APOE ε4-associated downregulation of the IL-7/IL-7R pathway in effector memory T cells: Implications for Alzheimer's disease.

INTRODUCTION: The apolipoprotein E (APOE) ε4 allele exerts a significant influence on peripheral inflammation and neuroinflammation, yet the underlying mechanisms remain elusive. METHODS: The present study enrolled 54 patients diagnosed with late-onset Alzheimer's disease (AD; including 28 APOE ε4 carriers and 26 non-carriers). Plasma inflammatory cytokine concentration was assessed, alongside bulk RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq) analysis of peripheral blood mononuclear cells (PBMCs). RESULTS: Plasma tumor necrosis factor α, interferon γ, and interleukin (IL)-33 levels increased in the APOE ε4 carriers but IL-7 expression notably decreased. A negative correlation was observed between plasma IL-7 level and the hippocampal atrophy degree. Additionally, the expression of IL-7R and CD28 also decreased in PBMCs of APOE ε4 carriers. ScRNA-seq data results indicated that the changes were mainly related to the CD4+ Tem (effector memory) and CD8+ Tem T cells. DISCUSSION: These findings shed light on the role of the downregulated IL-7/IL-7R pathway associated with the APOE ε4 allele in modulating neuroinflammation and hippocampal atrophy. HIGHLIGHTS: The apolipoprotein E (APOE) ε4 allele decreases plasma interleukin (IL)-7 and aggravates hippocampal atrophy in Alzheimer's disease. Plasma IL-7 level is negatively associated with the degree of hippocampal atrophy. The expression of IL-7R signaling decreased in peripheral blood mononuclear cells of APOE ε4 carriers Dysregulation of the IL-7/IL-7R signal pathways enriches T cells.

A multi-view fusion lightweight network for CRSwNPs prediction on CT images.

Accurate preoperative differentiation of the chronic rhinosinusitis (CRS) endotype between eosinophilic CRS (eCRS) and non-eosinophilic CRS (non-eCRS) is an important topic in predicting postoperative outcomes and administering personalized treatment. To this end, we have constructed a sinus CT dataset, which comprises CT scan data and pathological biopsy results from 192 patients of chronic rhinosinusitis with nasal polyps (CRSwNP), treated at the Second Affiliated Hospital of Shantou University Medical College between 2020 and 2022. To differentiate CRSwNP endotype on preoperative CT and improve efficiency at the same time, we developed a multi-view fusion model that contains a mini-architecture with each network of 10 layers by modifying the deep residual neural network. The proposed model is trained on a training set and evaluated on a test set. The multi-view deep learning fusion model achieved the area under the receiver-operating characteristics curve (AUC) of 0.991, accuracy of 0.965 and F1-Score of 0.970 in test set. We compared the performance of the mini-architecture with other lightweight networks on the same Sinus CT dataset. The experimental results demonstrate that the developed ResMini architecture contribute to competitive CRSwNP endotype identification modeling in terms of accuracy and parameter number.

NMR and MS reveal characteristic metabolome atlas and optimize esophageal squamous cell carcinoma early detection.

Metabolic changes precede malignant histology. However, it remains unclear whether detectable characteristic metabolome exists in esophageal squamous cell carcinoma (ESCC) tissues and biofluids for early diagnosis. Here, we conduct NMR- and MS-based metabolomics on 1,153 matched ESCC tissues, normal mucosae, pre- and one-week post-operative sera and urines from 560 participants across three hospitals, with machine learning and WGCNA. Aberrations in 'alanine, aspartate and glutamate metabolism' proved to be prevalent throughout the ESCC evolution, consistently identified by NMR and MS, and reflected in 16 serum and 10 urine metabolic signatures in both discovery and validation sets. NMR-based simplified panels of any five serum or urine metabolites outperform clinical serological tumor markers (AUC = 0.984 and 0.930, respectively), and are effective in distinguishing early-stage ESCC in test set (serum accuracy = 0.994, urine accuracy = 0.879). Collectively, NMR-based biofluid screening can reveal characteristic metabolic events of ESCC and be feasible for early detection (ChiCTR2300073613).

Repurposing of the PET Probe Prototype PiB for Label and Radiation-Free CEST MRI Molecular Imaging of Amyloid.

Positron emission tomography (PET) probes are specific and sensitive while suffering from radiation risk. It is worthwhile to explore the chemical emission saturation transfer (CEST) effects of the probe prototypes and repurpose them for CEST imaging to avoid radiation. In this study, we used 11C-PiB as an example of a PET probe for detecting amyloid and tested the feasibility of repurposing this PET probe prototype, PiB, for CEST imaging. After optimizing the parameters through preliminary phantom experiments, we used APP/PS1 transgenic mice and age-matched C57 mice for in vivo CEST magnetic resonance imaging (MRI) of amyloid. Furthermore, the pathological assessment was conducted on the same brain slices to evaluate the correlation between the CEST MRI signal abnormality and ß-amyloid deposition detected by immunohistochemical staining. In our results, the Z-spectra revealed an apparent CEST effect that peaked at approximately 6 ppm. APP/PS1 mice as young as 9 months injected with PiB showed a significantly higher CEST effect compared to the control groups. The hyperintense region was correlated with the Aß deposition shown by pathological staining. In conclusion, repurposing the PET probe prototype for CEST MRI imaging is feasible and enables label- and radiation-free detection of the amyloid while maintaining the sensitivity and specificity of the ligand. This study opens the door to developing CEST probes based on PET probe prototypes.

Role of Imaging Modalities and N-Acetylcysteine Treatment in Sepsis-Associated Encephalopathy.

Sepsis-associated encephalopathy is a severe systemic infection complication. Although early stages involve pathophysiological changes, detection using conventional imaging is challenging. Glutamate chemical exchange saturation transfer and diffusion kurtosis imaging can noninvasively investigate cellular and molecular events in early disease stages using magnetic resonance imaging (MRI). N-Acetylcysteine, an antioxidant and precursor of glutathione, regulates neurotransmitter glutamate metabolism and participates in neuroinflammation. We investigated the protective role of n-acetylcysteine in sepsis-associated encephalopathy using a rat model and monitored changes in brain using magnetic resonance (MR) molecular imaging. Bacterial lipopolysaccharide was injected intraperitoneally to induce a sepsis-associated encephalopathy model. Behavioral performance was assessed using the open-field test. Tumor necrosis factor α and glutathione levels were detected biochemically. Imaging was performed using a 7.0-T MRI scanner. Protein expression, cellular damage, and changes in blood-brain barrier permeability were assessed using western blotting, pathological staining, and Evans blue staining, respectively. Lipopolysaccharide-induced rats showed reduced anxiety and depression after treatment with n-acetylcysteine. MR molecular imaging can identify pathological processes at different disease stages. Furthermore, rats treated with n-acetylcysteine showed increased glutathione levels and decreased tumor necrosis factor α, suggesting enhanced antioxidant capacity and inhibition of inflammatory processes, respectively. Western blot analysis showed reduced expression of nuclear factor kappa B (p50) protein after treatment, suggesting that n-acetylcysteine inhibits inflammation via this signaling pathway. Finally, n-acetylcysteine-treated rats showed reduced cellular damage by pathology and reduced extravasation of their blood-brain barrier by Evans Blue staining. Thus, n-acetylcysteine might be a therapeutic option for sepsis-associated encephalopathy and other neuroinflammatory diseases. Furthermore, noninvasive "dynamic visual monitoring" of physiological and pathological changes related to sepsis-associated encephalopathy was achieved using MR molecular imaging for the first time, providing a more sensitive imaging basis for early diagnosis, identification, and prognosis.

Deep learning to reconstruct quasi-steady-state chemical exchange saturation transfer from a non-steady-state experiment.

The insufficiently long RF saturation duration and relaxation delay in chemical exchange saturation transfer (CEST)-MRI experiments may result in underestimation of CEST measurements. To maintain the CEST effect without prolonging the saturation duration and reach quasi-steady state (QUASS), a deep learning method was developed to reconstruct a QUASS CEST image pixel by pixel from non-steady-state CEST acquired in experiments. In this work, we established a tumor-bearing rat model on a 7 T horizontal bore small-animal MRI scanner, allowing ground-truth generation, after which a bidirectional long short-term memory network was formulated and trained on simulated CEST Z-spectra to reconstruct the QUASS CEST; finally, the ground truth yielded by experiments was used to evaluate the performance of the reconstruction model by comparing the estimates with the ground truth. For quantitation evaluation, linear regression analysis, structural similarity index (SSIM) and peak signal-to-noise ratio (peak SNR) were used to assess the proposed model in the QUASS CEST reconstruction. In the linear regression analysis of in vivo data, the coefficient of determination for six different representative frequency offsets was at least R2 = 0.9521. Using the SSIM and peak SNR as evaluation metrics, the reconstruction accuracies of in vivo QUASS CEST were found to be 0.9991 and 46.7076, respectively. Experimental results demonstrate that the proposed model provides a robust and accurate solution for QUASS CEST reconstruction using a deep learning mechanism.

Efficacy and safety of proton beam therapy for rhabdomyosarcoma: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to evaluate and conduct a meta-analysis on the efficacy and safety of proton beam therapy (PBT) for rhabdomyosarcoma (RMS). METHODS: We searched for articles using PubMed, Embase, Cochrane Library, and Web of Science databases from their inception to December 22, 2022. Two researchers independently screened literature and extracted data. Statistical analyses were performed using STATA version 14.0. RESULTS: We got 675 candidate articles, of which 11 studies were included in our study according to the inclusion and exclusion criteria. Of the 544 RMS patients who received PBT. The local control (LC) rate at 1, 2, 3, 4, and 5 years were 96% (95% confidence interval (CI) 0.91-1.01), 93% (95% CI 0.86-1.00), 78% (95% CI 0.71-0.85), 85% (95% CI 0.78-0.92), and 84% (95% CI 0.74-0.95), respectively. The progression-free survival (PFS) rate at 1, 2, 3, 4, and 5 years were 82% (95% CI 0.72-0.92), 73% (95% CI 0.61-0.84), 63% (95% CI 0.47-0.79), 64% (95% CI 0.54-0.74), and 76% (95% CI 0.59-0.94), respectively. The overall survival (OS) rate at 1, 2, 3, 4, and 5 years were 93% (95% CI 0.86-1.00), 85% (95% CI 0.76-0.95), 80% (95% CI 0.63-0.96), 71% (95% CI 0.62-0.80), and 82% (95% CI 0.71-0.94), respectively. Acute and late toxicities were mainly grades 1 to 2 in all studies. CONCLUSION: As an advantageous RT technique, PBT is an emerging option for patients with RMS, particularly children and adolescents patients. The data showed that PBT is a feasible, safe, and effective modality for RMS, showing promising LC, OS, PFS, and lower acute and late toxicities. PROSPERO registration number: CRD42022329154.

Combined Application of Quantitative Susceptibility Mapping and Diffusion Kurtosis Imaging Techniques to Investigate the Effect of Iron Deposition on Microstructural Changes in the Brain in Parkinson's Disease.

Objectives: Brain iron deposition and microstructural changes in brain tissue are associated with Parkinson's disease (PD). However, the correlation between these factors in Parkinson's disease has been little studied. This study aimed to use quantitative susceptibility mapping combined with diffusion kurtosis imaging to investigate the effects of iron deposition on microstructural tissue alterations in the brain. Methods: Quantitative susceptibility mapping and diffusion kurtosis imaging were performed on 24 patients with early PD, 13 patients with advanced PD, and 25 healthy controls. The mean values of magnetic susceptibility and diffusion kurtosis were calculated for the bilateral substantia nigra, red nucleus, putamen, globus pallidus, and caudate nucleus, and compared between the groups. Correlation analyses between the diffusion kurtosis of each nucleus and its magnetic susceptibility parameters in PD patients and healthy controls were performed. Results: The study found a significant increase in iron deposition in the substantia nigra, red nucleus, putamen and globus pallidus, bilaterally, in patients with PD. Mean kurtosis values were increased in the substantia nigra but decreased in the globus pallidus; axial kurtosis values were decreased in both the substantia nigra and red nucleus; radial kurtosis values were increased in the substantia nigra but showed an opposite trend in the globus pallidus and caudate nucleus. In the substantia nigra of patients with PD, magnetic susceptibility was positively correlated with mean and radial kurtosis values, and negatively correlated with axial kurtosis. None of these correlations were significantly different in the control group. In the putamen, magnetic susceptibility was positively correlated with mean, axial, and radial kurtosis only in patients with advanced-stage PD. Conclusion: Our study provides new evidence for brain iron content and microstructural alterations in patients with PD. Iron deposition may be a common mechanism for microstructural alterations in the substantia nigra and putamen of patients with PD. Tracking the dynamic changes in iron content and microstructure throughout the course of PD will help us to better understand the dynamics of iron metabolism and microstructural alterations in the pathogenesis of PD and to develop new approaches to monitor and treat PD.

XGboost Prediction Model Based on 3.0T Diffusion Kurtosis Imaging Improves the Diagnostic Accuracy of MRI BiRADS 4 Masses.

Background: The malignant probability of MRI BiRADS 4 breast lesions ranges from 2% to 95%, leading to unnecessary biopsies. The purpose of this study was to construct an optimal XGboost prediction model through a combination of DKI independently or jointly with other MR imaging features and clinical characterization, which was expected to reduce false positive rate of MRI BiRADS 4 masses and improve the diagnosis efficiency of breast cancer. Methods: 120 patients with 158 breast lesions were enrolled. DKI, Diffusion-weighted Imaging (DWI), Proton Magnetic Resonance Spectroscopy (1H-MRS) and Dynamic Contrast-Enhanced MRI (DCE-MRI) were performed on a 3.0-T scanner. Wilcoxon signed-rank test and χ2 test were used to compare patient's clinical characteristics, mean kurtosis (MK), mean diffusivity (MD), apparent diffusion coefficient (ADC), total choline (tCho) peak, extravascular extracellular volume fraction (Ve), flux rate constant (Kep) and volume transfer constant (Ktrans). ROC curve analysis was used to analyze the diagnostic performances of the imaging parameters. Spearman correlation analysis was performed to evaluate the associations of imaging parameters with prognostic factors and breast cancer molecular subtypes. The Least Absolute Shrinkage and Selectionator operator (lasso) and the area under the curve (AUC) of imaging parameters were used to select discriminative features for differentiating the breast benign lesions from malignant ones. Finally, an XGboost prediction model was constructed based on the discriminative features and its diagnostic efficiency was verified in BiRADS 4 masses. Results: MK derived from DKI performed better for differentiating between malignant and benign lesions than ADC, MD, tCho, Kep and Ktrans (p < 0.05). Also, MK was shown to be more strongly correlated with histological grade, Ki-67 expression and lymph node status. MD, MK, age, shape and menstrual status were selected to be the optimized feature subsets to construct an XGboost model, which exhibited superior diagnostic ability for breast cancer characterization and an improved evaluation of suspicious breast tumors in MRI BiRADS 4. Conclusions: DKI is promising for breast cancer diagnosis and prognostic factor assessment. An optimized XGboost model that included DKI, age, shape and menstrual status is effective in improving the diagnostic accuracy of BiRADS 4 masses.

Cerebrovascular reactivity changes in acute concussion: a controlled cohort study.

BACKGROUND: Evidence suggests that cerebrovascular reactivity (CVR) increases within the first week after the incidence of concussion, indicating a disruption of normal autoregulation. We sought to extend these findings by investigating the effects of acute concussion on the speed of CVR response and by visualizing global and regional impairments in individual patients with acute concussion. METHODS: Twelve patients aged 18-40 years who experienced concussion less than a week before this prospective study were included. Twelve age and sex-matched healthy subjects constituted the control group. In all subjects, CVR was assessed using blood oxygenation level-dependent (BOLD) echo-planar imaging with a 3.0T MRI scanner, in combination with changes in end-tidal partial pressure of CO2 (PETCO2). In each subject, we calculated the CVR amplitude and CVR response time in the gray and white matter using a step and ramp PETCO2 challenge. In addition, a separate group of 39 healthy controls who underwent the same evaluation was used to create atlases with voxel-wise mean and standard deviation of CVR amplitude and CVR response time. This allowed us to convert each metric of the 12 patients with concussion and the 12 healthy controls into z-score maps. These maps were then used to generate and compare z-scores for each of the two groups. Group differences were calculated using an unpaired t-test. RESULTS: All studies were well tolerated without any serious adverse events. Anatomical MRI was normal in all study subjects. No differences in CO2 stimulus and O2 targeting were observed between the two participant groups during BOLD MRI. With regard to the gray matter, the CVR magnitude step (P=0.117) and ramp + 10 (P=0.085) were not significantly different between patients with concussion and healthy controls. However, the tau value was significantly lower in patients with concussion than in the healthy controls (P=0.04). With regard to the white matter, the CVR magnitude step (P=0.003) and ramp + 10 (P=0.031) were significantly higher and the tau value (P=0.024) was significantly shorter in patients with concussion than in healthy controls. After z-score transformation, the z tau value was significantly lower in patients with concussion than in healthy controls (Grey matter P=0.021, White matter P=0.003). Comparison of the three parameters, z ramp + 10, z step, and z tau, between the two groups showed that z step (Grey matter P=0.035, White matter P=0.005) was the most sensitive parameter and that z ramp + 10 (Grey matter P=0.073, White matter P=0.126) was the least sensitive parameter. CONCLUSIONS: Concussion is associated with patient-specific abnormalities in BOLD cerebrovascular responsiveness that occur in the setting of normal global CVR. This study demonstrates that the measurement of CVR using BOLD MRI and precise CO2 control is a safe, reliable, reproducible, and clinically useful method for evaluating the state of patients with concussion. It has the potential to be an important tool for assessing the severity and duration of symptoms after concussion.

pH-Responsive Multifunctional Theranostic Rapamycin-Loaded Nanoparticles for Imaging and Treatment of Acute Ischemic Stroke.

Stroke is the second leading cause of death globally and the most common cause of severe disability. Several barriers need to be addressed more effectively to treat stroke, including efficient delivery of therapeutic agents, rapid release at the infarct site, precise imaging of the infarct site, and drug distribution monitoring. The present study aimed to develop a bio-responsive theranostic nanoplatform with signal-amplifying capability to deliver rapamycin (RAPA) to ischemic brain tissues and visually monitor drug distribution. A pH-sensitive theranostic RAPA-loaded nanoparticle system was designed since ischemic tissues have a low-pH microenvironment compared with normal tissues. The nanoparticles demonstrated good stability and biocompatibility and could efficiently load rapamycin, followed by its rapid release in acidic environments, thereby improving therapeutic accuracy. The nano-drug-delivery system also exhibited acid-enhanced magnetic resonance imaging (MRI) and near-infrared fluorescence (NIRF) imaging signal properties, enabling accurate multimodal imaging with minimal background noise, thus improving drug tracing and diagnostic accuracy. Finally, in vivo experiments confirmed that the nanoparticles preferentially aggregated in the ischemic hemisphere and exerted a neuroprotective effect in rats with transient middle cerebral artery occlusion (tMCAO). These pH-sensitive multifunctional theranostic nanoparticles could serve as a potential nanoplatform for drug tracing as well as the treatment and even diagnosis of acute ischemic stroke. Moreover, they could be a universal solution to achieve accurate in vivo imaging and treatment of other diseases.

1 H NMR-based metabolomics of paired esophageal tumor tissues and serum samples identifies specific serum biomarkers for esophageal cancer.

Serum metabolites of healthy controls and esophageal cancer (EC) patients have previously been compared to predict cancer-specific profiles. However, the association between metabolic alterations in serum samples and esophageal tissues in EC patients remains unclear. Here, we analyzed 50 pairs of EC tissues and distant noncancerous tissues, together with patient-matched serum samples, using 1 H NMR spectroscopy and pattern recognition algorithms. EC patients could be differentiated from the controls based on the metabolic profiles at tissue and serum levels. Some overlapping discriminatory metabolites, including valine, alanine, glucose, acetate, citrate, succinate and glutamate, were identified in both matrices. These results suggested deregulation of metabolic pathways, and potentially revealed the links between EC and several metabolic pathways, such as the tricarboxylic acid cycle, glutaminolysis, short-chain fatty acid metabolism, lipometabolism and pyruvate metabolism. Perturbation of the pyruvate metabolism was most strongly associated with EC progression. Consequently, an optimal serum metabolite biomarker panel comprising acetate and pyruvate was developed, as these two metabolites are involved in pyruvate metabolism, and changes in their serum levels were significantly correlated with alterations in the levels of some other esophageal tissue metabolites. In comparison with individual biomarkers, this panel exhibited better diagnostic efficiency for EC, with an AUC of 0.948 in the test set, and a good predictive ability of 82.5% in the validation set. Analysis of key genes related to pyruvate metabolism in EC patients revealed patterns corresponding to the changes in serum pyruvate and acetate levels. These correlation analyses demonstrate that there were distinct metabolic characteristics and pathway aberrations in the esophageal tumor tissue and in the serum. Changes in the serum metabolic signatures could reflect the alterations in the esophageal tumor profile, thereby emphasizing the importance of distinct serum metabolic profiles as potential noninvasive biomarkers for EC.

Quantitative metabolic characteristics in the peritumoral region of gliomas at 7T.

BACKGROUND: The determination of tumor peripheral is of great significance in clinical diagnosis and treatment. OBJECTIVE: In this study, we aim to obtain the metabolic condition in tumor peripheral of gliomas in vivo at 7T. METHODS: C6 glioma cells were implanted into the right basal ganglia of Sprague-Dawley (SD) rats under stereotactic guided to create the glioma models. The models were sequentially undergone MRI and MRS examination on an 7T MR scanner designed for animals 7 days after the operation. Neuro metabolites were investigated from the center of the tumor, solid part of the tumor, peritumoral region, and contralateral white matter, and be quantified using the LCmodel software. Glial fibrillary acidic protein (GFAP) immunohistochemistry and conventional hematoxylin and eosin (HE) staining were performed after the imaging protocol. RESULTS: Our results found that the inositol (Ins) and taurine (Tau) significantly defected in tumor peripheral compared to both tumor solid and normal tissues (P< 0.05). In contrast, the glutamate and glutamine (Glx) escalated and peaked at the tumor peripheral (P< 0.05). CONCLUSIONS: This study revealed that Ins, Tau, and Glx have the potential to provide specific biomarkers for the location of tumor peripheral of glioma.

The value of a shorter-delay arterial spin labeling protocol for detecting cerebrovascular impairment.

BACKGROUND: The aim of this study was to determine the relationship between blood oxygen level dependent (BOLD) cerebrovascular reactivity (CVR) and cerebral blood flow (CBF) obtained from arterial spin labeling (ASL) using different post labeling delays (PLD). METHODS: Forty-two patients with steno-occlusive diseases and impaired CVR were divided into two groups, one scanned with a 1.5-second (1.5-s) and the other with a 2.5-second (2.5-s) PLD ASL protocol. For all patients, a region of interest (ROI) was drawn around the CVR impairment. This affected ROI was then left-right flipped across the brain midline to obtain the control ROI. For both groups, the difference in grey matter CVR between affected and control ROI was first tested to confirm significance. The average grey matter CBF of affected and control ROIs were then compared. The same analysis method was used to compare affected and control hemispheres. RESULTS: In both groups of 1.5-s and 2.5-s PLD, CVR values in the affected ROI (-0.049±0.055 and -0.042±0.074%/mmHg, respectively) were significantly lower compared to that in the control ROI (0.152±0.054 and 0.152±0.053%/mmHg, respectively, P<0.0001). In the group with the 1.5-s PLD, CBF in the affected ROI (37.62±11.37 mL/100 g/min) was significantly lower compared to CBF in the control ROI (44.13±11.58 mL/100 g/min, P<0.05). However, in the group with the 2.5-s PLD, no significant differences could be seen between CBF in the affected ROI (40.50±14.82 mL/100 g/min) and CBF in the control ROI (39.68±12.49 mL/100 g/min, P=0.73). In the hemisphere-based analysis, CBF was significantly lower in the affected side than in the control side for the group with the 1.5-s PLD (P<0.05) when CVR was impaired (P<0.0001), but not for the group with the 2.5-s PLD (P=0.49). CONCLUSIONS: In conclusion, our study reveals and highlights the value of a shorter-PLD ASL protocol, which is able to reflect CVR impairment. At the same time, we offer a better understanding of the relationship between BOLD CVR and CBF obtained from ASL.

Noninvasive Detection of Extracellular pH in Human Benign and Malignant Liver Tumors Using CEST MRI.

PURPOSE: In this study, we aimed to use 3T magnetic resonance imaging (MRI), which is clinically available, to determine the extracellular pH (pHe) of liver tumors and prospectively evaluate the ability of chemical exchange saturation transfer (CEST) MRI to distinguish between benign and malignant liver tumors. METHODS: Different radiofrequency irradiation schemes were assessed for ioversol-based pH measurements at 3T. CEST effects were quantified in vitro using the asymmetric magnetization transfer ratio (MTRasym) at 4.3 ppm from the corrected Z spectrum. Generalized ratiometric analysis was conducted by rationing resolved ioversol CEST effects at 4.3 ppm at a flip angle of 60 and 350°. Fifteen patients recently diagnosed with hepatic carcinoma and five patients diagnosed with hepatic hemangioma [1 male; mean age, 48.6 (range, 37-59) years] were assessed. RESULTS: By conducting dual-power CEST MRI, the pH of solutions was determined to be 6.0-7.2 at 3T in vitro. In vivo, ioversol signal intensities in the tumor region showed that the extracellular pH in hepatic carcinoma was acidic(mean ± standard deviation, 6.66 ± 0.19), whereas the extracellular pH was more physiologically neutral in hemangioma (mean ± standard deviation, 7.34 ± 0.09).The lesion size was similar between CEST pH MRI and T2-weighted imaging. CONCLUSION: dual-power CEST MRI can detect extracellular pH in human liver tumors and can provide molecular-level diagnostic tools for differentiating benign and malignant liver tumors at 3T.

Glymphatic System Visualized by Chemical-Exchange-Saturation-Transfer Magnetic Resonance Imaging.

Dysfunction of the glymphatic system may play a significant role in the development of neurodegenerative diseases. However, in vivo imaging of the glymphatic system is challenging. In this study, we describe an unconventional MRI method for imaging the glymphatic system based on chemical exchange saturation transfer, which we tested in an in vivo porcine model of impaired glymphatic function. The blood, lymph, and cerebrospinal fluid (CSF) from one pig were used for testing the MRI effect in vitro at 7 Tesla (T). Unilateral deep cervical lymph node ligation models were then performed in 20 adult male Sprague-Dawley rats. The brains were scanned in vivo dynamically after surgery using the new MRI method. Behavioral tests were performed after each scanning session and the results were tested for correlations with the MRI signal intensity. Finally, the pathological assessment was conducted in the same brain slices. The special MRI effect in the lymph was evident at about 1.0 ppm in water and was distinguishable from those of blood and CSF. In the model group, the intensity of this MRI signal was significantly higher in the ipsilateral than in the contralateral hippocampus. The correlation between the signal abnormality and the behavioral score was significant (Pearson's, R2 = 0.9154, p < 0.005). We conclude that the novel MRI method can visualize the glymphatic system in vivo.

Novel nanomedicine with a chemical-exchange saturation transfer effect for breast cancer treatment in vivo.

BACKGROUND: Nanomedicine is a promising new approach to cancer treatment that avoids the disadvantages of traditional chemotherapy and improves therapeutic indices. However, the lack of a real-time visualization imaging technology to monitor drug distribution greatly limits its clinical application. Image-tracked drug delivery is of great clinical interest; it is useful for identifying those patients for whom the therapy is more likely to be beneficial. This paper discusses a novel nanomedicine that displays features of nanoparticles and facilitates functional magnetic resonance imaging but is challenging to prepare. RESULTS: To achieve this goal, we synthesized an acylamino-containing amphiphilic block copolymer (polyethylene glycol-polyacrylamide-polyacetonitrile, PEG-b-P(AM-co-AN)) by reversible addition-fragmentation chain transfer (RAFT) polymerization. The PEG-b-P(AM-co-AN) has chemical exchange saturation transfer (CEST) effects, which enable the use of CEST imaging for monitoring nanocarrier accumulation and providing molecular information of pathological tissues. Based on PEG-b-P(AM-co-AN), a new nanomedicine PEG-PAM-PAN@DOX was constructed by nano-precipitation. The self-assembling nature of PEG-PAM-PAN@DOX made the synthesis effective, straightforward, and biocompatible. In vitro studies demonstrate decreased cytotoxicity of PEG-PAM-PAN@DOX compared to free doxorubicin (half-maximal inhibitory concentration (IC50), mean ~ 0.62 µg/mL vs. ~ 5 µg/mL), and the nanomedicine more efficiently entered the cytoplasm and nucleus of cancer cells to kill them. Further, in vivo animal experiments showed that the nanomedicine developed was not only effective against breast cancer, but also displayed an excellent sensitive CEST effect for monitoring drug accumulation (at about 0.5 ppm) in tumor areas. The CEST signal of post-injection 2 h was significantly higher than that of pre-injection (2.17 ± 0.88% vs. 0. 09 ± 0.75%, p < 0.01). CONCLUSIONS: The nanomedicine with CEST imaging reflects the characterization of tumors and therapeutic functions has great potential medical applications.

Imaging of glutamate in acute traumatic brain injury using chemical exchange saturation transfer.

BACKGROUND: Chemical exchange saturation transfer (CEST) is an important contrast mechanism in the field of magnetic resonance imaging. Herein, we used CEST for glutamate (GluCEST) imaging to evaluate the Glu alterations in acute mild to moderate traumatic brain injury (TBI) and correlated such alterations with the cognitive outcome at 1-month postinjury. METHODS: Thirty-two patients with well-documented mild-to-moderate TBI and 15 healthy controls (HC group) underwent 3.0-Tesla magnetic resonance imaging (MRI) with GluCEST, and magnetic resonance spectroscopy (MRS) scans. The Montreal Cognitive Assessment (MoCA) examination was administered to all study subjects at 1-month postinjury for cognitive outcome acquisition and divided TBI patients into patients with good cognitive outcome (GCO group) and with poor cognitive outcome (PCO group). RESULTS: The GluCEST% values for the occipital gray matter (OGM) and bilateral parietooccipital white matter (PWM) were higher in the PCO group compared with the HC and GCO groups (P<0.05), whereas the GluCEST% value showed no significant differences between the GCO and HC groups (P>0.05). In comparison with HCs, TBI patients had a significantly increased GluCEST% value for the OGM and bilateral PWM (P<0.05). GluCEST performed better than MRS in the prediction of cognitive outcome for TBI patients (P<0.05). CONCLUSIONS: Glu is significantly increased in acute TBI and strongly correlates with the cognitive outcome at 1month postinjury. GluCEST may supply new insight into TBI and help to improve the accuracy of short-term outcome prediction.

An Amyloid-ß Targeting Chemical Exchange Saturation Transfer Probe for In Vivo Detection of Alzheimer's Disease.

A reliable and reproducible detection of Aß deposits would be beneficial for the early diagnosis of Alzheimer's disease (AD). In the present study, the feasibility of applying chemical exchange saturation transfer (CEST) for Aß deposit detection using angiopep-2 as a probe was evaluated, and it was demonstrated that CEST could detect angiopep-2 and Aß-angiopep-2 aggregates in vitro. Furthermore, APP/PS1 mice injected with angiopep-2 exhibited a significantly higher in vivo CEST effect when compared with controls. The distribution of Aß deposits detected by CEST imaging was consistent with the histological staining results. The present study is the first to report a reliable exogenous CEST probe to noninvasively evaluate Aß deposits in APP/PS1 mice. Furthermore, these results demonstrate the potential for clinical AD diagnosis and Aß-targeted drug therapy assessment using CEST imaging with the angiopep-2 probe.

Circulating tumor DNA detection is correlated to histologic types in patients with early-stage non-small-cell lung cancer.

OBJECTIVES: Circulating tumor DNA (ctDNA) testing in plasma in patients with non-small-cell lung cancer (NSCLC) has the potential to be a supplemental or surrogate tool for tissue biopsy. Detection of genomic abnormalities in ctDNA and their association with clinical characteristics in early-stage NSCLC need to be clarified. MATERIALS AND METHODS: Here, we comprehensively analyzed gene variations of 48 tumor tissues and 48 matched preoperative (pre-op) plasma and 25 postoperative (post-op) plasma from early-stage NSCLC patients using a targeted 546 genes capture-based next generation sequencing (NGS) assay. RESULTS: In early-stage NSCLC, the average mutation allele frequency (MAF) in pre-op plasma ctDNA was lower than that in tissue DNA (tDNA). The concordant gene variations between pre-op ctDNA and tDNA were difficult to detect. However, we found the tissue- pre-op plasma concordant ctDNA mutation detection ratio in lung squamous cell carcinoma (LUSC) was much higher than that in lung adenocarcinoma (LUAD). We also established a LUSC-LUAD classification model by a least absolute shrinkage and selection operator (LASSO) based approach to help separate LUAD from LUSC based on ctDNA profiling. This model included 14 gene mutations and extracted an accuracy of 89.2% in the training set and 91.5% in the testing set. Correlation analysis showed tDNA-ctDNA concordant ratio was related to histologic subtype, gene mutations and tumor size in early-stage NSCLC. CONCLUSION: This study suggests histology subtype and gene mutations could affect ctDNA detection in early-stage NSCLC. NGS-based ctDNA profile has the potential utility in LUSC-LUAD classification.