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1.
Artigo em Inglês | MEDLINE | ID: mdl-31972084

RESUMO

Secret information recorded by traditional single-encrypted invisible inks are easily to be cracked because they can only switch between "NONE" and "TRUTH". Developing double-encrypted systems makes the information reversibly switchable between "FALSE" and "TRUTH", which is helpful to ensure the secret information safely during transportation. Here, we prepared heat-developed invisible inks by hydrochromic molecules donor-acceptor Stenhouse adducts (DASAs) and oxazolidines (OXs), and promoted the invisible inks from single to double-encryption. DASAs coordinates with water molecules and form stable colorless cyclic DASAs·xH2O, which lose coordinated water molecules after heating and switch to colored linear DASAs. In contrary, OXs are colored with water and colorless after heating. Single-encrypted secrecy was realized by DASAs invisible inks. The information is invisible under encrypted state and becomes bright purple after heating. Vapor treating re-encrypted the information in ~5 min. Furthermore, the single-encryption was promoted to double-encryption by DASAs/OXs invisible inks system. Heating and vapor treating switch the information between the "FALSE" and "TRUTH" reversibly. The DASAs/OXs invisible inks system is applied for secrecy of texts, graphic images, and quick response (QR) codes.

2.
Surg Endosc ; 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31792690

RESUMO

BACKGROUND: The feasibility of endoscopic dissection for gastric gastrointestinal stromal tumor (gGIST) between 2 and 5 cm in size has been demonstrated. However, its impact on short-term and long-term outcomes, compared with laparoscopic resection, is unknown. The purpose of this study was to compare short-term and long-term outcomes between laparoscopic resection and endoscopic dissection for 2-5-cm gGIST. METHODS: A case-matched study was performed using the propensity score. To overcome selection bias, we performed a 1:1 match using six covariates, including age, sex, BMI, ASA score, tumor size, and tumor location. Short-term and long-term outcomes between laparoscopic resection and endoscopic dissection were compared. RESULTS: A total of 210 patients with 2-5-cm gGIST were enrolled between 2006 and 2017 in our gastrointestinal center. According to the intention-to-treat approach, 165 patients underwent laparoscopic resection, and 45 patients underwent endoscopic dissection. After the propensity score, 45 pairs were balanced and analyzed. There was no significant difference in the baseline characteristics between the laparoscopic and endoscopic groups after matching. The rate of complications was significantly higher in the endoscopic group compared with the laparoscopic group (P < 0.001). Perforations occurred in 16 patients in the endoscopic group (16/45, 35.6%). The postoperative hospital stay was significantly longer in the endoscopic group compared with the laparoscopic group (P < 0.001). There was no significant difference between the two groups in disease-free survival or overall survival. CONCLUSION: Laparoscopic resection is better than endoscopic dissection for 2-5-cm gGIST because of the lower complication rate and shorter hospital stay.

3.
Macromol Rapid Commun ; 40(9): e1900058, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30844103

RESUMO

In the present research, novel tri-block-copolymers bearing polyethylene glycol (PEG), azobenzene (Azo), and tetra-ortho-methoxy-substituted Azo (mAzo) segments are synthesized and explored. Light-controlled PEG-PmAzo-PAzo self-assemblies switching between multi-stationary states is realized. Under controlling of UV, blue, green, and red light, PEG-PmAzo-PAzo isomerize between 4 photostationary states. The enrichment of cis isomers of Azo and mAzo induces the self-assembly of PEG-PmAzo-PAzo in toluene. The morphologies and scale of the self-assemblies can be switched between four stationary states, which are investigated by dynamic light scattering, scanning electron microscopy, and transmission electron microscopy.


Assuntos
Luz , Polímeros/química , Compostos Azo/química , Difusão Dinâmica da Luz , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Polietilenoglicóis/química
4.
Onco Targets Ther ; 11: 7935-7945, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30510432

RESUMO

Background: TRIM37 is an ubiquitin E3 ligase. Growing evidence has demonstrated the high value of TRIM37 as a potential biomarker for diagnosis of certain cancers. However, the biological function of TRIM37 in lung cancer is still unknown. Materials and methods: In order to gain a deep insight into the function of TRIM37 in lung cancer cells, in the present study lentiviral vector was used to mediate RNA interference and overexpression of TRIM37 in lung cancer cells (H292, H358, and H1299). In addition, a specific AKT inhibitor LY294002 was utilized to examine the correlation between the expression of TRIM37 and AKT. Results: TRIM37 acts as a positive regulator of cell proliferation in lung cancer cells. Moreover, cell apoptosis analyses showed the antiapoptosis function of TRIM37, which was mainly dependent on the regulation of BCL2 and BAX. Our results also indicated that AKT might be a target of TRIM37 in lung cancer cells. Conclusion: This research not only helps in understanding the molecular mechanisms of TRIM37 in detail but also provides evidence to develop novel biomarkers for lung cancer diagnosis.

5.
Langmuir ; 34(50): 15537-15543, 2018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30452275

RESUMO

In this report, we designed surfaces with reversible green-light-switched wettability via donor-acceptor Stenhouse adducts (DASAs). Photoresponsive micro/nanoparticles were prepared by coating the surfaces of silica micro/nanoparticles with polydopamine and then postmodifying with DASA molecules. Then, the particles were immobilized on a glass substrate surfaces either with double-sided adhesive tape or cross-linking poly(dimethylsiloxane). Silica micro/nanoparticles with various diameters (0.2, 2.5, and 85 µm) were used to fabricate the photoresponsive surface. Green light irradiation switches the hydrophobic linear DASA to a hydrophilic cyclic isomer, which further increases the wettability and contact angle hysteresis on the surface. On the other hand, heating (100 °C) induces the cyclic-to-linear isomerization of DASA molecules and switches the surface back to hydrophobic. The wettability of the DASA-modified surface is reversible under alternate green light irradiation and heating.

6.
Adv Healthc Mater ; 7(23): e1800118, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30345648

RESUMO

Targeted therapy can improve the accuracy of diagnosis and treatment in the field of cancer management. Cellular surface engineering can enhance cell functions via mounting functional molecules onto cellular membranes. A novel amphiphilic hyperbranched polymer (AHP) conjugated with oleic acid (OA) and tumor-targeted ligand folic acid (FA) is employed. The lipophilic chain can self-assemble and infuse with the cytomembrane of bone marrow mesenchymal stem cells (BMSCs) with the end of FA left on the outside for targeting. The polymer tailored BMSCs can enhance tumor tropism in gastric cancer. BMSCs are characterized by the low immunogenicity and tumor tropism, which makes them promising targeting carriers. Regarding the integrated advantages of these two vectors, it is demonstrated that the functional amphiphilic AHP-OA-FA enhances the tumor tropism of BMSCs. Flow cytometry, standard MTT assay, and wound-healing assay show that AHP-OA-FA has no influence on CD expression, proliferative capacity, and cell motility of BMSCs, respectively. Furthermore, in vitro transwell assay and ex vivo fluorescence image verify that AHP-OA-FA enhances tumor tropism of BMSCs compared to BMSCs and AHP-OA-Rhodamine B-BMSCs. Finally, histological analysis demonstrates that AHP-OA-FA causes no damage to major organs. The results of this study suggest that living BMSCs self-assembled with a polymer might be a promising vehicle for targeted delivery to cancer cells.


Assuntos
Células-Tronco Mesenquimais/metabolismo , Polímeros/química , Animais , Células da Medula Óssea/citologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ácido Fólico/química , Ácido Fólico/farmacologia , Humanos , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Camundongos Nus , Neoplasias/metabolismo , Neoplasias/patologia , Ácido Oleico/química , Ácido Oleico/farmacologia , Imagem Óptica , Ratos , Ratos Sprague-Dawley , Rodaminas/química
7.
Mol Cancer ; 17(1): 69, 2018 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-29510730

RESUMO

BACKGROUND: Metabolic plasticity has been increasingly thought to be a determinant of tumor growth and metastasis. MACC1, a transcriptional regulator of MET, was recognized as an oncogene in gastric cancer (GC); however, its transcriptional or post-translational regulation was not clear. We previously reported the metabolic role of MACC1 in glycolysis to promote GC progression. MACC1-AS1 is the antisense lncRNA of MACC1, yet its function was previously unknown. METHODS: We profiled and analyzed the expression of MACC1-AS1 utilizing the TCGA database as well as in situ hybridization using 123 pairs of GC tissues and matched adjacent normal gastric mucosa tissues (ANTs). The biological role of MACC1-AS1 in cell growth and metastasis was determined by performing in vitro and in vivo functional experiments. Glycolysis and antioxidant capabilities were assayed to examine its metabolic function. Further, the specific regulatory effect of MACC1-AS1 on MACC1 was explored transcriptionally and post-transcriptionally. RESULTS: MACC1-AS1 was shown to be expressed significantly higher in GC tissues than in ANTs, which predicted poor prognosis in GC patients. MACC1-AS1 promoted GC cell proliferation and inhibited cell apoptosis under metabolic stress. Mechanistically, MACC1-AS1 stabilized MACC1 mRNA and post-transcriptionally augmented MACC1 expression. Further, MACC1-AS1 was shown to mediate metabolic plasticity through MACC1 upregulation and subsequent enhanced glycolysis and anti-oxidative capabilities, and this was suggested to be coordinated by the AMPK/Lin28 pathway. CONCLUSIONS: Elevated expression of MACC1-AS1 in gastric cancer tissues is linked to poor prognosis and promotes malignant phenotype upon cancer cells. MACC1-AS1 is elevated under metabolic stress and facilitates metabolic plasticity by promoting MACC1 expression through mRNA stabilization. Our study implicates lncRNA MACC1-AS1 as a valuable biomarker for GC diagnosis and prognosis.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , RNA Antissenso , RNA Longo não Codificante , Proteínas de Ligação a RNA/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Fatores de Transcrição/genética , Adulto , Idoso , Biomarcadores Tumorais , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Progressão da Doença , Metabolismo Energético , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Estabilidade de RNA , Transdução de Sinais , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Estresse Fisiológico
8.
Oncol Lett ; 15(4): 5405-5411, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29556292

RESUMO

Ferroptosis is an iron-dependent and peroxidation-driven form of cell death associated with multiple metabolic disorders and disrupted homeostasis. A number of metabolic processes and homeostasis are affected by ferroptosis. The molecules that regulate ferroptosis are involved in metabolic pathways that regulate cysteine exploitation, glutathione state, nicotinamide adenine dinucleotide phosphate function, lipid peroxidation and iron homeostasis. The present review summarizes the metabolic networks involved in ferroptosis based on previous studies, and discusses the function of ferroptosis in pathological processes, including cancer. Finally, the clinical significance of ferroptosis is highlighted, to provide evidence for further studies.

9.
Neoplasia ; 19(12): 1022-1032, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29144989

RESUMO

BACKGROUND: Ferroptosis is a recently discovered form of iron-dependent nonapoptotic cell death. It is characterized by loss of the activity of the lipid repair enzyme, glutathione peroxidase 4 (GPX4), and accumulation of lethal reactive lipid oxygen species. However, we still know relatively little about ferroptosis and its molecular mechanism in gastric cancer (GC) cells. Here, we demonstrate that erastin, a classic inducer of ferroptosis, induces this form of cell death in GC cells and that cysteine dioxygenase 1 (CDO1) plays an important role in this process. METHODS: We performed quantitative real-time polymerase chain reaction, Western blotting, cell viability assay, reactive oxygen species (ROS) assay, glutathione assay, lipid peroxidation assay, RNAi and gene transfection, immunofluorescent staining, dual-luciferase reporter assay, transmission electron microscopy, and chromatin immunoprecipitation assay to study the regulation of ferroptosis in GC cells. Mouse xenograft assay was used to figure out the mechanism in vivo. RESULTS: Silencing CDO1 inhibited erastin-induced ferroptosis in GC cells both in vitro and in vivo. Suppression of CDO1 restored cellular GSH levels, prevented ROS generation, and reduced malondialdehyde, one of the end products of lipid peroxidation. In addition, silencing COO1 maintained mitochondrial morphologic stability in erastin-treated cells. Mechanistically, c-Myb transcriptionally regulated CDO1, and inhibition of CDO1 expression upregulated GPX4 expression. CONCLUSIONS: Our findings give a better understanding of ferroptosis and its molecular mechanism in GC cells, gaining insight into ferroptosis-mediated cancer treatment.


Assuntos
Cisteína Dioxigenase/metabolismo , Piperazinas/metabolismo , Neoplasias Gástricas/metabolismo , Animais , Biomarcadores , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisteína Dioxigenase/genética , Modelos Animais de Doenças , Heme/metabolismo , Xenoenxertos , Humanos , Ferro/metabolismo , Camundongos , Modelos Biológicos , Proteínas Proto-Oncogênicas c-myb/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Gástricas/patologia
10.
Cell Physiol Biochem ; 42(6): 2569-2581, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28848087

RESUMO

BACKGROUND/AIMS: Increasing evidence has demonstrated a significant role of long non-coding RNAs (lncRNAs) in diverse biological processes, and many of which are likely to have functional roles in vascular remodeling. However, their functions in pulmonary arterial hypertension (PAH) remain largely unknown. Pulmonary vascular remodeling is an important pathological feature of PAH, leading to increased vascular resistance and reduced compliance. Pulmonary artery smooth muscle cells (PASMCs) dysfunction is involved in vascular remodeling. Long noncoding RNAs are potential regulators of PASMCs function. Herein, we determined whether long noncoding RNA-maternally expressed gene 3 (MEG3) was involved in PAH-related vascular remodeling. METHODS: The arterial wall thickness was examined by hematoxylin and eosin (H&E) staining in distal pulmonary arteries (PAs) isolated from lungs of healthy volunteers and PAH patients. The expression level of MEG3 was analyzed by qPCR. The effects of MEG3 on human PASMCs were assessed by cell counting Kit-8 assay, BrdU incorporation assay, flow cytometry, scratch-wound assay, immunofluorescence, and western blotting in human PASMCs. RESULTS: We revealed that the expression of MEG3 was significantly downregulated in lung and PAs of patients with PAH. MEG3 knockdown affected PASMCs proliferation and migration in vitro. Moreover, inhibition of MEG3 regulated the cell cycle progression and made more smooth muscle cells from the G0/G1 phase to the G2/M+S phase and the process could stimulate the expression of PCNA, Cyclin A and Cyclin E. In addition, we found that the p53 pathway was involved in MEG3-induced smooth muscle cell proliferation. CONCLUSIONS: This study identified MEG3 as a critical regulator in PAH and demonstrated the potential of gene therapy and drug development for treating PAH.


Assuntos
RNA Longo não Codificante/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Estudos de Casos e Controles , Pontos de Checagem do Ciclo Celular , Movimento Celular , Proliferação de Células , Células Cultivadas , Ciclina A/metabolismo , Ciclina E/metabolismo , Regulação para Baixo , Humanos , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Pulmão/metabolismo , Pulmão/patologia , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Artéria Pulmonar/citologia , Artéria Pulmonar/patologia , Interferência de RNA , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais
11.
Mol Cancer ; 16(1): 79, 2017 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-28407774

RESUMO

Cancer cells are frequently confronted with metabolic stress in tumor microenvironments due to their rapid growth and limited nutrient supply. Metabolic stress induces cell death through ROS-induced apoptosis. However, cancer cells can adapt to it by altering the metabolic pathways. AMPK and AKT are two primary effectors in response to metabolic stress: AMPK acts as an energy-sensing factor which rewires metabolism and maintains redox balance. AKT broadly promotes energy production in the nutrient abundance milieu, but the role of AKT under metabolic stress is in dispute. Recent studies show that AMPK and AKT display antagonistic roles under metabolic stress. Metabolic stress-induced ROS signaling lies in the hub between metabolic reprogramming and redox homeostasis. Here, we highlight the cross-talk between AMPK and AKT and their regulation on ROS production and elimination, which summarizes the mechanism of cancer cell adaptability under ROS stress and suggests potential options for cancer therapeutics.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Estresse Fisiológico , Animais , Progressão da Doença , Metabolismo Energético , Homeostase , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Oxirredução , Fosforilação , Ligação Proteica , Transdução de Sinais
12.
Plast Reconstr Surg Glob Open ; 4(6): e731, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27482479

RESUMO

For patients with extensive burns or donor site scarring, the limited availability of autologous and the inevitable rejection of allogeneic skin drive the need for new alternatives. Existing engineered biologic and synthetic skin analogs serve as temporary coverage until sufficient autologous skin is available. Here we report successful engraftment of a self-assembled bilayered skin construct derived from autologous skin punch biopsies in a porcine model. Dermal fibroblasts were stimulated to produce an extracellular matrix and were then seeded with epidermal progenitor cells to generate an epidermis. Autologous constructs were grafted onto partial- and full-thickness wounds. By gross examination and histology, skin construct vascularization and healing were comparable to autologous skin grafts and were superior to an autologous bilayered living cellular construct fabricated with fibroblasts cast in bovine collagen. This is the first demonstration of spontaneous vascularization and permanent engraftment of a self-assembled bilayered bioengineered skin that could supplement existing methods of reconstruction.

13.
Proc Natl Acad Sci U S A ; 109(8): 2772-7, 2012 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-21940501

RESUMO

Human breast cancers are broadly classified based on their gene-expression profiles into luminal- and basal-type tumors. These two major tumor subtypes express markers corresponding to the major differentiation states of epithelial cells in the breast: luminal (EpCAM(+)) and basal/myoepithelial (CD10(+)). However, there are also rare types of breast cancers, such as metaplastic carcinomas, where tumor cells exhibit features of alternate cell types that no longer resemble breast epithelium. Until now, it has been difficult to identify the cell type(s) in the human breast that gives rise to these various forms of breast cancer. Here we report that transformation of EpCAM(+) epithelial cells results in the formation of common forms of human breast cancer, including estrogen receptor-positive and estrogen receptor-negative tumors with luminal and basal-like characteristics, respectively, whereas transformation of CD10(+) cells results in the development of rare metaplastic tumors reminiscent of the claudin-low subtype. We also demonstrate the existence of CD10(+) breast cells with metaplastic traits that can give rise to skin and epidermal tissues. Furthermore, we show that the development of metaplastic breast cancer is attributable, in part, to the transformation of these metaplastic breast epithelial cells. These findings identify normal cellular precursors to human breast cancers and reveal the existence of a population of cells with epidermal progenitor activity within adult human breast tissues.


Assuntos
Neoplasias da Mama/patologia , Transformação Celular Neoplásica/patologia , Adulto , Antígenos de Neoplasias/metabolismo , Neoplasias da Mama/metabolismo , Moléculas de Adesão Celular/metabolismo , Transformação Celular Neoplásica/metabolismo , Molécula de Adesão da Célula Epitelial , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Epitélio/metabolismo , Epitélio/patologia , Feminino , Humanos , Metaplasia , Neprilisina/metabolismo , Fenótipo
14.
PLoS One ; 6(2): e17128, 2011 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-21386890

RESUMO

Human induced pluripotent stem (hiPS) cells offer a novel source of patient-specific cells for regenerative medicine. However, the biological potential of iPS-derived cells and their similarities to cells differentiated from human embryonic stem (hES) cells remain unclear. We derived fibroblast-like cells from two hiPS cell lines and show that their phenotypic properties and patterns of DNA methylation were similar to that of mature fibroblasts and to fibroblasts derived from hES cells. iPS-derived fibroblasts (iPDK) and their hES-derived counterparts (EDK) showed similar cell morphology throughout differentiation, and patterns of gene expression and cell surface markers were characteristic of mature fibroblasts. Array-based methylation analysis was performed for EDK, iPDK and their parental hES and iPS cell lines, and hierarchical clustering revealed that EDK and iPDK had closely-related methylation profiles. DNA methylation analysis of promoter regions associated with extracellular matrix (ECM)-production (COL1A1) by iPS- and hESC-derived fibroblasts and fibroblast lineage commitment (PDGFRß), revealed promoter demethylation linked to their expression, and patterns of transcription and methylation of genes related to the functional properties of mature stromal cells were seen in both hiPS- and hES-derived fibroblasts. iPDK cells also showed functional properties analogous to those of hES-derived and mature fibroblasts, as seen by their capacity to direct the morphogenesis of engineered human skin equivalents. Characterization of the functional behavior of ES- and iPS-derived fibroblasts in engineered 3D tissues demonstrates the utility of this tissue platform to predict the capacity of iPS-derived cells before their therapeutic application.


Assuntos
Diferenciação Celular/genética , Epigênese Genética/fisiologia , Fibroblastos/fisiologia , Perfilação da Expressão Gênica , Células-Tronco Pluripotentes Induzidas/fisiologia , Metaboloma , Biomarcadores/análise , Biomarcadores/metabolismo , Diferenciação Celular/fisiologia , Linhagem da Célula/genética , Linhagem da Célula/fisiologia , Células Cultivadas , Análise por Conglomerados , Metilação de DNA/fisiologia , Fibroblastos/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Glicoproteínas de Membrana/análise , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Fenótipo
15.
Stem Cell Res Ther ; 2(1): 10, 2011 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-21338517

RESUMO

INTRODUCTION: Pluripotent, human stem cells hold tremendous promise as a source of progenitor and terminally differentiated cells for application in future regenerative therapies. However, such therapies will be dependent upon the development of novel approaches that can best assess tissue outcomes of pluripotent stem cell-derived cells and will be essential to better predict their safety and stability following in vivo transplantation. METHODS: In this study we used engineered, human skin equivalents (HSEs) as a platform to characterize fibroblasts that have been derived from human embryonic stem (hES) cell. We characterized the phenotype and the secretion profile of two distinct hES-derived cell lines with properties of mesenchymal cells (EDK and H9-MSC) and compared their biological potential upon induction of differentiation to bone and fat and following their incorporation into the stromal compartment of engineered, HSEs. RESULTS: While both EDK and H9-MSC cell lines exhibited similar morphology and mesenchymal cell marker expression, they demonstrated distinct functional properties when incorporated into the stromal compartment of HSEs. EDK cells displayed characteristics of dermal fibroblasts that could support epithelial tissue development and enable re-epithelialization of wounds generated using a 3D tissue model of cutaneous wound healing, which was linked to elevated production of hepatocyte growth factor (HGF). Lentiviral shRNA-mediated knockdown of HGF resulted in a dramatic decrease of HGF secretion from EDK cells that led to a marked reduction in their ability to promote keratinocyte proliferation and re-epithelialization of cutaneous wounds. In contrast, H9-MSCs demonstrated features of mesenchymal stem cells (MSC) but not those of dermal fibroblasts, as they underwent multilineage differentiation in monolayer culture, but were unable to support epithelial tissue development and repair and produced significantly lower levels of HGF. CONCLUSIONS: Our findings demonstrate that hES-derived cells could be directed to specified and alternative mesenchymal cell fates whose function could be distinguished in engineered HSEs. Characterization of hES-derived mesenchymal cells in 3D, engineered HSEs demonstrates the utility of this tissue platform to predict the functional properties of hES-derived fibroblasts before their therapeutic transplantation.


Assuntos
Células-Tronco Embrionárias/citologia , Fibroblastos/citologia , Técnicas de Cultura de Células , Linhagem da Célula , Proliferação de Células , Fibroblastos/transplante , Fator de Crescimento de Hepatócito/antagonistas & inibidores , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Queratinócitos/citologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Engenharia Tecidual , Cicatrização
16.
PLoS One ; 5(5): e10528, 2010 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-20502640

RESUMO

The alpha6beta4 integrin plays a significant role in tumor growth, angiogenesis and metastasis through modulation of growth factor signaling, and is a potentially important therapeutic target. However, alpha6beta4-mediated cell-matrix adhesion is critical in normal keratinocyte attachment, signaling and anchorage to the basement membrane through its interaction with laminin-5, raising potential risks for targeted therapy. Bioengineered Human Skin Equivalent (HSE), which have been shown to mimic their normal and wounded counterparts, have been used here to investigate the consequences of targeting beta4 to establish toxic effects on normal tissue homeostasis and epithelial wound repair. We tested two antibodies directed to different beta4 epitopes, one adhesion-blocking (ASC-8) and one non-adhesion blocking (ASC-3), and determined that these antibodies were appropriately localized to the basal surface of keratinocytes at the basement membrane interface where beta4 is expressed. While normal tissue architecture was not altered, ASC-8 induced a sub-basal split at the basement membrane in non-wounded tissue. In addition, wound closure was significantly inhibited by ASC-8, but not by ASC-3, as the epithelial tongue only covered 40 percent of the wound area at 120 hours post-wounding. These results demonstrate beta4 adhesion-blocking antibodies may have adverse effects on normal tissue, whereas antibodies directed to other epitopes may provide safer alternatives for therapy. Taken together, we conclude that these three-dimensional tissue models provide a biologically relevant platform to identify toxic effects induced by candidate therapeutics, which will allow generation of findings that are more predictive of in vivo responses early in the drug development process.


Assuntos
Anticorpos Bloqueadores/farmacologia , Epitélio/metabolismo , Integrinas/imunologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Modelos Biológicos , Cicatrização/efeitos dos fármacos , Especificidade de Anticorpos/efeitos dos fármacos , Bioensaio , Moléculas de Adesão Celular/imunologia , Movimento Celular/efeitos dos fármacos , Epitélio/efeitos dos fármacos , Imunofluorescência , Humanos , Integrina beta4/imunologia , Masculino , Ligação Proteica/efeitos dos fármacos , Pele Artificial , Coloração e Rotulagem
18.
Brain Pathol ; 18(4): 517-9, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18422762

RESUMO

The INI1/SMARCB1 protein product (INI1), a component of a transcription complex, was recently implicated in the pathogenesis of schwannomas in two members of a single family with familial schwannomatosis. Tumors were found to have both constitutional and somatic mutations of the SMARCB1 gene and showed a mosaic pattern of loss of INI1 expression by immunohistochemistry, suggesting a tumor composition of mixed null and haploinsufficient cells. To determine if this finding could be extended to all tumors arising in familial schwannomatosis, and how it compares with other multiple schwannoma syndromes [sporadic schwannomatosis and neurofibromatosis 2 (NF2)] as well as to sporadic, solitary schwannomas, we performed an immunohistochemistry analysis on 45 schwannomas from patients with multiple schwannoma syndromes and on 38 solitary, sporadic schwannomas from non-syndromic patients. A mosaic pattern of INI1 expression was seen in 93% of tumors from familial schwannomatosis patients, 55% of tumors from sporadic schwannomatosis, 83% of NF2-associated tumors and only 5% of solitary, sporadic schwannomas. These results confirm a role for INI1/SMARCB1 in multiple schwannoma syndromes and suggest that a different pathway of tumorigenesis occurs in solitary, sporadic tumors.


Assuntos
Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Neoplasias dos Nervos Cranianos/genética , Neoplasias dos Nervos Cranianos/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/metabolismo , Neurilemoma/genética , Neurilemoma/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas Cromossômicas não Histona/análise , Neoplasias dos Nervos Cranianos/patologia , Análise Mutacional de DNA , Proteínas de Ligação a DNA/análise , Diagnóstico Diferencial , Regulação Neoplásica da Expressão Gênica/genética , Marcadores Genéticos/genética , Predisposição Genética para Doença/genética , Testes Genéticos , Genótipo , Humanos , Imuno-Histoquímica , Segunda Neoplasia Primária/patologia , Neurilemoma/patologia , Neurofibromina 2/genética , Proteína SMARCB1 , Fatores de Transcrição/análise
19.
Zhonghua Xin Xue Guan Bing Za Zhi ; 34(4): 345-8, 2006 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-16776930

RESUMO

OBJECTIVE: To evaluate the safety and feasibility of autologous peripheral blood mononuclear cells (PBMNCs) implantation after granulocyte-colony stimulating factor (G-CSF)-induced mobilization in patients with lower extremity arterial occlusive disease (AOD). METHODS: A total of 12 patients with AOD were enrolled in this study. Following administration of rhG-CSF (150 microg/d) for 5 days, PBMNCs were harvested and injected intramuscularly in the diseased extremities (3 x 10(9) per limb). RESULTS: One patient received left leg amputation due to uncontrolled ulcer 15 days post PBMNCs transplantation and the symptoms and signs were improved significantly in 9 patients and the symptoms and signs remained unchanged in another 2 aged patients (> 70 years). Doppler ultrasonography measurement showed that peak systolic velocity in diseased extremities was significantly increased post transplantation [(44.55 +/- 4.13) cm/s vs. (21.32 +/- 0.63) cm/s, P < 0.01]. Contrast lower limb angiogram showed increased collateral vessels post transplantation. One aged patient (80 years) who did not respond to autologous PBMNCs received heterologous PBMNCs transplantation (PBMNCs was harvested from a young relative of him) 3 months post autologous PBMNCs transplantation and observed for another 3 months and all observed parameters improved significantly. CONCLUSION: Implantation of autologous PBMNCs collected after G-CSF administration might offer a simple, safe, and effective therapy for the AOD patients.


Assuntos
Arteriopatias Oclusivas/terapia , Extremidade Inferior/irrigação sanguínea , Transplante de Células-Tronco de Sangue Periférico , Idoso , Idoso de 80 Anos ou mais , Arteriopatias Oclusivas/cirurgia , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Transplante Autólogo , Ultrassonografia Doppler
20.
Zhonghua Wai Ke Za Zhi ; 43(22): 1444-6, 2005 Nov 15.
Artigo em Chinês | MEDLINE | ID: mdl-16318810

RESUMO

OBJECTIVE: To investigate the operation of lung transplantation for end-stage emphysema. METHODS: From September 2002 to February 2005, 9 patients with chronic obstructive pulmonary disease (COPD) underwent lung transplantation. The types of surgery included single lung transplantation in 2 patients, lung transplantation with asynchronous contralateral lung volume reduction (one week later) in 1, single lung transplantation with synchronized contralateral lung volume reduction in 4, and bilateral sequential lung transplantation without cardiopulmonary bypass in 2. RESULTS: The volume of chest drainage was more than 2000 ml at the first postoperative day in 2 patients, one was reoperated for hemostasis and another was successfully responded to conservative therapy. The ventilation time was ranged from 3 to 22 days postoperatively. Two patients were received tracheotomy. Seven patients achieved good results, two of them had returned to work, and 1 patient had lived for 30 months. One patient was died of severe acute rejection (4A) at 15th postoperative day and 1 succumbed to multisystem organ failure due to severe bacterial infection combine fungal infection. CONCLUSION: End-stage emphysema is an indication for single lung transplantation. Single lung transplantation with contralateral lung volume reduction is a good way to utilize donor. If patient suffered from infection, double-lung transplantation should be considered first.


Assuntos
Transplante de Pulmão/métodos , Pneumonectomia/métodos , Enfisema Pulmonar/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/cirurgia , Resultado do Tratamento
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