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1.
Sci Total Environ ; 856(Pt 2): 159197, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36206906

RESUMO

This paper presents an analytical approach to calculate the effective diffusion coefficient of chlorides in concrete with both natural and recycled concrete aggregates. In the approach the concrete is treated as a composite consisting of three phases, namely mortar, natural aggregate plus interfacial transition zone, and recycled concrete aggregate plus interfacial transition zone. The effective diffusion coefficient of chlorides in the composite is calculated through two steps. The first step is to calculate the effective diffusion coefficients of chlorides in the natural aggregate plus interfacial transition zone and in the recycled concrete aggregate plus interfacial transition zone by using multilayer spherical approximation, the results of which provide the information about the quality of recycled concrete aggregate in terms of chloride penetration resistance. The second step is to calculate the effective diffusion coefficient of chlorides in the three-phase concrete composite by using effective medium approximation, the results of which provide the information about the influence of recycled concrete aggregate on the diffusivity of recycled aggregate concrete. The analytical expression of the effective diffusion coefficient is derived and carefully compared with the results obtained from both the experiments and numerical simulations, which demonstrates that the present analytical model is rational and reliable. The analytical expression presented can be used to predict the service life of recycled aggregate concrete exposed to chloride environment.

2.
Materials (Basel) ; 15(5)2022 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-35269179

RESUMO

The steel industry is responsible for one-third of all global industrial CO2 emissions, putting pressure on the industry to shift forward towards more environmentally friendly production methods. The metallurgical industry is under enormous pressure to reduce CO2 emissions as a result of growing environmental concerns about global warming. The reduction in CO2 emissions is normally fulfilled by recycling steel waste into alkali-activated cement. Numerous types of steel waste have been produced via three main production routes, including blast furnace, electric arc furnace, and basic oxygen furnace. To date, all of the steel waste has been incorporated into alkali activation system to enhance the properties. This review focuses on the current developments over the last ten years in the steelmaking industry. This work also summarizes the utilization of steel waste for improving cement properties through an alkali activation system. Finally, this work presents some future research opportunities with regard to the potential of steel waste to be utilized as an alkali-activated material.

3.
Polymers (Basel) ; 14(3)2022 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-35160600

RESUMO

Microcapsule-based self-healing concrete can effectively repair micro-cracks in concrete and improve the strength and durability of concrete structures. In this paper, in order to study the effect of epoxy resin on the cement matrix at a microscopic level, molecular dynamics were used to simulate the mechanical and interfacial properties of microcapsule-based self-healing concrete in which uniaxial tension was carried out along the z-axis. The radial distribution function, interface binding energy, and hydrogen bonding of the composite were investigated. The results show that the epoxy resin/C-S-H composite has the maximum stress strength when TEPA is used as the curing agent. Furthermore, the interface binding energy between epoxy resin and cement matrix increases with increasing strain before the stress reaches its peak value. The cured epoxy resin can enhance both the interfacial adhesion and the ductility of the composite, which can meet the needs of crack repair of microcapsule-based self-healing cementitious materials.

4.
Oncol Rep ; 47(2)2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34913075

RESUMO

T­cell acute lymphoblastic leukemia (T­ALL) is a common pediatric malignancy, characterized by the abnormal presence of immature T­cell progenitors. Conventional treatments for T­ALL fail to prevent or cure the disease, with a high­risk of recurrence after the first remission. Thus, medical options are in demand to develop novel therapies for patients suffering with T­ALL. Niclosamide, a traditional oral anti­helminthic drug, has been reported to be a potential anticancer agent that regulates intracellular signaling pathways. Few studies have yet investigated the effects of niclosamide on the development of T­ALL. Here, the present study aimed to investigate the anti­leukemia effects of niclosamide on T­ALL. We first hypothesized that the suppressive effects of niclosamide on the tumor growth of T­ALL are exerted by regulating autophagy and apoptosis. Following niclosamide treatment, T­ALL cell viability was evaluated using MTT assay, and apoptosis with Annexin V/propidium iodide staining. In T­ALL cells treated with niclosamide, changes in apoptosis­ and autophagy­related proteins were analyzed by western blotting. In addition, in an in vivo model, T­ALL xenograft mice were used to study the anti­leukemia effects of niclosamide. The results showed that niclosamide significantly reduced the viability of Jurkat and CCRF­CEM T­ALL cells in both a dose­ and time­dependent manner. Niclosamide significantly activated the early and late phases of apoptosis in Jurkat (at 2 µM) and CCRF­CEM cells (at 1 µM). Furthermore, niclosamide upregulated protein expression of cleaved caspase­3 and LC3B, while downregulated those of Bcl­2 and p62, in a dose­dependent manner in both Jurkat and CCRF­CEM cells. The in vivo results showed that niclosamide treatment significantly suppressed tumor growth and the disease progression in T­ALL xenograft mice by activating cleaved caspase­3 and LC3B. We conclude that niclosamide plays an anti­leukemia role, and that it represents a novel approach for the treatment of T­ALL.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Niclosamida/farmacologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Camundongos
5.
Materials (Basel) ; 14(22)2021 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-34832267

RESUMO

Underwater concrete is a cohesive self-consolidated concrete used for concreting underwater structures such as bridge piers. Conventional concrete used anti-washout admixture (AWA) to form a high-viscosity underwater concrete to minimise the dispersion of concrete material into the surrounding water. The reduction of quality for conventional concrete is mainly due to the washing out of cement and fine particles upon casting in the water. This research focused on the detailed investigations into the setting time, washout effect, compressive strength, and chemical composition analysis of alkali-activated fly ash (AAFA) paste through underwater placement in seawater and freshwater. Class C fly ash as source materials, sodium silicate, and sodium hydroxide solution as alkaline activator were used for this study. Specimens produced through underwater placement in seawater showed impressive performance with strength 71.10 MPa on 28 days. According to the Standard of the Japan Society of Civil Engineers (JSCE), the strength of specimens for underwater placement must not be lower than 80% of the specimen's strength prepared in dry conditions. As result, the AAFA specimens only showed 12.11% reduction in strength compared to the specimen prepared in dry conditions, thus proving that AAFA paste has high potential to be applied in seawater and freshwater applications.

6.
Cells ; 10(11)2021 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-34831338

RESUMO

The developmental potential within pluripotent cells in the canonical model is restricted to embryonic tissues, whereas totipotent cells can differentiate into both embryonic and extraembryonic tissues. Currently, the ability to culture in vitro totipotent cells possessing molecular and functional features like those of an early embryo in vivo has been a challenge. Recently, it was reported that treatment with a single spliceosome inhibitor, pladienolide B (plaB), can successfully reprogram mouse pluripotent stem cells into totipotent blastomere-like cells (TBLCs) in vitro. The TBLCs exhibited totipotency transcriptionally and acquired expanded developmental potential with the ability to yield various embryonic and extraembryonic tissues that may be employed as novel mouse developmental cell models. However, it is disputed whether TBLCs are 'true' totipotent stem cells equivalent to in vivo two-cell stage embryos. To address this question, single-cell RNA sequencing was applied to TBLCs and cells from early mouse embryonic developmental stages and the data were integrated using canonical correlation analyses. Differential expression analyses were performed between TBLCs and multi-embryonic cell stages to identify differentially expressed genes. Remarkably, a subpopulation within the TBLCs population expressed a high level of the totipotent-related genes Zscan4s and displayed transcriptomic features similar to mouse two-cell stage embryonic cells. This study underscores the subtle differences between in vitro derived TBLCs and in vivo mouse early developmental cell stages at the single-cell transcriptomic level. Our study has identified a new experimental model for stem cell biology, namely 'cluster 3', as a subpopulation of TBLCs that can be molecularly defined as near totipotent cells.


Assuntos
Blastômeros/citologia , Embrião de Mamíferos/citologia , Células-Tronco Embrionárias Murinas/citologia , Análise de Célula Única , Células-Tronco Totipotentes/citologia , Transcriptoma/genética , Animais , Análise por Conglomerados , Regulação da Expressão Gênica , Ontologia Genética , Camundongos , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Transdução de Sinais , Zigoto/metabolismo
7.
Polymers (Basel) ; 13(11)2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34064107

RESUMO

Microcapsules encapsulated within epoxy as a curing agent have been successfully applied in self-healing materials, in which the healing performance significantly depends on the binding behaviour of the epoxy curing agent with the cement matrix. In this paper, the binding energy was investigated by molecular dynamics simulation, which could overcome the shortcomings of traditional microscopic experimental methods. In addition to the construction of different molecular models of epoxy, curing agents, and dilutants, seven models were established to investigate the effects of chain length, curing agent, and epoxy resin chain direction on the interfacial binding energy. The results showed that an increase of chain length exhibited had limited effect on the binding energy, while the curing agent and the direction of the epoxy significantly affected the interfacial binding energy. Among different factors, the curing agent tetrethylenepentamine exhibited the highest value of interfacial binding energy by an increment of 31.03 kcal/mol, indicating a better binding ability of the microcapsule core and the cement matrix. This study provides a microscopic insight into the interface behaviour between the microcapsule core and the cement matrix.

8.
Materials (Basel) ; 14(4)2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33567696

RESUMO

This paper details analytical research results into a novel geopolymer concrete embedded with glass bubble as its thermal insulating material, fly ash as its precursor material, and a combination of sodium hydroxide (NaOH) and sodium silicate (Na2SiO3) as its alkaline activator to form a geopolymer system. The workability, density, compressive strength (per curing days), and water absorption of the sample loaded at 10% glass bubble (loading level determined to satisfy the minimum strength requirement of a load-bearing structure) were 70 mm, 2165 kg/m3, 52.58 MPa (28 days), 54.92 MPa (60 days), and 65.25 MPa (90 days), and 3.73 %, respectively. The thermal conductivity for geopolymer concrete decreased from 1.47 to 1.19 W/mK, while the thermal diffusivity decreased from 1.88 to 1.02 mm2/s due to increased specific heat from 0.96 to 1.73 MJ/m3K. The improved physicomechanical and thermal (insulating) properties resulting from embedding a glass bubble as an insulating material into geopolymer concrete resulted in a viable composite for use in the construction industry.

9.
Neoplasia ; 22(12): 789-799, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33142243

RESUMO

BRAF inhibitors were approved for the treatment of BRAF-mutant melanoma. However, most patients acquire the resistance to BRAF inhibitors after several months of treatment. miR-524-5p is considered as a tumor suppressor in many cancers, including melanoma. In this study, we investigated the biological functions of miR-524-5p in melanoma with acquired resistance to BRAF inhibitor and evaluated the endogenous miR-524-5p expression as a biomarker for melanoma. The results showed that the expression of miR-524-5p was 0.481-fold lower in melanoma tissues (n = 117) than in nevus tissues (n = 40). Overexpression of miR-524-5p significantly reduced proliferative, anchorage-independent growth, migratory and invasive abilities of BRAF inhibitor-resistant melanoma cells. Moreover, the introduction of miR-524-5p led to a reduced development of BRAF inhibitor-resistant melanoma in vivo. Remarkably, the MAPK/ERK signaling pathway was decreased after treatment with miR-524-5p. Furthermore, next-generation sequencing analysis implied that the complement system, leukocyte extravasation, liver X receptor/retinoid-X-receptor activation, and cAMP-mediated signaling may be related to miR-524-5p-induced pathways in the resistant cells. The miR-524-5p level was higher on average in complete response and long-term partial response patients than in progressive disease and short-term partial response patients treated with BRAF inhibitors. Our results proposed that miR-524-5p could be considered as a target for treatment BRAF inhibitor-resistant melanoma and a prognostic marker in the response of patients to BRAF inhibitors for melanoma.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , MicroRNAs/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Animais , Biomarcadores Tumorais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Regulação Neoplásica da Expressão Gênica , Humanos , Melanoma , Camundongos , Mutação , Interferência de RNA , Vemurafenib/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Materials (Basel) ; 13(2)2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31936072

RESUMO

This paper reported the effect of high temperature on the electro-mechanical behavior of carbon nanotube (CNT) reinforced epoxy composites. CNT/epoxy composites were fabricated by dispersing CNTs in the epoxy matrix using a solution casting method. Electrical conductivity measurements obtained for the CNT/epoxy composites indicated a steadily increasing directly proportional relationship with CNT concentration with a percolation threshold at 0.25 wt %, reaching a maximum of up to 0.01 S/m at 2.00 wt % CNTs. The electro-mechanical behavior of CNT/epoxy composites were investigated at a room temperature under the static and cyclic compressive loadings, resulting that the change in resistance of CNT/epoxy composites was reduced as increasing CNT concentration with good repeatability. This is due to well-networked CNTs conducting pathways created within the solid epoxy matrix observed by scanning electron microscopy. Temperature significantly affects the electro-mechanical behavior of CNT/epoxy composites. In particular, the electro-mechanical behavior of CNT/epoxy composites below the glass transition temperature showed the similar trend with those at room temperature, whereas the electro-mechanical behavior of CNT/epoxy composites above the glass transition temperature showed an opposite change in resistance with poor repeatability due to unstable CNT network in epoxy matrix.

11.
Am J Cancer Res ; 8(3): 514-525, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29637005

RESUMO

Mesenchymal stem cells (MSCs) have a high self-renewal potential and can differentiate into various types of cells, including adipocytes, osteoblasts, and chondrocytes. Previously, we reported that the enhancer of zeste homolog 2 (EZH2), the catalytic component of the Polycomb-repressive complex 2, and HDAC9c mediate the osteogenesis and adipogenesis of MSCs. In the current study, we identify the role of p38 in osteogenic differentiation from a MAPK antibody array screen and investigate the mechanisms underlying its transcriptional regulation. Our data show that YY1, a ubiquitously expressed transcription factor, and HDAC9c coordinate p38 transcriptional activity to promote its expression to facilitate the osteogenic potential of MSCs. Our results show that p38 mediates osteogenic differentiation, and this has significant implications in bone-related diseases, bone tissue engineering, and regenerative medicine.

12.
Ann Hematol ; 97(4): 697-707, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29349655

RESUMO

Total body irradiation (TBI) is frequently used in hematopoietic stem cell transplantation (HSCT) and is associated with many complications due to radiation injury to the normal cells, including normal stem cells. Nevertheless, the effects of TBI on the mesenchymal stromal stem cell (MSC) are not fully understood. Bone marrow-derived MSCs (BM-MSCs) isolated from normal adults were irradiated with 200 cGy twice daily for consecutive 3 days, a regimen identical to that used in TBI-conditioning HSCT. The characteristics, differentiation potential, cytogenetics, hematopoiesis-supporting function, and carcinogenicity of the irradiated BM-MSCs were then compared to the non-irradiated control. The irradiated and non-irradiated MSCs shared similar morphology, phenotype, and hematopoiesis-supporting function. However, irradiated MSCs showed much lower proliferative and differentiative potential. Irradiation also induced clonal cytogenetic abnormalities of MSCs. Nevertheless, the carcinogenicity of irradiated MSCs is low in vitro and in vivo. In parallel with the ex vivo irradiation experiments, decreased proliferative and differentiative abilities and clonal cytogenetic abnormalities can also be found in MSCs isolated from transplant recipients who had received TBI-based conditioning previously. Thus, TBI used in HSCT drastically injury MSCs and may contribute to the development of some long-term complications associated with clonal cytogenetic abnormality and poor adipogenesis and osteogenesis after TBI.


Assuntos
Apoptose/efeitos da radiação , Células da Medula Óssea/efeitos da radiação , Aberrações Cromossômicas/efeitos da radiação , Células-Tronco Hematopoéticas/efeitos da radiação , Células-Tronco Mesenquimais/efeitos da radiação , Lesões por Radiação/patologia , Irradiação Corporal Total/efeitos adversos , Adulto , Células-Tronco Adultas/efeitos da radiação , Células da Medula Óssea/citologia , Células da Medula Óssea/patologia , Diferenciação Celular/efeitos da radiação , Proliferação de Células/efeitos da radiação , Células Cultivadas , China , Transtornos Cromossômicos/etiologia , Transtornos Cromossômicos/patologia , Feminino , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/patologia , Hospitais Universitários , Humanos , Leucemia/patologia , Leucemia/terapia , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/patologia , Necrose , Lesões por Radiação/etiologia , Condicionamento Pré-Transplante/efeitos adversos , Células Tumorais Cultivadas , Adulto Jovem
13.
Cancer Med ; 6(2): 349-360, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28070990

RESUMO

Conventional cytogenetics can categorize patients with acute myeloid leukemia (AML) into favorable, intermediate, and unfavorable-risk groups; however, patients with intermediate-risk cytogenetics represent the major population with variable outcomes. Because molecular profiling can assist with AML prognosis and next-generation sequencing allows simultaneous sequencing of many target genes, we analyzed 260 genes in 112 patients with de novo AML who received standard treatment. Multivariate analysis showed that karyotypes and mutation status of TET2, PHF6, KIT, and NPM1mutation /FLT3- internal tandem duplication (ITD)negative were independent prognostic factors for the entire cohort. Among patients with intermediate-risk cytogenetics, patients with mutations in CEBPAdouble mutation , IDH2, and NPM1 in the absence of FLT3-ITD were associated with improved Overall survival (OS), similar to those with favorable-risk cytogenetics; patients with mutations in TET2, RUNX1, ASXL1, and DNMT3A were associated with reduced OS, similar to those with unfavorable-risk cytogenetics. We concluded that integration of cytogenetic and molecular profiling improves prognostic stratification of patients into three groups with more distinct prognoses (P < 0.001) and significantly reduces the number of patients classified as intermediate risk. In addition, our study demonstrates that next-generation sequencing (NGS)-based multi-gene sequencing is clinically applicable in establishing an accurate risk stratification system for guiding therapeutic decisions.


Assuntos
Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Leucemia Mieloide Aguda/genética , Mutação , Análise de Sequência de DNA/métodos , Adolescente , Adulto , Idoso , Criança , Análise Citogenética , Feminino , Redes Reguladoras de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Adulto Jovem
14.
Oncotarget ; 7(35): 57131-57144, 2016 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-27494834

RESUMO

During the process of tumorigenesis, inactivation of tumor suppressors is a critical step. EZH2, a histone methyltransferase, promotes cell growth and migration through catalyzing trimethylation of histone H3 at Lys 27 (H3K27me3) and plays an important role in tumorigenesis. Its expression can be controlled by phosphorylation. However, the regulation of EZH2 activity by tumor suppressor kinase is not well understood. In this study, we show that glycogen synthase kinase 3 beta (GSK3ß) negatively regulates H3K27 trimethylation. We also validate that GSKß physically interacts with EZH2, and their interaction occurs in the cytosol. GSK3ß phosphorylates EZH2 at Ser363 and Thr367 in vitro, and activating GSK3ß upregulates Thr367 phosphorylationin vivo. Cells expressing GSK3ß-non-phosphorylatable mutant EZH2 have higher H3K27 trimethylation and enhanced ability of cell migration and anchorage-independent growth. Inactivation of GSK3ß as measured by its phosphorylation at Ser9 is positively correlated with higher level of H3K27 trimethylation in tumor tissues from breast cancer patients. Our study indicated that GSK3ß phosphorylates EZH2 at Ser363 and Thr367, resulting in reduced H3K27 trimethylation and biological activity of EZH2 in breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Metilação de DNA , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Regulação Neoplásica da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/metabolismo , Histonas/química , Catálise , Linhagem Celular Tumoral , Movimento Celular , Citosol/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Mutação , Oncogenes , Fosforilação
15.
Stem Cells ; 34(8): 2183-93, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27250566

RESUMO

Mesenchymal stem cells (MSCs) are multipotent precursors that can undergo multilineage differentiation, including osteogenesis and adipogenesis, which are two mutually exclusive events. Previously, we demonstrated that enhancer of zeste homolog 2 (EZH2), the catalytic component of the Polycomb-repressive complex 2, mediates epigenetic silencing of histone deacetylase 9c (HDAC9c) in adipocytes but not in osteoblasts and that HDAC9c accelerates osteogenesis while attenuating adipogenesis of MSCs through inactivation of peroxisome proliferator-activated receptor gamma 2 activity. Importantly, disrupting the balance between adipogenesis and osteogenesis can lead to age-associated bone loss (osteoporosis) and obesity. Here, we investigated the relationship between age, and osteogenic and adipogenic differentiation potential of MSCs by comparing EZH2 and HDAC9c expression in osteoblasts and adipocytes of both human and mice origins to determine whether the EZH2-HDAC9c axis regulates age-associated osteoporosis and obesity. Our findings indicated that a decline in HDAC9c expression over time was accompanied by increased EZH2 expression and suggested that a therapeutic intervention for age-associated osteoporosis and obesity may be feasible by targeting the EZH2-HDAC9c axis. Stem Cells 2016;34:2183-2193.


Assuntos
Adipócitos/citologia , Envelhecimento/metabolismo , Diferenciação Celular , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Histona Desacetilases/metabolismo , Células-Tronco Mesenquimais/citologia , Osteoblastos/citologia , Proteínas Repressoras/metabolismo , Adipócitos/metabolismo , Adipogenia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Criança , Técnicas de Silenciamento de Genes , Humanos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Pessoa de Meia-Idade , Modelos Biológicos , Osteoblastos/metabolismo , Osteogênese , Adulto Jovem
16.
Cancer Res ; 76(6): 1451-62, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26759241

RESUMO

Epithelial-to-mesenchymal transition (EMT) is an essential physiologic process that promotes cancer cell migration, invasion, and metastasis. Several lines of evidence from both cellular and genetic studies suggest that AKT1/PKBα, but not AKT2 or AKT3, serves as a negative regulator of EMT and breast cancer metastasis. However, the underlying mechanism by which AKT1 suppresses EMT remains poorly defined. Here, we demonstrate that phosphorylation of Twist1 by AKT1 is required for ß-TrCP-mediated Twist1 ubiquitination and degradation. The clinically used AKT inhibitor MK-2206, which possesses higher specificity toward AKT1, stabilized Twist1 and enhanced EMT in breast cancer cells. However, we discovered that resveratrol, a naturally occurring compound, induced ß-TrCP-mediated Twist1 degradation to attenuate MK-2206-induced EMT in breast cancer cells. Taken together, our findings demonstrate that resveratrol counteracts the unexpected metastatic potential induced by anti-AKT therapy and therefore suggest that the addition of resveratrol to an anti-AKT therapeutic regimen may provide extra support for limiting EMT.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Transição Epitelial-Mesenquimal/fisiologia , Fosforilação/fisiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína 1 Relacionada a Twist/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Fosforilação/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Resveratrol , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Estilbenos/farmacologia , Proteínas Contendo Repetições de beta-Transducina/metabolismo
17.
Oncotarget ; 7(7): 8310-20, 2016 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-26824983

RESUMO

Since BRCA mutations are only responsible for 10-20% of cases of breast cancer in patients with early-onset or a family history and since next-generation sequencing technology allows the simultaneous sequencing of a large number of target genes, testing for multiple cancer-predisposing genes is now being considered, but its significance in clinical practice remains unclear. We then developed a sequencing panel containing 68 genes that had cancer risk association for patients with early-onset or familial breast cancer. A total of 133 patients were enrolled and 30 (22.6%) were found to carry germline deleterious mutations, 9 in BRCA1, 11 in BRCA2, 2 in RAD50, 2 in TP53 and one each in ATM, BRIP1, FANCI, MSH2, MUTYH, and RAD51C. Triple-negative breast cancer (TNBC) was associated with the highest mutation rate (45.5%, p = 0.025). Seven of the 9 BRCA1 mutations and the single FANCI mutation were in the TNBC group; 9 of the 11 BRCA2, 1 of the 2 RAD50 as well as BRIP1, MSH2, MUTYH, and RAD51C mutations were in the hormone receptor (HR)(+)Her2(-) group, and the other RAD50, ATM, and TP53 mutations were in the HR(+)Her2(+) group. Mutation carriers were considered as high-risk to develop malignancy and advised to receive cancer screening. Screening protocols of non-BRCA genes were based on their biologic functions; for example, patients carrying RAD51C mutation received a screening protocol similar to that for BRCA, since BRCA and RAD51C are both involved in homologous recombination. In conclusion, we consider that multiple gene sequencing in cancer risk assessment is clinically valuable.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Medição de Risco , Adulto , Idade de Início , Idoso , Neoplasias da Mama/classificação , Feminino , Genes Supressores de Tumor , Testes Genéticos , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
18.
Am J Transl Res ; 7(6): 1009-20, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26279746

RESUMO

Triple-negative breast cancer (TNBC), which is closely related to basal-like breast cancer, is a highly aggressive subtype of breast cancer that initially responds to chemotherapy but eventually develops resistance. This presents a major clinical challenge as there are currently no effective targeted therapies available due to its lack of HER2 and estrogen receptor expression. Here, we show that cyclin E and the enhancer of zeste 2 (EZH2) are closely co-expressed in TNBC patients, and cyclin E/CDK2 phosphorylates EZH2 at T416 (pT416-EZH2) in vivo. Phosphorylation of EZH2 at T416 enhances the ability of EZH2 to promote TNBC cell migration/invasion, tumorsphere formation, and in vivo tumor growth. In addition, high pT416-EZH2 correlates with poorer survival in TNBC patients. These findings suggest that pT416 has the potential to serve as a therapeutic biomarker for the aggressive forms of breast cancer and provide a rationale for the use of CDK2 inhibitors to treat TNBC.

19.
Oncotarget ; 6(27): 23807-19, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26247632

RESUMO

Conventional chemotherapy is commonly used to treat advanced non-resectable hepatocellular carcinoma (HCC) but this treatment modality has not demonstrated convincing survival benefit in HCC patients. Our previous studies indicated that targeted expression of therapeutic BikDD driven by a liver cancer-specific α-fetoprotein promoter/enhancer (eAFP) in the VISA backbone (eAFP-VISA-BikDD) significantly and specifically kills HCC cells in multiple orthotopic animal models. To enhance its therapeutic efficacy, we combined eAFP-VISA-BikDD with chemotherapeutic agents and found that eAFP-VISA-BikDD plus doxorubicin (Dox) or 5-fluorouracil (5-FU) demonstrated synergistic cytotoxicity in HCC cells. Specifically, the combination of eAFP-VISA-BikDD plus Dox markedly induced apoptosis via increased Bax mitochondrial translocation and cytoplasmic cytochrome c release. Compared with either agent alone, a low dose of Dox combined with eAFP-VISA-BikDD induced better antitumor effect and prolonged longer survival of mice in two orthotopic liver cancer xenograft models. Our findings provide strong preclinical support for evaluating the combined therapy of eAFP-VISA-BikDD and Dox in a clinical setting as a treatment option for HCC.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genética , Carcinoma Hepatocelular/tratamento farmacológico , Doxorrubicina/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Proteínas de Membrana/genética , alfa-Fetoproteínas/genética , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Animais , Proteínas Reguladoras de Apoptose/biossíntese , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Ativação Enzimática , Fluoruracila/farmacologia , Humanos , Marcação In Situ das Extremidades Cortadas , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Proteínas de Membrana/biossíntese , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Proteínas Mitocondriais , Regiões Promotoras Genéticas/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína X Associada a bcl-2/metabolismo
20.
Artigo em Inglês | MEDLINE | ID: mdl-25520914

RESUMO

Enhancer of Zeste homlog 2 (EZH2) is a catalytic subunit of epigenetic regulator Polycomb repressive complex 2 (PRC2), which trimethylates Lys 27 of histone H3, leading to silencing of the target genes that are involved in a variety of biological processes including tumor progression and stem cell maintenance. However, in addition to its canonical PRC2-dependent transcriptional repression function, EZH2 also acts as a gene activator in a noncanonical PRC2-independent manner. Overexpression of EZH2 has been detected in diverse cancers, and is associated with tumor malignancy. Moreover, activating mutations and inactivating mutations of EZH2 are also associated with certain types of cancer. Given EZH2's multi-faceted function and role in cancer, context-specific strategy for targeting EZH2/EZH2-mediated signaling could serve as future targeted therapy/personalized medicine for human cancer.

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