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Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality globally. Many herbal medicines and their bioactive compounds have shown anti-tumor properties. This study was conducted to examine the effect of psilostachyin C (PSC), a sesquiterpenoid lactone isolated from Artemisia vulgaris L., in the malignant properties of HCC cells. CCK-8, flow cytometry, wound healing, and Transwell assays revealed that 25 µM PSC treatment significantly suppressed proliferation, cell cycle progression, migration, and invasion of two HCC cell lines (Hep 3B and Huh7) while promoting cell apoptosis. Bioinformatics prediction suggests CREB binding protein (CREBBP) as a promising target of PSC. CREBBP activated transcription of GATA zinc finger domain containing 2B (GATAD2B) by binding to its promoter. CREBBP and GATAD2B were highly expressed in clinical HCC tissues and the acquired HCC cell lines, but their expression was reduced by PSC. Either upregulation of CREBBP or GATAD2B restored the malignant properties of HCC cells blocked by PSC. Collectively, this evidence demonstrates that PSC pocessess anti-tumor functions in HCC cells by blocking CREBBP-mediated transcription of GATAD2B.
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Carcinoma Hepatocelular , Compostos Heterocíclicos com 3 Anéis , Neoplasias Hepáticas , Pironas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Proteína de Ligação a CREB/genética , Proteína de Ligação a CREB/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão GênicaRESUMO
Oxidative DNA damage is closely associated with the occurrence of numerous human diseases and cancers. 8-Oxo-7,8-dihydroguanine (8-oxoG) is the most prevalent form of DNA damage, and it has become not only an oxidative stress biomarker but also a new epigenetic-like biomarker. However, few approaches are available for the locus-specific detection of 8-oxoG because of the low abundance of 8-oxoG damage in DNA and the limited sensitivity of existing assays. Herein, we demonstrate the elongation and ligation-mediated differential coding for label-free and locus-specific analysis of 8-oxoG in DNA. This assay is very simple without the involvement of any specific labeled probes, complicated steps, and large sample consumption. The utilization of Bsu DNA polymerase can specifically initiate a single-base extension reaction to incorporate dATP into the opposite position of 8-oxoG, endowing this assay with excellent selectivity. The introduction of cascade amplification reaction significantly enhances the sensitivity. The proposed method can monitor 8-oxoG with a limit of detection of 8.21 × 10-19 M (0.82 aM), and it can identify as low as 0.001% 8-oxoG damage from a complex mixture with excessive undamaged DNAs. This method can be further applied to measure 8-oxoG levels in the genomic DNA of human cells under diverse oxidative stress, holding prospect potential in the dynamic monitoring of critical 8-oxoG sites, early clinical diagnosis, and gene damage-related biomedical research.
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DNA Polimerase Dirigida por DNA , DNA , Guanina/análogos & derivados , Humanos , DNA/genética , DNA Polimerase Dirigida por DNA/metabolismo , Dano ao DNA , Biomarcadores , Reparo do DNARESUMO
BACKGROUND: The global dementia prevalence is surging, necessitating research into contributing factors. We aimed to investigate the association between metabolic syndrome (MetS), its components, serum uric acid (SUA) levels, and dementia risk. METHODS: Our prospective study comprised 466,788 participants without pre-existing MetS from the UK Biobank. We confirmed dementia diagnoses based on the ICD-10 criteria (F00-03). To evaluate the dementia risk concerning MetS, its components, and SUA levels, we applied Cox proportional hazards models, while adjusting for demographic factors. RESULTS: Over a median follow-up of 12.7 years, we identified 6845 dementia cases. Individuals with MetS had a 25% higher risk of all-cause dementia (hazard ratio [HR] = 1.25, 95% confidence interval [CI] = 1.19-1.31). The risk increased with the number of MetS components including central obesity, dyslipidemia for high-density lipoprotein (HDL) cholesterol, hypertension, hyperglycemia, and dyslipidemia for triglycerides. Particularly for those with all five components (HR = 1.76, 95% CI = 1.51-2.04). Dyslipidemia for HDL cholesterol, hypertension, hyperglycemia, and dyslipidemia for triglycerides were independently associated with elevated dementia risk (p < 0.01). MetS was further linked to an increased risk of all-cause dementia (11%) and vascular dementia (VD, 50%) among individuals with SUA levels exceeding 400 µmol/L (all-cause dementia: HR = 1.11, 95% CI = 1.02-1.21; VD: HR = 1.50, 95% CI = 1.28-1.77). CONCLUSIONS: Our study provides robust evidence supporting the association between MetS, its components, and dementia risk. These findings emphasize the importance of considering MetS and SUA levels in assessing dementia risk, offering valuable insights for prevention and management strategies.
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Demência , Dislipidemias , Hiperglicemia , Hipertensão , Síndrome Metabólica , Humanos , Ácido Úrico , Estudos Prospectivos , Fatores de Risco , Hipertensão/complicações , HDL-Colesterol , Triglicerídeos , Dislipidemias/complicações , Demência/etiologia , Demência/complicaçõesRESUMO
OBJECTIVE: This study aims to examine the impact of PE/PPE gene mutations on the transmission of Mycobacterium tuberculosis (M. tuberculosis) in China. METHODS: We collected the whole genome sequencing (WGS) data of 3202 M. tuberculosis isolates in China from 2007 to 2018 and investigated the clustering of strains from different lineages. To evaluate the potential role of PE/PPE gene mutations in the dissemination of the pathogen, we employed homoplastic analysis to detect homoplastic single nucleotide polymorphisms (SNPs) within these gene regions. Subsequently, logistic regression analysis was conducted to analyze the statistical association. RESULTS: Based on nationwide M. tuberculosis WGS data, it has been observed that the majority of the M. tuberculosis burden in China is caused by lineage 2 strains, followed by lineage 4. Lineage 2 exhibited a higher number of transmission clusters, totaling 446 clusters, of which 77 were cross-regional clusters. Conversely, there were only 52 transmission clusters in lineage 4, of which 9 were cross-regional clusters. In the analysis of lineage 2 isolates, regression results showed that 4 specific gene mutations, PE4 (position 190,394; c.46G > A), PE_PGRS10 (839,194; c.744 A > G), PE16 (1,607,005; c.620T > G) and PE_PGRS44 (2,921,883; c.333 C > A), were significantly associated with the transmission of M. tuberculosis. Mutations of PE_PGRS10 (839,334; c.884 A > G), PE_PGRS11 (847,613; c.1455G > C), PE_PGRS47 (3,054,724; c.811 A > G) and PPE66 (4,189,930; c.303G > C) exhibited significant associations with the cross-regional clusters. A total of 13 mutation positions showed a positive correlation with clustering size, indicating a positive association. For lineage 4 strains, no mutations were found to enhance transmission, but 2 mutation sites were identified as risk factors for cross-regional clusters. These included PE_PGRS4 (338,100; c.974 A > G) and PPE13 (976,897; c.1307 A > C). CONCLUSION: Our results indicate that some PE/PPE gene mutations can increase the risk of M. tuberculosis transmission, which might provide a basis for controlling the spread of tuberculosis.
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Mutação , Mycobacterium tuberculosis , Polimorfismo de Nucleotídeo Único , Tuberculose , Sequenciamento Completo do Genoma , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/classificação , Mycobacterium tuberculosis/isolamento & purificação , China/epidemiologia , Humanos , Tuberculose/transmissão , Tuberculose/microbiologia , Tuberculose/epidemiologia , Genoma Bacteriano , Feminino , Masculino , Proteínas de Bactérias/genética , AdultoRESUMO
Ecological divergence due to habitat difference plays a prominent role in the formation of new species, but the genetic architecture during ecological speciation and the mechanism underlying phenotypic divergence remain less understood. Two wild ancestors of rice (Oryza rufipogon and Oryza nivara) are a progenitor-derivative species pair with ecological divergence and provide a unique system for studying ecological adaptation/speciation. Here, we constructed a high-resolution linkage map and conducted a quantitative trait locus (QTL) analysis of 19 phenotypic traits using an F2 population generated from a cross between the two Oryza species. We identified 113 QTLs associated with interspecific divergence of 16 quantitative traits, with effect sizes ranging from 1.61% to 34.1% in terms of the percentage of variation explained (PVE). The distribution of effect sizes of QTLs followed a negative exponential, suggesting that a few genes of large effect and many genes of small effect were responsible for the phenotypic divergence. We observed 18 clusters of QTLs (QTL hotspots) on 11 chromosomes, significantly more than that expected by chance, demonstrating the importance of coinheritance of loci/genes in ecological adaptation/speciation. Analysis of effect direction and v-test statistics revealed that interspecific differentiation of most traits was driven by divergent natural selection, supporting the argument that ecological adaptation/speciation would proceed rapidly under coordinated selection on multiple traits. Our findings provide new insights into the understanding of genetic architecture of ecological adaptation and speciation in plants and help effective manipulation of specific genes or gene cluster in rice breeding.
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Oryza , Oryza/genética , Melhoramento Vegetal , Mapeamento Cromossômico , Fenótipo , Locos de Características Quantitativas/genéticaRESUMO
Plant JASMONATE ZIM-DOMAIN (JAZ) genes play crucial roles in regulating the biosynthesis of specialized metabolites and stressful responses. However, understanding of JAZs controlling these biological processes lags due to numerous JAZ copies. Here, we found that two leaf-specific CwJAZ4/9 genes from Curcuma wenyujin are strongly induced by methyl-jasmonate (MeJA) and negatively correlated with terpenoid biosynthesis. Yeast two-hybrid, luciferase complementation imaging and in vitro pull-down assays confirmed that CwJAZ4/9 proteins interact with CwMYC2 to form the CwJAZ4/9-CwMYC2 regulatory cascade. Furthermore, transgenic hairy roots showed that CwJAZ4/9 acts as repressors of MeJA-induced terpenoid biosynthesis by inhibiting the terpenoid pathway and jasmonate response, thus reducing terpenoid accumulation. In addition, we revealed that CwJAZ4/9 decreases salt sensitivity and sustains the growth of hairy roots under salt stress by suppressing the salt-mediated jasmonate responses. Transcriptome analysis for MeJA-mediated transgenic hairy root lines further confirmed that CwJAZ4/9 negatively regulates the terpenoid pathway genes and massively alters the expression of genes related to salt stress signaling and responses, and crosstalks of multiple phytohormones. Altogether, our results establish a genetic framework to understand how CwJAZ4/9 inhibits terpenoid biosynthesis and confers salt tolerance, which provides a potential strategy for producing high-value pharmaceutical terpenoids and improving resistant C. wenyujin varieties by a genetic approach.
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Acetatos , Curcuma , Ciclopentanos , Regulação da Expressão Gênica de Plantas , Oxilipinas , Proteínas de Plantas , Tolerância ao Sal , Terpenos , Oxilipinas/metabolismo , Ciclopentanos/metabolismo , Tolerância ao Sal/genética , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Terpenos/metabolismo , Acetatos/farmacologia , Acetatos/metabolismo , Curcuma/metabolismo , Curcuma/genética , Plantas Geneticamente Modificadas , Reguladores de Crescimento de Plantas/metabolismo , Raízes de Plantas/metabolismo , Raízes de Plantas/genética , Raízes de Plantas/efeitos dos fármacosRESUMO
Early tumor response prediction can help avoid overtreatment with unnecessary chemotherapy sessions. It is important to determine whether multiple apparent diffusion coefficient indices (S index, ADC-diff) are effective in the early prediction of pathological response to neoadjuvant chemotherapy (NAC) in breast cancer (BC). Patients with stage II and III BCs who underwent T1WI, diffusion-weighted imaging (DWI), and dynamic contrast-enhanced MRI using a 3 T system were included. They were divided into two groups: major histological responders (MHRs, Miller-Payne G4/5) and nonmajor histological responders (nMHRs, Miller-Payne G1-3). Three b values were used for DWI to derive the S index; ADC-diff values were obtained using b = 0 and 1000 s/mm2. The different interquartile ranges of percentile S-index and ADC-diff values after treatment were calculated and compared. The assessment was performed at baseline and after two and four NAC cycles. A total of 59 patients were evaluated. There are some correlations of interquartile ranges of S-index parameters and ADC-diff values with histopathological prognostic factors (such as estrogen receptor and human epidermal growth factor receptor 2 expression, all p < 0.05), but no significant differences were found in some other interquartile ranges of S-index parameters or ADC-diff values between progesterone receptor positive and negative or for Ki-67 tumors (all P > 0.05). No differences were found in the dynamic contrast-enhanced MRI characteristics between the two groups. HER-2 expression and kurtosis of the S-index distribution were screened out as independent risk factors for predicting MHR group (p < 0.05, area under the curve (AUC) = 0.811) before NAC. After early NAC (two cycles), only the 10th percentile S index was statistically significant between the two groups (p < 0.05, AUC = 0.714). No significant differences were found in ADC-diff value at any time point of NAC between the two groups (P > 0.1). These findings demonstrate that the S-index value may be used as an early predictor of pathological response to NAC in BC; the value of ADC-diff as an imaging biomarker of NAC needs to be further confirmed by ongoing multicenter prospective trials.
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BACKGROUND: Rectal Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) infections among men who have sex with men (MSM) are escalating public health concerns. This study aimed to explore (1) the reliability of self-reported sexual positioning as an indicator for rectal CT and NG screening, and (2) factors associated with rectal CT and NG infections in Shenzhen, China. METHODS: A cross-sectional study was conducted in 2 settings in Shenzhen, China, from April 1, 2021, to March 31, 2022. Data on sociodemographic characteristics, sexual behaviors, and basic CT knowledge were collected. Urine and self-collected rectal swabs were collected for CT and NG testing. RESULTS: In total, 195 MSM participated in the study, and 5.1% tested positive for urogenital CT, 29.2% for rectal CT, 1.0% for urogenital NG, and 8.2% for rectal NG. Among those who reported exclusively insertive anal sex, 69.2% of CT infections and 85.7% of NG infections would have remained undetected with urine testing alone. Risk factors for rectal CT infection included engaging in both insertive and receptive anal sex, with a significant association found for coinfection with rectal NG. CONCLUSIONS: Self-reported sexual positioning was found to be an unreliable indicator for CT and NG screening, as a substantial proportion of infections would have remained undetected. The findings suggest that CT and NG screening in China should be offered to all MSM regardless of self-reported sexual positioning, and that the dual CT/NG testing is recommended.
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Infecções por Chlamydia , Chlamydia trachomatis , Gonorreia , Homossexualidade Masculina , Neisseria gonorrhoeae , Autorrelato , Comportamento Sexual , Humanos , Masculino , Gonorreia/diagnóstico , Gonorreia/epidemiologia , Infecções por Chlamydia/diagnóstico , Infecções por Chlamydia/epidemiologia , China/epidemiologia , Estudos Transversais , Adulto , Neisseria gonorrhoeae/isolamento & purificação , Chlamydia trachomatis/isolamento & purificação , Programas de Rastreamento , Reto/microbiologia , Adulto Jovem , Fatores de Risco , Doenças Retais/microbiologia , Doenças Retais/diagnóstico , Doenças Retais/epidemiologia , Minorias Sexuais e de Gênero , Pessoa de Meia-Idade , Reprodutibilidade dos TestesRESUMO
BACKGROUND AND PURPOSE: In recent years, there has been extensive research on the role of exercise as an adjunctive therapy for cancer. However, the potential mechanisms underlying the anti-tumor therapy of exercise in lung cancer remain to be fully elucidated. As such, our study aims to confirm whether exercise-induced elevation of epinephrine can accelerate CD8+ T cell recruitment through modulation of chemokines and thus ultimately inhibit tumor progression. METHOD: C57BL/6 mice were subcutaneously inoculated with Lewis lung cancer cells (LLCs) to establish a subcutaneous tumor model. The tumor mice were randomly divided into different groups to performed a moderate-intensity exercise program on a treadmill for 5 consecutive days a week, 45 min a day. The blood samples and tumor tissues were collected after exercise for IHC, RT-qPCR, ELISA and Western blot. In addition, another group of mice received daily epinephrine treatment for two weeks (0.05 mg/mL, 200 µL i.p.) (EPI, n = 8) to replicate the effects of exercise on tumors in vivo. Lewis lung cancer cells were treated with different concentrations of epinephrine (0, 5, 10, 20 µM) to detect the effect of epinephrine on chemokine levels via ELISA and RT-qPCR. RESULTS: This study reveals that both pre- and post-cancer exercise effectively impede the tumor progression. Exercise led to an increase in EPI levels and the infiltration of CD8+ T cell into the lung tumor. Exercise-induced elevation of EPI is involved in the regulation of Ccl5 and Cxcl10 levels further leading to enhanced CD8+ T cell infiltration and ultimately inhibiting tumor progression. CONCLUSION: Exercise training enhance the anti-tumor immunity of lung cancer individuals. These findings will provide valuable insights for the future application of exercise therapy in clinical practice.
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Carcinoma Pulmonar de Lewis , Neoplasias Pulmonares , Animais , Camundongos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos C57BL , Linfócitos T CD8-Positivos , Quimiocinas , Carcinoma Pulmonar de Lewis/terapia , Carcinoma Pulmonar de Lewis/patologia , Microambiente Tumoral , Linhagem Celular TumoralRESUMO
BACKGROUND: Increasing attention has been given to the peritumoral region. However, conflicting findings have been reported regarding the relationship between peritumoral region features on MRI and the prognosis of breast cancer. PURPOSE: To evaluate the relationship between peritumoral region features on MRI and prognosis of breast cancer. MATERIALS AND METHODS: A retrospective meta-analysis of observational studies comparing either qualitative or quantitative assessments of peritumoral MRI features on breast cancer with poor prognosis and control subjects was performed for studies published till October 2022. Pooled odds ratios (ORs) or standardized mean differences and 95% confidence intervals (CIs) were estimated by using random-effects models. The heterogeneity across the studies was measured using the statistic I2. Sensitivity analyses were conducted to test this association according to different study characteristics. RESULTS: Twenty-four studies comprising 1853 breast cancers of poor prognosis and 2590 control participants were included in the analysis. Peritumoral edema was associated with non-luminal breast cancers (OR=3.56; 95%CI: 2.17, 5.83; p=.000), high expression of the Ki-67 index (OR=3.70; 95%CI: 2.41, 5.70; p =.000), high histological grade (OR=5.85; 95%CI: 3.89, 8.80; p=.000), lymph node metastasis (OR=2.83; 95%CI: 1.71, 4.67; p=.000), negative expression of HR (OR=3.15; 95%CI: 2.03, 4.88; p=.000), and lymphovascular invasion (OR=1.72; 95%CI: 1.28, 2.30; p=.000). The adjacent vessel sign was associated with greater odds of breast cancer with poor prognosis (OR=2.02; 95%CI: 1.68, 2.44; p=.000). Additionally, breast cancers with poor prognosis had higher peritumor-tumor ADC ratio (SMD=0.67; 95%CI: 0.54, 0.79; p=.000) and peritumoral ADCmean (SMD=0.29; 95%CI: 0.15, 0.42; p=.000). A peritumoral region of 2-20 mm away from the margin of the tumor is recommended. CONCLUSION: The presence of peritumoral edema and adjacent vessel signs, higher peritumor-tumor ADC ratio, and peritumoral ADCmean were significantly correlated with poor prognosis of breast cancer. CLINICAL RELEVANCE STATEMENT: MRI features of the peritumoral region can be used as a non-invasive index for the prognostic evaluation of invasive breast cancer. KEY POINTS: ⢠Peritumoral edema was positively associated with non-luminal breast cancer, high expression of the Ki-67 index, high histological grade, lymph node metastasis, negative expression of HR, and lymphovascular invasion. ⢠The adjacent vessel sign was associated with greater odds of breast cancers with poor prognosis. ⢠Breast cancers with poor prognosis had higher peritumor-tumor ADC ratio and peritumoral ADCmean.
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Semiconductive coordination polymers (CPs) have recently garnered a significant amount of attention due to their widespread application in many areas. The "through-space" approach has emerged as the most versatile strategy for constructing semiconductive CPs. However, this approach often leads to the formation of unidirectional charge transport paths, resulting in anisotropic electrically conductive performance and low average conductivities in pressed pellets, thus presenting significant challenges for the practical application of semiconductive CPs. Consequently, there is a strong desire to explore simpler and more versatile strategies for designing semiconductive CPs with dual or multiple charge transport paths. Herein, we report on two semiconductive potassium hydroxamate coordination polymers, denoted as [K(HONDI)(H2O)2]n (1) and [K(HONDI)]n (2). Both compounds theoretically possess dual charge transport paths, occurring internally and externally within the π-π stacking columns of the ligands. Conductivity measurements revealed that compounds 1 and 2 both exhibit semiconductive properties, with their electrical conductivities reaching 2.3 × 10-6 and 1.9 × 10-7 S/cm, respectively, at 30 °C. Their electrically conductive performance could be attributed to theoretically biaxial "band-like" charge transport inside crystals and "hopping" charge transport between grain boundaries.
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MicroRNAs (miRNAs) are a crucial type of non-coding RNAs involved in post-transcriptional regulation. The playing essential regulatory roles in the NF-κB signaling pathway and modulate the host immune response to diverse pathogens by targeting IκBα. However, the regulatory mechanism of miRNAs in relation with IκBα in Sebastes schlegelii remains unclear. In our study, we identified two copies of IkBα gene in black rockfish (Sebastes schlegelii), namely IkBα1 and IkBα2. Moreover, we have discovered that miRNA-530 can activate the NF-κB signaling pathway by inhibiting the expression of IκBα, thereby inducing the inflammatory response. This project comprehensively investigated the interactive regulatory roles of miRNA-530 in the NF-κB signaling pathway at both cellular and in vivo levels, while also elucidating the regulatory relationships between miRNA-530 and IκBα. In conclusion, our research confirmed that miRNA-530 can target the 3'UTR region of IκBα, resulting in a decrease in the expression of IκBα at the post-transcriptional level and inhibiting its translation. The findings contribute to the understanding of the regulatory network of non-coding RNA in teleosts and its subsequent regulation of the NF-κB signaling pathway by miRNAs.
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Regulação da Expressão Gênica , MicroRNAs , Inibidor de NF-kappaB alfa , NF-kappa B , Transdução de Sinais , MicroRNAs/genética , MicroRNAs/metabolismo , Animais , NF-kappa B/genética , NF-kappa B/metabolismo , Inibidor de NF-kappaB alfa/genética , Inibidor de NF-kappaB alfa/metabolismo , Regulação da Expressão Gênica/imunologia , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Imunidade Inata/genética , Peixes/genética , Peixes/imunologia , Perciformes/genética , Perciformes/imunologiaRESUMO
Detecting drug-drug interactions (DDIs) is an essential step in drug development and drug administration. Given the shortcomings of current experimental methods, the machine learning (ML) approach has become a reliable alternative, attracting extensive attention from the academic and industrial fields. With the rapid development of computational science and the growing popularity of cross-disciplinary research, a large number of DDI prediction studies based on ML methods have been published in recent years. To give an insight into the current situation and future direction of DDI prediction research, we systemically review these studies from three aspects: (1) the classic DDI databases, mainly including databases of drugs, side effects, and DDI information; (2) commonly used drug attributes, which focus on chemical, biological, and phenotypic attributes for representing drugs; (3) popular ML approaches, such as shallow learning-based, deep learning-based, recommender system-based, and knowledge graph-based methods for DDI detection. For each section, related studies are described, summarized, and compared, respectively. In the end, we conclude the research status of DDI prediction based on ML methods and point out the existing issues, future challenges, potential opportunities, and subsequent research direction.
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Bases de Conhecimento , Aprendizado de Máquina , Interações Medicamentosas , Preparações Farmacêuticas , Bases de Dados FactuaisRESUMO
BACKGROUND: To identify the factors influencing the early encapsulation of peripancreatic fluid/necrosis collections via contrast-enhanced computed tomography (CECT) and to determine the clinical significance of early encapsulation for determining the prognosis of acute pancreatitis (AP) patients. METHODS: AP patients who underwent CECT between 4 and 10 days after disease onset were enrolled in this study. Early encapsulation was defined as a continuous enhancing wall around peripancreatic fluid/necrosis collections on CECT. Univariate and multivariate logistic regression analyses were performed to assess the associations between the variables and early encapsulation. Clinical outcomes were compared between the non-encapsulation and early encapsulation groups with 1:1 propensity score matching. RESULTS: A total of 289 AP patients were enrolled. The intra-observer and inter-observer agreement were considered good (kappa statistics of 0.729 and 0.614, respectively) for identifying early encapsulation on CECT. The ratio of encapsulation increased with time, with a ratio of 12.5% on day 5 to 48.7% on day 9. Multivariate logistic regression analysis revealed that the longer time from onset to CECT examination (OR 1.55, 95% CI 1.23-1.97), high alanine aminotransferase level (OR 0.98, 95% CI 0.97-0.99), and high APACHE II score (OR 0.89, 95% CI 0.81-0.98) were found to be independent factors associated with delayed encapsulation. The incidence of persistent organ failure was significantly lower in the early encapsulation group after matching (22.4% vs 6.1%, p = 0.043). However, there was no difference in the incidence of infected pancreatic necrosis, surgical intervention, or in-hospital mortality. CONCLUSIONS: AP patients without early encapsulation of peripancreatic fluid/necrosis collections have a greater risk of persistent organ failure. In addition to longer time, the high APACHE II score and elevated alanine aminotransferase level are factors associated with delayed encapsulation.
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Pancreatite , Humanos , Pancreatite/diagnóstico por imagem , Pancreatite/cirurgia , Doença Aguda , Relevância Clínica , Alanina Transaminase , Prognóstico , Necrose/diagnóstico por imagemRESUMO
Aristolochic acids (AAs) have been identified as a significant risk factor for hepatocellular carcinoma (HCC). Ferroptosis is a type of regulated cell death involved in the tumor development. In this study, we investigated the molecular mechanisms by which AAs enhanced the growth of HCC. By conducting bioinformatics and RNA-Seq analyses, we found that AAs were closely correlated with ferroptosis. The physical interaction between p53 and AAs in HepG2 cells was validated by bioinformatics analysis and SPR assays with the binding pocket sites containing Pro92, Arg174, Asp207, Phe212, and His214 of p53. Based on the binding pocket that interacts with AAs, we designed a mutant and performed RNA-Seq profiling. Interestingly, we found that the binding pocket was responsible for ferroptosis, GADD45A, NRF2, and SLC7A11. Functionally, the interaction disturbed the binding of p53 to the promoter of GADD45A or NRF2, attenuating the role of p53 in enhancing GADD45A and suppressing NRF2; the mutant did not exhibit the same effects. Consequently, this event down-regulated GADD45A and up-regulated NRF2, ultimately inhibiting ferroptosis, suggesting that AAs hijacked p53 to down-regulate GADD45A and up-regulate NRF2 in HepG2 cells. Thus, AAs treatment resulted in the inhibition of ferroptosis via the p53/GADD45A/NRF2/SLC7A11 axis, which led to the enhancement of tumor growth. In conclusion, AAs-hijacked p53 restrains ferroptosis through the GADD45A/NRF2/SLC7A11 axis to enhance tumor growth. Our findings provide an underlying mechanism by which AAs enhance HCC and new insights into p53 in liver cancer. Therapeutically, the oncogene NRF2 is a promising target for liver cancer.
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Lymphocyte activation gene 3 (LAG3), an immune checkpoint molecule expressed on activated T cells, functions as a negative regulator of immune responses. Persistent antigen exposure in the tumor microenvironment results in sustained LAG3 expression on T cells, contributing to T cell dysfunction. Fibrinogen-like protein 1 (FGL1) has been identified as a major ligand of LAG3, and FGL1/LAG3 interaction forms a novel immune checkpoint pathway that results in tumor immune evasion. In addition, ubiquitin-specific peptidase 7 (USP7) plays a crucial role in cancer development. In this study we investigated the role of USP7 in modulation of FGL1-mediated liver cancer immune evasion. We showed that knockdown of USP7 or treatment with USP7 inhibitor P5091 suppressed liver cancer growth by promoting CD8+ T cell activity in Hepa1-6 xenograft mice and in HepG2 or Huh7 cells co-cultured with T cells, whereas USP7 overexpression produced the opposite effect. We found that USP7 upregulated FGL1 in HepG2 and Huh7 cells by deubiquitination of transcriptional factor PR domain zinc finger protein 1 (PRDM1), which transcriptionally activated FGL1, and attenuated the CD8+ T cell activity, leading to the liver cancer growth. Interestingly, USP7 could be transcriptionally stimulated by PRDM1 as well in a positive feedback loop. P5091, an inhibitor of USP7, was able to downregulate FGL1 expression, thus enhancing CD8+ T cell activity. In an immunocompetent liver cancer mouse model, the dual blockade of USP7 and LAG3 resulted in a superior antitumor activity compared with anti-LAG3 therapy alone. We conclude that USP7 diminishes CD8+ T cell activity by a USP7/PRDM1 positive feedback loop on FGL1 production in liver cancer; USP7 might be a promising target for liver cancer immunotherapy.
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Linfócitos T CD8-Positivos , Neoplasias Hepáticas , Peptidase 7 Específica de Ubiquitina , Regulação para Cima , Peptidase 7 Específica de Ubiquitina/metabolismo , Peptidase 7 Específica de Ubiquitina/antagonistas & inibidores , Peptidase 7 Específica de Ubiquitina/genética , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Linhagem Celular Tumoral , Camundongos Endogâmicos C57BL , Fibrinogênio , TiofenosRESUMO
The angiotensin II type 2 receptor (AT2R) is a well-established component of the renin-angiotensin system and is known to counteract classical activation of this system and protect against organ damage. Pharmacological activation of the AT2R has significant therapeutic benefits, including vasodilation, natriuresis, anti-inflammatory activity, and improved insulin sensitivity. However, the precise biological functions of the AT2R in maintaining homeostasis in liver tissue remain largely unexplored. In this study, we found that the AT2R facilitates liver repair and regeneration following acute injury by deactivating Hippo signaling and that interleukin-6 transcriptionally upregulates expression of the AT2R in hepatocytes through STAT3 acting as a transcription activator binding to promoter regions of the AT2R. Subsequently, elevated AT2R levels activate downstream signaling via heterotrimeric G protein Gα12/13-coupled signals to induce Yap activity, thereby contributing to repair and regeneration processes in the liver. Conversely, a deficiency in the AT2R attenuates regeneration of the liver while increasing susceptibility to acetaminophen-induced liver injury. Administration of an AT2R agonist significantly enhances the repair and regeneration capacity of injured liver tissue. Our findings suggest that the AT2R acts as an upstream regulator in the Hippo pathway and is a potential target in the treatment of liver damage.
Assuntos
Via de Sinalização Hippo , Interleucina-6 , Regeneração Hepática , Camundongos Endogâmicos C57BL , Proteínas Serina-Treonina Quinases , Receptor Tipo 2 de Angiotensina , Transdução de Sinais , Animais , Masculino , Camundongos , Acetaminofen , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Hepatócitos/metabolismo , Hepatócitos/efeitos dos fármacos , Interleucina-6/metabolismo , Fígado/metabolismo , Fígado/efeitos dos fármacos , Regeneração Hepática/efeitos dos fármacos , Regeneração Hepática/fisiologia , Camundongos Knockout , Proteínas Serina-Treonina Quinases/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Proteínas de Sinalização YAP/metabolismoRESUMO
BACKGROUND: Poor cardiovascular health (CVH) and physical frailty were reported to increase mortality risk, but their joint effects have not been fully elucidated. OBJECTIVES: We aimed to explore the separate and joint effects of CVH and frailty on mortality based on two perspectives of Life's Essential 8 (LE8) and Framingham Risk Score (FRS). METHODS: 21 062 participants in the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2018 were involved in this study. CVH was evaluated by the LE8 and FRS, and categorized into low, moderate and high CVH groups. Cox proportional hazard models were applied to estimate the separate and joint associations of CVH and frailty index (FI) with all-cause, cardiovascular disease (CVD) and cancer mortality. RESULTS: Over a median follow-up period of 87 months (95% CI: 86.0-88.0), 2036 deaths occurred. The separate linear dose-response relationships between CVH, frailty and mortality were observed (nonlinear P > .05). The combination of low CVH/frailty was negatively associated with all-cause mortality [hazard ratio (HR) and 95%CI: low LE8*FI, 5.30 (3.74, 7.52); high FRS*FI, 4.34 (3.20, 5.88)], CVD mortality [low LE8*FI, 6.57 (3.54, 12.22); high FRS*FI, 7.29 (3.92, 13.55)] and cancer mortality [low LE8*FI, 1.99 (1.14, 3.25); high FRS*FI, 2.32 (1.30, 4.15)], with high CVH/fit group as reference. Further stratified analyses showed that the combined burden of mortality from frailty and low CVH was greater among the young and females. CONCLUSIONS: Low CVH and frailty were independently and jointly correlated with greater risk of all-cause, CVD and cancer deaths, especially among the young and females.
Assuntos
Doenças Cardiovasculares , Causas de Morte , Fragilidade , Inquéritos Nutricionais , Humanos , Masculino , Feminino , Doenças Cardiovasculares/mortalidade , Fragilidade/mortalidade , Fragilidade/diagnóstico , Estudos Prospectivos , Pessoa de Meia-Idade , Idoso , Fatores de Risco , Neoplasias/mortalidade , Medição de Risco , Modelos de Riscos Proporcionais , Adulto , Estados Unidos/epidemiologia , Idoso Fragilizado/estatística & dados numéricosRESUMO
BACKGROUND: The purpose of this study was to evaluate the safety and efficacy of preoperative concurrent chemoradiotherapy (preCRT) for locally advanced rectal cancer in older people who were classified as "fit" by comprehensive geriatric assessment (CGA). METHODS: A single-arm, multicenter, phase II trial was designed. Patients were eligible for this study if they were aged 70 years or above and met the standards of "fit" (SIOG1) as evaluated by CGA and of the locally advanced risk category. The primary endpoint was 2-year disease-free survival (DFS). Patients were scheduled to receive preCRT (50 Gy) with raltitrexed (3 mg/m2 on days 1 and 22). RESULTS: One hundred and nine patients were evaluated by CGA, of whom eighty-six, eleven and twelve were classified into the fit, intermediate and frail category. Sixty-eight fit patients with a median age of 74 years were enrolled. Sixty-four patients (94.1%) finished radiotherapy without dose reduction. Fifty-four (79.3%) patients finished the prescribed raltitrexed therapy as planned. Serious toxicity (grade 3 or above) was observed in twenty-four patients (35.3%), and fourteen patients (20.6%) experienced non-hematological side effects. Within a median follow-up time of 36.0 months (range: 5.9-63.1 months), the 2-year overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS) rates were 89.6% (95% CI: 82.3-96.9), 92.4% (95% CI: 85.9-98.9) and 75.6% (95% CI: 65.2-86.0), respectively. Forty-eight patients (70.6%) underwent surgery (R0 resection 95.8%, R1 resection 4.2%), the corresponding R0 resection rate among the patients with positive mesorectal fascia status was 76.6% (36/47). CONCLUSION: This phase II trial suggests that preCRT is efficient with tolerable toxicities in older rectal cancer patients who were evaluated as fit based on CGA. TRIAL REGISTRATION: The registration number on ClinicalTrials.gov was NCT02992886 (14/12/2016).
Assuntos
Quimiorradioterapia , Avaliação Geriátrica , Neoplasias Retais , Humanos , Idoso , Masculino , Feminino , Neoplasias Retais/terapia , Idoso de 80 Anos ou mais , Avaliação Geriátrica/métodos , Quimiorradioterapia/métodos , Intervalo Livre de Doença , Cuidados Pré-Operatórios/métodos , Tiofenos/administração & dosagem , Tiofenos/uso terapêutico , Equipe de Assistência ao Paciente , Quinazolinas/administração & dosagem , Quinazolinas/uso terapêuticoRESUMO
BACKGROUND: No study has concentrated on the association of LE8 with cancer risk and death. We aim to examine the association of LE8 with death and cancer. METHODS: A total of 94733 adults aged 51.42 ± 12.46 years and 77551 participants aged 54.09±12.06 years were enrolled in longitudinal and trajectory analysis respectively. Baseline LE8 was divided into three groups based on the American Heart Association criteria and three trajectory patterns by latent mixture models. We reviewed medical records and clinical examinations to confirm incident cancer during the period from 2006 to 2020. Death information was collected from provincial vital statistics offices. Cox models were used. RESULTS: 12807 all-cause deaths and 5060 cancers were documented during a 14-year follow-up. Relative to participants with high LE8 at baseline, participants with lower levels of LE8 have a significantly increased risk of mortality and incident cancer. All these risks have an increasing trend with LE8 level decreasing. Meanwhile, the trajectory analysis recorded 7483 all-cause deaths and 3037 incident cancers after approximately 10 years. The associations of LE8 with death and cancer were identical to the longitudinal study. In the subtype cancer analysis, LE8 has a strong effect on colorectal cancer risk. Moreover, the cut point is 56.67 in the association between LE8 and death, while the cut point altered to 64.79 in the association between LE8 and incident cancers. These associations were enhanced among younger adults. CONCLUSIONS: There was a significant association of LE8 with death and cancer risk, especially for the young population.