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Liver regeneration is under metabolic and immune regulation. Despite increasing recognition of the involvement of neutrophils in regeneration, it is unclear how the liver signals to the bone marrow to release neutrophils after injury and how reparative neutrophils signal to hepatocytes to reenter the cell cycle. Here we report that loss of the liver tumour suppressor Lifr in mouse hepatocytes impairs, whereas overexpression of leukaemia inhibitory factor receptor (LIFR) promotes liver repair and regeneration after partial hepatectomy or toxic injury. In response to physical or chemical damage to the liver, LIFR from hepatocytes promotes the secretion of cholesterol and CXCL1 in a STAT3-dependent manner, leading to the efflux of bone marrow neutrophils to the circulation and damaged liver. Cholesterol, via its receptor ERRα, stimulates neutrophils to secrete hepatocyte growth factor to accelerate hepatocyte proliferation. Altogether, our findings reveal a LIFR-STAT3-CXCL1-CXCR2 axis and a LIFR-STAT3-cholesterol-ERRα-hepatocyte growth factor axis that form bidirectional hepatocyte-neutrophil cross-talk to repair and regenerate the liver.
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AIM: To evaluate real-world abatacept retention and clinical outcomes in patients with rheumatoid arthritis in Taiwan. METHODS: This prospective, observational study enrolled patients with rheumatoid arthritis aged ≥20 years who received abatacept in real-world practice. The primary endpoint was the abatacept retention rate at 24 months. Patients were categorized into subgroups based on abatacept treatment status and previous biological disease-modifying antirheumatic drug (bDMARD) therapy. Risk factors affecting abatacept retention were determined by regression analysis. RESULTS: A total of 212 patients were enrolled. The overall abatacept retention rate at 24 months among all patients was 59.9% (95% confidence interval 53.0%-66.6%). Patients who were ongoing users of abatacept and bDMARD-naïve had the highest retention rate (76.3%); of these, 31.6% achieved low disease activity or remission after 2 years. Previous treatment with bDMARDs was associated with an increased risk of abatacept discontinuation (hazard ratio 1.99; p = .002). The most common reasons for abatacept discontinuation were drug switch (11.3%) and loss to follow-up (6.1%). Abatacept was well-tolerated with no new safety signals. CONCLUSION: The 24-month retention rate of abatacept was 59.9%; abatacept was associated with improved clinical outcomes and was well-tolerated in the real-world setting in Taiwan.
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Abatacepte , Antirreumáticos , Artrite Reumatoide , Indução de Remissão , Humanos , Abatacepte/uso terapêutico , Abatacepte/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/diagnóstico , Taiwan/epidemiologia , Masculino , Feminino , Pessoa de Meia-Idade , Antirreumáticos/uso terapêutico , Antirreumáticos/efeitos adversos , Resultado do Tratamento , Estudos Prospectivos , Fatores de Tempo , Idoso , Fatores de Risco , Adulto , Substituição de Medicamentos , Adesão à MedicaçãoRESUMO
BACKGROUND AND AIMS: Transcriptome sequencing revealed high expression of DDR2 in oxaliplatin-resistant hepatocellular carcinoma (HCC). This study aimed to explore the role of DDR2 in oxaliplatin resistance and immune evasion in HCC. METHODS: Oxaliplatin-resistant HCC cell lines were established. The interaction between DDR2 and STAT3 was investigated, along with the mechanisms involved in DDR2/STAT3-mediated PD-L1 upregulation and polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) accumulation both in vitro and in vivo. RESULTS: DDR2 was found to induce the phosphorylation of STAT3, leading to its nuclear translocation. Conversely, the activation of STAT3 enhanced DDR2 expression. A positive feedback loop involving DDR2/STAT3 was identified in oxaliplatin-resistant HCC and associated with PD-L1 upregulation, and PMN-MDSCs accumulation was identified in oxaliplatin-resistant HCC. Knockdown of DDR2 and STAT3 sensitized oxaliplatin-resistant HCC cells to oxaliplatin and resulted in decreased PMN-MDSCs and increased CD8+ T cells in the tumor microenvironment. Enzyme-linked immunosorbent array and MDSC transwell migration assays indicated that oxaliplatin-resistant HCC cells recruited PMN-MDSCs through CCL20. Dual luciferase reporter assays demonstrated that STAT3 can directly enhance the transcription of PD-L1 and CCL20. Furthermore, treatment with a PD-L1 antibody in combination with CCL20 blockade had significant antitumor effects on oxaliplatin-resistant HCC. CONCLUSIONS: Our findings revealed a positive feedback mechanism involving DDR2 and STAT3 that mediates the immunosuppressive microenvironment and promotes oxaliplatin resistance and immune evasion via PD-L1 upregulation and PMN-MDSC recruitment. Targeting the DDR2/STAT3 pathway may be a promising therapeutic strategy to overcome immune escape and chemoresistance in HCC.
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BACKGROUND: Little evidence exists about whether a combination of healthy lifestyle factors is associated with a lower risk of depressive symptoms among Chinese population. We aimed to investigate the association between combined healthy lifestyle factors and risk of depressive symptoms. METHODS: We conducted a baseline survey from July 2021 to December 2023, including 53,642 Chinese adults from general population. A healthy lifestyle score was constructed based on six lifestyle factors (physical activity, smoking status, alcohol consumption, diet, sleep duration, and body mass index). Logistic regression models were used to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) adjusted for confounding variables. RESULTS: Each additional healthy lifestyle score was associated with a 20 % lower risk of having depressive symptoms (OR (95 % CI): 0.80 (0.78-0.81)). Compared with individuals with ≤2 healthy lifestyle factors, individuals with all the six healthy lifestyle factors had a 58 % reduced risk of having depressive symptoms (0.42 (0.37-0.47)). After stratification by gender, education and urbanization, the significant inverse association with healthy lifestyle score was stronger in women, individuals with high education, and urban residents. Besides, the significant negative association between healthy lifestyle score and depressive symptoms remained for different severity of depressive symptoms. LIMITATIONS: Given the cross-sectional nature of data, we cannot make causal inferences. CONCLUSIONS: Our study indicated that adherence to healthy lifestyle factors was associated with a reduced risk of having depressive symptoms among Chinese adults. The observed associations were modified by gender, education and urbanization. These findings warrant further verification in interventional studies.
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Objectives: This study aimed to identify predictors of remission or low disease activity (LDA) in patients with rheumatoid arthritis (RA) and low-ultrasound inflammation. Methods: A total of 80 patients with RA who fulfilled the 1987 ACR criteria for RA with a disease activity score of 28 joints (DAS28) > 3.2 were recruited. Over 1 year of therapy, we conducted blood tests every 6 months to examine erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), monocyte chemotactic protein-1 (MCP-1), neuraminidase 3 (Neu3), and α-2,3-sialyltrasnferse I (ST3Gal-1) levels in B cells and monocytes. Additionally, we evaluated physical function by using the Health Assessment Questionnaire-Disability Index (HAQ-DI). Data on demographic and clinical parameters were collected, and musculoskeletal ultrasonography was performed twice a year on 12 specific joints to assess synovial changes. One year later, we compared all collected data and laboratory or ultrasound results between patients achieving remission or LDA and those who did not in order to determine the predictors. Results: Age, the presence or absence of rheumatoid factor, and the number of conventional disease-modifying anti-rheumatic drugs used were not correlated with remission or LDA for DAS28 or Simplified Disease Activity Index formulas. However, male sex, low CRP levels, low ESR levels, and low HAQ-DI scores were associated with a higher likelihood of achieving remission or LDA for DAS28-ESR. Negative anticyclic citrullinated peptide (CCP) and low HAQ-DI scores were predictors of remission or LDA for DAS28-MCP-1. Interestingly, having less than two comorbidities is a good predictor of a combined remission/low disease activity state for SDAI and DAS28-MCP-1. Furthermore, Neu3 and ST3Gal-1 levels and ST3Gal-1/Neu3 ratios in B cells and monocytes had no significant correlation with total ultrasound scores. Nevertheless, monocyte ST3Gal-1 and Neu3 correlated significantly with DAS28-ESR >5.1 and DAS-MCP-1 >4.8 (both categories belong to high disease activity), respectively (rho = 0.609 with p = 0.012, and rho = 0.727 with p = 0.011, respectively). Monocyte ST3Gal-1/Neu3 ratios connected with DAS28-ESR >5.1 and 3.3 < SDAI ⦠11 (low disease activity), respectively (rho = 0.662 with p = 0.005, and rho = 0.342 with p = 0.048, respectively). Conclusions: In patients with RA in Taiwan, male sex, low CRP levels, low ESR levels, and low HAQ-DI scores are predictors of remission or LDA for DAS28-ESR, which differ from the predictors for DAS28-MCP-1. Moreover, monocyte ST3Gal-1, Neu3, and their ratios correlated with different disease activity categories of DAS28-ESR, DAS28-MCP-1, and SDAI scores.
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Background: Patients with hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) present a poor prognosis. Current systemic therapies offer limited benefits. Hepatic artery infusion chemotherapy (HAIC) is a local regional treatment for advanced HCC, particularly in selected patients such as patients with PVTT or high intrahepatic tumor burden. Objectives: The purpose of this study is to retrospectively evaluate the efficacy and safety of HAIC combined with anti-PD-1 immunotherapy for HCC patients with PVTT, and explore factors related to survival prognosis, providing clues for treatment decisions for HCC patients. Design: This is a single-center retrospective study conducted over 2 years on consecutive PVTT patients receiving HAIC combined anti-PD-1 antibodies. Methods: The primary endpoint was overall survival (OS). Univariate and multivariate analyses were performed to identify prognostic factors affecting OS. Treatment-associated adverse events were evaluated as well. Results: A total of 119 patients were analyzed. The median OS and PFS were 14.9 months and 6.9 months. A total of 31.1% of grade 3-4 adverse events were reported, with elevated transaminase and total bilirubin being the most common. The independent variables correlated with survival include treatment-related alpha-fetoprotein (AFP) response, the presence of extrahepatic organ metastasis, absolute value of platelet (PLT), neutrophil-to-lymphocyte ratio, and combined usage of tyrosine kinase inhibitors (TKIs). Conclusion: In HCC patients with PVTT, combination therapy with HAIC and anti-PD-1 antibodies might be a promising therapy. The efficacy and safety of this combination protocol on patients with HCC complicated by PVTT warrants further investigation prospectively, especially in combination with TKIs.
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MALAT1, one of the few highly conserved nuclear long noncoding RNAs (lncRNAs), is abundantly expressed in normal tissues. Previously, targeted inactivation and genetic rescue experiments identified MALAT1 as a suppressor of breast cancer lung metastasis. On the other hand, Malat1-knockout mice are viable and develop normally. On a quest to discover the fundamental roles of MALAT1 in physiological and pathological processes, we find that this lncRNA is downregulated during osteoclastogenesis in humans and mice. Remarkably, Malat1 deficiency in mice promotes osteoporosis and bone metastasis of melanoma and mammary tumor cells, which can be rescued by genetic add-back of Malat1. Mechanistically, Malat1 binds to Tead3 protein, a macrophage-osteoclast-specific Tead family member, blocking Tead3 from binding and activating Nfatc1, a master regulator of osteoclastogenesis, which results in the inhibition of Nfatc1-mediated gene transcription and osteoclast differentiation. Notably, single-cell transcriptome analysis of clinical bone samples reveals that reduced MALAT1 expression in pre-osteoclasts and osteoclasts is associated with osteoporosis and metastatic bone lesions. Altogether, these findings identify Malat1 as a lncRNA that protects against osteoporosis and bone metastasis.
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Osteoporose , RNA Longo não Codificante , Animais , Humanos , Camundongos , Macrófagos/metabolismo , Osteoclastos/metabolismo , Osteogênese/genética , Osteoporose/genética , RNA Longo não Codificante/metabolismoRESUMO
The goal of this study was to evaluate the performance of a convolutional neural network (CNN) with preoperative MRI and clinical factors in predicting the treatment response of unresectable hepatocellular carcinoma (HCC) patients receiving hepatic arterial infusion chemotherapy (HAIC). A total of 191 patients with unresectable HCC who underwent HAIC in our hospital between May 2019 and March 2022 were retrospectively recruited. We selected InceptionV4 from three representative CNN models, AlexNet, ResNet, and InceptionV4, according to the cross-entropy loss (CEL). We subsequently developed InceptionV4 to fuse the information from qualified pretreatment MRI data and patient clinical factors. Radiomic information was evaluated based on several constant sequences, including enhanced T1-weighted sequences (with arterial, portal, and delayed phases), T2 FSE sequences, and dual-echo sequences. The performance of InceptionV4 was cross-validated in the training cohort (n = 127) and internally validated in an independent cohort (n = 64), with comparisons against single important clinical factors and radiologists in terms of receiver operating characteristic (ROC) curves. Class activation mapping was used to visualize the InceptionV4 model. The InceptionV4 model achieved an AUC of 0.871 (95% confidence interval [CI] 0.761-0.981) in the cross-validation cohort and an AUC of 0.826 (95% CI 0.682-0.970) in the internal validation cohort; these two models performed better than did the other methods (AUC ranges 0.783-0.873 and 0.708-0.806 for cross- and internal validations, respectively; P < 0.01). The present InceptionV4 model, which integrates radiomic information and clinical factors, helps predict the treatment response of unresectable HCC patients receiving HAIC treatment.
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Carcinoma Hepatocelular , Infusões Intra-Arteriais , Neoplasias Hepáticas , Imageamento por Ressonância Magnética , Redes Neurais de Computação , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/diagnóstico por imagem , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , Resultado do Tratamento , Artéria Hepática/diagnóstico por imagem , Adulto , Curva ROC , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêuticoRESUMO
Dermal papilla cells (DPCs) are key regulators of hair follicle (HF) development and growth, which not only regulate HF growth and cycling but play a role in the pathogenesis of hair loss. The transcription factor Homeobox C13 (HOXC13) can modulate the growth and development of HFs. Nevertheless, the specific genes and pathways regulated by HOXC13 in DPCs have yet to be determined. Thus, to gain a better understanding of genomic binding sites involved in HOXC13-regulated HF development, chromatin immunoprecipitation followed by high throughput sequencing (ChIP-Seq) was performed on rabbit DPCs with pcDNA3.1-3 × Flag-HOXC13 overexpression. A complete set of 9670 enrichment peaks was acquired by applying HOXC13-Flag ChIP. Subsequently, the peak sequence was annotated to the rabbit genome, revealing that 6.1 % of the peaks were identified within in the promoter region. Thereafter, five annotated genes were verified using RT-qPCR. The peak-associated genes were mainly enriched in signaling pathways related to HF development, such as MAPK and PI3K-Akt. Furthermore, by using a dual-luciferase reporter assay, we found that HOXC13 can target the protein kinase cAMPdependent catalytic ß (PRKACB) promoter region (-1596 â¼ -1107 bp) and inhibit its transcription, which was consistent with data obtained from ChIP-seq analysis. Overexpression of PRKACB gene significantly modulated the expression of BCL2, WNT2, LEF1, and SFRP2 genes related to HF development as determined by RT-qPCR (P < 0.01, P < 0.05). The CCK-8 and flow cytometry assays showed that PRKACB significantly inhibited the proliferation of DPCs and promoted apoptosis (P < 0.01). In conclusion, our research revealed that PRKACB has the potential to serve as a novel target gene of HOXC13, contributing to the regulation of the proliferation and apoptosis of DPCs. The process of identifying global target genes can contribute to the understanding of the intricate pathways that HOXC13 regulates in the growth of HFs.
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Sequenciamento de Cromatina por Imunoprecipitação , Genes Homeobox , Animais , Coelhos , Folículo Piloso , Fosfatidilinositol 3-Quinases , Imunoprecipitação da CromatinaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Shenze Shugan capsule is a prescription of traditional Chinese medicine for nonalcoholic steatohepatitis treatment. It includes Rhei Radix et Rhizoma (RR), Cassiae Semen (CS) and Alismatis Rhizoma(AR), which widely contains rhein, emodin, aurantio-obtusin, alisol A and alisol B 23-monoacetate. AIM OF THE STUDY: In this study, we aimed to explore the safety of the medicine, and further elucidate the mechanism of apoptosis induction in HK-2 cells by five components, including rhein, emodin, aurantio-obtusin, alisol A and alisol B 23-monoacetate. MATERIALS AND METHODS: We investigated the nephrotoxicity of Shenze Shugan capsule, including RR, CS, AR and mixed herbs given for two months in rats. Superoxide dismutase (SOD) in kidney tissues, urea nitrogen (BUN) and creatinine (CRE) in serum were detected, and renal pathology analysis was performed. In cell experiments, the apoptotic rate and cell cycle distribution of HK-2 cells were tested by flow cytometry. The levels of mitochondrial membrane potential (ΔΨm) and related protein expression in mitochondrial pathway were measured as well. RESULTS: We confirmed that two months of administering high doses(60 times the dose for clinical use in adults) of RR, CS or mixed herbs upregulated the levels of CRE and RUN, inhibited SOD activity, and increased the degree of tubular degeneration and glomerular dilatation, but Shenze Shugan capsule has no significant differences in renal structure or renal function. In addition, we found that five components all concentration-dependently inhibited HK-2 cells proliferation and induced apoptosis, especially aurantio-obtusin as the novel nephrotoxic component. Rhein and emodin significantly induced S/M accumulation, but aurantio-obtusin, alisol A and alisol B 23-monoacetate significantly induced G1/M accumulation in HK-2 cells. Similarly, they could induce Caspase3 activation, loss of mitochondrial membrane potential (ΔΨm), and down-regulation of Bcl-2 and up-regulation of Bax. CONCLUSIONS: Through a two-month subchronic toxicity study in rats, our preliminary determination is that this formulation is safe and reliable for long-term use. Interestingly, the potentially toxic herbs such as RR, CS, AR can reduce toxicity by drug compatibility. When further exploring the mechanism of action of toxic herbs, we found that mitochondrial pathway is involved in the apoptosis of HK -2 cells induced by rhein, emodin, aurantio-obtusin, alisol A and alisol B 23-monoacetate. Our findings provide new ideas for safety studies of Shenze Shugan capsule.
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Emodina , Ratos , Animais , Antraquinonas/toxicidade , Apoptose , Superóxido DismutaseRESUMO
To assess the causal effect of particulate matter 2.5 (PM2.5) on human bone mineral density (BMD) and to explore the possible mechanism and proportion mediated by inflammation-related protein. The genetic correlation between PM2.5 and BMD was assessed using the Linkage Disequilibrium Score (LDSC), and the causal effect between PM2.5 and BMD was assessed by two-sample Mendelian randomization (TSMR). A 2-step Mendelian randomization (MR) approach was employed to evaluate the potential role of inflammation-associated protein as the mediator in the causal association between PM2.5 and BMD. The multivariate Mendelian randomization (MVMR) study was designed to perform mediation analyses, exclude possible confounders and calculate the proportion of mediation. Subsequently, we used Bayesian colocalization analysis to consolidate the MR results. Finally, using drug-target MR design, we evaluated the potential repurposing of tumor necrosis factor (TNF) inhibitors for the treatment of osteoporosis (OP). The results of the analyses show that BMD is negatively influenced by PM2.5 (Inverse variance weighted [IVW] beta [ß] = -0.288, 95% confidence interval [CI]: -0.534 - -0.042, P < 0.05). PM2.5 has a positive causal association with TNF (IVW ß = 1.564, 95% CI: 0.155 - 2.973, P < 0.05) and a negative causal association with protachykinin-1 (TAC-1) (IVW ß = -1.654, 95% CI: -3.063 - -0.244, P < 0.05). TNF has a negative causal association with BMD (Wald ratio ß = -0.082, 95% CI: -0.165 - 0.000, P < 0.05) and TAC-1 has a positive causal association with BMD (IVW ß = 0.042, 95% CI: 0.007 - 0.077, P < 0.05). After adjusting TNF and TAC-1, PM2.5 has no causal association with BMD (IVW ß = -0.200, 95% CI: -0.579 - 0.179, P > 0.05). After adjusting PM2.5 and TAC-1, there was still a negative causal association between TNF and BMD (IVW ß = -0.089, 95% CI: -0.166 - -0.012, P < 0.05). In the final drug-target MR study, the protective effect of TNF/TNF receptor 1 (TNFR1) inhibition on BMD was observed. For every 10% decrease of circulating C-reactive protein (CRP) achieved by TNF/TNF receptor 1 (TNFR1) blockade, ß was 0.540 (95% CI: 0.040-1.040) for BMD. We found a negative causal association between PM2.5 and BMD and that causal association was mediated by TNF. The results of drug-target MR do support TNFR1 as a promising target for OP prevention among the general population.
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Proteoma , Receptores Tipo I de Fatores de Necrose Tumoral , Humanos , Densidade Óssea/genética , Teorema de Bayes , Análise da Randomização Mendeliana , Fator de Necrose Tumoral alfa/genética , Inflamação , Material Particulado/toxicidade , Estudo de Associação Genômica AmplaRESUMO
BACKGROUND: Male patients with papillary thyroid carcinoma (PTC) tend to have poorer prognosis compared to females, partially attributable to a higher rate of lymph node metastasis (LNM). Developing a precise predictive model for LNM occurrence in male PTC patients is imperative. While preliminary predictive models exist, there is room to improve accuracy. Further research is needed to create optimized prognostic models specific to LNM prediction in male PTC cases. METHODS: We conducted a comprehensive search of publicly available microarray datasets to identify candidate genes continuously upregulated or downregulated during PTC progression in male patients only. Univariate Cox analysis and lasso regression were utilized to construct an 11-gene signature predictive of LNM. TIPARP emerged as a key candidate gene, which we validated at the protein level using immunohistochemical staining. A prognostic nomogram incorporating the signature and clinical factors was developed based on the TCGA cohort. RESULTS: The 11-gene signature demonstrated good discriminative performance for LNM prediction in training and validation datasets. High TIPARP expression associated with advanced stage, high T stage, and presence of LNM. A prognostic nomogram integrating the signature and clinical variables reliably stratified male PTC patients into high and low recurrence risk groups. CONCLUSIONS: We identified a robust 11-gene signature and prognostic nomogram for predicting LNM occurrence in male PTC patients. We propose TIPARP as a potential contributor to inferior outcomes in males, warranting further exploration as a prognostic biomarker and immunotherapeutic target. Our study provides insights into the molecular basis for gender disparities in PTC.
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Objective To investigate the value of magnetic resonance imaging(MRI)T2-mapping in evaluating the activity of Graves ophthalmopathy(GO).Methods A total of 64 patients with GO in the Department of Endocrinology,the First Affiliated Hospital of Chongqing Medical University from July 2019 to January 2021 were collected.Simple random grouping was performed by computer,with 49 cases as observation subjects,and 15 patients for diagnostic test.According to clinical activity score(CAS),49 GO patients were divided into active group(CAS≥3 points,48 eyes)and inactive group(CAS<3 points,50 eyes).Normal control group(NC group)included 31 patients(62 eyes).All subjects underwent 3.0T orbital MRI T2-mapping.Measuring the T2 relaxation time(T2RT)of superior rectus,inferior rectus,medial rectus,and lateral rectus on five layers behind the eyeball on T2-mapping coronal images,and select the maximum value of T2RT in the five layers for each extraocular muscle to represent the T2RT of this extraocular muscle.Finally,select the maximum T2RT values of the four extraocular muscles,expressed as extraocular muscle maximum T2RT.Compare the differences of the above 5 indicators(superior rectus T2RT,inferior rectus T2RT,medial rectus T2RT,lateral rectus T2RT,extraocular muscle maximum T2RT)between active group,inactive group and NC group.ROC curve was used to analyze the diagnostic value of the above 5 indicators for GO activity assessment,and the diagnostic threshold was obtained.Then,another 15 GO patients were performed for diagnostic tests evaluation to determine the indicators of high diagnostic efficacy and the threshold of diagnostic activity.Results The T2RT of all extraocular muscles in active group were significantly higher than those in inactive group and NC group,the difference was statistically significant(P<0.001).The threshold value of the five indicators were obtained by ROC curve analysis.The maximum T2RT cut-off values of superior rectus muscle,inferior rectus muscle,medial rectus muscle,lateral rectus muscle and extraocular muscles for judging activity were 80.200 ms,97.045 ms,94.355 ms,85.750 ms and 101.385 ms respectively.Another 15 GO patients were performed for diagnostic tests,the indexes with relatively high sensitivity,specificity,positive predictive value and negative predictive value were inferior rectus T2RT and extraocular muscle maximum T2RT,the cut-off values of GO activity were 97.045 ms and 101.385 ms,respectively;the sensitivity were 91.7%and 93.8%,respectively;the specificity all were 80.0%.Conclusions MRI T2-mapping sequence has a good value in assessment of GO activity.The inferior rectus T2RT and extraocular muscle maximum T2RT can be choosed to evaluate the activity of GO.
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Waste resource utilization of petroleum coke is crucial for achieving global carbon emission reduction. Herein, a series of N-doped microporous carbons were fabricated from petroleum coke using a one-pot synthesis method. The as-prepared samples had a large specific surface area (up to 2512 m2/g), a moderate-high N content (up to 4.82 at.%), and high population (55%) of ultra-micropores (<0.7 nm). Regulating the N content and ultra-microporosity led to efficient CO2 adsorption and separation. At ambient pressure, the optimal N-doped petroleum coke-based microporous carbon exhibited the highest CO2 uptake of 4.25 mmol/g at 25°C and 6.57 mmol/g at 0°C. These values are comparable or even better than those of numerous previously reported adsorbents prepared by multistep synthesis, primarily due to the existence of ultra-micropores. The sample exhibited excellent CO2/N2 selectivity at 25°C owing to the abundant basic pyridinic and pyrrolic N species; and showed superior CO2 adsorption-desorption cycling performance, which was maintained at 97% after 10 cycles at 25°C. Moreover, petroleum coke-based microporous carbon, with a considerably high specific surface area and hierarchical pore structure, exhibited excellent electrochemical performance over the N-doped sample, maintaining a favorable specific capacitance of 233.25 F/g at 0.5 A/g in 6 mol/L KOH aqueous electrolyte. This study provides insight into the influence of N-doping on the porous properties of petroleum coke-based carbon. Furthermore, the as-prepared carbons were found to be promising adsorbents for CO2 adsorption, CO2/N2 separation and electrochemical application.
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Carbono , Coque , Carbono/química , Dióxido de Carbono/química , Adsorção , PorosidadeRESUMO
Cuproptosis is a novel cell death mechanism caused by copper overload, with FDX1 serving as the key regulator. LncRNAs are known to play a significant role in the aberrant regulation of gene expression in hepatocellular carcinoma (HCC). In this study, we investigated the biological role of the LINC02362/hsa-miR-18a-5p/FDX1 axis in HCC. We first explored the expression pattern, prognostic value, biological functions, drug sensitivity, and immune effect of FDX1. Using bioinformatics techniques, we then predicted several potential target lncRNAs and miRNAs. We identified a lncRNA-miRNA-FDX1 axis based on the ceRNA mechanism. In vitro experiments were conducted to validate the relationship between the lncRNA-miRNA-FDX1 axis and its biological effects in HCC. Finally, we investigated the relationship between the LINC02362/hsa-miR-18a-5p/FDX1 axis and oxaliplatin-induced cuproptosis in HCC. Our findings indicated that FDX1 expression was downregulated in HCC tissues; however, elevated FDX1 expression correlates with improved prognosis and heightened sensitivity to oxaliplatin. We confirmed that LINC02362 binds to and directly regulates the expression of miR-18a-5p, with FDX1 a target of miR-18a-5p. Experimental results suggested that upregulating LINC02362/hsa-miR-18a-5p/FDX1 axis suppressed the proliferation of HCC cells. Furthermore, LINC02362 knockdown led to a reduction in copper concentration and resistance to elesclomol-Cu. We also discovered that augmenting the LINC02362/hsa-miR-18a-5p/FDX1 axis could bolster the sensitivity of HCC to oxaliplatin through cuproptosis. This work presents the LINC02362/hsa-miR-18a-5p/FDX1 axis as a novel pathway that triggers cuproptosis and enhances the sensitivity of HCC to oxaliplatin, presenting a promising therapeutic avenue to combat oxaliplatin resistance in HCC.
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Oxaliplatin is commonly used as the first-line chemotherapeutic agent for advanced hepatocellular carcinoma (HCC). Unfortunately, the acquired resistance, limits the effectiveness of oxaliplatin and the underlying mechanisms remain unknown. Therefore, we explored the role of NOD-like receptor protein 3 (NLRP3)/IL-1ß in mediating oxaliplatin resistance in HCC. We observed that NLRP3/IL-1ß expression was much higher in oxaliplatin-resistant HCC cells. To further understand its impact on drug resistance, we knocked down NLRP3 and observed that it sensitized HCC cells to the growth-inhibitory effects of oxaliplatin and induced cell apoptosis. NLRP3/IL-1ß overexpressing tumor cells also attracted polymorphonuclear myeloid-derived suppressor cells. Using mouse models, we demonstrated that NLRP3/IL-1ß inhibition by short hairpin RNA or MCC950 effectively overcame oxaliplatin resistance. Furthermore, NLRP3/IL-1ß inhibition resulted in reduced expression of PD-L1. We also found that PD-L1 antibody combined with NLRP3/IL-1ß blockade displayed significant antitumor effect in HCC. Overall, our study provides compelling evidence supporting the essential role of NLRP3/IL-1ß in conferring resistance to oxaliplatin and reshaping the immunosuppressive microenvironment in HCC. Targeting NLRP3/IL-1ß presents a potential therapeutic target for overcoming oxaliplatin resistance and reshaping microenvironment of HCC.
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To establish a high-quality, easy-to-use, and effective risk prediction model for hepatic encephalopathy, to help healthcare professionals with identifying people who are at high risk of getting hepatic encephalopathy, and to guide them to take early interventions to reduce the occurrence of hepatic encephalopathy. Patients (n = 1178) with decompensated cirrhosis who attended the First Affiliated Hospital of Guangxi University of Chinese Medicine between January 2016 and June 2022 were selected for the establishment and validation of a nomogram model for risk prediction of hepatic encephalopathy. In this study, we screened the risk factors for the development of hepatic encephalopathy in patients with decompensated cirrhosis by univariate analysis, LASSO regression and multifactor analysis, then established a nomogram model for predicting the risk of getting hepatic encephalopathy for patients with decompensated cirrhosis, and finally performed differentiation analysis, calibration analysis, clinical decision curve analysis and validation of the established model. A total of 1178 patients with decompensated cirrhosis who were hospitalized and treated at the First Affiliated Hospital of Guangxi University of Chinese Medicine between January 2016 and June 2022 were included for modeling and validation. Based on the results of univariate analysis, LASSO regression analysis and multifactor analysis, a final nomogram model with age, diabetes, ascites, spontaneous peritonitis, alanine transaminase, and blood potassium as predictors of hepatic encephalopathy risk prediction was created. The results of model differentiation analysis showed that the AUC of the model of the training set was 0.738 (95% CI 0.63-0.746), while the AUC of the model of the validation set was 0.667 (95% CI 0.541-0.706), and the two AUCs indicated a good discrimination of this nomogram model. According to the Cut-Off value determined by the Jorden index, when the Cut-Off value of the training set was set at 0.150, the sensitivity of the model was 72.8%, the specificity was 64.8%, the positive predictive value was 30.4%, and the negative predictive value was 91.9%; when the Cut-Off value of the validation set was set at 0.141, the sensitivity of the model was 69.7%, the specificity was 57.3%, the positive predictive value was 34.5%, and the negative predictive value was 84.7%. The calibration curve and the actual events curve largely overlap at the diagonal, indicating that the prediction with this model has less error. The Hosmer-Lemeshow test for goodness of fit was also applied, and the results showed that for the training set, χ2 = 1.237587, P = 0.998, and for the validation set, χ2 = 31.90904, P = 0.0202, indicating that there was no significant difference between the predicted and actual observed values. The results of the clinical decision curve analysis showed that the model had a good clinical benefit, compared with the two extreme clinical scenarios (all patients treated or none treated), and the model also had a good clinical benefit in the validation set. This study showed that aged over 55 years, complications of diabetes, ascites, and spontaneous bacterial peritonitis, abnormal glutamate aminotransferase and abnormal blood potassium are independent risks indicators for the development of hepatic encephalopathy in patients with decompensated cirrhosis. The nomogram model based on the indicators mentioned above can effectively and conveniently predict the risk of developing hepatic encephalopathy in patients with decompensated cirrhosis. The nomogram model established on this study can help clinical healthcare professionals to timely and early identify patients with high risk of developing hepatic encephalopathy.
Assuntos
Encefalopatia Hepática , Peritonite , Humanos , Idoso , Encefalopatia Hepática/diagnóstico , Encefalopatia Hepática/etiologia , Ascite , Nomogramas , Estudos Retrospectivos , China/epidemiologia , PotássioRESUMO
Cuproptosis is a novel type of copper-induced cell death and is considered as a new therapeutic target for many cancers. Distant metastases occur in about 40% of patients with advanced renal cell carcinoma (RCC), with a poor 5-year prognosis of about 10%. Through a series of comprehensive analyses, four differentially expressed cuproptosis-related lncRNAs (DECRLs) were identified as candidate biomarkers for RCC. The risk model constructed by using these four DECRLs can better predict the prognosis of patients with RCC, which is determined by the receiver operating characteristic (Time dependent area under curve value at 1-year, 3-year, 5-year, and 10-year were 0.82, 0.80, 0.76, and 0.73 respectively). There were significant differences in immune status between high-risk and low-risk RCC patients. The differentially expressed gene enrichment terms between high- and low-risk patients was also dominated by immune-related terms. The risk score was also correlated with immunotherapy as measured by the tumor immune dysfunction and exclusion (TIDE) score. In addition, we also found that the sensitivity of many chemotherapy drugs varies widely between high- and low-risk patients. The sensitivity of the three chemotherapy drugs (AZD4547, Vincristine, and WEHI-539) varied among high- and low-risk patients, and was significantly negatively correlated with risk values, suggesting that they could be used as clinical treatment drugs for RCC. Our study not only obtained four potential biomarkers, but also provided guidance for immunotherapy and chemotherapy treatment of RCC, as well as new research strategies for the screening of other cancer biomarkers and sensitive drugs.