Probing the Impact of Surface Functionalization Module on the Performance of Mitoxantrone Prodrug Nanoassemblies: Improving the Effectiveness and Safety.

Prodrug nanoassemblies are emerging as a novel drug delivery system for chemotherapy, comprising four fundamental modules: a drug module, a modification module, a response module, and a surface functionalization module. Among these modules, surface functionalization is an essential process to enhance the biocompatibility and stability of the nanoassemblies. Here, we selected mitoxantrone (MTO) as the drug module and DSPE-PEG2K as surface functionalization module to develop MTO prodrug nanoassemblies. We systematically evaluated the effect of surface functionalization module ratios (10%, 20%, 40%, and 60% of prodrug, WDSPE-mPEG2000/Wprodrug) on the prodrug nanoassemblies. The results indicated that 40% NPs significantly improved the self-assembly stability and cellular uptake of prodrug nanoassemblies. Compared with MTO solution, 40% NPs showed better tumor specificity and pharmacokinetics, resulting in potent antitumor activity with a good safety profile. These findings highlighted the pivotal role of the surface functionalization module in regulating the performance of mitoxantrone prodrug nanoassemblies for cancer treatment.

Satellite-Type Sulfur Atom Distribution in Trithiocarbonate Bond-Bridged Dimeric Prodrug Nanoassemblies: Achieving Both Stability and Activatability.

Homodimeric prodrug nanoassemblies (HDPNs) hold promise for improving the delivery efficiency of chemo-drugs. However, the key challenge lies in designing rational chemical linkers that can simultaneously ensure the chemical stability, self-assembly stability, and site-specific activation of prodrugs. The "in series" increase in sulfur atoms, such as trisulfide bond, can improve the assembly stability of HDPNs to a certain extent, but limits the chemical stability of prodrugs. Herein, trithiocarbonate bond (─SC(S)S─), with a stable "satellite-type" distribution of sulfur atoms, is developed via the insertion of a central carbon atom in trisulfide bonds. ─SC(S)S─ bond effectively addresses the existing predicament of HDPNs by improving the chemical and self-assembly stability of homodimeric prodrugs while maintaining the on-demand bioactivation. Furthermore, ─SC(S)S─ bond inhibits antioxidant defense system, leading to up-regulation of the cellular ROS and apoptosis of tumor cells. These improvements of ─SC(S)S─ bond endow the HDPNs with in vivo longevity and tumor specificity, ultimately enhancing the therapeutic outcomes. ─SC(S)S─ bond is, therefore, promising for overcoming the bottleneck of HDPNs for efficient oncological therapy.

Dobutamine-induced alternations in cerebral blood flow of healthy adults: a 3D pseudocontinuous arterial spin labeling study.

BACKGROUND: It is unclear whether dobutamine, commonly used clinically in echocardiography and short-term congestive heart failure treatment for promoting increased myocardial contractility, affects brain microcirculatory behavior. Cerebral microcirculation plays an important role in ensuring adequate oxygen transport. Therefore, we investigated the effects of dobutamine on cerebral hemodynamics. METHODS: Forty-eight healthy volunteers without cardiovascular or cerebrovascular disease underwent MRI to obtain cerebral blood flow (CBF) maps using 3D pseudocontinuous arterial spin labeling before and during the dobutamine stress test. Additionally, cerebrovascular morphology was obtained based on 3D-time-off-light (3D-TOF) magnetic resonance angiography (MRA). Electrocardiogram, heart rate (HR), respiration rate (RR), blood pressure, and blood oxygen were simultaneously recorded before and during dobutamine injection and during recovery (not during MRI). The anatomic features of the circle of Willis and the basilar artery (BA) diameter were assessed on MRA images by two radiologists with extensive neuroimaging experience. Binary logistic regression was used to test for the independent determinants of CBF changes. RESULTS: HR, RR, systolic (SBP), and diastolic blood pressure (DBP) significantly increased after dobutamine infusion. Blood oxygen levels remained similar. Compared to the CBF in the resting state, the CBF values exhibited significantly lower CBF levels in both grey matter and white matter. Furthermore, compared with the CBF in the resting state, that in the stress state was decreased in the anterior circulation, mainly in the frontal lobe (voxel level P < 0.001, pixel level P < 0.05). Logistic regression showed that body mass index (BMI; odds ratio [OR] 5.80, 95% confidence interval [CI] 1.60-21.01, P = 0.008], resting SBP (OR 0.64, 95% CI 0.45-0.92, P = 0.014), and BA diameter (OR 11.04, 95% CI 1.05-116.53, P = 0.046) were significantly associated with frontal lobe CBF changes. CONCLUSIONS: Dobutamine-induced stress significantly decreased CBF in the frontal lobe anterior circulation. Individuals with a high BMI and low SBP during the dobutamine stress test are more likely to have a stress-induced CBF decrease. Thus, attention should be paid to blood pressure, BMI, and cerebrovascular morphology of patients undergoing dobutamine stress echocardiography or those receiving intensive care or anesthesia.

A machine learning approach to predict cerebral perfusion status based on internal carotid artery blood flow.

BACKGROUND AND OBJECTIVE: Cerebral blood flow (CBF), or perfusion, is a prerequisite for maintaining brain metabolism and normal physiological functions. Diagnosing and evaluating cerebral perfusion status is crucial to managing brain disease. However, cerebral perfusion imaging devices are complicated to operate, should be controlled by specialized technicians, are often large, and are usually installed in fixed places such as hospitals. It is significantly difficult for clinicians to obtain the cerebral perfusion status in time. Considering that CBF is mainly supplied by the internal carotid artery (ICA), this study proposes a cerebral perfusion status prediction model that can automatically quantify the level of cerebral perfusion in patients by modeling the association between ICA blood flow and cerebral perfusion. MATERIALS AND METHODS: Forty-eight participants were enrolled in the study after screening. We collected participants' ICA ultrasound and brain magnetic resonance imaging (MRI) data before and after dobutamine injection based on a rigorous experimental paradigm and built an ICA-cerebral perfusion datasetdd. Support vector machine (SVM), k-nearest neighbor (KNN), decision tree (DT), random forest (RF), gradient boosting decision tree (GBDT), and extreme gradient boosting (XGBOOST) were used for early prediction of cerebral perfusion status. The SHAP analysis was adopted to reveal the impact of interpretable predictions for each feature. RESULTS: The XGBOOST model demonstrated the best overall classification performance with an accuracy of 78.01%, sensitivity of 96.67%, specificity of 98.23%, F1 score of 74.57%, Matthews correlation coefficient (MCC) of 62.17%, and area under the receiver operating characteristic curve (AUC) of 87.08%. Accelerated speed, peak systolic flow velocity, and resistance index of ICA blood flow are important factors for cerebral perfusion prediction. CONCLUSIONS: The proposed method paves a new avenue for the study of predicting cerebral perfusion status automatically and providesv a noninvasive, real-time, and low-cost alternative to brain perfusion imaging. Moreover, this analysis identifies highly predictive features for the cerebral perfusion status and gives clinicians an intuitive understanding of the influence of key features. The prediction models can serve as an early warning tool that offers sufficient time for clinicians to take early intervention measures.

Weighted Sparseness-Based Anomaly Detection for Hyperspectral Imagery.

Anomaly detection of hyperspectral remote sensing data has recently become more attractive in hyperspectral image processing. The low-rank and sparse matrix decomposition-based anomaly detection algorithm (LRaSMD) exhibits poor detection performance in complex scenes with multiple background edges and noise. Therefore, this study proposes a weighted sparse hyperspectral anomaly detection method. First, using the idea of matrix decomposition in mathematics, the original hyperspectral data matrix is reconstructed into three sub-matrices with low rank, small sparsity and representing noise, respectively. Second, to suppress the noise interference in the complex background, we employed the low-rank, background image as a reference, built a local spectral and spatial dictionary through the sliding window strategy, reconstructed the HSI pixels of the original data, and extracted the sparse coefficient. We proposed the sparse coefficient divergence evaluation index (SCDI) as a weighting factor to weight the sparse anomaly map to obtain a significant anomaly map to suppress the background edge, noise, and other residues caused by decomposition, and enhance the abnormal target. Finally, abnormal pixels are segmented based on the adaptive threshold. The experimental results demonstrate that, on a real-scene hyperspectral dataset with a complicated background, the proposed method outperforms the existing representative algorithms in terms of detection performance.

The effect of dobutamine on ocular blood flow of healthy adults: A 3D pseudocontinuous aterial spin labelling study.

Purpose: Ocular blood flow (OBF) is an important risk factor for incidence, prevalence and progression of some ocular disorders. To date, there are very limited therapeutic options to increase OBF. This study investigated the effect of dobutamine on OBF of heathy adults using 3D pseudocontinuous arterial spin labelling (3D-pcASL), and explored the risk factors associated with OBF. Methods: Forty-three healthy participants (86 eyes) were given an intravenous injection of dobutamine. We measured OBF using 3D-pcASL with a 3.0T- MRI scanner, OBF values were independently obtained by two doctors from the OBF map. We also collected physiological parameters using a vital signs monitor. The OBF and physiological parameters in the in the period before and after dobutamine injection states were obtained. Results: OBF increased significantly after dobutamine injection using paired t test method (from 22.43 ± 9.87 to 47.73 ± 14.02 ml/min/100g, p < 0.001). Age, heart rate and systolic blood pressure were the main risk factors affecting OBF using logistic regression analysis (all p values < 0.05). Conclusion: To the best of our knowledge, this is the first study observing the effect of dobutamine on OBF. Our findings indicated that intravenously injected dobutamine increased OBF, making it a possible option to counteract ocular vascular ischaemia in the future.

Altered spontaneous brain activity during dobutamine challenge in healthy young adults: A resting-state functional magnetic resonance imaging study.

Introduction: There is a growing interest in exploring brain-heart interactions. However, few studies have investigated the brain-heart interactions in healthy populations, especially in healthy young adults. The aim of this study was to explore the association between cardiovascular and spontaneous brain activities during dobutamine infusion in healthy young adults. Methods: Forty-eight right-handed healthy participants (43 males and 5 females, range: 22-34 years) underwent vital signs monitoring, cognitive function assessment and brain MRI scans. Cardiovascular function was evaluated using blood pressure and heart rate, while two resting-state functional magnetic resonance imaging (rs-fMRI) methods-regional homogeneity (ReHo) and amplitude of low-frequency fluctuation (ALFF)-were used together to reflect the local neural activity of the brain. Logistic regression was used to model the association between brain and heart. Results: Results showed that blood pressure and heart rate significantly increased after dobutamine infusion, and the performance in brain functional activity was the decrease in ReHo in the left gyrus rectus and in ALFF in the left frontal superior orbital. The results of logistic regression showed that the difference of diastolic blood pressure (DBP) had significant positive relationship with the degree of change of ReHo, while the difference of systolic blood pressure (SBP) had significant negative impact on the degree of change in ALFF. Discussion: These findings suggest that the brain-heart interactions exist in healthy young adults under acute cardiovascular alterations, and more attention should be paid to blood pressure changes in young adults and assessment of frontal lobe function to provide them with more effective health protection management.