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We model and demonstrate a self-matching photonic lantern (SMPL) device, which is designed to address the constraint of limited transverse modes generated by fiber lasers. The SMPL incorporates a FMF into the array at the input end of a traditional photonic lantern. The few-mode fiber at the output end is specifically configured to align with the few-mode fiber at the input, therefore named as SMPL. This paper details the design and fabrication of the SMPL device, validated by both simulation and experiment. The 980nm fundamental mode, injected via 980nm single-mode fibers, selectively excites corresponding higher-order modes at the few-mode port of the SMPL. Additionally, 1550nm fundamental and higher-order modes injected at the input end into the SMPL device demonstrates mode preservation and low-loss transmission characteristics. The SMPL is well-suited for developing a ring laser system, enabling selective excitation of 980nm pump light modes and facilitating closed-loop oscillation and transmission of 1550nm laser.
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PURPOSE: The unsatisfactory efficacy of PD-L1 antibodies in glioblastoma (GBM) is largely due to the temporal and spatial heterogeneity of PD-L1 expression. Molecular imaging can enhance understanding of the tumor immune microenvironment and guide immunotherapy. However, highly sensitive imaging agents capable of effectively visualizing PD-L1 heterogeneity are limited. This study introduces a novel PET tracer, offering improved imaging of PD-L1 heterogeneity in GBM xenografts, with a comparative analysis to [18F]AlF-NOTA-WL12. METHODS: [18F]AlF-NOTA-PCP2 was synthesized with high purity and its affinity for PD-L1 was characterized using surface plasmon resonance (SPR) and cell binding assays. Its specificity for PD-L1 was evaluated both in vitro using various cell lines and in vivo with GBM xenograft models in NOD/SCID mice. PET/CT imaging was conducted to evaluate the tracer's biodistribution, pharmacokinetics, and ability to quantify tumoral spatial heterogeneity of PD-L1 expression. A focused comparative analysis between [18F]AlF-NOTA-PCP2 and [18F]AlF-NOTA-WL12 was conducted, examining binding affinity, biodistribution, pharmacokinetics, and imaging effectiveness in GBM xenografts. Additionally, human radiation dosimetry estimates compared the safety profiles of both tracers. RESULTS: [18F]AlF-NOTA-PCP2 demonstrated high radiochemical purity (> 95%) and a strong affinity for PD-L1, comparable to [18F]AlF-NOTA-WL12. In vitro and in vivo studies confirmed its specificity for PD-L1, with increased uptake in PD-L1 expressing cells and tumors. Toxicological profiles indicated no significant abnormalities in serum biochemical indicators or major organ tissues. MicroPET/CT imaging showed [18F]AlF-NOTA-PCP2's effectiveness in visualizing PD-L1 expression levels and spatial heterogeneity in GBM xenografts. Comparative studies revealed [18F]AlF-NOTA-PCP2's improved pharmacokinetic properties, including higher tumor-to-blood ratios and lower nonspecific liver uptake, as well as reduced radiation exposure compared to [18F]AlF-NOTA-WL12. CONCLUSION: [18F]AlF-NOTA-PCP2 distinguishes itself as an exceptionally sensitive PET/CT tracer, adept at non-invasively and accurately quantifying PD-L1 expression and its spatial heterogeneity in tumors, especially in GBM. Its favorable pharmacokinetic properties, safety profile, and high affinity for PD-L1 highlight its potential for enhancing the precision of cancer immunotherapy and guiding individualized treatment strategies. While promising, its clinical translation, especially in brain imaging, necessitates further validation in clinical trials.
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Antígeno B7-H1 , Glioblastoma , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Glioblastoma/diagnóstico por imagem , Glioblastoma/metabolismo , Animais , Camundongos , Humanos , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Distribuição Tecidual , Traçadores Radioativos , Compostos Heterocíclicos com 1 Anel/química , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/metabolismo , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/químicaRESUMO
Immune checkpoint inhibitors (ICIs) are a powerful treatment modality for various types of cancer. The effectiveness of ICIs is intimately connected to the binding status of antibodies to receptors. However, validated means to accurately evaluate target specificity and predict antibody efficacy in vivo are lacking. A novel peptide-based probe called Al[18F]F-NOTA-PCP1 was developed and validated for its specificity to PD-L1 in A549, U87MG, GL261, and GL261-iPDL1 cell lines, as well as in xenograft models. Then the probe was used in PET/CT scans to determine the binding status of PD-L1 antibodies (atezolizumab, avelumab, and durvalumab) in U87MG xenograft model mice. Moreover, Al[18F]F-NOTA-PCP1 was used to evaluate the impact of different treatment times and doses. Al[18F]F-NOTA-PCP1 PET/CT can be used to evaluate the interaction between PD-L1 and antibodies to determine the effectiveness of immunotherapy. By quantifying target engagement, the probe has the potential to predict the efficacy of immunotherapy and optimize the dose and treatment schedules for PD-L1 immunotherapy. This imaging agent could be a valuable tool in guiding personalized treatment strategies and improving cancer patient outcomes.
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Compostos Heterocíclicos com 1 Anel , Neoplasias , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Animais , Camundongos , Antígeno B7-H1/metabolismo , Neoplasias/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , PeptídeosRESUMO
Fine-mode aerosol optical depth (fAOD) is a vital proxy for the concentration of anthropogenic aerosols in the atmosphere. Currently, the limited data length and high uncertainty of the satellite-based data diminish the applicability of fAOD for climate research. Here, we propose a novel pretrained deep learning framework that can extract information underlying each satellite pixel and use it to create new latent features that can be employed for improving retrieval accuracy in regions without in situ data. With the proposed model, we developed a new global fAOD (at 0.5 µm) data from 2001 to 2020, resulting in a 10% improvement in the overall correlation coefficient (R) during site-based independent validation and a 15% enhancement in non-AERONET site areas validation. Over the past two decades, there has been a noticeable downward trend in global fAOD (-1.39 × 10-3/year). Compared to the general deep-learning model, our method reduces the global trend's previously overestimated magnitude by 7% per year. China has experienced the most significant decline (-5.07 × 10-3/year), which is 3 times greater than the global trend. Conversely, India has shown a significant increase (7.86 × 10-4/year). This study bridges the gap between sparse in situ observations and abundant satellite measurements, thereby improving predictive models for global patterns of fAOD and other climate factors.
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Aerossóis , Aprendizado Profundo , Atmosfera/química , Monitoramento Ambiental/métodos , Imagens de SatélitesRESUMO
PURPOSE: Active radiation skin injury (ARSI) has the highest incidence of acute adverse reactions caused by radiotherapy (RT) in patients with head and neck cancer (HNC). This study aimed to screen risk factors that can facilitate the identification of HNC patients at high risk of ARSI. METHODS: Data from 255 stage III-IV HNC patients who underwent intensity-modulated radiation therapy (IMRT) were collected. The data from our medical records, including clinical characteristics and hematological indices before RT, were retrospectively collected and arranged. The Common Terminology Criteria for Adverse Events Criteria (CTCAE), Radiation Therapy Oncology Group Criteria (RTOG), World Health Organization Criteria (WHO), Oncology Nursing Society (ONS), Acute Radiation Dermatitis Graduation Scale, Douglas & Fowler and Radiation Dermatitis Severity Scale (RDSS) were used to assess ARSI. Of these, CTCAE was used for further analysis. Binary logistic regression analyses were used to identity risk factors. To establish the correction between each risk factor and the ARSI score, the odds ratio (OR) and 95% confidence interval (CI) were computed. RESULTS: The assessment results of the CTCAE with RTOG, WHO, ONS, Graduation Scale, Douglas & Fowler and RDSS have good consistency. After radiotherapy, 18.4% of patients had at least 3 (3 +) grade ARSI. Multivariate logistic regression analysis revealed that the KPS score, blood glucose level, white blood cell count, and plasma free thyroxine (FT4) concentration were independent risk factors for 3 + grade ARSI. A nomogram was constructed on the basis of these risk factors, which demonstrated good predictive power according to the area under the ROC curve (AUC). The satisfactory consistency and clinical efficacy of the nomogram were confirmed by calibration curves and decision curve analysis (DCA). CONCLUSION: A low KPS score, high blood glucose level, high white blood cell count, and high thyroid hormone prior to radiotherapy for stage III-IV HNC are independent risk factors for grade 3 + RSI.
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Neoplasias de Cabeça e Pescoço , Estadiamento de Neoplasias , Radioterapia de Intensidade Modulada , Humanos , Masculino , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Neoplasias de Cabeça e Pescoço/radioterapia , Neoplasias de Cabeça e Pescoço/patologia , Fatores de Risco , Prognóstico , Idoso , Radioterapia de Intensidade Modulada/efeitos adversos , Adulto , Radiodermite/etiologia , Radiodermite/patologia , Radiodermite/diagnóstico , Seguimentos , Lesões por Radiação/etiologia , Lesões por Radiação/patologia , Lesões por Radiação/diagnóstico , Lesões por Radiação/sangue , Lesões por Radiação/epidemiologia , Nomogramas , Idoso de 80 Anos ou maisRESUMO
BACKGROUND: Russeting is a major problem in many fruit crops. Russeting is caused by environmental factors such as wounding or moisture exposure of the fruit surface. Despite extensive research, the molecular sequence that triggers russet initiation remains unclear. Here, we present high-resolution transcriptomic data by controlled russet induction at very early stages of fruit development. During Phase I, a patch of the fruit surface is exposed to surface moisture. For Phase II, moisture exposure is terminated, and the formerly exposed surface remains dry. We targeted differentially expressed transcripts as soon as 24 h after russet induction. RESULTS: During moisture exposure (Phase I) of 'Pinova' apple, transcripts associated with the cell cycle, cell wall, and cuticle synthesis (SHN3) decrease, while those related to abiotic stress increase. NAC35 and MYB17 were the earliest induced genes during Phase I. They are therefore linked to the initial processes of cuticle microcracking. After moisture removal (Phase II), the expression of genes related to meristematic activity increased (WOX4 within 24 h, MYB84 within 48 h). Genes related to lignin synthesis (MYB52) and suberin synthesis (MYB93, WRKY56) were upregulated within 3 d after moisture removal. WOX4 and AP2B3 are the earliest differentially expressed genes induced in Phase II. They are therefore linked to early events in periderm formation. The expression profiles were consistent between two different seasons and mirrored differences in russet susceptibility in a comparison of cultivars. Furthermore, expression profiles during Phase II of moisture induction were largely identical to those following wounding. CONCLUSIONS: The combination of a unique controlled russet induction technique with high-resolution transcriptomic data allowed for the very first time to analyse the formation of cuticular microcracks and periderm in apple fruit immediately after the onset of triggering factors. This data provides valuable insights into the spatial-temporal dynamics of russeting, including the synthesis of cuticles, dedifferentiation of cells, and impregnation of cell walls with suberin and lignin.
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Malus , Malus/metabolismo , Frutas , Transcriptoma , Lignina/metabolismo , Perfilação da Expressão GênicaRESUMO
BACKGROUND: Locally advanced non-small cell lung cancer (NSCLC) with N1/N2 lymph node metastasis is challenging with poor survival. Neo-adjuvant chemo-immunotherapy has gained benefits in a proportion of these patients. However no specific biomarker has been proved to predict the effect before therapy. In addition, the relationship of nodal status and survival after neo-adjuvant chemo-immunotherapy is still not well stated. METHODS: A total of 75 resectable NSCLC patients with N1/N2 stage who received neo-adjuvant chemo-immunotherapy plus surgery were retrospectively studied. The clinical characteristics, surgical information and safety parameters were collected. The correlations of major pathological response (MPR) and pathological complete response (pCR) with clinical data were analyzed. The progression free disease(PFS) and overall survival(OS) were evaluated with pathological response and nodal status. RESULTS: Of the 75 patients, 69 (92%) patients experienced treatment related adverse effects, while grade 3-4 adverse effects occurred in 8 (10%) patients. All the patients received surgical R0 resection with a MPR rate of 60% and a pCR rate of 36%. 67% of N1 patients and 77% of N2 patients had nodal clearance after neo-adjuvant treatment. A significant difference was observed between pathological response with age, histology and multiple lymph node metastasis. The PFS was better in the MPR cohort. The PFS was 90.1% and 83.6% at the nodal clearance group at the time of 12 and 18 months, compared with 70.1% and 63.7% at the nodal residual group. CONCLUSIONS: The neo-adjuvant chemo-immunotherapy for locally advanced NSCLC with nodal positive was safe and feasible. The patients with elder age and squamous-cell carcinoma (SCC) were more likely to have better pathological response, while multiple nodal metastasis was a negative predictor. The clearance of lymph node resulted in significantly longer PFS and OS.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Idoso , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Terapia Neoadjuvante , Neoplasias Pulmonares/tratamento farmacológico , Estudos Retrospectivos , Metástase Linfática , Estadiamento de Neoplasias , ImunoterapiaRESUMO
Vomiting-induced pneumomediastinum is a rare presentation and can be a result of alveolar rupture (Mackler effect) or Boerhaave syndrome. Patients diagnosed with Boerhaave syndrome may present with the classic Mackler triad of vomiting, chest pain, and subcutaneous emphysema. However, there exists a large overlap of symptoms accompanying Boerhaave syndrome and the Macklin effect, including retrosternal chest pain, neck discomfort, cough, sore throat, dysphagia, dysphonia, and dyspnea. Boerhaave syndrome is a dangerous condition. Delayed diagnosis of Boerhaave syndrome may worsen sepsis and cause mortality. Therefore, early diagnosis and timely management are important to prevent further complications. Here, we present a case of vomiting-induced pneumomediastinum, which supports the use of bedside ultrasonography to aid in the diagnosis and rapid differentiation of etiology of pneumomediastinum.
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Enfisema Mediastínico , Humanos , Feminino , Enfisema Mediastínico/complicações , Sistemas Automatizados de Assistência Junto ao Leito , Vômito , Dor no Peito/etiologiaRESUMO
Zymomonas mobilis metabolizes sugar anaerobically through the Entner-Doudoroff pathway with less ATP generated for lower biomass accumulation to direct more sugar for product formation with improved yield, making it a suitable host to be engineered as microbial cell factories for producing bulk commodities with major costs from feedstock consumption. Self-flocculation of the bacterial cells presents many advantages, such as enhanced tolerance to environmental stresses, a prerequisite for achieving high product titers by using concentrated substrates. ZM401, a self-flocculating mutant developed from ZM4, the unicellular model strain of Z. mobilis, was employed in this work to explore the molecular mechanism underlying this self-flocculating phenotype. Comparative studies between ZM401 and ZM4 indicate that a frameshift caused by a single nucleotide deletion in the poly-T tract of ZMO1082 fused the putative gene with the open reading frame of ZMO1083, encoding the catalytic subunit BcsA of the bacterial cellulose synthase to catalyze cellulose biosynthesis. Furthermore, the single nucleotide polymorphism mutation in the open reading frame of ZMO1055, encoding a bifunctional GGDEF-EAL protein with apparent diguanylate cyclase/phosphodiesterase activities, resulted in the Ala526Val substitution, which consequently compromised in vivo specific phosphodiesterase activity for the degradation of cyclic diguanylic acid, leading to intracellular accumulation of the signaling molecule to activate cellulose biosynthesis. These discoveries are significant for engineering other unicellular strains from Z. mobilis with the self-flocculating phenotype for robust production. IMPORTANCE Stress tolerance is a prerequisite for microbial cell factories to be robust in production, particularly for biorefinery of lignocellulosic biomass to produce biofuels, bioenergy, and bio-based chemicals for sustainable socioeconomic development, since various inhibitors are released during the pretreatment to destroy the recalcitrant lignin-carbohydrate complex for sugar production through enzymatic hydrolysis of the cellulose component, and their detoxification is too costly for producing bulk commodities. Although tolerance to individual stress has been intensively studied, the progress seems less significant since microbial cells are inevitably suffering from multiple stresses simultaneously under production conditions. When self-flocculating, microbial cells are more tolerant to multiple stresses through the general stress response due to enhanced quorum sensing associated with the morphological change for physiological and metabolic advantages. Therefore, elucidation of the molecular mechanism underlying such a self-flocculating phenotype is significant for engineering microbial cells with the unique multicellular morphology through rational design to boost their production performance.
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Zymomonas , Celulose/metabolismo , Floculação , Diester Fosfórico Hidrolases/metabolismo , Açúcares/metabolismo , Zymomonas/genética , Zymomonas/metabolismoRESUMO
BACKGROUND AND AIMS: Methylation landscape is important for maintaining the silence of cannabinoid receptor-interacting protein 1 (CNRIP1) in some tumors. However, the role of CNRIP1 in intrahepatic cholangiocarcinoma (ICC) remains poorly defined. APPROACH AND RESULTS: In our study, we showed that CNRIP1 was down-regulated in ICC tissues, and low expression of CNRIP1 was significantly associated with poor prognosis of patients with ICC in 3-year overall survival and tumor-free survival. Investigating the genomic DNA methylation profile, we disclosed a CpG island site named CNRIP1 MS-2 (CNRIP1 methylation site-2) that contributes to the down-regulation of CNRIP1. In addition, the methylation level of CNRIP1 MS-2 was correlated to the pathological grade, metastasis, and tumor-node-metastasis classification in ICC. Notably, we observed that CNRIP1 suppressed tumor cell migration, invasion, and proliferation by inhibiting the activity of pyruvate kinase M2 (PKM2). Sustained overexpression of CNRIP1 suppressed the in vivo tumor growth in a mouse xenograft model. It was also found that CNRIP1 overexpression activated Parkin (an E3 ubiquitin ligase), which resulted in the protein degradation of PKM2 in ICC cells. CONCLUSIONS: We identified that CNRIP1 acted as a putative tumor suppressor in ICC, which suggested that CNRIP1 could be a candidate biomarker for predicting tumor recurrence in patients with ICC. Furthermore, these findings highlight a potential therapeutic approach in targeting the CNRIP1/Parkin/PKM2 pathway for the treatment of ICC.
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Neoplasias dos Ductos Biliares/etiologia , Proteínas de Transporte/metabolismo , Colangiocarcinoma/etiologia , Proteínas de Membrana/metabolismo , Hormônios Tireóideos/metabolismo , Animais , Apoptose , Neoplasias dos Ductos Biliares/metabolismo , Western Blotting , Proliferação de Células , Células Cultivadas , Colangiocarcinoma/metabolismo , Metilação de DNA , Regulação para Baixo , Humanos , Camundongos , Transplante de Neoplasias , Reação em Cadeia da Polimerase em Tempo Real , Ubiquitinação , Proteínas de Ligação a Hormônio da TireoideRESUMO
Methanotrophs capable of converting C1-based substrates play an important role in the global carbon cycle. As one of the essential macronutrient components in the medium, the uptake of nitrogen sources severely regulates the cell's metabolism. Although the feasibility of utilizing nitrogen gas (N2) by methanotrophs has been predicted, the mechanism remains unclear. Herein, the regulation of nitrogen fixation by an essential nitrogen-fixing regulator (NifA) was explored based on transcriptomic analyses of Methylomicrobium buryatense 5GB1. A deletion mutant of the nitrogen global regulator NifA was constructed, and the growth of M. buryatense 5GB1ΔnifA exhibited significant growth inhibition compared with wild-type strain after the depletion of nitrate source in the medium. Our transcriptome analyses elucidated that 22.0% of the genome was affected in expression by NifA in M. buryatense 5GB1. Besides genes associated with nitrogen assimilation such as nitrogenase structural genes, genes related to cofactor biosynthesis, electron transport, and post-transcriptional modification were significantly upregulated in the presence of NifA to enhance N2 fixation; other genes related to carbon metabolism, energy metabolism, membrane transport, and cell motility were strongly modulated by NifA to facilitate cell metabolisms. This study not only lays a comprehensive understanding of the physiological characteristics and nitrogen metabolism of methanotrophs, but also provides a potentially efficient strategy to achieve carbon and nitrogen co-utilization.Key points⢠N2 fixation ability of M. buryatense 5GB1 was demonstrated for the first time in experiments by regulating the supply of N2.⢠NifA positively regulates nif-related genes to facilitate the uptake of N2 in M. buryatense 5GB1.⢠NifA regulates a broad range of cellular functions beyond nif genes in M. buryatense 5GB1.
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Fixação de Nitrogênio , Transcriptoma , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Carbono/metabolismo , Perfilação da Expressão Gênica , Regulação Bacteriana da Expressão Gênica , Genes Bacterianos , Methylococcaceae , Nitrogênio/metabolismo , Fixação de Nitrogênio/genéticaRESUMO
For decades, optical fiber interferometers have been extensively studied and applied for their inherent advantages. With the rapid development of science and technology, fiber sensors with higher detection sensitivity are needed on many occasions. As an effective way to improve measurement sensitivity, Vernier effect fiber sensors have drawn great attention during the last decade. Similar to the Vernier caliper, the optical Vernier effect uses one interferometer as a fixed part of the Vernier scale and the other as a sliding part of the Vernier scale. This paper first illustrates the principle of the optical Vernier effect, then different configurations used to produce the Vernier effect are classified and discussed. Finally, the outlook for Vernier effect fiber sensors is presented.
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Fibras ÓpticasRESUMO
BACKGROUND: N6-methyladenosine (m6A) modification is an emerging layer of epigenetic regulation which is widely implicated in the tumorigenicity of hepatocellular carcinoma (HCC), offering a novel perspective for investigating molecular pathogenesis of this disease. The role of AlkB homolog 5 (ALKBH5), one of the m6A demethylases, has not been fully explored in HCC. Here we clarify the biological profile and potential mechanisms of ALKBH5 in HCC. METHODS: Expression of ALKBH5 and its correlation with clinicopathological characteristics of HCC were evaluated using tissue microarrays and online datasets. And biological effects of ALKBH5 in HCC were determined in vitro and in vivo. Subsequently, methylated RNA immunoprecipitation sequencing (MeRIP-seq) combined with RNA sequencing (RNA-seq), and following m6A dot blot, MeRIP-qPCR, RIP-qPCR or dual luciferase reporter assays were employed to screen and validate the candidate targets of ALKBH5. RESULTS: We demonstrated that ALKBH5 was down-regulated in HCC, and decreased ALKBH5 expression was an independent prognostic factor of worse survival in HCC patients. Functionally, ALKBH5 suppressed the proliferation and invasion capabilities of HCC cells in vitro and in vivo. Mechanistically, ALKBH5-mediated m6A demethylation led to a post-transcriptional inhibition of LY6/PLAUR Domain Containing 1 (LYPD1), which could be recognized and stabilized by the m6A effector IGF2BP1. In addition, we identified that LYPD1 induced oncogenic behaviors of tumors in contrast to ALKBH5. Dysregulation of ALKBH5/LYPD1 axis impelled the progression of HCC. CONCLUSION: Our study reveals that ALKBH5, characterized as a tumor suppressor, attenuates the expression of LYPD1 via an m6A-dependent manner in HCC cells. Our findings enrich the landscape of m6A-modulated tumor malignancy, and provide new insights into potential biomarkers and therapeutic targets of HCC treatment.
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Adenosina/análogos & derivados , Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Epigênese Genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Proteínas Supressoras de Tumor/genética , Adenosina/metabolismo , Animais , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Proteínas de Transporte , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Proteínas Ligadas por GPI/genética , Regulação Neoplásica da Expressão Gênica , Xenoenxertos , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Modelos Biológicos , Prognóstico , Ligação Proteica , Transdução de SinaisRESUMO
Homeobox B7 (HOXB7) protein is reported to be aberrantly expressed in a variety of cancers and to play an important role in multiple cellular processes. However, the specific mechanism by which HOXB7 promotes the malignant progression of intrahepatic cholangiocarcinoma (ICC) remains unclear. Therefore, we used quantitative real-time polymerase chain reaction (PCR) to detect the expression level of HOXB7 in 38 paired ICC tissue samples. Additionally, to assess correlation between HOXB7 and ICC prognosis, we performed immunohistochemistry (IHC) using 122 ICC tissues to detect HOXB7 expression. Cell Counting Kit-8 (CCK-8) and colony formation assays were employed to assess ICC cell proliferation, and Transwell assays were performed to estimate the invasion and migration abilities of ICC cells. The capillary tube formation assay was applied to explore the angiogenic effects of HOXB7. A xenograft tumor model was established in nude mice to assess the role of HOXB7 in tumor growth and lung metastasis. The results showed higher expression of HOXB7 in ICC tissues than in noncancerous tissues, and this increased expression was significantly associated with a poor prognosis. In addition, HOXB7 overexpression enhanced capillary tube formation, invasion and migration of ICC cells in vitro, whereas HOXB7 knockdown produced the opposite results in vitro. Moreover, the role of HOXB7 in promoting tumor growth and metastasis was verified in vivo. Further investigation revealed that the expression levels of MMP2, MMP9, VEGFa, and IL8 were elevated by HOXB7 and that the ERK pathway was activated. Our results demonstrate the prognostic value of HOXB7 and its role in metastasis and angiogenesis in ICC. HOXB7 upregulated MMP2, MMP9, VEGFa, and IL8 expression via the ERK pathway to accelerate the malignant progression of ICC.
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Neoplasias dos Ductos Biliares/metabolismo , Colangiocarcinoma/metabolismo , Proteínas de Homeodomínio/metabolismo , Neovascularização Patológica/metabolismo , Animais , Neoplasias dos Ductos Biliares/mortalidade , Carcinogênese , Linhagem Celular Tumoral , Movimento Celular , China/epidemiologia , Colangiocarcinoma/mortalidade , Humanos , Interleucina-8/metabolismo , Sistema de Sinalização das MAP Quinases , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Nus , Invasividade Neoplásica , Metástase Neoplásica , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND: N6-methyladenosine (m6A) methylation, a well-known modification with new epigenetic functions, has been reported to participate in the tumorigenesis of hepatocellular carcinoma (HCC), providing novel insights into the molecular pathogenesis of this disease. However, as the key component of m6A methylation, Wilms tumor 1-associated protein (WTAP) has not been well studied in HCC. Here we investigated the biological role and underlying mechanism of WTAP in liver cancer. METHODS: We determined the expression of WTAP and its correlation with clinicopathological features using tissue microarrays and the Cancer Genome Atlas (TCGA) dataset. And we clarified the effects of WTAP on HCC cells using cell proliferation assay, colony formation, Edu assay and subcutaneous xenograft experiments. We then applied RNA sequencing combined with gene expression omnibus (GEO) data to screen candidate targets of WTAP. Finally, we investigated the regulatory mechanism of WTAP in HCC by m6A dot blot assay, methylated RNA immunoprecipitation (MeRIP) assay, dual luciferase reporter assay, RNA immunoprecipitation (RIP) assay and Chromatin immunoprecipitation (ChIP) assay. RESULTS: We demonstrated that WTAP was highly expressed in HCC which indicated the poor prognosis, and that WTAP expression served as an independent predictor of HCC survival. Functionally, WTAP promoted the proliferation capability and tumor growth of HCC cells in vitro and in vivo. Furthermore, ETS proto-oncogene 1 (ETS1) was identified as the downstream effector of WTAP. The m6A modification regulated by WTAP led to post-transcriptional suppression of ETS1, with the implication of Hu-Antigen R (HuR) as an RNA stabilizer. Then ETS1 was found to inhibit the progression of HCC and could rescue the phenotype induced by WTAP deficiency. Moreover, WTAP modulated the G2/M phase of HCC cells through a p21/p27-dependent pattern mediated by ETS1. CONCLUSION: We have identified that WTAP is significantly up-regulated in HCC and promotes liver cancer development. WTAP-guided m6A modification contributes to the progression of HCC via the HuR-ETS1-p21/p27 axis. Our study is the first to report that WTAP-mediated m6A methylation has a crucial role in HCC oncogenesis, and highlights WTAP as a potential therapeutic target of HCC treatment.
Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteína Semelhante a ELAV 1/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Metiltransferases/metabolismo , Proteína Proto-Oncogênica c-ets-1/genética , Fatores de Processamento de RNA/metabolismo , Animais , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Ciclo Celular/genética , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Metilação de DNA , Modelos Animais de Doenças , Epigênese Genética , Feminino , Inativação Gênica , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Modelos Biológicos , Estadiamento de Neoplasias , Prognóstico , Proto-Oncogene Mas , Fatores de Processamento de RNA/genética , Carga Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We report on the first demonstration of a single-fiber optical tweezer that is utilized to stabilize and control the liquid droplet for dye lasing. In order to trap a liquid droplet with a diameter of 15-30 µm, an annular core micro-structured optical fiber is adopted. By using wavelength division multiplexing technology, we couple a trapping light source (980 nm) and a pumping light source (532 nm) into the annular core of the fiber to realize the trapping, controlling, and pumping of the oil droplet. We show that the laser emission spectrum tunes along the same size as the oil droplet. The lasing threshold of the oil droplet with the diameter of 24 µm is 0.7 µJ. The presented fiber-based optical manipulation of liquid droplet micro-lasers can be easily combined with the micro-fluidic chip technology and also may extend the application of optical fiber tweezers for micro-droplet lasing technology in the biological field.
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In the field of multiple features Object-Based Change Detection (OBCD) for very-high-resolution remotely sensed images, image objects have abundant features and feature selection affects the precision and efficiency of OBCD. Through object-based image analysis, this paper proposes a Genetic Particle Swarm Optimization (GPSO)-based feature selection algorithm to solve the optimization problem of feature selection in multiple features OBCD. We select the Ratio of Mean to Variance (RMV) as the fitness function of GPSO, and apply the proposed algorithm to the object-based hybrid multivariate alternative detection model. Two experiment cases on Worldview-2/3 images confirm that GPSO can significantly improve the speed of convergence, and effectively avoid the problem of premature convergence, relative to other feature selection algorithms. According to the accuracy evaluation of OBCD, GPSO is superior at overall accuracy (84.17% and 83.59%) and Kappa coefficient (0.6771 and 0.6314) than other algorithms. Moreover, the sensitivity analysis results show that the proposed algorithm is not easily influenced by the initial parameters, but the number of features to be selected and the size of the particle swarm would affect the algorithm. The comparison experiment results reveal that RMV is more suitable than other functions as the fitness function of GPSO-based feature selection algorithm.
Assuntos
Modelos Teóricos , Tecnologia de Sensoriamento Remoto/métodos , Algoritmos , Simulação por Computador , HumanosRESUMO
The high spatial resolution remotely sensed imagery has abundant detailed information of earth surface, and the multi-temporal change detection for the high resolution remotely sensed imagery can realize the variations of geographical unit. In terms of the high spatial resolution remotely sensed imagery, the traditional remote sensing change detection algorithms have obvious defects. In this paper, learning from the object-based image analysis idea, we proposed a semi-automatic threshold selection algorithm named OB-HMAD (object-based-hybrid-MAD), on the basis of object-based image analysis and multivariate alternative detection algorithm (MAD), which used the spectral features of remotely sensed imagery into the field of object-based change detection. Additionally, OB-HMAD algorithm has been compared with other the threshold segmentation algorithms by the change detection experiment. Firstly, we obtained the image object by the multi-solution segmentation algorithm. Secondly, we got the object-based difference image object using MAD and minimum noise fraction rotation (MNF) for improving the SNR of the image object. Then, the change objects or area are classified using histogram curvature analysis (HCA) method for the semi-automatic threshold selection, which determined the threshold by calculated the maximum value of curvature of the histogram, so the HCA algorithm has better automation than other threshold segmentation algorithms. Finally, the change detection results are validated using confusion matrix with the field sample data. Worldview-2 imagery of 2012 and 2013 in case study of Beijing were used to validate the proposed OB-HMAD algorithm. The experiment results indicated that OB-HMAD algorithm which integrated the multi-channel spectral information could be effectively used in multi-temporal high resolution remotely sensed imagery change detection, and it has basically solved the "salt and pepper" problem which always exists in the pixel-based change detection, and has mitigated the impact of building shadows and geometric registration error, and has improved the overall accuracy and kappa coefficient than other change detection algorithm, but it has more undetected error. By compared with the SNR of image object, we know that the MNF transformation could effectively improve to concentrate the change information.