells presented stronger cytotoxicity than CXCR5-CD8+ T cells. The expressions of granzyme A, granzyme B, and perforin were significantly higher in CXCR5+CD8+ T cells than in CXCR5-CD8+ T cells, with no significant difference in the level of degranulation. Tumor cells in DLBCL were known to secrete high level of interleukin 10 (IL-10). We therefore blocked the IL-10/IL-10R pathway, and found that the expressions of granzyme A, granzyme B, and perforin by CXCR5+CD8+ T cells were significantly elevated. Together, these results suggest that CXCR5+CD8+ T cells are potential candidates of CD8+ T cell-based immunotherapies, could mediate elimination of autologous tumor cells in DLBCL patients, but are also susceptible to IL-10-mediated suppression.


Assuntos
Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/imunologia , Imunoterapia Adotiva/métodos , Interleucina-10/metabolismo , Linfoma Difuso de Grandes Células B/imunologia , Adulto , Idoso , Antígenos CD19/metabolismo , Células Cultivadas , Microambiente Celular , Técnicas de Cocultura , Citotoxicidade Imunológica , Feminino , Humanos , Linfoma Difuso de Grandes Células B/terapia , Masculino , Pessoa de Meia-Idade , Receptores CXCR5/metabolismo , Evasão Tumoral , Microambiente Tumoral
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