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We propose a Vernier effect-based sensor for temperature and salinity measurements. This sensor utilizes the correlation speckle pattern generated by spatial multimode interference and has undergone testing to validate its effectiveness. The speckle demodulation method is used to solve the problem of inconsistent envelope measurement when tracking with different upper and lower envelopes. The device consists of two Fabry Perot interferometers (FPIs) created by connecting hole core fiber (HCF) and erbium-doped fiber (EDF) in series. The speckle image produced by the interferometers is analyzed using the Zero means normalized cross-correlation (ZNCC) technique. The ZNCC value demonstrates a linear relationship with salinity and temperature, allowing for the measurement of these parameters. The sensor exhibits a temperature detection sensitivity of -0.0224 /°C and a salinity detection sensitivity of -0.0439/%. The sensor offers several advantageous features, including its compact size, low-cost manufacturing, high sensitivity, stability, and convenient reflection measurements. These characteristics make it a valuable tool for various applications. The proposed Vernier effect-based temperature and salinity sensor shows great potential for simultaneous monitoring and measurement of temperature and salinity in environments such as marine settings or industrial processes where accurate control of these parameters is crucial.
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Rapid coherent Raman hyperspectral imaging shows great promise for applications in sensing, medical diagnostics, and dynamic metabolism monitoring. However, the spectral acquisition speed of current multiplex coherent anti-Stokes Raman scattering (CARS) microscopy is generally limited by the spectrometer integration time, and as the detection speed increases, the signal-to-noise ratio (SNR) of single spectrum will decrease, leading to a terrible imaging quality. In this Letter, we report a dual-comb coherent Raman hyperspectral microscopy imaging system developed by integrating two approaches, a rapid delay-spectral focusing method and deep learning. The spectral refresh rate is exploited by focusing the relative delay scanning in the effective Raman excitation region, enabling a spectral acquisition speed of 36â kHz, ≈4â frames/s, for a pixel resolution of 95 × 95â pixels and a spectral bandwidth no less than 200â cm-1. To improve the spectral SNR and imaging quality, the deep learning models are designed for spectral preprocessing and automatic unsupervised feature extraction. In addition, by changing the relative delay focusing region of the comb pairs, the detected spectral wavenumber region can be flexibly tuned to the high SNR region of the spectrum.
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The Vernier effect created using an incorporated Lyot-Sagnac loop is used to create an ultra-high sensitivity temperature sensor based on a ring laser cavity. Unlike standard double Sagnac loop systems, the proposed sensor is fused into a single Sagnac loop by adjusting the welding angle between two polarization-maintaining fibers (PMFs) to achieve effective temperature sensitivity amplification. The PMFs are separated into two arms of 0.8 m and 1 m in length, with a 45° angle difference between the fast axes. The sensor's performance is examined both theoretically and experimentally. The experimental results reveal that the Vernier amplification effect can be achieved via PMF rotating shaft welding. The temperature sensitivity in the laser cavity can reach 2.391 nm/°C, which is increased by a factor of more than eight times compared with a single Sagnac loop structure (0.298 nm/°C) with a length of 0.8 m without the Vernier effect at temperatures ranging from 20 °C to 30 °C. Furthermore, unlike traditional optical fiber sensing that uses a broadband light source (BBS) for detection, which causes issues such as low signal-to-noise ratio and broad bandwidth, the Sagnac loop can be employed as a filter by inserting itself into the fiber ring laser (FRL) cavity. When the external parameters change, the laser is offset by the interference general modulation, allowing the external temperature to be monitored. The superior performance of signal-to-noise ratios of up to 50 dB and bandwidths of less than 0.2 nm is achieved. The proposed sensor has a simple structure and high sensitivity and is expected to play a role in biological cell activity monitoring.
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A fiber speckle sensor (FSS) based on a tapered multimode fiber (TMMF) has been developed to measure liquid analyte refractive index (RI) in this work. By the lateral and axial offset of input light into TMMF, several high-order modes are excited in TMMF, and the speckle pattern is spatially modulated, which affects an asymmetrical speckle pattern with a random intensity distribution at the output of TMMF. When the TMMF is immersed in the liquid analyte with RI variation, it influences the guided modes, as well as the mode interference, in TMMF. A digital image correlations method with zero-mean normalized cross-correlation coefficient is explored to digitize the speckle image differences, analyzing the RI variation. It is found that the lateral- and axial-offsets-induced speckle sensor can enhance the RI sensitivity from 6.41 to 19.52 RIU-1 compared to the one without offset. The developed TMMF speckle sensor shows an RI resolution of 5.84 × 10-5 over a linear response range of 1.3164 to 1.3588 at 1550 nm. The experimental results indicate the FSS provides a simple, efficient, and economic approach to RI sensing, which exhibits an enormous potential in the image-based ocean-sensing application.
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BACKGROUND & AIMS: The hepatic manifestation of the metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), can lead to the development of hepatocellular carcinoma (HCC). Despite a strong causative link, NAFLD-HCC is often underrepresented in systematic genome explorations. METHODS: Herein, tumor-normal pairs from 100 patients diagnosed with NAFLD-HCC were subject to next-generation sequencing. Bioinformatic analyses were performed to identify key genomic, epigenomic and transcriptomic events associated with the pathogenesis of NAFLD-HCC. Establishment of primary patient-derived NAFLD-HCC culture was used as a representative human model for downstream in vitro investigations of the underlying CTNNB1 S45P driver mutation. A syngeneic immunocompetent mouse model was used to further test the involvement of CTNNB1mutand TNFRSF19 in reshaping the tumor microenvironment. RESULTS: Mutational processes operative in the livers of patients with NAFLD inferred susceptibility to tumor formation through defective DNA repair pathways. Dense promoter mutations and dysregulated transcription factors accentuated activated transcriptional regulation in NAFLD-HCC, in particular the enrichment of MAZ-MYC activities. Somatic events common in HCCs arising from NAFLD and viral hepatitis B infection underscore similar driver pathways, although an incidence shift highlights CTNNB1mut dominance in NAFLD-HCC (33%). Immune exclusion correlated evidently with CTNNB1mut. Chromatin immunoprecipitation-sequencing integrated with transcriptome and immune profiling revealed a unique transcriptional axis, wherein CTNNB1mut leads to an upregulation of TNFRSF19 which subsequently represses senescence-associated secretory phenotype-like cytokines (including IL6 and CXCL8). This phenomenon could be reverted by the Wnt-modulator ICG001. CONCLUSIONS: The unique mutational processes in the livers of patients with NAFLD and NAFLD-HCC allude to a "field effect" involving a gain-of-function role of CTNNB1 mutations in immune exclusion. LAY SUMMARY: The increasing prevalence of metabolic syndrome in adult populations means that NAFLD is poised to be the major cause of liver cancer in the 21st century. We showed a strong "field effect" in the livers of patients with NAFLD, wherein activated ß-catenin was involved in reshaping the tumor-immune microenvironment.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Síndrome Metabólica , Hepatopatia Gordurosa não Alcoólica , Receptores do Fator de Necrose Tumoral , beta Catenina , Adulto , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Hepatite B , Humanos , Evasão da Resposta Imune , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Camundongos , Mutação , Hepatopatia Gordurosa não Alcoólica/genética , Receptores do Fator de Necrose Tumoral/genética , Microambiente Tumoral , beta Catenina/genética , beta Catenina/metabolismoRESUMO
With the developments of the tunable laser source (TLS), there are increasing demands for high-resolution dynamic wavelength calibration in recent years. Considering mutual constraints between wide measurement range and high calibration resolution, we propose a dynamic wavelength calibration method based on an auxiliary Mach-Zehnder interferometer (MZI) and the synchrosqueezed wavelet transform (SSWT). Our proposed method can achieve a calibration resolution of 5 fm and a tuning range of 10 nm. Moreover, the measurement range and spatial resolution of the optical frequency domain reflectometer (OFDR) system are improved to â¼80 m and â¼mm, respectively. Our proposed approach can substantially reduce the subtle spectrum distortion (tens of fm) in coherent optical spectrum analyzer (COSA) systems.
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Trimethylamine N-oxide (TMAO) is produced from the phosphatidylcholine metabolism of gut flora and acts as a risk factor of cardiovascular disease. However, the underlying mechanisms for its proatherogenic action remain unclear. This study aimed to observe the effect of TMAO on endothelial cell pyroptosis and explore the underlying mechanisms. Our results showed that TMAO promoted the progression of atherosclerotic lesions in apolipoprotein E-deficient (apoE-/- ) mice fed a high-fat diet. Pyroptosis and succinate dehydrogenase complex subunit B (SDHB) upregulation were detected in the vascular endothelial cells of apoE-/- mice and in cultured human umbilical vein endothelial cells (HUVECs) treated with TMAO. Overexpression of SDHB in HUVECs enhanced pyroptosis and impaired mitochondria and high reactive oxygen species (ROS) level. Pyroptosis in the SDHB overexpression of endothelial cells was inhibited by the ROS scavenger NAC. In summary, TMAO promotes vascular endothelial cell pyroptosis via ROS induced through SDHB upregulation, thereby contributing to the progression of atherosclerotic lesions.
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Apolipoproteínas E/metabolismo , Aterosclerose/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Metilaminas/farmacologia , Piroptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Succinato Desidrogenase/metabolismo , Animais , Células Cultivadas , Humanos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacosRESUMO
Neuroinflammation has been involved in pathogenesis of Parkinson's disease (PD), a chronic neurodegenerative disease characterized neuropathologically by progressive dopaminergic neuronal loss in the substantia nigra (SN). We recently have shown that helper T (Th)17 cells facilitate dopaminergic neuronal loss in vitro. Herein, we demonstrated that interleukin (IL)-17A, a proinflammatory cytokine produced mainly by Th17 cells, contributed to PD pathogenesis depending on microglia. Mouse and rat models for PD were prepared by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or striatal injection of 1-methyl-4-phenylpyridinium (MPP+), respectively. Both in MPTP-treated mice and MPP+-treated rats, blood-brain barrier (BBB) was disrupted and IL-17A level increased in the SN but not in cortex. Effector T (Teff) cells that were adoptively transferred via tail veins infiltrated into the brain of PD mice but not into that of normal mice. The Teff cell transfer aggravated nigrostriatal dopaminergic neurodegeneration, microglial activation and motor impairment. Contrarily, IL-17A deficiency alleviated BBB disruption, dopaminergic neurodegeneration, microglial activation and motor impairment. Anti-IL-17A-neutralizing antibody that was injected into lateral cerebral ventricle in PD rats ameliorated the manifestations mentioned above. IL-17A activated microglia but did not directly affect dopaminergic neuronal survival in vitro. IL-17A exacerbated dopaminergic neuronal loss only in the presence of microglia, and silencing IL-17A receptor gene in microglia abolished the IL-17A effect. IL-17A-treated microglial medium that contained higher concentration of tumor necrosis factor (TNF)-α facilitated dopaminergic neuronal death. Further, TNF-α-neutralizing antibody attenuated MPP+-induced neurotoxicity. The findings suggest that IL-17A accelerates neurodegeneration in PD depending on microglial activation and at least partly TNF-α release.
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Interleucina-17/imunologia , Microglia/imunologia , Doença de Parkinson/imunologia , 1-Metil-4-fenilpiridínio/farmacologia , Animais , Morte Celular/imunologia , Corpo Estriado/imunologia , Modelos Animais de Doenças , Dopamina/imunologia , Neurônios Dopaminérgicos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Degeneração Neural/imunologia , Degeneração Neural/patologia , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/patologia , Neuroimunomodulação/imunologia , Ratos , Ratos Sprague-Dawley , Substância Negra/imunologia , Células Th17/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Colorectal cancer (CRC) is the third most common cancer worldwide, with more than 1.3 million new cases and 690 000 deaths each year. In China, the incidence of CRC has increased dramatically due to dietary and lifestyle changes, to become the fifth leading cause of cancer-related death. Here, we performed whole-exome sequencing in 50 rectal cancer cases among the Chinese population as part of the International Cancer Genome Consortium research project. Frequently mutated genes and enriched pathways were identified. Moreover, a previously unreported gene, PCDHB3, was found frequently mutated in 5.19% cases. Additionally, PCDHB3 expression was found decreased in 81.6% of CRC tissues and all eight CRC cell lines tested. Low expression and cytoplasmic localization of PCDHB3 predict poor prognosis in advanced CRC. Copy number decrease and/or CpG island hypermethylation contributes to the pervasive decreased expression of PCDHB3. PCDHB3 inhibits CRC cell proliferation, migration, and epithelial-mesenchymal transition. The tumor-suppressive effects of PCDHB3 are partially due to inhibition of NF-κB transcriptional activity through K63 deubiquitination of p50 at lysine 244/252, which increases the binding affinity of inactive p50 homodimer to κB DNA, resulting in competitive inhibition of the transcription of NF-κB target genes by p65 dimers. Our study identified PCDHB3 as a novel tumor suppressor in CRC via inhibition of the NF-κB pathway, and its expression and localization may serve as prognostic markers for advanced CRC. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Biomarcadores Tumorais/genética , Caderinas/genética , Neoplasias Colorretais/genética , Sequenciamento do Exoma , Inativação Gênica , Genes Supressores de Tumor , Mutação , Adulto , Idoso , Animais , Povo Asiático/genética , Biomarcadores Tumorais/metabolismo , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , China , Neoplasias Colorretais/etnologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Ilhas de CpG , Metilação de DNA , Regulação para Baixo , Feminino , Dosagem de Genes , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , NF-kappa B/genética , NF-kappa B/metabolismo , Fenótipo , ProtocaderinasRESUMO
Nasopharyngeal carcinoma is an Epstein-Barr Virus (EBV) associated malignancy which is highly prevalent in Southeast Asia. EBV-related antibodies have been widely used as screening markers for early nasopharyngeal carcinoma (NPC) detection. However, due to its low positive predictive rate, it is essential to develop new biomarkers to facilitate NPC early diagnosis or triage EBV serological high-risk individuals to improve the chance of NPC early detection. BART microRNAs, which are encoded by BamHI region of EBV, were reported to be abundant in NPC and have potential value in early diagnosis of NPC. Here, we quantified circulating level of 17 BART microRNAs in discovery stage based on previous microarray and sequencing data and, in particular, BART 2-5p, the sole candidate whose area under curve (AUC) was higher than 0.8, has been chosen for further study. In validation stage, the sensitivity, specificity and AUC of BART 2-5p was 93.9%, 89.8%, 0.972 (95%CI: 0.954-0.989), respectively, in Cohort 1 constituted by NPC patients and controls from Hong Kong. For validation Cohort 2 consisting of patients and controls from Guangzhou, the sensitivity, specificity and AUC was 94.2%, 83.5%, 0.959 (95%CI: 0.939-0.980), respectively. To evaluate its ability to distinguish preclinical NPC patients, we established a nested case-control study with serum samples prospectively collected from 22 NPC patients prior to their clinical diagnosis and 88 matched healthy high-risk controls in a screening trial. The sensitivity and specificity were 90.9% and 54.5%. Collectively, EBV microRNA BART2-5p may be a valuable biomarker for early detection of NPC.
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Detecção Precoce de Câncer/métodos , Herpesvirus Humano 4/genética , Programas de Rastreamento/métodos , MicroRNAs/sangue , Carcinoma Nasofaríngeo/diagnóstico , Neoplasias Nasofaríngeas/diagnóstico , RNA Viral/sangue , Adulto , Anticorpos Antivirais/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Herpesvirus Humano 4/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/sangue , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/sangue , Neoplasias Nasofaríngeas/genética , Estudos Prospectivos , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Oesophageal squamous cell carcinoma (ESCC) is the most common histological subtype of oesophageal cancer. The disease is particularly prevalent in southern China. The incidence of the disease is on the rise and its overall survival rate remains dismal. Identification and characterization of better molecular markers for early detection and therapeutic targeting are urgently needed. Here, we report levels of transmembrane and soluble neuropilin-2 (NRP2) to be significantly up-regulated in ESCC, and to correlate positively with advanced tumour stage, lymph node metastasis, less favourable R category and worse overall patient survival. NRP2 up-regulation in ESCC was in part a result of gene amplification at chromosome 2q. NRP2 overexpression promoted clonogenicity, angiogenesis and metastasis in ESCC in vitro, while NRP2 silencing by lentiviral knockdown or neutralizing antibody resulted in a contrary effect. This observation was extended in vivo in animal models of subcutaneous tumourigenicity and tail vein metastasis. Mechanistically, overexpression of NRP2 induced expression of ERK MAP kinase and the transcription factor ETV4, leading to enhanced MMP-2 and MMP-9 activity and, as a consequence, suppression of E-cadherin. In summary, NRP2 promotes tumourigenesis and metastasis in ESCC through deregulation of ERK-MAPK-ETV4-MMP-E-cadherin signalling. NRP2 represents a potential diagnostic or prognostic biomarker and therapeutic target for ESCC. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Proteínas E1A de Adenovirus/metabolismo , Biomarcadores Tumorais/metabolismo , Caderinas/metabolismo , Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Sistema de Sinalização das MAP Quinases/genética , Neuropilina-2/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas E1A de Adenovirus/genética , Animais , Antígenos CD , Biomarcadores Tumorais/genética , Caderinas/genética , Carcinogênese , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Estudos de Coortes , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Neuropilina-2/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-ets , Transcriptoma , Regulação para CimaRESUMO
OBJECTIVE: Using whole genome sequencing, we identified gene amplification of solute carrier family 12 member 5 (SLC12A5) located at 20q13.12 in colorectal cancer (CRC). We analysed its amplification, overexpression, biological effects and prognostic significance in CRC. DESIGN: SLC12A5 amplification status was evaluated by fluorescence in situ hybridisation (FISH). The effects of SLC12A5 re-expression or knockdown were determined in proliferation, apoptosis, invasion and metastasis assays. SLC12A5 target genes and related pathways were identified by reporter activity and cDNA microarray analyses. Clinical impact of SLC12A5 overexpression was assessed in 195 patients with CRC. RESULTS: Amplification of SLC12A5 was verified in 78 out of 191 (40.8%) patients with primary CRC by FISH, which was positively correlated with its protein overexpression (p<0.001). Biofunctional investigation of SLC12A5 revealed that SLC12A5 significantly increased cell proliferation, G1-S cell cycle transition, invasion/migration abilities, but suppressed apoptosis in vitro and promoted xenograft tumour growth as well as lung metastasis in vivo. The antiapoptosis effect by SLC12A5 was mediated through inhibiting apoptosis-inducing factor and endonuclease G-dependent apoptotic signalling pathway; and the pro-metastasis role was by regulating key elements of the matrix architecture, including matrix metallopeptidase and fibronectin. After a median follow-up of 50.16 months, multivariate analysis revealed that patients with SLC12A5 protein overexpression had a significant decrease in overall survival. Kaplan-Meier survival curves showed that SLC12A5 overexpression was significantly associated with shortened survival in patients with CRC. CONCLUSIONS: SLC12A5 plays a pivotal oncogenic role in colorectal carcinogenesis; its overexpression is an independent prognostic factor of patients with CRC.
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Neoplasias Colorretais/genética , Simportadores de Cloreto de Sódio-Potássio/genética , Apoptose , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Progressão da Doença , Feminino , Amplificação de Genes , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Invasividade Neoplásica , Metástase Neoplásica , Prognóstico , Taxa de Sobrevida , Análise Serial de TecidosRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most fatal malignancies worldwide, and CD133 is a popular cancer stem cell (CSC) marker for HCC. CD133(+) CSCs have been reported to resist conventional chemo- and radiotherapy, but little is known about their response to immune surveillance. Interferon-gamma (IFN-γ) is one of key cytokines that the immune system produce to eradicate cancer cells, so we investigated the function of IFN-γ on CD133+ HCC CSCs in this study. METHODS: The response of CD133(+) cells to IFN-γ was performed with functional assays (cell proliferation assay and tumor formation in nude mice), flow cytometry, immunofluorescence staining and RNA interference. RESULTS: We found that IFN-γ inhibited the proliferation of cell lines with low percentage of CD133(+) cells (wild-type human cells, BEL7402, QGY7701) but it did not affect the proliferation of cell lines with high percentage of CD133(+) cells (wild-type human cells, Huh7, PLC8024) in vivo and in vitro (nude mice). Flow cytometry analysis demonstrated that the percentage of CD133+ cells increased after IFN-γ treatment of low CD133(+) cell lines. Furthermore, IFN-γ induced the autophagy of low CD133(+) cell lines to decrease proliferation. CONCLUSION: CD133(+) HCC CSCs resisted IFN-γ-induced autophagy, which might also be a mechanism through which CSCs resist immune eradication.
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Antígenos CD/genética , Carcinoma Hepatocelular/genética , Glicoproteínas/genética , Interferon gama/metabolismo , Neoplasias Hepáticas/genética , Peptídeos/genética , Antígeno AC133 , Animais , Antígenos CD/biossíntese , Autofagia/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glicoproteínas/biossíntese , Humanos , Interferon gama/administração & dosagem , Neoplasias Hepáticas/patologia , Camundongos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND & AIMS: Solid tumors often become hypoxic, leading to activation of hypoxia-response genes. We investigated the effects of overexpression of the hypoxia response genes eIF5A2 in esophageal squamous cell carcinoma (ESCC). METHODS: We used quantitative real-time polymerase chain reaction and immunohistochemistry analyses to compare expression of eIF5A2 between paired ESCC samples and nontumor esophageal tissues, and fluorescence in situ hybridization to detect gene copy-number alterations. Luciferase reporter and chromatin immunoprecipitation assays were used to study interactions between eIF5A2 and hypoxia-inducible factor-1α (HIF1α). We determined the effects of eIF5A2 overexpression and knockdown in ESCC cell lines and growth of ESCC xenograft tumors in nude mice. RESULTS: Levels of eIF5A2 messenger RNA and protein were increased in >40% of ESCC samples compared with matched nontumor tissues, along with levels of HIF1α and vascular endothelial growth factor. Increased levels of EIF5A2 were significantly associated with ESCC metastasis to lymph nodes (P < .001) and tissue invasion (P = .037), and shorter survival times of patients (P < .001). Amplification of eIF5A2 was detected in 35.14% of ESCC samples that overexpressed eIF5A2. Hypoxia increased expression of eIF5A2 4- to 8-fold in ESCC cell lines; we observed bidirectional regulation between eIF5A2 and HIF1α. Transient transfection of ESCC cell lines with eIF5A2 increased their migratory and invasive abilities and markers of the epithelial to mesenchymal transition, and eIF5A2 knockdown or HIFα inhibition reduced these. In mice, xenograft tumors grown from ESCC cells that expressed eIF5A2 formed tumors more rapidly than cells that expressed only vector (controls); they also expressed higher levels of HIF1α and vascular endothelial growth factor, and formed more microvessels than controls. Knockdown of eIF5A2 in ESCC cells with interfering RNAs reduced their growth as xenograft tumors in mice, particularly when mice were given docetaxel or cisplatin. CONCLUSIONS: eIF5A2 is overexpressed by gene amplification or hypoxia in ESCCs, and associated with up-regulation of HIF1α, metastasis, and shorter survival times of patients. Increased expression of eIF5A2 increases metastasis and angiogenesis in ESCC via the HIF1α-mediated signaling pathway.
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Carcinoma de Células Escamosas/metabolismo , Movimento Celular , Neoplasias Esofágicas/metabolismo , Amplificação de Genes , Neovascularização Patológica , Fatores de Iniciação de Peptídeos/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/irrigação sanguínea , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/secundário , Hipóxia Celular , Linhagem Celular Tumoral , Cisplatino/farmacologia , Docetaxel , Transição Epitelial-Mesenquimal , Neoplasias Esofágicas/irrigação sanguínea , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Estimativa de Kaplan-Meier , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Fatores de Iniciação de Peptídeos/genética , Modelos de Riscos Proporcionais , Ligação Proteica , Interferência de RNA , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , Transdução de Sinais , Taxoides/farmacologia , Fatores de Tempo , Transfecção , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Fator de Iniciação de Tradução Eucariótico 5ARESUMO
UNLABELLED: Amplification of 1q is one of the most frequent chromosomal alterations in human hepatocellular carcinoma (HCC). In this study we identified and characterized a novel oncogene, Maelstrom (MAEL), at 1q24. Amplification and overexpression of MAEL was frequently detected in HCCs and significantly associated with HCC recurrence (P = 0.031) and poor outcome (P = 0.001). Functional study demonstrated that MAEL promoted cell growth, cell migration, and tumor formation in nude mice, all of which were effectively inhibited when MAEL was silenced with short hairpin RNA (shRNAs). Further study found that MAEL enhanced AKT activity with subsequent GSK-3ß phosphorylation and Snail stabilization, finally inducing epithelial-mesenchymal transition (EMT) and promoting tumor invasion and metastasis. In addition, MAEL up-regulated various stemness-related genes, multidrug resistance genes, and cancer stem cell (CSC) surface markers at the messenger RNA (mRNA) level. Functional study demonstrated that overexpression of MAEL increased self-renewal, chemoresistance, and tumor metastasis. CONCLUSION: MAEL is an oncogene that plays an important role in the development and progression of HCC by inducing EMT and enhancing the stemness of HCC.
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Carcinoma Hepatocelular/fisiopatologia , Proteínas de Transporte/fisiologia , Transição Epitelial-Mesenquimal/fisiologia , Quinase 3 da Glicogênio Sintase/fisiologia , Neoplasias Hepáticas/fisiopatologia , Metástase Neoplásica/fisiopatologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Fatores de Transcrição/fisiologia , Animais , Proteínas de Transporte/genética , Movimento Celular/fisiologia , Proliferação de Células , Proteínas de Ligação a DNA , Modelos Animais de Doenças , Progressão da Doença , Feminino , Glicogênio Sintase Quinase 3 beta , Humanos , Técnicas In Vitro , Masculino , Camundongos , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/fisiologia , Transdução de Sinais/fisiologia , Fatores de Transcrição da Família Snail , Regulação para Cima/fisiologiaRESUMO
Optical coherence tomography (OCT) inevitably suffers from the influence of speckles originating from multiple scattered photons owing to its low-coherence interferometry property. Although various deep learning schemes have been proposed for OCT despeckling, they typically suffer from the requirement for ground-truth images, which are difficult to collect in clinical practice. To alleviate the influences of speckles without requiring ground-truth images, this paper presents a self-supervised deep learning scheme, namely, Self2Self strategy (S2Snet), for OCT despeckling using a single noisy image. Specifically, in this study, the main deep learning architecture is the Self2Self network, with its partial convolution being updated with a gated convolution layer. Specifically, both the input images and their Bernoulli sampling instances are adopted as network input first, and then, a devised loss function is integrated into the network to remove the background noise. Finally, the denoised output is estimated using the average of multiple predicted outputs. Experiments with various OCT datasets are conducted to verify the effectiveness of the proposed S2Snet scheme. Results compared with those of the existing methods demonstrate that S2Snet not only outperforms those existing self-supervised deep learning methods but also achieves better performances than those non-deep learning ones in different cases. Specifically, S2Snet achieves an improvement of 3.41% and 2.37% for PSNR and SSIM, respectively, as compared to the original Self2Self network, while such improvements become 19.9% and 22.7% as compared with the well-known non-deep learning NWSR method.
RESUMO
The detection of trace cancer markers in body fluids such as blood/serum is crucial for cancer diseases screening and treatment, which requires high sensitivity and specificity of biosensors. In this study, a peanut structure cascaded lasso (PSCL) shaped fiber sensing probe based on fiber laser demodulation method was proposed to specifically detect the carcinoembryonic antigen related cell adhesion molecules 5 (CEACAM5) protein in serum. Thanks for the narrow linewidth and high signal-to-noise ratio (SNR) of the laser spectrum, it is easier to distinguish small spectral changes than interference spectrum. Adding the antibody modified magnetic microspheres (MMS) to form the sandwich structure of "antibody-antigen-antibody-MMS", and amplified the response caused by biomolecular binding. The limit of detection (LOD) for CEACAM5 in buffer could reach 0.11 ng/mL. Considering the common threshold of 5 ng/mL for CEA during medical screening and the cut off limit of 2.5 ng/mL for some kits, the LOD of proposed biosensor meets the actual needs. Human serum samples from a hospital were used to validate the real sensing capability of proposed biosensor. The deviation between the measured value in various serum samples and the clinical value ranged from 1.9 to 9.8 %. This sensing scheme holds great potential to serve as a point of care testing (POCT) device and extend to more biosensing applications.
Assuntos
Arachis , Neoplasias , Humanos , Microesferas , Moléculas de Adesão Celular , Lasers , Fenômenos Magnéticos , Antígeno Carcinoembrionário , Proteínas Ligadas por GPIRESUMO
Carcinoembryonic antigen (CEACAM5), as a broad-spectrum tumor biomarker, plays a crucial role in analyzing the therapeutic efficacy and progression of cancer. Herein, we propose a novel biosensor based on specklegrams of tapered multimode fiber (MMF) and two-dimensional convolutional neural networks (2D-CNNs) for the detection of CEACAM5. The microfiber is modified with CEA antibodies to specifically recognize antigens. The biosensor utilizes the interference effect of tapered MMF to generate highly sensitive specklegrams in response to different CEACAM5 concentrations. A zero mean normalized cross-correlation (ZNCC) function is explored to calculate the image matching degree of the specklegrams. Profiting from the extremely high detection limit of the speckle sensor, variations in the specklegrams of antibody concentrations from 1 to 1000 ng/mL are measured in the experiment. The surface sensitivity of the biosensor is 0.0012 (ng/mL)-1 within a range of 1 to 50 ng/mL. Moreover, a 2D-CNN was introduced to solve the problem of nonlinear detection surface sensitivity variation in a large dynamic range, and in the search for image features to improve evaluation accuracy, achieving more accurate CEACAM5 monitoring, with a maximum detection error of 0.358%. The proposed fiber specklegram biosensing scheme is easy to implement and has great potential in analyzing the postoperative condition of patients.
Assuntos
Técnicas Biossensoriais , Neoplasias , Humanos , Antígeno Carcinoembrionário , Proteínas Ligadas por GPIRESUMO
Morphological rearrangement of the endoplasmic reticulum (ER) is critical for metazoan mitosis. Yet, how the ER is remodeled by the mitotic signaling remains unclear. Here, we report that mitotic Aurora kinase A (AURKA) employs a small GTPase, Rab1A, to direct ER remodeling. During mitosis, AURKA phosphorylates Rab1A at Thr75. Structural analysis demonstrates that Thr75 phosphorylation renders Rab1A in a constantly active state by preventing interaction with GDP-dissociation inhibitor (GDI). Activated Rab1A is retained on the ER and induces the oligomerization of ER-shaping protein RTNs and REEPs, eventually triggering an increase of ER complexity. In various models, from Caenorhabditis elegans and Drosophila to mammals, inhibition of Rab1AThr75 phosphorylation by genetic modifications disrupts ER remodeling. Thus, our study reveals an evolutionarily conserved mechanism explaining how mitotic kinase controls ER remodeling and uncovers a critical function of Rab GTPases in metaphase.
Assuntos
Aurora Quinase A , Mitose , Animais , Fosforilação , Aurora Quinase A/metabolismo , Transdução de Sinais , Retículo Endoplasmático/metabolismo , Mamíferos/metabolismoRESUMO
Accurate and ultrasensitive evaluation of human epidermal growth factor receptor 2 (HER2) protein is key to early diagnosis and subtype differentiation of breast cancer. Single-cell analyses to reduce ineffective targeted therapies due to breast cancer heterogeneity and improve patient survival remain challenging. Herein, we reported a novel droplet microfluidic combined with an instant cation exchange signal amplification strategy for quantitative analysis of HER2 protein expression on single cells. In the 160 µm droplets produced by a tapered capillary bundle, abundant Immuno-CdS labeled on HER2-positive cells were replaced by Ag + to obtain Cd2+ that stimulated Rhod-5N fluorescence. This uniformly distributed and instantaneous fluorescence amplification strategy in droplets improves sensitivity and reduces signal fluctuation. Using HER2 modified PS microsphere to simulate single cells, we obtained a linear fitting of HER2-modified concentration and fluorescence intensity in microdroplets with the limit detection of 11.372 pg mL-1. Moreover, the relative standard deviation (RSD) was 4.2-fold lower than the traditional immunofluorescence technique (2.89% vs 12.21%). The HER2 protein on SK-BR-3 cells encapsulated in droplets was subsequently quantified, ranging from 9862.954 pg mL-1 and 205.26 pg mL-1, equivalent to 9.795 × 106 and 2.038 × 105 protein molecules. This detection system provides a universal platform for single-cell sensitive quantitative analysis and contributes to the evaluation of HER2-positive tumors.