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BACKGROUND: Chronic heart failure is a complex clinical syndrome. The Chinese herbal compound preparation Jianpi Huatan Quyu recipe has been used to treat chronic heart failure; however, the underlying molecular mechanism is still not clear. AIM: To identify the effective active ingredients of Jianpi Huatan Quyu recipe and explore its molecular mechanism in the treatment of chronic heart failure. METHODS: The effective active ingredients of eight herbs composing Jianpi Huatan Quyu recipe were identified using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. The target genes of chronic heart failure were searched in the Genecards database. The target proteins of active ingredients were mapped to chronic heart failure target genes to obtain the common drug-disease targets, which were then used to construct a key chemical component-target network using Cytoscape 3.7.2 software. The protein-protein interaction network was constructed using the String database. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed through the Metascape database. Finally, our previously published relevant articles were searched to verify the results obtained via network pharmacology. RESULTS: A total of 227 effective active ingredients for Jianpi Huatan Quyu recipe were identified, of which quercetin, kaempferol, 7-methoxy-2-methyl isoflavone, formononetin, and isorhamnetin may be key active ingredients and involved in the therapeutic effects of TCM by acting on STAT3, MAPK3, AKT1, JUN, MAPK1, TP53, TNF, HSP90AA1, p65, MAPK8, MAPK14, IL6, EGFR, EDN1, FOS, and other proteins. The pathways identified by KEGG enrichment analysis include pathways in cancer, IL-17 signaling pathway, PI3K-Akt signaling pathway, HIF-1 signaling pathway, calcium signaling pathway, cAMP signaling pathway, NF-kappaB signaling pathway, AMPK signaling pathway, etc. Previous studies on Jianpi Huatan Quyu recipe suggested that this Chinese compound preparation can regulate the TNF-α, IL-6, MAPK, cAMP, and AMPK pathways to affect the mitochondrial structure of myocardial cells, oxidative stress, and energy metabolism, thus achieving the therapeutic effects on chronic heart failure. CONCLUSION: The Chinese medicine compound preparation Jianpi Huatan Quyu recipe exerts therapeutic effects on chronic heart failure possibly by influencing the mitochondrial structure of cardiomyocytes, oxidative stress, energy metabolism, and other processes. Future studies are warranted to investigate the role of the IL-17 signaling pathway, PI3K-Akt signaling pathway, HIF-1 signaling pathway, and other pathways in mediating the therapeutic effects of Jianpi Huatan Quyu recipe on chronic heart failure.
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Spent lithium-ion batteries (LIBs) have emerged as a major source of waste due to their low recovery rate. The physical disposal of spent LIBs can lead to the leaching of their contents into the surrounding environment. While it is widely agreed that hazardous substances such as nickel and cobalt in the leachate can pose a threat to the environment and human health, the overall composition and toxicity of LIB leachate remain unclear. In this study, a chemical analysis of leachate from spent LIBs was conducted to identify its primary constituents. The ecotoxicological parameters of the model organism, rotifer Brachionus asplanchnoidis, were assessed to elucidate the toxicity of the LIB leachate. Subsequent experiments elucidated the impacts of the LIB leachate and its representative components on the malondialdehyde (MDA) level, antioxidant capacity, and enzyme activity of B. asplanchnoidis. The results indicate that both the LIB leachate and its components are harmful to individual rotifers due to the adverse effects of stress-induced disturbances in biochemical indicators, posing a threat to population development. The intensified poisoning phenomenon under combined stress suggests the presence of complex synergistic effects among the components of LIB leachate. Due to the likely environmental and biological hazards, LIBs should be strictly managed after disposal. Additionally, more economical and eco-friendly recycling and treatment technologies need to be developed and commercialized.
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Lítio , Malondialdeído , Estresse Oxidativo , Rotíferos , Poluentes Químicos da Água , Animais , Rotíferos/efeitos dos fármacos , Lítio/toxicidade , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Fontes de Energia Elétrica , Antioxidantes/metabolismoRESUMO
Background: Hepatocellular carcinoma (HCC) is often associated with the overexpression of multiple proteins and genes. For instance, patients with HCC and a high expression of the glypican-3 (GPC3) gene have a poor prognosis, and noninvasive assessment of GPC3 expression before surgery is helpful for clinical decision-making. Therefore, our primary aim in this study was to develop and validate multisequence magnetic resonance imaging (MRI) radiomics nomograms for predicting the expression of GPC3 in individuals diagnosed with HCC. Methods: We conducted a retrospective analysis of 143 patients with HCC, including 123 cases from our hospital and 20 cases from The Cancer Genome Atlas (TCGA) or The Cancer Imaging Archive (TCIA) public databases. We used preoperative multisequence MRI images of the patients for the radiomics analysis. We extracted and screened the imaging histologic features using fivefold cross-validation, Pearson correlation coefficient, and the least absolute shrinkage and selection operator (LASSO) analysis method. We used logistic regression (LR) to construct a radiomics model, developed nomograms based on the radiomics scores and clinical parameters, and evaluated the predictive performance of the nomograms using receiver operating characteristic (ROC) curves, calibration curves, and decision curves. Results: Our multivariate analysis results revealed that tumor morphology (P=0.015) and microvascular (P=0.007) infiltration could serve as independent predictors of GPC3 expression in patients with HCC. The nomograms integrating multisequence radiomics radiomics score, tumor morphology, and microvascular invasion had an area under the curve (AUC) value of 0.989. This approach was superior to both the radiomics model (AUC 0.979) and the clinical model (AUC 0.793). The sensitivity, specificity, and accuracy of 0.944, 0.800, and 0.913 for the test set, respectively, and the model's calibration curve demonstrated good consistency (Brier score =0.029). The decision curve analysis (DCA) indicated that the nomogram had a higher net clinical benefit for predicting the expression of GPC3. External validation of the model's prediction yielded an AUC value of 0.826. Conclusions: Our study findings highlight the close association of multisequence MRI imaging and radiomic features with GPC3 expression. Incorporating clinical parameters into nomograms can offer valuable preoperative insights into tailoring personalized treatment plans for patients diagnosed with HCC.
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Copper(II) chloride anionic coordination complexes with different imidazole-derived ligands due to the potential cytotoxic activity play the important role in protein. By investigating the experimental electron paramagnetic resonance (EPR) and ultraviolet-visible (UV-vis) spectra of [CuCl(C6H10N2)4]Cl, [CuCl(C6H10N2)4]Cl, [CuCl2(C4H6N2)4], and [Cu2Cl2(C5H8N2)6]Cl2·2H2O, the local structure of the corresponding Cu2+ centers and the role of different ligands are obtained. Based on the well-agreed EPR parameters and the d-d transitions (10Dq), the four Cu2+ centers show tetragonal and orthorhombic distortion, corresponding to the different anisotropies of EPR signals. In addition, the general rules of governing the impact of methanol in imidazolylalkyl derivatives are also discussed, especially the influence on the local environment (symmetry, distortion, covalency, and crystal field) of above four copper(II) chloride anionic coordination complexes. Therefore, the obtained results in this study will be beneficial to provide a theoretical basis for the experimental design of desired copper-containing imidazolyl alkyl derivatives.
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The enzyme phospholipase A2 (PLA2) plays a crucial role in acyl remodeling of phospholipids via the Lands' cycle, and consequently alters fatty acid compositions in triacylglycerol (TAG). In this study, a full-length cDNA sequence coding Myrmecia incisa phospholipase A2 (MiPLA2) was cloned using the technique of rapid amplification of cDNA ends. Comparison of the 1082-bp cDNA with its corresponding cloned DNA sequence revealed that MiPLA2 contained 3 introns. Mature MiPLA2 (mMiPLA2) had a conserved Ca2+-binding loop and a catalytic site motif that has been recognized in plant secretory PLA2 (sPLA2) proteins. Correspondingly, phylogenetic analysis illustrated that MiPLA2 was clustered within GroupXIA of plant sPLA2 proteins. To ascertain the function of MiPLA2, the cDNA coding for mMiPLA2 was subcloned into the vector pET-32a to facilitate the production of recombinant mMiPLA2 in Escherichia coli. Recombinant mMiPLA2 was purified and used for the in vitro enzyme reaction. Thin-layer chromatography profiles of the catalytic products generated by recombinant mMiPLA2 indicated a specificity for cleaving sn-2 acyl chains from phospholipids, thereby functionally characterizing MiPLA2. Although recombinant mMiPLA2 displayed a strong preference for phosphatidylethanolamine, it preferentially hydrolyzes arachidonic acid (ArA) at the sn-2 position of phosphatidylcholine. Results from the fused expression of p1300-sp-EGFP-mMiPLA2 illustrated that MiPLA2 was localized in the intercellular space of onion epidermis. Furthermore, the positive correlation between MiPLA2 transcription and free ArA levels were established. Consequently, the role of mMiPLA2 in the biosynthesis of ArA-rich TAG was elucidated. This study helps to understand how M. incisa preferentially uses ArA to synthesize TAG.
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Ácido Araquidônico , Fosfatidilcolinas , Fosfolipases A2 , Fosfolipases A2/metabolismo , Fosfolipases A2/genética , Ácido Araquidônico/metabolismo , Fosfatidilcolinas/metabolismo , Filogenia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Especificidade por Substrato , Sequência de Aminoácidos , Microalgas/genética , Microalgas/enzimologia , Microalgas/metabolismo , Clonagem MolecularRESUMO
The clinical efficacy of neoadjuvant immunotherapy plus chemotherapy remains elusive in localized epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Here, we report interim results of a Simon's two-stage design, phase 2 trial using neoadjuvant sintilimab with carboplatin and nab-paclitaxel in resectable EGFR-mutant NSCLC. All 18 patients undergo radical surgery, with one patient experiencing surgery delay. Fourteen patients exhibit confirmed radiological response, with 44% achieving major pathological response (MPR) and no pathological complete response (pCR). Similar genomic alterations are observed before and after treatment without influencing the efficacy of subsequent EGFR-tyrosine kinase inhibitors (TKIs) in vitro. Infiltration and T cell receptor (TCR) clonal expansion of CCR8+ regulatory T (Treg)hi/CXCL13+ exhausted T (Tex)lo cells define a subtype of EGFR-mutant NSCLC highly resistant to immunotherapy, with the phenotype potentially serving as a promising signature to predict immunotherapy efficacy. Informed circulating tumor DNA (ctDNA) detection in EGFR-mutant NSCLC could help identify patients nonresponsive to neoadjuvant immunochemotherapy. These findings provide supportive data for the utilization of neoadjuvant immunochemotherapy and insight into immune resistance in EGFR-mutant NSCLC.
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Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas , Receptores ErbB , Neoplasias Pulmonares , Mutação , Terapia Neoadjuvante , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/genética , Terapia Neoadjuvante/métodos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Mutação/genética , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Paclitaxel/uso terapêutico , Carboplatina/uso terapêutico , Adulto , Resultado do Tratamento , DNA Tumoral Circulante/genética , AlbuminasRESUMO
BACKGROUND: The role of novel circular RNAs (circRNAs) in colorectal cancer (CRC) remains to be determined. This study aimed to identify a novel circRNA involved in CRC pathogenesis, assess its diagnostic value, and construct a regulatory network. METHODS: Differential expression analysis was conducted using circRNA datasets to screen for differentially expressed circRNAs. The expression of selected circRNAs was validated in external datasets and clinical samples. Diagnostic value of plasma circRNA levels in CRC was assessed. A competing endogenous RNA (ceRNA) network was constructed for the circRNA using TCGA dataset. RESULTS: Analysis of datasets revealed that hsa_circ_101303 was significantly overexpressed in CRC tissues compared to normal tissues. The upregulation of hsa_circ_101303 in CRC tissues was further confirmed through the GSE138589 dataset and clinical samples. High expression of hsa_circ_101303 was associated with advanced N stage, M stage, and tumor stage in CRC. Plasma levels of hsa_circ_101303 were markedly elevated in CRC patients and exhibited moderate diagnostic ability for CRC (AUC = 0.738). The host gene of hsa_circ_101303 was also found to be related to the TNM stage of CRC. Nine miRNAs were identified as target miRNAs for hsa_circ_101303, and 27 genes were identified as targets of these miRNAs. Subsequently, a ceRNA network for hsa_circ_101303 was constructed to illustrate the interactions between the nine miRNAs and 27 genes. CONCLUSIONS: The study identifies hsa_circ_101303 as a highly expressed circRNA in CRC, which is associated with the progression of the disease. Plasma levels of hsa_circ_101303 show promising diagnostic potential for CRC. The ceRNA network for hsa_circ_101303 provides valuable insights into the regulatory mechanisms underlying CRC.
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Biomarcadores Tumorais , Neoplasias Colorretais , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , MicroRNAs , RNA Circular , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/sangue , Neoplasias Colorretais/patologia , RNA Circular/genética , RNA Circular/sangue , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/sangue , Masculino , Feminino , MicroRNAs/genética , MicroRNAs/sangue , Pessoa de Meia-Idade , Perfilação da Expressão Gênica , Estadiamento de NeoplasiasRESUMO
Objective: This study aimed to clarify the intervention effect of salidroside (SAL) on lung injury caused by PM 2.5 in mice and illuminate the function of SIRT1-PGC-1É axis. Methods: Specific pathogen-free (SPF) grade male C57BL/6 mice were randomly assigned to the following groups: control group, SAL group, PM 2.5 group, SAL+PM 2.5 group. On the first day, SAL was given by gavage, and on the second day, PM 2.5 suspension was given by intratracheal instillation. The whole experiment consist of a total of 10 cycles, lasting 20 days. At the end of treatment, blood samples and lung tissues were collected and analyzed. Observation of pathological changes in lung tissue using inverted microscopy and transmission electron microscopy. The expression of inflammatory, antioxidants, apoptosis, and SIRT1-PGC-1É proteins were detected by Western blotting. Results: Exposure to PM 2.5 leads to obvious morphological and pathologica changes in the lung of mice. PM 2.5 caused a decline in levels of antioxidant-related enzymes and protein expressions of HO-1, Nrf2, SOD2, SIRT1 and PGC-1É, and an increase in the protein expressions of IL-6, IL-1ß, Bax, caspase-9 and cleaved caspase-3. However, SAL reversed the aforementioned changes caused by PM 2.5 by activating the SIRT1-PGC-1α pathway. Conclusion: SAL can activate SIRT1-PGC-1É to ameliorate PM 2.5-induced lung injury.
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Glucosídeos , Lesão Pulmonar , Camundongos Endogâmicos C57BL , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Fenóis , Sirtuína 1 , Animais , Camundongos , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/metabolismo , Lesão Pulmonar/tratamento farmacológico , Tamanho da Partícula , Material Particulado/toxicidade , Material Particulado/efeitos adversos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Sirtuína 1/efeitos dos fármacos , Sirtuína 1/genética , Sirtuína 1/metabolismoRESUMO
LncRNAs have shown to regulate ferroptosis in colorectal cancer (CRC), but the mechanism remains largely unknown. This study unveiled the mechanism of SNHG4 underlying ferroptosis in CRC. RNA-seq and RT-PCR assay confirmed SNHG4 was decreased after Erastin treatment in CRC cells. Overexpression of SNHG4 inhibited and silence promoted CRC cells ferroptosis. SNHG4 was positively correlated to c-Myb in CRC tissues and both located in cytoplasm of CRC cells. RIP and RNA pull-down assays verified the interaction between SNHG4 and c-Myb. Silence of c-Myb alleviated the suppressing effect on ferroptosis by SNHG4 in CRC cells. Dual-luciferase reporter assay revealed that SNHG4 sponging miR-150-5p in CRC cells. Overexpression of SNHG4 decreased the miR-150-5p and increased c-Myb expression. c-Myb was a direct target gene of miR-150-5p in CRC cells. Moreover, effect of CDO1 on ferroptosis was regulated transcriptionally by c-Myb, overexpression of c-Myb reduce CDO1 expression and enhance the GPX4 levels. The animal models confirmed that regulatory effect of SNHG4 on miR-150-5p and c-Myb after inducing ferroptosis. We concluded that SNHG4 inhibited Erastin-induce ferroptosis in CRC, this effect is via sponging miR-150-5p to regulate c-Myb expression, and activated CDO1/GPX4 axis. These findings provide insights into the regulatory mechanism of SNHG4 on ferroptosis.
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Neoplasias Colorretais , Ferroptose , Regulação Neoplásica da Expressão Gênica , MicroRNAs , Proteínas Proto-Oncogênicas c-myb , RNA Longo não Codificante , Ferroptose/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Proteínas Proto-Oncogênicas c-myb/genética , Proteínas Proto-Oncogênicas c-myb/metabolismo , Animais , Camundongos , Linhagem Celular Tumoral , Masculino , Camundongos NusRESUMO
BACKGROUND: Previous studies have analyzed the risk factors for complications after ileostomy reversal for rectal cancer (RC), but there were significant differences in the reported risk factors for complications after stoma reversal. No studies have analyzed the risk factors for stoma-related complications and overall postoperative complications separately. AIM: To analyze the risk factors for overall complications and stoma-related complications after ileostomy reversal for patients with RC. METHODS: This was a retrospective study of 439 patients who underwent ileostomy reversal at a clinical center and were followed up between September 2012 and September 2022. Continuous variables are expressed as the mean ± SD and were analyzed with independent-sample t tests, while frequency variables are expressed as n (%), and the χ2 test or Fisher's exact test was used. Univariate and multivariate logistic regression analyses were used to identify predictors of overall complications and stoma-related complications. RESULTS: The overall complication rate after ileostomy reversal was 11.4%. Patients with lower preoperative albumin concentration (P < 0.01), greater blood loss (P = 0.017), and longer operative times (P < 0.01) were more likely to experience postoperative complications. The incidence of stoma-related complications was 6.4%. Analysis of the study showed that a higher body mass index (BMI) (P < 0.01), preoperative comorbid hypertension (P = 0.049), time from primary surgery to ileostomy reversal (P < 0.01) and longer operation time (P = 0.010) were more likely to result in stoma-related complications postoperatively. Multivariate logistic regression analysis revealed that a lower preoperative albumin level (P < 0.01, OR = 0.888, 95%CI: 0.828-0.958) was an independent risk factor for overall complications. Moreover, multivariate analysis revealed that BMI (P < 0.01, OR = 1.176, 95%CI: 1.041-1.330) and time from primary surgery to ileostomy reversal (P < 0.01, OR = 1.140, 95%CI: 1.038-1.252) were independent risk factors for stoma-related complications after stoma reversal. CONCLUSION: The preoperative albumin level was a predictor of overall complications. Preoperative BMI and the time from primary surgery to ileostomy reversal were predictors of stoma-related complications.
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Understanding land structure change and stability in the process of oasisization is particularly important for the desertification control in sandy land. Based on land use data of eight periods from 1980 to 2020, we extracted the spatial distribution information of oasis land in Mu Us Sandy Land, and analyzed the spatio-temporal variations of land transformation patterns and stability of oasis land with overlay analysis and grid analysis. The results showed that desertification in the Mu Us Sandy Land had reversed, with a significant process of oasis. The area of forest and grassland increased from 10.2% in 1980 to 73.7% in 2020, while the area of oasisization land increased from 32500 km2 in 1980 to 33900 km2 in 2020. The area of extremely severe, severe, and moderate desertification significantly decreased, while the area of non-desertification and mild desertification obviously increased. The four patterns of oasisization land transformation, including stability, fluctuation, expansion, and retreat, which accounted for 78.7%, 12.2%, 6.2%, and 2.9% of the oasisization land area in 2020, respectively. The oasisization land with low change intensity (the cumulative change intensity less than 0.12) in the Mu Us Sandy Land accounted for 82.7% of the total oasisization area, and the oasisization land in the sandy land was generally stable. Zoning management strategies should be applied according to the stability of sand belt and transformation pattern of oasisization land to achieve the goal of efficient system management and improvement, including eliminating sand hazards at desertification expansion areas with strong wind and sand activities, consolidating sand resources at oasisization areas where ecologically fragile desertification was frequent, and sustainably managing and utilizing sand resources at stable expansion of oases in forest- and grass-rich oasisization areas.
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Conservação dos Recursos Naturais , Ecossistema , China , Árvores/crescimento & desenvolvimento , Dióxido de Silício , Florestas , Pradaria , Areia , Poaceae/crescimento & desenvolvimentoRESUMO
Background: The MYCN copy number category is closely related to the prognosis of neuroblastoma (NB). Therefore, this study aimed to assess the predictive ability of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) radiomic features for MYCN copy number in NB. Methods: A retrospective analysis was performed on 104 pediatric patients with NB that had been confirmed by pathology. To develop the Bio-omics model (B-model), which incorporated clinical and biological aspects, PET/CT radiographic features, PET quantitative parameters, and significant features with multivariable stepwise logistic regression were preserved. Important radiomics features were identified through least absolute shrinkage and selection operator (LASSO) and univariable analysis. On the basis of radiomics features obtained from PET and CT scans, the radiomics model (R-model) was developed. The significant bio-omics and radiomics features were combined to establish a Multi-omics model (M-model). The above 3 models were established to differentiate MYCN wild from MYCN gain and MYCN amplification (MNA). The calibration curve and receiver operating characteristic (ROC) curve analyses were performed to verify the prediction performance. Post hoc analysis was conducted to compare whether the constructed M-model can distinguish MYCN gain from MNA. Results: The M-model showed excellent predictive performance in differentiating MYCN wild from MYCN gain and MNA, which was better than that of the B-model and R-model [area under the curve (AUC) 0.83, 95% confidence interval (CI): 0.74-0.92 vs. 0.81, 95% CI: 0.72-0.90 and 0.79, 95% CI: 0.69-0.89]. The calibration curve showed that the M-model had the highest reliability. Post hoc analysis revealed the great potential of the M-model in differentiating MYCN gain from MNA (AUC 0.95, 95% CI: 0.89-1). Conclusions: The M-model model based on bio-omics and radiomics features is an effective tool to distinguish MYCN copy number category in pediatric patients with NB.
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Oxaliplatin resistance poses a significant challenge in colorectal cancer (CRC) therapy, necessitating further investigation into the underlying molecular mechanisms. This study aimed to elucidate the regulatory role of SNHG4 in oxaliplatin resistance and ferroptosis in CRC. Our findings revealed that treatment with oxaliplatin led to downregulation of SNHG4 expression in CRC cells, while resistant CRC cells exhibited higher levels of SNHG4 compared to parental cells. Silencing SNHG4 attenuated oxaliplatin resistance and reduced the expression of resistance-related proteins MRD1 and MPR1. Furthermore, induction of ferroptosis effectively diminished oxaliplatin resistance in both parental and resistant CRC cells. Notably, ferroptosis induction resulted in decreased SNHG4 expression, whereas SNHG4 overexpression suppressed ferroptosis. Through FISH, RIP, and RNA pull-down assays, we identified the cytoplasmic localization of both SNHG4 and PTEN, establishing that SNHG4 directly targets PTEN, thereby reducing mRNA stability in CRC cells. Silencing PTEN abrogated the impact of SNHG4 on oxaliplatin resistance and ferroptosis in CRC cells. In vivo experiments further validated the influence of SNHG4 on oxaliplatin resistance and ferroptosis in CRC cells through PTEN regulation. In conclusion, SNHG4 promotes resistance to oxaliplatin in CRC cells by suppressing ferroptosis through instability of PTEN, thus serves as a target for patients with oxaliplatin-base chemoresistance.
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Neoplasias Colorretais , Resistencia a Medicamentos Antineoplásicos , Ferroptose , Oxaliplatina , PTEN Fosfo-Hidrolase , Animais , Humanos , Camundongos , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ferroptose/efeitos dos fármacos , Ferroptose/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Camundongos Nus , Oxaliplatina/farmacologia , PTEN Fosfo-Hidrolase/metabolismo , PTEN Fosfo-Hidrolase/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , MasculinoRESUMO
OBJECTIVES: To develop and validate an 18F-FDG PET/CT-based clinical-radiological-radiomics nomogram and evaluate its value in the diagnosis of MYCN amplification (MNA) in paediatric neuroblastoma (NB) patients. METHODS: A total of 104 patients with NB were retrospectively included. We constructed a nomogram to predict MNA based on radiomics signatures, clinical and radiological features. The multivariable logistic regression and the least absolute shrinkage and selection operator (LASSO) were used for feature selection. Radiomics models are constructed using decision trees (DT), logistic regression (LR) and support vector machine (SVM) classifiers. A clinical-radiological (C-R) model was developed using clinical and radiological features. A clinical-radiological-radiomics (C-R-R) model was developed using the C-R model of the best radiomics model. The prediction performance was verified by receiver operating characteristic (ROC) curve analysis, calibration curve analysis and decision curve analysis (DCA) in the training and validation cohorts. RESULTS: The present study showed that four radiomics signatures were significantly correlated with MNA. The SVM classifier was the best model of radiomics signature. The C-R-R model has the best discriminant ability to predict MNA, with AUCs of 0.860 (95% CI, 0.757-0.963) and 0.824 (95% CI, 0.657-0.992) in the training and validation cohorts, respectively. The calibration curve indicated that the C-R-R model has the goodness of fit and DCA confirms its clinical utility. CONCLUSION: Our research provides a non-invasive C-R-R model, which combines the radiomics signatures and clinical and radiological features based on 18F-FDGPET/CT images, shows excellent diagnostic performance in predicting MNA, and can provide useful biological information with stratified therapy. CRITICAL RELEVANCE STATEMENT: Radiomic signatures of 18F-FDG-based PET/CT can predict MYCN amplification in neuroblastoma. KEY POINTS: ⢠Radiomic signatures of 18F-FDG-based PET/CT can predict MYCN amplification in neuroblastoma. ⢠SF, LDH, necrosis and TLG are the independent risk factors of MYCN amplification. ⢠Clinical-radiological-radiomics model improved the predictive performance of MYCN amplification.
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INTRODUCTION: Minimal residual disease (MRD) has been an important biomarker for relapse prediction and treatment choice in patients with acute myeloid leukemia (AML). False-positive or false-negative MRD results due to the low specificity and sensitivity of techniques such as multiparameter flow cytometry (MFC), real-time quantitative polymerase chain reaction, and next-generation sequencing, as well as the biological characteristics of residual leukemia cells, including antigen shift, clone involution, heterogeneous genome of the blast cells, and lack of specific targets, all restrict the clinical use of MRD. AREAS COVERED: We summarized the challenges of the techniques for MRD detection, and their application in the clinical setting. We also discussed strategies to overcome these challenges, such as the MFC MRD method based on leukemia stem cells, single-cell DNA sequencing or single-cell RNA sequencing for the investigation of biological characteristics of residual leukemia cells, and the potential of omics techniques for MRD detection. We further noted out that prospective clinical trials are needed to answer clinical questions related to MRD in patients with AML. EXPERT OPINION: MRD is an important biomarker for individual therapy of patients with AML. In the future, it is important to increase the specificity and sensitivity of the detection techniques.
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Leucemia Mieloide Aguda , Humanos , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Estudos Prospectivos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Citometria de Fluxo/métodos , BiomarcadoresRESUMO
PURPOSE: The purpose of this study was to determine the speech recognition equivalence of Mandarin Bamford-Kowal-Bench (BKB) sentence lists with adults and children with normal hearing. METHOD: A total of 32 lists, each of nine sentences, were compiled from a corpus of BKB-like sentences with paired babble in Mandarin. Interlist equivalence, critical differences, and sensitivity of performance to signal-to-noise ratio (SNR) were examined. Experiment 1 included 64 native Mandarin-speaking adults with normal hearing. Experiment 2 included 54 native Mandarin-speaking children with normal hearing aged 4-6 years. RESULTS: Among the 32 sentence lists, 28 lists were confirmed to be equivalent in adults, with a mean SNR required for 50% correct (SNR50) of -5.9 ± 0.1 dB, a mean slope of 22.3%/dB ± 1.5%/dB, and a grand 95% critical difference subsequently calculated as 27.2% for score. From the 28 equivalent lists, 27 lists were selected and observed to be equivalent in children, with a mean SNR50 threshold of -2.0 ± 0.2 dB, a mean slope of 15.8%/dB ± 1.1%/dB, and a grand 95% critical difference of 24.6% for score. CONCLUSIONS: The Mandarin BKB sentences in babble noise test offers an opportunity for clinicians and researchers to assess speech understanding in adults and preschool children in an efficient manner. For comparisons of performance in different test conditions, 28 equivalent lists are available for adults and 27 equivalent lists for preschool children. The 95% critical difference values can be used for total percentage correct or SNR for 50% performance. Future work will examine the clinical utility for school-age children and children who are deaf and hard of hearing. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.24400066.
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Perda Auditiva , Percepção da Fala , Adulto , Humanos , Pré-Escolar , Ruído , Testes Auditivos , AudiçãoRESUMO
The liver can succumb to oxidant damage during the development of chronic liver diseases. Despite their physiological relevance to hepatic homeostasis, excessive reactive oxygen/nitrogen species (ROS/RNS) production under pathological conditions is detrimental to all liver constituents. Chronic oxidative stress coupled to unresolved inflammation sets in motion the activation of profibrogenic hepatic stellate cells (HSCs) and later pathogenesis of liver fibrosis, cirrhosis, and liver cancer. The liver antioxidant and repair systems, along with autophagic and ferroptotic machineries, are implicated in the onset and trajectory of disease development. In this review, we discuss the ROS/RNS-related mechanisms underlying liver fibrosis of distinct etiologies and highlight preclinical and clinical trials of antifibrotic therapies premised on remediating oxidative/nitrosative stress in hepatocytes or targeting HSC activation.
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BACKGROUND: Aberrant expression of miRNAs have been implicated in cancers, but the role of miRNAs in colorectal cancer (CRC) remains need to be elucidated. This study aimed to identify miRNAs that related to colorectal cancer (CRC) pathogenesis and determine the diagnostic value. METHODS: Three GEO datasets (GSE128449, GSE35602 and GSE49246) with 131 samples were used to screen miRNAs that differential expression between tumor and control tissues. The expression of the identified miRNAs was validated in 50 clinical tissue samples and the GSE35834 dataset. The clinical significance of these miRNAs was analyzed in the TCGA dataset and clinical tissue samples. The expression of miRNAs in tissues and plasma samples were tested by RT-PCR assay in clinical samples, and their diagnostic value was determined. RESULTS: The analysis of three GEO datasets revealed that miR-595 and miR-1237 were upregulated, while miR-126, miR-139, and miR-143 were downregulated in CRC tissues compared to control tissues. The differential expression of the five miRNAs in CRC tissues was confirmed using clinical tissue samples and GEO databases. There was no significant correlation between the TNM stage and tumor stage of CRC and any of the five miRNAs. Plasma expression of the miRNAs differed significantly between CRC and non-cancer patients, and each miRNA had moderate diagnostic value for CRC. Combining the five miRNAs provided better diagnostic potential for CRC than a single miRNA. CONCLUSIONS: This study demonstrated that five miRNAs were related to the pathogenesis of CRC, but independent of the stage of CRC; Plasma expression of these miRNAs have moderate diagnostic value, and combination of these miRNAs showed better diagnostic ability in CRC.
Assuntos
Neoplasias Colorretais , MicroRNAs , MicroRNAs/sangue , Neoplasias Colorretais/sangue , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , IdosoRESUMO
BACKGROUND: Oxaliplatin-based chemotherapy is the first-line treatment for colorectal cancer (CRC). Long noncoding RNAs (lncRNAs) have been implicated in chemotherapy sensitivity. This study aimed to identify lncRNAs related to oxaliplatin sensitivity and predict the prognosis of CRC patients underwent oxaliplatin-based chemotherapy. METHODS: Data from the Genomics of Drug Sensitivity in Cancer (GDSC) was used to screen for lncRNAs related to oxaliplatin sensitivity. Four machine learning algorithms (LASSO, Decision tree, Random-forest, and support vector machine) were applied to identify the key lncRNAs. A predictive model for oxaliplatin sensitivity and a prognostic model based on key lncRNAs were established. The published datasets, and cell experiments were used to verify the predictive value. RESULTS: A total of 805 tumor cell lines from GDSC were divided into oxaliplatin sensitive (top 1/3) and resistant (bottom 1/3) groups based on their IC50 values, and 113 lncRNAs, which were differentially expressed between the two groups, were selected and incorporated into four machine learning algorithms, and seven key lncRNAs were identified. The predictive model exhibited good predictions for oxaliplatin sensitivity. The prognostic model exhibited high performance in patients with CRC who underwent oxaliplatin-based chemotherapies. Four lncRNAs, including C20orf197, UCA1, MIR17HG, and MIR22HG, displayed consistent responses to oxaliplatin treatment in the validation analysis. CONCLUSION: Certain lncRNAs were associated with oxaliplatin sensitivity and predicted the response to oxaliplatin treatment. The prognostic models established based on the key lncRNAs could predict the prognosis of patients given oxaliplatin-based chemotherapy.
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BACKGROUND: Little is known about the role of serine peptidase inhibitor Kazal type 4 (SPINK4) in colorectal cancer (CRC) and ferroptosis. Therefore, this study aimed to determine the effect of SPINK4 on CRC pathogenesis and ferroptosis. METHODS: SPINK4 expression was analyzed in public datasets and examined using immunohistochemistry. The biological function of SPINK4 in CRC cell lines and its effect on ferroptosis were tested. An immunofluorescence assay was performed to determine the location of SPINK4 in cells, and mouse models were established to determine the effects of SPINK4 in vivo. RESULTS: CRC datasets and clinical samples analysis revealed that SPINK4 mRNA and protein levels were significantly reduced in CRC tissues compared to control tissues (P < 0.05). Two CRC cell lines (HCT116 and LoVo) were selected, and the in vitro and in vivo experiments showed that overexpression of SPINK4 greatly promotes the proliferation and metastasis of CRC cells and tumor growth (P < 0.05). The immunofluorescence assay indicated that SPINK4 is mainly located in the nucleoplasm and nucleus of CRC cells. Furthermore, SPINK4 expression was reduced after cell ferroptosis induced by Erastin, and overexpression of SPINK4 greatly inhibited ferroptosis in CRC cells. The results of mouse model further demonstrated that SPINK4 overexpression inhibited CRC cell ferroptosis and facilitated tumor growth. CONCLUSIONS: SPINK4 was decreased in CRC tissues and promoted cell proliferation and metastasis; overexpression of SPINK4 inhibited CRC cell ferroptosis.