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Oncogene ; 38(23): 4637-4654, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30742067


Chemotherapy is the preferred treatment for advanced stage gastric cancer (GC) patients and chemotherapy resistance is the major obstacle to effective cancer therapy. Increasing evidence suggests that mesenchymal stem cells (MSCs) make important contributions to development of drug resistance. However, the underlying mechanism remains elusive. In this study, we discovered that abundant MSCs in tumor tissues predicted a poor prognosis in GC patients. MSCs promoted stemness and chemoresistance in GC cells through fatty acid oxidation (FAO) in vitro and in vivo. Mechanically, transforming growth factor ß1 (TGF-ß1) secretion by MSCs activated SMAD2/3 through TGF-ß receptors and induced long non-coding RNA (lncRNA) MACC1-AS1 expression in GC cells, which promoted FAO-dependent stemness and chemoresistance through antagonizing miR-145-5p. Moreover, pharmacologic inhibition of FAO with etomoxir (ETX) attenuated MSC-induced FOLFOX regiment resistance in vivo. These results suggest that FAO plays an important role in MSC-mediated stemness and chemotherapy resistance in GC and FAO inhibitors in combination with chemotherapeutic drugs present as a promising strategy to overcome chemoresistance.

Theranostics ; 8(19): 5452-5468, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30555557


Omental metastasis occurs frequently in gastric cancer (GC) and is considered one of the major causes of gastric cancer-related mortality. Recent research indicated that omental adipocytes might mediate this metastatic predilection. Phosphatidylinositol transfer protein, cytoplasmic 1 (PITPNC1) was identified to have a crucial role in metastasis. However, whether PITPNC1 participates in the interaction between adipocytes and GC omental metastasis is unclear. Methods: We profiled and analyzed the expression of PITPNC1 through analysis of the TCGA database as well as immunohistochemistry staining using matched GC tissues, adjacent normal gastric mucosa tissues (ANTs), and omental metastatic tissues. The regulation of PITPNC1 by adipocytes was explored by co-culture systems. By using both PITPNC1 overexpression and silencing methods, the role of PITPNC1 in anoikis resistance and metastasis was determined through in vitro and in vivo experiments. Results: PITPNC1 was expressed at higher rates in GC tissues than in ANTs; notably, it was higher in omental metastatic lesions. Elevated expression of PITPNC1 predicted higher rates of omental metastasis and a poor prognosis. PITPNC1 promoted anoikis resistance through fatty acid metabolism by upregulating CD36 and CPT1B expression. Further, PITPNC1 was elevated by adipocytes and facilitated GC omental metastasis. Lastly, in vivo studies showed that PITPNC1 was a therapeutic indicator of fatty acid oxidation (FAO) inhibition. Conclusion: Elevated expression of PITPNC1 in GC is correlated with an advanced clinical stage and a poor prognosis. PITPNC1 promotes anoikis resistance through enhanced FAO, which is regulated by omental adipocytes and consequently facilitates GC omental metastasis. Targeting PITPNC1 might present a promising strategy to treat omental metastasis.

Adipócitos/patologia , Ácidos Graxos/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Neoplasias Peritoneais/fisiopatologia , Neoplasias Peritoneais/secundário , Neoplasias Gástricas/patologia , Neoplasias Gástricas/fisiopatologia , Adenocarcinoma/patologia , Adenocarcinoma/fisiopatologia , Animais , Anoikis , Antígenos CD36/biossíntese , Carnitina O-Palmitoiltransferase/biossíntese , Linhagem Celular Tumoral , Sobrevivência Celular , Técnicas de Cocultura , Modelos Animais de Doenças , Expressão Gênica , Inativação Gênica , Humanos , Imuno-Histoquímica , Proteínas de Membrana Transportadoras/análise , Proteínas de Membrana Transportadoras/genética , Camundongos Nus , Modelos Teóricos , Regulação para Cima
Integr Biol (Camb) ; 10(11): 705-718, 2018 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-30320857


Contact guidance or bidirectional migration along aligned fibers modulates many physiological and pathological processes such as wound healing and cancer invasion. Aligned 2D collagen fibrils epitaxially grown on mica substrates replicate many features of contact guidance seen in aligned 3D collagen fiber networks. However, these 2D collagen self-assembled substrates are difficult to image through, do not have known or tunable mechanical properties and cells degrade and mechanically detach collagen fibrils from the surface, leading to an inability to assess contact guidance over long times. Here, we describe the transfer of aligned collagen fibrils from mica substrates to three different functionalized target substrates: glass, polydimethylsiloxane (PDMS) and polyacrylamide (PA). Aligned collagen fibrils can be efficiently transferred to all three substrates. This transfer resulted in substrates that were to varying degrees resistant to cell-mediated collagen fibril deformation that resulted in detachment of the collagen fibril field, allowing for contact guidance to be observed over longer time periods. On these transferred substrates, cell speed is lowest on softer contact guidance cues for both MDA-MB-231 and MTLn3 cells. Intermediate stiffness resulted in the fastest migration. MTLn3 cell directionality was low on soft contact guidance cues, whereas MDA-MB-231 cell directionality marginally increased. It appears that the stiffness of the contact guidance cue regulates contact guidance differently between cell types. The development of this collagen fibril transfer method allows for the attachment of aligned collagen fibrils on substrates, particularly flexible substrates, that do not normally promote aligned collagen fibril growth, increasing the utility of this collagen self-assembly system for the fundamental examination of mechanical regulation of contact guidance.

Neoplasias da Mama/patologia , Colágeno/química , Neoplasias Mamárias Animais/patologia , Resinas Acrílicas/química , Silicatos de Alumínio/química , Animais , Neoplasias da Mama/metabolismo , Adesão Celular , Comunicação Celular , Linhagem Celular Tumoral , Movimento Celular , Dimetilpolisiloxanos/química , Matriz Extracelular/metabolismo , Feminino , Humanos , Neoplasias Mamárias Animais/metabolismo , Microscopia , Microscopia de Força Atômica , Microesferas , Invasividade Neoplásica , Conformação Proteica , Ratos , Cicatrização
Nanotechnology ; 29(35): 355603, 2018 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-29877867


DNA origami can be used to create a variety of complex and geometrically unique nanostructures that can be further modified to produce building blocks for applications such as in optical metamaterials. We describe a method for creating metal-coated nanostructures using DNA origami templates and a photochemical metallization technique. Triangular DNA origami forms were fabricated and coated with a thin metal layer by photochemical silver reduction while in solution or supported on a surface. The DNA origami template serves as a localized photosensitizer to facilitate reduction of silver ions directly from solution onto the DNA surface. The metallizing process is shown to result in a conformal metal coating, which grows in height to a self-limiting value with increasing photoreduction steps. Although this coating process results in a slight decrease in the triangle dimensions, the overall template shape is retained. Notably, this coating method exhibits characteristics of self-limiting and defect-filling growth, which results in a metal nanostructure that maps the shape of the original DNA template with a continuous and uniform metal layer and stops growing once all available DNA sites are exhausted.

DNA/química , Conformação de Ácido Nucleico , Processos Fotoquímicos , Prata/química , DNA/ultraestrutura , Microscopia de Força Atômica , Espectrofotometria Ultravioleta
Sensors (Basel) ; 16(10)2016 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-27690037


Yttria-stabilized zirconia (YSZ)-based thermal barrier coating (TBC) has been integrated with thermographic phosphors through air plasma spray (APS) for in-depth; non-contact temperature sensing. This coating consisted of a thin layer of Dy-doped YSZ (about 40 µm) on the bottom and a regular YSZ layer with a thickness up to 300 µm on top. A measurement system has been established; which included a portable; low-cost diode laser (405 nm); a photo-multiplier tube (PMT) and the related optics. Coating samples with different topcoat thickness were calibrated in a high-temperature furnace from room temperature to around 900 °C. The results convincingly showed that the current sensor and the measurement system was capable of in-depth temperature sensing over 800 °C with a YSZ top layer up to 300 µm. The topcoat thickness was found to have a strong effect on the luminescent signal level. Therefore; the measurement accuracy at high temperatures was reduced for samples with thick topcoats due to strong light attenuation. However; it seemed that the light transmissivity of YSZ topcoat increased with temperature; which would improve the sensor's performance at high temperatures. The current sensor and the measurement technology have shown great potential in on-line monitoring of TBC interface temperature.

Neuroreport ; 27(11): 796-801, 2016 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-27272690


This study used electroencephalogram measurements to investigate the effects of aging on oscillatory theta modulation during an audiovisual discrimination task. By a wavelet-based time-frequency analysis, age-related theta oscillation response differences were observed within a relatively restricted time range (0-500 ms) over frontal-central regions. Older adults showed stronger theta spectral power during visual and audiovisual stimuli in the left frontal regions; however, young adults showed stronger theta spectral power during auditory and audiovisual stimuli in the central regions. These findings suggest that multisensory oscillatory theta responses differ according to age, which further proves that the left frontal regions play an important role in audiovisual integration.

Envelhecimento/fisiologia , Percepção Auditiva/fisiologia , Lobo Frontal/fisiologia , Ritmo Teta/fisiologia , Percepção Visual/fisiologia , Estimulação Acústica , Adulto , Idoso , Análise de Variância , Mapeamento Encefálico , Eletroencefalografia , Lateralidade Funcional/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estimulação Luminosa , Tempo de Reação/fisiologia , Adulto Jovem