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Gut microbiota are linked to chronic inflammation and carcinogenesis. Chemotherapy failure is the major cause of recurrence and poor prognosis in colorectal cancer patients. Here, we investigated the contribution of gut microbiota to chemoresistance in patients with colorectal cancer. We found that Fusobacterium (F.) nucleatum was abundant in colorectal cancer tissues in patients with recurrence post chemotherapy, and was associated with patient clinicopathological characterisitcs. Furthermore, our bioinformatic and functional studies demonstrated that F. nucleatum promoted colorectal cancer resistance to chemotherapy. Mechanistically, F. nucleatum targeted TLR4 and MYD88 innate immune signaling and specific microRNAs to activate the autophagy pathway and alter colorectal cancer chemotherapeutic response. Thus, F. nucleatum orchestrates a molecular network of the Toll-like receptor, microRNAs, and autophagy to clinically, biologically, and mechanistically control colorectal cancer chemoresistance. Measuring and targeting F. nucleatum and its associated pathway will yield valuable insight into clinical management and may ameliorate colorectal cancer patient outcomes.
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Autofagia , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Fusobacterium nucleatum/fisiología , Microbioma Gastrointestinal , Animales , Antineoplásicos/uso terapéutico , Capecitabina/uso terapéutico , Neoplasias Colorrectales/metabolismo , Resistencia a Antineoplásicos , Xenoinjertos , Ratones , MicroARNs/metabolismo , Trasplante de Neoplasias , Compuestos de Platino/uso terapéutico , Recurrencia , Receptores Toll-Like/metabolismo , Microambiente TumoralRESUMEN
Valproic acid (VPA) is a primary medication for epilepsy, yet its hepatotoxicity consistently raises concerns among individuals. This study aims to establish an automated machine learning (autoML) model for forecasting the risk of abnormal increase of transaminase levels while undergoing VPA therapy for 1995 epilepsy patients. The study employed the two-tailed T test, Chi-square test, and binary logistic regression analysis, selecting six clinical parameters, including age, stature, leukocyte count, Total Bilirubin, oral dosage of VPA, and VPA concentration. These variables were used to build a risk prediction model using "H2O" autoML platform, achieving the best performance (AUC training = 0.855, AUC test = 0.789) in the training and testing data set. The model also exhibited robust accuracy (AUC valid = 0.742) in an external validation set, underscoring its credibility in anticipating VPA-induced transaminase abnormalities. The significance of the six variables was elucidated through importance ranking, partial dependence, and the TreeSHAP algorithm. This novel model offers enhanced versatility and explicability, rendering it suitable for clinicians seeking to refine parameter adjustments and address imbalanced data sets, thereby bolstering classification precision. To summarize, the personalized prediction model for VPA-treated epilepsy, established with an autoML model, displayed commendable predictive capability, furnishing clinicians with valuable insights for fostering pharmacovigilance.
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Anticonvulsivantes , Epilepsia , Aprendizaje Automático , Ácido Valproico , Humanos , Epilepsia/tratamiento farmacológico , Anticonvulsivantes/efectos adversos , Femenino , Masculino , Adulto , Adolescente , Persona de Mediana Edad , Adulto Joven , Niño , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Transaminasas/sangre , Preescolar , AncianoRESUMEN
Combatting land damage has become a global priority, and China has adopted a series of ecological engineering measures, especially in the agro-pastoral area with fragile ecological environment. The effectiveness of ecological engineering construction (EEC), from a comprehensive recognition encompassing its quality, quantity, and function, has remained largely unknown. To this end, Zhangbei County, a typical agro-pastoral ecotone of northern China, was chosen as our focal area. After summarizing the timelines, aims and results of the EEC during various periods in Zhangbei, the linear spectral mixture analysis was employed to process Landsat 5 TM images in 2000 and 2010, as well as Landsat 8 OLI images in 2020. Then, a comprehensive evaluation framework of EEC was established from the perspective of "quantity-quality-function", and the ecological effectiveness of EEC was evaluated from 2000 to 2020 in Zhangbei. Results revealed that EEC played a critical role in enhancing quantity, quality and function, in spite of that, there were still numerous regions showing varying degrees of degradation in terms of these aspects. Then, by extending the three-dimensional cube as the theoretical basis for the zoning management of EEC, we merged four zones according to the space matching relationship among quantity, quality and function of EEC, namely, Ecological conservation area, Ecological improvement area, Ecological restoration area and Ecological remodeling zone. More targeted ecological measures were required for specific matching relationship among quantity, quality and function of EEC. This study is expected to present an empirical case for assessing the ecological effectiveness of EEC in areas or countries with similar restoration demand and support regional management.
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Conservación de los Recursos Naturales , Ecología , China , Agricultura , Ecosistema , IngenieríaRESUMEN
The high-density Industrial Internet of Things needs to meet the requirements of high-density device access and massive data transmission, which requires the support of multiple-input multiple-output (MIMO) antenna cognitive systems to keep high throughput. In such a system, spectral efficiency (SE) optimization based on dynamic power allocation is an effective way to enhance the network throughput as the channel quality variations significantly affect the spectral efficiency performance. Deep learning methods have illustrated the ability to efficiently solve the non-convexity of resource allocation problems induced by the channel multi-path and inter-user interference effects. However, current real-valued deep-learning-based power allocation methods have failed to utilize the representational capacity of complex-valued data as they regard the complex-valued channel data as two parts: real and imaginary data. In this paper, we propose a complex-valued power allocation network (AttCVNN) with cross-channel and in-channel attention mechanisms to improve the model performance where the former considers the relationship between cognitive users and the primary user, i.e., inter-network users, while the latter focuses on the relationship among cognitive users, i.e., intra-network users. Comparison experiments indicate that the proposed AttCVNN notably outperforms both the equal power allocation method (EPM) and the real-valued and the complex-valued fully connected network (FNN, CVFNN) and shows a better convergence rate in the training phase than the real-valued convolutional neural network (AttCNN).
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Internet de las Cosas , Industrias , Internet , Redes Neurales de la Computación , Asignación de RecursosRESUMEN
It has become increasingly important to consider its productivity for agricultural soil health assessment. Moreover, one of the main challenges is that there are still few studies on addressing the complex dynamics of soil health assessment by the rapid and cross-regional method. Thus, we proposed a novel conceptual model to evaluate agricultural soil health in order to highlight the synergy and interaction of natural soil productivity and its external inputs; besides, the new proposed soil health index (SHI) can be used to rapidly quantify their influences of soil productivity on soil health assessment, based on the 10-day normalized difference vegetation index (NDVI) time series data. We applied the principal component analysis (PCA) to transform NDVI profiles into responses of crop primary productivity due to different drivers. The results demonstrated that soil productivity in our study area can be identified for different cropping systems by the PCA method; and different principle components (PCs) for the same cropping system can also be used to estimate contributions of natural soil productivity and human management productivity. The SHI indicator, defined by the equation of (PC1-PC2)/(PC1+PC2), was used to explore soil health in our study area. We found that soil in the orchard system was relatively healthier than that in other two cropping systems, indicating the natural soil productivity presented more contributions than that from external inputs. We concluded that it is useful to apply the SHI indicator into soil health assessment, especially considering the local natural situation and human management practices.
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Agricultura , Suelo , Producción de Cultivos , Eficiencia , HumanosRESUMEN
Despite their important contribution to the economic domain, active heat-releasing industrial plants have significant implications for human health and climate change. However, a spatially detailed dataset of various heat-releasing industrial sectors and large-scale characterization of heat emissions from industrial sources have not been reported yet. In this study, a dataset of heat-releasing industries was established using a national detection map of thermal anomalies produced by a novel and more accurate method employing daily nighttime visible infrared imaging radiometer suite thermal infrared images corresponding to 1 year. Subsequently, we quantified the dimensional features of heat radiation fluxes of China's industrial plants. A total of 12 114 industrial objects were structured in a two-level hierarchical dataset of heat-releasing industries, representing a magnitude of at least 1 order higher than the number enumerated in the state-of-the-art inventory of industrial heat sources across China. The satellite observations helped more completely characterize industrial heat plumes, which represent the industrial heat radiation fluxes with higher levels of densities that prevail in the central-eastern part of China having spatial clustering islands. Our results could be used to inform policy and environmental management in relation to meaningful dynamic industrial supervision, targeting extreme polluters and differentiated emission mitigation measurements.
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Calor , Industrias , China , Cambio Climático , Humanos , Análisis EspacialRESUMEN
OBJECTIVE To analyze the data of non-invasive prenatal testing based on specific loci of circulating cell-free fetal DNA (cffDNA). METHODS Selected loci of target chromosomes were analyzed by sequence capture and sequencing. Meanwhile, 600 loci were selected from other chromosomes for determining the concentration of cffDNA. RESULTS A total of 768 specific loci were captured on chromosomes 21 and 18, and used to determine whether the two were abnormal. When the minimum concentration of detected cffDNA was set at 3% and the threshold of Z score was set to [-6,6], the specificity of the analysis was 99.37% and the sensitivity was 100%. CONCLUSION A reliable, convenient and low-cost analytical method has been developed. The method requires less sequencing data for non-invasive prenatal testing, and can accurately detect abnormalities of fetal chromosomes 21 and 18, and simultaneously determine the concentration of cffDNA.
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Ácidos Nucleicos Libres de Células/genética , Feto/metabolismo , Sitios Genéticos/genética , Diagnóstico Prenatal/métodos , Algoritmos , Ácidos Nucleicos Libres de Células/química , Trastornos de los Cromosomas/diagnóstico , Trastornos de los Cromosomas/genética , Femenino , Frecuencia de los Genes , Humanos , Polimorfismo de Nucleótido Simple , Embarazo , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Análisis de Secuencia de ADN/métodosRESUMEN
Deregulation of the mammalian target of rapamycin pathway (mTOR pathway) is associated with human cancer. The relationship between mTOR pathway and histone acetylation is still unclear in gastric cancer (GC). Immunohistochemistry was used to examine the phosphorylation of mTOR and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) in GC tissues. MKN45 and SGC7901 cells were treated with the mTOR inhibitor rapamycin (RAPA) alone or in combination with the phosphatidylinositol 3-kinase inhibitor LY294002 and the histone deacetylase (HDAC) inhibitor trichostatin A (TSA). Small interfering RNA (siRNA) technology was also used to knockdown mTOR. Phosphorylated mTOR and phosphorylated 4E-BP1 were expressed in 71.1% and 68.4% of the human GC tissues tested, respectively; significantly higher than the levels in para-cancerous tissues (50% and 57.9%) and normal tissues (44.6% and 29%). RAPA markedly inhibited cell proliferation, induced G1 cell cycle arrest, and reduced phosphorylation of p70 S6 protein kinase (p70S6K) and 4E-BP1 in GC cells, particularly when used in combination with LY294002 or TSA. The mRNA expression of the tumour suppressor gene p21(WAF1) increased significantly in GC cells treated with both RAPA and TSA. Histone acetylation also increased after RAPA and TSA treatment or siRNA knockdown of mTOR. Our findings suggest that the mTOR pathway is activated in GC, and also that inhibition of mTOR enhances the ability of TSA to suppress cell proliferation and lead to cell cycle arrest via increasing histone acetylation and p21(WAF1) transcription in human MKN45 and SGC7901 GC cells.
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Inhibidores de Histona Desacetilasas/farmacología , Histonas/metabolismo , Ácidos Hidroxámicos/farmacología , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Acetilación , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adulto , Anciano , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proteínas de Ciclo Celular , Línea Celular Tumoral , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Humanos , Persona de Mediana Edad , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Fosfoproteínas/metabolismo , Fosforilación/efectos de los fármacos , Interferencia de ARN , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/genética , Regulación hacia Arriba/efectos de los fármacosRESUMEN
The polycomb group protein enhancer of zeste homologue 2 (EZH2), which has histone methyltransferase (HMT) activity, is overexpressed in malignant tumours. However, the role of EZH2 in colorectal cancer (CRC) invasion is little known. Here we investigated the clinical significance, biological effects, and mechanisms of EZH2 signalling. Knockdown of EZH2 significantly reduced cell invasion and secretion of matrix metalloproteinases 2/9 (MMP2/9) in in vitro studies. Knockdown of EZH2 dramatically increased overall survival and decreased metastasis of lung in in vivo studies. Conversely, overexpression of EZH2 significantly increased lung metastasis and shortened overall survival when compared with control tumours. EZH2-induced CRC cell invasion may depend on down-regulation of vitamin D receptor (VDR), which is considered to be a marker of CRC invasion. EZH2 regulates the histone trimethylation of lysine 27 (H3K27me3) in the VDR promoter. Moreover, we found that STAT3 directly binds to the EZH2 promoter and regulates VDR down-regulation in CRC cells. Significant inverse correlations were observed between the expression of EZH2 and pSTAT3 and that of VDR in CRC tissues compared with normal tissue in patients. We show the role of EZH2 in CRC metastasis and identify VDR as a target gene of EZH2. EZH2 expression may be directly regulated by STAT3, and STAT3 may play an important role in EZH2-mediated VDR down-regulation in CRC. This pathway may provide potential targets in aggressive CRC.
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Neoplasias Colorrectales/genética , Regulación Neoplásica de la Expresión Génica , Complejo Represivo Polycomb 2/metabolismo , Receptores de Calcitriol/metabolismo , Factor de Transcripción STAT3/metabolismo , Animales , Secuencia de Bases , Línea Celular Tumoral , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Regulación hacia Abajo , Proteína Potenciadora del Homólogo Zeste 2 , Histona Metiltransferasas , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Lisina/metabolismo , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Metilación , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Datos de Secuencia Molecular , Invasividad Neoplásica , Complejo Represivo Polycomb 2/genética , Interferencia de ARN , Receptores de Calcitriol/genética , Proteínas Recombinantes de Fusión , Factor de Transcripción STAT3/genética , Transducción de SeñalRESUMEN
Immune checkpoint blockade (ICB) therapy has improved treatment effects in multiple cancers. Gene mutations in the DNA damage repair pathway (DDR) may cause genomic instability and may relate to the efficacy of ICB. Checkpoint kinase 2 (CHEK2) and polymerase epsilon (POLE) are important genes in the DDR. In this study, we aimed to study the impact of CHEK2 deficiency mutations on the response to ICB. We found that tumors with CHEK2 mutations had a significantly higher tumor mutational burden (TMB) compared to those with CHEK2-WT in a pancancer database. We noted that CHEK2 deficiency mutations potentiated the anti-tumor effect of anti-PD-1 therapy in MC38 and B16 tumor-bearing mice with the decrease of tumor volume and tumor weight after anti-PD-1 treatment. Mechanistically, CHEK2 deficiency tumors were with the increased cytotoxic CD8+ T-cell infiltration, especially cytotoxic CD8+ T cells, and modulated the tumor-immune microenvironment with an upregulated immune inflammatory pathway and antigen presentation pathway after anti-PD-1 treatment. Furthermore, murine models with POLE mutations confirmed that CHEK2 deficiency shaped similar mutational and immune landscapes as POLE mutations after anti-PD-1 treatment. Taken together, our results demonstrated that CHEK2 deficiency mutations may increase the response to ICB (eg. anti-PD-1) by influencing the tumor immune microenvironment. This indicated that CHEK2 deficiency mutations were a potentially predictive biomarker and CHEK2 deficiency may potentiate response to immunotherapy.
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Inhibidores de Puntos de Control Inmunológico , Neoplasias , Ratones , Animales , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Linfocitos T CD8-positivos , Quinasa de Punto de Control 2/genética , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/patología , Mutación , Inmunoterapia/métodos , Microambiente TumoralRESUMEN
Detecting anomalies in massive volumes of multivariate time series data, particularly in the IoT domain, is critical for maintaining stable systems. Existing anomaly detection models based on reconstruction techniques face challenges in distinguishing normal and abnormal samples from unlabeled data, leading to performance degradation. Moreover, accurately reconstructing abnormal values and pinpointing anomalies remains a limitation. To address these issues, we introduce the Adversarial Time-Frequency Reconstruction Network for Unsupervised Anomaly Detection (ATF-UAD). ATF-UAD consists of a time reconstructor, a frequency reconstructor and a dual-view adversarial learning mechanism. The time reconstructor utilizes a parity sampling mechanism to weaken the dependency between neighboring points. Then attention mechanisms and graph convolutional networks (GCNs) are used to update the feature information for each point, which combines points with close feature relationships and dilutes the influence of abnormal points on normal points. The frequency reconstructor transforms the input sequence into the frequency domain using a Fourier transform and extracts the relationship between frequencies to reconstruct anomalous frequency bands. The dual-view adversarial learning mechanism aims to maximize the normal values in the reconstructed sequences and highlight anomalies and aid in their localization within the data. Through dual-view adversarial learning, ATF-UAD minimizes reconstructed value errors and maximizes the identification of residual outliers. We conducted extensive experiments on nine datasets from different domains, and ATF-UAD showed an average improvement of 6.94% in terms of F1 score compared to the state-of-the-art method.
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Aprendizaje , Femenino , Embarazo , Humanos , Factores de TiempoRESUMEN
The inkjet printing technology based on piezoelectric micro-jets can effectively realize the efficient and high-precision processing of special-shaped structures. In this work, a nozzle-driven piezoelectric micro-jet device is proposed, and its structure and micro-jet process are described. ANSYS two-phase, two-way fluid-structure coupling simulation analysis is carried out, and the mechanism of the piezoelectric micro-jet is described in detail. The effects of voltage amplitude, input signal frequency, nozzle diameter and oil viscosity on the injection performance of the proposed device are studied, and a set of effective control methods is summarized. The correctness of the piezoelectric micro-jet mechanism and the feasibility of the proposed nozzle-driven piezoelectric micro-jet device are proved by experiments, and an injection performance test is carried out. The experimental results are consistent with the ANSYS simulation results, which confirms the correctness of the experiment. Finally, the stability and superiority of the proposed device are verified via comparation experiments.
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Over-exploitation of groundwater due to intensive irrigation and anticipated climate change pose severe threats to the water and food security worldwide, particularly in the North China Plain (NCP). Limited irrigation has been recognized as an effective way to improve crop water productivity and slow the rapid decline of groundwater levels. Whether optimized limited irrigation strategies could achieve a balance between groundwater pumping and grain production in the NCP under future climate change deserves further study. In this study, an improved Soil and Water Assessment Tool (SWAT) model was used to simulate climate change impacts on shallow groundwater levels and crop production under limited irrigation strategies to suggest optimal irrigation management practices under future climate conditions in the NCP. The simulations of eleven limited irrigation strategies for winter wheat with targeted irrigations at different growth stages and with irrigated or rainfed summer maize were compared with future business-as-usual management. Climate change impacts showed that mean wheat (maize) yield under adequate irrigation was expected to increase by 13.2% (4.9%) during the middle time period (2041-2070) and by 11.2% (4.6%) during the late time period (2071-2100) under three SSPs compared to the historical period (1971-2000). Mean decline rate of shallow groundwater level slowed by approximately 1 m a-1 during the entire future period (2041-2100) under three SSPs with a greater reduction for SSP5-8.5. The average contribution rate of future climate toward the balance of shallow groundwater pumping and replenishment was 62.9%. Based on the simulated crop yields and decline rate of shallow groundwater level under the future climate, the most appropriate limited irrigation was achieved by applying irrigation during the jointing stage of wheat with rainfed maize, which could achieve the groundwater recovery and sustainable food production.
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Cambio Climático , Agua Subterránea , Producción de Cultivos , Agua , China , Triticum , Riego AgrícolaRESUMEN
Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy; however, their application is limited by the occurrence of immune-related adverse events. The gut microbiota plays important roles in the response to and toxicity of immunotherapy and Faecalibacterium prausnitzii (F. prausnitzii) has been shown to possess immunomodulatory potential. Here, we found that patients receiving ICIs who developed colitis had a lower abundance of F. prausnitzii. In vivo, immunocompetent mice administered with dextran sodium sulfate and immunodeficient NSG mice with human peripheral blood mononuclear cell transfer were treated with ICIs to study ICI-induced colitis. Dual CTLA4 and PD-1 blockade exacerbated autoimmune colitis, activated an inflammatory response, and promoted myeloid cell infiltration, with higher percentages of macrophages, dendritic cells, monocytes, and neutrophils. F. prausnitzii administration mitigated the exacerbated colitis induced by ICIs. Concomitantly, F. prausnitzii enhanced the antitumor immunity elicited by ICIs in tumor-bearing mice while abrogating colitis. In addition, administration of F. prausnitzii increased gut microbial alpha diversity and modulated the microbial composition, increasing a subset of gut probiotics and decreasing potential gut pathogens. F. prausnitzii abundance was reduced in mice that developed ICI-associated colitis. Together, this study shows that F. prausnitzii administration ameliorates ICI-induced colitis, reshapes the gut microbial composition, and enhances the antitumor activity of immunotherapy. SIGNIFICANCE: F. prausnitzii alleviates colitis while enhancing the tumor-suppressive effects of immune checkpoint blockade, indicating that supplementation with F. prausnitzii could be a treatment strategy to mitigate immunotherapy toxicity in patients with cancer.
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Colitis , Neoplasias , Humanos , Ratones , Animales , Faecalibacterium prausnitzii , Receptor de Muerte Celular Programada 1 , Leucocitos Mononucleares , Antígeno CTLA-4 , Colitis/inducido químicamenteRESUMEN
Colorectal carcinogenesis coincides with immune cell dysfunction. Metformin has been reported to play a role in stimulating antitumor immunity, suggesting it could be used to overcome immunosuppression in colorectal cancer. Herein, using single-cell RNA sequencing (scRNA-seq), we showed that metformin remodels the immune landscape of colorectal cancer. In particular, metformin treatment expanded the proportion of CD8+ T cells and potentiated their function. Analysis of the metabolic activities of cells in the colorectal cancer tumor microenvironment (TME) at a single-cell resolution demonstrated that metformin reprogrammed tryptophan metabolism, which was reduced in colorectal cancer cells and increased in CD8+ T cells. Untreated colorectal cancer cells outcompeted CD8+ T cells for tryptophan, leading to impaired CD8+ T-cell function. Metformin in turn reduced tryptophan uptake by colorectal cancer cells, thereby restoring tryptophan availability for CD8+ T cells and increasing their cytotoxicity. Metformin inhibited tryptophan uptake in colorectal cancer cells by downregulating MYC, which led to a reduction in the tryptophan transporter SLC7A5. This work highlights metformin as an essential regulator of T-cell antitumor immunity by reprogramming tryptophan metabolism, suggesting it could be a potential immunotherapeutic strategy for treating colorectal cancer. SIGNIFICANCE: Analysis of the impact of metformin on the colorectal cancer immunometabolic landscape at a single-cell resolution shows that metformin alters cancer cell tryptophan metabolism to stimulate CD8+ T-cell antitumor activity.
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Neoplasias Colorrectales , Metformina , Humanos , Metformina/farmacología , Metformina/uso terapéutico , Triptófano , Linfocitos T CD8-positivos , Terapia de Inmunosupresión , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Microambiente TumoralRESUMEN
Chronic inflammation and oncogenic pathway activation are key-contributing factors in colorectal cancer pathogenesis. However, colorectal intrinsic mechanisms linking these two factors in cancer development are poorly defined. Here, we show that intestinal epithelial cell (IEC)-specific deletion of Dot1l histone methyltransferase (Dot1lΔIEC ) reduced H3K79 dimethylation (H3K79me2) in IECs and inhibited intestinal tumor formation in ApcMin - and AOM-DSS-induced colorectal cancer models. IEC-Dot1l abrogation was accompanied by alleviative colorectal inflammation and reduced Wnt/ß-catenin signaling activation. Mechanistically, Dot1l deficiency resulted in an increase in Foxp3+RORÏ+ regulatory T (Treg) cells and a decrease in inflammatory Th17 and Th22 cells, thereby reducing local inflammation in the intestinal tumor microenvironment. Furthermore, Dot1l deficiency caused a reduction of H3K79me2 occupancies in the promoters of the Wnt/ß-catenin signaling genes, thereby diminishing Wnt/ß-catenin oncogenic signaling pathway activation in colorectal cancer cells. Clinically, high levels of tumor H3K79me2 were detected in patients with colorectal carcinomas as compared to adenomas, and negatively correlated with RORÏ+FOXP3+ Treg cells. Altogether, we conclude that DOT1L is an intrinsic molecular node connecting chronic immune activation and oncogenic signaling pathways in colorectal cancer. Our work suggests that targeting the DOT1L pathway may control colorectal carcinogenesis. Significance: IEC-intrinsic DOT1L controls T cell subset balance and key oncogenic pathway activation, impacting colorectal carcinogenesis.
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Neoplasias Colorrectales , N-Metiltransferasa de Histona-Lisina , Subgrupos de Linfocitos T , Carcinogénesis/metabolismo , Neoplasias Colorrectales/patología , Factores de Transcripción Forkhead/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Inflamación , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/patología , Microambiente Tumoral , Vía de Señalización Wnt , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
Aiming to identify rare high-penetrance mutations in new genes for the underlying predisposition in familial colorectal cancer (CRC), we performed whole-exome sequencing in 24 familial CRCs. Mutations in genes that regulate DNA repair (RMI1, PALB2, FANCI) were identified that were related to the Fanconi anemia DNA repair pathway. In one pedigree, we found a nonsense mutation in CHEK2. CHEK2 played an essential role in cell cycle and DNA damage repair. Somatic mutation analysis in CHEK2 variant carriers showed mutations in TP53, APC, and FBXW7. Loss of heterozygosity was found in carcinoma of CHEK2 variant carrier, and IHC showed loss of Chk2 expression in cancer tissue. We identified a second variant in CHEK2 in 126 sporadic CRCs. A KO cellular model for CHEK2 (CHEK2KO) was generated by CRISPR/Cas9. Functional experiments demonstrated that CHEK2KO cells showed defective cell cycle arrest and apoptosis, as well as reduced p53 phosphorylation, upon DNA damage. We associated germline mutations in genes that regulate the DNA repair pathway with the development of CRC. We identified CHEK2 as a regulator of DNA damage response and perhaps as a gene involved in CRC germline predisposition. These findings link CRC predisposition to the DNA repair pathway, supporting the connection between genome integrity and cancer risk.
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Quinasa de Punto de Control 2/genética , Neoplasias Colorrectales/genética , Reparación del ADN/genética , Predisposición Genética a la Enfermedad/genética , Proteína de la Poliposis Adenomatosa del Colon/genética , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis/genética , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/genética , Quinasa de Punto de Control 2/metabolismo , Neoplasias Colorrectales/metabolismo , Daño del ADN , Proteínas de Unión al ADN/genética , Proteína 7 que Contiene Repeticiones F-Box-WD/genética , Proteína del Grupo de Complementación N de la Anemia de Fanconi/genética , Proteínas del Grupo de Complementación de la Anemia de Fanconi/genética , Femenino , Técnicas de Inactivación de Genes , Mutación de Línea Germinal , Humanos , Pérdida de Heterocigocidad , Masculino , Persona de Mediana Edad , Linaje , Fosforilación/genética , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Secuenciación del Exoma , Adulto JovenRESUMEN
The research object of the present paper is the water quality of Han Shiqiao wetland water. Water spectrum and quality parameters were measured on the site and in the lab. The authors simulated the relationships between water quality parameters and the best bands or combination, and built the multiple linear regression equation to obtain characteristic spectrum of the key water quality parameters. Besides, several key issues involved in applying ASTER satellite imagery to water quality include atmospheric correction, discussing methods for ASTER data bands analysis, and choosing the best bands and band combination. Results indicated that although the simulation model is not universal, the analysis of spectral characteristics based on ground spectrometer could provide foundations for the choice of remote sensing characteristics bands. The band ratio of water quality parameters simulated from ASTER spectral characteristics moves to relatively long-wave band. Finally, based on the analysis of ASTER remote sensing characteristics bands, the authors built water quality parameters regression model. The models for water quality parameters were recommended, and the accuracies of these models were analyzed. Making use of regression model, we executed spatial distribution map of water quality parameters to achieve wetland water monitoring with remote sensing in terms of variation in space and with time.