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BACKGROUND: The beneficial effects of first-line programmed death-1 (PD-1) inhibitors plus chemotherapy in patients with low programmed death-ligand 1 (PD-L1)-expressing advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma are controversial. METHODS: We conducted a retrospective analysis of patients with G/GEJ adenocarcinoma who had undergone first-line treatment with PD-1 inhibitors plus chemotherapy between October 2017 and May 2022. The primary outcomes were objective response rate (ORR) and progression-free survival (PFS). SPSS software V27.0 was used for data analysis. RESULTS: Of 345 enrolled patients, 290 had measurable lesions. The overall ORR was 59.3%. PD-L1 status was available in 171 patients, and 67.8% of them were considered as low PD-L1 expression level (combined positive score (CPS) < 5). Patients with PD-L1 CPS < 5 showed a lower response rate (51.1% vs 70.8%, P = 0.024) and a worse PFS (P = 0.009) compared to those with PD-L1 CPS ≥ 5. In the PD-L1 low-expression cohort, patients with non-diffuse type, GEJ cancer, synchronous metastasis, distant lymph node metastasis, liver metastasis, non-peritoneal metastasis, and HER2 positive were significantly associated with higher response rates to PD-1 inhibitors plus chemotherapy (P < 0.05). The presence of peritoneal metastasis (P = 0.028) and diffuse type (P = 0.046) were identified as independent predictors of poor PFS in multivariate analysis of the PD-L1 CPS < 5 subgroup. When evaluated for correlation with overall survival (OS) in the PD-L1 low-expression subgroup, peritoneal metastasis was found to be the only independent prognostic factor of an increased risk of death (hazard ratio: 2.31, 95% CI 1.09-4.90; P = 0.029). CONCLUSIONS: PD-L1 CPS ≥ 5 is significantly associated with improved response and extended PFS in G/GEJ cancer patients treated with a combination of PD-1 inhibitors and chemotherapy. Specific subgroups within the low PD-L1-expressing population, such as those with non-diffuse-type tumors and without peritoneal metastases, may also benefit from immunotherapy combined with chemotherapy.
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Adenocarcinoma , Protocolos de Quimioterapia Combinada Antineoplásica , Antígeno B7-H1 , Biomarcadores Tumorais , Neoplasias Esofágicas , Junção Esofagogástrica , Inibidores de Checkpoint Imunológico , Neoplasias Gástricas , Humanos , Masculino , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Feminino , Pessoa de Meia-Idade , Junção Esofagogástrica/patologia , Junção Esofagogástrica/metabolismo , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inibidores , Idoso , Estudos Retrospectivos , Biomarcadores Tumorais/metabolismo , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Idoso de 80 Anos ou mais , PrognósticoRESUMO
Dental pulp stem cells (DPSCs) are mesenchymal stem cells (MSCs) derived from dental pulp tissue, which have high self-renewal ability and multi-lineage differentiation potential. With the discovery of the immunoregulatory ability of stem cells, DPSCs have attracted much attention because they have similar or even better immunomodulatory effects than MSCs from other sources. DPSCs and their exosomes can exert an immunomodulatory ability by acting on target immune cells to regulate cytokines. DPSCs can also migrate to the lesion site to differentiate into target cells to repair the injured tissue, and play an important role in tissue regeneration. The aim of this review is to summarize the molecular mechanism and target cells of the immunomodulatory effects of DPSCs, and the latest advances in preclinical research in the treatment of various immune-mediated diseases, providing new reflections for their clinical application. DPSCs may be a promising source of stem cells for the treatment of immune-mediated diseases.
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Polpa Dentária , Células-Tronco Mesenquimais , Células-Tronco , Diferenciação Celular , Proliferação de Células , Células CultivadasRESUMO
Colon cancer is the third most common cancer and the second leading cause of cancer-related death worldwide. Dysregulated RNA splicing factors have been reported to be associated with tumorigenesis and development in colon cancer. In this study, we interrogated clinical and RNA expression data of colon cancer patients from The Cancer Genome Atlas (TCGA) dataset and the Gene Expression Omnibus (GEO) database. Genes regulating RNA splicing correlated with survival in colon cancer were identified and a risk score model was constructed using Cox regression analyses. In the risk model, RNA splicing factor peroxisome proliferator-activated receptor-γ coactivator-1α (PPARGC1) is correlated with a good survival outcome, whereas Cdc2-like kinase 1(CLK1), CLK2, and A-kinase anchor protein 8-like (AKAP8L) with a bad survival outcome. The risk model has a good performance for clinical prognostic prediction both in the TCGA cohort and the other two validation cohorts. In the tumor microenvironment (TME) analysis, the immune score was higher in the low-risk group, and TME-related pathway gene expression was also higher in low-risk group. We further verified the mRNA and protein expression levels of these four genes in the adjacent nontumor, tumor, and liver metastasis tissues of colon cancer patients, which were consistent with bioinformatics analysis. In addition, knockdown of AKAP8L can suppress the proliferation and migration of colon cancer cells. Animal studies have also shown that AKAP8L knockdown can inhibit tumor growth in colon cancer in vivo. We established a prognostic risk model for colon cancer based on genes related to RNA splicing regulation and uncovered the role of AKAP8L in promoting colon cancer progression.
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Neoplasias do Colo , Regulação Neoplásica da Expressão Gênica , Proteínas de Ancoragem à Quinase A/genética , Proteínas de Ancoragem à Quinase A/metabolismo , Neoplasias do Colo/genética , Expressão Gênica , Humanos , Receptores Ativados por Proliferador de Peroxissomo/genética , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Prognóstico , Splicing de RNA/genética , Fatores de Processamento de RNA/genética , RNA Mensageiro/genética , Microambiente TumoralRESUMO
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a severe disease with high mortality, and is associated with poor prognosis and frequent lymphatic metastasis. Therefore, prognostic indicators for ESCC are urgently needed. A-kinase anchor-protein 8-like (AKAP8L) is a member of the A kinase anchor-protein (AKAPs) family and is overexpressed in many cancers. However, the role of AKAP8L in ESCC remains unclear. The aim of this study is to investigate the expression patterns and prognostic value of AKAP8L in ESCC. METHODS: The mRNA expression of AKAP8L was analyzed from the dataset of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Immunohistochemistry was applied to detect the AKAP8L expression in tissue microarray. Pearson's chi-square test was carried out for the correlation analysis of clinicopathological features and AKAP8L expression. The prognostic significance of clinicopathological features and AKAP8L expression was determined by univariate and multivariate Cox hazard models. Kaplan-Meier survival curve was used for survival analysis. RESULTS: We found that the mRNA level of AKAP8L was higher in tumor tissues than in adjacent tissues in TCGA and GEO dataset. High AKAP8L expression was associated with poor overall survival (OS) in ESCC patients (p = 0.0039). Besides, AKAP8L expression was highly expressed in patients with lymph node metastasis detected by ESCC tissue microarray (p = 0.0014). The comparison of the different clinicopathological features of ESCC between high and low AKAP8L expression groups revealed that high AKAP8L expression was related to lymph node stage (p = 0.041). Kaplan-Meier survival analysis revealed that high AKAP8L expression indicates an unfavorable progression-free survival (PFS) and OS in ESCC patients (p < 0.0001). Univariate and multivariate analyses confirmed that AKAP8L was an independent prognostic factor for PFS and OS in ESCC (p = 0.003 and p < 0.0001). CONCLUSIONS: In conclusion, this study demonstrated that high expression of AKAP8L is associated with poor prognosis of ESCC and can be considered an independent risk factor for ESCC.
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BACKGROUND: Both Response Evaluation Criteria in Solid Tumors (RECIST) and tumor regression grade (TRG) play key roles in evaluating tumor response. We analyzed the consistency of TRG and RECIST 1.1 for gastric cancer (GC) patients and compared their prognostic values. METHODS: Patients with GC who received preoperative chemotherapy or chemoimmunotherapy and had records of TRG from December 2013 to October 2021 were enrolled retrospectively. TRG 0-1 and 2-3 are considered as corresponding to complete response (CR)/partial response (PR) and stable disease (SD)/progress disease (PD) in RECIST 1.1, respectively. The primary endpoints were disease-free survival (DFS) and overall survival (OS). The consistency of RECIST and TRG was examined by kappa statistics. Survival analysis was performed using the Kaplan Meier method. RESULT: One hundred fifty seven GC patients were enrolled, including 125 with preoperative chemotherapy and 32 with chemoimmunotherapy. Among them, 56 patients had measurable lesions. Only 19.6% (11/56) of the patients had consistent results between RECIST 1.1 and TRG. TRG was correlated with both OS and DFS (P = 0.02 and 0.03, respectively) while response according to RECIST1.1 was not (P = 0.86 and 0.23, respectively). The median DFS had not reached in the TRG 0-1 group and was 16.13 months in TRG 2-3 group. TRG 2-3 was associated with young age and peritoneal or liver metastasis. Besides, preoperative chemoimmunotherapy had a significantly higher pCR rate than chemotherapy alone (34.4% vs 8.0%, P < 0.001). CONCLUSION: TRG was in poor agreement with RECIST 1.1. TRG was better than RECIST 1.1 in predicting DFS and OS for GC patients who received preoperative therapy.
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Neoplasias Gástricas , Intervalo Livre de Doença , Humanos , Terapia Neoadjuvante/métodos , Critérios de Avaliação de Resposta em Tumores Sólidos , Estudos Retrospectivos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND: The impact of HER2 somatic mutations in colorectal carcinoma (CRC) has not been well studied and its relationship with microsatellite instability-high (MSI-H) is yet to be fully elucidated. MATERIALS AND METHODS: From February 2017 to February 2020, the data of patients with CRC who underwent next-generation sequencing and had detailed record of clinicopathological information were investigated. HER2 alteration and its relationship with MSI-H were analyzed. RESULTS: Among 731 patients who underwent sequencing, 55 patients (7.5%) had HER2 alteration, including 29 (4.0%) with HER2 somatic mutations, 24 (3.3%) with HER2 gene amplification, and 2 patients (0.2%) with both HER2 mutations and amplification. R678Q was the most common mutated kinase domain, and no HER2 kinase domain in-frame insertions/deletions were found in HER2 mutated cases. MSI-H was found in 5.2% of our cohort and 36.8% of MSI-H patients had HER2 mutation. For HER2 mutated cases, 48.3% were MSI-H, whereas none of the HER2 amplification cases were MSI-H. MSI-H patients with HER2 mutation had significantly worse median progression-free survival for programmed death-1 (PD-1) antibody than those without HER2 alteration (p = .036). CONCLUSION: High MSI-H rate was found in HER2 mutated cases, but no MSI-H was found in HER2 amplification cases. MSI-H patients with HER2 mutated had worse progression-free survival for PD-1 antibody than those without. IMPLICATIONS FOR PRACTICE: This study highlights the high microsatellite instability-high (MSI-H) rate in HER2 mutated cases but no MSI-H in HER2 amplification cases. Moreover MSI-H patients with HER2 mutated had worse progression-free survival for programmed death-1 antibody than those without. Further research to explore the internal relationship between HER2 alteration and MSI-H is needed.
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Adenocarcinoma , Neoplasias Colorretais , Adenocarcinoma/genética , Neoplasias Colorretais/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Instabilidade de Microssatélites , Mutação , Intervalo Livre de ProgressãoRESUMO
Inspired by the enhanced photoluminescence of Au nanoclusters (AuNCs) with a rigid shell, the formation of rigid host-guest assemblies on AuNC surfaces was employed to screen novel electrochemiluminophores with 6-aza-2-thiothymine(ATT)-protected AuNCs (ATT-AuNCs) and l-arginine (ARG) as models for the first time. The rigid host-guest assemblies formed between ARG and ATT on the ATT-AuNC surface enabled aqueous-soluble ARG/ATT-AuNCs with a dramatically enhanced electrochemiluminescence (ECL) compared to ATT-AuNCs. This includes one cathodic ECL process (-1.30â V) and three anodic ECL processes (+0.78, 0.90, and 1.05â V) in a so-called half-scan experiment without a co-reactant, as well as a 70-fold enhanced oxidative-reduction ECL at +0.78â V with tri-n-propylamine as a co-reactant. Importantly, the ECL of the ARG/ATT-AuNCs is highly monochromatic with an emission maximum around 532â nm and a full width at half-maximum of 36â nm, which is of great interest for color-selective ECL assays.
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Tunable optics and electronics of II-VI nanocrystals (NCs) is mainly achieved by using the traditional size-dependent strategy. Herein, we show that the triggering energy (potential), intensity, and even reductive-oxidation electrochemiluminescence (ECL) spectra of highly passivated CdTe/CdS NCs of the same size can be adjusted by simply decorating the NCs with counterions, which proves that surface chemistry can bring about varied electrostatic interactions between the surface vacancies and electrochemically injected carriers for adjustable electrochemical redox induced radiative charge transfer. Potential-resolved ECL demonstrates that increasing the surface sulfur vacancies and decreasing the surface cadmium vacancies can clearly enhance the ECL intensity and lower ECL triggering energy. All the traditional accumulated ECL spectra of CdTe/CdS NCs with various surface vacancies are close to the photoluminescence spectrum of monodisperse NCs without surface treatment, indicating the ECL spectra are mainly dominated by the CdTe core, whereas the slightly redshifted ECL spectrum of CdTe/CdS NCs with excessive cadmium vacancies indicates that the electrostatic repulsion between surface cadmium vacancies and electrons partially consumes the energy of the electrochemically injected electrons. Interestingly, spooling ECL spectra of CdTe/CdS NCs with varied surface vacancies are slightly blueshifted with negatively scanned potential, indicating electrons can be injected into conduction band of higher energy levels in a potential modulated way.
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Determining the role of micro-nanobubbles (MNBs) in controlling the risk posed by pathogens to soil and groundwater during reclaimed water irrigation requires clarification of the mechanism of how MNBs block pathogenic bacteria. In this study, real-time bioluminescence imaging was used to investigate the effects of MNBs on the transport and spatiotemporal distribution of bioluminescent Escherichia coli 652T7 strain in porous media. The presence of MNBs significantly increased the retention of bacteria in the porous media, decreasing the maximum relative effluent concentration (C/C0) by 78 % from 0.97 (without MNBs) to 0.21 (with MNBs). The results suggested that MNBs provided additional sites at the air-water interface (AWI) for bacterial attachment and acted as physical obstacles to reduce bacterial passage. These effects varied with environmental conditions such as solution ionic strength and pore water velocity. The results indicated that MNBs enhanced electrostatic attachment of bacteria at the AWI and their mechanical straining in pores. This study suggests that adding MNBs in pathogen-containing water is an effective measure for increasing filtration efficiency and reducing the risk of pathogenic contamination during agricultural irrigation.
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Escherichia coli , Porosidade , Microbiologia da ÁguaRESUMO
This study aims to present a comprehensive study on the risks associated with the residual presence and transport of Escherichia coli (E. coli) in soil following the application of livestock manure in Chinese farmlands by integrating machine learning algorithms with mechanism-based models (Phydrus). We initially review 28 published papers to gather data on E. coli's die-off and attachment characteristics in soil. Machine learning models, including deep learning and gradient boosting machine, are employed to predict key parameters such as the die-off rate of E. coli and first-order attachment coefficient in soil. Then, Phydrus was used to simulate E. coli transport and survival in 23692 subregions in China. The model considered regional differences in E. coli residual risk and transport, influenced by soil properties, soil depths, precipitation, seasonal variations, and regional disparities. The findings indicate higher residual risks in regions such as the Northeast China, Eastern Qinghai-Tibet Plateau, and pronounced transport risks in the fringe of the Sichuan Basin fringe, the Loess Plateau, the North China Plain, the Northeast Plain, the Shigatse Basin, and the Shangri-La region. The study also demonstrates a significant reduction in both residual and transport risks one month after manure application, highlighting the importance of timing manure application and implementing region-specific standards. This research contributes to the broader understanding of pathogen behavior in agricultural soils and offers practical guidelines for managing the risks associated with manure use. This study's comprehensive method offers a potentially valuable tool for evaluating microbial contaminants in agricultural soils across the globe.
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Escherichia coli , Fazendas , Aprendizado de Máquina , Esterco , Microbiologia do Solo , China , Solo/química , Medição de Risco , Agricultura , Gado , Monitoramento Ambiental/métodos , AnimaisRESUMO
This study presents a comprehensive approach to estimating annual atrazine residues in China's agricultural soils, integrating machine learning algorithms and mechanism-based models. First, machine learning was used to predict essential parameters influencing atrazine's adsorption, degradation, and dispersivity of solute transport. The results demonstrated that soil organic matter was the most important input variable for predicting adsorption and degradation; clay content was the primary variable for predicting dispersivity. The SHapley Additive exPlanations (SHAP) contribution of various soil properties on target variables were also analyzed to reveal whether each input variable has a positive, negative, or complex effect. Subsequently, these parameters inform the construction of a detailed model across 23,692 subregions of China, with a 20 km × 20 km resolution. The model considered regional variations and soil layer heterogeneity, including rainfall, soil depth-specific properties, and parameters for adsorption, degradation, and dispersivity. Utilizing the convection-dispersion equations and the Phydrus, the model simulated atrazine's transport and degradation patterns across diverse soil environments after applying 250 mL of atrazine (40%) per Chinese mu. The outcomes provided a spatially explicit distribution of atrazine residues, specifying that the arid areas have the highest residual risk, followed by the Northeast, Southwest, and Southeast. Atrazine levels may exceed national drinking water standards at 50 cm depth in Inner Mongolia, the Qinghai-Tibet Plateau, and the Jungar Basin. This study's integrative approach may also offer valuable insights and tools for evaluating residues of various pesticides and herbicides in agricultural soils.
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Background: Early research indicates that cancer patients are more vulnerable to adverse outcomes and mortality when infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Nonetheless, the specific attributes of SARS-CoV-2 in lung Adenocarcinoma (LUAD) have not been extensively and methodically examined. Methods: We acquired 322 SARS-CoV-2 infection-related genes (CRGs) from the Human Protein Atlas database. Using an integrative machine learning approach with 10 algorithms, we developed a SARS-CoV-2 score (Cov-2S) signature across The Cancer Genome Atlas and datasets GSE72094, GSE68465, and GSE31210. Comprehensive multi-omics analysis, including assessments of genetic mutations and copy number variations, was conducted to deepen our understanding of the prognosis signature. We also analyzed the response of different Cov-2S subgroups to immunotherapy and identified targeted drugs for these subgroups, advancing personalized medicine strategies. The expression of Cov-2S genes was confirmed through qRT-PCR, with GGH emerging as a critical gene for further functional studies to elucidate its role in LUAD. Results: Out of 34 differentially expressed CRGs identified, 16 correlated with overall survival. We utilized 10 machine learning algorithms, creating 101 combinations, and selected the RFS as the optimal algorithm for constructing a Cov-2S based on the average C-index across four cohorts. This was achieved after integrating several essential clinicopathological features and 58 established signatures. We observed significant differences in biological functions and immune cell statuses within the tumor microenvironments of high and low Cov-2S groups. Notably, patients with a lower Cov-2S showed enhanced sensitivity to immunotherapy. We also identified five potential drugs targeting Cov-2S. In vitro experiments revealed a significant upregulation of GGH in LUAD, and its knockdown markedly inhibited tumor cell proliferation, migration, and invasion. Conclusion: Our research has pioneered the development of a consensus Cov-2S signature by employing an innovative approach with 10 machine learning algorithms for LUAD. Cov-2S reliably forecasts the prognosis, mirrors the tumor's local immune condition, and supports clinical decision-making in tumor therapies.
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Adenocarcinoma de Pulmão , COVID-19 , Neoplasias Pulmonares , Humanos , SARS-CoV-2/genética , Variações do Número de Cópias de DNA , COVID-19/genética , Prognóstico , Adenocarcinoma de Pulmão/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Microambiente Tumoral/genéticaRESUMO
BACKGROUND: Brain metastasis (BM) in gastric cancer (GC) is underestimated, and human epidermal growth factor receptor 2 (HER2) overexpression is a durable poor prognostic factor. We explored the relationship between the two and made a survival analysis. METHODS: HER2 expression and BM status were collected from GC patients who were diagnosed between December 2009 and May 2021. We collected GC patients diagnosed between 2010 and 2016 from the SEER database. The primary endpoint was survival from the diagnosis of BM. Multivariable logistic regression was used to determine potential risk factors of BM at diagnosis in SEER database. Survival analysis was performed using the Kaplan-Meier method. RESULT: There were 513 HER2-positive GC patients, including 16 (3.1%) with BM. Among 38 brain metastasis GC patients we collected, 16 (42.1%) patients were HER2 positive. We collected 34,199 GC patients from the SEER database and there were 260 (0.76%) patients with BM at diagnosis. GC patients that are male, white, of younger age, with primary lesions located in the proximal stomach or with distant lymph nodes, liver, bone, or lung metastasis are more likely to develop BM. The median overall survival time from diagnosis of BM was 12.73 months, and the survival time from brain metastasis of HER2-positive patients was numerically shorter, though the difference was not significant (5.30 months vs.16.13 months, P = 0.28.) CONCLUSION: The incidence of BM in patients with HER2-positive gastric cancer is 4.08 times higher than that in general patients. The median overall survival time from BM is shorter for HER2-positive patients.
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Neoplasias Encefálicas , Neoplasias Gástricas , Humanos , Masculino , Feminino , Neoplasias Gástricas/patologia , Receptor ErbB-2/metabolismo , Prognóstico , Análise de Sobrevida , Fatores de RiscoRESUMO
BACKGROUND AND PURPOSE: Liver cancer is the fourth leading cause of cancer-related death worldwide, with hepatocellular carcinoma (HCC) being the most common type of primary liver cancer. APG-1252 is a small molecule inhibitor targeting Bcl-2 and Bcl-xl. However, its anti-tumor effects in HCC, alone or in combination with Cabozantinib, have not been extensively studied. EXPERIMENTAL: Approach: TCGA database analysis was used to analysis the gene expression levels of Bcl-2 and Bcl-xl in HCC tissues. Western blot was employed to detect the protein expression levels. And the inhibitory effects of APG-1252 and Cabozantinib on the proliferation of HCC cell lines was detected by CCK-8. The effect on the migration and invasion of HCC cells was verified by transwell assay. Huh7 xenograft model in nude mice was used to investigate the combination antitumor effect in vivo. KEY RESULTS: Our study demonstrated that APG-1252 monotherapy inhibited the proliferation and migration ability of HCC cells, and induced HCC cells apoptosis. The combination of APG-1252 and Cabozantinib showed significant synergistic antitumor effects. Furthermore, the in vivo experiment demonstrated that the combination therapy exerted a synergistic effect in delaying tumor growth, notably downregulating MEK/ERK phosphorylation levels. In terms of mechanism, Cabozantinib treatment caused an increase in the phosphorylation levels of CREB and Bcl-xl proteins, while the combination with APG-1252 mitigated this effect, thereby enhanced the antitumor effect of Cabozantinib. CONCLUSION AND IMPLICATIONS: Our findings suggest that APG-1252 in combination with Cabozantinib offers a more effective treatment strategy for HCC patients, warranting further clinical investigation.
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Anilidas , Carcinoma Hepatocelular , Proliferação de Células , Neoplasias Hepáticas , Camundongos Nus , Piridinas , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína bcl-X , Animais , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Anilidas/farmacologia , Anilidas/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Proteína bcl-X/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Camundongos , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Camundongos Endogâmicos BALB C , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , MasculinoRESUMO
RNA modification, especially N6-methyladenosine, 5-methylcytosine, and N7-methylguanosine methylation, participates in the occurrence and progression of cancer through multiple pathways. The function and expression of these epigenetic regulators have gradually become a hot topic in cancer research. Mutation and regulation of noncoding RNA, especially lncRNA, play a major role in cancer. Generally, lncRNAs exert tumor-suppressive or oncogenic functions and its dysregulation can promote tumor occurrence and metastasis. In this review, we summarize N6-methyladenosine, 5-methylcytosine, and N7-methylguanosine modifications in lncRNAs. Furthermore, we discuss the relationship between epigenetic RNA modification and lncRNA interaction and cancer progression in various cancers. Therefore, this review gives a comprehensive understanding of the mechanisms by which RNA modification affects the progression of various cancers by regulating lncRNAs, which may shed new light on cancer research and provide new insights into cancer therapy.
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Neoplasias , RNA Longo não Codificante , Humanos , Neoplasias/genética , Neoplasias/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/genética , Animais , Processamento Pós-Transcricional do RNARESUMO
The addition of an arsenite-chloride solution into an arsenite-sulfate solution is extremely beneficial for the removal of As(III) via Fe(III) salt precipitation at pH 2.3. However, the applicability of this method to complicated high-As(III) metallurgical wastewaters still requires further verification. This work investigated the effects of nitrate and Fe/As molar ratio on As(III) immobilization using Fe(III) in three acid radical media including sulfate, chloride, and nitrate at pH 2.3. Our results indicated that 72.1â93.5% of As(III) was precipitated, which was 5â10% less than those obtained in the nitrate-free systems. The Fe/As molar ratio of 4 was the optimal condition with an average of 93% As(III) removal based on a broad sulfate/chloride molar ratio range (1:1â16). However, a maximum of 96% As(III) removal was observed under the Fe/As molar ratio of 1.5 and the sulfate/chloride condition of 1:16. The negative correlation between complexation and precipitation was attributed to the enhanced initial complexation by the synergistic effect of the mononitratoiron complex and FeH2AsO32+. The variation of Fe/As molar ratios resulted in the diverse solid species, thus further affecting the As(III) removal efficiency. Despite producing tooeleite as a major As(III) host phase, ferrihydrite and poorly crystalline ferric arsenite hydroxysulfate formed simultaneously at the Fe/As molar ratio of 4 participated in As(III) immobilization compared with the solid products at Fe/As molar ratios ≤ 2.
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Arsenitos , Arsenitos/análise , Compostos Férricos/química , Sulfatos , Cloretos , Águas Residuárias , Nitratos , Ferro/química , Óxidos de Enxofre , OxirreduçãoRESUMO
Escherichia coli, as an indicator of fecal contamination, can move from manure-amended soil to groundwater under rainfall or irrigation events. Predicting its vertical transport in the subsurface is essential for the development of engineering solutions to reduce the risk of microbiological contamination. In this study, we collected 377 datasets from 61 published papers addressing E. coli transport through saturated porous media and trained six types of machine learning algorithms to predict bacterial transport. Eight variables, including bacterial concentration, porous medium type, median grain size, ionic strength, pore water velocity, column length, saturated hydraulic conductivity, and organic matter content were used as input variables while the first-order attachment coefficient and spatial removal rate were set as target variables. The eight input variables have low correlations with the target variables, namely, they cannot predict target variables independently. However, using the predictive models, input variables can effectively predict the target variables. For scenarios with higher bacterial retention, such as smaller median grain size, the predictive models showed better performance. Among six types of machine learning algorithms, Gradient Boosting Machine and Extreme Gradient Boosting outperformed other algorithms. In most predictive models, pore water velocity, ionic strength, median grain size, and column length showed higher importance than other input variables. This study provided a valuable tool to evaluate the transport risk of E.coli in the subsurface under saturated water flow conditions. It also proved the feasibility of data-driven methods that could be used for predicting other contaminants' transport in the environment.
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INTRODUCTION: This study aimed to develop a prognostic nomogram for patients with gastric cancer (GC) based on the levels of programmed death 1 ligand 1 (PDL1) and carcinoembryonic antigen (CEA). METHODS: The nomogram was developed using data from a primary cohort of 247 patients who had been clinicopathologically diagnosed with GC, as well as a validation cohort of 63 patients. Furthermore, the nomogram divided the patients into three different risk groups for overall survival (OS)-the low-risk, middle-risk, and high-risk groups. Univariate and multivariate Cox hazard analyses were used to determine all of the factors included in the model. Decision curve analysis and receiver operating characteristic (ROC) curves were used to assess the accuracy of the nomogram. RESULTS: The Kaplan-Meier survival analysis revealed that metastasis stage, clinical stage, and CEA and PDL1 levels were predictors for progress-free survival (PFS) and OS of patients with GC. Metastasis stage, clinical stage, and CEA and PDL1 levels were found to be independent risk factors for the PFS and OS of patients with GC in a multivariate analysis, and the nomogram was based on these factors. The concordance index of the nomogram was 0.763 [95% confidence interval (CI) 0.740-0.787]. The area under the concentration-time curve of the nomogram model was 0.81 (95% CI 0.780-0.900). According to the decision curve analysis and ROC curves, the nomogram model had a higher overall net efficiency in forecasting OS than clinical stage, CEA and PDL1 levels. CONCLUSION: In conclusion, we proposed a novel nomogram that integrated PDL1 and CEA, and the proposed nomogram provided more accurate and useful prognostic predictions for patients with GC.
Assuntos
Nomogramas , Neoplasias Gástricas , Humanos , Antígeno Carcinoembrionário , Ligantes , PrognósticoRESUMO
Gastric mixed adenoneuroendocrine carcinoma (MANEC) is a clinically aggressive and heterogeneous tumor composed of adenocarcinoma (ACA) and neuroendocrine carcinoma (NEC). The genomic properties and evolutionary clonal origins of MANEC remain unclear. We conduct whole-exome and multiregional sequencing on 101 samples from 33 patients to elucidate their evolutionary paths. We identify four significantly mutated genes, TP53, RB1, APC, and CTNNB1. MANEC resembles chromosomal instability stomach adenocarcinoma in that whole-genome doubling in MANEC is predominant and occurs earlier than most copy-number losses. All tumors are of monoclonal origin, and NEC components show more aggressive genomic properties than their ACA counterparts. The phylogenetic trees show two tumor divergence patterns, including sequential and parallel divergence. Furthermore, ACA-to-NEC rather than NEC-to-ACA transition is confirmed by immunohistochemistry on 6 biomarkers in ACA- and NEC-dominant regions. These results provide insights into the clonal origin and tumor differentiation of MANEC.
Assuntos
Adenocarcinoma , Carcinoma Neuroendócrino , Neoplasias Gástricas , Humanos , Filogenia , Microdissecção , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/patologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , GenômicaRESUMO
EpsteinâBarr virus (EBV)-associated gastric cancer (GC) manifests an intriguing immunotherapy response. However, the cellular basis for EBV-imprinted tumour immunity and on-treatment response remains undefined. This study aimed to finely characterize the dynamic tumour immune contexture of human EBV (+) GC treated with immunochemotherapy by longitudinal scRNA-seq and paired scTCR/BCR-seq. EBV (+) GC exhibits an inflamed-immune phenotype with increased T-cell and B-cell infiltration. Immunochemotherapy triggers clonal revival and reinvigoration of effector T cells which step to determine treatment response. Typically, an antigen-specific ISG-15+CD8+ T-cell population is highly enriched in EBV (+) GC patients, which represents a transitory exhaustion state. Importantly, baseline intratumoural ISG-15+CD8+ T cells predict immunotherapy responsiveness among GC patients. Re-emerged clonotypes of pre-existing ISG-15+CD8+ T cells could be found after treatment, which gives rise to a CXCL13-expressing effector population in responsive EBV (+) tumours. However, LAG-3 retention may render the ISG-15+CD8+ T cells into a terminal exhaustion state in non-responsive EBV (+) tumours. In accordance, anti-LAG-3 therapy could effectively reduce tumour burden in refractory EBV (+) GC patients. Our results delineate a distinct implication of EBV-imprinted on-treatment T-cell immunity in GC, which could be leveraged to optimize the rational design of precision immunotherapy.