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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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Conservação dos Recursos Naturais , Ecologia , China , Agricultura , Ecossistema , EngenhariaRESUMO
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 , Aprendizado de Máquina , Ácido Valproico , Humanos , Epilepsia/tratamento farmacológico , Anticonvulsivantes/efeitos adversos , Feminino , Masculino , Adulto , Adolescente , Pessoa de Meia-Idade , Adulto Jovem , Criança , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Transaminases/sangue , Pré-Escolar , IdosoRESUMO
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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Inibidores de Checkpoint Imunológico , Neoplasias , Camundongos , Animais , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Linfócitos T CD8-Positivos , Quinase do Ponto de Checagem 2/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Mutação , Imunoterapia/métodos , Microambiente TumoralRESUMO
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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Aprendizagem , Feminino , Gravidez , Humanos , Fatores de TempoRESUMO
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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Colite , Neoplasias , Humanos , Camundongos , Animais , Faecalibacterium prausnitzii , Receptor de Morte Celular Programada 1 , Leucócitos Mononucleares , Antígeno CTLA-4 , Colite/induzido quimicamenteRESUMO
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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Mudança Climática , Água Subterrânea , Produção Agrícola , Água , China , Triticum , Irrigação AgrícolaRESUMO
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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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 Colorretais , Metformina , Humanos , Metformina/farmacologia , Metformina/uso terapêutico , Triptofano , Linfócitos T CD8-Positivos , Terapia de Imunossupressão , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Microambiente TumoralRESUMO
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 das Coisas , Indústrias , Internet , Redes Neurais de Computação , Alocação de RecursosRESUMO
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 Colorretais , Histona-Lisina N-Metiltransferase , Subpopulações de Linfócitos T , Carcinogênese/metabolismo , Neoplasias Colorretais/patologia , Fatores de Transcrição Forkhead/metabolismo , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Inflamação , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia , Microambiente Tumoral , Via de Sinalização Wnt , beta Catenina/genética , beta Catenina/metabolismoRESUMO
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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Quinase do Ponto de Checagem 2/genética , Neoplasias Colorretais/genética , Reparo do DNA/genética , Predisposição Genética para Doença/genética , Proteína da Polipose Adenomatosa do Colo/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose/genética , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Quinase do Ponto de Checagem 2/metabolismo , Neoplasias Colorretais/metabolismo , Dano ao DNA , Proteínas de Ligação a DNA/genética , Proteína 7 com Repetições F-Box-WD/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Feminino , Técnicas de Inativação de Genes , Mutação em Linhagem Germinativa , Humanos , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade , Linhagem , Fosforilação/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Sequenciamento do Exoma , Adulto JovemRESUMO
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 , Solo , Produção Agrícola , Eficiência , HumanosRESUMO
The enrichment of Enterotoxigenic Bacteroides fragilis (ETBF) has been identified in CRC patients and associated with worse prognosis. Cancer stem cells (CSCs) play essential roles in CRC development. However, whether ETBF is involved in CSCs regulation is unknown. To clarify the role of ETBF in CSCs properties, we performed extreme limited dilution assays (ELDA) in nude mice injected with ETBF-treated or untreated CRC cells subcutaneously, tumor organoids culture in azoxymethane (AOM) mouse model after gavaging with or without ETBF, and cell sphere formation assay after incubating CRC cell lines with or without ETBF. The results indicated that ETBF increased the stemness of CRC cells in vivo and in vitro. Furthermore, ETBF enhanced the expression of core stemness transcription factors Nanog homeobox (NANOG) and sex determining region Y-box 2 (SOX2). Histone H3 Lysine 9 trimethylation (H3K9me3) is critical in regulating CSCs properties. As an epigenetic and transcriptional regulator, JmjC-domain containing histone demethylase 2B (JMJD2B) is essential for embryonic stem cell (ESC) transformation and H3K9me3 demethylation. Mechanistically, ETBF infection significantly upregulated JMJD2B levels in CRC cell lines and nude mice xenograft model. JMJD2B epigenetically upregulated NANOG expression via demethylating its promoter H3K9me3, to mediate ETBF-induced stemness of CRC cells. Subsequently, we found that the Toll-like receptor 4 (TLR4) pathway, activated by ETBF, contributed to the enhanced expression of JMJD2B via nuclear transcription factor nuclear factor of activated T cells 5 (NFAT5). Finally, in human CRC samples, the amount of ETBF positively correlated with nuclear NFAT5, JMJD2B, and NANOG expression levels. In summary, ETBF upregulated JMJD2B levels in a TLR4-NFAT5-dependent pathway, and played an important role in stemness regulation, which promoted colorectal carcinogenesis.
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Bacteroides fragilis/patogenicidade , Neoplasias Colorretais/microbiologia , Neoplasias Colorretais/patologia , Histona Desmetilases com o Domínio Jumonji/metabolismo , Animais , Bacteroides fragilis/metabolismo , Carcinogênese/metabolismo , Carcinogênese/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Proteína Homeobox Nanog/genética , Proteína Homeobox Nanog/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/microbiologia , Células-Tronco Neoplásicas/patologia , Prognóstico , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Receptor 4 Toll-Like/metabolismo , Fatores de Transcrição/metabolismoRESUMO
Background: Novel coronavirus pneumonia (COVID-19) is prevalent around the world. We aimed to describe epidemiological features and clinical course in Shanghai. Methods: We retrospectively analysed 325 cases admitted at Shanghai Public Health Clinical Center, between January 20 and February 29, 2020. Results: 47.4% (154/325) had visited Wuhan within 2 weeks of illness onset. 57.2% occurred in 67 clusters; 40% were situated within 53 family clusters. 83.7% developed fever during the disease course. Median times from onset to first medical care, hospitalization and negative detection of nucleic acid by nasopharyngeal swab were 1, 4 and 8 days. Patients with mild disease using glucocorticoid tended to have longer viral shedding in blood and feces. At admission, 69.8% presented with lymphopenia and 38.8% had elevated D-dimers. Pneumonia was identified in 97.5% (314/322) of cases by chest CT scan. Severe-critical patients were 8% with a median time from onset to critical disease of 10.5 days. Half required oxygen therapy and 7.1% high-flow nasal oxygen. The case fatality rate was 0.92% with median time from onset to death of 16 days. Conclusion: COVID-19 cases in Shanghai were imported. Rapid identification, and effective control measures helped to contain the outbreak and prevent community transmission.
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Infecções por Coronavirus/epidemiologia , Pneumonia Viral/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19 , China/epidemiologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/terapia , Feminino , Seguimentos , Indicadores Básicos de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , Pneumonia Viral/terapia , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Eliminação de Partículas Virais , Adulto JovemRESUMO
BACKGROUND: The coexistence of colorectal polyps with laterally spreading tumors (LSTs) is commonly observed during colonoscopy. However, there are rare studies that assess the malignant risks for LSTs with colorectal polyps, which might largely contribute to further strategies of treatment and follow-up plans in LSTs. METHODS: We conducted a retrospective cohort study that enrolled 206 patients with LSTs in the Endoscopy Center and Endoscopy Research Institute, Renji Hospital, Shanghai Jiao Tong University, China. The subjects with LSTs were divided into two groups: the nonpolyp group with 89 patients and the polyp group with 117 patients. Binary logistic regression was used to identify the independent predictors of outcomes of interest. RESULTS: The risk of the polyps' coexistence phenomenon increased in males compared with females (OR = 2.138, p = 0.047), especially in those between 50 and 75 years old (OR = 7.074, p = 0.036). Tumor size (3-4 cm), LSTs with tubulovillous types, and history of polyps statistically increased the risk of the polyp coexistence phenomenon (OR = 5.768, p = 0.003; OR = 36.345, p = 0.024; OR = 13.245, p < 0.0001, respectively). LST-NG-PD (OR = 20.982, p = 0.017) and LSTs ≥ 5 cm (OR = 37.604, p = 0.038) notably increased the malignant risk of LSTs. When the simultaneous polyps are located in the right colon, the risk of malignant LSTs (OR = 58.540, p = 0.013) positively increased. CONCLUSION: The simultaneous colorectal polyps in the right colon were the most important risk factor to predict the malignant risk of LSTs.
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Genome-wide association studies (GWASs) implicate 16q22.1 locus in risk for colorectal cancer (CRC). However, the underlying oncogenic mechanisms remain unknown. Here, through comprehensive filtration, we prioritized rs7198799, a common SNP in the second intron of the CDH1, as the putative causal variant. In addition, we found an association of CRC-risk allele C of rs7198799 with elevated transcript level of biological plausible candidate gene ZFP90 via expression quantitative trait loci analysis. Mechanistically, causal variant rs7198799 resides in an enhancer element and remotely regulate ZFP90 expression by targeting the transcription factor NFATC2. Remarkably, CRISPR/Cas9-guided single-nucleotide editing demonstrated the direct effect of rs7198799 on ZFP90 expression and CRC cellular malignant phenotype. Furthermore, ZFP90 affects several oncogenic pathways, including BMP4, and promotes carcinogenesis in patients and in animal models with ZFP90 specific genetic manipulation. Taken together, these findings reveal a risk SNP-mediated long-range regulation on the NFATC2-ZFP90-BMP4 pathway underlying the initiation of CRC.
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Biomarcadores Tumorais/metabolismo , Cromossomos Humanos Par 16/genética , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Proteínas Repressoras/metabolismo , Proteínas Repressoras/fisiologia , Alelos , Animais , Antígenos CD/genética , Apoptose , Biomarcadores Tumorais/genética , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Caderinas/genética , Proliferação de Células , Estudos de Coortes , Neoplasias Colorretais/patologia , Estudo de Associação Genômica Ampla , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/metabolismo , Prognóstico , Regiões Promotoras Genéticas , Locos de Características Quantitativas , Proteínas Repressoras/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Long noncoding RNAs (lncRNAs) contribute to many steps in carcinogenesis and often serve as biomarkers or therapeutic targets for tumor diagnosis and therapy. Although the role of lncRNAs in tumor formation is becoming clear, whether lncRNAs mediate gut microbiota-induced colorectal cancer (CRC) is largely unknown. Enterotoxigenic Bacteroides fragilis (ETBF) is a well-known tumor-inducing bacterium in the human gut; however, its tumorigenic effect remains to be explored. In the present study, we revealed the mechanism by which a lncRNA participates in gut bacteria-induced carcinogenesis: Bacteroides fragilis-associated lncRNA1 (BFAL1) in CRC tissues mediates ETBF carcinogenesis. BFAL1 was highly expressed in CRC tissues compared with that in adjacent normal tissues. In vitro, BFAL1 was upregulated in ETBF-treated CRC cells. Mechanistically, ETBF promoted tumor growth via BFAL1 by activating the Ras homolog, which is the MTORC1 binding/mammalian target of the rapamycin (RHEB/mTOR) pathway. Furthermore, BFAL1 regulated RHEB expression by competitively sponging microRNAs miR-155-5p and miR-200a-3p. Clinically, both high expression of BFAL1 and high abundance of ETBF in CRC tissues predicted poor outcomes for patients with CRC. Thus, BFAL1 is a mediator of ETBF-induced carcinogenesis and may be a potential therapeutic target for ETBF-induced CRC.