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BACKGROUND: This study aimed to identify distinct patterns within the symptom cluster of fatigue, pain, and sleep disturbance among ovarian cancer patients receiving chemotherapy, to determine the factors predicting these patterns and their impact on quality of life. METHODS: The longitudinal study collected data from 151 ovarian cancer patients at three time points: before chemotherapy (T0), after the first chemotherapy cycle (T1), and following the completion of four cycles of chemotherapy (T2). Latent profile analysis and latent transition analysis were used to identify symptom patterns and evaluate changes in symptom patterns. A bias-adjusted three-step approach was utilized to examine predictor variables and distal outcomes associated with latent class membership. RESULTS: Three symptom patterns emerged: "All Low," "Moderate" (T0)/"Low pain and high sleep disturbance" (T1 and T2), and "All High." Patients with lower educational attainment and higher levels of anxiety and depression were found to be at an elevated risk of belonging to the "All High" class. All quality-of-life domains showed significant differences among the three subgroups, following an "All Low" > "All High" pattern (p < 0.05). Membership in three classes remained relatively stable over time, with probabilities of 0.749 staying within their groups from T0 to T2. CONCLUSIONS: This study underscores the existence of a diverse and heterogeneous experience within the symptom cluster of fatigue, pain, and sleep disturbance among ovarian cancer patients. Importantly, these patterns were stable throughout chemotherapy. Recognizing and understanding these patterns can inform the development of targeted interventions to alleviate the burden of symptom clusters in this population.
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Neoplasias Ovarianas , Transtornos do Sono-Vigília , Humanos , Feminino , Estudos Longitudinais , Síndrome , Qualidade de Vida , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/tratamento farmacológico , Dor , Fadiga/induzido quimicamente , Fadiga/epidemiologia , Transtornos do Sono-Vigília/induzido quimicamente , Transtornos do Sono-Vigília/epidemiologia , Depressão/epidemiologia , Depressão/etiologia , Depressão/diagnósticoRESUMO
Objective: To explore whether SLBZD can play a synergistic role in promoting the efficacy of PD-1 inhibitors in the treatment of colorectal cancer by influencing the intestinal microenvironment and Tumor microenvironment. Method: Shenling Baizhu Decoction (SLBZD) and tirelizumab (TLzmab) treated the colorectal mouse model. The tumor growth rate, tumor weight, and tumor growth inhibition rate were evaluated. Fecal microbiota was detected by 16S rDNA sequencing and immune cell was detected by the flow cytometry analysis. Result: Compared to tumor weight, there exist significant differences between each group among the three groups. Compared to tumor volume, there was no statistically significant difference in tumor size between the control group and the TLzmab group at 7 days. However, there was a statistical difference in tumor size among the three groups at 18 days. By analyzing the diversity of the Gut microbiota, the diversity decreased after TLzmab treatment with a statistically significant difference. Compared with the control group, the diversity of the TLzmab+SLBZD group increased. The proportion of lymphocytes in the blood was analyzed by flow cytometry. Compared with the control group, Myeloid-derived suppressor cells (MDSCs) decreased and T regulatory cells (Treg) increased significantly in the TLzmab group. Compared with the control group and TLzmab group, the TLzmab+SLBZD group showed a significant increase in M1 type macrophages, while the M2 type macrophages, MDSCs, and Treg showed a significant decrease. Conclusion: An imbalance of Gut microbiota and imbalance of tumor immune microenvironment will occur during TLzmab treatment, which will lead to poor therapeutic effect of TLzmab or drug resistance. SLBZD will increase the abundance of Gut microbiota, which will lead to the increase of M1 macrophages in the tumor immune microenvironment and the decrease of M2 macrophages and Treg cells, thus exerting the synergistic effect of TLzmab. This study provides a new way to explore the improvement of ICIs through traditional Chinese medicine.
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Diet, lifestyle, and gut microbiota composition are key risk factors for the progression of colon cancer. Probiotics are living microorganisms that can offer health benefits to the parasitifer when ingested in competent quantities. Several in vivo, in vitro, and clinical studies have demonstrated that probiotics can prevent and mitigate the development of colon cancer. The anti-colon cancer mechanisms of probiotics include the suppression of cell proliferation and the promotion of cancer cell apoptosis, immunomodulation, the modulation of intestinal microorganisms and their metabolism, strengthening the intestinal barrier, and antioxidant effects. This article describes the pathogenesis of colon cancer and the available therapeutic options. In addition, this paper reviews the mechanisms by which probiotics mitigate colon cancer as well as the mitigating effects of probiotic components and metabolites on colon cancer.
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Background: This study aims to explore the factors influencing the coagulation function of patients with chronic obstructive pulmonary disease (COPD) and its effects on thrombosis. Methods: A total of 155 COPD patients, including 118 patients with acute exacerbation of COPD (AECOPD) and 37 patients with stable COPD (SCOPD), were enrolled in this study. Meanwhile, 50 patients with gastrointestinal polyps found during physical examination and treated with surgery in the same period were enrolled as the control group. The basic data, routine blood tests, C-reactive protein (CRP), procalcitonin (PCT), and coagulation indexes of the three groups were collected, as well as arterial blood gas indexes of AECOPD patients. Results: The differences in erythrocyte count and hemoglobin among groups were not statistically significant. Compared with the SCOPD group and control group, white blood cell (WBC), neutrophil percentage, PCT, CRP, prothrombin time (PT), and fibrinogen (FIB) in the AECOPD group increased significantly, while the international normalized ratio (INR) decreased (P < 0.05). The differences in activated partial thromboplastin time (APTT) and D-dimer among groups were not statistically significant (P > 0.05). Thrombin time (TT) in the AECOPD group was shorter than that of the control group, and PT was longer than that of the SCOPD group (P < 0.05). Five patients with AECOPD and one patient with SCOPD had venous thrombosis. Conclusion: The abnormal coagulation function in AECOPD patients is related to the degree of infection and hypercapnia, which may be a risk factor for thrombosis.
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OBJECTIVE: To identify CT features and establish a diagnostic model for distinguishing non-ampullary duodenal neuroendocrine neoplasms (dNENs) from non-ampullary duodenal gastrointestinal stromal tumors (dGISTs) and to analyze overall survival outcomes of all dNENs patients. MATERIALS AND METHODS: This retrospective study included 98 patients with pathologically confirmed dNENs (n = 44) and dGISTs (n = 54). Clinical data and CT characteristics were collected. Univariate analyses and binary logistic regression analyses were performed to identify independent factors and establish a diagnostic model between non-ampullary dNENs (n = 22) and dGISTs (n = 54). The ROC curve was created to determine diagnostic ability. Cox proportional hazards models were created and Kaplan-Meier survival analyses were performed for survival analysis of dNENs (n = 44). RESULTS: Three CT features were identified as independent predictors of non-ampullary dNENs, including intraluminal growth pattern (OR 0.450; 95% CI 0.206-0.983), absence of intratumoral vessels (OR 0.207; 95% CI 0.053-0.807) and unenhanced lesion > 40.76 HU (OR 5.720; 95% CI 1.575-20.774). The AUC was 0.866 (95% CI 0.765-0.968), with a sensitivity of 90.91% (95% CI 70.8-98.9%), specificity of 77.78% (95% CI 64.4-88.0%), and total accuracy rate of 81.58%. Lymph node metastases (HR: 21.60), obstructive biliary and/or pancreatic duct dilation (HR: 5.82) and portal lesion enhancement ≤ 99.79 HU (HR: 3.02) were independent prognostic factors related to poor outcomes. CONCLUSION: We established a diagnostic model to differentiate non-ampullary dNENs from dGISTs. Besides, we found that imaging features on enhanced CT can predict OS of patients with dNENs.
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Neoplasias Duodenais , Tumores do Estroma Gastrointestinal , Tumores Neuroendócrinos , Humanos , Tumores do Estroma Gastrointestinal/diagnóstico por imagem , Estudos Retrospectivos , Tumores Neuroendócrinos/diagnóstico por imagem , Prognóstico , Neoplasias Duodenais/diagnóstico por imagem , Neoplasias Duodenais/patologia , Tomografia Computadorizada por Raios X/métodosRESUMO
BACKGROUND: Vitamin D might have anti-tumor effect, which is affected by the genes related to vitamin D metabolic pathway. Epigenetic mechanism may affect the expression level of vitamin D metabolic pathway related genes, then plays an important role in the occurrence and development of colorectal cancer. To date, no study has reported on the association between blood-based DNA methylation level of vitamin D metabolic pathway related genes and colorectal cancer risk. METHODS: A case-control study was conducted including 102 colorectal cancer cases and 102 sex- and age-frequency-matched controls in Guangzhou, China. CpG islands in the VDR, CYP24A1, CYP27B1 and CYP2R1 genes were chosen for DNA methylation analysis by MethylTarget sequencing. The receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of DNA methylation levels for colorectal cancer. Taking the point with the largest Youden index as the boundary value, the cumulative methylation levels of vitamin D metabolic pathway related genes were divided into hypomethylation and hypermethylation. Unconditional multivariable logistical regression model was used to calculate the adjusted odds ratio (aOR) and 95% confidence intervals (95% CIs) after adjusting for potential confounders. RESULTS: Among 153 CpG sites, 8 CpG sites were significantly different between the cases and the controls. The cumulative methylation level of all CpG sites in CYP2R1 was inversely associated with the risk of colorectal cancer (aOR, 0.49; 95% CI, 0.26-0.91). However, no significant association was found between cumulative methylation levels of all CpG sites in VDR, CYP24A1 and CYP27B1 and colorectal cancer risk. Significant inverse association was observed between cumulative methylation level of significant CpG sites in VDR (aOR, 0.28; 95% CI, 0.16-0.51) and CYP24A1 (aOR, 0.19; 95% CI, 0.09-0.40) and colorectal cancer risk. There were no significant associations between cumulative methylation levels of significant CpG sites in CYP2R1 and CYP27B1 and colorectal cancer risk. CONCLUSIONS: This study indicated that the cumulative methylation levels of significant CpG sites in VDR and CYP24A1 and all CpG sites in CYP2R1 were inversely associated with colorectal cancer risk.
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Neoplasias Colorretais , Vitamina D , Humanos , Metilação de DNA , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Estudos de Casos e Controles , Vitamina D3 24-Hidroxilase/genética , Vitaminas , Neoplasias Colorretais/genéticaRESUMO
OBJECTIVE: To investigate the diagnostic performance of a mammography-based radiomics model for distinguishing phyllodes tumors (PTs) from fibroadenomas (FAs) of the breast. MATERIALS AND METHODS: A total of 156 patients were retrospectively included (75 with PTs, 81 with FAs) and divided into training and validation groups at a ratio of 7:3. Radiomics features were extracted from craniocaudal and mediolateral oblique images. The least absolute shrinkage and selection operator (LASSO) algorithm and principal component analysis (PCA) were performed to select features. Three machine learning classifiers, including logistic regression (LR), K-nearest neighbor classifier (KNN) and support vector machine (SVM), were implemented in the radiomics model, imaging model and combined model. Receiver operating characteristic curves, area under the curve (AUC), sensitivity and specificity were computed. RESULTS: Among 1084 features, the LASSO algorithm selected 17 features, and PCA further selected 6 features. Three machine learning classifiers yielded the same AUC of 0.935 in the validation group for the radiomics model. In the imaging model, KNN yielded the highest accuracy rate of 89.4% and AUC of 0.947 in the validation set. For the combined model, the SVM classifier reached the highest AUC of 0.918 with an accuracy rate of 86.2%, sensitivity of 83.9%, and specificity of 89.4% in the training group. In the validation group, LR yielded the highest AUC of 0.973. The combined model had a relatively higher AUC than the radiomics model or imaging model, especially in the validation group. CONCLUSIONS: Mammography-based radiomics features demonstrate good diagnostic performance for discriminating PTs from FAs.
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Neoplasias da Mama , Fibroadenoma , Tumor Filoide , Humanos , Feminino , Fibroadenoma/diagnóstico por imagem , Tumor Filoide/diagnóstico por imagem , Estudos Retrospectivos , Neoplasias da Mama/diagnóstico por imagem , Mamografia , Aprendizado de MáquinaRESUMO
BACKGROUND: Corylifol A (CYA) is one of the main active components of Psoralea corylifolia L. CYA had been reported to have ameliorating effects on dexamethasone-induced atrophy of C2C12 mouse skeletal myotubes, but its effects on cancer cachexia were unclear. Here, we checked the influence of CYA on muscle atrophy in cancer cachexia mice and tried to clarify its mechanisms. METHODS: C26 tumour-bearing mice were applied as the animal model to examine the effects of CYA in attenuating cachexia symptoms. The in vitro cell models of TNF-α-induced C2C12 myotubes or ad-mRFP-GFP-LC3B-transfected C2C12 myotubes were used to check the influence of CYA on myotube atrophy based on both ubiquitin proteasome system (UPS) and autophagy-lysosome system. The possible direct targets of CYA were searched using the biotin-streptavidin pull-down assay and then confirmed using the Microscale thermophoresis binding assay. The levels of related signal proteins in both in vitro and in vivo experiments were examined using western blotting and immunocytochemical assay. RESULTS: The administration of CYA prevented body weight loss and muscle wasting in C26 tumour-bearing mice without affecting tumour growth. At the end of the experiment, the body weight of mice treated with 30 mg/kg of CYA (23.59 ± 0.94 g) was significantly higher than that of the C26 model group (21.66 ± 0.56 g) with P < 0.05. The values of gastrocnemius muscle weight/body weight of mice treated with 15 or 30 mg/kg CYA (0.53 ± 0.02% and 0.54 ± 0.01%, respectively) were both significantly higher than that of the C26 model group (0.45 ± 0.01%) with P < 0.01. CYA decreased both UPS-mediated protein degradation and autophagy in muscle tissues of C26 tumour-bearing mice as well as in C2C12 myotubes treated with TNF-α. The thousand-and-one amino acid kinase 1 (TAOK1) was found to be the direct binding target of CYA. CYA inhibited the activation of TAOK1 and its downstream p38-MAPK pathway thus decreased the level and nuclear location of FoxO3. siRNA knockdown of TAOK1 or regulation of the p38-MAPK pathway using activator or inhibitor could affect the ameliorating effects of CYA on myotube atrophy. CONCLUSIONS: CYA ameliorates cancer cachexia muscle atrophy by decreasing both UPS degradation and autophagy. The ameliorating effects of CYA on muscle atrophy might be based on its binding with TAOK1 and inhibiting the TAOK1/p38-MAPK/FoxO3 pathway.
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The tumor immunosuppressive microenvironment plays an important role in tumor progression. Alcohol is well-known as a regulator of the immune system and several studies have also reported that chronic alcohol intake can activate the immune system. However, it is unclear whether alcohol can affect liver cancer progression by regulating the immunosuppressive microenvironment. In this study, we investigated the effects of different alcohol concentrations on the growth of liver cancer and tumor immune microenvironment. We examined the growth of tumors in mice provided with water, or alcohol (for 2 weeks before tumor injection, and for 3 weeks after tumor injection). We found that alcohol consumption at 5% and 20% inhibited the growth of subcutaneous tumors in hepatocellular carcinoma-bearing mice, whereas 2% alcohol concentration did not significantly inhibit liver cancer growth. The ratio of myeloid-derived suppressor cells (MDSCs) in peripheral blood and spleen of mice treated with 5% or 20% alcohol for 2 weeks before tumor inoculation was downregulated. After tumor inoculation, the proportion of MDSCs in peripheral blood, spleen, and tumor of mice treated with 5% or 20% alcohol for another 3 weeks also decreased and the proportion of CD4+ T cells and CD8+ T cells increased. In addition, Alcohol consumption of 20% reduced levels of the inflammatory factor IL-6 by inhibiting JAK/STAT3 signaling. These results indicate that chronic alcohol consumption may inhibit the growth of liver cancer by regulating MDSCs.
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Hepatocellular carcinoma is characterized by a high infiltration of myeloid-derived suppressor cells (MDSC), which are key drivers of maintaining the immunosuppressive tumor microenvironment. Therefore, targeting MDSCs will improve immunotherapies for cancers. It has been shown that all-trans retinoic acid (ATRA) can differentiate MDSCs into mature myeloid cells. However, whether ATRA suppression of MDSCs function could inhibit the growth of liver cancer remains unknown. Here we found that ATRA significantly inhibited hepatocellular carcinoma promotion, tumor cell proliferation, and angiogenesis markers. Moreover, ATRA decreased the number of mononuclear myeloid-derived suppressor cells (M-MDSCs), granulocytic myeloid-derived suppressor cells (G-MDSCs) and tumor-associated macrophages (TAMs) in spleens. In addition, ATRA significantly reduced the intratumoral infiltrating G-MDSCs and the expression of protumor immunosuppressive molecules (arginase 1, iNOS, IDO and S100A8 + A9), which was accompanied by increased cytotoxic T cell infiltration. Our study demonstrates that ATRA not only has direct intrinsic inhibitory effect on tumor angiogenesis and fibrosis, but also reeducates the tumor microenvironment toward an antitumor phenotype by altering the relative proportion between protumor and antitumor immune cells. This information introduces ATRA as a potential druggable target for treatment of hepatocellular carcinoma.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Células Supressoras Mieloides , Humanos , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Tretinoína/farmacologia , Células Mieloides , Microambiente TumoralRESUMO
Objectives: DNA mismatch repair deficiency (dMMR) status has served as a positive predictive biomarker for immunotherapy and long-term prognosis in gastric cancer (GC). The aim of the present study was to develop a computed tomography (CT)-based nomogram for preoperatively predicting mismatch repair (MMR) status in GC. Methods: Data from a total of 159 GC patients between January 2020 and July 2021 with dMMR GC (n=53) and MMR-proficient (pMMR) GC (n=106) confirmed by postoperative immunohistochemistry (IHC) staining were retrospectively analyzed. All patients underwent abdominal contrast-enhanced CT. Significant clinical and CT imaging features associated with dMMR GC were extracted through univariate and multivariate analyses. Receiver operating characteristic (ROC) curve analysis, decision curve analysis (DCA) and internal validation of the cohort data were performed. Results: The nomogram contained four potential predictors of dMMR GC, including gender (odds ratio [OR] 9.83, 95% confidence interval [CI] 3.78-28.20, P < 0.001), age (OR 3.32, 95% CI 1.36-8.50, P = 0.010), tumor size (OR 5.66, 95% CI 2.12-16.27, P < 0.001) and normalized tumor enhancement ratio (NTER) (OR 0.15, 95% CI 0.06-0.38, P < 0.001). Using an optimal cutoff value of 6.6 points, the nomogram provided an area under the curve (AUC) of 0.895 and an accuracy of 82.39% in predicting dMMR GC. The calibration curve demonstrated a strong consistency between the predicted risk and observed dMMR GC. The DCA justified the relatively good performance of the nomogram model. Conclusion: The CT-based nomogram holds promise as a noninvasive, concise and accurate tool to predict MMR status in GC patients, which can assist in clinical decision-making.
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PURPOSE: We examined the association between whole grain and refined grain intake with all-cause, cancer and cardiovascular disease (CVD) mortality using the data from the Guangzhou Biobank Cohort Study. METHODS: 19,597 participants aged 50+ years were recruited from 2003 to 2006 and followed-up until April 2021. Multivariable Cox regression was used to calculate hazard radios (HRs) and 95% confidence intervals (CIs). Substitution analysis was used to replace a serving (50 g/day) of whole grain with a serving of refined grain. RESULTS: During 286,821 person-years of follow-up, 4385 deaths occurred, including 1450 from cancer, 1678 from CVD and 1257 from other causes. Compared with never whole grain intake, the highest intake category of whole grain (> 300 g/week) was associated with lower risk of all-cause (HR 0.90, 95% CI 0.82-0.98) and CVD mortality (HR 0.85, 0.74-0.98). Compared with the low-intake category of refined grain (< 500 g/day), the highest intake category (> 900 g/week) was associated with a lower risk of cancer mortality (HR 0.76, 0.62-0.95), but a higher risk of CVD mortality (HR 1.25, 1.03-1.51). No significant associations were found between whole grain intake and cancer mortality nor refined grain and all-cause mortality. The HRs of all-cause, cancer and CVD mortality substituting a serving of whole grain for refined grain were 0.96 (0.94-0.99), 1.01 (0.99-1.02) and 0.95 (0.90-0.99), respectively. CONCLUSION: We have first shown that in older Chinese, whole grain intake was associated with lower risk of all-cause and CVD mortality. Our results suggest that intake of whole grain of at least 300 g/week and refined grain of ≤ 900 g/day might be suitable for older Asian. Substituting 50 g/day of whole grain for refined grain was associated with a 4-5% lower risk of all-cause and CVD mortality.
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Doenças Cardiovasculares , Neoplasias , Humanos , Idoso , Grão Comestível , Estudos de Coortes , Seguimentos , Estudos Prospectivos , População do Leste Asiático , Fatores de Risco , DietaRESUMO
The family of high mobility group box (HMGB) proteins participates in various biological processes including immunity, inflammation, as well as cancer formation and progression. However, its role in thyroid cancer remains to be clarified. We performed quantitative RT-PCR (qRT-PCR), western blot, enzyme-linked immunosorbent, immunohistochemistry, and immunofluorescence assays to evaluate the expression level and subcellular location of HMGB3. The effects of HMGB3 knockdown on malignant biological behaviors of thyroid cancer were determined by cell proliferation assays, cell cycle and apoptosis assays, and transwell chamber migration and invasion assays. Differential expression genes (DEGs) altered by HMGB3 were analyzed using the Ingenuity Pathway Analysis (IPA) and TRRUST v2 database. HMGB3 correlated pathways predicted by bioinformatic analysis were then confirmed using western blot, co-immunoprecipitation, dual-luciferase reporter assay, and flow cytometry. We found that HMGB3 is overexpressed and its downregulation inhibits cell viability, promotes cell apoptosis and cell cycle arrest, and suppresses cell migration and invasion in thyroid cancer. In PTC, both tissue and serum levels of HMGB3 are elevated and are correlated with lymph node metastasis and advanced tumor stage. Mechanistically, we observed the translocation of HMGB3 in PTC, induced at least partially by hypoxia. Cytoplasmic HMGB3 activates nucleic-acid-mediated TLR3/NF-κB signaling and extracellular HMGB3 interacts with the transmembrane TREM1 receptor in PTC. This study demonstrates the oncogenic role of HMGB3 cytoplasmic and extracellular translocation in papillary thyroid cancers; we recommend its future use as a potential circulating biomarker and therapeutic target for PTC.
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Proteína HMGB3 , MicroRNAs , Neoplasias da Glândula Tireoide , Humanos , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/patologia , Receptor 3 Toll-Like/genética , Receptor 3 Toll-Like/metabolismo , Linhagem Celular Tumoral , Receptor Gatilho 1 Expresso em Células Mieloides/genética , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Neoplasias da Glândula Tireoide/genética , Proteína HMGB3/genética , Proteína HMGB3/metabolismo , Proliferação de Células/genética , MicroRNAs/genética , Movimento Celular/genética , Regulação Neoplásica da Expressão GênicaRESUMO
Cancer-derived exosomes are involved in the development of cancer cachexia. Carnosol, which exhibited ameliorating effects on cancer cachexia of C26 tumour-bearing mice in our previous study, alleviated atrophy of C2C12 myotubes induced by exosomes of C26 tumour cells in the present study. MiR-183-5p was found to be rich in C26 cells and C26 exosomes, and miR-183-5p mimic could directly induce atrophy of C2C12 myotubes. Carnosol at 5 to 20 µM could dose-dependently ameliorate the myotube atrophy induced by miR-183-5p. Four and a half LIM domain protein 1 (FHL1) was shown to be the direct target of miR-183-5p. Increase in myostatin, p-Smad3, MuRF-1, Atrogin-1, HIF-1α and p-STAT3 and decrease in mitochondrial respiration were also induced by miR-183-5p mimic in C2C12 myotubes. Carnosol could not affect the decrease in FHL-1 and the activation of STAT3 pathway but could significantly alleviate the increase in myostatin, p-Smad3, MuRF-1, Atrogin-1 and the decrease in mitochondrial respiration induced by miR-183-5p. The protective effects of carnosol on myotubes against atrophy of C2C12 myotubes induced by miR-183-5p, based on both its inhibiting effects on MuRF-1 and Atrogin-1-mediated protein degradation and its ability of keeping the mitochondrial respiration, might contribute to its ameliorating effects on cancer cachexia.
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Abietanos , MicroRNAs , Fibras Musculares Esqueléticas , Neoplasias , Animais , Camundongos , Atrofia , Caquexia/etiologia , Caquexia/prevenção & controle , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas com Domínio LIM/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Miostatina , Neoplasias/metabolismo , Abietanos/farmacologia , Linhagem Celular TumoralRESUMO
Aberrant expression of circular RNA (circRNA) is involved in the occurrence of various diseases and tumor development, in which plays a vital role, including hepatocellular carcinoma (HCC). Nevertheless, the regulation mechanism and biological function of circITCH in hepatocellular carcinoma (HCC) remain unclear. The expression level of circular RNA itchy E3 ubiquitin protein ligase (circ-ITCH) was identified and validated by real-time polymerase-chain reaction (RT-qPCR) in HCC cell lines. The stability of circITCH was confirmed by Ribonuclease R (RNase R) assay. Subsequently, through silencing and overexpression of circITCH to investigate the functional roles of circITCH in HCC proliferation, invasion, and apoptosis. We also carried out bioinformatics analysis, luciferase reporter assays to define the relationship between microRNA (miR)-184 and circITCH. Moreover, xenograft mouse models and immunohistochemistry were employed to assess the function of circITCH in HCC. CircITCH (hsa_circ_0001141) was a stable circRNA and downregulated in HCC cells. Overexpression of circITCH inhibited cell proliferation, migration, invasion, and promoted apoptosis in vitro and in vivo, whereas knockdown of circITCH had the opposite effects. Mechanistically, miR-184 could be sponged by circITCH, and its overexpression could mitigate the suppressive effects of circITCH overexpression on HCC progression. Through biological website to predict the target genes of miR-184 may be combined. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed to investigate mRNAs with significant functional enrichment and pathways, also which its relationship with HCC-related pathway and immune cells. Our findings reveal that circITCH served as a repressor to restrain HCC malignancy via miR-184. Therefore, circITCH may serve as a potential prognostic marker and therapeutic target for HCC.Abbreviations: HCC: hepatocellular carcinoma; CircRNA: Circular RNA; miRNA: MicroRNA; Circ-ITCH: circular RNA itchy E3 ubiquitin protein ligase; RT-qPCR: real-time polymerase-chain reaction; RNase R: Ribonuclease R; CeRNA: competing endogenous RNAs; SiRNA: small interfering RNA.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Nus , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética , RNA Interferente Pequeno , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
BACKGROUND: Considerable evidence implicates myeloid-derived suppressor cells (MDSCs) promote tumor progression and drug resistance. Sorafenib is the standard first-line therapy for advanced hepatocellular carcinoma (HCC). Clinical evidence indicates that sorafenib resistance is associated with increased MDSCs, by which MDSCs exerts these effects is obscure. This study aimed to investigate the mechanism of sorafenib resistance mediated by MDSCs. METHODS: A syngeneic mouse-liver cancer cell line BNL was subcutaneously injected to build a tumor-bearing mouse model, and syngeneic MDSCs were adoptive transferred into the tumor-bearing mouse. Tumor tissue was obtained, and transcriptomic analysis of the tumor was carried out on RNAseq data. A coculture system was used to verify the crosstalk between MDSCs and BNL cells. RESULTS: Adoptive MDSCs transfer into tumor-bearing mice induced an increase of tumor-infiltrating MDSCs, which led to tumor growth and impaired antitumor activity of sorafenib in BNL HCC models. MDSCs transfer contributed to tumor fibrosis and tumor-associated fibroblast (CAF) activation, associated with fibroblast growth factor (FGF1) upregulation. In contrast, MDSC depletion by anti-Ly6G+ reduced fibrosis and increased sorafenib antitumor efficacy. Intriguingly, tumor-infiltrating MDSCs barely expressed FGF1. IL-6 derived from MDSCs increased FGF1 expression in BNL liver cancer cells, and anti-IL-6 attenuated this effect in vitro. MAPK pathway, one of the sorafenib targets, is the downstream signaling of FGF1 and is reactivated by MDSCs-mediated FGF1 upregulation. CONCLUSIONS: Our finding demonstrated that MDSCs led to tumor growth and sorafenib resistance via FGF1 upregulation and subsequent indirect CAF activation. We offered a novel mechanism of MDSCs-driven HCC progression and sorafenib resistance.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Células Supressoras Mieloides , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Fator 1 de Crescimento de Fibroblastos/metabolismo , Fator 1 de Crescimento de Fibroblastos/uso terapêutico , Fibrose , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Camundongos , Células Supressoras Mieloides/metabolismo , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Regulação para CimaRESUMO
Isoquinoline alkaloid displays significant anti-gastric cancer effects due to its unique structure, which is attracting more and more attention for the development of anti-gastric cancer drugs. In this study, we explore the active components against gastric cancer from the Tibetan Medicine Corydalis hendersonii Hemsl, which is rich in isoquinoline alkaloids. 14 compounds including 2 previously undescribed natural products were obtained. Interestingly, an new active compound displays potent anti-gastric cancer activity. After accomplishing the total syntheses of the active compound and its derivatives, the anti-gastric cancer activity of the active compound was further investigated. In vitro experiments revealed that the active compound significantly attenuated the proliferative capacity, caused G2/M phase arrest, inhibited the cell migration and invasion, and induced cell apoptosis. Mechanistically, the active compound could increase the Bax/Bcl-2 ratio, elevate cytochrome c in the cytosol, and activate caspase-9/3, along with inactivating the upstream PI3K/Akt/mTOR signaling pathway. In addition, the active compound could also cause gastric cancer cell death by inhibiting topoisomerase I activity. More importantly, the anti-gastric cancer activity of the active compound was confirmed in MGC-803 xenograft nude mice in vivo. This work not only promotes the exploitation of Corydalis hendersonii Hemsl., but also provides some experience for discovering new entities from natural sources.
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Alcaloides , Corydalis , Neoplasias Gástricas , Alcaloides/química , Alcaloides/farmacologia , Alcaloides/uso terapêutico , Animais , Apoptose , Corydalis/química , Humanos , Isoquinolinas/química , Isoquinolinas/farmacologia , Isoquinolinas/uso terapêutico , Camundongos , Camundongos Nus , Fosfatidilinositol 3-Quinases , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismoRESUMO
BACKGROUND: The study aimed to compare the predictive values of three widely used nutritional assessment methods, body mass index (BMI), Nutritional Risk Screening 2002 (NRS 2002), and the prognostic nutritional index (PNI), for different clinical prognostic indicators of ovarian cancer patients. METHODS: Patients diagnosed with ovarian cancer treated in our hospital between January 2017 and March 2019 were retrospectively included. The three nutritional assessment methods were assessed, and multivariable analysis was conducted to explore predictive factors for clinical prognoses. Receiver operating characteristic (ROC) curves and the area under the ROC curve (AUROC) were generated to evaluate the discriminative abilities of the three nutritional assessment tools. RESULTS: A total of 442 patients were recruited. Multivariable analysis revealed that the PNI value predicted 1-year death and 1-year recurrence and that both the NRS 2002 score and the PNI value predicted 30-day readmission (P < 0.05). For PNI, AUROCs were 0.834 for predicting 1-year death and 0.719 for 1-year recurrence prediction; for NRS, the AUROC was 0.820 2002 for predicting 30-day readmission. The optimal cutoff values that maximized the prognostic prediction ability were PNI values of 47.75 g/L and 50.40 g/L for 1-year death and 1-year recurrence, respectively, and an NRS 2002 score of 3 points for 30-day readmission following discharge. CONCLUSION: For ovarian cancer patients, the PNI is better at predicting 1-year death and 30-day readmission after discharge, and the NRS 2002 is superior for predicting 1-year recurrence.
Assuntos
Avaliação Nutricional , Neoplasias Ovarianas , Feminino , Humanos , Estado Nutricional , Neoplasias Ovarianas/diagnóstico , Prognóstico , Estudos RetrospectivosRESUMO
The ESCRT protein CHMP2B and the RNA-binding protein TDP-43 are both associated with ALS and FTD. The pathogenicity of CHMP2B has mainly been considered a consequence of autophagy-endolysosomal dysfunction, whereas protein inclusions containing phosphorylated TDP-43 are a pathological hallmark of ALS and FTD. Intriguingly, TDP-43 pathology has not been associated with the FTD-causing CHMP2BIntron5 mutation. In this study, we identify CHMP2B as a modifier of TDP-43-mediated neurodegeneration in a Drosophila screen. Down-regulation of CHMP2B reduces TDP-43 phosphorylation and toxicity in flies and mammalian cells. Surprisingly, although CHMP2BIntron5 causes dramatic autophagy dysfunction, disturbance of autophagy does not alter TDP-43 phosphorylation levels. Instead, we find that inhibition of CK1, but not TTBK1/2 (all of which are kinases phosphorylating TDP-43), abolishes the modifying effect of CHMP2B on TDP-43 phosphorylation. Finally, we uncover that CHMP2B modulates CK1 protein levels by negatively regulating ubiquitination and the proteasome-mediated turnover of CK1. Together, our findings propose an autophagy-independent role and mechanism of CHMP2B in regulating CK1 abundance and TDP-43 phosphorylation.
Assuntos
Autofagia , Caseína Quinase I/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Animais , Morte Celular , Linhagem Celular Tumoral , Modelos Animais de Doenças , Neuroblastoma/patologia , Fosforilação , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina/metabolismoRESUMO
OBJECTIVE: To confirm the diagnostic performance of computed tomography (CT)-based texture analysis (CTTA) and magnetic resonance imaging (MRI)-based texture analysis for grading cartilaginous tumors in long bones and to compare these findings to radiological features. MATERIALS AND METHODS: Twenty-nine patients with enchondromas, 20 with low-grade chondrosarcomas and 16 with high-grade chondrosarcomas were included retrospectively. Clinical and radiological information and 9 histogram features extracted from CT, T1WI, and T2WI were evaluated. Binary logistic regression analysis was performed to determine predictive factors for grading cartilaginous tumors and to establish diagnostic models. Another 26 patients were included to validate each model. Receiver operating characteristic (ROC) curves were generated, and accuracy rate, sensitivity, specificity and positive/negative predictive values (PPV/NPV) were calculated. RESULTS: On imaging, endosteal scalloping, cortical destruction and calcification shape were predictive for grading cartilaginous tumors. For texture analysis, variance, mean, perc.01%, perc.10%, perc.99% and kurtosis were extracted after multivariate analysis. To differentiate benign cartilaginous tumors from low-grade chondrosarcomas, the imaging features model reached the highest accuracy rate (83.7%) and AUC (0.841), with a sensitivity of 75% and specificity of 93.1%. The CTTA feature model best distinguished low-grade and high-grade chondrosarcomas, with accuracies of 71.9%, and 80% in the training and validation groups, respectively; T1-TA and T2-TA could not distinguish them well. We found that the imaging feature model best differentiated benign and malignant cartilaginous tumors, with an accuracy rate of 89.2%, followed by the T1-TA feature model (80.4%). CONCLUSIONS: The imaging feature model and CTTA- or MRI-based texture analysis have the potential to differentiate cartilaginous tumors in long bones by grade. MRI-based texture analysis failed to grade chondrosarcomas.