RESUMO
MOTIVATION: Topologically associating domains (TADs) are fundamental building blocks of 3D genome. TAD-like domains in single cells are regarded as the underlying genesis of TADs discovered in bulk cells. Understanding the organization of TAD-like domains helps to get deeper insights into their regulatory functions. Unfortunately, it remains a challenge to identify TAD-like domains on single-cell Hi-C data due to its ultra-sparsity. RESULTS: We propose scKTLD, an in silico tool for the identification of TAD-like domains on single-cell Hi-C data. It takes Hi-C contact matrix as the adjacency matrix for a graph, embeds the graph structures into a low-dimensional space with the help of sparse matrix factorization followed by spectral propagation, and the TAD-like domains can be identified using a kernel-based changepoint detection in the embedding space. The results tell that our scKTLD is superior to the other methods on the sparse contact matrices, including downsampled bulk Hi-C data as well as simulated and experimental single-cell Hi-C data. Besides, we demonstrated the conservation of TAD-like domain boundaries at single-cell level apart from heterogeneity within and across cell types, and found that the boundaries with higher frequency across single cells are more enriched for architectural proteins and chromatin marks, and they preferentially occur at TAD boundaries in bulk cells, especially at those with higher hierarchical levels. AVAILABILITY AND IMPLEMENTATION: scKTLD is freely available at https://github.com/lhqxinghun/scKTLD.
Assuntos
Cromatina , Cromossomos , GenomaRESUMO
MOTIVATION: The emerging single-cell Hi-C technology provides opportunities to study dynamics of chromosomal organization. How to construct a pseudotime path using single-cell Hi-C contact matrices to order cells along developmental trajectory is a challenging topic, since these matrices produced by the technology are inherently high dimensional and sparse, they suffer from noises and biases, and the topology of trajectory underlying them may be diverse. RESULTS: We present scHiCPTR, an unsupervised graph-based pipeline to infer pseudotime from single-cell Hi-C contact matrices. It provides a workflow consisting of imputation and embedding, graph construction, dual graph refinement, pseudotime calculation and result visualization. Beyond the few existing methods, scHiCPTR ties to optimize graph structure by two parallel procedures of graph pruning, which help reduce the spurious cell links resulted from noises and determine a global developmental directionality. Besides, it has an ability to handle developmental trajectories with multiple topologies, including linear, bifurcated and circular ones, and is competitive with methods developed for single-cell RNA-seq data. The comparative results tell that our scHiCPTR can achieve higher performance in pseudotime inference, and the inferred developmental trajectory exhibit a reasonable biological significance. AVAILABILITY AND IMPLEMENTATION: scHiCPTR is freely available at https://github.com/lhqxinghun/scHiCPTR. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Assuntos
Análise de Célula Única , Sequenciamento do Exoma , Fluxo de TrabalhoRESUMO
BACKGROUND: The characteristics of patients with colorectal cancer who have benign mesenteric lymph node enlargement are not well documented. OBJECTIVE: The aim of this study is to assess the clinical and prognostic significance of benign mesenteric lymph node enlargement in patients with colorectal cancer. DESIGN: This is a prospective cohort study. SETTING: This study was conducted at multitertiary institutions. PATIENTS: We included 601 patients with stage 0, I, and II colorectal cancer in Tianjin, Shandong, and Zhejiang from January 2010 to April 2014. Patients underwent curative surgery and were separated into 2 groups by the presence of benign mesenteric lymph node enlargement: the enlargement group (n = 275) and the control group (n = 326). MAIN OUTCOME MEASURES: Univariate log rank and multivariate Cox regression analyses were constructed to identify risk factors for recurrence and mortality. RESULTS: The risk of recurrence in the enlargement group after curative resection was significantly lower than in the control group, with the 1-, 3-, and 5-year disease-free survival rates being 97.1%, 91.6%, and 86.9% in the enlargement group and 95.7%, 86.2%, and 78.2% in the control group (p = 0.004). The postoperative 1-, 3-, and 5-year overall survival rates were 99.6%, 94.9%, and 90.5% in the enlargement group and 99.4%, 91.4%, and 82.1% in the control group (p = 0.001). Patients in the enlargement group had a higher percentage of patients at a younger age, family tumor history, right-sided tumors, and larger tumor size compared with the control group. For patients in the enlargement group, no significant correlation was observed between the number of enlarged lymph nodes and disease-free survival or overall survival (p = 0.113 and 0.386). Adjusted Cox regression model showed that benign mesenteric lymph node enlargement was an independent prognostic risk factor for both disease-free survival (HR, 0.587; 95% CI, 0.399-0.861; p = 0.007) and overall survival (HR, 0.506; 95% CI, 0.328-0.779; p = 0.002). LIMITATIONS: No immunological results could be compared with clinicopathological findings. CONCLUSIONS: The study indicates that benign mesenteric lymph node enlargement can be a useful positive factor in predicting recurrence and long-term survival concerning patients with colorectal cancer. See Video Abstract at http://links.lww.com/DCR/B785. CARACTERSTICAS PRONSTICAS DE LOS PACIENTES PORTADORES DE CNCER COLORRECTAL CON AGRANDAMIENTO BENIGNO DE LOS GANGLIOS LINFTICOS MESENTRICOS UN ESTUDIO DE COHORTE MULTIINSTITUCIONAL: ANTECEDENTES:Las características de los pacientes portadores de cáncer colorrectal con agrandamiento benigno de los ganglios linfáticos mesentéricos no se encuentran bien documentados.OBJETIVO:El objetivo de este estudio es evaluar la importancia clínica y pronóstica del agrandamiento benigno de los ganglios linfáticos mesentéricos en pacientes con cáncer colorrectal.DISEÑO:Este es un estudio de cohorte de tipo prospectivo.AJUSTE:Este estudio se llevó a cabo en instituciones de educación superior.PACIENTES:Incluimos a 601 pacientes con cáncer colorrectal en estadio 0, I, II en Tianjin, Shandong y Zhejiang desde enero de 2010 hasta abril de 2014. Los pacientes fueron sometidos a cirugía curativa y fueron separaron en dos grupos tomando en cuenta la presencia del agrandamiento benigno de los ganglios linfáticos mesentéricos: grupo con agrandamiento (n = 275) y grupo control (n = 326).PRINCIPALES MEDIDAS DE RESULTADO:Se construyeron análisis de rango logarítmico de una variante y de regresión de Cox con variante múltiple para identificar los factores de riesgo de recurrencia y mortalidad.RESULTADOS:El riesgo de recurrencia en el grupo con agrandamiento tras la resección curativa fue significativamente menor que en el grupo de control, con tasas de periodo libre de enfermedad a los 1, 3 y 5 años de 97,1, 91,6, y 86,9% en el grupo de agrandamiento y con tasas de 95,7, 86,2, y 78,2% en el grupo control respectivamente (p = 0,004). Las tasas postoperatorias de supervivencia general a los 1, 3 y 5 años fueron 99,6, 94,9, y 90,5% en el grupo de agrandamiento y de 99,4, 91,4, y 82,1% en el grupo de control, respectivamente (p = 0,001). Los pacientes del grupo con agrandamiento tenían un porcentaje más elevado de menor edad, antecedente familiar tumoral, tumores del lado derecho y de mayor tamaño tumoral con respecto al grupo de control. Para los pacientes con agrandamiento, no se observó una correlación significativa entre el número de ganglios linfáticos agrandados y el periodo libre de enfermedad o la supervivencia general (p = 0,113 y 0,386). El modelo de regresión de Cox ajustado mostró que el agrandamiento benigno de los ganglios linfáticos mesentéricos era un factor de riesgo pronóstico independiente tanto para la supervivencia libre de enfermedad (cociente de riesgo 0,587; IC del 95%: 0,399-0,861; p = 0,007) como para la supervivencia global (cociente de riesgo 0,506; IC del 95%: 0,328- 0,779; p = 0,002).LIMITACIONES:No fue posible comparar los resultados inmunológicos con los hallazgos clínico-patológicos.CONCLUSIONES:El estudio indica que el agrandamiento benigno de los ganglios linfáticos mesentéricos puede ser un factor positivo útil para predecir la recurrencia y la supervivencia a largo plazo en pacientes con cáncer colorrectal. Consulte Video Resumen en http://links.lww.com/DCR/B785. (Traducción-Dr. Osvaldo Gauto).
Assuntos
Neoplasias Colorretais , Linfonodos , Estudos de Coortes , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Humanos , Linfonodos/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Estudos RetrospectivosRESUMO
OBJECTIVE: Watson for Oncology (WFO), an artificial intelligence from IBM Corporation, can provide a treatment plan by analyzing patient's disease characteristics. The present study was performed to examine the concordance between treatment recommendations proposed by WFO and the multidisciplinary tumor board at our center. The aim was to explore the feasibility of using WFO for breast cancer cases in China and to ascertain the ways to make WFO more suitable for Chinese patients with breast cancer. METHODS: Data from 302 breast cancer patients treated at the Second Affiliated Hospital of Xi'an Jiaotong University between October 2016 and February 2018 was retrieved and retrospectively analyzed by WFO. The recommendations were divided into 'recommended', 'considered' and 'not recommended' groups. Results were considered concordant when oncologists' recommendations were categorized as 'recommended' or 'for consideration' by WFO. RESULTS: The concordance rate of 200 subjects with postoperative adjuvant therapy was 77%. However, the rate was 27.5% in the remaining 102 cases with metastatic disease receiving either first-line or no treatment. Further analysis demonstrated that inconsistencies were mainly due to different choices of chemotherapy regimens. Subgroup study indicates that tumor stage, receptor status and age also had influences at the concordance rate. CONCLUSION: The results of this study suggest that WFO is a promising artificial intelligence system for the treatment of breast cancer. These findings can also serve as a reference framework for the inclusion of artificial intelligence in the ongoing medical reform in China.
Assuntos
Inteligência Artificial , Neoplasias da Mama/terapia , Diretrizes para o Planejamento em Saúde , Pesquisa Interdisciplinar , Oncologia , Adulto , Idoso , Neoplasias da Mama/patologia , China , Terapia Combinada , Feminino , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos RetrospectivosRESUMO
Accumulating evidence has identified microRNA-1179 (miR-1179) as a novel cancer-related miRNA that is dysregulated in multiple cancers and plays an important role in regulating cancer development and progression. However, little is known about the role of miR-1179 in non-small cell lung cancer (NSCLC). Thus, in the present study, we aimed to investigate the potential biological function and regulatory mechanism of miR-1179 in NSCLC. The results showed that decreased expression of miR-1179 expression was frequently detected in primary NSCLC tissues and cell lines. Overexpression of miR-1179 suppressed the growth and invasion of NSCLC cells in vitro while its inhibition promoted the opposite effect. Sperm-associated antigen 5 (SPAG5) was an identified as a target gene of miR-1179. Moreover, SPAG5 expression was increased in NSCLC cells and showed an inverse correlation with miR-1179 in NSCLC specimens. SPAG5 knockdown inhibited the growth and invasion of NSCLC cells, results that simulated a similar effect to miR-1179 overexpression. Mechanistic investigations showed that miR-1179 overexpression or SPAG5 knockdown significantly downregulated the activation of Akt signaling. Additionally, SPAG5 overexpression partially reversed the antitumor effect of miR-1179. Overall, our results demonstrated that miR-1179 inhibited the growth and invasion of NSCLC cells by targeting SPAG5 and inhibiting Akt, findings that highlight the importance of the miR-1179/SPAG5/Akt axis in the progression of NSCCL.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proteínas de Ciclo Celular/metabolismo , Neoplasias Pulmonares/metabolismo , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Invasividade NeoplásicaRESUMO
Esophageal adenocarcinoma (EAC) is one of the most common malignancies in the world which is associated the increased prevalence of obesity. In the context of obesity, leptin can directly contribute to progression of EAC. Adiponectin inhibits leptin-induced oncogenic signaling in EAC cells. However, the exact molecular mechanisms linking obesity, adipokines, and EAC remain far from completely understood. In the present study, we tested the role of ubiquitin-like with PHD and ring finger domains 1 (UHRF1) in adiponectin-induced protective effects against leptin-induced EAC cell proliferation. We found that globular adiponectin (gAD) significantly inhibited leptin-induced increase of cell proliferation and decrease of apoptosis in OE 19 cells. Moreover, leptin-induced increase of UHRF1 expression was suppressed by gAD. Compared with normal controls, UHRF1 expression was markedly increased in EAC tissues and cell lines. Silence of UHRF1 increased the expression of cleaved caspase 3 and 9 and Bax, reduced the expression of Bcl-2, promoted apoptosis, and inhibited cell proliferation in OE 19 cells. Overexpression of UHRF1 significantly blocked gAD-induced decrease of cell proliferation and increase of apoptosis in leptin-treated cells. Silence of adiponectin receptor 1/2 (AdipoR1/2) could inhibit gAD-induced decrease of cell proliferation and increase of apoptosis in leptin-treated cells. Silence of AdipoR2, but not AdipoR1, suppressed gAD-induced decrease of UHRF1 expression in leptin-treated cells. The results indicated that gAD inhibited the prooncogenic effects of leptin via AdipoR2-mediated suppression of UHRF1. Our study provides novel insights into the role of UHRF1 in the development of EAC and the mechanism of antitumor effect of gAD.
Assuntos
Adenocarcinoma/metabolismo , Adiponectina/metabolismo , Proteínas Estimuladoras de Ligação a CCAAT/biossíntese , Proliferação de Células , Neoplasias Esofágicas/metabolismo , Leptina/metabolismo , Proteínas de Neoplasias/metabolismo , Receptores de Adiponectina/metabolismo , Adenocarcinoma/patologia , Linhagem Celular Tumoral , Neoplasias Esofágicas/patologia , Humanos , Ubiquitina-Proteína LigasesRESUMO
BACKGROUND: Gastric cancer (GC) is a common malignant disease and microRNAs (miRNAs) have been shown to play important roles in GC tumorigenesis. As the clinical outcome of GC is closely correlated with the clinical stage at the time of diagnosis, early detection and prevention are crucial. This study was designed to evaluate the expression level of plasma miR-23b in patients with GC and investigate the relationship between plasma miR-23b expression level and the prognosis of GC. MATERIAL/METHODS: We recruited 138 patients diagnosed with GC and 50 healthy volunteers. Quantitative real-time PCR (qRT-PCR) was performed to evaluate the expression level of plasma miR-23b in all participants. The association between miR-23b expression and clinicopathological factors as well as survival rates was analyzed. Receiver operator curve (ROC) analysis was carried out to evaluate the diagnostic performance of plasma miR-23b for GC.Univariate and multivariate Cox regression analyses were conducted to determine whether plasma miR-23b was an independent predictor of survival. RESULTS: The expression levels of miR-23b were upregulated in plasma samples from GC patients (P<0.01) and were significantly associated with T stage, distant metastasis, and differentiation. Significantly shorter 5-year overall survival (OS) and disease-free survival (DFS) were observed in patients with higher expression of the miR-23b (P<0.01). The area under the curve (AUC) of high expression of plasma miR-23b to diagnose GC was 0.80 (95% CI: 0.74-0.86, P<0.001). Multivariate analysis revealed that enhanced expression of plasma miR-23b was an independent predictor of OS (P=0.015) and DFS (P=0.004). CONCLUSIONS: Our results indicated that plasma miR-23b was overexpressed in GC patients and high plasma miR-23b expression was associated with poor clinical outcome. Thus, plasma miR-23b may serve as a potential diagnostic biomarker and therapeutic target for GC.
Assuntos
Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias Gástricas/genética , Regulação para Cima/genética , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Masculino , MicroRNAs/sangue , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Sensibilidade e Especificidade , Neoplasias Gástricas/sangue , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/patologiaRESUMO
BACKGROUND: Deoxycholic acid (DCA) promotes the development and progression of esophageal adenocarcinoma (EAC) by inducing inflammation. Adiponectin is reported to have anti-inflammatory and anti-tumor effects. PURPOSE: This study investigated the effects of two types of adiponectin, full-length adiponectin (f-Ad) and globular adiponectin (g-Ad), on DCA-induced inflammation, and investigated the involvement of the reactive oxygen species (ROS)/NF-κB signaling pathway in inflammation in EAC. METHODS: OE19 cells were treated with DCA (50-300 µM) and/or f-Ad/g-Ad (10.0 µg/ml) or N-acetylcysteine (NAC). The viability of cells exposed to DCA was measured by use of the MTT assay. mRNA and protein levels of the inflammatory factors were examined by real-time PCR and ELISA. Intra-cellular ROS levels were determined by use of flow cytometry. Protein levels of total and p-NF-κB p65 were measured by western blot. RESULTS: DCA induced dose and time-dependent cytotoxicity. mRNA and protein expression of TNF-α, IL-8, and IL-6 in cells treated with DCA alone were up-regulated, and intra-cellular ROS and p-NF-κB p65 protein levels were also increased. g-Ad promoted inflammatory factor production, ROS levels, and p-NF-κB p65 protein expression whereas f-Ad had a suppressive effect. When combined with DCA, g-Ad enhanced the pro-inflammatory effect of DCA whereas f-Ad, similar to NAC, suppressed the effect. CONCLUSION: DCA has a pro-inflammatory effect in EAC. f-Ad has an anti-inflammatory effect whereas g-Ad seems to have a pro-inflammatory effect in an ROS/NF-κB p65-dependent manner. This indicates that f-Ad could be a potential anti-inflammatory reagent for cancer therapy.
Assuntos
Adenocarcinoma/prevenção & controle , Adiponectina/fisiologia , Neoplasias Esofágicas/prevenção & controle , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/fisiologia , Fator de Transcrição RelA/fisiologia , Adenocarcinoma/química , Adenocarcinoma/tratamento farmacológico , Adiponectina/uso terapêutico , Linhagem Celular Tumoral , Ácido Desoxicólico , Progressão da Doença , Avaliação Pré-Clínica de Medicamentos , Neoplasias Esofágicas/química , Neoplasias Esofágicas/tratamento farmacológico , Humanos , Inflamação/metabolismo , Inflamação/prevenção & controleRESUMO
Diallyl disulfide (DADS) is a natural organosulfur compound isolated from garlic. DADS has various biological properties, including anticancer, antiangiogenic, and antioxidant effects. However, the anticancer mechanisms of DADS in human esophageal carcinoma have not been elucidated, especially in vivo. In this study, MTT assay showed that DADS significantly reduced cell viability in human esophageal carcinoma ECA109 cells, but was relatively less toxic in normal liver cells. The pro-apoptotic effect of DADS on ECA109 cells was detected by Annexin V-FITC/propidium iodide (PI) staining. Flow cytometry analysis showed that DADS promoted apoptosis in a dose-dependent manner and the apoptosis rate could be decreased by caspase-3 inhibitor Ac-DEVD-CHO. Xenograft study in nude mice showed that DADS treatment inhibited the growth of ECA109 tumor in both 20 and 40 mg/kg DADS groups without obvious side effects. DADS inhibited ECA109 tumor proliferation by down-regulating proliferation cell nuclear antigen (PCNA). DADS induced apoptosis by activating a mitochondria-dependent pathway with the executor of caspase-3, increasing p53 level and Bax/Bcl-2 ratio, and downregulating the RAF/MEK/ERK pathway in ECA109 xenograft tumosr. Based on studies in cell culture and animal models, the findings here indicate that DADS is an effective and safe anti-cancer agent for esophageal carcinoma.
Assuntos
Compostos Alílicos/farmacologia , Antineoplásicos/farmacologia , Carcinoma/metabolismo , Dissulfetos/farmacologia , Neoplasias Esofágicas/metabolismo , Mitocôndrias/metabolismo , Compostos Alílicos/efeitos adversos , Compostos Alílicos/uso terapêutico , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinoma/tratamento farmacológico , Caspase 3/genética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Dissulfetos/efeitos adversos , Dissulfetos/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Humanos , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Antígeno Nuclear de Célula em Proliferação/genética , Antígeno Nuclear de Célula em Proliferação/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismoRESUMO
Groundwater resources are important water sources for people living in arid-semiarid China. To solve the problem of continuously declining groundwater levels, groundwater artificial recharge has been widely conducted by using available aquifers. However, the effects of land use changes on the available aquifer storage, especially on the remaining available aquifer storage (RAAS), have not been fully explored. Here, we quantitatively evaluated the effects of land use changes on the RAAS, exemplifying the Taoerhe alluvial-proluvial fan. Independent component analysis (ICA) is used to determine precipitation- and groundwater extraction-affected RAASs, and regression equations are established for land use type areas and precipitation- and groundwater extraction-affected RAASs through stepwise regression and all-subsets regression. An integrated model combining the future land use simulation (FLUS) model and Markov-chain model is established to predict three land use change scenarios in 2036, and the impacts of land use changes on the precipitation- and groundwater extraction-affected RAASs are evaluated. The results show that land use changes were generally active from 2000 to 2018; during this time, the RAAS showed a fluctuating upward trend. Rational land use changes are critical to the RAAS. In the 2036 baseline scenario, the precipitation-affected RAAS is the smallest and the groundwater extraction-affected RAAS is the largest among the three scenarios, contrary to the economic development scenario results. The woodland conservation scenario shows that the groundwater level can be maintained at a stable level with appropriate woodland protection measures to ensure the stability of the RAAS, providing the most promising results for groundwater development and utilization in the study area. These results temporally quantify the effects of land use changes on the precipitation- and groundwater extraction-affected RAASs and provide a reference for developing artificial recharge schemes in arid-semiarid regions and studying the effects of land use changes on available aquifer storages.
Assuntos
Água Subterrânea , Sistema Renina-Angiotensina , Clima Desértico , Monitoramento Ambiental/métodos , Humanos , ÁguaRESUMO
Phototheranostics stem from the recent advances in nanomedicines and bioimaging to diagnose and treat human diseases. Since tumors' diversity, heterogeneity, and instability limit the clinical application of traditional diagnostics and therapeutics, phototheranostics, which combine light-induced therapeutic and diagnostic modalities in a single platform, have been widely investigated. Numerous efforts have been made to develop phototheranostics for efficient light-induced antitumor therapeutics with minimal side effects. Herein, we review the fundamentals of phototheranostic nanomedicines with their biomedical applications. Furthermore, the progress of near-infrared fluorescence imaging and cancer treatments, including photodynamic therapy and photothermal therapy, along with chemotherapy, immunotherapy, and gene therapy, are summarized. This review also discusses the opportunities and challenges associated with the clinical translation of phototheranostics in pan-cancer research. Phototheranostics can pave the way for future research, improve the quality of life, and prolong cancer patients' survival times.
Assuntos
Nanopartículas , Neoplasias , Fotoquimioterapia , Humanos , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Imagem Óptica , Fotoquimioterapia/métodos , Qualidade de Vida , Nanomedicina Teranóstica/métodosRESUMO
The strategy of structure-inherent tumor targeting (SITT) with cyanine-based fluorophores is receiving more attention because no chemical conjugation of targeting moieties is required. However, the targeting mechanism behind SITT has not yet been well explained. Here, it is demonstrated that heptamethine-cyanine-based fluorophores possess not only targetability of tumor microenvironments without the need for additional targeting ligands but also second near-infrared spectral window (NIR-II) imaging capabilities, i.e., minimum scattering and ultralow autofluorescence. The new SITT mechanism suggests that bone-marrow-derived and/or tissue-resident/tumor-associated immune cells can be a principal target for cancer detection due to their abundance in tumoral tissues. Among the tested, SH1 provides ubiquitous tumor targetability and a high tumor-to-background ratio (TBR) ranging from 9.5 to 47 in pancreatic, breast, and lung cancer mouse models upon a single bolus intravenous injection. Furthermore, SH1 can be used to detect small cancerous tissues smaller than 2â¯mm in diameter in orthotopic lung cancer models. Thus, SH1 could be a promising cancer-targeting agent and have a bright future for intraoperative optical imaging and image-guided cancer surgery.
Assuntos
Neoplasias , Cirurgia Assistida por Computador , Animais , Corantes Fluorescentes , Camundongos , Neoplasias/diagnóstico por imagem , Imagem Óptica/métodos , Cirurgia Assistida por Computador/métodos , Microambiente TumoralRESUMO
Enormous efforts have been made to integrate various therapeutic interventions into multifunctional nanoplatforms, resulting in the advance of nanomedicine. Image-guided drug delivery plays a pivotal role in this field by providing specific targeting as well as image navigation for disease prognosis. Methods: We demonstrate image-guided surgery and drug delivery for the treatment of lung cancer using nanotheranostic H-dots loaded with gefitinib and genistein. Results: The surgical margin for lung tumors is determined by image guidance for precise tumor resection, while targeted anti-cancer drugs function simultaneously for synergistic combination therapy. Compared to conventional chemotherapies, H-dot complexes could improve the therapeutic efficacy of drugs while reducing the risk of adverse effects and drug resistance owing to their ideal biodistribution profiles, high targetability, low nonspecific tissue uptake, and fast renal excretion. Conclusions: These H-dot complexes have unlocked a unique framework for integrating multiple therapeutic and diagnostic modalities into one nanoplatform.
Assuntos
Antineoplásicos , Neoplasias Pulmonares , Nanopartículas , Antineoplásicos/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Nanomedicina Teranóstica/métodos , Distribuição TecidualRESUMO
Resistance to radiotherapy results in relapse and treatment failure in locally advanced esophageal squamous cell carcinoma (ESCC). High mobility group box 1 (HMGB1) is reported to be associated with the radioresistance in bladder and breast cancer. However, the role of HMGB1 in the radiotherapy response in ESCC has not been fully elucidated. Here, we investigated the role of HMGB1 to radioresistance in ESCC clinical samples and cell lines. We found that HMGB1 expression was associated with tumor recurrence after postoperative radiotherapy in locally advanced ESCC patients. HMGB1 knockdown in ESCC cells resulted in increased radiosensitivity both in vitro and in vivo. Autophagy level was found depressed in HMGB1 inhibition cells and activation of autophagy brought back cell's radioresistance. Our results demonstrate that HMGB1 activate autophagy and consequently promote radioresistance. HMGB1 may be used as a predictor of poor response to radiotherapy in ESCC patients. Our finding also highlights the importance of the utility of HMGB1 in ESCC radiosensitization.
Assuntos
Autofagia , Neoplasias Esofágicas/radioterapia , Carcinoma de Células Escamosas do Esôfago/radioterapia , Proteína HMGB1/metabolismo , Tolerância a Radiação/genética , Adulto , Idoso , Animais , Linhagem Celular Tumoral , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/cirurgia , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/cirurgia , Feminino , Técnicas de Silenciamento de Genes , Proteína HMGB1/genética , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico , RNA Interferente Pequeno/genética , Transfecção , Carga Tumoral/genéticaRESUMO
Improving the longterm survival of patients with hepatocellular carcinoma (HCC) remains a challenge due to metastasis and recurrence. In this study, we demonstrate that the overexpression of miR103 in HCC cells promotes epithelialmesenchymal transition (EMT), and is associated with an enhanced metastasis and poor outcomes, as shown by western blot analysis and immunohistochemistry. Mechanistically, using reporter luciferase assay we reveal that the serine/threonineprotein kinase, large tumor suppressor kinase 2 (LATS2), a key component of the Hippo signaling pathway, is a direct target of miR103 in HCC cells. Transwell assay, MTT assay and western blot analysis were performed to reveal that LATS2 can counteract the functional effects of miR103 on HCC metastasis, growth and EMT. The analyses of clinical data indicated that a high expression of miR103 correlated with a high expression of vimentin, but with a low expression of LATS2 and Ecadherin in HCC tissues. miR103 also reduced yesassociated protein (YAP) phosphorylation. On the whole, the findings of this study suggest that miR103 promotes HCC metastasis and EMT by directly inhibiting LATS2. Thus, targeting miR103/LATS2 may prove to be a promising therapeutic strategy for HCC.
Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , MicroRNAs/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Regiões 3' não Traduzidas , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Invasividade Neoplásica , Metástase Neoplásica , Transdução de Sinais , Regulação para CimaRESUMO
Tumor metastasis is the primary factor causing death of cancer patients and it is a study emphasis in cancer treatment to suppress tumor metastasis by inhibiting glycolysis, which is the main way of energy supply for cell mobility in tumor. In the present study, we aimed to explore the effect of quercetin, a bioactive flavonoid, on tumor metastasis and cell glycolysis and its related functionary mechanism in breast cancer progression. Firstly, trans-well invasion assay and wound healing assay indicated that quercetin effectively suppressed cell mobility. The corresponding western blot revealed that quercetin treatment down-regulated the expression of cell migration marker proteins, such as matrix metalloproteinase 2 (MMP-2), MMP-9 and vascular endothelial growth factor (VEGF). The further experiments exhibited that quercetin successfully blocked cell glycolysis by inhibiting the level of glucose uptake and the production of lactic acid, and also decreased the level of glycolysis-related proteins Pyruvate kinase M2 (PKM2), Glucose transporter1(GLUT1) and Lactate dehydrogenase A (LDHA). The above results revealed that quercetin might inhibit glycolysis to limit the migration of tumor cells by reducing the acidity of the tumor microenvironment. Moreover, our further investigation showed that quercetin induced obvious autophagy via inactivating the Akt-mTOR pathway. At the same time, the application of autophagy inhibitor 3-MA and Akt-mTOR pathway inducer IGF-1 further demonstrated that quercetin exerted inhibiting effect on cell mobility and glycolysis through Akt-mTOR pathway mediated autophagy induction. At last, the in vivo experiments also showed that quercetin treatment could suppress tumor growth and metastasis, inhibit glycolysis and induce autophagy through the inhibition of p-AKT/AKT. Taken together, we firstly revealed that quercetin suppressed the progression of breast cancer by inhibiting cell mobility and glycolysis through Akt-mTOR pathway mediated autophagy induction and may provide a potential therapeutic target for breast cancer treatment.
Assuntos
Autofagia , Neoplasias da Mama/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quercetina/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Esophageal-gastric junction adenocarcinoma (AEG) is an aggressive tumor with high incidence and dismal prognosis worldwide. Despite significant advances in therapeutic strategies, the 5-year survival rate still remains low. Diallyl disulfide (DADS), which is one of the major volatile components isolated from garlic, has been shown to have multi-targeted antitumor activities in a variety of cancer cells. However, the exact anti-metastatic effects and underlying molecular mechanisms of DADS in AEG have not been elucidated. The present study demonstrated that DADS inhibited cell viability of OE19 cells with low cytotoxicity to healthy hepatocytes, L02 cells, in vitro. Non-toxic doses of DADS were ≤10 µg/ml for a 24-h treatment. Our data showed that these non-toxic doses of DADS were found to block the metastasis of OE19 cells by suppressing MMPs, increasing u-PA and TIMPs, as well as altering the balance of MMPs/TIMPs, which at least in part resulted from the suppression of NF-κB and PI3K/AKT signaling pathways. The present study provides a previously neglected insight into the investigation of DADS in suppressing tumor metastasis and its underlying molecular mechanisms in vitro. Hence, DADS could be a promising anticancer agent for anti-metastatic treatment of AEG in the future.
Assuntos
Adenocarcinoma/metabolismo , Compostos Alílicos/farmacologia , Anticarcinógenos/farmacologia , Dissulfetos/farmacologia , Neoplasias Esofágicas/metabolismo , Junção Esofagogástrica/patologia , Transdução de Sinais/efeitos dos fármacos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Junção Esofagogástrica/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Técnicas In Vitro , Metaloproteinases da Matriz/metabolismo , NF-kappa B/metabolismo , Metástase Neoplásica , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Inibidores Teciduais de Metaloproteinases/metabolismoRESUMO
Barrett's esophagus (BE) is generally accepted as the only precursor to esophageal adenocarcinoma (EAC). Deoxycholic acid (DCA)-induced inflammation and apoptotic resistance play an important role in the carcinogenesis and progression from BE to EAC. Diallyl disulfide (DADS) is a garlic-derived natural organosulfur compound. This study investigated whether DADS has chemopreventive effects against BE and the potentially related signaling pathway. BAR-T cells were treated with DCA in the presence or absence of DADS. An MTT assay was used to detect the viability of the cells. The apoptosis rate of the cells was measured by light microscopy and flow cytometry. ROS levels were determined by fluorescence microscopy and flow cytometry. Real-time PCR and ELISA were used to detect mRNA and protein levels, respectively. The levels of target proteins were also determined by western blot analysis. DADS did not inhibit cell viability in a certain concentration range. DADS, similar to the NF-κB inhibitor PDTC, inhibited the DCA-induced ROS production, inflammatory factors, IκBα phosphorylation, and expression of p50 in the nucleus in a dose-dependent manner. DADS also increased the cell apoptosis rate through down-regulating the level of Bcl-2. DADS has low cytotoxicity in BAR-T cells. It has an anti-inflammatory effect in BAR-T cells through inhibiting ROS and the NF-κB signaling pathway. Further, it abolishes the apoptotic resistance induced by DCA in an NF-κB/Bcl-2 dependent manner. DADS may be a good candidate for BE and EAC chemical prevention and therapy.
Assuntos
Compostos Alílicos/farmacologia , Apoptose/efeitos dos fármacos , Dissulfetos/farmacologia , Inflamação/tratamento farmacológico , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Compostos Alílicos/uso terapêutico , Anti-Hipertensivos/farmacologia , Ácido Desoxicólico/farmacologia , Dissulfetos/uso terapêutico , Células Epiteliais/metabolismo , Humanos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
MiR-195, a novel cancer-related microRNA, was previously reported to play an important role in many malignancies. This study aimed to investigate the role of miR-195 mediated epithelial-mesenchymal transition (EMT) and the progression of hepatocellular carcinoma (HCC) as well as the underlying mechanisms. Our result demonstrated that miR-195 were significantly down regulated in HCC and its decreased expression is associated with poor clinical features of HCC patients. Oppositely, expression level of YAP was significantly higher in HCC tissues, and the level of YAP in metastatic tissues was significantly higher. We also found that a strong inversely association between low level expression of miR-195 and high level of YAP in HCC tissues. Notably, this study confirmed that miR-195, YAP and their combination were valuable predictors for the prognosis of HCC patients. We also explored that miR-195 inhibits HCC growth and metastatic capacity. Mechanistically, we confirm that miR-195 inhibits the migration, invasion and EMT of HCC cells by suppressing YAP. Lastly, we revealed YAP was not only the downstream of miR-195 in HCC, but also mediated the promoting effects of miR-195 on the metastasis and EMT of HCC cells. Taken together, miR-195 inhibits the metastasis and EMT in HCC by targeting YAP. MiR-195/YAP pathway may potentially act as novel biomarker and attractive therapeutic target in HCC.