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Chemoresistance is an important cause of treatment failure in bladder cancer, and identifying genes that confer drug resistance is an important step toward developing new therapeutic strategies to improve treatment outcomes. In the present study, we show that gemcitabine plus cisplatin (GEM/DDP) therapy induces NF-κB signaling, which promotes p65-mediated transcriptional activation of OIP5. OIP5 recruits the E3 ubiquitin ligase TRIP12 to bind to and degrade the phosphatase PPP1CB, thereby enhancing the transcription factor activity of YBX1. This in turn upregulates drug-resistance-related genes under the transcriptional control of YBX1, leading to chemoresistance. Moreover, PPP1CB degradation can enhance the phosphorylation activity of IKKß, triggering the NF-κB signaling cascade, which further stimulates OIP5 gene expression, thus forming a negative feedback regulatory loop. Consistently, elevated OIP5 expression was associated with chemoresistance and poor prognosis in patients with bladder cancer. Furthermore, we used a CRISPR/Cas9-based engineered gene circuit, which can monitor the progression of chemoresistance in real-time, to induce OIP5 knockout upon detection of increased NF-κB signaling. The gene circuit significantly inhibited tumor cell growth in vivo, underscoring the potential for synergy between gene therapy and chemotherapy in the treatment of cancer.
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Water pollution has been made worse by the widespread use of organic dyes and their discharge, which has coincided with the industry's rapid development. Piezoelectric catalysis, as an effective wastewater purification method with promising applications, can enhance the catalyst activity by collecting tiny vibrations in nature and is not limited by sunlight. In this work, we designed and synthesized intriguing WS2/Bi2WO6 heterojunction nanocomposites, investigated their shape, structure, and piezoelectric characteristics using a range of characterization techniques, and used ultrasound to accelerate the organic dye Rhodamine B (RhB) degradation in wastewater. In comparison to the pristine monomaterials, the results demonstrated that the heterojunction composites demonstrated excellent degradation and stability of RhB under ultrasonic circumstances. The existence of heterojunctions and the internal piezoelectric field created by ultrasonic driving work in concert to boost catalytic performance, and the organic dye's rate of degradation is further accelerated by the carriers that are mutually transferred between the composites.
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OBJECTIVES: Recent studies have indicated that radiomics may have excellent performance and clinical application prospects in the differential diagnosis of benign and malignant vertebral compression fractures (VCFs). However, multimodal magnetic resonance imaging (MRI)-based radiomics model is rarely used in the differential diagnosis of benign and malignant VCFs, and is limited to lumbar. Herein, this study intends to develop and validate MRI radiomics models for differential diagnoses of benign and malignant VCFs in patients. METHODS: This cross-sectional study involved 151 adult patients diagnosed with VCF in The First Affiliated Hospital of Soochow University in 2016-2021. The study was conducted in three steps: (i) the original MRI images were segmented, and the region of interest (ROI) was marked out; (ii) among the extracted features, those features with Pearson's correlation coefficient lower than 0.9 and the top 15 with the highest variance and Lasso regression coefficient less than and more than 0 were selected; (iii) MRI images and combined data were studied by logistic regression, decision tree, random forest and extreme gradient boosting (XGBoost) models in training set and the test set (ratio of 8:2), respectively; and the models were further verified and evaluated for the differential diagnosis performance. The evaluated indexes included area under receiver (AUC) of operating characteristic curve, accuracy, sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), and 95% confidence intervals (CIs). The AUCs were used to assess the predictive performance of different machine learning modes for benign and malignant VCFs. RESULTS: A total of 1144 radiomics features, and 14 clinical features were extracted. Finally, 12 radiomics features were included in the radiomics model, and 12 radiomics features with 14 clinical features were included in the combined model. In the radiomics model, the differential diagnosis performance in the logistic regression model with the AUC of 0.905 ± 0.026, accuracy of 0.817 ± 0.057, sensitivity of 0.831 ± 0.065, and negative predictive value of 0.813 ± 0.042, was superior to the other three. In the combined model, XGBoost model had the superior differential diagnosis performance with specificity (0.979 ± 0.026) and positive predictive value (0.971 ± 0.035). CONCLUSION: The multimodal MRI-based radiomics model performed well in the differential diagnosis of benign and malignant VCFs, which may provide a tool for clinicians to differentially diagnose VCFs.
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PURPOSE: Glutamate chemical exchange saturation transfer (GluCEST) is a non-invasive CEST imaging technique for detecting glutamate levels in tissues. We aimed to investigate the reproducibility of the 5T GluCEST technique in healthy volunteers and preliminarily explore its potential clinical application in patients with brain tumors. METHODS: Ten volunteers (4 males, mean age 29 years) underwent three 5T GluCEST imaging scans. The reproducibility of the three imaging GluCEST measurements was assessed using one-way repeated measures analysis of variance (ANOVA), generalized estimating equations, and linear mixed models. Twenty-eight patients with brain tumors (10 males, mean age 54 years) underwent a single GluCEST scan preoperatively, and t-tests were used to compare the differences in GluCEST values between different brain tumors. In addition, the diagnostic accuracy of GluCEST values in differentiating brain tumors was assessed using the receiver work characteristics (ROC) curve. RESULTS: The coefficients of variation of GluCEST values in healthy volunteers were less than 5% for intra-day, inter-day, and within-subjects and less than 10% for between-subjects. High-grade gliomas (HGG) had higher GluCEST values compared to low-grade gliomas (LGG) (P < 0.001). In addition, cerebellopontine angle (CPA) meningiomas had higher GluCEST values than acoustic neuromas (P < 0.001). The area under the curve (AUC) of the GluCEST value for differentiating CPA meningioma from acoustic neuroma was 0.93. CONCLUSION: 5T GluCEST images are highly reproducible in healthy brains. In addition, the 5T GluCEST technique has potential clinical applications in differentiating LGG from HGG and CPA meningiomas from acoustic neuromas.
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O6-methylguanine-DNA methyltransferase (MGMT) has been demonstrated to be an important prognostic and predictive marker in glioblastoma (GBM). To establish a reliable radiomics model based on MRI data to predict the MGMT promoter methylation status of GBM. A total of 183 patients with glioblastoma were included in this retrospective study. The visually accessible Rembrandt images (VASARI) features were extracted for each patient, and a total of 14676 multi-region features were extracted from enhanced, necrotic, "non-enhanced, and edematous" areas on their multiparametric MRI. Twelve individual radiomics models were constructed based on the radiomics features from different subregions and different sequences. Four single-sequence models, three single-region models and the combined radiomics model combining all individual models were constructed. Finally, the predictive performance of adding clinical factors and VASARI characteristics was evaluated. The ComRad model combining all individual radiomics models exhibited the best performance in test set 1 and test set 2, with the area under the receiver operating characteristic curve (AUC) of 0.839 (0.709-0.963) and 0.739 (0.581-0.897), respectively. The results indicated that the radiomics model combining multi-region and multi-parametric MRI features has exhibited promising performance in predicting MGMT methylation status in GBM. The Modeling scheme that combining all individual radiomics models showed best performance among all constructed moels.
Subject(s)
Brain Neoplasms , DNA Methylation , DNA Modification Methylases , DNA Repair Enzymes , Glioblastoma , Tumor Suppressor Proteins , Adult , Aged , Female , Humans , Male , Middle Aged , Brain Neoplasms/genetics , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/pathology , DNA Modification Methylases/genetics , DNA Repair Enzymes/genetics , Glioblastoma/genetics , Glioblastoma/diagnostic imaging , Glioblastoma/pathology , Magnetic Resonance Imaging/methods , Prognosis , Promoter Regions, Genetic , Radiomics , Retrospective Studies , ROC Curve , Tumor Suppressor Proteins/geneticsABSTRACT
Dyslipidemia plays a key role in metabolic syndrome (MS), intricately linked to type 2 diabetes mellitus (T2DM). This study aimed to investigate the differences in low-density lipoprotein cholesterol (LDL-C) subfraction levels between T2DM and T2DM with MS, and identify the risk factors associated with the disease. A total of 246 individuals diagnosed with T2DM, including 144 T2DM patients with MS, and 147 healthy subjects were recruited. All participants underwent a comprehensive clinical evaluation. Lipoprotein subfraction analysis was performed using the Lipoprint LDL system. Multivariate logistic regression analysis revealed that several lipid markers, including triglyceride (TG), LDL-C, large buoyant LDL-C (lbLDL-C), small dense LDL-C (sdLDL-C), LDLC2-5, and sdLDL-C/lbLDL-C ratio, were identified as independent risk factors for T2DM. Additionally, TG, sdLDL-C, LDLC-4, LDLC-5, and sdLDL-C/lbLDL-C ratio were found to be independent risk factors for T2DM with MS. Furthermore, the results of the receiver operating characteristic (ROC) curves demonstrated that sdLDL-C, LDLC-4, LDLC-3, and sdLDL-C/lbLDL-C ratio exhibited excellent predictive performance for the risk of T2DM (AUC > 0.9). The sdLDL-C/lbLDL-C ratio emerges as a shared independent risk factor for T2DM and MS complications. Furthermore, sdLDL-C/lbLDL-C ratio, along with LDL-4 and LDL-3, exhibits noteworthy predictive capabilities for T2DM.
Subject(s)
Biomarkers , Cholesterol, LDL , Diabetes Mellitus, Type 2 , Metabolic Syndrome , Humans , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/complications , Metabolic Syndrome/blood , Metabolic Syndrome/diagnosis , Metabolic Syndrome/epidemiology , Female , Male , Middle Aged , Risk Factors , Cholesterol, LDL/blood , Adult , Biomarkers/blood , Case-Control Studies , AgedABSTRACT
Driven by iron-dependent lipid peroxidation, ferroptosis is regulated by p53 and solute carrier family 7 member 11 (SLC7A11)/glutathione/glutathione peroxidase 4 (GPX4) axis in colorectal cancer (CRC). This study aimed to investigate the influence of curcumin (CUR) on ferroptosis in CRC. The efficacies of CUR on the malignant phenotype of CRC cells were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, wound healing, and clonogenic assays. The effects of CUR on ferroptosis of CRC cells were evaluated by transmission electron microscopy, lactate dehydrogenase release assay, Fe2+ staining, and analyses of reactive oxygen species, lipid peroxide, malondialdehyde, and glutathione levels. CUR's targets in ferroptosis were predicted by network pharmacological study and molecular docking. With SW620 xenograft tumors, the efficacy of CUR on CRC was investigated, and the effects of CUR on ferroptosis were assessed by detection of Fe2+, malondialdehyde, and glutathione levels. The effects of CUR on expressions of p53, SLC7A11, and GPX4 in CRC cells and tumors were analyzed by quantitative reverse transcription-polymerase chain reaction, western blotting, and immunohistochemistry. CUR suppressed the proliferation, migration, and clonogenesis of CRC cells and xenograft tumor growth by causing ferroptosis, with enhanced lactate dehydrogenase release and Fe2+, reactive oxygen species, lipid peroxide, and malondialdehyde levels, but attenuated glutathione level in CRC. In silico study indicated that CUR may bind p53, SLC7A11, and GPX4, consolidated by that CUR heightened p53 but attenuated SLC7A11 and GPX4 mRNA and protein levels in CRC. CUR may exert an inhibitory effect on CRC by inducing ferroptosis via regulation of p53 and SLC7A11/glutathione/GPX4 axis.
Subject(s)
Amino Acid Transport System y+ , Colorectal Neoplasms , Curcumin , Ferroptosis , Phospholipid Hydroperoxide Glutathione Peroxidase , Tumor Suppressor Protein p53 , Ferroptosis/drug effects , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Humans , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , Tumor Suppressor Protein p53/metabolism , Amino Acid Transport System y+/metabolism , Curcumin/pharmacology , Animals , Mice , Cell Line, Tumor , Signal Transduction/drug effects , Reactive Oxygen Species/metabolism , Glutathione/metabolism , Mice, Nude , Mice, Inbred BALB C , Xenograft Model Antitumor Assays , Lipid Peroxidation/drug effects , Glutathione Peroxidase/metabolism , Male , Molecular Docking Simulation , Cell Proliferation/drug effectsABSTRACT
Sleep disturbance usually accompanies anxiety disorders and exacerbates their incidence rates. The precise circuit mechanisms remain poorly understood. Here, we found that glutamatergic neurons in the posteroventral medial amygdala (MePVGlu neurons) are involved in arousal and anxiety-like behaviors. Excitation of MePVGlu neurons not only promoted wakefulness but also increased anxiety-like behaviors. Different projections of MePVGlu neurons played various roles in regulating anxiety-like behaviors and sleep-wakefulness. MePVGlu neurons promoted wakefulness through the MePVGlu/posteromedial cortical amygdaloid area (PMCo) pathway and the MePVGlu/bed nucleus of the stria terminals (BNST) pathway. In contrast, MePVGlu neurons increased anxiety-like behaviors through the MePVGlu/ventromedial hypothalamus (VMH) pathway. Chronic sleep disturbance increased anxiety levels and reduced reparative sleep, accompanied by the enhanced excitability of MePVGlu/PMCo and MePVGlu/VMH circuits but suppressed responses of glutamatergic neurons in the BNST. Inhibition of the MePVGlu neurons could rescue chronic sleep deprivation-induced phenotypes. Our findings provide important circuit mechanisms for chronic sleep disturbance-induced hyperarousal response and obsessive anxiety-like behavior and are expected to provide a promising strategy for treating sleep-related psychiatric disorders and insomnia.
Subject(s)
Amygdala , Anxiety , Arousal , Neurons , Animals , Arousal/physiology , Male , Amygdala/metabolism , Mice , Neurons/metabolism , Glutamic Acid/metabolism , Wakefulness/physiology , Sleep Deprivation/physiopathology , Sleep Deprivation/metabolism , Sleep/physiology , Neural Pathways , Disease Models, AnimalABSTRACT
Background: Motor impairment is the most prevalent consequence following a stroke. Interhemispheric homotopic connectivity, which varies regionally and hierarchically along the axis of the somatomotor-association cortex, plays a critical role in sustaining normal motor functions. However, the impact of strokes occurring in various locations on homotopic connectivity is not fully understood. This study aimed to explore how motor deficits resulting from acute strokes in different locations influence homotopic connectivity. Methods: Eighty-four acute ischemic stroke patients with dyskinesia were recruited and divided into four demographically-matched subgroups based on stroke locations: Group 1 (G1; frontoparietal, n = 15), Group 2 (G2; radiation coronal, n = 16), Group 3 (G3; basal ganglia, n = 30), and Group 4 (G4; brain stem, n = 23). An additional 37 demographically-matched healthy controls were also recruited in the study. Multimodal MRI data, motor function assessments, and cognitive tests were gathered for analysis. Interhemispheric homotopic functional and structural connectivity were measured using resting-state functional MRI and diffusion tensor imaging, respectively. These measurements were then correlated with motor function scores to investigate the relationships. Results: Voxel-mirrored homotopic connectivity (VMHC) analysis showed that strokes in the frontoparietal and basal ganglia regions led to diminished homotopic connectivity in the somatosensory/motor cortex. In contrast, strokes in the radiation coronal and brainstem regions affected subcortical motor circuits. Structural homotopic connectivity analysis using diffusion tensor imaging showed that frontoparietal and basal ganglia strokes predominantly affected association fibers, while radiation coronal and brainstem strokes caused widespread disruption in the integrity of both cortical-cortical and cortical-subcortical white matter fibers. Correlation analyses demonstrated significant associations between the Fugl-Meyer Assessment (FMA), Modified Barthel Index (MBI), and National Institutes of Health Stroke Scale (NIHSS) scores with the VMHC in the inferior temporal gyrus for G1 (G1; r = 0.838, p < 0.001; r = 0.793, p < 0.001; and r = -0.834, p < 0.001, respectively). No statistically significant associations were observed in Groups 2, 3, and 4. Conclusion: Our results suggest that motor deficits following strokes in various regions involve distinct pathways from cortical to subcortical areas. Alterations in lesion topography and regional functional homotopy provide new insights into the understanding of neural underpinnings of post-stroke dyskinesia.
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The ventral subiculum (vSUB), the major output structure of the hippocampal formation, regulates motivation, stress integration, and anxiety-like behaviors that rely on heightened arousal. However, the roles and underlying neural circuits of the vSUB in wakefulness are poorly known. Using in vivo fiber photometry and multichannel electrophysiological recordings in mice, we found that the vSUB glutamatergic neurons exhibited high activities during wakefulness. Moreover, activation of vSUB glutamatergic neurons caused an increase in wakefulness and anxiety-like behaviors and induced a rapid transition from sleep to wakefulness. In addition, optogenetic stimulation of vSUB glutamatergic terminals and retrograde-targeted chemogenetic activation of vSUB glutamatergic neurons revealed that vSUB promoted arousal by innervating the lateral hypothalamus (LH), nucleus accumbens (NAc) shell, and prefrontal cortex (PFC). Nevertheless, local microinjection of dopamine D1 or D2/D3 receptor antagonist blocked the wake-promoting effect induced by chemogenetic activation of vSUB pathways. Finally, chemogenetic inhibition of vSUB glutamatergic neurons decreased arousal. Altogether, our findings reveal a prominent contribution of vSUB glutamatergic neurons to the control of wakefulness through several pathways.
Subject(s)
Hippocampus , Mice, Inbred C57BL , Neural Pathways , Optogenetics , Wakefulness , Animals , Wakefulness/physiology , Wakefulness/drug effects , Male , Mice , Hippocampus/drug effects , Hippocampus/physiology , Neural Pathways/physiology , Neural Pathways/drug effects , Neurons/physiology , Neurons/drug effects , Prefrontal Cortex/physiology , Prefrontal Cortex/drug effects , Nucleus Accumbens/drug effects , Nucleus Accumbens/physiology , Glutamic Acid/metabolism , Anxiety/physiopathology , Arousal/physiology , Arousal/drug effectsABSTRACT
BACKGROUND: The use of peritumoral features to determine the survival time of patients with rectal cancer (RC) is still imprecise. PURPOSE: To explore the correlation between intratumoral, peritumoral and combined features, and overall survival (OS). STUDY TYPE: Retrospective. POPULATION: One hundred sixty-six RC patients (53 women, 113 men; average age: 55 ± 12 years) who underwent radical resection after neoadjuvant therapy. FIELD STRENGTH/SEQUENCE: 3 T; T2WI sagittal, T1WI axial, T2WI axial with fat suppression, and high-resolution T2WI axial sequences, enhanced T1WI axial and sagittal sequences with fat suppression. ASSESSMENT: Radiologist A segmented 166 patients, and radiologist B randomly segmented 30 patients. Intratumoral and peritumoral features were extracted, and features with good stability (ICC ≥0.75) were retained through intra-observer analysis. Seven classifiers, including Logistic Regression (LR), Support Vector Machine (SVM), K-Nearest Neighbors (KNN), Random Forest (RF), Extremely randomized trees (ET), eXtreme Gradient Boosting (XGBoost), and LightGBM (LGBM), were applied to select the classifier with the best performance. Next, the Rad-score of best classifier and the clinical features were selected to establish the models, thus, nomogram was built to identify the association with 1-, 3-, and 5-year OS. STATISTICAL TESTS: LASSO, regression analysis, ROC, DeLong method, Kaplan-Meier curve. P < 0.05 indicated a significant difference. RESULTS: Only Node (irregular tumor nodules in the surrounding mesentery) and ExtraMRF (lymph nodes outside the perirectal mesentery) were significantly different in 20 clinical features. Twelve intratumoral, 3 peritumoral, and 14 combined features related to OS were selected. LR, SVM, and RF classier showed the best efficacy in the intratumoral, peritumoral, and combined model, respectively. The combined model (AUC = 0.954 and 0.821) had better survival association than the intratumoral model (AUC = 0.833 and 0.813) and the peritumoral model (AUC = 0.824 and 0.687). DATA CONCLUSION: The proposed peritumoral model with radiomics features may serve as a tool to improve estimated survival time. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 4.
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Particulate matter (PM) is considered the fundamental component of atmospheric pollutants and is associated with the pathogenesis of many respiratory diseases. Fibroblast growth factor 10 (FGF10) mediates mesenchymal-epithelial signaling and has been linked with the repair process of PM-induced lung injury (PMLI). However, the pathogenic mechanism of PMLI and the specific FGF10 protective mechanism against this injury are still undetermined. PM was administered in vivo into murine airways or in vitro to human bronchial epithelial cells (HBECs), and the inflammatory response and ferroptosis-related proteins SLC7A11 and GPX4 were assessed. The present research investigates the FGF10-mediated regulation of ferroptosis in PMLI mice models in vivo and HBECs in vitro. The results showed that FGF10 pretreatment reduced PM-mediated oxidative damage and ferroptosis in vivo and in vitro. Furthermore, FGF10 pretreatment led to reduced oxidative stress, decreased secretion of inflammatory mediators, and activation of the Nrf2-dependent antioxidant signaling. Additionally, silencing of Nrf2 using siRNA in the context of FGF10 treatment attenuated the effect on ferroptosis. Altogether, both in vivo and in vitro assessments confirmed that FGF10 protects against PMLI by inhibiting ferroptosis via the Nrf2 signaling. Thus, FGF10 can be used as a novel ferroptosis suppressor and a potential treatment target in PMLI.
Subject(s)
Ferroptosis , Fibroblast Growth Factor 10 , Lung Injury , Mice, Inbred C57BL , NF-E2-Related Factor 2 , Oxidative Stress , Particulate Matter , Signal Transduction , Ferroptosis/drug effects , NF-E2-Related Factor 2/metabolism , Animals , Particulate Matter/toxicity , Humans , Signal Transduction/drug effects , Fibroblast Growth Factor 10/metabolism , Fibroblast Growth Factor 10/genetics , Mice , Oxidative Stress/drug effects , Lung Injury/chemically induced , Lung Injury/metabolism , Lung Injury/pathology , Lung Injury/prevention & control , Male , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Cell Line , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , Phospholipid Hydroperoxide Glutathione Peroxidase/genetics , Disease Models, Animal , Amino Acid Transport System y+ABSTRACT
PURPOSE: This study investigated and compared the effects of Gd enhancement on brain tumours with a half-dose of contrast medium at 5.0 T and with a full dose at 3.0 T. METHODS: Twelve subjects diagnosed with brain tumours were included in this study and underwent MRI after contrast agent injection at 3.0 T (full dose) or 5.0 T (half dose) with a 3D T1-weighted gradient echo sequence. The postcontrast images were compared by two independent neuroradiologists in terms of the signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR) and subjective image quality score on a ten-point Likert scale. Quantitative indices and subjective quality ratings were compared with paired Student's t tests, and interreader agreement was assessed with the intraclass correlation coefficient (ICC). RESULTS: A total of 16 enhanced tumour lesions were detected. The SNR was significantly greater at 5.0 T than at 3.0 T in grey matter, white matter and enhanced lesions (p < 0.001). The CNR was also significantly greater at 5.0 T than at 3.0 T for grey matter/tumour lesions, white matter/tumour lesions, and grey matter/white matter (p < 0.001). Subjective evaluation revealed that the internal structure and outline of the tumour lesions were more clearly displayed with a half-dose at 5.0 T (Likert scale 8.1 ± 0.3 at 3.0 T, 8.9 ± 0.3 at 5.0 T, p < 0.001), and the effects of enhancement in the lesions were comparable to those with a full dose at 3.0 T (7.8 ± 0.3 at 3.0 T, 8.7 ± 0.4 at 5.0 T, p < 0.001). All subjective scores were good to excellent at both 5.0 T and 3.0 T. CONCLUSION: Both quantitative and subjective evaluation parameters suggested that half-dose enhanced scanning via 5.0 T MRI might be feasible for meeting clinical diagnostic requirements, as the image quality remains optimal. Enhanced scanning at 5.0 T with a half-dose of contrast agents might benefit patients with conditions that require less intravenous contrast agent, such as renal dysfunction.
Subject(s)
Brain Neoplasms , Contrast Media , Humans , Feasibility Studies , Brain Neoplasms/diagnostic imaging , Gray Matter , RadiologistsABSTRACT
OBJECTIVE: To assess the performance of hybrid multi-dimensional magnetic resonance imaging (HM-MRI) in quantifying hematoxylin and eosin (H&E) staining results, grading and predicting isocitrate dehydrogenase (IDH) mutation status of gliomas. MATERIALS AND METHODS: Included were 71 glioma patients (mean age, 50.17 ± 13.38 years; 35 men). HM-MRI images were collected at five different echo times (80-200 ms) with seven b-values (0-3000 s/mm2). A modified three-compartment model with very-slow, slow and fast diffusion components was applied to calculate HM-MRI metrics, including fractions, diffusion coefficients and T2 values of each component. Pearson correlation analysis was performed between HM-MRI derived fractions and H&E staining derived percentages. HM-MRI metrics were compared between high-grade and low-grade gliomas, and between IDH-wild and IDH-mutant gliomas. Using receiver operational characteristic (ROC) analysis, the diagnostic performance of HM-MRI in grading and genotyping was compared with mono-exponential models. RESULTS: HM-MRI metrics FDvery-slow and FDslow demonstrated a significant correlation with the H&E staining results (p < .05). Besides, FDvery-slow showed the highest area under ROC curve (AUC = 0.854) for grading, while Dslow showed the highest AUC (0.845) for genotyping. Furthermore, a combination of HM-MRI metrics FDvery-slow and T2Dslow improved the diagnostic performance for grading (AUC = 0.876). DISCUSSION: HM-MRI can aid in non-invasive diagnosis of gliomas.
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Traumatic brain injury (TBI) leads to structural damage in the brain, and is one of the major causes of disability and death in the world. Herein, we developed a composite injectable hydrogel (HA/Gel) composed of hyaluronic acid (HA) and gelatin (Gel), loaded with vascular endothelial growth factor (VEGF) and salvianolic acid B (SAB) for treatment of TBI. The HA/Gel hydrogels were formed by the coupling of phenol-rich tyramine-modified HA (HA-TA) and tyramine-modified Gel (Gel-TA) catalyzed by horseradish peroxidase (HRP) in the presence of hydrogen peroxide (H2O2). SEM results showed that HA/Gel hydrogel had a porous structure. Rheological test results showed that the hydrogel possessed appropriate rheological properties, and UV spectrophotometry results showed that the hydrogel exhibited excellent SAB release performance. The results of LIVE/DEAD staining, CCK-8 and Phalloidin/DAPI fluorescence staining showed that the HA/Gel hydrogel possessed good cell biocompatibility. Moreover, the hydrogels loaded with SAB and VEGF (HA/Gel/SAB/VEGF) could effectively promote the proliferation of bone marrow mesenchymal stem cells (BMSCs). In addition, the results of H&E staining, CD31 and α-SMA immunofluorescence staining showed that the HA/Gel/SAB/VEGF hydrogel possessed good in vivo biocompatibility and pro-angiogenic ability. Furthermore, immunohistochemical results showed that the injection of HA/Gel/SAB/VEGF hydrogel to the injury site could effectively reduce the volume of defective tissues in traumatic brain injured mice. Our results suggest that the injection of HA/Gel hydrogel loaded with SAB and VEGF might provide a new approach for therapeutic brain tissue repair after traumatic brain injury.
Subject(s)
Benzofurans , Brain Injuries, Traumatic , Depsides , Gelatin , Hyaluronic Acid , Hydrogels , Vascular Endothelial Growth Factor A , Animals , Hydrogels/chemistry , Brain Injuries, Traumatic/drug therapy , Brain Injuries, Traumatic/pathology , Gelatin/chemistry , Hyaluronic Acid/chemistry , Mice , Vascular Endothelial Growth Factor A/metabolism , Benzofurans/chemistry , Benzofurans/pharmacology , Benzofurans/administration & dosage , Mesenchymal Stem Cells/drug effects , Mesenchymal Stem Cells/metabolism , Disease Models, Animal , Male , Cell Proliferation/drug effectsABSTRACT
Intrinsic immunosuppressive tumor microenvironment (ITM) and insufficient tumor infiltration of T cells severely impede the progress of glioblastoma (GBM) immunotherapy. In this study, it is identify that inhibiting the expression of glucose transporter 1 (GLUT1) can facilitate the prevention of lactate excretion from tumor glycolysis, which significantly alleviates the lactate-driven ITM by reducing immunosuppressive tumor-associated macrophages (TAMs) and regulatory T cells (Tregs). Simultaneously, the findings show that the generated inflammatory cytokine IFN-γ during immune activation aggravates the immune escape by upregulating immune checkpoint programmed death-ligand 1 (PD-L1) in tumor cells and TAMs. Therefore, an injectable thermogel loaded with a GLUT1 inhibitor BAY-876 and a PD-1/PD-L1 blocker BMS-1 (Gel@B-B) for dual-regulation of metabolism and immunity of GBM is developed. Consequently, in situ injection of Gel@B-B significantly delays tumor growth and prolongs the survival of the orthotopic GBM mouse model. By actively exposing tumor antigens to antigen-presenting cells, the GBM vaccine combined with Gel@B-B is found to significantly increase the fraction of effector T cells (Th1/CTLs) in the tumor microenvironment, thereby remarkably mitigating tumor recurrence long-term. This study may provide a promising strategy for GBM immunotherapy.
Subject(s)
B7-H1 Antigen , Glioblastoma , Immunotherapy , Lactic Acid , Animals , Humans , Mice , B7-H1 Antigen/immunology , B7-H1 Antigen/antagonists & inhibitors , Brain Neoplasms/immunology , Brain Neoplasms/therapy , Brain Neoplasms/drug therapy , Cell Line, Tumor , Disease Models, Animal , Gels , Glioblastoma/immunology , Glioblastoma/therapy , Glioblastoma/drug therapy , Immune Checkpoint Inhibitors/pharmacology , Immunotherapy/methods , Lactic Acid/metabolism , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , Tumor Microenvironment/drug effects , Tumor Microenvironment/immunology , Tumor-Associated Macrophages/immunology , Tumor-Associated Macrophages/drug effectsABSTRACT
BACKGROUND AND PURPOSE: Due to high chemical shift displacement, challenges emerge at ultra-high fields when measuring metabolites using 1H-MRS. Our goal was to investigate how well the high SNR and high bandwidth spin-echo (HISE) technique perform at 5T for detecting target metabolites in brain tumors. MATERIALS AND METHODS: Twenty-six subjects suspected of having brain tumors were enrolled. HISE and point-resolved spectroscopy (PRESS) single-voxel spectroscopy scans were collected with a 5T clinical scanner with an intermediate TE (TE = 144 ms). The main metabolites, including total NAA, Cr, and total Cho, were accessed and compared between HISE and PRESS using a paired Student t test, with full width at half maximum and SNR as covariates. The detection rate of specific metabolites, including lactate, alanine, and lipid, and subjective spectral quality were accessed and compared between HISE and PRESS. RESULTS: Twenty-three pathologically confirmed brain tumors were included. Only the full width at half maximum for total NAA was significantly lower with HISE than with PRESS (P < .05). HISE showed a significantly higher SNR for total NAA, Cr, and total Cho compared with PRESS (P < .05). Lactate was detected in 21 of the 23 cases using HISE, but in only 4 cases using PRESS. HISE detected alanine in 8 of 9 meningiomas, whereas PRESS detected alanine in just 3 meningiomas. PRESS found lipid in more cases than HISE, while HISE outperformed PRESS in terms of subjective spectral quality. CONCLUSIONS: HISE outperformed the clinical standard PRESS technique in detecting target metabolites of brain tumors at 5T, particularly lactate and alanine.
Subject(s)
Brain Neoplasms , Meningeal Neoplasms , Meningioma , Humans , Magnetic Resonance Spectroscopy/methods , Meningioma/diagnostic imaging , Reproducibility of Results , Brain Neoplasms/metabolism , Lactic Acid/metabolism , Alanine/metabolism , Lipids , Brain/metabolismABSTRACT
Armeniacae semen amarum-seeds of Prunus armeniaca L. (Rosaceae) (ASA), also known as Kuxingren in Chinese, is a traditional Chinese herbal drug commonly used for lung disease and intestinal disorders. It has long been used to treat coughs and asthma, as well as to lubricate the colon and reduce constipation. ASA refers to the dried ripe seed of diverse species of Rosaceae and contains a variety of phytochemical components, including glycosides, organic acids, amino acids, flavonoids, terpenes, phytosterols, phenylpropanoids, and other components. Extensive data shows that ASA exhibits various pharmacological activities, such as anticancer activity, anti-oxidation, antimicrobial activity, anti-inflammation, protection of cardiovascular, neural, respiratory and digestive systems, antidiabetic effects, and protection of the liver and kidney, and other activities. In clinical practice, ASA can be used as a single drug or in combination with other traditional Chinese medicines, forming ASA-containing formulas, to treat various afflictions. However, it is important to consider the potential adverse reactions and pharmacokinetic properties of ASA during its clinical use. Overall, with various bioactive components, diversified pharmacological actions and potent efficacies, ASA is a promising drug that merits in-depth study on its functional mechanisms to facilitate its clinical application.
ABSTRACT
Purpose: Current interpersonal sensitivity among college students is easily linked to mood disorders such as anxiety, depression and other mood disorders. This study aims to examine the mediating role of psychological capital and its dimensions in the relationship between interpersonal sensitivity and depressive symptoms among undergraduates. Methods: The cross-sectional survey was conducted by using cluster stratified random sampling method across six Chinese universities between November and December 2022. The questionnaire consists of the Interpersonal Sensitivity sub-scale, the Patient Health Questionnaire, the Psychological Capital Questionnaire and the Socio-Demographic Feature Questionnaire. Results: A total of 2580 respondents participated in the survey, with the majority being females (69.73%) and an average age of 19.22±1.28 years. Descriptive and correlation analyses were performed using SPSS v24.0, while direct and indirect effects were analyzed using PROCESS v3.4 macro. The findings revealed that interpersonal sensitivity had a significant direct effect on depression symptoms among undergraduates (ß =0.416, 95% Boot CI [0.380, 0.453], p < 0.001) Additionally, psychological capital and its components were found to be negatively correlated with depression (p < 0.001). Further analysis demonstrated that hope, optimism, and resilience significantly mediated the association between interpersonal sensitivity and depressive symptoms (indirect effect: hope = 0.056, optimism = 0.074, resilience = 0.099; p < 0.001 for all). Conclusion: These results suggest that psychological capital, including its dimensions of hope, optimism, and resilience plays a crucial role in mitigating the negative effects of interpersonal sensitivity on depressive symptoms among undergraduates.